WO2024053650A1 - COMPOUND HAVING INHIBITORY ACTIVITY AGAINST DIACYLGLYCEROL KINASE α AND/OR ζ, AND PHARMACEUTICAL USE THEREOF - Google Patents

COMPOUND HAVING INHIBITORY ACTIVITY AGAINST DIACYLGLYCEROL KINASE α AND/OR ζ, AND PHARMACEUTICAL USE THEREOF Download PDF

Info

Publication number
WO2024053650A1
WO2024053650A1 PCT/JP2023/032418 JP2023032418W WO2024053650A1 WO 2024053650 A1 WO2024053650 A1 WO 2024053650A1 JP 2023032418 W JP2023032418 W JP 2023032418W WO 2024053650 A1 WO2024053650 A1 WO 2024053650A1
Authority
WO
WIPO (PCT)
Prior art keywords
group
optionally substituted
general formula
cancer
alkyl
Prior art date
Application number
PCT/JP2023/032418
Other languages
French (fr)
Japanese (ja)
Inventor
真吾 山本
浩 河野
和裕 大槻
繁幸 高井
麻紀子 篠崎
和也 道木
Original Assignee
小野薬品工業株式会社
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 小野薬品工業株式会社 filed Critical 小野薬品工業株式会社
Publication of WO2024053650A1 publication Critical patent/WO2024053650A1/en

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • the present disclosure provides the following general formula (IY) having inhibitory activity on diacylglycerol kinase ⁇ and/or ⁇ (hereinafter sometimes abbreviated as DGK ⁇ and/or ⁇ , or DGK ⁇ and/or DGK ⁇ ).
  • the present invention relates to compounds or salts thereof, and pharmaceutical uses thereof.
  • Diacylglycerol kinase is a lipid kinase that phosphorylates diacylglycerol (DAG) and converts it to phosphatidic acid (PA), and 10 types of isozymes are known to exist in mammals. All isozymes have a highly homologous catalytic region and a C1 domain homologous to protein kinase C (PKC). The C1 domain has a zinc finger-like structure rich in cysteine and histidine, and is thought to be bound by phorbol ester/DAG (Non-Patent Document 1).
  • DAG is produced together with inositol trisphosphate (IP3) by phospholipase C ⁇ 1 (PLC ⁇ 1) activated by antigen stimulation via the T cell receptor (TCR).
  • IP3 inositol trisphosphate
  • PLC ⁇ 1 phospholipase C ⁇ 1
  • TCR T cell receptor
  • the generated DAG acts as a second messenger and activates multiple downstream signal pathways such as Ras-MAPK, NF- ⁇ B, and phosphatidylinositol triphosphate-Akt-mTOR pathways, thereby inducing T cell activation.
  • DGK ⁇ and DGK ⁇ are two major isozymes within T cells, and each of these isozymes negatively regulates T cell activation by controlling the strength of DAG signals downstream of TCR-mediated antigen stimulation.
  • TGF transforming growth factor
  • PGE2 prostaglandin E2
  • Non-patent Documents 4 to 6 it is known that DGK ⁇ deficiency enhances cytotoxic activity toward major histocompatibility complex (MHC) class I-deficient cells.
  • MHC major histocompatibility complex
  • drugs that inhibit one or both of DGK ⁇ and DGK ⁇ enhance the activation of immune cells including T cells, and are useful for diseases associated with decreased immune function and immune escape, such as cancer and infectious diseases. There is expected.
  • Patent Document 1 contains the general formula (A):
  • R 1A represents a halogen atom, a C1-4 alkyl group, etc.
  • R 2A represents a hydrogen atom, a halogen atom, etc.
  • R 3A represents a C1-4 alkyl group
  • R 4A represents a hydrogen atom or a C1-4 alkyl group. 4 alkyl group
  • ring A represents a C3-7 monocyclic carbocycle, etc.
  • X A represents a nitrogen atom or a carbon atom
  • T A represents a bond, etc.
  • U A represents 1 to 5 carbon atoms.
  • the definition of the group has been extracted from the necessary parts.
  • the compounds represented by, salts thereof, solvates thereof, or prodrugs thereof can be used to treat urinary excretion disorders, cancer, interstitial pneumonia or pulmonary fibrosis, scleroderma, pain, fibromyalgia, rheumatoid arthritis, etc. It is stated that it is useful.
  • R 1B is a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, a C1-3 alkyl substituted with 0 to 4 R 1aB , etc.
  • R 2B is a hydrogen atom, and 0 to 4 R 2aB is Substituted C1-3 alkyl, etc.
  • R 3B is a hydrogen atom, fluorine atom, chlorine atom, bromine atom, -CN, etc.
  • R 4B is -CH 2 R 4aB , etc.
  • R 5B is -CN, 0 to 4 C1-6 alkyl substituted with RgB
  • mB represents 1 to 3.
  • Necessary portions have been extracted from the definition of the group) or a salt thereof is effective against viral infections and cancer. It has been described that it is useful for the treatment of proliferative diseases such as.
  • An object of the present invention is to provide a compound that has inhibitory activity against DGK ⁇ and/or ⁇ .
  • the present inventors found that a compound represented by the general formula (IY) described below or a salt thereof (hereinafter sometimes abbreviated as the compound of the present invention) has been found to be suitable for DGK ⁇ and It has been found that the compound has inhibitory activity against/or ⁇ .
  • the present invention mainly provides the following embodiments.
  • R 1 is (1) methylene substituted with a 3- to 15-membered carbon ring optionally substituted with 1 to 5 R 11 , (2) substituted with 1 to 5 R 12 (3) Methylene substituted with a C2-4 alkenyl group optionally substituted with 1 to 5 R13 , or (4) Represents methylene substituted with a C2-4 alkynyl group optionally substituted with 1 to 5 R14 , R 11 , R 12 , R 13 and R 14 each independently represent (1) halogen, (2) C1-4 alkyl group, (3) C1-4 alkoxy group, (4) C1-4 haloalkyl group, (5) represents a C1-4 haloalkoxy group, or (6) a cyano group, and a plurality of R 11 , R 12 , R 13 and R 14 may be the same or different, respectively; R 2 is (1) a 3- to 15 -membered heterocycle optionally substituted with 1 to 5 R 15s, (2) a 3- to 15-membered heterocycle optionally substituted
  • each R Y may be the same or different;
  • X represents a nitrogen atom or CR7 , X 1 , X 2 , and X 3 each independently represent a nitrogen atom, CH, or CR 6 ,
  • R 6 is (1) halogen, (2) C1-4 alkyl group, (3) C1-4 alkoxy group, (4) C1-4 haloalkyl group, (5) C1-4 haloalkoxy group, (6) hydroxyl group , or (7) represents a cyano group
  • each R 6 may be the same or different;
  • Y 1 represents a nitrogen atom or CR 8
  • Y2 represents a nitrogen atom or CR9
  • Y 3 represents a nitrogen atom or CR 10Y ,
  • R 7 is (1) hydrogen atom, (2) halogen, (3) C1-4 alkyl
  • each hydrogen atom may be a deuterium atom or a tritium atom.
  • An agent for inhibiting progression, inhibiting recurrence, and/or treating DGK ⁇ and/or DGK ⁇ -related diseases which contains a compound represented by the general formula (IY) described in [1] or a salt thereof.
  • the compound of the present invention has inhibitory activity against DGK ⁇ and/or ⁇ , it can be used, for example, as an active ingredient of an agent for inhibiting the progression, inhibiting recurrence, and/or treating cancer or infectious disease.
  • halogen includes, for example, fluorine, chlorine, bromine, and iodine atoms.
  • the "C1-4 alkyl group” includes methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl, and 1,1-dimethylethyl group.
  • C1-4 alkyl group substituted with hydroxyl group includes hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxy-1-methylethyl, hydroxy-butyl, hydroxy-1-methylpropyl, hydroxy-2- Includes methylpropyl, and hydroxy-1,1-dimethylethyl groups.
  • groups for which the substitution position of the hydroxyl group is not described include all positional isomers.
  • the hydroxy-1-methylpropyl group includes 1-hydroxy-1-methylpropyl, 2-hydroxy-1-methylpropyl, 3-hydroxy-1-methylpropyl, and 1-(hydroxymethyl)propyl groups. It will be done.
  • the C1-4 alkyl group substituted with multiple hydroxyl groups also includes all positional isomers substituted with 2 to 3 hydroxyl groups.
  • C1-8 alkyl group includes methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 1,1-dimethylpropyl, 2,2-dimethylpropyl, hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl , 2,2-dimethylbutyl, 3,3-dimethylbutyl, heptyl, 1-methylhexyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 1,1-dimethylpentyl, 2 , 2-dimethylpentyl, 3,3-dimethylpentyl, 4,4-dimethylpentyl,
  • any C1-8 alkyl group is included in the present invention.
  • C5 alkyl groups 1,2-dimethylpropyl and 1-ethylpropyl groups are also included in the present invention.
  • C6-8 alkyl groups are also included in the present invention.
  • C2-4 alkenyl group includes ethenyl, 1-propenyl, 2-propenyl, 1-methylethenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-ethyl-1-ethenyl, 1- Included are methyl-1-propenyl, 2-methyl-1-propenyl, 1-methyl-2-propenyl, and 2-methyl-2-propenyl groups.
  • the "C2-4 alkynyl group” includes ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, and 3-butynyl groups.
  • C1-4 haloalkyl group includes fluoromethyl, fluoroethyl, fluoropropyl, fluoro-1-methylethyl, fluorobutyl, fluoro-1-methylpropyl, fluoro-2-methylpropyl, fluoro-1 , 1-dimethylethyl, difluoromethyl, difluoroethyl, difluoropropyl, difluoro-1-methylethyl, difluorobutyl, difluoro-1-methylpropyl, difluoro-2-methylpropyl, difluoro-1,1-dimethylethyl, trifluoro Methyl, trifluoroethyl, trifluoropropyl, trifluoro-1-methylethyl, trifluorobutyl, trifluoro-1-methylpropyl, trifluoro-2-methylpropyl, trifluoro-1,1-dimethylethyl, trifluoro Meth
  • groups whose halogen atom substitution positions are not described include all positional isomers.
  • the fluoro-1-methylpropyl group includes 1-fluoro-1-methylpropyl, 2-fluoro-1-methylpropyl, 3-fluoro-1-methylpropyl, and 1-(fluoromethyl)propyl groups. It will be done.
  • groups for which the number of halogen atoms substituted is not described include all the numbers of halogen atoms substituted.
  • heptafluoropropyl groups, nonafluoropropyl groups, and the like are also included in the "C1-4 haloalkyl group" of the present invention, although they are not specifically exemplified.
  • C1-4 haloalkyl group optionally substituted with a hydroxyl group includes fluoromethyl, fluoroethyl, fluoropropyl, fluoro-1-methylethyl, fluorobutyl, fluoro-1-methylpropyl, fluoro- 2-Methylpropyl, fluoro-1,1-dimethylethyl, difluoromethyl, difluoroethyl, difluoropropyl, difluoro-1-methylethyl, difluorobutyl, difluoro-1-methylpropyl, difluoro-2-methylpropyl, difluoro-1 , 1-dimethylethyl, trifluoromethyl, trifluoroethyl, trifluoropropyl, trifluoro-1-methylethyl, trifluorobutyl, trifluoro-1-methylpropyl, trifluoro-2-methylpropyl, trifluoro-1 , 1-dimethyl
  • groups whose halogen atom substitution positions are not described include all positional isomers.
  • the fluoro-1-methylpropyl group includes 1-fluoro-1-methylpropyl, 2-fluoro-1-methylpropyl, 3-fluoro-1-methylpropyl, and 1-(fluoromethyl)propyl groups. It will be done.
  • groups for which the number of halogen atoms substituted is not described include all the numbers of halogen atoms substituted.
  • C1-4 haloalkyl groups optionally substituted with a hydroxyl group
  • all C1-4 haloalkyl groups that are not substituted with a hydroxyl group in which at least one hydrogen atom is substituted with a hydroxyl group as long as they exist chemically stably, even if not specifically exemplified. This includes positional isomers, all numbers of halogen atoms, and all numbers of hydroxyl groups.
  • C1-8 haloalkyl group includes fluoromethyl, fluoroethyl, fluoropropyl, fluoro-1-methylethyl, fluorobutyl, fluoro-1-methylpropyl, fluoro-2-methylpropyl, fluoro-1 , 1-dimethylethyl, fluoropentyl, fluoro-1-methylbutyl, fluoro-2-methylbutyl, fluoro-3-methylbutyl, fluoro-1,1-dimethylpropyl, fluoro-2,2-dimethylpropyl, fluorohexyl, fluoro- 1-Methylpentyl, fluoro-2-methylpentyl, fluoro-3-methylpentyl, fluoro-4-methylpentyl, fluoro-1,1-dimethylbutyl, fluoro-2,2-dimethylbutyl, fluoro-3,3- Dimethylbutyl, fluorohept
  • groups whose halogen atom substitution positions are not described include all positional isomers.
  • the fluoro-1-methylpropyl group includes 1-fluoro-1-methylpropyl, 2-fluoro-1-methylpropyl, 3-fluoro-1-methylpropyl, and 1-(fluoromethyl)propyl groups. It will be done. Even if not specifically shown in this example, any C1-8 haloalkyl group is included in the present invention.
  • C5 haloalkyl groups include fluoro-1,2-dimethylpropyl, fluoro-1-ethylpropyl, difluoro-1,2-dimethylpropyl, difluoro-1-ethylpropyl, trifluoro-1,2-dimethylpropyl, Trifluoro-1-ethylpropyl, chloro-1,2-dimethylpropyl, chloro-1-ethylpropyl, dichloro-1,2-dimethylpropyl, dichloro-1-ethylpropyl, trichloro-1,2-dimethylpropyl, and Trichloro-1-ethylpropyl groups are also included in the invention.
  • C6-8 haloalkyl groups groups for which the number of halogen atoms substituted is not described include all the numbers of halogen atoms substituted.
  • groups for which the number of halogen atoms substituted include all the numbers of halogen atoms substituted.
  • a heptafluoropropyl group, a nonafluoropropyl group, etc. are also included in the "C1-8 haloalkyl group" of the present invention, although they are not specifically exemplified.
  • (C1-8 alkyl)carbonyl group includes methylcarbonyl, ethylcarbonyl, propylcarbonyl, 1-methylethylcarbonyl, butylcarbonyl, 1-methylpropylcarbonyl, 2-methylpropylcarbonyl, 1,1 -dimethylethylcarbonyl, pentylcarbonyl, 1-methylbutylcarbonyl, 2-methylbutylcarbonyl, 3-methylbutylcarbonyl, 1,1-dimethylpropylcarbonyl, 2,2-dimethylpropylcarbonyl, hexylcarbonyl, 1-methylpentylcarbonyl , 2-methylpentylcarbonyl, 3-methylpentylcarbonyl, 4-methylpentylcarbonyl, 1,1-dimethylbutylcarbonyl, 2,2-dimethylbutylcarbonyl, 3,3-dimethylbutylcarbonyl, heptylcarbonyl, 1-methylhexyl
  • any (C1-8 alkyl)carbonyl group is included in the present invention.
  • C5 alkylcarbonyl groups 1,2-dimethylpropylcarbonyl and 1-ethylpropylcarbonyl groups are also included in the present invention.
  • C1-4 alkoxycarbonyl group includes methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, 1-methylethoxycarbonyl, butoxycarbonyl, 1-methylpropoxycarbonyl, 2-methylpropoxycarbonyl, and 1,1- Contains dimethylethoxycarbonyl group.
  • (C1-4 alkyl)aminocarbonyl group includes methylaminocarbonyl, ethylaminocarbonyl, propylaminocarbonyl, 1-methylethylaminocarbonyl, butylaminocarbonyl, 1-methylpropylaminocarbonyl, 2- Includes methylpropylaminocarbonyl, and 1,1-dimethylethylaminocarbonyl groups.
  • di-(C1-4 alkyl)amino group includes dimethylamino, diethylamino, dipropylamino, di(1-methylethyl)amino, dibutylamino, di(1-methylpropyl)amino, di- Includes (2-methylpropyl)amino and di(1,1-dimethylethyl)amino groups.
  • C1-4 haloalkylamino group includes fluoromethylamino, fluoroethylamino, fluoropropylamino, fluoro-1-methylethylamino, fluorobutylamino, fluoro-1-methylpropylamino, fluoro-2 -Methylpropylamino, fluoro-1,1-dimethylethylamino, difluoromethylamino, difluoroethylamino, difluoropropylamino, difluoro-1-methylethylamino, difluorobutylamino, difluoro-1-methylpropylamino, difluoro-2 -Methylpropylamino, difluoro-1,1-dimethylethylamino, trifluoromethylamino, trifluoroethylamino, trifluoropropylamino, trifluoromethylamino, trifluoroethy
  • groups whose halogen atom substitution positions are not described include all positional isomers.
  • fluoro-1-methylpropylamino groups include 1-fluoro-1-methylpropylamino, 2-fluoro-1-methylpropylamino, 3-fluoro-1-methylpropylamino, and 1-(fluoromethyl) Contains a propylamino group.
  • di-(C1-4 alkyl)aminocarbonyl group includes dimethylaminocarbonyl, diethylaminocarbonyl, dipropylaminocarbonyl, di(1-methylethyl)aminocarbonyl, dibutylaminocarbonyl, di(1- Included are methylpropyl)aminocarbonyl, di(2-methylpropyl)aminocarbonyl, and di(1,1-dimethylethyl)aminocarbonyl groups. Also included are di-(C1-4 alkyl)aminocarbonyl groups substituted with different C1-4 alkyls, such as N-methyl-N-ethylaminocarbonyl groups.
  • the "C1-4 alkoxy group” includes methoxy, ethoxy, propoxy, 1-methylethoxy, butoxy, 1-methylpropoxy, 2-methylpropoxy, and 1,1-dimethylethoxy groups.
  • C1-4 haloalkoxy group includes fluoromethoxy, fluoroethoxy, fluoropropoxy, fluoro-1-methylethoxy, fluorobutoxy, fluoro-1-methylpropoxy, fluoro-2-methylpropoxy, fluoro- 1,1-dimethylethoxy, difluoromethoxy, difluoroethoxy, difluoropropoxy, difluoro-1-methylethoxy, difluorobutoxy, difluoro-1-methylpropoxy, difluoro-2-methylpropoxy, difluoro-1,1-dimethylethoxy, tri- Fluoromethoxy, trifluoroethoxy, trifluoropropoxy, trifluoro-1-methylethoxy, trifluorobutoxy, trifluoro-1-methylpropoxy, trifluoro-2-methylpropoxy, trifluoro-1,1-dimethylethoxy, chloro Methoxy, chloroethoxy, chloropropoxy, chloro-1-methylethoxy,
  • groups whose halogen atom substitution positions are not described include all positional isomers.
  • fluoro-1-methylpropoxy groups include 1-fluoro-1-methylpropoxy, 2-fluoro-1-methylpropoxy, 3-fluoro-1-methylpropoxy, and 1-(fluoromethyl)propoxy groups. It will be done.
  • (C1-4 alkyl)amino group includes methylamino, ethylamino, propylamino, 1-methylethylamino, butylamino, 1-methylpropylamino, 2-methylpropylamino, and 1, Contains a 1-dimethylethylamino group.
  • the "3- to 15-membered carbocycle” includes monocyclic, bicyclic, or tricyclic, unsaturated, partially saturated, or saturated 3- to 15-membered carbocycles.
  • monocyclic, bicyclic, or tricyclic unsaturated 3- to 15-membered carbon rings include benzene, pentalene, naphthalene, azulene, phenanthrene, anthracene, acenaphthylene, and biphenylene rings.
  • Examples of the monocyclic, bicyclic or tricyclic partially saturated or saturated 3- to 15-membered carbon ring include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclopentene, cyclohexene, cyclopentadiene, Cyclohexadiene, indene, dihydroindene (indane), fluorene, perhydropentalene, perhydroindene, perhydronaphthalene, perhydroazulene, perhydrofluorene, perhydrophenanthrene, perhydroanthracene, perhydroacenaphthylene, Examples include perhydrobiphenylene, bicyclo[1.1.1]pentane, bicyclo[3.2.1]octane, spiro[3.5]nonane, spiro[3.3]heptane, and adamantane ring.
  • a "3- to 15-membered heterocycle” includes a monocyclic, bicyclic, or tricyclic ring containing 1 to 4 nitrogen atoms, 1 to 2 oxygen atoms, and/or 1 sulfur atom. unsaturated, partially saturated, or saturated 3- to 15-membered heterocycles containing .
  • a monocyclic, bicyclic or tricyclic unsaturated 3- to 15-membered heterocycle containing 1 to 4 nitrogen atoms, 1 to 2 oxygen atoms and/or 1 sulfur atom for example, pyrrole, imidazole, triazole, tetrazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, azepine, diazepine, furan, pyran, oxepin, oxazepine, thiophene, thiaine (thiopyran), thiepine, oxazole, isoxazole, thiazole, iso Thiazole, oxadiazole, oxazine, oxadiazine, oxazepine, oxadiazepine, thiadiazole, thiazine, thiadiazine, thiazepine, thiadiazepine, indole
  • heterocycle examples include aziridine, oxirane, azetidine, oxetane, thiirane, thietane, pyrroline, pyrrolidine, imidazoline, imidazolidine, triazoline, triazolidine, tetrazoline, tetrazolidine, pyrazoline, pyrazolidine, piperidine, piperazine, tetrahydropyridine, tetrahydropyrimidine, Tetrahydropyridazine, dihydrofuran, tetrahydrofuran, dihydropyran, tetrahydropyran, dihydrothiophene, tetrahydrothiophene, dihydrothiaine (dihydrothiopyran), tetrahydrothiaine (dihydrothiopyran), tetrahydrothiaine (dihydrothiopyran), tetrahydrothiaine (dihydrothiopyran), te
  • the "3- to 15-membered heterocycle” also includes bridged rings and spiro rings.
  • Examples of the bridged 3- to 15-membered heterocycle include an 8-azabicyclo[3.2.1]octane ring.
  • Examples of the 3- to 15-membered heterocycle that is a spiro ring include 1-oxa-7-azaspiro[4.4]nonane and 2-azaspiro[3.3]heptane.
  • the "5- to 6-membered carbocycle” includes a monocyclic, unsaturated, partially saturated, or saturated 5- to 6-membered carbocycle.
  • the monocyclic unsaturated 5- to 6-membered carbon ring include cyclopentadiene and a benzene ring.
  • Examples of the monocyclic partially saturated or saturated 5- to 6-membered carbon ring include cyclopentane, cyclohexane, cyclopentene, cyclohexene, and cyclohexadiene rings.
  • 5- to 6-membered heterocycle refers to a monocyclic unsaturated ring containing 1 to 4 nitrogen atoms, 1 to 2 oxygen atoms and/or 1 sulfur atom, Includes partially saturated or saturated 5- to 6-membered heterocycles.
  • Examples of the monocyclic unsaturated 5- to 6-membered heterocycle containing 1 to 4 nitrogen atoms, 1 to 2 oxygen atoms, and/or 1 sulfur atom include pyrrole, imidazole, Triazole, tetrazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, furan, pyran, thiophene, thiaine (thiopyran), oxazole, isoxazole, thiazole, isothiazole, oxadiazole, oxazine, oxadiazine, thiadiazole, thiazine, and thiadiazine ring etc.
  • Examples of monocyclic partially saturated or saturated 5- to 6-membered heterocycles containing 1 to 4 nitrogen atoms, 1 to 2 oxygen atoms, and/or 1 sulfur atom include: Pyrroline, pyrrolidine, imidazoline, imidazolidine, triazoline, triazolidine, tetrazoline, tetrazolidine, pyrazoline, pyrazolidine, piperidine, piperazine, tetrahydropyridine, tetrahydropyrimidine, tetrahydropyridazine, dihydrofuran, tetrahydrofuran, dihydropyran, tetrahydropyran, dihydrothiophene, tetrahydrothiophene , Dihydrothiaine (Dihydrothiopyran), Tetrahydrothiaine (Tetrahydrothiopyran), Oxazoline (Dihydroxazole), Oxazolidine (Tetrahydroxazole), Dihydroisox
  • 5- to 7-membered heterocycle refers to a monocyclic unsaturated ring containing 1 to 4 nitrogen atoms, 1 to 2 oxygen atoms, and/or 1 sulfur atom, Includes partially saturated or saturated 5- to 7-membered heterocycles.
  • Examples of the monocyclic unsaturated 5- to 6-membered heterocycle containing 1 to 4 nitrogen atoms, 1 to 2 oxygen atoms, and/or 1 sulfur atom include pyrrole, imidazole, Triazole, tetrazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, azepine, diazepine, furan, pyran, thiophene, thiaine (thiopyran), thiepine, oxazole, isoxazole, thiazole, isothiazole, oxadiazole, oxazine, oxadiazine, oxazepine , oxadiazepine, thiadiazole, thiazine, thiadiazine, thiazepine, and thiadiazepine ring.
  • Examples of monocyclic partially saturated or saturated 5- to 7-membered heterocycles containing 1 to 4 nitrogen atoms, 1 to 2 oxygen atoms, and/or 1 sulfur atom include: Pyrroline, pyrrolidine, imidazoline, imidazolidine, triazoline, triazolidine, tetrazoline, tetrazolidine, pyrazoline, pyrazolidine, piperidine, piperazine, tetrahydropyridine, tetrahydropyrimidine, tetrahydropyridazine, dihydrofuran, tetrahydrofuran, dihydropyran, tetrahydropyran, dihydrothiophene, tetrahydrothiophene , Dihydrothiaine (Dihydrothiopyran), Tetrahydrothiaine (Tetrahydrothiopyran), Oxazoline (Dihydroxazole), Oxazolidine (Tetrahydroxazole), Dihydroiso
  • "3- to 6-membered saturated heterocycle” includes aziridine, oxirane, azetidine, oxetane, thiirane, thietane, pyrrolidine, imidazolidine, triazolidine, tetrazolidine, pyrazolidine, piperidine, piperazine, tetrahydrofuran, tetrahydropyran, and tetrahydrofuran.
  • "5- to 7-membered nitrogen-containing saturated heterocycle” includes pyrrolidine, imidazolidine, triazolidine, tetrazolidine, pyrazolidine, piperidine, piperazine, oxazolidine (tetrahydroxazole), tetrahydroisoxazole, oxadiazolidine (tetrahydroxazole), diazole), thiazolidine (tetrahydrothiazole), tetrahydroisothiazole, morpholine, thiomorpholine, perhydroazepine, perhydrodiazepine, perhydrothiepine, perhydroxazepine, perhydroxadiazepine, perhydrothiazepine, and Includes perhydrothiadiazepine, and 2-azaspiro[3.3]heptane rings.
  • examples of the "saturated or partially unsaturated 4- to 10-membered carbon ring” include cyclobutane, cyclohexane, cyclohexene, bicyclo[1.1.1]pentane, and bicyclo[3.1.1]heptane. , bicyclo[2.2.2]octane, spiro[3.3]heptane, spiro[3.5]nonane, bicyclo[3.1.0]hexane, cuban, adamantane, norbornene, and decahydronaphthalene, etc. Can be mentioned.
  • examples of the "6-membered saturated heterocycle containing one nitrogen atom, one oxygen atom, and/or one optionally oxidized sulfur atom” include tetrahydropyran, etc. It will be done.
  • a 4- to 10-membered saturated carbon ring that may contain one nitrogen atom, one oxygen atom, and/or one sulfur atom that may be oxidized includes: For example, cyclobutane, cyclohexane, bicyclo[1.1.1]pentane, bicyclo[3.1.1]heptane, bicyclo[2.2.2]octane, spiro[3.3]heptane, spiro[3.5] Examples include nonane, bicyclo[3.1.0]hexane, cuban, adamantane, decahydronaphthalene, and tetrahydropyran.
  • the "optionally oxidized sulfur atom” includes -S-, -S(O)-, and -SO 2 -.
  • the "C3-6 cycloalkyl group” includes cyclopropane, cyclobutane, cyclopentane, and cyclohexane rings.
  • the "(C3-6 cycloalkyl)carbonyl group” includes cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, and cyclohexylcarbonyl group.
  • the "C3-8 cycloalkyl group” includes cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, and cyclooctane rings.
  • C1-4 alkylsulfonyl group includes methylsulfonyl, ethylsulfonyl, propylsulfonyl, 1-methylethylsulfonyl, butylsulfonyl, 1-methylpropylsulfonyl, 2-methylpropylsulfonyl, and 1,1- Contains dimethylethylsulfonyl group.
  • C2-4 alkenylsulfonyl group includes ethenylsulfonyl, 1-propenylsulfonyl, 2-propenylsulfonyl, 1-methylethenylsulfonyl, 1-butenylsulfonyl, 2-butenylsulfonyl, 3- Butenylsulfonyl, 1-ethyl-1-ethenylsulfonyl, 1-methyl-1-propenylsulfonyl, 2-methyl-1-propenylsulfonyl, 1-methyl-2-propenylsulfonyl, and 2-methyl-2-propenylsulfonyl Contains groups.
  • R 1 is preferably (1) methylene substituted with a 3- to 15-membered carbon ring optionally substituted with 1 to 5 R 11 , or (2) 1 to 5 R 11 Methylene substituted with a 3- to 15-membered heterocycle optionally substituted with 12 , more preferably substituted with a 5- to 6-membered carbon ring optionally substituted with 1 to 5 R 11 More preferably, it is methylene substituted with benzene, which may be substituted with 1 to 5 R 11 groups.
  • R 11 is preferably (1) halogen, (2) C1-4 alkyl group, or (3) cyano group.
  • R 12 is preferably (1) halogen, (2) C1-4 alkyl group, or (3) cyano group.
  • the number of substitutions for R 11 or R 12 is not limited as long as it is 0 to 5, respectively, but it is preferably 0 to 3.
  • R 2 is preferably a 3- to 15-membered heterocycle optionally substituted with 1 to 5 R 15s , more preferably a 3- to 15-membered heterocycle optionally substituted with 1 to 5 R 15s .
  • a 5- to 7-membered heterocycle which may be substituted with 1 to 5 R 15
  • more preferably a 5- to 7-membered nitrogen-containing saturated heterocycle which may be substituted with 1 to 5 R 15
  • particularly preferably a 1 to 5 R 15 pyrrolidine or piperidine optionally substituted with R 15 .
  • R 15 is preferably (1) a C1-8 alkyl group optionally substituted with a C3-6 cycloalkyl group optionally substituted with 1 to 5 R 18s, (2) C1 -8 haloalkyl group or (3) C1-4 alkoxycarbonyl group, more preferably substituted with (1) C3-6 cycloalkyl group optionally substituted with 1-5 R 18 a C1-8 alkyl group, or (2) a C1-8 haloalkyl group, more preferably a C1-8 alkyl group optionally substituted with (1) a cyclopropyl group substituted with 1-5 R 18 an alkyl group, or (2) a C1-8 haloalkyl group, particularly preferably a (1-(trifluoromethyl)cyclopropyl)methyl group, 3,3,3-trifluoropropyl group, 2,2-dimethylpropyl group. It is the basis.
  • R 18 is preferably (1) a C1-4 haloalkyl group or (2) a cyano group.
  • the number of substitutions for R 18 is not limited as long as it is 0 to 5, but is preferably 0 to 3.
  • R 3 is preferably (1) a 3- to 15-membered carbon ring optionally substituted with 1 to 5 R 20s , (2) a 3- to 15-membered carbon ring optionally substituted with 1 to 5 R 21 or (3) -NR 22 R 23 , more preferably (1) a 5- to 6-membered heterocycle, each optionally substituted with 1 to 5 R 20 .
  • carbocycle or indane (2) a 5- to 6-membered heterocycle optionally substituted with 1 to 5 R 21s , or (3) -NR 22 R 23 , more preferably (1) each benzene or indane, or (2)-NR 22 R 23 , optionally substituted with 1 to 5 R 20 .
  • R 3Y is preferably (1) a 3- to 15-membered carbon ring optionally substituted with 1 to 5 R 20Y , (2) a 3- to 15-membered carbon ring optionally substituted with 1 to 5 R 21Y or (3) -NR 22 R 23 , more preferably (1) a 5- to 6-membered heterocycle, each optionally substituted with 1 to 5 R 20Y ; carbocycle or indane, (2) a 5- to 6-membered heterocycle optionally substituted with 1 to 5 R 21Y , or (3) -NR 22 R 23 , more preferably (1) each benzene or indane, or (2)-NR 22 R 23 , optionally substituted with 1 to 5 R 20Y .
  • R 20 is preferably (1) a C1-4 alkyl group optionally substituted with 1 to 5 R 27 (for example, a C1-4 haloalkyl group, or substituted with 1 to 3 hydroxyl groups). (2) halogen, (3) C3-6 cycloalkyl group optionally substituted with 1 to 5 R28 , or (4) 1 to 5 R28 It is a C1-4 alkoxy group (eg, a C1-4 haloalkoxy group) which may be substituted with R 27-1 .
  • R 20Y is preferably (1) a C1-4 alkyl group optionally substituted with 1 to 5 R 27Y (for example, a C1-4 haloalkyl group, or substituted with 1 to 3 hydroxyl groups). (2) halogen, (3) C3-6 cycloalkyl group optionally substituted with 1-5 R28Y , or (4) 1-5 It is a C1-4 alkoxy group (eg, a C1-4 haloalkoxy group) which may be substituted with R 27-1Y .
  • R 21 is preferably (1) a C1-4 alkyl group optionally substituted with 1-5 R 27 (for example, a C1-4 haloalkyl group, or substituted with 1-3 hydroxyl groups). (2) halogen, (3) C3-6 cycloalkyl group optionally substituted with 1-5 R28 , or (4) a C1-4 alkoxy group (preferably a C1-4 haloalkoxy group) optionally substituted with 1 to 5 R 27-1 .
  • R 21Y is preferably (1) a C1-4 alkyl group optionally substituted with 1 to 5 R 27Y (for example, a C1-4 haloalkyl group, or substituted with 1 to 3 hydroxyl groups). (2) halogen, (3) C3-6 cycloalkyl group optionally substituted with 1-5 R 28Y , or (4) a C1-4 alkoxy group (preferably a C1-4 haloalkoxy group) optionally substituted with 1 to 5 R 27-1Y .
  • the number of substitutions for R 20 or R 21 is not limited as long as it is 0 to 5 each, but it is preferably 0 to 3.
  • R 27 or R 27-1 is preferably (1) halogen, (2) hydroxyl group, (3) carbamoyl group, or (4) carboxyl group, and more preferably (1) hydroxyl group, or (2) a carboxyl group.
  • R 27Y or R 27-1Y is preferably (1) halogen, (2) hydroxyl group, (3) carbamoyl group, or (4) carboxyl group, and more preferably (1) hydroxyl group, or (2) a carboxyl group.
  • R 28 is preferably (1) halogen, (2) hydroxyl group, (3) carbamoyl group, or (4) carboxyl group, more preferably (1) hydroxyl group or (2) carboxyl group. It is.
  • R 28Y is preferably (1) halogen, (2) hydroxyl group, (3) carbamoyl group, or (4) carboxyl group, more preferably (1) hydroxyl group or (2) carboxyl group. It is.
  • the number of substitutions for R 27 , R 27-1 or R 28 is not limited as long as it is 0 to 5 each, but it is preferably 0 to 3.
  • the number of substitutions for R 27Y , R 27-1Y or R 28Y is not limited as long as it is 0 to 5, but is preferably 0 to 3.
  • R 22 is preferably (1) a 3- to 15-membered carbon ring optionally substituted with 1 to 5 R 30s , or (2) a 3- to 15-membered carbon ring optionally substituted with 1 to 5 R 31s .
  • a 3- to 15-membered heterocycle which may be optionally substituted, more preferably (1) a 5- to 6-membered carbocyclic ring optionally substituted with 1 to 5 R is a 5- to 6-membered heterocycle optionally substituted with R 31 , more preferably (1) benzene, cyclopentane, cyclohexane, optionally substituted with 1 to 5 R 30 , or ( 2) Pyridine optionally substituted with 1 to 5 R 31s .
  • R 23 is preferably (1) a hydrogen atom, (2) a C1-8 alkyl group optionally substituted with 1 to 5 R 29s , (3) 1 to 5 R 29- a C2-4 alkenyl group optionally substituted with 1 , or (4) a C2-4 alkynyl group optionally substituted with 1 to 5 R29-2 , more preferably (1) hydrogen atom, or (2) a C1-8 alkyl group (preferably a C1-4 haloalkyl group) optionally substituted with 1 to 5 R29s .
  • R 29 is preferably (1) halogen, (2) C3-8 cycloalkyl group optionally substituted with 1 to 5 R 33s , (3) C1-4 haloalkyl group, (4 ) C1-4 haloalkoxy group, (5) hydroxyl group, or (6) carboxyl group, more preferably (1) C3-8 cycloalkyl group optionally substituted with 1-5 R33 , (2) hydroxyl group, or (3) carboxyl group.
  • R 29-1 is preferably (1) halogen, (2) C3-8 cycloalkyl group optionally substituted with 1 to 5 R 33s , (3) C1-4 haloalkyl group, (4) C1-4 haloalkoxy group, (5) hydroxyl group, or (6) carboxyl group, more preferably (1) C3-8 cycloalkyl optionally substituted with 1-5 R 33 (2) hydroxyl group, or (3) carboxyl group.
  • R 29-2 is preferably (1) halogen, (2) a C3-8 cycloalkyl group optionally substituted with 1 to 5 R 33s , (3) a C1-4 haloalkyl group, (4) C1-4 haloalkoxy group, (5) hydroxyl group, or (6) carboxyl group, more preferably (1) C3-8 cycloalkyl optionally substituted with 1-5 R 33 (2) hydroxyl group, or (3) carboxyl group.
  • R 30 is preferably (1) a C1-4 alkyl group optionally substituted with 1 to 5 R 32s , (2) halogen, (3) substituted with 1 to 5 R 33s . (4) a C1-4 alkoxy group optionally substituted with 1 to 5 R 32-1 , (5) a hydroxyl group, or (6) a carboxyl group. , more preferably (1) a C1-4 alkyl group optionally substituted with 1-5 R 32 (preferably a C1-4 haloalkyl group), (2) halogen, (3) 1-5 R 32 or ( 4 ) a C1-4 alkoxy group optionally substituted with 1 to 5 R 32-1 (preferably a C1-4 halo alkoxy group).
  • R 31 is preferably (1) a C1-4 alkyl group optionally substituted with 1 to 5 R 32s , (2) halogen, (3) substituted with 1 to 5 R 33s . (4) a C1-4 alkoxy group optionally substituted with 1 to 5 R 32-1 , (5) a hydroxyl group, or (6) a carboxyl group. , more preferably (1) a C1-4 alkyl group optionally substituted with 1-5 R 32 (preferably a C1-4 haloalkyl group), (2) halogen, (3) 1-5 R 32 or ( 4 ) a C1-4 alkoxy group optionally substituted with 1 to 5 R 32-1 (preferably a C1-4 haloalkoxy basis).
  • the number of substitutions for R 30 or R 31 is not limited as long as it is 0 to 5 each, but it is preferably 0 to 3.
  • R 32 or R 32-1 is preferably (1) halogen, (2) hydroxyl group, (3) carbamoyl group, (4) carboxyl group, or (5) cyano group, and more preferably, (1) halogen, (2) carbamoyl group, or (3) carboxyl group.
  • R 33 is preferably (1) halogen, (2) hydroxyl group, (3) carbamoyl group, (4) carboxyl group, or (5) cyano group, more preferably (1) halogen, (2) a carbamoyl group, or (3) a carboxyl group.
  • R 4 is preferably (1) halogen, (2) C1-4 alkyl group, (3) C1-4 alkoxy group, (4) C1-4 haloalkyl group, or (5) C1-4 halo It is an alkoxy group.
  • R 5 is preferably (1) a C1-4 alkyl group, (2) a C1-4 haloalkyl group, or (3) a hydroxyl group.
  • R 6 is preferably (1) halogen, (2) C1-4 alkyl group, (3) C1-4 alkoxy group, (4) C1-4 haloalkyl group, or (5) C1-4 halo It is an alkoxy group, more preferably (1) halogen or (2) C1-4 alkyl group.
  • the "saturated or partially unsaturated 4- to 10-membered carbon ring" is preferably (The arrow on the right bonds with the nitrogen atom, and the arrow on the left bonds with the carbonyl group.)
  • the "6-membered saturated heterocycle containing one nitrogen atom, one oxygen atom, and/or one optionally oxidized sulfur atom” preferably includes: (The arrow on the right bonds with the nitrogen atom, and the arrow on the left bonds with the carbonyl group.)
  • R Y is preferably (1) halogen, (2) C1-4 alkyl group, (3) C1-4 alkoxy group, (4) C1-4 haloalkyl group, or (5) C1-4 halo It is an alkoxy group, more preferably (1) halogen or (2) C1-4 alkyl group.
  • X 1 is preferably CH or CR 6 .
  • X 2 is preferably CH or CR 6 .
  • X 3 is preferably CH or CR 6 .
  • Y 1 is preferably a nitrogen atom.
  • Y 2 is preferably a nitrogen atom.
  • Y3 is preferably CR10 .
  • CR 10Y is also preferred as Y 3 .
  • R 7 is preferably a hydrogen atom.
  • R 8 is preferably a hydrogen atom.
  • R 9 is preferably a hydrogen atom.
  • R 10 is preferably (1) a hydrogen atom, (2) a C1-4 alkyl group, (3) an amino group, (4) a carboxyl group, (5) a carbamoyl group, (6) a (C1-4 (alkyl) aminocarbonyl group, (7) -CONHR 39 , or (8) cyano group, and more preferably (1) a hydrogen atom or (2) a C1-4 alkyl group.
  • R 10Y is preferably (1) hydrogen atom, (2) C1-4 alkyl group, (3) amino group, (4) carboxyl group, (5) carbamoyl group, (6) (C1-4 (alkyl) aminocarbonyl group, (7) -CONHR 39 , or (8) cyano group, and more preferably (1) a hydrogen atom or (2) a C1-4 alkyl group.
  • r is preferably 0 or 1.
  • s is preferably 0 or 1.
  • the compound represented by the general formula (IY) is preferably a compound represented by the general formula (I) shown below.
  • the compound represented by general formula (I) or general formula (IY) is preferably general formula (I-1)
  • R 1-1 represents methylene substituted with a 5- to 6-membered carbon ring which may be substituted with 1 to 5 R 11
  • ring 1 is a 5- to 7-membered nitrogen-containing saturated
  • R 3-1 is (1) a 5- to 6-membered carbocyclic ring or indane, each optionally substituted with 1 to 5 R 20
  • (2) 1 to 5 R 21 represents a 5- to 6-membered heterocycle optionally substituted with or (3)-NR 22 R 23
  • R 15-1 is C3-6 optionally substituted with 1 to 5 R 18 represents a C1-8 alkyl group that may be substituted with a cycloalkyl group, or a C1-8 haloalkyl group
  • u represents an integer from 0 to 2, and other symbols have the same meanings as above.
  • ring2 is (1) a 5- to 6-membered carbon ring or indane, each optionally substituted with 1 to 5 R 20 , (2) substituted with 1 to 5 R 21 (represents a 5- to 6-membered heterocycle which may be 5- to 6-membered heterocycle, and other symbols have the same meanings as above), a compound represented by the general formula (I-1-1-2)
  • ring3 is a 5- to 6-membered carbocyclic ring optionally substituted with 1 to 5 R 30s , or a 5- to 6-membered heterocyclic ring optionally substituted with 1 to 5 R 31
  • R 23-1 is (1) a hydrogen atom, (2) a C1-8 alkyl group optionally substituted with 1 to 5 R 29s , (3) 1 to 5 R 29- a C2-4 alkenyl group optionally substituted with 1 , or (4) a C2-4 alkynyl group optionally substituted with 1 to 5 R29-2 (preferably (1) a hydrogen atom, or (2) represents a C1-8 alkyl group (preferably a C1-4 haloalkyl group) optionally substituted with 1 to 5 R29s , and other symbols have the same meanings as above.
  • the compound represented by general formula (I) or general formula (IY) includes general formula (I-1-1-1-1)
  • ring2-1 represents a 5- to 6-membered carbon ring or indane, each optionally substituted with 1 to 5 R20 , v1 represents an integer from 0 to 5, and other symbols have the same meanings as above) are also preferred.
  • the compound represented by general formula (I) or general formula (IY) includes general formula (I-1-1-1-2)
  • the compound represented by general formula (I) or general formula (IY) includes general formula (I-1-1-2-1)
  • ring3-1 represents a 5- to 6-membered carbon ring which may be substituted with 1 to 5 R30s
  • w1 represents an integer from 0 to 5, and other symbols have the same meanings as above.
  • the compound represented by general formula (I) or general formula (IY) includes general formula (I-1-1-2-2)
  • ring3-2 represents a 5- to 6-membered heterocycle optionally substituted with 1 to 5 R31s
  • w2 represents an integer of 0 to 5, and other symbols have the same meanings as above. ) is also preferable.
  • the compound is preferably: (1) 2-Methyl-2-propanyl (3S)-3-[2-anilino-7-(4- ⁇ [9-(2,4-difluorobenzyl)-5,6,8,9-tetrahydro-7H -pyrido[4',3':4,5]pyrrolo[2,3-b]pyridin-7-yl]carbonyl ⁇ phenyl)-8-oxo-7,8-dihydro-9H-purin-9-yl] -1-pyrrolidine carboxylate, (2) 1-(3- ⁇ 7-(4- ⁇ [9-(4-cyano-2-fluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4 ,5]pyrrolo[2,3-b]pyridin-7-yl]carbonyl ⁇ phenyl)-9-[1-(2,2-dimethylpropyl)-4-piperidinyl]-6-methyl-8-ox
  • the compound represented by general formula (I) or general formula (IY) is 2-methyl-2-propanyl (3S)-3-[2-anilino-7-(4- ⁇ [9-( 2,4-difluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[2,3-b]pyridin-7-yl]carbonyl ⁇ phenyl) -8-oxo-7,8-dihydro-9H-purin-9-yl]-1-pyrrolidinecarboxylate or a salt thereof is preferred.
  • the compound represented by general formula (I) or general formula (IY) includes 1-(3- ⁇ 7-(4- ⁇ [9-(4-cyano-2-fluorobenzyl)-5, 6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[2,3-b]pyridin-7-yl]carbonyl ⁇ phenyl)-9-[1-(2,2 -dimethylpropyl)-4-piperidinyl]-6-methyl-8-oxo-8,9-dihydro-7H-purin-2-yl ⁇ phenyl)cyclopropanecarboxylic acid, or a salt thereof is also preferred.
  • the compound represented by general formula (I) or general formula (IY) is 7-(4- ⁇ [9-(4-chloro-2-fluorobenzyl)-5,6,8,9- Tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[2,3-b]pyridin-7-yl]carbonyl ⁇ phenyl)-2- ⁇ [4-(difluoromethoxy)phenyl]amino ⁇ - 9-[1-(2,2-dimethylpropyl)-4-piperidinyl]-6-methyl-7,9-dihydro-8H-purin-8-one or a salt thereof is also preferred.
  • the compound represented by general formula (I) or general formula (IY) is 7-(4- ⁇ [9-(4-chloro-2-fluorobenzyl)-5,6,8,9- Tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[2,3-b]pyridin-7-yl]carbonyl ⁇ phenyl)-9-[1-(2,2-dimethylpropyl)-4 -piperidinyl]-2-[(3-fluorophenyl)amino]-6-methyl-7,9-dihydro-8H-purin-8-one or a salt thereof is also preferred.
  • the compound represented by general formula (I) or general formula (IY) is 9-[1-(2,2-dimethylpropyl)-4-piperidinyl]-7-(6- ⁇ [9- (2-fluoro-4-methylbenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[2,3-b]pyridin-7-yl]carbonyl ⁇ -3-pyridinyl)-6-methyl-2- ⁇ [4-(trifluoromethoxy)phenyl]amino ⁇ -7,9-dihydro-8H-purin-8-one or a salt thereof is also preferred.
  • the compound represented by general formula (I) or general formula (IY) includes 4-[(7- ⁇ [5-(9-[1-(2,2-dimethylpropyl)-4-piperidinyl) ]-6-Methyl-8-oxo-2- ⁇ [4-(trifluoromethoxy)phenyl]amino ⁇ -8,9-dihydro-7H-purin-7-yl)-2-pyridinyl]carbonyl ⁇ -5, 6,7,8-tetrahydro-9H-pyrido[4',3':4,5]pyrrolo[2,3-b]pyridin-9-yl)methyl]-3-fluorobenzonitrile or a salt thereof is also preferred .
  • the compound represented by the general formula (I) or the general formula (IY) is 3-fluoro-4-( ⁇ 7-[(5- ⁇ 2-[(3-fluorophenyl)amino]-6 -Methyl-8-oxo-9-(1- ⁇ [1-(trifluoromethyl)cyclopropyl]methyl ⁇ -4-piperidinyl)-8,9-dihydro-7H-purin-7-yl ⁇ -2-pyridinyl ) carbonyl]-5,6,7,8-tetrahydro-9H-pyrido[4',3':4,5]pyrrolo[2,3-b]pyridin-9-yl ⁇ methyl)benzonitrile, or a salt thereof is also preferable.
  • the compound represented by general formula (I) or general formula (IY) includes 4-[(7- ⁇ [5-(2- ⁇ [2-chloro-4-(trifluoromethoxy)phenyl]) amino ⁇ -9-[1-(2,2-dimethylpropyl)-4-piperidinyl]-6-methyl-8-oxo-8,9-dihydro-7H-purin-7-yl)-2-pyridinyl]carbonyl ⁇ -5,6,7,8-tetrahydro-9H-pyrido[4',3':4,5]pyrrolo[2,3-b]pyridin-9-yl)methyl]-3-fluorobenzonitrile, or Its salts are also preferred.
  • the compound represented by general formula (I) or general formula (IY) includes 2-(3- ⁇ 7-(6- ⁇ [9-(4-cyano-2-fluorobenzyl)-5, 6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[2,3-b]pyridin-7-yl]carbonyl ⁇ -3-pyridinyl)-9-[1-( Also preferred is 2,2-dimethylpropyl)-4-piperidinyl]-6-methyl-8-oxo-8,9-dihydro-7H-purin-2-yl ⁇ phenyl)-2-methylpropanoic acid or a salt thereof.
  • the compound represented by the general formula (I) or the general formula (IY) includes 4-( ⁇ 7-[(5- ⁇ 9-[1-(2,2-dimethylpropyl)-4-piperidinyl) ]-6-Methyl-2-[2-methyl-4-(trifluoromethoxy)phenyl]-8-oxo-8,9-dihydro-7H-purin-7-yl ⁇ -2-pyridinyl)carbonyl]-5 , 6,7,8-tetrahydro-9H-pyrido[4',3':4,5]pyrrolo[2,3-b]pyridin-9-yl ⁇ methyl)-3-fluorobenzonitrile, or a salt thereof preferable.
  • compounds represented by general formula (I) or general formula (IY) include 1- ⁇ [ ⁇ 7-(6- ⁇ [9-(4-cyano-2-fluorobenzyl)-5,6 ,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[2,3-b]pyridin-7-yl]carbonyl ⁇ -3-pyridinyl)-9-[1-(2 ,2-dimethylpropyl)-4-piperidinyl]-6-methyl-8-oxo-8,9-dihydro-7H-purin-2-yl ⁇ (cyclohexyl)amino]methyl ⁇ cyclobutanecarboxylic acid, or a salt thereof is also preferable.
  • the compound represented by general formula (I) or general formula (IY) is 7-(6- ⁇ [9-(4-chloro-2-fluorobenzyl)-5,6,8,9- Tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[2,3-b]pyridin-7-yl]carbonyl ⁇ -3-pyridinyl)-9-[1-(2,2-dimethylpropyl) )-4-piperidinyl]-2-[(3-fluorophenyl)amino]-6-methyl-7,9-dihydro-8H-purin-8-one or a salt thereof is also preferred.
  • alkyl groups include straight and branched chains.
  • geometric isomers E-form, Z-form, cis-form, trans-form
  • optical isomers due to the presence of asymmetric carbon atoms R, S-form, ⁇ -, ⁇ -configuration, enantiomers, diastereomers
  • optically active forms with optical rotation D, L, d, l forms
  • polar forms obtained by chromatographic separation highly polar forms, low polar forms
  • equilibrium compounds rotamers
  • optical isomers in the present invention are not limited to 100% pure ones, and may contain less than 50% of other optical isomers.
  • N-oxide form The compound represented by the general formula (IY) can be converted into an N-oxide form by a known method.
  • the N-oxide compound refers to a compound represented by the general formula (IY) in which the nitrogen atom is oxidized.
  • these N-oxide forms can be used as prodrugs thereof, as described in the following [Prodrugs], [Salts] and [Solvates] below. It may be a salt or a solvate thereof.
  • the compound represented by general formula (IY) or its N-oxide can also be made into a prodrug by a known method.
  • the prodrug refers to a compound that is converted into, for example, a compound represented by general formula (IY) or its N-oxide form by a reaction with enzymes, gastric acid, etc. in vivo.
  • the compound represented by the general formula (IY) or its N-oxide prodrug can be used in a physiological manner as described in "Molecular Design", Vol. 7, “Molecular Design”, Hirokawa Shoten, 1990, “Drug Development", It may be converted into the corresponding compound represented by general formula (IY) or its N-oxide form under appropriate conditions.
  • prodrugs of the compound represented by general formula (IY) or its N-oxide form include, for example, when the compound represented by general formula (IY) has an amino group, the amino group may be acylated or alkylated. or a phosphorylated compound (for example, the amino group of the compound represented by the general formula (IY) is eicosanoylated, alanylated, pentylaminocarbonylated, (5-methyl-2-oxo-1,3-dioxolene-4- compounds represented by the general formula (IY) have a hydroxyl group If the hydroxyl group of the compound is acylated, alkylated, phosphorylated, or borated (for example, the hydroxyl group of the compound represented by general formula (IY) is acetylated, palmitoylated, propanoylated, pivaloylated, or succinylated) , fumarylated, alanylated or dimethylaminomethylcarbonylated
  • the compound represented by the general formula (IY) or its N-oxide prodrug can be further prepared according to its pharmaceutically acceptable form, as described in the [Salts] section and the [Solvate] section below. It may be in the form of a salt or solvate.
  • salts The compound represented by general formula (IY), its N-oxide form, or its prodrug can be converted into a corresponding pharmaceutically acceptable salt by a known method.
  • pharmaceutically acceptable salts include alkali metal salts (e.g., lithium salts, sodium salts, potassium salts, etc.), alkaline earth metal salts (e.g., calcium salts, magnesium salts, barium salts, etc.) , ammonium salts, organic amine salts (e.g., aliphatic amine salts (e.g., methylamine salts, dimethylamine salts, cyclopentylamine salts, trimethylamine salts, triethylamine salts, dicyclohexylamine salts, monoethanolamine salts, diethanolamine salts, triethanolamine salts) salts, procaine salts, meglumine salts, diethanolamine salts, tris(hydroxymethyl)aminomethane salts, ethylenediamine salts and piperidine
  • benzylamine salts phenethylamine salts, N,N-dibenzylethylenediamine salts and benetamine salt, etc.
  • heterocyclic aromatic amine salts e.g., pyridine salt, picoline salt, quinoline salt, and isoquinoline salt, etc.
  • quaternary ammonium salts e.g., tetramethylammonium salt, tetraethylammonium salt, benzyltrimethylammonium salt, (benzyltriethylammonium salt, benzyltributylammonium salt, methyltrioctylammonium salt, tetrabutylammonium salt, etc.
  • basic amino acid salts such as arginine salt, lysine salt, etc., and N-methyl-D-glucamine salt, etc.
  • Adduct salts such as inorganic acid salts (e.g.
  • the pharmaceutically acceptable salt is preferably water-soluble.
  • Salts also include quaternary ammonium salts.
  • the quaternary ammonium salt refers to a compound represented by the general formula (IY) in which the nitrogen atom is quaternized with an R 0 group.
  • the R 0 group represents, for example, a C1-8 alkyl group which may be substituted with a phenyl group.
  • the compound represented by general formula (IY), its N-oxide, its prodrug, or a pharmaceutically acceptable salt thereof may exist in an unsolvated form, and may be present in an unsolvated form, such as water, ethanol, etc. may exist in a solvated form with a pharmaceutically acceptable solvent.
  • the solvate is preferably a hydrate.
  • the compound represented by general formula (IY), its N-oxide, its prodrug, or its pharmaceutically acceptable salt can also be converted into a solvate by a known method.
  • the solvate has low toxicity and is water soluble.
  • Suitable solvates include, for example, solvates with water and alcoholic solvents (eg, ethanol, etc.).
  • the hydrate may take the form of a hydrate such as a monohydrate to a pentahydrate, or a low hydrate such as a hemihydrate, but the hydrate of the compound of the present invention may be Examples of the hydrate form include monohydrate, dihydrate, trihydrate, and di-trihydrate. Further, the forms of these hydrates include clathrate hydrates. These hydrates can be obtained by, for example, precipitating the compound represented by the general formula (IY), its N-oxide, its prodrug, or a pharmaceutically acceptable salt thereof from a water-containing organic solvent. Can be done.
  • Co-crystal The compound represented by general formula (IY), its N-oxide, its prodrug, its pharmaceutically acceptable salt, or its solvate forms a co-crystal with an appropriate co-crystal forming agent. be able to.
  • the co-crystal is preferably a pharmaceutically acceptable co-crystal formed with a pharmaceutically acceptable co-crystal forming agent.
  • a co-crystal is defined as a crystal formed by two or more different molecules through intermolecular interactions other than ionic bonding. Further, the co-crystal may be a complex of a neutral molecule and a salt.
  • Co-crystals can be prepared by known methods, such as melt crystallization, recrystallization from a solvent or physically grinding the components together.
  • Suitable co-crystal forming agents include those described in WO 2006/007448 pamphlet, such as 4-aminobenzoic acid, 4-aminopyridine, adenine, alanine, acetylsalicylic acid and the like.
  • the compound represented by the general formula (IY), its N-oxide, its prodrug, its pharmaceutically acceptable salt, or its solvate has an isotope (for example, 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 35 S, 18 F, 36 Cl, 123 I, 125 I , etc.).
  • R 1 , R 2 , R 3 , R 3Y , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 and R 10Y in general formula (I) examples include compounds in which all or part of the hydrogen atoms constituting the compound are replaced with deuterium atoms or tritium atoms.
  • references to the compounds of the present invention refer to compounds represented by general formula (IY), pharmaceutically acceptable salts thereof, N-oxides thereof, solvates (e.g. hydrates) thereof, or co-crystals thereof; Alternatively, it includes an N-oxide of a pharmaceutically acceptable salt of the compound represented by general formula (IY), a solvate thereof (for example, a hydrate), or a co-crystal thereof.
  • the compounds of the present invention can be prepared by known methods, such as those described in Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 2nd Edition (Richard C. Larock, John Wiley & Sons Inc, 1999), or the methods or practices described below. It can be manufactured by appropriately improving the methods shown in the examples and using them in combination.
  • R 3 is benzene optionally substituted with 1 to 5 R 20 , and X 1 , X 2 , and X 3 are each independently, Compounds that are CH or CR 6 , i.e. general formula (IA)
  • E 1 , E 2 and E 3 each independently represent a leaving group (e.g., fluorine atom, bromine atom, chlorine atom, iodine atom, trifluoromethanesulfonic acid ester, p-toluenesulfonic acid ester, etc.)
  • P c represents a carboxyl group protecting group
  • R BO represents a boron-containing group (for example, -B(OH) 2 , -B(OCH 3 ) 2 , 3-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl), 3-(6-methyl-4,8-dioxo-1,3,6,2-dioxazaborocan-2-yl), trifluorobo other symbols have the same meanings as above.
  • the compound represented by the general formula (IV) can be produced by subjecting the compound represented by the general formula (II) and the compound represented by the general formula (III) to an amino group introduction reaction.
  • This amino group introduction reaction is known, for example, in an organic solvent (dichloromethane, tetrahydrofuran, 1,4-dioxane, dimethylformamide, dimethylacetamide, 1-methyl-2-pyrrolidone, dimethylsulfoxide, etc.) or without a solvent.
  • the reaction is carried out in the presence of a base (triethylamine, N,N-diisopropylethylamine, pyridine, 4-dimethylaminopyridine, N-methylmorpholine, etc.) at a temperature of room temperature to 180°C.
  • conversion to the desired salt may be performed by a known method.
  • the compound represented by the general formula (VI) can be produced by subjecting the compound represented by the general formula (IV) and the compound represented by the general formula (V) to a coupling reaction.
  • This coupling reaction is known, for example, using a base in an organic solvent (benzene, toluene, dimethylformamide, dimethylacetamide, 1,4-dioxane, tetrahydrofuran, methanol, acetonitrile, dimethoxyethane, acetone, or a mixed solution thereof, etc.).
  • an organic solvent benzene, toluene, dimethylformamide, dimethylacetamide, 1,4-dioxane, tetrahydrofuran, methanol, acetonitrile, dimethoxyethane, acetone, or a mixed solution thereof, etc.
  • conversion to the desired salt may be performed by a known method.
  • the compound represented by the general formula (VII) can be produced by subjecting the compound represented by the general formula (VI) to a cyclization reaction.
  • This cyclization reaction is known, for example, in an organic solvent (tetrahydrofuran, dimethylformamide, dimethylacetamide, dichloromethane, etc.) using a reagent (1,1'-carbonyldiimidazole (CDI), triphosgene, 2,2,2-trichloro ethyl carbon chloridate, etc.) in the presence or absence of a base (triethylamine, N,N-diisopropylethylamine, pyridine, 4-dimethylaminopyridine, N-methylmorpholine, etc.) at ice-cooling to reflux temperature. be exposed.
  • a base triethylamine, N,N-diisopropylethylamine, pyridine, 4-dimethylaminopyridine, N-methylmorpholine, etc.
  • conversion to the desired salt may be performed by a known method.
  • the compound represented by the general formula (VIII) can be produced by subjecting the compound represented by the general formula (VII) to a deprotection reaction of the protecting group of the carboxyl group.
  • protective groups for carboxyl groups include methyl group, ethyl group, allyl group, t-butyl group, trichloroethyl group, benzyl (Bn) group, phenacyl group, p-methoxybenzyl group, trityl group, and 2-chlorotrityl group.
  • a solid phase support to which these structures are bonded can be mentioned.
  • the protecting group for the carboxyl group is not particularly limited as long as it is a group that can be easily and selectively removed in addition to those mentioned above.
  • those described in P. G. M. Wuts, T. W. Greene, Green's Protective Groups in Organic Synthesis, Wiley, Fourth Edition, New York, 2007 are used.
  • the deprotection reaction of protecting groups of carboxyl groups is well known, for example, (1) Alkaline hydrolysis, (2) Deprotection reaction under acidic conditions, (3) Deprotection reaction by hydrolysis, (4) Deprotection reaction of silyl group, (5) Deprotection reaction using metal, (6) Examples include deprotection reactions using metal complexes.
  • Deprotection reaction by alkaline hydrolysis can be carried out using, for example, an alkali metal hydroxide (sodium hydroxide, potassium hydroxide, lithium hydroxide, etc.) in an organic solvent (methanol, tetrahydrofuran, 1,4-dioxane, etc.). , alkali metal silanol salts (potassium trimethylsilanolate, etc.), alkaline earth metal hydroxides (barium hydroxide, calcium hydroxide, etc.) or carbonates (sodium carbonate, potassium carbonate, etc.) or their aqueous solutions or mixtures thereof.
  • the test is carried out at a temperature of 0°C to 80°C.
  • the deprotection reaction under acidic conditions can be carried out, for example, in an organic solvent (dichloromethane, chloroform, 1,4-dioxane, ethyl acetate, anisole, etc.) with an organic acid (acetic acid, trifluoroacetic acid, methanesulfonic acid, p - tosylic acid, etc.) or inorganic acids (hydrochloric acid, sulfuric acid, etc.) or mixtures thereof (hydrogen bromide/acetic acid, etc.) in the presence or absence of 2,2,2-trifluoroethanol, from 0°C to 100°C. It is carried out at a temperature of °C.
  • the deprotection reaction by hydrolysis can be carried out using, for example, a solvent (tetrahydrofuran, 1,4-dioxane, dimethoxyethane, diethyl ether, methanol, ethanol, benzene, toluene, acetone, methyl ethyl ketone, acetonitrile, dimethylformamide, water, acetic acid).
  • a solvent tetrahydrofuran, 1,4-dioxane, dimethoxyethane, diethyl ether, methanol, ethanol, benzene, toluene, acetone, methyl ethyl ketone, acetonitrile, dimethylformamide, water, acetic acid.
  • a catalyst palladium-carbon, palladium black, palladium hydroxide-carbon, platinum oxide, Raney nickel, etc.
  • it is carried out at a temperature of 0°C to 200°C in the presence
  • the deprotection reaction of the silyl group is carried out, for example, using tetrabutylammonium fluoride in a water-miscible organic solvent (tetrahydrofuran, acetonitrile, etc.) at a temperature of 0°C to 40°C.
  • a water-miscible organic solvent tetrahydrofuran, acetonitrile, etc.
  • the deprotection reaction using a metal can be carried out, for example, in the presence of powdered zinc in an acidic solvent (acetic acid, a buffer solution with a pH of 4.2 to 7.2, or a mixture of such a solution and an organic solvent such as tetrahydrofuran). It is carried out at a temperature of 0°C to 40°C, with ultrasound applied if necessary.
  • an acidic solvent acetic acid, a buffer solution with a pH of 4.2 to 7.2, or a mixture of such a solution and an organic solvent such as tetrahydrofuran.
  • the deprotection reaction using a metal complex can be carried out using a trap reagent ( tributyltin hydride, triethylsilane, dimedone, morpholine, diethylamine, pyrrolidine, etc.), organic acids (acetic acid, formic acid, 2-ethylhexanoic acid, etc.) and/or organic acid salts (sodium 2-ethylhexanoate, 2-ethylhexanoic acid) metal complexes (tetrakis(triphenylphosphine)palladium (Pd( PPh3 ), bis(triphenylphosphine)palladium dichloride) in the presence or absence of phosphine-based reagents (triphenylphosphine, etc.) (PdCl 2 (PPh 3 ) 2 ), palladium acetate (Pd(OAc) 2 ), tris(triphenylphosphine) rh
  • conversion to the desired salt may be performed by a known method.
  • the compound represented by the general formula (X) can be produced by subjecting the compound represented by the general formula (VIII) and the compound represented by the general formula (IX) to an amidation reaction.
  • This amidation reaction is known, for example, (1) Method using acid halide, (2) method using mixed acid anhydride; (3) A method using a condensing agent may be mentioned.
  • a method using an acid halide involves, for example, adding a carboxylic acid to an acid halide agent (oxalyl chloride, thionyl chloride, etc.) in an organic solvent (chloroform, dichloromethane, diethyl ether, tetrahydrofuran, etc.) or without a solvent at -20°C.
  • an acid halide agent oxalyl chloride, thionyl chloride, etc.
  • organic solvent chloroform, dichloromethane, diethyl ether, tetrahydrofuran, etc.
  • the obtained acid halide can be reacted with an amine at 0°C to 40°C in an organic solvent (1,4-dioxane, tetrahydrofuran, etc.) using an alkaline aqueous solution (aqueous sodium bicarbonate or sodium hydroxide solution, etc.). You can also do it.
  • a method using a mixed acid anhydride includes, for example, adding a carboxylic acid to a base (pyridine, triethylamine, dimethylaniline, dimethylaminopyridine, diisopropyl, etc.) in an organic solvent (chloroform, dichloromethane, diethyl ether, tetrahydrofuran, etc.) or without a solvent.
  • ethylamine, etc. with an acid halide (pivaloyl chloride, tosyl chloride, mesyl chloride, etc.) or an acid derivative (ethyl chloroformate, isobutyl chloroformate, etc.) at 0°C to 40°C.
  • This is carried out by reacting a mixed acid anhydride with an amine in an organic solvent (chloroform, dichloromethane, diethyl ether, tetrahydrofuran, etc.) at 0°C to 40°C.
  • a method using a condensing agent is, for example, combining a carboxylic acid and an amine in an organic solvent (chloroform, dichloromethane, dimethylformamide, diethyl ether, tetrahydrofuran, etc.) or without a solvent, and a base (pyridine, triethylamine, dimethylaniline, etc.).
  • an organic solvent chloroform, dichloromethane, dimethylformamide, diethyl ether, tetrahydrofuran, etc.
  • a base pyridine, triethylamine, dimethylaniline, etc.
  • reaction (1), (2), and (3) are all carried out under anhydrous conditions in an inert gas (argon, nitrogen, etc.) atmosphere.
  • inert gas argon, nitrogen, etc.
  • conversion to the desired salt may be performed by a known method.
  • the compound represented by the general formula (IA) can be produced by subjecting the compound represented by the general formula (X) and the compound represented by the general formula (XI) to a coupling reaction.
  • This coupling reaction is known, for example, an organic solvent (benzene, toluene, dimethylformamide, 1,4-dioxane, tetrahydrofuran, methanol, acetonitrile, dimethoxyethane, acetone, 1-methyl-2-pyrrolidinone or a mixed solvent thereof).
  • an organic solvent benzene, toluene, dimethylformamide, 1,4-dioxane, tetrahydrofuran, methanol, acetonitrile, dimethoxyethane, acetone, 1-methyl-2-pyrrolidinone or a mixed solvent thereof.
  • bases sodium ethylate, sodium hydroxide, potassium hydroxide, triethylamine, sodium carbonate, sodium bicarbonate, potassium carbonate, cesium carbonate, thallium carbonate, tripotassium phosphate, cesium fluoride, barium hydroxide, or aqueous solutions thereof, or mixtures thereof
  • catalysts tetrakis(triphenylphosphine)palladium (Pd(PPh 3 ) 4 ), bis(triphenylphosphine)palladium dichloride (PdCl 2 (PPh 3 ) 2 ), palladium acetate (Pd(OAc) 2 ), palladium black, 1,1'-bis(diphenylphosphinoferrocene) dichloropalladium (PdCl 2 (dppf) 2 ), diallypalladium dichloride (PdCl 2 (allyl ) 2 ), phenylbis(triphenylphosphine)palla
  • conversion to the desired salt may be performed by a known method.
  • R 2 is a 5- to 7-membered nitrogen-containing saturated heterocycle, and R 15 substituted on the nitrogen atom is substituted with 1 to 5 R 18 .
  • ring1 represents a 5- to 7-membered nitrogen-containing saturated heterocycle
  • R 15-1 is substituted with a C3-6 cycloalkyl group optionally substituted with 1 to 5 R 18 .
  • R 15-1 represents an optional C1-8 alkyl group or C1-8 haloalkyl group, u represents an integer of 0 to 2, and other symbols have the same meanings as above
  • R 15-2 is substituted with a hydrogen atom or a C3-6 cycloalkyl group optionally substituted with 1 to 5 R 18 .
  • E4 represents a leaving group (e.g., fluorine atom, bromine atom, chlorine atom, iodine atom, trifluoromethanesulfonic acid ester, p-toluenesulfonic acid ester). etc.), P N-1 represents a protecting group for an amino group, and other symbols have the same meanings as above.
  • the compound represented by the general formula (IV-1) is produced by subjecting the compound represented by the general formula (II) and the compound represented by the general formula (III-1) to an amino group introduction reaction. be able to.
  • This reaction for introducing an amino group is similar to the reaction for producing the compound represented by the general formula (IV) described above.
  • conversion to the desired salt may be performed by a known method.
  • the compound represented by the general formula (VI-1) can be produced by subjecting the compound represented by the general formula (IV-1) and the compound represented by the general formula (V) to a coupling reaction. can.
  • This coupling reaction is similar to the reaction for producing the compound represented by general formula (VI) above.
  • conversion to the desired salt may be performed by a known method.
  • the compound represented by the general formula (VII-1) can be produced by subjecting the compound represented by the general formula (VI-1) to a cyclization reaction.
  • This cyclization reaction is similar to the reaction used to produce the compound represented by the aforementioned general formula (VII).
  • conversion to the desired salt may be performed by a known method.
  • the compound represented by the general formula (VIII-1) can be produced by subjecting the compound represented by the general formula (VII-1) to a deprotection reaction of the protecting group of the carboxyl group.
  • conversion to the desired salt may be performed by a known method.
  • the compound represented by the general formula (X-1) can be produced by subjecting the compound represented by the general formula (VIII-1) and the compound represented by the general formula (IX) to an amidation reaction. can.
  • This amidation reaction is similar to the reaction for producing the compound represented by the general formula (X) described above.
  • conversion to the desired salt may be performed by a known method.
  • the compound represented by the general formula (XVI-1) can be produced by subjecting the compound represented by the general formula (X-1) to a deprotection reaction of the protecting group of the amino group.
  • protecting groups for amino groups include benzyloxycarbonyl group, tert-butoxycarbonyl group, allyloxycarbonyl (Alloc) group, 1-methyl-1-(4-biphenyl)ethoxycarbonyl (Bpoc) group, and trifluoroacetyl group. group, 9-fluorenylmethoxycarbonyl group, benzyl (Bn) group, 4-methoxybenzyl group, benzyloxymethyl (BOM) group, and 2-(trimethylsilyl)ethoxymethyl (SEM) group.
  • the protecting group for the amino group is not particularly limited as long as it is a group that can be easily and selectively removed other than those mentioned above.
  • those described in P. G. M. Wuts, T. W. Greene, Green's Protective Groups in Organic Synthesis, Wiley, Fourth Edition, New York, 2007 are used.
  • Deprotection reactions of protecting groups for amino groups are known, for example, (1) Alkaline hydrolysis, (2) Deprotection reaction under acidic conditions, (3) Deprotection reaction by hydrolysis, (4) Deprotection reaction of silyl group, (5) Deprotection reaction using metal, (6) Examples include deprotection reactions using metal complexes.
  • Deprotection reaction by alkaline hydrolysis can be carried out using, for example, an alkali metal hydroxide (sodium hydroxide, potassium hydroxide, lithium hydroxide, etc.) in an organic solvent (methanol, tetrahydrofuran, 1,4-dioxane, etc.). , using alkaline earth metal hydroxides (barium hydroxide, calcium hydroxide, etc.) or carbonates (sodium carbonate, potassium carbonate, etc.) or their aqueous solutions or mixtures thereof at temperatures of 0°C to 40°C. It will be done.
  • an alkali metal hydroxide sodium hydroxide, potassium hydroxide, lithium hydroxide, etc.
  • organic solvent methanol, tetrahydrofuran, 1,4-dioxane, etc.
  • alkaline earth metal hydroxides barium hydroxide, calcium hydroxide, etc.
  • carbonates sodium carbonate, potassium carbonate, etc.
  • the deprotection reaction under acidic conditions can be carried out, for example, in an organic solvent (dichloromethane, chloroform, 1,4-dioxane, ethyl acetate, anisole, etc.) with an organic acid (acetic acid, trifluoroacetic acid, methanesulfonic acid, p -tosylic acid, etc.), or in an inorganic acid (hydrochloric acid, sulfuric acid, etc.) or a mixture thereof (hydrogen bromide/acetic acid, etc.) at a temperature of 0°C to 100°C.
  • the deprotection reaction by hydrolysis can be carried out using, for example, a solvent (tetrahydrofuran, 1,4-dioxane, dimethoxyethane, diethyl ether, methanol, ethanol, benzene, toluene, acetone, methyl ethyl ketone, acetonitrile, dimethylformamide, water, acetic acid). ethyl, acetic acid, etc., or a mixed solvent thereof), in the presence of a catalyst (palladium-carbon, palladium black, palladium hydroxide, platinum oxide, Raney nickel, etc.), under a hydrogen atmosphere at normal or pressurized pressure, or in the presence of ammonium formate. , at a temperature of 0°C to 200°C.
  • a solvent tetrahydrofuran, 1,4-dioxane, dimethoxyethane, diethyl ether, methanol, ethanol, benzene
  • the deprotection reaction of the silyl group is carried out, for example, in a water-miscible organic solvent (tetrahydrofuran, acetonitrile, etc.) using tetrabutylammonium fluoride or the like at a temperature of 0°C to 40°C.
  • a water-miscible organic solvent tetrahydrofuran, acetonitrile, etc.
  • tetrabutylammonium fluoride or the like at a temperature of 0°C to 40°C.
  • Deprotection reactions using metals can be performed, for example, in the presence of powdered zinc in an acidic solvent (acetic acid, a buffer solution with a pH of 4.2 to 7.2, or a mixed solvent of these solutions and an organic solvent such as tetrahydrofuran).
  • an acidic solvent acetic acid, a buffer solution with a pH of 4.2 to 7.2, or a mixed solvent of these solutions and an organic solvent such as tetrahydrofuran.
  • the process is carried out at a temperature of 0°C to 40°C, with ultrasonic waves applied if necessary.
  • the deprotection reaction using a metal complex can be carried out using a trap reagent ( tributyltin hydride, triethylsilane, dimedone, morpholine, diethylamine, pyrrolidine, etc.), organic acids (acetic acid, formic acid, 2-ethylhexanoic acid, etc.) and/or organic acid salts (sodium 2-ethylhexanoate, 2-ethylhexanoic acid) metal complexes (tetrakis(triphenylphosphine)palladium (Pd(PPh 3 ) 4 ), bis(triphenylphosphine dichloride), in the presence or absence of phosphine-based reagents (triphenylphosphine, etc.) ) using palladium (PdCl 2 (PPh 3 ) 2 ), palladium acetate (Pd(OAc) 2 ), tris(triphenylphosphine
  • conversion to the desired salt may be performed by a known method.
  • the compound represented by the general formula (XIX-1) is a compound represented by the general formula (XVI-1), a compound represented by the general formula (XVII-1), or a compound represented by the general formula (XVIII-1). can be produced by subjecting it to an alkylation reaction.
  • This alkylation reaction is known, and when using a compound represented by general formula (XVII-1), for example, organic solvents (dimethylformamide, dimethylacetamide, dimethyl sulfoxide, chloroform, dichloromethane, diethyl ether, tetrahydrofuran, methyl t-butyl ether, etc.), organic bases (triethylamine, N,N-diisopropylethylamine, pyridine, 4-dimethylaminopyridine, N-methylmorpholine, etc.), alkali metal hydroxides (sodium hydroxide, potassium hydroxide, lithium hydroxide, etc.), alkaline earth metal hydroxides (barium hydroxide, calcium hydroxide, etc.) or carbonates (sodium carbonate, potassium carbonate, etc.) or their aqueous solutions, or mixtures thereof.
  • organic solvents dimethylformamide, dimethylacetamide, dimethyl sulfoxide, chloroform, dichloromethan
  • the desired product can be obtained by a reductive amination reaction.
  • This reductive amination reaction is known, and the imine produced in the reaction may be isolated and then reduced, or the imine may be produced in the reaction system and reduced without isolation (in one pot). good.
  • This imine production reaction is known, and for example, in an organic solvent (methanol, ethanol, dichloromethane, chloroform, dichloroethane, benzene, toluene, or a mixed solvent thereof, etc.), a dehydrating agent (anhydrous magnesium sulfate, ) etc.) and in the presence or absence of an acid (hydrochloric acid, acetic acid, etc.) at 20° C. to reflux temperature.
  • Reduction reactions of imines include, for example, reducing agents (sodium triacetoxyborohydride, sodium cyanoborohydride, sodium borohydride, zinc borohydride, diisobutylaluminum hydride, 2-picoline borane complex, etc.) at a temperature of 0°C to 40°C, or in the presence of a solvent (tetrahydrofuran, 1,4 - In a catalyst (such as dioxane, dimethoxyethane, diethyl ether, methanol, ethanol, benzene, toluene, acetonitrile, dimethylformamide, water, ethyl acetate, acetic acid, or a mixed solvent thereof) (palladium on carbon, palladium black, palladium hydroxide) , platinum oxide, Raney nickel, etc.), in a hydrogen atmosphere under normal pressure or under pressure, and at a temperature of 0° C.
  • reducing agents sodium triacetoxyborohydride
  • reductive amination reactions performed without isolating the imine are known, for example, in an organic solvent (such as tetrahydrofuran, dichloroethane, dichloromethane, dimethylformamide, acetic acid, or a mixture thereof) with a reducing agent (triacetoxy hydrogenation reaction).
  • organic solvent such as tetrahydrofuran, dichloroethane, dichloromethane, dimethylformamide, acetic acid, or a mixture thereof
  • a reducing agent triacetoxy hydrogenation reaction.
  • the reaction can be carried out at a temperature of 0° C. to 40° C. in the presence of sodium boron, sodium cyanoborohydride, sodium borohydride, 2-picoline borane complex, etc.
  • a Lewis acid titanium tetrachloride, etc.
  • a tertiary amine triethylamine, diisopropylethylamine, etc.
  • organic solvent dichloroethane, dichloromethane, toluene, tetrahydrofuran, or a mixed solvent thereof, etc.
  • the reaction can be carried out at a temperature of 0° C. to 40° C. and further carried out at a temperature of 0° C. to 40° C. in the presence of a reducing agent (sodium triacetoxyborohydride, sodium cyanoborohydride, 2-picoline borane complex, etc.).
  • conversion to the desired salt may be performed by a known method.
  • the compound represented by general formula (IA-1) is produced by subjecting a compound represented by general formula (XIX-1) and a compound represented by general formula (XI) to a coupling reaction. be able to.
  • This coupling reaction is similar to the reaction for producing the compound represented by the general formula (IA) described above.
  • the compound represented by the general formula (IA-1) can also be produced by the method shown in the following reaction scheme 1-1c and reaction scheme 1-1d.
  • reaction scheme 1-1c and reaction scheme 1-1d all symbols have the same meanings as above.
  • the compound represented by the general formula (XXX-1) can be produced by subjecting the compound represented by the general formula (VII-1) to a deprotection reaction of the protecting group of the carboxyl group.
  • conversion to the desired salt may be performed by a known method.
  • the compound represented by the general formula (XXXI-1) can be produced by subjecting the compound represented by the general formula (XXX-1) and the compound represented by the general formula (XI) to a coupling reaction. can.
  • This coupling reaction is similar to the reaction for producing the compound represented by the general formula (IA) described above.
  • conversion to the desired salt may be performed by a known method.
  • the compound represented by the general formula (XXXII-1) can be produced by subjecting the compound represented by the general formula (XXXI-1) and the compound represented by the general formula (IX) to an amidation reaction. can.
  • This amidation reaction is similar to the reaction for producing the compound represented by general formula (X) described above.
  • conversion to the desired salt may be performed by a known method.
  • the compound represented by the general formula (XXXIII-1) can be produced by subjecting the compound represented by the general formula (XXXII-1) to a deprotection reaction of the protecting group of the amino group.
  • This deprotection reaction of the protecting group for the amino group is similar to the reaction for producing the compound represented by general formula (XVI-1) above.
  • conversion to the desired salt may be performed by a known method.
  • the compound represented by the general formula (IA-1) is a compound represented by the general formula (XXXIII-1), a compound represented by the general formula (XVII-1), or a compound represented by the general formula (XVIII-1). It can be produced by subjecting a compound to an alkylation reaction.
  • This alkylation reaction is similar to the reaction for producing the compound represented by general formula (XIX-1) above.
  • conversion to the desired salt may be performed by a known method.
  • the compound represented by the general formula (IA-1) can also be produced by the method shown in the following reaction scheme 1-1e.
  • Reaction Scheme 1-1e all symbols have the same meanings as above.
  • the compound represented by the general formula (XXXVIII-1) can be produced by subjecting the compound represented by the general formula (VII-1) to a deprotection reaction of the protecting group of the amino group.
  • This deprotection reaction of the protecting group for the amino group is similar to the reaction for producing the compound represented by general formula (XVI-1) above.
  • conversion to the desired salt may be performed by a known method.
  • the compound represented by the general formula (XXXIX-1) is a compound represented by the general formula (XXXVIII-1), a compound represented by the general formula (XVII-1), or a compound represented by the general formula (XVIII-1). can be produced by subjecting it to an alkylation reaction.
  • This alkylation reaction is similar to the reaction for producing the compound represented by general formula (XIX-1) above.
  • conversion to the desired salt may be performed by a known method.
  • the compound represented by the general formula (XL-1) can be produced by subjecting the compound represented by the general formula (XXXIX-1) to a deprotection reaction of the protecting group of the carboxyl group.
  • conversion to the desired salt may be performed by a known method.
  • the compound represented by the general formula (XLI-1) can be produced by subjecting the compound represented by the general formula (XL-1) and the compound represented by the general formula (XI) to a coupling reaction. can.
  • This coupling reaction is similar to the reaction for producing the compound represented by the general formula (IA) described above.
  • conversion to the desired salt may be performed by a known method.
  • the compound represented by the general formula (IA-1) is produced by subjecting the compound represented by the general formula (XLI-1) and the compound represented by the general formula (IX) to an amidation reaction. be able to.
  • This amidation reaction is similar to the reaction for producing the compound represented by general formula (X) described above.
  • conversion to the desired salt may be performed by a known method.
  • the compound represented by the general formula (XXXIX-1) can also be produced by the method shown in the following reaction scheme 1-1f.
  • reaction scheme 1-1f all symbols have the same meanings as above.
  • the compound represented by the general formula (IV-1f) is produced by subjecting the compound represented by the general formula (II) and the compound represented by the general formula (III-1f) to an amino group introduction reaction. be able to.
  • This reaction for introducing an amino group is similar to the reaction for producing the compound represented by the general formula (IV) described above.
  • conversion to the desired salt may be performed by a known method.
  • the compound represented by the general formula (VI-1f) can be produced by subjecting the compound represented by the general formula (IV-1f) and the compound represented by the general formula (V) to a coupling reaction. can.
  • This coupling reaction is similar to the reaction for producing the compound represented by general formula (VI) above.
  • conversion to the desired salt may be performed by a known method.
  • the compound represented by the general formula (XXXIX-1) can be produced by subjecting the compound represented by the general formula (VI-1f) to a cyclization reaction.
  • This cyclization reaction is similar to the reaction used to produce the compound represented by the aforementioned general formula (VII).
  • conversion to the desired salt may be performed by a known method.
  • R 3 is -NR 22 R 23
  • R 22 is benzene optionally substituted with 1 to 5 R 30
  • X 1 , X 2 , and X 3 are each independently CH or CR 6 , i.e. compounds of general formula (IB)
  • the compound represented by the general formula (IB) can be produced by subjecting the compound represented by the general formula (X) and the compound represented by the general formula (XII) to a coupling reaction.
  • This coupling reaction is known, for example, using a base in an organic solvent (benzene, toluene, dimethylformamide, dimethylacetamide, 1,4-dioxane, tetrahydrofuran, methanol, acetonitrile, dimethoxyethane, acetone, or a mixed solution thereof, etc.).
  • an organic solvent benzene, toluene, dimethylformamide, dimethylacetamide, 1,4-dioxane, tetrahydrofuran, methanol, acetonitrile, dimethoxyethane, acetone, or a mixed solution thereof, etc.
  • conversion to the desired salt may be performed by a known method.
  • R 2 is a 5- to 7-membered nitrogen-containing saturated heterocycle, and R 15 substituted on the nitrogen atom is C3 optionally substituted with 1 to 5 R 18 .
  • the compound represented by the general formula (IB-1) is produced by subjecting the compound represented by the general formula (XIX-1) and the compound represented by the general formula (XII) to a coupling reaction. be able to.
  • This coupling reaction is similar to the reaction for producing the compound represented by the general formula (IB) described above.
  • conversion to the desired salt may be performed by a known method.
  • the compound represented by the general formula (I-B-1) can also be produced by the method shown in the following reaction scheme 2-1c and reaction scheme 2-1d.
  • reaction scheme 2-1c and reaction scheme 2-1d all symbols have the same meanings as above.
  • the compound represented by the general formula (XXXI-2) can be produced by subjecting the compound represented by the general formula (XXX-1) and the compound represented by the general formula (XII) to a coupling reaction. can.
  • This coupling reaction is similar to the reaction for producing the compound represented by the general formula (IB) described above.
  • conversion to the desired salt may be performed by a known method.
  • the compound represented by the general formula (XXXII-2) can be produced by subjecting the compound represented by the general formula (XXXI-2) and the compound represented by the general formula (IX) to an amidation reaction. can.
  • This amidation reaction is similar to the reaction for producing the compound represented by general formula (X) described above.
  • conversion to the desired salt may be performed by a known method.
  • the compound represented by the general formula (XXXIII-2) can be produced by subjecting the compound represented by the general formula (XXXII-2) to a deprotection reaction of the protecting group of the amino group.
  • This deprotection reaction of the protecting group for the amino group is the same as the reaction for producing the compound represented by general formula (XVI-1) above.
  • conversion to the desired salt may be performed by a known method.
  • the compound represented by the general formula (I-B-1) is a compound represented by the general formula (XXXIII-2), a compound represented by the general formula (XVII-1), or a compound represented by the general formula (XVIII-1). It can be produced by subjecting a compound to an alkylation reaction.
  • This alkylation reaction is similar to the reaction for producing the compound represented by general formula (XIX-1) above.
  • conversion to the desired salt may be performed by a known method.
  • the compound represented by the general formula (IB-1) can also be produced by the method shown in the following reaction scheme 2-1e.
  • reaction scheme 2-1e all symbols have the same meanings as above.
  • the compound represented by the general formula (XLI-2) can be produced by subjecting the compound represented by the general formula (XL-1) and the compound represented by the general formula (XII) to a coupling reaction. can.
  • This coupling reaction is similar to the reaction for producing the compound represented by the general formula (IB) described above.
  • conversion to the desired salt may be performed by a known method.
  • the compound represented by the general formula (IB-1) is produced by subjecting the compound represented by the general formula (XLI-2) and the compound represented by the general formula (IX) to an amidation reaction. be able to.
  • This amidation reaction is similar to the reaction for producing the compound represented by general formula (X) described above.
  • conversion to the desired salt may be performed by a known method.
  • R 3 is -NR 22 R 23
  • R 23 is a hydrogen atom, a C1-8 alkyl group optionally substituted with 1 to 5 R 29 , A C2-4 alkenyl group optionally substituted with 1 to 5 R 29-1 , or a C2-4 alkynyl group optionally substituted with 1 to 5 R 29-2 , and X 1
  • X 2 and X 3 are each independently CH or CR 6 , that is, a compound of general formula (IC)
  • R 23-1 is a hydrogen atom, a C1-8 alkyl group optionally substituted with 1 to 5 R 29s , a C2-8 alkyl group optionally substituted with 1 to 5 R 29-1 4 alkenyl group, or a C2-4 alkynyl group optionally substituted with 1 to 5 R 29-2 , and other symbols have the same meanings as above.
  • the compound represented by It can be manufactured by the method shown in Process Formula 3. In Reaction Scheme 3, all symbols have the same meanings as above.
  • the compound represented by the general formula (IC) can be produced by subjecting the compound represented by the general formula (X) and the compound represented by the general formula (XXXIV) to an amino group introduction reaction. can.
  • This reaction for introducing an amino group is known, and for example, a base (in the presence or absence of fluoride salts (potassium fluoride, cesium fluoride, etc.)
  • a base in the presence or absence of fluoride salts (potassium fluoride, cesium fluoride, etc.)
  • fluoride salts potassium fluoride, cesium fluoride, etc.
  • conversion to the desired salt may be performed by a known method.
  • R 2 is a 5- to 7-membered nitrogen-containing saturated heterocycle, and R 15 substituted on the nitrogen atom is C3, which may be substituted with 1 to 5 R 18 .
  • the compound represented by the general formula (IC-1) can be obtained by subjecting the compound represented by the general formula (XIX-1) and the compound represented by the general formula (XXXIV) to an amino group introduction reaction. can be manufactured.
  • This reaction for introducing an amino group is similar to the reaction for producing the compound represented by the general formula (IC) described above.
  • conversion to the desired salt may be performed by a known method.
  • the compound represented by the general formula (IC-1) can also be produced by the method shown in the following reaction scheme 3-1c and reaction scheme 3-1d.
  • reaction scheme 3-1c and reaction scheme 3-1d all symbols have the same meanings as above.
  • the compound represented by the general formula (XXXI-3) is produced by subjecting the compound represented by the general formula (XXX-1) and the compound represented by the general formula (XXXIV) to an amino group introduction reaction. be able to.
  • This reaction for introducing an amino group is the same as the reaction for producing the compound represented by the general formula (IC-1) described above.
  • conversion to the desired salt may be performed by a known method.
  • the compound represented by the general formula (XXXII-3) can be produced by subjecting the compound represented by the general formula (XXXI-3) and the compound represented by the general formula (IX) to an amidation reaction. can.
  • This amidation reaction is similar to the reaction for producing the compound represented by general formula (X) described above.
  • conversion to the desired salt may be performed by a known method.
  • the compound represented by the general formula (XXXIII-3) can be produced by subjecting the compound represented by the general formula (XXXII-3) to a deprotection reaction of the protecting group of the amino group.
  • This deprotection reaction of the protecting group for the amino group is similar to the reaction for producing the compound represented by general formula (XVI-1) above.
  • conversion to the desired salt may be performed by a known method.
  • the compound represented by the general formula (IC-1) is a compound represented by the general formula (XXXIII-3), a compound represented by the general formula (XVII-1), or a compound represented by the general formula (XVIII-1). It can be produced by subjecting a compound to an alkylation reaction.
  • This alkylation reaction is similar to the reaction for producing the compound represented by general formula (XIX-1) above.
  • conversion to the desired salt may be performed by a known method.
  • the compound represented by the general formula (IC-1) can also be produced by the method shown in the following reaction scheme 3-1e.
  • Reaction Scheme 3-1e all symbols have the same meanings as above.
  • the compound represented by the general formula (XLI-3) is produced by subjecting the compound represented by the general formula (XL-1) and the compound represented by the general formula (XXXIV) to an amino group introduction reaction. be able to.
  • This reaction for introducing an amino group is similar to the reaction for producing the compound represented by the general formula (IC) described above.
  • conversion to the desired salt may be performed by a known method.
  • the compound represented by the general formula (IC-1) is produced by subjecting the compound represented by the general formula (XLI-3) and the compound represented by the general formula (IX) to an amidation reaction. be able to.
  • This amidation reaction is similar to the reaction for producing the compound represented by general formula (X) described above.
  • conversion to the desired salt may be performed by a known method.
  • P N-2 is a protecting group for an amino group (e.g., benzyloxycarbonyl group, tert-butoxycarbonyl group, allyloxycarbonyl (Alloc) group, 1-methyl-1-(4-biphenyl)ethoxy Carbonyl (Bpoc) group, trifluoroacetyl group, 9-fluorenylmethoxycarbonyl group, benzyl (Bn) group, 4-methoxybenzyl group, benzyloxymethyl (BOM) group, 2-(trimethylsilyl)ethoxymethyl (SEM) , fluorenylcarbonyl group, trityl group, o-nitrobenzenesulfenyl group, etc.), E 3 represents a leaving group, and other symbols have the same meanings as above.
  • an amino group e.g., benzyloxycarbonyl group, tert-butoxycarbonyl group, allyloxycarbonyl (Alloc) group, 1-methyl
  • the compound represented by the general formula (XV) can be produced by subjecting the compound represented by the general formula (XIII) and the compound represented by the general formula (XIV) to an alkylation reaction.
  • This alkylation reaction is known, for example, in an organic solvent (tetrahydrofuran, 1,4-dioxane, dimethylformamide, dimethylacetamide, 1-methyl-2-pyrrolidone, dimethylsulfoxide, etc.) with a base (sodium hydride, (potassium, sodium butoxide, potassium carbonate, cesium carbonate, etc.) and in the presence or absence of a catalyst (potassium iodide, sodium iodide, tetrabutylammonium iodide, etc.) at 0°C to reflux temperature. It will be held in an organic solvent (tetrahydrofuran, 1,4-dioxane, dimethylformamide, dimethylacetamide, 1-methyl-2-pyrrolidone, dimethylsulfoxide, etc.) with a base (sodium hydride, (potassium, sodium butoxide, potassium carbonate, cesium carbonate, etc.) and in the presence or absence of
  • conversion to the desired salt may be performed by a known method.
  • the compound represented by the general formula (IX) can be produced by subjecting the compound represented by the general formula (XV) to a deprotection reaction of the protecting group of the amino group.
  • This deprotection reaction of the protecting group for the amino group is similar to the reaction for producing the compound represented by general formula (XVI-1) above.
  • conversion to the desired salt may be performed by a known method.
  • the compound represented by the general formula (IV) is obtained by subjecting the compound represented by the general formula (XX) to an amino group introduction reaction, as shown in the following reaction scheme 5, and the resulting general formula (XXI).
  • the compounds shown can also be produced by subjecting them to reduction reactions.
  • Reaction Scheme 5 all symbols have the same meanings as above.
  • the compound represented by the general formula (XXI) can be produced by subjecting the compound represented by the general formula (XX) and the compound represented by the general formula (III) to an amino group introduction reaction.
  • This reaction for introducing amino groups is known, for example, in an organic solvent (dichloromethane, tetrahydrofuran, 1,4-dioxane, dimethylformamide, dimethylacetamide, 1-methyl-2-pyrrolidone, etc.) with a base (triethylamine, N,N-
  • a base triethylamine, N,N-
  • the reaction is carried out in the presence of diisopropylethylamine, pyridine, 4-dimethylaminopyridine, N-methylmorpholine, etc.
  • conversion to the desired salt may be performed by a known method.
  • the compound represented by the general formula (IV) can be produced by subjecting the compound represented by the general formula (XXI) to a reduction reaction.
  • This reduction reaction is known, for example, in a water-miscible solvent (ethanol, methanol, tetrahydrofuran, ethyl acetate, etc.), in the presence or absence of an acid (hydrochloric acid, hydrobromic acid, ammonium chloride, acetic acid, ammonium formate, etc.). It is carried out in the presence of metal reagents (zinc, iron, tin, tin chloride, iron chloride, samarium, indium, sodium borohydride-nickel chloride, etc.) at temperatures from 0°C to 150°C. It will be held in
  • conversion to the desired salt may be performed by a known method.
  • the compound represented by general formula (X) can also be produced by the method shown in Reaction Scheme 6 below.
  • P N-3 represents a protecting group for an amino group (e.g., 2,4-dimethoxybenzyl, 4-methoxybenzyl, etc.)
  • E 5 represents a leaving group (e.g., fluorine atom, bromine atom, chlorine atom, iodine atom, trifluoromethanesulfonic acid ester, p-toluenesulfonic acid ester, etc.), and other symbols have the same meanings as above.
  • the compound represented by the general formula (XXIII) can be produced by subjecting the compound represented by the general formula (II) and the compound represented by the general formula (XXII) to an amino group introduction reaction.
  • This reaction for introducing an amino group is similar to the reaction for producing the compound represented by the general formula (IV) described above.
  • conversion to the desired salt may be performed by a known method.
  • the compound represented by the general formula (XXIV) can be produced by subjecting the compound represented by the general formula (XXIII) to a cyclization reaction.
  • This cyclization reaction is similar to the reaction used to produce the compound represented by the aforementioned general formula (VII).
  • conversion to the desired salt may be performed by a known method.
  • the compound represented by the general formula (XXV) can be produced by subjecting the compound represented by the general formula (XXIV) and the compound represented by the general formula (XXXV) to a coupling reaction.
  • This coupling reaction is known, for example, in an organic solvent (dichloromethane, acetonitrile, etc.), a base (pyridine, triethylamine, N,N-diisopropylethylamine, etc.), a copper salt (for example, copper(II) acetate, etc.) and a drying agent. (for example, molecular sieves, etc.) by reacting at room temperature to 120°C.
  • an organic solvent dichloromethane, acetonitrile, etc.
  • a base pyridine, triethylamine, N,N-diisopropylethylamine, etc.
  • a copper salt for example, copper(II) acetate, etc.
  • a drying agent for example, molecular sieves, etc.
  • conversion to the desired salt may be performed by a known method.
  • the compound represented by the general formula (XXVI) can be produced by subjecting the compound represented by the general formula (XXV) to a deprotection reaction of the protecting group of the carboxyl group.
  • conversion to the desired salt may be performed by a known method.
  • the compound represented by the general formula (XXVII) can be produced by subjecting the compound represented by the general formula (XXVI) and the compound represented by the general formula (IX) to an amidation reaction.
  • This amidation reaction is similar to the reaction for producing the compound represented by the general formula (X) described above.
  • conversion to the desired salt may be performed by a known method.
  • the compound represented by the general formula (XXVIII) can be produced by subjecting the compound represented by the general formula (XXVII) to a deprotection reaction of the protecting group of the amino group.
  • This deprotection reaction of the protecting group for the amino group is similar to the reaction for producing the compound represented by general formula (XVI-1) above.
  • conversion to the desired salt may be performed by a known method.
  • the compound represented by the general formula (X) can be produced by subjecting the compound represented by the general formula (XXVIII) and the compound represented by the general formula (XXIX) to an alkylation reaction.
  • This alkylation reaction is known, for example, in an organic solvent (dimethylformamide, dimethylacetamide, dimethylsulfoxide, chloroform, dichloromethane, diethyl ether, tetrahydrofuran, methyl t-butyl ether, etc.) and an organic base (triethylamine, N,N-diisopropyl ether, etc.).
  • organic solvent dimethylformamide, dimethylacetamide, dimethylsulfoxide, chloroform, dichloromethane, diethyl ether, tetrahydrofuran, methyl t-butyl ether, etc.
  • organic base triethylamine, N,N-diisopropyl ether, etc.
  • alkali metal hydroxides sodium hydroxide, potassium hydroxide, lithium hydroxide, etc.
  • alkaline earth metal hydroxides barium hydroxide, etc.
  • carbonates sodium carbonate, potassium carbonate, etc.
  • alkali metal halide salts potassium iodide, sodium iodide, etc.
  • conversion to the desired salt may be performed by a known method.
  • R 3Y is benzene which may be substituted with 1 to 5 R 20Y
  • ringY is optionally substituted with 1 to 6 R Y.
  • ringS may be substituted with 1 to 6 R Y and contains one nitrogen atom, one oxygen atom, and/or one sulfur atom that may be oxidized. (represents a 4- to 10-membered saturated carbon ring, and other symbols have the same meanings as above),
  • R 3Y is -NR 22 R 23
  • R 22 is benzene optionally substituted with 1 to 5 R 30
  • ringY is optionally substituted with 1 to 6 R Y , a compound that is a 4- to 10-membered saturated carbocyclic ring that may contain one nitrogen atom, one oxygen atom, and/or one sulfur atom that may be oxidized, i.e., a compound of the general formula (I-B-2)
  • R 3Y is -NR 22 R 23
  • R 23 is a hydrogen atom, a C1-8 alkyl group optionally substituted with 1 to 5 R 29 , and substituted with 1 to 5 R 29-1 ; or a C2-4 alkynyl group which may be substituted with 1 to 5 R 29-2 , and ringY is substituted with 1 to 6 R Y.
  • reaction scheme 6-1 The compound represented by (in the formula, all symbols have the same meanings as above) can be produced by the method shown in the following reaction scheme 6-1.
  • ringS is optionally substituted with 1 to 6 R It represents a 4- to 10-membered saturated carbon ring which may contain atoms, and the other symbols have the same meanings as above.
  • the compound represented by general formula (IA-2) can be obtained by subjecting it to a coupling reaction using a compound represented by general formula (X-2) and a compound represented by general formula (XI-Y). can be manufactured.
  • This coupling reaction is similar to the reaction for producing the compound represented by the general formula (IA) described above.
  • conversion to the desired salt may be performed by a known method.
  • the compound represented by the general formula (IB-2) is produced by subjecting the compound represented by the general formula (X-2) and the compound represented by the general formula (XII) to a coupling reaction. be able to.
  • This coupling reaction is similar to the reaction for producing the compound represented by the general formula (IB) described above.
  • conversion to the desired salt may be performed by a known method.
  • the compound represented by the general formula (IC-2) can be obtained by subjecting the compound represented by the general formula (X-2) and the compound represented by the general formula (XXXIV) to an amino group introduction reaction. can be manufactured.
  • This reaction for introducing an amino group is similar to the reaction for producing the compound represented by the general formula (IC) described above.
  • conversion to the desired salt may be performed by a known method.
  • the compound represented by the general formula (XXV-1) can be produced by subjecting the compound represented by the general formula (XXIV) and the compound represented by the general formula (XXXV-1) to a Mitsunobu reaction. .
  • This Mitsunobu reaction is known, and is performed using an azo compound (diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate, 1,1'-(azo dicarbonyl)dipiperidine, 1,1'-azobis(N,N-dimethylformamide), etc.) and phosphine compounds (triphenylphosphine, tributylphosphine, trimethylphosphine, polymer-supported triphenylphosphine, etc.); The reaction is carried out at 0°C to 100°C in the presence of ranylidene) acetonitrile (CMBP).
  • CMBP ranylidene
  • conversion to the desired salt may be performed by a known method.
  • the compound represented by the general formula (XXV-1) can also be produced by subjecting the compound represented by the general formula (XXIV) and the compound represented by the general formula (XXXV-2) to an alkylation reaction. can.
  • This alkylation reaction is similar to the reaction for producing the compound represented by the general formula (X) described above.
  • conversion to the desired salt may be performed by a known method.
  • the compound represented by the general formula (XXVI-1) can be produced by subjecting the compound represented by the general formula (XXV-1) to a deprotection reaction of the protecting group of the carboxyl group.
  • conversion to the desired salt may be performed by a known method.
  • the compound represented by the general formula (XXVII-1) can be produced by subjecting the compound represented by the general formula (XXVI-1) and the compound represented by the general formula (IX) to an amidation reaction. can.
  • This amidation reaction is similar to the reaction for producing the compound represented by general formula (XXVII) described above.
  • conversion to the desired salt may be performed by a known method.
  • the compound represented by the general formula (XXVIII-1) can be produced by subjecting the compound represented by the general formula (XXVII-1) to a deprotection reaction of the protecting group of the amino group.
  • This deprotection reaction of the protecting group for the amino group is the same as the reaction for producing the compound represented by the aforementioned general formula (XXVIII).
  • conversion to the desired salt may be performed by a known method.
  • the compound represented by general formula (X-2) can be produced by subjecting a compound represented by general formula (XXVIII-1) and a compound represented by general formula (XXIX) to an alkylation reaction. can.
  • This alkylation reaction is similar to the reaction for producing the compound represented by the general formula (X) described above.
  • conversion to the desired salt may be performed by a known method.
  • the compound represented by the general formula (XXXVII) can be produced by subjecting the compound represented by the general formula (IX) and the compound represented by the general formula (XXXVI) to an amidation reaction.
  • This amidation reaction is similar to the reaction for producing the compound represented by the general formula (X) described above.
  • conversion to the desired salt may be performed by a known method.
  • the compound represented by the general formula (XXXVIII) can be produced by subjecting the compound represented by the general formula (XXXVII) and the compound represented by the general formula (IV) to a coupling reaction.
  • This coupling reaction is similar to the reaction for producing the compound represented by general formula (VI) above.
  • conversion to the desired salt may be performed by a known method.
  • the compound represented by the general formula (X) can be produced by subjecting the compound represented by the general formula (XXXVIII) to a cyclization reaction.
  • This cyclization reaction is similar to the reaction used to produce the compound represented by the aforementioned general formula (VII).
  • conversion to the desired salt may be performed by a known method.
  • the compound represented by the general formula (XLIII) can be produced by subjecting the compound represented by the general formula (XLII) to a dimethylaminomethylation reaction.
  • This dimethylaminomethylation reaction is known, and for example, in the presence of an acid (such as hydrogen chloride, sulfuric acid, acetic acid, trifluoroacetic acid, etc.) and an organic solvent (such as methanol, ethanol, 1-propanol, 2-propanol, 1 -butanol, water, or a mixed solvent thereof) with dimethylamine and formaldehyde at a temperature of 0°C to reflux.
  • an acid such as hydrogen chloride, sulfuric acid, acetic acid, trifluoroacetic acid, etc.
  • organic solvent such as methanol, ethanol, 1-propanol, 2-propanol, 1 -butanol, water, or a mixed solvent thereof
  • conversion to the desired salt may be performed by a known method.
  • the compound represented by the general formula (XLIV) can be produced by subjecting the compound represented by the general formula (XLIII) to a reaction for introducing a nitrile group.
  • This nitrile group introduction reaction is known, and examples include solvents (acetonitrile, tetrahydrofuran, methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, dimethylformamide, dimethylacetamide, 1-methyl-2-pyrrolidone, water). or a mixed solvent thereof) at 0°C to room temperature, and the resulting ammonium salt is reacted with a cyanating agent (potassium cyanide, sodium cyanide, etc.). The reaction is carried out at a temperature of 100°C to 100°C.
  • conversion to the desired salt may be performed by a known method.
  • the compound represented by the general formula (XLV) can be produced by subjecting the compound represented by the general formula (XLIV) to a reduction reaction.
  • This reduction reaction is known; for example, a reducing agent (lithium aluminum hydride, bis(2-methoxyethoxy)alkyl sodium hydride, diisobutylaluminum hydride, Lithium borohydride, sodium borohydride, nickel boride, borane-pyridine complex, borane-tetrahydrofuran complex, etc.) or in the presence of a reducing agent (lithium borohydride, sodium borohydride, etc.) and an acid (trifluoroacetic acid, etc.) ) at about -10°C to reflux temperature.
  • a reducing agent lithium aluminum hydride, bis(2-methoxyethoxy)alkyl sodium hydride, diisobutylaluminum hydride, Lithium borohydride, sodium borohydride, nickel boride, borane-pyridine complex, borane-tetrahydrofuran complex, etc.
  • a reducing agent lithium borohydride, sodium borohydride
  • inert solvents ether-based (e.g., tetrahydrofuran, 1,4-dioxane, dimethoxyethane, diethyl ether, etc.), alcohol-based (e.g., methanol, ethanol, etc.), benzene-based (e.g., benzene, toluene, etc.), ketone Hydrogenation in a nitrile system (e.g. acetone, methyl ethyl ketone, etc.), nitrile system (e.g. acetonitrile, etc.), amide system (e.g.
  • An inorganic acid e.g., hydrochloric acid, sulfuric acid, hypochlorous acid
  • a catalyst e.g., palladium on carbon, palladium black, palladium, palladium hydroxide, platinum dioxide, nickel, Raney nickel, ruthenium chloride, cobalt, rhodium-alumina, etc.
  • boric acid tetrafluoroboric acid, etc.
  • organic acids e.g., acetic acid, p-toluenesulfonic acid, oxalic acid, trifluoroacetic acid, formic acid, etc.
  • bases lithium hydroxide, sodium hydroxide, potassium hydroxide, carbonic acid, etc.
  • the reaction is carried out in the presence or absence of potassium, ammonia, triethylamine, etc.), in a hydrogen atmosphere at normal or pressurized pressure, or in the presence of ammonium formate at a temperature of 0°C to 200°C.
  • a salt thereof may be used.
  • conversion to the desired salt may be performed by a known method.
  • the compound represented by the general formula (XLVI) can be produced by subjecting the compound represented by the general formula (XLV) to a cyclization reaction.
  • This cyclization reaction includes, for example, organic solvents (e.g., tetrahydrofuran, dichloromethane, chloroform, benzene, toluene, xylene, hexane, heptane, etc.) in the presence of acids (e.g., hydrogen chloride, sulfuric acid, acetic acid, trifluoroacetic acid, etc.).
  • organic solvents e.g., tetrahydrofuran, dichloromethane, chloroform, benzene, toluene, xylene, hexane, heptane, etc.
  • acids e.g., hydrogen chloride, sulfuric acid, acetic acid, trifluoroacetic acid, etc.
  • conversion to the desired salt may be performed by a known method.
  • the compound represented by the general formula (XLVII) can be produced by subjecting the compound represented by the general formula (XLVI) to a reaction for introducing a protecting group for an amino group.
  • a protecting group for an amino group can be introduced using a protecting group introduction reaction.
  • protective groups such as tert-butoxycarbonyl group, benzyloxycarbonyl group, fluorenylcarbonyl group, trityl group, and o-nitrobenzenesulfenyl group, di-tert-butyl dicarbonate, benzyloxycarbonyl chloride, fluorenyl carbonyl group, etc.
  • olenylcarbonyl chloride trityl chloride, o-nitrobenzenesulfenyl chloride, etc.
  • a solvent such as dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, dioxane, toluene, ethyl acetate, or water at -50°C to 100°C.
  • the reaction can be carried out at °C.
  • amines such as triethylamine and diisopropylethylamine, organic acid salts such as sodium 2-ethylhexanoate and potassium 2-ethylhexanoate, or bases such as inorganic bases such as sodium hydroxide and potassium carbonate are used. It can be carried out.
  • conversion to the desired salt may be performed by a known method.
  • the compound represented by the general formula (XLVIII) can be produced by subjecting the compound represented by the general formula (XLVII) and the compound represented by the general formula (XIV) to an alkylation reaction.
  • This alkylation reaction is known, and is similar to the reaction used to produce the compound represented by the general formula (XV) described above.
  • conversion to the desired salt may be performed by a known method.
  • the compound represented by the general formula (IX-1) can be produced by subjecting the compound represented by the general formula (XLVIII) to a deprotection reaction of the protecting group of the amino group.
  • This deprotection reaction of the protecting group for the amino group is similar to the reaction for producing the compound represented by general formula (XVI-1) above.
  • conversion to the desired salt may be performed by a known method.
  • the compound represented by the general formula (XLIX) can be produced by subjecting the compound represented by the general formula (XLIV) and the compound represented by the general formula (XIV-1) to a benzylation reaction.
  • This benzylation reaction is known, and is the same as the reaction for producing the compound represented by the general formula (XV) described above.
  • conversion to the desired salt may be performed by a known method.
  • the compound represented by the general formula (L) can be produced by subjecting the compound represented by the general formula (XLIX) to a reduction reaction.
  • This reduction reaction is known; for example, a reducing agent (lithium aluminum hydride, bis(2-methoxyethoxy)alkyl sodium hydride, diisobutylaluminum hydride, Lithium borohydride, sodium borohydride, nickel boride, borane-pyridine complex, borane-tetrahydrofuran complex, etc.) or in the presence of a reducing agent (lithium borohydride, sodium borohydride, etc.) and an acid (trifluoroacetic acid, etc.) ) at about -10°C to reflux temperature.
  • a reducing agent lithium aluminum hydride, bis(2-methoxyethoxy)alkyl sodium hydride, diisobutylaluminum hydride, Lithium borohydride, sodium borohydride, nickel boride, borane-pyridine complex, borane-tetrahydrofuran complex, etc.
  • a reducing agent lithium borohydride, sodium borohydride
  • inert solvents ether-based (e.g., tetrahydrofuran, 1,4-dioxane, dimethoxyethane, diethyl ether, etc.), alcohol-based (e.g., methanol, ethanol, etc.), benzene-based (e.g., benzene, toluene, etc.), ketone Hydrogenation in a nitrile system (e.g. acetone, methyl ethyl ketone, etc.), nitrile system (e.g. acetonitrile, etc.), amide system (e.g.
  • An inorganic acid e.g., hydrochloric acid, sulfuric acid, hypochlorous acid, boric acid, tetrafluoroboric acid, etc.
  • an organic acid in the presence of a catalyst (e.g., palladium rhodium on carbon, platinum on carbon, Raney nickel, Raney cobalt, rhodium on carbon, etc.)
  • a catalyst e.g., palladium rhodium on carbon, platinum on carbon, Raney nickel, Raney cobalt, rhodium on carbon, etc.
  • bases lithium hydroxide, sodium hydroxide, potassium hydroxide, potassium carbonate, ammonia, triethylamine, etc.
  • the reaction is carried out at a temperature of 0° C. to 200° C. under a hydrogen atmosphere under normal pressure or increased pressure or in
  • conversion to the desired salt may be performed by a known method.
  • the compound represented by the general formula (IX-2) can be produced by subjecting the compound represented by the general formula (L) to a cyclization reaction.
  • This cyclization reaction includes, for example, organic solvents (e.g., tetrahydrofuran, dichloromethane, chloroform, benzene, toluene, xylene, hexane, heptane, etc.) in the presence of acids (e.g., hydrogen chloride, sulfuric acid, acetic acid, trifluoroacetic acid, etc.).
  • organic solvents e.g., tetrahydrofuran, dichloromethane, chloroform, benzene, toluene, xylene, hexane, heptane, etc.
  • acids e.g., hydrogen chloride, sulfuric acid, acetic acid, trifluoroacetic acid, etc.
  • conversion to the desired salt may be performed by a known method.
  • optically active compounds can be produced using optically active starting materials or reagents, or by optically resolving racemic production intermediates, and then converting them into compounds used in the present invention. Alternatively, it can also be produced by optically resolving a racemic compound.
  • This optical resolution method is known, for example, by forming a salt or complex with another optically active compound, recrystallizing it, and then isolating the target compound, or directly using a chiral column, etc. Examples include a method of separating.
  • reactions involving heating can be carried out using a water bath, oil bath, sand bath or microwave, as is clear to those skilled in the art.
  • a solid-phase supported reagent supported on a high molecular weight polymer eg, polystyrene, polyacrylamide, polypropylene, polyethylene glycol, etc.
  • a high molecular weight polymer eg, polystyrene, polyacrylamide, polypropylene, polyethylene glycol, etc.
  • the reaction product can be purified by conventional purification means, such as distillation under normal pressure or reduced pressure, high performance liquid chromatography using silica gel or magnesium silicate, thin layer chromatography, ion exchange resin, It can be purified by methods such as scavenger resin or column chromatography, washing, or recrystallization. Purification may be performed for each reaction or after completion of several reactions.
  • the toxicity of the compounds of the present invention is sufficiently low and they can be safely used as pharmaceuticals.
  • the compound of the present invention has inhibitory activity for one or both of DGK ⁇ and DGK ⁇ (preferably both inhibitory activities), it is possible to prevent the progression of diseases associated with DGK ⁇ and/or DGK ⁇ in mammals, particularly humans (human patients). It can be prescribed as a suppressive, anti-recurrence and/or therapeutic agent.
  • diseases related to DGK ⁇ and/or DGK ⁇ include cancer and infectious diseases. That is, the compound of the present invention can be formulated as an effective agent for inhibiting progression, inhibiting recurrence, and/or treating cancer or infectious disease.
  • cancer treatment refers to, for example, (a) to reduce the proliferation of cancer cells, (b) to reduce symptoms caused by cancer, and to improve the quality of life of cancer patients. , (c) to reduce the dose of other anti-cancer agents or adjuvant cancer treatments that have already been administered, and/or (d) to prolong the survival of cancer patients.
  • suppression of cancer progression means delaying cancer progression, stabilizing cancer-related symptoms, and reversing the progression of symptoms.
  • suppression of recurrence means preventive suppression of cancer recurrence in patients whose cancerous lesions have been completely or substantially eradicated or removed by cancer treatment or surgical cancer resection.
  • the compounds of the present invention can be used in patients with (a) cancer for which the therapeutic effect of other cancer treatments is insufficient or insufficient, or cancer patients whose disease has worsened after other cancer treatments; Patients with refractory and/or distant metastatic cancer; (c) cancer patients with TPS or CPS of 50% or more, 25% or more, 10% or more, 5% or more, or 1% or more; (d) MSI-H or a patient with cancer having dMMR, (e) a patient with malignant melanoma or non-small cell lung cancer who is BRAF V600E mutation positive, (f) a patient with cancer who is EGFR gene mutation positive or ALK fusion gene positive, or (g) It may be prescribed to cancer patients who frequently receive TMB.
  • the compounds of the present invention may be used in (a) cancer patients with no history of other cancer treatments, (b) TPS or CPS of less than 50%, less than 25%, less than 10%, less than 5%, or less than 1%. (c) patients with cancer who do not have MSI-H and/or dMMR or have MSI-L; (d) patients with malignant melanoma or non-small cell lung cancer who are BRAF V600 wild type; (e) patients with non-small cell lung cancer who are negative for EGFR gene mutations and/or negative for ALK fusion genes, or (f) patients with cancers in which TMB is infrequently present may be more required.
  • It can also be prescribed as a postoperative adjuvant therapy to prevent recurrence or metastasis after surgical resection of cancer, or as a neoadjuvant therapy performed before surgical resection.
  • anticancer drugs listed in the "Concomitant or combined drugs” section below, such as alkylating drugs, platinum preparations, antimetabolites (e.g., folic acid antimetabolites, pyridine metabolites).
  • drugs and cancer immunotherapeutics include treatments with drugs, as well as radiotherapy, hepatic artery chemoembolization (TACE), hepatic artery embolization (TAE), cancer vaccines, and immune cell therapy.
  • TACE hepatic artery chemoembolization
  • TAE hepatic artery embolization
  • cancer vaccines and immune cell therapy.
  • therapeutic effects of other cancer treatments are insufficient or insufficient” means, for example, that in the RECIST, which determines the tumor shrinkage effect, even if treatment with existing anticancer drugs is “stable (SD)” or “progressive (PD)” ” may be determined.
  • cancers targeted for progression inhibition, recurrence inhibition, and/or treatment by the compounds of the present invention include any solid cancer and blood cancer.
  • examples of epithelial cell cancer include malignant melanoma (e.g. , malignant melanoma in the skin, oral mucosal epithelium, or orbital cavity, etc.), non-small cell lung cancer (e.g., squamous non-small cell lung cancer and non-squamous non-small cell lung cancer), small cell lung cancer, head and neck cancer (e.g., oral cancer, nasopharyngeal cancer, oropharyngeal cancer, hypopharyngeal cancer, laryngeal cancer, salivary gland cancer, and tongue cancer), renal cell carcinoma (e.g., clear cell renal cell carcinoma), breast cancer, ovarian cancer (e.g., serous ovarian cancer and ovarian cancer).
  • malignant melanoma e.g. , malignant melanoma in the skin, oral mu
  • nasopharyngeal cancer adenocarcinoma
  • uterine cancer e.g. cervical cancer and endometrial cancer
  • anal cancer e.g. anal canal cancer
  • colorectal cancer e.g. MSI-H and/or dMMR positive colorectal cancer
  • rectal cancer colon cancer, hepatocellular carcinoma, esophageal cancer, gastric cancer, esophagogastric junction cancer, pancreatic cancer, urothelial cancer (e.g., bladder cancer, upper urinary tract cancer, ureteral cancer, renal pelvis cancer and urethral cancer), Prostate cancer, fallopian tube cancer, primary peritoneal cancer, malignant pleural mesothelioma, gallbladder cancer, bile duct cancer, biliary tract cancer, skin cancer (e.g.
  • testicular cancer uveal malignant melanoma and Merkel cell carcinoma
  • testicular cancer vaginal cancer
  • vulvar cancer penile cancer
  • small intestine cancer endocrine cancer
  • thyroid cancer parathyroid cancer
  • adrenal cancer spinal tumor
  • neuroblastoma medulloblastoma
  • ocular retinoblastoma neuroendocrine tumor
  • Examples include brain tumors (eg, gliomas (eg, glioblastoma and gliosarcoma) and meningiomas) and squamous cell carcinoma.
  • sarcomas include bone and soft tissue sarcomas (e.g., Ewing's sarcoma, pediatric rhabdomyosarcoma, leiomyosarcoma of the uterine corpus, chondrosarcoma, pulmonary sarcoma, osteosarcoma, congenital fibrosarcoma) and Kaposi sarcoma. Examples include sarcoma.
  • Blood cancers include, for example, multiple myeloma, malignant lymphoma (for example, non-Hodgkin's lymphoma (for example, follicular lymphoma, precursor B cell lymphoblastic lymphoma, chronic B lymphocytic leukemia, nodal marginal zone B Cellular lymphoma, diffuse large B-cell lymphoma, MALT lymphoma, primary splenic marginal zone B-cell lymphoma, hairy cell leukemia, primary mediastinal large B-cell lymphoma, Burkitt lymphoma, mantle cell lymphoma , mycosis fungoides, Sézary syndrome, chronic or acute lymphocytic leukemia, precursor T cell lymphoblastic lymphoma, chronic T lymphocytic leukemia, large granular T cell leukemia, large granular NK cell leukemia, peripheral T cellular lymphoma, extranodal NK/T-cell lymphoma, adult
  • cancers targeted for progression inhibition, recurrence inhibition, and/or treatment by the compounds of the present invention include childhood cancers and cancers of unknown primary origin.
  • Infectious diseases that are targeted for inhibition of progression, inhibition of recurrence, and/or treatment by the compounds of the present invention include symptoms caused by viral infection, parasitic infection, bacterial infection, or fungal infection.
  • viral infections include adenovirus, arenavirus, bunyavirus, calicivirus, coronavirus, filovirus, hepadnavirus, herpesvirus, orthomyxovirus, papovavirus, paramyxovirus, parvovirus, picornavirus, Poxviruses, reoviruses, retroviruses, rhabdoviruses, togaviruses, papillomaviruses (e.g., human papillomavirus (HPV)), human immunodeficiency virus (HIV), polioviruses, hepatitis viruses (e.g., hepatitis A virus) (HAV), hepatitis B virus (HBV), hepatitis C virus (HCV), hepatitis D virus (HDV), hepatitis E virus (HEV)), smallpox virus (e.g., variola major, variola minor), Vaccinia virus, influenza virus, rhinovirus, dengue
  • Parasitic infections include, for example, Acanthamoeba keratitis, amoebiasis, ascariasis, babesiosis, balantidiosis, raccoon ascariasis, Chagas disease, hepatic dystomiasis, cochliomia, cryptosporidiosis, taeniasis, and ascariasis.
  • Inworm disease echinococcosis, elephantiasis, pinworm disease, liver fluke disease, enlarged liver fluke disease, heartworm disease, giardiasis, gnathostomiasis, membranous tapeworm disease, isosporiasis, Katayama fever, leishmaniasis, Lyme diseases, malaria, fluke, onchocerciasis, lice infestation, scabies, schistosomiasis, African somnolosis, strongyloidiasis, taeniasis, toxocariasis, toxoplasmosis, trichinosis and whipworm. symptoms, etc.
  • bacterial infections include Mycobacterium tuberculosis, Bacillus anthrax, pathogenic bacteria, food poisoning bacteria, Salmonella enterica, Staphylococcus, Streptococcus, Clostridium tetani, Mycobacteria, Clostridium tetani, Yersinia pestis, Bacillus anthracis, and methicillin-resistant Staphylococcus aureus ( These include infections caused by antibiotic-resistant bacteria such as MRSA), Clostridium difficile, and other infectious bacteria.
  • Fungal infections include, for example, Aspergillus sp., Blastomyces dermatitidis, Candida yeasts (e.g., Candida albicans), Coccidioides, Cryptococcus neoformans, Cryptococcus gattii, dermatophytes, Fusarium sp., Histoplasma spp.
  • Infections caused by infections with P. capsulatum, Mucorina, Pneumocystis jirovesi, Sporothrix schenkii, Exellohyrum or Cladosporium can be mentioned.
  • the compound of the present invention or a pharmaceutical composition containing the compound of the present invention as an active ingredient can (a) inhibit the progression of cancer or infectious disease, inhibit recurrence, and/or (b) to reduce the dosage of other drugs prescribed in combination; (c) to reduce side effects of other drugs prescribed in combination; and/or (d) It may be prescribed in combination with one or more other drugs in order to enhance the immunopotentiating effect of other drugs prescribed in combination, ie, as an adjuvant.
  • the dosage form when prescribed in combination with other drugs may be in the form of a combination drug containing both components in one preparation, or as separate preparations. good.
  • the compound of the present invention and other drugs When used in combination, it is possible to supplement the prevention, symptom progression, recurrence, and/or therapeutic effects of other drugs, or to maintain or reduce the dosage or frequency of administration.
  • the compound of the present invention and other drugs When prescribed separately, they may be administered simultaneously for a certain period of time, and then only the compound of the present invention or the other drug may be administered.
  • the compound of the present invention, etc. may be administered first, and then other drugs may be administered, or the other drug may be administered first, and the compound of the present invention, etc. may be administered later. In the above administration, there may be a certain period in which both drugs are administered simultaneously.
  • the administration methods for each drug may be the same or different.
  • kits containing a preparation containing the compound of the present invention and another drug may also be provided.
  • the dosage of the other drug can be appropriately selected based on the clinically used dosage.
  • any two or more other drugs may be administered in combination at an appropriate ratio.
  • the other drugs include not only those that have been discovered to date but also those that will be discovered in the future.
  • anticancer agents that can be used in combination with the compounds of the present invention include, for example, alkylating drugs (e.g., dacarbazine, Nimustine, Temozolomide, Fotemustine, bendamustine, Cyclophosphamide, Ifosfamide, Carmustine, Chlorambucil, Procarbazine, etc.); Platinum preparations (e.g., Cisplatin, Carboplatin, Nedaplatin, and oxaliplatin, etc.), antimetabolites (e.g., folic acid antimetabolites (e.g., Pemetrexed, leucovorin, and Methotrexate, etc.), pyridine metabolism inhibitors (e.g., TS-1®) , 5-fluorouracil, UFT, Carmofur, Doxifluridine, FdUrd, Cytarabine and Capecitabine etc.), purine metabolism inhibitors (e.g.
  • alkylating drugs e.g.
  • cytokine preparations e.g. IFN- ⁇ 2a, IFN- ⁇ 2b, PEG-IFN) - ⁇ 2b, natural IFN- ⁇ , and Interleukin-2
  • antihormonal drugs e.g., Tamoxifen, Fulvestrant, Goserelin, Leuprorelin, Anastrozole, Letrozole, Exemestane, etc.
  • molecular target drugs cancer immunotherapy drugs, and other antibody drugs etc.
  • examples of molecular target drugs include ALK inhibitors (e.g., Crizotinib, Ceritinib, Ensartinib, Alectinib, and Lorlatinib), BCR-ABL inhibitors (e.g., Imatinib and Dasatinib), and EGFR inhibitors (e.g., Erlotinib, EGF816). , Afatinib, Osimertinib mesylate, Gefitinib and Rociletinib), B-Raf inhibitors (e.g.
  • Mek inhibitors e.g. Cobimetinib, Binimetinib, Selumetinib and Trametinib
  • CDK inhibitors e.g. Dinaciclib, Abemaciclib, Palbociclib and trilaciclib
  • Btk inhibitors e.g. ONO-4059, Ibrutinib and Acalabrutinib
  • PI3K- ⁇ / ⁇ inhibitors e.g. TGR-1202, INCB050465 and IPI-549
  • JAK-1/2 inhibitors e.g. Itacitinib and Ruxolitinib
  • ERK inhibitors e.g.
  • TGFbR1 inhibitors e.g. Galunisertib
  • Cancer cell stemness kinase inhibitors e.g. Amcasertib
  • FAK inhibitors e.g. Defactinib
  • Syk/FLT3 dual inhibitors e.g. TAK-659
  • ATR inhibitors e.g. AZD6738
  • Wee1 kinase inhibitors e.g. AZD1775
  • multityrosine kinase inhibitors e.g.
  • mTOR inhibitors e.g. Temsirolimus, Everolimus, Vistusertib, Irinotecan
  • HDAC inhibitors e.g. Vorinostat, Romidepsin, Entinostat, Chidamide, Mocetinostat, Citarinostat, Panobinostat, Valproate
  • PARP inhibitors e.g. Niraparib, Olaparib, Veliparib, Rucaparib, Beigene-290
  • aromatase inhibitors e.g.
  • EZH2 inhibitors e.g. tazemetostat
  • galectin-3 inhibitors e.g. GR-MD-02
  • STAT3 inhibitors e.g. Napabucasin
  • DNMT inhibitors e.g. Azacitidine
  • SMO inhibitors e.g. , Vismodegib
  • Hsp90 inhibitors e.g. XL888
  • ⁇ -tubulin specific inhibitors e.g. Glaziovianin A, Plinabulin
  • HIF2 ⁇ inhibitors e.g. PT2385
  • glutaminase inhibitors e.g. CB-839
  • E3 ligase inhibitors e.g.
  • Nrf2 activators e.g. Omaveloxolone
  • arginase inhibitors e.g. CB-1158
  • cell cycle inhibitors e.g. Trabectedin
  • Ephrin B4 inhibitors e.g.
  • IAP antagonists e.g., Birinapant
  • BET protein inhibitors e.g., CC-90010
  • LSD1 inhibitors e.g., CC-900111
  • CRBN regulators e.g., Avadomide
  • anti-Her2 antibodies e.g., Trastuzumab , Trastuzumab emtansine, Pertuzumab and Margetuximab
  • anti-EGFR antibodies e.g. Cetuximab, Panitumumab, Necitumumab and Nimotuzumab
  • anti-VEGF antibodies e.g. Bevacizumab
  • anti-VEGFR2 antibodies e.g.
  • Ramucirumab examples include anti-CD20 antibodies (e.g. Rituximab, Ofatumumab). , Ublituximab and Obinutuzumab), anti-CD30 antibodies (e.g. Brentuximab Vedotin), anti-CD38 antibodies (e.g. Daratumumab), anti-DR5 antibodies (e.g. DS-8273a), anti-CA125 antibodies (e.g. Oregovomab), anti-DLL4 antibodies (e.g.
  • anti-fucosyl GM1 antibodies e.g., BMS-986012
  • anti-gpNMB antibodies e.g., Glembatumumab vedotin
  • anti-Mesothelin antibodies e.g., BMS-986148
  • anti-MMP9 antibodies e.g., Andecaliximab
  • anti-GD2 antibodies For example, Dinutuximab- ⁇ ), anti-c-Met antibodies (e.g., ABT-399), anti-FOLR1 antibodies (e.g., Mirvetuximab soravtansine), anti-Fucosyl-GM1 antibodies (e.g., BMS-986012), anti-Ang2-VEGF bispecific anti-CD30-CD16A bispecific antibody (e.g.
  • anti-CD79b antibody e.g. Polatuzumab Vedotin
  • anti-FAP antibody/IL-2 fusion protein e.g. RO6874281
  • anti-CEA Antibodies/IL-2 fusion proteins e.g. Cergutuzumab amunaleukin
  • anti-CEA-CD3 bispecific antibodies e.g. RO6958688
  • anti-DLL3 antibodies e.g. Rovalpituzumab tesirine
  • anti-CD3-CD19 bispecific antibodies e.g. , Blinatumomab
  • anti-CD20-CD3 bispecific antibodies eg, REGN1979
  • Cancer immunotherapeutic drugs include, for example, anti-PD-1 antibodies (e.g., Nivolumab, Cemiplimab (REGN-2810), Pembrolizumab (MK-3475), Spartalizumab (PDR-001), Tislelizumab (BGB-A317), AMP -514 (MEDI0680), Dostarlimab (ANB011/TSR-042), Toripalimab (JS001), Camrelizumab (SHR-1210), Genolimzumab (CBT-501), Sintilimab (IBI308), STI-A1110, ENUM 388D4, ENUM 244C8, GLS010 , MGA012, AGEN2034, CS1003, HLX10, BAT-1306, AK105, AK103, BI 754091, LZM009, CMAB819, Sym021, GB226, SSI-361, JY034, HX008, ABBV181, BCD-
  • Incyte-1 to Incyte-6 compounds (WO2017/070089, WO2017/087777, WO20 17 /106634, WO2017/112730, WO2017/192961 and WO2017/205464), CAMC-1 to CAMC-4 (see WO2017/202273, WO2017/20274, WO2017/202275 and WO2017/202276), RG_1 (WO2017/1 18762) and DPPA-1 (see Angew. Chem. Int. Ed. 2015, 54, 11760-11764), etc.), PD-L1/VISTA antagonists (e.g. CA-170, etc.), PD-L1/TIM3 antagonists (e.g.
  • anti-PD-L2 antibodies e.g., PD-L1 fusion proteins, PD-L2 fusion proteins (e.g., AMP-224, etc.), anti-CTLA-4 antibodies (e.g., Ipilimumab (MDX-010), AGEN1884 and Tremelimumab, etc.), anti-LAG-3 antibodies (e.g. Relatlimab (BMS-986016/ONO-4482), LAG525, REGN3767 and MK-4280, etc.), LAG-3 fusion proteins (e.g. IMP321, etc.), anti-Tim3 antibodies (e.g.
  • anti-KIR antibodies e.g. Lililumab (BMS-986015/ONO-4483), IPH2101, LY3321367 and MK-4280, etc.
  • anti-BTLA antibodies e.g., Tiragolumab (MTIG-7192A/RG-6058/RO-7092284) and BMS-986207 (ONO-4686, etc.
  • TIGIT bispecific antibody e.g., anti-VISTA antibody (e.g., JNJ-61610588, etc.), anti-CD137 Antibodies (e.g.
  • Urelumab (ONO-4481/BMS-663513) and Utomilumab (PF-05082566), etc.
  • anti-CSF-1R antibodies/CSF-1R inhibitors e.g. Cabiralizumab (FPA008/BMS-986227/ONO-4687)
  • Emactuzumab (RG7155/RO5509554)
  • anti-OX40 antibodies e.g., MEDI6469, PF-04518600, MEDI0562, MEDI6383, Efizonerimod, GSK31 74998, BMS-986178 and MOXR0916, etc.
  • anti-HVEM antibodies anti-CD27 antibodies (e.g., Varlilumab (CDX-1127), etc.
  • anti-GITR antibodies e.g
  • IDO inhibitors e.g. Epacadostat, Indoximod and BMS-986205 etc.
  • TLR agonists e.g. Motolimod, CMP-001, etc.
  • adenosine A2A receptor antagonists e.g. Preladenant, AZD4635, PBF 509 and CPI-444, etc.
  • anti-NKG2A antibodies e.g.
  • Monalizumab, etc. anti-CSF-1 Antibodies (e.g., PD0360324, etc.), immune enhancers (e.g., PV-10, etc.), IL-15 superagonists (e.g., ALT-803, etc.), soluble LAG3 (e.g., IMP321, etc.), CD47 antagonists (e.g., ALX148) etc.) anti-CD47 antibodies (e.g., ONO-7913, etc.), SIRP ⁇ fusion proteins (e.g., TTI-621, TTI-622, ALX148, etc.), anti-CCR8 antibodies, IL-12 antagonists (e.g., M9241, etc.), IL- 12 fusion proteins, TGF ⁇ receptor fusion proteins (e.g., BMS-986416, etc.), anti-ILT4 antibodies (e.g., MK-4830, etc.), EP4 antagonists (e.g., ONO-4578, etc.), STING agonists (e
  • Nivolumab can be manufactured according to the method described in WO2006/121168
  • Pembrolizumab can be manufactured according to the method described in WO2008/156712
  • BMS-936559 can be manufactured according to the method described in WO2007/005874
  • Ipilimumab can be manufactured according to the method described in WO2001/014424.
  • antibody drugs examples include anti-IL-1 ⁇ antibodies (eg, Canakinumab, etc.) and anti-CCR2 antibodies (eg, Plozalizumab, etc.).
  • cancer treatments include radiotherapy, hepatic artery chemoembolization (TACE), hepatic artery embolization (TAE), cancer vaccines (e.g., synthetic peptides, DNA vaccines, and recombinant viruses, etc.), and immune cell therapy (e.g., CAR-T cells, etc.).
  • TACE hepatic artery chemoembolization
  • TAE hepatic artery embolization
  • cancer vaccines e.g., synthetic peptides, DNA vaccines, and recombinant viruses, etc.
  • immune cell therapy e.g., CAR-T cells, etc.
  • the compounds of the present invention or a combination of the compounds of the present invention and other drugs for the above-mentioned purposes are usually administered systemically or locally, orally or parenterally.
  • the dosage varies depending on age, body weight, symptoms, therapeutic effects, administration method, treatment time, etc., but is usually administered orally once to several times a day in the range of 1 ng to 2,000 mg per adult. or administered parenterally once to several times a day in the range of 0.1 ng to 200 mg per adult, or continuously administered intravenously for a period of 30 minutes to 24 hours a day. be done.
  • the dosage varies depending on various conditions, so there may be cases where a smaller amount than the above-mentioned dosage is sufficient, or there may be cases where it is necessary to administer beyond the range.
  • [formulation] When administering the compound of the present invention or a combination of the compound of the present invention and other drugs, solid or liquid preparations for oral administration, sustained release preparations or controlled release preparations for oral administration, or injection preparations for parenteral administration are used. It is used as an infusion, external preparation, inhaler, or suppository.
  • solid preparations for oral administration include tablets, pills, capsules, powders, and granules
  • examples of capsules include hard capsules and soft capsules.
  • the solid preparation may be prepared by formulating the compound of the present invention together with a pharmaceutically acceptable carrier.
  • pharmaceutically acceptable carriers used in formulating the solid dosage form include excipients (e.g., lactose, mannitol, glucose, microcrystalline cellulose, starch, etc.), binders (e.g., hydroxy propylcellulose, polyvinylpyrrolidone, magnesium aluminate metasilicate, etc.), disintegrants (e.g., cellulose calcium glycolate, etc.), lubricants (e.g., magnesium stearate, etc.), stabilizers, solubilizing agents (e.g., glutamic acid, aspartic acid, etc.).
  • excipients e.g., lactose, mannitol, glucose, microcrystalline cellulose, starch, etc.
  • binders e.g., hydroxy propylcellulose, polyvinylpyrrolidone, magnesium aluminate metasilicate, etc.
  • a coating agent for example, white sugar, gelatin, hydroxypropyl cellulose, hydroxypropyl methylcellulose phthalate, etc.
  • a coating agent for example, white sugar, gelatin, hydroxypropyl cellulose, hydroxypropyl methylcellulose phthalate, etc.
  • it may be included in a capsule containing gelatin.
  • Liquid preparations for oral administration may be in any form such as solutions, suspensions, emulsions, syrups, and elixirs. It may be dissolved, suspended, or emulsified in a mixture of (e.g., a mixture of Furthermore, the liquid preparation may contain a wetting agent, a suspending agent, an emulsifying agent, a sweetening agent, a flavoring agent, an aromatic agent, a preservative, a buffering agent, and the like.
  • Sustained release formulations for oral administration may contain, for example, gel-forming substances such as gum arabic, agar, polyvinylpyrrolidone, sodium alginate, propylene glycol alginate ester, carboxyvinyl polymer. , carboxymethylcellulose, sodium carboxymethylcellulose, guar gum, gelatin, hydroxypropylmethylcellulose, hydroxypropylcellulose, polyvinyl alcohol, methylcellulose or hydroxyethylmethylcellulose.
  • gel-forming substances such as gum arabic, agar, polyvinylpyrrolidone, sodium alginate, propylene glycol alginate ester, carboxyvinyl polymer.
  • carboxymethylcellulose sodium carboxymethylcellulose, guar gum, gelatin, hydroxypropylmethylcellulose, hydroxypropylcellulose, polyvinyl alcohol, methylcellulose or hydroxyethylmethylcellulose.
  • Injections or infusions for parenteral administration may be in the form of an aqueous solution, suspension, or emulsion, and may be prepared in a solvent (e.g., distilled water for injection, physiological saline, glucose solution, etc.) before use.
  • a solvent e.g., distilled water for injection, physiological saline, glucose solution, etc.
  • isotonic solutions e.g. solutions of sodium chloride, potassium chloride, glycerin, mannitol, sorbitol, boric acid, borax and propylene glycol, etc.
  • It may be formulated as a solid dosage form together with a pharmaceutically acceptable carrier.
  • the "pharmaceutically acceptable carrier” includes, for example, stabilizers (e.g., various amino acids, albumin, globulin, gelatin, mannitol, glucose, dextran, ethylene glycol, propylene glycol, polyethylene glycol, ascorbic acid, sulfite).
  • stabilizers e.g., various amino acids, albumin, globulin, gelatin, mannitol, glucose, dextran, ethylene glycol, propylene glycol, polyethylene glycol, ascorbic acid, sulfite.
  • solubilizing agents e.g., alcohols (e.g., ethanol, etc.), polyalcohols (e.g., propylene glycol, polyethylene glycol, etc.) and non-ionic surfactants (for example, polysorbate 20 (registered trademark), polysorbate 80 (registered trademark), HCO-50, etc.), suspending agents (for example, glyceryl monostearate, aluminum monostearate, methylcellulose, carboxymethylcellulose) , hydroxymethylcellulose and sodium lauryl sulfate, etc.), emulsifiers (e.g., gum arabic, sodium alginate, and tragacanth, etc.), soothing agents (e.g., benzyl alcohol, chlorobutanol, and sorbitol, etc.), buffers (e.g., phosphate buffers,
  • antioxidants include (1) water-soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite, etc., (2) ascorbyl palmitate, butylated hydroxyanisole, (3) using oil-soluble antioxidants such as butylated hydroxytoluene, lecithin, propyl gallate, alpha-tocopherol, etc.; and (3) metal chelating agents such as citric acid, ethylenediaminetetraacetic acid, sorbitol, tartaric acid, phosphoric acid, etc. Can be done.
  • water-soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite, etc.
  • ascorbyl palmitate butylated hydroxyanisole
  • oil-soluble antioxidants such as butylated hydroxytoluene, lecithin, propyl gallate, alpha-tocopherol,
  • the injection or infusion can be manufactured by sterilizing it in the final step or by using an aseptic method, for example, by sterilizing it by filtration with a filter or the like, and then filling it into a sterile container.
  • the injection or infusion can also be used by dissolving a sterile powder (which may contain a pharmaceutically acceptable carrier powder) in an appropriate solvent at the time of use by vacuum drying and lyophilization. .
  • Dosage forms of external preparations for parenteral administration include, for example, aerosols, inhalants, sprays, aerosols, ointments, gels, creams, poultices, patches, liniments, and nasal sprays. Can be mentioned.
  • the propellants, inhalants and sprays may contain, in addition to commonly used diluents, stabilizers such as sodium bisulfite and buffers to provide isotonic properties, such as sodium chloride, sodium citrate or citric acid. It may also contain isotonic agents such as.
  • stabilizers such as sodium bisulfite and buffers to provide isotonic properties, such as sodium chloride, sodium citrate or citric acid. It may also contain isotonic agents such as.
  • the method for producing the spray agent is described in detail in, for example, US Pat. No. 2,868,691 and US Pat. No. 3,095,355.
  • inhalants examples include liquid formulations for inhalation and powder formulations for inhalation, and the liquid formulation may be in the form of being dissolved or suspended in water or other appropriate medium before use.
  • inhalants are manufactured according to known methods, and for example, in the case of inhalable liquid preparations, preservatives (e.g. benzalkonium chloride and parabens, etc.), coloring agents, buffering agents (e.g. sodium phosphate), etc. and sodium acetate, etc.), isotonic agents (e.g., sodium chloride and concentrated glycerin, etc.), thickeners (e.g., carboxyvinyl polymers, etc.), absorption enhancers, etc., as necessary.
  • preservatives e.g. benzalkonium chloride and parabens, etc.
  • coloring agents e.g. sodium phosphate), etc. and sodium acetate, etc.
  • buffering agents e.g. sodium phosphate
  • isotonic agents e
  • lubricants for example, stearic acid and its salts, etc.
  • binders for example, starch and dextrins, etc.
  • excipients for example, lactose and cellulose, etc.
  • colorants It is prepared by appropriately mixing a preservative (for example, benzalkonium chloride, paraben, etc.), an absorption enhancer, etc. as necessary.
  • nebulizers eg, atomizers, nebulizers, etc.
  • powdered drug inhalation administrators are usually used.
  • the ointment is prepared according to a known or commonly used formulation, for example, by mixing or melting the compound of the present invention in an ointment base.
  • the ointment base is selected from those known or commonly used, such as higher fatty acids or higher fatty acid esters (e.g., adipic acid, myristic acid, palmitic acid, stearic acid, oleic acid, adipic acid ester, myristic acid esters, palmitic acid esters, stearic acid esters, oleic acid esters, etc.), waxes (e.g., beeswax, spermaceti, ceresin, etc.), surfactants (e.g., polyoxyethylene alkyl ether phosphates, etc.), high grade Alcohols (e.g., cetanol, stearyl alcohol, cetostearyl alcohol, etc.), silicone oils (e.g., dimethylpolysiloxane, etc.), hydro
  • ethylene glycol diethylene glycol, propylene glycol, polyethylene glycol and macrogol, etc.
  • vegetable oils such as castor oil, olive oil, sesame oil and turpentine oil, etc.
  • animal oils such as mink oil, egg yolk oil, squalane and squalene, etc.
  • water such as an absorption enhancer, or an anti-rash agent.
  • an absorption enhancer or an anti-rash agent.
  • it may contain a humectant, a preservative, a stabilizer, an antioxidant, a flavoring agent, and the like.
  • the gel is prepared according to a known or commonly used formulation, for example, by melting the compound of the present invention in a gel base.
  • the gel base is selected from those known or commonly used, such as lower alcohols (e.g., ethanol and isopropyl alcohol, etc.), gelling agents (e.g., carboxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, etc.). ethyl cellulose, etc.), neutralizing agents (e.g., triethanolamine and diisopropanolamine, etc.), surfactants (e.g., polyethylene glycol monostearate, etc.), gums, water, absorption enhancers, and anti-rash agents. It is used by mixing more than one species. Furthermore, it may contain a preservative, an antioxidant, a flavoring agent, etc.
  • Creams are prepared according to known or commonly used formulations, for example, by melting or emulsifying the compound of the present invention in a cream base.
  • the cream base is selected from those known or commonly used, such as higher fatty acid esters, lower alcohols, hydrocarbons, and polyhydric alcohols (such as propylene glycol and 1,3-butylene glycol). , higher alcohols (e.g., 2-hexyldecanol and cetanol, etc.), emulsifiers (e.g., polyoxyethylene alkyl ethers and fatty acid esters, etc.), water, absorption enhancers, and anti-rash agents. used. Furthermore, it may contain a preservative, an antioxidant, a flavoring agent, etc.
  • a poultice is prepared according to a known or commonly used formulation, for example, by melting the compound of the present invention in a poultice base, making a mixture, and spreading the mixture onto a support.
  • the poultice base is selected from those known or commonly used, such as thickeners (e.g., polyacrylic acid, polyvinylpyrrolidone, gum arabic, starch, gelatin, methyl cellulose, etc.), wetting agents (e.g. , urea, glycerin, propylene glycol, etc.), fillers (e.g., kaolin, zinc oxide, talc, calcium, magnesium, etc.), water, solubilizing agents, tackifiers, and anti-rash agents. It is used as Furthermore, it may contain a preservative, an antioxidant, a flavoring agent, etc.
  • the patch is prepared according to a known or commonly used formulation, for example, by melting the compound of the present invention in a patch base and spreading the mixture onto a support.
  • the base for the patch is selected from those known or commonly used, for example, a mixture of one or more selected from polymer bases, oils and fats, higher fatty acids, tackifiers, and anti-rash agents. It is used as Furthermore, it may contain a preservative, an antioxidant, a flavoring agent, etc.
  • the liniment agent is prepared according to a known or commonly used formulation, for example, the compound of the present invention is mixed with water, alcohol (such as ethanol and polyethylene glycol), higher fatty acids, glycerin, soap, emulsifying agents, suspending agents, etc. It is prepared by dissolving, suspending or emulsifying in one or more selected from the following. Furthermore, it may contain a preservative, an antioxidant, a flavoring agent, etc.
  • the present invention provides the following embodiments.
  • R 1 is (1) methylene substituted with a 3- to 15-membered carbon ring optionally substituted with 1 to 5 R 11 , (2) substituted with 1 to 5 R 12 (3) Methylene substituted with a C2-4 alkenyl group optionally substituted with 1 to 5 R13 , or (4) Represents methylene substituted with a C2-4 alkynyl group optionally substituted with 1 to 5 R14 , R 11 , R 12 , R 13 and R 14 each independently represent (1) halogen, (2) C1-4 alkyl group, (3) C1-4 alkoxy group, (4) C1-4 haloalkyl group, (5) represents a C1-4 haloalkoxy group, or (6) a cyano group, and a plurality of R 11 , R 12 , R 13 and R 14 may be the same or different, respectively; R 2 is (1) a 3- to 15 -membered heterocycle optionally substituted with 1 to 5 R 15s, (2) a 3- to 15-membered heterocycle optionally substituted
  • each R Y may be the same or different;
  • X represents a nitrogen atom or CR7 , X 1 , X 2 , and X 3 each independently represent a nitrogen atom, CH, or CR 6 ,
  • R 6 is (1) halogen, (2) C1-4 alkyl group, (3) C1-4 alkoxy group, (4) C1-4 haloalkyl group, (5) C1-4 haloalkoxy group, (6) hydroxyl group , or (7) represents a cyano group
  • each R 6 may be the same or different;
  • Y 1 represents a nitrogen atom or CR 8
  • Y2 represents a nitrogen atom or CR9
  • Y 3 represents a nitrogen atom or CR 10Y ,
  • R 7 is (1) hydrogen atom, (2) halogen, (3) C1-4 alkyl
  • R 1 is (1) methylene substituted with a 3- to 15-membered carbon ring optionally substituted with 1 to 5 R 11 , (2) optionally substituted with 1 to 5 R 12 methylene substituted with a 3- to 15-membered heterocycle, (3) methylene substituted with a C2-4 alkenyl group optionally substituted with 1 to 5 R 13 , or (4) 1 to 5 R 13 R 14 represents methylene substituted with an optionally substituted C2-4 alkynyl group, R 11 , R 12 , R 13 and R 14 each independently represent (1) halogen, (2) C1-4 alkyl group, (3) C1-4 alkoxy group, (4) C1-4 haloalkyl group, (5) represents a C1-4 haloalkoxy group, or (6) a cyano group, and a plurality of R 11 , R 12 , R 13 and R 14 may be the same or different, respectively; R 2 is (1) a 3- to 15 -membered heterocycle optionally
  • R 3Y or R 3 is (1) a 5- to 6-membered carbon ring or indane, each optionally substituted with 1 to 5 R 20Y or R 20 , (2) 1 to 5
  • R 3 is (1) a 5- to 6-membered carbocyclic ring or indane, each optionally substituted with 1 to 5 R 20 , (2) substituted with 1 to 5 R 21
  • the compound is (1) 1-(3- ⁇ 7-(4- ⁇ [9-(4-cyano-2-fluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4 ',3':4,5]pyrrolo[2,3-b]pyridin-7-yl]carbonyl ⁇ phenyl)-9-[1-(2,2-dimethylpropyl)-4-piperidinyl]-6-methyl -8-oxo-8,9-dihydro-7H-purin-2-yl ⁇ phenyl)cyclopropanecarboxylic acid, (2) 2-(3- ⁇ 7-(6- ⁇ [9-(4-cyano-2-fluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4 ,5]pyrrolo[2,3-b]pyridin-7-yl]carbonyl ⁇ -3-pyridinyl)-9-[1-(2,2-dimethylpropyl
  • the compound is (1) 7-(4- ⁇ [9-(4-chloro-2-fluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4 ,5]pyrrolo[2,3-b]pyridin-7-yl]carbonyl ⁇ phenyl)-2- ⁇ [4-(difluoromethoxy)phenyl]amino ⁇ -9-[1-(2,2-dimethylpropyl) -4-piperidinyl]-6-methyl-7,9-dihydro-8H-purin-8-one, (2) 7-(4- ⁇ [9-(4-chloro-2-fluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[2 ,3-b]pyridin-7-yl]carbonyl ⁇ phenyl)-9-[1-(2,2-dimethylpropyl)-4-piperidinyl]
  • the compound is (1) 1- ⁇ [ ⁇ 7-(6- ⁇ [9-(4-cyano-2-fluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4' ,3':4,5]pyrrolo[2,3-b]pyridin-7-yl]carbonyl ⁇ -3-pyridinyl)-9-[1-(2,2-dimethylpropyl)-4-piperidinyl]-6 -Methyl-8-oxo-8,9-dihydro-7H-purin-2-yl ⁇ (cyclohexyl)amino]methyl ⁇ cyclobutanecarboxylic acid, the compound according to [12], or a salt thereof;
  • Cancer rectal cancer, colon cancer, hepatocellular carcinoma, esophageal cancer, gastric cancer, esophagogastric junction cancer, pancreatic cancer, urothelial cancer, prostate cancer, fallopian tube cancer, primary peritoneal cancer, malignant pleural mesothelioma, gallbladder cancer , bile duct cancer, biliary tract cancer, skin cancer, testicular cancer (germ cell tumor), vaginal cancer, vulvar cancer, penile cancer, small intestine cancer, endocrine cancer, thyroid cancer, parathyroid cancer, adrenal cancer, spinal tumor, nerve bud cancer
  • the pharmaceutical composition according to [18] which is one or more cancers selected from cell carcinoma, medulloblastoma, ocular retinoblastoma, neuroendocrine tumor, brain tumor, and squamous cell carcinoma; [20]
  • the pharmaceutical composition according to [18], wherein the solid cancer is bone/soft tissue sarcoma or Kaposi's s
  • the solvent in parentheses shown at the point of chromatographic separation and TLC indicates the elution solvent or developing solvent used, and the proportions represent volume ratios.
  • the medium pressure preparative cartridge column used was Chromatorex Q-PACK SI or NH (Fuji Silysia Chemical), and the injection column silica gel or Amino (Yamazen).
  • reverse phase HPLC column purification was performed under the following conditions.
  • the numerical value shown in the NMR section is a 1 H-NMR measurement value (chemical shift value) using the measurement solvent listed in parentheses.
  • the compound names used in this specification are generally given by computer programs that perform naming according to IUPAC rules, ACD/Name (registered trademark) (version 6.00, manufactured by Advanced Chemistry Development Inc.), Chemdraw Ultra (version 6.00, manufactured by Advanced Chemistry Development Inc.), 12.0, manufactured by Cambridge Soft) or Lexichem Toolkit (version 1.4.2, manufactured by OpenEye Scientific Software), or named according to IUPAC nomenclature.
  • ACD/Name registered trademark
  • Chemdraw Ultra version 6.00, manufactured by Advanced Chemistry Development Inc.
  • 12.0 manufactured by Cambridge Soft
  • Lexichem Toolkit version 1.4.2, manufactured by OpenEye Scientific Software
  • Reference example 2 9-(2,4-difluorobenzyl)-6,7,8,9-tetrahydro-5H-pyrido[4',3':4,5]pyrrolo[2,3-b]pyridine dihydrochloride
  • Reference Example 1 The compound prepared in (5.1 g) was dissolved in methanol (10 mL), 4N hydrogen chloride/1,4-dioxane solution (32 mL) was added, and the mixture was stirred at room temperature for 40 minutes. The reaction solution was concentrated and azeotroped with toluene, and the resulting residue was filtered using 2-methoxy-2-methylpropane (hereinafter sometimes abbreviated as MTBE) to obtain the following physical properties.
  • MTBE 2-methoxy-2-methylpropane
  • Reference example 4 2-Methyl-2-propanyl 4-[(2-chloro-5- ⁇ [4-(methoxycarbonyl)phenyl]amino ⁇ -6-methyl-4-pyrimidinyl)amino]-1-piperidinecarboxylate in Reference Example 3
  • the produced compound (5.0 g) and methyl 4-iodobenzoate (4.6 g) were dissolved in anhydrous 1,2-dimethoxyethane (hereinafter sometimes abbreviated as DME) (50 mL).
  • DME 1,2-dimethoxyethane
  • Reference example 5 2-Methyl-2-propanyl 4- ⁇ 2-chloro-7-[4-(methoxycarbonyl)phenyl]-6-methyl-8-oxo-7,8-dihydro-9H-purin-9-yl ⁇ -1 - Piperidine carboxylate
  • THF tetrahydrofuran
  • CDI di-1H-imidazol-1-yl methanone
  • DBU 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine
  • Reference example 6 4-[2-chloro-6-methyl-9-(1- ⁇ [(2-methyl-2-propanyl)oxy]carbonyl ⁇ -4-piperidinyl)-8-oxo-8,9-dihydro-7H -purin-7-yl]benzoic acid
  • TMSOK Potassium trimethylsilanolate
  • Reference example 7 2-Methyl-2-propanyl 4-[2-chloro-7-(4- ⁇ [9-(2,4-difluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3 ':4,5]pyrrolo[2,3-b]pyridin-7-yl]carbonyl ⁇ phenyl)-6-methyl-8-oxo-7,8-dihydro-9H-purin-9-yl]-1- Piperidine carboxylate
  • the compound produced in Reference Example 2 (536 mg) and the compound produced in Reference Example 6 (650 mg) were dissolved in DMF (13 mL), and DIPEA (0.69 mL) and (dimethylamino)-N,N-dimethyl ( 3H-[1,2,3]triazolo[4,5-b]pyridin-3-yloxy)methaniminium hexafluorophosphate (hereinafter sometimes abbreviated as HATU) (658 mg) was added
  • Reference example 8 2-chloro-7-(4- ⁇ [9-(2,4-difluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[2, 3-b]pyridin-7-yl]carbonyl ⁇ phenyl)-6-methyl-9-(4-piperidinyl)-7,9-dihydro-8H-purin-8-one
  • Compound produced in Reference Example 7 (450 mg) was dissolved in methanol (4.5 mL), 4N hydrogen chloride/1,4-dioxane solution (2.9 mL) was added, and the mixture was stirred at room temperature for 2 hours.
  • Reference example 9 2-chloro-7-(4- ⁇ [9-(2,4-difluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[2, 3-b]pyridin-7-yl]carbonyl ⁇ phenyl)-9-[1-(2,2-dimethylpropyl)-4-piperidinyl]-6-methyl-7,9-dihydro-8H-purine-8-
  • the compound prepared in Reference Example 8 (390 mg) was dissolved in DMF (7.8 mL), pivalaldehyde (0.32 mL), acetic acid (0.33 mL), and sodium triacetoxyborohydride (618 mg) were added, and the mixture was stirred at room temperature for 4 hours.
  • Example 1 2-anilino-7-(4- ⁇ [9-(2,4-difluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[2, 3-b]pyridin-7-yl]carbonyl ⁇ phenyl)-9-[1-(2,2-dimethylpropyl)-4-piperidinyl]-6-methyl-7,9-dihydro-8H-purine-8-
  • the compound prepared in Reference Example 9 (390 mg) was dissolved in toluene (2.5 mL), aniline (94 mg), cesium carbonate (330 mg), Xantphos (44 mg), and palladium acetate (11 mg) were added, and the mixture was heated at 100°C in a nitrogen atmosphere.
  • Example 3 1- ⁇ 7-(4- ⁇ [9-(2,4-difluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[2,3 -b]pyridin-7-yl]carbonyl ⁇ phenyl)-9-[1-(2,2-dimethylpropyl)-4-piperidinyl]-6-methyl-8-oxo-8,9-dihydro-7H-purine -2-yl ⁇ -3-piperidinecarboxylic acid 2-trifluoroacetate
  • DMSO dimethyl sulfoxide
  • Example 4 2-anilino-7-(4- ⁇ [9-(2,4-difluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[2, 3-b]pyridin-7-yl]carbonyl ⁇ phenyl)-9-[(3S)-1-(2,2-dimethylpropyl)-3-piperidinyl]-6-methyl-7,9-dihydro-8H- Purin-8-one Using the compound produced in Reference Example 10 instead of the compound produced in Reference Example 9, the same operation as in Example 1 was carried out to obtain the title compound having the following physical property values.
  • Example 4-1 7-(4- ⁇ [9-(2,4-difluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[2,3-b] pyridin-7-yl]carbonyl ⁇ phenyl)-9-[(3S)-1-(2,2-dimethylpropyl)-3-piperidinyl]-6-methyl-2- ⁇ [2-(trifluoromethoxy)phenyl ]Amino ⁇ -7,9-dihydro-8H-purin-8-one 2-trifluoroacetate
  • 2-(trifluoromethoxy)aniline instead of aniline, and the reversed phase By HPLC column purification, the title compound having the following physical properties was obtained.
  • Example 6 7-(4- ⁇ [9-(2,4-difluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[2,3-b] pyridin-7-yl]carbonyl ⁇ phenyl)-9-[(3S)-1-(2,2-dimethylpropyl)-3-piperidinyl]-2-(4-methoxyphenyl)-6-methyl-7,9 -Dihydro-8H-purin-8-one
  • the compound prepared in Reference Example 10 (20 mg) was dissolved in NMP (0.4 mL), and (4-methoxyphenyl)boronic acid (16 mg) and tripotassium phosphate aqueous solution (0.054 mL) were dissolved in NMP (0.4 mL).
  • Reference example 13 2-Chloro-9-(2,4-dimethoxybenzyl)-6-methyl-7,9-dihydro-8H-purin-8-one
  • the compound (5.3 g) prepared in Reference Example 12 was dissolved in THF (30 mL). Then, CDI (5.6 g) and DBU (2.6 g) were added, and the mixture was stirred at room temperature for 16 hours. The reaction solution was diluted with ethyl acetate and washed successively with 1N hydrochloric acid, saturated aqueous sodium carbonate solution, and saturated brine.
  • Reference example 14 Methyl 4-[2-chloro-9-(2,4-dimethoxybenzyl)-6-methyl-8-oxo-8,9-dihydro-7H-purin-7-yl]benzoate Compound produced in Reference Example 13 (1.3 g) in acetonitrile (536 mL), [4-(methoxycarbonyl)phenyl]boronic acid (2.2 g) and N,N-diethylethanamine (hereinafter sometimes abbreviated as NEt 3 ) ( 11 mL), pyridine (30 mL), and copper(II) acetate (1.5 g). The inside of the reaction vessel was replaced with oxygen, and the mixture was stirred at room temperature for 21 hours.
  • reaction solution was concentrated, dissolved in ethyl acetate, and washed successively with aqueous ammonia, water, 1N hydrochloric acid, water, saturated sodium bicarbonate, and saturated brine.
  • Reference example 15 4-[2-chloro-9-(2,4-dimethoxybenzyl)-6-methyl-8-oxo-8,9-dihydro-7H-purin-7-yl]benzoic acid
  • THF tetrahydrofuran
  • TMSOK 844 mg
  • the reaction solution was diluted with water and adjusted to pH 2 or less with 1N hydrochloric acid.
  • Extraction was performed with ethyl acetate, and the resulting organic layer was washed with water and saturated brine. After drying over anhydrous sodium sulfate, the residue was concentrated under reduced pressure to obtain the title compound (1.5 g) having the following physical properties.
  • Reference example 16 2-chloro-7-(4- ⁇ [9-(2,4-difluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[2, 3-b]pyridin-7-yl]carbonyl ⁇ phenyl)-9-(2,4-dimethoxybenzyl)-6-methyl-7,9-dihydro-8H-purin-8-one
  • Compound produced in Reference Example 15 (1.6 g) and the compound produced in Reference Example 2 (1.2 g) were dissolved in DMF (15 mL), DIPEA (2.0 mL) and HATU (1.7 g) were added, and the mixture was stirred at room temperature for 15 hours.
  • Reference example 17 2-chloro-7-(4- ⁇ [9-(2,4-difluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[2, 3-b]pyridin-7-yl]carbonyl ⁇ phenyl)-6-methyl-7,9-dihydro-8H-purin-8-one sodium salt
  • the compound prepared in Reference Example 16 (2.1 g) was added with trifluoroacetic acid ( 26.7 mL) and triethylsilane (2.1 mL) were added and stirred at 70°C for 21 hours.
  • the reaction solution was cooled to room temperature and extracted with 2N aqueous sodium hydroxide solution and water.
  • the resulting aqueous layer was washed with MTBE, 2N hydrochloric acid was added, and the resulting precipitate was collected by filtration.
  • the filtered material was dissolved again in ethyl acetate and extracted with 2N aqueous sodium hydroxide solution.
  • the precipitate produced from the resulting aqueous layer was collected by filtration and washed with water and ethyl acetate to obtain the title compound (1.5 g) having the following physical properties.
  • Reference example 18 2-chloro-7-(4- ⁇ [9-(2,4-difluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[2, 3-b]pyridin-7-yl]carbonyl ⁇ phenyl)-6-methyl-9-[3-(4-morpholinyl)propyl]-7,9-dihydro-8H-purin-8-one
  • the obtained compound (18 mg) was dissolved in DMF (0.3 mL), 4-(3-chloropropyl)morpholine hydrochloride (18 mg) and cesium carbonate (59 mg) were added, and the mixture was stirred at 80° C. for 17 hours.
  • reaction solution was cooled to room temperature, diluted with water, and extracted with ethyl acetate.
  • the title compound (13 mg) was obtained.
  • Example 7 2-anilino-7-(4- ⁇ [9-(2,4-difluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[2, 3-b]pyridin-7-yl]carbonyl ⁇ phenyl)-6-methyl-9-[3-(4-morpholinyl)propyl]-7,9-dihydro-8H-purin-8-one
  • the same operation as in Example 1 was carried out using the compound (35 mg) produced in Reference Example 18 instead of the compound obtained above, to obtain the title compound (32 mg) having the following physical properties.
  • Example 7-1 2-anilino-7-(4- ⁇ [9-(2,4-difluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[2, 3-b]pyridin-7-yl]carbonyl ⁇ phenyl)-6-methyl-9-(tetrahydro-3-furanyl)-7,9-dihydro-8H-purin-8-one 2 trifluoroacetate LC-MS (A) retention time (min): 1.28; MS(ESI, Pos.): 713 (M + H) + ; 1 H-NMR (DMSO-d 6 ): ⁇ 1.85-2.02, 2.25-2.35, 2.55-2.61, 2.81-2.92, 3.60-3.75, 3.83-4.11, 4.13-4.24, 4.55-4.93, 5.03-5.15, 5.23- 5.62, 6.84-7.20, 7.23-7.37, 7.49-7.71, 7.78, 7.91
  • Example 7-2 2-anilino-7-(4- ⁇ [9-(2,4-difluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[2, 3-b]pyridin-7-yl]carbonyl ⁇ phenyl)-6-methyl-9- ⁇ 2-[methyl(2,2,2-trifluoroethyl)amino]ethyl ⁇ -7,9-dihydro-8H- Purin-8-one 2-trifluoroacetate LC-MS (A) retention time (min): 1.36; MS(ESI, Pos.): 782 (M + H) + ; 1 H-NMR (DMSO-d 6 ): ⁇ 1.86-2.03, 2.82-2.90, 3.01-3.07, 3.23-3.33, 3.43, 3.65-3.73, 3.96-4.04, 4.57-4.93, 5.24-5.61, 6.86-7.18, 7.23-7.37, 7.47-7.72
  • Example 7-3 3- ⁇ 3-[2-anilino-7-(4- ⁇ [9-(2,4-difluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4, 5] Pyrrolo[2,3-b]pyridin-7-yl]carbonyl ⁇ phenyl)-6-methyl-8-oxo-7,8-dihydro-9H-purin-9-yl]propyl ⁇ -5,5- Dimethyl-1,3-oxazolidine-2,4-dione LC-MS (A) retention time (min): 1.14; MS(ESI, Pos.): 812 (M + H) + ; 1 H-NMR (CDCl 3 ): ⁇ 1.55-1.59, 2.03-2.09, 2.32, 2.84-2.95, 3.63-3.73, 3.74-4.12, 4.03, 4.53-4.94, 5.19-5.60, 6.68-6.79, 6.86, 6.9 1- 7.13, 7.35
  • Reference example 19 2-chloro-7-(4- ⁇ [9-(2,4-difluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[2, 3-b]pyridin-7-yl]carbonyl ⁇ phenyl)-9-isopropyl-6-methyl-7,9-dihydro-8H-purin-8-one 4-(3-chloropropyl) used in Reference Example 18 The same operation as in Reference Example 18 was carried out using 2-iodopropane instead of morpholine hydrochloride to obtain the title compound having the following physical properties.
  • Example 8 7-(4- ⁇ [9-(2,4-difluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[2,3-b] Pyridin-7-yl]carbonyl ⁇ phenyl)-9-isopropyl-2,6-dimethyl-7,9-dihydro-8H-purin-8-one
  • the compound (39 mg) prepared in Reference Example 19 was dissolved in DME (1 mL).
  • Example 9 7-(4- ⁇ [9-(2,4-difluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[2,3-b] Pyridin-7-yl]carbonyl ⁇ phenyl)-9-isopropyl-6-methyl-8-oxo-8,9-dihydro-7H-purine-2-carbonitrile
  • DMSO N,N,N-tributyl-1-butanaminium cyanide
  • DBU 0.036 mL
  • reaction solution was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate.
  • Reference example 20 Methyl 4-[9-(2,4-dimethoxybenzyl)-6-methyl-8-oxo-8,9-dihydro-7H-purin-7-yl]benzoate
  • the compound prepared in Reference Example 14 (120 mg) Dissolved in THF (5 mL) and methanol (5 mL), added NEt 3 (0.043 mL) and 5% palladium-activated carbon (50% wet, 50 mg), purged the inside of the reaction vessel with hydrogen, and left at room temperature for 3 hours. Stirred. The reaction solution was filtered through Celite (trade name), and the resulting filtrate was concentrated under reduced pressure to obtain the title compound (120 mg) having the following physical properties.
  • Reference example 21 4-[9-(2,4-dimethoxybenzyl)-6-methyl-8-oxo-8,9-dihydro-7H-purin-7-yl]benzoic acid
  • the compound (120 mg) produced in Reference Example 20 was dissolved in THF. (0.6 mL) and methanol (0.6 mL), 2N aqueous sodium hydroxide solution (0.28 mL) was added, and the mixture was stirred at room temperature for 3 hours. 2N hydrochloric acid was added to the reaction solution to adjust the pH to about 3, followed by extraction with ethyl acetate, and the organic layer was washed with saturated brine.
  • Reference example 22 7-(4- ⁇ [9-(2,4-difluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[2,3-b] Pyridin-7-yl]carbonyl ⁇ phenyl)-9-(2,4-dimethoxybenzyl)-6-methyl-7,9-dihydro-8H-purin-8-one
  • Reference instead of the compound produced in Reference Example 15 Using the compound (106 mg) produced in Example 21, the same operation as in Reference Example 16 was performed to obtain the title compound (142 mg) having the following physical properties.
  • Reference example 23 7-(4- ⁇ [9-(2,4-difluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[2,3-b] Pyridin-7-yl]carbonyl ⁇ phenyl)-6-methyl-7,9-dihydro-8H-purin-8-one
  • the compound prepared in Reference Example 22 (142 mg) was added with trifluoroacetic acid (1.5 mL) and triethylsilane ( 0.16 mL) and stirred at 80°C for 16 hours.
  • the reaction solution was cooled to room temperature, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate.
  • Example 10 9-benzyl-7-(4- ⁇ [9-(2,4-difluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[2, 3-b]pyridin-7-yl]carbonyl ⁇ phenyl)-6-methyl-7,9-dihydro-8H-purin-8-one
  • the compound produced in Reference Example 23 was substituted for the compound produced in Reference Example 17.
  • 4-(3-chloropropyl)morpholine hydrochloride was replaced with (bromomethyl)benzene, and the same operation as in Reference Example 18 was carried out to obtain the title compound having the following physical properties.
  • Example 11 7-(4- ⁇ [9-(2,4-difluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[2,3-b] Pyridin-7-yl]carbonyl ⁇ phenyl)-6-methyl-9-phenyl-7,9-dihydro-8H-purin-8-one
  • the compound (49 mg) prepared in Reference Example 23 was dissolved in DMF (0.88 mL). Then, phenylboronic acid (32 mg), pyridine (0.072 mL), and copper(II) acetate (18 mg) were added, and the mixture was stirred at room temperature for 24 hours.
  • the reaction solution was diluted with ethyl acetate and washed with water and saturated brine.
  • the obtained compound 400 mg was dissolved in THF (10 mL), DIPEA (0.21 mL) and 1-phenylmethanamine (0.13 mL) were added, and the mixture was stirred at room temperature for 2 hours.
  • the reaction solution was diluted with ethyl acetate and washed with water and saturated brine.
  • Reference example 25 2-Methyl-2-propanyl (3R)-3- ⁇ [5-amino-2-(benzylamino)-6-methyl-4-pyrimidinyl]amino ⁇ -1-piperidinecarboxylate of the compound produced in Reference Example 11
  • the same operation as in Reference Example 12 was performed using the compound (300 mg) produced in Reference Example 24 instead, to obtain the title compound (275 mg) having the following physical property values.
  • Reference example 26 2-Methyl-2-propanyl (3R)-3-[2-(benzylamino)-6-methyl-8-oxo-7,8-dihydro-9H-purin-9-yl]-1-piperidinecarboxylate Reference Using the compound produced in Reference Example 25 (275 mg) instead of the compound produced in Example 12, the same operation as in Reference Example 13 was carried out to obtain the title compound (199 mg) having the following physical properties.
  • Example 12 2-Methyl-2-propanyl (3R)-3-[2-(benzylamino)-7-(4- ⁇ [9-(2,4-difluorobenzyl)-5,6,8,9-tetrahydro-7H -pyrido[4',3':4,5]pyrrolo[2,3-b]pyridin-7-yl]carbonyl ⁇ phenyl)-6-methyl-8-oxo-7,8-dihydro-9H-purine- 9-yl]-1-piperidinecarboxylate Using the compound produced in Reference Example 26 instead of the compound produced in Reference Example 13, the same operations as in Reference Example 14 ⁇ Reference Example 15 ⁇ Reference Example 16 were carried out to produce the following. The title compound having the physical property values was obtained.
  • Reference example 27 4-Methyl 1-(2-methyl-2-propanyl) 4-(2-chloro-6-methyl-8-oxo-7,8-dihydro-9H-purin-9-yl)-1,4-piperidine di Carboxylate Instead of 1-(2,4-dimethoxyphenyl)methanamine used in Reference Example 11, 4-methyl 1-(2-methyl-2-propanyl) 4-amino-1,4-piperidinecarboxylate was used. The same operations as Reference Example 11 ⁇ Reference Example 12 ⁇ Reference Example 13 were performed to obtain the title compound having the following physical property values.
  • Reference example 28 4-Methyl 1-(2-methyl-2-propanyl) 4-(7- ⁇ 4-[(benzyloxy)carbonyl]phenyl ⁇ -2-chloro-6-methyl-8-oxo-7,8-dihydro- 9H-purin-9-yl)-1,4-piperidinedicarboxylate
  • the compound produced in Reference Example 27 (195 mg) was substituted for the compound produced in Reference Example 13, and [4-(methoxycarbonyl)phenyl]boronic acid
  • Reference Example 14 was carried out using ⁇ 4-[(benzyloxy)carbonyl]phenyl ⁇ boronic acid instead of , to obtain the title compound (98 mg) having the following physical properties.
  • Reference example 29 4-Methyl 1-(2-methyl-2-propanyl) 4-(2-anilino-7- ⁇ 4-[(benzyloxy)carbonyl]phenyl ⁇ -6-methyl-8-oxo-7,8- Dihydro-9H-purin-9-yl)-1,4-piperidinedicarboxylate
  • the same procedure as in Example 1 was performed using the compound produced in Reference Example 28 (30 mg) instead of the compound produced in Reference Example 9.
  • the title compound (32 mg) having the following physical properties was obtained.
  • Example 13 4-Methyl 1-(2-methyl-2-propanyl) 4-[2-anilino-7-(4- ⁇ [9-(2,4-difluorobenzyl)-5,6,8,9-tetrahydro-7H -pyrido[4',3':4,5]pyrrolo[2,3-b]pyridin-7-yl]carbonyl ⁇ phenyl)-6-methyl-8-oxo-7,8-dihydro-9H-purine- [9-yl]-1,4-piperidinedicarboxylate
  • the compound (30 mg) prepared in Reference Example 29 was dissolved in THF (1.5 mL) and methanol (1.5 mL), and 5% palladium-activated carbon (50% wet, 30 mg) was added, the inside of the reaction vessel was replaced with hydrogen, and the mixture was stirred at room temperature for 2 hours.
  • the reaction solution was filtered through Celite (trade name), and the resulting filtrate was concentrated under reduced pressure. This was dissolved in DMF (2 mL), and the compound produced in Reference Example 2 (15 mg), NEt 3 (0.023 mL), and HATU (24 mg) were added, and the mixture was stirred at room temperature for 2 hours.
  • the title compound (33 mg) was obtained.
  • Reference example 30 2-Methyl-2-propanyl 9-(2,4-difluorobenzyl)-5-methoxy-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[2, 3-b] Pyridine-7-carboxylate
  • the compound prepared in Reference Example 1 (200 mg) and tetraethylammonium p-toluenesulfonate (1206 mg) were dissolved in methanol (20 mL). Electricity was applied to the reaction solution (DC power supply manufactured by Kikusui Co., Ltd.: PMC350-0.2A, 12 mA, anode: carbon felt, cathode: platinum plate) and stirred for 30 minutes.
  • Reference example 31 2-Methyl-2-propanyl 9-(2,4-difluorobenzyl)-5-hydroxy-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[2, 3-b] Pyridine-7-carboxylate
  • the compound prepared in Reference Example 30 (9.8 mg) was dissolved in 1,4-dioxane (0.16 mL), and water (0.040 mL) and 4-methylbenzenesulfonic acid hydrate were added. (0.87 mg) was added and stirred at room temperature for 4 hours. Water was added to the reaction solution, extracted with ethyl acetate, and the resulting organic layer was dried over anhydrous sodium sulfate.
  • Reference example 32 9-(2,4-difluorobenzyl)-6,7,8,9-tetrahydro-5H-pyrido[4',3':4,5]pyrrolo[2,3-b]pyridin-5-ol
  • the compound prepared in 31 (9.0 mg) was dissolved in dichloromethane (0.4 mL), trifluoroacetic acid (0.2 mL) was added, and the mixture was stirred at 0° C. for 90 minutes. A saturated aqueous sodium bicarbonate solution was added to the reaction mixture, extracted with ethyl acetate, and the resulting organic layer was dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure to obtain the title compound (5.1 mg) having the following physical properties.
  • Reference example 33 2-Methyl-2-propanyl (3S)-3- ⁇ 2-chloro-7-[4-(methoxycarbonyl)phenyl]-6-methyl-8-oxo-7,8-dihydro-9H-purine-9- yl ⁇ -1-piperidinecarboxylate 2-methyl-2-propanyl (3S)-3-amino- instead of 2-methyl-2-propanyl 4-amino-1-piperidinecarboxylate used in Reference Example 3 Using 1-piperidinecarboxylate, the same operations as Reference Example 3 ⁇ Reference Example 4 ⁇ Reference Example 5 were performed to obtain the title compound having the following physical property values.
  • Reference example 34 Methyl 4- ⁇ 2-chloro-9-[(3S)-1-(2,2-dimethylpropyl)-3-piperidinyl]-6-methyl-8-oxo-8,9-dihydro-7H-purine-7 -yl ⁇ benzoate Using the compound produced in Reference Example 33 instead of the compound produced in Reference Example 7, the same operations as in Reference Example 8 ⁇ Reference Example 9 were performed to obtain the title compound having the following physical property values.
  • Reference example 35 Methyl 4- ⁇ 2-anilino-9-[(3S)-1-(2,2-dimethylpropyl)-3-piperidinyl]-6-methyl-8-oxo-8,9-dihydro-7H-purine-7 -yl ⁇ benzoate Using the compound produced in Reference Example 34 (1.4 g) instead of the compound produced in Reference Example 9, the same operation as in Example 1 was carried out to obtain the title compound (1.1 g) was obtained.
  • Reference example 36 4- ⁇ 2-anilino-9-[(3S)-1-(2,2-dimethylpropyl)-3-piperidinyl]-6-methyl-8-oxo-8,9-dihydro-7H-purine-7- Benzoic acid monohydrochloride
  • the compound prepared in Reference Example 35 (106 mg) was dissolved in THF (2 mL), TMSOK (57 mg) was added, and the mixture was stirred at room temperature for 90 minutes.
  • a 4N hydrogen chloride/1,4-dioxane solution was added to the reaction mixture and concentrated to obtain the title compound (110 mg) having the following physical properties.
  • Example 14 2-anilino-7-(4- ⁇ [9-(2,4-difluorobenzyl)-5-hydroxy-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5] pyrrolo[2,3-b]pyridin-7-yl]carbonyl ⁇ phenyl)-9-[(3S)-1-(2,2-dimethylpropyl)-3-piperidinyl]-6-methyl-7,9- Dihydro-8H-purin-8-one
  • the compound produced in Reference Example 32 (5.1 mg) was substituted for the compound produced in Reference Example 2, and the compound produced in Reference Example 36 was substituted for the compound produced in Reference Example 6.
  • Reference example 38 2-Methyl-2-propanyl 3-[(5-amino-2-anilino-4-pyrimidinyl)amino]-1-piperidinecarboxylate
  • the compound prepared in Reference Example 37 (1.0 mg) was dissolved in DMF (100 mL).
  • 5% palladium-activated carbon (50% wet, 280 mg) was added, the inside of the reaction vessel was replaced with hydrogen, and the mixture was stirred at room temperature for 5 hours.
  • the reaction solution was filtered through Celite (trade name), the filtrate was diluted with a mixture of ethyl acetate and hexane (3:7), and washed with water and saturated brine.
  • Reference example 39 2-Methyl-2-propanyl 3-(2-anilino-8-oxo-7,8-dihydro-9H-purin-9-yl)-1-piperidinecarboxylate Reference Example instead of the compound produced in Reference Example 12 Using the compound (3.7 g) produced in Step 38, the same operation as in Reference Example 13 was performed to obtain the title compound (1.7 g) having the following physical properties.
  • Reference example 40 2-Methyl-2-propanyl 3- ⁇ 2-anilino-7-[4-(methoxycarbonyl)phenyl]-8-oxo-7,8-dihydro-9H-purin-9-yl ⁇ -1-piperidinecarboxylate Using the compound produced in Reference Example 39 (1.6 g) instead of the compound produced in Reference Example 13, the same operation as in Reference Example 14 was performed to obtain the title compound (690 mg) having the following physical property values.
  • Reference example 41 4-[2-anilino-9-(1- ⁇ [(2-methyl-2-propanyl)oxy]carbonyl ⁇ -3-piperidinyl)-8-oxo-8,9-dihydro-7H-purin-7-yl ] Benzoic acid Using the compound produced in Reference Example 40 (686 mg) instead of the compound produced in Reference Example 5, the same operation as in Reference Example 6 was performed to obtain the title compound (356 mg) having the following physical property values.
  • Reference example 42 2-Methyl-2-propanyl 3-[2-anilino-7-(4- ⁇ [9-(2,4-difluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3 ':4,5]pyrrolo[2,3-b]pyridin-7-yl]carbonyl ⁇ phenyl)-8-oxo-7,8-dihydro-9H-purin-9-yl]-1-piperidinecarboxylate
  • Reference Example 7 was performed using the compound produced in Reference Example 41 (207 mg) instead of the compound produced in Example 6 to obtain the title compound (287 mg) having the following physical properties.
  • Reference example 43 2-anilino-7-(4- ⁇ [9-(2,4-difluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[2, 3-b]pyridin-7-yl]carbonyl ⁇ phenyl)-9-(3-piperidinyl)-7,9-dihydro-8H-purin-8-one dihydrochloride
  • the compound prepared in Reference Example 42 (170 mg) Methanol (3 mL) was added to suspend the mixture, 4N hydrogen chloride/1,4-dioxane solution (1.0 mL) was added, and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated to obtain the title compound (167 mg) having the following physical properties.
  • Example 15 2-anilino-7-(4- ⁇ [9-(2,4-difluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[2, 3-b]pyridin-7-yl]carbonyl ⁇ phenyl)-9-[1-(3,3-dimethylbutyl)-3-piperidinyl]-7,9-dihydro-8H-purin-8-one
  • Reference Example 43 The compound prepared in (14 mg) was dissolved in dichloromethane (1.0 mL), 3,3-dimethylbutanal (18 mg) and sodium triacetoxyborohydride (38 mg) were added, and the mixture was stirred at room temperature for 4 hours.
  • Example 15-1 7-(4- ⁇ [9-(2,4-difluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[2,3-b] pyridin-7-yl]carbonyl ⁇ phenyl)-9-[1-(2,2-dimethylpropyl)-3-piperidinyl]-2-(2-pyridinylamino)-7,9-dihydro-8H-purine-8-
  • 2-aminopyridine in place of aniline used in Reference Example 37 and pivalaldehyde in place of 3,3-dimethylbutanal used in Example 15
  • Example 16 2-anilino-7-(4- ⁇ [9-(2,4-difluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[2, 3-b]pyridin-7-yl]carbonyl ⁇ phenyl)-9-[1-(3,3-dimethylbutanoyl)-3-piperidinyl]-7,9-dihydro-8H-purin-8-one
  • Reference example The compound prepared in 43 (10 mg) and 3,3-dimethylbutanoic acid (4.4 mg) were dissolved in DMF (0.5 mL), DIPEA (0.021 mL) and HATU (9.7 mg) were added, and the mixture was stirred at room temperature for 1 hour.
  • Example 19 2-Methyl-2-propanyl ⁇ 3-[2-anilino-7-(4- ⁇ [9-(2,4-difluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4', 3':4,5]pyrrolo[2,3-b]pyridin-7-yl]carbonyl ⁇ phenyl)-8-oxo-7,8-dihydro-9H-purin-9-yl]propyl ⁇ carbamate
  • Reference Example 37 Using 2-methyl-2-propanyl (3-aminopropyl) carbamate instead of 2-methyl-2-propanyl 3-amino-1-piperidinecarboxylate used in Reference Example 37 ⁇ Reference Example 38 ⁇ The same operations as Reference Example 39 ⁇ Reference Example 40 ⁇ Reference Example 41 ⁇ Reference Example 42 were performed to obtain the title compound having the following physical property values.
  • Reference example 45 2-anilino-9-[1-(2,2-dimethylpropyl)-4-piperidinyl]-7,9-dihydro-8H-purin-8-one
  • the compound prepared in Reference Example 44 was used.
  • the same operations as Reference Example 8 ⁇ Reference Example 9 were performed to obtain the title compound having the following physical property values.
  • Reference example 46 2-Methyl-2-propanyl 4-[(5-amino-6-chloro-4-pyrimidinyl)amino]-1-piperidinecarboxylate 4,6-dichloro-5-pyrimidinamine (3.5g) and 2-methyl- Dissolve 2-propanyl 4-amino-1-piperidinecarboxylate (6.4 g) in N,N-dimethylacetamide (hereinafter sometimes abbreviated as DMA) (18 mL), and add DIPEA (7.4 mL). In addition, the mixture was stirred at 120°C for 17 hours.
  • DMA N,N-dimethylacetamide
  • Reference example 47 2-Methyl-2-propanyl 4-(6-chloro-8-oxo-7,8-dihydro-9H-purin-9-yl)-1-piperidinecarboxylate Reference Example instead of the compound produced in Reference Example 12 Using the compound (4.4 g) prepared in 46, the same operation as in Reference Example 13 was performed to obtain the title compound (4.4 g) having the following physical properties.
  • Reference example 48 6-chloro-9-[1-(2,2-dimethylpropyl)-4-piperidinyl]-7,9-dihydro-8H-purin-8-one
  • the compound prepared in Reference Example 47 was used.
  • the same operations as in Reference Example 8 ⁇ Reference Example 9 were performed to obtain the title compound having the following physical property values.
  • Reference example 49 6-chloro-7-(4- ⁇ [9-(2,4-difluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[2, 3-b]pyridin-7-yl]carbonyl ⁇ phenyl)-9-[1-(2,2-dimethylpropyl)-4-piperidinyl]-7,9-dihydro-8H-purin-8-one
  • Reference Example 39 Using the compound produced in Reference Example 48 instead of the compound produced in Reference Example 48, the same operations as Reference Example 40 ⁇ Reference Example 41 ⁇ Reference Example 42 were performed to obtain the title compound having the following physical property values.
  • Example 21 7-(4- ⁇ [9-(2,4-difluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[2,3-b] Pyridin-7-yl]carbonyl ⁇ phenyl)-9-[1-(2,2-dimethylpropyl)-4-piperidinyl]-8-oxo-8,9-dihydro-7H-purine-6-carbonitrile 2-tri
  • the compound (20 mg) prepared in Fluoroacetate Reference Example 49 was dissolved in DMSO (0.4 mL), and N,N,N-tributyl-1-butanaminium cyanide (11 mg) and DBU (9.3 mg) were added.
  • Reference example 50 9-Benzyl-6-chloro-7,9-dihydro-8H-purin-8-one THF solution (10 mL) of 4,6-dichloro-5-pyrimidineamine (1.0 g) and (isocyanatomethyl)benzene (811 mg) ) was added potassium 2-methyl-2-butanolate (1.6 g), and the mixture was stirred at room temperature for 4 hours. The reaction solution was cooled to 0° C., 1N hydrochloric acid (54 mL) was added, and the mixture was stirred at room temperature for 10 minutes.
  • Reference example 51 6-Amino-9-benzyl-7,9-dihydro-8H-purin-8-one
  • the compound prepared in Reference Example 50 (3.9 g) was dissolved in DMF (30 mL), and sodium azide (1.9 g) was added. The mixture was stirred at 70°C for 16 hours.
  • the reaction solution was cooled to room temperature, water was added, and the mixture was extracted with dichloromethane. The obtained organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure, and the resulting residue was washed with a mixed solution of MTBE and hexane (1:4) and collected by filtration.
  • Example 22 6-Amino-9-benzyl-7-(4- ⁇ [9-(2,4-difluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5] pyrrolo[2,3-b]pyridin-7-yl]carbonyl ⁇ phenyl)-7,9-dihydro-8H-purin-8-one
  • the compound produced in Reference Example 51 was used.
  • the same operations as Reference Example 40 ⁇ Reference Example 41 ⁇ Reference Example 42 were performed to obtain the title compound having the following physical property values.
  • the reaction solution was ice-cooled, sodium hydride (60% paraffin oil suspension, 144 mg) was added, and the mixture was stirred for 30 minutes.
  • a saturated aqueous ammonium chloride solution was added to the reaction solution, stirred, and extracted with ethyl acetate.
  • the title compound (1.3 g) having the following physical properties was obtained.
  • Reference example 53 3-fluoro-4-(5,6,7,8-tetrahydro-9H-pyrido[4',3':4,5]pyrrolo[2,3-b]pyridin-9-ylmethyl)benzonitrile dihydrochloride
  • the compound (1.3 g) produced in Reference Example 52 was dissolved in methanol (2 mL), 4N hydrogen chloride/1,4-dioxane solution (7.8 mL) was added, and the mixture was stirred at room temperature for 40 minutes. The reaction solution was concentrated, washed with MTBE, and collected by filtration to obtain the title compound (1.1 g) having the following physical properties.
  • Reference example 54 2-Methyl-2-propanyl 4-[2-chloro-7-(4- ⁇ [9-(4-cyano-2-fluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[2,3-b]pyridin-7-yl]carbonyl ⁇ phenyl)-6-methyl-8-oxo-7,8-dihydro-9H-purin-9-yl]- 1-Piperidinecarboxylate
  • the compound produced in Reference Example 53 (872 mg) and the compound produced in Reference Example 6 (976 mg) were dissolved in DMF (10 mL), DIPEA (1.4 mL) and HATU (1.1 g) were added, and the mixture was heated at room temperature.
  • Reference example 55 4-[(7- ⁇ 4-[2-chloro-6-methyl-8-oxo-9-(4-piperidinyl)-8,9-dihydro-7H-purin-7-yl]benzoyl ⁇ -5,6 ,7,8-tetrahydro-9H-pyrido[4',3':4,5]pyrrolo[2,3-b]pyridin-9-yl)methyl]-3-fluorobenzonitrile dihydrochloride
  • Reference Example 54 The prepared compound (324 mg) was dissolved by adding 1,4-dioxane (0.32 mL) and 2-propanol (0.97 mL), and then 4N hydrogen chloride/1,4-dioxane solution (1.6 mL) was added and the mixture was dissolved at room temperature.
  • Reference example 56 4- ⁇ [7-(4- ⁇ 2-chloro-9-[1-(2,2-dimethylpropyl)-4-piperidinyl]-6-methyl-8-oxo-8,9-dihydro-7H-purine -7-yl ⁇ benzoyl)-5,6,7,8-tetrahydro-9H-pyrido[4',3':4,5]pyrrolo[2,3-b]pyridin-9-yl]methyl ⁇ -3 -Fluorobenzonitrile
  • the compound prepared in Reference Example 55 (280 mg) was dissolved in DMF (2.8 mL), and NEt 3 (0.16 mL) was added.
  • Example 23 1-(3- ⁇ 7-(4- ⁇ [9-(4-cyano-2-fluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5] pyrrolo[2,3-b]pyridin-7-yl]carbonyl ⁇ phenyl)-9-[1-(2,2-dimethylpropyl)-4-piperidinyl]-6-methyl-8-oxo-8,9- dihydro-7H-purin-2-yl ⁇ phenyl)cyclopropanecarboxylic acid
  • the compound (550 mg) produced in Reference Example 56 was dissolved in NMP (7.7 mL), and 1-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl ] Cyclopropanecarboxylic acid (637 mg), tripotassium phosphate aqueous solution (1.1 mL, 2 mol/L), [1,1'-bis(dip
  • Example 23-1 1-(3- ⁇ 7-(4- ⁇ [9-(4-cyano-2-fluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5] pyrrolo[2,3-b]pyridin-7-yl]carbonyl ⁇ phenyl)-9-[1-(2,2-dimethylpropyl)-4-piperidinyl]-6-methyl-8-oxo-8,9- dihydro-7H-purin-2-yl ⁇ phenyl)cyclobutanecarboxylic acid 1-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]cyclopropanecarboxylic acid The same operation as in Example 23 was carried out using 1-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]cyclobutanecarboxylic acid instead of , the title compound having the
  • Reference example 57 3-fluoro-4- ⁇ [7-(4-iodobenzoyl)-5,6,7,8-tetrahydro-9H-pyrido[4',3':4,5]pyrrolo[2,3-b]pyridine -9-yl]methyl ⁇ benzonitrile
  • the compound prepared in Reference Example 53 (1.2 g) and 4-iodobenzoic acid (960 mg) were dissolved in DMF (24 mL), and DIPEA (3.0 mL) and 4-(4,6 -Dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholin-4-ium chloride (hereinafter sometimes abbreviated as DMTMM) (2.1 g) was added and stirred at room temperature for 40 minutes.
  • DMTMM 4-(4,6 -Dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholin-4-ium chloride
  • Reference example 60 Ethyl 2-chloro-7-(4- ⁇ [9-(4-cyano-2-fluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo [2,3-b]pyridin-7-yl]carbonyl ⁇ phenyl)-9-(1- ⁇ [(2-methyl-2-propanyl)oxy]carbonyl ⁇ -4-piperidinyl)-8-oxo-8, 9-Dihydro-7H-purine-6-carboxylate
  • the compound prepared in Reference Example 59 110 mg
  • THF 1.1 mL
  • CDI 44 mg
  • DBU 31 mg
  • Reference example 61 Ethyl 2-chloro-7-(4- ⁇ [9-(4-cyano-2-fluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo [2,3-b]pyridin-7-yl]carbonyl ⁇ phenyl)-9-[1-(2,2-dimethylpropyl)-4-piperidinyl]-8-oxo-8,9-dihydro-7H-purine -6-Carboxylate Using the compound produced in Reference Example 60 instead of the compound produced in Reference Example 54, the same operations as in Reference Example 55 ⁇ Reference Example 56 were performed to obtain the title compound having the following physical property values. Ta.
  • Reference example 62 Ethyl 7-(4- ⁇ [9-(4-cyano-2-fluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[2,3 -b]pyridin-7-yl]carbonyl ⁇ phenyl)-9-[1-(2,2-dimethylpropyl)-4-piperidinyl]-8-oxo-2- ⁇ [4-(trifluoromethoxy)phenyl] amino ⁇ -8,9-dihydro-7H-purine-6-carboxylate
  • the compound prepared in Reference Example 61 (150 mg) was dissolved in DMF (1.5 mL) and toluene (1.5 mL), and further 4-(trihydro-7H-purine-6-carboxylate) was dissolved.
  • Reference example 63 7-(4- ⁇ [9-(4-cyano-2-fluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[2,3- b]pyridin-7-yl]carbonyl ⁇ phenyl)-9-[1-(2,2-dimethylpropyl)-4-piperidinyl]-8-oxo-2- ⁇ [4-(trifluoromethoxy)phenyl]amino ⁇ -8,9-dihydro-7H-purine-6-carboxylic acid
  • the compound (150 mg) prepared in Reference Example 62 was dissolved in THF (3 mL) and cooled to 0°C.
  • Example 24 7-(4- ⁇ [9-(4-cyano-2-fluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[2,3- b]pyridin-7-yl]carbonyl ⁇ phenyl)-9-[1-(2,2-dimethylpropyl)-4-piperidinyl]-N-hydroxy-8-oxo-2- ⁇ [4-(trifluoromethoxy) ) phenyl]amino ⁇ -8,9-dihydro-7H-purine-6-carboxamide 2 trifluoroacetate
  • the compound prepared in Reference Example 63 25 mg was dissolved in DMF (0.5 mL), and mixed with DIPEA (0.023 mL).
  • Reference example 65 2-Methyl-2-propanyl (3S)-3-[(2-chloro-5- ⁇ [4-(methoxycarbonyl)phenyl]amino ⁇ -4-pyrimidinyl)amino]-1-pyrrolidinecarboxylate
  • the prepared compound (5.4 g) and methyl 4-iodobenzoate (5.4 g) were dissolved in dehydrated DME (50 mL).
  • Cesium carbonate (11.1 g), Xantphos (1.2 g), and Pd 2 (dba) 3 (937 mg) were added to the solution. After purging the inside of the reaction vessel with nitrogen, the mixture was stirred at 80°C overnight.
  • reaction solution was cooled to room temperature and passed through an injection column Amino (trade name) to remove insoluble matter.
  • Reference example 66 2-Methyl-2-propanyl (3S)-3- ⁇ 2-chloro-7-[4-(methoxycarbonyl)phenyl]-8-oxo-7,8-dihydro-9H-purin-9-yl ⁇ -1 -Pyrrolidine carboxylate
  • the compound prepared in Reference Example 65 (5.2 g) was dissolved in THF (52 mL), CDI (3.8 g) and DBU (1.7 mL) were added, and the mixture was stirred at room temperature for 1 hour. Saturated ammonium chloride water was added to the reaction mixture, and the mixture was diluted with ethyl acetate.
  • Reference example 67 4- ⁇ 2-chloro-9-[(3S)-1- ⁇ [(2-methyl-2-propanyl)oxy]carbonyl ⁇ -3-pyrrolidinyl]-8-oxo-8,9-dihydro-7H-purine -7-yl ⁇ benzoic acid Using the compound produced in Reference Example 66 (400 mg) instead of the compound produced in Reference Example 5, the same operation as in Reference Example 6 was carried out to obtain the title compound ( 420 mg) was obtained.
  • Reference example 68 2-Methyl-2-propanyl (3S)-3-[2-chloro-7-(4- ⁇ [9-(4-cyano-2-fluorobenzyl)-5,6,8,9-tetrahydro-7H- Pyrido[4',3':4,5]pyrrolo[2,3-b]pyridin-7-yl]carbonyl ⁇ phenyl)-8-oxo-7,8-dihydro-9H-purin-9-yl]- 1-pyrrolidinecarboxylate Using the compound produced in Reference Example 67 instead of the compound produced in Reference Example 6, the same operation as in Reference Example 54 was carried out to obtain the title compound having the following physical property values.
  • Reference example 70 3-fluoro-4-( ⁇ 7-[4-(8-oxo-9-[(3S)-3-pyrrolidinyl]-2- ⁇ [4-(trifluoromethoxy)phenyl]amino ⁇ -8,9- dihydro-7H-purin-7-yl)benzoyl]-5,6,7,8-tetrahydro-9H-pyrido[4',3':4,5]pyrrolo[2,3-b]pyridin-9-yl ⁇ Methyl)benzonitrile
  • the compound prepared in Reference Example 69 (356 mg) was dissolved in methanol (4.0 mL), 4N hydrogen chloride/1,4-dioxane solution (1.0 mL) was added, and the mixture was stirred at room temperature for 4 hours.
  • Example 25 3-Fluoro-4-( ⁇ 7-[4-(9-[(3S)-1-(methylsulfonyl)-3-pyrrolidinyl]-8-oxo-2- ⁇ [4-(trifluoromethoxy)phenyl] amino ⁇ -8,9-dihydro-7H-purin-7-yl)benzoyl]-5,6,7,8-tetrahydro-9H-pyrido[4',3':4,5]pyrrolo[2,3- b] Pyridin-9-yl ⁇ methyl)benzonitrile trifluoroacetate
  • the compound prepared in Reference Example 70 (15 mg) was dissolved in DMF (0.15 mL), and DIPEA (0.010 mL) and methanesulfonic anhydride (4.0 mg) were dissolved.
  • Example 26 3-Fluoro-4-( ⁇ 7-[4-(8-oxo-9-[(3S)-1-(3,3,3-trifluoro-2,2-dimethylpropyl)-3-pyrrolidinyl]- 2- ⁇ [4-(trifluoromethoxy)phenyl]amino ⁇ -8,9-dihydro-7H-purin-7-yl)benzoyl]-5,6,7,8-tetrahydro-9H-pyrido[4', 3':4,5]pyrrolo[2,3-b]pyridin-9-yl ⁇ methyl)benzonitrile 2-trifluoroacetate
  • the compound prepared in Reference Example 70 (15 mg) was dissolved in DMF (0.15 mL), 3,3,3-trifluoro-2,2-dimethylpropyl trifluoromethanesulfonate (26 mg) and DIPEA (0.033 mL) were added, and the mixture was stirred at 60°C for 17 hours.
  • the reaction solution was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate.
  • the residue obtained by concentrating the organic layer was purified using a reverse phase HPLC column to obtain the title compound (4.9 mg) having the following physical properties.
  • the reaction solution was ice-cooled, sodium hydride (60% paraffin oil suspension, 878 mg) was added, and the mixture was stirred for 1 hour.
  • a saturated aqueous ammonium chloride solution was added to the reaction solution, stirred, and extracted with ethyl acetate.
  • the title compound (6.9 g) having the following physical properties was obtained.
  • Reference example 72 9-(4-chloro-2-fluorobenzyl)-6,7,8,9-tetrahydro-5H-pyrido[4',3':4,5]pyrrolo[2,3-b]pyridine dihydrochloride reference
  • the compound prepared in Example 71 (6.9 g) was dissolved in methanol (20 mL), 4N hydrogen chloride/1,4-dioxane solution (42 mL) was added, and the mixture was stirred at room temperature for 1 hour.
  • the reaction solution was concentrated, azeotropically distilled with toluene, and filtered using MTBE to obtain the title compound (6.6 g) having the following physical properties.
  • Reference example 73 2-Methyl-2-propanyl 4-[2-chloro-7-(4- ⁇ [9-(4-chloro-2-fluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[2,3-b]pyridin-7-yl]carbonyl ⁇ phenyl)-6-methyl-8-oxo-7,8-dihydro-9H-purin-9-yl]- 1-Piperidinecarboxylate Using the compound produced in Reference Example 72 (1.1 g) instead of the compound produced in Reference Example 2, the same operation as in Reference Example 7 was carried out to obtain the title compound (1.9 g) was obtained. LC-MS (A) retention time (min): 1.30; MS(ESI, Pos.): 785 (M + H) + .
  • Reference example 74 2-chloro-7-(4- ⁇ [9-(4-chloro-2-fluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[ 2,3-b]pyridin-7-yl]carbonyl ⁇ phenyl)-9-[1-(2,2-dimethylpropyl)-4-piperidinyl]-6-methyl-7,9-dihydro-8H-purine- 8-one Using the compound produced in Reference Example 73 instead of the compound produced in Reference Example 54, the same operation as in Reference Example 55 ⁇ Reference Example 56 was performed to obtain the title compound having the following physical property values.
  • Example 27 7-(4- ⁇ [9-(4-chloro-2-fluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[2,3- b]Pyridin-7-yl]carbonyl ⁇ phenyl)-2- ⁇ [4-(difluoromethoxy)phenyl]amino ⁇ -9-[1-(2,2-dimethylpropyl)-4-piperidinyl]-6-methyl -7,9-dihydro-8H-purin-8-one
  • the same operation as in Example 1 was carried out using the compound produced in Reference Example 74 instead of the compound produced in Reference Example 9, and 4-(difluoromethoxy)aniline was used instead of aniline, and the compound had the following physical property values.
  • Example 27-1 7-(4- ⁇ [9-(4-chloro-2-fluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[2,3- b]pyridin-7-yl]carbonyl ⁇ phenyl)-9-[1-(2,2-dimethylpropyl)-4-piperidinyl]-2-[(3-fluorophenyl)amino]-6-methyl-7, 9-dihydro-8H-purin-8-one
  • the same operation as in Example 27 was carried out using 3-fluoroaniline instead of 4-(difluoromethoxy)aniline to obtain the title compound having the following physical properties.
  • Example 28 7-(4- ⁇ [9-(4-chloro-2-fluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[2,3- b]pyridin-7-yl]carbonyl ⁇ phenyl)-2-[(cyclopentylmethyl)(2-hydroxy-2-methylpropyl)amino]-9-[1-(2,2-dimethylpropyl)-4-piperidinyl ]-6-Methyl-7,9-dihydro-8H-purin-8-one 2 trifluoroacetate
  • the compound prepared in Reference Example 74 50 mg
  • 1-[(cyclopentylmethyl)amino]-2-methyl-2 - Dissolve propanol (57 mg) in DMSO (0.5 mL), add DIPEA (0.057 mL) and cesium fluoride (50 mg), and use a microwave device at 100 °C for 30 minutes and at 120 °C for
  • Example 28-1 7-(4- ⁇ [9-(4-chloro-2-fluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[2,3- b]pyridin-7-yl]carbonyl ⁇ phenyl)-2-(cyclohexylamino)-9-[1-(2,2-dimethylpropyl)-4-piperidinyl]-6-methyl-7,9-dihydro-8H -Purin-8-one 2 trifluoroacetate 1-[(cyclopentylmethyl)amino]-2-methyl-2-propanol was replaced by cyclohexylamine, and the same operation as in Example 28 was carried out, and the following physical properties were obtained.
  • Reference example 75 1-( ⁇ 4-[2-chloro-7-(4- ⁇ [9-(4-chloro-2-fluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3' :4,5]pyrrolo[2,3-b]pyridin-7-yl]carbonyl ⁇ phenyl)-6-methyl-8-oxo-7,8-dihydro-9H-purin-9-yl]-1-piperidinyl ⁇ Carbonyl)cyclopropanecarbonitrile
  • the compound (1.9 g) produced in Reference Example 73 was suspended in methanol (19 mL), 4N hydrogen chloride/1,4-dioxane solution (6.0 mL) was added, and the mixture was stirred at room temperature for 3 hours.
  • Example 29 1-[(4- ⁇ 7-(4- ⁇ [9-(4-chloro-2-fluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5 ]pyrrolo[2,3-b]pyridin-7-yl]carbonyl ⁇ phenyl)-2-[(3-fluorophenyl)amino]-6-methyl-8-oxo-7,8-dihydro-9H-purine- 9-yl ⁇ -1-piperidinyl)carbonyl]cyclopropanecarbonitrile
  • the compound produced in Reference Example 75 was substituted for the compound produced in Reference Example 9, and 3-fluoroaniline was used in place of aniline.
  • Reference example 77 9-[2-fluoro-4-(trifluoromethyl)benzyl]-6,7,8,9-tetrahydro-5H-pyrido[4',3':4,5]pyrrolo[2,3-b]pyridine
  • the same operation as in Reference Example 2 was performed using the compound produced in Reference Example 76 instead of the compound produced in Dihydrochloride Reference Example 1 to obtain the title compound having the following physical properties.
  • Reference example 79 Methyl 4- ⁇ 2-chloro-8-oxo-9-[(3S)-1- ⁇ [1-(trifluoromethyl)cyclopropyl]methyl ⁇ -3-pyrrolidinyl]-8,9-dihydro-7H-purine -7-yl ⁇ benzoate
  • the compound prepared in Reference Example 78 (700 mg) was dissolved in DMA (17 mL), and 1-(bromomethyl)-1-(trifluoromethyl)cyclopropane (692 mg) and DIPEA (1.5 mL) were dissolved. , potassium iodide (283 mg) was added, and the mixture was stirred at 50°C overnight.
  • Reference example 80 Methyl 4-(8-oxo-2- ⁇ [4-(trifluoromethoxy)phenyl]amino ⁇ -9-[(3S)-1- ⁇ [1-(trifluoromethyl)cyclopropyl]methyl ⁇ -3- pyrrolidinyl]-8,9-dihydro-7H-purin-7-yl)benzoate
  • the same operation as in Reference Example 62 was performed using the compound produced in Reference Example 79 instead of the compound produced in Reference Example 61, The title compound having the following physical properties was obtained.
  • Reference example 81 4-(8-oxo-2- ⁇ [4-(trifluoromethoxy)phenyl]amino ⁇ -9-[(3S)-1- ⁇ [1-(trifluoromethyl)cyclopropyl]methyl ⁇ -3-pyrrolidinyl ]-8,9-dihydro-7H-purin-7-yl)benzoic acid
  • Reference Example 80 instead of the compound produced in Reference Example 35, the same operation as in Reference Example 36 was carried out, and the following The title compound having the physical property values was obtained.
  • Example 30 7-[4-( ⁇ 9-[2-fluoro-4-(trifluoromethyl)benzyl]-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[ 2,3-b]pyridin-7-yl ⁇ carbonyl)phenyl]-2- ⁇ [4-(trifluoromethoxy)phenyl]amino ⁇ -9-[(3S)-1- ⁇ [1-(trifluoromethyl ) cyclopropyl]methyl ⁇ -3-pyrrolidinyl]-7,9-dihydro-8H-purin-8-one 2 trifluoroacetate
  • the compound produced in Reference Example 77 was used as a reference.
  • Reference example 84 2-Methyl-2-propanyl 3- ⁇ 2-chloro-7-[4-(methoxycarbonyl)phenyl]-8-oxo-7,8-dihydro-9H-purin-9-yl ⁇ -1-piperidinecarboxylate Using 2-methyl-2-propanyl 3-amino-1-piperidinecarboxylate in place of 2-methyl-2-propanyl (3S)-3-amino-1-pyrrolidinecarboxylate used in Reference Example 64, reference The same operation as Example 64 ⁇ Reference Example 65 ⁇ Reference Example 66 was performed to obtain the title compound having the following physical property values.
  • Example 31 2-anilino-9-[1-(2,2-dimethylpropyl)-3-piperidinyl]-7- ⁇ 4-[(9- ⁇ [1-methyl-5-(trifluoromethyl)-1H-pyrazole- 3-yl]methyl ⁇ -5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[2,3-b]pyridin-7-yl)carbonyl]phenyl ⁇ - 7,9-dihydro-8H-purin-8-one
  • the compound produced in Reference Example 84 was used in place of the compound produced in Reference Example 5 used in Reference Example 6, and the compound produced in Reference Example 2 used in Reference Example 7 was used.
  • Reference example 86 9-(2-pentyn-1-yl)-6,7,8,9-tetrahydro-5H-pyrido[4',3':4,5]pyrrolo[2,3-b]pyridine dihydrochloride reference example
  • the same operation as in Reference Example 2 was carried out using the compound produced in Reference Example 85 instead of the compound produced in 1, to obtain the title compound having the following physical property values.
  • TLC: Rf 0.10 (petroleum ether: ethyl acetate 4:1).
  • Example 32 2-anilino-9-[(3S)-1-(2,2-dimethylpropyl)-3-piperidinyl]-7-(4- ⁇ [9-(2-pentyn-1-yl)-5,6, 8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[2,3-b]pyridin-7-yl]carbonyl ⁇ phenyl)-7,9-dihydro-8H-purine-8 -one 1 formate
  • the compound produced in Reference Example 87 was used in place of the compound produced in Reference Example 5 used in Reference Example 6, and the compound produced in Reference Example 86 was used in place of the compound produced in Reference Example 2 used in Reference Example 7.
  • Reference example 89 2-chloro-9-[1-(2,2-dimethylpropyl)-4-piperidinyl]-7-[4-(5,6,8,9-tetrahydro-7H-pyrido[4',3':4 ,5]pyrrolo[2,3-b]pyridin-7-ylcarbonyl)phenyl]-7,9-dihydro-8H-purin-8-one produced in Reference Example 88 instead of the compound produced in Reference Example 7 Using the compound, the same operations as in Reference Example 8 ⁇ Reference Example 9 were performed to obtain the title compound having the following physical property values.
  • Reference example 90 2-chloro-7-[4-( ⁇ 9-[4-(difluoromethoxy)benzyl]-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[2 ,3-b]pyridin-7-yl ⁇ carbonyl)phenyl]-9-[1-(2,2-dimethylpropyl)-4-piperidinyl]-7,9-dihydro-8H-purin-8-one
  • the compound prepared in step 89 (30 mg) was dissolved in DMF (0.6 mL), and 1-(bromomethyl)-4-(difluoromethoxy)benzene (12 mg) and sodium hydride (60% paraffin oil suspension, 2.0 mg) were added.
  • Example 33 7-[4-( ⁇ 9-[4-(difluoromethoxy)benzyl]-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[2,3-b ]pyridin-7-yl ⁇ carbonyl)phenyl]-9-[1-(2,2-dimethylpropyl)-4-piperidinyl]-2-[(2-fluorophenyl)amino]-7,9-dihydro-8H -Purin-8-one 2-trifluoroacetate
  • the same reaction procedure as in Example 1 was carried out using the compound produced in Reference Example 90 instead of the compound produced in Reference Example 9 and 2-fluoroaniline in place of aniline.
  • the reaction solution was ice-cooled, sodium hydride (60% paraffin oil suspension, 1.1 g) was added, and the mixture was stirred for 1 hour.
  • a saturated aqueous ammonium chloride solution was added to the reaction solution, stirred, and extracted with ethyl acetate.
  • the obtained organic layer was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • Reference example 92 9-(2-fluoro-4-methylbenzyl)-6,7,8,9-tetrahydro-5H-pyrido[4',3':4,5]pyrrolo[2,3-b]pyridine dihydrochloride reference
  • the compound prepared in Example 91 (8.2 g) was dissolved in methanol (25 mL), 4N hydrogen chloride/1,4-dioxane solution (52 mL) was added at 0° C., and the mixture was stirred at room temperature for 4 hours.
  • the reaction solution was diluted with MTBE and the precipitate was collected by filtration to obtain the title compound (6.2 g) having the following physical properties.
  • Reference example 93 Methyl 5-( ⁇ 2-chloro-4-methyl-6-[(1- ⁇ [(2-methyl-2-propanyl)oxy]carbonyl ⁇ -4-piperidinyl)amino]-5-pyrimidinyl ⁇ amino)-2 -Pyridinecarboxylate
  • the compound prepared in Reference Example 3 (1.0g) and methyl 5-bromopyridinecarboxylic acid (1.3g) were dissolved in dehydrated DME (29mL), and cesium carbonate (1.9g) and Xantphos (339mg) were dissolved. , Pd 2 (dba) 3 (268 mg) was added. After purging the inside of the reaction vessel with nitrogen, the mixture was stirred at 80°C for 4 hours.
  • Reference example 94 Methyl 5-[2-chloro-6-methyl-9-(1- ⁇ [(2-methyl-2-propanyl)oxy]carbonyl ⁇ -4-piperidinyl)-8-oxo-8,9-dihydro-7H- Purin-7-yl]-2-pyridinecarboxylate
  • the compound prepared in Reference Example 93 (3.3 g) was dissolved in THF (33 mL), CDI (2.2 g) and DBU (1.0 mL) were added, and the mixture was stirred at room temperature for 1 hour. Stirred. The reaction solution was diluted with ethyl acetate and washed with water and 1N hydrochloric acid.
  • Reference example 95 5-[2-chloro-6-methyl-9-(1- ⁇ [(2-methyl-2-propanyl)oxy]carbonyl ⁇ -4-piperidinyl)-8-oxo-8,9-dihydro-7H-purine -7-yl]-2-pyridinecarboxylic acid
  • THF 227 mL
  • TMSOK 2.9 g
  • 2N hydrochloric acid was added to the reaction mixture, extracted with ethyl acetate, and the resulting organic layer was washed with saturated brine.
  • Reference example 96 5-[6-methyl-9-(1- ⁇ [(2-methyl-2-propanyl)oxy]carbonyl ⁇ -4-piperidinyl)-8-oxo-2- ⁇ [4-(trifluoromethoxy)phenyl] amino ⁇ -8,9-dihydro-7H-purin-7-yl]-2-pyridinecarboxylic acid DMF (5.4 mL) and toluene (5.4 mL) were added to the compound (540 mg) prepared in Reference Example 95 and dissolved. , 4-(trifluoromethoxy)aniline (490 mg), cesium carbonate (1.1 g), Xantphos (130 mg), and palladium acetate (25 mg) were added, and the mixture was stirred at 120° C.
  • Reference example 98 7-(6- ⁇ [9-(2-fluoro-4-methylbenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[2,3- b] Pyridin-7-yl]carbonyl ⁇ -3-pyridinyl)-6-methyl-9-(4-piperidinyl)-2- ⁇ [4-(trifluoromethoxy)phenyl]amino ⁇ -7,9-dihydro- 8H-purin-8-one dihydrochloride Methanol (8.7 mL) was added to the compound prepared in Reference Example 97 (4.4 g), and then a 4N hydrogen chloride/1,4-dioxane solution (18 mL) was added at 0°C.
  • Example 34 9-[1-(2,2-dimethylpropyl)-4-piperidinyl]-7-(6- ⁇ [9-(2-fluoro-4-methylbenzyl)-5,6,8,9-tetrahydro-7H -pyrido[4',3':4,5]pyrrolo[2,3-b]pyridin-7-yl]carbonyl ⁇ -3-pyridinyl)-6-methyl-2- ⁇ [4-(trifluoromethoxy) phenyl]amino ⁇ -7,9-dihydro-8H-purin-8-one
  • the compound prepared in Reference Example 98 (30 mg) was dissolved in DMF (0.6 mL), and NEt 3 (0.024 mL) was added.
  • Example 34-1 7-(6- ⁇ [9-(2-fluoro-4-methylbenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[2,3- b]pyridin-7-yl]carbonyl ⁇ -3-pyridinyl)-6-methyl-2- ⁇ [4-(trifluoromethoxy)phenyl]amino ⁇ -9-[1-(3,3,3-trifluoro Propyl)-4-piperidinyl]-7,9-dihydro-8H-purin-8-one 2 trifluoroacetate Same as Example 34, using 3,3,3-trifluoropropanal in place of pivalaldehyde.
  • Reference example 99 2-Methyl-2-propanyl 4-[2-chloro-7-(6- ⁇ [9-(4-cyano-2-fluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[2,3-b]pyridin-7-yl]carbonyl ⁇ -3-pyridinyl)-6-methyl-8-oxo-7,8-dihydro-9H-purine-9- ]-1-piperidinecarboxylate
  • the compound produced in Reference Example 95 (196 mg) and the compound produced in Reference Example 53 (159 mg) were dissolved in DMF (2.0 mL), and DIPEA (0.27 mL) and HATU (228 mg) were dissolved.
  • Reference example 100 4- ⁇ [7-( ⁇ 5-[2-chloro-6-methyl-8-oxo-9-(4-piperidinyl)-8,9-dihydro-7H-purin-7-yl]-2-pyridinyl ⁇ carbonyl)-5,6,7,8-tetrahydro-9H-pyrido[4',3':4,5]pyrrolo[2,3-b]pyridin-9-yl]methyl ⁇ -3-fluorobenzonitrile 2 1,4-dioxane (10 mL) was added to the compound (2.6 g) prepared in Hydrochloride Reference Example 99, and a 4N hydrogen chloride/1,4-dioxane solution (11 mL) was added, followed by stirring at room temperature for 2 hours.
  • Reference example 101 4-( ⁇ 7-[(5- ⁇ 2-chloro-9-[1-(2,2-dimethylpropyl)-4-piperidinyl]-6-methyl-8-oxo-8,9-dihydro-7H- purin-7-yl ⁇ -2-pyridinyl)carbonyl]-5,6,7,8-tetrahydro-9H-pyrido[4',3':4,5]pyrrolo[2,3-b]pyridine-9- yl ⁇ methyl)-3-fluorobenzonitrile
  • the compound prepared in Reference Example 100 (3.1 g) was dissolved in DMF (26 mL), and NEt 3 (1.3 mL) was added.
  • Example 35 4-[(7- ⁇ [5-(9-[1-(2,2-dimethylpropyl)-4-piperidinyl]-6-methyl-8-oxo-2- ⁇ [4-(trifluoromethoxy)phenyl ]Amino ⁇ -8,9-dihydro-7H-purin-7-yl)-2-pyridinyl]carbonyl ⁇ -5,6,7,8-tetrahydro-9H-pyrido[4',3':4,5] Pyrrolo[2,3-b]pyridin-9-yl)methyl]-3-fluorobenzonitrile
  • DMF 1.0 mL
  • toluene 1.0 mL
  • Example 35-1 3-Fluoro-4-( ⁇ 7-[(5- ⁇ 2-[(3-fluorophenyl)amino]-6-methyl-8-oxo-9-(1- ⁇ [1-(trifluoromethyl)cyclo propyl]methyl ⁇ -4-piperidinyl)-8,9-dihydro-7H-purin-7-yl ⁇ -2-pyridinyl)carbonyl]-5,6,7,8-tetrahydro-9H-pyrido[4',3 ':4,5]pyrrolo[2,3-b]pyridin-9-yl ⁇ methyl)benzonitrile
  • 1-(trifluoromethyl)cyclopropanecarbaldehyde was used in place of pivalaldehyde used in Reference Example 101, and 3-trifluoroaniline was used in place of 4-(trifluoromethoxy)aniline used in Example 35.
  • Example 101 The same operation as in Example 35 was performed to obtain the title compound having the following physical property values.
  • Example 35-2 to 9 Using the corresponding aniline compound instead of 4-(trifluoromethoxy)aniline, the same operation as in Example 35 was carried out, and by purifying with a silica gel column or reverse phase HPLC column, or by adding hydrochloric acid after silica gel purification. By concentrating the mixture, the title compound having the following physical properties was obtained.
  • Example 35-2 4-[(7- ⁇ [5-(9-[1-(2,2-dimethylpropyl)-4-piperidinyl]-2- ⁇ [3,5-dimethyl-1-(2,2,2-tri- fluoroethyl)-1H-pyrazol-4-yl]amino ⁇ -6-methyl-8-oxo-8,9-dihydro-7H-purin-7-yl)-2-pyridinyl]carbonyl ⁇ -5,6,7 ,8-tetrahydro-9H-pyrido[4',3':4,5]pyrrolo[2,3-b]pyridin-9-yl)methyl]-3-fluorobenzonitrile
  • LC-MS A) retention time (min): 0.98; MS(ESI, Pos.): 904 (M + H) + ; 1 H-NMR (CDCl 3 ): ⁇ 0.86-0.92, 1.61-1.67, 1.97-2.04, 2.09, 2.19, 2.24, 2.29-2.41,
  • Example 35-3 4-[(7- ⁇ [5-(9-[1-(2,2-dimethylpropyl)-4-piperidinyl]-6-methyl-8-oxo-2- ⁇ [5-(trifluoromethoxy)- 2-pyridinyl]amino ⁇ -8,9-dihydro-7H-purin-7-yl)-2-pyridinyl]carbonyl ⁇ -5,6,7,8-tetrahydro-9H-pyrido[4',3':4 ,5]pyrrolo[2,3-b]pyridin-9-yl)methyl]-3-fluorobenzonitrile trihydrochloride LC-MS (A) retention time (min): 1.04; MS(ESI, Pos.): 889 (M + H) + ; 1 H-NMR (DMSO-d 6 ): ⁇ 1.22, 2.12-2.21, 2.94-3.05, 3.11-3.27, 3.29-3.36, 3.38-3.62, 3.76-3.83,
  • Example 35-4 4-( ⁇ 7-[(5- ⁇ 2-[(2,3-dimethyl-1H-indol-5-yl)amino]-9-[1-(2,2-dimethylpropyl)-4-piperidinyl] -6-methyl-8-oxo-8,9-dihydro-7H-purin-7-yl ⁇ -2-pyridinyl)carbonyl]-5,6,7,8-tetrahydro-9H-pyrido[4',3' :4,5]pyrrolo[2,3-b]pyridin-9-yl ⁇ methyl)-3-fluorobenzonitrile 2 trifluoroacetate LC-MS (A) retention time (min): 1.11; MS(ESI, Pos.): 871 (M + H) + ; 1 H-NMR (DMSO-d 6 ): ⁇ 0.76-1.13, 1.87-2.21, 2.24-2.34, 2.79-3.11, 3.17-3.33, 3.63-3.84, 4.00-4.
  • Example 35-5 4-[(7- ⁇ [5-(9-[1-(2,2-dimethylpropyl)-4-piperidinyl]-2- ⁇ [2-fluoro-4-(tetrahydro-2H-pyran-4-yl) ) phenyl]amino ⁇ -6-methyl-8-oxo-8,9-dihydro-7H-purin-7-yl)-2-pyridinyl]carbonyl ⁇ -5,6,7,8-tetrahydro-9H-pyrido[ 4',3':4,5]pyrrolo[2,3-b]pyridin-9-yl)methyl]-3-fluorobenzonitrile
  • LC-MS A) retention time (min): 1.08; MS(ESI, Pos.): 906 (M + H) + ; 1 H-NMR (CDCl 3 ): ⁇ 0.97, 1.72-1.84, 2.05-2.13, 2.15, 2.45, 2.67-2.88, 2.93-3.05, 3.46-3.59
  • Example 35-6 4-[(7- ⁇ [5-(9-[1-(2,2-dimethylpropyl)-4-piperidinyl]-6-methyl-2- ⁇ [2-methyl-4-(trifluoromethoxy)phenyl ]Amino ⁇ -8-oxo-8,9-dihydro-7H-purin-7-yl)-2-pyridinyl]carbonyl ⁇ -5,6,7,8-tetrahydro-9H-pyrido[4',3': 4,5]pyrrolo[2,3-b]pyridin-9-yl)methyl]-3-fluorobenzonitrile
  • LC-MS A) retention time (min): 1.16; MS(ESI, Pos.): 902 (M + H) + ; 1 H-NMR (CDCl 3 ): ⁇ 0.93, 1.68-1.81, 2.04-2.14, 2.37-2.47, 2.69-2.81, 2.93-3.03, 3.92-4.19, 4.27-4.42, 4.90, 5.38-5
  • Example 35-7 4-[(7- ⁇ [5-(2- ⁇ [2-chloro-4-(trifluoromethoxy)phenyl]amino ⁇ -9-[1-(2,2-dimethylpropyl)-4-piperidinyl]- 6-Methyl-8-oxo-8,9-dihydro-7H-purin-7-yl)-2-pyridinyl]carbonyl ⁇ -5,6,7,8-tetrahydro-9H-pyrido[4',3': 4,5]pyrrolo[2,3-b]pyridin-9-yl)methyl]-3-fluorobenzonitrile
  • LC-MS A) retention time (min): 1.18; MS(ESI, Pos.): 922 (M + H) + ; 1 H-NMR (CDCl 3 ): ⁇ 0.95, 1.71-1.83, 2.05-2.18, 2.41-2.51, 2.72-2.85, 2.99, 3.90-4.22, 4.33-4.45, 4.85-4.
  • Example 35-8 4-[(7- ⁇ [5-(9-[1-(2,2-dimethylpropyl)-4-piperidinyl]-6-methyl-8-oxo-2- ⁇ [4-(trifluoromethoxy)- 2-(trifluoromethyl)phenyl]amino ⁇ -8,9-dihydro-7H-purin-7-yl)-2-pyridinyl]carbonyl ⁇ -5,6,7,8-tetrahydro-9H-pyrido[4',3':4,5]pyrrolo[2,3-b]pyridin-9-yl)methyl]-3-fluorobenzonitrile
  • LC-MS A) retention time (min): 1.19; MS(ESI, Pos.): 956 (M + H) + ; 1 H-NMR (CDCl 3 ): ⁇ 0.93, 1.71-1.80, 2.05-2.14, 2.41-2.49, 2.67-2.79, 2.93-3.02, 3.90-4.22, 4.29-4.44
  • Example 35-9 1-[3-chloro-4-( ⁇ 7-(6- ⁇ [9-(4-cyano-2-fluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3' :4,5]pyrrolo[2,3-b]pyridin-7-yl]carbonyl ⁇ -3-pyridinyl)-9-[1-(2,2-dimethylpropyl)-4-piperidinyl]-6-methyl- 8-oxo-8,9-dihydro-7H-purin-2-yl ⁇ amino)phenyl]cyclopropanecarboxylic acid LC-MS (A) retention time (min): 1.08; MS(ESI, Pos.): 922 (M + H) + ; 1 H-NMR (CDCl 3 ): ⁇ 0.95, 1.23-1.31, 1.64-1.71, 1.71-1.81, 2.05-2.13, 2.16, 2.41-2.53, 2.73-2.87, 2.95-3.
  • Example 36 ( ⁇ 7-(6- ⁇ [9-(4-cyano-2-fluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[2, 3-b]pyridin-7-yl]carbonyl ⁇ -3-pyridinyl)-9-[1-(2,2-dimethylpropyl)-4-piperidinyl]-6-methyl-8-oxo-8,9-dihydro -7H-purin-2-yl ⁇ [4-(trifluoromethoxy)phenyl]amino)acetic acid
  • To the compound (50 mg) prepared in Reference Example 101 was added toluene (1.0 mL), and ethyl ⁇ [4-(trifluoro methoxy)phenyl]amino ⁇ acetate (44 mg), cesium carbonate (87 mg), Xantphos (7.7 mg), and palladium acetate (1.5 mg) were added, and the mixture was stirred at
  • Example 37 2-(3- ⁇ 7-(6- ⁇ [9-(4-cyano-2-fluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5] pyrrolo[2,3-b]pyridin-7-yl]carbonyl ⁇ -3-pyridinyl)-9-[1-(2,2-dimethylpropyl)-4-piperidinyl]-6-methyl-8-oxo-8 ,9-dihydro-7H-purin-2-yl ⁇ phenyl)-2-methylpropanoic acid
  • the compound (50 mg) produced in Reference Example 101 was dissolved in NMP (0.5 mL), and 2-methyl-2-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2) was dissolved in NMP (0.5 mL).
  • Examples 37-1 to 17 Using the corresponding boronic acid compound in place of 2-methyl-2-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propanecarboxylic acid, The same operation as in Example 37 was performed, and the title compound having the following physical property values was obtained by purifying with a silica gel column or a reverse phase HPLC column.
  • Example 37-1 4-( ⁇ 7-[(5- ⁇ 9-[1-(2,2-dimethylpropyl)-4-piperidinyl]-2-[2-methoxy-5-(trifluoromethoxy)phenyl]-6-methyl -8-oxo-8,9-dihydro-7H-purin-7-yl ⁇ -2-pyridinyl)carbonyl]-5,6,7,8-tetrahydro-9H-pyrido[4',3':4,5 ]pyrrolo[2,3-b]pyridin-9-yl ⁇ methyl)-3-fluorobenzonitrile 2-trifluoroacetate LC-MS (A) retention time (min): 1.14; MS(ESI, Pos.): 903 (M + H) + ; 1 H-NMR (DMSO-d 6 ): ⁇ 0.94-1.12, 1.87-2.19, 2.85-3.06, 3.10-3.24, 3.46-3.58, 3.63-3.87, 4.00-4.10,
  • Example 37-2 4-( ⁇ 7-[(5- ⁇ 2-(2,3-dihydro-1H-inden-4-yl)-9-[1-(2,2-dimethylpropyl)-4-piperidinyl]-6- Methyl-8-oxo-8,9-dihydro-7H-purin-7-yl ⁇ -2-pyridinyl)carbonyl]-5,6,7,8-tetrahydro-9H-pyrido[4',3':4, 5] Pyrrolo[2,3-b]pyridin-9-yl ⁇ methyl)-3-fluorobenzonitrile 2 trifluoroacetate LC-MS (A) retention time (min): 1.08; MS(ESI, Pos.): 829 (M + H) + ; 1 H-NMR (DMSO-d 6 ): ⁇ 1.04-1.14, 1.98-2.22, 2.86-3.15, 3.49-3.60, 3.67-3.82, 4.02-4.10, 4.96, 5.34-5.
  • Example 37-3 4-( ⁇ 7-[(5- ⁇ 9-[1-(2,2-dimethylpropyl)-4-piperidinyl]-6-methyl-2-[2-methyl-4-(trifluoromethoxy)phenyl] -8-oxo-8,9-dihydro-7H-purin-7-yl ⁇ -2-pyridinyl)carbonyl]-5,6,7,8-tetrahydro-9H-pyrido[4',3':4,5 ]pyrrolo[2,3-b]pyridin-9-yl ⁇ methyl)-3-fluorobenzonitrile
  • LC-MS A) retention time (min): 1.19; MS(ESI, Pos.): 887 (M + H) + ; 1 H-NMR (CDCl 3 ): ⁇ 0.90, 1.70-1.83, 2.13, 2.21-2.27, 2.42-2.51, 2.70-2.73, 2.78-2.91, 2.93-3.05, 3.92-4.24, 4.39-4.56, 4.87
  • Example 37-4 4-( ⁇ 7-[(5- ⁇ 9-[1-(2,2-dimethylpropyl)-4-piperidinyl]-2-[4-(1-hydroxycyclobutyl)phenyl]-6-methyl-8 -oxo-8,9-dihydro-7H-purin-7-yl ⁇ -2-pyridinyl)carbonyl]-5,6,7,8-tetrahydro-9H-pyrido[4',3':4,5]pyrrolo [2,3-b]pyridin-9-yl ⁇ methyl)-3-fluorobenzonitrile
  • LC-MS A) retention time (min): 1.06; MS(ESI, Pos.): 859 (M + H) + ; 1 H-NMR (CDCl 3 ): ⁇ 0.92-0.98, 1.70-1.83, 2.00-2.11, 2.18-2.27, 2.39-2.66, 2.83-3.06, 3.90-4.21, 4.45-4.57, 4.91, 5.40-5.64
  • Example 37-5 4-( ⁇ 7-[(5- ⁇ 9-[1-(2,2-dimethylpropyl)-4-piperidinyl]-2-[4-fluoro-2-(trifluoromethoxy)phenyl]-6-methyl -8-oxo-8,9-dihydro-7H-purin-7-yl ⁇ -2-pyridinyl)carbonyl]-5,6,7,8-tetrahydro-9H-pyrido[4',3':4,5 ]pyrrolo[2,3-b]pyridin-9-yl ⁇ methyl)-3-fluorobenzonitrile
  • LC-MS A) retention time (min): 1.26; MS(ESI, Pos.): 891 (M + H) + ; 1 H-NMR (CDCl 3 ): ⁇ 0.87-0.95, 1.69-1.84, 2.13-2.19, 2.21-2.28, 2.41-2.54, 2.78-2.93, 2.92-3.04, 3.92-4.22, 4.42-4
  • Example 37-6 1-(4- ⁇ 7-(6- ⁇ [9-(4-cyano-2-fluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5] pyrrolo[2,3-b]pyridin-7-yl]carbonyl ⁇ -3-pyridinyl)-9-[1-(2,2-dimethylpropyl)-4-piperidinyl]-6-methyl-8-oxo-8 ,9-dihydro-7H-purin-2-yl ⁇ phenyl)cyclopropanecarboxylic acid LC-MS (A) retention time (min): 1.06; MS(ESI, Pos.): 873 (M + H) + ; 1 H-NMR (CDCl 3 ): ⁇ 0.94, 1.17-1.29, 1.68-1.81, 2.14-2.27, 2.51, 2.84-3.04, 3.89-4.24, 4.38-4.61, 4.89, 5.33-5.66, 6.82-7.
  • Example 37-7 (5- ⁇ 7-(6- ⁇ [9-(4-cyano-2-fluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[ 2,3-b]pyridin-7-yl]carbonyl ⁇ -3-pyridinyl)-9-[1-(2,2-dimethylpropyl)-4-piperidinyl]-6-methyl-8-oxo-8,9 -dihydro-7H-purin-2-yl ⁇ -2-methoxyphenyl)acetic acid LC-MS (A) retention time (min): 1.04; MS(ESI, Pos.): 877 (M + H) + ; 1 H-NMR (CDCl 3 ): ⁇ 0.94, 1.70-1.82, 2.06-2.25, 2.43-2.58, 2.82-3.07, 3.74, 3.89, 3.93-4.23, 4.38-4.57, 4.90, 5.38-5.68, 6.87-7.0 8, 7.
  • Example 37-8 1-(3- ⁇ 7-(6- ⁇ [9-(4-cyano-2-fluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5] pyrrolo[2,3-b]pyridin-7-yl]carbonyl ⁇ -3-pyridinyl)-9-[1-(2,2-dimethylpropyl)-4-piperidinyl]-6-methyl-8-oxo-8 ,9-dihydro-7H-purin-2-yl ⁇ phenyl)cyclopropanecarboxylic acid LC-MS (A) retention time (min): 1.05; MS(ESI, Pos.): 873 (M + H) + ; 1 H-NMR (DMSO-d 6 ): ⁇ 0.93, 1.18-1.23, 1.47-1.57, 1.71-1.83, 2.06-2.21, 2.42-2.48, 2.73-3.01, 3.70-4.09, 4.27-4.42, 4.70
  • Example 37-9 6- ⁇ 7-(6- ⁇ [9-(4-cyano-2-fluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[2 ,3-b]pyridin-7-yl]carbonyl ⁇ -3-pyridinyl)-9-[1-(2,2-dimethylpropyl)-4-piperidinyl]-6-methyl-8-oxo-8,9- Dihydro-7H-purin-2-yl ⁇ -1-indanecarboxylic acid LC-MS (A) retention time (min): 1.03; MS(ESI, Pos.): 873 (M + H) + ; 1 H-NMR (CDCl 3 ): ⁇ 0.97, 1.73-1.88, 2.16-2.30, 2.32-2.70, 2.88-3.08, 3.10-3.26, 3.93-4.27, 4.43-4.61, 4.90, 5.36-5.64, 6.83-7.09 ,
  • Example 37-10 1-(4- ⁇ 7-(6- ⁇ [9-(4-cyano-2-fluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5] pyrrolo[2,3-b]pyridin-7-yl]carbonyl ⁇ -3-pyridinyl)-9-[1-(2,2-dimethylpropyl)-4-piperidinyl]-6-methyl-8-oxo-8 ,9-dihydro-7H-purin-2-yl ⁇ -2-fluorophenyl)cyclopropanecarboxylic acid 2-trifluoroacetate LC-MS (A) retention time (min): 1.04; MS(ESI, Pos.): 891 (M + H) + ; 1 H-NMR (DMSO-d 6 ): ⁇ 1.07-1.16, 1.16-1.29, 1.49-1.59, 1.97-2.13, 2.15-2.20, 2.82-2.94, 2.94-3.
  • Example 37-11 4-( ⁇ 7-[(5- ⁇ 9-[1-(2,2-dimethylpropyl)-4-piperidinyl]-2-[4-(2-hydroxy-2-propanyl)phenyl]-6-methyl -8-oxo-8,9-dihydro-7H-purin-7-yl ⁇ -2-pyridinyl)carbonyl]-5,6,7,8-tetrahydro-9H-pyrido[4',3':4,5 ]pyrrolo[2,3-b]pyridin-9-yl ⁇ methyl)-3-fluorobenzonitrile
  • LC-MS A) retention time (min): 1.05; MS(ESI, Pos.): 847 (M + H) + ; 1 H-NMR (CDCl 3 ): ⁇ 0.94-0.96, 1.64, 1.71-1.82, 2.18-2.27, 2.45-2.60, 2.84-3.07, 3.93-4.24, 4.39-4.59, 4.91, 5.39-5.66, 6.
  • Example 37-12 4-( ⁇ 7-[(5- ⁇ 9-[1-(2,2-dimethylpropyl)-4-piperidinyl]-2-[4-(1,1,1,3,3,3-hexafluoro -2-hydroxy-2-propanyl)phenyl]-6-methyl-8-oxo-8,9-dihydro-7H-purin-7-yl ⁇ -2-pyridinyl)carbonyl]-5,6,7,8- Tetrahydro-9H-pyrido[4',3':4,5]pyrrolo[2,3-b]pyridin-9-yl ⁇ methyl)-3-fluorobenzonitrile
  • LC-MS A) retention time (min): 1.12; MS(ESI, Pos.): 955 (M + H) + ; 1 H-NMR (CDCl 3 ): ⁇ 0.93-0.97, 1.73-1.83, 2.19-2.27, 2.52, 2.84-2.97, 2.82-3.06, 3.63-3.76, 3.92-4.
  • Example 37-13 1-(3- ⁇ 7-(6- ⁇ [9-(4-cyano-2-fluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5] pyrrolo[2,3-b]pyridin-7-yl]carbonyl ⁇ -3-pyridinyl)-9-[1-(2,2-dimethylpropyl)-4-piperidinyl]-6-methyl-8-oxo-8 ,9-dihydro-7H-purin-2-yl ⁇ phenyl)cyclobutanecarboxylic acid LC-MS (A) retention time (min): 1.09; MS(ESI, Pos.): 887 (M + H) + ; 1 H-NMR (CDCl 3 ): ⁇ 0.94, 1.73-1.86, 2.10-2.17, 2.18-2.28, 2.44-2.58, 2.61-2.70, 2.89-3.06, 3.92-4.21, 4.40-4.54, 4.90,
  • Example 37-14 1-(5- ⁇ 7-(6- ⁇ [9-(4-cyano-2-fluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5] pyrrolo[2,3-b]pyridin-7-yl]carbonyl ⁇ -3-pyridinyl)-9-[1-(2,2-dimethylpropyl)-4-piperidinyl]-6-methyl-8-oxo-8 ,9-dihydro-7H-purin-2-yl ⁇ -2-methoxyphenyl)cyclopropanecarboxylic acid LC-MS (A) retention time (min): 1.08; MS(ESI, Pos.): 903 (M + H) + ; 1 H-NMR (CDCl 3 ): ⁇ 0.94, 1.28-1.32, 1.70-1.82, 2.16-2.25, 2.44-2.55, 2.84-3.06, 3.94, 3.95-4.21, 4.39-4.53, 4.90
  • Example 37-15 1-(5- ⁇ 7-(6- ⁇ [9-(4-cyano-2-fluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5] pyrrolo[2,3-b]pyridin-7-yl]carbonyl ⁇ -3-pyridinyl)-9-[1-(2,2-dimethylpropyl)-4-piperidinyl]-6-methyl-8-oxo-8 ,9-dihydro-7H-purin-2-yl ⁇ -2-methylphenyl)cyclopropanecarboxylic acid LC-MS (A) retention time (min): 1.12; MS(ESI, Pos.): 887 (M + H) + ; 1 H-NMR (CDCl 3 ): ⁇ 0.94, 1.35, 1.72-1.85, 2.15-2.26, 2.44, 2.46-2.55, 2.84-3.06, 3.90-4.20, 4.42-4.52, 4.90, 5.37
  • Example 37-16 1-(3- ⁇ 7-(6- ⁇ [9-(4-cyano-2-fluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5] pyrrolo[2,3-b]pyridin-7-yl]carbonyl ⁇ -3-pyridinyl)-9-[1-(2,2-dimethylpropyl)-4-piperidinyl]-6-methyl-8-oxo-8 ,9-dihydro-7H-purin-2-yl ⁇ -5-methylphenyl)cyclopropanecarboxylic acid LC-MS (A) retention time (min): 1.10; MS(ESI, Pos.): 887 (M + H) + ; 1 H-NMR (CDCl 3 ): ⁇ 0.94, 1.34-1.39, 1.71-1.74, 1.75-1.79, 2.16-2.26, 2.45, 2.47-2.56, 2.90-3.04, 3.92-4.23, 4.39
  • Example 37-17 1-(3- ⁇ 7-(6- ⁇ [9-(4-cyano-2-fluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5] pyrrolo[2,3-b]pyridin-7-yl]carbonyl ⁇ -3-pyridinyl)-9-[1-(2,2-dimethylpropyl)-4-piperidinyl]-6-methyl-8-oxo-8 ,9-dihydro-7H-purin-2-yl ⁇ -5-fluorophenyl)cyclopropanecarboxylic acid LC-MS (A) retention time (min): 1.11; MS(ESI, Pos.): 891 (M + H) + ; 1 H-NMR (CDCl 3 ): ⁇ 0.94, 1.34-1.43, 1.72-1.80, 2.17-2.26, 2.45-2.57, 2.84-3.06, 3.91-4.21, 4.41-4.56, 4.85-4
  • Example 38 1-(3- ⁇ 7-(6- ⁇ [9-(4-cyano-2-fluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5] pyrrolo[2,3-b]pyridin-7-yl]carbonyl ⁇ -3-pyridinyl)-9-[1-(2,2-dimethylpropyl)-4-piperidinyl]-6-methyl-8-oxo-8 ,9-dihydro-7H-purin-2-yl ⁇ phenyl)cyclopropanecarboxamide 2-trifluoroacetate 2-methyl-2-[3-(4,4,5,5-tetramethyl-1,3,2- 1-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]cyclopropanecarboxylic acid instead of dioxaborolan-2-yl)phenyl]propanecarboxylic acid.
  • Example 37 The same operation as in Example 37 was carried out using the same.
  • the obtained compound (14 mg) was dissolved in DMF (0.14 mL), ammonium chloride (2.6 mg), DIPEA (0.014 mL), and HATU (12 mg) were added, and the mixture was stirred at room temperature for 90 minutes.
  • the reaction solution was diluted with ethyl acetate and washed with water.
  • the obtained organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting residue was purified with a reverse phase HPLC column to obtain the title compound (12 mg) having the following physical properties.
  • Reference example 102 Methyl 7-(6- ⁇ [9-(4-cyano-2-fluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[2,3 -b]pyridin-7-yl]carbonyl ⁇ -3-pyridinyl)-9-[1-(2,2-dimethylpropyl)-4-piperidinyl]-6-methyl-8-oxo-8,9-dihydro- 7H-Purine-2-carboxylate
  • the compound prepared in Reference Example 101 (374 mg) was dissolved in DMF (2.5 mL), and mixed with methanol (2.5 mL), NEt 3 (0.070 mL), Xantphos (43 mg), and palladium acetate (11 mg).
  • Reference example 103 7-(6- ⁇ [9-(4-cyano-2-fluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[2,3- b]pyridin-7-yl]carbonyl ⁇ -3-pyridinyl)-9-[1-(2,2-dimethylpropyl)-4-piperidinyl]-6-methyl-8-oxo-8,9-dihydro-7H -Purine-2-carboxylic acid
  • the compound prepared in Reference Example 102 (58 mg) was dissolved in THF (0.75 mL), TMSOK (19 mg) was added at 0°C, and the mixture was stirred at room temperature for 2 hours.
  • Example 39 7-(6- ⁇ [9-(4-cyano-2-fluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[2,3- b]pyridin-7-yl]carbonyl ⁇ -3-pyridinyl)-9-[1-(2,2-dimethylpropyl)-4-piperidinyl]-6-methyl-8-oxo-N-[trans-4- (Trifluoromethoxy)cyclohexyl]-8,9-dihydro-7H-purine-2-carboxamide 2-trifluoroacetate
  • the compound (30 mg) prepared in Reference Example 103 was dissolved in DMF (0.4 mL), and trans-4- (Trifluoromethoxy)cyclohexaneamine (7.6 mg), DIPEA (0.021 mL), and HATU (23 mg) were added and stirred at room temperature for 19 hours.
  • Reference example 104 4-( ⁇ 7-[(5- ⁇ 9-[1-(2,2-dimethylpropyl)-4-piperidinyl]-2-(hydroxymethyl)-6-methyl-8-oxo-8,9-dihydro -7H-purin-7-yl ⁇ -2-pyridinyl)carbonyl]-5,6,7,8-tetrahydro-9H-pyrido[4',3':4,5]pyrrolo[2,3-b]pyridine -9-yl ⁇ methyl)-3-fluorobenzonitrile
  • the compound prepared in Reference Example 103 38 mg was dissolved in THF (0.5 mL), and ethyl carbonochloridate (6.0 mg) and DIPEA (0.013 mL) were added.
  • Reference example 105 4-( ⁇ 7-[(5- ⁇ 9-[1-(2,2-dimethylpropyl)-4-piperidinyl]-2-formyl-6-methyl-8-oxo-8,9-dihydro-7H- purin-7-yl ⁇ -2-pyridinyl)carbonyl]-5,6,7,8-tetrahydro-9H-pyrido[4',3':4,5]pyrrolo[2,3-b]pyridine-9- yl ⁇ methyl)-3-fluorobenzonitrile
  • the compound (31 mg) prepared in Reference Example 104 was dissolved in dichloromethane (0.4 mL), and the mixture was heated at 0°C with DMSO (0.2 mL), sulfur trioxide pyridine complex (20 mg), and NEt 3 (0.035 mL) were added one after another and stirred at room temperature for 6 hours.
  • Example 40 4-( ⁇ 7-[(5- ⁇ 2-(difluoromethyl)-9-[1-(2,2-dimethylpropyl)-4-piperidinyl]-6-methyl-8-oxo-8,9-dihydro -7H-purin-7-yl ⁇ -2-pyridinyl)carbonyl]-5,6,7,8-tetrahydro-9H-pyrido[4',3':4,5]pyrrolo[2,3-b]pyridine -9-yl ⁇ methyl)-3-fluorobenzonitrile
  • the compound (31 mg) prepared in Reference Example 105 was dissolved in dichloromethane (0.4 mL), and 2-methoxy-N-(2-methoxyethyl)-N-(trifluorobenzonitrile) was dissolved in dichloromethane (0.4 mL).
  • Fluoro-lambda-4-sulfanyl)ethanamine (19 mg) was added and stirred at room temperature for 2 hours.
  • 2-Methoxy-N-(2-methoxyethyl)-N-(trifluoro-lambda-4-sulfanyl)ethanamine (30 mg) was added to the reaction solution, and the mixture was stirred at room temperature for 2 hours.
  • a saturated aqueous sodium bicarbonate solution was added to the reaction mixture, extracted with ethyl acetate, and dried over anhydrous sodium sulfate.
  • Example 41 4-( ⁇ 7-[(5- ⁇ 2-acetyl-9-[1-(2,2-dimethylpropyl)-4-piperidinyl]-6-methyl-8-oxo-8,9-dihydro-7H- purin-7-yl ⁇ -2-pyridinyl)carbonyl]-5,6,7,8-tetrahydro-9H-pyrido[4',3':4,5]pyrrolo[2,3-b]pyridine-9- yl ⁇ methyl)-3-fluorobenzonitrile
  • the compound prepared in Reference Example 101 (374 mg) was dissolved in DMA (7.5 mL), and tributyl(1-ethoxyvinyl)stannane (271 mg) and dichloropalladium-triphenylphosphine complex ( 35 mg) was added thereto, and the mixture was stirred at 100°C for 1 hour.
  • the reaction solution was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate.
  • the obtained organic layer was dried over anhydrous sodium sulfate, and then passed through an injection column Amino (trade name) and concentrated under reduced pressure.
  • the obtained compound (100 mg) was dissolved in THF (1 mL), 2N hydrochloric acid (1 mL) was added at 0°C, and the mixture was stirred at room temperature for 1 hour.
  • Example 42 4-( ⁇ 7-[(5- ⁇ 9-[1-(2,2-dimethylpropyl)-4-piperidinyl]-2-(2-hydroxy-2-propanyl)-6-methyl-8-oxo- 8,9-dihydro-7H-purin-7-yl ⁇ -2-pyridinyl)carbonyl]-5,6,7,8-tetrahydro-9H-pyrido[4',3':4,5]pyrrolo[2, 3-b]pyridin-9-yl ⁇ methyl)-3-fluorobenzonitrile
  • the compound prepared in Example 41 (20 mg) was dissolved in THF (1.0 mL), and bromo(methyl)magnesium (0.015 mL, 3.0 mol/ L, THF solution) was added at 0°C and stirred for 5 minutes.
  • Example 43 4-( ⁇ 7-[(5- ⁇ 9-[1-(2,2-dimethylpropyl)-4-piperidinyl]-2-(N-hydroxyethanimidoyl)-6-methyl-8-oxo-8 ,9-dihydro-7H-purin-7-yl ⁇ -2-pyridinyl)carbonyl]-5,6,7,8-tetrahydro-9H-pyrido[4',3':4,5]pyrrolo[2,3 -b]pyridin-9-yl ⁇ methyl)-3-fluorobenzonitrile
  • the compound prepared in Example 41 (11 mg) was dissolved in ethanol (0.15 mL), and sodium acetate (6.1 mg) and hydroxylamine hydrochloride (3.1 mg) were dissolved in ethanol (0.15 mL).
  • Reference example 108 2-Methyl-2-propanyl (3R,4S)-4-( ⁇ 2-chloro-5-[(6- ⁇ [9-(4-cyano-2-fluorobenzyl)-5,6,8,9- Tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[2,3-b]pyridin-7-yl]carbonyl ⁇ -3-pyridinyl)amino]-6-methyl-4-pyrimidinyl ⁇ amino) -3-Methyl-1-piperidinecarboxylate
  • the compound produced in Reference Example 107 200 mg
  • the compound produced in Reference Example 106 was substituted for methyl 5-bromopyridinecarboxylate (200 mg).
  • Reference example 109 2-Methyl-2-propanyl (3R,4S)-4-[2-chloro-7-(6- ⁇ [9-(4-cyano-2-fluorobenzyl)-5,6,8,9-tetrahydro- 7H-pyrido[4',3':4,5]pyrrolo[2,3-b]pyridin-7-yl]carbonyl ⁇ -3-pyridinyl)-6-methyl-8-oxo-7,8-dihydro- 9H-Purin-9-yl]-3-methyl-1-piperidinecarboxylate
  • the same procedure as in Reference Example 94 was carried out using the compound produced in Reference Example 108 (350 mg) instead of the compound produced in Reference Example 93.
  • the title compound (340 mg) having the following physical properties was obtained.
  • Reference example 110 3-Fluoro-4-[(7- ⁇ [5-(6-methyl-9-[(3R,4S)-3-methyl-4-piperidinyl]-8-oxo-2- ⁇ [4-(trifluoro methoxy)phenyl]amino ⁇ -8,9-dihydro-7H-purin-7-yl)-2-pyridinyl]carbonyl ⁇ -5,6,7,8-tetrahydro-9H-pyrido[4',3':4 ,5]pyrrolo[2,3-b]pyridin-9-yl)methyl]benzonitrile dihydrochloride Using the compound produced in Reference Example 109 (340 mg) in place of the compound produced in Reference Example 68, Reference Example 69 ⁇ The same operation as in Reference Example 70 was performed to obtain the title compound (160 mg) having the following physical property values.
  • Example 44 3-Fluoro-4-[(7- ⁇ [5-(9-[(3R,4S)-1-isobutyl-3-methyl-4-piperidinyl]-6-methyl-8-oxo-2- ⁇ [4 -(trifluoromethoxy)phenyl]amino ⁇ -8,9-dihydro-7H-purin-7-yl)-2-pyridinyl]carbonyl ⁇ -5,6,7,8-tetrahydro-9H-pyrido[4', 3':4,5]pyrrolo[2,3-b]pyridin-9-yl)methyl]benzonitrile 2-trifluoroacetate
  • the compound (50 mg) prepared in Reference Example 110 was dissolved in DMF (1 mL), and NEt 3 (0.042 mL) was added.
  • Example 45 4-[(7- ⁇ [5-(9- ⁇ (3R,4S)-1-[(1-cyanocyclopropyl)carbonyl]-3-methyl-4-piperidinyl ⁇ -6-methyl-8-oxo- 2- ⁇ [4-(trifluoromethoxy)phenyl]amino ⁇ -8,9-dihydro-7H-purin-7-yl)-2-pyridinyl]carbonyl ⁇ -5,6,7,8-tetrahydro-9H- Pyrido[4',3':4,5]pyrrolo[2,3-b]pyridin-9-yl)methyl]-3-fluorobenzonitrile trifluoroacetate
  • the compound (50 mg) produced in Reference Example 110 was dissolved in DMF.
  • Reference example 111 2-Methyl-2-propanyl 6-[2-chloro-7-(6- ⁇ [9-(4-cyano-2-fluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[2,3-b]pyridin-7-yl]carbonyl ⁇ -3-pyridinyl)-6-methyl-8-oxo-7,8-dihydro-9H-purine-9- yl]-2-azaspiro[3.3]heptane-2-carboxylate 2-methyl-2-propanyl 4-amino-1-piperidinecarboxylate used in Reference Example 3 Using propanyl 6-amino-2-azaspiro[3,3]heptane-2-carboxylate, the same operation as in Reference Example 3 ⁇ Reference Example 93 ⁇ Reference Example 94 ⁇ Reference Example 95 ⁇ Reference Example 99 was carried out, and the following was carried out.
  • Reference example 112 2-Methyl-2-propanyl 6-[7-(6- ⁇ [9-(4-cyano-2-fluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3'): 4,5]pyrrolo[2,3-b]pyridin-7-yl]carbonyl ⁇ -3-pyridinyl)-6-methyl-8-oxo-2- ⁇ [4-(trifluoromethoxy)phenyl]amino ⁇ - 7,8-dihydro-9H-purin-9-yl]-2-azaspiro[3.3]heptane-2-carboxylate
  • the compound prepared in Reference Example 111 180 mg was added with DMF (1.1 mL) and toluene (1.1 mL).
  • Reference example 113 4- ⁇ [7-( ⁇ 5-[9-(2-azaspiro[3.3]hept-6-yl)-6-methyl-8-oxo-2- ⁇ [4-(trifluoromethoxy)phenyl] amino ⁇ -8,9-dihydro-7H-purin-7-yl]-2-pyridinyl ⁇ carbonyl)-5,6,7,8-tetrahydro-9H-pyrido[4',3':4,5]pyrrolo [2,3-b]pyridin-9-yl]methyl ⁇ -3-fluorobenzonitrile
  • Methanol (1.4 mL) and methanesulfonic acid (0.10 mL) were added to the compound prepared in Reference Example 112 (144 mg) at 40°C.
  • Example 46 4-[(7- ⁇ [5-(9-[2-(2,2-dimethylpropyl)-2-azaspiro[3.3]hept-6-yl]-6-methyl-8-oxo-2- ⁇ [4-(trifluoromethoxy)phenyl]amino ⁇ -8,9-dihydro-7H-purin-7-yl)-2-pyridinyl]carbonyl ⁇ -5,6,7,8-tetrahydro-9H-pyrido[ 4',3':4,5]pyrrolo[2,3-b]pyridin-9-yl)methyl]-3-fluorobenzonitrile
  • the compound produced in Reference Example 113 The same operation as in Example 34 was performed using 28 mg) to obtain the title compound (14 mg) having the following physical properties.
  • Example 47 1- ⁇ [ ⁇ 7-(6- ⁇ [9-(4-cyano-2-fluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo [2,3-b]pyridin-7-yl]carbonyl ⁇ -3-pyridinyl)-9-[1-(2,2-dimethylpropyl)-4-piperidinyl]-6-methyl-8-oxo-8, 9-dihydro-7H-purin-2-yl ⁇ (cyclohexyl)amino]methyl ⁇ cyclobutanecarboxylic acid
  • the compound produced in Reference Example 101 (100 mg) was dissolved in dehydrated DMSO (1.0 mL), and 1-[(cyclohexylamino)methyl]cyclobutanecarboxylic hydrochloride (166 mg), cesium fluoride (101 mg), and cesium carbonate (436 mg) were dissolved in dehydrated DMSO (1.0 mL).

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Epidemiology (AREA)
  • Oncology (AREA)
  • Communicable Diseases (AREA)
  • Hematology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The present invention addresses the problem of providing a compound having inhibitory activity against DGK α and/or ζ.　As a result of diligent study, the inventors of the present invention found, as a substance that can solve the above problem, a compound which has inhibitory activity against DGK α and/or ζ and which is represented by general formula (IY) [where all symbols in the formula have the same meaning as set forth in the specification].　A compound according to the present invention, which is represented by general formula (IY), has inhibitory activity against DGK α and/or ζ, and thus can be used as an active ingredient in an agent for inhibiting the progression of, inhibiting the recurrence of, and/or for treating cancer or infectious diseases, for example.

Description

ジアシルグリセロールキナーゼαおよび／またはζ阻害活性を有する化合物およびその医薬用途Compounds having diacylglycerol kinase α and/or ζ inhibitory activity and their pharmaceutical uses
　本開示は、ジアシルグリセロールキナーゼαおよび／またはζ（以下、ＤＧＫαおよび／またはζ、もしくはＤＧＫαおよび／またはＤＧＫζと略記することがある。）の阻害活性を有する後述の一般式（ＩＹ）で示される化合物、またはその塩、ならびにそれらの医薬用途に関する。 The present disclosure provides the following general formula (IY) having inhibitory activity on diacylglycerol kinase α and/or ζ (hereinafter sometimes abbreviated as DGKα and/or ζ, or DGKα and/or DGKζ). The present invention relates to compounds or salts thereof, and pharmaceutical uses thereof.
　ジアシルグリセロールキナーゼ（DGK：diacylglycerol kinase）は、ジアシルグリセロール（DAG）をリン酸化し、ホスファチジン酸（PA）に変換する脂質キナーゼであり、哺乳類では10種類のアイソザイムが存在することが知られている。すべてのアイソザイムは、相同性の高い触媒領域とプロテインキナーゼC（PKC）と相同性のあるC1ドメインを持つ。C1ドメインは、システインとヒスチジンに富むジンクフィンガー様構造を有し、ホルボールエステル/DAGが結合すると考えられている（非特許文献１）。 Diacylglycerol kinase (DGK) is a lipid kinase that phosphorylates diacylglycerol (DAG) and converts it to phosphatidic acid (PA), and 10 types of isozymes are known to exist in mammals. All isozymes have a highly homologous catalytic region and a C1 domain homologous to protein kinase C (PKC). The C1 domain has a zinc finger-like structure rich in cysteine and histidine, and is thought to be bound by phorbol ester/DAG (Non-Patent Document 1).
　T細胞において、DAGは、T細胞受容体（TCR）を介した抗原刺激により活性化したホスホリパーゼCγ1（PLCγ1）によりイノシトール三リン酸（IP3）とともに産生される。生成したDAGはセカンドメッセンジャーとして、Ras-MAPK、NF-κB及びフォスファチジルイノシトール3リン酸-Akt-mTOR経路など複数の下流シグナル経路を活性化してT細胞の活性化を誘導する。 In T cells, DAG is produced together with inositol trisphosphate (IP3) by phospholipase Cγ1 (PLCγ1) activated by antigen stimulation via the T cell receptor (TCR). The generated DAG acts as a second messenger and activates multiple downstream signal pathways such as Ras-MAPK, NF-κB, and phosphatidylinositol triphosphate-Akt-mTOR pathways, thereby inducing T cell activation.
　DGKα及びDGKζは、T細胞内の2つの主要アイソザイムであり、これらのアイソザイムのそれぞれが、TCRを介した抗原刺激下流のDAGシグナルの強度を制御してT細胞の活性化を負に制御している。DGKα又はDGKζを欠損させたT細胞では、抗原刺激に伴う活性化が増強すること、二重阻害によりその活性化がさらに増強することが知られている（非特許文献２～５）。さらに、このDGK阻害を介したT細胞活性化は、トランスフォーミング増殖因子(TGF)-β、Adenosine、プロスタグランジンE2（PGE2）などの可溶性免疫抑制因子や、PD-1を介した抑制シグナル対しても抵抗性を示すことが知られている（非特許文献４～６）。また、NK細胞においても、DGKζの欠損により主要組織適合遺伝子複合体（MHC）クラスI欠損細胞への細胞傷害活性が増強することが知られている（非特許文献７）。 DGKα and DGKζ are two major isozymes within T cells, and each of these isozymes negatively regulates T cell activation by controlling the strength of DAG signals downstream of TCR-mediated antigen stimulation. There is. It is known that in T cells deficient in DGKα or DGKζ, activation associated with antigen stimulation is enhanced, and that activation is further enhanced by dual inhibition (Non-patent Documents 2 to 5). Furthermore, this DGK inhibition-mediated T cell activation responds to soluble immunosuppressive factors such as transforming growth factor (TGF)-β, Adenosine, prostaglandin E2 (PGE2), and PD-1-mediated inhibitory signals. It is also known that the virus exhibits resistance even in the face of cancer (Non-patent Documents 4 to 6). Furthermore, in NK cells, it is known that DGKζ deficiency enhances cytotoxic activity toward major histocompatibility complex (MHC) class I-deficient cells (Non-Patent Document 7).
　したがって、DGKα及びDGKζの一方、又は両方を阻害する薬剤は、T細胞をはじめとした免疫細胞の活性化を増強し、癌または感染症といった免疫機能低下や免疫回避が関連する疾患への有用性が期待される。 Therefore, drugs that inhibit one or both of DGKα and DGKζ enhance the activation of immune cells including T cells, and are useful for diseases associated with decreased immune function and immune escape, such as cancer and infectious diseases. There is expected.
　特許文献１には、一般式（Ａ）： Patent Document 1 contains the general formula (A):
（式中、Ｒ１Ａはハロゲン原子、Ｃ１～４アルキル基等を表わし、Ｒ２Ａは水素原子、ハロゲン原子等を表わし、Ｒ３ＡはＣ１～４アルキル基を表わし、Ｒ４Ａは水素原子またはＣ１～４アルキル基を表わし、環ＡＡはＣ３～７単環式炭素環等を表わし、ＸＡは窒素原子または炭素原子を表わし、ＴＡは結合手等を表わし、ＵＡは１～５個のＲ７Ａで置換されていてもよい３～７員単環、Ｃ５～１０の架橋炭素環もしくは５～１０員の架橋複素環（基中、Ｒ７Ａはハロゲン原子、Ｃ１～４アルキル基、水酸基、オキソ基、Ｃ１～４アルコキシ基、Ｃ１～４ハロアルコキシ基、シアノ基またはベンジルオキシ基を表わす。）等を表わし、ＹＡは結合手等を表わし、ＷＡは結合手等を表わし、ＺＡはメチレン基等を表わし、ｑＡは１～４の整数を表わし、ｒＡは各々０～５の整数を表わし、ｔＡは０～２の整数を表わす。基の定義は必要な部分を抜粋した。）で示される化合物、その塩、その溶媒和物またはそれらのプロドラッグが、尿排出障害、癌、間質性肺炎もしくは肺線維症、強皮症、疼痛、線維筋痛症または関節炎リウマチ等の治療に有用である旨記載されている。 (In the formula, R 1A represents a halogen atom, a C1-4 alkyl group, etc., R 2A represents a hydrogen atom, a halogen atom, etc., R 3A represents a C1-4 alkyl group, and R 4A represents a hydrogen atom or a C1-4 alkyl group. 4 alkyl group, ring A represents a C3-7 monocyclic carbocycle, etc., X A represents a nitrogen atom or a carbon atom, T A represents a bond, etc., and U A represents 1 to 5 carbon atoms. A 3- to 7-membered monocyclic ring, a C5-10 bridged carbocycle, or a 5- to 10-membered bridged heterocycle, which may be substituted with R 7A (in the group, R 7A is a halogen atom, a C1-4 alkyl group, a hydroxyl group, oxo group, C1-4 alkoxy group, C1-4 haloalkoxy group, cyano group, or benzyloxy group), Y A represents a bond, etc., W A represents a bond, etc., Z A represents a methylene group, etc., qA represents an integer from 1 to 4, rA each represents an integer from 0 to 5, and tA represents an integer from 0 to 2. The definition of the group has been extracted from the necessary parts.) The compounds represented by, salts thereof, solvates thereof, or prodrugs thereof can be used to treat urinary excretion disorders, cancer, interstitial pneumonia or pulmonary fibrosis, scleroderma, pain, fibromyalgia, rheumatoid arthritis, etc. It is stated that it is useful.
　また、特許文献２には、一般式（Ｂ）： Moreover, in Patent Document 2, general formula (B):
（式中、Ｒ１Ｂは、水素原子、フッ素原子、塩素原子、臭素原子、０～４のＲ１ａＢで置換されたＣ１－３アルキル等；Ｒ２Ｂは、水素原子、０～４のＲ２ａＢで置換されたＣ１－３アルキル等；Ｒ３Ｂは、水素原子、フッ素原子、塩素原子、臭素原子、－ＣＮ等；Ｒ４Ｂは、－ＣＨ２Ｒ４ａＢ等；Ｒ５Ｂは、―ＣＮ、０～４のＲｇＢで置換されたＣ１－６アルキル等；ｍＢは、１～３を表わす。基の定義は必要な部分を抜粋した。）で示される化合物またはその塩が、ウイルス感染症、および、癌などの増殖性疾患の治療に有用である旨記載されている。 (In the formula, R 1B is a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, a C1-3 alkyl substituted with 0 to 4 R 1aB , etc.; R 2B is a hydrogen atom, and 0 to 4 R 2aB is Substituted C1-3 alkyl, etc.; R 3B is a hydrogen atom, fluorine atom, chlorine atom, bromine atom, -CN, etc.; R 4B is -CH 2 R 4aB , etc.; R 5B is -CN, 0 to 4 C1-6 alkyl substituted with RgB ; mB represents 1 to 3. Necessary portions have been extracted from the definition of the group) or a salt thereof is effective against viral infections and cancer. It has been described that it is useful for the treatment of proliferative diseases such as.
　しかしながら、本発明で開示する後述の化合物、またはその塩は、何れの先行技術にも記載されていない。 However, the below-mentioned compound disclosed in the present invention or a salt thereof is not described in any prior art.
国際公開第２０１２／００５２２７号International Publication No. 2012/005227 国際公開第２０２０／００６０１８号International Publication No. 2020/006018
　本発明の課題は、ＤＧＫαおよび／またはζに対して阻害活性を有する化合物を提供することにある。 An object of the present invention is to provide a compound that has inhibitory activity against DGKα and/or ζ.
　本発明者らは、前記課題を解決すべく鋭意研究した結果、後述の一般式（ＩＹ）で示される化合物、またはその塩（以下、本発明化合物と略記することがある。）が、ＤＧＫαおよび／またはζに対して阻害活性を有することを見出した。 As a result of intensive research to solve the above problems, the present inventors found that a compound represented by the general formula (IY) described below or a salt thereof (hereinafter sometimes abbreviated as the compound of the present invention) has been found to be suitable for DGKα and It has been found that the compound has inhibitory activity against/or ζ.
　すなわち、本発明は、主に以下の実施態様を提供する。 That is, the present invention mainly provides the following embodiments.
［１］　一般式（ＩＹ） [1] General formula (IY)
（式中、Ｒ１は、（１）１～５個のＲ１１で置換されていてもよい３～１５員の炭素環で置換されたメチレン、（２）１～５個のＲ１２で置換されていてもよい３～１５員の複素環で置換されたメチレン、（３）１～５個のＲ１３で置換されていてもよいＣ２～４アルケニル基で置換されたメチレン、または（４）１～５個のＲ１４で置換されていてもよいＣ２～４アルキニル基で置換されたメチレンを表わし、
Ｒ１１、Ｒ１２、Ｒ１３およびＲ１４は、それぞれ独立して、（１）ハロゲン、（２）Ｃ１～４アルキル基、（３）Ｃ１～４アルコキシ基、（４）Ｃ１～４ハロアルキル基、（５）Ｃ１～４ハロアルコキシ基、または（６）シアノ基を表わし、複数のＲ１１、Ｒ１２、Ｒ１３およびＲ１４は、それぞれ同じでも異なっていてもよく、
Ｒ２は、（１）１～５個のＲ１５で置換されていてもよい３～１５員の複素環、（２）１～５個のＲ１６で置換されていてもよい３～１５員の炭素環、または（３）１～５個のＲ１７で置換されていてもよいＣ１～４アルキル基を表わし、
Ｒ１５、Ｒ１６およびＲ１７は、それぞれ独立して、
（１）１～５個のＲ１８で置換されていてもよいＣ３～６シクロアルキル基で置換されていてもよいＣ１～８アルキル基、（２）（Ｃ１～８アルキル）カルボニル基、（３）１～５個のＲ１９で置換された（Ｃ３～６シクロアルキル）カルボニル基、（４）Ｃ１～８ハロアルキル基、（５）５～６員の炭素環、（６）５～６員の複素環、（７）Ｃ１～４アルキルスルホニル基、（８）Ｃ２～４アルケニルスルホニル基、（９）Ｃ１～４アルコキシカルボニル基、（１０）Ｃ１～４ハロアルキルアミノ基、（１１）ｔ－ブチルオキシカルボニルアミノ基、または（１２）５，５－ジメチル－２，４－ジオキソオキサゾリジン－３－イル基を表わし、
複数のＲ１５、Ｒ１６およびＲ１７は、それぞれ同じでも異なっていてもよく、
Ｒ１８およびＲ１９は、それぞれ独立して、（１）ハロゲン、（２）Ｃ１～４アルキル基、（３）Ｃ１～４アルコキシ基、（４）Ｃ１～４ハロアルキル基、（５）Ｃ１～４ハロアルコキシ基、または（６）シアノ基を表わし、
複数のＲ１８およびＲ１９は、それぞれ同じでも異なっていてもよく、
Ｒ３Ｙは、（１）水素原子、（２）ハロゲン、（３）Ｃ１～４アルキル基、（４）Ｃ１～４アルコキシ基、（５）Ｃ１～４ハロアルキル基、（６）Ｃ１～４ハロアルコキシ基、（７）シアノ基、（８）１～５個のＲ２０Ｙで置換されていてもよい３～１５員の炭素環、（９）１～５個のＲ２１Ｙで置換されていてもよい３～１５員の複素環、（１０）－ＮＲ２２Ｒ２３、（１１）－ＯＲ２４、（１２）－ＣＯＮＲ２５Ｒ２６、（１３）（Ｃ１～８アルキル）カルボニル基、（１４）１～３個の水酸基で置換されたＣ１～４アルキル基、または（１５）１－（ヒドロキシイミノ）エチル基を表わし、
Ｒ２０ＹおよびＲ２１Ｙは、それぞれ独立して、（１）１～５個のＲ２７Ｙで置換されていてもよいＣ１～４アルキル基、（２）ハロゲン、（３）１～５個のＲ２８Ｙで置換されていてもよいＣ３～６シクロアルキル基、（４）１～５個のＲ２７－１Ｙで置換されていてもよいＣ１～４アルコキシ基、（５）水酸基、（６）カルバモイル基、（７）カルボキシル基、または（８）シアノ基を表わし、
複数のＲ２０ＹおよびＲ２１Ｙは、それぞれ同じでも異なっていてもよく、
Ｒ２７Ｙ、Ｒ２７－１ＹおよびＲ２８Ｙは、それぞれ独立して、（１）ハロゲン、（２）Ｃ１～４アルキル基、（３）Ｃ１～４アルコキシ基、（４）Ｃ１～４ハロアルキル基、（５）Ｃ１～４ハロアルコキシ基、（６）水酸基、（７）カルバモイル基、（８）カルボキシル基、（９）Ｃ１～４アルコキシカルボニル基、または（１０）シアノ基を表わし、
複数のＲ２７Ｙ、Ｒ２７－１ＹおよびＲ２８Ｙは、それぞれ同じでも異なっていてもよく、
Ｒ２２、Ｒ２３およびＲ２４は、それぞれ独立して、（１）水素原子、（２）１～５個のＲ２９で置換されていてもよいＣ１～８アルキル基、（３）１～５個のＲ２９－１で置換されていてもよいＣ２～４アルケニル基、（４）１～５個のＲ２９－２で置換されていてもよいＣ２～４アルキニル基、（５）１～５個のＲ３０で置換されていてもよい３～１５員の炭素環、または（６）１～５個のＲ３１で置換されていてもよい３～１５員の複素環を表わし、
Ｒ２９、Ｒ２９－１、Ｒ２９－２、Ｒ３０およびＲ３１は、それぞれ独立して、
（１）１～５個のＲ３２で置換されていてもよいＣ１～４アルキル基、（２）ハロゲン、（３）１～５個のＲ３３で置換されていてもよいＣ３～８シクロアルキル基、（４）１～５個のＲ３４で置換されていてもよい５～６員の炭素環、（５）１～５個のＲ３５で置換されていてもよい５～６員の複素環、（６）１～５個のＲ３２－１で置換されていてもよいＣ１～４アルコキシ基、（７）水酸基、（８）カルバモイル基、（９）カルボキシル基、または（１０）シアノ基を表わし、
複数のＲ２９、Ｒ２９－１、Ｒ２９－２、Ｒ３０およびＲ３１は、それぞれ同じでも異なっていてもよく、
Ｒ３２、Ｒ３２－１、Ｒ３３、Ｒ３４およびＲ３５は、それぞれ独立して、（１）ハロゲン、（２）Ｃ１～４アルキル基、（３）Ｃ１～４アルコキシ基、（４）Ｃ１～４ハロアルキル基、（５）Ｃ１～４ハロアルコキシ基、（６）水酸基、（７）カルバモイル基、（８）カルボキシル基、または（９）シアノ基を表わし、
複数のＲ３２、Ｒ３２－１、Ｒ３３、Ｒ３４およびＲ３５は、それぞれ同じでも異なっていてもよく、
Ｒ２５およびＲ２６は、それぞれ独立して、（１）水素原子、（２）１～５個のＲ３６で置換されていてもよいＣ１～８アルキル基、（３）１～５個のＲ３６－１で置換されていてもよいＣ２～４アルケニル基、（４）１～５個のＲ３６－２で置換されていてもよいＣ２～４アルキニル基、（５）１～５個のＲ３７で置換されていてもよい３～１５員の炭素環、または（６）１～５個のＲ３８で置換されていてもよい３～１５員の複素環を表わし、
Ｒ３６、Ｒ３６－１、Ｒ３６－２、Ｒ３７およびＲ３８は、それぞれ独立して、（１）Ｃ１～４アルキル基、（２）ハロゲン、（３）Ｃ３～８シクロアルキル基、（４）５～６員の炭素環、（５）５～６員の複素環、（６）Ｃ１～４アルコキシ基、（７）Ｃ１～４ハロアルキル基、（８）Ｃ１～４ハロアルコキシ基、（９）水酸基、（１０）カルボキシル基、（１１）カルバモイル基、または（１２）シアノ基を表わし、
複数のＲ３６、Ｒ３６－１、Ｒ３６－２、Ｒ３７およびＲ３８は、それぞれ同じでも異なっていてもよく、
Ｒ４は、（１）ハロゲン、（２）Ｃ１～４アルキル基、（３）Ｃ１～４アルコキシ基、（４）Ｃ１～４ハロアルキル基、（５）Ｃ１～４ハロアルコキシ基、（６）水酸基、または（７）シアノ基を表わし、
Ｒ５は、（１）ハロゲン、（２）Ｃ１～４アルキル基、（３）Ｃ１～４アルコキシ基、（４）Ｃ１～４ハロアルキル基、（５）Ｃ１～４ハロアルコキシ基、（６）水酸基、または（７）シアノ基を表わし、
ｒｉｎｇＹは、
（右の矢印は窒素原子と結合し、左の矢印はカルボニル基と結合する。）、または、１～６個のＲＹで置換されていてもよい、飽和または一部不飽和の４～１０員の炭素環、または、１～６個のＲＹで置換されていてもよい、１個の窒素原子、１個の酸素原子および／または酸化されていてもよい１個の硫黄原子を含有する６員の飽和複素環を表わし、ＲＹは、（１）ハロゲン、（２）Ｃ１～４アルキル基、（３）Ｃ１～４アルコキシ基、（４）Ｃ１～４ハロアルキル基、（５）Ｃ１～４ハロアルコキシ基、（６）水酸基、（７）オキソ基、または（８）シアノ基を表わし、
ＲＹが複数の場合、各ＲＹは同じでも異なっていてもよく、
Ｘは、窒素原子、またはＣＲ７を表わし、
Ｘ１、Ｘ２、およびＸ３は、それぞれ独立して、窒素原子、ＣＨ、またはＣＲ６を表わし、
Ｒ６は、（１）ハロゲン、（２）Ｃ１～４アルキル基、（３）Ｃ１～４アルコキシ基、（４）Ｃ１～４ハロアルキル基、（５）Ｃ１～４ハロアルコキシ基、（６）水酸基、または（７）シアノ基を表わし、
Ｒ６が複数の場合、各Ｒ６は同じでも異なっていてもよく、
Ｙ１は、窒素原子、またはＣＲ８を表わし、
Ｙ２は、窒素原子、またはＣＲ９を表わし、
Ｙ３は、窒素原子、またはＣＲ１０Ｙを表わし、
Ｒ７は、（１）水素原子、（２）ハロゲン、（３）Ｃ１～４アルキル基、（４）Ｃ１～４アルコキシ基、（５）Ｃ１～４ハロアルキル基、または（６）Ｃ１～４ハロアルコキシ基を表わし、
Ｒ８は、（１）水素原子、（２）ハロゲン、（３）Ｃ１～４アルキル基、（４）Ｃ１～４アルコキシ基、（５）Ｃ１～４ハロアルキル基、または（６）Ｃ１～４ハロアルコキシ基を表わし、
Ｒ９は、（１）水素原子、（２）ハロゲン、（３）Ｃ１～４アルキル基、（４）Ｃ１～４アルコキシ基、（５）Ｃ１～４ハロアルキル基、または（６）Ｃ１～４ハロアルコキシ基を表わし、
Ｒ１０Ｙは、（１）水素原子、（２）ハロゲン、（３）Ｃ１～４アルキル基、（４）Ｃ１～４アルコキシ基、（５）Ｃ１～４ハロアルキル基、（６）Ｃ１～４ハロアルコキシ基、（７）水酸基、（８）アミノ基、（９）カルボキシル基、（１０）カルバモイル基、（１１）（Ｃ１～４アルキル）アミノカルボニル基、（１２）ジ－（Ｃ１～４アルキル）アミノカルボニル基、（１３）－ＣＯ－（３～６員の飽和複素環）、（１４）－ＣＯＮＨＲ３９、（１５）Ｃ１～４アルコキシカルボニル基、または（１６）シアノ基を表わし、
Ｒ３９は、（１）シアノ基で置換されたＣ１～４アルキル基、（２）Ｃ１～４アルコキシ基、（３）Ｃ１～４ハロアルキル基、（４）Ｃ１～４ハロアルコキシ基、（５）水酸基、（６）アミノ基、（７）（Ｃ１～４アルキル）アミノ基、（８）ジ－（Ｃ１～４アルキル）アミノ基、（９）１～５個のＲ４０で置換されていてもよいＣ３～６シクロアルキル基、または（１０）１～５個のＲ４１で置換されていてもよい３～６員の飽和複素環を表わし、
Ｒ４０およびＲ４１は、それぞれ独立して、（１）ハロゲン、（２）Ｃ１～４アルキル基、（３）Ｃ１～４アルコキシ基、（４）Ｃ１～４ハロアルキル基、または（５）Ｃ１～４ハロアルコキシ基を表わし、
複数のＲ４０およびＲ４１は、それぞれ同じでも異なっていてもよく、
ｒは、０～３の整数を表わし、複数のＲ４は同じでも異なっていてもよく、
ｓは、０～３の整数を表わし、複数のＲ５は同じでも異なっていてもよい。
ここで、各水素原子は、重水素原子、または三重水素原子であってもよい。）で示される化合物、またはその塩；
［２］　［１］記載の一般式（ＩＹ）で示される化合物、またはその塩を含有する医薬組成物；
［３］　［１］記載の一般式（ＩＹ）で示される化合物、またはその塩を含有する、ＤＧＫαおよび／またはＤＧＫζ関連疾患の進行抑制、再発抑制および／または治療剤。 (In the formula, R 1 is (1) methylene substituted with a 3- to 15-membered carbon ring optionally substituted with 1 to 5 R 11 , (2) substituted with 1 to 5 R 12 (3) Methylene substituted with a C2-4 alkenyl group optionally substituted with 1 to 5 R13 , or (4) Represents methylene substituted with a C2-4 alkynyl group optionally substituted with 1 to 5 R14 ,
R 11 , R 12 , R 13 and R 14 each independently represent (1) halogen, (2) C1-4 alkyl group, (3) C1-4 alkoxy group, (4) C1-4 haloalkyl group, (5) represents a C1-4 haloalkoxy group, or (6) a cyano group, and a plurality of R 11 , R 12 , R 13 and R 14 may be the same or different, respectively;
R 2 is (1) a 3- to 15 -membered heterocycle optionally substituted with 1 to 5 R 15s, (2) a 3- to 15-membered heterocycle optionally substituted with 1 to 5 R 16 or (3) a C1-4 alkyl group optionally substituted with 1 to 5 R17 ;
R 15 , R 16 and R 17 are each independently,
(1) a C1-8 alkyl group optionally substituted with a C3-6 cycloalkyl group optionally substituted with 1-5 R18, (2) a (C1-8 alkyl)carbonyl group, (3 ) (C3-6 cycloalkyl) carbonyl group substituted with 1 to 5 R 19 , (4) C1-8 haloalkyl group, (5) 5- to 6-membered carbon ring, (6) 5- to 6-membered carbocyclic Heterocycle, (7) C1-4 alkylsulfonyl group, (8) C2-4 alkenylsulfonyl group, (9) C1-4 alkoxycarbonyl group, (10) C1-4 haloalkylamino group, (11) t-butyloxy Represents a carbonylamino group or (12) 5,5-dimethyl-2,4-dioxoxazolidin-3-yl group,
A plurality of R 15 , R 16 and R 17 may be the same or different,
R 18 and R 19 each independently represent (1) halogen, (2) C1-4 alkyl group, (3) C1-4 alkoxy group, (4) C1-4 haloalkyl group, (5) C1-4 represents a haloalkoxy group or (6) a cyano group,
A plurality of R 18 and R 19 may be the same or different,
R 3Y is (1) hydrogen atom, (2) halogen, (3) C1-4 alkyl group, (4) C1-4 alkoxy group, (5) C1-4 haloalkyl group, (6) C1-4 haloalkoxy group, (7) a cyano group, (8) a 3- to 15-membered carbon ring optionally substituted with 1 to 5 R 20Y , (9) optionally substituted with 1 to 5 R 21Y 3- to 15-membered heterocycle, (10)-NR 22 R 23 , (11)-OR 24 , (12)-CONR 25 R 26 , (13) (C1-8 alkyl) carbonyl group, (14) 1- Represents a C1-4 alkyl group substituted with three hydroxyl groups, or (15) 1-(hydroxyimino)ethyl group,
R 20Y and R 21Y each independently represent (1) a C1-4 alkyl group optionally substituted with 1 to 5 R 27Y , (2) halogen, (3) 1 to 5 R 28Y (4) C1-4 alkoxy group optionally substituted with 1 to 5 R 27-1Y , (5) hydroxyl group, (6) carbamoyl group, (7) represents a carboxyl group, or (8) a cyano group,
A plurality of R 20Y and R 21Y may be the same or different,
R 27Y , R 27-1Y and R 28Y each independently represent (1) halogen, (2) C1-4 alkyl group, (3) C1-4 alkoxy group, (4) C1-4 haloalkyl group, ( 5) represents a C1-4 haloalkoxy group, (6) a hydroxyl group, (7) a carbamoyl group, (8) a carboxyl group, (9) a C1-4 alkoxycarbonyl group, or (10) a cyano group,
A plurality of R 27Y , R 27-1Y and R 28Y may be the same or different,
R 22 , R 23 and R 24 each independently represent (1) a hydrogen atom, (2) a C1-8 alkyl group optionally substituted with 1 to 5 R 29s , (3) 1 to 5 (4) C2-4 alkynyl group optionally substituted with 1 to 5 R 29-2 , (5) 1 to 5 ( 6 ) a 3- to 15-membered heterocycle optionally substituted with 1 to 5 R 31 ;
R 29 , R 29-1 , R 29-2 , R 30 and R 31 are each independently,
(1) C1-4 alkyl group optionally substituted with 1-5 R 32 , (2) halogen, (3) C3-8 cycloalkyl optionally substituted with 1-5 R 33 group, (4) a 5- to 6-membered carbocyclic ring optionally substituted with 1 to 5 R 34s , (5) a 5- to 6-membered heterocyclic ring optionally substituted with 1 to 5 R 35 ring, (6) C1-4 alkoxy group optionally substituted with 1 to 5 R 32-1 , (7) hydroxyl group, (8) carbamoyl group, (9) carboxyl group, or (10) cyano group represents,
A plurality of R 29 , R 29-1 , R 29-2 , R 30 and R 31 may be the same or different,
R 32 , R 32-1 , R 33 , R 34 and R 35 each independently represent (1) halogen, (2) C1-4 alkyl group, (3) C1-4 alkoxy group, (4) C1 ~4 haloalkyl group, (5) C1~4 haloalkoxy group, (6) hydroxyl group, (7) carbamoyl group, (8) carboxyl group, or (9) cyano group,
A plurality of R 32 , R 32-1 , R 33 , R 34 and R 35 may be the same or different,
R 25 and R 26 each independently represent (1) a hydrogen atom, (2) a C1-8 alkyl group optionally substituted with 1 to 5 R 36 , (3) 1 to 5 R 36 C2-4 alkenyl group optionally substituted with 36-1 , (4) 1-5 R C2-4 alkynyl group optionally substituted with 36-2 , (5) 1-5 R Represents a 3- to 15-membered carbocycle optionally substituted with 37, or (6) a 3- to 15-membered heterocycle optionally substituted with 1 to 5 R 38 ,
R 36 , R 36-1 , R 36-2 , R 37 and R 38 each independently represent (1) a C1-4 alkyl group, (2) a halogen, (3) a C3-8 cycloalkyl group, ( 4) 5-6 membered carbocycle, (5) 5-6 membered heterocycle, (6) C1-4 alkoxy group, (7) C1-4 haloalkyl group, (8) C1-4 haloalkoxy group, ( 9) represents a hydroxyl group, (10) a carboxyl group, (11) a carbamoyl group, or (12) a cyano group,
A plurality of R 36 , R 36-1 , R 36-2 , R 37 and R 38 may be the same or different,
R 4 is (1) halogen, (2) C1-4 alkyl group, (3) C1-4 alkoxy group, (4) C1-4 haloalkyl group, (5) C1-4 haloalkoxy group, (6) hydroxyl group , or (7) represents a cyano group,
R 5 is (1) halogen, (2) C1-4 alkyl group, (3) C1-4 alkoxy group, (4) C1-4 haloalkyl group, (5) C1-4 haloalkoxy group, (6) hydroxyl group , or (7) represents a cyano group,
ringY is
(The arrow on the right bonds to the nitrogen atom, the arrow on the left bonds to the carbonyl group.), or a saturated or partially unsaturated 4-10, optionally substituted with 1-6 R Y containing 1 nitrogen atom, 1 oxygen atom and/or 1 sulfur atom which may be oxidized, optionally substituted with a membered carbocyclic ring, or 1 to 6 R Y Represents a 6-membered saturated heterocycle, R Y is (1) halogen, (2) C1-4 alkyl group, (3) C1-4 alkoxy group, (4) C1-4 haloalkyl group, (5) C1-4 alkyl group. 4-haloalkoxy group, (6) hydroxyl group, (7) oxo group, or (8) cyano group,
When there is a plurality of R Y , each R Y may be the same or different;
X represents a nitrogen atom or CR7 ,
X 1 , X 2 , and X 3 each independently represent a nitrogen atom, CH, or CR 6 ,
R 6 is (1) halogen, (2) C1-4 alkyl group, (3) C1-4 alkoxy group, (4) C1-4 haloalkyl group, (5) C1-4 haloalkoxy group, (6) hydroxyl group , or (7) represents a cyano group,
When there is a plurality of R 6 s, each R 6 may be the same or different;
Y 1 represents a nitrogen atom or CR 8 ,
Y2 represents a nitrogen atom or CR9 ,
Y 3 represents a nitrogen atom or CR 10Y ,
R 7 is (1) hydrogen atom, (2) halogen, (3) C1-4 alkyl group, (4) C1-4 alkoxy group, (5) C1-4 haloalkyl group, or (6) C1-4 halo represents an alkoxy group,
R 8 is (1) hydrogen atom, (2) halogen, (3) C1-4 alkyl group, (4) C1-4 alkoxy group, (5) C1-4 haloalkyl group, or (6) C1-4 halo represents an alkoxy group,
R 9 is (1) hydrogen atom, (2) halogen, (3) C1-4 alkyl group, (4) C1-4 alkoxy group, (5) C1-4 haloalkyl group, or (6) C1-4 halo represents an alkoxy group,
R 10Y is (1) hydrogen atom, (2) halogen, (3) C1-4 alkyl group, (4) C1-4 alkoxy group, (5) C1-4 haloalkyl group, (6) C1-4 haloalkoxy group, (7) hydroxyl group, (8) amino group, (9) carboxyl group, (10) carbamoyl group, (11) (C1-4 alkyl)aminocarbonyl group, (12) di-(C1-4 alkyl)amino Represents a carbonyl group, (13) -CO- (3- to 6-membered saturated heterocycle), (14) -CONHR 39 , (15) C1-4 alkoxycarbonyl group, or (16) cyano group,
R 39 is (1) a C1-4 alkyl group substituted with a cyano group, (2) a C1-4 alkoxy group, (3) a C1-4 haloalkyl group, (4) a C1-4 haloalkoxy group, (5) Even if substituted with hydroxyl group, (6) amino group, (7) (C1-4 alkyl) amino group, (8) di-(C1-4 alkyl) amino group, (9) 1 to 5 R 40 represents a good C3-6 cycloalkyl group, or (10) a 3-6 membered saturated heterocycle optionally substituted with 1-5 R41 ,
R 40 and R 41 are each independently (1) halogen, (2) C1-4 alkyl group, (3) C1-4 alkoxy group, (4) C1-4 haloalkyl group, or (5) C1-4 represents a 4-haloalkoxy group,
A plurality of R 40 and R 41 may be the same or different,
r represents an integer from 0 to 3, and multiple R 4 may be the same or different;
s represents an integer from 0 to 3, and plural R 5s may be the same or different.
Here, each hydrogen atom may be a deuterium atom or a tritium atom. ) or a salt thereof;
[2] A pharmaceutical composition containing a compound represented by the general formula (IY) described in [1] or a salt thereof;
[3] An agent for inhibiting progression, inhibiting recurrence, and/or treating DGKα and/or DGKζ-related diseases, which contains a compound represented by the general formula (IY) described in [1] or a salt thereof.
　本発明化合物は、ＤＧＫαおよび／またはζに対して阻害活性を有するため、例えば、癌もしくは感染症の進行抑制、再発抑制および／または治療剤の有効成分として使用できる。 Since the compound of the present invention has inhibitory activity against DGKα and/or ζ, it can be used, for example, as an active ingredient of an agent for inhibiting the progression, inhibiting recurrence, and/or treating cancer or infectious disease.
　本発明において、「ハロゲン」には、例えば、フッ素、塩素、臭素、ヨウ素原子が含まれる。 In the present invention, "halogen" includes, for example, fluorine, chlorine, bromine, and iodine atoms.
　本発明において、「Ｃ１～４アルキル基」には、メチル、エチル、プロピル、１－メチルエチル、ブチル、１－メチルプロピル、２－メチルプロピル、および１，１－ジメチルエチル基が含まれる。 In the present invention, the "C1-4 alkyl group" includes methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl, and 1,1-dimethylethyl group.
　本発明において、「水酸基で置換されたＣ１～４アルキル基」には、ヒドロキシメチル、ヒドロキシエチル、ヒドロキシプロピル、ヒドロキシ－１－メチルエチル、ヒドロキシ－ブチル、ヒドロキシ－１－メチルプロピル、ヒドロキシ－２－メチルプロピル、およびヒドロキシ－１，１－ジメチルエチル基が含まれる。本例示中、水酸基の置換位置が記載されていない基は、すべての位置異性体を包含するものとする。例えば、ヒドロキシ－１－メチルプロピル基には、１－ヒドロキシ－１－メチルプロピル、２－ヒドロキシ－１－メチルプロピル、３－ヒドロキシ－１－メチルプロピル、および１－（ヒドロキシメチル）プロピル基が含まれる。また、複数の水酸基で置換されたＣ１～４アルキル基は、具体的に開示しないが、２～３個の水酸基で置換されたすべての位置異性体も包含するものとする。 In the present invention, "C1-4 alkyl group substituted with hydroxyl group" includes hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxy-1-methylethyl, hydroxy-butyl, hydroxy-1-methylpropyl, hydroxy-2- Includes methylpropyl, and hydroxy-1,1-dimethylethyl groups. In this example, groups for which the substitution position of the hydroxyl group is not described include all positional isomers. For example, the hydroxy-1-methylpropyl group includes 1-hydroxy-1-methylpropyl, 2-hydroxy-1-methylpropyl, 3-hydroxy-1-methylpropyl, and 1-(hydroxymethyl)propyl groups. It will be done. Further, although not specifically disclosed, the C1-4 alkyl group substituted with multiple hydroxyl groups also includes all positional isomers substituted with 2 to 3 hydroxyl groups.
　本発明において、「Ｃ１～８アルキル基」には、メチル、エチル、プロピル、１－メチルエチル、ブチル、１－メチルプロピル、２－メチルプロピル、１，１－ジメチルエチル、ペンチル、１－メチルブチル、２－メチルブチル、３－メチルブチル、１，１－ジメチルプロピル、２，２－ジメチルプロピル、ヘキシル、１－メチルペンチル、２－メチルペンチル、３－メチルペンチル、４－メチルペンチル、１，１－ジメチルブチル、２，２－ジメチルブチル、３，３－ジメチルブチル、ヘプチル、１－メチルヘキシル、２－メチルヘキシル、３－メチルヘキシル、４－メチルヘキシル、５－メチルヘキシル、１，１－ジメチルペンチル、２，２－ジメチルペンチル、３，３－ジメチルペンチル、４，４－ジメチルペンチル、オクチル、１－メチルヘプチル、２－メチルヘプチル、３－メチルヘプチル、４－メチルヘプチル、５－メチルヘプチル、６－メチルヘプチル、１，１－ジメチルヘキシル、２，２－ジメチルヘキシル、３，３－ジメチルヘキシル、４，４－ジメチルヘキシル、および５，５－ジメチルヘキシル基が含まれる。本例示に具体的に示されていなくても、Ｃ１～８アルキル基であれば、本発明に含まれる。例えば、Ｃ５アルキル基としては、１，２－ジメチルプロピル、および１－エチルプロピル基も本発明に含まれる。Ｃ６～８アルキル基も同様である。 In the present invention, "C1-8 alkyl group" includes methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 1,1-dimethylpropyl, 2,2-dimethylpropyl, hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl , 2,2-dimethylbutyl, 3,3-dimethylbutyl, heptyl, 1-methylhexyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 1,1-dimethylpentyl, 2 , 2-dimethylpentyl, 3,3-dimethylpentyl, 4,4-dimethylpentyl, octyl, 1-methylheptyl, 2-methylheptyl, 3-methylheptyl, 4-methylheptyl, 5-methylheptyl, 6-methyl Included are heptyl, 1,1-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, and 5,5-dimethylhexyl groups. Even if not specifically shown in this example, any C1-8 alkyl group is included in the present invention. For example, as C5 alkyl groups, 1,2-dimethylpropyl and 1-ethylpropyl groups are also included in the present invention. The same applies to C6-8 alkyl groups.
　本発明において、「Ｃ２～４アルケニル基」には、エテニル、１－プロペニル、２－プロペニル、１－メチルエテニル、１－ブテニル、２－ブテニル、３－ブテニル、１－エチル－１－エテニル、１－メチル－１－プロペニル、２－メチル－１－プロペニル、１－メチル－２－プロペニル、および２－メチル－２－プロペニル基が含まれる。 In the present invention, "C2-4 alkenyl group" includes ethenyl, 1-propenyl, 2-propenyl, 1-methylethenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-ethyl-1-ethenyl, 1- Included are methyl-1-propenyl, 2-methyl-1-propenyl, 1-methyl-2-propenyl, and 2-methyl-2-propenyl groups.
　本発明において、「Ｃ２～４アルキニル基」には、エチニル、１－プロピニル、２－プロピニル、１－ブチニル、２－ブチニル、および３－ブチニル基が含まれる。 In the present invention, the "C2-4 alkynyl group" includes ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, and 3-butynyl groups.
　本発明において、「Ｃ１～４ハロアルキル基」には、フルオロメチル、フルオロエチル、フルオロプロピル、フルオロ－１－メチルエチル、フルオロブチル、フルオロ－１－メチルプロピル、フルオロ－２－メチルプロピル、フルオロ－１，１－ジメチルエチル、ジフルオロメチル、ジフルオロエチル、ジフルオロプロピル、ジフルオロ－１－メチルエチル、ジフルオロブチル、ジフルオロ－１－メチルプロピル、ジフルオロ－２－メチルプロピル、ジフルオロ－１，１－ジメチルエチル、トリフルオロメチル、トリフルオロエチル、トリフルオロプロピル、トリフルオロ－１－メチルエチル、トリフルオロブチル、トリフルオロ－１－メチルプロピル、トリフルオロ－２－メチルプロピル、トリフルオロ－１，１－ジメチルエチル、クロロメチル、クロロエチル、クロロプロピル、クロロ－１－メチルエチル、クロロブチル、クロロ－１－メチルプロピル、クロロ－２－メチルプロピル、クロロ－１，１－ジメチルエチル、ジクロロメチル、ジクロロエチル、ジクロロプロピル、ジクロロ－１－メチルエチル、ジクロロブチル、ジクロロ－１－メチルプロピル、ジクロロ－２－メチルプロピル、ジクロロ－１，１－ジメチルエチル、トリクロロメチル、トリクロロエチル、トリクロロプロピル、トリクロロ－１－メチルエチル、トリクロロブチル、トリクロロ－１－メチルプロピル、トリクロロ－２－メチルプロピル、トリクロロ－１，１－ジメチルエチル、および１，１，１，３，３，３－ヘキサフルオロ－２－プロピル基が含まれる。本例示中、ハロゲン原子の置換位置が記載されていない基は、すべての位置異性体を包含するものとする。例えば、フルオロ－１－メチルプロピル基には、１－フルオロ－１－メチルプロピル、２－フルオロ－１－メチルプロピル、３－フルオロ－１－メチルプロピル、および１－（フルオロメチル）プロピル基が含まれる。本例示中、ハロゲン原子の置換数が記載されていない基は、すべてのハロゲン原子の置換数を包含するものとする。例えば、ヘプタフルオロプロピル基やノナフルオロプロピル基等も、具体的には例示していないが、本発明の「Ｃ１～４ハロアルキル基」に含まれる。 In the present invention, "C1-4 haloalkyl group" includes fluoromethyl, fluoroethyl, fluoropropyl, fluoro-1-methylethyl, fluorobutyl, fluoro-1-methylpropyl, fluoro-2-methylpropyl, fluoro-1 , 1-dimethylethyl, difluoromethyl, difluoroethyl, difluoropropyl, difluoro-1-methylethyl, difluorobutyl, difluoro-1-methylpropyl, difluoro-2-methylpropyl, difluoro-1,1-dimethylethyl, trifluoro Methyl, trifluoroethyl, trifluoropropyl, trifluoro-1-methylethyl, trifluorobutyl, trifluoro-1-methylpropyl, trifluoro-2-methylpropyl, trifluoro-1,1-dimethylethyl, chloromethyl , chloroethyl, chloropropyl, chloro-1-methylethyl, chlorobutyl, chloro-1-methylpropyl, chloro-2-methylpropyl, chloro-1,1-dimethylethyl, dichloromethyl, dichloroethyl, dichloropropyl, dichloro-1 -Methyl ethyl, dichlorobutyl, dichloro-1-methylpropyl, dichloro-2-methylpropyl, dichloro-1,1-dimethylethyl, trichloromethyl, trichloroethyl, trichloropropyl, trichloro-1-methylethyl, trichlorobutyl, trichloro -1-methylpropyl, trichloro-2-methylpropyl, trichloro-1,1-dimethylethyl, and 1,1,1,3,3,3-hexafluoro-2-propyl groups. In this example, groups whose halogen atom substitution positions are not described include all positional isomers. For example, the fluoro-1-methylpropyl group includes 1-fluoro-1-methylpropyl, 2-fluoro-1-methylpropyl, 3-fluoro-1-methylpropyl, and 1-(fluoromethyl)propyl groups. It will be done. In this example, groups for which the number of halogen atoms substituted is not described include all the numbers of halogen atoms substituted. For example, heptafluoropropyl groups, nonafluoropropyl groups, and the like are also included in the "C1-4 haloalkyl group" of the present invention, although they are not specifically exemplified.
　本発明において、「水酸基で置換されていてもよいＣ１～４ハロアルキル基」には、フルオロメチル、フルオロエチル、フルオロプロピル、フルオロ－１－メチルエチル、フルオロブチル、フルオロ－１－メチルプロピル、フルオロ－２－メチルプロピル、フルオロ－１，１－ジメチルエチル、ジフルオロメチル、ジフルオロエチル、ジフルオロプロピル、ジフルオロ－１－メチルエチル、ジフルオロブチル、ジフルオロ－１－メチルプロピル、ジフルオロ－２－メチルプロピル、ジフルオロ－１，１－ジメチルエチル、トリフルオロメチル、トリフルオロエチル、トリフルオロプロピル、トリフルオロ－１－メチルエチル、トリフルオロブチル、トリフルオロ－１－メチルプロピル、トリフルオロ－２－メチルプロピル、トリフルオロ－１，１－ジメチルエチル、クロロメチル、クロロエチル、クロロプロピル、クロロ－１－メチルエチル、クロロブチル、クロロ－１－メチルプロピル、クロロ－２－メチルプロピル、クロロ－１，１－ジメチルエチル、ジクロロメチル、ジクロロエチル、ジクロロプロピル、ジクロロ－１－メチルエチル、ジクロロブチル、ジクロロ－１－メチルプロピル、ジクロロ－２－メチルプロピル、ジクロロ－１，１－ジメチルエチル、トリクロロメチル、トリクロロエチル、トリクロロプロピル、トリクロロ－１－メチルエチル、トリクロロブチル、トリクロロ－１－メチルプロピル、トリクロロ－２－メチルプロピル、トリクロロ－１，１－ジメチルエチル、およびヘキサフルオロ－２－プロピル基を含む水酸基で置換されていないＣ１～４ハロアルキル基や、水酸基で置換されていないＣ１～４ハロアルキル基の少なくとも１つの水素原子が水酸基で置換されたもの（例えば、ヘキサフルオロ－ヒドロキシ－２－プロピル基等）が含まれる。本例示中、ハロゲン原子の置換位置が記載されていない基は、すべての位置異性体を包含するものとする。例えば、フルオロ－１－メチルプロピル基には、１－フルオロ－１－メチルプロピル、２－フルオロ－１－メチルプロピル、３－フルオロ－１－メチルプロピル、および１－（フルオロメチル）プロピル基が含まれる。本例示中、ハロゲン原子の置換数が記載されていない基は、すべてのハロゲン原子の置換数を包含するものとする。例えば、ヘプタフルオロプロピル基やノナフルオロプロピル基等も、具体的には例示していないが、本発明の「水酸基で置換されていてもよいＣ１～４ハロアルキル基」に含まれる。本例示中、水酸基で置換されていないＣ１～４ハロアルキル基の少なくとも１つの水素原子が水酸基で置換されたものは、具体的に例示していなくても、化学的に安定に存在する限り、すべての位置異性体、すべてのハロゲン原子の置換数、およびすべての水酸基の置換数を包含するものとする。 In the present invention, "C1-4 haloalkyl group optionally substituted with a hydroxyl group" includes fluoromethyl, fluoroethyl, fluoropropyl, fluoro-1-methylethyl, fluorobutyl, fluoro-1-methylpropyl, fluoro- 2-Methylpropyl, fluoro-1,1-dimethylethyl, difluoromethyl, difluoroethyl, difluoropropyl, difluoro-1-methylethyl, difluorobutyl, difluoro-1-methylpropyl, difluoro-2-methylpropyl, difluoro-1 , 1-dimethylethyl, trifluoromethyl, trifluoroethyl, trifluoropropyl, trifluoro-1-methylethyl, trifluorobutyl, trifluoro-1-methylpropyl, trifluoro-2-methylpropyl, trifluoro-1 ,1-dimethylethyl, chloromethyl, chloroethyl, chloropropyl, chloro-1-methylethyl, chlorobutyl, chloro-1-methylpropyl, chloro-2-methylpropyl, chloro-1,1-dimethylethyl, dichloromethyl, dichloro Ethyl, dichloropropyl, dichloro-1-methylethyl, dichlorobutyl, dichloro-1-methylpropyl, dichloro-2-methylpropyl, dichloro-1,1-dimethylethyl, trichloromethyl, trichloroethyl, trichloropropyl, trichloro-1 - C1-4 haloalkyl unsubstituted with hydroxyl groups, including methylethyl, trichlorobutyl, trichloro-1-methylpropyl, trichloro-2-methylpropyl, trichloro-1,1-dimethylethyl, and hexafluoro-2-propyl groups and C1-4 haloalkyl groups that are not substituted with a hydroxyl group, but in which at least one hydrogen atom is substituted with a hydroxyl group (eg, hexafluoro-hydroxy-2-propyl group, etc.). In this example, groups whose halogen atom substitution positions are not described include all positional isomers. For example, the fluoro-1-methylpropyl group includes 1-fluoro-1-methylpropyl, 2-fluoro-1-methylpropyl, 3-fluoro-1-methylpropyl, and 1-(fluoromethyl)propyl groups. It will be done. In this example, groups for which the number of halogen atoms substituted is not described include all the numbers of halogen atoms substituted. For example, heptafluoropropyl groups, nonafluoropropyl groups, and the like are also included in the "C1-4 haloalkyl group optionally substituted with a hydroxyl group" of the present invention, although they are not specifically exemplified. In this example, all C1-4 haloalkyl groups that are not substituted with a hydroxyl group in which at least one hydrogen atom is substituted with a hydroxyl group, as long as they exist chemically stably, even if not specifically exemplified. This includes positional isomers, all numbers of halogen atoms, and all numbers of hydroxyl groups.
　本発明において、「Ｃ１～８ハロアルキル基」には、フルオロメチル、フルオロエチル、フルオロプロピル、フルオロ－１－メチルエチル、フルオロブチル、フルオロ－１－メチルプロピル、フルオロ－２－メチルプロピル、フルオロ－１，１－ジメチルエチル、フルオロペンチル、フルオロ－１－メチルブチル、フルオロ－２－メチルブチル、フルオロ－３－メチルブチル、フルオロ－１，１－ジメチルプロピル、フルオロ－２，２－ジメチルプロピル、フルオロヘキシル、フルオロ－１－メチルペンチル、フルオロ－２－メチルペンチル、フルオロ－３－メチルペンチル、フルオロ－４－メチルペンチル、フルオロ－１，１－ジメチルブチル、フルオロ－２，２－ジメチルブチル、フルオロ－３，３－ジメチルブチル、フルオロヘプチル、フルオロ－１－メチルヘキシル、フルオロ－２－メチルヘキシル、フルオロ－３－メチルヘキシル、フルオロ－４－メチルヘキシル、フルオロ－５－メチルヘキシル、フルオロ－１，１－ジメチルペンチル、フルオロ－２，２－ジメチルペンチル、フルオロ－３，３－ジメチルペンチル、フルオロ－４，４－ジメチルペンチル、フルオロオクチル、フルオロ－１－メチルヘプチル、フルオロ－２－メチルヘプチル、フルオロ－３－メチルヘプチル、フルオロ－４－メチルヘプチル、フルオロ－５－メチルヘプチル、フルオロ－６－メチルヘプチル、フルオロ－１，１－ジメチルヘキシル、フルオロ－２，２－ジメチルヘキシル、フルオロ－３，３－ジメチルヘキシル、フルオロ－４，４－ジメチルヘキシル、フルオロ－５，５－ジメチルヘキシル、ジフルオロメチル、ジフルオロエチル、ジフルオロプロピル、ジフルオロ－１－メチルエチル、ジフルオロブチル、ジフルオロ－１－メチルプロピル、ジフルオロ－２－メチルプロピル、ジフルオロ－１，１－ジメチルエチル、ジフルオロペンチル、ジフルオロ－１－メチルブチル、ジフルオロ－２－メチルブチル、ジフルオロ－３－メチルブチル、ジフルオロ－１，１－ジメチルプロピル、ジフルオロ－２，２－ジメチルプロピル、ジフルオロヘキシル、ジフルオロ－１－メチルペンチル、ジフルオロ－２－メチルペンチル、ジフルオロ－３－メチルペンチル、ジフルオロ－４－メチルペンチル、ジフルオロ－１，１－ジメチルブチル、ジフルオロ－２，２－ジメチルブチル、ジフルオロ－３，３－ジメチルブチル、ジフルオロヘプチル、ジフルオロ－１－メチルヘキシル、ジフルオロ－２－メチルヘキシル、ジフルオロ－３－メチルヘキシル、ジフルオロ－４－メチルヘキシル、ジフルオロ－５－メチルヘキシル、ジフルオロ－１，１－ジメチルペンチル、ジフルオロ－２，２－ジメチルペンチル、ジフルオロ－３，３－ジメチルペンチル、ジフルオロ－４，４－ジメチルペンチル、ジフルオロオクチル、ジフルオロ－１－メチルヘプチル、ジフルオロ－２－メチルヘプチル、ジフルオロ－３－メチルヘプチル、ジフルオロ－４－メチルヘプチル、ジフルオロ－５－メチルヘプチル、ジフルオロ－６－メチルヘプチル、ジフルオロ－１，１－ジメチルヘキシル、ジフルオロ－２，２－ジメチルヘキシル、ジフルオロ－３，３－ジメチルヘキシル、ジフルオロ－４，４－ジメチルヘキシル、ジフルオロ－５，５－ジメチルヘキシル、トリフルオロメチル、トリフルオロエチル、トリフルオロプロピル、トリフルオロ－１－メチルエチル、トリフルオロブチル、トリフルオロ－１－メチルプロピル、トリフルオロ－２－メチルプロピル、トリフルオロ－１，１－ジメチルエチル、トリフルオロペンチル、トリフルオロ－１－メチルブチル、トリフルオロ－２－メチルブチル、トリフルオロ－３－メチルブチル、トリフルオロ－１，１－ジメチルプロピル、トリフルオロ－２，２－ジメチルプロピル、トリフルオロヘキシル、トリフルオロ－１－メチルペンチル、トリフルオロ－２－メチルペンチル、トリフルオロ－３－メチルペンチル、トリフルオロ－４－メチルペンチル、トリフルオロ－１，１－ジメチルブチル、トリフルオロ－２，２－ジメチルブチル、トリフルオロ－３，３－ジメチルブチル、トリフルオロヘプチル、トリフルオロ－１－メチルヘキシル、トリフルオロ－２－メチルヘキシル、トリフルオロ－３－メチルヘキシル、トリフルオロ－４－メチルヘキシル、トリフルオロ－５－メチルヘキシル、トリフルオロ－１，１－ジメチルペンチル、トリフルオロ－２，２－ジメチルペンチル、トリフルオロ－３，３－ジメチルペンチル、トリフルオロ－４，４－ジメチルペンチル、トリフルオロオクチル、トリフルオロ－１－メチルヘプチル、トリフルオロ－２－メチルヘプチル、トリフルオロ－３－メチルヘプチル、トリフルオロ－４－メチルヘプチル、トリフルオロ－５－メチルヘプチル、トリフルオロ－６－メチルヘプチル、トリフルオロ－１，１－ジメチルヘキシル、トリフルオロ－２，２－ジメチルヘキシル、トリフルオロ－３，３－ジメチルヘキシル、トリフルオロ－４，４－ジメチルヘキシル、トリフルオロ－５，５－ジメチルヘキシル、クロロメチル、クロロエチル、クロロプロピル、クロロ－１－メチルエチル、クロロブチル、クロロ－１－メチルプロピル、クロロ－２－メチルプロピル、クロロ－１，１－ジメチルエチル、クロロペンチル、クロロ－１－メチルブチル、クロロ－２－メチルブチル、クロロ－３－メチルブチル、クロロ－１，１－ジメチルプロピル、クロロ－２，２－ジメチルプロピル、クロロヘキシル、クロロ－１－メチルペンチル、クロロ－２－メチルペンチル、クロロ－３－メチルペンチル、クロロ－４－メチルペンチル、クロロ－１，１－ジメチルブチル、クロロ－２，２－ジメチルブチル、クロロ－３，３－ジメチルブチル、クロロヘプチル、クロロ－１－メチルヘキシル、クロロ－２－メチルヘキシル、クロロ－３－メチルヘキシル、クロロ－４－メチルヘキシル、クロロ－５－メチルヘキシル、クロロ－１，１－ジメチルペンチル、クロロ－２，２－ジメチルペンチル、クロロ－３，３－ジメチルペンチル、クロロ－４，４－ジメチルペンチル、クロロオクチル、クロロ－１－メチルヘプチル、クロロ－２－メチルヘプチル、クロロ－３－メチルヘプチル、クロロ－４－メチルヘプチル、クロロ－５－メチルヘプチル、クロロ－６－メチルヘプチル、クロロ－１，１－ジメチルヘキシル、クロロ－２，２－ジメチルヘキシル、クロロ－３，３－ジメチルヘキシル、クロロ－４，４－ジメチルヘキシル、クロロ－５，５－ジメチルヘキシル、ジクロロメチル、ジクロロエチル、ジクロロプロピル、ジクロロ－１－メチルエチル、ジクロロブチル、ジクロロ－１－メチルプロピル、ジクロロ－２－メチルプロピル、ジクロロ－１，１－ジメチルエチル、ジクロロペンチル、ジクロロ－１－メチルブチル、ジクロロ－２－メチルブチル、ジクロロ－３－メチルブチル、ジクロロ－１，１－ジメチルプロピル、ジクロロ－２，２－ジメチルプロピル、ジクロロヘキシル、ジクロロ－１－メチルペンチル、ジクロロ－２－メチルペンチル、ジクロロ－３－メチルペンチル、ジクロロ－４－メチルペンチル、ジクロロ－１，１－ジメチルブチル、ジクロロ－２，２－ジメチルブチル、ジクロロ－３，３－ジメチルブチル、ジクロロヘプチル、ジクロロ－１－メチルヘキシル、ジクロロ－２－メチルヘキシル、ジクロロ－３－メチルヘキシル、ジクロロ－４－メチルヘキシル、ジクロロ－５－メチルヘキシル、ジクロロ－１，１－ジメチルペンチル、ジクロロ－２，２－ジメチルペンチル、ジクロロ－３，３－ジメチルペンチル、ジクロロ－４，４－ジメチルペンチル、ジクロロオクチル、ジクロロ－１－メチルヘプチル、ジクロロ－２－メチルヘプチル、ジクロロ－３－メチルヘプチル、ジクロロ－４－メチルヘプチル、ジクロロ－５－メチルヘプチル、ジクロロ－６－メチルヘプチル、ジクロロ－１，１－ジメチルヘキシル、ジクロロ－２，２－ジメチルヘキシル、ジクロロ－３，３－ジメチルヘキシル、ジクロロ－４，４－ジメチルヘキシル、ジクロロ－５，５－ジメチルヘキシル、トリクロロメチル、トリクロロエチル、トリクロロプロピル、トリクロロ－１－メチルエチル、トリクロロブチル、トリクロロ－１－メチルプロピル、トリクロロ－２－メチルプロピル、トリクロロ－１，１－ジメチルエチル、トリクロロペンチル、トリクロロ－１－メチルブチル、トリクロロ－２－メチルブチル、トリクロロ－３－メチルブチル、トリクロロ－１，１－ジメチルプロピル、トリクロロ－２，２－ジメチルプロピル、トリクロロヘキシル、トリクロロ－１－メチルペンチル、トリクロロ－２－メチルペンチル、トリクロロ－３－メチルペンチル、トリクロロ－４－メチルペンチル、トリクロロ－１，１－ジメチルブチル、トリクロロ－２，２－ジメチルブチル、トリクロロ－３，３－ジメチルブチル、トリクロロヘプチル、トリクロロ－１－メチルヘキシル、トリクロロ－２－メチルヘキシル、トリクロロ－３－メチルヘキシル、トリクロロ－４－メチルヘキシル、トリクロロ－５－メチルヘキシル、トリクロロ－１，１－ジメチルペンチル、トリクロロ－２，２－ジメチルペンチル、トリクロロ－３，３－ジメチルペンチル、トリクロロ－４，４－ジメチルペンチル、トリクロロオクチル、トリクロロ－１－メチルヘプチル、トリクロロ－２－メチルヘプチル、トリクロロ－３－メチルヘプチル、トリクロロ－４－メチルヘプチル、トリクロロ－５－メチルヘプチル、トリクロロ－６－メチルヘプチル、トリクロロ－１，１－ジメチルヘキシル、トリクロロ－２，２－ジメチルヘキシル、トリクロロ－３，３－ジメチルヘキシル、トリクロロ－４，４－ジメチルヘキシル、トリクロロ－５，５－ジメチルヘキシル、および１，１，１，３，３，３－ヘキサフルオロ－２－プロピル基が含まれる。本例示中、ハロゲン原子の置換位置が記載されていない基は、すべての位置異性体を包含するものとする。例えば、フルオロ－１－メチルプロピル基には、１－フルオロ－１－メチルプロピル、２－フルオロ－１－メチルプロピル、３－フルオロ－１－メチルプロピル、および１－（フルオロメチル）プロピル基が含まれる。本例示に具体的に示されていなくても、Ｃ１～８ハロアルキル基であれば、本発明に含まれる。例えば、Ｃ５ハロアルキル基としては、フルオロ－１，２－ジメチルプロピル、フルオロ－１－エチルプロピル、ジフルオロ－１，２－ジメチルプロピル、ジフルオロ－１－エチルプロピル、トリフルオロ－１，２－ジメチルプロピル、トリフルオロ－１－エチルプロピル、クロロ－１，２－ジメチルプロピル、クロロ－１－エチルプロピル、ジクロロ－１，２－ジメチルプロピル、ジクロロ－１－エチルプロピル、トリクロロ－１，２－ジメチルプロピル、およびトリクロロ－１－エチルプロピル基も本発明に含まれる。Ｃ６～８ハロアルキル基も同様である。本例示中、ハロゲン原子の置換数が記載されていない基は、すべてのハロゲン原子の置換数を包含するものとする。例えば、ヘプタフルオロプロピル基やノナフルオロプロピル基等も、具体的には例示していないが、本発明の「Ｃ１～８ハロアルキル基」に含まれる。 In the present invention, "C1-8 haloalkyl group" includes fluoromethyl, fluoroethyl, fluoropropyl, fluoro-1-methylethyl, fluorobutyl, fluoro-1-methylpropyl, fluoro-2-methylpropyl, fluoro-1 , 1-dimethylethyl, fluoropentyl, fluoro-1-methylbutyl, fluoro-2-methylbutyl, fluoro-3-methylbutyl, fluoro-1,1-dimethylpropyl, fluoro-2,2-dimethylpropyl, fluorohexyl, fluoro- 1-Methylpentyl, fluoro-2-methylpentyl, fluoro-3-methylpentyl, fluoro-4-methylpentyl, fluoro-1,1-dimethylbutyl, fluoro-2,2-dimethylbutyl, fluoro-3,3- Dimethylbutyl, fluoroheptyl, fluoro-1-methylhexyl, fluoro-2-methylhexyl, fluoro-3-methylhexyl, fluoro-4-methylhexyl, fluoro-5-methylhexyl, fluoro-1,1-dimethylpentyl, Fluoro-2,2-dimethylpentyl, fluoro-3,3-dimethylpentyl, fluoro-4,4-dimethylpentyl, fluorooctyl, fluoro-1-methylheptyl, fluoro-2-methylheptyl, fluoro-3-methylheptyl , fluoro-4-methylheptyl, fluoro-5-methylheptyl, fluoro-6-methylheptyl, fluoro-1,1-dimethylhexyl, fluoro-2,2-dimethylhexyl, fluoro-3,3-dimethylhexyl, fluoro -4,4-dimethylhexyl, fluoro-5,5-dimethylhexyl, difluoromethyl, difluoroethyl, difluoropropyl, difluoro-1-methylethyl, difluorobutyl, difluoro-1-methylpropyl, difluoro-2-methylpropyl, Difluoro-1,1-dimethylethyl, difluoropentyl, difluoro-1-methylbutyl, difluoro-2-methylbutyl, difluoro-3-methylbutyl, difluoro-1,1-dimethylpropyl, difluoro-2,2-dimethylpropyl, difluorohexyl , difluoro-1-methylpentyl, difluoro-2-methylpentyl, difluoro-3-methylpentyl, difluoro-4-methylpentyl, difluoro-1,1-dimethylbutyl, difluoro-2,2-dimethylbutyl, difluoro-3 , 3-dimethylbutyl, difluoroheptyl, difluoro-1-methylhexyl, difluoro-2-methylhexyl, difluoro-3-methylhexyl, difluoro-4-methylhexyl, difluoro-5-methylhexyl, difluoro-1,1- Dimethylpentyl, difluoro-2,2-dimethylpentyl, difluoro-3,3-dimethylpentyl, difluoro-4,4-dimethylpentyl, difluorooctyl, difluoro-1-methylheptyl, difluoro-2-methylheptyl, difluoro-3 -Methylheptyl, difluoro-4-methylheptyl, difluoro-5-methylheptyl, difluoro-6-methylheptyl, difluoro-1,1-dimethylhexyl, difluoro-2,2-dimethylhexyl, difluoro-3,3-dimethyl Hexyl, difluoro-4,4-dimethylhexyl, difluoro-5,5-dimethylhexyl, trifluoromethyl, trifluoroethyl, trifluoropropyl, trifluoro-1-methylethyl, trifluorobutyl, trifluoro-1-methyl Propyl, trifluoro-2-methylpropyl, trifluoro-1,1-dimethylethyl, trifluoropentyl, trifluoro-1-methylbutyl, trifluoro-2-methylbutyl, trifluoro-3-methylbutyl, trifluoro-1, 1-dimethylpropyl, trifluoro-2,2-dimethylpropyl, trifluorohexyl, trifluoro-1-methylpentyl, trifluoro-2-methylpentyl, trifluoro-3-methylpentyl, trifluoro-4-methylpentyl , trifluoro-1,1-dimethylbutyl, trifluoro-2,2-dimethylbutyl, trifluoro-3,3-dimethylbutyl, trifluoroheptyl, trifluoro-1-methylhexyl, trifluoro-2-methylhexyl , trifluoro-3-methylhexyl, trifluoro-4-methylhexyl, trifluoro-5-methylhexyl, trifluoro-1,1-dimethylpentyl, trifluoro-2,2-dimethylpentyl, trifluoro-3, 3-dimethylpentyl, trifluoro-4,4-dimethylpentyl, trifluorooctyl, trifluoro-1-methylheptyl, trifluoro-2-methylheptyl, trifluoro-3-methylheptyl, trifluoro-4-methylheptyl , trifluoro-5-methylheptyl, trifluoro-6-methylheptyl, trifluoro-1,1-dimethylhexyl, trifluoro-2,2-dimethylhexyl, trifluoro-3,3-dimethylhexyl, trifluoro- 4,4-dimethylhexyl, trifluoro-5,5-dimethylhexyl, chloromethyl, chloroethyl, chloropropyl, chloro-1-methylethyl, chlorobutyl, chloro-1-methylpropyl, chloro-2-methylpropyl, chloro- 1,1-dimethylethyl, chloropentyl, chloro-1-methylbutyl, chloro-2-methylbutyl, chloro-3-methylbutyl, chloro-1,1-dimethylpropyl, chloro-2,2-dimethylpropyl, chlorohexyl, chloro -1-methylpentyl, chloro-2-methylpentyl, chloro-3-methylpentyl, chloro-4-methylpentyl, chloro-1,1-dimethylbutyl, chloro-2,2-dimethylbutyl, chloro-3,3 -dimethylbutyl, chloroheptyl, chloro-1-methylhexyl, chloro-2-methylhexyl, chloro-3-methylhexyl, chloro-4-methylhexyl, chloro-5-methylhexyl, chloro-1,1-dimethylpentyl , chloro-2,2-dimethylpentyl, chloro-3,3-dimethylpentyl, chloro-4,4-dimethylpentyl, chlorooctyl, chloro-1-methylheptyl, chloro-2-methylheptyl, chloro-3-methyl heptyl, chloro-4-methylheptyl, chloro-5-methylheptyl, chloro-6-methylheptyl, chloro-1,1-dimethylhexyl, chloro-2,2-dimethylhexyl, chloro-3,3-dimethylhexyl, Chloro-4,4-dimethylhexyl, chloro-5,5-dimethylhexyl, dichloromethyl, dichloroethyl, dichloropropyl, dichloro-1-methylethyl, dichlorobutyl, dichloro-1-methylpropyl, dichloro-2-methylpropyl , dichloro-1,1-dimethylethyl, dichloropentyl, dichloro-1-methylbutyl, dichloro-2-methylbutyl, dichloro-3-methylbutyl, dichloro-1,1-dimethylpropyl, dichloro-2,2-dimethylpropyl, dichloro Hexyl, dichloro-1-methylpentyl, dichloro-2-methylpentyl, dichloro-3-methylpentyl, dichloro-4-methylpentyl, dichloro-1,1-dimethylbutyl, dichloro-2,2-dimethylbutyl, dichloro- 3,3-dimethylbutyl, dichloroheptyl, dichloro-1-methylhexyl, dichloro-2-methylhexyl, dichloro-3-methylhexyl, dichloro-4-methylhexyl, dichloro-5-methylhexyl, dichloro-1,1 -dimethylpentyl, dichloro-2,2-dimethylpentyl, dichloro-3,3-dimethylpentyl, dichloro-4,4-dimethylpentyl, dichlorooctyl, dichloro-1-methylheptyl, dichloro-2-methylheptyl, dichloro- 3-Methylheptyl, dichloro-4-methylheptyl, dichloro-5-methylheptyl, dichloro-6-methylheptyl, dichloro-1,1-dimethylhexyl, dichloro-2,2-dimethylhexyl, dichloro-3,3- Dimethylhexyl, dichloro-4,4-dimethylhexyl, dichloro-5,5-dimethylhexyl, trichloromethyl, trichloroethyl, trichloropropyl, trichloro-1-methylethyl, trichlorobutyl, trichloro-1-methylpropyl, trichloro-2 -Methylpropyl, trichloro-1,1-dimethylethyl, trichloropentyl, trichloro-1-methylbutyl, trichloro-2-methylbutyl, trichloro-3-methylbutyl, trichloro-1,1-dimethylpropyl, trichloro-2,2-dimethyl Propyl, trichlorohexyl, trichloro-1-methylpentyl, trichloro-2-methylpentyl, trichloro-3-methylpentyl, trichloro-4-methylpentyl, trichloro-1,1-dimethylbutyl, trichloro-2,2-dimethylbutyl , trichloro-3,3-dimethylbutyl, trichloroheptyl, trichloro-1-methylhexyl, trichloro-2-methylhexyl, trichloro-3-methylhexyl, trichloro-4-methylhexyl, trichloro-5-methylhexyl, trichloro- 1,1-dimethylpentyl, trichloro-2,2-dimethylpentyl, trichloro-3,3-dimethylpentyl, trichloro-4,4-dimethylpentyl, trichlorooctyl, trichloro-1-methylheptyl, trichloro-2-methylheptyl , trichloro-3-methylheptyl, trichloro-4-methylheptyl, trichloro-5-methylheptyl, trichloro-6-methylheptyl, trichloro-1,1-dimethylhexyl, trichloro-2,2-dimethylhexyl, trichloro-3 ,3-dimethylhexyl, trichloro-4,4-dimethylhexyl, trichloro-5,5-dimethylhexyl, and 1,1,1,3,3,3-hexafluoro-2-propyl groups. In this example, groups whose halogen atom substitution positions are not described include all positional isomers. For example, the fluoro-1-methylpropyl group includes 1-fluoro-1-methylpropyl, 2-fluoro-1-methylpropyl, 3-fluoro-1-methylpropyl, and 1-(fluoromethyl)propyl groups. It will be done. Even if not specifically shown in this example, any C1-8 haloalkyl group is included in the present invention. For example, C5 haloalkyl groups include fluoro-1,2-dimethylpropyl, fluoro-1-ethylpropyl, difluoro-1,2-dimethylpropyl, difluoro-1-ethylpropyl, trifluoro-1,2-dimethylpropyl, Trifluoro-1-ethylpropyl, chloro-1,2-dimethylpropyl, chloro-1-ethylpropyl, dichloro-1,2-dimethylpropyl, dichloro-1-ethylpropyl, trichloro-1,2-dimethylpropyl, and Trichloro-1-ethylpropyl groups are also included in the invention. The same applies to C6-8 haloalkyl groups. In this example, groups for which the number of halogen atoms substituted is not described include all the numbers of halogen atoms substituted. For example, a heptafluoropropyl group, a nonafluoropropyl group, etc. are also included in the "C1-8 haloalkyl group" of the present invention, although they are not specifically exemplified.
　本発明において、「（Ｃ１～８アルキル）カルボニル基」には、メチルカルボニル、エチルカルボニル、プロピルカルボニル、１－メチルエチルカルボニル、ブチルカルボニル、１－メチルプロピルカルボニル、２－メチルプロピルカルボニル、１，１－ジメチルエチルカルボニル、ペンチルカルボニル、１－メチルブチルカルボニル、２－メチルブチルカルボニル、３－メチルブチルカルボニル、１，１－ジメチルプロピルカルボニル、２，２－ジメチルプロピルカルボニル、ヘキシルカルボニル、１－メチルペンチルカルボニル、２－メチルペンチルカルボニル、３－メチルペンチルカルボニル、４－メチルペンチルカルボニル、１，１－ジメチルブチルカルボニル、２，２－ジメチルブチルカルボニル、３，３－ジメチルブチルカルボニル、ヘプチルカルボニル、１－メチルヘキシルカルボニル、２－メチルヘキシルカルボニル、３－メチルヘキシルカルボニル、４－メチルヘキシルカルボニル、５－メチルヘキシルカルボニル、１，１－ジメチルペンチルカルボニル、２，２－ジメチルペンチルカルボニル、３，３－ジメチルペンチルカルボニル、４，４－ジメチルペンチルカルボニル、オクチルカルボニル、１－メチルヘプチルカルボニル、２－メチルヘプチルカルボニル、３－メチルヘプチルカルボニル、４－メチルヘプチルカルボニル、５－メチルヘプチルカルボニル、６－メチルヘプチルカルボニル、１，１－ジメチルヘキシルカルボニル、２，２－ジメチルヘキシルカルボニル、３，３－ジメチルヘキシルカルボニル、４，４－ジメチルヘキシルカルボニル、および５，５－ジメチルヘキシルカルボニル基が含まれる。本例示に具体的に示されていなくても、（Ｃ１～８アルキル）カルボニル基であれば、本発明に含まれる。例えば、Ｃ５アルキルカルボニル基としては、１，２－ジメチルプロピルカルボニル、および１－エチルプロピルカルボニル基も本発明に含まれる。Ｃ６～８アルキルカルボニル基も同様である。 In the present invention, "(C1-8 alkyl)carbonyl group" includes methylcarbonyl, ethylcarbonyl, propylcarbonyl, 1-methylethylcarbonyl, butylcarbonyl, 1-methylpropylcarbonyl, 2-methylpropylcarbonyl, 1,1 -dimethylethylcarbonyl, pentylcarbonyl, 1-methylbutylcarbonyl, 2-methylbutylcarbonyl, 3-methylbutylcarbonyl, 1,1-dimethylpropylcarbonyl, 2,2-dimethylpropylcarbonyl, hexylcarbonyl, 1-methylpentylcarbonyl , 2-methylpentylcarbonyl, 3-methylpentylcarbonyl, 4-methylpentylcarbonyl, 1,1-dimethylbutylcarbonyl, 2,2-dimethylbutylcarbonyl, 3,3-dimethylbutylcarbonyl, heptylcarbonyl, 1-methylhexyl Carbonyl, 2-methylhexylcarbonyl, 3-methylhexylcarbonyl, 4-methylhexylcarbonyl, 5-methylhexylcarbonyl, 1,1-dimethylpentylcarbonyl, 2,2-dimethylpentylcarbonyl, 3,3-dimethylpentylcarbonyl, 4,4-dimethylpentylcarbonyl, octylcarbonyl, 1-methylheptylcarbonyl, 2-methylheptylcarbonyl, 3-methylheptylcarbonyl, 4-methylheptylcarbonyl, 5-methylheptylcarbonyl, 6-methylheptylcarbonyl, 1,1 -dimethylhexylcarbonyl, 2,2-dimethylhexylcarbonyl, 3,3-dimethylhexylcarbonyl, 4,4-dimethylhexylcarbonyl, and 5,5-dimethylhexylcarbonyl groups. Even if not specifically shown in this example, any (C1-8 alkyl)carbonyl group is included in the present invention. For example, as C5 alkylcarbonyl groups, 1,2-dimethylpropylcarbonyl and 1-ethylpropylcarbonyl groups are also included in the present invention. The same applies to the C6-8 alkylcarbonyl group.
　本発明において、「Ｃ１～４アルコキシカルボニル基」には、メトキシカルボニル、エトキシカルボニル、プロポキシカルボニル、１－メチルエトキシカルボニル、ブトキシカルボニル、１－メチルプロポキシカルボニル、２－メチルプロポキシカルボニル、および１，１－ジメチルエトキシカルボニル基が含まれる。 In the present invention, "C1-4 alkoxycarbonyl group" includes methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, 1-methylethoxycarbonyl, butoxycarbonyl, 1-methylpropoxycarbonyl, 2-methylpropoxycarbonyl, and 1,1- Contains dimethylethoxycarbonyl group.
　本発明において、「（Ｃ１～４アルキル）アミノカルボニル基」には、メチルアミノカルボニル、エチルアミノカルボニル、プロピルアミノカルボニル、１－メチルエチルアミノカルボニル、ブチルアミノカルボニル、１－メチルプロピルアミノカルボニル、２－メチルプロピルアミノカルボニル、および１，１－ジメチルエチルアミノカルボニル基が含まれる。 In the present invention, "(C1-4 alkyl)aminocarbonyl group" includes methylaminocarbonyl, ethylaminocarbonyl, propylaminocarbonyl, 1-methylethylaminocarbonyl, butylaminocarbonyl, 1-methylpropylaminocarbonyl, 2- Includes methylpropylaminocarbonyl, and 1,1-dimethylethylaminocarbonyl groups.
　本発明において、「ジ－（Ｃ１～４アルキル）アミノ基」には、ジメチルアミノ、ジエチルアミノ、ジプロピルアミノ、ジ（１－メチルエチル）アミノ、ジブチルアミノ、ジ（１－メチルプロピル）アミノ、ジ（２－メチルプロピル）アミノ、およびジ（１，１－ジメチルエチル）アミノ基が含まれる。 In the present invention, "di-(C1-4 alkyl)amino group" includes dimethylamino, diethylamino, dipropylamino, di(1-methylethyl)amino, dibutylamino, di(1-methylpropyl)amino, di- Includes (2-methylpropyl)amino and di(1,1-dimethylethyl)amino groups.
　本発明において、「Ｃ１～４ハロアルキルアミノ基」には、フルオロメチルアミノ、フルオロエチルアミノ、フルオロプロピルアミノ、フルオロ－１－メチルエチルアミノ、フルオロブチルアミノ、フルオロ－１－メチルプロピルアミノ、フルオロ－２－メチルプロピルアミノ、フルオロ－１，１－ジメチルエチルアミノ、ジフルオロメチルアミノ、ジフルオロエチルアミノ、ジフルオロプロピルアミノ、ジフルオロ－１－メチルエチルアミノ、ジフルオロブチルアミノ、ジフルオロ－１－メチルプロピルアミノ、ジフルオロ－２－メチルプロピルアミノ、ジフルオロ－１，１－ジメチルエチルアミノ、トリフルオロメチルアミノ、トリフルオロエチルアミノ、トリフルオロプロピルアミノ、トリフルオロ－１－メチルエチルアミノ、トリフルオロブチルアミノ、トリフルオロ－１－メチルプロピルアミノ、トリフルオロ－２－メチルプロピルアミノ、トリフルオロ－１，１－ジメチルエチルアミノ、クロロメチルアミノ、クロロエチルアミノ、クロロプロピルアミノ、クロロ－１－メチルエチルアミノ、クロロブチルアミノ、クロロ－１－メチルプロピルアミノ、クロロ－２－メチルプロピルアミノ、クロロ－１，１－ジメチルエチルアミノ、ジクロロメチルアミノ、ジクロロエチルアミノ、ジクロロプロピルアミノ、ジクロロ－１－メチルエチルアミノ、ジクロロブチルアミノ、ジクロロ－１－メチルプロピルアミノ、ジクロロ－２－メチルプロピルアミノ、ジクロロ－１，１－ジメチルエチルアミノ、トリクロロメチルアミノ、トリクロロエチルアミノ、トリクロロプロピルアミノ、トリクロロ－１－メチルエチルアミノ、トリクロロブチルアミノ、トリクロロ－１－メチルプロピルアミノ、トリクロロ－２－メチルプロピルアミノ、およびトリクロロ－１，１－ジメチルエチルアミノ基が含まれる。本例示中、ハロゲン原子の置換位置が記載されていない基は、すべての位置異性体を包含するものとする。例えば、フルオロ－１－メチルプロピルアミノ基には、１－フルオロ－１－メチルプロピルアミノ、２－フルオロ－１－メチルプロピルアミノ、３－フルオロ－１－メチルプロピルアミノ、および１－（フルオロメチル）プロピルアミノ基が含まれる。 In the present invention, "C1-4 haloalkylamino group" includes fluoromethylamino, fluoroethylamino, fluoropropylamino, fluoro-1-methylethylamino, fluorobutylamino, fluoro-1-methylpropylamino, fluoro-2 -Methylpropylamino, fluoro-1,1-dimethylethylamino, difluoromethylamino, difluoroethylamino, difluoropropylamino, difluoro-1-methylethylamino, difluorobutylamino, difluoro-1-methylpropylamino, difluoro-2 -Methylpropylamino, difluoro-1,1-dimethylethylamino, trifluoromethylamino, trifluoroethylamino, trifluoropropylamino, trifluoro-1-methylethylamino, trifluorobutylamino, trifluoro-1-methyl Propylamino, trifluoro-2-methylpropylamino, trifluoro-1,1-dimethylethylamino, chloromethylamino, chloroethylamino, chloropropylamino, chloro-1-methylethylamino, chlorobutylamino, chloro-1 -Methylpropylamino, chloro-2-methylpropylamino, chloro-1,1-dimethylethylamino, dichloromethylamino, dichloroethylamino, dichloropropylamino, dichloro-1-methylethylamino, dichlorobutylamino, dichloro-1 -Methylpropylamino, dichloro-2-methylpropylamino, dichloro-1,1-dimethylethylamino, trichloromethylamino, trichloroethylamino, trichloropropylamino, trichloro-1-methylethylamino, trichlorobutylamino, trichloro-1 -methylpropylamino, trichloro-2-methylpropylamino, and trichloro-1,1-dimethylethylamino groups. In this example, groups whose halogen atom substitution positions are not described include all positional isomers. For example, fluoro-1-methylpropylamino groups include 1-fluoro-1-methylpropylamino, 2-fluoro-1-methylpropylamino, 3-fluoro-1-methylpropylamino, and 1-(fluoromethyl) Contains a propylamino group.
　本発明において、「ジ－（Ｃ１～４アルキル）アミノカルボニル基」には、ジメチルアミノカルボニル、ジエチルアミノカルボニル、ジプロピルアミノカルボニル、ジ（１－メチルエチル）アミノカルボニル、ジブチルアミノカルボニル、ジ（１－メチルプロピル）アミノカルボニル、ジ（２－メチルプロピル）アミノカルボニル、およびジ（１，１－ジメチルエチル）アミノカルボニル基が含まれる。また、Ｎ－メチル－Ｎ－エチルアミノカルボニル基のような、異なるＣ１～４アルキルが置換するジ－（Ｃ１～４アルキル）アミノカルボニル基も含まれる。 In the present invention, "di-(C1-4 alkyl)aminocarbonyl group" includes dimethylaminocarbonyl, diethylaminocarbonyl, dipropylaminocarbonyl, di(1-methylethyl)aminocarbonyl, dibutylaminocarbonyl, di(1- Included are methylpropyl)aminocarbonyl, di(2-methylpropyl)aminocarbonyl, and di(1,1-dimethylethyl)aminocarbonyl groups. Also included are di-(C1-4 alkyl)aminocarbonyl groups substituted with different C1-4 alkyls, such as N-methyl-N-ethylaminocarbonyl groups.
　本発明において、「Ｃ１～４アルコキシ基」には、メトキシ、エトキシ、プロポキシ、１－メチルエトキシ、ブトキシ、１－メチルプロポキシ、２－メチルプロポキシ、および１，１－ジメチルエトキシ基が含まれる。 In the present invention, the "C1-4 alkoxy group" includes methoxy, ethoxy, propoxy, 1-methylethoxy, butoxy, 1-methylpropoxy, 2-methylpropoxy, and 1,1-dimethylethoxy groups.
　本発明において、「Ｃ１～４ハロアルコキシ基」には、フルオロメトキシ、フルオロエトキシ、フルオロプロポキシ、フルオロ－１－メチルエトキシ、フルオロブトキシ、フルオロ－１－メチルプロポキシ、フルオロ－２－メチルプロポキシ、フルオロ－１，１－ジメチルエトキシ、ジフルオロメトキシ、ジフルオロエトキシ、ジフルオロプロポキシ、ジフルオロ－１－メチルエトキシ、ジフルオロブトキシ、ジフルオロ－１－メチルプロポキシ、ジフルオロ－２－メチルプロポキシ、ジフルオロ－１，１－ジメチルエトキシ、トリフルオロメトキシ、トリフルオロエトキシ、トリフルオロプロポキシ、トリフルオロ－１－メチルエトキシ、トリフルオロブトキシ、トリフルオロ－１－メチルプロポキシ、トリフルオロ－２－メチルプロポキシ、トリフルオロ－１，１－ジメチルエトキシ、クロロメトキシ、クロロエトキシ、クロロプロポキシ、クロロ－１－メチルエトキシ、クロロブトキシ、クロロ－１－メチルプロポキシ、クロロ－２－メチルプロポキシ、クロロ－１，１－ジメチルエトキシ、ジクロロメトキシ、ジクロロエトキシ、ジクロロプロポキシ、ジクロロ－１－メチルエトキシ、ジクロロブトキシ、ジクロロ－１－メチルプロポキシ、ジクロロ－２－メチルプロポキシ、ジクロロ－１，１－ジメチルエトキシ、トリクロロメトキシ、トリクロロエトキシ、トリクロロプロポキシ、トリクロロ－１－メチルエトキシ、トリクロロブトキシ、トリクロロ－１－メチルプロポキシ、トリクロロ－２－メチルプロポキシ、およびトリクロロ－１，１－ジメチルエトキシ基が含まれる。本例示中、ハロゲン原子の置換位置が記載されていない基は、すべての位置異性体を包含するものとする。例えば、フルオロ－１－メチルプロポキシ基には、１－フルオロ－１－メチルプロポキシ、２－フルオロ－１－メチルプロポキシ、３－フルオロ－１－メチルプロポキシ、および１－（フルオロメチル）プロポキシ基が含まれる。 In the present invention, "C1-4 haloalkoxy group" includes fluoromethoxy, fluoroethoxy, fluoropropoxy, fluoro-1-methylethoxy, fluorobutoxy, fluoro-1-methylpropoxy, fluoro-2-methylpropoxy, fluoro- 1,1-dimethylethoxy, difluoromethoxy, difluoroethoxy, difluoropropoxy, difluoro-1-methylethoxy, difluorobutoxy, difluoro-1-methylpropoxy, difluoro-2-methylpropoxy, difluoro-1,1-dimethylethoxy, tri- Fluoromethoxy, trifluoroethoxy, trifluoropropoxy, trifluoro-1-methylethoxy, trifluorobutoxy, trifluoro-1-methylpropoxy, trifluoro-2-methylpropoxy, trifluoro-1,1-dimethylethoxy, chloro Methoxy, chloroethoxy, chloropropoxy, chloro-1-methylethoxy, chlorobutoxy, chloro-1-methylpropoxy, chloro-2-methylpropoxy, chloro-1,1-dimethylethoxy, dichloromethoxy, dichloroethoxy, dichloropropoxy, Dichloro-1-methylethoxy, dichlorobutoxy, dichloro-1-methylpropoxy, dichloro-2-methylpropoxy, dichloro-1,1-dimethylethoxy, trichloromethoxy, trichloroethoxy, trichloropropoxy, trichloro-1-methylethoxy, trichloro Included are butoxy, trichloro-1-methylpropoxy, trichloro-2-methylpropoxy, and trichloro-1,1-dimethylethoxy groups. In this example, groups whose halogen atom substitution positions are not described include all positional isomers. For example, fluoro-1-methylpropoxy groups include 1-fluoro-1-methylpropoxy, 2-fluoro-1-methylpropoxy, 3-fluoro-1-methylpropoxy, and 1-(fluoromethyl)propoxy groups. It will be done.
　本発明において、「（Ｃ１～４アルキル）アミノ基」には、メチルアミノ、エチルアミノ、プロピルアミノ、１－メチルエチルアミノ、ブチルアミノ、１－メチルプロピルアミノ、２－メチルプロピルアミノ、および１，１－ジメチルエチルアミノ基が含まれる。 In the present invention, "(C1-4 alkyl)amino group" includes methylamino, ethylamino, propylamino, 1-methylethylamino, butylamino, 1-methylpropylamino, 2-methylpropylamino, and 1, Contains a 1-dimethylethylamino group.
　本発明において、「３～１５員の炭素環」には、単環、二環もしくは三環式の、不飽和、一部飽和、もしくは飽和した３～１５員の炭素環が含まれる。単環、二環もしくは三環式の、不飽和の３～１５員の炭素環としては、例えば、ベンゼン、ペンタレン、ナフタレン、アズレン、フェナントレン、アントラセン、アセナフチレン、およびビフェニレン環等が挙げられる。単環、二環もしくは三環式の、一部飽和、もしくは飽和した３～１５員の炭素環としては、例えば、シクロプロパン、シクロブタン、シクロペンタン、シクロヘキサン、シクロヘプタン、シクロペンテン、シクロヘキセン、シクロペンタジエン、シクロヘキサジエン、インデン、ジヒドロインデン（インダン）、フルオレン、パーヒドロペンタレン、パーヒドロインデン、パーヒドロナフタレン、パーヒドロアズレン、パーヒドロフルオレン、パーヒドロフェナントレイン、パーヒドロアントラセン、パーヒドロアセナフチレン、パーヒドロビフェニレン、ビシクロ［１．１．１］ペンタン、ビシクロ［３．２．１］オクタン、スピロ［３．５］ノナン、スピロ［３．３］ヘプタン、およびアダマンタン環等が挙げられる。 In the present invention, the "3- to 15-membered carbocycle" includes monocyclic, bicyclic, or tricyclic, unsaturated, partially saturated, or saturated 3- to 15-membered carbocycles. Examples of monocyclic, bicyclic, or tricyclic unsaturated 3- to 15-membered carbon rings include benzene, pentalene, naphthalene, azulene, phenanthrene, anthracene, acenaphthylene, and biphenylene rings. Examples of the monocyclic, bicyclic or tricyclic partially saturated or saturated 3- to 15-membered carbon ring include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclopentene, cyclohexene, cyclopentadiene, Cyclohexadiene, indene, dihydroindene (indane), fluorene, perhydropentalene, perhydroindene, perhydronaphthalene, perhydroazulene, perhydrofluorene, perhydrophenanthrene, perhydroanthracene, perhydroacenaphthylene, Examples include perhydrobiphenylene, bicyclo[1.1.1]pentane, bicyclo[3.2.1]octane, spiro[3.5]nonane, spiro[3.3]heptane, and adamantane ring.
　本発明において、「３～１５員の複素環」には、単環、二環もしくは三環式の、１～４個の窒素原子、１～２個の酸素原子および／または１個の硫黄原子を含有する、不飽和、一部飽和、もしくは飽和した３～１５員の複素環が含まれる。単環、二環もしくは三環式の、１～４個の窒素原子、１～２個の酸素原子および／または１個の硫黄原子を含有する、不飽和の３～１５員の複素環としては、例えば、ピロール、イミダゾール、トリアゾール、テトラゾール、ピラゾール、ピリジン、ピラジン、ピリミジン、ピリダジン、アゼピン、ジアゼピン、フラン、ピラン、オキセピン、オキサゼピン、チオフェン、チアイン（チオピラン）、チエピン、オキサゾール、イソオキサゾール、チアゾール、イソチアゾール、オキサジアゾール、オキサアジン、オキサジアジン、オキサアゼピン、オキサジアゼピン、チアジアゾール、チアジン、チアジアジン、チアゼピン、チアジアゼピン、インドール、イソインドール、ベンゾフラン、イソベンゾフラン、ベンゾチオフェン、イソベンゾチオフェン、インダゾール、キノリン、イソキノリン、フタラジン、ナフチリジン、キノキサリン、キナゾリン、シンノリン、ベンゾオキサゾール、ベンゾオキサジアゾール、ベンゾチアゾール、ベンゾイミダゾール、カルバゾール、およびアクリジン環等が挙げられる。単環、二環もしくは三環式の、１～４個の窒素原子、１～２個の酸素原子および／または１個の硫黄原子を含有する、一部飽和、もしくは飽和した３～１５員の複素環としては、例えば、アジリジン、オキシラン、アゼチジン、オキセタン、チイラン、チエタン、ピロリン、ピロリジン、イミダゾリン、イミダゾリジン、トリアゾリン、トリアゾリジン、テトラゾリン、テトラゾリジン、ピラゾリン、ピラゾリジン、ピペリジン、ピペラジン、テトラヒドロピリジン、テトラヒドロピリミジン、テトラヒドロピリダジン、ジヒドロフラン、テトラヒドロフラン、ジヒドロピラン、テトラヒドロピラン、ジヒドロチオフェン、テトラヒドロチオフェン、ジヒドロチアイン（ジヒドロチオピラン）、テトラヒドロチアイン（テトラヒドロチオピラン）、オキサゾリン（ジヒドロオキサゾール）、オキサゾリジン（テトラヒドロオキサゾール）、ジヒドロイソオキサゾール、テトラヒドロイソオキサゾール、オキサジアゾリン（ジヒドロオキサジアゾール）、オキサジアゾリジン（テトラヒドロオキサジアゾール）、チアゾリン（ジヒドロチアゾール）、チアゾリジン（テトラヒドロチアゾール）、ジヒドロイソチアゾール、テトラヒドロイソチアゾール、モルホリン、チオモルホリン、インドリン、イソインドリン、ジヒドロベンゾフラン、パーヒドロベンゾフラン、ジヒドロイソベンゾフラン、パーヒドロイソベンゾフラン、ジヒドロベンゾチオフェン、パーヒドロベンゾチオフェン、ジヒドロイソベンゾチオフェン、パーヒドロイソベンゾチオフェン、ジヒドロインダゾール、パーヒドロインダゾール、ジヒドロキノリン、テトラヒドロキノリン、パーヒドロキノリン、ジヒドロイソキノリン、テトラヒドロイソキノリン、パーヒドロイソキノリン、ジヒドロフタラジン、テトラヒドロフタラジン、パーヒドロフタラジン、ジヒドロナフチリジン、テトラヒドロナフチリジン、パーヒドロナフチリジン、ジヒドロキノキサリン、テトラヒドロキノキサリン、パーヒドロキノキサリン、ジヒドロキナゾリン、テトラヒドロキナゾリン、パーヒドロキナゾリン、ジヒドロシンノリン、テトラヒドロシンノリン、パーヒドロシンノリン、ジヒドロベンゾオキサゾール、パーヒドロベンゾオキサゾール、ジヒドロベンゾチアゾール、パーヒドロベンゾチアゾール、ジヒドロベンゾイミダゾール、パーヒドロベンゾイミダゾール、ベンゾオキサゼピン、ベンゾオキサジアゼピン、ベンゾチアゼピン、ベンゾチアジアゼピン、ベンゾアゼピン、ベンゾジアゼピン、インドロオキソアゼピン、インドロテトラヒドロオキサゼピン、インドロオキサジアゼピン、インドロテトラヒドロオキサジアゼピン、インドロチアゼピン、インドロテトラヒドロチアゼピン、インドロチアジアゼピン、インドロテトラヒドロチアジアゼピン、インドロアゼピン、インドロテトラヒドロアゼピン、インドロジアゼピン、インドロテトラヒドロジアゼピン、ベンゾフラザン、ベンゾチアジアゾール、ベンゾトリアゾール、カンファー、イミダゾチアゾール、ジヒドロカルバゾール、テトラヒドロカルバゾール、パーヒドロカルバゾール、ジヒドロアクリジン、テトラヒドロアクリジン、パーヒドロアクリジン、ジオキソラン、ジオキサン、ジオキサジン、クロマン、パーヒドロアゼピン、パーヒドロジアゼピン、パーヒドロチエピン、パーヒドロオキサアゼピン、パーヒドロオキサジアゼピン、パーヒドロチアゼピン、および、パーヒドロチアジアゼピン環等が挙げられる。 In the present invention, a "3- to 15-membered heterocycle" includes a monocyclic, bicyclic, or tricyclic ring containing 1 to 4 nitrogen atoms, 1 to 2 oxygen atoms, and/or 1 sulfur atom. unsaturated, partially saturated, or saturated 3- to 15-membered heterocycles containing . As a monocyclic, bicyclic or tricyclic unsaturated 3- to 15-membered heterocycle containing 1 to 4 nitrogen atoms, 1 to 2 oxygen atoms and/or 1 sulfur atom, , for example, pyrrole, imidazole, triazole, tetrazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, azepine, diazepine, furan, pyran, oxepin, oxazepine, thiophene, thiaine (thiopyran), thiepine, oxazole, isoxazole, thiazole, iso Thiazole, oxadiazole, oxazine, oxadiazine, oxazepine, oxadiazepine, thiadiazole, thiazine, thiadiazine, thiazepine, thiadiazepine, indole, isoindole, benzofuran, isobenzofuran, benzothiophene, isobenzothiophene, indazole, quinoline, isoquinoline, phthalazine, naphthyridine , quinoxaline, quinazoline, cinnoline, benzoxazole, benzoxadiazole, benzothiazole, benzimidazole, carbazole, and acridine ring. monocyclic, bicyclic or tricyclic, partially saturated or saturated 3- to 15-membered, containing 1 to 4 nitrogen atoms, 1 to 2 oxygen atoms and/or 1 sulfur atom; Examples of the heterocycle include aziridine, oxirane, azetidine, oxetane, thiirane, thietane, pyrroline, pyrrolidine, imidazoline, imidazolidine, triazoline, triazolidine, tetrazoline, tetrazolidine, pyrazoline, pyrazolidine, piperidine, piperazine, tetrahydropyridine, tetrahydropyrimidine, Tetrahydropyridazine, dihydrofuran, tetrahydrofuran, dihydropyran, tetrahydropyran, dihydrothiophene, tetrahydrothiophene, dihydrothiaine (dihydrothiopyran), tetrahydrothiaine (tetrahydrothiopyran), oxazoline (dihydroxazole), oxazolidine (tetrahydroxazole), Dihydroisoxazole, tetrahydroisoxazole, oxadiazoline (dihydrooxadiazole), oxadiazolidine (tetrahydroxadiazole), thiazoline (dihydrothiazole), thiazolidine (tetrahydrothiazole), dihydroisothiazole, tetrahydroisothiazole, morpholine, Thiomorpholine, indoline, isoindoline, dihydrobenzofuran, perhydrobenzofuran, dihydroisobenzofuran, perhydroisobenzofuran, dihydrobenzothiophene, perhydrobenzothiophene, dihydroisobenzothiophene, perhydroisobenzothiophene, dihydroindazole, perhydroindazole , dihydroquinoline, tetrahydroquinoline, perhydroquinoline, dihydroisoquinoline, tetrahydroisoquinoline, perhydroisoquinoline, dihydrophthalazine, tetrahydrophthalazine, perhydrophthalazine, dihydronaphthyridine, tetrahydronaphthyridine, perhydronaphthyridine, dihydroquinoxaline, tetrahydroquinoxaline, Perhydroquinoxaline, dihydroquinazoline, tetrahydroquinazoline, perhydroquinazoline, dihydrocinnoline, tetrahydrocinnoline, perhydrocinnoline, dihydrobenzoxazole, perhydrobenzoxazole, dihydrobenzothiazole, perhydrobenzothiazole, dihydrobenzimidazole, Hydrobenzimidazole, benzoxazepine, benzoxadiazepine, benzothiazepine, benzothiadiazepine, benzazepine, benzodiazepine, indoloxoazepine, indrotetrahydroxazepine, indolooxadiazepine, indrotetrahydroxa Diazepine, Indrothiazepine, Indrotetrahydrothiazepine, Indorothiadiazepine, Indrotetrahydrothiadiazepine, Indoazepine, Indrotetrahydroazepine, Indolodiazepine, Indrotetrahydrodiazepine, Benzofurazan, Benzothiadiazole, Benzo Triazole, camphor, imidazothiazole, dihydrocarbazole, tetrahydrocarbazole, perhydrocarbazole, dihydroacridine, tetrahydroacridine, perhydroacridine, dioxolane, dioxane, dioxazine, chroman, perhydroazepine, perhydrodiazepine, perhydrothiepine, perhydroacridine Examples include hydrooxazepine, perhydroxadiazepine, perhydrothiazepine, and perhydrothiadiazepine ring.
　本発明において、「３～１５員の複素環」には、架橋された環やスピロ環も含まれる。架橋された３～１５員の複素環としては、例えば、８－アザビシクロ［３．２．１］オクタン環等が挙げられる。スピロ環である３～１５員の複素環としては、例えば、１－オキサ－７－アザスピロ［４．４］ノナン、および、２－アザスピロ［３．３］ヘプタン等が挙げられる。 In the present invention, the "3- to 15-membered heterocycle" also includes bridged rings and spiro rings. Examples of the bridged 3- to 15-membered heterocycle include an 8-azabicyclo[3.2.1]octane ring. Examples of the 3- to 15-membered heterocycle that is a spiro ring include 1-oxa-7-azaspiro[4.4]nonane and 2-azaspiro[3.3]heptane.
　本発明において、「５～６員の炭素環」には、単環の、不飽和、一部飽和、もしくは飽和した５～６員の炭素環が含まれる。単環の、不飽和の５～６員の炭素環としては、例えば、シクロペンタジエン、およびベンゼン環が挙げられる。単環の、一部飽和、もしくは飽和した５～６員の炭素環としては、例えば、シクロペンタン、シクロヘキサン、シクロペンテン、シクロヘキセン、およびシクロヘキサジエン環等が挙げられる。 In the present invention, the "5- to 6-membered carbocycle" includes a monocyclic, unsaturated, partially saturated, or saturated 5- to 6-membered carbocycle. Examples of the monocyclic unsaturated 5- to 6-membered carbon ring include cyclopentadiene and a benzene ring. Examples of the monocyclic partially saturated or saturated 5- to 6-membered carbon ring include cyclopentane, cyclohexane, cyclopentene, cyclohexene, and cyclohexadiene rings.
　本発明において、「５～６員の複素環」には、単環の、１～４個の窒素原子、１～２個の酸素原子および／または１個の硫黄原子を含有する、不飽和、一部飽和、もしくは飽和した５～６員の複素環が含まれる。単環の、１～４個の窒素原子、１～２個の酸素原子および／または１個の硫黄原子を含有する、不飽和の５～６員の複素環としては、例えば、ピロール、イミダゾール、トリアゾール、テトラゾール、ピラゾール、ピリジン、ピラジン、ピリミジン、ピリダジン、フラン、ピラン、チオフェン、チアイン（チオピラン）、オキサゾール、イソオキサゾール、チアゾール、イソチアゾール、オキサジアゾール、オキサジン、オキサジアジン、チアジアゾール、チアジン、およびチアジアジン環等が挙げられる。単環の、１～４個の窒素原子、１～２個の酸素原子および／または１個の硫黄原子を含有する、一部飽和、もしくは飽和した５～６員の複素環としては、例えば、ピロリン、ピロリジン、イミダゾリン、イミダゾリジン、トリアゾリン、トリアゾリジン、テトラゾリン、テトラゾリジン、ピラゾリン、ピラゾリジン、ピペリジン、ピペラジン、テトラヒドロピリジン、テトラヒドロピリミジン、テトラヒドロピリダジン、ジヒドロフラン、テトラヒドロフラン、ジヒドロピラン、テトラヒドロピラン、ジヒドロチオフェン、テトラヒドロチオフェン、ジヒドロチアイン（ジヒドロチオピラン）、テトラヒドロチアイン（テトラヒドロチオピラン）、オキサゾリン（ジヒドロオキサゾール）、オキサゾリジン（テトラヒドロオキサゾール）、ジヒドロイソオキサゾール、テトラヒドロイソオキサゾール、オキサジアゾリン（ジヒドロオキサジアゾール）、オキサジアゾリジン（テトラヒドロオキサジアゾール）、チアゾリン（ジヒドロチアゾール）、チアゾリジン（テトラヒドロチアゾール）、ジヒドロイソチアゾール、テトラヒドロイソチアゾール、モルホリン、チオモルホリン、ジオキソラン、ジオキサン、およびジオキサジン環等が挙げられる。 In the present invention, "5- to 6-membered heterocycle" refers to a monocyclic unsaturated ring containing 1 to 4 nitrogen atoms, 1 to 2 oxygen atoms and/or 1 sulfur atom, Includes partially saturated or saturated 5- to 6-membered heterocycles. Examples of the monocyclic unsaturated 5- to 6-membered heterocycle containing 1 to 4 nitrogen atoms, 1 to 2 oxygen atoms, and/or 1 sulfur atom include pyrrole, imidazole, Triazole, tetrazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, furan, pyran, thiophene, thiaine (thiopyran), oxazole, isoxazole, thiazole, isothiazole, oxadiazole, oxazine, oxadiazine, thiadiazole, thiazine, and thiadiazine ring etc. Examples of monocyclic partially saturated or saturated 5- to 6-membered heterocycles containing 1 to 4 nitrogen atoms, 1 to 2 oxygen atoms, and/or 1 sulfur atom include: Pyrroline, pyrrolidine, imidazoline, imidazolidine, triazoline, triazolidine, tetrazoline, tetrazolidine, pyrazoline, pyrazolidine, piperidine, piperazine, tetrahydropyridine, tetrahydropyrimidine, tetrahydropyridazine, dihydrofuran, tetrahydrofuran, dihydropyran, tetrahydropyran, dihydrothiophene, tetrahydrothiophene , Dihydrothiaine (Dihydrothiopyran), Tetrahydrothiaine (Tetrahydrothiopyran), Oxazoline (Dihydroxazole), Oxazolidine (Tetrahydroxazole), Dihydroisoxazole, Tetrahydroisoxazole, Oxadiazoline (Dihydroxadiazole), Oxa Examples include diazolidine (tetrahydroxadiazole), thiazoline (dihydrothiazole), thiazolidine (tetrahydrothiazole), dihydroisothiazole, tetrahydroisothiazole, morpholine, thiomorpholine, dioxolane, dioxane, and dioxazine ring.
　本発明において、「５～７員の複素環」には、単環の、１～４個の窒素原子、１～２個の酸素原子および／または１個の硫黄原子を含有する、不飽和、一部飽和、もしくは飽和した５～７員の複素環が含まれる。単環の、１～４個の窒素原子、１～２個の酸素原子および／または１個の硫黄原子を含有する、不飽和の５～６員の複素環としては、例えば、ピロール、イミダゾール、トリアゾール、テトラゾール、ピラゾール、ピリジン、ピラジン、ピリミジン、ピリダジン、アゼピン、ジアゼピン、フラン、ピラン、チオフェン、チアイン（チオピラン）、チエピン、オキサゾール、イソオキサゾール、チアゾール、イソチアゾール、オキサジアゾール、オキサジン、オキサジアジン、オキサアゼピン、オキサジアゼピン、チアジアゾール、チアジン、チアジアジン、チアゼピン、および、チアジアゼピン環等が挙げられる。単環の、１～４個の窒素原子、１～２個の酸素原子および／または１個の硫黄原子を含有する、一部飽和、もしくは飽和した５～７員の複素環としては、例えば、ピロリン、ピロリジン、イミダゾリン、イミダゾリジン、トリアゾリン、トリアゾリジン、テトラゾリン、テトラゾリジン、ピラゾリン、ピラゾリジン、ピペリジン、ピペラジン、テトラヒドロピリジン、テトラヒドロピリミジン、テトラヒドロピリダジン、ジヒドロフラン、テトラヒドロフラン、ジヒドロピラン、テトラヒドロピラン、ジヒドロチオフェン、テトラヒドロチオフェン、ジヒドロチアイン（ジヒドロチオピラン）、テトラヒドロチアイン（テトラヒドロチオピラン）、オキサゾリン（ジヒドロオキサゾール）、オキサゾリジン（テトラヒドロオキサゾール）、ジヒドロイソオキサゾール、テトラヒドロイソオキサゾール、オキサジアゾリン（ジヒドロオキサジアゾール）、オキサジアゾリジン（テトラヒドロオキサジアゾール）、チアゾリン（ジヒドロチアゾール）、チアゾリジン（テトラヒドロチアゾール）、ジヒドロイソチアゾール、テトラヒドロイソチアゾール、モルホリン、チオモルホリン、ジオキソラン、ジオキサン、ジオキサジン、パーヒドロアゼピン、パーヒドロジアゼピン、パーヒドロチエピン、パーヒドロオキサアゼピン、パーヒドロオキサジアゼピン、パーヒドロチアゼピン、およびパーヒドロチアジアゼピン環等が挙げられる。 In the present invention, "5- to 7-membered heterocycle" refers to a monocyclic unsaturated ring containing 1 to 4 nitrogen atoms, 1 to 2 oxygen atoms, and/or 1 sulfur atom, Includes partially saturated or saturated 5- to 7-membered heterocycles. Examples of the monocyclic unsaturated 5- to 6-membered heterocycle containing 1 to 4 nitrogen atoms, 1 to 2 oxygen atoms, and/or 1 sulfur atom include pyrrole, imidazole, Triazole, tetrazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, azepine, diazepine, furan, pyran, thiophene, thiaine (thiopyran), thiepine, oxazole, isoxazole, thiazole, isothiazole, oxadiazole, oxazine, oxadiazine, oxazepine , oxadiazepine, thiadiazole, thiazine, thiadiazine, thiazepine, and thiadiazepine ring. Examples of monocyclic partially saturated or saturated 5- to 7-membered heterocycles containing 1 to 4 nitrogen atoms, 1 to 2 oxygen atoms, and/or 1 sulfur atom include: Pyrroline, pyrrolidine, imidazoline, imidazolidine, triazoline, triazolidine, tetrazoline, tetrazolidine, pyrazoline, pyrazolidine, piperidine, piperazine, tetrahydropyridine, tetrahydropyrimidine, tetrahydropyridazine, dihydrofuran, tetrahydrofuran, dihydropyran, tetrahydropyran, dihydrothiophene, tetrahydrothiophene , Dihydrothiaine (Dihydrothiopyran), Tetrahydrothiaine (Tetrahydrothiopyran), Oxazoline (Dihydroxazole), Oxazolidine (Tetrahydroxazole), Dihydroisoxazole, Tetrahydroisoxazole, Oxadiazoline (Dihydroxadiazole), Oxa Diazolidine (tetrahydroxadiazole), thiazoline (dihydrothiazole), thiazolidine (tetrahydrothiazole), dihydroisothiazole, tetrahydroisothiazole, morpholine, thiomorpholine, dioxolane, dioxane, dioxazine, perhydroazepine, perhydrodiazepine, par Examples include hydrothiepine, perhydroxazepine, perhydroxadiazepine, perhydrothiazepine, perhydrothiadiazepine ring, and the like.
　本発明において、「３～６員の飽和複素環」には、アジリジン、オキシラン、アゼチジン、オキセタン、チイラン、チエタン、ピロリジン、イミダゾリジン、トリアゾリジン、テトラゾリジン、ピラゾリジン、ピペリジン、ピペラジン、テトラヒドロフラン、テトラヒドロピラン、テトラヒドロチオフェン、テトラヒドロチアイン（テトラヒドロチオピラン）、オキサゾリジン（テトラヒドロオキサゾール）、テトラヒドロイソオキサゾール、オキサジアゾリジン（テトラヒドロオキサジアゾール）、チアゾリジン（テトラヒドロチアゾール）、テトラヒドロイソチアゾール、モルホリン、チオモルホリン、ジオキソラン、およびジオキサン環が含まれる。 In the present invention, "3- to 6-membered saturated heterocycle" includes aziridine, oxirane, azetidine, oxetane, thiirane, thietane, pyrrolidine, imidazolidine, triazolidine, tetrazolidine, pyrazolidine, piperidine, piperazine, tetrahydrofuran, tetrahydropyran, and tetrahydrofuran. Thiophene, tetrahydrothiaine (tetrahydrothiopyran), oxazolidine (tetrahydroxazole), tetrahydroisoxazole, oxadiazolidine (tetrahydroxadiazole), thiazolidine (tetrahydrothiazole), tetrahydroisothiazole, morpholine, thiomorpholine, dioxolane, and dioxane Contains rings.
　本発明において、「５～７員の含窒素飽和複素環」には、ピロリジン、イミダゾリジン、トリアゾリジン、テトラゾリジン、ピラゾリジン、ピペリジン、ピペラジン、オキサゾリジン（テトラヒドロオキサゾール）、テトラヒドロイソオキサゾール、オキサジアゾリジン（テトラヒドロオキサジアゾール）、チアゾリジン（テトラヒドロチアゾール）、テトラヒドロイソチアゾール、モルホリン、チオモルホリン、パーヒドロアゼピン、パーヒドロジアゼピン、パーヒドロチエピン、パーヒドロオキサアゼピン、パーヒドロオキサジアゼピン、パーヒドロチアゼピン、およびパーヒドロチアジアゼピン、および２－アザスピロ［３．３］ヘプタン環が含まれる。 In the present invention, "5- to 7-membered nitrogen-containing saturated heterocycle" includes pyrrolidine, imidazolidine, triazolidine, tetrazolidine, pyrazolidine, piperidine, piperazine, oxazolidine (tetrahydroxazole), tetrahydroisoxazole, oxadiazolidine (tetrahydroxazole), diazole), thiazolidine (tetrahydrothiazole), tetrahydroisothiazole, morpholine, thiomorpholine, perhydroazepine, perhydrodiazepine, perhydrothiepine, perhydroxazepine, perhydroxadiazepine, perhydrothiazepine, and Includes perhydrothiadiazepine, and 2-azaspiro[3.3]heptane rings.
　本発明において、「飽和または一部不飽和の４～１０員の炭素環」としては、例えば、シクロブタン、シクロヘキサン、シクロヘキセン、ビシクロ［１．１．１］ペンタン、ビシクロ［３．１．１］ヘプタン、ビシクロ［２．２．２］オクタン、スピロ［３．３］ヘプタン、スピロ［３．５］ノナン、ビシクロ［３．１．０］ヘキサン、キュバン、アダマンタン、ノルボルネン、および、デカヒドロナフタレン等が挙げられる。 In the present invention, examples of the "saturated or partially unsaturated 4- to 10-membered carbon ring" include cyclobutane, cyclohexane, cyclohexene, bicyclo[1.1.1]pentane, and bicyclo[3.1.1]heptane. , bicyclo[2.2.2]octane, spiro[3.3]heptane, spiro[3.5]nonane, bicyclo[3.1.0]hexane, cuban, adamantane, norbornene, and decahydronaphthalene, etc. Can be mentioned.
　本発明において、「１個の窒素原子、１個の酸素原子および／または酸化されていてもよい１個の硫黄原子を含有する６員の飽和複素環」としては、例えば、テトラヒドロピラン等が挙げられる。 In the present invention, examples of the "6-membered saturated heterocycle containing one nitrogen atom, one oxygen atom, and/or one optionally oxidized sulfur atom" include tetrahydropyran, etc. It will be done.
　本発明において、「１個の窒素原子、１個の酸素原子および／または酸化されていてもよい１個の硫黄原子を含有していてもよい、４～１０員の飽和炭素環」としては、例えば、シクロブタン、シクロヘキサン、ビシクロ［１．１．１］ペンタン、ビシクロ［３．１．１］ヘプタン、ビシクロ［２．２．２］オクタン、スピロ［３．３］ヘプタン、スピロ［３．５］ノナン、ビシクロ［３．１．０］ヘキサン、キュバン、アダマンタン、デカヒドロナフタレン、およびテトラヒドロピラン等が挙げられる。 In the present invention, "a 4- to 10-membered saturated carbon ring that may contain one nitrogen atom, one oxygen atom, and/or one sulfur atom that may be oxidized" includes: For example, cyclobutane, cyclohexane, bicyclo[1.1.1]pentane, bicyclo[3.1.1]heptane, bicyclo[2.2.2]octane, spiro[3.3]heptane, spiro[3.5] Examples include nonane, bicyclo[3.1.0]hexane, cuban, adamantane, decahydronaphthalene, and tetrahydropyran.
　本発明において、「酸化されていてもよい硫黄原子」には、－Ｓ－、－Ｓ（Ｏ）－、および－ＳＯ２－が含まれる。 In the present invention, the "optionally oxidized sulfur atom" includes -S-, -S(O)-, and -SO 2 -.
　本発明において、「Ｃ３～６シクロアルキル基」には、シクロプロパン、シクロブタン、シクロペンタン、およびシクロヘキサン環が含まれる。 In the present invention, the "C3-6 cycloalkyl group" includes cyclopropane, cyclobutane, cyclopentane, and cyclohexane rings.
　本発明において、「（Ｃ３～６シクロアルキル）カルボニル基」には、シクロプロピルカルボニル、シクロブチルカルボニル、シクロペンチルカルボニル、およびシクロヘキシルカルボニル基が含まれる。 In the present invention, the "(C3-6 cycloalkyl)carbonyl group" includes cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, and cyclohexylcarbonyl group.
　本発明において、「Ｃ３～８シクロアルキル基」には、シクロプロパン、シクロブタン、シクロペンタン、シクロヘキサン、シクロヘプタン、およびシクロオクタン環が含まれる。 In the present invention, the "C3-8 cycloalkyl group" includes cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, and cyclooctane rings.
　本発明において、「Ｃ１～４アルキルスルホニル基」には、メチルスルホニル、エチルスルホニル、プロピルスルホニル、１－メチルエチルスルホニル、ブチルスルホニル、１－メチルプロピルスルホニル、２－メチルプロピルスルホニル、および１，１－ジメチルエチルスルホニル基が含まれる。 In the present invention, "C1-4 alkylsulfonyl group" includes methylsulfonyl, ethylsulfonyl, propylsulfonyl, 1-methylethylsulfonyl, butylsulfonyl, 1-methylpropylsulfonyl, 2-methylpropylsulfonyl, and 1,1- Contains dimethylethylsulfonyl group.
　本発明において、「Ｃ２～４アルケニルスルホニル基」には、エテニルスルホニル、１－プロペニルスルホニル、２－プロペニルスルホニル、１－メチルエテニルスルホニル、１－ブテニルスルホニル、２－ブテニルスルホニル、３－ブテニルスルホニル、１－エチル－１－エテニルスルホニル、１－メチル－１－プロペニルスルホニル、２－メチル－１－プロペニルスルホニル、１－メチル－２－プロペニルスルホニル、および２－メチル－２－プロペニルスルホニル基が含まれる。 In the present invention, "C2-4 alkenylsulfonyl group" includes ethenylsulfonyl, 1-propenylsulfonyl, 2-propenylsulfonyl, 1-methylethenylsulfonyl, 1-butenylsulfonyl, 2-butenylsulfonyl, 3- Butenylsulfonyl, 1-ethyl-1-ethenylsulfonyl, 1-methyl-1-propenylsulfonyl, 2-methyl-1-propenylsulfonyl, 1-methyl-2-propenylsulfonyl, and 2-methyl-2-propenylsulfonyl Contains groups.
　本発明において、Ｒ１として好ましくは、（１）１～５個のＲ１１で置換されていてもよい３～１５員の炭素環で置換されたメチレン、または（２）１～５個のＲ１２で置換されていてもよい３～１５員の複素環で置換されたメチレンであり、より好ましくは、１～５個のＲ１１で置換されていてもよい５～６員の炭素環で置換されたメチレンであり、さらに好ましくは、１～５個のＲ１１で置換されていてもよいベンゼンで置換されたメチレンである。 In the present invention, R 1 is preferably (1) methylene substituted with a 3- to 15-membered carbon ring optionally substituted with 1 to 5 R 11 , or (2) 1 to 5 R 11 Methylene substituted with a 3- to 15-membered heterocycle optionally substituted with 12 , more preferably substituted with a 5- to 6-membered carbon ring optionally substituted with 1 to 5 R 11 More preferably, it is methylene substituted with benzene, which may be substituted with 1 to 5 R 11 groups.
　本発明において、Ｒ１１として好ましくは、（１）ハロゲン、（２）Ｃ１～４アルキル基、または（３）シアノ基である。 In the present invention, R 11 is preferably (1) halogen, (2) C1-4 alkyl group, or (3) cyano group.
　本発明において、Ｒ１２として好ましくは、（１）ハロゲン、（２）Ｃ１～４アルキル基、または（３）シアノ基である。 In the present invention, R 12 is preferably (1) halogen, (2) C1-4 alkyl group, or (3) cyano group.
　本発明において、Ｒ１１又はＲ１２の置換数は、それぞれ０～５個であれば限定されないが、０～３個であることが好ましい。 In the present invention, the number of substitutions for R 11 or R 12 is not limited as long as it is 0 to 5, respectively, but it is preferably 0 to 3.
　本発明において、Ｒ２として好ましくは、１～５個のＲ１５で置換されていてもよい３～１５員の複素環であり、より好ましくは、１～５個のＲ１５で置換されていてもよい５～７員の複素環であり、さらに好ましくは、１～５個のＲ１５で置換されていてもよい５～７員の含窒素飽和複素環であり、特に好ましくは、１～５個のＲ１５で置換されていてもよいピロリジン、またはピペリジンである。 In the present invention, R 2 is preferably a 3- to 15-membered heterocycle optionally substituted with 1 to 5 R 15s , more preferably a 3- to 15-membered heterocycle optionally substituted with 1 to 5 R 15s . a 5- to 7-membered heterocycle which may be substituted with 1 to 5 R 15 , more preferably a 5- to 7-membered nitrogen-containing saturated heterocycle which may be substituted with 1 to 5 R 15 , particularly preferably a 1 to 5 R 15 pyrrolidine or piperidine optionally substituted with R 15 .
　本発明において、Ｒ１５として好ましくは、（１）１～５個のＲ１８で置換されていてもよいＣ３～６シクロアルキル基で置換されていてもよいＣ１～８アルキル基、（２）Ｃ１～８ハロアルキル基または（３）Ｃ１～４アルコキシカルボニル基であり、より好ましくは、（１）１～５個のＲ１８で置換されていてもよいＣ３～６シクロアルキル基で置換されていてもよいＣ１～８アルキル基、または（２）Ｃ１～８ハロアルキル基であり、さらに好ましくは、（１）１～５個のＲ１８で置換されたシクロプロピル基で置換されていてもよいＣ１～８アルキル基、または（２）Ｃ１～８ハロアルキル基であり、特に好ましくは、（１－（トリフルオロメチル）シクロプロピル）メチル基、３，３，３－トリフルオロプロピル基、２，２－ジメチルプロピル基である。 In the present invention, R 15 is preferably (1) a C1-8 alkyl group optionally substituted with a C3-6 cycloalkyl group optionally substituted with 1 to 5 R 18s, (2) C1 -8 haloalkyl group or (3) C1-4 alkoxycarbonyl group, more preferably substituted with (1) C3-6 cycloalkyl group optionally substituted with 1-5 R 18 a C1-8 alkyl group, or (2) a C1-8 haloalkyl group, more preferably a C1-8 alkyl group optionally substituted with (1) a cyclopropyl group substituted with 1-5 R 18 an alkyl group, or (2) a C1-8 haloalkyl group, particularly preferably a (1-(trifluoromethyl)cyclopropyl)methyl group, 3,3,3-trifluoropropyl group, 2,2-dimethylpropyl group. It is the basis.
　本発明において、Ｒ１８として好ましくは、（１）Ｃ１～４ハロアルキル基、または（２）シアノ基である。 In the present invention, R 18 is preferably (1) a C1-4 haloalkyl group or (2) a cyano group.
　本発明において、Ｒ１８の置換数は、０～５個であれば限定されないが、０～３個であることが好ましい。 In the present invention, the number of substitutions for R 18 is not limited as long as it is 0 to 5, but is preferably 0 to 3.
　本発明において、Ｒ３として好ましくは、（１）１～５個のＲ２０で置換されていてもよい３～１５員の炭素環、（２）１～５個のＲ２１で置換されていてもよい３～１５員の複素環、または（３）－ＮＲ２２Ｒ２３であり、より好ましくは、（１）それぞれ１～５個のＲ２０で置換されていてもよい、５～６員の炭素環またはインダン、（２）１～５個のＲ２１で置換されていてもよい５～６員の複素環、または（３）－ＮＲ２２Ｒ２３であり、さらに好ましくは、（１）それぞれ１～５個のＲ２０で置換されていてもよい、ベンゼンまたはインダン、または（２）－ＮＲ２２Ｒ２３である。 In the present invention, R 3 is preferably (1) a 3- to 15-membered carbon ring optionally substituted with 1 to 5 R 20s , (2) a 3- to 15-membered carbon ring optionally substituted with 1 to 5 R 21 or (3) -NR 22 R 23 , more preferably (1) a 5- to 6-membered heterocycle, each optionally substituted with 1 to 5 R 20 . carbocycle or indane, (2) a 5- to 6-membered heterocycle optionally substituted with 1 to 5 R 21s , or (3) -NR 22 R 23 , more preferably (1) each benzene or indane, or (2)-NR 22 R 23 , optionally substituted with 1 to 5 R 20 .
　本発明において、Ｒ３Ｙとして好ましくは、（１）１～５個のＲ２０Ｙで置換されていてもよい３～１５員の炭素環、（２）１～５個のＲ２１Ｙで置換されていてもよい３～１５員の複素環、または（３）－ＮＲ２２Ｒ２３であり、より好ましくは、（１）それぞれ１～５個のＲ２０Ｙで置換されていてもよい、５～６員の炭素環またはインダン、（２）１～５個のＲ２１Ｙで置換されていてもよい５～６員の複素環、または（３）－ＮＲ２２Ｒ２３であり、さらに好ましくは、（１）それぞれ１～５個のＲ２０Ｙで置換されていてもよい、ベンゼンまたはインダン、または（２）－ＮＲ２２Ｒ２３である。 In the present invention, R 3Y is preferably (1) a 3- to 15-membered carbon ring optionally substituted with 1 to 5 R 20Y , (2) a 3- to 15-membered carbon ring optionally substituted with 1 to 5 R 21Y or (3) -NR 22 R 23 , more preferably (1) a 5- to 6-membered heterocycle, each optionally substituted with 1 to 5 R 20Y ; carbocycle or indane, (2) a 5- to 6-membered heterocycle optionally substituted with 1 to 5 R 21Y , or (3) -NR 22 R 23 , more preferably (1) each benzene or indane, or (2)-NR 22 R 23 , optionally substituted with 1 to 5 R 20Y .
　本発明において、Ｒ２０として好ましくは、（１）１～５個のＲ２７で置換されていてもよいＣ１～４アルキル基（例えば、Ｃ１～４ハロアルキル基、または１～３個の水酸基で置換されていてもよいＣ１～４ハロアルキル基）、（２）ハロゲン、（３）１～５個のＲ２８で置換されていてもよいＣ３～６シクロアルキル基、または（４）１～５個のＲ２７－１で置換されていてもよいＣ１～４アルコキシ基（例えば、Ｃ１～４ハロアルコキシ基）である。 In the present invention, R 20 is preferably (1) a C1-4 alkyl group optionally substituted with 1 to 5 R 27 (for example, a C1-4 haloalkyl group, or substituted with 1 to 3 hydroxyl groups). (2) halogen, (3) C3-6 cycloalkyl group optionally substituted with 1 to 5 R28 , or (4) 1 to 5 R28 It is a C1-4 alkoxy group (eg, a C1-4 haloalkoxy group) which may be substituted with R 27-1 .
　本発明において、Ｒ２０Ｙとして好ましくは、（１）１～５個のＲ２７Ｙで置換されていてもよいＣ１～４アルキル基（例えば、Ｃ１～４ハロアルキル基、または１～３個の水酸基で置換されていてもよいＣ１～４ハロアルキル基）、（２）ハロゲン、（３）１～５個のＲ２８Ｙで置換されていてもよいＣ３～６シクロアルキル基、または（４）１～５個のＲ２７－１Ｙで置換されていてもよいＣ１～４アルコキシ基（例えば、Ｃ１～４ハロアルコキシ基）である。 In the present invention, R 20Y is preferably (1) a C1-4 alkyl group optionally substituted with 1 to 5 R 27Y (for example, a C1-4 haloalkyl group, or substituted with 1 to 3 hydroxyl groups). (2) halogen, (3) C3-6 cycloalkyl group optionally substituted with 1-5 R28Y , or (4) 1-5 It is a C1-4 alkoxy group (eg, a C1-4 haloalkoxy group) which may be substituted with R 27-1Y .
　本発明において、Ｒ２１として好ましくは、（１）１～５個のＲ２７で置換されていてもよいＣ１～４アルキル基（例えば、Ｃ１～４ハロアルキル基、または１～３個の水酸基で置換されていてもよいＣ１～４ハロアルキル基、好ましくは、Ｃ１～４ハロアルキル基）、（２）ハロゲン、（３）１～５個のＲ２８で置換されていてもよいＣ３～６シクロアルキル基、または（４）１～５個のＲ２７－１で置換されていてもよいＣ１～４アルコキシ基（好ましくは、Ｃ１～４ハロアルコキシ基）である。 In the present invention, R 21 is preferably (1) a C1-4 alkyl group optionally substituted with 1-5 R 27 (for example, a C1-4 haloalkyl group, or substituted with 1-3 hydroxyl groups). (2) halogen, (3) C3-6 cycloalkyl group optionally substituted with 1-5 R28 , or (4) a C1-4 alkoxy group (preferably a C1-4 haloalkoxy group) optionally substituted with 1 to 5 R 27-1 .
　本発明において、Ｒ２１Ｙとして好ましくは、（１）１～５個のＲ２７Ｙで置換されていてもよいＣ１～４アルキル基（例えば、Ｃ１～４ハロアルキル基、または１～３個の水酸基で置換されていてもよいＣ１～４ハロアルキル基、好ましくは、Ｃ１～４ハロアルキル基）、（２）ハロゲン、（３）１～５個のＲ２８Ｙで置換されていてもよいＣ３～６シクロアルキル基、または（４）１～５個のＲ２７－１Ｙで置換されていてもよいＣ１～４アルコキシ基（好ましくは、Ｃ１～４ハロアルコキシ基）である。 In the present invention, R 21Y is preferably (1) a C1-4 alkyl group optionally substituted with 1 to 5 R 27Y (for example, a C1-4 haloalkyl group, or substituted with 1 to 3 hydroxyl groups). (2) halogen, (3) C3-6 cycloalkyl group optionally substituted with 1-5 R 28Y , or (4) a C1-4 alkoxy group (preferably a C1-4 haloalkoxy group) optionally substituted with 1 to 5 R 27-1Y .
　本発明において、Ｒ２０又はＲ２１の置換数は、それぞれ０～５個であれば限定されないが、０～３個であることが好ましい。 In the present invention, the number of substitutions for R 20 or R 21 is not limited as long as it is 0 to 5 each, but it is preferably 0 to 3.
　本発明において、Ｒ２７またはＲ２７－１として好ましくは、それぞれ（１）ハロゲン、（２）水酸基、（３）カルバモイル基、または（４）カルボキシル基であり、より好ましくは、（１）水酸基、または（２）カルボキシル基である。 In the present invention, R 27 or R 27-1 is preferably (1) halogen, (2) hydroxyl group, (3) carbamoyl group, or (4) carboxyl group, and more preferably (1) hydroxyl group, or (2) a carboxyl group.
　本発明において、Ｒ２７ＹまたはＲ２７－１Ｙとして好ましくは、それぞれ（１）ハロゲン、（２）水酸基、（３）カルバモイル基、または（４）カルボキシル基であり、より好ましくは、（１）水酸基、または（２）カルボキシル基である。 In the present invention, R 27Y or R 27-1Y is preferably (1) halogen, (2) hydroxyl group, (3) carbamoyl group, or (4) carboxyl group, and more preferably (1) hydroxyl group, or (2) a carboxyl group.
　本発明において、Ｒ２８として好ましくは、（１）ハロゲン、（２）水酸基、（３）カルバモイル基、または（４）カルボキシル基であり、より好ましくは、（１）水酸基、または（２）カルボキシル基である。 In the present invention, R 28 is preferably (1) halogen, (2) hydroxyl group, (3) carbamoyl group, or (4) carboxyl group, more preferably (1) hydroxyl group or (2) carboxyl group. It is.
　本発明において、Ｒ２８Ｙとして好ましくは、（１）ハロゲン、（２）水酸基、（３）カルバモイル基、または（４）カルボキシル基であり、より好ましくは、（１）水酸基、または（２）カルボキシル基である。 In the present invention, R 28Y is preferably (1) halogen, (2) hydroxyl group, (3) carbamoyl group, or (4) carboxyl group, more preferably (1) hydroxyl group or (2) carboxyl group. It is.
　本発明において、Ｒ２７、Ｒ２７－１又はＲ２８の置換数は、それぞれ０～５個であれば限定されないが、０～３個であることが好ましい。 In the present invention, the number of substitutions for R 27 , R 27-1 or R 28 is not limited as long as it is 0 to 5 each, but it is preferably 0 to 3.
　本発明において、Ｒ２７Ｙ、Ｒ２７－１Ｙ又はＲ２８Ｙの置換数は、それぞれ０～５個であれば限定されないが、０～３個であることが好ましい。 In the present invention, the number of substitutions for R 27Y , R 27-1Y or R 28Y is not limited as long as it is 0 to 5, but is preferably 0 to 3.
　本発明において、Ｒ２２として好ましくは、（１）１～５個のＲ３０で置換されていてもよい３～１５員の炭素環、または（２）１～５個のＲ３１で置換されていてもよい３～１５員の複素環であり、より好ましくは、（１）１～５個のＲ３０で置換されていてもよい５～６員の炭素環、または（２）１～５個のＲ３１で置換されていてもよい５～６員の複素環であり、さらに好ましくは、（１）１～５個のＲ３０で置換されていてもよいベンゼン、シクロペンタン、シクロヘキサン、または（２）１～５個のＲ３１で置換されていてもよいピリジンである。 In the present invention, R 22 is preferably (1) a 3- to 15-membered carbon ring optionally substituted with 1 to 5 R 30s , or (2) a 3- to 15-membered carbon ring optionally substituted with 1 to 5 R 31s . a 3- to 15-membered heterocycle which may be optionally substituted, more preferably (1) a 5- to 6-membered carbocyclic ring optionally substituted with 1 to 5 R is a 5- to 6-membered heterocycle optionally substituted with R 31 , more preferably (1) benzene, cyclopentane, cyclohexane, optionally substituted with 1 to 5 R 30 , or ( 2) Pyridine optionally substituted with 1 to 5 R 31s .
　本発明において、Ｒ２３として好ましくは、（１）水素原子、（２）１～５個のＲ２９で置換されていてもよいＣ１～８アルキル基、（３）１～５個のＲ２９－１で置換されていてもよいＣ２～４アルケニル基、または（４）１～５個のＲ２９－２で置換されていてもよいＣ２～４アルキニル基であり、より好ましくは、（１）水素原子、または（２）１～５個のＲ２９で置換されていてもよいＣ１～８アルキル基（好ましくは、Ｃ１～４ハロアルキル基）である。 In the present invention, R 23 is preferably (1) a hydrogen atom, (2) a C1-8 alkyl group optionally substituted with 1 to 5 R 29s , (3) 1 to 5 R 29- a C2-4 alkenyl group optionally substituted with 1 , or (4) a C2-4 alkynyl group optionally substituted with 1 to 5 R29-2 , more preferably (1) hydrogen atom, or (2) a C1-8 alkyl group (preferably a C1-4 haloalkyl group) optionally substituted with 1 to 5 R29s .
　本発明において、Ｒ２９として好ましくは、（１）ハロゲン、（２）１～５個のＲ３３で置換されていてもよいＣ３～８シクロアルキル基、（３）Ｃ１～４ハロアルキル基、（４）Ｃ１～４ハロアルコキシ基、（５）水酸基、または（６）カルボキシル基であり、より好ましくは、（１）１～５個のＲ３３で置換されていてもよいＣ３～８シクロアルキル基、（２）水酸基、または（３）カルボキシル基である。 In the present invention, R 29 is preferably (1) halogen, (2) C3-8 cycloalkyl group optionally substituted with 1 to 5 R 33s , (3) C1-4 haloalkyl group, (4 ) C1-4 haloalkoxy group, (5) hydroxyl group, or (6) carboxyl group, more preferably (1) C3-8 cycloalkyl group optionally substituted with 1-5 R33 , (2) hydroxyl group, or (3) carboxyl group.
　本発明において、Ｒ２９－１として好ましくは、（１）ハロゲン、（２）１～５個のＲ３３で置換されていてもよいＣ３～８シクロアルキル基、（３）Ｃ１～４ハロアルキル基、（４）Ｃ１～４ハロアルコキシ基、（５）水酸基、または（６）カルボキシル基であり、より好ましくは、（１）１～５個のＲ３３で置換されていてもよいＣ３～８シクロアルキル基、（２）水酸基、または（３）カルボキシル基である。 In the present invention, R 29-1 is preferably (1) halogen, (2) C3-8 cycloalkyl group optionally substituted with 1 to 5 R 33s , (3) C1-4 haloalkyl group, (4) C1-4 haloalkoxy group, (5) hydroxyl group, or (6) carboxyl group, more preferably (1) C3-8 cycloalkyl optionally substituted with 1-5 R 33 (2) hydroxyl group, or (3) carboxyl group.
　本発明において、Ｒ２９－２として好ましくは、（１）ハロゲン、（２）１～５個のＲ３３で置換されていてもよいＣ３～８シクロアルキル基、（３）Ｃ１～４ハロアルキル基、（４）Ｃ１～４ハロアルコキシ基、（５）水酸基、または（６）カルボキシル基であり、より好ましくは、（１）１～５個のＲ３３で置換されていてもよいＣ３～８シクロアルキル基、（２）水酸基、または（３）カルボキシル基である。 In the present invention, R 29-2 is preferably (1) halogen, (2) a C3-8 cycloalkyl group optionally substituted with 1 to 5 R 33s , (3) a C1-4 haloalkyl group, (4) C1-4 haloalkoxy group, (5) hydroxyl group, or (6) carboxyl group, more preferably (1) C3-8 cycloalkyl optionally substituted with 1-5 R 33 (2) hydroxyl group, or (3) carboxyl group.
　本発明において、Ｒ３０として好ましくは、（１）１～５個のＲ３２で置換されていてもよいＣ１～４アルキル基、（２）ハロゲン、（３）１～５個のＲ３３で置換されていてもよいＣ３～８シクロアルキル基、（４）１～５個のＲ３２－１で置換されていてもよいＣ１～４アルコキシ基、（５）水酸基、または（６）カルボキシル基であり、より好ましくは、（１）１～５個のＲ３２で置換されていてもよいＣ１～４アルキル基（好ましくは、Ｃ１～４ハロアルキル基）、（２）ハロゲン、（３）１～５個のＲ３３で置換されていてもよいＣ３～８シクロアルキル基、または（４）１～５個のＲ３２－１で置換されていてもよいＣ１～４アルコキシ基（好ましくは、Ｃ１～４ハロアルコキシ基）である。 In the present invention, R 30 is preferably (1) a C1-4 alkyl group optionally substituted with 1 to 5 R 32s , (2) halogen, (3) substituted with 1 to 5 R 33s . (4) a C1-4 alkoxy group optionally substituted with 1 to 5 R 32-1 , (5) a hydroxyl group, or (6) a carboxyl group. , more preferably (1) a C1-4 alkyl group optionally substituted with 1-5 R 32 (preferably a C1-4 haloalkyl group), (2) halogen, (3) 1-5 R 32 or ( 4 ) a C1-4 alkoxy group optionally substituted with 1 to 5 R 32-1 (preferably a C1-4 halo alkoxy group).
　本発明において、Ｒ３１として好ましくは、（１）１～５個のＲ３２で置換されていてもよいＣ１～４アルキル基、（２）ハロゲン、（３）１～５個のＲ３３で置換されていてもよいＣ３～８シクロアルキル基、（４）１～５個のＲ３２－１で置換されていてもよいＣ１～４アルコキシ基、（５）水酸基、または（６）カルボキシル基であり、より好ましくは、（１）１～５個のＲ３２で置換されていてもよいＣ１～４アルキル基（好ましくは、Ｃ１～４ハロアルキル基）、（２）ハロゲン、（３）１～５個のＲ３３で置換されていてもよいＣ３～８シクロアルキル基、または（４）１～５個のＲ３２－１で置換されていてもよいＣ１～４アルコキシ基（好ましくはＣ１～４ハロアルコキシ基）である。 In the present invention, R 31 is preferably (1) a C1-4 alkyl group optionally substituted with 1 to 5 R 32s , (2) halogen, (3) substituted with 1 to 5 R 33s . (4) a C1-4 alkoxy group optionally substituted with 1 to 5 R 32-1 , (5) a hydroxyl group, or (6) a carboxyl group. , more preferably (1) a C1-4 alkyl group optionally substituted with 1-5 R 32 (preferably a C1-4 haloalkyl group), (2) halogen, (3) 1-5 R 32 or ( 4 ) a C1-4 alkoxy group optionally substituted with 1 to 5 R 32-1 (preferably a C1-4 haloalkoxy basis).
　本発明において、Ｒ３０又はＲ３１の置換数は、それぞれ０～５個であれば限定されないが、０～３個であることが好ましい。 In the present invention, the number of substitutions for R 30 or R 31 is not limited as long as it is 0 to 5 each, but it is preferably 0 to 3.
　本発明において、Ｒ３２またはＲ３２－１として好ましくは、（１）ハロゲン、（２）水酸基、（３）カルバモイル基、（４）カルボキシル基、または（５）シアノ基であり、より好ましくは、（１）ハロゲン、（２）カルバモイル基、または（３）カルボキシル基である。 In the present invention, R 32 or R 32-1 is preferably (1) halogen, (2) hydroxyl group, (3) carbamoyl group, (4) carboxyl group, or (5) cyano group, and more preferably, (1) halogen, (2) carbamoyl group, or (3) carboxyl group.
　本発明において、Ｒ３３として好ましくは、（１）ハロゲン、（２）水酸基、（３）カルバモイル基、（４）カルボキシル基、または（５）シアノ基であり、より好ましくは、（１）ハロゲン、（２）カルバモイル基、または（３）カルボキシル基である。 In the present invention, R 33 is preferably (1) halogen, (2) hydroxyl group, (3) carbamoyl group, (4) carboxyl group, or (5) cyano group, more preferably (1) halogen, (2) a carbamoyl group, or (3) a carboxyl group.
　本発明において、Ｒ４として好ましくは、（１）ハロゲン、（２）Ｃ１～４アルキル基、（３）Ｃ１～４アルコキシ基、（４）Ｃ１～４ハロアルキル基、または（５）Ｃ１～４ハロアルコキシ基である。 In the present invention, R 4 is preferably (1) halogen, (2) C1-4 alkyl group, (3) C1-4 alkoxy group, (4) C1-4 haloalkyl group, or (5) C1-4 halo It is an alkoxy group.
　本発明において、Ｒ５として好ましくは、（１）Ｃ１～４アルキル基、（２）Ｃ１～４ハロアルキル基、または（３）水酸基である。 In the present invention, R 5 is preferably (1) a C1-4 alkyl group, (2) a C1-4 haloalkyl group, or (3) a hydroxyl group.
　本発明において、Ｒ６として好ましくは、（１）ハロゲン、（２）Ｃ１～４アルキル基、（３）Ｃ１～４アルコキシ基、（４）Ｃ１～４ハロアルキル基、または（５）Ｃ１～４ハロアルコキシ基であり、より好ましくは、（１）ハロゲン、または（２）Ｃ１～４アルキル基である。 In the present invention, R 6 is preferably (1) halogen, (2) C1-4 alkyl group, (3) C1-4 alkoxy group, (4) C1-4 haloalkyl group, or (5) C1-4 halo It is an alkoxy group, more preferably (1) halogen or (2) C1-4 alkyl group.
　本発明において、ｒｉｎｇＹとして好ましくは、
（すべての記号は前記と同じ意味を表わす。）
である。 In the present invention, preferably as ringY,
(All symbols have the same meaning as above.)
It is.
　本発明において、「飽和または一部不飽和の４～１０員の炭素環」として好ましくは、
（右の矢印は窒素原子と結合し、左の矢印はカルボニル基と結合する。）である。 In the present invention, the "saturated or partially unsaturated 4- to 10-membered carbon ring" is preferably
(The arrow on the right bonds with the nitrogen atom, and the arrow on the left bonds with the carbonyl group.)
　本発明において、「１個の窒素原子、１個の酸素原子および／または酸化されていてもよい１個の硫黄原子を含有する６員の飽和複素環」として好ましくは、
（右の矢印は窒素原子と結合し、左の矢印はカルボニル基と結合する。）である。
　本発明において、ＲＹとして好ましくは、（１）ハロゲン、（２）Ｃ１～４アルキル基、（３）Ｃ１～４アルコキシ基、（４）Ｃ１～４ハロアルキル基、または（５）Ｃ１～４ハロアルコキシ基であり、より好ましくは、（１）ハロゲン、または（２）Ｃ１～４アルキル基である。 In the present invention, the "6-membered saturated heterocycle containing one nitrogen atom, one oxygen atom, and/or one optionally oxidized sulfur atom" preferably includes:
(The arrow on the right bonds with the nitrogen atom, and the arrow on the left bonds with the carbonyl group.)
In the present invention, R Y is preferably (1) halogen, (2) C1-4 alkyl group, (3) C1-4 alkoxy group, (4) C1-4 haloalkyl group, or (5) C1-4 halo It is an alkoxy group, more preferably (1) halogen or (2) C1-4 alkyl group.
　本発明において、Ｘ１として好ましくは、ＣＨ、またはＣＲ６である。 In the present invention, X 1 is preferably CH or CR 6 .
　本発明において、Ｘ２として好ましくは、ＣＨ、またはＣＲ６である。 In the present invention, X 2 is preferably CH or CR 6 .
　本発明において、Ｘ３として好ましくは、ＣＨ、またはＣＲ６である。 In the present invention, X 3 is preferably CH or CR 6 .
　本発明において、Ｙ１として好ましくは、窒素原子である。 In the present invention, Y 1 is preferably a nitrogen atom.
　本発明において、Ｙ２として好ましくは、窒素原子である。 In the present invention, Y 2 is preferably a nitrogen atom.
　本発明において、Ｙ３として好ましくは、ＣＲ１０である。 In the present invention, Y3 is preferably CR10 .
　本発明において、Ｙ３としては、ＣＲ１０Ｙも好ましい。 In the present invention, CR 10Y is also preferred as Y 3 .
　本発明において、Ｒ７として好ましくは、水素原子である。 In the present invention, R 7 is preferably a hydrogen atom.
　本発明において、Ｒ８として好ましくは、水素原子である。 In the present invention, R 8 is preferably a hydrogen atom.
　本発明において、Ｒ９として好ましくは、水素原子である。 In the present invention, R 9 is preferably a hydrogen atom.
　本発明において、Ｒ１０として好ましくは、（１）水素原子、（２）Ｃ１～４アルキル基、（３）アミノ基、（４）カルボキシル基、（５）カルバモイル基、（６）（Ｃ１～４アルキル）アミノカルボニル基、（７）－ＣＯＮＨＲ３９、または（８）シアノ基であり、より好ましくは、（１）水素原子、または（２）Ｃ１～４アルキル基である。 In the present invention, R 10 is preferably (1) a hydrogen atom, (2) a C1-4 alkyl group, (3) an amino group, (4) a carboxyl group, (5) a carbamoyl group, (6) a (C1-4 (alkyl) aminocarbonyl group, (7) -CONHR 39 , or (8) cyano group, and more preferably (1) a hydrogen atom or (2) a C1-4 alkyl group.
　本発明において、Ｒ１０Ｙとして好ましくは、（１）水素原子、（２）Ｃ１～４アルキル基、（３）アミノ基、（４）カルボキシル基、（５）カルバモイル基、（６）（Ｃ１～４アルキル）アミノカルボニル基、（７）－ＣＯＮＨＲ３９、または（８）シアノ基であり、より好ましくは、（１）水素原子、または（２）Ｃ１～４アルキル基である。 In the present invention, R 10Y is preferably (1) hydrogen atom, (2) C1-4 alkyl group, (3) amino group, (4) carboxyl group, (5) carbamoyl group, (6) (C1-4 (alkyl) aminocarbonyl group, (7) -CONHR 39 , or (8) cyano group, and more preferably (1) a hydrogen atom or (2) a C1-4 alkyl group.
　本発明において、ｒとして好ましくは、０または１である。 In the present invention, r is preferably 0 or 1.
　本発明において、ｓとして好ましくは、０または１である。 In the present invention, s is preferably 0 or 1.
　本発明において、一般式（ＩＹ）で示される化合物として好ましくは、後述に示す一般式（Ｉ）で示される化合物である。 In the present invention, the compound represented by the general formula (IY) is preferably a compound represented by the general formula (I) shown below.
　本発明において、一般式（Ｉ）または一般式（ＩＹ）で示される化合物として好ましくは、一般式（Ｉ－１） In the present invention, the compound represented by general formula (I) or general formula (IY) is preferably general formula (I-1)
（式中、ｔは、０～３の整数を表わし、その他の記号は前記と同じ意味を表わす。）で示される化合物であり、より好ましくは、一般式（Ｉ－１－１） (In the formula, t represents an integer of 0 to 3, and the other symbols have the same meanings as above.) More preferably, a compound represented by the general formula (I-1-1)
（式中、Ｒ１－１は、１～５個のＲ１１で置換されていてもよい５～６員の炭素環で置換されたメチレンを表わし、ｒｉｎｇ１は、５～７員の含窒素飽和複素環を表わし、Ｒ３－１は、（１）それぞれ１～５個のＲ２０で置換されていてもよい、５～６員の炭素環またはインダン、（２）１～５個のＲ２１で置換されていてもよい５～６員の複素環、または（３）－ＮＲ２２Ｒ２３を表わし、Ｒ１５－１は、１～５個のＲ１８で置換されていてもよいＣ３～６シクロアルキル基で置換されていてもよいＣ１～８アルキル基、またはＣ１～８ハロアルキル基を表わし、ｕは０～２の整数を表わし、その他の記号は前記と同じ意味を表わす。）で示される化合物であり、さらに好ましくは、一般式（Ｉ－１－１－１） (In the formula, R 1-1 represents methylene substituted with a 5- to 6-membered carbon ring which may be substituted with 1 to 5 R 11 , and ring 1 is a 5- to 7-membered nitrogen-containing saturated Represents a heterocycle, and R 3-1 is (1) a 5- to 6-membered carbocyclic ring or indane, each optionally substituted with 1 to 5 R 20 , (2) 1 to 5 R 21 represents a 5- to 6-membered heterocycle optionally substituted with or (3)-NR 22 R 23 , and R 15-1 is C3-6 optionally substituted with 1 to 5 R 18 represents a C1-8 alkyl group that may be substituted with a cycloalkyl group, or a C1-8 haloalkyl group, u represents an integer from 0 to 2, and other symbols have the same meanings as above. A compound, more preferably, general formula (I-1-1-1)
（式中、ｒｉｎｇ２は、（１）それぞれ１～５個のＲ２０で置換されていてもよい、５～６員の炭素環、またはインダン、（２）１～５個のＲ２１で置換されていてもよい５～６員の複素環を表わし、その他の記号は前記と同じ意味を表わす。）で示される化合物、一般式（Ｉ－１－１－２） (In the formula, ring2 is (1) a 5- to 6-membered carbon ring or indane, each optionally substituted with 1 to 5 R 20 , (2) substituted with 1 to 5 R 21 (represents a 5- to 6-membered heterocycle which may be 5- to 6-membered heterocycle, and other symbols have the same meanings as above), a compound represented by the general formula (I-1-1-2)
（式中、ｒｉｎｇ３は、１～５個のＲ３０で置換されていてもよい５～６員の炭素環、または１～５個のＲ３１で置換されていてもよい５～６員の複素環を表わし、Ｒ２３－１は、（１）水素原子、（２）１～５個のＲ２９で置換されていてもよいＣ１～８アルキル基、（３）１～５個のＲ２９－１で置換されていてもよいＣ２～４アルケニル基、または（４）１～５個のＲ２９－２で置換されていてもよいＣ２～４アルキニル基（好ましくは、（１）水素原子、または（２）１～５個のＲ２９で置換されていてもよいＣ１～８アルキル基（好ましくはＣ１～４ハロアルキル基））を表わし、その他の記号は前記と同じ意味を表わす。）で示される化合物、または一般式（Ｉ－１－１－３） (In the formula, ring3 is a 5- to 6-membered carbocyclic ring optionally substituted with 1 to 5 R 30s , or a 5- to 6-membered heterocyclic ring optionally substituted with 1 to 5 R 31 Represents a ring, and R 23-1 is (1) a hydrogen atom, (2) a C1-8 alkyl group optionally substituted with 1 to 5 R 29s , (3) 1 to 5 R 29- a C2-4 alkenyl group optionally substituted with 1 , or (4) a C2-4 alkynyl group optionally substituted with 1 to 5 R29-2 (preferably (1) a hydrogen atom, or (2) represents a C1-8 alkyl group (preferably a C1-4 haloalkyl group) optionally substituted with 1 to 5 R29s , and other symbols have the same meanings as above. Compound or general formula (I-1-1-3)
（式中、すべての記号は前記と同じ意味を表わす。）で示される化合物である。 (In the formula, all symbols have the same meanings as above.)
　本発明において、一般式（Ｉ）または一般式（ＩＹ）で示される化合物としては、一般式（Ｉ－１－１－１－１） In the present invention, the compound represented by general formula (I) or general formula (IY) includes general formula (I-1-1-1-1)
（式中、ｒｉｎｇ２－１はそれぞれ１～５個のＲ２０で置換されていてもよい、５～６員の炭素環、またはインダンを表わし、ｖ１は０～５の整数を表わし、その他の記号は前記と同じ意味を表わす。）で示される化合物も好ましい。 (In the formula, ring2-1 represents a 5- to 6-membered carbon ring or indane, each optionally substituted with 1 to 5 R20 , v1 represents an integer from 0 to 5, and other symbols have the same meanings as above) are also preferred.
　本発明において、一般式（Ｉ）または一般式（ＩＹ）で示される化合物としては、一般式（Ｉ－１－１－１－２） In the present invention, the compound represented by general formula (I) or general formula (IY) includes general formula (I-1-1-1-2)
（式中、（式中、ｒｉｎｇ２－２は１～５個のＲ２１で置換されていてもよい５～６員の複素環を表わし、ｖ２は０～５の整数を表わし、その他の記号は前記と同じ意味を表わす。）その他の記号は前記と同じ意味を表わす。）で示される化合物も好ましい。 (In the formula, (in the formula, ring2-2 represents a 5- to 6-membered heterocycle which may be substituted with 1 to 5 R21s , v2 represents an integer from 0 to 5, and other symbols are The other symbols have the same meanings as above.) Compounds represented by the following are also preferred.
　本発明において、一般式（Ｉ）または一般式（ＩＹ）で示される化合物としては、一般式（Ｉ－１－１－２－１） In the present invention, the compound represented by general formula (I) or general formula (IY) includes general formula (I-1-1-2-1)
（式中、ｒｉｎｇ３－１は１～５個のＲ３０で置換されていてもよい５～６員の炭素環を表わし、ｗ１は０～５の整数を表わし、その他の記号は前記と同じ意味を表わす。）で示される化合物も好ましい。 (In the formula, ring3-1 represents a 5- to 6-membered carbon ring which may be substituted with 1 to 5 R30s , w1 represents an integer from 0 to 5, and other symbols have the same meanings as above. ) is also preferable.
　本発明において、一般式（Ｉ）または一般式（ＩＹ）で示される化合物としては、一般式（Ｉ－１－１－２－２） In the present invention, the compound represented by general formula (I) or general formula (IY) includes general formula (I-1-1-2-2)
（式中、ｒｉｎｇ３－２は１～５個のＲ３１で置換されていてもよい５～６員の複素環を表わし、ｗ２は０～５の整数を表わし、その他の記号は前記と同じ意味を表わす。）で示される化合物も好ましい。 (In the formula, ring3-2 represents a 5- to 6-membered heterocycle optionally substituted with 1 to 5 R31s , w2 represents an integer of 0 to 5, and other symbols have the same meanings as above. ) is also preferable.
　本発明において、化合物として好ましくは、
（１）２－メチル－２－プロパニル　（３Ｓ）－３－［２－アニリノ－７－（４－｛［９－（２，４－ジフルオロベンジル）－５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－イル］カルボニル｝フェニル）－８－オキソ－７，８－ジヒドロ－９Ｈ－プリン－９－イル］－１－ピロリジンカルボキシラート、
（２）１－（３－｛７－（４－｛［９－（４－シアノ－２－フルオロベンジル）－５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－イル］カルボニル｝フェニル）－９－［１－（２，２－ジメチルプロピル）－４－ピペリジニル］－６－メチル－８－オキソ－８，９－ジヒドロ－７Ｈ－プリン－２－イル｝フェニル）シクロプロパンカルボン酸、
（３）７－（４－｛［９－（４－クロロ－２－フルオロベンジル）－５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－イル］カルボニル｝フェニル）－２－｛［４－（ジフルオロメトキシ）フェニル］アミノ｝－９－［１－（２，２－ジメチルプロピル）－４－ピペリジニル］－６－メチル－７，９－ジヒドロ－８Ｈ－プリン－８－オン、
（４）７－（４－｛［９－（４－クロロ－２－フルオロベンジル）－５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－イル］カルボニル｝フェニル）－９－［１－（２，２－ジメチルプロピル）－４－ピペリジニル］－２－［（３－フルオロフェニル）アミノ］－６－メチル－７，９－ジヒドロ－８Ｈ－プリン－８－オン、
（５）９－［１－（２，２－ジメチルプロピル）－４－ピペリジニル］－７－（６－｛［９－（２－フルオロ－４－メチルベンジル）－５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－イル］カルボニル｝－３－ピリジニル）－６－メチル－２－｛［４－（トリフルオロメトキシ）フェニル］アミノ｝－７，９－ジヒドロ－８Ｈ－プリン－８－オン、
（６）４－［（７－｛［５－（９－［１－（２，２－ジメチルプロピル）－４－ピペリジニル］－６－メチル－８－オキソ－２－｛［４－（トリフルオロメトキシ）フェニル］アミノ｝－８，９－ジヒドロ－７Ｈ－プリン－７－イル）－２－ピリジニル］カルボニル｝－５，６，７，８－テトラヒドロ－９Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－９－イル）メチル］－３－フルオロベンゾニトリル、
（７）３－フルオロ－４－（｛７－［（５－｛２－［（３－フルオロフェニル）アミノ］－６－メチル－８－オキソ－９－（１－｛［１－（トリフルオロメチル）シクロプロピル］メチル｝－４－ピペリジニル）－８，９－ジヒドロ－７Ｈ－プリン－７－イル｝－２－ピリジニル）カルボニル］－５，６，７，８－テトラヒドロ－９Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－９－イル｝メチル）ベンゾニトリル、
（８）４－［（７－｛［５－（２－｛［２－クロロ－４－（トリフルオロメトキシ）フェニル］アミノ｝－９－［１－（２，２－ジメチルプロピル）－４－ピペリジニル］－６－メチル－８－オキソ－８，９－ジヒドロ－７Ｈ－プリン－７－イル）－２－ピリジニル］カルボニル｝－５，６，７，８－テトラヒドロ－９Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－９－イル）メチル］－３－フルオロベンゾニトリル、
（９）２－（３－｛７－（６－｛［９－（４－シアノ－２－フルオロベンジル）－５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－イル］カルボニル｝－３－ピリジニル）－９－［１－（２，２－ジメチルプロピル）－４－ピペリジニル］－６－メチル－８－オキソ－８，９－ジヒドロ－７Ｈ－プリン－２－イル｝フェニル）－２－メチルプロパン酸、
（１０）４－（｛７－［（５－｛９－［１－（２，２－ジメチルプロピル）－４－ピペリジニル］－６－メチル－２－［２－メチル－４－（トリフルオロメトキシ）フェニル］－８－オキソ－８，９－ジヒドロ－７Ｈ－プリン－７－イル｝－２－ピリジニル）カルボニル］－５，６，７，８－テトラヒドロ－９Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－９－イル｝メチル）－３－フルオロベンゾニトリル、
（１１）１－｛［｛７－（６－｛［９－（４－シアノ－２－フルオロベンジル）－５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－イル］カルボニル｝－３－ピリジニル）－９－［１－（２，２－ジメチルプロピル）－４－ピペリジニル］－６－メチル－８－オキソ－８，９－ジヒドロ－７Ｈ－プリン－２－イル｝（シクロへキシル）アミノ］メチル｝シクロブタンカルボン酸、または、
（１２）７－（６－｛［９－（４－クロロ－２－フルオロベンジル）－５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－イル］カルボニル｝－３－ピリジニル）－９－［１－（２，２－ジメチルプロピル）－４－ピペリジニル］－２－［（３－フルオロフェニル）アミノ］－６－メチル－７，９－ジヒドロ－８Ｈ－プリン－８－オン、またはその塩が挙げられる。 In the present invention, the compound is preferably:
(1) 2-Methyl-2-propanyl (3S)-3-[2-anilino-7-(4-{[9-(2,4-difluorobenzyl)-5,6,8,9-tetrahydro-7H -pyrido[4',3':4,5]pyrrolo[2,3-b]pyridin-7-yl]carbonyl}phenyl)-8-oxo-7,8-dihydro-9H-purin-9-yl] -1-pyrrolidine carboxylate,
(2) 1-(3-{7-(4-{[9-(4-cyano-2-fluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4 ,5]pyrrolo[2,3-b]pyridin-7-yl]carbonyl}phenyl)-9-[1-(2,2-dimethylpropyl)-4-piperidinyl]-6-methyl-8-oxo-8 ,9-dihydro-7H-purin-2-yl}phenyl)cyclopropanecarboxylic acid,
(3) 7-(4-{[9-(4-chloro-2-fluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[2 ,3-b]pyridin-7-yl]carbonyl}phenyl)-2-{[4-(difluoromethoxy)phenyl]amino}-9-[1-(2,2-dimethylpropyl)-4-piperidinyl]- 6-methyl-7,9-dihydro-8H-purin-8-one,
(4) 7-(4-{[9-(4-chloro-2-fluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[2 ,3-b]pyridin-7-yl]carbonyl}phenyl)-9-[1-(2,2-dimethylpropyl)-4-piperidinyl]-2-[(3-fluorophenyl)amino]-6-methyl -7,9-dihydro-8H-purin-8-one,
(5) 9-[1-(2,2-dimethylpropyl)-4-piperidinyl]-7-(6-{[9-(2-fluoro-4-methylbenzyl)-5,6,8,9- Tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[2,3-b]pyridin-7-yl]carbonyl}-3-pyridinyl)-6-methyl-2-{[4-(tri fluoromethoxy)phenyl]amino}-7,9-dihydro-8H-purin-8-one,
(6) 4-[(7-{[5-(9-[1-(2,2-dimethylpropyl)-4-piperidinyl]-6-methyl-8-oxo-2-{[4-(trifluoro methoxy)phenyl]amino}-8,9-dihydro-7H-purin-7-yl)-2-pyridinyl]carbonyl}-5,6,7,8-tetrahydro-9H-pyrido[4',3':4 ,5]pyrrolo[2,3-b]pyridin-9-yl)methyl]-3-fluorobenzonitrile,
(7) 3-fluoro-4-({7-[(5-{2-[(3-fluorophenyl)amino]-6-methyl-8-oxo-9-(1-{[1-(trifluoro methyl)cyclopropyl]methyl}-4-piperidinyl)-8,9-dihydro-7H-purin-7-yl}-2-pyridinyl)carbonyl]-5,6,7,8-tetrahydro-9H-pyrido[4 ',3':4,5]pyrrolo[2,3-b]pyridin-9-yl}methyl)benzonitrile,
(8) 4-[(7-{[5-(2-{[2-chloro-4-(trifluoromethoxy)phenyl]amino}-9-[1-(2,2-dimethylpropyl)-4- piperidinyl]-6-methyl-8-oxo-8,9-dihydro-7H-purin-7-yl)-2-pyridinyl]carbonyl}-5,6,7,8-tetrahydro-9H-pyrido[4', 3':4,5]pyrrolo[2,3-b]pyridin-9-yl)methyl]-3-fluorobenzonitrile,
(9) 2-(3-{7-(6-{[9-(4-cyano-2-fluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4 ,5]pyrrolo[2,3-b]pyridin-7-yl]carbonyl}-3-pyridinyl)-9-[1-(2,2-dimethylpropyl)-4-piperidinyl]-6-methyl-8- oxo-8,9-dihydro-7H-purin-2-yl}phenyl)-2-methylpropanoic acid,
(10) 4-({7-[(5-{9-[1-(2,2-dimethylpropyl)-4-piperidinyl]-6-methyl-2-[2-methyl-4-(trifluoromethoxy) ) phenyl]-8-oxo-8,9-dihydro-7H-purin-7-yl}-2-pyridinyl)carbonyl]-5,6,7,8-tetrahydro-9H-pyrido[4',3': 4,5]pyrrolo[2,3-b]pyridin-9-yl}methyl)-3-fluorobenzonitrile,
(11) 1-{[{7-(6-{[9-(4-cyano-2-fluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4, 5] Pyrrolo[2,3-b]pyridin-7-yl]carbonyl}-3-pyridinyl)-9-[1-(2,2-dimethylpropyl)-4-piperidinyl]-6-methyl-8-oxo -8,9-dihydro-7H-purin-2-yl}(cyclohexyl)amino]methyl}cyclobutanecarboxylic acid, or
(12) 7-(6-{[9-(4-chloro-2-fluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[2 ,3-b]pyridin-7-yl]carbonyl}-3-pyridinyl)-9-[1-(2,2-dimethylpropyl)-4-piperidinyl]-2-[(3-fluorophenyl)amino]- Examples include 6-methyl-7,9-dihydro-8H-purin-8-one or a salt thereof.
　本発明において、一般式（Ｉ）または一般式（ＩＹ）で示される化合物としては、２－メチル－２－プロパニル　（３Ｓ）－３－［２－アニリノ－７－（４－｛［９－（２，４－ジフルオロベンジル）－５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－イル］カルボニル｝フェニル）－８－オキソ－７，８－ジヒドロ－９Ｈ－プリン－９－イル］－１－ピロリジンカルボキシラート、またはその塩が好ましい。 In the present invention, the compound represented by general formula (I) or general formula (IY) is 2-methyl-2-propanyl (3S)-3-[2-anilino-7-(4-{[9-( 2,4-difluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[2,3-b]pyridin-7-yl]carbonyl}phenyl) -8-oxo-7,8-dihydro-9H-purin-9-yl]-1-pyrrolidinecarboxylate or a salt thereof is preferred.
　本発明において、一般式（Ｉ）または一般式（ＩＹ）で示される化合物としては、１－（３－｛７－（４－｛［９－（４－シアノ－２－フルオロベンジル）－５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－イル］カルボニル｝フェニル）－９－［１－（２，２－ジメチルプロピル）－４－ピペリジニル］－６－メチル－８－オキソ－８，９－ジヒドロ－７Ｈ－プリン－２－イル｝フェニル）シクロプロパンカルボン酸、またはその塩も好ましい。 In the present invention, the compound represented by general formula (I) or general formula (IY) includes 1-(3-{7-(4-{[9-(4-cyano-2-fluorobenzyl)-5, 6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[2,3-b]pyridin-7-yl]carbonyl}phenyl)-9-[1-(2,2 -dimethylpropyl)-4-piperidinyl]-6-methyl-8-oxo-8,9-dihydro-7H-purin-2-yl}phenyl)cyclopropanecarboxylic acid, or a salt thereof is also preferred.
　本発明において、一般式（Ｉ）または一般式（ＩＹ）で示される化合物としては、７－（４－｛［９－（４－クロロ－２－フルオロベンジル）－５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－イル］カルボニル｝フェニル）－２－｛［４－（ジフルオロメトキシ）フェニル］アミノ｝－９－［１－（２，２－ジメチルプロピル）－４－ピペリジニル］－６－メチル－７，９－ジヒドロ－８Ｈ－プリン－８－オン、またはその塩も好ましい。 In the present invention, the compound represented by general formula (I) or general formula (IY) is 7-(4-{[9-(4-chloro-2-fluorobenzyl)-5,6,8,9- Tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[2,3-b]pyridin-7-yl]carbonyl}phenyl)-2-{[4-(difluoromethoxy)phenyl]amino}- 9-[1-(2,2-dimethylpropyl)-4-piperidinyl]-6-methyl-7,9-dihydro-8H-purin-8-one or a salt thereof is also preferred.
　本発明において、一般式（Ｉ）または一般式（ＩＹ）で示される化合物としては、７－（４－｛［９－（４－クロロ－２－フルオロベンジル）－５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－イル］カルボニル｝フェニル）－９－［１－（２，２－ジメチルプロピル）－４－ピペリジニル］－２－［（３－フルオロフェニル）アミノ］－６－メチル－７，９－ジヒドロ－８Ｈ－プリン－８－オン、またはその塩も好ましい。 In the present invention, the compound represented by general formula (I) or general formula (IY) is 7-(4-{[9-(4-chloro-2-fluorobenzyl)-5,6,8,9- Tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[2,3-b]pyridin-7-yl]carbonyl}phenyl)-9-[1-(2,2-dimethylpropyl)-4 -piperidinyl]-2-[(3-fluorophenyl)amino]-6-methyl-7,9-dihydro-8H-purin-8-one or a salt thereof is also preferred.
　本発明において、一般式（Ｉ）または一般式（ＩＹ）で示される化合物としては、９－［１－（２，２－ジメチルプロピル）－４－ピペリジニル］－７－（６－｛［９－（２－フルオロ－４－メチルベンジル）－５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－イル］カルボニル｝－３－ピリジニル）－６－メチル－２－｛［４－（トリフルオロメトキシ）フェニル］アミノ｝－７，９－ジヒドロ－８Ｈ－プリン－８－オン、またはその塩も好ましい。 In the present invention, the compound represented by general formula (I) or general formula (IY) is 9-[1-(2,2-dimethylpropyl)-4-piperidinyl]-7-(6-{[9- (2-fluoro-4-methylbenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[2,3-b]pyridin-7-yl]carbonyl }-3-pyridinyl)-6-methyl-2-{[4-(trifluoromethoxy)phenyl]amino}-7,9-dihydro-8H-purin-8-one or a salt thereof is also preferred.
　本発明において、一般式（Ｉ）または一般式（ＩＹ）で示される化合物としては、４－［（７－｛［５－（９－［１－（２，２－ジメチルプロピル）－４－ピペリジニル］－６－メチル－８－オキソ－２－｛［４－（トリフルオロメトキシ）フェニル］アミノ｝－８，９－ジヒドロ－７Ｈ－プリン－７－イル）－２－ピリジニル］カルボニル｝－５，６，７，８－テトラヒドロ－９Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－９－イル）メチル］－３－フルオロベンゾニトリル、またはその塩も好ましい。 In the present invention, the compound represented by general formula (I) or general formula (IY) includes 4-[(7-{[5-(9-[1-(2,2-dimethylpropyl)-4-piperidinyl) ]-6-Methyl-8-oxo-2-{[4-(trifluoromethoxy)phenyl]amino}-8,9-dihydro-7H-purin-7-yl)-2-pyridinyl]carbonyl}-5, 6,7,8-tetrahydro-9H-pyrido[4',3':4,5]pyrrolo[2,3-b]pyridin-9-yl)methyl]-3-fluorobenzonitrile or a salt thereof is also preferred .
　本発明において、一般式（Ｉ）または一般式（ＩＹ）で示される化合物としては、３－フルオロ－４－（｛７－［（５－｛２－［（３－フルオロフェニル）アミノ］－６－メチル－８－オキソ－９－（１－｛［１－（トリフルオロメチル）シクロプロピル］メチル｝－４－ピペリジニル）－８，９－ジヒドロ－７Ｈ－プリン－７－イル｝－２－ピリジニル）カルボニル］－５，６，７，８－テトラヒドロ－９Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－９－イル｝メチル）ベンゾニトリル、またはその塩も好ましい。 In the present invention, the compound represented by the general formula (I) or the general formula (IY) is 3-fluoro-4-({7-[(5-{2-[(3-fluorophenyl)amino]-6 -Methyl-8-oxo-9-(1-{[1-(trifluoromethyl)cyclopropyl]methyl}-4-piperidinyl)-8,9-dihydro-7H-purin-7-yl}-2-pyridinyl ) carbonyl]-5,6,7,8-tetrahydro-9H-pyrido[4',3':4,5]pyrrolo[2,3-b]pyridin-9-yl}methyl)benzonitrile, or a salt thereof is also preferable.
　本発明において、一般式（Ｉ）または一般式（ＩＹ）で示される化合物としては、４－［（７－｛［５－（２－｛［２－クロロ－４－（トリフルオロメトキシ）フェニル］アミノ｝－９－［１－（２，２－ジメチルプロピル）－４－ピペリジニル］－６－メチル－８－オキソ－８，９－ジヒドロ－７Ｈ－プリン－７－イル）－２－ピリジニル］カルボニル｝－５，６，７，８－テトラヒドロ－９Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－９－イル）メチル］－３－フルオロベンゾニトリル、またはその塩も好ましい。 In the present invention, the compound represented by general formula (I) or general formula (IY) includes 4-[(7-{[5-(2-{[2-chloro-4-(trifluoromethoxy)phenyl]) amino}-9-[1-(2,2-dimethylpropyl)-4-piperidinyl]-6-methyl-8-oxo-8,9-dihydro-7H-purin-7-yl)-2-pyridinyl]carbonyl }-5,6,7,8-tetrahydro-9H-pyrido[4',3':4,5]pyrrolo[2,3-b]pyridin-9-yl)methyl]-3-fluorobenzonitrile, or Its salts are also preferred.
　本発明において、一般式（Ｉ）または一般式（ＩＹ）で示される化合物としては、２－（３－｛７－（６－｛［９－（４－シアノ－２－フルオロベンジル）－５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－イル］カルボニル｝－３－ピリジニル）－９－［１－（２，２－ジメチルプロピル）－４－ピペリジニル］－６－メチル－８－オキソ－８，９－ジヒドロ－７Ｈ－プリン－２－イル｝フェニル）－２－メチルプロパン酸、またはその塩も好ましい。 In the present invention, the compound represented by general formula (I) or general formula (IY) includes 2-(3-{7-(6-{[9-(4-cyano-2-fluorobenzyl)-5, 6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[2,3-b]pyridin-7-yl]carbonyl}-3-pyridinyl)-9-[1-( Also preferred is 2,2-dimethylpropyl)-4-piperidinyl]-6-methyl-8-oxo-8,9-dihydro-7H-purin-2-yl}phenyl)-2-methylpropanoic acid or a salt thereof.
　本発明において、一般式（Ｉ）または一般式（ＩＹ）で示される化合物としては、４－（｛７－［（５－｛９－［１－（２，２－ジメチルプロピル）－４－ピペリジニル］－６－メチル－２－［２－メチル－４－（トリフルオロメトキシ）フェニル］－８－オキソ－８，９－ジヒドロ－７Ｈ－プリン－７－イル｝－２－ピリジニル）カルボニル］－５，６，７，８－テトラヒドロ－９Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－９－イル｝メチル）－３－フルオロベンゾニトリル、またはその塩も好ましい。 In the present invention, the compound represented by the general formula (I) or the general formula (IY) includes 4-({7-[(5-{9-[1-(2,2-dimethylpropyl)-4-piperidinyl) ]-6-Methyl-2-[2-methyl-4-(trifluoromethoxy)phenyl]-8-oxo-8,9-dihydro-7H-purin-7-yl}-2-pyridinyl)carbonyl]-5 , 6,7,8-tetrahydro-9H-pyrido[4',3':4,5]pyrrolo[2,3-b]pyridin-9-yl}methyl)-3-fluorobenzonitrile, or a salt thereof preferable.
　本発明において、一般式（Ｉ）または一般式（ＩＹ）で示される化合物としては、１－｛［｛７－（６－｛［９－（４－シアノ－２－フルオロベンジル）－５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－イル］カルボニル｝－３－ピリジニル）－９－［１－（２，２－ジメチルプロピル）－４－ピペリジニル］－６－メチル－８－オキソ－８，９－ジヒドロ－７Ｈ－プリン－２－イル｝（シクロへキシル）アミノ］メチル｝シクロブタンカルボン酸、またはその塩も好ましい。 In the present invention, compounds represented by general formula (I) or general formula (IY) include 1-{[{7-(6-{[9-(4-cyano-2-fluorobenzyl)-5,6 ,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[2,3-b]pyridin-7-yl]carbonyl}-3-pyridinyl)-9-[1-(2 ,2-dimethylpropyl)-4-piperidinyl]-6-methyl-8-oxo-8,9-dihydro-7H-purin-2-yl}(cyclohexyl)amino]methyl}cyclobutanecarboxylic acid, or a salt thereof is also preferable.
　本発明において、一般式（Ｉ）または一般式（ＩＹ）で示される化合物としては、７－（６－｛［９－（４－クロロ－２－フルオロベンジル）－５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－イル］カルボニル｝－３－ピリジニル）－９－［１－（２，２－ジメチルプロピル）－４－ピペリジニル］－２－［（３－フルオロフェニル）アミノ］－６－メチル－７，９－ジヒドロ－８Ｈ－プリン－８－オン、またはその塩も好ましい。 In the present invention, the compound represented by general formula (I) or general formula (IY) is 7-(6-{[9-(4-chloro-2-fluorobenzyl)-5,6,8,9- Tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[2,3-b]pyridin-7-yl]carbonyl}-3-pyridinyl)-9-[1-(2,2-dimethylpropyl) )-4-piperidinyl]-2-[(3-fluorophenyl)amino]-6-methyl-7,9-dihydro-8H-purin-8-one or a salt thereof is also preferred.
［異性体］
　本発明において特に指示しない限り、異性体はこれをすべて包含する。例えば、アルキル基には直鎖のものおよび分枝鎖のものが含まれる。さらに、二重結合、環、縮合環における幾何異性体（Ｅ体、Ｚ体、シス体、トランス体）、不斉炭素原子の存在等による光学異性体（Ｒ、Ｓ体、α、β配置、エナンチオマー、ジアステレオマー）、旋光性を有する光学活性体（Ｄ、Ｌ、ｄ、ｌ体）、クロマトグラフ分離による極性体（高極性体、低極性体）、平衡化合物、回転異性体、これらの任意の割合の混合物、ラセミ混合物は、すべて本発明に含まれる。また、本発明においては、互変異性体による異性体をもすべて包含する。 [isomer]
In the present invention, unless otherwise specified, all isomers are included. For example, alkyl groups include straight and branched chains. Furthermore, geometric isomers (E-form, Z-form, cis-form, trans-form) in double bonds, rings, and condensed rings, optical isomers due to the presence of asymmetric carbon atoms (R, S-form, α-, β-configuration, enantiomers, diastereomers), optically active forms with optical rotation (D, L, d, l forms), polar forms obtained by chromatographic separation (highly polar forms, low polar forms), equilibrium compounds, rotamers, these All mixtures and racemic mixtures in any proportion are included in the present invention. Furthermore, the present invention includes all tautomeric isomers.
　また、本発明における光学異性体は、１００％純粋なものだけでなく、５０％未満のその他の光学異性体が含まれていてもよい。 Furthermore, the optical isomers in the present invention are not limited to 100% pure ones, and may contain less than 50% of other optical isomers.
　本発明においては、特に断わらない限り、当業者にとって明らかなように記号 In the present invention, unless otherwise specified, symbols will be used as is clear to those skilled in the art.
は紙面の向こう側（すなわちα配置）に結合していることを表し、 represents that it is connected to the other side of the paper (i.e. α configuration),
は紙面の手前側（すなわちβ配置）に結合していることを表し、 indicates that it is connected to the front side of the paper (i.e. β configuration),
はα配置、β配置またはそれらの任意の比率の混合物であることを表す。 represents an α-configuration, a β-configuration, or a mixture thereof in any ratio.
［Ｎ－オキシド体］
　一般式（ＩＹ）で示される化合物は、公知の方法でＮ－オキシド体にすることができる。Ｎ－オキシド体とは、一般式（ＩＹ）で示される化合物の窒素原子が、酸化されたものを表す。また、これらＮ－オキシド体は、さらに下記［プロドラッグ］の項目、下記［塩］の項目および下記［溶媒和物］の項目に記載のように、そのプロドラッグ、その薬学的に許容される塩またはその溶媒和物となっていてもよい。 [N-oxide form]
The compound represented by the general formula (IY) can be converted into an N-oxide form by a known method. The N-oxide compound refers to a compound represented by the general formula (IY) in which the nitrogen atom is oxidized. In addition, these N-oxide forms can be used as prodrugs thereof, as described in the following [Prodrugs], [Salts] and [Solvates] below. It may be a salt or a solvate thereof.
［プロドラッグ］
　一般式（ＩＹ）で示される化合物またはそのＮ－オキシド体は、公知の方法により、プロドラッグにすることもできる。当該プロドラッグは、生体内において酵素や胃酸等による反応により、例えば、一般式（ＩＹ）で示される化合物またはそのＮ－オキシド体に変換される化合物をいう。なお、一般式（ＩＹ）で示される化合物またはそのＮ－オキシド体のプロドラッグは、廣川書店１９９０年刊「医薬品の開発」第７巻「分子設計」１６３～１９８頁に記載されているような生理的条件で、対応する一般式（ＩＹ）で示される化合物またはそのＮ－オキシド体に変化するものであってもよい。 [Prodrug]
The compound represented by general formula (IY) or its N-oxide can also be made into a prodrug by a known method. The prodrug refers to a compound that is converted into, for example, a compound represented by general formula (IY) or its N-oxide form by a reaction with enzymes, gastric acid, etc. in vivo. In addition, the compound represented by the general formula (IY) or its N-oxide prodrug can be used in a physiological manner as described in "Molecular Design", Vol. 7, "Molecular Design", Hirokawa Shoten, 1990, "Drug Development", It may be converted into the corresponding compound represented by general formula (IY) or its N-oxide form under appropriate conditions.
　一般式（ＩＹ）で示される化合物またはそのＮ－オキシド体のその他のプロドラッグとしては、例えば、一般式（ＩＹ）で示される化合物がアミノ基を有する場合、当該アミノ基がアシル化、アルキル化またはリン酸化された化合物（例えば、一般式（ＩＹ）で示される化合物のアミノ基がエイコサノイル化、アラニル化、ペンチルアミノカルボニル化、（５－メチル－２－オキソ－１，３－ジオキソレン－４－イル）メトキシカルボニル化、テトラヒドロフラニル化、ピロリジルメチル化、ピバロイルオキシメチル化、アセトキシメチル化またはｔｅｒｔ－ブチル化された化合物等）が挙げられ、一般式（ＩＹ）で示される化合物が水酸基を有する場合、当該水酸基がアシル化、アルキル化、リン酸化またはホウ酸化された化合物（例えば、一般式（ＩＹ）で示される化合物の水酸基がアセチル化、パルミトイル化、プロパノイル化、ピバロイル化、サクシニル化、フマリル化、アラニル化またはジメチルアミノメチルカルボニル化された化合物等）が挙げられ、一般式（ＩＹ）で示される化合物がカルボキシ基を有する場合、当該カルボキシ基がエステル化またはアミド化された化合物（例えば、一般式（ＩＹ）で示される化合物のカルボキシ基がエチルエステル化、フェニルエステル化、カルボキシメチルエステル化、ジメチルアミノメチルエステル化、ピバロイルオキシメチルエステル化、１－｛（エトキシカルボニル）オキシ｝エチルエステル化、フタリジルエステル化、（５－メチル－２－オキソ－１，３－ジオキソレン－４－イル）メチルエステル化、１－｛［（シクロヘキシルオキシ）カルボニル］オキシ｝エチルエステル化またはメチルアミド化された化合物等）等が挙げられる。これら化合物はそれ自体公知の方法によって製造することができる。なお、一般式（ＩＹ）で示される化合物またはそのＮ－オキシド体のプロドラッグは、さらに下記［塩］の項目および下記［溶媒和物］の項目に記載のように、それらの薬学的に許容される塩あるいは溶媒和物となっていてもよい。 Other prodrugs of the compound represented by general formula (IY) or its N-oxide form include, for example, when the compound represented by general formula (IY) has an amino group, the amino group may be acylated or alkylated. or a phosphorylated compound (for example, the amino group of the compound represented by the general formula (IY) is eicosanoylated, alanylated, pentylaminocarbonylated, (5-methyl-2-oxo-1,3-dioxolene-4- compounds represented by the general formula (IY) have a hydroxyl group If the hydroxyl group of the compound is acylated, alkylated, phosphorylated, or borated (for example, the hydroxyl group of the compound represented by general formula (IY) is acetylated, palmitoylated, propanoylated, pivaloylated, or succinylated) , fumarylated, alanylated or dimethylaminomethylcarbonylated compounds), and when the compound represented by the general formula (IY) has a carboxyl group, compounds in which the carboxy group is esterified or amidated ( For example, the carboxy group of the compound represented by the general formula (IY) is ethyl esterified, phenyl esterified, carboxymethyl esterified, dimethylaminomethyl esterified, pivaloyloxymethyl esterified, 1-{(ethoxycarbonyl)oxy }Ethyl esterification, phthalidyl esterification, (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl esterification, 1-{[(cyclohexyloxy)carbonyl]oxy}ethyl esterification or methylamide compounds, etc.). These compounds can be produced by methods known per se. In addition, the compound represented by the general formula (IY) or its N-oxide prodrug can be further prepared according to its pharmaceutically acceptable form, as described in the [Salts] section and the [Solvate] section below. It may be in the form of a salt or solvate.
［塩］
　一般式（ＩＹ）で示される化合物、そのＮ－オキシド体もしくはそれらのプロドラッグは、公知の方法で相当する薬学的に許容される塩に変換することができる。ここで、薬学的に許容される塩としては、例えば、アルカリ金属塩（例えば、リチウム塩、ナトリウム塩およびカリウム塩等）、アルカリ土類金属塩（例えば、カルシウム塩、マグネシウム塩およびバリウム塩等）、アンモニウム塩、有機アミン塩（例えば、脂肪族アミン塩（例えば、メチルアミン塩、ジメチルアミン塩、シクロペンチルアミン塩、トリメチルアミン塩、トリエチルアミン塩、ジシクロヘキシルアミン塩、モノエタノールアミン塩、ジエタノールアミン塩、トリエタノールアミン塩、プロカイン塩、メグルミン塩、ジエタノールアミン塩、トリス（ヒドロキシメチル）アミノメタン塩、エチレンジアミン塩およびピペリジン塩等）、アラルキルアミン塩（例えば、ベンジルアミン塩、フェネチルアミン塩、Ｎ，Ｎ－ジベンジルエチレンジアミン塩およびベネタミン塩等）、ヘテロ環芳香族アミン塩（例えば、ピリジン塩、ピコリン塩、キノリン塩およびイソキノリン塩等）、第四級アンモニウム塩（例えば、テトラメチルアンモニウム塩、テトラエチルアンモニウム塩、ベンジルトリメチルアンモニウム塩、ベンジルトリエチルアンモニウム塩、ベンジルトリブチルアンモニウム塩、メチルトリオクチルアンモニウム塩およびテトラブチルアンモニウム塩等）、塩基性アミノ酸塩（例えば、アルギニン塩、リシン塩等）およびＮ－メチル－Ｄ－グルカミン塩等）、酸付加物塩（例えば、無機酸塩（例えば、塩酸塩、臭化水素酸塩、ヨウ化水素酸塩、硫酸塩、リン酸塩および硝酸塩等）および有機酸塩（例えば、酢酸塩、トリフルオロ酢酸塩、乳酸塩、酒石酸塩、シュウ酸塩、フマル酸塩、マレイン酸塩、安息香酸塩、クエン酸塩、メタンスルホン酸塩、エタンスルホン酸塩、ベンゼンスルホン酸塩、トルエンスルホン酸塩、イセチオン酸塩、グルクロン酸塩およびグルコン酸塩等）等）等が挙げられる。薬学的に許容される塩は、水溶性のものが好ましい。 [salt]
The compound represented by general formula (IY), its N-oxide form, or its prodrug can be converted into a corresponding pharmaceutically acceptable salt by a known method. Here, examples of pharmaceutically acceptable salts include alkali metal salts (e.g., lithium salts, sodium salts, potassium salts, etc.), alkaline earth metal salts (e.g., calcium salts, magnesium salts, barium salts, etc.) , ammonium salts, organic amine salts (e.g., aliphatic amine salts (e.g., methylamine salts, dimethylamine salts, cyclopentylamine salts, trimethylamine salts, triethylamine salts, dicyclohexylamine salts, monoethanolamine salts, diethanolamine salts, triethanolamine salts) salts, procaine salts, meglumine salts, diethanolamine salts, tris(hydroxymethyl)aminomethane salts, ethylenediamine salts and piperidine salts), aralkylamine salts (e.g. benzylamine salts, phenethylamine salts, N,N-dibenzylethylenediamine salts and benetamine salt, etc.), heterocyclic aromatic amine salts (e.g., pyridine salt, picoline salt, quinoline salt, and isoquinoline salt, etc.), quaternary ammonium salts (e.g., tetramethylammonium salt, tetraethylammonium salt, benzyltrimethylammonium salt, (benzyltriethylammonium salt, benzyltributylammonium salt, methyltrioctylammonium salt, tetrabutylammonium salt, etc.), basic amino acid salts (such as arginine salt, lysine salt, etc., and N-methyl-D-glucamine salt, etc.), acids Adduct salts, such as inorganic acid salts (e.g. hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate and nitrate, etc.) and organic acid salts (e.g. acetate, trifluoroacetic acid) Salt, lactate, tartrate, oxalate, fumarate, maleate, benzoate, citrate, methanesulfonate, ethanesulfonate, benzenesulfonate, toluenesulfonate, isethionic acid salts, glucuronates, gluconates, etc.). The pharmaceutically acceptable salt is preferably water-soluble.
　さらに塩には、四級アンモニウム塩も含まれる。四級アンモニウム塩とは、一般式（ＩＹ）で示される化合物の窒素原子が、Ｒ０基によって四級化されたものを表わす。ここでＲ０基は、例えば、フェニル基によって置換されていてもよいＣ１～８アルキル基等を表わす。 Salts also include quaternary ammonium salts. The quaternary ammonium salt refers to a compound represented by the general formula (IY) in which the nitrogen atom is quaternized with an R 0 group. Here, the R 0 group represents, for example, a C1-8 alkyl group which may be substituted with a phenyl group.
［溶媒和物］
　一般式（ＩＹ）で示される化合物、そのＮ－オキシド体、それらのプロドラッグまたはそれらの薬学的に許容される塩は、溶媒和していない形態で存在してもよいし、水、エタノールなどの薬学的に許容できる溶媒と溶媒和した形態で存在してもよい。溶媒和物として好ましくは水和物である。 [Solvate]
The compound represented by general formula (IY), its N-oxide, its prodrug, or a pharmaceutically acceptable salt thereof may exist in an unsolvated form, and may be present in an unsolvated form, such as water, ethanol, etc. may exist in a solvated form with a pharmaceutically acceptable solvent. The solvate is preferably a hydrate.
　一般式（ＩＹ）で示される化合物、そのＮ－オキシド体、それらのプロドラッグまたはそれらの薬学的に許容される塩は、公知の方法で溶媒和物に変換することもできる。溶媒和物は低毒性かつ水溶性であることが好ましい。適当な溶媒和物としては、例えば、水、アルコール系の溶媒（例えば、エタノール等）との溶媒和物が挙げられる。ここで、水和物としては、例えば、１水和物ないし５水和物などの水和物や、半水和物などの低水和物などの形態を取り得るが、本発明化合物の水和物の形態としては、例えば、１水和物、２水和物、３水和物および２～３水和物が挙げられる。また、これら水和物の形態には、包接水和物が含まれる。これら水和物は、一般式（ＩＹ）で示される化合物、そのＮ－オキシド体、それらのプロドラッグもしくはそれらの薬学的に許容される塩を、例えば、含水有機溶媒から析出させることで得ることができる。 The compound represented by general formula (IY), its N-oxide, its prodrug, or its pharmaceutically acceptable salt can also be converted into a solvate by a known method. Preferably, the solvate has low toxicity and is water soluble. Suitable solvates include, for example, solvates with water and alcoholic solvents (eg, ethanol, etc.). Here, the hydrate may take the form of a hydrate such as a monohydrate to a pentahydrate, or a low hydrate such as a hemihydrate, but the hydrate of the compound of the present invention may be Examples of the hydrate form include monohydrate, dihydrate, trihydrate, and di-trihydrate. Further, the forms of these hydrates include clathrate hydrates. These hydrates can be obtained by, for example, precipitating the compound represented by the general formula (IY), its N-oxide, its prodrug, or a pharmaceutically acceptable salt thereof from a water-containing organic solvent. Can be done.
［共結晶］
　一般式（ＩＹ）で示される化合物、そのＮ－オキシド体、それらのプロドラッグ、それらの薬学的に許容される塩またはそれらの溶媒和物は、適切な共結晶形成剤と共結晶を形成することができる。共結晶としては、薬学的に許容される共結晶形成剤と形成される、薬学的に許容されるものが好ましい。共結晶は、２種以上の異なる分子がイオン結合とは異なる分子間相互作用で形成される結晶として定義される。また、共結晶は中性分子と塩の複合体であってもよい。共結晶は、公知の方法、例えば、融解結晶化、溶媒からの再結晶または成分を一緒に物理的に粉砕することにより、調製することができる。適当な共結晶形成剤としては、国際公開第２００６／００７４４８号パンフレットに記載のもの、例えば、４－アミノ安息香酸、４－アミノピリジン、アデニン、アラニン、アセチルサリチル酸等が挙げられる。 [Co-crystal]
The compound represented by general formula (IY), its N-oxide, its prodrug, its pharmaceutically acceptable salt, or its solvate forms a co-crystal with an appropriate co-crystal forming agent. be able to. The co-crystal is preferably a pharmaceutically acceptable co-crystal formed with a pharmaceutically acceptable co-crystal forming agent. A co-crystal is defined as a crystal formed by two or more different molecules through intermolecular interactions other than ionic bonding. Further, the co-crystal may be a complex of a neutral molecule and a salt. Co-crystals can be prepared by known methods, such as melt crystallization, recrystallization from a solvent or physically grinding the components together. Suitable co-crystal forming agents include those described in WO 2006/007448 pamphlet, such as 4-aminobenzoic acid, 4-aminopyridine, adenine, alanine, acetylsalicylic acid and the like.
［放射性同位体］
　一般式（ＩＹ）で示される化合物、そのＮ－オキシド体、それらのプロドラッグ、それらの薬学的に許容される塩またはそれらの溶媒和物は、同位元素（例えば、２Ｈ、３Ｈ、１１Ｃ、１３Ｃ、１４Ｃ、１３Ｎ、１５Ｎ、１５Ｏ、１７Ｏ、１８Ｏ、３５Ｓ、１８Ｆ、３６Ｃｌ、１２３Ｉ、１２５Ｉ等）等で標識されていてもよい。例えば、一般式（Ｉ）におけるＲ１、Ｒ２、Ｒ３、Ｒ３Ｙ、Ｒ４、Ｒ５、Ｒ６、Ｒ７、Ｒ８、Ｒ９、Ｒ１０およびＲ１０Ｙのうちの一以上の基を構成する水素原子の全部または一部が、重水素原子または三重水素原子に置換された化合物が挙げられる。 [Radioactive isotope]
The compound represented by the general formula (IY), its N-oxide, its prodrug, its pharmaceutically acceptable salt, or its solvate has an isotope (for example, 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 35 S, 18 F, 36 Cl, 123 I, 125 I , etc.). For example, one or more groups of R 1 , R 2 , R 3 , R 3Y , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 and R 10Y in general formula (I) Examples include compounds in which all or part of the hydrogen atoms constituting the compound are replaced with deuterium atoms or tritium atoms.
　本発明化合物に関する言及はすべて、一般式（ＩＹ）で示される化合物、その薬学的に許容される塩、そのＮ－オキシド体、その溶媒和物（例えば、水和物）、もしくはその共結晶、または一般式（ＩＹ）で示される化合物の薬学的に許容される塩のＮ－オキシド体、その溶媒和物（例えば、水和物）、もしくはその共結晶を包含する。 All references to the compounds of the present invention refer to compounds represented by general formula (IY), pharmaceutically acceptable salts thereof, N-oxides thereof, solvates (e.g. hydrates) thereof, or co-crystals thereof; Alternatively, it includes an N-oxide of a pharmaceutically acceptable salt of the compound represented by general formula (IY), a solvate thereof (for example, a hydrate), or a co-crystal thereof.
［本発明化合物の製造方法］
　本発明化合物は、公知の方法、例えば、Comprehensive Organic Transformations : A Guide to Functional Group Preparations, 2nd Edition (Richard C. Larock, John Wiley & Sons Inc, 1999)に記載された方法、以下に示す方法または実施例に示す方法等を適宜改良し、組み合わせて用いることで製造することができる。 [Method for producing the compound of the present invention]
The compounds of the present invention can be prepared by known methods, such as those described in Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 2nd Edition (Richard C. Larock, John Wiley & Sons Inc, 1999), or the methods or practices described below. It can be manufactured by appropriately improving the methods shown in the examples and using them in combination.
　一般式（Ｉ）で示される化合物のうち、Ｒ３が、１～５個のＲ２０で置換されていてもよいベンゼンであり、Ｘ１、Ｘ２、およびＸ３が、それぞれ独立して、ＣＨまたはＣＲ６である化合物、すなわち一般式（Ｉ－Ａ） In the compound represented by general formula (I), R 3 is benzene optionally substituted with 1 to 5 R 20 , and X 1 , X 2 , and X 3 are each independently, Compounds that are CH or CR 6 , i.e. general formula (IA)
（式中、ｖは０～３の整数を表わし、その他の記号は前記と同じ意味を表わす。）で示される化合物は、以下の反応工程式１で示される方法で製造することができる。反応工程式１中、Ｅ１、Ｅ２およびＥ３はそれぞれ独立して脱離基（例えば、フッ素原子、臭素原子、塩素原子、ヨウ素原子、トリフルオロメタンスルホン酸エステル、ｐ－トルエンスルホン酸エステル等）を表わし、Ｐｃはカルボキシル基の保護基を表わし、ＲＢＯは含ホウ素基（例えば、－Ｂ（ＯＨ）２、－Ｂ（ＯＣＨ３）２、３－（４，４，５，５－テトラメチル－１，３，２－ジオキサボロラン－２－イル）、３－（６－メチル－４，８－ジオキソ－１，３，６，２－ジオキサザボロカン－２－イル）、トリフルオロボレート　カリウム塩等）を表わし、その他の記号は前記と同じ意味を表わす。 The compound represented by (wherein v represents an integer of 0 to 3, and the other symbols have the same meanings as above) can be produced by the method shown in Reaction Scheme 1 below. In Reaction Scheme 1, E 1 , E 2 and E 3 each independently represent a leaving group (e.g., fluorine atom, bromine atom, chlorine atom, iodine atom, trifluoromethanesulfonic acid ester, p-toluenesulfonic acid ester, etc.) ), P c represents a carboxyl group protecting group, and R BO represents a boron-containing group (for example, -B(OH) 2 , -B(OCH 3 ) 2 , 3-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl), 3-(6-methyl-4,8-dioxo-1,3,6,2-dioxazaborocan-2-yl), trifluorobo other symbols have the same meanings as above.
　一般式（ＩＶ）で示される化合物は、一般式（ＩＩ）で示される化合物と、一般式（ＩＩＩ）で示される化合物を用いて、アミノ基の導入反応に付すことにより製造することができる。 The compound represented by the general formula (IV) can be produced by subjecting the compound represented by the general formula (II) and the compound represented by the general formula (III) to an amino group introduction reaction.
　このアミノ基の導入反応は公知であり、例えば、有機溶媒（ジクロロメタン、テトラヒドロフラン、１，４－ジオキサン、ジメチルホルムアミド、ジメチルアセトアミド、１－メチル－２－ピロリドン、ジメチルスルホキシド等）中もしくは無溶媒で、塩基（トリエチルアミン、Ｎ，Ｎ－ジイソプロピルエチルアミン、ピリジン、４－ジメチルアミノピリジン、Ｎ－メチルモルホリン等）の存在下、室温～１８０℃の温度で反応させることで行われる。 This amino group introduction reaction is known, for example, in an organic solvent (dichloromethane, tetrahydrofuran, 1,4-dioxane, dimethylformamide, dimethylacetamide, 1-methyl-2-pyrrolidone, dimethylsulfoxide, etc.) or without a solvent. The reaction is carried out in the presence of a base (triethylamine, N,N-diisopropylethylamine, pyridine, 4-dimethylaminopyridine, N-methylmorpholine, etc.) at a temperature of room temperature to 180°C.
　さらに必要であれば、この反応に引き続いて公知の方法によって、目的の塩に変換する操作を行ってもよい。 Furthermore, if necessary, subsequent to this reaction, conversion to the desired salt may be performed by a known method.
　一般式（ＶＩ）で示される化合物は、一般式（ＩＶ）で示される化合物と、一般式（Ｖ）で示される化合物を用いて、カップリング反応に付すことにより製造することができる。 The compound represented by the general formula (VI) can be produced by subjecting the compound represented by the general formula (IV) and the compound represented by the general formula (V) to a coupling reaction.
　このカップリング反応は公知であり、例えば、有機溶媒（ベンゼン、トルエン、ジメチルホルムアミド、ジメチルアセトアミド、１，４－ジオキサン、テトラヒドロフラン、メタノール、アセトニトリル、ジメトキシエタン、アセトンまたはそれらの混合溶液等）中、塩基（ナトリウムエチラート、ナトリウムブトキシド、水酸化ナトリウム、水酸化カリウム、トリエチルアミン、炭酸ナトリウム、炭酸水素ナトリウム、炭酸カリウム、炭酸セシウム、炭酸タリウム、リン酸三カリウム、フッ化セシウム、水酸化バリウム、フッ化テトラブチルアンモニウム、リチウムビス（トリメチルシリル）アミド（ＬＨＭＤＳ）等、）またはこれらの混合物、ホスフィンリガンド（（９，９）－ジメチル－９Ｈ－キサンテン－４，５－ジイル）ビス（ジフェニルホスフィン）（Ｘａｎｔｐｈоｓ）、ジシクロへキシル（２‘，４’，６‘－トリイソプロピル－３，６－ジメトキシ－２－ビフェニル）ホスフィン（ＢｒｅｔｔＰｈоｓ）等）および触媒（テトラキス（トリフェニルホスフィン）パラジウム（Ｐｄ（ＰＰｈ３）４）、二塩化ビス（トリフェニルホスフィン）パラジウム（ＰｄＣｌ２（ＰＰｈ３）２）、酢酸パラジウム（Ｐｄ（ＯＡｃ）２）、パラジウム黒、１，１’－ビス（ジフェニルホスフィノフェロセン）ジクロロパラジウム（ＰｄＣｌ２（ｄｐｐｆ）２）、二塩化ジアリルパラジウム（ＰｄＣｌ２（ａｌｌｙｌ）２）、ヨウ化フェニルビス（トリフェニルホスフィン）パラジウム（ＰｈＰｄＩ（ＰＰｈ３）２）、（１Ｅ，４Ｅ）－１，５－ジフェニル－１，４－ペンタジエン－３－オン－パラジウム（Pｄ２（ｄｂａ）３）等）存在下、室温～１５０℃の温度で反応させることで行われる。 This coupling reaction is known, for example, using a base in an organic solvent (benzene, toluene, dimethylformamide, dimethylacetamide, 1,4-dioxane, tetrahydrofuran, methanol, acetonitrile, dimethoxyethane, acetone, or a mixed solution thereof, etc.). (Sodium ethylate, sodium butoxide, sodium hydroxide, potassium hydroxide, triethylamine, sodium carbonate, sodium bicarbonate, potassium carbonate, cesium carbonate, thallium carbonate, tripotassium phosphate, cesium fluoride, barium hydroxide, tetrafluoride butylammonium, lithium bis(trimethylsilyl)amide (LHMDS), etc.) or mixtures thereof, phosphine ligands ((9,9)-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (Xantphos), dicyclohexyl(2',4',6'-triisopropyl-3,6-dimethoxy-2-biphenyl)phosphine (BrettPhоs, etc.) and catalysts (tetrakis(triphenylphosphine)palladium (Pd(PPh 3 ) 4 ) , bis(triphenylphosphine)palladium dichloride (PdCl 2 (PPh 3 ) 2 ), palladium acetate (Pd(OAc) 2 ), palladium black, 1,1'-bis(diphenylphosphinoferrocene) dichloropalladium (PdCl 2 (dppf) 2 ), diallypalladium dichloride (PdCl 2 (allyl) 2 ), phenylbis(triphenylphosphine)palladium iodide (PhPdI(PPh 3 ) 2 ), (1E,4E)-1,5-diphenyl- The reaction is carried out in the presence of 1,4-pentadien-3-one-palladium (Pd 2 (dba) 3 ) or the like at a temperature of room temperature to 150°C.
　さらに必要であれば、この反応に引き続いて公知の方法によって、目的の塩に変換する操作を行ってもよい。 Furthermore, if necessary, subsequent to this reaction, conversion to the desired salt may be performed by a known method.
　一般式（ＶＩＩ）で示される化合物は、一般式（ＶＩ）で示される化合物を、環化反応に付すことにより製造することができる。 The compound represented by the general formula (VII) can be produced by subjecting the compound represented by the general formula (VI) to a cyclization reaction.
　この環化反応は公知であり、例えば、有機溶媒（テトラヒドロフラン、ジメチルホルムアミド、ジメチルアセトアミド、ジクロロメタン等）中、試薬（１，１’－カルボニルジイミダゾール（ＣＤＩ）、トリホスゲン、２，２，２－トリクロロエチル　カーボンクロリデート等）を用いて、塩基（トリエチルアミン、Ｎ，Ｎ－ジイソプロピルエチルアミン、ピリジン、４－ジメチルアミノピリジン、Ｎ－メチルモルホリン等）の存在下もしくは非存在下、氷冷～還流温度で行われる。 This cyclization reaction is known, for example, in an organic solvent (tetrahydrofuran, dimethylformamide, dimethylacetamide, dichloromethane, etc.) using a reagent (1,1'-carbonyldiimidazole (CDI), triphosgene, 2,2,2-trichloro ethyl carbon chloridate, etc.) in the presence or absence of a base (triethylamine, N,N-diisopropylethylamine, pyridine, 4-dimethylaminopyridine, N-methylmorpholine, etc.) at ice-cooling to reflux temperature. be exposed.
　さらに必要であれば、この反応に引き続いて公知の方法によって、目的の塩に変換する操作を行ってもよい。 Furthermore, if necessary, subsequent to this reaction, conversion to the desired salt may be performed by a known method.
　一般式（ＶＩＩＩ）で示される化合物は、一般式（ＶＩＩ）で示される化合物を、カルボキシル基の保護基の脱保護反応に付すことにより製造することができる。 The compound represented by the general formula (VIII) can be produced by subjecting the compound represented by the general formula (VII) to a deprotection reaction of the protecting group of the carboxyl group.
　カルボキシル基の保護基としては、例えばメチル基、エチル基、アリル基、ｔ－ブチル基、トリクロロエチル基、ベンジル（Ｂｎ）基、フェナシル基、ｐ－メトキシベンジル基、トリチル基、２－クロロトリチル基またはそれらの構造が結合した固相担体等が挙げられる。 Examples of protective groups for carboxyl groups include methyl group, ethyl group, allyl group, t-butyl group, trichloroethyl group, benzyl (Bn) group, phenacyl group, p-methoxybenzyl group, trityl group, and 2-chlorotrityl group. Alternatively, a solid phase support to which these structures are bonded can be mentioned.
　カルボキシル基の保護基としては、上記した以外にも容易にかつ選択的に脱離できる基であれば特に限定されない。例えば、P. G. M. Wuts, T. W. Greene, Green's Protective Groups in Organic Synthesis, Wiley, Fourth Edition, New York, 2007に記載されたものが用いられる。 The protecting group for the carboxyl group is not particularly limited as long as it is a group that can be easily and selectively removed in addition to those mentioned above. For example, those described in P. G. M. Wuts, T. W. Greene, Green's Protective Groups in Organic Synthesis, Wiley, Fourth Edition, New York, 2007 are used.
　カルボキシル基の保護基の脱保護反応は、よく知られており、例えば、
（１）アルカリ加水分解、
（２）酸性条件下における脱保護反応、
（３）加水素分解による脱保護反応、
（４）シリル基の脱保護反応、
（５）金属を用いた脱保護反応、
（６）金属錯体を用いた脱保護反応等が挙げられる。 The deprotection reaction of protecting groups of carboxyl groups is well known, for example,
(1) Alkaline hydrolysis,
(2) Deprotection reaction under acidic conditions,
(3) Deprotection reaction by hydrolysis,
(4) Deprotection reaction of silyl group,
(5) Deprotection reaction using metal,
(6) Examples include deprotection reactions using metal complexes.
　これらの方法を具体的に説明すると、
　（１）アルカリ加水分解による脱保護反応は、例えば、有機溶媒（メタノール、テトラヒドロフラン、１，４－ジオキサン等）中、アルカリ金属の水酸化物（水酸化ナトリウム、水酸化カリウム、水酸化リチウム等）、アルカリ金属のシラノール塩（カリウムトリメチルシラノラート等）、アルカリ土類金属の水酸化物（水酸化バリウム、水酸化カルシウム等）または炭酸塩（炭酸ナトリウム、炭酸カリウム等）あるいはその水溶液もしくはこれらの混合物を用いて、０℃～８０℃の温度で行なわれる。 To explain these methods specifically,
(1) Deprotection reaction by alkaline hydrolysis can be carried out using, for example, an alkali metal hydroxide (sodium hydroxide, potassium hydroxide, lithium hydroxide, etc.) in an organic solvent (methanol, tetrahydrofuran, 1,4-dioxane, etc.). , alkali metal silanol salts (potassium trimethylsilanolate, etc.), alkaline earth metal hydroxides (barium hydroxide, calcium hydroxide, etc.) or carbonates (sodium carbonate, potassium carbonate, etc.) or their aqueous solutions or mixtures thereof. The test is carried out at a temperature of 0°C to 80°C.
　（２）酸条件下での脱保護反応は、例えば、有機溶媒（ジクロロメタン、クロロホルム、１，４－ジオキサン、酢酸エチル、アニソール等）中、有機酸（酢酸、トリフルオロ酢酸、メタンスルホン酸、ｐ－トシル酸等）、または無機酸（塩酸、硫酸等）もしくはこれらの混合物（臭化水素／酢酸等）中、２，２，２－トリフルオロエタノールの存在下または非存在下、０℃～１００℃の温度で行なわれる。 (2) The deprotection reaction under acidic conditions can be carried out, for example, in an organic solvent (dichloromethane, chloroform, 1,4-dioxane, ethyl acetate, anisole, etc.) with an organic acid (acetic acid, trifluoroacetic acid, methanesulfonic acid, p - tosylic acid, etc.) or inorganic acids (hydrochloric acid, sulfuric acid, etc.) or mixtures thereof (hydrogen bromide/acetic acid, etc.) in the presence or absence of 2,2,2-trifluoroethanol, from 0°C to 100°C. It is carried out at a temperature of °C.
　（３）加水素分解による脱保護反応は、例えば、溶媒（テトラヒドロフラン、１，４－ジオキサン、ジメトキシエタン、ジエチルエーテル、メタノール、エタノール、ベンゼン、トルエン、アセトン、メチルエチルケトン、アセトニトリル、ジメチルホルムアミド、水、酢酸エチル、酢酸またはそれらの２つ以上の混合溶媒等）中、触媒（パラジウム－炭素、パラジウム黒、水酸化パラジウム－炭素、酸化白金、ラネーニッケル等）の存在下、常圧または加圧下の水素雰囲気下またはギ酸アンモニウム存在下、０℃～２００℃の温度で行なわれる。 (3) The deprotection reaction by hydrolysis can be carried out using, for example, a solvent (tetrahydrofuran, 1,4-dioxane, dimethoxyethane, diethyl ether, methanol, ethanol, benzene, toluene, acetone, methyl ethyl ketone, acetonitrile, dimethylformamide, water, acetic acid). in the presence of a catalyst (palladium-carbon, palladium black, palladium hydroxide-carbon, platinum oxide, Raney nickel, etc.) in a hydrogen atmosphere at normal or pressurized pressure. Alternatively, it is carried out at a temperature of 0°C to 200°C in the presence of ammonium formate.
　（４）シリル基の脱保護反応は、例えば、水と混和しうる有機溶媒（テトラヒドロフラン、アセトニトリル等）中、テトラブチルアンモニウムフルオライドを用いて、０℃～４０℃の温度で行なわれる。 (4) The deprotection reaction of the silyl group is carried out, for example, using tetrabutylammonium fluoride in a water-miscible organic solvent (tetrahydrofuran, acetonitrile, etc.) at a temperature of 0°C to 40°C.
　（５）金属を用いた脱保護反応は、例えば、酸性溶媒（酢酸、ｐＨ4.2～7.2の緩衝液またはそれらの溶液とテトラヒドロフラン等の有機溶媒との混合液）中、粉末亜鉛の存在下、必要であれば超音波をかけながら、０℃～４０℃の温度で行なわれる。 (5) The deprotection reaction using a metal can be carried out, for example, in the presence of powdered zinc in an acidic solvent (acetic acid, a buffer solution with a pH of 4.2 to 7.2, or a mixture of such a solution and an organic solvent such as tetrahydrofuran). It is carried out at a temperature of 0°C to 40°C, with ultrasound applied if necessary.
　（６）金属錯体を用いる脱保護反応は、例えば、有機溶媒（ジクロロメタン、ジメチルホルムアミド、テトラヒドロフラン、酢酸エチル、アセトニトリル、１，４－ジオキサン、エタノール等）、水またはそれらの混合溶媒中、トラップ試薬（水素化トリブチルスズ、トリエチルシラン、ジメドン、モルホリン、ジエチルアミン、ピロリジン等）、有機酸（酢酸、ギ酸、２－エチルヘキサン酸等）および／または有機酸塩（２－エチルヘキサン酸ナトリウム、２－エチルヘキサン酸カリウム等）の存在下、ホスフィン系試薬（トリフェニルホスフィン等）の存在下または非存在下、金属錯体（テトラキス（トリフェニルホスフィン）パラジウム（Ｐｄ（ＰＰｈ３）、二塩化ビス（トリフェニルホスフィン）パラジウム（ＰｄＣｌ２（ＰＰｈ３）２）、酢酸パラジウム（Ｐｄ（ＯＡｃ）２）、塩化トリス（トリフェニルホスフィン）ロジウム（ＲｈＣｌ（ＰＰｈ３）３）等）を用いて、０℃～４０℃の温度で行なわれる。 (6) The deprotection reaction using a metal complex can be carried out using a trap reagent ( tributyltin hydride, triethylsilane, dimedone, morpholine, diethylamine, pyrrolidine, etc.), organic acids (acetic acid, formic acid, 2-ethylhexanoic acid, etc.) and/or organic acid salts (sodium 2-ethylhexanoate, 2-ethylhexanoic acid) metal complexes (tetrakis(triphenylphosphine)palladium (Pd( PPh3 ), bis(triphenylphosphine)palladium dichloride) in the presence or absence of phosphine-based reagents (triphenylphosphine, etc.) (PdCl 2 (PPh 3 ) 2 ), palladium acetate (Pd(OAc) 2 ), tris(triphenylphosphine) rhodium chloride (RhCl(PPh 3 ) 3 ), etc.) at a temperature of 0°C to 40°C. It is done.
　また、上記以外にも、例えば、「Comprehensive Organic Transformations : A Guide to Functional Group Preparations, 2nd Edition (Richard C. Larock, John Wiley & Sons Inc, 1999)」および「P. G. M. Wuts, T. W. Greene, Green's Protective Groups in Organic Synthesis, Wiley, Fourth Edition, New York, 2007」に記載された方法によって、脱保護反応を行なうことができる。 In addition to the above, for example, "Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 2nd Edition (Richard C. Larock, John Wiley & Sons Inc, 1999)" and "P. G. M. Wuts, T. The deprotection reaction can be carried out by the method described in W. Greene, Green's Protective Groups in Organic Synthesis, Wiley, Fourth Edition, New York, 2007.
　さらに必要であれば、この反応に引き続いて公知の方法によって、目的の塩に変換する操作を行ってもよい。 Further, if necessary, subsequent to this reaction, conversion to the desired salt may be performed by a known method.
　一般式（Ｘ）で示される化合物は、一般式（ＶＩＩＩ）で示される化合物と、一般式（ＩＸ）で示される化合物を用いて、アミド化反応に付すことにより製造することができる。 The compound represented by the general formula (X) can be produced by subjecting the compound represented by the general formula (VIII) and the compound represented by the general formula (IX) to an amidation reaction.
　このアミド化反応は公知であり、例えば、
（１）酸ハライドを用いる方法、
（２）混合酸無水物を用いる方法、
（３）縮合剤を用いる方法などが挙げられる。 This amidation reaction is known, for example,
(1) Method using acid halide,
(2) method using mixed acid anhydride;
(3) A method using a condensing agent may be mentioned.
　これらの方法を具体的に説明すると、
　（１）酸ハライドを用いる方法は、例えば、カルボン酸を有機溶媒（クロロホルム、ジクロロメタン、ジエチルエーテル、テトラヒドロフラン等）中もしくは無溶媒で、酸ハライド化剤（オキサリルクロライド、チオニルクロライド等）と－２０℃～還流温度で反応させ、得られた酸ハライドを塩基（ピリジン、トリエチルアミン、ジメチルアニリン、ジメチルアミノピリジン、ジイソプロピルエチルアミン等）の存在下、アミンと有機溶媒（クロロホルム、ジクロロメタン、ジエチルエーテル、テトラヒドロフラン等）中、０℃～４０℃の温度で反応させることにより行なわれる。また、得られた酸ハライドを有機溶媒（１，４－ジオキサン、テトラヒドロフラン等）中、アルカリ水溶液（重曹水または水酸化ナトリウム溶液等）を用いて、アミンと０℃～４０℃で反応させることにより行なうこともできる。 To explain these methods specifically,
(1) A method using an acid halide involves, for example, adding a carboxylic acid to an acid halide agent (oxalyl chloride, thionyl chloride, etc.) in an organic solvent (chloroform, dichloromethane, diethyl ether, tetrahydrofuran, etc.) or without a solvent at -20°C. ~React at reflux temperature, and the resulting acid halide is mixed with an amine in an organic solvent (chloroform, dichloromethane, diethyl ether, tetrahydrofuran, etc.) in the presence of a base (pyridine, triethylamine, dimethylaniline, dimethylaminopyridine, diisopropylethylamine, etc.). , by reacting at a temperature of 0°C to 40°C. Alternatively, the obtained acid halide can be reacted with an amine at 0°C to 40°C in an organic solvent (1,4-dioxane, tetrahydrofuran, etc.) using an alkaline aqueous solution (aqueous sodium bicarbonate or sodium hydroxide solution, etc.). You can also do it.
　（２）混合酸無水物を用いる方法は、例えば、カルボン酸を有機溶媒（クロロホルム、ジクロロメタン、ジエチルエーテル、テトラヒドロフラン等）中もしくは無溶媒で、塩基（ピリジン、トリエチルアミン、ジメチルアニリン、ジメチルアミノピリジン、ジイソプロピルエチルアミン等）の存在下、酸ハライド（ピバロイルクロライド、トシルクロライド、メシルクロライド等）、または酸誘導体（クロロギ酸エチル、クロロギ酸イソブチル等）と、０℃～４０℃で反応させ、得られた混合酸無水物を有機溶媒（クロロホルム、ジクロロメタン、ジエチルエーテル、テトラヒドロフラン等）中、アミンと０℃～４０℃で反応させることにより行なわれる。 (2) A method using a mixed acid anhydride includes, for example, adding a carboxylic acid to a base (pyridine, triethylamine, dimethylaniline, dimethylaminopyridine, diisopropyl, etc.) in an organic solvent (chloroform, dichloromethane, diethyl ether, tetrahydrofuran, etc.) or without a solvent. ethylamine, etc.) with an acid halide (pivaloyl chloride, tosyl chloride, mesyl chloride, etc.) or an acid derivative (ethyl chloroformate, isobutyl chloroformate, etc.) at 0°C to 40°C. This is carried out by reacting a mixed acid anhydride with an amine in an organic solvent (chloroform, dichloromethane, diethyl ether, tetrahydrofuran, etc.) at 0°C to 40°C.
　（３）縮合剤を用いる方法は、例えば、カルボン酸とアミンを、有機溶媒（クロロホルム、ジクロロメタン、ジメチルホルムアミド、ジエチルエーテル、テトラヒドロフラン等）中、もしくは無溶媒で、塩基（ピリジン、トリエチルアミン、ジメチルアニリン、ジメチルアミノピリジン、Ｎ，Ｎ－ジイソプロピルエチルアミン等）の存在下または非存在下、縮合剤（１，３－ジシクロヘキシルカルボジイミド（ＤＣＣ）、１－エチル－３－［３－（ジメチルアミノ）プロピル］カルボジイミド（ＥＤＣ）、１，１’－カルボニルジイミダゾール（ＣＤＩ）、２－クロロ－１－メチルピリジニウムヨウ素、１－プロピルホスホン酸環状無水物（１－ｐｒｏｐａｎｅｐｈｏｓｐｈｏｎｉｃ　ａｃｉｄ　ｃｙｃｌｉｃ　ａｎｈｙｄｒｉｄｅ、ＰＰＡ）、４－（４，６－ジメトキシ－１，３，５－トリアジン－２－イル）－４－メチルモルホリン－４－イウム　クロライド（ＤＭＴＭＭ）、（ジメチルアミノ）－Ｎ，Ｎ－ジメチル（３Ｈ－［１，２，３］トリアゾロ［４，５－b］ピリジン－３－イルオキシ）メタニミニウムヘキサフルオロホスファート（ＨＡＴＵ）、クロロ（ジメチルアミノ）－Ｎ，Ｎ－ジメチルメタンイミニウム　ヘキサフルオロホスファート（ＴＣＦＨ）等）を用い、１－ヒドロキシベンズトリアゾール（ＨＯＢｔ）の存在下もしくは非存在下で、０℃～４０℃で反応させることにより行なわれる。 (3) A method using a condensing agent is, for example, combining a carboxylic acid and an amine in an organic solvent (chloroform, dichloromethane, dimethylformamide, diethyl ether, tetrahydrofuran, etc.) or without a solvent, and a base (pyridine, triethylamine, dimethylaniline, etc.). dimethylaminopyridine, N,N-diisopropylethylamine, etc.) in the presence or absence of a condensing agent (1,3-dicyclohexylcarbodiimide (DCC), 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide ( EDC), 1,1'-carbonyldiimidazole (CDI), 2-chloro-1-methylpyridinium iodine, 1-propanephosphonic acid cyclic anhydride (PPA), 4-(4,6 -dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholin-4-ium chloride (DMTMM), (dimethylamino)-N,N-dimethyl(3H-[1,2,3]triazolo [4,5-b]pyridin-3-yloxy)methaniminium hexafluorophosphate (HATU), chloro(dimethylamino)-N,N-dimethylmethaniminium hexafluorophosphate (TCFH), etc.), The reaction is carried out at 0°C to 40°C in the presence or absence of 1-hydroxybenztriazole (HOBt).
　これら（１）、（２）および（３）の反応は、いずれも不活性ガス（アルゴン、窒素など）雰囲気下、無水条件で行なうことが望ましい。 It is desirable that the reactions (1), (2), and (3) are all carried out under anhydrous conditions in an inert gas (argon, nitrogen, etc.) atmosphere.
　さらに必要であれば、この反応に引き続いて公知の方法によって、目的の塩に変換する操作を行ってもよい。 Furthermore, if necessary, subsequent to this reaction, conversion to the desired salt may be performed by a known method.
　一般式（Ｉ－Ａ）で示される化合物は、一般式（Ｘ）で示される化合物と、一般式（ＸＩ）で示される化合物を用いて、カップリング反応に付すことにより製造することができる。 The compound represented by the general formula (IA) can be produced by subjecting the compound represented by the general formula (X) and the compound represented by the general formula (XI) to a coupling reaction.
　このカップリング反応は公知であり、例えば、有機溶媒（ベンゼン、トルエン、ジメチルホルムアミド、１，４－ジオキサン、テトラヒドロフラン、メタノール、アセトニトリル、ジメトキシエタン、アセトン、１－メチル－２－ピロリジノンまたはそれらの混合溶媒など）中、塩基（ナトリウムエチラート、水酸化ナトリウム、水酸化カリウム、トリエチルアミン、炭酸ナトリウム、炭酸水素ナトリウム、炭酸カリウム、炭酸セシウム、炭酸タリウム、リン酸三カリウム、フッ化セシウム、水酸化バリウム、フッ化テトラブチルアンモニウムなど）あるいはそれらの水溶液、もしくはそれらの混合物と、および触媒（テトラキス（トリフェニルホスフィン）パラジウム（Ｐｄ（ＰＰｈ３）４）、二塩化ビス（トリフェニルホスフィン）パラジウム（ＰｄＣｌ２（ＰＰｈ３）２）、酢酸パラジウム（Ｐｄ（ＯＡｃ）２）、パラジウム黒、１，１’－ビス（ジフェニルホスフィノフェロセン）ジクロロパラジウム（ＰｄＣｌ２（ｄｐｐｆ）２）、二塩化ジアリルパラジウム（ＰｄＣｌ２（ａｌｌｙｌ）２）、ヨウ化フェニルビス（トリフェニルホスフィン）パラジウム（ＰｈＰｄＩ（ＰＰｈ３）２）、（１Ｅ，４Ｅ）－１，５－ジフェニル－１，４－ペンタジエン－３－オン－パラジウム（Pｄ２（ｄｂａ）３）等）存在下、室温～１５０℃で反応させることにより行うことができる。 This coupling reaction is known, for example, an organic solvent (benzene, toluene, dimethylformamide, 1,4-dioxane, tetrahydrofuran, methanol, acetonitrile, dimethoxyethane, acetone, 1-methyl-2-pyrrolidinone or a mixed solvent thereof). etc.), bases (sodium ethylate, sodium hydroxide, potassium hydroxide, triethylamine, sodium carbonate, sodium bicarbonate, potassium carbonate, cesium carbonate, thallium carbonate, tripotassium phosphate, cesium fluoride, barium hydroxide, or aqueous solutions thereof, or mixtures thereof, and catalysts (tetrakis(triphenylphosphine)palladium (Pd(PPh 3 ) 4 ), bis(triphenylphosphine)palladium dichloride (PdCl 2 (PPh 3 ) 2 ), palladium acetate (Pd(OAc) 2 ), palladium black, 1,1'-bis(diphenylphosphinoferrocene) dichloropalladium (PdCl 2 (dppf) 2 ), diallypalladium dichloride (PdCl 2 (allyl ) 2 ), phenylbis(triphenylphosphine)palladium iodide (PhPdI(PPh 3 ) 2 ), (1E,4E)-1,5-diphenyl-1,4-pentadien-3-one-palladium (Pd 2 ( dba) 3 ), etc.), by reacting at room temperature to 150°C.
　さらに必要であれば、この反応に引き続いて公知の方法によって、目的の塩に変換する操作を行ってもよい。 Furthermore, if necessary, subsequent to this reaction, conversion to the desired salt may be performed by a known method.
　一般式（Ｉ－Ａ）で示される化合物のうち、Ｒ２が５～７員の含窒素飽和複素環であり、窒素原子に置換するＲ１５が、１～５個のＲ１８で置換されていてもよいＣ３～６シクロアルキル基で置換されていてもよいＣ１～８アルキル基、またはＣ１～８ハロアルキル基である化合物、すなわち、一般式（Ｉ－Ａ－１） In the compound represented by the general formula (IA), R 2 is a 5- to 7-membered nitrogen-containing saturated heterocycle, and R 15 substituted on the nitrogen atom is substituted with 1 to 5 R 18 . A compound that is a C1-8 alkyl group optionally substituted with a C3-6 cycloalkyl group or a C1-8 haloalkyl group, that is, general formula (I-A-1)
（式中、ｒｉｎｇ１は、５～７員の含窒素飽和複素環を表わし、Ｒ１５－１は、１～５個のＲ１８で置換されていてもよいＣ３～６シクロアルキル基で置換されていてもよいＣ１～８アルキル基、またはＣ１～８ハロアルキル基を表わし、uは０～２の整数を表わし、その他の記号は前記と同じ意味を表わす。）で示される化合物は、以下の反応工程式１－１ａおよび反応工程式１－１ｂで示される方法で製造することができる。反応工程式１－１ａおよび反応工程式１－１ｂ中、Ｒ１５－２は、水素原子、または１～５個のＲ１８で置換されていてもよいＣ３～６シクロアルキル基で置換されていてもよいＣ１～７アルキル基、またはC１～７ハロアルキル基を表わし、Ｅ４は脱離基（例えば、フッ素原子、臭素原子、塩素原子、ヨウ素原子、トリフルオロメタンスルホン酸エステル、ｐ－トルエンスルホン酸エステル等）を表わし、ＰＮ－１はアミノ基の保護基を表わし、その他の記号は前記と同じ意味を表わす。 (In the formula, ring1 represents a 5- to 7-membered nitrogen-containing saturated heterocycle, and R 15-1 is substituted with a C3-6 cycloalkyl group optionally substituted with 1 to 5 R 18 . (represents an optional C1-8 alkyl group or C1-8 haloalkyl group, u represents an integer of 0 to 2, and other symbols have the same meanings as above) can be used in the following reaction steps. It can be produced by the method shown in Formula 1-1a and Reaction Scheme 1-1b. In Reaction Scheme 1-1a and Reaction Scheme 1-1b, R 15-2 is substituted with a hydrogen atom or a C3-6 cycloalkyl group optionally substituted with 1 to 5 R 18 . E4 represents a leaving group (e.g., fluorine atom, bromine atom, chlorine atom, iodine atom, trifluoromethanesulfonic acid ester, p-toluenesulfonic acid ester). etc.), P N-1 represents a protecting group for an amino group, and other symbols have the same meanings as above.
　一般式（ＩＶ－１）で示される化合物は、一般式（ＩＩ）で示される化合物と、一般式（ＩＩＩ－１）で示される化合物を用いて、アミノ基の導入反応に付すことにより製造することができる。 The compound represented by the general formula (IV-1) is produced by subjecting the compound represented by the general formula (II) and the compound represented by the general formula (III-1) to an amino group introduction reaction. be able to.
　このアミノ基の導入反応は、前述の一般式（ＩＶ）で示される化合物を製造する際の反応と同様である。 This reaction for introducing an amino group is similar to the reaction for producing the compound represented by the general formula (IV) described above.
　さらに必要であれば、この反応に引き続いて公知の方法によって、目的の塩に変換する操作を行ってもよい。 Furthermore, if necessary, subsequent to this reaction, conversion to the desired salt may be performed by a known method.
　一般式（ＶＩ－１）で示される化合物は、一般式（ＩＶ－１）で示される化合物と、一般式（Ｖ）で示される化合物を用いて、カップリング反応に付すことにより製造することができる。 The compound represented by the general formula (VI-1) can be produced by subjecting the compound represented by the general formula (IV-1) and the compound represented by the general formula (V) to a coupling reaction. can.
　このカップリング反応は、前述の一般式（ＶＩ）で示される化合物を製造する際の反応と同様である。 This coupling reaction is similar to the reaction for producing the compound represented by general formula (VI) above.
　さらに必要であれば、この反応に引き続いて公知の方法によって、目的の塩に変換する操作を行ってもよい。 Furthermore, if necessary, subsequent to this reaction, conversion to the desired salt may be performed by a known method.
　一般式（ＶＩＩ－１）で示される化合物は、一般式（ＶＩ－１）で示される化合物を、環化反応に付すことにより製造することができる。 The compound represented by the general formula (VII-1) can be produced by subjecting the compound represented by the general formula (VI-1) to a cyclization reaction.
　この環化反応は、前述の一般式（ＶＩＩ）で示される化合物を製造する際の反応と同様である。 This cyclization reaction is similar to the reaction used to produce the compound represented by the aforementioned general formula (VII).
　さらに必要であれば、この反応に引き続いて公知の方法によって、目的の塩に変換する操作を行ってもよい。 Furthermore, if necessary, subsequent to this reaction, conversion to the desired salt may be performed by a known method.
　一般式（ＶＩＩＩ－１）で示される化合物は、一般式（ＶＩＩ－１）で示される化合物を、カルボキシル基の保護基の脱保護反応に付すことにより製造することができる。 The compound represented by the general formula (VIII-1) can be produced by subjecting the compound represented by the general formula (VII-1) to a deprotection reaction of the protecting group of the carboxyl group.
　このカルボキシル基の保護基の脱保護反応は、前述の一般式（ＶＩＩＩ）で示される化合物を製造する際の反応と同様である。 This deprotection reaction of the carboxyl group protecting group is the same as the reaction for producing the compound represented by the aforementioned general formula (VIII).
　さらに必要であれば、この反応に引き続いて公知の方法によって、目的の塩に変換する操作を行ってもよい。 Further, if necessary, subsequent to this reaction, conversion to the desired salt may be performed by a known method.
　一般式（Ｘ－１）で示される化合物は、一般式（ＶＩＩＩ－１）で示される化合物と、一般式（ＩＸ）で示される化合物を用いて、アミド化反応に付すことにより製造することができる。 The compound represented by the general formula (X-1) can be produced by subjecting the compound represented by the general formula (VIII-1) and the compound represented by the general formula (IX) to an amidation reaction. can.
　このアミド化反応は、前述の一般式（Ｘ）で示される化合物を製造する際の反応と同様である。 This amidation reaction is similar to the reaction for producing the compound represented by the general formula (X) described above.
　さらに必要であれば、この反応に引き続いて公知の方法によって、目的の塩に変換する操作を行ってもよい。 Further, if necessary, subsequent to this reaction, conversion to the desired salt may be performed by a known method.
　一般式（ＸＶＩ－１）で示される化合物は、一般式（Ｘ－１）で示される化合物を、アミノ基の保護基の脱保護反応に付すことにより製造することができる。 The compound represented by the general formula (XVI-1) can be produced by subjecting the compound represented by the general formula (X-1) to a deprotection reaction of the protecting group of the amino group.
　アミノ基の保護基としては、例えば、ベンジルオキシカルボニル基、ｔｅｒｔ－ブトキシカルボニル基、アリルオキシカルボニル（Ａｌｌｏｃ）基、１－メチル－１－（４－ビフェニル）エトキシカルボニル（Ｂｐｏｃ）基、トリフルオロアセチル基、９－フルオレニルメトキシカルボニル基、ベンジル（Ｂｎ）基、４－メトキシベンジル基、ベンジルオキシメチル（ＢＯＭ）基、および２－（トリメチルシリル）エトキシメチル（ＳＥＭ）基などが挙げられる。 Examples of protecting groups for amino groups include benzyloxycarbonyl group, tert-butoxycarbonyl group, allyloxycarbonyl (Alloc) group, 1-methyl-1-(4-biphenyl)ethoxycarbonyl (Bpoc) group, and trifluoroacetyl group. group, 9-fluorenylmethoxycarbonyl group, benzyl (Bn) group, 4-methoxybenzyl group, benzyloxymethyl (BOM) group, and 2-(trimethylsilyl)ethoxymethyl (SEM) group.
　アミノ基の保護基としては、上記した以外にも容易にかつ選択的に脱離できる基であれば特に限定されない。例えば、P. G. M. Wuts, T. W. Greene, Green's Protective Groups in Organic Synthesis, Wiley, Fourth Edition, New York, 2007に記載されたものが用いられる。 The protecting group for the amino group is not particularly limited as long as it is a group that can be easily and selectively removed other than those mentioned above. For example, those described in P. G. M. Wuts, T. W. Greene, Green's Protective Groups in Organic Synthesis, Wiley, Fourth Edition, New York, 2007 are used.
　アミノ基の保護基の脱保護反応は公知であり、例えば、
（１）アルカリ加水分解、
（２）酸性条件下における脱保護反応、
（３）加水素分解による脱保護反応、
（４）シリル基の脱保護反応、
（５）金属を用いた脱保護反応、
（６）金属錯体を用いた脱保護反応などが挙げられる。 Deprotection reactions of protecting groups for amino groups are known, for example,
(1) Alkaline hydrolysis,
(2) Deprotection reaction under acidic conditions,
(3) Deprotection reaction by hydrolysis,
(4) Deprotection reaction of silyl group,
(5) Deprotection reaction using metal,
(6) Examples include deprotection reactions using metal complexes.
　これらの方法を具体的に説明すると、
　（１）アルカリ加水分解による脱保護反応は、例えば、有機溶媒（メタノール、テトラヒドロフラン、１，４－ジオキサン等）中、アルカリ金属の水酸化物（水酸化ナトリウム、水酸化カリウム、水酸化リチウム等）、アルカリ土類金属の水酸化物（水酸化バリウム、水酸化カルシウムなど）または炭酸塩（炭酸ナトリウム、炭酸カリウム等）あるいはその水溶液もしくはこれらの混合物を用いて、０℃～４０℃の温度で行なわれる。 To explain these methods specifically,
(1) Deprotection reaction by alkaline hydrolysis can be carried out using, for example, an alkali metal hydroxide (sodium hydroxide, potassium hydroxide, lithium hydroxide, etc.) in an organic solvent (methanol, tetrahydrofuran, 1,4-dioxane, etc.). , using alkaline earth metal hydroxides (barium hydroxide, calcium hydroxide, etc.) or carbonates (sodium carbonate, potassium carbonate, etc.) or their aqueous solutions or mixtures thereof at temperatures of 0°C to 40°C. It will be done.
　（２）酸条件下での脱保護反応は、例えば、有機溶媒（ジクロロメタン、クロロホルム、１，４－ジオキサン、酢酸エチル、アニソール等）中、有機酸（酢酸、トリフルオロ酢酸、メタンスルホン酸、ｐ－トシル酸等）、または無機酸（塩酸、硫酸等）もしくはこれらの混合物（臭化水素／酢酸等）中、０℃～１００℃の温度で行なわれる。 (2) The deprotection reaction under acidic conditions can be carried out, for example, in an organic solvent (dichloromethane, chloroform, 1,4-dioxane, ethyl acetate, anisole, etc.) with an organic acid (acetic acid, trifluoroacetic acid, methanesulfonic acid, p -tosylic acid, etc.), or in an inorganic acid (hydrochloric acid, sulfuric acid, etc.) or a mixture thereof (hydrogen bromide/acetic acid, etc.) at a temperature of 0°C to 100°C.
　（３）加水素分解による脱保護反応は、例えば、溶媒（テトラヒドロフラン、１，４－ジオキサン、ジメトキシエタン、ジエチルエーテル、メタノール、エタノール、ベンゼン、トルエン、アセトン、メチルエチルケトン、アセトニトリル、ジメチルホルムアミド、水、酢酸エチル、酢酸等、もしくはそれらの混合溶媒）中、触媒（パラジウム－炭素、パラジウム黒、水酸化パラジウム、酸化白金、ラネーニッケル等）の存在下、常圧または加圧下の水素雰囲気下またはギ酸アンモニウム存在下、０℃～２００℃の温度で行なわれる。 (3) The deprotection reaction by hydrolysis can be carried out using, for example, a solvent (tetrahydrofuran, 1,4-dioxane, dimethoxyethane, diethyl ether, methanol, ethanol, benzene, toluene, acetone, methyl ethyl ketone, acetonitrile, dimethylformamide, water, acetic acid). ethyl, acetic acid, etc., or a mixed solvent thereof), in the presence of a catalyst (palladium-carbon, palladium black, palladium hydroxide, platinum oxide, Raney nickel, etc.), under a hydrogen atmosphere at normal or pressurized pressure, or in the presence of ammonium formate. , at a temperature of 0°C to 200°C.
　（４）シリル基の脱保護反応は、例えば、水と混和しうる有機溶媒（テトラヒドロフラン、アセトニトリル等）中、テトラブチルアンモニウムフルオライド等を用いて、０℃～４０℃の温度で行なわれる。 (4) The deprotection reaction of the silyl group is carried out, for example, in a water-miscible organic solvent (tetrahydrofuran, acetonitrile, etc.) using tetrabutylammonium fluoride or the like at a temperature of 0°C to 40°C.
　（５）金属を用いた脱保護反応は、例えば、酸性溶媒（酢酸、ｐＨ４．２～７．２の緩衝液またはそれらの溶液とテトラヒドロフランなどの有機溶媒との混合溶媒）中、粉末亜鉛の存在下、必要であれば超音波をかけながら、０℃～４０℃の温度で行なわれる。 (5) Deprotection reactions using metals can be performed, for example, in the presence of powdered zinc in an acidic solvent (acetic acid, a buffer solution with a pH of 4.2 to 7.2, or a mixed solvent of these solutions and an organic solvent such as tetrahydrofuran). The process is carried out at a temperature of 0°C to 40°C, with ultrasonic waves applied if necessary.
　（６）金属錯体を用いる脱保護反応は、例えば、有機溶媒（ジクロロメタン、ジメチルホルムアミド、テトラヒドロフラン、酢酸エチル、アセトニトリル、１，４－ジオキサン、エタノール等）、水またはそれらの混合溶媒中、トラップ試薬（水素化トリブチルスズ、トリエチルシラン、ジメドン、モルホリン、ジエチルアミン、ピロリジン等）、有機酸（酢酸、ギ酸、２－エチルヘキサン酸等）および／または有機酸塩（２－エチルヘキサン酸ナトリウム、２－エチルヘキサン酸カリウム等）の存在下、ホスフィン系試薬（トリフェニルホスフィンなど）の存在下または非存在下、金属錯体（テトラキス（トリフェニルホスフィン）パラジウム（Ｐｄ（ＰＰｈ３）４）、二塩化ビス（トリフェニルホスフィン）パラジウム（ＰｄＣｌ２（ＰＰｈ３）２）、酢酸パラジウム（Ｐｄ（ＯＡｃ）２）、塩化トリス（トリフェニルホスフィン）ロジウム（ＲｈＣｌ（ＰＰｈ３）３）等）を用いて、０℃～４０℃の温度で行なわれる。 (6) The deprotection reaction using a metal complex can be carried out using a trap reagent ( tributyltin hydride, triethylsilane, dimedone, morpholine, diethylamine, pyrrolidine, etc.), organic acids (acetic acid, formic acid, 2-ethylhexanoic acid, etc.) and/or organic acid salts (sodium 2-ethylhexanoate, 2-ethylhexanoic acid) metal complexes (tetrakis(triphenylphosphine)palladium (Pd(PPh 3 ) 4 ), bis(triphenylphosphine dichloride), in the presence or absence of phosphine-based reagents (triphenylphosphine, etc.) ) using palladium (PdCl 2 (PPh 3 ) 2 ), palladium acetate (Pd(OAc) 2 ), tris(triphenylphosphine) rhodium chloride (RhCl(PPh 3 ) 3 ), etc.) at 0°C to 40°C. It is done at temperature.
　また、上記以外にも、例えば、「Comprehensive Organic Transformations : A Guide to Functional Group Preparations, 2nd Edition (Richard C. Larock, John Wiley & Sons Inc, 1999)」および「P. G. M. Wuts, T. W. Greene, Green's Protective Groups in Organic Synthesis, Wiley, Fourth Edition, New York, 2007」に記載された方法によって、脱保護反応を行なうことができる。 In addition to the above, for example, "Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 2nd Edition (Richard C. Larock, John Wiley & Sons Inc, 1999)" and "P. G. M. Wuts, T. The deprotection reaction can be carried out by the method described in W. Greene, Green's Protective Groups in Organic Synthesis, Wiley, Fourth Edition, New York, 2007.
　さらに必要であれば、この反応に引き続いて公知の方法によって、目的の塩に変換する操作を行ってもよい。 Furthermore, if necessary, subsequent to this reaction, conversion to the desired salt may be performed by a known method.
　一般式（ＸＩＸ－１）で示される化合物は、一般式（ＸＶＩ－１）で示される化合物と、一般式（ＸＶＩＩ－１）で示される化合物、または一般式（ＸＶＩＩＩ－１）で示される化合物を用いて、アルキル化反応に付すことにより製造することができる。 The compound represented by the general formula (XIX-1) is a compound represented by the general formula (XVI-1), a compound represented by the general formula (XVII-1), or a compound represented by the general formula (XVIII-1). can be produced by subjecting it to an alkylation reaction.
　このアルキル化反応は公知であり、一般式（ＸＶＩＩ－１）で示される化合物を用いる場合、例えば有機溶媒（ジメチルホルムアミド、ジメチルアセトアミド、ジメチルスルホキシド、クロロホルム、ジクロロメタン、ジエチルエーテル、テトラヒドロフラン、メチル　ｔ－ブチル　エーテル等）中、有機塩基（トリエチルアミン、Ｎ，Ｎ－ジイソプロピルエチルアミン、ピリジン、４－ジメチルアミノピリジン、Ｎ－メチルモルホリン等）、アルカリ金属の水酸化物（水酸化ナトリウム、水酸化カリウム、水酸化リチウム等）、アルカリ土類金属の水酸化物（水酸化バリウム、水酸化カルシウム等）もしくは炭酸塩（炭酸ナトリウム、炭酸カリウム等）またはその水溶液あるいはこれらの混合物の存在下、アルカリ金属ハロゲン化物塩（ヨウ化カリウム、ヨウ化ナトリウム等）の存在下もしくは非存在下、０℃～１００℃で反応させることで行われる。 This alkylation reaction is known, and when using a compound represented by general formula (XVII-1), for example, organic solvents (dimethylformamide, dimethylacetamide, dimethyl sulfoxide, chloroform, dichloromethane, diethyl ether, tetrahydrofuran, methyl t-butyl ether, etc.), organic bases (triethylamine, N,N-diisopropylethylamine, pyridine, 4-dimethylaminopyridine, N-methylmorpholine, etc.), alkali metal hydroxides (sodium hydroxide, potassium hydroxide, lithium hydroxide, etc.), alkaline earth metal hydroxides (barium hydroxide, calcium hydroxide, etc.) or carbonates (sodium carbonate, potassium carbonate, etc.) or their aqueous solutions, or mixtures thereof. The reaction is carried out at 0°C to 100°C in the presence or absence of potassium chloride, sodium iodide, etc.).
　一般式（ＸＶＩＩＩ－１）で示される化合物を用いる場合、還元的アミノ化反応によって目的物を得ることができる。 When using a compound represented by general formula (XVIII-1), the desired product can be obtained by a reductive amination reaction.
　この還元的アミノ化反応は公知であり、反応で生成するイミンを単離した後、還元してもよく、また反応系中にイミンを生成させ、単離せずに（ワンポットで）還元してもよい。このイミンの生成反応は公知であり、例えば、有機溶媒（メタノール、エタノール、ジクロロメタン、クロロホルム、ジクロロエタン、ベンゼン、トルエン、またはそれらの混合溶媒等）中、脱水剤（無水硫酸マグネシウム、モレキュラーシーブ（商品名）等）の存在下もしくは非存在下、酸（塩酸、酢酸等）の存在下もしくは非存在下、２０℃～還流温度で行うことができる。イミンの還元反応も公知であり、例えば、有機溶媒（テトラヒドロフラン、ジエチルエーテル、ジクロロエタン、ジクロロメタン、ジメチルホルムアミド、酢酸、メタノール、エタノール、またはそれらの混合物等）中、還元剤（トリアセトキシ水素化ホウ素ナトリウム、シアノ水素化ホウ素ナトリウム、水素化ホウ素ナトリウム、水素化ホウ素亜鉛、ジイソブチルアルミニウムヒドリド、２－ピコリンボラン錯体等）の存在下、０℃～４０℃の温度で行うか、または溶媒（テトラヒドロフラン、１，４－ジオキサン、ジメトキシエタン、ジエチルエーテル、メタノール、エタノール、ベンゼン、トルエン、アセトニトリル、ジメチルホルムアミド、水、酢酸エチル、酢酸、またはそれらの混合溶媒等）中、触媒（パラジウム－炭素、パラジウム黒、水酸化パラジウム、酸化白金、ラネーニッケル等）の存在下、常圧または加圧下の水素雰囲気下、０℃～２００℃の温度で行うことができる。また、イミンを単離せずに行う還元的アミノ化反応は公知であり、例えば、有機溶媒（テトラヒドロフラン、ジクロロエタン、ジクロロメタン、ジメチルホルムアミド、酢酸、またはそれらの混合物等）中、還元剤（トリアセトキシ水素化ホウ素ナトリウム、シアノ水素化ホウ素ナトリウム、水素化ホウ素ナトリウム、２－ピコリンボラン錯体等）の存在下、０℃～４０℃の温度で行うことができる。 This reductive amination reaction is known, and the imine produced in the reaction may be isolated and then reduced, or the imine may be produced in the reaction system and reduced without isolation (in one pot). good. This imine production reaction is known, and for example, in an organic solvent (methanol, ethanol, dichloromethane, chloroform, dichloroethane, benzene, toluene, or a mixed solvent thereof, etc.), a dehydrating agent (anhydrous magnesium sulfate, ) etc.) and in the presence or absence of an acid (hydrochloric acid, acetic acid, etc.) at 20° C. to reflux temperature. Reduction reactions of imines are also known and include, for example, reducing agents (sodium triacetoxyborohydride, sodium cyanoborohydride, sodium borohydride, zinc borohydride, diisobutylaluminum hydride, 2-picoline borane complex, etc.) at a temperature of 0°C to 40°C, or in the presence of a solvent (tetrahydrofuran, 1,4 - In a catalyst (such as dioxane, dimethoxyethane, diethyl ether, methanol, ethanol, benzene, toluene, acetonitrile, dimethylformamide, water, ethyl acetate, acetic acid, or a mixed solvent thereof) (palladium on carbon, palladium black, palladium hydroxide) , platinum oxide, Raney nickel, etc.), in a hydrogen atmosphere under normal pressure or under pressure, and at a temperature of 0° C. to 200° C. In addition, reductive amination reactions performed without isolating the imine are known, for example, in an organic solvent (such as tetrahydrofuran, dichloroethane, dichloromethane, dimethylformamide, acetic acid, or a mixture thereof) with a reducing agent (triacetoxy hydrogenation reaction). The reaction can be carried out at a temperature of 0° C. to 40° C. in the presence of sodium boron, sodium cyanoborohydride, sodium borohydride, 2-picoline borane complex, etc.).
　また、例えば、有機溶媒（ジクロロエタン、ジクロロメタン、トルエン、テトラヒドロフランまたはそれらの混合溶媒等）中、三級アミン（トリエチルアミン、ジイソプロピルエチルアミン等）の存在下、ルイス酸（四塩化チタン等）を用いて、０℃～４０℃で反応させ、さらに、還元剤（トリアセトキシ水素化ホウ素ナトリウム、シアノ水素化ホウ素ナトリウム、２－ピコリンボラン錯体等）の存在下、０℃～４０℃の温度で行うこともできる。 For example, using a Lewis acid (titanium tetrachloride, etc.) in the presence of a tertiary amine (triethylamine, diisopropylethylamine, etc.) in an organic solvent (dichloroethane, dichloromethane, toluene, tetrahydrofuran, or a mixed solvent thereof, etc.), The reaction can be carried out at a temperature of 0° C. to 40° C. and further carried out at a temperature of 0° C. to 40° C. in the presence of a reducing agent (sodium triacetoxyborohydride, sodium cyanoborohydride, 2-picoline borane complex, etc.).
　さらに必要であれば、この反応に引き続いて公知の方法によって、目的の塩に変換する操作を行ってもよい。 Furthermore, if necessary, subsequent to this reaction, conversion to the desired salt may be performed by a known method.
　一般式（Ｉ－Ａ－１）で示される化合物は、一般式（ＸＩＸ－１）で示される化合物と、一般式（ＸＩ）で示される化合物を用いて、カップリング反応に付すことにより製造することができる。 The compound represented by general formula (IA-1) is produced by subjecting a compound represented by general formula (XIX-1) and a compound represented by general formula (XI) to a coupling reaction. be able to.
　このカップリング反応は、前述の一般式（Ｉ－Ａ）で示される化合物を製造する際の反応と同様である。 This coupling reaction is similar to the reaction for producing the compound represented by the general formula (IA) described above.
　一般式（Ｉ－Ａ－１）で示される化合物は、以下の反応工程式１－１ｃおよび反応工程式１－１ｄで示される方法で製造することもできる。反応工程式１－１ｃおよび反応工程式１－１ｄ中、すべての記号は前記と同じ意味を表わす。 The compound represented by the general formula (IA-1) can also be produced by the method shown in the following reaction scheme 1-1c and reaction scheme 1-1d. In Reaction Scheme 1-1c and Reaction Scheme 1-1d, all symbols have the same meanings as above.
　一般式（ＸＸＸ－１）で示される化合物は、一般式（ＶＩＩ－１）で示される化合物を、カルボキシル基の保護基の脱保護反応に付すことにより製造することができる。 The compound represented by the general formula (XXX-1) can be produced by subjecting the compound represented by the general formula (VII-1) to a deprotection reaction of the protecting group of the carboxyl group.
　このカルボキシル基の保護基の脱保護反応は、前述の一般式（ＶＩＩＩ）で示される化合物を製造する際の反応と同様である。 This deprotection reaction of the protecting group for the carboxyl group is the same as the reaction for producing the compound represented by the aforementioned general formula (VIII).
　さらに必要であれば、この反応に引き続いて公知の方法によって、目的の塩に変換する操作を行ってもよい。 Furthermore, if necessary, subsequent to this reaction, conversion to the desired salt may be performed by a known method.
　一般式（ＸＸＸＩ－１）で示される化合物は、一般式（ＸＸＸ－１）で示される化合物と、一般式（ＸＩ）で示される化合物を用いて、カップリング反応に付すことにより製造することができる。 The compound represented by the general formula (XXXI-1) can be produced by subjecting the compound represented by the general formula (XXX-1) and the compound represented by the general formula (XI) to a coupling reaction. can.
　このカップリング反応は、前述の一般式（Ｉ－Ａ）で示される化合物を製造する際の反応と同様である。 This coupling reaction is similar to the reaction for producing the compound represented by the general formula (IA) described above.
　さらに必要であれば、この反応に引き続いて公知の方法によって、目的の塩に変換する操作を行ってもよい。 Furthermore, if necessary, subsequent to this reaction, conversion to the desired salt may be performed by a known method.
　一般式（ＸＸＸＩＩ－１）で示される化合物は、一般式（ＸＸＸＩ－１）で示される化合物と、一般式（ＩＸ）で示される化合物を用いて、アミド化反応に付すことにより製造することができる。 The compound represented by the general formula (XXXII-1) can be produced by subjecting the compound represented by the general formula (XXXI-1) and the compound represented by the general formula (IX) to an amidation reaction. can.
　このアミド化反応は、このアミド化反応は、前述の一般式（Ｘ）で示される化合物を製造する際の反応と同様である。 This amidation reaction is similar to the reaction for producing the compound represented by general formula (X) described above.
　さらに必要であれば、この反応に引き続いて公知の方法によって、目的の塩に変換する操作を行ってもよい。 Furthermore, if necessary, subsequent to this reaction, conversion to the desired salt may be performed by a known method.
　一般式（ＸＸＸＩＩＩ－１）で示される化合物は、一般式（ＸＸＸＩＩ－１）で示される化合物を、アミノ基の保護基の脱保護反応に付すことにより製造することができる。 The compound represented by the general formula (XXXIII-1) can be produced by subjecting the compound represented by the general formula (XXXII-1) to a deprotection reaction of the protecting group of the amino group.
　このアミノ基の保護基の脱保護反応は、前述の一般式（ＸＶＩ－１）で示される化合物を製造する際の反応と同様である。 This deprotection reaction of the protecting group for the amino group is similar to the reaction for producing the compound represented by general formula (XVI-1) above.
　さらに必要であれば、この反応に引き続いて公知の方法によって、目的の塩に変換する操作を行ってもよい。 Furthermore, if necessary, subsequent to this reaction, conversion to the desired salt may be performed by a known method.
　一般式（Ｉ－Ａ－１）で示される化合物は、一般式（ＸＸＸＩＩＩ－１）で示される化合物と、一般式（ＸＶＩＩ－１）で示される化合物、または一般式（ＸＶＩＩＩ－１）で示される化合物を用いて、アルキル化反応に付すことにより製造することができる。 The compound represented by the general formula (IA-1) is a compound represented by the general formula (XXXIII-1), a compound represented by the general formula (XVII-1), or a compound represented by the general formula (XVIII-1). It can be produced by subjecting a compound to an alkylation reaction.
　このアルキル化反応は、前述の一般式（ＸＩＸ－１）で示される化合物を製造する際の反応と同様である。 This alkylation reaction is similar to the reaction for producing the compound represented by general formula (XIX-1) above.
　さらに必要であれば、この反応に引き続いて公知の方法によって、目的の塩に変換する操作を行ってもよい。 Furthermore, if necessary, subsequent to this reaction, conversion to the desired salt may be performed by a known method.
　一般式（Ｉ－Ａ－１）で示される化合物は、以下の反応工程式１－１ｅで示される方法で製造することもできる。反応工程式１－１ｅ中、すべての記号は前記と同じ意味を表わす。 The compound represented by the general formula (IA-1) can also be produced by the method shown in the following reaction scheme 1-1e. In Reaction Scheme 1-1e, all symbols have the same meanings as above.
　一般式（ＸＸＸＶＩＩＩ－１）で示される化合物は、一般式（ＶＩＩ－１）で示される化合物を、アミノ基の保護基の脱保護反応に付すことにより製造することができる。 The compound represented by the general formula (XXXVIII-1) can be produced by subjecting the compound represented by the general formula (VII-1) to a deprotection reaction of the protecting group of the amino group.
　このアミノ基の保護基の脱保護反応は、前述の一般式（ＸＶＩ－１）で示される化合物を製造する際の反応と同様である。 This deprotection reaction of the protecting group for the amino group is similar to the reaction for producing the compound represented by general formula (XVI-1) above.
　さらに必要であれば、この反応に引き続いて公知の方法によって、目的の塩に変換する操作を行ってもよい。 Furthermore, if necessary, subsequent to this reaction, conversion to the desired salt may be performed by a known method.
　一般式（ＸＸＸＩＸ－１）で示される化合物は、一般式（ＸＸＸＶＩＩＩ－１）で示される化合物と、一般式（ＸＶＩＩ－１）で示される化合物、または一般式（ＸＶＩＩＩ－１）で示される化合物を用いて、アルキル化反応に付すことにより製造することができる。 The compound represented by the general formula (XXXIX-1) is a compound represented by the general formula (XXXVIII-1), a compound represented by the general formula (XVII-1), or a compound represented by the general formula (XVIII-1). can be produced by subjecting it to an alkylation reaction.
　このアルキル化反応は、前述の一般式（ＸＩＸ－１）で示される化合物を製造する際の反応と同様である。 This alkylation reaction is similar to the reaction for producing the compound represented by general formula (XIX-1) above.
　さらに必要であれば、この反応に引き続いて公知の方法によって、目的の塩に変換する操作を行ってもよい。 Furthermore, if necessary, subsequent to this reaction, conversion to the desired salt may be performed by a known method.
　一般式（ＸＬ－１）で示される化合物は、一般式（ＸＸＸＩＸ－１）で示される化合物を、カルボキシル基の保護基の脱保護反応に付すことにより製造することができる。 The compound represented by the general formula (XL-1) can be produced by subjecting the compound represented by the general formula (XXXIX-1) to a deprotection reaction of the protecting group of the carboxyl group.
　このカルボキシル基の保護基の脱保護反応は、前述の一般式（ＶＩＩＩ）で示される化合物を製造する際の反応と同様である。 This deprotection reaction of the carboxyl group protecting group is the same as the reaction for producing the compound represented by the aforementioned general formula (VIII).
　さらに必要であれば、この反応に引き続いて公知の方法によって、目的の塩に変換する操作を行ってもよい。 Furthermore, if necessary, subsequent to this reaction, conversion to the desired salt may be performed by a known method.
　一般式（ＸＬＩ－１）で示される化合物は、一般式（ＸＬ－１）で示される化合物と、一般式（ＸＩ）で示される化合物を用いて、カップリング反応に付すことにより製造することができる。 The compound represented by the general formula (XLI-1) can be produced by subjecting the compound represented by the general formula (XL-1) and the compound represented by the general formula (XI) to a coupling reaction. can.
　このカップリング反応は、前述の一般式（Ｉ－Ａ）で示される化合物を製造する際の反応と同様である。 This coupling reaction is similar to the reaction for producing the compound represented by the general formula (IA) described above.
　さらに必要であれば、この反応に引き続いて公知の方法によって、目的の塩に変換する操作を行ってもよい。 Furthermore, if necessary, subsequent to this reaction, conversion to the desired salt may be performed by a known method.
　一般式（Ｉ－Ａ－１）で示される化合物は、一般式（ＸＬＩ－１）で示される化合物と、一般式（ＩＸ）で示される化合物を用いて、アミド化反応に付すことにより製造することができる。 The compound represented by the general formula (IA-1) is produced by subjecting the compound represented by the general formula (XLI-1) and the compound represented by the general formula (IX) to an amidation reaction. be able to.
　このアミド化反応は、このアミド化反応は、前述の一般式（Ｘ）で示される化合物を製造する際の反応と同様である。 This amidation reaction is similar to the reaction for producing the compound represented by general formula (X) described above.
　さらに必要であれば、この反応に引き続いて公知の方法によって、目的の塩に変換する操作を行ってもよい。 Furthermore, if necessary, subsequent to this reaction, conversion to the desired salt may be performed by a known method.
　一般式（ＸＸＸＩＸ－１）で示される化合物は、以下の反応工程式１－１ｆで示される方法で製造することもできる。反応工程式１－１ｆ中、すべての記号は前記と同じ意味を表わす。 The compound represented by the general formula (XXXIX-1) can also be produced by the method shown in the following reaction scheme 1-1f. In reaction scheme 1-1f, all symbols have the same meanings as above.
　一般式（ＩＶ－１ｆ）で示される化合物は、一般式（ＩＩ）で示される化合物と、一般式（ＩＩＩ－１ｆ）で示される化合物を用いて、アミノ基の導入反応に付すことにより製造することができる。 The compound represented by the general formula (IV-1f) is produced by subjecting the compound represented by the general formula (II) and the compound represented by the general formula (III-1f) to an amino group introduction reaction. be able to.
　このアミノ基の導入反応は、前述の一般式（ＩＶ）で示される化合物を製造する際の反応と同様である。 This reaction for introducing an amino group is similar to the reaction for producing the compound represented by the general formula (IV) described above.
　さらに必要であれば、この反応に引き続いて公知の方法によって、目的の塩に変換する操作を行ってもよい。 Furthermore, if necessary, subsequent to this reaction, conversion to the desired salt may be performed by a known method.
　一般式（ＶＩ－１ｆ）で示される化合物は、一般式（ＩＶ－１ｆ）で示される化合物と、一般式（Ｖ）で示される化合物を用いて、カップリング反応に付すことにより製造することができる。 The compound represented by the general formula (VI-1f) can be produced by subjecting the compound represented by the general formula (IV-1f) and the compound represented by the general formula (V) to a coupling reaction. can.
　このカップリング反応は、前述の一般式（ＶＩ）で示される化合物を製造する際の反応と同様である。 This coupling reaction is similar to the reaction for producing the compound represented by general formula (VI) above.
　さらに必要であれば、この反応に引き続いて公知の方法によって、目的の塩に変換する操作を行ってもよい。 Furthermore, if necessary, subsequent to this reaction, conversion to the desired salt may be performed by a known method.
　一般式（ＸＸＸＩＸ－１）で示される化合物は、一般式（ＶＩ－１ｆ）で示される化合物を、環化反応に付すことにより製造することができる。 The compound represented by the general formula (XXXIX-1) can be produced by subjecting the compound represented by the general formula (VI-1f) to a cyclization reaction.
　この環化反応は、前述の一般式（ＶＩＩ）で示される化合物を製造する際の反応と同様である。 This cyclization reaction is similar to the reaction used to produce the compound represented by the aforementioned general formula (VII).
　さらに必要であれば、この反応に引き続いて公知の方法によって、目的の塩に変換する操作を行ってもよい。 Furthermore, if necessary, subsequent to this reaction, conversion to the desired salt may be performed by a known method.
　一般式（Ｉ）で示される化合物のうち、Ｒ３が－ＮＲ２２Ｒ２３であり、Ｒ２２が、１～５個のＲ３０で置換されていてもよいベンゼンであり、Ｘ１、Ｘ２、およびＸ３が、それぞれ独立して、ＣＨまたはＣＲ６である化合物、すなわち、一般式（Ｉ－Ｂ） In the compound represented by general formula (I), R 3 is -NR 22 R 23 , R 22 is benzene optionally substituted with 1 to 5 R 30 , and X 1 , X 2 , and X 3 are each independently CH or CR 6 , i.e. compounds of general formula (IB)
（式中、ｗは０～３の整数を表わし、その他の記号は前記と同じ意味を表わす。）で示される化合物は、以下の反応工程式２で示される方法で製造することができる。反応工程式２中、すべての記号は前記と同じ意味を表わす。 The compound represented by (wherein w represents an integer of 0 to 3, and the other symbols have the same meanings as above) can be produced by the method shown in Reaction Scheme 2 below. In Reaction Scheme 2, all symbols have the same meanings as above.
　一般式（Ｉ－Ｂ）で示される化合物は、一般式（Ｘ）で示される化合物と、一般式（ＸＩＩ）で示される化合物を用いて、カップリング反応に付すことにより製造することができる。 The compound represented by the general formula (IB) can be produced by subjecting the compound represented by the general formula (X) and the compound represented by the general formula (XII) to a coupling reaction.
　このカップリング反応は公知であり、例えば、有機溶媒（ベンゼン、トルエン、ジメチルホルムアミド、ジメチルアセトアミド、１，４－ジオキサン、テトラヒドロフラン、メタノール、アセトニトリル、ジメトキシエタン、アセトンまたはそれらの混合溶液等）中、塩基（ナトリウムエチラート、ナトリウムブトキシド、水酸化ナトリウム、水酸化カリウム、トリエチルアミン、炭酸ナトリウム、炭酸水素ナトリウム、炭酸カリウム、炭酸セシウム、炭酸タリウム、リン酸三カリウム、フッ化セシウム、水酸化バリウム、フッ化テトラブチルアンモニウム、リチウムビス（トリメチルシリル）アミド（ＬＨＭＤＳ）等、）またはこれらの混合物、ホスフィンリガンド（（９，９）－ジメチル－９Ｈ－キサンテン－４，５－ジイル）ビス（ジフェニルホスフィン）（Ｘａｎｔｐｈоｓ）、ジシクロへキシル（２‘，４’，６‘－トリイソプロピル－３，６－ジメトキシ－２－ビフェニル）ホスフィン（ＢｒｅｔｔＰｈоｓ）等）および触媒（テトラキス（トリフェニルホスフィン）パラジウム（Ｐｄ（ＰＰｈ３）４）、二塩化ビス（トリフェニルホスフィン）パラジウム（ＰｄＣｌ２（ＰＰｈ３）２）、酢酸パラジウム（Ｐｄ（ＯＡｃ）２）、パラジウム黒、１，１’－ビス（ジフェニルホスフィノフェロセン）ジクロロパラジウム（ＰｄＣｌ２（ｄｐｐｆ）２）、二塩化ジアリルパラジウム（ＰｄＣｌ２（ａｌｌｙｌ）２）、ヨウ化フェニルビス（トリフェニルホスフィン）パラジウム（ＰｈＰｄＩ（ＰＰｈ３）２）、（１Ｅ，４Ｅ）－１，５－ジフェニル－１，４－ペンタジエン－３－オン－パラジウム（Pｄ２（ｄｂａ）３）等）存在下、室温～１５０℃の温度で反応させることで行われる。 This coupling reaction is known, for example, using a base in an organic solvent (benzene, toluene, dimethylformamide, dimethylacetamide, 1,4-dioxane, tetrahydrofuran, methanol, acetonitrile, dimethoxyethane, acetone, or a mixed solution thereof, etc.). (Sodium ethylate, sodium butoxide, sodium hydroxide, potassium hydroxide, triethylamine, sodium carbonate, sodium bicarbonate, potassium carbonate, cesium carbonate, thallium carbonate, tripotassium phosphate, cesium fluoride, barium hydroxide, tetrafluoride butylammonium, lithium bis(trimethylsilyl)amide (LHMDS), etc.) or mixtures thereof, phosphine ligands ((9,9)-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (Xantphos), dicyclohexyl(2',4',6'-triisopropyl-3,6-dimethoxy-2-biphenyl)phosphine (BrettPhоs, etc.) and catalysts (tetrakis(triphenylphosphine)palladium (Pd(PPh 3 ) 4 ) , bis(triphenylphosphine)palladium dichloride (PdCl 2 (PPh 3 ) 2 ), palladium acetate (Pd(OAc) 2 ), palladium black, 1,1'-bis(diphenylphosphinoferrocene) dichloropalladium (PdCl 2 (dppf) 2 ), diallypalladium dichloride (PdCl 2 (allyl) 2 ), phenylbis(triphenylphosphine)palladium iodide (PhPdI(PPh 3 ) 2 ), (1E,4E)-1,5-diphenyl- The reaction is carried out in the presence of 1,4-pentadien-3-one-palladium (Pd 2 (dba) 3 ) or the like at a temperature of room temperature to 150°C.
　さらに必要であれば、この反応に引き続いて公知の方法によって、目的の塩に変換する操作を行ってもよい。 Furthermore, if necessary, subsequent to this reaction, conversion to the desired salt may be performed by a known method.
　一般式（Ｉ－Ｂ）のうち、Ｒ２が５～７員の含窒素飽和複素環であり、窒素原子に置換するＲ１５が、１～５個のＲ１８で置換されていてもよいＣ３～６シクロアルキル基で置換されていてもよいＣ１～８アルキル基、またはＣ１～８ハロアルキル基である化合物、すなわち、一般式（Ｉ－Ｂ－１） In general formula (IB), R 2 is a 5- to 7-membered nitrogen-containing saturated heterocycle, and R 15 substituted on the nitrogen atom is C3 optionally substituted with 1 to 5 R 18 . A compound that is a C1-8 alkyl group optionally substituted with ~6 cycloalkyl group or a C1-8 haloalkyl group, that is, general formula (I-B-1)
（式中、すべての記号は前記と同じ意味を表わす。）で示される化合物は、以下の反応工程式２－１で示される方法で製造することができる。すべての記号は前記と同じ意味を表わす。 The compound represented by (in the formula, all symbols have the same meanings as above) can be produced by the method shown in the following reaction scheme 2-1. All symbols have the same meaning as above.
　一般式（Ｉ－Ｂ－１）で示される化合物は、一般式（ＸＩＸ－１）で示される化合物と、一般式（ＸＩＩ）で示される化合物を用いて、カップリング反応に付すことにより製造することができる。 The compound represented by the general formula (IB-1) is produced by subjecting the compound represented by the general formula (XIX-1) and the compound represented by the general formula (XII) to a coupling reaction. be able to.
　このカップリング反応は、前述の一般式（Ｉ－Ｂ）で示される化合物を製造する際の反応と同様である。 This coupling reaction is similar to the reaction for producing the compound represented by the general formula (IB) described above.
　さらに必要であれば、この反応に引き続いて公知の方法によって、目的の塩に変換する操作を行ってもよい。 Furthermore, if necessary, subsequent to this reaction, conversion to the desired salt may be performed by a known method.
　一般式（Ｉ－Ｂ－１）で示される化合物は、以下の反応工程式２－１ｃおよび反応工程式２－１ｄで示される方法で製造することもできる。反応工程式２－１ｃおよび反応工程式２－１ｄ中、すべての記号は前記と同じ意味を表わす。 The compound represented by the general formula (I-B-1) can also be produced by the method shown in the following reaction scheme 2-1c and reaction scheme 2-1d. In Reaction Scheme 2-1c and Reaction Scheme 2-1d, all symbols have the same meanings as above.
　一般式（ＸＸＸＩ－２）で示される化合物は、一般式（ＸＸＸ－１）で示される化合物と、一般式（ＸＩＩ）で示される化合物を用いて、カップリング反応に付すことにより製造することができる。 The compound represented by the general formula (XXXI-2) can be produced by subjecting the compound represented by the general formula (XXX-1) and the compound represented by the general formula (XII) to a coupling reaction. can.
　このカップリング反応は、前述の一般式（Ｉ－Ｂ）で示される化合物を製造する際の反応と同様である。 This coupling reaction is similar to the reaction for producing the compound represented by the general formula (IB) described above.
　さらに必要であれば、この反応に引き続いて公知の方法によって、目的の塩に変換する操作を行ってもよい。 Furthermore, if necessary, subsequent to this reaction, conversion to the desired salt may be performed by a known method.
　一般式（ＸＸＸＩＩ－２）で示される化合物は、一般式（ＸＸＸＩ－２）で示される化合物と、一般式（ＩＸ）で示される化合物を用いて、アミド化反応に付すことにより製造することができる。 The compound represented by the general formula (XXXII-2) can be produced by subjecting the compound represented by the general formula (XXXI-2) and the compound represented by the general formula (IX) to an amidation reaction. can.
　このアミド化反応は、このアミド化反応は、前述の一般式（Ｘ）で示される化合物を製造する際の反応と同様である。 This amidation reaction is similar to the reaction for producing the compound represented by general formula (X) described above.
　さらに必要であれば、この反応に引き続いて公知の方法によって、目的の塩に変換する操作を行ってもよい。 Furthermore, if necessary, subsequent to this reaction, conversion to the desired salt may be performed by a known method.
　一般式（ＸＸＸＩＩＩ－２）で示される化合物は、一般式（ＸＸＸＩＩ－２）で示される化合物を、アミノ基の保護基の脱保護反応に付すことにより製造することができる。 The compound represented by the general formula (XXXIII-2) can be produced by subjecting the compound represented by the general formula (XXXII-2) to a deprotection reaction of the protecting group of the amino group.
　このアミノ基の保護基の脱保護反応は、前述の一般式（ＸＶＩ－１）で示される化合物を製造する際の反応と同様である。 This deprotection reaction of the protecting group for the amino group is the same as the reaction for producing the compound represented by general formula (XVI-1) above.
　さらに必要であれば、この反応に引き続いて公知の方法によって、目的の塩に変換する操作を行ってもよい。 Furthermore, if necessary, subsequent to this reaction, conversion to the desired salt may be performed by a known method.
　一般式（Ｉ－Ｂ－１）で示される化合物は、一般式（ＸＸＸＩＩＩ－２）で示される化合物と、一般式（ＸＶＩＩ－１）で示される化合物、または一般式（ＸＶＩＩＩ－１）で示される化合物を用いて、アルキル化反応に付すことにより製造することができる。 The compound represented by the general formula (I-B-1) is a compound represented by the general formula (XXXIII-2), a compound represented by the general formula (XVII-1), or a compound represented by the general formula (XVIII-1). It can be produced by subjecting a compound to an alkylation reaction.
　このアルキル化反応は、前述の一般式（ＸＩＸ－１）で示される化合物を製造する際の反応と同様である。 This alkylation reaction is similar to the reaction for producing the compound represented by general formula (XIX-1) above.
　さらに必要であれば、この反応に引き続いて公知の方法によって、目的の塩に変換する操作を行ってもよい。 Furthermore, if necessary, subsequent to this reaction, conversion to the desired salt may be performed by a known method.
　一般式（Ｉ－Ｂ－１）で示される化合物は、以下の反応工程式２－１ｅで示される方法で製造することもできる。反応工程式２－１ｅ中、すべての記号は前記と同じ意味を表わす。 The compound represented by the general formula (IB-1) can also be produced by the method shown in the following reaction scheme 2-1e. In Reaction Scheme 2-1e, all symbols have the same meanings as above.
　一般式（ＸＬＩ－２）で示される化合物は、一般式（ＸＬ－１）で示される化合物と、一般式（ＸＩＩ）で示される化合物を用いて、カップリング反応に付すことにより製造することができる。 The compound represented by the general formula (XLI-2) can be produced by subjecting the compound represented by the general formula (XL-1) and the compound represented by the general formula (XII) to a coupling reaction. can.
　このカップリング反応は、前述の一般式（Ｉ－Ｂ）で示される化合物を製造する際の反応と同様である。 This coupling reaction is similar to the reaction for producing the compound represented by the general formula (IB) described above.
　さらに必要であれば、この反応に引き続いて公知の方法によって、目的の塩に変換する操作を行ってもよい。 Further, if necessary, subsequent to this reaction, conversion to the desired salt may be performed by a known method.
　一般式（Ｉ－Ｂ－１）で示される化合物は、一般式（ＸＬＩ－２）で示される化合物と、一般式（ＩＸ）で示される化合物を用いて、アミド化反応に付すことにより製造することができる。 The compound represented by the general formula (IB-1) is produced by subjecting the compound represented by the general formula (XLI-2) and the compound represented by the general formula (IX) to an amidation reaction. be able to.
　このアミド化反応は、このアミド化反応は、前述の一般式（Ｘ）で示される化合物を製造する際の反応と同様である。 This amidation reaction is similar to the reaction for producing the compound represented by general formula (X) described above.
　さらに必要であれば、この反応に引き続いて公知の方法によって、目的の塩に変換する操作を行ってもよい。 Furthermore, if necessary, subsequent to this reaction, conversion to the desired salt may be performed by a known method.
　一般式（Ｉ）で示される化合物のうち、Ｒ３が－ＮＲ２２Ｒ２３であり、Ｒ２３が、水素原子、１～５個のＲ２９で置換されていてもよいＣ１～８アルキル基、１～５個のＲ２９－１で置換されていてもよいＣ２～４アルケニル基、または１～５個のＲ２９－２で置換されていてもよいＣ２～４アルキニル基であり、Ｘ１、Ｘ２、およびＸ３が、それぞれ独立して、ＣＨまたはＣＲ６である化合物、すなわち、一般式（Ｉ－Ｃ） Among the compounds represented by general formula (I), R 3 is -NR 22 R 23 , and R 23 is a hydrogen atom, a C1-8 alkyl group optionally substituted with 1 to 5 R 29 , A C2-4 alkenyl group optionally substituted with 1 to 5 R 29-1 , or a C2-4 alkynyl group optionally substituted with 1 to 5 R 29-2 , and X 1 , A compound in which X 2 and X 3 are each independently CH or CR 6 , that is, a compound of general formula (IC)
（式中、Ｒ２３－１は水素原子、１～５個のＲ２９で置換されていてもよいＣ１～８アルキル基、１～５個のＲ２９－１で置換されていてもよいＣ２～４アルケニル基、または１～５個のＲ２９－２で置換されていてもよいＣ２～４アルキニル基を表わし、その他の記号は前記と同じ意味を表わす。）で示される化合物は、以下の反応工程式３で示される方法で製造することができる。反応工程式３中、すべての記号は前記と同じ意味を表わす。 (In the formula, R 23-1 is a hydrogen atom, a C1-8 alkyl group optionally substituted with 1 to 5 R 29s , a C2-8 alkyl group optionally substituted with 1 to 5 R 29-1 4 alkenyl group, or a C2-4 alkynyl group optionally substituted with 1 to 5 R 29-2 , and other symbols have the same meanings as above.) The compound represented by It can be manufactured by the method shown in Process Formula 3. In Reaction Scheme 3, all symbols have the same meanings as above.
　一般式（Ｉ－Ｃ）で示される化合物は、一般式（Ｘ）で示される化合物と、一般式（ＸＸＸＩＶ）で示される化合物を用いて、アミノ基の導入反応に付すことにより製造することができる。 The compound represented by the general formula (IC) can be produced by subjecting the compound represented by the general formula (X) and the compound represented by the general formula (XXXIV) to an amino group introduction reaction. can.
　このアミノ基の導入反応は公知であり、例えば、有機溶媒（ジクロロメタン、ジクロロエタン、テトラヒドロフラン、１，４－ジオキサン、ジメチルホルムアミド、ジメチルアセトアミド、１－メチル－２－ピロリドン、ジメチルスルホキシド等）中、塩基（トリエチルアミン、Ｎ，Ｎ－ジイソプロピルエチルアミン、ピリジン、４－ジメチルアミノピリジン、Ｎ－メチルモルホリン等）の存在下もしくは非存在下、フッ化物塩（フッ化カリウム、フッ化セシウム等）の存在下もしくは非存在下、室温～１８０℃の温度で反応させることで行われる。 This reaction for introducing an amino group is known, and for example, a base ( in the presence or absence of fluoride salts (potassium fluoride, cesium fluoride, etc.) The reaction is carried out at temperatures ranging from room temperature to 180°C.
　さらに必要であれば、この反応に引き続いて公知の方法によって、目的の塩に変換する操作を行ってもよい。 Furthermore, if necessary, subsequent to this reaction, conversion to the desired salt may be performed by a known method.
　一般式（Ｉ－Ｃ）のうち、Ｒ２が５～７員の含窒素飽和複素環であり、窒素原子に置換するＲ１５が、１～５個のＲ１８で置換されていてもよいＣ３～６シクロアルキル基で置換されていてもよいＣ１～８アルキル基、またはＣ１～８ハロアルキル基である化合物、すなわち、一般式（Ｉ－Ｃ－１） In general formula (IC), R 2 is a 5- to 7-membered nitrogen-containing saturated heterocycle, and R 15 substituted on the nitrogen atom is C3, which may be substituted with 1 to 5 R 18 . A compound that is a C1-8 alkyl group optionally substituted with ~6 cycloalkyl group or a C1-8 haloalkyl group, that is, general formula (IC-1)
（式中、すべての記号は前記と同じ意味を表わす。）で示される化合物は、以下の反応工程式３－１で示される方法で製造することができる。すべての記号は前記と同じ意味を表わす。 The compound represented by (in the formula, all symbols have the same meanings as above) can be produced by the method shown in the following reaction scheme 3-1. All symbols have the same meaning as above.
　一般式（Ｉ－Ｃ－１）で示される化合物は、一般式（ＸＩＸ－１）で示される化合物と、一般式（ＸＸＸＩＶ）で示される化合物を用いて、アミノ基の導入反応に付すことにより製造することができる。 The compound represented by the general formula (IC-1) can be obtained by subjecting the compound represented by the general formula (XIX-1) and the compound represented by the general formula (XXXIV) to an amino group introduction reaction. can be manufactured.
　このアミノ基の導入反応は、前述の一般式（Ｉ－Ｃ）で示される化合物を製造する際の反応と同様である。 This reaction for introducing an amino group is similar to the reaction for producing the compound represented by the general formula (IC) described above.
　さらに必要であれば、この反応に引き続いて公知の方法によって、目的の塩に変換する操作を行ってもよい。 Furthermore, if necessary, subsequent to this reaction, conversion to the desired salt may be performed by a known method.
　一般式（Ｉ－Ｃ－１）で示される化合物は、以下の反応工程式３－１ｃおよび反応工程式３－１ｄで示される方法で製造することもできる。反応工程式３－１ｃおよび反応工程式３－１ｄ中、すべての記号は前記と同じ意味を表わす。 The compound represented by the general formula (IC-1) can also be produced by the method shown in the following reaction scheme 3-1c and reaction scheme 3-1d. In Reaction Scheme 3-1c and Reaction Scheme 3-1d, all symbols have the same meanings as above.
　一般式（ＸＸＸＩ－３）で示される化合物は、一般式（ＸＸＸ－１）で示される化合物と、一般式（ＸＸＸＩＶ）で示される化合物を用いて、アミノ基の導入反応に付すことにより製造することができる。 The compound represented by the general formula (XXXI-3) is produced by subjecting the compound represented by the general formula (XXX-1) and the compound represented by the general formula (XXXIV) to an amino group introduction reaction. be able to.
　このアミノ基の導入反応は、前述の一般式（Ｉ－Ｃ－１）で示される化合物を製造する際の反応と同様である。 This reaction for introducing an amino group is the same as the reaction for producing the compound represented by the general formula (IC-1) described above.
　さらに必要であれば、この反応に引き続いて公知の方法によって、目的の塩に変換する操作を行ってもよい。 Furthermore, if necessary, subsequent to this reaction, conversion to the desired salt may be performed by a known method.
　一般式（ＸＸＸＩＩ－３）で示される化合物は、一般式（ＸＸＸＩ－３）で示される化合物と、一般式（ＩＸ）で示される化合物を用いて、アミド化反応に付すことにより製造することができる。 The compound represented by the general formula (XXXII-3) can be produced by subjecting the compound represented by the general formula (XXXI-3) and the compound represented by the general formula (IX) to an amidation reaction. can.
　このアミド化反応は、このアミド化反応は、前述の一般式（Ｘ）で示される化合物を製造する際の反応と同様である。 This amidation reaction is similar to the reaction for producing the compound represented by general formula (X) described above.
　さらに必要であれば、この反応に引き続いて公知の方法によって、目的の塩に変換する操作を行ってもよい。 Furthermore, if necessary, subsequent to this reaction, conversion to the desired salt may be performed by a known method.
　一般式（ＸＸＸＩＩＩ－３）で示される化合物は、一般式（ＸＸＸＩＩ－３）で示される化合物を、アミノ基の保護基の脱保護反応に付すことにより製造することができる。 The compound represented by the general formula (XXXIII-3) can be produced by subjecting the compound represented by the general formula (XXXII-3) to a deprotection reaction of the protecting group of the amino group.
　このアミノ基の保護基の脱保護反応は、前述の一般式（ＸＶＩ－１）で示される化合物を製造する際の反応と同様である。 This deprotection reaction of the protecting group for the amino group is similar to the reaction for producing the compound represented by general formula (XVI-1) above.
　さらに必要であれば、この反応に引き続いて公知の方法によって、目的の塩に変換する操作を行ってもよい。 Furthermore, if necessary, subsequent to this reaction, conversion to the desired salt may be performed by a known method.
　一般式（Ｉ－Ｃ－１）で示される化合物は、一般式（ＸＸＸＩＩＩ－３）で示される化合物と、一般式（ＸＶＩＩ－１）で示される化合物、または一般式（ＸＶＩＩＩ－１）で示される化合物を用いて、アルキル化反応に付すことにより製造することができる。 The compound represented by the general formula (IC-1) is a compound represented by the general formula (XXXIII-3), a compound represented by the general formula (XVII-1), or a compound represented by the general formula (XVIII-1). It can be produced by subjecting a compound to an alkylation reaction.
　このアルキル化反応は、前述の一般式（ＸＩＸ－１）で示される化合物を製造する際の反応と同様である。 This alkylation reaction is similar to the reaction for producing the compound represented by general formula (XIX-1) above.
　さらに必要であれば、この反応に引き続いて公知の方法によって、目的の塩に変換する操作を行ってもよい。 Furthermore, if necessary, subsequent to this reaction, conversion to the desired salt may be performed by a known method.
　一般式（Ｉ－Ｃ－１）で示される化合物は、以下の反応工程式３－１ｅで示される方法で製造することもできる。反応工程式３－１ｅ中、すべての記号は前記と同じ意味を表わす。 The compound represented by the general formula (IC-1) can also be produced by the method shown in the following reaction scheme 3-1e. In Reaction Scheme 3-1e, all symbols have the same meanings as above.
　一般式（ＸＬＩ－３）で示される化合物は、一般式（ＸＬ－１）で示される化合物と、一般式（ＸＸＸＩＶ）で示される化合物を用いて、アミノ基の導入反応に付すことにより製造することができる。 The compound represented by the general formula (XLI-3) is produced by subjecting the compound represented by the general formula (XL-1) and the compound represented by the general formula (XXXIV) to an amino group introduction reaction. be able to.
　このアミノ基の導入反応は、前述の一般式（Ｉ－Ｃ）で示される化合物を製造する際の反応と同様である。 This reaction for introducing an amino group is similar to the reaction for producing the compound represented by the general formula (IC) described above.
　さらに必要であれば、この反応に引き続いて公知の方法によって、目的の塩に変換する操作を行ってもよい。 Furthermore, if necessary, subsequent to this reaction, conversion to the desired salt may be performed by a known method.
　一般式（Ｉ－Ｃ－１）で示される化合物は、一般式（ＸＬＩ－３）で示される化合物と、一般式（ＩＸ）で示される化合物を用いて、アミド化反応に付すことにより製造することができる。 The compound represented by the general formula (IC-1) is produced by subjecting the compound represented by the general formula (XLI-3) and the compound represented by the general formula (IX) to an amidation reaction. be able to.
　このアミド化反応は、このアミド化反応は、前述の一般式（Ｘ）で示される化合物を製造する際の反応と同様である。 This amidation reaction is similar to the reaction for producing the compound represented by general formula (X) described above.
　さらに必要であれば、この反応に引き続いて公知の方法によって、目的の塩に変換する操作を行ってもよい。 Furthermore, if necessary, subsequent to this reaction, conversion to the desired salt may be performed by a known method.
　一般式（ＩＸ）で示される化合物は、以下の反応工程式４で示される方法で製造することができる。反応工程式４中、ＰＮ－２はアミノ基の保護基（例えば、ベンジルオキシカルボニル基、ｔｅｒｔ－ブトキシカルボニル基、アリルオキシカルボニル（Ａｌｌｏｃ）基、１－メチル－１－（４－ビフェニル）エトキシカルボニル（Ｂｐｏｃ）基、トリフルオロアセチル基、９－フルオレニルメトキシカルボニル基、ベンジル（Ｂｎ）基、４－メトキシベンジル基、ベンジルオキシメチル（ＢＯＭ）基、２－（トリメチルシリル）エトキシメチル（ＳＥＭ）、フルオレニルカルボニル基、トリチル基、およびｏ－ニトロベンゼンスルフェニル基等）を表わし、Ｅ３は脱離基を表わし、その他の記号は前記と同じ意味を表わす。 The compound represented by the general formula (IX) can be produced by the method shown in Reaction Scheme 4 below. In reaction scheme 4, P N-2 is a protecting group for an amino group (e.g., benzyloxycarbonyl group, tert-butoxycarbonyl group, allyloxycarbonyl (Alloc) group, 1-methyl-1-(4-biphenyl)ethoxy Carbonyl (Bpoc) group, trifluoroacetyl group, 9-fluorenylmethoxycarbonyl group, benzyl (Bn) group, 4-methoxybenzyl group, benzyloxymethyl (BOM) group, 2-(trimethylsilyl)ethoxymethyl (SEM) , fluorenylcarbonyl group, trityl group, o-nitrobenzenesulfenyl group, etc.), E 3 represents a leaving group, and other symbols have the same meanings as above.
　一般式（ＸＶ）で示される化合物は、一般式（ＸＩＩＩ）で示される化合物と、一般式（ＸＩＶ）で示される化合物を用いて、アルキル化反応に付すことにより製造することができる。 The compound represented by the general formula (XV) can be produced by subjecting the compound represented by the general formula (XIII) and the compound represented by the general formula (XIV) to an alkylation reaction.
　このアルキル化反応は公知であり、例えば、有機溶媒（テトラヒドロフラン、１，４－ジオキサン、ジメチルホルムアミド、ジメチルアセトアミド、１－メチル－２－ピロリドン、ジメチルスルホキシド等）中、塩基（水素化ナトリウム、水素化カリウム、ナトリウムブトキシド、炭酸カリウム、炭酸セシウム等）の存在下、触媒（ヨウ化カリウム、ヨウ化ナトリウム、ヨウ化テトラブチルアンモニウム等）の存在下または非存在下、０℃～還流温度で反応させることで行われる。 This alkylation reaction is known, for example, in an organic solvent (tetrahydrofuran, 1,4-dioxane, dimethylformamide, dimethylacetamide, 1-methyl-2-pyrrolidone, dimethylsulfoxide, etc.) with a base (sodium hydride, (potassium, sodium butoxide, potassium carbonate, cesium carbonate, etc.) and in the presence or absence of a catalyst (potassium iodide, sodium iodide, tetrabutylammonium iodide, etc.) at 0°C to reflux temperature. It will be held in
　さらに必要であれば、この反応に引き続いて公知の方法によって、目的の塩に変換する操作を行ってもよい。 Further, if necessary, subsequent to this reaction, conversion to the desired salt may be performed by a known method.
　一般式（ＩＸ）で示される化合物は、一般式（ＸＶ）で示される化合物を、アミノ基の保護基の脱保護反応に付すことにより製造することができる。 The compound represented by the general formula (IX) can be produced by subjecting the compound represented by the general formula (XV) to a deprotection reaction of the protecting group of the amino group.
　このアミノ基の保護基の脱保護反応は、前述の一般式（ＸＶＩ－１）で示される化合物を製造する際の反応と同様である。 This deprotection reaction of the protecting group for the amino group is similar to the reaction for producing the compound represented by general formula (XVI-1) above.
　さらに必要であれば、この反応に引き続いて公知の方法によって、目的の塩に変換する操作を行ってもよい。 Furthermore, if necessary, subsequent to this reaction, conversion to the desired salt may be performed by a known method.
　一般式（ＩＶ）で示される化合物は、以下の反応工程式５に示すように、一般式（ＸＸ）で示される化合物をアミノ基の導入反応に付し、得られた一般式（ＸＸＩ）で示される化合物を還元反応に付して製造することもできる。反応工程式５中、すべての記号は前記と同じ意味を表わす。 The compound represented by the general formula (IV) is obtained by subjecting the compound represented by the general formula (XX) to an amino group introduction reaction, as shown in the following reaction scheme 5, and the resulting general formula (XXI). The compounds shown can also be produced by subjecting them to reduction reactions. In Reaction Scheme 5, all symbols have the same meanings as above.
　一般式（ＸＸＩ）で示される化合物は、一般式（ＸＸ）で示される化合物と、一般式（ＩＩＩ）で示される化合物を用いて、アミノ基の導入反応に付すことにより製造することができる。 The compound represented by the general formula (XXI) can be produced by subjecting the compound represented by the general formula (XX) and the compound represented by the general formula (III) to an amino group introduction reaction.
　このアミノ基の導入反応は公知であり、例えば有機溶媒（ジクロロメタン、テトラヒドロフラン、１，４－ジオキサン、ジメチルホルムアミド、ジメチルアセトアミド、１－メチル－２－ピロリドン等）中、塩基（トリエチルアミン、Ｎ，Ｎ－ジイソプロピルエチルアミン、ピリジン、４－ジメチルアミノピリジン、Ｎ－メチルモルホリン等）の存在下、－２０℃～室温の温度で反応させることで行われる。 This reaction for introducing amino groups is known, for example, in an organic solvent (dichloromethane, tetrahydrofuran, 1,4-dioxane, dimethylformamide, dimethylacetamide, 1-methyl-2-pyrrolidone, etc.) with a base (triethylamine, N,N- The reaction is carried out in the presence of diisopropylethylamine, pyridine, 4-dimethylaminopyridine, N-methylmorpholine, etc.) at a temperature of -20°C to room temperature.
　さらに必要であれば、この反応に引き続いて公知の方法によって、目的の塩に変換する操作を行ってもよい。 Furthermore, if necessary, subsequent to this reaction, conversion to the desired salt may be performed by a known method.
　一般式（ＩＶ）で示される化合物は、一般式（ＸＸＩ）で示される化合物を、還元反応に付すことにより製造することができる。 The compound represented by the general formula (IV) can be produced by subjecting the compound represented by the general formula (XXI) to a reduction reaction.
　この還元反応は公知であり、例えば水に混和する溶媒（エタノール、メタノール、テトラヒドロフラン、酢酸エチル等）中、酸（塩酸、臭化水素酸、塩化アンモニウム、酢酸、ギ酸アンモニウム等）の存在下または非存在下、金属試薬（亜鉛、鉄、スズ、塩化スズ、塩化鉄、サマリウム、インジウム、水素化ホウ素ナトリウム－塩化ニッケル等）を用いて、０℃～１５０℃の温度で行なわれる。で行われる。 This reduction reaction is known, for example, in a water-miscible solvent (ethanol, methanol, tetrahydrofuran, ethyl acetate, etc.), in the presence or absence of an acid (hydrochloric acid, hydrobromic acid, ammonium chloride, acetic acid, ammonium formate, etc.). It is carried out in the presence of metal reagents (zinc, iron, tin, tin chloride, iron chloride, samarium, indium, sodium borohydride-nickel chloride, etc.) at temperatures from 0°C to 150°C. It will be held in
　さらに必要であれば、この反応に引き続いて公知の方法によって、目的の塩に変換する操作を行ってもよい。 Furthermore, if necessary, subsequent to this reaction, conversion to the desired salt may be performed by a known method.
　一般式（Ｘ）で示される化合物は、以下の反応工程式６で示される方法で製造することもできる。反応工程式６中、ＰＮ－３はアミノ基の保護基（例えば、２，４－ジメトキシベンジル、４－メトキシベンジル等）を表わし、Ｅ５は脱離基（例えば、フッ素原子、臭素原子、塩素原子、ヨウ素原子、トリフルオロメタンスルホン酸エステル、ｐ－トルエンスルホン酸エステル等）を表わし、その他の記号は前記と同じ意味を表わす。 The compound represented by general formula (X) can also be produced by the method shown in Reaction Scheme 6 below. In Reaction Scheme 6, P N-3 represents a protecting group for an amino group (e.g., 2,4-dimethoxybenzyl, 4-methoxybenzyl, etc.), and E 5 represents a leaving group (e.g., fluorine atom, bromine atom, chlorine atom, iodine atom, trifluoromethanesulfonic acid ester, p-toluenesulfonic acid ester, etc.), and other symbols have the same meanings as above.
　一般式（ＸＸＩＩＩ）で示される化合物は、一般式（ＩＩ）で示される化合物と、一般式（ＸＸＩＩ）で示される化合物を用いて、アミノ基の導入反応に付すことにより製造することができる。 The compound represented by the general formula (XXIII) can be produced by subjecting the compound represented by the general formula (II) and the compound represented by the general formula (XXII) to an amino group introduction reaction.
　このアミノ基の導入反応は、前述の一般式（ＩＶ）で示される化合物を製造する際の反応と同様である。 This reaction for introducing an amino group is similar to the reaction for producing the compound represented by the general formula (IV) described above.
　さらに必要であれば、この反応に引き続いて公知の方法によって、目的の塩に変換する操作を行ってもよい。 Furthermore, if necessary, subsequent to this reaction, conversion to the desired salt may be performed by a known method.
　一般式（ＸＸＩＶ）で示される化合物は、一般式（ＸＸＩＩＩ）で示される化合物を、環化反応に付すことにより製造することができる。 The compound represented by the general formula (XXIV) can be produced by subjecting the compound represented by the general formula (XXIII) to a cyclization reaction.
　この環化反応は、前述の一般式（ＶＩＩ）で示される化合物を製造する際の反応と同様である。 This cyclization reaction is similar to the reaction used to produce the compound represented by the aforementioned general formula (VII).
　さらに必要であれば、この反応に引き続いて公知の方法によって、目的の塩に変換する操作を行ってもよい。 Furthermore, if necessary, subsequent to this reaction, conversion to the desired salt may be performed by a known method.
　一般式（ＸＸＶ）で示される化合物は、一般式（ＸＸＩＶ）で示される化合物と、一般式（ＸＸＸＶ）で示される化合物を用いて、カップリング反応に付すことにより製造することができる。 The compound represented by the general formula (XXV) can be produced by subjecting the compound represented by the general formula (XXIV) and the compound represented by the general formula (XXXV) to a coupling reaction.
　このカップリング反応は公知であり、例えば有機溶媒（ジクロロメタン、アセトニトリル等）中、塩基（ピリジン、トリエチルアミン、Ｎ，Ｎ－ジイソプロピルエチルアミン等）、銅塩（例えば、酢酸銅（II）等）および乾燥剤（例えば、モレキュラーシーブス等）の存在下、室温～１２０℃で反応させることにより行われる。 This coupling reaction is known, for example, in an organic solvent (dichloromethane, acetonitrile, etc.), a base (pyridine, triethylamine, N,N-diisopropylethylamine, etc.), a copper salt (for example, copper(II) acetate, etc.) and a drying agent. (for example, molecular sieves, etc.) by reacting at room temperature to 120°C.
　さらに必要であれば、この反応に引き続いて公知の方法によって、目的の塩に変換する操作を行ってもよい。 Furthermore, if necessary, subsequent to this reaction, conversion to the desired salt may be performed by a known method.
　一般式（ＸＸＶＩ）で示される化合物は、一般式（ＸＸＶ）で示される化合物を、カルボキシル基の保護基の脱保護反応に付すことにより製造することができる。 The compound represented by the general formula (XXVI) can be produced by subjecting the compound represented by the general formula (XXV) to a deprotection reaction of the protecting group of the carboxyl group.
　このカルボキシル基の保護基の脱保護反応は、前述の一般式（ＶＩＩＩ）で示される化合物を製造する際の反応と同様である。 This deprotection reaction of the carboxyl group protecting group is the same as the reaction for producing the compound represented by the aforementioned general formula (VIII).
　さらに必要であれば、この反応に引き続いて公知の方法によって、目的の塩に変換する操作を行ってもよい。 Furthermore, if necessary, subsequent to this reaction, conversion to the desired salt may be performed by a known method.
　一般式（ＸＸＶＩＩ）で示される化合物は、一般式（ＸＸＶＩ）で示される化合物と、一般式（ＩＸ）で示される化合物を用いて、アミド化反応に付すことにより製造することができる。 The compound represented by the general formula (XXVII) can be produced by subjecting the compound represented by the general formula (XXVI) and the compound represented by the general formula (IX) to an amidation reaction.
　このアミド化反応は、前述の一般式（Ｘ）で示される化合物を製造する際の反応と同様である。 This amidation reaction is similar to the reaction for producing the compound represented by the general formula (X) described above.
　さらに必要であれば、この反応に引き続いて公知の方法によって、目的の塩に変換する操作を行ってもよい。 Furthermore, if necessary, subsequent to this reaction, conversion to the desired salt may be performed by a known method.
　一般式（ＸＸＶＩＩＩ）で示される化合物は、一般式（ＸＸＶＩＩ）で示される化合物を、アミノ基の保護基の脱保護反応に付すことにより製造することができる。 The compound represented by the general formula (XXVIII) can be produced by subjecting the compound represented by the general formula (XXVII) to a deprotection reaction of the protecting group of the amino group.
　このアミノ基の保護基の脱保護反応は、前述の一般式（ＸＶＩ－１）で示される化合物を製造する際の反応と同様である。 This deprotection reaction of the protecting group for the amino group is similar to the reaction for producing the compound represented by general formula (XVI-1) above.
　さらに必要であれば、この反応に引き続いて公知の方法によって、目的の塩に変換する操作を行ってもよい。 Furthermore, if necessary, subsequent to this reaction, conversion to the desired salt may be performed by a known method.
　一般式（Ｘ）で示される化合物は、一般式（ＸＸＶＩＩＩ）で示される化合物と、一般式（ＸＸＩＸ）で示される化合物を用いて、アルキル化反応に付すことにより製造することができる。 The compound represented by the general formula (X) can be produced by subjecting the compound represented by the general formula (XXVIII) and the compound represented by the general formula (XXIX) to an alkylation reaction.
　このアルキル化反応は公知であり、例えば有機溶媒（ジメチルホルムアミド、ジメチルアセトアミド、ジメチルスルホキシド、クロロホルム、ジクロロメタン、ジエチルエーテル、テトラヒドロフラン、メチル　ｔ－ブチル　エーテル等）中、有機塩基（トリエチルアミン、Ｎ，Ｎ－ジイソプロピルエチルアミン、ピリジン、４－ジメチルアミノピリジン、Ｎ－メチルモルホリン等）、アルカリ金属の水酸化物（水酸化ナトリウム、水酸化カリウム、水酸化リチウム等）、アルカリ土類金属の水酸化物（水酸化バリウム、水酸化カルシウム等）もしくは炭酸塩（炭酸ナトリウム、炭酸カリウム等）またはその水溶液あるいはこれらの混合物の存在下、アルカリ金属ハロゲン化物塩（ヨウ化カリウム、ヨウ化ナトリウム等）の存在下、または非存在下、０℃～１００℃で反応させることで行われる。 This alkylation reaction is known, for example, in an organic solvent (dimethylformamide, dimethylacetamide, dimethylsulfoxide, chloroform, dichloromethane, diethyl ether, tetrahydrofuran, methyl t-butyl ether, etc.) and an organic base (triethylamine, N,N-diisopropyl ether, etc.). ethylamine, pyridine, 4-dimethylaminopyridine, N-methylmorpholine, etc.), alkali metal hydroxides (sodium hydroxide, potassium hydroxide, lithium hydroxide, etc.), alkaline earth metal hydroxides (barium hydroxide, etc.) , calcium hydroxide, etc.) or carbonates (sodium carbonate, potassium carbonate, etc.) or their aqueous solutions, or mixtures thereof, in the presence or absence of alkali metal halide salts (potassium iodide, sodium iodide, etc.) The reaction is carried out at 0°C to 100°C.
　さらに必要であれば、この反応に引き続いて公知の方法によって、目的の塩に変換する操作を行ってもよい。 Furthermore, if necessary, subsequent to this reaction, conversion to the desired salt may be performed by a known method.
　一般式（ＩＹ）で示される化合物のうち、Ｒ３Ｙが、１～５個のＲ２０Ｙで置換されていてもよいベンゼンであり、ｒｉｎｇＹが、１～６個のＲＹで置換されていてもよく、１個の窒素原子、１個の酸素原子および／または酸化されていてもよい１個の硫黄原子を含有していてもよい、４～１０員の飽和炭素環である化合物、すなわち一般式（Ｉ－Ａ－２）
 In the compound represented by general formula (IY), R 3Y is benzene which may be substituted with 1 to 5 R 20Y , and ringY is optionally substituted with 1 to 6 R Y. Compounds that are 4- to 10-membered saturated carbocycles, which may often contain one nitrogen atom, one oxygen atom and/or one sulfur atom, which may be oxidized, i.e. (I-A-2)
（式中、ｒｉｎｇＳは１～６個のＲＹで置換されていてもよく、１個の窒素原子、１個の酸素原子および／または酸化されていてもよい１個の硫黄原子を含有していてもよい、４～１０員の飽和炭素環を表わし、その他の記号は前記と同じ意味を表わす。）で示される化合物、 (In the formula, ringS may be substituted with 1 to 6 R Y and contains one nitrogen atom, one oxygen atom, and/or one sulfur atom that may be oxidized. (represents a 4- to 10-membered saturated carbon ring, and other symbols have the same meanings as above),
Ｒ３Ｙが－ＮＲ２２Ｒ２３であり、Ｒ２２が、１～５個のＲ３０で置換されていてもよいベンゼンであり、ｒｉｎｇＹが、１～６個のＲＹで置換されていてもよく、１個の窒素原子、１個の酸素原子および／または酸化されていてもよい１個の硫黄原子を含有していてもよい、４～１０員の飽和炭素環である化合物、すなわち、一般式（Ｉ－Ｂ－２） R 3Y is -NR 22 R 23 , R 22 is benzene optionally substituted with 1 to 5 R 30 , and ringY is optionally substituted with 1 to 6 R Y , a compound that is a 4- to 10-membered saturated carbocyclic ring that may contain one nitrogen atom, one oxygen atom, and/or one sulfur atom that may be oxidized, i.e., a compound of the general formula (I-B-2)
（式中、すべての記号は前記と同じ意味を表わす。）で示される化合物、および、
Ｒ３Ｙが－ＮＲ２２Ｒ２３であり、Ｒ２３が、水素原子、１～５個のＲ２９で置換されていてもよいＣ１～８アルキル基、１～５個のＲ２９－１で置換されていてもよいＣ２～４アルケニル基、または１～５個のＲ２９－２で置換されていてもよいＣ２～４アルキニル基であり、ｒｉｎｇＹが、１～６個のＲＹで置換されていてもよく、１個の窒素原子、１個の酸素原子および／または酸化されていてもよい１個の硫黄原子を含有していてもよい、４～１０員の飽和炭素環である化合物、すなわち、一般式（Ｉ－Ｃ－２） (In the formula, all symbols have the same meanings as above.) and
R 3Y is -NR 22 R 23 , and R 23 is a hydrogen atom, a C1-8 alkyl group optionally substituted with 1 to 5 R 29 , and substituted with 1 to 5 R 29-1 ; or a C2-4 alkynyl group which may be substituted with 1 to 5 R 29-2 , and ringY is substituted with 1 to 6 R Y. A compound that is a 4- to 10-membered saturated carbocycle, which may contain one nitrogen atom, one oxygen atom, and/or one optionally oxidized sulfur atom, that is, General formula (IC-2)
（式中、すべての記号は前記と同じ意味を表わす。）で示される化合物は、以下の反応工程式６－１で示される方法で製造することができる。反応工程式６－１中、ｒｉｎｇＳは、１～６個のＲＹで置換されていてもよく、１個の窒素原子、１個の酸素原子および／または酸化されていてもよい１個の硫黄原子を含有していてもよい、４～１０員の飽和炭素環を表わし、その他の記号は前記と同じ意味を表わす。 The compound represented by (in the formula, all symbols have the same meanings as above) can be produced by the method shown in the following reaction scheme 6-1. In Reaction Scheme 6-1, ringS is optionally substituted with 1 to 6 R It represents a 4- to 10-membered saturated carbon ring which may contain atoms, and the other symbols have the same meanings as above.
　一般式（Ｉ－Ａ－２）で示される化合物は、一般式（Ｘ－２）で示される化合物と、一般式（ＸＩ－Ｙ）で示される化合物を用いて、カップリング反応に付すことにより製造することができる。 The compound represented by general formula (IA-2) can be obtained by subjecting it to a coupling reaction using a compound represented by general formula (X-2) and a compound represented by general formula (XI-Y). can be manufactured.
　このカップリング反応は、前述の一般式（Ｉ－Ａ）で示される化合物を製造する際の反応と同様である。 This coupling reaction is similar to the reaction for producing the compound represented by the general formula (IA) described above.
　さらに必要であれば、この反応に引き続いて公知の方法によって、目的の塩に変換する操作を行ってもよい。 Furthermore, if necessary, subsequent to this reaction, conversion to the desired salt may be performed by a known method.
　一般式（Ｉ－Ｂ－２）で示される化合物は、一般式（Ｘ－２）で示される化合物と、一般式（ＸＩＩ）で示される化合物を用いて、カップリング反応に付すことにより製造することができる。 The compound represented by the general formula (IB-2) is produced by subjecting the compound represented by the general formula (X-2) and the compound represented by the general formula (XII) to a coupling reaction. be able to.
　このカップリング反応は、前述の一般式（Ｉ－Ｂ）で示される化合物を製造する際の反応と同様である。 This coupling reaction is similar to the reaction for producing the compound represented by the general formula (IB) described above.
　さらに必要であれば、この反応に引き続いて公知の方法によって、目的の塩に変換する操作を行ってもよい。 Furthermore, if necessary, subsequent to this reaction, conversion to the desired salt may be performed by a known method.
　一般式（Ｉ－Ｃ－２）で示される化合物は、一般式（Ｘ－２）で示される化合物と、一般式（ＸＸＸＩＶ）で示される化合物を用いて、アミノ基の導入反応に付すことにより製造することができる。 The compound represented by the general formula (IC-2) can be obtained by subjecting the compound represented by the general formula (X-2) and the compound represented by the general formula (XXXIV) to an amino group introduction reaction. can be manufactured.
　このアミノ基の導入反応は、前述の一般式（Ｉ－Ｃ）で示される化合物を製造する際の反応と同様である。 This reaction for introducing an amino group is similar to the reaction for producing the compound represented by the general formula (IC) described above.
　さらに必要であれば、この反応に引き続いて公知の方法によって、目的の塩に変換する操作を行ってもよい。 Furthermore, if necessary, subsequent to this reaction, conversion to the desired salt may be performed by a known method.
　一般式（Ｘ－２）で示される化合物は、以下の反応工程式６－２で示される方法で製造することができる。反応工程式６－２中、すべての記号は前記と同じ意味を表わす。 The compound represented by the general formula (X-2) can be produced by the method shown in the following reaction scheme 6-2. In Reaction Scheme 6-2, all symbols have the same meanings as above.
　一般式（ＸＸＶ－１）で示される化合物は、一般式（ＸＸＩＶ）で示される化合物と、一般式（ＸＸＸＶ－１）で示される化合物を用いて、光延反応に付すことにより製造することができる。 The compound represented by the general formula (XXV-1) can be produced by subjecting the compound represented by the general formula (XXIV) and the compound represented by the general formula (XXXV-1) to a Mitsunobu reaction. .
　この光延反応は公知であり、有機溶媒（ジクロロメタン、ジエチルエーテル、テトラヒドロフラン、アセトニトリル、ベンゼン、トルエン等）中、アゾ化合物（アゾジカルボン酸ジエチル（ＤＥＡＤ）、アゾジカルボン酸ジイソプロピル、１，１’－（アゾジカルボニル）ジピペリジン、１，１’－アゾビス（Ｎ，Ｎ－ジメチルホルムアミド）等）およびホスフィン化合物（トリフェニルホスフィン、トリブチルホスフィン、トリメチルホスフィン、ポリマーサポートトリフェニルホスフィン等）の存在下、または（トリブチルホスホラニリデン）アセトニトリル（ＣＭＢＰ）存在下、０℃～１００℃で行われる。 This Mitsunobu reaction is known, and is performed using an azo compound (diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate, 1,1'-(azo dicarbonyl)dipiperidine, 1,1'-azobis(N,N-dimethylformamide), etc.) and phosphine compounds (triphenylphosphine, tributylphosphine, trimethylphosphine, polymer-supported triphenylphosphine, etc.); The reaction is carried out at 0°C to 100°C in the presence of ranylidene) acetonitrile (CMBP).
　さらに必要であれば、この反応に引き続いて公知の方法によって、目的の塩に変換する操作を行ってもよい。 Furthermore, if necessary, subsequent to this reaction, conversion to the desired salt may be performed by a known method.
　一般式（ＸＸＶ－１）で示される化合物は、一般式（ＸＸＩＶ）で示される化合物と、一般式（ＸＸＸＶ－２）で示される化合物を用いて、アルキル化反応に付すことにより製造することもできる。 The compound represented by the general formula (XXV-1) can also be produced by subjecting the compound represented by the general formula (XXIV) and the compound represented by the general formula (XXXV-2) to an alkylation reaction. can.
　このアルキル化反応は、前述の一般式（Ｘ）で示される化合物を製造する際の反応と同様である。 This alkylation reaction is similar to the reaction for producing the compound represented by the general formula (X) described above.
　さらに必要であれば、この反応に引き続いて公知の方法によって、目的の塩に変換する操作を行ってもよい。 Furthermore, if necessary, subsequent to this reaction, conversion to the desired salt may be performed by a known method.
　一般式（ＸＸＶＩ－１）で示される化合物は、一般式（ＸＸＶ－１）で示される化合物を、カルボキシル基の保護基の脱保護反応に付すことにより製造することができる。 The compound represented by the general formula (XXVI-1) can be produced by subjecting the compound represented by the general formula (XXV-1) to a deprotection reaction of the protecting group of the carboxyl group.
　このカルボキシル基の保護基の脱保護反応は、前述の一般式（ＸＸＶＩ）で示される化合物を製造する際の反応と同様である。 This deprotection reaction of the carboxyl group protecting group is the same as the reaction for producing the compound represented by the aforementioned general formula (XXVI).
　さらに必要であれば、この反応に引き続いて公知の方法によって、目的の塩に変換する操作を行ってもよい。 Furthermore, if necessary, subsequent to this reaction, conversion to the desired salt may be performed by a known method.
　一般式（ＸＸＶＩＩ－１）で示される化合物は、一般式（ＸＸＶＩ－１）で示される化合物と、一般式（ＩＸ）で示される化合物を用いて、アミド化反応に付すことにより製造することができる。 The compound represented by the general formula (XXVII-1) can be produced by subjecting the compound represented by the general formula (XXVI-1) and the compound represented by the general formula (IX) to an amidation reaction. can.
　このアミド化反応は、前述の一般式（ＸＸＶＩＩ）で示される化合物を製造する際の反応と同様である。 This amidation reaction is similar to the reaction for producing the compound represented by general formula (XXVII) described above.
　さらに必要であれば、この反応に引き続いて公知の方法によって、目的の塩に変換する操作を行ってもよい。 Furthermore, if necessary, subsequent to this reaction, conversion to the desired salt may be performed by a known method.
　一般式（ＸＸＶＩＩＩ－１）で示される化合物は、一般式（ＸＸＶＩＩ－１）で示される化合物を、アミノ基の保護基の脱保護反応に付すことにより製造することができる。 The compound represented by the general formula (XXVIII-1) can be produced by subjecting the compound represented by the general formula (XXVII-1) to a deprotection reaction of the protecting group of the amino group.
　このアミノ基の保護基の脱保護反応は、前述の一般式（ＸＸＶＩＩＩ）で示される化合物を製造する際の反応と同様である。 This deprotection reaction of the protecting group for the amino group is the same as the reaction for producing the compound represented by the aforementioned general formula (XXVIII).
　さらに必要であれば、この反応に引き続いて公知の方法によって、目的の塩に変換する操作を行ってもよい。 Furthermore, if necessary, subsequent to this reaction, conversion to the desired salt may be performed by a known method.
　一般式（Ｘ－２）で示される化合物は、一般式（ＸＸＶＩＩＩ－１）で示される化合物と、一般式（ＸＸＩＸ）で示される化合物を用いて、アルキル化反応に付すことにより製造することができる。 The compound represented by general formula (X-2) can be produced by subjecting a compound represented by general formula (XXVIII-1) and a compound represented by general formula (XXIX) to an alkylation reaction. can.
　このアルキル化反応は、前述の一般式（Ｘ）で示される化合物を製造する際の反応と同様である。 This alkylation reaction is similar to the reaction for producing the compound represented by the general formula (X) described above.
　さらに必要であれば、この反応に引き続いて公知の方法によって、目的の塩に変換する操作を行ってもよい。 Furthermore, if necessary, subsequent to this reaction, conversion to the desired salt may be performed by a known method.
　一般式（Ｘ）で示される化合物は、以下の反応工程式７で示される方法で製造することもできる。反応工程式７中、すべての記号は前記と同じ意味を表わす。 The compound represented by general formula (X) can also be produced by the method shown in Reaction Scheme 7 below. In Reaction Scheme 7, all symbols have the same meanings as above.
　一般式（ＸＸＸＶＩＩ）で示される化合物は、一般式（ＩＸ）で示される化合物と、一般式（ＸＸＸＶＩ）で示される化合物を用いて、アミド化反応に付すことにより製造することができる。 The compound represented by the general formula (XXXVII) can be produced by subjecting the compound represented by the general formula (IX) and the compound represented by the general formula (XXXVI) to an amidation reaction.
　このアミド化反応は、前述の一般式（Ｘ）で示される化合物を製造する際の反応と同様である。 This amidation reaction is similar to the reaction for producing the compound represented by the general formula (X) described above.
　さらに必要であれば、この反応に引き続いて公知の方法によって、目的の塩に変換する操作を行ってもよい。 Furthermore, if necessary, subsequent to this reaction, conversion to the desired salt may be performed by a known method.
　一般式（ＸＸＸＶＩＩＩ）で示される化合物は、一般式（ＸＸＸＶＩＩ）で示される化合物と、一般式（ＩＶ）で示される化合物を用いて、カップリング反応に付すことにより製造することができる。 The compound represented by the general formula (XXXVIII) can be produced by subjecting the compound represented by the general formula (XXXVII) and the compound represented by the general formula (IV) to a coupling reaction.
　このカップリング反応は、前述の一般式（ＶＩ）で示される化合物を製造する際の反応と同様である。 This coupling reaction is similar to the reaction for producing the compound represented by general formula (VI) above.
　さらに必要であれば、この反応に引き続いて公知の方法によって、目的の塩に変換する操作を行ってもよい。 Furthermore, if necessary, subsequent to this reaction, conversion to the desired salt may be performed by a known method.
　一般式（Ｘ）で示される化合物は、一般式（ＸＸＸＶＩＩＩ）で示される化合物を、環化反応に付すことにより製造することができる。 The compound represented by the general formula (X) can be produced by subjecting the compound represented by the general formula (XXXVIII) to a cyclization reaction.
　この環化反応は、前述の一般式（ＶＩＩ）で示される化合物を製造する際の反応と同様である。 This cyclization reaction is similar to the reaction used to produce the compound represented by the aforementioned general formula (VII).
　さらに必要であれば、この反応に引き続いて公知の方法によって、目的の塩に変換する操作を行ってもよい。 Furthermore, if necessary, subsequent to this reaction, conversion to the desired salt may be performed by a known method.
　一般式（ＩＸ）で示される化合物のうち、ｓが０である化合物、すなわち一般式（ＩＸ－１） Among the compounds represented by general formula (IX), compounds where s is 0, that is, general formula (IX-1)
（式中、すべての記号は前記と同じ意味を表わす。）で示される化合物は、以下の反応工程式８で示される方法で製造することができる。反応工程式８中、すべての記号は前記と同じ意味を表わす。 The compound represented by (in the formula, all symbols have the same meanings as above) can be produced by the method shown in Reaction Scheme 8 below. In Reaction Scheme 8, all symbols have the same meanings as above.
　一般式（ＸＬＩＩＩ）で示される化合物は、一般式（ＸＬＩＩ）で示される化合物を、ジメチルアミノメチル化反応に付すことにより製造することができる。 The compound represented by the general formula (XLIII) can be produced by subjecting the compound represented by the general formula (XLII) to a dimethylaminomethylation reaction.
　このジメチルアミノメチル化反応は公知であり、例えば、酸（例えば、塩化水素、硫酸、酢酸、トリフルオロ酢酸等）存在下、有機溶媒（例えば、メタノール、エタノール、１－プロパノール、２－プロパノール、１－ブタノール、水、もしくはそれらの混合溶媒等）中、ジメチルアミン、およびホルムアルデヒドと０℃～還流温度で反応させることで行われる。 This dimethylaminomethylation reaction is known, and for example, in the presence of an acid (such as hydrogen chloride, sulfuric acid, acetic acid, trifluoroacetic acid, etc.) and an organic solvent (such as methanol, ethanol, 1-propanol, 2-propanol, 1 -butanol, water, or a mixed solvent thereof) with dimethylamine and formaldehyde at a temperature of 0°C to reflux.
　さらに必要であれば、この反応に引き続いて公知の方法によって、目的の塩に変換する操作を行ってもよい。 Furthermore, if necessary, subsequent to this reaction, conversion to the desired salt may be performed by a known method.
　一般式（ＸＬＩＶ）で示される化合物は、一般式（ＸＬＩＩＩ）で示される化合物を、ニトリル基の導入反応に付すことにより製造することができる。 The compound represented by the general formula (XLIV) can be produced by subjecting the compound represented by the general formula (XLIII) to a reaction for introducing a nitrile group.
　このニトリル基の導入反応は公知であり、例えば、溶媒（アセトニトリル、テトラヒドロフラン、メタノール、エタノール、１－プロパノール、２－プロパノール、１－ブタノール、ジメチルホルムアミド、ジメチルアセトアミド、１－メチル－２－ピロリドン、水、もしくはそれらの混合溶媒等）中、メチル化剤（硫酸ジメチル、ヨウ化メチル等）と０℃～室温で反応させ、得られたアンモニウム塩をシアノ化剤（シアン化カリウム、シアン化ナトリウム等）と０℃～１００℃の温度で反応させることで行われる。 This nitrile group introduction reaction is known, and examples include solvents (acetonitrile, tetrahydrofuran, methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, dimethylformamide, dimethylacetamide, 1-methyl-2-pyrrolidone, water). or a mixed solvent thereof) at 0°C to room temperature, and the resulting ammonium salt is reacted with a cyanating agent (potassium cyanide, sodium cyanide, etc.). The reaction is carried out at a temperature of 100°C to 100°C.
　さらに必要であれば、この反応に引き続いて公知の方法によって、目的の塩に変換する操作を行ってもよい。 Furthermore, if necessary, subsequent to this reaction, conversion to the desired salt may be performed by a known method.
　一般式（ＸＬＶ）で示される化合物は、一般式（ＸＬＩＶ）で示される化合物を、還元反応に付すことにより製造することができる。 The compound represented by the general formula (XLV) can be produced by subjecting the compound represented by the general formula (XLIV) to a reduction reaction.
　この還元反応は公知であり、例えば、有機溶媒（メタノール、エタノール、テトラヒドロフラン、ジエチルエーテル等）中で還元剤（水素化リチウムアルミニウム、水素化ビス（2-メトキシエトキシ）アルキルナトリウム、水素化ジイソブチルアルミニウム、水素化ホウ素リチウム、水素化ホウ素ナトリウム、ホウ化ニッケル、ボラン－ピリジン錯体、ボラン－テトラヒドロフラン錯体等）存在下、もしくは還元剤（水素化ホウ素リチウム、水素化ホウ素ナトリウム等）と酸（トリフルオロ酢酸等）存在下、約－１０℃～還流温度で反応させることにより行なわれる。
また、不活性溶媒（エーテル系（例えば、テトラヒドロフラン、１，４－ジオキサン、ジメトキシエタン、ジエチルエーテル等）、アルコール系（例えば、メタノール、エタノール等）、ベンゼン系（例えば、ベンゼン、トルエン等）、ケトン系（例えば、アセトン、メチルエチルケトン等）、ニトリル系（例えば、アセトニトリル等）、アミド系（例えば、ジメチルホルムアミド等）、水、酢酸エチル、酢酸またはそれらの２つ以上の混合溶媒等）中、水素化触媒（例えば、パラジウム炭素、パラジウム黒、パラジウム、水酸化パラジウム、二酸化白金、ニッケル、ラネーニッケル、塩化ルテニウム、コバルト、ロジウム－アルミナ等）の存在下、無機酸（例えば、塩酸、硫酸、次亜塩素酸、ホウ酸、テトラフルオロホウ酸等）または有機酸（例えば、酢酸、ｐ－トルエンスルホン酸、シュウ酸、トリフルオロ酢酸、ギ酸等）または塩基（水酸化リチウム、水酸化ナトリウム、水酸カリウム、炭酸カリウム、アンモニア、トリエチルアミン等）の存在下または非存在下、常圧または加圧下の水素雰囲気下またはギ酸アンモニウム存在下、０℃～２００℃の温度で行なわれる。無機酸または有機酸を用いる場合には、その塩を用いてもよい。 This reduction reaction is known; for example, a reducing agent (lithium aluminum hydride, bis(2-methoxyethoxy)alkyl sodium hydride, diisobutylaluminum hydride, Lithium borohydride, sodium borohydride, nickel boride, borane-pyridine complex, borane-tetrahydrofuran complex, etc.) or in the presence of a reducing agent (lithium borohydride, sodium borohydride, etc.) and an acid (trifluoroacetic acid, etc.) ) at about -10°C to reflux temperature.
In addition, inert solvents (ether-based (e.g., tetrahydrofuran, 1,4-dioxane, dimethoxyethane, diethyl ether, etc.), alcohol-based (e.g., methanol, ethanol, etc.), benzene-based (e.g., benzene, toluene, etc.), ketone Hydrogenation in a nitrile system (e.g. acetone, methyl ethyl ketone, etc.), nitrile system (e.g. acetonitrile, etc.), amide system (e.g. dimethylformamide, etc.), water, ethyl acetate, acetic acid, or a mixed solvent of two or more thereof). An inorganic acid (e.g., hydrochloric acid, sulfuric acid, hypochlorous acid) in the presence of a catalyst (e.g., palladium on carbon, palladium black, palladium, palladium hydroxide, platinum dioxide, nickel, Raney nickel, ruthenium chloride, cobalt, rhodium-alumina, etc.) , boric acid, tetrafluoroboric acid, etc.) or organic acids (e.g., acetic acid, p-toluenesulfonic acid, oxalic acid, trifluoroacetic acid, formic acid, etc.) or bases (lithium hydroxide, sodium hydroxide, potassium hydroxide, carbonic acid, etc.). The reaction is carried out in the presence or absence of potassium, ammonia, triethylamine, etc.), in a hydrogen atmosphere at normal or pressurized pressure, or in the presence of ammonium formate at a temperature of 0°C to 200°C. When using an inorganic acid or an organic acid, a salt thereof may be used.
　さらに必要であれば、この反応に引き続いて公知の方法によって、目的の塩に変換する操作を行ってもよい。 Furthermore, if necessary, subsequent to this reaction, conversion to the desired salt may be performed by a known method.
　一般式（ＸＬＶＩ）で示される化合物は、一般式（ＸＬＶ）で示される化合物を、環化反応に付すことにより製造することができる。 The compound represented by the general formula (XLVI) can be produced by subjecting the compound represented by the general formula (XLV) to a cyclization reaction.
　この環化反応は公知であり、例えば、酸（例えば、塩化水素、硫酸、酢酸、トリフルオロ酢酸等）存在下、有機溶媒（例えば、テトラヒドロフラン、ジクロロメタン、クロロホルム、ベンゼン、トルエン、キシレン、ヘキサン、ヘプタン、シクロヘキサン、ジエチルエーテル、１，４－ジオキサン、アセトン、エチルメチルケトン、アセトニトリル、ジメチルスルホキシド、ジメチルホルムアミド、ジメチルアセタミド、酢酸エチル等）中、ホルムアルデヒドと０℃～還流温度で反応させることで行われる。 This cyclization reaction is known, and includes, for example, organic solvents (e.g., tetrahydrofuran, dichloromethane, chloroform, benzene, toluene, xylene, hexane, heptane, etc.) in the presence of acids (e.g., hydrogen chloride, sulfuric acid, acetic acid, trifluoroacetic acid, etc.). , cyclohexane, diethyl ether, 1,4-dioxane, acetone, ethylmethylketone, acetonitrile, dimethylsulfoxide, dimethylformamide, dimethylacetamide, ethyl acetate, etc.) at 0°C to reflux temperature. be exposed.
　さらに必要であれば、この反応に引き続いて公知の方法によって、目的の塩に変換する操作を行ってもよい。 Furthermore, if necessary, subsequent to this reaction, conversion to the desired salt may be performed by a known method.
　一般式（ＸＬＶＩＩ）で示される化合物は、一般式（ＸＬＶＩ）で示される化合物を、アミノ基の保護基の導入反応に付すことにより製造することができる。 The compound represented by the general formula (XLVII) can be produced by subjecting the compound represented by the general formula (XLVI) to a reaction for introducing a protecting group for an amino group.
　このアミノ基の保護基の導入は公知であり、例えば、「P. G. M. Wuts, T. W. Greene, Green's Protective Groups in Organic Synthesis, Wiley, Fourth Edition, New York, 2007」に記載の保護基導入反応を用いて、アミノ基の保護基を導入することができる。例えば、ｔｅｒｔ－ブトキシカルボニル基、ベンジルオキシカルボニル基、フルオレニルカルボニル基、トリチル基、ｏ－ニトロベンゼンスルフェニル基等の保護基導入においては、ジ－ｔｅｒｔ－ブチルジカーボネート、ベンジルオキシカルボニルクロリド、フルオレニルカルボニルクロリド、トリチルクロリド、ｏ－ニトロベンゼンスルフェニルクロリド等をそれぞれ用いて、ジクロロメタン、クロロホルム、１，２－ジクロロエタン、テトラヒドロフラン、ジオキサン、トルエン、酢酸エチルまたは水等の溶媒中、－５０℃～１００℃で反応させて行うことができる。この際、必要により、トリエチルアミン、ジイソプロピルエチルアミン等のアミン類、２－エチルヘキサン酸ナトリウムおよび２－エチルヘキサン酸カリウム等の有機酸塩または水酸化ナトリウムおよび炭酸カリウム等の無機塩基等の塩基を用いて行うことができる。 Introduction of a protecting group for an amino group is known, for example, as described in "P. G. M. Wuts, T. W. Greene, Green's Protective Groups in Organic Synthesis, Wiley, Fourth Edition, New York, 2007". A protecting group for an amino group can be introduced using a protecting group introduction reaction. For example, when introducing protective groups such as tert-butoxycarbonyl group, benzyloxycarbonyl group, fluorenylcarbonyl group, trityl group, and o-nitrobenzenesulfenyl group, di-tert-butyl dicarbonate, benzyloxycarbonyl chloride, fluorenyl carbonyl group, etc. Using olenylcarbonyl chloride, trityl chloride, o-nitrobenzenesulfenyl chloride, etc., in a solvent such as dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, dioxane, toluene, ethyl acetate, or water at -50°C to 100°C. The reaction can be carried out at ℃. At this time, if necessary, amines such as triethylamine and diisopropylethylamine, organic acid salts such as sodium 2-ethylhexanoate and potassium 2-ethylhexanoate, or bases such as inorganic bases such as sodium hydroxide and potassium carbonate are used. It can be carried out.
　さらに必要であれば、この反応に引き続いて公知の方法によって、目的の塩に変換する操作を行ってもよい。 Furthermore, if necessary, subsequent to this reaction, conversion to the desired salt may be performed by a known method.
　一般式（ＸＬＶＩＩＩ）で示される化合物は、一般式(ＸＬＶＩＩ)で示される化合物と、一般式（ＸＩＶ）で示される化合物を、アルキル化反応に付すことにより製造することができる。 The compound represented by the general formula (XLVIII) can be produced by subjecting the compound represented by the general formula (XLVII) and the compound represented by the general formula (XIV) to an alkylation reaction.
　このアルキル化反応は公知であり、このアルキル化反応は、前述の一般式（ＸＶ）で示される化合物を製造する際の反応と同様である。 This alkylation reaction is known, and is similar to the reaction used to produce the compound represented by the general formula (XV) described above.
　さらに必要であれば、この反応に引き続いて公知の方法によって、目的の塩に変換する操作を行ってもよい。 Furthermore, if necessary, subsequent to this reaction, conversion to the desired salt may be performed by a known method.
　一般式（ＩＸ－１）で示される化合物は、一般式（ＸＬＶＩＩＩ）で示される化合物を、アミノ基の保護基の脱保護反応に付すことにより製造することができる。 The compound represented by the general formula (IX-1) can be produced by subjecting the compound represented by the general formula (XLVIII) to a deprotection reaction of the protecting group of the amino group.
　このアミノ基の保護基の脱保護反応は、前述の一般式（ＸＶＩ－１）で示される化合物を製造する際の反応と同様である。 This deprotection reaction of the protecting group for the amino group is similar to the reaction for producing the compound represented by general formula (XVI-1) above.
　さらに必要であれば、この反応に引き続いて公知の方法によって、目的の塩に変換する操作を行ってもよい。 Furthermore, if necessary, subsequent to this reaction, conversion to the desired salt may be performed by a known method.
　一般式（ＩＸ－１）で示される化合物のうち、Ｒ１がベンジル基である化合物、すなわち一般式（ＩＸ－２） Among the compounds represented by general formula (IX-1), compounds in which R 1 is a benzyl group, that is, general formula (IX-2)
（式中、ｋは０～５の整数を表わし、その他の記号は前記と同じ意味を表わす。）で示される化合物は、以下の反応工程式９で示される方法で製造することができる。反応工程式９中、すべての記号は前記と同じ意味を表わす。 The compound represented by (wherein k represents an integer from 0 to 5, and the other symbols have the same meanings as above) can be produced by the method shown in Reaction Scheme 9 below. In Reaction Scheme 9, all symbols have the same meanings as above.
　一般式（ＸＬＩＸ）で示される化合物は、一般式(ＸＬＩＶ)で示される化合物と、一般式（ＸＩＶ－１）で示される化合物を、ベンジル化反応に付すことにより製造することができる。 The compound represented by the general formula (XLIX) can be produced by subjecting the compound represented by the general formula (XLIV) and the compound represented by the general formula (XIV-1) to a benzylation reaction.
　このベンジル化反応は公知であり、このベンジル化反応は、前述の一般式（ＸＶ）で示される化合物を製造する際の反応と同様である。 This benzylation reaction is known, and is the same as the reaction for producing the compound represented by the general formula (XV) described above.
　さらに必要であれば、この反応に引き続いて公知の方法によって、目的の塩に変換する操作を行ってもよい。 Furthermore, if necessary, subsequent to this reaction, conversion to the desired salt may be performed by a known method.
　一般式（Ｌ）で示される化合物は、一般式（ＸＬＩＸ）で示される化合物を、還元反応に付すことにより製造することができる。 The compound represented by the general formula (L) can be produced by subjecting the compound represented by the general formula (XLIX) to a reduction reaction.
　この還元反応は公知であり、例えば、有機溶媒（メタノール、エタノール、テトラヒドロフラン、ジエチルエーテル等）中で還元剤（水素化リチウムアルミニウム、水素化ビス（2-メトキシエトキシ）アルキルナトリウム、水素化ジイソブチルアルミニウム、水素化ホウ素リチウム、水素化ホウ素ナトリウム、ホウ化ニッケル、ボラン－ピリジン錯体、ボラン－テトラヒドロフラン錯体等）存在下、もしくは還元剤（水素化ホウ素リチウム、水素化ホウ素ナトリウム等）と酸（トリフルオロ酢酸等）存在下、約－１０℃～還流温度で反応させることにより行なわれる。 This reduction reaction is known; for example, a reducing agent (lithium aluminum hydride, bis(2-methoxyethoxy)alkyl sodium hydride, diisobutylaluminum hydride, Lithium borohydride, sodium borohydride, nickel boride, borane-pyridine complex, borane-tetrahydrofuran complex, etc.) or in the presence of a reducing agent (lithium borohydride, sodium borohydride, etc.) and an acid (trifluoroacetic acid, etc.) ) at about -10°C to reflux temperature.
また、不活性溶媒（エーテル系（例えば、テトラヒドロフラン、１，４－ジオキサン、ジメトキシエタン、ジエチルエーテル等）、アルコール系（例えば、メタノール、エタノール等）、ベンゼン系（例えば、ベンゼン、トルエン等）、ケトン系（例えば、アセトン、メチルエチルケトン等）、ニトリル系（例えば、アセトニトリル等）、アミド系（例えば、ジメチルホルムアミド等）、水、酢酸エチル、酢酸またはそれらの２つ以上の混合溶媒等）中、水素化触媒（例えば、パラジウムロジウム炭素、白金炭素、ラネーニッケル、ラネーコバルト、ロジウム炭素等）の存在下、無機酸（例えば、塩酸、硫酸、次亜塩素酸、ホウ酸、テトラフルオロホウ酸等）または有機酸（例えば、酢酸、ｐ－トルエンスルホン酸、シュウ酸、トリフルオロ酢酸、ギ酸等）または塩基（水酸化リチウム、水酸化ナトリウム、水酸カリウム、炭酸カリウム、アンモニア、トリエチルアミン等）の存在下または非存在下、常圧または加圧下の水素雰囲気下またはギ酸アンモニウム存在下、０℃～２００℃の温度で行なわれる。無機酸または有機酸を用いる場合には、その塩を用いてもよい。 In addition, inert solvents (ether-based (e.g., tetrahydrofuran, 1,4-dioxane, dimethoxyethane, diethyl ether, etc.), alcohol-based (e.g., methanol, ethanol, etc.), benzene-based (e.g., benzene, toluene, etc.), ketone Hydrogenation in a nitrile system (e.g. acetone, methyl ethyl ketone, etc.), nitrile system (e.g. acetonitrile, etc.), amide system (e.g. dimethylformamide, etc.), water, ethyl acetate, acetic acid, or a mixed solvent of two or more thereof). An inorganic acid (e.g., hydrochloric acid, sulfuric acid, hypochlorous acid, boric acid, tetrafluoroboric acid, etc.) or an organic acid in the presence of a catalyst (e.g., palladium rhodium on carbon, platinum on carbon, Raney nickel, Raney cobalt, rhodium on carbon, etc.) (e.g., acetic acid, p-toluenesulfonic acid, oxalic acid, trifluoroacetic acid, formic acid, etc.) or bases (lithium hydroxide, sodium hydroxide, potassium hydroxide, potassium carbonate, ammonia, triethylamine, etc.) in the presence or absence of The reaction is carried out at a temperature of 0° C. to 200° C. under a hydrogen atmosphere under normal pressure or increased pressure or in the presence of ammonium formate. When using an inorganic acid or an organic acid, a salt thereof may be used.
　さらに必要であれば、この反応に引き続いて公知の方法によって、目的の塩に変換する操作を行ってもよい。 Furthermore, if necessary, subsequent to this reaction, conversion to the desired salt may be performed by a known method.
　一般式（ＩＸ－２）で示される化合物は、一般式（Ｌ）で示される化合物を、環化反応に付すことにより製造することができる。 The compound represented by the general formula (IX-2) can be produced by subjecting the compound represented by the general formula (L) to a cyclization reaction.
　この環化反応は公知であり、例えば、酸（例えば、塩化水素、硫酸、酢酸、トリフルオロ酢酸等）存在下、有機溶媒（例えば、テトラヒドロフラン、ジクロロメタン、クロロホルム、ベンゼン、トルエン、キシレン、ヘキサン、ヘプタン、シクロヘキサン、ジエチルエーテル、１，４－ジオキサン、アセトン、エチルメチルケトン、アセトニトリル、ジメチルスルホキシド、ジメチルホルムアミド、ジメチルアセタミド、酢酸エチル等）中、ホルムアルデヒドと０℃～還流温度で反応させることで行われる。 This cyclization reaction is known, and includes, for example, organic solvents (e.g., tetrahydrofuran, dichloromethane, chloroform, benzene, toluene, xylene, hexane, heptane, etc.) in the presence of acids (e.g., hydrogen chloride, sulfuric acid, acetic acid, trifluoroacetic acid, etc.). , cyclohexane, diethyl ether, 1,4-dioxane, acetone, ethylmethylketone, acetonitrile, dimethylsulfoxide, dimethylformamide, dimethylacetamide, ethyl acetate, etc.) at 0°C to reflux temperature. be exposed.
　さらに必要であれば、この反応に引き続いて公知の方法によって、目的の塩に変換する操作を行ってもよい。 Furthermore, if necessary, subsequent to this reaction, conversion to the desired salt may be performed by a known method.
　本明細書中の各反応において、出発原料として用いた化合物や添加される化合物または試薬、例えば、一般式（ＩＩ）、（ＩＩＩ）、（ＩＩＩ－１）、（ＩＩＩ－１ｆ）、（Ｖ）、（ＩＸ）、（ＸＩ）、（ＸＩＩ）、（ＸＩＩＩ）、（ＸＩＶ）、（ＸＩＶ－１）、（ＸＶＩＩ－１）、（ＸＶＩＩＩ－１）、（ＸＸ）、（ＸＸＩＩ）、（ＸＸＩＸ）、（ＸＸＸＩＶ）、（ＸＸＸＶ）、（ＸＸＸＶＩ）、（ＸＸＸＶＩ－１）、（ＸＸＸＶＩ－２）、および（ＸＬＩＩ）で示される化合物は、公知であるかあるいは公知の方法または実施例に記載の方法に準じて製造することができる。 In each reaction herein, the compound used as a starting material and the compound or reagent added, for example, general formula (II), (III), (III-1), (III-1f), (V) , (IX), (XI), (XII), (XIII), (XIV), (XIV-1), (XVII-1), (XVIII-1), (XX), (XXII), (XXIX) , (XXXIV), (XXXV), (XXXVI), (XXXVI-1), (XXXVI-2), and (XLII) are known or can be prepared by known methods or by the methods described in Examples. It can be manufactured according to.
　本発明に用いられる化合物のうち、光学活性を有する化合物は、光学活性を有する出発原料または試薬を用いて製造するか、ラセミ体の製造中間体を光学分割し、次いで本発明に用いられる化合物に導くか、あるいはラセミ体の化合物を光学分割することで製造することもできる。この光学分割の方法は公知であり、例えば、他の光学活性な化合物と塩・錯体等を形成させ、再結晶を行った後、目的とする化合物を単離するかあるいは直接キラルカラム等を用いて分離する方法等が挙げられる。 Among the compounds used in the present invention, optically active compounds can be produced using optically active starting materials or reagents, or by optically resolving racemic production intermediates, and then converting them into compounds used in the present invention. Alternatively, it can also be produced by optically resolving a racemic compound. This optical resolution method is known, for example, by forming a salt or complex with another optically active compound, recrystallizing it, and then isolating the target compound, or directly using a chiral column, etc. Examples include a method of separating.
　本明細書中の各反応において、加熱を伴う反応は、当業者にとって明らかなように、水浴、油浴、砂浴またはマイクロウェーブを用いて行なうことができる。 In each reaction herein, reactions involving heating can be carried out using a water bath, oil bath, sand bath or microwave, as is clear to those skilled in the art.
　本明細書中の各反応において、適宜、高分子ポリマー（例えば、ポリスチレン、ポリアクリルアミド、ポリプロピレンまたはポリエチレングリコール等）に担持させた固相担持試薬を用いてもよい。 In each reaction herein, a solid-phase supported reagent supported on a high molecular weight polymer (eg, polystyrene, polyacrylamide, polypropylene, polyethylene glycol, etc.) may be used as appropriate.
　本明細書中の各反応において、反応生成物は通常の精製手段、例えば、常圧下または減圧下における蒸留、シリカゲルまたはケイ酸マグネシウムを用いた高速液体クロマトグラフィー、薄層クロマトグラフィー、イオン交換樹脂、スカベンジャー樹脂あるいはカラムクロマトグラフィー、洗浄または再結晶等の方法により精製することができる。精製は反応ごとに行なってもよいし、いくつかの反応終了後に行なってもよい。 In each reaction herein, the reaction product can be purified by conventional purification means, such as distillation under normal pressure or reduced pressure, high performance liquid chromatography using silica gel or magnesium silicate, thin layer chromatography, ion exchange resin, It can be purified by methods such as scavenger resin or column chromatography, washing, or recrystallization. Purification may be performed for each reaction or after completion of several reactions.
　［毒性］
　本発明化合物の毒性は十分に低いものであり、医薬品として安全に使用することができる。 [toxicity]
The toxicity of the compounds of the present invention is sufficiently low and they can be safely used as pharmaceuticals.
［医薬品への適用］
　本発明化合物は、ＤＧＫα及びＤＧＫζの一方、又は両方の阻害活性（好ましくは両方の阻害活性）を有するため、哺乳動物、特にヒト（ヒト患者）において、ＤＧＫαおよび／またはＤＧＫζが関連する疾患の進行抑制、再発抑制および／または治療剤として処方することができる。ＤＧＫαおよび／またはＤＧＫζが関連する疾患としては、例えば、癌または感染症を例示することができる。すなわち、本発明化合物は、癌または感染症の有効な進行抑制、再発抑制、および／または治療剤として処方することができる。 [Application to pharmaceuticals]
Since the compound of the present invention has inhibitory activity for one or both of DGKα and DGKζ (preferably both inhibitory activities), it is possible to prevent the progression of diseases associated with DGKα and/or DGKζ in mammals, particularly humans (human patients). It can be prescribed as a suppressive, anti-recurrence and/or therapeutic agent. Examples of diseases related to DGKα and/or DGKζ include cancer and infectious diseases. That is, the compound of the present invention can be formulated as an effective agent for inhibiting progression, inhibiting recurrence, and/or treating cancer or infectious disease.
　なお、本明細書において「癌治療」とは、例えば、（ａ）癌細胞の増殖を減少させるため、（ｂ）癌に起因する症状を低減させるため、癌患者の生活の質を向上させるため、（ｃ）既に投与されている他の抗癌剤または癌治療補助薬の用量を低減させるため、および／または（ｄ）癌患者の生存期間を延長させるために行われる治療を含む。また、「癌の進行抑制」とは、癌の進行を遅延、癌に関連する症状を安定化および症状の進行を後退させることを意味する。「再発抑制」とは、癌治療あるいは癌外科的切除術によって癌病変が完全にもしくは実質的に消滅または取り除かれた患者における癌再発を予防的に抑止することを意味する。 In this specification, "cancer treatment" refers to, for example, (a) to reduce the proliferation of cancer cells, (b) to reduce symptoms caused by cancer, and to improve the quality of life of cancer patients. , (c) to reduce the dose of other anti-cancer agents or adjuvant cancer treatments that have already been administered, and/or (d) to prolong the survival of cancer patients. Furthermore, "suppression of cancer progression" means delaying cancer progression, stabilizing cancer-related symptoms, and reversing the progression of symptoms. "Suppression of recurrence" means preventive suppression of cancer recurrence in patients whose cancerous lesions have been completely or substantially eradicated or removed by cancer treatment or surgical cancer resection.
　さらに、本発明化合物は、（ａ）他の癌治療による治療効果が不十分あるいは十分ではない癌もしくは他の癌治療後に増悪した癌患者、（ｂ）根治もしくは切除不能、転移性、再発性、難治性および／または遠隔転移性の癌の患者、（ｃ）ＴＰＳまたはＣＰＳが５０％以上、２５％以上、１０％以上、５％以上もしくは１％以上である癌患者、（ｄ）ＭＳＩ－ＨもしくはｄＭＭＲを有する癌の患者、（ｅ）ＢＲＡＦ　Ｖ６００Ｅ変異陽性である悪性黒色腫もしくは非小細胞肺癌の患者、（ｆ）ＥＧＦＲ遺伝子変異陽性またはＡＬＫ融合遺伝子陽性である癌の患者、または（ｇ）ＴＭＢが高頻度である癌の患者に処方することがある。 Furthermore, the compounds of the present invention can be used in patients with (a) cancer for which the therapeutic effect of other cancer treatments is insufficient or insufficient, or cancer patients whose disease has worsened after other cancer treatments; Patients with refractory and/or distant metastatic cancer; (c) cancer patients with TPS or CPS of 50% or more, 25% or more, 10% or more, 5% or more, or 1% or more; (d) MSI-H or a patient with cancer having dMMR, (e) a patient with malignant melanoma or non-small cell lung cancer who is BRAF V600E mutation positive, (f) a patient with cancer who is EGFR gene mutation positive or ALK fusion gene positive, or (g) It may be prescribed to cancer patients who frequently receive TMB.
　また、一方で、本発明化合物は、（ａ）他の癌治療による治療歴のない癌患者、（ｂ）ＴＰＳまたはＣＰＳが５０％未満、２５％未満、１０％未満、５％未満もしくは１％未満である癌患者、（ｃ）ＭＳＩ－Ｈおよび／またはｄＭＭＲを有しない、もしくはＭＳＩ－Ｌを有する癌の患者、（ｄ）ＢＲＡＦ　Ｖ６００野生型である悪性黒色腫もしくは非小細胞肺癌の患者、（ｅ）ＥＧＦＲ遺伝子変異陰性および／またはＡＬＫ融合遺伝子陰性である非小細胞肺癌の患者、または（ｆ）ＴＭＢが低頻度である癌の患者への処方がより求められる場合もある。 On the other hand, the compounds of the present invention may be used in (a) cancer patients with no history of other cancer treatments, (b) TPS or CPS of less than 50%, less than 25%, less than 10%, less than 5%, or less than 1%. (c) patients with cancer who do not have MSI-H and/or dMMR or have MSI-L; (d) patients with malignant melanoma or non-small cell lung cancer who are BRAF V600 wild type; (e) patients with non-small cell lung cancer who are negative for EGFR gene mutations and/or negative for ALK fusion genes, or (f) patients with cancers in which TMB is infrequently present may be more required.
　また、癌の外科的切除術後の再発あるいは転移を予防的に抑止する術後補助療法または外科的切除前に行われる術前補助療法として処方することもできる。 It can also be prescribed as a postoperative adjuvant therapy to prevent recurrence or metastasis after surgical resection of cancer, or as a neoadjuvant therapy performed before surgical resection.
　ここで、「他の癌治療」としては、下記の「併用または配合剤」の項目に記載された抗癌剤、すなわち、アルキル化薬、白金製剤、代謝拮抗剤（例えば、葉酸代謝拮抗薬、ピリジン代謝阻害薬およびプリン代謝阻害薬）、リボヌクレオチドリダクターゼ阻害薬、ヌクレオチドアナログ、トポイソメラーゼ阻害薬、微小管重合阻害薬、微小管脱重合阻害薬、抗腫瘍性抗生物質、サイトカイン製剤、抗ホルモン薬、分子標的薬および癌免疫治療薬として各々例示された薬剤による治療ならびに放射線療法、肝動脈化学塞栓療法（TACE）、肝動脈塞栓療法（TAE）、癌ワクチンおよび免疫細胞療法が挙げられる。また、「他の癌治療による治療効果が不十分あるいは十分ではない」とは、例えば、その腫瘍収縮効果判定ＲＥＣＩＳＴにおいて、既存の抗癌剤による治療によっても「安定（ＳＤ）」あるいは「進行（ＰＤ）」と判定される場合が挙げられる。 Here, "other cancer treatments" include the anticancer drugs listed in the "Concomitant or combined drugs" section below, such as alkylating drugs, platinum preparations, antimetabolites (e.g., folic acid antimetabolites, pyridine metabolites). inhibitors and purine metabolism inhibitors), ribonucleotide reductase inhibitors, nucleotide analogs, topoisomerase inhibitors, microtubule polymerization inhibitors, microtubule depolymerization inhibitors, antitumor antibiotics, cytokine preparations, antihormonal drugs, molecular targets Examples of drugs and cancer immunotherapeutics include treatments with drugs, as well as radiotherapy, hepatic artery chemoembolization (TACE), hepatic artery embolization (TAE), cancer vaccines, and immune cell therapy. In addition, "therapeutic effects of other cancer treatments are insufficient or insufficient" means, for example, that in the RECIST, which determines the tumor shrinkage effect, even if treatment with existing anticancer drugs is "stable (SD)" or "progressive (PD)" ” may be determined.
　本発明化合物が進行抑制、再発抑制および／または治療の対象とする癌には、何れの固形癌および血液癌も含まれ、固形癌のうち、上皮細胞癌としては、例えば、悪性黒色腫（例えば、皮膚、口腔粘膜上皮または眼窩内等における悪性黒色腫）、非小細胞肺癌（例えば、扁平非小細胞肺癌および非扁平非小細胞肺癌）、小細胞肺癌、頭頸部癌（例えば、口腔癌、上咽頭癌、中咽頭癌、下咽頭癌、喉頭癌、唾液腺癌および舌癌）、腎細胞癌（例えば、淡明細胞型腎細胞癌）、乳癌、卵巣癌（例えば、漿液性卵巣癌および卵巣明細胞腺癌）、鼻咽頭癌、子宮癌（例えば、子宮頸癌および子宮体癌）、肛門癌（例えば、肛門管癌）、大腸癌（例えば、ＭＳＩ－Ｈおよび／またはｄＭＭＲ陽性大腸癌）、直腸癌、結腸癌、肝細胞癌、食道癌、胃癌、食道胃接合部癌、膵癌、尿路上皮癌（例えば、膀胱癌、上部尿路癌、尿管癌、腎盂癌および尿道癌）、前立腺癌、卵管癌、原発性腹膜癌、悪性胸膜中皮腫、胆嚢癌、胆管癌、胆道癌、皮膚癌（例えば、ブドウ膜悪性黒色腫およびメルケル細胞癌）、精巣癌（胚細胞腫瘍）、膣癌、外陰部癌、陰茎癌、小腸癌、内分泌系癌、甲状腺癌、副甲状腺癌、副腎癌、脊椎腫瘍、神経芽細胞腫、髄芽腫、眼網膜芽細胞腫、神経内分泌腫瘍、脳腫瘍（例えば、神経膠腫（例えば、神経膠芽腫および神経膠肉腫）および髄膜腫）および扁平上皮癌等が挙げられる。 Cancers targeted for progression inhibition, recurrence inhibition, and/or treatment by the compounds of the present invention include any solid cancer and blood cancer. Among solid cancers, examples of epithelial cell cancer include malignant melanoma (e.g. , malignant melanoma in the skin, oral mucosal epithelium, or orbital cavity, etc.), non-small cell lung cancer (e.g., squamous non-small cell lung cancer and non-squamous non-small cell lung cancer), small cell lung cancer, head and neck cancer (e.g., oral cancer, nasopharyngeal cancer, oropharyngeal cancer, hypopharyngeal cancer, laryngeal cancer, salivary gland cancer, and tongue cancer), renal cell carcinoma (e.g., clear cell renal cell carcinoma), breast cancer, ovarian cancer (e.g., serous ovarian cancer and ovarian cancer). clear cell adenocarcinoma), nasopharyngeal cancer, uterine cancer (e.g. cervical cancer and endometrial cancer), anal cancer (e.g. anal canal cancer), colorectal cancer (e.g. MSI-H and/or dMMR positive colorectal cancer) , rectal cancer, colon cancer, hepatocellular carcinoma, esophageal cancer, gastric cancer, esophagogastric junction cancer, pancreatic cancer, urothelial cancer (e.g., bladder cancer, upper urinary tract cancer, ureteral cancer, renal pelvis cancer and urethral cancer), Prostate cancer, fallopian tube cancer, primary peritoneal cancer, malignant pleural mesothelioma, gallbladder cancer, bile duct cancer, biliary tract cancer, skin cancer (e.g. uveal malignant melanoma and Merkel cell carcinoma), testicular cancer (germ cell tumor) , vaginal cancer, vulvar cancer, penile cancer, small intestine cancer, endocrine cancer, thyroid cancer, parathyroid cancer, adrenal cancer, spinal tumor, neuroblastoma, medulloblastoma, ocular retinoblastoma, neuroendocrine tumor, Examples include brain tumors (eg, gliomas (eg, glioblastoma and gliosarcoma) and meningiomas) and squamous cell carcinoma.
　また、固形癌のうち、肉腫としては、骨・軟部肉腫（例えば、ユーイング肉腫、小児横紋筋肉腫、子宮体部平滑筋肉腫、軟骨肉腫、肺肉腫、骨肉腫、先天性繊維肉腫）およびカポジ肉腫等が挙げられる。 Among solid cancers, sarcomas include bone and soft tissue sarcomas (e.g., Ewing's sarcoma, pediatric rhabdomyosarcoma, leiomyosarcoma of the uterine corpus, chondrosarcoma, pulmonary sarcoma, osteosarcoma, congenital fibrosarcoma) and Kaposi sarcoma. Examples include sarcoma.
　また、血液癌としては、例えば、多発性骨髄腫、悪性リンパ腫（例えば、非ホジキンリンパ腫（例えば、濾胞性リンパ腫、前駆Ｂ細胞リンパ芽球性リンパ腫、慢性Ｂリンパ性白血病、節性辺縁帯Ｂ細胞性リンパ腫、びまん性大細胞型Ｂ細胞性リンパ腫、ＭＡＬＴリンパ腫、脾原発辺縁帯Ｂ細胞性リンパ腫、ヘアリーセル白血病、原発性縦隔大細胞型Ｂ細胞性リンパ腫、バーキットリンパ腫、マントル細胞リンパ腫、菌状息肉症、セザリー症候群、慢性または急性リンパ球性白血病、前駆Ｔ細胞リンパ芽球性リンパ腫、慢性Ｔリンパ球性白血病、大顆粒Ｔ細胞性白血病、大顆粒ＮＫ細胞性白血病、末梢性Ｔ細胞リンパ腫、節外性ＮＫ／Ｔ細胞リンパ腫、成人Ｔ細胞白血病、血管中心性リンパ腫、腸管Ｔ細胞性リンパ腫、ホジキン様／ホジキン関連未分化大細胞リンパ腫、Ｂ細胞リンパ芽球性白血病、Ｔ細胞リンパ芽球性白血病、リンパ形質細胞性リンパ腫、および中枢神経系原発悪性リンパ腫）およびホジキンリンパ腫（例えば、古典的ホジキンリンパ腫および結節性リンパ球優位型ホジキンリンパ腫））および白血病（例えば、急性骨髄性白血病および慢性骨髄性白血病）、骨髄異形成症候群および骨髄増殖症候群等が挙げられる。 Blood cancers include, for example, multiple myeloma, malignant lymphoma (for example, non-Hodgkin's lymphoma (for example, follicular lymphoma, precursor B cell lymphoblastic lymphoma, chronic B lymphocytic leukemia, nodal marginal zone B Cellular lymphoma, diffuse large B-cell lymphoma, MALT lymphoma, primary splenic marginal zone B-cell lymphoma, hairy cell leukemia, primary mediastinal large B-cell lymphoma, Burkitt lymphoma, mantle cell lymphoma , mycosis fungoides, Sézary syndrome, chronic or acute lymphocytic leukemia, precursor T cell lymphoblastic lymphoma, chronic T lymphocytic leukemia, large granular T cell leukemia, large granular NK cell leukemia, peripheral T cellular lymphoma, extranodal NK/T-cell lymphoma, adult T-cell leukemia, angiocentric lymphoma, intestinal T-cell lymphoma, Hodgkin-like/Hodgkin-associated anaplastic large cell lymphoma, B-cell lymphoblastic leukemia, T-cell lymphoma blastic leukemia, lymphoplasmacytic lymphoma, and primary central nervous system lymphoma) and Hodgkin lymphoma (e.g., classic Hodgkin lymphoma and nodular lymphocyte-predominant Hodgkin lymphoma)) and leukemia (e.g., acute myeloid leukemia and Chronic myeloid leukemia), myelodysplastic syndrome, myeloproliferative syndrome, etc.
　さらに、本発明化合物が進行抑制、再発抑制および／または治療の対象とする癌には、小児癌および原発不明癌も含まれる。 Furthermore, cancers targeted for progression inhibition, recurrence inhibition, and/or treatment by the compounds of the present invention include childhood cancers and cancers of unknown primary origin.
　本発明化合物が進行抑制、再発抑制および／または治療の対象とする感染症には、ウイルス感染、寄生虫感染、細菌感染または真菌感染に起因する症状が含まれる。 Infectious diseases that are targeted for inhibition of progression, inhibition of recurrence, and/or treatment by the compounds of the present invention include symptoms caused by viral infection, parasitic infection, bacterial infection, or fungal infection.
　ウイルス感染症としては、例えば、アデノウイルス、アレナウイルス、ブンヤウイルス、カリチウイルス、コロナウイルス、フィロウイルス、ヘパドナウイルス、ヘルペスウイルス、オルソミクソウイルス、パポバウイルス、パラミクソウイルス、パルボウイルス、ピコルナウイルス、ポックスウイルス、レオウイルス、レトロウイルス、ラブドウイルス、トガウイルス、乳頭腫ウイルス（例えば、ヒト乳頭腫ウイルス（ＨＰＶ））、ヒト免疫不全ウイルス（ＨＩＶ）、ポリオウイルス、肝炎ウイルス（例えば、Ａ型肝炎ウイルス（ＨＡＶ）、Ｂ型肝炎ウイルス（ＨＢＶ）、Ｃ型肝炎ウイルス（ＨＣＶ）、Ｄ型肝炎ウイルス（ＨＤＶ）、Ｅ型肝炎ウイルス（ＨＥＶ））、天然痘ウイルス（例えば、大痘瘡、小痘瘡）、ワクシニアウイルス、インフルエンザウイルス、ライノウイルス、デング熱ウイルス、ウマ脳炎ウイルス、風疹ウイルス、黄熱病ウイルス、ノーウォークウイルス、ヒトＴ細胞白血病ウイルス（ＨＴＬＶ－Ｉ）、ヘアリーセル白血病ウイルス（ＨＴＬＶ－ＩＩ）、カリフォルニア脳炎ウイルス、ハンタウイルス（出血性熱）、狂犬病ウイルス、エボラ熱ウイルス、マールブルグウイルス、麻疹ウイルス、流行性耳下腺炎ウイルス、呼吸系発疹ウイルス（ＲＳＶ）、単純ヘルペス１型（口腔ヘルペス）、単純ヘルペス２型（陰部ヘルペス）、帯状ヘルペス（水痘・帯状疱疹ウイルス）、サイトメガロウイルス（ＣＭＶ）、エプスタイン－バーウイルス（ＥＢＶ）、フラビウイルス、口蹄疫ウイルス、チクングニヤウイルス、ラッサウイルス、アレナウイルスまたは発癌性ウイルスによる感染症が挙げられる。 Examples of viral infections include adenovirus, arenavirus, bunyavirus, calicivirus, coronavirus, filovirus, hepadnavirus, herpesvirus, orthomyxovirus, papovavirus, paramyxovirus, parvovirus, picornavirus, Poxviruses, reoviruses, retroviruses, rhabdoviruses, togaviruses, papillomaviruses (e.g., human papillomavirus (HPV)), human immunodeficiency virus (HIV), polioviruses, hepatitis viruses (e.g., hepatitis A virus) (HAV), hepatitis B virus (HBV), hepatitis C virus (HCV), hepatitis D virus (HDV), hepatitis E virus (HEV)), smallpox virus (e.g., variola major, variola minor), Vaccinia virus, influenza virus, rhinovirus, dengue virus, equine encephalitis virus, rubella virus, yellow fever virus, Norwalk virus, human T-cell leukemia virus (HTLV-I), hairy cell leukemia virus (HTLV-II), California encephalitis Viruses, hantavirus (haemorrhagic fever), rabies virus, Ebola virus, Marburg virus, measles virus, mumps virus, respiratory rash virus (RSV), herpes simplex type 1 (oral herpes), herpes simplex Type 2 (genital herpes), herpes zoster (varicella-zoster virus), cytomegalovirus (CMV), Epstein-Barr virus (EBV), flavivirus, foot-and-mouth disease virus, chikungunya virus, Lassa virus, arenavirus or oncogenic virus Infectious diseases caused by
　寄生虫感染症としては、例えば、アカントアメーバ角膜炎、アメーバ症、回虫症、バベシア症、バランチジウム症、アライグマ回虫症、シャガス病、肝ジストマ症、コクリオミイヤ、クリプトスポリジウム症、裂頭条虫症、メジナ虫症、エキノコックス症、象皮病、蟯虫症、肝蛭症、肥大肝蛭病、糸状虫症、ジアルジア虫症、顎口虫症、膜様条虫疾患、イソスポラ症、片山熱、リーシュマニア症、ライム病、マラリア、横川吸虫症、ハエウジ病、オンコセルカ症、シラミ寄生症、疥癬、住血吸虫症、アフリカ睡眠症、糞線虫症、テニヤ条虫症、トキソカラ症、トキソプラスマ症、旋毛虫症および鞭虫症等が挙げられる。 Parasitic infections include, for example, Acanthamoeba keratitis, amoebiasis, ascariasis, babesiosis, balantidiosis, raccoon ascariasis, Chagas disease, hepatic dystomiasis, cochliomia, cryptosporidiosis, taeniasis, and ascariasis. Inworm disease, echinococcosis, elephantiasis, pinworm disease, liver fluke disease, enlarged liver fluke disease, heartworm disease, giardiasis, gnathostomiasis, membranous tapeworm disease, isosporiasis, Katayama fever, leishmaniasis, Lyme diseases, malaria, fluke, onchocerciasis, lice infestation, scabies, schistosomiasis, African somnolosis, strongyloidiasis, taeniasis, toxocariasis, toxoplasmosis, trichinosis and whipworm. symptoms, etc.
　細菌感染症としては、例えば、結核菌、炭疽菌、病原性細菌、食中毒菌、サルモネラ菌、ブドウ球菌、連鎖球菌、破傷風菌、ミコバクテリア、破傷風菌、ペスト菌、炭疽菌およびメチシリン耐性黄色ブドウ球菌（ＭＲＳＡ）等の抗生物質耐性菌ならびにクロストリジウム－ディフィシレ、その他感染性細菌の感染に起因する感染症が挙げられる。 Examples of bacterial infections include Mycobacterium tuberculosis, Bacillus anthrax, pathogenic bacteria, food poisoning bacteria, Salmonella enterica, Staphylococcus, Streptococcus, Clostridium tetani, Mycobacteria, Clostridium tetani, Yersinia pestis, Bacillus anthracis, and methicillin-resistant Staphylococcus aureus ( These include infections caused by antibiotic-resistant bacteria such as MRSA), Clostridium difficile, and other infectious bacteria.
　真菌感染症としては、例えば、アスペルギルス種、ブラストミセス・デルマティティディス、カンジダ属酵母（例えば、カンジダアルビカンス）、コクシジオイデス、クリプトコックス・ネオフォルマンス、クリプトコッカス・ガッティ、皮膚糸状菌、フザリウム種、ヒストプラスマ・カプスラーツム、ケカビ亜門、ニューモシスチス・ジロベシ、スポロトリックス・シェンキィ、エキセロハイラム属またはクラドスポリウムの感染に起因する感染症が挙げられる。 Fungal infections include, for example, Aspergillus sp., Blastomyces dermatitidis, Candida yeasts (e.g., Candida albicans), Coccidioides, Cryptococcus neoformans, Cryptococcus gattii, dermatophytes, Fusarium sp., Histoplasma spp. Infections caused by infections with P. capsulatum, Mucorina, Pneumocystis jirovesi, Sporothrix schenkii, Exellohyrum or Cladosporium can be mentioned.
［併用または配合剤］
　本発明化合物または本発明化合物を有効成分として含む医薬組成物（以下、「本発明化合物等」と略記することがある。）は、（ａ）癌もしくは感染症の進行抑制、再発抑制および／または治療効果の増強のために、（ｂ）組み合わせて処方される他の薬剤の投与量の低減のために、（ｃ）組み合わせて処方される他の薬剤の副作用の軽減のために、および／または（ｄ）組み合わせて処方される他の薬剤の免疫増強作用を高めるために、すなわち、アジュバントとして、一種以上の他の薬剤とともに組み合わせて処方してもよい。本発明において、他の薬剤とともに組み合わせて処方する場合の投与形態には、１つの製剤中に両成分を配合した配合剤の形態であっても、また別々の製剤としての投与形態であってもよい。その併用により、その他の薬剤の予防、症状進展抑制、再発抑制および／または治療効果を補完したり、投与量あるいは投与回数を維持ないし低減したりすることができる。本発明化合物等と他の薬剤を別々に処方する場合には、一定期間同時投与し、その後、本発明化合物等のみあるいは他の薬剤のみを投与してもよい。また、本発明化合物等を先に投与し、その投与の後に他の薬剤を投与してもよいし、他の薬剤を先に投与し、本発明化合物等を後に投与してもよく、また、上記投与において、一定期間、両薬剤が同時に投与される期間があってもよい。また、各々の薬剤の投与方法は同じでも異なっていてもよい。薬剤の性質により、本発明化合物を含む製剤と他の薬剤を含む製剤のキットとして提供することもできる。ここで、他の薬剤の投与量は、臨床上用いられている用量を基準として適宜選択することができる。また、他の薬剤は任意の２種以上を適宜の割合で組み合わせて投与してもよい。また、前記他の薬剤には、現在までに見出されているものだけでなく今後見出されるものも含まれる。 [Concomitant use or combination agents]
The compound of the present invention or a pharmaceutical composition containing the compound of the present invention as an active ingredient (hereinafter sometimes abbreviated as "compound of the present invention, etc.") can (a) inhibit the progression of cancer or infectious disease, inhibit recurrence, and/or (b) to reduce the dosage of other drugs prescribed in combination; (c) to reduce side effects of other drugs prescribed in combination; and/or (d) It may be prescribed in combination with one or more other drugs in order to enhance the immunopotentiating effect of other drugs prescribed in combination, ie, as an adjuvant. In the present invention, the dosage form when prescribed in combination with other drugs may be in the form of a combination drug containing both components in one preparation, or as separate preparations. good. When used in combination, it is possible to supplement the prevention, symptom progression, recurrence, and/or therapeutic effects of other drugs, or to maintain or reduce the dosage or frequency of administration. When the compound of the present invention and other drugs are prescribed separately, they may be administered simultaneously for a certain period of time, and then only the compound of the present invention or the other drug may be administered. Furthermore, the compound of the present invention, etc. may be administered first, and then other drugs may be administered, or the other drug may be administered first, and the compound of the present invention, etc. may be administered later. In the above administration, there may be a certain period in which both drugs are administered simultaneously. Furthermore, the administration methods for each drug may be the same or different. Depending on the nature of the drug, a kit containing a preparation containing the compound of the present invention and another drug may also be provided. Here, the dosage of the other drug can be appropriately selected based on the clinically used dosage. Furthermore, any two or more other drugs may be administered in combination at an appropriate ratio. In addition, the other drugs include not only those that have been discovered to date but also those that will be discovered in the future.
　癌治療において、本発明化合物等とともに組み合わせて使用することができる抗癌剤としては、例えば、アルキル化薬（例えば、dacarbazine、Nimustine、Temozolomide、Fotemustine、bendamustine、Cyclophosphamide、Ifosfamide、Carmustine、ChlorambucilおよびProcarbazine等）、白金製剤（例えば、Cisplatin、Carboplatin、Nedaplatinおよびoxaliplatin等）、代謝拮抗剤（例えば、葉酸代謝拮抗薬（例えば、Pemetrexed、leucovorinおよびMethotrexate等）、ピリジン代謝阻害薬（例えば、TS-1（登録商標）、5-fluorouracil、UFT、Carmofur、Doxifluridine、FdUrd、CytarabineおよびCapecitabine等）、プリン代謝阻害薬（例えば、Fludarabine、CladribineおよびNelarabine等）、リボヌクレオチドリダクターゼ阻害薬、ヌクレオチドアナログ（例えば、Gemcitabine等））、トポイソメラーゼ阻害薬（例えば、Irinotecan、NogitecanおよびEtoposide等）、微小管重合阻害薬（例えば、Vinblastine、Vincristine、Vindesine、Vinorelbine、Eribulin等）、微小管脱重合阻害薬（例えば、DocetaxelおよびPaclitaxel）、抗腫瘍性抗生物質（例えば、Bleomycin、Mitomycin C、Doxorubicin、Daunorubicin、Idarubicin、Etoposide、Mitoxantrone、Vinblastine、Vincristine、Peplomycin、Amrubicin、AclarubicinおよびEpirubicin等）、サイトカイン製剤（例えば、ＩＦＮ－α２ａ、ＩＦＮ－α２ｂ、ペグＩＦＮ－α２ｂ、天然型ＩＦＮ－βおよびInterleukin－２等）、抗ホルモン薬（例えば、Tamoxifen、Fulvestrant、Goserelin、Leuprorelin、Anastrozole、LetrozoleおよびExemestane等）、分子標的薬、癌免疫治療薬およびその他の抗体医薬等が挙げられる。 In cancer treatment, anticancer agents that can be used in combination with the compounds of the present invention include, for example, alkylating drugs (e.g., dacarbazine, Nimustine, Temozolomide, Fotemustine, bendamustine, Cyclophosphamide, Ifosfamide, Carmustine, Chlorambucil, Procarbazine, etc.); Platinum preparations (e.g., Cisplatin, Carboplatin, Nedaplatin, and oxaliplatin, etc.), antimetabolites (e.g., folic acid antimetabolites (e.g., Pemetrexed, leucovorin, and Methotrexate, etc.), pyridine metabolism inhibitors (e.g., TS-1®) , 5-fluorouracil, UFT, Carmofur, Doxifluridine, FdUrd, Cytarabine and Capecitabine etc.), purine metabolism inhibitors (e.g. Fludarabine, Cladribine and Nelarabine etc.), ribonucleotide reductase inhibitors, nucleotide analogues (e.g. Gemcitabine etc.), Topoisomerase inhibitors (such as Irinotecan, Nogitecan and Etoposide), microtubule polymerization inhibitors (such as Vinblastine, Vincristine, Vindesine, Vinorelbine, Eribulin, etc.), microtubule depolymerization inhibitors (such as Docetaxel and Paclitaxel), antitumor antibiotics (e.g. Bleomycin, Mitomycin C, Doxorubicin, Daunorubicin, Idarubicin, Etoposide, Mitoxantrone, Vinblastine, Vincristine, Peplomycin, Amrubicin, Aclarubicin and Epirubicin, etc.), cytokine preparations (e.g. IFN-α2a, IFN-α2b, PEG-IFN) - α2b, natural IFN-β, and Interleukin-2), antihormonal drugs (e.g., Tamoxifen, Fulvestrant, Goserelin, Leuprorelin, Anastrozole, Letrozole, Exemestane, etc.), molecular target drugs, cancer immunotherapy drugs, and other antibody drugs etc.
　ここで、分子標的薬としては、例えば、ＡＬＫ阻害剤（例えば、Crizotinib、Ceritinib、Ensartinib、AlectinibおよびLorlatinib）、ＢＣＲ－ＡＢＬ阻害剤（例えば、ImatinibおよびDasatinib）、ＥＧＦＲ阻害剤（例えば、Erlotinib、EGF816、Afatinib、Osimertinib　メシル酸塩、GefitinibおよびRociletinib）、Ｂ－Ｒａｆ阻害剤（例えば、Sorafenib、Vemurafenib、TAK-580、Dabrafenib、Encorafenib、LXH254、EmurafenibおよびBGB-3111）、ＶＥＧＦＲ阻害剤（例えば、Bevacizumab、Apatinib、Lenvatinib、AfliberceptおよびAxitinib）、ＦＧＦＲ阻害剤（例えば、AZD4547、B-701、FGF401およびINCB054828）、ｃ－Ｍｅｔ阻害剤（例えば、Savolitinib、merestinib、Capmatinib、INC280およびGlesatinib）、Ａｘｌ阻害剤（例えば、ONO-7475およびBGB324）、Ｍｅｋ阻害剤（例えば、Cobimetinib、Binimetinib、SelumetinibおよびTrametinib）、ＣＤＫ阻害剤（例えば、Dinaciclib、Abemaciclib、Palbociclibおよびtrilaciclib）、Ｂｔｋ阻害剤（例えば、ONO-4059、IbrutinibおよびAcalabrutinib）、ＰＩ３Ｋ－δ／γ阻害剤（例えば、TGR-1202、INCB050465およびIPI-549）、ＪＡＫ－１／２阻害剤（例えば、ItacitinibおよびRuxolitinib）、ＥＲＫ阻害剤（例えば、SCH 900353）、ＴＧＦｂＲ１阻害剤（例えば、Galunisertib）、Cancer cell stemness　キナーゼ阻害剤（例えば、Amcasertib）、ＦＡＫ阻害剤（例えば、Defactinib）、Ｓｙｋ／ＦＬＴ３　ｄｕａｌ阻害剤（例えば、TAK-659）、ＡＴＲ阻害剤（例えば、AZD6738）、Ｗｅｅ１キナーゼ阻害剤（例えば、AZD1775）、マルチチロシンキナーゼ阻害剤（例えば、Sunitinib、Pazopanib、Cabozantinib、Regorafenib、Nintedanib、SitravatinibおよびMidostaurin）、ｍＴＯＲ阻害剤（例えば、Temsirolimus、Everolimus、Vistusertib、Irinotecan）、ＨＤＡＣ阻害剤（例えば、Vorinostat、Romidepsin、Entinostat、Chidamide、Mocetinostat、Citarinostat、Panobinostat、Valproate）、ＰＡＲＰ阻害剤（例えば、Niraparib、Olaparib、Veliparib、Rucaparib、Beigene-290）、アロマターゼ阻害剤（例えば、Exemestane、Letrozole）、ＥＺＨ２阻害剤（例えば、tazemetostat）、ガレクチン－３阻害剤（例えば、GR-MD-02）、ＳＴＡＴ３阻害剤（例えば、Napabucasin）、ＤＮＭＴ阻害剤（例えば、Azacitidine）、ＳＭＯ阻害剤（例えば、Vismodegib）、Ｈｓｐ９０阻害剤（例えば、XL888）、γ－チューブリン特異的阻害剤（例えば、Glaziovianin A、Plinabulin）、ＨＩＦ２α阻害剤（例えば、PT2385）、グルタミナーゼ阻害剤（例えば、CB-839）、Ｅ３リガーゼ阻害剤（例えば、Avadomide）、Ｎｒｆ２活性化剤（例えば、Omaveloxolone）、アルギナーゼ阻害剤（例えば、CB-1158）、細胞周期阻害剤（例えば、Trabectedin）、Ephrin B4阻害剤（例えば、sEphB4-HAS）、ＩＡＰ拮抗剤（例えば、Birinapant）、BETタンパク阻害剤（例えば、CC-90010）、ＬＳＤ１阻害剤（例えば、CC-90011）、ＣＲＢＮ制御剤（例えば、Avadomide）抗Ｈｅｒ２抗体（例えば、Trastuzumab、Trastuzumab emtansine、PertuzumabおよびMargetuximab）、抗ＥＧＦＲ抗体（例えば、Cetuximab、Panitumumab、NecitumumabおよびNimotuzumab）抗ＶＥＧＦ抗体（例えば、Bevacizumab）、抗ＶＥＧＦＲ２抗体（例えば、Ramucirumab）、抗ＣＤ２０抗体（例えば、Rituximab、Ofatumumab、UblituximabおよびObinutuzumab）、抗ＣＤ３０抗体（例えば、Brentuximab Vedotin）、抗ＣＤ３８抗体（例えば、Daratumumab）、抗ＤＲ５抗体（例えば、DS-8273a）、抗ＣＡ１２５抗体（例えば、Oregovomab）、抗ＤＬＬ４抗体（例えば、Demcizumab）、抗フコシルＧＭ１抗体（例えば、BMS-986012）、抗ｇｐＮＭＢ抗体（例えば、Glembatumumab vedotin）、抗Mesothelin抗体（例えば、BMS-986148）、抗ＭＭＰ９抗体（例えば、Andecaliximab）、抗ＧＤ２抗体（例えば、Dinutuximab－β）、抗ｃ－Ｍｅｔ抗体（例えば、ABT-399）、抗ＦＯＬＲ１抗体（例えば、Mirvetuximab soravtansine）、抗Ｆｕｃｏｓｙｌ－ＧＭ１抗体（例えば、BMS-986012）、抗Ａｎｇ２－ＶＥＧＦ二重特異性抗体（例えば、Vanucizumab）、抗ＣＤ３０－ＣＤ１６Ａ二重特異性抗体（例えば、AFM13）、抗ＣＤ７９ｂ抗体（例えば、Polatuzumab Vedotin）、抗ＦＡＰ抗体／ＩＬ－２融合蛋白質（例えば、RO6874281）、抗ＣＥＡ抗体／ＩＬ－２融合蛋白質（例えば、Cergutuzumab amunaleukin）、抗ＣＥＡ－ＣＤ３二重特異性抗体（例えば、RO6958688）、抗ＤＬＬ３抗体（例えば、Rovalpituzumab tesirine）、抗ＣＤ３－ＣＤ１９二重特異性抗体（例えば、Blinatumomab）および抗ＣＤ２０－ＣＤ３二重特異性抗体（例えば、REGN1979）等が挙げられる。 Here, examples of molecular target drugs include ALK inhibitors (e.g., Crizotinib, Ceritinib, Ensartinib, Alectinib, and Lorlatinib), BCR-ABL inhibitors (e.g., Imatinib and Dasatinib), and EGFR inhibitors (e.g., Erlotinib, EGF816). , Afatinib, Osimertinib mesylate, Gefitinib and Rociletinib), B-Raf inhibitors (e.g. Sorafenib, Vemurafenib, TAK-580, Dabrafenib, Encorafenib, LXH254, Emurafenib and BGB-3111), VEGFR inhibitors (e.g. Bevacizumab, Apatinib, Lenvatinib, Aflibercept and Axitinib), FGFR inhibitors (e.g. AZD4547, B-701, FGF401 and INCB054828), c-Met inhibitors (e.g. Savolitinib, merestinib, Capmatinib, INC280 and Glesatinib), Axl inhibitors (e.g. , ONO-7475 and BGB324), Mek inhibitors (e.g. Cobimetinib, Binimetinib, Selumetinib and Trametinib), CDK inhibitors (e.g. Dinaciclib, Abemaciclib, Palbociclib and trilaciclib), Btk inhibitors (e.g. ONO-4059, Ibrutinib and Acalabrutinib), PI3K-δ/γ inhibitors (e.g. TGR-1202, INCB050465 and IPI-549), JAK-1/2 inhibitors (e.g. Itacitinib and Ruxolitinib), ERK inhibitors (e.g. SCH 900353), TGFbR1 inhibitors (e.g. Galunisertib), Cancer cell stemness kinase inhibitors (e.g. Amcasertib), FAK inhibitors (e.g. Defactinib), Syk/FLT3 dual inhibitors (e.g. TAK-659), ATR inhibitors (e.g. AZD6738) ), Wee1 kinase inhibitors (e.g. AZD1775), multityrosine kinase inhibitors (e.g. Sunitinib, Pazopanib, Cabozantinib, Regorafenib, Nintedanib, Sitravatinib and Midostaurin), mTOR inhibitors (e.g. Temsirolimus, Everolimus, Vistusertib, Irinotecan), HDAC inhibitors (e.g. Vorinostat, Romidepsin, Entinostat, Chidamide, Mocetinostat, Citarinostat, Panobinostat, Valproate), PARP inhibitors (e.g. Niraparib, Olaparib, Veliparib, Rucaparib, Beigene-290), aromatase inhibitors (e.g. Exemestane, Letrozole), EZH2 inhibitors (e.g. tazemetostat), galectin-3 inhibitors (e.g. GR-MD-02), STAT3 inhibitors (e.g. Napabucasin), DNMT inhibitors (e.g. Azacitidine), SMO inhibitors (e.g. , Vismodegib), Hsp90 inhibitors (e.g. XL888), γ-tubulin specific inhibitors (e.g. Glaziovianin A, Plinabulin), HIF2α inhibitors (e.g. PT2385), glutaminase inhibitors (e.g. CB-839), E3 ligase inhibitors (e.g. Avadomide), Nrf2 activators (e.g. Omaveloxolone), arginase inhibitors (e.g. CB-1158), cell cycle inhibitors (e.g. Trabectedin), Ephrin B4 inhibitors (e.g. sEphB4- HAS), IAP antagonists (e.g., Birinapant), BET protein inhibitors (e.g., CC-90010), LSD1 inhibitors (e.g., CC-90011), CRBN regulators (e.g., Avadomide), anti-Her2 antibodies (e.g., Trastuzumab , Trastuzumab emtansine, Pertuzumab and Margetuximab), anti-EGFR antibodies (e.g. Cetuximab, Panitumumab, Necitumumab and Nimotuzumab), anti-VEGF antibodies (e.g. Bevacizumab), anti-VEGFR2 antibodies (e.g. Ramucirumab), anti-CD20 antibodies (e.g. Rituximab, Ofatumumab). , Ublituximab and Obinutuzumab), anti-CD30 antibodies (e.g. Brentuximab Vedotin), anti-CD38 antibodies (e.g. Daratumumab), anti-DR5 antibodies (e.g. DS-8273a), anti-CA125 antibodies (e.g. Oregovomab), anti-DLL4 antibodies (e.g. , Demcizumab), anti-fucosyl GM1 antibodies (e.g., BMS-986012), anti-gpNMB antibodies (e.g., Glembatumumab vedotin), anti-Mesothelin antibodies (e.g., BMS-986148), anti-MMP9 antibodies (e.g., Andecaliximab), anti-GD2 antibodies ( For example, Dinutuximab-β), anti-c-Met antibodies (e.g., ABT-399), anti-FOLR1 antibodies (e.g., Mirvetuximab soravtansine), anti-Fucosyl-GM1 antibodies (e.g., BMS-986012), anti-Ang2-VEGF bispecific anti-CD30-CD16A bispecific antibody (e.g. AFM13), anti-CD79b antibody (e.g. Polatuzumab Vedotin), anti-FAP antibody/IL-2 fusion protein (e.g. RO6874281), anti-CEA Antibodies/IL-2 fusion proteins (e.g. Cergutuzumab amunaleukin), anti-CEA-CD3 bispecific antibodies (e.g. RO6958688), anti-DLL3 antibodies (e.g. Rovalpituzumab tesirine), anti-CD3-CD19 bispecific antibodies (e.g. , Blinatumomab) and anti-CD20-CD3 bispecific antibodies (eg, REGN1979).
　また、癌免疫治療薬としては、例えば、抗ＰＤ－１抗体（例えば、Nivolumab、Cemiplimab（REGN-2810）、Pembrolizumab（MK-3475）、Spartalizumab（PDR-001）、Tislelizumab（BGB-A317）、AMP-514（MEDI0680）、Dostarlimab（ANB011/TSR-042）、Toripalimab（JS001）、Camrelizumab（SHR-1210）、Genolimzumab（CBT-501）、Sintilimab（IBI308）、STI-A1110、ENUM 388D4、ENUM 244C8、GLS010、MGA012、AGEN2034、CS1003、HLX10、BAT-1306、AK105、AK103、BI 754091、LZM009、CMAB819、Sym021、GB226、SSI-361、JY034、HX008、ABBV181、BCD-100、PF-06801591、CX-188、JNJ-63723283およびAB122等）、抗ＰＤ－Ｌ１抗体（例えば、Atezolizumab（RG7446/MPDL3280A）、Avelumab（PF-06834635/MSB0010718C）、Durvalumab（MEDI4736）、BMS-936559、STI-1014、KN035、LY3300054、HLX20、SHR-1316、CS1001、MSB2311、BGB-A333、KL-A167、CK-301、AK106、AK104、ZKAB001、FAZ053、CBT-502、JS003およびCX-072等）、ＰＤ－１拮抗剤（例えば、AUNP-12、BMS-M1～BMS-M10の各化合物（WO2014/151634、WO2016/039749、WO2016/057624、WO2016/077518、WO2016/100285、WO2016/100608、WO2016/126646、WO2016/149351、WO2017/151830およびWO2017/176608参照）、BMS-1、BMS-2、BMS-3、BMS-8、BMS-37、BMS-200、BMS-202、BMS-230、BMS-242、BMS-1001およびBMS-1166（WO2015/034820、WO2015/160641、WO2017/066227およびOncotarget. 2017 Sep 22; 8(42): 72167-72181.参照）、Incyte-1～Incyte-6の各化合物（WO2017/070089、WO2017/087777、WO2017/106634、WO2017/112730、WO2017/192961およびWO2017/205464参照）、CAMC-1～CAMC-4（WO2017/202273、WO2017/202274、WO2017/202275およびWO2017/202276参照）、RG_1（WO2017/118762参照）およびDPPA-1（Angew. Chem. Int. Ed. 2015, 54, 11760-11764参照）等）、ＰＤ－Ｌ１／ＶＩＳＴＡ拮抗剤（例えば、CA-170等）、ＰＤ－Ｌ１／ＴＩＭ３拮抗剤（例えば、CA-327等）、抗ＰＤ－Ｌ２抗体、ＰＤ－Ｌ１融合タンパク質、ＰＤ－Ｌ２融合タンパク質（例えば、AMP-224等）、抗ＣＴＬＡ－４抗体（例えば、Ipilimumab（MDX-010）、AGEN1884およびTremelimumab等）、抗ＬＡＧ－３抗体（例えば、Relatlimab（BMS-986016／ONO-4482）、LAG525、REGN3767およびMK-4280等）、ＬＡＧ－３融合蛋白質（例えば、IMP321等）、抗Ｔｉｍ３抗体（例えば、MBG453、TSR-022およびBMS-986258／ONO-7807等）、抗ＫＩＲ抗体（例えば、Lirilumab（BMS-986015/ONO-4483）、IPH2101、LY3321367およびMK-4280等）、抗ＢＴＬＡ抗体、抗ＴＩＧＩＴ抗体（例えば、Tiragolumab（MTIG-7192A／RG-6058/RO-7092284）およびBMS-986207（ONO-4686等）、TIGIT二重特異性抗体、抗ＶＩＳＴＡ抗体（例えば、JNJ-61610588等）、抗ＣＤ１３７抗体（例えば、Urelumab（ONO-4481/BMS-663513）およびUtomilumab（PF-05082566）等）、抗ＣＳＦ－１Ｒ抗体・ＣＳＦ－１Ｒ阻害剤（例えば、Cabiralizumab（FPA008/BMS-986227／ONO-4687）、Emactuzumab（RG7155/RO5509554）、LY3022855、MCS-110、IMC-CS4、AMG820、Pexidartinib、BLZ945およびARRY-382等）、抗ＯＸ４０抗体（例えば、MEDI6469、PF-04518600、MEDI0562、MEDI6383、Efizonerimod、GSK3174998、BMS-986178およびMOXR0916等）、抗ＨＶＥＭ抗体、抗ＣＤ２７抗体（例えば、Varlilumab（CDX-1127）等）、抗ＧＩＴＲ抗体（例えば、MK-4166、INCAGN01876、GWN323およびTRX-518等）、抗ＣＤ２８抗体、抗ＣＣＲ４抗体（例えば、Mogamulizumab等）、抗Ｂ７－Ｈ３抗体（例えば、Enoblituzumab等）、抗ＩＣＯＳアゴニスト抗体（例えば、JTX-2011およびGSK3359609等）、抗ＣＤ４抗体（例えば、MTRX-1011A、TRX-1、Ibalizumab、huB-F5、Zanolimumab、4162W94、Clenoliximab、Keliximab、AD-519、PRO-542、Cedelizumab、TNX-355、Dacetuzumab、Tregalizumab、Priliximab、MDX-CD4、CAMPATH-9およびIT1208等）、抗ＤＥＣ－２０５抗体／ＮＹ－ＥＳＯ－１融合蛋白質（例えば、CDX-1401等）、抗ＳＬＡＭＦ７抗体（例えば、Elotuzumab等）、抗ＣＤ７３抗体（例えば、OleclumabおよびBMS-986179等）、抗ＣＤ１２２抗体（例えば、NKTR-214等）、抗ＣＤ４０アゴニスト抗体（例えば、ABBV-428、APX005MおよびRO7009789等）、ＩＤＯ阻害剤（例えば、Epacadostat、IndoximodおよびBMS-986205等）、ＴＬＲアゴニスト（例えば、Motolimod、CMP-001、G100、IMO-2125、SD-101およびMEDI9197等）、アデノシンＡ２Ａ受容体拮抗剤（例えば、Preladenant、AZD4635、PBF 509およびCPI-444等）、抗ＮＫＧ２Ａ抗体（例えば、Monalizumab等）、抗ＣＳＦ－１抗体（例えば、PD0360324等）、免疫増強剤（例えば、PV-10等）、ＩＬ－１５スーパーアゴニスト（例えば、ALT-803等）、可溶性ＬＡＧ３（例えば、IMP321等）、ＣＤ４７拮抗剤（例えば、ALX148等）抗CD47抗体（例えば、ONO-7913等）、SIRPα融合蛋白質（例えば、TTI-621、TTI-622、ALX148等）、抗CCR8抗体、ＩＬ－１２拮抗剤（例えば、M9241等）、IL-12融合蛋白質、TGFβ 受容体融合蛋白質（例えば、BMS-986416等）抗ILT4抗体（例えば、MK-4830等）、EP4拮抗剤（例えば、ONO-4578等）、STING作動薬（例えば、ONO-7914等）およびＴ細胞エンゲージャー（Blinatumomab、BRiTE等）等が挙げられる。なお、Nivolumabは、WO2006/121168に記載された方法に準じて製造することができ、Pembrolizumabは、WO2008/156712に記載された方法に準じて製造することができ、BMS-936559は、WO2007/005874に記載された方法に準じて製造することができ、Ipilimumabは、WO2001/014424に記載された方法に準じて製造することができる。 Cancer immunotherapeutic drugs include, for example, anti-PD-1 antibodies (e.g., Nivolumab, Cemiplimab (REGN-2810), Pembrolizumab (MK-3475), Spartalizumab (PDR-001), Tislelizumab (BGB-A317), AMP -514 (MEDI0680), Dostarlimab (ANB011/TSR-042), Toripalimab (JS001), Camrelizumab (SHR-1210), Genolimzumab (CBT-501), Sintilimab (IBI308), STI-A1110, ENUM 388D4, ENUM 244C8, GLS010 , MGA012, AGEN2034, CS1003, HLX10, BAT-1306, AK105, AK103, BI 754091, LZM009, CMAB819, Sym021, GB226, SSI-361, JY034, HX008, ABBV181, BCD-100, PF-06801591, CX-1 88, JNJ-63723283 and AB122, etc.), anti-PD-L1 antibodies (e.g., Atezolizumab (RG7446/MPDL3280A), Avelumab (PF-06834635/MSB0010718C), Durvalumab (MEDI4736), BMS-936559, STI-1014, KN035, LY3300054, HLX20 , SHR-1316, CS1001, MSB2311, BGB-A333, KL-A167, CK-301, AK106, AK104, ZKAB001, FAZ053, CBT-502, JS003 and CX-072, etc.), PD-1 antagonists (e.g., AUNP -12, each compound of BMS-M1 to BMS-M10 (WO2014/151634, WO2016/039749, WO2016/057624, WO2016/077518, WO2016/100285, WO2016/100608, WO2016/126646, WO2016/149351 , WO2017/151830 and (see WO2017/176608), BMS-1, BMS-2, BMS-3, BMS-8, BMS-37, BMS-200, BMS-202, BMS-230, BMS-242, BMS-1001 and BMS-1166 ( WO2015/034820, WO2015/160641, WO2017/066227 and Oncotarget. 2017 Sep 22; 8(42): 72167-72181.), Incyte-1 to Incyte-6 compounds (WO2017/070089, WO2017/087777, WO20 17 /106634, WO2017/112730, WO2017/192961 and WO2017/205464), CAMC-1 to CAMC-4 (see WO2017/202273, WO2017/20274, WO2017/202275 and WO2017/202276), RG_1 (WO2017/1 18762) and DPPA-1 (see Angew. Chem. Int. Ed. 2015, 54, 11760-11764), etc.), PD-L1/VISTA antagonists (e.g. CA-170, etc.), PD-L1/TIM3 antagonists (e.g. , CA-327, etc.), anti-PD-L2 antibodies, PD-L1 fusion proteins, PD-L2 fusion proteins (e.g., AMP-224, etc.), anti-CTLA-4 antibodies (e.g., Ipilimumab (MDX-010), AGEN1884 and Tremelimumab, etc.), anti-LAG-3 antibodies (e.g. Relatlimab (BMS-986016/ONO-4482), LAG525, REGN3767 and MK-4280, etc.), LAG-3 fusion proteins (e.g. IMP321, etc.), anti-Tim3 antibodies (e.g. , MBG453, TSR-022 and BMS-986258/ONO-7807, etc.), anti-KIR antibodies (e.g. Lililumab (BMS-986015/ONO-4483), IPH2101, LY3321367 and MK-4280, etc.), anti-BTLA antibodies, anti-TIGIT Antibodies (e.g., Tiragolumab (MTIG-7192A/RG-6058/RO-7092284) and BMS-986207 (ONO-4686, etc.), TIGIT bispecific antibody, anti-VISTA antibody (e.g., JNJ-61610588, etc.), anti-CD137 Antibodies (e.g. Urelumab (ONO-4481/BMS-663513) and Utomilumab (PF-05082566), etc.), anti-CSF-1R antibodies/CSF-1R inhibitors (e.g. Cabiralizumab (FPA008/BMS-986227/ONO-4687)) , Emactuzumab (RG7155/RO5509554), LY3022855, MCS-110, IMC-CS4, AMG820, Pexidartinib, BLZ945 and ARRY-382, etc.), anti-OX40 antibodies (e.g., MEDI6469, PF-04518600, MEDI0562, MEDI6383, Efizonerimod, GSK31 74998, BMS-986178 and MOXR0916, etc.), anti-HVEM antibodies, anti-CD27 antibodies (e.g., Varlilumab (CDX-1127), etc.), anti-GITR antibodies (e.g., MK-4166, INCAGN01876, GWN323, and TRX-518, etc.), anti-CD28 antibodies , anti-CCR4 antibodies (e.g., Mogamulizumab, etc.), anti-B7-H3 antibodies (e.g., Enoblituzumab, etc.), anti-ICOS agonist antibodies (e.g., JTX-2011 and GSK3359609, etc.), anti-CD4 antibodies (e.g., MTRX-1011A, TRX- 1, Ibalizumab, huB-F5, Zanolimumab, 4162W94, Clenoliximab, Keliximab, AD-519, PRO-542, Cedelizumab, TNX-355, Dacetuzumab, Tregalizumab, Priliximab, MDX-CD4, CAMPATH-9 and IT1208, etc.), anti-DEC -205 antibody/NY-ESO-1 fusion protein (e.g., CDX-1401, etc.), anti-SLAMF7 antibody (e.g., Elotuzumab, etc.), anti-CD73 antibody (e.g., Oleclumab and BMS-986179, etc.), anti-CD122 antibody (e.g., NKTR-214 etc.), anti-CD40 agonist antibodies (e.g. ABBV-428, APX005M and RO7009789 etc.), IDO inhibitors (e.g. Epacadostat, Indoximod and BMS-986205 etc.), TLR agonists (e.g. Motolimod, CMP-001, etc.) G100, IMO-2125, SD-101 and MEDI9197, etc.), adenosine A2A receptor antagonists (e.g. Preladenant, AZD4635, PBF 509 and CPI-444, etc.), anti-NKG2A antibodies (e.g. Monalizumab, etc.), anti-CSF-1 Antibodies (e.g., PD0360324, etc.), immune enhancers (e.g., PV-10, etc.), IL-15 superagonists (e.g., ALT-803, etc.), soluble LAG3 (e.g., IMP321, etc.), CD47 antagonists (e.g., ALX148) etc.) anti-CD47 antibodies (e.g., ONO-7913, etc.), SIRPα fusion proteins (e.g., TTI-621, TTI-622, ALX148, etc.), anti-CCR8 antibodies, IL-12 antagonists (e.g., M9241, etc.), IL- 12 fusion proteins, TGFβ receptor fusion proteins (e.g., BMS-986416, etc.), anti-ILT4 antibodies (e.g., MK-4830, etc.), EP4 antagonists (e.g., ONO-4578, etc.), STING agonists (e.g., ONO-7914) etc.) and T cell engagers (Blinatumomab, BRiTE, etc.). In addition, Nivolumab can be manufactured according to the method described in WO2006/121168, Pembrolizumab can be manufactured according to the method described in WO2008/156712, and BMS-936559 can be manufactured according to the method described in WO2007/005874. Ipilimumab can be manufactured according to the method described in WO2001/014424.
　その他の抗体医薬としては、例えば、抗ＩＬ－１β抗体（例えば、Canakinumab等）および抗ＣＣＲ２抗体（例えば、Plozalizumab等）等が挙げられる。 Examples of other antibody drugs include anti-IL-1β antibodies (eg, Canakinumab, etc.) and anti-CCR2 antibodies (eg, Plozalizumab, etc.).
　さらに、その他の癌治療としては、放射線療法、肝動脈化学塞栓療法（TACE）、肝動脈塞栓療法（TAE）、癌ワクチン（例えば合成ペプチド、ＤＮＡワクチンおよび組み換えウイルス等）および免疫細胞療法（例えば樹状細胞、ＣＡＲ－Ｔ細胞等）が挙げられる。 In addition, other cancer treatments include radiotherapy, hepatic artery chemoembolization (TACE), hepatic artery embolization (TAE), cancer vaccines (e.g., synthetic peptides, DNA vaccines, and recombinant viruses, etc.), and immune cell therapy (e.g., CAR-T cells, etc.).
［処方］
　本発明化合物等または本発明化合物と他の薬剤の併用剤を上記の目的で用いるには、通常、全身的または局所的に、経口または非経口の形で投与される。投与量は、年齢、体重、症状、治療効果、投与方法、処理時間等により異なるが、通常、成人一人当たり、一回につき、１ｎｇから２，０００ｍｇの範囲で一日一回から数回経口投与されるか、または成人一人当たり、一回につき、０．１ｎｇから２００ｍｇの範囲で一日一回から数回非経口投与されるか、または一日３０分から２４時間の範囲で静脈内に持続投与される。もちろん前記したように、投与量は種々の条件により変動するため、上記投与量より少ない量で十分な場合もあるし、また範囲を越えて投与の必要な場合もある。 [Prescription]
When using the compounds of the present invention or a combination of the compounds of the present invention and other drugs for the above-mentioned purposes, they are usually administered systemically or locally, orally or parenterally. The dosage varies depending on age, body weight, symptoms, therapeutic effects, administration method, treatment time, etc., but is usually administered orally once to several times a day in the range of 1 ng to 2,000 mg per adult. or administered parenterally once to several times a day in the range of 0.1 ng to 200 mg per adult, or continuously administered intravenously for a period of 30 minutes to 24 hours a day. be done. Of course, as mentioned above, the dosage varies depending on various conditions, so there may be cases where a smaller amount than the above-mentioned dosage is sufficient, or there may be cases where it is necessary to administer beyond the range.
［製剤］
　本発明化合物等または本発明化合物と他の薬剤の併用剤を投与する際には、経口投与用固形剤もしくは液剤、経口投与用の徐放性製剤もしくは放出制御製剤または非経口投与用の注射剤、輸液、外用剤、吸入剤もしくは坐剤等として用いられる。 [formulation]
When administering the compound of the present invention or a combination of the compound of the present invention and other drugs, solid or liquid preparations for oral administration, sustained release preparations or controlled release preparations for oral administration, or injection preparations for parenteral administration are used. It is used as an infusion, external preparation, inhaler, or suppository.
　経口投与用固形剤には、例えば、錠剤、丸剤、カプセル剤、散剤および顆粒剤等が挙げられ、カプセル剤には、ハードカプセルおよびソフトカプセル等が挙げられる。 Examples of solid preparations for oral administration include tablets, pills, capsules, powders, and granules, and examples of capsules include hard capsules and soft capsules.
　当該固形剤は、例えば、本発明化合物を薬学的に許容される担体とともに製剤化してもよい。ここで、当該固形剤の製剤化に用いられる薬学的に許容される担体としては、例えば、賦形剤（例えば、ラクトース、マンニトール、グルコース、微結晶セルロースおよびデンプン等）、結合剤（例えば、ヒドロキシプロピルセルロース、ポリビニルピロリドンおよびメタケイ酸アルミン酸マグネシウム等）、崩壊剤（例えば、繊維素グリコール酸カルシウム等）、滑沢剤（例えば、ステアリン酸マグネシウム等）、安定剤、溶解補助剤（例えば、グルタミン酸、アスパラギン酸等）等が挙げられる。また、必要によりコーティング剤（例えば、白糖、ゼラチン、ヒドロキシプロピルセルロースおよびヒドロキシプロピルメチルセルロースフタレート等）で被覆していてもよいし、または２以上の層で被覆していてもよい。さらに、ゼラチンを含有するカプセルに包含されていてもよい。 For example, the solid preparation may be prepared by formulating the compound of the present invention together with a pharmaceutically acceptable carrier. Here, examples of pharmaceutically acceptable carriers used in formulating the solid dosage form include excipients (e.g., lactose, mannitol, glucose, microcrystalline cellulose, starch, etc.), binders (e.g., hydroxy propylcellulose, polyvinylpyrrolidone, magnesium aluminate metasilicate, etc.), disintegrants (e.g., cellulose calcium glycolate, etc.), lubricants (e.g., magnesium stearate, etc.), stabilizers, solubilizing agents (e.g., glutamic acid, aspartic acid, etc.). Further, if necessary, it may be coated with a coating agent (for example, white sugar, gelatin, hydroxypropyl cellulose, hydroxypropyl methylcellulose phthalate, etc.), or it may be coated with two or more layers. Furthermore, it may be included in a capsule containing gelatin.
　経口投与用液剤には、水剤、懸濁剤、乳剤、シロップ剤およびエリキシル剤等の何れの形態であってもよく、例えば、本発明化合物を、希釈剤（例えば、精製水、エタノールまたはそれらの混液等）に溶解、懸濁または乳化し、製剤化してもよい。さらに、当該液剤は、湿潤剤、懸濁化剤、乳化剤、甘味剤、風味剤、芳香剤、保存剤または緩衝剤等を含有していてもよい。 Liquid preparations for oral administration may be in any form such as solutions, suspensions, emulsions, syrups, and elixirs. It may be dissolved, suspended, or emulsified in a mixture of (e.g., a mixture of Furthermore, the liquid preparation may contain a wetting agent, a suspending agent, an emulsifying agent, a sweetening agent, a flavoring agent, an aromatic agent, a preservative, a buffering agent, and the like.
　経口投与用の徐放性製剤は、例えば、ゲル形成物質を含んでいてもよく、当該ゲル形成物質としては、例えば、アラビアゴム、カンテン、ポリビニルピロリドン、アルギン酸ナトリウム、アルギン酸プロピレングリコールエステル、カルボキシビニルポリマー、カルボキシメチルセルロース、カルボキシメチルセルロースナトリウム、グアガム、ゼラチン、ヒドロキシプロピルメチルセルロース、ヒドロキシプロピルセルロース、ポリビニルアルコール、メチルセルロースまたはヒドロキシエチルメチルセルロース等が挙げられる。 Sustained release formulations for oral administration may contain, for example, gel-forming substances such as gum arabic, agar, polyvinylpyrrolidone, sodium alginate, propylene glycol alginate ester, carboxyvinyl polymer. , carboxymethylcellulose, sodium carboxymethylcellulose, guar gum, gelatin, hydroxypropylmethylcellulose, hydroxypropylcellulose, polyvinyl alcohol, methylcellulose or hydroxyethylmethylcellulose.
　非経口投与用の注射剤または輸液は、水溶液、懸濁液または乳濁液の何れの形態であってもよく、また、用時に溶剤（例えば、注射用蒸留水、生理食塩水、ブドウ糖溶液および等張液（例えば、塩化ナトリウム、塩化カリウム、グリセリン、マンニトール、ソルビトール、ホウ酸、ホウ砂およびプロピレングリコール等の溶液）等）を加えることにより、溶解、懸濁または乳濁して使用されるよう、薬学的に許容される担体とともに、固形剤として製剤化されていてもよい。ここで、「薬学的に許容される担体」としては、例えば、安定剤（例えば、各種アミノ酸、アルブミン、グロブリン、ゼラチン、マンニトール、グルコース、デキストラン、エチレングリコール、プロピレングリコール、ポリエチレングリコール、アスコルビン酸、亜硫酸水素ナトリウム、チオ硫酸ナトリウム、エデト酸ナトリウム、クエン酸ナトリウムおよびジブチルヒドロキシトルエン等）、溶解補助剤（例えば、アルコール（例えば、エタノール等）、ポリアルコール（例えば、プロピレングリコール、ポリエチレングリコール等）および非イオン性界面活性剤（例えば、ポリソルベート２０（登録商標）、ポリソルベート８０（登録商標）およびＨＣＯ－５０等）等）、懸濁化剤（例えば、モノステアリン酸グリセリン、モノステアリン酸アルミニウム、メチルセルロース、カルボキシメチルセルロース、ヒドロキシメチルセルロースおよびラウリル硫酸ナトリウム等）、乳化剤（例えば、アラビアゴム、アルギン酸ナトリウムおよびトラガント等）、無痛化剤（例えば、ベンジルアルコール、クロロブタノールおよびソルビトール等）、緩衝剤（例えば、リン酸緩衝液、酢酸緩衝液、ホウ酸緩衝液、炭酸緩衝液、クエン酸緩衝液、トリス緩衝液、グルタミン酸緩衝液およびイプシロンアミノカプロン酸緩衝液等）、保存剤（例えば、パラオキシ安息香酸メチル、パラオキシ安息香酸エチル、パラオキシ安息香酸プロピル、パラオキシ安息香酸ブチル、クロロブタノール、ベンジルアルコール、塩化ベンザルコニウム、デヒドロ酢酸ナトリウム、エデト酸ナトリウム、ホウ酸およびホウ砂等）、防腐剤（例えば、塩化ベンザルコニウム、パラオキシ安息香酸およびクロロブタノール等）、ｐＨ調整剤（例えば、塩酸、水酸化ナトリウム、リン酸および酢酸等）および抗酸化剤等が挙げられる。抗酸化剤として、例えば、（１）アスコルビン酸、システインハイドロクロライド、重硫酸ナトリウム、メタ重亜硫酸ナトリウムおよび亜硫酸ナトリウム等のような水溶性抗酸化剤、（２）アスコルビルパルミテート、ブチル化ハイドロキシアニソール、ブチル化ハイドロキシトルエン、レシチン、プロピルガレートおよびα－トコフェロール等のような油溶性抗酸化剤および（３）クエン酸、エチレンジアミン四酢酸、ソルビトール、酒石酸およびリン酸等のような金属キレート剤等を用いることができる。 Injections or infusions for parenteral administration may be in the form of an aqueous solution, suspension, or emulsion, and may be prepared in a solvent (e.g., distilled water for injection, physiological saline, glucose solution, etc.) before use. For use by dissolving, suspending or emulsifying by adding isotonic solutions (e.g. solutions of sodium chloride, potassium chloride, glycerin, mannitol, sorbitol, boric acid, borax and propylene glycol, etc.), It may be formulated as a solid dosage form together with a pharmaceutically acceptable carrier. Here, the "pharmaceutically acceptable carrier" includes, for example, stabilizers (e.g., various amino acids, albumin, globulin, gelatin, mannitol, glucose, dextran, ethylene glycol, propylene glycol, polyethylene glycol, ascorbic acid, sulfite). sodium hydrogen, sodium thiosulfate, sodium edetate, sodium citrate and dibutylated hydroxytoluene, etc.), solubilizing agents (e.g., alcohols (e.g., ethanol, etc.), polyalcohols (e.g., propylene glycol, polyethylene glycol, etc.) and non-ionic surfactants (for example, polysorbate 20 (registered trademark), polysorbate 80 (registered trademark), HCO-50, etc.), suspending agents (for example, glyceryl monostearate, aluminum monostearate, methylcellulose, carboxymethylcellulose) , hydroxymethylcellulose and sodium lauryl sulfate, etc.), emulsifiers (e.g., gum arabic, sodium alginate, and tragacanth, etc.), soothing agents (e.g., benzyl alcohol, chlorobutanol, and sorbitol, etc.), buffers (e.g., phosphate buffers, acetate buffer, borate buffer, carbonate buffer, citrate buffer, Tris buffer, glutamate buffer and epsilon aminocaproate buffer, etc.), preservatives (for example, methyl paraoxybenzoate, ethyl paraoxybenzoate, paraoxybenzoate, etc.) Propyl benzoate, butyl paraoxybenzoate, chlorobutanol, benzyl alcohol, benzalkonium chloride, sodium dehydroacetate, sodium edetate, boric acid and borax, etc.), preservatives (such as benzalkonium chloride, paraoxybenzoic acid and chlorobutanol, etc.), pH adjusters (for example, hydrochloric acid, sodium hydroxide, phosphoric acid, acetic acid, etc.), and antioxidants. Examples of antioxidants include (1) water-soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite, etc., (2) ascorbyl palmitate, butylated hydroxyanisole, (3) using oil-soluble antioxidants such as butylated hydroxytoluene, lecithin, propyl gallate, alpha-tocopherol, etc.; and (3) metal chelating agents such as citric acid, ethylenediaminetetraacetic acid, sorbitol, tartaric acid, phosphoric acid, etc. Can be done.
　当該注射剤または輸液は、その最終工程において滅菌するかあるいは無菌操作法、例えば、フィルター等で濾過して滅菌し、次いで無菌的な容器に充填することによって製造することができる。また、当該注射剤または輸液は、真空乾燥および凍結乾燥による無菌粉末（薬学的に許容できる担体の粉末を含んでいてもよい。）を、適切な溶剤に用時溶解して使用することもできる。 The injection or infusion can be manufactured by sterilizing it in the final step or by using an aseptic method, for example, by sterilizing it by filtration with a filter or the like, and then filling it into a sterile container. In addition, the injection or infusion can also be used by dissolving a sterile powder (which may contain a pharmaceutically acceptable carrier powder) in an appropriate solvent at the time of use by vacuum drying and lyophilization. .
　非経口投与用の外用剤の剤形には、例えば、噴霧剤、吸入剤、スプレー剤、エアゾル剤、軟膏剤、ゲル剤、クリーム剤、湿布剤、貼付剤、リニメント剤および点鼻剤等が挙げられる。 Dosage forms of external preparations for parenteral administration include, for example, aerosols, inhalants, sprays, aerosols, ointments, gels, creams, poultices, patches, liniments, and nasal sprays. Can be mentioned.
　当該噴霧剤、吸入剤およびスプレー剤は、一般的に用いられる希釈剤以外に亜硫酸水素ナトリウムのような安定剤と等張性を与えるような緩衝剤、例えば、塩化ナトリウム、クエン酸ナトリウムあるいはクエン酸のような等張剤を含有していてもよい。なお、スプレー剤の製造方法は、例えば、米国特許第２８６８６９１号および同第３０９５３５５号に詳しく記載されている。 The propellants, inhalants and sprays may contain, in addition to commonly used diluents, stabilizers such as sodium bisulfite and buffers to provide isotonic properties, such as sodium chloride, sodium citrate or citric acid. It may also contain isotonic agents such as. The method for producing the spray agent is described in detail in, for example, US Pat. No. 2,868,691 and US Pat. No. 3,095,355.
　当該吸入剤としては、吸入用液剤または吸入用粉末剤が挙げられ、当該液剤は、用時に水または他の適当な媒体に溶解または懸濁させて使用する形態であってもよい。これらの吸入剤は公知の方法に準じて製造され、例えば、吸入用液剤の場合には、防腐剤（例えば、塩化ベンザルコニウムおよびパラベン等）、着色剤、緩衝化剤（例えば、リン酸ナトリウムおよび酢酸ナトリウム等）、等張化剤（例えば、塩化ナトリウムおよび濃グリセリン等）、増粘剤（例えば、カルボキシビニルポリマー等）および吸収促進剤等を必要に応じて適宜混合して調製され、一方、吸入用粉末剤の場合には、滑沢剤（例えば、ステアリン酸およびその塩等）、結合剤（例えば、デンプンおよびデキストリン等）、賦形剤（例えば、乳糖およびセルロース等）、着色剤、防腐剤（例えば、塩化ベンザルコニウムおよびパラベン等）および吸収促進剤等を必要に応じて適宜混合して調製される。吸入用液剤を投与する際には、通常噴霧器（例えば、アトマイザーおよびネブライザー等）が使用され、一方、吸入用粉末剤を投与する際には、通常、粉末薬剤用吸入投与器が使用される。 Examples of such inhalants include liquid formulations for inhalation and powder formulations for inhalation, and the liquid formulation may be in the form of being dissolved or suspended in water or other appropriate medium before use. These inhalants are manufactured according to known methods, and for example, in the case of inhalable liquid preparations, preservatives (e.g. benzalkonium chloride and parabens, etc.), coloring agents, buffering agents (e.g. sodium phosphate), etc. and sodium acetate, etc.), isotonic agents (e.g., sodium chloride and concentrated glycerin, etc.), thickeners (e.g., carboxyvinyl polymers, etc.), absorption enhancers, etc., as necessary. , in the case of powders for inhalation, lubricants (for example, stearic acid and its salts, etc.), binders (for example, starch and dextrins, etc.), excipients (for example, lactose and cellulose, etc.), colorants, It is prepared by appropriately mixing a preservative (for example, benzalkonium chloride, paraben, etc.), an absorption enhancer, etc. as necessary. When administering liquid drugs for inhalation, nebulizers (eg, atomizers, nebulizers, etc.) are usually used, while when administering powder drugs for inhalation, powdered drug inhalation administrators are usually used.
　当該軟膏剤は、公知または通常使用されている処方により調製され、例えば、本発明化合物を軟膏基剤に混和または溶融させて調製される。ここで、軟膏基剤は、公知あるいは通常使用されているものから選ばれ、例えば、高級脂肪酸または高級脂肪酸エステル（例えば、アジピン酸、ミリスチン酸、パルミチン酸、ステアリン酸、オレイン酸、アジピン酸エステル、ミリスチン酸エステル、パルミチン酸エステル、ステアリン酸エステルおよびオレイン酸エステル等）、ロウ類（例えば、ミツロウ、鯨ロウおよびセレシン等）、界面活性剤（例えば、ポリオキシエチレンアルキルエーテルリン酸エステル等）、高級アルコール（例えば、セタノール、ステアリルアルコールおよびセトステアリルアルコール等）、シリコン油（例えば、ジメチルポリシロキサン等）、炭化水素類（例えば、親水ワセリン、白色ワセリン、精製ラノリンおよび流動パラフィン等）、グリコール類（例えば、エチレングリコール、ジエチレングリコール、プロピレングリコール、ポリエチレングリコールおよびマクロゴール等）、植物油（例えば、ヒマシ油、オリーブ油、ごま油およびテレピン油等）、動物油（例えば、ミンク油、卵黄油、スクワランおよびスクワレン等）、水、吸収促進剤またはかぶれ防止剤から選ばれる１種以上を混合して用いられる。さらに、保湿剤、保存剤、安定化剤、抗酸化剤または着香剤等を含んでいてもよい。 The ointment is prepared according to a known or commonly used formulation, for example, by mixing or melting the compound of the present invention in an ointment base. Here, the ointment base is selected from those known or commonly used, such as higher fatty acids or higher fatty acid esters (e.g., adipic acid, myristic acid, palmitic acid, stearic acid, oleic acid, adipic acid ester, myristic acid esters, palmitic acid esters, stearic acid esters, oleic acid esters, etc.), waxes (e.g., beeswax, spermaceti, ceresin, etc.), surfactants (e.g., polyoxyethylene alkyl ether phosphates, etc.), high grade Alcohols (e.g., cetanol, stearyl alcohol, cetostearyl alcohol, etc.), silicone oils (e.g., dimethylpolysiloxane, etc.), hydrocarbons (e.g., hydrophilic petrolatum, white petrolatum, purified lanolin, liquid paraffin, etc.), glycols (e.g. , ethylene glycol, diethylene glycol, propylene glycol, polyethylene glycol and macrogol, etc.), vegetable oils (such as castor oil, olive oil, sesame oil and turpentine oil, etc.), animal oils (such as mink oil, egg yolk oil, squalane and squalene, etc.), water. , an absorption enhancer, or an anti-rash agent. Furthermore, it may contain a humectant, a preservative, a stabilizer, an antioxidant, a flavoring agent, and the like.
　ゲル剤は、公知または通常使用されている処方により調製され、例えば、本発明化合物をゲル基剤に溶融させて調製される。ここで、ゲル基剤は、公知あるいは通常使用されているものから選ばれ、例えば、低級アルコール（例えば、エタノールおよびイソプロピルアルコール等）、ゲル化剤（例えば、カルボキシメチルセルロース、ヒドロキシエチルセルロース、ヒドロキシプロピルセルロースおよびエチルセルロース等）、中和剤（例えば、トリエタノールアミンおよびジイソプロパノールアミン等）、界面活性剤（例えば、モノステアリン酸ポリエチレングリコール等）、ガム類、水、吸収促進剤およびかぶれ防止剤から選ばれる１種以上を混合して用いられる。さらに、保存剤、抗酸化剤または着香剤等を含んでいてもよい。 The gel is prepared according to a known or commonly used formulation, for example, by melting the compound of the present invention in a gel base. Here, the gel base is selected from those known or commonly used, such as lower alcohols (e.g., ethanol and isopropyl alcohol, etc.), gelling agents (e.g., carboxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, etc.). ethyl cellulose, etc.), neutralizing agents (e.g., triethanolamine and diisopropanolamine, etc.), surfactants (e.g., polyethylene glycol monostearate, etc.), gums, water, absorption enhancers, and anti-rash agents. It is used by mixing more than one species. Furthermore, it may contain a preservative, an antioxidant, a flavoring agent, etc.
　クリーム剤は、公知または通常使用されている処方により調製され、例えば、本発明化合物をクリーム基剤に溶融または乳化させて製造される。ここで、クリーム基剤は、公知あるいは通常使用されているものから選ばれ、例えば、高級脂肪酸エステル、低級アルコール、炭化水素類、多価アルコール（例えば、プロピレングリコールおよび１，３－ブチレングリコール等）、高級アルコール（例えば、２－ヘキシルデカノールおよびセタノール等）、乳化剤（例えば、ポリオキシエチレンアルキルエーテル類および脂肪酸エステル類等）、水、吸収促進剤およびかぶれ防止剤から選ばれる１種以上を混合して用いられる。さらに、保存剤、抗酸化剤または着香剤等を含んでいてもよい。 Creams are prepared according to known or commonly used formulations, for example, by melting or emulsifying the compound of the present invention in a cream base. Here, the cream base is selected from those known or commonly used, such as higher fatty acid esters, lower alcohols, hydrocarbons, and polyhydric alcohols (such as propylene glycol and 1,3-butylene glycol). , higher alcohols (e.g., 2-hexyldecanol and cetanol, etc.), emulsifiers (e.g., polyoxyethylene alkyl ethers and fatty acid esters, etc.), water, absorption enhancers, and anti-rash agents. used. Furthermore, it may contain a preservative, an antioxidant, a flavoring agent, etc.
　湿布剤は、公知または通常使用されている処方により調製され、例えば、本発明化合物を湿布基剤に溶融させ、練合物とし支持体上に展延塗布して調製される。ここで、湿布基剤は、公知あるいは通常使用されているものから選ばれ、例えば、増粘剤（例えば、ポリアクリル酸、ポリビニルピロリドン、アラビアゴム、デンプン、ゼラチンおよびメチルセルロース等）、湿潤剤（例えば、尿素、グリセリンおよびプロピレングリコール等）、充填剤（例えば、カオリン、酸化亜鉛、タルク、カルシウムおよびマグネシウム等）、水、溶解補助剤、粘着付与剤およびかぶれ防止剤から選ばれる１種以上を混合して用いられる。さらに、保存剤、抗酸化剤または着香剤等を含んでいてもよい。 A poultice is prepared according to a known or commonly used formulation, for example, by melting the compound of the present invention in a poultice base, making a mixture, and spreading the mixture onto a support. Here, the poultice base is selected from those known or commonly used, such as thickeners (e.g., polyacrylic acid, polyvinylpyrrolidone, gum arabic, starch, gelatin, methyl cellulose, etc.), wetting agents (e.g. , urea, glycerin, propylene glycol, etc.), fillers (e.g., kaolin, zinc oxide, talc, calcium, magnesium, etc.), water, solubilizing agents, tackifiers, and anti-rash agents. It is used as Furthermore, it may contain a preservative, an antioxidant, a flavoring agent, etc.
　貼付剤は、公知または通常使用されている処方により調製され、例えば、本発明化合物を貼付剤用基剤に溶融させ、支持体上に展延塗布して調製される。ここで、貼付剤用基剤は、公知あるいは通常使用されているものから選ばれ、例えば、高分子基剤、油脂、高級脂肪酸、粘着付与剤およびかぶれ防止剤から選ばれる１種以上を混合して用いられる。さらに、保存剤、抗酸化剤または着香剤等を含んでいてもよい。 The patch is prepared according to a known or commonly used formulation, for example, by melting the compound of the present invention in a patch base and spreading the mixture onto a support. Here, the base for the patch is selected from those known or commonly used, for example, a mixture of one or more selected from polymer bases, oils and fats, higher fatty acids, tackifiers, and anti-rash agents. It is used as Furthermore, it may contain a preservative, an antioxidant, a flavoring agent, etc.
　リニメント剤は、公知または通常使用されている処方により調製され、例えば、本発明化合物を、水、アルコール（例えば、エタノールおよびポリエチレングリコール等）、高級脂肪酸、グリセリン、セッケン、乳化剤および懸濁化剤等から選ばれる１種以上に溶解、懸濁または乳化させて調製される。さらに、保存剤、抗酸化剤または着香剤等を含んでいてもよい。 The liniment agent is prepared according to a known or commonly used formulation, for example, the compound of the present invention is mixed with water, alcohol (such as ethanol and polyethylene glycol), higher fatty acids, glycerin, soap, emulsifying agents, suspending agents, etc. It is prepared by dissolving, suspending or emulsifying in one or more selected from the following. Furthermore, it may contain a preservative, an antioxidant, a flavoring agent, etc.
　他に定義されない限り、本明細書中で使用される全ての技術的、科学的用語、および略語は、本発明の分野に属する当業者によって普通に理解されるものと同様の意味を有する。 Unless otherwise defined, all technical and scientific terms and abbreviations used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.
　本発明は、一態様において、下記の実施態様を提供する。 In one aspect, the present invention provides the following embodiments.
［１］
　一般式（ＩＹ）
 [1]
General formula (IY)
（式中、Ｒ１は、（１）１～５個のＲ１１で置換されていてもよい３～１５員の炭素環で置換されたメチレン、（２）１～５個のＲ１２で置換されていてもよい３～１５員の複素環で置換されたメチレン、（３）１～５個のＲ１３で置換されていてもよいＣ２～４アルケニル基で置換されたメチレン、または（４）１～５個のＲ１４で置換されていてもよいＣ２～４アルキニル基で置換されたメチレンを表わし、
Ｒ１１、Ｒ１２、Ｒ１３およびＲ１４は、それぞれ独立して、（１）ハロゲン、（２）Ｃ１～４アルキル基、（３）Ｃ１～４アルコキシ基、（４）Ｃ１～４ハロアルキル基、（５）Ｃ１～４ハロアルコキシ基、または（６）シアノ基を表わし、複数のＲ１１、Ｒ１２、Ｒ１３およびＲ１４は、それぞれ同じでも異なっていてもよく、
Ｒ２は、（１）１～５個のＲ１５で置換されていてもよい３～１５員の複素環、（２）１～５個のＲ１６で置換されていてもよい３～１５員の炭素環、または（３）１～５個のＲ１７で置換されていてもよいＣ１～４アルキル基を表わし、
Ｒ１５、Ｒ１６およびＲ１７は、それぞれ独立して、
（１）１～５個のＲ１８で置換されていてもよいＣ３～６シクロアルキル基で置換されていてもよいＣ１～８アルキル基、（２）（Ｃ１～８アルキル）カルボニル基、（３）１～５個のＲ１９で置換された（Ｃ３～６シクロアルキル）カルボニル基、（４）Ｃ１～８ハロアルキル基、（５）５～６員の炭素環、（６）５～６員の複素環、（７）Ｃ１～４アルキルスルホニル基、（８）Ｃ２～４アルケニルスルホニル基、（９）Ｃ１～４アルコキシカルボニル基、（１０）Ｃ１～４ハロアルキルアミノ基、（１１）ｔ－ブチルオキシカルボニルアミノ基、または（１２）５，５－ジメチル－２，４－ジオキソオキサゾリジン－３－イル基を表わし、
複数のＲ１５、Ｒ１６およびＲ１７は、それぞれ同じでも異なっていてもよく、
Ｒ１８およびＲ１９は、それぞれ独立して、（１）ハロゲン、（２）Ｃ１～４アルキル基、（３）Ｃ１～４アルコキシ基、（４）Ｃ１～４ハロアルキル基、（５）Ｃ１～４ハロアルコキシ基、または（６）シアノ基を表わし、
複数のＲ１８およびＲ１９は、それぞれ同じでも異なっていてもよく、
Ｒ３Ｙは、（１）水素原子、（２）ハロゲン、（３）Ｃ１～４アルキル基、（４）Ｃ１～４アルコキシ基、（５）Ｃ１～４ハロアルキル基、（６）Ｃ１～４ハロアルコキシ基、（７）シアノ基、（８）１～５個のＲ２０Ｙで置換されていてもよい３～１５員の炭素環、（９）１～５個のＲ２１Ｙで置換されていてもよい３～１５員の複素環、（１０）－ＮＲ２２Ｒ２３、（１１）－ＯＲ２４、（１２）－ＣＯＮＲ２５Ｒ２６、（１３）（Ｃ１～８アルキル）カルボニル基、（１４）１～３個の水酸基で置換されたＣ１～４アルキル基、または（１５）１－（ヒドロキシイミノ）エチル基を表わし、
Ｒ２０ＹおよびＲ２１Ｙは、それぞれ独立して、（１）１～５個のＲ２７Ｙで置換されていてもよいＣ１～４アルキル基、（２）ハロゲン、（３）１～５個のＲ２８Ｙで置換されていてもよいＣ３～６シクロアルキル基、（４）１～５個のＲ２７－１Ｙで置換されていてもよいＣ１～４アルコキシ基、（５）水酸基、（６）カルバモイル基、（７）カルボキシル基、または（８）シアノ基を表わし、
複数のＲ２０ＹおよびＲ２１Ｙは、それぞれ同じでも異なっていてもよく、
Ｒ２７Ｙ、Ｒ２７－１ＹおよびＲ２８Ｙは、それぞれ独立して、（１）ハロゲン、（２）Ｃ１～４アルキル基、（３）Ｃ１～４アルコキシ基、（４）Ｃ１～４ハロアルキル基、（５）Ｃ１～４ハロアルコキシ基、（６）水酸基、（７）カルバモイル基、（８）カルボキシル基、（９）Ｃ１～４アルコキシカルボニル基、または（１０）シアノ基を表わし、
複数のＲ２７Ｙ、Ｒ２７－１ＹおよびＲ２８Ｙは、それぞれ同じでも異なっていてもよく、
Ｒ２２、Ｒ２３およびＲ２４は、それぞれ独立して、（１）水素原子、（２）１～５個のＲ２９で置換されていてもよいＣ１～８アルキル基、（３）１～５個のＲ２９－１で置換されていてもよいＣ２～４アルケニル基、（４）１～５個のＲ２９－２で置換されていてもよいＣ２～４アルキニル基、（５）１～５個のＲ３０で置換されていてもよい３～１５員の炭素環、または（６）１～５個のＲ３１で置換されていてもよい３～１５員の複素環を表わし、
Ｒ２９、Ｒ２９－１、Ｒ２９－２、Ｒ３０およびＲ３１は、それぞれ独立して、
（１）１～５個のＲ３２で置換されていてもよいＣ１～４アルキル基、（２）ハロゲン、（３）１～５個のＲ３３で置換されていてもよいＣ３～８シクロアルキル基、（４）１～５個のＲ３４で置換されていてもよい５～６員の炭素環、（５）１～５個のＲ３５で置換されていてもよい５～６員の複素環、（６）１～５個のＲ３２－１で置換されていてもよいＣ１～４アルコキシ基、（７）水酸基、（８）カルバモイル基、（９）カルボキシル基、または（１０）シアノ基を表わし、
複数のＲ２９、Ｒ２９－１、Ｒ２９－２、Ｒ３０およびＲ３１は、それぞれ同じでも異なっていてもよく、
Ｒ３２、Ｒ３２－１、Ｒ３３、Ｒ３４およびＲ３５は、それぞれ独立して、（１）ハロゲン、（２）Ｃ１～４アルキル基、（３）Ｃ１～４アルコキシ基、（４）Ｃ１～４ハロアルキル基、（５）Ｃ１～４ハロアルコキシ基、（６）水酸基、（７）カルバモイル基、（８）カルボキシル基、または（９）シアノ基を表わし、
複数のＲ３２、Ｒ３２－１、Ｒ３３、Ｒ３４およびＲ３５は、それぞれ同じでも異なっていてもよく、
Ｒ２５およびＲ２６は、それぞれ独立して、（１）水素原子、（２）１～５個のＲ３６で置換されていてもよいＣ１～８アルキル基、（３）１～５個のＲ３６－１で置換されていてもよいＣ２～４アルケニル基、（４）１～５個のＲ３６－２で置換されていてもよいＣ２～４アルキニル基、（５）１～５個のＲ３７で置換されていてもよい３～１５員の炭素環、または（６）１～５個のＲ３８で置換されていてもよい３～１５員の複素環を表わし、
Ｒ３６、Ｒ３６－１、Ｒ３６－２、Ｒ３７およびＲ３８は、それぞれ独立して、（１）Ｃ１～４アルキル基、（２）ハロゲン、（３）Ｃ３～８シクロアルキル基、（４）５～６員の炭素環、（５）５～６員の複素環、（６）Ｃ１～４アルコキシ基、（７）Ｃ１～４ハロアルキル基、（８）Ｃ１～４ハロアルコキシ基、（９）水酸基、（１０）カルボキシル基、（１１）カルバモイル基、または（１２）シアノ基を表わし、
複数のＲ３６、Ｒ３６－１、Ｒ３６－２、Ｒ３７およびＲ３８は、それぞれ同じでも異なっていてもよく、
Ｒ４は、（１）ハロゲン、（２）Ｃ１～４アルキル基、（３）Ｃ１～４アルコキシ基、（４）Ｃ１～４ハロアルキル基、（５）Ｃ１～４ハロアルコキシ基、（６）水酸基、または（７）シアノ基を表わし、
Ｒ５は、（１）ハロゲン、（２）Ｃ１～４アルキル基、（３）Ｃ１～４アルコキシ基、（４）Ｃ１～４ハロアルキル基、（５）Ｃ１～４ハロアルコキシ基、（６）水酸基、または（７）シアノ基を表わし、
ｒｉｎｇＹは、
（右の矢印は窒素原子と結合し、左の矢印はカルボニル基と結合する。）、または、１～６個のＲＹで置換されていてもよい、飽和または一部不飽和の４～１０員の炭素環、または、１～６個のＲＹで置換されていてもよい、１個の窒素原子、１個の酸素原子および／または酸化されていてもよい１個の硫黄原子を含有する６員の飽和複素環を表わし、ＲＹは、（１）ハロゲン、（２）Ｃ１～４アルキル基、（３）Ｃ１～４アルコキシ基、（４）Ｃ１～４ハロアルキル基、（５）Ｃ１～４ハロアルコキシ基、（６）水酸基、（７）オキソ基、または（８）シアノ基を表わし、
ＲＹが複数の場合、各ＲＹは同じでも異なっていてもよく、
Ｘは、窒素原子、またはＣＲ７を表わし、
Ｘ１、Ｘ２、およびＸ３は、それぞれ独立して、窒素原子、ＣＨ、またはＣＲ６を表わし、
Ｒ６は、（１）ハロゲン、（２）Ｃ１～４アルキル基、（３）Ｃ１～４アルコキシ基、（４）Ｃ１～４ハロアルキル基、（５）Ｃ１～４ハロアルコキシ基、（６）水酸基、または（７）シアノ基を表わし、
Ｒ６が複数の場合、各Ｒ６は同じでも異なっていてもよく、
Ｙ１は、窒素原子、またはＣＲ８を表わし、
Ｙ２は、窒素原子、またはＣＲ９を表わし、
Ｙ３は、窒素原子、またはＣＲ１０Ｙを表わし、
Ｒ７は、（１）水素原子、（２）ハロゲン、（３）Ｃ１～４アルキル基、（４）Ｃ１～４アルコキシ基、（５）Ｃ１～４ハロアルキル基、または（６）Ｃ１～４ハロアルコキシ基を表わし、
Ｒ８は、（１）水素原子、（２）ハロゲン、（３）Ｃ１～４アルキル基、（４）Ｃ１～４アルコキシ基、（５）Ｃ１～４ハロアルキル基、または（６）Ｃ１～４ハロアルコキシ基を表わし、
Ｒ９は、（１）水素原子、（２）ハロゲン、（３）Ｃ１～４アルキル基、（４）Ｃ１～４アルコキシ基、（５）Ｃ１～４ハロアルキル基、または（６）Ｃ１～４ハロアルコキシ基を表わし、
Ｒ１０Ｙは、（１）水素原子、（２）ハロゲン、（３）Ｃ１～４アルキル基、（４）Ｃ１～４アルコキシ基、（５）Ｃ１～４ハロアルキル基、（６）Ｃ１～４ハロアルコキシ基、（７）水酸基、（８）アミノ基、（９）カルボキシル基、（１０）カルバモイル基、（１１）（Ｃ１～４アルキル）アミノカルボニル基、（１２）ジ－（Ｃ１～４アルキル）アミノカルボニル基、（１３）－ＣＯ－（３～６員の飽和複素環）、（１４）－ＣＯＮＨＲ３９、（１５）Ｃ１～４アルコキシカルボニル基、または（１６）シアノ基を表わし、
Ｒ３９は、（１）シアノ基で置換されたＣ１～４アルキル基、（２）Ｃ１～４アルコキシ基、（３）Ｃ１～４ハロアルキル基、（４）Ｃ１～４ハロアルコキシ基、（５）水酸基、（６）アミノ基、（７）（Ｃ１～４アルキル）アミノ基、（８）ジ－（Ｃ１～４アルキル）アミノ基、（９）１～５個のＲ４０で置換されていてもよいＣ３～６シクロアルキル基、または（１０）１～５個のＲ４１で置換されていてもよい３～６員の飽和複素環を表わし、
Ｒ４０およびＲ４１は、それぞれ独立して、（１）ハロゲン、（２）Ｃ１～４アルキル基、（３）Ｃ１～４アルコキシ基、（４）Ｃ１～４ハロアルキル基、または（５）Ｃ１～４ハロアルコキシ基を表わし、
複数のＲ４０およびＲ４１は、それぞれ同じでも異なっていてもよく、
ｒは、０～３の整数を表わし、複数のＲ４は同じでも異なっていてもよく、
ｓは、０～３の整数を表わし、複数のＲ５は同じでも異なっていてもよい。
ここで、各水素原子は、重水素原子、または三重水素原子であってもよい。）で示される化合物、またはその塩； (In the formula, R 1 is (1) methylene substituted with a 3- to 15-membered carbon ring optionally substituted with 1 to 5 R 11 , (2) substituted with 1 to 5 R 12 (3) Methylene substituted with a C2-4 alkenyl group optionally substituted with 1 to 5 R13 , or (4) Represents methylene substituted with a C2-4 alkynyl group optionally substituted with 1 to 5 R14 ,
R 11 , R 12 , R 13 and R 14 each independently represent (1) halogen, (2) C1-4 alkyl group, (3) C1-4 alkoxy group, (4) C1-4 haloalkyl group, (5) represents a C1-4 haloalkoxy group, or (6) a cyano group, and a plurality of R 11 , R 12 , R 13 and R 14 may be the same or different, respectively;
R 2 is (1) a 3- to 15 -membered heterocycle optionally substituted with 1 to 5 R 15s, (2) a 3- to 15-membered heterocycle optionally substituted with 1 to 5 R 16 or (3) a C1-4 alkyl group optionally substituted with 1 to 5 R17 ;
R 15 , R 16 and R 17 are each independently,
(1) a C1-8 alkyl group optionally substituted with a C3-6 cycloalkyl group optionally substituted with 1-5 R18, (2) a (C1-8 alkyl)carbonyl group, (3 ) (C3-6 cycloalkyl) carbonyl group substituted with 1 to 5 R 19 , (4) C1-8 haloalkyl group, (5) 5- to 6-membered carbon ring, (6) 5- to 6-membered carbocyclic Heterocycle, (7) C1-4 alkylsulfonyl group, (8) C2-4 alkenylsulfonyl group, (9) C1-4 alkoxycarbonyl group, (10) C1-4 haloalkylamino group, (11) t-butyloxy Represents a carbonylamino group or (12) 5,5-dimethyl-2,4-dioxoxazolidin-3-yl group,
A plurality of R 15 , R 16 and R 17 may be the same or different,
R 18 and R 19 each independently represent (1) halogen, (2) C1-4 alkyl group, (3) C1-4 alkoxy group, (4) C1-4 haloalkyl group, (5) C1-4 represents a haloalkoxy group or (6) a cyano group,
A plurality of R 18 and R 19 may be the same or different,
R 3Y is (1) hydrogen atom, (2) halogen, (3) C1-4 alkyl group, (4) C1-4 alkoxy group, (5) C1-4 haloalkyl group, (6) C1-4 haloalkoxy group, (7) a cyano group, (8) a 3- to 15-membered carbon ring optionally substituted with 1 to 5 R 20Y , (9) optionally substituted with 1 to 5 R 21Y 3- to 15-membered heterocycle, (10)-NR 22 R 23 , (11)-OR 24 , (12)-CONR 25 R 26 , (13) (C1-8 alkyl) carbonyl group, (14) 1- Represents a C1-4 alkyl group substituted with three hydroxyl groups, or (15) 1-(hydroxyimino)ethyl group,
R 20Y and R 21Y each independently represent (1) a C1-4 alkyl group optionally substituted with 1 to 5 R 27Y , (2) halogen, (3) 1 to 5 R 28Y (4) C1-4 alkoxy group optionally substituted with 1 to 5 R 27-1Y , (5) hydroxyl group, (6) carbamoyl group, (7) represents a carboxyl group, or (8) a cyano group,
A plurality of R 20Y and R 21Y may be the same or different,
R 27Y , R 27-1Y and R 28Y each independently represent (1) halogen, (2) C1-4 alkyl group, (3) C1-4 alkoxy group, (4) C1-4 haloalkyl group, ( 5) represents a C1-4 haloalkoxy group, (6) a hydroxyl group, (7) a carbamoyl group, (8) a carboxyl group, (9) a C1-4 alkoxycarbonyl group, or (10) a cyano group,
A plurality of R 27Y , R 27-1Y and R 28Y may be the same or different,
R 22 , R 23 and R 24 each independently represent (1) a hydrogen atom, (2) a C1-8 alkyl group optionally substituted with 1 to 5 R 29s , (3) 1 to 5 (4) C2-4 alkynyl group optionally substituted with 1 to 5 R 29-2 , (5) 1 to 5 ( 6 ) a 3- to 15-membered heterocycle optionally substituted with 1 to 5 R 31 ;
R 29 , R 29-1 , R 29-2 , R 30 and R 31 are each independently,
(1) C1-4 alkyl group optionally substituted with 1-5 R 32 , (2) halogen, (3) C3-8 cycloalkyl optionally substituted with 1-5 R 33 group, (4) a 5- to 6-membered carbocyclic ring optionally substituted with 1 to 5 R 34s , (5) a 5- to 6-membered heterocyclic ring optionally substituted with 1 to 5 R 35 ring, (6) C1-4 alkoxy group optionally substituted with 1 to 5 R 32-1 , (7) hydroxyl group, (8) carbamoyl group, (9) carboxyl group, or (10) cyano group represents,
A plurality of R 29 , R 29-1 , R 29-2 , R 30 and R 31 may be the same or different,
R 32 , R 32-1 , R 33 , R 34 and R 35 each independently represent (1) halogen, (2) C1-4 alkyl group, (3) C1-4 alkoxy group, (4) C1 ~4 haloalkyl group, (5) C1~4 haloalkoxy group, (6) hydroxyl group, (7) carbamoyl group, (8) carboxyl group, or (9) cyano group,
A plurality of R 32 , R 32-1 , R 33 , R 34 and R 35 may be the same or different,
R 25 and R 26 each independently represent (1) a hydrogen atom, (2) a C1-8 alkyl group optionally substituted with 1 to 5 R 36 , (3) 1 to 5 R 36 C2-4 alkenyl group optionally substituted with 36-1 , (4) 1-5 R C2-4 alkynyl group optionally substituted with 36-2 , (5) 1-5 R Represents a 3- to 15-membered carbocycle optionally substituted with 37, or (6) a 3- to 15-membered heterocycle optionally substituted with 1 to 5 R 38 ,
R 36 , R 36-1 , R 36-2 , R 37 and R 38 each independently represent (1) a C1-4 alkyl group, (2) a halogen, (3) a C3-8 cycloalkyl group, ( 4) 5-6 membered carbocycle, (5) 5-6 membered heterocycle, (6) C1-4 alkoxy group, (7) C1-4 haloalkyl group, (8) C1-4 haloalkoxy group, ( 9) represents a hydroxyl group, (10) a carboxyl group, (11) a carbamoyl group, or (12) a cyano group,
A plurality of R 36 , R 36-1 , R 36-2 , R 37 and R 38 may be the same or different,
R 4 is (1) halogen, (2) C1-4 alkyl group, (3) C1-4 alkoxy group, (4) C1-4 haloalkyl group, (5) C1-4 haloalkoxy group, (6) hydroxyl group , or (7) represents a cyano group,
R 5 is (1) halogen, (2) C1-4 alkyl group, (3) C1-4 alkoxy group, (4) C1-4 haloalkyl group, (5) C1-4 haloalkoxy group, (6) hydroxyl group , or (7) represents a cyano group,
ringY is
(The arrow on the right bonds to the nitrogen atom, the arrow on the left bonds to the carbonyl group.), or a saturated or partially unsaturated 4-10, optionally substituted with 1-6 R Y containing 1 nitrogen atom, 1 oxygen atom and/or 1 sulfur atom which may be oxidized, optionally substituted with a membered carbocyclic ring, or 1 to 6 R Y Represents a 6-membered saturated heterocycle, R Y is (1) halogen, (2) C1-4 alkyl group, (3) C1-4 alkoxy group, (4) C1-4 haloalkyl group, (5) C1-4 alkyl group. 4-haloalkoxy group, (6) hydroxyl group, (7) oxo group, or (8) cyano group,
When there is a plurality of R Y , each R Y may be the same or different;
X represents a nitrogen atom or CR7 ,
X 1 , X 2 , and X 3 each independently represent a nitrogen atom, CH, or CR 6 ,
R 6 is (1) halogen, (2) C1-4 alkyl group, (3) C1-4 alkoxy group, (4) C1-4 haloalkyl group, (5) C1-4 haloalkoxy group, (6) hydroxyl group , or (7) represents a cyano group,
When there is a plurality of R 6 s, each R 6 may be the same or different;
Y 1 represents a nitrogen atom or CR 8 ,
Y2 represents a nitrogen atom or CR9 ,
Y 3 represents a nitrogen atom or CR 10Y ,
R 7 is (1) hydrogen atom, (2) halogen, (3) C1-4 alkyl group, (4) C1-4 alkoxy group, (5) C1-4 haloalkyl group, or (6) C1-4 halo represents an alkoxy group,
R 8 is (1) hydrogen atom, (2) halogen, (3) C1-4 alkyl group, (4) C1-4 alkoxy group, (5) C1-4 haloalkyl group, or (6) C1-4 halo represents an alkoxy group,
R 9 is (1) hydrogen atom, (2) halogen, (3) C1-4 alkyl group, (4) C1-4 alkoxy group, (5) C1-4 haloalkyl group, or (6) C1-4 halo represents an alkoxy group,
R 10Y is (1) hydrogen atom, (2) halogen, (3) C1-4 alkyl group, (4) C1-4 alkoxy group, (5) C1-4 haloalkyl group, (6) C1-4 haloalkoxy group, (7) hydroxyl group, (8) amino group, (9) carboxyl group, (10) carbamoyl group, (11) (C1-4 alkyl)aminocarbonyl group, (12) di-(C1-4 alkyl)amino Represents a carbonyl group, (13) -CO- (3- to 6-membered saturated heterocycle), (14) -CONHR 39 , (15) C1-4 alkoxycarbonyl group, or (16) cyano group,
R 39 is (1) a C1-4 alkyl group substituted with a cyano group, (2) a C1-4 alkoxy group, (3) a C1-4 haloalkyl group, (4) a C1-4 haloalkoxy group, (5) Even if substituted with hydroxyl group, (6) amino group, (7) (C1-4 alkyl) amino group, (8) di-(C1-4 alkyl) amino group, (9) 1-5 R 40 (10) a 3- to 6-membered saturated heterocycle optionally substituted with 1 to 5 R 41 ;
R 40 and R 41 are each independently (1) halogen, (2) C1-4 alkyl group, (3) C1-4 alkoxy group, (4) C1-4 haloalkyl group, or (5) C1-4 represents a 4-haloalkoxy group,
A plurality of R 40 and R 41 may be the same or different,
r represents an integer from 0 to 3, and multiple R 4 may be the same or different;
s represents an integer from 0 to 3, and plural R 5s may be the same or different.
Here, each hydrogen atom may be a deuterium atom or a tritium atom. ) or a salt thereof;
［２］　一般式（Ｉ）
（式中、
Ｒ１は、（１）１～５個のＲ１１で置換されていてもよい３～１５員の炭素環で置換されたメチレン、（２）１～５個のＲ１２で置換されていてもよい３～１５員の複素環で置換されたメチレン、（３）１～５個のＲ１３で置換されていてもよいＣ２～４アルケニル基で置換されたメチレン、または（４）１～５個のＲ１４で置換されていてもよいＣ２～４アルキニル基で置換されたメチレンを表わし、
Ｒ１１、Ｒ１２、Ｒ１３およびＲ１４は、それぞれ独立して、（１）ハロゲン、（２）Ｃ１～４アルキル基、（３）Ｃ１～４アルコキシ基、（４）Ｃ１～４ハロアルキル基、（５）Ｃ１～４ハロアルコキシ基、または（６）シアノ基を表わし、複数のＲ１１、Ｒ１２、Ｒ１３およびＲ１４は、それぞれ同じでも異なっていてもよく、
Ｒ２は、（１）１～５個のＲ１５で置換されていてもよい３～１５員の複素環、（２）１～５個のＲ１６で置換されていてもよい３～１５員の炭素環、または（３）１～５個のＲ１７で置換されていてもよいＣ１～４アルキル基を表わし、
Ｒ１５、Ｒ１６およびＲ１７は、それぞれ独立して、
（１）１～５個のＲ１８で置換されていてもよいＣ３～６シクロアルキル基で置換されていてもよいＣ１～８アルキル基、（２）（Ｃ１～８アルキル）カルボニル基、（３）１～５個のＲ１９で置換された（Ｃ３～６シクロアルキル）カルボニル基、（４）Ｃ１～８ハロアルキル基、（５）５～６員の炭素環、（６）５～６員の複素環、（７）Ｃ１～４アルキルスルホニル基、（８）Ｃ２～４アルケニルスルホニル基、（９）Ｃ１～４アルコキシカルボニル基、（１０）Ｃ１～４ハロアルキルアミノ基、（１１）ｔ－ブチルオキシカルボニルアミノ基、または（１２）５，５－ジメチル－２，４－ジオキソオキサゾリジン－３－イル基を表わし、
複数のＲ１５、Ｒ１６およびＲ１７は、それぞれ同じでも異なっていてもよく、
Ｒ１８およびＲ１９は、それぞれ独立して、（１）ハロゲン、（２）Ｃ１～４アルキル基、（３）Ｃ１～４アルコキシ基、（４）Ｃ１～４ハロアルキル基、（５）Ｃ１～４ハロアルコキシ基、または（６）シアノ基を表わし、
複数のＲ１８およびＲ１９は、それぞれ同じでも異なっていてもよく、
Ｒ３は、（１）水素原子、（２）ハロゲン、（３）Ｃ１～４アルキル基、（４）Ｃ１～４アルコキシ基、（５）Ｃ１～４ハロアルキル基、（６）Ｃ１～４ハロアルコキシ基、（７）シアノ基、（８）１～５個のＲ２０で置換されていてもよい３～１５員の炭素環、（９）１～５個のＲ２１で置換されていてもよい３～１５員の複素環、（１０）－ＮＲ２２Ｒ２３、（１１）－ＯＲ２４、（１２）－ＣＯＮＲ２５Ｒ２６、（１３）（Ｃ１～８アルキル）カルボニル基、（１４）水酸基で置換されたＣ１～４アルキル基、または（１５）１－（ヒドロキシイミノ）エチル基を表わし、
Ｒ２０およびＲ２１は、それぞれ独立して、（１）１～５個のＲ２７で置換されていてもよいＣ１～４アルキル基、（２）ハロゲン、（３）１～５個のＲ２８で置換されていてもよいＣ３～６シクロアルキル基、（４）１～５個のＲ２７－１で置換されていてもよいＣ１～４アルコキシ基、（５）水酸基、（６）カルバモイル基、（７）カルボキシル基、または（８）シアノ基を表わし、
複数のＲ２０およびＲ２１は、それぞれ同じでも異なっていてもよく、
Ｒ２７、Ｒ２７－１およびＲ２８は、それぞれ独立して、（１）ハロゲン、（２）Ｃ１～４アルキル基、（３）Ｃ１～４アルコキシ基、（４）Ｃ１～４ハロアルキル基、（５）Ｃ１～４ハロアルコキシ基、（６）水酸基、（７）カルバモイル基、（８）カルボキシル基、または（９）シアノ基を表わし、
複数のＲ２７、Ｒ２７－１およびＲ２８は、それぞれ同じでも異なっていてもよく、
Ｒ２２、Ｒ２３およびＲ２４は、それぞれ独立して、（１）水素原子、（２）１～５個のＲ２９で置換されていてもよいＣ１～８アルキル基、（３）１～５個のＲ２９－１で置換されていてもよいＣ２～４アルケニル基、（４）１～５個のＲ２９－２で置換されていてもよいＣ２～４アルキニル基、（５）１～５個のＲ３０で置換されていてもよい３～１５員の炭素環、または（６）１～５個のＲ３１で置換されていてもよい３～１５員の複素環を表わし、
Ｒ２９、Ｒ２９－１、Ｒ２９－２、Ｒ３０およびＲ３１は、それぞれ独立して、
（１）１～５個のＲ３２で置換されていてもよいＣ１～４アルキル基、（２）ハロゲン、（３）１～５個のＲ３３で置換されていてもよいＣ３～８シクロアルキル基、（４）１～５個のＲ３４で置換されていてもよい５～６員の炭素環、（５）１～５個のＲ３５で置換されていてもよい５～６員の複素環、（６）１～５個のＲ３２－１で置換されていてもよいＣ１～４アルコキシ基、（７）水酸基、（８）カルバモイル基、（９）カルボキシル基、または（１０）シアノ基を表わし、
複数のＲ２９、Ｒ２９－１、Ｒ２９－２、Ｒ３０およびＲ３１は、それぞれ同じでも異なっていてもよく、
Ｒ３２、Ｒ３２－１、Ｒ３３、Ｒ３４およびＲ３５は、それぞれ独立して、（１）ハロゲン、（２）Ｃ１～４アルキル基、（３）Ｃ１～４アルコキシ基、（４）Ｃ１～４ハロアルキル基、（５）Ｃ１～４ハロアルコキシ基、（６）水酸基、（７）カルバモイル基、（８）カルボキシル基、または（９）シアノ基を表わし、
複数のＲ３２、Ｒ３２－１、Ｒ３３、Ｒ３４およびＲ３５は、それぞれ同じでも異なっていてもよく、
Ｒ２５およびＲ２６は、それぞれ独立して、（１）水素原子、（２）１～５個のＲ３６で置換されていてもよいＣ１～８アルキル基、（３）１～５個のＲ３６－１で置換されていてもよいＣ２～４アルケニル基、（４）１～５個のＲ３６－２で置換されていてもよいＣ２～４アルキニル基、（５）１～５個のＲ３７で置換されていてもよい３～１５員の炭素環、または（６）１～５個のＲ３８で置換されていてもよい３～１５員の複素環を表わし、
Ｒ３６、Ｒ３６－１、Ｒ３６－２、Ｒ３７およびＲ３８は、それぞれ独立して、（１）Ｃ１～４アルキル基、（２）ハロゲン、（３）Ｃ３～８シクロアルキル基、（４）５～６員の炭素環、（５）５～６員の複素環、（６）Ｃ１～４アルコキシ基、（７）Ｃ１～４ハロアルキル基、（８）Ｃ１～４ハロアルコキシ基、（９）水酸基、（１０）カルボキシル基、（１１）カルバモイル基、または（１２）シアノ基を表わし、
複数のＲ３６、Ｒ３６－１、Ｒ３６－２、Ｒ３７およびＲ３８は、それぞれ同じでも異なっていてもよく、
Ｒ４は、（１）ハロゲン、（２）Ｃ１～４アルキル基、（３）Ｃ１～４アルコキシ基、（４）Ｃ１～４ハロアルキル基、（５）Ｃ１～４ハロアルコキシ基、（６）水酸基、または（７）シアノ基を表わし、
Ｒ５は、（１）ハロゲン、（２）Ｃ１～４アルキル基、（３）Ｃ１～４アルコキシ基、（４）Ｃ１～４ハロアルキル基、（５）Ｃ１～４ハロアルコキシ基、（６）水酸基、または（７）シアノ基を表わし、
Ｘは、窒素原子、またはＣＲ７を表わし、
Ｘ１、Ｘ２、およびＸ３は、それぞれ独立して、窒素原子、ＣＨ、またはＣＲ６を表わし、
Ｒ６は、（１）ハロゲン、（２）Ｃ１～４アルキル基、（３）Ｃ１～４アルコキシ基、（４）Ｃ１～４ハロアルキル基、（５）Ｃ１～４ハロアルコキシ基、（６）水酸基、または（７）シアノ基を表わし、
Ｒ６が複数の場合、各Ｒ６は同じでも異なっていてもよく、
Ｙ１は、窒素原子、またはＣＲ８を表わし、
Ｙ２は、窒素原子、またはＣＲ９を表わし、
Ｙ３は、窒素原子、またはＣＲ１０を表わし、
Ｒ７は、（１）水素原子、（２）ハロゲン、（３）Ｃ１～４アルキル基、（４）Ｃ１～４アルコキシ基、（５）Ｃ１～４ハロアルキル基、または（６）Ｃ１～４ハロアルコキシ基を表わし、
Ｒ８は、（１）水素原子、（２）ハロゲン、（３）Ｃ１～４アルキル基、（４）Ｃ１～４アルコキシ基、（５）Ｃ１～４ハロアルキル基、または（６）Ｃ１～４ハロアルコキシ基を表わし、
Ｒ９は、（１）水素原子、（２）ハロゲン、（３）Ｃ１～４アルキル基、（４）Ｃ１～４アルコキシ基、（５）Ｃ１～４ハロアルキル基、または（６）Ｃ１～４ハロアルコキシ基を表わし、
Ｒ１０は、（１）水素原子、（２）ハロゲン、（３）Ｃ１～４アルキル基、（４）Ｃ１～４アルコキシ基、（５）Ｃ１～４ハロアルキル基、（６）Ｃ１～４ハロアルコキシ基、（７）水酸基、（８）アミノ基、（９）カルボキシル基、（１０）カルバモイル基、（１１）（Ｃ１～４アルキル）アミノカルボニル基、（１２）ジ－（Ｃ１～４アルキル）アミノカルボニル基、（１３）－ＣＯ－（３～６員の飽和複素環）、（１４）－ＣＯＮＨＲ３９、または（１５）シアノ基を表わし、
Ｒ３９は、（１）シアノ基で置換されたＣ１～４アルキル基、（２）Ｃ１～４アルコキシ基、（３）Ｃ１～４ハロアルキル基、（４）Ｃ１～４ハロアルコキシ基、（５）水酸基、（６）アミノ基、（７）（Ｃ１～４アルキル）アミノ基、（８）ジ－（Ｃ１～４アルキル）アミノ基、（９）１～５個のＲ４０で置換されていてもよいＣ３～６シクロアルキル基、または（１０）１～５個のＲ４１で置換されていてもよい３～６員の飽和複素環を表わし、
Ｒ４０およびＲ４１は、それぞれ独立して、（１）ハロゲン、（２）Ｃ１～４アルキル基、（３）Ｃ１～４アルコキシ基、（４）Ｃ１～４ハロアルキル基、または（５）Ｃ１～４ハロアルコキシ基を表わし、
複数のＲ４０およびＲ４１は、それぞれ同じでも異なっていてもよく、
ｒは、０～３の整数を表わし、複数のＲ４は同じでも異なっていてもよく、
ｓは、０～３の整数を表わし、複数のＲ５は同じでも異なっていてもよい。
ここで、各水素原子は、重水素原子、または三重水素原子であってもよい。）で示される［１］記載の化合物、またはその塩； [2] General formula (I)
(In the formula,
R 1 is (1) methylene substituted with a 3- to 15-membered carbon ring optionally substituted with 1 to 5 R 11 , (2) optionally substituted with 1 to 5 R 12 methylene substituted with a 3- to 15-membered heterocycle, (3) methylene substituted with a C2-4 alkenyl group optionally substituted with 1 to 5 R 13 , or (4) 1 to 5 R 13 R 14 represents methylene substituted with an optionally substituted C2-4 alkynyl group,
R 11 , R 12 , R 13 and R 14 each independently represent (1) halogen, (2) C1-4 alkyl group, (3) C1-4 alkoxy group, (4) C1-4 haloalkyl group, (5) represents a C1-4 haloalkoxy group, or (6) a cyano group, and a plurality of R 11 , R 12 , R 13 and R 14 may be the same or different, respectively;
R 2 is (1) a 3- to 15 -membered heterocycle optionally substituted with 1 to 5 R 15s, (2) a 3- to 15-membered heterocycle optionally substituted with 1 to 5 R 16 or (3) a C1-4 alkyl group optionally substituted with 1 to 5 R17 ;
R 15 , R 16 and R 17 are each independently,
(1) a C1-8 alkyl group optionally substituted with a C3-6 cycloalkyl group optionally substituted with 1-5 R18, (2) a (C1-8 alkyl)carbonyl group, (3 ) (C3-6 cycloalkyl) carbonyl group substituted with 1 to 5 R 19 , (4) C1-8 haloalkyl group, (5) 5- to 6-membered carbon ring, (6) 5- to 6-membered carbocyclic Heterocycle, (7) C1-4 alkylsulfonyl group, (8) C2-4 alkenylsulfonyl group, (9) C1-4 alkoxycarbonyl group, (10) C1-4 haloalkylamino group, (11) t-butyloxy Represents a carbonylamino group or (12) 5,5-dimethyl-2,4-dioxoxazolidin-3-yl group,
A plurality of R 15 , R 16 and R 17 may be the same or different,
R 18 and R 19 each independently represent (1) halogen, (2) C1-4 alkyl group, (3) C1-4 alkoxy group, (4) C1-4 haloalkyl group, (5) C1-4 represents a haloalkoxy group or (6) a cyano group,
A plurality of R 18 and R 19 may be the same or different,
R 3 is (1) hydrogen atom, (2) halogen, (3) C1-4 alkyl group, (4) C1-4 alkoxy group, (5) C1-4 haloalkyl group, (6) C1-4 haloalkoxy group, (7) a cyano group, (8) a 3- to 15-membered carbon ring optionally substituted with 1 to 5 R 20 , (9) optionally substituted with 1 to 5 R 21 3- to 15-membered heterocycle, (10)-NR 22 R 23 , (11)-OR 24 , (12)-CONR 25 R 26 , (13) (C1-8 alkyl) carbonyl group, (14) hydroxyl group Represents a substituted C1-4 alkyl group or (15) 1-(hydroxyimino)ethyl group,
R 20 and R 21 each independently represent (1) a C1-4 alkyl group optionally substituted with 1 to 5 R 27s , (2) halogen, (3) 1 to 5 R 28 (4) a C1-4 alkoxy group optionally substituted with 1 to 5 R27-1 , (5) a hydroxyl group, (6) a carbamoyl group, (7) represents a carboxyl group, or (8) a cyano group,
A plurality of R 20 and R 21 may be the same or different,
R 27 , R 27-1 and R 28 each independently represent (1) halogen, (2) C1-4 alkyl group, (3) C1-4 alkoxy group, (4) C1-4 haloalkyl group, ( 5) represents a C1-4 haloalkoxy group, (6) hydroxyl group, (7) carbamoyl group, (8) carboxyl group, or (9) cyano group,
A plurality of R 27 s , R 27-1 and R 28 may be the same or different,
R 22 , R 23 and R 24 each independently represent (1) a hydrogen atom, (2) a C1-8 alkyl group optionally substituted with 1 to 5 R 29s , (3) 1 to 5 (4) C2-4 alkynyl group optionally substituted with 1 to 5 R 29-2 , (5) 1 to 5 ( 6 ) a 3- to 15-membered heterocycle optionally substituted with 1 to 5 R 31 ;
R 29 , R 29-1 , R 29-2 , R 30 and R 31 are each independently,
(1) C1-4 alkyl group optionally substituted with 1-5 R 32 , (2) halogen, (3) C3-8 cycloalkyl optionally substituted with 1-5 R 33 group, (4) a 5- to 6-membered carbocyclic ring optionally substituted with 1 to 5 R 34s , (5) a 5- to 6-membered heterocyclic ring optionally substituted with 1 to 5 R 35 ring, (6) C1-4 alkoxy group optionally substituted with 1 to 5 R 32-1 , (7) hydroxyl group, (8) carbamoyl group, (9) carboxyl group, or (10) cyano group represents,
A plurality of R 29 , R 29-1 , R 29-2 , R 30 and R 31 may be the same or different,
R 32 , R 32-1 , R 33 , R 34 and R 35 each independently represent (1) halogen, (2) C1-4 alkyl group, (3) C1-4 alkoxy group, (4) C1 ~4 haloalkyl group, (5) C1~4 haloalkoxy group, (6) hydroxyl group, (7) carbamoyl group, (8) carboxyl group, or (9) cyano group,
A plurality of R 32 , R 32-1 , R 33 , R 34 and R 35 may be the same or different,
R 25 and R 26 each independently represent (1) a hydrogen atom, (2) a C1-8 alkyl group optionally substituted with 1 to 5 R 36 , (3) 1 to 5 R 36 C2-4 alkenyl group optionally substituted with 36-1 , (4) 1-5 R C2-4 alkynyl group optionally substituted with 36-2 , (5) 1-5 R Represents a 3- to 15-membered carbocycle optionally substituted with 37, or (6) a 3- to 15-membered heterocycle optionally substituted with 1 to 5 R 38 ,
R 36 , R 36-1 , R 36-2 , R 37 and R 38 each independently represent (1) a C1-4 alkyl group, (2) a halogen, (3) a C3-8 cycloalkyl group, ( 4) 5-6 membered carbocycle, (5) 5-6 membered heterocycle, (6) C1-4 alkoxy group, (7) C1-4 haloalkyl group, (8) C1-4 haloalkoxy group, ( 9) represents a hydroxyl group, (10) a carboxyl group, (11) a carbamoyl group, or (12) a cyano group,
A plurality of R 36 , R 36-1 , R 36-2 , R 37 and R 38 may be the same or different,
R 4 is (1) halogen, (2) C1-4 alkyl group, (3) C1-4 alkoxy group, (4) C1-4 haloalkyl group, (5) C1-4 haloalkoxy group, (6) hydroxyl group , or (7) represents a cyano group,
R 5 is (1) halogen, (2) C1-4 alkyl group, (3) C1-4 alkoxy group, (4) C1-4 haloalkyl group, (5) C1-4 haloalkoxy group, (6) hydroxyl group , or (7) represents a cyano group,
X represents a nitrogen atom or CR7 ,
X 1 , X 2 , and X 3 each independently represent a nitrogen atom, CH, or CR 6 ,
R 6 is (1) halogen, (2) C1-4 alkyl group, (3) C1-4 alkoxy group, (4) C1-4 haloalkyl group, (5) C1-4 haloalkoxy group, (6) hydroxyl group , or (7) represents a cyano group,
When there is a plurality of R 6 s, each R 6 may be the same or different;
Y 1 represents a nitrogen atom or CR 8 ,
Y2 represents a nitrogen atom or CR9 ,
Y3 represents a nitrogen atom or CR10 ,
R 7 is (1) hydrogen atom, (2) halogen, (3) C1-4 alkyl group, (4) C1-4 alkoxy group, (5) C1-4 haloalkyl group, or (6) C1-4 halo represents an alkoxy group,
R 8 is (1) hydrogen atom, (2) halogen, (3) C1-4 alkyl group, (4) C1-4 alkoxy group, (5) C1-4 haloalkyl group, or (6) C1-4 halo represents an alkoxy group,
R 9 is (1) hydrogen atom, (2) halogen, (3) C1-4 alkyl group, (4) C1-4 alkoxy group, (5) C1-4 haloalkyl group, or (6) C1-4 halo represents an alkoxy group,
R 10 is (1) hydrogen atom, (2) halogen, (3) C1-4 alkyl group, (4) C1-4 alkoxy group, (5) C1-4 haloalkyl group, (6) C1-4 haloalkoxy group, (7) hydroxyl group, (8) amino group, (9) carboxyl group, (10) carbamoyl group, (11) (C1-4 alkyl)aminocarbonyl group, (12) di-(C1-4 alkyl)amino Represents a carbonyl group, (13) -CO- (3- to 6-membered saturated heterocycle), (14) -CONHR 39 , or (15) cyano group,
R 39 is (1) a C1-4 alkyl group substituted with a cyano group, (2) a C1-4 alkoxy group, (3) a C1-4 haloalkyl group, (4) a C1-4 haloalkoxy group, (5) Even if substituted with hydroxyl group, (6) amino group, (7) (C1-4 alkyl) amino group, (8) di-(C1-4 alkyl) amino group, (9) 1 to 5 R 40 represents a good C3-6 cycloalkyl group, or (10) a 3-6 membered saturated heterocycle optionally substituted with 1-5 R41 ,
R 40 and R 41 are each independently (1) halogen, (2) C1-4 alkyl group, (3) C1-4 alkoxy group, (4) C1-4 haloalkyl group, or (5) C1-4 represents a 4-haloalkoxy group,
A plurality of R 40 and R 41 may be the same or different,
r represents an integer from 0 to 3, and multiple R 4 may be the same or different;
s represents an integer from 0 to 3, and plural R 5s may be the same or different.
Here, each hydrogen atom may be a deuterium atom or a tritium atom. ) or a salt thereof;
［３］　一般式（Ｉ－１）
（式中、ｔは、０～３の整数を表わし、その他の記号は［２］と同じ意味を表わす。）で示される［１］または［２］記載の化合物、またはその塩； [3] General formula (I-1)
(In the formula, t represents an integer of 0 to 3, and the other symbols have the same meanings as [2].) The compound described in [1] or [2], or a salt thereof;
［４］　Ｒ２が、１～５個のＲ１５で置換されていてもよい５～７員の含窒素飽和複素環である、［１］～［３］のいずれかに記載の化合物、またはその塩； [4] The compound according to any one of [1] to [3], wherein R 2 is a 5- to 7-membered nitrogen-containing saturated heterocycle optionally substituted with 1 to 5 R 15 , or The salt;
［５］　Ｒ１が、１～５個のＲ１１で置換されていてもよい５～６員の炭素環で置換されたメチレンである、［１］～［４］のいずれかに記載の化合物、またはその塩； [5] The compound according to any one of [1] to [4], wherein R 1 is methylene substituted with a 5- to 6-membered carbon ring optionally substituted with 1 to 5 R 11 , or its salt;
［６］　Ｒ３ＹまたはＲ３が、（１）それぞれ１～５個のＲ２０ＹまたはＲ２０で置換されていてもよい、５～６員の炭素環またはインダン、（２）１～５個のＲ２１ＹまたはＲ２１で置換されていてもよい５～６員の複素環、または（３）－ＮＲ２２Ｒ２３である、［１］～［５］のいずれかに記載の化合物、またはその塩； [6] R 3Y or R 3 is (1) a 5- to 6-membered carbon ring or indane, each optionally substituted with 1 to 5 R 20Y or R 20 , (2) 1 to 5 The compound according to any one of [1] to [5], which is a 5- to 6-membered heterocycle optionally substituted with R 21Y or R 21 , or (3)-NR 22 R 23 , or a salt thereof ;
［６－１］　Ｒ３が、（１）それぞれ１～５個のＲ２０で置換されていてもよい、５～６員の炭素環またはインダン、（２）１～５個のＲ２１で置換されていてもよい５～６員の複素環、または（３）－ＮＲ２２Ｒ２３である、［１］～［５］のいずれかに記載の化合物、またはその塩； [6-1] R 3 is (1) a 5- to 6-membered carbocyclic ring or indane, each optionally substituted with 1 to 5 R 20 , (2) substituted with 1 to 5 R 21 The compound according to any one of [1] to [5], or a salt thereof, which is a 5- to 6-membered heterocycle, or (3) -NR 22 R 23 , which may be
［７］　一般式（Ｉ－１－１）
（式中、Ｒ１－１は、１～５個のＲ１１で置換されていてもよい５～６員の炭素環で置換されたメチレンを表わし、ｒｉｎｇ１は、５～７員の含窒素飽和複素環を表わし、Ｒ３－１は、（１）それぞれ１～５個のＲ２０で置換されていてもよい、５～６員の炭素環またはインダン、（２）１～５個のＲ２１で置換されていてもよい５～６員の複素環、または（３）－ＮＲ２２Ｒ２３を表わし、Ｒ１５－１は、１～５個のＲ１８で置換されていてもよいＣ３～６シクロアルキル基で置換されていてもよいＣ１～８アルキル基、またはＣ１～８ハロアルキル基を表わし、ｕは０～２の整数を表わし、その他の記号は［２］と同じ意味を表わす。）で示される［１］～［６］のいずれかに記載の化合物、またはその塩； [7] General formula (I-1-1)
(In the formula, R 1-1 represents methylene substituted with a 5- to 6-membered carbon ring which may be substituted with 1 to 5 R 11 , and ring 1 is a 5- to 7-membered nitrogen-containing saturated Represents a heterocycle, and R 3-1 is (1) a 5- to 6-membered carbocyclic ring or indane, each optionally substituted with 1 to 5 R 20 , (2) 1 to 5 R 21 represents a 5- to 6-membered heterocycle optionally substituted with or (3)-NR 22 R 23 , and R 15-1 is C3-6 optionally substituted with 1 to 5 R 18 represents a C1-8 alkyl group or a C1-8 haloalkyl group which may be substituted with a cycloalkyl group, u represents an integer from 0 to 2, and other symbols have the same meanings as [2].) The compound according to any one of [1] to [6] shown, or a salt thereof;
［８］　一般式（Ｉ－１－１－１）
（式中、ｒｉｎｇ２は、（１）それぞれ１～５個のＲ２０で置換されていてもよい、５～６員の炭素環、またはインダン、（２）１～５個のＲ２１で置換されていてもよい５～６員の複素環を表わし、その他の記号は［２］および［７］と同じ意味を表わす。）で示される［７］に記載の化合物、またはその塩； [8] General formula (I-1-1-1)
(In the formula, ring2 is (1) a 5- to 6-membered carbon ring or indane, each optionally substituted with 1 to 5 R 20 , (2) substituted with 1 to 5 R 21 (represents a 5- to 6-membered heterocycle which may be 5- to 6-membered heterocycle, other symbols have the same meanings as [2] and [7]), or a salt thereof;
［９］　化合物が、（１）１－（３－｛７－（４－｛［９－（４－シアノ－２－フルオロベンジル）－５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－イル］カルボニル｝フェニル）－９－［１－（２，２－ジメチルプロピル）－４－ピペリジニル］－６－メチル－８－オキソ－８，９－ジヒドロ－７Ｈ－プリン－２－イル｝フェニル）シクロプロパンカルボン酸、
（２）２－（３－｛７－（６－｛［９－（４－シアノ－２－フルオロベンジル）－５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－イル］カルボニル｝－３－ピリジニル）－９－［１－（２，２－ジメチルプロピル）－４－ピペリジニル］－６－メチル－８－オキソ－８，９－ジヒドロ－７Ｈ－プリン－２－イル｝フェニル）－２－メチルプロパン酸、または、
（３）４－（｛７－［（５－｛９－［１－（２，２－ジメチルプロピル）－４－ピペリジニル］－６－メチル－２－［２－メチル－４－（トリフルオロメトキシ）フェニル］－８－オキソ－８，９－ジヒドロ－７Ｈ－プリン－７－イル｝－２－ピリジニル）カルボニル］－５，６，７，８－テトラヒドロ－９Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－９－イル｝メチル）－３－フルオロベンゾニトリルである、［８］記載の化合物、またはその塩； [9] The compound is (1) 1-(3-{7-(4-{[9-(4-cyano-2-fluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4 ',3':4,5]pyrrolo[2,3-b]pyridin-7-yl]carbonyl}phenyl)-9-[1-(2,2-dimethylpropyl)-4-piperidinyl]-6-methyl -8-oxo-8,9-dihydro-7H-purin-2-yl}phenyl)cyclopropanecarboxylic acid,
(2) 2-(3-{7-(6-{[9-(4-cyano-2-fluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4 ,5]pyrrolo[2,3-b]pyridin-7-yl]carbonyl}-3-pyridinyl)-9-[1-(2,2-dimethylpropyl)-4-piperidinyl]-6-methyl-8- oxo-8,9-dihydro-7H-purin-2-yl}phenyl)-2-methylpropanoic acid, or
(3) 4-({7-[(5-{9-[1-(2,2-dimethylpropyl)-4-piperidinyl]-6-methyl-2-[2-methyl-4-(trifluoromethoxy) )phenyl]-8-oxo-8,9-dihydro-7H-purin-7-yl}-2-pyridinyl)carbonyl]-5,6,7,8-tetrahydro-9H-pyrido[4',3': 4,5]pyrrolo[2,3-b]pyridin-9-yl}methyl)-3-fluorobenzonitrile, the compound according to [8], or a salt thereof;
［１０］　一般式（Ｉ－１－１－２）
（式中、ｒｉｎｇ３は、１～５個のＲ３０で置換されていてもよい５～６員の炭素環、または１～５個のＲ３１で置換されていてもよい５～６員の複素環を表わし、Ｒ２３－１は、（１）水素原子、（２）１～５個のＲ２９で置換されていてもよいＣ１～８アルキル基、（３）１～５個のＲ２９－１で置換されていてもよいＣ２～４アルケニル基、または（４）１～５個のＲ２９－２で置換されていてもよいＣ２～４アルキニル基を表わし、その他の記号は［２］および［７］と同じ意味を表わす。）で示される［７］に記載の化合物、またはその塩； [10] General formula (I-1-1-2)
(In the formula, ring3 is a 5- to 6-membered carbocyclic ring optionally substituted with 1 to 5 R 30s , or a 5- to 6-membered heterocyclic ring optionally substituted with 1 to 5 R 31 Represents a ring, and R 23-1 is (1) a hydrogen atom, (2) a C1-8 alkyl group optionally substituted with 1 to 5 R 29s , (3) 1 to 5 R 29- represents a C2-4 alkenyl group optionally substituted with 1 , or (4) a C2-4 alkynyl group optionally substituted with 1 to 5 R29-2 ; other symbols are [2] and The compound according to [7], which has the same meaning as [7], or a salt thereof;
［１１］　化合物が、（１）７－（４－｛［９－（４－クロロ－２－フルオロベンジル）－５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－イル］カルボニル｝フェニル）－２－｛［４－（ジフルオロメトキシ）フェニル］アミノ｝－９－［１－（２，２－ジメチルプロピル）－４－ピペリジニル］－６－メチル－７，９－ジヒドロ－８Ｈ－プリン－８－オン、
（２）７－（４－｛［９－（４－クロロ－２－フルオロベンジル）－５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－イル］カルボニル｝フェニル）－９－［１－（２，２－ジメチルプロピル）－４－ピペリジニル］－２－［（３－フルオロフェニル）アミノ］－６－メチル－７，９－ジヒドロ－８Ｈ－プリン－８－オン、
（３）９－［１－（２，２－ジメチルプロピル）－４－ピペリジニル］－７－（６－｛［９－（２－フルオロ－４－メチルベンジル）－５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－イル］カルボニル｝－３－ピリジニル）－６－メチル－２－｛［４－（トリフルオロメトキシ）フェニル］アミノ｝－７，９－ジヒドロ－８Ｈ－プリン－８－オン、
（４）４－［（７－｛［５－（９－［１－（２，２－ジメチルプロピル）－４－ピペリジニル］－６－メチル－８－オキソ－２－｛［４－（トリフルオロメトキシ）フェニル］アミノ｝－８，９－ジヒドロ－７Ｈ－プリン－７－イル）－２－ピリジニル］カルボニル｝－５，６，７，８－テトラヒドロ－９Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－９－イル）メチル］－３－フルオロベンゾニトリル、
（５）３－フルオロ－４－（｛７－［（５－｛２－［（３－フルオロフェニル）アミノ］－６－メチル－８－オキソ－９－（１－｛［１－（トリフルオロメチル）シクロプロピル］メチル｝－４－ピペリジニル）－８，９－ジヒドロ－７Ｈ－プリン－７－イル｝－２－ピリジニル）カルボニル］－５，６，７，８－テトラヒドロ－９Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－９－イル｝メチル）ベンゾニトリル、
（６）４－［（７－｛［５－（２－｛［２－クロロ－４－（トリフルオロメトキシ）フェニル］アミノ｝－９－［１－（２，２－ジメチルプロピル）－４－ピペリジニル］－６－メチル－８－オキソ－８，９－ジヒドロ－７Ｈ－プリン－７－イル）－２－ピリジニル］カルボニル｝－５，６，７，８－テトラヒドロ－９Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－９－イル）メチル］－３－フルオロベンゾニトリル、または、
（７）７－（６－｛［９－（４－クロロ－２－フルオロベンジル）－５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－イル］カルボニル｝－３－ピリジニル）－９－［１－（２，２－ジメチルプロピル）－４－ピペリジニル］－２－［（３－フルオロフェニル）アミノ］－６－メチル－７，９－ジヒドロ－８Ｈ－プリン－８－オンである、［１０］記載の化合物、またはその塩； [11] The compound is (1) 7-(4-{[9-(4-chloro-2-fluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4 ,5]pyrrolo[2,3-b]pyridin-7-yl]carbonyl}phenyl)-2-{[4-(difluoromethoxy)phenyl]amino}-9-[1-(2,2-dimethylpropyl) -4-piperidinyl]-6-methyl-7,9-dihydro-8H-purin-8-one,
(2) 7-(4-{[9-(4-chloro-2-fluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[2 ,3-b]pyridin-7-yl]carbonyl}phenyl)-9-[1-(2,2-dimethylpropyl)-4-piperidinyl]-2-[(3-fluorophenyl)amino]-6-methyl -7,9-dihydro-8H-purin-8-one,
(3) 9-[1-(2,2-dimethylpropyl)-4-piperidinyl]-7-(6-{[9-(2-fluoro-4-methylbenzyl)-5,6,8,9- Tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[2,3-b]pyridin-7-yl]carbonyl}-3-pyridinyl)-6-methyl-2-{[4-(tri fluoromethoxy)phenyl]amino}-7,9-dihydro-8H-purin-8-one,
(4) 4-[(7-{[5-(9-[1-(2,2-dimethylpropyl)-4-piperidinyl]-6-methyl-8-oxo-2-{[4-(trifluoro methoxy)phenyl]amino}-8,9-dihydro-7H-purin-7-yl)-2-pyridinyl]carbonyl}-5,6,7,8-tetrahydro-9H-pyrido[4',3':4 ,5]pyrrolo[2,3-b]pyridin-9-yl)methyl]-3-fluorobenzonitrile,
(5) 3-fluoro-4-({7-[(5-{2-[(3-fluorophenyl)amino]-6-methyl-8-oxo-9-(1-{[1-(trifluoro methyl)cyclopropyl]methyl}-4-piperidinyl)-8,9-dihydro-7H-purin-7-yl}-2-pyridinyl)carbonyl]-5,6,7,8-tetrahydro-9H-pyrido[4 ',3':4,5]pyrrolo[2,3-b]pyridin-9-yl}methyl)benzonitrile,
(6) 4-[(7-{[5-(2-{[2-chloro-4-(trifluoromethoxy)phenyl]amino}-9-[1-(2,2-dimethylpropyl)-4- piperidinyl]-6-methyl-8-oxo-8,9-dihydro-7H-purin-7-yl)-2-pyridinyl]carbonyl}-5,6,7,8-tetrahydro-9H-pyrido[4', 3':4,5]pyrrolo[2,3-b]pyridin-9-yl)methyl]-3-fluorobenzonitrile, or
(7) 7-(6-{[9-(4-chloro-2-fluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[2 ,3-b]pyridin-7-yl]carbonyl}-3-pyridinyl)-9-[1-(2,2-dimethylpropyl)-4-piperidinyl]-2-[(3-fluorophenyl)amino]- The compound according to [10], which is 6-methyl-7,9-dihydro-8H-purin-8-one, or a salt thereof;
［１２］　一般式（Ｉ－１－１－３）
（式中、すべての記号は［２］、［７］および［１０］と同じ意味を表わす。）で示される［７］に記載の化合物、またはその塩； [12] General formula (I-1-1-3)
(In the formula, all symbols represent the same meanings as [2], [7] and [10].) The compound according to [7], or a salt thereof;
［１３］　化合物が、（１）１－｛［｛７－（６－｛［９－（４－シアノ－２－フルオロベンジル）－５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－イル］カルボニル｝－３－ピリジニル）－９－［１－（２，２－ジメチルプロピル）－４－ピペリジニル］－６－メチル－８－オキソ－８，９－ジヒドロ－７Ｈ－プリン－２－イル｝（シクロへキシル）アミノ］メチル｝シクロブタンカルボン酸である、［１２］記載の化合物、またはその塩； [13] The compound is (1) 1-{[{7-(6-{[9-(4-cyano-2-fluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4' ,3':4,5]pyrrolo[2,3-b]pyridin-7-yl]carbonyl}-3-pyridinyl)-9-[1-(2,2-dimethylpropyl)-4-piperidinyl]-6 -Methyl-8-oxo-8,9-dihydro-7H-purin-2-yl}(cyclohexyl)amino]methyl}cyclobutanecarboxylic acid, the compound according to [12], or a salt thereof;
［１４］　［１］記載の一般式（ＩＹ）で示される化合物、またはその塩を含有する医薬組成物；
［１４－１］　さらに薬学的に許容される担体を含有する、［１４］記載の医薬組成物；
［１５］　ＤＧＫαおよび／またはＤＧＫζ阻害剤である［１４］記載の医薬組成物；
［１６］　ＤＧＫαおよび／またはＤＧＫζ関連疾患の進行抑制、再発抑制および／または治療剤である［１４］または［１５］記載の医薬組成物；
［１７］　ＤＧＫαおよび／またはＤＧＫζ関連疾患が、癌または感染症である［１６］記載の医薬組成物；
［１８］　癌が、固形癌または血液癌である、［１７］記載の医薬組成物；
［１９］　固形癌が、悪性黒色腫、非小細胞肺癌、小細胞肺癌、頭頸部癌、腎細胞癌、乳癌、卵巣癌、卵巣明細胞腺癌、鼻咽頭癌、子宮癌、肛門癌、大腸癌、直腸癌、結腸癌、肝細胞癌、食道癌、胃癌、食道胃接合部癌、膵癌、尿路上皮癌、前立腺癌、卵管癌、原発性腹膜癌、悪性胸膜中皮腫、胆嚢癌、胆管癌、胆道癌、皮膚癌、精巣癌（胚細胞腫瘍）、膣癌、外陰部癌、陰茎癌、小腸癌、内分泌系癌、甲状腺癌、副甲状腺癌、副腎癌、脊椎腫瘍、神経芽細胞腫、髄芽腫、眼網膜芽細胞腫、神経内分泌腫瘍、脳腫瘍および扁平上皮癌から選択される１以上の癌である、［１８］記載の医薬組成物；
［２０］　固形癌が、骨・軟部肉腫またはカポジ肉腫である、［１８］記載の医薬組成物；
［２１］　血液癌が、多発性骨髄腫、悪性リンパ腫、白血病、骨髄異形成症候群および骨髄増殖症候群から選択される１以上の癌である、［１８］記載の医薬組成物；
［２２］　［１］記載の一般式（ＩＹ）で示される化合物、またはその塩を含有する、ＤＧＫαおよび／またはＤＧＫζ関連疾患の進行抑制、再発抑制および／または治療剤；
［２３］　［１］記載の一般式（ＩＹ）で示される化合物、またはその塩の有効量を哺乳動物に投与することを特徴とするＤＧＫαおよび／またはＤＧＫζ関連疾患の進行抑制、再発抑制および／または治療方法；
［２４］　ＤＧＫαおよび／またはＤＧＫζ関連疾患の進行抑制、再発抑制および／または治療に使用される［１］記載の一般式（ＩＹ）で示される化合物、またはその塩；ならびに、
［２５］　ＤＧＫαおよび／またはＤＧＫζ関連疾患の進行抑制、再発抑制および／または治療剤の製造のための［１］記載の一般式（ＩＹ）で示される化合物、またはその塩の使用。 [14] A pharmaceutical composition containing the compound represented by the general formula (IY) described in [1] or a salt thereof;
[14-1] The pharmaceutical composition according to [14], further comprising a pharmaceutically acceptable carrier;
[15] The pharmaceutical composition according to [14], which is a DGKα and/or DGKζ inhibitor;
[16] The pharmaceutical composition according to [14] or [15], which is an agent for inhibiting progression, inhibiting recurrence, and/or treating DGKα and/or DGKζ-related diseases;
[17] The pharmaceutical composition according to [16], wherein the DGKα and/or DGKζ-related disease is cancer or an infectious disease;
[18] The pharmaceutical composition according to [17], wherein the cancer is a solid cancer or a blood cancer;
[19] Solid cancers include malignant melanoma, non-small cell lung cancer, small cell lung cancer, head and neck cancer, renal cell carcinoma, breast cancer, ovarian cancer, ovarian clear cell adenocarcinoma, nasopharyngeal cancer, uterine cancer, anal cancer, and large intestine cancer. Cancer, rectal cancer, colon cancer, hepatocellular carcinoma, esophageal cancer, gastric cancer, esophagogastric junction cancer, pancreatic cancer, urothelial cancer, prostate cancer, fallopian tube cancer, primary peritoneal cancer, malignant pleural mesothelioma, gallbladder cancer , bile duct cancer, biliary tract cancer, skin cancer, testicular cancer (germ cell tumor), vaginal cancer, vulvar cancer, penile cancer, small intestine cancer, endocrine cancer, thyroid cancer, parathyroid cancer, adrenal cancer, spinal tumor, nerve bud cancer The pharmaceutical composition according to [18], which is one or more cancers selected from cell carcinoma, medulloblastoma, ocular retinoblastoma, neuroendocrine tumor, brain tumor, and squamous cell carcinoma;
[20] The pharmaceutical composition according to [18], wherein the solid cancer is bone/soft tissue sarcoma or Kaposi's sarcoma;
[21] The pharmaceutical composition according to [18], wherein the blood cancer is one or more cancers selected from multiple myeloma, malignant lymphoma, leukemia, myelodysplastic syndrome, and myeloproliferative syndrome;
[22] An agent for inhibiting progression, inhibiting recurrence, and/or treating DGKα and/or DGKζ-related diseases, containing a compound represented by the general formula (IY) described in [1], or a salt thereof;
[23] Suppression of progression, suppression of recurrence, and/or suppression of DGKα- and/or DGKζ-related diseases, characterized by administering to a mammal an effective amount of the compound represented by the general formula (IY) described in [1], or a salt thereof. or treatment method;
[24] A compound represented by the general formula (IY) described in [1], or a salt thereof, which is used for inhibiting the progression, inhibiting recurrence, and/or treating DGKα and/or DGKζ-related diseases; and
[25] Use of the compound represented by general formula (IY) described in [1] or a salt thereof for inhibiting the progression, inhibiting recurrence, and/or producing a therapeutic agent for DGKα and/or DGKζ-related diseases.
　本明細書において、明示的に引用されるすべての特許文献および非特許文献もしくは参考文献の内容は、全て本明細書の一部としてここに引用し得る。 In this specification, the contents of all patent documents and non-patent documents or references explicitly cited may be cited here as part of this specification.
　本発明を以下の実施例によってさらに詳しく説明するが、本発明の範囲はこれに限定されない。本発明の記載に基づき種々の変更または修飾が当業者には可能であり、これらの変更または修飾も本発明に含まれる。 The present invention will be explained in more detail with reference to the following examples, but the scope of the present invention is not limited thereto. Various changes or modifications can be made by those skilled in the art based on the description of the present invention, and these changes or modifications are also included in the present invention.
　以下、実施例および生物学的実施例によって本発明を詳述するが、本発明はこれらに限定されるものではない。 Hereinafter, the present invention will be explained in detail with reference to Examples and Biological Examples, but the present invention is not limited thereto.
　クロマトグラフィーによる分離の箇所およびＴＬＣに示されている括弧内の溶媒は、使用した溶出溶媒または展開溶媒を示し、割合は体積比を表す。中圧分取用カートリッジカラムは、Ｃｈｒоｍａｔоｒｅｘ　Ｑ－ＰＡＣＫ　ＳＩまたはＮＨ（富士シリシア化学）、及びインジェクトカラム　シリカゲルまたはアミノ（山善）を用いた。また、逆相ＨＰＬＣカラム精製は、以下の条件で実施した。
カラム：ＹＭＣ　Ｔｒｉａｒｔ　Ｃ １８　３０ｍｍ×７５ｍｍ、５μｍ；流量：４０ｍＬ／分；移動相Ａ：０．１％トリフルオロ酢酸（以下、ＴＦＡと略記することがある。）水溶液；移動相Ｂ：０．１％ＴＦＡアセトニトリル溶液：グラジエント（移動相（Ａ）：移動相（Ｂ）の比率を記載）： ０～０．５０分：（９０％：１０％）；０．５０～９．００分：（９０％：１０％）から（２０％：８０％）；９．０１～１１．００分：（０％：１００％））
　ＬＣＭＳは、Ｓｈｉｍａｄｚｕ　Ｎｅｘｅｒａ　Ｘ２（Ａ）またはＷａｔｅｒｓ　ｉ－ｃｌａｓｓ（Ｂ）システムを使用し、以下の条件で実施した。
カラム：ＹＭＣ　Ｔｒｉａｒｔ　Ｃ １８　２．０ｍｍ×３０ｍｍ、１．９μｍ；流量：１．０ｍＬ／分；温度：３０℃；移動相Ａ：０．１％ＴＦＡ水溶液；移動相Ｂ：０．１％ＴＦＡアセトニトリル溶液：グラジエント（移動相（Ａ）：移動相（Ｂ）の比率を記載）：
０～０．１０分：（９５％：５％）；０．１０～１．２０分：（９５％：５％）から（５％：９５％）；１．２０～１．５０分：（５％：９５％）。 The solvent in parentheses shown at the point of chromatographic separation and TLC indicates the elution solvent or developing solvent used, and the proportions represent volume ratios. The medium pressure preparative cartridge column used was Chromatorex Q-PACK SI or NH (Fuji Silysia Chemical), and the injection column silica gel or Amino (Yamazen). In addition, reverse phase HPLC column purification was performed under the following conditions.
Column: YMC Triart C 18 30 mm x 75 mm, 5 μm; Flow rate: 40 mL/min; Mobile phase A: 0.1% trifluoroacetic acid (hereinafter sometimes abbreviated as TFA) aqueous solution; Mobile phase B: 0.1 % TFA acetonitrile solution: Gradient (describe the ratio of mobile phase (A): mobile phase (B)): 0 to 0.50 minutes: (90%: 10%); 0.50 to 9.00 minutes: (90 %: 10%) to (20%: 80%); 9.01 to 11.00 minutes: (0%: 100%))
LCMS was performed using a Shimadzu Nexera X2 (A) or Waters i-class (B) system under the following conditions.
Column: YMC Triart C 18 2.0 mm x 30 mm, 1.9 μm; Flow rate: 1.0 mL/min; Temperature: 30°C; Mobile phase A: 0.1% TFA aqueous solution; Mobile phase B: 0.1% TFA acetonitrile Solution: Gradient (describe the ratio of mobile phase (A):mobile phase (B)):
0 to 0.10 minutes: (95%: 5%); 0.10 to 1.20 minutes: (95%: 5%) to (5%: 95%); 1.20 to 1.50 minutes: ( 5%:95%).
　ＮＭＲの箇所に示した数値は、その括弧内に記載した測定溶媒を用いた時の１Ｈ－ＮＭＲの測定値（化学シフト値）である。 The numerical value shown in the NMR section is a 1 H-NMR measurement value (chemical shift value) using the measurement solvent listed in parentheses.
　本明細書中に用いた化合物名は、一般的にＩＵＰＡＣの規則に準じて命名を行なうコンピュータプログラム、ACD/Name（登録商標）（バージョン6.00、Advanced Chemistry Development Inc.社製）、Chemdraw Ultra（バージョン12.0、Cambridge Soft社製）もしくはLexichem Toolkit（バージョン1.4.2、OpenEye Scientific Software社製）を用いるか、またはＩＵＰＡＣ命名法に準じて命名したものである。 The compound names used in this specification are generally given by computer programs that perform naming according to IUPAC rules, ACD/Name (registered trademark) (version 6.00, manufactured by Advanced Chemistry Development Inc.), Chemdraw Ultra (version 6.00, manufactured by Advanced Chemistry Development Inc.), 12.0, manufactured by Cambridge Soft) or Lexichem Toolkit (version 1.4.2, manufactured by OpenEye Scientific Software), or named according to IUPAC nomenclature.
参考例１
２－メチル－２－プロパニル　９－（２，４－ジフルオロベンジル）－５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－カルボキシラート
　２－メチル－２－プロパニル　５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－カルボキシラート（CAS：１３５４８０１－０７－２、4.0ｇ）と、１－（ブロモメチル）－２，４－ジフルオロベンゼン（2.1ｍＬ）をジメチルホルムアミド（以下、ＤＭＦと略記することがある。）（40ｍＬ）に溶解した。反応液を氷冷し、水素化ナトリウム（60％パラフィンオイル懸濁液、703ｍｇ）を加えて、４０分攪拌した。反応液に飽和塩化アンモニウム水溶液を加えて攪拌し、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄した後、無水硫酸ナトリウムを加えて乾燥し、減圧濃縮して得られた残渣をシリカゲルクロマトグラフィー（ヘキサン：酢酸エチル＝４：１）で精製することにより、以下の物性値を有する標題化合物（5.1ｇ）を得た。
TLC：Rf 0.42（ヘキサン：酢酸エチル＝４：１）；
１H-NMR(CDCl３)：δ　 1.47, 2.79, 3.74, 4.53, 5.45, 6.73, 6.77-7.04, 7.08, 7.80, 8.29。 Reference example 1
2-Methyl-2-propanyl 9-(2,4-difluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[2,3-b] Pyridine-7-carboxylate 2-methyl-2-propanyl 5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[2,3-b]pyridine-7-carboxy Lato (CAS: 1354801-07-2, 4.0 g) and 1-(bromomethyl)-2,4-difluorobenzene (2.1 mL) were added to dimethylformamide (hereinafter sometimes abbreviated as DMF) (40 mL). Dissolved. The reaction solution was ice-cooled, sodium hydride (60% paraffin oil suspension, 703 mg) was added, and the mixture was stirred for 40 minutes. A saturated aqueous ammonium chloride solution was added to the reaction solution, stirred, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried with anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting residue was purified by silica gel chromatography (hexane: ethyl acetate = 4:1) to produce the following: The title compound (5.1 g) having physical properties was obtained.
TLC: Rf 0.42 (hexane: ethyl acetate = 4:1);
1H -NMR ( CDCl3 ): δ 1.47, 2.79, 3.74, 4.53, 5.45, 6.73, 6.77-7.04, 7.08, 7.80, 8.29.
参考例２
９－（２，４－ジフルオロベンジル）－６，７，８，９－テトラヒドロ－５Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン　２塩酸塩
　参考例１で製造した化合物（5.1ｇ）をメタノール（10ｍＬ）に溶解し、４Ｎ塩化水素／１，４－ジオキサン溶液（32ｍＬ）を加えて室温で４０分攪拌した。反応液を濃縮してトルエンで共沸し、得られた残渣を２－メトキシ－２－メチルプロパン（以下、ＭＴＢＥと略記することがある。）を用いてろ取することにより、以下の物性値を有する標題化合物（4.6ｇ）を得た。
TLC：Rf 0.37（ジクロロメタン：メタノール＝９：１）；
１H-NMR(DMSO-d６)：δ　 2.98, 3.43, 4.35, 5.53, 6.97-7.03, 7.06, 7.13-7.33, 8.03, 8.29, 9.94。 Reference example 2
9-(2,4-difluorobenzyl)-6,7,8,9-tetrahydro-5H-pyrido[4',3':4,5]pyrrolo[2,3-b]pyridine dihydrochloride Reference Example 1 The compound prepared in (5.1 g) was dissolved in methanol (10 mL), 4N hydrogen chloride/1,4-dioxane solution (32 mL) was added, and the mixture was stirred at room temperature for 40 minutes. The reaction solution was concentrated and azeotroped with toluene, and the resulting residue was filtered using 2-methoxy-2-methylpropane (hereinafter sometimes abbreviated as MTBE) to obtain the following physical properties. The title compound (4.6 g) was obtained.
TLC: Rf 0.37 (dichloromethane:methanol = 9:1);
1H -NMR (DMSO- d6 ): δ 2.98, 3.43, 4.35, 5.53, 6.97-7.03, 7.06, 7.13-7.33, 8.03, 8.29, 9.94.
参考例３
２－メチル－２－プロパニル　４－［（５－アミノ－２－クロロ－６－メチル－４－ピリミジニル）アミノ］－１－ピペリジンカルボキシラート
　２－メチル－２－プロパニル　４－アミノ－１－ピぺリジンカルボキシラート（2.6ｇ）と、２，４－ジクロロ－６－メチル－５－ピリミジンアミン（2.2ｇ）にＮ－エチル－Ｎ－イソプロピル－２－プロパンアミン（以下、ＤＩＰＥＡと略記することがある。）（4.7ｍＬ）を加えて、１００℃で終夜攪拌した。室温まで冷却後、酢酸エチルで反応液を希釈し、水と飽和食塩水で有機層を洗浄した。有機層を無水硫酸ナトリウムで乾燥し、減圧濃縮して得られた残渣をシリカゲルクロマトグラフィー（ヘキサン：酢酸エチル＝３：１→１：４）で精製することにより、以下の物性値を有する標題化合物（2.8ｇ）を得た。
LC－MS（A）保持時間（分）：1.11；
MS(ESI, Pos.)： 342 (M + H)＋；
１H-NMR(DMSO-d６)：δ　 1.24-1.37, 1.39-1.42, 1.82-1.91, 2.12, 2.80-3.00, 3.85-4.06, 4.66, 6.51。 Reference example 3
2-Methyl-2-propanyl 4-[(5-amino-2-chloro-6-methyl-4-pyrimidinyl)amino]-1-piperidinecarboxylate 2-methyl-2-propanyl 4-amino-1-pipe Lysine carboxylate (2.6g), 2,4-dichloro-6-methyl-5-pyrimidineamine (2.2g) and N-ethyl-N-isopropyl-2-propanamine (hereinafter sometimes abbreviated as DIPEA) ) (4.7 mL) and stirred at 100°C overnight. After cooling to room temperature, the reaction solution was diluted with ethyl acetate, and the organic layer was washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting residue was purified by silica gel chromatography (hexane:ethyl acetate = 3:1 → 1:4) to obtain the title compound having the following physical properties. (2.8g) was obtained.
LC-MS (A) retention time (min): 1.11;
MS(ESI, Pos.): 342 (M + H) + ;
1H -NMR (DMSO- d6 ): δ 1.24-1.37, 1.39-1.42, 1.82-1.91, 2.12, 2.80-3.00, 3.85-4.06, 4.66, 6.51.
参考例４
２－メチル－２－プロパニル　４－［（２－クロロ－５－｛［４－（メトキシカルボニル）フェニル］アミノ｝－６－メチル－４－ピリミジニル）アミノ］－１－ピペリジンカルボキシラート
　参考例３で製造した化合物（5.0ｇ）と４－ヨード安息香酸メチル（4.6ｇ）に無水１，２－ジメトキシエタン（以下、ＤＭＥと略記することがある。）（50ｍＬ）を加えて溶解した。その溶液に、炭酸セシウム（7.1ｇ）及び（９，９）－ジメチル－９Ｈ－キサンテン－４，５－ジイル）ビス（ジフェニルホスフィン）（以下、Ｘａｎｔｐｈｏｓと略記することがある。）（510ｍｇ）、（１Ｅ，４Ｅ）－１，５－ジフェニル－１，４－ペンタジエン－３－オン－パラジウム錯体（３：２）（以下、Pd２（dba）３と略記することがある。）（400ｍｇ）を加えた。反応容器内を窒素置換後、８０℃で４時間攪拌した。反応液をＤＭＥ（100ｍＬ）で希釈して８０℃で１５分攪拌し、セライト（商品名）を通して不溶物を除去した。ろ液を濃縮して得られた残渣に、ヘキサン：酢酸エチル混合液（２：１）（60ｍＬ）を加えて攪拌し、ろ取することにより、以下の物性値を有する標題化合物を得た（6.6ｇ）。
LC－MS（A）保持時間（分）：1.14；
MS(ESI, Pos.)： 476 (M + H)＋；
１H-NMR(CDCl３)：δ　 1.18-1.35, 1.43, 1.89-1.98, 2.22, 2.90, 3.83-3.91, 3.95-4.20, 5.09, 5.23, 6.51-6.57, 7.88-7.94。 Reference example 4
2-Methyl-2-propanyl 4-[(2-chloro-5-{[4-(methoxycarbonyl)phenyl]amino}-6-methyl-4-pyrimidinyl)amino]-1-piperidinecarboxylate in Reference Example 3 The produced compound (5.0 g) and methyl 4-iodobenzoate (4.6 g) were dissolved in anhydrous 1,2-dimethoxyethane (hereinafter sometimes abbreviated as DME) (50 mL). To the solution, cesium carbonate (7.1 g) and (9,9)-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (hereinafter sometimes abbreviated as Xantphos) (510 mg), (1E,4E)-1,5-diphenyl-1,4-pentadien-3-one-palladium complex (3:2) (hereinafter sometimes abbreviated as Pd 2 (dba) 3 ) (400 mg) added. After purging the inside of the reaction vessel with nitrogen, the mixture was stirred at 80°C for 4 hours. The reaction solution was diluted with DME (100 mL), stirred at 80° C. for 15 minutes, and passed through Celite (trade name) to remove insoluble materials. A hexane:ethyl acetate mixture (2:1) (60 mL) was added to the residue obtained by concentrating the filtrate, and the mixture was stirred and collected by filtration to obtain the title compound having the following physical properties ( 6.6g).
LC-MS (A) retention time (min): 1.14;
MS(ESI, Pos.): 476 (M + H) + ;
1H -NMR ( CDCl3 ): δ 1.18-1.35, 1.43, 1.89-1.98, 2.22, 2.90, 3.83-3.91, 3.95-4.20, 5.09, 5.23, 6.51-6.57, 7.88-7.94.
参考例５
２－メチル－２－プロパニル　４－｛２－クロロ－７－［４－（メトキシカルボニル）フェニル］－６－メチル－８－オキソ－７，８－ジヒドロ－９Ｈ－プリン－９－イル｝－１－ピペリジンカルボキシラート
　参考例４で製造した化合物（1.7ｇ）をテトラヒドロフラン（以下、ＴＨＦと略記することがある。）（17ｍＬ）に溶解し、ジ－１Ｈ－イミダゾール－１－イル　メタノン（以下、ＣＤＩと略記することがある。）（1.2ｇ）及び２，３，４，６，７，８，９，１０－オクタヒドロピリミド[１，２－a]アゼピン（以下、ＤＢＵと略記することがある。）（540ｍｇ）を加えて室温で２時間攪拌した。反応液を酢酸エチルで希釈し、水及び０．１Ｎ塩酸、飽和食塩水で順次洗浄した。有機層を無水硫酸ナトリウムで乾燥後、減圧濃縮して以下の物性値を有する標題化合物（1.8ｇ）を得た。
TLC：Rf 0.54（ヘキサン：酢酸エチル＝１：１）；
１H-NMR(CDCl３)：δ　 1.50, 1.76-1.86, 2.09, 2.59, 2.76-2.93, 3.97, 4.23-4.61, 4.52-4.63, 7.45-7.52, 8.20-8.25。 Reference example 5
2-Methyl-2-propanyl 4-{2-chloro-7-[4-(methoxycarbonyl)phenyl]-6-methyl-8-oxo-7,8-dihydro-9H-purin-9-yl}-1 - Piperidine carboxylate The compound prepared in Reference Example 4 (1.7 g) was dissolved in tetrahydrofuran (hereinafter sometimes abbreviated as THF) (17 mL), and di-1H-imidazol-1-yl methanone (hereinafter referred to as CDI ) (1.2g) and 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine (hereinafter sometimes abbreviated as DBU) ) (540 mg) was added and stirred at room temperature for 2 hours. The reaction solution was diluted with ethyl acetate and washed successively with water, 0.1N hydrochloric acid, and saturated brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the title compound (1.8 g) having the following physical properties.
TLC: Rf 0.54 (hexane: ethyl acetate = 1:1);
1H -NMR ( CDCl3 ): δ 1.50, 1.76-1.86, 2.09, 2.59, 2.76-2.93, 3.97, 4.23-4.61, 4.52-4.63, 7.45-7.52, 8.20-8.25.
参考例６
４－［２－クロロ－６－メチル－９－（１－｛［（２－メチル－２－プロパ二ル）オキシ］カルボニル｝－４－ピペリジニル）－８－オキソ－８，９－ジヒドロ－７Ｈ－プリン－７－イル］安息香酸
　参考例５で製造した化合物（469ｍｇ）をＴＨＦ（18ｍＬ）に溶解し、０℃に冷却した。そこへカリウム　トリメチルシラノラート（以下、ＴＭＳＯＫと略記することがある。）（239ｍｇ）を加えて室温で３時間攪拌した。反応液に１Ｎ塩酸を加えてｐＨ＝２とし、酢酸エチルで抽出した。得られた有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥して、減圧濃縮し、以下の物性値を有する標題化合物（450ｍｇ）を得た。
LC－MS（A）保持時間（分）：1.15；
MS(ESI, Pos.)： 488 (M + H)＋；
１H-NMR(CDCl３)：δ　 1.50, 1.76-1.86, 2.11, 2.48-2.66, 2.74-2.95, 4.24-4.44, 4.52-4.62, 7.49-7.53, 8.26-8.31。 Reference example 6
4-[2-chloro-6-methyl-9-(1-{[(2-methyl-2-propanyl)oxy]carbonyl}-4-piperidinyl)-8-oxo-8,9-dihydro-7H -purin-7-yl]benzoic acid The compound prepared in Reference Example 5 (469 mg) was dissolved in THF (18 mL) and cooled to 0°C. Potassium trimethylsilanolate (hereinafter sometimes abbreviated as TMSOK) (239 mg) was added thereto, and the mixture was stirred at room temperature for 3 hours. The reaction solution was adjusted to pH=2 by adding 1N hydrochloric acid, and extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the title compound (450 mg) having the following physical properties.
LC-MS (A) retention time (min): 1.15;
MS(ESI, Pos.): 488 (M + H) + ;
1H -NMR ( CDCl3 ): δ 1.50, 1.76-1.86, 2.11, 2.48-2.66, 2.74-2.95, 4.24-4.44, 4.52-4.62, 7.49-7.53, 8.26-8.31.
参考例７
２－メチル－２－プロパニル　４－［２－クロロ－７－（４－｛［９－（２，４－ジフルオロベンジル）－５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－イル］カルボニル｝フェニル）－６－メチル－８－オキソ－７，８－ジヒドロ－９Ｈ－プリン－９－イル］－１－ピペリジンカルボキシラート
　参考例２で製造した化合物（536ｍｇ）と参考例６で製造した化合物（650ｍｇ）をＤＭＦ（13ｍＬ）に溶解し、ＤＩＰＥＡ（0.69ｍＬ）と（ジメチルアミノ）－Ｎ，Ｎ－ジメチル（３Ｈ－［１，２，３］トリアゾロ［４，５－b］ピリジン－３－イルオキシ）メタニミニウムヘキサフルオロホスファート（以下、ＨＡＴＵと略記することがある。）（658ｍｇ）を加えて室温で２時間攪拌した。反応液に水を加えて希釈し、ヘキサン：酢酸エチル混合液（３：７）で抽出した。有機層を水と飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥して減圧濃縮した。得られた残渣をシリカゲルクロマトグラフィー（ヘキサン：酢酸エチル＝２：１→０：１）で精製することにより、以下の物性値を有する標題化合物（1.0ｇ）を得た。
LC－MS（A）保持時間（分）：1.27；
MS(ESI, Pos.)： 769 (M + H)＋；
１H-NMR(DMSO-d６)：δ　 1.44, 1.82, 2.25-2.40, 2.79-3.00, 3.60-4.16, 4.51, 4.59-4.91, 5.22-5.61, 6.84-7.08, 7.09-7.38, 7.65, 7.93, 8.24。 Reference example 7
2-Methyl-2-propanyl 4-[2-chloro-7-(4-{[9-(2,4-difluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3 ':4,5]pyrrolo[2,3-b]pyridin-7-yl]carbonyl}phenyl)-6-methyl-8-oxo-7,8-dihydro-9H-purin-9-yl]-1- Piperidine carboxylate The compound produced in Reference Example 2 (536 mg) and the compound produced in Reference Example 6 (650 mg) were dissolved in DMF (13 mL), and DIPEA (0.69 mL) and (dimethylamino)-N,N-dimethyl ( 3H-[1,2,3]triazolo[4,5-b]pyridin-3-yloxy)methaniminium hexafluorophosphate (hereinafter sometimes abbreviated as HATU) (658 mg) was added and the mixture was heated at room temperature. Stirred for 2 hours. The reaction solution was diluted with water and extracted with a hexane:ethyl acetate mixture (3:7). The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (hexane:ethyl acetate = 2:1→0:1) to obtain the title compound (1.0 g) having the following physical properties.
LC-MS (A) retention time (min): 1.27;
MS(ESI, Pos.): 769 (M + H) + ;
1 H-NMR (DMSO-d 6 ): δ 1.44, 1.82, 2.25-2.40, 2.79-3.00, 3.60-4.16, 4.51, 4.59-4.91, 5.22-5.61, 6.84-7.08, 7.09-7.38, 7.65, 7.93, 8.24.
参考例８
２－クロロ－７－（４－｛［９－（２，４－ジフルオロベンジル）－５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－イル］カルボニル｝フェニル）－６－メチル－９－（４－ピペリジニル）－７，９－ジヒドロ－８Ｈ－プリン－８－オン
　参考例７で製造した化合物（450ｍｇ）をメタノール（4.5ｍＬ）に溶解し、４Ｎ塩化水素／１，4－ジオキサン溶液（2.9ｍＬ）を加えて室温で２時間攪拌した。反応液を減圧濃縮し、得られた残渣をメタノールに溶解して、インジェクトカラム　アミノ（商品名）を通した。得られたろ液を濃縮することにより、以下の物性値を有する標題化合物（390ｍｇ）を得た。
LC－MS（A）保持時間（分）：0.96；
MS(ESI, Pos.)： 669 (M + H)＋。 Reference example 8
2-chloro-7-(4-{[9-(2,4-difluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[2, 3-b]pyridin-7-yl]carbonyl}phenyl)-6-methyl-9-(4-piperidinyl)-7,9-dihydro-8H-purin-8-one Compound produced in Reference Example 7 (450 mg) was dissolved in methanol (4.5 mL), 4N hydrogen chloride/1,4-dioxane solution (2.9 mL) was added, and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was dissolved in methanol and passed through an injection column Amino (trade name). By concentrating the obtained filtrate, the title compound (390 mg) having the following physical properties was obtained.
LC-MS (A) retention time (min): 0.96;
MS(ESI, Pos.): 669 (M + H) + .
参考例９
２－クロロ－７－（４－｛［９－（２，４－ジフルオロベンジル）－５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－イル］カルボニル｝フェニル）－９－［１－（２，２－ジメチルプロピル）－４－ピペリジニル］－６－メチル－７，９－ジヒドロ－８Ｈ－プリン－８－オン
　参考例８で製造した化合物（390ｍｇ）をＤＭＦ（7.8ｍＬ）に溶解し、ピバルアルデヒド（0.32ｍＬ）と酢酸（0.33ｍＬ）、トリアセトキシ水素化ホウ素ナトリウム（618ｍｇ）を加えて室温４時間攪拌した。反応液を氷冷し、飽和炭酸水素ナトリウム水溶液を加えた。酢酸エチルで抽出後、有機層を水で洗浄し、インジェクトカラム　アミノ（商品名）を通して濃縮し、以下の物性値を有する標題化合物（406ｍｇ）を得た。
LC－MS（A）保持時間（分）：1.06；
MS(ESI, Pos.)： 739 (M + H)＋。 Reference example 9
2-chloro-7-(4-{[9-(2,4-difluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[2, 3-b]pyridin-7-yl]carbonyl}phenyl)-9-[1-(2,2-dimethylpropyl)-4-piperidinyl]-6-methyl-7,9-dihydro-8H-purine-8- The compound prepared in Reference Example 8 (390 mg) was dissolved in DMF (7.8 mL), pivalaldehyde (0.32 mL), acetic acid (0.33 mL), and sodium triacetoxyborohydride (618 mg) were added, and the mixture was stirred at room temperature for 4 hours. Stirred. The reaction solution was cooled with ice, and saturated aqueous sodium hydrogen carbonate solution was added. After extraction with ethyl acetate, the organic layer was washed with water and concentrated through an injection column Amino (trade name) to obtain the title compound (406 mg) having the following physical properties.
LC-MS (A) retention time (min): 1.06;
MS(ESI, Pos.): 739 (M + H) + .
実施例１
２－アニリノ－７－（４－｛［９－（２，４－ジフルオロベンジル）－５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－イル］カルボニル｝フェニル）－９－［１－（２，２－ジメチルプロピル）－４－ピペリジニル］－６－メチル－７，９－ジヒドロ－８Ｈ－プリン－８－オン
　参考例９で製造した化合物（390ｍｇ）をトルエン（2.5ｍＬ）に溶解し、アニリン（94ｍｇ）及び炭酸セシウム（330ｍｇ）、Xantphos（44ｍｇ）、酢酸パラジウム（11ｍｇ）を加え、窒素雰囲気で１００℃で１時間攪拌した。反応液を室温に冷却した後、酢酸エチルで希釈し、有機層を水で２回と飽和食塩水で洗浄した。無水硫酸ナトリウムで乾燥後、有機層を減圧濃縮し、得られた残渣をシリカゲルクロマトグラフィー（富士シリシア　ＮＨ（商品名）、ヘキサン：酢酸エチル＝３：１→１：２）で精製することにより、以下の物性値を有する標題化合物（315ｍｇ）を得た。
LC－MS（A）保持時間（分）：1.04；
MS(ESI, Pos.)： 796 (M + H)＋；
１H-NMR(CDCl３)：δ　 0.95, 1.66-1.81, 1.99-2.07, 2.14, 2.38-2.53, 2.73-3.05, 3.69-4.16, 4.28-4.45, 4.55-4.95, 5.14-5.65, 6.66-7.06, 7.07-7.15, 7.33-7.40, 7.41-7.67, 7.67-7.74, 7.78-7.87, 8.32。 Example 1
2-anilino-7-(4-{[9-(2,4-difluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[2, 3-b]pyridin-7-yl]carbonyl}phenyl)-9-[1-(2,2-dimethylpropyl)-4-piperidinyl]-6-methyl-7,9-dihydro-8H-purine-8- The compound prepared in Reference Example 9 (390 mg) was dissolved in toluene (2.5 mL), aniline (94 mg), cesium carbonate (330 mg), Xantphos (44 mg), and palladium acetate (11 mg) were added, and the mixture was heated at 100°C in a nitrogen atmosphere. The mixture was stirred for 1 hour. After the reaction solution was cooled to room temperature, it was diluted with ethyl acetate, and the organic layer was washed twice with water and with saturated brine. After drying over anhydrous sodium sulfate, the organic layer was concentrated under reduced pressure, and the resulting residue was purified by silica gel chromatography (Fuji Silysia NH (trade name), hexane: ethyl acetate = 3:1 → 1:2). The title compound (315 mg) having the following physical properties was obtained.
LC-MS (A) retention time (min): 1.04;
MS(ESI, Pos.): 796 (M + H) + ;
1 H-NMR (CDCl 3 ): δ 0.95, 1.66-1.81, 1.99-2.07, 2.14, 2.38-2.53, 2.73-3.05, 3.69-4.16, 4.28-4.45, 4.55-4.95, 5.14-5.65, 6.66-7.06 , 7.07-7.15, 7.33-7.40, 7.41-7.67, 7.67-7.74, 7.78-7.87, 8.32.
実施例１－１
２－メチル－２－プロパニル　３－［２－アニリノ－７－（４－｛［９－（２，４－ジフルオロベンジル）－５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－イル］カルボニル｝フェニル）－６－メチル－８－オキソ－７，８－ジヒドロ－９Ｈ－プリン－９－イル］－１－ピペリジンカルボキシラート
　参考例３で用いた２－メチル－２－プロパニル　４－アミノ－１－ピぺリジンカルボキシラートの代わりに２－メチル－２－プロパニル　３－アミノ－１－ピぺリジンカルボキシラートを用いて、参考例３→参考例４→参考例５→参考例６→参考例７→実施例１と同様の操作を行い、以下の物性値を有する標題化合物を得た。
LC－MS（A）保持時間（分）：1.25；
MS(ESI, Pos.)： 826 (M + H)＋；
１H-NMR(CDCl３)：δ　 1.39-1.53, 1.62-1.77, 1.81-1.94, 1.95-2.12, 2.51-2.69, 2.70-2.84, 2.84-3.01, 3.65-4.35, 4.38-4.54, 4.54-4.99, 5.19-5.67, 6.66-6.81, 6.81-6.89, 6.89-7.07, 7.07-7.14, 7.30-7.39, 7.40-7.70, 7.77-7.87, 8.22-8.40。 Example 1-1
2-Methyl-2-propanyl 3-[2-anilino-7-(4-{[9-(2,4-difluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3 ':4,5]pyrrolo[2,3-b]pyridin-7-yl]carbonyl}phenyl)-6-methyl-8-oxo-7,8-dihydro-9H-purin-9-yl]-1- Piperidinecarboxylate 2-methyl-2-propanyl 3-amino-1-piperidinecarboxylate was used instead of 2-methyl-2-propanyl 4-amino-1-piperidinecarboxylate used in Reference Example 3. Then, the same operations as in Reference Example 3 → Reference Example 4 → Reference Example 5 → Reference Example 6 → Reference Example 7 → Example 1 were performed to obtain the title compound having the following physical property values.
LC-MS (A) retention time (min): 1.25;
MS(ESI, Pos.): 826 (M + H) + ;
1 H-NMR (CDCL 3 ): δ 1.39-1.53, 1.62-1.77, 1.81-1.94, 1.95-2.69, 2.70-2.84, 2.84-3.01, 2.84-3.01, 3.65-4.35, 4.38-4.54, 4.54-499, 4.54-499 5.19-5.67, 6.66-6.81, 6.81-6.89, 6.89-7.07, 7.07-7.14, 7.30-7.39, 7.40-7.70, 7.77-7.87, 8.22-8.40.
実施例２
２－シクロペンチル－７－（４－｛［９－（２，４－ジフルオロベンジル）－５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－イル］カルボニル｝フェニル）－９－［１－（２，２－ジメチルプロピル）－４－ピペリジニル］－６－メチル－７，９－ジヒドロ－８Ｈ－プリン－８－オン　２トリフルオロ酢酸塩
　参考例９で製造した化合物（20ｍｇ）をＴＨＦ（0.2ｍＬ）に溶解し、ブロモ（シクロペンチル）亜鉛（0.3ｍＬ、0.5 mol/L、ＴＨＦ溶液）及びパラジウム－トリス（２－メチル－２－プロパニル）ホスフィン（１：２）（2.8ｍｇ）を加えて、窒素雰囲気下１００℃で２時間攪拌した。反応液を氷冷し、飽和塩化アンモニウム水溶液を加えて、酢酸エチルで抽出した。有機層を濃縮して得られた残渣を逆相HPLCカラム精製することにより、以下の物性値を有する標題化合物（11ｍｇ）を得た。
LC－MS（A）保持時間（分）：1.06；
MS(ESI, Pos.)： 773 (M + H)＋；
１H-NMR(DMSO-d６)：δ　 1.02-1.16, 1.60-1.74, 1.74-1.85, 1.85-2.14, 2.81-3.07, 3.19-3.29, 3.62-3.73, 4.62-4.93, 5.19-5.62, 6.82-7.40, 7.45-7.81, 7.90-8.01, 8.19-8.31, 8.69-8.84, 8.92-9.02。 Example 2
2-Cyclopentyl-7-(4-{[9-(2,4-difluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[2, 3-b]pyridin-7-yl]carbonyl}phenyl)-9-[1-(2,2-dimethylpropyl)-4-piperidinyl]-6-methyl-7,9-dihydro-8H-purine-8- On 2-trifluoroacetate The compound prepared in Reference Example 9 (20 mg) was dissolved in THF (0.2 mL), and bromo(cyclopentyl)zinc (0.3 mL, 0.5 mol/L, THF solution) and palladium-tris (2- Methyl-2-propanyl)phosphine (1:2) (2.8 mg) was added, and the mixture was stirred at 100° C. for 2 hours under a nitrogen atmosphere. The reaction solution was cooled with ice, a saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. The residue obtained by concentrating the organic layer was purified using a reverse phase HPLC column to obtain the title compound (11 mg) having the following physical properties.
LC-MS (A) retention time (min): 1.06;
MS(ESI, Pos.): 773 (M + H) + ;
1 H-NMR (DMSO-d 6 ): δ 1.02-1.16, 1.60-1.74, 1.74-1.85, 1.85-2.14, 2.81-3.07, 3.19-3.29, 3.62-3.73, 4.62-4.93, 5.19-5.62, 6.82- 7.40, 7.45-7.81, 7.90-8.01, 8.19-8.31, 8.69-8.84, 8.92-9.02.
実施例３
１－｛７－（４－｛［９－（２，４－ジフルオロベンジル）－５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－イル］カルボニル｝フェニル）－９－［１－（２，２－ジメチルプロピル）－４－ピペリジニル］－６－メチル－８－オキソ－８，９－ジヒドロ－７Ｈ－プリン－２－イル｝－３－ピペリジンカルボン酸　２トリフルオロ酢酸塩
　参考例９で製造した化合物（15ｍｇ）にジメチルスルホキシド（以下、ＤＭＳＯと略記することがある。）（0.3ｍＬ）を加え、さらに３－ピペリジンカルボン酸（6.6ｍｇ）及びフッ化セシウム（7.7ｍｇ）、ＤＩＰＥＡ（0.035ｍＬ）を加えて１００℃で１５時間攪拌した。不溶物を綿栓でろ別し、ろ液を逆相HPLCカラム精製することにより、以下の物性値を有する標題化合物（15ｍｇ）を得た。
LC－MS（A）保持時間（分）：1.03；
MS(ESI, Pos.)： 832 (M + H)＋；
１H-NMR(DMSO-d６)：δ　 1.03-1.13, 1.40-1.57, 1.57-1.77, 1.77-2.09, 2.36-2.46, 2.82-2.97, 3.01-3.14, 3.15-3.27, 3.31-3.35, 3.59-3.73, 3.96-4.07, 4.20-4.29, 4.44-4.55, 4.55-4.80, 4.81-4.90, 5.18-5.60, 6.85-7.22, 7.28-7.40, 7.44-7.76, 7.90-7.98, 8.12-8.31, 8.46-8.78, 8.86-9.05。 Example 3
1-{7-(4-{[9-(2,4-difluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[2,3 -b]pyridin-7-yl]carbonyl}phenyl)-9-[1-(2,2-dimethylpropyl)-4-piperidinyl]-6-methyl-8-oxo-8,9-dihydro-7H-purine -2-yl}-3-piperidinecarboxylic acid 2-trifluoroacetate Dimethyl sulfoxide (hereinafter sometimes abbreviated as DMSO) (0.3 mL) was added to the compound prepared in Reference Example 9 (15 mg), and -Piperidinecarboxylic acid (6.6 mg), cesium fluoride (7.7 mg), and DIPEA (0.035 mL) were added, and the mixture was stirred at 100°C for 15 hours. Insoluble materials were filtered off using a cotton plug, and the filtrate was purified using a reverse phase HPLC column to obtain the title compound (15 mg) having the following physical properties.
LC-MS (A) retention time (min): 1.03;
MS(ESI, Pos.): 832 (M + H) + ;
1 H-NMR (DMSO-d 6 ): δ 1.03-1.13, 1.40-1.57, 1.57-1.77, 1.77-2.09, 2.36-2.46, 2.82-2.97, 3.01-3.14, 3.15-3.27, 3.31-3.35, 3.59- 3.73, 3.96-4.07, 4.20-4.29, 4.44-4.55, 4.55-4.80, 4.81-4.90, 5.18-5.60, 6.85-7.22, 7.28-7.40, 7.44-7.76, 7.90-7.98, 8.12-8. 31, 8.46-8.78, 8.86-9.05.
参考例１０
２－クロロ－７－（４－｛［９－（２，４－ジフルオロベンジル）－５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－イル］カルボニル｝フェニル）－９－［（３Ｓ）－１－（２，２－ジメチルプロピル）－３－ピペリジニル］－６－メチル－７，９－ジヒドロ－８Ｈ－プリン－８－オン
　参考例３で用いた２－メチル－２－プロパニル　４－アミノ－１－ピぺリジンカルボキシラートの代わりに２－メチル－２－プロパニル　（３Ｓ）－３－アミノ－１－ピぺリジンカルボキシラートを用いて、参考例３→参考例４→参考例５→参考例６→参考例７→参考例８→参考例９と同様の操作を行い、以下の物性値を有する標題化合物を得た。 Reference example 10
2-chloro-7-(4-{[9-(2,4-difluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[2, 3-b]pyridin-7-yl]carbonyl}phenyl)-9-[(3S)-1-(2,2-dimethylpropyl)-3-piperidinyl]-6-methyl-7,9-dihydro-8H- Purin-8-one 2-Methyl-2-propanyl (3S)-3-amino-1-piperidine was used instead of 2-methyl-2-propanyl 4-amino-1-piperidinecarboxylate used in Reference Example 3. Using peridine carboxylate, the same operations as in Reference Example 3 → Reference Example 4 → Reference Example 5 → Reference Example 6 → Reference Example 7 → Reference Example 8 → Reference Example 9 were performed to obtain the title compound having the following physical property values. I got it.
TLC：Rf 0.28（ヘキサン：酢酸エチル＝１：１）；
１H-NMR (CDCl３)：δ　 0.87, 1.72-1.82, 1.83-1.95, 2.06-2.22, 2.31-2.43, 2.77-2.95, 3.17, 3.69-4.17, 4.54-4.93, 5.21-5.59, 6.68-6.79, 6.85, 6.91-7.06, 7.11, 7.37-7.70, 7.82, 8.32。 TLC: Rf 0.28 (hexane: ethyl acetate = 1:1);
1 H-NMR (CDCl 3 ): δ 0.87, 1.72-1.82, 1.83-1.95, 2.06-2.22, 2.31-2.43, 2.77-2.95, 3.17, 3.69-4.17, 4.54-4.93, 5.21-5.59, 6.68-6.79 , 6.85, 6.91-7.06, 7.11, 7.37-7.70, 7.82, 8.32.
実施例４
２－アニリノ－７－（４－｛［９－（２，４－ジフルオロベンジル）－５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－イル］カルボニル｝フェニル）－９－［（３Ｓ）－１－（２，２－ジメチルプロピル）－３－ピペリジニル］－６－メチル－７，９－ジヒドロ－８Ｈ－プリン－８－オン
　参考例９で製造した化合物の代わりに参考例１０で製造した化合物を用いて、実施例１と同様の操作を行い、以下の物性値を有する標題化合物を得た。
LC－MS（A）保持時間（分）：1.13；
MS(ESI, Pos.)： 796 (M + H)＋；
１H-NMR(CDCl３)：δ　 0.89, 1.73-1.83, 1.83-1.94, 2.04, 2.09-2.21, 2.33-2.53, 2.81-2.97, 3.23, 3.69-4.10, 4.56-4.92, 5.22-5.59, 6.68-6.79, 6.81-6.97, 6.97-7.13, 7.30-7.38, 7.45-7.67, 7.69, 7.82, 8.32。 Example 4
2-anilino-7-(4-{[9-(2,4-difluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[2, 3-b]pyridin-7-yl]carbonyl}phenyl)-9-[(3S)-1-(2,2-dimethylpropyl)-3-piperidinyl]-6-methyl-7,9-dihydro-8H- Purin-8-one Using the compound produced in Reference Example 10 instead of the compound produced in Reference Example 9, the same operation as in Example 1 was carried out to obtain the title compound having the following physical property values.
LC-MS (A) retention time (min): 1.13;
MS(ESI, Pos.): 796 (M + H) + ;
1 H-NMR (CDCl 3 ): δ 0.89, 1.73-1.83, 1.83-1.94, 2.04, 2.09-2.21, 2.33-2.53, 2.81-2.97, 3.23, 3.69-4.10, 4.56-4.92, 5.22-5.59, 6.6 8- 6.79, 6.81-6.97, 6.97-7.13, 7.30-7.38, 7.45-7.67, 7.69, 7.82, 8.32.
実施例４－１
７－（４－｛［９－（２，４－ジフルオロベンジル）－５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－イル］カルボニル｝フェニル）－９－［（３Ｓ）－１－（２，２－ジメチルプロピル）－３－ピペリジニル］－６－メチル－２－｛［２－（トリフルオロメトキシ）フェニル］アミノ｝－７，９－ジヒドロ－８Ｈ－プリン－８－オン　２トリフルオロ酢酸塩
　アニリンの代わりに２－（トリフルオロメトキシ）アニリンを用いて、実施例４と同様の操作を行い、逆相HPLCカラム精製することにより、以下の物性値を有する標題化合物を得た。
LC－MS（A）保持時間（分）：1.14；
MS(ESI, Pos.)： 880 (M + H)＋；
１H-NMR(DMSO-d６)：δ　 1.07, 1.76-2.09, 2.24-2.37, 2.55, 2.80-2.96, 3.02-3.20, 3.59-4.07, 4.58-5.03, 5.24-5.64, 6.73-7.26, 7.30-7.48, 7.51-7.72, 7.90-8.07, 8.20-8.30, 8.73-8.98。 Example 4-1
7-(4-{[9-(2,4-difluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[2,3-b] pyridin-7-yl]carbonyl}phenyl)-9-[(3S)-1-(2,2-dimethylpropyl)-3-piperidinyl]-6-methyl-2-{[2-(trifluoromethoxy)phenyl ]Amino}-7,9-dihydro-8H-purin-8-one 2-trifluoroacetate The same operation as in Example 4 was carried out using 2-(trifluoromethoxy)aniline instead of aniline, and the reversed phase By HPLC column purification, the title compound having the following physical properties was obtained.
LC-MS (A) retention time (min): 1.14;
MS(ESI, Pos.): 880 (M + H) + ;
1 H-NMR (DMSO-d 6 ): δ 1.07, 1.76-2.09, 2.24-2.37, 2.55, 2.80-2.96, 3.02-3.20, 3.59-4.07, 4.58-5.03, 5.24-5.64, 6.73-7.26, 7.30- 7.48, 7.51-7.72, 7.90-8.07, 8.20-8.30, 8.73-8.98.
実施例５
２－（シクロペンチルオキシ）－７－（４－｛［９－（２，４－ジフルオロベンジル）－５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－イル］カルボニル｝フェニル）－９－［（３Ｒ）－１－（２，２－ジメチルプロピル）－３－ピペリジニル］－６－メチル－７，９－ジヒドロ－８Ｈ－プリン－８－オン　２トリフルオロ酢酸塩
　参考例３で用いた２－メチル－２－プロパニル　４－アミノ－１－ピぺリジンカルボキシラートの代わりに２－メチル－２－プロパニル　（３Ｒ）－３－アミノ－１－ピぺリジンカルボキシラートを用いて、参考例３→参考例４→参考例５→参考例６→参考例７→参考例８→参考例９→参考例１０と同様の操作で製造した化合物（18ｍｇ）を１－メチル－２－ピロリジノン（以下、ＮＭＰと略記することがある。）（0.19ｍＬ）に溶解し、シクロペンタノール（6.5ｍｇ）と炭酸セシウム（25ｍｇ）を加えて１１０℃で終夜攪拌した。反応液を逆相HPLCカラム精製することにより、以下の物性値を有する標題化合物（1.3ｍｇ）を得た。
LC－MS（A）保持時間（分）：1.14；
MS(ESI, Pos.)： 789 (M + H)＋；
１H-NMR(DMSO-d６)：δ　 1.00-1.11, 1.56-1.66, 1.66-1.79, 1.91-2.11, 2.81-2.90, 3.07-3.25, 3.62-3.80, 3.90-4.15, 4.79-5.06, 5.27-5.44, 5.51-5.65, 6.36-6.72, 6.88-7.17, 7.23-7.41, 7.48-7.82, 7.92-7.97, 8.19-8.33, 8.64-8.77。 Example 5
2-(cyclopentyloxy)-7-(4-{[9-(2,4-difluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo [2,3-b]pyridin-7-yl]carbonyl}phenyl)-9-[(3R)-1-(2,2-dimethylpropyl)-3-piperidinyl]-6-methyl-7,9-dihydro -8H-purin-8-one 2-trifluoroacetate 2-methyl-2-propanyl (3R) instead of 2-methyl-2-propanyl 4-amino-1-piperidinecarboxylate used in Reference Example 3 Using -3-amino-1-piperidinecarboxylate, the same procedure as in Reference Example 3 → Reference Example 4 → Reference Example 5 → Reference Example 6 → Reference Example 7 → Reference Example 8 → Reference Example 9 → Reference Example 10 The compound (18 mg) produced by this procedure was dissolved in 1-methyl-2-pyrrolidinone (hereinafter sometimes abbreviated as NMP) (0.19 mL), and cyclopentanol (6.5 mg) and cesium carbonate (25 mg) were added. In addition, the mixture was stirred at 110°C overnight. The reaction solution was purified using a reverse phase HPLC column to obtain the title compound (1.3 mg) having the following physical properties.
LC-MS (A) retention time (min): 1.14;
MS(ESI, Pos.): 789 (M + H) + ;
1 H-NMR (DMSO-d 6 ): δ 1.00-1.11, 1.56-1.66, 1.66-1.79, 1.91-2.11, 2.81-2.90, 3.07-3.25, 3.62-3.80, 3.90-4.15, 4.79-5.06, 5.27- 5.44, 5.51-5.65, 6.36-6.72, 6.88-7.17, 7.23-7.41, 7.48-7.82, 7.92-7.97, 8.19-8.33, 8.64-8.77.
実施例６
７－（４－｛［９－（２，４－ジフルオロベンジル）－５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－イル］カルボニル｝フェニル）－９－［（３Ｓ）－１－（２，２－ジメチルプロピル）－３－ピペリジニル］－２－（４－メトキシフェニル）－６－メチル－７，９－ジヒドロ－８Ｈ－プリン－８－オン
　参考例１０で製造した化合物（20ｍｇ）をＮＭＰ（0.4ｍＬ）に溶解し、（４－メトキシフェニル）ボロン酸（16ｍｇ）及びリン酸三カリウム水溶液（0.054ｍＬ、2mol/L）、［１，１’－ビス（ジフェニルホスフィノ）フェロセン］パラジウム（ＩＩ）ジクロリド　ジクロロメタン錯体（8.8ｍｇ）を加えて１００℃で４時間攪拌した。反応液を室温に冷却して水を加え、酢酸エチルで抽出した。得られた有機層を無水硫酸ナトリウムで乾燥後、減圧濃縮して得られた残渣をシリカゲルクロマトグラフィー（富士シリシア　ＮＨ（商品名）、ヘキサン：酢酸エチル＝７：３→０：１）で精製することにより、以下の物性値を有する標題化合物（4.4ｍｇ）を得た。
LC－MS（A）保持時間（分）：1.16；
MS(ESI, Pos.)： 811 (M + H)＋；
１H-NMR (CDCl３)：δ　 0.89, 1.76-1.85, 1.90-1.99, 2.14-2.24, 2.36-2.46, 2.50-2.61, 2.83-2.98, 3.28, 3.74-4.13, 3.89, 4.67-4.95, 5.28-5.59, 6.68-6.79, 6.80-6.96, 6.97-7.03, 7.07-7.13, 7.44-7.70, 7.78-7.85, 8.28-8.41。 Example 6
7-(4-{[9-(2,4-difluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[2,3-b] pyridin-7-yl]carbonyl}phenyl)-9-[(3S)-1-(2,2-dimethylpropyl)-3-piperidinyl]-2-(4-methoxyphenyl)-6-methyl-7,9 -Dihydro-8H-purin-8-one The compound prepared in Reference Example 10 (20 mg) was dissolved in NMP (0.4 mL), and (4-methoxyphenyl)boronic acid (16 mg) and tripotassium phosphate aqueous solution (0.054 mL) were dissolved in NMP (0.4 mL). . The reaction solution was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The obtained organic layer is dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting residue is purified by silica gel chromatography (Fuji Silysia NH (trade name), hexane:ethyl acetate = 7:3 → 0:1). As a result, the title compound (4.4 mg) having the following physical properties was obtained.
LC-MS (A) retention time (min): 1.16;
MS(ESI, Pos.): 811 (M + H) + ;
1 H-NMR (CDCl 3 ): δ 0.89, 1.76-1.85, 1.90-1.99, 2.14-2.24, 2.36-2.46, 2.50-2.61, 2.83-2.98, 3.28, 3.74-4.13, 3.89, 4.67-4.95, 5.2 8- 5.59, 6.68-6.79, 6.80-6.96, 6.97-7.03, 7.07-7.13, 7.44-7.70, 7.78-7.85, 8.28-8.41.
参考例１１
２－クロロ－Ｎ－（２，４－ジメトキシベンジル）－６－メチル－５－ニトロ－４－ピリミジンアミン
　２，４－ジクロロ－６－メチル－５－ニトロピリミジン（1.0ｇ）をＴＨＦ（20ｍＬ）に溶解し、－７０℃に冷却した。そこへ、１－（２，４－ジメトキシフェニル）メタンアミン（804ｍｇ）のＴＨＦ溶液（10ｍＬ）とＤＩＰＥＡ（1.25ｍＬ）を加えて－７０℃で２時間攪拌した。反応液を室温に戻した後、酢酸エチルで希釈し、有機層を水及び飽和食塩水で洗浄した。有機層を硫酸マグネシウムで乾燥して減圧濃縮し、得られた残渣をシリカゲルクロマトグラフィー（ヘキサン：酢酸エチル＝９：１→１：１）で精製することにより、以下の物性値を有する標題化合物（1.0ｇ）を得た。
TLC：Rf 0.27（ヘキサン：酢酸エチル＝９：１）；
１H-NMR(CDCl３)：δ　 2.70., 3.81, 3.88, 4.70, 6.43-6.51, 7.23-7.28, 8.71。 Reference example 11
2-Chloro-N-(2,4-dimethoxybenzyl)-6-methyl-5-nitro-4-pyrimidineamine 2,4-dichloro-6-methyl-5-nitropyrimidine (1.0 g) was dissolved in THF (20 mL). and cooled to -70°C. A THF solution (10 mL) of 1-(2,4-dimethoxyphenyl)methanamine (804 mg) and DIPEA (1.25 mL) were added thereto, and the mixture was stirred at -70°C for 2 hours. After the reaction solution was returned to room temperature, it was diluted with ethyl acetate, and the organic layer was washed with water and saturated brine. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure, and the resulting residue was purified by silica gel chromatography (hexane:ethyl acetate = 9:1 → 1:1) to obtain the title compound ( 1.0g) was obtained.
TLC: Rf 0.27 (hexane: ethyl acetate = 9:1);
1H -NMR ( CDCl3 ): δ 2.70., 3.81, 3.88, 4.70, 6.43-6.51, 7.23-7.28, 8.71.
参考例１２
２－クロロ－Ｎ－４－（２，４－ジメトキシベンジル）－６－メチル－４，５－ピリミジンジアミン
　亜鉛（15ｇ）と塩化アンモニウム（7.5ｇ）を水（5ｍＬ）に懸濁させ、参考例１１で製造した化合物（7.9ｇ）の酢酸エチル溶液（20ｍＬ）を加えて室温で５時間攪拌した。反応液をセライト（商品名）でろ過して不溶物を除去し、ろ液を飽和食塩水で洗浄した。得られた有機層を硫酸マグネシウムで乾燥後、減圧濃縮し、以下の物性値を有する標題化合物（5.3ｇ）を得た。
TLC：Rf 0.37（ヘキサン：酢酸エチル＝３：７）。 Reference example 12
2-chloro-N-4-(2,4-dimethoxybenzyl)-6-methyl-4,5-pyrimidinediaminezinc (15 g) and ammonium chloride (7.5 g) were suspended in water (5 mL), A solution of the compound prepared in step 11 (7.9 g) in ethyl acetate (20 mL) was added, and the mixture was stirred at room temperature for 5 hours. The reaction solution was filtered through Celite (trade name) to remove insoluble matter, and the filtrate was washed with saturated brine. The obtained organic layer was dried over magnesium sulfate and then concentrated under reduced pressure to obtain the title compound (5.3 g) having the following physical properties.
TLC: Rf 0.37 (hexane: ethyl acetate = 3:7).
参考例１３
２－クロロ－９－（２，４－ジメトキシベンジル）－６－メチル－７，９－ジヒドロ－８Ｈ－プリン－８－オン
　参考例１２で製造した化合物（5.3ｇ）をＴＨＦ（30ｍＬ）に溶解し、ＣＤＩ（5.6ｇ）とＤＢＵ（2.6ｇ）を加えて室温で１６時間攪拌した。反応液を酢酸エチルで希釈し、１Ｎ塩酸と飽和炭酸ナトリウム水溶液、飽和食塩水で順次洗浄した。得られた有機層を硫酸マグネシウムで乾燥し、減圧濃縮して得られた残渣をＭＴＢＥで洗浄して、ろ取することにより、以下の物性値を有する標題化合物（5.8ｇ）を得た。
TLC：Rf 0.43（ヘキサン：酢酸エチル＝３：７）；
１H-NMR(CDCl３)：δ　 2.50, 3.78, 3.80, 5.07, 6.38-6.45, 7.17, 9.16-9.27。 Reference example 13
2-Chloro-9-(2,4-dimethoxybenzyl)-6-methyl-7,9-dihydro-8H-purin-8-one The compound (5.3 g) prepared in Reference Example 12 was dissolved in THF (30 mL). Then, CDI (5.6 g) and DBU (2.6 g) were added, and the mixture was stirred at room temperature for 16 hours. The reaction solution was diluted with ethyl acetate and washed successively with 1N hydrochloric acid, saturated aqueous sodium carbonate solution, and saturated brine. The obtained organic layer was dried over magnesium sulfate, concentrated under reduced pressure, and the resulting residue was washed with MTBE and collected by filtration to obtain the title compound (5.8 g) having the following physical properties.
TLC: Rf 0.43 (hexane: ethyl acetate = 3:7);
1H -NMR ( CDCl3 ): δ 2.50, 3.78, 3.80, 5.07, 6.38-6.45, 7.17, 9.16-9.27.
参考例１４
メチル　４－［２－クロロ－９－（２，４－ジメトキシベンジル）－６－メチル－８－オキソ－８，９－ジヒドロ－７Ｈ－プリン－７－イル］ベンゾアート
　参考例１３で製造した化合物（1.3ｇ）をアセトニトリル（536ｍＬ）に溶解し、［４－（メトキシカルボニル)フェニル］ボロン酸（2.2ｇ）及びＮ，Ｎ－ジエチルエタンアミン（以下、ＮＥｔ３と略記することがある。）（11ｍＬ）、ピリジン（30ｍＬ）、酢酸銅（ＩＩ）（1.5ｇ）を加えた。反応容器内を酸素に置換して、室温で２１時間攪拌した。反応液を濃縮して酢酸エチルに溶解し、アンモニア水、水、１Ｎ塩酸、水、飽和炭酸水素ナトリウム、飽和食塩水で、順次洗浄した。得られた有機層を無水硫酸ナトリウムで乾燥後、減圧濃縮して得られた残渣をシリカゲルクロマトグラフィー（ヘキサン：酢酸エチル＝６７：３３）で精製することにより、以下の物性値を有する標題化合物（1.5ｇ）を得た。
TLC：Rf 0.23（ヘキサン：酢酸エチル＝２：１）；
１H-NMR(CDCl３)：δ　 2.09, 3.79, 3.82, 3.96, 5.14, 6.41-6.47, 7.27-7.31, 7.43-7.48, 8.16-8.23。 Reference example 14
Methyl 4-[2-chloro-9-(2,4-dimethoxybenzyl)-6-methyl-8-oxo-8,9-dihydro-7H-purin-7-yl]benzoate Compound produced in Reference Example 13 (1.3 g) in acetonitrile (536 mL), [4-(methoxycarbonyl)phenyl]boronic acid (2.2 g) and N,N-diethylethanamine (hereinafter sometimes abbreviated as NEt 3 ) ( 11 mL), pyridine (30 mL), and copper(II) acetate (1.5 g). The inside of the reaction vessel was replaced with oxygen, and the mixture was stirred at room temperature for 21 hours. The reaction solution was concentrated, dissolved in ethyl acetate, and washed successively with aqueous ammonia, water, 1N hydrochloric acid, water, saturated sodium bicarbonate, and saturated brine. The obtained organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting residue was purified by silica gel chromatography (hexane: ethyl acetate = 67:33) to obtain the title compound ( 1.5g) was obtained.
TLC: Rf 0.23 (hexane: ethyl acetate = 2:1);
1H -NMR ( CDCl3 ): δ 2.09, 3.79, 3.82, 3.96, 5.14, 6.41-6.47, 7.27-7.31, 7.43-7.48, 8.16-8.23.
参考例１５
４－［２－クロロ－９－（２，４－ジメトキシベンジル）－６－メチル－８－オキソ－８，９－ジヒドロ－７Ｈ－プリン－７－イル］安息香酸
　参考例１４で製造した化合物（1.5ｇ）をＴＨＦ（30ｍＬ）に溶解し、ＴＭＳＯＫ（844ｍｇ）を加えて室温で９０分攪拌した。反応液を水で希釈し、１Ｎ塩酸でｐＨ２以下とした。酢酸エチルで抽出し、得られた有機層を水及び飽和食塩水で洗浄した。無水硫酸ナトリウムで乾燥後、減圧濃縮して、以下の物性値を有する標題化合物（1.5ｇ）を得た。
TLC：Rf 0.31（ジクロロメタン：メタノール＝９：１）；
１H-NMR(DMSO-d６)：δ　 1.99, 3.69-3.76, 3.79-3.87, 4.96, 6.46, 6.60, 7.03, 7.65-7.73, 8.08-8.15, 13.25。 Reference example 15
4-[2-chloro-9-(2,4-dimethoxybenzyl)-6-methyl-8-oxo-8,9-dihydro-7H-purin-7-yl]benzoic acid Compound produced in Reference Example 14 ( 1.5 g) was dissolved in THF (30 mL), TMSOK (844 mg) was added, and the mixture was stirred at room temperature for 90 minutes. The reaction solution was diluted with water and adjusted to pH 2 or less with 1N hydrochloric acid. Extraction was performed with ethyl acetate, and the resulting organic layer was washed with water and saturated brine. After drying over anhydrous sodium sulfate, the residue was concentrated under reduced pressure to obtain the title compound (1.5 g) having the following physical properties.
TLC: Rf 0.31 (dichloromethane:methanol = 9:1);
1H -NMR (DMSO- d6 ): δ 1.99, 3.69-3.76, 3.79-3.87, 4.96, 6.46, 6.60, 7.03, 7.65-7.73, 8.08-8.15, 13.25.
参考例１６
２－クロロ－７－（４－｛［９－（２，４－ジフルオロベンジル）－５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－イル］カルボニル｝フェニル）－９－（２，４－ジメトキシベンジル）－６－メチル－７，９－ジヒドロ－８Ｈ－プリン－８－オン
　参考例１５で製造した化合物（1.6ｇ）と参考例２で製造した化合物（1.2ｇ）をＤＭＦ（15ｍＬ）に溶解し、ＤＩＰＥＡ（2.0ｍＬ）とＨＡＴＵ（1.7ｇ）を加えて室温で１５時間攪拌した。反応液を水で希釈し、酢酸エチルで抽出した。有機層を無水硫酸ナトリウムで乾燥し、濃縮した。得られた残渣をシリカゲルクロマトグラフィー（ヘキサン：酢酸エチル＝３３：６７）で精製することにより、以下の物性値を有する標題化合物（2.1ｇ）を得た。
TLC：Rf 0.30（ヘキサン：酢酸エチル＝１：２）；
１H-NMR(CDCl３)：δ　 2.11, 2.78-2.98, 3.79, 3.83, 4.50-4.97, 5.16, 5.24-5.60, 6.43-6.48, 6.65-7.03, 7.11, 7.28-7.35, 7.38-7.69, 7.82, 8.32。 Reference example 16
2-chloro-7-(4-{[9-(2,4-difluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[2, 3-b]pyridin-7-yl]carbonyl}phenyl)-9-(2,4-dimethoxybenzyl)-6-methyl-7,9-dihydro-8H-purin-8-one Compound produced in Reference Example 15 (1.6 g) and the compound produced in Reference Example 2 (1.2 g) were dissolved in DMF (15 mL), DIPEA (2.0 mL) and HATU (1.7 g) were added, and the mixture was stirred at room temperature for 15 hours. The reaction solution was diluted with water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated. The obtained residue was purified by silica gel chromatography (hexane: ethyl acetate = 33:67) to obtain the title compound (2.1 g) having the following physical properties.
TLC: Rf 0.30 (hexane: ethyl acetate = 1:2);
1 H-NMR (CDCl 3 ): δ 2.11, 2.78-2.98, 3.79, 3.83, 4.50-4.97, 5.16, 5.24-5.60, 6.43-6.48, 6.65-7.03, 7.11, 7.28-7.35, 7.38-7.69, 7. 82, 8.32.
参考例１７
２－クロロ－７－（４－｛［９－（２，４－ジフルオロベンジル）－５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－イル］カルボニル｝フェニル）－６－メチル－７，９－ジヒドロ－８Ｈ－プリン－８－オン　ナトリウム塩
　参考例１６で製造した化合物（2.1ｇ）にトリフルオロ酢酸（26.7ｍＬ）とトリエチルシラン（2.1ｍＬ）を加えて７０℃で２１時間攪拌した。反応液を室温へ冷却し、２Ｎ水酸化ナトリウム水溶液及び水で抽出した。得られた水層をＭＴＢＥで洗浄して２Ｎ塩酸を加え、生じた析出物をろ取した。ろ取物を再度酢酸エチルに溶解し、２Ｎ水酸化ナトリウム水溶液で抽出した。得られた水層から生じた析出物をろ取し、水及び酢酸エチルで洗浄することにより、以下の物性値を有する標題化合物（1.5ｇ）を得た。
TLC：Rf 0.43（酢酸エチル）；
１H-NMR(DMSO-d６)：δ　 1.87, 2.86, 3.61-4.08, 4.65-4.90, 5.19-5.62, 6.81-7.19, 7.19-7.81, 7.93, 8.24。 Reference example 17
2-chloro-7-(4-{[9-(2,4-difluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[2, 3-b]pyridin-7-yl]carbonyl}phenyl)-6-methyl-7,9-dihydro-8H-purin-8-one sodium salt The compound prepared in Reference Example 16 (2.1 g) was added with trifluoroacetic acid ( 26.7 mL) and triethylsilane (2.1 mL) were added and stirred at 70°C for 21 hours. The reaction solution was cooled to room temperature and extracted with 2N aqueous sodium hydroxide solution and water. The resulting aqueous layer was washed with MTBE, 2N hydrochloric acid was added, and the resulting precipitate was collected by filtration. The filtered material was dissolved again in ethyl acetate and extracted with 2N aqueous sodium hydroxide solution. The precipitate produced from the resulting aqueous layer was collected by filtration and washed with water and ethyl acetate to obtain the title compound (1.5 g) having the following physical properties.
TLC: Rf 0.43 (ethyl acetate);
1H -NMR (DMSO- d6 ): δ 1.87, 2.86, 3.61-4.08, 4.65-4.90, 5.19-5.62, 6.81-7.19, 7.19-7.81, 7.93, 8.24.
参考例１８
２－クロロ－７－（４－｛［９－（２，４－ジフルオロベンジル）－５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－イル］カルボニル｝フェニル）－６－メチル－９－［３－（４－モルホリニル）プロピル］－７，９－ジヒドロ－８Ｈ－プリン－８－オン
　参考例１７で製造した化合物（18ｍｇ）をＤＭＦ（0.3ｍＬ）に溶解し、４－（３－クロロプロピル）モルホリン塩酸塩（18ｍｇ）と炭酸セシウム（59ｍｇ）を加えて８０℃で１７時間攪拌した。反応液を室温へ冷却し、水で希釈して酢酸エチルで抽出した。有機層を無水硫酸ナトリウムで乾燥し、減圧濃縮して得られた残渣をシリカゲルクロマトグラフィー（富士シリシア　ＮＨ（商品名）、ヘキサン：酢酸エチル＝３３：６７）で精製することにより、以下の物性値を有する標題化合物（13ｍｇ）を得た。
LC－MS（A）保持時間（分）：0.99；
MS(ESI, Pos.)： 713 (M + H)＋；
１H-NMR(CDCl３)：δ　 2.01-2.07, 2.13, 2.43, 2.46-2.52, 2.85-2.93, 3.61-3.82, 4.13, 4.52-4.95, 5.19-5.58, 6.64-6.79, 6.85, 6.92-7.03, 7.11, 7.36-7.71, 7.82, 8.33。 Reference example 18
2-chloro-7-(4-{[9-(2,4-difluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[2, 3-b]pyridin-7-yl]carbonyl}phenyl)-6-methyl-9-[3-(4-morpholinyl)propyl]-7,9-dihydro-8H-purin-8-one Manufactured according to Reference Example 17 The obtained compound (18 mg) was dissolved in DMF (0.3 mL), 4-(3-chloropropyl)morpholine hydrochloride (18 mg) and cesium carbonate (59 mg) were added, and the mixture was stirred at 80° C. for 17 hours. The reaction solution was cooled to room temperature, diluted with water, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting residue was purified by silica gel chromatography (Fuji Silysia NH (trade name), hexane:ethyl acetate = 33:67) to obtain the following physical properties. The title compound (13 mg) was obtained.
LC-MS (A) retention time (min): 0.99;
MS(ESI, Pos.): 713 (M + H) + ;
1 H-NMR (CDCl 3 ): δ 2.01-2.07, 2.13, 2.43, 2.46-2.52, 2.85-2.93, 3.61-3.82, 4.13, 4.52-4.95, 5.19-5.58, 6.64-6.79, 6.85, 6.92-7.0 3, 7.11, 7.36-7.71, 7.82, 8.33.
実施例７
２－アニリノ－７－（４－｛［９－（２，４－ジフルオロベンジル）－５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－イル］カルボニル｝フェニル）－６－メチル－９－［３－（４－モルホリニル）プロピル］－７，９－ジヒドロ－８Ｈ－プリン－８－オン
　参考例９で製造した化合物の代わりに参考例１８で製造した化合物（35ｍｇ）を用いて、実施例１と同様の操作を行い、以下の物性値を有する標題化合物（32ｍｇ）を得た。
LC－MS（A）保持時間（分）：0.98；
MS(ESI, Pos.)： 770 (M + H)＋；
１H-NMR(CDCl３)：δ　 2.05-2.12, 2.43, 2.51, 2.88, 3.58-3.74, 3.72-4.11, 4.50-4.96, 5.22-5.62, 6.66-6.79, 6.81-6.89, 6.90-7.05, 7.11, 7.33, 7.42-7.71, 7.78-7.86, 8.32。 Example 7
2-anilino-7-(4-{[9-(2,4-difluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[2, 3-b]pyridin-7-yl]carbonyl}phenyl)-6-methyl-9-[3-(4-morpholinyl)propyl]-7,9-dihydro-8H-purin-8-one Manufactured according to Reference Example 9 The same operation as in Example 1 was carried out using the compound (35 mg) produced in Reference Example 18 instead of the compound obtained above, to obtain the title compound (32 mg) having the following physical properties.
LC-MS (A) retention time (min): 0.98;
MS(ESI, Pos.): 770 (M + H) + ;
1 H-NMR (CDCl 3 ): δ 2.05-2.12, 2.43, 2.51, 2.88, 3.58-3.74, 3.72-4.11, 4.50-4.96, 5.22-5.62, 6.66-6.79, 6.81-6.89, 6.90-7.05, 7.1 1, 7.33, 7.42-7.71, 7.78-7.86, 8.32.
実施例７－１～３
　４－（３－クロロプロピル）モルホリン塩酸塩の代わりに相当するアミン化合物を用いて、参考例１８→実施例７と同様の操作を行い、シリカゲルカラム精製もしくは逆相HPLCカラム精製することにより、以下の物性値を有する標題化合物を得た。 Examples 7-1 to 3
Using the corresponding amine compound instead of 4-(3-chloropropyl)morpholine hydrochloride, the same operation as in Reference Example 18 → Example 7 was carried out, and the following was obtained by purifying with a silica gel column or reversed phase HPLC column. The title compound having the physical property values was obtained.
実施例７－１
２－アニリノ－７－（４－｛［９－（２，４－ジフルオロベンジル）－５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－イル］カルボニル｝フェニル）－６－メチル－９－（テトラヒドロ－３－フラニル）－７，９－ジヒドロ－８Ｈ－プリン－８－オン　２トリフルオロ酢酸塩
LC－MS（A）保持時間（分）：1.28；
MS(ESI, Pos.)： 713 (M + H)＋；
１H-NMR(DMSO-d６)：δ　 1.85-2.02, 2.25-2.35, 2.55-2.61, 2.81-2.92, 3.60-3.75, 3.83-4.11, 4.13-4.24, 4.55-4.93, 5.03-5.15, 5.23-5.62, 6.84-7.20, 7.23-7.37, 7.49-7.71, 7.78, 7.91-7.98, 8.21-8.29, 9.43。 Example 7-1
2-anilino-7-(4-{[9-(2,4-difluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[2, 3-b]pyridin-7-yl]carbonyl}phenyl)-6-methyl-9-(tetrahydro-3-furanyl)-7,9-dihydro-8H-purin-8-one 2 trifluoroacetate
LC-MS (A) retention time (min): 1.28;
MS(ESI, Pos.): 713 (M + H) + ;
1 H-NMR (DMSO-d 6 ): δ 1.85-2.02, 2.25-2.35, 2.55-2.61, 2.81-2.92, 3.60-3.75, 3.83-4.11, 4.13-4.24, 4.55-4.93, 5.03-5.15, 5.23- 5.62, 6.84-7.20, 7.23-7.37, 7.49-7.71, 7.78, 7.91-7.98, 8.21-8.29, 9.43.
実施例７－２
２－アニリノ－７－（４－｛［９－（２，４－ジフルオロベンジル）－５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－イル］カルボニル｝フェニル）－６－メチル－９－｛２－［メチル（２，２，２－トリフルオロエチル）アミノ］エチル｝－７，９－ジヒドロ－８Ｈ－プリン－８－オン　２トリフルオロ酢酸塩
LC－MS（A）保持時間（分）：1.36；
MS(ESI, Pos.)： 782 (M + H)＋；
１H-NMR(DMSO-d６)：δ　 1.86-2.03, 2.82-2.90, 3.01-3.07, 3.23-3.33, 3.43, 3.65-3.73, 3.96-4.04, 4.57-4.93, 5.24-5.61, 6.86-7.18, 7.23-7.37, 7.47-7.72, 7.80, 7.90-7.97, 8.22-8.28, 9.46。 Example 7-2
2-anilino-7-(4-{[9-(2,4-difluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[2, 3-b]pyridin-7-yl]carbonyl}phenyl)-6-methyl-9-{2-[methyl(2,2,2-trifluoroethyl)amino]ethyl}-7,9-dihydro-8H- Purin-8-one 2-trifluoroacetate
LC-MS (A) retention time (min): 1.36;
MS(ESI, Pos.): 782 (M + H) + ;
1 H-NMR (DMSO-d 6 ): δ 1.86-2.03, 2.82-2.90, 3.01-3.07, 3.23-3.33, 3.43, 3.65-3.73, 3.96-4.04, 4.57-4.93, 5.24-5.61, 6.86-7.18, 7.23-7.37, 7.47-7.72, 7.80, 7.90-7.97, 8.22-8.28, 9.46.
実施例７－３
３－｛３－［２－アニリノ－７－（４－｛［９－（２，４－ジフルオロベンジル）－５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－イル］カルボニル｝フェニル）－６－メチル－８－オキソ－７，８－ジヒドロ－９Ｈ－プリン－９－イル］プロピル｝－５，５－ジメチル－１，３－オキサゾリジン－２，４－ジオン
LC－MS（A）保持時間（分）：1.14；
MS(ESI, Pos.)： 812 (M + H)＋；
１H-NMR (CDCl３)：δ　 1.55-1.59, 2.03-2.09, 2.32, 2.84-2.95, 3.63-3.73, 3.74-4.12, 4.03, 4.53-4.94, 5.19-5.60, 6.68-6.79, 6.86, 6.91-7.13, 7.35, 7.45-7.72, 7.83, 8.32。 Example 7-3
3-{3-[2-anilino-7-(4-{[9-(2,4-difluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4, 5] Pyrrolo[2,3-b]pyridin-7-yl]carbonyl}phenyl)-6-methyl-8-oxo-7,8-dihydro-9H-purin-9-yl]propyl}-5,5- Dimethyl-1,3-oxazolidine-2,4-dione
LC-MS (A) retention time (min): 1.14;
MS(ESI, Pos.): 812 (M + H) + ;
1 H-NMR (CDCl 3 ): δ 1.55-1.59, 2.03-2.09, 2.32, 2.84-2.95, 3.63-3.73, 3.74-4.12, 4.03, 4.53-4.94, 5.19-5.60, 6.68-6.79, 6.86, 6.9 1- 7.13, 7.35, 7.45-7.72, 7.83, 8.32.
参考例１９
２－クロロ－７－（４－｛［９－（２，４－ジフルオロベンジル）－５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－イル］カルボニル｝フェニル）－９－イソプロピル－６－メチル－７，９－ジヒドロ－８Ｈ－プリン－８－オン
　参考例１８で使用した４－（３－クロロプロピル）モルホリン塩酸塩の代わりに、２－ヨードプロパンを用いて、参考例１８と同様の操作を行い、以下の物性値を有する標題化合物を得た。
TLC：Rf 0.39（ヘキサン：酢酸エチル＝１：２）；
１H-NMR(CDCl３)：δ　 1.64, 2.11, 2.83-2.91, 3.64-4.18, 4.53-4.95, 5.20-5.60, 6.67-6.80, 6.80-6.91, 6.91-7.05, 7.11, 7.37-7.71, 7.82, 8.32。 Reference example 19
2-chloro-7-(4-{[9-(2,4-difluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[2, 3-b]pyridin-7-yl]carbonyl}phenyl)-9-isopropyl-6-methyl-7,9-dihydro-8H-purin-8-one 4-(3-chloropropyl) used in Reference Example 18 The same operation as in Reference Example 18 was carried out using 2-iodopropane instead of morpholine hydrochloride to obtain the title compound having the following physical properties.
TLC: Rf 0.39 (hexane: ethyl acetate = 1:2);
1 H-NMR (CDCl 3 ): δ 1.64, 2.11, 2.83-2.91, 3.64-4.18, 4.53-4.95, 5.20-5.60, 6.67-6.80, 6.80-6.91, 6.91-7.05, 7.11, 7.37-7.71, 7.8 2, 8.32.
実施例８
７－（４－｛［９－（２，４－ジフルオロベンジル）－５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－イル］カルボニル｝フェニル）－９－イソプロピル－２，６－ジメチル－７，９－ジヒドロ－８Ｈ－プリン－８－オン
　参考例１９で製造した化合物（39ｍｇ）をＤＭＥ（1ｍＬ）に溶解し、トリメチルボロキシン（39ｍｇ）及びリン酸三カリウム水溶液（0.062ｍＬ、2mol/L）、［１，１’－ビス（ジフェニルホスフィノ）フェロセン］パラジウム（ＩＩ）ジクロリド　ジクロロメタン錯体（4.5mg）を加えて、マイクロウェーブ装置を用いて１４０℃で１時間攪拌した。反応液を室温に冷却して水を加え、酢酸エチルで抽出した。得られた有機層を無水硫酸ナトリウムで乾燥後、減圧濃縮して得られた残渣をプレパラティブTLC（ジクロロメタン：メタノール＝９：１）で精製することにより、以下の物性値を有する標題化合物（30ｍｇ）を得た。
LC－MS（A）保持時間（分）：0.96；
MS(ESI, Pos.)： 608 (M + H)＋；
１H-NMR((CDCl３)：δ　 1.64, 2.03-2.15, 2.67, 2.81-2.98, 3.70-4.17, 4.57-4.95, 5.31-5.61, 6.66-6.78, 6.81-6.91, 6.90-7.05, 7.11, 7.41-7.71, 7.82, 8.32。 Example 8
7-(4-{[9-(2,4-difluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[2,3-b] Pyridin-7-yl]carbonyl}phenyl)-9-isopropyl-2,6-dimethyl-7,9-dihydro-8H-purin-8-one The compound (39 mg) prepared in Reference Example 19 was dissolved in DME (1 mL). Dissolve trimethylboroxine (39 mg), tripotassium phosphate aqueous solution (0.062 mL, 2 mol/L), and [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane complex (4.5 mg). In addition, the mixture was stirred at 140° C. for 1 hour using a microwave device. The reaction solution was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The obtained organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting residue was purified by preparative TLC (dichloromethane:methanol = 9:1) to obtain the title compound (30 mg) having the following physical properties. ) was obtained.
LC-MS (A) retention time (min): 0.96;
MS(ESI, Pos.): 608 (M + H) + ;
1 H-NMR ((CDCl 3 ): δ 1.64, 2.03-2.15, 2.67, 2.81-2.98, 3.70-4.17, 4.57-4.95, 5.31-5.61, 6.66-6.78, 6.81-6.91, 6.90-7.05, 7.11, 7. 41 -7.71, 7.82, 8.32.
実施例９
７－（４－｛［９－（２，４－ジフルオロベンジル）－５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－イル］カルボニル｝フェニル）－９－イソプロピル－６－メチル－８－オキソ－８，９－ジヒドロ－７Ｈ－プリン－２－カルボニトリル
　参考例１９で製造した化合物（69ｍｇ）をＤＭＳＯ（1ｍＬ）に溶解し、N，N，N－トリブチル－１－ブタンアミニウム　シアニド（88ｍｇ）及びＤＢＵ（0.036ｍＬ）を加えて１００℃で２時間攪拌した。反応液を室温に冷却して水を加え、酢酸エチルで抽出した。得られた有機層を無水硫酸ナトリウムで乾燥後、減圧濃縮して得られた残渣をシリカゲルクロマトグラフィー（ヘキサン：酢酸エチル＝３３：６７）で精製することにより、以下の物性値を有する標題化合物（64ｍｇ）を得た。
LC－MS（A）保持時間（分）：1.23；
MS(ESI, Pos.)： 619 (M + H)＋；
１H-NMR(CDCl３)：δ　 1.63-1.69, 2.15, 2.84-3.03, 3.69-4.10, 4.53-5.00, 5.22-5.61, 6.69-6.78, 6.77-6.90, 6.91-7.04, 7.11, 7.39-7.73, 7.82, 8.32。 Example 9
7-(4-{[9-(2,4-difluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[2,3-b] Pyridin-7-yl]carbonyl}phenyl)-9-isopropyl-6-methyl-8-oxo-8,9-dihydro-7H-purine-2-carbonitrile The compound (69 mg) prepared in Reference Example 19 was dissolved in DMSO ( N,N,N-tributyl-1-butanaminium cyanide (88 mg) and DBU (0.036 mL) were added, and the mixture was stirred at 100°C for 2 hours. The reaction solution was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The obtained organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting residue was purified by silica gel chromatography (hexane: ethyl acetate = 33:67) to obtain the title compound ( 64 mg) was obtained.
LC-MS (A) retention time (min): 1.23;
MS(ESI, Pos.): 619 (M + H) + ;
1 H-NMR (CDCl 3 ): δ 1.63-1.69, 2.15, 2.84-3.03, 3.69-4.10, 4.53-5.00, 5.22-5.61, 6.69-6.78, 6.77-6.90, 6.91-7.04, 7.11, 7.39-7.73 , 7.82, 8.32.
参考例２０
メチル　４－［９－（２，４－ジメトキシベンジル）－６－メチル－８－オキソ－８，９－ジヒドロ－７Ｈ－プリン－７－イル］ベンゾアート
　参考例１４で製造した化合物（120ｍｇ）をＴＨＦ（5ｍＬ）とメタノール（5ｍＬ）に溶解し、ＮＥｔ３（0.043ｍＬ）及び５％パラジウム－活性炭素（50％ｗｅｔ、50ｍｇ）を加えて、反応容器内を水素へ置換し、室温で３時間攪拌した。反応液をセライト（商品名）でろ過し、得られたろ液を減圧濃縮して以下の物性値を有する標題化合物（120ｍｇ）を得た。
LC－MS（B）保持時間（分）：0.86；
MS(ESI, Pos.)： 435 (M + H)＋；
１H-NMR(CDCl３)：δ　 3.77-3.84, 3.96, 5.18, 6.41-6.45, 6.45, 7.23, 7.46-7.53, 8.18-8.23, 8.64。 Reference example 20
Methyl 4-[9-(2,4-dimethoxybenzyl)-6-methyl-8-oxo-8,9-dihydro-7H-purin-7-yl]benzoate The compound prepared in Reference Example 14 (120 mg) Dissolved in THF (5 mL) and methanol (5 mL), added NEt 3 (0.043 mL) and 5% palladium-activated carbon (50% wet, 50 mg), purged the inside of the reaction vessel with hydrogen, and left at room temperature for 3 hours. Stirred. The reaction solution was filtered through Celite (trade name), and the resulting filtrate was concentrated under reduced pressure to obtain the title compound (120 mg) having the following physical properties.
LC-MS (B) retention time (min): 0.86;
MS(ESI, Pos.): 435 (M + H) + ;
1H -NMR ( CDCl3 ): δ 3.77-3.84, 3.96, 5.18, 6.41-6.45, 6.45, 7.23, 7.46-7.53, 8.18-8.23, 8.64.
参考例２１
４－［９－（２，４－ジメトキシベンジル）－６－メチル－８－オキソ－８，９－ジヒドロ－７Ｈ－プリン－７－イル］安息香酸
　参考例２０で製造した化合物（120ｍｇ）をＴＨＦ（0.6ｍＬ）とメタノール（0.6ｍＬ）に溶解し、２Ｎ水酸化ナトリウム水溶液（0.28ｍＬ）を加えて室温で３時間攪拌した。反応液に２Ｎ塩酸を加えてｐHを３程度に合わせて酢酸エチルで抽出し、有機層を飽和食塩水で洗浄した。有機層を無水硫酸ナトリウムで乾燥後、減圧濃縮して以下の物性値を有する標題化合物（106ｍｇ）を得た。
LC－MS（B）保持時間（分）：0.76；
MS(ESI, Pos.)： 421 (M + H)＋。 Reference example 21
4-[9-(2,4-dimethoxybenzyl)-6-methyl-8-oxo-8,9-dihydro-7H-purin-7-yl]benzoic acid The compound (120 mg) produced in Reference Example 20 was dissolved in THF. (0.6 mL) and methanol (0.6 mL), 2N aqueous sodium hydroxide solution (0.28 mL) was added, and the mixture was stirred at room temperature for 3 hours. 2N hydrochloric acid was added to the reaction solution to adjust the pH to about 3, followed by extraction with ethyl acetate, and the organic layer was washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the title compound (106 mg) having the following physical properties.
LC-MS (B) retention time (min): 0.76;
MS(ESI, Pos.): 421 (M + H) + .
参考例２２
７－（４－｛［９－（２，４－ジフルオロベンジル）－５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－イル］カルボニル｝フェニル）－９－（２，４－ジメトキシベンジル）－６－メチル－７，９－ジヒドロ－８Ｈ－プリン－８－オン
　参考例１５で製造した化合物の代わりに参考例２１で製造した化合物（106ｍｇ）を用いて、参考例１６と同様の操作を行い、以下の物性値を有する標題化合物（142ｍｇ）を得た。
LC－MS（B）保持時間（分）：0.96；
MS(ESI, Pos.)： 702 (M + H)＋；
１H-NMR(DMSO-d６)：δ　 2.05, 2.87, 3.61-4.09, 3.75, 3.83, 4.64-4.92, 5.03, 5.24-5.61, 6.45, 6.61, 6.88-7.17, 7.23-7.41, 7.51-7.74, 7.94, 8.25, 8.55。 Reference example 22
7-(4-{[9-(2,4-difluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[2,3-b] Pyridin-7-yl]carbonyl}phenyl)-9-(2,4-dimethoxybenzyl)-6-methyl-7,9-dihydro-8H-purin-8-one Reference instead of the compound produced in Reference Example 15 Using the compound (106 mg) produced in Example 21, the same operation as in Reference Example 16 was performed to obtain the title compound (142 mg) having the following physical properties.
LC-MS (B) retention time (min): 0.96;
MS(ESI, Pos.): 702 (M + H) + ;
1 H-NMR (DMSO-D 6 ): δ 2.05, 2.87, 3.61-4.09, 3.75, 3.83, 5.64-4.92, 5.24-5.61, 6.45, 6.61, 6.88-7.17, 7.51-7.74, 7.51-7.74 7.94, 8.25, 8.55.
参考例２３
７－（４－｛［９－（２，４－ジフルオロベンジル）－５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－イル］カルボニル｝フェニル）－６－メチル－７，９－ジヒドロ－８Ｈ－プリン－８－オン
　参考例２２で製造した化合物（142ｍｇ）にトリフルオロ酢酸（1.5ｍＬ）とトリエチルシラン（0.16ｍＬ）を加えて８０℃で１６時間攪拌した。反応液を室温へ冷却し、飽和炭酸水素ナトリウム水溶液を加えて、酢酸エチルで抽出した。得られた有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥し、減圧濃縮することにより、以下の物性値を有する標題化合物（89ｍｇ）を得た。
LC－MS（B）保持時間（分）：0.76；
MS(ESI, Pos.)：552 (M + H)＋。 Reference example 23
7-(4-{[9-(2,4-difluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[2,3-b] Pyridin-7-yl]carbonyl}phenyl)-6-methyl-7,9-dihydro-8H-purin-8-one The compound prepared in Reference Example 22 (142 mg) was added with trifluoroacetic acid (1.5 mL) and triethylsilane ( 0.16 mL) and stirred at 80°C for 16 hours. The reaction solution was cooled to room temperature, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the title compound (89 mg) having the following physical properties.
LC-MS (B) retention time (min): 0.76;
MS(ESI, Pos.): 552 (M + H) + .
実施例１０
９－ベンジル－７－（４－｛［９－（２，４－ジフルオロベンジル）－５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－イル］カルボニル｝フェニル）－６－メチル－７，９－ジヒドロ－８Ｈ－プリン－８－オン
　参考例１７で製造した化合物の代わりに参考例２３で製造した化合物を、４－（３－クロロプロピル）モルホリン塩酸塩の代わりに（ブロモメチル）ベンゼンを用いて、参考例１８と同様の操作を行い、以下の物性値を有する標題化合物を得た。
LC－MS（B）保持時間（分）：0.94；
MS(ESI, Pos.)： 642 (M + H)＋；
１H-NMR (DMSO-d６)：δ　 2.01-2.08, 2.84-2.90, 3.59-4.01, 4.55-4.96, 5.14, 5.21-5.64, 6.84-7.10, 7.14, 7.29-7.45, 7.53-7.77, 7.94, 8.25, 8.59。 Example 10
9-benzyl-7-(4-{[9-(2,4-difluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[2, 3-b]pyridin-7-yl]carbonyl}phenyl)-6-methyl-7,9-dihydro-8H-purin-8-one The compound produced in Reference Example 23 was substituted for the compound produced in Reference Example 17. , 4-(3-chloropropyl)morpholine hydrochloride was replaced with (bromomethyl)benzene, and the same operation as in Reference Example 18 was carried out to obtain the title compound having the following physical properties.
LC-MS (B) retention time (min): 0.94;
MS(ESI, Pos.): 642 (M + H) + ;
1 H-NMR (DMSO-d 6 ): δ 2.01-2.08, 2.84-2.90, 3.59-4.01, 4.55-4.96, 5.14, 5.21-5.64, 6.84-7.10, 7.14, 7.29-7.45, 7.53-7.77, 7.94, 8.25, 8.59.
実施例１１
７－（４－｛［９－（２，４－ジフルオロベンジル）－５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－イル］カルボニル｝フェニル）－６－メチル－９－フェニル－７，９－ジヒドロ－８Ｈ－プリン－８－オン
　参考例２３で製造した化合物（49ｍｇ）をＤＭＦ（0.88ｍＬ）に溶解し、フェニルボロン酸（32ｍｇ）及びピリジン（0.072ｍＬ）、酢酸銅（ＩＩ）（18ｍｇ）を加えて室温で２４時間攪拌した。反応液にアンモニア水を加えて酢酸エチルで抽出し、水及び飽和食塩水で洗浄した。得られた有機層を無水硫酸ナトリウムで乾燥後、減圧濃縮して得られた残渣をプレパラティブＴＬＣ（酢酸エチル）で精製することにより、以下の物性値を有する標題化合物（15ｍｇ）を得た。
LC－MS（B）保持時間（分）：0.94；
MS(ESI, Pos.)： 628 (M + H)＋；
１H-NMR(CDCl３)：δ　 2.20, 2.84-3.00, 3.73-4.11, 4.57-4.97, 5.32-5.62, 6.68-6.79, 6.81-6.92, 6.92-7.03, 7.11, 7.42-7.51, 7.52-7.76, 7.83, 8.32, 8.62-8.69。 Example 11
7-(4-{[9-(2,4-difluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[2,3-b] Pyridin-7-yl]carbonyl}phenyl)-6-methyl-9-phenyl-7,9-dihydro-8H-purin-8-one The compound (49 mg) prepared in Reference Example 23 was dissolved in DMF (0.88 mL). Then, phenylboronic acid (32 mg), pyridine (0.072 mL), and copper(II) acetate (18 mg) were added, and the mixture was stirred at room temperature for 24 hours. Aqueous ammonia was added to the reaction mixture, extracted with ethyl acetate, and washed with water and saturated brine. The obtained organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting residue was purified by preparative TLC (ethyl acetate) to obtain the title compound (15 mg) having the following physical properties.
LC-MS (B) retention time (min): 0.94;
MS(ESI, Pos.): 628 (M + H) + ;
1 H-NMR (CDCl 3 ): δ 2.20, 2.84-3.00, 3.73-4.11, 4.57-4.97, 5.32-5.62, 6.68-6.79, 6.81-6.92, 6.92-7.03, 7.11, 7.42-7.51, 7.52-7.76 , 7.83, 8.32, 8.62-8.69.
参考例２４
２－メチル－２－プロパニル　（３Ｒ）－３－｛［２－（ベンジルアミノ）－６－メチル－５－ニトロ－４－ピリミジニル］アミノ｝－１－ピペリジンカルボキシラート
　２，４－ジクロロ－６－メチル－５－ニトロピリミジン（1.5ｇ）をＴＨＦ（30ｍＬ）に溶解し、０℃でＤＩＰＥＡ（1.9ｍＬ）と２－メチル－２－プロパニル　（３Ｒ）－３－アミノ－１－ピぺリジンカルボキシラート（1.5ｇ）のＴＨＦ溶液（10ｍＬ）を加えた。０℃で２時間攪拌後、室温で終夜攪拌した。反応液を酢酸エチルで希釈して水と飽和食塩水で洗浄した。有機層を硫酸マグネシウムで乾燥し、減圧濃縮して得られた残渣をシリカゲルクロマトグラフィー（ヘキサン：酢酸エチル＝９：１→１：１）で精製した。得られた化合物（400ｍｇ）をＴＨＦ（10ｍＬ）に溶解し、ＤＩＰＥＡ（0.21ｍＬ）と１－フェニルメタンアミン（0.13ｍＬ）を加えて室温で２時間攪拌した。反応液を酢酸エチルで希釈して水と飽和食塩水で洗浄した。有機層を硫酸マグネシウムで乾燥し、減圧濃縮して得られた残渣をシリカゲルクロマトグラフィー（ヘキサン：酢酸エチル＝４：１→３：２）で精製することにより、以下の物性値を有する標題化合物（303ｍｇ）を得た。
TLC：Rf 0.45（ヘキサン：酢酸エチル＝7：3）。 Reference example 24
2-Methyl-2-propanyl (3R)-3-{[2-(benzylamino)-6-methyl-5-nitro-4-pyrimidinyl]amino}-1-piperidinecarboxylate 2,4-dichloro-6- Methyl-5-nitropyrimidine (1.5 g) was dissolved in THF (30 mL) and 2-methyl-2-propanyl (3R)-3-amino-1-piperidinecarboxylate was added with DIPEA (1.9 mL) at 0°C. (1.5 g) in THF (10 mL) was added. After stirring at 0°C for 2 hours, the mixture was stirred at room temperature overnight. The reaction solution was diluted with ethyl acetate and washed with water and saturated brine. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure, and the resulting residue was purified by silica gel chromatography (hexane:ethyl acetate = 9:1→1:1). The obtained compound (400 mg) was dissolved in THF (10 mL), DIPEA (0.21 mL) and 1-phenylmethanamine (0.13 mL) were added, and the mixture was stirred at room temperature for 2 hours. The reaction solution was diluted with ethyl acetate and washed with water and saturated brine. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure, and the resulting residue was purified by silica gel chromatography (hexane:ethyl acetate = 4:1 → 3:2) to obtain the title compound ( 303 mg) was obtained.
TLC: Rf 0.45 (hexane: ethyl acetate = 7:3).
参考例２５
２－メチル－２－プロパニル　（３Ｒ）－３－｛［５－アミノ－２－（ベンジルアミノ）－６－メチル－４－ピリミジニル］アミノ｝－１－ピペリジンカルボキシラート
　参考例１１で製造した化合物の代わりに参考例２４で製造した化合物（300ｍｇ）を用いて、参考例１２と同様の操作を行い、以下の物性値を有する標題化合物（275ｍｇ）を得た。
TLC：Rf 0.35（富士シリシア　ＮＨ（商品名）、酢酸エチル）。 Reference example 25
2-Methyl-2-propanyl (3R)-3-{[5-amino-2-(benzylamino)-6-methyl-4-pyrimidinyl]amino}-1-piperidinecarboxylate of the compound produced in Reference Example 11 The same operation as in Reference Example 12 was performed using the compound (300 mg) produced in Reference Example 24 instead, to obtain the title compound (275 mg) having the following physical property values.
TLC: Rf 0.35 (Fuji Silicia NH (trade name), ethyl acetate).
参考例２６
２－メチル－２－プロパニル　（３Ｒ）－３－［２－（ベンジルアミノ）－６－メチル－８－オキソ－７，８－ジヒドロ－９Ｈ－プリン－９－イル］－１－ピペリジンカルボキシラート
　参考例１２で製造した化合物の代わりに参考例２５で製造した化合物（275ｍｇ）を用いて、参考例１３と同様の操作を行い、以下の物性値を有する標題化合物（199ｍｇ）を得た。
TLC：Rf 0.25（富士シリシア　ＮＨ（商品名）、酢酸エチル）；
１H-NMR(CDCl３)：δ　 1.40-1.48, 1.72-1.89, 2.33, 2.49-2.76, 3.43-3.62, 3.90-4.38, 4.58, 5.18-5.30, 7.27-7.38, 7.69。 Reference example 26
2-Methyl-2-propanyl (3R)-3-[2-(benzylamino)-6-methyl-8-oxo-7,8-dihydro-9H-purin-9-yl]-1-piperidinecarboxylate Reference Using the compound produced in Reference Example 25 (275 mg) instead of the compound produced in Example 12, the same operation as in Reference Example 13 was carried out to obtain the title compound (199 mg) having the following physical properties.
TLC: Rf 0.25 (Fuji Silicia NH (trade name), ethyl acetate);
1H -NMR ( CDCl3 ): δ 1.40-1.48, 1.72-1.89, 2.33, 2.49-2.76, 3.43-3.62, 3.90-4.38, 4.58, 5.18-5.30, 7.27-7.38, 7.69.
実施例１２
２－メチル－２－プロパニル　（３Ｒ）－３－［２－（ベンジルアミノ）－７－（４－｛［９－（２，４－ジフルオロベンジル）－５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－イル］カルボニル｝フェニル）－６－メチル－８－オキソ－７，８－ジヒドロ－９Ｈ－プリン－９－イル］－１－ピペリジンカルボキシラート
　参考例１３で製造した化合物の代わりに参考例２６で製造した化合物を用いて、参考例１４→参考例１５→参考例１６と同様の操作を行い、以下の物性値を有する標題化合物を得た。
LC－MS（A）保持時間（分）：1.20；
MS(ESI, Pos.)： 840 (M + H)＋；
１H-NMR(CDCl３)：δ　 1.40-1.51, 1.71-1.82, 1.84-1.94, 1.97, 2.29-2.48, 2.55-2.77, 2.88, 3.60, 3.72-4.21, 4.36, 4.52-4.97, 5.21-5.62, 6.68-6.79, 6.80-7.00, 7.10, 7.22-7.26, 7.27-7.41, 7.47, 7.60, 7.82, 8.32。 Example 12
2-Methyl-2-propanyl (3R)-3-[2-(benzylamino)-7-(4-{[9-(2,4-difluorobenzyl)-5,6,8,9-tetrahydro-7H -pyrido[4',3':4,5]pyrrolo[2,3-b]pyridin-7-yl]carbonyl}phenyl)-6-methyl-8-oxo-7,8-dihydro-9H-purine- 9-yl]-1-piperidinecarboxylate Using the compound produced in Reference Example 26 instead of the compound produced in Reference Example 13, the same operations as in Reference Example 14 → Reference Example 15 → Reference Example 16 were carried out to produce the following. The title compound having the physical property values was obtained.
LC-MS (A) retention time (min): 1.20;
MS(ESI, Pos.): 840 (M + H) + ;
1 H-NMR (CDCl 3 ): δ 1.40-1.51, 1.71-1.82, 1.84-1.94, 1.97, 2.29-2.48, 2.55-2.77, 2.88, 3.60, 3.72-4.21, 4.36, 4.52-4.97, 5.21-5.6 2, 6.68-6.79, 6.80-7.00, 7.10, 7.22-7.26, 7.27-7.41, 7.47, 7.60, 7.82, 8.32.
参考例２７
４－メチル　１－（２－メチル－２－プロパニル）　４－（２－クロロ－６－メチル－８－オキソ－７，８－ジヒドロ－９Ｈ－プリン－９－イル）－１，４－ピペリジンジカルボキシラート
　参考例１１で用いた１－（２，４－ジメトキシフェニル）メタンアミンの代わりに４－メチル　１－（２－メチル－２－プロパニル）　４－アミノ－１，４－ピぺリジンカルボキシラートを用いて、参考例１１→参考例１２→参考例１３と同様の操作を行い、以下の物性値を有する標題化合物を得た。
TLC：Rf 0.60（ヘキサン：酢酸エチル＝１：４）；
１H-NMR(CDCl３)：δ　 1.47, 2.21-2.36, 2.51, 3.07-3.23, 3.29-3.56, 3.76, 9.25-9.49。 Reference example 27
4-Methyl 1-(2-methyl-2-propanyl) 4-(2-chloro-6-methyl-8-oxo-7,8-dihydro-9H-purin-9-yl)-1,4-piperidine di Carboxylate Instead of 1-(2,4-dimethoxyphenyl)methanamine used in Reference Example 11, 4-methyl 1-(2-methyl-2-propanyl) 4-amino-1,4-piperidinecarboxylate was used. The same operations as Reference Example 11→Reference Example 12→Reference Example 13 were performed to obtain the title compound having the following physical property values.
TLC: Rf 0.60 (hexane: ethyl acetate = 1:4);
1H -NMR ( CDCl3 ): δ 1.47, 2.21-2.36, 2.51, 3.07-3.23, 3.29-3.56, 3.76, 9.25-9.49.
参考例２８
４－メチル　１－（２－メチル－２－プロパニル）　４－（７－｛４－［（ベンジルオキシ）カルボニル］フェニル｝－２－クロロ－６－メチル－８－オキソ－７，８－ジヒドロ－９Ｈ－プリン－９－イル）－１，４－ピペリジンジカルボキシラート
　参考例１３で製造した化合物の代わりに参考例２７で製造した化合物（195ｍｇ）を、［４－（メトキシカルボニル)フェニル］ボロン酸の代わりに｛４－［（ベンジルオキシ）カルボニル］フェニル｝ボロン酸を用いて、参考例１４と同様の操作を行い、以下の物性値を有する標題化合物（98ｍｇ）を得た。
TLC：Rf 0.30（富士シリシア　ＮＨ（商品名）、ヘキサン：酢酸エチル＝３：１）；
１H-NMR(CDCl３)：δ　 1.48, 2.07, 2.24-2.39, 3.10-3.23, 3.44-3.60, 3.64-3.75, 3.78, 5.40, 7.35-7.51, 8.21-8.27。 Reference example 28
4-Methyl 1-(2-methyl-2-propanyl) 4-(7-{4-[(benzyloxy)carbonyl]phenyl}-2-chloro-6-methyl-8-oxo-7,8-dihydro- 9H-purin-9-yl)-1,4-piperidinedicarboxylate The compound produced in Reference Example 27 (195 mg) was substituted for the compound produced in Reference Example 13, and [4-(methoxycarbonyl)phenyl]boronic acid The same operation as in Reference Example 14 was carried out using {4-[(benzyloxy)carbonyl]phenyl}boronic acid instead of , to obtain the title compound (98 mg) having the following physical properties.
TLC: Rf 0.30 (Fuji Silysia NH (trade name), hexane: ethyl acetate = 3:1);
1H -NMR ( CDCl3 ): δ 1.48, 2.07, 2.24-2.39, 3.10-3.23, 3.44-3.60, 3.64-3.75, 3.78, 5.40, 7.35-7.51, 8.21-8.27.
参考例２９
４－メチル　１－（２－メチル－２－プロパ二ル）　４－（２－アニリノ－７－｛４－［（ベンジルオキシ）カルボニル］フェニル｝－６－メチル－８－オキソ－７，８－ジヒドロ－９Ｈ－プリン－９－イル）－１，４－ピペリジンジカルボキシラート
　参考例９で製造した化合物の代わりに参考例２８で製造した化合物（30ｍｇ）を用いて、実施例１と同様の操作を行い、以下の物性値を有する標題化合物（32ｍｇ）を得た。
TLC：Rf 0.28（富士シリシア　ＮＨ（商品名）、ヘキサン：酢酸エチル＝７：３）；
１H-NMR(CDCl３)：δ　 1.46, 2.01, 2.25-2.38, 3.14-3.29, 3.48-3.60, 3.65-3.77, 5.40, 6.91, 7.03, 7.28-7.54, 8.22。 Reference example 29
4-Methyl 1-(2-methyl-2-propanyl) 4-(2-anilino-7-{4-[(benzyloxy)carbonyl]phenyl}-6-methyl-8-oxo-7,8- Dihydro-9H-purin-9-yl)-1,4-piperidinedicarboxylate The same procedure as in Example 1 was performed using the compound produced in Reference Example 28 (30 mg) instead of the compound produced in Reference Example 9. The title compound (32 mg) having the following physical properties was obtained.
TLC: Rf 0.28 (Fuji Silicia NH (trade name), hexane: ethyl acetate = 7:3);
1H -NMR ( CDCl3 ): δ 1.46, 2.01, 2.25-2.38, 3.14-3.29, 3.48-3.60, 3.65-3.77, 5.40, 6.91, 7.03, 7.28-7.54, 8.22.
実施例１３
４－メチル　１－（２－メチル－２－プロパニル）　４－［２－アニリノ－７－（４－｛［９－（２，４－ジフルオロベンジル）－５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－イル］カルボニル｝フェニル）－６－メチル－８－オキソ－７，８－ジヒドロ－９Ｈ－プリン－９－イル］－１，４－ピペリジンジカルボキシラート
　参考例２９で製造した化合物（30ｍｇ）をＴＨＦ（1.5ｍＬ）とメタノール（1.5ｍＬ）に溶解し、５％パラジウム－活性炭素（50％ｗｅｔ、30ｍｇ）を加えて、反応容器内を水素へ置換し、室温で２時間攪拌した。反応液をセライト（商品名）でろ過し、得られたろ液を減圧濃縮した。これをＤＭＦ（2ｍＬ）に溶解し、参考例２で製造した化合物（15ｍｇ）とＮＥｔ３（0.023ｍＬ）、ＨＡＴＵ（24ｍｇ）を加えて室温で２時間攪拌した。反応液を水で希釈し、酢酸エチルで抽出した。得られた有機層を硫酸マグネシウムで乾燥し、減圧濃縮して得られた残渣をシリカゲルクロマトグラフィー（ヘキサン：酢酸エチル＝２：３→３：７）で精製することにより、以下の物性値を有する標題化合物（33ｍｇ）を得た。
LC－MS（A）保持時間（分）：1.27；
MS(ESI, Pos.)： 884 (M + H)＋；
１H-NMR(CDCl３)：δ　 1.42-1.54, 2.04, 2.24-2.44, 2.82-2.96, 3.16-3.32, 3.48-3.61, 3.66-4.17, 4.54-4.94, 5.26-5.56, 6.69-6.78, 6.79-6.99, 6.99-7.08, 7.11, 7.27-7.39, 7.40-7.69, 7.75-7.87, 8.27-8.35。 Example 13
4-Methyl 1-(2-methyl-2-propanyl) 4-[2-anilino-7-(4-{[9-(2,4-difluorobenzyl)-5,6,8,9-tetrahydro-7H -pyrido[4',3':4,5]pyrrolo[2,3-b]pyridin-7-yl]carbonyl}phenyl)-6-methyl-8-oxo-7,8-dihydro-9H-purine- [9-yl]-1,4-piperidinedicarboxylate The compound (30 mg) prepared in Reference Example 29 was dissolved in THF (1.5 mL) and methanol (1.5 mL), and 5% palladium-activated carbon (50% wet, 30 mg) was added, the inside of the reaction vessel was replaced with hydrogen, and the mixture was stirred at room temperature for 2 hours. The reaction solution was filtered through Celite (trade name), and the resulting filtrate was concentrated under reduced pressure. This was dissolved in DMF (2 mL), and the compound produced in Reference Example 2 (15 mg), NEt 3 (0.023 mL), and HATU (24 mg) were added, and the mixture was stirred at room temperature for 2 hours. The reaction solution was diluted with water and extracted with ethyl acetate. The obtained organic layer was dried over magnesium sulfate, concentrated under reduced pressure, and the resulting residue was purified by silica gel chromatography (hexane: ethyl acetate = 2:3 → 3:7) to obtain a product having the following physical property values. The title compound (33 mg) was obtained.
LC-MS (A) retention time (min): 1.27;
MS(ESI, Pos.): 884 (M + H) + ;
1 H-NMR (CDCl 3 ): δ 1.42-1.54, 2.04, 2.24-2.44, 2.82-2.96, 3.16-3.32, 3.48-3.61, 3.66-4.17, 4.54-4.94, 5.26-5.56, 6.69-6.78, 6.79 - 6.99, 6.99-7.08, 7.11, 7.27-7.39, 7.40-7.69, 7.75-7.87, 8.27-8.35.
参考例３０
２－メチル－２－プロパニル　９－（２，４－ジフルオロベンジル）－５－メトキシ－５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－カルボキシラート
　参考例１で製造した化合物（200ｍｇ）とテトラエチルアンモニウム　ｐ－トルエンスルホネート（1206ｍｇ）をメタノール（20ｍＬ）に溶解した。反応液を通電し（菊水社製直流電源：PMC350－0.2A、12ｍＡ、陽極：カーボンフェルト、陰極：白金板）、３０分攪拌した。反応液に酢酸エチルを加えて攪拌し、析出した結晶をろ別した。ろ液を減圧濃縮して得られた残渣をシリカゲルクロマトグラフィー（ヘキサン：酢酸エチル＝４：１）で精製することにより、以下の物性値を有する標題化合物（9.8ｍｇ）を得た。
TLC：Rf 0.28（ヘキサン：酢酸エチル＝３：１）；
１H-NMR(CDCl３)：δ　 1.42-1.54, 3.20-3.47, 3.53, 4.08-4.45, 4.55-4.68, 4.73-5.10, 5.37-5.54, 6.69-6.78, 6.83, 6.90-7.15, 7.94, 8.31。 Reference example 30
2-Methyl-2-propanyl 9-(2,4-difluorobenzyl)-5-methoxy-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[2, 3-b] Pyridine-7-carboxylate The compound prepared in Reference Example 1 (200 mg) and tetraethylammonium p-toluenesulfonate (1206 mg) were dissolved in methanol (20 mL). Electricity was applied to the reaction solution (DC power supply manufactured by Kikusui Co., Ltd.: PMC350-0.2A, 12 mA, anode: carbon felt, cathode: platinum plate) and stirred for 30 minutes. Ethyl acetate was added to the reaction solution and stirred, and the precipitated crystals were filtered off. The residue obtained by concentrating the filtrate under reduced pressure was purified by silica gel chromatography (hexane: ethyl acetate = 4:1) to obtain the title compound (9.8 mg) having the following physical properties.
TLC: Rf 0.28 (hexane: ethyl acetate = 3:1);
1 H-NMR (CDCl 3 ): δ 1.42-1.54, 3.20-3.47, 3.53, 4.08-4.45, 4.55-4.68, 4.73-5.10, 5.37-5.54, 6.69-6.78, 6.83, 6.90-7.15, 7.94, 8.3 1.
参考例３１
２－メチル－２－プロパニル　９－（２，４－ジフルオロベンジル）－５－ヒドロキシ－５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－カルボキシラート
　参考例３０で製造した化合物（9.8ｍｇ）を１，４－ジオキサン（0.16ｍＬ）に溶解し、水（0.040ｍＬ）と４－メチルベンゼンスルホン酸水和物（0.87ｍｇ）を加えて室温で４時間攪拌した。反応液に水を加えて酢酸エチルで抽出し、得られた有機層を無水硫酸ナトリウムで乾燥した。有機層を減圧濃縮して得られた残渣をプレパラティブＴＬＣ（ヘキサン：酢酸エチル＝１：１）で精製し、以下の物性値を有する標題化合物（9.0ｍｇ）を得た。
TLC：Rf 0.38（ヘキサン：酢酸エチル＝１：１）；
１H-NMR(CDCl３)：δ　 1.49, 3.47, 4.11-4.31, 4.76-5.09, 5.36-5.55, 6.71-6.87, 6.95-7.13, 7.13, 8.01, 8.32。 Reference example 31
2-Methyl-2-propanyl 9-(2,4-difluorobenzyl)-5-hydroxy-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[2, 3-b] Pyridine-7-carboxylate The compound prepared in Reference Example 30 (9.8 mg) was dissolved in 1,4-dioxane (0.16 mL), and water (0.040 mL) and 4-methylbenzenesulfonic acid hydrate were added. (0.87 mg) was added and stirred at room temperature for 4 hours. Water was added to the reaction solution, extracted with ethyl acetate, and the resulting organic layer was dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure, and the resulting residue was purified by preparative TLC (hexane: ethyl acetate = 1:1) to obtain the title compound (9.0 mg) having the following physical properties.
TLC: Rf 0.38 (hexane: ethyl acetate = 1:1);
1H -NMR ( CDCl3 ): δ 1.49, 3.47, 4.11-4.31, 4.76-5.09, 5.36-5.55, 6.71-6.87, 6.95-7.13, 7.13, 8.01, 8.32.
参考例３２
９－（２，４－ジフルオロベンジル）－６，７，８，９－テトラヒドロ－５Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－５－オール
　参考例３１で製造した化合物（9.0ｍｇ）をジクロロメタン（0.4ｍＬ）に溶解し、トリフルオロ酢酸（0.2ｍＬ）を加えて０℃で９０分攪拌した。反応液に飽和炭酸水素ナトリウム水溶液を加えて酢酸エチルで抽出し、得られた有機層を無水硫酸ナトリウムで乾燥した。有機層を減圧濃縮し、以下の物性値を有する標題化合物（5.1ｍｇ）を得た。
TLC：Rf 0.22（ジクロロメタン：メタノール＝９：１）；
１H-NMR(CDCl３)：δ　 3.04, 3.28, 3.75-4.01, 4.91, 5.19-5.52, 6.68-6.87, 6.97, 7.12, 7.99, 8.31。 Reference example 32
9-(2,4-difluorobenzyl)-6,7,8,9-tetrahydro-5H-pyrido[4',3':4,5]pyrrolo[2,3-b]pyridin-5-ol Reference example The compound prepared in 31 (9.0 mg) was dissolved in dichloromethane (0.4 mL), trifluoroacetic acid (0.2 mL) was added, and the mixture was stirred at 0° C. for 90 minutes. A saturated aqueous sodium bicarbonate solution was added to the reaction mixture, extracted with ethyl acetate, and the resulting organic layer was dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure to obtain the title compound (5.1 mg) having the following physical properties.
TLC: Rf 0.22 (dichloromethane:methanol = 9:1);
1H -NMR ( CDCl3 ): δ 3.04, 3.28, 3.75-4.01, 4.91, 5.19-5.52, 6.68-6.87, 6.97, 7.12, 7.99, 8.31.
参考例３３
２－メチル－２－プロパニル　（３Ｓ）－３－｛２－クロロ－７－［４－（メトキシカルボニル）フェニル］－６－メチル－８－オキソ－７，８－ジヒドロ－９Ｈ－プリン－９－イル｝－１－ピペリジンカルボキシラート
　参考例３で用いた２－メチル－２－プロパニル　４－アミノ－１－ピぺリジンカルボキシラートの代わりに２－メチル－２－プロパニル　（３Ｓ）－３－アミノ－１－ピぺリジンカルボキシラートを用いて、参考例３→参考例４→参考例５と同様の操作を行い、以下の物性値を有する標題化合物を得た。
TLC：Rf 0.35（ヘキサン：酢酸エチル＝２：１）；
１H-NMR(CDCl３)：δ　 1.47, 1.61-1.81, 1.82-1.90, 1.95-2.03, 2.09, 2.43-2.61, 2.68-2.86, 3.59-3.75, 3.93-4.00, 4.07-4.29, 4.43-4.54, 7.49, 8.23。 Reference example 33
2-Methyl-2-propanyl (3S)-3-{2-chloro-7-[4-(methoxycarbonyl)phenyl]-6-methyl-8-oxo-7,8-dihydro-9H-purine-9- yl}-1-piperidinecarboxylate 2-methyl-2-propanyl (3S)-3-amino- instead of 2-methyl-2-propanyl 4-amino-1-piperidinecarboxylate used in Reference Example 3 Using 1-piperidinecarboxylate, the same operations as Reference Example 3→Reference Example 4→Reference Example 5 were performed to obtain the title compound having the following physical property values.
TLC: Rf 0.35 (hexane: ethyl acetate = 2:1);
1 H-NMR (CDCl 3 ): δ 1.47, 1.61-1.81, 1.82-1.90, 1.95-2.03, 2.09, 2.43-2.61, 2.68-2.86, 3.59-3.75, 3.93-4.00, 4.07-4.29, 4.43-4.54 , 7.49, 8.23.
参考例３４
メチル　４－｛２－クロロ－９－［（３Ｓ）－１－（２，２－ジメチルプロピル）－３－ピペリジニル］－６－メチル－８－オキソ－８，９－ジヒドロ－７Ｈ－プリン－７－イル｝ベンゾアート
　参考例７で製造した化合物の代わりに参考例３３で製造した化合物を用いて、参考例８→参考例９と同様の操作を行い、以下の物性値を有する標題化合物を得た。
LC－MS（A）保持時間（分）：0.96；
MS(ESI, Pos.)： 472 (M + H)＋。 Reference example 34
Methyl 4-{2-chloro-9-[(3S)-1-(2,2-dimethylpropyl)-3-piperidinyl]-6-methyl-8-oxo-8,9-dihydro-7H-purine-7 -yl}benzoate Using the compound produced in Reference Example 33 instead of the compound produced in Reference Example 7, the same operations as in Reference Example 8 → Reference Example 9 were performed to obtain the title compound having the following physical property values. Ta.
LC-MS (A) retention time (min): 0.96;
MS(ESI, Pos.): 472 (M + H) + .
参考例３５
メチル　４－｛２－アニリノ－９－［（３Ｓ）－１－（２，２－ジメチルプロピル）－３－ピペリジニル］－６－メチル－８－オキソ－８，９－ジヒドロ－７Ｈ－プリン－７－イル｝ベンゾアート
　参考例９で製造した化合物の代わりに参考例３４で製造した化合物（1.4ｇ）を用いて、実施例１と同様の操作を行い、以下の物性値を有する標題化合物（1.1ｇ）を得た。
LC－MS（A）保持時間（分）：1.01；
MS(ESI, Pos.)：529 (M + H)＋。 Reference example 35
Methyl 4-{2-anilino-9-[(3S)-1-(2,2-dimethylpropyl)-3-piperidinyl]-6-methyl-8-oxo-8,9-dihydro-7H-purine-7 -yl}benzoate Using the compound produced in Reference Example 34 (1.4 g) instead of the compound produced in Reference Example 9, the same operation as in Example 1 was carried out to obtain the title compound (1.1 g) was obtained.
LC-MS (A) retention time (min): 1.01;
MS(ESI, Pos.): 529 (M + H) + .
参考例３６
４－｛２－アニリノ－９－［（３Ｓ）－１－（２，２－ジメチルプロピル）－３－ピペリジニル］－６－メチル－８－オキソ－８，９－ジヒドロ－７Ｈ－プリン－７－イル｝安息香酸　１塩酸塩
　参考例３５で製造した化合物（106ｍｇ）をＴＨＦ（2ｍＬ）に溶解し、ＴＭＳＯＫ（57ｍｇ）を加えて室温で９０分攪拌した。反応液に４Ｎ塩化水素／１，4－ジオキサン溶液加えて濃縮し、以下の物性値を有する標題化合物（110ｍｇ）を得た。
TLC：Rf 0.35（ジクロロメタン：メタノール＝９：１）。 Reference example 36
4-{2-anilino-9-[(3S)-1-(2,2-dimethylpropyl)-3-piperidinyl]-6-methyl-8-oxo-8,9-dihydro-7H-purine-7- Benzoic acid monohydrochloride The compound prepared in Reference Example 35 (106 mg) was dissolved in THF (2 mL), TMSOK (57 mg) was added, and the mixture was stirred at room temperature for 90 minutes. A 4N hydrogen chloride/1,4-dioxane solution was added to the reaction mixture and concentrated to obtain the title compound (110 mg) having the following physical properties.
TLC: Rf 0.35 (dichloromethane:methanol=9:1).
実施例１４
２－アニリノ－７－（４－｛［９－（２，４－ジフルオロベンジル）－５－ヒドロキシ－５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－イル］カルボニル｝フェニル）－９－［（３Ｓ）－１－（２，２－ジメチルプロピル）－３－ピペリジニル］－６－メチル－７，９－ジヒドロ－８Ｈ－プリン－８－オン
　参考例２で製造した化合物の代わりに参考例３２で製造した化合物（5.1ｍｇ）を、参考例６で製造した化合物の代わりに参考例３６で製造した化合物を用いて、参考例７と同様の操作を行い、以下の物性値を有する標題化合物（6.8ｍｇ）を得た。
LC－MS（A）保持時間（分）：1.06；
MS(ESI, Pos.)： 812 (M + H)＋；
１H-NMR (CDCl３)：δ　 0.86-0.90, 1.73-1.81, 1.85-1.93, 2.01-2.06, 2.08-2.21, 2.29-2.53, 2.75-2.94, 3.23, 3.46-3.72, 4.11-4.21, 4.25-4.45, 4.63, 5.07, 5.28-5.67, 6.68-6.78, 6.86, 6.98-7.12, 7.16, 7.34, 7.48, 7.63-7.88, 8.00, 8.34。 Example 14
2-anilino-7-(4-{[9-(2,4-difluorobenzyl)-5-hydroxy-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5] pyrrolo[2,3-b]pyridin-7-yl]carbonyl}phenyl)-9-[(3S)-1-(2,2-dimethylpropyl)-3-piperidinyl]-6-methyl-7,9- Dihydro-8H-purin-8-one The compound produced in Reference Example 32 (5.1 mg) was substituted for the compound produced in Reference Example 2, and the compound produced in Reference Example 36 was substituted for the compound produced in Reference Example 6. Using this product, the same operation as in Reference Example 7 was performed to obtain the title compound (6.8 mg) having the following physical properties.
LC-MS (A) retention time (min): 1.06;
MS(ESI, Pos.): 812 (M + H) + ;
1 H-NMR (CDCl 3 ): δ 0.86-0.90, 1.73-1.81, 1.85-1.93, 2.01-2.06, 2.08-2.21, 2.29-2.53, 2.75-2.94, 3.23, 3.46-3.72, 4.11-4.21, 4.25 - 4.45, 4.63, 5.07, 5.28-5.67, 6.68-6.78, 6.86, 6.98-7.12, 7.16, 7.34, 7.48, 7.63-7.88, 8.00, 8.34.
参考例３７
２－メチル－２－プロパニル　３－［（２－アニリノ－５－ニトロ－４－ピリミジニル）アミノ］－１－ピペリジンカルボキシラート
　２，４－ジクロロ－５－ニトロピリミジン（4.8ｇ）をＴＨＦ（40ｍＬ）に溶解し、２－メチル－２－プロパニル　３－アミノ－１－ピぺリジンカルボキシラート（5.0ｇ）とＤＩＰＥＡ（8.5ｍＬ）のＴＨＦ溶液（10ｍＬ）を０℃で加えた。０℃で１時間攪拌した後、反応液にアニリン（2.3ｇ）とＤＩＰＥＡ（8.5ｍＬ）の混合液を加え、室温で５時間攪拌した。反応液を酢酸エチルとメタノールの混合液（１：１）で希釈し、生じた析出物をろ取することにより、以下の物性値を有する標題化合物（5.9ｇ）を得た。
LC－MS（A）保持時間（分）：1.27；
MS(ESI, Pos.)： 415 (M + H)＋。 Reference example 37
2-Methyl-2-propanyl 3-[(2-anilino-5-nitro-4-pyrimidinyl)amino]-1-piperidinecarboxylate 2,4-dichloro-5-nitropyrimidine (4.8 g) was dissolved in THF (40 mL). A THF solution (10 mL) of 2-methyl-2-propanyl 3-amino-1-piperidinecarboxylate (5.0 g) and DIPEA (8.5 mL) was added at 0°C. After stirring at 0° C. for 1 hour, a mixed solution of aniline (2.3 g) and DIPEA (8.5 mL) was added to the reaction solution, and the mixture was stirred at room temperature for 5 hours. The reaction solution was diluted with a mixture of ethyl acetate and methanol (1:1), and the resulting precipitate was collected by filtration to obtain the title compound (5.9 g) having the following physical properties.
LC-MS (A) retention time (min): 1.27;
MS(ESI, Pos.): 415 (M + H) + .
参考例３８
２－メチル－２－プロパニル　３－［（５－アミノ－２－アニリノ－４－ピリミジニル）アミノ］－１－ピペリジンカルボキシラート
　参考例３７で製造した化合物（1.0ｍｇ）をＤＭＦ（100ｍＬ）に溶解し、５％パラジウム－活性炭素（50％ｗｅｔ、280ｍｇ）を加えて、反応容器内を水素へ置換し、室温で５時間攪拌した。反応液をセライト（商品名）でろ過し、ろ液を酢酸エチルとヘキサンの混合液（３：７）で希釈し、水と飽和食塩水で洗浄した。得られた有機層を無水硫酸ナトリウムで乾燥し、減圧濃縮することにより、以下の物性値を有する標題化合物（680ｍｇ）を得た。
LC－MS（A）保持時間（分）：1.00；
MS(ESI, Pos.)： 385 (M + H)＋。 Reference example 38
2-Methyl-2-propanyl 3-[(5-amino-2-anilino-4-pyrimidinyl)amino]-1-piperidinecarboxylate The compound prepared in Reference Example 37 (1.0 mg) was dissolved in DMF (100 mL). , 5% palladium-activated carbon (50% wet, 280 mg) was added, the inside of the reaction vessel was replaced with hydrogen, and the mixture was stirred at room temperature for 5 hours. The reaction solution was filtered through Celite (trade name), the filtrate was diluted with a mixture of ethyl acetate and hexane (3:7), and washed with water and saturated brine. The obtained organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the title compound (680 mg) having the following physical properties.
LC-MS (A) retention time (min): 1.00;
MS(ESI, Pos.): 385 (M + H) + .
参考例３９
２－メチル－２－プロパニル　３－（２－アニリノ－８－オキソ－７，８－ジヒドロ－９Ｈ－プリン－９－イル）－１－ピペリジンカルボキシラート
　参考例１２で製造した化合物の代わりに参考例３８で製造した化合物（3.7ｇ）を用いて、参考例１３と同様の操作を行い、以下の物性値を有する標題化合物（1.7ｇ）を得た。
LC－MS（A）保持時間（分）：1.00；
MS(ESI, Pos.)： 411 (M + H)＋。 Reference example 39
2-Methyl-2-propanyl 3-(2-anilino-8-oxo-7,8-dihydro-9H-purin-9-yl)-1-piperidinecarboxylate Reference Example instead of the compound produced in Reference Example 12 Using the compound (3.7 g) produced in Step 38, the same operation as in Reference Example 13 was performed to obtain the title compound (1.7 g) having the following physical properties.
LC-MS (A) retention time (min): 1.00;
MS(ESI, Pos.): 411 (M + H) + .
参考例４０
２－メチル－２－プロパニル　３－｛２－アニリノ－７－［４－（メトキシカルボニル）フェニル］－８－オキソ－７，８－ジヒドロ－９Ｈ－プリン－９－イル｝－１－ピペリジンカルボキシラート
　参考例１３で製造した化合物の代わりに参考例３９で製造した化合物（1.6ｇ）を用いて、参考例１４と同様の操作を行い、以下の物性値を有する標題化合物（690ｍｇ）を得た。
LC－MS（A）保持時間（分）：1.20；
MS(ESI, Pos.)：545 (M + H)＋；
１H-NMR(DMSO-d６)：δ　 1.42, 1.46-1.59, 1.80-1.89, 1.94-2.03, 2.68-2.83, 3.46-3.69, 3.90, 4.01-4.19, 4.27, 6.93, 7.28, 7.76, 7.81-7.86, 8.11-8.15, 8.31, 9.55。 Reference example 40
2-Methyl-2-propanyl 3-{2-anilino-7-[4-(methoxycarbonyl)phenyl]-8-oxo-7,8-dihydro-9H-purin-9-yl}-1-piperidinecarboxylate Using the compound produced in Reference Example 39 (1.6 g) instead of the compound produced in Reference Example 13, the same operation as in Reference Example 14 was performed to obtain the title compound (690 mg) having the following physical property values.
LC-MS (A) retention time (min): 1.20;
MS(ESI, Pos.): 545 (M + H) + ;
1 H-NMR (DMSO-D 6 ): δ 1.42, 1.46-1.59, 1.80-1.89, 1.94-2.03, 2.94-2.83, 2.68-2.03, 3.46-3.69, 3.46-3.69, 3.90, 4.01-4.19, 4.01-4.19, 4.93, 7.93, 7.76, 7.81- 7.86, 8.11-8.15, 8.31, 9.55.
参考例４１
４－［２－アニリノ－９－（１－｛［（２－メチル－２－プロパニル）オキシ］カルボニル｝－３－ピペリジニル）－８－オキソ－８，９－ジヒドロ－７Ｈ－プリン－７－イル］安息香酸
　参考例５で製造した化合物の代わりに参考例４０で製造した化合物（686ｍｇ）を用いて、参考例６と同様の操作を行い、以下の物性値を有する標題化合物（356ｍｇ）を得た。
LC－MS（A）保持時間（分）：1.16；
MS(ESI, Pos.)：531 (M + H)＋。 Reference example 41
4-[2-anilino-9-(1-{[(2-methyl-2-propanyl)oxy]carbonyl}-3-piperidinyl)-8-oxo-8,9-dihydro-7H-purin-7-yl ] Benzoic acid Using the compound produced in Reference Example 40 (686 mg) instead of the compound produced in Reference Example 5, the same operation as in Reference Example 6 was performed to obtain the title compound (356 mg) having the following physical property values. Ta.
LC-MS (A) retention time (min): 1.16;
MS(ESI, Pos.): 531 (M + H) + .
参考例４２
２－メチル－２－プロパニル　３－［２－アニリノ－７－（４－｛［９－（２，４－ジフルオロベンジル）－５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－イル］カルボニル｝フェニル）－８－オキソ－７，８－ジヒドロ－９Ｈ－プリン－９－イル］－１－ピペリジンカルボキシラート
　参考例６で製造した化合物の代わりに参考例４１で製造した化合物（207ｍｇ）を用いて、参考例７と同様の操作を行い、以下の物性値を有する標題化合物（287ｍｇ）を得た。
LC－MS（A）保持時間（分）：1.28；
MS(ESI, Pos.)： 812 (M + H)＋；
１H-NMR (CDCl３)：δ　 1.43-1.53, 1.64-1.77, 1.83-1.95, 1.99-2.04, 2.55-2.69, 2.72-2.96, 3.69-3.86, 4.09-4.37, 4.49, 4.55-4.93, 5.25-5.59, 6.68-6.79, 6.81-6.89, 6.90-7.00, 7.02-7.13, 7.35, 7.51-7.70, 7.83, 8.11, 8.32。 Reference example 42
2-Methyl-2-propanyl 3-[2-anilino-7-(4-{[9-(2,4-difluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3 ':4,5]pyrrolo[2,3-b]pyridin-7-yl]carbonyl}phenyl)-8-oxo-7,8-dihydro-9H-purin-9-yl]-1-piperidinecarboxylate Reference The same operation as in Reference Example 7 was performed using the compound produced in Reference Example 41 (207 mg) instead of the compound produced in Example 6 to obtain the title compound (287 mg) having the following physical properties.
LC-MS (A) retention time (min): 1.28;
MS(ESI, Pos.): 812 (M + H) + ;
1 H-NMR (CDCl 3 ): δ 1.43-1.53, 1.64-1.77, 1.83-1.95, 1.99-2.04, 2.55-2.69, 2.72-2.96, 3.69-3.86, 4.09-4.37, 4.49, 4.55-4.93, 5.25 - 5.59, 6.68-6.79, 6.81-6.89, 6.90-7.00, 7.02-7.13, 7.35, 7.51-7.70, 7.83, 8.11, 8.32.
参考例４３
２－アニリノ－７－（４－｛［９－（２，４－ジフルオロベンジル）－５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－イル］カルボニル｝フェニル）－９－（３－ピペリジニル）－７，９－ジヒドロ－８Ｈ－プリン－８－オン　２塩酸塩
　参考例４２で製造した化合物（170ｍｇ）にメタノール（3ｍＬ）を加えて懸濁し、４Ｎ塩化水素／１，4－ジオキサン溶液（1.0ｍＬ）を加えて室温で２時間攪拌した。反応液を濃縮して、以下の物性値を有する標題化合物（167ｍｇ）を得た。
LC－MS（A）保持時間（分）：1.02；
MS(ESI, Pos.)： 712 (M + H)＋。 Reference example 43
2-anilino-7-(4-{[9-(2,4-difluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[2, 3-b]pyridin-7-yl]carbonyl}phenyl)-9-(3-piperidinyl)-7,9-dihydro-8H-purin-8-one dihydrochloride The compound prepared in Reference Example 42 (170 mg) Methanol (3 mL) was added to suspend the mixture, 4N hydrogen chloride/1,4-dioxane solution (1.0 mL) was added, and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated to obtain the title compound (167 mg) having the following physical properties.
LC-MS (A) retention time (min): 1.02;
MS(ESI, Pos.): 712 (M + H) + .
実施例１５
２－アニリノ－７－（４－｛［９－（２，４－ジフルオロベンジル）－５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－イル］カルボニル｝フェニル）－９－［１－（３，３－ジメチルブチル）－３－ピペリジニル］－７，９－ジヒドロ－８Ｈ－プリン－８－オン
　参考例４３で製造した化合物（14ｍｇ）をジクロロメタン（1.0ｍＬ）に溶解し、３，３－ジメチルブタナール（18ｍｇ）とトリアセトキシ水素化ホウ素ナトリウム（38ｍｇ）を加えて室温で４時間攪拌した。反応液を氷冷し、飽和炭酸水素ナトリウム水溶液を加えた。酢酸エチルで抽出後、有機層を水と飽和食塩水で洗浄した。無水硫酸ナトリウムで乾燥し、減圧濃縮して得られた残渣をシリカゲルクロマトグラフィー（ヘキサン：酢酸エチル＝１：１→０：１）で精製することにより、以下の物性値を有する標題化合物（4.9ｍｇ）を得た。
LC－MS（A）保持時間（分）：1.15；
MS(ESI, Pos.)： 796 (M + H)＋；
１H-NMR(DMSO-d６)：δ　 0.91, 1.50-1.67, 1.80-1.93, 2.05-2.19, 2.82-2.99, 3.14-3.32, 3.63-3.75, 3.79-3.89, 3.95-4.07, 4.58-4.93, 5.26-5.67, 6.93-7.10, 7.11-7.18, 7.28-7.37, 7.51-7.81, 7.94, 8.20-8.39, 9.54, 9.60-9.75。 Example 15
2-anilino-7-(4-{[9-(2,4-difluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[2, 3-b]pyridin-7-yl]carbonyl}phenyl)-9-[1-(3,3-dimethylbutyl)-3-piperidinyl]-7,9-dihydro-8H-purin-8-one Reference Example 43 The compound prepared in (14 mg) was dissolved in dichloromethane (1.0 mL), 3,3-dimethylbutanal (18 mg) and sodium triacetoxyborohydride (38 mg) were added, and the mixture was stirred at room temperature for 4 hours. The reaction solution was cooled with ice, and saturated aqueous sodium hydrogen carbonate solution was added. After extraction with ethyl acetate, the organic layer was washed with water and saturated brine. The residue obtained by drying with anhydrous sodium sulfate and concentration under reduced pressure was purified by silica gel chromatography (hexane:ethyl acetate = 1:1 → 0:1) to obtain the title compound (4.9 mg) having the following physical properties. ) was obtained.
LC-MS (A) retention time (min): 1.15;
MS(ESI, Pos.): 796 (M + H) + ;
1 H-NMR (DMSO-d 6 ): δ 0.91, 1.50-1.67, 1.80-1.93, 2.05-2.19, 2.82-2.99, 3.14-3.32, 3.63-3.75, 3.79-3.89, 3.95-4.07, 4.58-4.93, 5.26-5.67, 6.93-7.10, 7.11-7.18, 7.28-7.37, 7.51-7.81, 7.94, 8.20-8.39, 9.54, 9.60-9.75.
実施例１５－１
７－（４－｛［９－（２，４－ジフルオロベンジル）－５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－イル］カルボニル｝フェニル）－９－［１－（２，２－ジメチルプロピル）－３－ピペリジニル］－２－（２－ピリジニルアミノ）－７，９－ジヒドロ－８Ｈ－プリン－８－オン
　参考例３７で用いたアニリンの代わりに２－アミノピリジンを、実施例１５で用いた３，３－ジメチルブタナールの代わりにピバルアルデヒドを用いて、参考例３７→参考例３８→参考例３９→参考例４０→参考例４１→参考例４２→参考例４３→実施例１５と同様の操作を行い、以下の物性値を有する標題化合物を得た。
LC－MS（A）保持時間（分）：0.96；
MS(ESI, Pos.)： 783 (M + H)＋；
１H-NMR(CDCl３)：δ　 0.84-0.91, 1.75-1.85, 1.93, 2.08-2.24, 2.32-2.52, 2.82-2.98, 3.15-3.25, 3.70-4.16, 4.41, 4.54-4.94, 5.24-5.60, 6.50, 6.64, 6.68-6.79, 6.85, 6.89-7.00, 7.11, 7.42, 7.51-7.73, 7.83, 8.07, 8.17, 8.29-8.34, 8.41。 Example 15-1
7-(4-{[9-(2,4-difluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[2,3-b] pyridin-7-yl]carbonyl}phenyl)-9-[1-(2,2-dimethylpropyl)-3-piperidinyl]-2-(2-pyridinylamino)-7,9-dihydro-8H-purine-8- On Using 2-aminopyridine in place of aniline used in Reference Example 37 and pivalaldehyde in place of 3,3-dimethylbutanal used in Example 15, Reference Example 37 → Reference Example 38 → Reference Example 39→Reference Example 40→Reference Example 41→Reference Example 42→Reference Example 43→The same operation as in Example 15 was performed to obtain the title compound having the following physical property values.
LC-MS (A) retention time (min): 0.96;
MS(ESI, Pos.): 783 (M + H) + ;
1 H-NMR (CDCl 3 ): δ 0.84-0.91, 1.75-1.85, 1.93, 2.08-2.24, 2.32-2.52, 2.82-2.98, 3.15-3.25, 3.70-4.16, 4.41, 4.54-4.94, 5.24-5.60 , 6.50, 6.64, 6.68-6.79, 6.85, 6.89-7.00, 7.11, 7.42, 7.51-7.73, 7.83, 8.07, 8.17, 8.29-8.34, 8.41.
実施例１６
２－アニリノ－７－（４－｛［９－（２，４－ジフルオロベンジル）－５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－イル］カルボニル｝フェニル）－９－［１－（３，３－ジメチルブタノイル）－３－ピペリジニル］－７，９－ジヒドロ－８Ｈ－プリン－８－オン
　参考例４３で製造した化合物（10ｍｇ）と３，３－ジメチルブタン酸（4.4ｍｇ）をＤＭＦ（0.5ｍＬ）に溶解し、ＤＩＰＥＡ（0.021ｍＬ）とＨＡＴＵ（9.7ｍｇ）を加えて室温で１時間攪拌した。反応液を酢酸エチルで希釈し、水と飽和食塩水で洗浄した。有機層を無水硫酸ナトリウムで乾燥後、減圧濃縮して得られた残渣をシリカゲルクロマトグラフィー（ヘキサン：酢酸エチル＝１：１→０：１）で精製することにより、以下の物性値を有する標題化合物（7.6ｍｇ）を得た。
LC－MS（A）保持時間（分）：1.23；
MS(ESI, Pos.)： 810 (M + H)＋；
１H-NMR(CDCl３)：δ　 1.08, 1.91-2.02, 2.05-2.12, 2.28-2.38, 2.56-2.77, 2.80, 2.86-2.96, 3.04-3.65, 3.71-3.88, 3.69-4.09, 4.40-4.55, 4.56-4.97, 5.23-5.62, 6.68-6.79, 6.79-6.99, 7.00-7.14, 7.35, 7.50-7.72, 7.83, 8.12, 8.32。 Example 16
2-anilino-7-(4-{[9-(2,4-difluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[2, 3-b]pyridin-7-yl]carbonyl}phenyl)-9-[1-(3,3-dimethylbutanoyl)-3-piperidinyl]-7,9-dihydro-8H-purin-8-one Reference example The compound prepared in 43 (10 mg) and 3,3-dimethylbutanoic acid (4.4 mg) were dissolved in DMF (0.5 mL), DIPEA (0.021 mL) and HATU (9.7 mg) were added, and the mixture was stirred at room temperature for 1 hour. . The reaction solution was diluted with ethyl acetate and washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting residue was purified by silica gel chromatography (hexane: ethyl acetate = 1:1 → 0:1) to obtain the title compound having the following physical properties. (7.6 mg) was obtained.
LC-MS (A) retention time (min): 1.23;
MS(ESI, Pos.): 810 (M + H) + ;
1 H-NMR (CDCl 3 ): δ 1.08, 1.91-2.02, 2.05-2.12, 2.28-2.38, 2.56-2.77, 2.80, 2.86-2.96, 3.04-3.65, 3.71-3.88, 3.69-4.09, 4.40-4.55 , 4.56-4.97, 5.23-5.62, 6.68-6.79, 6.79-6.99, 7.00-7.14, 7.35, 7.50-7.72, 7.83, 8.12, 8.32.
実施例１７
２－メチル－２－プロパニル　（３Ｓ）－３－［２－アニリノ－７－（４－｛［９－（２，４－ジフルオロベンジル）－５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－イル］カルボニル｝フェニル）－８－オキソ－７，８－ジヒドロ－９Ｈ－プリン－９－イル］－１－ピロリジンカルボキシラート
　参考例３７で用いた２－メチル－２－プロパニル　３－アミノ－１－ピぺリジンカルボキシラートの代わりに２－メチル－２－プロパニル　（３Ｓ）－３－アミノ－１－ピロリジンカルボキシラートを用いて、参考例３７→参考例３８→参考例３９→参考例４０→参考例４１→参考例４２と同様の操作を行い、以下の物性値を有する標題化合物を得た。
LC－MS（A）保持時間（分）：1.21；
MS(ESI, Pos.)： 798 (M + H)＋；
１H-NMR (CDCl３)：δ　 1.43-1.54, 2.05, 2.23-2.36, 2.82-3.01, 3.43-3.59, 3.69-4.15, 4.56-4.93, 5.07-5.22, 5.23-5.60, 6.67-7.00, 7.02-7.15, 7.35, 7.56-7.69, 7.82, 8.12, 8.32。 Example 17
2-Methyl-2-propanyl (3S)-3-[2-anilino-7-(4-{[9-(2,4-difluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[ 4',3':4,5]pyrrolo[2,3-b]pyridin-7-yl]carbonyl}phenyl)-8-oxo-7,8-dihydro-9H-purin-9-yl]-1- Pyrrolidine carboxylate
Using 2-methyl-2-propanyl (3S)-3-amino-1-pyrrolidinecarboxylate instead of 2-methyl-2-propanyl 3-amino-1-piperidinecarboxylate used in Reference Example 37. , Reference Example 37→Reference Example 38→Reference Example 39→Reference Example 40→Reference Example 41→Reference Example 42 were performed to obtain the title compound having the following physical property values.
LC-MS (A) retention time (min): 1.21;
MS(ESI, Pos.): 798 (M + H) + ;
1 H-NMR (CDCl 3 ): δ 1.43-1.54, 2.05, 2.23-2.36, 2.82-3.01, 3.43-3.59, 3.69-4.15, 4.56-4.93, 5.07-5.22, 5.23-5.60, 6.67-7.00, 7.02 - 7.15, 7.35, 7.56-7.69, 7.82, 8.12, 8.32.
実施例１８
２－メチル－２－プロパニル　（３Ｓ）－３－［２－アニリノ－７－（４－｛［９－（２，４－ジフルオロベンジル）－５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－イル］カルボニル｝－３－フルオロフェニル）－８－オキソ－７，８－ジヒドロ－９Ｈ－プリン－９－イル］－１－ピロリジンカルボキシラート
　参考例３７で用いた２－メチル－２－プロパニル　３－アミノ－１－ピぺリジンカルボキシラートの代わりに２－メチル－２－プロパニル　（３Ｓ）－３－アミノ－１－ピロリジンカルボキシラートを、参考例４０で用いた［４－（メトキシカルボニル)フェニル］ボロン酸の代わりに［３－フルオロ－４－（メトキシカルボニル)フェニル］ボロン酸を用いて、参考例３７→参考例３８→参考例３９→参考例４０→参考例４１→参考例４２と同様の操作を行い、以下の物性値を有する標題化合物を得た。
LC－MS（A）保持時間（分）：1.24；
MS(ESI, Pos.)： 816 (M + H)＋；
１H-NMR(DMSO-d６)：δ　 1.36-1.50, 2.19-2.35, 2.70-2.93, 3.61-3.77, 3.83-3.93, 3.94-4.12, 4.66, 4.91, 5.01-5.19, 5.30-5.39, 5.44-5.59, 6.89-7.00, 7.01-7.16, 7.23-7.36, 7.47-7.57, 7.59-7.72, 7.73-7.79, 7.97, 8.19-8.27, 8.28-8.38, 9.54-9.63。 Example 18
2-Methyl-2-propanyl (3S)-3-[2-anilino-7-(4-{[9-(2,4-difluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[ 4',3':4,5]pyrrolo[2,3-b]pyridin-7-yl]carbonyl}-3-fluorophenyl)-8-oxo-7,8-dihydro-9H-purin-9-yl ]-1-pyrrolidinecarboxylate 2-methyl-2-propanyl (3S)-3-amino-1 instead of 2-methyl-2-propanyl 3-amino-1-piperidinecarboxylate used in Reference Example 37 - Pyrrolidine carboxylate, using [3-fluoro-4-(methoxycarbonyl)phenyl]boronic acid instead of [4-(methoxycarbonyl)phenyl]boronic acid used in Reference Example 40, Reference Example 37 → Reference The same operation as Example 38→Reference Example 39→Reference Example 40→Reference Example 41→Reference Example 42 was performed to obtain the title compound having the following physical property values.
LC-MS (A) retention time (min): 1.24;
MS(ESI, Pos.): 816 (M + H) + ;
1 H-NMR (DMSO-d 6 ): δ 1.36-1.50, 2.19-2.35, 2.70-2.93, 3.61-3.77, 3.83-3.93, 3.94-4.12, 4.66, 4.91, 5.01-5.19, 5.30-5.39, 5.44- 5.59, 6.89-7.00, 7.01-7.16, 7.23-7.36, 7.47-7.57, 7.59-7.72, 7.73-7.79, 7.97, 8.19-8.27, 8.28-8.38, 9.54-9.63.
実施例１９
２－メチル－２－プロパニル　｛３－［２－アニリノ－７－（４－｛［９－（２，４－ジフルオロベンジル）－５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－イル］カルボニル｝フェニル）－８－オキソ－７，８－ジヒドロ－９Ｈ－プリン－９－イル］プロピル｝カーバメート
　参考例３７で用いた２－メチル－２－プロパニル　３－アミノ－１－ピぺリジンカルボキシラートの代わりに２－メチル－２－プロパニル　（３－アミノプロピル）カーバメートを用いて、参考例３７→参考例３８→参考例３９→参考例４０→参考例４１→参考例４２と同様の操作を行い、以下の物性値を有する標題化合物を得た。
LC－MS（A）保持時間（分）：1.27；
MS(ESI, Pos.)： 786 (M + H)＋；
１H-NMR(DMSO-d６)：δ　 1.36, 1.89-2.01, 2.80-2.88, 3.02-3.09, 3.64-4.07, 4.56-4.92, 5.28-5.65, 6.84-6.95, 6.98-7.18, 7.25-7.37, 7.48-7.84, 7.94, 8.20-8.29, 9.57。 Example 19
2-Methyl-2-propanyl {3-[2-anilino-7-(4-{[9-(2,4-difluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4', 3':4,5]pyrrolo[2,3-b]pyridin-7-yl]carbonyl}phenyl)-8-oxo-7,8-dihydro-9H-purin-9-yl]propyl}carbamate Reference Example 37 Using 2-methyl-2-propanyl (3-aminopropyl) carbamate instead of 2-methyl-2-propanyl 3-amino-1-piperidinecarboxylate used in Reference Example 37 → Reference Example 38 → The same operations as Reference Example 39 → Reference Example 40 → Reference Example 41 → Reference Example 42 were performed to obtain the title compound having the following physical property values.
LC-MS (A) retention time (min): 1.27;
MS(ESI, Pos.): 786 (M + H) + ;
1 H-NMR (DMSO-d 6 ): δ 1.36, 1.89-2.01, 2.80-2.88, 3.02-3.09, 3.64-4.07, 4.56-4.92, 5.28-5.65, 6.84-6.95, 6.98-7.18, 7.25-7.37, 7.48-7.84, 7.94, 8.20-8.29, 9.57.
参考例４４
２－メチル－２－プロパニル　４－（２－アニリノ－８－オキソ－７，８－ジヒドロ－９Ｈ－プリン－９－イル）－１－ピペリジンカルボキシラート
　参考例３７で用いた２－メチル－２－プロパニル　３－アミノ－１－ピぺリジンカルボキシラートの代わりに２－メチル－２－プロパニル　４－アミノ－１－ピぺリジンカルボキシラートを用いて、参考例３７→参考例３８→参考例３９と同様の操作を行い、以下の物性値を有する標題化合物を得た。
LC－MS（A）保持時間（分）：0.94；
MS(ESI, Pos.)： 411 (M + H)＋。 Reference example 44
2-Methyl-2-propanyl 4-(2-anilino-8-oxo-7,8-dihydro-9H-purin-9-yl)-1-piperidinecarboxylate 2-Methyl-2- used in Reference Example 37 Same as Reference Example 37→Reference Example 38→Reference Example 39 using 2-methyl-2-propanyl 4-amino-1-piperidinecarboxylate instead of propanyl 3-amino-1-piperidinecarboxylate. The title compound having the following physical properties was obtained.
LC-MS (A) retention time (min): 0.94;
MS(ESI, Pos.): 411 (M + H) + .
参考例４５
２－アニリノ－９－［１－（２，２－ジメチルプロピル）－４－ピペリジニル］－７，９－ジヒドロ－８Ｈ－プリン－８－オン
　参考例７で製造した化合物の代わりに参考例４４で製造した化合物を用いて、参考例８→参考例９と同様の操作を行い、以下の物性値を有する標題化合物を得た。
LC－MS（A）保持時間（分）：0.77；
MS(ESI, Pos.)： 381 (M + H)＋。 Reference example 45
2-anilino-9-[1-(2,2-dimethylpropyl)-4-piperidinyl]-7,9-dihydro-8H-purin-8-one Instead of the compound produced in Reference Example 7, the compound prepared in Reference Example 44 was used. Using the produced compound, the same operations as Reference Example 8→Reference Example 9 were performed to obtain the title compound having the following physical property values.
LC-MS (A) retention time (min): 0.77;
MS(ESI, Pos.): 381 (M + H) + .
実施例２０
２－アニリノ－７－（４－｛［９－（２，４－ジフルオロベンジル）－５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－イル］カルボニル｝－２－メチルフェニル）－９－［１－（２，２－ジメチルプロピル）－４－ピペリジニル］－７，９－ジヒドロ－８Ｈ－プリン－８－オン　２トリフルオロ酢酸塩
　参考例３９で製造した化合物の代わりに参考例４５で製造した化合物を、参考例４０で用いた［４－（メトキシカルボニル)フェニル］ボロン酸の代わりに［４－（メトキシカルボニル)－２－メチルフェニル］ボロン酸を用いて、参考例４０→参考例４１→参考例４２と同様の操作を行い、逆相HPLCカラム精製することにより、以下の物性値を有する標題化合物を得た。
LC－MS（A）保持時間（分）：1.13；
MS(ESI, Pos.)： 796 (M + H)＋；
１H-NMR(DMSO-d６)：δ　 1.01-1.14, 2.03-2.28, 2.82-2.91, 3.04-3.10, 3.14-3.22, 3.29-3.35, 3.66-3.74, 3.90-4.09, 4.53-4.92, 5.28-5.63, 6.89-6.97, 7.00-7.16, 7.25-7.39, 7.42-7.60, 7.63-7.70, 7.71-7.79, 7.97, 8.18-8.29, 8.66-8.91, 9.38-9.52。 Example 20
2-anilino-7-(4-{[9-(2,4-difluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[2, 3-b]pyridin-7-yl]carbonyl}-2-methylphenyl)-9-[1-(2,2-dimethylpropyl)-4-piperidinyl]-7,9-dihydro-8H-purine-8- [4-( methoxycarbonyl )phenyl]boronic acid used in Reference Example 40 was used in place of the compound produced in Reference Example 45 in place of the compound produced in Reference Example 39. Using carbonyl)-2-methylphenyl]boronic acid, the same operations as Reference Example 40 → Reference Example 41 → Reference Example 42 were carried out, and the title compound having the following physical property values was obtained by purifying with a reverse phase HPLC column. Obtained.
LC-MS (A) retention time (min): 1.13;
MS(ESI, Pos.): 796 (M + H) + ;
1 H-NMR (DMSO-d 6 ): δ 1.01-1.14, 2.03-2.28, 2.82-2.91, 3.04-3.10, 3.14-3.22, 3.29-3.35, 3.66-3.74, 3.90-4.09, 4.53-4.92, 5.28- 5.63, 6.89-6.97, 7.00-7.16, 7.25-7.39, 7.42-7.60, 7.63-7.70, 7.71-7.79, 7.97, 8.18-8.29, 8.66-8.91, 9.38-9.52.
参考例４６
２－メチル－２－プロパニル　４－［（５－アミノ－６－クロロ－４－ピリミジニル）アミノ］－１－ピペリジンカルボキシラート
　４，６－ジクロロ－５－ピリミジンアミン（3.5ｇ）と２－メチル－２－プロパニル　４－アミノ－１－ピぺリジンカルボキシラート（6.4ｇ）をＮ，Ｎ－ジメチルアセトアミド（以下、ＤＭＡと略記することがある。）（18ｍＬ）に溶解し、ＤＩＰＥＡ（7.4ｍＬ）を加えて１２０℃で１７時間攪拌した。反応液を室温に冷却し、水を加えて生じた析出をヘキサンと酢酸エチルの混合液（１：１）で洗浄し、ろ取することにより、以下の物性値を有する標題化合物（4.4ｇ）を得た。
LC－MS（A）保持時間（分）：0.91；
MS(ESI, Pos.)： 328 (M + H)＋。 Reference example 46
2-Methyl-2-propanyl 4-[(5-amino-6-chloro-4-pyrimidinyl)amino]-1-piperidinecarboxylate 4,6-dichloro-5-pyrimidinamine (3.5g) and 2-methyl- Dissolve 2-propanyl 4-amino-1-piperidinecarboxylate (6.4 g) in N,N-dimethylacetamide (hereinafter sometimes abbreviated as DMA) (18 mL), and add DIPEA (7.4 mL). In addition, the mixture was stirred at 120°C for 17 hours. The reaction solution was cooled to room temperature, water was added, and the resulting precipitate was washed with a mixture of hexane and ethyl acetate (1:1) and collected by filtration to obtain the title compound (4.4 g) having the following physical properties. I got it.
LC-MS (A) retention time (min): 0.91;
MS(ESI, Pos.): 328 (M + H) + .
参考例４７
２－メチル－２－プロパニル　４－（６－クロロ－８－オキソ－７，８－ジヒドロ－９Ｈ－プリン－９－イル）－１－ピペリジンカルボキシラート
　参考例１２で製造した化合物の代わりに参考例４６で製造した化合物（4.4ｇ）を用いて、参考例１３と同様の操作を行い、以下の物性値を有する標題化合物（4.4ｇ）を得た。
LC－MS（A）保持時間（分）：1.00；
MS(ESI, Pos.)： 354 (M + H)＋。 Reference example 47
2-Methyl-2-propanyl 4-(6-chloro-8-oxo-7,8-dihydro-9H-purin-9-yl)-1-piperidinecarboxylate Reference Example instead of the compound produced in Reference Example 12 Using the compound (4.4 g) prepared in 46, the same operation as in Reference Example 13 was performed to obtain the title compound (4.4 g) having the following physical properties.
LC-MS (A) retention time (min): 1.00;
MS(ESI, Pos.): 354 (M + H) + .
参考例４８
６－クロロ－９－［１－（２，２－ジメチルプロピル）－４－ピペリジニル］－７，９－ジヒドロ－８Ｈ－プリン－８－オン
　参考例７で製造した化合物の代わりに参考例４７で製造した化合物を用いて、参考例８→参考例９と同様の操作を行い、以下の物性値を有する標題化合物を得た。
LC－MS（A）保持時間（分）：0.73；
MS(ESI, Pos.)： 324 (M + H)＋。 Reference example 48
6-chloro-9-[1-(2,2-dimethylpropyl)-4-piperidinyl]-7,9-dihydro-8H-purin-8-one Instead of the compound produced in Reference Example 7, the compound prepared in Reference Example 47 was used. Using the produced compound, the same operations as in Reference Example 8→Reference Example 9 were performed to obtain the title compound having the following physical property values.
LC-MS (A) retention time (min): 0.73;
MS(ESI, Pos.): 324 (M + H) + .
参考例４９
６－クロロ－７－（４－｛［９－（２，４－ジフルオロベンジル）－５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－イル］カルボニル｝フェニル）－９－［１－（２，２－ジメチルプロピル）－４－ピペリジニル］－７，９－ジヒドロ－８Ｈ－プリン－８－オン
　参考例３９で製造した化合物の代わりに参考例４８で製造した化合物を用いて、参考例４０→参考例４１→参考例４２と同様の操作を行い、以下の物性値を有する標題化合物を得た。
LC－MS（A）保持時間（分）：1.01；
MS(ESI, Pos.)： 725 (M + H)＋。 Reference example 49
6-chloro-7-(4-{[9-(2,4-difluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[2, 3-b]pyridin-7-yl]carbonyl}phenyl)-9-[1-(2,2-dimethylpropyl)-4-piperidinyl]-7,9-dihydro-8H-purin-8-one Reference Example 39 Using the compound produced in Reference Example 48 instead of the compound produced in Reference Example 48, the same operations as Reference Example 40 → Reference Example 41 → Reference Example 42 were performed to obtain the title compound having the following physical property values.
LC-MS (A) retention time (min): 1.01;
MS(ESI, Pos.): 725 (M + H) + .
実施例２１
７－（４－｛［９－（２，４－ジフルオロベンジル）－５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－イル］カルボニル｝フェニル）－９－［１－（２，２－ジメチルプロピル）－４－ピペリジニル］－８－オキソ－８，９－ジヒドロ－７Ｈ－プリン－６－カルボニトリル　２トリフルオロ酢酸塩
　参考例４９で製造した化合物（20ｍｇ）をＤＭＳＯ（0.4ｍＬ）に溶解し、Ｎ，Ｎ，Ｎ－トリブチル－１－ブタンアミニウム　シアニド（11ｍｇ）及びＤＢＵ（9.3ｍｇ）を加えて１００℃で５時間攪拌した。反応液を室温に冷却して水を加え、酢酸エチルで抽出した。得られた有機層を無水硫酸ナトリウムで乾燥後、減圧濃縮して得られた残渣を逆相HPLCカラム精製することにより、以下の物性値を有する標題化合物（7.6ｍｇ）を得た。
LC－MS（A）保持時間（分）：1.00；
MS(ESI, Pos.)： 716 (M + H)＋；
１H-NMR(DMSO-d６)：δ　 1.06-1.11, 2.05, 2.77-2.91, 2.91-3.05, 3.29-3.34, 3.57-3.74, 4.00-4.07, 4.53-4.93, 5.13-5.65, 6.94-7.22, 7.26-7.43, 7.56-7.79, 7.89-8.06, 8.33, 8.70-8.97。 Example 21
7-(4-{[9-(2,4-difluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[2,3-b] Pyridin-7-yl]carbonyl}phenyl)-9-[1-(2,2-dimethylpropyl)-4-piperidinyl]-8-oxo-8,9-dihydro-7H-purine-6-carbonitrile 2-tri The compound (20 mg) prepared in Fluoroacetate Reference Example 49 was dissolved in DMSO (0.4 mL), and N,N,N-tributyl-1-butanaminium cyanide (11 mg) and DBU (9.3 mg) were added. The mixture was stirred at ℃ for 5 hours. The reaction solution was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The obtained organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting residue was purified with a reverse phase HPLC column to obtain the title compound (7.6 mg) having the following physical properties.
LC-MS (A) retention time (min): 1.00;
MS(ESI, Pos.): 716 (M + H) + ;
1 H-NMR (DMSO-d 6 ): δ 1.06-1.11, 2.05, 2.77-2.91, 2.91-3.05, 3.29-3.34, 3.57-3.74, 4.00-4.07, 4.53-4.93, 5.13-5.65, 6.94-7.22, 7.26-7.43, 7.56-7.79, 7.89-8.06, 8.33, 8.70-8.97.
参考例５０
９－ベンジル－６－クロロ－７，９－ジヒドロ－８Ｈ－プリン－８－オン
　４，６－ジクロロ－５－ピリミジンアミン（1.0ｇ）と（イソシアナートメチル）ベンゼン（811ｍｇ）のＴＨＦ溶液（10ｍＬ）にカリウム　２－メチル－２－ブタノラート（1.6ｇ）を加え、室温で４時間攪拌した。反応液を０℃に冷却し、１Ｎ塩酸（54ｍＬ）を加えて室温で１０分攪拌した。生じた析出物を水及びヘキサンと酢酸エチルの混合液（１：１）で洗浄し、以下の物性値を有する標題化合物（966ｍｇ）を得た。
TLC：Rf 0.45（ヘキサン：酢酸エチル＝１：１）；
１H-NMR(CDCl３)：δ　 5.11, 7.29-7.36, 7.45-7.54, 8.30-8.45, 8.51。 Reference example 50
9-Benzyl-6-chloro-7,9-dihydro-8H-purin-8-one THF solution (10 mL) of 4,6-dichloro-5-pyrimidineamine (1.0 g) and (isocyanatomethyl)benzene (811 mg) ) was added potassium 2-methyl-2-butanolate (1.6 g), and the mixture was stirred at room temperature for 4 hours. The reaction solution was cooled to 0° C., 1N hydrochloric acid (54 mL) was added, and the mixture was stirred at room temperature for 10 minutes. The resulting precipitate was washed with water and a mixture of hexane and ethyl acetate (1:1) to obtain the title compound (966 mg) having the following physical properties.
TLC: Rf 0.45 (hexane: ethyl acetate = 1:1);
1H -NMR ( CDCl3 ): δ 5.11, 7.29-7.36, 7.45-7.54, 8.30-8.45, 8.51.
参考例５１
６－アミノ－９－ベンジル－７，９－ジヒドロ－８Ｈ－プリン－８－オン
　参考例５０で製造した化合物（3.9ｇ）をＤＭＦ（30ｍＬ）に溶解し、アジ化ナトリウム（1.9ｇ）を加えて７０℃で１６時間攪拌した。反応液を室温に冷却し、水を加えてジクロロメタンで抽出した。得られた有機層を水と飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した。有機層を減圧濃縮し、得られた残渣をＭＴＢＥとヘキサンの混合液（１：４）で洗浄し、ろ取した。得られた化合物（3.5ｇ）をＴＨＦ（20ｍＬ）に溶解し、トリメチルホスフィン（13ｍＬ、1.0 mol／Ｌ、ＴＨＦ溶液、）を加えて７０℃で１６時間攪拌した。続けて水（3ｍＬ）を反応液に加えて、７０℃で２時間攪拌した。反応液を濃縮し、得られた残渣を逆相シリカゲルカラムクロマトグラフィー（水：アセトニトリル＝９：１→１：９）で精製し、以下の物性値を有する標題化合物（1.0ｇ）を得た。
LC－MS（B）保持時間（分）：0.53；
MS(ESI, Pos.)： 242 (M + H)＋。 Reference example 51
6-Amino-9-benzyl-7,9-dihydro-8H-purin-8-one The compound prepared in Reference Example 50 (3.9 g) was dissolved in DMF (30 mL), and sodium azide (1.9 g) was added. The mixture was stirred at 70°C for 16 hours. The reaction solution was cooled to room temperature, water was added, and the mixture was extracted with dichloromethane. The obtained organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure, and the resulting residue was washed with a mixed solution of MTBE and hexane (1:4) and collected by filtration. The obtained compound (3.5 g) was dissolved in THF (20 mL), trimethylphosphine (13 mL, 1.0 mol/L, THF solution) was added, and the mixture was stirred at 70° C. for 16 hours. Subsequently, water (3 mL) was added to the reaction solution, and the mixture was stirred at 70° C. for 2 hours. The reaction solution was concentrated, and the resulting residue was purified by reverse phase silica gel column chromatography (water:acetonitrile=9:1→1:9) to obtain the title compound (1.0 g) having the following physical properties.
LC-MS (B) retention time (min): 0.53;
MS(ESI, Pos.): 242 (M + H) + .
実施例２２
６－アミノ－９－ベンジル－７－（４－｛［９－（２，４－ジフルオロベンジル）－５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－イル］カルボニル｝フェニル）－７，９－ジヒドロ－８Ｈ－プリン－８－オン
　参考例３９で製造した化合物の代わりに参考例５１で製造した化合物を用いて、参考例４０→参考例４１→参考例４２と同様の操作を行い、以下の物性値を有する標題化合物を得た。
LC－MS（B）保持時間（分）：0.90；
MS(ESI, Pos.)： 643 (M + H)＋；
１H-NMR(DMSO-d６)：δ　 2.77-2.88, 3.65-4.04, 4.63-4.90, 5.00-5.09, 5.27-5.61, 5.93-6.11, 6.90-7.18, 7.23-7.42, 7.44-7.68, 7.92, 8.14-8.18, 8.19-8.26。 Example 22
6-Amino-9-benzyl-7-(4-{[9-(2,4-difluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5] pyrrolo[2,3-b]pyridin-7-yl]carbonyl}phenyl)-7,9-dihydro-8H-purin-8-one Instead of the compound produced in Reference Example 39, the compound produced in Reference Example 51 was used. The same operations as Reference Example 40→Reference Example 41→Reference Example 42 were performed to obtain the title compound having the following physical property values.
LC-MS (B) retention time (min): 0.90;
MS(ESI, Pos.): 643 (M + H) + ;
1 H-NMR (DMSO-d 6 ): δ 2.77-2.88, 3.65-4.04, 4.63-4.90, 5.00-5.09, 5.27-5.61, 5.93-6.11, 6.90-7.18, 7.23-7.42, 7.44-7.68, 7.92, 8.14-8.18, 8.19-8.26.
参考例５２
２－メチル－２－プロパニル　９－（４－シアノ－２－フルオロベンジル）－５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－カルボキシラート
　２－メチル－２－プロパニル　５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－カルボキシラート（CAS：１３５４８０１－０７－２、820ｍｇ）と、４－（クロロメチル）－３－フルオロベンゾニトリル（560ｍｇ）をＤＭＦ（8.2ｍＬ）に溶解した。反応液を氷冷し、水素化ナトリウム（60％パラフィンオイル懸濁液、144ｍｇ）を加えて、３０分攪拌した。反応液に飽和塩化アンモニウム水溶液を加えて攪拌し、酢酸エチルで抽出した。得られた有機層を飽和食塩水で洗浄した後、無水硫酸ナトリウムを加えて乾燥し、減圧濃縮して得られた残渣をシリカゲルクロマトグラフィー（ヘキサン：酢酸エチル＝６７：３３）で精製することにより、以下の物性値を有する標題化合物（1.3ｇ）を得た。
TLC：Rf 0.40（ヘキサン：酢酸エチル＝２：１）；
１H-NMR(CDCl３)：δ　 1.47, 2.81, 3.75, 4.51, 5.52, 6.83-7.06, 7.10, 7.39, 7.82, 8.27。 Reference example 52
2-Methyl-2-propanyl 9-(4-cyano-2-fluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[2,3- b] Pyridine-7-carboxylate 2-methyl-2-propanyl 5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[2,3-b]pyridine-7 -carboxylate (CAS: 1354801-07-2, 820 mg) and 4-(chloromethyl)-3-fluorobenzonitrile (560 mg) were dissolved in DMF (8.2 mL). The reaction solution was ice-cooled, sodium hydride (60% paraffin oil suspension, 144 mg) was added, and the mixture was stirred for 30 minutes. A saturated aqueous ammonium chloride solution was added to the reaction solution, stirred, and extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, dried by adding anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting residue was purified by silica gel chromatography (hexane: ethyl acetate = 67:33). The title compound (1.3 g) having the following physical properties was obtained.
TLC: Rf 0.40 (hexane: ethyl acetate = 2:1);
1H -NMR ( CDCl3 ): δ 1.47, 2.81, 3.75, 4.51, 5.52, 6.83-7.06, 7.10, 7.39, 7.82, 8.27.
参考例５３
３－フルオロ－４－（５，６，７，８－テトラヒドロ－９Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－９－イルメチル）ベンゾニトリル　２塩酸塩
　参考例５２で製造した化合物（1.3ｇ）をメタノール（2ｍＬ）に溶解し、４Ｎ塩化水素／１，4－ジオキサン溶液（7.8ｍＬ）を加えて室温で４０分攪拌した。反応液を濃縮しＭＴＢＥを用いて洗浄し、ろ取することにより、以下の物性値を有する標題化合物（1.1ｇ）を得た。
TLC：Rf 0.39（ジクロロメタン：メタノール＝９：１）；
１H-NMR(DMSO-d６)：δ　 2.99, 3.40-3.56, 4.37, 5.61, 6.99, 7.18, 7.59, 7.93, 8.02, 8.26, 9.76。 Reference example 53
3-fluoro-4-(5,6,7,8-tetrahydro-9H-pyrido[4',3':4,5]pyrrolo[2,3-b]pyridin-9-ylmethyl)benzonitrile dihydrochloride The compound (1.3 g) produced in Reference Example 52 was dissolved in methanol (2 mL), 4N hydrogen chloride/1,4-dioxane solution (7.8 mL) was added, and the mixture was stirred at room temperature for 40 minutes. The reaction solution was concentrated, washed with MTBE, and collected by filtration to obtain the title compound (1.1 g) having the following physical properties.
TLC: Rf 0.39 (dichloromethane:methanol = 9:1);
1H -NMR (DMSO- d6 ): δ 2.99, 3.40-3.56, 4.37, 5.61, 6.99, 7.18, 7.59, 7.93, 8.02, 8.26, 9.76.
参考例５４
２－メチル－２－プロパニル　４－［２－クロロ－７－（４－｛［９－（４－シアノ－２－フルオロベンジル）－５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－イル］カルボニル｝フェニル）－６－メチル－８－オキソ－７，８－ジヒドロ－９Ｈ－プリン－９－イル］－１－ピペリジンカルボキシラート
　参考例５３で製造した化合物（872ｍｇ）と参考例６で製造した化合物（976ｍｇ）をＤＭＦ（10ｍＬ）に溶解し、ＤＩＰＥＡ（1.4ｍＬ）とＨＡＴＵ（1.1ｇ）を加えて室温で２時間攪拌した。反応液に飽和炭酸水素ナトリウム水溶液を加えて、酢酸エチルで抽出した。有機層を水と飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥して減圧濃縮した。得られた残渣をシリカゲルクロマトグラフィー（ヘキサン：酢酸エチル＝１：３）で精製することにより、以下の物性値を有する標題化合物（1.0ｇ）を得た。
LC－MS（A）保持時間（分）：1.26；
MS(ESI, Pos.)： 776 (M + H)＋；
１H-NMR(CDCl３)：δ　 1.45-1.55, 1.76-1.92, 2.11, 2.53-2.69, 2.78-3.00, 3.69-4.11, 4.24-4.42, 4.47-4.94, 5.31-5.67, 6.89-7.00, 7.14, 7.28-7.36, 7.37-7.73, 7.85, 8.31。 Reference example 54
2-Methyl-2-propanyl 4-[2-chloro-7-(4-{[9-(4-cyano-2-fluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[2,3-b]pyridin-7-yl]carbonyl}phenyl)-6-methyl-8-oxo-7,8-dihydro-9H-purin-9-yl]- 1-Piperidinecarboxylate The compound produced in Reference Example 53 (872 mg) and the compound produced in Reference Example 6 (976 mg) were dissolved in DMF (10 mL), DIPEA (1.4 mL) and HATU (1.1 g) were added, and the mixture was heated at room temperature. The mixture was stirred for 2 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (hexane: ethyl acetate = 1:3) to obtain the title compound (1.0 g) having the following physical properties.
LC-MS (A) retention time (min): 1.26;
MS(ESI, Pos.): 776 (M + H) + ;
1 H-NMR (CDCl 3 ): δ 1.45-1.55, 1.76-1.92, 2.11, 2.53-2.69, 2.78-3.00, 3.69-4.11, 4.24-4.42, 4.47-4.94, 5.31-5.67, 6.89-7.00, 7.14 , 7.28-7.36, 7.37-7.73, 7.85, 8.31.
参考例５５
４－［（７－｛４－［２－クロロ－６－メチル－８－オキソ－９－（４－ピペリジニル）－８，９－ジヒドロ－７Ｈ－プリン－７－イル］ベンゾイル｝－５，６，７，８－テトラヒドロ－９Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－９－イル）メチル］－３－フルオロベンゾニトリル　２塩酸塩
　参考例５４で製造した化合物（324ｍｇ）を１，４－ジオキサン（0.32ｍＬ）と２－プロパノール（0.97ｍＬ）を加えて溶解し、さらに４Ｎ塩化水素／１，4－ジオキサン溶液（1.6ｍＬ）を加えて室温で１時間攪拌した。反応液をＭＴＢＥで希釈し、析出物をろ取することにより、以下の物性値を有する標題化合物（280ｍｇ）を得た。
LC－MS（A）保持時間（分）：0.94；
MS(ESI, Pos.)： 676 (M + H)＋。 Reference example 55
4-[(7-{4-[2-chloro-6-methyl-8-oxo-9-(4-piperidinyl)-8,9-dihydro-7H-purin-7-yl]benzoyl}-5,6 ,7,8-tetrahydro-9H-pyrido[4',3':4,5]pyrrolo[2,3-b]pyridin-9-yl)methyl]-3-fluorobenzonitrile dihydrochloride Reference Example 54 The prepared compound (324 mg) was dissolved by adding 1,4-dioxane (0.32 mL) and 2-propanol (0.97 mL), and then 4N hydrogen chloride/1,4-dioxane solution (1.6 mL) was added and the mixture was dissolved at room temperature. Stirred for 1 hour. The reaction solution was diluted with MTBE and the precipitate was collected by filtration to obtain the title compound (280 mg) having the following physical properties.
LC-MS (A) retention time (min): 0.94;
MS(ESI, Pos.): 676 (M + H) + .
参考例５６
４－｛［７－（４－｛２－クロロ－９－［１－（２，２－ジメチルプロピル）－４－ピペリジニル］－６－メチル－８－オキソ－８，９－ジヒドロ－７Ｈ－プリン－７－イル｝ベンゾイル）－５，６，７，８－テトラヒドロ－９Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－９－イル］メチル｝－３－フルオロベンゾニトリル
　参考例５５で製造した化合物（280ｍｇ）をＤＭＦ（2.8ｍＬ）に溶解し、ＮＥｔ３（0.16ｍＬ）を加えた。得られた混合液に、ピバルアルデヒド（169ｍｇ）と酢酸（0.23ｍＬ）、トリアセトキシ水素化ホウ素ナトリウム（250ｍｇ）を加えて室温で３時間攪拌した。反応液を氷冷し、飽和炭酸水素ナトリウム水溶液を加えた。ヘキサンと酢酸エチルの混合液（３：７）で抽出後、有機層を飽和炭酸水素ナトリウム水溶液と水で洗浄し、無水硫酸ナトリウムで乾燥した。減圧濃縮して得られた残渣をシリカゲルクロマトグラフィー（富士シリシア　ＮＨ（商品名）、ヘキサン：酢酸エチル＝３：１→０：１）で精製することにより、以下の物性値を有する標題化合物（230ｍｇ）を得た。
LC－MS（A）保持時間（分）：1.02；
MS(ESI, Pos.)： 746 (M + H)＋；
１H-NMR(CDCl３)：δ　 0.90, 1.62-1.80, 2.13, 2.41-2.50, 2.65-2.80, 2.85-3.01, 3.70-4.12, 4.43, 4.50-4.92, 5.34-5.66, 6.94, 7.14, 7.27-7.36, 7.39-7.72, 7.85, 8.31。 Reference example 56
4-{[7-(4-{2-chloro-9-[1-(2,2-dimethylpropyl)-4-piperidinyl]-6-methyl-8-oxo-8,9-dihydro-7H-purine -7-yl}benzoyl)-5,6,7,8-tetrahydro-9H-pyrido[4',3':4,5]pyrrolo[2,3-b]pyridin-9-yl]methyl}-3 -Fluorobenzonitrile The compound prepared in Reference Example 55 (280 mg) was dissolved in DMF (2.8 mL), and NEt 3 (0.16 mL) was added. To the resulting mixture were added pivalaldehyde (169 mg), acetic acid (0.23 mL), and sodium triacetoxyborohydride (250 mg), and the mixture was stirred at room temperature for 3 hours. The reaction solution was cooled with ice, and saturated aqueous sodium hydrogen carbonate solution was added. After extraction with a mixture of hexane and ethyl acetate (3:7), the organic layer was washed with a saturated aqueous sodium bicarbonate solution and water, and dried over anhydrous sodium sulfate. The residue obtained by concentration under reduced pressure was purified by silica gel chromatography (Fuji Silysia NH (trade name), hexane:ethyl acetate = 3:1 → 0:1) to obtain the title compound (230 mg) having the following physical property values. ) was obtained.
LC-MS (A) retention time (min): 1.02;
MS(ESI, Pos.): 746 (M + H) + ;
1 H-NMR (CDCl 3 ): δ 0.90, 1.62-1.80, 2.13, 2.41-2.50, 2.65-2.80, 2.85-3.01, 3.70-4.12, 4.43, 4.50-4.92, 5.34-5.66, 6.94, 7.14, 7. 27- 7.36, 7.39-7.72, 7.85, 8.31.
実施例２３
１－（３－｛７－（４－｛［９－（４－シアノ－２－フルオロベンジル）－５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－イル］カルボニル｝フェニル）－９－［１－（２，２－ジメチルプロピル）－４－ピペリジニル］－６－メチル－８－オキソ－８，９－ジヒドロ－７Ｈ－プリン－２－イル｝フェニル）シクロプロパンカルボン酸
　参考例５６で製造した化合物（550ｍｇ）をＮＭＰ（7.7ｍＬ）に溶解し、１－［３－（４，４，５，５－テトラメチル－１，３，２－ジオキサボロラン－２－イル）フェニル］シクロプロパンカルボン酸（637ｍｇ）、リン酸三カリウム水溶液（1.1ｍＬ、2mol/L）、［１，１’－ビス（ジフェニルホスフィノ）フェロセン］パラジウム（ＩＩ）ジクロリド　ジクロロメタン錯体（120ｍｇ）を加えてマイクロウェーブ装置を用いて１４０℃で１時間攪拌した。反応液を室温に冷却後、酢酸エチルで希釈して水を加えた。得られた有機層を水と飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した。減圧濃縮して得られた残渣をシリカゲルクロマトグラフィー（酢酸エチル：メタノール＝１：０→４：１）で精製することにより、以下の物性値を有する標題化合物（275ｍｇ）を得た。
LC－MS（A）保持時間（分）：1.07；
MS(ESI, Pos.)： 872 (M + H)＋；
１H-NMR(CDCl３)：δ　 0.94, 1.34-1.42, 1.68-1.82, 2.11-2.26, 2.51, 2.88-3.03, 3.75-4.11, 4.48, 4.54-4.91, 5.33-5.65, 6.93, 7.14, 7.27-7.33, 7.40-7.70, 7.85, 8.31, 8.39, 8.45。 Example 23
1-(3-{7-(4-{[9-(4-cyano-2-fluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5] pyrrolo[2,3-b]pyridin-7-yl]carbonyl}phenyl)-9-[1-(2,2-dimethylpropyl)-4-piperidinyl]-6-methyl-8-oxo-8,9- dihydro-7H-purin-2-yl}phenyl)cyclopropanecarboxylic acid
The compound (550 mg) produced in Reference Example 56 was dissolved in NMP (7.7 mL), and 1-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl ] Cyclopropanecarboxylic acid (637 mg), tripotassium phosphate aqueous solution (1.1 mL, 2 mol/L), [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane complex (120 mg) were added. The mixture was stirred at 140° C. for 1 hour using a microwave device. After the reaction solution was cooled to room temperature, it was diluted with ethyl acetate and water was added. The obtained organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by concentration under reduced pressure was purified by silica gel chromatography (ethyl acetate:methanol=1:0→4:1) to obtain the title compound (275 mg) having the following physical properties.
LC-MS (A) retention time (min): 1.07;
MS(ESI, Pos.): 872 (M + H) + ;
1 H-NMR (CDCl 3 ): δ 0.94, 1.34-1.42, 1.68-1.82, 2.11-2.26, 2.51, 2.88-3.03, 3.75-4.11, 4.48, 4.54-4.91, 5.33-5.65, 6.93, 7.14, 7. 27- 7.33, 7.40-7.70, 7.85, 8.31, 8.39, 8.45.
実施例２３－１
１－（３－｛７－（４－｛［９－（４－シアノ－２－フルオロベンジル）－５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－イル］カルボニル｝フェニル）－９－［１－（２，２－ジメチルプロピル）－４－ピペリジニル］－６－メチル－８－オキソ－８，９－ジヒドロ－７Ｈ－プリン－２－イル｝フェニル）シクロブタンカルボン酸
　１－［３－（４，４，５，５－テトラメチル－１，３，２－ジオキサボロラン－２－イル）フェニル］シクロプロパンカルボン酸の代わりに１－［３－（４，４，５，５－テトラメチル－１，３，２－ジオキサボロラン－２－イル）フェニル］シクロブタンカルボン酸を用いて、実施例２３と同様の操作を行い、以下の物性値を有する標題化合物を得た。
LC－MS（A）保持時間（分）：1.10；
MS(ESI, Pos.)： 886 (M + H)＋；
１H-NMR(CDCl３)：δ　 0.94, 1.73-1.84, 1.90-2.01, 2.08-2.23, 2.45-2.55, 2.61-2.70, 2.87-2.99, 3.00-3.08, 3.74-4.15, 4.40-4.52, 4.54-4.93, 5.32-5.69, 6.89-7.02, 7.14, 7.27-7.33, 7.39-7.56, 7.65, 7.86, 8.30-8.34, 8.47。 Example 23-1
1-(3-{7-(4-{[9-(4-cyano-2-fluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5] pyrrolo[2,3-b]pyridin-7-yl]carbonyl}phenyl)-9-[1-(2,2-dimethylpropyl)-4-piperidinyl]-6-methyl-8-oxo-8,9- dihydro-7H-purin-2-yl}phenyl)cyclobutanecarboxylic acid 1-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]cyclopropanecarboxylic acid The same operation as in Example 23 was carried out using 1-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]cyclobutanecarboxylic acid instead of , the title compound having the following physical properties was obtained.
LC-MS (A) retention time (min): 1.10;
MS(ESI, Pos.): 886 (M + H) + ;
1 H-NMR (CDCl 3 ): δ 0.94, 1.73-1.84, 1.90-2.01, 2.08-2.23, 2.45-2.55, 2.61-2.70, 2.87-2.99, 3.00-3.08, 3.74-4.15, 4.40-4.52, 4.54 - 4.93, 5.32-5.69, 6.89-7.02, 7.14, 7.27-7.33, 7.39-7.56, 7.65, 7.86, 8.30-8.34, 8.47.
参考例５７
３－フルオロ－４－｛［７－（４－ヨードベンゾイル）－５，６，７，８－テトラヒドロ－９Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－９－イル］メチル｝ベンゾニトリル
　参考例５３で製造した化合物（1.2ｇ）と４－ヨード安息香酸（960ｍｇ）をＤＭＦ（24ｍＬ）に溶解し、ＤＩＰＥＡ（3.0ｍＬ）と４－（４，６－ジメトキシ－１，３，５－トリアジン－２－イル）－４－メチルモルホリン－４－イウム　クロライド（以下、ＤＭＴＭＭと略記することがある。）（2.1ｇ）を加えて室温で４０分攪拌した。反応液に水を加えて、酢酸エチルで抽出した。有機層を水で洗浄後、インジェクトカラム　アミノ（商品名）を通し、得られたろ液を濃縮した。残渣をヘキサンと酢酸エチルの混合液（２：１）で洗浄し、以下の物性値を有する標題化合物（1.6ｇ）を得た。
LC－MS（A）保持時間（分）：1.20；
MS(ESI, Pos.)： 537 (M + H)＋；
１H-NMR(CDCl３)：δ　 2.87, 3.64-4.06, 4.40-4.88, 5.28-5.66, 6.92, 7.09-7.25, 7.27-7.34, 7.40, 7.72-7.88, 8.30。 Reference example 57
3-fluoro-4-{[7-(4-iodobenzoyl)-5,6,7,8-tetrahydro-9H-pyrido[4',3':4,5]pyrrolo[2,3-b]pyridine -9-yl]methyl}benzonitrile The compound prepared in Reference Example 53 (1.2 g) and 4-iodobenzoic acid (960 mg) were dissolved in DMF (24 mL), and DIPEA (3.0 mL) and 4-(4,6 -Dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholin-4-ium chloride (hereinafter sometimes abbreviated as DMTMM) (2.1 g) was added and stirred at room temperature for 40 minutes. . Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. After washing the organic layer with water, it was passed through an injection column Amino (trade name), and the obtained filtrate was concentrated. The residue was washed with a mixture of hexane and ethyl acetate (2:1) to obtain the title compound (1.6 g) having the following physical properties.
LC-MS (A) retention time (min): 1.20;
MS(ESI, Pos.): 537 (M + H) + ;
1H -NMR ( CDCl3 ): δ 2.87, 3.64-4.06, 4.40-4.88, 5.28-5.66, 6.92, 7.09-7.25, 7.27-7.34, 7.40, 7.72-7.88, 8.30.
参考例５８
エチル　５－アミノ－２－クロロ－６－［（１－｛［（２－メチル－２－プロパニル）オキシ］カルボニル｝－４－ピペリジニル）アミノ］－４－ピリミジンカルボキシラート
　２－メチル－２－プロパニル　４－アミノ－１－ピぺリジンカルボキシラート（1.0ｇ）と、エチル　５－アミノ－２、６－ジクロロ－４－ピリミジンカルボキシラート（2.2ｇ）をＤＭＡ（5ｍＬ）に溶解し、ＤＩＰＥＡ（1.1ｍＬ）を加えて、１００℃で終夜攪拌した。室温まで冷却後、反応液に水を加えて酢酸エチルで抽出した。有機層を減圧濃縮し、得られた残渣をシリカゲルクロマトグラフィー（ヘキサン：酢酸エチル＝１：１→０：１）で精製することにより、以下の物性値を有する標題化合物（1.6ｇ）を得た。
LC－MS（A）保持時間（分）：1.10；
MS(ESI, Pos.)： 400 (M + H)＋；
１H-NMR(CDCl３)：δ　 1.34-1.44, 1.46, 2.03-2.15, 2.93, 4.04-4.29, 4.43, 5.30, 5.52。 Reference example 58
Ethyl 5-amino-2-chloro-6-[(1-{[(2-methyl-2-propanyl)oxy]carbonyl}-4-piperidinyl)amino]-4-pyrimidinecarboxylate 2-methyl-2-propanyl 4-Amino-1-piperidinecarboxylate (1.0g) and ethyl 5-amino-2,6-dichloro-4-pyrimidinecarboxylate (2.2g) were dissolved in DMA (5mL) and DIPEA (1.1mL). ) and stirred at 100°C overnight. After cooling to room temperature, water was added to the reaction solution and extracted with ethyl acetate. The organic layer was concentrated under reduced pressure, and the resulting residue was purified by silica gel chromatography (hexane: ethyl acetate = 1:1 → 0:1) to obtain the title compound (1.6 g) having the following physical properties. .
LC-MS (A) retention time (min): 1.10;
MS(ESI, Pos.): 400 (M + H) + ;
1H -NMR ( CDCl3 ): δ 1.34-1.44, 1.46, 2.03-2.15, 2.93, 4.04-4.29, 4.43, 5.30, 5.52.
参考例５９
エチル　２－クロロ－５－［（４－｛［９－（４－シアノ－２－フルオロベンジル）－５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－イル］カルボニル｝フェニル）アミノ］－６－［（１－｛［（２－メチル－２－プロパニル）オキシ］カルボニル｝－４－ピペリジニル）アミノ］－４－ピリミジンカルボキシラート
　参考例５７で製造した化合物（590ｍｇ）と参考例５８で製造した化合物（400ｍｇ）に１，４－ジオキサン（8ｍＬ）を加えて溶解した。その溶液に、炭酸セシウム（489ｍｇ）及びXantphos（116ｍｇ）、Pd２（dba）３（92ｍｇ）を加えた。反応容器中を窒素置換後、１００℃で４時間攪拌した。反応液を室温に冷却し、水を加えて酢酸エチルで抽出した。有機層を減圧濃縮し、得られた残渣をシリカゲルクロマトグラフィー（ヘキサン：酢酸エチル＝７：３→０：１）で精製することにより、以下の物性値を有する標題化合物（110ｍｇ）を得た。
LC－MS（A）保持時間（分）：1.26；
MS(ESI, Pos.)： 808 (M + H)＋。 Reference example 59
Ethyl 2-chloro-5-[(4-{[9-(4-cyano-2-fluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5] pyrrolo[2,3-b]pyridin-7-yl]carbonyl}phenyl)amino]-6-[(1-{[(2-methyl-2-propanyl)oxy]carbonyl}-4-piperidinyl)amino]- 4-Pyrimidinecarboxylate The compound produced in Reference Example 57 (590 mg) and the compound produced in Reference Example 58 (400 mg) were dissolved in 1,4-dioxane (8 mL). Cesium carbonate (489 mg), Xantphos (116 mg), and Pd 2 (dba) 3 (92 mg) were added to the solution. After purging the inside of the reaction vessel with nitrogen, the mixture was stirred at 100°C for 4 hours. The reaction solution was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was concentrated under reduced pressure, and the resulting residue was purified by silica gel chromatography (hexane:ethyl acetate = 7:3→0:1) to obtain the title compound (110 mg) having the following physical properties.
LC-MS (A) retention time (min): 1.26;
MS(ESI, Pos.): 808 (M + H) + .
参考例６０（実施例２３－Ａ）
エチル　２－クロロ－７－（４－｛［９－（４－シアノ－２－フルオロベンジル）－５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－イル］カルボニル｝フェニル）－９－（１－｛［（２－メチル－２－プロパニル）オキシ］カルボニル｝－４－ピペリジニル）－８－オキソ－８，９－ジヒドロ－７Ｈ－プリン－６－カルボキシラート
　参考例５９で製造した化合物（110ｍｇ）をＴＨＦ（1.1ｍＬ）に溶解し、ＣＤＩ（44ｍｇ）とＤＢＵ（31ｍｇ）を加えて室温で２０分攪拌した。反応液に飽和塩化アンモニウム水を加えて酢酸エチルで希釈した。得られた有機層を、飽和塩化アンモニウム水で洗浄し、減圧濃縮して得られた残渣をシリカゲルクロマトグラフィー（ヘキサン：酢酸エチル＝１：１→０：１）で精製することにより、以下の物性値を有する標題化合物（40ｍｇ）を得た。
LC－MS（A）保持時間（分）：1.28；
MS(ESI, Pos.)： 834 (M + H)＋；
１H-NMR(CDCl３)：δ　 1.26, 1.47-1.55, 1.80-1.94, 2.54-2.72, 2.78-3.01, 3.73-4.08, 4.09-4.16, 4.24-4.92, 5.37-5.68, 6.89-7.00, 7.10-7.17, 7.29-7.70, 7.84, 8.31。 Reference example 60 (Example 23-A)
Ethyl 2-chloro-7-(4-{[9-(4-cyano-2-fluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo [2,3-b]pyridin-7-yl]carbonyl}phenyl)-9-(1-{[(2-methyl-2-propanyl)oxy]carbonyl}-4-piperidinyl)-8-oxo-8, 9-Dihydro-7H-purine-6-carboxylate The compound prepared in Reference Example 59 (110 mg) was dissolved in THF (1.1 mL), CDI (44 mg) and DBU (31 mg) were added, and the mixture was stirred at room temperature for 20 minutes. . Saturated ammonium chloride water was added to the reaction mixture, and the mixture was diluted with ethyl acetate. The obtained organic layer was washed with saturated ammonium chloride water, concentrated under reduced pressure, and the resulting residue was purified by silica gel chromatography (hexane: ethyl acetate = 1:1 → 0:1) to obtain the following physical properties. The title compound (40 mg) was obtained.
LC-MS (A) retention time (min): 1.28;
MS(ESI, Pos.): 834 (M + H) + ;
1 H-NMR (CDCl 3 ): δ 1.26, 1.47-1.55, 1.80-1.94, 2.54-2.72, 2.78-3.01, 3.73-4.08, 4.09-4.16, 4.24-4.92, 5.37-5.68, 6.89-7.00, 7.10 - 7.17, 7.29-7.70, 7.84, 8.31.
参考例６１
エチル　２－クロロ－７－（４－｛［９－（４－シアノ－２－フルオロベンジル）－５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－イル］カルボニル｝フェニル）－９－［１－（２，２－ジメチルプロピル）－４－ピペリジニル］－８－オキソ－８，９－ジヒドロ－７Ｈ－プリン－６－カルボキシラート
　参考例５４で製造した化合物の代わりに参考例６０で製造した化合物を用いて、参考例５５→参考例５６と同様の操作を行い、以下の物性値を有する標題化合物を得た。
LC－MS（A）保持時間（分）：1.08；
MS(ESI, Pos.)： 804 (M + H)＋；
１H-NMR(CDCl３)：δ　 0.86-0.96, 1.22-1.29, 1.69-1.83, 2.14, 2.41-2.51, 2.65-2.81, 2.84-3.02, 3.73-4.08, 4.38-4.92, 5.31-5.65, 6.89-7.00, 7.13, 7.27-7.37, 7.37-7.68, 7.85, 8.30。 Reference example 61
Ethyl 2-chloro-7-(4-{[9-(4-cyano-2-fluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo [2,3-b]pyridin-7-yl]carbonyl}phenyl)-9-[1-(2,2-dimethylpropyl)-4-piperidinyl]-8-oxo-8,9-dihydro-7H-purine -6-Carboxylate Using the compound produced in Reference Example 60 instead of the compound produced in Reference Example 54, the same operations as in Reference Example 55 → Reference Example 56 were performed to obtain the title compound having the following physical property values. Ta.
LC-MS (A) retention time (min): 1.08;
MS(ESI, Pos.): 804 (M + H) + ;
1 H-NMR (CDCl 3 ): δ 0.86-0.96, 1.22-1.29, 1.69-1.83, 2.14, 2.41-2.51, 2.65-2.81, 2.84-3.02, 3.73-4.08, 4.38-4.92, 5.31-5.65, 6.89 - 7.00, 7.13, 7.27-7.37, 7.37-7.68, 7.85, 8.30.
参考例６２
エチル　７－（４－｛［９－（４－シアノ－２－フルオロベンジル）－５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－イル］カルボニル｝フェニル）－９－［１－（２，２－ジメチルプロピル）－４－ピペリジニル］－８－オキソ－２－｛［４－（トリフルオロメトキシ）フェニル］アミノ｝－８，９－ジヒドロ－７Ｈ－プリン－６－カルボキシラート
　参考例６１で製造した化合物（150ｍｇ）にＤＭＦ（1.5ｍＬ）とトルエン（1.5ｍＬ）を加えて溶解し、さらに４－（トリフルオロメトキシ）アニリン（50ｍｇ）及び炭酸セシウム（182ｍｇ）、Xantphos（22ｍｇ）、酢酸パラジウム（4.2ｍｇ）を加え、窒素雰囲気で１００℃で１時間攪拌した。反応液を室温に冷却した後、水を加えて酢酸エチルで抽出した。有機層を減圧濃縮し、得られた残渣をシリカゲルクロマトグラフィー（富士シリシア　ＮＨ（商品名）、ヘキサン：酢酸エチル＝１：１→０：１）で精製することにより、以下の物性値を有する標題化合物（160ｍｇ）を得た。
LC－MS（A）保持時間（分）：1.20；
MS(ESI, Pos.)： 945 (M + H)＋。 Reference example 62
Ethyl 7-(4-{[9-(4-cyano-2-fluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[2,3 -b]pyridin-7-yl]carbonyl}phenyl)-9-[1-(2,2-dimethylpropyl)-4-piperidinyl]-8-oxo-2-{[4-(trifluoromethoxy)phenyl] amino}-8,9-dihydro-7H-purine-6-carboxylate The compound prepared in Reference Example 61 (150 mg) was dissolved in DMF (1.5 mL) and toluene (1.5 mL), and further 4-(trihydro-7H-purine-6-carboxylate) was dissolved. Fluoromethoxy)aniline (50 mg), cesium carbonate (182 mg), Xantphos (22 mg), and palladium acetate (4.2 mg) were added, and the mixture was stirred at 100° C. for 1 hour in a nitrogen atmosphere. After the reaction solution was cooled to room temperature, water was added and extracted with ethyl acetate. The organic layer was concentrated under reduced pressure, and the resulting residue was purified by silica gel chromatography (Fuji Silysia NH (trade name), hexane:ethyl acetate = 1:1 → 0:1) to obtain the title compound having the following physical properties. A compound (160 mg) was obtained.
LC-MS (A) retention time (min): 1.20;
MS(ESI, Pos.): 945 (M + H) + .
参考例６３
７－（４－｛［９－（４－シアノ－２－フルオロベンジル）－５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－イル］カルボニル｝フェニル）－９－［１－（２，２－ジメチルプロピル）－４－ピペリジニル］－８－オキソ－２－｛［４－（トリフルオロメトキシ）フェニル］アミノ｝－８，９－ジヒドロ－７Ｈ－プリン－６－カルボン酸
　参考例６２で製造した化合物（150ｍｇ）をＴＨＦ（3ｍＬ）に溶解し、０℃に冷却した。そこへＴＭＳＯＫ（34ｍｇ）を加えて０℃で２時間攪拌した。反応液に４Ｎ塩化水素／１，4－ジオキサン溶液を加えて中和し、減圧濃縮することにより、以下の物性値を有する標題化合物（120ｍｇ）を得た。
LC－MS（A）保持時間（分）：1.02；
MS(ESI, Pos.)： 917 (M + H)＋。 Reference example 63
7-(4-{[9-(4-cyano-2-fluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[2,3- b]pyridin-7-yl]carbonyl}phenyl)-9-[1-(2,2-dimethylpropyl)-4-piperidinyl]-8-oxo-2-{[4-(trifluoromethoxy)phenyl]amino }-8,9-dihydro-7H-purine-6-carboxylic acid The compound (150 mg) prepared in Reference Example 62 was dissolved in THF (3 mL) and cooled to 0°C. TMSOK (34 mg) was added thereto and stirred at 0°C for 2 hours. The reaction solution was neutralized by adding 4N hydrogen chloride/1,4-dioxane solution and concentrated under reduced pressure to obtain the title compound (120 mg) having the following physical properties.
LC-MS (A) retention time (min): 1.02;
MS(ESI, Pos.): 917 (M + H) + .
実施例２４
７－（４－｛［９－（４－シアノ－２－フルオロベンジル）－５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－イル］カルボニル｝フェニル）－９－［１－（２，２－ジメチルプロピル）－４－ピペリジニル］－Ｎ－ヒドロキシ－８－オキソ－２－｛［４－（トリフルオロメトキシ）フェニル］アミノ｝－８，９－ジヒドロ－７Ｈ－プリン－６－カルボキサミド　２トリフルオロ酢酸塩
　参考例６３で製造した化合物（25ｍｇ）をＤＭＦ（0.5ｍＬ）に溶解し、ＤＩＰＥＡ（0.023ｍＬ）とエチル　カルボノクロリデート（8.9ｍｇ）を加えて室温で１０分攪拌した。さらに２－（アミノオキシ）テトラヒドロ－２H－ピラン（16ｍｇ）を加えて１０分攪拌した。反応液に飽和炭酸水素ナトリウム水溶液を加えて酢酸エチルで抽出し、有機層を減圧濃縮した。得られた残渣をメタノール（0.25ｍＬ）に溶解し、４Ｎ塩化水素／１，4－ジオキサン溶液（0.12ｍＬ）を加えて室温で３０分攪拌した。反応液を減圧濃縮し、得られた残渣を逆相HPLCカラム精製することにより、以下の物性値を有する標題化合物（11ｍｇ）を得た。
LC－MS（A）保持時間（分）：1.02；
MS(ESI, Pos.)： 932 (M + H)＋；
１H-NMR(DMSO-d６)：δ　 1.00-1.13, 1.99-2.22, 2.79-3.02, 3.02-3.24, 3.54-4.07, 4.46-4.91, 5.36-5.77, 6.90-7.23, 7.23-7.71, 7.71-8.02, 8.15-8.31, 8.62-8.99, 8.99-9.25, 9.68-9.86, 10.94-11.11。 Example 24
7-(4-{[9-(4-cyano-2-fluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[2,3- b]pyridin-7-yl]carbonyl}phenyl)-9-[1-(2,2-dimethylpropyl)-4-piperidinyl]-N-hydroxy-8-oxo-2-{[4-(trifluoromethoxy) ) phenyl]amino}-8,9-dihydro-7H-purine-6-carboxamide 2 trifluoroacetate The compound prepared in Reference Example 63 (25 mg) was dissolved in DMF (0.5 mL), and mixed with DIPEA (0.023 mL). Ethyl carbonochloridate (8.9 mg) was added and stirred at room temperature for 10 minutes. Furthermore, 2-(aminooxy)tetrahydro-2H-pyran (16 mg) was added and stirred for 10 minutes. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, extracted with ethyl acetate, and the organic layer was concentrated under reduced pressure. The obtained residue was dissolved in methanol (0.25 mL), 4N hydrogen chloride/1,4-dioxane solution (0.12 mL) was added, and the mixture was stirred at room temperature for 30 minutes. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified with a reverse phase HPLC column to obtain the title compound (11 mg) having the following physical properties.
LC-MS (A) retention time (min): 1.02;
MS(ESI, Pos.): 932 (M + H) + ;
1 H-NMR (DMSO-d 6 ): δ 1.00-1.13, 1.99-2.22, 2.79-3.02, 3.02-3.24, 3.54-4.07, 4.46-4.91, 5.36-5.77, 6.90-7.23, 7.23-7.71, 7.71- 8.02, 8.15-8.31, 8.62-8.99, 8.99-9.25, 9.68-9.86, 10.94-11.11.
参考例６４
２－メチル－２－プロパニル　（３Ｓ）－３－［（５－アミノ－２－クロロ－４－ピリミジニル）アミノ］－１－ピロリジンカルボキシラート
　２－メチル－２－プロパニル　（３Ｓ）－３－アミノ－１－ピロリジンカルボキシラート（7.0ｇ）と、２，４－ジクロロ－５－ピリミジンアミン（5.0ｇ）をＤＭＡ（35ｍＬ）に溶解し、ＤＩＰＥＡ（11.6ｍＬ）を加えて、１００℃で終夜攪拌した。室温まで冷却後、酢酸エチルで反応液を希釈し、有機層を１Ｎ塩酸と水、飽和食塩水で順次洗浄した。無水硫酸ナトリウムで乾燥し、減圧濃縮して得られた残渣をシリカゲルクロマトグラフィー（富士シリシア　ＮＨ（商品名）、ヘキサン：酢酸エチル＝３：７→０：１）で精製することにより、以下の物性値を有する標題化合物（5.4ｇ）を得た。
LC－MS（A）保持時間（分）：0.88；
MS(ESI, Pos.)： 314 (M + H)＋。 Reference example 64
2-Methyl-2-propanyl (3S)-3-[(5-amino-2-chloro-4-pyrimidinyl)amino]-1-pyrrolidinecarboxylate 2-methyl-2-propanyl (3S)-3-amino- 1-Pyrrolidinecarboxylate (7.0g) and 2,4-dichloro-5-pyrimidineamine (5.0g) were dissolved in DMA (35mL), DIPEA (11.6mL) was added, and the mixture was stirred at 100°C overnight. After cooling to room temperature, the reaction solution was diluted with ethyl acetate, and the organic layer was washed successively with 1N hydrochloric acid, water, and saturated brine. The residue obtained by drying with anhydrous sodium sulfate and concentration under reduced pressure was purified by silica gel chromatography (Fuji Silysia NH (trade name), hexane:ethyl acetate = 3:7 → 0:1) to obtain the following physical properties. The title compound (5.4 g) was obtained with a value of .
LC-MS (A) retention time (min): 0.88;
MS(ESI, Pos.): 314 (M + H) + .
参考例６５
２－メチル－２－プロパニル　（３Ｓ）－３－［（２－クロロ－５－｛［４－（メトキシカルボニル）フェニル］アミノ｝－４－ピリミジニル）アミノ］－１－ピロリジンカルボキシラート
　参考例６４で製造した化合物（5.4ｇ）と４－ヨード安息香酸メチル（5.4ｇ）に脱水ＤＭＥ（50ｍＬ）を加えて溶解した。その溶液に、炭酸セシウム（11.1ｇ）及びXantphos（1.2ｇ）、Pd２（dba）３（937ｍｇ）を加えた。反応容器中を窒素置換後、８０℃で終夜攪拌した。反応液を室温まで冷却し、インジェクトカラム　アミノ（商品名）を通して不溶物を除去した。ろ液を濃縮して得られた残渣をシリカゲルクロマトグラフィー（富士シリシア　ＮＨ（商品名）、ヘキサン：酢酸エチル＝３：７→１：１）で精製することにより、以下の物性値を有する標題化合物（5.2ｇ）を得た。
LC－MS（A）保持時間（分）：1.13；
MS(ESI, Pos.)： 448 (M + H)＋。 Reference example 65
2-Methyl-2-propanyl (3S)-3-[(2-chloro-5-{[4-(methoxycarbonyl)phenyl]amino}-4-pyrimidinyl)amino]-1-pyrrolidinecarboxylate In Reference Example 64 The prepared compound (5.4 g) and methyl 4-iodobenzoate (5.4 g) were dissolved in dehydrated DME (50 mL). Cesium carbonate (11.1 g), Xantphos (1.2 g), and Pd 2 (dba) 3 (937 mg) were added to the solution. After purging the inside of the reaction vessel with nitrogen, the mixture was stirred at 80°C overnight. The reaction solution was cooled to room temperature and passed through an injection column Amino (trade name) to remove insoluble matter. The residue obtained by concentrating the filtrate was purified by silica gel chromatography (Fuji Silysia NH (trade name), hexane:ethyl acetate = 3:7 → 1:1) to obtain the title compound having the following physical properties. (5.2g) was obtained.
LC-MS (A) retention time (min): 1.13;
MS(ESI, Pos.): 448 (M + H) + .
参考例６６
２－メチル－２－プロパニル　（３Ｓ）－３－｛２－クロロ－７－［４－（メトキシカルボニル）フェニル］－８－オキソ－７，８－ジヒドロ－９Ｈ－プリン－９－イル｝－１－ピロリジンカルボキシラート
　参考例６５で製造した化合物（5.2ｇ）をＴＨＦ（52ｍＬ）に溶解し、ＣＤＩ（3.8ｇ）とＤＢＵ（1.7ｍＬ）を加えて室温で１時間攪拌した。反応液に飽和塩化アンモニウム水を加えて酢酸エチルで希釈した。得られた有機層を飽和塩化アンモニウム水と飽和食塩水で洗浄し、減圧濃縮することにより、以下の物性値を有する標題化合物（6.0ｇ）を得た。
LC－MS（A）保持時間（分）：1.18；
MS(ESI, Pos.)： 474 (M + H)＋；
１H-NMR(CDCl３)：δ　 1.49, 2.22-2.36, 2.75-2.94, 3.42-3.58, 3.73-3.87, 3.89-3.96, 3.97, 5.12-5.22, 7.63, 8.21-8.27。 Reference example 66
2-Methyl-2-propanyl (3S)-3-{2-chloro-7-[4-(methoxycarbonyl)phenyl]-8-oxo-7,8-dihydro-9H-purin-9-yl}-1 -Pyrrolidine carboxylate The compound prepared in Reference Example 65 (5.2 g) was dissolved in THF (52 mL), CDI (3.8 g) and DBU (1.7 mL) were added, and the mixture was stirred at room temperature for 1 hour. Saturated ammonium chloride water was added to the reaction mixture, and the mixture was diluted with ethyl acetate. The obtained organic layer was washed with saturated ammonium chloride water and saturated brine, and concentrated under reduced pressure to obtain the title compound (6.0 g) having the following physical properties.
LC-MS (A) retention time (min): 1.18;
MS(ESI, Pos.): 474 (M + H) + ;
1H -NMR ( CDCl3 ): δ 1.49, 2.22-2.36, 2.75-2.94, 3.42-3.58, 3.73-3.87, 3.89-3.96, 3.97, 5.12-5.22, 7.63, 8.21-8.27.
参考例６７
４－｛２－クロロ－９－［（３Ｓ）－１－｛［（２－メチル－２－プロパニル）オキシ］カルボニル｝－３－ピロリジニル］－８－オキソ－８，９－ジヒドロ－７Ｈ－プリン－７－イル｝安息香酸
　参考例５で製造した化合物の代わりに参考例６６で製造した化合物（400ｍｇ）を用いて、参考例６と同様の操作を行い、以下の物性値を有する標題化合物（420ｍｇ）を得た。
LC－MS（A）保持時間（分）：1.08；
MS(ESI, Pos.)： 460 (M + H)＋。 Reference example 67
4-{2-chloro-9-[(3S)-1-{[(2-methyl-2-propanyl)oxy]carbonyl}-3-pyrrolidinyl]-8-oxo-8,9-dihydro-7H-purine -7-yl}benzoic acid Using the compound produced in Reference Example 66 (400 mg) instead of the compound produced in Reference Example 5, the same operation as in Reference Example 6 was carried out to obtain the title compound ( 420 mg) was obtained.
LC-MS (A) retention time (min): 1.08;
MS(ESI, Pos.): 460 (M + H) + .
参考例６８
２－メチル－２－プロパニル　（３Ｓ）－３－［２－クロロ－７－（４－｛［９－（４－シアノ－２－フルオロベンジル）－５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－イル］カルボニル｝フェニル）－８－オキソ－７，８－ジヒドロ－９Ｈ－プリン－９－イル］－１－ピロリジンカルボキシラート
　参考例６で製造した化合物の代わりに参考例６７で製造した化合物を用いて、参考例５４と同様の操作を行い、以下の物性値を有する標題化合物を得た。
LC－MS（A）保持時間（分）：1.21；
MS(ESI, Pos.)： 748 (M + H)＋；
１H-NMR(CDCl３)：δ　 1.46-1.52, 2.31, 2.85-2.97, 3.50, 3.75-4.10, 4.45-4.91, 5.19, 5.40-5.66, 6.89-6.97, 7.14, 7.27-7.35, 7.42, 7.46-7.58, 7.61-7.73, 7.85, 8.20, 8.31。 Reference example 68
2-Methyl-2-propanyl (3S)-3-[2-chloro-7-(4-{[9-(4-cyano-2-fluorobenzyl)-5,6,8,9-tetrahydro-7H- Pyrido[4',3':4,5]pyrrolo[2,3-b]pyridin-7-yl]carbonyl}phenyl)-8-oxo-7,8-dihydro-9H-purin-9-yl]- 1-pyrrolidinecarboxylate Using the compound produced in Reference Example 67 instead of the compound produced in Reference Example 6, the same operation as in Reference Example 54 was carried out to obtain the title compound having the following physical property values.
LC-MS (A) retention time (min): 1.21;
MS(ESI, Pos.): 748 (M + H) + ;
1 H-NMR (CDCl 3 ): δ 1.46-1.52, 2.31, 2.85-2.97, 3.50, 3.75-4.10, 4.45-4.91, 5.19, 5.40-5.66, 6.89-6.97, 7.14, 7.27-7.35, 7.42, 7. 46- 7.58, 7.61-7.73, 7.85, 8.20, 8.31.
参考例６９
２－メチル－２－プロパニル　（３Ｓ）－３－［７－（４－｛［９－（４－シアノ－２－フルオロベンジル）－５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－イル］カルボニル｝フェニル）－８－オキソ－２－｛［４－（トリフルオロメトキシ）フェニル］アミノ｝－７，８－ジヒドロ－９Ｈ－プリン－９－イル］－１－ピロリジンカルボキシラート
　参考例６１で製造した化合物の代わりに参考例６８で製造した化合物を用いて、参考例６２と同様の操作を行い、以下の物性値を有する標題化合物を得た。
LC－MS（A）保持時間（分）：1.30；
MS(ESI, Pos.)： 889 (M + H)＋。 Reference example 69
2-Methyl-2-propanyl (3S)-3-[7-(4-{[9-(4-cyano-2-fluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[2,3-b]pyridin-7-yl]carbonyl}phenyl)-8-oxo-2-{[4-(trifluoromethoxy)phenyl]amino}-7,8 -dihydro-9H-purin-9-yl]-1-pyrrolidinecarboxylate Using the compound produced in Reference Example 68 instead of the compound produced in Reference Example 61, the same operation as in Reference Example 62 was carried out, and the following was obtained. The title compound having physical properties was obtained.
LC-MS (A) retention time (min): 1.30;
MS(ESI, Pos.): 889 (M + H) + .
参考例７０
３－フルオロ－４－（｛７－［４－（８－オキソ－９－［（３Ｓ）－３－ピロリジニル］－２－｛［４－（トリフルオロメトキシ）フェニル］アミノ｝－８，９－ジヒドロ－７Ｈ－プリン－７－イル）ベンゾイル］－５，６，７，８－テトラヒドロ－９Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－９－イル｝メチル）ベンゾニトリル
　参考例６９で製造した化合物（356ｍｇ）をメタノール（4.0ｍＬ）に溶解し、４Ｎ塩化水素／１，4－ジオキサン溶液（1.0ｍＬ）を加えて室温で４時間攪拌した。反応液に飽和炭酸水素ナトリウム水溶液を加えて中和し、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄後、減圧濃縮することにより以下の物性値を有する標題化合物（300ｍｇ）を得た。
LC－MS（A）保持時間（分）：1.08；
MS(ESI, Pos.)： 789 (M + H)＋。 Reference example 70
3-fluoro-4-({7-[4-(8-oxo-9-[(3S)-3-pyrrolidinyl]-2-{[4-(trifluoromethoxy)phenyl]amino}-8,9- dihydro-7H-purin-7-yl)benzoyl]-5,6,7,8-tetrahydro-9H-pyrido[4',3':4,5]pyrrolo[2,3-b]pyridin-9-yl }Methyl)benzonitrile The compound prepared in Reference Example 69 (356 mg) was dissolved in methanol (4.0 mL), 4N hydrogen chloride/1,4-dioxane solution (1.0 mL) was added, and the mixture was stirred at room temperature for 4 hours. The reaction mixture was neutralized by adding saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The organic layer was washed with saturated brine and concentrated under reduced pressure to obtain the title compound (300 mg) having the following physical properties.
LC-MS (A) retention time (min): 1.08;
MS(ESI, Pos.): 789 (M + H) + .
実施例２５
３－フルオロ－４－（｛７－［４－（９－［（３Ｓ）－１－（メチルスルホニル）－３－ピロリジニル］－８－オキソ－２－｛［４－（トリフルオロメトキシ）フェニル］アミノ｝－８，９－ジヒドロ－７Ｈ－プリン－７－イル）ベンゾイル］－５，６，７，８－テトラヒドロ－９Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－９－イル｝メチル）ベンゾニトリル　トリフルオロ酢酸塩
　参考例７０で製造した化合物（15ｍｇ）をＤＭＦ（0.15ｍＬ）に溶解し、ＤＩＰＥＡ（0.010ｍＬ）とメタンスルホン酸無水物（4.0ｍｇ）を加えて室温で１時間攪拌した。反応液を逆相HPLCカラム精製することにより、以下の物性値を有する標題化合物（11ｍｇ）を得た。
LC－MS（A）保持時間（分）：1.28；
MS(ESI, Pos.)： 867 (M + H)＋；
１H-NMR(DMSO-d６)：δ　 2.29-2.41, 2.68-2.82, 2.82-2.93, 3.01, 3.38-3.51, 3.65-3.80, 3.80-3.88, 4.47-4.93, 5.15-5.30, 5.38-5.75, 6.66-7.08, 7.09-7.19, 7.31, 7.36-7.82, 7.85-8.00, 8.17-8.34, 9.79。 Example 25
3-Fluoro-4-({7-[4-(9-[(3S)-1-(methylsulfonyl)-3-pyrrolidinyl]-8-oxo-2-{[4-(trifluoromethoxy)phenyl] amino}-8,9-dihydro-7H-purin-7-yl)benzoyl]-5,6,7,8-tetrahydro-9H-pyrido[4',3':4,5]pyrrolo[2,3- b] Pyridin-9-yl}methyl)benzonitrile trifluoroacetate The compound prepared in Reference Example 70 (15 mg) was dissolved in DMF (0.15 mL), and DIPEA (0.010 mL) and methanesulfonic anhydride (4.0 mg) were dissolved. ) and stirred at room temperature for 1 hour. The reaction solution was purified using a reverse phase HPLC column to obtain the title compound (11 mg) having the following physical properties.
LC-MS (A) retention time (min): 1.28;
MS(ESI, Pos.): 867 (M + H) + ;
1 H-NMR (DMSO-d 6 ): δ 2.29-2.41, 2.68-2.82, 2.82-2.93, 3.01, 3.38-3.51, 3.65-3.80, 3.80-3.88, 4.47-4.93, 5.15-5.30, 5.38-5.75, 6.66-7.08, 7.09-7.19, 7.31, 7.36-7.82, 7.85-8.00, 8.17-8.34, 9.79.
実施例２６
３－フルオロ－４－（｛７－［４－（８－オキソ－９－［（３Ｓ）－１－（３，３，３－トリフルオロ－２，２－ジメチルプロピル）－３－ピロリジニル］－２－｛［４－（トリフルオロメトキシ）フェニル］アミノ｝－８，９－ジヒドロ－７Ｈ－プリン－７－イル）ベンゾイル］－５，６，７，８－テトラヒドロ－９Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－９－イル｝メチル）ベンゾニトリル　２トリフルオロ酢酸塩
　参考例７０で製造した化合物（15ｍｇ）をＤＭＦ（0.15ｍＬ）に溶解し、３，３，３－トリフルオロ－２，２－ジメチルプロピル　トリフルオロメタンスルホナート（26ｍｇ）とＤＩＰＥＡ（0.033ｍＬ）を加えて、６０℃で１７時間攪拌した。反応液を室温に冷却し、水を加えて酢酸エチルで抽出した。有機層を濃縮して得られた残渣を逆相HPLCカラム精製することにより、以下の物性値を有する標題化合物（4.9ｍｇ）を得た。
LC－MS（A）保持時間（分）：1.15；
MS(ESI, Pos.)： 913 (M + H)＋；
１H-NMR(DMSO-d６)：δ　 1.20-1.37, 2.81-2.94, 3.60-4.05, 4.51-4.95, 4.98-5.31, 5.34-5.77, 6.96-7.25, 7.27-7.37, 7.41-7.80, 7.80-7.91, 7.91-8.05, 8.18-8.40, 9.62-9.84。 Example 26
3-Fluoro-4-({7-[4-(8-oxo-9-[(3S)-1-(3,3,3-trifluoro-2,2-dimethylpropyl)-3-pyrrolidinyl]- 2-{[4-(trifluoromethoxy)phenyl]amino}-8,9-dihydro-7H-purin-7-yl)benzoyl]-5,6,7,8-tetrahydro-9H-pyrido[4', 3':4,5]pyrrolo[2,3-b]pyridin-9-yl}methyl)benzonitrile 2-trifluoroacetate The compound prepared in Reference Example 70 (15 mg) was dissolved in DMF (0.15 mL), 3,3,3-trifluoro-2,2-dimethylpropyl trifluoromethanesulfonate (26 mg) and DIPEA (0.033 mL) were added, and the mixture was stirred at 60°C for 17 hours. The reaction solution was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The residue obtained by concentrating the organic layer was purified using a reverse phase HPLC column to obtain the title compound (4.9 mg) having the following physical properties.
LC-MS (A) retention time (min): 1.15;
MS(ESI, Pos.): 913 (M + H) + ;
1 H-NMR (DMSO-d 6 ): δ 1.20-1.37, 2.81-2.94, 3.60-4.05, 4.51-4.95, 4.98-5.31, 5.34-5.77, 6.96-7.25, 7.27-7.37, 7.41-7.80, 7.80- 7.91, 7.91-8.05, 8.18-8.40, 9.62-9.84.
参考例７１
２－メチル－２－プロパニル　９－（４－クロロ－２－フルオロベンジル）－５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－カルボキシラート
　２－メチル－２－プロパニル　５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－カルボキシラート（CAS：１３５４８０１－０７－２、5.0ｇ）と、１－（ブロモメチル）－４－クロロ－２－フルオロベンゼン（3.1ｍＬ）をＤＭＦ（50ｍＬ）に溶解した。反応液を氷冷し、水素化ナトリウム（60％パラフィンオイル懸濁液、878ｍｇ）を加えて、１時間攪拌した。反応液に飽和塩化アンモニウム水溶液を加えて攪拌し、酢酸エチルで抽出した。得られた有機層を飽和食塩水で洗浄した後、無水硫酸ナトリウムを加えて乾燥し、減圧濃縮して得られた残渣をシリカゲルクロマトグラフィー（ヘキサン：酢酸エチル＝９：１）で精製することにより、以下の物性値を有する標題化合物（6.9ｇ）を得た。
TLC：Rf 0.18（ヘキサン：酢酸エチル＝９：１）；
１H-NMR(CDCl３)：δ　 1.47, 2.79, 3.74, 4.52, 5.45, 6.74-6.93, 6.94-7.01, 7.05-7.14, 7.80, 8.28。 Reference example 71
2-Methyl-2-propanyl 9-(4-chloro-2-fluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[2,3- b] Pyridine-7-carboxylate 2-methyl-2-propanyl 5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[2,3-b]pyridine-7 -carboxylate (CAS: 1354801-07-2, 5.0 g) and 1-(bromomethyl)-4-chloro-2-fluorobenzene (3.1 mL) were dissolved in DMF (50 mL). The reaction solution was ice-cooled, sodium hydride (60% paraffin oil suspension, 878 mg) was added, and the mixture was stirred for 1 hour. A saturated aqueous ammonium chloride solution was added to the reaction solution, stirred, and extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, dried by adding anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting residue was purified by silica gel chromatography (hexane: ethyl acetate = 9:1). The title compound (6.9 g) having the following physical properties was obtained.
TLC: Rf 0.18 (hexane: ethyl acetate = 9:1);
1H -NMR ( CDCl3 ): δ 1.47, 2.79, 3.74, 4.52, 5.45, 6.74-6.93, 6.94-7.01, 7.05-7.14, 7.80, 8.28.
参考例７２
９－（４－クロロ－２－フルオロベンジル）－６，７，８，９－テトラヒドロ－５Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン　２塩酸塩
　参考例７１で製造した化合物（6.9ｇ）をメタノール（20ｍＬ）に溶解し、４Ｎ塩化水素／１，4－ジオキサン溶液（42ｍＬ）を加えて室温で１時間攪拌した。反応液を濃縮してトルエンで共沸し、ＭＴＢＥを用いてろ取することにより、以下の物性値を有する標題化合物（6.6ｇ）を得た。
TLC：Rf 0.38（ジクロロメタン：メタノール＝９：１）；
１H-NMR(DMSO-d６)：δ　 2.98, 3.41-3.51, 4.36, 5.52, 6.97, 7.15-7.22, 7.49, 8.01, 8.27, 9.72。 Reference example 72
9-(4-chloro-2-fluorobenzyl)-6,7,8,9-tetrahydro-5H-pyrido[4',3':4,5]pyrrolo[2,3-b]pyridine dihydrochloride reference The compound prepared in Example 71 (6.9 g) was dissolved in methanol (20 mL), 4N hydrogen chloride/1,4-dioxane solution (42 mL) was added, and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated, azeotropically distilled with toluene, and filtered using MTBE to obtain the title compound (6.6 g) having the following physical properties.
TLC: Rf 0.38 (dichloromethane:methanol = 9:1);
1H -NMR (DMSO- d6 ): δ 2.98, 3.41-3.51, 4.36, 5.52, 6.97, 7.15-7.22, 7.49, 8.01, 8.27, 9.72.
参考例７３
２－メチル－２－プロパニル　４－［２－クロロ－７－（４－｛［９－（４－クロロ－２－フルオロベンジル）－５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－イル］カルボニル｝フェニル）－６－メチル－８－オキソ－７，８－ジヒドロ－９Ｈ－プリン－９－イル］－１－ピペリジンカルボキシラート
　参考例２で製造した化合物の代わりに参考例７２で製造した化合物（1.1ｇ）を用いて、参考例７と同様の操作を行い、以下の物性値を有する標題化合物（1.9ｇ）を得た。
LC－MS（A）保持時間（分）：1.30；
MS(ESI, Pos.)： 785 (M + H)＋。 Reference example 73
2-Methyl-2-propanyl 4-[2-chloro-7-(4-{[9-(4-chloro-2-fluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[2,3-b]pyridin-7-yl]carbonyl}phenyl)-6-methyl-8-oxo-7,8-dihydro-9H-purin-9-yl]- 1-Piperidinecarboxylate Using the compound produced in Reference Example 72 (1.1 g) instead of the compound produced in Reference Example 2, the same operation as in Reference Example 7 was carried out to obtain the title compound (1.9 g) was obtained.
LC-MS (A) retention time (min): 1.30;
MS(ESI, Pos.): 785 (M + H) + .
参考例７４
２－クロロ－７－（４－｛［９－（４－クロロ－２－フルオロベンジル）－５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－イル］カルボニル｝フェニル）－９－［１－（２，２－ジメチルプロピル）－４－ピペリジニル］－６－メチル－７，９－ジヒドロ－８Ｈ－プリン－８－オン
　参考例５４で製造した化合物の代わりに参考例７３で製造した化合物を用いて、参考例５５→参考例５６と同様の操作を行い、以下の物性値を有する標題化合物を得た。
LC－MS（A）保持時間（分）：1.09；
MS(ESI, Pos.)： 755 (M + H)＋。 Reference example 74
2-chloro-7-(4-{[9-(4-chloro-2-fluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[ 2,3-b]pyridin-7-yl]carbonyl}phenyl)-9-[1-(2,2-dimethylpropyl)-4-piperidinyl]-6-methyl-7,9-dihydro-8H-purine- 8-one Using the compound produced in Reference Example 73 instead of the compound produced in Reference Example 54, the same operation as in Reference Example 55 → Reference Example 56 was performed to obtain the title compound having the following physical property values.
LC-MS (A) retention time (min): 1.09;
MS(ESI, Pos.): 755 (M + H) + .
実施例２７
７－（４－｛［９－（４－クロロ－２－フルオロベンジル）－５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－イル］カルボニル｝フェニル）－２－｛［４－（ジフルオロメトキシ）フェニル］アミノ｝－９－［１－（２，２－ジメチルプロピル）－４－ピペリジニル］－６－メチル－７，９－ジヒドロ－８Ｈ－プリン－８－オン
　参考例９で製造した化合物の代わりに参考例７４で製造した化合物を、アニリンの代わりに４－（ジフルオロメトキシ）アニリンを用いて、実施例１と同様の操作を行い、以下の物性値を有する標題化合物を得た。
LC－MS（A）保持時間（分）：1.11；
MS(ESI, Pos.)： 878 (M + H)＋；
１H-NMR (CDCl３)：δ　 0.96, 1.70-1.80, 2.03, 2.14, 2.45, 2.75-2.86, 2.87-3.05, 3.72-4.10, 4.30-4.42, 4.50-4.92, 5.23-5.60, 6.24-6.67, 6.81-6.91, 6.95-7.04, 7.09-7.18, 7.40-7.65, 7.65-7.71, 7.83, 8.32。 Example 27
7-(4-{[9-(4-chloro-2-fluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[2,3- b]Pyridin-7-yl]carbonyl}phenyl)-2-{[4-(difluoromethoxy)phenyl]amino}-9-[1-(2,2-dimethylpropyl)-4-piperidinyl]-6-methyl -7,9-dihydro-8H-purin-8-one
The same operation as in Example 1 was carried out using the compound produced in Reference Example 74 instead of the compound produced in Reference Example 9, and 4-(difluoromethoxy)aniline was used instead of aniline, and the compound had the following physical property values. The title compound was obtained.
LC-MS (A) retention time (min): 1.11;
MS(ESI, Pos.): 878 (M + H) + ;
1 H-NMR (CDCl 3 ): δ 0.96, 1.70-1.80, 2.03, 2.14, 2.45, 2.75-2.86, 2.87-3.05, 3.72-4.10, 4.30-4.42, 4.50-4.92, 5.23-5.60, 6.24-6.6 7, 6.81-6.91, 6.95-7.04, 7.09-7.18, 7.40-7.65, 7.65-7.71, 7.83, 8.32.
実施例２７－１
７－（４－｛［９－（４－クロロ－２－フルオロベンジル）－５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－イル］カルボニル｝フェニル）－９－［１－（２，２－ジメチルプロピル）－４－ピペリジニル］－２－［（３－フルオロフェニル）アミノ］－６－メチル－７，９－ジヒドロ－８Ｈ－プリン－８－オン
　４－（ジフルオロメトキシ）アニリンの代わりに３－フルオロアニリンを用いて、実施例２７と同様の操作を行い、以下の物性値を有する標題化合物を得た。
LC－MS（A）保持時間（分）：1.15；
MS(ESI, Pos.)： 830 (M + H)＋；
１H-NMR(CDCl３)：δ　 0.93, 1.69-1.80, 2.05, 2.14, 2.45, 2.71-2.85, 2.85-3.02, 3.65-4.18, 4.29-4.43, 4.49-4.93, 5.20-5.60, 6.67-6.75, 6.80-7.03, 7.04-7.08, 7.08-7.17, 7.27-7.36, 7.41-7.69, 7.83, 8.32。 Example 27-1
7-(4-{[9-(4-chloro-2-fluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[2,3- b]pyridin-7-yl]carbonyl}phenyl)-9-[1-(2,2-dimethylpropyl)-4-piperidinyl]-2-[(3-fluorophenyl)amino]-6-methyl-7, 9-dihydro-8H-purin-8-one
The same operation as in Example 27 was carried out using 3-fluoroaniline instead of 4-(difluoromethoxy)aniline to obtain the title compound having the following physical properties.
LC-MS (A) retention time (min): 1.15;
MS(ESI, Pos.): 830 (M + H) + ;
1 H-NMR (CDCl 3 ): δ 0.93, 1.69-1.80, 2.05, 2.14, 2.45, 2.71-2.85, 2.85-3.02, 3.65-4.18, 4.29-4.43, 4.49-4.93, 5.20-5.60, 6.67-6.7 5, 6.80-7.03, 7.04-7.08, 7.08-7.17, 7.27-7.36, 7.41-7.69, 7.83, 8.32.
実施例２８
７－（４－｛［９－（４－クロロ－２－フルオロベンジル）－５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－イル］カルボニル｝フェニル）－２－［（シクロペンチルメチル）（２－ヒドロキシ－２－メチルプロピル）アミノ］－９－［１－（２，２－ジメチルプロピル）－４－ピペリジニル］－６－メチル－７，９－ジヒドロ－８Ｈ－プリン－８－オン　２トリフルオロ酢酸塩
　参考例７４で製造した化合物（50ｍｇ）と１－［（シクロペンチルメチル）アミノ］－２－メチル－２－プロパノール（57ｍｇ）をＤＭＳＯ（0.5ｍＬ）に溶解し、ＤＩＰＥＡ（0.057ｍＬ）とフッ化セシウム（50ｍｇ）を加えて，マイクロウェーブ装置を使用して、１００℃で３０分、１２０℃で４時間攪拌した。反応液を室温に冷却して不溶物を除去した後、逆相HPLCカラム精製することにより、以下の物性値を有する標題化合物（11ｍｇ）を得た。
LC－MS（A）保持時間（分）：1.11；
MS(ESI, Pos.)： 890 (M + H)＋；
１H-NMR(CDCl３)：δ　 1.13-1.22, 1.24-1.40, 1.50-1.63, 1.63-1.79, 2.02-2.08, 2.08-2.33, 2.84-3.09, 3.39-3.53, 3.63-3.85, 3.91-4.16, 4.50-4.64, 4.67-4.93, 5.29-5.63, 6.83-6.93, 6.95-7.04, 7.09-7.17, 7.22, 7.38-7.70, 7.96, 8.40。 Example 28
7-(4-{[9-(4-chloro-2-fluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[2,3- b]pyridin-7-yl]carbonyl}phenyl)-2-[(cyclopentylmethyl)(2-hydroxy-2-methylpropyl)amino]-9-[1-(2,2-dimethylpropyl)-4-piperidinyl ]-6-Methyl-7,9-dihydro-8H-purin-8-one 2 trifluoroacetate The compound prepared in Reference Example 74 (50 mg) and 1-[(cyclopentylmethyl)amino]-2-methyl-2 - Dissolve propanol (57 mg) in DMSO (0.5 mL), add DIPEA (0.057 mL) and cesium fluoride (50 mg), and use a microwave device at 100 °C for 30 minutes and at 120 °C for 4 hours. Stirred. The reaction solution was cooled to room temperature to remove insoluble materials, and then purified using a reverse phase HPLC column to obtain the title compound (11 mg) having the following physical properties.
LC-MS (A) retention time (min): 1.11;
MS(ESI, Pos.): 890 (M + H) + ;
1 H-NMR (CDCL 3 ): δ 1.13-1.22, 1.24-1.40, 1.50-1.63, 1.63-1.79, 2.02-2.08, 2.08-2.33, 2.84-3.09, 3.39-3.53, 3.39-3.53, 3.63-385, 3.91-4.16, 3.91-4.16 4.50-4.64, 4.67-4.93, 5.29-5.63, 6.83-6.93, 6.95-7.04, 7.09-7.17, 7.22, 7.38-7.70, 7.96, 8.40.
実施例２８－１
７－（４－｛［９－（４－クロロ－２－フルオロベンジル）－５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－イル］カルボニル｝フェニル）－２－（シクロヘキシルアミノ）－９－［１－（２，２－ジメチルプロピル）－４－ピペリジニル］－６－メチル－７，９－ジヒドロ－８Ｈ－プリン－８－オン　２トリフルオロ酢酸塩
　１－［（シクロペンチルメチル）アミノ］－２－メチル－２－プロパノールの代わりにシクロヘキシルアミンを用いて、実施例２８と同様の操作を行い、以下の物性値を有する標題化合物を得た。
LC－MS（A）保持時間（分）：1.03；
MS(ESI, Pos.)： 818 (M + H)＋；
１H-NMR(DMSO-d６)：δ　 1.03-1.13, 1.13-1.40, 1.48-1.68, 1.68-1.92, 1.92-2.07, 2.78-2.98, 3.02-3.12, 3.16-3.26, 3.73-4.06, 4.40-4.91, 5.19-5.66, 6.63-6.86, 6.86-7.37, 7.37-7.75, 7.82-8.06, 8.16-8.30, 8.61-8.98。 Example 28-1
7-(4-{[9-(4-chloro-2-fluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[2,3- b]pyridin-7-yl]carbonyl}phenyl)-2-(cyclohexylamino)-9-[1-(2,2-dimethylpropyl)-4-piperidinyl]-6-methyl-7,9-dihydro-8H -Purin-8-one 2 trifluoroacetate 1-[(cyclopentylmethyl)amino]-2-methyl-2-propanol was replaced by cyclohexylamine, and the same operation as in Example 28 was carried out, and the following physical properties were obtained. The title compound was obtained with a value of .
LC-MS (A) retention time (min): 1.03;
MS(ESI, Pos.): 818 (M + H) + ;
1 H-NMR (DMSO-d 6 ): δ 1.03-1.13, 1.13-1.40, 1.48-1.68, 1.68-1.92, 1.92-2.07, 2.78-2.98, 3.02-3.12, 3.16-3.26, 3.73-4.06, 4.40- 4.91, 5.19-5.66, 6.63-6.86, 6.86-7.37, 7.37-7.75, 7.82-8.06, 8.16-8.30, 8.61-8.98.
参考例７５
１－（｛４－［２－クロロ－７－（４－｛［９－（４－クロロ－２－フルオロベンジル）－５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－イル］カルボニル｝フェニル）－６－メチル－８－オキソ－７，８－ジヒドロ－９Ｈ－プリン－９－イル］－１－ピペリジニル｝カルボニル）シクロプロパンカルボニトリル
　参考例７３で製造した化合物（1.9ｇ）をメタノール（19ｍＬ）に懸濁し、４Ｎ塩化水素／１，4－ジオキサン溶液（6.0ｍＬ）を加えて室温で３時間攪拌した。反応液を濃縮し、得られた残渣の一部（30mg）をＤＭＦ（0.6ｍＬ）に溶解した。そこに、１－シアノシクロプロパンカルボン酸（6.9ｍｇ）とＤＩＰＥＡ（0.036ｍＬ）、ＤＭＴＭＭ（34ｍｇ）を加えて室温で２時間攪拌した。反応液に水を加えて酢酸エチルで抽出し、得られた有機層をインジェクトカラム　アミノ（商品名）に通して濃縮することにより、以下の物性値を有する標題化合物（30ｍｇ）を得た。
LC－MS（A）保持時間（分）：1.18；
MS(ESI, Pos.)： 778 (M + H)＋。 Reference example 75
1-({4-[2-chloro-7-(4-{[9-(4-chloro-2-fluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3' :4,5]pyrrolo[2,3-b]pyridin-7-yl]carbonyl}phenyl)-6-methyl-8-oxo-7,8-dihydro-9H-purin-9-yl]-1-piperidinyl }Carbonyl)cyclopropanecarbonitrile The compound (1.9 g) produced in Reference Example 73 was suspended in methanol (19 mL), 4N hydrogen chloride/1,4-dioxane solution (6.0 mL) was added, and the mixture was stirred at room temperature for 3 hours. . The reaction solution was concentrated, and a portion (30 mg) of the resulting residue was dissolved in DMF (0.6 mL). 1-cyanocyclopropanecarboxylic acid (6.9 mg), DIPEA (0.036 mL), and DMTMM (34 mg) were added thereto, and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction solution and extracted with ethyl acetate, and the resulting organic layer was passed through an injection column Amino (trade name) and concentrated to obtain the title compound (30 mg) having the following physical properties.
LC-MS (A) retention time (min): 1.18;
MS(ESI, Pos.): 778 (M + H) + .
実施例２９
１－［（４－｛７－（４－｛［９－（４－クロロ－２－フルオロベンジル）－５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－イル］カルボニル｝フェニル）－２－［（３－フルオロフェニル）アミノ］－６－メチル－８－オキソ－７，８－ジヒドロ－９Ｈ－プリン－９－イル｝－１－ピペリジニル）カルボニル］シクロプロパンカルボニトリル
　参考例９で製造した化合物の代わりに参考例７５で製造した化合物を、アニリンの代わりに３－フルオロアニリンを用いて、実施例１と同様の操作を行い、以下の物性値を有する標題化合物を得た。
LC－MS（A）保持時間（分）：1.18；
MS(ESI, Pos.)： 853 (M + H)＋；
１H-NMR(CDCl３)：δ　 1.61-1.68, 1.94-2.04, 2.06, 2.62-3.10, 3.26-3.48, 3.73-4.16, 4.54-4.94, 5.23-5.63, 6.71, 6.82-6.91, 6.95-7.03, 7.07-7.17, 7.40-7.54, 7.61-7.71, 7.83, 8.32。 Example 29
1-[(4-{7-(4-{[9-(4-chloro-2-fluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5 ]pyrrolo[2,3-b]pyridin-7-yl]carbonyl}phenyl)-2-[(3-fluorophenyl)amino]-6-methyl-8-oxo-7,8-dihydro-9H-purine- 9-yl}-1-piperidinyl)carbonyl]cyclopropanecarbonitrile The compound produced in Reference Example 75 was substituted for the compound produced in Reference Example 9, and 3-fluoroaniline was used in place of aniline. A similar operation was performed to obtain the title compound having the following physical properties.
LC-MS (A) retention time (min): 1.18;
MS(ESI, Pos.): 853 (M + H) + ;
1 H-NMR (CDCl 3 ): δ 1.61-1.68, 1.94-2.04, 2.06, 2.62-3.10, 3.26-3.48, 3.73-4.16, 4.54-4.94, 5.23-5.63, 6.71, 6.82-6.91, 6.95-7.03 , 7.07-7.17, 7.40-7.54, 7.61-7.71, 7.83, 8.32.
参考例７６
２－メチル－２－プロパニル　９－［２－フルオロ－４－（トリフルオロメチル）ベンジル］－５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－カルボキシラート
　１－（ブロモメチル）－２，４－ジフルオロベンゼンの代わりに１－（ブロモメチル）－２－フルオロ－４－（トリフルオロメチル）ベンゼンを用いて、参考例１と同様の操作を行い、以下の物性値を有する標題化合物を得た。
LC－MS（A）保持時間（分）：1.28；
MS(ESI, Pos.)： 450 (M + H)＋。 Reference example 76
2-Methyl-2-propanyl 9-[2-fluoro-4-(trifluoromethyl)benzyl]-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[ 2,3-b]pyridine-7-carboxylate Using 1-(bromomethyl)-2-fluoro-4-(trifluoromethyl)benzene instead of 1-(bromomethyl)-2,4-difluorobenzene, reference The same operation as in Example 1 was performed to obtain the title compound having the following physical properties.
LC-MS (A) retention time (min): 1.28;
MS(ESI, Pos.): 450 (M + H) + .
参考例７７
９－［２－フルオロ－４－（トリフルオロメチル）ベンジル］－６，７，８，９－テトラヒドロ－５Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン　２塩酸塩
　参考例１で製造した化合物の代わりに参考例７６で製造した化合物を用いて、参考例２と同様の操作を行い、以下の物性値を有する標題化合物を得た。
LC－MS（A）保持時間（分）：0.90；
MS(ESI, Pos.)： 350 (M + H)＋；
１H-NMR(DMSO-d６)：δ　 2.99, 3.46, 4.38, 5.62, 7.06, 7.18, 7.49, 7.75, 8.02, 8.27, 9.72。 Reference example 77
9-[2-fluoro-4-(trifluoromethyl)benzyl]-6,7,8,9-tetrahydro-5H-pyrido[4',3':4,5]pyrrolo[2,3-b]pyridine The same operation as in Reference Example 2 was performed using the compound produced in Reference Example 76 instead of the compound produced in Dihydrochloride Reference Example 1 to obtain the title compound having the following physical properties.
LC-MS (A) retention time (min): 0.90;
MS(ESI, Pos.): 350 (M + H) + ;
1H -NMR (DMSO- d6 ): δ 2.99, 3.46, 4.38, 5.62, 7.06, 7.18, 7.49, 7.75, 8.02, 8.27, 9.72.
参考例７８
メチル　４－｛２－クロロ－８－オキソ－９－［（３Ｓ）－３－ピロリジニル］－８，９－ジヒドロ－７Ｈ－プリン－７－イル｝ベンゾアート　１塩酸塩
　参考例６６で製造した化合物（3.0ｇ）をメタノール（63ｍＬ）に懸濁し、４Ｎ塩化水素／１，4－ジオキサン溶液（23ｍＬ）を加えて室温で終夜攪拌した。反応液を濃縮することにより、以下の物性値を有する標題化合物（2.6ｇ）を得た。
LC－MS（A）保持時間（分）：0.81；
MS(ESI, Pos.)： 374 (M + H)＋。 Reference example 78
Methyl 4-{2-chloro-8-oxo-9-[(3S)-3-pyrrolidinyl]-8,9-dihydro-7H-purin-7-yl}benzoate monohydrochloride Compound produced in Reference Example 66 (3.0 g) was suspended in methanol (63 mL), 4N hydrogen chloride/1,4-dioxane solution (23 mL) was added, and the mixture was stirred at room temperature overnight. By concentrating the reaction solution, the title compound (2.6 g) having the following physical properties was obtained.
LC-MS (A) retention time (min): 0.81;
MS(ESI, Pos.): 374 (M + H) + .
参考例７９
メチル　４－｛２－クロロ－８－オキソ－９－［（３Ｓ）－１－｛［１－（トリフルオロメチル）シクロプロピル］メチル｝－３－ピロリジニル］－８，９－ジヒドロ－７Ｈ－プリン－７－イル｝ベンゾアート
　参考例７８で製造した化合物（700ｍｇ）をＤＭＡ（17ｍＬ）に溶解し、１－（ブロモメチル）－１－（トリフルオロメチル）シクロプロパン（692ｍｇ）とＤＩＰＥＡ（1.5ｍＬ）、ヨウ化カリウム（283ｍｇ）を加えて５０℃で終夜攪拌した。反応液に飽和塩化アンモニウム水溶液を加えて酢酸エチルで抽出し、得られた有機層を無水硫酸ナトリウムで乾燥した。減圧濃縮して得られた残渣をシリカゲルクロマトグラフィー（ヘキサン：酢酸エチル＝３：２→２：３）で精製することにより、以下の物性値を有する標題化合物（500ｍｇ）を得た。
LC－MS（A）保持時間（分）：0.91；
MS(ESI, Pos.)： 496 (M + H)＋；
１H-NMR(CDCl３)：δ　 0.60-0.75, 0.96-1.05, 2.28-2.45, 2.70-2.89, 3.09, 3.30, 3.93-3.98, 5.17-5.27, 7.62-7.66, 8.20, 8.22-8.28。 Reference example 79
Methyl 4-{2-chloro-8-oxo-9-[(3S)-1-{[1-(trifluoromethyl)cyclopropyl]methyl}-3-pyrrolidinyl]-8,9-dihydro-7H-purine -7-yl}benzoate The compound prepared in Reference Example 78 (700 mg) was dissolved in DMA (17 mL), and 1-(bromomethyl)-1-(trifluoromethyl)cyclopropane (692 mg) and DIPEA (1.5 mL) were dissolved. , potassium iodide (283 mg) was added, and the mixture was stirred at 50°C overnight. A saturated aqueous ammonium chloride solution was added to the reaction mixture, extracted with ethyl acetate, and the resulting organic layer was dried over anhydrous sodium sulfate. The residue obtained by concentration under reduced pressure was purified by silica gel chromatography (hexane:ethyl acetate = 3:2→2:3) to obtain the title compound (500 mg) having the following physical properties.
LC-MS (A) retention time (min): 0.91;
MS(ESI, Pos.): 496 (M + H) + ;
1H -NMR ( CDCl3 ): δ 0.60-0.75, 0.96-1.05, 2.28-2.45, 2.70-2.89, 3.09, 3.30, 3.93-3.98, 5.17-5.27, 7.62-7.66, 8.20, 8.22-8.28.
参考例８０
メチル　４－（８－オキソ－２－｛［４－（トリフルオロメトキシ）フェニル］アミノ｝－９－［（３Ｓ）－１－｛［１－（トリフルオロメチル）シクロプロピル］メチル｝－３－ピロリジニル］－８，９－ジヒドロ－７Ｈ－プリン－７－イル）ベンゾアート
　参考例６１で製造した化合物の代わりに参考例７９で製造した化合物を用いて、参考例６２と同様の操作を行い、以下の物性値を有する標題化合物を得た。
LC－MS（A）保持時間（分）：1.11；
MS(ESI, Pos.)： 637 (M + H)＋。 Reference example 80
Methyl 4-(8-oxo-2-{[4-(trifluoromethoxy)phenyl]amino}-9-[(3S)-1-{[1-(trifluoromethyl)cyclopropyl]methyl}-3- pyrrolidinyl]-8,9-dihydro-7H-purin-7-yl)benzoate The same operation as in Reference Example 62 was performed using the compound produced in Reference Example 79 instead of the compound produced in Reference Example 61, The title compound having the following physical properties was obtained.
LC-MS (A) retention time (min): 1.11;
MS(ESI, Pos.): 637 (M + H) + .
参考例８１
４－（８－オキソ－２－｛［４－（トリフルオロメトキシ）フェニル］アミノ｝－９－［（３Ｓ）－１－｛［１－（トリフルオロメチル）シクロプロピル］メチル｝－３－ピロリジニル］－８，９－ジヒドロ－７Ｈ－プリン－７－イル）安息香酸
　参考例３５で製造した化合物の代わりに参考例８０で製造した化合物を用いて、参考例３６と同様の操作を行い、以下の物性値を有する標題化合物を得た。
LC－MS（A）保持時間（分）：1.03；
MS(ESI, Pos.)： 623 (M + H)＋。 Reference example 81
4-(8-oxo-2-{[4-(trifluoromethoxy)phenyl]amino}-9-[(3S)-1-{[1-(trifluoromethyl)cyclopropyl]methyl}-3-pyrrolidinyl ]-8,9-dihydro-7H-purin-7-yl)benzoic acid Using the compound produced in Reference Example 80 instead of the compound produced in Reference Example 35, the same operation as in Reference Example 36 was carried out, and the following The title compound having the physical property values was obtained.
LC-MS (A) retention time (min): 1.03;
MS(ESI, Pos.): 623 (M + H) + .
実施例３０
７－［４－（｛９－［２－フルオロ－４－（トリフルオロメチル）ベンジル］－５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－イル｝カルボニル）フェニル］－２－｛［４－（トリフルオロメトキシ）フェニル］アミノ｝－９－［（３Ｓ）－１－｛［１－（トリフルオロメチル）シクロプロピル］メチル｝－３－ピロリジニル］－７，９－ジヒドロ－８Ｈ－プリン－８－オン　２トリフルオロ酢酸塩
　参考例２で製造した化合物の代わりに参考例７７で製造した化合物を、参考例６で製造した化合物の代わりに参考例８１で製造した化合物を用いて、参考例７と同様の反応操作を行い、逆相HPLCカラム精製することにより、以下の物性値を有する標題化合物を得た。
LC－MS（A）保持時間（分）：1.16；
MS(ESI, Pos.)： 954 (M + H)＋；
１H-NMR(DMSO-d６)：δ　 1.03-1.32, 2.80-2.96, 3.65-3.83, 3.83-4.30, 4.56-4.95, 5.14-5.74, 7.01-7.25, 7.25-7.38, 7.45-8.08, 8.14-8.44, 9.22-9.46, 9.65-9.80。 Example 30
7-[4-({9-[2-fluoro-4-(trifluoromethyl)benzyl]-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[ 2,3-b]pyridin-7-yl}carbonyl)phenyl]-2-{[4-(trifluoromethoxy)phenyl]amino}-9-[(3S)-1-{[1-(trifluoromethyl ) cyclopropyl]methyl}-3-pyrrolidinyl]-7,9-dihydro-8H-purin-8-one 2 trifluoroacetate Instead of the compound produced in Reference Example 2, the compound produced in Reference Example 77 was used as a reference. Using the compound produced in Reference Example 81 instead of the compound produced in Example 6, the same reaction procedure as in Reference Example 7 was carried out, and the title compound having the following physical property values was obtained by purifying with a reverse phase HPLC column. Ta.
LC-MS (A) retention time (min): 1.16;
MS(ESI, Pos.): 954 (M + H) + ;
1 H-NMR (DMSO-d 6 ): δ 1.03-1.32, 2.80-2.96, 3.65-3.83, 3.83-4.30, 4.56-4.95, 5.14-5.74, 7.01-7.25, 7.25-7.38, 7.45-8.08, 8.14- 8.44, 9.22-9.46, 9.65-9.80.
参考例８２
２－メチル－２－プロパニル　９－｛［１－メチル－５－（トリフルオロメチル）－１Ｈ－ピラゾール－３－イル］メチル｝－５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－カルボキシラート
　１－（ブロモメチル）－２，４－ジフルオロベンゼンの代わりに３－（クロロメチル）－１－メチル－５－（トリフルオロメチル）－１H－ピラゾールを用いて、参考例１と同様の操作を行い、以下の物性値を有する標題化合物を得た。
TLC：Rf 0.40（石油エーテル：酢酸エチル＝１：１）。 Reference example 82
2-Methyl-2-propanyl 9-{[1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl]methyl}-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[2,3-b]pyridine-7-carboxylate 3-(chloromethyl)-1-methyl-5- instead of 1-(bromomethyl)-2,4-difluorobenzene The same operation as in Reference Example 1 was performed using (trifluoromethyl)-1H-pyrazole to obtain the title compound having the following physical properties.
TLC: Rf 0.40 (petroleum ether: ethyl acetate = 1:1).
参考例８３
９－｛［１－メチル－５－（トリフルオロメチル）－１Ｈ－ピラゾール－３－イル］メチル｝－６，７，８，９－テトラヒドロ－５Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン　２塩酸塩
　参考例１で製造した化合物の代わりに参考例８２で製造した化合物を用いて、参考例２と同様の操作を行い、以下の物性値を有する標題化合物を得た。
TLC：Rf 0.10（石油エーテル：酢酸エチル＝１：１）。 Reference example 83
9-{[1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl]methyl}-6,7,8,9-tetrahydro-5H-pyrido[4',3':4,5 ]Pyrrolo[2,3-b]pyridine dihydrochloride Using the compound produced in Reference Example 82 instead of the compound produced in Reference Example 1, the same operation as in Reference Example 2 was carried out to obtain a compound having the following physical property values. The title compound was obtained.
TLC: Rf 0.10 (petroleum ether: ethyl acetate = 1:1).
参考例８４
２－メチル－２－プロパニル　３－｛２－クロロ－７－［４－（メトキシカルボニル）フェニル］－８－オキソ－７，８－ジヒドロ－９Ｈ－プリン－９－イル｝－１－ピペリジンカルボキシラート
　参考例６４で用いた２－メチル－２－プロパニル　（３Ｓ）－３－アミノ－１－ピロリジンカルボキシラートの代わりに２－メチル－２－プロパニル　３－アミノ－１－ピペリジンカルボキシラートを用いて、参考例６４→参考例６５→参考例６６と同様の操作を行い、以下の物性値を有する標題化合物を得た。
LC－MS（A）保持時間（分）：1.26；
MS(ESI, Pos.)： 488 (M + H)＋；
１H-NMR(CDCl３)：δ　 1.47, 1.57-1.73, 1.88, 2.02, 2.53, 2.79, 3.68, 3.97, 4.07-4.30, 4.46-4.57, 7.64, 8.20-8.22, 8.22-8.27。 Reference example 84
2-Methyl-2-propanyl 3-{2-chloro-7-[4-(methoxycarbonyl)phenyl]-8-oxo-7,8-dihydro-9H-purin-9-yl}-1-piperidinecarboxylate Using 2-methyl-2-propanyl 3-amino-1-piperidinecarboxylate in place of 2-methyl-2-propanyl (3S)-3-amino-1-pyrrolidinecarboxylate used in Reference Example 64, reference The same operation as Example 64 → Reference Example 65 → Reference Example 66 was performed to obtain the title compound having the following physical property values.
LC-MS (A) retention time (min): 1.26;
MS(ESI, Pos.): 488 (M + H) + ;
1H -NMR ( CDCl3 ): δ 1.47, 1.57-1.73, 1.88, 2.02, 2.53, 2.79, 3.68, 3.97, 4.07-4.30, 4.46-4.57, 7.64, 8.20-8.22, 8.22-8.27.
実施例３１
２－アニリノ－９－［１－（２，２－ジメチルプロピル）－３－ピペリジニル］－７－｛４－［（９－｛［１－メチル－５－（トリフルオロメチル）－１Ｈ－ピラゾール－３－イル］メチル｝－５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－イル）カルボニル］フェニル｝－７，９－ジヒドロ－８Ｈ－プリン－８－オン
　参考例６で用いた参考例５で製造した化合物の代わりに参考例８４で製造した化合物を、参考例７で用いた参考例２で製造した化合物の代わりに参考例８３で製造した化合物を用いて、参考例６→参考例７→参考例８→参考例９→実施例１と同様の操作を行い、以下の物性値を有する標題化合物を得た。
LC－MS（A）保持時間（分）：1.06；
MS(ESI, Pos.)： 818 (M + H)＋；
１H-NMR(DMSO-d６)：δ　 0.87, 1.60-1.73, 1.73-1.83, 1.83-1.92, 2.07-2.21, 2.25-2.34, 2.34-2.46, 2.78-2.95, 3.05-3.19, 3.58-3.77, 3.87-4.08, 4.42-4.54, 4.82-5.05, 5.17-5.59, 6.45-6.75, 6.91-6.98, 7.08-7.15, 7.23-7.32, 7.62-7.84, 7.86-7.95, 8.17-8.32, 9.54。 Example 31
2-anilino-9-[1-(2,2-dimethylpropyl)-3-piperidinyl]-7-{4-[(9-{[1-methyl-5-(trifluoromethyl)-1H-pyrazole- 3-yl]methyl}-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[2,3-b]pyridin-7-yl)carbonyl]phenyl}- 7,9-dihydro-8H-purin-8-one The compound produced in Reference Example 84 was used in place of the compound produced in Reference Example 5 used in Reference Example 6, and the compound produced in Reference Example 2 used in Reference Example 7 was used. Using the compound produced in Reference Example 83 instead of the compound, the same operations as in Reference Example 6 → Reference Example 7 → Reference Example 8 → Reference Example 9 → Example 1 were performed to obtain the title compound having the following physical property values. Obtained.
LC-MS (A) retention time (min): 1.06;
MS(ESI, Pos.): 818 (M + H) + ;
1 H-NMR (DMSO-d 6 ): δ 0.87, 1.60-1.73, 1.73-1.83, 1.83-1.92, 2.07-2.21, 2.25-2.34, 2.34-2.46, 2.78-2.95, 3.05-3.19, 3.58-3.77, 3.87-4.08, 4.42-4.54, 4.82-5.05, 5.17-5.59, 6.45-6.75, 6.91-6.98, 7.08-7.15, 7.23-7.32, 7.62-7.84, 7.86-7.95, 8.17-8.32, 9. 54.
参考例８５
２－メチル－２－プロパニル　９－（２－ペンチン－１－イル）－５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－カルボキシラート
　１－（ブロモメチル）－２，４－ジフルオロベンゼンの代わりに１－ブロモ－２－ペンチンを用いて、参考例１と同様の操作を行い、以下の物性値を有する標題化合物を得た。
TLC：Rf 0.30（石油エーテル：酢酸エチル＝７：３）。 Reference example 85
2-Methyl-2-propanyl 9-(2-pentyn-1-yl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[2,3-b ] Pyridine-7-carboxylate Using 1-bromo-2-pentyne instead of 1-(bromomethyl)-2,4-difluorobenzene, the same operation as in Reference Example 1 was carried out to obtain the title having the following physical property values. The compound was obtained.
TLC: Rf 0.30 (petroleum ether: ethyl acetate = 7:3).
参考例８６
９－（２－ペンチン－１－イル）－６，７，８，９－テトラヒドロ－５Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン　２塩酸塩
　参考例１で製造した化合物の代わりに参考例８５で製造した化合物を用いて、参考例２と同様の操作を行い、以下の物性値を有する標題化合物を得た。
TLC：Rf 0.10（石油エーテル：酢酸エチル＝４：１）。 Reference example 86
9-(2-pentyn-1-yl)-6,7,8,9-tetrahydro-5H-pyrido[4',3':4,5]pyrrolo[2,3-b]pyridine dihydrochloride reference example The same operation as in Reference Example 2 was carried out using the compound produced in Reference Example 85 instead of the compound produced in 1, to obtain the title compound having the following physical property values.
TLC: Rf 0.10 (petroleum ether: ethyl acetate = 4:1).
参考例８７
２－メチル－２－プロパニル　（３Ｓ）－３－｛２－クロロ－７－［４－（メトキシカルボニル）フェニル］－８－オキソ－７，８－ジヒドロ－９Ｈ－プリン－９－イル｝－１－ピペリジンカルボキシラート
　参考例６４で用いた２－メチル－２－プロパニル　（３Ｓ）－３－アミノ－１－ピロリジンカルボキシラートの代わりに２－メチル－２－プロパニル　（３Ｓ）－３－アミノ－１－ピぺリジンカルボキシラートを用いて、参考例６４→参考例６５→参考例６６と同様の操作を行い、以下の物性値を有する標題化合物を得た。
TLC：Rf 0.31（ヘキサン：酢酸エチル＝２：１）；
１H-NMR(CDCl３)：δ　 1.47, 1.57-1.73, 1.88, 2.01, 2.54, 2.80, 3.68, 3.97, 4.06-4.34, 4.51, 7.64, 8.19-8.22, 8.22-8.27。 Reference example 87
2-Methyl-2-propanyl (3S)-3-{2-chloro-7-[4-(methoxycarbonyl)phenyl]-8-oxo-7,8-dihydro-9H-purin-9-yl}-1 -Piperidinecarboxylate 2-methyl-2-propanyl (3S)-3-amino-1- instead of 2-methyl-2-propanyl (3S)-3-amino-1-pyrrolidinecarboxylate used in Reference Example 64 Using piperidine carboxylate, the same operations as Reference Example 64 → Reference Example 65 → Reference Example 66 were performed to obtain the title compound having the following physical properties.
TLC: Rf 0.31 (hexane: ethyl acetate = 2:1);
1H -NMR ( CDCl3 ): δ 1.47, 1.57-1.73, 1.88, 2.01, 2.54, 2.80, 3.68, 3.97, 4.06-4.34, 4.51, 7.64, 8.19-8.22, 8.22-8.27.
実施例３２
２－アニリノ－９－［（３Ｓ）－１－（２，２－ジメチルプロピル）－３－ピペリジニル］－７－（４－｛［９－（２－ペンチン－１－イル）－５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－イル］カルボニル｝フェニル）－７，９－ジヒドロ－８Ｈ－プリン－８－オン　１ギ酸塩
　参考例６で用いた参考例５で製造した化合物の代わりに参考例８７で製造した化合物を、参考例７で用いた参考例２で製造した化合物の代わりに参考例８６で製造した化合物を用いて、参考例６→参考例７→参考例８→参考例９→実施例１と同様の操作を行い、以下の物性値を有する標題化合物を得た。
LC－MS（A）保持時間（分）：1.05；
MS(ESI, Pos.)： 722 (M + H)＋；
１H-NMR(DMSO-d６)：δ　 0.87, 1.01-1.12, 1.59-1.72, 1.75-1.82, 1.83-1.92, 2.08-2.23, 2.26-2.34, 2.36-2.44, 2.77-2.92, 3.09-3.17, 3.68-4.10, 4.42-4.52, 4.91-5.21, 6.92-6.97, 7.08-7.15, 7.24-7.32, 7.67-7.73, 7.74-7.84, 7.88-7.94, 8.19-8.32, 9.54。 Example 32
2-anilino-9-[(3S)-1-(2,2-dimethylpropyl)-3-piperidinyl]-7-(4-{[9-(2-pentyn-1-yl)-5,6, 8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[2,3-b]pyridin-7-yl]carbonyl}phenyl)-7,9-dihydro-8H-purine-8 -one 1 formate The compound produced in Reference Example 87 was used in place of the compound produced in Reference Example 5 used in Reference Example 6, and the compound produced in Reference Example 86 was used in place of the compound produced in Reference Example 2 used in Reference Example 7. Using the produced compound, the same operations as in Reference Example 6 → Reference Example 7 → Reference Example 8 → Reference Example 9 → Example 1 were performed to obtain the title compound having the following physical property values.
LC-MS (A) retention time (min): 1.05;
MS(ESI, Pos.): 722 (M + H) + ;
1 H-NMR (DMSO-d 6 ): δ 0.87, 1.01-1.12, 1.59-1.72, 1.75-1.82, 1.83-1.92, 2.08-2.23, 2.26-2.34, 2.36-2.44, 2.77-2.92, 3.09-3.17, 3.68-4.10, 4.42-4.52, 4.91-5.21, 6.92-6.97, 7.08-7.15, 7.24-7.32, 7.67-7.73, 7.74-7.84, 7.88-7.94, 8.19-8.32, 9.54.
参考例８８
２－メチル－２－プロパニル　４－｛２－クロロ－８－オキソ－７－［４－（５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－イルカルボニル）フェニル］－７，８－ジヒドロ－９Ｈ－プリン－９－イル｝－１－ピペリジンカルボキシラート
　参考例３で用いた２、４－ジクロロ－６－メチル－５－ピリミジンアミンの代わりに２、４－ジクロロ－５－ピリミジンアミンを、参考例７で用いた参考例２で製造した化合物の代わりに６，７，８，９－テトラヒドロ－５Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン　１塩酸塩（CAS：１３５４８０１－０６－１）を用いて、参考例３→参考例４→参考例５→参考例６→参考例７と同様の操作を行い、以下の物性値を有する標題化合物を得た。
LC－MS（A）保持時間（分）：1.03；
MS(ESI, Pos.)： 629 (M + H)＋；
１H-NMR(CDCl３)：δ　 1.51, 1.79-1.90, 2.62, 2.82-2.96, 3.75-4.19, 4.34, 4.61, 4.71-5.14, 7.10, 7.61-7.74, 7.82, 8.19, 8.28, 9.19-10.52。 Reference example 88
2-Methyl-2-propanyl 4-{2-chloro-8-oxo-7-[4-(5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[ 2,3-b]pyridin-7-ylcarbonyl)phenyl]-7,8-dihydro-9H-purin-9-yl}-1-piperidinecarboxylate 2,4-dichloro-6- used in Reference Example 3 2,4-dichloro-5-pyrimidineamine was used instead of methyl-5-pyrimidineamine, and 6,7,8,9-tetrahydro-5H-pyrido was used instead of the compound produced in Reference Example 2 used in Reference Example 7. Reference Example 3 → Reference Example 4 → Reference Example 5 → Reference Example 6→The same operation as in Reference Example 7 was performed to obtain the title compound having the following physical properties.
LC-MS (A) retention time (min): 1.03;
MS(ESI, Pos.): 629 (M + H) + ;
1 H-NMR (CDCl 3 ): δ 1.51, 1.79-1.90, 2.62, 2.82-2.96, 3.75-4.19, 4.34, 4.61, 4.71-5.14, 7.10, 7.61-7.74, 7.82, 8.19, 8.28, 9.19-1 0.52.
参考例８９
２－クロロ－９－［１－（２，２－ジメチルプロピル）－４－ピペリジニル］－７－［４－（５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－イルカルボニル）フェニル］－７，９－ジヒドロ－８Ｈ－プリン－８－オン
　参考例７で製造した化合物の代わりに参考例８８で製造した化合物を用いて、参考例８→参考例９と同様の操作を行い、以下の物性値を有する標題化合物を得た。
LC－MS（A）保持時間（分）：0.81；
MS(ESI, Pos.)： 599 (M + H)＋。 Reference example 89
2-chloro-9-[1-(2,2-dimethylpropyl)-4-piperidinyl]-7-[4-(5,6,8,9-tetrahydro-7H-pyrido[4',3':4 ,5]pyrrolo[2,3-b]pyridin-7-ylcarbonyl)phenyl]-7,9-dihydro-8H-purin-8-one produced in Reference Example 88 instead of the compound produced in Reference Example 7 Using the compound, the same operations as in Reference Example 8→Reference Example 9 were performed to obtain the title compound having the following physical property values.
LC-MS (A) retention time (min): 0.81;
MS(ESI, Pos.): 599 (M + H) + .
参考例９０
２－クロロ－７－［４－（｛９－［４－（ジフルオロメトキシ）ベンジル］－５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－イル｝カルボニル）フェニル］－９－［１－（２，２－ジメチルプロピル）－４－ピペリジニル］－７，９－ジヒドロ－８Ｈ－プリン－８－オン
　参考例８９で製造した化合物（30ｍｇ）をＤＭＦ（0.6ｍＬ）に溶解し、１－（ブロモメチル）－４－（ジフルオロメトキシ）ベンゼン（12ｍｇ）と水素化ナトリウム（60％パラフィンオイル懸濁液、2.0ｍｇ）を加えて室温で９０分攪拌した。反応液に飽和塩化アンモニウム水溶液を加えて酢酸エチルで抽出した。得られた有機層を無水硫酸ナトリウムで乾燥し、減圧濃縮して、以下の物性値を示す標題化合物（37ｍｇ）を得た。
LC－MS（A）保持時間（分）：1.01；
MS(ESI, Pos.)： 755 (M + H)＋。 Reference example 90
2-chloro-7-[4-({9-[4-(difluoromethoxy)benzyl]-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[2 ,3-b]pyridin-7-yl}carbonyl)phenyl]-9-[1-(2,2-dimethylpropyl)-4-piperidinyl]-7,9-dihydro-8H-purin-8-one Reference example The compound prepared in step 89 (30 mg) was dissolved in DMF (0.6 mL), and 1-(bromomethyl)-4-(difluoromethoxy)benzene (12 mg) and sodium hydride (60% paraffin oil suspension, 2.0 mg) were added. was added and stirred at room temperature for 90 minutes. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the title compound (37 mg) exhibiting the following physical properties.
LC-MS (A) retention time (min): 1.01;
MS(ESI, Pos.): 755 (M + H) + .
実施例３３
７－［４－（｛９－［４－（ジフルオロメトキシ）ベンジル］－５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－イル｝カルボニル）フェニル］－９－［１－（２，２－ジメチルプロピル）－４－ピペリジニル］－２－［（２－フルオロフェニル）アミノ］－７，９－ジヒドロ－８Ｈ－プリン－８－オン　２トリフルオロ酢酸塩
　参考例９で製造した化合物の代わりに参考例９０で製造した化合物を、アニリンの代わりに２－フルオロアニリンを用いて、実施例１と同様の反応操作を行い、逆相HPLCカラム精製することにより、以下の物性値を有する標題化合物を得た。
LC－MS（A）保持時間（分）：1.08；
MS(ESI, Pos.)： 830 (M + H)＋；
１H-NMR(DMSO-d６)：δ　 0.97-1.14, 1.96-2.15, 2.76-2.97, 3.01-3.07, 3.63-3.74, 4.46-4.94, 5.46-5.81, 6.91-7.40, 7.56-8.03, 8.18-8.34, 8.66-8.99。 Example 33
7-[4-({9-[4-(difluoromethoxy)benzyl]-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[2,3-b ]pyridin-7-yl}carbonyl)phenyl]-9-[1-(2,2-dimethylpropyl)-4-piperidinyl]-2-[(2-fluorophenyl)amino]-7,9-dihydro-8H -Purin-8-one 2-trifluoroacetate The same reaction procedure as in Example 1 was carried out using the compound produced in Reference Example 90 instead of the compound produced in Reference Example 9 and 2-fluoroaniline in place of aniline. The title compound having the following physical property values was obtained by performing reverse phase HPLC column purification.
LC-MS (A) retention time (min): 1.08;
MS(ESI, Pos.): 830 (M + H) + ;
1 H-NMR (DMSO-d 6 ): δ 0.97-1.14, 1.96-2.15, 2.76-2.97, 3.01-3.07, 3.63-3.74, 4.46-4.94, 5.46-5.81, 6.91-7.40, 7.56-8.03, 8.18- 8.34, 8.66-8.99.
参考例９１
２－メチル－２－プロパニル　９－（２－フルオロ－４－メチルベンジル）－５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－カルボキシラート
　２－メチル－２－プロパニル　５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－カルボキシラート（CAS：１３５４８０１－０７－２、6.0ｇ）と、１－（ブロモメチル）－２－フルオロ－４－メチルベンゼン（4.9ｇ）をＤＭＦ（60ｍＬ）に溶解した。反応液を氷冷し、水素化ナトリウム（60％パラフィンオイル懸濁液、1.1ｇ）を加えて、１時間攪拌した。反応液に飽和塩化アンモニウム水溶液を加えて攪拌し、酢酸エチルで抽出した。得られた有機層を水で洗浄した後、無水硫酸ナトリウムを加えて乾燥し、減圧濃縮した。得られた残渣をシリカゲルクロマトグラフィー（ヘキサン：酢酸エチル＝９：１→１：１）で精製することにより、以下の物性値を有する標題化合物（8.2ｇ）を得た。
LC－MS（A）保持時間（分）：1.20；
MS(ESI, Pos.)： 396 (M + H)＋；
１H-NMR(CDCl３)：δ　 1.45, 2.21-2.34, 2.79, 3.73, 4.52, 5.46, 6.71-6.94, 7.06, 7.79, 8.29。 Reference example 91
2-Methyl-2-propanyl 9-(2-fluoro-4-methylbenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[2,3- b] Pyridine-7-carboxylate 2-methyl-2-propanyl 5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[2,3-b]pyridine-7 -carboxylate (CAS: 1354801-07-2, 6.0 g) and 1-(bromomethyl)-2-fluoro-4-methylbenzene (4.9 g) were dissolved in DMF (60 mL). The reaction solution was ice-cooled, sodium hydride (60% paraffin oil suspension, 1.1 g) was added, and the mixture was stirred for 1 hour. A saturated aqueous ammonium chloride solution was added to the reaction solution, stirred, and extracted with ethyl acetate. The obtained organic layer was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (hexane:ethyl acetate = 9:1→1:1) to obtain the title compound (8.2 g) having the following physical properties.
LC-MS (A) retention time (min): 1.20;
MS(ESI, Pos.): 396 (M + H) + ;
1H -NMR ( CDCl3 ): δ 1.45, 2.21-2.34, 2.79, 3.73, 4.52, 5.46, 6.71-6.94, 7.06, 7.79, 8.29.
参考例９２
９－（２－フルオロ－４－メチルベンジル）－６，７，８，９－テトラヒドロ－５Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン　２塩酸塩
　参考例９１で製造した化合物（8.2ｇ）をメタノール（25ｍＬ）に溶解し、０℃で４Ｎ塩化水素／１，4－ジオキサン溶液（52ｍＬ）を加え、室温で４時間攪拌した。反応液をＭＴＢＥで希釈し、析出物をろ取することにより、以下の物性値を有する標題化合物（6.2ｇ）を得た。
LC－MS（A）保持時間（分）：0.84；
MS(ESI, Pos.)： 296 (M + H)＋；
１H-NMR(DMSO-d６)：δ　 2.27, 2.98, 3.44-3.48, 4.33, 5.49, 6.84-6.92, 7.07, 7.17, 8.01, 8.28, 9.78。 Reference example 92
9-(2-fluoro-4-methylbenzyl)-6,7,8,9-tetrahydro-5H-pyrido[4',3':4,5]pyrrolo[2,3-b]pyridine dihydrochloride reference The compound prepared in Example 91 (8.2 g) was dissolved in methanol (25 mL), 4N hydrogen chloride/1,4-dioxane solution (52 mL) was added at 0° C., and the mixture was stirred at room temperature for 4 hours. The reaction solution was diluted with MTBE and the precipitate was collected by filtration to obtain the title compound (6.2 g) having the following physical properties.
LC-MS (A) retention time (min): 0.84;
MS(ESI, Pos.): 296 (M + H) + ;
1H -NMR (DMSO- d6 ): δ 2.27, 2.98, 3.44-3.48, 4.33, 5.49, 6.84-6.92, 7.07, 7.17, 8.01, 8.28, 9.78.
参考例９３
メチル　５－（｛２－クロロ－４－メチル－６－［（１－｛［（２－メチル－２－プロパニル）オキシ］カルボニル｝－４－ピペリジニル）アミノ］－５－ピリミジニル｝アミノ）－２－ピリジンカルボキシラート
　参考例３で製造した化合物（1.0ｇ）とメチル　５－ブロモピリジンカルボン酸（1.3ｇ）に脱水ＤＭＥ（29ｍＬ）を加えて溶解し、炭酸セシウム（1.9ｇ）及びXantphos（339ｍｇ）、Pd２（dba）３（268ｍｇ）を加えた。反応容器内を窒素置換後、８０℃で４時間攪拌した。反応液をセライト（商品名）に通して不溶物を除去し、ろ液を濃縮して得られた残渣をシリカゲルクロマトグラフィー（ヘキサン：酢酸エチル＝３：１→１：０）で精製することにより、以下の物性値を有する標題化合物（890ｍｇ）を得た。
LC－MS（A）保持時間（分）：1.01；
MS(ESI, Pos.)： 477 (M + H)＋；
１H-NMR(DMSO-d６)：δ　 1.37, 1.70, 2.06, 2.72-2.88, 3.79, 3.83-3.94, 3.99-4.11, 6.66, 7.23, 7.82, 8.01-8.11。 Reference example 93
Methyl 5-({2-chloro-4-methyl-6-[(1-{[(2-methyl-2-propanyl)oxy]carbonyl}-4-piperidinyl)amino]-5-pyrimidinyl}amino)-2 -Pyridinecarboxylate The compound prepared in Reference Example 3 (1.0g) and methyl 5-bromopyridinecarboxylic acid (1.3g) were dissolved in dehydrated DME (29mL), and cesium carbonate (1.9g) and Xantphos (339mg) were dissolved. , Pd 2 (dba) 3 (268 mg) was added. After purging the inside of the reaction vessel with nitrogen, the mixture was stirred at 80°C for 4 hours. The reaction solution was passed through Celite (trade name) to remove insoluble matter, the filtrate was concentrated, and the resulting residue was purified by silica gel chromatography (hexane: ethyl acetate = 3:1 → 1:0). The title compound (890 mg) having the following physical properties was obtained.
LC-MS (A) retention time (min): 1.01;
MS(ESI, Pos.): 477 (M + H) + ;
1H -NMR (DMSO- d6 ): δ 1.37, 1.70, 2.06, 2.72-2.88, 3.79, 3.83-3.94, 3.99-4.11, 6.66, 7.23, 7.82, 8.01-8.11.
参考例９４
メチル　５－［２－クロロ－６－メチル－９－（１－｛［（２－メチル－２－プロパニル）オキシ］カルボニル｝－４－ピペリジニル）－８－オキソ－８，９－ジヒドロ－７Ｈ－プリン－７－イル］－２－ピリジンカルボキシラート
　参考例９３で製造した化合物（3.3ｇ）をＴＨＦ（33ｍＬ）に溶解し、ＣＤＩ（2.2ｇ）とＤＢＵ（1.0ｍＬ）を加えて室温で１時間攪拌した。反応液を酢酸エチルで希釈し、水と１Ｎ塩酸で洗浄した。得られた有機層を飽和塩化アンモニウム水と飽和食塩水で洗浄し、減圧濃縮することにより、以下の物性値を有する標題化合物（3.3ｇ）を得た。
LC－MS（A）保持時間（分）：1.11；
MS(ESI, Pos.)： 503 (M + H)＋；
１H-NMR(CDCl３)：δ　 1.48-1.51, 1.81, 2.16, 2.53-2.65, 2.75-2.94, 4.07, 4.25-4.41, 4.53-4.62, 7.97, 8.35, 8.77。 Reference example 94
Methyl 5-[2-chloro-6-methyl-9-(1-{[(2-methyl-2-propanyl)oxy]carbonyl}-4-piperidinyl)-8-oxo-8,9-dihydro-7H- Purin-7-yl]-2-pyridinecarboxylate The compound prepared in Reference Example 93 (3.3 g) was dissolved in THF (33 mL), CDI (2.2 g) and DBU (1.0 mL) were added, and the mixture was stirred at room temperature for 1 hour. Stirred. The reaction solution was diluted with ethyl acetate and washed with water and 1N hydrochloric acid. The obtained organic layer was washed with saturated ammonium chloride water and saturated brine, and concentrated under reduced pressure to obtain the title compound (3.3 g) having the following physical properties.
LC-MS (A) retention time (min): 1.11;
MS(ESI, Pos.): 503 (M + H) + ;
1H -NMR ( CDCl3 ): δ 1.48-1.51, 1.81, 2.16, 2.53-2.65, 2.75-2.94, 4.07, 4.25-4.41, 4.53-4.62, 7.97, 8.35, 8.77.
参考例９５
５－［２－クロロ－６－メチル－９－（１－｛［（２－メチル－２－プロパニル）オキシ］カルボニル｝－４－ピペリジニル）－８－オキソ－８，９－ジヒドロ－７Ｈ－プリン－７－イル］－２－ピリジンカルボン酸
　参考例９４で製造した化合物（5.7ｇ）をＴＨＦ（227ｍＬ）に溶解し、０℃でＴＭＳＯＫ（2.9ｇ）を加えて２０分攪拌した。反応液に２Ｎ塩酸を加えて酢酸エチルで抽出し、得られた有機層を飽和食塩水で洗浄した。無水硫酸ナトリウムで乾燥後、減圧濃縮して、以下の物性値を有する標題化合物（5.4ｇ）を得た。
LC－MS（A）保持時間（分）：1.03；
MS(ESI, Pos.)： 489 (M + H)＋；
１H-NMR(DMSO-d６)：δ　 1.44, 1.82, 2.01, 2.23-2.40, 2.91, 4.01-4.17, 4.46-4.56, 8.15-8.20, 8.25, 8.87, 13.52。 Reference example 95
5-[2-chloro-6-methyl-9-(1-{[(2-methyl-2-propanyl)oxy]carbonyl}-4-piperidinyl)-8-oxo-8,9-dihydro-7H-purine -7-yl]-2-pyridinecarboxylic acid The compound (5.7 g) prepared in Reference Example 94 was dissolved in THF (227 mL), and TMSOK (2.9 g) was added at 0° C. and stirred for 20 minutes. 2N hydrochloric acid was added to the reaction mixture, extracted with ethyl acetate, and the resulting organic layer was washed with saturated brine. After drying over anhydrous sodium sulfate, the residue was concentrated under reduced pressure to obtain the title compound (5.4 g) having the following physical properties.
LC-MS (A) retention time (min): 1.03;
MS(ESI, Pos.): 489 (M + H) + ;
1H -NMR (DMSO- d6 ): δ 1.44, 1.82, 2.01, 2.23-2.40, 2.91, 4.01-4.17, 4.46-4.56, 8.15-8.20, 8.25, 8.87, 13.52.
参考例９６
５－［６－メチル－９－（１－｛［（２－メチル－２－プロパニル）オキシ］カルボニル｝－４－ピペリジニル）－８－オキソ－２－｛［４－（トリフルオロメトキシ）フェニル］アミノ｝－８，９－ジヒドロ－７Ｈ－プリン－７－イル］－２－ピリジンカルボン酸
　参考例９５で製造した化合物（540ｍｇ）にＤＭＦ（5.4ｍＬ）とトルエン（5.4ｍＬ）を加えて溶解し、４－（トリフルオロメトキシ）アニリン（490ｍｇ）及び炭酸セシウム（1.1ｇ）、Xantphos（130ｍｇ）、酢酸パラジウム（25ｍｇ）を加え、窒素雰囲気下、１２０℃で１時間攪拌した。反応液を室温に冷却した後、酢酸エチルで希釈し、１Ｎ塩酸を加えて酢酸エチルで抽出した。有機層を飽和塩化アンモニウム水溶液と飽和食塩水で洗浄し、減圧濃縮することにより、以下の物性値を有する標題化合物（690ｍｇ）を得た。
LC－MS（A）保持時間（分）：1.13；
MS(ESI, Pos.)： 630 (M + H)＋。 Reference example 96
5-[6-methyl-9-(1-{[(2-methyl-2-propanyl)oxy]carbonyl}-4-piperidinyl)-8-oxo-2-{[4-(trifluoromethoxy)phenyl] amino}-8,9-dihydro-7H-purin-7-yl]-2-pyridinecarboxylic acid DMF (5.4 mL) and toluene (5.4 mL) were added to the compound (540 mg) prepared in Reference Example 95 and dissolved. , 4-(trifluoromethoxy)aniline (490 mg), cesium carbonate (1.1 g), Xantphos (130 mg), and palladium acetate (25 mg) were added, and the mixture was stirred at 120° C. for 1 hour under a nitrogen atmosphere. After the reaction solution was cooled to room temperature, it was diluted with ethyl acetate, 1N hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous ammonium chloride solution and saturated brine, and concentrated under reduced pressure to obtain the title compound (690 mg) having the following physical properties.
LC-MS (A) retention time (min): 1.13;
MS(ESI, Pos.): 630 (M + H) + .
参考例９７
２－メチル－２－プロパニル　４－［７－（６－｛［９－（２－フルオロ－４－メチルベンジル）－５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－イル］カルボニル｝－３－ピリジニル）－６－メチル－８－オキソ－２－｛［４－（トリフルオロメトキシ）フェニル］アミノ｝－７，８－ジヒドロ－９Ｈ－プリン－９－イル］－１－ピぺリジンカルボキシラート
　参考例９６で製造した化合物（500ｍｇ）にＤＭＦ（10ｍＬ）を加えて溶解し、参考例９２で製造した化合物（290ｍｇ）とＤＩＰＥＡ（0.68ｍＬ）、ＤＭＴＭＭ（483ｍｇ）を加えて室温で１時間攪拌した。反応液に０℃で水を加えて、酢酸エチルで抽出し、得られた有機層を水で洗浄した。減圧濃縮して得られた残渣をシリカゲルクロマトグラフィー（富士シリシア　ＮＨ（商品名）、ヘキサン：酢酸エチル＝１：１→０：１）で精製することにより、以下の物性値を有する標題化合物（100ｍｇ）を得た。
LC－MS（A）保持時間（分）：1.36；
MS(ESI, Pos.)： 907 (M + H)＋；
１H-NMR(CDCl３)：δ　 1.51, 1.80-1.92, 2.07-2.13, 2.30, 2.66, 2.89, 2.96, 3.88-4.16, 4.27-4.48, 4.48-4.62, 4.91, 5.29-5.57, 6.75-6.84, 6.88-6.93, 7.01-7.05, 7.11, 7.20, 7.64-7.69, 7.79-7.84, 7.88-7.95, 8.30-8.33, 8.70。 Reference example 97
2-Methyl-2-propanyl 4-[7-(6-{[9-(2-fluoro-4-methylbenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3'): 4,5]pyrrolo[2,3-b]pyridin-7-yl]carbonyl}-3-pyridinyl)-6-methyl-8-oxo-2-{[4-(trifluoromethoxy)phenyl]amino}- 7,8-dihydro-9H-purin-9-yl]-1-piperidinecarboxylate DMF (10 mL) was added to the compound produced in Reference Example 96 (500 mg) and dissolved, resulting in the compound produced in Reference Example 92. (290 mg), DIPEA (0.68 mL), and DMTMM (483 mg) were added and stirred at room temperature for 1 hour. Water was added to the reaction solution at 0°C, extracted with ethyl acetate, and the resulting organic layer was washed with water. The residue obtained by concentration under reduced pressure was purified by silica gel chromatography (Fuji Silysia NH (trade name), hexane:ethyl acetate = 1:1 → 0:1) to obtain the title compound (100 mg) having the following physical property values. ) was obtained.
LC-MS (A) retention time (min): 1.36;
MS(ESI, Pos.): 907 (M + H) + ;
1 H-NMR (CDCl 3 ): δ 1.51, 1.80-1.92, 2.07-2.13, 2.30, 2.66, 2.89, 2.96, 3.88-4.16, 4.27-4.48, 4.48-4.62, 4.91, 5.29-5.57, 6.75-6. 84, 6.88-6.93, 7.01-7.05, 7.11, 7.20, 7.64-7.69, 7.79-7.84, 7.88-7.95, 8.30-8.33, 8.70.
参考例９８
７－（６－｛［９－（２－フルオロ－４－メチルベンジル）－５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－イル］カルボニル｝－３－ピリジニル）－６－メチル－９－（４－ピペリジニル）－２－｛［４－（トリフルオロメトキシ）フェニル］アミノ｝－７，９－ジヒドロ－８Ｈ－プリン－８－オン　２塩酸塩
　参考例９７で製造した化合物（4.4ｇ）にメタノール（8.7ｍＬ）を加え、さらに０℃で４Ｎ塩化水素／１，4－ジオキサン溶液（18ｍＬ）を加えて室温で３０分攪拌した。反応液を濃縮し、得られた残渣をＭＴＢＥでろ取することにより、以下の物性値を有する標題化合物（4.8ｇ）を得た。
LC－MS（A）保持時間（分）：1.13；
MS(ESI, Pos.)： 807 (M + H)＋；
１H-NMR(DMSO-d６)：δ　 1.93-2.04, 2.05-2.13, 2.14-2.30, 2.63-2.77, 2.88, 3.10-3.19, 3.42-3.53, 3.68-4.07, 4.57-4.70, 4.75-4.93, 5.28-5.59, 6.71-7.19, 7.35, 7.80-7.91, 7.94-8.01, 8.09-8.18, 8.23-8.29, 8.54-8.86, 9.10-9.25, 9.73。 Reference example 98
7-(6-{[9-(2-fluoro-4-methylbenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[2,3- b] Pyridin-7-yl]carbonyl}-3-pyridinyl)-6-methyl-9-(4-piperidinyl)-2-{[4-(trifluoromethoxy)phenyl]amino}-7,9-dihydro- 8H-purin-8-one dihydrochloride Methanol (8.7 mL) was added to the compound prepared in Reference Example 97 (4.4 g), and then a 4N hydrogen chloride/1,4-dioxane solution (18 mL) was added at 0°C. The mixture was stirred at room temperature for 30 minutes. The reaction solution was concentrated, and the resulting residue was filtered with MTBE to obtain the title compound (4.8 g) having the following physical properties.
LC-MS (A) retention time (min): 1.13;
MS(ESI, Pos.): 807 (M + H) + ;
1 H-NMR (DMSO-d 6 ): δ 1.93-2.04, 2.05-2.13, 2.14-2.30, 2.63-2.77, 2.88, 3.10-3.19, 3.42-3.53, 3.68-4.07, 4.57-4.70, 4.75-4.93, 5.28-5.59, 6.71-7.19, 7.35, 7.80-7.91, 7.94-8.01, 8.09-8.18, 8.23-8.29, 8.54-8.86, 9.10-9.25, 9.73.
実施例３４
９－［１－（２，２－ジメチルプロピル）－４－ピペリジニル］－７－（６－｛［９－（２－フルオロ－４－メチルベンジル）－５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－イル］カルボニル｝－３－ピリジニル）－６－メチル－２－｛［４－（トリフルオロメトキシ）フェニル］アミノ｝－７，９－ジヒドロ－８Ｈ－プリン－８－オン
　参考例９８で製造した化合物（30ｍｇ）をＤＭＦ（0.6ｍＬ）に溶解し、ＮＥｔ３（0.024ｍＬ）を加えた。さらにピバルアルデヒド（16ｍｇ）と酢酸（0.020ｍＬ）、トリアセトキシ水素化ホウ素ナトリウム（38ｍｇ）を加えて室温で５時間攪拌した。反応液に飽和炭酸水素ナトリウム水溶液を加えて酢酸エチルで抽出し、有機層を水と飽和食塩水で洗浄した。無水硫酸ナトリウムで乾燥後、有機層を減圧濃縮して得られた残渣をシリカゲルクロマトグラフィー（富士シリシア　ＮＨ（商品名）、ヘキサン：酢酸エチル＝５：１→２：３）で精製することにより、以下の物性値を有する標題化合物（20ｍｇ）を得た。
LC－MS（A）保持時間（分）：1.17；
MS(ESI, Pos.)： 877 (M + H)＋；
１H-NMR (CDCl３)：δ　 0.95, 1.71-1.80, 2.05-2.11, 2.15, 2.20-2.31, 2.45, 2.74-2.86, 2.93-3.03, 3.85-4.18, 4.31-4.41, 4.91, 5.28-5.57, 6.75-6.84, 6.88-6.93, 7.06-7.11, 7.20-7.25, 7.69-7.74, 7.79-7.84, 7.88-7.95, 8.29-8.33, 8.56-8.72。 Example 34
9-[1-(2,2-dimethylpropyl)-4-piperidinyl]-7-(6-{[9-(2-fluoro-4-methylbenzyl)-5,6,8,9-tetrahydro-7H -pyrido[4',3':4,5]pyrrolo[2,3-b]pyridin-7-yl]carbonyl}-3-pyridinyl)-6-methyl-2-{[4-(trifluoromethoxy) phenyl]amino}-7,9-dihydro-8H-purin-8-one
The compound prepared in Reference Example 98 (30 mg) was dissolved in DMF (0.6 mL), and NEt 3 (0.024 mL) was added. Furthermore, pivalaldehyde (16 mg), acetic acid (0.020 mL), and sodium triacetoxyborohydride (38 mg) were added, and the mixture was stirred at room temperature for 5 hours. A saturated aqueous sodium bicarbonate solution was added to the reaction mixture, extracted with ethyl acetate, and the organic layer was washed with water and saturated brine. After drying over anhydrous sodium sulfate, the organic layer was concentrated under reduced pressure and the resulting residue was purified by silica gel chromatography (Fuji Silysia NH (trade name), hexane: ethyl acetate = 5:1 → 2:3). The title compound (20 mg) having the following physical properties was obtained.
LC-MS (A) retention time (min): 1.17;
MS(ESI, Pos.): 877 (M + H) + ;
1 H-NMR (CDCl 3 ): δ 0.95, 1.71-1.80, 2.05-2.11, 2.15, 2.20-2.31, 2.45, 2.74-2.86, 2.93-3.03, 3.85-4.18, 4.31-4.41, 4.91, 5.28-5.5 7, 6.75-6.84, 6.88-6.93, 7.06-7.11, 7.20-7.25, 7.69-7.74, 7.79-7.84, 7.88-7.95, 8.29-8.33, 8.56-8.72.
実施例３４－１
７－（６－｛［９－（２－フルオロ－４－メチルベンジル）－５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－イル］カルボニル｝－３－ピリジニル）－６－メチル－２－｛［４－（トリフルオロメトキシ）フェニル］アミノ｝－９－［１－（３，３，３－トリフルオロプロピル）－４－ピペリジニル］－７，９－ジヒドロ－８Ｈ－プリン－８－オン　２トリフルオロ酢酸塩
　ピバルアルデヒドの代わりに３，３，３－トリフルオロプロパナールを用いて、実施例３４と同様の操作を行い、逆相HPLCカラム精製することにより、以下の物性値を有する標題化合物を得た。
LC－MS（A）保持時間（分）：1.11；
MS(ESI, Pos.)： 903 (M + H)＋；
１H-NMR(DMSO-d６)：δ　 1.92-2.05, 2.11-2.24, 2.24-2.31, 2.69-2.83, 2.83-2.95, 3.14-3.29, 3.88, 3.98-4.11, 4.54-4.68, 4.71-4.96, 5.19-5.62, 6.67-7.02, 7.03-7.21, 7.24-7.34, 7.77-7.99, 7.99-8.29, 8.60-8.86, 9.62-9.92。 Example 34-1
7-(6-{[9-(2-fluoro-4-methylbenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[2,3- b]pyridin-7-yl]carbonyl}-3-pyridinyl)-6-methyl-2-{[4-(trifluoromethoxy)phenyl]amino}-9-[1-(3,3,3-trifluoro Propyl)-4-piperidinyl]-7,9-dihydro-8H-purin-8-one 2 trifluoroacetate Same as Example 34, using 3,3,3-trifluoropropanal in place of pivalaldehyde. The title compound having the following physical properties was obtained by performing the following operations and purifying with a reverse phase HPLC column.
LC-MS (A) retention time (min): 1.11;
MS(ESI, Pos.): 903 (M + H) + ;
1 H-NMR (DMSO-d 6 ): δ 1.92-2.05, 2.11-2.24, 2.24-2.31, 2.69-2.83, 2.83-2.95, 3.14-3.29, 3.88, 3.98-4.11, 4.54-4.68, 4.71-4.96, 5.19-5.62, 6.67-7.02, 7.03-7.21, 7.24-7.34, 7.77-7.99, 7.99-8.29, 8.60-8.86, 9.62-9.92.
参考例９９
２－メチル－２－プロパニル　４－［２－クロロ－７－（６－｛［９－（４－シアノ－２－フルオロベンジル）－５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－イル］カルボニル｝－３－ピリジニル）－６－メチル－８－オキソ－７，８－ジヒドロ－９Ｈ－プリン－９－イル］－１－ピペリジンカルボキシラート
　参考例９５で製造した化合物（196ｍｇ）と参考例５３で製造した化合物（159ｍｇ）をＤＭＦ（2.0ｍＬ）に溶解し、ＤＩＰＥＡ（0.27ｍＬ）とＨＡＴＵ（228ｍｇ）を加えて室温で１８時間攪拌した。反応液に飽和炭酸水素ナトリウム水溶液を加えて、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥し、減圧濃縮して得られた残渣をシリカゲルクロマトグラフィー（ヘキサン：酢酸エチル＝３３：６７）で精製することにより、以下の物性値を有する標題化合物（294ｍｇ）を得た。
LC－MS（A）保持時間（分）：1.22；
MS(ESI, Pos.)： 777 (M + H)＋；
１H-NMR(CDCl３)：δ　 1.46-1.53, 1.79-1.90, 2.11-2.19, 2.54-2.68, 2.82-3.06, 3.89-4.19, 4.24-4.46, 4.54-4.67, 4.78-4.93, 5.39-5.64, 6.87-7.06, 7.13, 7.22-7.33, 7.40-7.45, 7.82-7.96, 8.30, 8.53-8.71。 Reference example 99
2-Methyl-2-propanyl 4-[2-chloro-7-(6-{[9-(4-cyano-2-fluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[2,3-b]pyridin-7-yl]carbonyl}-3-pyridinyl)-6-methyl-8-oxo-7,8-dihydro-9H-purine-9- ]-1-piperidinecarboxylate The compound produced in Reference Example 95 (196 mg) and the compound produced in Reference Example 53 (159 mg) were dissolved in DMF (2.0 mL), and DIPEA (0.27 mL) and HATU (228 mg) were dissolved. In addition, the mixture was stirred at room temperature for 18 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting residue was purified by silica gel chromatography (hexane: ethyl acetate = 33:67) to obtain the following physical properties. The title compound (294 mg) was obtained.
LC-MS (A) retention time (min): 1.22;
MS(ESI, Pos.): 777 (M + H) + ;
1 H-NMR (CDCL 3 ): δ 1.46-1.53, 1.79-1.90, 2.11-2.19, 2.54-2.68, 2.82-3.06, 3.89-4.19, 4.24-4.46, 4.54-4.93, 4.78-4.93, 5.39-5.64 6.87-7.06, 7.13, 7.22-7.33, 7.40-7.45, 7.82-7.96, 8.30, 8.53-8.71.
参考例１００
４－｛［７－（｛５－［２－クロロ－６－メチル－８－オキソ－９－（４－ピペリジニル）－８，９－ジヒドロ－７Ｈ－プリン－７－イル］－２－ピリジニル｝カルボニル）－５，６，７，８－テトラヒドロ－９Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－９－イル］メチル｝－３－フルオロベンゾニトリル　２塩酸塩
　参考例９９で製造した化合物（2.6ｇ）に１，４－ジオキサン（10ｍＬ）を加え、４Ｎ塩化水素／１，4－ジオキサン溶液（11ｍＬ）を加えて室温で２時間攪拌した。反応液をＭＴＢＥで希釈し、ろ取することにより、以下の物性値を有する標題化合物（3.1ｇ）を得た。
LC－MS（A）保持時間（分）：0.92；
MS(ESI, Pos.)： 677 (M + H)＋。 Reference example 100
4-{[7-({5-[2-chloro-6-methyl-8-oxo-9-(4-piperidinyl)-8,9-dihydro-7H-purin-7-yl]-2-pyridinyl} carbonyl)-5,6,7,8-tetrahydro-9H-pyrido[4',3':4,5]pyrrolo[2,3-b]pyridin-9-yl]methyl}-3-fluorobenzonitrile 2 1,4-dioxane (10 mL) was added to the compound (2.6 g) prepared in Hydrochloride Reference Example 99, and a 4N hydrogen chloride/1,4-dioxane solution (11 mL) was added, followed by stirring at room temperature for 2 hours. The reaction solution was diluted with MTBE and collected by filtration to obtain the title compound (3.1 g) having the following physical properties.
LC-MS (A) retention time (min): 0.92;
MS(ESI, Pos.): 677 (M + H) + .
参考例１０１
４－（｛７－［（５－｛２－クロロ－９－［１－（２，２－ジメチルプロピル）－４－ピペリジニル］－６－メチル－８－オキソ－８，９－ジヒドロ－７Ｈ－プリン－７－イル｝－２－ピリジニル）カルボニル］－５，６，７，８－テトラヒドロ－９Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－９－イル｝メチル）－３－フルオロベンゾニトリル
　参考例１００で製造した化合物（3.1ｇ）をＤＭＦ（26ｍＬ）に溶解し、ＮＥｔ３（1.3ｍＬ）を加えた。さらにピバルアルデヒド（1.3ｇ）と酢酸（1.7ｍＬ）、トリアセトキシ水素化ホウ素ナトリウム（1.9ｇ）を加えて室温で５時間攪拌した。反応液に飽和炭酸水素ナトリウム水溶液を加えて酢酸エチルで抽出し、有機層を飽和炭酸水素ナトリウム水溶液と水で洗浄した。無水硫酸ナトリウムで乾燥後、有機層を減圧濃縮して得られた残渣をシリカゲルクロマトグラフィー（富士シリシア　ＮＨ（商品名）、ヘキサン：酢酸エチル＝４：１→２：３）で精製することにより、以下の物性値を有する標題化合物（2.1ｇ）を得た。
LC－MS（A）保持時間（分）：1.01；
MS(ESI, Pos.)： 747 (M + H)＋；
１H-NMR(CDCl３)：δ　 0.87-0.93, 1.68-1.79, 2.13, 2.17, 2.45, 2.65-2.78, 2.92-3.04, 3.89-4.20, 4.38-4.48, 4.83-4.94, 5.39-5.64, 6.88-7.08, 7.13, 7.24-7.32, 7.40-7.46, 7.83-7.95, 8.30, 8.54-8.72。 Reference example 101
4-({7-[(5-{2-chloro-9-[1-(2,2-dimethylpropyl)-4-piperidinyl]-6-methyl-8-oxo-8,9-dihydro-7H- purin-7-yl}-2-pyridinyl)carbonyl]-5,6,7,8-tetrahydro-9H-pyrido[4',3':4,5]pyrrolo[2,3-b]pyridine-9- yl}methyl)-3-fluorobenzonitrile The compound prepared in Reference Example 100 (3.1 g) was dissolved in DMF (26 mL), and NEt 3 (1.3 mL) was added. Furthermore, pivalaldehyde (1.3 g), acetic acid (1.7 mL), and sodium triacetoxyborohydride (1.9 g) were added, and the mixture was stirred at room temperature for 5 hours. A saturated aqueous sodium bicarbonate solution was added to the reaction mixture, extracted with ethyl acetate, and the organic layer was washed with a saturated aqueous sodium bicarbonate solution and water. After drying with anhydrous sodium sulfate, the organic layer was concentrated under reduced pressure and the resulting residue was purified by silica gel chromatography (Fuji Silysia NH (trade name), hexane: ethyl acetate = 4:1 → 2:3). The title compound (2.1 g) having the following physical properties was obtained.
LC-MS (A) retention time (min): 1.01;
MS(ESI, Pos.): 747 (M + H) + ;
1 H-NMR (CDCl 3 ): δ 0.87-0.93, 1.68-1.79, 2.13, 2.17, 2.45, 2.65-2.78, 2.92-3.04, 3.89-4.20, 4.38-4.48, 4.83-4.94, 5.39-5.64, 6.8 8- 7.08, 7.13, 7.24-7.32, 7.40-7.46, 7.83-7.95, 8.30, 8.54-8.72.
実施例３５
４－［（７－｛［５－（９－［１－（２，２－ジメチルプロピル）－４－ピペリジニル］－６－メチル－８－オキソ－２－｛［４－（トリフルオロメトキシ）フェニル］アミノ｝－８，９－ジヒドロ－７Ｈ－プリン－７－イル）－２－ピリジニル］カルボニル｝－５，６，７，８－テトラヒドロ－９Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－９－イル）メチル］－３－フルオロベンゾニトリル
　参考例１０１で製造した化合物（100ｍｇ）にＤＭＦ（1.0ｍＬ）とトルエン（1.0ｍＬ）を加えて溶解し、４－（トリフルオロメトキシ）アニリン（28ｍｇ）及び炭酸セシウム（87ｍｇ）、Xantphos（15ｍｇ）、酢酸パラジウム（3.0ｍｇ）を加え、窒素雰囲気下で１１０℃で２時間攪拌した。反応液を室温に冷却した後、酢酸エチルで希釈し、インジェクトカラム　アミノ（商品名）に通して濃縮した。残渣をヘキサンと酢酸エチルの混合液（９：１）に溶解し、水で洗浄して減圧濃縮し、残渣をシリカゲルクロマトグラフィー（富士シリシア　ＮＨ（商品名）、ヘキサン：酢酸エチル＝１：１→３：７）で精製することにより、以下の物性値を有する標題化合物（60ｍｇ）を得た。
LC－MS（A）保持時間（分）：1.14；
MS(ESI, Pos.)： 888 (M + H)＋；
１H-NMR (CDCl３)：δ　 0.95, 1.70-1.83, 2.05-2.11, 2.15, 2.41-2.50, 2.72-2.88, 2.93-3.06, 3.90-4.21, 4.29-4.44, 4.86-4.93, 5.38-5.63, 6.89-7.07, 7.07-7.14, 7.21-7.25, 7.27-7.32, 7.40-7.48, 7.72, 7.84-7.92, 8.30, 8.58-8.73。 Example 35
4-[(7-{[5-(9-[1-(2,2-dimethylpropyl)-4-piperidinyl]-6-methyl-8-oxo-2-{[4-(trifluoromethoxy)phenyl ]Amino}-8,9-dihydro-7H-purin-7-yl)-2-pyridinyl]carbonyl}-5,6,7,8-tetrahydro-9H-pyrido[4',3':4,5] Pyrrolo[2,3-b]pyridin-9-yl)methyl]-3-fluorobenzonitrile
Add and dissolve DMF (1.0 mL) and toluene (1.0 mL) to the compound produced in Reference Example 101 (100 mg), and dissolve 4-(trifluoromethoxy)aniline (28 mg), cesium carbonate (87 mg), and Xantphos (15 mg). , palladium acetate (3.0 mg) was added, and the mixture was stirred at 110° C. for 2 hours under a nitrogen atmosphere. After the reaction solution was cooled to room temperature, it was diluted with ethyl acetate, passed through an injection column Amino (trade name), and concentrated. The residue was dissolved in a mixture of hexane and ethyl acetate (9:1), washed with water, concentrated under reduced pressure, and subjected to silica gel chromatography (Fuji Silicia NH (trade name), hexane:ethyl acetate = 1:1→ 3:7) to obtain the title compound (60 mg) having the following physical properties.
LC-MS (A) retention time (min): 1.14;
MS(ESI, Pos.): 888 (M + H) + ;
1 H-NMR (CDCl 3 ): δ 0.95, 1.70-1.83, 2.05-2.11, 2.15, 2.41-2.50, 2.72-2.88, 2.93-3.06, 3.90-4.21, 4.29-4.44, 4.86-4.93, 5.38-5.63 , 6.89-7.07, 7.07-7.14, 7.21-7.25, 7.27-7.32, 7.40-7.48, 7.72, 7.84-7.92, 8.30, 8.58-8.73.
実施例３５－１
３－フルオロ－４－（｛７－［（５－｛２－［（３－フルオロフェニル）アミノ］－６－メチル－８－オキソ－９－（１－｛［１－（トリフルオロメチル）シクロプロピル］メチル｝－４－ピペリジニル）－８，９－ジヒドロ－７Ｈ－プリン－７－イル｝－２－ピリジニル）カルボニル］－５，６，７，８－テトラヒドロ－９Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－９－イル｝メチル）ベンゾニトリル
　参考例１０１で用いたピバルアルデヒドの代わりに１－（トリフルオロメチル）シクロプロパンカルボアルデヒドを、実施例３５で用いた４－（トリフルオロメトキシ）アニリンの代わりに３－トリフルオロアニリンを用いて、参考例１０１→実施例３５と同様の操作を行い、以下の物性値を有する標題化合物を得た。
LC－MS（A）保持時間（分）：1.12；
MS(ESI, Pos.)： 874 (M + H)＋；
１H-NMR((CDCl３)：δ　 0.73, 1.01-1.06, 1.78-1.88, 2.06-2.13, 2.13-2.23, 2.64, 2.71-2.83, 3.00, 3.14, 3.93-4.17, 4.43-4.45, 4.90, 5.37-5.64, 6.68-6.79, 6.87-7.07, 7.08, 7.12, 7.27-7.33, 7.40-7.48, 7.58-7.66, 7.83-7.92, 8.30, 8.56-8.72。 Example 35-1
3-Fluoro-4-({7-[(5-{2-[(3-fluorophenyl)amino]-6-methyl-8-oxo-9-(1-{[1-(trifluoromethyl)cyclo propyl]methyl}-4-piperidinyl)-8,9-dihydro-7H-purin-7-yl}-2-pyridinyl)carbonyl]-5,6,7,8-tetrahydro-9H-pyrido[4',3 ':4,5]pyrrolo[2,3-b]pyridin-9-yl}methyl)benzonitrile
1-(trifluoromethyl)cyclopropanecarbaldehyde was used in place of pivalaldehyde used in Reference Example 101, and 3-trifluoroaniline was used in place of 4-(trifluoromethoxy)aniline used in Example 35. , Reference Example 101 → The same operation as in Example 35 was performed to obtain the title compound having the following physical property values.
LC-MS (A) retention time (min): 1.12;
MS(ESI, Pos.): 874 (M + H) + ;
1 H-NMR ((CDCl 3 ): δ 0.73, 1.01-1.06, 1.78-1.88, 2.06-2.13, 2.13-2.23, 2.64, 2.71-2.83, 3.00, 3.14, 3.93-4.17, 4.43-4.45, 4.90, 5 .37 -5.64, 6.68-6.79, 6.87-7.07, 7.08, 7.12, 7.27-7.33, 7.40-7.48, 7.58-7.66, 7.83-7.92, 8.30, 8.56-8.72.
実施例３５－２～９
　４－（トリフルオロメトキシ）アニリンの代わりに対応するアニリン化合物を用いて、実施例３５と同様の操作を行い、シリカゲルカラム精製もしくは逆相HPLCカラム精製することにより、また、シリカゲル精製後に塩酸を加えて濃縮することにより、以下の物性値を有する標題化合物を得た。 Examples 35-2 to 9
Using the corresponding aniline compound instead of 4-(trifluoromethoxy)aniline, the same operation as in Example 35 was carried out, and by purifying with a silica gel column or reverse phase HPLC column, or by adding hydrochloric acid after silica gel purification. By concentrating the mixture, the title compound having the following physical properties was obtained.
実施例３５－２
４－［（７－｛［５－（９－［１－（２，２－ジメチルプロピル）－４－ピペリジニル］－２－｛［３，５－ジメチル－１－（２，２，２－トリフルオロエチル）－１Ｈ－ピラゾール－４－イル］アミノ｝－６－メチル－８－オキソ－８，９－ジヒドロ－７Ｈ－プリン－７－イル）－２－ピリジニル］カルボニル｝－５，６，７，８－テトラヒドロ－９Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－９－イル）メチル］－３－フルオロベンゾニトリル
LC－MS（A）保持時間（分）：0.98；
MS(ESI, Pos.)： 904 (M + H)＋；
１H-NMR(CDCl３)：δ　 0.86-0.92, 1.61-1.67, 1.97-2.04, 2.09, 2.19, 2.24, 2.29-2.41, 2.56-2.68, 2.90, 2.95-3.02, 3.89-4.16, 4.18-4.30, 4.59, 4.89, 5.36-5.63, 6.05, 6.85-7.04, 7.12, 7.28-7.36, 7.36-7.47, 7.82-7.92, 8.29, 8.54-8.74。 Example 35-2
4-[(7-{[5-(9-[1-(2,2-dimethylpropyl)-4-piperidinyl]-2-{[3,5-dimethyl-1-(2,2,2-tri- fluoroethyl)-1H-pyrazol-4-yl]amino}-6-methyl-8-oxo-8,9-dihydro-7H-purin-7-yl)-2-pyridinyl]carbonyl}-5,6,7 ,8-tetrahydro-9H-pyrido[4',3':4,5]pyrrolo[2,3-b]pyridin-9-yl)methyl]-3-fluorobenzonitrile
LC-MS (A) retention time (min): 0.98;
MS(ESI, Pos.): 904 (M + H) + ;
1 H-NMR (CDCl 3 ): δ 0.86-0.92, 1.61-1.67, 1.97-2.04, 2.09, 2.19, 2.24, 2.29-2.41, 2.56-2.68, 2.90, 2.95-3.02, 3.89-4.16, 4.18-4.3 0, 4.59, 4.89, 5.36-5.63, 6.05, 6.85-7.04, 7.12, 7.28-7.36, 7.36-7.47, 7.82-7.92, 8.29, 8.54-8.74.
実施例３５－３
４－［（７－｛［５－（９－［１－（２，２－ジメチルプロピル）－４－ピペリジニル］－６－メチル－８－オキソ－２－｛［５－（トリフルオロメトキシ）－２－ピリジニル］アミノ｝－８，９－ジヒドロ－７Ｈ－プリン－７－イル）－２－ピリジニル］カルボニル｝－５，６，７，８－テトラヒドロ－９Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－９－イル）メチル］－３－フルオロベンゾニトリル　３塩酸塩
LC－MS（A）保持時間（分）：1.04；
MS(ESI, Pos.)： 889 (M + H)＋；
１H-NMR (DMSO-d６)：δ　 1.22, 2.12-2.21, 2.94-3.05, 3.11-3.27, 3.29-3.36, 3.38-3.62, 3.76-3.83, 3.83-4.19, 4.65-4.92, 5.01, 5.50-5.91, 7.03-7.13, 7.24-7.30, 7.62-7.76, 7.87-7.93, 7.98-8.25, 8.25-8.51, 8.65-8.95, 9.25-9.90, 10.01-10.50。 Example 35-3
4-[(7-{[5-(9-[1-(2,2-dimethylpropyl)-4-piperidinyl]-6-methyl-8-oxo-2-{[5-(trifluoromethoxy)- 2-pyridinyl]amino}-8,9-dihydro-7H-purin-7-yl)-2-pyridinyl]carbonyl}-5,6,7,8-tetrahydro-9H-pyrido[4',3':4 ,5]pyrrolo[2,3-b]pyridin-9-yl)methyl]-3-fluorobenzonitrile trihydrochloride
LC-MS (A) retention time (min): 1.04;
MS(ESI, Pos.): 889 (M + H) + ;
1 H-NMR (DMSO-d 6 ): δ 1.22, 2.12-2.21, 2.94-3.05, 3.11-3.27, 3.29-3.36, 3.38-3.62, 3.76-3.83, 3.83-4.19, 4.65-4.92, 5.01, 5.50- 5.91, 7.03-7.13, 7.24-7.30, 7.62-7.76, 7.87-7.93, 7.98-8.25, 8.25-8.51, 8.65-8.95, 9.25-9.90, 10.01-10.50.
実施例３５－４
４－（｛７－［（５－｛２－［（２，３－ジメチル－１Ｈ－インドール－５－イル）アミノ］－９－［１－（２，２－ジメチルプロピル）－４－ピペリジニル］－６－メチル－８－オキソ－８，９－ジヒドロ－７Ｈ－プリン－７－イル｝－２－ピリジニル）カルボニル］－５，６，７，８－テトラヒドロ－９Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－９－イル｝メチル）－３－フルオロベンゾニトリル　２トリフルオロ酢酸塩
LC－MS（A）保持時間（分）：1.11；
MS(ESI, Pos.)： 871 (M + H)＋；
１H-NMR(DMSO-d６)：δ　 0.76-1.13, 1.87-2.21, 2.24-2.34, 2.79-3.11, 3.17-3.33, 3.63-3.84, 4.00-4.11, 4.51-4.97, 5.38-5.74, 6.89-7.26, 7.49-7.67, 7.72-8.03, 8.03-8.28, 8.59-8.90, 9.03-9.15, 10.43-10.61。 Example 35-4
4-({7-[(5-{2-[(2,3-dimethyl-1H-indol-5-yl)amino]-9-[1-(2,2-dimethylpropyl)-4-piperidinyl] -6-methyl-8-oxo-8,9-dihydro-7H-purin-7-yl}-2-pyridinyl)carbonyl]-5,6,7,8-tetrahydro-9H-pyrido[4',3' :4,5]pyrrolo[2,3-b]pyridin-9-yl}methyl)-3-fluorobenzonitrile 2 trifluoroacetate
LC-MS (A) retention time (min): 1.11;
MS(ESI, Pos.): 871 (M + H) + ;
1 H-NMR (DMSO-d 6 ): δ 0.76-1.13, 1.87-2.21, 2.24-2.34, 2.79-3.11, 3.17-3.33, 3.63-3.84, 4.00-4.11, 4.51-4.97, 5.38-5.74, 6.89- 7.26, 7.49-7.67, 7.72-8.03, 8.03-8.28, 8.59-8.90, 9.03-9.15, 10.43-10.61.
実施例３５－５
４－［（７－｛［５－（９－［１－（２，２－ジメチルプロピル）－４－ピペリジニル］－２－｛［２－フルオロ－４－（テトラヒドロ－２Ｈ－ピラン－４－イル）フェニル］アミノ｝－６－メチル－８－オキソ－８，９－ジヒドロ－７Ｈ－プリン－７－イル）－２－ピリジニル］カルボニル｝－５，６，７，８－テトラヒドロ－９Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－９－イル）メチル］－３－フルオロベンゾニトリル
LC－MS（A）保持時間（分）：1.08；
MS(ESI, Pos.)： 906 (M + H)＋；
１H-NMR(CDCl３)：δ　 0.97, 1.72-1.84, 2.05-2.13, 2.15, 2.45, 2.67-2.88, 2.93-3.05, 3.46-3.59, 3.93-4.19, 4.32-4.44, 4.90, 5.40-5.64, 6.86-7.15, 7.20-7.24, 7.28-7.33, 7.40-7.47, 7.83-7.92, 8.29, 8.50-8.56, 8.60-8.75。 Example 35-5
4-[(7-{[5-(9-[1-(2,2-dimethylpropyl)-4-piperidinyl]-2-{[2-fluoro-4-(tetrahydro-2H-pyran-4-yl) ) phenyl]amino}-6-methyl-8-oxo-8,9-dihydro-7H-purin-7-yl)-2-pyridinyl]carbonyl}-5,6,7,8-tetrahydro-9H-pyrido[ 4',3':4,5]pyrrolo[2,3-b]pyridin-9-yl)methyl]-3-fluorobenzonitrile
LC-MS (A) retention time (min): 1.08;
MS(ESI, Pos.): 906 (M + H) + ;
1 H-NMR (CDCl 3 ): δ 0.97, 1.72-1.84, 2.05-2.13, 2.15, 2.45, 2.67-2.88, 2.93-3.05, 3.46-3.59, 3.93-4.19, 4.32-4.44, 4.90, 5.40-5.6 4, 6.86-7.15, 7.20-7.24, 7.28-7.33, 7.40-7.47, 7.83-7.92, 8.29, 8.50-8.56, 8.60-8.75.
実施例３５－６
４－［（７－｛［５－（９－［１－（２，２－ジメチルプロピル）－４－ピペリジニル］－６－メチル－２－｛［２－メチル－４－（トリフルオロメトキシ）フェニル］アミノ｝－８－オキソ－８，９－ジヒドロ－７Ｈ－プリン－７－イル）－２－ピリジニル］カルボニル｝－５，６，７，８－テトラヒドロ－９Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－９－イル）メチル］－３－フルオロベンゾニトリル
LC－MS（A）保持時間（分）：1.16；
MS(ESI, Pos.)： 902 (M + H)＋；
１H-NMR (CDCl３)：δ　 0.93, 1.68-1.81, 2.04-2.14, 2.37-2.47, 2.69-2.81, 2.93-3.03, 3.92-4.19, 4.27-4.42, 4.90, 5.38-5.63, 6.79, 6.87-7.07, 7.06-7.20, 7.28-7.32, 7.39-7.48, 7.84-7.92, 8.28-8.33, 8.58-8.73。 Example 35-6
4-[(7-{[5-(9-[1-(2,2-dimethylpropyl)-4-piperidinyl]-6-methyl-2-{[2-methyl-4-(trifluoromethoxy)phenyl ]Amino}-8-oxo-8,9-dihydro-7H-purin-7-yl)-2-pyridinyl]carbonyl}-5,6,7,8-tetrahydro-9H-pyrido[4',3': 4,5]pyrrolo[2,3-b]pyridin-9-yl)methyl]-3-fluorobenzonitrile
LC-MS (A) retention time (min): 1.16;
MS(ESI, Pos.): 902 (M + H) + ;
1 H-NMR (CDCl 3 ): δ 0.93, 1.68-1.81, 2.04-2.14, 2.37-2.47, 2.69-2.81, 2.93-3.03, 3.92-4.19, 4.27-4.42, 4.90, 5.38-5.63, 6.79, 6.8 7- 7.07, 7.06-7.20, 7.28-7.32, 7.39-7.48, 7.84-7.92, 8.28-8.33, 8.58-8.73.
実施例３５－７
４－［（７－｛［５－（２－｛［２－クロロ－４－（トリフルオロメトキシ）フェニル］アミノ｝－９－［１－（２，２－ジメチルプロピル）－４－ピペリジニル］－６－メチル－８－オキソ－８，９－ジヒドロ－７Ｈ－プリン－７－イル）－２－ピリジニル］カルボニル｝－５，６，７，８－テトラヒドロ－９Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－９－イル）メチル］－３－フルオロベンゾニトリル
LC－MS（A）保持時間（分）：1.18；
MS(ESI, Pos.)： 922 (M + H)＋；
１H-NMR(CDCl３)：δ　 0.95, 1.71-1.83, 2.05-2.18, 2.41-2.51, 2.72-2.85, 2.99, 3.90-4.22, 4.33-4.45, 4.85-4.94, 5.37-5.65, 6.87-7.07, 7.13, 7.21-7.25, 7.29-7.34, 7.37-7.48, 7.57, 7.83-7.94, 8.30, 8.58-8.75。 Example 35-7
4-[(7-{[5-(2-{[2-chloro-4-(trifluoromethoxy)phenyl]amino}-9-[1-(2,2-dimethylpropyl)-4-piperidinyl]- 6-Methyl-8-oxo-8,9-dihydro-7H-purin-7-yl)-2-pyridinyl]carbonyl}-5,6,7,8-tetrahydro-9H-pyrido[4',3': 4,5]pyrrolo[2,3-b]pyridin-9-yl)methyl]-3-fluorobenzonitrile
LC-MS (A) retention time (min): 1.18;
MS(ESI, Pos.): 922 (M + H) + ;
1 H-NMR (CDCl 3 ): δ 0.95, 1.71-1.83, 2.05-2.18, 2.41-2.51, 2.72-2.85, 2.99, 3.90-4.22, 4.33-4.45, 4.85-4.94, 5.37-5.65, 6.87-7.07 , 7.13, 7.21-7.25, 7.29-7.34, 7.37-7.48, 7.57, 7.83-7.94, 8.30, 8.58-8.75.
実施例３５－８
４－［（７－｛［５－（９－［１－（２，２－ジメチルプロピル）－４－ピペリジニル］－６－メチル－８－オキソ－２－｛［４－（トリフルオロメトキシ）－２－（トリフルオロメチル）フェニル］アミノ｝－８，９－ジヒドロ－７Ｈ－プリン－７－イル）－２－ピリジニル］カルボニル｝－５，６，７，８－テトラヒドロ－９Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－９－イル）メチル］－３－フルオロベンゾニトリル
LC－MS（A）保持時間（分）：1.19；
MS(ESI, Pos.)： 956 (M + H)＋；
１H-NMR(CDCl３)：δ　 0.93, 1.71-1.80, 2.05-2.14, 2.41-2.49, 2.67-2.79, 2.93-3.02, 3.90-4.22, 4.29-4.44, 4.86-4.92, 5.38-5.65, 6.86-7.07, 7.13, 7.29-7.36, 7.40-7.50, 7.84-7.92, 8.30, 8.58-8.72。 Example 35-8
4-[(7-{[5-(9-[1-(2,2-dimethylpropyl)-4-piperidinyl]-6-methyl-8-oxo-2-{[4-(trifluoromethoxy)- 2-(trifluoromethyl)phenyl]amino}-8,9-dihydro-7H-purin-7-yl)-2-pyridinyl]carbonyl}-5,6,7,8-tetrahydro-9H-pyrido[4',3':4,5]pyrrolo[2,3-b]pyridin-9-yl)methyl]-3-fluorobenzonitrile
LC-MS (A) retention time (min): 1.19;
MS(ESI, Pos.): 956 (M + H) + ;
1 H-NMR (CDCl 3 ): δ 0.93, 1.71-1.80, 2.05-2.14, 2.41-2.49, 2.67-2.79, 2.93-3.02, 3.90-4.22, 4.29-4.44, 4.86-4.92, 5.38-5.65, 6.86 - 7.07, 7.13, 7.29-7.36, 7.40-7.50, 7.84-7.92, 8.30, 8.58-8.72.
実施例３５－９
１－［３－クロロ－４－（｛７－（６－｛［９－（４－シアノ－２－フルオロベンジル）－５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－イル］カルボニル｝－３－ピリジニル）－９－［１－（２，２－ジメチルプロピル）－４－ピペリジニル］－６－メチル－８－オキソ－８，９－ジヒドロ－７Ｈ－プリン－２－イル｝アミノ）フェニル］シクロプロパンカルボン酸
LC－MS（A）保持時間（分）：1.08；
MS(ESI, Pos.)： 922 (M + H)＋；
１H-NMR(CDCl３)：δ　 0.95, 1.23-1.31, 1.64-1.71, 1.71-1.81, 2.05-2.13, 2.16, 2.41-2.53, 2.73-2.87, 2.95-3.03, 3.90-4.19, 4.32-4.44, 4.90, 5.36-5.63, 6.86-7.07, 7.12, 7.29-7.46, 7.61, 7.83-7.93, 8.30, 8.60-8.73。 Example 35-9
1-[3-chloro-4-({7-(6-{[9-(4-cyano-2-fluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3' :4,5]pyrrolo[2,3-b]pyridin-7-yl]carbonyl}-3-pyridinyl)-9-[1-(2,2-dimethylpropyl)-4-piperidinyl]-6-methyl- 8-oxo-8,9-dihydro-7H-purin-2-yl}amino)phenyl]cyclopropanecarboxylic acid
LC-MS (A) retention time (min): 1.08;
MS(ESI, Pos.): 922 (M + H) + ;
1 H-NMR (CDCl 3 ): δ 0.95, 1.23-1.31, 1.64-1.71, 1.71-1.81, 2.05-2.13, 2.16, 2.41-2.53, 2.73-2.87, 2.95-3.03, 3.90-4.19, 4.32-4.44 , 4.90, 5.36-5.63, 6.86-7.07, 7.12, 7.29-7.46, 7.61, 7.83-7.93, 8.30, 8.60-8.73.
実施例３６
（｛７－（６－｛［９－（４－シアノ－２－フルオロベンジル）－５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－イル］カルボニル｝－３－ピリジニル）－９－［１－（２，２－ジメチルプロピル）－４－ピペリジニル］－６－メチル－８－オキソ－８，９－ジヒドロ－７Ｈ－プリン－２－イル｝［４－（トリフルオロメトキシ）フェニル］アミノ）酢酸
　参考例１０１で製造した化合物（50ｍｇ）にトルエン（1.0ｍＬ）を加えて、エチル｛［４－（トリフルオロメトキシ）フェニル］アミノ｝アセテート（44ｍｇ）及び炭酸セシウム（87ｍｇ）、Xantphos（7.7ｍｇ）、酢酸パラジウム（1.5ｍｇ）を加え、窒素雰囲気で１２０℃で３０分攪拌した。反応液を室温に冷却した後、酢酸エチルで希釈し、セライト（商品名）に通して濃縮した。残渣をシリカゲルクロマトグラフィー（富士シリシア　ＮＨ（商品名）、ヘキサン：酢酸エチル＝３：２→１：４）で精製した。得られた化合物をＴＨＦ（2ｍＬ）に溶解し、ＴＭＳＯＫ（16ｍｇ）を加えて室温で１６時間と、さらに４０℃で３時間攪拌した。反応液を室温に冷却し、２Ｎ塩酸を加えて酢酸エチルで抽出した。得られた有機層を硫酸マグネシウムで乾燥し、減圧濃縮して得られた残渣をプレパラティブＴＬＣ（ジクロロメタン：メタノール＝９：１）で精製することにより、以下の物性値を有する標題化合物（12ｍｇ）を得た。
LC－MS（A）保持時間（分）：1.13；
MS(ESI, Pos.)： 946 (M + H)＋；
１H-NMR(CD３OD)：δ　 1.01, 1.71-1.87, 1.91-2.00, 2.35-2.55, 2.57-2.77, 2.78-2.93, 2.98, 3.08-3.28, 3.83-4.18, 4.25-4.42, 4.42-4.52, 4.71-4.97, 5.41-5.71, 6.79-6.90, 7.16, 7.24, 7.32-7.47, 7.53-7.66, 7.73-7.88, 7.94-8.11, 8.20, 8.52-8.79。 Example 36
({7-(6-{[9-(4-cyano-2-fluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[2, 3-b]pyridin-7-yl]carbonyl}-3-pyridinyl)-9-[1-(2,2-dimethylpropyl)-4-piperidinyl]-6-methyl-8-oxo-8,9-dihydro -7H-purin-2-yl}[4-(trifluoromethoxy)phenyl]amino)acetic acid To the compound (50 mg) prepared in Reference Example 101 was added toluene (1.0 mL), and ethyl {[4-(trifluoro methoxy)phenyl]amino}acetate (44 mg), cesium carbonate (87 mg), Xantphos (7.7 mg), and palladium acetate (1.5 mg) were added, and the mixture was stirred at 120° C. for 30 minutes in a nitrogen atmosphere. After the reaction solution was cooled to room temperature, it was diluted with ethyl acetate, passed through Celite (trade name), and concentrated. The residue was purified by silica gel chromatography (Fuji Silysia NH (trade name), hexane:ethyl acetate = 3:2→1:4). The obtained compound was dissolved in THF (2 mL), TMSOK (16 mg) was added, and the mixture was stirred at room temperature for 16 hours and further at 40°C for 3 hours. The reaction solution was cooled to room temperature, 2N hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The obtained organic layer was dried over magnesium sulfate, concentrated under reduced pressure, and the resulting residue was purified by preparative TLC (dichloromethane:methanol = 9:1) to obtain the title compound (12 mg) having the following physical properties. I got it.
LC-MS (A) retention time (min): 1.13;
MS(ESI, Pos.): 946 (M + H) + ;
1 H-NMR (CD 3 OD): δ 1.01, 1.71-1.87, 1.91-2.00, 2.35-2.55, 2.57-2.77, 2.78-2.93, 2.98, 3.08-3.28, 3.83-4.18, 4.25-4.42, 4.42-4.5 2 , 4.71-4.97, 5.41-5.71, 6.79-6.90, 7.16, 7.24, 7.32-7.47, 7.53-7.66, 7.73-7.88, 7.94-8.11, 8.20, 8.52-8.79.
実施例３７
２－（３－｛７－（６－｛［９－（４－シアノ－２－フルオロベンジル）－５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－イル］カルボニル｝－３－ピリジニル）－９－［１－（２，２－ジメチルプロピル）－４－ピペリジニル］－６－メチル－８－オキソ－８，９－ジヒドロ－７Ｈ－プリン－２－イル｝フェニル）－２－メチルプロパン酸
　参考例１０１で製造した化合物（50ｍｇ）をＮＭＰ（0.5ｍＬ）に溶解し、２－メチル－２－［３－（４，４，５，５－テトラメチル－１，３，２－ジオキサボロラン－２－イル）フェニル］プロパンカルボン酸（58ｍｇ）、リン酸三カリウム水溶液（0.1ｍＬ、2mol/L）、［１，１’－ビス（ジフェニルホスフィノ）フェロセン］パラジウム（ＩＩ）ジクロリド　ジクロロメタン錯体（11ｍｇ）を加えてマイクロウェーブ装置を用いて１４０℃で５０分攪拌した。反応液を室温に冷却して酢酸エチルで希釈して水を加えた。酢酸エチルで抽出し、得られた有機層を水で洗浄した。無水硫酸ナトリウムで乾燥後、減圧濃縮して得られた残渣をプレパラティブＴＬＣ（ジクロロメタン：メタノール：アンモニア水＝２０：５：１）で精製することにより、以下の物性値を有する標題化合物（26ｍｇ）を得た。
LC－MS（A）保持時間（分）：1.07；
MS(ESI, Pos.)： 875 (M + H)＋；
１H-NMR(CDCl３)：δ　 0.92-0.99, 1.75-1.90, 2.20, 2.43-2.55, 2.91-3.03, 3.04-3.14, 3.93-4.16, 4.40-4.55, 4.90, 5.39-5.63, 6.88-7.08, 7.12, 7.27-7.33, 7.40-7.52, 7.84-7.94, 8.26-8.31, 8.58-8.75。 Example 37
2-(3-{7-(6-{[9-(4-cyano-2-fluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5] pyrrolo[2,3-b]pyridin-7-yl]carbonyl}-3-pyridinyl)-9-[1-(2,2-dimethylpropyl)-4-piperidinyl]-6-methyl-8-oxo-8 ,9-dihydro-7H-purin-2-yl}phenyl)-2-methylpropanoic acid
The compound (50 mg) produced in Reference Example 101 was dissolved in NMP (0.5 mL), and 2-methyl-2-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2) was dissolved in NMP (0.5 mL). -yl)phenyl]propanecarboxylic acid (58mg), tripotassium phosphate aqueous solution (0.1mL, 2mol/L), [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane complex (11mg) was added and stirred for 50 minutes at 140°C using a microwave device. The reaction solution was cooled to room temperature, diluted with ethyl acetate, and water was added. Extraction was performed with ethyl acetate, and the resulting organic layer was washed with water. After drying over anhydrous sodium sulfate, the residue obtained by concentration under reduced pressure was purified by preparative TLC (dichloromethane: methanol: aqueous ammonia = 20:5:1) to obtain the title compound (26 mg) having the following physical properties. I got it.
LC-MS (A) retention time (min): 1.07;
MS(ESI, Pos.): 875 (M + H) + ;
1 H-NMR (CDCl 3 ): δ 0.92-0.99, 1.75-1.90, 2.20, 2.43-2.55, 2.91-3.03, 3.04-3.14, 3.93-4.16, 4.40-4.55, 4.90, 5.39-5.63, 6.88-7.08 , 7.12, 7.27-7.33, 7.40-7.52, 7.84-7.94, 8.26-8.31, 8.58-8.75.
実施例３７－１～１７
　２－メチル－２－［３－（４，４，５，５－テトラメチル－１，３，２－ジオキサボロラン－２－イル）フェニル］プロパンカルボン酸の代わりに対応するボロン酸化合物を用いて、実施例３７と同様の操作を行い、シリカゲルカラム精製もしくは逆相HPLCカラム精製することにより、以下の物性値を有する標題化合物を得た。 Examples 37-1 to 17
Using the corresponding boronic acid compound in place of 2-methyl-2-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propanecarboxylic acid, The same operation as in Example 37 was performed, and the title compound having the following physical property values was obtained by purifying with a silica gel column or a reverse phase HPLC column.
実施例３７－１
４－（｛７－［（５－｛９－［１－（２，２－ジメチルプロピル）－４－ピペリジニル］－２－［２－メトキシ－５－（トリフルオロメトキシ）フェニル］－６－メチル－８－オキソ－８，９－ジヒドロ－７Ｈ－プリン－７－イル｝－２－ピリジニル）カルボニル］－５，６，７，８－テトラヒドロ－９Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－９－イル｝メチル）－３－フルオロベンゾニトリル　２トリフルオロ酢酸塩
LC－MS（A）保持時間（分）：1.14；
MS(ESI, Pos.)： 903 (M + H)＋；
１H-NMR(DMSO-d６)：δ　 0.94-1.12, 1.87-2.19, 2.85-3.06, 3.10-3.24, 3.46-3.58, 3.63-3.87, 4.00-4.10, 4.32-4.43, 4.62-4.98, 5.39-5.71, 6.93-7.21, 7.21-7.38, 7.39-7.67, 7.70-8.02, 8.12-8.29, 8.49-8.60, 8.60-8.76, 8.85-9.05。 Example 37-1
4-({7-[(5-{9-[1-(2,2-dimethylpropyl)-4-piperidinyl]-2-[2-methoxy-5-(trifluoromethoxy)phenyl]-6-methyl -8-oxo-8,9-dihydro-7H-purin-7-yl}-2-pyridinyl)carbonyl]-5,6,7,8-tetrahydro-9H-pyrido[4',3':4,5 ]pyrrolo[2,3-b]pyridin-9-yl}methyl)-3-fluorobenzonitrile 2-trifluoroacetate
LC-MS (A) retention time (min): 1.14;
MS(ESI, Pos.): 903 (M + H) + ;
1 H-NMR (DMSO-d 6 ): δ 0.94-1.12, 1.87-2.19, 2.85-3.06, 3.10-3.24, 3.46-3.58, 3.63-3.87, 4.00-4.10, 4.32-4.43, 4.62-4.98, 5.39- 5.71, 6.93-7.21, 7.21-7.38, 7.39-7.67, 7.70-8.02, 8.12-8.29, 8.49-8.60, 8.60-8.76, 8.85-9.05.
実施例３７－２
４－（｛７－［（５－｛２－（２，３－ジヒドロ－１Ｈ－インデン－４－イル）－９－［１－（２，２－ジメチルプロピル）－４－ピペリジニル］－６－メチル－８－オキソ－８，９－ジヒドロ－７Ｈ－プリン－７－イル｝－２－ピリジニル）カルボニル］－５，６，７，８－テトラヒドロ－９Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－９－イル｝メチル）－３－フルオロベンゾニトリル　２トリフルオロ酢酸塩
LC－MS（A）保持時間（分）：1.08；
MS(ESI, Pos.)： 829 (M + H)＋；
１H-NMR(DMSO-d６)：δ　 1.04-1.14, 1.98-2.22, 2.86-3.15, 3.49-3.60, 3.67-3.82, 4.02-4.10, 4.96, 5.34-5.73, 6.95-7.06, 7.12-7.19, 7.22-7.41, 7.48-7.67, 7.75-7.87, 7.89-8.02, 8.02-8.08, 8.12-8.28, 8.63-8.75, 8.83-8.99。 Example 37-2
4-({7-[(5-{2-(2,3-dihydro-1H-inden-4-yl)-9-[1-(2,2-dimethylpropyl)-4-piperidinyl]-6- Methyl-8-oxo-8,9-dihydro-7H-purin-7-yl}-2-pyridinyl)carbonyl]-5,6,7,8-tetrahydro-9H-pyrido[4',3':4, 5] Pyrrolo[2,3-b]pyridin-9-yl}methyl)-3-fluorobenzonitrile 2 trifluoroacetate
LC-MS (A) retention time (min): 1.08;
MS(ESI, Pos.): 829 (M + H) + ;
1 H-NMR (DMSO-d 6 ): δ 1.04-1.14, 1.98-2.22, 2.86-3.15, 3.49-3.60, 3.67-3.82, 4.02-4.10, 4.96, 5.34-5.73, 6.95-7.06, 7.12-7.19, 7.22-7.41, 7.48-7.67, 7.75-7.87, 7.89-8.02, 8.02-8.08, 8.12-8.28, 8.63-8.75, 8.83-8.99.
実施例３７－３
４－（｛７－［（５－｛９－［１－（２，２－ジメチルプロピル）－４－ピペリジニル］－６－メチル－２－［２－メチル－４－（トリフルオロメトキシ）フェニル］－８－オキソ－８，９－ジヒドロ－７Ｈ－プリン－７－イル｝－２－ピリジニル）カルボニル］－５，６，７，８－テトラヒドロ－９Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－９－イル｝メチル）－３－フルオロベンゾニトリル
LC－MS（A）保持時間（分）：1.19；
MS(ESI, Pos.)： 887 (M + H)＋；
１H-NMR (CDCl３)：δ　 0.90, 1.70-1.83, 2.13, 2.21-2.27, 2.42-2.51, 2.70-2.73, 2.78-2.91, 2.93-3.05, 3.92-4.24, 4.39-4.56, 4.87-4.97, 5.41-5.63, 6.88-7.08, 7.11-7.19, 7.27-7.33, 7.39-7.49, 7.82-7.88, 7.91-8.03, 8.30, 8.62-8.78。 Example 37-3
4-({7-[(5-{9-[1-(2,2-dimethylpropyl)-4-piperidinyl]-6-methyl-2-[2-methyl-4-(trifluoromethoxy)phenyl] -8-oxo-8,9-dihydro-7H-purin-7-yl}-2-pyridinyl)carbonyl]-5,6,7,8-tetrahydro-9H-pyrido[4',3':4,5 ]pyrrolo[2,3-b]pyridin-9-yl}methyl)-3-fluorobenzonitrile
LC-MS (A) retention time (min): 1.19;
MS(ESI, Pos.): 887 (M + H) + ;
1 H-NMR (CDCl 3 ): δ 0.90, 1.70-1.83, 2.13, 2.21-2.27, 2.42-2.51, 2.70-2.73, 2.78-2.91, 2.93-3.05, 3.92-4.24, 4.39-4.56, 4.87-4.97 , 5.41-5.63, 6.88-7.08, 7.11-7.19, 7.27-7.33, 7.39-7.49, 7.82-7.88, 7.91-8.03, 8.30, 8.62-8.78.
実施例３７－４
４－（｛７－［（５－｛９－［１－（２，２－ジメチルプロピル）－４－ピペリジニル］－２－［４－（１－ヒドロキシシクロブチル）フェニル］－６－メチル－８－オキソ－８，９－ジヒドロ－７Ｈ－プリン－７－イル｝－２－ピリジニル）カルボニル］－５，６，７，８－テトラヒドロ－９Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－９－イル｝メチル）－３－フルオロベンゾニトリル
LC－MS（A）保持時間（分）：1.06；
MS(ESI, Pos.)： 859 (M + H)＋；
１H-NMR(CDCl３)：δ　 0.92-0.98, 1.70-1.83, 2.00-2.11, 2.18-2.27, 2.39-2.66, 2.83-3.06, 3.90-4.21, 4.45-4.57, 4.91, 5.40-5.64, 6.87-7.09, 7.13, 7.27-7.33, 7.40-7.48, 7.63, 7.84-7.97, 8.30, 8.48, 8.62-8.78。 Example 37-4
4-({7-[(5-{9-[1-(2,2-dimethylpropyl)-4-piperidinyl]-2-[4-(1-hydroxycyclobutyl)phenyl]-6-methyl-8 -oxo-8,9-dihydro-7H-purin-7-yl}-2-pyridinyl)carbonyl]-5,6,7,8-tetrahydro-9H-pyrido[4',3':4,5]pyrrolo [2,3-b]pyridin-9-yl}methyl)-3-fluorobenzonitrile
LC-MS (A) retention time (min): 1.06;
MS(ESI, Pos.): 859 (M + H) + ;
1 H-NMR (CDCl 3 ): δ 0.92-0.98, 1.70-1.83, 2.00-2.11, 2.18-2.27, 2.39-2.66, 2.83-3.06, 3.90-4.21, 4.45-4.57, 4.91, 5.40-5.64, 6.87 - 7.09, 7.13, 7.27-7.33, 7.40-7.48, 7.63, 7.84-7.97, 8.30, 8.48, 8.62-8.78.
実施例３７－５
４－（｛７－［（５－｛９－［１－（２，２－ジメチルプロピル）－４－ピペリジニル］－２－［４－フルオロ－２－（トリフルオロメトキシ）フェニル］－６－メチル－８－オキソ－８，９－ジヒドロ－７Ｈ－プリン－７－イル｝－２－ピリジニル）カルボニル］－５，６，７，８－テトラヒドロ－９Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－９－イル｝メチル）－３－フルオロベンゾニトリル
LC－MS（A）保持時間（分）：1.26；
MS(ESI, Pos.)： 891 (M + H)＋；
１H-NMR (CDCl３)：δ　 0.87-0.95, 1.69-1.84, 2.13-2.19, 2.21-2.28, 2.41-2.54, 2.78-2.93, 2.92-3.04, 3.92-4.22, 4.42-4.53, 4.91, 5.39-5.64, 6.88-7.08, 7.08-7.17, 7.27-7.33, 7.41-7.48, 7.84-7.97, 8.15-8.21, 8.30, 8.61-8.77。 Example 37-5
4-({7-[(5-{9-[1-(2,2-dimethylpropyl)-4-piperidinyl]-2-[4-fluoro-2-(trifluoromethoxy)phenyl]-6-methyl -8-oxo-8,9-dihydro-7H-purin-7-yl}-2-pyridinyl)carbonyl]-5,6,7,8-tetrahydro-9H-pyrido[4',3':4,5 ]pyrrolo[2,3-b]pyridin-9-yl}methyl)-3-fluorobenzonitrile
LC-MS (A) retention time (min): 1.26;
MS(ESI, Pos.): 891 (M + H) + ;
1 H-NMR (CDCl 3 ): δ 0.87-0.95, 1.69-1.84, 2.13-2.19, 2.21-2.28, 2.41-2.54, 2.78-2.93, 2.92-3.04, 3.92-4.22, 4.42-4.53, 4.91, 5.39 - 5.64, 6.88-7.08, 7.08-7.17, 7.27-7.33, 7.41-7.48, 7.84-7.97, 8.15-8.21, 8.30, 8.61-8.77.
実施例３７－６
１－（４－｛７－（６－｛［９－（４－シアノ－２－フルオロベンジル）－５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－イル］カルボニル｝－３－ピリジニル）－９－［１－（２，２－ジメチルプロピル）－４－ピペリジニル］－６－メチル－８－オキソ－８，９－ジヒドロ－７Ｈ－プリン－２－イル｝フェニル）シクロプロパンカルボン酸
LC－MS（A）保持時間（分）：1.06；
MS(ESI, Pos.)： 873 (M + H)＋；
１H-NMR(CDCl３)：δ　 0.94, 1.17-1.29, 1.68-1.81, 2.14-2.27, 2.51, 2.84-3.04, 3.89-4.24, 4.38-4.61, 4.89, 5.33-5.66, 6.82-7.08, 7.12, 7.21-7.33, 7.39-7.49, 7.82-7.96, 8.30, 8.39, 8.60-8.77。 Example 37-6
1-(4-{7-(6-{[9-(4-cyano-2-fluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5] pyrrolo[2,3-b]pyridin-7-yl]carbonyl}-3-pyridinyl)-9-[1-(2,2-dimethylpropyl)-4-piperidinyl]-6-methyl-8-oxo-8 ,9-dihydro-7H-purin-2-yl}phenyl)cyclopropanecarboxylic acid
LC-MS (A) retention time (min): 1.06;
MS(ESI, Pos.): 873 (M + H) + ;
1 H-NMR (CDCl 3 ): δ 0.94, 1.17-1.29, 1.68-1.81, 2.14-2.27, 2.51, 2.84-3.04, 3.89-4.24, 4.38-4.61, 4.89, 5.33-5.66, 6.82-7.08, 7.1 2, 7.21-7.33, 7.39-7.49, 7.82-7.96, 8.30, 8.39, 8.60-8.77.
実施例３７－７
（５－｛７－（６－｛［９－（４－シアノ－２－フルオロベンジル）－５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－イル］カルボニル｝－３－ピリジニル）－９－［１－（２，２－ジメチルプロピル）－４－ピペリジニル］－６－メチル－８－オキソ－８，９－ジヒドロ－７Ｈ－プリン－２－イル｝－２－メトキシフェニル）酢酸
LC－MS（A）保持時間（分）：1.04；
MS(ESI, Pos.)： 877 (M + H)＋；
１H-NMR(CDCl３)：δ　 0.94, 1.70-1.82, 2.06-2.25, 2.43-2.58, 2.82-3.07, 3.74, 3.89, 3.93-4.23, 4.38-4.57, 4.90, 5.38-5.68, 6.87-7.08, 7.09-7.15, 7.27-7.34, 7.38-7.49, 7.83-7.94, 8.28-8.40, 8.54-8.78。 Example 37-7
(5-{7-(6-{[9-(4-cyano-2-fluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[ 2,3-b]pyridin-7-yl]carbonyl}-3-pyridinyl)-9-[1-(2,2-dimethylpropyl)-4-piperidinyl]-6-methyl-8-oxo-8,9 -dihydro-7H-purin-2-yl}-2-methoxyphenyl)acetic acid
LC-MS (A) retention time (min): 1.04;
MS(ESI, Pos.): 877 (M + H) + ;
1 H-NMR (CDCl 3 ): δ 0.94, 1.70-1.82, 2.06-2.25, 2.43-2.58, 2.82-3.07, 3.74, 3.89, 3.93-4.23, 4.38-4.57, 4.90, 5.38-5.68, 6.87-7.0 8, 7.09-7.15, 7.27-7.34, 7.38-7.49, 7.83-7.94, 8.28-8.40, 8.54-8.78.
実施例３７－８
１－（３－｛７－（６－｛［９－（４－シアノ－２－フルオロベンジル）－５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－イル］カルボニル｝－３－ピリジニル）－９－［１－（２，２－ジメチルプロピル）－４－ピペリジニル］－６－メチル－８－オキソ－８，９－ジヒドロ－７Ｈ－プリン－２－イル｝フェニル）シクロプロパンカルボン酸
LC－MS（A）保持時間（分）：1.05；
MS(ESI, Pos.)： 873 (M + H)＋；
１H-NMR (DMSO-d６)：δ　 0.93, 1.18-1.23, 1.47-1.57, 1.71-1.83, 2.06-2.21, 2.42-2.48, 2.73-3.01, 3.70-4.09, 4.27-4.42, 4.70-4.94, 5.37-5.71, 6.99, 7.15, 7.41-7.49, 7.52-7.64, 7.74-8.01, 8.15-8.35, 8.65-8.90, 12.19-12.69。 Example 37-8
1-(3-{7-(6-{[9-(4-cyano-2-fluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5] pyrrolo[2,3-b]pyridin-7-yl]carbonyl}-3-pyridinyl)-9-[1-(2,2-dimethylpropyl)-4-piperidinyl]-6-methyl-8-oxo-8 ,9-dihydro-7H-purin-2-yl}phenyl)cyclopropanecarboxylic acid
LC-MS (A) retention time (min): 1.05;
MS(ESI, Pos.): 873 (M + H) + ;
1 H-NMR (DMSO-d 6 ): δ 0.93, 1.18-1.23, 1.47-1.57, 1.71-1.83, 2.06-2.21, 2.42-2.48, 2.73-3.01, 3.70-4.09, 4.27-4.42, 4.70-4.94, 5.37-5.71, 6.99, 7.15, 7.41-7.49, 7.52-7.64, 7.74-8.01, 8.15-8.35, 8.65-8.90, 12.19-12.69.
実施例３７－９
６－｛７－（６－｛［９－（４－シアノ－２－フルオロベンジル）－５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－イル］カルボニル｝－３－ピリジニル）－９－［１－（２，２－ジメチルプロピル）－４－ピペリジニル］－６－メチル－８－オキソ－８，９－ジヒドロ－７Ｈ－プリン－２－イル｝－１－インダンカルボン酸
LC－MS（A）保持時間（分）：1.03；
MS(ESI, Pos.)： 873 (M + H)＋；
１H-NMR(CDCl３)：δ　 0.97, 1.73-1.88, 2.16-2.30, 2.32-2.70, 2.88-3.08, 3.10-3.26, 3.93-4.27, 4.43-4.61, 4.90, 5.36-5.64, 6.83-7.09, 7.09-7.16, 7.28-7.36, 7.39-7.46, 7.83-7.95, 8.26-8.37, 8.44-8.59, 8.58-8.78。 Example 37-9
6-{7-(6-{[9-(4-cyano-2-fluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[2 ,3-b]pyridin-7-yl]carbonyl}-3-pyridinyl)-9-[1-(2,2-dimethylpropyl)-4-piperidinyl]-6-methyl-8-oxo-8,9- Dihydro-7H-purin-2-yl}-1-indanecarboxylic acid
LC-MS (A) retention time (min): 1.03;
MS(ESI, Pos.): 873 (M + H) + ;
1 H-NMR (CDCl 3 ): δ 0.97, 1.73-1.88, 2.16-2.30, 2.32-2.70, 2.88-3.08, 3.10-3.26, 3.93-4.27, 4.43-4.61, 4.90, 5.36-5.64, 6.83-7.09 , 7.09-7.16, 7.28-7.36, 7.39-7.46, 7.83-7.95, 8.26-8.37, 8.44-8.59, 8.58-8.78.
実施例３７－１０
１－（４－｛７－（６－｛［９－（４－シアノ－２－フルオロベンジル）－５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－イル］カルボニル｝－３－ピリジニル）－９－［１－（２，２－ジメチルプロピル）－４－ピペリジニル］－６－メチル－８－オキソ－８，９－ジヒドロ－７Ｈ－プリン－２－イル｝－２－フルオロフェニル）シクロプロパンカルボン酸　２トリフルオロ酢酸塩
LC－MS（A）保持時間（分）：1.04；
MS(ESI, Pos.)： 891 (M + H)＋；
１H-NMR(DMSO-d６)：δ　 1.07-1.16, 1.16-1.29, 1.49-1.59, 1.97-2.13, 2.15-2.20, 2.82-2.94, 2.94-3.22, 3.32-3.62, 4.02-4.11, 4.70-5.00, 5.34-5.76, 6.96-7.08, 7.10-7.20, 7.38-7.53, 7.53-7.68, 7.73-7.88, 7.88-8.01, 8.03-8.13, 8.13-8.28, 8.61-9.08。 Example 37-10
1-(4-{7-(6-{[9-(4-cyano-2-fluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5] pyrrolo[2,3-b]pyridin-7-yl]carbonyl}-3-pyridinyl)-9-[1-(2,2-dimethylpropyl)-4-piperidinyl]-6-methyl-8-oxo-8 ,9-dihydro-7H-purin-2-yl}-2-fluorophenyl)cyclopropanecarboxylic acid 2-trifluoroacetate
LC-MS (A) retention time (min): 1.04;
MS(ESI, Pos.): 891 (M + H) + ;
1 H-NMR (DMSO-d 6 ): δ 1.07-1.16, 1.16-1.29, 1.49-1.59, 1.97-2.13, 2.15-2.20, 2.82-2.94, 2.94-3.22, 3.32-3.62, 4.02-4.11, 4.70- 5.00, 5.34-5.76, 6.96-7.08, 7.10-7.20, 7.38-7.53, 7.53-7.68, 7.73-7.88, 7.88-8.01, 8.03-8.13, 8.13-8.28, 8.61-9.08.
実施例３７－１１
４－（｛７－［（５－｛９－［１－（２，２－ジメチルプロピル）－４－ピペリジニル］－２－［４－（２－ヒドロキシ－２－プロパニル）フェニル］－６－メチル－８－オキソ－８，９－ジヒドロ－７Ｈ－プリン－７－イル｝－２－ピリジニル）カルボニル］－５，６，７，８－テトラヒドロ－９Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－９－イル｝メチル）－３－フルオロベンゾニトリル
LC－MS（A）保持時間（分）：1.05；
MS(ESI, Pos.)： 847 (M + H)＋；
１H-NMR(CDCl３)：δ　 0.94-0.96, 1.64, 1.71-1.82, 2.18-2.27, 2.45-2.60, 2.84-3.07, 3.93-4.24, 4.39-4.59, 4.91, 5.39-5.66, 6.85-7.08, 7.08-7.17, 7.29-7.32, 7.39-7.49, 7.61, 7.81-7.99, 8.30, 8.44, 8.60-8.78。 Example 37-11
4-({7-[(5-{9-[1-(2,2-dimethylpropyl)-4-piperidinyl]-2-[4-(2-hydroxy-2-propanyl)phenyl]-6-methyl -8-oxo-8,9-dihydro-7H-purin-7-yl}-2-pyridinyl)carbonyl]-5,6,7,8-tetrahydro-9H-pyrido[4',3':4,5 ]pyrrolo[2,3-b]pyridin-9-yl}methyl)-3-fluorobenzonitrile
LC-MS (A) retention time (min): 1.05;
MS(ESI, Pos.): 847 (M + H) + ;
1 H-NMR (CDCl 3 ): δ 0.94-0.96, 1.64, 1.71-1.82, 2.18-2.27, 2.45-2.60, 2.84-3.07, 3.93-4.24, 4.39-4.59, 4.91, 5.39-5.66, 6.85-7.08 , 7.08-7.17, 7.29-7.32, 7.39-7.49, 7.61, 7.81-7.99, 8.30, 8.44, 8.60-8.78.
実施例３７－１２
４－（｛７－［（５－｛９－［１－（２，２－ジメチルプロピル）－４－ピペリジニル］－２－［４－（１，１，１，３，３，３－ヘキサフルオロ－２－ヒドロキシ－２－プロパニル）フェニル］－６－メチル－８－オキソ－８，９－ジヒドロ－７Ｈ－プリン－７－イル｝－２－ピリジニル）カルボニル］－５，６，７，８－テトラヒドロ－９Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－９－イル｝メチル）－３－フルオロベンゾニトリル
LC－MS（A）保持時間（分）：1.12；
MS(ESI, Pos.)： 955 (M + H)＋；
１H-NMR(CDCl３)：δ　 0.93-0.97, 1.73-1.83, 2.19-2.27, 2.52, 2.84-2.97, 2.82-3.06, 3.63-3.76, 3.92-4.20, 4.46-4.57, 4.91, 5.40-5.64, 6.85-7.09, 7.13, 7.27-7.32, 7.38-7.48, 7.71, 7.81-7.97, 8.30, 8.55, 8.62-8.78。 Example 37-12
4-({7-[(5-{9-[1-(2,2-dimethylpropyl)-4-piperidinyl]-2-[4-(1,1,1,3,3,3-hexafluoro -2-hydroxy-2-propanyl)phenyl]-6-methyl-8-oxo-8,9-dihydro-7H-purin-7-yl}-2-pyridinyl)carbonyl]-5,6,7,8- Tetrahydro-9H-pyrido[4',3':4,5]pyrrolo[2,3-b]pyridin-9-yl}methyl)-3-fluorobenzonitrile
LC-MS (A) retention time (min): 1.12;
MS(ESI, Pos.): 955 (M + H) + ;
1 H-NMR (CDCl 3 ): δ 0.93-0.97, 1.73-1.83, 2.19-2.27, 2.52, 2.84-2.97, 2.82-3.06, 3.63-3.76, 3.92-4.20, 4.46-4.57, 4.91, 5.40-5.64 , 6.85-7.09, 7.13, 7.27-7.32, 7.38-7.48, 7.71, 7.81-7.97, 8.30, 8.55, 8.62-8.78.
実施例３７－１３
１－（３－｛７－（６－｛［９－（４－シアノ－２－フルオロベンジル）－５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－イル］カルボニル｝－３－ピリジニル）－９－［１－（２，２－ジメチルプロピル）－４－ピペリジニル］－６－メチル－８－オキソ－８，９－ジヒドロ－７Ｈ－プリン－２－イル｝フェニル）シクロブタンカルボン酸
LC－MS（A）保持時間（分）：1.09；
MS(ESI, Pos.)： 887 (M + H)＋；
１H-NMR(CDCl３)：δ　 0.94, 1.73-1.86, 2.10-2.17, 2.18-2.28, 2.44-2.58, 2.61-2.70, 2.89-3.06, 3.92-4.21, 4.40-4.54, 4.90, 5.38-5.63, 6.85-7.07, 7.13, 7.25-7.34, 7.40-7.49, 7.84-7.94, 8.29-8.36, 8.46, 8.60-8.77。 Example 37-13
1-(3-{7-(6-{[9-(4-cyano-2-fluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5] pyrrolo[2,3-b]pyridin-7-yl]carbonyl}-3-pyridinyl)-9-[1-(2,2-dimethylpropyl)-4-piperidinyl]-6-methyl-8-oxo-8 ,9-dihydro-7H-purin-2-yl}phenyl)cyclobutanecarboxylic acid
LC-MS (A) retention time (min): 1.09;
MS(ESI, Pos.): 887 (M + H) + ;
1 H-NMR (CDCl 3 ): δ 0.94, 1.73-1.86, 2.10-2.17, 2.18-2.28, 2.44-2.58, 2.61-2.70, 2.89-3.06, 3.92-4.21, 4.40-4.54, 4.90, 5.38-5.63 , 6.85-7.07, 7.13, 7.25-7.34, 7.40-7.49, 7.84-7.94, 8.29-8.36, 8.46, 8.60-8.77.
実施例３７－１４
１－（５－｛７－（６－｛［９－（４－シアノ－２－フルオロベンジル）－５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－イル］カルボニル｝－３－ピリジニル）－９－［１－（２，２－ジメチルプロピル）－４－ピペリジニル］－６－メチル－８－オキソ－８，９－ジヒドロ－７Ｈ－プリン－２－イル｝－２－メトキシフェニル）シクロプロパンカルボン酸
LC－MS（A）保持時間（分）：1.08；
MS(ESI, Pos.)： 903 (M + H)＋；
１H-NMR(CDCl３)：δ　 0.94, 1.28-1.32, 1.70-1.82, 2.16-2.25, 2.44-2.55, 2.84-3.06, 3.94, 3.95-4.21, 4.39-4.53, 4.90, 5.39-5.64, 6.87-7.09, 7.13, 7.28-7.33, 7.40-7.48, 7.84-7.96, 8.28-8.35, 8.41, 8.61-8.77。 Example 37-14
1-(5-{7-(6-{[9-(4-cyano-2-fluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5] pyrrolo[2,3-b]pyridin-7-yl]carbonyl}-3-pyridinyl)-9-[1-(2,2-dimethylpropyl)-4-piperidinyl]-6-methyl-8-oxo-8 ,9-dihydro-7H-purin-2-yl}-2-methoxyphenyl)cyclopropanecarboxylic acid
LC-MS (A) retention time (min): 1.08;
MS(ESI, Pos.): 903 (M + H) + ;
1 H-NMR (CDCl 3 ): δ 0.94, 1.28-1.32, 1.70-1.82, 2.16-2.25, 2.44-2.55, 2.84-3.06, 3.94, 3.95-4.21, 4.39-4.53, 4.90, 5.39-5.64, 6.8 7- 7.09, 7.13, 7.28-7.33, 7.40-7.48, 7.84-7.96, 8.28-8.35, 8.41, 8.61-8.77.
実施例３７－１５
１－（５－｛７－（６－｛［９－（４－シアノ－２－フルオロベンジル）－５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－イル］カルボニル｝－３－ピリジニル）－９－［１－（２，２－ジメチルプロピル）－４－ピペリジニル］－６－メチル－８－オキソ－８，９－ジヒドロ－７Ｈ－プリン－２－イル｝－２－メチルフェニル）シクロプロパンカルボン酸
LC－MS（A）保持時間（分）：1.12；
MS(ESI, Pos.)： 887 (M + H)＋；
１H-NMR(CDCl３)：δ　 0.94, 1.35, 1.72-1.85, 2.15-2.26, 2.44, 2.46-2.55, 2.84-3.06, 3.90-4.20, 4.42-4.52, 4.90, 5.37-5.63, 6.86-7.07, 7.13, 7.28-7.32, 7.40-7.47, 7.84-7.96, 8.28-8.35, 8.61-8.78。 Example 37-15
1-(5-{7-(6-{[9-(4-cyano-2-fluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5] pyrrolo[2,3-b]pyridin-7-yl]carbonyl}-3-pyridinyl)-9-[1-(2,2-dimethylpropyl)-4-piperidinyl]-6-methyl-8-oxo-8 ,9-dihydro-7H-purin-2-yl}-2-methylphenyl)cyclopropanecarboxylic acid
LC-MS (A) retention time (min): 1.12;
MS(ESI, Pos.): 887 (M + H) + ;
1 H-NMR (CDCl 3 ): δ 0.94, 1.35, 1.72-1.85, 2.15-2.26, 2.44, 2.46-2.55, 2.84-3.06, 3.90-4.20, 4.42-4.52, 4.90, 5.37-5.63, 6.86-7.0 7, 7.13, 7.28-7.32, 7.40-7.47, 7.84-7.96, 8.28-8.35, 8.61-8.78.
実施例３７－１６
１－（３－｛７－（６－｛［９－（４－シアノ－２－フルオロベンジル）－５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－イル］カルボニル｝－３－ピリジニル）－９－［１－（２，２－ジメチルプロピル）－４－ピペリジニル］－６－メチル－８－オキソ－８，９－ジヒドロ－７Ｈ－プリン－２－イル｝－５－メチルフェニル）シクロプロパンカルボン酸
LC－MS（A）保持時間（分）：1.10；
MS(ESI, Pos.)： 887 (M + H)＋；
１H-NMR(CDCl３)：δ　 0.94, 1.34-1.39, 1.71-1.74, 1.75-1.79, 2.16-2.26, 2.45, 2.47-2.56, 2.90-3.04, 3.92-4.23, 4.39-4.54, 4.90, 5.39-5.63, 6.87-7.09, 7.13, 7.27-7.32, 7.40-7.45, 7.84-7.96, 8.22-8.32, 8.61-8.78。 Example 37-16
1-(3-{7-(6-{[9-(4-cyano-2-fluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5] pyrrolo[2,3-b]pyridin-7-yl]carbonyl}-3-pyridinyl)-9-[1-(2,2-dimethylpropyl)-4-piperidinyl]-6-methyl-8-oxo-8 ,9-dihydro-7H-purin-2-yl}-5-methylphenyl)cyclopropanecarboxylic acid
LC-MS (A) retention time (min): 1.10;
MS(ESI, Pos.): 887 (M + H) + ;
1 H-NMR (CDCl 3 ): δ 0.94, 1.34-1.39, 1.71-1.74, 1.75-1.79, 2.16-2.26, 2.45, 2.47-2.56, 2.90-3.04, 3.92-4.23, 4.39-4.54, 4.90, 5.3 9- 5.63, 6.87-7.09, 7.13, 7.27-7.32, 7.40-7.45, 7.84-7.96, 8.22-8.32, 8.61-8.78.
実施例３７－１７
１－（３－｛７－（６－｛［９－（４－シアノ－２－フルオロベンジル）－５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－イル］カルボニル｝－３－ピリジニル）－９－［１－（２，２－ジメチルプロピル）－４－ピペリジニル］－６－メチル－８－オキソ－８，９－ジヒドロ－７Ｈ－プリン－２－イル｝－５－フルオロフェニル）シクロプロパンカルボン酸
LC－MS（A）保持時間（分）：1.11；
MS(ESI, Pos.)： 891 (M + H)＋；
１H-NMR(CDCl３)：δ　 0.94, 1.34-1.43, 1.72-1.80, 2.17-2.26, 2.45-2.57, 2.84-3.06, 3.91-4.21, 4.41-4.56, 4.85-4.94, 5.40-5.63, 6.87-7.08, 7.11-7.22, 7.25-7.34, 7.38-7.48, 7.84-7.96, 8.09, 8.26, 8.30, 8.60-8.76。 Example 37-17
1-(3-{7-(6-{[9-(4-cyano-2-fluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5] pyrrolo[2,3-b]pyridin-7-yl]carbonyl}-3-pyridinyl)-9-[1-(2,2-dimethylpropyl)-4-piperidinyl]-6-methyl-8-oxo-8 ,9-dihydro-7H-purin-2-yl}-5-fluorophenyl)cyclopropanecarboxylic acid
LC-MS (A) retention time (min): 1.11;
MS(ESI, Pos.): 891 (M + H) + ;
1 H-NMR (CDCl 3 ): δ 0.94, 1.34-1.43, 1.72-1.80, 2.17-2.26, 2.45-2.57, 2.84-3.06, 3.91-4.21, 4.41-4.56, 4.85-4.94, 5.40-5.63, 6.87 - 7.08, 7.11-7.22, 7.25-7.34, 7.38-7.48, 7.84-7.96, 8.09, 8.26, 8.30, 8.60-8.76.
実施例３７－１８
メチル（３－｛７－（６－｛［９－（４－シアノ－２－フルオロベンジル）－５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－イル］カルボニル｝－３－ピリジニル）－９－［１－（２，２－ジメチルプロピル）－４－ピペリジニル］－６－メチル－８－オキソ－８，９－ジヒドロ－７Ｈ－プリン－２－イル｝フェニル）アセテート
LC－MS（A）保持時間（分）：1.14；
MS(ESI, Pos.)： 861 (M + H)＋；
１H-NMR(DMSO-d６)：δ　 0.93, 1.70-1.84, 2.06-2.24, 2.74-3.01, 3.65, 3.72-4.08, 4.29-4.48, 4.68-4.99, 5.36-5.73, 6.94-7.05, 7.11-7.20, 7.37-7.44, 7.44-7.51, 7.52-7.67, 7.75-8.01, 8.11-8.27, 8.27-8.38, 8.59-9.00。 Example 37-18
Methyl (3-{7-(6-{[9-(4-cyano-2-fluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo [2,3-b]pyridin-7-yl]carbonyl}-3-pyridinyl)-9-[1-(2,2-dimethylpropyl)-4-piperidinyl]-6-methyl-8-oxo-8, 9-dihydro-7H-purin-2-yl}phenyl)acetate
LC-MS (A) retention time (min): 1.14;
MS(ESI, Pos.): 861 (M + H) + ;
1 H-NMR (DMSO-d 6 ): δ 0.93, 1.70-1.84, 2.06-2.24, 2.74-3.01, 3.65, 3.72-4.08, 4.29-4.48, 4.68-4.99, 5.36-5.73, 6.94-7.05, 7.11- 7.20, 7.37-7.44, 7.44-7.51, 7.52-7.67, 7.75-8.01, 8.11-8.27, 8.27-8.38, 8.59-9.00.
実施例３８
１－（３－｛７－（６－｛［９－（４－シアノ－２－フルオロベンジル）－５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－イル］カルボニル｝－３－ピリジニル）－９－［１－（２，２－ジメチルプロピル）－４－ピペリジニル］－６－メチル－８－オキソ－８，９－ジヒドロ－７Ｈ－プリン－２－イル｝フェニル）シクロプロパンカルボキサミド　２トリフルオロ酢酸塩
　２－メチル－２－［３－（４，４，５，５－テトラメチル－１，３，２－ジオキサボロラン－２－イル）フェニル］プロパンカルボン酸の代わりに１－［３－（４，４，５，５－テトラメチル－１，３，２－ジオキサボロラン－２－イル）フェニル］シクロプロパンカルボン酸を用いて、実施例３７と同様の操作を行なった。得られた化合物（14ｍｇ）をＤＭＦ（0.14ｍＬ）に溶解し、塩化アンモニウム（2.6ｍｇ）とＤＩＰＥＡ（0.014ｍＬ）、ＨＡＴＵ（12ｍｇ）を加えて室温で９０分攪拌した。反応液を酢酸エチルで希釈して、水で洗浄した。得られた有機層を無水硫酸ナトリウムで乾燥後、減圧濃縮して得られた残渣を逆相HPLCカラム精製することにより、以下の物性値を有する標題化合物（12ｍｇ）を得た。
LC－MS（A）保持時間（分）：1.04；
MS(ESI, Pos.)： 872 (M + H)＋；
１H-NMR(CDCl３)：δ　 0.77-1.06, 1.17-1.38, 1.64-1.75, 2.11-2.32, 2.87-3.14, 3.91-4.24, 4.40-4.65, 4.83-4.95, 5.29-5.70, 6.85-7.10, 7.10-7.17, 7.29-7.35, 7.39-7.63, 7.81-8.01, 8.25-8.52, 8.53-8.80。 Example 38
1-(3-{7-(6-{[9-(4-cyano-2-fluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5] pyrrolo[2,3-b]pyridin-7-yl]carbonyl}-3-pyridinyl)-9-[1-(2,2-dimethylpropyl)-4-piperidinyl]-6-methyl-8-oxo-8 ,9-dihydro-7H-purin-2-yl}phenyl)cyclopropanecarboxamide 2-trifluoroacetate 2-methyl-2-[3-(4,4,5,5-tetramethyl-1,3,2- 1-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]cyclopropanecarboxylic acid instead of dioxaborolan-2-yl)phenyl]propanecarboxylic acid. The same operation as in Example 37 was carried out using the same. The obtained compound (14 mg) was dissolved in DMF (0.14 mL), ammonium chloride (2.6 mg), DIPEA (0.014 mL), and HATU (12 mg) were added, and the mixture was stirred at room temperature for 90 minutes. The reaction solution was diluted with ethyl acetate and washed with water. The obtained organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting residue was purified with a reverse phase HPLC column to obtain the title compound (12 mg) having the following physical properties.
LC-MS (A) retention time (min): 1.04;
MS(ESI, Pos.): 872 (M + H) + ;
1 H-NMR (CDCL 3 ): δ 0.77-1.06, 1.17-1.38, 1.64-1.75, 2.11-2.32, 2.87-324, 3.91-4.24, 4.40-4.65, 4.40-4.65, 4.83-4.95, 5.29-5.70 7.10-7.17, 7.29-7.35, 7.39-7.63, 7.81-8.01, 8.25-8.52, 8.53-8.80.
参考例１０２
メチル　７－（６－｛［９－（４－シアノ－２－フルオロベンジル）－５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－イル］カルボニル｝－３－ピリジニル）－９－［１－（２，２－ジメチルプロピル）－４－ピペリジニル］－６－メチル－８－オキソ－８，９－ジヒドロ－７Ｈ－プリン－２－カルボキシラート
　参考例１０１で製造した化合物（374ｍｇ）をＤＭＦ（2.5ｍＬ）に溶解し、メタノール（2.5ｍＬ）とＮＥｔ３（0.070ｍＬ）、Xantphos（43ｍｇ）、酢酸パラジウム（11ｍｇ）を加えた。反応容器内を一酸化炭素に置換して、７０℃で１７時間攪拌した。反応液を室温に冷却して酢酸エチルで希釈し、水を加えた。酢酸エチルで抽出し、得られた有機層を飽和食塩水で洗浄した。無水硫酸ナトリウムで乾燥後、減圧濃縮して得られた残渣をシリカゲルクロマトグラフィー（ヘキサン：酢酸エチル＝３３：６７→酢酸エチル：メタノール＝９：１）で精製することにより、以下の物性値を有する標題化合物（347ｍｇ）を得た。
LC－MS（A）保持時間（分）：1.03；
MS(ESI, Pos.)： 771 (M + H)＋；
１H-NMR(CDCl３)：δ　 0.85-0.94, 1.70-1.81, 2.11-2.19, 2.24-2.31, 2.49, 2.71-2.85, 2.93-3.03, 3.90-4.24, 4.06, 4.59, 4.83-4.96, 5.39-5.64, 6.86-7.09, 7.13, 7.27-7.33, 7.37-7.46, 7.82-7.96, 8.30, 8.57-8.76。 Reference example 102
Methyl 7-(6-{[9-(4-cyano-2-fluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[2,3 -b]pyridin-7-yl]carbonyl}-3-pyridinyl)-9-[1-(2,2-dimethylpropyl)-4-piperidinyl]-6-methyl-8-oxo-8,9-dihydro- 7H-Purine-2-carboxylate The compound prepared in Reference Example 101 (374 mg) was dissolved in DMF (2.5 mL), and mixed with methanol (2.5 mL), NEt 3 (0.070 mL), Xantphos (43 mg), and palladium acetate (11 mg). ) was added. The inside of the reaction vessel was replaced with carbon monoxide, and the mixture was stirred at 70°C for 17 hours. The reaction solution was cooled to room temperature, diluted with ethyl acetate, and water was added. Extraction was performed with ethyl acetate, and the resulting organic layer was washed with saturated brine. After drying over anhydrous sodium sulfate, the residue obtained by concentration under reduced pressure was purified by silica gel chromatography (hexane: ethyl acetate = 33:67 → ethyl acetate: methanol = 9:1), which had the following physical property values. The title compound (347 mg) was obtained.
LC-MS (A) retention time (min): 1.03;
MS(ESI, Pos.): 771 (M + H) + ;
1 H-NMR (CDCl 3 ): δ 0.85-0.94, 1.70-1.81, 2.11-2.19, 2.24-2.31, 2.49, 2.71-2.85, 2.93-3.03, 3.90-4.24, 4.06, 4.59, 4.83-4.96, 5.3 9- 5.64, 6.86-7.09, 7.13, 7.27-7.33, 7.37-7.46, 7.82-7.96, 8.30, 8.57-8.76.
参考例１０３
７－（６－｛［９－（４－シアノ－２－フルオロベンジル）－５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－イル］カルボニル｝－３－ピリジニル）－９－［１－（２，２－ジメチルプロピル）－４－ピペリジニル］－６－メチル－８－オキソ－８，９－ジヒドロ－７Ｈ－プリン－２－カルボン酸
　参考例１０２で製造した化合物（58ｍｇ）をＴＨＦ（0.75ｍＬ）に溶解し、０℃でＴＭＳＯＫ（19ｍｇ）を加えて室温で２時間攪拌した。反応液に１Ｎ塩酸を加えてジクロロメタンとメタノールの混合液（９：１）で抽出し、得られた有機層を無水硫酸ナトリウムで乾燥後、減圧濃縮して、以下の物性値を有する標題化合物（46ｍｇ）を得た。
LC－MS（A）保持時間（分）：0.95；
MS(ESI, Pos.)： 757 (M + H)＋。 Reference example 103
7-(6-{[9-(4-cyano-2-fluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[2,3- b]pyridin-7-yl]carbonyl}-3-pyridinyl)-9-[1-(2,2-dimethylpropyl)-4-piperidinyl]-6-methyl-8-oxo-8,9-dihydro-7H -Purine-2-carboxylic acid The compound prepared in Reference Example 102 (58 mg) was dissolved in THF (0.75 mL), TMSOK (19 mg) was added at 0°C, and the mixture was stirred at room temperature for 2 hours. 1N hydrochloric acid was added to the reaction mixture and extracted with a mixture of dichloromethane and methanol (9:1). The obtained organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the title compound ( 46 mg) was obtained.
LC-MS (A) retention time (min): 0.95;
MS(ESI, Pos.): 757 (M + H) + .
実施例３９
７－（６－｛［９－（４－シアノ－２－フルオロベンジル）－５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－イル］カルボニル｝－３－ピリジニル）－９－［１－（２，２－ジメチルプロピル）－４－ピペリジニル］－６－メチル－８－オキソ－Ｎ－［トランス－４－（トリフルオロメトキシ）シクロヘキシル］－８，９－ジヒドロ－７Ｈ－プリン－２－カルボキサミド　２トリフルオロ酢酸塩
　参考例１０３で製造した化合物（30ｍｇ）をＤＭＦ（0.4ｍＬ）に溶解し、トランス－４－（トリフルオロメトキシ）シクロへキサンアミン（7.6ｍｇ）とＤＩＰＥＡ（0.021ｍＬ）、ＨＡＴＵ（23ｍｇ）を加えて室温で１９時間攪拌した。反応液に飽和炭酸水素ナトリウム水溶液を加えて酢酸エチルで抽出した。得られた有機層を無水硫酸ナトリウムで乾燥後、減圧濃縮して得られた残渣を逆相HPLCカラム精製することにより、以下の物性値を有する標題化合物（18ｍｇ）を得た。
LC－MS（A）保持時間（分）：1.11；
MS(ESI, Pos.)： 922 (M + H)＋；
１H-NMR(DMSO-d６)：δ　 1.07-1.12, 1.53-1.72, 1.87-2.11, 2.13-2.17, 2.85-3.07, 3.26-3.33, 3.45-3.57, 3.64-3.90, 3.98-4.10, 4.27-4.42, 4.67-4.96, 5.33-5.75, 6.96-7.05, 7.09-7.24, 7.44-7.69, 7.73-7.88, 7.88-8.06, 8.09-8.32, 8.33-8.56, 8.60-9.03。 Example 39
7-(6-{[9-(4-cyano-2-fluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[2,3- b]pyridin-7-yl]carbonyl}-3-pyridinyl)-9-[1-(2,2-dimethylpropyl)-4-piperidinyl]-6-methyl-8-oxo-N-[trans-4- (Trifluoromethoxy)cyclohexyl]-8,9-dihydro-7H-purine-2-carboxamide 2-trifluoroacetate The compound (30 mg) prepared in Reference Example 103 was dissolved in DMF (0.4 mL), and trans-4- (Trifluoromethoxy)cyclohexaneamine (7.6 mg), DIPEA (0.021 mL), and HATU (23 mg) were added and stirred at room temperature for 19 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting residue was purified with a reverse phase HPLC column to obtain the title compound (18 mg) having the following physical properties.
LC-MS (A) retention time (min): 1.11;
MS(ESI, Pos.): 922 (M + H) + ;
1 H-NMR (DMSO-d 6 ): δ 1.07-1.12, 1.53-1.72, 1.87-2.11, 2.13-2.17, 2.85-3.07, 3.26-3.33, 3.45-3.57, 3.64-3.90, 3.98-4.10, 4.27- 4.42, 4.67-4.96, 5.33-5.75, 6.96-7.05, 7.09-7.24, 7.44-7.69, 7.73-7.88, 7.88-8.06, 8.09-8.32, 8.33-8.56, 8.60-9.03.
参考例１０４
４－（｛７－［（５－｛９－［１－（２，２－ジメチルプロピル）－４－ピペリジニル］－２－（ヒドロキシメチル）－６－メチル－８－オキソ－８，９－ジヒドロ－７Ｈ－プリン－７－イル｝－２－ピリジニル）カルボニル］－５，６，７，８－テトラヒドロ－９Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－９－イル｝メチル）－３－フルオロベンゾニトリル
　参考例１０３で製造した化合物（38ｍｇ）をＴＨＦ（0.5ｍＬ）に溶解し、エチル　カルボノクロリデート（6.0ｍｇ）とＤＩＰＥＡ（0.013ｍＬ）を加えて０℃で１時間攪拌した。反応液に水素化ホウ素ナトリウム（4.5ｍｇ）と水（0.1ｍＬ）を加えてさらに室温で３時間攪拌した。反応液に飽和炭酸水素ナトリウム水溶液を加えて酢酸エチルで抽出した。得られた有機層を無水硫酸ナトリウムで乾燥後、減圧濃縮して得られた残渣をプレパラティブＴＬＣ（富士シリシア　ＮＨ（商品名）、酢酸エチル）で精製することにより、以下の物性値を有する標題化合物（13ｍｇ）を得た。
LC－MS（A）保持時間（分）：0.92；
MS(ESI, Pos.)： 743 (M + H)＋；
１H-NMR(CDCl３)：δ　 0.85-0.96, 1.69-1.79, 2.12-2.21, 2.45, 2.67-2.83, 2.93-3.03, 3.91-4.22, 4.44, 4.79, 4.84-4.94, 5.30, 5.39-5.64, 6.88-7.08, 7.13, 7.28-7.34, 7.39-7.47, 7.83-7.96, 8.30, 8.52-8.73。 Reference example 104
4-({7-[(5-{9-[1-(2,2-dimethylpropyl)-4-piperidinyl]-2-(hydroxymethyl)-6-methyl-8-oxo-8,9-dihydro -7H-purin-7-yl}-2-pyridinyl)carbonyl]-5,6,7,8-tetrahydro-9H-pyrido[4',3':4,5]pyrrolo[2,3-b]pyridine -9-yl}methyl)-3-fluorobenzonitrile The compound prepared in Reference Example 103 (38 mg) was dissolved in THF (0.5 mL), and ethyl carbonochloridate (6.0 mg) and DIPEA (0.013 mL) were added. The mixture was stirred at 0°C for 1 hour. Sodium borohydride (4.5 mg) and water (0.1 mL) were added to the reaction solution, and the mixture was further stirred at room temperature for 3 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by preparative TLC (Fuji Silysia NH (trade name), ethyl acetate) to obtain the title compound having the following physical property values. A compound (13 mg) was obtained.
LC-MS (A) retention time (min): 0.92;
MS(ESI, Pos.): 743 (M + H) + ;
1 H-NMR (CDCl 3 ): δ 0.85-0.96, 1.69-1.79, 2.12-2.21, 2.45, 2.67-2.83, 2.93-3.03, 3.91-4.22, 4.44, 4.79, 4.84-4.94, 5.30, 5.39-5.6 4, 6.88-7.08, 7.13, 7.28-7.34, 7.39-7.47, 7.83-7.96, 8.30, 8.52-8.73.
参考例１０５
４－（｛７－［（５－｛９－［１－（２，２－ジメチルプロピル）－４－ピペリジニル］－２－ホルミル－６－メチル－８－オキソ－８，９－ジヒドロ－７Ｈ－プリン－７－イル｝－２－ピリジニル）カルボニル］－５，６，７，８－テトラヒドロ－９Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－９－イル｝メチル）－３－フルオロベンゾニトリル
　参考例１０４で製造した化合物（31ｍｇ）をジクロロメタン（0.4ｍＬ）に溶解し、０℃でＤＭＳＯ（0.2ｍＬ）と三酸化硫黄ピリジン錯体（20ｍｇ）、ＮＥｔ３（0.035ｍＬ）を順次加えて室温で６時間攪拌した。反応液に水を加えて酢酸エチルで抽出し、無水硫酸ナトリウムで乾燥した。得られた有機層を減圧濃縮し、以下の物性値を有する標題化合物（31ｍｇ）を得た。
TLC：Rf 0.47（酢酸エチル：メタノール＝９：１）。 Reference example 105
4-({7-[(5-{9-[1-(2,2-dimethylpropyl)-4-piperidinyl]-2-formyl-6-methyl-8-oxo-8,9-dihydro-7H- purin-7-yl}-2-pyridinyl)carbonyl]-5,6,7,8-tetrahydro-9H-pyrido[4',3':4,5]pyrrolo[2,3-b]pyridine-9- yl}methyl)-3-fluorobenzonitrile The compound (31 mg) prepared in Reference Example 104 was dissolved in dichloromethane (0.4 mL), and the mixture was heated at 0°C with DMSO (0.2 mL), sulfur trioxide pyridine complex (20 mg), and NEt 3 (0.035 mL) were added one after another and stirred at room temperature for 6 hours. Water was added to the reaction solution, extracted with ethyl acetate, and dried over anhydrous sodium sulfate. The obtained organic layer was concentrated under reduced pressure to obtain the title compound (31 mg) having the following physical properties.
TLC: Rf 0.47 (ethyl acetate:methanol=9:1).
実施例４０
４－（｛７－［（５－｛２－（ジフルオロメチル）－９－［１－（２，２－ジメチルプロピル）－４－ピペリジニル］－６－メチル－８－オキソ－８，９－ジヒドロ－７Ｈ－プリン－７－イル｝－２－ピリジニル）カルボニル］－５，６，７，８－テトラヒドロ－９Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－９－イル｝メチル）－３－フルオロベンゾニトリル
　参考例１０５で製造した化合物（31ｍｇ）をジクロロメタン（0.4ｍＬ）に溶解し、２－メトキシ－N－（２－メトキシエチル）－N－（トリフルオロ－ランブダ－４－スルファニル）エタンアミン（19ｍｇ）を加えて室温で２時間攪拌した。反応液に２－メトキシ－N－（２－メトキシエチル）－N－（トリフルオロ－ランブダ－４－スルファニル）エタンアミン（30ｍｇ）を追加し、室温で２時間攪拌した。反応液に飽和炭酸水素ナトリウム水溶液を加えて酢酸エチルで抽出し、無水硫酸ナトリウムで乾燥した。得られた有機層を減圧濃縮し、得られた残渣をプレパラティブＴＬＣ（富士シリシア　ＮＨ（商品名）、ヘキサン：酢酸エチル＝１：２）で精製することにより、以下の物性値を有する標題化合物（4.5ｍｇ）を得た。
LC－MS（A）保持時間（分）：1.05；
MS(ESI, Pos.)： 763 (M + H)＋；
１H-NMR(CDCl３)：δ　 0.88-0.94, 1.69-1.80, 2.11-2.17, 2.20-2.25, 2.47, 2.68-2.84, 2.91-3.05, 3.86-4.22, 4.43-4.54, 4.84-4.95, 5.37-5.64, 6.44-6.80, 6.88-7.09, 7.13, 7.28-7.34, 7.39-7.46, 7.83-7.96, 8.30, 8.54-8.73。 Example 40
4-({7-[(5-{2-(difluoromethyl)-9-[1-(2,2-dimethylpropyl)-4-piperidinyl]-6-methyl-8-oxo-8,9-dihydro -7H-purin-7-yl}-2-pyridinyl)carbonyl]-5,6,7,8-tetrahydro-9H-pyrido[4',3':4,5]pyrrolo[2,3-b]pyridine -9-yl}methyl)-3-fluorobenzonitrile The compound (31 mg) prepared in Reference Example 105 was dissolved in dichloromethane (0.4 mL), and 2-methoxy-N-(2-methoxyethyl)-N-(trifluorobenzonitrile) was dissolved in dichloromethane (0.4 mL). Fluoro-lambda-4-sulfanyl)ethanamine (19 mg) was added and stirred at room temperature for 2 hours. 2-Methoxy-N-(2-methoxyethyl)-N-(trifluoro-lambda-4-sulfanyl)ethanamine (30 mg) was added to the reaction solution, and the mixture was stirred at room temperature for 2 hours. A saturated aqueous sodium bicarbonate solution was added to the reaction mixture, extracted with ethyl acetate, and dried over anhydrous sodium sulfate. The obtained organic layer was concentrated under reduced pressure, and the obtained residue was purified by preparative TLC (Fuji Silysia NH (trade name), hexane: ethyl acetate = 1:2) to obtain the title compound having the following physical property values. (4.5 mg) was obtained.
LC-MS (A) retention time (min): 1.05;
MS(ESI, Pos.): 763 (M + H) + ;
1 H-NMR (CDCl 3 ): δ 0.88-0.94, 1.69-1.80, 2.11-2.17, 2.20-2.25, 2.47, 2.68-2.84, 2.91-3.05, 3.86-4.22, 4.43-4.54, 4.84-4.95, 5.37 - 5.64, 6.44-6.80, 6.88-7.09, 7.13, 7.28-7.34, 7.39-7.46, 7.83-7.96, 8.30, 8.54-8.73.
実施例４１
４－（｛７－［（５－｛２－アセチル－９－［１－（２，２－ジメチルプロピル）－４－ピペリジニル］－６－メチル－８－オキソ－８，９－ジヒドロ－７Ｈ－プリン－７－イル｝－２－ピリジニル）カルボニル］－５，６，７，８－テトラヒドロ－９Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－９－イル｝メチル）－３－フルオロベンゾニトリル
　参考例１０１で製造した化合物（374ｍｇ）をＤＭＡ（7.5ｍＬ）に溶解し、トリブチル（１－エトキシビニル）スタナン（271ｍｇ）とジクロロパラジウム－トリフェニルホスフィン錯体（35ｍｇ）を加え、１００℃で１時間攪拌した。反応液を室温に冷却して水を加え、酢酸エチルで抽出した。得られた有機層を無水硫酸ナトリウムで乾燥後、インジェクトカラム　アミノ（商品名）を通して減圧濃縮した。得られた残渣をシリカゲルクロマトグラフィー（富士シリシア　ＮＨ（商品名）、ヘキサン：酢酸エチル＝３３：６７）で精製した。得られた化合物（100ｍｇ）をＴＨＦ（1ｍＬ）に溶解し、０℃で２Ｎ塩酸（1ｍＬ）を加えて室温で１時間攪拌した。反応液を飽和炭酸水素ナトリウム水溶液にあけて酢酸エチルで抽出した。得られた有機層を無水硫酸ナトリウムで乾燥して減圧濃縮し、得られた残渣をシリカゲルクロマトグラフィー（富士シリシア　ＮＨ（商品名）、ヘキサン：酢酸エチル＝３３：６７→酢酸エチル：メタノール＝９：１）で精製することにより、以下の物性値を有する標題化合物（59ｍｇ）を得た。
LC－MS（A）保持時間（分）：1.04；
MS(ESI, Pos.)： 755 (M + H)＋；
１H-NMR(CDCl３)：δ　 0.87-0.96, 1.67-1.82, 2.10-2.21, 2.23-2.30, 2.50, 2.73-2.89, 2.93-3.07, 3.89-4.25, 4.47-4.60, 4.83-4.96, 5.38-5.65, 6.87-7.09, 7.13, 7.28-7.34, 7.39-7.47, 7.83-7.98, 8.30, 8.54-8.75。 Example 41
4-({7-[(5-{2-acetyl-9-[1-(2,2-dimethylpropyl)-4-piperidinyl]-6-methyl-8-oxo-8,9-dihydro-7H- purin-7-yl}-2-pyridinyl)carbonyl]-5,6,7,8-tetrahydro-9H-pyrido[4',3':4,5]pyrrolo[2,3-b]pyridine-9- yl}methyl)-3-fluorobenzonitrile The compound prepared in Reference Example 101 (374 mg) was dissolved in DMA (7.5 mL), and tributyl(1-ethoxyvinyl)stannane (271 mg) and dichloropalladium-triphenylphosphine complex ( 35 mg) was added thereto, and the mixture was stirred at 100°C for 1 hour. The reaction solution was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The obtained organic layer was dried over anhydrous sodium sulfate, and then passed through an injection column Amino (trade name) and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (Fuji Silysia NH (trade name), hexane:ethyl acetate = 33:67). The obtained compound (100 mg) was dissolved in THF (1 mL), 2N hydrochloric acid (1 mL) was added at 0°C, and the mixture was stirred at room temperature for 1 hour. The reaction solution was poured into a saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The obtained organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the obtained residue was subjected to silica gel chromatography (Fuji Silysia NH (trade name), hexane: ethyl acetate = 33:67 → ethyl acetate: methanol = 9: By purifying in step 1), the title compound (59 mg) having the following physical properties was obtained.
LC-MS (A) retention time (min): 1.04;
MS(ESI, Pos.): 755 (M + H) + ;
1 H-NMR (CDCl 3 ): δ 0.87-0.96, 1.67-1.82, 2.10-2.21, 2.23-2.30, 2.50, 2.73-2.89, 2.93-3.07, 3.89-4.25, 4.47-4.60, 4.83-4.96, 5.38 - 5.65, 6.87-7.09, 7.13, 7.28-7.34, 7.39-7.47, 7.83-7.98, 8.30, 8.54-8.75.
実施例４２
４－（｛７－［（５－｛９－［１－（２，２－ジメチルプロピル）－４－ピペリジニル］－２－（２－ヒドロキシ－２－プロパニル）－６－メチル－８－オキソ－８，９－ジヒドロ－７Ｈ－プリン－７－イル｝－２－ピリジニル）カルボニル］－５，６，７，８－テトラヒドロ－９Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－９－イル｝メチル）－３－フルオロベンゾニトリル
　実施例４１で製造した化合物（20ｍｇ）をＴＨＦ（1.0ｍＬ）に溶解し、ブロモ（メチル）マグネシウム（0.015 ｍＬ、3.0 mol/L、ＴＨＦ溶液）を０℃で加えて５分攪拌した。反応液に飽和塩化アンモニウム水溶液を加えて酢酸エチルで抽出した。得られた有機層を無水硫酸ナトリウムで乾燥し、減圧濃縮して得られた残渣をプレパラティブＴＬＣ（富士シリシア　ＮＨ（商品名）、ヘキサン：酢酸エチル＝１：２）で精製することにより、以下の物性値を有する標題化合物（2.5ｍｇ）を得た。
LC－MS（A）保持時間（分）：0.99；
MS(ESI, Pos.)： 771 (M + H)＋；
１H-NMR(CDCl３)：δ　 0.91, 1.60-1.64, 1.68-1.78, 2.13-2.21, 2.47, 2.72-2.87, 2.93-3.03, 3.90-4.23, 4.37-4.49, 4.76-4.81, 4.85-4.94, 5.39-5.64, 6.86-7.08, 7.13, 7.28-7.34, 7.40-7.47, 7.82-7.95, 8.28-8.32, 8.57-8.75。 Example 42
4-({7-[(5-{9-[1-(2,2-dimethylpropyl)-4-piperidinyl]-2-(2-hydroxy-2-propanyl)-6-methyl-8-oxo- 8,9-dihydro-7H-purin-7-yl}-2-pyridinyl)carbonyl]-5,6,7,8-tetrahydro-9H-pyrido[4',3':4,5]pyrrolo[2, 3-b]pyridin-9-yl}methyl)-3-fluorobenzonitrile The compound prepared in Example 41 (20 mg) was dissolved in THF (1.0 mL), and bromo(methyl)magnesium (0.015 mL, 3.0 mol/ L, THF solution) was added at 0°C and stirred for 5 minutes. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting residue was purified by preparative TLC (Fuji Silysia NH (trade name), hexane: ethyl acetate = 1:2) to obtain the following. The title compound (2.5 mg) having the physical property values was obtained.
LC-MS (A) retention time (min): 0.99;
MS(ESI, Pos.): 771 (M + H) + ;
1 H-NMR (CDCl 3 ): δ 0.91, 1.60-1.64, 1.68-1.78, 2.13-2.21, 2.47, 2.72-2.87, 2.93-3.03, 3.90-4.23, 4.37-4.49, 4.76-4.81, 4.85-4.94 , 5.39-5.64, 6.86-7.08, 7.13, 7.28-7.34, 7.40-7.47, 7.82-7.95, 8.28-8.32, 8.57-8.75.
実施例４３
４－（｛７－［（５－｛９－［１－（２，２－ジメチルプロピル）－４－ピペリジニル］－２－（Ｎ－ヒドロキシエタンイミドイル）－６－メチル－８－オキソ－８，９－ジヒドロ－７Ｈ－プリン－７－イル｝－２－ピリジニル）カルボニル］－５，６，７，８－テトラヒドロ－９Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－９－イル｝メチル）－３－フルオロベンゾニトリル
　実施例４１で製造した化合物（11ｍｇ）をエタノール（0.15ｍＬ）に溶解し、酢酸ナトリウム（6.1ｍｇ）とヒドロキシルアミン塩酸塩（3.1ｍｇ）を加えて０℃で１時間攪拌した。反応液に飽和炭酸水素ナトリウム水溶液を加えて酢酸エチルで抽出した。得られた有機層を無水硫酸ナトリウムで乾燥し、減圧濃縮して得られた残渣をプレパラティブＴＬＣ（富士シリシア　ＮＨ（商品名）、酢酸エチル：メタノール＝９：１）で精製することにより、以下の物性値を有する標題化合物（8.6ｍｇ）を得た。
LC－MS（A）保持時間（分）：1.02；
MS(ESI, Pos.)： 770 (M + H)＋；
１H-NMR(CDCl３)：δ　 0.87-0.95, 1.74-1.83, 2.13-2.19, 2.20-2.26, 2.44-2.46, 2.47-2.54, 2.76-2.91, 2.95-3.05, 3.92-4.22, 4.47-4.58, 4.85-4.95, 5.39-5.65, 6.88-7.08, 7.13, 7.28-7.34, 7.39-7.47, 7.84-7.96, 8.30, 8.57-8.75, 10.05。 Example 43
4-({7-[(5-{9-[1-(2,2-dimethylpropyl)-4-piperidinyl]-2-(N-hydroxyethanimidoyl)-6-methyl-8-oxo-8 ,9-dihydro-7H-purin-7-yl}-2-pyridinyl)carbonyl]-5,6,7,8-tetrahydro-9H-pyrido[4',3':4,5]pyrrolo[2,3 -b]pyridin-9-yl}methyl)-3-fluorobenzonitrile The compound prepared in Example 41 (11 mg) was dissolved in ethanol (0.15 mL), and sodium acetate (6.1 mg) and hydroxylamine hydrochloride (3.1 mg) were dissolved in ethanol (0.15 mL). mg) and stirred at 0°C for 1 hour. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting residue was purified by preparative TLC (Fuji Silysia NH (trade name), ethyl acetate:methanol = 9:1) to obtain the following. The title compound (8.6 mg) having the physical property values was obtained.
LC-MS (A) retention time (min): 1.02;
MS(ESI, Pos.): 770 (M + H) + ;
1 H-NMR (CDCL 3 ): δ 0.87-0.95, 1.74-1.83, 2.13-2.19, 2.44-2.46, 2.47-2.54, 2.76-2.91, 2.95-3.05, 3.92-4.05, 3.92-4.22, 4.47-4.58, 4.47-4.58, 4.47-4.58 4.85-4.95, 5.39-5.65, 6.88-7.08, 7.13, 7.28-7.34, 7.39-7.47, 7.84-7.96, 8.30, 8.57-8.75, 10.05.
参考例１０６
４－（｛７－［（５－ブロモ－２－ピリジニル）カルボニル］－５，６，７，８－テトラヒドロ－９Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－９－イル｝メチル）－３－フルオロベンゾニトリル
　４－ヨード安息香酸の代わりに５－ブロモ－２－ピリジンカルボン酸（404ｍｇ）をもちいて、参考例５７と同様の操作を行い、以下の物性値を有する標題化合物（632ｍｇ）を得た。
LC－MS（A）保持時間（分）：1.11；
MS(ESI, Pos.)： 490 (M + H)＋；
１H-NMR(CDCl３)：δ　 2.96, 3.86-4.16, 4.77-4.88, 5.32-5.62, 6.87-6.97, 7.12, 7.19-7.44, 7.60-7.66, 7.80-7.87, 7.92-8.01, 8.29, 8.51-8.72。 Reference example 106
4-({7-[(5-bromo-2-pyridinyl)carbonyl]-5,6,7,8-tetrahydro-9H-pyrido[4',3':4,5]pyrrolo[2,3-b ]Pyridin-9-yl}methyl)-3-fluorobenzonitrile Using 5-bromo-2-pyridinecarboxylic acid (404 mg) instead of 4-iodobenzoic acid, the same operation as in Reference Example 57 was carried out, and the following was obtained. The title compound (632 mg) having physical property values was obtained.
LC-MS (A) retention time (min): 1.11;
MS(ESI, Pos.): 490 (M + H) + ;
1 H-NMR (CDCl 3 ): δ 2.96, 3.86-4.16, 4.77-4.88, 5.32-5.62, 6.87-6.97, 7.12, 7.19-7.44, 7.60-7.66, 7.80-7.87, 7.92-8.01, 8.29, 8.5 1- 8.72.
参考例１０７
２－メチル－２－プロパニル　（３Ｒ，４Ｓ）－４－［（５－アミノ－２－クロロ－６－メチル－４－ピリミジニル）アミノ］－３－メチル－１－ピペリジンカルボキシラート
　２－メチル－２－プロパニル　４－アミノ－１－ピぺリジンカルボキシラートの代わりに２－メチル－２－プロパニル　（３Ｒ，４Ｓ）－４－アミノ－３－メチル－１－ピぺリジンカルボキシラート（397ｍｇ）を用いて、参考例３と同様の操作を行い、以下の物性値を有する標題化合物（500ｍｇ）を得た。
LC－MS（A）保持時間（分）：0.94；
MS(ESI, Pos.)： 356 (M + H)＋。 Reference example 107
2-Methyl-2-propanyl (3R,4S)-4-[(5-amino-2-chloro-6-methyl-4-pyrimidinyl)amino]-3-methyl-1-piperidinecarboxylate 2-methyl-2 -Propanyl Using 2-methyl-2-propanyl (3R,4S)-4-amino-3-methyl-1-piperidinecarboxylate (397 mg) in place of 4-amino-1-piperidinecarboxylate. The same operation as in Reference Example 3 was performed to obtain the title compound (500 mg) having the following physical properties.
LC-MS (A) retention time (min): 0.94;
MS(ESI, Pos.): 356 (M + H) + .
参考例１０８
２－メチル－２－プロパニル　（３Ｒ，４Ｓ）－４－（｛２－クロロ－５－［（６－｛［９－（４－シアノ－２－フルオロベンジル）－５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－イル］カルボニル｝－３－ピリジニル）アミノ］－６－メチル－４－ピリミジニル｝アミノ）－３－メチル－１－ピペリジンカルボキシラート
　参考例３で製造した化合物の代わりに参考例１０７で製造した化合物（200ｍｇ）を、メチル　５－ブロモピリジンカルボン酸の代わりに参考例１０６で製造した化合物（397ｍｇ）を用いて、参考例９３と同様の操作を行い、以下の物性値を有する標題化合物（350ｍｇ）を得た。
LC－MS（A）保持時間（分）：1.19；
MS(ESI, Pos.)： 765 (M + H)＋。 Reference example 108
2-Methyl-2-propanyl (3R,4S)-4-({2-chloro-5-[(6-{[9-(4-cyano-2-fluorobenzyl)-5,6,8,9- Tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[2,3-b]pyridin-7-yl]carbonyl}-3-pyridinyl)amino]-6-methyl-4-pyrimidinyl}amino) -3-Methyl-1-piperidinecarboxylate The compound produced in Reference Example 107 (200 mg) was substituted for the compound produced in Reference Example 3, and the compound produced in Reference Example 106 was substituted for methyl 5-bromopyridinecarboxylate (200 mg). The same operation as in Reference Example 93 was performed using 397 mg) to obtain the title compound (350 mg) having the following physical property values.
LC-MS (A) retention time (min): 1.19;
MS(ESI, Pos.): 765 (M + H) + .
参考例１０９
２－メチル－２－プロパニル　（３Ｒ，４Ｓ）－４－［２－クロロ－７－（６－｛［９－（４－シアノ－２－フルオロベンジル）－５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－イル］カルボニル｝－３－ピリジニル）－６－メチル－８－オキソ－７，８－ジヒドロ－９Ｈ－プリン－９－イル］－３－メチル－１－ピペリジンカルボキシラート
　参考例９３で製造した化合物の代わりに参考例１０８で製造した化合物（350ｍｇ）を用いて、参考例９４と同様の操作を行い、以下の物性値を有する標題化合物（340ｍｇ）を得た。
LC－MS（A）保持時間（分）：1.27；
MS(ESI, Pos.)： 791 (M + H)＋。 Reference example 109
2-Methyl-2-propanyl (3R,4S)-4-[2-chloro-7-(6-{[9-(4-cyano-2-fluorobenzyl)-5,6,8,9-tetrahydro- 7H-pyrido[4',3':4,5]pyrrolo[2,3-b]pyridin-7-yl]carbonyl}-3-pyridinyl)-6-methyl-8-oxo-7,8-dihydro- 9H-Purin-9-yl]-3-methyl-1-piperidinecarboxylate The same procedure as in Reference Example 94 was carried out using the compound produced in Reference Example 108 (350 mg) instead of the compound produced in Reference Example 93. The title compound (340 mg) having the following physical properties was obtained.
LC-MS (A) retention time (min): 1.27;
MS(ESI, Pos.): 791 (M + H) + .
参考例１１０
３－フルオロ－４－［（７－｛［５－（６－メチル－９－［（３Ｒ，４Ｓ）－３－メチル－４－ピペリジニル］－８－オキソ－２－｛［４－（トリフルオロメトキシ）フェニル］アミノ｝－８，９－ジヒドロ－７Ｈ－プリン－７－イル）－２－ピリジニル］カルボニル｝－５，６，７，８－テトラヒドロ－９Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－９－イル）メチル］ベンゾニトリル　２塩酸塩
　参考例６８で製造した化合物の代わりに参考例１０９で製造した化合物（340ｍｇ）を用いて、参考例６９→参考例７０と同様の操作を行い、以下の物性値を有する標題化合物（160ｍｇ）を得た。
LC－MS（A）保持時間（分）：1.10；
MS(ESI, Pos.)： 832 (M + H)＋。 Reference example 110
3-Fluoro-4-[(7-{[5-(6-methyl-9-[(3R,4S)-3-methyl-4-piperidinyl]-8-oxo-2-{[4-(trifluoro methoxy)phenyl]amino}-8,9-dihydro-7H-purin-7-yl)-2-pyridinyl]carbonyl}-5,6,7,8-tetrahydro-9H-pyrido[4',3':4 ,5]pyrrolo[2,3-b]pyridin-9-yl)methyl]benzonitrile dihydrochloride Using the compound produced in Reference Example 109 (340 mg) in place of the compound produced in Reference Example 68, Reference Example 69→The same operation as in Reference Example 70 was performed to obtain the title compound (160 mg) having the following physical property values.
LC-MS (A) retention time (min): 1.10;
MS(ESI, Pos.): 832 (M + H) + .
実施例４４
３－フルオロ－４－［（７－｛［５－（９－［（３Ｒ，４Ｓ）－１－イソブチル－３－メチル－４－ピペリジニル］－６－メチル－８－オキソ－２－｛［４－（トリフルオロメトキシ）フェニル］アミノ｝－８，９－ジヒドロ－７Ｈ－プリン－７－イル）－２－ピリジニル］カルボニル｝－５，６，７，８－テトラヒドロ－９Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－９－イル）メチル］ベンゾニトリル　２トリフルオロ酢酸塩
　参考例１１０で製造した化合物（50ｍｇ）をＤＭＦ（1ｍＬ）に溶解し、ＮＥｔ３（0.042ｍＬ）を加えた。さらに２－メチルプロパナール（1.3ｇ）と酢酸（0.034ｍＬ）、トリアセトキシ水素化ホウ素ナトリウム（64ｍｇ）を加えて室温で３時間攪拌した。反応液に飽和炭酸水素ナトリウム水溶液を加えて酢酸エチルで抽出し、有機層を飽和炭酸水素ナトリウム水溶液と水で洗浄した。無水硫酸ナトリウムで乾燥後、有機層を減圧濃縮して得られた残渣を逆相HPLCカラム精製することにより、以下の物性値を有する標題化合物（44ｍｇ）を得た。
LC－MS（A）保持時間（分）：1.25；
MS(ESI, Pos.)： 888 (M + H)＋；
１H-NMR(DMSO-d６)：δ　 0.89-1.06, 1.12-1.26, 1.90-2.08, 2.08-2.36, 2.64-2.71, 2.77-3.13, 3.54-4.16, 4.62-5.04, 5.35-5.75, 6.87-7.39, 7.50-7.70, 7.70-8.03, 8.03-8.33, 8.61-8.91, 8.91-9.11, 9.60-9.77。 Example 44
3-Fluoro-4-[(7-{[5-(9-[(3R,4S)-1-isobutyl-3-methyl-4-piperidinyl]-6-methyl-8-oxo-2-{[4 -(trifluoromethoxy)phenyl]amino}-8,9-dihydro-7H-purin-7-yl)-2-pyridinyl]carbonyl}-5,6,7,8-tetrahydro-9H-pyrido[4', 3':4,5]pyrrolo[2,3-b]pyridin-9-yl)methyl]benzonitrile 2-trifluoroacetate The compound (50 mg) prepared in Reference Example 110 was dissolved in DMF (1 mL), and NEt 3 (0.042 mL) was added. Further, 2-methylpropanal (1.3 g), acetic acid (0.034 mL), and sodium triacetoxyborohydride (64 mg) were added, and the mixture was stirred at room temperature for 3 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, extracted with ethyl acetate, and the organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and water. After drying over anhydrous sodium sulfate, the organic layer was concentrated under reduced pressure and the resulting residue was purified using a reverse phase HPLC column to obtain the title compound (44 mg) having the following physical properties.
LC-MS (A) retention time (min): 1.25;
MS(ESI, Pos.): 888 (M + H) + ;
1 H-NMR (DMSO-d 6 ): δ 0.89-1.06, 1.12-1.26, 1.90-2.08, 2.08-2.36, 2.64-2.71, 2.77-3.13, 3.54-4.16, 4.62-5.04, 5.35-5.75, 6.87- 7.39, 7.50-7.70, 7.70-8.03, 8.03-8.33, 8.61-8.91, 8.91-9.11, 9.60-9.77.
実施例４５
４－［（７－｛［５－（９－｛（３Ｒ，４Ｓ）－１－［（１－シアノシクロプロピル）カルボニル］－３－メチル－４－ピペリジニル｝－６－メチル－８－オキソ－２－｛［４－（トリフルオロメトキシ）フェニル］アミノ｝－８，９－ジヒドロ－７Ｈ－プリン－７－イル）－２－ピリジニル］カルボニル｝－５，６，７，８－テトラヒドロ－９Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－９－イル）メチル］－３－フルオロベンゾニトリル　トリフルオロ酢酸塩
　参考例１１０で製造した化合物（50ｍｇ）をＤＭＦ（1ｍＬ）に溶解し、ＮＥｔ３（0.042ｍＬ）を加えた。さらに１－シアノシクロプロパンカルボン酸（10ｍｇ）とＤＭＴＭＭ（57ｍｇ）を加えて室温で４時間攪拌した。反応液を逆相HPLCカラム精製することにより、以下の物性値を有する標題化合物（36ｍｇ）を得た。
LC－MS（A）保持時間（分）：1.43；
MS(ESI, Pos.)： 925 (M + H)＋；
１H-NMR(DMSO-d６)：δ　 0.87-1.10, 1.59-1.75, 1.89-2.07, 2.41-2.49, 2.78-2.94, 3.06-3.28, 3.69-3.79, 3.94-4.14, 4.14-4.31, 4.38-4.55, 4.64-4.99, 5.38-5.75, 6.89-7.34, 7.49-7.66, 7.73-7.91, 7.91-8.00, 8.07-8.28, 8.57-8.89, 9.64-9.73。 Example 45
4-[(7-{[5-(9-{(3R,4S)-1-[(1-cyanocyclopropyl)carbonyl]-3-methyl-4-piperidinyl}-6-methyl-8-oxo- 2-{[4-(trifluoromethoxy)phenyl]amino}-8,9-dihydro-7H-purin-7-yl)-2-pyridinyl]carbonyl}-5,6,7,8-tetrahydro-9H- Pyrido[4',3':4,5]pyrrolo[2,3-b]pyridin-9-yl)methyl]-3-fluorobenzonitrile trifluoroacetate The compound (50 mg) produced in Reference Example 110 was dissolved in DMF. (1 mL) and added NEt 3 (0.042 mL). Furthermore, 1-cyanocyclopropanecarboxylic acid (10 mg) and DMTMM (57 mg) were added, and the mixture was stirred at room temperature for 4 hours. The reaction solution was purified using a reverse phase HPLC column to obtain the title compound (36 mg) having the following physical properties.
LC-MS (A) retention time (min): 1.43;
MS(ESI, Pos.): 925 (M + H) + ;
1 H-NMR (DMSO-d 6 ): δ 0.87-1.10, 1.59-1.75, 1.89-2.07, 2.41-2.49, 2.78-2.94, 3.06-3.28, 3.69-3.79, 3.94-4.14, 4.14-4.31, 4.38- 4.55, 4.64-4.99, 5.38-5.75, 6.89-7.34, 7.49-7.66, 7.73-7.91, 7.91-8.00, 8.07-8.28, 8.57-8.89, 9.64-9.73.
参考例１１１
２－メチル－２－プロパニル　６－［２－クロロ－７－（６－｛［９－（４－シアノ－２－フルオロベンジル）－５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－イル］カルボニル｝－３－ピリジニル）－６－メチル－８－オキソ－７，８－ジヒドロ－９Ｈ－プリン－９－イル］－２－アザスピロ［３．３］ヘプタン－２－カルボキシラート
　参考例３で用いた２－メチル－２－プロパニル　４－アミノ－１－ピぺリジンカルボキシラートの代わりに２－メチル－２－プロパニル　６－アミノ－２－アザスピロ［３，３］ヘプタン－２－カルボキシラートを用いて、参考例３→参考例９３→参考例９４→参考例９５→参考例９９と同様の操作を行い、以下の物性値を有する標題化合物を得た。
LC－MS（A）保持時間（分）：1.25；
MS(ESI, Pos.)： 789 (M + H)＋；
１H-NMR(CDCl３)：δ　 1.44, 2.09-2.17, 2.62-2.73, 2.94-3.03, 3.19-3.32, 3.93-4.15, 4.84-4.92, 4.92-5.06, 5.38-5.64, 6.87-7.08, 7.11, 7.22-7.34, 7.38-7.45, 7.81-8.01, 8.29, 8.47-8.73。 Reference example 111
2-Methyl-2-propanyl 6-[2-chloro-7-(6-{[9-(4-cyano-2-fluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[2,3-b]pyridin-7-yl]carbonyl}-3-pyridinyl)-6-methyl-8-oxo-7,8-dihydro-9H-purine-9- yl]-2-azaspiro[3.3]heptane-2-carboxylate 2-methyl-2-propanyl 4-amino-1-piperidinecarboxylate used in Reference Example 3 Using propanyl 6-amino-2-azaspiro[3,3]heptane-2-carboxylate, the same operation as in Reference Example 3 → Reference Example 93 → Reference Example 94 → Reference Example 95 → Reference Example 99 was carried out, and the following was carried out. The title compound having the physical property values was obtained.
LC-MS (A) retention time (min): 1.25;
MS(ESI, Pos.): 789 (M + H) + ;
1 H-NMR (CDCl 3 ): δ 1.44, 2.09-2.17, 2.62-2.73, 2.94-3.03, 3.19-3.32, 3.93-4.15, 4.84-4.92, 4.92-5.06, 5.38-5.64, 6.87-7.08, 7.11 , 7.22-7.34, 7.38-7.45, 7.81-8.01, 8.29, 8.47-8.73.
参考例１１２
２－メチル－２－プロパニル　６－［７－（６－｛［９－（４－シアノ－２－フルオロベンジル）－５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－イル］カルボニル｝－３－ピリジニル）－６－メチル－８－オキソ－２－｛［４－（トリフルオロメトキシ）フェニル］アミノ｝－７，８－ジヒドロ－９Ｈ－プリン－９－イル］－２－アザスピロ［３．３］ヘプタン－２－カルボキシラート
　参考例１１１で製造した化合物（180ｍｇ）にＤＭＦ（1.1ｍＬ）とトルエン（1.1ｍＬ）を加えて溶解し、さらに４－（トリフルオロメトキシ）アニリン（81ｍｇ）及び炭酸セシウム（148ｍｇ）、Xantphos（40ｍｇ）、酢酸パラジウム（10ｍｇ）を加え、窒素雰囲気で１１５℃で１時間攪拌した。反応液を室温に冷却した後、酢酸エチルで希釈して、水を加えた。有機層を水と飽和食塩水で洗浄し、インジェクトカラム　アミノ（商品名）に通した。得られたろ液を減圧濃縮し、残渣をシリカゲルクロマトグラフィー（富士シリシア　ＮＨ（商品名）、ヘキサン：酢酸エチル＝３：２→０：１）で精製することにより、以下の物性値を有する標題化合物（147ｍｇ）を得た。
LC－MS（A）保持時間（分）：1.31；
MS(ESI, Pos.)： 930 (M + H)＋；
１H-NMR(CDCl３)：δ　 1.46, 2.05-2.11, 2.61-2.71, 2.99, 3.24-3.39, 3.94-4.18, 4.85-4.99, 5.34-5.63, 6.86-7.09, 7.10-7.15, 7.21, 7.27-7.36, 7.39-7.46, 7.59-7.65, 7.82-7.93, 8.30, 8.52-8.72。 Reference example 112
2-Methyl-2-propanyl 6-[7-(6-{[9-(4-cyano-2-fluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3'): 4,5]pyrrolo[2,3-b]pyridin-7-yl]carbonyl}-3-pyridinyl)-6-methyl-8-oxo-2-{[4-(trifluoromethoxy)phenyl]amino}- 7,8-dihydro-9H-purin-9-yl]-2-azaspiro[3.3]heptane-2-carboxylate The compound prepared in Reference Example 111 (180 mg) was added with DMF (1.1 mL) and toluene (1.1 mL). ) was added and dissolved, and further 4-(trifluoromethoxy)aniline (81 mg), cesium carbonate (148 mg), Xantphos (40 mg), and palladium acetate (10 mg) were added, and the mixture was stirred at 115° C. for 1 hour in a nitrogen atmosphere. After the reaction solution was cooled to room temperature, it was diluted with ethyl acetate, and water was added. The organic layer was washed with water and saturated brine, and passed through an injection column Amino (trade name). The obtained filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (Fuji Silysia NH (trade name), hexane:ethyl acetate = 3:2 → 0:1) to obtain the title compound having the following physical properties. (147 mg) was obtained.
LC-MS (A) retention time (min): 1.31;
MS(ESI, Pos.): 930 (M + H) + ;
1 H-NMR (CDCl 3 ): δ 1.46, 2.05-2.11, 2.61-2.71, 2.99, 3.24-3.39, 3.94-4.18, 4.85-4.99, 5.34-5.63, 6.86-7.09, 7.10-7.15, 7.21, 7.2 7- 7.36, 7.39-7.46, 7.59-7.65, 7.82-7.93, 8.30, 8.52-8.72.
参考例１１３
４－｛［７－（｛５－［９－（２－アザスピロ［３．３］ヘプト－６－イル）－６－メチル－８－オキソ－２－｛［４－（トリフルオロメトキシ）フェニル］アミノ｝－８，９－ジヒドロ－７Ｈ－プリン－７－イル］－２－ピリジニル｝カルボニル）－５，６，７，８－テトラヒドロ－９Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－９－イル］メチル｝－３－フルオロベンゾニトリル
　参考例１１２で製造した化合物（144ｍｇ）にメタノール（1.4ｍＬ）とメタンスルホン酸（0.10ｍＬ）を加えて４０℃で１時間攪拌した。反応液を室温に冷却した後、飽和炭酸水素ナトリウム水溶液を加えて酢酸エチルで抽出した。得られた有機層を水と飽和食塩水で洗浄して無水硫酸ナトリウムで乾燥し、減圧濃縮することにより、以下の物性値を有する標題化合物（124ｍｇ）を得た。
LC－MS（A）保持時間（分）：1.06；
MS(ESI, Pos.)： 830 (M + H)＋。 Reference example 113
4-{[7-({5-[9-(2-azaspiro[3.3]hept-6-yl)-6-methyl-8-oxo-2-{[4-(trifluoromethoxy)phenyl] amino}-8,9-dihydro-7H-purin-7-yl]-2-pyridinyl}carbonyl)-5,6,7,8-tetrahydro-9H-pyrido[4',3':4,5]pyrrolo [2,3-b]pyridin-9-yl]methyl}-3-fluorobenzonitrile Methanol (1.4 mL) and methanesulfonic acid (0.10 mL) were added to the compound prepared in Reference Example 112 (144 mg) at 40°C. The mixture was stirred for 1 hour. After the reaction solution was cooled to room temperature, saturated aqueous sodium hydrogen carbonate solution was added and extracted with ethyl acetate. The obtained organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the title compound (124 mg) having the following physical properties.
LC-MS (A) retention time (min): 1.06;
MS(ESI, Pos.): 830 (M + H) + .
実施例４６
４－［（７－｛［５－（９－［２－（２，２－ジメチルプロピル）－２－アザスピロ［３．３］ヘプト－６－イル］－６－メチル－８－オキソ－２－｛［４－（トリフルオロメトキシ）フェニル］アミノ｝－８，９－ジヒドロ－７Ｈ－プリン－７－イル）－２－ピリジニル］カルボニル｝－５，６，７，８－テトラヒドロ－９Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－９－イル）メチル］－３－フルオロベンゾニトリル
　参考例９８で製造した化合物の代わりに参考例１１３で製造した化合物（28ｍｇ）を用いて、実施例３４と同様の操作を行い、以下の物性値を有する標題化合物（14ｍｇ）を得た。
LC－MS（A）保持時間（分）：1.14；
MS(ESI, Pos.)： 900 (M + H)＋；
１H-NMR(CDCl３)：δ　 0.88, 2.03-2.10, 2.23, 2.53-2.63, 2.99, 3.21-3.34, 3.35-3.39, 3.39-3.43, 3.91-4.22, 4.84-4.95, 5.39-5.64, 6.85-7.08, 7.09-7.15, 7.19, 7.28-7.34, 7.38-7.46, 7.59-7.66, 7.83-7.92, 8.29, 8.53-8.71。 Example 46
4-[(7-{[5-(9-[2-(2,2-dimethylpropyl)-2-azaspiro[3.3]hept-6-yl]-6-methyl-8-oxo-2- {[4-(trifluoromethoxy)phenyl]amino}-8,9-dihydro-7H-purin-7-yl)-2-pyridinyl]carbonyl}-5,6,7,8-tetrahydro-9H-pyrido[ 4',3':4,5]pyrrolo[2,3-b]pyridin-9-yl)methyl]-3-fluorobenzonitrile Instead of the compound produced in Reference Example 98, the compound produced in Reference Example 113 ( The same operation as in Example 34 was performed using 28 mg) to obtain the title compound (14 mg) having the following physical properties.
LC-MS (A) retention time (min): 1.14;
MS(ESI, Pos.): 900 (M + H) + ;
1 H-NMR (CDCl 3 ): δ 0.88, 2.03-2.10, 2.23, 2.53-2.63, 2.99, 3.21-3.34, 3.35-3.39, 3.39-3.43, 3.91-4.22, 4.84-4.95, 5.39-5.64, 6.8 5- 7.08, 7.09-7.15, 7.19, 7.28-7.34, 7.38-7.46, 7.59-7.66, 7.83-7.92, 8.29, 8.53-8.71.
実施例４７
１－｛［｛７－（６－｛［９－（４－シアノ－２－フルオロベンジル）－５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－イル］カルボニル｝－３－ピリジニル）－９－［１－（２，２－ジメチルプロピル）－４－ピペリジニル］－６－メチル－８－オキソ－８，９－ジヒドロ－７Ｈ－プリン－２－イル｝（シクロへキシル）アミノ］メチル｝シクロブタンカルボン酸
　参考例１０１で製造した化合物（100ｍｇ）を脱水ＤＭＳＯ（1.0ｍＬ）に溶解し、１－［（シクロヘキシルアミノ）メチル］シクロブタンカルボン酸塩酸塩（166ｍｇ）及びフッ化セシウム（101ｍｇ）、炭酸セシウム（436ｍｇ）を加えて１００℃で９時間攪拌した。反応液を室温に冷却し、飽和塩化アンモニウム水溶液を加えて酢酸エチルで抽出した。得られた有機層を水で洗浄して無水硫酸ナトリウムで乾燥し、減圧濃縮して得られた残渣をシリカゲルクロマトグラフィー（酢酸エチル：メタノール＝１：０→４：１）で精製することにより、以下の物性値を有する標題化合物（7ｍｇ）を得た。
LC－MS（A）保持時間（分）：1.14；
MS(ESI, Pos.)： 922 (M + H)＋；
１H-NMR(CDCl３)：δ　 0.99, 1.44-1.57, 1.61-1.95, 1.95-2.03, 2.07-2.19, 2.23, 2.33-2.46, 2.89-3.22, 3.71, 3.89-4.11, 4.25-4.65, 4.89, 5.33-5.73, 6.81-7.07, 7.12, 7.23-7.34, 7.34-7.49, 7.73-7.98, 8.29, 8.49-8.75。 Example 47
1-{[{7-(6-{[9-(4-cyano-2-fluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo [2,3-b]pyridin-7-yl]carbonyl}-3-pyridinyl)-9-[1-(2,2-dimethylpropyl)-4-piperidinyl]-6-methyl-8-oxo-8, 9-dihydro-7H-purin-2-yl}(cyclohexyl)amino]methyl}cyclobutanecarboxylic acid
The compound produced in Reference Example 101 (100 mg) was dissolved in dehydrated DMSO (1.0 mL), and 1-[(cyclohexylamino)methyl]cyclobutanecarboxylic hydrochloride (166 mg), cesium fluoride (101 mg), and cesium carbonate (436 mg) were dissolved in dehydrated DMSO (1.0 mL). ) and stirred at 100°C for 9 hours. The reaction solution was cooled to room temperature, a saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with water, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting residue was purified by silica gel chromatography (ethyl acetate: methanol = 1:0 → 4:1). The title compound (7 mg) having the following physical properties was obtained.
LC-MS (A) retention time (min): 1.14;
MS(ESI, Pos.): 922 (M + H) + ;
1 H-NMR (CDCl 3 ): δ 0.99, 1.44-1.57, 1.61-1.95, 1.95-2.03, 2.07-2.19, 2.23, 2.33-2.46, 2.89-3.22, 3.71, 3.89-4.11, 4.25-4.65, 4.8 9, 5.33-5.73, 6.81-7.07, 7.12, 7.23-7.34, 7.34-7.49, 7.73-7.98, 8.29, 8.49-8.75.
実施例４７－１～４
　１－［（シクロヘキシルアミノ）メチル］シクロブタンカルボン酸塩酸塩の代わりに対応するアミノ酸化合物を用いて、実施例４７と同様の操作を行い、シリカゲルカラム精製もしくは逆相HPLCカラム精製することにより、以下の物性値を有する標題化合物を得た。 Examples 47-1 to 4
Using the corresponding amino acid compound instead of 1-[(cyclohexylamino)methyl]cyclobutanecarboxylic hydrochloride, the same operation as in Example 47 was carried out, and the following was obtained by purifying with a silica gel column or a reverse phase HPLC column. The title compound having physical properties was obtained.
実施例４７－１
［｛７－（６－｛［９－（４－シアノ－２－フルオロベンジル）－５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－イル］カルボニル｝－３－ピリジニル）－９－［１－（２，２－ジメチルプロピル）－４－ピペリジニル］－６－メチル－８－オキソ－８，９－ジヒドロ－７Ｈ－プリン－２－イル｝（シクロへプチル）アミノ］酢酸　２トリフルオロ酢酸塩
LC－MS（A）保持時間（分）：1.09；
MS(ESI, Pos.)： 882 (M + H)＋；
１H-NMR(DMSO-d６)：δ　 0.85-0.92, 0.98-1.15, 1.36-1.77, 1.77-2.02, 2.03-2.17, 2.34-2.43, 2.63-2.97, 3.66-3.81, 3.98-4.25, 4.57-4.95, 5.33-5.71, 6.88-7.06, 7.08-7.19, 7.47-7.69, 7.71-7.89, 7.89-8.01, 8.01-8.17, 8.18-8.29, 8.52-8.84。 Example 47-1
[{7-(6-{[9-(4-cyano-2-fluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[2, 3-b]pyridin-7-yl]carbonyl}-3-pyridinyl)-9-[1-(2,2-dimethylpropyl)-4-piperidinyl]-6-methyl-8-oxo-8,9-dihydro -7H-purin-2-yl}(cycloheptyl)amino]acetic acid 2-trifluoroacetate
LC-MS (A) retention time (min): 1.09;
MS(ESI, Pos.): 882 (M + H) + ;
1 H-NMR (DMSO-d 6 ): δ 0.85-0.92, 0.98-1.15, 1.36-1.77, 1.77-2.02, 2.03-2.17, 2.34-2.43, 2.63-2.97, 3.66-3.81, 3.98-4.25, 4.57- 4.95, 5.33-5.71, 6.88-7.06, 7.08-7.19, 7.47-7.69, 7.71-7.89, 7.89-8.01, 8.01-8.17, 8.18-8.29, 8.52-8.84.
実施例４７－２
３－［｛７－（６－｛［９－（４－シアノ－２－フルオロベンジル）－５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－イル］カルボニル｝－３－ピリジニル）－９－［１－（２，２－ジメチルプロピル）－４－ピペリジニル］－６－メチル－８－オキソ－８，９－ジヒドロ－７Ｈ－プリン－２－イル｝（シクロペンチル）アミノ］－２，２－ジメチルプロパン酸
LC－MS（A）保持時間（分）：1.13；
MS(ESI, Pos.)： 896 (M + H)＋；
１H-NMR(CDCl３)：δ　 1.02, 1.24-1.27, 1.67-1.93, 1.95-2.01, 2.26-2.40, 2.94-3.03, 3.15-3.35, 3.67-3.90, 3.91-4.16, 4.36-4.58, 4.86-4.93, 5.37-5.63, 6.86-7.08, 7.09-7.14, 7.25-7.34, 7.40-7.47, 7.79-7.89, 8.29, 8.54-8.69。 Example 47-2
3-[{7-(6-{[9-(4-cyano-2-fluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[ 2,3-b]pyridin-7-yl]carbonyl}-3-pyridinyl)-9-[1-(2,2-dimethylpropyl)-4-piperidinyl]-6-methyl-8-oxo-8,9 -dihydro-7H-purin-2-yl}(cyclopentyl)amino]-2,2-dimethylpropanoic acid
LC-MS (A) retention time (min): 1.13;
MS(ESI, Pos.): 896 (M + H) + ;
1 H-NMR (CDCl 3 ): δ 1.02, 1.24-1.27, 1.67-1.93, 1.95-2.01, 2.26-2.40, 2.94-3.03, 3.15-3.35, 3.67-3.90, 3.91-4.16, 4.36-4.58, 4.86 - 4.93, 5.37-5.63, 6.86-7.08, 7.09-7.14, 7.25-7.34, 7.40-7.47, 7.79-7.89, 8.29, 8.54-8.69.
実施例４７－３
１－｛［｛７－（６－｛［９－（４－シアノ－２－フルオロベンジル）－５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－イル］カルボニル｝－３－ピリジニル）－９－［１－（２，２－ジメチルプロピル）－４－ピペリジニル］－６－メチル－８－オキソ－８，９－ジヒドロ－７Ｈ－プリン－２－イル｝（シクロペンチル）アミノ］メチル｝シクロブタンカルボン酸
LC－MS（A）保持時間（分）：1.12；
MS(ESI, Pos.)： 908 (M + H)＋；
１H-NMR (CDCl３)：δ　 1.03, 1.61-1.79, 1.82-2.03, 2.07-2.15, 2.30, 2.33-2.48, 2.93-3.03, 3.10-3.28, 3.87, 3.91-4.17, 4.34-4.47, 4.68-4.81, 4.89, 5.36-5.64, 6.86-7.08, 7.12, 7.24-7.33, 7.38-7.47, 7.78-7.90, 8.29, 8.53-8.70。 Example 47-3
1-{[{7-(6-{[9-(4-cyano-2-fluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo [2,3-b]pyridin-7-yl]carbonyl}-3-pyridinyl)-9-[1-(2,2-dimethylpropyl)-4-piperidinyl]-6-methyl-8-oxo-8, 9-dihydro-7H-purin-2-yl}(cyclopentyl)amino]methyl}cyclobutanecarboxylic acid
LC-MS (A) retention time (min): 1.12;
MS(ESI, Pos.): 908 (M + H) + ;
1 H-NMR (CDCl 3 ): δ 1.03, 1.61-1.79, 1.82-2.03, 2.07-2.15, 2.30, 2.33-2.48, 2.93-3.03, 3.10-3.28, 3.87, 3.91-4.17, 4.34-4.47, 4.6 8- 4.81, 4.89, 5.36-5.64, 6.86-7.08, 7.12, 7.24-7.33, 7.38-7.47, 7.78-7.90, 8.29, 8.53-8.70.
実施例４７－４
４－（｛７－［（５－｛９－［１－（２，２－ジメチルプロピル）－４－ピペリジニル］－６－メチル－８－オキソ－２－フェノキシ－８，９－ジヒドロ－７Ｈ－プリン－７－イル｝－２－ピリジニル）カルボニル］－５，６，７，８－テトラヒドロ－９Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－９－イル｝メチル）－３－フルオロベンゾニトリル　２トリフルオロ酢酸塩
LC－MS（A）保持時間（分）：1.06；
MS(ESI, Pos.)： 805 (M + H)＋；
１H-NMR(DMSO-d６)：δ　 1.00-1.14, 1.80-1.94, 1.95-2.13, 2.66-2.80, 2.77-2.94, 2.94-3.11, 3.62-3.81, 3.97-4.42, 4.57-4.98, 5.36-5.72, 6.92-7.09, 7.09-7.34, 7.37-7.68, 7.71-8.01, 8.01-8.28, 8.32-8.55, 8.60-8.93。 Example 47-4
4-({7-[(5-{9-[1-(2,2-dimethylpropyl)-4-piperidinyl]-6-methyl-8-oxo-2-phenoxy-8,9-dihydro-7H- purin-7-yl}-2-pyridinyl)carbonyl]-5,6,7,8-tetrahydro-9H-pyrido[4',3':4,5]pyrrolo[2,3-b]pyridine-9- yl}methyl)-3-fluorobenzonitrile 2-trifluoroacetate
LC-MS (A) retention time (min): 1.06;
MS(ESI, Pos.): 805 (M + H) + ;
1 H-NMR (DMSO-d 6 ): δ 1.00-1.14, 1.80-1.94, 1.95-2.13, 2.66-2.80, 2.77-2.94, 2.94-3.11, 3.62-3.81, 3.97-4.42, 4.57-4.98, 5.36- 5.72, 6.92-7.09, 7.09-7.34, 7.37-7.68, 7.71-8.01, 8.01-8.28, 8.32-8.55, 8.60-8.93.
実施例４８
１－｛［｛７－（６－｛［９－（４－シアノ－２－フルオロベンジル）－５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－イル］カルボニル｝－３－ピリジニル）－９－［１－（２，２－ジメチルプロピル）－４－ピペリジニル］－６－メチル－８－オキソ－８，９－ジヒドロ－７Ｈ－プリン－２－イル｝（シクロヘキシル）アミノ］メチル｝シクロブタンカルボキサミド
　実施例４７で製造した化合物（782ｍｇ）をＤＭＦ（17ｍＬ）に溶解し、塩化アンモニウム（181ｍｇ）とＤＩＰＥＡ（0.73ｍＬ）、ＨＡＴＵ（644ｍｇ）を加えて室温で１７時間攪拌した。反応液に飽和炭酸水素ナトリウム水溶液を加えて酢酸エチルで抽出し、得られた有機層を水で洗浄して無水硫酸ナトリウムで乾燥した。減圧濃縮して得られた残渣をシリカゲルクロマトグラフィー（富士シリシア　ＮＨ（商品名）、ヘキサン：酢酸エチル＝３３：６７→０：１）で精製することにより、以下の物性値を有する標題化合物（742ｍｇ）を得た。
LC－MS（A）保持時間（分）：1.15；
MS(ESI, Pos.)： 921 (M + H)＋；
１H-NMR(CDCl３)：δ　 0.91, 1.40-1.56, 1.61-1.93, 1.93-2.07, 2.07-2.23, 2.31-2.47, 2.73-2.93, 2.93-3.07, 3.77, 3.89-4.14, 4.20-4.37, 4.89, 5.16-5.37, 5.38-5.65, 6.85-7.06, 7.08-7.21, 7.25-7.34, 7.38-7.48, 7.80-7.90, 8.29, 8.56-8.73。 Example 48
1-{[{7-(6-{[9-(4-cyano-2-fluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo [2,3-b]pyridin-7-yl]carbonyl}-3-pyridinyl)-9-[1-(2,2-dimethylpropyl)-4-piperidinyl]-6-methyl-8-oxo-8, 9-dihydro-7H-purin-2-yl}(cyclohexyl)amino]methyl}cyclobutanecarboxamide The compound prepared in Example 47 (782 mg) was dissolved in DMF (17 mL), and ammonium chloride (181 mg) and DIPEA (0.73 mL) were dissolved. ) and HATU (644 mg) were added and stirred at room temperature for 17 hours. A saturated aqueous sodium bicarbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate, and the resulting organic layer was washed with water and dried over anhydrous sodium sulfate. The residue obtained by concentration under reduced pressure was purified by silica gel chromatography (Fuji Silysia NH (trade name), hexane:ethyl acetate = 33:67 → 0:1) to obtain the title compound (742 mg) having the following physical property values. ) was obtained.
LC-MS (A) retention time (min): 1.15;
MS(ESI, Pos.): 921 (M + H) + ;
1 H-NMR (CDCl 3 ): δ 0.91, 1.40-1.56, 1.61-1.93, 1.93-2.07, 2.07-2.23, 2.31-2.47, 2.73-2.93, 2.93-3.07, 3.77, 3.89-4.14, 4.20-4.37 , 4.89, 5.16-5.37, 5.38-5.65, 6.85-7.06, 7.08-7.21, 7.25-7.34, 7.38-7.48, 7.80-7.90, 8.29, 8.56-8.73.
参考例１１４
エチル　２－クロロ－７－（６－｛［９－（４－シアノ－２－フルオロベンジル）－５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－イル］カルボニル｝－３－ピリジニル）－９－（１－｛［（２－メチル－２－プロパニル）オキシ］カルボニル｝－４－ピペリジニル）－８－オキソ－８，９－ジヒドロ－７Ｈ－プリン－６－カルボキシラート
　参考例５９で用いた参考例５７で製造した化合物の代わりに参考例１０６で製造した化合物を用いて、参考例５９→参考例６０と同様の操作を行い、以下の物性値を有する標題化合物を得た。
LC－MS（A）保持時間（分）：1.25；
MS(ESI, Pos.)： 835 (M + H)＋。 Reference example 114
Ethyl 2-chloro-7-(6-{[9-(4-cyano-2-fluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo [2,3-b]pyridin-7-yl]carbonyl}-3-pyridinyl)-9-(1-{[(2-methyl-2-propanyl)oxy]carbonyl}-4-piperidinyl)-8-oxo -8,9-dihydro-7H-purine-6-carboxylate Using the compound produced in Reference Example 106 instead of the compound produced in Reference Example 57 used in Reference Example 59, the procedure was as follows: Reference Example 59 → Reference Example 60. A similar operation was performed to obtain the title compound having the following physical properties.
LC-MS (A) retention time (min): 1.25;
MS(ESI, Pos.): 835 (M + H) + .
参考例１１５（実施例４８－Ａ）
エチル　７－（６－｛［９－（４－シアノ－２－フルオロベンジル）－５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－イル］カルボニル｝－３－ピリジニル）－９－（１－｛［（２－メチル－２－プロパニル）オキシ］カルボニル｝－４－ピペリジニル）－８－オキソ－２－｛［４－（トリフルオロメトキシ）フェニル］アミノ｝－８，９－ジヒドロ－７Ｈ－プリン－６－カルボキシラート
　参考例６１で製造した化合物の代わりに参考例１１４で製造した化合物（400ｍｇ）を用いて、参考例６２と同様の操作を行い、以下の物性値を有する標題化合物（360ｍｇ）を得た。
LC－MS（A）保持時間（分）：1.38；
MS(ESI, Pos.)： 976 (M + H)＋；
１H-NMR(CDCl３)：δ　 1.07-1.14, 1.52, 1.83-1.97, 2.56-2.74, 2.79-2.95, 2.95-3.02, 3.91-4.20, 4.28-4.49, 4.51-4.67, 4.84-4.91, 5.41-5.66, 6.90-7.00, 7.12, 7.20-7.25, 7.32, 7.42, 7.65-7.70, 7.70-7.91, 8.29, 8.47-8.64。 Reference example 115 (Example 48-A)
Ethyl 7-(6-{[9-(4-cyano-2-fluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[2,3 -b]pyridin-7-yl]carbonyl}-3-pyridinyl)-9-(1-{[(2-methyl-2-propanyl)oxy]carbonyl}-4-piperidinyl)-8-oxo-2-{ [4-(trifluoromethoxy)phenyl]amino}-8,9-dihydro-7H-purine-6-carboxylate Using the compound produced in Reference Example 114 (400 mg) instead of the compound produced in Reference Example 61 The same operation as in Reference Example 62 was performed to obtain the title compound (360 mg) having the following physical properties.
LC-MS (A) retention time (min): 1.38;
MS(ESI, Pos.): 976 (M + H) + ;
1 H-NMR (CDCl 3 ): δ 1.07-1.14, 1.52, 1.83-1.97, 2.56-2.74, 2.79-2.95, 2.95-3.02, 3.91-4.20, 4.28-4.49, 4.51-4.67, 4.84-4.91, 5.41 - 5.66, 6.90-7.00, 7.12, 7.20-7.25, 7.32, 7.42, 7.65-7.70, 7.70-7.91, 8.29, 8.47-8.64.
実施例４９
７－（６－｛［９－（４－シアノ－２－フルオロベンジル）－５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－イル］カルボニル｝－３－ピリジニル）－９－（１－｛［（２－メチル－２－プロパニル）オキシ］カルボニル｝－４－ピペリジニル）－８－オキソ－２－｛［４－（トリフルオロメトキシ）フェニル］アミノ｝－８，９－ジヒドロ－７Ｈ－プリン－６－カルボン酸
　参考例６２で製造した化合物の代わりに参考例１１５で製造した化合物（400ｍｇ）を用いて、参考例６３と同様の操作を行い、以下の物性値を有する標題化合物（360ｍｇ）を得た。
LC－MS（A）保持時間（分）：1.27；
MS(ESI, Pos.)： 948 (M + H)＋；
１H-NMR(DMSO-d６)：δ　 1.38-1.48, 1.68-1.94, 2.35-2.46, 2.75-3.04, 3.25-3.32, 3.64-4.05, 4.05-4.33, 4.39-4.62, 4.62-4.96, 5.39-5.71, 6.87-7.32, 7.42-7.77, 7.77-8.01, 8.03-8.14, 8.16-8.32, 8.42-8.65, 9.73-10.06。 Example 49
7-(6-{[9-(4-cyano-2-fluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[2,3- b]Pyridin-7-yl]carbonyl}-3-pyridinyl)-9-(1-{[(2-methyl-2-propanyl)oxy]carbonyl}-4-piperidinyl)-8-oxo-2-{[ 4-(trifluoromethoxy)phenyl]amino}-8,9-dihydro-7H-purine-6-carboxylic acid Using the compound produced in Reference Example 115 (400 mg) instead of the compound produced in Reference Example 62, The same operation as in Reference Example 63 was performed to obtain the title compound (360 mg) having the following physical properties.
LC-MS (A) retention time (min): 1.27;
MS(ESI, Pos.): 948 (M + H) + ;
1 H-NMR (DMSO-d 6 ): δ 1.38-1.48, 1.68-1.94, 2.35-2.46, 2.75-3.04, 3.25-3.32, 3.64-4.05, 4.05-4.33, 4.39-4.62, 4.62-4.96, 5.39- 5.71, 6.87-7.32, 7.42-7.77, 7.77-8.01, 8.03-8.14, 8.16-8.32, 8.42-8.65, 9.73-10.06.
参考例１１６（実施例４９－Ａ）
エチル　２－クロロ－７－（６－｛［９－（４－シアノ－２－フルオロベンジル）－５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－イル］カルボニル｝－３－ピリジニル）－９－［１－（２，２－ジメチルプロピル）－４－ピペリジニル］－８－オキソ－８，９－ジヒドロ－７Ｈ－プリン－６－カルボキシラート
　参考例６０で製造した化合物の代わりに参考例１１４で製造した化合物を用いて、参考例６１と同様の操作を行い、以下の物性値を有する標題化合物を得た。
LC－MS（A）保持時間（分）：1.06；
MS(ESI, Pos.)： 805 (M + H)＋；
１H-NMR(DMSO-d６)：δ　 0.84-0.93, 1.00-1.07, 1.69-1.83, 2.09-2.15, 2.35-2.46, 2.57-2.68, 2.81-3.01, 3.66-3.97, 3.97-4.13, 4.25-4.44, 4.65-5.00, 5.34-5.78, 6.94-7.07, 7.10-7.19, 7.49-7.68, 7.70-7.82, 7.81-7.90, 7.91-8.02, 8.02-8.30, 8.47-8.75。 Reference example 116 (Example 49-A)
Ethyl 2-chloro-7-(6-{[9-(4-cyano-2-fluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo [2,3-b]pyridin-7-yl]carbonyl}-3-pyridinyl)-9-[1-(2,2-dimethylpropyl)-4-piperidinyl]-8-oxo-8,9-dihydro- 7H-Purine-6-carboxylate Using the compound produced in Reference Example 114 instead of the compound produced in Reference Example 60, the same operation as in Reference Example 61 was performed to obtain the title compound having the following physical property values. .
LC-MS (A) retention time (min): 1.06;
MS(ESI, Pos.): 805 (M + H) + ;
1 H-NMR (DMSO-d 6 ): δ 0.84-0.93, 1.00-1.07, 1.69-1.83, 2.09-2.15, 2.35-2.46, 2.57-2.68, 2.81-3.01, 3.66-3.97, 3.97-4.13, 4.25- 4.44, 4.65-5.00, 5.34-5.78, 6.94-7.07, 7.10-7.19, 7.49-7.68, 7.70-7.82, 7.81-7.90, 7.91-8.02, 8.02-8.30, 8.47-8.75.
参考例１１７
７－（６－｛［９－（４－シアノ－２－フルオロベンジル）－５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－イル］カルボニル｝－３－ピリジニル）－９－［１－（２，２－ジメチルプロピル）－４－ピペリジニル］－８－オキソ－２－｛［４－（トリフルオロメトキシ）フェニル］アミノ｝－８，９－ジヒドロ－７Ｈ－プリン－６－カルボン酸
　参考例６１で製造した化合物の代わりに参考例１１６で製造した化合物を用いて、参考例６２→参考例６３と同様の操作を行い、以下の物性値を有する標題化合物を得た。
LC－MS（A）保持時間（分）：1.02；
MS(ESI, Pos.)： 918 (M + H)＋。 Reference example 117
7-(6-{[9-(4-cyano-2-fluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[2,3- b]Pyridin-7-yl]carbonyl}-3-pyridinyl)-9-[1-(2,2-dimethylpropyl)-4-piperidinyl]-8-oxo-2-{[4-(trifluoromethoxy) phenyl]amino}-8,9-dihydro-7H-purine-6-carboxylic acid Using the compound produced in Reference Example 116 instead of the compound produced in Reference Example 61, the same procedure as in Reference Example 62 → Reference Example 63 was carried out. The operation was carried out to obtain the title compound having the following physical properties.
LC-MS (A) retention time (min): 1.02;
MS(ESI, Pos.): 918 (M + H) + .
実施例５０
７－（６－｛［９－（４－シアノ－２－フルオロベンジル）－５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－イル］カルボニル｝－３－ピリジニル）－９－［１－（２，２－ジメチルプロピル）－４－ピペリジニル］－Ｎ－メチル－８－オキソ－２－｛［４－（トリフルオロメトキシ）フェニル］アミノ｝－８，９－ジヒドロ－７Ｈ－プリン－６－カルボキサミド　２トリフルオロ酢酸塩
　参考例１１７で製造した化合物（20ｍｇ）をＤＭＦ（0.4ｍＬ）に溶解し、ＤＩＰＥＡ（0.038ｍＬ）とメチルアミン塩酸塩（3.4ｍｇ）、ＤＭＴＭＭ（18ｍｇ）を加えて１０分攪拌した。反応液を逆相HPLCカラム精製することにより、以下の物性値を有する標題化合物（12ｍｇ）を得た。
LC－MS（A）保持時間（分）：1.03；
MS(ESI, Pos.)： 931 (M + H)＋；
１H-NMR(DMSO-d６)：δ　 1.02-1.14, 2.04-2.20, 2.41-2.48, 2.80-2.98, 3.07, 3.18-3.25, 3.27-3.33, 3.61-3.78, 3.97-4.38, 4.57-4.95, 5.36-5.74, 6.90-7.07, 7.11-7.20, 7.26-7.42, 7.43-7.57, 7.58-7.66, 7.71-8.02, 8.18-8.27, 8.27-8.64, 8.64-8.98, 9.79-9.88。 Example 50
7-(6-{[9-(4-cyano-2-fluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[2,3- b]pyridin-7-yl]carbonyl}-3-pyridinyl)-9-[1-(2,2-dimethylpropyl)-4-piperidinyl]-N-methyl-8-oxo-2-{[4-( Trifluoromethoxy)phenyl]amino}-8,9-dihydro-7H-purine-6-carboxamide 2 trifluoroacetate The compound prepared in Reference Example 117 (20 mg) was dissolved in DMF (0.4 mL), and DIPEA (0.038 mL), methylamine hydrochloride (3.4 mg), and DMTMM (18 mg) were added and stirred for 10 minutes. The reaction solution was purified using a reverse phase HPLC column to obtain the title compound (12 mg) having the following physical properties.
LC-MS (A) retention time (min): 1.03;
MS(ESI, Pos.): 931 (M + H) + ;
1 H-NMR (DMSO-d 6 ): δ 1.02-1.14, 2.04-2.20, 2.41-2.48, 2.80-2.98, 3.07, 3.18-3.25, 3.27-3.33, 3.61-3.78, 3.97-4.38, 4.57-4.95, 5.36-5.74, 6.90-7.07, 7.11-7.20, 7.26-7.42, 7.43-7.57, 7.58-7.66, 7.71-8.02, 8.18-8.27, 8.27-8.64, 8.64-8.98, 9.79-9.88.
実施例５０－１～７
　メチルアミン塩酸塩の代わりに対応するアミン化合物を用いて、実施例５０と同様の操作を行い、反応液を濃縮してろ取することにより、または、シリカゲルカラム精製もしくは逆相HPLCカラム精製することにより、以下の物性値を有する標題化合物を得た。 Examples 50-1 to 7
By carrying out the same operation as in Example 50 using the corresponding amine compound instead of methylamine hydrochloride, concentrating the reaction solution and collecting it by filtration, or by purifying with a silica gel column or reversed phase HPLC column. , the title compound having the following physical properties was obtained.
実施例５０－１
７－（６－｛［９－（４－シアノ－２－フルオロベンジル）－５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－イル］カルボニル｝－３－ピリジニル）－９－［１－（２，２－ジメチルプロピル）－４－ピペリジニル］－８－オキソ－２－｛［４－（トリフルオロメトキシ）フェニル］アミノ｝－８，９－ジヒドロ－７Ｈ－プリン－６－カルボヒドラジド
LC－MS（A）保持時間（分）：1.06；
MS(ESI, Pos.)： 932 (M + H)＋；
１H-NMR (CDCl３)：δ　 0.95, 1.71-1.82, 2.14, 2.40-2.49, 2.71-2.83, 2.94-3.03, 3.79-3.86, 3.94-4.17, 4.34-4.46, 4.86-4.96, 5.39-5.63, 6.84-7.04, 7.07-7.14, 7.27-7.32, 7.36-7.44, 7.63, 7.70-7.87, 8.28, 8.40-8.59。 Example 50-1
7-(6-{[9-(4-cyano-2-fluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[2,3- b]Pyridin-7-yl]carbonyl}-3-pyridinyl)-9-[1-(2,2-dimethylpropyl)-4-piperidinyl]-8-oxo-2-{[4-(trifluoromethoxy) phenyl]amino}-8,9-dihydro-7H-purine-6-carbohydrazide
LC-MS (A) retention time (min): 1.06;
MS(ESI, Pos.): 932 (M + H) + ;
1 H-NMR (CDCl 3 ): δ 0.95, 1.71-1.82, 2.14, 2.40-2.49, 2.71-2.83, 2.94-3.03, 3.79-3.86, 3.94-4.17, 4.34-4.46, 4.86-4.96, 5.39-5.63 , 6.84-7.04, 7.07-7.14, 7.27-7.32, 7.36-7.44, 7.63, 7.70-7.87, 8.28, 8.40-8.59.
実施例５０－２
７－（６－｛［９－（４－シアノ－２－フルオロベンジル）－５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－イル］カルボニル｝－３－ピリジニル）－９－［１－（２，２－ジメチルプロピル）－４－ピペリジニル］－Ｎ－ヒドロキシ－８－オキソ－２－｛［４－（トリフルオロメトキシ）フェニル］アミノ｝－８，９－ジヒドロ－７Ｈ－プリン－６－カルボキサミド　２塩酸塩
LC－MS（A）保持時間（分）：1.07；
MS(ESI, Pos.)： 933 (M + H)＋；
１H-NMR(DMSO-d６)：δ　 1.05-1.15, 2.03-2.16, 2.78-2.95, 2.98-3.09, 3.14-3.22, 3.24-3.39, 3.68-4.08, 4.53-4.83, 4.90, 5.39-5.77, 6.93-7.18, 7.27-7.40, 7.48-8.04, 8.16-8.28, 8.42-8.69, 8.91-9.62, 9.85, 9.98-10.18, 10.77, 11.15。 Example 50-2
7-(6-{[9-(4-cyano-2-fluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[2,3- b]pyridin-7-yl]carbonyl}-3-pyridinyl)-9-[1-(2,2-dimethylpropyl)-4-piperidinyl]-N-hydroxy-8-oxo-2-{[4-( trifluoromethoxy)phenyl]amino}-8,9-dihydro-7H-purine-6-carboxamide dihydrochloride
LC-MS (A) retention time (min): 1.07;
MS(ESI, Pos.): 933 (M + H) + ;
1 H-NMR (DMSO-d 6 ): δ 1.05-1.15, 2.03-2.16, 2.78-2.95, 2.98-3.09, 3.14-3.22, 3.24-3.39, 3.68-4.08, 4.53-4.83, 4.90, 5.39-5.77, 6.93-7.18, 7.27-7.40, 7.48-8.04, 8.16-8.28, 8.42-8.69, 8.91-9.62, 9.85, 9.98-10.18, 10.77, 11.15.
実施例５０－３
７－（６－｛［９－（４－シアノ－２－フルオロベンジル）－５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－イル］カルボニル｝－３－ピリジニル）－９－［１－（２，２－ジメチルプロピル）－４－ピペリジニル］－Ｎ－（１－メチル－３－アゼチジニル）－８－オキソ－２－｛［４－（トリフルオロメトキシ）フェニル］アミノ｝－８，９－ジヒドロ－７Ｈ－プリン－６－カルボキサミド　２トリフルオロ酢酸塩
LC－MS（A）保持時間（分）：0.98；
MS(ESI, Pos.)： 986 (M + H)＋；
１H-NMR(DMSO-d６)：δ　 0.97-1.14, 1.98-2.18, 2.74-2.96, 3.03-3.23, 3.64-4.09, 4.09-4.26, 4.26-4.48, 4.53-4.85, 4.85-4.98, 5.40-5.74, 6.93-7.28, 7.29-7.48, 7.48-7.74, 7.74-8.05, 8.19-8.67, 8.68-9.06, 9.24-9.54, 9.54-10.04。 Example 50-3
7-(6-{[9-(4-cyano-2-fluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[2,3- b]pyridin-7-yl]carbonyl}-3-pyridinyl)-9-[1-(2,2-dimethylpropyl)-4-piperidinyl]-N-(1-methyl-3-azetidinyl)-8-oxo -2-{[4-(trifluoromethoxy)phenyl]amino}-8,9-dihydro-7H-purine-6-carboxamide 2 trifluoroacetate
LC-MS (A) retention time (min): 0.98;
MS(ESI, Pos.): 986 (M + H) + ;
1 H-NMR (DMSO-d 6 ): δ 0.97-1.14, 1.98-2.18, 2.74-2.96, 3.03-3.23, 3.64-4.09, 4.09-4.26, 4.26-4.48, 4.53-4.85, 4.85-4.98, 5.40- 5.74, 6.93-7.28, 7.29-7.48, 7.48-7.74, 7.74-8.05, 8.19-8.67, 8.68-9.06, 9.24-9.54, 9.54-10.04.
実施例５０－４
７－（６－｛［９－（４－シアノ－２－フルオロベンジル）－５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－イル］カルボニル｝－３－ピリジニル）－Ｎ－シクロプロピル－９－［１－（２，２－ジメチルプロピル）－４－ピペリジニル］－８－オキソ－２－｛［４－（トリフルオロメトキシ）フェニル］アミノ｝－８，９－ジヒドロ－７Ｈ－プリン－６－カルボキサミド　２トリフルオロ酢酸塩
LC－MS（A）保持時間（分）：1.08；
MS(ESI, Pos.)： 957 (M + H)＋；
１H-NMR(DMSO-d６)：δ　 0.25-0.42, 0.42-0.55, 0.56-0.66, 1.02-1.16, 1.96-2.23, 2.78-3.01, 3.04-3.12, 3.16-3.25, 3.30-3.33, 3.65-3.87, 3.99-4.40, 4.51-5.00, 5.40-5.74, 6.90-7.26, 7.27-7.42, 7.42-7.66, 7.66-7.91, 7.91-8.04, 8.20-8.30, 8.34-8.48, 8.52-8.69, 8.69-8.99, 9.81-9.93。 Example 50-4
7-(6-{[9-(4-cyano-2-fluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[2,3- b]pyridin-7-yl]carbonyl}-3-pyridinyl)-N-cyclopropyl-9-[1-(2,2-dimethylpropyl)-4-piperidinyl]-8-oxo-2-{[4- (trifluoromethoxy)phenyl]amino}-8,9-dihydro-7H-purine-6-carboxamide 2 trifluoroacetate
LC-MS (A) retention time (min): 1.08;
MS(ESI, Pos.): 957 (M + H) + ;
1 H-NMR (DMSO-d 6 ): δ 0.25-0.42, 0.42-0.55, 0.56-0.66, 1.02-1.16, 1.96-2.23, 2.78-3.01, 3.04-3.12, 3.16-3.25, 3.30-3.33, 3.65- 3.87, 3.99-4.40, 4.51-5.00, 5.40-5.74, 6.90-7.26, 7.27-7.42, 7.42-7.66, 7.66-7.91, 7.91-8.04, 8.20-8.30, 8.34-8.48, 8.52-8. 69, 8.69-8.99, 9.81-9.93.
実施例５０－５
７－（６－｛［９－（４－シアノ－２－フルオロベンジル）－５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－イル］カルボニル｝－３－ピリジニル）－９－［１－（２，２－ジメチルプロピル）－４－ピペリジニル］－Ｎ’－メチル－８－オキソ－２－｛［４－（トリフルオロメトキシ）フェニル］アミノ｝－８，９－ジヒドロ－７Ｈ－プリン－６－カルボヒドラジド　３塩酸塩
LC－MS（A）保持時間（分）：1.09；
MS(ESI, Pos.)： 946 (M + H)＋；
１H-NMR(DMSO-d６)：δ　 1.06-1.14, 2.02-2.22, 2.53-2.58, 2.79-2.92, 2.98-3.10, 3.15-3.25, 3.69-4.08, 4.54-4.80, 4.83-4.96, 5.34-5.76, 6.93-7.05, 7.09-7.20, 7.28-7.42, 7.47-8.05, 8.20-8.25, 8.38-8.71, 8.84-9.12, 9.34-9.57, 9.87-10.00, 10.94-11.31。 Example 50-5
7-(6-{[9-(4-cyano-2-fluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[2,3- b]pyridin-7-yl]carbonyl}-3-pyridinyl)-9-[1-(2,2-dimethylpropyl)-4-piperidinyl]-N'-methyl-8-oxo-2-{[4- (Trifluoromethoxy)phenyl]amino}-8,9-dihydro-7H-purine-6-carbohydrazide trihydrochloride
LC-MS (A) retention time (min): 1.09;
MS(ESI, Pos.): 946 (M + H) + ;
1 H-NMR (DMSO-d 6 ): δ 1.06-1.14, 2.02-2.22, 2.53-2.58, 2.79-2.92, 2.98-3.10, 3.15-3.25, 3.69-4.08, 4.54-4.80, 4.83-4.96, 5.34- 5.76, 6.93-7.05, 7.09-7.20, 7.28-7.42, 7.47-8.05, 8.20-8.25, 8.38-8.71, 8.84-9.12, 9.34-9.57, 9.87-10.00, 10.94-11.31.
実施例５０－６
７－（６－｛［９－（４－シアノ－２－フルオロベンジル）－５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－イル］カルボニル｝－３－ピリジニル）－９－［１－（２，２－ジメチルプロピル）－４－ピペリジニル］－８－オキソ－Ｎ－（１－ピペリジニル）－２－｛［４－（トリフルオロメトキシ）フェニル］アミノ｝－８，９－ジヒドロ－７Ｈ－プリン－６－カルボキサミド　２トリフルオロ酢酸塩
LC－MS（A）保持時間（分）：1.09；
MS(ESI, Pos.)： 1000 (M + H)＋；
１H-NMR(DMSO-d６)：δ　 0.99-1.15, 1.15-1.33, 1.42-1.57, 2.02-2.26, 2.43-2.48, 2.54-2.58, 2.70-3.02, 3.02-3.25, 3.63-3.81, 3.96-4.06, 4.53-4.83, 4.86-4.96, 5.49-5.74, 6.89-7.24, 7.26-7.40, 7.51-7.65, 7.65-8.01, 8.16-8.27, 8.43-8.64, 8.64-8.98, 9.37-9.58, 9.84-9.96。 Example 50-6
7-(6-{[9-(4-cyano-2-fluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[2,3- b]Pyridin-7-yl]carbonyl}-3-pyridinyl)-9-[1-(2,2-dimethylpropyl)-4-piperidinyl]-8-oxo-N-(1-piperidinyl)-2-{ [4-(trifluoromethoxy)phenyl]amino}-8,9-dihydro-7H-purine-6-carboxamide 2 trifluoroacetate
LC-MS (A) retention time (min): 1.09;
MS(ESI, Pos.): 1000 (M + H) + ;
1 H-NMR (DMSO-d 6 ): δ 0.99-1.15, 1.15-1.33, 1.42-1.57, 2.02-2.26, 2.43-2.48, 2.54-2.58, 2.70-3.02, 3.02-3.25, 3.63-3.81, 3.96- 4.06, 4.53-4.83, 4.86-4.96, 5.49-5.74, 6.89-7.24, 7.26-7.40, 7.51-7.65, 7.65-8.01, 8.16-8.27, 8.43-8.64, 8.64-8.98, 9.37-9. 58, 9.84-9.96.
実施例５０－７
７－（６－｛［９－（４－シアノ－２－フルオロベンジル）－５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－イル］カルボニル｝－３－ピリジニル）－９－［１－（２，２－ジメチルプロピル）－４－ピペリジニル］－８－オキソ－Ｎ－［（３Ｓ）－テトラヒドロ－３－フラニル］－２－｛［４－（トリフルオロメトキシ）フェニル］アミノ｝－８，９－ジヒドロ－７Ｈ－プリン－６－カルボキサミド　２トリフルオロ酢酸塩
LC－MS（A）保持時間（分）：1.06；
MS(ESI, Pos.)： 987 (M + H)＋；
１H-NMR(DMSO-d６)：δ　 1.01-1.15, 1.52-1.72, 1.94-2.23, 2.59-2.65, 2.79-3.03, 3.03-3.11, 3.16-3.22, 3.26-3.32, 3.48-3.61, 3.61-3.82, 3.88-4.09, 4.91, 5.37-5.77, 6.89-7.07, 7.07-7.21, 7.27-7.43, 7.48-7.65, 7.65-7.91, 7.91-8.02, 8.19-8.44, 8.50-8.96, 9.84-10.03。 Example 50-7
7-(6-{[9-(4-cyano-2-fluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[2,3- b]pyridin-7-yl]carbonyl}-3-pyridinyl)-9-[1-(2,2-dimethylpropyl)-4-piperidinyl]-8-oxo-N-[(3S)-tetrahydro-3- Furanyl]-2-{[4-(trifluoromethoxy)phenyl]amino}-8,9-dihydro-7H-purine-6-carboxamide 2 trifluoroacetate
LC-MS (A) retention time (min): 1.06;
MS(ESI, Pos.): 987 (M + H) + ;
1 H-NMR (DMSO-d 6 ): δ 1.01-1.15, 1.52-1.72, 1.94-2.23, 2.59-2.65, 2.79-3.03, 3.03-3.11, 3.16-3.22, 3.26-3.32, 3.48-3.61, 3.61- 3.82, 3.88-4.09, 4.91, 5.37-5.77, 6.89-7.07, 7.07-7.21, 7.27-7.43, 7.48-7.65, 7.65-7.91, 7.91-8.02, 8.19-8.44, 8.50-8.96, 9 .84-10.03.
実施例５１
７－（６－｛［９－（４－シアノ－２－フルオロベンジル）－５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－イル］カルボニル｝－３－ピリジニル）－９－［１－（２，２－ジメチルプロピル）－４－ピペリジニル］－８－オキソ－２－｛［４－（トリフルオロメトキシ）フェニル］アミノ｝－８，９－ジヒドロ－７Ｈ－プリン－６－カルボニトリル
　参考例１１７で製造した化合物（60ｍｇ）をＤＭＦ（1.2ｍＬ）に溶解し、ＤＩＰＥＡ（0.056ｍＬ）とアンモニア（0.019ｍＬ、3.0mol/L、メタノール溶液）、ＤＭＴＭＭ（40ｍｇ）を加えて２時間攪拌した。反応液に水を加えて酢酸エチルで抽出し、得られた有機層を減圧濃縮した。残渣をシリカゲルクロマトグラフィー（ヘキサン：酢酸エチル＝３：７→酢酸エチル：メタノール＝９：１）で精製した。得られた化合物（20ｍｇ）をＴＨＦ（0.4ｍＬ）に溶解し、０℃でＮＥｔ３（0.030ｍＬ）と無水トリフルオロ酢酸（0.015ｍＬ）を加えて３０分攪拌した。反応液に水を加えて酢酸エチルで抽出し、得られた有機層を減圧濃縮した。残渣をシリカゲルクロマトグラフィー（ヘキサン：酢酸エチル＝１：１→０：１）で精製することにより、以下の物性値を有する標題化合物（11ｍｇ）を得た。
LC－MS（A）保持時間（分）：1.16；
MS(ESI, Pos.)： 899 (M + H)＋；
１H-NMR(CDCl３)：δ　 0.95, 1.73-1.81, 2.14, 2.38-2.48, 2.66-2.78, 2.95-3.04, 3.85-4.22, 4.31-4.43, 4.76-4.91, 5.38-5.62, 6.87-6.93, 7.11, 7.19-7.25, 7.29-7.46, 7.67, 7.84, 7.92-8.03, 8.25-8.30, 8.59-8.84。 Example 51
7-(6-{[9-(4-cyano-2-fluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[2,3- b]Pyridin-7-yl]carbonyl}-3-pyridinyl)-9-[1-(2,2-dimethylpropyl)-4-piperidinyl]-8-oxo-2-{[4-(trifluoromethoxy) phenyl]amino}-8,9-dihydro-7H-purine-6-carbonitrile The compound prepared in Reference Example 117 (60 mg) was dissolved in DMF (1.2 mL), and DIPEA (0.056 mL) and ammonia (0.019 mL, 3.0 mol/L, methanol solution) and DMTMM (40 mg) were added and stirred for 2 hours. Water was added to the reaction solution, extracted with ethyl acetate, and the resulting organic layer was concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane: ethyl acetate = 3:7 → ethyl acetate: methanol = 9:1). The obtained compound (20 mg) was dissolved in THF (0.4 mL), NEt 3 (0.030 mL) and trifluoroacetic anhydride (0.015 mL) were added at 0° C., and the mixture was stirred for 30 minutes. Water was added to the reaction solution, extracted with ethyl acetate, and the resulting organic layer was concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane:ethyl acetate = 1:1→0:1) to obtain the title compound (11 mg) having the following physical properties.
LC-MS (A) retention time (min): 1.16;
MS(ESI, Pos.): 899 (M + H) + ;
1 H-NMR (CDCl 3 ): δ 0.95, 1.73-1.81, 2.14, 2.38-2.48, 2.66-2.78, 2.95-3.04, 3.85-4.22, 4.31-4.43, 4.76-4.91, 5.38-5.62, 6.87-6.93 , 7.11, 7.19-7.25, 7.29-7.46, 7.67, 7.84, 7.92-8.03, 8.25-8.30, 8.59-8.84.
参考例１１８
２－クロロ－７－（６－｛［９－（４－シアノ－２－フルオロベンジル）－５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－イル］カルボニル｝－３－ピリジニル）－９－［１－（２，２－ジメチルプロピル）－４－ピペリジニル］－８－オキソ－８，９－ジヒドロ－７Ｈ－プリン－６－カルボン酸
　参考例６２で製造した化合物の代わりに参考例１１６で製造した化合物（828ｍｇ）を用いて、参考例６３と同様の操作を行い、以下の物性値を有する標題化合物（800ｍｇ）を得た。
LC－MS（A）保持時間（分）：0.94；
MS(ESI, Pos.)： 777 (M + H)＋。 Reference example 118
2-chloro-7-(6-{[9-(4-cyano-2-fluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[ 2,3-b]pyridin-7-yl]carbonyl}-3-pyridinyl)-9-[1-(2,2-dimethylpropyl)-4-piperidinyl]-8-oxo-8,9-dihydro-7H - Purine-6-carboxylic acid Using the compound produced in Reference Example 116 (828 mg) instead of the compound produced in Reference Example 62, the same operation as in Reference Example 63 was carried out to obtain the title compound ( 800 mg) was obtained.
LC-MS (A) retention time (min): 0.94;
MS(ESI, Pos.): 777 (M + H) + .
参考例１１９
２－クロロ－７－（６－｛［９－（４－シアノ－２－フルオロベンジル）－５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－イル］カルボニル｝－３－ピリジニル）－９－［１－（２，２－ジメチルプロピル）－４－ピペリジニル］－８－オキソ－８，９－ジヒドロ－７Ｈ－プリン－６－カルボキサミド
　参考例１１８で製造した化合物（800ｍｇ）をＤＭＦ（16ｍＬ）に溶解し、塩化アンモニウム（88ｍｇ）とＤＩＰＥＡ（0.71ｍＬ）、ＨＡＴＵ（626ｍｇ）を加えて室温で３０分攪拌した。反応液に水を加えて酢酸エチルで抽出した。得られた有機層を水で洗浄して無水硫酸ナトリウムで乾燥した。減圧濃縮して得られた残渣をシリカゲルクロマトグラフィー（ヘキサン：酢酸エチル＝１：１→０：１）で精製することにより、以下の物性値を有する標題化合物（500ｍｇ）を得た。
LC－MS（A）保持時間（分）：0.97；
MS(ESI, Pos.)： 776 (M + H)＋。 Reference example 119
2-chloro-7-(6-{[9-(4-cyano-2-fluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[ 2,3-b]pyridin-7-yl]carbonyl}-3-pyridinyl)-9-[1-(2,2-dimethylpropyl)-4-piperidinyl]-8-oxo-8,9-dihydro-7H - Purine-6-carboxamide The compound prepared in Reference Example 118 (800 mg) was dissolved in DMF (16 mL), and ammonium chloride (88 mg), DIPEA (0.71 mL), and HATU (626 mg) were added, and the mixture was stirred at room temperature for 30 minutes. . Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with water and dried over anhydrous sodium sulfate. The residue obtained by concentration under reduced pressure was purified by silica gel chromatography (hexane:ethyl acetate = 1:1→0:1) to obtain the title compound (500 mg) having the following physical properties.
LC-MS (A) retention time (min): 0.97;
MS(ESI, Pos.): 776 (M + H) + .
実施例５２
７－（６－｛［９－（４－シアノ－２－フルオロベンジル）－５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－イル］カルボニル｝－３－ピリジニル）－９－［１－（２，２－ジメチルプロピル）－４－ピペリジニル］－８－オキソ－２－［３－（トリフルオロメトキシ）フェニル］－８，９－ジヒドロ－７Ｈ－プリン－６－カルボキサミド　２トリフルオロ酢酸塩
　参考例１１９で製造した化合物（50ｍｇ）をＮＭＰ（1.0ｍＬ）に溶解し、［３－（トリフルオロメトキシ）フェニル］ボロン酸（27ｍｇ）、リン酸三カリウム水溶液（0.064ｍＬ、2mol/L）、［１，１’－ビス（ジフェニルホスフィノ）フェロセン］パラジウム（ＩＩ）ジクロリド　ジクロロメタン錯体（11ｍｇ）を加えてマイクロウェーブ装置を用いて１４０℃で１時間攪拌した。反応液を室温に冷却し、水を加えてセライト（商品名）に通した。ろ液を酢酸エチルで抽出し、有機層を濃縮して得られた残渣を逆相HPLCカラム精製することにより、以下の物性値を有する標題化合物（8.3ｍｇ）を得た。
LC－MS（A）保持時間（分）：1.06；
MS(ESI, Pos.)： 902 (M + H)＋；
１H-NMR(DMSO-d６)：δ　 1.06-1.18, 1.96-2.24, 2.84-3.16, 3.48-3.68, 3.69-3.84, 3.99-4.41, 4.63-5.06, 5.39-5.76, 6.91-7.28, 7.45-7.87, 7.87-8.01, 8.16-8.28, 8.28-8.69, 8.69-8.86, 8.92-9.06。 Example 52
7-(6-{[9-(4-cyano-2-fluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[2,3- b]pyridin-7-yl]carbonyl}-3-pyridinyl)-9-[1-(2,2-dimethylpropyl)-4-piperidinyl]-8-oxo-2-[3-(trifluoromethoxy)phenyl ]-8,9-dihydro-7H-purine-6-carboxamide 2 trifluoroacetate The compound (50 mg) prepared in Reference Example 119 was dissolved in NMP (1.0 mL), and [3-(trifluoromethoxy)phenyl] Add boronic acid (27 mg), tripotassium phosphate aqueous solution (0.064 mL, 2 mol/L), [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane complex (11 mg), and use a microwave device. The mixture was stirred at 140° C. for 1 hour. The reaction solution was cooled to room temperature, water was added, and the mixture was passed through Celite (trade name). The filtrate was extracted with ethyl acetate, the organic layer was concentrated, and the resulting residue was purified with a reverse phase HPLC column to obtain the title compound (8.3 mg) having the following physical properties.
LC-MS (A) retention time (min): 1.06;
MS(ESI, Pos.): 902 (M + H) + ;
1 H-NMR (DMSO-d 6 ): δ 1.06-1.18, 1.96-2.24, 2.84-3.16, 3.48-3.68, 3.69-3.84, 3.99-4.41, 4.63-5.06, 5.39-5.76, 6.91-7.28, 7.45- 7.87, 7.87-8.01, 8.16-8.28, 8.28-8.69, 8.69-8.86, 8.92-9.06.
実施例５２－１
７－（６－｛［９－（４－シアノ－２－フルオロベンジル）－５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－イル］カルボニル｝－３－ピリジニル）－２－（３，４－ジヒドロ－２Ｈ－クロメン－８－イル）－９－［１－（２，２－ジメチルプロピル）－４－ピペリジニル］－８－オキソ－８，９－ジヒドロ－７Ｈ－プリン－６－カルボキサミド　２トリフルオロ酢酸塩
　［３－（トリフルオロメトキシ）フェニル］ボロン酸の代わりに対応するボロン酸化合物を用いて、実施例５２と同様の操作を行い、逆相HPLCカラム精製することにより、以下の物性値を有する標題化合物を得た。
LC－MS（A）保持時間（分）：0.99；
MS(ESI, Pos.)： 874 (M + H)＋；
１H-NMR(DMSO-d６)：δ　 0.99-1.13, 1.92-2.17, 2.78-3.14, 3.19-3.33, 3.46-3.55, 3.58-3.82, 4.00-4.38, 4.59-4.96, 5.34-5.79, 6.84-7.25, 7.32-7.84, 7.84-8.11, 8.18-8.41, 8.44-8.67, 8.67-9.00。 Example 52-1
7-(6-{[9-(4-cyano-2-fluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[2,3- b]pyridin-7-yl]carbonyl}-3-pyridinyl)-2-(3,4-dihydro-2H-chromen-8-yl)-9-[1-(2,2-dimethylpropyl)-4- Piperidinyl]-8-oxo-8,9-dihydro-7H-purine-6-carboxamide 2 Trifluoroacetate [3-(trifluoromethoxy)phenyl]Performed using the corresponding boronic acid compound instead of [3-(trifluoromethoxy)phenyl]boronic acid. The same operation as in Example 52 was carried out, and the title compound having the following physical properties was obtained by purification using a reverse phase HPLC column.
LC-MS (A) retention time (min): 0.99;
MS(ESI, Pos.): 874 (M + H) + ;
1 H-NMR (DMSO-d 6 ): δ 0.99-1.13, 1.92-2.17, 2.78-3.14, 3.19-3.33, 3.46-3.55, 3.58-3.82, 4.00-4.38, 4.59-4.96, 5.34-5.79, 6.84- 7.25, 7.32-7.84, 7.84-8.11, 8.18-8.41, 8.44-8.67, 8.67-9.00.
参考例１２０
２－メチル－２－プロパニル　４－［（６－クロロ－２－メチル－３－ニトロ－４－ピリジニル）アミノ］－１－ピペリジンカルボキシラート
　4，６－ジクロロ－２－メチル－３－ニトロピリジン（355ｍｇ）のＴＨＦ溶液（7.0ｍＬ）にＤＩＰＥＡ（0.45ｍＬ）を加え、さらに０℃で２－メチル－２－プロパニル　４－アミノ－１－ピぺリジンカルボキシラート（360ｍｇ）のＴＨＦ溶液（3.0ｍＬ）を加えた。反応液を室温で２日攪拌した後、酢酸エチルで希釈し、有機層を水と飽和食塩水で洗浄した。有機層を硫酸マグネシウムで乾燥し、減圧濃縮して得られた残渣をシリカゲルクロマトグラフィー（ヘキサン：酢酸エチル＝９：１→３：２）で精製することにより、以下の物性値を有する標題化合物（380ｍｇ）を得た。
TLC：Rf 0.26（ヘキサン：酢酸エチル＝４：１）；
１H-NMR(CDCl３)：δ　 1.42-1.55, 1.98-2.07, 2.68, 3.02, 3.49-3.64, 3.98-4.11, 6.61, 7.23-7.29。 Reference example 120
2-Methyl-2-propanyl 4-[(6-chloro-2-methyl-3-nitro-4-pyridinyl)amino]-1-piperidinecarboxylate 4,6-dichloro -2-methyl-3-nitropyridine ( DIPEA (0.45 mL) was added to a THF solution (7.0 mL) of 2-methyl-2-propanyl 4-amino-1-piperidinecarboxylate (360 mg) at 0°C. added. After stirring the reaction solution at room temperature for 2 days, it was diluted with ethyl acetate, and the organic layer was washed with water and saturated brine. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (hexane:ethyl acetate = 9:1→3:2) to obtain the title compound ( 380 mg) was obtained.
TLC: Rf 0.26 (hexane: ethyl acetate = 4:1);
1H -NMR ( CDCl3 ): δ 1.42-1.55, 1.98-2.07, 2.68, 3.02, 3.49-3.64, 3.98-4.11, 6.61, 7.23-7.29.
参考例１２１
２－メチル－２－プロパニル　４－［（３－アミノ－６－クロロ－２－メチル－４－ピリジニル）アミノ］－１－ピペリジンカルボキシラート
　亜鉛（670ｍｇ）と塩化アンモニウム（329ｍｇ）に水（4.0ｍＬ）を加えた懸濁液に、参考例１２０で製造した化合物（380ｍｇ）の酢酸エチル溶液（20ｍＬ）を加えて室温で２時間攪拌した。さらに亜鉛（670ｍｇ）を追加して室温で１時間攪拌した後、反応液をセライト（商品名）に通して不溶物を除去し、ろ液を飽和食塩水で洗浄した。得られた有機層を硫酸マグネシウムで乾燥後、減圧濃縮し、得られた残渣をシリカゲルクロマトグラフィー（ヘキサン：酢酸エチル＝２：３→０：１）で精製することにより、以下の物性値を有する標題化合物（279ｍｇ）を得た。
TLC：Rf 0.28（ヘキサン：酢酸エチル＝３：７）；
１H-NMR(CDCl３)：δ　 1.35-1.45, 1.47, 1.98-2.05, 2.38, 2.81-3.02, 3.36-3.45, 3.99-4.20, 4.26, 6.40。 Reference example 121
2-Methyl-2-propanyl 4-[(3-amino-6-chloro-2-methyl-4-pyridinyl)amino]-1-piperidinecarboxylate Zinc (670 mg) and ammonium chloride (329 mg) in water (4.0 mL) ) was added to the suspension, an ethyl acetate solution (20 mL) of the compound produced in Reference Example 120 (380 mg) was added, and the mixture was stirred at room temperature for 2 hours. After further adding zinc (670 mg) and stirring at room temperature for 1 hour, the reaction solution was passed through Celite (trade name) to remove insoluble matter, and the filtrate was washed with saturated brine. The obtained organic layer was dried over magnesium sulfate, concentrated under reduced pressure, and the obtained residue was purified by silica gel chromatography (hexane: ethyl acetate = 2:3 → 0:1) to obtain a product having the following physical property values. The title compound (279 mg) was obtained.
TLC: Rf 0.28 (hexane: ethyl acetate = 3:7);
1H -NMR ( CDCl3 ): δ 1.35-1.45, 1.47, 1.98-2.05, 2.38, 2.81-3.02, 3.36-3.45, 3.99-4.20, 4.26, 6.40.
参考例１２２
２－メチル－２－プロパニル　４－［６－クロロ－３－（６－｛［９－（４－シアノ－２－フルオロベンジル）－５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－イル］カルボニル｝－３－ピリジニル）－４－メチル－２－オキソ－２，３－ジヒドロ－１Ｈ－イミダゾ［４，５－ｃ］ピリジン－１－イル］－１－ピペリジンカルボキシラート
　参考例９３で用いた参考例３で製造した化合物の代わりに参考例１２１で製造した化合物を用いて、参考例９３→参考例９４→参考例９５→参考例９９と同様の操作を行い、以下の物性値を有する標題化合物を得た。
TLC：Rf 0.34（ヘキサン：酢酸エチル＝１：４）；
１H-NMR(CDCl３)：δ　 1.52, 1.85-1.97, 2.07-2.14, 2.20-2.38, 2.82-3.11, 3.81-4.09, 4.28-4.55, 4.76-5.07, 5.41-5.64, 6.87-7.15, 7.22-7.34, 7.38-7.48, 7.73-7.95, 8.29, 8.51-8.76。 Reference example 122
2-Methyl-2-propanyl 4-[6-chloro-3-(6-{[9-(4-cyano-2-fluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[2,3-b]pyridin-7-yl]carbonyl}-3-pyridinyl)-4-methyl-2-oxo-2,3-dihydro-1H-imidazo[4, 5-c]pyridin-1-yl]-1-piperidinecarboxylate Using the compound produced in Reference Example 121 instead of the compound produced in Reference Example 3 used in Reference Example 93, Reference Example 93 → Reference Example 94 → Reference Example 95 → The same operation as in Reference Example 99 was performed to obtain the title compound having the following physical property values.
TLC: Rf 0.34 (hexane: ethyl acetate = 1:4);
1 H-NMR (CDCl 3 ): δ 1.52, 1.85-1.97, 2.07-2.14, 2.20-2.38, 2.82-3.11, 3.81-4.09, 4.28-4.55, 4.76-5.07, 5.41-5.64, 6.87-7.15, 7.22 - 7.34, 7.38-7.48, 7.73-7.95, 8.29, 8.51-8.76.
実施例５３
４－［（７－｛［５－（１－［１－（２，２－ジメチルプロピル）－４－ピペリジニル］－４－メチル－２－オキソ－６－｛［４－（トリフルオロメトキシ）フェニル］アミノ｝－１，２－ジヒドロ－３Ｈ－イミダゾ［４，５－ｃ］ピリジン－３－イル）－２－ピリジニル］カルボニル｝－５，６，７，８－テトラヒドロ－９Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－９－イル）メチル］－３－フルオロベンゾニトリル
　参考例１００で用いた参考例９９で製造した化合物の代わりに参考例１２２で製造した化合物を用いて、参考例１００→参考例１０１→実施例３５と同様の操作を行い、以下の物性値を有する標題化合物を得た。
LC－MS（A）保持時間（分）：1.05；
MS(ESI, Pos.)： 887 (M + H)＋；
１H-NMR(CDCl３)：δ　 0.89, 1.73-1.87, 2.01-2.15, 2.34-2.50, 2.91-3.03, 3.85-4.21, 4.21-4.37, 4.90, 5.38-5.64, 6.53, 6.70-6.76, 6.85-7.08, 7.08-7.15, 7.17-7.25, 7.25-7.34, 7.35-7.47, 7.82-7.93, 8.29, 8.53-8.73。 Example 53
4-[(7-{[5-(1-[1-(2,2-dimethylpropyl)-4-piperidinyl]-4-methyl-2-oxo-6-{[4-(trifluoromethoxy)phenyl ]Amino}-1,2-dihydro-3H-imidazo[4,5-c]pyridin-3-yl)-2-pyridinyl]carbonyl}-5,6,7,8-tetrahydro-9H-pyrido[4',3':4,5]pyrrolo[2,3-b]pyridin-9-yl)methyl]-3-fluorobenzonitrile In place of the compound produced in Reference Example 99 used in Reference Example 100, the compound prepared in Reference Example 122 was used. Using the produced compound, the same operations as Reference Example 100→Reference Example 101→Example 35 were performed to obtain the title compound having the following physical property values.
LC-MS (A) retention time (min): 1.05;
MS(ESI, Pos.): 887 (M + H) + ;
1 H-NMR (CDCl 3 ): δ 0.89, 1.73-1.87, 2.01-2.15, 2.34-2.50, 2.91-3.03, 3.85-4.21, 4.21-4.37, 4.90, 5.38-5.64, 6.53, 6.70-6.76, 6.8 5- 7.08, 7.08-7.15, 7.17-7.25, 7.25-7.34, 7.35-7.47, 7.82-7.93, 8.29, 8.53-8.73.
参考例１２３
２－メチル－２－プロパニル　４－［２－クロロ－７－（６－｛［９－（４－クロロ－２－フルオロベンジル）－５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－イル］カルボニル｝－３－ピリジニル）－６－メチル－８－オキソ－７，８－ジヒドロ－９Ｈ－プリン－９－イル］－１－ピペリジンカルボキシラート
　参考例５３で製造した化合物の代わりに参考例７２で製造した化合物（257ｍｇ）を用いて、参考例９９と同様の操作を行い、以下の物性値を有する標題化合物（500ｍｇ）を得た。
LC－MS（A）保持時間（分）：1.29；
MS(ESI, Pos.)： 786 (M + H)＋。 Reference example 123
2-Methyl-2-propanyl 4-[2-chloro-7-(6-{[9-(4-chloro-2-fluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[2,3-b]pyridin-7-yl]carbonyl}-3-pyridinyl)-6-methyl-8-oxo-7,8-dihydro-9H-purine-9- yl]-1-piperidinecarboxylate Using the compound produced in Reference Example 72 (257 mg) instead of the compound produced in Reference Example 53, the same operation as in Reference Example 99 was performed to obtain the title compound having the following physical property values. (500 mg) was obtained.
LC-MS (A) retention time (min): 1.29;
MS(ESI, Pos.): 786 (M + H) + .
参考例１２４
２－メチル－２－プロパニル　４－｛７－（６－｛［９－（４－クロロ－２－フルオロベンジル）－５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－イル］カルボニル｝－３－ピリジニル）－２－［（３－フルオロフェニル）アミノ］－６－メチル－８－オキソ－７，８－ジヒドロ－９Ｈ－プリン－９－イル｝－１－ピペリジンカルボキシラート
　参考例１２３で製造した化合物（373ｍｇ）にＤＭＦ（3.7ｍＬ）とトルエン（3.7ｍＬ）を加えて溶解し、さらに３－フルオロアニリン（63ｍｇ）及び炭酸セシウム（463ｍｇ）、Xantphos（55ｍｇ）、酢酸パラジウム（11ｍｇ）を加え、窒素雰囲気下、９０℃で５時間攪拌した。反応液を室温に冷却した後、酢酸エチルで希釈して、インジェクト　アミノ（商品名）に通した。ろ液を減圧濃縮し、残渣をシリカゲルクロマトグラフィー（富士シリシア　ＮＨ（商品名）、ヘキサン：酢酸エチル＝３：１→１：１）で精製することにより、以下の物性値を有する標題化合物（392ｍｇ）を得た。
LC－MS（A）保持時間（分）：1.32；
MS(ESI, Pos.)： 861 (M + H)＋。 Reference example 124
2-Methyl-2-propanyl 4-{7-(6-{[9-(4-chloro-2-fluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3'): 4,5]pyrrolo[2,3-b]pyridin-7-yl]carbonyl}-3-pyridinyl)-2-[(3-fluorophenyl)amino]-6-methyl-8-oxo-7,8- Dihydro-9H-purin-9-yl}-1-piperidinecarboxylate The compound prepared in Reference Example 123 (373 mg) was dissolved in DMF (3.7 mL) and toluene (3.7 mL), and 3-fluoroaniline ( 63 mg), cesium carbonate (463 mg), Xantphos (55 mg), and palladium acetate (11 mg) were added, and the mixture was stirred at 90° C. for 5 hours under a nitrogen atmosphere. After the reaction solution was cooled to room temperature, it was diluted with ethyl acetate and passed through Inject Amino (trade name). The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (Fuji Silysia NH (trade name), hexane:ethyl acetate = 3:1 → 1:1) to obtain the title compound (392 mg) having the following physical property values. ) was obtained.
LC-MS (A) retention time (min): 1.32;
MS(ESI, Pos.): 861 (M + H) + .
参考例１２５
７－（６－｛［９－（４－クロロ－２－フルオロベンジル）－５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－イル］カルボニル｝－３－ピリジニル）－２－［（３－フルオロフェニル）アミノ］－６－メチル－９－（４－ピペリジニル）－７，９－ジヒドロ－８Ｈ－プリン－８－オン
　参考例１２４で製造した化合物（392ｍｇ）をジクロロメタン（2.2ｍＬ）に溶解し、トリフルオロ酢酸（0.45ｍＬ）を加えて室温で２時間攪拌した。反応液に飽和炭酸水素ナトリウム水溶液を加えて、酢酸エチルで抽出し、得られた有機層を飽和食塩水で洗浄した。有機層を減圧濃縮し、以下の物性値を有する標題化合物（521ｍｇ）を得た。
LC－MS（A）保持時間（分）：1.05；
MS(ESI, Pos.)： 761 (M + H)＋。 Reference example 125
7-(6-{[9-(4-chloro-2-fluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[2,3- b]Pyridin-7-yl]carbonyl}-3-pyridinyl)-2-[(3-fluorophenyl)amino]-6-methyl-9-(4-piperidinyl)-7,9-dihydro-8H-purine- 8-one The compound prepared in Reference Example 124 (392 mg) was dissolved in dichloromethane (2.2 mL), trifluoroacetic acid (0.45 mL) was added, and the mixture was stirred at room temperature for 2 hours. A saturated aqueous sodium bicarbonate solution was added to the reaction mixture, extracted with ethyl acetate, and the resulting organic layer was washed with saturated brine. The organic layer was concentrated under reduced pressure to obtain the title compound (521 mg) having the following physical properties.
LC-MS (A) retention time (min): 1.05;
MS(ESI, Pos.): 761 (M + H) + .
実施例５４
７－（６－｛［９－（４－クロロ－２－フルオロベンジル）－５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－イル］カルボニル｝－３－ピリジニル）－９－［１－（２，２－ジメチルプロピル）－４－ピペリジニル］－２－［（３－フルオロフェニル）アミノ］－６－メチル－７，９－ジヒドロ－８Ｈ－プリン－８－オン
　参考例９８で製造した化合物の代わりに参考例１２５で製造した化合物（200ｍｇ）を用いて、実施例３４と同様の操作を行い、以下の物性値を有する標題化合物（160ｍｇ）を得た。
LC－MS（A）保持時間（分）：1.11；
MS(ESI, Pos.)： 831 (M + H)＋；
１H-NMR(CDCl３)：δ　 0.93, 1.70-1.79, 2.07-2.16, 2.45, 2.70-2.84, 2.93-3.03, 3.90-4.19, 4.31-4.42, 4.86-4.94, 5.30-5.56, 6.69-6.75, 6.78-7.01, 7.06-7.16, 7.27-7.35, 7.61, 7.80-7.93, 8.30, 8.52-8.73。 Example 54
7-(6-{[9-(4-chloro-2-fluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[2,3- b]pyridin-7-yl]carbonyl}-3-pyridinyl)-9-[1-(2,2-dimethylpropyl)-4-piperidinyl]-2-[(3-fluorophenyl)amino]-6-methyl -7,9-dihydro-8H-purin-8-one
Using the compound produced in Reference Example 125 (200 mg) instead of the compound produced in Reference Example 98, the same operation as in Example 34 was performed to obtain the title compound (160 mg) having the following physical properties.
LC-MS (A) retention time (min): 1.11;
MS(ESI, Pos.): 831 (M + H) + ;
1 H-NMR (CDCl 3 ): δ 0.93, 1.70-1.79, 2.07-2.16, 2.45, 2.70-2.84, 2.93-3.03, 3.90-4.19, 4.31-4.42, 4.86-4.94, 5.30-5.56, 6.69-6.75 , 6.78-7.01, 7.06-7.16, 7.27-7.35, 7.61, 7.80-7.93, 8.30, 8.52-8.73.
実施例５４－１～５
　参考例１２４で用いた３－フルオロアニリンの代わりに相当するアニリン化合物を、実施例５４で用いたピバルアルデヒドの代わりに１－（トリフルオロメチル）シクロプロパンカルボアルデヒドを用いて、参考例１２４→参考例１２５→実施例５４と同様の操作を行い、シリカゲル精製もしくは逆相HPLCカラム精製することにより、以下の物性値を有する標題化合物を得た。 Examples 54-1 to 5
Reference Example 124→ Reference Example 125 → The same operation as Example 54 was performed, and the title compound having the following physical property values was obtained by purifying with silica gel or purifying with a reverse phase HPLC column.
実施例５４－１
７－（６－｛［９－（４－クロロ－２－フルオロベンジル）－５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－イル］カルボニル｝－３－ピリジニル）－２－［（２，６－ジフルオロフェニル）アミノ］－６－メチル－９－（１－｛［１－（トリフルオロメチル）シクロプロピル］メチル｝－４－ピペリジニル）－７，９－ジヒドロ－８Ｈ－プリン－８－オン　２トリフルオロ酢酸塩
LC－MS（A）保持時間（分）：1.07；
MS(ESI, Pos.)： 901 (M + H)＋；
１H-NMR(DMSO-d６)：δ　 1.03-1.37, 1.69-2.04, 2.04-2.23, 2.65-2.91, 3.12-3.33, 3.61-3.82, 3.98-4.07, 4.33-4.58, 4.63-4.97, 5.24-5.66, 6.84-6.98, 7.06-7.36, 7.48-7.55, 7.72-7.89, 7.90-8.00, 8.04-8.17, 8.17-8.27, 8.31-8.47, 8.50-8.63, 8.66-8.87, 9.41-9.53。 Example 54-1
7-(6-{[9-(4-chloro-2-fluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[2,3- b]pyridin-7-yl]carbonyl}-3-pyridinyl)-2-[(2,6-difluorophenyl)amino]-6-methyl-9-(1-{[1-(trifluoromethyl)cyclopropyl ]Methyl}-4-piperidinyl)-7,9-dihydro-8H-purin-8-one 2 trifluoroacetate
LC-MS (A) retention time (min): 1.07;
MS(ESI, Pos.): 901 (M + H) + ;
1 H-NMR (DMSO-d 6 ): δ 1.03-1.37, 1.69-2.04, 2.04-2.23, 2.65-2.91, 3.12-3.33, 3.61-3.82, 3.98-4.07, 4.33-4.58, 4.63-4.97, 5.24- 5.66, 6.84-6.98, 7.06-7.36, 7.48-7.55, 7.72-7.89, 7.90-8.00, 8.04-8.17, 8.17-8.27, 8.31-8.47, 8.50-8.63, 8.66-8.87, 9.41-9. 53.
実施例５４－２
７－（６－｛［９－（４－クロロ－２－フルオロベンジル）－５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－イル］カルボニル｝－３－ピリジニル）－２－［（２，４－ジフルオロフェニル）アミノ］－６－メチル－９－（１－｛［１－（トリフルオロメチル）シクロプロピル］メチル｝－４－ピペリジニル）－７，９－ジヒドロ－８Ｈ－プリン－８－オン　２トリフルオロ酢酸塩
LC－MS（A）保持時間（分）：1.13；
MS(ESI, Pos.)： 901 (M + H)＋；
１H-NMR(DMSO-d６)：δ　 1.07-1.30, 1.91-2.05, 2.06-2.22, 2.66-2.93, 3.13-3.29, 3.60-3.79, 3.94-4.06, 4.38-4.68, 4.68-4.95, 5.21-5.69, 6.81-7.00, 7.09-7.19, 7.19-7.41, 7.48-7.56, 7.76-8.06, 8.07-8.20, 8.20-8.27, 8.59-8.97, 9.41-9.61。 Example 54-2
7-(6-{[9-(4-chloro-2-fluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[2,3- b]pyridin-7-yl]carbonyl}-3-pyridinyl)-2-[(2,4-difluorophenyl)amino]-6-methyl-9-(1-{[1-(trifluoromethyl)cyclopropyl ]Methyl}-4-piperidinyl)-7,9-dihydro-8H-purin-8-one 2 trifluoroacetate
LC-MS (A) retention time (min): 1.13;
MS(ESI, Pos.): 901 (M + H) + ;
1 H-NMR (DMSO-d 6 ): δ 1.07-1.30, 1.91-2.05, 2.06-2.22, 2.66-2.93, 3.13-3.29, 3.60-3.79, 3.94-4.06, 4.38-4.68, 4.68-4.95, 5.21- 5.69, 6.81-7.00, 7.09-7.19, 7.19-7.41, 7.48-7.56, 7.76-8.06, 8.07-8.20, 8.20-8.27, 8.59-8.97, 9.41-9.61.
実施例５４－３
７－（６－｛［９－（４－クロロ－２－フルオロベンジル）－５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－イル］カルボニル｝－３－ピリジニル）－２－［（３，４－ジフルオロフェニル）アミノ］－６－メチル－９－（１－｛［１－（トリフルオロメチル）シクロプロピル］メチル｝－４－ピペリジニル）－７，９－ジヒドロ－８Ｈ－プリン－８－オン　２トリフルオロ酢酸塩
LC－MS（A）保持時間（分）：1.12；
MS(ESI, Pos.)： 901 (M + H)＋；
１H-NMR(DMSO-d６)：δ　 1.07-1.41, 1.93-2.06, 2.06-2.26, 2.74-2.93, 3.14-3.29, 3.65-3.79, 4.00-4.09, 4.48-4.65, 4.70-4.95, 5.24-5.66, 6.86-7.00, 7.08-7.25, 7.25-7.38, 7.42-7.55, 7.75-8.01, 8.06-8.19, 8.20-8.27, 8.54-8.88, 9.40-9.61, 9.61-9.74。 Example 54-3
7-(6-{[9-(4-chloro-2-fluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[2,3- b]pyridin-7-yl]carbonyl}-3-pyridinyl)-2-[(3,4-difluorophenyl)amino]-6-methyl-9-(1-{[1-(trifluoromethyl)cyclopropyl ]Methyl}-4-piperidinyl)-7,9-dihydro-8H-purin-8-one 2 trifluoroacetate
LC-MS (A) retention time (min): 1.12;
MS(ESI, Pos.): 901 (M + H) + ;
1 H-NMR (DMSO-d 6 ): δ 1.07-1.41, 1.93-2.06, 2.06-2.26, 2.74-2.93, 3.14-3.29, 3.65-3.79, 4.00-4.09, 4.48-4.65, 4.70-4.95, 5.24- 5.66, 6.86-7.00, 7.08-7.25, 7.25-7.38, 7.42-7.55, 7.75-8.01, 8.06-8.19, 8.20-8.27, 8.54-8.88, 9.40-9.61, 9.61-9.74.
実施例５４－４
７－（６－｛［９－（４－クロロ－２－フルオロベンジル）－５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－イル］カルボニル｝－３－ピリジニル）－２－｛［３－（ジフルオロメトキシ）フェニル］アミノ｝－６－メチル－９－（１－｛［１－（トリフルオロメチル）シクロプロピル］メチル｝－４－ピペリジニル）－７，９－ジヒドロ－８Ｈ－プリン－８－オン　２トリフルオロ酢酸塩
LC－MS（A）保持時間（分）：1.14；
MS(ESI, Pos.)： 931 (M + H)＋；
１H-NMR(DMSO-d６)：δ　 1.06-1.35, 1.92-2.07, 2.09-2.27, 2.74-2.94, 3.11-3.23, 3.65-4.10, 4.50-4.66, 4.66-4.96, 5.26-5.66, 6.70-6.76, 6.83-7.00, 7.05-7.27, 7.27-7.38, 7.47-7.62, 7.71-7.79, 7.79-8.00, 8.04-8.20, 8.20-8.27, 8.57-8.86, 9.47-9.63, 9.63-9.72。 Example 54-4
7-(6-{[9-(4-chloro-2-fluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[2,3- b]pyridin-7-yl]carbonyl}-3-pyridinyl)-2-{[3-(difluoromethoxy)phenyl]amino}-6-methyl-9-(1-{[1-(trifluoromethyl)cyclo propyl]methyl}-4-piperidinyl)-7,9-dihydro-8H-purin-8-one 2 trifluoroacetate
LC-MS (A) retention time (min): 1.14;
MS(ESI, Pos.): 931 (M + H) + ;
1 H-NMR (DMSO-d 6 ): δ 1.06-1.35, 1.92-2.07, 2.09-2.27, 2.74-2.94, 3.11-3.23, 3.65-4.10, 4.50-4.66, 4.66-4.96, 5.26-5.66, 6.70- 6.76, 6.83-7.00, 7.05-7.27, 7.27-7.38, 7.47-7.62, 7.71-7.79, 7.79-8.00, 8.04-8.20, 8.20-8.27, 8.57-8.86, 9.47-9.63, 9.63-9. 72.
実施例５４－５
７－（６－｛［９－（４－クロロ－２－フルオロベンジル）－５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－イル］カルボニル｝－３－ピリジニル）－６－メチル－２－｛［２－（トリフルオロメトキシ）フェニル］アミノ｝－９－（１－｛［１－（トリフルオロメチル）シクロプロピル］メチル｝－４－ピペリジニル）－７，９－ジヒドロ－８Ｈ－プリン－８－オン　２トリフルオロ酢酸塩
LC－MS（A）保持時間（分）：1.18；
MS(ESI, Pos.)： 949 (M + H)＋；
１H-NMR(DMSO-d６)：δ　 1.09-1.32, 1.91-2.02, 2.03-2.21, 2.69-2.92, 3.15-3.34, 3.63-3.80, 3.99-4.41, 4.45-4.62, 4.67-4.95, 5.25-5.60, 6.82-7.54, 7.76-8.00, 8.03-8.20, 8.20-8.28, 8.43-8.57, 8.57-8.87, 9.34-9.61。 Example 54-5
7-(6-{[9-(4-chloro-2-fluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[2,3- b]Pyridin-7-yl]carbonyl}-3-pyridinyl)-6-methyl-2-{[2-(trifluoromethoxy)phenyl]amino}-9-(1-{[1-(trifluoromethyl) cyclopropyl]methyl}-4-piperidinyl)-7,9-dihydro-8H-purin-8-one 2 trifluoroacetate
LC-MS (A) retention time (min): 1.18;
MS(ESI, Pos.): 949 (M + H) + ;
1 H-NMR (DMSO-d 6 ): δ 1.09-1.32, 1.91-2.02, 2.03-2.21, 2.69-2.92, 3.15-3.34, 3.63-3.80, 3.99-4.41, 4.45-4.62, 4.67-4.95, 5.25- 5.60, 6.82-7.54, 7.76-8.00, 8.03-8.20, 8.20-8.28, 8.43-8.57, 8.57-8.87, 9.34-9.61.
実施例５４－６～７
　参考例１２４で用いた３－フルオロアニリンの代わりに相当するアニリン化合物を用いて、参考例１２４→参考例１２５→実施例５４と同様の操作を行い、シリカゲル精製もしくは逆相HPLCカラム精製することにより、以下の物性値を有する標題化合物を得た。 Example 54-6 to 7
By using the corresponding aniline compound instead of 3-fluoroaniline used in Reference Example 124, performing the same operation as Reference Example 124 → Reference Example 125 → Example 54, and purifying with silica gel or reversed phase HPLC column. , the title compound having the following physical properties was obtained.
実施例５４－６
７－（６－｛［９－（４－クロロ－２－フルオロベンジル）－５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－イル］カルボニル｝－３－ピリジニル）－２－［（３，５－ジフルオロフェニル）アミノ］－９－［１－（２，２－ジメチルプロピル）－４－ピペリジニル］－６－メチル－７，９－ジヒドロ－８Ｈ－プリン－８－オン
LC－MS（A）保持時間（分）：1.18；
MS(ESI, Pos.)： 849 (M + H)＋；
１H-NMR(CDCl３)：δ　 0.91, 1.69-1.81, 2.07-2.16, 2.45, 2.68-2.81, 2.93-3.04, 3.89-4.19, 4.31-4.42, 4.85-4.94, 5.30-5.57, 6.46, 6.82, 6.93-6.96, 6.98, 7.07-7.16, 7.27-7.32, 7.81-7.92, 8.29-8.33, 8.51-8.72。 Example 54-6
7-(6-{[9-(4-chloro-2-fluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[2,3- b]pyridin-7-yl]carbonyl}-3-pyridinyl)-2-[(3,5-difluorophenyl)amino]-9-[1-(2,2-dimethylpropyl)-4-piperidinyl]-6 -Methyl-7,9-dihydro-8H-purin-8-one
LC-MS (A) retention time (min): 1.18;
MS(ESI, Pos.): 849 (M + H) + ;
1 H-NMR (CDCl 3 ): δ 0.91, 1.69-1.81, 2.07-2.16, 2.45, 2.68-2.81, 2.93-3.04, 3.89-4.19, 4.31-4.42, 4.85-4.94, 5.30-5.57, 6.46, 6.8 2, 6.93-6.96, 6.98, 7.07-7.16, 7.27-7.32, 7.81-7.92, 8.29-8.33, 8.51-8.72.
実施例５４－７
７－（６－｛［９－（４－クロロ－２－フルオロベンジル）－５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－イル］カルボニル｝－３－ピリジニル）－２－｛［２－（ジフルオロメトキシ）フェニル］アミノ｝－９－［１－（２，２－ジメチルプロピル）－４－ピペリジニル］－６－メチル－７，９－ジヒドロ－８Ｈ－プリン－８－オン　２トリフルオロ酢酸塩　
LC－MS（A）保持時間（分）：1.09；
MS(ESI, Pos.)： 879 (M + H)＋；
１H-NMR(DMSO-d６)：δ　 0.96-1.15, 1.92-2.11, 2.80-3.01, 3.01-3.18, 3.64-3.83, 3.96-4.39, 4.52-4.69, 4.69-4.94, 5.14-5.65, 6.85-7.01, 7.03-7.41, 7.50-7.59, 7.74-8.04, 8.05-8.30, 8.55-8.75, 8.77-8.91。 Example 54-7
7-(6-{[9-(4-chloro-2-fluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[2,3- b]Pyridin-7-yl]carbonyl}-3-pyridinyl)-2-{[2-(difluoromethoxy)phenyl]amino}-9-[1-(2,2-dimethylpropyl)-4-piperidinyl]- 6-Methyl-7,9-dihydro-8H-purin-8-one 2 trifluoroacetate
LC-MS (A) retention time (min): 1.09;
MS(ESI, Pos.): 879 (M + H) + ;
1 H-NMR (DMSO-d 6 ): δ 0.96-1.15, 1.92-2.11, 2.80-3.01, 3.01-3.18, 3.64-3.83, 3.96-4.39, 4.52-4.69, 4.69-4.94, 5.14-5.65, 6.85- 7.01, 7.03-7.41, 7.50-7.59, 7.74-8.04, 8.05-8.30, 8.55-8.75, 8.77-8.91.
実施例５５
７－（６－｛［９－（４－クロロ－２－フルオロベンジル）－５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－イル］カルボニル｝－３－ピリジニル）－２－［（３－フルオロフェニル）アミノ］－６－メチル－９－（１－｛［１－（トリフルオロメチル）シクロプロピル］カルボニル｝－４－ピペリジニル）－７，９－ジヒドロ－８Ｈ－プリン－８－オン　トリフルオロ酢酸塩
　参考例１１０で製造した化合物の代わりに参考例１２５で製造した化合物（20ｍｇ）を用いて、実施例４５と同様の操作を行い、以下の物性値を有する標題化合物（9.3ｍｇ）を得た。
LC－MS（A）保持時間（分）：1.24；
MS(ESI, Pos.)： 897 (M + H)＋；
１H-NMR(DMSO-d６)：δ　 1.10-1.31, 1.31-1.38, 1.93-2.06, 2.41-2.49, 2.79-2.93, 3.70-3.79, 4.01-4.08, 4.32-4.70, 4.70-4.95, 5.25-5.62, 6.63-6.78, 6.83-6.98, 7.10-7.28, 7.44-7.59, 7.59-7.72, 7.75-7.90, 7.90-7.99, 8.08-8.20, 8.20-8.29, 8.57-8.88, 9.67-9.77。 Example 55
7-(6-{[9-(4-chloro-2-fluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[2,3- b]pyridin-7-yl]carbonyl}-3-pyridinyl)-2-[(3-fluorophenyl)amino]-6-methyl-9-(1-{[1-(trifluoromethyl)cyclopropyl]carbonyl }-4-piperidinyl)-7,9-dihydro-8H-purin-8-one trifluoroacetate The compound produced in Reference Example 125 (20 mg) was used instead of the compound produced in Reference Example 110, and the Example The same operation as in 45 was performed to obtain the title compound (9.3 mg) having the following physical properties.
LC-MS (A) retention time (min): 1.24;
MS(ESI, Pos.): 897 (M + H) + ;
1 H-NMR (DMSO-d 6 ): δ 1.10-1.31, 1.31-1.38, 1.93-2.06, 2.41-2.49, 2.79-2.93, 3.70-3.79, 4.01-4.08, 4.32-4.70, 4.70-4.95, 5.25- 5.62, 6.63-6.78, 6.83-6.98, 7.10-7.28, 7.44-7.59, 7.59-7.72, 7.75-7.90, 7.90-7.99, 8.08-8.20, 8.20-8.29, 8.57-8.88, 9.67-9. 77.
実施例５５－１
７－（６－｛［９－（４－クロロ－２－フルオロベンジル）－５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－イル］カルボニル｝－３－ピリジニル）－６－メチル－２－｛［４－（トリフルオロメトキシ）フェニル］アミノ｝－９－（１－｛［１－（トリフルオロメチル）シクロプロピル］カルボニル｝－４－ピペリジニル）－７，９－ジヒドロ－８Ｈ－プリン－８－オン　トリフルオロ酢酸塩
　参考例１２４で用いた３－フルオロアニリンの代わりに４－（トリフルオロメトキシ）アニリンを用いて、参考例１２４→参考例１２５→実施例５５と同様の操作を行い、逆相HPLCカラム精製することにより、以下の物性値を有する標題化合物を得た。
LC－MS（A）保持時間（分）：1.42；
MS(ESI, Pos.)： 963 (M + H)＋；
１H-NMR(DMSO-d６)：δ　 1.04-1.28, 1.30-1.39, 1.88-2.07, 2.83-2.90, 3.68-4.09, 4.30-4.68, 4.68-4.96, 5.25-5.63, 6.82-7.01, 7.07-7.28, 7.28-7.57, 7.75-8.02, 8.05-8.28, 8.53-8.87, 9.66-9.81。 Example 55-1
7-(6-{[9-(4-chloro-2-fluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[2,3- b]Pyridin-7-yl]carbonyl}-3-pyridinyl)-6-methyl-2-{[4-(trifluoromethoxy)phenyl]amino}-9-(1-{[1-(trifluoromethyl) cyclopropyl]carbonyl}-4-piperidinyl)-7,9-dihydro-8H-purin-8-one Trifluoroacetate 4-(trifluoromethoxy)aniline was used in place of 3-fluoroaniline used in Reference Example 124. The same operations as Reference Example 124→Reference Example 125→Example 55 were carried out using the same method, and the title compound having the following physical property values was obtained by purifying with a reverse phase HPLC column.
LC-MS (A) retention time (min): 1.42;
MS(ESI, Pos.): 963 (M + H) + ;
1 H-NMR (DMSO-d 6 ): δ 1.04-1.28, 1.30-1.39, 1.88-2.07, 2.83-2.90, 3.68-4.09, 4.30-4.68, 4.68-4.96, 5.25-5.63, 6.82-7.01, 7.07- 7.28, 7.28-7.57, 7.75-8.02, 8.05-8.28, 8.53-8.87, 9.66-9.81.
実施例５６
７－（６－｛［９－（４－クロロ－２－フルオロベンジル）－５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－イル］カルボニル｝－３－ピリジニル）－２－［（３－フルオロフェニル）アミノ］－６－メチル－９－［１－（２，２，２－トリフルオロエチル）－４－ピペリジニル］－７，９－ジヒドロ－８Ｈ－プリン－８－オン　２トリフルオロ酢酸塩
　参考例１２５で製造した化合物（25ｍｇ）をＤＭＦ（0.25ｍＬ）に溶解し、２，２，２－トリフルオロエチル　トリフルオロメタンスルホナート（7.6ｍｇ）とＤＩＰＥＡ（0.017ｍＬ）を加えて、４５℃で５時間攪拌した。反応液を室温に冷却し、逆相HPLCカラム精製することにより、以下の物性値を有する標題化合物（6.5ｍｇ）を得た。
LC－MS（A）保持時間（分）：1.26；
MS(ESI, Pos.)： 843 (M + H)＋；
１H-NMR(DMSO-d６)：δ　 1.77-1.86, 1.93-2.07, 2.59-2.71, 2.81-2.94, 3.04-3.19, 3.25-3.33, 3.70-4.11, 4.26, 4.67-4.95, 5.25-5.63, 6.66-6.75, 6.82-7.00, 7.09-7.37, 7.46-7.67, 7.73-7.99, 8.04-8.29, 8.58-8.88, 9.63-9.79。 Example 56
7-(6-{[9-(4-chloro-2-fluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[2,3- b]pyridin-7-yl]carbonyl}-3-pyridinyl)-2-[(3-fluorophenyl)amino]-6-methyl-9-[1-(2,2,2-trifluoroethyl)-4 -piperidinyl]-7,9-dihydro-8H-purin-8-one 2-trifluoroacetate The compound prepared in Reference Example 125 (25 mg) was dissolved in DMF (0.25 mL), and 2,2,2-trifluoroacetate was dissolved in DMF (0.25 mL). Ethyl trifluoromethanesulfonate (7.6 mg) and DIPEA (0.017 mL) were added, and the mixture was stirred at 45°C for 5 hours. The reaction solution was cooled to room temperature and purified using a reverse phase HPLC column to obtain the title compound (6.5 mg) having the following physical properties.
LC-MS (A) retention time (min): 1.26;
MS(ESI, Pos.): 843 (M + H) + ;
1 H-NMR (DMSO-d 6 ): δ 1.77-1.86, 1.93-2.07, 2.59-2.71, 2.81-2.94, 3.04-3.19, 3.25-3.33, 3.70-4.11, 4.26, 4.67-4.95, 5.25-5.63, 6.66-6.75, 6.82-7.00, 7.09-7.37, 7.46-7.67, 7.73-7.99, 8.04-8.29, 8.58-8.88, 9.63-9.79.
参考例１２６
２－クロロ－７－（６－｛［９－（４－クロロ－２－フルオロベンジル）－５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－イル］カルボニル｝－３－ピリジニル）－９－［１－（２，２－ジメチルプロピル）－４－ピペリジニル］－６－メチル－７，９－ジヒドロ－８Ｈ－プリン－８－オン
　参考例１００で用いた参考例９９で製造した化合物の代わりに参考例１２３で製造した化合物を用いて、参考例１００→参考例１０１と同様の操作を行い、以下の物性値を有する標題化合物を得た。
LC－MS（A）保持時間（分）：1.05；
MS(ESI, Pos.)： 756 (M + H)＋；
１H-NMR(CDCl３)：δ　 0.85-0.95, 1.67-1.78, 2.11-2.18, 2.45, 2.65-2.79, 2.93-3.00, 3.87-4.19, 4.37-4.53, 4.83-4.96, 5.30-5.56, 6.80-7.01, 7.06-7.16, 7.79-7.94, 8.26-8.33, 8.48-8.72。 Reference example 126
2-chloro-7-(6-{[9-(4-chloro-2-fluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[ 2,3-b]pyridin-7-yl]carbonyl}-3-pyridinyl)-9-[1-(2,2-dimethylpropyl)-4-piperidinyl]-6-methyl-7,9-dihydro-8H - Purin-8-one Using the compound produced in Reference Example 123 instead of the compound produced in Reference Example 99 used in Reference Example 100, the same operation as in Reference Example 100 → Reference Example 101 was performed to obtain the following physical properties. The title compound was obtained with a value of .
LC-MS (A) retention time (min): 1.05;
MS(ESI, Pos.): 756 (M + H) + ;
1 H-NMR (CDCl 3 ): δ 0.85-0.95, 1.67-1.78, 2.11-2.18, 2.45, 2.65-2.79, 2.93-3.00, 3.87-4.19, 4.37-4.53, 4.83-4.96, 5.30-5.56, 6.80 - 7.01, 7.06-7.16, 7.79-7.94, 8.26-8.33, 8.48-8.72.
実施例５７
（２Ｒ）－１－｛７－（６－｛［９－（４－クロロ－２－フルオロベンジル）－５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－イル］カルボニル｝－３－ピリジニル）－９－［１－（２，２－ジメチルプロピル）－４－ピペリジニル］－６－メチル－８－オキソ－８，９－ジヒドロ－７Ｈ－プリン－２－イル｝－２－ピロリジンカルボキサミド　２トリフルオロ酢酸塩
　参考例１２６で製造した化合物（15ｍｇ）と（２Ｒ）－ピロリジン－２－カルボキサミド（23ｍｇ）にＤＭＳＯ（0.30ｍＬ）を加え、さらにフッ化セシウム（7.5ｍｇ）とＤＩＰＥＡ（0.051ｍＬ）を加えて１００℃で１８時間攪拌した。反応液を室温に冷却し、逆相HPLCカラム精製することにより、以下の物性値を有する標題化合物（16ｍｇ）を得た。
LC－MS（A）保持時間（分）：0.99；
MS(ESI, Pos.)： 834 (M + H)＋；
１H-NMR(DMSO-d６)：δ　 1.04-1.19, 1.84-2.05, 2.77-2.93, 3.04-3.19, 3.65-3.82, 3.95-4.09, 4.33-4.44, 4.48-4.65, 4.64-4.96, 5.27-5.65, 7.00, 7.08-7.17, 7.17-7.38, 7.48-7.58, 7.62-7.89, 7.90-8.00, 8.00-8.17, 8.18-8.31, 8.49-8.83。 Example 57
(2R)-1-{7-(6-{[9-(4-chloro-2-fluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5 ]pyrrolo[2,3-b]pyridin-7-yl]carbonyl}-3-pyridinyl)-9-[1-(2,2-dimethylpropyl)-4-piperidinyl]-6-methyl-8-oxo- DMSO ( Then, cesium fluoride (7.5 mg) and DIPEA (0.051 mL) were added, and the mixture was stirred at 100°C for 18 hours. The reaction solution was cooled to room temperature and purified by reverse phase HPLC column to obtain the title compound (16 mg) having the following physical properties.
LC-MS (A) retention time (min): 0.99;
MS(ESI, Pos.): 834 (M + H) + ;
1 H-NMR (DMSO-d 6 ): δ 1.04-1.19, 1.84-2.05, 2.77-2.93, 3.04-3.19, 3.65-3.82, 3.95-4.09, 4.33-4.44, 4.48-4.65, 4.64-4.96, 5.27- 5.65, 7.00, 7.08-7.17, 7.17-7.38, 7.48-7.58, 7.62-7.89, 7.90-8.00, 8.00-8.17, 8.18-8.31, 8.49-8.83.
実施例５７－１～５
　参考例１２６で用いたピバルアルデヒドの代わりに１－（トリフルオロメチル）シクロプロパンカルボアルデヒドを、実施例５７で用いた（２Ｒ）－ピロリジン－２－カルボキサミドの代わりに対応するアミン化合物を用いて、参考例１２６→実施例５７と同様の操作を行い、シリカゲル精製もしくは逆相HPLCカラム精製することにより、以下の物性値を有する標題化合物を得た。 Examples 57-1 to 5
1-(trifluoromethyl)cyclopropanecarbaldehyde was used in place of pivalaldehyde used in Reference Example 126, and a corresponding amine compound was used in place of (2R)-pyrrolidine-2-carboxamide used in Example 57. , Reference Example 126→Example 57 and purification using silica gel or reverse phase HPLC column to obtain the title compound having the following physical properties.
実施例５７－１
７－（６－｛［９－（４－クロロ－２－フルオロベンジル）－５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－イル］カルボニル｝－３－ピリジニル）－６－メチル－９－（１－｛［１－（トリフルオロメチル）シクロプロピル］メチル｝－４－ピペリジニル）－２－［（３，３，３－トリフルオロプロピル）アミノ］－７，９－ジヒドロ－８Ｈ－プリン－８－オン
LC－MS（A）保持時間（分）：0.99；
MS(ESI, Pos.)： 885 (M + H)＋；
１H-NMR (CDCl３)：δ　 0.68, 0.96-1.06, 1.72-1.83, 1.97-2.03, 2.09-2.22, 2.42-2.54, 2.58-2.64, 2.67-2.81, 2.94-3.00, 3.06-3.15, 3.71, 3.90-4.17, 4.27-4.41, 4.85-4.92, 5.13, 5.31-5.56, 6.77-7.02, 7.05-7.15, 7.81-7.91, 8.30, 8.50-8.71。 Example 57-1
7-(6-{[9-(4-chloro-2-fluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[2,3- b]pyridin-7-yl]carbonyl}-3-pyridinyl)-6-methyl-9-(1-{[1-(trifluoromethyl)cyclopropyl]methyl}-4-piperidinyl)-2-[(3 ,3,3-trifluoropropyl)amino]-7,9-dihydro-8H-purin-8-one
LC-MS (A) retention time (min): 0.99;
MS(ESI, Pos.): 885 (M + H) + ;
1 H-NMR (CDCl 3 ): δ 0.68, 0.96-1.06, 1.72-1.83, 1.97-2.03, 2.09-2.22, 2.42-2.54, 2.58-2.64, 2.67-2.81, 2.94-3.00, 3.06-3.15, 3.71 , 3.90-4.17, 4.27-4.41, 4.85- 4.92, 5.13, 5.31-5.56, 6.77-7.02, 7.05-7.15, 7.81-7.91, 8.30, 8.50-8.71.
実施例５７－２
７－（６－｛［９－（４－クロロ－２－フルオロベンジル）－５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－イル］カルボニル｝－３－ピリジニル）－２－｛［（２，２－ジフルオロシクロプロピル）メチル］アミノ｝－６－メチル－９－（１－｛［１－（トリフルオロメチル）シクロプロピル］メチル｝－４－ピペリジニル）－７，９－ジヒドロ－８Ｈ－プリン－８－オン
LC－MS（A）保持時間（分）：1.00；
MS(ESI, Pos.)： 879 (M + H)＋；
１H-NMR (CDCl３)：δ　 0.69, 0.95-1.07, 1.13-1.22, 1.43-1.52, 1.71-1.82, 1.97-2.03, 2.11-2.21, 2.57-2.66, 2.68-2.85, 2.93-3.01, 3.05-3.15, 3.33-3.43, 3.68-3.83, 3.89-4.17, 4.29-4.42, 4.85-4.93, 5.14, 5.28-5.56, 6.77-7.00, 7.06-7.16, 7.81-7.90, 8.28-8.32, 8.51-8.72。 Example 57-2
7-(6-{[9-(4-chloro-2-fluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[2,3- b]pyridin-7-yl]carbonyl}-3-pyridinyl)-2-{[(2,2-difluorocyclopropyl)methyl]amino}-6-methyl-9-(1-{[1-(trifluoro methyl)cyclopropyl]methyl}-4-piperidinyl)-7,9-dihydro-8H-purin-8-one
LC-MS (A) retention time (min): 1.00;
MS(ESI, Pos.): 879 (M + H) + ;
1 H-NMR (CDCl 3 ): δ 0.69, 0.95-1.07, 1.13-1.22, 1.43-1.52, 1.71-1.82, 1.97-2.03, 2.11-2.21, 2.57-2.66, 2.68-2.85, 2.93-3.01, 3.05 - 3.15, 3.33-3.43, 3.68-3.83, 3.89-4.17, 4.29-4.42, 4.85-4.93, 5.14, 5.28-5.56, 6.77-7.00, 7.06-7.16, 7.81-7.90, 8.28-8.32, 8 .51-8.72.
実施例５７－３
７－（６－｛［９－（４－クロロ－２－フルオロベンジル）－５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－イル］カルボニル｝－３－ピリジニル）－６－メチル－２－（１－オキサ－７－アザスピロ［４．４］ノン－７－イル）－９－（１－｛［１－（トリフルオロメチル）シクロプロピル］メチル｝－４－ピペリジニル）－７，９－ジヒドロ－８Ｈ－プリン－８－オン
LC－MS（A）保持時間（分）：0.97；
MS(ESI, Pos.)： 899 (M + H)＋；
１H-NMR (CDCl３)：δ　 0.68, 0.96-1.03, 1.67-1.78, 1.93-2.08, 2.12-2.24, 2.63, 2.75-2.92, 2.93-3.03, 3.02-3.11, 3.49, 3.66-3.80, 3.87-4.17, 4.27-4.39, 4.84-4.92, 5.29-5.56, 6.76-7.00, 7.06-7.15, 7.81-7.88, 8.28-8.32, 8.53-8.70。 Example 57-3
7-(6-{[9-(4-chloro-2-fluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[2,3- b]pyridin-7-yl]carbonyl}-3-pyridinyl)-6-methyl-2-(1-oxa-7-azaspiro[4.4]non-7-yl)-9-(1-{[1 -(trifluoromethyl)cyclopropyl]methyl}-4-piperidinyl)-7,9-dihydro-8H-purin-8-one
LC-MS (A) retention time (min): 0.97;
MS(ESI, Pos.): 899 (M + H) + ;
1 H-NMR (CDCl 3 ): δ 0.68, 0.96-1.03, 1.67-1.78, 1.93-2.08, 2.12-2.24, 2.63, 2.75-2.92, 2.93-3.03, 3.02-3.11, 3.49, 3.66-3.80, 3.8 7- 4.17, 4.27-4.39, 4.84-4.92, 5.29-5.56, 6.76-7.00, 7.06-7.15, 7.81-7.88, 8.28-8.32, 8.53-8.70.
実施例５７－４
７－（６－｛［９－（４－クロロ－２－フルオロベンジル）－５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－イル］カルボニル｝－３－ピリジニル）－６－メチル－２－［４－（トリフルオロメトキシ）－１－ピペリジニル］－９－（１－｛［１－（トリフルオロメチル）シクロプロピル］メチル｝－４－ピペリジニル）－７，９－ジヒドロ－８Ｈ－プリン－８－オン
LC－MS（A）保持時間（分）：1.11；
MS(ESI, Pos.)： 941 (M + H)＋；
１H-NMR(DMSO-d６)：δ　 1.08-1.32, 1.60-1.72, 1.74-1.80, 1.86-1.96, 1.97-2.18, 2.72-2.91, 3.27-3.29, 3.56-3.82, 3.97-4.40, 4.46-4.61, 4.68-4.93, 5.25-5.61, 6.80-7.38, 7.47-7.55, 7.72-8.00, 8.00-8.13, 8.20-8.26, 8.28-8.46, 8.48-8.86, 9.43-9.58。 Example 57-4
7-(6-{[9-(4-chloro-2-fluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[2,3- b]Pyridin-7-yl]carbonyl}-3-pyridinyl)-6-methyl-2-[4-(trifluoromethoxy)-1-piperidinyl]-9-(1-{[1-(trifluoromethyl) cyclopropyl]methyl}-4-piperidinyl)-7,9-dihydro-8H-purin-8-one
LC-MS (A) retention time (min): 1.11;
MS(ESI, Pos.): 941 (M + H) + ;
1 H-NMR (DMSO-d 6 ): δ 1.08-1.32, 1.60-1.72, 1.74-1.80, 1.86-1.96, 1.97-2.18, 2.72-2.91, 3.27-3.29, 3.56-3.82, 3.97-4.40, 4.46- 4.61, 4.68-4.93, 5.25-5.61, 6.80-7.38, 7.47-7.55, 7.72-8.00, 8.00-8.13, 8.20-8.26, 8.28-8.46, 8.48-8.86, 9.43-9.58.
実施例５７－５
７－（６－｛［９－（４－クロロ－２－フルオロベンジル）－５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－イル］カルボニル｝－３－ピリジニル）－２－［シクロペンチル（３－ヒドロキシ－３－メチルブチル）アミノ］－６－メチル－９－（１－｛［１－（トリフルオロメチル）シクロプロピル］メチル｝－４－ピペリジニル）－７，９－ジヒドロ－８Ｈ－プリン－８－オン
LC－MS（A）保持時間（分）：1.07；
MS(ESI, Pos.)： 943 (M + H)＋；
１H-NMR (CDCl３)：δ　 0.68, 0.97-1.05, 1.24-1.26, 1.36-1.48, 1.51-1.89, 1.91-2.04, 2.11-2.22, 2.56-2.66, 2.70-2.86, 2.92-3.00, 3.04-3.14, 3.54-3.69, 3.86-4.22, 4.24-4.43, 4.80-4.95, 5.28-5.58, 6.78-7.00, 7.05-7.16, 7.81-7.94, 8.28-8.32, 8.49-8.71。 Example 57-5
7-(6-{[9-(4-chloro-2-fluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[2,3- b]pyridin-7-yl]carbonyl}-3-pyridinyl)-2-[cyclopentyl(3-hydroxy-3-methylbutyl)amino]-6-methyl-9-(1-{[1-(trifluoromethyl) cyclopropyl]methyl}-4-piperidinyl)-7,9-dihydro-8H-purin-8-one
LC-MS (A) retention time (min): 1.07;
MS(ESI, Pos.): 943 (M + H) + ;
1 H-NMR (CDCl 3 ): δ 0.68, 0.97-1.05, 1.24-1.26, 1.36-1.48, 1.51-1.89, 1.91-2.04, 2.11-2.22, 2.56-2.66, 2.70-2.86, 2.92-3.00, 3.04 - 3.14, 3.54-3.69, 3.86-4.22, 4.24-4.43, 4.80-4.95, 5.28-5.58, 6.78-7.00, 7.05-7.16, 7.81-7.94, 8.28-8.32, 8.49-8.71.
実施例５８
［｛７－（６－｛［９－（４－クロロ－２－フルオロベンジル）－５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－イル］カルボニル｝－３－ピリジニル）－９－［１－（２，２－ジメチルプロピル）－４－ピペリジニル］－６－メチル－８－オキソ－８，９－ジヒドロ－７Ｈ－プリン－２－イル｝（メチル）アミノ］酢酸　２トリフルオロ酢酸塩
　参考例１２６で製造した化合物（15ｍｇ）と２－（メチルアミノ）酢酸（23ｍｇ）にＤＭＳＯ（0.30ｍＬ）を加え、さらにフッ化セシウム（7.5ｍｇ）と炭酸セシウム（65ｍｇ）を加えて１００℃で１８時間攪拌した。反応液を室温に冷却し、逆相HPLCカラム精製することにより、以下の物性値を有する標題化合物（21ｍｇ）を得た。
LC－MS（A）保持時間（分）：1.00；
MS(ESI, Pos.)： 809 (M + H)＋；
１H-NMR(DMSO-d６)：δ　 0.98-1.16, 1.75-2.08, 2.81-2.96, 3.01-3.09, 3.16-3.25, 3.25-3.33, 3.63-3.78, 4.01-4.07, 4.27-4.38, 4.65-4.96, 5.27-5.61, 6.53-6.61, 6.82-6.92, 6.92-6.99, 7.06-7.19, 7.20-7.39, 7.45-7.55, 7.72-7.88, 7.88-8.01, 8.02-8.19, 8.19-8.27, 8.30-8.45, 8.50-8.60, 8.68-8.86, 8.88。 Example 58
[{7-(6-{[9-(4-chloro-2-fluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[2, 3-b]pyridin-7-yl]carbonyl}-3-pyridinyl)-9-[1-(2,2-dimethylpropyl)-4-piperidinyl]-6-methyl-8-oxo-8,9-dihydro -7H-purin-2-yl}(methyl)amino]acetic acid 2-trifluoroacetate DMSO (0.30 mL) was added to the compound prepared in Reference Example 126 (15 mg) and 2-(methylamino)acetic acid (23 mg), Furthermore, cesium fluoride (7.5 mg) and cesium carbonate (65 mg) were added, and the mixture was stirred at 100°C for 18 hours. The reaction solution was cooled to room temperature and purified using a reverse phase HPLC column to obtain the title compound (21 mg) having the following physical properties.
LC-MS (A) retention time (min): 1.00;
MS(ESI, Pos.): 809 (M + H) + ;
1 H-NMR (DMSO-d 6 ): δ 0.98-1.16, 1.75-2.08, 2.81-2.96, 3.01-3.09, 3.16-3.25, 3.25-3.33, 3.63-3.78, 4.01-4.07, 4.27-4.38, 4.65- 4.96, 5.27-5.61, 6.53-6.61, 6.82-6.92, 6.92-6.99, 7.06-7.19, 7.20-7.39, 7.45-7.55, 7.72-7.88, 7.88-8.01, 8.02-8.19, 8.19-8. 27, 8.30-8.45, 8.50-8.60, 8.68-8.86, 8.88.
実施例５８－１
３－｛［７－（６－｛［９－（４－クロロ－２－フルオロベンジル）－５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－イル］カルボニル｝－３－ピリジニル）－６－メチル－８－オキソ－９－（１－｛［１－（トリフルオロメチル）シクロプロピル］メチル｝－４－ピペリジニル）－８，９－ジヒドロ－７Ｈ－プリン－２－イル］（シクロへキシル）アミノ｝プロパン酸
　参考例１２６で用いたピバルアルデヒドの代わりに１－（トリフルオロメチル）シクロプロパンカルボアルデヒドを用いて、実施例５８で用いた２－（メチルアミノ）酢酸の代わりに３－（シクロへキシルアミノ）プロパン酸を用いて、参考例１２６→実施例５８と同様の操作を行い、以下の物性値を有する標題化合物を得た。
LC－MS（A）保持時間（分）：1.09；
MS(ESI, Pos.)： 943 (M + H)＋；
１H-NMR(DMSO-d６)：δ　 1.10-1.41, 1.45-1.58, 1.58-1.72, 1.77-1.84, 1.85-1.97, 2.04-2.24, 2.74-2.94, 3.17-3.27, 3.58-3.80, 3.96-4.39, 4.39-4.61, 4.65-4.95, 5.27-5.63, 6.84-6.99, 6.99-7.26, 7.29-7.33, 7.48-7.54, 7.72-7.88, 7.91-7.98, 8.02-8.15, 8.20-8.29, 8.51-8.82, 9.21-9.40。 Example 58-1
3-{[7-(6-{[9-(4-chloro-2-fluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[ 2,3-b]pyridin-7-yl]carbonyl}-3-pyridinyl)-6-methyl-8-oxo-9-(1-{[1-(trifluoromethyl)cyclopropyl]methyl}-4- 1-( trifluoromethyl)cyclopropanecarbaldehyde was used in place of pivalaldehyde used in Reference Example 126. Using 3-(cyclohexylamino)propanoic acid instead of 2-(methylamino)acetic acid used in Example 58, the same operation as Reference Example 126 → Example 58 was performed, and the following physical property values were obtained. The title compound was obtained.
LC-MS (A) retention time (min): 1.09;
MS(ESI, Pos.): 943 (M + H) + ;
1 H-NMR (DMSO-d 6 ): δ 1.10-1.41, 1.45-1.58, 1.58-1.72, 1.77-1.84, 1.85-1.97, 2.04-2.24, 2.74-2.94, 3.17-3.27, 3.58-3.80, 3.96- 4.39, 4.39-4.61, 4.65-4.95, 5.27-5.63, 6.84-6.99, 6.99-7.26, 7.29-7.33, 7.48-7.54, 7.72-7.88, 7.91-7.98, 8.02-8.15, 8.20-8. 29, 8.51-8.82, 9.21-9.40.
参考例１２７
２－メチル－２－プロパニル　（３－エキソ）－３－［２－クロロ－７－（６－｛［９－（４－クロロ－２－フルオロベンジル）－５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－イル］カルボニル｝－３－ピリジニル）－６－メチル－８－オキソ－７，８－ジヒドロ－９Ｈ－プリン－９－イル］－８－アザビシクロ［３．２．１］オクタン－８－カルボキシラート
　参考例３で用いた２－メチル－２－プロパニル　４－アミノ－１－ピぺリジンカルボキシラートの代わりに２－メチル－２－プロパニル　（３－エキソ）－３－アミノ－８－アザビシクロ［３．２．１］オクタン－８－カルボキシラートを用いて、参考例３→参考例９３→参考例９４→参考例９５→参考例１２３と同様の操作を行い、以下の物性値を有する標題化合物を得た。
LC－MS（A）保持時間（分）：1.33；
MS(ESI, Pos.)： 812 (M + H)＋；
１H-NMR(CDCl３)：δ　 1.54-1.57, 1.69-1.74, 1.82-1.94, 2.07-2.17, 2.75-2.85, 2.93-3.02, 3.89-4.17, 4.28-4.38, 4.38-4.49, 4.83-5.04, 5.32-5.56, 6.79-7.02, 7.05-7.16, 7.81-7.95, 8.31, 8.46-8.73。 Reference example 127
2-Methyl-2-propanyl (3-exo)-3-[2-chloro-7-(6-{[9-(4-chloro-2-fluorobenzyl)-5,6,8,9-tetrahydro- 7H-pyrido[4',3':4,5]pyrrolo[2,3-b]pyridin-7-yl]carbonyl}-3-pyridinyl)-6-methyl-8-oxo-7,8-dihydro- 9H-purin-9-yl]-8-azabicyclo[3.2.1]octane-8-carboxylate 2-methyl-2-propanyl 4-amino-1-piperidinecarboxylate used in Reference Example 3 Using 2-methyl-2-propanyl (3-exo)-3-amino-8-azabicyclo[3.2.1]octane-8-carboxylate instead, Reference Example 3 → Reference Example 93 → Reference Example 94 → Reference Example 95 → The same operation as in Reference Example 123 was performed to obtain the title compound having the following physical property values.
LC-MS (A) retention time (min): 1.33;
MS(ESI, Pos.): 812 (M + H) + ;
1 H-NMR (CDCL 3 ): δ 1.54-1.57, 1.69-1.74, 1.82-1.94, 2.07-2.17, 2.75-2.85, 2.93-3.02, 3.89-4.17, 4.28-4.38, 4.38-4.49, 4.83-5.04, 4.83-5.04 5.32-5.56, 6.79-7.02, 7.05-7.16, 7.81-7.95, 8.31, 8.46-8.73.
参考例１２８
２－メチル－２－プロパニル　（３－エキソ）－３－｛７－（６－｛［９－（４－クロロ－２－フルオロベンジル）－５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－イル］カルボニル｝－３－ピリジニル）－２－［（２，２－ジメチルプロピル）アミノ］－６－メチル－８－オキソ－７，８－ジヒドロ－９Ｈ－プリン－９－イル｝－８－アザビシクロ［３．２．１］オクタン－８－カルボキシラート
　参考例１２７で製造した化合物（200ｍｇ）と２，２－ジメチル－１－プロパンアミン（214ｍｇ）にＤＭＳＯ（4.0ｍＬ）を加え、さらにフッ化セシウム（93ｍｇ）とＤＩＰＥＡ（0.43ｍＬ）を加えて１００℃で１８時間攪拌した。反応液を室温に冷却して水を加え、酢酸エチルで抽出した。有機層を飽和塩化アンモニウム水溶液、水、飽和食塩水で順次洗浄し、減圧濃縮した。得られた残渣をシリカゲルクロマトグラフィー（富士シリシア　ＮＨ（商品名）、ヘキサン：酢酸エチル＝７：３→１：１）で精製することにより、以下の物性値を有する標題化合物（200ｍｇ）を得た。
LC－MS（A）保持時間（分）：1.24；
MS(ESI, Pos.)： 863 (M + H)＋。 Reference example 128
2-Methyl-2-propanyl (3-exo)-3-{7-(6-{[9-(4-chloro-2-fluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[ 4',3':4,5]pyrrolo[2,3-b]pyridin-7-yl]carbonyl}-3-pyridinyl)-2-[(2,2-dimethylpropyl)amino]-6-methyl- 8-oxo-7,8-dihydro-9H-purin-9-yl}-8-azabicyclo[3.2.1]octane-8-carboxylate The compound prepared in Reference Example 127 (200 mg) and 2,2- DMSO (4.0 mL) was added to dimethyl-1-propanamine (214 mg), cesium fluoride (93 mg) and DIPEA (0.43 mL) were added, and the mixture was stirred at 100°C for 18 hours. The reaction solution was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with saturated ammonium chloride aqueous solution, water, and saturated brine, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (Fuji Silysia NH (trade name), hexane: ethyl acetate = 7:3 → 1:1) to obtain the title compound (200 mg) having the following physical property values. .
LC-MS (A) retention time (min): 1.24;
MS(ESI, Pos.): 863 (M + H) + .
実施例５９
７－（６－｛［９－（４－クロロ－２－フルオロベンジル）－５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－イル］カルボニル｝－３－ピリジニル）－２－［（２，２－ジメチルプロピル）アミノ］－６－メチル－９－［（３－エキソ）－８－｛［１－（トリフルオロメチル）シクロプロピル］メチル｝－８－アザビシクロ［３．２．１］オクタ－３－イル］－７，９－ジヒドロ－８Ｈ－プリン－８－オン
　参考例９８で用いた参考例９７で製造した化合物の代わりに参考例１２８で製造した化合物を、実施例３４で使用したピバルアルデヒドの代わりに１－（トリフルオロメチル）シクロプロパンカルボアルデヒドを用いて、参考例９８→実施例３４と同様の操作を行い、以下の物性値を有する標題化合物を得た。
LC－MS（A）保持時間（分）：1.06；
MS(ESI, Pos.)： 885 (M + H)＋；
１H-NMR (CDCl３)：δ　 1.01, 1.29-1.38, 1.93-2.08, 2.08-2.27, 2.47-2.57, 2.96-3.07, 3.13-3.30, 3.40-3.51, 3.93-4.21, 4.35, 4.86-4.99, 5.42-5.65, 6.85-7.16, 7.28-7.33, 7.83-7.89, 7.97, 8.06-8.12, 8.42-8.67, 9.66-9.92。 Example 59
7-(6-{[9-(4-chloro-2-fluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[2,3- b]pyridin-7-yl]carbonyl}-3-pyridinyl)-2-[(2,2-dimethylpropyl)amino]-6-methyl-9-[(3-exo)-8-{[1-( trifluoromethyl)cyclopropyl]methyl}-8-azabicyclo[3.2.1]oct-3-yl]-7,9-dihydro-8H-purin-8-one In Reference Example 97 used in Reference Example 98 The compound produced in Reference Example 128 was used in place of the produced compound, and 1-(trifluoromethyl)cyclopropanecarbaldehyde was used in place of the pivalaldehyde used in Example 34. Reference Example 98→Example 34 A similar operation was performed to obtain the title compound having the following physical properties.
LC-MS (A) retention time (min): 1.06;
MS(ESI, Pos.): 885 (M + H) + ;
1 H-NMR (CDCl 3 ): δ 1.01, 1.29-1.38, 1.93-2.08, 2.08-2.27, 2.47-2.57, 2.96-3.07, 3.13-3.30, 3.40-3.51, 3.93-4.21, 4.35, 4.86-4.99 , 5.42-5.65, 6.85-7.16, 7.28-7.33, 7.83-7.89, 7.97, 8.06-8.12, 8.42-8.67, 9.66-9.92.
参考例１２９
２－クロロ－７－（６－｛［９－（２，４－ジフルオロベンジル）－５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－イル］カルボニル｝－３－ピリジニル）－９－［１－（２，２－ジメチルプロピル）－４－ピペリジニル］－６－メチル－７，９－ジヒドロ－８Ｈ－プリン－８－オン
　参考例９９で用いた参考例５３で製造した化合物の代わりに参考例２で製造した化合物を用いて、参考例９９→参考例１００→参考例１０１と同様の操作を行い、以下の物性値を有する標題化合物を得た。
LC－MS（A）保持時間（分）：1.01；
MS(ESI, Pos.)： 740 (M + H)＋；
１H-NMR(CDCl３)：δ　 0.87-0.93, 1.66-1.76, 2.10-2.19, 2.41-2.50, 2.65-2.78, 2.91-3.01, 3.87-4.21, 4.38-4.48, 4.85-4.96, 5.28-5.56, 6.62-7.16, 7.81-7.95, 8.31, 8.54-8.72。 Reference example 129
2-chloro-7-(6-{[9-(2,4-difluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[2, 3-b]pyridin-7-yl]carbonyl}-3-pyridinyl)-9-[1-(2,2-dimethylpropyl)-4-piperidinyl]-6-methyl-7,9-dihydro-8H-purine -8-one Using the compound produced in Reference Example 2 instead of the compound produced in Reference Example 53 used in Reference Example 99, the same operation as Reference Example 99 → Reference Example 100 → Reference Example 101 was performed, and the following was obtained. The title compound having the physical property values was obtained.
LC-MS (A) retention time (min): 1.01;
MS(ESI, Pos.): 740 (M + H) + ;
1 H-NMR (CDCL 3 ): δ 0.87-0.93, 1.66-1.76, 2.10-2.19, 2.41-2.50, 2.65-2.78, 2.91-3.01, 2.91-3.01, 3.87-4.21, 4.38-4.96, 4.85-4.96, 5.28-56, 5.28-56 6.62-7.16, 7.81-7.95, 8.31, 8.54-8.72.
実施例６０
７－（６－｛［９－（２，４－ジフルオロベンジル）－５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－イル］カルボニル｝－３－ピリジニル）－９－［１－（２，２－ジメチルプロピル）－４－ピペリジニル］－２－［３－ヒドロキシ－３－（トリフルオロメチル）－１－アゼジチニル］－６－メチル－７，９－ジヒドロ－８Ｈ－プリン－８－オン　２トリフルオロ酢酸塩
　参考例１２６で製造した化合物の代わりに参考例１２９で製造した化合物（15ｍｇ）を、（２Ｒ）－ピロリジン－２－カルボキサミドの代わりに３－（トリフルオロメチル）－３－アゼチジノール塩酸塩（4ｍｇ）を用いて、実施例５７と同様の操作を行い、以下の物性値を有する標題化合物（21ｍｇ）を得た。
LC－MS（A）保持時間（分）：1.00；
MS(ESI, Pos.)： 845 (M + H)＋；
１H-NMR(DMSO-d６)：δ　 1.09, 1.87-2.07, 2.83-3.10, 3.22-3.34, 3.62-3.77, 3.97-4.14, 4.22-4.34, 4.47-4.93, 5.25-5.65, 6.86-7.08, 7.08-7.28, 7.29-7.36, 7.35-7.53, 7.74-8.02, 8.16, 8.20-8.29, 8.32-8.38, 8.50-8.59, 8.64-8.86, 8.86-8.99。 Example 60
7-(6-{[9-(2,4-difluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[2,3-b] pyridin-7-yl]carbonyl}-3-pyridinyl)-9-[1-(2,2-dimethylpropyl)-4-piperidinyl]-2-[3-hydroxy-3-(trifluoromethyl)-1- [Azeditinyl]-6-methyl-7,9-dihydro-8H-purin-8-one 2 trifluoroacetate Instead of the compound produced in Reference Example 126, the compound (15 mg) produced in Reference Example 129 was used as (2R) - Using 3-(trifluoromethyl)-3-azetidinol hydrochloride (4 mg) instead of pyrrolidine-2-carboxamide, the same operation as in Example 57 was carried out to obtain the title compound (21 mg) having the following physical property values. I got it.
LC-MS (A) retention time (min): 1.00;
MS(ESI, Pos.): 845 (M + H) + ;
1 H-NMR (DMSO-d 6 ): δ 1.09, 1.87-2.07, 2.83-3.10, 3.22-3.34, 3.62-3.77, 3.97-4.14, 4.22-4.34, 4.47-4.93, 5.25-5.65, 6.86-7.08, 7.08-7.28, 7.29-7.36, 7.35-7.53, 7.74-8.02, 8.16, 8.20-8.29, 8.32-8.38, 8.50-8.59, 8.64-8.86, 8.86-8.99.
実施例６０－１
７－（６－｛［９－（２，４－ジフルオロベンジル）－５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－イル］カルボニル｝－３－ピリジニル）－９－［１－（２，２－ジメチルプロピル）－４－ピペリジニル］－２－［４－ヒドロキシ－４－（トリフルオロメチル）－１－ピペリジニル］－６－メチル－７，９－ジヒドロ－８Ｈ－プリン－８－オン　２トリフルオロ酢酸塩
　３－（トリフルオロメチル）－３－アゼチジノール塩酸塩の代わりに４－（トリフルオロメチル）－４－ピペリジノールを用いて、実施例６０と同様の操作を行い、逆相HPLCカラム精製することにより、以下の物性値を有する標題化合物を得た。
LC－MS（A）保持時間（分）：1.03；
MS(ESI, Pos.)： 873 (M + H)＋；
１H-NMR(DMSO-d６)：δ　 1.03-1.12, 1.58-1.80, 1.86-2.06, 2.82-3.07, 3.09-3.21, 3.23-3.35, 3.61-3.77, 4.00-4.07, 4.56-4.70, 4.85, 5.24-5.64, 6.08-6.19, 6.96-7.21, 7.27-7.36, 7.75-8.00, 8.05-8.17, 8.19-8.31, 8.62-8.84, 8.87-9.03。 Example 60-1
7-(6-{[9-(2,4-difluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[2,3-b] pyridin-7-yl]carbonyl}-3-pyridinyl)-9-[1-(2,2-dimethylpropyl)-4-piperidinyl]-2-[4-hydroxy-4-(trifluoromethyl)-1- piperidinyl]-6-methyl-7,9-dihydro-8H-purin-8-one 2 trifluoroacetate 4-(trifluoromethyl)-4 instead of 3-(trifluoromethyl)-3-azetidinol hydrochloride The same operation as in Example 60 was carried out using -piperidinol, and the title compound having the following physical property values was obtained by purifying with a reverse phase HPLC column.
LC-MS (A) retention time (min): 1.03;
MS(ESI, Pos.): 873 (M + H) + ;
1 H-NMR (DMSO-d 6 ): δ 1.03-1.12, 1.58-1.80, 1.86-2.06, 2.82-3.07, 3.09-3.21, 3.23-3.35, 3.61-3.77, 4.00-4.07, 4.56-4.70, 4.85, 5.24-5.64, 6.08-6.19, 6.96-7.21, 7.27-7.36, 7.75-8.00, 8.05-8.17, 8.19-8.31, 8.62-8.84, 8.87-9.03.
参考例１３０
２－メチル－２－プロパニル　９－［４－（ジフルオロメトキシ）－２－フルオロベンジル］－５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－カルボキシラート
　１－（ブロモメチル）－２，４－ジフルオロベンゼンの代わりに１－（ブロモメチル）－４－（ジフルオロメトキシ）－２－フルオロベンゼンを用いて、参考例１と同様の操作を行い、以下の物性値を有する標題化合物を得た。
TLC：Rf 0.36（ヘキサン：酢酸エチル＝４：１）；
１H-NMR(CDCl３)：δ　 1.47, 2.79, 3.68-3.80, 4.54, 5.46, 6.22-6.68, 6.77, 6.84-7.12, 7.80, 8.28。 Reference example 130
2-Methyl-2-propanyl 9-[4-(difluoromethoxy)-2-fluorobenzyl]-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[2 , 3-b] Pyridine-7-carboxylate Using 1-(bromomethyl)-4-(difluoromethoxy)-2-fluorobenzene instead of 1-(bromomethyl)-2,4-difluorobenzene, Reference Example 1 The same operation as above was performed to obtain the title compound having the following physical properties.
TLC: Rf 0.36 (hexane: ethyl acetate = 4:1);
1H -NMR ( CDCl3 ): δ 1.47, 2.79, 3.68-3.80, 4.54, 5.46, 6.22-6.68, 6.77, 6.84-7.12, 7.80, 8.28.
参考例１３１
９－［４－（ジフルオロメトキシ）－２－フルオロベンジル］－６，７，８，９－テトラヒドロ－５Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン　２塩酸塩
　参考例１で製造した化合物の代わりに参考例１３０で製造した化合物を用いて、参考例２と同様の操作を行い、以下の物性値を有する標題化合物を得た。
TLC：Rf 0.47（ジクロロメタン：メタノール＝９：１）；
１H-NMR(DMSO-d６)：δ　 2.98, 3.45, 4.37, 5.51, 6.94, 7.01-7.10, 7.12-7.49, 8.00, 8.28, 9.77。 Reference example 131
9-[4-(difluoromethoxy)-2-fluorobenzyl]-6,7,8,9-tetrahydro-5H-pyrido[4',3':4,5]pyrrolo[2,3-b]pyridine 2 The same operation as in Reference Example 2 was carried out using the compound produced in Reference Example 130 instead of the compound produced in Hydrochloride Reference Example 1 to obtain the title compound having the following physical property values.
TLC: Rf 0.47 (dichloromethane:methanol = 9:1);
1H -NMR (DMSO- d6 ): δ 2.98, 3.45, 4.37, 5.51, 6.94, 7.01-7.10, 7.12-7.49, 8.00, 8.28, 9.77.
実施例６１
７－［６－（｛９－［４－（ジフルオロメトキシ）－２－フルオロベンジル］－５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－イル｝カルボニル）－３－ピリジニル］－２－［（３－フルオロフェニル）アミノ］－６－メチル－９－（１－｛［１－（トリフルオロメチル）シクロプロピル］メチル｝－４－ピペリジニル）－７，９－ジヒドロ－８Ｈ－プリン－８－オン
　参考例１２３で用いた参考例７２で製造した化合物の代わりに参考例１３１で製造した化合物を、実施例５４で用いたピバルアルデヒドの代わりに１－（トリフルオロメチル）シクロプロパンカルボアルデヒド用いて、参考例１２３→参考例１２４→参考例１２５→実施例５４と同様の操作を行い、以下の物性値を有する標題化合物を得た。
LC－MS（A）保持時間（分）：1.11；
MS(ESI, Pos.)： 915 (M + H)＋；
１H-NMR (CDCl３)：δ　 0.73, 0.97-1.08, 1.75-1.87, 2.06-2.12, 2.17, 2.64, 2.70-2.83, 2.93-3.02, 3.10-3.18, 3.90-4.20, 4.33-4.43, 4.90-4.97, 5.28-5.57, 6.24-6.70, 6.70-6.79, 6.87-7.14, 7.27-7.33, 7.61, 7.81-7.92, 8.31, 8.58-8.72。 Example 61
7-[6-({9-[4-(difluoromethoxy)-2-fluorobenzyl]-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[2 ,3-b]pyridin-7-yl}carbonyl)-3-pyridinyl]-2-[(3-fluorophenyl)amino]-6-methyl-9-(1-{[1-(trifluoromethyl)cyclo Propyl]methyl}-4-piperidinyl)-7,9-dihydro-8H-purin-8-one The compound produced in Reference Example 131 was used in place of the compound produced in Reference Example 72 used in Reference Example 123. Using 1-(trifluoromethyl)cyclopropanecarbaldehyde instead of pivalaldehyde used in 54, the same operation as in Reference Example 123 → Reference Example 124 → Reference Example 125 → Example 54 was performed, and the following physical property values were obtained. The title compound was obtained.
LC-MS (A) retention time (min): 1.11;
MS(ESI, Pos.): 915 (M + H) + ;
1 H-NMR (CDCl 3 ): δ 0.73, 0.97-1.08, 1.75-1.87, 2.06-2.12, 2.17, 2.64, 2.70-2.83, 2.93-3.02, 3.10-3.18, 3.90-4.20, 4.33-4.43, 4.9 0- 4.97, 5.28-5.57, 6.24-6.70, 6.70-6.79, 6.87-7.14, 7.27-7.33, 7.61, 7.81-7.92, 8.31, 8.58-8.72.
参考例１３２
２－メチル－２－プロパニル　９－（４－クロロベンジル）－５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－カルボキシラート
　１－（ブロモメチル）－２，４－ジフルオロベンゼンの代わりに１－（ブロモメチル）－４－クロロベンゼンを用いて、参考例１と同様の操作を行い、以下の物性値を有する標題化合物を得た。
１H-NMR(CDCl３)：δ　 1.36-1.57, 2.79, 3.72, 4.47, 5.41, 7.04-7.11, 7.80, 8.29。 Reference example 132
2-Methyl-2-propanyl 9-(4-chlorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[2,3-b]pyridine- 7-Carboxylate Using 1-(bromomethyl)-4-chlorobenzene instead of 1-(bromomethyl)-2,4-difluorobenzene, the same operation as in Reference Example 1 was performed to obtain the title compound having the following physical properties. I got it.
1H -NMR ( CDCl3 ): δ 1.36-1.57, 2.79, 3.72, 4.47, 5.41, 7.04-7.11, 7.80, 8.29.
参考例１３３
９－（４－クロロベンジル）－６，７，８，９－テトラヒドロ－５Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン　２塩酸塩
　参考例１で製造した化合物の代わりに参考例１３２で製造した化合物を用いて、参考例２と同様の操作を行い、以下の物性値を有する標題化合物を得た。
１H-NMR(DMSO-d６)：δ　 2.97, 3.40-3.48, 4.32, 5.49, 7.15-7.21, 7.38, 8.00, 8.29, 9.67。 Reference example 133
9-(4-chlorobenzyl)-6,7,8,9-tetrahydro-5H-pyrido[4',3':4,5]pyrrolo[2,3-b]pyridine dihydrochloride Manufactured according to Reference Example 1 The same operation as in Reference Example 2 was carried out using the compound prepared in Reference Example 132 instead of the compound prepared in Reference Example 132 to obtain the title compound having the following physical property values.
1H -NMR (DMSO- d6 ): δ 2.97, 3.40-3.48, 4.32, 5.49, 7.15-7.21, 7.38, 8.00, 8.29, 9.67.
参考例１３４
２－メチル－２－プロパニル　（３Ｓ）－３－［（３－アミノ－６－ブロモ－２－ピラジニル）アミノ］－１－ピペリジンカルボキシラート
　２－メチル－２－プロパニル　（３Ｓ）－３－アミノ－１－ピぺリジンカルボキシラート（5.9ｇ）と３，５－ジブロモ－２－ピラジンアミン（5.0ｇ）にＮＭＰ（5.0ｍＬ）とＮＥｔ３（4.1ｍＬ）を加えて、１２０℃で１６時間攪拌した。反応液を室温まで冷却し、水を加えて酢酸エチルで抽出した。有機層を水で洗浄し、無水硫酸ナトリウムで乾燥し、減圧濃縮して以下の物性値を有する標題化合物（4.7ｇ）を得た。
LC－MS（A）保持時間（分）：0.97；
MS(ESI, Pos.)： 372 (M + H)＋。 Reference example 134
2-Methyl-2-propanyl (3S)-3-[(3-amino-6-bromo-2-pyrazinyl)amino]-1-piperidinecarboxylate 2-methyl -2-propanyl (3S)-3-amino- NMP (5.0 mL) and NEt 3 (4.1 mL) were added to 1-piperidinecarboxylate (5.9 g) and 3,5-dibromo-2-pyrazine amine (5.0 g), and the mixture was stirred at 120°C for 16 hours. . The reaction solution was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the title compound (4.7 g) having the following physical properties.
LC-MS (A) retention time (min): 0.97;
MS(ESI, Pos.): 372 (M + H) + .
参考例１３５
２－メチル－２－プロパニル　（３Ｓ）－３－［６－ブロモ－３－（６－｛［９－（４－クロロベンジル）－５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－イル］カルボニル｝－３－ピリジニル）－２－オキソ－２，３－ジヒドロ－１Ｈ－イミダゾ［４，５－ｂ］ピラジン－１－イル］－１－ピペリジンカルボキシラート
　参考例１３で用いた参考例１２で製造した化合物の代わりに参考例１３４で製造した化合物を、参考例１４で用いたメチル　４－ヨードベンゾアートの代わりにメチル　５－ブロモ－２－ピリジンカルボキシラートを、参考例１６で用いた参考例２で製造した化合物の代わりに参考例１３３で製造した化合物を用いて、参考例１３→参考例１４→参考例１５→参考例１６と同様の操作を行い、以下の物性値を有する標題化合物を得た。
LC－MS（A）保持時間（分）：1.36；
MS(ESI, Pos.)： 798 (M + H)＋；
１H-NMR(CDCl３)：δ　 1.48, 1.57-1.78, 1.81-1.98, 2.43-2.64, 2.71-2.88, 2.92-3.03, 3.57-3.77, 3.89-4.35, 4.46-4.60, 4.69-4.90, 5.27-5.54, 6.91, 7.02-7.17, 7.17-7.35, 7.71-7.96, 8.12, 8.22-8.42, 8.92-9.24。 Reference example 135
2-Methyl-2-propanyl (3S)-3-[6-bromo-3-(6-{[9-(4-chlorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[2,3-b]pyridin-7-yl]carbonyl}-3-pyridinyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b] pyrazin-1-yl]-1-piperidinecarboxylate The compound produced in Reference Example 134 was used in place of the compound produced in Reference Example 12 used in Reference Example 13, and the compound produced in Reference Example 134 was used in place of the compound produced in Reference Example 13. Using methyl 5-bromo-2-pyridinecarboxylate instead, and using the compound produced in Reference Example 133 instead of the compound produced in Reference Example 2 used in Reference Example 16, Reference Example 13 → Reference Example 14 → Reference The same operation as in Example 15→Reference Example 16 was performed to obtain the title compound having the following physical properties.
LC-MS (A) retention time (min): 1.36;
MS(ESI, Pos.): 798 (M + H) + ;
1 H-NMR (CDCl 3 ): δ 1.48, 1.57-1.78, 1.81-1.98, 2.43-2.64, 2.71-2.88, 2.92-3.03, 3.57-3.77, 3.89-4.35, 4.46-4.60, 4.69-4.90, 5.27 - 5.54, 6.91, 7.02-7.17, 7.17-7.35, 7.71-7.96, 8.12, 8.22-8.42, 8.92-9.24.
実施例６２
５－アニリノ－１－（６－｛［９－（４－クロロベンジル）－５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－イル］カルボニル｝－３－ピリジニル）－３－［（３Ｓ）－１－（２，２－ジメチルプロピル）－３－ピペリジニル］－１，３－ジヒドロ－２Ｈ－イミダゾ［４，５－ｂ］ピラジン－２－オン
　参考例８で用いた参考例７で製造した化合物の代わりに参考例１３５で製造した化合物を用いて、参考例８→参考例９→実施例１と同様の操作を行い、以下の物性値を有する標題化合物を得た。
LC－MS（A）保持時間（分）：1.12；
MS(ESI, Pos.)： 781 (M + H)＋；
１H-NMR(CDCl３)：δ　 0.87-0.91, 1.73-1.85, 1.89-1.99, 2.09-2.22, 2.32-2.48, 2.80-2.89, 2.90-3.01, 3.20, 3.90-4.16, 4.63-4.75, 4.76-4.87, 5.27-5.51, 6.43, 6.93, 7.06-7.13, 7.23-7.27, 7.34-7.47, 7.66-7.71, 7.75-7.87, 8.28-8.32, 8.43, 9.14-9.28。 Example 62
5-anilino-1-(6-{[9-(4-chlorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[2,3- b]pyridin-7-yl]carbonyl}-3-pyridinyl)-3-[(3S)-1-(2,2-dimethylpropyl)-3-piperidinyl]-1,3-dihydro-2H-imidazo[4 , 5-b] Pyrazin-2-one Using the compound produced in Reference Example 135 instead of the compound produced in Reference Example 7 used in Reference Example 8, the same procedure as in Reference Example 8 → Reference Example 9 → Example 1 The title compound having the following physical properties was obtained.
LC-MS (A) retention time (min): 1.12;
MS(ESI, Pos.): 781 (M + H) + ;
1 H-NMR (CDCl 3 ): δ 0.87-0.91, 1.73-1.85, 1.89-1.99, 2.09-2.22, 2.32-2.48, 2.80-2.89, 2.90-3.01, 3.20, 3.90-4.16, 4.63-4.75, 4.76 - 4.87, 5.27-5.51, 6.43, 6.93, 7.06-7.13, 7.23-7.27, 7.34-7.47, 7.66-7.71, 7.75-7.87, 8.28-8.32, 8.43, 9.14-9.28.
参考例１３６
２－メチル－２－プロパニル　４－［（３－アミノ－６－ブロモ－２－ピラジニル）アミノ］－１－ピペリジンカルボキシラート
　２－メチル－２－プロパニル　（３Ｓ）－３－アミノ－１－ピぺリジンカルボキシラートの代わりに２－メチル－２－プロパニル　４－アミノ－１－ピぺリジンカルボキシラート（4.8ｇ）を用いて、参考例１３４と同様の操作を行い、以下の物性値を有する標題化合物（1.5ｇ）を得た。
LC－MS（A）保持時間（分）：0.97；
MS(ESI, Pos.)： 372 (M + H)＋。 Reference example 136
2-Methyl-2-propanyl 4-[(3-amino-6-bromo-2-pyrazinyl)amino]-1-piperidinecarboxylate 2-methyl-2-propanyl (3S)-3-amino-1-pipe The same operation as in Reference Example 134 was carried out using 2-methyl-2-propanyl 4-amino-1-piperidinecarboxylate (4.8 g) in place of lysine carboxylate, and the title compound having the following physical properties was obtained. (1.5g) was obtained.
LC-MS (A) retention time (min): 0.97;
MS(ESI, Pos.): 372 (M + H) + .
参考例１３７
２－メチル－２－プロパニル　４－［６－ブロモ－３－（６－｛［９－（２，４－ジフルオロベンジル）－５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－イル］カルボニル｝－３－ピリジニル）－２－オキソ－２，３－ジヒドロ－１Ｈ－イミダゾ［４，５－ｂ］ピラジン－１－イル］－１－ピペリジンカルボキシラート
　参考例１３で用いた参考例１２で製造した化合物の代わりに参考例１３６で製造した化合物を、参考例１４で用いたメチル　４－ヨードベンゾアートの代わりにメチル　５－ブロモ－２－ピリジンカルボキシラートを用いて、参考例１３→参考例１４→参考例１５→参考例１６と同様の操作を行い、以下の物性値を有する標題化合物を得た。
LC－MS（A）保持時間（分）：1.31；
MS(ESI, Pos.)： 800 (M + H)＋；
１H-NMR(CDCl３)：δ　 1.52, 1.81-1.93, 2.53-2.67, 2.82-2.93, 2.92-3.01, 3.89-4.17, 4.25-4.45, 4.54-4.67, 4.85-4.94, 5.29-5.56, 6.60-6.98, 7.10, 7.78-7.92, 8.08-8.13, 8.27-8.35, 9.04-9.20。 Reference example 137
2-Methyl-2-propanyl 4-[6-bromo-3-(6-{[9-(2,4-difluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3 ':4,5]pyrrolo[2,3-b]pyridin-7-yl]carbonyl}-3-pyridinyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyrazine- 1-yl]-1-piperidinecarboxylate The compound produced in Reference Example 136 was used in place of the compound produced in Reference Example 12 used in Reference Example 13, and the compound produced in Reference Example 136 was used in place of the methyl 4-iodobenzoate used in Reference Example 14. Using methyl 5-bromo-2-pyridinecarboxylate, the same operations as Reference Example 13 → Reference Example 14 → Reference Example 15 → Reference Example 16 were performed to obtain the title compound having the following physical property values.
LC-MS (A) retention time (min): 1.31;
MS(ESI, Pos.): 800 (M + H) + ;
1 H-NMR (CDCl 3 ): δ 1.52, 1.81-1.93, 2.53-2.67, 2.82-2.93, 2.92-3.01, 3.89-4.17, 4.25-4.45, 4.54-4.67, 4.85-4.94, 5.29-5.56, 6.60 - 6.98, 7.10, 7.78-7.92, 8.08-8.13, 8.27-8.35, 9.04-9.20.
参考例１３８
５－ブロモ－１－（６－｛［９－（２，４－ジフルオロベンジル）－５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－イル］カルボニル｝－３－ピリジニル）－３－［１－（２，２－ジメチルプロピル）－４－ピペリジニル］－１，３－ジヒドロ－２Ｈ－イミダゾ［４，５－ｂ］ピラジン－２－オン
　参考例７で製造した化合物の代わりに参考例１３７で製造した化合物を用いて、参考例８→参考例９と同様の操作を行い、以下の物性値を有する標題化合物を得た。
LC－MS（A）保持時間（分）：1.06；
MS(ESI, Pos.)： 770 (M + H)＋。 Reference example 138
5-Bromo-1-(6-{[9-(2,4-difluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[2, 3-b]pyridin-7-yl]carbonyl}-3-pyridinyl)-3-[1-(2,2-dimethylpropyl)-4-piperidinyl]-1,3-dihydro-2H-imidazo[4,5 -b] Pyrazin-2-one Using the compound produced in Reference Example 137 instead of the compound produced in Reference Example 7, the same operation as in Reference Example 8 → Reference Example 9 was performed to obtain a title having the following physical property values. The compound was obtained.
LC-MS (A) retention time (min): 1.06;
MS(ESI, Pos.): 770 (M + H) + .
実施例６３
１－（６－｛［９－（２，４－ジフルオロベンジル）－５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－イル］カルボニル｝－３－ピリジニル）－３－［１－（２，２－ジメチルプロピル）－４－ピペリジニル］－５－フェニル－１，３－ジヒドロ－２Ｈ－イミダゾ［４，５－ｂ］ピラジン－２－オン
　参考例１３８で製造した化合物（35ｍｇ）をＤＭＥ（0.35ｍＬ）に溶解し、フェニルボロン酸（28ｍｇ）及びリン酸三カリウム水溶液（0.045ｍＬ、2mol/L）、［１，１’－ビス（ジフェニルホスフィノ）フェロセン］パラジウム（ＩＩ）ジクロリド　ジクロロメタン錯体（3.7mg）を加えてマイクロウェーブ装置を用いて１４０℃で１時間攪拌した。反応液を室温に冷却後、酢酸エチルで希釈し、セライト（商品名）に通して不溶物を除去した。ろ液を酢酸エチルで抽出して水で洗浄し、得られた有機層を無水硫酸ナトリウムで乾燥した。減圧濃縮して得られた残渣をシリカゲルクロマトグラフィー（富士シリシア　ＮＨ（商品名）、ヘキサン：酢酸エチル＝７：３→１：４）で精製することにより、以下の物性値を有する標題化合物（30ｍｇ）を得た。
LC－MS（A）保持時間（分）：1.12；
MS(ESI, Pos.)： 768 (M + H)＋；
１H-NMR (CDCl３)：δ　 0.94, 1.75-1.86, 2.19, 2.47-2.58, 2.83-2.95, 2.95-3.03, 3.87-4.21, 4.47-4.62, 4.88-4.94, 5.27-5.59, 6.62-7.01, 7.05-7.14, 7.44-7.55, 7.75-7.96, 8.03-8.08, 8.29-8.32, 8.43-8.50, 9.18-9.34。 Example 63
1-(6-{[9-(2,4-difluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[2,3-b] pyridin-7-yl]carbonyl}-3-pyridinyl)-3-[1-(2,2-dimethylpropyl)-4-piperidinyl]-5-phenyl-1,3-dihydro-2H-imidazo[4,5 -b] Pyrazin-2-one The compound (35 mg) prepared in Reference Example 138 was dissolved in DME (0.35 mL), and phenylboronic acid (28 mg) and tripotassium phosphate aqueous solution (0.045 mL, 2 mol/L), [ 1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane complex (3.7 mg) was added, and the mixture was stirred at 140°C for 1 hour using a microwave device. The reaction solution was cooled to room temperature, diluted with ethyl acetate, and passed through Celite (trade name) to remove insoluble matter. The filtrate was extracted with ethyl acetate and washed with water, and the resulting organic layer was dried over anhydrous sodium sulfate. The residue obtained by concentration under reduced pressure was purified by silica gel chromatography (Fuji Silysia NH (trade name), hexane:ethyl acetate = 7:3 → 1:4) to obtain the title compound (30 mg) having the following physical properties. ) was obtained.
LC-MS (A) retention time (min): 1.12;
MS(ESI, Pos.): 768 (M + H) + ;
1 H-NMR (CDCl 3 ): δ 0.94, 1.75-1.86, 2.19, 2.47-2.58, 2.83-2.95, 2.95-3.03, 3.87-4.21, 4.47-4.62, 4.88-4.94, 5.27-5.59, 6.62-7.01 , 7.05-7.14, 7.44-7.55, 7.75-7.96, 8.03-8.08, 8.29-8.32, 8.43-8.50, 9.18-9.34.
参考例１３９
２－メチル－２－プロパニル　（３Ｓ）－３－［６－ブロモ－３－（４－｛［９－（２，４－ジフルオロベンジル）－５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－イル］カルボニル｝フェニル）－２－オキソ－２，３－ジヒドロ－１Ｈ－イミダゾ［４，５－ｂ］ピラジン－１－イル］－１－ピペリジンカルボキシラート
　参考例１２で製造した化合物の代わりに参考例１３４で製造した化合物を用いて、参考例１３→参考例１４→参考例１５→参考例１６と同様の操作を行い、以下の物性値を有する標題化合物を得た。
LC－MS（A）保持時間（分）：1.35；
MS(ESI, Pos.)： 800 (M + H)＋；
１H-NMR(CDCl３)：δ　 1.47, 1.60-1.76, 1.79-1.92, 1.98-2.09, 2.43-2.62, 2.72-2.91, 3.58-3.72, 3.72-4.10, 4.17-4.31, 4.45-4.92, 5.24-5.57, 6.62-6.87, 6.88-6.98, 7.05-7.12, 7.40-7.68, 7.75-7.91, 8.07, 8.30。 Reference example 139
2-Methyl-2-propanyl (3S)-3-[6-bromo-3-(4-{[9-(2,4-difluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[ 4',3':4,5]pyrrolo[2,3-b]pyridin-7-yl]carbonyl}phenyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyrazine -1-yl]-1-piperidinecarboxylate Using the compound produced in Reference Example 134 instead of the compound produced in Reference Example 12, the same procedure as in Reference Example 13 → Reference Example 14 → Reference Example 15 → Reference Example 16 was carried out. The operation was carried out to obtain the title compound having the following physical properties.
LC-MS (A) retention time (min): 1.35;
MS(ESI, Pos.): 800 (M + H) + ;
1 H-NMR (CDCl 3 ): δ 1.47, 1.60-1.76, 1.79-1.92, 1.98-2.09, 2.43-2.62, 2.72-2.91, 3.58-3.72, 3.72-4.10, 4.17-4.31, 4.45-4.92, 5.24 - 5.57, 6.62-6.87, 6.88-6.98, 7.05-7.12, 7.40-7.68, 7.75-7.91, 8.07, 8.30.
実施例６４
１－（４－｛［９－（２，４－ジフルオロベンジル）－５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－イル］カルボニル｝フェニル）－３－［（３Ｓ）－１－（２，２－ジメチルプロピル）－３－ピペリジニル］－５－［（３－フルオロフェニル）アミノ］－１，３－ジヒドロ－２Ｈ－イミダゾ［４，５－ｂ］ピラジン－２－オン　２トリフルオロ酢酸塩
　参考例８で用いた参考例７で製造した化合物の代わりに参考例１３９で製造した化合物を、実施例１で用いたアニリンの代わりに３－フルオロアニリンを用いて、参考例８→参考例９→実施例１と同様の操作を行い、逆相HPLCカラム精製することにより、以下の物性値を有する標題化合物を得た。
LC－MS（A）保持時間（分）：1.11；
MS(ESI, Pos.)： 800 (M + H)＋；
１H-NMR(DMSO-d６)：δ　 1.08, 2.03-2.22, 2.41-2.49, 2.90, 2.96-3.07, 3.08-3.23, 3.63-3.83, 3.82-3.91, 3.95-4.08, 4.57-4.90, 4.94-5.11, 5.23-5.64, 6.71-6.80, 6.86-7.43, 7.47-7.79, 7.80-7.97, 8.20-8.30, 8.76-8.95, 9.64。 Example 64
1-(4-{[9-(2,4-difluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[2,3-b] pyridin-7-yl]carbonyl}phenyl)-3-[(3S)-1-(2,2-dimethylpropyl)-3-piperidinyl]-5-[(3-fluorophenyl)amino]-1,3- Dihydro-2H-imidazo[4,5-b]pyrazin-2-one 2 trifluoroacetate The compound produced in Reference Example 139 was used in Example 1 instead of the compound produced in Reference Example 7 used in Reference Example 8. By using 3-fluoroaniline instead of the aniline used in Reference Example 8 → Reference Example 9 → Example 1 and purifying with a reverse phase HPLC column, the title compound having the following physical property values was obtained. I got it.
LC-MS (A) retention time (min): 1.11;
MS(ESI, Pos.): 800 (M + H) + ;
1 H-NMR (DMSO-d 6 ): δ 1.08, 2.03-2.22, 2.41-2.49, 2.90, 2.96-3.07, 3.08-3.23, 3.63-3.83, 3.82-3.91, 3.95-4.08, 4.57-4.90, 4.94- 5.11, 5.23-5.64, 6.71-6.80, 6.86-7.43, 7.47-7.79, 7.80-7.97, 8.20-8.30, 8.76-8.95, 9.64.
実施例６４－１
５－アニリノ－１－（４－｛［９－（２，４－ジフルオロベンジル）－５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－イル］カルボニル｝フェニル）－３－［（３Ｓ）－１－（２，２－ジメチルプロピル）－３－ピペリジニル］－１，３－ジヒドロ－２Ｈ－イミダゾ［４，５－ｂ］ピラジン－２－オン
　３－フルオロアニリンの代わりにアニリンを用いて、実施例６４と同様の操作を行い、以下の物性値を有する標題化合物を得た。
LC－MS（A）保持時間（分）：1.11；
MS(ESI, Pos.)： 782 (M + H)＋；
１H-NMR (CDCl３)：δ　 0.89, 1.74-1.82, 1.88-1.97, 2.09-2.22, 2.32-2.48, 2.79-2.97, 3.20, 3.71-4.12, 4.55-4.93, 5.25-5.59, 6.40, 6.68-6.79, 6.79-7.00, 7.03-7.12, 7.31-7.39, 7.42-7.58, 7.62, 7.68, 7.79-7.85, 7.96, 8.31。 Example 64-1
5-anilino-1-(4-{[9-(2,4-difluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[2, 3-b]pyridin-7-yl]carbonyl}phenyl)-3-[(3S)-1-(2,2-dimethylpropyl)-3-piperidinyl]-1,3-dihydro-2H-imidazo[4, 5-b] Pyrazin-2-one Using aniline instead of 3-fluoroaniline, the same operation as in Example 64 was carried out to obtain the title compound having the following physical properties.
LC-MS (A) retention time (min): 1.11;
MS(ESI, Pos.): 782 (M + H) + ;
1 H-NMR (CDCl 3 ): δ 0.89, 1.74-1.82, 1.88-1.97, 2.09-2.22, 2.32-2.48, 2.79-2.97, 3.20, 3.71-4.12, 4.55-4.93, 5.25-5.59, 6.40, 6.6 8- 6.79, 6.79-7.00, 7.03-7.12, 7.31-7.39, 7.42-7.58, 7.62, 7.68, 7.79-7.85, 7.96, 8.31.
参考例１４０
２－メチル－２－プロパニル　４－［６－ブロモ－３－（４－｛［９－（２，４－ジフルオロベンジル）－５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－イル］カルボニル｝フェニル）－２－オキソ－２，３－ジヒドロ－１Ｈ－イミダゾ［４，５－ｂ］ピラジン－１－イル］－１－ピペリジンカルボキシラート
　参考例１２で製造した化合物の代わりに参考例１３６で製造した化合物を用いて、参考例１３→参考例１４→参考例１５→参考例１６と同様の操作を行い、以下の物性値を有する標題化合物を得た。
LC－MS（A）保持時間（分）：1.32；
MS(ESI, Pos.)： 799 (M + H)＋。 Reference example 140
2-Methyl-2-propanyl 4-[6-bromo-3-(4-{[9-(2,4-difluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3 ':4,5]pyrrolo[2,3-b]pyridin-7-yl]carbonyl}phenyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-1-yl ]-1-Piperidinecarboxylate Using the compound produced in Reference Example 136 instead of the compound produced in Reference Example 12, the same operation as in Reference Example 13 → Reference Example 14 → Reference Example 15 → Reference Example 16 was carried out, The title compound having the following physical properties was obtained.
LC-MS (A) retention time (min): 1.32;
MS(ESI, Pos.): 799 (M + H) + .
実施例６５
５－アニリノ－１－（４－｛［９－（２，４－ジフルオロベンジル）－５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－イル］カルボニル｝フェニル）－３－［１－（２，２－ジメチルプロピル）－４－ピペリジニル］－１，３－ジヒドロ－２Ｈ－イミダゾ［４，５－ｂ］ピラジン－２－オン
　参考例７で製造した化合物の代わりに参考例１４０で製造した化合物を用いて、参考例８→参考例９→実施例１と同様の操作を行い、以下の物性値を有する標題化合物を得た。
LC－MS（A）保持時間（分）：1.10；
MS(ESI, Pos.)： 782 (M + H)＋；
１H-NMR (CDCl３)：δ　 0.94, 1.73-1.82, 2.15, 2.42-2.50, 2.70-3.05, 3.72-4.15, 4.36-4.49, 4.56-4.92, 5.21-5.55, 6.41, 6.67-6.78, 6.79-6.88, 6.88-6.97, 7.05, 7.10, 7.37, 7.48, 7.59-7.70, 7.82, 7.91-8.00, 8.31。 Example 65
5-anilino-1-(4-{[9-(2,4-difluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[2, 3-b]pyridin-7-yl]carbonyl}phenyl)-3-[1-(2,2-dimethylpropyl)-4-piperidinyl]-1,3-dihydro-2H-imidazo[4,5-b] Pyrazin-2-one Using the compound produced in Reference Example 140 instead of the compound produced in Reference Example 7, the same operation as in Reference Example 8 → Reference Example 9 → Example 1 was performed to obtain a product having the following physical property values. The title compound was obtained.
LC-MS (A) retention time (min): 1.10;
MS(ESI, Pos.): 782 (M + H) + ;
1 H-NMR (CDCl 3 ): δ 0.94, 1.73-1.82, 2.15, 2.42-2.50, 2.70-3.05, 3.72-4.15, 4.36-4.49, 4.56-4.92, 5.21-5.55, 6.41, 6.67-6.78, 6.7 9- 6.88, 6.88-6.97, 7.05, 7.10, 7.37, 7.48, 7.59-7.70, 7.82, 7.91-8.00, 8.31.
参考例１４１
２－メチル－２－プロパニル　４－（２－クロロ－８－オキソ－７，８－ジヒドロ－９Ｈ－プリン－９－イル）－１－ピぺリジンカルボキシラート
　２，４－ジクロロ－６－メチル－５－ニトロピリミジン及び１－（２，４－ジメトキシフェニル）メタンアミンの代わりに、２，４－ジクロロ－５－ニトロピリミジン及び２－メチル－２－プロパニル　４－アミノ－１－ピぺリジンカルボキシラートを用いて、参考例１１→参考例１２→参考例１３と同様の操作を行い、以下の物性値を有する標題化合物を得た。
LC－MS（A）保持時間（分）：1.00；
MS(ESI, Pos.)： 354 (M + H)＋。 Reference example 141
2-Methyl-2-propanyl 4-(2-chloro-8-oxo-7,8-dihydro-9H-purin-9-yl)-1-piperidinecarboxylate 2,4-dichloro-6-methyl- 2,4-dichloro-5-nitropyrimidine and 2-methyl-2-propanyl 4-amino-1-piperidinecarboxylate were used instead of 5-nitropyrimidine and 1-(2,4-dimethoxyphenyl)methanamine. The same operations as Reference Example 11→Reference Example 12→Reference Example 13 were performed to obtain the title compound having the following physical property values.
LC-MS (A) retention time (min): 1.00;
MS(ESI, Pos.): 354 (M + H) + .
参考例１４２
２－メチル－２－プロパニル　４－｛２－クロロ－７－［トランス－４－（メトキシカルボニル）シクロへキシル］－８－オキソ－７，８－ジヒドロ－９Ｈ－プリン－９－イル｝－１－ピぺリジンカルボキシラート
　参考例１４１で製造した化合物（200ｍｇ）とメチル　シス－４－ヒドロキシシクロヘキシルカルボキシラート（134ｍｇ）をトルエン（2ｍＬ）に懸濁させ、（トリブチルホスホラニリデン）アセトニトリル（204ｍｇ）を加えて１００℃で４時間攪拌した。反応液を室温に冷却した後、酢酸エチルで希釈して、析出物をろ取した。ろ液をインジェクト　アミノ（商品名）に通した後、減圧濃縮し、残渣をシリカゲルクロマトグラフィー（富士シリシア　ＮＨ（商品名）、ヘキサン：酢酸エチル＝３：２→２：３）で精製した。得られた残渣と先に得られたろ取物を合わせて酢酸エチルで洗浄し、以下の物性値を有する標題化合物（83ｍｇ）を得た。
LC－MS（A）保持時間（分）：1.21；
MS(ESI, Pos.)： 494 (M + H)＋。 Reference example 142
2-Methyl-2-propanyl 4-{2-chloro-7-[trans-4-(methoxycarbonyl)cyclohexyl]-8-oxo-7,8-dihydro-9H-purin-9-yl}-1 -Piperidinecarboxylate The compound prepared in Reference Example 141 (200mg) and methyl cis-4-hydroxycyclohexylcarboxylate (134mg) were suspended in toluene (2mL), and (tributylphosphoranylidene)acetonitrile (204mg) was suspended in toluene (2mL). In addition, the mixture was stirred at 100°C for 4 hours. After the reaction solution was cooled to room temperature, it was diluted with ethyl acetate, and the precipitate was collected by filtration. The filtrate was passed through Inject Amino (trade name), concentrated under reduced pressure, and the residue was purified by silica gel chromatography (Fuji Silysia NH (trade name), hexane:ethyl acetate = 3:2→2:3). The obtained residue and the filtered material obtained earlier were combined and washed with ethyl acetate to obtain the title compound (83 mg) having the following physical properties.
LC-MS (A) retention time (min): 1.21;
MS(ESI, Pos.): 494 (M + H) + .
参考例１４３
２－メチル－２－プロパニル　４－［２－クロロ－７－（トランス－４－｛［９－（２，４－ジフルオロベンジル）－５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－イル］カルボニル｝シクロへキシル）－８－オキソ－７，８－ジヒドロ－９Ｈ－プリン－９－イル］－１－ピぺリジンカルボキシラート
　参考例５で製造した化合物の代わりに参考例１４２（80ｍｇ）で製造した化合物を用いて、参考例６→参考例７と同様の操作を行い、以下の物性値を有する標題化合物（20ｍｇ）を得た。
LC－MS（A）保持時間（分）：1.28；
MS(ESI, Pos.)： 761 (M + H)＋。 Reference example 143
2-Methyl-2-propanyl 4-[2-chloro-7-(trans-4-{[9-(2,4-difluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[2,3-b]pyridin-7-yl]carbonyl}cyclohexyl)-8-oxo-7,8-dihydro-9H-purin-9-yl]-1- Piperidine carboxylate Using the compound produced in Reference Example 142 (80 mg) instead of the compound produced in Reference Example 5, the same operation as in Reference Example 6 → Reference Example 7 was carried out, and a title having the following physical property values was obtained. A compound (20 mg) was obtained.
LC-MS (A) retention time (min): 1.28;
MS(ESI, Pos.): 761 (M + H) + .
実施例６６
２－メチル－２－プロパニル　４－［２－アニリノ－７－（トランス－４－｛［９－（２，４－ジフルオロベンジル）－５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－イル］カルボニル｝シクロへキシル）－８－オキソ－７，８－ジヒドロ－９Ｈ－プリン－９－イル］－１－ピぺリジンカルボキシラート
　参考例９で製造した化合物の代わりに参考例１４３（17ｍｇ）で製造した化合物を用いて、実施例１同様の操作を行い、以下の物性値を有する標題化合物（4.3ｍｇ）を得た。
LC－MS（A）保持時間（分）：1.22；
MS(ESI, Pos.)： 818 (M + H)＋；
１H-NMR(CDCl３)：δ　1.23-1.40, 1.45-1.54, 1.70-1.93, 1.93-2.15, 2.46-2.75, 2.76-2.99, 3.78-4.01, 4.14-4.56, 4.63-4.76, 5.41-5.59, 6.65-6.88, 6.88-6.98, 6.98-7.06, 7.06-7.21, 7.28-7.41, 7.56-7.67, 7.77-7.87, 7.99-8.08, 8.26-8.37。 Example 66
2-Methyl-2-propanyl 4-[2-anilino-7-(trans-4-{[9-(2,4-difluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[2,3-b]pyridin-7-yl]carbonyl}cyclohexyl)-8-oxo-7,8-dihydro-9H-purin-9-yl]-1- Piperidine Carboxylate Using the compound produced in Reference Example 143 (17 mg) instead of the compound produced in Reference Example 9, the same operation as Example 1 was carried out to obtain the title compound (4.3 mg) having the following physical property values. I got it.
LC-MS (A) retention time (min): 1.22;
MS(ESI, Pos.): 818 (M + H) + ;
1 H-NMR (CDCL 3 ): δ 1.23-1.40, 1.45-1.54, 1.70-1.93, 1.93-2.15, 2.46-2.75, 2.76-2.99, 2.78-4.01, 4.14-4.56, 4.63-4.56, 5.41-56, 5.41-56 6.65-6.88, 6.88-6.98, 6.98-7.06, 7.06-7.21, 7.28-7.41, 7.56-7.67, 7.77-7.87, 7.99-8.08, 8.26-8.37.
［薬理実施例］
生物学的実施例１：ヒトリコンビナントDGKαおよびDGKζに対する阻害作用の評価
　被験化合物によるヒトリコンビナントDGKα（カルナバイオ社、12-401-20N）阻害作用を以下の方法で測定した。ADP産生量の検出には、ADP-GloＴＭ　Kinase Assay（Promega社）を使用した。被験化合物は10mMになるようにＤＭＳＯで溶解し、ＤＭＳＯで段階希釈した。384ウェルプレート（Greiner Bio-one社）へ、化合物のＤＭＳＯ溶液30nLを添加した（酵素反応時のＤＭＳＯ濃度は1%）。そこへ、50mM MOPS(pH 7.2)、0.75ｍMジオキシトレイトール（DTT）、0.0075% Triton（登録商標）X-100、5mM MgCl２、100μM ATP、ミセル化した基質（0.81mM 1-2-dioleoyl-sn-glycerol、6.4mM 1-palmitoyl-2-oleoyl-sn-glycero-3-phospho-L-serine、1μM CaCl２、50mM octyl β-D-Glucopyranoside）を含む反応液と最後にDGKα（2nM）を添加して、室温で2時間反応させた（反応液量は3μL/well）。その後、ADP-Glo Reagentを3μL添加し、室温で40分間置いたのちにKinase Detection Reagentを6μL添加し、室温で15分間静置した。ルミネセンスの測定にはViewLux（PerkinElmer社）を用いた。IC５０値（50%阻害濃度）は、化合物非添加（ＤＭＳＯのみ）のwellのルミネセンス値を0%阻害、酵素非添加かつ化合物非添加のwellのルミネセンス値を100%阻害として、4 Parameter Logistic Model（XLfit、IDBS社）を用いて算出した。 [Pharmacology Examples]
Biological Example 1: Evaluation of the inhibitory effect on human recombinant DGKα and DGKζ The inhibitory effect of the test compound on human recombinant DGKα (Carna Bio Inc., 12-401-20N) was measured by the following method. ADP-Glo ™ Kinase Assay (Promega) was used to detect the amount of ADP produced. The test compound was dissolved in DMSO to a concentration of 10 mM and serially diluted with DMSO. 30 nL of a DMSO solution of the compound was added to a 384-well plate (Greiner Bio-one) (DMSO concentration during enzyme reaction was 1%). Thereto, 50mM MOPS (pH 7.2), 0.75mM dioxythreitol (DTT), 0.0075% Triton (registered trademark) -sn-glycerol, 6.4mM 1-palmitoyl-2-oleoyl-sn-glycero-3-phospho-L-serine, 1μM CaCl2, 50mM octyl β-D-Glucopyranoside) and finally DGKα (2nM). was added and allowed to react at room temperature for 2 hours (reaction solution volume: 3 μL/well). Thereafter, 3 μL of ADP-Glo Reagent was added, and the mixture was left at room temperature for 40 minutes, and then 6 μL of Kinase Detection Reagent was added and left at room temperature for 15 minutes. ViewLux (PerkinElmer) was used to measure luminescence. The IC 50 value (50% inhibitory concentration) is calculated using 4 Parameters, where the luminescence value in wells without compound addition (DMSO only) is 0% inhibition, and the luminescence value in wells without enzyme and compound addition is 100% inhibition. Calculated using Logistic Model (XLfit, IDBS).
　被験化合物によるヒトリコンビナントDGKζ（カルナバイオ社、12-410-20N）阻害作用も上記DGKαの方法に準じた。ただしATP濃度は50μM、DGKζ濃度は0.6nMとした。 The inhibitory effect of human recombinant DGKζ (CarnaBio Inc., 12-410-20N) by the test compound was also determined according to the method for DGKα described above. However, the ATP concentration was 50 μM and the DGKζ concentration was 0.6 nM.
　各実施例において示される本発明化合物のIC５０値を表１－１および１－２に示す。 The IC 50 values of the compounds of the present invention shown in each example are shown in Tables 1-1 and 1-2.
　［結果］
　本発明化合物は、上記酵素阻害活性の評価において強力なＤＧＫαおよび／またはζ阻害活性を示した。 [result]
The compounds of the present invention showed strong DGKα and/or ζ inhibitory activity in the enzyme inhibitory activity evaluation described above.
生物学的実施例２：ヒトT細胞性白血病細胞株Jurkat細胞におけるIL-2産生作用の評価
　Jurkat細胞をT細胞受容体（TCR）刺激（抗CD3抗体刺激）した際のIL-2産生能に対する被験物質の作用を評価した。 Biological Example 2: Evaluation of IL-2 production effect in human T-cell leukemia cell line Jurkat cells The effect of the test substance was evaluated.
　抗ヒトCD3抗体(BioLegend)10μg/ｍＬを100μLずつ96穴プレートに添加し、4℃で一晩静置し、抗ヒトCD3抗体コートプレートを準備した。実験使用前に抗ヒトCD3抗体溶液を除去し、リン酸緩衝液（PBS）で一回洗浄後にJurkat培養培地（10％FBS，100 units/ｍＬペニシリン、100μg/ｍＬストレプトマイシンを添加したRPMI培地）を添加して37℃で1時間以上ブロッキングした。Jurkat細胞と化合物を37℃で1時間プレインキュベーションした。ブロッキングした抗ヒトCD3抗体コートプレートのJurkat培養培地を除去し、プレインキュベーション後の細胞懸濁液を（細胞数1.8×10５ cells/200μL/well）添加した。37℃，5％CO2，95％Air条件下で18～24時間インキュベーションした後、培養上清を回収し、Human IL-2 Quantikine ELISA Kit（R&D Systems）若しくはLumit Immunoassay Cellular System human IL-2 Kit（Promega） を用いてIL-2濃度を測定した。媒体対照群としてＤＭＳＯ、陽性対照群としてDGKαおよび／またはζ阻害剤である２－メチル－２－プロパニル　３－［２－アニリノ－７－（４－｛［９－（２，４－ジフルオロベンジル）－５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－イル］カルボニル｝フェニル）－６－メチル－８－オキソ－７，８－ジヒドロ－９Ｈ－プリン－９－イル］－１－ピペリジンカルボキシラート（実施例１－１に記載の化合物）を各プレートに設定した。陽性対照群及び媒体対照群のIL-2濃度をそれぞれ100％及び0％としてEC５０値（μmol/L）を算出した。 100 μL of 10 μg/mL of anti-human CD3 antibody (BioLegend) was added to each 96-well plate and allowed to stand at 4° C. overnight to prepare an anti-human CD3 antibody coated plate. Before experimental use, remove the anti-human CD3 antibody solution and wash once with phosphate buffered saline (PBS), then add Jurkat culture medium (RPMI medium supplemented with 10% FBS, 100 units/mL penicillin, and 100 μg/mL streptomycin). and blocking was performed at 37°C for over 1 hour. Jurkat cells and compounds were preincubated for 1 hour at 37°C. The Jurkat culture medium of the blocked anti-human CD3 antibody-coated plate was removed, and the pre-incubated cell suspension was added (cell number: 1.8×10 5 cells/200 μL/well). After incubating for 18 to 24 hours at 37°C, 5% CO2, and 95% Air, the culture supernatant was collected and used with Human IL-2 Quantikine ELISA Kit (R&D Systems) or Lumit Immunoassay Cellular System human IL-2 Kit ( IL-2 concentration was measured using Promega). DMSO as vehicle control group, DGKα and/or ζ inhibitor 2-methyl-2-propanyl 3-[2-anilino-7-(4-{[9-(2,4-difluorobenzyl)) as positive control group. -5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[2,3-b]pyridin-7-yl]carbonyl}phenyl)-6-methyl-8- Oxo-7,8-dihydro-9H-purin-9-yl]-1-piperidinecarboxylate (compound described in Example 1-1) was set up on each plate. The EC50 value (μmol/L) was calculated by setting the IL-2 concentrations of the positive control group and vehicle control group to 100% and 0%, respectively.
　各実施例において示される本発明化合物のEC５０値を表２に示す。 Table 2 shows the EC 50 values of the compounds of the present invention shown in each example.
　［結果］
　本発明化合物は、上記抗腫瘍作用の評価において強力なT細胞の活性化作用を示した。 [result]
The compound of the present invention showed a strong T cell activation effect in the above-mentioned antitumor effect evaluation.
生物学的実施例３：マウス大腸癌細胞株ＭＣ３８皮下担癌モデルにおける抗腫瘍作用の評価
　Ｃ５７／ＢＬ６マウス由来大腸癌細胞株ＭＣ３８を同種同系マウス（Ｃ５７／ＢＬ６、雌、６週齢（ジャクソン・ラボラトリー・ジャパン株式会社））の右側腹部に皮下移植し（ここで、移植日をＤａｙ０とした。）、ＭＣ３８皮下担癌マウスを作製した。移植6又は8日後に、腫瘍体積に基づき群分けを実施し、群分け翌日から媒体及び化合物を1日2回経口投与した。試験は媒体群及び化合物群を各10匹設定し、表３に記載の投与量及び投与期間で実施した。腫瘍体積は以下の式より算出した。 Biological Example 3: Evaluation of antitumor effect in mouse colon cancer cell line MC38 subcutaneous tumor-bearing model. Colon cancer cell line MC38 derived from C57/BL6 mice was cultured in allogeneic syngeneic mice (C57/BL6, female, 6 weeks old (Jackson). The mouse was subcutaneously transplanted into the right flank of a mouse (Laboratory Japan Co., Ltd.) (here, the date of transplantation was designated as Day 0) to produce MC38 subcutaneous tumor-bearing mice. Six or eight days after transplantation, mice were divided into groups based on tumor volume, and the vehicle and compound were orally administered twice a day from the day after grouping. The test was conducted with 10 animals each in the vehicle group and the compound group, using the dosage and administration period shown in Table 3. Tumor volume was calculated using the following formula.
　　　［腫瘍体積（ｍｍ３）］＝［長径（ｍｍ）］×［短径（ｍｍ）］２×０．５
　化合物による腫瘍体積増殖抑制率（TGI：Tumor Growth Inhibition、％）は、以下の式より算出した。 [Tumor volume (mm 3 )] = [longer diameter (mm)] × [breadth axis (mm)] 2 ×0.5
The tumor volume growth inhibition rate (TGI: Tumor Growth Inhibition, %) by the compound was calculated using the following formula.
　　　TGI＝（1－最終投与翌日の化合物群の腫瘍体積/最終投与翌日の媒体群の腫瘍体積）×100
　各実施例において示される本発明化合物のTGIを表３に示す。 TGI = (1 - tumor volume of the compound group on the day after the final administration/tumor volume of the vehicle group on the day after the final administration) x 100
Table 3 shows the TGI of the compounds of the present invention shown in each example.
　［結果］
　本発明化合物は、上記抗腫瘍作用の評価において強力な抗腫瘍効果を示した。 [result]
The compound of the present invention showed a strong antitumor effect in the above evaluation of antitumor effect.
［製剤実施例］
製剤例１
　以下の各成分を常法により混合した後打錠して、一錠中に５ｍｇの活性成分を含有する錠剤１万錠を得ることができる。
・４－［（７－｛［５－（２－｛［２－クロロ－４－（トリフルオロメトキシ）フェニル］アミノ｝－９－［１－（２，２－ジメチルプロピル）－４－ピペリジニル］－６－メチル－８－オキソ－８，９－ジヒドロ－７Ｈ－プリン－７－イル）－２－ピリジニル］カルボニル｝－５，６，７，８－テトラヒドロ－９Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－９－イル）メチル］－３－フルオロベンゾニトリル ５０ｇ
・カルボキシメチルセルロースカルシウム ２０ｇ
・ステアリン酸マグネシウム １０ｇ
・微結晶セルロース ９２０ｇ [Formulation Examples]
Formulation example 1
By mixing the following ingredients in a conventional manner and then tableting, 10,000 tablets each containing 5 mg of the active ingredient can be obtained.
・4-[(7-{[5-(2-{[2-chloro-4-(trifluoromethoxy)phenyl]amino}-9-[1-(2,2-dimethylpropyl)-4-piperidinyl] -6-Methyl-8-oxo-8,9-dihydro-7H-purin-7-yl)-2-pyridinyl]carbonyl}-5,6,7,8-tetrahydro-9H-pyrido[4',3' :4,5]pyrrolo[2,3-b]pyridin-9-yl)methyl]-3-fluorobenzonitrile 50g
・Carboxymethylcellulose calcium 20g
・Magnesium stearate 10g
・Microcrystalline cellulose 920g
製剤例２
　以下の各成分を常法により混合した後打錠して、一錠中に５ｍｇの活性成分を含有する錠剤１万錠を得ることができる。
・９－［１－（２，２－ジメチルプロピル）－４－ピペリジニル］－７－（６－｛［９－（２－フルオロ－４－メチルベンジル）－５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－イル］カルボニル｝－３－ピリジニル）－６－メチル－２－｛［４－（トリフルオロメトキシ）フェニル］アミノ｝－７，９－ジヒドロ－８Ｈ－プリン－８－オン ５０ｇ
・カルボキシメチルセルロースカルシウム ２０ｇ
・ステアリン酸マグネシウム １０ｇ
・微結晶セルロース ９２０ｇ Formulation example 2
The following ingredients are mixed in a conventional manner and then tableted to obtain 10,000 tablets each containing 5 mg of the active ingredient.
・9-[1-(2,2-dimethylpropyl)-4-piperidinyl]-7-(6-{[9-(2-fluoro-4-methylbenzyl)-5,6,8,9-tetrahydro- 7H-pyrido[4',3':4,5]pyrrolo[2,3-b]pyridin-7-yl]carbonyl}-3-pyridinyl)-6-methyl-2-{[4-(trifluoromethoxy) ) phenyl]amino}-7,9-dihydro-8H-purin-8-one 50g
・Carboxymethylcellulose calcium 20g
・Magnesium stearate 10g
・Microcrystalline cellulose 920g
製剤例３
　以下の各成分を常法により混合した後、溶液を常法により滅菌し、５ｍＬずつアンプルに充填し、常法により凍結乾燥し、１アンプル中２０ｍｇの活性成分を含有するアンプル１万本を得ることができる。
・（５－｛７－（６－｛［９－（４－シアノ－２－フルオロベンジル）－５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－イル］カルボニル｝－３－ピリジニル）－９－［１－（２，２－ジメチルプロピル）－４－ピペリジニル］－６－メチル－８－オキソ－８，９－ジヒドロ－７Ｈ－プリン－２－イル｝－２－メトキシフェニル）酢酸 ２００ｇ
・マンニトール ２０ｇ
・蒸留水 ５０Ｌ Formulation example 3
After mixing the following components in a conventional manner, the solution is sterilized in a conventional manner, filled into ampoules of 5 mL each, and lyophilized in a conventional manner to obtain 10,000 ampoules containing 20 mg of active ingredient per ampoule. be able to.
・(5-{7-(6-{[9-(4-cyano-2-fluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo [2,3-b]pyridin-7-yl]carbonyl}-3-pyridinyl)-9-[1-(2,2-dimethylpropyl)-4-piperidinyl]-6-methyl-8-oxo-8, 9-dihydro-7H-purin-2-yl}-2-methoxyphenyl)acetic acid 200g
・Mannitol 20g
・Distilled water 50L
　本発明化合物は、ＤＧＫαおよび／またはζに対する阻害活性を有するため、それを有効成分として含む医薬品は、例えば、がんもしくは感染症の進行抑制、再発抑制および／または治療剤として有用である。 Since the compound of the present invention has inhibitory activity against DGKα and/or ζ, pharmaceuticals containing it as an active ingredient are useful, for example, as agents for suppressing the progression, suppressing recurrence, and/or treating cancer or infectious diseases.

Claims (25)

  1. 　一般式（ＩＹ）
    （式中、Ｒ１は、（１）１～５個のＲ１１で置換されていてもよい３～１５員の炭素環で置換されたメチレン、（２）１～５個のＲ１２で置換されていてもよい３～１５員の複素環で置換されたメチレン、（３）１～５個のＲ１３で置換されていてもよいＣ２～４アルケニル基で置換されたメチレン、または（４）１～５個のＲ１４で置換されていてもよいＣ２～４アルキニル基で置換されたメチレンを表わし、
    Ｒ１１、Ｒ１２、Ｒ１３およびＲ１４は、それぞれ独立して、（１）ハロゲン、（２）Ｃ１～４アルキル基、（３）Ｃ１～４アルコキシ基、（４）Ｃ１～４ハロアルキル基、（５）Ｃ１～４ハロアルコキシ基、または（６）シアノ基を表わし、複数のＲ１１、Ｒ１２、Ｒ１３およびＲ１４は、それぞれ同じでも異なっていてもよく、
    Ｒ２は、（１）１～５個のＲ１５で置換されていてもよい３～１５員の複素環、（２）１～５個のＲ１６で置換されていてもよい３～１５員の炭素環、または（３）１～５個のＲ１７で置換されていてもよいＣ１～４アルキル基を表わし、
    Ｒ１５、Ｒ１６およびＲ１７は、それぞれ独立して、
    （１）１～５個のＲ１８で置換されていてもよいＣ３～６シクロアルキル基で置換されていてもよいＣ１～８アルキル基、（２）（Ｃ１～８アルキル）カルボニル基、（３）１～５個のＲ１９で置換された（Ｃ３～６シクロアルキル）カルボニル基、（４）Ｃ１～８ハロアルキル基、（５）５～６員の炭素環、（６）５～６員の複素環、（７）Ｃ１～４アルキルスルホニル基、（８）Ｃ２～４アルケニルスルホニル基、（９）Ｃ１～４アルコキシカルボニル基、（１０）Ｃ１～４ハロアルキルアミノ基、（１１）ｔ－ブチルオキシカルボニルアミノ基、または（１２）５，５－ジメチル－２，４－ジオキソオキサゾリジン－３－イル基を表わし、
    複数のＲ１５、Ｒ１６およびＲ１７は、それぞれ同じでも異なっていてもよく、
    Ｒ１８およびＲ１９は、それぞれ独立して、（１）ハロゲン、（２）Ｃ１～４アルキル基、（３）Ｃ１～４アルコキシ基、（４）Ｃ１～４ハロアルキル基、（５）Ｃ１～４ハロアルコキシ基、または（６）シアノ基を表わし、
    複数のＲ１８およびＲ１９は、それぞれ同じでも異なっていてもよく、
    Ｒ３Ｙは、（１）水素原子、（２）ハロゲン、（３）Ｃ１～４アルキル基、（４）Ｃ１～４アルコキシ基、（５）Ｃ１～４ハロアルキル基、（６）Ｃ１～４ハロアルコキシ基、（７）シアノ基、（８）１～５個のＲ２０Ｙで置換されていてもよい３～１５員の炭素環、（９）１～５個のＲ２１Ｙで置換されていてもよい３～１５員の複素環、（１０）－ＮＲ２２Ｒ２３、（１１）－ＯＲ２４、（１２）－ＣＯＮＲ２５Ｒ２６、（１３）（Ｃ１～８アルキル）カルボニル基、（１４）１～３個の水酸基で置換されたＣ１～４アルキル基、または（１５）１－（ヒドロキシイミノ）エチル基を表わし、
    Ｒ２０ＹおよびＲ２１Ｙは、それぞれ独立して、（１）１～５個のＲ２７Ｙで置換されていてもよいＣ１～４アルキル基、（２）ハロゲン、（３）１～５個のＲ２８Ｙで置換されていてもよいＣ３～６シクロアルキル基、（４）１～５個のＲ２７－１Ｙで置換されていてもよいＣ１～４アルコキシ基、（５）水酸基、（６）カルバモイル基、（７）カルボキシル基、または（８）シアノ基を表わし、
    複数のＲ２０ＹおよびＲ２１Ｙは、それぞれ同じでも異なっていてもよく、
    Ｒ２７Ｙ、Ｒ２７－１ＹおよびＲ２８Ｙは、それぞれ独立して、（１）ハロゲン、（２）Ｃ１～４アルキル基、（３）Ｃ１～４アルコキシ基、（４）Ｃ１～４ハロアルキル基、（５）Ｃ１～４ハロアルコキシ基、（６）水酸基、（７）カルバモイル基、（８）カルボキシル基、（９）Ｃ１～４アルコキシカルボニル基、または（１０）シアノ基を表わし、
    複数のＲ２７Ｙ、Ｒ２７－１ＹおよびＲ２８Ｙは、それぞれ同じでも異なっていてもよく、
    Ｒ２２、Ｒ２３およびＲ２４は、それぞれ独立して、（１）水素原子、（２）１～５個のＲ２９で置換されていてもよいＣ１～８アルキル基、（３）１～５個のＲ２９－１で置換されていてもよいＣ２～４アルケニル基、（４）１～５個のＲ２９－２で置換されていてもよいＣ２～４アルキニル基、（５）１～５個のＲ３０で置換されていてもよい３～１５員の炭素環、または（６）１～５個のＲ３１で置換されていてもよい３～１５員の複素環を表わし、
    Ｒ２９、Ｒ２９－１、Ｒ２９－２、Ｒ３０およびＲ３１は、それぞれ独立して、
    （１）１～５個のＲ３２で置換されていてもよいＣ１～４アルキル基、（２）ハロゲン、（３）１～５個のＲ３３で置換されていてもよいＣ３～８シクロアルキル基、（４）１～５個のＲ３４で置換されていてもよい５～６員の炭素環、（５）１～５個のＲ３５で置換されていてもよい５～６員の複素環、（６）１～５個のＲ３２－１で置換されていてもよいＣ１～４アルコキシ基、（７）水酸基、（８）カルバモイル基、（９）カルボキシル基、または（１０）シアノ基を表わし、
    複数のＲ２９、Ｒ２９－１、Ｒ２９－２、Ｒ３０およびＲ３１は、それぞれ同じでも異なっていてもよく、
    Ｒ３２、Ｒ３２－１、Ｒ３３、Ｒ３４およびＲ３５は、それぞれ独立して、（１）ハロゲン、（２）Ｃ１～４アルキル基、（３）Ｃ１～４アルコキシ基、（４）Ｃ１～４ハロアルキル基、（５）Ｃ１～４ハロアルコキシ基、（６）水酸基、（７）カルバモイル基、（８）カルボキシル基、または（９）シアノ基を表わし、
    複数のＲ３２、Ｒ３２－１、Ｒ３３、Ｒ３４およびＲ３５は、それぞれ同じでも異なっていてもよく、
    Ｒ２５およびＲ２６は、それぞれ独立して、（１）水素原子、（２）１～５個のＲ３６で置換されていてもよいＣ１～８アルキル基、（３）１～５個のＲ３６－１で置換されていてもよいＣ２～４アルケニル基、（４）１～５個のＲ３６－２で置換されていてもよいＣ２～４アルキニル基、（５）１～５個のＲ３７で置換されていてもよい３～１５員の炭素環、または（６）１～５個のＲ３８で置換されていてもよい３～１５員の複素環を表わし、
    Ｒ３６、Ｒ３６－１、Ｒ３６－２、Ｒ３７およびＲ３８は、それぞれ独立して、（１）Ｃ１～４アルキル基、（２）ハロゲン、（３）Ｃ３～８シクロアルキル基、（４）５～６員の炭素環、（５）５～６員の複素環、（６）Ｃ１～４アルコキシ基、（７）Ｃ１～４ハロアルキル基、（８）Ｃ１～４ハロアルコキシ基、（９）水酸基、（１０）カルボキシル基、（１１）カルバモイル基、または（１２）シアノ基を表わし、
    複数のＲ３６、Ｒ３６－１、Ｒ３６－２、Ｒ３７およびＲ３８は、それぞれ同じでも異なっていてもよく、
    Ｒ４は、（１）ハロゲン、（２）Ｃ１～４アルキル基、（３）Ｃ１～４アルコキシ基、（４）Ｃ１～４ハロアルキル基、（５）Ｃ１～４ハロアルコキシ基、（６）水酸基、または（７）シアノ基を表わし、
    Ｒ５は、（１）ハロゲン、（２）Ｃ１～４アルキル基、（３）Ｃ１～４アルコキシ基、（４）Ｃ１～４ハロアルキル基、（５）Ｃ１～４ハロアルコキシ基、（６）水酸基、または（７）シアノ基を表わし、
    ｒｉｎｇＹは、
    （右の矢印は窒素原子と結合し、左の矢印はカルボニル基と結合する。）、または、１～６個のＲＹで置換されていてもよい、飽和または一部不飽和の４～１０員の炭素環、または、１～６個のＲＹで置換されていてもよい、１個の窒素原子、１個の酸素原子および／または酸化されていてもよい１個の硫黄原子を含有する６員の飽和複素環を表わし、ＲＹは、（１）ハロゲン、（２）Ｃ１～４アルキル基、（３）Ｃ１～４アルコキシ基、（４）Ｃ１～４ハロアルキル基、（５）Ｃ１～４ハロアルコキシ基、（６）水酸基、（７）オキソ基、または（８）シアノ基を表わし、
    ＲＹが複数の場合、各ＲＹは同じでも異なっていてもよく、
    Ｘは、窒素原子、またはＣＲ７を表わし、
    Ｘ１、Ｘ２、およびＸ３は、それぞれ独立して、窒素原子、ＣＨ、またはＣＲ６を表わし、
    Ｒ６は、（１）ハロゲン、（２）Ｃ１～４アルキル基、（３）Ｃ１～４アルコキシ基、（４）Ｃ１～４ハロアルキル基、（５）Ｃ１～４ハロアルコキシ基、（６）水酸基、または（７）シアノ基を表わし、
    Ｒ６が複数の場合、各Ｒ６は同じでも異なっていてもよく、
    Ｙ１は、窒素原子、またはＣＲ８を表わし、
    Ｙ２は、窒素原子、またはＣＲ９を表わし、
    Ｙ３は、窒素原子、またはＣＲ１０Ｙを表わし、
    Ｒ７は、（１）水素原子、（２）ハロゲン、（３）Ｃ１～４アルキル基、（４）Ｃ１～４アルコキシ基、（５）Ｃ１～４ハロアルキル基、または（６）Ｃ１～４ハロアルコキシ基を表わし、
    Ｒ８は、（１）水素原子、（２）ハロゲン、（３）Ｃ１～４アルキル基、（４）Ｃ１～４アルコキシ基、（５）Ｃ１～４ハロアルキル基、または（６）Ｃ１～４ハロアルコキシ基を表わし、
    Ｒ９は、（１）水素原子、（２）ハロゲン、（３）Ｃ１～４アルキル基、（４）Ｃ１～４アルコキシ基、（５）Ｃ１～４ハロアルキル基、または（６）Ｃ１～４ハロアルコキシ基を表わし、
    Ｒ１０Ｙは、（１）水素原子、（２）ハロゲン、（３）Ｃ１～４アルキル基、（４）Ｃ１～４アルコキシ基、（５）Ｃ１～４ハロアルキル基、（６）Ｃ１～４ハロアルコキシ基、（７）水酸基、（８）アミノ基、（９）カルボキシル基、（１０）カルバモイル基、（１１）（Ｃ１～４アルキル）アミノカルボニル基、（１２）ジ－（Ｃ１～４アルキル）アミノカルボニル基、（１３）－ＣＯ－（３～６員の飽和複素環）、（１４）－ＣＯＮＨＲ３９、（１５）Ｃ１～４アルコキシカルボニル基、または（１６）シアノ基を表わし、
    Ｒ３９は、（１）シアノ基で置換されたＣ１～４アルキル基、（２）Ｃ１～４アルコキシ基、（３）Ｃ１～４ハロアルキル基、（４）Ｃ１～４ハロアルコキシ基、（５）水酸基、（６）アミノ基、（７）（Ｃ１～４アルキル）アミノ基、（８）ジ－（Ｃ１～４アルキル）アミノ基、（９）１～５個のＲ４０で置換されていてもよいＣ３～６シクロアルキル基、または（１０）１～５個のＲ４１で置換されていてもよい３～６員の飽和複素環を表わし、
    Ｒ４０およびＲ４１は、それぞれ独立して、（１）ハロゲン、（２）Ｃ１～４アルキル基、（３）Ｃ１～４アルコキシ基、（４）Ｃ１～４ハロアルキル基、または（５）Ｃ１～４ハロアルコキシ基を表わし、
    複数のＲ４０およびＲ４１は、それぞれ同じでも異なっていてもよく、
    ｒは、０～３の整数を表わし、複数のＲ４は同じでも異なっていてもよく、
    ｓは、０～３の整数を表わし、複数のＲ５は同じでも異なっていてもよい。
    ここで、各水素原子は、重水素原子、または三重水素原子であってもよい。）で示される化合物、またはその塩。     General formula (IY)
    (In the formula, R 1 is (1) methylene substituted with a 3- to 15-membered carbon ring optionally substituted with 1 to 5 R 11 , (2) substituted with 1 to 5 R 12 (3) Methylene substituted with a C2-4 alkenyl group optionally substituted with 1 to 5 R13 , or (4) Represents methylene substituted with a C2-4 alkynyl group optionally substituted with 1 to 5 R14 ,
    R 11 , R 12 , R 13 and R 14 each independently represent (1) halogen, (2) C1-4 alkyl group, (3) C1-4 alkoxy group, (4) C1-4 haloalkyl group, (5) represents a C1-4 haloalkoxy group, or (6) a cyano group, and a plurality of R 11 , R 12 , R 13 and R 14 may be the same or different, respectively;
    R 2 is (1) a 3- to 15 -membered heterocycle optionally substituted with 1 to 5 R 15s, (2) a 3- to 15-membered heterocycle optionally substituted with 1 to 5 R 16 or (3) a C1-4 alkyl group optionally substituted with 1 to 5 R17 ;
    R 15 , R 16 and R 17 are each independently,
    (1) a C1-8 alkyl group optionally substituted with a C3-6 cycloalkyl group optionally substituted with 1-5 R18, (2) a (C1-8 alkyl)carbonyl group, (3 ) (C3-6 cycloalkyl) carbonyl group substituted with 1 to 5 R 19 , (4) C1-8 haloalkyl group, (5) 5- to 6-membered carbon ring, (6) 5- to 6-membered carbocyclic Heterocycle, (7) C1-4 alkylsulfonyl group, (8) C2-4 alkenylsulfonyl group, (9) C1-4 alkoxycarbonyl group, (10) C1-4 haloalkylamino group, (11) t-butyloxy Represents a carbonylamino group or (12) 5,5-dimethyl-2,4-dioxoxazolidin-3-yl group,
    A plurality of R 15 , R 16 and R 17 may be the same or different,
    R 18 and R 19 each independently represent (1) halogen, (2) C1-4 alkyl group, (3) C1-4 alkoxy group, (4) C1-4 haloalkyl group, (5) C1-4 represents a haloalkoxy group or (6) a cyano group,
    A plurality of R 18 and R 19 may be the same or different,
    R 3Y is (1) hydrogen atom, (2) halogen, (3) C1-4 alkyl group, (4) C1-4 alkoxy group, (5) C1-4 haloalkyl group, (6) C1-4 haloalkoxy group, (7) a cyano group, (8) a 3- to 15-membered carbon ring optionally substituted with 1 to 5 R 20Y , (9) optionally substituted with 1 to 5 R 21Y 3- to 15-membered heterocycle, (10)-NR 22 R 23 , (11)-OR 24 , (12)-CONR 25 R 26 , (13) (C1-8 alkyl) carbonyl group, (14) 1- Represents a C1-4 alkyl group substituted with three hydroxyl groups, or (15) 1-(hydroxyimino)ethyl group,
    R 20Y and R 21Y each independently represent (1) a C1-4 alkyl group optionally substituted with 1 to 5 R 27Y , (2) halogen, (3) 1 to 5 R 28Y (4) a C1-4 alkoxy group optionally substituted with 1 to 5 R 27-1Y , (5) a hydroxyl group, (6) a carbamoyl group, (7) represents a carboxyl group, or (8) a cyano group,
    A plurality of R 20Y and R 21Y may be the same or different,
    R 27Y , R 27-1Y and R 28Y each independently represent (1) halogen, (2) C1-4 alkyl group, (3) C1-4 alkoxy group, (4) C1-4 haloalkyl group, ( 5) represents a C1-4 haloalkoxy group, (6) a hydroxyl group, (7) a carbamoyl group, (8) a carboxyl group, (9) a C1-4 alkoxycarbonyl group, or (10) a cyano group,
    A plurality of R 27Y , R 27-1Y and R 28Y may be the same or different,
    R 22 , R 23 and R 24 each independently represent (1) a hydrogen atom, (2) a C1-8 alkyl group optionally substituted with 1 to 5 R 29s , (3) 1 to 5 (4) C2-4 alkynyl group optionally substituted with 1 to 5 R 29-2 , (5) 1 to 5 ( 6 ) a 3- to 15-membered heterocycle optionally substituted with 1 to 5 R 31 ;
    R 29 , R 29-1 , R 29-2 , R 30 and R 31 are each independently,
    (1) C1-4 alkyl group optionally substituted with 1-5 R 32 , (2) halogen, (3) C3-8 cycloalkyl optionally substituted with 1-5 R 33 group, (4) a 5- to 6-membered carbocyclic ring optionally substituted with 1 to 5 R 34s , (5) a 5- to 6-membered heterocyclic ring optionally substituted with 1 to 5 R 35 ring, (6) C1-4 alkoxy group optionally substituted with 1 to 5 R 32-1 , (7) hydroxyl group, (8) carbamoyl group, (9) carboxyl group, or (10) cyano group represents,
    A plurality of R 29 , R 29-1 , R 29-2 , R 30 and R 31 may be the same or different,
    R 32 , R 32-1 , R 33 , R 34 and R 35 each independently represent (1) halogen, (2) C1-4 alkyl group, (3) C1-4 alkoxy group, (4) C1 ~4 haloalkyl group, (5) C1~4 haloalkoxy group, (6) hydroxyl group, (7) carbamoyl group, (8) carboxyl group, or (9) cyano group,
    A plurality of R 32 , R 32-1 , R 33 , R 34 and R 35 may be the same or different,
    R 25 and R 26 each independently represent (1) a hydrogen atom, (2) a C1-8 alkyl group optionally substituted with 1 to 5 R 36 , (3) 1 to 5 R 36 C2-4 alkenyl group optionally substituted with 36-1 , (4) 1-5 R C2-4 alkynyl group optionally substituted with 36-2 , (5) 1-5 R Represents a 3- to 15-membered carbocycle optionally substituted with 37, or (6) a 3- to 15-membered heterocycle optionally substituted with 1 to 5 R 38 ,
    R 36 , R 36-1 , R 36-2 , R 37 and R 38 each independently represent (1) a C1-4 alkyl group, (2) a halogen, (3) a C3-8 cycloalkyl group, ( 4) 5-6 membered carbocycle, (5) 5-6 membered heterocycle, (6) C1-4 alkoxy group, (7) C1-4 haloalkyl group, (8) C1-4 haloalkoxy group, ( 9) represents a hydroxyl group, (10) a carboxyl group, (11) a carbamoyl group, or (12) a cyano group,
    A plurality of R 36 , R 36-1 , R 36-2 , R 37 and R 38 may be the same or different,
    R 4 is (1) halogen, (2) C1-4 alkyl group, (3) C1-4 alkoxy group, (4) C1-4 haloalkyl group, (5) C1-4 haloalkoxy group, (6) hydroxyl group , or (7) represents a cyano group,
    R 5 is (1) halogen, (2) C1-4 alkyl group, (3) C1-4 alkoxy group, (4) C1-4 haloalkyl group, (5) C1-4 haloalkoxy group, (6) hydroxyl group , or (7) represents a cyano group,
    ringY is
    (The arrow on the right bonds to the nitrogen atom, the arrow on the left bonds to the carbonyl group.), or a saturated or partially unsaturated 4-10, optionally substituted with 1-6 R Y containing 1 nitrogen atom, 1 oxygen atom and/or 1 sulfur atom which may be oxidized, optionally substituted with a membered carbocyclic ring, or 1 to 6 R Y Represents a 6-membered saturated heterocycle, R Y is (1) halogen, (2) C1-4 alkyl group, (3) C1-4 alkoxy group, (4) C1-4 haloalkyl group, (5) C1-4 alkyl group. 4-haloalkoxy group, (6) hydroxyl group, (7) oxo group, or (8) cyano group,
    When there is a plurality of R Y , each R Y may be the same or different;
    X represents a nitrogen atom or CR7 ,
    X 1 , X 2 , and X 3 each independently represent a nitrogen atom, CH, or CR 6 ,
    R 6 is (1) halogen, (2) C1-4 alkyl group, (3) C1-4 alkoxy group, (4) C1-4 haloalkyl group, (5) C1-4 haloalkoxy group, (6) hydroxyl group , or (7) represents a cyano group,
    When there is a plurality of R 6 s, each R 6 may be the same or different;
    Y 1 represents a nitrogen atom or CR 8 ,
    Y2 represents a nitrogen atom or CR9 ,
    Y 3 represents a nitrogen atom or CR 10Y ,
    R 7 is (1) hydrogen atom, (2) halogen, (3) C1-4 alkyl group, (4) C1-4 alkoxy group, (5) C1-4 haloalkyl group, or (6) C1-4 halo represents an alkoxy group,
    R 8 is (1) hydrogen atom, (2) halogen, (3) C1-4 alkyl group, (4) C1-4 alkoxy group, (5) C1-4 haloalkyl group, or (6) C1-4 halo represents an alkoxy group,
    R 9 is (1) hydrogen atom, (2) halogen, (3) C1-4 alkyl group, (4) C1-4 alkoxy group, (5) C1-4 haloalkyl group, or (6) C1-4 halo represents an alkoxy group,
    R 10Y is (1) hydrogen atom, (2) halogen, (3) C1-4 alkyl group, (4) C1-4 alkoxy group, (5) C1-4 haloalkyl group, (6) C1-4 haloalkoxy group, (7) hydroxyl group, (8) amino group, (9) carboxyl group, (10) carbamoyl group, (11) (C1-4 alkyl)aminocarbonyl group, (12) di-(C1-4 alkyl)amino Represents a carbonyl group, (13) -CO- (3- to 6-membered saturated heterocycle), (14) -CONHR 39 , (15) C1-4 alkoxycarbonyl group, or (16) cyano group,
    R 39 is (1) a C1-4 alkyl group substituted with a cyano group, (2) a C1-4 alkoxy group, (3) a C1-4 haloalkyl group, (4) a C1-4 haloalkoxy group, (5) Even if substituted with hydroxyl group, (6) amino group, (7) (C1-4 alkyl) amino group, (8) di-(C1-4 alkyl) amino group, (9) 1-5 R 40 (10) a 3- to 6-membered saturated heterocycle optionally substituted with 1 to 5 R 41 ;
    R 40 and R 41 are each independently (1) halogen, (2) C1-4 alkyl group, (3) C1-4 alkoxy group, (4) C1-4 haloalkyl group, or (5) C1-4 represents a 4-haloalkoxy group,
    A plurality of R 40 and R 41 may be the same or different,
    r represents an integer from 0 to 3, and multiple R 4 may be the same or different;
    s represents an integer from 0 to 3, and plural R 5s may be the same or different.
    Here, each hydrogen atom may be a deuterium atom or a tritium atom. ) or its salt.
  2. 　一般式（Ｉ）
    （式中、Ｒ１は、（１）１～５個のＲ１１で置換されていてもよい３～１５員の炭素環で置換されたメチレン、（２）１～５個のＲ１２で置換されていてもよい３～１５員の複素環で置換されたメチレン、（３）１～５個のＲ１３で置換されていてもよいＣ２～４アルケニル基で置換されたメチレン、または（４）１～５個のＲ１４で置換されていてもよいＣ２～４アルキニル基で置換されたメチレンを表わし、
    Ｒ１１、Ｒ１２、Ｒ１３およびＲ１４は、それぞれ独立して、（１）ハロゲン、（２）Ｃ１～４アルキル基、（３）Ｃ１～４アルコキシ基、（４）Ｃ１～４ハロアルキル基、（５）Ｃ１～４ハロアルコキシ基、または（６）シアノ基を表わし、複数のＲ１１、Ｒ１２、Ｒ１３およびＲ１４は、それぞれ同じでも異なっていてもよく、
    Ｒ２は、（１）１～５個のＲ１５で置換されていてもよい３～１５員の複素環、（２）１～５個のＲ１６で置換されていてもよい３～１５員の炭素環、または（３）１～５個のＲ１７で置換されていてもよいＣ１～４アルキル基を表わし、
    Ｒ１５、Ｒ１６およびＲ１７は、それぞれ独立して、
    （１）１～５個のＲ１８で置換されていてもよいＣ３～６シクロアルキル基で置換されていてもよいＣ１～８アルキル基、（２）（Ｃ１～８アルキル）カルボニル基、（３）１～５個のＲ１９で置換された（Ｃ３～６シクロアルキル）カルボニル基、（４）Ｃ１～８ハロアルキル基、（５）５～６員の炭素環、（６）５～６員の複素環、（７）Ｃ１～４アルキルスルホニル基、（８）Ｃ２～４アルケニルスルホニル基、（９）Ｃ１～４アルコキシカルボニル基、（１０）Ｃ１～４ハロアルキルアミノ基、（１１）ｔ－ブチルオキシカルボニルアミノ基、または（１２）５，５－ジメチル－２，４－ジオキソオキサゾリジン－３－イル基を表わし、
    複数のＲ１５、Ｒ１６およびＲ１７は、それぞれ同じでも異なっていてもよく、
    Ｒ１８およびＲ１９は、それぞれ独立して、（１）ハロゲン、（２）Ｃ１～４アルキル基、（３）Ｃ１～４アルコキシ基、（４）Ｃ１～４ハロアルキル基、（５）Ｃ１～４ハロアルコキシ基、または（６）シアノ基を表わし、
    複数のＲ１８およびＲ１９は、それぞれ同じでも異なっていてもよく、
    Ｒ３は、（１）水素原子、（２）ハロゲン、（３）Ｃ１～４アルキル基、（４）Ｃ１～４アルコキシ基、（５）Ｃ１～４ハロアルキル基、（６）Ｃ１～４ハロアルコキシ基、（７）シアノ基、（８）１～５個のＲ２０で置換されていてもよい３～１５員の炭素環、（９）１～５個のＲ２１で置換されていてもよい３～１５員の複素環、（１０）－ＮＲ２２Ｒ２３、（１１）－ＯＲ２４、（１２）－ＣＯＮＲ２５Ｒ２６、（１３）（Ｃ１～８アルキル）カルボニル基、（１４）１～３個の水酸基で置換されたＣ１～４アルキル基、または（１５）１－（ヒドロキシイミノ）エチル基を表わし、
    Ｒ２０およびＲ２１は、それぞれ独立して、（１）１～５個のＲ２７で置換されていてもよいＣ１～４アルキル基、（２）ハロゲン、（３）１～５個のＲ２８で置換されていてもよいＣ３～６シクロアルキル基、（４）１～５個のＲ２７－１で置換されていてもよいＣ１～４アルコキシ基、（５）水酸基、（６）カルバモイル基、（７）カルボキシル基、または（８）シアノ基を表わし、
    複数のＲ２０およびＲ２１は、それぞれ同じでも異なっていてもよく、
    Ｒ２７、Ｒ２７－１およびＲ２８は、それぞれ独立して、（１）ハロゲン、（２）Ｃ１～４アルキル基、（３）Ｃ１～４アルコキシ基、（４）Ｃ１～４ハロアルキル基、（５）Ｃ１～４ハロアルコキシ基、（６）水酸基、（７）カルバモイル基、（８）カルボキシル基、または（９）シアノ基を表わし、
    複数のＲ２７、Ｒ２７－１およびＲ２８は、それぞれ同じでも異なっていてもよく、
    Ｒ２２、Ｒ２３およびＲ２４は、それぞれ独立して、（１）水素原子、（２）１～５個のＲ２９で置換されていてもよいＣ１～８アルキル基、（３）１～５個のＲ２９－１で置換されていてもよいＣ２～４アルケニル基、（４）１～５個のＲ２９－２で置換されていてもよいＣ２～４アルキニル基、（５）１～５個のＲ３０で置換されていてもよい３～１５員の炭素環、または（６）１～５個のＲ３１で置換されていてもよい３～１５員の複素環を表わし、
    Ｒ２９、Ｒ２９－１、Ｒ２９－２、Ｒ３０およびＲ３１は、それぞれ独立して、
    （１）１～５個のＲ３２で置換されていてもよいＣ１～４アルキル基、（２）ハロゲン、（３）１～５個のＲ３３で置換されていてもよいＣ３～８シクロアルキル基、（４）１～５個のＲ３４で置換されていてもよい５～６員の炭素環、（５）１～５個のＲ３５で置換されていてもよい５～６員の複素環、（６）１～５個のＲ３２－１で置換されていてもよいＣ１～４アルコキシ基、（７）水酸基、（８）カルバモイル基、（９）カルボキシル基、または（１０）シアノ基を表わし、
    複数のＲ２９、Ｒ２９－１、Ｒ２９－２、Ｒ３０およびＲ３１は、それぞれ同じでも異なっていてもよく、
    Ｒ３２、Ｒ３２－１、Ｒ３３、Ｒ３４およびＲ３５は、それぞれ独立して、（１）ハロゲン、（２）Ｃ１～４アルキル基、（３）Ｃ１～４アルコキシ基、（４）Ｃ１～４ハロアルキル基、（５）Ｃ１～４ハロアルコキシ基、（６）水酸基、（７）カルバモイル基、（８）カルボキシル基、または（９）シアノ基を表わし、
    複数のＲ３２、Ｒ３２－１、Ｒ３３、Ｒ３４およびＲ３５は、それぞれ同じでも異なっていてもよく、
    Ｒ２５およびＲ２６は、それぞれ独立して、（１）水素原子、（２）１～５個のＲ３６で置換されていてもよいＣ１～８アルキル基、（３）１～５個のＲ３６－１で置換されていてもよいＣ２～４アルケニル基、（４）１～５個のＲ３６－２で置換されていてもよいＣ２～４アルキニル基、（５）１～５個のＲ３７で置換されていてもよい３～１５員の炭素環、または（６）１～５個のＲ３８で置換されていてもよい３～１５員の複素環を表わし、
    Ｒ３６、Ｒ３６－１、Ｒ３６－２、Ｒ３７およびＲ３８は、それぞれ独立して、（１）Ｃ１～４アルキル基、（２）ハロゲン、（３）Ｃ３～８シクロアルキル基、（４）５～６員の炭素環、（５）５～６員の複素環、（６）Ｃ１～４アルコキシ基、（７）Ｃ１～４ハロアルキル基、（８）Ｃ１～４ハロアルコキシ基、（９）水酸基、（１０）カルボキシル基、（１１）カルバモイル基、または（１２）シアノ基を表わし、
    複数のＲ３６、Ｒ３６－１、Ｒ３６－２、Ｒ３７およびＲ３８は、それぞれ同じでも異なっていてもよく、
    Ｒ４は、（１）ハロゲン、（２）Ｃ１～４アルキル基、（３）Ｃ１～４アルコキシ基、（４）Ｃ１～４ハロアルキル基、（５）Ｃ１～４ハロアルコキシ基、（６）水酸基、または（７）シアノ基を表わし、
    Ｒ５は、（１）ハロゲン、（２）Ｃ１～４アルキル基、（３）Ｃ１～４アルコキシ基、（４）Ｃ１～４ハロアルキル基、（５）Ｃ１～４ハロアルコキシ基、（６）水酸基、または（７）シアノ基を表わし、
    Ｘは、窒素原子、またはＣＲ７を表わし、
    Ｘ１、Ｘ２、およびＸ３は、それぞれ独立して、窒素原子、ＣＨ、またはＣＲ６を表わし、
    Ｒ６は、（１）ハロゲン、（２）Ｃ１～４アルキル基、（３）Ｃ１～４アルコキシ基、（４）Ｃ１～４ハロアルキル基、（５）Ｃ１～４ハロアルコキシ基、（６）水酸基、または（７）シアノ基を表わし、
    Ｒ６が複数の場合、各Ｒ６は同じでも異なっていてもよく、
    Ｙ１は、窒素原子、またはＣＲ８を表わし、
    Ｙ２は、窒素原子、またはＣＲ９を表わし、
    Ｙ３は、窒素原子、またはＣＲ１０を表わし、
    Ｒ７は、（１）水素原子、（２）ハロゲン、（３）Ｃ１～４アルキル基、（４）Ｃ１～４アルコキシ基、（５）Ｃ１～４ハロアルキル基、または（６）Ｃ１～４ハロアルコキシ基を表わし、
    Ｒ８は、（１）水素原子、（２）ハロゲン、（３）Ｃ１～４アルキル基、（４）Ｃ１～４アルコキシ基、（５）Ｃ１～４ハロアルキル基、または（６）Ｃ１～４ハロアルコキシ基を表わし、
    Ｒ９は、（１）水素原子、（２）ハロゲン、（３）Ｃ１～４アルキル基、（４）Ｃ１～４アルコキシ基、（５）Ｃ１～４ハロアルキル基、または（６）Ｃ１～４ハロアルコキシ基を表わし、
    Ｒ１０は、（１）水素原子、（２）ハロゲン、（３）Ｃ１～４アルキル基、（４）Ｃ１～４アルコキシ基、（５）Ｃ１～４ハロアルキル基、（６）Ｃ１～４ハロアルコキシ基、（７）水酸基、（８）アミノ基、（９）カルボキシル基、（１０）カルバモイル基、（１１）（Ｃ１～４アルキル）アミノカルボニル基、（１２）ジ－（Ｃ１～４アルキル）アミノカルボニル基、（１３）－ＣＯ－（３～６員の飽和複素環）、（１４）－ＣＯＮＨＲ３９、または（１５）シアノ基を表わし、
    Ｒ３９は、（１）シアノ基で置換されたＣ１～４アルキル基、（２）Ｃ１～４アルコキシ基、（３）Ｃ１～４ハロアルキル基、（４）Ｃ１～４ハロアルコキシ基、（５）水酸基、（６）アミノ基、（７）（Ｃ１～４アルキル）アミノ基、（８）ジ－（Ｃ１～４アルキル）アミノ基、（９）１～５個のＲ４０で置換されていてもよいＣ３～６シクロアルキル基、または（１０）１～５個のＲ４１で置換されていてもよい３～６員の飽和複素環を表わし、
    Ｒ４０およびＲ４１は、それぞれ独立して、（１）ハロゲン、（２）Ｃ１～４アルキル基、（３）Ｃ１～４アルコキシ基、（４）Ｃ１～４ハロアルキル基、または（５）Ｃ１～４ハロアルコキシ基を表わし、
    複数のＲ４０およびＲ４１は、それぞれ同じでも異なっていてもよく、
    ｒは、０～３の整数を表わし、複数のＲ４は同じでも異なっていてもよく、
    ｓは、０～３の整数を表わし、複数のＲ５は同じでも異なっていてもよい。
    ここで、各水素原子は、重水素原子、または三重水素原子であってもよい。）で示される請求項１記載の化合物、またはその塩。     General formula (I)
    (In the formula, R 1 is (1) methylene substituted with a 3- to 15-membered carbon ring optionally substituted with 1 to 5 R 11 , (2) substituted with 1 to 5 R 12 (3) methylene substituted with a C2-4 alkenyl group optionally substituted with 1 to 5 R 13 , or (4) Represents methylene substituted with a C2-4 alkynyl group optionally substituted with 1 to 5 R14 ,
    R 11 , R 12 , R 13 and R 14 each independently represent (1) halogen, (2) C1-4 alkyl group, (3) C1-4 alkoxy group, (4) C1-4 haloalkyl group, (5) represents a C1-4 haloalkoxy group, or (6) a cyano group, and a plurality of R 11 , R 12 , R 13 and R 14 may be the same or different, respectively;
    R 2 is (1) a 3- to 15 -membered heterocycle optionally substituted with 1 to 5 R 15s, (2) a 3- to 15-membered heterocycle optionally substituted with 1 to 5 R 16 or (3) a C1-4 alkyl group optionally substituted with 1 to 5 R17 ,
    R 15 , R 16 and R 17 are each independently,
    (1) a C1-8 alkyl group optionally substituted with a C3-6 cycloalkyl group optionally substituted with 1-5 R18, (2) a (C1-8 alkyl)carbonyl group, (3 ) (C3-6 cycloalkyl) carbonyl group substituted with 1-5 R 19 , (4) C1-8 haloalkyl group, (5) 5-6 membered carbon ring, (6) 5-6 membered carbocycle Heterocycle, (7) C1-4 alkylsulfonyl group, (8) C2-4 alkenylsulfonyl group, (9) C1-4 alkoxycarbonyl group, (10) C1-4 haloalkylamino group, (11) t-butyloxy Represents a carbonylamino group or (12) 5,5-dimethyl-2,4-dioxoxazolidin-3-yl group,
    A plurality of R 15 , R 16 and R 17 may be the same or different,
    R 18 and R 19 each independently represent (1) halogen, (2) C1-4 alkyl group, (3) C1-4 alkoxy group, (4) C1-4 haloalkyl group, (5) C1-4 represents a haloalkoxy group or (6) a cyano group,
    A plurality of R 18 and R 19 may be the same or different,
    R 3 is (1) hydrogen atom, (2) halogen, (3) C1-4 alkyl group, (4) C1-4 alkoxy group, (5) C1-4 haloalkyl group, (6) C1-4 haloalkoxy group, (7) a cyano group, (8) a 3- to 15-membered carbon ring optionally substituted with 1 to 5 R 20 , (9) optionally substituted with 1 to 5 R 21 3- to 15-membered heterocycle, (10)-NR 22 R 23 , (11)-OR 24 , (12)-CONR 25 R 26 , (13) (C1-8 alkyl) carbonyl group, (14) 1- Represents a C1-4 alkyl group substituted with three hydroxyl groups, or (15) 1-(hydroxyimino)ethyl group,
    R 20 and R 21 each independently represent (1) a C1-4 alkyl group optionally substituted with 1 to 5 R 27s , (2) halogen, (3) 1 to 5 R 28 (4) a C1-4 alkoxy group optionally substituted with 1 to 5 R27-1 , (5) a hydroxyl group, (6) a carbamoyl group, (7) represents a carboxyl group, or (8) a cyano group,
    A plurality of R 20 and R 21 may be the same or different,
    R 27 , R 27-1 and R 28 each independently represent (1) halogen, (2) C1-4 alkyl group, (3) C1-4 alkoxy group, (4) C1-4 haloalkyl group, ( 5) represents a C1-4 haloalkoxy group, (6) hydroxyl group, (7) carbamoyl group, (8) carboxyl group, or (9) cyano group,
    A plurality of R 27 , R 27-1 and R 28 may be the same or different,
    R 22 , R 23 and R 24 each independently represent (1) a hydrogen atom, (2) a C1-8 alkyl group optionally substituted with 1 to 5 R 29s , (3) 1 to 5 (4) C2-4 alkynyl group optionally substituted with 1 to 5 R 29-2 , (5) 1 to 5 ( 6 ) a 3- to 15-membered heterocycle optionally substituted with 1 to 5 R 31 ;
    R 29 , R 29-1 , R 29-2 , R 30 and R 31 are each independently,
    (1) C1-4 alkyl group optionally substituted with 1-5 R 32 , (2) halogen, (3) C3-8 cycloalkyl optionally substituted with 1-5 R 33 group, (4) a 5- to 6-membered carbocyclic ring optionally substituted with 1 to 5 R 34s , (5) a 5- to 6-membered heterocyclic ring optionally substituted with 1 to 5 R 35 ring, (6) C1-4 alkoxy group optionally substituted with 1 to 5 R 32-1 , (7) hydroxyl group, (8) carbamoyl group, (9) carboxyl group, or (10) cyano group represents,
    A plurality of R 29 , R 29-1 , R 29-2 , R 30 and R 31 may be the same or different,
    R 32 , R 32-1 , R 33 , R 34 and R 35 each independently represent (1) halogen, (2) C1-4 alkyl group, (3) C1-4 alkoxy group, (4) C1 ~4 haloalkyl group, (5) C1~4 haloalkoxy group, (6) hydroxyl group, (7) carbamoyl group, (8) carboxyl group, or (9) cyano group,
    A plurality of R 32 , R 32-1 , R 33 , R 34 and R 35 may be the same or different,
    R 25 and R 26 each independently represent (1) a hydrogen atom, (2) a C1-8 alkyl group optionally substituted with 1 to 5 R 36 , (3) 1 to 5 R 36 C2-4 alkenyl group optionally substituted with 36-1 , (4) 1-5 R C2-4 alkynyl group optionally substituted with 36-2 , (5) 1-5 R Represents a 3- to 15-membered carbocycle optionally substituted with 37, or (6) a 3- to 15-membered heterocycle optionally substituted with 1 to 5 R 38 ,
    R 36 , R 36-1 , R 36-2 , R 37 and R 38 each independently represent (1) a C1-4 alkyl group, (2) a halogen, (3) a C3-8 cycloalkyl group, ( 4) 5-6 membered carbocycle, (5) 5-6 membered heterocycle, (6) C1-4 alkoxy group, (7) C1-4 haloalkyl group, (8) C1-4 haloalkoxy group, ( 9) represents a hydroxyl group, (10) a carboxyl group, (11) a carbamoyl group, or (12) a cyano group,
    A plurality of R 36 , R 36-1 , R 36-2 , R 37 and R 38 may be the same or different, respectively,
    R 4 is (1) halogen, (2) C1-4 alkyl group, (3) C1-4 alkoxy group, (4) C1-4 haloalkyl group, (5) C1-4 haloalkoxy group, (6) hydroxyl group , or (7) represents a cyano group,
    R 5 is (1) halogen, (2) C1-4 alkyl group, (3) C1-4 alkoxy group, (4) C1-4 haloalkyl group, (5) C1-4 haloalkoxy group, (6) hydroxyl group , or (7) represents a cyano group,
    X represents a nitrogen atom or CR7 ,
    X 1 , X 2 , and X 3 each independently represent a nitrogen atom, CH, or CR 6 ,
    R 6 is (1) halogen, (2) C1-4 alkyl group, (3) C1-4 alkoxy group, (4) C1-4 haloalkyl group, (5) C1-4 haloalkoxy group, (6) hydroxyl group , or (7) represents a cyano group,
    When there is a plurality of R 6 s, each R 6 may be the same or different;
    Y 1 represents a nitrogen atom or CR 8 ,
    Y2 represents a nitrogen atom or CR9 ,
    Y3 represents a nitrogen atom or CR10 ,
    R 7 is (1) hydrogen atom, (2) halogen, (3) C1-4 alkyl group, (4) C1-4 alkoxy group, (5) C1-4 haloalkyl group, or (6) C1-4 halo represents an alkoxy group,
    R 8 is (1) hydrogen atom, (2) halogen, (3) C1-4 alkyl group, (4) C1-4 alkoxy group, (5) C1-4 haloalkyl group, or (6) C1-4 halo represents an alkoxy group,
    R 9 is (1) hydrogen atom, (2) halogen, (3) C1-4 alkyl group, (4) C1-4 alkoxy group, (5) C1-4 haloalkyl group, or (6) C1-4 halo represents an alkoxy group,
    R 10 is (1) hydrogen atom, (2) halogen, (3) C1-4 alkyl group, (4) C1-4 alkoxy group, (5) C1-4 haloalkyl group, (6) C1-4 haloalkoxy group, (7) hydroxyl group, (8) amino group, (9) carboxyl group, (10) carbamoyl group, (11) (C1-4 alkyl)aminocarbonyl group, (12) di-(C1-4 alkyl)amino Represents a carbonyl group, (13) -CO- (3- to 6-membered saturated heterocycle), (14) -CONHR 39 , or (15) cyano group,
    R 39 is (1) a C1-4 alkyl group substituted with a cyano group, (2) a C1-4 alkoxy group, (3) a C1-4 haloalkyl group, (4) a C1-4 haloalkoxy group, (5) Even if substituted with hydroxyl group, (6) amino group, (7) (C1-4 alkyl) amino group, (8) di-(C1-4 alkyl) amino group, (9) 1-5 R 40 (10) a 3- to 6-membered saturated heterocycle optionally substituted with 1 to 5 R 41 ;
    R 40 and R 41 are each independently (1) halogen, (2) C1-4 alkyl group, (3) C1-4 alkoxy group, (4) C1-4 haloalkyl group, or (5) C1-4 represents a 4-haloalkoxy group,
    A plurality of R 40 and R 41 may be the same or different,
    r represents an integer from 0 to 3, and multiple R 4 may be the same or different;
    s represents an integer from 0 to 3, and plural R 5s may be the same or different.
    Here, each hydrogen atom may be a deuterium atom or a tritium atom. ) or a salt thereof according to claim 1.
  3. 　一般式（Ｉ－１）
    （式中、ｔは、０～３の整数を表わし、その他の記号は請求項２と同じ意味を表わす。）で示される請求項１または２記載の化合物、またはその塩。     General formula (I-1)
    The compound according to claim 1 or 2, or a salt thereof, represented by the formula (wherein, t represents an integer of 0 to 3, and other symbols have the same meanings as in claim 2).
  4. 　Ｒ２が、１～５個のＲ１５で置換されていてもよい５～７員の含窒素飽和複素環である、請求項１～３のいずれかに記載の化合物、またはその塩。 The compound or a salt thereof according to any one of claims 1 to 3, wherein R 2 is a 5- to 7-membered nitrogen-containing saturated heterocycle optionally substituted with 1 to 5 R 15s .
  5. 　Ｒ１が、１～５個のＲ１１で置換されていてもよい５～６員の炭素環で置換されたメチレンである、請求項１～４のいずれかに記載の化合物、またはその塩。 The compound or a salt thereof according to any one of claims 1 to 4, wherein R 1 is methylene substituted with a 5- to 6-membered carbon ring optionally substituted with 1 to 5 R 11 .
  6. 　Ｒ３が、（１）それぞれ１～５個のＲ２０で置換されていてもよい、５～６員の炭素環またはインダン、（２）１～５個のＲ２１で置換されていてもよい５～６員の複素環、または（３）－ＮＲ２２Ｒ２３である、請求項１～５のいずれかに記載の化合物、またはその塩。 R 3 is (1) a 5- to 6-membered carbocyclic ring or indane, each optionally substituted with 1 to 5 R 20 , (2) optionally substituted with 1 to 5 R 21 The compound according to any one of claims 1 to 5, or a salt thereof, which is a 5- to 6-membered heterocycle or (3)-NR 22 R 23 .
  7. 　一般式（Ｉ－１－１）
    （式中、Ｒ１－１は、１～５個のＲ１１で置換されていてもよい５～６員の炭素環で置換されたメチレンを表わし、ｒｉｎｇ１は、５～７員の含窒素飽和複素環を表わし、Ｒ３－１は、（１）それぞれ１～５個のＲ２０で置換されていてもよい、５～６員の炭素環またはインダン、（２）１～５個のＲ２１で置換されていてもよい５～６員の複素環、または（３）－ＮＲ２２Ｒ２３を表わし、Ｒ１５－１は、１～５個のＲ１８で置換されていてもよいＣ３～６シクロアルキル基で置換されていてもよいＣ１～８アルキル基、またはＣ１～８ハロアルキル基を表わし、ｕは０～２の整数を表わし、その他の記号は請求項２と同じ意味を表わす。）で示される請求項１～６のいずれかに記載の化合物、またはその塩。     General formula (I-1-1)
    (In the formula, R 1-1 represents methylene substituted with a 5- to 6-membered carbon ring which may be substituted with 1 to 5 R 11 , and ring 1 is a 5- to 7-membered nitrogen-containing saturated Represents a heterocycle, and R 3-1 is (1) a 5- to 6-membered carbocyclic ring or indane, each optionally substituted with 1 to 5 R 20 , (2) 1 to 5 R 21 represents a 5- to 6-membered heterocycle optionally substituted with or (3)-NR 22 R 23 , and R 15-1 is C3-6 optionally substituted with 1 to 5 R 18 represents a C1-8 alkyl group or a C1-8 haloalkyl group which may be substituted with a cycloalkyl group, u represents an integer from 0 to 2, and other symbols have the same meanings as in claim 2). The compound according to any one of claims 1 to 6, or a salt thereof.
  8. 　一般式（Ｉ－１－１－１）
    （式中、ｒｉｎｇ２は、（１）それぞれ１～５個のＲ２０で置換されていてもよい、５～６員の炭素環、またはインダン、（２）１～５個のＲ２１で置換されていてもよい５～６員の複素環を表わし、その他の記号は請求項２および７と同じ意味を表わす。）で示される請求項７記載の化合物、またはその塩。     General formula (I-1-1-1)
    (In the formula, ring2 is (1) a 5- to 6-membered carbon ring or indane, each optionally substituted with 1 to 5 R 20 , (2) substituted with 1 to 5 R 21 8. The compound according to claim 7, or a salt thereof, which represents a 5- to 6-membered heterocycle which may be 5- to 6-membered heterocycle, and other symbols have the same meanings as in claims 2 and 7.
  9. 　化合物が、（１）１－（３－｛７－（４－｛［９－（４－シアノ－２－フルオロベンジル）－５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－イル］カルボニル｝フェニル）－９－［１－（２，２－ジメチルプロピル）－４－ピペリジニル］－６－メチル－８－オキソ－８，９－ジヒドロ－７Ｈ－プリン－２－イル｝フェニル）シクロプロパンカルボン酸、
    （２）２－（３－｛７－（６－｛［９－（４－シアノ－２－フルオロベンジル）－５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－イル］カルボニル｝－３－ピリジニル）－９－［１－（２，２－ジメチルプロピル）－４－ピペリジニル］－６－メチル－８－オキソ－８，９－ジヒドロ－７Ｈ－プリン－２－イル｝フェニル）－２－メチルプロパン酸、または、
    （３）４－（｛７－［（５－｛９－［１－（２，２－ジメチルプロピル）－４－ピペリジニル］－６－メチル－２－［２－メチル－４－（トリフルオロメトキシ）フェニル］－８－オキソ－８，９－ジヒドロ－７Ｈ－プリン－７－イル｝－２－ピリジニル）カルボニル］－５，６，７，８－テトラヒドロ－９Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－９－イル｝メチル）－３－フルオロベンゾニトリルである、請求項８記載の化合物、またはその塩。     The compound is (1) 1-(3-{7-(4-{[9-(4-cyano-2-fluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3 ':4,5]pyrrolo[2,3-b]pyridin-7-yl]carbonyl}phenyl)-9-[1-(2,2-dimethylpropyl)-4-piperidinyl]-6-methyl-8- oxo-8,9-dihydro-7H-purin-2-yl}phenyl)cyclopropanecarboxylic acid,
    (2) 2-(3-{7-(6-{[9-(4-cyano-2-fluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4 ,5]pyrrolo[2,3-b]pyridin-7-yl]carbonyl}-3-pyridinyl)-9-[1-(2,2-dimethylpropyl)-4-piperidinyl]-6-methyl-8- oxo-8,9-dihydro-7H-purin-2-yl}phenyl)-2-methylpropanoic acid, or
    (3) 4-({7-[(5-{9-[1-(2,2-dimethylpropyl)-4-piperidinyl]-6-methyl-2-[2-methyl-4-(trifluoromethoxy) ) phenyl]-8-oxo-8,9-dihydro-7H-purin-7-yl}-2-pyridinyl)carbonyl]-5,6,7,8-tetrahydro-9H-pyrido[4',3': 9. The compound according to claim 8, which is 4,5]pyrrolo[2,3-b]pyridin-9-yl}methyl)-3-fluorobenzonitrile, or a salt thereof.
  10. 　一般式（Ｉ－１－１－２）
    （式中、ｒｉｎｇ３は、１～５個のＲ３０で置換されていてもよい５～６員の炭素環、または１～５個のＲ３１で置換されていてもよい５～６員の複素環を表わし、Ｒ２３－１は、（１）水素原子、（２）１～５個のＲ２９で置換されていてもよいＣ１～８アルキル基、（３）１～５個のＲ２９－１で置換されていてもよいＣ２～４アルケニル基、または（４）１～５個のＲ２９－２で置換されていてもよいＣ２～４アルキニル基を表わし、その他の記号は請求項２および７と同じ意味を表わす。）で示される請求項７記載の化合物、またはその塩。     General formula (I-1-1-2)
    (In the formula, ring3 is a 5- to 6-membered carbocyclic ring optionally substituted with 1 to 5 R 30s , or a 5- to 6-membered heterocyclic ring optionally substituted with 1 to 5 R 31 Represents a ring, and R 23-1 is (1) a hydrogen atom, (2) a C1-8 alkyl group optionally substituted with 1 to 5 R 29s , (3) 1 to 5 R 29- represents a C2-4 alkenyl group optionally substituted with 1 , or (4) a C2-4 alkynyl group optionally substituted with 1 to 5 R29-2 , and other symbols refer to claims 2 and 7) or a salt thereof according to claim 7.
  11. 　化合物が、（１）７－（４－｛［９－（４－クロロ－２－フルオロベンジル）－５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－イル］カルボニル｝フェニル）－２－｛［４－（ジフルオロメトキシ）フェニル］アミノ｝－９－［１－（２，２－ジメチルプロピル）－４－ピペリジニル］－６－メチル－７，９－ジヒドロ－８Ｈ－プリン－８－オン、
    （２）７－（４－｛［９－（４－クロロ－２－フルオロベンジル）－５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－イル］カルボニル｝フェニル）－９－［１－（２，２－ジメチルプロピル）－４－ピペリジニル］－２－［（３－フルオロフェニル）アミノ］－６－メチル－７，９－ジヒドロ－８Ｈ－プリン－８－オン、
    （３）９－［１－（２，２－ジメチルプロピル）－４－ピペリジニル］－７－（６－｛［９－（２－フルオロ－４－メチルベンジル）－５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－イル］カルボニル｝－３－ピリジニル）－６－メチル－２－｛［４－（トリフルオロメトキシ）フェニル］アミノ｝－７，９－ジヒドロ－８Ｈ－プリン－８－オン、
    （４）４－［（７－｛［５－（９－［１－（２，２－ジメチルプロピル）－４－ピペリジニル］－６－メチル－８－オキソ－２－｛［４－（トリフルオロメトキシ）フェニル］アミノ｝－８，９－ジヒドロ－７Ｈ－プリン－７－イル）－２－ピリジニル］カルボニル｝－５，６，７，８－テトラヒドロ－９Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－９－イル）メチル］－３－フルオロベンゾニトリル、
    （５）３－フルオロ－４－（｛７－［（５－｛２－［（３－フルオロフェニル）アミノ］－６－メチル－８－オキソ－９－（１－｛［１－（トリフルオロメチル）シクロプロピル］メチル｝－４－ピペリジニル）－８，９－ジヒドロ－７Ｈ－プリン－７－イル｝－２－ピリジニル）カルボニル］－５，６，７，８－テトラヒドロ－９Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－９－イル｝メチル）ベンゾニトリル、
    （６）４－［（７－｛［５－（２－｛［２－クロロ－４－（トリフルオロメトキシ）フェニル］アミノ｝－９－［１－（２，２－ジメチルプロピル）－４－ピペリジニル］－６－メチル－８－オキソ－８，９－ジヒドロ－７Ｈ－プリン－７－イル）－２－ピリジニル］カルボニル｝－５，６，７，８－テトラヒドロ－９Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－９－イル）メチル］－３－フルオロベンゾニトリル、または、
    （７）７－（６－｛［９－（４－クロロ－２－フルオロベンジル）－５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－イル］カルボニル｝－３－ピリジニル）－９－［１－（２，２－ジメチルプロピル）－４－ピペリジニル］－２－［（３－フルオロフェニル）アミノ］－６－メチル－７，９－ジヒドロ－８Ｈ－プリン－８－オンである、請求項１０記載の化合物、またはその塩。     The compound is (1) 7-(4-{[9-(4-chloro-2-fluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5] pyrrolo[2,3-b]pyridin-7-yl]carbonyl}phenyl)-2-{[4-(difluoromethoxy)phenyl]amino}-9-[1-(2,2-dimethylpropyl)-4- piperidinyl]-6-methyl-7,9-dihydro-8H-purin-8-one,
    (2) 7-(4-{[9-(4-chloro-2-fluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[2 ,3-b]pyridin-7-yl]carbonyl}phenyl)-9-[1-(2,2-dimethylpropyl)-4-piperidinyl]-2-[(3-fluorophenyl)amino]-6-methyl -7,9-dihydro-8H-purin-8-one,
    (3) 9-[1-(2,2-dimethylpropyl)-4-piperidinyl]-7-(6-{[9-(2-fluoro-4-methylbenzyl)-5,6,8,9- Tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[2,3-b]pyridin-7-yl]carbonyl}-3-pyridinyl)-6-methyl-2-{[4-(tri fluoromethoxy)phenyl]amino}-7,9-dihydro-8H-purin-8-one,
    (4) 4-[(7-{[5-(9-[1-(2,2-dimethylpropyl)-4-piperidinyl]-6-methyl-8-oxo-2-{[4-(trifluoro methoxy)phenyl]amino}-8,9-dihydro-7H-purin-7-yl)-2-pyridinyl]carbonyl}-5,6,7,8-tetrahydro-9H-pyrido[4',3':4 ,5]pyrrolo[2,3-b]pyridin-9-yl)methyl]-3-fluorobenzonitrile,
    (5) 3-fluoro-4-({7-[(5-{2-[(3-fluorophenyl)amino]-6-methyl-8-oxo-9-(1-{[1-(trifluoro methyl)cyclopropyl]methyl}-4-piperidinyl)-8,9-dihydro-7H-purin-7-yl}-2-pyridinyl)carbonyl]-5,6,7,8-tetrahydro-9H-pyrido[4 ',3':4,5]pyrrolo[2,3-b]pyridin-9-yl}methyl)benzonitrile,
    (6) 4-[(7-{[5-(2-{[2-chloro-4-(trifluoromethoxy)phenyl]amino}-9-[1-(2,2-dimethylpropyl)-4- piperidinyl]-6-methyl-8-oxo-8,9-dihydro-7H-purin-7-yl)-2-pyridinyl]carbonyl}-5,6,7,8-tetrahydro-9H-pyrido[4', 3':4,5]pyrrolo[2,3-b]pyridin-9-yl)methyl]-3-fluorobenzonitrile, or
    (7) 7-(6-{[9-(4-chloro-2-fluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3':4,5]pyrrolo[2 ,3-b]pyridin-7-yl]carbonyl}-3-pyridinyl)-9-[1-(2,2-dimethylpropyl)-4-piperidinyl]-2-[(3-fluorophenyl)amino]- The compound according to claim 10, which is 6-methyl-7,9-dihydro-8H-purin-8-one, or a salt thereof.
  12. 　一般式（Ｉ－１－１－３）
    （式中、すべての記号は請求項２、７および１０と同じ意味を表わす。）で示される請求項７記載の化合物、またはその塩。     General formula (I-1-1-3)
    (In the formula, all symbols have the same meanings as in claims 2, 7 and 10.) The compound according to claim 7, or a salt thereof.
  13. 　化合物が、（１）１－｛［｛７－（６－｛［９－（４－シアノ－２－フルオロベンジル）－５，６，８，９－テトラヒドロ－７Ｈ－ピリド［４’，３’：４，５］ピロロ［２，３－ｂ］ピリジン－７－イル］カルボニル｝－３－ピリジニル）－９－［１－（２，２－ジメチルプロピル）－４－ピペリジニル］－６－メチル－８－オキソ－８，９－ジヒドロ－７Ｈ－プリン－２－イル｝（シクロへキシル）アミノ］メチル｝シクロブタンカルボン酸である、請求項１２記載の化合物、またはその塩。 The compound is (1) 1-{[{7-(6-{[9-(4-cyano-2-fluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrido[4',3' :4,5]pyrrolo[2,3-b]pyridin-7-yl]carbonyl}-3-pyridinyl)-9-[1-(2,2-dimethylpropyl)-4-piperidinyl]-6-methyl- 13. The compound according to claim 12, which is 8-oxo-8,9-dihydro-7H-purin-2-yl}(cyclohexyl)amino]methyl}cyclobutanecarboxylic acid, or a salt thereof.
  14. 　請求項１記載の一般式（ＩＹ）で示される化合物、またはその塩と薬学的に許容される担体とを含有してなる医薬組成物。 A pharmaceutical composition comprising a compound represented by general formula (IY) according to claim 1 or a salt thereof and a pharmaceutically acceptable carrier.
  15. 　ＤＧＫαおよび／またはＤＧＫζ阻害剤である請求項１４記載の医薬組成物。 The pharmaceutical composition according to claim 14, which is a DGKα and/or DGKζ inhibitor.
  16. 　ＤＧＫαおよび／またはＤＧＫζ関連疾患の進行抑制、再発抑制および／または治療剤である請求項１４または１５記載の医薬組成物。 The pharmaceutical composition according to claim 14 or 15, which is an agent for inhibiting progression, inhibiting recurrence, and/or treating DGKα and/or DGKζ-related diseases.
  17. 　ＤＧＫαおよび／またはＤＧＫζ関連疾患が、癌または感染症である請求項１６記載の医薬組成物。 The pharmaceutical composition according to claim 16, wherein the DGKα and/or DGKζ-related disease is cancer or an infectious disease.
  18. 　癌が、固形癌または血液癌である、請求項１７記載の医薬組成物。 18. The pharmaceutical composition according to claim 17, wherein the cancer is a solid cancer or a blood cancer.
  19. 　固形癌が、悪性黒色腫、非小細胞肺癌、小細胞肺癌、頭頸部癌、腎細胞癌、乳癌、卵巣癌、卵巣明細胞腺癌、鼻咽頭癌、子宮癌、肛門癌、大腸癌、直腸癌、結腸癌、肝細胞癌、食道癌、胃癌、食道胃接合部癌、膵癌、尿路上皮癌、前立腺癌、卵管癌、原発性腹膜癌、悪性胸膜中皮腫、胆嚢癌、胆管癌、胆道癌、皮膚癌、精巣癌（胚細胞腫瘍）、膣癌、外陰部癌、陰茎癌、小腸癌、内分泌系癌、甲状腺癌、副甲状腺癌、副腎癌、脊椎腫瘍、神経芽細胞腫、髄芽腫、眼網膜芽細胞腫、神経内分泌腫瘍、脳腫瘍および扁平上皮癌から選択される１以上の癌である、請求項１８記載の医薬組成物。 Solid cancers include malignant melanoma, non-small cell lung cancer, small cell lung cancer, head and neck cancer, renal cell carcinoma, breast cancer, ovarian cancer, ovarian clear cell adenocarcinoma, nasopharyngeal cancer, uterine cancer, anal cancer, colorectal cancer, and rectal cancer. Cancer, colon cancer, hepatocellular carcinoma, esophageal cancer, gastric cancer, esophagogastric junction cancer, pancreatic cancer, urothelial cancer, prostate cancer, fallopian tube cancer, primary peritoneal cancer, malignant pleural mesothelioma, gallbladder cancer, bile duct cancer , biliary tract cancer, skin cancer, testicular cancer (germ cell tumor), vaginal cancer, vulvar cancer, penile cancer, small intestine cancer, endocrine cancer, thyroid cancer, parathyroid cancer, adrenal cancer, spinal tumor, neuroblastoma, The pharmaceutical composition according to claim 18, which is one or more cancers selected from medulloblastoma, ocular retinoblastoma, neuroendocrine tumor, brain tumor, and squamous cell carcinoma.
  20. 　固形癌が、骨・軟部肉腫またはカポジ肉腫である、請求項１８記載の医薬組成物。 The pharmaceutical composition according to claim 18, wherein the solid cancer is bone/soft tissue sarcoma or Kaposi's sarcoma.
  21. 　血液癌が、多発性骨髄腫、悪性リンパ腫、白血病、骨髄異形成症候群および骨髄増殖症候群から選択される１以上の癌である、請求項１８記載の医薬組成物。 The pharmaceutical composition according to claim 18, wherein the blood cancer is one or more cancers selected from multiple myeloma, malignant lymphoma, leukemia, myelodysplastic syndrome, and myeloproliferative syndrome.
  22. 　請求項１記載の一般式（ＩＹ）で示される化合物、またはその塩を含有する、ＤＧＫαおよび／またはＤＧＫζ関連疾患の進行抑制、再発抑制および／または治療剤。 An agent for inhibiting the progression, inhibiting recurrence, and/or treating DGKα and/or DGKζ-related diseases, which comprises a compound represented by the general formula (IY) according to claim 1, or a salt thereof.
  23. 　請求項１記載の一般式（ＩＹ）で示される化合物、またはその塩の有効量を哺乳動物に投与することを特徴とするＤＧＫαおよび／またはＤＧＫζ関連疾患の進行抑制、再発抑制および／または治療方法。 A method for inhibiting the progression, inhibiting recurrence, and/or treating a DGKα and/or DGKζ-related disease, which comprises administering to a mammal an effective amount of the compound represented by the general formula (IY) according to claim 1, or a salt thereof. .
  24. 　ＤＧＫαおよび／またはＤＧＫζ関連疾患の進行抑制、再発抑制および／または治療に使用される請求項１記載の一般式（ＩＹ）で示される化合物、またはその塩。 The compound represented by general formula (IY) according to claim 1, or a salt thereof, which is used for inhibiting progression, inhibiting recurrence, and/or treating DGKα and/or DGKζ-related diseases.
  25. 　ＤＧＫαおよび／またはＤＧＫζ関連疾患の進行抑制、再発抑制および／または治療剤の製造のための請求項１記載の一般式（ＩＹ）で示される化合物、またはその塩の使用。 Use of the compound represented by general formula (IY) according to claim 1, or a salt thereof, for inhibiting the progression, inhibiting recurrence, and/or producing a therapeutic agent for DGKα and/or DGKζ-related diseases.
PCT/JP2023/032418 2022-09-06 2023-09-05 COMPOUND HAVING INHIBITORY ACTIVITY AGAINST DIACYLGLYCEROL KINASE α AND/OR ζ, AND PHARMACEUTICAL USE THEREOF WO2024053650A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2022-141321 2022-09-06
JP2022141321 2022-09-06

Publications (1)

Publication Number Publication Date
WO2024053650A1 true WO2024053650A1 (en) 2024-03-14

Family

ID=90191235

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2023/032418 WO2024053650A1 (en) 2022-09-06 2023-09-05 COMPOUND HAVING INHIBITORY ACTIVITY AGAINST DIACYLGLYCEROL KINASE α AND/OR ζ, AND PHARMACEUTICAL USE THEREOF

Country Status (1)

Country Link
WO (1) WO2024053650A1 (en)

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012005227A1 (en) * 2010-07-06 2012-01-12 小野薬品工業株式会社 Tetrahydrocarboline derivative
WO2021105117A1 (en) * 2019-11-28 2021-06-03 Bayer Aktiengesellschaft Substituted aminoquinolones as dgkalpha inhibitors for immune activation

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012005227A1 (en) * 2010-07-06 2012-01-12 小野薬品工業株式会社 Tetrahydrocarboline derivative
WO2021105117A1 (en) * 2019-11-28 2021-06-03 Bayer Aktiengesellschaft Substituted aminoquinolones as dgkalpha inhibitors for immune activation

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
HARABUCHI SHOHEI, KHAN OMAR, BASSIRI HAMID, YOSHIDA TAKU, OKADA YOHEI, TAKIZAWA MASAOMI, IKEDA OSAMU, KATADA AKIHIRO, KAMBAYASHI T: "Manipulation of diacylglycerol and ERK-mediated signaling differentially controls CD8+ T cell responses during chronic viral infection", FRONTIERS IN IMMUNOLOGY, FRONTIERS MEDIA, LAUSANNE, CH, vol. 13, Lausanne, CH , XP093147819, ISSN: 1664-3224, DOI: 10.3389/fimmu.2022.1032113 *
SAÏDANI NADIA, BOTTÉ CYRILLE Y., DELIGNY MICHAEL, BONNEAU ANNE-LAURE, READER JANETTE, LASSELIN RONALD, MERER GOULVEN, NIEPCERON AL: "Discovery of Compounds Blocking the Proliferation of Toxoplasma gondii and Plasmodium falciparum in a Chemical Space Based on Piperidinyl-Benzimidazolone Analogs", ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, AMERICAN SOCIETY FOR MICROBIOLOGY, US, vol. 58, no. 5, 1 May 2014 (2014-05-01), US , pages 2586 - 2597, XP093147816, ISSN: 0066-4804, DOI: 10.1128/AAC.01445-13 *

Similar Documents

Publication Publication Date Title
CN112204009B (en) Modulators of integrated stress pathways
JP6994767B2 (en) CXCR4 inhibitor and its use
JP6466456B2 (en) Tricyclic compounds as anticancer agents
US9586967B2 (en) Pyrrolo pyrimidine derivative
JP6666147B2 (en) Cyclic ether pyrazol-4-yl-heterocyclyl-carboxamide compounds and methods of use
BR112021006905A2 (en) compound, salt and solvate thereof and sting agonistic agent, pharmaceutical composition comprising said compound and use thereof to suppress the progression of, suppress the recurrence of and/or treat cancer or infectious disease
JP2023509375A (en) Isoindolinone and indazole compounds for the degradation of EGFR
CA3163107A1 (en) Substituted aminoquinolones as dgkalpha inhibitors for immune activation
EP3312182A1 (en) Brk inhibitory compound
JP2020532542A (en) Cyclic dinucleotide as an anticancer drug
JP7384535B2 (en) Quinazoline compounds and their preparation, use and pharmaceutical compositions
KR20210150491A (en) Phosphatidylinositol 3-kinase inhibitor
KR20150083833A (en) Heteroaromatic compounds as pi3 kinase modulators and methods of use
JP2020536897A (en) Cyclic dinucleotide as an anticancer drug
US20230339902A1 (en) Tricyclic ligands for degradation of ikzf2 or ikzf4
JP2022547777A (en) Hydantoin derivative
JP2021513562A (en) Cyclic dinucleotide as an anticancer drug
JP2023545509A (en) Tricyclic compounds that degrade neosubstrates for medical therapy
JP2024519215A (en) CDK2 degraders and their uses
WO2024039901A2 (en) Cdk2 degraders and uses thereof
WO2024053650A1 (en) COMPOUND HAVING INHIBITORY ACTIVITY AGAINST DIACYLGLYCEROL KINASE α AND/OR ζ, AND PHARMACEUTICAL USE THEREOF
KR20230172548A (en) MEK inhibitors and uses thereof
WO2019049891A1 (en) METHOD FOR TREATING CANCER BY COMBINATION OF Trk INHIBITOR AND KINASE INHIBITOR
RU2779018C1 (en) Benzolactams as protein kinase inhibitors

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 23863188

Country of ref document: EP

Kind code of ref document: A1