WO2015146928A1

WO2015146928A1 - Heterocyclic compound

Info

Publication number: WO2015146928A1
Application number: PCT/JP2015/058777
Authority: WO
Inventors: 徹哉塚本; 善久中田; 倫代望月; 隆文高井; 智也湯川; 善右塩川; 泰祐加藤; 正記瀬藤; 歩佐藤; 猛史湯川
Original assignee: 武田薬品工業株式会社
Priority date: 2014-03-24
Filing date: 2015-03-23
Publication date: 2015-10-01

Abstract

Provided is a compound, or a salt thereof, that has an excellent PKC inhibitory action, and that is useful as a prophylactic or therapeutic agent for immunological diseases, inflammatory diseases, etc. A compound represented by formula (I) (the symbols in the formula are as described in the Specification), or a salt thereof, has an excellent PKC inhibitory action, and is useful as a prophylactic or therapeutic agent for immunological diseases, inflammatory diseases, etc.

Description

Heterocyclic compounds

The present invention relates to a heterocyclic compound having an inhibitory action on protein kinase C (sometimes abbreviated as “PKC” in the present specification) and useful for the treatment of immune diseases, inflammatory diseases, and the like, and a medicament containing them It relates to compositions and the like.

(Background of the Invention)
In the immune system, T cells play an important role as part of an acquired immune mechanism that eliminates foreign antigens such as viruses and bacteria and cancer. On the other hand, it is known that excessive T cell activation is involved in the development of autoimmune diseases and causes adverse reactions to the human body such as rejection associated with transplantation. It is considered to be a promising therapeutic target in these diseases (Non-patent Document 1). This includes rejection in organ transplantation such as kidney transplantation, liver transplantation, heart transplantation, lung transplantation, pancreas transplantation, small intestine transplantation, rejection in bone marrow transplantation, graft-versus-host disease, Behcet's disease, psoriasis vulgaris, pustular In diseases such as psoriasis, psoriatic erythroderma, arthritic psoriasis, aplastic anemia, erythroblastosis, nephrotic syndrome, systemic myasthenia gravis, atopic dermatitis, ulcerative colitis, It is also clear from the fact that calcineurin inhibitors (Tacrolimus and Cyclosporin A), which are drugs that suppress activation, are approved in Japan as prophylactic or therapeutic agents (Non-patent Documents 2 and 3).
The PKC family consists of at least 12 types and is known to be expressed in various tissues. In addition, the PKC family is expressed in immunocompetent cells such as T cells, B cells, and macrophages and plays an important role in various immune responses, and is therefore considered to be involved in immune diseases and inflammatory diseases (non-) Patent Document 4).
Among them, PKC-θ is a phosphorylase that is selectively expressed in T cells, plays a role in the activation of T cells, is responsible for the transmission of stimuli to T cell receptors into cells. .
Inhibition of PKC-θ is known to suppress T cell activation (Non-patent Document 5), and PKC-θ-deficient mice are used in multiple sclerosis models, inflammatory bowel disease models, grafts. It has been reported to be resistant in somatic host disease models, rheumatoid arthritis models, and asthma models (Non-Patent Documents 6 to 8).
Based on the above, PKC (eg, PKC-θ) inhibitors are used for rejection in organ transplantation such as kidney transplantation, liver transplantation, heart transplantation, lung transplantation, pancreatic transplantation, small intestine transplantation, rejection reaction in bone marrow transplantation, graft Anti-host disease, Behcet's disease, psoriasis vulgaris, pustular psoriasis, erythrodermic psoriasis, psoriatic arthritis, aplastic anemia, erythroblastosis, nephrotic syndrome, systemic myasthenia gravis, atopic dermatitis It becomes a prophylactic or therapeutic agent in various immune diseases and inflammatory diseases such as ulcerative colitis and asthma.

Examples of the compound having a structure similar to the compound described in the present specification include the following.
(1) The following formula:

[Where
R ¹ is —NR ⁹ R ¹⁰ —, —NR ⁹ COR ⁹ —, —S (O) _n R ¹² — and the like (R ⁹ , R ¹⁰ and R ¹² are each independently C _3-6 cycloalkyl, C _4-7 cycloalkylalkyl, n represents 0-2), cyano, C _1-4 haloalkyl, etc., or C _1-6 alkyl, C _3-6 cycloalkyl, etc. (each ^{^{^{^{, -NR 9 R 10 -, -}}}} NR 9 COR 9 -, - indicates may be substituted with _{^{etc.) - S (O) n R}} 12;
A ¹ and A ² independently represent N or CR ⁵ ;
W represents ═O, ═S, —H or (—H, —H);
X represents N or CR ¹ ;
Y represents —C (R ^Y ) ₂ —, —N—R ^Y — or the like (R ^Y represents H or the like);
R ² represents H, halogen, cyano, C _1-4 alkyl, C _3-6 cycloalkyl and the like; B represents R ³ , NHR ^{3 and the} like;
R ³ represents C _1-10 alkyl or the like;
R ⁴ represents H, —OR ¹⁰ , —COR ⁹ , halogen, C _1-6 alkyl, C _3-6 cycloalkyl and the like;
R ⁵ represents H, halogen, C _1-10 alkyl, C _2-10 alkenyl, C _3-6 cycloalkyl or the like. ]
The compound shown by (patent document 1).

(2) The following formula:

[Where:
B represents an optionally substituted 6-membered aromatic heterocycle;
C is an optionally substituted 3-8 membered monocycle (having 0-3 heteroatoms), an optionally substituted C _8-12 bicyclic ring (0-5 heteroatoms) Having
R ¹ and R ² are independently H, halogen, —OR ′ (R ′ may be substituted with H, C _1-6 alkyl (—OR, —N (R) ₂ , cyano, oxo, etc.). And cyano, C _1-10 aliphatic compounds (which may be substituted with halogen, —OR, —N (R) ₂ , cyano, etc.), etc.]
The compound shown by (patent document 2).

(3) The following formula:

[Where:
B represents an optionally substituted 5-membered aromatic heterocyclic ring;
R ¹ and R ² independently represent H, halogen, —OR ′, cyano, C _1-10 aliphatic compound (halogen, —OR, —N (R) ₂ , —C (O) R, cyano, Optionally substituted with oxo, etc.), C _3-8 alicyclic compounds (halogen, —OR, —N (R) ₂ , cyano, oxo, C _1-6 alkyl (halogen, —OR, —N ( R) ₂ , —C (O) R, optionally substituted with cyano, oxo, etc.)) and the like;
X represents C or N;
R ^X is absent or represents H;
C is an optionally substituted 3-8 membered monocycle (having 0-3 heteroatoms), an optionally substituted C _8-12 bicyclic ring (0-5 heteroatoms) Having
R represents H or C _1-6 alkyl;
R ′ represents H or C _1-6 alkyl (which may be substituted with halogen, —OR, —N (R) ₂ , —C (O) R, cyano, oxo, etc.)]
The compound shown by (patent document 3).

(4) The following formula:

[Where:
B represents an optionally substituted 6-membered aromatic heterocycle;
R ¹ and R ² independently represent H, halogen, —OR ′, cyano, C _1-10 aliphatic compound (halogen, —OR, —N (R) ₂ , —C (O) R, cyano, Optionally substituted with oxo, etc.), C _3-8 alicyclic compounds ( _optionally substituted with halogen, —OR, —N (R) ₂ , cyano, oxo, C _1-6 alkyl, etc.) Etc .;
R ³ is absent or represents H, C _1-6 alkyl (optionally substituted with halogen, —OR, —N (R) ₂ , —C (O) R, cyano, oxo, etc.) ;
R ⁴ is an optionally substituted C _1-10 aliphatic compound, an optionally substituted 3-8 membered monocycle (having 0-3 heteroatoms), an optionally substituted C _{8 Represents} a _-12 bicyclic ring (having 0-5 heteroatoms);
R represents H or C _1-6 alkyl;
R ′ represents H or C _1-6 alkyl (optionally substituted with halogen, —OR, —N (R) ₂ , —C (O) R, cyano, oxo, etc.);
Q represents N, O or S]
The compound shown by (patent document 4).

(5) The following formula:

[Where:
B represents an optionally substituted 5-membered aromatic heterocyclic ring;
R ₁ and R ₂ independently represent H, halogen, cyano, —OR ′, C _1-10 aliphatic compound (halogen, —OR, —N (R) ₂ , —C (O) R, cyano, Optionally substituted with oxo, etc.), C _3-8 alicyclic compounds (halogen, —OR, —N (R) ₂ , cyano, oxo, C _1-6 alkyl (halogen, —OR, —N ( R) ₂ , —C (O) R, optionally substituted with cyano, oxo, etc.))
R ₃ is absent or is H, C _1-6 alkyl (optionally substituted with halogen, —OR, —N (R) ₂ , —C (O) R, cyano, oxo, etc.) Show;
R ₄ is an optionally substituted C _1-10 aliphatic compound, an optionally substituted 3-8 membered monocycle (having 0-3 heteroatoms), an optionally substituted C _{8 Represents} a _-12 bicyclic ring (having 0-5 heteroatoms);
Q represents N, O or S;
R ^X is absent or represents H]
The compound shown by (patent document 5).

(6) The following formula:

[Where:
X ₁ represents CH or N;
X ₂ represents C or N;
Y ₁ represents — (CR _6a R _6b ) _m —Z ₁ — (CR _7a R _7b ) _n —;
Y ₂ represents — (CR _8a R _8b ) _p —Z ₂ — (CR _9a R _9b ) _q —;
Y ₃ represents — (CR _10a R _10b ) _r —Z ₃ — (CR _11a R _11b ) _s —;
Y ₄ represents — (CH ₂ ) _t —Z ₄ —:
Z ₁ -Z ₃ independently represents a bond, O, S, C (O) or the like;
Z ₄ represents a bond, O or N;
m, n, p, q, r and s independently represent 0-6;
t represents 0-2;
R _6a -R _11b independently represents a bond, H, —OH, C _1-3 alkoxy or C _1-3 alkyl;
R ₁ , R ₂ and R ₃ are independently H, halogen, alkoxy, cyano, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocycloalkyl, substituted Represents optionally substituted heteroaryl;
R ₄ represents H, O or the like;
R ₅ and R ₁₃ independently represent H, halogen, OH, lower alkyl, etc .;
R ₁₄ represents a lower cycloalkyl which may be absent or substituted, a phenyl which may be substituted, etc.]
The compound shown by (patent document 6).

(7) The following formula:

[Where:
X ₁ represents CH or N;
X ₂ represents CR ₁₃ or N;
Y ₁ represents — (CR _6a R _6b ) _m —Z ₁ — (CR _7a R _7b ) _n —;
Y ₂ represents — (CR _8a R _8b ) _p —Z ₂ — (CR _9a R _9b ) _q —;
Y ₃ represents — (CR _10a R _10b ) _r —Z ₃ — (CR _11a R _11b ) _s —;
Y ₄ represents — (CH ₂ ) _t —Z ₄ —;
Z ₁ -Z ₃ independently represents a bond, O, S, C (O) or the like;
Z ₄ represents a bond, O or N;
m, n, p, q, r and s independently represent 0-6;
t represents 0-2;
R _6a -R _11b are independently represents bond, H, _-OH, a _{C 1-3} alkoxy or _{C 1-3} alkyl and the like;
R ₁ , R ₂ and R ₃ are independently H, halogen, optionally substituted alkoxy, cyano, optionally substituted lower cycloalkyl, optionally substituted aryl, substituted A heterocycloalkyl, an optionally substituted heteroaryl, etc .;
R ₄ represents H, O, S, halogen, cyano, lower alkyl, lower alkenyl, aryl, lower heteroaryl or the like;
R ₅ and R ₁₃ independently represent H, halogen, lower alkyl, lower alkene or the like;
When X ₂ is N, R ₁₃ is absent;
R ₁₄ is absent or represents lower cycloalkyl, phenyl (which may each be substituted with C _1-3 alkyl or the like) and the like;
R ₁₆ represents lower alkyl, carbonyl, heteroaryl or the like]
The compound shown by (patent document 7).

(8) The following formula:

The compound shown by (nonpatent literature 9).

(9) The following formula:

[Where:
R ¹ represents an optionally substituted phenyl or an optionally substituted aromatic heterocyclic group;
R ² represents a hydrogen atom or a methyl group;
R ³ represents a 5- (R ⁵ ) -1H-imidazol-4-yl group or a 4- (R ⁵ ) -1H-imidazol-5-yl group;
R ⁴ represents a hydrogen atom, an amino group or a methylamino group;
R ⁵ represents a methyl group or an ethyl group]
The compound shown by (patent document 8).

(10) The following formula:

[Where:
X represents carbonyl or the like;
R ² and R ³ represent a hydrogen atom, halogen, lower alkyl, imidazolyl, imidazolylmethyl or —N (R ⁴ ) —R ⁵ ;
R ⁴ and R ⁵ represent a hydrogen atom or lower alkyl, or combine with each other to form a 5- or 6-membered heterocyclic ring.
The compound shown by (patent document 9).

International Publication No. WO02 / 092090 Pamphlet International Publication No. WO2010 / 011772 Pamphlet International Publication No. WO2010 / 011768 Pamphlet International Publication No. WO2010 / 011756 Pamphlet International Publication No. WO2010 / 011762 Pamphlet International Publication No. WO2010 / 068483 Pamphlet International Publication No. WO2011 / 149950 Pamphlet International Publication No. WO92 / 21658 Pamphlet International Publication No. WO91 / 009024 Pamphlet

An object of the present invention is to provide a compound having excellent PKC inhibitory activity and useful as a preventive or therapeutic agent for immune diseases, inflammatory diseases and the like.

As a result of intensive studies to solve the above problems, the present inventors have found that a compound represented by the following formula or a salt thereof has an excellent PKC inhibitory activity, and has completed the present invention.

That is, the present invention
[1] Formula (I):

[Where:
Ring A represents a nitrogen-containing unsaturated heterocyclic ring which may be further substituted;
Ring B represents a C _6-14 aromatic hydrocarbon ring which may be further substituted or an aromatic heterocyclic ring which may be further substituted;
L represents an optionally substituted C _1-2 alkylene;
X ¹ represents N or CR ¹ ;
X ² represents N or CR ² ;
X ³ represents N or CR ³ ;
X ⁴ represents N or CR ⁴ ;
R ¹ , R ² , R ³ and R ⁴ independently represent a hydrogen atom or a substituent;
X ⁵ represents CR ^5a , CR ^5b R ^5c , NR ^5d or a bond;
R ^5a , R ^5b , R ^5c and R ^5d independently represent a hydrogen atom or a substituent, or R ^5b and R ^5c may ^combine together to form an optionally substituted ring. Often;
X ⁶ represents CR ^6a R ^6b or NR ^6c ;
R ^6a , R ^6b and R ^6c independently represent a hydrogen atom or a substituent, or R ^6a and R ^6b may together form an optionally substituted ring;
R ⁷ represents a hydrogen atom or a substituent. ]
Or a salt thereof (hereinafter sometimes referred to as compound (I));
[2] The ring A is a monocyclic nitrogen-containing unsaturated heterocyclic ring which may be further substituted, or may be further substituted, the formula (A):

[Where:
Ring A ¹ represents an optionally further substituted 5- or 6-membered aromatic ring, or an optionally further substituted 5- or 6-membered non-aromatic unsaturated ring;
Ring A ² represents an optionally substituted 5- or 6-membered aromatic ring, or an optionally substituted 5- or 6-membered non-aromatic unsaturated ring;
At least one of the ring constituent atoms of ring A ¹ or ring A ² is a nitrogen atom. ]
A bicyclic nitrogen-containing unsaturated heterocycle represented by:
Ring B is a benzene ring which may be further substituted, or a thiophene ring which may be further substituted or a pyridine ring which may be further substituted;
L is C _1-2 alkylene;
X ¹ is N or CR ¹ and R ¹ is a hydrogen atom or a halogen atom;
X ² is N or CR ² and R ² is a hydrogen atom or a halogen atom;
X ³ is N or CR ³ , R ³ is a hydrogen atom or a halogen atom;
X ⁴ is N or CR ⁴ and R ⁴ is a hydrogen atom or a C _1-6 alkyl group;
X ⁵ is CR ^5b R ^5c or a bond, and R ^5b and R ^5c are independently a hydrogen atom or a substituent;
X ⁶ is CR ^6a R ^6b and R ^6a and R ^6b are independently a hydrogen atom or a substituent, or R ^6a and R ^6b may be substituted together to be substituted. Forming a ring;
R ⁷ is a hydrogen atom or an optionally substituted C _1-6 alkyl group;
[1] The compound according to [1] or a salt thereof;
[3] Ring A is a monocyclic nitrogen-containing unsaturated heterocyclic ring which may be further substituted with one or two substituents selected from a hydroxy group and an oxo group, or a halogen atom, hydroxy Selected from a group, an oxo group, an optionally substituted C _1-6 alkyl group, an optionally substituted C _1-6 alkoxy group, and an optionally substituted non-aromatic heterocyclic-oxy group; The ring A ¹ may be further substituted with three substituents, the ring A ¹ is a pyrrole ring, a pyrazole ring, an imidazole ring, a pyridine ring or an imidazoline ring, and the ring A ² is a thiophene ring, a pyridine ring or a pyrimidine ring A bicyclic nitrogen-containing unsaturated heterocyclic ring represented by the formula (A);
Ring B is
1 selected from (1) (i) a halogen atom, (ii) a cyano group, (iii) a C _1-6 alkyl group optionally substituted with a halogen atom or an amino group, and (iv) a C _1-6 alkoxy group A benzene ring optionally further substituted with up to 5 substituents,
(2) a thiophene ring, or (3) a pyridine ring;
L _{_{is, -CH 2 -, - CH 2}} CH 2 - or -CH (CH ₃₎ - and is,
X ¹ is N or CR ¹ and R ¹ is a hydrogen atom or a fluorine atom;
X ² is N or CR ² and R ² is a hydrogen atom or a fluorine atom;
X ³ is N or CR ³ , R ³ is a hydrogen atom or a fluorine atom;
X ⁴ is N or CR ⁴ and R ⁴ is a hydrogen atom or methyl;
X ⁵ is CR ^5b R ^5c or a bond, and R ^5b and R ^5c are hydrogen atoms;
X ⁶ is CR ^6a R ^6b , and R ^6a and R ^6b are a hydrogen atom, or independently, a C _1-6 alkyl group which may be substituted with a hydroxy group or a C _6-14 aryl group Or R ^6a and R ^6b together form a C _3-10 cycloalkane ring;
R ⁷ is a hydrogen atom or a C _1-6 alkyl group;
[2] The compound or a salt thereof according to [2];
[4] 2,2-Dimethyl-7- (2-oxo-2,3-dihydro-1H-imidazo [4,5-b] pyridin-1-yl) -1-((1R) -1-phenylethyl ) -2,3-dihydroquinazolin-4 (1H) -one or a salt thereof;
[5] 4-Benzyl-6- (2-oxo-2,3-dihydro-1H-imidazo [4,5-b] pyridin-1-yl) -3,4-dihydroisoquinolin-1 (2H) -one Or a salt thereof;
[6] 1-Benzyl-8- (2-oxo-2,3-dihydro-1H-imidazo [4,5-b] pyridin-1-yl) -1,2,3,4-tetrahydro-5H-pyrido [2,3-e] [1,4] diazepin-5-one or a salt thereof;
[7] A medicament comprising the compound or salt thereof according to [1];
[8] The medicament according to [7], which is a protein kinase C inhibitor;
[9] The medicament according to [7], which is a preventive or therapeutic agent for immune diseases and / or inflammatory diseases;
[10] The medicament according to [7], which is a prophylactic or therapeutic agent for inflammatory bowel disease, psoriasis or atopic dermatitis;
[11] The compound or salt thereof according to [1] for use in the prevention or treatment of immune diseases and / or inflammatory diseases;
[12] The compound or salt thereof according to [1] for use in the prevention or treatment of inflammatory bowel disease, psoriasis or atopic dermatitis;
[13] A method for inhibiting protein kinase C in a mammal, comprising administering an effective amount of the compound or salt thereof according to [1] to the mammal;
[14] A method for preventing or treating an immune disease or inflammatory disease in a mammal, comprising administering an effective amount of the compound or salt thereof according to [1] to the mammal;
[15] A method for preventing or treating inflammatory bowel disease, psoriasis or atopic dermatitis in a mammal, comprising administering an effective amount of the compound or salt thereof according to [1] to the mammal;
[16] Use of the compound or a salt thereof according to [1] for producing an agent for preventing or treating immune diseases and / or inflammatory diseases;
[17] Use of the compound or a salt thereof according to [1] for producing a preventive or therapeutic agent for inflammatory bowel disease, psoriasis or atopic dermatitis;
Etc.

Compound (I) has excellent PKC (eg, PKC-θ) inhibitory activity and is useful as a preventive or therapeutic agent for immune diseases and inflammatory diseases.

(Detailed description of the invention)
Hereinafter, the definition of each substituent used in the present specification will be described in detail. Unless otherwise specified, each substituent has the following definition.
In the present specification, examples of the “halogen atom” include fluorine, chlorine, bromine and iodine.
In the present specification, examples of the “C _1-6 alkyl group” include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl. , Isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl.
In the present specification, the "optionally halogenated C _1-6 alkyl group", for example, 1 to 7, preferably which may have 1 to 5 halogen atoms C _1-6 An alkyl group is mentioned. Specific examples include methyl, chloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl, ethyl, 2-bromoethyl, 2,2,2-trifluoroethyl, tetrafluoroethyl, pentafluoroethyl, propyl, 2,2- Difluoropropyl, 3,3,3-trifluoropropyl, isopropyl, butyl, 4,4,4-trifluorobutyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 5,5,5-tri Examples include fluoropentyl, hexyl, and 6,6,6-trifluorohexyl.
In the present specification, examples of the “C _2-6 alkenyl group” include ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 3- Examples include methyl-2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 3-hexenyl and 5-hexenyl.
In the present specification, examples of the “C _2-6 alkynyl group” include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3- Examples include pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 4-methyl-2-pentynyl.
In the present specification, examples of the “C _3-10 cycloalkyl group” include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo [2.2.1] heptyl, and bicyclo [2.2. 2] Octyl, bicyclo [3.2.1] octyl, and adamantyl.
In the present specification, the "optionally halogenated C _3-10 also be cycloalkyl group", for example, 1 to 7, preferably which may have 1 to 5 halogen atoms C _{3- A 10} cycloalkyl group. Specific examples include cyclopropyl, 2,2-difluorocyclopropyl, 2,3-difluorocyclopropyl, cyclobutyl, difluorocyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
In the present specification, examples of the “C _3-10 cycloalkenyl group” include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl.
In the present specification, examples of the “C _6-14 aryl group” include phenyl, 1-naphthyl, 2-naphthyl, 1-anthryl, 2-anthryl, and 9-anthryl.
In the present specification, examples of the “C _7-16 aralkyl group” include benzyl, phenethyl, naphthylmethyl, and phenylpropyl.

In the present specification, examples of the “C _1-6 alkoxy group” include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy and hexyloxy.
In the present specification, the "optionally halogenated C _1-6 alkoxy group", for example, 1 to 7, preferably which may have 1 to 5 halogen atoms C _1-6 An alkoxy group is mentioned. Specific examples include methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, 2,2,2-trifluoroethoxy, propoxy, isopropoxy, butoxy, 4,4,4-trifluorobutoxy, isobutoxy, sec-butoxy, pentyl. Examples include oxy and hexyloxy.
In the present specification, examples of the “C _3-10 cycloalkyloxy group” include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, and cyclooctyloxy.
In the present specification, examples of the “C _1-6 alkylthio group” include methylthio, ethylthio, propylthio, isopropylthio, butylthio, sec-butylthio, tert-butylthio, pentylthio and hexylthio.
In the present specification, the "optionally halogenated C _1-6 alkylthio group optionally", for example, 1 to 7, preferably which may have 1 to 5 halogen atoms C _1-6 An alkylthio group is mentioned. Specific examples include methylthio, difluoromethylthio, trifluoromethylthio, ethylthio, propylthio, isopropylthio, butylthio, 4,4,4-trifluorobutylthio, pentylthio, hexylthio.
In the present specification, examples of the “C _1-6 alkyl-carbonyl group” include acetyl, propanoyl, butanoyl, 2-methylpropanoyl, pentanoyl, 3-methylbutanoyl, 2-methylbutanoyl, 2,2- Examples include dimethylpropanoyl, hexanoyl, and heptanoyl.
In the present specification, examples of the “ _optionally halogenated C _1-6 alkyl-carbonyl group” include C ₁ optionally having 1 to 7, preferably 1 to 5 halogen atoms. _{A -6} alkyl-carbonyl group is mentioned. Specific examples include acetyl, chloroacetyl, trifluoroacetyl, trichloroacetyl, propanoyl, butanoyl, pentanoyl and hexanoyl.
In the present specification, examples of the “C _1-6 alkoxy-carbonyl group” include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, Examples include pentyloxycarbonyl and hexyloxycarbonyl.
In the present specification, examples of the “C _6-14 aryl-carbonyl group” include benzoyl, 1-naphthoyl and 2-naphthoyl.
In the present specification, examples of the “C _7-16 aralkyl-carbonyl group” include phenylacetyl and phenylpropionyl.
In the present specification, examples of the “5- to 14-membered aromatic heterocyclic carbonyl group” include nicotinoyl, isonicotinoyl, thenoyl and furoyl.
In the present specification, examples of the “3- to 14-membered non-aromatic heterocyclic carbonyl group” include morpholinylcarbonyl, piperidinylcarbonyl, and pyrrolidinylcarbonyl.

In the present specification, examples of the “mono- or di-C _1-6 alkyl-carbamoyl group” include methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl, diethylcarbamoyl, N-ethyl-N-methylcarbamoyl.
In the present specification, examples of the “mono- or di-C _7-16 aralkyl-carbamoyl group” include benzylcarbamoyl and phenethylcarbamoyl.
In the present specification, examples of the “C _1-6 alkylsulfonyl group” include methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, sec-butylsulfonyl and tert-butylsulfonyl.
In the present specification, the "optionally halogenated C _1-6 alkyl sulfonyl group", for example, 1 to 7, preferably which may have 1 to 5 halogen atoms C _{1- 6} alkylsulfonyl group is mentioned. Specific examples include methylsulfonyl, difluoromethylsulfonyl, trifluoromethylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, 4,4,4-trifluorobutylsulfonyl, pentylsulfonyl, hexylsulfonyl.
In the present specification, examples of the “C _6-14 arylsulfonyl group” include phenylsulfonyl, 1-naphthylsulfonyl and 2-naphthylsulfonyl.

In the present specification, examples of the “substituent” include a halogen atom, a cyano group, a nitro group, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, an acyl group, and a substituted group. An optionally substituted amino group, an optionally substituted carbamoyl group, an optionally substituted thiocarbamoyl group, an optionally substituted sulfamoyl group, an optionally substituted hydroxy group, an optionally substituted sulfanyl ( SH) group and optionally substituted silyl group.
In the present specification, examples of the “hydrocarbon group” (including the “hydrocarbon group” in the “optionally substituted hydrocarbon group”) include, for example, a C _1-6 alkyl group, a C _2-6 alkenyl group, Examples thereof include a C _2-6 alkynyl group, a C _3-10 cycloalkyl group, a C _3-10 cycloalkenyl group, a C _6-14 aryl group, and a C _7-16 aralkyl group.

In the present specification, examples of the “optionally substituted hydrocarbon group” include a hydrocarbon group which may have a substituent selected from the following substituent group A.
[Substituent group A]
(1) a halogen atom,
(2) Nitro group,
(3) a cyano group,
(4) an oxo group,
(5) a hydroxy group,
(6) an optionally halogenated C _1-6 alkoxy group,
(7) C _6-14 aryloxy group (eg, phenoxy, naphthoxy),
(8) C _7-16 aralkyloxy group (eg, benzyloxy),
(9) 5- to 14-membered aromatic heterocyclic oxy group (eg, pyridyloxy),
(10) 3 to 14-membered non-aromatic heterocyclic oxy group (eg, morpholinyloxy, piperidinyloxy),
(11) C _1-6 alkyl-carbonyloxy group (eg, acetoxy, propanoyloxy),
(12) C _6-14 aryl-carbonyloxy group (eg, benzoyloxy, 1-naphthoyloxy, 2-naphthoyloxy),
(13) C _1-6 alkoxy-carbonyloxy group (eg, methoxycarbonyloxy, ethoxycarbonyloxy, propoxycarbonyloxy, butoxycarbonyloxy),
(14) mono- or di-C _1-6 alkyl-carbamoyloxy group (eg, methylcarbamoyloxy, ethylcarbamoyloxy, dimethylcarbamoyloxy, diethylcarbamoyloxy),
(15) C _6-14 aryl-carbamoyloxy group (eg, phenylcarbamoyloxy, naphthylcarbamoyloxy),
(16) a 5- to 14-membered aromatic heterocyclic carbonyloxy group (eg, nicotinoyloxy),
(17) 3 to 14-membered non-aromatic heterocyclic carbonyloxy group (eg, morpholinylcarbonyloxy, piperidinylcarbonyloxy),
(18) an optionally halogenated C _1-6 alkylsulfonyloxy group (eg, methylsulfonyloxy, trifluoromethylsulfonyloxy),
(19) a C _6-14 arylsulfonyloxy group (eg, phenylsulfonyloxy, toluenesulfonyloxy) _optionally substituted with a C _1-6 alkyl group,
(20) an optionally halogenated C _1-6 alkylthio group,
(21) a 5- to 14-membered aromatic heterocyclic group,
(22) a 3- to 14-membered non-aromatic heterocyclic group,
(23) formyl group,
(24) a carboxy group,
(25) an optionally halogenated C _1-6 alkyl-carbonyl group,
(26) a C _6-14 aryl-carbonyl group,
(27) a 5- to 14-membered aromatic heterocyclic carbonyl group,
(28) a 3- to 14-membered non-aromatic heterocyclic carbonyl group,
(29) a C _1-6 alkoxy-carbonyl group,
(30) C _6-14 aryloxy-carbonyl group (eg, phenyloxycarbonyl, 1-naphthyloxycarbonyl, 2-naphthyloxycarbonyl),
(31) C _7-16 aralkyloxy-carbonyl group (eg, benzyloxycarbonyl, phenethyloxycarbonyl),
(32) a carbamoyl group,
(33) a thiocarbamoyl group,
(34) mono- or di-C _1-6 alkyl-carbamoyl group,
(35) C _6-14 aryl-carbamoyl group (eg, phenylcarbamoyl),
(36) 5- to 14-membered aromatic heterocyclic carbamoyl group (eg, pyridylcarbamoyl, thienylcarbamoyl),
(37) 3 to 14-membered non-aromatic heterocyclic carbamoyl group (eg, morpholinylcarbamoyl, piperidinylcarbamoyl),
(38) an optionally halogenated C _1-6 alkylsulfonyl group,
(39) a C _6-14 arylsulfonyl group,
(40) 5- to 14-membered aromatic heterocyclic sulfonyl group (eg, pyridylsulfonyl, thienylsulfonyl),
(41) an optionally halogenated C _1-6 alkylsulfinyl group,
(42) C _6-14 arylsulfinyl group (eg, phenylsulfinyl, 1-naphthylsulfinyl, 2-naphthylsulfinyl),
(43) a 5- to 14-membered aromatic heterocyclic sulfinyl group (eg, pyridylsulfinyl, thienylsulfinyl),
(44) an amino group,
(45) Mono- or di-C _1-6 alkylamino group (eg, methylamino, ethylamino, propylamino, isopropylamino, butylamino, dimethylamino, diethylamino, dipropylamino, dibutylamino, N-ethyl-N -Methylamino),
(46) mono- or di-C _6-14 arylamino group (eg, phenylamino),
(47) a 5- to 14-membered aromatic heterocyclic amino group (eg, pyridylamino),
(48) C _7-16 aralkylamino group (eg, benzylamino),
(49) formylamino group,
(50) C _1-6 alkyl-carbonylamino group (eg, acetylamino, propanoylamino, butanoylamino),
(51) (C _1-6 alkyl) (C _1-6 alkyl-carbonyl) amino group (eg, N-acetyl-N-methylamino),
(52) C _6-14 aryl-carbonylamino group (eg, phenylcarbonylamino, naphthylcarbonylamino),
(53) C _1-6 alkoxy-carbonylamino group (eg, methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino, butoxycarbonylamino, tert-butoxycarbonylamino),
(54) C _7-16 aralkyloxy-carbonylamino group (eg, benzyloxycarbonylamino),
(55) C _1-6 alkylsulfonylamino group (eg, methylsulfonylamino, ethylsulfonylamino),
(56) a C _6-14 arylsulfonylamino group (eg, phenylsulfonylamino, toluenesulfonylamino) _optionally substituted with a C _1-6 alkyl group,
(57) an optionally halogenated C _1-6 alkyl group,
(58) a C _2-6 alkenyl group,
(59) C _2-6 alkynyl group,
(60) C _3-10 cycloalkyl group,
(61) a C _3-10 cycloalkenyl group, and (62) a C _6-14 aryl group.

The number of the substituents in the “optionally substituted hydrocarbon group” is, for example, 1 to 5, preferably 1 to 3. When the number of substituents is 2 or more, each substituent may be the same or different.
In the present specification, examples of the “heterocyclic group” (including the “heterocyclic group” in the “optionally substituted heterocyclic group”) include, for example, a nitrogen atom, a sulfur atom and a ring atom other than a carbon atom. (I) an aromatic heterocyclic group, (ii) a non-aromatic heterocyclic group, and (iii) a 7 to 10-membered heterocyclic bridge group each containing 1 to 4 heteroatoms selected from oxygen atoms .

In the present specification, the “aromatic heterocyclic group” (including the “5- to 14-membered aromatic heterocyclic group”) is, for example, selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom as a ring-constituting atom. And 5- to 14-membered (preferably 5- to 10-membered) aromatic heterocyclic group containing 1 to 4 heteroatoms.
Suitable examples of the “aromatic heterocyclic group” include thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, 1,2,4-oxadiazolyl, 1 5-, 6-membered monocyclic aromatic heterocyclic groups such as 1,3,4-oxadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, triazolyl, tetrazolyl, triazinyl;
Benzothiophenyl, benzofuranyl, benzoimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzotriazolyl, imidazopyridinyl, thienopyridinyl, furopyridinyl, pyrrolopyridinyl, pyrazolopyridinyl, oxazolo Pyridinyl, thiazolopyridinyl, imidazopyrazinyl, imidazopyrimidinyl, thienopyrimidinyl, furopyrimidinyl, pyrrolopyrimidinyl, pyrazolopyrimidinyl, oxazolopyrimidinyl, thiazolopyrimidinyl, pyrazolotriazinyl, naphtho [2,3 -B] thienyl, phenoxathiinyl, indolyl, isoindolyl, 1H-indazolyl, purinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quina And 8- to 14-membered condensed polycyclic (preferably 2 or 3 ring) aromatic heterocyclic groups such as linyl, cinnolinyl, carbazolyl, β-carbolinyl, phenanthridinyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl .

In the present specification, examples of the “non-aromatic heterocyclic group” (including the “3- to 14-membered non-aromatic heterocyclic group”) include, for example, a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom as a ring-constituting atom. 3 to 14-membered (preferably 4 to 10-membered) non-aromatic heterocyclic group containing 1 to 4 heteroatoms selected from
Suitable examples of the “non-aromatic heterocyclic group” include aziridinyl, oxiranyl, thiylyl, azetidinyl, oxetanyl, thietanyl, tetrahydrothienyl, tetrahydrofuranyl, pyrrolinyl, pyrrolidinyl, imidazolinyl, imidazolidinyl, oxazolinyl, oxazolidinyl, pyrazolidinyl, pyrazolinyl, pyrazolinyl Thiazolinyl, thiazolidinyl, tetrahydroisothiazolyl, tetrahydrooxazolyl, tetrahydroisoxazolyl, piperidinyl, piperazinyl, tetrahydropyridinyl, dihydropyridinyl, dihydrothiopyranyl, tetrahydropyrimidinyl, tetrahydropyridazinyl, dihydropyrani , Tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, azepanyl, diaze Cycloalkenyl, azepinyl, oxepanyl, azocanyl, 3 to 8-membered monocyclic non-aromatic heterocyclic group such as Jiazokaniru;
Dihydrobenzofuranyl, dihydrobenzimidazolyl, dihydrobenzoxazolyl, dihydrobenzothiazolyl, dihydrobenzoisothiazolyl, dihydronaphtho [2,3-b] thienyl, tetrahydroisoquinolyl, tetrahydroquinolyl, 4H-quinolidinyl, Indolinyl, isoindolinyl, tetrahydrothieno [2,3-c] pyridinyl, tetrahydrobenzoazepinyl, tetrahydroquinoxalinyl, tetrahydrophenanthridinyl, hexahydrophenothiazinyl, hexahydrophenoxazinyl, tetrahydrophthalazinyl, tetrahydro Naphthyridinyl, tetrahydroquinazolinyl, tetrahydrocinnolinyl, tetrahydrocarbazolyl, tetrahydro-β-carbolinyl, tetrahydroacridinyl, tetrahydro Rofenajiniru, tetrahydrothiophenyl key Sante alkenyl, 9 to 14 membered fused polycyclic, such as octahydro-isoquinolylmethyl (preferably 2 or tricyclic), and the non-aromatic heterocyclic group.

In the present specification, preferable examples of the “7 to 10-membered heterocyclic bridged ring group” include quinuclidinyl and 7-azabicyclo [2.2.1] heptanyl.
In the present specification, examples of the “nitrogen-containing heterocyclic group” include those containing at least one nitrogen atom as a ring-constituting atom among the “heterocyclic groups”.
In the present specification, examples of the “optionally substituted heterocyclic group” include a heterocyclic group which may have a substituent selected from the substituent group A described above.
The number of substituents in the “optionally substituted heterocyclic group” is, for example, 1 to 3. When the number of substituents is 2 or more, each substituent may be the same or different.

In the present specification, the “acyl group” is, for example, “1 selected from a halogen atom, an optionally halogenated C _1-6 alkoxy group, a hydroxy group, a nitro group, a cyano group, an amino group, and a carbamoyl group. C _1-6 alkyl group, C _2-6 alkenyl group, C _3-10 cycloalkyl group, C _3-10 cycloalkenyl group, C _6-14 aryl each optionally having 3 substituents Formyl optionally having 1 or 2 substituents selected from the group, a C _7-16 aralkyl group, a 5- to 14-membered aromatic heterocyclic group and a 3- to 14-membered non-aromatic heterocyclic group ” Group, carboxy group, carbamoyl group, thiocarbamoyl group, sulfino group, sulfo group, sulfamoyl group and phosphono group.
The “acyl group” also includes a hydrocarbon-sulfonyl group, a heterocyclic-sulfonyl group, a hydrocarbon-sulfinyl group, and a heterocyclic-sulfinyl group.
Here, the hydrocarbon-sulfonyl group is a sulfonyl group to which a hydrocarbon group is bonded, the heterocyclic-sulfonyl group is a sulfonyl group to which a heterocyclic group is bonded, and the hydrocarbon-sulfinyl group is a hydrocarbon group. A sulfinyl group to which is bonded and a heterocyclic-sulfinyl group mean a sulfinyl group to which a heterocyclic group is bonded.
As preferable examples of the “acyl group”, a formyl group, a carboxy group, a C _1-6 alkyl-carbonyl group, a C _2-6 alkenyl-carbonyl group (eg, crotonoyl), a C _3-10 cycloalkyl-carbonyl group ( Examples, cyclobutanecarbonyl, cyclopentanecarbonyl, cyclohexanecarbonyl, cycloheptanecarbonyl), C _3-10 cycloalkenyl-carbonyl group (eg, 2-cyclohexenecarbonyl), C _6-14 aryl-carbonyl group, C _7-16 aralkyl- Carbonyl group, 5- to 14-membered aromatic heterocyclic carbonyl group, 3- to 14-membered non-aromatic heterocyclic carbonyl group, C _1-6 alkoxy-carbonyl group, C _6-14 aryloxy-carbonyl group (eg, phenyloxycarbonyl) , _{naphthyloxycarbonyl), C 7- 6} aralkyloxy - carbonyl group (e.g., benzyloxycarbonyl, phenethyloxycarbonyl carbonyl), a carbamoyl group, mono- - or di _{-C 1-6} alkyl - carbamoyl group, mono- - or di _{-C 2-6} alkenyl - carbamoyl group (e.g. , Diallylcarbamoyl), mono- or di-C _3-10 cycloalkyl-carbamoyl group (eg, cyclopropylcarbamoyl), mono- or di-C _6-14 aryl-carbamoyl group (eg, phenylcarbamoyl), mono- or Di-C _7-16 aralkyl-carbamoyl group, 5- to 14-membered aromatic heterocyclic carbamoyl group (eg, pyridylcarbamoyl), thiocarbamoyl group, mono- or di-C _1-6 alkyl-thiocarbamoyl group (eg, methylthio) Carbamoyl, N-ethyl-N-methyl Okarubamoiru), mono - or di _{-C 2-6} alkenyl - thiocarbamoyl group (e.g., diallyl thio carbamoyl), mono - or di _{-C 3-10} cycloalkyl - thiocarbamoyl group (e.g., cyclopropyl thiocarbamoyl, cyclohexyl Thiocarbamoyl), mono- or di-C _6-14 aryl-thiocarbamoyl group (eg, phenylthiocarbamoyl), mono- or di-C _7-16 aralkyl-thiocarbamoyl group (eg, benzylthiocarbamoyl, phenethylthiocarbamoyl) ) 5- to 14-membered aromatic heterocyclic thiocarbamoyl group (eg, pyridylthiocarbamoyl), sulfino group, C _1-6 alkylsulfinyl group (eg, methylsulfinyl, ethylsulfinyl), sulfo group, C _1-6 alkylsulfonyl _{group, C 6- 4} arylsulfonyl group, a phosphono group, a mono - or di -C _1-6 alkyl phosphono group (e.g., dimethylphosphono, diethylphosphono, diisopropylphosphono, dibutylphosphono) and the like.

In the present specification, examples of the “optionally substituted amino group” include, for example, a “C _1-6 alkyl group _optionally having 1 to 3 substituents selected from the substituent group A” C _2-6 alkenyl group, C _3-10 cycloalkyl group, C _6-14 aryl group, C _7-16 aralkyl group, C _1-6 alkyl-carbonyl group, C _6-14 aryl-carbonyl group, C _{7 -16} aralkyl-carbonyl group, 5- to 14-membered aromatic heterocyclic carbonyl group, 3- to 14-membered non-aromatic heterocyclic carbonyl group, C _1-6 alkoxy-carbonyl group, 5- to 14-membered aromatic heterocyclic group, carbamoyl Groups, mono- or di-C _1-6 alkyl-carbamoyl groups, mono- or di-C _7-16 aralkyl-carbamoyl groups, C _1-6 alkylsulfonyl groups and C _{6- And an} amino group optionally having 1 or 2 substituents selected from ₁₄ arylsulfonyl groups.
Suitable examples of the optionally substituted amino group include an amino group, a mono- or di- (optionally halogenated C _1-6 alkyl) amino group (eg, methylamino, trifluoromethylamino, Dimethylamino, ethylamino, diethylamino, propylamino, dibutylamino), mono- or di-C _2-6 alkenylamino groups (eg, diallylamino), mono- or di-C _3-10 cycloalkylamino groups (eg, Cyclopropylamino, cyclohexylamino), mono- or di-C _6-14 arylamino group (eg, phenylamino), mono- or di-C _7-16 aralkylamino group (eg, benzylamino, dibenzylamino), mono - or di - (optionally halogenated C _1-6 alkyl) - carbonyl amino group (e.g., a Chiruamino, propionylamino), mono- - or di _{-C 6-14} aryl - carbonyl amino group (e.g., benzoylamino), mono - or di _{-C 7-16} aralkyl - carbonyl amino group (e.g., benzyl carbonyl amino), mono -Or di-5 to 14-membered aromatic heterocyclic carbonylamino group (eg, nicotinoylamino, isonicotinoylamino), mono- or di-3 to 14-membered non-aromatic heterocyclic carbonylamino group (eg, piperidyl) Nylcarbonylamino), mono- or di-C _1-6 alkoxy-carbonylamino group (eg, tert-butoxycarbonylamino), 5- to 14-membered aromatic heterocyclic amino group (eg, pyridylamino), carbamoylamino group, ( mono - or di _{-C 1-6} alkyl - carbamoyl) amino group (e.g., methylcarbamoyl Carbamoylamino), (mono - or di _{-C 7-16} aralkyl - carbamoyl) amino group (e.g., benzylcarbamoyl _{amino), C 1-6} alkylsulfonylamino group (e.g., methylsulfonylamino, ethylsulfonylamino), _{C 6 -14} arylsulfonylamino group (eg, phenylsulfonylamino), (C _1-6 alkyl) (C _1-6 alkyl-carbonyl) amino group (eg, N-acetyl-N-methylamino), (C _1-6 Alkyl) (C _6-14 aryl-carbonyl) amino group (eg, N-benzoyl-N-methylamino).

In the present specification, examples of the “optionally substituted carbamoyl group” include, for example, a “C _1-6 alkyl group _optionally having 1 to 3 substituents selected from the substituent group A” C _2-6 alkenyl group, C _3-10 cycloalkyl group, C _6-14 aryl group, C _7-16 aralkyl group, C _1-6 alkyl-carbonyl group, C _6-14 aryl-carbonyl group, C _{7 -16} aralkyl-carbonyl group, 5- to 14-membered aromatic heterocyclic carbonyl group, 3- to 14-membered non-aromatic heterocyclic carbonyl group, C _1-6 alkoxy-carbonyl group, 5- to 14-membered aromatic heterocyclic group, carbamoyl group, mono - or di _{-C 1-6} alkyl - carbamoyl group and mono- - or di _{-C 7-16} aralkyl - 1 or 2 substituents selected from a carbamoyl group The have include a carbamoyl group which may.
Suitable examples of the optionally substituted carbamoyl group include a carbamoyl group, a mono- or di-C _1-6 alkyl-carbamoyl group, a mono- or di-C _2-6 alkenyl-carbamoyl group (eg, diallylcarbamoyl group). ), Mono- or di-C _3-10 cycloalkyl-carbamoyl groups (eg cyclopropylcarbamoyl, cyclohexylcarbamoyl), mono- or di-C _6-14 aryl-carbamoyl groups (eg phenylcarbamoyl), mono- or Di-C _7-16 aralkyl-carbamoyl group, mono- or di-C _1-6 alkyl-carbonyl-carbamoyl group (eg acetylcarbamoyl, propionylcarbamoyl), mono- or di-C _6-14 aryl-carbonyl-carbamoyl Groups (eg, benzoylcarbamoyl) A 5- to 14-membered aromatic heterocyclic carbamoyl group (eg, pyridylcarbamoyl) can be mentioned.

In the present specification, examples of the “optionally substituted thiocarbamoyl group” include, for example, “C _1-6 alkyl each optionally having 1 to 3 substituents selected from Substituent Group A” Group, C _2-6 alkenyl group, C _3-10 cycloalkyl group, C _6-14 aryl group, C _7-16 aralkyl group, C _1-6 alkyl-carbonyl group, C _6-14 aryl-carbonyl group, C _7-16 aralkyl-carbonyl group, 5- to 14-membered aromatic heterocyclic carbonyl group, 3- to 14-membered non-aromatic heterocyclic carbonyl group, C _1-6 alkoxy-carbonyl group, 5- to 14-membered aromatic heterocyclic group, carbamoyl group, mono - or di _{-C 1-6} alkyl - carbamoyl group and mono- - or di _{-C 7-16} aralkyl - one or two location selected from a carbamoyl group Have a group "include good thiocarbamoyl group.
Suitable examples of the thiocarbamoyl group which may be substituted include a thiocarbamoyl group, a mono- or di-C _1-6 alkyl-thiocarbamoyl group (eg, methylthiocarbamoyl, ethylthiocarbamoyl, dimethylthiocarbamoyl, diethylthio). Carbamoyl, N-ethyl-N-methylthiocarbamoyl), mono- or di-C _2-6 alkenyl-thiocarbamoyl group (eg diallylthiocarbamoyl), mono- or di-C _3-10 cycloalkyl-thiocarbamoyl group ( Examples, cyclopropylthiocarbamoyl, cyclohexylthiocarbamoyl), mono- or di-C _6-14 aryl-thiocarbamoyl group (eg, phenylthiocarbamoyl), mono- or di-C _7-16 aralkyl-thiocarbamoyl group (eg, , Benzylthioca Bamoiru, phenethyl thio carbamoyl), mono - or di _{-C 1-6} alkyl - carbonyl - thiocarbamoyl group (e.g., acetyl thiocarbamoyl, propionylthio carbamoyl), mono - or di _{-C 6-14} aryl - carbonyl - thiocarbamoyl Groups (eg, benzoylthiocarbamoyl), 5- to 14-membered aromatic heterocyclic thiocarbamoyl groups (eg, pyridylthiocarbamoyl).

In the present specification, examples of the “optionally substituted sulfamoyl group” include a “C _1-6 alkyl group each optionally having 1 to 3 substituents selected from the substituent group A”. C _2-6 alkenyl group, C _3-10 cycloalkyl group, C _6-14 aryl group, C _7-16 aralkyl group, C _1-6 alkyl-carbonyl group, C _6-14 aryl-carbonyl group, C _{7 -16} aralkyl-carbonyl group, 5- to 14-membered aromatic heterocyclic carbonyl group, 3- to 14-membered non-aromatic heterocyclic carbonyl group, C _1-6 alkoxy-carbonyl group, 5- to 14-membered aromatic heterocyclic group, carbamoyl group, mono - or di _{-C 1-6} alkyl - carbamoyl group and mono- - or di _{-C 7-16} aralkyl - 1 or 2 substituents selected from a carbamoyl group Have a "include sulfamoyl group.
Preferable examples of the optionally substituted sulfamoyl group include sulfamoyl group, mono- or di-C _1-6 alkyl-sulfamoyl group (eg, methylsulfamoyl, ethylsulfamoyl, dimethylsulfamoyl, diethyl). Sulfamoyl, N-ethyl-N-methylsulfamoyl), mono- or di-C _2-6 alkenyl-sulfamoyl groups (eg diallylsulfamoyl), mono- or di-C _3-10 cycloalkyl- Sulfamoyl group (eg, cyclopropylsulfamoyl, cyclohexylsulfamoyl), mono- or di-C _6-14 aryl-sulfamoyl group (eg, phenylsulfamoyl), mono- or di-C _7-16 aralkyl- Sulfamoyl group (eg, benzylsulfamoyl, phenethylsulfamoy) ), Mono - or di _{-C 1-6} alkyl - carbonyl - sulfamoyl group (e.g., acetyl sulfamoyl, propionitrile acylsulfamoyl), mono - or di _{-C 6-14} aryl - carbonyl - sulfamoyl group (e.g., benzoyl Sulfamoyl) and 5- to 14-membered aromatic heterocyclic sulfamoyl groups (eg, pyridylsulfamoyl).

In the present specification, examples of the “optionally substituted hydroxy group” include a “C _1-6 alkyl group each optionally having 1 to 3 substituents selected from the substituent group A”. C _2-6 alkenyl group, C _3-10 cycloalkyl group, C _6-14 aryl group, C _7-16 aralkyl group, C _1-6 alkyl-carbonyl group, C _6-14 aryl-carbonyl group, C _{7 -16} aralkyl-carbonyl group, 5- to 14-membered aromatic heterocyclic carbonyl group, 3- to 14-membered non-aromatic heterocyclic carbonyl group, C _1-6 alkoxy-carbonyl group, 5- to 14-membered aromatic heterocyclic group, carbamoyl Groups, mono- or di-C _1-6 alkyl-carbamoyl groups, mono- or di-C _7-16 aralkyl-carbamoyl groups, C _1-6 alkylsulfonyl groups and C _{And a} hydroxy group optionally having a substituent selected from _6-14 arylsulfonyl groups.
Suitable examples of the optionally substituted hydroxy group include a hydroxy group, a C _1-6 alkoxy group, a C _2-6 alkenyloxy group (eg, allyloxy, 2-butenyloxy, 2-pentenyloxy, 3-hexenyloxy). ), C _3-10 cycloalkyloxy group (eg, cyclohexyloxy), C _6-14 aryloxy group (eg, phenoxy, naphthyloxy), C _7-16 aralkyloxy group (eg, benzyloxy, phenethyloxy), C _1-6 alkyl-carbonyloxy group (eg, acetyloxy, propionyloxy, butyryloxy, isobutyryloxy, pivaloyloxy), C _6-14 aryl-carbonyloxy group (eg, benzoyloxy), C _7-16 aralkyl- A carbonyloxy group (eg benzylcarbonyloxy) ), 5 to 14-membered aromatic heterocyclic carbonyloxy group (e.g., nicotinoyl oxy), 3 to 14-membered non-aromatic heterocyclic carbonyloxy group (e.g., piperidinylcarbonyl oxy), C _1-6 alkoxy - carbonyl An oxy group (eg, tert-butoxycarbonyloxy), a 5- to 14-membered aromatic heterocyclic oxy group (eg, pyridyloxy), a carbamoyloxy group, a C _1-6 alkyl-carbamoyloxy group (eg, methylcarbamoyloxy), C _7-16 aralkyl-carbamoyloxy group (eg, benzylcarbamoyloxy), C _1-6 alkylsulfonyloxy group (eg, methylsulfonyloxy, ethylsulfonyloxy), C _6-14 arylsulfonyloxy group (eg, phenylsulfonyl) Oxy).

In the present specification, examples of the “optionally substituted sulfanyl group” include a “C _1-6 alkyl group _optionally having 1 to 3 substituents selected from the substituent group A”. C _2-6 alkenyl group, C _3-10 cycloalkyl group, C _6-14 aryl group, C _7-16 aralkyl group, C _1-6 alkyl-carbonyl group, C _6-14 aryl-carbonyl group and 5 to Examples thereof include a sulfanyl group optionally having a substituent selected from a 14-membered aromatic heterocyclic group and a halogenated sulfanyl group.
Preferable examples of the optionally substituted sulfanyl group include a sulfanyl (—SH) group, a C _1-6 alkylthio group, a C _2-6 alkenylthio group (eg, allylthio, 2-butenylthio, 2-pentenylthio, 3-hexenylthio), C _3-10 cycloalkylthio group (eg, cyclohexylthio), C _6-14 arylthio group (eg, phenylthio, naphthylthio), C _7-16 aralkylthio group (eg, benzylthio, phenethylthio), C _1-6 alkyl-carbonylthio group (eg, acetylthio, propionylthio, butyrylthio, isobutyrylthio, pivaloylthio), C _6-14 aryl-carbonylthio group (eg, benzoylthio), 5- to 14-membered aromatic heterocyclic thio group (Eg, pyridylthio), halogenated thio groups (eg, pentafluorothio) E).

In the present specification, examples of the “optionally substituted silyl group” include a “C _1-6 alkyl group each optionally having 1 to 3 substituents selected from the substituent group A” A silyl group optionally having 1 to 3 substituents selected from a C _2-6 alkenyl group, a C _3-10 cycloalkyl group, a C _6-14 aryl group and a C _7-16 aralkyl group ” Can be mentioned.
Preferable examples of the optionally substituted silyl group include a tri-C _1-6 alkylsilyl group (eg, trimethylsilyl, tert-butyl (dimethyl) silyl).

In this specification, examples of the “C _1-6 alkylene group” include —CH ₂ —, — (CH ₂ ) ₂ —, — (CH ₂ ) ₃ —, — (CH ₂ ) ₄ —, — (CH ₂ ) ₅ —, — (CH ₂ ) ₆ —, —CH (CH ₃ ) —, —C (CH ₃ ) ₂ —, —CH (C ₂ H ₅ ) —, —CH (C ₃ H ₇ ) —, —CH (CH (CH ₃ ) ₂ ) —, — (CH (CH ₃ )) ₂ —, —CH ₂ —CH (CH ₃ ) —, —CH (CH ₃ ) —CH ₂ —, —CH ₂ —CH _{_{_{_{2 -C (CH 3) 2 -}}}} , - C (CH 3) 2 -CH 2 -CH 2 -, - CH 2 -CH 2 -CH 2 -C (CH 3) 2 -, - C (CH 3) 2 And —CH ₂ —CH ₂ —CH ₂ —.
In the present specification, examples of the “C _2-6 alkenylene group” include —CH═CH—, —CH ₂ —CH═CH—, —CH═CH—CH ₂ —, —C (CH ₃ ) ₂ —. CH═CH—, —CH═CH—C (CH ₃ ) ₂ —, —CH ₂ —CH═CH—CH ₂ —, —CH ₂ —CH ₂ —CH═CH—, —CH═CH—CH ₂ — _{_{CH 2 -, - CH = CH}} -CH = CH -, - CH = CH-CH 2 -CH 2 -CH 2 -, - CH 2 -CH 2 -CH 2 -CH = CH- and the like.
In the present specification, examples of the “C _2-6 alkynylene group” include —C≡C—, —CH ₂ —C≡C—, —C≡C—CH ₂ —, —C (CH ₃ ) ₂ —. _{C≡C -, - C≡C-C (} CH 3) 2 -, - CH 2 -C≡C-CH 2 -, - CH 2 -CH 2 -C≡C -, - C≡C-CH 2 - _{CH 2 -, - C≡C-C≡C} -, - C≡C-CH 2 -CH 2 -CH 2 -, - CH 2 -CH 2 -CH 2 -C≡C- , and the like.

In the present specification, examples of the “hydrocarbon ring” include a C _6-14 aromatic hydrocarbon ring, a C _3-10 cycloalkane, and a C _3-10 cycloalkene.
In the present specification, examples of the “C _6-14 aromatic hydrocarbon ring” include benzene and naphthalene.
In the present specification, examples of “C _3-10 cycloalkane” include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, and cyclooctane.
In the present specification, examples of “C _3-10 cycloalkene” include cyclopropene, cyclobutene, cyclopentene, cyclohexene, cycloheptene, and cyclooctene.
In the present specification, examples of the “heterocycle” include aromatic heterocycles each containing 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom, and an oxygen atom in addition to a carbon atom as a ring-constituting atom. Non-aromatic heterocycles may be mentioned.

In the present specification, the “aromatic heterocycle” is, for example, a 5- to 14-membered member containing 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom as a ring constituent atom ( Preferred is a 5- to 10-membered aromatic heterocyclic ring. Preferable examples of the “aromatic heterocyclic ring” include thiophene, furan, pyrrole, imidazole, pyrazole, thiazole, isothiazole, oxazole, isoxazole, pyridine, pyrazine, pyrimidine, pyridazine, 1,2,4-oxadi 5- to 6-membered monocyclic aromatic heterocycle such as azole, 1,3,4-oxadiazole, 1,2,4-thiadiazole, 1,3,4-thiadiazole, triazole, tetrazole, triazine;
Benzothiophene, benzofuran, benzimidazole, benzoxazole, benzoisoxazole, benzothiazole, benzoisothiazole, benzotriazole, imidazopyridine, thienopyridine, furopyridine, pyrrolopyridine, pyrazolopyridine, oxazolopyridine, thiazolopyridine, imidazopyrazine, Imidazopyrimidine, thienopyrimidine, furopyrimidine, pyrrolopyrimidine, pyrazolopyrimidine, oxazolopyrimidine, thiazolopyrimidine, pyrazolopyrimidine, pyrazolotriazine, naphtho [2,3-b] thiophene, phenoxathiin, indol, Isoindole, 1H-indazole, purine, isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, cal Tetrazole, beta-carboline, phenanthridine, acridine, phenazine, phenothiazine, 8 to 14 membered fused polycyclic, such as phenoxazine (preferably 2 or tricyclic) and aromatic heterocycle.

In the present specification, the “non-aromatic heterocycle” includes, for example, a 3 to 14 member containing 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom as a ring constituent atom. (Preferably 4 to 10 membered) non-aromatic heterocycle. Suitable examples of the “non-aromatic heterocycle” include aziridine, oxirane, thiirane, azetidine, oxetane, thietane, tetrahydrothiophene, tetrahydrofuran, pyrroline, pyrrolidine, imidazoline, imidazolidine, oxazoline, oxazolidine, pyrazoline, pyrazolidine, thiazoline. , Thiazolidine, tetrahydroisothiazole, tetrahydrooxazole, tetrahydroisoxazole, piperidine, piperazine, tetrahydropyridine, dihydropyridine, dihydrothiopyran, tetrahydropyrimidine, tetrahydropyridazine, dihydropyran, tetrahydropyran, tetrahydrothiopyran, morpholine, thiomorpholine, azepanine, 3 types such as diazepan, azepine, azocan, diazocan, oxepane 8-membered monocyclic non-aromatic heterocyclic ring and;
Dihydrobenzofuran, dihydrobenzimidazole, dihydrobenzoxazole, dihydrobenzothiazole, dihydrobenzoisothiazole, dihydronaphtho [2,3-b] thiophene, tetrahydroisoquinoline, tetrahydroquinoline, 4H-quinolidine, indoline, isoindoline, tetrahydrothieno [2 , 3-c] pyridine, tetrahydrobenzazepine, tetrahydroquinoxaline, tetrahydrophenanthridine, hexahydrophenothiazine, hexahydrophenoxazine, tetrahydrophthalazine, tetrahydronaphthyridine, tetrahydroquinazoline, tetrahydrocinnoline, tetrahydrocarbazole, tetrahydro-β-carboline Tetrahydroacridine, tetrahydrophenazine, tetrahydrothi Xanthene, 9 to 14 membered fused polycyclic, such as octahydro-isoquinoline (preferably 2 or tricyclic) non-aromatic heterocyclic ring.
In the present specification, examples of the “nitrogen-containing heterocycle” include those containing at least one nitrogen atom as a ring-constituting atom among the “heterocycle”.

In the present specification, the “nitrogen-containing unsaturated heterocycle” of the “optionally substituted nitrogen-containing unsaturated heterocycle” includes one or more multiple bonds (eg, Those containing a double bond or a triple bond), and examples of the substituent include the above-mentioned “substituent”. The “nitrogen-containing unsaturated heterocycle” includes a nitrogen-containing aromatic heterocycle.

In the present specification, “C _1-2 alkylene” of “optionally substituted C _1-2 alkylene” includes those having 1 or 2 carbon atoms in the above “C _1-6 alkylene group”. Examples of the substituent include the above-mentioned “substituent”.

In the present specification, examples of the “ring” of the “optionally substituted ring” include the above “hydrocarbon ring” and “heterocycle”, and the substituent includes the above “substituent”. .
In the present specification, the “aromatic ring” of the “optionally substituted 5- or 6-membered aromatic ring” includes a benzene ring and the above “aromatic heterocycle” having 5 or 6 carbon atoms. Examples of the substituent include the above-mentioned “substituent”.
In the present specification, the “non-aromatic unsaturated ring” of the “optionally substituted 5-membered or 6-membered non-aromatic unsaturated ring” is the carbon number of the above “C _3-10 cycloalkene”. Of the above-mentioned “heterocycle” having 5 or 6 carbon atoms and containing one or more multiple bonds (eg, double bonds, triple bonds), and the substituents thereof. As the above, the above-mentioned “substituent” can be mentioned.

Below, the definition of each symbol in Formula (I) is explained in full detail.
Ring A represents a nitrogen-containing unsaturated heterocyclic ring which may be further substituted.
Examples of the “nitrogen-containing unsaturated heterocycle” of the “optionally substituted nitrogen-containing unsaturated heterocycle” represented by ring A include monocyclic or bicyclic nitrogen-containing unsaturated heterocycles.
Examples of the “substituent” of the “optionally substituted nitrogen-containing unsaturated heterocyclic ring” represented by ring A include a halogen atom (eg, fluorine atom), a hydroxy group, an oxo group, and an optionally substituted C _{A 1-6} alkyl group (eg, methyl, ethyl), an optionally substituted C _1-6 alkoxy group (eg, methoxy), an optionally substituted non-aromatic heterocyclic-oxy group (eg, tetrahydropyrani) Ruoxy).

Ring A is preferably further substituted, formula (A):

[Where:
Ring A ¹ represents an optionally further substituted 5- or 6-membered aromatic ring, or an optionally further substituted 5- or 6-membered non-aromatic unsaturated ring;
Ring A ² represents an optionally substituted 5- or 6-membered aromatic ring, or an optionally substituted 5- or 6-membered non-aromatic unsaturated ring;
At least one of the ring constituent atoms of ring A ¹ or ring A ² is a nitrogen atom. ]
It is a bicyclic nitrogen-containing unsaturated heterocyclic ring represented by these.

Here, in the present specification, in the above formula (A) (when ring A ¹ and ring A ² have one shared bond to form a bicyclic ring), formation of the bicyclic ring It is assumed that the bond multiplicity of the ring A ^{1 and} the bond multiplicity of the ring A ² involved in is the same. For example, the formula (A) is

, Ring A ¹ is an imidazole ring, ring A ² is a pyridine ring, and formula (A) is

The ring A ¹ is an imidazoline ring and the ring A ² is a pyridine ring.

Examples of the “aromatic ring” of the “(further) optionally substituted 5-membered or 6-membered aromatic ring” represented by ring A ¹ or ring A ² include pyrrole ring, thiophene ring, pyrazole ring, imidazole ring, pyridine And a ring and a pyrimidine ring.
Examples of the “non-aromatic unsaturated ring” of the “(further) optionally substituted 5- or 6-membered non-aromatic unsaturated ring” represented by ring A ¹ or ring A ² include imidazoline ring, tetrahydropyrazine A ring is mentioned.
“(Further) optionally substituted 5- or 6-membered aromatic ring” or “(further) optionally substituted 5- or 6-membered unsaturated ring” represented by ring A ¹ or ring A ² As the “substituent”, a halogen atom (eg, fluorine atom), a hydroxy group, an oxo group, an optionally substituted C _1-6 alkyl group (eg, methyl, ethyl), an optionally substituted C _{A 1-6} alkoxy group (eg, methoxy) and a non-aromatic heterocyclic-oxy group (eg, tetrahydropyranyloxy) which may be substituted.

Ring A is more preferably a halogen atom (eg, fluorine atom), a hydroxy group, an oxo group, an optionally substituted C _1-6 alkyl group (eg, methyl, ethyl), an optionally substituted C 1 to 3 (preferably 1 or 2) selected from a _1-6 alkoxy group (eg, methoxy) and an optionally substituted non-aromatic heterocyclic-oxy group (eg, tetrahydropyranyloxy) Ring A ¹ which may be further substituted with a substituent is pyrrole ring, pyrazole ring, imidazole ring, thiophene ring, pyridine ring, imidazoline ring or tetrahydropyrazine ring, and ring A ² is pyrrole ring, thiophene ring, pyridine It is a bicyclic nitrogen-containing unsaturated heterocycle represented by the formula (A) which is a ring or a pyrimidine ring.
Ring A is even more preferably a 1H-imidazo [4,5-b] pyridine ring further substituted with a hydroxy group or a 1H-pyrrolo [2,3-b] pyridine ring further substituted with methyl.

In another embodiment of the present invention, ring A is preferably an optionally substituted monocyclic nitrogen-containing unsaturated heterocycle (eg, imidazolidine ring, imidazoline ring), more preferably, It is a monocyclic nitrogen-containing unsaturated heterocyclic ring (eg, imidazolidine ring, imidazoline ring) which may be further substituted with one or two substituents selected from a hydroxy group and an oxo group.

In the present specification, ring A includes any tautomer when tautomers (enol form and keto form) exist. For example, when Ring A is imidazo [4,5-b] pyridine, further substituted with hydroxy, the formula:

There are two tautomers (enol form (a) and keto form (b)) shown by the following formula, and ring A includes both tautomers.

Ring B represents a C _6-14 aromatic hydrocarbon ring which may be further substituted or an aromatic heterocyclic ring which may be further substituted.
The “C _6-14 aromatic hydrocarbon ring” of the “ _optionally substituted C _6-14 aromatic hydrocarbon ring” represented by ring B includes a benzene ring.
Examples of the “aromatic heterocycle” of the “optionally substituted aromatic heterocycle” represented by ring B include a thiophene ring and a pyridine ring.
As the “substituent” of the “optionally substituted C _6-14 aromatic hydrocarbon ring” and the “optionally substituted aromatic heterocycle” represented by ring B, a halogen atom (eg, A fluorine atom, a chlorine atom), a cyano group, an optionally substituted C _1-6 alkyl group (eg, methyl), and an optionally substituted C _1-6 alkoxy group (eg, methoxy).

Ring B is preferably a benzene ring which may be further substituted, or a thiophene ring or a pyridine ring which may be further substituted, more preferably a halogen atom (eg, fluorine atom, chlorine atom), 1 to 5 (preferably 1 to 5) selected from a cyano group, an optionally substituted C _1-6 alkyl group (eg, methyl) and an optionally substituted C _1-6 alkoxy group (eg, methoxy) A benzene ring which may be further substituted with three, more preferably 1 or 2) substituents, or a thiophene ring or a pyridine ring which may be further substituted respectively, and still more preferably,
(1) (i) substituted with 1 to 3 substituents selected from halogen atoms (eg, fluorine atoms, chlorine atoms), (ii) cyano groups, (iii) halogen atoms (eg, fluorine atoms) and amino groups 1 to 5 (preferably 1 to 3, more preferably 1) selected from a C _1-6 alkyl group (eg, methyl) and (iv) a C _1-6 alkoxy group (eg, methoxy) Or a benzene ring optionally further substituted with 2) substituents,
(2) a thiophene ring, or (3) a pyridine ring.

L represents C _1-2 alkylene which may be substituted.
Examples of the “substituent” of the “optionally substituted C _1-2 alkylene” represented by L include a C _1-6 alkyl group (eg, methyl).
L is _{preferably, C 1-2} alkylene _{_{_{(e.g., -CH 2 -, - CH 2}}} CH 2 -, - CH (CH 3) -) , more preferably an, -CH ₂ - it is.

X ¹ represents N or CR ¹ , X ² represents N or CR ² , X ³ represents N or CR ³ , X ⁴ represents N or CR ⁴ , R ¹ , R ² , R ³ and R ⁴ independently represent a hydrogen atom or a substituent.
Examples of the “substituent” represented by R ¹ , R ² , R ³ or R ⁴ include a halogen atom (eg, fluorine atom) and a C _1-6 alkyl group (eg, methyl).
X ¹ is preferably N or CR ¹ (R ¹ is a hydrogen atom or a halogen atom (eg, a fluorine atom)), more preferably N or CR ¹ (R ¹ is a hydrogen atom or A fluorine atom), and even more preferably CR ¹ (R ¹ is a hydrogen atom).
X ² is preferably N or CR ² (R ² is a hydrogen atom or a halogen atom (eg, fluorine atom)), more preferably N or CR ² (R ² is a hydrogen atom or A fluorine atom), and even more preferably CR ² (R ² is a hydrogen atom).
X ³ is preferably N or CR ³ (R ³ is a hydrogen atom or a halogen atom (eg, fluorine atom)), and more preferably N or CR ³ (R ³ is a hydrogen atom or A fluorine atom), and even more preferably N or CR ³ (R ³ is a hydrogen atom).
X ⁴ is preferably N or CR ⁴ (R ⁴ is a hydrogen atom or a C _1-6 alkyl group (eg, methyl)), more preferably N or CR ⁴ (R ⁴ is A hydrogen atom or methyl), and even more preferably N or CR ⁴ (R ⁴ is a hydrogen atom).

X ⁵ represents CR ^5a , CR ^5b R ^5c , NR ^5d or a bond, and R ^5a , R ^5b , R ^5c and R ^5d independently represent a hydrogen atom or a substituent, or R ^5b And R ^5c together may form an ^optionally substituted ring.
^Examples of the “substituent” represented by R ^5a , R ^5b , R ^5c or R ^5d include an oxo group.
Examples of the “ring” of the “optionally substituted ring” formed by R ^5b and R ^5c together include a C _3-10 cycloalkane ring (eg, cyclopentane ring). " _{Includes a} C _1-6 alkyl group (eg, methyl, hydroxymethyl) optionally substituted with a hydroxy group, a carbamoyl group, and a hydroxy group.
X ⁵ is preferably CR ^5b R ^5c (R ^5b and R ^5c are each independently a hydrogen atom or a substituent) or a bond, and more preferably CR ^5b R ^5c (R ^5b and R ^5c is a hydrogen atom.) Or a bond, and even more preferably a bond.

X ⁶ represents CR ^6a R ^6b or NR ^6c , and R ^6a , R ^6b and R ^6c independently represent a hydrogen atom or a substituent, or R ^6a and R ^6b are substituted together May form a ring which may be
Examples of the “substituent” represented by R ^6a , R ^6b or R ^6c include an optionally substituted C _1-6 alkyl group (eg, methyl).
Examples of the “ring” of the “optionally substituted ring” formed by R ^6a and R ^6b together include a C _3-10 cycloalkane ring (eg, cyclopentane ring). " _{Includes a} C _1-6 alkyl group (eg, methyl, hydroxymethyl) optionally substituted with a hydroxy group, a carbamoyl group, and a hydroxy group.
X ⁶ is preferably CR ^6a R ^6b (R ^6a and R ^6b are each independently a hydrogen atom or a substituent), and more preferably CR ^6a R ^6b (R ^6a and R ^6b are Is independently a hydrogen atom or an optionally substituted C _1-6 alkyl group (eg, methyl).), And even more preferably, CR ^6a R ^6b (R ^6a and R ^6b are independently And a C _1-6 alkyl group (eg, methyl) optionally substituted with a hydroxy group or a C _6-14 aryl group (eg, phenyl).
Alternatively, in another embodiment of the present invention, X ⁵ is preferably CR ^6a R ^6b (where R ^6a and R ^6b are taken together to represent an ^optionally substituted C _3-10 cycloalkane ring (eg, And more preferably CR ^6a R ^6b (R ^6a and R ^6b together form a C _3-10 cycloalkane ring (eg, a cyclopentane ring). ).

R ⁷ represents a hydrogen atom or a substituent.
Examples of the “substituent” represented by R ⁷ include an optionally substituted C _1-6 alkyl group (eg, methyl).
R ⁷ is preferably a hydrogen atom or an optionally substituted C _1-6 alkyl group (eg, methyl), more preferably a hydrogen atom or a C _1-6 alkyl group (eg, methyl). Even more preferably, it is a hydrogen atom.

Preferable examples of compound (I) include the following compounds.
[Compound I-1]
Ring A is a monocyclic nitrogen-containing unsaturated heterocyclic ring (eg, imidazolidine ring, imidazoline ring) which may be further substituted, or may be further substituted in the above formula (A) A bicyclic nitrogen-containing unsaturated heterocycle represented by
Ring B is a benzene ring which may be further substituted, or a thiophene ring or a pyridine ring which may be further substituted respectively;
L is C _1-2 alkylene (eg, —CH ₂ —, —CH ₂ CH ₂ —, —CH (CH ₃ ) —);
X ¹ is N or CR ¹ (R ¹ is a hydrogen atom or a halogen atom (eg, fluorine atom));
X ² is N or CR ² (R ² is a hydrogen atom or a halogen atom (eg, fluorine atom));
X ³ is N or CR ³ (R ³ is a hydrogen atom or a halogen atom (eg, fluorine atom));
X ⁴ is N or CR ⁴ (R ⁴ is a hydrogen atom or a C _1-6 alkyl group (eg, methyl));
X ⁵ is CR ^5b R ^5c (R ^5b and R ^5c are each independently a hydrogen atom or a substituent) or a bond;
X ⁶ is CR ^6a R ^6b (R ^6a and R ^6b are each independently a hydrogen atom or a substituent, or R ^6a and R ^6b are taken together to form an optionally substituted ring. Forming);
R ⁷ is a hydrogen atom or an optionally substituted C _1-6 alkyl group (eg, methyl);
Compound (I).

[Compound I-2]
Whether ring A is a monocyclic nitrogen-containing unsaturated heterocyclic ring (eg, imidazolidine ring, imidazoline ring) which may be further substituted with one or two substituents selected from a hydroxy group and an oxo group Or a halogen atom (eg, fluorine atom), a hydroxy group, an oxo group, an optionally substituted C _1-6 alkyl group (eg, methyl, ethyl), an optionally substituted C _1-6 alkoxy group Further substituted with 1 to 3 (preferably 1 or 2) substituents selected from (eg, methoxy) and optionally substituted non-aromatic heterocyclic-oxy group (eg, tetrahydropyranyloxy) Ring A ¹ is a pyrrole ring, pyrazole ring, imidazole ring, thiophene ring, pyridine ring, imidazoline ring or tetrahydropyrazine ring, and ring A ² is pyrrole A bicyclic nitrogen-containing unsaturated heterocyclic ring represented by the above formula (A) which is a ring, a thiophene ring, a pyridine ring or a pyrimidine ring;
Ring B is a halogen atom (eg, fluorine atom, chlorine atom), a cyano group, an optionally substituted C _1-6 alkyl group (eg, methyl) and an optionally substituted C _1-6 alkoxy group ( A benzene ring which may be further substituted with 1 to 5 (preferably 1 to 3, more preferably 1 or 2) substituents selected from eg methoxy), or each may be further substituted A thiophene ring or a pyridine ring;
L is C _1-2 alkylene (eg, —CH ₂ —, —CH ₂ CH ₂ —, —CH (CH ₃ ) —);
X ¹ is N or CR ¹ (R ¹ is a hydrogen atom or a fluorine atom);
X ² is N or CR ² (R ² is a hydrogen atom or a fluorine atom);
X ³ is N or CR ³ (R ³ is a hydrogen atom or a fluorine atom);
X ⁴ is N or CR ⁴ (R ⁴ is a hydrogen atom or methyl);
X ⁵ is CR ^5b R ^5c (R ^5b and R ^5c are hydrogen atoms) or a bond;
X ⁶ is CR ^6a R ^6b (R ^6a and R ^6b are each independently a hydrogen atom or an optionally substituted C _1-6 alkyl group (eg, methyl), or R ^6a and R ^6b ^6b together form an optionally substituted C _3-10 cycloalkane ring (eg, cyclopentane ring));
R ⁷ is a hydrogen atom or a C _1-6 alkyl group (eg, methyl);
Compound (I).

[Compound I-3]
Whether ring A is a monocyclic nitrogen-containing unsaturated heterocyclic ring (eg, imidazolidine ring, imidazoline ring) which may be further substituted with one or two substituents selected from a hydroxy group and an oxo group Or a halogen atom (eg, fluorine atom), a hydroxy group, an oxo group, an optionally substituted C _1-6 alkyl group (eg, methyl, ethyl), an optionally substituted C _1-6 alkoxy group Further substituted with 1 to 3 (preferably 1 or 2) substituents selected from (eg, methoxy) and optionally substituted non-aromatic heterocyclic-oxy group (eg, tetrahydropyranyloxy) Ring A ¹ is a pyrrole ring, pyrazole ring, imidazole ring, thiophene ring, pyridine ring, imidazoline ring or tetrahydropyrazine ring, and ring A ² is pyrrole A bicyclic nitrogen-containing unsaturated heterocyclic ring represented by the above formula (A) which is a ring, a thiophene ring, a pyridine ring or a pyrimidine ring;
Ring B is
(1) (i) substituted with 1 to 3 substituents selected from halogen atoms (eg, fluorine atoms, chlorine atoms), (ii) cyano groups, (iii) halogen atoms (eg, fluorine atoms) and amino groups 1 to 5 (preferably 1 to 3, more preferably 1) selected from a C _1-6 alkyl group (eg, methyl) and (iv) a C _1-6 alkoxy group (eg, methoxy) Or a benzene ring optionally further substituted with 2) substituents,
(2) a thiophene ring, or (3) a pyridine ring;
L _{_{is, -CH 2 -, - CH 2}} CH 2 - or -CH (CH ₃₎ - and is,
X ¹ is N or CR ¹ (R ¹ is a hydrogen atom or a fluorine atom);
X ² is N or CR ² (R ² is a hydrogen atom or a fluorine atom);
X ³ is N or CR ³ (R ³ is a hydrogen atom or a fluorine atom);
X ⁴ is N or CR ⁴ (R ⁴ is a hydrogen atom or methyl);
X ⁵ is CR ^5b R ^5c (R ^5b and R ^5c are hydrogen atoms) or a bond;
X ⁶ represents CR ^6a R ^6b (R ^6a and R ^6b are each a hydrogen atom, or independently, a C _1-6 alkyl optionally substituted with a hydroxy group or a C _6-14 aryl group (eg, phenyl)) A group (eg, methyl) or R ^6a and R ^6b together form a C _3-10 cycloalkane ring (eg, a cyclopentane ring));
R ⁷ is a hydrogen atom or a C _1-6 alkyl group (eg, methyl);
Compound (I).

[Compound I-4]
Ring A is a 1H-imidazo [4,5-b] pyridine ring further substituted with hydroxy or a 1H-pyrrolo [2,3-b] pyridine ring further substituted with methyl;
Ring B is
(1) (i) substituted with 1 to 3 substituents selected from halogen atoms (eg, fluorine atoms, chlorine atoms), (ii) cyano groups, (iii) halogen atoms (eg, fluorine atoms) and amino groups 1 to 5 (preferably 1 to 3, more preferably 1) selected from a C _1-6 alkyl group (eg, methyl) and (iv) a C _1-6 alkoxy group (eg, methoxy) Or a benzene ring optionally further substituted with 2) substituents,
(2) a thiophene ring, or (3) a pyridine ring;
L is —CH ₂ —;
X ¹ is CR ¹ (R ¹ is a hydrogen atom);
X ² is CR ² (R ² is a hydrogen atom);
X ³ is N or CR ³ (R ³ is a hydrogen atom);
X ⁴ is N or CR ⁴ (R ⁴ is a hydrogen atom);
X ⁵ is a bond;
X ⁶ is CR ^6a R ^6b (R ^6a and R ^6b are each independently a hydrogen atom, or a C _1-6 alkyl optionally substituted with a hydroxy group or a C _6-14 aryl group (eg, phenyl)) A group (eg, methyl) or R ^6a and R ^6b together form a C _3-10 cycloalkane ring (eg, a cyclopentane ring));
R ⁷ is a hydrogen atom;
Compound (I).

[Compound I-5]
1 to 3 (preferably 1 or 2) of ring A selected from a hydroxy group, an oxo group, a C _1-6 alkyl group (eg, methyl) and a C _1-6 alkoxy group (eg, methoxy) Ring A ¹ which may be further substituted with a substituent is pyrrole ring, pyrazole ring, thiophene ring, pyridine ring, imidazoline ring or tetrahydropyrazine ring, and ring A ² is pyrrole ring, thiophene ring, pyridine ring or pyrimidine A bicyclic nitrogen-containing unsaturated heterocyclic ring represented by the above formula (A) which is a ring;
Ring B is
(1) a benzene ring which may be further substituted with a C _1-6 alkyl group (eg, methyl) _optionally substituted with 1 to 3 halogen atoms (eg, fluorine atom),
(2) a thiophene ring, or (3) a pyridine ring;
L _{_{is, -CH 2 -, - CH 2}} CH 2 - or -CH (CH ₃₎ - and is,
X ¹ is N or CR ¹ (R ¹ is a hydrogen atom or a fluorine atom);
X ² is N or CR ² (R ² is a hydrogen atom);
X ³ is N or CR ³ (R ³ is a hydrogen atom);
X ⁴ is N or CR ⁴ (R ⁴ is a hydrogen atom or methyl);
X ⁵ is CR ^5b R ^5c (R ^5b and R ^5c are hydrogen atoms) or a bond;
X ⁶ is CR ^6a R ^6b (R ^6a and R ^6b are a hydrogen atom or independently a C _1-6 alkyl group (eg, methyl));
R ⁷ is a hydrogen atom or a C _1-6 alkyl group (eg, methyl);
Compound (I).

Specific examples of compound (I) include, for example, the compounds of Examples 1 to 93. Among them,
2,2-Dimethyl-7- (2-oxo-2,3-dihydro-1H-imidazo [4,5-b] pyridin-1-yl) -1-((1R) -1-phenylethyl) -2 , 3-Dihydroquinazolin-4 (1H) -one or a salt thereof (Example 14);
4-Benzyl-6- (2-oxo-2,3-dihydro-1H-imidazo [4,5-b] pyridin-1-yl) -3,4-dihydroisoquinolin-1 (2H) -one or a salt thereof Example 48; and 1-benzyl-8- (2-oxo-2,3-dihydro-1H-imidazo [4,5-b] pyridin-1-yl) -1,2,3,4-tetrahydro -5H-pyrido [2,3-e] [1,4] diazepin-5-one or a salt thereof (Example 88)
Is preferred.

When compound (I) is a salt, examples of such salts include metal salts, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, basic or acidic amino acids, and the like. Examples include salts. Preferable examples of the metal salt include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt, magnesium salt and barium salt; aluminum salt and the like. Preferable examples of the salt with organic base include, for example, trimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine, N, N′-dibenzyl. Examples include salts with ethylenediamine and the like. Preferable examples of the salt with inorganic acid include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like. Preferable examples of the salt with organic acid include, for example, formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzene And salts with sulfonic acid, p-toluenesulfonic acid and the like. Preferable examples of salts with basic amino acids include salts with arginine, lysine, ornithine and the like, and preferable examples of salts with acidic amino acids include salts with aspartic acid, glutamic acid and the like. Is mentioned.
Of these, pharmaceutically acceptable salts are preferred. For example, when the compound has an acidic functional group, inorganic salts such as alkali metal salts (eg, sodium salts, potassium salts, etc.), alkaline earth metal salts (eg, calcium salts, magnesium salts, etc.), ammonium salts In addition, when the compound has a basic functional group, for example, a salt with an inorganic acid such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, or acetic acid, phthalic acid, fumaric acid, And salts with organic acids such as acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid.

The production method of the compound of the present invention will be described below.

The raw materials and reagents used in each step in the following production method and the obtained compound may each form a salt. Examples of such salts include those similar to the salts of the aforementioned compound of the present invention.

When the compound obtained in each step is a free compound, it can be converted into a target salt by a method known per se. On the contrary, when the compound obtained in each step is a salt, it can be converted into a free form or other types of desired salts by a method known per se.

The compound obtained in each step remains in the reaction solution or is obtained as a crude product and can be used in the next reaction. Alternatively, the compound obtained in each step is concentrated from the reaction mixture according to a conventional method. , Crystallization, recrystallization, distillation, solvent extraction, fractional distillation, chromatography and the like, and can be isolated and / or purified.

When the raw materials and reagent compounds for each step are commercially available, commercially available products can be used as they are.

In the reaction in each step, the reaction time may vary depending on the reagent and solvent to be used, but unless otherwise specified, is usually 1 minute to 48 hours, preferably 10 minutes to 8 hours.

In the reaction in each step, the reaction temperature may vary depending on the reagent and solvent to be used, but is usually −78 ° C. to 300 ° C., preferably −78 ° C. to 150 ° C., unless otherwise specified.

In the reaction in each step, the pressure may vary depending on the reagent and solvent used, but unless otherwise specified, is usually 1 to 20 atmospheres, preferably 1 to 3 atmospheres.

In the reaction of each step, for example, a Microwave synthesizer such as an initiator manufactured by Biotage may be used. The reaction temperature may vary depending on the reagent and solvent to be used, but unless otherwise specified, is usually room temperature to 300 ° C., preferably 50 ° C. to 250 ° C. The reaction time may vary depending on the reagent and solvent to be used, but unless otherwise specified, is usually 1 minute to 48 hours, preferably 1 minute to 8 hours.

In the reaction in each step, unless otherwise specified, the reagent is used in an amount of 0.5 equivalent to 20 equivalents, preferably 0.8 equivalent to 5 equivalents, relative to the substrate. When a reagent is used as a catalyst, the reagent is used in an amount of 0.001 equivalent to 1 equivalent, preferably 0.01 equivalent to 0.2 equivalent, relative to the substrate. When the reagent also serves as a reaction solvent, the amount of solvent is used as the reagent.

In the reaction in each step, unless otherwise specified, these reactions are performed without solvent or dissolved or suspended in a suitable solvent. Specific examples of the solvent include the solvents described in the examples or the following.
Alcohols: methanol, ethanol, tert-butyl alcohol, 2-methoxyethanol, etc .;
Ethers: diethyl ether, diphenyl ether, tetrahydrofuran, 1,2-dimethoxyethane, etc .;
Aromatic hydrocarbons: chlorobenzene, toluene, xylene, etc .;
Saturated hydrocarbons: cyclohexane, hexane, etc .;
Amides: N, N-dimethylformamide, N-methylpyrrolidone, etc .;
Halogenated hydrocarbons: dichloromethane, carbon tetrachloride, etc .;
Nitriles: acetonitrile, etc.
Sulfoxides: dimethyl sulfoxide and the like;
Aromatic organic bases: pyridine, etc .;
Acid anhydrides: acetic anhydride, etc .;
Organic acids: formic acid, acetic acid, trifluoroacetic acid, etc .;
Inorganic acids: hydrochloric acid, sulfuric acid, etc .;
Esters: ethyl acetate and the like;
Ketones: acetone, methyl ethyl ketone, etc .;
water.
Two or more of the above solvents may be mixed and used at an appropriate ratio.

When a base is used in the reaction in each step, for example, the following bases or the bases described in the examples are used.
Inorganic bases: sodium hydroxide, magnesium hydroxide, etc .;
Basic salts: sodium carbonate, calcium carbonate, sodium bicarbonate, etc .;
Organic bases: triethylamine, diethylamine, pyridine, 4-dimethylaminopyridine, N, N-dimethylaniline, 1,4-diazabicyclo [2.2.2] octane, 1,8-diazabicyclo [5.4.0]- 7-undecene, imidazole, piperidine and the like;
Metal alkoxides: sodium ethoxide, potassium tert-butoxide and the like;
Alkali metal hydrides: sodium hydride, etc .;
Metal amides: sodium amide, lithium diisopropylamide, lithium hexamethyldisilazide, etc .;
Organic lithiums: n-butyllithium and the like.

When an acid or an acidic catalyst is used in the reaction in each step, for example, the following acids and acidic catalysts, or acids and acidic catalysts described in the examples are used.
Inorganic acids: hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, phosphoric acid, etc .;
Organic acids: acetic acid, trifluoroacetic acid, citric acid, p-toluenesulfonic acid, 10-camphorsulfonic acid, etc .;
Lewis acid: boron trifluoride diethyl ether complex, zinc iodide, anhydrous aluminum chloride, anhydrous zinc chloride, anhydrous iron chloride and the like.

Unless otherwise specified, the reaction in each step is a method known per se, for example, the 5th edition Experimental Chemistry Course, Volumes 13 to 19 (Edited by The Chemical Society of Japan); New Experimental Chemistry Course, Volumes 14 to 15 (Japan) Chemistry Society); Fine Organic Chemistry Revised 2nd Edition (L.F.Tietze, Th.Eicher, Nankodo); Revised Organic Personal Name Reaction, its mechanism and points (by Hideo Togo, Kodansha); ORGANIC SYNTHES Collective Volume I-VII ( John Wiley & Sons Inc); Modern Organic Synthesis in the Laboratory A Collection of Standard Exploratory Procedures (Jie Jack Li, UF by JIE Jack Li) IVERSITY publication); Comprehensive Heterocyclic Chemistry III, Vol. 1 to Vol. 14 (Elsevier Japan Co., Ltd.); Organic synthesis strategy learned from name reaction (translated by Kiyoshi Tomioka, published by Doujin Chemical); Comprehensive Organic Transformations (VCH Publishers Inc.) published in 1989, etc., Or it carries out according to the method described in the Example.

In each step, the protection or deprotection reaction of the functional group is carried out according to a method known per se, for example, “Protective Groups in Organic Synthesis, 4th Ed.” (Theodora W. Greene, Peter G. M., et al., Wiley-Interscience). The method described in Thimeme's 2004 “Protecting Groups 3rd Ed.” (By PJ Kocienski) or the like, or the method described in the examples.
Examples of protecting groups for hydroxyl groups such as alcohol and phenolic hydroxyl groups include ether-type protecting groups such as methoxymethyl ether, benzyl ether, t-butyldimethylsilyl ether, and tetrahydropyranyl ether; carboxylate-type protecting groups such as acetate Sulfonic acid ester type protecting groups such as methanesulfonic acid ester; carbonate ester type protecting groups such as t-butyl carbonate.
Examples of the protecting group for the carbonyl group of the aldehyde include an acetal-type protecting group such as dimethylacetal; and a cyclic acetal-type protecting group such as cyclic 1,3-dioxane.
Examples of the protecting group for the carbonyl group of the ketone include a ketal-type protecting group such as dimethyl ketal; a cyclic ketal-type protecting group such as cyclic 1,3-dioxane; an oxime-type protecting group such as O-methyloxime; N, N— And hydrazone-type protecting groups such as dimethylhydrazone.
Examples of the protecting group for carboxyl group include ester-type protecting groups such as methyl ester; amide-type protecting groups such as N, N-dimethylamide.
Examples of the thiol-protecting group include ether-type protecting groups such as benzylthioether; ester-type protecting groups such as thioacetate ester, thiocarbonate, and thiocarbamate.
Examples of protecting groups for amino groups and aromatic heterocycles such as imidazole, pyrrole and indole include carbamate-type protecting groups such as benzylcarbamate; amide-type protecting groups such as acetamide; alkylamines such as N-triphenylmethylamine Type protecting groups, and sulfonamide type protecting groups such as methanesulfonamide.
The protecting group can be removed by a method known per se, for example, acid, base, ultraviolet light, hydrazine, phenylhydrazine, sodium N-methyldithiocarbamate, tetrabutylammonium fluoride, palladium acetate, trialkylsilyl halide (for example, trimethylsilyl iodide). And trimethylsilyl bromide) or a reduction method.

When performing the reduction reaction in each step, the reducing agent used is lithium aluminum hydride, sodium triacetoxyborohydride, sodium cyanoborohydride, diisobutylaluminum hydride (DIBAL-H), sodium borohydride Metal hydrides such as hydrogenated triacetoxy boron tetramethylammonium; boranes such as borane tetrahydrofuran complex; Raney nickel; Raney cobalt; hydrogen; formic acid and the like. In the case of reducing a carbon-carbon double bond or triple bond, there are methods using a catalyst such as palladium-carbon or a Lindlar catalyst.

In each step, when an oxidation reaction is carried out, the oxidizing agent used includes peracids such as m-chloroperbenzoic acid (MCPBA), hydrogen peroxide and t-butyl hydroperoxide; tetrabutylammonium perchlorate, etc. Perchlorates; Chlorates such as sodium chlorate; Chlorites such as sodium chlorite; Periodic acids such as sodium periodate; High-valent iodine reagents such as iodosylbenzene; Manganese dioxide; Reagents having manganese such as potassium manganate; Leads such as lead tetraacetate; Reagents having chromium such as pyridinium chlorochromate (PCC), pyridinium dichromate (PDC), Jones reagent; N-bromosuccinimide (NBS) Halogen compounds such as oxygen; ozone; sulfur trioxide / pyridine complex; male tetroxide Um; selenium dioxide; 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) and the like.

In each step, when a radical cyclization reaction is performed, the radical initiator used is an azo compound such as azobisisobutyronitrile (AIBN); 4-4′-azobis-4-cyanopentanoic acid (ACPA) Water-soluble radical initiators such as triethylboron in the presence of air or oxygen, and benzoyl peroxide. Examples of the radical reaction reagent used include tributylstannane, tristrimethylsilylsilane, 1,1,2,2-tetraphenyldisilane, diphenylsilane, and samarium iodide.

In each step, when a Wittig reaction is performed, examples of Wittig reagents used include alkylidene phosphoranes. The alkylidene phosphoranes can be prepared by a method known per se, for example, by reacting a phosphonium salt with a strong base.

In each step, when performing Horner-Emmons reaction, the reagents used include phosphonoacetate esters such as methyl dimethylphosphonoacetate and ethyl ethyl diethylphosphonoacetate; bases such as alkali metal hydrides and organolithiums Can be mentioned.

In each step, when the Friedel-Crafts reaction is performed, examples of the reagent used include Lewis acid and acid chloride or an alkylating agent (eg, alkyl halides, alcohols, olefins, etc.). Alternatively, an organic acid or an inorganic acid can be used in place of the Lewis acid, and an acid anhydride such as acetic anhydride can be used in place of the acid chloride.

In each step, when an aromatic nucleophilic substitution reaction is performed, a nucleophile (eg, amines, imidazole, etc.) and a base (eg, basic salts, organic bases, etc.) are used as reagents.

In each step, a nucleophilic addition reaction with a carbanion, a nucleophilic 1,4-addition reaction with a carbanion (Michael addition reaction), or a nucleophilic substitution reaction with a carbanion, a base used to generate a carbanion Examples thereof include organic lithiums, metal alkoxides, inorganic bases, and organic bases.

In each step, when the Grignard reaction is performed, examples of the Grignard reagent include arylmagnesium halides such as phenylmagnesium bromide; alkylmagnesium halides such as methylmagnesium bromide. The Grignard reagent can be prepared by a method known per se, for example, by reacting alkyl halide or aryl halide with metal magnesium using ether or tetrahydrofuran as a solvent.

In each step, when the Knoevenagel condensation reaction is performed, reagents include an active methylene compound (eg, malonic acid, diethyl malonate, malononitrile, etc.) sandwiched between two electron-withdrawing groups and a base (eg, organic bases, Metal alkoxides and inorganic bases) are used.

In each step, when performing the Vilsmeier-Haack reaction, phosphoryl chloride and an amide derivative (eg, N, N-dimethylformamide, etc.) are used as reagents.

In each step, when an azidation reaction of alcohols, alkyl halides, and sulfonates is performed, examples of the azidation agent used include diphenylphosphoryl azide (DPPA), trimethylsilyl azide, and sodium azide. For example, when an alcohol is azidated, there are a method using diphenylphosphoryl azide and 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), a method using trimethylsilyl azide and a Lewis acid, and the like.

In each step, when a reductive amination reaction is carried out, examples of the reducing agent used include sodium triacetoxyborohydride, sodium cyanoborohydride, hydrogen, formic acid and the like. When the substrate is an amine compound, examples of the carbonyl compound used include paraformaldehyde, aldehydes such as acetaldehyde, and ketones such as cyclohexanone. When the substrate is a carbonyl compound, examples of amines used include primary amines such as ammonia and methylamine; secondary amines such as dimethylamine and the like.

In each step, when Mitsunobu reaction is performed, azodicarboxylic acid esters (eg, diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate (DIAD), etc.) and triphenylphosphine are used as reagents.

In each step, when an esterification reaction, an amidation reaction, or a urealation reaction is performed, the reagents used include acyl halides such as acid chloride and acid bromide; acid anhydrides, active ester compounds, and sulfate ester compounds. And activated carboxylic acids. Examples of carboxylic acid activators include carbodiimide condensing agents such as 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (WSCD); 4- (4,6-dimethoxy-1,3,5- Triazine condensing agents such as triazin-2-yl) -4-methylmorpholinium chloride-n-hydrate (DMT-MM); carbonate condensing agents such as 1,1-carbonyldiimidazole (CDI); diphenyl Azide phosphate (DPPA); benzotriazol-1-yloxy-trisdimethylaminophosphonium salt (BOP reagent); 2-chloro-1-methyl-pyridinium iodide (Mukayama reagent); thionyl chloride; haloformates such as ethyl chloroformate Lower alkyl; O- (7-azabenzotriazol-1-yl) -N, N, N ′, N′— Tetramethyl uronium hexafluorophosphate (HATU); and the like, or combinations thereof; sulfate. When a carbodiimide condensing agent is used, additives such as 1-hydroxybenzotriazole (HOBt), N-hydroxysuccinimide (HOSu), dimethylaminopyridine (DMAP) may be further added to the reaction.

In each step, when a coupling reaction is performed, the metal catalyst used is palladium acetate (II), tetrakis (triphenylphosphine) palladium (0), dichlorobis (triphenylphosphine) palladium (II), dichlorobis (triethyl). Palladium compounds such as phosphine) palladium (II), tris (dibenzylideneacetone) dipalladium (0), 1,1′-bis (diphenylphosphino) ferrocenepalladium (II) chloride, palladium (II) acetate; tetrakis (tri Nickel compounds such as phenylphosphine) nickel (0); rhodium compounds such as tris (triphenylphosphine) rhodium (III) chloride; cobalt compounds; copper compounds such as copper oxide and copper iodide (I); platinum compounds and the like It is done. Furthermore, a base may be added to the reaction, and examples of such a base include inorganic bases and basic salts.

In each step, when a thiocarbonylation reaction is performed, diphosphorus pentasulfide is typically used as the thiocarbonylating agent. In addition to diphosphorus pentasulfide, 2,4-bis (4-methoxyphenyl) is used. A reagent having a 1,3,2,4-dithiadiphosphetane-2,4-disulfide structure such as -1,3,2,4-dithiadiphosphetane-2,4-disulfide (Lawesson reagent) It may be used.

In each process, when the Wohl-Ziegler reaction is performed, halogenating agents used include N-iodosuccinimide, N-bromosuccinimide (NBS), N-chlorosuccinimide (NCS), bromine, sulfuryl chloride, etc. Is mentioned. Furthermore, the reaction can be accelerated by adding a radical initiator such as heat, light, benzoyl peroxide, or azobisisobutyronitrile to the reaction.

In each step, when a halogenation reaction of a hydroxy group is performed, the halogenating agent used is an acid halide of hydrohalic acid and an inorganic acid. Specifically, in chlorination, hydrochloric acid, thionyl chloride, oxy Examples of bromination such as phosphorus chloride include 48% hydrobromic acid. Alternatively, a method of obtaining an alkyl halide from alcohol by the action of triphenylphosphine and carbon tetrachloride or carbon tetrabromide may be used. Alternatively, a method of synthesizing an alkyl halide through a two-step reaction in which an alcohol is converted into a sulfonate ester and then reacted with lithium bromide, lithium chloride, or sodium iodide may be used.

In each step, when performing an Arbuzov reaction, examples of the reagent used include alkyl halides such as ethyl bromoacetate; phosphites such as triethyl phosphite and tri (isopropyl) phosphite.

In each step, when a sulfonic acid esterification reaction is performed, examples of the sulfonating agent used include methanesulfonyl chloride, p-toluenesulfonyl chloride, methanesulfonic acid anhydride, p-toluenesulfonic acid anhydride, and the like.

In each step, when a hydrolysis reaction is performed, an acid or a base is used as a reagent. When acid hydrolysis reaction of t-butyl ester is performed, formic acid or triethylsilane may be added in order to reductively trap the t-butyl cation produced as a by-product.

In each step, when a dehydration reaction is performed, examples of the dehydrating agent used include sulfuric acid, diphosphorus pentoxide, phosphorus oxychloride, N, N'-dicyclohexylcarbodiimide, alumina, and polyphosphoric acid.

Compound (I) can be produced by the method shown in the following scheme A or a method analogous thereto or the method described in Examples when X ⁴ is N and X ⁵ is a bond.

[Scheme A]

[Wherein, LG represents a leaving group, and other symbols are as defined above. ]
As the leaving group represented by LG, for example, a halogen atom (for example, a chlorine atom, a bromine atom, an iodine atom, etc.), an optionally substituted sulfonyloxy group (for example, 1 to 3 halogen atoms are substituted). which may be C _1-6 alkylsulfonyloxy group (e.g., methanesulfonyloxy group, ethanesulfonyloxy group, etc. trifluoromethanesulfonyloxy group); 1 to be substituted with 3 C _1-6 alkyl groups Good C _6-14 arylsulfonyloxy group (eg, benzenesulfonyloxy group, p-toluenesulfonyloxy group, etc.); C _7-14 aralkylsulfonyloxy group (eg, benzylsulfonyloxy group, etc.), [(oxide) Phenyl-λ4-sulfanilidene] dimethylammonium group, etc. It is below.
Compound (I) can be produced by a coupling reaction of compound (V). Metal catalysts and their ligands include bis (di-tert-butyl (4-dimethylaminophenyl) phosphine) dichloropalladium (II) or tris (dibenzylideneacetone) dipalladium (0) and 2-dicyclohexylphosphino- 2 ′, 6′-diisopropoxy-1,1′-biphenyl and the like.
Compound (II) used as a raw material in this method may be a commercially available product, or can be produced by a method known per se or a method analogous thereto.

Compound (I) can be prepared by the method shown in the following scheme B when X ¹ is CH, X ² is CH, X ³ is CH, X ⁴ is CH, X ⁵ is a bond and X ⁶ is CH ₂ or It can be produced by a similar method or a method described in Examples.

[Scheme B]

[Wherein each symbol has the same meaning as described above. ]
Compound (VIII) can be produced by bromination reaction of compound (VII). Examples of bromination reagents include N-bromosuccinimide and azobisisobutyronitrile.
Compound (XI) can be produced by a reduction reaction of compound (X). Examples of the reducing agent include borane-tetrahydrofuran complex.
Compound (I) can be produced by a coupling reaction of compound (XI). Metal catalysts and their ligands include bis (di-tert-butyl (4-dimethylaminophenyl) phosphine) dichloropalladium (II) or tris (dibenzylideneacetone) dipalladium (0) and 2-dicyclohexylphosphino- 2 ′, 6′-diisopropoxy-1,1′-biphenyl and the like.
Compound (VI) used as a starting material in this method may be a commercially available product, or can be produced by a method known per se or a method analogous thereto.

Compound (I) is a compound represented by the following scheme C when X ¹ is CH, X ² is CH, X ³ is CH, X ⁴ is CH, X ⁵ is a bond and X ⁶ is CCH ₃ CH ₃ or It can be produced by a method according to this or the method described in the Examples.

[Scheme C]

[Wherein the symbols are as defined above. ]
Compound (XV) can be produced by nucleophilic substitution reaction of compound (XIV). Examples of the nucleophilic substitution reagent include chloroacetonitrile.
Compound (XVI) can be produced by subjecting compound (XV) to deprotection. Examples of the deprotecting reagent include thiourea.
Compound (I) can be produced by a coupling reaction of compound (XVIII). Metal catalysts and their ligands include bis (di-tert-butyl (4-dimethylaminophenyl) phosphine) dichloropalladium (II) or tris (dibenzylideneacetone) dipalladium (0) and 2-dicyclohexylphosphino- 2 ′, 6′-diisopropoxy-1,1′-biphenyl and the like.
As compound (XII) used as a starting material in this method, a commercially available product may be used as it is, or it may be produced by a method known per se or a method analogous thereto.

Compound (I) is prepared by the method shown in the following scheme D or when X ¹ is CH, X ² is CH, X ³ is N, X ⁴ is CH, X ⁵ is a bond and X ⁶ is CH _2. It can be produced by a similar method or a method described in Examples.

[Scheme D]

[Wherein the symbols are as defined above. ]
Compound (XXI) can be produced by a nucleophilic addition reaction of compound (XX). Examples of the nucleophile include paramethoxybenzylamine.
Compound (XXIV) can be produced by chlorination reaction of compound (XXIII). Examples of the chlorinating reagent include phosphorus oxychloride.
Compound (I) can be produced by a coupling reaction of compound (XXIV). Metal catalysts and their ligands include bis (di-tert-butyl (4-dimethylaminophenyl) phosphine) dichloropalladium (II) or tris (dibenzylideneacetone) dipalladium (0) and 2-dicyclohexylphosphino- 2 ′, 6′-diisopropoxy-1,1′-biphenyl and the like.
As the compound (XIX) used as a starting material in this method, a commercially available product may be used as it is, or it can be produced by a method known per se or a method analogous thereto.

Compound (I) is prepared by the method shown in the following scheme E or when X ¹ is CH, X ² is N, X ³ is CH, X ⁴ is CH, X ⁵ is a bond, and X ⁶ is CH _2. It can be produced by a similar method or a method described in Examples.

[Scheme E]

[Wherein the symbols are as defined above. ]
Compound (XXVI) can be produced by iodination reaction of compound (XXV). Examples of the iodination reagent include lithium tetramethylpiperidide and iodine.
Compound (I) can be produced by a coupling reaction of compound (XXXIII) and a deprotection reaction of compound (XXXIV) obtained thereby. Metal catalysts and their ligands include bis (di-tert-butyl (4-dimethylaminophenyl) phosphine) dichloropalladium (II) or tris (dibenzylideneacetone) dipalladium (0) and 2-dicyclohexylphosphino- 2 ′, 6′-diisopropoxy-1,1′-biphenyl and the like.
Compound (XXV) used as a starting material in this method may be a commercially available product, or can be produced by a method known per se or a method analogous thereto.

Compound (I) is prepared by the method shown in the following scheme F or when X ¹ is N, X ² is CH, X ³ is CH, X ⁴ is CH, X ⁵ is a bond, and X ⁶ is CH _2. It can be produced by a similar method or a method described in Examples.

[Scheme F]

[Wherein the symbols are as defined above. ]
Compound (XXXVI) can be produced by iodination reaction of compound (XXXV). Examples of the iodination reagent include tetramethylpiperidine, normal butyl lithium, iodine and the like.
Compound (I) can be produced by coupling reaction of compound (XLI) and deprotection reaction of compound (XLII) obtained thereby. Metal catalysts and their ligands include bis (di-tert-butyl (4-dimethylaminophenyl) phosphine) dichloropalladium (II) or tris (dibenzylideneacetone) dipalladium (0) and 2-dicyclohexylphosphino- 2 ′, 6′-diisopropoxy-1,1′-biphenyl and the like.
As the compound (XXXV) used as a starting material in this method, a commercially available product may be used as it is, or it can be produced by a method known per se or a method analogous thereto.

Compound (I) can be prepared by the method shown in the following scheme G when X ¹ is CH, X ² is N, X ³ is N, X ⁴ is CH, X ⁵ is a bond and X ⁶ is CH ₂ or It can be produced by a similar method or a method described in Examples.

[Scheme G]

[Wherein the symbols are as defined above. ]
Compound (XLVI) can be produced by cyclization reaction and dehydration reaction of compound (XLV). Examples of the reagent include S-methylisothiourea.
Compound (I) can be produced by a coupling reaction of compound (XLVII). Metal catalysts and their ligands include bis (di-tert-butyl (4-dimethylaminophenyl) phosphine) dichloropalladium (II) or tris (dibenzylideneacetone) dipalladium (0) and 2-dicyclohexylphosphino- 2 ′, 6′-diisopropoxy-1,1′-biphenyl and the like.
As the compound (XLIII) used as a raw material in this method, a commercially available product may be used as it is, or it may be produced by a method known per se or a method analogous thereto.

Compound (I) is prepared by the method shown in Scheme H below or when X ¹ is CH, X ² is CH, X ³ is CH, X ⁴ is N, X ⁵ is CH ₂ and X ⁶ is CH _2. It can be produced by a similar method or a method described in Examples.

[Scheme H]

[Wherein the symbols are as defined above. ]
Compound (XLIX) can be produced by subjecting compound (XLVIII) to an alkylation reaction. Examples of the alkylating reagent include benzyl bromide.
Compound (I) can be produced by a coupling reaction of compound (XLIX). Metal catalysts and their ligands include bis (di-tert-butyl (4-dimethylaminophenyl) phosphine) dichloropalladium (II) or tris (dibenzylideneacetone) dipalladium (0) and 2-dicyclohexylphosphino- 2 ′, 6′-diisopropoxy-1,1′-biphenyl and the like.
As the compound (XLVIII) used as a starting material in this method, a commercially available product may be used as it is, or it may be produced by a method known per se or a method analogous thereto.

Compound (I) can be prepared by the method shown in Scheme I below or when X ¹ is CH, X ² is CH, X ³ is N, X ⁴ is N, X ⁵ is CH ₂ and X ⁶ is CH _2. It can be produced by a similar method or a method described in Examples.

[Scheme I]

[Wherein the symbols are as defined above. ]
Compound (I) can be produced by a coupling reaction of compound (LI). Metal catalysts and their ligands include bis (di-tert-butyl (4-dimethylaminophenyl) phosphine) dichloropalladium (II) or tris (dibenzylideneacetone) dipalladium (0) and 2-dicyclohexylphosphino- 2 ′, 6′-diisopropoxy-1,1′-biphenyl and the like.
As the compound (L) used as a raw material in this method, a commercially available product may be used as it is, or it may be produced by a method known per se or a method analogous thereto.

The compound (I) thus obtained can be isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, transfer dissolution, chromatography, and the like.

The compound of the present invention obtained by each of the above production methods can be isolated and purified by known means such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, transfer dissolution, chromatography and the like. Moreover, each raw material compound used in each of the above production methods can be isolated and purified by the same known means as described above. On the other hand, you may use these raw material compounds as a reaction mixture as it is as a raw material of the following process, without isolating.
The compound (I) produced by such a method can be isolated and purified by usual separation means such as recrystallization, distillation, chromatography and the like.
When compound (I) contains optical isomers, stereoisomers, positional isomers, and rotational isomers, these are also included as compound (I), and synthetic methods and separation methods known per se (for example, , Concentration, solvent extraction, column chromatography, recrystallization, etc.), each can be obtained as a single product. For example, when compound (I) has an optical isomer, the optical isomer resolved from the compound is also encompassed in compound (I).

The optical isomer can be produced by a method known per se. Specifically, an optical isomer is obtained by using an optically active synthetic intermediate or by optically resolving the final racemate according to a conventional method.
As the optical resolution method, a method known per se, for example, fractional recrystallization method, chiral column method, diastereomer method and the like are used.

1) Fractional recrystallization method Racemate and optically active compound (for example, (+)-mandelic acid, (−)-mandelic acid, (+)-tartaric acid, (−)-tartaric acid, (+)-1-phenethylamine, (-)-1-phenethylamine, cinchonine, (-)-cinchonidine, brucine, etc.) to form a salt, which is separated by fractional recrystallization, and if desired, a free optical isomer is obtained through a neutralization step. Method.
2) Chiral column method A method in which a racemate or a salt thereof is separated by applying to an optical isomer separation column (chiral column). For example, in the case of liquid chromatography, a mixture of optical isomers is added to a chiral column such as ENANTIO-OVM (manufactured by Tosoh Corporation) or CHIRAL series (manufactured by Daicel Corporation), and water, various buffer solutions (eg, phosphate buffer) are added. Liquid, etc.) and an organic solvent (eg, ethanol, methanol, isopropanol, acetonitrile, trifluoroacetic acid, diethylamine, etc.) are developed as a single or mixed solution to separate optical isomers. Further, for example, in the case of gas chromatography, separation is performed using a chiral column such as CP-Chirasil-DeX CB (manufactured by GL Sciences).
3) Diastereomer method A mixture of racemates is converted into a mixture of diastereomers by chemical reaction with an optically active reagent, and this is converted into a single substance through ordinary separation means (for example, fractional recrystallization, chromatography method, etc.). And then obtaining an optical isomer by separating the optically active reagent site by chemical treatment such as hydrolysis reaction. For example, when the compound (I) has a hydroxy or a primary or secondary amino in the molecule, the compound and an optically active organic acid (for example, MTPA [α-methoxy-α- (trifluoromethyl) phenylacetic acid], ( -)-Menthoxyacetic acid etc.) are subjected to a condensation reaction to obtain ester or amide diastereomers, respectively. On the other hand, when the compound (I) has a carboxylic acid group, an amide or ester diastereomer is obtained by subjecting the compound and an optically active amine or alcohol reagent to a condensation reaction. The separated diastereomer is converted into the optical isomer of the original compound by subjecting it to an acid hydrolysis or basic hydrolysis reaction.

Compound (I) may be a crystal.
Crystals of compound (I) can be produced by applying crystallization methods known per se to compound (I) for crystallization.
Here, examples of the crystallization method include a crystallization method from a solution, a crystallization method from a vapor, a crystallization method from a melt, and the like.

The “crystallization from solution” includes a state in which the compound is not saturated by changing factors related to the solubility of the compound (solvent composition, pH, temperature, ionic strength, redox state, etc.) or the amount of the solvent. In general, a method of shifting from a supersaturated state to a supersaturated state is exemplified, and specific examples include a concentration method, a slow cooling method, a reaction method (diffusion method, electrolysis method), a hydrothermal growth method, and a flux method. Examples of the solvent used include aromatic hydrocarbons (eg, benzene, toluene, xylene, etc.), halogenated hydrocarbons (eg, dichloromethane, chloroform, etc.), saturated hydrocarbons (eg, hexane, heptane, cyclohexane). Etc.), ethers (eg, diethyl ether, diisopropyl ether, tetrahydrofuran, 1,4-dioxane, etc.), nitriles (eg, acetonitrile, etc.), ketones (eg, acetone, etc.), sulfoxides (eg, dimethyl sulfoxide, etc.) ), Acid amides (eg, N, N-dimethylformamide, etc.), esters (eg, ethyl acetate, etc.), alcohols (eg, methanol, ethanol, isopropyl alcohol, etc.), water and the like. These solvents may be used alone or in admixture of two or more at an appropriate ratio (eg, 1: 1 to 1: 100 (volume ratio)). A seed crystal can also be used as needed.

Examples of the “crystallization method from vapor” include a vaporization method (sealed tube method, air flow method), a gas phase reaction method, a chemical transport method, and the like.

Examples of the “crystallization from the melt” include normal freezing method (pulling method, temperature gradient method, Bridgman method), zone melting method (zone leveling method, float zone method), special growth method (VLS method). , Liquid phase epitaxy method) and the like.

As a preferred example of the crystallization method, compound (I) is dissolved in a suitable solvent (eg, alcohol such as methanol, ethanol, etc.) at a temperature of 20 to 120 ° C., and the resulting solution is dissolved. Examples thereof include a method of cooling to a temperature or lower (for example, 0 to 50 ° C., preferably 0 to 20 ° C.).
The crystals of the present invention thus obtained can be isolated by, for example, filtration.
As a method for analyzing the obtained crystal, a crystal analysis method by powder X-ray diffraction is generally used. Furthermore, examples of the method for determining the crystal orientation include a mechanical method and an optical method.

The crystal of compound (I) obtained by the above production method (hereinafter abbreviated as “crystal of the present invention”) has high purity, high quality, low hygroscopicity, and is stored for a long time under normal conditions. Is very stable. In addition, it has excellent biological properties (eg, pharmacokinetics (absorbability, distribution, metabolism, excretion), expression of drug efficacy, etc.) and is extremely useful as a medicine.

In the present specification, the specific optical rotation ([α] _D ) is a ratio measured using, for example, an optical polarimeter (JASCO, P-1030 polarimeter (No. AP-2)) or the like. Means optical rotation.
In the present specification, the melting point means a melting point measured using, for example, a trace melting point measuring device (Yanako, MP-500D type) or a DSC (Differential Scanning Calorimetry) apparatus (SEIKO, EXSTAR6000).

Compound (I) may be used as a prodrug. A prodrug of compound (I) is a compound that is converted to compound (I) by a reaction with an enzyme, gastric acid, or the like under physiological conditions in vivo, that is, compound (I) that is enzymatically oxidized, reduced, hydrolyzed, etc. A compound that changes to compound (I) by hydrolysis or the like due to gastric acid or the like.
As a prodrug of compound (I), for example,
(1) A compound in which amino of compound (I) is acylated, alkylated or phosphorylated (for example, amino of compound (I) is eicosanoylated, alanylated, pentylaminocarbonylated, (5-methyl-2- Oxo-1,3-dioxolen-4-yl) methoxycarbonylation, tetrahydrofuranylation, pyrrolidylmethylation, pivaloyloxymethylation, tert-butylation, ethoxycarbonylation, tert-butoxycarbonylation, acetylation, Cyclopropylcarbonylated compounds, etc.);
(2) Compound in which hydroxy of compound (I) is acylated, alkylated, phosphorylated, borated (for example, hydroxy of compound (I) is acetylated, palmitoylated, propanoylated, pivaloylated, succinylated , Fumarylated, alanylated, dimethylaminomethylcarbonylated compounds, etc.);
(3) Compound (I) in which carboxy is esterified or amidated (for example, compound (I) in which carboxy is ethyl esterified, phenyl esterified, carboxymethyl esterified, dimethylaminomethyl esterified, Valoyloxymethyl esterification, ethoxycarbonyloxyethyl esterification, phthalidyl esterification, (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl esterification, cyclohexyloxycarbonylethyl esterification, methylamide Compound etc.);
Etc. These compounds can be produced from compound (I) by a method known per se.
The prodrug of compound (I) changes to compound (I) under physiological conditions as described in Hirokawa Shoten, 1990, “Development of Drugs”, Volume 7, Molecular Design, pages 163 to 198. There may be.

In the present specification, compound (I) and prodrugs thereof may be collectively abbreviated as “the compound of the present invention”.

Compound (I) may be a hydrate, a non-hydrate, a solvate, or a non-solvate.
Compounds labeled with isotopes (eg, ³ H, ¹⁴ C, ³⁵ S, ¹²⁵ I, etc.) are also encompassed in compound (I).
Further, a deuterium converter obtained by converting ¹ H into ² H (D) is also encompassed in compound (I).
Tautomers are also encompassed in compound (I).
Compound (I) may be a pharmaceutically acceptable cocrystal or cocrystal salt. Here, co-crystals or co-crystal salts are two or more unique at room temperature, each having different physical properties (eg structure, melting point, heat of fusion, hygroscopicity, solubility and stability). It means a crystalline substance composed of a simple solid. The cocrystal or cocrystal salt can be produced according to a cocrystallization method known per se.
Compound (I) may be used as a PET tracer.

Since the compound of the present invention has an excellent PKC (particularly PKC-θ) inhibitory action, it is also useful as a safe pharmaceutical based on this action.
For example, the medicament of the present invention comprising the compound of the present invention is a PKC (in particular, a mouse, rat, hamster, rabbit, cat, dog, cow, sheep, monkey, human etc.). It can be used as a prophylactic or therapeutic agent for PKC-θ) -related diseases and T cell-related diseases, more specifically, as prophylactic or therapeutic agents for the diseases described in (1) to (5) below.
(1) Inflammatory diseases (eg, acute pancreatitis, chronic pancreatitis, asthma, adult respiratory distress syndrome, chronic obstructive pulmonary disease (COPD), inflammatory bone disease, inflammatory lung disease, inflammatory bowel disease, celiac disease, hepatitis Systemic inflammatory response syndrome (SIRS), inflammation after surgery or trauma, pneumonia, nephritis, meningitis, cystitis, sore throat, gastric mucosal damage, meningitis, spondylitis, arthritis, dermatitis, chronic pneumonia , Bronchitis, pulmonary infarction, silicosis, pulmonary sarcoidosis, diabetic nephropathy, uveitis, purulent dysplasia, ventilation, etc.);
(2) Immune disease (eg, rheumatoid arthritis), psoriasis (psoriasis), inflammatory bowel disease (eg, Crohn's disease, ulcerative colitis, etc.) , Sjogren's syndrome, Behcet's syndrome, multiple sclerosis, systemic lupus erythematosus, lupus nephritis, discoid lupus erythematosus ), Castleman's disease, ankylosing spondylitis, polymyositis, dermatomyositis (DM), nodular polyarteritis (PN), mixed connective tissue disease (MCTD), scleroderma, deep Lupus erythematosus, chronic thyroiditis, Graves disease, autoimmune gastritis, type I and type II diabetes, autoimmune hemolytic anemia, autoimmune neutropenia, platelets Adolescent, atopic dermatitis, chronic active hepatitis, myasthenia gravis, graft-versus-host disease, Addison's disease, abnormal immune response, arthritis, dermatitis, radiation dermatitis, primary biliary cirrhosis etc);
(3) bone or joint degenerative diseases (eg, rheumatoid arthritis, osteoporosis, osteoarthritis, etc.);
(4) Neoplastic disease [eg, malignant tumor, neovascular glaucoma, infantile hemangioma, multiple myeloma, chronic sarcoma, metastatic melanoma, Kaposi's sarcoma, vascular proliferation, cachexia, Cancer (eg, colorectal cancer (eg, familial colorectal cancer, hereditary non-polyposis colorectal cancer, gastrointestinal stromal tumor)), lung cancer (eg, non-small cell lung cancer, small cell lung cancer, malignant mesothelioma) ), Mesothelioma, pancreatic cancer (eg, pancreatic duct cancer), stomach cancer (eg, papillary adenocarcinoma, mucinous adenocarcinoma, adenosquamous carcinoma), breast cancer (eg, invasive ductal carcinoma, non-invasive) Breast cancer, inflammatory breast cancer, etc.), ovarian cancer (eg, epithelial ovarian cancer, extragonadal germ cell tumor, ovarian germ cell tumor, ovarian low-grade tumor, etc.), prostate cancer (eg, hormone) Dependent prostate cancer, hormone-independent prostate cancer, etc.), liver cancer (eg, primary liver cancer, extrahepatic bile duct cancer, etc.), thyroid gland (Eg, medullary thyroid cancer), kidney cancer (eg, renal cell carcinoma, transitional cell carcinoma of the renal pelvis and ureter), uterine cancer, brain tumor (eg, pineal gland cell tumor, ciliary cell stellate cell) Tumor, diffuse astrocytoma, anaplastic astrocytoma), melanoma, sarcoma, bladder cancer, blood cancer including multiple myeloma, pituitary adenoma, glioma, acoustic schwannoma, Retinal sarcoma, pharyngeal cancer, laryngeal cancer, tongue cancer, thymoma, esophageal cancer, duodenal cancer, colon cancer, rectal cancer, hepatocellular carcinoma, pancreatic endocrine tumor, bile duct cancer, gallbladder cancer, penile cancer, ureteral cancer, testicular tumor , Vulvar cancer, cervical cancer, uterine body cancer, uterine sarcoma, choriocarcinoma, vaginal cancer, skin cancer, mycosis fungoides, basal cell tumor, soft tissue sarcoma, malignant lymphoma, Hodgkin's disease, myelodysplastic syndrome, adult T cell leukemia, chronic myeloproliferative disorder, pancreatic endocrine tumor, fibrous histiocytoma, leiomyosarcoma, rhabdomyosarcoma, primary unknown Leukemia (eg, acute leukemia (eg, acute lymphocytic leukemia, acute myeloid leukemia)), chronic leukemia (eg, chronic lymphocytic leukemia, chronic myelogenous leukemia), myelogenic syndrome, etc.) Uterine sarcoma (eg, uterine mesoderm mixed tumor, uterine leiomyosarcoma, endometrial stromal tumor, etc.), myelofibrosis, etc.];
(5) Central diseases (eg, schizophrenia, Alzheimer's disease (eg, Alzheimer type dementia)).

The medicament of the present invention is preferably an immune disease, inflammatory disease, bone or joint degenerative disease, central disease or neoplastic disease, more preferably graft-versus-host disease, aplasticity Anemia (aplastic 、 anemia), systemic lupus erythematosus, lupus nephritis, pemphigus, inflammatory bowel disease (preferably Crohn's disease) or ulcerative Colitis (ulcerative colitis), erythroblast 癆 (pure red cell aplasia), myasthenia Gravis, asthma, vasculitis, ankylosing spondylitis (spondylarthritis ankylopoietica), rheumatoid arthritis (Rheumatoid arthritis), psoriasis (psoriasis), Sjogren's syndrome (Sjogren's syndrome), atopic dermatitis, Behcet's disease (Beh cet's syndrome, multiple sclerosis, Alzheimer's disease (preferably dementia of Alzheimer type), adult respiratory distress syndrome (adult respiratory distress syndrome), celiac disease celiac disease, Castleman's disease, leukemia, uterine leiomyosarcoma, prostate cancer, multiple myeloma, cachexia, bone marrow Myelofibrosis, nephrotic syndrome, kidney transplant, liver transplant, liver transplant, cardiac transplant, lung transplant, pancreas transplant, small intestine Prediction of rejection in transplantation (small bowel transplant), hematopoietic stem cell transplant, etc. Or it can be used as a therapeutic agent.

Here, “prevention” of the disease refers to, for example, a patient who has not developed the disease, which is expected to have a high risk of onset due to some factor related to the disease, or who has developed the subjective symptom. This means that a drug containing the compound of the present invention is administered to a patient who is not, or that a drug containing the compound of the present invention is administered to a patient who is concerned about recurrence of the disease after treatment of the disease.

The medicament of the present invention has excellent pharmacokinetics (eg, blood drug half-life), low toxicity (eg, HERG inhibition, CYP inhibition, CYP induction), and reduction in drug interaction is observed. The compound of the present invention is mixed with a pharmacologically acceptable carrier as it is or according to a method known per se generally used in the preparation of pharmaceutical preparations to form a pharmaceutical composition, which is used as the pharmaceutical of the present invention. be able to. The medicament of the present invention is given orally or parenterally to mammals (eg, humans, monkeys, cows, horses, pigs, mice, rats, hamsters, rabbits, cats, dogs, sheep, goats, etc.). Safe to administer.
The medicament containing the compound of the present invention is a pharmacologically acceptable compound of the present compound alone or with the compound of the present invention according to a method known per se as a method for producing a pharmaceutical preparation (eg, a method described in the Japanese Pharmacopoeia). It can be used as a pharmaceutical composition mixed with a carrier to be prepared. Examples of the medicament containing the compound of the present invention include tablets (including sugar-coated tablets, film-coated tablets, sublingual tablets, orally disintegrating tablets, buccal tablets, etc.), pills, powders, granules, capsules (soft capsules, microcapsules). Capsules), lozenges, syrups, solutions, emulsions, suspensions, controlled release formulations (eg, immediate release formulations, sustained release formulations, sustained release microcapsules), aerosols, films ( Eg, orally disintegrating film, oral mucosa adhesive film), injection (eg, subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection), instillation, transdermal preparation, cream, Ointments, lotions, patches, suppositories (eg, rectal suppositories, vaginal suppositories), pellets, nasal agents, pulmonary agents (eg, inhalants), eye drops, etc., orally or parenterally (Eg, intravenous, intramuscular, subcutaneous, internal organ, nasal cavity , Intradermal, instillation, intracerebral, intrarectal, intravaginal, intraperitoneal, tumor interior, proximal tumors, can be safely administered into a lesion, etc.).

The content of the compound of the present invention in the medicament of the present invention is about 0.01% to about 100% by weight of the whole medicament.
The dose of the compound of the present invention varies depending on the administration subject, administration route, disease and the like. For example, the active ingredient (compound (I ) Of about 0.01 mg / kg body weight to about 500 mg / kg body weight, preferably about 0.1 mg / kg body weight to about 50 mg / kg body weight, more preferably about 1 mg / kg body weight to 30 mg / kg body weight. It may be administered once to several times a day.

Examples of the pharmacologically acceptable carrier that may be used in the production of the medicament of the present invention include various organic or inorganic carrier substances commonly used as pharmaceutical materials. For example, excipients and lubricants in solid preparations , Binders and disintegrants, solvents in liquid preparations, solubilizers, suspending agents, tonicity agents, buffers and soothing agents. If necessary, additives such as conventional preservatives, antioxidants, colorants, sweeteners, adsorbents, wetting agents and the like can be used in appropriate amounts.

Examples of the excipient include lactose, sucrose, D-mannitol, starch, corn starch, crystalline cellulose, light anhydrous silicic acid and the like.
Examples of the lubricant include magnesium stearate, calcium stearate, talc, colloidal silica and the like.
Examples of the binder include crystalline cellulose, sucrose, D-mannitol, dextrin, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, starch, sucrose, gelatin, methylcellulose, sodium carboxymethylcellulose and the like.
Examples of the disintegrant include starch, carboxymethyl cellulose, carboxymethyl cellulose calcium, carboxymethyl starch sodium, L-hydroxypropyl cellulose, and the like.
Examples of the solvent include water for injection, alcohol, propylene glycol, macrogol, sesame oil, corn oil, olive oil and the like.
Examples of the solubilizer include polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate and the like.
Examples of the suspending agent include surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, and glyceryl monostearate; And hydrophilic polymers such as sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, and the like.

Examples of the isotonic agent include glucose, D-sorbitol, sodium chloride, glycerin, D-mannitol and the like.
Examples of the buffer include buffer solutions of phosphate, acetate, carbonate, citrate and the like.
Examples of soothing agents include benzyl alcohol.
Examples of the preservative include p-hydroxybenzoates, chlorobutanol, benzyl alcohol, phenylethyl alcohol, dehydroacetic acid, sorbic acid and the like.
Examples of the antioxidant include sulfite, ascorbic acid, α-tocopherol and the like.

In the prevention and treatment of various diseases, the compound of the present invention can be used together with other drugs. Hereinafter, the pharmaceutical used when the compound of the present invention is used in combination with another drug is referred to as “the combination agent of the present invention”.
For example, the compound of the present invention can be used in combination with the following drugs.
(1) Nonsteroidal anti-inflammatory drugs (NSAIDs)
(I) Classic NSAIDs
Arcofenac, aceclofenac, sulindac, tolmetine, etodolac, fenoprofen, thiaprofenic acid, meclofenamic acid, meloxicam, teoxicam, lornoxicam, nabumetone, acetaminophen, phenacetin, ethenamide, sulpyrine, antipyrine, migrenin, aspirin, fefenamic acid, mefenamic acid Diclofenac sodium, loxoprofen sodium, phenylbutazone, indomethacin, ibuprofen, ketoprofen, naproxen, oxaprozin, flurbiprofen, fenbufen, pranoprofen, fructaphenine, piroxicam, epilisol, thiaramide hydrochloride, zaltoprofen, gabexate mesilate, camostat mesylate, Urinastatin, colchicine, Robeneshido, sulfinpyrazone, benzbromarone, allopurinol, sodium gold thiomalate, sodium hyaluronate, sodium salicylate, morphine hydrochloride, salicylic acid, atropine, scopolamine, morphine, pethidine, levorphanol, oxymorphone or a salt thereof.
(Ii) cyclooxygenase inhibitors (COX-1 selective inhibitors, COX-2 selective inhibitors, etc.)
Salicylic acid derivatives (eg, celecoxib, aspirin), etoroxib, valdecoxib, diclofenac, indomethacin, loxoprofen, etc.
(Iii) Nitric oxide free NSAIDs
(Iv) JAK inhibitors Tofacitinib (Tofacitinib), Ruxolitinib (Ruxolitinib) and the like.

(2) Disease-modifying anti-rheumatic drugs (DMARDs)
(I) Gold formulation Auranofin et al.
(Ii) Penicillamine D-penicillamine.
(Iii) Amino salicylic acid preparation Sulfasalazine, mesalamine, olsalazine, balsalazide.
(Iv) Antimalarial drug chloroquine and the like.
(V) pyrimidine synthesis inhibitor leflunomide and the like.
(Vi) Prograph

(3) Anti-cytokine drug (I) protein preparation (i) TNF inhibitor etanercept, infliximab, adalimumab, certolizumab Pegor, golimumab, PASSTNF-α, soluble TNF-α receptor, TNF-α binding protein, anti-TNF-α antibody etc.
(Ii) Interleukin-1 inhibitor Anakinra (interleukin-1 receptor antagonist), soluble interleukin-1 receptor and the like.
(Iii) Interleukin-6 inhibitor Tocilizumab (anti-interleukin-6 receptor antibody), anti-interleukin-6 antibody and the like.
(Iv) Interleukin-10 drug Interleukin-10 and the like.
(V) Interleukin-12 / 23 inhibitor Ustekinumab, briakinumab (anti-interleukin-12 / 23 antibody) and the like.
(II) Non-protein preparation (i) MAPK inhibitor BMS-582949 and the like.
(Ii) Gene regulators Inhibitors of molecules related to signal transduction such as NF-κ, NF-κB, IKK-1, IKK-2, AP-1.
(Iii) Cytokine production inhibitor iguratimod, tetomilast and the like.
(Iv) TNF-α converting enzyme inhibitor (v) interleukin-1β converting enzyme inhibitor VX-765 and the like.
(Vi) Interleukin-6 antagonist HMPL-004 and the like.
(Vii) Interleukin-8 inhibitor IL-8 antagonist, CXCR1 & CXCR2 antagonist, reparexin and the like.
(Viii) Chemokine antagonist CCR9 antagonist (CCX-282, CCX-025), MCP-1 antagonist and the like.
(Ix) Interleukin-2 receptor antagonist Denileukine, Defuchitox and the like.
(X) Therapeutic vaccines
TNF-α vaccine and the like.
(Xi) Gene therapy drug Gene therapy drug for enhancing expression of genes having anti-inflammatory activity such as interleukin-4, interleukin-10, soluble interleukin-1 receptor, soluble TNF-α receptor .
(Xii) Antisense compound ISIS-104838 and the like.

(4) Integrin inhibitors Natalizumab, vedolizumab, AJM300, TRK-170, E-6007, etc.

(5) Immunomodulatory drugs (immunosuppressive drugs)
Methotrexate, cyclophosphamide, MX-68, atiprimod dihydrochloride, BMS-188667, CKD-461, limexolone, cyclosporine, tacrolimus, gusperimus, sirolimus, everolimus, azathioprine, anti-lymph serum, dry sulfonated immunoglobulin, erythropoi Etine, colony stimulating factor, interleukin, interferon, etc.

(6) Steroid drugs Dexamethasone, hexestrol, methimazole, betamethasone, triamcinolone, triamcinolone acetonide, fluocinonide, fluocinolone acetonide, prednisolone, methylprednisolone, cortisone acetate, hydrocortisone, fluorometholone, estriol propionate, estriol etc.

(7) Angiotensin converting enzyme inhibitor enalapril, captopril, ramipril, lisinopril, cilazapril, perindopril and the like.

(8) Angiotensin II receptor antagonist candesartan, cilexetil (TCV-116), valsartan, irbesartan, olmesartan, eprosartan and the like.

(9) Diuretics Hydrochlorothiazide, spironolactone, furosemide, indapamide, bendrofluazide, cyclopenthiazide and the like.

(10) Cardiotonic drugs Digoxin, dobutamine and the like.

(11) β receptor antagonist carvedilol, metoprolol, atenolol and the like.

(12) Ca sensitivity enhancer MCC-135 and the like.

(13) Ca channel antagonist nifedipine, diltiazem, verapamil and the like.

(14) Antiplatelet drugs, anticoagulants heparin, aspirin, warfarin and the like.

(15) HMG-CoA reductase inhibitor atorvastatin, simvastatin and the like.

(16) Contraceptives (i) Sex hormones or derivatives thereof Progesterone or derivatives thereof (progesterone, 17α-hydroxyprogesterone, medroxyprogesterone, medroxyprogesterone acetate, norethisterone, norethisterone enanthate, norethindrone, norethindrone acetate, norethinodrel, levonorgestrel , Norgestrel, etinodiol diacetate, desogestrel, norgestimate, guestden, progestin, etonogestrel, drospirenone, dienogest, trimegestone, nestron, chromadianone acetate, mifepristone, nomegestrol acetate, Org-30659, TX-525, EMM-310525) or Progesterone or its derivative and follicular hormone or its derivative (Ladiol, estradiol benzoate, estradiol cypionate, estradiol dipropionate, estradiol enanthate, estradiol hexahydrobenzoate, estradiol phenylpropionate, estradiol undecanoate, estradiol valerate, estrone, ethinyl estradiol, mestranol) Agents etc.
(Ii) Anti-follicular hormone drugs Olmeroxifene, mifepristone, Org-33628 and the like.
(Iii) Spermicide Uchel cell and the like.

(17) Others (i) T cell inhibitor (ii) Inosine monophosphate dehydrogenase (IMPDH) inhibitor Mycophenolate mofetil and the like.
(Iii) Adhesion molecule inhibitor ISIS-2302, selectin inhibitor, ELAM-1, VCAM-1, ICAM-1, etc.
(Iv) thalidomide (v) cathepsin inhibitor (vi) matrix metalloprotease (MMPs) inhibitor V-85546 and the like.
(Vii) Glucose-6-phosphate dehydrogenase inhibitor (viii) Dihydrorotate dehydrogenase (DHODH) inhibitor (ix) Phosphodiesterase IV (PDEIV) inhibitor Roflumilast, CG-1088 and the like.
(X) Phospholipase A2 inhibitor (xi) iNOS inhibitor VAS-203 and the like.
(Xii) Microtubule stimulant paclitaxel and the like.
(Xiii) Microtubule inhibitor Rheumacon and the like.
(Xiv) MHC class II antagonist (xv) Prostacyclin agonist iloprost and the like.
(Xvi) CD4 antagonist zanolimumab and the like.
(Xvii) CD23 antagonist (xviii) LTB4 receptor antagonist DW-1305 and the like.
(Xix) 5-lipoxygenase inhibitor zileuton and the like.
(Xx) Cholinesterase inhibitor galantamine and the like.
(Xxi) tyrosine kinase inhibitor Tyk2 inhibitor (WO20101422752) and the like.
(Xxii) Cathepsin B inhibitor (xxiii) Adenosine deaminase inhibitor Pentostatin and the like.
(Xxiv) Osteogenic stimulant (xxv) Dipeptidyl peptidase inhibitor (xxvi) Collagen agonist (xxvii) Capsaicin cream (xxviii) Hyaluronic acid derivative Synbisque (hylan GF 20), Orthobisque and the like.
(Xxix) Glucosamine sulfate (xxx) Amiprirose (xxxi) CD-20 inhibitor Rituximab, ibritumomab, tositumomab, ofatumuma and the like.
(Xxxii) BAFF inhibitor belimumab, tabalumab, atacicept, A-623 and the like.
(Xxxiii) CD52 inhibitor alemtuzumab and the like.
(Xxxiv) IL-17 inhibitor secukinumab (AIN-457), LY-2439821, AMG827 and the like.
(Xxxv) PDE4 inhibitor Roflumilast, Apremilast.
(Xxxvi) Human lymphocyte / thymocyte antibody Anti-human thymocyte rabbit immunoglobulin, anti-human thymocyte equine immunoglobulin and the like.
(Xxxvii) anti-CD3 antibody visilizumab and the like.
(Xxxviii) anti-CD25 antibody basiliximab, daclizumab and the like.
(Xxxix) CTLA-4-Ig
Abatacept, Beratacept, etc.

Examples of concomitant drugs other than the above include, for example, antibacterial drugs, antifungal drugs, antiprotozoal drugs, antibiotics, antitussives and expectorants, sedatives, anesthetics, antiulcer drugs, antiarrhythmic drugs, antihypertensive diuretics, anticoagulants Drugs, tranquilizers, antipsychotics, antitumor drugs, antihyperlipidemic drugs, muscle relaxants, antiepileptic drugs, antidepressants, antiallergic drugs, cardiotonic drugs, antiarrhythmic drugs, vasodilators, vasoconstriction Drugs, antihypertensive diuretics, antidiabetics, narcotic antagonists, vitamins, vitamin derivatives, anti-asthma, frequent urinary / urinary incontinence, antidiarrheal, atopic dermatitis, allergic rhinitis, pressurization Examples include drugs, endotoxin antagonists or antibodies, signal transduction inhibitors, inflammatory mediator action inhibitors, inflammatory mediator action inhibitory antibodies, anti-inflammatory mediator action inhibitory drugs, anti-inflammatory mediator action inhibitory antibodies, and the like. Specific examples include the following.

(1) Antibacterial drugs (i) Sulfa drugs Sulfamethizol, sulfisoxazole, sulfamonomethoxine, sulfamethizol, salazosulfapyridine, sulfadiazine silver and the like.
(Ii) Quinoline antibacterial agents Nalidixic acid, pipemidic acid trihydrate, enoxacin, norfloxacin, ofloxacin, tosufloxacin tosylate, ciprofloxacin hydrochloride, lomefloxacin hydrochloride, sparfloxacin, fleroxacin and the like.
(Iii) Antituberculosis drugs Isoniazid, ethambutol (ethambutol hydrochloride), paraaminosalicylic acid (calcium paraaminosalicylate), pyrazinamide, etionamide, prothionamide, rifampicin, streptomycin sulfate, kanamycin sulfate, cycloserine and the like.
(Iv) Mycobacterial drugs Diaphenylsulfone, rifampicillin and the like.
(V) Antiviral drugs idoxuridine, acyclovir, vitarabine, ganciclovir, foscarnet and the like.
(Vi) Anti-HIV drugs zidovudine, didanosine, zarcitabine, indinavir sulfate ethanol adduct, ritonavir and the like.
(Vii) Antispirocheta drugs (viii) Antibiotics Tetracycline hydrochloride, ampicillin, piperacillin, gentamicin, dibekacin, cannendomycin, libidomycin, tobramycin, amikacin, fradiomycin, sisomycin, tetracycline, oxytetracycline, loritetracycline, doxycycline, doxycycline, doxycycline Piperacillin, ticarcillin, cephalothin, cefapirin, cephaloridine, cefaclor, cephalexin, cefloxazine, cefadroxyl, cefamandol, cephoam, cefuroxime, cefothium, cefothium hexetyl, cefuroxime xetilyl, cefdinir ceftefirfide , Cefmenoxime, cefpodoxime Proxetyl, cefpirom, cefazoplan, cefepime, cefsulosin, cefmenoxime, cefmetazole, cefminox, cefoxitin, cefbuperazone, latamoquinacef, flomoxef, cefazoline, cefotaxime, cefoperamine, ceftizoxime, Of Antibiotics (J. Antibiotics), 38,877-885 (1985)], azole compounds [2-[(1R, 2R) -2- (2,4-difluorophenyl) -2-hydroxy- 1-methyl-3- (1H-1,2,4-triazol-1-yl) propyl] -4- [4- (2,2,3,3-tetrafluoro Propoxy) phenyl] -3- (2H, 4H) -1,2,4- triazolone, fluconazole, itraconazole, imipenem, meropenem, trimethoprim, sulfamethoxazole, etc.] and the like.

(2) Antifungal drugs (i) Polyethylene antibiotics (eg, amphotericin B, nystatin, tricomycin)
(Ii) griseofulvin, pyrrolnitrin, etc. (iii) cytosine antimetabolite (eg, flucytosine)
(Iv) Imidazole derivatives (eg, econazole, clotrimazole, miconazole nitrate, bifonazole, croconazole)
(V) Triazole derivatives (eg, fluconazole, itraconazole)
(Vi) thiocarbamic acid derivatives (eg, trinaphthol) and the like.

(3) Antiprotozoal drugs Metronidazole, tinidazole, diethylcarbamazine citrate, quinine hydrochloride, quinine sulfate and the like.

(4) Antitussive / Antidepressant Ephedrine hydrochloride, noscapine hydrochloride, codeine phosphate, dihydrocodeine phosphate, isoproterenol hydrochloride, ephedrine hydrochloride, methylephedrine hydrochloride, noscapine hydrochloride, aloclamide, chlorfedianol, picoperidamine, cloperastine, protochlorol , Isoproterenol, salbutamol, tereptaline, oxypetebanol, morphine hydrochloride, dextropetrphan hydrobromide, oxycodone hydrochloride, dimorphan phosphate, tipipedin hibenzate, pentoxyberine citrate, clofedanol hydrochloride, benzonate, guaifenesin, Bromhexine hydrochloride, ambroxol hydrochloride, acetylcysteine, ethylcysteine hydrochloride, carbocysteine, etc.

(5) Sedatives Chlorpromazine hydrochloride, atropine sulfate, phenobarbital, barbital, amobarbital, pentobarbital, thiopental sodium, thiamylal sodium, nitrazepam, estazolam, flurazapam, haloxazolam, triazolam, flunitrazepam, bromvaleryl urea, chlorphos chloral trihydrate Sodium etc.

(6) Anesthetic (6-1) Local anesthetic Cocaine hydrochloride, procaine hydrochloride, lidocaine, dibucaine hydrochloride, tetracaine hydrochloride, mepivacaine hydrochloride, bupivacaine hydrochloride, oxybuprocaine hydrochloride, ethyl aminobenzoate, oxesazein and the like.
(6-2) General anesthetic (i) Inhalation anesthetic (eg, ether, halothane, nitrous oxide, influrane, enflurane),
(Ii) intravenous anesthetics (eg, ketamine hydrochloride, droperidol, sodium thiopental, thiamylal sodium, pentobarbital) and the like.

(7) Anti-ulcer drugs Histidine hydrochloride, lansoprazole, metoclopramide, pirenzepine, cimetidine, ranitidine, famotidine, urogastrin, oxesasein, proglumide, omeprazole, sucralfate, sulpiride, cetraxate, gefarnate, aldioxa, tepregone, prostaglandin, etc.

(8) Arrhythmia drug (i) Sodium channel blocker (eg, quinidine, procainamide, disopyramide, azimarin, lidocaine, mexiletine, phenytoin),
(Ii) β-blockers (eg, propranolol, alprenolol, bufetrol, hydrochloride, oxprenolol, atenolol, acebutolol, metoprolol, bisoprolol, pindolol, carteolol, arotinolol hydrochloride),
(Iii) potassium channel blockers (eg, amiodarone),
(Iv) Calcium channel blockers (eg, verapamil, diltiazem) and the like.

(9) Antihypertensive diuretic hexamethonium bromide, clonidine hydrochloride, hydrochlorothiazide, trichloromethiazide, furosemide, ethacrynic acid, bumetanide, mefluside, azosemide, spironolactone, potassium canrenoate, triamterene, amiloride, acetazolamide, D-mannitol, isosorbide, aminosorbide etc.

(10) Anticoagulant heparin sodium, sodium citrate, activated protein C, tissue factor pathway inhibitor, antithrombin III, dalteparin sodium, warfarin potassium, argatroban, gabexate, sodium citrate, ozagrel sodium, icosapentarate, Beraprost sodium, alprostadil, ticlopidine hydrochloride, pentoxifylline, dipyridamole, tisokinase, urokinase, streptokinase and the like.

(11) Tranquilizers Diazepam, lorazepam, oxazepam, chlordiazepoxide, medazepam, oxazolam, cloxazolam, clothiazepam, bromazepam, etizolam, fludiazepam, hydroxyzine and the like.

(12) Antipsychotics Chlorpromazine hydrochloride, prochlorperazine, trifluoroperazine, thioridazine hydrochloride, perphenazine maleate, fluphenazine enanthate, prochlorperazine maleate, levomepromazine maleate, promethazine hydrochloride, haloperidol, bromperidol , Spiperone, reserpine, clocapramine hydrochloride, sulpiride, zotepine and the like.

(13) Anti-tumor drug 6-O- (N-chloroacetylcarbamoyl) fumagillol, bleomycin, methotrexate, actinomycin D, mitomycin C, daunorubicin, adriamycin, neocartinostatin, cytosine arabinoside, fluorouracil, tetrahydrofuryl-5 -Fluorouracil, picibanil, lentinan, levamisole, bestatin, azimexone, glycyrrhizin, doxorubicin hydrochloride, aclarubicin hydrochloride, bleomycin hydrochloride, hepromycin sulfate, vincristine sulfate, vinblastine sulfate, irinotecan, cyclophosphamide, melphalan, dusulfan hydrochloride, thiotepa, procarbazine hydrochloride , Cisplatin, azathioprine, mercaptopurine, tegafur, carmofur, cytarabine , Methyltestosterone, testosterone propionate, testosterone enanthate, mepithiostan, phosfestol, chlormadinone acetate, leuprorelin acetate, buserelin acetate, bortezomib, lenalidomide, clofarabine, azacitidine, imatinib, etc.

(14) Antihyperlipidemic drug clofibrate, ethyl 2-chloro-3- [4- (2-methyl-2-phenylpropoxy) phenyl] propionate [Chem. Pharm. Bull, 38, 2792-2996 (1990)], pravastatin, simvastatin, probucol, bezafibrate, clinofibrate, nicomol, cholestyramine, dextran sulfate sodium and the like.

(15) Muscle relaxants Pridinol, tubocurarine, pancuronium, tolperisone hydrochloride, chlorphenesin carbamate, baclofen, chlormezanone, mephenesin, clozoxazone, eperisone, tizanidine and the like.

(16) Antiepileptic drugs Phenytoin, ethosuximide, acetazolamide, chlordiazepoxide, tripetadione, carbamazepine, phenobarbital, primidone, sultiam, sodium valproate, clonazepam, diazepam, nitrazepam and the like.

(17) Antidepressant imipramine, clomipramine, noxiptylline, phenelzine, amitriptyline hydrochloride, nortriptyline hydrochloride, amoxapine, mianserin hydrochloride, maprotiline hydrochloride, sulpiride, fluvoxamine maleate, trazodone hydrochloride, and the like.

(18) Antiallergic drugs diphenhydramine, chlorpheniramine, tripelenamine, methodiramine, clemizole, diphenylpyraline, methoxyphenamine, cromoglycate sodium, tranilast, repirinast, amlexanox, ibudilast, ketotifen, terfenadine, mequitazine, azelastine hydrochloride, epinastine hydrochloride , Pranlukast hydrate, seratrodast, etc.

(19) Cardiotonic drugs Transbioxocamphor, telephilol, aminophylline, ethylephrine, dopamine, dobutamine, denopamine, vesinaline, amrinone, pimobendan, ubidecarenone, digitoxin, digoxin, methyldigoxin, lanatoside C, G-strophantin and the like.

(20) Vasodilators Oxyfedrine, diltiazem, trazoline, hexobenzine, bamethane, clonidine, methyldopa, guanabenz and the like.

(21) Vasoconstricting agents dopamine, dobutamine denopamine and the like.

(22) Antihypertensive diuretics Hexamethonium bromide, pentolinium, mecamylamine, ecarazine, clonidine, diltiazem, nifedipine and the like.

(23) Antidiabetic drugs Tolbutamide, chlorpropamide, acetohexamide, glibenclamide, tolazamide, acarbose, epalrestat, troglitazone, glucagon, grimidine, glipzide, phenformin, pformin, metformin, and the like.

(24) narcotic antagonists levalorphan, nalolphine, naloxone or a salt thereof.

(25) Fat-soluble vitamin drugs (i) Vitamin A: Vitamin A1, Vitamin A2 and Retinol palmitate (ii) Vitamin D: Vitamin D1, D2, D3, D4 and D5
(Iii) Vitamin E: α-tocopherol, β-tocopherol, γ-tocopherol, δ-tocopherol, dl-α-tocopherol nicotinate (iv) Vitamin K: vitamins K1, K2, K3 and K4
(V) Folic acid (vitamin M), folinate calcium and the like.

(26) Vitamin derivatives Various vitamin derivatives, for example, vitamin D3 derivatives such as 5,6-trans-cholecalciferol, 2,5-hydroxycholecalciferol, 1-α-hydroxycholecalciferol, 5,6-trans -Vitamin D2 derivatives such as ergocalciferol.

(27) Anti-asthma drugs Isoprenaline hydrochloride, salbutamol sulfate, procaterol hydrochloride, terbutaline sulfate, trimethoquinol hydrochloride, tulobuterol hydrochloride, orciprenaline sulfate, fenoterol hydrobromide, ephedrine hydrochloride, iprotropium bromide, oxitropium bromide, bromide Flutropium, theophylline, aminophylline, sodium cromoglycate, tranilast, repirinast, amlexanone, ibudilast, ketotifen, terfenadine, mequitazine, azelastine, epinastine, ozagrel hydrochloride, pranlukast hydrate, seratrodast, dexamethasone, prednisolone hydrocolicone , Beclomethasone propionate and the like.

(28) Frequent urine and urinary incontinence treatment flavoxate hydrochloride and the like.

(29) Atopic dermatitis therapeutic agent sodium cromoglycate and the like.

(30) Allergic rhinitis therapeutic agent Sodium cromoglycate, chlorpheniramine maleate, alimemazine tartrate, clemastine fumarate, homochlorcyclidine hydrochloride, fexofenadine, mequitazine and the like.

(31) Pressor drugs Dopamine, dobutamine, denopamine, digitoxin, digoxin, methyldigoxin, lanatoside C, G-strophantin and the like.

(32) Hematopoietic stem cell pre-transplant drug busulfan, fludarabine, cladribine, etoposide.

(33) Others Hydroxycam, diacerine, megestrol acetic acid, falselogolin, clofazimine, etretinate, bisphonic acid, defibrotide, prostaglandins and the like.

In the combined use, the administration time of the compound of the present invention and the concomitant drug is not limited, and the compound of the present invention and the concomitant drug may be administered to the administration subject at the same time or may be administered with a time difference. The dose of the concomitant drug may be determined according to the dose used clinically, and can be appropriately selected depending on the administration subject, administration route, disease, combination and the like.
The administration form of the combination is not particularly limited as long as the compound of the present invention and the concomitant drug are combined at the time of administration. Examples of such administration forms include (1) administration of a single preparation obtained by simultaneously formulating the compound of the present invention and a concomitant drug, and (2) obtained by separately formulating the compound of the present invention and the concomitant drug. Simultaneous administration of the two preparations by the same administration route, (3) administration of the two preparations obtained by separately formulating the compound of the present invention and the concomitant drug at different time intervals by the same administration route, (4) Simultaneous administration of two types of preparations obtained by separately formulating the compound of the present invention and a concomitant drug by different administration routes, (5) Two types of preparations obtained by formulating the compound of the present invention and a concomitant drug separately Administration with a time difference in the administration route (for example, administration of a concomitant drug after administration of the compound of the present invention, or administration in the reverse order) and the like.
The compounding ratio of the compound of the present invention and the concomitant drug in the concomitant drug of the present invention can be appropriately selected depending on the administration subject, administration route, disease and the like.
For example, the content of the compound of the present invention in the concomitant drug of the present invention varies depending on the form of the preparation, but is usually about 0.01 to 100% by weight, preferably about 0.1 to 50% by weight, based on the whole preparation, More preferably, it is about 0.5 to 20% by weight.

The content of the concomitant drug in the concomitant drug of the present invention varies depending on the form of the preparation, but is usually about 0.01 to 100% by weight, preferably about 0.1 to 50% by weight, more preferably about the whole preparation. About 0.5 to 20% by weight.
The content of additives such as carriers in the combination agent of the present invention varies depending on the form of the preparation, but is usually about 1 to 99.99% by weight, preferably about 10 to 90% by weight, based on the whole preparation. .
The same content may be used when the compound of the present invention and the concomitant drug are formulated separately.
The dose varies depending on the type of the compound of the present invention, administration route, symptom, patient age, etc. For example, when administered orally to a graft-versus-host disease patient (body weight of about 60 kg), 1 kg body weight per day About 0.1 mg / kg body weight to about 50 mg / kg body weight, preferably about 1 mg / kg body weight to 30 mg / kg body weight per day as a free form of compound (I) may be administered once to several times a day. Good.
When the pharmaceutical composition of the present invention is a sustained-release preparation, the dosage is the type and content of compound (I), the dosage form, the duration of drug release, the animal to be administered (for example, mouse, rat, hamster, guinea pig) Mammals such as rabbits, cats, dogs, cows, horses, pigs, sheep, monkeys, humans, etc.), depending on the purpose of administration, for example, about 0.1 per week when applied by parenteral administration About 100 mg of compound (I) may be released from the dosage formulation.

The amount of the concomitant drug can be set as long as side effects do not become a problem. The daily dose as a concomitant drug varies depending on the degree of symptoms, age of the subject, sex, weight, sensitivity difference, timing of administration, interval, nature of the pharmaceutical preparation, formulation, type, type of active ingredient, etc. Although not limited, the amount of the drug is usually about 0.001 to 2000 mg per kg body weight of the mammal by oral administration, preferably about 0.01 to 500 mg, more preferably about 0.1 to 100 mg. This is usually administered in 1 to 4 divided doses per day.
When administering the concomitant drug of the present invention, the compound of the present invention and the concomitant drug may be administered at the same time, or may be administered with a time difference. When administered at a time difference, the time difference varies depending on the active ingredient, dosage form, and administration method to be administered. For example, when administering the concomitant drug first, within 1 minute to 3 days after administering the concomitant drug, preferably Examples include a method of administering the compound of the present invention within 10 minutes to 1 day, more preferably within 15 minutes to 1 hour. In the case where the compound of the present invention is administered first, the concomitant drug is administered within 1 minute to 1 day, preferably within 10 minutes to 6 hours, more preferably within 15 minutes to 1 hour after the administration of the compound of the present invention. Is mentioned.

The present invention is further explained in detail by the following examples, test examples and formulation examples, which are not intended to limit the present invention, and may be changed without departing from the scope of the present invention.
In the following examples, “room temperature” usually indicates about 10 ° C. to about 35 ° C. The ratio shown in the mixed solvent is a volume ratio unless otherwise specified. Unless otherwise indicated, “%” indicates “% by weight”.
In silica gel column chromatography, when NH is described, aminopropylsilane-bonded silica gel, when Diol is described, 3- (2,3-dihydroxypropoxy) propylsilane-bonded silica gel, when DiNH is described, N- (2-Aminoethyl) -3-aminopropylsilane bonded silica gel was used. In HPLC (high performance liquid chromatography), when it was described as C18, octadecyl-bonded silica gel was used. The ratio of elution solvent indicates a volume ratio unless otherwise specified.
The following abbreviations are used in the following examples.
Mp: melting point
MS: Mass spectrum
[M + H] ⁺ , [MH] ⁻ : Molecular ion peak
M: Molar concentration
N: Regulation
CDCl ₃ : Deuterated chloroform
DMSO-d ₆ : Heavy dimethyl sulfoxide
¹ H NMR: proton nuclear magnetic resonance
LC / MS: Liquid chromatograph mass spectrometer
ESI: ElectroSpray Ionization
APCI: Atomospheric Pressure Chemical Ionization
THF: tetrahydrofuran
DME: 1,2-dimethoxyethane
DMF: N, N-dimethylformamide
DMA: N, N-dimethylacetamide
HATU: 2- (7-azabenzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate
HOBt: 1-hydroxybenzotriazole

¹ H NMR was measured by Fourier transform NMR. For analysis, ACD / SpecManager (trade name) was used. Peaks with very gentle protons such as hydroxyl groups and amino groups are not described.
MS was measured by LC / MS. As the ionization method, the ESI method or the APCI method was used. The data is the actual measurement (found). Usually, a molecular ion peak is observed, but in the case of a compound having a tert-butoxycarbonyl group, a peak from which a tert-butoxycarbonyl group or a tert-butyl group is eliminated may be observed as a fragment ion. In the case of a compound having a hydroxyl group, a peak from which H ₂ O is eliminated may be observed as a fragment ion. In the case of a salt, a free molecular ion peak or a fragment ion peak is usually observed.

Example 14
2,2-Dimethyl-7- (2-oxo-2,3-dihydro-1H-imidazo [4,5-b] pyridin-1-yl) -1-((1R) -1-phenylethyl) -2 , 3-Dihydroquinazolin-4 (1H) -one

A) (R) -4-Bromo-2-((1-phenylethyl) amino) benzamide (R) -1-phenyl in a solution of 4-bromo-2-fluorobenzonitrile (1.5 g) in DMSO (10 mL) Ethaneamine (1.2 g) and potassium carbonate (2.1 g) were added, and the mixture was stirred at 100 ° C. overnight. After the reaction mixture was cooled to room temperature, hydrogen peroxide (1.3 g) was added to the reaction mixture, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was added to water, and the precipitate was collected by filtration and dried under reduced pressure to give the title compound (2.2 g).
¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.22-1.50 (3H, m), 4.55-4.77 (1H, m), 6.18-8.96 (11H, m).

B) (R) -7-Bromo-2,2-dimethyl-1- (1-phenylethyl) -2,3-dihydroquinazolin-4 (1H) -one (R) -4-Bromo-2-(( 2-Methoxyprop-1-ene (1.48 mL) and methanesulfonic acid (30 mg) were added to a solution of 1-phenylethyl) amino) benzamide (1.0 g) in acetone (20 mL), and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (hexane / ethyl acetate) to give the title compound (800 mg).
¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.51 (3H, s), 1.63 (3H, s), 1.72 (3H, d, J = 6.8 Hz), 5.21 (1H, q, J = 6.8 Hz) , 6.40 (1H, d, J = 1.5 Hz), 6.80 (1H, dd, J = 8.1, 1.7 Hz), 7.18-7.30 (2H, m), 7.36-7.40 (3H, m), 7.61 (1H, d , J = 8.3 Hz), 8.30 (1H, s).

C) 2,2-Dimethyl-7- (2-oxo-2,3-dihydro-1H-imidazo [4,5-b] pyridin-1-yl) -1-((1R) -1-phenylethyl) -2,3-Dihydroquinazolin-4 (1H) -one tert-butyl (3-aminopyridin-2-yl) carbamate (105 mg) and sodium tert-butoxide (80 mg) in tert-butyl alcohol (3 mL) Add tris (dibenzylideneacetone) dipalladium (0) (38.2 mg) and 2-dicyclohexylphosphino-2 ', 6'-diisopropoxy-1,1'-biphenyl (78 mg) to the solution at 100 ° C. Stir for 3 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate / methanol) to give the title compound (103 mg).
¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.57 (3H, s), 1.66-1.81 (6H, m), 5.23 (1H, q, J = 7.1 Hz), 5.95 (1H, d, J = 6.8 Hz), 6.32 (1H, d, J = 1.9 Hz), 6.72 (1H, dd, J = 7.9, 5.3 Hz), 6.86 (1H, dd, J = 8.3, 1.9 Hz), 7.30-7.49 (5H, m ), 7.79-7.94 (2H, m), 8.30 (1H, s), 11.79 (1H, s).
MS (ESI +): [M + H] ⁺ 414.3.

Example 48
4-Benzyl-6- (2-oxo-2,3-dihydro-1H-imidazo [4,5-b] pyridin-1-yl) -3,4-dihydroisoquinolin-1 (2H) -one

A) Methyl 4-bromo-2-methylbenzoate To a solution of 4-bromo-2-methylbenzoic acid (50.55 g) in methanol (500 mL) was added dropwise thionyl chloride (68.6 mL), and the reaction mixture was refluxed. Stir for 2.5 hours. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with aqueous sodium bicarbonate and extracted with ethyl acetate. The organic layer was separated, washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (58.6 g).
¹ H NMR (300 MHz, CDCl ₃ ) δ 2.58 (3H, s), 3.88 (3H, s), 7.35-7.40 (1H, m), 7.42 (1H, s), 7.78 (1H, d, J = 8.3 Hz).

B) Methyl 4-bromo-2- (bromomethyl) benzoate A solution of methyl 4-bromo-2-methylbenzoate (26.6 g) in trifluoromethylbenzene (100 mL) and azobisisobutyronitrile (0.955 g) and N-bromosuccinimide (21.7 g) was added and the reaction mixture was stirred at 70 ° C. under a nitrogen atmosphere for 3 hours. The solid was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane / ethyl acetate) and washed with diisopropyl ether and hexane to give the title compound (29.5 g).
¹ H NMR (300 MHz, CDCl ₃ ) δ 3.94 (3H, s), 4.90 (2H, s), 7.51 (1H, dd, J = 8.5, 2.1 Hz), 7.63 (1H, d, J = 1.9 Hz) , 7.84 (1H, d, J = 8.7 Hz).

C) Methyl 4-bromo-2- (cyanomethyl) benzoate To a solution of methyl 4-bromo-2- (bromomethyl) benzoate (46 g) in acetonitrile (300 mL) was added trimethylsilanecarbonitrile (40.0 mL). The reaction mixture was stirred at room temperature for 10 minutes, and 1M tetra-n-butylammonium fluoride THF solution (299 mL) was added. The reaction mixture was concentrated under reduced pressure. Water was added to the residue and extracted with ethyl acetate. The organic layer was separated, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate / methanol) and recrystallized from diisopropyl ether and hexane to obtain the title compound (23.5 g).
¹ H NMR (300 MHz, DMSO-d ₆ ) δ 3.87 (3H, s), 4.26 (2H, s), 7.72-7.78 (1H, m), 7.83 (1H, d, J = 1.9 Hz), 7.90 ( (1H, d, J = 8.3 Hz).

D) Methyl 4-bromo-2- (1-cyano-2-phenylethyl) benzoate Methyl 4-bromo-2- (cyanomethyl) benzoate (8.0 g) and benzyl bromide (4.11 mL) in THF (100 mL) To the solution, 1.3M lithium hexamethyldisilazide THF solution (26.6 mL) was added dropwise at 0 ° C. The reaction mixture was stirred at room temperature for 3 hours. 1M Hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane / ethyl acetate) to give the title compound (10.7 g).
¹ H NMR (300 MHz, DMSO-d ₆ ) δ 3.16-3.24 (2H, m), 3.87 (3H, s), 5.22 (1H, dd, J = 8.5, 6.6 Hz), 7.20-7.39 (6H, m ), 7.71-7.77 (1H, m), 7.82-7.85 (1H, m).

E) 4-Benzyl-6-bromo-3,4-dihydroisoquinolin-1 (2H) -one methyl 4-bromo-2- (1-cyano-2-phenylethyl) benzoate (3.0 g) in THF (10 To the solution, 1.1 M borane THF complex THF solution (23.77 mL) was added at room temperature. The reaction mixture was stirred at 70 ° C. for 2 hours under nitrogen atmosphere. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane / ethyl acetate) to give the title compound (710 mg).
¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.67-2.82 (1H, m), 2.83-2.95 (1H, m), 2.99-3.22 (2H, m), 3.34-3.42 (1H, m), 7.14 -7.38 (5H, m), 7.48 (1H, d, J = 1.9 Hz), 7.56 (1H, dd, J = 8.3, 1.9 Hz), 7.79 (1H, d, J = 8.3 Hz), 7.89-8.00 ( 1H, m).

F) 4-Benzyl-6- (2-oxo-2,3-dihydro-1H-imidazo [4,5-b] pyridin-1-yl) -3,4-dihydroisoquinolin-1 (2H) -one 4 -Benzyl-6-bromo-3,4-dihydroisoquinolin-1 (2H) -one (1500 mg), tert-butyl (3-aminopyridin-2-yl) carbamate (1092 mg), sodium tert-butoxide (912 mg), tris (dibenzylideneacetone) dipalladium (0) (434 mg) and 2-dicyclohexylphosphino-2 ', 6'-diisopropoxy-1,1'-biphenyl (885 mg) in tert-butyl alcohol (5 mL) The solution was stirred at 100 ° C. overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate / methanol) to give the title compound (330 mg).
¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.91 (2H, d, J = 9.1 Hz), 3.30 (2H, s), 3.43-3.60 (1H, m), 6.81-7.11 (2H, m), 7.19-7.45 (5H, m), 7.48-7.69 (1H, m), 7.90-8.12 (3H, m), 11.91 (1H, s).
MS (ESI +): [M + H] ⁺ 371.2.

Example 67
4-Benzyl-3,3-dimethyl-6- (2-oxo-2,3-dihydro-1H-imidazo [4,5-b] pyridin-1-yl) -3,4-dihydroisoquinoline-1 (2H )-on

A) Methyl 2- (3-bromophenyl) -3-phenylpropanoate Diisopropylamine (4.24 g) in tetrahydrofuran (50 mL) was diluted with normal butyl lithium in 2.5 M hexane (16.8 mL) at -78 ° C and nitrogen. It added under atmosphere and stirred at -78 degreeC for 30 minutes. A solution of methyl (3-bromophenyl) acetate (9.16 g) in tetrahydrofuran (100 mL) was added to the reaction mixture at −78 ° C. in a nitrogen atmosphere, and the mixture was stirred for 1 hr. To the reaction mixture, benzyl bromide (7.18 g) was added at −78 ° C. under a nitrogen atmosphere, and the mixture was stirred at room temperature for 16 hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (pentane / ethyl acetate) to give the title compound (9.40 g).
¹ H NMR (400 MHz, CDCl ₃ ) δ 2.90-3.05 (1H, m), 3.30-3.45 (1H, m), 3.62 (3H, s), 3.75-3.85 (1H, m), 7.10 (2H, d , J = 6.8 Hz), 7.15-7.30 (5H, m), 7.35-7.45 (1H, m), 7.47 (1H, s).

B) 3- (3-Bromophenyl) -2-methyl-4-phenylbutan-2-ol methyl 2- (3-bromophenyl) -3-phenylpropanoate (9.40 g) in tetrahydrofuran (150 mL) To the solution, 3M diethyl ether solution (40.0 mL) of methylmagnesium bromide was added under a nitrogen atmosphere under ice cooling, and the mixture was stirred at room temperature for 16 hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (9.1 g).
¹ H NMR (400 MHz, CDCl ₃ ) δ 1.23 (3H, s), 1.30 (3H, s), 2.80-2.90 (1H, m), 2.91-3.00 (1H, m), 3.25-3.35 (1H, m ), 6.97 (2H, d, J = 7.2 Hz), 7.00-7.20 (5H, m), 7.25-7.33 (1H, m), 7.37 (1H, s).

C) N- [3- (3-Bromophenyl) -2-methyl-4-phenylbutan-2-yl] -2-chloroacetamide 3- (3-Bromophenyl) -2-methyl-4-phenylbutane- To a solution of 2-ol (8.10 g) and chloroacetonitrile (19.3 g) in acetic acid (4.57 g), concentrated sulfuric acid (10.2 g) was added dropwise at −10 ° C. under a nitrogen atmosphere. The reaction mixture was stirred at room temperature under a nitrogen atmosphere for 5 hours. Ice water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was washed with pentane to obtain the title compound (9.9 g).
MS (ESI +): [M + H] ⁺ 395.9

D) 3- (3-Bromophenyl) -2-methyl-4-phenylbutan-2-amine N- [3- (3-bromophenyl) -2-methyl-4-phenylbutan-2-yl] -2 -A mixed solution of -chloroacetamide (9.90 g) and thiourea (2.28 g) in acetic acid (20 mL) and ethanol (100 mL) was stirred under refluxing nitrogen atmosphere for 16 hours. The reaction mixture was cooled to room temperature and the precipitate was filtered and washed with ethanol. The filtrate was concentrated under reduced pressure, 2M aqueous sodium hydroxide solution was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the title compound (7.1 g).
MS (ESI +): [M + H] ⁺ 319.7.

E) 4-Benzyl-6-bromo-3,3-dimethyl-1,2,3,4-tetrahydroisoquinoline 3- (3-bromophenyl) -2-methyl-4-phenylbutan-2-amine (4.00 g ) In dichloroethane (42 mL) was added paraformaldehyde (756 mg) and trifluoroacetic acid (18 mL) at room temperature. The reaction mixture was stirred at reflux under a nitrogen atmosphere for 16 hours. The reaction mixture was cooled to room temperature and the solvent was removed under reduced pressure. To the residue was added saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product (4.0 g) containing the title compound.
MS (ESI +): [M + H] ⁺ 331.7.

F) 4-Benzyl-6-bromo-3,3-dimethyl-1,4-dimethyl-1,4-dihydroisoquinolin-1 (2H) -one obtained from E To a mixed solution of crude purified product (4.00 g) containing 2,3,4-tetrahydroisoquinoline (4.00 g) in dichloromethane (10 mL) and water (50 mL) was added iodosylbenzene (3.19 g) and potassium bromide (1.44 g) at room temperature. Added in. The reaction mixture was stirred at room temperature for 16 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (pentane / ethyl acetate) to give the title compound (800 mg).
MS (ESI +): [M + H] ⁺ 345.8.

G) 4-Benzyl-3,3-dimethyl-6- (2-oxo-2,3-dihydro-1H-imidazo [4,5-b] pyridin-1-yl) -3,4-dihydroisoquinoline-1 (2H) -one 4-benzyl-6-bromo-3,3-dimethyl-3,4-dihydroisoquinolin-1 (2H) -one (200 mg), tert-butyl (3-aminopyridin-2-yl) Carbamate (182 mg), sodium tert-butoxide (279 mg), tris (dibenzylideneacetone) dipalladium (0) (53 mg) and 2-dicyclohexylphosphino-2 ', 6'-diisopropoxy-1,1 A solution of '-biphenyl (54 mg) in tert-butyl alcohol (5 mL) was stirred at 110 ° C. under a nitrogen atmosphere for 16 hours. The reaction mixture was cooled to room temperature, the reaction mixture was added to water and extracted with ethyl acetate. The organic layer was separated, washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (pentane / ethyl acetate) and washed with pentane and ethyl acetate to give the title compound (43 mg).
¹ H NMR (400 MHz, CDCl ₃ ): δ 1.30 (3H, s), 1.54 (3H, s), 2.70-2.80 (1H, m), 2.90-3.00 (1H, m), 3.25-3.35 (1H, m), 5.95 (1H, brs), 6.15 (1H, dd, J = 8.0, 1.2 Hz), 6.58 (1H, d, J = 2.0 Hz), 6.85 (1H, dd, J = 8.0, 5.3 Hz), 6.89-6.97 (2H, m), 7.19-7.26 (3H, m), 7.61 (1H, dd, J = 8.3, 2.0 Hz), 8.04 (1H, dd, J = 5.3, 1.2 Hz), 8.25 (1H, d, J = 8.3 Hz), 9.54 (1H, brs).

Example 69
8-Benzyl-2- (1H-pyrrolo [2,3-b] pyridin-3-yl) -7,8-dihydro-1,6-naphthyridin-5 (6H) -one

A) Ethyl 2-vinylnicotinate Ethyl 2-chloronicotinate (5.90 g), sodium bicarbonate (5.34 g) and 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane ( Tetrakis (triphenylphosphine) palladium (0) (1.84 g) was added to a mixed solution of 5.14 g) of dimethoxyethane (20 mL) and water (2 mL) at room temperature. The reaction mixture was stirred at 80 ° C. under a nitrogen atmosphere overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane / ethyl acetate) to give the title compound (4.75 g).
MS (ESI +): [M + H] ⁺ 178.2.

B) of 6- (4-methoxybenzyl) -7,8-dihydro-1,6-naphthyridin-5 (6H) -one ethyl 2-vinylnicotinate (1.04 g) and 4-methoxybenzylamine (0.886 g) The dimethylacetamide (5 mL) solution was stirred at 180 ° C. for 30 minutes under microwave irradiation. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane / ethyl acetate) to give the title compound (3.40 g).
MS (ESI +): [M + H] ⁺ 269.2.

C) 8-Benzyl-6- (4-methoxybenzyl) -7,8-dihydro-1,6-naphthyridin-5 (6H) -one 6- (4-methoxybenzyl) -7,8-dihydro-1, To a solution of 6-naphthyridin-5 (6H) -one (650 mg) in tetrahydrofuran (10 mL) was added 1M tetrahydrofuran solution (2.91 mL) of lithium hexamethyldisilazide at -78 ° C. The reaction mixture was stirred at −78 ° C. under a nitrogen atmosphere for 10 minutes. Benzyl bromide (497 mg) was added to the reaction mixture at −78 ° C., and the mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. To the reaction mixture was added lithium diisopropylamide in 1M tetrahydrofuran (2.88 mL) at -78 ° C, and the mixture was stirred at room temperature overnight under a nitrogen atmosphere. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane / ethyl acetate) to give the title compound (375 mg).
MS (ESI +): [M + H] ⁺ 359.3.

D) 8-Benzyl-6- (4-methoxybenzyl) -5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridine-1-oxide 8-benzyl-6- (4-methoxybenzyl) To a solution of -7,8-dihydro-1,6-naphthyridin-5 (6H) -one (375 mg) in ethyl acetate (10 mL) was added metachloroperbenzoic acid (284 mg) under ice cooling. The reaction mixture was stirred at room temperature overnight. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by NH silica gel chromatography (hexane / ethyl acetate) to give the title compound (390 mg).
MS (ESI +): [M + H] ⁺ 375.2.

E) 8-Benzyl-2-chloro-7,8-dihydro-1,6-naphthyridin-5 (6H) -one 8-benzyl-6- (4-methoxybenzyl) -5-oxo-5,6,7 , 8-Tetrahydro-1,6-naphthyridine-1-oxide (390 mg) and phosphorus oxychloride (2 mL) were stirred at 80 ° C. for 2 hours. The reaction mixture was added to water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by NH silica gel chromatography (hexane / ethyl acetate) to give the title compound (55 mg).
MS (ESI +): [M + H] ⁺ 273.2, 275.2.

F) 8-Benzyl-2- (1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridin-3-yl) -7,8-dihydro-1,6-naphthyridine-5 (6H)- On 8-benzyl-2-chloro-7,8-dihydro-1,6-naphthyridin-5 (6H) -one (55 mg), sodium bicarbonate (34 mg) and 1- (phenylsulfonyl) -3- ( 4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrrolo [2,3-b] pyridine (77 mg) in dimethoxyethane (2 mL) and water (0.2 tetrakis (triphenylphosphine) palladium (0) (23 mg) was added to a mixed solution at room temperature. The reaction mixture was stirred at 90 ° C. under a nitrogen atmosphere overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by NH silica gel chromatography (hexane / ethyl acetate) to give the title compound (37 mg).
MS (ESI +): [M + H] ⁺ 495.3.

G) 8-Benzyl-2- (1H-pyrrolo [2,3-b] pyridin-3-yl) -7,8-dihydro-1,6-naphthyridin-5 (6H) -one 8-benzyl-2- (1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridin-3-yl) -7,8-dihydro-1,6-naphthyridin-5 (6H) -one (37 mg) in tetrahydrofuran ( 3M) and methanol (1 mL) were mixed with 2M aqueous sodium hydroxide solution (0.075 mL) at room temperature, and stirred at 40 ° C. for 2 hours. To the reaction mixture was added 8M aqueous sodium hydroxide solution (0.281 mL) at room temperature, and the mixture was stirred at 60 ° C. for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was washed with diisopropyl ether and ethyl acetate to give the title compound (11 mg).
¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.78-2.96 (1H, m), 3.12-3.27 (1H, m), 3.34-3.52 (3H, m), 7.14-7.42 (6H, m), 7.93 (2H, d, J = 8.3 Hz), 8.13 (1H, d, J = 8.3 Hz), 8.29 (1H, dd, J = 4.5, 1.5 Hz), 8.39 (1H, s), 8.71 (1H, dd, J = 7.9, 1.5 Hz), 12.19 (1H, brs).

Example 75
4-Benzyl-6- (2-oxo-2,3-dihydro-1H-imidazo [4,5-b] pyridin-1-yl) -3,4-dihydro-2,7-naphthyridine-1 (2H) -on

A) 4-Iodo-6-methoxypyridine-3-carboxylic acid 2,2,6,6-tetramethylpiperidine in tetrahydrofuran (100 mL) solution with 2.5M hexane solution of normal butyl lithium (39.2 mL) at -78 ° C In a nitrogen atmosphere. The reaction mixture was stirred at -78 ° C for 1 hour. The reaction mixture was added to a solution of 6-methoxypyridine-3-carboxylic acid (5.00 g) in tetrahydrofuran (50 mL) at −78 ° C. under a nitrogen atmosphere, and the mixture was stirred at −78 ° C. for 2 hours. The reaction mixture was added to a solution of iodine (24.9 g) in tetrahydrofuran (50 mL) at −78 ° C. under a nitrogen atmosphere, and the mixture was stirred at room temperature for 16 hr. Water was added to the reaction mixture, and tetrahydrofuran was removed under reduced pressure. The aqueous phase was washed with methyl tetrabutyl ether, adjusted to pH 4 with 1M aqueous hydrochloric acid, and extracted with ethyl acetate. The organic layer was separated, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give a crude product (5.40 g) containing the title compound.
MS (ESI +): [M + H] ⁺ 279.6.

B) Methyl 4-iodo-6-methoxypyridine-3-carboxylate solution of 4-iodo-6-methoxypyridine-3-carboxylic acid obtained with A (950 mg) in methanol (30 mL) To the solution was added 2.0M hexane solution (10.0 mL) of trimethylsilyldiazomethane under ice-cooling, and the mixture was stirred at room temperature for 16 hours. Acetic acid (2 mL) was added to the reaction mixture, and the solvent was removed under reduced pressure. A saturated aqueous sodium hydrogen carbonate solution and ethyl acetate were added to the residue, and the organic layer was concentrated. The residue was purified by silica gel chromatography (pentane / ethyl acetate) to obtain a crude product (700 mg) containing the title compound.
MS (ESI +): [M + H] ⁺ 293.7.

C) Methyl 4-[(E) -2-ethoxyethenyl] -6-methoxypyridine-3-carboxylate Methyl 4-iodo-6-methoxypyridine-3-carboxylate (7.20 g), (Z) -ethoxy Etheneboronic acid pinacol ester (5.37 g), 2-dicyclohexylphosphino-2 ', 6'-dimethoxybiphenyl (1.01 g), palladium (II) acetate (276 mg) and acetonitrile containing potassium phosphate (10.4 g) ( A mixed solution of 90 mL) and water (60 mL) was stirred under reflux conditions for 2 hours under a nitrogen atmosphere. Water was added to the reaction mixture, acetonitrile was removed under reduced pressure, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (pentane / ethyl acetate) to give the title compound (5.10 g).
¹ H NMR (300 MHz, CDCl ₃ ) δ 1.36 (3H, t, J = 6.8 Hz), 3.88 (3H, s), 3.93-4.02 (5H, m), 6.69 (1H, s), 6.77 (1H, d, J = 12.8 Hz), 7.12 (1H, d, J = 13.2 Hz), 8.73 (1H, s).

D) Methyl 6-methoxy-4- (2-oxoethyl) pyridine-3-carboxylate Methyl 4-[(E) -2-ethoxyethenyl] -6-methoxypyridine-3-carboxylate (5.10 g) A mixed solution of fluoroacetic acid (100 mL) and dichloromethane (100 mL) was stirred at 25 ° C. for 5 hours. The solvent was removed under reduced pressure to obtain a crude product (5.30 g) containing the title compound.
MS (ESI +): [M + H] ⁺ 209.8.

E) Dichloromethane (200 mL) containing the crude product (5.30 g) obtained from 6-methoxy-2- (4-methoxybenzyl) -3,4-dihydro-2,7-naphthyridin-1 (2H) -one D 4-methoxybenzylamine (6.85 g) was added to the solution, and the mixture was stirred at 25 ° C. for 3 hours. Sodium cyanoborohydride (3.15 g) was added to the reaction mixture, and the mixture was stirred at room temperature for 16 hours. Dichloromethane was removed under reduced pressure, toluene (100 mL) and acetic acid (3 mL) were added to the residue, and the mixture was stirred under reflux conditions for 3 hours. The mixture was cooled to room temperature, diluted with ethyl acetate, washed with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (pentane / ethyl acetate) and preparative liquid chromatography to obtain the title compound (1.90 g).
MS (ESI +): [M + H] ⁺ 298.8.

F) 4-Benzyl-6-methoxy-2- (4-methoxybenzyl) -3,4-dihydro-2,7-naphthyridin-1 (2H) -one 6-methoxy-2- (4-methoxybenzyl)- To a solution of 3,4-dihydro-2,7-naphthyridin-1 (2H) -one (1.50 g) in tetrahydrofuran (25 mL) was added a 2.0M solution of lithium diisopropylamide in tetrahydrofuran (3.0 mL) at -78 ° C under a nitrogen atmosphere. added. The reaction mixture was stirred at −78 ° C. for 30 minutes, benzyl bromide (940 mL) was added dropwise, and the mixture was stirred at room temperature for 16 hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (pentane / ethyl acetate) to obtain the title compound (1.25 g).
MS (ESI +): [M + H] ⁺ 389.0.

G) 4-Benzyl-6-hydroxy-2- (4-methoxybenzyl) -3,4-dihydro-2,7-naphthyridin-1 (2H) -one 4-benzyl-6-methoxy-2- (4- To a solution of (methoxybenzyl) -3,4-dihydro-2,7-naphthyridin-1 (2H) -one (1.50 g) in acetic acid (12 mL) was added 36% aqueous hydrochloric acid (6 mL), and the mixture was refluxed for 16 Stir for hours. The reaction mixture was cooled to room temperature and the solvent was removed under reduced pressure. To the residue was added saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give a crude product containing the title compound.
MS (ESI +): [M + H] ⁺ 254.8.

H) 4-Benzyl-7- (4-methoxybenzyl) -8-oxo-5,6,7,8-tetrahydro-2,7-naphthyridin-3-yltrifluoromethanesulfonate G A crude product (600 mg) containing 6-hydroxy-2- (4-methoxybenzyl) -3,4-dihydro-2,7-naphthyridin-1 (2H) -one and pyridine (379 mg) in dichloromethane (20 mL) To the solution was added trifluoromethanesulfonic anhydride (677 mg) under ice cooling, and the mixture was stirred at room temperature for 16 hours. The solvent was removed under reduced pressure and the residue was dissolved in dichloromethane. The organic layer was washed with 1M aqueous hydrochloric acid solution, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (pentane / ethyl acetate) to give the title compound (380 mg).
MS (ESI +): [M + H] ⁺ 507.0.

I) 4-Benzyl-2- (4-methoxybenzyl) -6- (2-oxo-2,3-dihydro-1H-imidazo [4,5-b] pyridin-1-yl) -3,4-dihydro -2,7-naphthyridin-1 (2H) -one 5-benzyl-7- (4-methoxybenzyl) -8-oxo-5,6,7,8-tetrahydro-2,7-naphthyridin-3-yltrifluor Lomethanesulfonate (200 mg), tert-butyl (3-aminopyridin-2-yl) carbamate (100 mg), tris (dibenzylideneacetone) dipalladium (0) (37 mg), xanthophos (23 mg) and carbonic acid A toluene (5 mL) solution containing cesium (193 mg) was stirred under a nitrogen atmosphere for 16 hours under reflux conditions. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give a crude product (250 mg) containing the title compound. Obtained.
MS (ESI +): [M + H] ⁺ 492.0.

J) 4-Benzyl-6- (2-oxo-2,3-dihydro-1H-imidazo [4,5-b] pyridin-1-yl) -3,4-dihydro-2,7-naphthyridine-1 ( 2H) -one I obtained 4-benzyl-2- (4-methoxybenzyl) -6- (2-oxo-2,3-dihydro-1H-imidazo [4,5-b] pyridin-1-yl ) -3,4-dihydro-2,7-naphthyridin-1 (2H) -one in a crude product (250 mg) mixed with trifluoroacetic acid (4 mL) and trifluoromethanesulfonic acid (1 mL) Stir for 3 hours under reflux conditions. The reaction mixture was cooled to room temperature and the solvent was removed under reduced pressure. The residue was dissolved in dichloromethane (50 mL), washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by preparative liquid chromatography to give the title compound (23 mg).
¹ H NMR (400 MHz, DMSO-d ₆ ) δ 2.78-2.87 (1H, m), 2.94-3.02 (1H, m), 3.09-3.16 (1H, m), 3.22-3.35 (2H, m), 7.12 (1H, dd, J = 7.6, 5.2 Hz), 7.20-7.35 (5H, m), 8.04-8.08 (2H, m), 8.13 (1H, s), 8.34 (1H, d, J = 8.0 Hz), 8.93 (1H, s), 11.96 (1H, brs).

Example 77
8-Benzyl-2- (2-oxo-2,3-dihydro-1H-imidazo [4,5-b] pyridin-1-yl) -7,8-dihydropyrido [4,3-d] pyrimidine-5 ( 6H) -ON

A) tert-butyl 5-benzyl-2,4-dioxopiperidine-1-carboxylate tert-butyl 2,4-dioxopiperidine-1-carboxylate (500 mg) and benzyl bromide (1.61 g) in tetrahydrofuran ( 30 mL) A solution of lithium hexamethyldisilazide in 1.0M tetrahydrofuran (5.9 mL) was added to the solution at −20 ° C. under a nitrogen atmosphere. The reaction mixture was stirred at −20 ° C. for 3 hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture under ice cooling, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (pentane / ethyl acetate) to give the title compound (150 mg).
MS (ESI +): [M + Na] ⁺ 325.8.

B) 5-benzyl-3-[(dimethylamino) methylidene] piperidine-2,4-dione tert-butyl 5-benzyl-2,4-dioxopiperidine-1-carboxylate (3.00 g) of N, N- The dimethylformamide dimethyl acetal (20 mL) solution was stirred at 50 ° C. for 16 hours. The reaction mixture was cooled to room temperature, and the solvent was removed under reduced pressure to obtain a crude product (3.10 g) containing the title compound.
MS (ESI +): [M + H] ⁺ 258.9.

C) 5-Benzyl-3-[(dimethylamino) methylidene obtained from 8-benzyl-2- (methylsulfanyl) -7,8-dihydropyrido [4,3-d] pyrimidin-5 (6H) -one B ] A solution of piperidine-2,4-dione (400 mg), methylcarbamimidothioate 0.5sulfate (583 mg) and sodium acetate in N, N-dimethylformamide (5 mL) at 80 ° C. The mixture was stirred for 16 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, diluted by adding water, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (pentane / ethyl acetate) to give the title compound (150 mg).
MS (ESI +): [M + H] ⁺ 285.8.

D) 8-Benzyl-2- (methylsulfonyl) -7,8-dihydropyrido [4,3-d] pyrimidin-5 (6H) -one 8-benzyl-2- (methylsulfanyl) -7,8-dihydropyrido [ To a solution of 4,3-d] pyrimidin-5 (6H) -one (80 mg) in dichloromethane (5 mL) was added metachloroperbenzoic acid (150 mg) under ice cooling, and the mixture was stirred at room temperature for 16 hours. Dilute the reaction mixture with dichloromethane (30 mL), wash with saturated aqueous sodium thiosulfate, saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride, dry over anhydrous magnesium sulfate, remove the solvent under reduced pressure and remove the title compound. A crudely purified product (100 mg) was obtained.
MS (ESI +): [M + Na] ⁺ 339.8.

E) 8-Benzyl-2- (2-oxo-2,3-dihydro-1H-imidazo [4,5-b] pyridin-1-yl) -7,8-dihydropyrido [4,3-d] pyrimidine- Crude product containing 8-benzyl-2- (methylsulfonyl) -7,8-dihydropyrido [4,3-d] pyrimidin-5 (6H) -one obtained from 5 (6H) -one D (180 mg ), Tert-butyl (3-aminopyridin-2-yl) carbamate (180 mg) and diisopropylethylamine (300 mg) in dioxane (10 mL) were stirred under refluxing conditions for 16 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, washed with 1M aqueous hydrochloric acid solution, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by preparative liquid chromatography to give the title compound (11 mg).
¹ H NMR (400 MHz, DMSO-d ₆ ) δ 2.86-2.94 (1H, m), 3.26-3.37 (2H, m), 3.38-3.55 (2H, m), 7.05 (1H, dd, J = 8.0, 1.2 Hz), 7.22-7.30 (3H, m), 7.31-7.37 (2H, m), 7.79 (1H, dd, J = 8.0, 1.2 Hz), 8.05 (1H, dd, J = 5.2, 1.2 Hz), 8.24 (1H, brs), 9.15 (1H, s), 11.98 (1H, brs).

Example 78
1-Benzyl-7- (4-methoxy-7H-pyrrolo [2,3-d] pyrimidin-5-yl) -2,2-dimethyl-2,3-dihydroquinazolin-4 (1H) -one

A) 5-Bromo-4-chloro-7-((2- (trimethylsilyl) ethoxy) methyl) -7H-pyrrolo [2,3-d] pyrimidine 5-bromo-4-chloro-7H-pyrrolo [2,3 To a solution of -d] pyrimidine (10 g) in DMF (143 mL) was added sodium hydride (2.07 g) under ice-cooling. The reaction mixture was stirred for 30 minutes under ice cooling. 2-Trimethylsilylethyloxymethyl chloride (9.14 mL) was added to the reaction mixture under ice cooling, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with water and stirred at room temperature for 4 hours. The precipitate was collected by filtration and washed with water to give the title compound (15.5 g).
¹ H NMR (300 MHz, DMSO-d ₆ ) δ 0.09 (9H, s), 0.79-0.88 (2H, m), 3.49-3.57 (2H, m), 5.62 (2H, s), 8.16 (1H, s ), 8.73 (1H, s).

B) 5-Bromo-4-methoxy-7-((2- (trimethylsilyl) ethoxy) methyl) -7H-pyrrolo [2,3-d] pyrimidine 5-bromo-4-chloro-7-((2- ( To a solution of trimethylsilyl) ethoxy) methyl) -7H-pyrrolo [2,3-d] pyrimidine (1.00 g) in THF (28 mL) was added 28% sodium methoxide methanol solution (0.638 g) under a nitrogen atmosphere under ice cooling. added. The reaction mixture was stirred at room temperature for 3 hours under nitrogen atmosphere. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by NH silica gel chromatography (hexane / ethyl acetate) to give the title compound (830 mg).
¹ H NMR (300 MHz, CDCl ₃ ) δ 0.05 (9H, s), 0.86-0.96 (2H, m), 3.47-3.57 (2H, m), 4.15 (3H, s), 5.57 (2H, s), 7.20 (1H, s), 8.46 (1H, s).

C) 2- (Benzylamino) -4- (4-methoxy-7-((2- (trimethylsilyl) ethoxy) methyl) -7H-pyrrolo [2,3-d] pyrimidin-5-yl) benzoic acid 2- Dichloro [1,1 'in a DME (20 mL) solution of (benzylamino) -4-bromobenzamide (500 mg), bis (pinacolato) diboron (624 mg) and potassium acetate (482 mg) under a nitrogen atmosphere -Bis (diphenylphosphino) ferrocene] palladium (120 mg) was added. The reaction mixture was stirred at 80 ° C. overnight under a nitrogen atmosphere, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The resulting crude product, 5-bromo-4-methoxy-7-((2- (trimethylsilyl) ethoxy) methyl) -7H-pyrrolo [2,3-d] pyrimidine (100 mg), bis (di-tert -Butyl (4-dimethylaminophenyl) phosphine) dichloropalladium (II) (219.8 mg) and potassium carbonate (116 mg) in DME (5 mL) and water (0.5 mL) at 100 ° C under microwave irradiation Stir for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane / ethyl acetate) to give the title compound (8 mg).
¹ H NMR (300 MHz, CDCl ₃ ) δ 0.05 (9H, s), 0.86-0.98 (2H, m), 3.51-3.62 (2H, m), 3.99 (3H, s), 4.57 (2H, s), 5.64 (2H, s), 6.93 (1H, dd, J = 8.3, 1.5 Hz), 7.11 (1H, d, J = 1.1 Hz), 7.26-7.44 (7H, m), 8.02 (1H, d, J = 8.3 Hz), 8.51 (1H, s).

D) 1-Benzyl-7- (4-methoxy-7H-pyrrolo [2,3-d] pyrimidin-5-yl) -2,2-dimethyl-2,3-dihydroquinazolin-4 (1H) -one 2 Of (benzylamino) -4- (4-methoxy-7-((2- (trimethylsilyl) ethoxy) methyl) -7H-pyrrolo [2,3-d] pyrimidin-5-yl) benzoic acid (8 mg) The TFA (0.1 mL) solution was stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure, and 8N ammonia-methanol solution (0.20 mL) was added to the residue at room temperature. The reaction mixture was stirred at room temperature for 3 hours. The solvent was distilled off under reduced pressure. Add 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride to a solution of the residue and 1H-benzo [d] [1,2,3] triazol-1-ol ammonia salt (8.13 mg) in DMF (2 mL). (8.29 mg) was added at room temperature. The reaction mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. To a solution of the residue and p-toluenesulfonic acid monohydrate (8 mg) in acetone (2 mL), 2-methoxyprop-1-ene (2 mL) was added dropwise under water cooling. The reaction mixture was stirred at room temperature for 5 minutes. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate / methanol) to give the title compound (3.1 mg).
¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.49 (6H, s), 3.83 (3H, s), 4.62 (2H, s), 6.91 (1H, s), 7.00-7.09 (1H, m), 7.14-7.24 (1H, m), 7.26-7.42 (4H, m), 7.51 (1H, s), 7.72 (1H, d, J = 7.9 Hz), 8.13 (1H, s), 8.36 (1H, s) , 12.28 (1H, brs).
MS (ESI +): [M + H] ⁺ 414.3.

Example 81
1-Benzyl-8- (2-oxo-2,3-dihydro-1H-imidazo [4,5-b] pyridin-1-yl) -1,2,3,4-tetrahydro-5H-1,4- Benzodiazepine-5-one

8-Bromo-3,4-dihydro-1H-benzo [e] [1,4] diazepin-5 (2H) -one (150 mg) in toluene (5 mL) in triethylamine (0.099 mL) and bromomethylbenzene (117 mg) was added at room temperature. The reaction mixture was stirred at 60 ° C. overnight under a nitrogen atmosphere. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give a crude product (80 mg) containing the title compound. Crude product obtained, tert-butyl (3-aminopyridin-2-yl) carbamate (61 mg), sodium tert-butoxide (46 mg), tris (dibenzylideneacetone) dipalladium (0) (22 mg) And 2-dicyclohexylphosphino-2 ′, 6′-diisopropoxy-1,1′-biphenyl (45 mg) in tert-butyl alcohol (5 mL) were stirred at 100 ° C. for 3 hours under an argon atmosphere. . Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by NH silica gel chromatography (ethyl acetate / methanol) to give the title compound (34 mg).
¹ H NMR (300 MHz, DMSO-d ₆ ) δ 3.34 (4H, s), 4.46 (2H, s), 6.61 (1H, dd, J = 7.7, 1.3 Hz), 6.85 (1H, dd, J = 7.9 , 5.3 Hz), 6.95 (1H, d, J = 1.9 Hz), 7.07 (1H, dd, J = 8.3, 1.9 Hz), 7.21-7.46 (5H, m), 7.68 (1H, d, J = 8.3 Hz) ), 7.94 (1H, dd, J = 5.1, 1.3 Hz), 8.30 (1H, brs), 11.80 (1H, brs).

Example 88
1-Benzyl-8- (2-oxo-2,3-dihydro-1H-imidazo [4,5-b] pyridin-1-yl) -1,2,3,4-tetrahydro-5H-pyrido [2, 3-e] [1,4] diazepine-5-one

A) 1-Benzyl-8-chloro-3,4-dihydro-1H-pyrido [2,3-e] [1,4] diazepin-5 (2H) -one 2,6-dichloronicotinic acid (384 mg) , N-benzylethane-1,2-diamine (330 mg) and triethylamine (0.279 mL) in DMF (3 mL) were added hexafluorophosphoric acid (benzotriazol-1-yloxy) tripyrrolidinophosphonium DMF (2 mL) The solution was added. The reaction mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was dissolved in DMF (3 mL), and potassium carbonate (553 mg) was added. The reaction mixture was stirred at 100 ° C. overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by NH silica gel chromatography (hexane / ethyl acetate) to give the title compound (100 mg).
¹ H NMR (300 MHz, CDCl ₃ ) δ 3.58 (4H, d, J = 8.3 Hz), 4.95 (2H, s), 6.38 (1H, brs), 6.73 (1H, d, J = 8.3 Hz), 7.26 -7.41 (5H, m), 8.31 (1H, d, J = 8.3 Hz).

B) 1-Benzyl-8- (2-oxo-2,3-dihydro-1H-imidazo [4,5-b] pyridin-1-yl) -1,2,3,4-tetrahydro-5H-pyrido [ 2,3-e] [1,4] diazepine-5-one 1-benzyl-8-chloro-3,4-dihydro-1H-pyrido [2,3-e] [1,4] diazepine-5 (2H ) -One (100 mg), tert-butyl (3-aminopyridin-2-yl) carbamate (87 mg), sodium tert-butoxide (67 mg), tris (dibenzylideneacetone) dipalladium (0) (32 mg ) And 2-dicyclohexylphosphino-2 ', 6'-diisopropoxy-1,1'-biphenyl (65 mg) in tert-butyl alcohol (5 mL) and stirred at 100 ° C for 3 hours under argon atmosphere did. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by NH silica gel chromatography (ethyl acetate / methanol) and washed with ethyl acetate to give the title compound (10 mg).
¹ H NMR (300 MHz, DMSO-d ₆ ) δ 3.41-3.54 (2H, m), 3.61-3.73 (2H, m), 4.93 (2H, s), 6.52 (1H, dd, J = 7.9, 5.3 Hz ), 7.20-7.33 (3H, m), 7.34-7.42 (2H, m), 7.43-7.53 (2H, m), 7.88 (1H, dd, J = 5.1, 1.3 Hz), 8.23-8.32 (1H, m ), 8.35 (1H, d, J = 8.7 Hz), 11.92 (1H, brs).

Example compounds prepared according to the above methods or methods similar thereto are shown in the following table. MS in the table indicates actual measurement.

Reference compounds prepared according to the above methods or methods similar thereto are shown in the following table. MS in the table indicates actual measurement.

Test Example 1 PKC Theta Enzyme Inhibition Test The PKC theta enzyme inhibitory activity of the test compound was measured by the TR-FRET method. First, it was diluted with assay buffer (20 mM Tris-HCl (pH 7.5), 5 mM MgAcetate, 0.1 mM CaCl ₂ , 1 mM DTT, 0.01% Tween 20, 0.05% BSA, 10% PKC Activator (Millipore)). A test compound was added in an amount of 2 μL to a 384 well plate. Next, add 2 μL each of the PKC theta 3 pM and the fluorescence-labeled peptide substrate (Fluorescein-PKC Substrate, Life Technologies) diluted to 1.2 μM with the assay buffer, and then prepare with the assay buffer to 60 μM. The enzyme reaction was started by adding 2 μL of the prepared ATP solution. After reacting at room temperature for 1 hour, 6 μL of TR-FRET Dilution Buffer (Life Technologies) prepared to become 20 mM EDTA, 0.6 nM terbium-labeled anti-phosphorylated serine antibody (Life Technologies) was added. After standing at room temperature for 1 hour, fluorescence intensity (excitation wavelength: 340 nm, fluorescence wavelength: 520 nm, delay time: 100 microseconds) was measured with a plate reader Envision (Perkin Elmer). The inhibitory activity of each compound was calculated as a relative activity value with 100% inhibition of the fluorescence intensity of wells without enzyme. The results are shown in Table 12.

Formulation Example 1 (Manufacture of capsules)
1) 30 mg of the compound of Example 1
2) Fine powder cellulose 10 mg
3) Lactose 19 mg
4) Magnesium stearate 1 mg
60 mg total
1), 2), 3) and 4) are mixed and filled into gelatin capsules.

Formulation Example 2 (Manufacture of tablets)
1) Compound of Example 1 30 g
2) Lactose 50 g
3) Corn starch 15 g
4) Carboxymethylcellulose calcium 44 g
5) Magnesium stearate 1 g
1000 tablets total 140 g
The total amount of 1), 2) and 3) and 30 g of 4) are kneaded with water, and after vacuum drying, the particles are sized. 14 g of 4) and 1 g of 5) are mixed with the sized powder, and tableted with a tableting machine. In this way, 1000 tablets containing 30 mg of the compound of Example 1 per tablet are obtained.

The compound of the present invention has an excellent PKC inhibitory action and is useful as a preventive or therapeutic agent for immune diseases, inflammatory diseases and the like.

This application is based on Japanese Patent Application No. 2014-060896 filed in Japan, the contents of which are incorporated in full herein.

Claims

Formula (I):

[Where:
Ring A represents a nitrogen-containing unsaturated heterocyclic ring which may be further substituted;
Ring B represents a C 6-14 aromatic hydrocarbon ring which may be further substituted or an aromatic heterocyclic ring which may be further substituted;
L represents an optionally substituted C 1-2 alkylene;
X 1 represents N or CR 1 ;
X 2 represents N or CR 2 ;
X 3 represents N or CR 3 ;
X 4 represents N or CR 4 ;
R 1 , R 2 , R 3 and R 4 independently represent a hydrogen atom or a substituent;
X 5 represents CR 5a , CR 5b R 5c , NR 5d or a bond;
R 5a , R 5b , R 5c and R 5d independently represent a hydrogen atom or a substituent, or R 5b and R 5c may combine together to form an optionally substituted ring. Often;
X 6 represents CR 6a R 6b or NR 6c ;
R 6a , R 6b and R 6c independently represent a hydrogen atom or a substituent, or R 6a and R 6b may together form an optionally substituted ring;
R 7 represents a hydrogen atom or a substituent. ]
Or a salt thereof.
Ring A is a monocyclic nitrogen-containing unsaturated heterocyclic ring which may be further substituted, or may be further substituted, Formula (A):

[Where:
Ring A 1 represents an optionally further substituted 5- or 6-membered aromatic ring, or an optionally further substituted 5- or 6-membered non-aromatic unsaturated ring;
Ring A 2 represents an optionally substituted 5- or 6-membered aromatic ring, or an optionally substituted 5- or 6-membered non-aromatic unsaturated ring;
At least one of the ring constituent atoms of ring A 1 or ring A 2 is a nitrogen atom. ]
A bicyclic nitrogen-containing unsaturated heterocycle represented by:
Ring B is a benzene ring which may be further substituted, or a thiophene ring which may be further substituted or a pyridine ring which may be further substituted;
L is C 1-2 alkylene;
X 1 is N or CR 1 and R 1 is a hydrogen atom or a halogen atom;
X 2 is N or CR 2 and R 2 is a hydrogen atom or a halogen atom;
X 3 is N or CR 3 , R 3 is a hydrogen atom or a halogen atom;
X 4 is N or CR 4 and R 4 is a hydrogen atom or a C 1-6 alkyl group;
X 5 is CR 5b R 5c or a bond, and R 5b and R 5c are independently a hydrogen atom or a substituent;
X 6 is CR 6a R 6b and R 6a and R 6b are independently a hydrogen atom or a substituent, or R 6a and R 6b may be substituted together to be substituted. Forming a ring;
R 7 is a hydrogen atom or an optionally substituted C 1-6 alkyl group;
The compound according to claim 1 or a salt thereof.
Ring A is a monocyclic nitrogen-containing unsaturated heterocyclic ring which may be further substituted with one or two substituents selected from a hydroxy group and an oxo group, or a halogen atom, a hydroxy group, an oxo group 1 to 3 groups selected from a group, an optionally substituted C 1-6 alkyl group, an optionally substituted C 1-6 alkoxy group and an optionally substituted non-aromatic heterocyclic-oxy group may be further substituted with a substituent, ring a 1 is a pyrrole ring, a pyrazole ring, an imidazole ring, a pyridine ring or an imidazoline ring, ring a 2 is thiophene ring, the formula is a pyridine ring or a pyrimidine ring (a Is a bicyclic nitrogen-containing unsaturated heterocycle represented by:
Ring B is
1 selected from (1) (i) a halogen atom, (ii) a cyano group, (iii) a C 1-6 alkyl group optionally substituted with a halogen atom or an amino group, and (iv) a C 1-6 alkoxy group A benzene ring optionally further substituted with up to 5 substituents,
(2) a thiophene ring, or (3) a pyridine ring;
L is, -CH 2 -, - CH 2 CH 2 - or -CH (CH 3) - and is,
X 1 is N or CR 1 and R 1 is a hydrogen atom or a fluorine atom;
X 2 is N or CR 2 and R 2 is a hydrogen atom or a fluorine atom;
X 3 is N or CR 3 , R 3 is a hydrogen atom or a fluorine atom;
X 4 is N or CR 4 and R 4 is a hydrogen atom or methyl;
X 5 is CR 5b R 5c or a bond, and R 5b and R 5c are hydrogen atoms;
X 6 is CR 6a R 6b , and R 6a and R 6b are a hydrogen atom, or independently, a C 1-6 alkyl group which may be substituted with a hydroxy group or a C 6-14 aryl group Or R 6a and R 6b together form a C 3-10 cycloalkane ring;
R 7 is a hydrogen atom or a C 1-6 alkyl group;
The compound according to claim 2 or a salt thereof.
2,2-Dimethyl-7- (2-oxo-2,3-dihydro-1H-imidazo [4,5-b] pyridin-1-yl) -1-((1R) -1-phenylethyl) -2 , 3-Dihydroquinazolin-4 (1H) -one or a salt thereof.
4-Benzyl-6- (2-oxo-2,3-dihydro-1H-imidazo [4,5-b] pyridin-1-yl) -3,4-dihydroisoquinolin-1 (2H) -one or a salt thereof .
1-Benzyl-8- (2-oxo-2,3-dihydro-1H-imidazo [4,5-b] pyridin-1-yl) -1,2,3,4-tetrahydro-5H-pyrido [2, 3-e] [1,4] diazepin-5-one or a salt thereof.
A medicament comprising the compound according to claim 1 or a salt thereof.
The medicament according to claim 7, which is a protein kinase C inhibitor.
The medicament according to claim 7, which is a preventive or therapeutic agent for immune diseases and / or inflammatory diseases.
The medicament according to claim 7, which is a prophylactic or therapeutic agent for inflammatory bowel disease, psoriasis or atopic dermatitis.
The compound or a salt thereof according to claim 1, for use in the prevention or treatment of immune diseases and / or inflammatory diseases.
The compound or a salt thereof according to claim 1, for use in the prevention or treatment of inflammatory bowel disease, psoriasis or atopic dermatitis.
A method for inhibiting protein kinase C in a mammal, comprising administering an effective amount of the compound or salt thereof according to claim 1 to the mammal.
A method for preventing or treating an immune disease and / or an inflammatory disease in a mammal, comprising administering an effective amount of the compound according to claim 1 or a salt thereof to the mammal.
A method for preventing or treating inflammatory bowel disease, psoriasis or atopic dermatitis in a mammal, comprising administering an effective amount of the compound according to claim 1 or a salt thereof to the mammal.
Use of the compound according to claim 1 or a salt thereof for producing a prophylactic or therapeutic agent for immune diseases and / or inflammatory diseases.
Use of the compound or a salt thereof according to claim 1 for producing a preventive or therapeutic agent for inflammatory bowel disease, psoriasis or atopic dermatitis.