WO2020082921A1 - Nitrogen heteroaryl amide derivative, preparation method therefor, and application thereof - Google Patents

Nitrogen heteroaryl amide derivative, preparation method therefor, and application thereof Download PDF

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Publication number
WO2020082921A1
WO2020082921A1 PCT/CN2019/104957 CN2019104957W WO2020082921A1 WO 2020082921 A1 WO2020082921 A1 WO 2020082921A1 CN 2019104957 W CN2019104957 W CN 2019104957W WO 2020082921 A1 WO2020082921 A1 WO 2020082921A1
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group
deuterium
alkyl
cycloalkyl
membered
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PCT/CN2019/104957
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French (fr)
Chinese (zh)
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赵保卫
寻国良
危明松
张鸣鸣
杨舒群
喻红平
陈椎
徐耀昌
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上海和誉生物医药科技有限公司
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Priority to CN201980055929.5A priority Critical patent/CN112601745B/en
Publication of WO2020082921A1 publication Critical patent/WO2020082921A1/en

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    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
    • C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the invention belongs to the field of pharmaceutical synthesis, and in particular relates to a azaarylamide derivative and a preparation method and application thereof.
  • the retinoic acid-related orphan receptor (ROR) family contains three members ROR ⁇ , - ⁇ and - ⁇ .
  • ROR ⁇ is indispensable in the development of the cerebellum, and ROR ⁇ is mainly expressed in the brain and retina, both of which play important functions in the normal development of the retina.
  • ROR ⁇ is divided into two subtypes of ROR ⁇ 1 and ROR ⁇ 2 (ROR ⁇ t) according to different transcriptional shear positions.
  • the former is mainly expressed in liver, skeletal muscle and kidney, while ROR ⁇ t is mainly expressed in immune organs.
  • the mice lacking ROR ⁇ t lack lymph nodes and Peyer's patches and other lymphoid organs.
  • the development and maturation of T cells is also affected. The number of various T cells is lower than that of normal mice.
  • T helper cells play an indispensable and important role.
  • CD4-positive T helper cells can differentiate into a series of regulatory helper cells such as Th1, Th2, Th17 and Treg under the induction of different cytokines in the microenvironment.
  • Th1 and Th2 play an important role in the process of antigen recognition, presentation and activation of T effector cells.
  • Treg is a type of regulatory cell that promotes immune suppression.
  • Th17 is a new type of T helper cell discovered in recent years, characterized by the secretion of interleukin 17 (IL-17) cytokine.
  • Th17 cells were originally thought to play a role in immune function by recruiting neutrophils in the fight against bacterial fungal infections.
  • ROR ⁇ t can directly affect the abundance and activity of Th17 cells by regulating ROR ⁇ t activity through small molecule compounds.
  • the level of cytokines (such as IL-17A) secreted by Th17 cells increases significantly, and the survival and immune activation capabilities of Th17 cells are greatly enhanced.
  • enhanced activation of Th17 cells can reduce the number of immunosuppressive Treg cells and reduce the expression of immunosuppressive receptors (such as PD-1) in tumor-infiltrating lymphocytes.
  • the small molecule ROR ⁇ t agonists that can be taken orally can enhance the ability of the immune system to recognize and kill tumor cells by activating Th17 cells, and may become a new class of anti-PD-1 and PD-L1 antibodies in clinical practice.
  • Tumor small molecule drugs can be taken orally to enhance the ability of the immune system to recognize and kill tumor cells by activating Th17 cells, and may become a new class of anti-PD-1 and PD-L1 antibodies in clinical practice.
  • the object of the present invention is to provide a small molecule agonist of ROR ⁇ t.
  • the first aspect of the present invention provides a compound of formula (I), its stereoisomer, prodrug or pharmaceutically acceptable salt thereof:
  • Ring A is selected from C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 5-10 aryl or 5-10 membered heteroaryl;
  • X 1 , X 2 and X 5 are each independently selected from C (R 8 ) or N;
  • X 3 and X 4 are each independently selected from C or N;
  • Y is selected from C (R 9 ) or N;
  • R 2 is selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl , 3-10 membered heterocyclic group, C 5-10 aryl group, 5-10 membered heteroaryl group, -C 0-8 -S (O) r R 23 , -C 0-8 -OR 24 , -C 0 -8 -C (O) OR 24 , -C 0-8 -C (O) R 25 , -C 0-8 -OC (O) R 25 , -C 0-8 -NR 26 R 27 , -C 0 -8 -C (O) NR 26 R 27 or -C 0-8 -N (R 26 ) -C (O) R 25 , the above groups are optionally further selected by one or more selected from deuterium, halogen, cyano , Nitro,
  • R 3 and R 4 are each independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, 3-10 membered heterocyclic group, C 5-10 aryl group, 5-10 membered heteroaryl group, -C 0-8 -S (O) r R 23 , -C 0- 8- OR 24 , -C 0-8 -C (O) OR 24 , -C 0-8 -C (O) R 25 , -C 0-8 -OC (O) R 25 , -C 0-8 -NR 26 R 27 , -C 0-8 -C (O) NR 26 R 27 or -C 0-8 -N (R 26 ) -C (O) R 25 , or, R 3 and R 4 and the carbon directly connected to it Atoms together form C (O), 3-10 membered
  • R 6 is selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl , 3-10 membered heterocyclic group, C 5-10 aryl group, 5-10 membered heteroaryl group, -C 0-8 -S (O) r R 23 , -C 0-8 -OR 24 , -C 0 -8 -C (O) OR 24 , -C 0-8 -C (O) R 25 , -C 0-8 -OC (O) R 25 , -C 0-8 -NR 26 R 27 , -C 0 -8 -C (O) NR 26 R 27 or -C 0-8 -N (R 26 )-C (O) R 25 , the above groups are optionally further selected by one or more selected from deuterium, halogen, cyano , Nitro, azi
  • Each R 7 is independently selected from hydrogen, deuterium, halogen, cyano, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, 3-10 Heterocyclic group, C 5-10 aryl group, 5-10 membered heteroaryl group, -P (O) (R 28 ) 2 , -SF 5 , -C 0-8 -S (O) r R 23 ,- C 0-8 -OR 24 , -C 0-8 -C (O) OR 24 , -C 0-8 -C (O) R 25 , -C 0-8 -OC (O) R 25 , -C 0 -8 -NR 26 R 27 , -C 0-8 -C (O) NR 26 R 27 or -C 0-8 -N (R 26 ) -C (O) R 25 , the above groups are optionally further Or more selected from deuterium, halogen
  • Each R 8 and R 9 are independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl , C 3-10 cycloalkyl, 3-10 membered heterocyclic group, C 5-10 aryl group, 5-10 membered heteroaryl group, -C 0-8 -S (O) r R 23 , -C 0- 8 -OR 24 , -C 0-8 -C (O) OR 24 , -C 0-8 -C (O) R 25 , -C 0-8 -OC (O) R 25 , -C 0-8- NR 26 R 27 , -C 0-8 -C (O) NR 26 R 27 or -C 0-8 -N (R 26 ) -C (O) R 25 , the above groups are optionally further substituted by one or more Selected from deuterium, halogen, cyan
  • R 10, R 11, R 13 , R 14, R 15, R 16 are each independently selected from hydrogen, deuterium, halo, cyano, nitro, azido, C 1- 10 alkyl group, C 2-10 chain, Alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 5-10 aryl, 5-10 membered heteroaryl, -C 0-8 -S ( O) r R 23 , -C 0-8 -OR 24 , -C 0-8 -C (O) OR 24 , -C 0-8 -C (O) R 25 , -C 0-8 -OC (O ) R 25 , -C 0-8 -NR 26 R 27 , -C 0-8 -C (O) NR 26 R 27 or -C 0-8 -N (R 26 ) -C (O) R 25 , or , R 10 and R 11 , R 13 and R 14
  • R 21 and R 22 are each independently selected from hydrogen, deuterium, C 1-10 alkyl, C 2-10 alkenyl, C 3-10 cycloalkyl, 3-10 membered heterocyclic group, C 5-10 aromatic Group or a 5-10 membered heteroaryl group, R 21 and R 22 together with the nitrogen atom directly connected thereto form a 4-10 membered heterocyclic group;
  • Each R 23 is independently selected from hydrogen, deuterium, hydroxyl, C 1-10 alkyl, C 1-10 alkoxy, C 2-10 alkenyl, C 3-10 cycloalkyl, C 3-10 Cycloalkoxy, 3-10 membered heterocyclyl, 3-10 membered heterocyclyloxy, C 5-10 aryl, C 5-10 aryloxy, 5-10 membered heteroaryl, 5-10 membered hetero Aryloxy or -NR 26 R 27 , the above groups are optionally further selected from one or more selected from deuterium, halogen, hydroxyl, carbonyl, C 1-10 alkyl, C 1-10 alkoxy, C 3-10 cycloalkyl, C 3-10 cycloalkoxy, 3-10 membered heterocyclyl, 3-10 membered heterocyclic group, C 5- 10 aryl group, C 5-10 aryloxy, 5-10 membered heteroaryl Substituted by aryl, 5-10 membered heteroaryloxy or -NR 26 R
  • Each R 24 is independently selected from hydrogen, deuterium, C 1-10 alkyl, C 2-10 alkenyl, C 3-10 cycloalkyl, 3-10 membered heterocyclic group, C 5-10 aryl Or 5-10 membered heteroaryl, the above groups are optionally further selected from one or more selected from deuterium, halogen, hydroxyl, carbonyl, cyano, C 1-10 alkyl, C 1-10 alkoxy, C 3 -10 cycloalkyl, C 3-10 cycloalkoxy, 3-10 membered heterocyclic group, 3-10 membered heterocyclicoxy group, C 5-10 aryl group, C 5-10 aryloxy group, 5-10 Substituted by a heteroaryl group, a 5-10 membered heteroaryloxy group or a substituent of -NR 26 R 27 ;
  • Each R 25 is independently selected from hydrogen, deuterium, hydroxyl, C 1-10 alkyl, C 1-10 alkoxy, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 Cycloalkyl, C 3-10 cycloalkoxy, 3-10 membered heterocyclyl, 3-10 membered heterocyclyloxy, C 5-10 aryl, C 5-10 aryloxy, 5-10 membered hetero Aryl, 5-10 membered heteroaryloxy or -NR 26 R 27 , the above groups are optionally further selected from one or more selected from deuterium, halogen, hydroxyl, cyano, C 1-10 alkyl, C 1- 10 alkoxy, C 3-10 cycloalkyl, C 3-10 cycloalkoxy, 3-10 membered heterocyclyl, 3-10 membered heterocyclyloxy, C 5-10 aryl, C 5-10 Substituted by aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy
  • Each R 26 and R 27 is independently selected from hydrogen, deuterium, hydroxyl, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, 3 -10 membered heterocyclic group, C 5-10 aryl group, 5-10 membered heteroaryl group, methoxy group, sulfonyl group, methanesulfonyl group, isopropylsulfonyl group, cyclopropylsulfonyl group, p-toluenesulfonyl group, amino group , Monoalkylamino, dialkylamino or C 1-10 alkanoyl, the above groups are optionally further selected by one or more selected from deuterium, halogen, hydroxyl, C 1-8 alkyl, C 1-10 alkoxy Group, C 3-10 cycloalkyl, C 3-10 cycloalkoxy, 3-10 membered heterocyclic group, 3-10 membered hetero
  • R 26 and R 27 together with the nitrogen atom to which they are directly connected form a 4-10 membered heterocyclic group, and the above group is optionally further selected from one or more selected from deuterium, halogen, hydroxyl, C 1-10 alkyl, C 1-10 alkoxy, C 3-10 cycloalkyl, C 3-10 cycloalkoxy, 3-10 membered heterocyclyl, 3-10 membered heterocyclyloxy, C 5-10 aryl, C 5-10 aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, amino, monoalkylamino, dialkylamino or C 1-10 alkanoyl substituents;
  • R 28 is each independently selected from C 1-10 alkyl or phenyl, and the above groups are optionally further selected from one or more selected from deuterium, halogen, hydroxyl, cyano, C 1-8 alkyl, C 1-10 Substituted by substituents of alkoxy, C 3-10 cycloalkyl, C 3-10 cycloalkoxy, 3-10 membered heterocyclic group, 3-10 membered heterocyclic oxy group or phenyl group;
  • R 2 is selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 5-8 aryl, 5-8 membered hetero Aryl, -C 0-4 -S (O) r R 23 , -C 0-4 -OR 24 , -C 0-4 -C (O) OR 24 , -C 0-4 -C (O) R 25 , -C 0-4 -OC (O) R 25 , -C 0-4 -NR 26 R 27 , -C 0-4 -C (O) NR 26 R 27 or -C 0-4 -N (R 26 ) -C (O) R 25 , the above groups are optional
  • R 2 is selected from hydrogen, deuterium, fluorine, chlorine, cyano, methyl, ethyl , Isopropyl, vinyl, allyl, ethynyl, cyclopropyl, 3-oxetanyl, 3-azetidinyl, phenyl, pyridyl, diazole, triazole, methyl Sulfonyl, aminosulfonyl, methoxy, methoxyyl, carboxyl, acetyl, acetoxy, amino, dimethylamino, aminoacyl or acetamido, the above groups are optionally further selected by one or more Deuterium, fluorine, chlorine, cyano, methyl, trifluoromethyl, cyclopropyl, phenyl, pyridyl, methanesulfonyl, hydroxy,
  • each of R 8 and R 9 in the compound of formula (I), its stereoisomer, prodrug or pharmaceutically acceptable salt thereof is independently selected from hydrogen, deuterium, halogen, cyano, Nitro, azido, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 5-8 Aryl, 5-8 membered heteroaryl, -C 0-4 -S (O) r R 23 , -C 0-4 -OR 24 , -C 0- 4 -C (O) OR 24 , -C 0 -4 -C (O) R 25 , -C 0-4 -OC (O) R 25 , -C 0-4 -NR 26 R 27 , -C 0-4 -C (O) NR 26 R 27 or- C 0-4 -N (R 26 ) -C (O) R 25 , the above
  • each of R 8 and R 9 in the compound of formula (I), its stereoisomer, prodrug or pharmaceutically acceptable salt thereof is independently selected from hydrogen, deuterium, fluorine, chlorine, Cyano, methyl, ethyl, isopropyl, vinyl, allyl, ethynyl, cyclopropyl, 3-oxetanyl, 3-azetidinyl, phenyl, pyridyl, di Azole, triazole, mesyl, aminosulfonyl, hydroxy, methoxy, methoxy, carboxy, acetyl, acetoxy, amino, dimethylamino, aminoacyl or acetamido, the above groups
  • R 3 and R 4 are each independently selected from hydrogen, deuterium, halogen, cyano, nitro , Azido, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic group, C 5-8 aryl , 5-8 membered heteroaryl, -C 0-4 -S (O) r R 23 , -C 0-4 -OR 24 , -C 0- 4 -C (O) OR 24 , -C 0-4 -C (O) R 25 , -C 0-4 -OC (O) R 25 , -C 0-4 -NR 26 R 27 , -C 0-4 -C (O) NR 26 R 27 or -C 0 -4 -N (R 26 ) -C (O)
  • R 3 and R 4 are each independently selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, C 3-6 cycloalkyl, 4-6 membered heterocyclyl, phenyl, pyridyl, diazole, triazole, methanesulfonyl, aminosulfonyl, hydroxyl, methoxy, Methoxy, ethoxy, carboxy, acetyl, acetoxy, amino, dimethylamino, aminoacyl or acetylamino, or R 3 and R 4 together with the carbon atom to which they are directly attached form C (O) , 3-6 membered cycloalkyl, 3-6 membered heterocyclic group, the above groups are optionally further selected from one or more selected from deuterium, fluorine, chlorine, cyano, methyl, trifluoromethyl,
  • R 1 is selected from C 1-4 alkyl, C 3-6 cycloalkyl, 3 -6 membered heterocyclic group, phenyl, pyridyl, diazole, triazole, amino or dimethylamino, the above groups are optionally further selected by one or more groups A plurality of substituents selected from deuterium, fluorine, chlorine, cyano, methyl, trifluoromethyl, cyclopropyl, phenyl, pyridyl, mesyl, hydroxy, methoxy, carboxy, or amino are substituted.
  • R 6 is selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, phenyl, 5-8 membered heteroaryl, -C 0-4 -S ( O) r R 23 , -C 0-4 -OR 24 , -C 0-4 -C (O) OR 24 , -C 0-4 -C (O) R 25 , -C 0-4 -OC (O ) R 25 , -C 0-4 -NR 26 R 27 , -C 0-4 -C (O) NR 26 R 27 or -C 0-4 -N (R 26 ) -C (O) R 25 , above
  • R 6 is selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alky
  • R 6 is selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, -OR 24 , -C ( O) OR 24 , -C (O) R 25 or -NR 26 R 27 , the above groups are optionally further selected by one or more selected from deuterium, fluorine, chlorine, cyano, methyl, ethyl, isopropyl , Vinyl, allyl, ethynyl, trifluoromethyl, difluoromethyl, cyclopropyl, cyclobutyl, 3-oxetanyl, 3-azetidinyl, piperidinyl, piper Azinyl,
  • each R 7 in the compound of formula (I), its stereoisomer, prodrug or pharmaceutically acceptable salt thereof is independently selected from hydrogen, deuterium, fluorine, chlorine, cyano, C 1- 4 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 5-8 aryl, 5-8 membered heteroaryl, -P (O) (R 28 ) 2 , -SF 5 , -S (O) r R 23 , -C 0-4 -OR 24 , -C 0-4 -C (O) OR 24 , -C 0-4 -C (O) R 25 , -C 0-4- OC (O) R 25 , -C 0-4 -NR 26 R 27 , -C 0-4 -C (O) NR 26 R 27 or -C 0-4 -N (R 26 ) -C (O) R 25 , the above group is optionally further selected from one or more
  • each R 7 in the compound of formula (I), its stereoisomer, prodrug or pharmaceutically acceptable salt thereof is independently selected from hydrogen, deuterium, halogen, cyano, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 5-8 aryl, 5-8 membered heteroaryl, -P (O) (CH 3 ) 2 , -P (O) H 2 , -SF 5 , sulfonyl, methanesulfonyl, isopropylsulfonyl, aminosulfonyl, -OR 24 , -C (O) R 25 , -C (O) OH, -C (O) NR 26 R 27 , amino or dimethylamino, the above groups are optionally further selected by one or more selected from deuterium, fluorine, chlorine, cyano, methyl
  • R 10 , R 11 , R 13 , R 14 , R 15 , R 16 are each independently selected from hydrogen, deuterium, fluorine, chlorine, C 1-4 alkyl, C 3-8 cycloalkyl, 3-8 membered hetero Cyclic group, C 5-8 aryl group, 5-8 membered heteroaryl group, -C 0-4 -SR 23 , -C 0-4 -OR 24 or -NH 2 , or, R 10 and R 11 , R 13 Together with R 14 , R 15 and R 16 and the carbon atom to which they are directly connected, each independently forms C (O), a 3-8 membered cycloalkyl group, a 3-8 membered heterocyclic group, and the above groups are optionally further or more substituents selected from deuterium, fluoro, chloro, cyano, C 1-4 alkyl, halo-substituted C 1- 4 alkyl group, C 3-8 cycloalkyl, 3-8 membered heterocycly
  • R 17 and R 18 are each independently selected from hydrogen, deuterium, fluorine, cyano, methyl, trifluoromethyl, trideuteromethyl, cyclopropylmethyl or ethyl;
  • R 23 , R 24 , R 26 and R 27 are as described for the compound of formula (I).
  • the aforementioned compound of formula (I), its stereoisomer, prodrug or pharmaceutically acceptable salt thereof has the structure of the compound of formula (II) as follows:
  • X 1 and X 2 are each independently selected from C (R 8 ) or N;
  • Y is selected from CH or N;
  • R 1 is selected from C 1-4 alkyl, C 3-6 cycloalkyl, phenyl, amino or dimethylamino, the above groups are optionally further substituted by one or more Or more substituents selected from deuterium, fluorine, chlorine, cyano, methyl, trifluoromethyl, cyclopropyl, phenyl, hydroxyl, methoxy, carboxyl or amino;
  • Each R 7 is independently selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, phenyl, -P (O) (CH 3 ) 2 , -P (O) H 2 , -SF 5 , sulfonyl, methanesulfonyl, isopropylsulfonyl, aminosulfonyl, methoxy, ethoxy, isopropoxy, -C (O) R 25 , -C (O) OH, -C (O) NR 26 R 27 , amino or dimethylamino, the above groups are optionally further selected by one or more selected from deuterium, fluorine, chlorine, cyano, methyl , Ethyl, isopropyl, trifluoromethyl, difluoromethyl, cyclopropyl, cyclobutyl, 3-oxetanyl, 3-a
  • Each R 8 is independently selected from hydrogen, deuterium, fluorine, chlorine, cyano, methyl, ethyl, isopropyl, cyclopropyl, 3-oxetanyl, 3-azetidinyl, Hydroxy, methoxy, ethoxy, isopropoxy, carboxy, amino or dimethylamino, the above groups are optionally further selected by one or more selected from deuterium, fluorine, chlorine, cyano, methyl, tri Substituted by substituents of fluoromethyl, cyclopropyl, phenyl, pyridyl, hydroxy, methoxy, carboxy, or amino;
  • Ring A, R 23 , R 24 , R 25 , R 26 , R 27 , and m2 are as described for the compound of formula (I).
  • the aforementioned compound of formula (I), its stereoisomer, prodrug or pharmaceutically acceptable salt thereof has the structure of the compound of formula (III) as follows:
  • R 10 and R 11 are each independently selected from hydrogen, deuterium, fluorine, chlorine, methyl, trifluoromethyl, trideuteromethyl, cyclopropylmethyl, methoxymethyl, aminomethyl, benzyl, ethyl , Isopropyl, cyclopropyl, 3-oxetanyl, hydroxy, methoxy, trifluoromethoxy, difluoromethoxy, trideuteromethoxy, dideuteromethoxy or -NH 2 Or, R 10 and R 11 together with the carbon atom directly connected to them form C (O), cyclopropyl, cyclobutyl, 3-oxetanyl;
  • Rings A, R 1 , R 6 , R 7 , R 8 and m2 are as described above.
  • the aforementioned compound of formula (I), its stereoisomer, prodrug or pharmaceutically acceptable salt thereof has the structure selected from the compound of formula (IV) as follows:
  • R 1 is independently selected from methyl, ethyl, isopropyl, cyclopropyl, trifluoromethyl, trideuteromethyl, cyclopropylmethyl or amino;
  • R 3 is each independently selected from hydrogen, deuterium, fluorine, chlorine, methyl, ethyl, isopropyl, cyclopropyl, 3-oxetanyl, 3-azetidinyl, hydroxy, methoxy , Ethoxyl, carboxyl or amino, the above groups are optionally further selected by one or more selected from deuterium, fluorine, chlorine, methyl, trifluoromethyl, cyclopropyl, hydroxyl, methoxy, carboxyl or amino Substituted by a substituent;
  • R 6 is each independently selected from hydrogen, deuterium, fluorine, chlorine, cyano, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, 3-oxetanyl, 3- Azetidinyl, methoxy, ethoxy, carboxyl, methoxycarbonyl, ethoxycarbonyl, amino or dimethylamino, the above groups are optionally further selected by one or more selected from deuterium, fluorine, chlorine, cyanide Group, methyl, ethyl, isopropyl, vinyl, allyl, ethynyl, trifluoromethyl, difluoromethyl, cyclopropyl, cyclobutyl, hydroxy, methoxy, trifluoromethoxy Substituted by the substituent of the group, trideuteromethoxy, carboxyl or amino;
  • Each R 8 is independently selected from hydrogen, deuterium, fluorine, chlorine, cyano, methyl, ethyl, isopropyl, cyclopropyl, 3-oxetanyl, 3-azetidinyl, Hydroxy, methoxy, ethoxy, isopropoxy, carboxy, amino or dimethylamino, the above groups are optionally further selected by one or more selected from deuterium, fluorine, chlorine, cyano, methyl, tri Substituted by substituents of fluoromethyl, cyclopropyl, hydroxy, methoxy, carboxy, or amino;
  • R 10 and R 11 are each independently selected from hydrogen, deuterium, fluorine, chlorine, methyl, trifluoromethyl, trideuteromethyl, cyclopropylmethyl, methoxymethyl, aminomethyl, benzyl, ethyl , Isopropyl, cyclopropyl, 3-oxetanyl, hydroxy, methoxy, trifluoromethoxy, difluoromethoxy, trideuteromethoxy, dideuteromethoxy or -NH 2 Or, R 10 and R 11 together with the carbon atom directly connected to them form C (O), cyclopropyl, cyclobutyl, 3-oxetanyl;
  • Each R 25 is independently selected from hydrogen, deuterium, fluorine, chlorine, hydroxyl, methyl, ethyl or isopropyl;
  • Each R 26 , R 27 is independently selected from hydrogen, deuterium, hydroxyl, methyl, ethyl, isopropyl, cyclopropyl, phenyl, methoxy, sulfonyl, methanesulfonyl, amino, monoalkane Amino group, dialkylamino group or C 1-10 alkanoyl group, the above groups are optionally further selected from one or more selected from deuterium, halogen, hydroxyl, methyl, ethyl, isopropyl, cyclopropyl, phenyl , Methoxy, amino, monoalkylamino, dialkylamino or C 1-10 alkanoyl substituents;
  • Rings A and m2 are as described above.
  • R 10 and R 11 are each independently selected from hydrogen, deuterium, fluorine, chlorine, methyl, trifluoromethyl, trideuteromethyl, cyclopropylmethyl, methoxymethyl, aminomethyl, benzyl, ethyl , Isopropyl, cyclopropyl, 3-oxetanyl, hydroxy, methoxy, trifluoromethoxy, difluoromethoxy, trideuteromethoxy, dideuteromethoxy or -NH 2 Or, R 10 and R 11 together with the carbon atom directly connected to them form C (O), cyclopropyl, cyclobutyl, 3-oxetanyl;
  • Each R 25 is independently selected from hydrogen, deuterium, fluorine, chlorine, hydroxyl, methyl, ethyl or isopropyl;
  • Each R 26 , R 27 is independently selected from hydrogen, deuterium, hydroxyl, methyl, ethyl, isopropyl, cyclopropyl, phenyl, methoxy, sulfonyl, methanesulfonyl, amino, monoalkane Amino group, dialkylamino group or C 1-10 alkanoyl group, the above groups are optionally further selected from one or more selected from deuterium, halogen, hydroxyl, methyl, ethyl, isopropyl, cyclopropyl, phenyl , Methoxy, amino, monoalkylamino, dialkylamino or C 1-10 alkanoyl substituents.
  • R 10 and R 11 are each independently selected from hydrogen, deuterium, fluorine, chlorine, methyl, trifluoromethyl, trideuteromethyl, cyclopropylmethyl, methoxymethyl, aminomethyl, benzyl, ethyl , Isopropyl, cyclopropyl, 3-oxetanyl, hydroxy, methoxy, trifluoromethoxy, difluoromethoxy, trideuteromethoxy, dideuteromethoxy or -NH 2 Or, R 10 and R 11 together with the carbon atom directly connected to them form C (O), cyclopropyl, cyclobutyl, 3-oxetanyl;
  • Each R 25 is independently selected from hydrogen, deuterium, fluorine, chlorine, hydroxyl, methyl, ethyl or isopropyl;
  • Each R 26 , R 27 is independently selected from hydrogen, deuterium, hydroxyl, methyl, ethyl, isopropyl, cyclopropyl, phenyl, methoxy, sulfonyl, methanesulfonyl, amino, monoalkane Amino group, dialkylamino group or C 1-10 alkanoyl group, the above groups are optionally further selected from one or more selected from deuterium, halogen, hydroxyl, methyl, ethyl, isopropyl, cyclopropyl, phenyl , Methoxy, amino, monoalkylamino, dialkylamino or C 1-10 alkanoyl substituents.
  • the aforementioned compound of formula (I), its stereoisomers, prodrugs or pharmaceutically acceptable salts thereof include but are not limited to the following compounds:
  • the second aspect of the present invention provides a method for preparing the aforementioned compound of formula (I), its stereoisomer, prodrug or pharmaceutically acceptable salt thereof, comprising the following steps: the compound of formula Ia and the compound of formula Ib or its acid salt Coupling gives the compound of formula I:
  • a third aspect of the present invention provides a pharmaceutical composition, which comprises the aforementioned compound of formula (I), its stereoisomer, prodrug or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • the fourth aspect of the present invention provides a compound of the aforementioned formula (I), its stereoisomers, prodrugs or pharmaceutically acceptable salts thereof, or the aforementioned pharmaceutical composition in the preparation for the treatment of one or more tumors, cancers, and metabolites The application of drugs in diseases, autoimmune diseases or disorders.
  • the fifth aspect of the present invention provides a compound of the aforementioned formula (I), its stereoisomer, prodrug or pharmaceutically acceptable salt thereof, or the aforementioned pharmaceutical composition, which is used for the treatment of one or more tumors, cancers, Drugs for metabolic diseases, autoimmune diseases or disorders.
  • the compound of the present invention has a strong inhibitory effect on ROR ⁇ t kinase activity, can be widely used in the preparation of therapeutic drugs, and is expected to be developed into a new generation of ROR ⁇ t agonist drugs. On this basis, the present invention has been completed.
  • Alkyl refers to a straight-chain or branched-chain saturated aliphatic hydrocarbon group.
  • C 1-8 alkyl refers to a straight-chain alkyl group containing 1 to 8 carbon atoms and a branched-chain alkyl group, including but Not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2- Dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl Group, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethyl Butyl, 2-eth
  • the alkyl group may be optionally substituted or unsubstituted.
  • Cycloalkyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, for example, "C 3-10 cycloalkyl” refers to a cycloalkyl group containing 3 to 10 carbon atoms, divided into monocyclic Cycloalkyl, polycyclic cycloalkyl, where:
  • Monocyclic cycloalkyls include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, Cyclooctyl, etc.
  • Polycyclic cycloalkyls include spiro, fused and bridged cycloalkyls.
  • “Spirocycloalkyl” refers to a polycyclic group that shares a carbon atom (called a spiro atom) between single rings. These may contain one or more (preferably 1, 2 or 3) double bonds, but no ring has Completely conjugated ⁇ electron system. According to the number of spiro atoms shared between rings, spirocycloalkyl groups are classified into monospirocycloalkyl groups, dispirocycloalkyl groups or polyspirocycloalkyl groups. Spirocycloalkyl groups include but are not limited to:
  • “Fused cycloalkyl” refers to an all-carbon polycyclic group in which each ring in the system shares a pair of adjacent carbon atoms with other rings in the system, where one or more rings (preferably 1 or 2) may contain one Or multiple double bonds (preferably 1, 2 or 3), but none of the rings has a completely conjugated ⁇ electron system. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl groups. Condensed cycloalkyl groups include but are not limited to:
  • Bridged cycloalkyl means an all-carbon polycyclic group in which any two rings share two carbon atoms that are not directly connected. These may contain one or more double bonds (preferably 1, 2 or 3), but none of them The ring has a completely conjugated ⁇ electron system. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl groups. Bridged cycloalkyl groups include but are not limited to:
  • the cycloalkyl ring can be fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring connected to the parent structure is a cycloalkyl group, including but not limited to indanyl, tetrahydronaphthyl , Benzocycloheptyl and so on.
  • the cycloalkyl group may be optionally substituted or unsubstituted.
  • Heterocyclyl means a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent in which one or more (preferably 1, 2, 3 or 4) ring atoms are selected from nitrogen, oxygen or S (O) r (where r is an integer of 0, 1, 2), but does not include the ring portion of -OO-, -OS-, or -SS-, and the remaining ring atoms are carbon.
  • ring r is an integer of 0, 1, 2
  • Monocyclic heterocyclic groups include but are not limited to pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl and the like.
  • Polycyclic heterocyclic groups include spiro, fused and bridged heterocyclic groups.
  • “Spiroheterocyclyl” refers to a polycyclic heterocyclic group that shares an atom (called a spiro atom) between single rings, wherein one or more ring atoms are selected from nitrogen, oxygen, or S (O) r (where r is an integer) 0, 1, 2) heteroatoms, the remaining ring atoms are carbon. These may contain one or more double bonds (preferably 1, 2, 3 or 4), but none of the rings has a completely conjugated ⁇ electron system.
  • Spiro heterocyclic groups are classified into mono-spiro heterocyclic groups, di-spiro heterocyclic groups, or poly-spiro heterocyclic groups according to the number of spiro atoms shared between rings.
  • Spiroheterocyclic groups include but are not limited to:
  • “Fused heterocyclic group” refers to a polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with other rings in the system.
  • One or more rings may contain one or more (Preferably 1, 2 or 3) double bonds, but none of the rings has a fully conjugated ⁇ -electron system, wherein one or more (preferably 1, 2, 3 or 4) ring atoms are selected from nitrogen, oxygen or S (O) r (where r is an integer of 0, 1, 2), and the remaining ring atoms are carbon.
  • the fused heterocyclic groups include but are not limited to:
  • Bridge heterocyclic group means a polycyclic heterocyclic group in which any two rings share two atoms that are not directly connected, these may contain one or more (preferably 1, 2 or 3) double bonds, but no one ring ⁇ electron system with complete conjugation, where one or more ring atoms (preferably 1, 2, 3 or 4) are selected from nitrogen, oxygen or S (O) r (where r is an integer of 0, 1, 2) Heteroatoms, the remaining ring atoms are carbon. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups.
  • the bridged heterocyclic groups include but are not limited to:
  • the heterocyclic ring may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring connected to the parent structure is a heterocyclic group, including but not limited to:
  • the heterocyclic group may be optionally substituted or unsubstituted.
  • Aryl refers to an all-carbon monocyclic or fused polycyclic (that is, a ring sharing adjacent pairs of carbon atoms) group, a polycyclic ring having a conjugated ⁇ -electron system (that is, a ring with adjacent pairs of carbon atoms) ) Group, for example, "C 5-10 aryl” refers to an all-carbon aryl group containing 5-10 carbons, and “5-10 membered aryl” refers to an all-carbon aryl group containing 5-10 carbons, including but Not limited to phenyl and naphthyl.
  • the aryl ring may be fused to a heteroaryl, heterocyclic or cycloalkyl ring, wherein the ring connected to the parent structure is an aryl ring, including but not limited to:
  • the aryl group may be substituted or unsubstituted.
  • Heteroaryl refers to a heteroaromatic system containing 1 to 4 heteroatoms, including heteroatoms of nitrogen, oxygen, and S (O) r (where r is an integer of 0, 1, 2), for example, 5-8 membered heteroaryl refers to heteroaromatic systems containing 5-8 ring atoms, 5-10 membered heteroaryl refers to heteroaromatic systems containing 5-10 ring atoms, including but not limited to furyl, thiophene Group, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, etc.
  • the heteroaryl ring may be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring, including but not limited to:
  • the heteroaryl group may be optionally substituted or unsubstituted.
  • Alkenyl refers to at least two carbon atoms and at least one carbon - carbon double bond as defined above consisting of an alkyl group, e.g., C 2- 8 alkenyl group means a straight chain comprising 2-8 carbon atoms or a branched Alkenyl. Including but not limited to vinyl, 1-propenyl, 2-propenyl, 1-, 2- or 3-butenyl and the like.
  • the alkenyl group may be substituted or unsubstituted.
  • Alkynyl refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon triple bond, for example, C 2-8 alkynyl refers to a straight or branched chain containing 2-8 carbons Alkynyl. Including but not limited to ethynyl, 1-propynyl, 2-propynyl, 1-, 2- or 3-butynyl and the like.
  • the alkynyl group may be substituted or unsubstituted.
  • Alkoxy refers to -O- (alkyl), where alkyl is as defined above, for example, “C 1-8 alkoxy” refers to alkyloxy containing 1-8 carbons, including but not Limited to methoxy, ethoxy, propoxy, butoxy, etc.
  • the alkoxy group may be optionally substituted or unsubstituted.
  • Cycloalkoxy refers to -O- (unsubstituted cycloalkyl), where cycloalkyl is as defined above, for example, “C 3-10 cycloalkoxy” refers to those containing 3-10 carbons Cycloalkyloxy, including but not limited to cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, etc.
  • the cycloalkoxy group may be optionally substituted or unsubstituted.
  • 3-10 membered heterocyclic oxy means and -O- (unsubstituted 3-10 membered heterocyclyl), wherein the definition of 3-10 membered heterocyclyl is as described above, 3-10 membered heterocyclyloxy It may be optionally substituted or unsubstituted.
  • 5-10 membered heteroaryloxy refers to -O- (unsubstituted 5-10 membered heteroaryl), where 5-10 membered heteroaryl is as defined above, 5-10 membered heteroaryloxy It may be optionally substituted or unsubstituted.
  • C 1-8 alkanoyl refers to the monovalent radical remaining after removing the hydroxyl group of the C 1-8 alkyl acid, and is usually also expressed as "C 0-7 -C (O)-", for example, “C 1 -C (O)-"means acetyl;” C 2 -C (O)-"means propionyl;” C 3 -C (O)-"means butyryl or isobutyryl.
  • -C 0-8 -OR 24 means that the oxygen atom in -OR 24 is connected to a C 0-8 alkyl group, where C 0 alkyl refers to a bond, and C 1-8 alkyl is as defined above.
  • -C 0-8 -C (O) R 25 means that the carbonyl group in -C (O) R 25 is attached to C 0-8 alkyl, where C 0 alkyl refers to a bond, and C 1-8 alkyl Is defined as above.
  • Halo-substituted C 1-8 alkyl refers to 1-8 carbon alkyl groups on the alkyl optionally substituted by fluorine, chlorine, bromine, and iodine atoms, including but not limited to difluoromethyl, dialkyl Chloromethyl, dibromomethyl, trifluoromethyl, trichloromethyl, tribromomethyl, etc.
  • the hydrogen on the "halogen substituted C 1-8 alkoxy" alkyl group is optionally substituted with 1-8 carbon alkoxy groups substituted by fluorine, chlorine, bromine, or iodine atoms. Including but not limited to difluoromethoxy, dichloromethoxy, dibromomethoxy, trifluoromethoxy, trichloromethoxy, tribromomethoxy, etc.
  • Halogen means fluorine, chlorine, bromine or iodine.
  • DCM dichloromethane.
  • DMF means N, N-dimethylformamide.
  • THF means tetrahydrofuran.
  • PE means petroleum ether.
  • EA / EtOAc means ethyl acetate.
  • DMSO means dimethyl Sulfoxide.
  • MeCN means acetonitrile.
  • DME means dimethyl ether.
  • DIEA means N, N-diisopropylethylamine.
  • KAc means potassium acetate.
  • K 3 PO 4 is Refers to potassium phosphate.
  • NMP refers to N-methylpyrrolidone.
  • M-CPBA refers to m-chloroperoxybenzoic acid.
  • Pd / C refers to palladium carbon.
  • HATU refers to 2- (7-oxidation Benzotriazole) -N, N, N ', N'-tetramethylurea hexafluorophosphate.
  • Pd (dppf) Cl 2 means [1,1'-bis (diphenylphosphine) di Ferrocene] Palladium dichloride.
  • DIBAL-H refers to diisobutylaluminum hydride.
  • LiBH (i-Bu) 3 refers to lithium triisobutylborohydride.
  • X-phos means 2-dicyclohexylphosphonium-2 ', 4 ', 6'-triisopropylbiphenyl.
  • heterocyclic group optionally substituted with an alkyl group means that an alkyl group may but need not be present, and the description includes the case where the heterocyclic group is substituted with an alkyl group and the case where the heterocyclic group is not substituted with an alkyl group .
  • Substituted means that one or more (preferably 1, 2, 3, or 4) hydrogen atoms in the group are substituted with a corresponding number of substituents independently of each other. It goes without saying that the substituents are only at their possible chemical positions, and those skilled in the art can determine (through experiment or theory) possible or impossible substitutions without undue effort.
  • an amino group or hydroxyl group having free hydrogen may be unstable when combined with a carbon atom having an unsaturated bond (such as an olefin).
  • “Pharmaceutical composition” means a mixture containing one or more compounds described herein or a physiological / pharmaceutically acceptable salt or prodrug thereof with other chemical components, and other components such as physiological / pharmaceutically acceptable carriers And excipients.
  • the purpose of the pharmaceutical composition is to promote the administration to the living body, facilitate the absorption of the active ingredient and thus exert the biological activity.
  • the structure of the compound of the present invention is determined by nuclear magnetic resonance (NMR) or / and liquid chromatography-mass spectrometry (LC-MS). NMR chemical shifts ( ⁇ ) are given in parts per million (ppm). The measurement of NMR was performed by Bruker AVANCE-400 / 500 NMR instrument. The solvents were deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated methanol (CD 3 OD) and deuterated chloroform (CDCl 3 ), internal standard. It is tetramethylsilane (TMS).
  • DMSO-d 6 deuterated dimethyl sulfoxide
  • CD 3 OD deuterated methanol
  • CDCl 3 deuterated chloroform
  • TMS tetramethylsilane
  • Liquid chromatography-mass spectrometry LC-MS was measured with an Agilent 6120 mass spectrometer. HPLC was measured using Agilent 1200DAD high-pressure liquid chromatograph (Sunfire C18 150 ⁇ 4.6mm chromatographic column) and Waters 2695-2996 high-pressure liquid chromatograph (Gimini C18 150 ⁇ 4.6mm chromatographic column).
  • the thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate.
  • the specifications adopted by TLC are 0.15mm ⁇ 0.20mm, and the specifications adopted by thin layer chromatography separation and purification products are 0.4mm ⁇ 0.5mm.
  • Column chromatography generally uses Yantai Yellow Sea silica gel 200-300 mesh silica gel as a carrier.
  • the starting materials in the examples of the present invention are known and can be purchased on the market, or can be synthesized using or following methods known in the art.
  • Step 1 Synthesis of ethyl 3-bromo-2-carbonylvalerate
  • Step 2 Synthesis of ethyl 7-bromo-3-ethylimidazo [1,2-a] pyridine-2-carboxylate
  • Step 3 Synthesis of (7-bromo-3-ethylimidazo [1,2-a] pyridin-2-yl) methanol
  • Step 4 Synthesis of 7-bromo-3-ethylimidazo [1,2-a] pyridine-2-carbaldehyde
  • Step 5 Synthesis of 3-ethyl-2-formylimidazo [1,2-a] pyridine-7-carboxylic acid methyl ester
  • Step 2 Synthesis of 2-((tert-butyldimethylsilyl) oxo) acetaldehyde
  • Oxalyl chloride (3.45g, 27.4mmol) was dissolved in anhydrous dichloromethane (100mL), the solution was cooled to -78 ° C, DMSO (4.23g, 54.7mmol) was slowly added, and the reaction solution was stirred at -78 ° C for 30 minutes After that, a solution of 2-((tert-butyldimethylsilyl) oxo) ethanol (4.02g, 22.8mmol) in anhydrous dichloromethane (50mL) was slowly added dropwise, and the reaction solution was stirred at -78 ° C for 1 After 1 hour, triethylamine (11.5g, 114.0mmol) was slowly added dropwise.
  • reaction solution was stirred at -78 ° C for 1 hour.
  • the resulting reaction solution was dichloromethane (50mL) ) Extraction, the organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated to give crude 2-((tert-butyldimethylsilyl) oxo) acetaldehyde (3.95 g, 95%).
  • Step 3 Synthesis of (R, E) -N- (2-((tert-butyldimethylsilyl) oxo) ethylene) -2-methylpropane-2-sulfinamide
  • Step 4 (R) -N-((R) -2-((tert-butyldimethylsilyl) oxo) -1- (4- (ethylthio) phenyl) ethyl) Synthesis of -2-methylpropane-2-sulfinamide
  • reaction solution was stirred at -78 ° C for 2 hours. LCMS showed that the reaction was complete.
  • the reaction solution was quenched with saturated ammonium chloride solution (50 mL). The mixture was concentrated to remove tetrahydrofuran, the remaining aqueous solution was extracted with dichloromethane (50 mL), the organic phase was dried and filtered, and the filtrate was concentrated.
  • Step 5 Synthesis of (R) -2-amino-2- (4- (ethylthio) phenyl) ethanol
  • Step 6 Synthesis of (R) -2-amino-2- (4- (ethylsulfonyl) phenyl) ethanol
  • Step 1 Synthesis of 4-ethylsulfonyl benzaldehyde
  • Step 3 Synthesis of 2-amino-2- (4-ethylsulfonylphenyl) ethanol
  • the mixed solution was extracted with ethyl acetate (200 mL), the organic phase was washed with H 2 O (100 mL) and discarded, and the aqueous phases were combined, and the pH was adjusted continuously to 9-10.
  • Step 4 Synthesis of (R) -2-amino-2- (4-ethylsulfonylphenyl) ethanol and (S) -2-amino-2- (4-ethylsulfonylphenyl) ethanol
  • the racemic mixture (15.0g, 65.2mmol) was resolved by chiral column to obtain:
  • Step 1 Synthesis of 1-bromo-4- (ethylsulfonyl) benzene
  • Step 3 Synthesis of (4- (ethylsulfonyl) phenyl) methylamine
  • Step 3 Synthesis of (5- (ethylsulfonyl) -pyridin-2-yl) methylamine hydrochloride
  • Step 1 Synthesis of methyl 3-ethyl-2- (hydroxy (2- (trifluoromethyl) phenyl) methyl) imidazo [1,2-a] pyridine-7-carboxylate
  • Step 2 Synthesis of 3-ethyl-2- (hydroxy (2- (trifluoromethyl) phenyl) methyl) imidazo [1,2-a] pyridine-7-carboxylic acid
  • Step 2 Synthesis of 3- (difluoromethoxy) -5-fluoro-N-methoxy-N-methylbenzamide
  • Step 3 Synthesis of 1- (3- (difluoromethoxy) -5-fluorophenyl) butane-1-one
  • Step 4 Synthesis of 2-bromo-1- (3- (difluoromethoxy) -5-fluorophenyl) butane-1-one
  • Step 5 Synthesis of 2- (3- (difluoromethoxy) -5-fluorophenyl) -3-ethylimidazo [1,2-a] pyridine-7-carboxylic acid methyl ester
  • Step 6 Synthesis of 2- (3- (difluoromethoxy) -5-fluorophenyl) -3-ethylimidazo [1,2-a] pyridine-7-carboxylic acid
  • Step 1 Synthesis of methyl 3-ethyl-2-((2- (trifluoromethyl) piperidin-1-yl) methyl) imidazo [1,2-a] pyridine-7-carboxylate
  • Step 2 Synthesis of 3-ethyl-2-((2- (trifluoromethyl) piperidin-1-yl) methyl) imidazo [1,2-a] pyridine-7-carboxylic acid
  • Step 1 Synthesis of 7-bromo-3-ethylimidazo [1,2-a] pyridine-2-carboxylic acid
  • Step 2 Synthesis of (7-bromo-3-ethylimidazo [1,2-a] pyridin-2-yl) (2- (trifluoromethyl) piperidin-1-yl) methanone
  • Step 3 Synthesis of 3-ethyl-2- (2- (trifluoromethyl) piperidine-1-carbonyl) imidazo [1,2-a] pyridine-7-carbonitrile
  • Step 4 Synthesis of 3-ethyl-2- (2- (trifluoromethyl) piperidine-1-carbonyl) imidazo [1,2-a] pyridine-7-carboxylic acid
  • Step 1 Synthesis of N '-((7-bromo-3-ethylimidazo [1,2-a] pyridin-2-yl) methylene) benzenesulfonyl hydrazide
  • Step 2 Synthesis of 7-bromo-2- (4-chloro-2- (trifluoromethyl) benzyl) -3-ethylimidazo [1,2-a] pyridine
  • Step 3 Synthesis of 2- (4-chloro-2- (trifluoromethyl) benzyl) -3-ethylimidazo [1,2-a] pyridine-7-carboxylic acid methyl ester
  • Step 4 Synthesis of 2- (4-chloro-2- (trifluoromethyl) benzyl) -3-ethylimidazo [1,2-a] pyridine-7-carboxylic acid
  • Step 1 Synthesis of methyl 3-ethyl-2- (hydroxymethyl) imidazo [1,2-a] pyridine-7-carboxylate
  • Step 2 Synthesis of methyl 3-ethyl-2-((2- (trifluoromethyl) phenoxy) methyl) imidazo [1,2-a] pyridine-7-carboxylate
  • Step 3 Synthesis of 3-ethyl-2-((2- (trifluoromethyl) phenoxy) methyl) imidazo [1,2-a] pyridine-7-carboxylic acid
  • Step 1 Synthesis of methyl 3-ethyl-2- (hydroxymethyl) imidazo [1,2-a] pyridine-7-carboxylate
  • Step 2 Synthesis of methyl 3-ethyl-2-((toluenesulfonyloxy) methyl) imidazo [1,2-a] pyridine-7-carboxylate
  • Step 3 Synthesis of methyl 2-((2-chloro-6-fluorophenoxy) methyl) -3-ethylimidazo [1,2-a] pyridine-7-carboxylate
  • Step 4 Synthesis of 2-((2-chloro-6-fluorophenoxy) methyl) -3-ethylimidazo [1,2-a] pyridine-7-carboxylic acid
  • Step 1 Synthesis of (2-chloro-6- (trifluoromethyl) phenyl) methanol
  • Step 2 Synthesis of 2- (bromomethyl) -1-chloro-3- (trifluoromethyl) benzene
  • Step 5 Synthesis of (E) -2- (2-chloro-6- (trifluoromethyl) styryl) -3-ethylimidazo [1,2-a] pyridine-7-carboxylic acid
  • Step 1 Synthesis of ethyl 3-bromo-2-carbonylbutyrate
  • Step 2 Synthesis of ethyl 7-bromo-3-methylimidazo [1,2-a] pyridine-2-carboxylate
  • Step 3 Synthesis of (7-bromo-3-methylimidazo [1,2-a] pyridin-2-yl) methanol
  • Step 4 Synthesis of 7-bromo-3-methylimidazo [1,2-a] pyridine-2-carbaldehyde
  • Step 5 Synthesis of N '-((7-bromo-3-methylimidazo [1,2-a] pyridin-2-yl) methylene) benzenesulfonyl hydrazide
  • Step 6 Synthesis of 7-bromo-2- (4-chloro-2- (trifluoromethyl) benzyl) -3-methylimidazo [1,2-a] pyridine
  • Step 7 Synthesis of 2- (4-chloro-2- (trifluoromethyl) benzyl) -3-methylimidazo [1,2-a] pyridine-7-carbonitrile
  • Step 8 Synthesis of methyl 2- (4-chloro-2- (trifluoromethyl) benzyl) -3-methylimidazo [1,2-a] pyridine-7-carboxylate
  • Step 9 Synthesis of 2- (4-chloro-2- (trifluoromethyl) benzyl) -3-methylimidazo [1,2-a] pyridine-7-carboxylic acid
  • Step 1 Synthesis of ethyl 4-methyl-2-carbonylvalerate
  • the second step to the tenth step are prepared by referring to the synthetic method in Intermediate 15, 2- (4-chloro-2- (trifluoromethyl) benzyl) -3-isopropylimidazo [1,2- a] Pyridine-7-carboxylic acid ESI-MS 397.2 [M + H] + .
  • Step 1 Synthesis of ethyl 2- (cyclopropylmethyl) -1,3-disulfane-2-carboxylate
  • Step 2 Synthesis of ethyl 3-cyclopropyl-2-carbonylpropionate
  • the third step to the eleventh step are prepared by referring to the synthesis method in Intermediate 15, 2- (4-chloro-2- (trifluoromethyl) benzyl) -3-cyclopropylimidazo [1,2 -a] pyridine-7-carboxylic acid ESI-MS 395.2 [M + H] + .
  • Step 3 Synthesis of (R) -2-amino-2- (5- (ethylthio) pyridin-2-yl) ethane-1-ol
  • Step 4 Synthesis of tert-butyl (R)-(1- (5- (ethylthio) pyridin-2-yl) -2-hydroxyethyl) carbamate
  • Step 5 Synthesis of tert-butyl (R)-(1- (5- (ethylsulfonyl) pyridin-2-yl) -2-hydroxyethyl) carbamate
  • Step 6 Synthesis of (R) -2-amino-2- (5- (ethylsulfonyl) pyridin-2-yl) ethane-1-ol
  • Step 1 Synthesis of ethyl 2- (4- (ethylthio) phenyl) -2-carbonylacetate
  • Step 2 Synthesis of ethyl R-2-((tert-butylsulfinyl) imino) -2- (4- (ethylthio) phenyl) ethyl acetate
  • Step 3 Synthesis of ethyl (R) -2-(((R) -tert-butylsulfinyl) amino) -2- (4- (ethylthio) phenyl) acetate
  • Step 4 Synthesis of (R) -2-amino-2- (4- (ethylthio) phenyl) ethyl acetate
  • Step 5 Synthesis of (R) -2-amino-2- (4- (ethylsulfonyl) phenyl) ethyl acetate
  • Butyric acid (10g, 118.3mmol), thionyl chloride (14.1g, 118.3mmol) were dissolved in 1,2-dichloroethane (100mL), the reaction solution was stirred at 80 ° C for 16 hours, cooled to room temperature, and reacted A solution of methyl 2-aminoisonicotinate (12.0 g, 78.9 mmol) and triethylamine (24.1 g, 236.7 mmol) in 1,2-dichloroethane (50 mL) was slowly added dropwise.
  • reaction solution was further stirred at room temperature for 1 hour, and the reaction solution was washed successively with saturated NaHCO 3 (100 mL), H 2 O (100 mL), and saturated brine (100 mL).
  • Step 2 Synthesis of methyl 2-chloro-3-ethylimidazo [1,2-a] pyridine-7-carboxylate
  • Step 2 Synthesis of 1- (4-bromo-2-fluorophenyl) -2-methylpropane-1-one
  • Step 1 Synthesis of 3-ethyl-2- (3-fluoro-4-isobutyrylphenyl) imidazo [1,2-a] pyridine-7-carboxylic acid methyl ester
  • Step 2 Synthesis of 3-ethyl-2- (3-fluoro-4-isobutylphenyl) imidazo [1,2-a] pyridine-7-carboxylic acid methyl ester
  • Step 3 Synthesis of 3-ethyl-2- (3-fluoro-4-isobutylphenyl) imidazo [1,2-a] pyridine-7-carboxylic acid
  • the first step methyl 3-ethyl-2- (hydroxy (3- (trifluoromethyl) pyridin-2-yl) methyl) imidazo [1,2-a] pyridine-7-carboxylate synthesis
  • Step 2 Synthesis of 3-ethyl-2- (hydroxy (3- (trifluoromethyl) pyridin-2-yl) methyl) imidazo [1,2-a] pyridine-7-carboxylic acid
  • the first step methyl 3-ethyl-2- (fluoro (3- (trifluoromethyl) pyridin-2-yl) methyl) imidazo [1,2-a] pyridine-7-carboxylate synthesis
  • Step 2 Synthesis of 3-ethyl-2- (fluoro (3- (trifluoromethyl) pyridin-2-yl) methyl) imidazo [1,2-a] pyridine-7-carboxylic acid
  • Example 2 The preparation of Example 2 is obtained by referring to the synthesis method of Example 1:
  • the nuclear magnetic data of the compound prepared in Example 2 are as follows:
  • Example 4 The preparation of Example 4 is prepared by referring to the synthesis method of Example 3:
  • the nuclear magnetic data of the compound prepared in Example 4 are as follows:
  • Example 13 is prepared by referring to the synthesis method of Example 12:
  • the nuclear magnetic data of the compound prepared in Example 13 are as follows:
  • Examples 14-48 were prepared with reference to the synthesis method of Example 3 or 9:
  • the nuclear magnetic data of the compound prepared in Example 14 are as follows:
  • the nuclear magnetic data of the compound prepared in Example 15 are as follows:
  • the nuclear magnetic data of the compound prepared in Example 16 are as follows:
  • the nuclear magnetic data of the compound prepared in Example 17 are as follows:
  • the nuclear magnetic data of the compound prepared in Example 18 are as follows:
  • the nuclear magnetic data of the compound prepared in Example 19 are as follows:
  • the nuclear magnetic data of the compound prepared in Example 20 are as follows:
  • the nuclear magnetic data of the compound prepared in Example 21 are as follows:
  • the nuclear magnetic data of the compound prepared in Example 22 are as follows:
  • the nuclear magnetic data of the compound prepared in Example 23 are as follows:
  • the nuclear magnetic data of the compound prepared in Example 24 are as follows:
  • the nuclear magnetic data of the compound prepared in Example 25 are as follows:
  • the nuclear magnetic data of the compound prepared in Example 26 are as follows:
  • the nuclear magnetic data of the compound prepared in Example 27 are as follows:
  • the nuclear magnetic data of the compound prepared in Example 28 are as follows:
  • the nuclear magnetic data of the compound prepared in Example 29 are as follows:
  • the nuclear magnetic data of the compound prepared in Example 30 are as follows:
  • the nuclear magnetic data of the compound prepared in Example 31 are as follows:
  • the nuclear magnetic data of the compound prepared in Example 32 are as follows:
  • the nuclear magnetic data of the compound prepared in Example 33 are as follows:
  • the nuclear magnetic data of the compound prepared in Example 34 are as follows:
  • the nuclear magnetic data of the compound prepared in Example 35 are as follows:
  • the nuclear magnetic data of the compound prepared in Example 36 are as follows:
  • the nuclear magnetic data of the compound prepared in Example 37 are as follows:
  • the nuclear magnetic data of the compound prepared in Example 38 are as follows:
  • the nuclear magnetic data of the compound prepared in Example 39 are as follows:
  • the nuclear magnetic data of the compound prepared in Example 40 are as follows:
  • the nuclear magnetic data of the compound prepared in Example 41 are as follows:
  • the nuclear magnetic data of the compound prepared in Example 42 are as follows:
  • the nuclear magnetic data of the compound prepared in Example 43 are as follows:
  • the nuclear magnetic data of the compound prepared in Example 44 are as follows:
  • the nuclear magnetic data of the compound prepared in Example 45 are as follows:
  • the nuclear magnetic data of the compound prepared in Example 46 are as follows:
  • the nuclear magnetic data of the compound prepared in Example 47 are as follows:
  • the nuclear magnetic data of the compound prepared in Example 48 are as follows:
  • TR-FRET Time-resolved fluorescence resonance energy transfer detection
  • This experiment is a TR-FRET compound screening experiment of ROR ⁇ t nuclear receptor agonist.
  • His-tagged ROR ⁇ t-LBD receptor When the His-tagged ROR ⁇ t-LBD receptor is combined with a receptor agonist, it may increase the recruitment of biotin-tagged co-activator peptides.
  • Europium-His-ROR ⁇ t-LBD is indirectly labeled by the donor (Eu) by binding to the Eu-anti-His antibody. Once Eu is activated by an energy source (such as a flash lamp or laser), the energy will be bound to the isophycocyanin-chain
  • an energy source such as a flash lamp or laser
  • the ROR ⁇ t reporter gene detection method was used to evaluate the activation and specificity of the compound to ROR ⁇ t.
  • the plasmid pfn26a-ROR ⁇ t-LBD and pGl4.35 (Promega, Cat.No.E1370) were co-transformed with HEK293 cells (Cell Bank of the Chinese Academy of Sciences, Cat. -100mg) In the presence of conditions, add compounds to evaluate its efficacy.
  • the specific experimental process is as follows:
  • test compound is evaluated by 4 times gradient dilution to evaluate the dose effect effect, starting from 50 ⁇ M;
  • the compounds of the present invention have obvious agonistic effects and specificity on ROR ⁇ t nuclear receptors, and are expected to be developed into a new generation of ROR ⁇ t agonists to meet the clinical application needs.

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Abstract

Provided are a nitrogen heteroaryl amide derivative having the structure of formula (I), a preparation method therefor, and application thereof. Definitions of various substituents are as described in the specification and the claims. The series of compounds can be widely applied to preparation of drugs for treating one or more tumors, cancers, metabolic diseases, and autoimmune diseases or disorders, and are expected to be developed as a new generation of RORγt agonist drugs.

Description

一种氮杂芳基酰胺衍生物及其制备方法和应用Azaaryl amide derivative and preparation method and application thereof 技术领域Technical field
本发明属于药物合成领域，具体涉及一种氮杂芳基酰胺衍生物及其制备方法和应用。The invention belongs to the field of pharmaceutical synthesis, and in particular relates to a azaarylamide derivative and a preparation method and application thereof.
背景技术Background technique
维果酸相关孤儿受体(ROR)家族包含RORα、-β和-γ三个成员。RORα在小脑发育中不可或缺，RORβ则主要表达在脑部和视网膜中，两者在视网膜的正常发育中发挥重要功能。RORγ根据转录剪切位置不同分为RORγ1与RORγ2(RORγt)两个亚型，前者主要表达在肝脏、骨骼肌和肾脏中，而RORγt主要表达在免疫器官中。缺失RORγt的小鼠缺少淋巴结和派氏结等淋巴器官，T细胞发育成熟过程也受到影响，各类T细胞数量均比正常小鼠有所降低。The retinoic acid-related orphan receptor (ROR) family contains three members RORα, -β and -γ. RORα is indispensable in the development of the cerebellum, and RORβ is mainly expressed in the brain and retina, both of which play important functions in the normal development of the retina. RORγ is divided into two subtypes of RORγ1 and RORγ2 (RORγt) according to different transcriptional shear positions. The former is mainly expressed in liver, skeletal muscle and kidney, while RORγt is mainly expressed in immune organs. The mice lacking RORγt lack lymph nodes and Peyer's patches and other lymphoid organs. The development and maturation of T cells is also affected. The number of various T cells is lower than that of normal mice.
在人体免疫系统中，T辅助细胞扮演着不可或缺的重要角色。CD4阳性的T辅助细胞在微环境中不同细胞因子的诱导作用下，能够分化为Th1，Th2，Th17，Treg等一系列调节性辅助细胞。Th1与Th2在抗原识别、呈递以及激活T效应细胞等过程中发挥重要作用。Treg则是一类促进免疫抑制的调节细胞。Th17是近年来发现的一类新型T辅助细胞，以分泌白介素17(IL-17)细胞因子为特征。Th17细胞最初被认为主要在抵抗细菌真菌类感染中通过募集中性粒细胞发挥免疫功能，后续研究发现该类细胞与自身免疫病和恶性肿瘤的发生发展有密切联系。因此，通过抑制Th17细胞分化治疗自身免疫病和激活Th17细胞分化治疗恶性肿瘤成为免疫及肿瘤基础研究和转化医学的热点。In the human immune system, T helper cells play an indispensable and important role. CD4-positive T helper cells can differentiate into a series of regulatory helper cells such as Th1, Th2, Th17 and Treg under the induction of different cytokines in the microenvironment. Th1 and Th2 play an important role in the process of antigen recognition, presentation and activation of T effector cells. Treg is a type of regulatory cell that promotes immune suppression. Th17 is a new type of T helper cell discovered in recent years, characterized by the secretion of interleukin 17 (IL-17) cytokine. Th17 cells were originally thought to play a role in immune function by recruiting neutrophils in the fight against bacterial fungal infections. Subsequent studies have found that these cells are closely related to the occurrence and development of autoimmune diseases and malignant tumors. Therefore, the treatment of autoimmune diseases by inhibiting the differentiation of Th17 cells and the treatment of malignant tumors by activating the differentiation of Th17 cells have become the focus of basic research in immunology and tumor and translational medicine.
RORγt作为CD4+Th17细胞分化中的关键转录因子，通过小分子化合物调节RORγt活性能够直接影响Th17细胞的丰度和活性。激活RORγt后，Th17细胞分泌的细胞因子(如IL-17A)水平明显上升，Th17细胞本身的存活和免疫激活能力大幅增强。同时，Th17细胞活化增强能够减少免疫抑制类的Treg细胞数量，降低免疫抑制类受体(如PD-1)在肿瘤浸润淋巴细胞的表达。基于上述的作用机制，可口服的小分子RORγt激动剂能够通过激活Th17细胞进而增强免疫系统识别并杀伤肿瘤细胞的能力，在临床上可能成为继PD-1、PD-L1抗体之后一类新型抗肿瘤小分子药物。As a key transcription factor in the differentiation of CD4 + Th17 cells, RORγt can directly affect the abundance and activity of Th17 cells by regulating RORγt activity through small molecule compounds. After RORγt is activated, the level of cytokines (such as IL-17A) secreted by Th17 cells increases significantly, and the survival and immune activation capabilities of Th17 cells are greatly enhanced. At the same time, enhanced activation of Th17 cells can reduce the number of immunosuppressive Treg cells and reduce the expression of immunosuppressive receptors (such as PD-1) in tumor-infiltrating lymphocytes. Based on the above mechanism of action, the small molecule RORγt agonists that can be taken orally can enhance the ability of the immune system to recognize and kill tumor cells by activating Th17 cells, and may become a new class of anti-PD-1 and PD-L1 antibodies in clinical practice. Tumor small molecule drugs.
发明内容Summary of the invention
本发明的目的在于提供一种RORγt小分子激动剂。The object of the present invention is to provide a small molecule agonist of RORγt.
本发明第一方面提供一种式(I)化合物、其立体异构体、前药或其药学上可接受盐：The first aspect of the present invention provides a compound of formula (I), its stereoisomer, prodrug or pharmaceutically acceptable salt thereof:
Figure PCTCN2019104957-appb-000001
Figure PCTCN2019104957-appb-000001
其中，among them,
环A选自C 3-10环烷基、3-10元杂环基、C 5-10芳基或5-10元杂芳基； Ring A is selected from C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 5-10 aryl or 5-10 membered heteroaryl;
X 1、X 2、X 5各自独立地选自C(R 8)或N； X 1 , X 2 and X 5 are each independently selected from C (R 8 ) or N;
X 3、X 4各自独立地选自C或N； X 3 and X 4 are each independently selected from C or N;
Y选自C(R 9)或N； Y is selected from C (R 9 ) or N;
L选自键、-[C(R 10R 11)] n-、-[C(R 13R 14)] p-N(R 12)-[C(R 15R 16)] q-、-[C(R 13R 14)] p-O-[C(R 15R 16)] q-、-[C(R 13R 14)] p-S(O) r-[C(R 15R 16)] q-、-C(R 17)＝C(R 18)-、-N(R 19)-S(O) 2-或-N(R 20)-C(O)-； L is selected from bond,-[C (R 10 R 11 )] n -,-[C (R 13 R 14 )] p -N (R 12 )-[C (R 15 R 16 )] q -,-[ C (R 13 R 14 )] p -O- [C (R 15 R 16 )] q -,-[C (R 13 R 14 )] p -S (O) r- [C (R 15 R 16 ) ] q- , -C (R 17 ) = C (R 18 )-, -N (R 19 ) -S (O) 2 -or -N (R 20 ) -C (O)-;
R 1选自C 1-10烷基、C 2-10链烯基、C 3-10环烷基、3-10元杂环基、C 5-10芳基、5-10元杂芳基或-NR 21R 22，上述基团任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、卤取代C 1-10烷基、C 3-10环烷基、3-10元杂环基、C 5-10芳基、5-10元杂芳基、＝O、-C 0-8-S(O) rR 23、-C 0-8-O-R 24、-C 0-8-C(O)OR 24、-C 0-8-C(O)R 25、-C 0-8-O-C(O)R 25、-C 0-8-NR 26R 27、-C 0-8-C(O)NR 26R 27或-C 0-8-N(R 26)-C(O)R 25的取代基所取代； R 1 is selected from C 1-10 alkyl, C 2-10 alkenyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 5-10 aryl, 5-10 membered heteroaryl or -NR 21 R 22 , the above groups are optionally further selected from one or more selected from deuterium, halogen, cyano, nitro, azido, C 1-10 alkyl, C 2-10 alkenyl, C 2 -10 alkynyl, halogen substituted C 1-10 alkyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 5-10 aryl, 5-10 membered heteroaryl, = O,- C 0-8 -S (O) r R 23 , -C 0-8 -OR 24 , -C 0-8 -C (O) OR 24 , -C 0-8 -C (O) R 25 , -C 0-8 -OC (O) R 25 , -C 0-8 -NR 26 R 27 , -C 0-8 -C (O) NR 26 R 27 or -C 0-8 -N (R 26 ) -C (O) substituted by the substituent of R 25 ;
R 2选自氢、氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、C 3-10环烷基、3-10元杂环基、C 5-10芳基、5-10元杂芳基、-C 0-8-S(O) rR 23、-C 0-8-O-R 24、-C 0-8-C(O)OR 24、-C 0-8-C(O)R 25、-C 0-8-O-C(O)R 25、-C 0-8-NR 26R 27、-C 0-8-C(O)NR 26R 27或-C 0-8-N(R 26)-C(O)R 25，上述基团任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、卤取代C 1-10烷基、C 3-10环烷基、3-10元杂环基、C 5-10芳基、5-10元杂芳基、＝O、-C 0-8-S(O) rR 23、-C 0-8-O-R 24、-C 0-8-C(O)OR 24、-C 0-8-C(O)R 25、-C 0-8-O-C(O)R 25、-C 0-8-NR 26R 27、-C 0-8-C(O)NR 26R 27或-C 0-8-N(R 26)-C(O)R 25的取代基所取代； R 2 is selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl , 3-10 membered heterocyclic group, C 5-10 aryl group, 5-10 membered heteroaryl group, -C 0-8 -S (O) r R 23 , -C 0-8 -OR 24 , -C 0 -8 -C (O) OR 24 , -C 0-8 -C (O) R 25 , -C 0-8 -OC (O) R 25 , -C 0-8 -NR 26 R 27 , -C 0 -8 -C (O) NR 26 R 27 or -C 0-8 -N (R 26 ) -C (O) R 25 , the above groups are optionally further selected by one or more selected from deuterium, halogen, cyano , Nitro, azido, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, halogen substituted C 1-10 alkyl, C 3-10 cycloalkyl, 3- 10-membered heterocyclic group, C 5-10 aryl group, 5-10 membered heteroaryl group, = O, -C 0-8 -S (O) r R 23 , -C 0-8 -OR 24 , -C 0 -8 -C (O) OR 24 , -C 0-8 -C (O) R 25 , -C 0-8 -OC (O) R 25 , -C 0-8 -NR 26 R 27 , -C 0 -8 -C (O) NR 26 R 27 or -C 0-8 -N (R 26 ) -C (O) R 25 substituent;
R 3、R 4各自独立地选自氢、氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、C 3-10环烷基、3-10元杂环基、C 5-10芳基、5-10元杂芳基、-C 0-8-S(O) rR 23、-C 0- 8-O-R 24、-C 0-8-C(O)OR 24、-C 0-8-C(O)R 25、-C 0-8-O-C(O)R 25、-C 0-8-NR 26R 27、-C 0-8-C(O)NR 26R 27或-C 0-8-N(R 26)-C(O)R 25，或者，R 3与R 4和其直接相连的碳原子一起形成C(O)、3-10元环烷基、3-10元杂环基，上述基团任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、卤取代C 1-10烷基、C 3-10环烷基、3-10元杂环基、C 5- 10芳基、5-10元杂芳基、＝O、-C 0-8-S(O) rR 23、-C 0-8-O-R 24、-C 0-8-C(O)OR 24、-C 0-8-C(O)R 25、-C 0-8-O-C(O)R 25、-C 0-8-NR 26R 27、-C 0-8-C(O)NR 26R 27或-C 0-8-N(R 26)-C(O)R 25的取代基所取代； R 3 and R 4 are each independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, 3-10 membered heterocyclic group, C 5-10 aryl group, 5-10 membered heteroaryl group, -C 0-8 -S (O) r R 23 , -C 0- 8- OR 24 , -C 0-8 -C (O) OR 24 , -C 0-8 -C (O) R 25 , -C 0-8 -OC (O) R 25 , -C 0-8 -NR 26 R 27 , -C 0-8 -C (O) NR 26 R 27 or -C 0-8 -N (R 26 ) -C (O) R 25 , or, R 3 and R 4 and the carbon directly connected to it Atoms together form C (O), 3-10 membered cycloalkyl, 3-10 membered heterocyclic group, the above groups are optionally further selected by one or more selected from deuterium, halogen, cyano, nitro, azido , C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, halogen substituted C 1-10 alkyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 5- 10 aryl, 5-10 membered heteroaryl, = O, -C 0-8 -S (O) r R 23 , -C 0-8 -OR 24 , -C 0-8 -C (O) OR 24 , -C 0-8 -C (O) R 25 , -C 0-8 -OC (O) R 25 , -C 0-8 -NR 26 R 27 , -C 0-8 -C (O) NR 26 R 27 or -C 0-8 -N (R 26 ) -C (O) R 25 substituent;
R 5选自氢、氘、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、C 3-10环烷基、3-10元杂环基、C 5-10芳基、5-10元杂芳基、-C 0-8-S(O) rR 23、-C 0-8-C(O)OR 24或-C 0-8-C(O)R 25，上述基团任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、卤取代C 1-10烷基、C 3-10环烷基、3-10元杂环基、C 5-10芳基、5-10元杂芳基、＝O、-C 0- 8-S(O) rR 23、-C 0-8-O-R 24、-C 0-8-C(O)OR 24、-C 0-8-C(O)R 25、-C 0-8-O-C(O)R 25、-C 0-8-NR 26R 27、-C 0- 8-C(O)NR 26R 27或-C 0-8-N(R 26)-C(O)R 25的取代基所取代； R 5 is selected from hydrogen, deuterium, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, 3-10 membered heterocyclic group, C 5- 10 aryl, 5-10 membered heteroaryl, -C 0-8 -S (O) r R 23 , -C 0-8 -C (O) OR 24 or -C 0-8 -C (O) R 25 , the above groups are optionally further selected from one or more selected from deuterium, halogen, cyano, nitro, azido, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkyne group, a halo substituted C 1-10 alkyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 5-10 aryl, 5-10 membered heteroaryl, = O, -C 0- 8 -S (O) r R 23 , -C 0-8 -OR 24 , -C 0-8 -C (O) OR 24 , -C 0-8 -C (O) R 25 , -C 0-8- OC (O) R 25 , -C 0-8 -NR 26 R 27 , -C 0- 8 -C (O) NR 26 R 27 or -C 0-8 -N (R 26 ) -C (O) R Substituted by a substituent of 25 ;
R 6选自氢、氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、C 3-10环烷基、3-10元杂环基、C 5-10芳基、5-10元杂芳基、-C 0-8-S(O) rR 23、-C 0-8-O-R 24、-C 0-8-C(O)OR 24、-C 0-8-C(O)R 25、-C 0-8-O-C(O)R 25、-C 0-8-NR 26R 27、-C 0-8-C(O)NR 26R 27或-C 0-8-N(R 26)- C(O)R 25，上述基团任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、卤取代C 1-10烷基、C 3-10环烷基、3-10元杂环基、C 5-10芳基、5-10元杂芳基、＝O、-C 0-8-S(O) rR 23、-C 0-8-O-R 24、-C 0-8-C(O)OR 24、-C 0-8-C(O)R 25、-C 0-8-O-C(O)R 25、-C 0-8-NR 26R 27、-C 0-8-C(O)NR 26R 27或-C 0-8-N(R 26)-C(O)R 25的取代基所取代； R 6 is selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl , 3-10 membered heterocyclic group, C 5-10 aryl group, 5-10 membered heteroaryl group, -C 0-8 -S (O) r R 23 , -C 0-8 -OR 24 , -C 0 -8 -C (O) OR 24 , -C 0-8 -C (O) R 25 , -C 0-8 -OC (O) R 25 , -C 0-8 -NR 26 R 27 , -C 0 -8 -C (O) NR 26 R 27 or -C 0-8 -N (R 26 )-C (O) R 25 , the above groups are optionally further selected by one or more selected from deuterium, halogen, cyano , Nitro, azido, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, halogen substituted C 1-10 alkyl, C 3-10 cycloalkyl, 3- 10-membered heterocyclic group, C 5-10 aryl group, 5-10 membered heteroaryl group, = O, -C 0-8 -S (O) r R 23 , -C 0-8 -OR 24 , -C 0 -8 -C (O) OR 24 , -C 0-8 -C (O) R 25 , -C 0-8 -OC (O) R 25 , -C 0-8 -NR 26 R 27 , -C 0 -8 -C (O) NR 26 R 27 or -C 0-8 -N (R 26 ) -C (O) R 25 substituent;
各R 7独立地选自氢、氘、卤素、氰基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、C 3-10环烷基、3-10元杂环基、C 5-10芳基、5-10元杂芳基、-P(O)(R 28) 2、-SF 5、-C 0-8-S(O) rR 23、-C 0-8-O-R 24、-C 0-8-C(O)OR 24、-C 0-8-C(O)R 25、-C 0-8-O-C(O)R 25、-C 0-8-NR 26R 27、-C 0-8-C(O)NR 26R 27或-C 0-8-N(R 26)-C(O)R 25，上述基团任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、卤取代C 1-10烷基、C 3-10环烷基、3-10元杂环基、C 5-10芳基、5-10元杂芳基、＝O、-C 0-8-S(O) rR 23、-C 0-8-O-R 24、-C 0-8-C(O)OR 24、-C 0-8-C(O)R 25、-C 0-8-O-C(O)R 25、-C 0-8-NR 26R 27、-C 0-8-C(O)NR 26R 27或-C 0-8-N(R 26)-C(O)R 25的取代基所取代； Each R 7 is independently selected from hydrogen, deuterium, halogen, cyano, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, 3-10 Heterocyclic group, C 5-10 aryl group, 5-10 membered heteroaryl group, -P (O) (R 28 ) 2 , -SF 5 , -C 0-8 -S (O) r R 23 ,- C 0-8 -OR 24 , -C 0-8 -C (O) OR 24 , -C 0-8 -C (O) R 25 , -C 0-8 -OC (O) R 25 , -C 0 -8 -NR 26 R 27 , -C 0-8 -C (O) NR 26 R 27 or -C 0-8 -N (R 26 ) -C (O) R 25 , the above groups are optionally further Or more selected from deuterium, halogen, cyano, nitro, azido, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, halogen substituted C 1-10 alkyl , C 3-10 cycloalkyl, 3-10 membered heterocyclic group, C 5-10 aryl group, 5-10 membered heteroaryl group, = O, -C 0-8 -S (O) r R 23 ,- C 0-8 -OR 24 , -C 0-8 -C (O) OR 24 , -C 0-8 -C (O) R 25 , -C 0-8 -OC (O) R 25 , -C 0 -8 -NR 26 R 27 , -C 0-8 -C (O) NR 26 R 27 or -C 0-8 -N (R 26 ) -C (O) R 25 substituent;
每个R 8、R 9各自独立地选自氢、氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、C 3-10环烷基、3-10元杂环基、C 5-10芳基、5-10元杂芳基、-C 0-8-S(O) rR 23、-C 0-8-O-R 24、-C 0-8-C(O)OR 24、-C 0-8-C(O)R 25、-C 0-8-O-C(O)R 25、-C 0-8-NR 26R 27、-C 0-8-C(O)NR 26R 27或-C 0-8-N(R 26)-C(O)R 25，上述基团任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、卤取代C 1-10烷基、C 3-10环烷基、3-10元杂环基、C 5-10芳基、5-10元杂芳基、＝O、-C 0-8-S(O) rR 23、-C 0-8-O-R 24、-C 0-8-C(O)OR 24、-C 0-8-C(O)R 25、-C 0-8-O-C(O)R 25、-C 0-8-NR 26R 27、-C 0-8-C(O)NR 26R 27或-C 0-8-N(R 26)-C(O)R 25的取代基所取代； Each R 8 and R 9 are independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl , C 3-10 cycloalkyl, 3-10 membered heterocyclic group, C 5-10 aryl group, 5-10 membered heteroaryl group, -C 0-8 -S (O) r R 23 , -C 0- 8 -OR 24 , -C 0-8 -C (O) OR 24 , -C 0-8 -C (O) R 25 , -C 0-8 -OC (O) R 25 , -C 0-8- NR 26 R 27 , -C 0-8 -C (O) NR 26 R 27 or -C 0-8 -N (R 26 ) -C (O) R 25 , the above groups are optionally further substituted by one or more Selected from deuterium, halogen, cyano, nitro, azido, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, halogen substituted C 1-10 alkyl, C 3 -10 cycloalkyl, 3-10 membered heterocyclic group, C 5-10 aryl group, 5-10 membered heteroaryl group, = O, -C 0-8 -S (O) r R 23 , -C 0- 8 -OR 24 , -C 0-8 -C (O) OR 24 , -C 0-8 -C (O) R 25 , -C 0-8 -OC (O) R 25 , -C 0-8- NR 26 R 27 , -C 0-8 -C (O) NR 26 R 27 or -C 0-8 -N (R 26 ) -C (O) R 25 substituents;
R 10、R 11、R 13、R 14、R 15、R 16各自独立地选自氢、氘、卤素、氰基、硝基、叠氮基、C 1- 10烷基、C 2-10链烯基、C 2-10链炔基、C 3-10环烷基、3-10元杂环基、C 5-10芳基、5-10元杂芳基、-C 0-8-S(O) rR 23、-C 0-8-O-R 24、-C 0-8-C(O)OR 24、-C 0-8-C(O)R 25、-C 0-8-O-C(O)R 25、-C 0-8-NR 26R 27、-C 0-8-C(O)NR 26R 27或-C 0-8-N(R 26)-C(O)R 25，或者，R 10与R 11、R 13与R 14、R 15与R 16和其直接相连的碳原子一起各自独立地形成C(O)、3-10元环烷基、3-10元杂环基，上述基团任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、卤取代C 1-10烷基、C 3-10环烷基、3-10元杂环基、C 5-10芳基、5-10元杂芳基、＝O、-C 0- 8-S(O) rR 23、-C 0-8-O-R 24、-C 0-8-C(O)OR 24、-C 0-8-C(O)R 25、-C 0-8-O-C(O)R 25、-C 0-8-NR 26R 27、-C 0- 8-C(O)NR 26R 27或-C 0-8-N(R 26)-C(O)R 25的取代基所取代； R 10, R 11, R 13 , R 14, R 15, R 16 are each independently selected from hydrogen, deuterium, halo, cyano, nitro, azido, C 1- 10 alkyl group, C 2-10 chain, Alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 5-10 aryl, 5-10 membered heteroaryl, -C 0-8 -S ( O) r R 23 , -C 0-8 -OR 24 , -C 0-8 -C (O) OR 24 , -C 0-8 -C (O) R 25 , -C 0-8 -OC (O ) R 25 , -C 0-8 -NR 26 R 27 , -C 0-8 -C (O) NR 26 R 27 or -C 0-8 -N (R 26 ) -C (O) R 25 , or , R 10 and R 11 , R 13 and R 14 , R 15 and R 16 together with the carbon atoms directly connected to them independently form C (O), 3-10 membered cycloalkyl group, 3-10 membered heterocyclic group , The above groups are optionally further selected from one or more selected from deuterium, halogen, cyano, nitro, azido, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl , halo-substituted C 1-10 alkyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 5-10 aryl, 5-10 membered heteroaryl, = O, -C 0- 8 - S (O) r R 23 , -C 0-8 -OR 24 , -C 0-8 -C (O) OR 24 , -C 0-8 -C (O) R 25 , -C 0-8 -OC (O) R 25 , -C 0-8 -NR 26 R 27 , -C 0- 8 -C (O) NR 26 R 27 or -C 0-8 -N (R 26 ) -C (O) R 25 Fetch Substitution is substituted;
R 12、R 19、R 20各自独立地选自氢、氘、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、C 3-10环烷基、3-10元杂环基、C 5-10芳基、5-10元杂芳基、-C 0-8-S(O) rR 23、-C 0-8-C(O)OR 24或-C 0-8-C(O)R 25，上述基团任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、卤取代C 1-10烷基、C 3-10环烷基、3-10元杂环基、C 5-10芳基、5-10元杂芳基、＝O、-C 0-8-S(O) rR 23、-C 0-8-O-R 24、-C 0-8-C(O)OR 24、-C 0-8-C(O)R 25、-C 0-8-O-C(O)R 25、-C 0-8-NR 26R 27、-C 0-8-C(O)NR 26R 27或-C 0-8-N(R 26)-C(O)R 25的取代基所取代； R 12 , R 19 , and R 20 are each independently selected from hydrogen, deuterium, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, 3- 10-membered heterocyclic group, C 5-10 aryl group, 5-10 membered heteroaryl group, -C 0-8 -S (O) r R 23 , -C 0-8 -C (O) OR 24 or -C 0-8 -C (O) R 25 , the above groups are optionally further selected by one or more selected from deuterium, halogen, cyano, nitro, azido, C 1-10 alkyl, C 2-10 chain Alkenyl, C 2-10 alkynyl, halogen substituted C 1-10 alkyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 5-10 aryl, 5-10 membered heteroaryl , = O, -C 0-8 -S (O) r R 23 , -C 0-8 -OR 24 , -C 0-8 -C (O) OR 24 , -C 0-8 -C (O) R 25 , -C 0-8 -OC (O) R 25 , -C 0-8 -NR 26 R 27 , -C 0-8 -C (O) NR 26 R 27 or -C 0-8 -N ( R 26 ) -C (O) R 25 substituent;
R 17、R 18各自独立地选自氢、氘、卤素、氰基或C 1-10烷基，上述基团任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、卤取代C 1-10烷基、C 3-10环烷基、3-10元杂环基、C 5-10芳基、5-10元杂芳基、＝O、-C 0-8-S(O) rR 23、- C 0-8-O-R 24、-C 0-8-C(O)OR 24、-C 0-8-C(O)R 25、-C 0-8-O-C(O)R 25、-C 0-8-NR 26R 27、-C 0-8-C(O)NR 26R 27或-C 0-8-N(R 26)-C(O)R 25的取代基所取代； R 17 and R 18 are each independently selected from hydrogen, deuterium, halogen, cyano or C 1-10 alkyl, and the above groups are optionally further selected from one or more selected from deuterium, halogen, cyano, nitro, and Nitrogen group, C 1-10 alkyl group, C 2-10 alkenyl group, C 2-10 alkynyl group, halogen substituted C 1-10 alkyl group, C 3-10 cycloalkyl group, 3-10 membered heterocyclic group , C 5-10 aryl, 5-10 membered heteroaryl, = O, -C 0-8 -S (O) r R 23 ,-C 0-8 -OR 24 , -C 0-8 -C ( O) OR 24 , -C 0-8 -C (O) R 25 , -C 0-8 -OC (O) R 25 , -C 0-8 -NR 26 R 27 , -C 0-8 -C ( O) NR 26 R 27 or -C 0-8 -N (R 26 ) -C (O) R 25 substituent;
R 21、R 22各自独立地选自氢、氘、C 1-10烷基、C 2-10链烯基、C 3-10环烷基、3-10元杂环基、C 5-10芳基或5-10元杂芳基，R 21、R 22和其直接相连的氮原子一起形成4-10元杂环基； R 21 and R 22 are each independently selected from hydrogen, deuterium, C 1-10 alkyl, C 2-10 alkenyl, C 3-10 cycloalkyl, 3-10 membered heterocyclic group, C 5-10 aromatic Group or a 5-10 membered heteroaryl group, R 21 and R 22 together with the nitrogen atom directly connected thereto form a 4-10 membered heterocyclic group;
每个R 23各自独立地选自氢、氘、羟基、C 1-10烷基、C 1-10烷氧基、C 2-10链烯基、C 3-10环烷基、C 3-10环烷氧基、3-10元杂环基、3-10元杂环氧基、C 5-10芳基、C 5-10芳氧基、5-10元杂芳基、5-10元杂芳氧基或-NR 26R 27，上述基团任选进一步被一个或多个选自氘、卤素、羟基、羰基、C 1-10烷基、C 1-10烷氧基、C 3-10环烷基、C 3-10环烷氧基、3-10元杂环基、3-10元杂环氧基、C 5- 10芳基、C 5-10芳氧基、5-10元杂芳基、5-10元杂芳氧基或-NR 26R 27的取代基所取代； Each R 23 is independently selected from hydrogen, deuterium, hydroxyl, C 1-10 alkyl, C 1-10 alkoxy, C 2-10 alkenyl, C 3-10 cycloalkyl, C 3-10 Cycloalkoxy, 3-10 membered heterocyclyl, 3-10 membered heterocyclyloxy, C 5-10 aryl, C 5-10 aryloxy, 5-10 membered heteroaryl, 5-10 membered hetero Aryloxy or -NR 26 R 27 , the above groups are optionally further selected from one or more selected from deuterium, halogen, hydroxyl, carbonyl, C 1-10 alkyl, C 1-10 alkoxy, C 3-10 cycloalkyl, C 3-10 cycloalkoxy, 3-10 membered heterocyclyl, 3-10 membered heterocyclic group, C 5- 10 aryl group, C 5-10 aryloxy, 5-10 membered heteroaryl Substituted by aryl, 5-10 membered heteroaryloxy or -NR 26 R 27 substituents;
每个R 24各自独立地选自氢、氘、C 1-10烷基、C 2-10链烯基、C 3-10环烷基、3-10元杂环基、C 5-10芳基或5-10元杂芳基，上述基团任选进一步被一个或多个选自氘、卤素、羟基、羰基、氰基、C 1-10烷基、C 1-10烷氧基、C 3-10环烷基、C 3-10环烷氧基、3-10元杂环基、3-10元杂环氧基、C 5-10芳基、C 5-10芳氧基、5-10元杂芳基、5-10元杂芳氧基或-NR 26R 27的取代基所取代； Each R 24 is independently selected from hydrogen, deuterium, C 1-10 alkyl, C 2-10 alkenyl, C 3-10 cycloalkyl, 3-10 membered heterocyclic group, C 5-10 aryl Or 5-10 membered heteroaryl, the above groups are optionally further selected from one or more selected from deuterium, halogen, hydroxyl, carbonyl, cyano, C 1-10 alkyl, C 1-10 alkoxy, C 3 -10 cycloalkyl, C 3-10 cycloalkoxy, 3-10 membered heterocyclic group, 3-10 membered heterocyclicoxy group, C 5-10 aryl group, C 5-10 aryloxy group, 5-10 Substituted by a heteroaryl group, a 5-10 membered heteroaryloxy group or a substituent of -NR 26 R 27 ;
每个R 25各自独立地选自氢、氘、羟基、C 1-10烷基、C 1-10烷氧基、C 2-10链烯基、C 2-10链炔基、C 3-10环烷基、C 3-10环烷氧基、3-10元杂环基、3-10元杂环氧基、C 5-10芳基、C 5-10芳氧基、5-10元杂芳基、5-10元杂芳氧基或-NR 26R 27，上述基团任选进一步被一个或多个选自氘、卤素、羟基、氰基、C 1-10烷基、C 1-10烷氧基、C 3-10环烷基、C 3-10环烷氧基、3-10元杂环基、3-10元杂环氧基、C 5-10芳基、C 5-10芳氧基、5-10元杂芳基、5-10元杂芳氧基或-NR 26R 27的取代基所取代； Each R 25 is independently selected from hydrogen, deuterium, hydroxyl, C 1-10 alkyl, C 1-10 alkoxy, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 Cycloalkyl, C 3-10 cycloalkoxy, 3-10 membered heterocyclyl, 3-10 membered heterocyclyloxy, C 5-10 aryl, C 5-10 aryloxy, 5-10 membered hetero Aryl, 5-10 membered heteroaryloxy or -NR 26 R 27 , the above groups are optionally further selected from one or more selected from deuterium, halogen, hydroxyl, cyano, C 1-10 alkyl, C 1- 10 alkoxy, C 3-10 cycloalkyl, C 3-10 cycloalkoxy, 3-10 membered heterocyclyl, 3-10 membered heterocyclyloxy, C 5-10 aryl, C 5-10 Substituted by aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy or -NR 26 R 27 substituents;
每个R 26、R 27各自独立地选自氢、氘、羟基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、C 3-10环烷基、3-10元杂环基、C 5-10芳基、5-10元杂芳基、甲氧基、磺酰基、甲磺酰基、异丙磺酰基、环丙基磺酰基、对甲苯磺酰基、氨基、单烷基氨基、二烷基氨基或C 1-10烷酰基，上述基团任选进一步被一个或多个选自氘、卤素、羟基、C 1-8烷基、C 1-10烷氧基、C 3-10环烷基、C 3-10环烷氧基、3-10元杂环基、3-10元杂环氧基、C 5-10芳基、C 5-10芳氧基、5-10元杂芳基、5-10元杂芳氧基、氨基、单烷基氨基、二烷基氨基或C 1-10烷酰基的取代基所取代； Each R 26 and R 27 is independently selected from hydrogen, deuterium, hydroxyl, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, 3 -10 membered heterocyclic group, C 5-10 aryl group, 5-10 membered heteroaryl group, methoxy group, sulfonyl group, methanesulfonyl group, isopropylsulfonyl group, cyclopropylsulfonyl group, p-toluenesulfonyl group, amino group , Monoalkylamino, dialkylamino or C 1-10 alkanoyl, the above groups are optionally further selected by one or more selected from deuterium, halogen, hydroxyl, C 1-8 alkyl, C 1-10 alkoxy Group, C 3-10 cycloalkyl, C 3-10 cycloalkoxy, 3-10 membered heterocyclic group, 3-10 membered heterocyclicoxy group, C 5-10 aryl group, C 5-10 aryloxy group , 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, amino, monoalkylamino, dialkylamino or C 1-10 alkanoyl substituents;
或者，R 26、R 27和其直接相连的氮原子一起形成4-10元杂环基，上述基团任选进一步被一个或多个选自氘、卤素、羟基、C 1-10烷基、C 1-10烷氧基、C 3-10环烷基、C 3-10环烷氧基、3-10元杂环基、3-10元杂环氧基、C 5-10芳基、C 5-10芳氧基、5-10元杂芳基、5-10元杂芳氧基、氨基、单烷基氨基、二烷基氨基或C 1-10烷酰基的取代基所取代； Alternatively, R 26 and R 27 together with the nitrogen atom to which they are directly connected form a 4-10 membered heterocyclic group, and the above group is optionally further selected from one or more selected from deuterium, halogen, hydroxyl, C 1-10 alkyl, C 1-10 alkoxy, C 3-10 cycloalkyl, C 3-10 cycloalkoxy, 3-10 membered heterocyclyl, 3-10 membered heterocyclyloxy, C 5-10 aryl, C 5-10 aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, amino, monoalkylamino, dialkylamino or C 1-10 alkanoyl substituents;
R 28各自独立地选自C 1-10烷基或苯基，上述基团任选进一步被一个或多个选自氘、卤素、羟基、氰基、C 1-8烷基、C 1-10烷氧基、C 3-10环烷基、C 3-10环烷氧基、3-10元杂环基、3-10元杂环氧基或苯基的取代基所取代； R 28 is each independently selected from C 1-10 alkyl or phenyl, and the above groups are optionally further selected from one or more selected from deuterium, halogen, hydroxyl, cyano, C 1-8 alkyl, C 1-10 Substituted by substituents of alkoxy, C 3-10 cycloalkyl, C 3-10 cycloalkoxy, 3-10 membered heterocyclic group, 3-10 membered heterocyclic oxy group or phenyl group;
m1为0～3的整数；m2为0～5的整数；n为0～2的整数；每个p各自独立地为0～2的整数；每个q各自独立地为0～2的整数；每个r各自独立地为0～2的整数。m1 is an integer from 0 to 3; m2 is an integer from 0 to 5; n is an integer from 0 to 2; each p is independently an integer from 0 to 2; each q is independently an integer from 0 to 2; Each r is independently an integer from 0 to 2.
作为优选的方案，所述式(I)化合物、其立体异构体、前药或其药学上可接受盐中R 2选自氢、氘、卤素、氰基、硝基、叠氮基、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-8环烷基、 3-8元杂环基、C 5-8芳基、5-8元杂芳基、-C 0-4-S(O) rR 23、-C 0-4-O-R 24、-C 0-4-C(O)OR 24、-C 0-4-C(O)R 25、-C 0-4-O-C(O)R 25、-C 0-4-NR 26R 27、-C 0-4-C(O)NR 26R 27或-C 0-4-N(R 26)-C(O)R 25，上述基团任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、卤取代C 1-4烷基、C 3-8环烷基、3-8元杂环基、C 5-8芳基、5-8元杂芳基、＝O、-C 0-4-S(O) rR 23、-C 0-4-O-R 24、-C 0-4-C(O)OR 24、-C 0-4-C(O)R 25、-C 0-4-O-C(O)R 25、-C 0-4-NR 26R 27、-C 0-4-C(O)NR 26R 27或-C 0-4-N(R 26)-C(O)R 25的取代基所取代，R 23、R 24、R 25、R 26、R 27如式(I)化合物所述。 As a preferred solution, in the compound of formula (I), its stereoisomer, prodrug or pharmaceutically acceptable salt thereof, R 2 is selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 5-8 aryl, 5-8 membered hetero Aryl, -C 0-4 -S (O) r R 23 , -C 0-4 -OR 24 , -C 0-4 -C (O) OR 24 , -C 0-4 -C (O) R 25 , -C 0-4 -OC (O) R 25 , -C 0-4 -NR 26 R 27 , -C 0-4 -C (O) NR 26 R 27 or -C 0-4 -N (R 26 ) -C (O) R 25 , the above groups are optionally further selected from one or more selected from deuterium, halogen, cyano, nitro, azido, C 1-4 alkyl, C 2-4 alkene Group, C 2-4 alkynyl, halogen substituted C 1-4 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 5-8 aryl, 5-8 membered heteroaryl, = O, -C 0-4 -S (O) r R 23 , -C 0-4 -OR 24 , -C 0-4 -C (O) OR 24 , -C 0-4 -C (O) R 25 , -C 0-4 -OC (O) R 25 , -C 0-4 -NR 26 R 27 , -C 0-4 -C (O) NR 26 R 27 or -C 0-4 -N (R 26 ) -C (O) R 25 is substituted by a substituent, and R 23 , R 24 , R 25 , R 26 , and R 27 are as described for the compound of formula (I).
作为进一步优选的方案，所述式(I)化合物、其立体异构体、前药或其药学上可接受盐中R 2选自氢、氘、氟、氯、氰基、甲基、乙基、异丙基、乙烯基、烯丙基、乙炔基、环丙基、3-氧杂环丁基、3-氮杂环丁基、苯基、吡啶基、二氮唑、三氮唑、甲磺酰基、氨基磺酰基、甲氧基、甲氧酰基、羧基、乙酰基、乙酰氧基、氨基、二甲基氨基、氨基酰基或乙酰氨基，上述基团任选进一步被一个或多个选自氘、氟、氯、氰基、甲基、三氟甲基、环丙基、苯基、吡啶基、甲磺酰基、羟基、甲氧基、羧基或氨基的取代基所取代。 As a further preferred solution, in the compound of formula (I), its stereoisomer, prodrug or pharmaceutically acceptable salt thereof, R 2 is selected from hydrogen, deuterium, fluorine, chlorine, cyano, methyl, ethyl , Isopropyl, vinyl, allyl, ethynyl, cyclopropyl, 3-oxetanyl, 3-azetidinyl, phenyl, pyridyl, diazole, triazole, methyl Sulfonyl, aminosulfonyl, methoxy, methoxyyl, carboxyl, acetyl, acetoxy, amino, dimethylamino, aminoacyl or acetamido, the above groups are optionally further selected by one or more Deuterium, fluorine, chlorine, cyano, methyl, trifluoromethyl, cyclopropyl, phenyl, pyridyl, methanesulfonyl, hydroxy, methoxy, carboxy, or amino substituents are substituted.
作为优选的方案，所述式(I)化合物、其立体异构体、前药或其药学上可接受盐中每个R 8、R 9各自独立地选自氢、氘、卤素、氰基、硝基、叠氮基、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-8环烷基、3-8元杂环基、C 5-8芳基、5-8元杂芳基、-C 0-4-S(O) rR 23、-C 0-4-O-R 24、-C 0- 4-C(O)OR 24、-C 0-4-C(O)R 25、-C 0-4-O-C(O)R 25、-C 0-4-NR 26R 27、-C 0-4-C(O)NR 26R 27或-C 0-4-N(R 26)-C(O)R 25，上述基团任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、卤取代C 1-4烷基、C 3-8环烷基、3-8元杂环基、C 5-8芳基、5-8元杂芳基、＝O、-C 0-4-S(O) rR 23、-C 0-4-O-R 24、-C 0-4-C(O)OR 24、-C 0-4-C(O)R 25、-C 0-4-O-C(O)R 25、-C 0-4-NR 26R 27、-C 0-4-C(O)NR 26R 27或-C 0-4-N(R 26)-C(O)R 25的取代基所取代，R 23、R 24、R 25、R 26、R 27如式(I)化合物所述。 As a preferred solution, each of R 8 and R 9 in the compound of formula (I), its stereoisomer, prodrug or pharmaceutically acceptable salt thereof is independently selected from hydrogen, deuterium, halogen, cyano, Nitro, azido, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 5-8 Aryl, 5-8 membered heteroaryl, -C 0-4 -S (O) r R 23 , -C 0-4 -OR 24 , -C 0- 4 -C (O) OR 24 , -C 0 -4 -C (O) R 25 , -C 0-4 -OC (O) R 25 , -C 0-4 -NR 26 R 27 , -C 0-4 -C (O) NR 26 R 27 or- C 0-4 -N (R 26 ) -C (O) R 25 , the above groups are optionally further selected from one or more selected from deuterium, halogen, cyano, nitro, azido, C 1-4 alkyl Group, C 2-4 alkenyl, C 2-4 alkynyl, halogen substituted C 1-4 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic group, C 5-8 aryl, 5-8 membered heteroaryl, = O, -C 0-4 -S (O) r R 23 , -C 0-4 -OR 24 , -C 0-4 -C (O) OR 24 , -C 0 -4 -C (O) R 25 , -C 0-4 -OC (O) R 25 , -C 0-4 -NR 26 R 27 , -C 0-4 -C (O) NR 26 R 27 or- The substituents of C 0-4 -N (R 26 ) -C (O) R 25 are substituted, and R 23 , R 24 , R 25 , R 26 and R 27 are as described for the compound of formula (I).
作为进一步优选的方案，所述式(I)化合物、其立体异构体、前药或其药学上可接受盐中每个R 8、R 9各自独立地选自氢、氘、氟、氯、氰基、甲基、乙基、异丙基、乙烯基、烯丙基、乙炔基、环丙基、3-氧杂环丁基、3-氮杂环丁基、苯基、吡啶基、二氮唑、三氮唑、甲磺酰基、氨基磺酰基、羟基、甲氧基、甲氧酰基、羧基、乙酰基、乙酰氧基、氨基、二甲基氨基、氨基酰基或乙酰氨基，上述基团任选进一步被一个或多个选自氘、氟、氯、氰基、甲基、三氟甲基、环丙基、苯基、吡啶基、甲磺酰基、羟基、甲氧基、羧基或氨基的取代基所取代。 As a further preferred solution, each of R 8 and R 9 in the compound of formula (I), its stereoisomer, prodrug or pharmaceutically acceptable salt thereof is independently selected from hydrogen, deuterium, fluorine, chlorine, Cyano, methyl, ethyl, isopropyl, vinyl, allyl, ethynyl, cyclopropyl, 3-oxetanyl, 3-azetidinyl, phenyl, pyridyl, di Azole, triazole, mesyl, aminosulfonyl, hydroxy, methoxy, methoxy, carboxy, acetyl, acetoxy, amino, dimethylamino, aminoacyl or acetamido, the above groups Optionally further one or more selected from deuterium, fluorine, chlorine, cyano, methyl, trifluoromethyl, cyclopropyl, phenyl, pyridyl, mesyl, hydroxy, methoxy, carboxy, or amino Is replaced by the substituent.
作为优选的方案，所述式(I)化合物、其立体异构体、前药或其药学上可接受盐中R 3、R 4各自独立地选自氢、氘、卤素、氰基、硝基、叠氮基、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-8环烷基、3-8元杂环基、C 5-8芳基、5-8元杂芳基、-C 0-4-S(O) rR 23、-C 0-4-O-R 24、-C 0- 4-C(O)OR 24、-C 0-4-C(O)R 25、-C 0-4-O-C(O)R 25、-C 0-4-NR 26R 27、-C 0-4-C(O)NR 26R 27或-C 0-4-N(R 26)-C(O)R 25，或者，R 3与R 4和其直接相连的碳原子一起形成C(O)、3-8元环烷基、3-8元杂环基，上述基团任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-4烷基、C 2- 4链烯基、C 2-4链炔基、卤取代C 1-4烷基、C 3-8环烷基、3-8元杂环基、C 5-8芳基、5-8元杂芳 基、＝O、-C 0-4-S(O) rR 23、-C 0-4-O-R 24、-C 0-4-C(O)OR 24、-C 0-4-C(O)R 25、-C 0-4-O-C(O)R 25、-C 0- 4-NR 26R 27、-C 0-4-C(O)NR 26R 27或-C 0-4-N(R 26)-C(O)R 25的取代基所取代，R 23、R 24、R 25、R 26、R 27如式(I)化合物所述。 As a preferred embodiment, in the compound of formula (I), its stereoisomer, prodrug or pharmaceutically acceptable salt thereof, R 3 and R 4 are each independently selected from hydrogen, deuterium, halogen, cyano, nitro , Azido, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic group, C 5-8 aryl , 5-8 membered heteroaryl, -C 0-4 -S (O) r R 23 , -C 0-4 -OR 24 , -C 0- 4 -C (O) OR 24 , -C 0-4 -C (O) R 25 , -C 0-4 -OC (O) R 25 , -C 0-4 -NR 26 R 27 , -C 0-4 -C (O) NR 26 R 27 or -C 0 -4 -N (R 26 ) -C (O) R 25 , or, R 3 and R 4 together with the carbon atom directly connected to form C (O), 3-8 membered cycloalkyl, 3-8 membered hetero cycloalkyl group, the above groups optionally further substituted with one or more groups selected from deuterium, halogen, cyano, nitro, azido, C 1-4 alkyl, C 2- 4 alkenyl, C 2-4 chain Alkynyl, halogen substituted C 1-4 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 5-8 aryl, 5-8 membered heteroaryl, = O, -C 0- 4 -S (O) r R 23 , -C 0-4 -OR 24 , -C 0-4 -C (O) OR 24 , -C 0-4 -C (O) R 25 , -C 0-4 -OC (O) R 25 , -C 0- 4 -NR 26 R 27 , -C 0-4 -C (O) NR 26 R 27 or -C 0-4 -N (R 26 ) -C (O) R 2 The substituent of 5 is substituted, and R 23 , R 24 , R 25 , R 26 and R 27 are as described for the compound of formula (I).
作为进一步优选的方案，所述式(I)化合物、其立体异构体、前药或其药学上可接受盐中R 3、R 4各自独立地选自氢、氘、卤素、氰基、C 1-4烷基、C 3-6环烷基、4-6元杂环基、苯基、吡啶基、二氮唑、三氮唑、甲磺酰基、氨基磺酰基、羟基、甲氧基、甲氧酰基、乙氧酰基、羧基、乙酰基、乙酰氧基、氨基、二甲基氨基、氨基酰基或乙酰氨基，或者，R 3与R 4和其直接相连的碳原子一起形成C(O)、3-6元环烷基、3-6元杂环基，上述基团任选进一步被一个或多个选自氘、氟、氯、氰基、甲基、三氟甲基、环丙基、苯基、吡啶基、＝O、甲磺酰基、羟基、甲氧基、羧基或氨基的取代基所取代。 As a further preferred solution, in the compound of formula (I), its stereoisomer, prodrug or pharmaceutically acceptable salt thereof, R 3 and R 4 are each independently selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, C 3-6 cycloalkyl, 4-6 membered heterocyclyl, phenyl, pyridyl, diazole, triazole, methanesulfonyl, aminosulfonyl, hydroxyl, methoxy, Methoxy, ethoxy, carboxy, acetyl, acetoxy, amino, dimethylamino, aminoacyl or acetylamino, or R 3 and R 4 together with the carbon atom to which they are directly attached form C (O) , 3-6 membered cycloalkyl, 3-6 membered heterocyclic group, the above groups are optionally further selected from one or more selected from deuterium, fluorine, chlorine, cyano, methyl, trifluoromethyl, cyclopropyl , Phenyl, pyridyl, = 0, mesyl, hydroxy, methoxy, carboxy, or amino substituents.
作为优选的方案，所述式(I)化合物、其立体异构体、前药或其药学上可接受盐中R 1选自C 1-4烷基、C 2-4链烯基、C 3-8环烷基、3-8元杂环基、C 5-8芳基、5-8元杂芳基或-NR 21R 22，上述基团任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、卤取代C 1-4烷基、C 3-8环烷基、3-8元杂环基、C 5-8芳基、5-8元杂芳基、＝O、-C 0- 4-S(O) rR 23、-C 0-4-O-R 24、-C 0-4-C(O)OR 24、-C 0-4-C(O)R 25、-C 0-4-O-C(O)R 25、-C 0-4-NR 26R 27、-C 0- 4-C(O)NR 26R 27或-C 0-4-N(R 26)-C(O)R 25的取代基所取代，R 21、R 22、R 23、R 24、R 25、R 26、R 27如式(I)化合物所述。 As a preferred solution, in the compound of formula (I), its stereoisomer, prodrug or pharmaceutically acceptable salt thereof, R 1 is selected from C 1-4 alkyl, C 2-4 alkenyl, C 3 -8 cycloalkyl, 3-8 membered heterocyclic group, C 5-8 aryl group, 5-8 membered heteroaryl group or -NR 21 R 22 , the above groups are optionally further selected by one or more deuterium, Halogen, cyano, nitro, azido, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halogen substituted C 1-4 alkyl, C 3-8 cycloalkane Group, 3-8 membered heterocyclic group, C 5-8 aryl group, 5-8 membered heteroaryl group, = O, -C 0- 4 -S (O) r R 23 , -C 0-4 -OR 24 , -C 0-4 -C (O) OR 24 , -C 0-4 -C (O) R 25 , -C 0-4 -OC (O) R 25 , -C 0-4 -NR 26 R 27 , -C 0- 4 -C (O) NR 26 R 27 or -C 0-4 -N (R 26 ) -C (O) R 25 substituent, R 21 , R 22 , R 23 , R 24 , R 25 , R 26 and R 27 are as described for the compound of formula (I).
作为进一步优选的方案，所述式(I)化合物、其立体异构体、前药或其药学上可接受盐中R 1选自C 1-4烷基、C 3-6环烷基、3-6元杂环基、苯基、吡啶基、二氮唑、三氮唑、氨基或二甲基氨基，上述基团任选进一步被一个或多个选自上述基团任选进一步被一个或多个选自氘、氟、氯、氰基、甲基、三氟甲基、环丙基、苯基、吡啶基、甲磺酰基、羟基、甲氧基、羧基或氨基的取代基所取代。 As a further preferred solution, in the compound of formula (I), its stereoisomer, prodrug or pharmaceutically acceptable salt thereof, R 1 is selected from C 1-4 alkyl, C 3-6 cycloalkyl, 3 -6 membered heterocyclic group, phenyl, pyridyl, diazole, triazole, amino or dimethylamino, the above groups are optionally further selected by one or more groups A plurality of substituents selected from deuterium, fluorine, chlorine, cyano, methyl, trifluoromethyl, cyclopropyl, phenyl, pyridyl, mesyl, hydroxy, methoxy, carboxy, or amino are substituted.
作为优选的方案，所述式(I)化合物、其立体异构体、前药或其药学上可接受盐中R 6选自氢、氘、卤素、氰基、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-8环烷基、3-8元杂环基、苯基、5-8元杂芳基、-C 0-4-S(O) rR 23、-C 0-4-O-R 24、-C 0-4-C(O)OR 24、-C 0-4-C(O)R 25、-C 0-4-O-C(O)R 25、-C 0-4-NR 26R 27、-C 0-4-C(O)NR 26R 27或-C 0-4-N(R 26)-C(O)R 25，上述基团任选进一步被一个或多个选自氘、卤素、氰基、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、卤取代C 1-4烷基、C 3-8环烷基、3-8元杂环基、苯基、5-8元杂芳基、＝O、-S(O) rR 23、-O-R 24、-C(O)OR 24、-C(O)R 25、-O-C(O)R 25、-NR 26R 27、-C(O)NR 26R 27或-N(R 26)-C(O)R 25的取代基所取代，R 23、R 24、R 25、R 26、R 27如式(I)化合物所述。 As a preferred solution, in the compound of formula (I), its stereoisomer, prodrug or pharmaceutically acceptable salt thereof, R 6 is selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, phenyl, 5-8 membered heteroaryl, -C 0-4 -S ( O) r R 23 , -C 0-4 -OR 24 , -C 0-4 -C (O) OR 24 , -C 0-4 -C (O) R 25 , -C 0-4 -OC (O ) R 25 , -C 0-4 -NR 26 R 27 , -C 0-4 -C (O) NR 26 R 27 or -C 0-4 -N (R 26 ) -C (O) R 25 , above The group is optionally further substituted with one or more selected from deuterium, halogen, cyano, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halogen substituted C 1-4 alkyl , C 3-8 cycloalkyl, 3-8 membered heterocyclic group, phenyl, 5-8 membered heteroaryl, = O, -S (O) r R 23 , -OR 24 , -C (O) OR 24 , -C (O) R 25 , -OC (O) R 25 , -NR 26 R 27 , -C (O) NR 26 R 27 or -N (R 26 ) -C (O) R 25 substituent Instead, R 23 , R 24 , R 25 , R 26 and R 27 are as described for the compound of formula (I).
作为进一步优选的方案，所述式(I)化合物、其立体异构体、前药或其药学上可接受盐中R 6选自氢、氘、卤素、氰基、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-6环烷基、3-6元杂环基、苯基、5-6元杂芳基、-O-R 24、-C(O)OR 24、-C(O)R 25或-NR 26R 27，上述基团任选进一步被一个或多个选自氘、氟、氯、氰基、甲基、乙基、异丙基、乙烯基、烯丙基、乙炔基、三氟甲基、二氟甲基、环丙基、环丁基、3-氧杂环丁基、3-氮杂环丁基、哌啶基、哌嗪基、吗啉基、苯基、二氮唑、三氮唑、＝O、磺酰基、甲磺酰基、异丙磺酰基、氨基磺酰基、羟基、甲氧基、 三氟甲氧基、三氘甲氧基、羧基、甲氧羰基、乙氧羰基、乙酰基、乙酰氧基、氨基、二甲氨基或乙酰氨基的取代基所取代，R 24、R 25、R 26、R 27如式(I)化合物所述。 As a further preferred solution, in the compound of formula (I), its stereoisomer, prodrug or pharmaceutically acceptable salt thereof, R 6 is selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, -OR 24 , -C ( O) OR 24 , -C (O) R 25 or -NR 26 R 27 , the above groups are optionally further selected by one or more selected from deuterium, fluorine, chlorine, cyano, methyl, ethyl, isopropyl , Vinyl, allyl, ethynyl, trifluoromethyl, difluoromethyl, cyclopropyl, cyclobutyl, 3-oxetanyl, 3-azetidinyl, piperidinyl, piper Azinyl, morpholinyl, phenyl, diazole, triazole, = O, sulfonyl, methanesulfonyl, isopropylsulfonyl, aminosulfonyl, hydroxyl, methoxy, trifluoromethoxy, tri Deuterium methoxy, carboxy, methoxycarbonyl, ethoxycarbonyl, acetyl, acetoxy, amino, dimethylamino or acetamido substituents are substituted, R 24 , R 25 , R 26 , R 27 are as the formula ( I) Compound description.
作为优选的方案，所述式(I)化合物、其立体异构体、前药或其药学上可接受盐中各R 7独立地选自氢、氘、氟、氯、氰基、C 1-4烷基、C 3-8环烷基、3-8元杂环基、C 5-8芳基、5-8元杂芳基、-P(O)(R 28) 2、-SF 5、-S(O) rR 23、-C 0-4-O-R 24、-C 0-4-C(O)OR 24、-C 0-4-C(O)R 25、-C 0-4-O-C(O)R 25、-C 0-4-NR 26R 27、-C 0-4-C(O)NR 26R 27或-C 0-4-N(R 26)-C(O)R 25，上述基团任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、卤取代C 1-4烷基、C 3-8环烷基、3-8元杂环基、C 5-8芳基、5-8元杂芳基、＝O、-C 0-4-S(O) rR 23、-C 0-4-O-R 24、-C 0-4-C(O)OR 24、-C 0-4-C(O)R 25、-C 0-4-O-C(O)R 25、-C 0-4-NR 26R 27、-C 0-4-C(O)NR 26R 27或-C 0-4-N(R 26)-C(O)R 25的取代基所取代，R 23、R 24、R 25、R 26、R 27、R 28如式(I)化合物所述。 As a preferred embodiment, each R 7 in the compound of formula (I), its stereoisomer, prodrug or pharmaceutically acceptable salt thereof is independently selected from hydrogen, deuterium, fluorine, chlorine, cyano, C 1- 4 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 5-8 aryl, 5-8 membered heteroaryl, -P (O) (R 28 ) 2 , -SF 5 , -S (O) r R 23 , -C 0-4 -OR 24 , -C 0-4 -C (O) OR 24 , -C 0-4 -C (O) R 25 , -C 0-4- OC (O) R 25 , -C 0-4 -NR 26 R 27 , -C 0-4 -C (O) NR 26 R 27 or -C 0-4 -N (R 26 ) -C (O) R 25 , the above group is optionally further selected from one or more selected from deuterium, halogen, cyano, nitro, azido, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkyne Group, halogen substituted C 1-4 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic group, C 5-8 aryl group, 5-8 membered heteroaryl group, = O, -C 0-4 -S (O) r R 23 , -C 0-4 -OR 24 , -C 0-4 -C (O) OR 24 , -C 0-4 -C (O) R 25 , -C 0-4- OC (O) R 25 , -C 0-4 -NR 26 R 27 , -C 0-4 -C (O) NR 26 R 27 or -C 0-4 -N (R 26 ) -C (O) R Substituted by the substituent of 25 , and R 23 , R 24 , R 25 , R 26 , R 27 and R 28 are as described for the compound of formula (I).
作为进一步优选的方案，所述式(I)化合物、其立体异构体、前药或其药学上可接受盐中各R 7独立地选自氢、氘、卤素、氰基、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-8环烷基、3-8元杂环基、C 5-8芳基、5-8元杂芳基、-P(O)(CH 3) 2、-P(O)H 2、-SF 5、磺酰基、甲磺酰基、异丙磺酰基、氨基磺酰基、-O-R 24、-C(O)R 25、-C(O)OH、-C(O)NR 26R 27、氨基或二甲氨基，上述基团任选进一步被一个或多个选自氘、氟、氯、氰基、甲基、乙基、异丙基、乙烯基、烯丙基、乙炔基、三氟甲基、二氟甲基、环丙基、环丁基、3-氧杂环丁基、3-氮杂环丁基、哌啶基、哌嗪基、吗啉基、苯基、二氮唑、三氮唑、＝O、磺酰基、甲磺酰基、异丙磺酰基、氨基磺酰基、羟基、甲氧基、三氟甲氧基、三氘甲氧基、羧基、甲氧羰基、乙氧羰基、乙酰基、乙酰氧基、氨基、二甲氨基或乙酰氨基的取代基所取代，R 24、R 25、R 26、R 27如式(I)化合物所述。 As a further preferred embodiment, each R 7 in the compound of formula (I), its stereoisomer, prodrug or pharmaceutically acceptable salt thereof is independently selected from hydrogen, deuterium, halogen, cyano, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 5-8 aryl, 5-8 membered heteroaryl, -P (O) (CH 3 ) 2 , -P (O) H 2 , -SF 5 , sulfonyl, methanesulfonyl, isopropylsulfonyl, aminosulfonyl, -OR 24 , -C (O) R 25 , -C (O) OH, -C (O) NR 26 R 27 , amino or dimethylamino, the above groups are optionally further selected by one or more selected from deuterium, fluorine, chlorine, cyano, methyl, ethyl Group, isopropyl, vinyl, allyl, ethynyl, trifluoromethyl, difluoromethyl, cyclopropyl, cyclobutyl, 3-oxetanyl, 3-azetidinyl, Piperidinyl, piperazinyl, morpholinyl, phenyl, diazole, triazole, = 0, sulfonyl, methanesulfonyl, isopropylsulfonyl, aminosulfonyl, hydroxyl, methoxy, trifluoro Methoxy, trideuteromethoxy, carboxy, methoxycarbonyl, ethoxycarbonyl, acetyl, acetoxy, amino, dimethylamino or acetylamino Substituted by a substituent, R 24 , R 25 , R 26 and R 27 are as described for the compound of formula (I).
作为优选的方案，所述式(I)化合物、其立体异构体、前药或其药学上可接受盐中L选自-[C(R 10R 11)] n-、-NH 2-、-CH 2-NH-、-NH-CH 2-、-[C(R 13R 14)] p-O-[C(R 15R 16)] q-、-S-、-S-CH 2-、-S(O) 2-、-S(O) 2-CH 2-、-C(R 17)＝C(R 18)-、-NH-S(O) 2-、-NH-C(O)-或-N(CH 3)-C(O)-； As a preferred solution, L in the compound of formula (I), its stereoisomer, prodrug or pharmaceutically acceptable salt thereof is selected from-[C (R 10 R 11 )] n- , -NH 2- , -CH 2 -NH-, -NH-CH 2 -,-[C (R 13 R 14 )] p -O- [C (R 15 R 16 )] q- , -S-, -S-CH 2- , -S (O) 2 -, - S (O) 2 -CH 2 -, - C (R 17) = C (R 18) -, - NH-S (O) 2 -, - NH-C (O ) -Or-N (CH 3 ) -C (O)-;
R 10、R 11、R 13、R 14、R 15、R 16各自独立地选自氢、氘、氟、氯、C 1-4烷基、C 3-8环烷基、3-8元杂环基、C 5-8芳基、5-8元杂芳基、-C 0-4-S-R 23、-C 0-4-O-R 24或-NH 2，或者，R 10与R 11、R 13与R 14、R 15与R 16和其直接相连的碳原子一起各自独立地形成C(O)、3-8元环烷基、3-8元杂环基，上述基团任选进一步被一个或多个选自氘、氟、氯、氰基、C 1-4烷基、卤取代C 1- 4烷基、C 3-8环烷基、3-8元杂环基、苯基、5-8元杂芳基、＝O、-O-R 24、-C(O)OR 24或-NR 26R 27或的取代基所取代； R 10 , R 11 , R 13 , R 14 , R 15 , R 16 are each independently selected from hydrogen, deuterium, fluorine, chlorine, C 1-4 alkyl, C 3-8 cycloalkyl, 3-8 membered hetero Cyclic group, C 5-8 aryl group, 5-8 membered heteroaryl group, -C 0-4 -SR 23 , -C 0-4 -OR 24 or -NH 2 , or, R 10 and R 11 , R 13 Together with R 14 , R 15 and R 16 and the carbon atom to which they are directly connected, each independently forms C (O), a 3-8 membered cycloalkyl group, a 3-8 membered heterocyclic group, and the above groups are optionally further or more substituents selected from deuterium, fluoro, chloro, cyano, C 1-4 alkyl, halo-substituted C 1- 4 alkyl group, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, phenyl, 5 -8-membered heteroaryl, = O, -OR 24 , -C (O) OR 24 or -NR 26 R 27 or substituents;
R 17、R 18各自独立地选自氢、氘、氟、氰基、甲基、三氟甲基、三氘甲基、环丙甲基或乙基； R 17 and R 18 are each independently selected from hydrogen, deuterium, fluorine, cyano, methyl, trifluoromethyl, trideuteromethyl, cyclopropylmethyl or ethyl;
R 23、R 24、R 26、R 27如式(I)化合物所述。 R 23 , R 24 , R 26 and R 27 are as described for the compound of formula (I).
作为更进一步优选的方案，前述式(I)化合物、其立体异构体、前药或其药学上可接受盐具有如下式(Ⅱ)化合物结构：As a further preferred solution, the aforementioned compound of formula (I), its stereoisomer, prodrug or pharmaceutically acceptable salt thereof has the structure of the compound of formula (II) as follows:
Figure PCTCN2019104957-appb-000002
Figure PCTCN2019104957-appb-000002
其中，X 1、X 2各自独立地选自C(R 8)或N； Wherein, X 1 and X 2 are each independently selected from C (R 8 ) or N;
Y选自CH或N；L选自-[C(R 10R 11)] n-、-NH 2-、-O-[C(R 15R 16)] q-、-S-、-S(O) 2-或-CH＝CH-； Y is selected from CH or N; L is selected from-[C (R 10 R 11 )] n- , -NH 2- , -O- [C (R 15 R 16 )] q- , -S-, -S ( O) 2 -or -CH = CH-;
R 1选自C 1-4烷基、C 3-6环烷基、苯基、氨基或二甲基氨基，上述基团任选进一步被一个或多个选自上述基团任选进一步被一个或多个选自氘、氟、氯、氰基、甲基、三氟甲基、环丙基、苯基、羟基、甲氧基、羧基或氨基的取代基所取代； R 1 is selected from C 1-4 alkyl, C 3-6 cycloalkyl, phenyl, amino or dimethylamino, the above groups are optionally further substituted by one or more Or more substituents selected from deuterium, fluorine, chlorine, cyano, methyl, trifluoromethyl, cyclopropyl, phenyl, hydroxyl, methoxy, carboxyl or amino;
R 3、R 4各自独立地选自氢、氘、卤素、C 1-4烷基、C 3-6环烷基、3-氧杂环丁基、3-氮杂环丁基、羟基、甲氧基、乙氧酰基、羧基、氨基、甲基氨基或二甲基氨基，或者，R 3与R 4和其直接相连的碳原子一起形成C(O)、环丙基、环丁基、3-氧杂环丁基或3-氮杂环丁基，上述基团任选进一步被一个或多个选自氘、氟、氯、甲基、三氟甲基、环丙基、苯基、吡啶基、＝O、羟基、甲氧基、羧基或氨基的取代基所取代； R 3 and R 4 are each independently selected from hydrogen, deuterium, halogen, C 1-4 alkyl, C 3-6 cycloalkyl, 3-oxetanyl, 3-azetidinyl, hydroxy, methyl Oxygen, ethoxyacyl, carboxyl, amino, methylamino or dimethylamino, or R 3 and R 4 together with the carbon atom directly connected to form C (O), cyclopropyl, cyclobutyl, 3 -Oxetanyl or 3-azetidinyl, the above groups are optionally further selected from one or more of deuterium, fluorine, chlorine, methyl, trifluoromethyl, cyclopropyl, phenyl, pyridine Substituent, = O, hydroxy, methoxy, carboxy, or amino substituents;
R 6选自氢、氘、卤素、氰基、C 1-4烷基、C 3-6环烷基、3-6元杂环基、苯基、吡啶基、二氮唑、三氮唑、-O-R 24、-C(O)OR 24或-NR 26R 27，上述基团任选进一步被一个或多个选自氘、氟、氯、氰基、甲基、乙基、异丙基、乙烯基、烯丙基、乙炔基、三氟甲基、二氟甲基、环丙基、环丁基、3-氧杂环丁基、3-氮杂环丁基、哌啶基、哌嗪基、吗啉基、苯基、二氮唑、三氮唑、＝O、磺酰基、甲磺酰基、异丙磺酰基、氨基磺酰基、羟基、甲氧基、三氟甲氧基、三氘甲氧基、羧基、甲氧羰基、乙氧羰基、乙酰基、乙酰氧基、氨基、二甲氨基或乙酰氨基的取代基所取代； R 6 is selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic group, phenyl, pyridyl, diazole, triazole, -OR 24 , -C (O) OR 24 or -NR 26 R 27 , the above groups are optionally further selected from one or more selected from deuterium, fluorine, chlorine, cyano, methyl, ethyl, isopropyl, Vinyl, allyl, ethynyl, trifluoromethyl, difluoromethyl, cyclopropyl, cyclobutyl, 3-oxetanyl, 3-azetidinyl, piperidinyl, piperazine Group, morpholinyl, phenyl, diazole, triazole, = 0, sulfonyl, methanesulfonyl, isopropylsulfonyl, aminosulfonyl, hydroxyl, methoxy, trifluoromethoxy, trideuterium Substituted by a substituent of methoxy, carboxy, methoxycarbonyl, ethoxycarbonyl, acetyl, acetoxy, amino, dimethylamino or acetylamino;
每个R 7独立地选自氢、氘、卤素、氰基、C 1-4烷基、C 3-6环烷基、3-6元杂环基、苯基、-P(O)(CH 3) 2、-P(O)H 2、-SF 5、磺酰基、甲磺酰基、异丙磺酰基、氨基磺酰基、甲氧基、乙氧基、异丙氧基、-C(O)R 25、-C(O)OH、-C(O)NR 26R 27、氨基或二甲氨基，上述基团任选进一步被一个或多个选自氘、氟、氯、氰基、甲基、乙基、异丙基、三氟甲基、二氟甲基、环丙基、环丁基、3-氧杂环丁基、3-氮杂环丁基、哌啶基、哌嗪基、吗啉基、苯基、＝O、磺酰基、甲磺酰基、异丙磺酰基、氨基磺酰基、羟基、甲氧基、三氟甲氧基、三氘甲氧基、羧基、甲氧羰基、乙氧羰基、乙酰基、乙酰氧基、氨基、二甲氨基或乙酰氨基的取代基所取代； Each R 7 is independently selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, phenyl, -P (O) (CH 3 ) 2 , -P (O) H 2 , -SF 5 , sulfonyl, methanesulfonyl, isopropylsulfonyl, aminosulfonyl, methoxy, ethoxy, isopropoxy, -C (O) R 25 , -C (O) OH, -C (O) NR 26 R 27 , amino or dimethylamino, the above groups are optionally further selected by one or more selected from deuterium, fluorine, chlorine, cyano, methyl , Ethyl, isopropyl, trifluoromethyl, difluoromethyl, cyclopropyl, cyclobutyl, 3-oxetanyl, 3-azetidinyl, piperidinyl, piperazinyl, Morpholinyl, phenyl, = 0, sulfonyl, methanesulfonyl, isopropylsulfonyl, aminosulfonyl, hydroxy, methoxy, trifluoromethoxy, trideuteromethoxy, carboxy, methoxycarbonyl, Substitution by ethoxycarbonyl, acetyl, acetoxy, amino, dimethylamino or acetylamino substituents;
每个R 8各自独立地选自氢、氘、氟、氯、氰基、甲基、乙基、异丙基、环丙基、3-氧杂环丁基、3-氮杂环丁基、羟基、甲氧基、乙氧基、异丙氧基、羧基、氨基或二甲基氨基，上述基团任选进一步被一个或多个选自氘、氟、氯、氰基、甲基、三氟甲基、环丙基、苯基、吡啶基、羟基、甲氧基、羧基或氨基的取代基所取代； Each R 8 is independently selected from hydrogen, deuterium, fluorine, chlorine, cyano, methyl, ethyl, isopropyl, cyclopropyl, 3-oxetanyl, 3-azetidinyl, Hydroxy, methoxy, ethoxy, isopropoxy, carboxy, amino or dimethylamino, the above groups are optionally further selected by one or more selected from deuterium, fluorine, chlorine, cyano, methyl, tri Substituted by substituents of fluoromethyl, cyclopropyl, phenyl, pyridyl, hydroxy, methoxy, carboxy, or amino;
R 10、R 11、R 15、R 16各自独立地选自氢、氘、氟、氯、C 1-4烷基、C 3-8环烷基、3-8元杂环基、C 5-8芳基、5-8元杂芳基、-C 0-4-S-R 23、-C 0-4-O-R 24或-NH 2，或者，R 10与R 11、R 15与R 16和 其直接相连的碳原子一起各自独立地形成C(O)、3-8元环烷基、3-8元杂环基，上述基团任选进一步被一个或多个选自氘、氟、氯、氰基、C 1-4烷基、卤取代C 1-4烷基、C 3-8环烷基、3-8元杂环基、苯基、5-8元杂芳基、＝O、-O-R 24、-C(O)OR 24或-NR 26R 27或的取代基所取代； R 10 , R 11 , R 15 , R 16 are each independently selected from hydrogen, deuterium, fluorine, chlorine, C 1-4 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic group, C 5- 8 aryl, 5-8 membered heteroaryl, -C 0-4 -SR 23 , -C 0-4 -OR 24 or -NH 2 , or R 10 and R 11 , R 15 and R 16 and their direct The connected carbon atoms together independently form C (O), a 3-8 membered cycloalkyl group, a 3-8 membered heterocyclic group, the above groups are optionally further selected by one or more selected from deuterium, fluorine, chlorine, cyanide Group, C 1-4 alkyl, halogen substituted C 1-4 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic group, phenyl group, 5-8 membered heteroaryl, = O, -OR 24 , -C (O) OR 24 or -NR 26 R 27 or substituents;
环A、R 23、R 24、R 25、R 26、R 27、m2如式(I)化合物所述。 Ring A, R 23 , R 24 , R 25 , R 26 , R 27 , and m2 are as described for the compound of formula (I).
作为更进一步优选的方案，前述式(I)化合物、其立体异构体、前药或其药学上可接受盐具有如下式(Ⅲ)化合物结构：As a further preferred solution, the aforementioned compound of formula (I), its stereoisomer, prodrug or pharmaceutically acceptable salt thereof has the structure of the compound of formula (III) as follows:
Figure PCTCN2019104957-appb-000003
Figure PCTCN2019104957-appb-000003
其中，X 1、X 2各自独立地选自C(R 8)或N；每个Y各自独立地选自CH或N；每个L各自独立地选自-[C(R 10R 11)] n-、-O-CH 2-、-O-CH(CH 3)-、-O-CH(OH)-或-CH＝CH-； Wherein, X 1 and X 2 are each independently selected from C (R 8 ) or N; each Y is independently selected from CH or N; each L is independently selected from-[C (R 10 R 11 )] n- , -O-CH 2- , -O-CH (CH 3 )-, -O-CH (OH)-or -CH = CH-;
R 3各自独立地选自氢、氘、卤素、C 1-4烷基、C 3-6环烷基、3-氧杂环丁基、3-氮杂环丁基、羟基、甲氧基、乙氧酰基、羧基、氨基、甲基氨基或二甲基氨基，上述基团任选进一步被一个或多个选自氘、氟、氯、甲基、三氟甲基、环丙基、苯基、吡啶基、＝O、羟基、甲氧基、羧基或氨基的取代基所取代； R 3 is each independently selected from hydrogen, deuterium, halogen, C 1-4 alkyl, C 3-6 cycloalkyl, 3-oxetanyl, 3-azetidinyl, hydroxy, methoxy, Ethoxyl, carboxyl, amino, methylamino or dimethylamino, the above groups are optionally further selected from one or more selected from deuterium, fluorine, chlorine, methyl, trifluoromethyl, cyclopropyl, phenyl , Pyridyl, = 0, hydroxyl, methoxy, carboxy, or amino substituents;
R 10、R 11各自独立地选自氢、氘、氟、氯、甲基、三氟甲基、三氘甲基、环丙甲基、甲氧甲基、氨甲基、苄基、乙基、异丙基、环丙基、3-氧杂环丁基、羟基、甲氧基、三氟甲氧基、二氟甲氧基、三氘甲氧基、二氘甲氧基或-NH 2，或者，R 10与R 11和其直接相连的碳原子一起形成C(O)、环丙基、环丁基、3-氧杂环丁基； R 10 and R 11 are each independently selected from hydrogen, deuterium, fluorine, chlorine, methyl, trifluoromethyl, trideuteromethyl, cyclopropylmethyl, methoxymethyl, aminomethyl, benzyl, ethyl , Isopropyl, cyclopropyl, 3-oxetanyl, hydroxy, methoxy, trifluoromethoxy, difluoromethoxy, trideuteromethoxy, dideuteromethoxy or -NH 2 Or, R 10 and R 11 together with the carbon atom directly connected to them form C (O), cyclopropyl, cyclobutyl, 3-oxetanyl;
环A、R 1、R 6、R 7、R 8、m2如前所述。 Rings A, R 1 , R 6 , R 7 , R 8 and m2 are as described above.
作为更进一步优选的方案，前述式(I)化合物、其立体异构体、前药或其药学上可接受盐具有如下选自式(Ⅳ)化合物结构：As a further preferred solution, the aforementioned compound of formula (I), its stereoisomer, prodrug or pharmaceutically acceptable salt thereof has the structure selected from the compound of formula (IV) as follows:
Figure PCTCN2019104957-appb-000004
Figure PCTCN2019104957-appb-000004
其中，每个Y各自独立地选自CH或N；每个L各自独立地选自键、-C(R 10R 11)-、-O-CH 2-、-O-CH(CH 3)-、-O-CH(OH)-或-CH＝CH-； Wherein each Y is independently selected from CH or N; each L is independently selected from a bond, -C (R 10 R 11 )-, -O-CH 2- , -O-CH (CH 3 )- , -O-CH (OH)-or -CH = CH-;
R 1各自独立地选自甲基、乙基、异丙基、环丙基、三氟甲基、三氘甲基、环丙甲基或氨基； R 1 is independently selected from methyl, ethyl, isopropyl, cyclopropyl, trifluoromethyl, trideuteromethyl, cyclopropylmethyl or amino;
R 3各自独立地选自氢、氘、氟、氯、甲基、乙基、异丙基、环丙基、3-氧杂环丁基、3-氮杂环丁基、羟基、甲氧基、乙氧酰基、羧基或氨基，上述基团任选进一步被一个或多个选自氘、氟、氯、甲基、三氟甲基、环丙基、羟基、甲氧基、羧基或氨基的取代基所取代； R 3 is each independently selected from hydrogen, deuterium, fluorine, chlorine, methyl, ethyl, isopropyl, cyclopropyl, 3-oxetanyl, 3-azetidinyl, hydroxy, methoxy , Ethoxyl, carboxyl or amino, the above groups are optionally further selected by one or more selected from deuterium, fluorine, chlorine, methyl, trifluoromethyl, cyclopropyl, hydroxyl, methoxy, carboxyl or amino Substituted by a substituent;
R 6各自独立地选自氢、氘、氟、氯、氰基、甲基、乙基、异丙基、环丙基、环丁基、环戊基、3-氧杂环丁基、3-氮杂环丁基、甲氧基、乙氧基、羧基、甲氧羰基、乙氧羰基、氨基 或二甲氨基，上述基团任选进一步被一个或多个选自氘、氟、氯、氰基、甲基、乙基、异丙基、乙烯基、烯丙基、乙炔基、三氟甲基、二氟甲基、环丙基、环丁基、羟基、甲氧基、三氟甲氧基、三氘甲氧基、羧基或氨基的取代基所取代； R 6 is each independently selected from hydrogen, deuterium, fluorine, chlorine, cyano, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, 3-oxetanyl, 3- Azetidinyl, methoxy, ethoxy, carboxyl, methoxycarbonyl, ethoxycarbonyl, amino or dimethylamino, the above groups are optionally further selected by one or more selected from deuterium, fluorine, chlorine, cyanide Group, methyl, ethyl, isopropyl, vinyl, allyl, ethynyl, trifluoromethyl, difluoromethyl, cyclopropyl, cyclobutyl, hydroxy, methoxy, trifluoromethoxy Substituted by the substituent of the group, trideuteromethoxy, carboxyl or amino;
每个R 7各自独立地选自氢、氘、卤素、氰基、C 1-4烷基、C 3-6环烷基、3-6元杂环基、苯基、-P(O)(CH 3) 2、-P(O)H 2、-SF 5、甲磺酰基、甲氧基、乙氧基、异丙氧基、-C(O)R 25或-C(O)NR 26R 27，上述基团任选进一步被一个或多个选自氘、氟、氯、氰基、甲基、乙基、异丙基、三氟甲基、二氟甲基、环丙基、环丁基、3-氧杂环丁基、3-氮杂环丁基、哌啶基、哌嗪基、吗啉基、苯基、＝O、磺酰基、甲磺酰基、异丙磺酰基、氨基磺酰基、羟基、甲氧基、三氟甲氧基、三氘甲氧基、羧基、甲氧羰基、乙氧羰基、乙酰基、乙酰氧基、氨基、二甲氨基或乙酰氨基的取代基所取代； Each R 7 is independently selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, phenyl, -P (O) ( CH 3 ) 2 , -P (O) H 2 , -SF 5 , methanesulfonyl, methoxy, ethoxy, isopropoxy, -C (O) R 25 or -C (O) NR 26 R 27 , the above groups are optionally further selected from one or more selected from deuterium, fluorine, chlorine, cyano, methyl, ethyl, isopropyl, trifluoromethyl, difluoromethyl, cyclopropyl, cyclobutane Group, 3-oxetanyl, 3-azetidinyl, piperidinyl, piperazinyl, morpholinyl, phenyl, = 0, sulfonyl, methanesulfonyl, isopropylsulfonyl, sulfamoyl Substitution by acyl, hydroxy, methoxy, trifluoromethoxy, trideuteromethoxy, carboxy, methoxycarbonyl, ethoxycarbonyl, acetyl, acetoxy, amino, dimethylamino, or acetylamino substituents ;
每个R 8各自独立地选自氢、氘、氟、氯、氰基、甲基、乙基、异丙基、环丙基、3-氧杂环丁基、3-氮杂环丁基、羟基、甲氧基、乙氧基、异丙氧基、羧基、氨基或二甲基氨基，上述基团任选进一步被一个或多个选自氘、氟、氯、氰基、甲基、三氟甲基、环丙基、羟基、甲氧基、羧基或氨基的取代基所取代； Each R 8 is independently selected from hydrogen, deuterium, fluorine, chlorine, cyano, methyl, ethyl, isopropyl, cyclopropyl, 3-oxetanyl, 3-azetidinyl, Hydroxy, methoxy, ethoxy, isopropoxy, carboxy, amino or dimethylamino, the above groups are optionally further selected by one or more selected from deuterium, fluorine, chlorine, cyano, methyl, tri Substituted by substituents of fluoromethyl, cyclopropyl, hydroxy, methoxy, carboxy, or amino;
R 10、R 11各自独立地选自氢、氘、氟、氯、甲基、三氟甲基、三氘甲基、环丙甲基、甲氧甲基、氨甲基、苄基、乙基、异丙基、环丙基、3-氧杂环丁基、羟基、甲氧基、三氟甲氧基、二氟甲氧基、三氘甲氧基、二氘甲氧基或-NH 2，或者，R 10与R 11和其直接相连的碳原子一起形成C(O)、环丙基、环丁基、3-氧杂环丁基； R 10 and R 11 are each independently selected from hydrogen, deuterium, fluorine, chlorine, methyl, trifluoromethyl, trideuteromethyl, cyclopropylmethyl, methoxymethyl, aminomethyl, benzyl, ethyl , Isopropyl, cyclopropyl, 3-oxetanyl, hydroxy, methoxy, trifluoromethoxy, difluoromethoxy, trideuteromethoxy, dideuteromethoxy or -NH 2 Or, R 10 and R 11 together with the carbon atom directly connected to them form C (O), cyclopropyl, cyclobutyl, 3-oxetanyl;
每个R 25各自独立地选自氢、氘、氟、氯、羟基、甲基、乙基或异丙基； Each R 25 is independently selected from hydrogen, deuterium, fluorine, chlorine, hydroxyl, methyl, ethyl or isopropyl;
每个R 26、R 27各自独立地选自氢、氘、羟基、甲基、乙基、异丙基、环丙基、苯基、甲氧基、磺酰基、甲磺酰基、氨基、单烷基氨基、二烷基氨基或C 1-10烷酰基，上述基团任选进一步被一个或多个选自氘、卤素、羟基、甲基、乙基、异丙基、环丙基、苯基、甲氧基、氨基、单烷基氨基、二烷基氨基或C 1-10烷酰基的取代基所取代； Each R 26 , R 27 is independently selected from hydrogen, deuterium, hydroxyl, methyl, ethyl, isopropyl, cyclopropyl, phenyl, methoxy, sulfonyl, methanesulfonyl, amino, monoalkane Amino group, dialkylamino group or C 1-10 alkanoyl group, the above groups are optionally further selected from one or more selected from deuterium, halogen, hydroxyl, methyl, ethyl, isopropyl, cyclopropyl, phenyl , Methoxy, amino, monoalkylamino, dialkylamino or C 1-10 alkanoyl substituents;
环A、m2如前所述。Rings A and m2 are as described above.
作为更进一步优选的方案，前述式(I)化合物、其立体异构体、前药或其药学上可接受盐中环A与其直接相连的基团L、R 7一起形成如下结构： As a further preferred solution, the compound of formula (I), its stereoisomer, prodrug or pharmaceutically acceptable salt thereof, ring A, together with the directly connected groups L and R 7 form the following structure:
Figure PCTCN2019104957-appb-000005
Figure PCTCN2019104957-appb-000005
其中，每个L各自独立地选自键、-C(R 10R 11)-、-O-CH 2-、-O-CH(CH 3)-、-O-CH(OH)-或-CH＝CH-； Where each L is independently selected from the group consisting of bond, -C (R 10 R 11 )-, -O-CH 2- , -O-CH (CH 3 )-, -O-CH (OH)-or -CH = CH-;
每个R 7a、R 7b、R 7c、R 7d各自独立地选自氢、氘、氟、氯、氰基、C 1-4烷基、C 3-6环烷基、3-6元杂环基、苯基、-P(O)(CH 3) 2、-P(O)H 2、-SF 5、甲磺酰基、甲氧基、乙氧基或异丙氧基、-C(O)R 25或-C(O)NR 26R 27，上述基团任选进一步被一个或多个选自氘、氟、氯、氰基、甲基、乙基、异丙基、三氟甲基、二氟甲基、环丙基、环丁基、苯基、＝O、羟基、甲氧基、三氟甲氧基、三氘甲氧基、羧基或氨基的取代基所取代； Each R 7a , R 7b , R 7c , R 7d is independently selected from hydrogen, deuterium, fluorine, chlorine, cyano, C 1-4 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocycle Group, phenyl, -P (O) (CH 3 ) 2 , -P (O) H 2 , -SF 5 , methanesulfonyl, methoxy, ethoxy or isopropoxy, -C (O) R 25 or -C (O) NR 26 R 27 , the above groups are optionally further selected from one or more selected from deuterium, fluorine, chlorine, cyano, methyl, ethyl, isopropyl, trifluoromethyl, Difluoromethyl, cyclopropyl, cyclobutyl, phenyl, = 0, hydroxyl, methoxy, trifluoromethoxy, trideuteromethoxy, carboxyl or amino substituents;
R 10、R 11各自独立地选自氢、氘、氟、氯、甲基、三氟甲基、三氘甲基、环丙甲基、甲氧甲基、氨甲基、苄基、乙基、异丙基、环丙基、3-氧杂环丁基、羟基、甲氧基、三氟甲氧基、二氟甲氧基、三氘甲氧基、二氘甲氧基或-NH 2，或者，R 10与R 11和其直接相连的碳原子一起形成C(O)、环丙基、环丁基、3-氧杂环丁基； R 10 and R 11 are each independently selected from hydrogen, deuterium, fluorine, chlorine, methyl, trifluoromethyl, trideuteromethyl, cyclopropylmethyl, methoxymethyl, aminomethyl, benzyl, ethyl , Isopropyl, cyclopropyl, 3-oxetanyl, hydroxy, methoxy, trifluoromethoxy, difluoromethoxy, trideuteromethoxy, dideuteromethoxy or -NH 2 Or, R 10 and R 11 together with the carbon atom directly connected to them form C (O), cyclopropyl, cyclobutyl, 3-oxetanyl;
每个R 25各自独立地选自氢、氘、氟、氯、羟基、甲基、乙基或异丙基； Each R 25 is independently selected from hydrogen, deuterium, fluorine, chlorine, hydroxyl, methyl, ethyl or isopropyl;
每个R 26、R 27各自独立地选自氢、氘、羟基、甲基、乙基、异丙基、环丙基、苯基、甲氧基、磺酰基、甲磺酰基、氨基、单烷基氨基、二烷基氨基或C 1-10烷酰基，上述基团任选进一步被一个或多个选自氘、卤素、羟基、甲基、乙基、异丙基、环丙基、苯基、甲氧基、氨基、单烷基氨基、二烷基氨基或C 1-10烷酰基的取代基所取代。 Each R 26 , R 27 is independently selected from hydrogen, deuterium, hydroxyl, methyl, ethyl, isopropyl, cyclopropyl, phenyl, methoxy, sulfonyl, methanesulfonyl, amino, monoalkane Amino group, dialkylamino group or C 1-10 alkanoyl group, the above groups are optionally further selected from one or more selected from deuterium, halogen, hydroxyl, methyl, ethyl, isopropyl, cyclopropyl, phenyl , Methoxy, amino, monoalkylamino, dialkylamino or C 1-10 alkanoyl substituents.
作为更进一步优选的方案，前述式(I)化合物、其立体异构体、前药或其药学上可接受盐中环A与其直接相连的基团L、R 7一起形成如下结构： As a further preferred solution, the compound of formula (I), its stereoisomer, prodrug or pharmaceutically acceptable salt thereof, ring A, together with the directly connected groups L and R 7 form the following structure:
Figure PCTCN2019104957-appb-000006
Figure PCTCN2019104957-appb-000006
其中，每个R 7a、R 7b、R 7c、R 7d各自独立地选自氢、氘、氟、氯、氰基、C 1-4烷基、C 3-6环烷基、3-6元杂环基、苯基、-P(O)(CH 3) 2、-P(O)H 2、-SF 5、甲磺酰基、甲氧基、乙氧基、异丙氧基、-C(O)R 25或-C(O)NR 26R 27，上述基团任选进一步被一个或多个选自氘、氟、氯、氰基、甲基、乙基、异丙基、三氟甲基、二氟甲基、环丙基、环丁基、苯基、＝O、羟基、甲氧基、三氟甲氧基、三氘甲氧基、羧基或氨基的取代基所取代； Where each R 7a , R 7b , R 7c , R 7d is independently selected from hydrogen, deuterium, fluorine, chlorine, cyano, C 1-4 alkyl, C 3-6 cycloalkyl, 3-6 member Heterocyclyl, phenyl, -P (O) (CH 3 ) 2 , -P (O) H 2 , -SF 5 , methanesulfonyl, methoxy, ethoxy, isopropoxy, -C ( O) R 25 or -C (O) NR 26 R 27 , the above groups are optionally further selected from one or more selected from deuterium, fluorine, chlorine, cyano, methyl, ethyl, isopropyl, trifluoromethyl Substituted by the substituents of the group, difluoromethyl, cyclopropyl, cyclobutyl, phenyl, = 0, hydroxy, methoxy, trifluoromethoxy, trideuteromethoxy, carboxyl or amino;
R 10、R 11各自独立地选自氢、氘、氟、氯、甲基、三氟甲基、三氘甲基、环丙甲基、甲氧甲基、氨甲基、苄基、乙基、异丙基、环丙基、3-氧杂环丁基、羟基、甲氧基、三氟甲氧基、二氟甲氧基、三氘甲氧基、二氘甲氧基或-NH 2，或者，R 10与R 11和其直接相连的碳原子一起形成C(O)、环丙基、环丁基、3-氧杂环丁基； R 10 and R 11 are each independently selected from hydrogen, deuterium, fluorine, chlorine, methyl, trifluoromethyl, trideuteromethyl, cyclopropylmethyl, methoxymethyl, aminomethyl, benzyl, ethyl , Isopropyl, cyclopropyl, 3-oxetanyl, hydroxy, methoxy, trifluoromethoxy, difluoromethoxy, trideuteromethoxy, dideuteromethoxy or -NH 2 Or, R 10 and R 11 together with the carbon atom directly connected to them form C (O), cyclopropyl, cyclobutyl, 3-oxetanyl;
每个R 25各自独立地选自氢、氘、氟、氯、羟基、甲基、乙基或异丙基； Each R 25 is independently selected from hydrogen, deuterium, fluorine, chlorine, hydroxyl, methyl, ethyl or isopropyl;
每个R 26、R 27各自独立地选自氢、氘、羟基、甲基、乙基、异丙基、环丙基、苯基、甲氧基、磺酰基、甲磺酰基、氨基、单烷基氨基、二烷基氨基或C 1-10烷酰基，上述基团任选进一步被一个或多个选自氘、卤素、羟基、甲基、乙基、异丙基、环丙基、苯基、甲氧基、氨基、单烷基氨基、二烷基氨基或C 1-10烷酰基的取代基所取代。 Each R 26 , R 27 is independently selected from hydrogen, deuterium, hydroxyl, methyl, ethyl, isopropyl, cyclopropyl, phenyl, methoxy, sulfonyl, methanesulfonyl, amino, monoalkane Amino group, dialkylamino group or C 1-10 alkanoyl group, the above groups are optionally further selected from one or more selected from deuterium, halogen, hydroxyl, methyl, ethyl, isopropyl, cyclopropyl, phenyl , Methoxy, amino, monoalkylamino, dialkylamino or C 1-10 alkanoyl substituents.
作为最优选的方案，前述式(I)化合物、其立体异构体、前药或其药学上可接受盐包括但不限于如下化合物：As the most preferred solution, the aforementioned compound of formula (I), its stereoisomers, prodrugs or pharmaceutically acceptable salts thereof include but are not limited to the following compounds:
Figure PCTCN2019104957-appb-000007
Figure PCTCN2019104957-appb-000007
Figure PCTCN2019104957-appb-000008
Figure PCTCN2019104957-appb-000008
Figure PCTCN2019104957-appb-000009
Figure PCTCN2019104957-appb-000009
Figure PCTCN2019104957-appb-000010
Figure PCTCN2019104957-appb-000010
Figure PCTCN2019104957-appb-000011
Figure PCTCN2019104957-appb-000011
Figure PCTCN2019104957-appb-000012
Figure PCTCN2019104957-appb-000012
Figure PCTCN2019104957-appb-000013
Figure PCTCN2019104957-appb-000013
本发明第二方面提供一种前述式(I)化合物、其立体异构体、前药或其药学上可接受盐的制备方法，包括如下步骤：式Ia化合物与式Ib化合物或其酸式盐偶联得到式I化合物：The second aspect of the present invention provides a method for preparing the aforementioned compound of formula (I), its stereoisomer, prodrug or pharmaceutically acceptable salt thereof, comprising the following steps: the compound of formula Ia and the compound of formula Ib or its acid salt Coupling gives the compound of formula I:
Figure PCTCN2019104957-appb-000014
Figure PCTCN2019104957-appb-000014
其中，环A、L、X 1、X 2、X 3、X 4、X 5、Y、R 1、R 2、R 3、R 4、R 5、R 6、R 7、m 1、m 2如式(I)化合物所述。 Among them, rings A, L, X 1 , X 2 , X 3 , X 4 , X 5 , Y, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , m 1 , m 2 As described in the compound of formula (I).
本发明第三方面提供一种药物组合物，其包括前述式(I)化合物、其立体异构体、前药或其药学上可接受盐及可药用的载体。A third aspect of the present invention provides a pharmaceutical composition, which comprises the aforementioned compound of formula (I), its stereoisomer, prodrug or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
本发明第四方面提供一种前述式(I)化合物、其立体异构体、前药或其药学上可接受盐，或前述药物组合物在制备治疗一种或多种肿瘤、癌症、代谢性疾病、自身免疫性疾病或紊乱药物中的应用。The fourth aspect of the present invention provides a compound of the aforementioned formula (I), its stereoisomers, prodrugs or pharmaceutically acceptable salts thereof, or the aforementioned pharmaceutical composition in the preparation for the treatment of one or more tumors, cancers, and metabolites The application of drugs in diseases, autoimmune diseases or disorders.
本发明第五方面提供一种前述式(I)化合物、其立体异构体、前药或其药学上可接受盐，或前述药物组合物，其用作治疗一种或多种肿瘤、癌症、代谢性疾病、自身免疫性疾病或紊乱的药物。The fifth aspect of the present invention provides a compound of the aforementioned formula (I), its stereoisomer, prodrug or pharmaceutically acceptable salt thereof, or the aforementioned pharmaceutical composition, which is used for the treatment of one or more tumors, cancers, Drugs for metabolic diseases, autoimmune diseases or disorders.
具体实施方式detailed description
本申请的发明人经过广泛而深入地研究，首次研发出一种具有式(Ⅰ)结构的氮杂芳基酰胺衍生物及其制备方法和应用。本发明化合物对RORγt激酶活性具有很强的抑制作用，可广泛应用于制备治疗的药物，有望开发成新一代RORγt激动剂药物。在此基础上，完成了本发明。After extensive and in-depth research, the inventor of the present application has developed for the first time a azaarylamide derivative having the structure of formula (I), its preparation method and application. The compound of the present invention has a strong inhibitory effect on RORγt kinase activity, can be widely used in the preparation of therapeutic drugs, and is expected to be developed into a new generation of RORγt agonist drugs. On this basis, the present invention has been completed.
详细说明：除非有相反陈述，下列用在说明书和权利要求书中的术语具有下述含义。Detailed description: Unless stated to the contrary, the following terms used in the specification and claims have the following meanings.
“烷基”指直链或含支链的饱和脂族烃基团，例如，“C 1-8烷基”指包括1至8个碳原子的直链烷基和含支链烷基，包括但不限于甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1，1-二甲基丙基、1，2-二甲基丙基、2，2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1，1，2-三甲基丙基、1，1-二甲基丁基、1，2-二甲基丁基、2，2-二甲基丁基、1，3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2，3-二甲基丁基、正庚基、2-甲基己基、3-甲基己基、4-甲基己基、5-甲基己基、2，3-二甲基戊基、2，4-二甲基戊基、2，2-二甲基戊基、3，3-二甲基戊基、2-乙基戊基、3-乙基戊基、正辛基、2，3-二甲基己基、2，4-二甲基己基、2，5-二甲基己基、2，2-二甲基己基、3，3-二甲基己基、4，4-二甲基己基、2-乙基己基、3-乙基己基、4-乙基己基、2-甲基-2-乙基戊基、2-甲基-3-乙基戊基或其各种支链异构体等。 "Alkyl" refers to a straight-chain or branched-chain saturated aliphatic hydrocarbon group. For example, "C 1-8 alkyl" refers to a straight-chain alkyl group containing 1 to 8 carbon atoms and a branched-chain alkyl group, including but Not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2- Dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl Group, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethyl Butyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methyl Hexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5- Dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethyl Hexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl or various branched chain iso Constructs, etc.
烷基可以是任选取代的或未取代的，当被取代时，取代基优选为一个或多个(优选1、2、3或4个)以下基团，独立地选自氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、卤取代C 1-10烷基、C 3-10环烷基、3-10元杂环基、C 5-10芳基、5-10元杂芳基、＝O、-C 0-8-S(O) rR 23、-C 0-8-O-R 24、-C 0-8-C(O)OR 24、-C 0-8-C(O)R 25、-C 0-8-O-C(O)R 25、-C 0-8-NR 26R 27、-C 0-8-C(O)NR 26R 27或-C 0-8-N(R 26)-C(O)R 25的取代基所取代。 The alkyl group may be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more (preferably 1, 2, 3 or 4) groups, independently selected from deuterium, halogen, cyanide Group, nitro, azido, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, halogen substituted C 1-10 alkyl, C 3-10 cycloalkyl, 3 -10 membered heterocyclic group, C 5-10 aryl group, 5-10 membered heteroaryl group, = O, -C 0-8 -S (O) r R 23 , -C 0-8 -OR 24 , -C 0-8 -C (O) OR 24 , -C 0-8 -C (O) R 25 , -C 0-8 -OC (O) R 25 , -C 0-8 -NR 26 R 27 , -C 0-8 -C (O) NR 26 R 27 or -C 0-8 -N (R 26 ) -C (O) R 25 is substituted.
“环烷基”指饱和或部分不饱和单环或多环环状烃取代基，例如，“C 3-10环烷基”指包括3至10个碳原子的环烷基，分为单环环烷基、多环环烷基，其中： "Cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, for example, "C 3-10 cycloalkyl" refers to a cycloalkyl group containing 3 to 10 carbon atoms, divided into monocyclic Cycloalkyl, polycyclic cycloalkyl, where:
单环环烷基包括但不限于环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环庚基、环庚三烯基、环辛基等。Monocyclic cycloalkyls include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, Cyclooctyl, etc.
多环环烷基包括螺环、稠环和桥环的环烷基。“螺环烷基”指单环之间共用一个碳原子(称螺原子)的多环基团，这些可以含有一个或多个(优选1、2或3个)双键，但没有一个环具有完全共轭的π电子系统。根据环与环之间共用螺原子的数目将螺环烷基分为单螺环烷基、双螺环烷基基或多螺环烷基，螺环烷基包括但不限于：Polycyclic cycloalkyls include spiro, fused and bridged cycloalkyls. "Spirocycloalkyl" refers to a polycyclic group that shares a carbon atom (called a spiro atom) between single rings. These may contain one or more (preferably 1, 2 or 3) double bonds, but no ring has Completely conjugated π electron system. According to the number of spiro atoms shared between rings, spirocycloalkyl groups are classified into monospirocycloalkyl groups, dispirocycloalkyl groups or polyspirocycloalkyl groups. Spirocycloalkyl groups include but are not limited to:
Figure PCTCN2019104957-appb-000015
Figure PCTCN2019104957-appb-000015
“稠环烷基”指系统中的每个环与体系中的其他环共享毗邻的一对碳原子的全碳多环基团，其中一个或多个环(优选1或2个)可以含有一个或多个双键(优选1、2或3个)，但没有 一个环具有完全共轭的π电子系统。根据组成环的数目可以分为双环、三环、四环或多环稠环烷基，稠环烷基包括但不限于："Fused cycloalkyl" refers to an all-carbon polycyclic group in which each ring in the system shares a pair of adjacent carbon atoms with other rings in the system, where one or more rings (preferably 1 or 2) may contain one Or multiple double bonds (preferably 1, 2 or 3), but none of the rings has a completely conjugated π electron system. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl groups. Condensed cycloalkyl groups include but are not limited to:
Figure PCTCN2019104957-appb-000016
Figure PCTCN2019104957-appb-000016
“桥环烷基”指任意两个环共用两个不直接连接的碳原子的全碳多环基团，这些可以含有一个或多个双键(优选1、2或3个)，但没有一个环具有完全共轭的π电子系统。根据组成环的数目可以分为双环、三环、四环或多环桥环烷基，桥环烷基包括但不限于："Bridged cycloalkyl" means an all-carbon polycyclic group in which any two rings share two carbon atoms that are not directly connected. These may contain one or more double bonds (preferably 1, 2 or 3), but none of them The ring has a completely conjugated π electron system. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl groups. Bridged cycloalkyl groups include but are not limited to:
Figure PCTCN2019104957-appb-000017
Figure PCTCN2019104957-appb-000017
所述环烷基环可以稠合于芳基、杂芳基或杂环烷基环上，其中与母体结构连接在一起的环为环烷基，包括但不限于茚满基、四氢萘基、苯并环庚烷基等。The cycloalkyl ring can be fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring connected to the parent structure is a cycloalkyl group, including but not limited to indanyl, tetrahydronaphthyl , Benzocycloheptyl and so on.
环烷基可以是任选取代的或未取代的，当被取代时，取代基优选为一个或多个(优选1、2、3或4个)以下基团，独立地选自氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、卤取代C 1-10烷基、C 3-10环烷基、3-10元杂环基、C 5-10芳基、5-10元杂芳基、＝O、-C 0-8-S(O) rR 23、-C 0-8-O-R 24、-C 0-8-C(O)OR 24、-C 0-8-C(O)R 25、-C 0-8-O-C(O)R 25、-C 0- 8-NR 26R 27、-C 0-8-C(O)NR 26R 27或-C 0-8-N(R 26)-C(O)R 25的取代基所取代。 The cycloalkyl group may be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more (preferably 1, 2, 3, or 4) groups, independently selected from deuterium, halogen, Cyano, nitro, azido, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, halogen substituted C 1-10 alkyl, C 3-10 cycloalkyl, 3-10 membered heterocyclic group, C 5-10 aryl group, 5-10 membered heteroaryl group, = O, -C 0-8 -S (O) r R 23 , -C 0-8 -OR 24 ,- C 0-8 -C (O) OR 24 , -C 0-8 -C (O) R 25 , -C 0-8 -OC (O) R 25 , -C 0- 8 -NR 26 R 27 ,- C 0-8 -C (O) NR 26 R 27 or -C 0-8 -N (R 26 ) -C (O) R 25 is substituted.
“杂环基”指饱和或部分不饱和单环或多环环状烃取代基，其中一个或多个(优选1、2、3或4个)环原子选自氮、氧或S(O) r(其中r是整数0、1、2)的杂原子，但不包括-O-O-、-O-S-或-S-S-的环部分，其余环原子为碳。例如，“5-10元杂环基”指包含5至10个环原子的环基，“3-10元杂环基”指包含3至10个环原子的环基。 "Heterocyclyl" means a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent in which one or more (preferably 1, 2, 3 or 4) ring atoms are selected from nitrogen, oxygen or S (O) r (where r is an integer of 0, 1, 2), but does not include the ring portion of -OO-, -OS-, or -SS-, and the remaining ring atoms are carbon. For example, "5-10 membered heterocyclic group" refers to a cyclic group containing 5 to 10 ring atoms, and "3-10 membered heterocyclic group" refers to a cyclic group containing 3 to 10 ring atoms.
单环杂环基包括但不限于吡咯烷基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、高哌嗪基等。Monocyclic heterocyclic groups include but are not limited to pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl and the like.
多环杂环基包括螺环、稠环和桥环的杂环基。“螺杂环基”指单环之间共用一个原子(称螺原子)的多环杂环基团，其中一个或多个环原子选自氮、氧或S(O) r(其中r是整数0、1、2)的杂原子，其余环原子为碳。这些可以含有一个或多个双键(优选1、2、3或4个)，但没有一个环具有完全共轭的π电子系统。根据环与环之间共用螺原子的数目将螺杂环基分为单螺杂环基、双螺杂环基或多螺杂环基。螺杂环基包括但不限于： Polycyclic heterocyclic groups include spiro, fused and bridged heterocyclic groups. "Spiroheterocyclyl" refers to a polycyclic heterocyclic group that shares an atom (called a spiro atom) between single rings, wherein one or more ring atoms are selected from nitrogen, oxygen, or S (O) r (where r is an integer) 0, 1, 2) heteroatoms, the remaining ring atoms are carbon. These may contain one or more double bonds (preferably 1, 2, 3 or 4), but none of the rings has a completely conjugated π electron system. Spiro heterocyclic groups are classified into mono-spiro heterocyclic groups, di-spiro heterocyclic groups, or poly-spiro heterocyclic groups according to the number of spiro atoms shared between rings. Spiroheterocyclic groups include but are not limited to:
Figure PCTCN2019104957-appb-000018
Figure PCTCN2019104957-appb-000018
“稠杂环基”指系统中的每个环与体系中的其他环共享毗邻的一对原子的多环杂环基团，一个或多个环(优选1或2个)可以含有一个或多个(优选1、2或3个)双键，但没有一个环具有完全共轭的π电子系统，其中一个或多个(优选1、2、3或4个)环原子选自氮、氧或S(O) r(其中r是整数0、1、2)的杂原子，其余环原子为碳。根据组成环的数目可以分为双环、三环、四环或多环稠杂环烷基，稠杂环基包括但不限于： "Fused heterocyclic group" refers to a polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with other rings in the system. One or more rings (preferably 1 or 2) may contain one or more (Preferably 1, 2 or 3) double bonds, but none of the rings has a fully conjugated π-electron system, wherein one or more (preferably 1, 2, 3 or 4) ring atoms are selected from nitrogen, oxygen or S (O) r (where r is an integer of 0, 1, 2), and the remaining ring atoms are carbon. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocycloalkyl groups. The fused heterocyclic groups include but are not limited to:
Figure PCTCN2019104957-appb-000019
Figure PCTCN2019104957-appb-000019
“桥杂环基”指任意两个环共用两个不直接连接的原子的多环杂环基团，这些可以含有一个或多个(优选1、2或3个)双键，但没有一个环具有完全共轭的π电子系统，其中一个或多个环原子(优选1、2、3或4个)选自氮、氧或S(O) r(其中r是整数0、1、2)的杂原子，其余环原子为碳。根据组成环的数目可以分为双环、三环、四环或多环桥杂环基，桥杂环基包括但不限于： "Bridge heterocyclic group" means a polycyclic heterocyclic group in which any two rings share two atoms that are not directly connected, these may contain one or more (preferably 1, 2 or 3) double bonds, but no one ring Π electron system with complete conjugation, where one or more ring atoms (preferably 1, 2, 3 or 4) are selected from nitrogen, oxygen or S (O) r (where r is an integer of 0, 1, 2) Heteroatoms, the remaining ring atoms are carbon. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups. The bridged heterocyclic groups include but are not limited to:
Figure PCTCN2019104957-appb-000020
Figure PCTCN2019104957-appb-000020
所述杂环基环可以稠合于芳基、杂芳基或环烷基环上，其中与母体结构连接在一起的环为杂环基，包括但不限于：The heterocyclic ring may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring connected to the parent structure is a heterocyclic group, including but not limited to:
Figure PCTCN2019104957-appb-000021
Figure PCTCN2019104957-appb-000021
杂环基可以是任选取代的或未取代的，当被取代时，取代基优选为一个或多个(优选1、2、3或4个)以下基团，独立地选自氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、卤取代C 1-10烷基、C 3-10环烷基、3-10元杂环基、C 5-10芳基、5-10元杂芳基、＝O、-C 0-8-S(O) rR 23、-C 0-8-O-R 24、-C 0-8-C(O)OR 24、-C 0-8-C(O)R 25、-C 0-8-O-C(O)R 25、-C 0- 8-NR 26R 27、-C 0-8-C(O)NR 26R 27或-C 0-8-N(R 26)-C(O)R 25的取代基所取代。 The heterocyclic group may be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more (preferably 1, 2, 3 or 4) groups, independently selected from deuterium, halogen, Cyano, nitro, azido, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, halogen substituted C 1-10 alkyl, C 3-10 cycloalkyl, 3-10 membered heterocyclic group, C 5-10 aryl group, 5-10 membered heteroaryl group, = O, -C 0-8 -S (O) r R 23 , -C 0-8 -OR 24 ,- C 0-8 -C (O) OR 24 , -C 0-8 -C (O) R 25 , -C 0-8 -OC (O) R 25 , -C 0- 8 -NR 26 R 27 ,- C 0-8 -C (O) NR 26 R 27 or -C 0-8 -N (R 26 ) -C (O) R 25 is substituted.
“芳基”指全碳单环或稠合多环(也就是共享毗邻碳原子对的环)基团，具有共轭的π电子体系的多环(即其带有相邻对碳原子的环)基团，例如，“C 5-10芳基”指含有5-10个碳的全碳芳基，“5-10元芳基”指含有5-10个碳的全碳芳基，包括但不限于苯基和萘基。所述芳基环可以稠合于杂芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为芳基环，包括但不限于： "Aryl" refers to an all-carbon monocyclic or fused polycyclic (that is, a ring sharing adjacent pairs of carbon atoms) group, a polycyclic ring having a conjugated π-electron system (that is, a ring with adjacent pairs of carbon atoms) ) Group, for example, "C 5-10 aryl" refers to an all-carbon aryl group containing 5-10 carbons, and "5-10 membered aryl" refers to an all-carbon aryl group containing 5-10 carbons, including but Not limited to phenyl and naphthyl. The aryl ring may be fused to a heteroaryl, heterocyclic or cycloalkyl ring, wherein the ring connected to the parent structure is an aryl ring, including but not limited to:
Figure PCTCN2019104957-appb-000022
Figure PCTCN2019104957-appb-000022
芳基可以是取代的或未取代的，当被取代时，取代基优选为一个或多个(优选1、2、3或4个)以下基团，独立地选自氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、C 2-10链烯基、C 2- 10链炔基、卤取代C 1-10烷基、C 3-10环烷基、3-10元杂环基、C 5-10芳基、5-10元杂芳基、＝O、-C 0-8-S(O) rR 23、-C 0-8-O-R 24、-C 0-8-C(O)OR 24、-C 0-8-C(O)R 25、-C 0-8-O-C(O)R 25、-C 0-8-NR 26R 27、-C 0-8-C(O)NR 26R 27或-C 0-8-N(R 26)-C(O)R 25的取代基所取代。 The aryl group may be substituted or unsubstituted. When substituted, the substituent is preferably one or more (preferably 1, 2, 3, or 4) groups independently selected from deuterium, halogen, cyano, nitro, azido, C 1-10 alkyl, C 2-10 alkenyl, C 2- 10 alkynyl group, a halo substituted C 1-10 alkyl, C 3-10 cycloalkyl, 3-10 Heterocyclic group, C 5-10 aryl group, 5-10 membered heteroaryl group, = O, -C 0-8 -S (O) r R 23 , -C 0-8 -OR 24 , -C 0- 8 -C (O) OR 24 , -C 0-8 -C (O) R 25 , -C 0-8 -OC (O) R 25 , -C 0-8 -NR 26 R 27 , -C 0- 8 -C (O) NR 26 R 27 or -C 0-8 -N (R 26 ) -C (O) R 25 substituent.
“杂芳基”指包含1至4个杂原子的杂芳族体系，所述杂原子包括氮、氧和S(O)r(其中r是整数0、1、2)的杂原子，例如，5-8元杂芳基指含有5-8个环原子的杂芳族体系，5-10元杂芳基指含有5-10个环原子的杂芳族体系，包括但不限于呋喃基、噻吩基、吡啶基、吡咯基、N-烷基吡咯基、嘧啶基、吡嗪基、咪唑基、四唑基等。所述杂芳基环可以稠合于芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为杂芳基环，包括但不限于："Heteroaryl" refers to a heteroaromatic system containing 1 to 4 heteroatoms, including heteroatoms of nitrogen, oxygen, and S (O) r (where r is an integer of 0, 1, 2), for example, 5-8 membered heteroaryl refers to heteroaromatic systems containing 5-8 ring atoms, 5-10 membered heteroaryl refers to heteroaromatic systems containing 5-10 ring atoms, including but not limited to furyl, thiophene Group, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, etc. The heteroaryl ring may be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring, including but not limited to:
Figure PCTCN2019104957-appb-000023
Figure PCTCN2019104957-appb-000023
杂芳基可以是任选取代的或未取代的，当被取代时，取代基优选为一个或多个以下基团，独立地选自氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、卤取代C 1-10烷基、C 3-10环烷基、3-10元杂环基、C 5-10芳基、5-10元杂芳基、＝O、-C 0-8-S(O) rR 23、-C 0-8-O-R 24、-C 0-8-C(O)OR 24、-C 0-8-C(O)R 25、-C 0-8-O-C(O)R 25、-C 0-8-NR 26R 27、-C 0-8-C(O)NR 26R 27或-C 0-8-N(R 26)-C(O)R 25的取代基所取代。 The heteroaryl group may be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, independently selected from deuterium, halogen, cyano, nitro, azido, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, halogen substituted C 1-10 alkyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 5- 10 aryl, 5-10 membered heteroaryl, = O, -C 0-8 -S (O) r R 23 , -C 0-8 -OR 24 , -C 0-8 -C (O) OR 24 , -C 0-8 -C (O) R 25 , -C 0-8 -OC (O) R 25 , -C 0-8 -NR 26 R 27 , -C 0-8 -C (O) NR 26 R 27 or -C 0-8 -N (R 26 ) -C (O) R 25 is substituted.
“烯基”指由至少两个碳原子和至少一个碳-碳双键组成的如上述定义的烷基，例如，C 2- 8链烯基指含有2-8个碳的直链或含支链烯基。包括但不限于乙烯基、1-丙烯基、2-丙烯基、1-，2-或3-丁烯基等。 "Alkenyl" refers to at least two carbon atoms and at least one carbon - carbon double bond as defined above consisting of an alkyl group, e.g., C 2- 8 alkenyl group means a straight chain comprising 2-8 carbon atoms or a branched Alkenyl. Including but not limited to vinyl, 1-propenyl, 2-propenyl, 1-, 2- or 3-butenyl and the like.
烯基可以是取代的或未取代的，当被取代时，取代基优选为一个或多个(优选1、2、3或4个)以下基团，独立地选自氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、C 2-10链烯基、C 2- 10链炔基、卤取代C 1-10烷基、C 3-10环烷基、3-10元杂环基、C 5-10芳基、5-10元杂芳基、＝O、-C 0-8-S(O) rR 23、-C 0-8-O-R 24、-C 0-8-C(O)OR 24、-C 0-8-C(O)R 25、-C 0-8-O-C(O)R 25、-C 0-8-NR 26R 27、-C 0-8-C(O)NR 26R 27或-C 0-8-N(R 26)-C(O)R 25的取代基所取代。 The alkenyl group may be substituted or unsubstituted. When substituted, the substituent is preferably one or more (preferably 1, 2, 3, or 4) groups, independently selected from deuterium, halogen, cyano, nitro, azido, C 1-10 alkyl, C 2-10 alkenyl, C 2- 10 alkynyl group, a halo substituted C 1-10 alkyl, C 3-10 cycloalkyl, 3-10 Heterocyclic group, C 5-10 aryl group, 5-10 membered heteroaryl group, = O, -C 0-8 -S (O) r R 23 , -C 0-8 -OR 24 , -C 0- 8 -C (O) OR 24 , -C 0-8 -C (O) R 25 , -C 0-8 -OC (O) R 25 , -C 0-8 -NR 26 R 27 , -C 0- 8 -C (O) NR 26 R 27 or -C 0-8 -N (R 26 ) -C (O) R 25 substituent.
“炔基”指至少两个碳原子和至少一个碳-碳三键组成的如上所定义的烷基，例如，C 2-8链炔基指含有2-8个碳的直链或含支链炔基。包括但不限于乙炔基、1-丙炔基、2-丙炔基、1-，2-或3-丁炔基等。 "Alkynyl" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon triple bond, for example, C 2-8 alkynyl refers to a straight or branched chain containing 2-8 carbons Alkynyl. Including but not limited to ethynyl, 1-propynyl, 2-propynyl, 1-, 2- or 3-butynyl and the like.
炔基可以是取代的或未取代的，当被取代时，取代基优选为一个或多个(优选1、2、3或4个)以下基团，独立地选自氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、C 2-10链烯基、C 2- 10链炔基、卤取代C 1-10烷基、C 3-10环烷基、3-10元杂环基、C 5-10芳基、5-10元杂芳基、＝O、-C 0-8-S(O) rR 23、-C 0-8-O-R 24、-C 0-8-C(O)OR 24、-C 0-8-C(O)R 25、-C 0-8-O-C(O)R 25、-C 0-8-NR 26R 27、-C 0-8-C(O)NR 26R 27或-C 0-8-N(R 26)-C(O)R 25的取代基所取代。 The alkynyl group may be substituted or unsubstituted. When substituted, the substituent is preferably one or more (preferably 1, 2, 3, or 4) groups, independently selected from deuterium, halogen, cyano, nitro, azido, C 1-10 alkyl, C 2-10 alkenyl, C 2- 10 alkynyl group, a halo substituted C 1-10 alkyl, C 3-10 cycloalkyl, 3-10 Heterocyclic group, C 5-10 aryl group, 5-10 membered heteroaryl group, = O, -C 0-8 -S (O) r R 23 , -C 0-8 -OR 24 , -C 0- 8 -C (O) OR 24 , -C 0-8 -C (O) R 25 , -C 0-8 -OC (O) R 25 , -C 0-8 -NR 26 R 27 , -C 0- 8 -C (O) NR 26 R 27 or -C 0-8 -N (R 26 ) -C (O) R 25 substituent.
“烷氧基”指-O-(烷基)，其中烷基的定义如上所述，例如，“C 1-8烷氧基”指含1-8个碳的烷基氧基，包括但不限于甲氧基、乙氧基、丙氧基、丁氧基等。 "Alkoxy" refers to -O- (alkyl), where alkyl is as defined above, for example, "C 1-8 alkoxy" refers to alkyloxy containing 1-8 carbons, including but not Limited to methoxy, ethoxy, propoxy, butoxy, etc.
烷氧基可以是任选取代的或未取代的，当被取代时，取代基，优选为一个或多个(优选1、2、3或4个)以下基团，独立地选自氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、卤取代C 1-10烷基、C 3-10环烷基、3-10元杂环基、C 5-10芳基、5-10元杂芳基、＝O、-C 0-8-S(O) rR 23、-C 0-8-O-R 24、-C 0-8-C(O)OR 24、-C 0-8-C(O)R 25、-C 0-8-O-C(O)R 25、-C 0-8-NR 26R 27、-C 0-8-C(O)NR 26R 27或-C 0-8-N(R 26)-C(O)R 25的取代基所取代。 The alkoxy group may be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more (preferably 1, 2, 3, or 4) groups independently selected from deuterium and halogen , Cyano, nitro, azido, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, halogen substituted C 1-10 alkyl, C 3-10 cycloalkyl , 3-10 membered heterocyclic group, C 5-10 aryl group, 5-10 membered heteroaryl group, = O, -C 0-8 -S (O) r R 23 , -C 0-8 -OR 24 , -C 0-8 -C (O) OR 24 , -C 0-8 -C (O) R 25 , -C 0-8 -OC (O) R 25 , -C 0-8 -NR 26 R 27 , -C 0-8 -C (O) NR 26 R 27 or -C 0-8 -N (R 26 ) -C (O) R 25 substituent.
“环烷氧基”指和-O-(未取代的环烷基)，其中环烷基的定义如上所述，例如，“C 3-10环烷氧基”指含3-10个碳的环烷基氧基，包括但不限于环丙氧基、环丁氧基、环戊氧基、环己氧基等。 "Cycloalkoxy" refers to -O- (unsubstituted cycloalkyl), where cycloalkyl is as defined above, for example, "C 3-10 cycloalkoxy" refers to those containing 3-10 carbons Cycloalkyloxy, including but not limited to cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, etc.
环烷氧基可以是任选取代的或未取代的，当被取代时，取代基优选为一个或多个(优选1、2、3或4个)以下基团，独立地选自氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、卤取代C 1-10烷基、C 3-10环烷基、3-10元杂环基、C 5-10芳基、5-10元杂芳基、＝O、-C 0-8-S(O) rR 23、-C 0-8-O-R 24、-C 0-8-C(O)OR 24、-C 0-8-C(O)R 25、-C 0-8-O-C(O)R 25、-C 0-8-NR 26R 27、-C 0-8-C(O)NR 26R 27或-C 0-8-N(R 26)-C(O)R 25的取代基所取代。 The cycloalkoxy group may be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more (preferably 1, 2, 3, or 4) groups independently selected from deuterium and halogen , Cyano, nitro, azido, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, halogen substituted C 1-10 alkyl, C 3-10 cycloalkyl , 3-10 membered heterocyclic group, C 5-10 aryl group, 5-10 membered heteroaryl group, = O, -C 0-8 -S (O) r R 23 , -C 0-8 -OR 24 , -C 0-8 -C (O) OR 24 , -C 0-8 -C (O) R 25 , -C 0-8 -OC (O) R 25 , -C 0-8 -NR 26 R 27 , -C 0-8 -C (O) NR 26 R 27 or -C 0-8 -N (R 26 ) -C (O) R 25 substituent.
“3-10元杂环氧基”指和-O-(未取代的3-10元杂环基)，其中3-10元杂环基的定义如上所述，3-10元杂环氧基可以是任选取代的或未取代的，当被取代时，取代基优选为一个或多个(优选1、2、3或4个)以下基团，独立地选自氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、卤取代C 1-10烷基、C 3-10环烷基、3-10元杂环基、C 5-10芳基、5-10元杂芳基、＝O、-C 0-8-S(O) rR 23、-C 0-8-O-R 24、-C 0-8-C(O)OR 24、-C 0-8-C(O)R 25、-C 0-8-O-C(O)R 25、-C 0-8-NR 26R 27、-C 0-8-C(O)NR 26R 27或-C 0-8-N(R 26)-C(O)R 25的取代基所取代。 "3-10 membered heterocyclic oxy" means and -O- (unsubstituted 3-10 membered heterocyclyl), wherein the definition of 3-10 membered heterocyclyl is as described above, 3-10 membered heterocyclyloxy It may be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more (preferably 1, 2, 3 or 4) the following groups, independently selected from deuterium, halogen, cyano, Nitro, azido, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, halogen substituted C 1-10 alkyl, C 3-10 cycloalkyl, 3-10 Heterocyclic group, C 5-10 aryl group, 5-10 membered heteroaryl group, = O, -C 0-8 -S (O) r R 23 , -C 0-8 -OR 24 , -C 0- 8 -C (O) OR 24 , -C 0-8 -C (O) R 25 , -C 0-8 -OC (O) R 25 , -C 0-8 -NR 26 R 27 , -C 0- 8 -C (O) NR 26 R 27 or -C 0-8 -N (R 26 ) -C (O) R 25 substituent.
“C 5-10芳氧基”指和-O-(未取代的C 5-10芳基)，其中C 5-10芳基的定义如上所述，C 5-10芳氧基可以是任选取代的或未取代的，当被取代时，取代基优选为一个或多个(优选1、2、3或4个)以下基团，独立地选自氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、C 2-10链烯基、C 2- 10链炔基、卤取代C 1-10烷基、C 3-10环烷基、3-10元杂环基、C 5-10芳基、5-10元杂芳基、＝O、-C 0-8-S(O) rR 23、-C 0-8-O-R 24、-C 0-8-C(O)OR 24、-C 0-8-C(O)R 25、-C 0-8-O-C(O)R 25、-C 0-8-NR 26R 27、-C 0-8-C(O)NR 26R 27或-C 0-8-N(R 26)-C(O)R 25的取代基所取代。 "C 5-10 aryloxy" refers to -O- (unsubstituted C 5-10 aryl), where C 5-10 aryl is as defined above, C 5-10 aryloxy can be optional Substituted or unsubstituted, when substituted, the substituent is preferably one or more (preferably 1, 2, 3 or 4) the following groups, independently selected from deuterium, halogen, cyano, nitro, and nitrogen group, C 1-10 alkyl, C 2-10 alkenyl, C 2- 10 alkynyl group, a halo substituted C 1-10 alkyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl , C 5-10 aryl, 5-10 membered heteroaryl, = O, -C 0-8 -S (O) r R 23 , -C 0-8 -OR 24 , -C 0-8 -C ( O) OR 24 , -C 0-8 -C (O) R 25 , -C 0-8 -OC (O) R 25 , -C 0-8 -NR 26 R 27 , -C 0-8 -C ( O) NR 26 R 27 or -C 0-8 -N (R 26 ) -C (O) R 25 substituent.
“5-10元杂芳氧基”指和-O-(未取代的5-10元杂芳基)，其中5-10元杂芳基的定义如上所述，5-10元杂芳氧基可以是任选取代的或未取代的，当被取代时，取代基优选为一个或多个(优选1、2、3或4个)以下基团，独立地选自氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、卤取代C 1-10烷基、C 3-10环烷基、3-10元杂环基、C 5-10芳基、5-10元杂芳基、＝O、-C 0-8-S(O) rR 23、-C 0-8-O-R 24、-C 0-8-C(O)OR 24、-C 0-8-C(O)R 25、-C 0-8-O-C(O)R 25、-C 0-8-NR 26R 27、-C 0-8-C(O)NR 26R 27或-C 0-8-N(R 26)-C(O)R 25的取代基所取代。 "5-10 membered heteroaryloxy" refers to -O- (unsubstituted 5-10 membered heteroaryl), where 5-10 membered heteroaryl is as defined above, 5-10 membered heteroaryloxy It may be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more (preferably 1, 2, 3 or 4) the following groups, independently selected from deuterium, halogen, cyano, Nitro, azido, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, halogen substituted C 1-10 alkyl, C 3-10 cycloalkyl, 3-10 Heterocyclic group, C 5-10 aryl group, 5-10 membered heteroaryl group, = O, -C 0-8 -S (O) r R 23 , -C 0-8 -OR 24 , -C 0- 8 -C (O) OR 24 , -C 0-8 -C (O) R 25 , -C 0-8 -OC (O) R 25 , -C 0-8 -NR 26 R 27 , -C 0- 8 -C (O) NR 26 R 27 or -C 0-8 -N (R 26 ) -C (O) R 25 substituent.
“C 1-8烷酰基”指C 1-8烷基酸去掉羟基后剩下的一价原子团，通常也表示为“C 0-7-C(O)-”，例如，“C 1-C(O)-”是指乙酰基；“C 2-C(O)-”是指丙酰基；“C 3-C(O)-”是指丁酰基或异丁酰基。 "C 1-8 alkanoyl" refers to the monovalent radical remaining after removing the hydroxyl group of the C 1-8 alkyl acid, and is usually also expressed as "C 0-7 -C (O)-", for example, "C 1 -C (O)-"means acetyl;" C 2 -C (O)-"means propionyl;" C 3 -C (O)-"means butyryl or isobutyryl.
“-C 0-8-S(O) rR 23”指-S(O) rR 23中的硫原子连接在C 0-8烷基上，其中C 0烷基是指键，C 1-8烷基的定义如上所述。 "-C 0-8 -S (O) r R 23 " means that the sulfur atom in -S (O) r R 23 is attached to a C 0-8 alkyl group, wherein the C 0 alkyl group refers to a bond, C 1- The definition of 8 alkyl is as described above.
“-C 0-8-O-R 24”指-O-R 24中的氧原子连接在C 0-8烷基上，其中C 0烷基是指键，C 1-8烷基的定义如上所述。 "-C 0-8 -OR 24 " means that the oxygen atom in -OR 24 is connected to a C 0-8 alkyl group, where C 0 alkyl refers to a bond, and C 1-8 alkyl is as defined above.
“-C 0-8-C(O)OR 24”指-C(O)OR 24中的羰基连接在C 0-8烷基上，其中C 0烷基是指键，C 1-8烷基的定义如上所述。 "-C 0-8 -C (O) OR 24 " means that the carbonyl group in -C (O) OR 24 is connected to C 0-8 alkyl, where C 0 alkyl refers to a bond, and C 1-8 alkyl Is defined as above.
“-C 0-8-C(O)R 25”指-C(O)R 25中的羰基连接在C 0-8烷基上，其中C 0烷基是指键，C 1-8烷基的定义如上所述。 "-C 0-8 -C (O) R 25 " means that the carbonyl group in -C (O) R 25 is attached to C 0-8 alkyl, where C 0 alkyl refers to a bond, and C 1-8 alkyl Is defined as above.
“-C 0-8-O-C(O)R 25”指-O-C(O)R 25中的氧原子连接在C 0-8烷基上，其中C 0烷基是指键，C 1-8烷基的定义如上所述。 "-C 0-8 -OC (O) R 25 " means that the oxygen atom in -OC (O) R 25 is connected to C 0-8 alkyl, where C 0 alkyl refers to a bond, and C 1-8 alkyl The definition of base is as described above.
“-C 0-8-NR 26R 27”指-NR 26R 27中的氮原子连接在C 0-8烷基上，其中C 0烷基是指键，C 1-8烷基的定义如上所述。 "-C 0-8 -NR 26 R 27 " means that the nitrogen atom in -NR 26 R 27 is connected to C 0-8 alkyl, wherein C 0 alkyl refers to a bond, and C 1-8 alkyl is as defined above Said.
“-C 0-8-C(O)NR 26R 27”指-C(O)NR 26R 27中的羰基连接在C 0-8烷基上，其中C 0烷基是指键，C 1-8烷基的定义如上所述。 "-C 0-8 -C (O) NR 26 R 27 " means that the carbonyl group in -C (O) NR 26 R 27 is connected to a C 0-8 alkyl group, where C 0 alkyl means a bond, C 1 The definition of -8 alkyl is as described above.
“-C 0-8-N(R 26)-C(O)R 25”指-N(R 26)-C(O)R 25中的氮原子连接在C 0-8烷基上，其中C 0烷基是指键，C 1-8烷基的定义如上所述。 "-C 0-8 -N (R 26 ) -C (O) R 25 " means that the nitrogen atom in -N (R 26 ) -C (O) R 25 is attached to a C 0-8 alkyl group, where C 0 alkyl means a bond, and C 1-8 alkyl is as defined above.
“卤取代C 1-8烷基”指烷基上的氢任选的被氟、氯、溴、碘原子取代的1-8个碳烷基基团，包括但不限于二氟甲基、二氯甲基、二溴甲基、三氟甲基、三氯甲基、三溴甲基等。 "Halo-substituted C 1-8 alkyl" refers to 1-8 carbon alkyl groups on the alkyl optionally substituted by fluorine, chlorine, bromine, and iodine atoms, including but not limited to difluoromethyl, dialkyl Chloromethyl, dibromomethyl, trifluoromethyl, trichloromethyl, tribromomethyl, etc.
“卤取代C 1-8烷氧基”烷基上的氢任选的被氟、氯、溴、碘原子取代的1-8个碳烷氧基基团。包括但不限于二氟甲氧基、二氯甲氧基、二溴甲氧基、三氟甲氧基、三氯甲氧基、三溴甲氧基等。 The hydrogen on the "halogen substituted C 1-8 alkoxy" alkyl group is optionally substituted with 1-8 carbon alkoxy groups substituted by fluorine, chlorine, bromine, or iodine atoms. Including but not limited to difluoromethoxy, dichloromethoxy, dibromomethoxy, trifluoromethoxy, trichloromethoxy, tribromomethoxy, etc.
“卤素”指氟、氯、溴或碘。“DCM“是指二氯甲烷。”“DMF”是指N，N-二甲基甲酰胺。“THF”是指四氢呋喃。“PE”是指石油醚。“EA/EtOAc”是指乙酸乙酯。“DMSO”是指二甲基亚砜。“MeCN”是指乙腈。“DME”是指二甲醚。“DIEA”是指N,N-二异丙基乙胺。“KOAc”是指醋酸钾。“K 3PO 4”是指磷酸钾。“NMP”是指N-甲基吡咯烷酮。“m-CPBA”是指间氯过氧苯甲酸。“Pd/C”是指钯碳。“HATU”是指2-(7-氧化苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸盐。“Pd(dppf)Cl 2”是指[1,1'-双(二苯基磷)二茂铁]二氯化钯。“DIBAL-H”是指二异丁基氢化铝。“LiBH(i-Bu) 3”是指三异丁基硼氢化锂。“P(tBu)3-Pd-G2”是指氯[(三-TERT-三丁基膦)-2-(2-氨基联苯)]钯(II)。“X-phos”是指2-二环己基磷-2',4',6'-三异丙基联苯。 "Halogen" means fluorine, chlorine, bromine or iodine. "DCM" means dichloromethane. "DMF" means N, N-dimethylformamide. "THF" means tetrahydrofuran. "PE" means petroleum ether. "EA / EtOAc" means ethyl acetate. "DMSO" means dimethyl Sulfoxide. "MeCN" means acetonitrile. "DME" means dimethyl ether. "DIEA" means N, N-diisopropylethylamine. "KOAc" means potassium acetate. "K 3 PO 4 " is Refers to potassium phosphate. "NMP" refers to N-methylpyrrolidone. "M-CPBA" refers to m-chloroperoxybenzoic acid. "Pd / C" refers to palladium carbon. "HATU" refers to 2- (7-oxidation Benzotriazole) -N, N, N ', N'-tetramethylurea hexafluorophosphate. "Pd (dppf) Cl 2 " means [1,1'-bis (diphenylphosphine) di Ferrocene] Palladium dichloride. "DIBAL-H" refers to diisobutylaluminum hydride. "LiBH (i-Bu) 3 " refers to lithium triisobutylborohydride. "P (tBu) 3-Pd- "G2" means chloro [(tri-TERT-tributylphosphine) -2- (2-aminobiphenyl)] palladium (II). "X-phos" means 2-dicyclohexylphosphonium-2 ', 4 ', 6'-triisopropylbiphenyl.
“任选”或“任选地”意味着随后所描述地事件或环境可以但不必发生，该说明包括该事件或环境发生或不发生地场合。例如，“任选被烷基取代的杂环基团”意味着烷基可以但不必须存在，该说明包括杂环基团被烷基取代的情形和杂环基团不被烷基取代的情形。"Optional" or "optionally" means that the subsequently described event or environment may but need not occur, and the description includes the occasion where the event or environment occurs or does not occur. For example, "heterocyclic group optionally substituted with an alkyl group" means that an alkyl group may but need not be present, and the description includes the case where the heterocyclic group is substituted with an alkyl group and the case where the heterocyclic group is not substituted with an alkyl group .
“取代的”指基团中的一个或多个(优选1、2、3或4个)氢原子彼此独立地被相应数目的取代基取代。不言而喻，取代基仅处在它们的可能的化学位置，本领域技术人员能够在不付出过多努力的情况下确定(通过实验或理论)可能或不可能的取代。例如，具有游离氢的氨基或羟基与具有不饱和键的碳原子(如烯烃)结合时可能是不稳定的。"Substituted" means that one or more (preferably 1, 2, 3, or 4) hydrogen atoms in the group are substituted with a corresponding number of substituents independently of each other. It goes without saying that the substituents are only at their possible chemical positions, and those skilled in the art can determine (through experiment or theory) possible or impossible substitutions without undue effort. For example, an amino group or hydroxyl group having free hydrogen may be unstable when combined with a carbon atom having an unsaturated bond (such as an olefin).
“药物组合物”表示含有一种或多种本文所述化合物或其生理学上/可药用的盐或前体药物与其他化学组分的混合物，以及其他组分例如生理学/可药用的载体和赋形剂。药物组合物的目的是促进对生物体的给药，利于活性成分的吸收进而发挥生物活性。"Pharmaceutical composition" means a mixture containing one or more compounds described herein or a physiological / pharmaceutically acceptable salt or prodrug thereof with other chemical components, and other components such as physiological / pharmaceutically acceptable carriers And excipients. The purpose of the pharmaceutical composition is to promote the administration to the living body, facilitate the absorption of the active ingredient and thus exert the biological activity.
下面结合实施例对本发明做进一步详细、完整地说明，但决非限制本发明，本发明也并非仅局限于实施例的内容。The present invention will be further described in detail and completely in conjunction with the following examples, but by no means limits the present invention, and the present invention is not limited to the contents of the examples.
本发明的化合物结构是通过核磁共振(NMR)或/和液质联用色谱(LC-MS)来确定的。NMR化学位移(δ)以百万分之一(ppm)的单位给出。NMR的测定是用Bruker AVANCE-400/500核磁仪，测定溶剂为氘代二甲基亚砜(DMSO-d 6)，氘代甲醇(CD 3OD)和氘代氯仿(CDCl 3)，内标为四甲基硅烷(TMS)。 The structure of the compound of the present invention is determined by nuclear magnetic resonance (NMR) or / and liquid chromatography-mass spectrometry (LC-MS). NMR chemical shifts (δ) are given in parts per million (ppm). The measurement of NMR was performed by Bruker AVANCE-400 / 500 NMR instrument. The solvents were deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated methanol (CD 3 OD) and deuterated chloroform (CDCl 3 ), internal standard. It is tetramethylsilane (TMS).
液质联用色谱LC-MS的测定用Agilent 6120质谱仪。HPLC的测定使用安捷伦1200DAD高压液相色谱仪(Sunfire C18 150×4.6mm色谱柱)和Waters 2695-2996高压液相色谱仪(Gimini C18 150×4.6mm色谱柱)。Liquid chromatography-mass spectrometry LC-MS was measured with an Agilent 6120 mass spectrometer. HPLC was measured using Agilent 1200DAD high-pressure liquid chromatograph (Sunfire C18 150 × 4.6mm chromatographic column) and Waters 2695-2996 high-pressure liquid chromatograph (Gimini C18 150 × 4.6mm chromatographic column).
薄层层析硅胶板使用烟台黄海HSGF254或青岛GF254硅胶板，TLC采用的规格是0.15mm～0.20mm，薄层层析分离纯化产品采用的规格是0.4mm～0.5mm。柱层析一般使用烟台黄海硅胶200～300目硅胶为载体。The thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate. The specifications adopted by TLC are 0.15mm ～ 0.20mm, and the specifications adopted by thin layer chromatography separation and purification products are 0.4mm ～ 0.5mm. Column chromatography generally uses Yantai Yellow Sea silica gel 200-300 mesh silica gel as a carrier.
本发明实施例中的起始原料是已知的并且可以在市场上买到，或者可以采用或按照本领域已知的方法来合成。The starting materials in the examples of the present invention are known and can be purchased on the market, or can be synthesized using or following methods known in the art.
在无特殊说明的情况下，本发明的所有反应均在连续的磁力搅拌下，在干燥氮气或氩气氛下进行，溶剂为干燥溶剂，反应温度单位为摄氏度(℃)。Unless otherwise specified, all reactions of the present invention are carried out under continuous magnetic stirring under a dry nitrogen or argon atmosphere, the solvent is a dry solvent, and the reaction temperature is in degrees Celsius (° C).
一、中间体的制备1. Preparation of intermediates
1、3-乙基-2-甲酰基咪唑并[1,2-a]吡啶-7-羧酸甲酯的制备1. Preparation of 3-ethyl-2-formylimidazo [1,2-a] pyridine-7-carboxylic acid methyl ester
Figure PCTCN2019104957-appb-000024
Figure PCTCN2019104957-appb-000024
第一步：3-溴-2-羰基戊酸乙酯的合成Step 1: Synthesis of ethyl 3-bromo-2-carbonylvalerate
将2-羰基戊酸乙酯(25.0g,173.6mmol)溶于二氯甲烷(100mL)中，室温下缓慢滴加液溴(41.7g,260.4mmol)，反应液在室温下搅拌1小时，反应液依次用饱和亚硫酸钠水溶液(200mL*2)，饱和碳酸氢钠水溶液(200mL)，水(200mL)，饱和氯化钠水溶液(200mL)洗涤。有机相干燥过滤，滤液浓缩，所得粗品3-溴-2-羰基戊酸乙酯直接用于下一步反应。Ethyl 2-carbonylvalerate (25.0g, 173.6mmol) was dissolved in dichloromethane (100mL), and liquid bromine (41.7g, 260.4mmol) was slowly added dropwise at room temperature. The reaction solution was stirred at room temperature for 1 hour to react The solution was washed successively with saturated aqueous sodium sulfite solution (200 mL * 2), saturated aqueous sodium bicarbonate solution (200 mL), water (200 mL), and saturated aqueous sodium chloride solution (200 mL). The organic phase was dried and filtered, and the filtrate was concentrated. The resulting crude ethyl 3-bromo-2-carbonylvalerate was directly used in the next reaction.
1H NMR(400MHz,CDCl 3)δ4.98(dd,J＝8.2,6.0Hz,1H),4.39(qd,J＝7.1,1.4Hz,2H),2.23–2.08(m,1H),2.08–1.94(m,1H),1.40(t,J＝7.1Hz,3H),1.08(t,J＝7.3Hz,3H)。 1 H NMR (400 MHz, CDCl 3 ) δ 4.98 (dd, J = 8.2, 6.0 Hz, 1H), 4.39 (qd, J = 7.1, 1.4 Hz, 2H), 2.23–2.08 (m, 1H), 2.08– 1.94 (m, 1H), 1.40 (t, J = 7.1 Hz, 3H), 1.08 (t, J = 7.3 Hz, 3H).
第二步：7-溴-3-乙基咪唑并[1,2-a]吡啶-2-羧酸乙酯的合成Step 2: Synthesis of ethyl 7-bromo-3-ethylimidazo [1,2-a] pyridine-2-carboxylate
将3-溴-2-羰基戊酸乙酯(39.0g,173.6mmol),4-溴吡啶-2-胺(25.0g,144.5mmol)溶于乙醇(200mL)中，反应液加热回流24小时，反应结束后，将反应液浓缩干，剩余物溶于二氯甲烷(300mL)，溶液依次用饱和碳酸氢钠水溶液(200mL*2)，水(200mL)，饱和氯化钠水溶液(200mL)洗涤。有机相干燥过滤，滤液浓缩，所得剩余物通过快速硅胶柱层析分离(0～40％乙酸乙酯：石油醚)后得到7-溴-3-乙基咪唑并[1,2-a]吡啶-2-羧酸乙酯(23.2g,54％)。Ethyl 3-bromo-2-carbonylvalerate (39.0g, 173.6mmol), 4-bromopyridin-2-amine (25.0g, 144.5mmol) were dissolved in ethanol (200mL), and the reaction solution was heated to reflux for 24 hours, After the reaction was completed, the reaction solution was concentrated to dryness, and the residue was dissolved in dichloromethane (300 mL). The solution was washed successively with saturated aqueous sodium bicarbonate solution (200 mL * 2), water (200 mL), and saturated aqueous sodium chloride solution (200 mL). The organic phase was dried and filtered, and the filtrate was concentrated. The resulting residue was separated by flash silica gel column chromatography (0-40% ethyl acetate: petroleum ether) to obtain 7-bromo-3-ethylimidazo [1,2-a] pyridine Ethyl-2-carboxylate (23.2 g, 54%).
1H NMR(400MHz,CDCl 3)δ7.96–7.65(m,2H),6.98(dd,J＝7.3,2.0Hz,1H),4.47(q,J＝7.1Hz,2H),3.30(q,J＝7.5Hz,2H),1.45(t,J＝7.1Hz,3H),1.27(t,J＝7.5Hz,3H).ESI-MS：297.1[M+1] +。 1 H NMR (400 MHz, CDCl 3 ) δ 7.96–7.65 (m, 2H), 6.98 (dd, J = 7.3, 2.0 Hz, 1H), 4.47 (q, J = 7.1 Hz, 2H), 3.30 (q, J = 7.5 Hz, 2H), 1.45 (t, J = 7.1 Hz, 3H), 1.27 (t, J = 7.5 Hz, 3H). ESI-MS: 297.1 [M + 1] + .
第三步：(7-溴-3-乙基咪唑并[1,2-a]吡啶-2-基)甲醇的合成Step 3: Synthesis of (7-bromo-3-ethylimidazo [1,2-a] pyridin-2-yl) methanol
将7-溴-3-乙基咪唑并[1,2-a]吡啶-2-羧酸乙酯(23.2g,78.1mmol)溶于四氢呋喃(200mL)中，分批缓慢加入硼氢化锂(5.1g,234.3mmol)，反应液在室温下搅拌5小时，反应结束后， 将反应液浓缩干，剩余物加入二氯甲烷(100mL)和水(100mL)，分液，水相用混合溶液(二氯甲烷：甲醇＝10:1)(50mL*3)萃取，合并有机相后干燥过滤，滤液浓缩，剩余物通过快速硅胶柱层析分离(0～10％甲醇：二氯甲烷)后得到(7-溴-3-乙基咪唑并[1,2-a]吡啶-2-基)甲醇(10.0g,51％)。7-Bromo-3-ethylimidazo [1,2-a] pyridine-2-carboxylic acid ethyl ester (23.2 g, 78.1 mmol) was dissolved in tetrahydrofuran (200 mL), and lithium borohydride (5.1 g, 234.3 mmol). The reaction solution was stirred at room temperature for 5 hours. After the reaction was completed, the reaction solution was concentrated to dryness. The residue was added with dichloromethane (100 mL) and water (100 mL). Chloromethane: methanol = 10: 1) (50mL * 3) extraction, combined organic phase, dried and filtered, the filtrate was concentrated, the residue was separated by flash silica gel column chromatography (0-10% methanol: dichloromethane) to obtain (7 -Bromo-3-ethylimidazo [1,2-a] pyridin-2-yl) methanol (10.0 g, 51%).
1H NMR(400MHz,CDCl 3)δ7.86(s,2H),6.89(s,1H),4.91(s,2H),3.74(d,J＝6.1Hz,1H),2.97(s,2H),1.28(d,J＝6.6Hz,3H).ESI-MS 255.2[M+1] +。 1 H NMR (400 MHz, CDCl 3 ) δ 7.86 (s, 2H), 6.89 (s, 1H), 4.91 (s, 2H), 3.74 (d, J = 6.1 Hz, 1H), 2.97 (s, 2H) , 1.28 (d, J = 6.6 Hz, 3H). ESI-MS 255.2 [M + 1] + .
第四步：7-溴-3-乙基咪唑并[1,2-a]吡啶-2-甲醛的合成Step 4: Synthesis of 7-bromo-3-ethylimidazo [1,2-a] pyridine-2-carbaldehyde
将(7-溴-3-乙基咪唑并[1,2-a]吡啶-2-基)甲醇(10.0g,39.2mmol)溶于二氯甲烷(100mL)中，加入二氧化锰(17.0g,196.0mmol)，反应液在室温下搅拌16小时，反应结束后，将反应液通过硅藻土过滤，滤液浓缩干，剩余物通过快速硅胶柱层析分离(0～30％乙酸乙酯：石油醚)后得到7-溴-3-乙基咪唑并[1,2-a]吡啶-2-甲醛(9.3g,94％)。(7-Bromo-3-ethylimidazo [1,2-a] pyridin-2-yl) methanol (10.0g, 39.2mmol) was dissolved in dichloromethane (100mL), and manganese dioxide (17.0g) was added , 196.0 mmol), the reaction solution was stirred at room temperature for 16 hours. After the reaction was completed, the reaction solution was filtered through celite, the filtrate was concentrated to dryness, and the residue was separated by flash silica gel column chromatography (0-30% ethyl acetate: petroleum Ether) to give 7-bromo-3-ethylimidazo [1,2-a] pyridine-2-carbaldehyde (9.3 g, 94%).
1H NMR(400MHz,CDCl 3)δ10.22(s,1H),8.05–7.63(m,2H),7.02(dd,J＝7.4,2.0Hz,1H),3.28(q,J＝7.6Hz,2H),1.29(t,J＝7.5Hz,3H).ESI-MS 253.2[M+1] +。 1 H NMR (400 MHz, CDCl 3 ) δ 10.22 (s, 1H), 8.05–7.63 (m, 2H), 7.02 (dd, J = 7.4, 2.0 Hz, 1H), 3.28 (q, J = 7.6 Hz, 2H), 1.29 (t, J = 7.5 Hz, 3H). ESI-MS 253.2 [M + 1] + .
第五步：3-乙基-2-甲酰基咪唑并[1,2-a]吡啶-7-羧酸甲酯的合成Step 5: Synthesis of 3-ethyl-2-formylimidazo [1,2-a] pyridine-7-carboxylic acid methyl ester
将7-溴-3-乙基咪唑并[1,2-a]吡啶-2-甲醛(9.3g,36.9mmol)，[1,1'-双(二苯基膦基)二茂铁]二氯化钯(500mg)，三乙胺(15mL)溶于甲醇(100mL)中，密闭反应用一氧化碳加压至1.0MPa，加热至80℃搅拌16小时，反应结束后，将反应液通过硅藻土过滤，滤液浓缩干，剩余物通过快速硅胶柱层析分离(0～30％乙酸乙酯：石油醚)后得到3-乙基-2-甲酰基咪唑并[1,2-a]吡啶-7-羧酸甲酯(7.97g,93％)。7-Bromo-3-ethylimidazo [1,2-a] pyridine-2-carbaldehyde (9.3g, 36.9mmol), [1,1'-bis (diphenylphosphino) ferrocene] di Palladium chloride (500mg) and triethylamine (15mL) were dissolved in methanol (100mL). The sealed reaction was pressurized with carbon monoxide to 1.0MPa, heated to 80 ° C and stirred for 16 hours. After the reaction was completed, the reaction solution was passed through celite After filtration, the filtrate was concentrated to dryness, and the residue was separated by flash silica gel column chromatography (0-30% ethyl acetate: petroleum ether) to obtain 3-ethyl-2-formylimidazo [1,2-a] pyridine-7 -Methyl carboxylate (7.97 g, 93%).
1H NMR(400MHz,CDCl 3)δ10.28(s,1H),8.39(t,J＝1.3Hz,1H),8.09–7.92(m,1H),7.50(dd,J＝7.3,1.7Hz,1H),3.99(s,3H),3.33(q,J＝7.6Hz,2H),1.32(t,J＝7.6Hz,3H)。ESI-MS 233.0[M+1] +。 1 H NMR (400 MHz, CDCl 3 ) δ 10.28 (s, 1H), 8.39 (t, J = 1.3 Hz, 1H), 8.09–7.92 (m, 1H), 7.50 (dd, J = 7.3, 1.7 Hz, 1H), 3.99 (s, 3H), 3.33 (q, J = 7.6 Hz, 2H), 1.32 (t, J = 7.6 Hz, 3H). ESI-MS 233.0 [M + 1] + .
2、(R)-2-氨基-2-(4-(乙基磺酰)苯基)乙醇的制备2. Preparation of (R) -2-amino-2- (4- (ethylsulfonyl) phenyl) ethanol
方法一：method one:
Figure PCTCN2019104957-appb-000025
Figure PCTCN2019104957-appb-000025
第一步：4-溴苯乙硫醚的合成Step 1: Synthesis of 4-bromophenylethyl sulfide
将4-溴苯硫醇(5.0g,26.4mmol)溶于乙腈(50mL)，加入碳酸铯(17.2g,52.8mmol),碘乙烷(6.2g,39.7mmol)，反应液在室温下搅拌16小时，将反应液通过硅藻土过滤，滤液浓缩，剩余物通过快速硅胶柱分离(0～5％EtOAc:PE)后得到4-溴苯乙硫醚(5.53g,96％)。4-Bromobenzenethiol (5.0g, 26.4mmol) was dissolved in acetonitrile (50mL), cesium carbonate (17.2g, 52.8mmol), ethyl iodide (6.2g, 39.7mmol) was added, and the reaction solution was stirred at room temperature for 16 After hours, the reaction solution was filtered through celite, and the filtrate was concentrated. The residue was separated through a flash silica gel column (0 to 5% EtOAc: PE) to obtain 4-bromophenyl ethyl sulfide (5.53 g, 96%).
1H NMR(400MHz,CDCl 3)δ7.44–7.35(m,2H),7.23–7.12(m,2H),2.92(q,J＝7.4Hz,2H),1.30(t,J＝7.4Hz,3H)。 1 H NMR (400 MHz, CDCl 3 ) δ 7.44 – 7.35 (m, 2H), 7.23 – 7.12 (m, 2H), 2.92 (q, J = 7.4 Hz, 2H), 1.30 (t, J = 7.4 Hz, 3H).
第二步：2-((叔-丁基二甲基甲硅烷基)氧代)乙醛的合成Step 2: Synthesis of 2-((tert-butyldimethylsilyl) oxo) acetaldehyde
将草酰氯(3.45g,27.4mmol)溶于无水二氯甲烷(100mL)中，将溶液冷至-78℃，缓慢加入DMSO(4.23g,54.7mmol),反应液在-78℃搅拌30分钟，之后缓慢滴加2-((叔-丁基二甲基甲硅烷基)氧代)乙醇(4.02g,22.8mmol)的无水二氯甲烷(50mL)溶液，反应液在-78℃搅拌1小时，之后缓慢滴加三乙胺(11.5g,114.0mmol),反应液在-78℃搅拌1小时，将反应液用2N HCl酸化至pH＝4～5，所得反应液用二氯甲烷(50mL)萃取，合并有机相，用无水硫酸镁干燥，过滤，滤液浓缩得到粗品2-((叔-丁基二甲基甲硅烷基)氧代)乙醛(3.95g,95％)。Oxalyl chloride (3.45g, 27.4mmol) was dissolved in anhydrous dichloromethane (100mL), the solution was cooled to -78 ° C, DMSO (4.23g, 54.7mmol) was slowly added, and the reaction solution was stirred at -78 ° C for 30 minutes After that, a solution of 2-((tert-butyldimethylsilyl) oxo) ethanol (4.02g, 22.8mmol) in anhydrous dichloromethane (50mL) was slowly added dropwise, and the reaction solution was stirred at -78 ° C for 1 After 1 hour, triethylamine (11.5g, 114.0mmol) was slowly added dropwise. The reaction solution was stirred at -78 ° C for 1 hour. The reaction solution was acidified with 2N HCl to pH = 4-5. The resulting reaction solution was dichloromethane (50mL) ) Extraction, the organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated to give crude 2-((tert-butyldimethylsilyl) oxo) acetaldehyde (3.95 g, 95%).
1H NMR(400MHz,CDCl 3)δ9.59(t,J＝0.9Hz,1H),4.11(d,J＝0.9Hz,2H),0.82(s,9H),-0.00(s,6H)。 1 H NMR (400 MHz, CDCl 3 ) δ 9.59 (t, J = 0.9 Hz, 1H), 4.11 (d, J = 0.9 Hz, 2H), 0.82 (s, 9H), -0.00 (s, 6H).
第三步：(R,E)-N-(2-((叔-丁基二甲基甲硅烷基)氧代)亚乙基)-2-甲基丙烷-2-亚磺酰胺的合成Step 3: Synthesis of (R, E) -N- (2-((tert-butyldimethylsilyl) oxo) ethylene) -2-methylpropane-2-sulfinamide
将2-((叔-丁基二甲基甲硅烷基)氧代)乙醛(3.95g,22.7mmol)，(R)-2-甲基丙烷-2-亚磺酰胺(2.72g,22.7mmol)溶于二氯甲烷(50mL)，室温下加入无水硫酸镁(5.45g,45.4mmol)。反应液在室温下搅拌16小时。LCMS显示反应结束，反应液通过硅藻土过滤，滤液浓缩后用快速硅胶柱层析[洗脱剂:0～10％石油醚：乙酸乙酯]得到(R,E)-N-(2-((叔-丁基二甲基甲硅烷基)氧代)亚乙基)-2-甲基丙烷-2-亚磺酰胺(3.3g,52％)。ESI-MS 278.4[M+1] +。 Combine 2-((tert-butyldimethylsilyl) oxo) acetaldehyde (3.95g, 22.7mmol), (R) -2-methylpropane-2-sulfinamide (2.72g, 22.7mmol) ) Was dissolved in dichloromethane (50mL), and anhydrous magnesium sulfate (5.45g, 45.4mmol) was added at room temperature. The reaction solution was stirred at room temperature for 16 hours. LCMS showed that the reaction was over, the reaction solution was filtered through celite, and the filtrate was concentrated and then flash silica gel column chromatography [eluent: 0-10% petroleum ether: ethyl acetate] to obtain (R, E) -N- (2- ((Tert-butyldimethylsilyl) oxo) ethylene) -2-methylpropane-2-sulfinamide (3.3 g, 52%). ESI-MS 278.4 [M + 1] + .
1H NMR(400MHz,CDCl 3)δ7.96(t,J＝3.0Hz,1H),4.44(d,J＝3.0Hz,2H),1.11(s,9H),0.82(s,9H),-0.00(s,6H)。 1 H NMR (400 MHz, CDCl 3 ) δ 7.96 (t, J = 3.0 Hz, 1H), 4.44 (d, J = 3.0 Hz, 2H), 1.11 (s, 9H), 0.82 (s, 9H),- 0.00 (s, 6H).
第四步：(R)-N-((R)-2-((叔-丁基二甲基甲硅烷基)氧代)-1-(4-(乙硫基)苯基)乙基)-2-甲基丙烷-2-亚磺酰胺的合成Step 4: (R) -N-((R) -2-((tert-butyldimethylsilyl) oxo) -1- (4- (ethylthio) phenyl) ethyl) Synthesis of -2-methylpropane-2-sulfinamide
将4-溴苯乙硫醚(2.8g,12.95mmol)溶于无水四氢呋喃(50mL)中，缓慢滴加正丁基锂(5.2mL,2.5M四氢呋喃溶液,12.95mmol)，反应液在-78℃搅拌20分钟，之后向反应液中滴加(R,E)-N-(2-((叔-丁基二甲基甲硅烷基)氧代)亚乙基)-2-甲基丙烷-2-亚磺酰胺(3.0g,10.79mmol)的四氢呋喃(5mL)溶液，反应液在-78℃搅拌2小时，LCMS显示反应完全，将反应液用饱和氯化铵溶液(50mL)淬灭，所得混合液浓缩除去四氢呋喃，剩余水溶液用二氯甲烷(50mL)萃取，有机相干燥过滤，滤液浓缩，所得剩余物通过快速硅胶柱分离[洗脱剂:0～5％石油醚：乙酸乙酯]得到(R)-N-((R)-2-((叔-丁基二甲基甲硅烷基)氧代)-1-(4-(乙硫基)苯基)乙基)-2-甲基丙烷-2-亚磺酰胺(1.17g,26％)。ESI-MS 416.4[M+1] +。 4-Bromophenylethyl sulfide (2.8g, 12.95mmol) was dissolved in anhydrous tetrahydrofuran (50mL), n-butyllithium (5.2mL, 2.5M tetrahydrofuran solution, 12.95mmol) was slowly added dropwise, the reaction solution was at -78 After stirring at ℃ for 20 minutes, (R, E) -N- (2-((tert-butyldimethylsilyl) oxo) ethylene) -2-methylpropane was added dropwise to the reaction solution A solution of 2-sulfinamide (3.0 g, 10.79 mmol) in tetrahydrofuran (5 mL). The reaction solution was stirred at -78 ° C for 2 hours. LCMS showed that the reaction was complete. The reaction solution was quenched with saturated ammonium chloride solution (50 mL). The mixture was concentrated to remove tetrahydrofuran, the remaining aqueous solution was extracted with dichloromethane (50 mL), the organic phase was dried and filtered, and the filtrate was concentrated. The resulting residue was separated by flash silica gel column [eluent: 0 to 5% petroleum ether: ethyl acetate] (R) -N-((R) -2-((tert-butyldimethylsilyl) oxo) -1- (4- (ethylthio) phenyl) ethyl) -2-methyl Propane-2-sulfinamide (1.17 g, 26%). ESI-MS 416.4 [M + 1] + .
1H NMR(400MHz,CDCl 3)δ7.28–7.14(m,4H),4.44(ddd,J＝9.1,4.1,1.9Hz,1H),4.21(d,J＝1.9Hz,1H),3.77–3.66(m,1H),3.59–3.48(m,1H),2.89(q,J＝7.4Hz,2H),1.27(t,J＝7.3Hz,3H),1.17(d,J＝4.9Hz,9H),0.85(s,9H),0.05(s,3H),0.00(s,3H)。 1 H NMR (400 MHz, CDCl 3 ) δ 7.28–7.14 (m, 4H), 4.44 (ddd, J = 9.1, 4.1, 1.9 Hz, 1H), 4.21 (d, J = 1.9 Hz, 1H), 3.77– 3.66 (m, 1H), 3.59–3.48 (m, 1H), 2.89 (q, J = 7.4 Hz, 2H), 1.27 (t, J = 7.3 Hz, 3H), 1.17 (d, J = 4.9 Hz, 9H ), 0.85 (s, 9H), 0.05 (s, 3H), 0.00 (s, 3H).
第五步：(R)-2-氨基-2-(4-(乙硫基)苯基)乙醇的合成Step 5: Synthesis of (R) -2-amino-2- (4- (ethylthio) phenyl) ethanol
将(R)-N-((R)-2-((叔-丁基二甲基甲硅烷基)氧代)-1-(4-(乙硫基)苯基)乙基)-2-甲基丙烷-2-亚磺酰胺(1.16g,2.8mmol)溶于二氧六环(5mL)中，加入盐酸二氧六环中(5mL,4M)，反应液在室温下搅拌1小时，LCMS显示反应完全，反应液浓缩干得到粗品(R)-2-氨基-2-(4-(乙硫基)苯基)乙醇(1.2g,100％)。ESI-MS 181.1[M+H-NH 3] +。 (R) -N-((R) -2-((tert-butyldimethylsilyl) oxo) -1- (4- (ethylthio) phenyl) ethyl) -2- Methylpropane-2-sulfinamide (1.16g, 2.8mmol) was dissolved in dioxane (5mL), added to dioxane hydrochloride (5mL, 4M), the reaction solution was stirred at room temperature for 1 hour, LCMS The reaction was shown to be complete, and the reaction solution was concentrated to dryness to obtain crude (R) -2-amino-2- (4- (ethylthio) phenyl) ethanol (1.2 g, 100%). ESI-MS 181.1 [M + H-NH 3 ] + .
第六步：(R)-2-氨基-2-(4-(乙基磺酰)苯基)乙醇的合成Step 6: Synthesis of (R) -2-amino-2- (4- (ethylsulfonyl) phenyl) ethanol
将粗品(R)-2-氨基-2-(4-(乙硫基)苯基)乙醇(1.2g,2.8mmol)溶于水(20mL)中，加入过氧硫酸氢钾复合盐(3.4g,5.6mmol)。反应液在室温下搅拌2小时，LCMS显示反应完全，将反应液用氨水调节pH＝8～9，所得反应液直接冻干，所得冻干粉溶于二氯甲烷甲醇混合液(100mL,1:1)，溶液过滤，滤液浓缩，剩余物通过快速硅胶柱分离[洗脱剂:0～20％二氯甲烷：甲醇]得到(R)-2-氨基-2-(4-(乙基磺酰)苯基)乙醇(605mg,95％)。ESI-MS 230.2[M+1] +。 The crude (R) -2-amino-2- (4- (ethylthio) phenyl) ethanol (1.2g, 2.8mmol) was dissolved in water (20mL), and potassium peroxysulfate composite salt (3.4g) was added , 5.6 mmol). The reaction solution was stirred at room temperature for 2 hours. LCMS showed that the reaction was complete. The reaction solution was adjusted to pH = 8-9 with ammonia water. The resulting reaction solution was directly lyophilized. The resulting lyophilized powder was dissolved in a mixed solution of dichloromethane and methanol (100 mL, 1: 1), the solution is filtered, the filtrate is concentrated, and the residue is separated by a flash silica gel column [eluent: 0-20% dichloromethane: methanol] to obtain (R) -2-amino-2- (4- (ethylsulfonyl ) Phenyl) ethanol (605 mg, 95%). ESI-MS 230.2 [M + 1] + .
1H NMR(400MHz,Methanol-d 4)δ8.03–7.96(m,2H),7.74(d,J＝8.4Hz,2H),4.51(dd,J＝7.1,4.3Hz,1H),3.95(dd,J＝11.6,4.3Hz,1H),3.83(dd,J＝11.6,7.1Hz,1H),3.23(q,J＝7.4Hz,2H),1.22(t,J＝7.4Hz,3H)。 1 H NMR (400MHz, Methanol-d 4 ) δ8.03-7.96 (m, 2H), 7.74 (d, J = 8.4Hz, 2H), 4.51 (dd, J = 7.1, 4.3Hz, 1H), 3.95 ( dd, J = 11.6, 4.3 Hz, 1H), 3.83 (dd, J = 11.6, 7.1 Hz, 1H), 3.23 (q, J = 7.4 Hz, 2H), 1.22 (t, J = 7.4 Hz, 3H).
方法二：Method Two:
Figure PCTCN2019104957-appb-000026
Figure PCTCN2019104957-appb-000026
第一步：4-乙基磺酰苯甲醛的合成Step 1: Synthesis of 4-ethylsulfonyl benzaldehyde
将对氟苯甲醛(23.0g,185.5mmol)，乙基亚磺酸钠(25.0g,222.6mmol)溶于DMSO(60mL)，反应在120℃中搅拌16小时，反应结束后，将反应液在缓慢淬灭至冰水混合物(约400mL)中，将混合物过滤，所得滤饼用乙醇(10mL)洗涤，收集滤饼得到4-乙基磺酰苯甲醛(35.1g,95％)。Dissolve p-fluorobenzaldehyde (23.0g, 185.5mmol) and sodium ethylsulfinate (25.0g, 222.6mmol) in DMSO (60mL). The reaction was stirred at 120 ° C for 16 hours. After the reaction was completed, the reaction solution was It was slowly quenched into an ice-water mixture (about 400 mL), the mixture was filtered, the resulting filter cake was washed with ethanol (10 mL), and the filter cake was collected to obtain 4-ethylsulfonylbenzaldehyde (35.1 g, 95%).
1H NMR(400MHz,CDCl 3)δ10.07(s,1H),8.02(s,4H),3.10(q,J＝7.4Hz,2H),1.23(t,J＝7.4Hz,3H)。 1 H NMR (400 MHz, CDCl 3 ) δ 10.07 (s, 1H), 8.02 (s, 4H), 3.10 (q, J = 7.4 Hz, 2H), 1.23 (t, J = 7.4 Hz, 3H).
第二步：2-(4-乙基磺酰苯基)噁丙环的合成Step 2: Synthesis of 2- (4-ethylsulfonylphenyl) oxapropane
将4-乙基磺酰苯甲醛(35.1g,177.3mmol)，三甲基碘化锍(41.6g,203.9mmol)溶于无水DMF(150mL)，向溶液中加入氢氧化钾(19.8g,354.6mmol)。反应液在氮气保护下24℃中搅拌1小时，LCMS显示反应结束，反应液用H 2O(50mL)淬灭，并用1N HCl酸化至pH＝7～8。所得混合溶液用乙酸乙酯萃取(3*100mL)。合并有机相并用饱和食盐水(50mL)洗涤，有机相用硫酸镁干燥，过滤，滤液浓缩直接得到2-(4-乙基磺酰苯基)噁丙环(33.1g,88％)所得粗品直接用于下一步反应。 Dissolve 4-ethylsulfonylbenzaldehyde (35.1g, 177.3mmol), trimethylsulfonium iodide (41.6g, 203.9mmol) in anhydrous DMF (150mL), and add potassium hydroxide (19.8g, 354.6 mmol). The reaction solution was stirred at 24 ° C for 1 hour under the protection of nitrogen. LCMS showed that the reaction was completed. The reaction solution was quenched with H 2 O (50 mL) and acidified with 1N HCl to pH = 7-8. The resulting mixed solution was extracted with ethyl acetate (3 * 100 mL). The organic phases were combined and washed with saturated brine (50 mL). The organic phase was dried over magnesium sulfate, filtered, and the filtrate was concentrated to give 2- (4-ethylsulfonylphenyl) oxacyclopropane (33.1 g, 88%) directly. Used for the next reaction.
1H NMR(400MHz,CDCl 3)δ7.81(d,J＝8.4Hz,2H),7.41(d,J＝8.4Hz,2H),3.88(dd,J＝4.1,2.5Hz,1H),3.15(dd,J＝5.5,4.1Hz,1H),3.04(q,J＝7.5Hz,2H),2.72(dd,J＝5.5,2.5Hz,1H),1.20(t,J＝7.4Hz,3H)。 1 H NMR (400 MHz, CDCl 3 ) δ 7.81 (d, J = 8.4 Hz, 2H), 7.41 (d, J = 8.4 Hz, 2H), 3.88 (dd, J = 4.1, 2.5 Hz, 1H), 3.15 (dd, J = 5.5, 4.1 Hz, 1H), 3.04 (q, J = 7.5 Hz, 2H), 2.72 (dd, J = 5.5, 2.5 Hz, 1H), 1.20 (t, J = 7.4 Hz, 3H) .
第三步：2-氨基-2-(4-乙基磺酰苯基)乙醇的合成Step 3: Synthesis of 2-amino-2- (4-ethylsulfonylphenyl) ethanol
将2-(4-乙基磺酰苯基)噁丙环(33.1g,156.1mmol)溶于乙腈(300mL)，0℃下缓慢滴加浓硫酸(16.5mL,312.2mmol)。反应液在0～24℃搅拌2小时，之后H 2O(50mL)加入，反应液在室温下继续搅拌8小时和加热至50℃下搅拌16小时。LCMS显示反应结束，反应液用1N氢氧化钠溶液调节pH至3～4。混合溶液用乙酸乙酯(200mL)萃取，有机相用H 2O(100mL)洗涤后弃去，合并水相，并继续调节pH至9～10。所得水溶液用正丁醇(5*100mL)萃取，合并有机相(不包括乙酸乙酯相)，用硫酸镁干燥，过滤浓缩，剩余物通过快速硅胶柱分离(DCM:MeOH＝0～30％)，得到2-氨基-2-(4-乙基磺酰苯基)乙醇(15.0g,43％)。 2- (4-Ethylsulfonylphenyl) oxapropane (33.1 g, 156.1 mmol) was dissolved in acetonitrile (300 mL), and concentrated sulfuric acid (16.5 mL, 312.2 mmol) was slowly added dropwise at 0 ° C. The reaction solution was stirred at 0-24 ° C for 2 hours, after which H 2 O (50 mL) was added, and the reaction solution was further stirred at room temperature for 8 hours and heated to 50 ° C for 16 hours. LCMS showed that the reaction was over, and the reaction solution was adjusted to pH 3-4 with 1N sodium hydroxide solution. The mixed solution was extracted with ethyl acetate (200 mL), the organic phase was washed with H 2 O (100 mL) and discarded, and the aqueous phases were combined, and the pH was adjusted continuously to 9-10. The resulting aqueous solution was extracted with n-butanol (5 * 100 mL), the organic phases were combined (excluding the ethyl acetate phase), dried over magnesium sulfate, filtered and concentrated, and the residue was separated by a flash silica gel column (DCM: MeOH = 0-30%) To give 2-amino-2- (4-ethylsulfonylphenyl) ethanol (15.0 g, 43%).
1H NMR(400MHz,Methanol-d 4)δ7.87(d,J＝8.4Hz,2H),7.67(d,J＝8.4Hz,2H),4.12(dd,J＝7.0,5.1Hz,1H),3.74(dd,J＝10.9,5.1Hz,1H),3.64(dd,J＝10.9,7.0Hz,1H),3.22(q,J＝7.4Hz,2H),1.23(t,J＝7.4Hz,3H).ESI-MS 230.2[M+H] +。 1 H NMR (400 MHz, Methanol-d 4 ) δ 7.87 (d, J = 8.4 Hz, 2H), 7.67 (d, J = 8.4 Hz, 2H), 4.12 (dd, J = 7.0, 5.1 Hz, 1H) , 3.74 (dd, J = 10.9, 5.1 Hz, 1H), 3.64 (dd, J = 10.9, 7.0 Hz, 1H), 3.22 (q, J = 7.4 Hz, 2H), 1.23 (t, J = 7.4 Hz, 3H). ESI-MS 230.2 [M + H] + .
第四步：(R)-2-氨基-2-(4-乙基磺酰苯基)乙醇和(S)-2-氨基-2-(4-乙基磺酰苯基)乙醇的合成所得消旋混合物(15.0g,65.2mmol)经手性柱拆分得到：Step 4: Synthesis of (R) -2-amino-2- (4-ethylsulfonylphenyl) ethanol and (S) -2-amino-2- (4-ethylsulfonylphenyl) ethanol The racemic mixture (15.0g, 65.2mmol) was resolved by chiral column to obtain:
(R)-2-氨基-2-(4-乙基磺酰苯基)乙醇(6.0g,40％) 1H NMR(400MHz,Methanol-d 4)δ7.78(d,J＝8.4Hz,2H),7.55(d,J＝8.3Hz,2H),3.98(dd,J＝6.9,5.2Hz,1H),3.61(dd,J＝10.9,5.1Hz,1H),3.51(dd,J＝10.9,7.0Hz,1H),3.10(q,J＝7.4Hz,2H),1.11(t,J＝7.4Hz,3H).ESI-MS 230.2[M+H] +。 (R) -2-amino-2- (4-ethylsulfonylphenyl) ethanol (6.0g, 40%) 1 H NMR (400MHz, Methanol-d 4 ) δ 7.78 (d, J = 8.4Hz, 2H), 7.55 (d, J = 8.3 Hz, 2H), 3.98 (dd, J = 6.9, 5.2 Hz, 1H), 3.61 (dd, J = 10.9, 5.1 Hz, 1H), 3.51 (dd, J = 10.9 , 7.0 Hz, 1H), 3.10 (q, J = 7.4 Hz, 2H), 1.11 (t, J = 7.4 Hz, 3H). ESI-MS 230.2 [M + H] + .
(S)-2-氨基-2-(4-乙基磺酰苯基)乙醇(5.5g,36％) 1H NMR(400MHz,Methanol-d 4)δ7.89(d,J＝8.3Hz,2H),7.67(d,J＝8.3Hz,2H),4.09(dd,J＝6.9,5.2Hz,1H),3.73(dd,J＝10.8,5.1Hz,1H),3.63(dd,J＝10.8,6.9Hz,1H),3.21(q,J＝7.4Hz,2H),1.23(t,J＝7.4Hz,3H).ESI-MS 230.2[M+H] +。 (S) -2-amino-2- (4-ethylsulfonylphenyl) ethanol (5.5g, 36%) 1 H NMR (400MHz, Methanol-d 4 ) δ 7.89 (d, J = 8.3Hz, 2H), 7.67 (d, J = 8.3 Hz, 2H), 4.09 (dd, J = 6.9, 5.2 Hz, 1H), 3.73 (dd, J = 10.8, 5.1 Hz, 1H), 3.63 (dd, J = 10.8 , 6.9 Hz, 1H), 3.21 (q, J = 7.4 Hz, 2H), 1.23 (t, J = 7.4 Hz, 3H). ESI-MS 230.2 [M + H] + .
3、(4-(乙基磺酰)苯基)甲胺的制备3. Preparation of (4- (ethylsulfonyl) phenyl) methylamine
Figure PCTCN2019104957-appb-000027
Figure PCTCN2019104957-appb-000027
第一步：1-溴-4-(乙基磺酰)苯的合成Step 1: Synthesis of 1-bromo-4- (ethylsulfonyl) benzene
将(4-溴苯基)(乙基)硫烷(4.4g,20.37mmol)溶于二氯甲烷(120mL)溶液中，降温到0℃。缓慢加入间氯过氧苯甲酸(8.76g,50.92mmol)，0℃继续反应2个小时。反应完成后加入1N氢氧化钠水溶液，二氯甲烷(20mL*2)萃取，有机层无水硫酸钠干燥，浓缩后柱析[展开剂:PE/EA＝4：1]得到化合物1-溴-4-(乙基磺酰)苯(200mg,33％)。ESI-MS 249[M+1] +。 (4-Bromophenyl) (ethyl) sulfane (4.4 g, 20.37 mmol) was dissolved in dichloromethane (120 mL) solution, and the temperature was lowered to 0 ° C. Add m-chloroperoxybenzoic acid (8.76g, 50.92mmol) slowly and continue the reaction at 0 ° C for 2 hours. After completion of the reaction, 1N aqueous sodium hydroxide solution was added, extracted with dichloromethane (20 mL * 2), the organic layer was dried over anhydrous sodium sulfate, and concentrated to column analysis [developing agent: PE / EA = 4: 1] to obtain compound 1-bromo- 4- (ethylsulfonyl) benzene (200 mg, 33%). ESI-MS 249 [M + 1] + .
第二步：4-(乙基磺酰)苯甲腈的合成Step 2: Synthesis of 4- (ethylsulfonyl) benzonitrile
将1-溴-4-(乙基磺酰)苯(5g,20.16mmol)溶于DMF(50mL)中，加入氰化锌(3.5g,30.24mmol)和四三苯基膦钯(2.3g,2mmol),氮气保护下，加热到80℃反应16个小时。反应完成后加入100毫升水，乙酸乙酯(50mL*2)萃取，有机层水洗，盐水洗后，无水硫酸钠干燥，浓 缩后柱析[展开剂:PE/EA＝4：1]得到化合物4-(乙基磺酰)苯甲腈(3.8g,97％)。ESI-MS 196[M+H] +。 Dissolve 1-bromo-4- (ethylsulfonyl) benzene (5g, 20.16mmol) in DMF (50mL), add zinc cyanide (3.5g, 30.24mmol) and tetratriphenylphosphine palladium (2.3g, 2mmol), under the protection of nitrogen, heated to 80 ℃ for 16 hours. After the reaction was completed, 100 ml of water was added, extracted with ethyl acetate (50 mL * 2), the organic layer was washed with water, washed with brine, dried over anhydrous sodium sulfate, and concentrated to column analysis [developing agent: PE / EA = 4: 1] to obtain the compound 4- (Ethylsulfonyl) benzonitrile (3.8 g, 97%). ESI-MS 196 [M + H] + .
第三步：(4-(乙基磺酰)苯基)甲胺的合成Step 3: Synthesis of (4- (ethylsulfonyl) phenyl) methylamine
将4-(乙基磺酰)苯甲腈(220mg,1.13mmol)溶于10mL氨甲醇中，加入雷尼镍(30mg)，氢气环境下室温反应16个小时，反应液过滤，滤液浓缩后得到化合物(4-(乙基磺酰)苯基)甲胺(190mg,85％)。ESI-MS 200[M+H] +。 Dissolve 4- (ethylsulfonyl) benzonitrile (220 mg, 1.13 mmol) in 10 mL of ammonia methanol, add Raney nickel (30 mg), react at room temperature for 16 hours under hydrogen atmosphere, filter the reaction solution, and concentrate the filtrate to obtain The compound (4- (ethylsulfonyl) phenyl) methanamine (190 mg, 85%). ESI-MS 200 [M + H] + .
4、(5-(乙基磺酰基)-吡啶-2-基)甲胺盐酸盐的制备4. Preparation of (5- (ethylsulfonyl) -pyridin-2-yl) methylamine hydrochloride
Figure PCTCN2019104957-appb-000028
Figure PCTCN2019104957-appb-000028
第一步：5-(乙硫基)吡啶甲腈的合成Step 1: Synthesis of 5- (ethylthio) pyridinecarbonitrile
往250mL单口瓶中加入5-溴-2-吡啶甲腈(8.0g,43.7mmol)，乙硫醇钠(4.04g,48.1mmol)，碳酸钾(7.84g,56.8mmol)，NMP(55mL)。室温搅拌反应过夜。加入水(100mL)，过滤，固体用冰水洗涤，干燥得产物5-(乙硫基)吡啶甲腈(5.3g,67％)。ESI-MS:164.8[M+1] +。 To a 250 mL single-necked bottle was added 5-bromo-2-pyridinecarbonitrile (8.0 g, 43.7 mmol), sodium ethanethiolate (4.04 g, 48.1 mmol), potassium carbonate (7.84 g, 56.8 mmol), NMP (55 mL). The reaction was stirred at room temperature overnight. Water (100 mL) was added, filtered, the solid was washed with ice water, and dried to give the product 5- (ethylthio) pyridinecarbonitrile (5.3 g, 67%). ESI-MS: 164.8 [M + 1] + .
第二步:5-(乙基磺酰基)-2-吡啶甲腈的合成Step 2: Synthesis of 5- (ethylsulfonyl) -2-pyridinecarbonitrile
往100mL单口瓶中加入5-(乙硫基)吡啶甲腈(2.5g，90％，13.7mmol)，二氯甲烷(50mL)，冰浴下搅拌10分钟，m-CPBA(6.95g，34.3mmol)分批加入到反应液中，然后室温反应过夜，用2N的碳酸钠溶液洗涤，有机层旋干过硅胶柱分离(石油醚：乙酸乙酯＝2:1-1:1)得到5-(乙基磺酰基)-2-吡啶甲腈(2.4g,85％)。ESI-MS:196.8[M+1] +。 To a 100mL single-necked bottle, add 5- (ethylthio) pyridinecarbonitrile (2.5g, 90%, 13.7mmol), dichloromethane (50mL), stir for 10 minutes under ice bath, m-CPBA (6.95g, 34.3mmol) ) Was added to the reaction solution in batches, then reacted overnight at room temperature, washed with 2N sodium carbonate solution, and the organic layer was spin-dried and separated through a silica gel column (petroleum ether: ethyl acetate = 2: 1-1: 1) to obtain 5- ( Ethylsulfonyl) -2-pyridinecarbonitrile (2.4g, 85%). ESI-MS: 196.8 [M + 1] + .
第三步:(5-(乙基磺酰基)-吡啶-2-基)甲胺盐酸盐的合成Step 3: Synthesis of (5- (ethylsulfonyl) -pyridin-2-yl) methylamine hydrochloride
往250mL单口瓶中加入5-(乙基磺酰基)2-吡啶甲腈(1.44g，6.97mmol)，甲醇(100mL)，Pd/C(700mg，10％)。反应液室温氢气条件下搅拌两小时，硅藻土过滤，旋干。残余物质通过快速硅胶柱分离(0～50％EtOAc:PE)得到(5-(乙基磺酰基)-吡啶-2-基)甲胺(400mg),溶于甲醇(100mL)，加入盐酸甲醇溶液(1.4mL,4M,5.70mmol),搅拌一小时，浓缩后真空干燥得到白色固体产物(5-(乙基磺酰基)-吡啶-2-基)甲胺盐酸盐(546mg,27％)。ESI-MS:201.0[M+1] +。 To a 250 mL single-necked bottle was added 5- (ethylsulfonyl) 2-pyridinecarbonitrile (1.44 g, 6.97 mmol), methanol (100 mL), Pd / C (700 mg, 10%). The reaction solution was stirred under hydrogen at room temperature for two hours, and the celite was filtered and spin-dried. The residual material was separated by a flash silica gel column (0-50% EtOAc: PE) to obtain (5- (ethylsulfonyl) -pyridin-2-yl) methylamine (400 mg), dissolved in methanol (100 mL), and added hydrochloric acid methanol solution (1.4 mL, 4M, 5.70 mmol), stirred for one hour, concentrated and dried in vacuo to give the product (5- (ethylsulfonyl) -pyridin-2-yl) methanamine hydrochloride (546 mg, 27%) as a white solid. ESI-MS: 201.0 [M + 1] + .
5、3-乙基-2-(羟基(2-(三氟甲基)苯基)甲基)咪唑并[1,2-a]吡啶-7-羧酸的制备5. Preparation of 3-ethyl-2- (hydroxy (2- (trifluoromethyl) phenyl) methyl) imidazo [1,2-a] pyridine-7-carboxylic acid
Figure PCTCN2019104957-appb-000029
Figure PCTCN2019104957-appb-000029
第一步：甲基3-乙基-2-(羟基(2-(三氟甲基)苯基)甲基)咪唑并[1,2-a]吡啶-7-羧酸酯的合成Step 1: Synthesis of methyl 3-ethyl-2- (hydroxy (2- (trifluoromethyl) phenyl) methyl) imidazo [1,2-a] pyridine-7-carboxylate
将镁屑(111mg,4.44mmol)和一颗碘粒悬浮于无水四氢呋喃(15mL)中，加热至60℃,然后滴加1-溴-2-(三氟甲基)苯(1.0g,4.44mmol)的四氢呋喃溶液(2mL)，反应液在60℃下搅拌约1小时至碘颜色消失，镁屑几乎消耗完，冷却至室温。然后将上述自制的格氏试剂滴加入甲基3-乙基-2-甲酰基咪唑并[1,2-a]吡啶-7-羧酸酯(1.03g,4.44mmol)的四氢呋喃溶液(10mL)中，室温搅拌2小时。将反应液用甲醇淬灭，所得反应液浓缩干，剩余物通过快速硅胶 柱分离(0～33％EtOAC:PE)后得到甲基3-乙基-2-(羟基(2-(三氟甲基)苯基)甲基)咪唑并[1,2-a]吡啶-7-羧酸酯(290mg,15.5％)。ESI-MS 379.2[M+1] +。 Suspend magnesium filings (111mg, 4.44mmol) and one iodine particle in anhydrous tetrahydrofuran (15mL), heat to 60 ° C, and then dropwise add 1-bromo-2- (trifluoromethyl) benzene (1.0g, 4.44 mmol) of tetrahydrofuran solution (2 mL), the reaction solution was stirred at 60 ° C. for about 1 hour until the color of iodine disappeared, the magnesium scraps were almost consumed, and cooled to room temperature. Then the above-made Grignard reagent was added dropwise to a solution of methyl 3-ethyl-2-formylimidazo [1,2-a] pyridine-7-carboxylate (1.03g, 4.44mmol) in tetrahydrofuran (10mL) Medium, stirring at room temperature for 2 hours. The reaction solution was quenched with methanol, and the resulting reaction solution was concentrated to dryness. The residue was separated through a flash silica gel column (0 to 33% EtOAC: PE) to obtain methyl 3-ethyl-2- (hydroxy (2- (trifluoromethyl Yl) phenyl) methyl) imidazo [1,2-a] pyridine-7-carboxylate (290 mg, 15.5%). ESI-MS 379.2 [M + 1] + .
第二步：3-乙基-2-(羟基(2-(三氟甲基)苯基)甲基)咪唑并[1,2-a]吡啶-7-羧酸的合成Step 2: Synthesis of 3-ethyl-2- (hydroxy (2- (trifluoromethyl) phenyl) methyl) imidazo [1,2-a] pyridine-7-carboxylic acid
将甲基3-乙基-2-(羟基(2-(三氟甲基)苯基)甲基)咪唑并[1,2-a]吡啶-7-羧酸酯(90mg,0.21mmol),一水合氢氧化锂(45mg,1.07mmol)溶于四氢呋喃-水(3:1,3mL)中，反应在室温搅拌2小时，LCMS显示反应完全，将反应液用2N HCl酸化至pH＝6，乙酸乙酯萃取，有机相干燥、过滤、浓缩得到粗品3-乙基-2-(羟基(2-(三氟甲基)苯基)甲基)咪唑并[1,2-a]吡啶-7-羧酸(80mg)，直接用于下一步反应。ESI-MS 365.4[M+1] +。 Methyl 3-ethyl-2- (hydroxy (2- (trifluoromethyl) phenyl) methyl) imidazo [1,2-a] pyridine-7-carboxylate (90mg, 0.21mmol), Lithium hydroxide monohydrate (45mg, 1.07mmol) was dissolved in tetrahydrofuran-water (3: 1, 3mL), the reaction was stirred at room temperature for 2 hours, LCMS showed the reaction was complete, the reaction was acidified with 2N HCl to pH = 6, acetic acid Extract with ethyl ester, dry the organic phase, filter and concentrate to obtain crude 3-ethyl-2- (hydroxy (2- (trifluoromethyl) phenyl) methyl) imidazo [1,2-a] pyridine-7- Carboxylic acid (80mg), used directly in the next reaction. ESI-MS 365.4 [M + 1] + .
6、2-(3-(二氟甲氧基)-5-氟苯基)-3-乙基咪唑并[1,2-a]吡啶-7-羧酸的制备6. Preparation of 2- (3- (difluoromethoxy) -5-fluorophenyl) -3-ethylimidazo [1,2-a] pyridine-7-carboxylic acid
Figure PCTCN2019104957-appb-000030
Figure PCTCN2019104957-appb-000030
第一步：3-(二氟甲氧基)-5-氟苯甲酸的合成Step 1: Synthesis of 3- (difluoromethoxy) -5-fluorobenzoic acid
将3-氟-5-羟基苯甲酸(3.22g,20.6mmol),一氯二氟醋酸钠(4.69g,30.9mmol),碳酸铯(20.1g,61.9mmol)溶于DMF(50mL)。反应液在110℃下搅拌16小时。LCMS显示反应结束，反应浓缩。剩余产物直接用于下一步反应。3-fluoro-5-hydroxybenzoic acid (3.22g, 20.6mmol), sodium chlorodifluoroacetate (4.69g, 30.9mmol), cesium carbonate (20.1g, 61.9mmol) was dissolved in DMF (50mL). The reaction solution was stirred at 110 ° C for 16 hours. LCMS showed that the reaction was over and the reaction was concentrated. The remaining product was used directly in the next reaction.
第二步：3-(二氟甲氧基)-5-氟-N-甲氧基-N-甲基苯酰胺的合成Step 2: Synthesis of 3- (difluoromethoxy) -5-fluoro-N-methoxy-N-methylbenzamide
将上一步粗品3-(二氟甲氧基)-5-氟苯甲酸溶于DMF(50mL),依次加入二甲羟胺盐酸盐(4.0g,41.2mmol)，HATU(15.6g,41.2mmol)，反应液在室温搅拌6小时。LCMS显示反应结束，反应液浓缩，剩余物用乙酸乙酯(200mL)水(200mL)分层，合并有机相，硫酸钠干燥，浓缩后快速硅胶柱层析分离[洗脱剂:0～50％石油醚：乙酸乙酯]得到3-(二氟甲氧基)-5-氟-N-甲氧基-N-甲基苯酰胺(1.15g,两步22％)。Dissolve the crude 3- (difluoromethoxy) -5-fluorobenzoic acid from the previous step in DMF (50mL), then add dimethylolamine hydrochloride (4.0g, 41.2mmol), HATU (15.6g, 41.2mmol) The reaction solution was stirred at room temperature for 6 hours. LCMS showed that the reaction was over, and the reaction solution was concentrated. The residue was separated with ethyl acetate (200 mL) and water (200 mL). The organic phases were combined and dried over sodium sulfate. After concentration, the silica gel column chromatography was separated [eluent: 0-50% Petroleum ether: ethyl acetate] gave 3- (difluoromethoxy) -5-fluoro-N-methoxy-N-methylbenzamide (1.15 g, 22% in two steps).
1H NMR(400MHz,CDCl 3)δ7.31–7.17(m,2H),7.05(dt,J＝8.9,2.3Hz,1H),6.48(t,J＝72.9Hz,1H),3.50(s,3H),3.30(s,3H)。 1 H NMR (400 MHz, CDCl 3 ) δ 7.31–7.17 (m, 2H), 7.05 (dt, J = 8.9, 2.3 Hz, 1H), 6.48 (t, J = 72.9 Hz, 1H), 3.50 (s, 3H), 3.30 (s, 3H).
第三步：1-(3-(二氟甲氧基)-5-氟苯基)丁烷-1-酮的合成Step 3: Synthesis of 1- (3- (difluoromethoxy) -5-fluorophenyl) butane-1-one
将3-(二氟甲氧基)-5-氟-N-甲氧基-N-甲基苯酰胺(1.15g,4.62mmol)溶于无水四氢呋喃(30mL)。反应冷至-78℃，缓慢滴加正丙基氯化镁(4.62mmol,2M四氢呋喃溶液,9.23mmol)，反应液从-78℃缓慢升温至室温，搅拌2小时。LCMS显示反应结束，把它倒入饱和氯化铵 溶液(50mL)中，用乙酸乙酯萃取(30mL*2)，合并有机相，硫酸钠干燥，浓缩后快速硅胶柱层析分离[洗脱剂:0～20％石油醚：乙酸乙酯]得到1-(3-(二氟甲氧基)-5-氟苯基)丁烷-1-酮(1.02g，95％)。3- (Difluoromethoxy) -5-fluoro-N-methoxy-N-methylbenzamide (1.15 g, 4.62 mmol) was dissolved in anhydrous tetrahydrofuran (30 mL). The reaction was cooled to -78 ° C, n-propyl magnesium chloride (4.62 mmol, 2M tetrahydrofuran solution, 9.23 mmol) was slowly added dropwise, and the reaction solution was slowly warmed from -78 ° C to room temperature and stirred for 2 hours. LCMS showed that the reaction was over, poured it into saturated ammonium chloride solution (50 mL), extracted with ethyl acetate (30 mL * 2), combined organic phases, dried over sodium sulfate, concentrated and separated by flash silica gel column chromatography [eluent : 0-20% petroleum ether: ethyl acetate] to give 1- (3- (difluoromethoxy) -5-fluorophenyl) butane-1-one (1.02 g, 95%).
1H NMR(400MHz,CDCl 3)δ7.50–7.38(m,2H),6.99(dt,J＝8.8,2.3Hz,1H),6.50(t,J＝72.7Hz,1H),2.83(t,J＝7.2Hz,2H),1.70(h,J＝7.3Hz,2H),0.93(t,J＝7.4Hz,3H)。 1 H NMR (400 MHz, CDCl 3 ) δ 7.50 – 7.38 (m, 2H), 6.99 (dt, J = 8.8, 2.3 Hz, 1H), 6.50 (t, J = 72.7 Hz, 1H), 2.83 (t, J = 7.2 Hz, 2H), 1.70 (h, J = 7.3 Hz, 2H), 0.93 (t, J = 7.4 Hz, 3H).
第四步：2-溴-1-(3-(二氟甲氧基)-5-氟苯基)丁烷-1-酮的合成Step 4: Synthesis of 2-bromo-1- (3- (difluoromethoxy) -5-fluorophenyl) butane-1-one
将1-(3-(二氟甲氧基)-5-氟苯基)丁烷-1-酮(1.02g,4.39mmol)溶于二氯甲烷(20mL)，室温下滴加液溴(1.4g,8.28mmol)，反应液在室温搅拌3小时。LCMS显示反应结束，反应液浓缩，剩余物加入二氯甲烷(10mL*2)和水(20mL)，分液，合并有机相，硫酸钠干燥，浓缩后快速硅胶柱层析分离[洗脱剂:0～20％石油醚：乙酸乙酯]得到2-溴-1-(3-(二氟甲氧基)-5-氟苯基)丁烷-1-酮(1.21g，88％)。1- (3- (Difluoromethoxy) -5-fluorophenyl) butan-1-one (1.02g, 4.39mmol) was dissolved in dichloromethane (20mL), and liquid bromine (1.4 g, 8.28 mmol), and the reaction solution was stirred at room temperature for 3 hours. LCMS showed that the reaction was over, the reaction solution was concentrated, the residue was added with dichloromethane (10mL * 2) and water (20mL), the liquid was separated, the organic phases were combined, dried over sodium sulfate, concentrated and separated by flash silica gel column chromatography [eluent: 0-20% petroleum ether: ethyl acetate] to give 2-bromo-1- (3- (difluoromethoxy) -5-fluorophenyl) butane-1-one (1.21 g, 88%).
1H NMR(400MHz,CDCl 3)δ7.55–7.40(m,2H),7.02(dt,J＝8.7,2.3Hz,1H),6.49(t,J＝72.5Hz,1H),4.83(dd,J＝7.8,6.3Hz,1H),2.22–1.98(m,2H),1.00(t,J＝7.3Hz,3H)。 1 H NMR (400 MHz, CDCl 3 ) δ 7.55–7.40 (m, 2H), 7.02 (dt, J = 8.7, 2.3 Hz, 1H), 6.49 (t, J = 72.5 Hz, 1H), 4.83 (dd, J = 7.8, 6.3 Hz, 1H), 2.22-1.98 (m, 2H), 1.00 (t, J = 7.3 Hz, 3H).
第五步：2-(3-(二氟甲氧基)-5-氟苯基)-3-乙基咪唑并[1,2-a]吡啶-7-羧酸甲酯的合成Step 5: Synthesis of 2- (3- (difluoromethoxy) -5-fluorophenyl) -3-ethylimidazo [1,2-a] pyridine-7-carboxylic acid methyl ester
将2-溴-1-(3-(二氟甲氧基)-5-氟苯基)丁烷-1-酮(384mg,1.23mmol)，2-氨基异烟酸甲酯(281mg,1.85mmol)溶于乙醇(10mL)，反应液在80℃下反应4小时。LCMS显示反应结束，反应液浓缩除去甲醇，剩余加入乙酸乙酯(30mL)饱和碳酸氢钠(30mL)，分液，有机相硫酸钠干燥，浓缩后快速硅胶柱层析分离[洗脱剂:0～50％石油醚：乙酸乙酯]得到2-(3-(二氟甲氧基)-5-氟苯基)-3-乙基咪唑并[1,2-a]吡啶-7-羧酸甲酯(58mg,13％)。ESI-MS 365.0[M+1] +。 Combine 2-bromo-1- (3- (difluoromethoxy) -5-fluorophenyl) butane-1-one (384mg, 1.23mmol), methyl 2-aminoisonicotinate (281mg, 1.85mmol) ) Was dissolved in ethanol (10 mL), and the reaction solution was reacted at 80 ° C for 4 hours. LCMS showed that the reaction was over, the reaction solution was concentrated to remove methanol, ethyl acetate (30 mL) saturated sodium bicarbonate (30 mL) was added to the rest, the liquid was separated, the organic phase was dried over sodium sulfate, concentrated and separated by flash silica gel column chromatography [eluent: 0 ~ 50% petroleum ether: ethyl acetate] to give 2- (3- (difluoromethoxy) -5-fluorophenyl) -3-ethylimidazo [1,2-a] pyridine-7-carboxylic acid Methyl ester (58mg, 13%). ESI-MS 365.0 [M + 1] + .
第六步：2-(3-(二氟甲氧基)-5-氟苯基)-3-乙基咪唑并[1,2-a]吡啶-7-羧酸的合成Step 6: Synthesis of 2- (3- (difluoromethoxy) -5-fluorophenyl) -3-ethylimidazo [1,2-a] pyridine-7-carboxylic acid
将甲基2-(3-(二氟甲氧基)-5-氟苯基)-3-乙基咪唑并[1,2-a]吡啶-7-羧酸酯(56mg,0.15mM)溶于甲醇/水(甲醇10ml,水5ml)的混合溶液。向反应液中加入氢氧化钠(100mg,2.5mM)，在氮气保护下加热到90℃反应3小时。待反应液冷却至室温，将甲醇减压浓缩后，加入少量水，将反应液直接冻干处理得到2-(3-(二氟甲氧基)-5-氟苯基)-3-乙基咪唑并[1,2-a]吡啶-7-羧酸粗品(141mg)，直接用作下一步反应。ESI-MS 350.8[M+H] +。 Dissolve methyl 2- (3- (difluoromethoxy) -5-fluorophenyl) -3-ethylimidazo [1,2-a] pyridine-7-carboxylate (56mg, 0.15mM) In methanol / water (methanol 10ml, water 5ml) mixed solution. Sodium hydroxide (100 mg, 2.5 mM) was added to the reaction solution, which was heated to 90 ° C. under nitrogen protection for 3 hours. After the reaction solution is cooled to room temperature, the methanol is concentrated under reduced pressure, a small amount of water is added, and the reaction solution is directly lyophilized to obtain 2- (3- (difluoromethoxy) -5-fluorophenyl) -3-ethyl Crude imidazo [1,2-a] pyridine-7-carboxylic acid (141 mg) was used directly in the next reaction. ESI-MS 350.8 [M + H] + .
7、3-乙基-2-((2-(三氟甲基)哌啶-1-基)甲基)咪唑并[1,2-a]吡啶-7-羧酸的制备7. Preparation of 3-ethyl-2-((2- (trifluoromethyl) piperidin-1-yl) methyl) imidazo [1,2-a] pyridine-7-carboxylic acid
Figure PCTCN2019104957-appb-000031
Figure PCTCN2019104957-appb-000031
第一步：3-乙基-2-((2-(三氟甲基)哌啶-1-基)甲基)咪唑并[1,2-a]吡啶-7-羧酸甲酯的合成Step 1: Synthesis of methyl 3-ethyl-2-((2- (trifluoromethyl) piperidin-1-yl) methyl) imidazo [1,2-a] pyridine-7-carboxylate
3-乙基-2-甲酰基咪唑并[1,2-a]吡啶-7-羧酸甲酯(200mg,0.86mmol)，2-(三氟甲基)哌啶(200mg,1.29mmol)溶于二氯甲烷(10mL)中，反应液在室温下搅拌1小时，之后向反应液中加入醋酸硼氢化钠(545mg,2.58mmol)，反应液在室温下继续搅拌16小时，反应结束后，将反应液用二氯甲烷(50mL)和水(50mL)分层萃取，有机相干燥过滤，滤液浓缩，剩余物通过快速硅胶柱层析分离(0～30％乙酸乙酯：石油醚)后得到3-乙基-2-((2-(三氟甲基)哌啶-1-基)甲基)咪唑并[1,2-a]吡啶-7-羧酸甲酯(214mg,67％)。ESI-MS 370.2[M+1] +。 3-ethyl-2-formylimidazo [1,2-a] pyridine-7-carboxylic acid methyl ester (200mg, 0.86mmol), 2- (trifluoromethyl) piperidine (200mg, 1.29mmol) dissolved In dichloromethane (10 mL), the reaction solution was stirred at room temperature for 1 hour. After that, sodium borohydride acetate (545 mg, 2.58 mmol) was added to the reaction solution. The reaction solution was further stirred at room temperature for 16 hours. The reaction solution was extracted in layers with dichloromethane (50 mL) and water (50 mL), the organic phase was dried and filtered, and the filtrate was concentrated. The residue was separated by flash silica gel column chromatography (0-30% ethyl acetate: petroleum ether) to obtain 3 -Ethyl-2-((2- (trifluoromethyl) piperidin-1-yl) methyl) imidazo [1,2-a] pyridine-7-carboxylic acid methyl ester (214 mg, 67%). ESI-MS 370.2 [M + 1] + .
第二步：3-乙基-2-((2-(三氟甲基)哌啶-1-基)甲基)咪唑并[1,2-a]吡啶-7-羧酸的合成Step 2: Synthesis of 3-ethyl-2-((2- (trifluoromethyl) piperidin-1-yl) methyl) imidazo [1,2-a] pyridine-7-carboxylic acid
将3-乙基-2-((2-(三氟甲基)哌啶-1-基)甲基)咪唑并[1,2-a]吡啶-7-羧酸甲酯(214mg,0.58mmol)，氢氧化钠(116mg,2.90mmol)溶于甲醇(10mL)，水(10mL)中，反应液在80℃搅拌1小时，反应结束后，将反应液用2N盐酸酸化至pH＝4～5，所得反应液浓缩干得到粗品3-乙基-2-((2-(三氟甲基)哌啶-1-基)甲基)咪唑并[1,2-a]吡啶-7-羧酸，直接用于下一步反应。ESI-MS 356.2[M+1] +。 3-ethyl-2-((2- (trifluoromethyl) piperidin-1-yl) methyl) imidazo [1,2-a] pyridine-7-carboxylic acid methyl ester (214 mg, 0.58 mmol ), Sodium hydroxide (116mg, 2.90mmol) was dissolved in methanol (10mL), water (10mL), the reaction solution was stirred at 80 ℃ for 1 hour, after the reaction was completed, the reaction solution was acidified with 2N hydrochloric acid to pH = 4 ~ 5 The resulting reaction solution was concentrated to dryness to obtain crude 3-ethyl-2-((2- (trifluoromethyl) piperidin-1-yl) methyl) imidazo [1,2-a] pyridine-7-carboxylic acid , Directly used in the next reaction. ESI-MS 356.2 [M + 1] + .
中间体8的制备参照中间体7的合成方法制备得到：The preparation of intermediate 8 can be obtained by referring to the synthesis method of intermediate 7:
Figure PCTCN2019104957-appb-000032
Figure PCTCN2019104957-appb-000032
9、3-乙基-2-(2-(三氟甲基)哌啶-1-羰基)咪唑并[1,2-a]吡啶-7-羧酸的制备9. Preparation of 3-ethyl-2- (2- (trifluoromethyl) piperidine-1-carbonyl) imidazo [1,2-a] pyridine-7-carboxylic acid
Figure PCTCN2019104957-appb-000033
Figure PCTCN2019104957-appb-000033
第一步：7-溴-3-乙基咪唑并[1,2-a]吡啶-2-羧酸的合成Step 1: Synthesis of 7-bromo-3-ethylimidazo [1,2-a] pyridine-2-carboxylic acid
将乙基7-溴-3-乙基咪唑并[1,2-a]吡啶-2-羧酸酯(1.1g,3.70mmol)，一水合氢氧化锂(311mg,7.40mmol)溶于甲醇(30mL)和水(30mL)中，反应液在80℃搅拌1小时，反应结束后，将反应液用2N盐酸酸化至pH＝4～5，所得反应液浓缩干得到粗品7-溴-3-乙基咪唑并[1,2-a]吡啶-2-羧酸(950mg,95％)，直接用于下一步反应。ESI-MS 268.9[M+1] +。 Dissolve ethyl 7-bromo-3-ethylimidazo [1,2-a] pyridine-2-carboxylate (1.1g, 3.70mmol) and lithium hydroxide monohydrate (311mg, 7.40mmol) in methanol ( 30mL) and water (30mL), the reaction solution was stirred at 80 ℃ for 1 hour, after the reaction was completed, the reaction solution was acidified with 2N hydrochloric acid to pH = 4 ~ 5, the resulting reaction solution was concentrated to dryness to obtain crude 7-bromo-3-ethyl The imidazo [1,2-a] pyridine-2-carboxylic acid (950 mg, 95%) was directly used in the next reaction. ESI-MS 268.9 [M + 1] + .
第二步：(7-溴-3-乙基咪唑并[1,2-a]吡啶-2-基)(2-(三氟甲基)哌啶-1-基)甲酮的合成Step 2: Synthesis of (7-bromo-3-ethylimidazo [1,2-a] pyridin-2-yl) (2- (trifluoromethyl) piperidin-1-yl) methanone
将7-溴-3-乙基咪唑并[1,2-a]吡啶-2-羧酸(800mg,2.97mmol)，2-三氟甲基哌啶(500mg,3.27mmol)溶于二氯甲烷(30mL)，室温下下加入HATU(2.25g,5.94mmol)和二异丙基乙胺(1.15g,8.91mmol)。反应液在室温下搅拌16小时。LCMS显示反应结束，把反应液倒入水(30mL)中，用二氯甲烷萃取(20mL*2)，合并有机相，硫酸钠干燥，浓缩后快速硅胶柱分离[洗脱剂：0～50％乙酸乙酯：石油醚]得到(7-溴-3-乙基咪唑并[1,2-a]吡啶-2-基)(2-(三氟甲基)哌啶-1-基)甲酮(207mg，17％)。ESI-MS 404.2[M+1] +。 Dissolve 7-bromo-3-ethylimidazo [1,2-a] pyridine-2-carboxylic acid (800 mg, 2.97 mmol), 2-trifluoromethylpiperidine (500 mg, 3.27 mmol) in dichloromethane (30 mL), HATU (2.25 g, 5.94 mmol) and diisopropylethylamine (1.15 g, 8.91 mmol) were added at room temperature. The reaction solution was stirred at room temperature for 16 hours. LCMS showed that the reaction was over, the reaction solution was poured into water (30 mL), extracted with dichloromethane (20 mL * 2), the organic phases were combined, dried over sodium sulfate, concentrated and separated by a quick silica gel column [eluent: 0-50% Ethyl acetate: petroleum ether] gives (7-bromo-3-ethylimidazo [1,2-a] pyridin-2-yl) (2- (trifluoromethyl) piperidin-1-yl) methanone (207 mg, 17%). ESI-MS 404.2 [M + 1] + .
第三步：3-乙基-2-(2-(三氟甲基)哌啶-1-羰基)咪唑并[1,2-a]吡啶-7-甲腈的合成Step 3: Synthesis of 3-ethyl-2- (2- (trifluoromethyl) piperidine-1-carbonyl) imidazo [1,2-a] pyridine-7-carbonitrile
将(7-溴-3-乙基咪唑并[1,2-a]吡啶-2-基)(2-(三氟甲基)哌啶-1-基)甲酮(207mg,0.51mmol)，四三苯基膦钯(30mg)，氰化锌(118mg,1.02mmol)溶于N,N-二甲基甲酰胺(30mL)中，氮气鼓泡15分钟，反应液用微波加热至120℃搅拌1小时，反应结束后，将反应液通过硅藻土过滤，滤液浓缩干，剩余物通过快速硅胶柱层析分离[0～30％乙酸乙酯：石油醚]得到3-乙基-2-(2-(三氟甲基)哌啶-1-羰基)咪唑并[1,2-a]吡啶-7-甲腈(85mg,47％)。ESI-MS 351.4[M+1] +。 (7-Bromo-3-ethylimidazo [1,2-a] pyridin-2-yl) (2- (trifluoromethyl) piperidin-1-yl) methanone (207 mg, 0.51 mmol), Tetratriphenylphosphine palladium (30mg) and zinc cyanide (118mg, 1.02mmol) were dissolved in N, N-dimethylformamide (30mL), nitrogen was bubbled for 15 minutes, and the reaction solution was heated to 120 ° C with microwave and stirred After 1 hour, the reaction solution was filtered through celite, the filtrate was concentrated to dryness, and the residue was separated by flash silica gel column chromatography [0-30% ethyl acetate: petroleum ether] to obtain 3-ethyl-2- ( 2- (trifluoromethyl) piperidine-1-carbonyl) imidazo [1,2-a] pyridine-7-carbonitrile (85 mg, 47%). ESI-MS 351.4 [M + 1] + .
第四步：3-乙基-2-(2-(三氟甲基)哌啶-1-羰基)咪唑并[1,2-a]吡啶-7-羧酸的合成Step 4: Synthesis of 3-ethyl-2- (2- (trifluoromethyl) piperidine-1-carbonyl) imidazo [1,2-a] pyridine-7-carboxylic acid
将3-乙基-2-(2-(三氟甲基)哌啶-1-羰基)咪唑并[1,2-a]吡啶-7-甲腈(85mg,0.24mmol)，氢氧化钠(97mg,2.43mmol)溶于甲醇(10mL)，水(10mL)中，反应液在80℃搅拌16小时，反应结束后，将反应液用2N盐酸酸化至pH＝4～5，所得反应液浓缩干，所得残余物用反相柱层析分离[洗脱剂：0～60％乙腈：水]得到3-乙基-2-(2-(三氟甲基)哌啶-1-羰基)咪唑并[1,2-a]吡啶-7-羧酸(63mg,71％)。ESI-MS 370.2[M+1] +。 3-Ethyl-2- (2- (trifluoromethyl) piperidine-1-carbonyl) imidazo [1,2-a] pyridine-7-carbonitrile (85mg, 0.24mmol), sodium hydroxide ( 97mg, 2.43mmol) was dissolved in methanol (10mL), water (10mL), the reaction solution was stirred at 80 ℃ for 16 hours, after the reaction was completed, the reaction solution was acidified with 2N hydrochloric acid to pH = 4 ~ 5, the resulting reaction solution was concentrated to dryness , The resulting residue was separated by reverse phase column chromatography [eluent: 0-60% acetonitrile: water] to obtain 3-ethyl-2- (2- (trifluoromethyl) piperidine-1-carbonyl) imidazo [1,2-a] pyridine-7-carboxylic acid (63 mg, 71%). ESI-MS 370.2 [M + 1] + .
10、2-(4-氯-2-(三氟甲基)苯甲基)-3-乙基咪唑并[1,2-a]吡啶-7-羧酸的制备10. Preparation of 2- (4-chloro-2- (trifluoromethyl) benzyl) -3-ethylimidazo [1,2-a] pyridine-7-carboxylic acid
Figure PCTCN2019104957-appb-000034
Figure PCTCN2019104957-appb-000034
第一步：N'-((7-溴-3-乙基咪唑并[1,2-a]吡啶-2-基)亚甲基)苯磺酰肼的合成Step 1: Synthesis of N '-((7-bromo-3-ethylimidazo [1,2-a] pyridin-2-yl) methylene) benzenesulfonyl hydrazide
将7-溴-3-乙基咪唑并[1,2-a]吡啶-2-甲醛(925mg,3.65mmol)，苯磺酰肼(944mg,5.48mmol)溶于甲醇(50mL)中，反应液在80℃下搅拌2小时，反应结束后，将反应液浓缩干得到粗品N'-((7-溴-3-乙基咪唑并[1,2-a]吡啶-2-基)亚甲基)苯磺酰肼，直接用于下一步反应(1.41g,95％)。ESI-MS 407.2[M+1] +。 7-Bromo-3-ethylimidazo [1,2-a] pyridine-2-carbaldehyde (925mg, 3.65mmol), benzenesulfonyl hydrazide (944mg, 5.48mmol) was dissolved in methanol (50mL), the reaction solution After stirring at 80 ° C for 2 hours, the reaction solution was concentrated and dried to obtain crude N '-((7-bromo-3-ethylimidazo [1,2-a] pyridin-2-yl) methylene ) Benzenesulfonyl hydrazide, used directly in the next reaction (1.41g, 95%). ESI-MS 407.2 [M + 1] + .
第二步：7-溴-2-(4-氯-2-(三氟甲基)苯甲基)-3-乙基咪唑并[1,2-a]吡啶的合成Step 2: Synthesis of 7-bromo-2- (4-chloro-2- (trifluoromethyl) benzyl) -3-ethylimidazo [1,2-a] pyridine
将N'-((7-溴-3-乙基咪唑并[1,2-a]吡啶-2-基)亚甲基)苯磺酰肼(1.41g,3.46mmol)，4-氯-2-(三氟甲基)苯硼酸(1.16g,5.20mmol)，碳酸钾(955mg,6.92mmol)溶于1,4-二氧六环(50mL)中，反应在110℃下搅拌16小时，反应结束后，将反应液通过硅藻土过滤，滤液浓缩干，剩余物加入二氯甲烷(50mL)和水(50mL)，分液出有机相，干燥，滤液浓缩至干，剩余物通过快速硅胶柱层析分离(0～30％乙酸乙酯：石油醚)得到7-溴-2-(4-氯-2-(三氟甲基)苯甲基)-3-乙基咪唑并[1,2-a]吡啶(398mg,27％)。N '-((7-Bromo-3-ethylimidazo [1,2-a] pyridin-2-yl) methylene) benzenesulfonyl hydrazide (1.41g, 3.46mmol), 4-chloro-2 -(Trifluoromethyl) phenylboronic acid (1.16g, 5.20mmol), potassium carbonate (955mg, 6.92mmol) was dissolved in 1,4-dioxane (50mL), the reaction was stirred at 110 ℃ for 16 hours, the reaction After the end, the reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated to dryness. The residue was added with dichloromethane (50 mL) and water (50 mL). The organic phase was separated and dried. The filtrate was concentrated to dryness, and the residue was passed through a flash silica gel column Chromatographic separation (0-30% ethyl acetate: petroleum ether) gave 7-bromo-2- (4-chloro-2- (trifluoromethyl) benzyl) -3-ethylimidazo [1,2 -a] pyridine (398 mg, 27%).
1H NMR(400MHz,CDCl 3)δ7.86–7.71(m,2H),7.63(d,J＝2.3Hz,1H),7.36(dd,J＝8.3,2.3Hz,1H),7.21(d,J＝8.4Hz,1H),6.93(dd,J＝7.1,2.1Hz,1H),4.26(s,2H),2.83(q,J＝7.6Hz,2H),1.12(t,J＝7.5Hz,3H).ESI-MS 417.2[M+1] +。 1 H NMR (400 MHz, CDCl 3 ) δ 7.86–7.71 (m, 2H), 7.63 (d, J = 2.3 Hz, 1H), 7.36 (dd, J = 8.3, 2.3 Hz, 1 H), 7.21 (d, J = 8.4 Hz, 1H), 6.93 (dd, J = 7.1, 2.1 Hz, 1H), 4.26 (s, 2H), 2.83 (q, J = 7.6 Hz, 2H), 1.12 (t, J = 7.5 Hz, 3H). ESI-MS 417.2 [M + 1] + .
第三步：2-(4-氯-2-(三氟甲基)苯甲基)-3-乙基咪唑并[1,2-a]吡啶-7-羧酸甲酯的合成Step 3: Synthesis of 2- (4-chloro-2- (trifluoromethyl) benzyl) -3-ethylimidazo [1,2-a] pyridine-7-carboxylic acid methyl ester
将7-溴-2-(4-氯-2-(三氟甲基)苯甲基)-3-乙基咪唑并[1,2-a]吡啶(220mg,0.52mmol)，Pd(dppf)Cl 2(50mg)，三乙胺(2mL)溶于甲醇(30mL)中，密闭反应用一氧化碳加压至1.0MPa，加热至80℃搅拌16小时，反应结束后，将反应液通过硅藻土过滤，滤液浓缩干，剩余物通过快速硅胶柱层析分离(0～30％乙酸乙酯：石油醚)得到2-(4-氯-2-(三氟甲基)苯甲基)-3-乙基咪唑并[1,2-a]吡啶-7-羧酸甲酯(190mg,92％)。 7-Bromo-2- (4-chloro-2- (trifluoromethyl) benzyl) -3-ethylimidazo [1,2-a] pyridine (220mg, 0.52mmol), Pd (dppf) Cl 2 (50 mg) and triethylamine (2 mL) were dissolved in methanol (30 mL). The sealed reaction was pressurized with carbon monoxide to 1.0 MPa, heated to 80 ° C. and stirred for 16 hours. After the reaction was completed, the reaction solution was filtered through Celite The filtrate was concentrated to dryness, and the residue was separated by flash silica gel column chromatography (0-30% ethyl acetate: petroleum ether) to obtain 2- (4-chloro-2- (trifluoromethyl) benzyl) -3-ethyl Methyl imidazo [1,2-a] pyridine-7-carboxylate (190 mg, 92%).
1H NMR(400MHz,CDCl 3)δ8.33(s,1H),7.95(d,J＝7.2Hz,1H),7.65(d,J＝2.3Hz,1H),7.45(dd,J＝7.1,1.7Hz,1H),7.37(dd,J＝8.4,2.2Hz,1H),7.24(d,J＝8.5Hz,1H),4.33(s,2H),3.96(s,3H),2.88(q,J＝7.6Hz,2H),1.14(t,J＝7.6Hz,3H).ESI-MS 397.4[M+1] +。 1 H NMR (400 MHz, CDCl 3 ) δ 8.33 (s, 1H), 7.95 (d, J = 7.2 Hz, 1H), 7.65 (d, J = 2.3 Hz, 1H), 7.45 (dd, J = 7.1, 1.7Hz, 1H), 7.37 (dd, J = 8.4, 2.2Hz, 1H), 7.24 (d, J = 8.5Hz, 1H), 4.33 (s, 2H), 3.96 (s, 3H), 2.88 (q, J = 7.6 Hz, 2H), 1.14 (t, J = 7.6 Hz, 3H). ESI-MS 397.4 [M + 1] + .
第四步：2-(4-氯-2-(三氟甲基)苯甲基)-3-乙基咪唑并[1,2-a]吡啶-7-羧酸的合成Step 4: Synthesis of 2- (4-chloro-2- (trifluoromethyl) benzyl) -3-ethylimidazo [1,2-a] pyridine-7-carboxylic acid
将2-(4-氯-2-(三氟甲基)苯甲基)-3-乙基咪唑并[1,2-a]吡啶-7-羧酸甲酯(90mg,0.22mmol)，一水合氢氧化锂(95mg,2.22mmol)溶于甲醇(10mL)，水(10mL)中，反应液在80℃搅拌2小时，反应结束后，将反应液用2N HCl酸化至pH＝4～5，所得反应液浓缩干得到粗品2-(4-氯-2-(三氟甲基)苯甲基)-3-乙基咪唑并[1,2-a]吡啶-7-羧酸，直接用于下一步反应。ESI-MS 383.4[M+1] +。 Methyl 2- (4-chloro-2- (trifluoromethyl) benzyl) -3-ethylimidazo [1,2-a] pyridine-7-carboxylate (90mg, 0.22mmol), one Lithium hydroxide hydrate (95 mg, 2.22 mmol) was dissolved in methanol (10 mL) and water (10 mL). The reaction solution was stirred at 80 ° C. for 2 hours. After the reaction was completed, the reaction solution was acidified with 2N HCl to pH = 4-5. The resulting reaction solution was concentrated to dryness to obtain crude 2- (4-chloro-2- (trifluoromethyl) benzyl) -3-ethylimidazo [1,2-a] pyridine-7-carboxylic acid, which was used directly Next reaction. ESI-MS 383.4 [M + 1] + .
中间体11的制备参照中间体10的合成方法制备得到：The preparation of intermediate 11 can be obtained by referring to the synthesis method of intermediate 10:
Figure PCTCN2019104957-appb-000035
Figure PCTCN2019104957-appb-000035
12、3-乙基-2-((2-(三氟甲基)苯氧基)甲基)咪唑并[1,2-a]吡啶-7-羧酸的制备12. Preparation of 3-ethyl-2-((2- (trifluoromethyl) phenoxy) methyl) imidazo [1,2-a] pyridine-7-carboxylic acid
Figure PCTCN2019104957-appb-000036
Figure PCTCN2019104957-appb-000036
第一步：甲基3-乙基-2-(羟甲基)咪唑并[1,2-a]吡啶-7-羧酸酯的合成Step 1: Synthesis of methyl 3-ethyl-2- (hydroxymethyl) imidazo [1,2-a] pyridine-7-carboxylate
将甲基3-乙基-2-甲酰基咪唑并[1,2-a]吡啶-7-羧酸酯(500mg,2.15mmol)溶于甲醇(20mL)中，缓慢分批加入硼氢化钠(163mg,4.31mmol)，反应液在室温下搅拌1小时，反应结束后，将反应液浓缩干，剩余物加入二氯甲烷(50mL)和水(50mL)，分液，水相用混合溶液(二氯甲烷：甲醇＝10:1)(50mL*3)萃取，合并有机相干燥过滤，滤液浓缩，剩余物通过快速硅胶柱层析分离[0～10％甲醇：二氯甲烷]得到甲基3-乙基-2-(羟甲基)咪唑并[1,2-a]吡啶-7-羧酸酯(385mg,77％)。ESI-MS 235.2[M+1] +。 Methyl 3-ethyl-2-formylimidazo [1,2-a] pyridine-7-carboxylate (500 mg, 2.15 mmol) was dissolved in methanol (20 mL), and sodium borohydride was slowly added in portions ( 163mg, 4.31mmol), the reaction solution was stirred at room temperature for 1 hour, after the reaction was completed, the reaction solution was concentrated to dryness, the residue was added dichloromethane (50mL) and water (50mL), liquid separation, the aqueous phase mixed solution (two Chloromethane: methanol = 10: 1) (50mL * 3) extraction, the combined organic phase was dried and filtered, the filtrate was concentrated, the residue was separated by flash silica gel column chromatography [0 ~ 10% methanol: dichloromethane] to obtain methyl 3- Ethyl-2- (hydroxymethyl) imidazo [1,2-a] pyridine-7-carboxylate (385 mg, 77%). ESI-MS 235.2 [M + 1] + .
第二步：甲基3-乙基-2-((2-(三氟甲基)苯氧基)甲基)咪唑并[1,2-a]吡啶-7-羧酸酯的合成Step 2: Synthesis of methyl 3-ethyl-2-((2- (trifluoromethyl) phenoxy) methyl) imidazo [1,2-a] pyridine-7-carboxylate
将甲基3-乙基-2-(羟甲基)咪唑并[1,2-a]吡啶-7-羧酸酯(105mg,0.45mmol),2-(三氟甲基)苯酚(108mg,0.67mmol)，三苯基膦(233mg,0.89mmol)溶于四氢呋喃(15mL)中，氮气保护下加入偶氮二甲酸二异丙酯(183mg,0.89mmol)，反应液在室温下搅拌6小时，LCMS显示反应完全，将反应液通过硅藻土过滤，滤液浓缩干，直接用于下一步反应。ESI-MS 379.2[M+1] +。 Methyl 3-ethyl-2- (hydroxymethyl) imidazo [1,2-a] pyridine-7-carboxylate (105mg, 0.45mmol), 2- (trifluoromethyl) phenol (108mg, 0.67mmol), triphenylphosphine (233mg, 0.89mmol) was dissolved in tetrahydrofuran (15mL), diisopropyl azodicarboxylate (183mg, 0.89mmol) was added under nitrogen protection, the reaction solution was stirred at room temperature for 6 hours, LCMS showed the reaction was complete, the reaction solution was filtered through celite, and the filtrate was concentrated to dryness, which was directly used in the next reaction. ESI-MS 379.2 [M + 1] + .
第三步：3-乙基-2-((2-(三氟甲基)苯氧基)甲基)咪唑并[1,2-a]吡啶-7-羧酸的合成Step 3: Synthesis of 3-ethyl-2-((2- (trifluoromethyl) phenoxy) methyl) imidazo [1,2-a] pyridine-7-carboxylic acid
将甲基3-乙基-2-((2-(三氟甲基)苯氧基)甲基)咪唑并[1,2-a]吡啶-7-羧酸酯(125mg,0.33mmol)，一水合氢氧化锂(70mg,1.65mmol)溶于四氢呋喃(10mL)，水(10mL)中，反应在80℃搅拌2小时，反应结束后，将反应液用2N盐酸酸化至pH＝4～5，所得反应液浓缩干，浓缩后反相柱分离[洗脱剂：0～60％乙腈：水]得到3-乙基-2-((2-(三氟甲基)苯氧基)甲基)咪唑并[1,2-a]吡啶-7-羧酸(109mg,66％)。ESI-MS 365.2[M+1] +。 Methyl 3-ethyl-2-((2- (trifluoromethyl) phenoxy) methyl) imidazo [1,2-a] pyridine-7-carboxylate (125mg, 0.33mmol), Lithium hydroxide monohydrate (70 mg, 1.65 mmol) was dissolved in tetrahydrofuran (10 mL), water (10 mL), and the reaction was stirred at 80 ° C. for 2 hours. After the reaction was completed, the reaction solution was acidified with 2N hydrochloric acid to pH = 4-5. The resulting reaction solution was concentrated to dryness, and after concentration, it was separated by a reverse phase column [eluent: 0-60% acetonitrile: water] to obtain 3-ethyl-2-((2- (trifluoromethyl) phenoxy) methyl) Imidazo [1,2-a] pyridine-7-carboxylic acid (109 mg, 66%). ESI-MS 365.2 [M + 1] + .
13、2-((2-氯-6-氟苯氧基)甲基)-3-乙基咪唑并[1,2-a]吡啶-7-羧酸的制备13. Preparation of 2-((2-chloro-6-fluorophenoxy) methyl) -3-ethylimidazo [1,2-a] pyridine-7-carboxylic acid
Figure PCTCN2019104957-appb-000037
Figure PCTCN2019104957-appb-000037
第一步：甲基3-乙基-2-(羟甲基)咪唑并[1,2-a]吡啶-7-羧酸酯的合成Step 1: Synthesis of methyl 3-ethyl-2- (hydroxymethyl) imidazo [1,2-a] pyridine-7-carboxylate
将甲基3-乙基-2-甲酰基咪唑并[1,2-a]吡啶-7-羧酸酯(500mg,2.15mmol)溶于甲醇(20mL)中，缓慢分批加入硼氢化钠(163mg,4.31mmol)，反应液在室温下搅拌1小时，反应结束后，将反应液浓缩干，剩余物用二氯甲烷(50mL)和水(50mL)分层萃取，水相用混合溶液(二氯甲烷：甲醇＝10:1)(50mL*3)萃取，合并有机相干燥过滤，滤液浓缩，剩余物通过快速硅胶柱分离[0～10％甲醇：二氯甲烷]后得到甲基3-乙基-2-(羟甲基)咪唑并[1,2-a]吡啶-7-羧酸酯(385mg,77％)。ESI-MS 235.2[M+1] +。 Methyl 3-ethyl-2-formylimidazo [1,2-a] pyridine-7-carboxylate (500 mg, 2.15 mmol) was dissolved in methanol (20 mL), and sodium borohydride was slowly added in portions ( 163mg, 4.31mmol), the reaction solution was stirred at room temperature for 1 hour, after the reaction was completed, the reaction solution was concentrated to dryness, the residue was extracted in layers with dichloromethane (50mL) and water (50mL), the aqueous phase was mixed solution (two Chloromethane: methanol = 10: 1) (50mL * 3) extraction, combined organic phase was dried and filtered, the filtrate was concentrated, the residue was separated by flash silica gel column [0 ~ 10% methanol: dichloromethane] to obtain methyl 3-ethyl Yl-2- (hydroxymethyl) imidazo [1,2-a] pyridine-7-carboxylate (385 mg, 77%). ESI-MS 235.2 [M + 1] + .
第二步：甲基3-乙基-2-((甲苯磺酰氧代)甲基)咪唑并[1,2-a]吡啶-7-羧酸酯的合成Step 2: Synthesis of methyl 3-ethyl-2-((toluenesulfonyloxy) methyl) imidazo [1,2-a] pyridine-7-carboxylate
将甲基3-乙基-2-(羟甲基)咪唑并[1,2-a]吡啶-7-羧酸酯(110mg,0.47mmol)，二异丙基乙胺(181mg,1.40mmol)溶于二氯甲烷(5mL)中，加入对甲苯磺酰氯(133mg,0.70mmol)，反应液在室温下搅拌1小时，反应结束后，将反应液依次用饱和碳酸氢钠水溶液(10mL)，水(10mL)，饱和氯化钠水溶液(10mL)洗涤，有机相干燥浓缩干得到粗品甲基3-乙基-2-((甲苯磺酰氧代)甲基)咪唑并[1,2-a]吡啶-7-羧酸酯，直接用于下一步反应。ESI-MS389.1[M+H] +。 Methyl 3-ethyl-2- (hydroxymethyl) imidazo [1,2-a] pyridine-7-carboxylate (110mg, 0.47mmol), diisopropylethylamine (181mg, 1.40mmol) Dissolved in dichloromethane (5mL), added p-toluenesulfonyl chloride (133mg, 0.70mmol), the reaction solution was stirred at room temperature for 1 hour, after the reaction was completed, the reaction solution was sequentially saturated aqueous sodium hydrogen carbonate (10mL), water (10mL), washed with saturated aqueous sodium chloride solution (10mL), and the organic phase was dried and concentrated to give crude methyl 3-ethyl-2-((toluenesulfonyloxy) methyl) imidazo [1,2-a] Pyridine-7-carboxylate, used directly in the next reaction. ESI-MS389.1 [M + H] + .
第三步：甲基2-((2-氯-6-氟苯氧基)甲基)-3-乙基咪唑并[1,2-a]吡啶-7-羧酸酯的合成Step 3: Synthesis of methyl 2-((2-chloro-6-fluorophenoxy) methyl) -3-ethylimidazo [1,2-a] pyridine-7-carboxylate
将甲基3-乙基-2-((甲苯磺酰氧代)甲基)咪唑并[1,2-a]吡啶-7-羧酸酯(150mg,0.38mmol)，2-氯-6-氟苯酚(85mg,0.58mmol)，碳酸钾(107mg,0.77mmol)溶于乙腈(10mL)中，反应液在80℃下搅拌16小时，反应结束后，反应液浓缩，剩余物用二氯甲烷(50mL)和水(50mL)分层萃取，有机相干燥过滤，滤液浓缩，剩余物通过快速硅胶柱层析分离[0～30％乙酸乙酯：石油醚]得到甲基2-((2-氯-6-氟苯氧基)甲基)-3-乙基咪唑并[1,2-a]吡啶-7-羧酸酯(66mg,48％)。ESI-MS 363.1[M+H] +。 Methyl 3-ethyl-2-((toluenesulfonyloxy) methyl) imidazo [1,2-a] pyridine-7-carboxylate (150mg, 0.38mmol), 2-chloro-6- Fluorophenol (85 mg, 0.58 mmol) and potassium carbonate (107 mg, 0.77 mmol) were dissolved in acetonitrile (10 mL). The reaction solution was stirred at 80 ° C. for 16 hours. After the reaction was completed, the reaction solution was concentrated, and the residue was diluted with dichloromethane ( 50mL) and water (50mL) were extracted in layers, the organic phase was dried and filtered, the filtrate was concentrated, and the residue was separated by flash silica gel column chromatography [0-30% ethyl acetate: petroleum ether] to obtain methyl 2-((2-chloro -6-fluorophenoxy) methyl) -3-ethylimidazo [1,2-a] pyridine-7-carboxylate (66 mg, 48%). ESI-MS 363.1 [M + H] + .
第四步：2-((2-氯-6-氟苯氧基)甲基)-3-乙基咪唑并[1,2-a]吡啶-7-羧酸的合成Step 4: Synthesis of 2-((2-chloro-6-fluorophenoxy) methyl) -3-ethylimidazo [1,2-a] pyridine-7-carboxylic acid
将甲基2-((2-氯-6-氟苯氧基)甲基)-3-乙基咪唑并[1,2-a]吡啶-7-羧酸酯(66mg,0.18mmol)，一水合氢氧化锂(39mg,0.91mmol)溶于甲醇(5mL)，水(5mL)中，反应液在80℃搅 拌2小时，反应结束后，将反应液用2N盐酸酸化至pH＝4～5，所得反应液浓缩干，剩余物用反相柱层析分离[洗脱剂：0～80％乙腈：水]得到2-((2-氯-6-氟苯氧基)甲基)-3-乙基咪唑并[1,2-a]吡啶-7-羧酸(53.0mg,84％)。ESI-MS 349.2[M+1] +。 Methyl 2-((2-chloro-6-fluorophenoxy) methyl) -3-ethylimidazo [1,2-a] pyridine-7-carboxylate (66mg, 0.18mmol), one Lithium hydroxide hydrate (39mg, 0.91mmol) was dissolved in methanol (5mL), water (5mL), the reaction solution was stirred at 80 ℃ for 2 hours, after the reaction was completed, the reaction solution was acidified with 2N hydrochloric acid to pH = 4 ~ 5, The resulting reaction solution was concentrated to dryness, and the residue was separated by reverse-phase column chromatography [eluent: 0 to 80% acetonitrile: water] to obtain 2-((2-chloro-6-fluorophenoxy) methyl) -3- Ethyl imidazo [1,2-a] pyridine-7-carboxylic acid (53.0 mg, 84%). ESI-MS 349.2 [M + 1] + .
14、(E)-2-(2-氯-6-(三氟甲基)苯乙烯基)-3-乙基咪唑并[1,2-a]吡啶-7-羧酸的制备14. Preparation of (E) -2- (2-chloro-6- (trifluoromethyl) styryl) -3-ethylimidazo [1,2-a] pyridine-7-carboxylic acid
Figure PCTCN2019104957-appb-000038
Figure PCTCN2019104957-appb-000038
第一步：(2-氯-6-(三氟甲基)苯基)甲醇的合成Step 1: Synthesis of (2-chloro-6- (trifluoromethyl) phenyl) methanol
将2-氯-6-(三氟甲基)苯甲醛(2.4g,11.5mmol)溶于甲醇(50mL)中，缓慢分批加入硼氢化钠(657mg,17.3mmol)，反应液在室温下搅拌1小时，TLC显示反应完全，将反应液浓缩干，剩余物加入二氯甲烷(40mL)和水(40mL)，分液，有机相干燥过滤，滤液浓缩，剩余物通过快速硅胶柱层析分离[0～30％乙酸乙酯：石油醚]得到(2-氯-6-(三氟甲基)苯基)甲醇(2.25g,93％)。Dissolve 2-chloro-6- (trifluoromethyl) benzaldehyde (2.4g, 11.5mmol) in methanol (50mL), slowly add sodium borohydride (657mg, 17.3mmol) in portions, and stir the reaction at room temperature After 1 hour, TLC showed that the reaction was complete. The reaction solution was concentrated to dryness. The residue was added with dichloromethane (40mL) and water (40mL). The liquid was separated, the organic phase was dried and filtered, and the filtrate was concentrated. The residue was separated by flash silica gel column chromatography [ 0-30% ethyl acetate: petroleum ether] gave (2-chloro-6- (trifluoromethyl) phenyl) methanol (2.25 g, 93%).
第二步：2-(溴甲基)-1-氯-3-(三氟甲基)苯的合成Step 2: Synthesis of 2- (bromomethyl) -1-chloro-3- (trifluoromethyl) benzene
将(2-氯-6-(三氟甲基)苯基)甲醇(850mg,4.05mmol)溶于二氯甲烷(100mL)中，依次缓慢加入三苯基膦(1.59g,6.07mmol)，四溴化碳(1.34g,4.05mmol)。反应液在室温下搅拌30分钟，TLC显示反应完全，反应浓缩得到粗品2-(溴甲基)-1-氯-3-(三氟甲基)苯(1.10g,98％)，直接用于下一步反应。Dissolve (2-chloro-6- (trifluoromethyl) phenyl) methanol (850 mg, 4.05 mmol) in dichloromethane (100 mL), and slowly add triphenylphosphine (1.59 g, 6.07 mmol), followed by four Carbon bromide (1.34g, 4.05mmol). The reaction solution was stirred at room temperature for 30 minutes. TLC showed that the reaction was complete. The reaction was concentrated to obtain crude 2- (bromomethyl) -1-chloro-3- (trifluoromethyl) benzene (1.10g, 98%), which was directly Next reaction.
第三步：叶立德试剂的合成Step 3: Synthesis of Ye Lide reagent
将2-(溴甲基)-1-氯-3-(三氟甲基)苯(1.1g,4.03mmol)，三苯基膦(1.58g,6.04mmol)溶于乙酸乙酯(50mL)中，反应液加热至80℃搅拌4小时，大量白色固体生成，反应冷至室温，过滤，滤饼用乙酸乙酯(20mL*3)洗涤。滤饼烘干得到产品(2.1g,58％)。ESI-MS 455.8[M-Br] +。 Dissolve 2- (bromomethyl) -1-chloro-3- (trifluoromethyl) benzene (1.1g, 4.03mmol), triphenylphosphine (1.58g, 6.04mmol) in ethyl acetate (50mL) The reaction solution was heated to 80 ° C and stirred for 4 hours. A large amount of white solid was formed. The reaction was cooled to room temperature, filtered, and the filter cake was washed with ethyl acetate (20 mL * 3). The cake was dried to obtain the product (2.1g, 58%). ESI-MS 455.8 [M-Br] + .
第四步：甲基(E)-2-(2-氯-6-(三氟甲基)苯乙烯基)-3-乙基咪唑并[1,2-a]吡啶-7-羧酸酯的合成Step 4: Methyl (E) -2- (2-chloro-6- (trifluoromethyl) styryl) -3-ethylimidazo [1,2-a] pyridine-7-carboxylate Synthesis
将叶立德试剂(830mg,1.55mmol)，叔丁醇钠(253mg,2.58mmol)溶于无水四氢呋喃(30mL)中，反应液在室温下搅拌30分钟，加入甲基3-乙基-2-甲酰基咪唑并[1,2-a]吡啶-7-羧酸酯(300mg，1.29mmol)，反应液在室温下继续搅拌16小时，反应结束后，将反应液浓缩，剩余物用二氯甲烷(50mL)和水(50mL)分层萃取，有机相干燥过滤，滤液浓缩，剩余物通过快速硅胶柱层析分离[0～30％乙酸乙酯：石油醚]得到甲基(E)-2-(2-氯-6-(三氟甲基)苯乙烯基)-3-乙基咪唑并[1,2-a]吡啶-7-羧酸酯(121mg,19％)。ESI-MS 409.2[M+H] +。 Dissolve Yelide reagent (830 mg, 1.55 mmol) and sodium tert-butoxide (253 mg, 2.58 mmol) in anhydrous tetrahydrofuran (30 mL), stir the reaction at room temperature for 30 minutes, and add methyl 3-ethyl-2-methyl Acylimidazo [1,2-a] pyridine-7-carboxylate (300mg, 1.29mmol), the reaction solution was stirred at room temperature for 16 hours, after the reaction was completed, the reaction solution was concentrated, the residue was dichloromethane ( 50mL) and water (50mL) were separated and extracted, the organic phase was dried and filtered, and the filtrate was concentrated. The residue was separated by flash silica gel column chromatography [0-30% ethyl acetate: petroleum ether] to obtain methyl (E) -2- ( 2-chloro-6- (trifluoromethyl) styryl) -3-ethylimidazo [1,2-a] pyridine-7-carboxylate (121 mg, 19%). ESI-MS 409.2 [M + H] + .
第五步：(E)-2-(2-氯-6-(三氟甲基)苯乙烯基)-3-乙基咪唑并[1,2-a]吡啶-7-羧酸的合成Step 5: Synthesis of (E) -2- (2-chloro-6- (trifluoromethyl) styryl) -3-ethylimidazo [1,2-a] pyridine-7-carboxylic acid
将甲基(E)-2-(2-氯-6-(三氟甲基)苯乙烯基)-3-乙基咪唑并[1,2-a]吡啶-7-羧酸酯(121mg,0.29mmol)，一水合氢氧化锂(25mg,0.59mmol)溶于甲醇(10mL)和水(10mL)中，反应液在90℃搅拌1小时，反应结束后，将反应液用2N盐酸酸化至pH＝4～5，所得反应液浓缩干， 剩余物通过反相柱层析分离得到(E)-2-(2-氯-6-(三氟甲基)苯乙烯基)-3-乙基咪唑并[1,2-a]吡啶-7-羧酸(5.3mg,5％)。ESI-MS 395.0[M+1] +。 The methyl (E) -2- (2-chloro-6- (trifluoromethyl) styryl) -3-ethylimidazo [1,2-a] pyridine-7-carboxylate (121mg, 0.29mmol), lithium hydroxide monohydrate (25mg, 0.59mmol) was dissolved in methanol (10mL) and water (10mL), the reaction solution was stirred at 90 ℃ for 1 hour, after the reaction was completed, the reaction solution was acidified with 2N hydrochloric acid to pH = 4-5, the resulting reaction solution was concentrated to dryness, and the residue was separated by reverse-phase column chromatography to obtain (E) -2- (2-chloro-6- (trifluoromethyl) styryl) -3-ethylimidazole P [1,2-a] pyridine-7-carboxylic acid (5.3 mg, 5%). ESI-MS 395.0 [M + 1] + .
15、2-(4-氯-2-(三氟甲基)苯甲基)-3-甲基咪唑并[1,2-a]吡啶-7-羧酸的制备15. Preparation of 2- (4-chloro-2- (trifluoromethyl) benzyl) -3-methylimidazo [1,2-a] pyridine-7-carboxylic acid
Figure PCTCN2019104957-appb-000039
Figure PCTCN2019104957-appb-000039
第一步：3-溴-2-羰基丁酸乙酯的合成Step 1: Synthesis of ethyl 3-bromo-2-carbonylbutyrate
将2-羰基丁酸乙酯(15.0g,115mmol)溶于二氯甲烷(150mL)中，室温下缓慢滴加液溴(6.9mL,138mmol)，反应液在室温下搅拌过夜。反应液依次用饱和亚硫酸钠(2*200mL)，饱和碳酸氢钠(200mL)，水(200mL)，饱和氯化钠(200mL)洗涤。有机相干燥过滤，滤液浓缩至干得到粗品3-溴-2-羰基丁酸乙酯(23g,86％)，直接用于下一步反应。Ethyl 2-carbonylbutyrate (15.0 g, 115 mmol) was dissolved in dichloromethane (150 mL), and liquid bromine (6.9 mL, 138 mmol) was slowly added dropwise at room temperature, and the reaction solution was stirred at room temperature overnight. The reaction solution was washed sequentially with saturated sodium sulfite (2 * 200 mL), saturated sodium bicarbonate (200 mL), water (200 mL), and saturated sodium chloride (200 mL). The organic phase was dried and filtered, and the filtrate was concentrated to dryness to obtain crude ethyl 3-bromo-2-carbonylbutyrate (23 g, 86%), which was directly used in the next reaction.
1H NMR(500MHz,CDCl 3)：δ5.20(q,J＝6.8Hz,1H),4.43-4.35(m,2H),1.84(d,J＝6.7Hz,3H),1.42(t,J＝7.1Hz,3H)。 1 H NMR (500 MHz, CDCl 3 ): δ 5.20 (q, J = 6.8 Hz, 1H), 4.43-4.35 (m, 2H), 1.84 (d, J = 6.7 Hz, 3H), 1.42 (t, J = 7.1 Hz, 3H).
第二步：7-溴-3-甲基咪唑并[1,2-a]吡啶-2-羧酸乙酯的合成Step 2: Synthesis of ethyl 7-bromo-3-methylimidazo [1,2-a] pyridine-2-carboxylate
将3-溴-2-羰基丁酸乙酯(6.5g,31.2mmol),4-溴吡啶-2-胺(4.5g,26mmol)溶于乙醇(60mL)中，反应液加热回流24小时，反应结束后，将反应液浓缩干，剩余物用乙醇打浆，过滤，洗涤得到7-溴-3-甲基咪唑并[1,2-a]吡啶-2-羧酸乙酯(5.8g,80％)。ESI-MS 283.1[M+1] +。 Ethyl 3-bromo-2-carbonylbutyrate (6.5g, 31.2mmol), 4-bromopyridin-2-amine (4.5g, 26mmol) was dissolved in ethanol (60mL), the reaction solution was heated to reflux for 24 hours, the reaction After the end, the reaction solution was concentrated to dryness, the residue was slurried with ethanol, filtered and washed to obtain 7-bromo-3-methylimidazo [1,2-a] pyridine-2-carboxylic acid ethyl ester (5.8g, 80% ). ESI-MS 283.1 [M + 1] + .
第三步：(7-溴-3-甲基咪唑并[1,2-a]吡啶-2-基)甲醇的合成Step 3: Synthesis of (7-bromo-3-methylimidazo [1,2-a] pyridin-2-yl) methanol
将7-溴-3-甲基咪唑并[1,2-a]吡啶-2-羧酸乙酯(5.0g,17.7mmol)溶于四氢呋喃(50mL)中，0℃下缓慢滴加DIBAL-H(26.6mL,53.1mmol)，反应液在室温下搅拌2小时，反应结束后，反应液先后用水(2mL)，NaOH(15％,2mL)，水(5mL)淬灭。混合物浓缩过柱分离[二氯甲烷：甲醇＝10:1]得到(7-溴-3-甲基咪唑并[1,2-a]吡啶-2-基)甲醇(2.0g,48％)。ESI-MS 241[M+1] +。 Dissolve 7-bromo-3-methylimidazo [1,2-a] pyridine-2-carboxylic acid ethyl ester (5.0 g, 17.7 mmol) in tetrahydrofuran (50 mL), and slowly add DIBAL-H dropwise at 0 ° C (26.6 mL, 53.1 mmol). The reaction solution was stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was quenched with water (2 mL), NaOH (15%, 2 mL), and water (5 mL). The mixture was concentrated and separated through a column [dichloromethane: methanol = 10: 1] to obtain (7-bromo-3-methylimidazo [1,2-a] pyridin-2-yl) methanol (2.0 g, 48%). ESI-MS 241 [M + 1] + .
第四步：7-溴-3-甲基咪唑并[1,2-a]吡啶-2-甲醛的合成Step 4: Synthesis of 7-bromo-3-methylimidazo [1,2-a] pyridine-2-carbaldehyde
将(7-溴-3-甲基咪唑并[1,2-a]吡啶-2-基)甲醇(2.0g,8.3mmol)溶于二氯甲烷(40mL)中，加入二氧化锰(10.8g,125mmol)，反应液在室温下搅拌16小时，反应结束后，将反应液通过硅藻土过滤，滤液浓缩干后得到7-溴-3-甲基咪唑并[1,2-a]吡啶-2-甲醛(1.5g,86％)。ESI-MS 239[M+1] +。 (7-Bromo-3-methylimidazo [1,2-a] pyridin-2-yl) methanol (2.0g, 8.3mmol) was dissolved in dichloromethane (40mL), and manganese dioxide (10.8g) was added , 125mmol), the reaction solution was stirred at room temperature for 16 hours, after the reaction was completed, the reaction solution was filtered through celite, and the filtrate was concentrated to dryness to obtain 7-bromo-3-methylimidazo [1,2-a] pyridine- 2-Formaldehyde (1.5g, 86%). ESI-MS 239 [M + 1] + .
第五步：N'-((7-溴-3-甲基咪唑并[1,2-a]吡啶-2-基)亚甲基)苯磺酰肼的合成Step 5: Synthesis of N '-((7-bromo-3-methylimidazo [1,2-a] pyridin-2-yl) methylene) benzenesulfonyl hydrazide
将7-溴-3-甲基咪唑并[1,2-a]吡啶-2-甲醛(1.5g,62.8mmol)，苯磺酰肼(1.13g,65.9mmol)溶于乙醇(20mL)中，反应液在80℃下搅拌2小时，反应结束后，将反应液浓缩干得到粗品 N'-((7-溴-3-甲基咪唑并[1,2-a]吡啶-2-基)亚甲基)苯磺酰肼(2.6g,100％)，直接用于下一步反应。ESI-MS 393[M+1] +。 7-Bromo-3-methylimidazo [1,2-a] pyridine-2-carbaldehyde (1.5g, 62.8mmol), benzenesulfonyl hydrazide (1.13g, 65.9mmol) was dissolved in ethanol (20mL), The reaction solution was stirred at 80 ° C for 2 hours. After the reaction was completed, the reaction solution was concentrated to dryness to obtain crude N '-((7-bromo-3-methylimidazo [1,2-a] pyridin-2-yl) Methyl) benzenesulfonyl hydrazide (2.6g, 100%), used directly in the next reaction. ESI-MS 393 [M + 1] + .
第六步：7-溴-2-(4-氯-2-(三氟甲基)苯甲基)-3-甲基咪唑并[1,2-a]吡啶的合成Step 6: Synthesis of 7-bromo-2- (4-chloro-2- (trifluoromethyl) benzyl) -3-methylimidazo [1,2-a] pyridine
将N'-((7-溴-3-甲基咪唑并[1,2-a]吡啶-2-基)亚甲基)苯磺酰肼(0.6g,1.53mmol)，4-氯-2-(三氟甲基)苯硼酸(686mg,3.06mmol)，碳酸钠(1.3g,12.2mmol)溶于1,4-二氧六环(25mL)中，反应液在110℃下搅拌48小时，反应结束后，将反应液通过硅藻土过滤，滤液浓缩干，剩余物加入二氯甲烷(50mL)和水(50mL)，分液，有机相干燥过滤，滤液浓缩，剩余物通过快速硅胶柱分离[DCM：MeOH＝50：1)]得到7-溴-2-(4-氯-2-(三氟甲基)苯甲基)-3-甲基咪唑并[1,2-a]吡啶(380mg,62％)。ESI-MS 403[M+1] +。 N '-((7-Bromo-3-methylimidazo [1,2-a] pyridin-2-yl) methylene) benzenesulfonyl hydrazide (0.6g, 1.53mmol), 4-chloro-2 -(Trifluoromethyl) phenylboronic acid (686mg, 3.06mmol), sodium carbonate (1.3g, 12.2mmol) dissolved in 1,4-dioxane (25mL), the reaction solution was stirred at 110 ℃ for 48 hours, After the reaction was completed, the reaction solution was filtered through celite, and the filtrate was concentrated to dryness. The residue was added with dichloromethane (50 mL) and water (50 mL). The liquid was separated. The organic phase was dried and filtered, and the filtrate was concentrated. [DCM: MeOH = 50: 1)] to give 7-bromo-2- (4-chloro-2- (trifluoromethyl) benzyl) -3-methylimidazo [1,2-a] pyridine ( 380mg, 62%). ESI-MS 403 [M + 1] + .
第七步：2-(4-氯-2-(三氟甲基)苯甲基)-3-甲基咪唑并[1,2-a]吡啶-7-甲腈的合成Step 7: Synthesis of 2- (4-chloro-2- (trifluoromethyl) benzyl) -3-methylimidazo [1,2-a] pyridine-7-carbonitrile
将7-溴-2-(4-氯-2-(三氟甲基)苯甲基)-3-甲基咪唑并[1,2-a]吡啶(350mg,0.87mmol),氰化锌(507mg,4.33mmol)，四三苯基膦钯(100mg,0.087mmol)溶于二甲基甲酰胺(10mL)，加热搅拌过夜。反应液用水洗涤，干燥，过滤。有机相浓缩过柱[PE：EA＝1:1]得到2-(4-氯-2-(三氟甲基)苯甲基)-3-甲基咪唑并[1,2-a]吡啶-7-甲腈(270mg,90％)。ESI-MS 350[M+1] +。 7-Bromo-2- (4-chloro-2- (trifluoromethyl) benzyl) -3-methylimidazo [1,2-a] pyridine (350mg, 0.87mmol), zinc cyanide ( 507mg, 4.33mmol), tetratriphenylphosphine palladium (100mg, 0.087mmol) was dissolved in dimethylformamide (10mL), heated and stirred overnight. The reaction solution was washed with water, dried and filtered. The organic phase was concentrated through the column [PE: EA = 1: 1] to give 2- (4-chloro-2- (trifluoromethyl) benzyl) -3-methylimidazo [1,2-a] pyridine- 7-carbonitrile (270 mg, 90%). ESI-MS 350 [M + 1] + .
第八步：甲基2-(4-氯-2-(三氟甲基)苯甲基)-3-甲基咪唑并[1,2-a]吡啶-7-羧酸酯的合成Step 8: Synthesis of methyl 2- (4-chloro-2- (trifluoromethyl) benzyl) -3-methylimidazo [1,2-a] pyridine-7-carboxylate
将7-溴-2-(4-氯-2-(三氟甲基)苯甲基)-3-甲基咪唑并[1,2-a]吡啶(450mg,1.28mmol)甲醇(20mL),0℃下加入二氯亚砜(5mL)，反应液加热回流一小时。反应液浓缩得到甲基2-(4-氯-2-(三氟甲基)苯甲基)-3-甲基咪唑并[1,2-a]吡啶-7-羧酸酯(550mg,100％)。ESI-MS 383[M+1] +。 7-Bromo-2- (4-chloro-2- (trifluoromethyl) benzyl) -3-methylimidazo [1,2-a] pyridine (450mg, 1.28mmol) in methanol (20mL), Dichlorosulfoxide (5 mL) was added at 0 ° C, and the reaction solution was heated to reflux for one hour. The reaction solution was concentrated to obtain methyl 2- (4-chloro-2- (trifluoromethyl) benzyl) -3-methylimidazo [1,2-a] pyridine-7-carboxylate (550 mg, 100 %). ESI-MS 383 [M + 1] + .
第九步：2-(4-氯-2-(三氟甲基)苯甲基)-3-甲基咪唑并[1,2-a]吡啶-7-羧酸的合成Step 9: Synthesis of 2- (4-chloro-2- (trifluoromethyl) benzyl) -3-methylimidazo [1,2-a] pyridine-7-carboxylic acid
将2-(4-氯-2-(三氟甲基)苯甲基)-3-乙基咪唑并[1,2-a]吡啶-7-羧酸甲酯(500mg,1.31mmol)，一水合氢氧化锂(275mg,6.55mmol)溶于甲醇(15mL)和水(2mL)中，反应液在80℃搅拌1小时，反应结束后，将反应液用2N HCl酸化至pH＝4～5，将所得反应液浓缩干得到粗品2-(4-氯-2-(三氟甲基)苯甲基)-3-甲基咪唑并[1,2-a]吡啶-7-羧酸(450mg,94％)，直接用于下一步反应。ESI-MS 369[M+1] +。 2- (4-chloro-2- (trifluoromethyl) benzyl) -3-ethylimidazo [1,2-a] pyridine-7-carboxylic acid methyl ester (500 mg, 1.31 mmol), one Lithium hydroxide hydrate (275 mg, 6.55 mmol) was dissolved in methanol (15 mL) and water (2 mL). The reaction solution was stirred at 80 ° C. for 1 hour. After the reaction was completed, the reaction solution was acidified with 2N HCl to pH = 4-5. The resulting reaction solution was concentrated to dryness to obtain crude 2- (4-chloro-2- (trifluoromethyl) benzyl) -3-methylimidazo [1,2-a] pyridine-7-carboxylic acid (450 mg, 94%), used directly in the next reaction. ESI-MS 369 [M + 1] + .
16、2-(4-氯-2-(三氟甲基)苯甲基)-3-异丙基咪唑并[1,2-a]吡啶-7-羧酸的制备16. Preparation of 2- (4-chloro-2- (trifluoromethyl) benzyl) -3-isopropylimidazo [1,2-a] pyridine-7-carboxylic acid
Figure PCTCN2019104957-appb-000040
Figure PCTCN2019104957-appb-000040
第一步：4-甲基-2-羰基戊酸乙酯的合成Step 1: Synthesis of ethyl 4-methyl-2-carbonylvalerate
将草酸二乙酯(22g,150mmol)溶于四氢呋喃(180mL)中，-78℃下缓慢滴加异丙基溴化 镁(83mL,166mmol)，反应液在室温下搅拌过夜，反应液依次用饱和氯化铵淬灭，四氢呋喃旋掉，反应混合物用乙酸乙酯萃取(300mL*2)，有机相干燥，过滤，浓缩至干得到粗品4-甲基-2-羰基戊酸乙酯(22g,纯度约50％)，直接用于下一步反应。Diethyl oxalate (22g, 150mmol) was dissolved in tetrahydrofuran (180mL), isopropyl magnesium bromide (83mL, 166mmol) was slowly added dropwise at -78 ° C, the reaction solution was stirred at room temperature overnight, and the reaction solution was saturated with After quenching with ammonium chloride, spinning off the tetrahydrofuran, the reaction mixture was extracted with ethyl acetate (300 mL * 2), the organic phase was dried, filtered, and concentrated to dryness to give crude ethyl 4-methyl-2-carbonylvalerate (22 g, purity About 50%), used directly in the next reaction.
1H NMR(500MHz,CDCl 3):δ4.20(q,J＝7.1Hz,2H),2.64(d,J＝6.9Hz,2H),2.15-2.07(m,1H),1.35–1.19(m,3H),0.94–0.82(m,6H)。 1 H NMR (500 MHz, CDCl 3 ): δ 4.20 (q, J = 7.1 Hz, 2H), 2.64 (d, J = 6.9 Hz, 2H), 2.15-2.07 (m, 1H), 1.35-1.19 (m , 3H), 0.94-0.82 (m, 6H).
第二步到第十步参照中间体15中的合成方法制备得到，2-(4-氯-2-(三氟甲基)苯甲基)-3-异丙基咪唑并[1,2-a]吡啶-7-羧酸ESI-MS 397.2[M+H] +。 The second step to the tenth step are prepared by referring to the synthetic method in Intermediate 15, 2- (4-chloro-2- (trifluoromethyl) benzyl) -3-isopropylimidazo [1,2- a] Pyridine-7-carboxylic acid ESI-MS 397.2 [M + H] + .
17、3-异丙基-2-(2-(三氟甲氧基)苯甲基)咪唑并[1,2-a]吡啶-7-羧酸的制备17. Preparation of 3-isopropyl-2- (2- (trifluoromethoxy) benzyl) imidazo [1,2-a] pyridine-7-carboxylic acid
Figure PCTCN2019104957-appb-000041
Figure PCTCN2019104957-appb-000041
参照中间体16的合成方法制备得到ESI-MS 379[M+H] +。 The ESI-MS 379 [M + H] + was prepared according to the synthesis method of Intermediate 16.
18、2-(4-氯-2-(三氟甲基)苯甲基)-3-环丙基咪唑并[1,2-a]吡啶-7-羧酸的制备18. Preparation of 2- (4-chloro-2- (trifluoromethyl) benzyl) -3-cyclopropylimidazo [1,2-a] pyridine-7-carboxylic acid
Figure PCTCN2019104957-appb-000042
Figure PCTCN2019104957-appb-000042
第一步：2-(环丙基甲基)-1,3-二硫烷-2-羧酸乙酯的合成Step 1: Synthesis of ethyl 2- (cyclopropylmethyl) -1,3-disulfane-2-carboxylate
将1,3-二硫烷-2-羧酸乙酯(7.0g,36.5mmol)和(溴甲基)环丙烷(5.9g,43.7mmol)溶于二甲基甲酰胺(20mL),然后将此溶液在0℃下缓慢滴加到氢化钠(1.75g,43.7mmol)的甲苯(60mL)溶液中，反应液在室温下搅拌过夜，反应液依次用饱和氯化铵淬灭，四氢呋喃旋掉，反应混合物用甲基叔丁醚萃取(150mL*2)，有机相用盐水洗涤，干燥，过滤，浓缩至干得到粗品2-(环丙基甲基)-1,3-二硫烷-2-羧酸乙酯(7.7g,85％)，直接用于下一步反应。ESI-MS 247[M+1] +。 Dissolve ethyl 1,3-disulfane-2-carboxylate (7.0 g, 36.5 mmol) and (bromomethyl) cyclopropane (5.9 g, 43.7 mmol) in dimethylformamide (20 mL), and then This solution was slowly added dropwise to a solution of sodium hydride (1.75 g, 43.7 mmol) in toluene (60 mL) at 0 ° C. The reaction solution was stirred at room temperature overnight. The reaction solution was quenched with saturated ammonium chloride in turn, and tetrahydrofuran was spinned off. The reaction mixture was extracted with methyl tert-butyl ether (150 mL * 2), and the organic phase was washed with brine, dried, filtered, and concentrated to dryness to obtain crude 2- (cyclopropylmethyl) -1,3-disulfane-2- Ethyl carboxylate (7.7g, 85%) was directly used in the next reaction. ESI-MS 247 [M + 1] + .
第二步：3-环丙基-2-羰基丙酸乙酯的合成Step 2: Synthesis of ethyl 3-cyclopropyl-2-carbonylpropionate
将2-(环丙基甲基)-1,3-二硫烷-2-羧酸乙酯(7.7g,31.3mmol)溶于乙腈(20mL)，然后将此溶液在0℃下缓慢滴加到N-溴代丁二酰亚胺(33.4g,188mmol)的乙腈/水(100mL/30mL)的混合溶液中，反应液在室温下搅拌2小时，反应液用饱和亚硫酸氢钠淬灭，将乙腈蒸出，剩余物用二氯甲烷萃取(150mL*2)，有机相用饱和碳酸氢钠水溶液，饱和食盐水洗涤，干燥，过滤，浓缩至干得到粗品3-环丙基-2-羰基丙酸乙酯(9.2g)，直接用于下一步反应。Ethyl 2- (cyclopropylmethyl) -1,3-disulfane-2-carboxylate (7.7g, 31.3mmol) was dissolved in acetonitrile (20mL), then this solution was slowly added dropwise at 0 ° Into a mixed solution of N-bromosuccinimide (33.4 g, 188 mmol) in acetonitrile / water (100 mL / 30 mL), the reaction solution was stirred at room temperature for 2 hours, and the reaction solution was quenched with saturated sodium bisulfite, Acetonitrile was distilled off, the residue was extracted with dichloromethane (150 mL * 2), the organic phase was washed with saturated aqueous sodium bicarbonate solution, saturated brine, dried, filtered, and concentrated to dryness to give crude 3-cyclopropyl-2-carbonyl Ethyl propionate (9.2g), used directly in the next reaction.
第三步到第十一步参照中间体15中的合成方法制备得到，2-(4-氯-2-(三氟甲基)苯甲基)-3-环丙基咪唑并[1,2-a]吡啶-7-羧酸ESI-MS 395.2[M+H] +。 The third step to the eleventh step are prepared by referring to the synthesis method in Intermediate 15, 2- (4-chloro-2- (trifluoromethyl) benzyl) -3-cyclopropylimidazo [1,2 -a] pyridine-7-carboxylic acid ESI-MS 395.2 [M + H] + .
19、2-(4-氯-2-(三氟甲基)苯甲基)-3-环丁基咪唑并[1,2-a]吡啶-7-羧酸的制备19. Preparation of 2- (4-chloro-2- (trifluoromethyl) benzyl) -3-cyclobutylimidazo [1,2-a] pyridine-7-carboxylic acid
Figure PCTCN2019104957-appb-000043
Figure PCTCN2019104957-appb-000043
参照中间体17中的合成方法制备得到，2-(4-氯-2-(三氟甲基)苯甲基)-3-环丁基咪唑并[1,2-a]吡啶-7-羧酸ESI-MS 409.2[M+H] +。 Prepared according to the synthesis method in Intermediate 17, 2- (4-chloro-2- (trifluoromethyl) benzyl) -3-cyclobutylimidazo [1,2-a] pyridine-7-carboxy Acid ESI-MS 409.2 [M + H] + .
20、(R)-2-氨基-2-(5-(乙基磺酰)吡啶-2-基)乙烷-1-醇的制备20. Preparation of (R) -2-amino-2- (5- (ethylsulfonyl) pyridin-2-yl) ethane-1-ol
Figure PCTCN2019104957-appb-000044
Figure PCTCN2019104957-appb-000044
第一步：2-溴-5-(乙硫基)吡啶的合成Step 1: Synthesis of 2-bromo-5- (ethylthio) pyridine
将2-溴-5-氟吡啶(10.0g,57.0mmol)溶于无水N,N-二甲基甲酰胺(40mL)中，室温下加入乙硫醇钠(4.6g,55.2mmol)，反应液在室温下搅拌17小时，反应液使用乙酸乙酯(30ml*3)萃取，合并有机相，干燥过滤，滤液浓缩，所得剩余物通过快速硅胶柱分离[洗脱剂：乙酸乙酯：石油醚＝0％-2％]得到2-溴-5-(乙硫基)吡啶(4.5g,37％)。ESI-MS 218.2[M+H] +。 Dissolve 2-bromo-5-fluoropyridine (10.0g, 57.0mmol) in anhydrous N, N-dimethylformamide (40mL), add sodium ethanethiolate (4.6g, 55.2mmol) at room temperature, and react The solution was stirred at room temperature for 17 hours, the reaction solution was extracted with ethyl acetate (30ml * 3), the organic phases were combined, dried and filtered, and the filtrate was concentrated. The resulting residue was separated by a flash silica gel column [eluent: ethyl acetate: petroleum ether = 0% -2%] to give 2-bromo-5- (ethylthio) pyridine (4.5 g, 37%). ESI-MS 218.2 [M + H] + .
第二步：(R)-N-((R)-2-((叔-丁基二甲基甲硅烷基)氧代)-1-(5-(乙硫基)吡啶-2-基)乙基)-2-甲基丙烷-2-亚磺酰胺的合成The second step: (R) -N-((R) -2-((tert-butyldimethylsilyl) oxo) -1- (5- (ethylthio) pyridin-2-yl) Synthesis of ethyl) -2-methylpropane-2-sulfinamide
将2-溴-5-(乙硫基)吡啶(1.5g,6.9mmol)溶于甲苯(4ml)，在氮气保护和-78℃条件加入正丁基锂(3ml,2.5M正己烷溶液)，继续在-78℃下搅拌反应1小时后，将(R,E)-N-(2-((叔-丁基二甲基甲硅烷基)氧代)亚乙基)-2-甲基丙烷-2-亚磺酰胺(2.3g,8.2mmol)的甲苯(4ml)溶液滴加入上述反应液，在-78℃条件下继续反应1小时，然后升至室温反应18小时。反应结束后，将反应液加入水(30ml)中，使用乙酸乙酯(20ml*3)萃取，合并有机相，干燥过滤，滤液浓缩，所得剩余物通过快速硅胶柱分离[洗脱剂：乙酸乙酯：石油醚＝20％-30％]得到(R)-N-((R)-2-((叔-丁基二甲基甲硅烷基)氧代)-1-(5-(乙硫基)吡啶-2-基)乙基)-2-甲基丙烷-2-亚磺酰胺(0.94g,33％)。ESI-MS 417.2[M+H] +。 Dissolve 2-bromo-5- (ethylthio) pyridine (1.5g, 6.9mmol) in toluene (4ml), add n-butyllithium (3ml, 2.5M n-hexane solution) under nitrogen protection and -78 ℃ After continuing to stir the reaction at -78 ° C for 1 hour, the (R, E) -N- (2-((tert-butyldimethylsilyl) oxo) ethylene) -2-methylpropane A solution of -2-sulfinamide (2.3 g, 8.2 mmol) in toluene (4 ml) was added dropwise to the above reaction solution, the reaction was continued at -78 ° C for 1 hour, and then the temperature was raised to room temperature for 18 hours. After the reaction was completed, the reaction solution was added to water (30ml), extracted with ethyl acetate (20ml * 3), the organic phases were combined, dried and filtered, and the filtrate was concentrated. The resulting residue was separated by a flash silica gel column [eluent: ethyl acetate Ester: Petroleum ether = 20% -30%] gives (R) -N-((R) -2-((tert-butyldimethylsilyl) oxo) -1- (5- (ethylsulfide Yl) pyridin-2-yl) ethyl) -2-methylpropane-2-sulfinamide (0.94 g, 33%). ESI-MS 417.2 [M + H] + .
第三步：(R)-2-氨基-2-(5-(乙硫基)吡啶-2-基)乙烷-1-醇的合成Step 3: Synthesis of (R) -2-amino-2- (5- (ethylthio) pyridin-2-yl) ethane-1-ol
将(R)-N-((R)-2-((叔-丁基二甲基甲硅烷基)氧代)-1-(5-(乙硫基)吡啶-2-基)乙基)-2-甲基丙烷-2-亚磺酰胺(0.94g,2.3mmol)溶于氯化氢的二氧六环溶液(8ml,4.0M)中，反应液在室温下 搅拌1.5小时，反应结束后，将反应液浓缩干后得到粗品(R)-2-氨基-2-(5-(乙硫基)吡啶-2-基)乙烷-1-醇，直接作为下一步原料使用。ESI-MS 199.2[M+H] +。 (R) -N-((R) -2-((tert-butyldimethylsilyl) oxo) -1- (5- (ethylthio) pyridin-2-yl) ethyl) -2-Methylpropane-2-sulfinamide (0.94g, 2.3mmol) was dissolved in a solution of hydrogen chloride in dioxane (8ml, 4.0M). The reaction solution was stirred at room temperature for 1.5 hours. After the reaction solution was concentrated to dryness, crude (R) -2-amino-2- (5- (ethylthio) pyridin-2-yl) ethane-1-ol was obtained, which was directly used as the raw material for the next step. ESI-MS 199.2 [M + H] + .
第四步：叔-丁基(R)-(1-(5-(乙硫基)吡啶-2-基)-2-羟基乙基)氨基甲酸酯的合成Step 4: Synthesis of tert-butyl (R)-(1- (5- (ethylthio) pyridin-2-yl) -2-hydroxyethyl) carbamate
将粗品(R)-2-氨基-2-(5-(乙硫基)吡啶-2-基)乙烷-1-醇溶于四氢呋喃(10mL)和水(10ml)的混合溶液中，加入碳酸钾将体系的pH调为9，然后加入二-叔-丁基二碳酸酯(1.1g,4.9mmol)，反应液在室温下搅拌2小时，反应结束后，使用乙酸乙酯(30ml*3)萃取，合并有机相，使用饱和氯化钠(60ml*2)水洗，干燥过滤，减压浓缩至干得到粗品叔-丁基(R)-(1-(5-(乙硫基)吡啶-2-基)-2-羟基乙基)氨基甲酸酯(1.4g)。ESI-MS 299.4[M+H] +。 Dissolve crude (R) -2-amino-2- (5- (ethylthio) pyridin-2-yl) ethane-1-ol in a mixed solution of tetrahydrofuran (10mL) and water (10ml), and add carbonic acid Potassium adjusted the pH of the system to 9, then di-tert-butyl dicarbonate (1.1g, 4.9mmol) was added, and the reaction solution was stirred at room temperature for 2 hours. After the reaction was completed, ethyl acetate (30ml * 3) was used Extract, combine organic phases, wash with saturated sodium chloride (60ml * 2), dry filter, concentrate to dryness under reduced pressure to obtain crude tert-butyl (R)-(1- (5- (ethylthio) pyridine-2 -Yl) -2-hydroxyethyl) carbamate (1.4g). ESI-MS 299.4 [M + H] + .
第五步：叔-丁基(R)-(1-(5-(乙基磺酰)吡啶-2-基)-2-羟基乙基)氨基甲酸酯的合成Step 5: Synthesis of tert-butyl (R)-(1- (5- (ethylsulfonyl) pyridin-2-yl) -2-hydroxyethyl) carbamate
将叔-丁基(R)-(1-(5-(乙硫基)吡啶-2-基)-2-羟基乙基)氨基甲酸酯(1.4g)粗品溶于二氯甲烷(30ml)，在冰浴条件下加入间氯过氧苯甲酸(0.99g,5.7mmol)，继续在冰浴下反应20分钟，然后升至室温下反应40分钟。反应完成后，依次使用氢氧化钠(1M)水溶液，饱和亚硫酸钠(30ml*2)水溶液洗，然后使用乙酸乙酯(30ml*3)萃取，合并有机相，干燥过滤，减压浓缩，剩余物通过快速硅胶柱分离[洗脱剂：乙酸乙酯：石油醚＝0％-100％]得到叔-丁基(R)-(1-(5-(乙基磺酰)吡啶-2-基)-2-羟基乙基)氨基甲酸酯(0.40g,52％)。ESI-MS 331.4[M+H] +。 Dissolve crude tert-butyl (R)-(1- (5- (ethylthio) pyridin-2-yl) -2-hydroxyethyl) carbamate (1.4g) in dichloromethane (30ml) , Add m-chloroperoxybenzoic acid (0.99g, 5.7mmol) under ice bath condition, continue to react in ice bath for 20 minutes, then warm to room temperature for 40 minutes. After the reaction was completed, it was washed successively with aqueous sodium hydroxide (1M), saturated aqueous sodium sulfite (30ml * 2), and then extracted with ethyl acetate (30ml * 3). The organic phases were combined, dried and filtered, and concentrated under reduced pressure. The residue was passed through Rapid silica gel column separation [eluent: ethyl acetate: petroleum ether = 0% -100%] to give tert-butyl (R)-(1- (5- (ethylsulfonyl) pyridin-2-yl)- 2-hydroxyethyl) carbamate (0.40 g, 52%). ESI-MS 331.4 [M + H] + .
第六步：(R)-2-氨基-2-(5-(乙基磺酰)吡啶-2-基)乙烷-1-醇的合成Step 6: Synthesis of (R) -2-amino-2- (5- (ethylsulfonyl) pyridin-2-yl) ethane-1-ol
将叔-丁基(R)-(1-(5-(乙基磺酰)吡啶-2-基)-2-羟基乙基)氨基甲酸酯(0.40g,1.2mmol)溶于氯化氢的二氧六环溶液(8ml,4.0M)。反应液在室温下搅拌3小时，反应结束后，将反应液浓缩干后得到粗品(R)-2-氨基-2-(5-(乙基磺酰)吡啶-2-基)乙烷-1-醇(0.35g,四步总收率65％)，直接作为下一步原料使用。ESI-MS 231.2[M+H] +。 Dissolve tert-butyl (R)-(1- (5- (ethylsulfonyl) pyridin-2-yl) -2-hydroxyethyl) carbamate (0.40 g, 1.2 mmol) in hydrogen chloride Oxygen ring solution (8ml, 4.0M). The reaction solution was stirred at room temperature for 3 hours. After the reaction was completed, the reaction solution was concentrated to dryness to obtain crude (R) -2-amino-2- (5- (ethylsulfonyl) pyridin-2-yl) ethane-1 -Alcohol (0.35g, total yield in four steps 65%), used directly as raw material for the next step. ESI-MS 231.2 [M + H] + .
21、(R)-2-氨基-2-(4-(乙基磺酰)苯基)乙酸乙酯的制备21. Preparation of (R) -2-amino-2- (4- (ethylsulfonyl) phenyl) ethyl acetate
Figure PCTCN2019104957-appb-000045
Figure PCTCN2019104957-appb-000045
第一步：2-(4-(乙硫基)苯基)-2-羰基乙酸乙酯的合成Step 1: Synthesis of ethyl 2- (4- (ethylthio) phenyl) -2-carbonylacetate
将草酰氯单乙酯(11.8g,86.9mmol)，三氯化铝(14.5g,104.3mmol)溶于无水DCM(150mL)中，冰浴下缓慢滴加苯乙硫醚(10.0g,72.5mmol)，反应液在0～24℃中搅拌2小时，反应结束后，将反应液在缓慢淬灭至冰水混合物(约200mL)中，反应分层萃取，有机相用硫酸镁干燥，过滤，滤液浓缩后通过快速硅胶柱分离[PE:EA＝0～30％]得到2-(4-(乙硫基)苯基)-2-羰基乙酸乙酯(5.9g,34％)。Dissolve monoethyl oxalyl chloride (11.8 g, 86.9 mmol) and aluminum trichloride (14.5 g, 104.3 mmol) in anhydrous DCM (150 mL), and slowly add phenylethyl sulfide (10.0 g, 72.5) dropwise under ice bath mmol), and the reaction solution was stirred at 0-24 ° C for 2 hours. After the reaction was completed, the reaction solution was slowly quenched into an ice-water mixture (about 200 mL). The reaction was extracted in layers, and the organic phase was dried over magnesium sulfate and filtered. After the filtrate was concentrated, it was separated by a flash silica gel column [PE: EA = 0 to 30%] to obtain ethyl 2- (4- (ethylthio) phenyl) -2-carbonylacetate (5.9 g, 34%).
1H NMR(500MHz,CDCl 3)δ7.93(d,J＝8.6Hz,2H),7.33(d,J＝8.6Hz,2H),4.46(q,J＝7.1Hz,2H),3.06(q,J＝7.4Hz,2H),1.44(t,J＝6.4Hz,3H),1.41(t,J＝5.9Hz,3H)。 1 H NMR (500 MHz, CDCl 3 ) δ 7.93 (d, J = 8.6 Hz, 2H), 7.33 (d, J = 8.6 Hz, 2H), 4.46 (q, J = 7.1 Hz, 2H), 3.06 (q , J = 7.4 Hz, 2H), 1.44 (t, J = 6.4 Hz, 3H), 1.41 (t, J = 5.9 Hz, 3H).
第二步：R-2-((叔-丁基亚硫酰基)亚氨基)-2-(4-(乙硫基)苯基)乙酸乙酯的合成Step 2: Synthesis of ethyl R-2-((tert-butylsulfinyl) imino) -2- (4- (ethylthio) phenyl) ethyl acetate
将2-(4-(乙硫基)苯基)-2-羰基乙酸乙酯(4.5g,18.9mmol)，R-叔丁基亚磺酰胺(2.7g,22.7mmol)溶于无水THF(50mL)中，加入钛酸四乙酯(6.5g,28.4mmol)。反应液在80℃中搅拌6小时，LCMS显示反应结束，反应液用饱和碳酸钠(200mL)淬灭，所得混合溶液通过硅藻土过滤，滤饼用乙酸乙酯(200mL)洗涤。滤液分层，有机相用饱和食盐水(50mL)洗涤，有机相用硫酸镁干燥，过滤，滤液浓缩，剩余物通过快速硅胶柱分离[PE:EA＝0～25％]得到R-2-((叔-丁基亚硫酰基)亚氨基)-2-(4-(乙硫基)苯基)乙酸乙酯(3.48g,54％)。ESI-MS 342.2[M+1] +。 Ethyl 2- (4- (ethylthio) phenyl) -2-carbonylacetate (4.5g, 18.9mmol), R-tert-butylsulfinamide (2.7g, 22.7mmol) was dissolved in anhydrous THF ( 50mL), tetraethyl titanate (6.5g, 28.4mmol) was added. The reaction solution was stirred at 80 ° C for 6 hours. LCMS indicated that the reaction was completed. The reaction solution was quenched with saturated sodium carbonate (200 mL). The resulting mixed solution was filtered through Celite, and the filter cake was washed with ethyl acetate (200 mL). The filtrate was separated into layers, the organic phase was washed with saturated brine (50 mL), the organic phase was dried over magnesium sulfate, filtered, and the filtrate was concentrated, and the residue was separated by a flash silica gel column [PE: EA = 0-25%] to obtain R-2- ( (Tert-Butylsulfinyl) imino) -2- (4- (ethylthio) phenyl) ethyl acetate (3.48 g, 54%). ESI-MS 342.2 [M + 1] + .
1H NMR(500MHz,CDCl 3)δ7.59(d,J＝8.7Hz,2H),7.22(d,J＝8.6Hz,2H),4.42–4.31(m,2H),2.94(q,J＝7.4Hz,2H),1.33(t,J＝7.2Hz,3H),1.30(t,J＝7.4Hz,3H),1.26(s,9H)。 1 H NMR (500 MHz, CDCl 3 ) δ 7.59 (d, J = 8.7 Hz, 2H), 7.22 (d, J = 8.6 Hz, 2H), 4.42–4.31 (m, 2H), 2.94 (q, J = 7.4 Hz, 2H), 1.33 (t, J = 7.2 Hz, 3H), 1.30 (t, J = 7.4 Hz, 3H), 1.26 (s, 9H).
第三步：(R)-2-(((R)-叔-丁基亚硫酰基)氨基)-2-(4-(乙硫基)苯基)乙酸乙酯的合成Step 3: Synthesis of ethyl (R) -2-(((R) -tert-butylsulfinyl) amino) -2- (4- (ethylthio) phenyl) acetate
将R-2-((叔-丁基亚硫酰基)亚氨基)-2-(4-(乙硫基)苯基)乙酸乙酯(3.48g,10.26mmol)溶于无水THF(100)中，在-78℃下缓慢滴加LiBH(i-Bu) 3(11.3mL,1M,11.29mmol)。反应液在-78℃搅拌3h。LCMS显示反应结束，在-78℃下加入饱和氯化铵水溶液(200mL)淬灭。缓慢升至室温后，反应液浓缩，剩余物用乙酸乙酯(2*150mL)分层，有机相用硫酸镁干燥，过滤，滤液浓缩所得剩余物通过快速硅胶柱分离[PE:EA＝0～20％]得到(R)-2-(((R)-叔-丁基亚硫酰基)氨基)-2-(4-(乙硫基)苯基)乙酸乙酯(2.71g,77％)。ESI-MS 344.2[M+1] +。 Dissolve ethyl R-2-((tert-butylsulfinyl) imino) -2- (4- (ethylthio) phenyl) acetate (3.48 g, 10.26 mmol) in anhydrous THF (100) In, LiBH (i-Bu) 3 (11.3 mL, 1 M, 11.29 mmol) was slowly added dropwise at -78 ° C. The reaction solution was stirred at -78 ° C for 3h. LCMS showed that the reaction was over, and quenched by adding saturated aqueous ammonium chloride solution (200 mL) at -78 ° C. After slowly warming to room temperature, the reaction solution was concentrated, the residue was separated with ethyl acetate (2 * 150mL), the organic phase was dried over magnesium sulfate, filtered, and the residue obtained by concentration of the filtrate was separated by a fast silica gel column [PE: EA = 0 ~ 20%) ethyl acetate (R) -2-(((R) -tert-butylsulfinyl) amino) -2- (4- (ethylthio) phenyl) acetate (2.71 g, 77%) . ESI-MS 344.2 [M + 1] + .
1H NMR(500MHz,CDCl 3)δ7.28(s,4H),5.02(d,J＝4.2Hz,1H),4.57(d,J＝4.2Hz,1H),4.23(dq,J＝10.8,7.1Hz,1H),4.13(dq,J＝10.8,7.1Hz,1H),2.96(q,J＝7.4Hz,2H),1.33(t,J＝7.4Hz,3H),1.24(s,9H),1.21(t,J＝7.1Hz,3H)。 1 H NMR (500 MHz, CDCl 3 ) δ 7.28 (s, 4H), 5.02 (d, J = 4.2 Hz, 1H), 4.57 (d, J = 4.2 Hz, 1H), 4.23 (dq, J = 10.8, 7.1Hz, 1H), 4.13 (dq, J = 10.8, 7.1Hz, 1H), 2.96 (q, J = 7.4Hz, 2H), 1.33 (t, J = 7.4Hz, 3H), 1.24 (s, 9H) , 1.21 (t, J = 7.1 Hz, 3H).
第四步：(R)-2-氨基-2-(4-(乙硫基)苯基)乙酸乙酯的合成Step 4: Synthesis of (R) -2-amino-2- (4- (ethylthio) phenyl) ethyl acetate
将(R)-2-(((R)-叔-丁基亚硫酰基)氨基)-2-(4-(乙硫基)苯基)乙酸乙酯(1.0g,2.91mmol)，溶于HCl二氧六环溶液(10mL,4M)中，反应液在室温下搅拌1小时，反应结束后，反应液浓缩得到粗品(R)-2-氨基-2-(4-(乙硫基)苯基)乙酸乙酯(720mg,95％)，直接用于下一步反应，ESI-MS 240.3[M+1] +。 (R) -2-(((R) -tert-butylsulfinyl) amino) -2- (4- (ethylthio) phenyl) ethyl acetate (1.0g, 2.91mmol), dissolved in In HCl dioxane solution (10mL, 4M), the reaction solution was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was concentrated to obtain crude (R) -2-amino-2- (4- (ethylthio) benzene Base) ethyl acetate (720 mg, 95%), used directly in the next reaction, ESI-MS 240.3 [M + 1] + .
第五步：(R)-2-氨基-2-(4-(乙基磺酰)苯基)乙酸乙酯的合成Step 5: Synthesis of (R) -2-amino-2- (4- (ethylsulfonyl) phenyl) ethyl acetate
将(R)-2-氨基-2-(4-(乙硫基)苯基)乙酸乙酯(720mg,2.90mmol)，溶于无水DCM(30mL)，向溶液中加入m-CPBA(1.46g,7.25mmol)。反应液在室温下搅拌2小时，LCMS显示反应结束，反应液依次用饱和NaHCO 3(10mL)，H 2O(10mL)，饱和食盐水(10mL)洗涤，有机相用硫酸镁干燥，过滤，滤液浓缩，所得剩余物通过快速硅胶柱分离[PE:EA＝0～100％]得到(R)-2-氨基-2-(4-(乙基磺酰)苯基)乙酸乙酯(223mg,28％)，ESI-MS 272.3[M+1] +。 (R) -2-Amino-2- (4- (ethylthio) phenyl) ethyl acetate (720 mg, 2.90 mmol) was dissolved in anhydrous DCM (30 mL), and m-CPBA (1.46) was added to the solution g, 7.25 mmol). The reaction solution was stirred at room temperature for 2 hours. LCMS indicated that the reaction was completed. The reaction solution was washed with saturated NaHCO 3 (10 mL), H 2 O (10 mL), saturated brine (10 mL) in this order, and the organic phase was dried over magnesium sulfate, filtered, and the filtrate After concentration, the obtained residue was separated through a flash silica gel column [PE: EA = 0 to 100%] to obtain ethyl (R) -2-amino-2- (4- (ethylsulfonyl) phenyl) acetate (223 mg, 28 %), ESI-MS 272.3 [M + 1] + .
22、(R)-2-氨基-2-(4-(乙基磺酰)苯基)乙酸乙酯的制备22. Preparation of (R) -2-amino-2- (4- (ethylsulfonyl) phenyl) ethyl acetate
Figure PCTCN2019104957-appb-000046
Figure PCTCN2019104957-appb-000046
第一步：2-丁酰胺基异烟酸甲酯的合成Step 1: Synthesis of 2-butyramido isonicotinic acid methyl ester
将丁酸(10g,118.3mmol)，氯化亚砜(14.1g,118.3mmol)溶于1,2-二氯乙烷(100mL)，反应液在80℃搅拌16小时，冷却至室温，向反应液中缓慢滴加2-氨基异烟酸甲酯(12.0g, 78.9mmol)，三乙胺(24.1g,236.7mmol)的1,2-二氯乙烷(50mL)溶液。反应液在室温下继续搅拌1小时，反应液依次用饱和NaHCO 3(100mL)，H 2O(100mL)，饱和食盐水(100mL)洗涤。有机相用硫酸镁干燥，过滤，滤液通过快速硅胶柱分离[PE:EA＝0～40％]得到2-丁酰胺基异烟酸甲酯(9.3g,53％)，ESI-MS 223.2[M+1] +。 Butyric acid (10g, 118.3mmol), thionyl chloride (14.1g, 118.3mmol) were dissolved in 1,2-dichloroethane (100mL), the reaction solution was stirred at 80 ° C for 16 hours, cooled to room temperature, and reacted A solution of methyl 2-aminoisonicotinate (12.0 g, 78.9 mmol) and triethylamine (24.1 g, 236.7 mmol) in 1,2-dichloroethane (50 mL) was slowly added dropwise. The reaction solution was further stirred at room temperature for 1 hour, and the reaction solution was washed successively with saturated NaHCO 3 (100 mL), H 2 O (100 mL), and saturated brine (100 mL). The organic phase was dried with magnesium sulfate and filtered, and the filtrate was separated by a fast silica gel column [PE: EA = 0 to 40%] to obtain methyl 2-butyridoisonicotinate (9.3g, 53%), ESI-MS 223.2 [M +1] + .
第二步：2-氯-3-乙基咪唑并[1,2-a]吡啶-7-羧酸甲酯的合成Step 2: Synthesis of methyl 2-chloro-3-ethylimidazo [1,2-a] pyridine-7-carboxylate
将2-丁酰胺基异烟酸甲酯(9.3g,41.9mmol)，氯化亚砜(4.5mL,62.8mmol)溶于1,2-二氯乙烷100mL)，反应液在90℃下搅拌16小时。LCMS显示反应结束，反应液浓缩，剩余物溶于DCM(200mL)，分液，有机相依次用饱和NaHCO 3(100mL)，H 2O(100mL)，饱和食盐水(100mL)洗涤，无水硫酸镁干燥，过滤浓缩，剩余物通过快速硅胶柱分离[PE:EA＝0～40％]得到2-氯-3-乙基咪唑并[1,2-a]吡啶-7-羧酸甲酯(5.7g,57％)，ESI-MS 239.2[M+1] +。 Dissolve methyl 2-butyramidoisonicotinate (9.3g, 41.9mmol), thionyl chloride (4.5mL, 62.8mmol) in 1,2-dichloroethane (100mL), and stir the reaction solution at 90 ° C 16 hours. LCMS showed that the reaction was over, the reaction solution was concentrated, the residue was dissolved in DCM (200 mL), the liquid was separated, and the organic phase was washed with saturated NaHCO 3 (100 mL), H 2 O (100 mL), saturated brine (100 mL), and anhydrous sulfuric acid. Magnesium was dried, filtered and concentrated, and the residue was separated through a fast silica gel column [PE: EA = 0 to 40%] to obtain 2-chloro-3-ethylimidazo [1,2-a] pyridine-7-carboxylic acid methyl ester ( 5.7 g, 57%), ESI-MS 239.2 [M + 1] + .
23、4-溴-1-(二氟甲氧基)-2-氟苯的制备23. Preparation of 4-bromo-1- (difluoromethoxy) -2-fluorobenzene
Figure PCTCN2019104957-appb-000047
Figure PCTCN2019104957-appb-000047
将4-溴-2-氟苯酚(3.0g,15.7mmol)，一氯二氟醋酸钠(3.6g,23.5mmol)，碳酸钾(6.5g,47.1mmol)溶于DMF(20mL)中，反应液在120℃下搅拌16h。LCMS显示反应结束，向反应液加入乙酸乙酯(100mL)和H 2O(100mL)。分离有机相，有机相用饱和食盐水(3*50mL)洗涤，硫酸镁干燥，过滤浓缩，剩余物通过快速硅胶柱分离[PE:EA＝0～15％]得到4-溴-1-(二氟甲氧基)-2-氟苯(1.4g,37％)。 Dissolve 4-bromo-2-fluorophenol (3.0g, 15.7mmol), sodium chlorodifluoroacetate (3.6g, 23.5mmol), potassium carbonate (6.5g, 47.1mmol) in DMF (20mL), the reaction solution Stir at 120 ° C for 16h. LCMS showed that the reaction was over, and ethyl acetate (100 mL) and H 2 O (100 mL) were added to the reaction solution. The organic phase was separated. The organic phase was washed with saturated brine (3 * 50 mL), dried over magnesium sulfate, filtered and concentrated, and the residue was separated through a fast silica gel column [PE: EA = 0 to 15%] to obtain 4-bromo-1- (bis Fluoromethoxy) -2-fluorobenzene (1.4 g, 37%).
1H NMR(500MHz,CDCl 3)δ7.38(dd,J＝9.7,2.3Hz,1H),7.30(dd,J＝8.8,1.9Hz,1H),7.16(t,J＝8.5Hz,1H),6.56(t,J＝73.0Hz,1H). 1 H NMR (500 MHz, CDCl 3 ) δ 7.38 (dd, J = 9.7, 2.3 Hz, 1H), 7.30 (dd, J = 8.8, 1.9 Hz, 1H), 7.16 (t, J = 8.5 Hz, 1H) , 6.56 (t, J = 73.0 Hz, 1H).
24、1-(2-氟-4-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)苯基)-2-甲基丙烷-1-酮的制备24. 1- (2-fluoro-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) -2-methylpropane- 1-keto preparation
Figure PCTCN2019104957-appb-000048
Figure PCTCN2019104957-appb-000048
第一步：4-溴-2-氟-N-甲氧基-N-甲基苯酰胺的合成Step 1: Synthesis of 4-bromo-2-fluoro-N-methoxy-N-methylbenzamide
将4-溴-2-氟苯甲酸(4.5g,20.5mmol)，N,O-二甲基盐酸羟胺(2.4g,24.6mmol)，HATU(11.7g,30.8mmol)，DIEA(5.3g,41.1mmol)溶于DCM(50mL)，反应在室温下搅拌2h，LCMS显示反应结束，反应依次用饱和NaHCO 3(100mL)，H 2O(100mL)，饱和食盐水(100mL)洗涤，硫酸镁干燥，过滤浓缩，剩余物通过快速硅胶柱分离[PE:EA＝0～30％]得到4-溴-2-氟-N-甲氧基-N-甲基苯酰胺(4.0g,74％)，ESI-MS 262.2[M+1] +。 Combine 4-bromo-2-fluorobenzoic acid (4.5g, 20.5mmol), N, O-dimethyl hydroxylamine hydrochloride (2.4g, 24.6mmol), HATU (11.7g, 30.8mmol), DIEA (5.3g, 41.1) mmol) was dissolved in DCM (50mL), the reaction was stirred at room temperature for 2h, LCMS showed the reaction, the reaction was washed successively with saturated NaHCO 3 (100mL), H 2 O (100mL), saturated brine (100 mL), dried over magnesium sulfate, It was concentrated by filtration, and the residue was separated by a fast silica gel column [PE: EA = 0 to 30%] to obtain 4-bromo-2-fluoro-N-methoxy-N-methylbenzamide (4.0 g, 74%), ESI -MS 262.2 [M + 1] + .
第二步：1-(4-溴-2-氟苯基)-2-甲基丙烷-1-酮的合成Step 2: Synthesis of 1- (4-bromo-2-fluorophenyl) -2-methylpropane-1-one
将4-溴-2-氟-N-甲氧基-N-甲基苯酰胺(600mg,2.3mmol)溶于无水THF(20mL)中，室温氮气保护下滴加异丙基氯化镁氯化锂(2.6mL,1.3M四氢呋喃溶液,3.45mmol)。反应液在室温下搅拌3h。LCMS显示反应结束，用饱和氯化铵(30mL)淬灭反应，加入乙酸乙酯(50mL)，分离有机相，硫酸镁干燥，过滤浓缩，剩余物通过快速硅胶柱分离[PE:EA＝0～30％]得到1-(4-溴-2-氟苯基)-2-甲基丙烷-1-酮(390mg,69％)，直接用于下一步反应。Dissolve 4-bromo-2-fluoro-N-methoxy-N-methylbenzamide (600mg, 2.3mmol) in anhydrous THF (20mL), dropwise add lithium isopropylmagnesium chloride under nitrogen at room temperature (2.6mL, 1.3M tetrahydrofuran solution, 3.45mmol). The reaction solution was stirred at room temperature for 3h. LCMS showed that the reaction was over. The reaction was quenched with saturated ammonium chloride (30 mL), ethyl acetate (50 mL) was added, the organic phase was separated, dried over magnesium sulfate, filtered and concentrated, and the residue was separated by flash silica gel column [PE: EA = 0 ~ 30%] to give 1- (4-bromo-2-fluorophenyl) -2-methylpropan-1-one (390 mg, 69%), which was used directly in the next reaction.
第三步：1-(2-氟-4-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)苯基)-2-甲基丙烷-1-酮的合成The third step: 1- (2-fluoro-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl) phenyl) -2-methyl Synthesis of propane-1-one
将1-(4-溴-2-氟苯基)-2-甲基丙烷-1-酮(390mg,1.60mmol),双频哪醇硼酸酯(605mg,2.39mmol),Pd(dppf)Cl 2(50mg),KOAc(468mg,4.77mmol)溶于1,4-二氧六环(10mL)中，反应液在氮气保护100℃下搅拌2h。LCMS显示反应结束，反应液浓缩，剩余物通过快速硅胶柱分离[PE:EA＝0～20％]得到1-(2-氟-4-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)苯基)-2-甲基丙烷-1-酮(450mg,96％)，直接用于下一步反应。 1- (4-Bromo-2-fluorophenyl) -2-methylpropane-1-one (390 mg, 1.60 mmol), bis-pinacol borate (605 mg, 2.39 mmol), Pd (dppf) Cl 2 (50mg), KOAc (468mg, 4.77mmol) was dissolved in 1,4-dioxane (10mL), and the reaction solution was stirred under nitrogen protection at 100 ° C for 2h. LCMS showed that the reaction was over, the reaction solution was concentrated, and the residue was separated by a fast silica gel column [PE: EA = 0 to 20%] to obtain 1- (2-fluoro-4- (4,4,5,5-tetramethyl-1 , 3,2-dioxaborolan-2-yl) phenyl) -2-methylpropane-1-one (450 mg, 96%), which was directly used in the next reaction.
中间体25,26的制备参照中间体24的合成方法制备得到：The preparation of intermediates 25 and 26 can be obtained by referring to the synthesis method of intermediate 24:
Figure PCTCN2019104957-appb-000049
Figure PCTCN2019104957-appb-000049
27、4,4,5,5-四甲基-2-(2,2,6,6-四甲基-3,6-二氢-2H-吡喃-4-基)-1,3,2-二噁硼戊环的制备27. 4,4,5,5-tetramethyl-2- (2,2,6,6-tetramethyl-3,6-dihydro-2H-pyran-4-yl) -1,3, Preparation of 2-dioxaborolane
Figure PCTCN2019104957-appb-000050
Figure PCTCN2019104957-appb-000050
第一步：2,2,6,6-四甲基-3,6-二氢-2H-吡喃-4-基4,4,4,4,4,4,4,4,4-九氟-4λ 12-丁-1,3-二炔-1-磺酸酯的合成 The first step: 2,2,6,6-tetramethyl-3,6-dihydro-2H-pyran-4-yl 4,4,4,4,4,4,4,4,4-nine Synthesis of Fluorine-4λ 12 -butane-1,3-diyne-1-sulfonate
氮气保护LDA(4.1g,2N,38.4mmol)，溶液冷至-78℃，缓慢滴加2,2,6,6-四甲基四氢-4H-吡喃-4-酮(5.0g,32.0mmol)的THF(80mL)溶液。反应液在-78℃下搅拌1h，全氟丁基磺酰氟(11.6g,38.4mmol)加入反应液，反应液在-78℃～0℃下搅拌16小时。反应结束，用饱和NaHCO 3(100mL)淬灭反应，混合液用乙酸乙酯(3*50mL)萃取，合并有机相并用饱和食盐水(50mL)洗涤，有机相用硫酸镁干燥，过滤，滤液浓缩，剩余物通过快速硅胶柱分离(PE:EA＝0～20％)得到2,2,6,6-四甲基-3,6-二氢-2H-吡喃-4-基4,4,4,4,4,4,4,4,4-九氟-4λ 12-丁-1,3-二炔-1-磺酸酯(10g,71％)，直接用于下一步反应。 Nitrogen protection LDA (4.1g, 2N, 38.4mmol), the solution was cooled to -78 ℃, slowly add 2,2,6,6-tetramethyltetrahydro-4H-pyran-4-one (5.0g, 32.0 mmol) in THF (80 mL). The reaction solution was stirred at -78 ° C for 1 h, perfluorobutylsulfonyl fluoride (11.6 g, 38.4 mmol) was added to the reaction solution, and the reaction solution was stirred at -78 ° C to 0 ° C for 16 hours. At the end of the reaction, the reaction was quenched with saturated NaHCO 3 (100 mL), the mixture was extracted with ethyl acetate (3 * 50 mL), the organic phases were combined and washed with saturated brine (50 mL), the organic phase was dried over magnesium sulfate, filtered, and the filtrate was concentrated ， The residue was separated by a fast silica gel column (PE: EA = 0 ～ 20%) to obtain 2,2,6,6-tetramethyl-3,6-dihydro-2H-pyran-4-yl 4,4, 4,4,4,4,4,4,4-nonafluoro-4λ 12 -butane-1,3-diyn-1-sulfonate (10 g, 71%), which was directly used in the next reaction.
第二步：4,4,5,5-四甲基-2-(2,2,6,6-四甲基-3,6-二氢-2H-吡喃-4-基)-1,3,2-二噁硼戊环的合成The second step: 4,4,5,5-tetramethyl-2- (2,2,6,6-tetramethyl-3,6-dihydro-2H-pyran-4-yl) -1, Synthesis of 3,2-dioxaborolane
将2,2,6,6-四甲基-3,6-二氢-2H-吡喃-4-基4,4,4,4,4,4,4,4,4-九氟-4λ 12-丁-1,3-二炔-1-磺酸酯(10.0g,22.8mmol)，双频哪醇联硼酸酯(6.3g,25.1mmol),Pd(dppf)Cl 2(930mg,1.14mmol)，醋酸钾(6.7g,68.4mmol)溶于DME(100mL)，反应液在氮气保护下80℃中搅拌16小时。反应结束后，反应液通过硅藻土过滤，滤液浓缩，剩余物通过快速硅胶柱分离[PE:EA＝0～5％]得到4,4,5,5-四甲基-2-(2,2,6,6-四甲基-3,6-二氢-2H-吡喃-4-基)-1,3,2-二噁硼戊环(2.3g,38％)，直接用于下一步反应。 2,2,6,6-tetramethyl-3,6-dihydro-2H-pyran-4-yl 4,4,4,4,4,4,4,4,4-nonafluoro-4λ 12 -butane-1,3-diyn-1-sulfonate (10.0g, 22.8mmol), bis-pinacol biborate (6.3g, 25.1mmol), Pd (dppf) Cl 2 (930mg, 1.14 mmol), potassium acetate (6.7 g, 68.4 mmol) was dissolved in DME (100 mL), and the reaction solution was stirred at 80 ° C. for 16 hours under nitrogen protection. After the reaction was completed, the reaction solution was filtered through celite, the filtrate was concentrated, and the residue was separated through a fast silica gel column [PE: EA = 0 to 5%] to obtain 4,4,5,5-tetramethyl-2- (2, 2,6,6-tetramethyl-3,6-dihydro-2H-pyran-4-yl) -1,3,2-dioxaborolane (2.3g, 38%), used directly under One step reaction.
28、3-乙基-2-(2,2,6,6-四甲基-3,6-二氢-2H-吡喃-4-基)咪唑并[1,2-a]吡啶-7-羧酸的制备28. 3-ethyl-2- (2,2,6,6-tetramethyl-3,6-dihydro-2H-pyran-4-yl) imidazo [1,2-a] pyridine-7 -Preparation of carboxylic acid
Figure PCTCN2019104957-appb-000051
Figure PCTCN2019104957-appb-000051
将2-氯-3-乙基咪唑并[1,2-a]吡啶-7-羧酸甲酯(150mg,0.63mmol，4,4,5,5-四甲基-2-(2,2,6,6-四甲基-3,6-二氢-2H-吡喃-4-基)-1,3,2-二噁硼戊环(250mg,0.94mmol)，P(tBu)3-Pd-G2(30mg)，X-phos(50mg)，K 3PO 4(400mg,1.89mmol)溶于1,4-二氧六环(8mL)，H 2O(2mL)中，反应液在110℃氮气保护下搅拌16h。LCMS显示反应结束，反应液直接浓缩至干，剩余物通过反相快速硅胶柱分离[H 2O:MeCN＝0～80％]得到3-乙基-2-(2,2,6,6-四甲基-3,6-二氢-2H-吡喃-4-基)咪唑并[1,2-a]吡啶-7-羧酸(115mg,55％)ESI-MS 329.2[M+1] +。 2-chloro-3-ethylimidazo [1,2-a] pyridine-7-carboxylic acid methyl ester (150mg, 0.63mmol, 4,4,5,5-tetramethyl-2- (2,2 , 6,6-tetramethyl-3,6-dihydro-2H-pyran-4-yl) -1,3,2-dioxaborolane (250mg, 0.94mmol), P (tBu) 3- Pd-G2 (30mg), X-phos (50mg), K 3 PO 4 (400mg, 1.89mmol) were dissolved in 1,4-dioxane (8mL), H 2 O (2mL), the reaction solution was at 110 Stir under nitrogen for 16h at ℃. LCMS showed that the reaction was over, the reaction solution was directly concentrated to dryness, and the residue was separated by reverse phase flash silica gel column [H 2 O: MeCN = 0 to 80%] to give 3-ethyl-2- (2 , 2,6,6-tetramethyl-3,6-dihydro-2H-pyran-4-yl) imidazo [1,2-a] pyridine-7-carboxylic acid (115 mg, 55%) ESI- MS 329.2 [M + 1] + .
中间体29～31的制备参照中间体28的合成方法制备得到：The preparation of intermediates 29 to 31 can be obtained by referring to the synthesis method of intermediate 28:
Figure PCTCN2019104957-appb-000052
Figure PCTCN2019104957-appb-000052
32、3-乙基-2-(3-氟-4-异丁基苯基)咪唑并[1,2-a]吡啶-7-羧酸的制备32. Preparation of 3-ethyl-2- (3-fluoro-4-isobutylphenyl) imidazo [1,2-a] pyridine-7-carboxylic acid
Figure PCTCN2019104957-appb-000053
Figure PCTCN2019104957-appb-000053
第一步：3-乙基-2-(3-氟-4-异丁酰苯基)咪唑并[1,2-a]吡啶-7-羧酸甲酯的合成Step 1: Synthesis of 3-ethyl-2- (3-fluoro-4-isobutyrylphenyl) imidazo [1,2-a] pyridine-7-carboxylic acid methyl ester
将3-乙基-2-(3-氟-4-异丁酰苯基)咪唑并[1,2-a]吡啶-7-羧酸(490mg,1.38mmol)溶于无水甲醇(20mL)中，室温下缓慢滴加氯化亚砜(3mL)。反应液在80℃下搅拌16h。LCMS显示反应结束，反应液浓缩至干，剩余物溶于DCM(50mL)，依次用饱和NaHCO 3(50mL)，H 2O(50mL)，饱和食盐水(50mL)洗涤，硫酸镁干燥，过滤浓缩，剩余物通过快速硅胶柱分离[PE:EA＝0～40％]得到3-乙基-2-(3-氟-4-异丁酰苯基)咪唑并[1,2-a]吡啶-7-羧酸甲酯(380mg,75％)，ESI-MS 369.2[M+1] +。 3-Ethyl-2- (3-fluoro-4-isobutyrylphenyl) imidazo [1,2-a] pyridine-7-carboxylic acid (490 mg, 1.38 mmol) was dissolved in anhydrous methanol (20 mL) In the middle, sulfoxide chloride (3 mL) was slowly added dropwise at room temperature. The reaction solution was stirred at 80 ° C for 16h. LCMS showed the reaction was completed, the reaction solution was concentrated to dryness, the residue was dissolved in DCM (50mL), washed with saturated NaHCO 3 (50mL), H 2 O (50mL), saturated brine (50mL), dried over magnesium sulfate, filtered and concentrated , The residue was separated by a fast silica gel column [PE: EA = 0 to 40%] to give 3-ethyl-2- (3-fluoro-4-isobutyrylphenyl) imidazo [1,2-a] pyridine- Methyl 7-carboxylate (380 mg, 75%), ESI-MS 369.2 [M + 1] + .
第二步：3-乙基-2-(3-氟-4-异丁基苯基)咪唑并[1,2-a]吡啶-7-羧酸甲酯的合成Step 2: Synthesis of 3-ethyl-2- (3-fluoro-4-isobutylphenyl) imidazo [1,2-a] pyridine-7-carboxylic acid methyl ester
将3-乙基-2-(3-氟-4-异丁酰苯基)咪唑并[1,2-a]吡啶-7-羧酸甲酯(50mg,0.14mmol)溶于无水DCM(10mL)，室温下依次向溶液加入三氟化硼乙醚(0.5mL)，三乙基硅氢(1mL)。反应液在室温下搅拌16h，LCMS显示反应结束，反应液依次用饱和NaHCO 3(10mL)，H 2O(10 mL)，饱和食盐水(10mL)洗涤，硫酸镁干燥，过滤浓缩得到3-乙基-2-(3-氟-4-异丁基苯基)咪唑并[1,2-a]吡啶-7-羧酸甲酯(50mg,99％)，产品直接用于下一步反应，ESI-MS 355.2[M+1] +。 Dissolve 3-ethyl-2- (3-fluoro-4-isobutyrylphenyl) imidazo [1,2-a] pyridine-7-carboxylic acid methyl ester (50 mg, 0.14 mmol) in anhydrous DCM ( 10mL), and boron trifluoride etherate (0.5mL) and triethylsilyl hydrogen (1mL) were added to the solution at room temperature. The reaction solution was stirred at room temperature for 16 h. LCMS indicated that the reaction was completed. The reaction solution was washed with saturated NaHCO 3 (10 mL), H 2 O (10 mL), saturated brine (10 mL), dried over magnesium sulfate, filtered and concentrated to obtain 3-ethylbenzene. 2- (3-fluoro-4-isobutylphenyl) imidazo [1,2-a] pyridine-7-carboxylic acid methyl ester (50mg, 99%), the product is directly used in the next reaction, ESI -MS 355.2 [M + 1] + .
第三步：3-乙基-2-(3-氟-4-异丁基苯基)咪唑并[1,2-a]吡啶-7-羧酸的合成Step 3: Synthesis of 3-ethyl-2- (3-fluoro-4-isobutylphenyl) imidazo [1,2-a] pyridine-7-carboxylic acid
将3-乙基-2-(3-氟-4-异丁基苯基)咪唑并[1,2-a]吡啶-7-羧酸甲酯(50mg,0.14mmol)，NaOH(29mg,0.71mmol)溶于甲醇(8mL),H 2O(4mL)中，反应液在80℃下搅拌1h，LCMS显示反应结束，反应液用1N HCl调节pH＝3～4。混合溶液用DCM(2*10mL)萃取，合并有机相硫酸镁干燥，过滤浓缩至干得到3-乙基-2-(3-氟-4-异丁基苯基)咪唑并[1,2-a]吡啶-7-羧酸(42mg,91％)。产品直接用于下一步反应。 3-ethyl-2- (3-fluoro-4-isobutylphenyl) imidazo [1,2-a] pyridine-7-carboxylic acid methyl ester (50mg, 0.14mmol), NaOH (29mg, 0.71 mmol) was dissolved in methanol (8 mL), H 2 O (4 mL), the reaction solution was stirred at 80 ° C. for 1 h, LCMS showed that the reaction was completed, and the reaction solution was adjusted to pH = 3 ~ 4 with 1N HCl. The mixed solution was extracted with DCM (2 * 10mL), the combined organic phase was dried over magnesium sulfate, filtered and concentrated to dryness to obtain 3-ethyl-2- (3-fluoro-4-isobutylphenyl) imidazo [1,2- a] Pyridine-7-carboxylic acid (42 mg, 91%). The product is directly used in the next reaction.
33、3-乙基-2-(羟基(3-(三氟甲基)吡啶-2-基)甲基)咪唑并[1,2-a]吡啶-7-羧酸的制备33. Preparation of 3-ethyl-2- (hydroxy (3- (trifluoromethyl) pyridin-2-yl) methyl) imidazo [1,2-a] pyridine-7-carboxylic acid
Figure PCTCN2019104957-appb-000054
Figure PCTCN2019104957-appb-000054
第一步：甲基3-乙基-2-(羟基(3-(三氟甲基)吡啶-2-基)甲基)咪唑并[1,2-a]吡啶-7-羧酸酯的合成The first step: methyl 3-ethyl-2- (hydroxy (3- (trifluoromethyl) pyridin-2-yl) methyl) imidazo [1,2-a] pyridine-7-carboxylate synthesis
将甲基3-乙基-2-甲酰基咪唑并[1,2-a]吡啶-7-羧酸酯(400mg,1.76mmol)溶于四氢呋喃(6mL)中，-78℃缓慢滴加正丁基锂(0.70mL,2.5M正己烷溶液,1.76mmol)，并于-78℃搅拌20分钟。再在上述反应液中滴加2-溴-3-(三氟甲基)吡啶(400mg,1.76mmol)的四氢呋喃溶液(3mL)，反应液在-78℃下搅拌2小时，反应结束后，用5毫升甲醇淬灭反应，并加入2滴稀盐酸(2M)，将反应液浓缩干，剩余物通过快速硅胶柱层析分离[0～100％：乙酸乙酯：石油醚，15分钟；2％甲醇：乙酸乙酯，6分钟]得到甲基3-乙基-2-(羟基(3-(三氟甲基)吡啶-2-基)甲基)咪唑并[1,2-a]吡啶-7-羧酸酯(130mg,17％)，ESI-MS 380.2[M+1] +。 Dissolve methyl 3-ethyl-2-formylimidazo [1,2-a] pyridine-7-carboxylate (400mg, 1.76mmol) in tetrahydrofuran (6mL), and slowly add n-butyl dropwise at -78 ℃ Lithium (0.70 mL, 2.5 M n-hexane solution, 1.76 mmol), and stirred at -78 ° C for 20 minutes. Then, a solution of 3-bromo-3- (trifluoromethyl) pyridine (400 mg, 1.76 mmol) in tetrahydrofuran (3 mL) was added dropwise to the above reaction solution. The reaction solution was stirred at -78 ° C for 2 hours. After the reaction was completed, use Quench the reaction with 5 mL of methanol, add 2 drops of dilute hydrochloric acid (2M), concentrate the reaction solution to dryness, and separate the residue by flash silica gel column chromatography [0-100%: ethyl acetate: petroleum ether, 15 minutes; 2% Methanol: ethyl acetate, 6 minutes] to give methyl 3-ethyl-2- (hydroxy (3- (trifluoromethyl) pyridin-2-yl) methyl) imidazo [1,2-a] pyridine- 7-carboxylate (130 mg, 17%), ESI-MS 380.2 [M + 1] + .
第二步：3-乙基-2-(羟基(3-(三氟甲基)吡啶-2-基)甲基)咪唑并[1,2-a]吡啶-7-羧酸的合成Step 2: Synthesis of 3-ethyl-2- (hydroxy (3- (trifluoromethyl) pyridin-2-yl) methyl) imidazo [1,2-a] pyridine-7-carboxylic acid
将甲基3-乙基-2-(羟基(3-(三氟甲基)吡啶-2-基)甲基)咪唑并[1,2-a]吡啶-7-羧酸酯(130mg,85％纯度,0.29mmol)，一水合氢氧化锂(73mg,1.74mmol)溶于四氢呋喃-水(3:1,2mL)中，反应液在室温下搅拌2小时，LCMS显示反应完全，冷却至0℃，用6M盐酸调节反应液pH至6，用乙酸乙酯萃取(20mL*2)，有机相合并，用饱和食盐水洗，无水硫酸钠干燥，过滤浓缩得到粗品3-乙基-2-(羟基(3-(三氟甲基)吡啶-2-基)甲基)咪唑并[1,2-a]吡啶-7-羧酸(125mg),产品直接用于下一步反应，ESI-MS 366.4[M+1] +。 Methyl 3-ethyl-2- (hydroxy (3- (trifluoromethyl) pyridin-2-yl) methyl) imidazo [1,2-a] pyridine-7-carboxylate (130mg, 85 % Purity, 0.29mmol), lithium hydroxide monohydrate (73mg, 1.74mmol) was dissolved in tetrahydrofuran-water (3: 1,2mL), the reaction solution was stirred at room temperature for 2 hours, LCMS showed the reaction was complete, cooled to 0 ℃ , Adjust the pH of the reaction solution to 6 with 6M hydrochloric acid, extract with ethyl acetate (20mL * 2), combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, filter and concentrate to obtain crude 3-ethyl-2- (hydroxyl (3- (trifluoromethyl) pyridin-2-yl) methyl) imidazo [1,2-a] pyridine-7-carboxylic acid (125mg), the product is directly used in the next reaction, ESI-MS 366.4 [ M + 1] + .
34、3-乙基-2-(氟(3-(三氟甲基)吡啶-2-基)甲基)咪唑并[1,2-a]吡啶-7-羧酸的制备34. Preparation of 3-ethyl-2- (fluoro (3- (trifluoromethyl) pyridin-2-yl) methyl) imidazo [1,2-a] pyridine-7-carboxylic acid
Figure PCTCN2019104957-appb-000055
Figure PCTCN2019104957-appb-000055
第一步：甲基3-乙基-2-(氟(3-(三氟甲基)吡啶-2-基)甲基)咪唑并[1,2-a]吡啶-7-羧酸酯的合成The first step: methyl 3-ethyl-2- (fluoro (3- (trifluoromethyl) pyridin-2-yl) methyl) imidazo [1,2-a] pyridine-7-carboxylate synthesis
将甲基3-乙基-2-(羟基(3-(三氟甲基)吡啶-2-基)甲基)咪唑并[1,2-a]吡啶-7-羧酸酯(60mg,0.13mmol)溶于二氯甲烷(3mL)中，0℃下缓慢滴加三氟化二乙胺基硫(0.086mL,0.65mmol)，并于室温下搅拌3小时。冷却至0℃，用冰水淬灭反应，并用二氯甲烷萃取(20mL*2)，有机 相合并，用无水硫酸钠干燥，过滤浓缩。剩余物通过快速硅胶柱层析分离[0～100％：乙酸乙酯：石油醚]得到甲基3-乙基-2-(氟(3-(三氟甲基)吡啶-2-基)甲基)咪唑并[1,2-a]吡啶-7-羧酸酯(30mg,58％)。ESI-MS 382.2[M+1] +。 Methyl 3-ethyl-2- (hydroxy (3- (trifluoromethyl) pyridin-2-yl) methyl) imidazo [1,2-a] pyridine-7-carboxylate (60mg, 0.13 mmol) was dissolved in dichloromethane (3 mL), diethylaminosulfur trifluoride (0.086 mL, 0.65 mmol) was slowly added dropwise at 0 ° C, and stirred at room temperature for 3 hours. Cool to 0 ° C, quench the reaction with ice water, and extract with dichloromethane (20 mL * 2), combine the organic phases, dry over anhydrous sodium sulfate, and concentrate by filtration. The residue was separated by flash silica gel column chromatography [0 ～ 100%: ethyl acetate: petroleum ether] to obtain methyl 3-ethyl-2- (fluoro (3- (trifluoromethyl) pyridin-2-yl) methyl Group) imidazo [1,2-a] pyridine-7-carboxylate (30 mg, 58%). ESI-MS 382.2 [M + 1] + .
第二步：3-乙基-2-(氟(3-(三氟甲基)吡啶-2-基)甲基)咪唑并[1,2-a]吡啶-7-羧酸的合成Step 2: Synthesis of 3-ethyl-2- (fluoro (3- (trifluoromethyl) pyridin-2-yl) methyl) imidazo [1,2-a] pyridine-7-carboxylic acid
将甲基3-乙基-2-(氟(3-(三氟甲基)吡啶-2-基)甲基)咪唑并[1,2-a]吡啶-7-羧酸酯(30mg,0.075mmol),一水合氢氧化锂(13mg,0.30mmol)溶于四氢呋喃-水(3:1,2mL)中，反应液在室温下搅拌2小时，LCMS显示反应完全，冷却至0℃，用6M盐酸调节反应液pH至6，用乙酸乙酯萃取(20mL*2)，有机相合并，用饱和食盐水洗，无水硫酸钠干燥，过滤浓缩得到粗品3-乙基-2-(氟(3-(三氟甲基)吡啶-2-基)甲基)咪唑并[1,2-a]吡啶-7-羧酸(25mg)，并直接用于下一步反应，ESI-MS 368.2[M+1] +。 Methyl 3-ethyl-2- (fluoro (3- (trifluoromethyl) pyridin-2-yl) methyl) imidazo [1,2-a] pyridine-7-carboxylate (30mg, 0.075 mmol), lithium hydroxide monohydrate (13mg, 0.30mmol) was dissolved in tetrahydrofuran-water (3: 1,2mL), the reaction solution was stirred at room temperature for 2 hours, LCMS showed the reaction was complete, cooled to 0 ℃, with 6M hydrochloric acid The pH of the reaction solution was adjusted to 6, extracted with ethyl acetate (20mL * 2), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to obtain crude 3-ethyl-2- (fluoro (3- ( Trifluoromethyl) pyridin-2-yl) methyl) imidazo [1,2-a] pyridine-7-carboxylic acid (25mg), and used directly in the next reaction, ESI-MS 368.2 [M + 1] + .
二、具体实施例化合物的制备2. Preparation of specific examples
实施例1：3-乙基-N-(4-(乙基磺酰)苯甲基)-2-((2-(三氟甲基)哌啶-1-基)甲基)咪唑并[1,2-a]吡啶-7-甲酰胺的制备Example 1: 3-ethyl-N- (4- (ethylsulfonyl) benzyl) -2-((2- (trifluoromethyl) piperidin-1-yl) methyl) imidazo [ Preparation of 1,2-a] pyridine-7-carboxamide
Figure PCTCN2019104957-appb-000056
Figure PCTCN2019104957-appb-000056
将3-乙基-2-((2-(三氟甲基)哌啶-1-基)甲基)咪唑并[1,2-a]吡啶-7-羧酸(206mg，0.58mmol)，(4-(乙基磺酰)苯基)甲胺(115mg,0.58mmol)溶于二氯甲烷(10mL)，室温下下加入HATU(441mg，1.16mmol)和三乙胺(1mL)。反应液在室温下搅拌16小时。反应结束后，把反应液倒入水(10mL)中，用二氯甲烷萃取(10mL*2)，合并有机相，无水硫酸钠干燥，浓缩后反相柱层析分离[洗脱剂：0～80％乙腈：水]得到3-乙基-N-(4-(乙基磺酰)苯甲基)-2-((2-(三氟甲基)哌啶-1-基)甲基)咪唑并[1,2-a]吡啶-7-甲酰胺(15.7mg,5％)。ESI-MS 537.4[M+1] +。 3-ethyl-2-((2- (trifluoromethyl) piperidin-1-yl) methyl) imidazo [1,2-a] pyridine-7-carboxylic acid (206 mg, 0.58 mmol), (4- (Ethylsulfonyl) phenyl) methylamine (115 mg, 0.58 mmol) was dissolved in dichloromethane (10 mL), and HATU (441 mg, 1.16 mmol) and triethylamine (1 mL) were added at room temperature. The reaction solution was stirred at room temperature for 16 hours. After the reaction was completed, the reaction solution was poured into water (10 mL), extracted with dichloromethane (10 mL * 2), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated and separated by reversed-phase column chromatography [eluent: 0 ~ 80% acetonitrile: water] to give 3-ethyl-N- (4- (ethylsulfonyl) benzyl) -2-((2- (trifluoromethyl) piperidin-1-yl) methyl ) Imidazo [1,2-a] pyridine-7-carboxamide (15.7 mg, 5%). ESI-MS 537.4 [M + 1] + .
1H NMR(400MHz,CDCl 3)δ8.08(s,1H),7.99(d,J＝7.2Hz,1H),7.86–7.77(m,2H),7.53(d,J＝8.1Hz,2H),7.39(dd,J＝7.2,1.8Hz,1H),7.17(s,1H),4.76(d,J＝6.0Hz,2H),4.14(d,J＝13.7Hz,1H),3.93(d,J＝13.7Hz,1H),3.25(dq,J＝9.0,4.6,4.1Hz,1H),3.10(q,J＝7.4Hz,2H),3.05–2.95(m,2H),2.87(s,1H),2.49(d,J＝12.2Hz,1H),1.96(s,3H),1.84(d,J＝5.3Hz,2H),1.67(s,1H),1.26(td,J＝7.5,3.9Hz,6H)。 1 H NMR (400 MHz, CDCl 3 ) δ 8.08 (s, 1H), 7.99 (d, J = 7.2 Hz, 1H), 7.86–7.77 (m, 2H), 7.53 (d, J = 8.1 Hz, 2H) , 7.39 (dd, J = 7.2, 1.8 Hz, 1H), 7.17 (s, 1H), 4.76 (d, J = 6.0 Hz, 2H), 4.14 (d, J = 13.7 Hz, 1H), 3.93 (d, J = 13.7 Hz, 1H), 3.25 (dq, J = 9.0, 4.6, 4.1 Hz, 1H), 3.10 (q, J = 7.4 Hz, 2H), 3.05–2.95 (m, 2H), 2.87 (s, 1H ), 2.49 (d, J = 12.2 Hz, 1H), 1.96 (s, 3H), 1.84 (d, J = 5.3 Hz, 2H), 1.67 (s, 1H), 1.26 (td, J = 7.5, 3.9 Hz , 6H).
实施例2的制备参照实施例1的合成方法制备得到：The preparation of Example 2 is obtained by referring to the synthesis method of Example 1:
Figure PCTCN2019104957-appb-000057
Figure PCTCN2019104957-appb-000057
实施例2制备得到的化合物核磁数据如下：The nuclear magnetic data of the compound prepared in Example 2 are as follows:
1H NMR(400MHz,Methanol-d 4)δ8.81(d,J＝7.2Hz,1H),8.38(s,1H),7.96–7.84(m,3H),7.78(s,2H),7.66(d,J＝8.0Hz,2H),7.52(dt,J＝14.2,7.2Hz,3H),4.74(s,2H),4.60–4.44 (m,2H),4.37(d,J＝15.0Hz,1H),3.73(d,J＝11.9Hz,1H),3.38(t,J＝12.1Hz,1H),3.20(q,J＝7.4Hz,2H),2.98(d,J＝7.8Hz,2H),2.32(t,J＝13.8Hz,1H),2.24–2.10(m,2H),2.01(d,J＝7.2Hz,2H),1.84(t,J＝13.3Hz,1H),1.27–1.10(m,6H).ESI-MS 545.4[M+1] +。 1 H NMR (400 MHz, Methanol-d 4 ) δ 8.81 (d, J = 7.2 Hz, 1H), 8.38 (s, 1H), 7.96–7.84 (m, 3H), 7.78 (s, 2H), 7.66 ( d, J = 8.0 Hz, 2H), 7.52 (dt, J = 14.2, 7.2 Hz, 3H), 4.74 (s, 2H), 4.60–4.44 (m, 2H), 4.37 (d, J = 15.0 Hz, 1H ), 3.73 (d, J = 11.9 Hz, 1H), 3.38 (t, J = 12.1 Hz, 1H), 3.20 (q, J = 7.4 Hz, 2H), 2.98 (d, J = 7.8 Hz, 2H), 2.32 (t, J = 13.8 Hz, 1H), 2.24-2.10 (m, 2H), 2.01 (d, J = 7.2 Hz, 2H), 1.84 (t, J = 13.3 Hz, 1H), 1.27-1.10 (m , 6H). ESI-MS 545.4 [M + 1] + .
实施例3：2-(4-氯-2-(三氟甲基)苯甲基)-3-乙基-N-(4-(乙基磺酰)苯甲基)咪唑并[1,2-a]吡啶-7-甲酰胺的制备Example 3: 2- (4-chloro-2- (trifluoromethyl) benzyl) -3-ethyl-N- (4- (ethylsulfonyl) benzyl) imidazo [1,2 -a] Preparation of pyridine-7-carboxamide
Figure PCTCN2019104957-appb-000058
Figure PCTCN2019104957-appb-000058
将2-(4-氯-2-(三氟甲基)苯甲基)-3-乙基咪唑并[1,2-a]吡啶-7-羧酸(51mg，0.13mmol),(4-(乙基磺酰)苯基)甲胺(40mg,0.20mmol)溶于二氯甲烷(5mL)，室温下下加入HATU(152mg,0.40mmol)和三乙胺(1mL)。反应液在室温下搅拌4小时。反应结束后，把反应液倒入水(10mL)中，用二氯甲烷萃取(10mL*2)，合并有机相，无水硫酸钠干燥，浓缩后反相柱分离[洗脱剂：0～80％乙腈：水]得到2-(4-氯-2-(三氟甲基)苯甲基)-3-乙基-N-(4-(乙基磺酰)苯甲基)咪唑并[1,2-a]吡啶-7-甲酰胺(27.5mg,37％)。ESI-MS 564.4[M+1] +。 2- (4-chloro-2- (trifluoromethyl) benzyl) -3-ethylimidazo [1,2-a] pyridine-7-carboxylic acid (51 mg, 0.13 mmol), (4- (Ethylsulfonyl) phenyl) methylamine (40 mg, 0.20 mmol) was dissolved in dichloromethane (5 mL), and HATU (152 mg, 0.40 mmol) and triethylamine (1 mL) were added at room temperature. The reaction solution was stirred at room temperature for 4 hours. After completion of the reaction, the reaction solution was poured into water (10 mL), extracted with dichloromethane (10 mL * 2), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated and separated by reverse phase column [eluent: 0 to 80 % Acetonitrile: water] to give 2- (4-chloro-2- (trifluoromethyl) benzyl) -3-ethyl-N- (4- (ethylsulfonyl) benzyl) imidazo [1 , 2-a] pyridine-7-carboxamide (27.5 mg, 37%). ESI-MS 564.4 [M + 1] + .
1H NMR(400MHz,CDCl 3)δ8.23(s,1H),8.01(d,J＝7.0Hz,1H),7.81(d,J＝7.7Hz,2H),7.62(s,1H),7.51(dd,J＝18.4,7.5Hz,3H),7.35(d,J＝7.9Hz,1H),7.20(d,J＝8.5Hz,1H),4.73(d,J＝4.4Hz,2H),4.29(s,2H),3.09(q,J＝7.4Hz,2H),2.90(d,J＝7.8Hz,2H),1.26(t,J＝7.4Hz,3H),1.16(t,J＝7.5Hz,3H)。 1 H NMR (400 MHz, CDCl 3 ) δ 8.23 (s, 1H), 8.01 (d, J = 7.0 Hz, 1H), 7.81 (d, J = 7.7 Hz, 2H), 7.62 (s, 1H), 7.51 (dd, J = 18.4, 7.5 Hz, 3H), 7.35 (d, J = 7.9 Hz, 1H), 7.20 (d, J = 8.5 Hz, 1H), 4.73 (d, J = 4.4 Hz, 2H), 4.29 (s, 2H), 3.09 (q, J = 7.4Hz, 2H), 2.90 (d, J = 7.8Hz, 2H), 1.26 (t, J = 7.4Hz, 3H), 1.16 (t, J = 7.5Hz , 3H).
实施例4的制备参照实施例3的合成方法制备得到：The preparation of Example 4 is prepared by referring to the synthesis method of Example 3:
Figure PCTCN2019104957-appb-000059
Figure PCTCN2019104957-appb-000059
实施例4制备得到的化合物核磁数据如下：The nuclear magnetic data of the compound prepared in Example 4 are as follows:
1H NMR(400MHz,CDCl 3)δ8.10(t,J＝1.2Hz,1H),7.96(d,J＝7.2Hz,1H),7.84–7.72(m,2H),7.58(d,J＝5.7Hz,1H),7.50(d,J＝8.1Hz,2H),7.40(dd,J＝7.1,1.8Hz,1H),7.24–7.20(m,2H),7.18–7.10(m,1H),4.70(d,J＝6.0Hz,2H),4.17(s,2H),3.08(q,J＝7.4Hz,2H),2.93(q,J＝7.6Hz,2H),1.24(t,J＝7.5Hz,3H),1.17(t,J＝7.5Hz,3H).ESI-MS 546.2[M+1] +。 1 H NMR (400 MHz, CDCl 3 ) δ 8.10 (t, J = 1.2 Hz, 1H), 7.96 (d, J = 7.2 Hz, 1H), 7.84–7.72 (m, 2H), 7.58 (d, J = 5.7Hz, 1H), 7.50 (d, J = 8.1Hz, 2H), 7.40 (dd, J = 7.1, 1.8Hz, 1H), 7.24–7.20 (m, 2H), 7.18–7.10 (m, 1H), 4.70 (d, J = 6.0 Hz, 2H), 4.17 (s, 2H), 3.08 (q, J = 7.4 Hz, 2H), 2.93 (q, J = 7.6 Hz, 2H), 1.24 (t, J = 7.5 Hz, 3H), 1.17 (t, J = 7.5 Hz, 3H). ESI-MS 546.2 [M + 1] + .
实施例5：3-乙基-N-(4-(乙基磺酰)苯甲基)-2-((2-(三氟甲基)苯氧基)甲基)咪唑并[1,2-a]吡啶-7-甲酰胺的制备Example 5: 3-ethyl-N- (4- (ethylsulfonyl) benzyl) -2-((2- (trifluoromethyl) phenoxy) methyl) imidazo [1,2 -a] Preparation of pyridine-7-carboxamide
Figure PCTCN2019104957-appb-000060
Figure PCTCN2019104957-appb-000060
将3-乙基-2-((2-(三氟甲基)苯氧基)甲基)咪唑并[1,2-a]吡啶-7-羧酸(54mg,0.15mmol)，(4-(乙基磺酰)苯基)甲胺(36mg,0.18mmol)溶于二氯甲烷(10mL)，室温下下加入HATU(171mg,0.45mmol)和二异丙基乙胺(0.5mL)。反应液在室温下搅拌2小时。反应结束后，把反应 液倒入水(10mL)中，用二氯甲烷萃取(10mL*2)，合并有机相，硫酸钠干燥，浓缩后反相柱分离[洗脱剂：0～80％乙腈：水]得到3-乙基-N-(4-(乙基磺酰)苯甲基)-2-((2-(三氟甲基)苯氧基)甲基)咪唑并[1,2-a]吡啶-7-甲酰胺(12.5mg,15％)。ESI-MS 546.2[M+1] +。 3-ethyl-2-((2- (trifluoromethyl) phenoxy) methyl) imidazo [1,2-a] pyridine-7-carboxylic acid (54 mg, 0.15 mmol), (4- (Ethylsulfonyl) phenyl) methylamine (36 mg, 0.18 mmol) was dissolved in dichloromethane (10 mL), and HATU (171 mg, 0.45 mmol) and diisopropylethylamine (0.5 mL) were added at room temperature. The reaction solution was stirred at room temperature for 2 hours. After the reaction, the reaction solution was poured into water (10 mL), extracted with dichloromethane (10 mL * 2), the organic phases were combined, dried over sodium sulfate, concentrated and separated by reverse phase column [eluent: 0-80% acetonitrile : Water] to give 3-ethyl-N- (4- (ethylsulfonyl) benzyl) -2-((2- (trifluoromethyl) phenoxy) methyl) imidazo [1,2 -a] pyridine-7-formamide (12.5 mg, 15%). ESI-MS 546.2 [M + 1] + .
1H NMR(400MHz,CDCl 3)δ8.10(s,1H),8.00(d,J＝7.2Hz,1H),7.85(d,J＝8.2Hz,2H),7.55(t,J＝8.1Hz,3H),7.46(t,J＝8.0Hz,1H),7.40(d,J＝7.1Hz,1H),7.11(s,1H),7.01(t,J＝7.6Hz,1H),5.40(s,2H),4.76(d,J＝5.9Hz,2H),3.14–3.08(m,2H),3.08–3.02(m,2H),1.28(d,J＝7.4Hz,3H),1.24(d,J＝7.0Hz,3H)。 1 H NMR (400 MHz, CDCl 3 ) δ 8.10 (s, 1H), 8.00 (d, J = 7.2 Hz, 1H), 7.85 (d, J = 8.2 Hz, 2H), 7.55 (t, J = 8.1 Hz , 3H), 7.46 (t, J = 8.0Hz, 1H), 7.40 (d, J = 7.1Hz, 1H), 7.11 (s, 1H), 7.01 (t, J = 7.6Hz, 1H), 5.40 (s , 2H), 4.76 (d, J = 5.9Hz, 2H), 3.14–3.08 (m, 2H), 3.08–3.02 (m, 2H), 1.28 (d, J = 7.4Hz, 3H), 1.24 (d, J = 7.0 Hz, 3H).
实施例6：2-((2-氯-6-氟苯氧基)甲基)-3-乙基-N-(4-(乙基磺酰)苯甲基)咪唑并[1,2-a]吡啶-7-甲酰胺的制备Example 6: 2-((2-chloro-6-fluorophenoxy) methyl) -3-ethyl-N- (4- (ethylsulfonyl) benzyl) imidazo [1,2- a] Preparation of pyridine-7-formamide
Figure PCTCN2019104957-appb-000061
Figure PCTCN2019104957-appb-000061
将2-((2-氯-6-氟苯氧基)甲基)-3-乙基咪唑并[1,2-a]吡啶-7-羧酸(53mg,0.15mmol)，(4-(乙基磺酰)苯基)甲胺(46mg,0.23mmol)溶于二氯甲烷(10mL)，室温下下加入HATU(174mg,0.45mmol)和吡啶(0.5mL)。反应液在室温下搅拌2小时。反应结束后，把它倒入水(10mL)中，用二氯甲烷萃取(10mL*2)，合并有机相，硫酸钠干燥，浓缩后反相柱层析分离[洗脱剂：0～80％乙腈：水]得到2-((2-氯-6-氟苯氧基)甲基)-3-乙基-N-(4-(乙基磺酰)苯甲基)咪唑并[1,2-a]吡啶-7-甲酰胺(10.4mg,13％)。ESI-MS 530.2[M+1] +。 2-((2-chloro-6-fluorophenoxy) methyl) -3-ethylimidazo [1,2-a] pyridine-7-carboxylic acid (53mg, 0.15mmol), (4- ( Ethylsulfonyl) phenyl) methylamine (46 mg, 0.23 mmol) was dissolved in dichloromethane (10 mL), and HATU (174 mg, 0.45 mmol) and pyridine (0.5 mL) were added at room temperature. The reaction solution was stirred at room temperature for 2 hours. After the reaction, it was poured into water (10 mL), extracted with dichloromethane (10 mL * 2), the organic phases were combined, dried over sodium sulfate, concentrated and separated by reverse phase column chromatography [eluent: 0 to 80% Acetonitrile: water] to give 2-((2-chloro-6-fluorophenoxy) methyl) -3-ethyl-N- (4- (ethylsulfonyl) benzyl) imidazo [1,2 -a] pyridine-7-carboxamide (10.4 mg, 13%). ESI-MS 530.2 [M + 1] + .
1H NMR(400MHz,CDCl 3)δ8.29(s,1H),8.03(d,J＝7.2Hz,1H),7.83(d,J＝8.0Hz,3H),7.57(d,J＝8.1Hz,2H),7.49(d,J＝7.3Hz,1H),7.00(dd,J＝8.6,4.0Hz,2H),5.27(s,2H),4.74(d,J＝5.7Hz,2H),3.16–3.09(m,2H),3.09–3.05(m,2H),1.33–1.28(m,3H),1.25(d,J＝7.5Hz,3H)。 1 H NMR (400 MHz, CDCl 3 ) δ 8.29 (s, 1H), 8.03 (d, J = 7.2 Hz, 1H), 7.83 (d, J = 8.0 Hz, 3H), 7.57 (d, J = 8.1 Hz , 2H), 7.49 (d, J = 7.3 Hz, 1H), 7.00 (dd, J = 8.6, 4.0 Hz, 2H), 5.27 (s, 2H), 4.74 (d, J = 5.7 Hz, 2H), 3.16 –3.09 (m, 2H), 3.09–3.05 (m, 2H), 1.33–1.28 (m, 3H), 1.25 (d, J = 7.5Hz, 3H).
实施例7：3-乙基-N-(4-(乙基磺酰)苯甲基)-2-(2-(三氟甲基)哌啶-1-羰基)咪唑并[1,2-a]吡啶-7-甲酰胺的制备Example 7: 3-ethyl-N- (4- (ethylsulfonyl) benzyl) -2- (2- (trifluoromethyl) piperidine-1-carbonyl) imidazo [1,2- a] Preparation of pyridine-7-formamide
Figure PCTCN2019104957-appb-000062
Figure PCTCN2019104957-appb-000062
将3-乙基-2-(2-(三氟甲基)哌啶-1-羰基)咪唑并[1,2-a]吡啶-7-羧酸(63mg,0.17mmol)，(4-(乙基磺酰)苯基)甲胺(51mg,0.25mmol)溶于二氯甲烷(10mL)，室温下下加入HATU(194mg,0.51mmol)和吡啶(0.5mL)。反应液在室温下搅拌2小时。反应结束后，把反应液倒入水(10mL)中，用二氯甲烷萃取(10mL*2)，合并有机相，无水硫酸钠干燥，浓缩后反相柱分离[洗脱剂：0～80％乙腈：水]得到3-乙基-N-(4-(乙基磺酰)苯甲基)-2-(2-(三氟甲基)哌啶-1-羰基)咪唑并[1,2-a]吡啶-7-甲酰胺(28.9mg,31％)。ESI-MS 551.4[M+1] +。 3-ethyl-2- (2- (trifluoromethyl) piperidine-1-carbonyl) imidazo [1,2-a] pyridine-7-carboxylic acid (63 mg, 0.17 mmol), (4- ( Ethylsulfonyl) phenyl) methylamine (51 mg, 0.25 mmol) was dissolved in dichloromethane (10 mL), and HATU (194 mg, 0.51 mmol) and pyridine (0.5 mL) were added at room temperature. The reaction solution was stirred at room temperature for 2 hours. After completion of the reaction, the reaction solution was poured into water (10 mL), extracted with dichloromethane (10 mL * 2), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated and separated by reverse phase column [eluent: 0 to 80 % Acetonitrile: water] to give 3-ethyl-N- (4- (ethylsulfonyl) benzyl) -2- (2- (trifluoromethyl) piperidine-1-carbonyl) imidazo [1, 2-a] pyridine-7-formamide (28.9 mg, 31%). ESI-MS 551.4 [M + 1] + .
1H NMR(400MHz,Methanol-d 4)δ8.80(s,1H),8.32(s,1H),7.89(d,J＝8.1Hz,2H),7.84(s,1H),7.66(d,J＝8.1Hz,2H),5.44(s,1H),4.74(s,2H),3.87(d,J＝13.5Hz,1H),3.42(s,1H),3.21(t,J＝7.4Hz,2H),3.17–3.09(m,2H),2.20(d,J＝14.5Hz,1H),1.94(s,2H),1.80(s,2H),1.57(s,1H),1.35(t,J＝7.5Hz,3H),1.20(t,J＝7.4Hz,3H)。 1 H NMR (400 MHz, Methanol-d 4 ) δ 8.80 (s, 1H), 8.32 (s, 1H), 7.89 (d, J = 8.1 Hz, 2H), 7.84 (s, 1H), 7.66 (d, J = 8.1 Hz, 2H), 5.44 (s, 1H), 4.74 (s, 2H), 3.87 (d, J = 13.5 Hz, 1H), 3.42 (s, 1H), 3.21 (t, J = 7.4 Hz, 2H), 3.17–3.09 (m, 2H), 2.20 (d, J = 14.5 Hz, 1H), 1.94 (s, 2H), 1.80 (s, 2H), 1.57 (s, 1H), 1.35 (t, J = 7.5 Hz, 3H), 1.20 (t, J = 7.4 Hz, 3H).
实施例8：(E)-2-(2-氯-6-(三氟甲基)苯乙烯基)-3-乙基-N-(4-(乙基磺酰)苯甲基)咪唑并[1,2-a]吡啶-7-甲酰胺的制备Example 8: (E) -2- (2-chloro-6- (trifluoromethyl) styryl) -3-ethyl-N- (4- (ethylsulfonyl) benzyl) imidazo Preparation of [1,2-a] pyridine-7-formamide
Figure PCTCN2019104957-appb-000063
Figure PCTCN2019104957-appb-000063
将(E)-2-(2-氯-6-(三氟甲基)苯乙烯基)-3-乙基咪唑并[1,2-a]吡啶-7-羧酸(5.3mg,0.0134mmol)，(4-(乙基磺酰)苯基)甲胺(4.0mg,0.02mmol)溶于二氯甲烷(3mL)，室温下下加入HATU(16mg,0.04mmol)和吡啶(0.5mL)。反应在室温下搅拌1小时。反应结束后，把反应液倒入水(10mL)中，用二氯甲烷萃取(10mL*2)，合并有机相，硫酸钠干燥，浓缩后反相柱层析分离[洗脱剂：0～80％乙腈：水]得到(E)-2-(2-氯-6-(三氟甲基)苯乙烯基)-3-乙基-N-(4-(乙基磺酰)苯甲基)咪唑并[1,2-a]吡啶-7-甲酰胺(2.5mg,5％)。ESI-MS 576.2[M+1] +。 (E) -2- (2-chloro-6- (trifluoromethyl) styryl) -3-ethylimidazo [1,2-a] pyridine-7-carboxylic acid (5.3 mg, 0.0134 mmol ), (4- (ethylsulfonyl) phenyl) methylamine (4.0 mg, 0.02 mmol) was dissolved in dichloromethane (3 mL), and HATU (16 mg, 0.04 mmol) and pyridine (0.5 mL) were added at room temperature. The reaction was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was poured into water (10 mL), extracted with dichloromethane (10 mL * 2), the organic phases were combined, dried over sodium sulfate, concentrated and separated by reversed-phase column chromatography [eluent: 0 to 80 % Acetonitrile: water] gives (E) -2- (2-chloro-6- (trifluoromethyl) styryl) -3-ethyl-N- (4- (ethylsulfonyl) benzyl) Imidazo [1,2-a] pyridine-7-carboxamide (2.5 mg, 5%). ESI-MS 576.2 [M + 1] + .
1H NMR(400MHz,CDCl 3)δ8.15(s,1H),7.97(d,J＝7.1Hz,1H),7.81(d,J＝8.0Hz,2H),7.64(d,J＝8.1Hz,2H),7.50(d,J＝8.2Hz,2H),7.44–7.28(m,3H),6.97(d,J＝16.2Hz,1H),4.73(d,J＝5.8Hz,2H),3.10(q,J＝7.5Hz,2H),3.02(q,J＝7.7Hz,2H),1.29–1.24(m,6H)。 1 H NMR (400 MHz, CDCl 3 ) δ 8.15 (s, 1H), 7.97 (d, J = 7.1 Hz, 1H), 7.81 (d, J = 8.0 Hz, 2H), 7.64 (d, J = 8.1 Hz , 2H), 7.50 (d, J = 8.2Hz, 2H), 7.44-7.28 (m, 3H), 6.97 (d, J = 16.2Hz, 1H), 4.73 (d, J = 5.8Hz, 2H), 3.10 (q, J = 7.5 Hz, 2H), 3.02 (q, J = 7.7 Hz, 2H), 1.29-1.24 (m, 6H).
实施例9：(R)-2-(4-氯-2-(三氟甲基)苯甲基)-3-乙基-N-(1-(4-(乙基磺酰)苯基)-2-羟基乙基)咪唑并[1,2-a]吡啶-7-甲酰胺的制备Example 9: (R) -2- (4-chloro-2- (trifluoromethyl) benzyl) -3-ethyl-N- (1- (4- (ethylsulfonyl) phenyl) Preparation of -2-hydroxyethyl) imidazo [1,2-a] pyridine-7-carboxamide
Figure PCTCN2019104957-appb-000064
Figure PCTCN2019104957-appb-000064
将2-(4-氯-2-(三氟甲基)苯甲基)-3-乙基咪唑并[1,2-a]吡啶-7-羧酸(45mg,0.11mmol),(R)-2-氨基-2-(4-(乙基磺酰)苯基)乙醇(25mg,0.11mmol)溶于二氯甲烷(5mL)，室温下下加入HATU(130mg,0.37mmol)和吡啶(0.5mL)。反应液在室温下搅拌2小时。LCMS显示反应结束，把反应液倒入水(10mL)中，用二氯甲烷萃取(10mL*2)，合并有机相，然后用无水硫酸钠干燥，浓缩后反相柱层析分离[洗脱剂:0～80％MeCN：H 2O]得到(R)-2-(4-氯-2-(三氟甲基)苯甲基)-3-乙基-N-(1-(4-(乙基磺酰)苯基)-2-羟基乙基)咪唑并[1,2-a]吡啶-7-甲酰胺(7.9mg，12％)。ESI-MS 594.2[M+1] +。 2- (4-chloro-2- (trifluoromethyl) benzyl) -3-ethylimidazo [1,2-a] pyridine-7-carboxylic acid (45mg, 0.11mmol), (R) -2-Amino-2- (4- (ethylsulfonyl) phenyl) ethanol (25mg, 0.11mmol) was dissolved in dichloromethane (5mL), and HATU (130mg, 0.37mmol) and pyridine (0.5 mL). The reaction solution was stirred at room temperature for 2 hours. LCMS showed that the reaction was over, the reaction solution was poured into water (10 mL), extracted with dichloromethane (10 mL * 2), the organic phases were combined, then dried over anhydrous sodium sulfate, concentrated and separated by reverse phase column chromatography [elution Agent: 0 ～ 80% MeCN: H 2 O] to obtain (R) -2- (4-chloro-2- (trifluoromethyl) benzyl) -3-ethyl-N- (1- (4- (Ethylsulfonyl) phenyl) -2-hydroxyethyl) imidazo [1,2-a] pyridine-7-carboxamide (7.9 mg, 12%). ESI-MS 594.2 [M + 1] + .
1H NMR(400MHz,CDCl 3)δ8.28(s,1H),8.12(d,J＝7.2Hz,1H),7.94(d,J＝7.2Hz,1H),7.73–7.57(m,3H),7.50(d,J＝8.1Hz,2H),7.40(dd,J＝7.1,1.6Hz,1H),7.34(dd,J＝8.5,2.2Hz,1H),7.07(d,J＝8.4Hz,1H),5.31(dt,J＝8.0,4.1Hz,1H),4.18(q,J＝16.7Hz,2H),4.05–3.89(m,2H),3.02(q,J＝7.4Hz,2H),2.87(dt,J＝8.9,6.9Hz,2H),1.22(t,J＝7.4Hz,3H),1.13(t,J＝7.5Hz,3H)。 1 H NMR (400 MHz, CDCl 3 ) δ 8.28 (s, 1H), 8.12 (d, J = 7.2 Hz, 1H), 7.94 (d, J = 7.2 Hz, 1H), 7.73–7.57 (m, 3H) , 7.50 (d, J = 8.1 Hz, 2H), 7.40 (dd, J = 7.1, 1.6 Hz, 1H), 7.34 (dd, J = 8.5, 2.2 Hz, 1H), 7.07 (d, J = 8.4 Hz, 1H), 5.31 (dt, J = 8.0, 4.1Hz, 1H), 4.18 (q, J = 16.7Hz, 2H), 4.05–3.89 (m, 2H), 3.02 (q, J = 7.4Hz, 2H), 2.87 (dt, J = 8.9, 6.9 Hz, 2H), 1.22 (t, J = 7.4 Hz, 3H), 1.13 (t, J = 7.5 Hz, 3H).
实施例10：3-乙基-N-((5-(乙基磺酰)吡啶-2-基)甲基)-2-(羟基(2-(三氟甲基)苯基)甲基)咪唑并[1,2-a]吡啶-7-甲酰胺的制备Example 10: 3-ethyl-N-((5- (ethylsulfonyl) pyridin-2-yl) methyl) -2- (hydroxy (2- (trifluoromethyl) phenyl) methyl) Preparation of imidazo [1,2-a] pyridine-7-carboxamide
Figure PCTCN2019104957-appb-000065
Figure PCTCN2019104957-appb-000065
将3-乙基-2-(羟基(2-(三氟甲基)苯基)甲基)咪唑并[1,2-a]吡啶-7-羧酸(80mg,0.21mmol),(5-(乙基磺酰)吡啶-2-基)甲胺盐酸盐(60mg,0.22mmol)溶于N,N-二甲基甲酰胺(3mL)，室温下下加入和三乙胺(1mL)和HATU(160mg,0.42mmol)。反应液在室温下搅拌2小时。LCMS显示反应结束，把它倒入水(15mL)中，用乙酸乙酯萃取(20mL*2)，合并有机相，硫酸钠干燥，浓缩后反相柱层析分离[洗脱剂:0～80％MeCN：0.01％TFA/H 2O]得到3-乙基-N-((5-(乙基磺酰)吡啶-2-基)甲基)-2-(羟基(2-(三氟甲基)苯基)甲基)咪唑并[1,2-a]吡啶-7-甲酰胺三氟乙酸盐(83.2mg,58％)。ESI-MS 547.4[M+1] +。 3-ethyl-2- (hydroxy (2- (trifluoromethyl) phenyl) methyl) imidazo [1,2-a] pyridine-7-carboxylic acid (80mg, 0.21mmol), (5- (Ethylsulfonyl) pyridin-2-yl) methylamine hydrochloride (60 mg, 0.22 mmol) was dissolved in N, N-dimethylformamide (3 mL), and triethylamine (1 mL) was added at room temperature. HATU (160 mg, 0.42 mmol). The reaction solution was stirred at room temperature for 2 hours. LCMS showed that the reaction was over, poured it into water (15mL), extracted with ethyl acetate (20mL * 2), combined organic phase, dried over sodium sulfate, concentrated and separated by reverse phase column chromatography [eluent: 0 ～ 80 % MeCN: 0.01% TFA / H 2 O] to give 3-ethyl-N-((5- (ethylsulfonyl) pyridin-2-yl) methyl) -2- (hydroxy (2- (trifluoromethyl Yl) phenyl) methyl) imidazo [1,2-a] pyridine-7-carboxamide trifluoroacetate (83.2 mg, 58%). ESI-MS 547.4 [M + 1] + .
1H NMR(400MHz,DMSO-d 6)δ9.65(s,1H),8.97(d,J＝2.0Hz,1H),8.78(s,1H),8.28-8.25(m,2H),7.89-7.88(m,1H),7.78-7.72(m,3H),7.65(d,J＝8.0Hz,1H),7.58(d,J＝7.2Hz,1H),6.35(s,1H),4.73(d,J＝5.6Hz,2H),3.40(q,J＝7.6Hz,2H),2.95-2.90(m,2H),1.13(t,J＝7.2Hz,3H),1.02(t,J＝7.2Hz,3H)。 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.65 (s, 1H), 8.97 (d, J = 2.0 Hz, 1H), 8.78 (s, 1H), 8.28-8.25 (m, 2H), 7.89- 7.88 (m, 1H), 7.78-7.72 (m, 3H), 7.65 (d, J = 8.0 Hz, 1H), 7.58 (d, J = 7.2 Hz, 1H), 6.35 (s, 1H), 4.73 (d , J = 5.6 Hz, 2H), 3.40 (q, J = 7.6 Hz, 2H), 2.95-2.90 (m, 2H), 1.13 (t, J = 7.2 Hz, 3H), 1.02 (t, J = 7.2 Hz , 3H).
实施例11：3-乙基-N-((5-(乙基磺酰)吡啶-2-基)甲基)-2-(2-(三氟甲基)苯甲酰)咪唑并[1,2-a]吡啶-7-甲酰胺的制备Example 11: 3-ethyl-N-((5- (ethylsulfonyl) pyridin-2-yl) methyl) -2- (2- (trifluoromethyl) benzoyl) imidazo [1 , 2-a] pyridine-7-carboxamide
Figure PCTCN2019104957-appb-000066
Figure PCTCN2019104957-appb-000066
将3-乙基-N-((5-(乙基磺酰)吡啶-2-基)甲基)-2-(羟基(2-(三氟甲基)苯基)甲基)咪唑并[1,2-a]吡啶-7-甲酰胺(40mg,0.069mmol)溶于二氯甲烷(15mL)中,冰浴下加入高碘杂己环(44mg,0.104mmol)，反应液在室温下搅拌2小时。LCMS显示反应结束，过滤，滤饼用二氯甲烷洗涤。合并滤液，依次用饱和碳酸氢钠溶液和饱和食盐水各洗涤一次。有机相用硫酸钠干燥，浓缩后反相柱层析分离[洗脱剂:0～80％MeCN：H 2O]得到3-乙基-N-((5-(乙基磺酰)吡啶-2-基)甲基)-2-(2-(三氟甲基)苯甲酰)咪唑并[1,2-a]吡啶-7-甲酰胺(19.0mg,51％)。ESI-MS 545.4[M+1] +。 3-ethyl-N-((5- (ethylsulfonyl) pyridin-2-yl) methyl) -2- (hydroxy (2- (trifluoromethyl) phenyl) methyl) imidazo [ 1,2-a] pyridine-7-carboxamide (40mg, 0.069mmol) was dissolved in dichloromethane (15mL), and iodoxane (44mg, 0.104mmol) was added under ice bath, and the reaction solution was stirred at room temperature 2 hours. LCMS showed that the reaction was over, filtered and the filter cake was washed with dichloromethane. The filtrates were combined and washed successively with saturated sodium bicarbonate solution and saturated brine once. The organic phase was dried over sodium sulfate, concentrated and separated by reverse phase column chromatography [eluent: 0 to 80% MeCN: H 2 O] to obtain 3-ethyl-N-((5- (ethylsulfonyl) pyridine- 2-yl) methyl) -2- (2- (trifluoromethyl) benzoyl) imidazo [1,2-a] pyridine-7-carboxamide (19.0 mg, 51%). ESI-MS 545.4 [M + 1] + .
1H NMR(400MHz,DMSO-d 6)δ9.42(t,J＝6.0Hz,1H),8.96(d,J＝2.0Hz,1H),8.67(d,J＝7.2Hz,1H),8.24(dd,J＝8.0,2.4Hz,1H),8.19(s,1H),7.87(d,J＝7.6Hz,1H),7.80-7.74(m,2H),7.65-7.63(m,2H),7.46(d,J＝7.2Hz,1H),4.69(d,J＝6.0Hz,2H),3.42-3.36(m,4H),1.25(t,J＝7.2Hz,3H),1.12(t,J＝7.2Hz,3H)。 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.42 (t, J = 6.0 Hz, 1H), 8.96 (d, J = 2.0 Hz, 1H), 8.67 (d, J = 7.2 Hz, 1H), 8.24 (dd, J = 8.0, 2.4Hz, 1H), 8.19 (s, 1H), 7.87 (d, J = 7.6Hz, 1H), 7.80-7.74 (m, 2H), 7.65-7.63 (m, 2H), 7.46 (d, J = 7.2 Hz, 1H), 4.69 (d, J = 6.0 Hz, 2H), 3.42-3.36 (m, 4H), 1.25 (t, J = 7.2 Hz, 3H), 1.12 (t, J = 7.2 Hz, 3H).
实施例12：(R)-2-(3-(二氟甲氧基)-5-氟苯基)-3-乙基-N-(1-(4-(乙基磺酰)苯基)-2-羟基乙基)咪唑并[1,2-a]吡啶-7-甲酰胺的制备Example 12: (R) -2- (3- (difluoromethoxy) -5-fluorophenyl) -3-ethyl-N- (1- (4- (ethylsulfonyl) phenyl) Preparation of -2-hydroxyethyl) imidazo [1,2-a] pyridine-7-carboxamide
Figure PCTCN2019104957-appb-000067
Figure PCTCN2019104957-appb-000067
将2-(3-(二氟甲氧基)-5-氟苯基)-3-乙基咪唑并[1,2-a]吡啶-7-羧酸粗品(72mg,0.21mM)，(R)-2-氨基-2-(4-(乙基磺酰)苯基)乙烷-1-醇(54mg,0.24mM)和HATU(135mg,0.36mM)加入DMF(5ml)中，反应液在室温条件下搅拌反应5小时。向反应液中加入适量水，用乙酸乙酯萃取3次，合并有机相，无水硫酸镁干燥，过滤，减压浓缩后，使用反向柱分离得到(R)-2-(3-(二氟甲氧基)-5-氟苯基)-3-乙基-N-(1-(4-(乙基磺酰)苯基)-2-羟基乙基)咪唑并[1,2-a]吡啶-7-甲酰胺(1.9mg)。ESI-MS 562.2[M+H] +。 The crude 2- (3- (difluoromethoxy) -5-fluorophenyl) -3-ethylimidazo [1,2-a] pyridine-7-carboxylic acid (72mg, 0.21mM), (R ) -2-amino-2- (4- (ethylsulfonyl) phenyl) ethane-1-ol (54mg, 0.24mM) and HATU (135mg, 0.36mM) were added to DMF (5ml), the reaction solution was The reaction was stirred at room temperature for 5 hours. Add an appropriate amount of water to the reaction solution, extract three times with ethyl acetate, combine the organic phases, dry over anhydrous magnesium sulfate, filter, concentrate under reduced pressure, and separate using a reverse column to obtain (R) -2- (3- (two Fluoromethoxy) -5-fluorophenyl) -3-ethyl-N- (1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) imidazo [1,2-a ] Pyridine-7-carboxamide (1.9 mg). ESI-MS 562.2 [M + H] + .
1H NMR(400MHz,CDCl 3)δ8.66(s,1H),8.52(d,J＝7.3Hz,1H),8.04(d,J＝7.2Hz,1H),7.55(d,J＝7.2Hz,1H),7.45(q,J＝8.2Hz,4H),7.22(s,1H),7.18(d,J＝9.1Hz,1H),6.90(d,J＝9.1Hz,1H),6.64(m,1H),5.36–5.28(m,1H),4.14(dd,J＝11.8,3.4Hz,1H),4.05(dd,J＝11.9,4.3Hz,1H),3.15–3.08(m,2H),2.97(q,J＝7.4Hz,2H),1.29(t,J＝7.5Hz,3H),1.19(t,J＝7.4Hz,3H)。 1 H NMR (400 MHz, CDCl 3 ) δ 8.66 (s, 1H), 8.52 (d, J = 7.3 Hz, 1H), 8.04 (d, J = 7.2 Hz, 1H), 7.55 (d, J = 7.2 Hz , 1H), 7.45 (q, J = 8.2Hz, 4H), 7.22 (s, 1H), 7.18 (d, J = 9.1Hz, 1H), 6.90 (d, J = 9.1Hz, 1H), 6.64 (m , 1H), 5.36–5.28 (m, 1H), 4.14 (dd, J = 11.8, 3.4Hz, 1H), 4.05 (dd, J = 11.9, 4.3Hz, 1H), 3.15–3.08 (m, 2H), 2.97 (q, J = 7.4 Hz, 2H), 1.29 (t, J = 7.5 Hz, 3H), 1.19 (t, J = 7.4 Hz, 3H).
实施例13参照实施例12的合成方法制备得到：Example 13 is prepared by referring to the synthesis method of Example 12:
Figure PCTCN2019104957-appb-000068
Figure PCTCN2019104957-appb-000068
实施例13制备得到的化合物核磁数据如下：The nuclear magnetic data of the compound prepared in Example 13 are as follows:
1H NMR(400MHz,CDCl 3)δ8.19(s,1H),8.05(d,J＝7.2Hz,1H),7.82(d,J＝8.0Hz,2H),7.53(d,J＝8.1Hz,2H),7.47(dd,J＝7.2,1.6Hz,1H),7.37–7.29(m,3H),6.89(d,J＝9.1Hz,1H),6.60(m,1H),4.76(d,J＝5.8Hz,2H),3.12(dd,J＝14.7,7.4Hz,4H),1.38(t,J＝7.5Hz,3H),1.27(t,J＝7.4Hz,3H)。 1 H NMR (400 MHz, CDCl 3 ) δ 8.19 (s, 1H), 8.05 (d, J = 7.2 Hz, 1H), 7.82 (d, J = 8.0 Hz, 2H), 7.53 (d, J = 8.1 Hz , 2H), 7.47 (dd, J = 7.2, 1.6Hz, 1H), 7.37–7.29 (m, 3H), 6.89 (d, J = 9.1Hz, 1H), 6.60 (m, 1H), 4.76 (d, J = 5.8 Hz, 2H), 3.12 (dd, J = 14.7, 7.4 Hz, 4H), 1.38 (t, J = 7.5 Hz, 3H), 1.27 (t, J = 7.4 Hz, 3H).
实施例14-48参照实施例3或者9的合成方法制备得到：Examples 14-48 were prepared with reference to the synthesis method of Example 3 or 9:
Figure PCTCN2019104957-appb-000069
Figure PCTCN2019104957-appb-000069
Figure PCTCN2019104957-appb-000070
Figure PCTCN2019104957-appb-000070
Figure PCTCN2019104957-appb-000071
Figure PCTCN2019104957-appb-000071
Figure PCTCN2019104957-appb-000072
Figure PCTCN2019104957-appb-000072
实施例14制备得到的化合物核磁数据如下：The nuclear magnetic data of the compound prepared in Example 14 are as follows:
1H NMR(500MHz,Methanol-d 4)δ8.28(d,J＝7.2Hz,1H),8.04(t,J＝1.3Hz,1H),7.89(d,J＝8.4Hz,2H),7.71(d,J＝2.2Hz,1H),7.64(d,J＝8.2Hz,2H),7.50(dd,J＝8.3,2.3Hz,1H),7.44(dd,J＝7.1,1.8Hz,1H),7.17(d,J＝8.4Hz,1H),4.71(s,2H),4.33(s,2H),3.19(q,J＝7.4Hz,2H),2.46(s,3H),1.20(t,J＝7.4Hz,3H)。 1 H NMR (500 MHz, Methanol-d 4 ) δ 8.28 (d, J = 7.2 Hz, 1H), 8.04 (t, J = 1.3 Hz, 1H), 7.89 (d, J = 8.4 Hz, 2H), 7.71 (d, J = 2.2 Hz, 1H), 7.64 (d, J = 8.2 Hz, 2H), 7.50 (dd, J = 8.3, 2.3 Hz, 1H), 7.44 (dd, J = 7.1, 1.8 Hz, 1H) , 7.17 (d, J = 8.4 Hz, 1H), 4.71 (s, 2H), 4.33 (s, 2H), 3.19 (q, J = 7.4 Hz, 2H), 2.46 (s, 3H), 1.20 (t, J = 7.4 Hz, 3H).
实施例15制备得到的化合物核磁数据如下：The nuclear magnetic data of the compound prepared in Example 15 are as follows:
1H NMR(500MHz,Methanol-d 4)δ8.98(d,J＝2.2Hz,1H),8.33–8.20(m,2H),8.08(d,J＝1.0Hz,1H),7.72(d,J＝2.3Hz,1H),7.67(d,J＝8.3Hz,1H),7.50(dd,J＝8.5,2.2Hz,1H), 7.46(dd,J＝7.2,1.8Hz,1H),7.18(d,J＝8.4Hz,1H),4.82(s,2H),4.34(s,2H),3.28(q,J＝7.4Hz,2H),2.47(s,3H),1.25(t,J＝7.4Hz,3H)。 1 H NMR (500 MHz, Methanol-d 4 ) δ 8.98 (d, J = 2.2 Hz, 1H), 8.33 – 8.20 (m, 2H), 8.08 (d, J = 1.0 Hz, 1 H), 7.72 (d, J = 2.3 Hz, 1H), 7.67 (d, J = 8.3 Hz, 1H), 7.50 (dd, J = 8.5, 2.2 Hz, 1H), 7.46 (dd, J = 7.2, 1.8 Hz, 1H), 7.18 ( d, J = 8.4Hz, 1H), 4.82 (s, 2H), 4.34 (s, 2H), 3.28 (q, J = 7.4Hz, 2H), 2.47 (s, 3H), 1.25 (t, J = 7.4 Hz, 3H).
实施例16制备得到的化合物核磁数据如下：The nuclear magnetic data of the compound prepared in Example 16 are as follows:
1H NMR(500MHz,Methanol-d 4)δ8.28(d,J＝7.2Hz,1H),8.09(t,J＝1.3Hz,1H),7.95–7.81(m,2H),7.75–7.65(m,3H),7.52-7.42(m,2H),7.16(d,J＝8.3Hz,1H),5.29(t,J＝6.5Hz,1H),4.34(s,2H),3.92(d,J＝6.5Hz,2H),3.19(q,J＝7.4Hz,2H),2.46(s,3H),1.21(t,J＝7.4Hz,3H)。 1 H NMR (500 MHz, Methanol-d 4 ) δ 8.28 (d, J = 7.2 Hz, 1H), 8.09 (t, J = 1.3 Hz, 1H), 7.95–7.81 (m, 2H), 7.75–7.65 ( m, 3H), 7.52-7.42 (m, 2H), 7.16 (d, J = 8.3 Hz, 1H), 5.29 (t, J = 6.5 Hz, 1H), 4.34 (s, 2H), 3.92 (d, J = 6.5 Hz, 2H), 3.19 (q, J = 7.4 Hz, 2H), 2.46 (s, 3H), 1.21 (t, J = 7.4 Hz, 3H).
实施例17制备得到的化合物核磁数据如下：The nuclear magnetic data of the compound prepared in Example 17 are as follows:
1H NMR(500MHz,Methanol-d 4)δ8.25(d,J＝7.2Hz,1H),8.06(d,J＝1.0Hz,1H),7.89(d,J＝8.4Hz,2H),7.70(d,J＝8.4Hz,2H),7.41(dd,J＝7.2,1.8Hz,1H),7.36–7.18(m,4H),5.29(t,J＝6.5Hz,1H),4.21(s,2H),4.03–3.86(m,2H),3.19(q,J＝7.4Hz,2H),2.47(s,3H),1.20(t,J＝7.4Hz,3H)。 1 H NMR (500 MHz, Methanol-d 4 ) δ 8.25 (d, J = 7.2 Hz, 1H), 8.06 (d, J = 1.0 Hz, 1H), 7.89 (d, J = 8.4 Hz, 2H), 7.70 (d, J = 8.4 Hz, 2H), 7.41 (dd, J = 7.2, 1.8 Hz, 1H), 7.36–7.18 (m, 4H), 5.29 (t, J = 6.5 Hz, 1H), 4.21 (s, 2H), 4.03-3.86 (m, 2H), 3.19 (q, J = 7.4 Hz, 2H), 2.47 (s, 3H), 1.20 (t, J = 7.4 Hz, 3H).
实施例18制备得到的化合物核磁数据如下：The nuclear magnetic data of the compound prepared in Example 18 are as follows:
1H NMR(500MHz,Methanol-d 4)δ8.34(d,J＝7.6Hz,1H),8.11–8.06(m,1H),7.93–7.86(m,2H),7.76–7.66(m,2H),7.40(dd,J＝7.2,1.8Hz,1H),7.36–7.19(m,4H),5.29(t,J＝6.4Hz,1H),4.22(s,2H),3.92(d,J＝6.7Hz,2H),3.19(q,J＝7.4Hz,2H),2.98(q,J＝7.6Hz,2H),1.21(t,J＝7.4Hz,3H),1.13(t,J＝7.5Hz,3H)。 1 H NMR (500MHz, Methanol-d 4 ) δ 8.34 (d, J = 7.6 Hz, 1H), 8.11–8.06 (m, 1H), 7.93–7.86 (m, 2H), 7.76–7.66 (m, 2H ), 7.40 (dd, J = 7.2, 1.8 Hz, 1H), 7.36-7.19 (m, 4H), 5.29 (t, J = 6.4 Hz, 1H), 4.22 (s, 2H), 3.92 (d, J = 6.7Hz, 2H), 3.19 (q, J = 7.4Hz, 2H), 2.98 (q, J = 7.6Hz, 2H), 1.21 (t, J = 7.4Hz, 3H), 1.13 (t, J = 7.5Hz , 3H).
实施例19制备得到的化合物核磁数据如下：The nuclear magnetic data of the compound prepared in Example 19 are as follows:
1H NMR(500MHz,Methanol-d 4)δ8.48(d,J＝7.2Hz,1H),8.10(d,J＝1.8Hz,1H),7.90(d,J＝8.5Hz,2H),7.78–7.65(m,3H),7.48(dd,J＝8.5,2.2Hz,1H),7.41(dd,J＝7.3,1.9Hz,1H),6.99(d,J＝8.4Hz,1H),5.30(t,J＝6.5Hz,1H),4.40(s,2H),3.92(d,J＝6.7Hz,2H),3.50(p,J＝7.1Hz,1H),3.20(q,J＝7.4Hz,2H),1.38(d,J＝7.1Hz,6H),1.21(t,J＝7.4Hz,3H)。 1 H NMR (500 MHz, Methanol-d 4 ) δ 8.48 (d, J = 7.2 Hz, 1H), 8.10 (d, J = 1.8 Hz, 1H), 7.90 (d, J = 8.5 Hz, 2H), 7.78 –7.65 (m, 3H), 7.48 (dd, J = 8.5,2.2Hz, 1H), 7.41 (dd, J = 7.3,1.9Hz, 1H), 6.99 (d, J = 8.4Hz, 1H), 5.30 ( t, J = 6.5Hz, 1H), 4.40 (s, 2H), 3.92 (d, J = 6.7Hz, 2H), 3.50 (p, J = 7.1Hz, 1H), 3.20 (q, J = 7.4Hz, 2H), 1.38 (d, J = 7.1 Hz, 6H), 1.21 (t, J = 7.4 Hz, 3H).
实施例20制备得到的化合物核磁数据如下：The nuclear magnetic data of the compound prepared in Example 20 are as follows:
1H NMR(500MHz,Methanol-d 4)δ8.99(d,J＝2.4Hz,1H),8.50(d,J＝7.3Hz,1H),8.27(dd,J＝8.3,2.3Hz,1H),8.09(d,J＝2.1Hz,1H),7.73(d,J＝2.4Hz,1H),7.68(d,J＝8.3Hz,1H),7.49(dd,J＝8.4,2.3Hz,1H),7.43(dd,J＝7.3,1.9Hz,1H),7.00(d,J＝8.4Hz,1H),4.82(s,2H),4.40(s,2H),3.51-3.49(m,1H),3.30(q,J＝7.4Hz,2H),1.39(d,J＝7.2Hz,6H),1.25(t,J＝7.4Hz,3H)。 1 H NMR (500 MHz, Methanol-d 4 ) δ 8.99 (d, J = 2.4 Hz, 1H), 8.50 (d, J = 7.3 Hz, 1H), 8.27 (dd, J = 8.3, 2.3 Hz, 1H) , 8.09 (d, J = 2.1 Hz, 1H), 7.73 (d, J = 2.4 Hz, 1H), 7.68 (d, J = 8.3 Hz, 1H), 7.49 (dd, J = 8.4, 2.3 Hz, 1H) , 7.43 (dd, J = 7.3, 1.9 Hz, 1H), 7.00 (d, J = 8.4 Hz, 1H), 4.82 (s, 2H), 4.40 (s, 2H), 3.51-3.49 (m, 1H), 3.30 (q, J = 7.4 Hz, 2H), 1.39 (d, J = 7.2 Hz, 6H), 1.25 (t, J = 7.4 Hz, 3H).
实施例21制备得到的化合物核磁数据如下：The nuclear magnetic data of the compound prepared in Example 21 are as follows:
1H NMR(500MHz,Methanol-d 4)δ8.49(d,J＝7.3Hz,1H),8.05(d,J＝1.7Hz,1H),7.93–7.85(m,2H),7.73(d,J＝2.4Hz,1H),7.64(d,J＝8.0Hz,2H),7.48(dd,J＝8.4,2.3Hz,1H),7.42(dd,J＝7.3,1.9Hz,1H),6.99(d,J＝8.3Hz,1H),4.71(s,2H),4.40(s,2H),3.51(p,J＝7.1Hz,1H),3.20(q,J＝7.4Hz,2H),1.38(d,J＝7.1Hz,6H),1.20(t,J＝7.4Hz,3H)。 1 H NMR (500 MHz, Methanol-d 4 ) δ 8.49 (d, J = 7.3 Hz, 1H), 8.05 (d, J = 1.7 Hz, 1H), 7.93–7.85 (m, 2H), 7.73 (d, J = 2.4 Hz, 1H), 7.64 (d, J = 8.0 Hz, 2H), 7.48 (dd, J = 8.4, 2.3 Hz, 1H), 7.42 (dd, J = 7.3, 1.9 Hz, 1H), 6.99 ( d, J = 8.3Hz, 1H), 4.71 (s, 2H), 4.40 (s, 2H), 3.51 (p, J = 7.1Hz, 1H), 3.20 (q, J = 7.4Hz, 2H), 1.38 ( d, J = 7.1 Hz, 6H), 1.20 (t, J = 7.4 Hz, 3H).
实施例22制备得到的化合物核磁数据如下：The nuclear magnetic data of the compound prepared in Example 22 are as follows:
1H NMR(500MHz,Methanol-d 4)δ8.48(d,J＝7.3Hz,1H),8.14–8.04(m,1H),7.90(d,J＝8.3Hz,2H),7.71(d,J＝8.4Hz,2H),7.41(dd,J＝7.3,1.9Hz,1H),7.32(d,J＝4.4Hz,2H),7.28–7.19(m,1H),7.07(d,J＝7.7Hz,1H),5.30(t,J＝6.5Hz,1H),4.28(s,2H),3.92(d,J＝6.5Hz,2H),3.53(p,J＝7.2Hz,1H),3.19(q,J＝7.4Hz,2H),1.37(d,J＝7.2Hz,6H),1.21(t,J＝7.4Hz,3H)。 1 H NMR (500 MHz, Methanol-d 4 ) δ 8.48 (d, J = 7.3 Hz, 1H), 8.14–8.04 (m, 1H), 7.90 (d, J = 8.3 Hz, 2H), 7.71 (d, J = 8.4 Hz, 2H), 7.41 (dd, J = 7.3, 1.9 Hz, 1H), 7.32 (d, J = 4.4 Hz, 2H), 7.28–7.19 (m, 1H), 7.07 (d, J = 7.7 Hz, 1H), 5.30 (t, J = 6.5Hz, 1H), 4.28 (s, 2H), 3.92 (d, J = 6.5Hz, 2H), 3.53 (p, J = 7.2Hz, 1H), 3.19 ( q, J = 7.4 Hz, 2H), 1.37 (d, J = 7.2 Hz, 6H), 1.21 (t, J = 7.4 Hz, 3H).
实施例23制备得到的化合物核磁数据如下：The nuclear magnetic data of the compound prepared in Example 23 are as follows:
1H NMR(400MHz,Methanol-d 4)δ8.55(d,J＝7.2Hz,1H),8.08(d,J＝1.6Hz,1H),7.90(d,J＝8.1Hz,2H),7.78–7.64(m,3H),7.47(ddd,J＝7.0,5.3,1.9Hz,2H),7.05(d,J＝8.4Hz,1H),5.30(t,J＝6.4Hz,1H),4.41(s,2H),3.93(d,J＝6.4Hz,2H),3.19(q,J＝7.4Hz,2H),1.97–1.72(m,1H),1.21(t,J＝7.4Hz,3H),1.12(dd,J＝8.1,2.0Hz,2H),0.70–0.52(m,2H)。 1 H NMR (400 MHz, Methanol-d 4 ) δ 8.55 (d, J = 7.2 Hz, 1H), 8.08 (d, J = 1.6 Hz, 1H), 7.90 (d, J = 8.1 Hz, 2H), 7.78 –7.64 (m, 3H), 7.47 (ddd, J = 7.0,5.3,1.9Hz, 2H), 7.05 (d, J = 8.4Hz, 1H), 5.30 (t, J = 6.4Hz, 1H), 4.41 ( s, 2H), 3.93 (d, J = 6.4Hz, 2H), 3.19 (q, J = 7.4Hz, 2H), 1.97–1.72 (m, 1H), 1.21 (t, J = 7.4Hz, 3H), 1.12 (dd, J = 8.1, 2.0 Hz, 2H), 0.70-0.52 (m, 2H).
实施例24制备得到的化合物核磁数据如下：The nuclear magnetic data of the compound prepared in Example 24 are as follows:
1H NMR(400MHz,Methanol-d 4)δ8.57(d,J＝7.1Hz,1H),8.10(d,J＝1.6Hz,1H),7.92(d,J＝8.1Hz,2H),7.78–7.66(m,3H),7.49(td,J＝6.9,1.9Hz,2H),7.08(d,J＝8.4Hz,1H),5.32(t,J＝6.4Hz,1H),4.43(s,2H),3.95(d,J＝6.4Hz,2H),3.22(q,J＝7.4Hz,2H),1.96–1.82(m,1H),1.23(t,J＝7.4Hz,3H),1.15(dd,J＝8.1,2.1Hz,2H),0.64(dd,J＝5.3,1.7Hz,2H)。 1 H NMR (400 MHz, Methanol-d 4 ) δ 8.57 (d, J = 7.1 Hz, 1H), 8.10 (d, J = 1.6 Hz, 1H), 7.92 (d, J = 8.1 Hz, 2H), 7.78 –7.66 (m, 3H), 7.49 (td, J = 6.9,1.9Hz, 2H), 7.08 (d, J = 8.4Hz, 1H), 5.32 (t, J = 6.4Hz, 1H), 4.43 (s, 2H), 3.95 (d, J = 6.4Hz, 2H), 3.22 (q, J = 7.4Hz, 2H), 1.96-1.82 (m, 1H), 1.23 (t, J = 7.4Hz, 3H), 1.15 ( dd, J = 8.1, 2.1 Hz, 2H), 0.64 (dd, J = 5.3, 1.7 Hz, 2H).
实施例25制备得到的化合物核磁数据如下：The nuclear magnetic data of the compound prepared in Example 25 are as follows:
1H NMR(400MHz,Methanol-d 4)δ8.33(d,J＝7.2Hz,1H),8.08(d,J＝1.6Hz,1H),7.90(d,J＝8.1Hz,2H),7.79–7.65(m,3H),7.49(dd,J＝8.5,2.2Hz,1H),7.40(dd,J＝7.3,1.7Hz,1H),7.01(d,J＝8.4Hz,1H),5.30(t,J＝6.4Hz,1H),4.41(s,2H),4.12–3.85(m,3H),3.19(q,J＝7.4Hz,2H),2.55–2.30(m,4H),2.26–2.08(m,1H),1.99–1.84(m,1H),1.21(t,J＝7.4Hz,3H)。 1 H NMR (400 MHz, Methanol-d 4 ) δ 8.33 (d, J = 7.2 Hz, 1H), 8.08 (d, J = 1.6 Hz, 1H), 7.90 (d, J = 8.1 Hz, 2H), 7.79 –7.65 (m, 3H), 7.49 (dd, J = 8.5,2.2Hz, 1H), 7.40 (dd, J = 7.3,1.7Hz, 1H), 7.01 (d, J = 8.4Hz, 1H), 5.30 ( t, J = 6.4Hz, 1H), 4.41 (s, 2H), 4.12–3.85 (m, 3H), 3.19 (q, J = 7.4Hz, 2H), 2.55–2.30 (m, 4H), 2.26–2.08 (m, 1H), 1.99–1.84 (m, 1H), 1.21 (t, J = 7.4 Hz, 3H).
实施例26制备得到的化合物核磁数据如下：The nuclear magnetic data of the compound prepared in Example 26 are as follows:
1H NMR(400MHz,Methanol-d 4)δ8.40(d,J＝7.2Hz,1H),8.13(d,J＝1.6Hz,1H),7.92(d,J＝8.1Hz,2H),7.79–7.68(m,3H),7.53(dd,J＝8.5,2.2Hz,1H),7.49(dd,J＝7.2,1.7Hz,1H),5.32(t,J＝6.4Hz,1H),4.46(s,2H),4.10–3.88(m,3H),3.22(q,J＝7.4Hz,2H),2.58–2.34(m,4H),2.30–2.12(m,1H),2.04–1.88(m,1H),1.23(t,J＝7.4Hz,3H)。 1 H NMR (400 MHz, Methanol-d 4 ) δ 8.40 (d, J = 7.2 Hz, 1H), 8.13 (d, J = 1.6 Hz, 1H), 7.92 (d, J = 8.1 Hz, 2H), 7.79 –7.68 (m, 3H), 7.53 (dd, J = 8.5,2.2Hz, 1H), 7.49 (dd, J = 7.2,1.7Hz, 1H), 5.32 (t, J = 6.4Hz, 1H), 4.46 ( s, 2H), 4.10–3.88 (m, 3H), 3.22 (q, J = 7.4Hz, 2H), 2.58–2.34 (m, 4H), 2.30–2.12 (m, 1H), 2.04–1.88 (m, 1H), 1.23 (t, J = 7.4 Hz, 3H).
实施例27制备得到的化合物核磁数据如下：The nuclear magnetic data of the compound prepared in Example 27 are as follows:
1H NMR(500MHz,Chloroform-d)δ9.00(d,J＝2.2Hz,1H),8.34–8.23(m,2H),8.14(dd,J＝8.2,2.4Hz,1H),8.00(d,J＝7.2Hz,1H),7.69(d,J＝8.2Hz,1H),7.65(d,J＝2.2Hz,1H),7.45(dd,J＝7.2,1.7Hz,1H),7.39(dd,J＝8.3,2.2Hz,1H),5.46(dt,J＝7.9,4.3Hz,1H),4.30(s,2H),4.22(dd,J＝11.6,4.4Hz,1H),4.08(dd,J＝11.6,4.3Hz,1H),3.15(q,J＝7.4Hz,2H),2.91(q,J＝7.6Hz,2H),1.33(t,J＝7.4Hz,3H),1.18(t,J＝7.5Hz,3H)。 1 H NMR (500 MHz, Chloroform-d) δ 9.00 (d, J = 2.2 Hz, 1H), 8.34–8.23 (m, 2H), 8.14 (dd, J = 8.2, 2.4 Hz, 1H), 8.00 (d , J = 7.2Hz, 1H), 7.69 (d, J = 8.2Hz, 1H), 7.65 (d, J = 2.2Hz, 1H), 7.45 (dd, J = 7.2, 1.7Hz, 1H), 7.39 (dd , J = 8.3, 2.2 Hz, 1H), 5.46 (dt, J = 7.9, 4.3 Hz, 1H), 4.30 (s, 2H), 4.22 (dd, J = 11.6, 4.4 Hz, 1H), 4.08 (dd, J = 11.6, 4.3Hz, 1H), 3.15 (q, J = 7.4Hz, 2H), 2.91 (q, J = 7.6Hz, 2H), 1.33 (t, J = 7.4Hz, 3H), 1.18 (t, J = 7.5Hz, 3H).
实施例28制备得到的化合物核磁数据如下：The nuclear magnetic data of the compound prepared in Example 28 are as follows:
1H NMR(500MHz,CDCl 3)δ8.98(d,J＝2.2Hz,1H),8.43(d,J＝7.1Hz,1H),8.33(s,1H),8.17–8.10(m,2H),7.67(d,J＝8.2Hz,1H),7.62(d,J＝2.3Hz,1H),7.47(dd,J＝5.4,2.7Hz,1H),7.38–7.33(m,1H),7.03(d,J＝8.4Hz,1H),5.41(q,J＝4.9Hz,1H),4.34(s,2H),4.18(dd,J＝11.6,4.7Hz,1H),4.05(dd,J＝11.6,4.2Hz,1H),3.40(p,J＝7.2Hz,2H),3.13(q,J＝7.4Hz,2H),1.39(dd,J＝7.2,2.3Hz,6H),1.30(t,J＝7.4Hz,3H)。 1 H NMR (500 MHz, CDCl 3 ) δ 8.98 (d, J = 2.2 Hz, 1H), 8.43 (d, J = 7.1 Hz, 1H), 8.33 (s, 1H), 8.17–8.10 (m, 2H) , 7.67 (d, J = 8.2 Hz, 1H), 7.62 (d, J = 2.3 Hz, 1H), 7.47 (dd, J = 5.4, 2.7 Hz, 1H), 7.38–7.33 (m, 1H), 7.03 ( d, J = 8.4Hz, 1H), 5.41 (q, J = 4.9Hz, 1H), 4.34 (s, 2H), 4.18 (dd, J = 11.6, 4.7Hz, 1H), 4.05 (dd, J = 11.6 , 4.2Hz, 1H), 3.40 (p, J = 7.2Hz, 2H), 3.13 (q, J = 7.4Hz, 2H), 1.39 (dd, J = 7.2, 2.3Hz, 6H), 1.30 (t, J = 7.4 Hz, 3H).
实施例29制备得到的化合物核磁数据如下：The nuclear magnetic data of the compound prepared in Example 29 are as follows:
1H NMR(500MHz,CDCl 3)δ8.92(d,J＝2.2Hz,1H),8.52(d,J＝7.1Hz,1H),8.38(s,1H),8.04(dd,J＝8.2,2.4Hz,1H),7.94(d,J＝7.2Hz,1H),7.66(d,J＝8.1Hz,1H),7.62(d,J＝2.3Hz,1H),7.52(dd,J＝7.1,1.7Hz,1H),7.42–7.37(m,1H),7.28(s,1H),5.43(dt,J＝7.3,4.3Hz,1H),4.27(d,J＝5.9Hz,2H),4.22(dd,J＝11.7,4.6Hz,1H),4.09(dd,J＝11.7,4.2Hz,1H),3.77(s,1H),3.11(q,J＝7.4Hz,2H),2.42(s,3H),1.29(t,J＝7.4Hz,3H)。 1 H NMR (500 MHz, CDCl 3 ) δ 8.92 (d, J = 2.2 Hz, 1H), 8.52 (d, J = 7.1 Hz, 1H), 8.38 (s, 1H), 8.04 (dd, J = 8.2, 2.4 Hz, 1H), 7.94 (d, J = 7.2 Hz, 1H), 7.66 (d, J = 8.1 Hz, 1H), 7.62 (d, J = 2.3 Hz, 1H), 7.52 (dd, J = 7.1, 1.7Hz, 1H), 7.42-7.37 (m, 1H), 7.28 (s, 1H), 5.43 (dt, J = 7.3, 4.3Hz, 1H), 4.27 (d, J = 5.9Hz, 2H), 4.22 ( dd, J = 11.7, 4.6Hz, 1H), 4.09 (dd, J = 11.7, 4.2Hz, 1H), 3.77 (s, 1H), 3.11 (q, J = 7.4Hz, 2H), 2.42 (s, 3H ), 1.29 (t, J = 7.4 Hz, 3H).
实施例30制备得到的化合物核磁数据如下：The nuclear magnetic data of the compound prepared in Example 30 are as follows:
1H NMR(500MHz,CDCl 3)δ8.94(s,1H),8.81(s,1H),8.08(d,J＝7.1Hz,1H),8.03(d,J＝8.6Hz,1H),7.74(d,J＝8.2Hz,1H),7.67(d,J＝7.2Hz,1H),6.23(s,1H),5.46(s,1H),4.29(dd,J＝11.9,4.6Hz,1H),4.27–4.20(m,1H),3.14–3.05(m,4H),2.46(s,2H),1.39(d,J＝1.1Hz,6H),1.35(s,6H),1.34–1.26(m,6H)。 1 H NMR (500 MHz, CDCl 3 ) δ 8.94 (s, 1H), 8.81 (s, 1H), 8.08 (d, J = 7.1 Hz, 1H), 8.03 (d, J = 8.6 Hz, 1H), 7.74 (d, J = 8.2Hz, 1H), 7.67 (d, J = 7.2Hz, 1H), 6.23 (s, 1H), 5.46 (s, 1H), 4.29 (dd, J = 11.9, 4.6Hz, 1H) , 4.27–4.20 (m, 1H), 3.14–3.05 (m, 4H), 2.46 (s, 2H), 1.39 (d, J = 1.1 Hz, 6H), 1.35 (s, 6H), 1.34–1.26 (m , 6H).
实施例31制备得到的化合物核磁数据如下：The nuclear magnetic data of the compound prepared in Example 31 are as follows:
1H NMR(500MHz,DMSO-d 6)δ9.09(d,J＝7.6Hz,1H),9.00(d,J＝2.4Hz,1H),8.55(d,J＝7.2Hz,1H),8.33(t,J＝1.3Hz,1H),8.27(dd,J＝8.3,2.4Hz,1H),7.79–7.72(m,2H),7.70–7.67(m,1H),7.52(t,J＝8.4Hz,1H),7.43(dd,J＝7.2,1.8Hz,1H),7.33(t,1H),5.25(d,J＝5.9Hz,1H),5.12(s,1H),3.89(dd,J＝11.5,6.7Hz,2H),3.41(q,J＝7.3Hz,2H),3.20(q,J＝7.4Hz,2H),1.27(t,J＝7.5Hz,3H),1.14(t,J＝7.3Hz,3H)。 1 H NMR (500 MHz, DMSO-d 6 ) δ 9.09 (d, J = 7.6 Hz, 1H), 9.00 (d, J = 2.4 Hz, 1H), 8.55 (d, J = 7.2 Hz, 1H), 8.33 (t, J = 1.3 Hz, 1H), 8.27 (dd, J = 8.3, 2.4 Hz, 1H), 7.79–7.72 (m, 2H), 7.70–7.67 (m, 1H), 7.52 (t, J = 8.4 Hz, 1H), 7.43 (dd, J = 7.2, 1.8 Hz, 1H), 7.33 (t, 1H), 5.25 (d, J = 5.9Hz, 1H), 5.12 (s, 1H), 3.89 (dd, J = 11.5, 6.7Hz, 2H), 3.41 (q, J = 7.3Hz, 2H), 3.20 (q, J = 7.4Hz, 2H), 1.27 (t, J = 7.5Hz, 3H), 1.14 (t, J = 7.3 Hz, 3H).
实施例32制备得到的化合物核磁数据如下：The nuclear magnetic data of the compound prepared in Example 32 are as follows:
1H NMR(500MHz,CDCl 3)δ8.87(s,1H),8.83(s,1H),8.13(d,J＝7.0Hz,1H),8.02(s,1H),7.77(s,1H),7.70(d,J＝7.0Hz,1H),7.55(d,J＝10.4Hz,1H),7.51(d,J＝8.7Hz,1H),7.48–7.43(m,1H),5.47(s,1H),4.28(dd,J＝12.0,4.4Hz,1H),4.20(dd,J＝11.9,3.6Hz,1H),3.14(d,J＝7.6Hz,2H),3.10(d,J＝7.3Hz,2H),1.39(t,J＝7.5Hz,3H),1.28(t,J＝7.3Hz,3H)。 1 H NMR (500 MHz, CDCl 3 ) δ 8.87 (s, 1H), 8.83 (s, 1H), 8.13 (d, J = 7.0 Hz, 1H), 8.02 (s, 1H), 7.77 (s, 1H) , 7.70 (d, J = 7.0 Hz, 1H), 7.55 (d, J = 10.4 Hz, 1H), 7.51 (d, J = 8.7 Hz, 1H), 7.48–7.43 (m, 1H), 5.47 (s, 1H), 4.28 (dd, J = 12.0, 4.4 Hz, 1H), 4.20 (dd, J = 11.9, 3.6 Hz, 1H), 3.14 (d, J = 7.6 Hz, 2H), 3.10 (d, J = 7.3 Hz, 2H), 1.39 (t, J = 7.5 Hz, 3H), 1.28 (t, J = 7.3 Hz, 3H).
实施例33制备得到的化合物核磁数据如下：The nuclear magnetic data of the compound prepared in Example 33 are as follows:
1H NMR(500MHz,DMSO-d 6)δ9.10(d,J＝7.5Hz,1H),9.00(d,J＝2.4Hz,1H),8.52(d,J＝7.2Hz,1H),8.30(t,J＝1.3Hz,1H),8.27(dd,J＝8.3,2.4Hz,1H),7.74(d,J＝8.2Hz,1H),7.60(dd,J＝12.7,2.1Hz,1H),7.56(dd,J＝8.4,1.2Hz,1H),7.41(dd,J＝7.2,1.8Hz,1H),7.32(t,J＝8.8Hz,1H),5.25(q,J＝6.8Hz,1H),4.71(p,J＝6.1Hz,1H),3.95–3.84(m,2H),3.42(t,J＝7.3Hz,2H),3.18(q,J＝7.4Hz,2H),1.34(d,J＝6.0Hz,6H),1.28(t,J＝7.5Hz,3H),1.14(t,J＝7.4Hz,3H)。 1 H NMR (500 MHz, DMSO-d 6 ) δ 9.10 (d, J = 7.5 Hz, 1H), 9.00 (d, J = 2.4 Hz, 1H), 8.52 (d, J = 7.2 Hz, 1H), 8.30 (t, J = 1.3 Hz, 1H), 8.27 (dd, J = 8.3, 2.4 Hz, 1H), 7.74 (d, J = 8.2 Hz, 1H), 7.60 (dd, J = 12.7, 2.1 Hz, 1H) , 7.56 (dd, J = 8.4, 1.2 Hz, 1H), 7.41 (dd, J = 7.2, 1.8 Hz, 1H), 7.32 (t, J = 8.8 Hz, 1H), 5.25 (q, J = 6.8 Hz, 1H), 4.71 (p, J = 6.1Hz, 1H), 3.95–3.84 (m, 2H), 3.42 (t, J = 7.3Hz, 2H), 3.18 (q, J = 7.4Hz, 2H), 1.34 ( d, J = 6.0 Hz, 6H), 1.28 (t, J = 7.5 Hz, 3H), 1.14 (t, J = 7.4 Hz, 3H).
实施例34制备得到的化合物核磁数据如下：The nuclear magnetic data of the compound prepared in Example 34 are as follows:
1H NMR(500MHz,DMSO-d 6)δ9.09(d,J＝7.8Hz,1H),8.56(d,J＝7.2Hz,1H),8.32(t,J＝1.3Hz,1H),7.89–7.83(m,3H),7.76(dd,J＝8.6,2.0Hz,1H),7.74–7.68(m,3H),7.42(dd,J＝7.1,1.8Hz,1H),5.21–5.16(m,1H),5.15(s,1H),3.79(t,J＝9.4Hz,1H),3.73(d,J＝8.3Hz,1H),3.27(t,J＝7.3Hz,2H),3.21(q,J＝7.4Hz,2H),1.28(t,J＝7.5Hz,3H),1.10(t,J＝7.3Hz,3H)。 1 H NMR (500 MHz, DMSO-d 6 ) δ 9.09 (d, J = 7.8 Hz, 1H), 8.56 (d, J = 7.2 Hz, 1H), 8.32 (t, J = 1.3 Hz, 1H), 7.89 –7.83 (m, 3H), 7.76 (dd, J = 8.6,2.0Hz, 1H), 7.74–7.68 (m, 3H), 7.42 (dd, J = 7.1,1.8Hz, 1H), 5.21–5.16 (m , 1H), 5.15 (s, 1H), 3.79 (t, J = 9.4Hz, 1H), 3.73 (d, J = 8.3Hz, 1H), 3.27 (t, J = 7.3Hz, 2H), 3.21 (q , J = 7.4 Hz, 2H), 1.28 (t, J = 7.5 Hz, 3H), 1.10 (t, J = 7.3 Hz, 3H).
实施例35制备得到的化合物核磁数据如下：The nuclear magnetic data of the compound prepared in Example 35 are as follows:
1H NMR(500MHz,DMSO-d 6)δ9.05(d,J＝7.8Hz,1H),8.51(d,J＝7.2Hz,1H),8.29(s,1H),7.86(d,J＝8.1Hz,2H),7.70(d,J＝8.1Hz,2H),7.60(dd,J＝12.6,2.1Hz,1H),7.58–7.54(m,1H),7.39(dd,J＝7.2,1.7Hz,1H),7.31(t,J＝8.8Hz,1H),5.18(q,J＝7.2Hz,1H),5.14(s,1H),4.71(p,J＝6.1Hz,1H),3.79(s,1H),3.75–3.69(m,1H),3.28(q,J＝7.3Hz,2H),3.17(q,J＝7.4Hz,2H),1.33(d,J＝6.0Hz,6H),1.27(t,J＝7.5Hz,3H),1.10(t,J＝7.3Hz,3H)。 1 H NMR (500 MHz, DMSO-d 6 ) δ 9.05 (d, J = 7.8 Hz, 1H), 8.51 (d, J = 7.2 Hz, 1H), 8.29 (s, 1H), 7.86 (d, J = 8.1Hz, 2H), 7.70 (d, J = 8.1 Hz, 2H), 7.60 (dd, J = 12.6, 2.1 Hz, 1H), 7.58–7.54 (m, 1H), 7.39 (dd, J = 7.2, 1.7 Hz, 1H), 7.31 (t, J = 8.8Hz, 1H), 5.18 (q, J = 7.2Hz, 1H), 5.14 (s, 1H), 4.71 (p, J = 6.1Hz, 1H), 3.79 ( s, 1H), 3.75-3.69 (m, 1H), 3.28 (q, J = 7.3Hz, 2H), 3.17 (q, J = 7.4Hz, 2H), 1.33 (d, J = 6.0Hz, 6H), 1.27 (t, J = 7.5 Hz, 3H), 1.10 (t, J = 7.3 Hz, 3H).
实施例36制备得到的化合物核磁数据如下：The nuclear magnetic data of the compound prepared in Example 36 are as follows:
1H NMR(500MHz,CDCl 3)δ8.36(s,1H),7.98(d,J＝7.2Hz,1H),7.72(d,J＝8.0Hz,2H),7.57(d,J＝8.1Hz,2H),7.43(d,J＝7.1Hz,1H),6.10(d,J＝1.6Hz,1H),5.46–5.28(m,1H), 4.24–4.03(m,2H),3.05(p,J＝7.3Hz,4H),2.45(s,2H),1.38(s,6H),1.34(s,6H),1.29(t,J＝7.5Hz,3H),1.25(t,J＝7.4Hz,3H)。 1 H NMR (500 MHz, CDCl 3 ) δ 8.36 (s, 1H), 7.98 (d, J = 7.2 Hz, 1H), 7.72 (d, J = 8.0 Hz, 2H), 7.57 (d, J = 8.1 Hz , 2H), 7.43 (d, J = 7.1Hz, 1H), 6.10 (d, J = 1.6Hz, 1H), 5.46-5.28 (m, 1H), 4.24-4.03 (m, 2H), 3.05 (p, J = 7.3Hz, 4H), 2.45 (s, 2H), 1.38 (s, 6H), 1.34 (s, 6H), 1.29 (t, J = 7.5Hz, 3H), 1.25 (t, J = 7.4Hz, 3H).
实施例37制备得到的化合物核磁数据如下：The nuclear magnetic data of the compound prepared in Example 37 are as follows:
1H NMR(500MHz,CDCl 3)δ8.53(s,1H),8.37(s,1H),8.03(d,J＝7.2Hz,1H),7.67(d,J＝8.2Hz,2H),7.60–7.50(m,4H),7.49–7.42(m,1H),7.35(t,J＝8.1Hz,1H),6.64(t,J＝73.2Hz,1H),5.33(s,1H),4.18–3.99(m,2H),3.12(q,J＝7.6Hz,2H),3.03(q,J＝7.4Hz,2H),1.33(t,J＝7.5Hz,3H),1.24(t,J＝7.4Hz,3H)。 1 H NMR (500 MHz, CDCl 3 ) δ 8.53 (s, 1H), 8.37 (s, 1H), 8.03 (d, J = 7.2 Hz, 1H), 7.67 (d, J = 8.2 Hz, 2H), 7.60 –7.50 (m, 4H), 7.49–7.42 (m, 1H), 7.35 (t, J = 8.1Hz, 1H), 6.64 (t, J = 73.2Hz, 1H), 5.33 (s, 1H), 4.18– 3.99 (m, 2H), 3.12 (q, J = 7.6Hz, 2H), 3.03 (q, J = 7.4Hz, 2H), 1.33 (t, J = 7.5Hz, 3H), 1.24 (t, J = 7.4 Hz, 3H).
实施例38制备得到的化合物核磁数据如下：The nuclear magnetic data of the compound prepared in Example 38 are as follows:
1H NMR(500MHz,CDCl 3)δ8.24(s,1H),8.05(d,J＝7.2Hz,1H),7.91(d,J＝8.4Hz,2H),7.75(d,J＝6.4Hz,1H),7.69(d,J＝8.4Hz,2H),7.64(dd,J＝11.3,2.0Hz,1H),7.57(dt,J＝8.5,1.5Hz,1H),7.42(dd,J＝7.2,1.7Hz,1H),7.37(t,J＝8.2Hz,1H),6.62(t,J＝73.3Hz,1H),5.83(d,J＝6.3Hz,1H),4.31(dq,J＝10.7,7.1Hz,1H),4.23(dq,J＝10.8,7.1Hz,1H),3.18–3.13(q,J＝7.4Hz,2H),3.13–3.09(q,J＝7.1Hz,2H),1.39(t,J＝7.6Hz,3H),1.29(t,J＝7.4Hz,3H),1.26(t,J＝7.1Hz,3H)。 1 H NMR (500 MHz, CDCl 3 ) δ 8.24 (s, 1H), 8.05 (d, J = 7.2 Hz, 1H), 7.91 (d, J = 8.4 Hz, 2H), 7.75 (d, J = 6.4 Hz , 1H), 7.69 (d, J = 8.4 Hz, 2H), 7.64 (dd, J = 11.3, 2.0 Hz, 1H), 7.57 (dt, J = 8.5, 1.5 Hz, 1H), 7.42 (dd, J = 7.2, 1.7 Hz, 1H), 7.37 (t, J = 8.2 Hz, 1H), 6.62 (t, J = 73.3 Hz, 1H), 5.83 (d, J = 6.3 Hz, 1H), 4.31 (dq, J = 10.7, 7.1Hz, 1H), 4.23 (dq, J = 10.8, 7.1Hz, 1H), 3.18–3.13 (q, J = 7.4Hz, 2H), 3.13–3.09 (q, J = 7.1Hz, 2H), 1.39 (t, J = 7.6 Hz, 3H), 1.29 (t, J = 7.4 Hz, 3H), 1.26 (t, J = 7.1 Hz, 3H).
实施例39制备得到的化合物核磁数据如下：The nuclear magnetic data of the compound prepared in Example 39 are as follows:
1H NMR(500MHz,CDCl 3)δ9.02(d,J＝2.2Hz,1H),8.20(s,1H),8.17(dd,J＝8.2,2.3Hz,1H),8.01(d,J＝7.2Hz,1H),7.93(s,1H),7.64(d,J＝2.3Hz,1H),7.56(d,J＝8.2Hz,1H),7.46(d,J＝7.1Hz,1H),7.37(dd,J＝8.4,2.3Hz,1H),7.23(d,J＝8.4Hz,1H),4.89(d,J＝4.9Hz,2H),4.31(s,2H),3.17(q,J＝7.5Hz,2H),2.90(q,J＝7.6Hz,2H),1.32(t,J＝7.4Hz,3H),1.17(t,J＝7.5Hz,3H)。 1 H NMR (500 MHz, CDCl 3 ) δ 9.02 (d, J = 2.2 Hz, 1H), 8.20 (s, 1H), 8.17 (dd, J = 8.2, 2.3 Hz, 1H), 8.01 (d, J = 7.2Hz, 1H), 7.93 (s, 1H), 7.64 (d, J = 2.3Hz, 1H), 7.56 (d, J = 8.2Hz, 1H), 7.46 (d, J = 7.1Hz, 1H), 7.37 (dd, J = 8.4, 2.3 Hz, 1H), 7.23 (d, J = 8.4 Hz, 1H), 4.89 (d, J = 4.9 Hz, 2H), 4.31 (s, 2H), 3.17 (q, J = 7.5 Hz, 2H), 2.90 (q, J = 7.6 Hz, 2H), 1.32 (t, J = 7.4 Hz, 3H), 1.17 (t, J = 7.5 Hz, 3H).
实施例40制备得到的化合物核磁数据如下：The nuclear magnetic data of the compound prepared in Example 40 are as follows:
1H NMR(500MHz,CDCl 3)δ8.97-8.90(m,1H),8.83-8.85(m,1H),8.13(s,1H),7.69(s,2H),7.59(s,2H),7.52(s,1H),7.44(s,1H),7.35(d,J＝9.2Hz,1H),5.33(s,1H),4.11(d,J＝19.3Hz,2H),3.59(s,3H),3.40(s,3H),3.15(s,2H),3.03(s,2H),1.37(s,3H),1.24(d,J＝7.9Hz,3H)。 1 H NMR (500 MHz, CDCl 3 ) δ 8.97-8.90 (m, 1H), 8.83-8.85 (m, 1H), 8.13 (s, 1H), 7.69 (s, 2H), 7.59 (s, 2H), 7.52 (s, 1H), 7.44 (s, 1H), 7.35 (d, J = 9.2 Hz, 1H), 5.33 (s, 1H), 4.11 (d, J = 19.3 Hz, 2H), 3.59 (s, 3H ), 3.40 (s, 3H), 3.15 (s, 2H), 3.03 (s, 2H), 1.37 (s, 3H), 1.24 (d, J = 7.9 Hz, 3H).
实施例41制备得到的化合物核磁数据如下：The nuclear magnetic data of the compound prepared in Example 41 are as follows:
1H NMR(500MHz,CDCl 3)δ8.41(s,1H),8.20(d,J＝7.5Hz,1H),8.01(d,J＝7.2Hz,1H),7.91(t,J＝7.8Hz,1H),7.53(d,J＝8.0Hz,1H),7.49–7.41(m,4H),7.37(d,J＝8.1Hz,2H),5.32(dt,J＝7.3,3.7Hz,1H),4.14(dd,J＝11.9,3.5Hz,1H),4.03(dd,J＝11.9,3.9Hz,1H),3.48(p,J＝6.9Hz,1H),3.14(dp,J＝24.0,7.9Hz,3H),2.96(q,J＝7.5Hz,2H),1.29(t,J＝7.5Hz,3H),1.26(d,J＝6.9Hz,6H),1.18(t,J＝7.4Hz,3H)。 1 H NMR (500 MHz, CDCl 3 ) δ 8.41 (s, 1H), 8.20 (d, J = 7.5 Hz, 1H), 8.01 (d, J = 7.2 Hz, 1H), 7.91 (t, J = 7.8 Hz , 1H), 7.53 (d, J = 8.0Hz, 1H), 7.49-7.41 (m, 4H), 7.37 (d, J = 8.1Hz, 2H), 5.32 (dt, J = 7.3, 3.7Hz, 1H) , 4.14 (dd, J = 11.9, 3.5 Hz, 1H), 4.03 (dd, J = 11.9, 3.9 Hz, 1H), 3.48 (p, J = 6.9 Hz, 1H), 3.14 (dp, J = 24.0, 7.9 Hz, 3H), 2.96 (q, J = 7.5Hz, 2H), 1.29 (t, J = 7.5Hz, 3H), 1.26 (d, J = 6.9Hz, 6H), 1.18 (t, J = 7.4Hz, 3H).
实施例42制备得到的化合物核磁数据如下：The nuclear magnetic data of the compound prepared in Example 42 are as follows:
1H NMR(500MHz,CDCl 3)δ8.89(d,J＝2.4Hz,1H),8.43(d,J＝8.6Hz,2H),8.05–7.96(m,2H),7.63(d,J＝8.2Hz,1H),7.48(dd,J＝7.1,1.6Hz,1H),7.40(dd,J＝7.9,1.7Hz,1H),7.36(d,J＝1.7Hz,1H),7.26(s,1H),5.46(dt,J＝7.9,4.0Hz,1H),4.28(dd,J＝11.7,4.1Hz,1H),4.13(dd,J＝11.6,4.1Hz,1H),3.15–3.11(m,2H),3.08(q,J＝7.4Hz,2H),3.04(d,J＝4.7Hz,1H),2.57(d,J＝7.1Hz,2H),1.95(dq,J＝13.6,6.7Hz,1H),1.35(t,J＝7.5Hz,3H),1.28(t,J＝7.5Hz,3H),0.96(d,J＝6.6Hz,6H)。 1 H NMR (500 MHz, CDCl 3 ) δ 8.89 (d, J = 2.4 Hz, 1H), 8.43 (d, J = 8.6 Hz, 2H), 8.05–7.96 (m, 2H), 7.63 (d, J = 8.2Hz, 1H), 7.48 (dd, J = 7.1, 1.6Hz, 1H), 7.40 (dd, J = 7.9, 1.7Hz, 1H), 7.36 (d, J = 1.7Hz, 1H), 7.26 (s, 1H), 5.46 (dt, J = 7.9, 4.0 Hz, 1H), 4.28 (dd, J = 11.7, 4.1 Hz, 1H), 4.13 (dd, J = 11.6, 4.1 Hz, 1H), 3.15–3.11 (m , 2H), 3.08 (q, J = 7.4Hz, 2H), 3.04 (d, J = 4.7Hz, 1H), 2.57 (d, J = 7.1Hz, 2H), 1.95 (dq, J = 13.6, 6.7Hz , 1H), 1.35 (t, J = 7.5 Hz, 3H), 1.28 (t, J = 7.5 Hz, 3H), 0.96 (d, J = 6.6 Hz, 6H).
实施例43制备得到的化合物核磁数据如下：The nuclear magnetic data of the compound prepared in Example 43 are as follows:
1H NMR(500MHz,CDCl 3)δ8.62(s,1H),8.49(s,1H),8.02(d,J＝7.1Hz,1H),7.58(d,J＝8.2Hz,2H),7.53(d,J＝7.1Hz,1H),7.47(d,J＝8.2Hz,2H),7.31(d,J＝7.3Hz,1H),7.25–7.19(m,2H),5.30(s,1H),4.12(dd,J＝11.8,3.6Hz,1H),4.04(dd,J＝11.9,5.0Hz,1H),3.11(dt,J＝18.4,8.0Hz,2H),2.99(q,J＝7.4Hz,2H),2.97(s,1H),2.58(d,J＝7.3Hz,2H),1.96(dt,J＝13.7,6.7Hz,1H),1.31(t,J＝7.6Hz,3H),1.21(t,J＝7.4Hz,3H),0.97(d,J＝6.6Hz,6H)。 1 H NMR (500 MHz, CDCl 3 ) δ 8.62 (s, 1H), 8.49 (s, 1H), 8.02 (d, J = 7.1 Hz, 1H), 7.58 (d, J = 8.2 Hz, 2H), 7.53 (d, J = 7.1 Hz, 1H), 7.47 (d, J = 8.2 Hz, 2H), 7.31 (d, J = 7.3 Hz, 1H), 7.25–7.19 (m, 2H), 5.30 (s, 1H) , 4.12 (dd, J = 11.8, 3.6 Hz, 1H), 4.04 (dd, J = 11.9, 5.0 Hz, 1H), 3.11 (dt, J = 18.4, 8.0 Hz, 2H), 2.99 (q, J = 7.4 Hz, 2H), 2.97 (s, 1H), 2.58 (d, J = 7.3Hz, 2H), 1.96 (dt, J = 13.7, 6.7Hz, 1H), 1.31 (t, J = 7.6Hz, 3H), 1.21 (t, J = 7.4 Hz, 3H), 0.97 (d, J = 6.6 Hz, 6H).
实施例44制备得到的化合物核磁数据如下：The nuclear magnetic data of the compound prepared in Example 44 are as follows:
1H NMR(400MHz,DMSO-d 6)δ8.87(d,J＝7.6Hz,1H),8.41(d,J＝7.2Hz,1H),8.20(d,J＝2.0Hz,1H),8.13(t,J＝7.6Hz,1H),7.85-7.81(m,2H),7.72(t,J＝7.6Hz,1H),7.68-7.64(m,3H),7.48(t,J＝7.6Hz,1H),7.30(d,J＝7.2Hz,1H),6.27(d,J＝4.8Hz,1H),6.09(q,J＝5.2Hz,1H),5.14-5.11(m,1H),5.07-5.03(m,1H),3.74-3.65(m,2H),3.29-3.23(m,2H),3.12-3.06(m,2H),1.19-1.16(m,3H),1.11-1.07(m,3H)。 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.87 (d, J = 7.6 Hz, 1H), 8.41 (d, J = 7.2 Hz, 1H), 8.20 (d, J = 2.0 Hz, 1H), 8.13 (t, J = 7.6Hz, 1H), 7.85-7.81 (m, 2H), 7.72 (t, J = 7.6Hz, 1H), 7.68-7.64 (m, 3H), 7.48 (t, J = 7.6Hz, 1H), 7.30 (d, J = 7.2Hz, 1H), 6.27 (d, J = 4.8Hz, 1H), 6.09 (q, J = 5.2Hz, 1H), 5.14-5.11 (m, 1H), 5.07- 5.03 (m, 1H), 3.74-3.65 (m, 2H), 3.29-3.23 (m, 2H), 3.12-3.06 (m, 2H), 1.19-1.16 (m, 3H), 1.11-1.07 (m, 3H) ).
实施例45制备得到的化合物核磁数据如下：The nuclear magnetic data of the compound prepared in Example 45 are as follows:
1H NMR(400MHz,CDCl 3)δ9.01(d,J＝2.0Hz,1H),8.96-8.95(m,1H),8.16(dd,J＝8.0,2.0Hz,1H),8.10(brs,1H),8.01(d,J＝8.0Hz,1H),7.98(d,J＝6.8Hz,1H),7.71(brs,1H),7.53–7.51(m,1H),7.48–7.44(m,1H),7.39(dd,J＝7.2,2.0Hz,1H),6.42(s,1H),4.86-4.84(m,2H),3.16(q,J＝7.6Hz,2H),3.08(d,J＝7.6Hz,2H),1.37-1.23(m,6H)。 1 H NMR (400 MHz, CDCl 3 ) δ 9.01 (d, J = 2.0 Hz, 1H), 8.96-8.95 (m, 1H), 8.16 (dd, J = 8.0, 2.0 Hz, 1H), 8.10 (brs, 1H), 8.01 (d, J = 8.0Hz, 1H), 7.98 (d, J = 6.8Hz, 1H), 7.71 (brs, 1H), 7.53–7.51 (m, 1H), 7.48–7.44 (m, 1H) ), 7.39 (dd, J = 7.2, 2.0 Hz, 1H), 6.42 (s, 1H), 4.86-4.84 (m, 2H), 3.16 (q, J = 7.6 Hz, 2H), 3.08 (d, J = 7.6Hz, 2H), 1.37-1.23 (m, 6H).
实施例46制备得到的化合物核磁数据如下：The nuclear magnetic data of the compound prepared in Example 46 are as follows:
1H NMR(400MHz,DMSO-d 6)δ8.87-8.54(m,2H),8.41(d,J＝6.8Hz,1H),8.20-8.18(m,1H),8.15(s,1H),7.83(d,J＝7.6Hz,2H),7.66-7.64(m,2H),7.59–7.56(m,1H),7.32–7.29(m,1H),6.31(s,1H),6.09-6.07(m,1H),5.15-5.03(m,2H),3.76-3.65(m,2H),3.29-3.16(m,4H),1.20(t,J＝7.6Hz,3H),1.09(t,J＝7.2Hz,3H)。 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.87-8.54 (m, 2H), 8.41 (d, J = 6.8 Hz, 1H), 8.20-8.18 (m, 1H), 8.15 (s, 1H), 7.83 (d, J = 7.6 Hz, 2H), 7.66-7.64 (m, 2H), 7.59–7.56 (m, 1H), 7.32–7.29 (m, 1H), 6.31 (s, 1H), 6.09-6.07 ( m, 1H), 5.15-5.03 (m, 2H), 3.76-3.65 (m, 2H), 3.29-3.16 (m, 4H), 1.20 (t, J = 7.6Hz, 3H), 1.09 (t, J = 7.2Hz, 3H).
实施例47制备得到的化合物核磁数据如下：The nuclear magnetic data of the compound prepared in Example 47 are as follows:
1H NMR(400MHz,DMSO-d 6)δ9.37(t,J＝6.0Hz,1H),8.96(d,J＝2.0Hz,1H),8.90(d,J＝4.4Hz,1H),8.53(d,J＝7.2Hz,1H),8.31(d,J＝7.6Hz,1H),8.24(dd,J＝8.0,2.0Hz,1H),8.12(s,1H),7.70–7.67(m,1H),7.62(d,J＝8.4Hz,1H),7.41(dd,J＝7.2,1.6Hz,1H),7.21(d,J＝46.8Hz,1H),4.69(d,J＝6.0Hz,2H),3.38(q,J＝7.2Hz,2H),3.17(q,J＝7.2Hz,2H),1.20(t,J＝7.2Hz,3H),1.12(t,J＝7.2Hz,3H)。 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.37 (t, J = 6.0 Hz, 1H), 8.96 (d, J = 2.0 Hz, 1H), 8.90 (d, J = 4.4 Hz, 1H), 8.53 (d, J = 7.2Hz, 1H), 8.31 (d, J = 7.6Hz, 1H), 8.24 (dd, J = 8.0, 2.0Hz, 1H), 8.12 (s, 1H), 7.70-7.67 (m, 1H), 7.62 (d, J = 8.4 Hz, 1H), 7.41 (dd, J = 7.2, 1.6 Hz, 1H), 7.21 (d, J = 46.8 Hz, 1H), 4.69 (d, J = 6.0 Hz, 2H), 3.38 (q, J = 7.2Hz, 2H), 3.17 (q, J = 7.2Hz, 2H), 1.20 (t, J = 7.2Hz, 3H), 1.12 (t, J = 7.2Hz, 3H) .
实施例48制备得到的化合物核磁数据如下：The nuclear magnetic data of the compound prepared in Example 48 are as follows:
1H NMR(400MHz,Methanol-d 4):δ8.49(d,J＝7.3Hz,1H),8.12(d,J＝1.7Hz,1H),7.92(d,J＝7.9Hz,2H),7.78–7.68(m,3H),7.50(dd,J＝8.5,2.1Hz,1H),7.43(dt,J＝7.2,1.3Hz,1H),7.02(d,J＝8.4Hz,1H),5.32(t,J＝6.4Hz,1H),4.43(s,2H),3.95(d,J＝6.4Hz,2H),3.52(p,J＝7.2Hz,1H),3.21(q,J＝7.4Hz,2H),1.40(d,J＝7.1Hz,6H),1.23(t,J＝7.4Hz,3H)。 1 H NMR (400 MHz, Methanol-d 4 ): δ 8.49 (d, J = 7.3 Hz, 1H), 8.12 (d, J = 1.7 Hz, 1H), 7.92 (d, J = 7.9 Hz, 2H), 7.78–7.68 (m, 3H), 7.50 (dd, J = 8.5, 2.1 Hz, 1H), 7.43 (dt, J = 7.2, 1.3 Hz, 1H), 7.02 (d, J = 8.4 Hz, 1H), 5.32 (t, J = 6.4Hz, 1H), 4.43 (s, 2H), 3.95 (d, J = 6.4Hz, 2H), 3.52 (p, J = 7.2Hz, 1H), 3.21 (q, J = 7.4Hz , 2H), 1.40 (d, J = 7.1 Hz, 6H), 1.23 (t, J = 7.4 Hz, 3H).
实施例49：(R)-2-(2-(4-(二氟甲氧基)-3-氟苯基)-3-乙基咪唑并[1,2-a]吡啶-7-碳杂草酰氨基)-2-(4-(乙基磺酰)苯基)乙酸的制备Example 49: (R) -2- (2- (4- (difluoromethoxy) -3-fluorophenyl) -3-ethylimidazo [1,2-a] pyridine-7-carbo Preparation of oxalamido) -2- (4- (ethylsulfonyl) phenyl) acetic acid
Figure PCTCN2019104957-appb-000073
Figure PCTCN2019104957-appb-000073
将(R)-2-(2-(4-(二氟甲氧基)-3-氟苯基)-3-乙基咪唑并[1,2-a]吡啶-7-碳杂草酰氨基)-2-(4-(乙基磺酰)苯基)乙酸乙酯(20mg,0.03mmol)，一水合氢氧化锂(14mg,0.3mmol)溶于甲醇(5mL)/H 2O(2mL)中，反应液在24℃下搅拌1h，LCMS显示反应结束，反应浓缩干，剩余物加入DCM(10mL)和H 2O(10mL)，分出有机相浓缩，剩余物先通过制备板(DCM:MeOH＝15:1)再经过反相柱分离(H 2O:MeCN＝0～80％)得到(R)-2-(2-(4-(二氟甲氧基)-3-氟苯基)-3-乙基咪唑并[1,2-a]吡啶-7-碳杂草酰氨基)-2-(4-(乙基磺酰)苯基)乙酸(2.3mg,6％)。ESI-MS 576.2[M+1] +。 (R) -2- (2- (4- (difluoromethoxy) -3-fluorophenyl) -3-ethylimidazo [1,2-a] pyridine-7-carboxamido ) -2- (4- (ethylsulfonyl) phenyl) ethyl acetate (20 mg, 0.03 mmol), lithium hydroxide monohydrate (14 mg, 0.3 mmol) dissolved in methanol (5 mL) / H 2 O (2 mL) During the reaction, the reaction solution was stirred at 24 ° C for 1 h. LCMS indicated that the reaction was over. The reaction was concentrated and dried. The residue was added with DCM (10 mL) and H 2 O (10 mL). The organic phase was separated and concentrated. MeOH = 15: 1) Separated by reverse phase column (H 2 O: MeCN = 0 ~ 80%) to obtain (R) -2- (2- (4- (difluoromethoxy) -3-fluorophenyl ) -3-ethylimidazo [1,2-a] pyridine-7-carboxamido) -2- (4- (ethylsulfonyl) phenyl) acetic acid (2.3 mg, 6%). ESI-MS 576.2 [M + 1] + .
1H NMR(500MHz,DMSO-d 6)δ8.75(d,J＝6.2Hz,1H),8.53(d,J＝7.2Hz,1H),8.38(s,3H),8.17(s,1H),7.77(d,J＝8.3Hz,2H),7.73–7.64(m,3H),7.51(t,J＝8.4Hz,1H),7.38(dd,J＝7.2,1.8Hz,1H),7.33(t,J＝73.2Hz,1H),5.11(d,J＝6.1Hz,1H),3.25(q,J＝7.3Hz,2H),3.19(q,J＝7.6Hz,2H),1.27(t,J＝7.5Hz,3H),1.10(t,J＝7.3Hz,3H)。 1 H NMR (500 MHz, DMSO-d 6 ) δ 8.75 (d, J = 6.2 Hz, 1H), 8.53 (d, J = 7.2 Hz, 1H), 8.38 (s, 3H), 8.17 (s, 1H) , 7.77 (d, J = 8.3 Hz, 2H), 7.73-7.64 (m, 3H), 7.51 (t, J = 8.4 Hz, 1H), 7.38 (dd, J = 7.2, 1.8 Hz, 1H), 7.33 ( t, J = 73.2 Hz, 1H), 5.11 (d, J = 6.1 Hz, 1H), 3.25 (q, J = 7.3 Hz, 2H), 3.19 (q, J = 7.6 Hz, 2H), 1.27 (t, J = 7.5 Hz, 3H), 1.10 (t, J = 7.3 Hz, 3H).
生物学测试评价Biological test evaluation
一、时间分辨荧光共振能量转移检测(TR-FRET)1. Time-resolved fluorescence resonance energy transfer detection (TR-FRET)
本实验为RORγt核受体激动剂的TR-FRET化合物筛选实验。当His-标记的RORγt-LBD受体与受体激动剂相结合时，它可能会增加生物素标记的共激活剂肽的募集。Europium-His-RORγt-LBD通过结合Eu-anti-His抗体来被供体(Eu)间接标记,一旦Eu被能量源(如闪光灯或激光)激活,能量将会以绑定异藻蓝素-链霉亲合素(allophycocyanin-streptavidin)的方式转移到异藻蓝素(allophycocyanin)间接标记的共激活剂上面。This experiment is a TR-FRET compound screening experiment of RORγt nuclear receptor agonist. When the His-tagged RORγt-LBD receptor is combined with a receptor agonist, it may increase the recruitment of biotin-tagged co-activator peptides. Europium-His-RORγt-LBD is indirectly labeled by the donor (Eu) by binding to the Eu-anti-His antibody. Once Eu is activated by an energy source (such as a flash lamp or laser), the energy will be bound to the isophycocyanin-chain The method of allophycocyanin-streptavidin is transferred to the co-activator indirectly labeled by allophycocyanin.
1、配制10X缓冲液(500mM Tris-HCl,500mM KCl,and 10mM Na-EDTA)，调整pH值为7.0，并且储存在4℃条件下备用,使用之前恢复常温，再进行实验；1. Prepare 10X buffer solution (500 mM Tris-HCl, 500 mM KCl, and 10 mM Na-EDTA), adjust the pH to 7.0, and store at 4 ℃ for future use, return to normal temperature before use, and then conduct the experiment;
2、用纯水把10X缓冲液稀释到1X,然后加入终浓度为0.01％的Triton X-100和1mM的DTT来配制成assay buffer溶液；2. Dilute the 10X buffer to 1X with pure water, then add Triton X-100 and 1mM DTT with a final concentration of 0.01% to prepare an assay buffer solution;
3、用DMSO来配制1000X的化合物储备液，并且从高浓度1000nM/10000nM起按5倍的梯度稀释7个浓度，然后再用assay buffer溶液配制成10X的化合物浓度，最后吸2μL的量加入20μL的体系中；3. Use DMSO to prepare a 1000X compound stock solution, and dilute the 7 concentrations from a high concentration of 1000nM / 10000nM in a 5-fold gradient, then use the buffer solution to make a 10X compound concentration, and finally absorb 2μL and add 20μL. In the system;
4、解冻5X RORγt-LBD，然后再用assay buffer溶液配制成5X的浓度，使得终浓度为30nM，整个操作都在冰上进行；4. Thaw 5X RORγt-LBD, and then prepare the concentration of 5X with assay buffer solution, so that the final concentration is 30nM, and the entire operation is carried out on ice;
5、解冻5X SRC peptide，然后再用assay buffer溶液配制成5X的浓度，使得终浓度为500nM，整个操作都在冰上进行；5. Thaw 5X SRC peptide, and then prepare the concentration of 5X with assay buffer solution, so that the final concentration is 500nM, and the entire operation is performed on ice;
6、加入4μL/孔的RORγt-LBD受体到384板孔里，no RORγt-LBD组加入等量的assay buffer；6. Add 4 μL / well of RORγt-LBD receptor to the 384-well plate, and add equal amount of assay buffer to the no RORγt-LBD group;
7、加入2μL的化合物到384板孔里；7. Add 2 μL of compound to the wells of 384 plates;
8、加入4μL/孔的SRC peptide到384板孔里；8. Add 4μL / well SRC peptide to 384 wells;
9、用Lance detection buffer来稀释2X Eu-anti-6X His/APC-Streptavidin，使得终浓度分别为0.25nM和5nM，然后再加入10μL/孔的2X Eu-anti-6xHis/APC-Streptavidin到384板孔里；9. Use Lance detection buffer to dilute 2XEu-anti-6XHis / APC-Streptavidin so that the final concentrations are 0.25nM and 5nM, and then add 10μL / well of 2XEu-anti-6xHis / APC-Streptavidin to 384 plates Kongli
10、在4℃孵育反应过夜；10. Incubate the reaction overnight at 4 ° C;
11、第二天上午,将384孔板在室温放置1小时，然后使用EnVision在665/615的波长条件下读取相应的信号值，然后使用graphpad prism 7.0软件来计算相应化合物的激动活性。具体试验结果见表1。11. The next morning, place the 384-well plate at room temperature for 1 hour, then use EnVision to read the corresponding signal value at the wavelength of 665/615, and then use graphpadprism7.0 software to calculate the agonistic activity of the corresponding compound. The specific test results are shown in Table 1.
二、RORγt报告基因检测2. RORγt reporter gene detection
本实验采用RORγt报告基因检测方法来评价化合物对RORγt的激活和特异性。使用HEK 293细胞(中科院细胞库，Cat.No.GNHu18)共转质粒pfn26a-RORγt-LBD以及pGl4.35(Promega，Cat.No.E1370)，在拮抗剂Ursolic acid(Selleck，Cat.No.S2370-100mg)存在条件下，加入化合物评价其功效。具体实验过程如下：In this experiment, the RORγt reporter gene detection method was used to evaluate the activation and specificity of the compound to RORγt. The plasmid pfn26a-RORγt-LBD and pGl4.35 (Promega, Cat.No.E1370) were co-transformed with HEK293 cells (Cell Bank of the Chinese Academy of Sciences, Cat. -100mg) In the presence of conditions, add compounds to evaluate its efficacy. The specific experimental process is as follows:
1、将已共转了质粒的细胞按照30000细胞/40μL/孔的新鲜DMEM培养基(Gibco,cat.No.1773536)含有10％胎牛血清(Gibco,Cat.No.10099-141)接种到96孔板(Corning，Cat.No3610)；1. Inoculate cells that have been co-transformed with plasmids into 10 000 cells / 40 μL / well of fresh DMEM medium (Gibco, cat. No. 1773536) containing 10% fetal bovine serum (Gibco, Cat. No. 10099-141) 96-well plate (Corning, Cat. No3610);
2、加入5μL包含20μM Ursolic acid的培养基；2. Add 5μL of medium containing 20μM Ursolic acid;
3、测试化合物按4倍梯度稀释来评价剂量效应作用，从50μM开始；3. The test compound is evaluated by 4 times gradient dilution to evaluate the dose effect effect, starting from 50 μM;
4、加入5μL包含10倍其最终浓度的化合物稀释液的培养基；4. Add 5 μL of medium containing 10 times its final concentration of compound dilution;
5、细胞于37℃，5％CO 2下孵育24小时后，加入50μL检测试剂使用读板器(PerkinElmer，Envision)检测萤火虫萤光，再加入50μL第二种检测试剂检测海肾萤光。 5. After incubating the cells at 37 ° C under 5% CO 2 for 24 hours, add 50 μL of detection reagent to detect firefly fluorescence using a plate reader (PerkinElmer, Envision), and then add 50 μL of the second detection reagent to detect Renilla fluorescence.
6、使用Graphpad Prism中四参数曲线拟合来测定半数最大激活化合物浓度(EC 50)。具体试验结果见表1。 6. Four-parameter curve fitting in Graphpad Prism was used to determine the half-maximum active compound concentration (EC 50 ). The specific test results are shown in Table 1.
表1试验结果Table 1 Test results
Figure PCTCN2019104957-appb-000074
Figure PCTCN2019104957-appb-000074
Figure PCTCN2019104957-appb-000075
Figure PCTCN2019104957-appb-000075
从具体实施例化合物酶学和细胞活性数据来看，本发明系列化合物对RORγt核受体具有明显的的激动效果和特异性，有望开发成新一代RORγt激动剂，满足临床应用需求。Judging from the enzymology and cell activity data of the compounds in the specific examples, the compounds of the present invention have obvious agonistic effects and specificity on RORγt nuclear receptors, and are expected to be developed into a new generation of RORγt agonists to meet the clinical application needs.
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。All documents mentioned in the present invention are cited as references in this application, just as each document is individually cited as a reference. In addition, it should be understood that after reading the above teaching content of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the appended claims of the present application.

Claims (18)

  1. 式(I)化合物、其立体异构体、前药或其药学上可接受盐：Compound of formula (I), its stereoisomers, prodrugs or pharmaceutically acceptable salts thereof:
    Figure PCTCN2019104957-appb-100001
    Figure PCTCN2019104957-appb-100001
    其中，环A选自C 3-10环烷基、3-10元杂环基、C 5-10芳基或5-10元杂芳基； Wherein, Ring A is selected from C 3-10 cycloalkyl, 3-10 membered heterocyclic group, C 5-10 aryl group or 5-10 membered heteroaryl group;
    X 1、X 2、X 5各自独立地选自C(R 8)或N； X 1 , X 2 and X 5 are each independently selected from C (R 8 ) or N;
    X 3、X 4各自独立地选自C或N； X 3 and X 4 are each independently selected from C or N;
    Y选自C(R 9)或N； Y is selected from C (R 9 ) or N;
    L选自-[C(R 10R 11)] n-、-[C(R 13R 14)] p-N(R 12)-[C(R 15R 16)] q-、-[C(R 13R 14)] p-O-[C(R 15R 16)] q-、-[C(R 13R 14)] p-S(O) r-[C(R 15R 16)] q-、-C(R 17)＝C(R 18)-、-N(R 19)-S(O) 2-或-N(R 20)-C(O)-； L is selected from-[C (R 10 R 11 )] n -,-[C (R 13 R 14 )] p -N (R 12 )-[C (R 15 R 16 )] q -,-[C ( R 13 R 14 )] p -O- [C (R 15 R 16 )] q -,-[C (R 13 R 14 )] p -S (O) r- [C (R 15 R 16 )] q -, -C (R 17 ) = C (R 18 )-, -N (R 19 ) -S (O) 2 -or -N (R 20 ) -C (O)-;
    R 1选自C 1-10烷基、C 2-10链烯基、C 3-10环烷基、3-10元杂环基、C 5-10芳基、5-10元杂芳基或-NR 21R 22，上述基团任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、卤取代C 1-10烷基、C 3-10环烷基、3-10元杂环基、C 5-10芳基、5-10元杂芳基、＝O、-C 0-8-S(O) rR 23、-C 0-8-O-R 24、-C 0-8-C(O)OR 24、-C 0-8-C(O)R 25、-C 0-8-O-C(O)R 25、-C 0-8-NR 26R 27、-C 0-8-C(O)NR 26R 27或-C 0-8-N(R 26)-C(O)R 25的取代基所取代； R 1 is selected from C 1-10 alkyl, C 2-10 alkenyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 5-10 aryl, 5-10 membered heteroaryl or -NR 21 R 22 , the above groups are optionally further selected from one or more selected from deuterium, halogen, cyano, nitro, azido, C 1-10 alkyl, C 2-10 alkenyl, C 2 -10 alkynyl, halogen substituted C 1-10 alkyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 5-10 aryl, 5-10 membered heteroaryl, = O,- C 0-8 -S (O) r R 23 , -C 0-8 -OR 24 , -C 0-8 -C (O) OR 24 , -C 0-8 -C (O) R 25 , -C 0-8 -OC (O) R 25 , -C 0-8 -NR 26 R 27 , -C 0-8 -C (O) NR 26 R 27 or -C 0-8 -N (R 26 ) -C (O) substituted by the substituent of R 25 ;
    R 2选自氢、氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、C 3-10环烷基、3-10元杂环基、C 5-10芳基、5-10元杂芳基、-C 0-8-S(O) rR 23、-C 0-8-O-R 24、-C 0-8-C(O)OR 24、-C 0-8-C(O)R 25、-C 0-8-O-C(O)R 25、-C 0-8-NR 26R 27、-C 0-8-C(O)NR 26R 27或-C 0-8-N(R 26)-C(O)R 25，上述基团任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、卤取代C 1-10烷基、C 3-10环烷基、3-10元杂环基、C 5-10芳基、5-10元杂芳基、＝O、-C 0-8-S(O) rR 23、-C 0-8-O-R 24、-C 0-8-C(O)OR 24、-C 0-8-C(O)R 25、-C 0-8-O-C(O)R 25、-C 0-8-NR 26R 27、-C 0-8-C(O)NR 26R 27或-C 0-8-N(R 26)-C(O)R 25的取代基所取代； R 2 is selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl , 3-10 membered heterocyclic group, C 5-10 aryl group, 5-10 membered heteroaryl group, -C 0-8 -S (O) r R 23 , -C 0-8 -OR 24 , -C 0 -8 -C (O) OR 24 , -C 0-8 -C (O) R 25 , -C 0-8 -OC (O) R 25 , -C 0-8 -NR 26 R 27 , -C 0 -8 -C (O) NR 26 R 27 or -C 0-8 -N (R 26 ) -C (O) R 25 , the above groups are optionally further selected by one or more selected from deuterium, halogen, cyano , Nitro, azido, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, halogen substituted C 1-10 alkyl, C 3-10 cycloalkyl, 3- 10-membered heterocyclic group, C 5-10 aryl group, 5-10 membered heteroaryl group, = O, -C 0-8 -S (O) r R 23 , -C 0-8 -OR 24 , -C 0 -8 -C (O) OR 24 , -C 0-8 -C (O) R 25 , -C 0-8 -OC (O) R 25 , -C 0-8 -NR 26 R 27 , -C 0 -8 -C (O) NR 26 R 27 or -C 0-8 -N (R 26 ) -C (O) R 25 substituent;
    R 3、R 4各自独立地选自氢、氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、C 3-10环烷基、3-10元杂环基、C 5-10芳基、5-10元杂芳基、-C 0-8-S(O) rR 23、-C 0- 8-O-R 24、-C 0-8-C(O)OR 24、-C 0-8-C(O)R 25、-C 0-8-O-C(O)R 25、-C 0-8-NR 26R 27、-C 0-8-C(O)NR 26R 27或-C 0-8-N(R 26)-C(O)R 25，或者，R 3与R 4和其直接相连的碳原子一起形成C(O)、3-10元环烷基、3-10元杂环基，上述基团任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、卤取代C 1-10烷基、C 3-10环烷基、3-10元杂环基、C 5- 10芳基、5-10元杂芳基、＝O、-C 0-8-S(O) rR 23、-C 0-8-O-R 24、-C 0-8-C(O)OR 24、-C 0-8-C(O)R 25、-C 0-8-O-C(O)R 25、-C 0-8-NR 26R 27、-C 0-8-C(O)NR 26R 27或-C 0-8-N(R 26)-C(O)R 25的取代基所取代； R 3 and R 4 are each independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, 3-10 membered heterocyclic group, C 5-10 aryl group, 5-10 membered heteroaryl group, -C 0-8 -S (O) r R 23 , -C 0- 8- OR 24 , -C 0-8 -C (O) OR 24 , -C 0-8 -C (O) R 25 , -C 0-8 -OC (O) R 25 , -C 0-8 -NR 26 R 27 , -C 0-8 -C (O) NR 26 R 27 or -C 0-8 -N (R 26 ) -C (O) R 25 , or, R 3 and R 4 and the carbon directly connected to it Atoms together form C (O), 3-10 membered cycloalkyl, 3-10 membered heterocyclic group, the above groups are optionally further selected by one or more selected from deuterium, halogen, cyano, nitro, azido , C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, halogen substituted C 1-10 alkyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 5- 10 aryl, 5-10 membered heteroaryl, = O, -C 0-8 -S (O) r R 23 , -C 0-8 -OR 24 , -C 0-8 -C (O) OR 24 , -C 0-8 -C (O) R 25 , -C 0-8 -OC (O) R 25 , -C 0-8 -NR 26 R 27 , -C 0-8 -C (O) NR 26 R 27 or -C 0-8 -N (R 26 ) -C (O) R 25 substituent;
    R 5选自氢、氘、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、C 3-10环烷基、3-10元杂环基、C 5-10芳基、5-10元杂芳基、-C 0-8-S(O) rR 23、-C 0-8-C(O)OR 24或-C 0-8-C(O)R 25，上述基团任选进 一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、卤取代C 1-10烷基、C 3-10环烷基、3-10元杂环基、C 5-10芳基、5-10元杂芳基、＝O、-C 0- 8-S(O) rR 23、-C 0-8-O-R 24、-C 0-8-C(O)OR 24、-C 0-8-C(O)R 25、-C 0-8-O-C(O)R 25、-C 0-8-NR 26R 27、-C 0- 8-C(O)NR 26R 27或-C 0-8-N(R 26)-C(O)R 25的取代基所取代； R 5 is selected from hydrogen, deuterium, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, 3-10 membered heterocyclic group, C 5- 10 aryl, 5-10 membered heteroaryl, -C 0-8 -S (O) r R 23 , -C 0-8 -C (O) OR 24 or -C 0-8 -C (O) R 25 , the above groups are optionally further selected from one or more selected from deuterium, halogen, cyano, nitro, azido, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkyne group, a halo substituted C 1-10 alkyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 5-10 aryl, 5-10 membered heteroaryl, = O, -C 0- 8 -S (O) r R 23 , -C 0-8 -OR 24 , -C 0-8 -C (O) OR 24 , -C 0-8 -C (O) R 25 , -C 0-8- OC (O) R 25 , -C 0-8 -NR 26 R 27 , -C 0- 8 -C (O) NR 26 R 27 or -C 0-8 -N (R 26 ) -C (O) R Substituted by a substituent of 25 ;
    R 6选自氢、氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、C 3-10环烷基、3-10元杂环基、C 5-10芳基、5-10元杂芳基、-C 0-8-S(O) rR 23、-C 0-8-O-R 24、-C 0-8-C(O)OR 24、-C 0-8-C(O)R 25、-C 0-8-O-C(O)R 25、-C 0-8-NR 26R 27、-C 0-8-C(O)NR 26R 27或-C 0-8-N(R 26)-C(O)R 25，上述基团任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、卤取代C 1-10烷基、C 3-10环烷基、3-10元杂环基、C 5-10芳基、5-10元杂芳基、＝O、-C 0-8-S(O) rR 23、-C 0-8-O-R 24、-C 0-8-C(O)OR 24、-C 0-8-C(O)R 25、-C 0-8-O-C(O)R 25、-C 0-8-NR 26R 27、-C 0-8-C(O)NR 26R 27或-C 0-8-N(R 26)-C(O)R 25的取代基所取代； R 6 is selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl , 3-10 membered heterocyclic group, C 5-10 aryl group, 5-10 membered heteroaryl group, -C 0-8 -S (O) r R 23 , -C 0-8 -OR 24 , -C 0 -8 -C (O) OR 24 , -C 0-8 -C (O) R 25 , -C 0-8 -OC (O) R 25 , -C 0-8 -NR 26 R 27 , -C 0 -8 -C (O) NR 26 R 27 or -C 0-8 -N (R 26 ) -C (O) R 25 , the above groups are optionally further selected by one or more selected from deuterium, halogen, cyano , Nitro, azido, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, halogen substituted C 1-10 alkyl, C 3-10 cycloalkyl, 3- 10-membered heterocyclic group, C 5-10 aryl group, 5-10 membered heteroaryl group, = O, -C 0-8 -S (O) r R 23 , -C 0-8 -OR 24 , -C 0 -8 -C (O) OR 24 , -C 0-8 -C (O) R 25 , -C 0-8 -OC (O) R 25 , -C 0-8 -NR 26 R 27 , -C 0 -8 -C (O) NR 26 R 27 or -C 0-8 -N (R 26 ) -C (O) R 25 substituent;
    各R 7独立地选自氢、氘、卤素、氰基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、C 3-10环烷基、3-10元杂环基、C 5-10芳基、5-10元杂芳基、-P(O)(R 28) 2、-SF 5、-C 0-8-S(O) rR 23、-C 0-8-O-R 24、-C 0-8-C(O)OR 24、-C 0-8-C(O)R 25、-C 0-8-O-C(O)R 25、-C 0-8-NR 26R 27、-C 0-8-C(O)NR 26R 27或-C 0-8-N(R 26)-C(O)R 25，上述基团任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、卤取代C 1-10烷基、C 3-10环烷基、3-10元杂环基、C 5-10芳基、5-10元杂芳基、＝O、-C 0-8-S(O) rR 23、-C 0-8-O-R 24、-C 0-8-C(O)OR 24、-C 0-8-C(O)R 25、-C 0-8-O-C(O)R 25、-C 0-8-NR 26R 27、-C 0-8-C(O)NR 26R 27或-C 0-8-N(R 26)-C(O)R 25的取代基所取代； Each R 7 is independently selected from hydrogen, deuterium, halogen, cyano, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, 3-10 Heterocyclic group, C 5-10 aryl group, 5-10 membered heteroaryl group, -P (O) (R 28 ) 2 , -SF 5 , -C 0-8 -S (O) r R 23 ,- C 0-8 -OR 24 , -C 0-8 -C (O) OR 24 , -C 0-8 -C (O) R 25 , -C 0-8 -OC (O) R 25 , -C 0 -8 -NR 26 R 27 , -C 0-8 -C (O) NR 26 R 27 or -C 0-8 -N (R 26 ) -C (O) R 25 , the above groups are optionally further Or more selected from deuterium, halogen, cyano, nitro, azido, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, halogen substituted C 1-10 alkyl , C 3-10 cycloalkyl, 3-10 membered heterocyclic group, C 5-10 aryl group, 5-10 membered heteroaryl group, = O, -C 0-8 -S (O) r R 23 ,- C 0-8 -OR 24 , -C 0-8 -C (O) OR 24 , -C 0-8 -C (O) R 25 , -C 0-8 -OC (O) R 25 , -C 0 -8 -NR 26 R 27 , -C 0-8 -C (O) NR 26 R 27 or -C 0-8 -N (R 26 ) -C (O) R 25 substituent;
    每个R 8、R 9各自独立地选自氢、氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、C 3-10环烷基、3-10元杂环基、C 5-10芳基、5-10元杂芳基、-C 0-8-S(O) rR 23、-C 0-8-O-R 24、-C 0-8-C(O)OR 24、-C 0-8-C(O)R 25、-C 0-8-O-C(O)R 25、-C 0-8-NR 26R 27、-C 0-8-C(O)NR 26R 27或-C 0-8-N(R 26)-C(O)R 25，上述基团任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、卤取代C 1-10烷基、C 3-10环烷基、3-10元杂环基、C 5-10芳基、5-10元杂芳基、＝O、-C 0-8-S(O) rR 23、-C 0-8-O-R 24、-C 0-8-C(O)OR 24、-C 0-8-C(O)R 25、-C 0-8-O-C(O)R 25、-C 0-8-NR 26R 27、-C 0-8-C(O)NR 26R 27或-C 0-8-N(R 26)-C(O)R 25的取代基所取代； Each R 8 and R 9 are independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl , C 3-10 cycloalkyl, 3-10 membered heterocyclic group, C 5-10 aryl group, 5-10 membered heteroaryl group, -C 0-8 -S (O) r R 23 , -C 0- 8 -OR 24 , -C 0-8 -C (O) OR 24 , -C 0-8 -C (O) R 25 , -C 0-8 -OC (O) R 25 , -C 0-8- NR 26 R 27 , -C 0-8 -C (O) NR 26 R 27 or -C 0-8 -N (R 26 ) -C (O) R 25 , the above groups are optionally further substituted by one or more Selected from deuterium, halogen, cyano, nitro, azido, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, halogen substituted C 1-10 alkyl, C 3 -10 cycloalkyl, 3-10 membered heterocyclic group, C 5-10 aryl group, 5-10 membered heteroaryl group, = O, -C 0-8 -S (O) r R 23 , -C 0- 8 -OR 24 , -C 0-8 -C (O) OR 24 , -C 0-8 -C (O) R 25 , -C 0-8 -OC (O) R 25 , -C 0-8- NR 26 R 27 , -C 0-8 -C (O) NR 26 R 27 or -C 0-8 -N (R 26 ) -C (O) R 25 substituents;
    R 10、R 11、R 13、R 14、R 15、R 16各自独立地选自氢、氘、卤素、氰基、硝基、叠氮基、C 1- 10烷基、C 2-10链烯基、C 2-10链炔基、C 3-10环烷基、3-10元杂环基、C 5-10芳基、5-10元杂芳基、-C 0-8-S(O) rR 23、-C 0-8-O-R 24、-C 0-8-C(O)OR 24、-C 0-8-C(O)R 25、-C 0-8-O-C(O)R 25、-C 0-8-NR 26R 27、-C 0-8-C(O)NR 26R 27或-C 0-8-N(R 26)-C(O)R 25，或者，R 10与R 11、R 13与R 14、R 15与R 16和其直接相连的碳原子一起各自独立地形成C(O)、3-10元环烷基、3-10元杂环基，上述基团任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、卤取代C 1-10烷基、C 3-10环烷基、3-10元杂环基、C 5-10芳基、5-10元杂芳基、＝O、-C 0- 8-S(O) rR 23、-C 0-8-O-R 24、-C 0-8-C(O)OR 24、-C 0-8-C(O)R 25、-C 0-8-O-C(O)R 25、-C 0-8-NR 26R 27、-C 0- 8-C(O)NR 26R 27或-C 0-8-N(R 26)-C(O)R 25的取代基所取代； R 10, R 11, R 13 , R 14, R 15, R 16 are each independently selected from hydrogen, deuterium, halo, cyano, nitro, azido, C 1- 10 alkyl group, C 2-10 chain, Alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 5-10 aryl, 5-10 membered heteroaryl, -C 0-8 -S ( O) r R 23 , -C 0-8 -OR 24 , -C 0-8 -C (O) OR 24 , -C 0-8 -C (O) R 25 , -C 0-8 -OC (O ) R 25 , -C 0-8 -NR 26 R 27 , -C 0-8 -C (O) NR 26 R 27 or -C 0-8 -N (R 26 ) -C (O) R 25 , or , R 10 and R 11 , R 13 and R 14 , R 15 and R 16 together with the carbon atoms directly connected to them independently form C (O), 3-10 membered cycloalkyl group, 3-10 membered heterocyclic group , The above groups are optionally further selected from one or more selected from deuterium, halogen, cyano, nitro, azido, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl , halo-substituted C 1-10 alkyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 5-10 aryl, 5-10 membered heteroaryl, = O, -C 0- 8 - S (O) r R 23 , -C 0-8 -OR 24 , -C 0-8 -C (O) OR 24 , -C 0-8 -C (O) R 25 , -C 0-8 -OC (O) R 25 , -C 0-8 -NR 26 R 27 , -C 0- 8 -C (O) NR 26 R 27 or -C 0-8 -N (R 26 ) -C (O) R 25 Fetch Substitution is substituted;
    R 12、R 19、R 20各自独立地选自氢、氘、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、C 3-10环烷基、3-10元杂环基、C 5-10芳基、5-10元杂芳基、-C 0-8-S(O) rR 23、-C 0-8-C(O)OR 24或-C 0-8- C(O)R 25，上述基团任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、卤取代C 1-10烷基、C 3-10环烷基、3-10元杂环基、C 5-10芳基、5-10元杂芳基、＝O、-C 0-8-S(O) rR 23、-C 0-8-O-R 24、-C 0-8-C(O)OR 24、-C 0-8-C(O)R 25、-C 0-8-O-C(O)R 25、-C 0-8-NR 26R 27、-C 0-8-C(O)NR 26R 27或-C 0-8-N(R 26)-C(O)R 25的取代基所取代； R 12 , R 19 , and R 20 are each independently selected from hydrogen, deuterium, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, 3- 10-membered heterocyclic group, C 5-10 aryl group, 5-10 membered heteroaryl group, -C 0-8 -S (O) r R 23 , -C 0-8 -C (O) OR 24 or -C 0-8 -C (O) R 25 , the above groups are optionally further selected from one or more selected from deuterium, halogen, cyano, nitro, azido, C 1-10 alkyl, C 2-10 chain Alkenyl, C 2-10 alkynyl, halogen substituted C 1-10 alkyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 5-10 aryl, 5-10 membered heteroaryl , = O, -C 0-8 -S (O) r R 23 , -C 0-8 -OR 24 , -C 0-8 -C (O) OR 24 , -C 0-8 -C (O) R 25 , -C 0-8 -OC (O) R 25 , -C 0-8 -NR 26 R 27 , -C 0-8 -C (O) NR 26 R 27 or -C 0-8 -N ( R 26 ) -C (O) R 25 substituent;
    R 17、R 18各自独立地选自氢、氘、卤素、氰基或C 1-10烷基，上述基团任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、卤取代C 1-10烷基、C 3-10环烷基、3-10元杂环基、C 5-10芳基、5-10元杂芳基、＝O、-C 0-8-S(O) rR 23、-C 0-8-O-R 24、-C 0-8-C(O)OR 24、-C 0-8-C(O)R 25、-C 0-8-O-C(O)R 25、-C 0-8-NR 26R 27、-C 0-8-C(O)NR 26R 27或-C 0-8-N(R 26)-C(O)R 25的取代基所取代； R 17 and R 18 are each independently selected from hydrogen, deuterium, halogen, cyano or C 1-10 alkyl, and the above groups are optionally further selected from one or more selected from deuterium, halogen, cyano, nitro, and Nitrogen group, C 1-10 alkyl group, C 2-10 alkenyl group, C 2-10 alkynyl group, halogen substituted C 1-10 alkyl group, C 3-10 cycloalkyl group, 3-10 membered heterocyclic group , C 5-10 aryl, 5-10 membered heteroaryl, = O, -C 0-8 -S (O) r R 23 , -C 0-8 -OR 24 , -C 0-8 -C ( O) OR 24 , -C 0-8 -C (O) R 25 , -C 0-8 -OC (O) R 25 , -C 0-8 -NR 26 R 27 , -C 0-8 -C ( O) NR 26 R 27 or -C 0-8 -N (R 26 ) -C (O) R 25 substituent;
    R 21、R 22各自独立地选自氢、氘、C 1-10烷基、C 2-10链烯基、C 3-10环烷基、3-10元杂环基、C 5-10芳基或5-10元杂芳基，R 21、R 22和其直接相连的氮原子一起形成4-10元杂环基； R 21 and R 22 are each independently selected from hydrogen, deuterium, C 1-10 alkyl, C 2-10 alkenyl, C 3-10 cycloalkyl, 3-10 membered heterocyclic group, C 5-10 aromatic Group or a 5-10 membered heteroaryl group, R 21 and R 22 together with the nitrogen atom directly connected thereto form a 4-10 membered heterocyclic group;
    每个R 23各自独立地选自氢、氘、羟基、C 1-10烷基、C 1-10烷氧基、C 2-10链烯基、C 3-10环烷基、C 3-10环烷氧基、3-10元杂环基、3-10元杂环氧基、C 5-10芳基、C 5-10芳氧基、5-10元杂芳基、5-10元杂芳氧基或-NR 26R 27，上述基团任选进一步被一个或多个选自氘、卤素、羟基、羰基、C 1-10烷基、C 1-10烷氧基、C 3-10环烷基、C 3-10环烷氧基、3-10元杂环基、3-10元杂环氧基、C 5- 10芳基、C 5-10芳氧基、5-10元杂芳基、5-10元杂芳氧基或-NR 26R 27的取代基所取代； Each R 23 is independently selected from hydrogen, deuterium, hydroxyl, C 1-10 alkyl, C 1-10 alkoxy, C 2-10 alkenyl, C 3-10 cycloalkyl, C 3-10 Cycloalkoxy, 3-10 membered heterocyclyl, 3-10 membered heterocyclyloxy, C 5-10 aryl, C 5-10 aryloxy, 5-10 membered heteroaryl, 5-10 membered hetero Aryloxy or -NR 26 R 27 , the above groups are optionally further selected from one or more selected from deuterium, halogen, hydroxyl, carbonyl, C 1-10 alkyl, C 1-10 alkoxy, C 3-10 cycloalkyl, C 3-10 cycloalkoxy, 3-10 membered heterocyclyl, 3-10 membered heterocyclic group, C 5- 10 aryl group, C 5-10 aryloxy, 5-10 membered heteroaryl Substituted by aryl, 5-10 membered heteroaryloxy or -NR 26 R 27 substituents;
    每个R 24各自独立地选自氢、氘、C 1-10烷基、C 2-10链烯基、C 3-10环烷基、3-10元杂环基、C 5-10芳基或5-10元杂芳基，上述基团任选进一步被一个或多个选自氘、卤素、羟基、羰基、氰基、C 1-10烷基、C 1-10烷氧基、C 3-10环烷基、C 3-10环烷氧基、3-10元杂环基、3-10元杂环氧基、C 5-10芳基、C 5-10芳氧基、5-10元杂芳基、5-10元杂芳氧基或-NR 26R 27的取代基所取代； Each R 24 is independently selected from hydrogen, deuterium, C 1-10 alkyl, C 2-10 alkenyl, C 3-10 cycloalkyl, 3-10 membered heterocyclic group, C 5-10 aryl Or 5-10 membered heteroaryl, the above groups are optionally further selected from one or more selected from deuterium, halogen, hydroxyl, carbonyl, cyano, C 1-10 alkyl, C 1-10 alkoxy, C 3 -10 cycloalkyl, C 3-10 cycloalkoxy, 3-10 membered heterocyclic group, 3-10 membered heterocyclicoxy group, C 5-10 aryl group, C 5-10 aryloxy group, 5-10 Substituted by a heteroaryl group, a 5-10 membered heteroaryloxy group or a substituent of -NR 26 R 27 ;
    每个R 25各自独立地选自氢、氘、羟基、C 1-10烷基、C 1-10烷氧基、C 2-10链烯基、C 2-10链炔基、C 3-10环烷基、C 3-10环烷氧基、3-10元杂环基、3-10元杂环氧基、C 5-10芳基、C 5-10芳氧基、5-10元杂芳基、5-10元杂芳氧基或-NR 26R 27，上述基团任选进一步被一个或多个选自氘、卤素、羟基、氰基、C 1-10烷基、C 1-10烷氧基、C 3-10环烷基、C 3-10环烷氧基、3-10元杂环基、3-10元杂环氧基、C 5-10芳基、C 5-10芳氧基、5-10元杂芳基、5-10元杂芳氧基或-NR 26R 27的取代基所取代； Each R 25 is independently selected from hydrogen, deuterium, hydroxyl, C 1-10 alkyl, C 1-10 alkoxy, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 Cycloalkyl, C 3-10 cycloalkoxy, 3-10 membered heterocyclyl, 3-10 membered heterocyclyloxy, C 5-10 aryl, C 5-10 aryloxy, 5-10 membered hetero Aryl, 5-10 membered heteroaryloxy or -NR 26 R 27 , the above groups are optionally further selected from one or more selected from deuterium, halogen, hydroxyl, cyano, C 1-10 alkyl, C 1- 10 alkoxy, C 3-10 cycloalkyl, C 3-10 cycloalkoxy, 3-10 membered heterocyclyl, 3-10 membered heterocyclyloxy, C 5-10 aryl, C 5-10 Substituted by aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy or -NR 26 R 27 substituents;
    每个R 26、R 27各自独立地选自氢、氘、羟基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、C 3-10环烷基、3-10元杂环基、C 5-10芳基、5-10元杂芳基、甲氧基、磺酰基、甲磺酰基、异丙磺酰基、环丙基磺酰基、对甲苯磺酰基、氨基、单烷基氨基、二烷基氨基或C 1-10烷酰基，上述基团任选进一步被一个或多个选自氘、卤素、羟基、C 1-8烷基、C 1-10烷氧基、C 3-10环烷基、C 3-10环烷氧基、3-10元杂环基、3-10元杂环氧基、C 5-10芳基、C 5-10芳氧基、5-10元杂芳基、5-10元杂芳氧基、氨基、单烷基氨基、二烷基氨基或C 1-10烷酰基的取代基所取代； Each R 26 and R 27 is independently selected from hydrogen, deuterium, hydroxyl, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, 3 -10 membered heterocyclic group, C 5-10 aryl group, 5-10 membered heteroaryl group, methoxy group, sulfonyl group, methanesulfonyl group, isopropylsulfonyl group, cyclopropylsulfonyl group, p-toluenesulfonyl group, amino group , Monoalkylamino, dialkylamino or C 1-10 alkanoyl, the above groups are optionally further selected by one or more selected from deuterium, halogen, hydroxyl, C 1-8 alkyl, C 1-10 alkoxy Group, C 3-10 cycloalkyl, C 3-10 cycloalkoxy, 3-10 membered heterocyclic group, 3-10 membered heterocyclicoxy group, C 5-10 aryl group, C 5-10 aryloxy group , 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, amino, monoalkylamino, dialkylamino or C 1-10 alkanoyl substituents;
    或者，R 26、R 27和其直接相连的氮原子一起形成4-10元杂环基，上述基团任选进一步被一个或多个选自氘、卤素、羟基、C 1-10烷基、C 1-10烷氧基、C 3-10环烷基、C 3-10环烷氧基、3-10元杂环基、3-10元杂环氧基、C 5-10芳基、C 5-10芳氧基、5-10元杂芳基、5-10元杂芳氧基、氨基、单烷基氨基、二烷基氨基或C 1-10烷酰基的取代基所取代； Alternatively, R 26 and R 27 together with the nitrogen atom to which they are directly connected form a 4-10 membered heterocyclic group, and the above group is optionally further selected from one or more selected from deuterium, halogen, hydroxyl, C 1-10 alkyl, C 1-10 alkoxy, C 3-10 cycloalkyl, C 3-10 cycloalkoxy, 3-10 membered heterocyclyl, 3-10 membered heterocyclyloxy, C 5-10 aryl, C 5-10 aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, amino, monoalkylamino, dialkylamino or C 1-10 alkanoyl substituents;
    R 28各自独立地选自C 1-10烷基或苯基，上述基团任选进一步被一个或多个选自氘、卤素、羟基、氰基、C 1-8烷基、C 1-10烷氧基、C 3-10环烷基、C 3-10环烷氧基、3-10元杂环基、3-10元杂环氧基或苯基的取代基所取代； R 28 is each independently selected from C 1-10 alkyl or phenyl, and the above groups are optionally further selected from one or more selected from deuterium, halogen, hydroxyl, cyano, C 1-8 alkyl, C 1-10 Substituted by substituents of alkoxy, C 3-10 cycloalkyl, C 3-10 cycloalkoxy, 3-10 membered heterocyclic group, 3-10 membered heterocyclic oxy group or phenyl group;
    m1为0～3的整数；m2为0～5的整数；n为0～2的整数；每个p各自独立地为0～2的整数；每个q各自独立地为0～2的整数；每个r各自独立地为0～2的整数。m1 is an integer from 0 to 3; m2 is an integer from 0 to 5; n is an integer from 0 to 2; each p is independently an integer from 0 to 2; each q is independently an integer from 0 to 2; Each r is independently an integer from 0 to 2.
  2. 根据权利要求1所述的式(I)化合物、其立体异构体、前药或其药学上可接受盐，其特征在于，R 2选自氢、氘、卤素、氰基、硝基、叠氮基、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-8环烷基、3-8元杂环基、C 5-8芳基、5-8元杂芳基、-C 0-4-S(O) rR 23、-C 0-4-O-R 24、-C 0-4-C(O)OR 24、-C 0-4-C(O)R 25、-C 0-4-O-C(O)R 25、-C 0-4-NR 26R 27、-C 0-4-C(O)NR 26R 27或-C 0-4-N(R 26)-C(O)R 25，上述基团任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、卤取代C 1-4烷基、C 3-8环烷基、3-8元杂环基、C 5-8芳基、5-8元杂芳基、＝O、-C 0-4-S(O) rR 23、-C 0-4-O-R 24、-C 0-4-C(O)OR 24、-C 0-4-C(O)R 25、-C 0-4-O-C(O)R 25、-C 0-4-NR 26R 27、-C 0-4-C(O)NR 26R 27或-C 0-4-N(R 26)-C(O)R 25的取代基所取代，R 23、R 24、R 25、R 26、R 27如权利要求1所述； The compound of formula (I), stereoisomers, prodrugs or pharmaceutically acceptable salts thereof according to claim 1, wherein R 2 is selected from hydrogen, deuterium, halogen, cyano, nitro, and Nitrogen, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 5-8 aryl, 5 -8 membered heteroaryl, -C 0-4 -S (O) r R 23 , -C 0-4 -OR 24 , -C 0-4 -C (O) OR 24 , -C 0-4 -C (O) R 25 , -C 0-4 -OC (O) R 25 , -C 0-4 -NR 26 R 27 , -C 0-4 -C (O) NR 26 R 27 or -C 0-4 -N (R 26 ) -C (O) R 25 , the above groups are optionally further selected from one or more selected from deuterium, halogen, cyano, nitro, azido, C 1-4 alkyl, C 2 -4 alkenyl, C 2-4 alkynyl, halogen substituted C 1-4 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 5-8 aryl, 5-8 membered Heteroaryl, = O, -C 0-4 -S (O) r R 23 , -C 0-4 -OR 24 , -C 0-4 -C (O) OR 24 , -C 0-4 -C (O) R 25 , -C 0-4 -OC (O) R 25 , -C 0-4 -NR 26 R 27 , -C 0-4 -C (O) NR 26 R 27 or -C 0-4 -N (R 26 ) -C (O) R 25 substituent, R 23 , R 24 , R 25 , R 26 and R 27 are as claimed in claim 1;
    优选的，R 2选自氢、氘、氟、氯、氰基、甲基、乙基、异丙基、乙烯基、烯丙基、乙炔基、环丙基、3-氧杂环丁基、3-氮杂环丁基、苯基、吡啶基、二氮唑、三氮唑、甲磺酰基、氨基磺酰基、甲氧基、甲氧酰基、羧基、乙酰基、乙酰氧基、氨基、二甲基氨基、氨基酰基或乙酰氨基，上述基团任选进一步被一个或多个选自氘、氟、氯、氰基、甲基、三氟甲基、环丙基、苯基、吡啶基、甲磺酰基、羟基、甲氧基、羧基或氨基的取代基所取代。 Preferably, R 2 is selected from hydrogen, deuterium, fluorine, chlorine, cyano, methyl, ethyl, isopropyl, vinyl, allyl, ethynyl, cyclopropyl, 3-oxetanyl, 3-azacyclobutyl, phenyl, pyridyl, diazoazole, triazole, mesyl, sulfamoyl, methoxy, methoxy, carboxy, acetyl, acetoxy, amino, di Methylamino, aminoacyl or acetamido, the above groups are optionally further selected from one or more selected from deuterium, fluorine, chlorine, cyano, methyl, trifluoromethyl, cyclopropyl, phenyl, pyridyl, Substituted by substituents of mesyl, hydroxy, methoxy, carboxy or amino.
  3. 根据权利要求1所述的式(I)化合物、其立体异构体、前药或其药学上可接受盐，其特征在于，每个R 8、R 9各自独立地选自氢、氘、卤素、氰基、硝基、叠氮基、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-8环烷基、3-8元杂环基、C 5-8芳基、5-8元杂芳基、-C 0-4-S(O) rR 23、-C 0-4-O-R 24、-C 0-4-C(O)OR 24、-C 0-4-C(O)R 25、-C 0-4-O-C(O)R 25、-C 0-4-NR 26R 27、-C 0-4-C(O)NR 26R 27或-C 0-4-N(R 26)-C(O)R 25，上述基团任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、卤取代C 1-4烷基、C 3-8环烷基、3-8元杂环基、C 5-8芳基、5-8元杂芳基、＝O、-C 0-4-S(O) rR 23、-C 0-4-O-R 24、-C 0-4-C(O)OR 24、-C 0-4-C(O)R 25、-C 0-4-O-C(O)R 25、-C 0-4-NR 26R 27、-C 0-4-C(O)NR 26R 27或-C 0-4-N(R 26)-C(O)R 25的取代基所取代，R 23、R 24、R 25、R 26、R 27如权利要求1所述； The compound of formula (I), a stereoisomer, a prodrug or a pharmaceutically acceptable salt thereof according to claim 1, wherein each R 8 and R 9 are independently selected from hydrogen, deuterium and halogen , Cyano, nitro, azido, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 5-8 aryl, 5-8 membered heteroaryl, -C 0-4 -S (O) r R 23 , -C 0-4 -OR 24 , -C 0-4 -C (O) OR 24 , -C 0-4 -C (O) R 25 , -C 0-4 -OC (O) R 25 , -C 0-4 -NR 26 R 27 , -C 0-4 -C (O) NR 26 R 27 or -C 0-4 -N (R 26 ) -C (O) R 25 , the above groups are optionally further selected by one or more selected from deuterium, halogen, cyano, nitro, azido, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halogen substituted C 1-4 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic group, C 5- 8 aryl, 5-8 membered heteroaryl, = O, -C 0-4 -S (O) r R 23 , -C 0-4 -OR 24 , -C 0-4 -C (O) OR 24 , -C 0-4 -C (O) R 25 , -C 0-4 -OC (O) R 25 , -C 0-4 -NR 26 R 27 , -C 0-4 -C (O) NR 26 R 27 or -C 0-4 -N (R 26) -C (O) R 25 group substituted with substituents, R 23, R 24, R 25, R 26, R 27 as claimed in claim 1
    优选的，每个R 8、R 9各自独立地选自氢、氘、氟、氯、氰基、甲基、乙基、异丙基、乙烯基、烯丙基、乙炔基、环丙基、3-氧杂环丁基、3-氮杂环丁基、苯基、吡啶基、二氮唑、三氮唑、甲磺酰基、氨基磺酰基、羟基、甲氧基、甲氧酰基、羧基、乙酰基、乙酰氧基、氨基、二甲基氨基、氨基酰基或乙酰氨基，上述基团任选进一步被一个或多个选自氘、氟、氯、氰基、甲基、三氟甲基、环丙基、苯基、吡啶基、甲磺酰基、羟基、甲氧基、羧基或氨基的取代基所取代。 Preferably, each R 8 and R 9 are independently selected from hydrogen, deuterium, fluorine, chlorine, cyano, methyl, ethyl, isopropyl, vinyl, allyl, ethynyl, cyclopropyl, 3-oxetanyl, 3-azetidinyl, phenyl, pyridyl, diazole, triazole, mesyl, sulfamoyl, hydroxy, methoxy, methoxy, carboxy, Acetyl, acetoxy, amino, dimethylamino, aminoacyl or acetylamino, the above groups are optionally further selected from one or more of deuterium, fluorine, chlorine, cyano, methyl, trifluoromethyl, Substituted by the substituents of cyclopropyl, phenyl, pyridyl, mesyl, hydroxy, methoxy, carboxy, or amino.
  4. 根据权利要求1所述的式(I)化合物、其立体异构体、前药或其药学上可接受盐，其特征在于，R 3、R 4各自独立地选自氢、氘、卤素、氰基、硝基、叠氮基、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-8环烷基、3-8元杂环基、C 5-8芳基、5-8元杂芳基、-C 0-4-S(O) rR 23、-C 0- 4-O-R 24、-C 0-4-C(O)OR 24、-C 0-4-C(O)R 25、-C 0-4-O-C(O)R 25、-C 0-4-NR 26R 27、-C 0-4-C(O)NR 26R 27或-C 0-4-N(R 26)-C(O)R 25，或者，R 3与R 4和其直接相连的碳原子一起形成C(O)、3-8元环烷基、3-8元杂环基，上述基团任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、卤取代C 1-4烷基、C 3-8环烷基、3-8元杂环基、C 5-8芳基、5-8元杂芳基、＝O、-C 0-4-S(O) rR 23、-C 0-4-O-R 24、-C 0-4-C(O)OR 24、-C 0-4-C(O)R 25、-C 0-4-O-C(O)R 25、-C 0-4-NR 26R 27、-C 0-4-C(O)NR 26R 27或-C 0-4-N(R 26)-C(O)R 25的取代基所取代，R 23、R 24、R 25、R 26、R 27如权利要求1所述； The compound of formula (I), its stereoisomer, prodrug or pharmaceutically acceptable salt thereof according to claim 1, wherein R 3 and R 4 are each independently selected from hydrogen, deuterium, halogen, cyanide Group, nitro group, azido group, C 1-4 alkyl group, C 2-4 alkenyl group, C 2-4 alkynyl group, C 3-8 cycloalkyl group, 3-8 membered heterocyclic group, C 5 -8 aryl, 5-8 membered heteroaryl, -C 0-4 -S (O) r R 23 , -C 0- 4 -OR 24 , -C 0-4 -C (O) OR 24 ,- C 0-4 -C (O) R 25 , -C 0-4 -OC (O) R 25 , -C 0-4 -NR 26 R 27 , -C 0-4 -C (O) NR 26 R 27 Or -C 0-4 -N (R 26 ) -C (O) R 25 , or, R 3 and R 4 together with the carbon atom to which they are directly connected form C (O), 3-8 membered cycloalkyl, 3 -8 membered heterocyclic group, the above groups are optionally further selected from one or more selected from deuterium, halogen, cyano, nitro, azido, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halogen substituted C 1-4 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic group, C 5-8 aryl group, 5-8 membered heteroaryl group, = O, -C 0-4 -S (O) r R 23 , -C 0-4 -OR 24 , -C 0-4 -C (O) OR 24 , -C 0-4 -C (O) R 25 ,- C 0-4 -OC (O) R 25 , -C 0-4 -NR 26 R 27 , -C 0-4 -C (O) NR 26 R 27 or -C 0-4 -N ( R 26 ) -C (O) R 25 is substituted, and R 23 , R 24 , R 25 , R 26 and R 27 are as claimed in claim 1;
    优选的，R 3、R 4各自独立地选自氢、氘、卤素、氰基、C 1-4烷基、C 3-6环烷基、4-6元杂环基、苯基、吡啶基、二氮唑、三氮唑、甲磺酰基、氨基磺酰基、羟基、甲氧基、甲氧酰基、乙氧酰基、羧基、乙酰基、乙酰氧基、氨基、二甲基氨基、氨基酰基或乙酰氨基，或者，R 3与R 4和其直接相连的碳原子一起形成C(O)、3-6元环烷基、3-6元杂环基，上述基团任选进一步被一个或多个选自氘、氟、氯、氰基、甲基、三氟甲基、环丙基、苯基、吡啶基、＝O、甲磺酰基、羟基、甲氧基、羧基或氨基的取代基所取代。 Preferably, R 3 and R 4 are each independently selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, C 3-6 cycloalkyl, 4-6 membered heterocyclic group, phenyl, pyridyl , Diazole, triazole, mesyl, aminosulfonyl, hydroxy, methoxy, methoxy, ethoxy, carboxy, acetyl, acetoxy, amino, dimethylamino, aminoacyl or Acetylamino, or R 3 and R 4 together with the carbon atom to which they are directly attached form C (O), a 3-6 membered cycloalkyl group, a 3-6 membered heterocyclic group, the above groups are optionally further substituted by one or more A substituent selected from the group consisting of deuterium, fluorine, chlorine, cyano, methyl, trifluoromethyl, cyclopropyl, phenyl, pyridyl, = 0, mesyl, hydroxy, methoxy, carboxy, or amino Replace.
  5. 根据权利要求1所述的式(I)化合物、其立体异构体、前药或其药学上可接受盐，其特征在于，R 1选自C 1-4烷基、C 2-4链烯基、C 3-8环烷基、3-8元杂环基、C 5-8芳基、5-8元杂芳基或-NR 21R 22，上述基团任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1- 4烷基、C 2-4链烯基、C 2-4链炔基、卤取代C 1-4烷基、C 3-8环烷基、3-8元杂环基、C 5-8芳基、5-8元杂芳基、＝O、-C 0-4-S(O) rR 23、-C 0-4-O-R 24、-C 0-4-C(O)OR 24、-C 0-4-C(O)R 25、-C 0-4-O-C(O)R 25、-C 0-4-NR 26R 27、-C 0-4-C(O)NR 26R 27或-C 0-4-N(R 26)-C(O)R 25的取代基所取代，R 21、R 22、R 23、R 24、R 25、R 26、R 27如权利要求1所述； The compound of formula (I), a stereoisomer, a prodrug or a pharmaceutically acceptable salt thereof according to claim 1, wherein R 1 is selected from C 1-4 alkyl and C 2-4 alkene Group, C 3-8 cycloalkyl group, 3-8 membered heterocyclic group, C 5-8 aryl group, 5-8 membered heteroaryl group or -NR 21 R 22 , the above groups are optionally further substituted by one or more selected from deuterium, halogen, cyano, nitro, azido, C 1- 4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 alkyl substituted with halo, C 3 -8 cycloalkyl, 3-8 membered heterocyclic group, C 5-8 aryl group, 5-8 membered heteroaryl group, = O, -C 0-4 -S (O) r R 23 , -C 0- 4 -OR 24 , -C 0-4 -C (O) OR 24 , -C 0-4 -C (O) R 25 , -C 0-4 -OC (O) R 25 , -C 0-4- NR 26 R 27 , -C 0-4 -C (O) NR 26 R 27 or -C 0-4 -N (R 26 ) -C (O) R 25 substituent, R 21 , R 22 , R 23 , R 24 , R 25 , R 26 and R 27 are as claimed in claim 1;
    优选的，R 1选自C 1-4烷基、C 3-6环烷基、3-6元杂环基、苯基、吡啶基、二氮唑、三氮唑、氨基或二甲基氨基，上述基团任选进一步被一个或多个选自上述基团任选进一步被一个或多个选自氘、氟、氯、氰基、甲基、三氟甲基、环丙基、苯基、吡啶基、甲磺酰基、羟基、甲氧基、羧基或氨基的取代基所取代。 Preferably, R 1 is selected from C 1-4 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic group, phenyl, pyridyl, diazole, triazole, amino or dimethylamino , The above groups are optionally further selected by one or more of the above groups, optionally further selected by one or more of the groups selected from deuterium, fluorine, chlorine, cyano, methyl, trifluoromethyl, cyclopropyl, phenyl , Pyridyl, mesyl, hydroxy, methoxy, carboxy, or amino substituents.
  6. 根据权利要求1所述的式(I)化合物、其立体异构体、前药或其药学上可接受盐，其特征在于，R 6选自氢、氘、卤素、氰基、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-8环烷基、3-8元杂环基、苯基、5-8元杂芳基、-C 0-4-S(O) rR 23、-C 0-4-O-R 24、-C 0-4-C(O)OR 24、-C 0-4-C(O)R 25、-C 0-4-O-C(O)R 25、-C 0-4-NR 26R 27、-C 0-4-C(O)NR 26R 27或-C 0-4-N(R 26)-C(O)R 25，上述基团任选进一步被一个或多个选自氘、卤素、氰基、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、卤取代C 1-4烷基、C 3-8环烷基、3-8元杂环基、苯基、5-8元杂芳基、＝O、-S(O) rR 23、-O-R 24、-C(O)OR 24、-C(O)R 25、-O-C(O)R 25、-NR 26R 27、-C(O)NR 26R 27或-N(R 26)-C(O)R 25的取代基所取代，R 23、R 24、R 25、R 26、R 27如权利要求1所述； The compound of formula (I), its stereoisomer, prodrug or pharmaceutically acceptable salt thereof according to claim 1, wherein R 6 is selected from hydrogen, deuterium, halogen, cyano, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, phenyl, 5-8 membered heteroaryl, -C 0- 4 -S (O) r R 23 , -C 0-4 -OR 24 , -C 0-4 -C (O) OR 24 , -C 0-4 -C (O) R 25 , -C 0-4 -OC (O) R 25 , -C 0-4 -NR 26 R 27 , -C 0-4 -C (O) NR 26 R 27 or -C 0-4 -N (R 26 ) -C (O) R 25 , the above groups are optionally further substituted by one or more selected from deuterium, halogen, cyano, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halogen C 1 -4 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, phenyl, 5-8 membered heteroaryl, = O, -S (O) r R 23 , -OR 24 , -C (O) OR 24 , -C (O) R 25 , -OC (O) R 25 , -NR 26 R 27 , -C (O) NR 26 R 27 or -N (R 26 ) -C (O) R Substituted by a substituent of 25 , R 23 , R 24 , R 25 , R 26 and R 27 are as claimed in claim 1;
    优选的，R 6选自氢、氘、卤素、氰基、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-6环烷基、3-6元杂环基、苯基、5-6元杂芳基、-O-R 24、-C(O)OR 24、-C(O)R 25或-NR 26R 27，上述基团任选进一步被一个或多个选自氘、氟、氯、氰基、甲基、乙基、异丙基、乙烯基、烯丙基、乙炔基、三氟甲基、二氟甲基、环丙基、环丁基、3-氧杂环丁基、3-氮杂环丁基、哌啶基、哌嗪基、吗啉基、苯基、二氮唑、三氮唑、＝O、磺酰基、甲磺酰基、异丙磺酰基、氨基磺酰基、羟基、甲氧基、三氟甲氧基、三氘甲氧基、羧基、甲氧羰基、乙氧羰基、乙酰基、乙酰氧基、氨基、二甲氨基或乙酰氨基的取代基所取代，R 24、R 25、R 26、R 27如权利要求1所述。 Preferably, R 6 is selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 Heterocyclic group, phenyl group, 5-6 membered heteroaryl group, -OR 24 , -C (O) OR 24 , -C (O) R 25 or -NR 26 R 27 , the above groups are optionally further Or more selected from deuterium, fluorine, chlorine, cyano, methyl, ethyl, isopropyl, vinyl, allyl, ethynyl, trifluoromethyl, difluoromethyl, cyclopropyl, cyclobutane Group, 3-oxetanyl, 3-azetidinyl, piperidinyl, piperazinyl, morpholinyl, phenyl, diazole, triazole, = 0, sulfonyl, mesyl , Isopropylsulfonyl, aminosulfonyl, hydroxy, methoxy, trifluoromethoxy, trideuteromethoxy, carboxy, methoxycarbonyl, ethoxycarbonyl, acetyl, acetoxy, amino, dimethylamino Or substituted by a substituent of acetamido, R 24 , R 25 , R 26 and R 27 are as claimed in claim 1.
  7. 根据权利要求1所述的式(I)化合物、其立体异构体、前药或其药学上可接受盐，其特征在于，各R 7独立地选自氢、氘、氟、氯、氰基、C 1-4烷基、C 3-8环烷基、3-8元杂环基、C 5- 8芳基、5-8元杂芳基、-P(O)(R 28) 2、-SF 5、-S(O) rR 23、-C 0-4-O-R 24、-C 0-4-C(O)OR 24、-C 0-4-C(O)R 25、-C 0-4-O-C(O)R 25、-C 0-4-NR 26R 27、-C 0-4-C(O)NR 26R 27或-C 0-4-N(R 26)-C(O)R 25，上述基团任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、卤取代C 1-4烷基、C 3-8环烷基、3-8元杂环基、C 5-8芳基、5-8元杂芳基、＝O、-C 0-4-S(O) rR 23、-C 0-4-O-R 24、-C 0-4-C(O)OR 24、-C 0-4-C(O)R 25、-C 0-4-O-C(O)R 25、-C 0-4-NR 26R 27、-C 0-4-C(O)NR 26R 27或-C 0-4-N(R 26)-C(O)R 25的取代基所取代，R 23、R 24、R 25、R 26、R 27、R 28如权利要求1所述； The compound of formula (I), its stereoisomer, prodrug or pharmaceutically acceptable salt thereof according to claim 1, wherein each R 7 is independently selected from hydrogen, deuterium, fluorine, chlorine, cyano , C 1-4 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic group, C 5- 8 aryl group, 5-8 membered heteroaryl group, -P (O) (R 28 ) 2 , -SF 5 , -S (O) r R 23 , -C 0-4 -OR 24 , -C 0-4 -C (O) OR 24 , -C 0-4 -C (O) R 25 , -C 0-4 -OC (O) R 25 , -C 0-4 -NR 26 R 27 , -C 0-4 -C (O) NR 26 R 27 or -C 0-4 -N (R 26 ) -C (O) R 25 , the above group is optionally further selected from one or more selected from deuterium, halogen, cyano, nitro, azido, C 1-4 alkyl, C 2-4 alkenyl, C 2 -4 alkynyl, halogen substituted C 1-4 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 5-8 aryl, 5-8 membered heteroaryl, = O,- C 0-4 -S (O) r R 23 , -C 0-4 -OR 24 , -C 0-4 -C (O) OR 24 , -C 0-4 -C (O) R 25 , -C 0-4 -OC (O) R 25 , -C 0-4 -NR 26 R 27 , -C 0-4 -C (O) NR 26 R 27 or -C 0-4 -N (R 26 ) -C (O) R 25 group substituted with a substituent, R 23, R 24, R 25, R 26, R 27, R 28 as in claim 1;
    优选的，各R 7独立地选自氢、氘、卤素、氰基、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3- 8环烷基、3-8元杂环基、C 5-8芳基、5-8元杂芳基、-P(O)(CH 3) 2、-P(O)H 2、-SF 5、磺酰基、甲磺酰基、异丙磺酰基、氨基磺酰基、-O-R 24、-C(O)R 25、-C(O)OH、-C(O)NR 26R 27、氨基或二甲氨基，上述基团任选进一步被一个或多个选自氘、氟、氯、氰基、甲基、乙基、异丙基、乙烯基、烯丙基、乙炔基、三氟甲基、二氟甲基、环丙基、环丁基、3-氧杂环丁基、3-氮杂环丁基、哌啶基、哌嗪基、吗啉基、苯基、二氮唑、三氮唑、＝O、磺酰基、甲磺酰基、异丙磺酰基、氨基磺酰基、羟基、甲氧基、三氟甲氧基、三氘甲氧基、羧基、甲氧羰基、乙氧羰基、乙酰基、乙酰氧基、氨基、二甲氨基或乙酰氨基的取代基所取代，R 24、R 25、R 26、R 27如权利要求1所述。 Preferably, each R 7 is independently selected from hydrogen, deuterium, halo, cyano, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3- 8 cycloalkyl, 3-8 membered heterocyclic group, C 5-8 aryl group, 5-8 membered heteroaryl group, -P (O) (CH 3 ) 2 , -P (O) H 2 , -SF 5 , sulfonyl, methyl Sulfonyl, isopropylsulfonyl, aminosulfonyl, -OR 24 , -C (O) R 25 , -C (O) OH, -C (O) NR 26 R 27 , amino or dimethylamino, the above groups Optionally further one or more selected from deuterium, fluorine, chlorine, cyano, methyl, ethyl, isopropyl, vinyl, allyl, ethynyl, trifluoromethyl, difluoromethyl, cyclic Propyl, cyclobutyl, 3-oxetanyl, 3-azetidinyl, piperidinyl, piperazinyl, morpholinyl, phenyl, diazole, triazole, = 0, sulfonate Acyl, methanesulfonyl, isopropylsulfonyl, aminosulfonyl, hydroxy, methoxy, trifluoromethoxy, trideuteromethoxy, carboxy, methoxycarbonyl, ethoxycarbonyl, acetyl, acetoxy, The amino, dimethylamino or acetamido substituent is substituted, and R 24 , R 25 , R 26 and R 27 are as claimed in claim 1.
  8. 根据权利要求1所述的式(I)化合物、其立体异构体、前药或其药学上可接受盐，其特征在于，L选自-[C(R 10R 11)] n-、-NH 2-、-CH 2-NH-、-NH-CH 2-、-[C(R 13R 14)] p-O-[C(R 15R 16)] q-、-S-、-S-CH 2-、-S(O) 2-、-S(O) 2-CH 2-、-C(R 17)＝C(R 18)-、-NH-S(O) 2-、-NH-C(O)-或-N(CH 3)-C(O)-； The compound of formula (I), a stereoisomer, a prodrug or a pharmaceutically acceptable salt thereof according to claim 1, wherein L is selected from-[C (R 10 R 11 )] n -,- NH 2- , -CH 2 -NH-, -NH-CH 2 -,-[C (R 13 R 14 )] p -O- [C (R 15 R 16 )] q- , -S-, -S -CH 2- , -S (O) 2- , -S (O) 2 -CH 2- , -C (R 17 ) = C (R 18 )-, -NH-S (O) 2- , -NH -C (O)-or -N (CH 3 ) -C (O)-;
    R 10、R 11、R 13、R 14、R 15、R 16各自独立地选自氢、氘、氟、氯、C 1-4烷基、C 3-8环烷基、3-8元杂环基、C 5-8芳基、5-8元杂芳基、-C 0-4-S-R 23、-C 0-4-O-R 24或-NH 2，或者，R 10与R 11、R 13与R 14、R 15与R 16和其直接相连的碳原子一起各自独立地形成C(O)、3-8元环烷基、3-8元杂环基，上述基团任选进一步被一个或多个选自氘、氟、氯、氰基、C 1-4烷基、卤取代C 1- 4烷基、C 3-8环烷基、3-8元杂环基、苯基、5-8元杂芳基、＝O、-O-R 24、-C(O)OR 24或-NR 26R 27或的取代基所取代； R 10 , R 11 , R 13 , R 14 , R 15 , R 16 are each independently selected from hydrogen, deuterium, fluorine, chlorine, C 1-4 alkyl, C 3-8 cycloalkyl, 3-8 membered hetero Cyclic group, C 5-8 aryl group, 5-8 membered heteroaryl group, -C 0-4 -SR 23 , -C 0-4 -OR 24 or -NH 2 , or, R 10 and R 11 , R 13 Together with R 14 , R 15 and R 16 and the carbon atom to which they are directly connected, each independently forms C (O), a 3-8 membered cycloalkyl group, a 3-8 membered heterocyclic group, and the above groups are optionally further or more substituents selected from deuterium, fluoro, chloro, cyano, C 1-4 alkyl, halo-substituted C 1- 4 alkyl group, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, phenyl, 5 -8-membered heteroaryl, = O, -OR 24 , -C (O) OR 24 or -NR 26 R 27 or substituents;
    R 17、R 18各自独立地选自氢、氘、氟、氰基、甲基、三氟甲基、三氘甲基、环丙甲基或乙基； R 17 and R 18 are each independently selected from hydrogen, deuterium, fluorine, cyano, methyl, trifluoromethyl, trideuteromethyl, cyclopropylmethyl or ethyl;
    R 23、R 24、R 26、R 27如权利要求1所述。 R 23 , R 24 , R 26 and R 27 are as claimed in claim 1.
  9. 根据权利要求1～8任一所述的式(I)化合物、其立体异构体、前药或其药学上可接受盐，其特征在于，选自式(Ⅱ)化合物：The compound of formula (I), its stereoisomer, prodrug or pharmaceutically acceptable salt thereof according to any one of claims 1 to 8, characterized in that it is selected from compounds of formula (II):
    Figure PCTCN2019104957-appb-100002
    Figure PCTCN2019104957-appb-100002
    其中，X 1、X 2各自独立地选自C(R 8)或N；Y选自CH或N；L选自-[C(R 10R 11)] n-、-NH 2-、-O-[C(R 15R 16)] q-、-S-、-S(O) 2-或-CH＝CH-； Wherein, X 1 and X 2 are each independently selected from C (R 8 ) or N; Y is selected from CH or N; L is selected from-[C (R 10 R 11 )] n- , -NH 2- , -O -[C (R 15 R 16 )] q- , -S-, -S (O) 2 -or -CH = CH-;
    R 1选自C 1-4烷基、C 3-6环烷基、苯基、氨基或二甲基氨基，上述基团任选进一步被一个或多个选自上述基团任选进一步被一个或多个选自氘、氟、氯、氰基、甲基、三氟甲基、环丙基、苯基、羟基、甲氧基、羧基或氨基的取代基所取代； R 1 is selected from C 1-4 alkyl, C 3-6 cycloalkyl, phenyl, amino or dimethylamino, the above groups are optionally further substituted by one or more Or more substituents selected from deuterium, fluorine, chlorine, cyano, methyl, trifluoromethyl, cyclopropyl, phenyl, hydroxyl, methoxy, carboxyl or amino;
    R 3、R 4各自独立地选自氢、氘、卤素、C 1-4烷基、C 3-6环烷基、3-氧杂环丁基、3-氮杂环丁基、羟基、甲氧基、乙氧酰基、羧基、氨基、甲基氨基或二甲基氨基，或者，R 3与R 4和其直接相连的碳原子一起形成C(O)、环丙基、环丁基、3-氧杂环丁基或3-氮杂环丁基，上述基团任选进一步被一个或多个选自氘、氟、氯、甲基、三氟甲基、环丙基、苯基、吡啶基、＝O、羟基、甲氧基、羧基或氨基的取代基所取代； R 3 and R 4 are each independently selected from hydrogen, deuterium, halogen, C 1-4 alkyl, C 3-6 cycloalkyl, 3-oxetanyl, 3-azetidinyl, hydroxy, methyl Oxygen, ethoxyacyl, carboxyl, amino, methylamino or dimethylamino, or R 3 and R 4 together with the carbon atom directly connected to form C (O), cyclopropyl, cyclobutyl, 3 -Oxetanyl or 3-azetidinyl, the above groups are optionally further selected from one or more of deuterium, fluorine, chlorine, methyl, trifluoromethyl, cyclopropyl, phenyl, pyridine Substituent, = O, hydroxy, methoxy, carboxy, or amino substituents;
    R 6选自氢、氘、卤素、氰基、C 1-4烷基、C 3-6环烷基、3-6元杂环基、苯基、吡啶基、二氮唑、三氮唑、-O-R 24、-C(O)OR 24或-NR 26R 27，上述基团任选进一步被一个或多个选自氘、氟、氯、氰基、甲基、乙基、异丙基、乙烯基、烯丙基、乙炔基、三氟甲基、二氟甲基、环丙基、环丁基、3-氧杂环丁基、3-氮杂环丁基、哌啶基、哌嗪基、吗啉基、苯基、二氮唑、三氮唑、＝O、磺酰基、甲磺酰基、异丙磺酰基、氨基磺酰基、羟基、甲氧基、三氟甲氧基、三氘甲氧基、羧基、甲氧羰基、乙氧羰基、乙酰基、乙酰氧基、氨基、二甲氨基或乙酰氨基的取代基所取代； R 6 is selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic group, phenyl, pyridyl, diazole, triazole, -OR 24 , -C (O) OR 24 or -NR 26 R 27 , the above groups are optionally further selected from one or more selected from deuterium, fluorine, chlorine, cyano, methyl, ethyl, isopropyl, Vinyl, allyl, ethynyl, trifluoromethyl, difluoromethyl, cyclopropyl, cyclobutyl, 3-oxetanyl, 3-azetidinyl, piperidinyl, piperazine Group, morpholinyl, phenyl, diazole, triazole, = 0, sulfonyl, methanesulfonyl, isopropylsulfonyl, aminosulfonyl, hydroxyl, methoxy, trifluoromethoxy, trideuterium Substituted by a substituent of methoxy, carboxy, methoxycarbonyl, ethoxycarbonyl, acetyl, acetoxy, amino, dimethylamino or acetylamino;
    每个R 7独立地选自氢、氘、卤素、氰基、C 1-4烷基、C 3-6环烷基、3-6元杂环基、苯基、-P(O)(CH 3) 2、-P(O)H 2、-SF 5、磺酰基、甲磺酰基、异丙磺酰基、氨基磺酰基、甲氧基、乙氧基、异丙氧基、-C(O)R 25、-C(O)OH、-C(O)NR 26R 27、氨基或二甲氨基，上述基团任选进一步被一个或多个选自氘、氟、氯、氰基、甲基、乙基、异丙基、三氟甲基、二氟甲基、环丙基、环丁基、3-氧杂环丁基、3-氮杂环丁基、哌啶基、哌嗪基、吗啉基、苯基、＝O、磺酰基、甲磺酰基、异丙磺酰基、氨基磺酰基、羟基、甲氧基、三氟甲氧基、三氘甲氧基、羧基、甲氧羰基、乙氧羰基、乙酰基、乙酰氧基、氨基、二甲氨基或乙酰氨基的取代基所取代； Each R 7 is independently selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, phenyl, -P (O) (CH 3 ) 2 , -P (O) H 2 , -SF 5 , sulfonyl, methanesulfonyl, isopropylsulfonyl, aminosulfonyl, methoxy, ethoxy, isopropoxy, -C (O) R 25 , -C (O) OH, -C (O) NR 26 R 27 , amino or dimethylamino, the above groups are optionally further selected by one or more selected from deuterium, fluorine, chlorine, cyano, methyl , Ethyl, isopropyl, trifluoromethyl, difluoromethyl, cyclopropyl, cyclobutyl, 3-oxetanyl, 3-azetidinyl, piperidinyl, piperazinyl, Morpholinyl, phenyl, = 0, sulfonyl, methanesulfonyl, isopropylsulfonyl, aminosulfonyl, hydroxy, methoxy, trifluoromethoxy, trideuteromethoxy, carboxy, methoxycarbonyl, Substitution by ethoxycarbonyl, acetyl, acetoxy, amino, dimethylamino or acetylamino substituents;
    每个R 8各自独立地选自氢、氘、氟、氯、氰基、甲基、乙基、异丙基、环丙基、3-氧杂环丁基、3-氮杂环丁基、羟基、甲氧基、乙氧基、异丙氧基、羧基、氨基或二甲基氨基，上 述基团任选进一步被一个或多个选自氘、氟、氯、氰基、甲基、三氟甲基、环丙基、苯基、吡啶基、羟基、甲氧基、羧基或氨基的取代基所取代； Each R 8 is independently selected from hydrogen, deuterium, fluorine, chlorine, cyano, methyl, ethyl, isopropyl, cyclopropyl, 3-oxetanyl, 3-azetidinyl, Hydroxy, methoxy, ethoxy, isopropoxy, carboxy, amino or dimethylamino, the above groups are optionally further selected by one or more selected from deuterium, fluorine, chlorine, cyano, methyl, tri Substituted by substituents of fluoromethyl, cyclopropyl, phenyl, pyridyl, hydroxy, methoxy, carboxy, or amino;
    R 10、R 11、R 15、R 16各自独立地选自氢、氘、氟、氯、C 1-4烷基、C 3-8环烷基、3-8元杂环基、C 5-8芳基、5-8元杂芳基、-C 0-4-S-R 23、-C 0-4-O-R 24或-NH 2，或者，R 10与R 11、R 15与R 16和其直接相连的碳原子一起各自独立地形成C(O)、3-8元环烷基、3-8元杂环基，上述基团任选进一步被一个或多个选自氘、氟、氯、氰基、C 1-4烷基、卤取代C 1-4烷基、C 3-8环烷基、3-8元杂环基、苯基、5-8元杂芳基、＝O、-O-R 24、-C(O)OR 24或-NR 26R 27或的取代基所取代； R 10 , R 11 , R 15 , R 16 are each independently selected from hydrogen, deuterium, fluorine, chlorine, C 1-4 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic group, C 5- 8 aryl, 5-8 membered heteroaryl, -C 0-4 -SR 23 , -C 0-4 -OR 24 or -NH 2 , or R 10 and R 11 , R 15 and R 16 and their direct The connected carbon atoms together independently form C (O), a 3-8 membered cycloalkyl group, a 3-8 membered heterocyclic group, the above groups are optionally further selected by one or more selected from deuterium, fluorine, chlorine, cyanide Group, C 1-4 alkyl, halogen substituted C 1-4 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic group, phenyl group, 5-8 membered heteroaryl, = O, -OR 24 , -C (O) OR 24 or -NR 26 R 27 or substituents;
    环A、R 23、R 24、R 25、R 26、R 27、m2如权利要求1所述。 Ring A, R 23 , R 24 , R 25 , R 26 , R 27 and m2 are as defined in claim 1.
  10. 根据权利要求9所述的式(I)化合物、其立体异构体、前药或其药学上可接受盐，其特征在于，选自式(Ⅲ)化合物：The compound of formula (I), its stereoisomer, prodrug or pharmaceutically acceptable salt thereof according to claim 9, characterized in that it is selected from compounds of formula (III):
    Figure PCTCN2019104957-appb-100003
    Figure PCTCN2019104957-appb-100003
    其中，X 1、X 2各自独立地选自C(R 8)或N；每个Y各自独立地选自CH或N；每个L各自独立地选自-[C(R 10R 11)] n-、-O-CH 2-、-O-CH(CH 3)-、-O-CH(OH)-或-CH＝CH-； Wherein, X 1 and X 2 are each independently selected from C (R 8 ) or N; each Y is independently selected from CH or N; each L is independently selected from-[C (R 10 R 11 )] n- , -O-CH 2- , -O-CH (CH 3 )-, -O-CH (OH)-or -CH = CH-;
    R 3选自氢、氘、卤素、C 1-4烷基、C 3-6环烷基、3-氧杂环丁基、3-氮杂环丁基、羟基、甲氧基、乙氧酰基、羧基、氨基、甲基氨基或二甲基氨基，上述基团任选进一步被一个或多个选自氘、氟、氯、甲基、三氟甲基、环丙基、苯基、吡啶基、＝O、羟基、甲氧基、羧基或氨基的取代基所取代； R 3 is selected from hydrogen, deuterium, halogen, C 1-4 alkyl, C 3-6 cycloalkyl, 3-oxetanyl, 3-azetidinyl, hydroxy, methoxy, ethoxyacyl , Carboxy, amino, methylamino or dimethylamino, the above groups are optionally further selected from one or more selected from deuterium, fluorine, chlorine, methyl, trifluoromethyl, cyclopropyl, phenyl, pyridyl , = O, hydroxy, methoxy, carboxy, or amino substituents;
    R 10、R 11各自独立地选自氢、氘、氟、氯、甲基、三氟甲基、三氘甲基、环丙甲基、甲氧甲基、氨甲基、苄基、乙基、异丙基、环丙基、3-氧杂环丁基、羟基、甲氧基、三氟甲氧基、二氟甲氧基、三氘甲氧基、二氘甲氧基或-NH 2，或者，R 10与R 11和其直接相连的碳原子一起形成C(O)、环丙基、环丁基、3-氧杂环丁基； R 10 and R 11 are each independently selected from hydrogen, deuterium, fluorine, chlorine, methyl, trifluoromethyl, trideuteromethyl, cyclopropylmethyl, methoxymethyl, aminomethyl, benzyl, ethyl , Isopropyl, cyclopropyl, 3-oxetanyl, hydroxy, methoxy, trifluoromethoxy, difluoromethoxy, trideuteromethoxy, dideuteromethoxy or -NH 2 Or, R 10 and R 11 together with the carbon atom directly connected to them form C (O), cyclopropyl, cyclobutyl, 3-oxetanyl;
    环A、R 1、R 6、R 7、R 8、m2如权利要求9所述。 Ring A, R 1 , R 6 , R 7 , R 8 and m2 are as described in claim 9.
  11. 根据权利要求10所述的式(I)化合物、其立体异构体、前药或其药学上可接受盐，其特征在于，选自式(Ⅳ)化合物：The compound of formula (I), its stereoisomer, prodrug or pharmaceutically acceptable salt thereof according to claim 10, characterized in that it is selected from compounds of formula (IV):
    Figure PCTCN2019104957-appb-100004
    Figure PCTCN2019104957-appb-100004
    其中，每个Y各自独立地选自CH或N；每个L各自独立地选自键、-C(R 10R 11)-、-O-CH 2-、-O-CH(CH 3)-、-O-CH(OH)-或-CH＝CH-； Wherein each Y is independently selected from CH or N; each L is independently selected from a bond, -C (R 10 R 11 )-, -O-CH 2- , -O-CH (CH 3 )- , -O-CH (OH)-or -CH = CH-;
    R 1各自独立地选自甲基、乙基、异丙基、环丙基、三氟甲基、三氘甲基、环丙甲基或氨基； R 1 is independently selected from methyl, ethyl, isopropyl, cyclopropyl, trifluoromethyl, trideuteromethyl, cyclopropylmethyl or amino;
    R 3各自独立地选自氢、氘、氟、氯、甲基、乙基、异丙基、环丙基、3-氧杂环丁基、3-氮杂环丁基、羟基、甲氧基、乙氧酰基、羧基或氨基，上述基团任选进一步被一个或多个选自氘、氟、氯、甲基、三氟甲基、环丙基、羟基、甲氧基、羧基或氨基的取代基所取代； R 3 is each independently selected from hydrogen, deuterium, fluorine, chlorine, methyl, ethyl, isopropyl, cyclopropyl, 3-oxetanyl, 3-azetidinyl, hydroxy, methoxy , Ethoxyl, carboxyl or amino, the above groups are optionally further selected by one or more selected from deuterium, fluorine, chlorine, methyl, trifluoromethyl, cyclopropyl, hydroxyl, methoxy, carboxyl or amino Substituted by a substituent;
    R 6各自独立地选自氢、氘、氟、氯、氰基、甲基、乙基、异丙基、环丙基、环丁基、环戊基、3-氧杂环丁基、3-氮杂环丁基、甲氧基、乙氧基、羧基、甲氧羰基、乙氧羰基、氨基或二甲氨基，上述基团任选进一步被一个或多个选自氘、氟、氯、氰基、甲基、乙基、异丙基、乙烯基、烯丙基、乙炔基、三氟甲基、二氟甲基、环丙基、环丁基、羟基、甲氧基、三氟甲氧基、三氘甲氧基、羧基或氨基的取代基所取代； R 6 is each independently selected from hydrogen, deuterium, fluorine, chlorine, cyano, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, 3-oxetanyl, 3- Azetidinyl, methoxy, ethoxy, carboxyl, methoxycarbonyl, ethoxycarbonyl, amino or dimethylamino, the above groups are optionally further selected by one or more selected from deuterium, fluorine, chlorine, cyanide Group, methyl, ethyl, isopropyl, vinyl, allyl, ethynyl, trifluoromethyl, difluoromethyl, cyclopropyl, cyclobutyl, hydroxy, methoxy, trifluoromethoxy Substituted by the substituent of the group, trideuteromethoxy, carboxyl or amino;
    每个R 7各自独立地选自氢、氘、卤素、氰基、C 1-4烷基、C 3-6环烷基、3-6元杂环基、苯基、-P(O)(CH 3) 2、-P(O)H 2、-SF 5、甲磺酰基、甲氧基、乙氧基、异丙氧基、-C(O)R 25或-C(O)NR 26R 27，上述基团任选进一步被一个或多个选自氘、氟、氯、氰基、甲基、乙基、异丙基、三氟甲基、二氟甲基、环丙基、环丁基、3-氧杂环丁基、3-氮杂环丁基、哌啶基、哌嗪基、吗啉基、苯基、＝O、磺酰基、甲磺酰基、异丙磺酰基、氨基磺酰基、羟基、甲氧基、三氟甲氧基、三氘甲氧基、羧基、甲氧羰基、乙氧羰基、乙酰基、乙酰氧基、氨基、二甲氨基或乙酰氨基的取代基所取代； Each R 7 is independently selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, phenyl, -P (O) ( CH 3 ) 2 , -P (O) H 2 , -SF 5 , methanesulfonyl, methoxy, ethoxy, isopropoxy, -C (O) R 25 or -C (O) NR 26 R 27 , the above groups are optionally further selected from one or more selected from deuterium, fluorine, chlorine, cyano, methyl, ethyl, isopropyl, trifluoromethyl, difluoromethyl, cyclopropyl, cyclobutane Group, 3-oxetanyl, 3-azetidinyl, piperidinyl, piperazinyl, morpholinyl, phenyl, = 0, sulfonyl, methanesulfonyl, isopropylsulfonyl, sulfamoyl Substitution by acyl, hydroxy, methoxy, trifluoromethoxy, trideuteromethoxy, carboxy, methoxycarbonyl, ethoxycarbonyl, acetyl, acetoxy, amino, dimethylamino, or acetylamino substituents ;
    每个R 8各自独立地选自氢、氘、氟、氯、氰基、甲基、乙基、异丙基、环丙基、3-氧杂环丁基、3-氮杂环丁基、羟基、甲氧基、乙氧基、异丙氧基、羧基、氨基或二甲基氨基，上述基团任选进一步被一个或多个选自氘、氟、氯、氰基、甲基、三氟甲基、环丙基、羟基、甲氧基、羧基或氨基的取代基所取代； Each R 8 is independently selected from hydrogen, deuterium, fluorine, chlorine, cyano, methyl, ethyl, isopropyl, cyclopropyl, 3-oxetanyl, 3-azetidinyl, Hydroxy, methoxy, ethoxy, isopropoxy, carboxy, amino or dimethylamino, the above groups are optionally further selected by one or more selected from deuterium, fluorine, chlorine, cyano, methyl, tri Substituted by substituents of fluoromethyl, cyclopropyl, hydroxy, methoxy, carboxy, or amino;
    R 10、R 11各自独立地选自氢、氘、氟、氯、甲基、三氟甲基、三氘甲基、环丙甲基、甲氧甲基、氨甲基、苄基、乙基、异丙基、环丙基、3-氧杂环丁基、羟基、甲氧基、三氟甲氧基、二氟甲氧基、三氘甲氧基、二氘甲氧基或-NH 2，或者，R 10与R 11和其直接相连的碳原子一起形成C(O)、环丙基、环丁基、3-氧杂环丁基； R 10 and R 11 are each independently selected from hydrogen, deuterium, fluorine, chlorine, methyl, trifluoromethyl, trideuteromethyl, cyclopropylmethyl, methoxymethyl, aminomethyl, benzyl, ethyl , Isopropyl, cyclopropyl, 3-oxetanyl, hydroxy, methoxy, trifluoromethoxy, difluoromethoxy, trideuteromethoxy, dideuteromethoxy or -NH 2 Or, R 10 and R 11 together with the carbon atom directly connected to them form C (O), cyclopropyl, cyclobutyl, 3-oxetanyl;
    每个R 25各自独立地选自氢、氘、氟、氯、羟基、甲基、乙基或异丙基； Each R 25 is independently selected from hydrogen, deuterium, fluorine, chlorine, hydroxyl, methyl, ethyl or isopropyl;
    每个R 26、R 27各自独立地选自氢、氘、羟基、甲基、乙基、异丙基、环丙基、苯基、甲氧基、磺酰基、甲磺酰基、氨基、单烷基氨基、二烷基氨基或C 1-10烷酰基，上述基团任选进一步被一个或多个选自氘、卤素、羟基、甲基、乙基、异丙基、环丙基、苯基、甲氧基、氨基、单烷基氨基、二烷基氨基或C 1-10烷酰基的取代基所取代； Each R 26 , R 27 is independently selected from hydrogen, deuterium, hydroxyl, methyl, ethyl, isopropyl, cyclopropyl, phenyl, methoxy, sulfonyl, methanesulfonyl, amino, monoalkane Amino group, dialkylamino group or C 1-10 alkanoyl group, the above groups are optionally further selected from one or more selected from deuterium, halogen, hydroxyl, methyl, ethyl, isopropyl, cyclopropyl, phenyl , Methoxy, amino, monoalkylamino, dialkylamino or C 1-10 alkanoyl substituents;
    环A、m2如权利要求10所述。Ring A, m2 are as claimed in claim 10.
  12. 根据权利要求10或11所述的式(I)化合物、其立体异构体、前药或其药学上可接受盐，其特征在于，环A与其直接相连的基团L、R 7一起形成如下结构： The compound of formula (I), a stereoisomer, a prodrug or a pharmaceutically acceptable salt thereof according to claim 10 or 11, wherein ring A and its directly connected groups L and R 7 are formed together as follows structure:
    Figure PCTCN2019104957-appb-100005
    Figure PCTCN2019104957-appb-100005
    其中，每个L各自独立地选自键、-C(R 10R 11)-、-O-CH 2-、-O-CH(CH 3)-、-O-CH(OH)-或-CH＝CH-； Where each L is independently selected from the group consisting of bond, -C (R 10 R 11 )-, -O-CH 2- , -O-CH (CH 3 )-, -O-CH (OH)-or -CH = CH-;
    每个R 7a、R 7b、R 7c、R 7d各自独立地选自氢、氘、氟、氯、氰基、C 1-4烷基、C 3-6环烷基、3-6元杂环基、苯基、-P(O)(CH 3) 2、-P(O)H 2、-SF 5、甲磺酰基、甲氧基、乙氧基、异丙氧基、-C(O)R 25或-C(O)NR 26R 27，上述基团任选进一步被一个或多个选自氘、氟、氯、氰基、甲基、乙基、异丙基、三氟甲基、二氟甲基、环丙基、环丁基、苯基、＝O、羟基、甲氧基、三氟甲氧基、三氘甲氧基、羧基或氨基的取代基所取代； Each R 7a , R 7b , R 7c , R 7d is independently selected from hydrogen, deuterium, fluorine, chlorine, cyano, C 1-4 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocycle Group, phenyl, -P (O) (CH 3 ) 2 , -P (O) H 2 , -SF 5 , methanesulfonyl, methoxy, ethoxy, isopropoxy, -C (O) R 25 or -C (O) NR 26 R 27 , the above groups are optionally further selected from one or more selected from deuterium, fluorine, chlorine, cyano, methyl, ethyl, isopropyl, trifluoromethyl, Difluoromethyl, cyclopropyl, cyclobutyl, phenyl, = 0, hydroxyl, methoxy, trifluoromethoxy, trideuteromethoxy, carboxyl or amino substituents;
    R 10、R 11各自独立地选自氢、氘、氟、氯、甲基、三氟甲基、三氘甲基、环丙甲基、甲氧甲基、氨甲基、苄基、乙基、异丙基、环丙基、3-氧杂环丁基、羟基、甲氧基、三氟甲氧基、二氟甲氧基、三氘甲氧基、二氘甲氧基或-NH 2，或者，R 10与R 11和其直接相连的碳原子一起形成C(O)、环丙基、环丁基、3-氧杂环丁基； R 10 and R 11 are each independently selected from hydrogen, deuterium, fluorine, chlorine, methyl, trifluoromethyl, trideuteromethyl, cyclopropylmethyl, methoxymethyl, aminomethyl, benzyl, ethyl , Isopropyl, cyclopropyl, 3-oxetanyl, hydroxy, methoxy, trifluoromethoxy, difluoromethoxy, trideuteromethoxy, dideuteromethoxy or -NH 2 Or, R 10 and R 11 together with the carbon atom directly connected to them form C (O), cyclopropyl, cyclobutyl, 3-oxetanyl;
    每个R 25各自独立地选自氢、氘、氟、氯、羟基、甲基、乙基或异丙基； Each R 25 is independently selected from hydrogen, deuterium, fluorine, chlorine, hydroxyl, methyl, ethyl or isopropyl;
    每个R 26、R 27各自独立地选自氢、氘、羟基、甲基、乙基、异丙基、环丙基、苯基、甲氧基、磺酰基、甲磺酰基、氨基、单烷基氨基、二烷基氨基或C 1-10烷酰基，上述基团任选进一步被一个或多个选自氘、卤素、羟基、甲基、乙基、异丙基、环丙基、苯基、甲氧基、氨基、单烷基氨基、二烷基氨基或C 1-10烷酰基的取代基所取代。 Each R 26 , R 27 is independently selected from hydrogen, deuterium, hydroxyl, methyl, ethyl, isopropyl, cyclopropyl, phenyl, methoxy, sulfonyl, methanesulfonyl, amino, monoalkane Amino group, dialkylamino group or C 1-10 alkanoyl group, the above groups are optionally further selected from one or more selected from deuterium, halogen, hydroxyl, methyl, ethyl, isopropyl, cyclopropyl, phenyl , Methoxy, amino, monoalkylamino, dialkylamino or C 1-10 alkanoyl substituents.
  13. 根据权利要求12所述的式(I)化合物、其立体异构体、前药或其药学上可接受盐，其特征在于，环A与其直接相连的基团L、R 7一起形成如下结构： The compound of formula (I), its stereoisomers, prodrugs or pharmaceutically acceptable salts thereof according to claim 12, wherein ring A and its directly connected groups L and R 7 together form the following structure:
    Figure PCTCN2019104957-appb-100006
    Figure PCTCN2019104957-appb-100006
    其中，每个R 7a、R 7b、R 7c、R 7d各自独立地选自氢、氘、氟、氯、氰基、C 1-4烷基、C 3-6环烷基、3-6元杂环基、苯基、-P(O)(CH 3) 2、-P(O)H 2、-SF 5、甲磺酰基、甲氧基、乙氧基、异丙氧基、-C(O)R 25或-C(O)NR 26R 27，上述基团任选进一步被一个或多个选自氘、氟、氯、氰基、甲基、乙基、异丙基、三氟甲基、二氟甲基、环丙基、环丁基、苯基、＝O、羟基、甲氧基、三氟甲氧基、三氘甲氧基、羧基或氨基的取代基所取代； Where each R 7a , R 7b , R 7c , R 7d is independently selected from hydrogen, deuterium, fluorine, chlorine, cyano, C 1-4 alkyl, C 3-6 cycloalkyl, 3-6 member Heterocyclyl, phenyl, -P (O) (CH 3 ) 2 , -P (O) H 2 , -SF 5 , methanesulfonyl, methoxy, ethoxy, isopropoxy, -C ( O) R 25 or -C (O) NR 26 R 27 , the above groups are optionally further selected from one or more selected from deuterium, fluorine, chlorine, cyano, methyl, ethyl, isopropyl, trifluoromethyl Substituted by the substituents of the group, difluoromethyl, cyclopropyl, cyclobutyl, phenyl, = 0, hydroxy, methoxy, trifluoromethoxy, trideuteromethoxy, carboxyl or amino;
    R 10、R 11各自独立地选自氢、氘、氟、氯、甲基、三氟甲基、三氘甲基、环丙甲基、甲氧甲基、氨甲基、苄基、乙基、异丙基、环丙基、3-氧杂环丁基、羟基、甲氧基、三氟甲氧基、二氟甲氧基、三氘甲氧基、二氘甲氧基或-NH 2，或者，R 10与R 11和其直接相连的碳原子一起形成C(O)、环丙基、环丁基、3-氧杂环丁基； R 10 and R 11 are each independently selected from hydrogen, deuterium, fluorine, chlorine, methyl, trifluoromethyl, trideuteromethyl, cyclopropylmethyl, methoxymethyl, aminomethyl, benzyl, ethyl , Isopropyl, cyclopropyl, 3-oxetanyl, hydroxy, methoxy, trifluoromethoxy, difluoromethoxy, trideuteromethoxy, dideuteromethoxy or -NH 2 Or, R 10 and R 11 together with the carbon atom directly connected to them form C (O), cyclopropyl, cyclobutyl, 3-oxetanyl;
    每个R 25各自独立地选自氢、氘、氟、氯、羟基、甲基、乙基、异丙基或-NR 26R 27； Each R 25 is independently selected from hydrogen, deuterium, fluorine, chlorine, hydroxyl, methyl, ethyl, isopropyl or -NR 26 R 27 ;
    每个R 26、R 27各自独立地选自氢、氘、羟基、甲基、乙基、异丙基、环丙基、苯基、甲氧基、磺酰基、甲磺酰基、氨基、单烷基氨基、二烷基氨基或C 1-10烷酰基，上述基团任选进一步被一个或多个选自氘、卤素、羟基、甲基、乙基、异丙基、环丙基、苯基、甲氧基、氨基、单烷基氨基、二烷基氨基或C 1-10烷酰基的取代基所取代。 Each R 26 , R 27 is independently selected from hydrogen, deuterium, hydroxyl, methyl, ethyl, isopropyl, cyclopropyl, phenyl, methoxy, sulfonyl, methanesulfonyl, amino, monoalkane Amino group, dialkylamino group or C 1-10 alkanoyl group, the above groups are optionally further selected from one or more selected from deuterium, halogen, hydroxyl, methyl, ethyl, isopropyl, cyclopropyl, phenyl , Methoxy, amino, monoalkylamino, dialkylamino or C 1-10 alkanoyl substituents.
  14. 根据权利要求1～13任一所述的式(I)化合物、其立体异构体、前药或其药学上可接受盐，其特征在于，选自如下化合物：The compound of formula (I), its stereoisomer, prodrug or pharmaceutically acceptable salt thereof according to any one of claims 1 to 13, characterized in that it is selected from the following compounds:
    Figure PCTCN2019104957-appb-100007
    Figure PCTCN2019104957-appb-100007
    Figure PCTCN2019104957-appb-100008
    Figure PCTCN2019104957-appb-100008
    Figure PCTCN2019104957-appb-100009
    Figure PCTCN2019104957-appb-100009
    Figure PCTCN2019104957-appb-100010
    Figure PCTCN2019104957-appb-100010
    Figure PCTCN2019104957-appb-100011
    Figure PCTCN2019104957-appb-100011
    Figure PCTCN2019104957-appb-100012
    Figure PCTCN2019104957-appb-100012
    Figure PCTCN2019104957-appb-100013
    Figure PCTCN2019104957-appb-100013
  15. 权利要求1～14任一所述的式(I)化合物、其立体异构体、前药或其药学上可接受盐的制备方法，其特征在于，包括如下步骤：式Ia化合物与式Ib化合物或其酸式盐偶联得到式I化合物：The preparation method of the compound of formula (I), its stereoisomer, prodrug or pharmaceutically acceptable salt thereof according to any one of claims 1 to 14, characterized in that it comprises the following steps: the compound of formula Ia and the compound of formula Ib Or its acid salt is coupled to obtain the compound of formula I:
    Figure PCTCN2019104957-appb-100014
    Figure PCTCN2019104957-appb-100014
    其中，环A、L、X 1、X 2、X 3、X 4、X 5、Y、R 1、R 2、R 3、R 4、R 5、R 6、R 7、m 1、m 2如权利要求1所述。 Among them, rings A, L, X 1 , X 2 , X 3 , X 4 , X 5 , Y, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , m 1 , m 2 According to claim 1.
  16. 一种药物组合物，其包括权利要求1～14任一所述的式(I)化合物、其立体异构体、前药或其药学上可接受盐及可药用的载体。A pharmaceutical composition comprising the compound of formula (I) according to any one of claims 1 to 14, its stereoisomer, prodrug or pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
  17. 根据权利要求1～14任一所述的式(I)化合物、其立体异构体、前药或其药学上可接受盐，或权利要求16所述的药物组合物在制备治疗一种或多种肿瘤、癌症、代谢性疾病、自身免疫性疾病或紊乱药物中的应用。The compound of formula (I) according to any one of claims 1 to 14, its stereoisomer, prodrug or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 16 The use of drugs in tumors, cancers, metabolic diseases, autoimmune diseases or disorders.
  18. 根据权利要求1～14任一所述的式(I)化合物、其立体异构体、前药或其药学上可接受盐，或权利要求16所述的药物组合物，其用作治疗一种或多种肿瘤、癌症、代谢性疾病、自身免疫性疾病或紊乱的药物。The compound of formula (I) according to any one of claims 1 to 14, a stereoisomer, a prodrug or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 16, which is used as a therapeutic Or a variety of drugs for tumors, cancers, metabolic diseases, autoimmune diseases or disorders.
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