Compounds and compositions as PDGF receptor kinase inhibitors

Abstract

The present invention relates to compounds and compositions that are PDGF receptor kinase inhibitors. The purpose of the present invention is to provide a compound having inhibitory activity against PDGF receptor kinase. For example, the present invention includes a compound represented by formula [1], a pharmaceutically acceptable salt of the compound, or a solvate of the compound. The compounds of the present invention have inhibitory activity against PDGF receptor kinase. Due to its activity against PDGF receptor kinase, the compound of the present invention is useful as a therapeutic agent for respiratory diseases, cancer, smooth muscle proliferative diseases, vascular proliferative diseases, autoimmune / inflammatory diseases, metabolic diseases, vascular obstructive diseases, and the like. # imgabs0 #

Description

This application is a divisional application of the invention patent with application date of December 11, 2020, application number 202080086329.8, and invention name “Compounds and compositions as PDGF receptor kinase inhibitors”. Technical Field

[0001] The present invention relates to a preventive and / or therapeutic agent for pulmonary hypertension comprising a novel heterocyclic derivative as an effective ingredient. Background Art

[0002] Regarding pulmonary arterial hypertension (PAH), large-scale seminars on pulmonary hypertension are held every 5 years in Western countries, and at the Dana Point Conference in 2008, pulmonary hypertension was defined as an average value (mean PAP) of pulmonary artery pressure (PAP) measured using a resting right heart catheter test of 25 mmHg or more, and this definition was continued at the Nice Conference in 2013. In the Dana Point classification, pulmonary hypertension is divided into five groups, namely, Group 1: PAH, Group 2: pulmonary hypertension caused by left heart disease, Group 3: pulmonary hypertension caused by lung disease and / or hypoxemia, Group 4: chronic thromboembolic pulmonary hypertension (CTEPH), and Group 5: pulmonary hypertension caused by a multifactorial mechanism with unknown details. This basic structure is maintained in the revised clinical classification of pulmonary hypertension (Nice classification

[2013] ) (Non-patent document 1).

[0003] In addition, an updated definition of pulmonary hypertension was proposed at the 6th World Symposium on Pulmonary Hypertension (NICE Conference 2018). In this proposal, 24 mmHg ≥ mean pulmonary artery pressure (mPAP) > 20 mmHg is also defined as included in the above pulmonary hypertension.

[0004] Platelet-derived growth factor (PDGF) may stimulate the migration of arterial smooth muscle cells from the interior of the artery to the intimal layer, where the muscle cells may proliferate. Cell proliferation induced by all isoforms of PDGF is mediated by ligand binding to the PDGF receptor.

[0005] The PDGF receptor belongs to the class III tyrosine kinase family and consists of two receptor subtypes, referred to as type A (or alpha) and type B (or beta). Other members of the PDGF receptor family include colony stimulating factor 1 receptor (CSF1R), KIT, and FLT3.

[0006] KIT is another receptor tyrosine kinase belonging to the PDGF receptor family and is usually expressed on hematopoietic progenitor cells, mast cells and embryonic cells. It is known that the expression of KIT is involved in several cancers, including mast cell leukemia, germ cell tumors, small cell lung cancer, gastrointestinal stromal tumors (GIST), acute myeloid leukemia (AML), neuroblastoma, melanoma, ovarian cancer and breast cancer (Non-Patent Document 1).

[0007] Imatinib has an inhibitory effect against PDGF receptor kinase and showed efficacy in the P3 study for pulmonary hypertension. However, due to side effects (such as bone marrow suppression), it was not well tolerated and therefore was not approved.

[0008] Patent Document 1 describes that the compound of the general formula [1] or a pharmaceutically acceptable salt thereof is an inhibitor of PDGF receptor kinase or PDGF receptor kinase and KIT.

[0009] However, until now, the relationship between myelosuppression and inhibition of KIT, a receptor tyrosine kinase involved in myeloid hematopoiesis, has been unknown.

[0010] Reference List Patent Literature PTL 8: WO 2013 / 033620 Non-patent literature NPL 1: Smolich et al., Blood, 97, 1413-1421. Summary of the invention

[0011] Technical issues The problem that the present invention attempts to solve is to provide a preventive and / or therapeutic agent for pulmonary hypertension having an excellent balance between effectiveness and safety.

[0012] Solution to the problem The present inventors have found the relationship between the myelosuppressive effect and the inhibitory effect against KIT, which is a receptor tyrosine kinase involved in myelopoiesis. That is, the present inventors have found that a compound represented by the following general formula [1] or a pharmaceutically acceptable salt thereof or a solvate thereof (hereinafter referred to as the compound of the present invention) having high inhibitory activity against PDGF receptor kinase among the inhibitory activity against KIT kinase exhibits an inhibitory effect against the proliferation of pulmonary artery smooth muscle cells and has a reduced inhibitory effect against erythrocyte colony formation, thereby completing the present invention.

[0013] That is, the present invention discloses the following (Item 1) to (Item 8).

[0014] (Item 1) A compound represented by the following formula [1]: [Formula 1] in R 1 is a hydrogen atom, a halogen atom, a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C2-C6 alkenyl group, a C2-C6 haloalkenyl group, a C2-C6 alkynyl group, a C2-C6 haloalkynyl group, a C1-C6 alkoxy group, a hydroxyl group, a carboxyl group, an alkylcarbonyloxy group, an amino group, a monoalkylamino group, a dialkylamino group, an aminoalkyl group, an alkylcarbonylamino group, a nitro group, an optionally substituted C3-C6 cycloalkyl group, an optionally substituted C3-C6 cycloalkenyl group, an optionally substituted heterocycloalkyl group, an optionally substituted aryl group, or an optionally substituted heteroaryl group; R 2 For the key hand, -(CR a R b ) m -NR c -、-NR c -(CR a R b ) m -、-(CR a R b ) m -O-、-O-(CR a R b ) m -、-(CR a R b ) m -、-NR c -、-O-、-NR c -CO-NR c -、-CR a =CR b -or-C≡C-, where R 2 R a is a hydrogen atom, a halogen atom, a C1-C6 alkyl group or a C1-C6 haloalkyl group, and R 2 R b is a hydrogen atom, a halogen atom, a C1-C6 alkyl group or a C1-C6 haloalkyl group, or R 2 R a and R b Together with the carbon atoms to which they are bonded, they form C=O, R 2 Each R in c are independently a hydrogen atom, a C1-C6 alkyl group or a C1-C6 haloalkyl group, and m is an integer from 0 to 3; Het is a 5-10 membered heteroaryl group; L 1 For the key hand, -(CR a R b ) m -NR c -、-NR c -(CR a R b ) m -、-(CR a R b ) m -O-、-O-(CR a R b ) m -、-(CR a R b ) m -、-NR c -、-O-、-NR c -CO-NR c -、-CR a =CR b -or-C≡C-, where L 1 R a is a hydrogen atom, a halogen atom, a C1-C6 alkyl group or a C1-C6 haloalkyl group, and L 1 R b is a hydrogen atom, a halogen atom, a C1-C6 alkyl group or a C1-C6 haloalkyl group, or L 1 R a and R b Together with the carbon atoms to which they are bonded, they form C=O, L 1 Each R in c are independently a hydrogen atom, a C1-C6 alkyl group or a C1-C6 haloalkyl group, and L 1 Where m is an integer from 0 to 3; X is N or CR 3 ,in R 3 is a hydrogen atom, a halogen atom, a C1-C6 alkyl group or a C1-C6 haloalkyl group; R 4 is a hydrogen atom, a halogen atom or a methyl group; L 2 For the key hand, -(CR a R b ) m -NR c -、-NR c -(CR a Rb ) m -、-(CR a R b ) m -O-、-O-(CR a R b ) m -、-(CR a R b ) m -、-NR c -、-O-、-NR c -CO-NR c -、-CR a =CR b -or-C≡C-, where L 2 R a is a hydrogen atom, a halogen atom, a C1-C6 alkyl group or a C1-C6 haloalkyl group, and L 2 R b is a hydrogen atom, a halogen atom, a C1-C6 alkyl group or a C1-C6 haloalkyl group, or L 2 R a and R b Together with the carbon atoms to which they are bonded, they form C=O, L 2 Each R in c are independently a hydrogen atom, a C1-C6 alkyl group or a C1-C6 haloalkyl group, and L 2 Where m is an integer from 0 to 3; R 5 is a hydrogen atom, a halogen atom, a hydroxyl group, an amino group, a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C1-C6 alkoxy group or a C1-C6 haloalkoxy group; and R 6 is a hydrogen atom, a halogen atom, a C1-C6 alkyl group, a C1-C6 haloalkyl group or an optionally substituted phenyl group, and R 7 is a hydrogen atom, a halogen atom, a C1-C6 alkyl group, a C1-C6 haloalkyl group, a hydroxyalkyl group, an optionally substituted phenyl group or an optionally substituted C3-C6 cycloalkyl group, or R 6 and R 7 Together with the carbon atom to which they are bonded, they form a C3-C6 cycloalkyl group, an optionally substituted aryl group or an optionally substituted heteroaryl group, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0015] (Item 2) The compound according to item 1, wherein: R 1 is a hydrogen atom, a halogen atom, a C1-C6 alkyl group, a C2-C6 alkenyl group, a C1-C6 alkoxy group, an amino group, a monoalkylamino group, a dialkylamino group, an aminoalkyl group, an alkylcarbonylamino group, an optionally substituted C3-C6 cycloalkyl group, an optionally substituted heterocycloalkyl group, an optionally substituted aryl group, or an optionally substituted heteroaryl group; R 2 For the key hand, -(CR a R b ) m -NR c -、-(CR a R b ) m -O-、-(CR a R b ) m -、-NR c -、-O-、-NR c -CO-NR c -、-CR a =CR b -or-C≡C-; L 1 For the key hand, -(CR a R b ) m -NR c -、-NR c -(CR a R b ) m -、-(CR a R b ) m -O-、-O-(CR a R b ) m -、-(CR a R b ) m -、-NR c -、-CR a =CR b -or-C≡C-, where L 1 R a is a hydrogen atom, a halogen atom or a C1-C6 alkyl group, and L 1 R b is a hydrogen atom, a halogen atom or a C1-C6 alkyl group, or L 1 R a and L 1 R b Together with the carbon atoms to which they are bonded, they form C=O, L1 Each R in c are independently a hydrogen atom, a C1-C6 alkyl group or a C1-C6 haloalkyl group, and L 1 Where m is an integer from 0 to 2; X is N or CR 3 ,in R 3 is a hydrogen atom, a halogen atom, a C1-C6 alkyl group or a C1-C6 haloalkyl group; R 4 is a hydrogen atom, a halogen atom or a methyl group; L 2 For-(CR a R b ) m -NR c -or-NR c -CO-NR c -,in L 2 R a and R b Together with the carbon atoms to which they are bonded, they form C=O, L 2 Each R in c are independently hydrogen atoms, and L 2 where m is 1; R 5 is hydroxyl; and R 6 is a hydrogen atom, a C1-C6 alkyl group or an optionally substituted phenyl group, and R 7 is a hydrogen atom, a C1-C6 alkyl group, a hydroxyalkyl group or an optionally substituted phenyl group, or R 6 and R 7 Together with the carbon atoms to which they are bonded, they form a C3-C6 cycloalkyl group or an optionally substituted aryl group. or a pharmaceutically acceptable salt or solvate thereof.

[0016] (Item 3) The compound according to item 1, wherein: R 1 is a hydrogen atom, a C1-C6 alkoxy group, an amino group, a monoalkylamino group, an optionally substituted C3-C6 cycloalkyl group, an optionally substituted heterocycloalkyl group, an optionally substituted aryl group or an optionally substituted heteroaryl group; R 2 For the key hand, -(CR a R b ) m -O-、-(CR aR b ) m -or-NR c -; L 1 For-(CR a R b ) m -NR c -、-NR c -(CR a R b ) m -or-CR a =CR b -,in L 1 R a is a hydrogen atom or a halogen atom, and L 1 R b is a hydrogen atom, or L 1 R a and R b Together with the carbon atoms to which they are bonded, they form C=O, L 1 Each R in c are independently hydrogen atoms, and L 1 Where m is 0 or 1; X is N or CR 3 ,in R 3 is a hydrogen atom; R 4 is a halogen atom or a methyl group; L 2 For-(CR a R b ) m -NR c -,in L 2 R a and R b Together with the carbon atoms to which they are bonded, they form C=O, L 2 Each R in c are independently hydrogen atoms, and L 2 where m is 1; R 5 is hydroxyl; and R 6 and R 7 Together with the carbon atoms to which they are bonded, they form a C3-C6 cycloalkyl group. or a pharmaceutically acceptable salt or solvate thereof.

[0017] (Item 3) The compound according to item 1, which is selected from the following (1) to (207): (1) 2-(cyclopropylamino)-N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)-1,3-thiazole-5-carboxamide, (2) N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)-5-phenylpyridine-3-carboxamide, (3) 2-(cyclopropylmethyl)-N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)-1,3-thiazole-5-carboxamide, (4) 5-(cyclopropylamino)-N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)pyridine-3-carboxamide, (5) N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)-2-phenyl-1,3-oxazole-5-carboxamide, (6) N-(5-{[(1S)-2-hydroxy-1-phenylethyl]carbamoyl}-2-methylphenyl)-5-phenylpyridine-3-carboxamide, (7) N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)-5-[(propan-2-yl)oxy]pyridine-3-carboxamide, (8) 2-[(cyclopropylmethyl)amino]-N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)-1,3-thiazole-5-carboxamide, (9) 5-(4-chlorophenyl)-N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)pyridine-3-carboxamide, (10) N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)-2-propyl-1,3-thiazole-5-carboxamide, (11) 5-(3-chlorophenyl)-N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)pyridine-3-carboxamide, (12) N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)-5-(2-methylphenyl)pyridine-3-carboxamide, (13) 5-(2-chlorophenyl)-N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)pyridine-3-carboxamide, (14) N-(5-{[(2S)-1-hydroxypentan-2-yl]carbamoyl}-2-methylphenyl)-5-phenylpyridine-3-carboxamide, (15) 5-[(E)-2-cyclopropylvinyl]-N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)pyridine-3-carboxamide, (16) 5-[(cyclopropylmethyl)amino]-N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)pyridine-3-carboxamide, (17) 5-[cyclopropyl(methyl)amino]-N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)pyridine-3-carboxamide, (18) N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)-5-(4-methoxyphenyl)pyridine-3-carboxamide, (19) 5-(4-fluorophenyl)-N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)pyridine-3-carboxamide, (20) 5-(3-fluorophenyl)-N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)pyridine-3-carboxamide, (21) N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)-5-[4-(trifluoromethyl)phenyl]pyridine-3-carboxamide, (22) N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)-5-[3-(trifluoromethyl)phenyl]pyridine-3-carboxamide, (23) N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)-5-(2-methylprop-1-en-1-yl)pyridine-3-carboxamide, (24) 5-(cyclopropylmethoxy)-N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)pyridine-3-carboxamide, (25) 2-[(3,3-difluorocyclobutyl)amino]-N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)-1,3-thiazole-5-carboxamide, (26) 2-[(2-cyclopropylethyl)amino]-N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)-1,3-thiazole-5-carboxamide, (27) N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)-2-[(propan-2-yl)amino]-1,3-thiazole-5-carboxamide, (28) 5-[(4,4-difluorocyclohexyl)oxy]-N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)pyridine-3-carboxamide, (29) 5-(2-fluorophenyl)-N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)pyridine-3-carboxamide, (30) 5-(2,3-difluorophenyl)-N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)pyridine-3-carboxamide, (31) 5-(2,4-difluorophenyl)-N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)pyridine-3-carboxamide, (32) 5-(3,5-difluorophenyl)-N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)pyridine-3-carboxamide, (33) 5-(2-fluoro-4-methoxyphenyl)-N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)pyridine-3-carboxamide, (34) N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)-5-[3-(trifluoromethoxy)phenyl]pyridine-3-carboxamide, (35) N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)-5-[2-(trifluoromethoxy)phenyl]pyridine-3-carboxamide, (36) 5-[2-fluoro-4-(trifluoromethyl)phenyl]-N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)pyridine-3-carboxamide, (37) 5-(2,6-difluorophenyl)-N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)pyridine-3-carboxamide, (38) 2-(tert-butylamino)-N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)-1,3-thiazole-5-carboxamide, (39) N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)-2-[(1-methylcyclopropyl)amino]-1,3-thiazole-5-carboxamide, (40) N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)-2-[(1-methylcyclobutyl)amino]-1,3-thiazole-5-carboxamide, (41) 2-[(2,2-dimethylpropyl)amino]-N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)-1,3-thiazole-5-carboxamide, (42) N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)-5-(3,4,5-trifluorophenyl)pyridine-3-carboxamide, (43) 5-(4-cyclopropylphenyl)-N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)pyridine-3-carboxamide, (44) N-(2-chloro-5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}phenyl)-5-(cyclopropylmethoxy)pyridine-3-carboxamide, (45) N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)imidazo[2,1-b][1,3]thiazole-5-carboxamide, (46) 5-(cyclopropylmethoxy)-N-(3-fluoro-5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)pyridine-3-carboxamide, (47) 5-[(3,3-difluorocyclobutyl)oxy]-N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)pyridine-3-carboxamide, (48) 2-(cyclopropylmethyl)-N-(3-fluoro-5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)-1,3-thiazole-5-carboxamide, (49) N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)-5-methoxypyridine-3-carboxamide, (50) 5-ethoxy-N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)pyridine-3-carboxamide, (51) N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)-5-[(pyridin-2-yl)oxy]pyridine-3-carboxamide, (52) N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)-5-[(pyrimidin-2-yl)oxy]pyridine-3-carboxamide, (53) N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)-5-[(1-methylcyclopropyl)methoxy]pyridine-3-carboxamide, (54) 5-[(3,3-difluorocyclobutyl)methoxy]-N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)pyridine-3-carboxamide, (55) N-(2-chloro-5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}phenyl)-2-(cyclopropylmethyl)-1,3-thiazole-5-carboxamide, (56) 5-(cyclopropylmethoxy)-N-(2-fluoro-5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}phenyl)pyridine-3-carboxamide, (57) 3-[(5-bromopyridin-3-yl)ethynyl]-4-chloro-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide, (58) 4-chloro-N-[(1S,2S)-2-hydroxycyclohexyl]-3-[(5-phenylpyridin-3-yl)ethynyl]benzamide, (59) N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-[(5-methylpyridin-3-yl)ethynyl]benzamide, (60) N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-[(5-phenylpyridin-3-yl)ethynyl]benzamide, (61) 3-[(5-bromopyridin-3-yl)ethynyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide, (62) N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-{[5-(pyrimidin-2-yl)pyridin-3-yl]ethynyl}benzamide, (63) N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-{[5-(pyrazin-2-yl)pyridin-3-yl]ethynyl}benzamide, (64) 4-chloro-N-[(1S,2S)-2-hydroxycyclohexyl]-3-{[5-(pyrimidin-2-yl)pyridin-3-yl]ethynyl}benzamide, (65) 3-[(6-aminopyridin-3-yl)ethynyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide, (66) 3-[([2,3'-bipyridyl]-5'-yl)ethynyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide, (67) 3-[(5-cyclopropylpyridin-3-yl)ethynyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide, (68) 3-[(6-cyclopropylpyrazin-2-yl)ethynyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide, (69) 3-{[6-(2-fluorophenyl)pyrazin-2-yl]ethynyl}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide, (70) 3-{[6-(3-fluorophenyl)pyrazin-2-yl]ethynyl}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide, (71) 3-{[6-(4-fluorophenyl)pyrazin-2-yl]ethynyl}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide, (72) 3-({6-[(cyclopropylmethyl)amino]pyrazin-2-yl}ethynyl)-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide, (73) 5-[(5-cyclopropylpyridin-3-yl)ethynyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-6-methylpyridine-3-carboxamide, (74) 3-[(6-bromopyrazin-2-yl)ethynyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide, (75) N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-[(6-phenylpyrazin-2-yl)ethynyl]benzamide, (76) 3-[(5-bromopyridin-3-yl)ethynyl]-N-[(1S,2S)-1,3-dihydroxy-1-phenylpropan-2-yl]-4-methylbenzamide, (77)N 1 -[(1S,2S)-2-Hydroxycyclohexyl]-4-methyl-N 3 -(5-phenylpyridin-3-yl)benzene-1,3-dicarboxamide, (78) N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-{[2-(pyridin-3-yl)pyrimidin-4-yl]amino}benzamide, (79) N-[(1S,2S)-2-hydroxycyclohexyl]-3-{[2-(isoquinolin-4-yl)pyrimidin-4-yl]amino}-4-methylbenzamide, (80) N-[(1S,2S)-1,3-dihydroxy-1-phenylpropan-2-yl]-3-{[2-(isoquinolin-4-yl)pyrimidin-4-yl]amino}-4-methylbenzamide, (81) 3-[([2,3'-bipyridyl]-6-yl)amino]-5-fluoro-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide, (82) N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-{[2-(methylamino)quinazolin-5-yl]amino}benzamide, (83) 3-(2-amino-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-N-[(1S,2S)-1,3-dihydroxy-1-phenylpropan-2-yl]-4-methylbenzamide, (84) N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-{[(1S)-1-(5-phenylpyridin-3-yl)ethyl]amino}benzamide, (85) 3-{[(1S)-1-([3,3'-bipyridyl]-5-yl)ethyl]amino}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide, (86) N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-({(1S)-1-[5-(phenylethynyl)pyridin-3-yl]ethyl}amino)benzamide, (87) 3-{[(1S)-1-([3,4'-bipyridyl]-5-yl)ethyl]amino}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide, (88) N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-({(1S)-1-[5-(pyrimidin-2-yl)pyridin-3-yl]ethyl}amino)benzamide, (89) 3-{[(1S)-1-([2,3'-bipyridyl]-5'-yl)ethyl]amino}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide, (90) 3-{[(1S)-1-([3,3'-bipyridyl]-5-yl)ethyl]amino}-4-chloro-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide, (91) 3-{[(5-bromopyridin-3-yl)methyl]amino}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide, (92) N-[(1S,2S)-2-Hydroxycyclohexyl]-4-methyl-3-{[(5-phenylpyridin-3-yl)methyl]amino}benzamide, (93) 3-{[([3,3'-bipyridyl]-5-yl)methyl]amino}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide, (94) 3-({[5-(cyclopropylethynyl)pyridin-3-yl]methyl}amino)-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide, (95) N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-({[5-(pyrimidin-2-yl)pyridin-3-yl]methyl}amino)benzamide, (96) N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-{[(quinolin-3-yl)methyl]amino}benzamide, (97) N-[(1S,2S)-2-hydroxycyclohexyl]-3-[({5-[(1-hydroxycyclopropyl)ethynyl]pyridin-3-yl}methyl)amino]-4-methylbenzamide, (98) 3-[({5-[4-(2-aminopropan-2-yl)phenyl]pyridin-3-yl}methyl)amino]-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide, (99) 3-({[5-(4-aminophenyl)pyridin-3-yl]methyl}amino)-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide, (100) 3-({[5-(3,5-difluorophenyl)pyridin-3-yl]methyl}amino)-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide, (101) N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-{[(6-phenylpyrazin-2-yl)methyl]amino}benzamide, (102) N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-({[5-(thiophen-2-yl)pyridin-3-yl]methyl}amino)benzamide, (103) N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-({[5-(thiophen-3-yl)pyridin-3-yl]methyl}amino)benzamide, (104) 4-chloro-N-[(1S,2S)-2-hydroxycyclohexyl]-3-({[5-(pyrimidin-2-yl)pyridin-3-yl]methyl}amino)benzamide, (105) N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-{[(pyrazolo[5,1-b][1,3]thiazol-7-yl)methyl]amino}benzamide, (106) 3-fluoro-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-5-({[5-(pyrimidin-2-yl)pyridin-3-yl]methyl}amino)benzamide, (107) 3-({[5-(5-fluoropyrimidin-2-yl)pyridin-3-yl]methyl}amino)-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide, (108) N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-{[(thieno[3,2-b]pyridin-6-yl)methyl]amino}benzamide, (109) N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-{[(1H-pyrazolo[3,4-b]pyridin-5-yl)methyl]amino}benzamide, (110) N-[(1S,2S)-2-hydroxycyclohexyl]-3-{[(imidazo[1,2-b]pyridazin-3-yl)methyl]amino}-4-methylbenzamide, (111) N-[(1S,2S)-2-hydroxycyclohexyl]-3-({[5-(imidazo[1,2-a]pyrazin-6-yl)pyridin-3-yl]methyl}amino)-4-methylbenzamide, (112) N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-({[1-(pyridin-2-yl)-1H-pyrazol-4-yl]methyl}amino)benzamide, (113) 3-{[(2-aminopyrimidin-5-yl)methyl]amino}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide, (114) 3-({[2-(cyclopropylamino)pyrimidin-5-yl]methyl}amino)-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide, (115) N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-({[5-(pyrazin-2-yl)pyridin-3-yl]methyl}amino)benzamide, (116) 3-{[(6-acetylaminopyridin-3-yl)methyl]amino}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide, (117) 3-[({6-[(cyclopropylmethyl)amino]pyridin-3-yl}methyl)amino]-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide, (118) 3-{[([2,2'-bipyridyl]-5-yl)methyl]amino}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide, (119) N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-{[(pyrazolo[1,5-a]pyrimidin-3-yl)methyl]amino}benzamide, (120) 3-[({6-[(cyclopropanecarbonyl)amino]pyridin-3-yl}methyl)amino]-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide, (121) N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-{[(2-phenylpyrimidin-5-yl)methyl]amino}benzamide, (122) N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-({[6-(1H-pyrazol-1-yl)pyridin-3-yl]methyl}amino)benzamide, (123) N-[(1S,2S)-2-hydroxycyclohexyl]-6-methyl-5-{[(pyrazolo[1,5-a]pyridin-3-yl)methyl]amino}pyridine-3-carboxamide, (124) methyl {5-[(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylanilino)methyl]pyridin-2-yl}carbamate, (125) N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-[({6-[(oxan-4-yl)amino]pyridin-3-yl}methyl)amino]benzamide, (126) N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-[({2-[(pyridin-2-yl)amino]pyrimidin-5-yl}methyl)amino]benzamide, (127) N-{5-[(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylanilino)methyl]pyridin-2-yl}morpholine-4-carboxamide, (128) N-[(1S,2S)-2-hydroxycyclohexyl]-3-({[2-(4-methoxyphenyl)pyrimidin-5-yl]methyl}amino)-4-methylbenzamide, (129) N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-{[(6-{[(pyridin-3-yl)carbamoyl]amino}pyridin-3-yl)methyl]amino}benzamide, (130) 3-({[6-(cyclobutylamino)pyridin-3-yl]methyl}amino)-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide (131) 3-{[(5-aminopyrazin-2-yl)methyl]amino}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide, (132) N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-[({2-[(oxan-4-yl)amino]pyrimidin-5-yl}methyl)amino]benzamide, (133) 3-{[(6-{[cyclopropyl(methyl)carbamoyl]amino}pyridin-3-yl)methyl]amino}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide, (134) N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-[({6-[(propan-2-yl)amino]pyridin-3-yl}methyl)amino]benzamide, (135) N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-{[(2-{[(3R)-oxolan-3-yl]amino}pyrimidin-5-yl)methyl]amino}benzamide, (136) N-[(1S,2S)-2-Hydroxycyclohexyl]-4-methyl-3-{[(2-{[(3S)-oxolan-3-yl]amino}pyrimidin-5-yl)methyl]amino}benzamide (137) N-{5-[(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylanilino)methyl]pyridin-2-yl}oxane-4-carboxamide, (138) N-[(1S,2S)-2-hydroxycyclohexyl]-3-{[(6-{[(1r,3r)-3-methoxycyclobutane-1-carbonyl]amino}pyridin-3-yl)methyl]amino}-4-methylbenzamide, (139) N-{5-[(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylanilino)methyl]pyridin-2-yl}oxolane-3-carboxamide, (140) N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-({[6-(1H-1,2,3-triazol-1-yl)pyridin-3-yl]methyl}amino)benzamide, (141) N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-[({6-[(oxetan-3-yl)amino]pyridin-3-yl}methyl)amino]benzamide, (142) 3-{[(2-aminopyrimidin-5-yl)methyl]amino}-4-chloro-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide, (143) 3-{[(2-aminopyrimidin-5-yl)methyl]amino}-5-fluoro-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide, (144) 3-{[(3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)methyl]amino}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide, (145) N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-({[5-(2H-1,2,3-triazol-2-yl)pyridin-3-yl]methyl}amino)benzamide, (146) 3-{[([3,3'-bipyridyl]-5-yl)amino]methyl}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide, (147) N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-({[5-(pyrimidin-2-yl)pyridin-3-yl]amino}methyl)benzamide, (148) 3-{[([2,3'-bipyridyl]-5'-yl)amino]methyl}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide, (149) N-[(1R,2R)-2-hydroxycyclohexyl]-4-methyl-3-({[5-(pyrimidin-2-yl)pyridin-3-yl]amino}methyl)benzamide, (150) N-[(1S,2S)-2-hydroxycyclohexyl]-3-({[5-(pyrimidin-2-yl)pyridin-3-yl]amino}methyl)benzamide, (151) 4-fluoro-N-[(1S,2S)-2-hydroxycyclohexyl]-3-({[5-(pyrimidin-2-yl)pyridin-3-yl]amino}methyl)benzamide, (152) 3-{[(5-bromopyridin-3-yl)amino]methyl}-N-[(1S,2S)-1,3-dihydroxy-1-phenylpropan-2-yl]-4-methylbenzamide, (153) N-[(1S,2S)-1,3-dihydroxy-1-phenylpropan-2-yl]-4-methyl-3-{[(5-phenylpyridin-3-yl)amino]methyl}benzamide, (154) 3-{[(5-cyclopropylpyridin-3-yl)amino]methyl}-N-[(1S,2S)-1,3-dihydroxy-1-phenylpropan-2-yl]-4-methylbenzamide, (155) 3-{[([2,3'-bipyridyl]-5'-yl)amino]methyl}-N-[(1S,2S)-1,3-dihydroxy-1-phenylpropan-2-yl]-4-methylbenzamide, (156) N-[(1S,2S)-1,3-dihydroxy-1-phenylpropan-2-yl]-4-methyl-3-{[(6-phenylpyrazin-2-yl)amino]methyl}benzamide, (157) 5-({[5-(cyclopropylethynyl)pyridin-3-yl]amino}methyl)-N-[(1S,2S)-2-hydroxycyclohexyl]-6-methylpyridine-3-carboxamide, (158) N-[3-({[6-(3,4-dimethoxyphenyl)pyrazin-2-yl]amino}methyl)phenyl]-N'-[(1R,2S)-2-hydroxycyclohexyl]urea, (159) N-[(1R,2S)-2-hydroxycyclohexyl]-N'-[3-({[5-(pyrimidin-2-yl)pyridin-3-yl]amino}methyl)phenyl]urea, (160) N-[2-fluoro-5-({[5-(pyrimidin-2-yl)pyridin-3-yl]amino}methyl)phenyl]-N'-[(1R,2S)-2-hydroxycyclohexyl]urea, (161) N-[4-fluoro-3-({[5-(pyrimidin-2-yl)pyridin-3-yl]amino}methyl)phenyl]-N'-[(1R,2S)-2-hydroxycyclohexyl]urea, (162) N-[(1R,2S)-2-hydroxycyclohexyl]-N'-[4-methyl-3-({[5-(pyrimidin-2-yl)pyridin-3-yl]amino}methyl)phenyl]urea, (163) N-[(1R,2S)-2-hydroxycyclohexyl]-N'-[2-methyl-5-({[5-(pyrimidin-2-yl)pyridin-3-yl]amino}methyl)phenyl]urea, (164) N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-{1-[(6-phenylpyrazin-2-yl)amino]ethyl}benzamide, (165) 3-[([3,3'-bipyridyl]-5-yl)methoxy]-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide, (166) N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-{[5-(pyrimidin-2-yl)pyridin-3-yl]methoxy}benzamide, (167) 4-chloro-N-[(1S,2S)-2-hydroxycyclohexyl]-3-{[5-(pyrimidin-2-yl)pyridin-3-yl]methoxy}benzamide, (168) 3-{[([3,3'-bipyridyl]-5-yl)oxy]methyl}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide, (169) N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-({[5-(pyrimidin-2-yl)pyridin-3-yl]oxy}methyl)benzamide, (170) 4-chloro-N-[(1S,2S)-2-hydroxycyclohexyl]-3-({[5-(pyrimidin-2-yl)pyridin-3-yl]oxy}methyl)benzamide, (171) N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-{1-[5-(pyrimidin-2-yl)pyridin-3-yl]ethoxy}benzamide, (172) N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-[1-(5-phenylpyridin-3-yl)ethoxy]benzamide, (173) N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-[(E)-2-(5-phenylpyridin-3-yl)vinyl]benzamide, (174) N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-[2-(5-phenylpyridin-3-yl)ethyl]benzamide, (175) N-[(1S,2S)-2-Hydroxycyclohexyl]-4-methyl-3-{[methyl(5-phenylpyridin-3-yl)amino]methyl}benzamide, (176) 3-{[ethyl(5-phenylpyridin-3-yl)amino]methyl}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide, (177) 3-[(Z)-2-([2,3'-bipyridyl]-5'-yl)-2-fluorovinyl]-4-fluoro-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide, (178) 4-fluoro-3-{(Z)-2-fluoro-2-[5-(pyrimidin-2-yl)pyridin-3-yl]vinyl}-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide, (179) 3-[(Z)-2-fluoro-2-(imidazo[1,2-b]pyridazin-3-yl)vinyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide, (180) 5-[(Z)-2-([2,3'-bipyridyl]-5'-yl)-2-fluorovinyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-6-methylpyridine-3-carboxamide, (181) 3-[(Z)-2-fluoro-2-{5-[(4-methylpiperazin-1-yl)methyl]pyridin-3-yl}vinyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide, (182) 3-[(Z)-2-fluoro-2-{5-[(morpholin-4-yl)methyl]pyridin-3-yl}vinyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide, (183) 3-[(Z)-2-{6-[(cyclopropylmethyl)amino]pyridin-3-yl}-2-fluorovinyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide, (184) 4-fluoro-3-{(Z)-2-fluoro-2-[5-(morpholin-4-yl)pyridin-3-yl]vinyl}-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide, (185) 4-fluoro-3-[(Z)-2-fluoro-2-{5-[(oxan-4-yl)amino]pyridin-3-yl}vinyl]-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide, (186) 4-fluoro-3-[(Z)-2-fluoro-2-{5-[(4-methylpiperazin-1-yl)methyl]pyridin-3-yl}vinyl]-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide, (187) 5-{(Z)-2-[5-(cyclopropylmethoxy)pyridin-3-yl]-2-fluorovinyl}-N-[(1S,2S)-2-hydroxycyclohexyl]-6-methylpyridine-3-carboxamide, (188) 5-{(Z)-2-fluoro-2-[5-(morpholin-4-yl)pyridin-3-yl]vinyl}-N-[(1S,2S)-2-hydroxycyclohexyl]-6-methylpyridine-3-carboxamide, (189) 5-[(Z)-2-(6-aminopyridin-3-yl)-2-fluorovinyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-6-methylpyridine-3-carboxamide, (190) 5-[(Z)-2-(2-aminopyrimidin-5-yl)-2-fluorovinyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-6-methylpyridine-3-carboxamide, (191) 3-[(Z)-2-(6-aminopyridin-3-yl)-2-fluorovinyl]-4-fluoro-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide, (192) 3-[(Z)-2-(2-aminopyrimidin-5-yl)-2-fluorovinyl]-4-fluoro-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide, (193) 3-[(Z)-2-fluoro-2-{5-[(1-methylpiperidin-4-yl)amino]pyridin-3-yl}vinyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide, (194) 3-[(Z)-2-{5-[(4-ethylpiperazin-1-yl)methyl]pyridin-3-yl}-2-fluorovinyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide, (195) 5-[(Z)-2-fluoro-2-{5-[(oxetan-3-yl)amino]pyridin-3-yl}vinyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-6-methylpyridine-3-carboxamide, (196) 4-fluoro-3-[(Z)-2-fluoro-2-{5-[(oxetan-3-yl)amino]pyridin-3-yl}vinyl]-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide, (197) 3-[(Z)-2-(6-{[2-(dimethylamino)ethyl]amino}pyridin-3-yl)-2-fluorovinyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide, (198) 3-[(Z)-2-(5-{[2-(dimethylamino)ethyl]amino}pyridin-3-yl)-2-fluorovinyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide, (199) 5-[(Z)-2-{6-[(cyclopropylmethyl)amino]pyridin-3-yl}-2-fluorovinyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-6-methylpyridine-3-carboxamide, (200) 3-[(Z)-2-fluoro-2-{5-[(4-methylpiperazin-1-yl)methyl]pyridin-3-yl}vinyl]-N-[(1S,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]-4-methylbenzamide, (201) 3-[(Z)-2-fluoro-2-{5-[(4-methylpiperazin-1-yl)methyl]pyridin-3-yl}vinyl]-N-(2-hydroxy-3,3-dimethylbutyl)-4-methylbenzamide, (202) 3-[(Z)-2-{2-[(cyclopropylmethyl)amino]pyrimidin-5-yl}-2-fluorovinyl]-4-fluoro-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide, (203) 3-{(Z)-2-[2-(cyclopropylamino)pyrimidin-5-yl]-2-fluorovinyl}-4-fluoro-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide, (204) 3-[(Z)-2-(2-amino-4-methylpyrimidin-5-yl)-2-fluorovinyl]-4-fluoro-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide, (205) 4-fluoro-3-{(Z)-2-fluoro-2-[2-(methylamino)pyrimidin-5-yl]vinyl}-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide, (206) 3-[(Z)-2-(5-aminopyrazin-2-yl)-2-fluorovinyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide, and (207) 4-Fluoro-3-[(Z)-2-fluoro-2-(5-fluoropyridin-3-yl)vinyl]-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide or a pharmaceutically acceptable salt or solvate thereof.

[0018] (Item 5) The compound according to item 1, which is selected from the following (1) to (15): (1) 2-(cyclopropylmethyl)-N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)-1,3-thiazole-5-carboxamide, (2) 5-[cyclopropyl(methyl)amino]-N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)pyridine-3-carboxamide, (3) 5-(3-fluorophenyl)-N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)pyridine-3-carboxamide, (4) 5-(cyclopropylmethoxy)-N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)pyridine-3-carboxamide, (5) 5-ethoxy-N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)pyridine-3-carboxamide, (6) 3-{[(2-aminopyrimidin-5-yl)methyl]amino}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide, (7) N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-{[(pyrazolo[1,5-a]pyrimidin-3-yl)methyl]amino}benzamide, (8) N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-[({2-[(oxan-4-yl)amino]pyrimidin-5-yl}methyl)amino]benzamide, (9) N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-({[6-(1H-1,2,3-triazol-1-yl)pyridin-3-yl]methyl}amino)benzamide, (10) 3-{[([2,3'-bipyridyl]-5'-yl)amino]methyl}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide, (11) 5-[(Z)-2-(6-aminopyridin-3-yl)-2-fluorovinyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-6-methylpyridine-3-carboxamide, (12) 3-[(Z)-2-{5-[(4-ethylpiperazin-1-yl)methyl]pyridin-3-yl}-2-fluorovinyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide, (13) 4-fluoro-3-{(Z)-2-fluoro-2-[2-(methylamino)pyrimidin-5-yl]vinyl}-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide, (14) 3-[(Z)-2-(5-aminopyrazin-2-yl)-2-fluorovinyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide, and (15) 4-fluoro-3-[(Z)-2-fluoro-2-(5-fluoropyridin-3-yl)vinyl]-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide or a pharmaceutically acceptable salt or solvate thereof.

[0019] (Item 6) A pharmaceutical composition comprising the compound according to any one of items 1 to 5 or a pharmaceutically acceptable salt or solvate thereof as an active ingredient.

[0020] (Item 7) A PDGF receptor kinase inhibitor comprising the compound according to any one of items 1 to 5 or a pharmaceutically acceptable salt or solvate thereof as an active ingredient.

[0021] (Item 8) A therapeutic agent for pulmonary hypertension, scleroderma, asthma, bronchiolitis obliterans, pulmonary fibrosis, acute myeloid leukemia (AML), hypereosinophilic syndrome, T-lymphocytic leukemia, chronic myelomonocytic leukemia (CMML), chronic myeloid leukemia (CML), chronic eosinophilic leukemia, dermatofibrosarcoma protuberans, glioma, ovarian cancer, vascular restenosis, atherosclerosis / arteriosclerosis obliterans, moyamoya disease (idiopathic circle of Willis occlusion), leiomyoma, lymphangioleiomyomatosis or age-related macular degeneration (AMD), wherein PDGF receptor kinase is involved, and the therapeutic agent comprises the compound according to any one of items 1 to 5 or a pharmaceutically acceptable salt or solvate thereof as an active ingredient.

[0022] Advantageous Effects of the Invention Since the compounds of the present invention inhibit PDGF receptor kinase, they are useful as therapeutic agents for diseases in which PDGF receptor kinase is involved (e.g., respiratory diseases, cancer, smooth muscle proliferative diseases, vascular proliferative diseases, autoimmune / inflammatory diseases, metabolic diseases, vascular occlusive diseases, etc.). DETAILED DESCRIPTION

[0023] The meaning of each term used in this specification will be described below. Unless otherwise specified, each term is used with the same meaning whether used alone or in combination with other terms.

[0024] The term "halogen atom" refers to a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.

[0025] Examples of the "alkyl group" may include, for example, a straight or branched alkyl group having 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, and more preferably 1 to 3 carbon atoms. Specific examples thereof may include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, sec-pentyl, 1-ethylpropyl, 1,2-dimethylpropyl, tert-pentyl, 2-methylbutyl, isopentyl, neopentyl, n-hexyl, sec-hexyl, 1-ethylbutyl, isohexyl, neohexyl, 1,1-dimethylbutyl, 2-ethylbutyl, 1,2,2-trimethylpropyl, 2,2-dimethylbutyl, and the like.

[0026] As the alkyl moiety in the "monoalkylamino", "alkylcarbonyloxy", "monoalkylamino", "dialkylamino", "alkylcarbonylamino", "alkylsulfonyl", "aminoalkyl" and "alkylcarbonyl", there can be mentioned the same "alkyl" as mentioned above.

[0027] The term "alkenyl" refers to a straight or branched hydrocarbon group having one or more double bonds at any position and having 2 to 10 carbon atoms, preferably 2 to 8 carbon atoms, more preferably 2 to 6 carbon atoms, and further preferably 2 to 4 carbon atoms. Specific examples thereof may include vinyl, allyl, 2-methylpropenyl, propenyl, isopropenyl, butenyl, isobutenyl, isoprenyl, butadienyl, pentenyl, isopentenyl, pentadienyl, hexenyl, isohexenyl, hexadienyl, etc.

[0028] The term "amino" refers to -NH2.

[0029] The term "aminoalkyl" refers to a group in which a hydrogen atom bonded to a carbon atom in the above-mentioned "alkyl" is substituted by an amino group. Specific examples thereof may include, for example, aminomethyl, 1-aminoethyl, 2-aminoethyl, 1-aminopropyl, 2-aminopropyl, 2-aminopropyl-2-yl, 3-aminopropyl, and the like.

[0030] The term "monoalkylamino" refers to a group in which one hydrogen atom bonded to the nitrogen atom in the amino group is substituted with the above-mentioned "alkyl". Specific examples may include methylamino, ethylamino, isopropylamino and the like.

[0031] The term "hydroxyalkyl" refers to a group in which a hydrogen atom bonded to a carbon atom in the above-mentioned "alkyl" is substituted by a hydroxyl group. Specific examples thereof may include, for example, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1-hydroxypropyl, 2-hydroxypropyl, and the like.

[0032] The term "alkylcarbonyl" refers to a group in which the above-mentioned "alkyl" is bonded to a carbonyl group. Examples thereof may include, for example, methylcarbonyl, ethylcarbonyl, propylcarbonyl, isopropylcarbonyl, tert-butylcarbonyl, isobutylcarbonyl, sec-butylcarbonyl, pentylcarbonyl, isopentylcarbonyl, hexylcarbonyl, and the like.

[0033] The term "haloalkyl" refers to a group in which the hydrogen atom in the above-mentioned "alkyl" is substituted by the above-mentioned "halogen atom". Specific examples thereof may include, for example, fluoromethyl, chloromethyl, fluoroethyl, difluoromethyl, dichloromethyl, difluoroethyl, trifluoromethyl, trichloromethyl, trifluoroethyl, etc.

[0034] The term "alkoxy" refers to a group in which the above-mentioned "alkyl" is bonded to an oxygen atom. Examples thereof may include, for example, a straight or branched alkoxy group having 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms. Specific examples thereof may include, for example, a methoxy group, an ethoxy group, a n-propoxy group, an isopropoxy group, a n-butoxy group, an isobutoxy group, a sec-butoxy group, a tert-butoxy group, a n-pentoxy group, a n-hexoxy group, and the like.

[0035] As the alkoxy moiety in the "haloalkoxy group", the same "alkoxy group" as mentioned above can be mentioned.

[0036] Examples of "aryl" may include, for example, monocyclic to tricyclic aromatic hydrocarbon groups having 6 to 14 carbon atoms. Specific examples thereof may include phenyl, 1-naphthyl, 2-naphthyl, 1-anthryl, 2-anthryl, 9-anthryl, 1-phenanthrenyl, 2-phenanthrenyl, 3-phenanthrenyl, 4-phenanthrenyl, 10-phenanthrenyl, etc. Among them, phenyl is preferred.

[0037] Examples of the "cycloalkyl group" may include monocyclic to tricyclic cyclic non-aromatic hydrocarbon groups, and specific examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.

[0038] The above-mentioned "non-aromatic carbocyclic group" may be a bridged hydrocarbon group. Examples of such a bridged hydrocarbon group may include, for example, the following: Bicyclo[2.2.1]heptyl (e.g., bicyclo[2.2.1]hept-1-yl, bicyclo[2.2.1]hept-2-yl and bicyclo[2.2.1]hept-7-yl); Bicyclo[1.1.1]pentyl (e.g., bicyclo[1.1.1]pent-1-yl and bicyclo[1.1.1]pent-2-yl); Bicyclo[4.1.0]heptyl (e.g., bicyclo[4.1.0]hept-1-yl, bicyclo[4.1.0]hept-2-yl, bicyclo[4.1.0]hept-3-yl and bicyclo[4.1.0]hept-7-yl); Bicyclo[2.2.2]octyl (e.g., bicyclo[2.2.2]oct-1-yl and bicyclo[2.2.2]oct-2-yl); Bicyclo[3.1.1]heptyl (e.g., bicyclo[3.1.1]hept-1-yl, bicyclo[3.1.1]hept-2-yl, bicyclo[3.1.1]hept-3-yl and bicyclo[3.1.1]hept-6-yl); and ·Cuban-1-yl.

[0039] The above-mentioned "non-aromatic carbocyclic group" may be a spirocyclic group. Examples of such spirocyclic groups may include, for example, the following: · spiro[3.3]heptyl (eg, spiro[3.3]hept-1-yl and spiro[3.3]hept-2-yl); Spiro[4.4]nonyl (e.g., spiro[4.4]non-1-yl and spiro[4.4]non-2-yl); spiro[5.5]undecyl (e.g., spiro[5.5]undec-1-yl, spiro[5.5]undec-2-yl, and spiro[5.5]undec-3-yl); and - Spiro[2.5]octyl (eg, spiro[2.5]oct-1-yl, spiro[2.5]oct-4-yl, spiro[2.5]oct-5-yl and spiro[2.5]oct-6-yl).

[0040] Examples of the "heteroaryl group" may include, for example, a monocyclic to tricyclic aromatic ring having 6 to 14 carbon atoms and having 1 to 3 heteroatoms selected from nitrogen atoms, oxygen atoms and sulfur atoms as constituent atoms. Specific examples thereof may include, for example, the following: Furyl (e.g., 2-furyl and 3-furyl); · Thienyl (e.g., 2-thienyl and 3-thienyl); · pyrrolyl (e.g., 1-pyrrolyl, 2-pyrrolyl, and 3-pyrrolyl); Imidazolyl (e.g., 1-imidazolyl, 2-imidazolyl, and 4-imidazolyl); · pyrazolyl (e.g., 1-pyrazolyl, 3-pyrazolyl and 4-pyrazolyl); · triazolyl (e.g., 1,2,4-triazol-1-yl, 1,2,4-triazol-3-yl and 1,2,4-triazol-4-yl); Tetrazolyl (e.g., 1-tetrazolyl, 2-tetrazolyl, and 5-tetrazolyl); Oxazolyl (e.g., 2-oxazolyl, 4-oxazolyl and 5-oxazolyl); Isoxazolyl (e.g., 3-isoxazolyl, 4-isoxazolyl and 5-isoxazolyl); Oxadiazolyl (e.g., 1,3,4-oxadiazol-2-yl); · thiazolyl (e.g., 2-thiazolyl, 4-thiazolyl and 5-thiazolyl); · thiadiazolyl (e.g., 1,3,4-thiadiazolyl, 1,2,4-thiadiazolyl and 1,2,3-thiadiazolyl); · isothiazolyl (e.g., 3-isothiazolyl, 4-isothiazolyl and 5-isothiazolyl); · pyridyl (e.g., 2-pyridyl, 3-pyridyl and 4-pyridyl); · pyridazinyl (e.g., 3-pyridazinyl and 4-pyridazinyl); · pyrimidinyl (e.g., 2-pyrimidinyl, 4-pyrimidinyl and 5-pyrimidinyl); · pyrazinyl (e.g., 2-pyrazinyl); benzothiadiazolyl (e.g., 1,2,3-benzothiadiazol-4-yl, 1,2,3-benzothiadiazol-5-yl, 2,1,3-benzothiadiazol-4-yl and 2,1,3-benzothiadiazol-5-yl); benzothiazolyl (e.g., benzothiazol-2-yl, benzothiazol-4-yl, benzothiazol-5-yl, benzothiazol-6-yl and benzothiazol-7-yl); Indolyl (e.g., indol-3-yl, indol-4-yl, indol-5-yl, indol-6-yl and indol-7-yl); benzothiophene (e.g., 1-benzothiophene-2-yl, 1-benzothiophene-3-yl, 1-benzothiophene-4-yl, 1-benzothiophene-5-yl, 1-benzothiophene-6-yl and 1-benzothiophene-7-yl); 1,1-dioxo-1-benzothiophene (e.g., 1,1-dioxo-1-benzothiophene-2-yl, 1,1-dioxo-1-benzothiophene-3-yl, 1,1-dioxo-1-benzothiophene-4-yl, 1,1-dioxo-1-benzothiophene-5-yl, 1,1-dioxo-1-benzothiophene-6-yl and 1,1-dioxo-1-benzothiophene-7-yl); Quinolinyl (quinolin-2-yl, quinolin-3-yl, quinolin-4-yl, quinolin-5-yl, quinolin-6-yl, quinolin-7-yl and quinolin-8-yl); and ·1,3-Benzoxazol-2-yl.

[0041] Examples of "heterocycloalkyl" may include a cyclic non-aromatic heterocyclic group having one ring or two or more rings and having one or more heteroatoms selected from nitrogen atoms, oxygen atoms and sulfur atoms in the ring, and the heteroatoms may be the same as or different from each other. Specific examples thereof may include, for example, the following: Oxetane (e.g., 2-oxetane and 3-oxetane); azetidinyl (e.g., 2-azetidinyl and 3-azetidinyl); Tetrahydropyranyl (e.g., 2-tetrahydropyranyl, 3-tetrahydropyranyl and 4-tetrahydropyranyl); 1,4-dioxane (e.g., 1,4-dioxane-2-yl); 1,3-dioxanyl (e.g., 1,3-dioxan-2-yl, 1,3-dioxan-4-yl, and 1,3-dioxan-5-yl); Pyrrolidinyl (e.g., 1-pyrrolidinyl, 2-pyrrolidinyl, and 3-pyrrolidinyl); Piperidinyl (e.g., 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, and 4-piperidinyl); Piperazinyl (e.g., 1-piperazinyl, 2-piperazinyl, and 3-piperazinyl); azepanyl (e.g., 1-azepanyl, 2-azepanyl, 3-azepanyl, and 4-azepanyl); · azocanyl (e.g., 1-azocyl, 2-azocyl, 3-azocyl, 4-azocyl, and 5-azocyl); Homopiperidinyl (e.g., 2-homopiperidinyl, 3-homopiperidinyl, and 4-homopiperidinyl); Morpholinyl (e.g., 2-morpholinyl, 3-morpholinyl, and 4-morpholinyl); · thiomorpholinyl (e.g., 2-thiomorpholinyl, 3-thiomorpholinyl, and 4-thiomorpholinyl); and Tetrahydrofuranyl (2-tetrahydrofuranyl and 3-tetrahydrofuranyl).

[0042] The above-mentioned "heterocycloalkyl" may be a bridged cyclic group. Examples of such a bridged cyclic group may include, for example, the following: 3-azabicyclo[3.2.1]octyl (e.g., 3-azabicyclo[3.2.1]oct-1-yl, 3-azabicyclo[3.2.1]oct-2-yl, 3-azabicyclo[3.2.1]oct-3-yl, 3-azabicyclo[3.2.1]oct-6-yl and 3-azabicyclo[3.2.1]oct-8-yl); Quinuclidinyl (e.g., quinuclidin-2-yl, quinuclidin-3-yl, and quinuclidin-4-yl); and 6-oxa-3-azabicyclo[3.1.1]heptyl (e.g., 6-oxa-3-azabicyclo[3.1.1]hept-1-yl, 6-oxa-3-azabicyclo[3.1.1]hept-2-yl, 6-oxa-3-azabicyclo[3.1.1]hept-3-yl and 6-oxa-3-azabicyclo[3.1.1]hept-7-yl).

[0043] The above-mentioned "heterocycloalkyl" may be a spirocyclic group. Examples of such spirocyclic groups may include, for example, the following: 6-azaspiro[2.5]oct-1-yl (e.g., 6-azaspiro[2.5]oct-1-yl, 6-azaspiro[2.5]oct-4-yl and 6-azaspiro[2.5]oct-5-yl); 3,9-diazaspiro[5.5]undec-1-yl (e.g., 3,9-diazaspiro[5.5]undec-1-yl, 3,9-diazaspiro[5.5]undec-2-yl and 3,9-diazaspiro[5.5]undec-3-yl); 2,7-diazaspiro[3.5]nonan-1-yl (e.g., 2,7-diazaspiro[3.5]nonan-1-yl, 2,7-diazaspiro[3.5]nonan-2-yl, 2,7-diazaspiro[3.5]nonan-5-yl, 2,7-diazaspiro[3.5]nonan-6-yl and 2,7-diazaspiro[3.5]nonan-7-yl); 7-azaspiro[3.5]nonyl (7-azaspiro[3.5]non-1-yl, 7-azaspiro[3.5]non-2-yl, 7-azaspiro[3.5]non-5-yl and 7-azaspiro[3.5]non-6-yl); and · 2,5-diazabicyclo[2.2.1]heptyl (2,5-diazabicyclo[2.2.1]hept-1-yl, 2,5-diazabicyclo[2.2.1]hept-2-yl, 2,5-diazabicyclo[2.2.1]hept-3-yl and 2,5-diazabicyclo[2.2.1]hept-7-yl).

[0044] Hereinafter, each symbol in formula [1] will be described.

[0045] R in formula [1] 1It is a hydrogen atom, a halogen atom, a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C2-C6 alkenyl group, a C2-C6 haloalkenyl group, a C2-C6 alkynyl group, a C2-C6 haloalkynyl group, a C1-C6 alkoxy group, a hydroxyl group, a carboxyl group, an alkylcarbonyloxy group, an amino group, a monoalkylamino group, a dialkylamino group, an alkylcarbonylamino group, a nitro group, an optionally substituted C3-C6 cycloalkyl group, an optionally substituted C3-C6 cycloalkenyl group, an optionally substituted heterocycloalkyl group, an optionally substituted aryl group or an optionally substituted heteroaryl group.

[0046] It is preferably a hydrogen atom, a halogen atom, a C1-C6 alkyl group, a C2-C6 alkenyl group, an amino group, a monoalkylamino group, a dialkylamino group, an alkylcarbonylamino group, an optionally substituted C3-C6 cycloalkyl group, an optionally substituted heterocycloalkyl group, an optionally substituted aryl group or an optionally substituted heteroaryl group.

[0047] It is more preferably an optionally substituted heterocycloalkyl group, an optionally substituted aryl group or an optionally substituted heteroaryl group.

[0048] It is further preferably oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, piperidinyl, piperazinyl, phenyl, pyridinyl, pyrimidinyl, pyrazinyl, isoquinolinyl, thienyl, pyrazolyl, imidazo[1,2-a]pyrazinyl, 1,2,3-triazolyl or imidazo[1,2-b]pyridazinyl.

[0049] R 2 For the key hand, -(CR a R b ) m -NR c -、-NR c -(CR a R b ) m -、-(CR a R b ) m -O-、-O-(CR a R b ) m -、-(CR a R b ) m -、-NR c -、-O-、-NR c -CO-NR c -、-CR a =CR b -or-C≡C-.

[0050] It is preferably a bonding hand, -(CR a R b ) m -NR c -、-(CR aR b ) m -O-、-(CR a R b ) m -、-NR c -、-O-、-NR c -CO-NR c -、-CR a =CR b -or-C≡C-.

[0051] It is more preferably a bonding hand, -(CR a R b ) m -NR c -or-NR c -.

[0052] R 2 R a It is a hydrogen atom, a halogen atom, a C1-C6 alkyl group or a C1-C6 haloalkyl group.

[0053] It is preferably a hydrogen atom, or a and R b The bonded carbon atoms together form C=O.

[0054] R 2 R b It is a hydrogen atom, a halogen atom, a C1-C6 alkyl group or a C1-C6 haloalkyl group.

[0055] It is preferably a hydrogen atom, or a and R b The bonded carbon atoms together form C=O.

[0056] R 2 Each R in c are independently a hydrogen atom, a C1-C6 alkyl group or a C1-C6 haloalkyl group.

[0057] It is preferably a hydrogen atom.

[0058] Het is a 5- to 10-membered heteroaryl group.

[0059] It is preferably thiazolyl, pyridyl, oxazolyl, pyrazinyl, pyrimidinyl, pyrazolyl, imidazothiazolyl, quinazolinyl, quinolinyl, 7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl, thieno[3,2-b]pyridinyl, imidazo[1,2-b]pyridazinyl, imidazo[1,2-a]pyrazinyl, pyrazolo[1,5-a]pyrimidinyl, 3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazinyl, pyrazolo[5,1-b]thiazolyl, pyrazolo[3,4-b]pyridinyl or pyrazolo[1,5-a]pyridinyl.

[0060] It is more preferably thiazolyl, pyridyl or pyrimidinyl.

[0061] L 1 For the key hand, -(CR a R b ) m -NR c -、-NR c -(CR a R b ) m -、-(CR a R b ) m -O-、-O-(CR a R b ) m -、-(CR a R b ) m -、-NR c -、-O-、-NR c -CO-NR c -、-CR a =CR b -or-C≡C-.

[0062] It is preferably a bonding hand, -(CR a R b ) m -NR c -、-NR c -(CR a R b ) m -、-(CR a R b ) m -O-、-O-(CR a R b ) m -、-(CR a R b ) m -、-NR c -、-CR a =CRb -or-C≡C-.

[0063] It is further preferably -(CR a R b ) m -NR c -、-NR c -(CR a R b ) m -、-NR c -、-CR a =CR b -or-C≡C-.

[0064] L 1 R a is a hydrogen atom, a halogen atom, a C1-C6 alkyl group or a C1-C6 haloalkyl group, or a and R b The bonded carbon atoms together form C=O.

[0065] It is preferably a hydrogen atom, a halogen atom or a C1-C6 alkyl group, or a and R b The bonded carbon atoms together form C=O.

[0066] L 1 R b is a hydrogen atom, a halogen atom, a C1-C6 alkyl group or a C1-C6 haloalkyl group, or a and R b The bonded carbon atoms together form C=O.

[0067] It is preferably a hydrogen atom, or a and R b The bonded carbon atoms together form C=O.

[0068] L 1 Each R in c are independently a hydrogen atom, a C1-C6 alkyl group or a C1-C6 haloalkyl group.

[0069] It is preferably a hydrogen atom or a C1-C6 alkyl group.

[0070] It is more preferably a hydrogen atom.

[0071] L 2 For-(CR a R b ) m -NR c -、-NR c -(CR a R b ) m -、-(CRa R b ) m -O-、-O-(CR a R b ) m -、-(CR a R b ) m -、-NR c -、-O-、-NR c -CO-NR c -、-CR a =CR b -or-C≡C-.

[0072] It is preferably a bonding hand, -(CR a R b ) m -NR c -or-NR c -CO-NR c -.

[0073] It is more preferably a bonding hand or -(CR a R b ) m -NR c -.

[0074] L 2 R a is a hydrogen atom, a halogen atom, a C1-C6 alkyl group or a C1-C6 haloalkyl group, or b Together with the carbon atom to which they are bonded they form C=O.

[0075] L 2 R a Preferred with R b Together with the carbon atom to which they are bonded they form C=O.

[0076] L 2 R b is a hydrogen atom, a halogen atom, a C1-C6 alkyl group or a C1-C6 haloalkyl group, or a Together with the carbon atom to which they are bonded they form C=O.

[0077] L 2 R b Preferred with R a Together with the carbon atom to which they are bonded they form C=O.

[0078] L 2 R c is a hydrogen atom, a C1-C6 alkyl group or a C1-C6 haloalkyl group.

[0079] Preferably, L2 Each R in c are independently hydrogen atoms.

[0080] R 4 is a hydrogen atom, a halogen atom or a methyl group.

[0081] It is preferably a halogen atom or a methyl group.

[0082] R 5 It is a hydrogen atom, a halogen atom, a hydroxyl group, an amino group, a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C1-C6 alkoxy group or a C1-C6 haloalkoxy group.

[0083] It is preferably a hydroxyl group.

[0084] R 6 is a hydrogen atom, a halogen atom, a C1-C6 alkyl group, a C1-C6 haloalkyl group or an optionally substituted phenyl group.

[0085] R 7 is a hydrogen atom, a halogen atom, a C1-C6 alkyl group, a C1-C6 haloalkyl group, a hydroxyalkyl group, an optionally substituted phenyl group or a C3-C6 cycloalkyl group.

[0086] Or, R 6 and R 7 Together with the carbon atom to which they are bonded, they form a C3-C6 cycloalkyl group, an optionally substituted aryl group or an optionally substituted heteroaryl group.

[0087] R 6 Preferred is a hydrogen atom, a C1-C6 alkyl group or an optionally substituted phenyl group.

[0088] R 7 Preferred is a C1-C6 alkyl group, a hydroxyalkyl group or an optionally substituted phenyl group.

[0089] Or, R 6 and R 7 Preferably, they form together with the carbon atom to which they are bonded a C3-C6 cycloalkyl group or an optionally substituted aryl group.

[0090] R 6 and R 7 It is further preferred that they form a C3-C6 cycloalkyl group together with the carbon atom to which they are bonded.

[0091] More specifically, the compounds of the present invention include the compounds shown in Table 1 below, depending on L 1 Type.

[0092] [Table 1] (In the table, R 1 , R 2 , R4 , R 5 , R 6 , R 7 , R c , L 1 , L 2 and Het are as defined above. ) 1-A: Compound [1], wherein L 1 For-(CR a R b ) m -NR c -, m is 1, and R a and R b Together with the carbon atom to which they are bonded they form C=O.

[0093] 1-B: Compound [1], wherein L 1 It is -C≡C-.

[0094] 1-C: Compound [1], wherein L 1 For-NR c -(CR a R b ) m -, m is 1, and R a and R b Together with the carbon atom to which they are bonded they form C=O.

[0095] 1-D: Compound [1], wherein L 1 For-NR c -.

[0096] 1-E: Compound [1], wherein L 1 For-(CR a R b ) m -NR c -, m is 1, and R a and R b Each is a hydrogen atom.

[0097] 1-F: Compound [1], wherein L 1 For-NR c -(CR a R b ) m -, m is 1, and R a and R b Each is a hydrogen atom.

[0098] [Table 2] (In the table, R 1 , R 2 , R4 , R 5 , R 6 , R 7 , R c , L 1 , L 2 and Het are as defined above. ) 1-G: Compound [1], wherein L 1 For-(CR a R b ) m -O-, m is 1, and R a and R b Each is a hydrogen atom.

[0099] 1-H: Compound [1], where L 1 O-(CR a R b ) m -, m is 1, and R a and R b Each is a hydrogen atom.

[0100] 1-I: Compound [1], wherein L 1 For-CR a =CR b -, and R a and R b Each is H.

[0101] 1-J: Compound [1], wherein L 1 For-(CR a R b ) m -, m is 2, and R a and R b Each is H.

[0102] 1-K: Compound [1], wherein L 1 For-CR a =CR b -, R a is a halogen atom, and R b For H.

[0103] R in compound 1-A 1 It is preferably H, a halogen atom, a C1-C6 alkyl group, a C2-C6 alkenyl group, a C1-C6 alkoxy group, an amino group, an alkylcarbonylamino group, an optionally substituted C3-C6 cycloalkyl group, an optionally substituted heterocycloalkyl group, an optionally substituted aryl group or an optionally substituted heteroaryl group, and is more preferably a C1-C6 alkyl group, a C1-C6 alkoxy group, an optionally substituted C3-C6 cycloalkyl group, an optionally substituted heterocycloalkyl group, an optionally substituted aryl group or an optionally substituted heteroaryl group.

[0104] R in compound 1-A 2 Preferably the bonding hand, -(CR a R b ) m -NR c -、-(CR a R b ) m -O-、-(CR a R b ) m -、-NR c -, -O- or -CR a =CR b -, and more preferably a bonding hand, -(CR a R b ) m -NR c -、-(CR a R b ) m -O-、-(CR a R b ) m -、-NR c -or-O-.

[0105] R in compound 1-A 2 The m of is preferably 0, 1 or 2, and more preferably 0 or 1.

[0106] Het in compound 1-A is preferably a thiazolyl group, a pyridyl group, an oxazolyl group or an imidazothiazolyl group, and more preferably a thiazolyl group or a pyridyl group.

[0107] R in compound 1-A 4 Preferred is a halogen atom or a methyl group, and more preferred is a methyl group.

[0108] L in compound 1-A 2 Preferably -(CR a R b ) m -NR c -.

[0109] L in compound 1-A 2 The m is preferably 1.

[0110] R in compound 1-A 5 A hydroxy group is preferred.

[0111] R in compound 1-A 6 Preferably H or C1-C6 alkyl, or with R 7 Together with the carbon atoms to which they are bonded, they form a C3-C6 cycloalkyl group, and more preferably with R 7Together with the carbon atom to which they are bonded, they form a C3-C6 cycloalkyl group.

[0112] R in compound 1-A 7 Preferably C1-C6 alkyl or optionally substituted phenyl, or with R 6 Together with the carbon atoms to which they are bonded, they form a C3-C6 cycloalkyl group, and more preferably with R 6 Together with the carbon atom to which they are bonded, they form a C3-C6 cycloalkyl group.

[0113] R in compound 1-B 1 It is preferably H, a halogen atom, a C1-C6 alkyl group, an amino group, an optionally substituted C3-C6 cycloalkyl group, an optionally substituted aryl group or an optionally substituted heteroaryl group, and more preferably a halogen atom, an optionally substituted C3-C6 cycloalkyl group, an optionally substituted aryl group or an optionally substituted heteroaryl group.

[0114] R in compound 1-B 2 Preferably a bonding hand or -(CR a R b ) m -NR c -, and more preferably a bonding hand.

[0115] R in compound 1-B 2 m is preferably 0 or 1.

[0116] Het in compound 1-B is preferably pyridyl or pyrazinyl.

[0117] R in compound 1-B 4 Preferred is a halogen atom or a methyl group, and more preferred is a methyl group.

[0118] L in compound 1-B 2 Preferably -(CR a R b ) m -NR c -.

[0119] L in compound 1-B 2 The m is preferably 1.

[0120] R in compound 1-B 5 A hydroxy group is preferred.

[0121] R in compound 1-B 6 Preferably, optionally substituted phenyl or R 7 Together with the carbon atoms to which they are bonded, they form a C3-C6 cycloalkyl group, and more preferably with R 7 Together with the carbon atom to which they are bonded, they form a C3-C6 cycloalkyl group.

[0122] R in compound 1-B 7 Preferably, hydroxyalkyl or R 6 Together with the carbon atoms to which they are bonded, they form a C3-C6 cycloalkyl group, and more preferably with R 6 Together with the carbon atom to which they are bonded, they form a C3-C6 cycloalkyl group.

[0123] R in compound 1-C 1 Preferred is H, a halogen atom, a C1-C6 alkyl group, a C2-C6 alkenyl group, a C1-C6 alkoxy group, an amino group, an alkylcarbonylamino group, an optionally substituted C3-C6 cycloalkyl group, an optionally substituted heterocycloalkyl group, an optionally substituted aryl group or an optionally substituted heteroaryl group, and more preferably an optionally substituted aryl group.

[0124] R in compound 1-C 2 Preferably the bonding hand, -(CR a R b ) m -NR c -、-(CR a R b ) m -O-、-(CR a R b ) m -、-NR c -, -O- or -CR a =CR b -, and more preferably a bonding hand.

[0125] Het in compound 1-C is preferably a thiazolyl group, a pyridyl group, an oxazolyl group or an imidazothiazolyl group, and more preferably a pyridyl group.

[0126] R in compound 1-C 4 Preferred is a halogen atom or a methyl group, and more preferred is a methyl group.

[0127] R in compound 1-C 5 A hydroxy group is preferred.

[0128] R in compound 1-C 6 Preferably H or C1-C6 alkyl, or with R 7 Together with the carbon atoms to which they are bonded, they form a C3-C6 cycloalkyl group, and more preferably with R 7 Together with the carbon atom to which they are bonded, they form a C3-C6 cycloalkyl group.

[0129] R in compound 1-C 7 Preferably C1-C6 alkyl or optionally substituted phenyl, or with R 6 Together with the carbon atoms to which they are bonded, they form a C3-C6 cycloalkyl group, and more preferably with R 6Together with the carbon atom to which they are bonded, they form a C3-C6 cycloalkyl group.

[0130] R in compound 1-D 1 It is preferably H, a halogen atom, a C1-C6 alkyl group, a C2-C6 alkenyl group, a C1-C6 alkoxy group, a monoalkylamino group, an optionally substituted C3-C6 cycloalkyl group, an optionally substituted heterocycloalkyl group, an optionally substituted aryl group or an optionally substituted heteroaryl group, and more preferably a monoalkylamino group or an optionally substituted heteroaryl group.

[0131] R in compound 1-D 2 Preferably the bonding hand, -(CR a R b ) m -NR c -、-(CR a R b ) m -O-、-(CR a R b ) m -、-NR c -, -O- or -CR a =CR b -, and more preferably a bonding hand.

[0132] Het in compound 1-D is preferably a pyrimidinyl group, a pyridinyl group or a quinazolinyl group, and more preferably a pyrimidinyl group.

[0133] R in compound 1-D 4 Preferred is a halogen atom or a methyl group, and more preferred is a methyl group.

[0134] R in compound 1-D 5 A hydroxy group is preferred.

[0135] R in compound 1-D 6 Preferably, it is an optionally substituted aryl group, or with R 7 Together with the carbon atoms to which they are bonded, they form a C3-C6 cycloalkyl group, and more preferably with R 7 Together with the carbon atom to which they are bonded, they form a C3-C6 cycloalkyl group.

[0136] R in compound 1-D 7 Preferably, hydroxyalkyl or optionally substituted phenyl, or with R 6 Together with the carbon atoms to which they are bonded, they form a C3-C6 cycloalkyl group, and more preferably with R 6 Together with the carbon atom to which they are bonded, they form a C3-C6 cycloalkyl group.

[0137] R in compound 1-E 1It is preferably H, a halogen atom, a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C2-C6 alkenyl group, a C2-C6 haloalkenyl group, a C2-C6 alkynyl group, a C2-C6 haloalkynyl group, a C1-C6 alkoxy group, a hydroxyl group, a carboxyl group, an alkylcarbonyloxy group, an amino group, an aminoalkyl group, a monoalkylamino group, a dialkylamino group, an alkylcarbonylamino group, a nitro group, an optionally substituted C3-C6 cycloalkyl group, an optionally substituted C3-C6 cycloalkenyl group, an optionally substituted heterocycloalkyl group, an optionally substituted aryl group or an optionally substituted heteroaryl group, and more preferably H, an amino group, an optionally substituted C3-C6 cycloalkyl group, an optionally substituted heterocycloalkyl group, an optionally substituted aryl group or an optionally substituted heteroaryl group.

[0138] R in compound 1-E 2 Preferably the bonding hand, -(CR a R b ) m -NR c -、-NR c -、-NR c -CO-NR c - or -C≡C-, and more preferably a bonding hand, -(CR a R b ) m -NR c -or-NR c -.

[0139] R in compound 1-E 2 m is preferably 0 or 1.

[0140] Het in compound 1-E is preferably thiazolyl, pyridyl, oxazolyl, pyrazinyl, pyrimidinyl, pyrazolyl, imidazothiazolyl, quinazolinyl, quinolinyl, 7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl, thieno[3,2-b]pyridinyl, 1H-pyrrolo[2,3-b]pyridinyl, imidazo[1,2-b]pyridazinyl, imidazole pyridyl, pyrazolyl, pyrimidinyl, pyrazolo[1,5-a]pyrimidinyl, 3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazinyl, pyrazolol[5,1-b]thiazolyl, pyrazolol[3,4-b]pyridinyl or pyrazolo[1,5-a]pyridinyl, and more preferably pyridyl, pyrazinyl, pyrimidinyl or pyrazolo[1,5-a]pyrimidinyl.

[0141] R in compound 1-E 4 Preferred is H, a halogen atom or a methyl group, and more preferred is a halogen atom or a methyl group.

[0142] L in compound 1-E 2 Preferably -(CR a R b )m -NR c -.

[0143] L in compound 1-E 2 The m is preferably 1.

[0144] R in compound 1-E 5 A hydroxy group is preferred.

[0145] R in compound 1-E 6 More preferably with R 7 Together with the carbon atom to which they are bonded, they form a C3-C6 cycloalkyl group.

[0146] R in compound 1-E 7 More preferably with R 6 Together with the carbon atom to which they are bonded, they form a C3-C6 cycloalkyl group.

[0147] R in compound 1-F 1 It is preferably a halogen atom, an optionally substituted C3-C6 cycloalkyl group, an optionally substituted aryl group or an optionally substituted heteroaryl group, and more preferably an optionally substituted C3-C6 cycloalkyl group, an optionally substituted aryl group or an optionally substituted heteroaryl group.

[0148] R in compound 1-F 2 It is preferably a bonding hand or -C≡C-, and is preferably a bonding hand.

[0149] Het in compound 1-F is preferably a pyridyl group or a pyrazinyl group, and more preferably a pyridyl group.

[0150] R in compound 1-F 4 Preferred is H, a halogen atom or a methyl group, and more preferred is H or a methyl group.

[0151] L in compound 1-F 2 Preferably -(CR a R b ) m -NR c -or-NR c -CO-NR c -.

[0152] L in compound 1-F 2 The m is preferably 1.

[0153] R in compound 1-F 5 A hydroxy group is preferred.

[0154] R in compound 1-F 6 Preferably, optionally substituted phenyl or R 7Together with the carbon atoms to which they are bonded, they form a C3-C6 cycloalkyl group, and more preferably with R 7 Together with the carbon atom to which they are bonded, they form a C3-C6 cycloalkyl group.

[0155] R in compound 1-F 7 Preferably, hydroxyalkyl or R 6 Together with the carbon atoms to which they are bonded, they form a C3-C6 cycloalkyl group, and more preferably with R 6 Together with the carbon atom to which they are bonded, they form a C3-C6 cycloalkyl group.

[0156] R in compound 1-G 1 Preferred is an optionally substituted aryl group or an optionally substituted heteroaryl group, and more preferred is an optionally substituted heteroaryl group.

[0157] R in compound 1-G 2 Preferably a bonding hand.

[0158] Het in compound 1-G is preferably pyridyl.

[0159] R in compound 1-G 4 Preferred is H, a halogen atom or a methyl group, and more preferred is a halogen atom or a methyl group.

[0160] R in compound 1-G 5 A hydroxy group is preferred.

[0161] R in compound 1-G 6 Preferred with R 7 Together with the carbon atom to which they are bonded, they form a C3-C6 cycloalkyl group.

[0162] R in compound 1-G 7 Preferred with R 6 Together with the carbon atom to which they are bonded, they form a C3-C6 cycloalkyl group.

[0163] R in compound 1-H 1 Preferred is optionally substituted heteroaryl.

[0164] R in compound 1-H 2 Preferably a bonding hand.

[0165] Het in compound 1-H is preferably pyridyl.

[0166] R in compound 1-H 4 Preferred is a halogen atom or a methyl group, and more preferred is a methyl group.

[0167] R in compound 1-H 5 A hydroxy group is preferred.

[0168] R in compound 1-H 6 Preferred with R 7 Together with the carbon atom to which they are bonded, they form a C3-C6 cycloalkyl group.

[0169] R in compound 1-H 7 Preferred with R 6 Together with the carbon atom to which they are bonded, they form a C3-C6 cycloalkyl group.

[0170] R in compound 1-I 1 Preferred is optionally substituted aryl.

[0171] R in compound 1-I 2 Preferably a bonding hand.

[0172] Het in compound 1-I is preferably pyridyl.

[0173] R in compound 1-I 4 Preferred is methyl.

[0174] R in compound 1-I 5 A hydroxy group is preferred.

[0175] R in compound 1-I 6 Preferred with R 7 Together with the carbon atom to which they are bonded, they form a C3-C6 cycloalkyl group.

[0176] R in compound 1-I 7 Preferred with R 6 Together with the carbon atom to which they are bonded, they form a C3-C6 cycloalkyl group.

[0177] R in compound 1-J 1 Preferred is optionally substituted aryl.

[0178] R in compound 1-J 2 Preferably a bonding hand.

[0179] Het in compound 1-J is preferably pyridyl.

[0180] R in compound 1-J 4 Preferred is methyl.

[0181] R in compound 1-J 5 A hydroxy group is preferred.

[0182] R in compound 1-J 6 Preferred with R 7 Together with the carbon atom to which they are bonded, they form a C3-C6 cycloalkyl group.

[0183] R in compound 1-J 7 Preferred with R6 Together with the carbon atom to which they are bonded, they form a C3-C6 cycloalkyl group.

[0184] R in compound 1-K 1 It is preferably H, a halogen atom, an amino group, a monoalkylamino group, a dialkylamino group, an optionally substituted cycloalkyl group, an optionally substituted heterocycloalkyl group or an optionally substituted heteroaryl group, and more preferably a halogen atom, an amino group, an optionally substituted cycloalkyl group, an optionally substituted heterocycloalkyl group or an optionally substituted heteroaryl group.

[0185] R in compound 1-K 2 Preferably the bonding hand, -(CR a R b ) m -NR c -、-(CR a R b ) m -O-、-(CR a R b ) m -or-NR c -, and more preferably a bonding hand, -(CR a R b ) m -NR c -、-(CR a R b ) m -or-NR c -.

[0186] Het in compound 1-K is preferably a pyridyl group, a pyrimidyl group, a pyrazinyl group or an imidazo[1,2-b]pyridazinyl group, and more preferably a pyridyl group, a pyrimidyl group or a pyrazinyl group.

[0187] R in compound 1-K 4 Preferred is a halogen atom or a methyl group.

[0188] L in compound 1-K 2 Preferably -(CR a R b ) m -NR c -.

[0189] L in compound 1-K 2 The m is preferably 1.

[0190] R in compound 1-K 5 A hydroxy group is preferred.

[0191] R in compound 1-K 6 Preferably C1-C6 alkyl, or with R 7Together with the carbon atoms to which they are bonded, they form a C3-C6 cycloalkyl group or an optionally substituted aryl group, and more preferably, R 7 Together with the carbon atom to which they are bonded, they form a C3-C6 cycloalkyl group.

[0192] R in compound 1-K 7 Preferably C1-C6 alkyl, or with R 6 Together with the carbon atoms to which they are bonded, they form a C3-C6 cycloalkyl group or an optionally substituted aryl group, and more preferably, R 6 Together with the carbon atom to which they are bonded, they form a C3-C6 cycloalkyl group.

[0193] The compound of the present invention can be produced, for example, by a known compound or an intermediate that can be easily synthesized according to the following method, the embodiments described later, or a known method. In the production of the compound of the present invention, when the raw material has a substituent that affects the reaction, the reaction is usually carried out after the raw material is protected with an appropriate protecting group in advance by a known method. After the reaction, the protecting group can be removed by a known method.

[0194] The compound represented by formula [1] can be used as a drug as is, but can also be prepared in the form of a pharmaceutically acceptable salt, solvate or a salt of the solvate used according to a known method. Examples of pharmaceutically acceptable salts include, for example, salts formed with inorganic acids (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid); salts formed with organic acids (e.g., acetic acid, malic acid, lactic acid, citric acid, tartaric acid, maleic acid, succinic acid, fumaric acid, p-toluenesulfonic acid, benzenesulfonic acid and methanesulfonic acid); salts formed with alkali metals (e.g., lithium, potassium and sodium); salts formed with alkaline earth metals (e.g., magnesium and calcium); and salts formed with organic bases (e.g., ammonium salts). These salts can be formed by commonly practiced methods.

[0195] For example, when the compound of the present invention is a hydrochloride, it can be obtained by dissolving the compound represented by formula [1] in a hydrogen chloride alcohol solution, a hydrogen chloride ethyl acetate solution, a hydrogen chloride 1,4-dioxane solution, a hydrogen chloride cyclopentyl methyl ether solution or a hydrogen chloride ether solution.

[0196] In the compounds of the present invention, for those having asymmetric carbons, respective stereoisomers and mixtures thereof are included in the present invention. For example, stereoisomers can be produced as follows: utilizing their alkalinity, according to known methods, using optically active acids (tartaric acid, dibenzoyltartaric acid, mandelic acid, 10-camphorsulfonic acid, etc.) to optically distinguish them from racemates, or using pre-prepared optically active compounds as raw materials. In addition, stereoisomers can also be produced by optical resolution using chiral columns or by asymmetric synthesis.

[0197] The compounds of the present invention are not limited to specific isomers but include all possible isomers and racemates.

[0198] (Method for producing the compound of the present invention) For example, the compound of the present invention can be produced from a known compound or an intermediate easily produced from a known compound according to the following method, the Examples described later, or a known method.

[0199] If the solvent, reagent and raw material used in each step of the following production method are commercially available, such commercially available products can be used as is. In addition, the compound obtained and the raw material used in each step in the following production method can form a salt, and can be converted to another type of salt or free form by a known method. Alternatively, when the compound obtained or the raw material used in each step in the following production method is a free form, they can be converted into required salts by a known method. The example of such a salt can include a salt similar to the salt used in the above-mentioned compound of the present invention.

[0200] The compound of the present invention represented by formula [1] or its pharmaceutically acceptable salt can form a solvate (e.g., a hydrate, etc.) and / or a crystalline polymorph, and the present invention also includes such various types of solvates and crystalline polymorphs. For "solvate", the compound represented by formula [1] can be coordinated with any number of solvent molecules (e.g., water molecules, etc.). By keeping the compound represented by formula [1] or its pharmaceutically acceptable salt in the atmosphere, it absorbs water, and the adsorbed water can adhere thereto or can form a hydrate. In addition, by recrystallizing the compound represented by formula [1] or its pharmaceutically acceptable salt, its crystalline polymorph can be formed.

[0201] In the production of the compound of the present invention, when the raw material has a substituent that can affect the reaction, a protecting group can be introduced into the substituent in advance by a known method, and by removing the protecting group as required after the reaction, the target compound can be obtained. In order to introduce such a protecting group and remove the protecting group, suitable conditions for use can be selected, such as in Wuts and Greene, "Greene's Protective Groups in Organic Synthesis", 4th edition, John Wiley & Sons Inc., 2006; or PJ Kocienski, "Protecting Groups", 3rd edition, Thieme, shown in 2005.

[0202] The compound obtained in each step of the following production method can be separated or purified according to a conventional method (such as solvent extraction, concentration, distillation, sublimation, recrystallization, reprecipitation and chromatography). Alternatively, the compound can be used as a reaction mixture or a crude product for subsequent steps.

[0203] Unless otherwise specified, the reaction of each step in the following production method is carried out according to a known method as described in, for example, RC Larock, "Comprehensive Organic Transformations: A Guide to Functional Group Preparations", 2nd edition, John Wiley & Sons, Inc., 1999; The Chemical Society of Japan, "Experimental Chemistry", 4th edition, Maruzen, 1992; L. Kuerti and B. Czako, "Strategic Applications of Named Reactions in Organic Synthesis", translated by Kiyoshi Tomioka, Kagaku-Dojin Publishing Company, Inc., 2006; G.S. Z. Weifel and M.H. Nantz, "Modern Organic Synthesis: An Introduction", translated by Tamejiro Hiyama, Kagaku-Dojin Publishing Company, Inc., 2009, or in a manner similar to that described in the Examples, and is appropriately modified or combined.

[0204] The above compound of the present invention (1-A: where L 1 For-(CR a R b ) m -NR c - and R a and R b Together with the carbon atoms to which they are bonded, they form C=O compounds; 1-B: L 1 A compound with -C≡C-; 1-C: where L 1 For-NR c -(CR a R b ) m - and R a and R bTogether with the carbon atoms to which they are bonded, they form C=O compounds; 1-D: where L 1 For-NR c -compounds; 1-E: where L 1 For-(CR a R b ) m -NR c - and R a and R b A compound which is independently H, a halogen atom, a C1-C6 alkyl group or a C1-C6 haloalkyl group; 1-F: L 1 NR c -(CR a R b ) m - and R a and R b Each is independently H, a halogen atom, a C1-C6 alkyl group or a C 1- C6 haloalkyl compounds; 1-G: where L 1 For-(CR a R b ) m -O- and R a and R b A compound which is independently H, a halogen atom, a C1-C6 alkyl group or a C1-C6 haloalkyl group; 1-H: L 1 O-(CR a R b ) m - and R a and R b A compound which is independently H, a halogen atom, a C1-C6 alkyl group or a C1-C6 haloalkyl group; 1-I: where L 1 For-CR a =CR b - and R a and R b Each of the compounds is H; 1-J: L 1 For-(CR a R b ) m - and R a and R b compounds each of which is H; and 1-K: where L 1 For-CR a =CR b -, Ra is a halogen atom and R b Compounds with H For example, it can be produced by the general synthesis method shown below. For extraction, purification, etc., treatments performed in ordinary organic chemical experiments can be performed.

[0205] Method for producing compound [1-A] [Formula 2] (In the formula, R 1 , R 2 , R 4 , R 5 , R 6 , R 7 , R c , Het and X are as defined above. ) Step 1 This step is a step of obtaining compound 1-A by condensing compound 1 or a reactive compound thereof and amine compound 2 in the presence of a condensing agent.

[0206] Examples of the reactive compound of Compound 1 may include, for example, those generally used in amide condensation reactions, such as acid halides (eg, acid chlorides and acid bromides), mixed acid anhydrides, imidazolides, and activated amides.

[0207] Suitably, the amounts of the condensing agent and the amine compound 2 used in this step should be in the range of 1 to 3 molar equivalents relative to the compound 1.

[0208] Examples of the condensing agent used in this step include, for example, 1,1'-carbonyldiimidazole (hereinafter referred to as "CDI"), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (hereinafter referred to as "EDCI"), diisopropylcarbodiimide (hereinafter referred to as "DIC"), diethyl cyanophosphate, O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (hereinafter referred to as "HBTU"), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (hereinafter referred to as "HATU"), and the like.

[0209] In this step, a base may be used as needed. Examples of the base that can be used may include, for example, organic bases such as TEA, DIPEA, N,N-dimethylaniline, and DBU.

[0210] Suitably, such a base is used in an amount ranging from 1 molar equivalent to 10 molar equivalents relative to compound 1.

[0211] In this step, additives such as 1-hydroxybenzotriazole (hereinafter referred to as "HOBt"), N-hydroxysuccinimide and 1-hydroxy-7-azabenzotriazole (hereinafter referred to as "HOAt") may also be added as needed.

[0212] When the above-mentioned additives are used in this step, it is suitable that the amount of such additives used is in the range of 0.1 molar equivalent to 3 molar equivalents relative to Compound 1.

[0213] Although there are no particular limitations on the solvent used as long as it does not participate in the reaction, examples thereof may include, for example, hydrocarbons such as toluene and xylene; ethers such as 1,4-dioxane, THF and DME; amides such as DMF and DMA; halogenated hydrocarbons such as dichloromethane and chloroform; nitriles such as acetonitrile and propionitrile; and mixed solvents thereof.

[0214] Suitably, the reaction temperature should usually be within the range of -20°C to 150°C, though it varies depending on the types of starting materials and reagents used. In addition, a microwave reaction apparatus may be used as necessary.

[0215] Suitably, the reaction time should usually be within the range of 0.1 hour to 72 hours, though it varies depending on the type of starting material used and the reaction temperature.

[0216] In addition, L 2 For-(CR a R b ) m -NR c (where R a and R b Together with the carbon atom to which they are bonded, they form C=O and m and R c Compound [1] (Compound 1-AA) as defined above can also be produced by the following method.

[0217] Method for producing compound [1-AA] [Formula 3] (In the formula, R 1 , R 2 , R 4 , R 5 , R 6 , R 7 , R c , Het and X are as defined above. R is an alkyl group, and examples thereof may include, for example, a methyl group, an ethyl group and an n-butyl group. ) Step 1 This step is a step of obtaining compound 1-AA by condensing compound 1 or a reactive compound thereof and amine compound 3 in the presence of a condensing agent. Compound 1-AA can be produced by the same method as step 1 of the method for producing the above-mentioned compound 1-A.

[0218] Step 2 This step is a step of obtaining compound 5 by condensing compound 1 or a reactive compound thereof and amine compound 4 in the presence of a condensing agent. Compound 5 can be produced by the same method as step 1 of the method for producing compound 1-A described above.

[0219] Step 3 This step is a step of obtaining compound 6 by hydrolyzing the ester portion of the above compound 5 in a suitable solvent in the presence of a suitable acid or base.

[0220] Examples of the acid used in this step may include inorganic acids such as hydrochloric acid and sulfuric acid; and organic acids such as trifluoroacetic acid (hereinafter referred to as "TFA"), methanesulfonic acid and toluenesulfonic acid. Examples of the base may include inorganic bases such as sodium hydroxide, potassium hydroxide and lithium hydroxide.

[0221] Suitably, the amount of the acid or base used in this step should be in the range of 1 molar equivalent to 10 molar equivalents relative to compound 5. If necessary, an excess amount of the acid or base may be used relative to compound 5.

[0222] Although there is no limitation on the solvent used as long as it does not participate in the reaction, examples thereof may include, for example, alcohols such as methanol, ethanol and 2-propanol; ethers such as THF, diethyl ether, 1,4-dioxane and DME; nitriles such as acetonitrile and propionitrile; ketones such as acetone; water; and mixed solvents thereof.

[0223] Although the reaction temperature varies depending on the types of starting materials and reagents used, the reaction can be performed usually in the range of 20° C. to 200° C., preferably 20° C. to 100° C. In addition, a microwave reaction apparatus can be used as necessary.

[0224] Suitably, the reaction time should usually be in the range of 0.5 hour to 4 days, though it varies depending on the type of starting material used and the reaction temperature.

[0225] Step 4 This step is a step of obtaining compound 1-AA by condensing compound 6 or a reactive compound thereof and amine compound 7 in the presence of a condensing agent, and compound 1-AA can be produced by the same method as step 1 of the method for producing the above-mentioned compound 1-A.

[0226] Method for producing compound [1-B] [Formula 4] (In the formula, R 1 , R 2 , R 4 , R 5 , R 6 , R 7 , R c , Het, X and L 2 As defined above. Y is a leaving group, and examples thereof may include, for example, a bromine atom, an iodine atom, a methanesulfonate group, and a trifluoromethanesulfonate group.) Step 1 This step is a step of obtaining Compound 1-B by subjecting Compound 8 and Compound 9 to a coupling reaction in the presence of a transition metal (eg, palladium).

[0227] For the present reaction, conditions generally used for coupling reactions using transition metals (particularly Sonogashira coupling reactions) can be applied, and it can be carried out by methods described in the literature (e.g., Sonogashira et al., J. Organomet. Chem. 2002, 653, 46-49; and Negishi et al., Chem. Rev. 2003, 103, 1979-2017).

[0228] Suitably, the amount of compound 9 used relative to compound 8 should be in the range of 0.5 molar equivalent to 3 molar equivalents.

[0229] There is no particular limitation on the organometallic catalyst used in the present reaction. Preferred examples of the organometallic catalyst may include metal catalysts such as tris(dibenzylideneacetone)bispalladium-chloroform adduct (hereinafter referred to as "Pd2(dba)3·CHCl3"), tris(dibenzylideneacetone)bispalladium (hereinafter referred to as "Pd2(dba)3"), tetrakistriphenylphosphine palladium (hereinafter referred to as "Pd(PPh3)4"), [1,1'-bis(diphenylphosphino)ferrocene]-dichloropalladium(II)-dichloromethane adduct (hereinafter referred to as "Pd(dppf)Cl2·CH2Cl2"), Bis(triphenylphosphine)palladium(II) dichloride (hereinafter referred to as "PdCl2(PPh3)2"), [1,1'-bis(di-tert-butylphosphino)ferrocene]-dichloropalladium(II) (hereinafter referred to as "Pd(dtbpf)Cl2"), bis(tricyclohexylphosphine)palladium(II) dichloride (hereinafter referred to as "PdCl2(PCy3)2"), palladium(II) acetate (hereinafter referred to as "Pd(OAc)2") and [1,3-bis(diphenylphosphino)propane]nickel(II) and mixtures of these metal catalysts.

[0230] Suitably, the amount of the transition metal used relative to compound 8 should be, for example, in the range of 0.01 molar equivalent to 0.3 molar equivalent.

[0231] In this step, a base or salt can be used as needed. Examples of the base or salt used may include, for example, a base or salt such as potassium carbonate, cesium carbonate, sodium carbonate, sodium bicarbonate, sodium acetate, potassium acetate, trisodium phosphate, tripotassium phosphate and solutions thereof; and triethylamine (hereinafter referred to as "TEA"), N,N-diisopropylethylamine (hereinafter referred to as "DIPEA"), lithium chloride and copper (I) iodide.

[0232] Suitably, the amount of the base used should be, for example, in the range of 1 to 4 molar equivalents relative to compound 8 .

[0233] In this step, appropriate ligands can be used as needed. Examples of ligands that can be used may include, for example, 1,1'-bis(diphenylphosphino)ferrocene (hereinafter referred to as "dppf"), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (hereinafter referred to as "Xantphos"), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (hereinafter referred to as "XPhos"), 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (hereinafter referred to as "BINAP"), 2-dicyclohexylphosphino-2',6'-diisopropylbiphenyl (hereinafter referred to as "RuPhos"), triphenylphosphine (hereinafter referred to as "PPh3"), tricyclohexylphosphine (hereinafter referred to as "PCy3"), etc.

[0234] Suitably, the amount of the ligand used should be, for example, in the range of 1 molar equivalent to 5 molar equivalents relative to the transition metal used.

[0235] Although there are no particular limitations on the solvent used in this step as long as it does not participate in the reaction, examples thereof may include, for example, hydrocarbons such as toluene and xylene; ethers such as 1,4-dioxane, tetrahydrofuran (hereinafter referred to as "THF") and dimethoxyethane (hereinafter referred to as "DME"); amides such as N,N-dimethylformamide (hereinafter referred to as "DMF"), N,N-dimethylacetamide (hereinafter referred to as "DMA") and N-methylpyrrolidone (hereinafter referred to as "NMP"); alcohols such as ethanol, 2-propanol and tert-butanol; water; and mixed solvents thereof.

[0236] Suitably, the reaction temperature should usually be in the range of 20° C. to 200° C., though it varies depending on the types of starting materials and reagents used. In addition, a microwave reaction apparatus may be used as necessary.

[0237] Suitably, the reaction time should usually be in the range of 0.1 hour to 24 hours, though it varies depending on the type of starting material used and the reaction temperature.

[0238] Where L 2 For-(CR a R b ) m -NR c -(where R a and R b Compounds which, together with the carbon atom to which they are bonded, form C=O) (Compound 1-BB) can also be produced as follows.

[0239] Method for producing compound [1-BB] [Formula 5] (In the formula, R 1 , R 2 , R 4 , R 5 , R 6 , R 7 , R c , Het, X, Y and R are as defined above. Z is a leaving group, and examples thereof may include, for example, trimethylsilyl and triethylsilyl. ) Step 1 This step is a step of obtaining alkyne compound 12 by subjecting compound 10 and compound 11 to coupling in the presence of a transition metal such as palladium, and alkyne compound 12 can be produced by the same method as step 1 of the method for producing compound 1-B.

[0240] Step 2 This step is a step of deprotecting Z to obtain compound 13, and can be performed with reference to, for example, Wuts and Greene, "Greene's Protective Groups in Organic Synthesis", 4th edition, John Wiley & Sons Inc., 2006; or PJ Kocienski, "Protecting Groups", 3rd edition, Thieme, 2005.

[0241] Step 3 This step is a step of obtaining Compound 15 by subjecting Compound 13 and Compound 14 to coupling in the presence of a transition metal such as palladium, and Compound 15 can be produced by the same method as Step 1 of the method for producing Compound 1-B.

[0242] Step 4 This step is a step of obtaining compound 16 by hydrolyzing the ester portion of compound 15 in a suitable solvent in the presence of a suitable acid or base, and compound 16 can be produced by the same method as step 3 of the method for producing compound 1-AA.

[0243] Step 5 This step is a step of obtaining compound 1-BB by condensing compound 16 or a reactive compound thereof and amine compound 17 in the presence of a condensing agent, and compound 1-BB can be produced by the same method as step 1 of the method for producing the above-mentioned compound 1-A.

[0244] Method for producing compound [1-C] [Formula 6] (In the formula, R 1 , R 2 , R 4 , R 5 , R 6 , R 7 , R c , Het and X are as defined above. ) Step 1 This step is a step of obtaining compound 1-C by condensing compound 19 or a reactive compound thereof and amine compound 18 in the presence of a condensing agent, and compound 1-C can be produced by the same method as step 1 of the method for producing the above-mentioned compound 1-A.

[0245] Method for producing compound [1-D] [Formula 7] (In the formula, R 1 , R 2 , R 4 , R 5 , R 6 , R 7 , R c , L 2 , Het and X are as defined above. Y is a leaving group, and examples thereof may include, for example, a bromine atom, an iodine atom and a trifluoromethanesulfonate. ) Step 1 This step is a step of obtaining Compound 1-D by subjecting Compound 20 and Compound 21 to a coupling reaction in the presence of a transition metal (eg, palladium).

[0246] For the present reaction, conditions generally used for coupling reactions using transition metals (particularly the coupling reaction of Buchwald et al.) can be applied, and it can be carried out by the methods described in the literature (e.g. Buchwald et al., J. Am. Chem. Soc. 1994, 116, 7901-7902.; Buchwald et al., Org. Synth. 2002, 78, 23-28.; and Hartwig et al., Acc. Chem. Res. 2008, 41, 1534-1544).

[0247] Suitably, the amount of compound 21 used relative to compound 20 should be in the range of 0.5 molar equivalent to 3 molar equivalents.

[0248] There is no particular limitation on the organometallic catalyst used in the present reaction. Preferred examples of the organometallic catalyst may include metal catalysts such as tris(dibenzylideneacetone)bispalladium-chloroform adduct (hereinafter referred to as "Pd2(dba)3·CHCl3"), tris(dibenzylideneacetone)bispalladium (hereinafter referred to as "Pd2(dba)3"), tetrakistriphenylphosphine palladium (hereinafter referred to as "Pd(PPh3)4"), [1,1'-bis(diphenylphosphino)ferrocene]-dichloropalladium(II)-dichloromethane adduct (hereinafter referred to as "Pd(dppf)Cl2·CH2Cl2"), Bis(triphenylphosphine)palladium(II) dichloride (hereinafter referred to as "PdCl2(PPh3)2"), [1,1'-bis(di-tert-butylphosphino)ferrocene]-dichloropalladium(II) (hereinafter referred to as "Pd(dtbpf)Cl2"), bis(tricyclohexylphosphine)palladium(II) dichloride (hereinafter referred to as "PdCl2(PCy3)2"), palladium(II) acetate (hereinafter referred to as "Pd(OAc)2") and [1,3-bis(diphenylphosphino)propane]nickel(II) and mixtures of these metal catalysts.

[0249] Suitably, the amount of the transition metal used relative to compound 20 should be, for example, in the range of 0.01 molar equivalent to 0.3 molar equivalent.

[0250] In this step, a base or salt can be used as needed. Examples of the base or salt used may include, for example, a base or salt such as potassium carbonate, cesium carbonate, sodium carbonate, sodium bicarbonate, sodium acetate, potassium acetate, trisodium phosphate, tripotassium phosphate and solutions thereof; and triethylamine (hereinafter referred to as "TEA"), N,N-diisopropylethylamine (hereinafter referred to as "DIPEA"), lithium chloride and copper (I) iodide.

[0251] Suitably, the amount of the base used should be in the range of 1 to 4 molar equivalents relative to compound 20, for example.

[0252] In this step, appropriate ligands can be used as needed. Examples of ligands that can be used may include, for example, 1,1'-bis(diphenylphosphino)ferrocene (hereinafter referred to as "dppf"), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (hereinafter referred to as "Xantphos"), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (hereinafter referred to as "XPhos"), 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (hereinafter referred to as "BINAP"), 2-dicyclohexylphosphino-2',6'-diisopropylbiphenyl (hereinafter referred to as "RuPhos"), triphenylphosphine (hereinafter referred to as "PPh3"), tricyclohexylphosphine (hereinafter referred to as "PCy3"), etc.

[0253] Suitably, the amount of the ligand used should be, for example, in the range of 1 molar equivalent to 5 molar equivalents relative to the transition metal used.

[0254] Although there are no particular limitations on the solvent used in this step as long as it does not participate in the reaction, examples thereof may include, for example, hydrocarbons such as toluene and xylene; ethers such as 1,4-dioxane, tetrahydrofuran (hereinafter referred to as "THF") and dimethoxyethane (hereinafter referred to as "DME"); amides such as N,N-dimethylformamide (hereinafter referred to as "DMF"), N,N-dimethylacetamide (hereinafter referred to as "DMA") and N-methylpyrrolidone (hereinafter referred to as "NMP"); alcohols such as ethanol, 2-propanol and tert-butanol; water; and mixed solvents thereof.

[0255] Suitably, the reaction temperature should usually be in the range of 20° C. to 200° C., though it varies depending on the types of starting materials and reagents used. In addition, a microwave reaction apparatus may be used as necessary.

[0256] Suitably, the reaction time should usually be in the range of 0.1 hour to 24 hours, though it varies depending on the type of starting material used and the reaction temperature.

[0257] Method for producing compound [1-E] [Formula 8] (In the formula, R 1 , R 2 , R 4 , R 5 , R 6 , R 7 , R a , R b , R c , L 2 , Het, X and Y are as defined above. ) Step 1 This step is a step of obtaining compound 1-E by subjecting compound 22 and compound 23 to a coupling reaction in the presence of a transition metal such as palladium, and compound 1-E can be produced by the same method as step 1 of the method for producing the above-mentioned compound 1-D.

[0258] Where L 1 For-(CR a R b ) m -NR c - and R a and R b Compounds each of which is H can also be produced as follows.

[0259] Method for producing compound [1-EE] [Formula 9] (In the formula, R 1 , R 2 , R 4 , R 5 , R 6 , R 7 , R c , L 2 , Het and X are as defined above. ) Step 1 Step 1 This step is a step of obtaining compound 1-EE by reductive amination reaction of compound 24 and compound 23, and can be performed according to a method known as reductive amination reaction. In this step, imine formation (first step) and reduction of the imine moiety (second step) can be performed sequentially.

[0260] Suitably, the amount of compound 23 used relative to compound 24 should be in the range of 1 molar equivalent to 2.5 molar equivalents.

[0261] In this step, an acid or a suitable Lewis acid may be used as required. Examples of the acid that can be used in the reaction may include, for example, acetic acid, etc., and examples of the Lewis acid that can be used may include, for example, tetraisopropyl orthotitanate.

[0262] When an acid is used in this step, it is suitable that the amount of the acid used is in the range of 2 to 3 molar equivalents relative to the amount of compound 24.

[0263] When a Lewis acid is used in this step, it is suitable that the amount of the Lewis acid used is in the range of 1.5 molar equivalents to 2 molar equivalents relative to the amount of compound 24.

[0264] Although the solvent used in this step is not particularly limited as long as it does not participate in the reaction, examples thereof may include, for example, hydrocarbons such as toluene and xylene; ethers such as 1,4-dioxane, THF and DME; halogenated hydrocarbons such as dichloromethane; and mixed solvents thereof.

[0265] In the present step, it is appropriate that the reaction temperature should usually be within a range of 0°C to 100°C, though it varies depending on the types of starting materials and reagents used.

[0266] In this step, it is appropriate that the reaction time should usually be in the range of 0.1 hour to 48 hours, though it varies depending on the type of raw material used and the reaction temperature.

[0267] Examples of the reducing agent used in this step may include, for example, sodium triacetoxyborohydride, sodium cyanoborohydride, and the like.

[0268] Suitably, the amount of the reducing agent used in this step should be in the range of 1 to 2 molar equivalents relative to compound 24.

[0269] Although the solvent used in this step is not particularly limited as long as it does not participate in the reaction, examples thereof may include, for example, hydrocarbons such as toluene and xylene; ethers such as 1,4-dioxane, THF and DME; halogenated hydrocarbons such as dichloromethane; and mixed solvents thereof.

[0270] Method for producing compound [1-F] [Formula 10] (In the formula, R 1 , R 2 , R 4 , R 5 , R 6 , R 7 , R a , R b , R c , L 2 , Het, X and Y are as defined above. ) Step 1 This step is a step of obtaining compound 1-F by reacting compound 25 with compound 26 in the presence of a base.

[0271] Suitably, the amount of compound 26 used relative to compound 25 should be in the range of 0.5 molar equivalent to 3 molar equivalents.

[0272] Examples of the base used in the present reaction may include pyridine, TEA, DIPEA, potassium carbonate and sodium bicarbonate.

[0273] Suitably, the amount of the base used should be in the range of 1 molar equivalent to 10 molar equivalents relative to compound 25.

[0274] Although there are no particular limitations on the solvent used as long as it does not participate in the reaction, examples thereof may include, for example, alcohols such as isopropanol, 1-butanol and 2-methoxyethanol; ethers such as THF and 1,4-dioxane; amides such as DMF, DMA and NMP; hydrocarbons such as benzene and toluene; dimethyl sulfoxide (hereinafter referred to as "DMSO"); acetonitrile; and a mixed solvent thereof.

[0275] In this step, it is appropriate that the reaction temperature should usually be in the range of 20° C. to 200° C., though it varies depending on the types of raw materials and reagents used. In addition, a microwave reaction apparatus may be used as necessary.

[0276] Suitably, the reaction time should usually be within the range of 1 hour to 24 hours, though it varies depending on the type of starting material used and the reaction temperature.

[0277] Where L 1 For-NR c -(CR a R b ) m - and R a and R b Compounds each of which is H can also be produced as follows.

[0278] Method for producing compound [1-FF] [Formula 11] (In the formula, R 1 , R 2 , R 4 , R 5 , R 6 , R 7 , R c , L 2 , Het and X are as defined above. ) Step 1 This step is a step of obtaining compound 1-FF by reductive amination reaction of compound 27 and compound 28, and compound 1-FF can be produced by the same method as step 1 of the method for producing the above-mentioned compound 1-EE.

[0279] Method for producing compound [1-G] [Formula 12] (In the formula, R 1 , R 2 , R 4, R 5 , R 6 , R 7 , R c , L 2 , Het and X are as defined above. ) Step 1 This step is a step of obtaining the ether compound 1-G by the Mitsunobu reaction of the alcohol compound 29 and the alcohol compound 30, and can be performed according to a known method.

[0280] This step is usually carried out in the presence of an azodicarboxylate reagent and a phosphine reagent in an appropriate solvent.

[0281] Suitably, the amount of compound 29 used relative to compound 30 should be in the range of 0.5 molar equivalents to 1.5 molar equivalents.

[0282] Examples of the azodicarboxylate reagent used may include, for example, diethyl azodicarboxylate (hereinafter referred to as "DEAD"), diisopropyl azodicarboxylate (hereinafter referred to as "DIAD"), bis(2-methoxyethyl) azodicarboxylate (hereinafter referred to as "DMEAD"), and the like.

[0283] Examples of the phosphine reagent used may include, for example, triphenylphosphine, tributylphosphine, and the like.

[0284] Suitably, the amount of the azodicarboxylate reagent used should be in the range of 1 to 2 molar equivalents relative to compound 29.

[0285] Suitably, the amount of the phosphine reagent used should be in the range of 1 to 2 molar equivalents relative to compound 29.

[0286] Although the solvent used is not particularly limited as long as it does not participate in the reaction, examples thereof may include, for example, hydrocarbons such as toluene and xylene; ethers such as 1,4-dioxane, THF, and DME; and mixed solvents thereof.

[0287] In the present step, it is appropriate that the reaction temperature should usually be within a range of 0°C to 100°C, though it varies depending on the types of starting materials and reagents used.

[0288] Suitably, the reaction time should usually be within the range of 0.5 hour to 24 hours, though it varies depending on the type of starting material used and the reaction temperature.

[0289] Method for producing compound [1-H] [Formula 13] (In the formula, R 1 , R 2 , R4 , R 5 , R 6 , R 7 , R c , L 2 , Het and X are as defined above. ) Step 1 This step is a step of obtaining ether compound 1-H by Mitsunobu reaction of alcohol compound 31 and alcohol compound 32, and compound 1-H can be produced by the same method as step 1 of the method for producing the above-mentioned compound 1-G.

[0290] Method for producing compound [1-I] [Formula 14] (In the formula, R 1 , R 2 , R 4 , R 5 , R 6 , R 7 , R c , L 2 , Het and X are as defined above. Y is a leaving group, and examples thereof may include, for example, a bromine atom, an iodine atom and a trifluoromethanesulfonate. ) Step 1 This step is a step of obtaining compound 1-I by subjecting compound 33 and compound 34 to a coupling reaction in the presence of a transition metal (eg, palladium).

[0291] For the present reaction, conditions generally used for coupling reactions using transition metals (particularly Heck reaction) can be applied, and it can be carried out by the methods described in the literature (e.g., Org. Synth. 2005, 81, 63-76.; Heck et al., J. Org. Chem. 1972, 37, 2320-2322.; and Beletskaya et al., Chem. Rev. 2000, 100, 3009-3066).

[0292] Suitably, the amount of compound 33 used relative to compound 34 should be in the range of 0.5 molar equivalent to 3 molar equivalents.

[0293] There is no particular limitation on the organometallic catalyst used in the present reaction. Preferred examples of the organometallic catalyst may include metal catalysts such as tris(dibenzylideneacetone)bispalladium-chloroform adduct (hereinafter referred to as "Pd2(dba)3·CHCl3"), tris(dibenzylideneacetone)bispalladium (hereinafter referred to as "Pd2(dba)3"), tetrakistriphenylphosphine palladium (hereinafter referred to as "Pd(PPh3)4"), [1,1'-bis(diphenylphosphino)ferrocene]-dichloropalladium(II)-dichloromethane adduct (hereinafter referred to as "Pd(dppf)Cl2·CH2Cl2"), Bis(triphenylphosphine)palladium(II) dichloride (hereinafter referred to as "PdCl2(PPh3)2"), [1,1'-bis(di-tert-butylphosphino)ferrocene]-dichloropalladium(II) (hereinafter referred to as "Pd(dtbpf)Cl2"), bis(tricyclohexylphosphine)palladium(II) dichloride (hereinafter referred to as "PdCl2(PCy3)2"), palladium(II) acetate (hereinafter referred to as "Pd(OAc)2") and [1,3-bis(diphenylphosphino)propane]nickel(II) and mixtures of these metal catalysts.

[0294] Suitably, the amount of the transition metal used should be, for example, in the range of 0.01 to 0.3 molar equivalents relative to compound 33 .

[0295] In this step, a base or salt can be used as needed. Examples of the base or salt used may include, for example, a base or salt such as potassium carbonate, cesium carbonate, sodium carbonate, sodium bicarbonate, sodium acetate, potassium acetate, trisodium phosphate, tripotassium phosphate and solutions thereof; and triethylamine (hereinafter referred to as "TEA"), N,N-diisopropylethylamine (hereinafter referred to as "DIPEA"), lithium chloride and copper (I) iodide.

[0296] Suitably, the amount of the base used should be in the range of 1 to 4 molar equivalents relative to compound 33, for example.

[0297] In this step, appropriate ligands can be used as needed. Examples of ligands that can be used may include, for example, 1,1'-bis(diphenylphosphino)ferrocene (hereinafter referred to as "dppf"), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (hereinafter referred to as "Xantphos"), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (hereinafter referred to as "XPhos"), 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (hereinafter referred to as "BINAP"), 2-dicyclohexylphosphino-2',6'-diisopropylbiphenyl (hereinafter referred to as "RuPhos"), triphenylphosphine (hereinafter referred to as "PPh3"), tricyclohexylphosphine (hereinafter referred to as "PCy3"), etc.

[0298] Suitably, the amount of the ligand used should be, for example, in the range of 1 molar equivalent to 5 molar equivalents relative to the transition metal used.

[0299] Although there are no particular limitations on the solvent used in this step as long as it does not participate in the reaction, examples thereof may include, for example, hydrocarbons such as toluene and xylene; ethers such as 1,4-dioxane, tetrahydrofuran (hereinafter referred to as "THF") and dimethoxyethane (hereinafter referred to as "DME"); amides such as N,N-dimethylformamide (hereinafter referred to as "DMF"), N,N-dimethylacetamide (hereinafter referred to as "DMA") and N-methylpyrrolidone (hereinafter referred to as "NMP"); alcohols such as ethanol, 2-propanol and tert-butanol; water; and mixed solvents thereof.

[0300] Suitably, the reaction temperature should usually be in the range of 20° C. to 200° C., though it varies depending on the types of starting materials and reagents used. In addition, a microwave reaction apparatus may be used as necessary.

[0301] Suitably, the reaction time should usually be in the range of 0.1 hour to 24 hours, though it varies depending on the type of starting material used and the reaction temperature.

[0302] Method for producing compound [1-K] [Formula 15] (In the formula, R 1 , R 2 , R 4 , R 5 , R 6 , R 7 , R a , L 2 , Het and X are as defined above. Y is a leaving group, and examples thereof may include, for example, a bromine atom, an iodine atom and a trifluoromethanesulfonate group. AA and R BB Each represents a hydroxyl group, or R AA and R BB Together they are -OC(CH3)2-C(CH3)2-O-, -O-(CH2)3-O- or O-CH2-C(CH3)2-CH2-O-. ) Step 1 This step is a step of obtaining compound 1-K by subjecting compound 35 and compound 36 to a coupling reaction in the presence of a transition metal (eg, palladium).

[0303] For the present reaction, conditions generally used for coupling reactions using transition metals (particularly Suzuki-Miyaura coupling reaction) can be applied, and it can be performed by the methods described in the literature (eg Suzuki et al., Chem. Rev., 1995, 95, 2457-2483).

[0304] Suitably, the amount of compound 36 used relative to compound 35 should be in the range of 0.5 molar equivalent to 3 molar equivalents.

[0305] There is no particular limitation on the organometallic catalyst used in the present reaction. Preferred examples of the organometallic catalyst may include metal catalysts such as tris(dibenzylideneacetone)bispalladium-chloroform adduct (hereinafter referred to as "Pd2(dba)3·CHCl3"), tris(dibenzylideneacetone)bispalladium (hereinafter referred to as "Pd2(dba)3"), tetrakistriphenylphosphine palladium (hereinafter referred to as "Pd(PPh3)4"), [1,1'-bis(diphenylphosphino)ferrocene]-dichloropalladium(II)-dichloromethane adduct (hereinafter referred to as "Pd(dppf)Cl2·CH2Cl2"), Bis(triphenylphosphine)palladium(II) dichloride (hereinafter referred to as "PdCl2(PPh3)2"), [1,1'-bis(di-tert-butylphosphino)ferrocene]-dichloropalladium(II) (hereinafter referred to as "Pd(dtbpf)Cl2"), bis(tricyclohexylphosphine)palladium(II) dichloride (hereinafter referred to as "PdCl2(PCy3)2)", palladium(II) acetate (hereinafter referred to as "Pd(OAc)2") and [1,3-bis(diphenylphosphino)propane]nickel(II) and mixtures of these metal catalysts.

[0306] Suitably, the amount of the transition metal used relative to compound 35 should be, for example, in the range of 0.01 molar equivalent to 0.3 molar equivalent.

[0307] In this step, a base or salt can be used as needed. Examples of the base or salt used may include, for example, a base or salt such as potassium carbonate, cesium carbonate, sodium carbonate, sodium bicarbonate, sodium acetate, potassium acetate, trisodium phosphate, tripotassium phosphate and solutions thereof; and triethylamine (hereinafter referred to as "TEA"), N,N-diisopropylethylamine (hereinafter referred to as "DIPEA"), lithium chloride and copper (I) iodide.

[0308] Suitably, the amount of the base used should be in the range of 1 molar equivalent to 4 molar equivalents relative to compound 35, for example.

[0309] In this step, appropriate ligands can be used as needed. Examples of ligands that can be used may include, for example, 1,1'-bis(diphenylphosphino)ferrocene (hereinafter referred to as "dppf"), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (hereinafter referred to as "Xantphos"), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (hereinafter referred to as "XPhos"), 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (hereinafter referred to as "BINAP"), 2-dicyclohexylphosphino-2',6'-diisopropylbiphenyl (hereinafter referred to as "RuPhos"), triphenylphosphine (hereinafter referred to as "PPh3"), tricyclohexylphosphine (hereinafter referred to as "PCy3"), etc.

[0310] Suitably, the amount of the ligand used should be, for example, in the range of 1 molar equivalent to 5 molar equivalents relative to the transition metal used.

[0311] Although there are no particular limitations on the solvent used in this step as long as it does not participate in the reaction, examples thereof may include, for example, hydrocarbons such as toluene and xylene; ethers such as 1,4-dioxane, tetrahydrofuran (hereinafter referred to as "THF") and dimethoxyethane (hereinafter referred to as "DME"); amides such as N,N-dimethylformamide (hereinafter referred to as "DMF"), N,N-dimethylacetamide (hereinafter referred to as "DMA") and N-methylpyrrolidone (hereinafter referred to as "NMP"); alcohols such as ethanol, 2-propanol and tert-butanol; water; and mixed solvents thereof.

[0312] Suitably, the reaction temperature should usually be in the range of 20° C. to 200° C., though it varies depending on the types of starting materials and reagents used. In addition, a microwave reaction apparatus may be used as necessary.

[0313] Suitably, the reaction time should usually be in the range of 0.1 hour to 24 hours, though it varies depending on the type of starting material used and the reaction temperature.

[0314] The compounds of the present invention have inhibitory activity against PDGF receptor kinase, as demonstrated in the following test examples. In addition, since the compounds of the present invention have inhibitory activity against PDGF receptor kinase, they are effectively used for respiratory diseases, cancer, smooth muscle proliferative diseases, vascular proliferative diseases, autoimmune / inflammatory diseases, metabolic diseases and vascular occlusive diseases.

[0315] Furthermore, the inhibitory activity of the compounds of the present invention against PDGF receptor kinase is highly selective over the inhibitory activity against KIT kinase, as demonstrated in the following test examples, and thus the compounds of the present invention can be expected to provide PDGF receptor kinase inhibitors with suppressed undesirable effects, such as myelosuppression.

[0316] Therefore, the compound of the present invention or a pharmaceutically acceptable salt thereof can be used as a preventive or therapeutic agent for diseases in which PDGF receptor kinase is involved, for example.

[0317] Examples of respiratory diseases to which the compound of the present invention or a pharmaceutically acceptable salt thereof can be applied may include pulmonary diseases and pulmonary hypertension. First, pulmonary hypertension is classified according to etiology and pathology as follows.

[0318] Pulmonary arterial hypertension (PAH); Pulmonary hypertension caused by left heart disease Left heart failure with preserved ejection fraction, Left heart failure with reduced ejection fraction, Valvular disease, and Congenital / acquired cardiovascular conditions leading to post-capillary PH; Pulmonary hypertension due to lung disease and / or hypoxemia due to the following conditions Chronic obstructive pulmonary disease (COPD), Interstitial (restrictive) lung disease, Other lung diseases involving a mixture of restrictive and obstructive symptoms, Hypoxic conditions caused by lung disease, and Developmental disabilities; Pulmonary hypertension caused by pulmonary artery occlusion Chronic thromboembolic pulmonary hypertension (CTEPH), and pulmonary hypertension due to the following diseases (sarcoma, angiosarcoma, malignant tumors, non-malignant tumors, vasculitis caused by connective tissue diseases, congenital pulmonary artery stenosis, parasites, etc., and pulmonary tumor thrombotic microangiopathy (PTTM)); and Pulmonary hypertension caused by multifactorial mechanisms with unknown details as indicated below Hematological diseases (chronic hemolytic anemia, myeloproliferative diseases, etc.), systemic and metabolic diseases (e.g., pulmonary Langerhans cell histiocytosis, Gaucher disease, glycogen storage disease, neurofibromatosis, sarcoidosis, etc.), Other (eg, chronic renal failure with or without dialysis, fibrosing mediastinitis, etc.) and Complex congenital heart malformations.

[0319] For example, the above-mentioned pulmonary arterial hypertension (PAH) includes the following: Idiopathic PAH; Hereditary PAH (especially abnormalities in BMPR2, TBX4, ACVRL1, ENG, SMAD9, KCNK3, SMAD1, CAV1, SMAD4, ATP13A3, SOX17, AQP1, GDF2, or unknown genes); Drug- and toxin-induced PAH; PAH caused by disease (here, "disease" includes, for example, connective tissue disease, HIV infection, portal hypertension, congenital shunt heart disease, and schistosomiasis); PAH long-term responders to calcium channel blockers, pulmonary veno-occlusive disease / pulmonary capillary hemangiomatosis (PVOD / PCH) (including PVOD / PCH with EIF2AK4 mutations); and Persistent pulmonary hypertension of the newborn (PPHN).

[0320] Examples of inflammatory diseases and autoimmune diseases to which the compounds of the present invention or pharmaceutically acceptable salts thereof can be applied may include scleroderma, asthma, bronchiolitis obliterans, pulmonary fibrosis, systemic lupus erythematosus (SLE), mixed connective tissue disease (MCTD), Sjögren's syndrome, polymyositis / dermatomyositis, Crohn's disease, ulcerative colitis, cytopenias, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), allergic rhinitis, allergic sinusitis, interstitial lung disease, idiopathic interstitial pneumonia, chronic obstructive pulmonary disease (COPD), combined pulmonary fibrosis and emphysema (CPFE), adult respiratory distress syndrome (ARDS), psoriasis, rheumatoid arthritis, mastocytosis, allergic syndrome, angioedema, erythema nodosum, erythema multiforme, cutaneous vasculitis, skin inflammation / diseases, urticaria, and allergic contact dermatitis.

[0321] Examples of cancers to which the compounds of the present invention or pharmaceutically acceptable salts thereof can be applied may include acute myeloid leukemia (AML), hypereosinophilic syndrome, T-lymphocytic leukemia, chronic myelomonocytic leukemia (CMML), chronic myeloid leukemia (CML), chronic eosinophilic leukemia, myelofibrosis, dermatofibrosarcoma protuberans, glioma, ovarian cancer, endometrial cancer, hepatocellular carcinoma, thyroid cancer, small cell lung cancer, non-small cell lung cancer, renal cancer, soft tissue sarcoma, neuroendocrine tumors, skin cancer, mesothelioma, bile duct cancer, head and neck squamous cell carcinoma, colorectal cancer, stromal tumors, adenocarcinoma, pancreatic cancer, mastocytosis and gastrointestinal stromal tumors (GIST).

[0322] Examples of smooth muscle proliferative diseases to which the compounds of the present invention or pharmaceutically acceptable salts thereof can be applied may include vascular restenosis, atherosclerosis / arteriosclerosis obliterans, moyamoya disease (idiopathic Willis circle occlusion), leiomyoma, lymphangioleiomyomatosis, Williams syndrome, tuberous sclerosis, angina pectoris, myocardial infarction, peripheral arterial disease, hypertrophic / dilated cardiomyopathy and systolic / diastolic cardiomyopathy.

[0323] Examples of vascular proliferative diseases to which the compound of the present invention or a pharmaceutically acceptable salt thereof can be applied may include age-related macular degeneration (AMD), Osler's disease (hereditary hemorrhagic telangiectasia), hemangioma, tumor angiogenesis, and arteriovenous fistula.

[0324] Examples of metabolic diseases to which the compound of the present invention or a pharmaceutically acceptable salt thereof can be applied may include diabetes (type 1 diabetes or type 2 diabetes).

[0325] The compound of the present invention can be used as a therapeutic agent for the above-mentioned various diseases in mammals (e.g., humans, mice, rats, rabbits, dogs, cats, cattle, horses, pigs and monkeys) as it is, or as a pharmaceutical composition containing, for example, 0.001% to 99.5%, preferably 0.1% to 90% of the compound, which is obtained by mixing the compound with a pharmacologically acceptable carrier or the like.

[0326] Although considering the patient's condition (such as age, body weight and the type and severity of the disease, route of administration), the type of the compound of the present invention (whether it is a salt and the type of salt), it is desirable to adjust the dosage as a drug, but it is generally suitable that for adults, in the case of oral administration, the effective amount of the compound of the present invention or its pharmaceutically acceptable salt should be in the range of 0.01mg to 5g / adult per day, preferably in the range of 1mg to 500mg / adult per day. In some cases, a smaller amount may be sufficient, or a larger amount may be required. Typically, the dosage can be administered once a day, or can be divided and administered several times a day, or in the case of intravenous administration, the dosage can be administered quickly or continuously within 24 hours.

[0327] One or more hydrogen, carbon and / or other atoms in the compounds of the present invention may be replaced by an isotope of hydrogen, carbon and / or other atoms. Examples of such isotopes include 2 H. 3 H. 11 C. 13 C. 14 C. 15 N. 18 O. 17 O. 31 P. 32 P. 35 S. 18 F. 123 I and 36 Cl, namely hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine and chlorine. Compounds substituted with such isotopes may also be used as pharmaceutical products, and the present invention includes all radiolabeled products of the compounds of the present invention.

[0328] Hereinafter, the present invention will be described in further detail with reference to Comparative Examples, Examples, and Test Examples; however, the present invention is not limited to those Examples. Example

[0329] In the examples, the following abbreviations will be used.

[0330] TFA: trifluoroacetic acid Pd-C: Palladium-Carbon Pd2(dba)3: tris(dibenzylideneacetone)palladium Pd(PPh3)4: Tetrakistriphenylphosphine palladium PdCl2(PPh3)2: Bis(triphenylphosphine)palladium(II) dichloride Pd(OAc)2: Palladium(II) acetate Xantphos: 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene BINAP: 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl PPh3: triphenylphosphine Boc2O: di-tert-butyl dicarbonate HATU: O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate HBTU: O-(Benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate THF: Tetrahydrofuran DME: dimethoxyethane DMF: dimethylformamide DMSO: dimethyl sulfoxide NMP: N-methylpyrrolidone DIPEA: N,N-diisopropylethylamine TEA: triethylamine BH3-THF: Borane-tetrahydrofuran complex CDCl3: deuterated chloroform TLC: Thin layer chromatography MS: mass spectrometry LCMS: High performance liquid chromatography-mass spectrometry ESI: Electron Spray Ionization M: molar concentration (mol / L) MS was measured with LCMS. ESI was used as the method for ionization. The observed values ​​of mass spectrometry are expressed as m / z.

[0331] The measurement conditions of LCMS are as follows: Analytical instrument: ACQUITY UPLC MS / PDA system (manufactured by Waters Corporation); Mass spectrometer: Waters 3100MS detector; Photodiode array detector: ACQUITY PDA detector (UV detection wavelength: 210-400 nm); Column: Acquity BEH C18, 1.7μm, 2.1×50mm; Flow rate: 0.5 mL / min; Column temperature: 40°C; Solvents; Solution A: 0.1% formic acid / H2O (v / v; same below) Solution B: 0.1% formic acid / acetonitrile.

[0332] Measured using a JNM-ECS400 nuclear magnetic resonance spectrometer (manufactured by JEOL RESONANCE Inc.) 1 H NMR spectroscopy. Observed peaks are expressed as chemical shift values ​​δ (ppm) (s = singlet, d = doublet, t = triplet, q = quartet, brs = broad singlet, m = multiplet, dd = double of doublets, ddd = double of doublets, and dt = double of triplets).

[0333] In the microwave experiments, Initiator 60 (manufactured by Biotage AB) was used. This allows temperatures of 40°C to 250°C to be achieved and pressures of up to 20 bar can be reached.

[0334] The names of compounds in the present specification are given by using naming software ACD / NAME (registered trademark, Advanced Chemistry Development Inc.) conforming to the IUPAC rules, by using ChemBioDraw (version 14.0, manufactured by Cambridge Soft Corporation) or according to the IUPAC naming rules.

[0335] In the names of the compounds, the descriptors "r" and "s" (lower case) refer to the stereochemistry of the pseudoasymmetric carbon atoms according to IUPAC rules.

[0336] Reference Example 1: 5-[(Cyclopropylmethyl)amino]pyridine-3-carboxylic acid [Step 1] Production of 5-[(Cyclopropylmethyl)amino]pyridine-3-carboxylic acid methyl ester 1,4-Dioxane (139 mL) was added to 5-bromopyridine-3-carboxylic acid methyl ester (15.0 g), 1-cyclopropylmethylamine (9.9 g), BINAP (8.6 g), cesium carbonate (45.2 g) and Pd(OAc)2 (1.6 g). After degassing, the reaction mixture was stirred at 80°C under an argon atmosphere overnight. The insoluble matter was filtered off with celite (R), and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (8.4 g). MS (m / z): 207.2 [M+H] + [Step 2] Production of 5-[(cyclopropylmethyl)amino]pyridine-3-carboxylic acid To a solution of methyl 5-[(cyclopropylmethyl)amino]pyridine-3-carboxylate (8.4 g) obtained in step 1 in THF (81 mL) and methanol (81 mL) were added lithium hydroxide monohydrate (3.4 g) and water (81 mL), and the reaction mixture was stirred at room temperature overnight. The solvent was distilled off under reduced pressure. The reaction mixture was diluted with water and then neutralized by adding 1M hydrochloric acid. The precipitated sediment was collected by filtration to obtain the title compound (6.8 g). MS (m / z): 193.2 [M+H] + Reference Example 2: 5-[Cyclopropyl(methyl)amino]pyridine-3-carboxylic acid [Step 1] Production of 5-[Cyclopropyl(methyl)amino]pyridine-3-carboxylic acid methyl ester The title compound (6.6 g) was obtained by the method described in Step 1 of Reference Example 1 by using N-methylcyclopropylamine (9.9 g) instead of 1-cyclopropylmethylamine. MS (m / z): 207.4 [M+H] + [Step 2] Production of 5-[cyclopropyl(methyl)amino]pyridine-3-carboxylic acid The title compound (4.3 g) was obtained by the method described in Step 2 of Reference Example 1 by using 5-[cyclopropyl(methyl)amino]pyridine-3-carboxylic acid methyl ester (6.6 g) obtained in Step 1 instead of 5-[(cyclopropylmethyl)amino]pyridine-3-carboxylic acid methyl ester. MS (m / z): 193.4 [M+H] + Reference Example 3: 5-[(3,3-difluorocyclobutyl)oxy]pyridine-3-carboxylic acid [Step 1] Production of 5-[(3,3-difluorocyclobutyl)oxy]pyridine-3-carboxylic acid methyl ester To a solution of methyl 5-hydroxypyridine-3-carboxylate (250 mg), 3,3-difluorocyclobutane-1-ol (212 mg) and PPh3 (599 mg) in THF (4.1 mL) was added diisopropyl azodicarboxylate (40% in toluene, 1.12 mL), and the reaction mixture was stirred at 60°C for 2 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography to obtain the title compound (170 mg). MS (m / z): 244.4 [M+H] + [Step 2] Production of 5-[(3,3-difluorocyclobutyl)oxy]pyridine-3-carboxylic acid The title compound (84 mg) was obtained by the method described in Step 2 of Reference Example 1 by using methyl 5-[(3,3-difluorocyclobutyl)oxy]pyridine-3-carboxylate (170 mg) obtained in Step 1 instead of methyl 5-[(cyclopropylmethyl)amino]pyridine-3-carboxylate.

[0337] Reference Example 4: 5-[(4,4-difluorocyclohexyl)oxy]pyridine-3-carboxylic acid [Step 1] Production of 5-[(4,4-difluorocyclohexyl)oxy]pyridine-3-carboxylic acid methyl ester The title compound (450 mg) was obtained by the method described in Step 1 of Reference Example 3 by using 4,4-difluorocyclohexan-1-ol instead of 3,3-difluorocyclobutan-1-ol. MS (m / z): 272.2 [M+H] + [Step 2] Production of 5-[(4,4-difluorocyclohexyl)oxy]pyridine-3-carboxylic acid The title compound (350 mg) was obtained by the method described in Step 2 of Reference Example 1 by using 5-[(4,4-difluorocyclohexyl)oxy]pyridine-3-carboxylic acid methyl ester (450 mg) obtained in Step 1 instead of 5-[(cyclopropylmethyl)amino]pyridine-3-carboxylic acid methyl ester. MS (m / z): 258.2 [M+H] + Reference Example 5: 5-[(1-methylcyclopropyl)methoxy]pyridine-3-carboxylic acid [Step 1] Production of 5-[(1-methylcyclopropyl)methoxy]pyridine-3-carboxylic acid methyl ester The title compound (540 mg) was obtained by the method described in Step 1 of Reference Example 3 by using (1-methylcyclopropyl)methanol (500 mg) instead of 3,3-difluorocyclobutan-1-ol. MS (m / z): 222.1 [M+H] + [Step 2] Production of 5-[(1-methylcyclopropyl)methoxy]pyridine-3-carboxylic acid The title compound (340 mg) was obtained by the method described in Step 2 of Reference Example 1 by using 5-[(1-methylcyclopropyl)methoxy]pyridine-3-carboxylic acid methyl ester (540 mg) obtained in Step 1 instead of 5-[(cyclopropylmethyl)amino]pyridine-3-carboxylic acid methyl ester. MS (m / z): 208.2 [M+H] + Reference Example 6: 5-[(3,3-difluorocyclobutyl)methoxy]pyridine-3-carboxylic acid [Step 1] Production of 5-[(3,3-difluorocyclobutyl)methoxy]pyridine-3-carboxylic acid methyl ester The title compound (1.10 g) was obtained by the method described in Step 1 of Reference Example 3 by using (3,3-difluorocyclobutyl)methanol (500 mg) instead of 3,3-difluorocyclobutan-1-ol. MS (m / z): 258.1 [M+H] + [Step 2] Production of 5-[(3,3-difluorocyclobutyl)methoxy]pyridine-3-carboxylic acid The title compound (580 mg) was obtained by the method described in Step 2 of Reference Example 1 by using 5-[(3,3-difluorocyclobutyl)methoxy]pyridine-3-carboxylic acid methyl ester (1.10 g) obtained in Step 1 instead of 5-[(cyclopropylmethyl)amino]pyridine-3-carboxylic acid methyl ester. MS (m / z): 244.2 [M+H] + Reference Example 7: 3-amino-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide To a suspension of 3-amino-4-methylbenzoic acid (5.00 g), (1S, 2S)-2-aminocyclohexan-1-ol hydrochloride (5.52 g) and HBTU (15.1 g) in THF (165 mL) was added DIPEA (17.2 mL), and the reaction mixture was stirred at room temperature for 2 hours. The reaction solution was diluted with ethyl acetate, and the organic layer was washed with a saturated aqueous sodium bicarbonate solution and a saturated saline solution. The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. Ethyl acetate was added to the obtained residue to suspend it, and the precipitate was collected by filtration to obtain the title compound (6.10 g). MS (m / z): 249.2 [M+H] + Reference Example 8: Methyl 4-chloro-3-ethynylbenzoate [Step 1] Production of methyl 4-chloro-3-[(trimethylsilyl)ethynyl]benzoate To 4-chloro-3-iodobenzoic acid methyl ester (8.15g), ethynyl (trimethyl) silane (2.78g), copper iodide (570mg), Pd (PPh3) 4 (3.18g) and TEA (55mL) was added THF (27.5mL). After degassing, the reaction mixture was stirred overnight at 45°C under an argon atmosphere. Insoluble matter was filtered out with celite (R), and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (6.8g).

[0338] [Step 2] Production of methyl 4-chloro-3-ethynylbenzoate The methyl 4-chloro-3-[(trimethylsilyl)ethynyl]benzoate (6.8 g) obtained in step 1 was dissolved in THF (85 mL), TBAF (1 M THF solution, 31 mL) was added thereto, and the reaction mixture was stirred at room temperature for 30 minutes. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography to obtain the title compound (2.6 g).

[0339] Reference Example 9: 3-ethynyl-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide The title compound (570 mg) was obtained by the method described in Reference Example 7 by using 3-ethynyl-4-methylbenzoic acid (500 mg) instead of 3-amino-4-methylbenzoic acid. MS (m / z): 258.2 [M+H] + Reference Example 10: 2-(5-ethynylpyridin-3-yl)pyrimidine [Step 1] Production of 2-[5-(methoxymethoxy)pyridin-3-yl]pyrimidine 1,4-Dioxane (73 mL) was added to 3-bromo-5-(methoxymethoxy)pyridine (4.0 g), bis(pinacolato)diboron (5.6 g), potassium acetate (3.6 g) and Pd(dppf)Cl2·CH2Cl2 (1.5 g). After degassing, the reaction mixture was stirred at 80°C for 2.5 hours under an argon atmosphere. Then, 2-bromopyrimidine (3.5 g), potassium carbonate (5.1 g) and water (0.5 mL) were added thereto, and the reaction mixture was stirred at 85°C overnight. The reaction solution was diluted with ethyl acetate, and the organic layer was washed with water. The organic layer was dried over anhydrous sodium sulfate, and then the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain the title compound (3.6 g). MS (m / z): 218.4 [M+H] + [Step 2] Production of 5-(pyrimidin-2-yl)pyridin-3-ol 2-[5-(Methoxymethoxy)pyridin-3-yl]pyrimidine (4.11 g) obtained in step 1 was dissolved in THF (38 mL), 35% hydrochloric acid (1.4 mL) was added thereto, and the reaction mixture was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure. A sodium bicarbonate aqueous solution was added to the obtained residue to neutralize it. The resulting precipitate was collected by filtration to obtain the title compound (2.51 g). MS (m / z): 174.4 [M+H] + [Step 3] Production of 5-(pyrimidin-2-yl)pyridin-3-yl trifluoromethanesulfonate Under ice cooling, trifluoromethanesulfonic anhydride (2.27 mL) was added dropwise to a solution of 5-(pyrimidin-2-yl)pyridin-3-ol (2.00 g) and TEA (2.10 mL) obtained in step 2 in dichloromethane (38 mL) under ice cooling, and the reaction mixture was stirred at the same temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography to obtain the title compound (770 mg). MS (m / z): 306.4 [M+H] + [Step 4] Production of 2-{5-[(trimethylsilyl)ethynyl]pyridin-3-yl}pyrimidine The title compound (570 mg) was obtained by the method described in Step 1 of Reference Example 8 by using 5-(pyrimidin-2-yl)pyridin-3-yl trifluoromethanesulfonate (770 mg) obtained in Step 3 instead of methyl 4-chloro-3-iodobenzoate. MS (m / z): 254.5 [M+H] + [Step 5] Production of 2-(5-ethynylpyridin-3-yl)pyrimidine The title compound (350 mg) was obtained by the method described in Step 2 of Reference Example 8 by using 2-{5-[(trimethylsilyl)ethynyl]pyridin-3-yl}pyrimidine (570 mg) obtained in Step 4 instead of methyl 4-chloro-3-[(trimethylsilyl)ethynyl]benzoate. MS (m / z): 182.4 [M+H] + Reference Example 11: 3-Bromo-4-chloro-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide By using 3-bromo-4-chlorobenzoic acid (250 mg) instead of 3-amino-4-methylbenzoic acid, the title compound (315 mg) was obtained by the method described in Reference Example 7. MS (m / z): 332.4 [M+H] + Reference Example 12: 6-Bromo-N-(cyclopropylmethyl)pyrazin-2-amine 1-Cyclopropylmethylamine (449 mg) and potassium carbonate (871 mg) were added to a solution of 2,6-dibromopyrazine (500 mg) in DMF (1 mL), and the reaction mixture was sealed in a pressure-resistant stainless steel container and stirred at 120 ° C for 8 hours. The reaction solution was diluted with ethyl acetate. After washing with water and saturated saline solution, the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain the title compound (400 mg).

[0340] Reference Example 13: 5-ethynyl-N-[(1S,2S)-2-hydroxycyclohexyl]-6-methylpyridine-3-carboxamide [Step 1] Production of 5-bromo-N-[(1S,2S)-2-hydroxycyclohexyl]-6-methylpyridine-3-carboxamide The title compound (380 mg) was obtained by the method described in Reference Example 7 by using 5-bromo-6-methylpyridine-3-carboxylic acid (250 mg) instead of 3-amino-4-methylbenzoic acid. MS (m / z): 313.4 [M+H] + [Step 2] Production of N-[(1S,2S)-2-hydroxycyclohexyl]-6-methyl-5-[(trimethylsilyl)ethynyl]pyridine-3-carboxamide By using 5-bromo-N-[(1S,2S)-2-hydroxycyclohexyl]-6-methylpyridine-3-carboxamide (100 mg) obtained in step 1 instead of methyl 4-chloro-3-iodobenzoate, the title compound (40 mg) was obtained by the method described in step 1 of reference example 8. MS (m / z): 331.5 [M+H] + [Step 3] Production of 5-ethynyl-N-[(1S,2S)-2-hydroxycyclohexyl]-6-methylpyridine-3-carboxamide By using N-[(1S,2S)-2-hydroxycyclohexyl]-6-methyl-5-[(trimethylsilyl)ethynyl]pyridine-3-carboxamide (40 mg) obtained in Step 2 instead of methyl 4-chloro-3-[(trimethylsilyl)ethynyl]benzoate, the title compound (23 mg) was obtained by the method described in Step 2 of Reference Example 8. MS (m / z): 259.5 [M+H] + Reference Example 14: 2-(Isoquinolin-4-yl)pyrimidin-4-amine 1,4-Dioxane (5 mL) was added to 2-chloropyrimidine-4-amine (200 mg), isoquinolin-4-ylboronic acid (294 mg), 1M sodium carbonate aqueous solution (3.1 mL) and Pd(dppf)Cl2.CH2Cl2 (126 mg). After degassing and replacing with argon, the reaction mixture was stirred at 90°C for 2 hours under an argon atmosphere. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography to obtain the title compound (300 mg).

[0341] Reference Example 15: (1S)-1-(5-phenylpyridin-3-yl)ethan-1-amine The title compound (280 mg) was obtained by the method described in Reference Example 14 by using (1S)-1-(5-bromopyridin-3-yl)ethan-1-amine hydrochloride (300 mg) and phenylboronic acid (185 mg) instead of 2-chloropyrimidin-4-amine and isoquinolin-4-ylboronic acid. MS (m / z): 199.2 [M+H] + Reference Example 16: (1S)-1-([3,3'-bipyridine]-5-yl)ethan-1-amine [Step 1] Production of (SS)-N-[(1E)-1-(5-bromopyridin-3-yl)ethylidene]-2-methylpropane-2-sulfenamide 1-(5-bromopyridin-3-yl)ethan-1-one (25 g) and (SS)-2-methylpropane-2-sulfenamide (18.2 g) were dissolved in THF (500 mL), tetraethyl orthotitanate (57 g) was added thereto, and the reaction mixture was stirred at 65° C. overnight. The reaction solution was diluted with ethyl acetate, and water was added thereto. The reaction solution was filtered through celite (R) and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (34 g). MS (m / z): 303.0 [M+H] + [Step 2] Production of (SS)-N-[(1S)-1-(5-bromopyridin-3-yl)ethyl]-2-methylpropane-2-sulfinamide A suspension of dichloro(p-isopropyltoluene)ruthenium(II) dimer (6.86 g), 2-amino-2-methyl-1-propanol (2.14 mL) and 4A molecular sieves (34 g) in 2-propanol (560 mL) was stirred at 80° C. for 30 minutes under an argon atmosphere. Then, while the reaction solution was stirred at 50° C., a solution of (SS)-N-[(1E)-1-(5-bromopyridin-3-yl)ethylidene]-2-methylpropane-2-sulfinamide (34 g) obtained in Step 1 in 2-propanol (9 mL) and potassium tert-butoxide (6.29 g) were added thereto, and the reaction mixture was stirred at the same temperature for 6 hours. The reaction solution was filtered through celite(R) and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (24.2 g). MS (m / z): 305.1 [M+H] + [Step 3] Production of (SS)-N-[(1S)-1-([3,3'-bipyridyl]-5-yl)ethyl]-2-methylpropane-2-sulfenamide By using (SS)-N-[(1S)-1-(5-bromopyridin-3-yl)ethyl]-2-methylpropane-2-sulfenamide (23.2 g) obtained in Step 2 and pyridin-3-ylboronic acid (11.2 g) instead of 2-chloropyrimidin-4-amine and isoquinolin-4-ylboronic acid, the title compound (22.7 g) was obtained by the method described in Reference Example 14. MS (m / z): 304.2 [M+H] + [Step 4] Production of (1S)-1-([3,3'-bipyridyl]-5-yl)ethan-1-amine To a solution of (SS)-N-[(1S)-1-([3,3'-bipyridyl]-5-yl)ethyl]-2-methylpropane-2-sulfenamide (22.7 g) obtained in step 3 in methanol (150 mL) was added hydrogen chloride (2M methanol solution, 5.46 mL) under ice cooling, and the reaction mixture was stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by column chromatography using amino-modified spherical silica gel to obtain the title compound (12.9 g). MS (m / z): 200.2 [M+H] + Reference Example 17: (1S)-1-[5-(phenylethynyl)pyridin-3-yl]ethan-1-amine dihydrochloride [Step 1] Production of (SS)-2-methyl-N-{(1S)-1-[5-(phenylethynyl)pyridin-3-yl]ethyl}propane-2-sulfinamide By using (SS)-N-[(1S)-1-(5-bromopyridin-3-yl)ethyl]-2-methylpropane-2-sulfinamide (500 mg) obtained in Step 2 of Reference Example 16 and ethynylbenzene (335 mg) instead of methyl 4-chloro-3-iodobenzoate and ethynyl(trimethyl)silane, the title compound (530 mg) was obtained by the method described in Step 1 of Reference Example 8. MS (m / z): 327.2 [M+H] + [Step 2]: Production of (1S)-1-[5-(phenylethynyl)pyridin-3-yl]ethan-1-amine dihydrochloride To a solution of (SS)-2-methyl-N-{(1S)-1-[5-(phenylethynyl)pyridin-3-yl]ethyl}propane-2-sulfenamide (530 mg) obtained in step 1 in methanol (8.1 mL) was added hydrogen chloride (2M methanol solution, 0.18 mL) under ice cooling, and the reaction mixture was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure, and ethyl acetate was added to the obtained residue to suspend it. The precipitate was collected by filtration to obtain the title compound (500 mg). MS (m / z): 223.2 [M+H] + Reference Example 18: (1S)-1-[5-(pyrimidin-2-yl)pyridin-3-yl]ethan-1-amine [Step 1] Production of (SS)-2-methyl-N-{(1S)-1-[5-(pyrimidin-2-yl)pyridin-3-yl]ethyl}propane-2-sulfinamide By using (SS)-N-[(1S)-1-(5-bromopyridin-3-yl)ethyl]-2-methylpropane-2-sulfinamide (600 mg) obtained in Step 2 of Reference Example 16 instead of 3-bromo-5-(methoxymethoxy)pyridine, the title compound (420 mg) was obtained by the method described in Step 1 of Reference Example 10. MS (m / z): 305.4 [M+H] + [Step 2]: Production of (1S)-1-[5-(pyrimidin-2-yl)pyridin-3-yl]ethan-1-amine The title compound (200 mg) was obtained by the method described in Step 4 of Reference Example 16 by using (SS)-2-methyl-N-{(1S)-1-[5-(pyrimidin-2-yl)pyridin-3-yl]ethyl}propane-2-sulfinamide (420 mg) obtained in Step 1 instead of (SS)-N-[(1S)-1-([3,3'-bipyridyl]-5-yl)ethyl]-2-methylpropane-2-sulfinamide. MS (m / z): 201.3 [M+H] + Reference Example 19: Production of (pyrazolo[5,1-b][1,3]thiazole-7-carbaldehyde [Step 1] (pyrazolo[5,1-b][1,3]thiazol-7-yl)methanol To a solution of pyrazolo[5,1-b][1,3]thiazole-7-carboxylic acid (100 mg) in THF (2 mL) was added lithium aluminum hydride (1 M hexane solution, 1.5 mL), and the reaction mixture was stirred at 50° C. for 5 hours. Methanol and potassium sodium L-(+)-tartrate tetrahydrate were added to the reaction solution at 0° C., and the reaction mixture was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography to obtain the title compound (57 mg). MS (m / z): 155.3 [M+H] + [Step 2] Production of pyrazolo[5,1-b][1,3]thiazole-7-carbaldehyde To a solution of (pyrazolo[5,1-b][1,3]thiazol-7-yl)methanol (57 mg) obtained in step 1 in THF (1.2 mL) was added manganese dioxide (160 mg), and the reaction mixture was stirred at room temperature overnight. After filtering the reaction solution to remove insoluble matter, the filtrate was concentrated under reduced pressure to obtain the title compound (42 mg).

[0342] Reference Example 20: 5-amino-N-[(1S,2S)-2-hydroxycyclohexyl]-6-methylpyridine-3-carboxamide The title compound (1.17 g) was obtained by the method described in Reference Example 7 using 5-amino-6-methylpyridine-3-carboxylic acid (915 mg) instead of 3-amino-4-methylbenzoic acid. MS (m / z): 250.2 [M+H] + Reference Example 21: Production of (5-formylpyridin-2-yl)phenylcarbamate from N-(5-formylpyridin-2-yl)morpholine-4-carboxamide [Step 1] To a solution of 6-aminopyridine-3-carboxaldehyde (250 mg) in THF (5.1 mL) was added TEA (0.57 mL) and phenyl chloroformate (304 mg), and the reaction mixture was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography to obtain the title compound (246 mg). MS (m / z): 243.2 [M+H] + [Step 2] Production of N-(5-formylpyridin-2-yl)morpholine-4-carboxamide To a solution of phenyl (5-formylpyridin-2-yl)carbamate (40 mg) obtained in step 1 in NMP (0.34 mL) were added morpholine (43 mg) and TEA (0.072 mL), and the reaction mixture was stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography to obtain the title compound (246 mg). MS (m / z): 236.1 [M+H] + Reference Example 22: N-Cyclopropyl-N'-(5-formylpyridin-2-yl)-N-methylurea The title compound (21 mg) was obtained by the method described in Step 2 of Reference Example 21 by using N-methylcyclopropylamine (94 mg) instead of morpholine. MS (m / z): 220.1 [M+H] + Reference Example 23: tert-Butyl 7-formyl-2,3-dihydro-4H-pyrido[3,2-b][1,4]oxazine-4-carboxylate [Step 1] Production of tert-butyl 7-bromo-2,3-dihydro-4H-pyrido[3,2-b][1,4]oxazine-4-carboxylate To a solution of 7-bromo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine (160 mg) in THF (2.5 mL) were added TEA (0.01 mL), Boc2O (0.19 mL) and DMAP (4.5 mg), and the reaction mixture was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography to obtain the title compound (177 mg). MS (m / z): 315.1 [M+H] + [Step 2] Production of tert-butyl 7-vinyl-2,3-dihydro-4H-pyrido[3,2-b][1,4]oxazine-4-carboxylate By using tert-butyl 7-bromo-2,3-dihydro-4H-pyrido[3,2-b][1,4]oxazine-4-carboxylate (177 mg) obtained in step 1 and 2-vinyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (172 mg) instead of 2-chloropyrimidin-4-amine and isoquinolin-4-ylboronic acid, the title compound (118 mg) was obtained by the method described in Reference Example 14. MS (m / z): 263.2 [M+H] + [Step 3] Production of tert-butyl 7-formyl-2,3-dihydro-4H-pyrido[3,2-b][1,4]oxazine-4-carboxylate In a solution of tert-butyl 7-vinyl-2,3-dihydro-4H-pyrido[3,2-b][1,4]oxazine-4-carboxylate (118 mg) obtained in step 2 in dichloromethane (2 mL), O3 was bubbled at -78 ° C for 30 minutes. Then, argon was bubbled into the solution until it became colorless. Triphenylphosphine (142 mg) was added thereto, and the reaction mixture was stirred at room temperature overnight. Water was added to the reaction solution, and the reaction mixture was extracted with dichloromethane. After the organic layer was dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure to obtain the title compound as a crude product.

[0343] Reference Example 24: 6-(1H-1,2,3-triazol-1-yl)pyridine-3-carboxaldehyde [Step 1] Production of 5-vinyl-2-(1H-1,2,3-triazol-1-yl)pyridine The title compound (90 mg) was obtained by the method described in Reference Example 14 by using 5-bromo-2-(1H-1,2,3-triazol-1-yl)pyridine (142 mg) (for example, synthesized by the method described in WO 2006 / 038100) and 2-vinyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (117 mg) instead of 2-chloropyrimidin-4-amine and isoquinolin-4-ylboronic acid. MS (m / z): 173.1 [M+H] + [Step 2] Production of 6-(1H-1,2,3-triazol-1-yl)pyridine-3-carboxaldehyde The title compound (306 mg) was obtained as a crude product by the method described in Step 3 of Reference Example 23 by using 5-vinyl-2-(1H-1,2,3-triazol-1-yl)pyridine (90 mg) obtained in Step 1 instead of tert-butyl 7-vinyl-2,3-dihydro-4H-pyrido[3,2-b][1,4]oxazine-4-carboxylate. MS (m / z): 175.1 [M+H]+ Reference Example 25: 5-(2H-1,2,3-triazol-2-yl)pyridine-3-carboxaldehyde [Step 1] Production of [5-(2H-1,2,3-triazol-2-yl)pyridin-3-yl]methanol To 5-(2H-1,2,3-triazole-2-yl)pyridine-3-carboxylic acid methyl ester (44 mg) (for example, synthesized by the method described in Angew.Chem.Int.Ed.2011,50,8944-8947.) Sodium borohydride (41 mg) is added to a solution in methanol (2.2 mL), and the reaction mixture is stirred at room temperature overnight. Water is added to the reaction solution, and the solvent is evaporated under reduced pressure. The residue is purified by silica gel column chromatography to obtain the title compound.

[0344] [Step 2] Production of 5-(2H-1,2,3-triazol-2-yl)pyridine-3-carboxaldehyde The title compound (22 mg) was obtained by the method as described in step 2 of Reference Example 19 by using [5-(2H-1,2,3-triazol-2-yl)pyridin-3-yl]methanol obtained in step 1 instead of pyrazolo[5,1-b][1,3]thiazol-7-yl)methanol.

[0345] Reference Example 26: 3-Formyl-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide The title compound (134 mg) was obtained by the method described in Reference Example 7 by using 3-formyl-4-methylbenzoic acid (100 mg) instead of 3-amino-4-methylbenzoic acid. MS (m / z): 262.5 [M+H] + Reference Example 27: 5-(Pyrimidin-2-yl)pyridin-3-amine dihydrochloride [Step 1] Production of di-tert-butyl (5-bromopyridin-3-yl)-2-iminodicarbonate The title compound (40.0 g) was obtained by the method as described in Step 1 of Reference Example 23 by using 5-bromopyridin-3-amine (25.0 g) instead of 7-bromo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine. MS (m / z): 373.4 [M+H] + [Step 2] Production of di-tert-butyl [5-(pyrimidin-2-yl)pyridin-3-yl]-2-iminodicarbonate The title compound (14.3 g) was obtained by the method described in Step 1 of Reference Example 10 by using di-tert-butyl (5-bromopyridin-3-yl)-2-imidodicarbonate (30.0 g) obtained in Step 1 instead of 3-bromo-5-(methoxymethoxy)pyridine. MS (m / z): 373.5 [M+H] + [Step 3] Production of 5-(pyrimidin-2-yl)pyridin-3-amine dihydrochloride To a solution of di-tert-butyl [5-(pyrimidin-2-yl)pyridin-3-yl]-2-iminodicarbonate (14.3 g) obtained in step 2 in ethanol (128 mL) was added hydrogen chloride (4M ethyl acetate solution, 14 mL), and the reaction mixture was stirred at 60° C. for 3 hours. The reaction solution was concentrated under reduced pressure, and the residue was suspended in ethyl acetate to collect the precipitate by filtration. The precipitate was washed with ethyl acetate and then dried to obtain the title compound (3.5 g). MS (m / z): 173.4 [M+H] + Reference Example 28: 3-Formyl-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide By using 3-formylbenzoic acid (500 mg) instead of 3-amino-4-methylbenzoic acid, the title compound (590 mg) was obtained by the method described in Reference Example 7. MS (m / z): 248.5 [M+H] + Reference Example 29: 4-Fluoro-3-formyl-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide The title compound (300 mg) was obtained by the method described in Reference Example 7 by using 4-fluoro-3-formylbenzoic acid (300 mg) instead of 3-amino-4-methylbenzoic acid. MS (m / z): 266.5 [M+H] + Reference Example 30: 5-Formyl-N-[(1S,2S)-2-hydroxycyclohexyl]-6-methylpyridine-3-carboxamide [Step 1] Production of 5-vinyl-N-[(1S,2S)-2-hydroxycyclohexyl]-6-methylpyridine-3-carboxamide The title compound (614 mg) was obtained by the method described in Reference Example 14 by using 5-bromo-N-[(1S,2S)-2-hydroxycyclohexyl]-6-methylpyridine-3-carboxamide (750 mg) obtained in Step 1 of Reference Example 13 and 2-vinyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (479 mg) instead of 2-chloropyrimidin-4-amine and isoquinolin-4-ylboronic acid. MS (m / z): 261.2 [M+H]+ [Step 2] Production of 5-formyl-N-[(1S,2S)-2-hydroxycyclohexyl]-6-methylpyridine-3-carboxamide The title compound (360 mg) was obtained by the method described in Step 3 of Reference Example 23 by using 5-vinyl-N-[(1S,2S)-2-hydroxycyclohexyl]-6-methylpyridine-3-carboxamide (614 mg) obtained in Step 1 instead of tert-butyl 7-vinyl-2,3-dihydro-4H-pyrido[3,2-b][1,4]oxazine-4-carboxylate. MS (m / z): 263.2 [M+H] + Reference Example 31: Methyl 4-chloro-3-(hydroxymethyl)benzoate At 0°C, sodium borohydride (38 mg) was added to a solution of methyl 4-chloro-3-formylbenzoate (200 mg) in methanol (3.4 mL) and THF (3.4 mL), and the reaction mixture was stirred at room temperature overnight. Water was added to the reaction solution, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (130 mg).

[0346] Reference Example 32: Methyl 3-[(ethylamino)methyl]-4-methylbenzoate To a solution of methyl 3-formyl-4-methylbenzoate (500 mg) in methanol (11 mL) was added ethylamine (2 M methanol solution, 2.8 mL), and the reaction mixture was stirred at room temperature for 30 minutes. Then, sodium borohydride (159 mg) was added thereto, and the reaction mixture was stirred at room temperature for 2 hours. Water was added to the reaction solution, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (423 mg). MS (m / z): 208.2 [M+H] + Reference Example 33: 5-Formyl-6-methylpyridine-3-carboxylic acid ethyl ester [Step 1] Production of 5-vinyl-6-methylpyridine-3-carboxylic acid ethyl ester The title compound (3.0 g) was obtained by the method described in Reference Example 14 by using ethyl 5-bromo-6-methylpyridine-3-carboxylate (4.2 g) and 2-vinyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (3.7 g) instead of 2-chloropyrimidin-4-amine and isoquinolin-4-ylboronic acid. MS (m / z): 192.1 [M+H] + [Step 2] Production of ethyl 5-formyl-6-methylpyridine-3-carboxylate The title compound (2.7 g) was obtained by the method described in Step 3 of Reference Example 23 by using ethyl 5-vinyl-6-methylpyridine-3-carboxylate (3.0 g) obtained in Step 1 instead of tert-butyl 7-vinyl-2,3-dihydro-4H-pyrido[3,2-b][1,4]oxazine-4-carboxylate. MS (m / z): 194.1 [M+H] + Reference Example 34: 1-[(5-bromopyridin-3-yl)methyl]-4-methylpiperazine To a solution of 5-bromopyridine-3-carboxaldehyde (500 mg) in dichloromethane (11 mL) were added acetic acid (0.15 mL) and 1-methylpiperazine (808 mg), and the reaction mixture was stirred at room temperature for 1 hour. Then, sodium triacetoxyborohydride (1.14 g) was added thereto, and the reaction mixture was stirred at room temperature for 2 hours. Water was added to the reaction solution, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (700 mg). MS (m / z): 270.1 [M+H] + Reference Example 35: 4-[(5-bromopyridin-3-yl)methyl]morpholine The title compound (570 mg) was obtained by the method described in Reference Example 34 by using morpholine (703 mg) instead of 1-methylpiperazine. MS (m / z): 257.1 [M+H] + Reference Example 36: 5-Bromo-N-(oxan-4-yl)pyridin-3-amine The title compound (230 mg) was obtained by the method described in Step 1 of Reference Example 1 by using 3,5-dibromopyridine and 4-oxacyclohexane (256 mg) instead of 5-bromopyridine-3-carboxylic acid methyl ester and 1-cyclopropylmethylamine. MS (m / z): 257.0 [M+H] + Reference Example 37: 5-Bromo-N-(1-methylpiperidin-4-yl)pyridin-3-amine The title compound (300 mg) was obtained by the method described in Step 1 of Reference Example 1 by using 3,5-dibromopyridine and 1-methylpiperidin-4-amine (304 mg) instead of 5-bromopyridine-3-carboxylic acid methyl ester and 1-cyclopropylmethylamine. MS (m / z): 270.1 [M+H] + Reference Example 38: 1-[(5-bromopyridin-3-yl)methyl]-4-ethylpiperazine The title compound (680 mg) was obtained by the method described in Reference Example 34 by using 1-ethylpiperazine (921 mg) instead of 1-methylpiperazine. MS (m / z): 284.1 [M+H] + Reference Example 39: 5-Bromo-N-(oxetan-3-yl)pyridin-3-amine The title compound (410 mg) was obtained by the method described in Step 1 of Reference Example 1 by using 3,5-dibromopyridine (1.00 g) and oxetan-3-amine (309 mg) instead of 5-bromopyridine-3-carboxylic acid methyl ester and 1-cyclopropylmethylamine. MS (m / z): 229.3 [M+H] + Reference Example 40: Di-tert-butyl 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl-2-iminodicarbonate [Step 1] Production of 2-[bis(tert-butoxycarbonyl)amino]-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate The title compound (960 mg) was obtained by the method as described in Step 1 of Reference Example 23 by using 2-amino-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylic acid benzyl ester (600 mg) instead of 7-bromo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine.

[0347] [Step 2] Production of di-tert-butyl 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl-2-iminodicarbonate After degassing, under an argon atmosphere, 5% Pd-C (400 mg) was added to a solution of 2-[bis(tert-butoxycarbonyl)amino]-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylic acid benzyl ester (960 mg) obtained in step 1 in methanol (100 mL), while stirring the solution at room temperature. Under a hydrogen atmosphere, the reaction mixture was stirred at room temperature for 4 hours. The reaction solution was filtered through celite (R), and the solvent was then distilled off under reduced pressure to obtain the title compound (700 mg).

[0348] Reference Example 41: 3-amino-N-[(1S,2S)-2-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl]-4-methylbenzamide To a solution of 3-amino-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide (800 mg) obtained in Reference Example 7 in dichloromethane (16 mL) were added tert-butyldimethylsilyl trifluoromethanesulfonate (1.11 g) and 2,6-lutidine (690 mg), and the reaction mixture was stirred at room temperature overnight. The reaction solution was diluted with ethyl acetate. After washing with water and a saturated saline solution, the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound (661 mg). MS (m / z): 363.3 [M+H] + Reference Example 42: Methyl 3-(aminomethyl)-4-methylbenzoate [Step 1] Production of methyl 3-[(hydroxyimino)methyl]-4-methylbenzoate To a solution of methyl 3-formyl-4-methylbenzoate (1.00 g) in methanol (20 mL) was added 50% aqueous hydroxylamine solution (1.32 mL), and the reaction mixture was stirred at 50° C. for 2 hours. The reaction solution was concentrated under reduced pressure, and ethyl acetate was added to the obtained residue. The organic layer was washed with water and a saturated saline solution. The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure to obtain the title compound (1.02 g). MS (m / z): 194.4 [M+H] + [Step 2] Production of methyl 3-(aminomethyl)-4-methylbenzoate To methyl 3-[(hydroxyimino)methyl]-4-methylbenzoate (1.02 g) obtained in step 1 was added hydrogen chloride (2 M methanol solution, 15 mL). After degassing, 5% Pd-C (500 mg) was added under an argon atmosphere while the reaction mixture was stirred at room temperature. Under a hydrogen atmosphere, the reaction mixture was stirred at room temperature for 3 hours. The reaction solution was filtered through celite (R), and the solvent was then evaporated under reduced pressure. Aqueous sodium hydroxide solution was added to the obtained residue to alkalize it, and the mixture was then extracted with ethyl acetate. The organic layer was washed with a saturated saline solution, and dried over anhydrous magnesium sulfate, and the solvent was then evaporated under reduced pressure to obtain the title compound (820 mg). MS (m / z): 180.4 [M+H] + Reference Example 43: 3-Bromo-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide The title compound (23.0 g) was obtained by the method described in Reference Example 7 by using 3-bromo-4-methylbenzoic acid (16.6 g) instead of 3-amino-4-methylbenzoic acid. MS (m / z): 312.0 [M+H] + Example 1: 2-(Cyclopropylamino)-N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)-1,3-thiazole-5-carboxamide [Step 1] Production of methyl 3-[(2-bromo-1,3-thiazole-5-carbonyl)amino]-4-methylbenzoate To a solution of 2-bromo-1,3-thiazole-5-carboxylic acid (2.20 g) in DMF (20 mL), 3-amino-4-methylbenzoic acid methyl ester (1.75 g), HATU (4.83 g) and DIPEA (3.66 mL) were sequentially added, and the reaction mixture was stirred at room temperature for 6 hours. The reaction solution was diluted with ethyl acetate, and the organic layer was washed with saturated sodium bicarbonate aqueous solution and saturated saline solution. The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (1.02 g).

[0349] [Step 2] Production of methyl 3-{[2-(cyclopropylamino)-1,3-thiazole-5-carbonyl]amino}-4-methylbenzoate To a solution of methyl 3-[(2-bromo-1,3-thiazole-5-carbonyl)amino]-4-methylbenzoate (150 mg) obtained in step 1 in NMP (0.5 mL) was added cyclopropylamine (121 mg), and the reaction mixture was stirred at 80° C. for 6 hours. After the reaction solution was cooled, it was purified by silica gel column chromatography to obtain the title compound (105 mg).

[0350] [Step 3] Production of 3-{[2-(cyclopropylamino)-1,3-thiazole-5-carbonyl]amino}-4-methylbenzoic acid By using methyl 3-{[2-(cyclopropylamino)-1,3-thiazole-5-carbonyl]amino}-4-methylbenzoate (103 mg) obtained in step 2 instead of methyl 5-[(cyclopropylmethyl)amino]pyridine-3-carboxylate, the title compound (90 mg) was obtained by the method described in step 2 of reference example 1.

[0351] [Step 4] Production of 2-(cyclopropylamino)-N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)-1,3-thiazole-5-carboxamide To a solution of 3-{[2-(cyclopropylamino)-1,3-thiazole-5-carbonyl]amino}-4-methylbenzoic acid (30 mg) obtained in step 3 in DMF (1 mL) were sequentially added HATU (54 mg) and DIPEA (0.065 mL), and the reaction mixture was stirred at room temperature for 10 minutes. Then, (1S,2S)-2-aminocyclohexan-1-ol hydrochloride (22 mg) was added thereto, and the reaction mixture was stirred at room temperature for 1 hour. The reaction solution was diluted with ethyl acetate, and the organic layer was washed with a saturated sodium bicarbonate aqueous solution and a saturated saline solution. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was then evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (16 mg).

[0352] Example 2: N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)-5-phenylpyridine-3-carboxamide [Step 1] Production of methyl 3-[(5-bromopyridine-3-carbonyl)amino]-4-methylbenzoate The title compound (1.70 g) was obtained by the method as described in Step 1 of Example 1 by using 5-bromopyridine-3-carboxylic acid (1.00 g) instead of 2-bromo-1,3-thiazole-5-carboxylic acid. MS (m / z): 349.0 [M+H] + [Step 2] Production of 3-[(5-bromopyridine-3-carbonyl)amino]-4-methylbenzoic acid The title compound (505 mg) was obtained by the method described in Step 2 of Reference Example 1, using methyl 3-[(5-bromopyridine-3-carbonyl)amino]-4-methylbenzoate (650 mg) obtained in Step 1 instead of methyl 5-[(cyclopropylmethyl)amino]pyridine-3-carboxylate. MS (m / z): 335.0 [M+H] + [Step 3] Production of 5-bromo-N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)pyridine-3-carboxamide By using 3-[(5-bromopyridine-3-carbonyl)amino]-4-methylbenzoic acid (505 mg) obtained in Step 2 instead of 3-{[2-(cyclopropylamino)-1,3-thiazole-5-carbonyl]amino}-4-methylbenzoic acid, the title compound (650 mg) was obtained by the method described in Step 4 of Example 1. MS (m / z): 432.1 [M+H] + [Step 4] Production of N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)-5-phenylpyridine-3-carboxamide By using 5-bromo-N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)pyridine-3-carboxamide (50 mg) obtained in step 3 and phenylboronic acid (17 mg) instead of 2-chloropyrimidin-4-amine and isoquinolin-4-ylboronic acid, the title compound (40 mg) was obtained by the method described in Reference Example 14.

[0353] Example 3: 2-(Cyclopropylmethyl)-N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)-1,3-thiazole-5-carboxamide [Step 1] Production of methyl 3-{[2-(cyclopropylmethyl)-1,3-thiazole-5-carbonyl]amino}-4-methylbenzoate The title compound (160 mg) was obtained by the method described in Step 1 of Example 1 by using 2-(cyclopropylmethyl)-1,3-thiazole-5-carboxylic acid (100 mg) instead of 2-bromo-1,3-thiazole-5-carboxylic acid. MS (m / z): 331.5 [M+H] + [Step 2] Production of 3-{[2-(cyclopropylmethyl)-1,3-thiazole-5-carbonyl]amino}-4-methylbenzoic acid The title compound (145 mg) was obtained by the method described in Step 2 of Reference Example 1, using methyl 3-{[2-(cyclopropylmethyl)-1,3-thiazole-5-carbonyl]amino}-4-methylbenzoate (160 mg) obtained in Step 1 instead of methyl 5-[(cyclopropylmethyl)amino]pyridine-3-carboxylate. MS (m / z): 317.4 [M+H] + [Step 3] Production of 2-(cyclopropylmethyl)-N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)-1,3-thiazole-5-carboxamide By using 3-{[2-(cyclopropylmethyl)-1,3-thiazole-5-carbonyl]amino}-4-methylbenzoic acid (40 mg) obtained in step 2 instead of 3-{[2-(cyclopropylamino)-1,3-thiazole-5-carbonyl]amino}-4-methylbenzoic acid, the title compound (38 mg) was obtained by the method described in step 4 of Example 1.

[0354] Example 5: N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)-2-phenyl-1,3-oxazole-5-carboxamide The title compound (53 mg) was obtained by the method as described in Step 1 of Example 1, using 2-phenyl-1,3-oxazole-5-carboxylic acid (30 mg) and 3-amino-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide (43 mg) obtained in Reference Example 7 instead of 2-bromo-1,3-thiazole-5-carboxylic acid and methyl 3-amino-4-methylbenzoate.

[0355] Example 6: N-(5-{[(1S)-2-hydroxy-1-phenylethyl]carbamoyl}-2-methylphenyl)-5-phenylpyridine-3-carboxamide [Step 1] Production of methyl 4-methyl-3-[(5-phenylpyridine-3-carbonyl)amino]benzoate The title compound (1.00 g) was obtained by the method described in Reference Example 14 by using methyl 3-[(5-bromopyridine-3-carbonyl)amino]-4-methylbenzoate (1.00 g) obtained in Step 1 of Example 2 and phenylboronic acid (419 mg) instead of 2-chloropyrimidin-4-amine and isoquinolin-4-ylboronic acid. MS (m / z): 347.2 [M+H] + [Step 2] Production of 4-methyl-3-[(5-phenylpyridine-3-carbonyl)amino]benzoic acid The title compound (910 mg) was obtained by the method described in Step 2 of Reference Example 1 by using methyl 4-methyl-3-[(5-phenylpyridine-3-carbonyl)amino]benzoate (1.00 g) obtained in Step 1 instead of methyl 5-[(cyclopropylmethyl)amino]pyridine-3-carboxylate. MS (m / z): 333.2 [M+H] + [Step 3] Production of N-(5-{[(1S)-2-hydroxy-1-phenylethyl]carbamoyl}-2-methylphenyl)-5-phenylpyridine-3-carboxamide By using 4-methyl-3-[(5-phenylpyridine-3-carbonyl)amino]benzoic acid (40 mg) and (2S)-2-amino-2-phenylethan-1-ol (25 mg) obtained in Step 2 instead of 3-{[2-(cyclopropylamino)-1,3-thiazole-5-carbonyl]amino}-4-methylbenzoic acid and (1S,2S)-2-aminocyclohexan-1-ol hydrochloride, the title compound (38 mg) was obtained by the method described in Step 4 of Example 1.

[0356] Example 17: 5-[Cyclopropyl(methyl)amino]-N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)pyridine-3-carboxamide The title compound (43 mg) was obtained by the method described in step 1 of Example 1, using 5-[cyclopropyl(methyl)amino]pyridine-3-carboxylic acid (70 mg) obtained in Reference Example 2 and 3-amino-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide (90 mg) obtained in Reference Example 7 instead of 2-bromo-1,3-thiazole-5-carboxylic acid and methyl 3-amino-4-methylbenzoate.

[0357] Example 20: 5-(3-Fluorophenyl)-N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)pyridine-3-carboxamide The title compound (43 mg) was obtained by the method described in Reference Example 14 by using 5-bromo-N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)pyridine-3-carboxamide (61 mg) obtained in step 3 of Example 2 and (3-fluorophenyl)boric acid (28 mg) instead of 2-chloropyrimidin-4-amine and isoquinolin-4-ylboronic acid.

[0358] Example 24: 5-(Cyclopropylmethoxy)-N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)pyridine-3-carboxamide The title compound (58 mg) was obtained by the method described in step 1 of Example 1, using 5-(cyclopropylmethoxy)pyridine-3-carboxylic acid (40 mg) and 3-amino-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide (57 mg) obtained in reference example 7 instead of 2-bromo-1,3-thiazole-5-carboxylic acid and methyl 3-amino-4-methylbenzoate.

[0359] Example 26: 2-[(2-cyclopropylethyl)amino]-N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)-1,3-thiazole-5-carboxamide [Step 1] Production of 3-[(2-chloro-1,3-thiazole-5-carbonyl)amino]-4-methylbenzoic acid methyl ester Under ice cooling, a solution of 2-chloro-1,3-thiazole-5-carbonyl chloride (8.31 g) in THF (80 mL) was added dropwise to a stirred solution of 3-amino-4-methylbenzoic acid methyl ester (6.89 g) in THF (80 mL), and the reaction mixture was stirred at the same temperature for 30 minutes. The reaction solution was diluted with ethyl acetate, and the organic layer was washed with a saturated aqueous sodium bicarbonate solution and a saturated saline solution. The organic layer was dried over anhydrous sodium sulfate, and the solvent was then evaporated under reduced pressure. Water was added to the obtained residue to suspend it, and the sediment was collected by filtration to obtain the title compound (12.5 g). MS (m / z): 311.4 [M+H] + [Step 2] Production of 3-[(2-chloro-1,3-thiazole-5-carbonyl)amino]-4-methylbenzoic acid The title compound (10.4 g) was obtained by the method described in Step 2 of Reference Example 1, using methyl 3-[(2-chloro-1,3-thiazole-5-carbonyl)amino]-4-methylbenzoate (12.5 g) obtained in Step 1 instead of methyl 5-[(cyclopropylmethyl)amino]pyridine-3-carboxylate. MS (m / z): 297.4 [M+H] + [Step 3] Production of 2-chloro-N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)-1,3-thiazole-5-carboxamide By using 3-[(2-chloro-1,3-thiazole-5-carbonyl)amino]-4-methylbenzoic acid (7.5 g) obtained in Step 2 instead of 3-{[2-(cyclopropylamino)-1,3-thiazole-5-carbonyl]amino}-4-methylbenzoic acid, the title compound (9.8 g) was obtained by the method described in Step 4 of Example 1. MS (m / z): 394.2 [M+H] + [Step 4] Production of N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)-5-phenylpyridine-3-carboxamide By using 2-chloro-N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)-1,3-thiazole-5-carboxamide (90 mg) obtained in Step 3 and 2-cyclopropylethan-1-amine (249 mg) instead of methyl 3-[(2-bromo-1,3-thiazole-5-carbonyl)amino]-4-methylbenzoate and cyclopropylamine, the title compound (72 mg) was obtained by the method described in Step 2 of Example 1.

[0360] Example 57: 3-[(5-bromopyridin-3-yl)ethynyl]-4-chloro-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide [Step 1] Production of 3-[(5-bromopyridin-3-yl)ethynyl]-4-chlorobenzoic acid methyl ester The title compound (1.60 g) was obtained by the method described in step 1 of Reference Example 8, using methyl 4-chloro-3-ethynylbenzoate (1.01 g) and 3-bromo-5-iodopyridine (1.47 g) obtained in Reference Example 8 instead of ethynyl(trimethyl)silane and methyl 4-chloro-3-iodobenzoate. MS (m / z): 350.0 [M+H] + [Step 2] Production of 3-[(5-bromopyridin-3-yl)ethynyl]-4-chlorobenzoic acid The title compound (360 mg) was obtained by the method described in Step 2 of Reference Example 1 by using methyl 3-[(5-bromopyridin-3-yl)ethynyl]-4-chlorobenzoate (600 mg) obtained in Step 1 instead of methyl 5-[(cyclopropylmethyl)amino]pyridine-3-carboxylate. MS (m / z): 335.9 [M+H] + [Step 3] Production of 3-[(5-bromopyridin-3-yl)ethynyl]-4-chloro-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide By using 3-[(5-bromopyridin-3-yl)ethynyl]-4-chlorobenzoic acid (370 mg) obtained in step 2 instead of 3-{[2-(cyclopropylamino)-1,3-thiazole-5-carbonyl]amino}-4-methylbenzoic acid, the title compound (170 mg) was obtained by the method described in step 4 of Example 1.

[0361] Example 58: 4-Chloro-N-[(1S,2S)-2-hydroxycyclohexyl]-3-[(5-phenylpyridin-3-yl)ethynyl]benzamide The title compound (5 mg) was obtained by the method described in Reference Example 14, using 3-[(5-bromopyridin-3-yl)ethynyl]-4-chloro-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide (50 mg) obtained in Example 57 and phenylboronic acid (15 mg) instead of 2-chloropyrimidin-4-amine and isoquinolin-4-ylboronic acid.

[0362] Example 59: N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-[(5-methylpyridin-3-yl)ethynyl]benzamide The title compound (14 mg) was obtained by the method described in step 1 of reference example 8, using 3-ethynyl-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide (30 mg) obtained in reference example 9 and 3-bromo-5-methylpyridine (30 mg) instead of ethynyl(trimethyl)silane and methyl 4-chloro-3-iodobenzoate.

[0363] Example 61: 3-[(5-Bromopyridin-3-yl)ethynyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide The title compound (14.5 g) was obtained by the method described in step 1 of reference example 8, using 3-ethynyl-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide (20.5 g) obtained in reference example 9 and 3-bromo-5-iodopyridine (24.8 g) instead of ethynyl(trimethyl)silane and methyl 4-chloro-3-iodobenzoate.

[0364] Example 62: N-[(1S, 2S)-2-hydroxycyclohexyl]-4-methyl-3-{[5-(pyrimidin-2-yl)pyridin-3-yl]ethynyl}benzamide To 3-[(5-bromopyridin-3-yl)ethynyl]-N-[(1S, 2S)-2-hydroxycyclohexyl]-4-methylbenzamide (30 mg) obtained in Example 61, 2-(tributylstannyl)pyrimidine (54 mg), Pd(PPh3)4 (17 mg), copper iodide (7 mg) and cesium fluoride (22 mg) were added DMF (0.5 mL), and the mixture was stirred at 150°C for 30 minutes using a microwave reaction apparatus. After the reaction solution was cooled, it was purified by silica gel column chromatography to obtain the title compound (15 mg).

[0365] Example 67: 3-[(5-Cyclopropylpyridin-3-yl)ethynyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide The title compound (250 mg) was obtained by the method described in Reference Example 14, using 3-[(5-bromopyridin-3-yl)ethynyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide (400 mg) obtained in Example 61 and cyclopropylboronic acid (249 mg) instead of 2-chloropyrimidin-4-amine and isoquinolin-4-ylboronic acid.

[0366] Example 76: 3-[(5-bromopyridin-3-yl)ethynyl]-N-[(1S,2S)-1,3-dihydroxy-1-phenylpropan-2-yl]-4-methylbenzamide [Step 1] Production of 3-[(5-bromopyridin-3-yl)ethynyl]-4-methylbenzoic acid The title compound (47 mg) was obtained by the method described in Step 1 of Reference Example 8 by using 3-ethynyl-4-methylbenzoic acid (40 mg) and 3-bromo-5-iodopyridine (71 mg) instead of ethynyl(trimethyl)silane and methyl 4-chloro-3-iodobenzoate. MS (m / z): 316.2 [M+H] + [Step 2] Production of 3-[(5-bromopyridin-3-yl)ethynyl]-N-[(1S,2S)-1,3-dihydroxy-1-phenylpropan-2-yl]-4-methylbenzamide By using 3-[(5-bromopyridin-3-yl)ethynyl]-4-methylbenzoic acid (25 mg) and (1S,2S)-2-amino-1-phenylpropane-1,3-diol (16 mg) obtained in Step 1 instead of 3-{[2-(cyclopropylamino)-1,3-thiazole-5-carbonyl]amino}-4-methylbenzoic acid and (1S,2S)-2-aminocyclohexan-1-ol hydrochloride, the title compound (28 mg) was obtained by the method described in Step 4 of Example 1.

[0367] Example 77: N 1 -[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-N3-(5-phenylpyridin-3-yl)benzene-1,3-dicarboxamide [Step 1] Production of 5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylbenzoic acid methyl ester The title compound (600 mg) was obtained by the method described in Step 4 of Example 1 by using 3-(methoxycarbonyl)-4-methylbenzoic acid (500 mg) instead of 3-{[2-(cyclopropylamino)-1,3-thiazole-5-carbonyl]amino}-4-methylbenzoic acid. MS (m / z): 292.3 [M+H] + [Step 2] Production of 5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylbenzoic acid The title compound (430 mg) was obtained by the method described in Step 2 of Reference Example 1 by using methyl 5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylbenzoate (600 mg) obtained in Step 1 instead of methyl 5-[(cyclopropylmethyl)amino]pyridine-3-carboxylate. MS (m / z): 278.3 [M+H] + [Step 3] Produce N 3-(5-bromopyridin-3-yl)-N1-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzene-1,3-dicarboxamide The title compound (166 mg) was obtained by the method described in Step 1 of Example 1 by using 5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylbenzoic acid (200 mg) and 5-bromopyridin-3-amine (137 mg) obtained in Step 2 instead of 2-bromo-1,3-thiazole-5-carboxylic acid and methyl 3-amino-4-methylbenzoate. MS (m / z): 432.3 [M+H] + [Step 4] Produce N 1 -[(1S,2S)-2-Hydroxycyclohexyl]-4-methyl-N3-(5-phenylpyridin-3-yl)benzene-1,3-dicarboxamide was prepared by using N 3 -(5-bromopyridin-3-yl)-N1-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzene-1,3-dicarboxamide (50 mg) and phenylboronic acid (17 mg) instead of 2-chloropyrimidin-4-amine and isoquinolin-4-ylboronic acid, and the title compound (40 mg) was obtained by the method described in Reference Example 14.

[0368] Example 78: N-[(1S,2S)-2-Hydroxycyclohexyl]-4-methyl-3-{[2-(pyridin-3-yl)pyrimidin-4-yl]amino}benzamide [Step 1] Production of methyl 4-methyl-3-{[2-(pyridin-3-yl)pyrimidin-4-yl]amino}benzoate The title compound (280 mg) was obtained by the method as described in Step 1 of Reference Example 1 by using methyl 3-bromo-4-methylbenzoate (350 mg) and 2-(pyridin-3-yl)pyrimidin-4-amine (263 mg) instead of methyl 5-bromopyridine-3-carboxylate and 1-cyclopropylmethylamine.

[0369] [Step 2] Production of 4-methyl-3-{[2-(pyridin-3-yl)pyrimidin-4-yl]amino}benzoic acid The title compound (180 mg) was obtained by the method described in Step 2 of Reference Example 1 by using methyl 4-methyl-3-{[2-(pyridin-3-yl)pyrimidin-4-yl]amino}benzoate (280 mg) obtained in Step 1 instead of methyl 5-[(cyclopropylmethyl)amino]pyridine-3-carboxylate.

[0370] [Step 3] Production of N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-{[2-(pyridin-3-yl)pyrimidin-4-yl]amino}benzamide The title compound (50 mg) was obtained by the method as described in step 4 of Example 1, by using 4-methyl-3-{[2-(pyridin-3-yl)pyrimidin-4-yl]amino}benzoic acid (50 mg) instead of 3-{[2-(cyclopropylamino)-1,3-thiazole-5-carbonyl]amino}-4-methylbenzoic acid.

[0371] Example 83: 3-(2-Amino-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-N-[(1S,2S)-1,3-dihydroxy-1-phenylpropan-2-yl]-4-methylbenzamide [Step 1] Production of methyl 3-{2-[bis(tert-butoxycarbonyl)amino]-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl}-4-methylbenzoate By using methyl 3-bromo-4-methylbenzoate (84 mg) obtained in Reference Example 40 and di-tert-butyl 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl-2-iminodicarbonate (86 mg) instead of methyl 5-bromopyridine-3-carboxylate and 1-cyclopropylmethylamine, the title compound (54 mg) was obtained by the method described in Step 1 of Reference Example 1. MS (m / z): 499.6 [M+H] + [Step 2] Production of methyl 3-(2-amino-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-4-methylbenzoate To methyl 3-{2-[bis(tert-butoxycarbonyl)amino]-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl}-4-methylbenzoate (70 mg) obtained in step 1 was added hydrogen chloride (2M methanol solution, 2.1 mL), and the reaction mixture was stirred at 50° C. for 5 hours. After the reaction solution was cooled, it was purified by silica gel column chromatography to obtain the title compound (10 mg). MS (m / z): 299.5 [M+H] + [Step 3] Production of 3-(2-amino-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-4-methylbenzoic acid The title compound was obtained by the method described in Step 2 of Reference Example 1, using methyl 3-(2-amino-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-4-methylbenzoate (10 mg) obtained in Step 2 instead of methyl 5-[(cyclopropylmethyl)amino]pyridine-3-carboxylate. MS (m / z): 285.3 [M+H] + [Step 4] Production of 3-(2-amino-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-N-[(1S,2S)-1,3-dihydroxy-1-phenylpropan-2-yl]-4-methylbenzamide By using 3-(2-amino-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-4-methylbenzoic acid and (1S,2S)-2-amino-1-phenylpropane-1,3-diol (11 mg) obtained in Step 3 instead of 3-{[2-(cyclopropylamino)-1,3-thiazole-5-carbonyl]amino}-4-methylbenzoic acid and (1S,2S)-2-aminocyclohexan-1-ol hydrochloride, the title compound (6 mg) was obtained by the method described in Step 4 of Example 1.

[0372] Example 84: N-[(1S,2S)-2-Hydroxycyclohexyl]-4-methyl-3-{[(1S)-1-(5-phenylpyridin-3-yl)ethyl]amino}benzamide [Step 1] Production of methyl 4-methyl-3-{[(1S)-1-(5-phenylpyridin-3-yl)ethyl]amino}benzoate The title compound (220 mg) was obtained by the method described in Step 1 of Reference Example 1 by using methyl 3-bromo-4-methylbenzoate (324 mg) and (1S)-1-(5-phenylpyridin-3-yl)ethan-1-amine (280 mg) obtained in Reference Example 15 instead of methyl 5-bromopyridine-3-carboxylate and 1-cyclopropylmethylamine. MS (m / z): 347.3 [M+H] + [Step 2] Production of 4-methyl-3-{[(1S)-1-(5-phenylpyridin-3-yl)ethyl]amino}benzoic acid The title compound (180 mg) was obtained by the method described in Step 2 of Reference Example 1, using methyl 4-methyl-3-{[(1S)-1-(5-phenylpyridin-3-yl)ethyl]amino}benzoate (220 mg) obtained in Step 1 instead of methyl 5-[(cyclopropylmethyl)amino]pyridine-3-carboxylate. MS (m / z): 333.3 [M+H] + [Step 3] Production of N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-{[(1S)-1-(5-phenylpyridin-3-yl)ethyl]amino}benzamide By using 4-methyl-3-{[(1S)-1-(5-phenylpyridin-3-yl)ethyl]amino}benzoic acid (50 mg) obtained in step 2 instead of 3-{[2-(cyclopropylamino)-1,3-thiazole-5-carbonyl]amino}-4-methylbenzoic acid, the title compound (60 mg) was obtained by the method described in step 4 of Example 1.

[0373] Example 85: 3-{[(1S)-1-([3,3'-bipyridyl]-5-yl)ethyl]amino}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide [Step 1] Production of methyl 3-{[(1S)-1-([3,3'-bipyridyl]-5-yl)ethyl]amino}-4-methylbenzoate The title compound (10.3 g) was obtained by the method described in Step 1 of Reference Example 1 by using methyl 3-bromo-4-methylbenzoate (13.9 g) obtained in Reference Example 16 and (1S)-1-([3,3'-bipyridyl]-5-yl)ethan-1-amine (11.0 g) instead of methyl 5-bromopyridine-3-carboxylate and 1-cyclopropylmethylamine. MS (m / z): 348.3 [M+H] + [Step 2] Production of 3-{[(1S)-1-([3,3'-bipyridyl]-5-yl)ethyl]amino}-4-methylbenzoic acid The title compound (8.7 g) was obtained by the method described in Step 2 of Reference Example 1, using methyl 3-{[(1S)-1-([3,3'-bipyridyl]-5-yl)ethyl]amino}-4-methylbenzoate (10.3 g) obtained in Step 1 instead of methyl 5-[(cyclopropylmethyl)amino]pyridine-3-carboxylate. MS (m / z): 334.4 [M+H] + [Step 3] Production of 3-{[(1S)-1-([3,3'-bipyridyl]-5-yl)ethyl]amino}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide The title compound (9.4 g) was obtained by the method as described in Step 4 of Example 1, by using 3-{[(1S)-1-([3,3'-bipyridyl]-5-yl)ethyl]amino}-4-methylbenzoic acid (8.7 g) obtained in Step 2 instead of 3-{[2-(cyclopropylamino)-1,3-thiazole-5-carbonyl]amino}-4-methylbenzoic acid.

[0374] Example 87: 3-{[(1S)-1-([3,4'-bipyridyl]-5-yl)ethyl]amino}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide [Step 1] Production of methyl 3-{[(1R)-1-(5-bromopyridin-3-yl)ethyl]amino}-4-methylbenzoate The title compound (1.80 g) was obtained by the method described in Step 1 of Reference Example 1 by using methyl 3-iodo-4-methylbenzoate (6.49 g) and (1S)-1-(5-bromopyridin-3-yl)ethan-1-amine (3.78 g) instead of methyl 5-bromopyridine-3-carboxylate and 1-cyclopropylmethylamine. MS (m / z): 349.0 [M+H] + [Step 2] Production of 3-{[(1R)-1-(5-bromopyridin-3-yl)ethyl]amino}-4-methylbenzoic acid The title compound (820 mg) was obtained by the method described in Step 2 of Reference Example 1, using methyl 3-{[(1R)-1-(5-bromopyridin-3-yl)ethyl]amino}-4-methylbenzoate (1.00 g) obtained in Step 1 instead of methyl 5-[(cyclopropylmethyl)amino]pyridine-3-carboxylate. MS (m / z): 335.1 [M+H] + [Step 3] Production of 3-{[(1S)-1-(5-bromopyridin-3-yl)ethyl]amino}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide By using 3-{[(1R)-1-(5-bromopyridin-3-yl)ethyl]amino}-4-methylbenzoic acid (820 mg) obtained in Step 2 instead of 3-{[2-(cyclopropylamino)-1,3-thiazole-5-carbonyl]amino}-4-methylbenzoic acid, the title compound (920 mg) was obtained by the method described in Step 4 of Example 1. MS (m / z): 432.3 [M+H] + [Step 4] Production of 3-{[(1S)-1-([3,4'-bipyridyl]-5-yl)ethyl]amino}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide By using 3-{[(1S)-1-(5-bromopyridin-3-yl)ethyl]amino}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide (30 mg) obtained in Step 3 and pyridin-4-ylboronic acid (10 mg) instead of 2-chloropyrimidin-4-amine and isoquinolin-4-ylboronic acid, the title compound (9 mg) was obtained by the method described in Reference Example 14.

[0375] Example 89: 3-{[(1S)-1-([2,3'-bipyridyl]-5'-yl)ethyl]amino}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide [Step 1] Production of methyl 3-{[(1S)-1-([2,3'-bipyridyl]-5'-yl)ethyl]amino}-4-methylbenzoate By using methyl 3-{[(1R)-1-(5-bromopyridin-3-yl)ethyl]amino}-4-methylbenzoate (150 mg) obtained in Step 1 of Example 87 and 2-bromopyridine (170 mg) instead of 3-bromo-5-(methoxymethoxy)pyridine and 2-bromopyrimidine, the title compound (90 mg) was obtained by the method described in Step 1 of Reference Example 10. MS (m / z): 348.2 [M+H] + [Step 2] Production of 3-{[(1S)-1-([2,3'-bipyridyl]-5'-yl)ethyl]amino}-4-methylbenzoic acid The title compound (86 mg) was obtained by the method described in Step 2 of Reference Example 1, using methyl 3-{[(1S)-1-([2,3'-bipyridyl]-5'-yl)ethyl]amino}-4-methylbenzoate (90 mg) obtained in Step 1 instead of methyl 5-[(cyclopropylmethyl)amino]pyridine-3-carboxylate. MS (m / z): 334.2 [M+H] + [Step 3] Production of 3-{[(1S)-1-([2,3'-bipyridyl]-5'-yl)ethyl]amino}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide By using 3-{[(1S)-1-([2,3'-bipyridyl]-5'-yl)ethyl]amino}-4-methylbenzoic acid (70 mg) obtained in Step 2 instead of 3-{[2-(cyclopropylamino)-1,3-thiazole-5-carbonyl]amino}-4-methylbenzoic acid, the title compound (10 mg) was obtained by the method described in Step 4 of Example 1.

[0376] Example 91: 3-{[(5-bromopyridin-3-yl)methyl]amino}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide The title compound (2.0 g) was obtained by the method described in Reference Example 34 by using 3-amino-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide (1.6 g) obtained in Reference Example 7 instead of 1-methylpiperazine.

[0377] Example 92: N-[(1S,2S)-2-Hydroxycyclohexyl]-4-methyl-3-{[(5-phenylpyridin-3-yl)methyl]amino}benzamide The title compound (23 mg) was obtained by the method described in Reference Example 14 by using 3-{[(5-bromopyridin-3-yl)methyl]amino}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide (30 mg) and phenylboronic acid (10 mg) obtained in Example 91 instead of 2-chloropyrimidin-4-amine and isoquinolin-4-ylboronic acid.

[0378] Example 94: 3-({[5-(Cyclopropylethynyl)pyridin-3-yl]methyl}amino)-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide The title compound (64 mg) was obtained by the method described in Step 1 of Reference Example 8, using ethynylcyclopropane (63 mg) and 3-{[(5-bromopyridin-3-yl)methyl]amino}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide (100 mg) obtained in Example 91 instead of ethynyl(trimethyl)silane and methyl 4-chloro-3-iodobenzoate.

[0379] Example 95: N-[(1S,2S)-2-Hydroxycyclohexyl]-4-methyl-3-({[5-(pyrimidin-2-yl)pyridin-3-yl]methyl}amino)benzamide [Step 1] Production of methyl 3-{[(5-bromopyridin-3-yl)methyl]amino}-4-methylbenzoate The title compound (13.0 g) was obtained by the method described in Reference Example 34 by using methyl 3-amino-4-methylbenzoate (9.0 g) instead of 1-methylpiperazine. MS (m / z): 335.3 [M+H] + [Step 2] Production of methyl 4-methyl-3-({[5-(pyrimidin-2-yl)pyridin-3-yl]methyl}amino)benzoate By using methyl 3-{[(5-bromopyridin-3-yl)methyl]amino}-4-methylbenzoate (13.0 g) obtained in step 1 instead of 3-bromo-5-(methoxymethoxy)pyridine, the title compound (9.0 g) was obtained by the method described in step 1 of reference example 10. MS (m / z): 335.5 [M+H] + [Step 3] Production of 4-methyl-3-({[5-(pyrimidin-2-yl)pyridin-3-yl]methyl}amino)benzoic acid The title compound (6.6 g) was obtained by the method described in Step 2 of Reference Example 1, using methyl 4-methyl-3-({[5-(pyrimidin-2-yl)pyridin-3-yl]methyl}amino)benzoate (9.0 g) obtained in Step 2 instead of methyl 5-[(cyclopropylmethyl)amino]pyridine-3-carboxylate. MS (m / z): 321.5 [M+H] + [Step 4] Production of N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-({[5-(pyrimidin-2-yl)pyridin-3-yl]methyl}amino)benzamide By using 4-methyl-3-({[5-(pyrimidin-2-yl)pyridin-3-yl]methyl}amino)benzoic acid (6.0 g) obtained in step 3 instead of 3-{[2-(cyclopropylamino)-1,3-thiazole-5-carbonyl]amino}-4-methylbenzoic acid, the title compound (5.5 g) was obtained by the method described in step 4 of Example 1.

[0380] Example 96: N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-{[(quinolin-3-yl)methyl]amino}benzamide [Step 1] Production of 4-methyl-3-{[(quinolin-3-yl)methyl]amino}benzoic acid methyl ester The title compound (230 mg) was obtained by the method as described in Reference Example 34 by using methyl 3-amino-4-methylbenzoate (210 mg) and quinoline-3-carbaldehyde (200 mg) instead of 1-methylpiperazine and 5-bromopyridine-3-carbaldehyde.

[0381] [Step 2] Production of 4-methyl-3-{[(quinolin-3-yl)methyl]amino}benzoic acid The title compound (200 mg) was obtained by the method described in Step 2 of Reference Example 1 by using methyl 4-methyl-3-{[(quinolin-3-yl)methyl]amino}benzoate (230 mg) obtained in Step 1 instead of methyl 5-[(cyclopropylmethyl)amino]pyridine-3-carboxylate.

[0382] [Step 3] Production of N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-{[(quinolin-3-yl)methyl]amino}benzamide By using 4-methyl-3-{[(quinolin-3-yl)methyl]amino}benzoic acid (40 mg) obtained in step 2 instead of 3-{[2-(cyclopropylamino)-1,3-thiazole-5-carbonyl]amino}-4-methylbenzoic acid, the title compound (43 mg) was obtained by the method described in step 4 of Example 1.

[0383] Example 98: 3-[({5-[4-(2-aminopropan-2-yl)phenyl]pyridin-3-yl}methyl)amino]-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide The title compound (41 mg) was obtained by the method described in Step 1 of Reference Example 10, using 3-{[(5-bromopyridin-3-yl)methyl]amino}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide (80 mg) obtained in Example 91 and 2-(4-bromophenyl)propan-2-amine (49 mg) instead of 3-bromo-5-(methoxymethoxy)pyridine and 2-bromopyrimidine.

[0384] Example 101: N-[(1S,2S)-2-Hydroxycyclohexyl]-4-methyl-3-{[(6-phenylpyrazin-2-yl)methyl]amino}benzamide [Step 1] Production of methyl 3-{[(6-chloropyrazin-2-yl)methyl]amino}-4-methylbenzoate The title compound (150 mg) was obtained by the method as described in Reference Example 34 by using methyl 3-amino-4-methylbenzoate (449 mg) and 6-chloropyrazine-2-carbaldehyde (774 mg) instead of 1-methylpiperazine and 5-bromopyridine-3-carbaldehyde.

[0385] [Step 2] Production of methyl 4-methyl-3-{[(6-phenylpyrazin-2-yl)methyl]amino}benzoate The title compound (66 mg) was obtained by the method described in Reference Example 14, using methyl 3-{[(6-chloropyrazin-2-yl)methyl]amino}-4-methylbenzoate (70 mg) obtained in Step 1 and phenylboronic acid (35 mg) instead of 2-chloropyrimidin-4-amine and isoquinolin-4-ylboronic acid.

[0386] [Step 3] Production of 4-methyl-3-{[(6-phenylpyrazin-2-yl)methyl]amino}benzoic acid The title compound (55 mg) was obtained by the method described in Step 2 of Reference Example 1 by using methyl 4-methyl-3-{[(6-phenylpyrazin-2-yl)methyl]amino}benzoate (66 mg) obtained in Step 2 instead of methyl 5-[(cyclopropylmethyl)amino]pyridine-3-carboxylate.

[0387] [Step 4] Production of N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-{[(6-phenylpyrazin-2-yl)methyl]amino}benzamide By using 4-methyl-3-{[(6-phenylpyrazin-2-yl)methyl]amino}benzoic acid (25 mg) obtained in Step 3 instead of 3-{[2-(cyclopropylamino)-1,3-thiazole-5-carbonyl]amino}-4-methylbenzoic acid, the title compound (19 mg) was obtained by the method described in Step 4 of Example 1.

[0388] Example 109: N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-{[(1H-pyrazolo[3,4-b]pyridin-5-yl)methyl]amino}benzamide The title compound (84 mg) was obtained by the method described in Reference Example 34, using 3-amino-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide (73 mg) obtained in Reference Example 7 and 1H-pyrazolo[3,4-b]pyridine-5-carbaldehyde (43 mg) instead of 1-methylpiperazine and 5-bromopyridine-3-carbaldehyde.

[0389] Example 110: N-[(1S,2S)-2-hydroxycyclohexyl]-3-{[(imidazo[1,2-b]pyridazin-3-yl)methyl]amino}-4-methylbenzamide The title compound (18 mg) was obtained by the method described in Reference Example 34, using 3-amino-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide (24 mg) obtained in Reference Example 7 and imidazo[1,2-b]pyridazine-3-carbaldehyde (15 mg) instead of 1-methylpiperazine and 5-bromopyridine-3-carbaldehyde.

[0390] Example 113: 3-{[(2-aminopyrimidin-5-yl)methyl]amino}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide [Step 1] Production of 3-{[(2-chloropyrimidin-5-yl)methyl]amino}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide By using 3-amino-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide (513 mg) obtained in Reference Example 7 and 2-chloropyrimidine-5-carbaldehyde (310 mg) instead of 1-methylpiperazine and 5-bromopyridine-3-carbaldehyde, the title compound (320 mg) was obtained by the method described in Reference Example 34. MS (m / z): 375.5 [M+H] + [Step 2] Production of 3-{[(2-aminopyrimidin-5-yl)methyl]amino}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide To 3-{[(2-chloropyrimidin-5-yl)methyl]amino}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide (320 mg) obtained in step 1, 1,4-dioxane (8 mL) and 28% aqueous ammonia solution (4 mL) were added, and the reaction mixture was sealed in a pressure-resistant stainless steel container and stirred at 100° C. for 8 hours. After the reaction solution was cooled, it was purified by silica gel column chromatography to obtain the title compound (173 mg).

[0391] Example 116: 3-{[(6-acetylaminopyridin-3-yl)methyl]amino}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide [Step 1] Production of 3-{[(6-bromopyridin-3-yl)methyl]amino}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide By using 3-amino-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide (380 mg) obtained in Reference Example 7 and 6-bromopyridine-3-carboxaldehyde (300 mg) instead of 1-methylpiperazine and 5-bromopyridine-3-carboxaldehyde, the title compound (370 mg) was obtained by the method described in Reference Example 34. MS (m / z): 418.5 [M+H] + [Step 2] Production of 3-{[(6-acetylaminopyridin-3-yl)methyl]amino}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide The title compound (22 mg) was obtained by the method described in Step 1 of Reference Example 1, using 3-{[(6-bromopyridin-3-yl)methyl]amino}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide (50 mg) obtained in Step 1 and acetamide (18 mg) instead of methyl 5-bromopyridine-3-carboxylate and 1-cyclopropylmethylamine.

[0392] Example 118: 3-{[([2,2'-bipyridyl]-5-yl)methyl]amino}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide The title compound (23 mg) was obtained by the method described in Example 62, using 3-{[(6-bromopyridin-3-yl)methyl]amino}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide (60 mg) obtained in step 1 of Example 116 and 2-(tributylstannyl)pyridine (79 mg) instead of 3-[(5-bromopyridin-3-yl)ethynyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide and 2-(tributylstannyl)pyrimidine.

[0393] Example 122: N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-({[6-(1H-pyrazol-1-yl)pyridin-3-yl]methyl}amino)benzamide Using a microwave reaction apparatus, a mixture of 3-{[(6-bromopyridin-3-yl)methyl]amino}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide (60 mg) obtained in step 1 of Example 116, 1H-pyrazole (20 mg), copper iodide (11 mg), potassium phosphate (91 mg), trans-N,N'-dimethylcyclohexane-1,2-diamine (0.014 mL) and DMF (0.36 mL) was reacted at 100°C for 30 minutes. 1H-pyrazole (20 mg), copper iodide (11 mg) and trans-N,N'-dimethylcyclohexane-1,2-diamine (0.014 mL) were added to the reaction solution, and the reaction mixture was reacted for another 30 minutes at 100° C. using a microwave reaction apparatus. After the reaction solution was cooled, it was purified by silica gel column chromatography to obtain the title compound (34 mg).

[0394] Example 129: N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-{[(6-{[(pyridin-3-yl)carbamoyl]amino}pyridin-3-yl)methyl]amino}benzamide [Step 1] Production of 3-{[(6-aminopyridin-3-yl)methyl]amino}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide By using 3-amino-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide (203 mg) obtained in Reference Example 7 and 6-aminopyridine-3-carbaldehyde (100 mg) instead of 1-methylpiperazine and 5-bromopyridine-3-carbaldehyde, the title compound (149 mg) was obtained by the method described in Reference Example 34. MS (m / z): 355.6 [M+H] + [Step 2] Production of N-[(1S, 2S)-2-hydroxycyclohexyl]-4-methyl-3-{[(6-{[(pyridin-3-yl)carbamoyl]amino}pyridin-3-yl)methyl]amino}benzamide A mixture of 3-{[(6-aminopyridin-3-yl)methyl]amino}-N-[(1S, 2S)-2-hydroxycyclohexyl]-4-methylbenzamide (35 mg) obtained in Step 1, 3-isocyanatopyridine (14 mg), potassium carbonate (20 mg) and DMF (0.33 mL) was reacted at 80° C. for 30 minutes using a microwave reaction apparatus. After the reaction solution was cooled, it was purified by silica gel column chromatography to obtain the title compound (5.8 mg).

[0395] Example 131: 3-{[(5-aminopyrazin-2-yl)methyl]amino}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide [Step 1] Production of methyl 3-[({5-[(tert-butoxycarbonyl)amino]pyrazin-2-yl}methyl)amino]-4-methylbenzoate To a solution of tert-butyl [5-(bromomethyl)pyrazin-2-yl]carbamate (1.44 g) and methyl 3-amino-4-methylbenzoate (561 mg) in DMF (12 mL) was added potassium carbonate (1.76 g), and the reaction mixture was stirred at room temperature overnight. The reaction solution was diluted with ethyl acetate. After washing with water and a saturated saline solution, the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain the title compound (360 mg). MS (m / z): 373.5 [M+H] + [Step 2] Production of 3-[({5-[(tert-butoxycarbonyl)amino]pyrazin-2-yl}methyl)amino]-4-methylbenzoic acid By using methyl 3-[({5-[(tert-butoxycarbonyl)amino]pyrazin-2-yl}methyl)amino]-4-methylbenzoate (160 mg) obtained in Step 1 instead of methyl 5-[(cyclopropylmethyl)amino]pyridine-3-carboxylate, the title compound (125 mg) was obtained by the method described in Step 2 of Reference Example 1. MS (m / z): 359.3 [M+H] + [Step 3] Production of tert-butyl {5-[(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylanilino)methyl]pyrazin-2-yl}carbamate The title compound (105 mg) was obtained by the method described in step 4 of Example 1 by using 3-[({5-[(tert-butoxycarbonyl)amino]pyrazin-2-yl}methyl)amino]-4-methylbenzoic acid (125 mg) obtained in step 2 instead of 3-{[2-(cyclopropylamino)-1,3-thiazole-5-carbonyl]amino}-4-methylbenzoic acid. MS (m / z): 456.6 [M+H] + [Step 4] Production of 3-{[(5-aminopyrazine-2-yl)methyl]amino}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide To a solution of tert-butyl {5-[(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylanilino)methyl]pyrazine-2-yl}carbamate (95 mg) obtained in step 3 in dichloromethane (2 mL) was added trifluoroacetic acid (0.16 mL), and the reaction mixture was stirred at room temperature for 2 hours. Methanol (2 mL) and 2M aqueous sodium hydroxide solution (2 mL) were added to the residue obtained by concentrating the reaction solution under reduced pressure, and the reaction mixture was stirred at room temperature for 1 hour. The reaction solution was diluted with water, and the reaction mixture was extracted with chloroform. The organic layer was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography to obtain the title compound (40 mg).

[0396] Example 138: N-[(1S,2S)-2-hydroxycyclohexyl]-3-{[(6-{[(1r,3r)-3-methoxycyclobutane-1-carbonyl]amino}pyridin-3-yl)methyl]amino}-4-methylbenzamide [Step 1] Production of 3-{[(6-aminopyridin-3-yl)methyl]amino}-N-[(1S,2S)-2-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl]-4-methylbenzamide The title compound (223 mg) was obtained by the method described in Reference Example 34 by using 3-amino-N-[(1S,2S)-2-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl]-4-methylbenzamide (468 mg) obtained in Reference Example 41 and 6-aminopyridine-3-carbaldehyde (150 mg) instead of 1-methylpiperazine and 5-bromopyridine-3-carbaldehyde. MS (m / z): 469.4 [M+H] + [Step 2] Production of N-[(1S,2S)-2-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl]-3-{[(6-{[(1r,3r)-3-methoxycyclobutane-1-carbonyl]amino}pyridin-3-yl)methyl]amino}-4-methylbenzamide The title compound (60 mg) was obtained by the method described in Step 1 of Example 1, using (1r,3r)-3-methoxycyclobutane-1-carboxylic acid (36 mg) and 3-{[(6-aminopyridin-3-yl)methyl]amino}-N-[(1S,2S)-2-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl]-4-methylbenzamide (30 mg) obtained in Step 1 instead of 2-bromo-1,3-thiazole-5-carboxylic acid and methyl 3-amino-4-methylbenzoate.

[0397] [Step 3] Production of N-[(1S,2S)-2-hydroxycyclohexyl]-3-{[(6-{[(1r,3r)-3-methoxycyclobutane-1-carbonyl]amino}pyridin-3-yl)methyl]amino}-4-methylbenzamide The title compound (8 mg) was obtained by the method described in step 2 of Reference Example 8, using N-[(1S,2S)-2-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl]-3-{[(6-{[(1r,3r)-3-methoxycyclobutane-1-carbonyl]amino}pyridin-3-yl)methyl]amino}-4-methylbenzamide (60 mg) obtained in step 2 instead of methyl 4-chloro-3-[(trimethylsilyl)ethynyl]benzoate.

[0398] Example 140: N-[(1S,2S)-2-Hydroxycyclohexyl]-4-methyl-3-({[6-(1H-1,2,3-triazol-1-yl)pyridin-3-yl]methyl}amino)benzamide The title compound (74 mg) was obtained by the method described in Reference Example 34 by using 3-amino-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide (136 mg) obtained in Reference Example 7 and 6-(1H-1,2,3-triazol-1-yl)pyridine-3-carbaldehyde (306 mg) obtained in Reference Example 24 instead of 1-methylpiperazine and 5-bromopyridine-3-carbaldehyde.

[0399] Example 142: 3-{[(2-aminopyrimidin-5-yl)methyl]amino}-4-chloro-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide [Step 1] Production of methyl 4-chloro-3-{[(2-chloropyrimidin-5-yl)methyl]amino}benzoate The title compound (376 mg) was obtained by the method described in Reference Example 34 by using methyl 3-amino-4-chlorobenzoate (1.00 g) and 2-chloropyrimidine-5-carbaldehyde (806 mg) instead of 1-methylpiperazine and 5-bromopyridine-3-carbaldehyde. MS (m / z): 312.3 [M+H] + [Step 2] Production of 3-{[(2-aminopyrimidin-5-yl)methyl]amino}-4-chlorobenzoic acid 1,4-dioxane (0.86 mL) and 28% aqueous ammonia solution (0.86 mL) were added to methyl 4-chloro-3-{[(2-chloropyrimidin-5-yl)methyl]amino}benzoate (199 mg) obtained in step 1, and the reaction mixture was sealed in a pressure-resistant stainless steel container and stirred at 100°C for 2 days. Ethanol (3.2 mL) and 2M aqueous sodium hydroxide solution (3.2 mL) were added to the residue obtained by concentrating the reaction solution under reduced pressure, and the reaction mixture was stirred at 90°C overnight. The solvent was evaporated under reduced pressure. The reaction mixture was diluted with water and then neutralized by adding hydrochloric acid. The precipitated sediment was collected by filtration to obtain the title compound (102 mg). MS (m / z): 279.4 [M+H] + [Step 3] Production of 3-{[(2-aminopyrimidin-5-yl)methyl]amino}-4-chloro-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide By using 3-{[(2-aminopyrimidin-5-yl)methyl]amino}-4-chlorobenzoic acid (50 mg) obtained in step 2 instead of 3-{[2-(cyclopropylamino)-1,3-thiazole-5-carbonyl]amino}-4-methylbenzoic acid, the title compound (36 mg) was obtained by the method described in step 4 of Example 1.

[0400] Example 144: 3-{[(3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)methyl]amino}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide [Step 1] Production of tert-7-[(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylanilino)methyl]-2,3-dihydro-4H-pyrido[3,2-b][1,4]oxazine-4-carboxylic acid Butyl ester The title compound (124 mg) was obtained by using 3-amino-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide (134 mg) obtained in Reference Example 7 and tert-butyl 7-formyl-2,3-dihydro-4H-pyrido[3,2-b][1,4]oxazine-4-carboxylate obtained in Reference Example 23 instead of 1-methylpiperazine and 5-bromopyridine-3-carbaldehyde by the method described in Reference Example 34. MS (m / z): 497.3 [M+H] + [Step 2] Production of 3-{[(3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)methyl]amino}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide To a solution of tert-butyl 7-[(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylanilino)methyl]-2,3-dihydro-4H-pyrido[3,2-b][1,4]oxazine-4-carboxylate (59 mg) obtained in step 1 in dichloromethane (1.4 mL) was added trifluoroacetic acid (0.7 mL), and the reaction mixture was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography to obtain the title compound (37 mg).

[0401] Example 147: N-[(1S,2S)-2-Hydroxycyclohexyl]-4-methyl-3-({[5-(pyrimidin-2-yl)pyridin-3-yl]amino}methyl)benzamide [Step 1] Production of methyl 3-{[(5-bromopyridin-3-yl)amino]methyl}-4-methylbenzoate The title compound (2.3 g) was obtained by the method described in Reference Example 34 by using 5-bromopyridin-3-amine (1.5 g) and methyl 3-formyl-4-methylbenzoate (1.5 g) instead of 1-methylpiperazine and 5-bromopyridine-3-carbaldehyde. MS (m / z): 335.4 [M+H] + [Step 2] Production of methyl 4-methyl-3-({[5-(pyrimidin-2-yl)pyridin-3-yl]amino}methyl)benzoate By using methyl 3-{[(5-bromopyridin-3-yl)amino]methyl}-4-methylbenzoate (170 mg) obtained in step 1 instead of 3-bromo-5-(methoxymethoxy)pyridine, the title compound (35 mg) was obtained by the method described in step 1 of reference example 10. MS (m / z): 335.5 [M+H] + [Step 3] Production of 4-methyl-3-({[5-(pyrimidin-2-yl)pyridin-3-yl]amino}methyl)benzoic acid The title compound (33 mg) was obtained by the method described in Step 2 of Reference Example 1, using methyl 4-methyl-3-({[5-(pyrimidin-2-yl)pyridin-3-yl]amino}methyl)benzoate (35 mg) obtained in Step 2 instead of methyl 5-[(cyclopropylmethyl)amino]pyridine-3-carboxylate. MS (m / z): 321.5 [M+H] + [Step 4] Production of N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-({[5-(pyrimidin-2-yl)pyridin-3-yl]amino}methyl)benzamide By using 4-methyl-3-({[5-(pyrimidin-2-yl)pyridin-3-yl]amino}methyl)benzoic acid (33 mg) obtained in step 3 instead of 3-{[2-(cyclopropylamino)-1,3-thiazole-5-carbonyl]amino}-4-methylbenzoic acid, the title compound (6 mg) was obtained by the method described in step 4 of Example 1.

[0402] Example 148: 3-{[([2,3'-bipyridyl]-5'-yl)amino]methyl}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide [Step 1] Production of 3-{[(5-bromopyridin-3-yl)amino]methyl}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide By using 5-bromopyridin-3-amine (437 mg) obtained in Reference Example 26 and 3-formyl-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide (600 mg) instead of 1-methylpiperazine and 5-bromopyridine-3-carbaldehyde, the title compound (560 mg) was obtained by the method described in Reference Example 34. MS (m / z): 418.6 [M+H] + [Step 2] Production of 3-{[([2,3'-bipyridyl]-5'-yl)amino]methyl}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide The title compound (10 mg) was obtained by the method described in Step 1 of Reference Example 10, using 3-{[(5-bromopyridin-3-yl)amino]methyl}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide (80 mg) obtained in Step 1 and 2-bromopyridine (36 mg) instead of 3-bromo-5-(methoxymethoxy)pyridine and 2-bromopyrimidine.

[0403] Example 152: 3-{[(5-bromopyridin-3-yl)amino]methyl}-N-[(1S,2S)-1,3-dihydroxy-1-phenylpropan-2-yl]-4-methylbenzamide [Step 1] Production of 3-{[(5-bromopyridin-3-yl)amino]methyl}-4-methylbenzoic acid The title compound (950 mg) was obtained by the method described in Step 2 of Reference Example 1, using methyl 3-{[(5-bromopyridin-3-yl)amino]methyl}-4-methylbenzoate (1.0 g) obtained in Step 1 of Example 147 instead of methyl 5-[(cyclopropylmethyl)amino]pyridine-3-carboxylate. MS (m / z): 321.4 [M+H] + [Step 2] Production of 3-{[(5-bromopyridin-3-yl)amino]methyl}-N-[(1S,2S)-1,3-dihydroxy-1-phenylpropan-2-yl]-4-methylbenzamide The title compound (500 mg) was obtained by the method as described in Step 4 of Example 1, using 3-{[(5-bromopyridin-3-yl)amino]methyl}-4-methylbenzoic acid (350 mg) and (1S,2S)-2-amino-1-phenylpropane-1,3-diol (219 mg) obtained in Step 1 instead of 3-{[2-(cyclopropylamino)-1,3-thiazole-5-carbonyl]amino}-4-methylbenzoic acid and (1S,2S)-2-aminocyclohexan-1-ol hydrochloride.

[0404] Example 153: N-[(1S,2S)-1,3-dihydroxy-1-phenylpropan-2-yl]-4-methyl-3-{[(5-phenylpyridin-3-yl)amino]methyl}benzamide The title compound (29 mg) was obtained by the method described in Reference Example 14 by using 3-{[(5-bromopyridin-3-yl)amino]methyl}-N-[(1S,2S)-1,3-dihydroxy-1-phenylpropan-2-yl]-4-methylbenzamide (50 mg) obtained in Example 152 and phenylboronic acid (16 mg) instead of 2-chloropyrimidin-4-amine and isoquinolin-4-ylboronic acid.

[0405] Example 155: 3-{[([2,3'-bipyridyl]-5'-yl)amino]methyl}-N-[(1S,2S)-1,3-dihydroxy-1-phenylpropan-2-yl]-4-methylbenzamide The title compound (20 mg) was obtained by the method described in Example 62 by using 3-{[(5-bromopyridin-3-yl)amino]methyl}-N-[(1S,2S)-1,3-dihydroxy-1-phenylpropan-2-yl]-4-methylbenzamide (50 mg) and 2-(tributylstannyl)pyridine (51 mg) obtained in Example 152 instead of 3-[(5-bromopyridin-3-yl)ethynyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide and 2-(tributylstannyl)pyrimidine.

[0406] Example 156: N-[(1S,2S)-1,3-dihydroxy-1-phenylpropan-2-yl]-4-methyl-3-{[(6-phenylpyrazin-2-yl)amino]methyl}benzamide [Step 1] Production of methyl 3-{[(6-chloropyrazin-2-yl)amino]methyl}-4-methylbenzoate A mixture of 2,6-dichloropyrazine (300 mg), methyl 3-(aminomethyl)-4-methylbenzoate (397 mg) obtained in Reference Example 42, NMP (4 mL) and DIPEA (1.05 mL) was stirred at 100° C. for 4 hours. The reaction solution was diluted with ethyl acetate, and the organic layer was washed with water and a saturated saline solution. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography to obtain the title compound (423 mg). MS (m / z): 292.5 [M+H] + [Step 2] Production of 3-{[(6-chloropyrazin-2-yl)amino]methyl}-4-methylbenzoic acid The title compound (520 mg) was obtained by the method described in Step 2 of Reference Example 1, using methyl 3-{[(6-chloropyrazin-2-yl)amino]methyl}-4-methylbenzoate (580 mg) obtained in Step 1 instead of methyl 5-[(cyclopropylmethyl)amino]pyridine-3-carboxylate. MS (m / z): 278.4 [M+H] + [Step 3] Production of 3-{[(6-chloropyrazin-2-yl)amino]methyl}-N-[(1S,2S)-1,3-dihydroxy-1-phenylpropan-2-yl]-4-methylbenzamide The title compound (420 mg) was obtained by the method as described in Step 4 of Example 1, using 3-{[(6-chloropyrazin-2-yl)amino]methyl}-4-methylbenzoic acid (300 mg) and (1S,2S)-2-amino-1-phenylpropane-1,3-diol (217 mg) obtained in Step 2 instead of 3-{[2-(cyclopropylamino)-1,3-thiazole-5-carbonyl]amino}-4-methylbenzoic acid and (1S,2S)-2-aminocyclohexan-1-ol hydrochloride. MS (m / z): 427.6 [M+H] + [Step 4] Production of N-[(1S,2S)-1,3-dihydroxy-1-phenylpropan-2-yl]-4-methyl-3-{[(6-phenylpyrazin-2-yl)amino]methyl}benzamide By using 3-{[(6-chloropyrazin-2-yl)amino]methyl}-N-[(1S,2S)-1,3-dihydroxy-1-phenylpropan-2-yl]-4-methylbenzamide (50 mg) obtained in Step 3 and phenylboronic acid (17 mg) instead of 2-chloropyrimidin-4-amine and isoquinolin-4-ylboronic acid, the title compound (36 mg) was obtained by the method described in Reference Example 14.

[0407] Example 158: N-[3-({[6-(3,4-dimethoxyphenyl)pyrazin-2-yl]amino}methyl)phenyl]-N'-[(1R,2S)-2-hydroxycyclohexyl]urea [Step 1] Production of N-[(3-aminophenyl)methyl]-6-chloropyrazin-2-amine The title compound (1.22 g) was obtained by the procedure as described in step 3 of Example 156 by using 3-(aminomethyl)aniline (1.23 g) instead of methyl 3-(aminomethyl)-4-methylbenzoate.

[0408] [Step 2] Production of N-[(3-aminophenyl)methyl]-6-(3,4-dimethoxyphenyl)pyrazin-2-amine By using N-[(3-aminophenyl)methyl]-6-chloropyrazin-2-amine (160 mg) obtained in Step 1 and (3,4-dimethoxyphenyl)boronic acid (149 mg) instead of 2-chloropyrimidin-4-amine and isoquinolin-4-ylboronic acid, the title compound (190 mg) was obtained by the method described in Reference Example 14.

[0409] [Step 3] Production of N-[3-({[6-(3,4-dimethoxyphenyl)pyrazin-2-yl]amino}methyl)phenyl]-N'-[(1R,2S)-2-hydroxycyclohexyl]urea To N-[(3-aminophenyl)methyl]-6-(3,4-dimethoxyphenyl)pyrazin-2-amine (40 mg) obtained in step 2 was added THF (1 mL), TEA (0.20 mL) and triphosgene (18 mg), and the reaction mixture was stirred at room temperature for 10 minutes. Then, (1S,2R)-2-aminocyclohexan-1-ol hydrochloride (180 mg) was added thereto, and the reaction mixture was stirred at the same temperature for 2 hours. The reaction solution was purified by silica gel column chromatography to obtain the title compound (37 mg).

[0410] Example 159: N-[(1R,2S)-2-Hydroxycyclohexyl]-N'-[3-({[5-(pyrimidin-2-yl)pyridin-3-yl]amino}methyl)phenyl]urea [Step 1] Production of N-[(3-nitrophenyl)methyl]-5-(pyrimidin-2-yl)pyridin-3-amine The title compound (40 mg) was obtained by the method described in Reference Example 34 by using 5-(pyrimidin-2-yl)pyridin-3-amine (100 mg) and 3-nitrobenzaldehyde (88 mg) obtained in Reference Example 27 instead of 1-methylpiperazine and 5-bromopyridine-3-carbaldehyde.

[0411] [Step 2] Production of N-[(3-aminophenyl)methyl]-5-(pyrimidin-2-yl)pyridin-3-amine After degassing, under argon atmosphere, 10% Pd-C (50 mg) was added to a solution of N-[(3-nitrophenyl)methyl]-5-(pyrimidin-2-yl)pyridin-3-amine (40 mg) obtained in step 1 in methanol (5 mL) and THF (5 mL), while the solution was stirred at room temperature. Under hydrogen atmosphere, the reaction mixture was stirred at room temperature for 4 hours. The reaction solution was filtered through celite (R), and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (20 mg).

[0412] [Step 3] Production of N-[(1R,2S)-2-hydroxycyclohexyl]-N'-[3-({[5-(pyrimidin-2-yl)pyridin-3-yl]amino}methyl)phenyl]urea By using N-[(3-aminophenyl)methyl]-5-(pyrimidin-2-yl)pyridin-3-amine (20 mg) obtained in step 2 instead of N-[(3-aminophenyl)methyl]-6-(3,4-dimethoxyphenyl)pyrazin-2-amine, the title compound (13 mg) was obtained by the method described in step 3 of Example 158.

[0413] Example 161: N-[4-fluoro-3-({[5-(pyrimidin-2-yl)pyridin-3-yl]amino}methyl)phenyl]-N'-[(1R,2S)-2-hydroxycyclohexyl]urea [Step 1] Production of N-[(2-fluoro-5-nitrophenyl)methyl]-5-(pyrimidin-2-yl)pyridin-3-amine The title compound (150 mg) was obtained by the method described in Reference Example 34 by using 5-(pyrimidin-2-yl)pyridin-3-amine (133 mg) and 2-fluoro-5-nitrobenzaldehyde (196 mg) obtained in Reference Example 27 instead of 1-methylpiperazine and 5-bromopyridine-3-carbaldehyde.

[0414] [Step 2] Production of tert-butyl [(2-fluoro-5-nitrophenyl)methyl][5-(pyrimidin-2-yl)pyridin-3-yl]carbamate The title compound (105 mg) was obtained by the method described in Step 1 of Reference Example 23, using N-[(2-fluoro-5-nitrophenyl)methyl]-5-(pyrimidin-2-yl)pyridin-3-amine (150 mg) obtained in Step 1 instead of 7-bromo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine.

[0415] [Step 3] Production of tert-butyl [(5-amino-2-fluorophenyl) methyl] [5-(pyrimidin-2-yl) pyridin-3-yl] carbamate To a solution of tert-butyl [(2-fluoro-5-nitrophenyl) methyl] [5-(pyrimidin-2-yl) pyridin-3-yl] carbamate (104 mg) obtained in step 2 in ethanol (2 mL) and water (0.2 mL) was added tin (II) chloride dihydrate (221 mg), and the reaction mixture was stirred at 65 ° C for 2 hours. Aqueous sodium hydroxide solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated saline solution, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (72 mg).

[0416] [Step 4] Production of tert-butyl {[2-fluoro-5-({[(1R,2S)-2-hydroxycyclohexyl]carbamoyl}amino)phenyl]methyl}[5-(pyrimidin-2-yl)pyridin-3-yl]carbamate By using tert-butyl [(5-amino-2-fluorophenyl)methyl][5-(pyrimidin-2-yl)pyridin-3-yl]carbamate (70 mg) obtained in step 3 instead of N-[(3-aminophenyl)methyl]-6-(3,4-dimethoxyphenyl)pyrazin-2-amine, the title compound (82 mg) was obtained by the method described in step 3 of Example 158.

[0417] [Step 5] Production of N-[4-fluoro-3-({[5-(pyrimidin-2-yl)pyridin-3-yl]amino}methyl)phenyl]-N'-[(1R,2S)-2-hydroxycyclohexyl]urea To a solution of tert-butyl {[2-fluoro-5-({[(1R,2S)-2-hydroxycyclohexyl]carbamoyl}amino)phenyl]methyl}[5-(pyrimidin-2-yl)pyridin-3-yl]carbamate (80 mg) obtained in step 4 in methanol (0.3 mL) was added hydrogen chloride (4M 1,4-dioxane solution, 1 mL), and the reaction mixture was stirred at room temperature for 2 hours. The reaction solution was purified by silica gel column chromatography to obtain the title compound (50 mg).

[0418] Example 164: N-[(1S,2S)-2-Hydroxycyclohexyl]-4-methyl-3-{1-[(6-phenylpyrazin-2-yl)amino]ethyl}benzamide [Step 1] Production of methyl 3-{1-[(6-chloropyrazin-2-yl)amino]ethyl}-4-methylbenzoate The title compound (75 mg) was obtained by the method as described in step 3 of Example 156 by using methyl 3-(1-aminoethyl)-4-methylbenzoate (218 mg) instead of methyl 3-(aminomethyl)-4-methylbenzoate.

[0419] [Step 2] Production of methyl 4-methyl-3-{1-[(6-phenylpyrazin-2-yl)amino]ethyl}benzoate The title compound (80 mg) was obtained by the method described in Reference Example 14 by using methyl 3-{1-[(6-chloropyrazin-2-yl)amino]ethyl}-4-methylbenzoate (75 mg) obtained in Step 1 and phenylboronic acid (36 mg) instead of 2-chloropyrimidin-4-amine and isoquinolin-4-ylboronic acid.

[0420] [Step 3] Production of 4-methyl-3-{1-[(6-phenylpyrazin-2-yl)amino]ethyl}benzoic acid The title compound (67 mg) was obtained by the method described in Step 2 of Reference Example 1, by using methyl 4-methyl-3-{1-[(6-phenylpyrazin-2-yl)amino]ethyl}benzoate (77 mg) obtained in Step 2 instead of methyl 5-[(cyclopropylmethyl)amino]pyridine-3-carboxylate.

[0421] [Step 4] Production of N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-{1-[(6-phenylpyrazin-2-yl)amino]ethyl}benzamide The title compound (17 mg) was obtained by the method as described in step 4 of Example 1, by using 4-methyl-3-{1-[(6-phenylpyrazin-2-yl)amino]ethyl}benzoic acid (30 mg) obtained in step 3 instead of 3-{[2-(cyclopropylamino)-1,3-thiazole-5-carbonyl]amino}-4-methylbenzoic acid.

[0422] Example 165: 3-[([3,3'-bipyridyl]-5-yl)methoxy]-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide [Step 1] Production of methyl 3-[(5-bromopyridin-3-yl)methoxy]-4-methylbenzoate The title compound (1.16 g) was obtained by the method described in Step 1 of Reference Example 3 by using methyl 3-hydroxy-4-methylbenzoate (750 mg) and (5-bromopyridin-3-yl)methanol (933 mg) instead of methyl 5-hydroxypyridine-3-carboxylate and 3,3-difluorocyclobutan-1-ol. MS (m / z): 336.4 [M+H] + [Step 2] Production of methyl 3-[([3,3'-bipyridyl]-5-yl)methoxy]-4-methylbenzoate The title compound (103 mg) was obtained by the method described in Reference Example 14 by using methyl 3-[(5-bromopyridin-3-yl)methoxy]-4-methylbenzoate (150 mg) obtained in step 1 and pyridin-3-ylboronic acid (66 mg) instead of 2-chloropyrimidin-4-amine and isoquinolin-4-ylboronic acid. MS (m / z): 335.5 [M+H] + [Step 3] Production of 3-[([3,3'-bipyridyl]-5-yl)methoxy]-4-methylbenzoic acid The title compound (100 mg) was obtained by the method described in Step 2 of Reference Example 1 by using methyl 3-[([3,3'-bipyridyl]-5-yl)methoxy]-4-methylbenzoate (103 mg) obtained in Step 2 instead of methyl 5-[(cyclopropylmethyl)amino]pyridine-3-carboxylate. MS (m / z): 321.6 [M+H] + [Step 4] Production of 3-[([3,3'-bipyridine]-5-yl)methoxy]-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide By using 3-[([3,3'-bipyridine]-5-yl)methoxy]-4-methylbenzoic acid (50 mg) obtained in Step 3 instead of 3-{[2-(cyclopropylamino)-1,3-thiazole-5-carbonyl]amino}-4-methylbenzoic acid, the title compound (47 mg) was obtained by the method described in Step 4 of Example 1.

[0423] Example 166: N-[(1S,2S)-2-Hydroxycyclohexyl]-4-methyl-3-{[5-(pyrimidin-2-yl)pyridin-3-yl]methoxy}benzamide [Step 1] Production of methyl 4-methyl-3-{[5-(pyrimidin-2-yl)pyridin-3-yl]methoxy}benzoate The title compound (127 mg) was obtained by the method described in Step 1 of Reference Example 10, using methyl 3-[(5-bromopyridin-3-yl)methoxy]-4-methylbenzoate (250 mg) obtained in Step 1 of Example 165 instead of 3-bromo-5-(methoxymethoxy)pyridine. MS (m / z): 336.4 [M+H] + [Step 2] Production of 4-methyl-3-{[5-(pyrimidin-2-yl)pyridin-3-yl]methoxy}benzoic acid The title compound (101 mg) was obtained by the method described in Step 2 of Reference Example 1 by using methyl 4-methyl-3-{[5-(pyrimidin-2-yl)pyridin-3-yl]methoxy}benzoate (127 mg) obtained in Step 1 instead of methyl 5-[(cyclopropylmethyl)amino]pyridine-3-carboxylate.

[0424] [Step 3] Production of N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-{[5-(pyrimidin-2-yl)pyridin-3-yl]methoxy}benzamide The title compound (76 mg) was obtained by the method as described in step 4 of Example 1, by using 4-methyl-3-{[5-(pyrimidin-2-yl)pyridin-3-yl]methoxy}benzoic acid (60 mg) obtained in step 2 instead of 3-{[2-(cyclopropylamino)-1,3-thiazole-5-carbonyl]amino}-4-methylbenzoic acid.

[0425] Example 170: 4-Chloro-N-[(1S,2S)-2-hydroxycyclohexyl]-3-({[5-(pyrimidin-2-yl)pyridin-3-yl]oxy}methyl)benzamide [Step 1] Production of methyl 4-chloro-3-({[5-(pyrimidin-2-yl)pyridin-3-yl]oxy}methyl)benzoate The title compound (50 mg) was obtained by the method described in Step 1 of Reference Example 3 by using 5-(pyrimidin-2-yl)pyridin-3-ol (123 mg) obtained in Step 2 of Reference Example 10 and methyl 4-chloro-3-(hydroxymethyl)benzoate (130 mg) obtained in Reference Example 31 instead of methyl 5-hydroxypyridine-3-carboxylate and 3,3-difluorocyclobutan-1-ol. MS (m / z): 356.4 [M+H] + [Step 2] Production of 4-chloro-3-({[5-(pyrimidin-2-yl)pyridin-3-yl]oxy}methyl)benzoic acid The title compound (43 mg) was obtained by the method described in Step 2 of Reference Example 1, using methyl 4-chloro-3-({[5-(pyrimidin-2-yl)pyridin-3-yl]oxy}methyl)benzoate (50 mg) obtained in Step 1 instead of methyl 5-[(cyclopropylmethyl)amino]pyridine-3-carboxylate. MS (m / z): 342.4 [M+H] + [Step 3] Production of 4-chloro-N-[(1S,2S)-2-hydroxycyclohexyl]-3-({[5-(pyrimidin-2-yl)pyridin-3-yl]oxy}methyl)benzamide By using 4-chloro-3-({[5-(pyrimidin-2-yl)pyridin-3-yl]oxy}methyl)benzoic acid (43 mg) obtained in step 2 instead of 3-{[2-(cyclopropylamino)-1,3-thiazole-5-carbonyl]amino}-4-methylbenzoic acid, the title compound (39 mg) was obtained by the method described in step 4 of Example 1.

[0426] Example 172: N-[(1S,2S)-2-Hydroxycyclohexyl]-4-methyl-3-[1-(5-phenylpyridin-3-yl)ethoxy]benzamide [Step 1] Production of methyl 3-[1-(5-bromopyridin-3-yl)ethoxy]-4-methylbenzoate The title compound (650 mg) was obtained by the method described in Step 1 of Reference Example 3 by using methyl 3-hydroxy-4-methylbenzoate (432 mg) and 1-(5-bromopyridin-3-yl)ethan-1-ol (500 mg) instead of methyl 5-hydroxypyridine-3-carboxylate and 3,3-difluorocyclobutan-1-ol. MS (m / z): 350.3 [M+H] + [Step 2] Production of 3-[1-(5-bromopyridin-3-yl)ethoxy]-4-methylbenzoic acid The title compound (350 mg) was obtained by the method described in Step 2 of Reference Example 1 by using methyl 3-[1-(5-bromopyridin-3-yl)ethoxy]-4-methylbenzoate (450 mg) obtained in Step 1 instead of methyl 5-[(cyclopropylmethyl)amino]pyridine-3-carboxylate. MS (m / z): 336.3 [M+H] + [Step 3] Production of 3-[1-(5-bromopyridin-3-yl)ethoxy]-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide The title compound (350 mg) was obtained by the method described in Step 4 of Example 1 by using 3-[1-(5-bromopyridin-3-yl)ethoxy]-4-methylbenzoic acid (350 mg) obtained in Step 2 instead of 3-{[2-(cyclopropylamino)-1,3-thiazole-5-carbonyl]amino}-4-methylbenzoic acid. MS (m / z): 433.5 [M+H] + [Step 4] Production of N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-[1-(5-phenylpyridin-3-yl)ethoxy]benzamide By using 3-[1-(5-bromopyridin-3-yl)ethoxy]-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide (50 mg) obtained in Step 3 and phenylboronic acid (17 mg) instead of 2-chloropyrimidin-4-amine and isoquinolin-4-ylboronic acid, the title compound (30 mg) was obtained by the method described in Reference Example 14.

[0427] Example 173: N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-[(E)-2-(5-phenylpyridin-3-yl)vinyl]benzamide [Step 1] Production of 3-vinyl-N-[(1R,2R)-2-hydroxycyclohexyl]-4-methylbenzamide The title compound (13.0 g) was obtained by the method described in Reference Example 14 by using 3-bromo-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide (20.0 g) obtained in Reference Example 43 and 2-vinyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (11.8 g) instead of 2-chloropyrimidin-4-amine and isoquinolin-4-ylboronic acid. MS (m / z): 260.2 [M+H] + [Step 2] Production of N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-[(E)-2-(5-phenylpyridin-3-yl)vinyl]benzamide A mixture of 3-vinyl-N-[(1R,2R)-2-hydroxycyclohexyl]-4-methylbenzamide (30 mg) obtained in Step 1, 3-bromo-5-phenylpyridine (27 mg), TEA (0.024 mL), tri(2-methylphenyl)phosphine (11 mg), Pd(OAc)2 (3.9 mg) and acetonitrile (0.58 mL) was reacted at 100° C. for 80 minutes using a microwave reaction apparatus. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography to obtain the title compound (24 mg).

[0428] Example 174: After degassing, to a solution of N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-[2-(5-phenylpyridin-3-yl)ethyl]benzamide (15 mg) obtained in Example 173 in ethanol (5 mL) was added 10% Pd-C (7.7 mg) under argon atmosphere, while stirring the solution at room temperature. Under a hydrogen atmosphere, the reaction mixture was stirred at room temperature overnight. The reaction solution was filtered through celite (R), and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (7 mg).

[0429] Example 175: N-[(1S,2S)-2-Hydroxycyclohexyl]-4-methyl-3-{[methyl(5-phenylpyridin-3-yl)amino]methyl}benzamide [Step 1] Production of methyl 3-{[(5-bromopyridin-3-yl)(methyl)amino]methyl}-4-methylbenzoate Under ice cooling, to a solution of methyl 3-{[(5-bromopyridin-3-yl)amino]methyl}-4-methylbenzoate (850 mg) obtained in step 1 of Example 147 in THF (10 mL) was added 60% sodium hydride (79 mg), and the reaction mixture was stirred at room temperature for 20 minutes. Then, iodomethane (720 mg) was added thereto, and the reaction mixture was stirred at the same temperature overnight. Under ice cooling, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated saline solution, and dried over anhydrous sodium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (200 mg). MS (m / z): 349.4 [M+H] + [Step 2] Production of 3-{[(5-bromopyridin-3-yl)(methyl)amino]methyl}-4-methylbenzoic acid The title compound (170 mg) was obtained by the method described in Step 2 of Reference Example 1, using methyl 3-{[(5-bromopyridin-3-yl)(methyl)amino]methyl}-4-methylbenzoate (200 mg) obtained in Step 1 instead of methyl 5-[(cyclopropylmethyl)amino]pyridine-3-carboxylate. MS (m / z): 335.4 [M+H] + [Step 3] Production of 3-{[(5-bromopyridin-3-yl)(methyl)amino]methyl}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide By using 3-{[(5-bromopyridin-3-yl)(methyl)amino]methyl}-4-methylbenzoic acid (170 mg) obtained in Step 2 instead of 3-{[2-(cyclopropylamino)-1,3-thiazole-5-carbonyl]amino}-4-methylbenzoic acid, the title compound (147 mg) was obtained by the method described in Step 4 of Example 1. MS (m / z): 432.6 [M+H] + [Step 4] Production of N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-{[methyl(5-phenylpyridin-3-yl)amino]methyl}benzamide By using 3-{[(5-bromopyridin-3-yl)(methyl)amino]methyl}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide (30 mg) obtained in Step 3 and phenylboronic acid (9.3 mg) instead of 2-chloropyrimidin-4-amine and isoquinolin-4-ylboronic acid, the title compound (24 mg) was obtained by the method described in Reference Example 14.

[0430] Example 177: 3-[(Z)-2-([2,3'-bipyridyl]-5'-yl)-2-fluorovinyl]-4-fluoro-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide [Step 1] Production of 3-(2,2-difluorovinyl)-4-fluoro-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide To a solution of 4-fluoro-3-formyl-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide (500 mg) obtained in Reference Example 29 and triphenylphosphine (593 mg) in DMF (3.8 mL) was added dropwise at 100° C. over 30 minutes. A solution of sodium monochlorodifluoroacetate (431 mg) in DMF (0.94 mL) was added, and the reaction mixture was stirred at the same temperature for 30 minutes. Under ice cooling, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated saline solution, dried over anhydrous sodium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (200 mg). MS (m / z): 300.1 [M+H] + [Step 2] Production of 4-fluoro-3-[(Z)-2-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)vinyl]-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide To 3-(2,2-difluorovinyl)-4-fluoro-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide (100 mg) obtained in Step 1, bis(pinacolato)diboron (170 mg), potassium acetate (39 mg), tricyclohexylphosphine (19 mg) and copper (I) chloride (3.3 mg) were added THF (2.2 mL), and after degassing, the reaction mixture was stirred overnight at 40° C. under an argon atmosphere. To the reaction solution was added a saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline solution and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure to give the title compound (130 mg).

[0431] [Step 3] Production of 3-[(Z)-2-([2,3'-bipyridyl]-5'-yl)-2-fluorovinyl]-4-fluoro-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide The title compound (10 mg) was obtained by the method described in Reference Example 14 by using 5'-bromo-2,3'-bipyridine (45 mg) and 4-fluoro-3-[(Z)-2-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)vinyl]-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide (65 mg) obtained in step 2 instead of 2-chloropyrimidin-4-amine and isoquinolin-4-ylboronic acid.

[0432] Example 180: 5-[(Z)-2-([2,3'-bipyridyl]-5'-yl)-2-fluorovinyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-6-methylpyridine-3-carboxamide [Step 1] Production of ethyl 5-(2,2-difluorovinyl)-6-methylpyridine-3-carboxylate The title compound (2.80 g) was obtained by the method described in Step 1 of Example 177 by using ethyl 5-formyl-6-methylpyridine-3-carboxylate (2.65 g) obtained in Reference Example 33 instead of 4-fluoro-3-formyl-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide. MS (m / z): 228.1 [M+H] + [Step 2] Production of ethyl 5-[(Z)-2-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)vinyl]-6-methylpyridine-3-carboxylate The title compound (280 mg) was obtained by the method as described in step 2 of Example 177 by using ethyl 5-(2,2-difluorovinyl)-6-methylpyridine-3-carboxylate (200 mg) obtained in step 1 instead of 3-(2,2-difluorovinyl)-4-fluoro-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide.

[0433] [Step 3] Production of ethyl 5-[(Z)-2-([2,3'-bipyridyl]-5'-yl)-2-fluorovinyl]-6-methylpyridine-3-carboxylate The title compound (230 mg) was obtained by the method described in Reference Example 14 using 5'-bromo-2,3'-bipyridyl (196 mg) and ethyl 5-[(Z)-2-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)vinyl]-6-methylpyridine-3-carboxylate (280 mg) obtained in Step 2 instead of 2-chloropyrimidin-4-amine and isoquinolin-4-ylboronic acid. MS (m / z): 364.2 [M+H] + [Step 4] Production of 5-[(Z)-2-([2,3'-bipyridyl]-5'-yl)-2-fluorovinyl]-6-methylpyridine-3-carboxylic acid By using ethyl 5-[(Z)-2-([2,3'-bipyridyl]-5'-yl)-2-fluorovinyl]-6-methylpyridine-3-carboxylate (230 mg) obtained in Step 3 instead of methyl 5-[(cyclopropylmethyl)amino]pyridine-3-carboxylate, the title compound (165 mg) was obtained by the method described in Step 2 of Reference Example 1. MS (m / z): 336.1 [M+H] + [Step 5] Production of 5-[(Z)-2-([2,3'-bipyridine]-5'-yl)-2-fluorovinyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-6-methylpyridine-3-carboxamide By using 5-[(Z)-2-([2,3'-bipyridine]-5'-yl)-2-fluorovinyl]-6-methylpyridine-3-carboxylic acid (120 mg) obtained in Step 4 instead of 3-{[2-(cyclopropylamino)-1,3-thiazole-5-carbonyl]amino}-4-methylbenzoic acid, the title compound (77 mg) was obtained by the method described in Step 4 of Example 1.

[0434] Example 192: 3-[(Z)-2-(2-aminopyrimidin-5-yl)-2-fluorovinyl]-4-fluoro-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide [Step 1] Production of methyl 3-(2,2-difluorovinyl)-4-fluorobenzoate The title compound (1.30 g) was obtained by the method as described in step 1 of Example 177 by using methyl 4-fluoro-3-formylbenzoate (1.27 g) instead of 4-fluoro-3-formyl-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide.

[0435] [Step 2] Production of 3-[(Z)-2-(2-aminopyrimidin-5-yl)-2-fluorovinyl]-4-fluorobenzoic acid methyl ester To 3-(2,2-difluorovinyl)-4-fluorobenzoic acid methyl ester (130 mg), bis(pinacolato)diboron (305 mg), potassium acetate (118 mg), tricyclohexylphosphine (34 mg) and copper (I) chloride (22 mg) obtained in step 1 was added THF (4 mL), and after degassing, the reaction mixture was stirred at 40 ° C for 8 hours under an argon atmosphere. Saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated saline solution, and dried over anhydrous sodium sulfate, and then the solvent was evaporated under reduced pressure. 5-Bromopyrimidin-2-amine (105 mg), potassium carbonate (166 mg), Pd(dppf)Cl2.CH2Cl2 (49 mg), 1,4-dioxane (2 mL) and water (0.2 mL) were added to the obtained residue, and after degassing, the reaction mixture was stirred at 85° C. overnight under an argon atmosphere. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography to obtain the title compound (200 mg). MS (m / z): 292.1 [M+H] + [Step 3] Production of 3-[(Z)-2-(2-aminopyrimidin-5-yl)-2-fluorovinyl]-4-fluorobenzoic acid The title compound (36 mg) was obtained by the method described in Step 2 of Reference Example 1, using methyl 3-[(Z)-2-(2-aminopyrimidin-5-yl)-2-fluorovinyl]-4-fluorobenzoate (200 mg) obtained in Step 2 instead of methyl 5-[(cyclopropylmethyl)amino]pyridine-3-carboxylate. MS (m / z): 278.1 [M+H] + [Step 4] Production of 3-[(Z)-2-(2-aminopyrimidin-5-yl)-2-fluorovinyl]-4-fluoro-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide By using 3-[(Z)-2-(2-aminopyrimidin-5-yl)-2-fluorovinyl]-4-fluorobenzoic acid (36 mg) obtained in Step 3 instead of 3-{[2-(cyclopropylamino)-1,3-thiazole-5-carbonyl]amino}-4-methylbenzoic acid, the title compound (4 mg) was obtained by the method described in Step 4 of Example 1.

[0436] Example 194: 3-[(Z)-2-{5-[(4-ethylpiperazin-1-yl)methyl]pyridin-3-yl}-2-fluorovinyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide [Step 1] Production of methyl 3-(2,2-difluorovinyl)-4-methylbenzoate The title compound (15.0 g) was obtained by the method as described in step 1 of Example 177 by using methyl 3-formyl-4-methylbenzoate (13.4 g) instead of 4-fluoro-3-formyl-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide. MS (m / z): 213.1 [M+H] + [Step 2] Production of methyl 3-[(Z)-2-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)vinyl]-4-methylbenzoate The title compound (8.6 g) was obtained by the method as described in step 2 of Example 177 by using methyl 3-(2,2-difluorovinyl)-4-methylbenzoate (6.0 g) obtained in step 1 instead of 3-(2,2-difluorovinyl)-4-fluoro-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide.

[0437] [Step 3] Production of methyl 3-[(Z)-2-fluoro-2-{5-[(4-ethylpiperazin-1-yl)methyl]pyridin-3-yl}vinyl]-4-methylbenzoate The title compound (7.5 g) was obtained by the method described in Reference Example 14 by using 1-[(5-bromopyridin-3-yl)methyl]-4-ethylpiperazine (6.3 g) obtained in Reference Example 38 and methyl 3-[(Z)-2-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)vinyl]-4-methylbenzoate (8.5 g) obtained in Step 2 instead of 2-chloropyrimidin-4-amine and isoquinolin-4-ylboronic acid. MS (m / z): 398.3 [M+H] + [Step 4] Production of 3-[(Z)-2-fluoro-2-{5-[(4-ethylpiperazin-1-yl)methyl]pyridin-3-yl}vinyl]-4-methylbenzoic acid By using methyl 3-[(Z)-2-fluoro-2-{5-[(4-ethylpiperazin-1-yl)methyl]pyridin-3-yl}vinyl]-4-methylbenzoate (7.5 g) obtained in Step 3 instead of methyl 5-[(cyclopropylmethyl)amino]pyridine-3-carboxylate, the title compound (4.7 g) was obtained by the method described in Step 2 of Reference Example 1. MS (m / z): 384.5 [M+H] + [Step 5] Production of 3-[(Z)-2-{5-[(4-ethylpiperazin-1-yl)methyl]pyridin-3-yl}-2-fluorovinyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide The title compound (3.4 g) was obtained by the method as described in Step 4 of Example 1, by using 3-[(Z)-2-fluoro-2-{5-[(4-ethylpiperazin-1-yl)methyl]pyridin-3-yl}vinyl]-4-methylbenzoic acid (4.7 g) obtained in Step 4 instead of 3-{[2-(cyclopropylamino)-1,3-thiazole-5-carbonyl]amino}-4-methylbenzoic acid.

[0438] Example 199: 5-[(Z)-2-{6-[(cyclopropylmethyl)amino]pyridin-3-yl}-2-fluorovinyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-6-methylpyridine-3-carboxamide [Step 1] Production of 5-[(Z)-2-(6-aminopyridin-3-yl)-2-fluorovinyl]-6-methylpyridine-3-carboxylic acid ethyl ester By using 5-bromopyridin-2-amine (114 mg) obtained in Step 2 of Example 180 and 5-[(Z)-2-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)vinyl]-6-methylpyridine-3-carboxylic acid ethyl ester instead of 2-chloropyrimidin-4-amine and isoquinolin-4-ylboronic acid, the title compound (40 mg) was obtained by the method described in Reference Example 14. MS (m / z): 302.1 [M+H] + [Step 2] Production of ethyl 5-[(Z)-2-{6-[(cyclopropylmethyl)amino]pyridin-3-yl}-2-fluorovinyl]-6-methylpyridine-3-carboxylate By using ethyl 5-[(Z)-2-(6-aminopyridin-3-yl)-2-fluorovinyl]-6-methylpyridine-3-carboxylate (60 mg) obtained in step 1 and cyclopropanecarboxaldehyde (19 mg) instead of 1-methylpiperazine and 5-bromopyridine-3-carboxaldehyde, the title compound (12 mg) was obtained by the method described in Reference Example 34. MS (m / z): 356.5 [M+H] + [Step 3] Production of 5-[(Z)-2-{6-[(cyclopropylmethyl)amino]pyridin-3-yl}-2-fluorovinyl]-6-methylpyridine-3-carboxylic acid By using ethyl 5-[(Z)-2-{6-[(cyclopropylmethyl)amino]pyridin-3-yl}-2-fluorovinyl]-6-methylpyridine-3-carboxylate (12 mg) obtained in Step 2 instead of methyl 5-[(cyclopropylmethyl)amino]pyridine-3-carboxylate, the title compound (11 mg) was obtained by the method described in Step 2 of Reference Example 1.

[0439] [Step 4] Production of 5-[(Z)-2-{6-[(cyclopropylmethyl)amino]pyridin-3-yl}-2-fluorovinyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-6-methylpyridine-3-carboxamide By using 5-[(Z)-2-{6-[(cyclopropylmethyl)amino]pyridin-3-yl}-2-fluorovinyl]-6-methylpyridine-3-carboxylic acid (11 mg) obtained in step 3 instead of 3-{[2-(cyclopropylamino)-1,3-thiazole-5-carbonyl]amino}-4-methylbenzoic acid, the title compound (10 mg) was obtained by the method described in step 4 of Example 1.

[0440] The compounds of Reference Examples and Examples are shown in Table 3 to Table 29 described below.

[0441] In the table, the referenced reference example means that the compound in question was produced by the method described in the method for producing the compound having the reference example number corresponding to the number using the corresponding starting materials, and for example, the reference example compound having the referenced reference example number 1 means that it was produced by the method described in reference example 1.

[0442] In the table, the referenced example means that the compound in question was produced by the method described in the method for producing the compound with the example number corresponding to that number using the corresponding starting materials, and for example, the example compound with the referenced example number 1 means that it was produced by the method described in Example 1.

[0443] In the table, chemical names refer to the names of compounds corresponding to reference example numbers and example numbers. In addition, data refer to instrumental analysis data such as mass spectrum data (m / z value), 1H NMR data (δ (ppm) of peak) and elemental analysis data (composition (%) of C, H and N).

[0444] [Table 3] [Table 4] [Table 5] [Table 6] [Table 7] [Table 8] [Table 9] [Table 10] [Table 11] [Table 12] [Table 13] [Table 14] [Table 15] [Table 16] [Table 17] [Table 18] [Table 19] [Table 20] [Table 21] [Table 22] [Table 23] [Table 24] [Table 25] [Table 26] [Table 27] [Table 28] [Table 29] Hereinafter, biological test examples for the compounds of the present invention will be shown.

[0445] <Test Example 1: PDGFR-β tyrosine kinase inhibition> 1. Preparation of Test Substances The test substance was prepared to 10 mM with dimethyl sulfoxide (DMSO) and diluted with DMSO to reach a concentration of 0.001-1000 μM. The DMSO solution was diluted 8-fold with assay buffer 1 (50 mM HEPES (pH 7.0), 0.02% NaN3, 0.01% bovine serum albumin, 0.1 mM orthovanadate, 1 mM dithiothreitol, 5 mM MgCl2, and 1 mM MnCl2), and further diluted 5-fold with assay buffer 2 (50 mM HEPES (pH 7.0), 0.02% NaN3, 0.01% bovine serum albumin, 0.1 mM orthovanadate, 1 mM dithiothreitol, 5 mM MgCl2, 1 mM MnCl2, and 40 nM supplemented enzyme buffer (cisbio)).

[0446] 2. Measurement of PDGFR-β Tyrosine Kinase Inhibition For measurement, the HTRF KinEASE-TK kit from Cisbio Bioassays SAS was used. To each 384-well plate, 4 μL of the test substance solution was added, followed by 2 μL of PDGFR-β enzyme solution (final concentration of 1 ng / L, CarnaBiosciences, Inc.), and 4 μL of substrate solution obtained by adding 0.6 μM ATP to TK substrate-3-biotin (cisbio), and the solution was reacted at 30°C for 30 minutes, with the final concentration of the test substance being 0.01-10,000 nM.

[0447] Thereafter, 10 μL of a detection solution (cisbio) was added to each well and allowed to react for 1 hour at 30° C. The fluorescence intensity was measured using a microplate reader (Spectra Max M5, Molecular device).

[0448] 3. Analysis of measurement results Using the fluorescence intensity ratio of each condition, the inhibition rate was calculated when the values ​​of the positive control (1% DMSO solution) and the negative control (enzyme (-)) were defined as 0% and 100%, respectively. Subsequently, nonlinear regression analysis of the two-parameter logistic model of log concentration and inhibition rate was performed using the SAS system (SAS Institute Inc.) to estimate the concentration of the test substance that inhibits PDGFR-β tyrosine kinase activity by 50% (IC 50 value).

[0449] The results are shown in Tables 30 to 33 below.

[0450] [Table 30] [Table 31] [Table 32] [Table 33] <Test Example 2: Inhibitory Effect on Proliferation of Cells Transfected with TEL-PDGFRβ and TEL-KIT Fusion Genes> 1. Preparation of Cells Transfected with TEL-PDGFRβ and TEL-KIT Fusion Genes The human TEL-PDGFRβ fusion gene (see, e.g., CELL, 1994, 77, 307-316) or human TEL-KIT fusion gene is inserted into the multiple cloning site of the retroviral expression vector pMYs-IRES-GFP to make a vector for gene transfection. For the human TEL-KIT fusion gene, an amino acid sequence important for the enzymatic activity of the KIT gene (accession number NP_000213.1, amino acids 521-928) was identified, and it was appropriately combined with the amino acid sequence of the TEL gene to produce a sequence that exhibits activation when there is no ligand factor. Subsequently, a transfection reagent (FuGENE6, Promega Corporation) was used to introduce the vector for gene transfection into packaging cells derived from the human fetal kidney cell line PLAT-E in the logarithmic growth phase. Since the culture supernatant of PLAT-E after gene transfection contains viral particles for gene transfection, it is collected and used as a culture medium for gene transfection. The medium for gene transfection was added to the plate coated with RetroNectin and incubated to allow viral particles to adhere to the plate. Then, the mouse pre-B cell line Ba / F3 in the logarithmic growth phase was inoculated on the plate and infected with the virus to produce cells that proliferate in a PDGFRβ or KIT-dependent manner.

[0451] 2. Preparation of Test Substances The test substance was prepared to 10 mM with dimethyl sulfoxide (DMSO), and diluted with DMSO to achieve a concentration of 0.0001-3 mM. In addition, it was diluted 100 times with distilled water.

[0452] 3. Measurement of inhibitory effect on proliferation of TEL-PDGFRβ or TEL-KIT expressing cells On the day after TEL-PDGFRβ and TEL-KIT expressing cells were seeded on 96-well plates, the prepared test substance solution was added thereto at a final concentration of 0.1-10,000 nM. After 72 hours, the tetrazolium salt compound was reduced by the mitochondrial dehydrogenase of the living cells to produce formazan. The amount of viable cells was measured.

[0453] 4. Analysis of measurement results Based on each condition When the negative control (0.1% DMSO solution) and blank (medium only) The inhibition rate of cell proliferation was calculated when the amount of α was defined as 0% and 100%, respectively. Subsequently, nonlinear regression analysis of the logarithmic dose and the inhibition rate of cell proliferation using a two-parameter logistic model was performed using the SAS system (SAS Institute Inc.) to estimate the IC 50 value.

[0454] The results are shown in Tables 34 to 38 below.

[0455] [Table 34] [Table 35] [Table 36] [Table 37] [Table 38] <Test Example 3: Inhibitory effect on proliferation of pulmonary artery smooth muscle cells> 1. Preparation of Test Substances The test substance was prepared to 10 mM with dimethyl sulfoxide (DMSO) and diluted with DMSO to a concentration of 0.003-3 mM. In addition, it was diluted 50 times with distilled water.

[0456] 2. Measurement of the Inhibitory Effect on Proliferation of Pulmonary Artery Smooth Muscle Cells On the day after healthy human-derived pulmonary artery smooth muscle cells were seeded onto 96-well plates using smooth muscle cell proliferation medium, the proliferation medium was replaced with 0.1% FBS medium and the cells were cultured for another day. The test substance solution was diluted 10 times with a medium containing BrdU and human PDGF-BB (final concentration of 10 ng / mL, Sigma-Aldrich) and added to the cells in equal amounts to achieve a final concentration of 3-10,000 nM. In addition, BrdU and 0.1% DMSO solution were added to the human PDGF-BB negative control. After 1 day of culture, the amount of BrdU absorbed by the proliferating cells was measured using an anti-BrdU antibody.

[0457] 3. Analysis of measurement results Based on the amount of BrdU under each condition, the inhibition rate of cell proliferation was calculated when the amount of BrdU in the positive control (human PDGF-BB (+)) and the negative control (human PDGF-BB (-)) was defined as 0% and 100%, respectively. Subsequently, nonlinear regression analysis of the logarithmic dose and the inhibition rate of cell proliferation using a two-parameter logistic model was performed using the SAS system (SAS Institute Inc.) to estimate the IC 50 value.

[0458] The results are shown in Tables 39 to 46 below.

[0459] [Table 39] [Table 40] [Table 41] [Table 42] [Table 43] [Table 44] [Table 45] [Table 46] <Test Example 4: Inhibitory effect on erythrocyte colony formation> 1. Preparation of Test Substances The test substance was prepared to 10 mM with dimethyl sulfoxide (DMSO), and diluted with DMSO to achieve a concentration of 0.1 to 3 mM, thereby preparing a test substance solution having a concentration 1000 times the final concentration.

[0460] 2. Measurement of Inhibitory Effects on Erythrocyte Colony Formation Human bone marrow CD34-positive hematopoietic stem cells were thawed and the cells were suspended in MethoCult medium. Then, the test substance solution was added thereto to reach a final concentration of 0.1-10 μM. The cells were seeded onto a 35 mm dish and cultured for 14 days. The number of erythroid progenitor cell-derived cell colonies was measured under a microscope.

[0461] 3. Analysis of measurement results Based on the number of colonies under each condition, the inhibition rate against colony formation was calculated when the negative control (0.1% DMSO solution) was defined as 100%, and nonlinear regression analysis of the logarithmic dose and the two-parameter logistic model against the inhibition rate of colony formation was performed using the SAS system (SAS Institute Inc.) to estimate the IC 50 The results are shown in Table 47 below.

[0462] [Table 47] Formulation Examples The following formulation examples are illustrative only and are not intended to limit the scope of the present invention in any way.

[0463] Preparation Example 1: Tablet (oral) In one formulated tablet of 80 mg The mixed powder of the components in the above proportions is compressed into oral tablets by conventional methods.

[0464] Industrial Applicability Since the compound of the present invention has inhibitory activity against PDGF receptor kinase, it is useful as a therapeutic agent for respiratory diseases, cancer, smooth muscle proliferative diseases, vascular proliferative diseases, autoimmune / inflammatory diseases, metabolic diseases, vascular occlusive diseases, and the like.

Claims

1. A compound represented by the following formula [1]: [Formula 1] in R 1 is a hydrogen atom, a halogen atom, a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C2-C6 alkenyl group, a C2-C6 haloalkenyl group, a C2-C6 alkynyl group, a C2-C6 haloalkynyl group, a C1-C6 alkoxy group, a hydroxyl group, a carboxyl group, an alkylcarbonyloxy group, an amino group, a monoalkylamino group, a dialkylamino group, an aminoalkyl group, an alkylcarbonylamino group, a nitro group, an optionally substituted C3-C6 cycloalkyl group, an optionally substituted C3-C6 cycloalkenyl group, an optionally substituted heterocycloalkyl group, an optionally substituted aryl group, or an optionally substituted heteroaryl group; R 2 For the key hand, -(CR a R b ) m -NR c -、-NR c -(CR a R b ) m -、-(CR a R b ) m -O-、-O-(CR a R b ) m -、-(CR a R b ) m -、-NR c -、-O-、-NR c -CO-NR c -、-CR a =CR b -or-C≡C-, where R 2 R a is a hydrogen atom, a halogen atom, a C1-C6 alkyl group or a C1-C6 haloalkyl group, and R 2 R b is a hydrogen atom, a halogen atom, a C1-C6 alkyl group or a C1-C6 haloalkyl group, or R 2 R a and R b Together with the carbon atoms to which they are bonded, they form C=O, R 2 Each R in c are independently a hydrogen atom, a C1-C6 alkyl group or a C1-C6 haloalkyl group, and m is an integer from 0 to 3; Het is a 5-10 membered heteroaryl group; L 1 For the key hand, -(CR a R b ) m -NR c -、-NR c -(CR a R b ) m -、-(CR a R b ) m -O-、-O-(CR a R b ) m -、-(CR a R b ) m -、-NR c -、-O-、-NR c -CO-NR c -、-CR a =CR b -or-C≡C-, where L 1 R a is a hydrogen atom, a halogen atom, a C1-C6 alkyl group or a C1-C6 haloalkyl group, and L 1 R b is a hydrogen atom, a halogen atom, a C1-C6 alkyl group or a C1-C6 haloalkyl group, or L 1 R a and R b Together with the carbon atoms to which they are bonded, they form C=O, L 1 Each R in c are independently a hydrogen atom, a C1-C6 alkyl group or a C1-C6 haloalkyl group, and L 1 Where m is an integer from 0 to 3; X is N or CR 3 ,in R 3 is a hydrogen atom, a halogen atom, a C1-C6 alkyl group or a C1-C6 haloalkyl group; R 4 is a hydrogen atom, a halogen atom or a methyl group; L 2 For the key hand, -(CR a R b ) m -NR c -、-NR c -(CR a R b ) m -、-(CR a R b ) m -O-、-O-(CR a R b ) m -、-(CR a R b ) m -、-NR c -、-O-、-NR c -CO-NR c -、-CR a =CR b -or-C≡C-, where L 2 R a is a hydrogen atom, a halogen atom, a C1-C6 alkyl group or a C1-C6 haloalkyl group, and L 2 R b is a hydrogen atom, a halogen atom, a C1-C6 alkyl group or a C1-C6 haloalkyl group, or L 2 R a and R b Together with the carbon atoms to which they are bonded, they form C=O, L 2 Each R in c are independently a hydrogen atom, a C1-C6 alkyl group or a C1-C6 haloalkyl group, and L 2 Where m is an integer from 0 to 3; R 5 is a hydrogen atom, a halogen atom, a hydroxyl group, an amino group, a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C1-C6 alkoxy group or a C1-C6 haloalkoxy group; and R 6 is a hydrogen atom, a halogen atom, a C1-C6 alkyl group, a C1-C6 haloalkyl group or an optionally substituted phenyl group, and R 7 is a hydrogen atom, a halogen atom, a C1-C6 alkyl group, a C1-C6 haloalkyl group, a hydroxyalkyl group, an optionally substituted phenyl group or an optionally substituted C3-C6 cycloalkyl group, or R 6 and R 7 Together with the carbon atom to which they are bonded, they form a C3-C6 cycloalkyl group, an optionally substituted aryl group or an optionally substituted heteroaryl group, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

2. The compound according to claim 1, wherein: R 1 is a hydrogen atom, a halogen atom, a C1-C6 alkyl group, a C2-C6 alkenyl group, a C1-C6 alkoxy group, an amino group, a monoalkylamino group, a dialkylamino group, an aminoalkyl group, an alkylcarbonylamino group, an optionally substituted C3-C6 cycloalkyl group, an optionally substituted heterocycloalkyl group, an optionally substituted aryl group, or an optionally substituted heteroaryl group; R 2 For the key hand, -(CR a R b ) m -NR c -、-(CR a R b ) m -O-、-(CR a R b ) m -、-NR c -、-O-、-NR c -CO-NR c -、-CR a =CR b -or-C≡C-; L 1 For the key hand, -(CR a R b ) m -NR c -、-NR c -(CR a R b ) m -、-(CR a R b ) m -O-、-O-(CR a R b ) m -、-(CR a R b ) m -、-NR c -、-CR a =CR b -or-C≡C-, where L 1 R a is a hydrogen atom, a halogen atom or a C1-C6 alkyl group, and L 1 R b is a hydrogen atom, a halogen atom or a C1-C6 alkyl group, or L 1 R a and L 1 R b Together with the carbon atoms to which they are bonded, they form C=O, L 1 Each R in c are independently a hydrogen atom, a C1-C6 alkyl group or a C1-C6 haloalkyl group, and L 1 Where m is an integer from 0 to 2; X is N or CR 3 ,in R 3 is a hydrogen atom, a halogen atom, a C1-C6 alkyl group or a C1-C6 haloalkyl group; R 4 is a hydrogen atom, a halogen atom or a methyl group; L 2 For-(CR a R b ) m -NR c -or-NR c -CO-NR c -,in L 2 R a and R b Together with the carbon atoms to which they are bonded, they form C=O, L 2 Each R in c are independently hydrogen atoms, and L 2 where m is 1; R 5 is hydroxyl; and R 6 is a hydrogen atom, a C1-C6 alkyl group or an optionally substituted phenyl group, and R 7 is a hydrogen atom, a C1-C6 alkyl group, a hydroxyalkyl group or an optionally substituted phenyl group, or R 6 and R 7 Together with the carbon atoms to which they are bonded, they form a C3-C6 cycloalkyl group or an optionally substituted aryl group. or a pharmaceutically acceptable salt or solvate thereof.

3. The compound according to claim 1, wherein: R 1 is a hydrogen atom, a C1-C6 alkoxy group, an amino group, a monoalkylamino group, an optionally substituted C3-C6 cycloalkyl group, an optionally substituted heterocycloalkyl group, an optionally substituted aryl group or an optionally substituted heteroaryl group; R 2 For the key hand, -(CR a R b ) m -O-、-(CR a R b ) m -or-NR c -; L 1 For-(CR a R b ) m -NR c -、-NR c -(CR a R b ) m -or-CR a =CR b -,in L 1 R a is a hydrogen atom or a halogen atom, and L 1 R b is a hydrogen atom, or L 1 R a and R b Together with the carbon atoms to which they are bonded, they form C=O, L 1 Each R in c are independently hydrogen atoms, and L 1 Where m is 0 or 1; X is N or CR 3 ,in R 3 is a hydrogen atom; R 4 is a halogen atom or a methyl group; L 2 For-(CR a R b ) m -NR c -,in L 2 R a and R b Together with the carbon atoms to which they are bonded, they form C=O, L 2 Each R in c are independently hydrogen atoms, and L 2 where m is 1; R 5 is hydroxyl; and R 6 and R 7 Together with the carbon atoms to which they are bonded, they form a C3-C6 cycloalkyl group. or a pharmaceutically acceptable salt or solvate thereof.

4. The compound according to claim 1, which is selected from the following (1) to (207): (1) 2-(cyclopropylamino)-N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)-1,3-thiazole-5-carboxamide, (2) N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)-5-phenylpyridine-3-carboxamide, (3) 2-(cyclopropylmethyl)-N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)-1,3-thiazole-5-carboxamide, (4) 5-(cyclopropylamino)-N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)pyridine-3-carboxamide, (5) N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)-2-phenyl-1,3-oxazole-5-carboxamide, (6) N-(5-{[(1S)-2-hydroxy-1-phenylethyl]carbamoyl}-2-methylphenyl)-5-phenylpyridine-3-carboxamide, (7) N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)-5-[(propan-2-yl)oxy]pyridine-3-carboxamide, (8) 2-[(cyclopropylmethyl)amino]-N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)-1,3-thiazole-5-carboxamide, (9) 5-(4-chlorophenyl)-N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)pyridine-3-carboxamide, (10) N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)-2-propyl-1,3-thiazole-5-carboxamide, (11) 5-(3-chlorophenyl)-N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)pyridine-3-carboxamide, (12) N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)-5-(2-methylphenyl)pyridine-3-carboxamide, (13) 5-(2-chlorophenyl)-N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)pyridine-3-carboxamide, (14) N-(5-{[(2S)-1-hydroxypentan-2-yl]carbamoyl}-2-methylphenyl)-5-phenylpyridine-3-carboxamide, (15) 5-[(E)-2-cyclopropylvinyl]-N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)pyridine-3-carboxamide, (16) 5-[(cyclopropylmethyl)amino]-N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)pyridine-3-carboxamide, (17) 5-[cyclopropyl(methyl)amino]-N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)pyridine-3-carboxamide, (18) N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)-5-(4-methoxyphenyl)pyridine-3-carboxamide, (19) 5-(4-fluorophenyl)-N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)pyridine-3-carboxamide, (20) 5-(3-fluorophenyl)-N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)pyridine-3-carboxamide, (21) N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)-5-[4-(trifluoromethyl)phenyl]pyridine-3-carboxamide, (22) N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)-5-[3-(trifluoromethyl)phenyl]pyridine-3-carboxamide, (23) N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)-5-(2-methylprop-1-en-1-yl)pyridine-3-carboxamide, (24) 5-(cyclopropylmethoxy)-N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)pyridine-3-carboxamide, (25) 2-[(3,3-difluorocyclobutyl)amino]-N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)-1,3-thiazole-5-carboxamide, (26) 2-[(2-cyclopropylethyl)amino]-N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)-1,3-thiazole-5-carboxamide, (27) N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)-2-[(propan-2-yl)amino]-1,3-thiazole-5-carboxamide, (28) 5-[(4,4-difluorocyclohexyl)oxy]-N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)pyridine-3-carboxamide, (29) 5-(2-fluorophenyl)-N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)pyridine-3-carboxamide, (30) 5-(2,3-difluorophenyl)-N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)pyridine-3-carboxamide, (31) 5-(2,4-difluorophenyl)-N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)pyridine-3-carboxamide, (32) 5-(3,5-difluorophenyl)-N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)pyridine-3-carboxamide, (33) 5-(2-fluoro-4-methoxyphenyl)-N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)pyridine-3-carboxamide, (34) N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)-5-[3-(trifluoromethoxy)phenyl]pyridine-3-carboxamide, (35) N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)-5-[2-(trifluoromethoxy)phenyl]pyridine-3-carboxamide, (36) 5-[2-fluoro-4-(trifluoromethyl)phenyl]-N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)pyridine-3-carboxamide, (37) 5-(2,6-difluorophenyl)-N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)pyridine-3-carboxamide, (38) 2-(tert-butylamino)-N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)-1,3-thiazole-5-carboxamide, (39) N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)-2-[(1-methylcyclopropyl)amino]-1,3-thiazole-5-carboxamide, (40) N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)-2-[(1-methylcyclobutyl)amino]-1,3-thiazole-5-carboxamide, (41) 2-[(2,2-dimethylpropyl)amino]-N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)-1,3-thiazole-5-carboxamide, (42) N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)-5-(3,4,5-trifluorophenyl)pyridine-3-carboxamide, (43) 5-(4-cyclopropylphenyl)-N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)pyridine-3-carboxamide, (44) N-(2-chloro-5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}phenyl)-5-(cyclopropylmethoxy)pyridine-3-carboxamide, (45) N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)imidazo[2,1-b][1,3]thiazole-5-carboxamide, (46) 5-(cyclopropylmethoxy)-N-(3-fluoro-5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)pyridine-3-carboxamide, (47) 5-[(3,3-difluorocyclobutyl)oxy]-N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)pyridine-3-carboxamide, (48) 2-(cyclopropylmethyl)-N-(3-fluoro-5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)-1,3-thiazole-5-carboxamide, (49) N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)-5-methoxypyridine-3-carboxamide, (50) 5-ethoxy-N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)pyridine-3-carboxamide, (51) N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)-5-[(pyridin-2-yl)oxy]pyridine-3-carboxamide, (52) N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)-5-[(pyrimidin-2-yl)oxy]pyridine-3-carboxamide, (53) N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)-5-[(1-methylcyclopropyl)methoxy]pyridine-3-carboxamide, (54) 5-[(3,3-difluorocyclobutyl)methoxy]-N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)pyridine-3-carboxamide, (55) N-(2-chloro-5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}phenyl)-2-(cyclopropylmethyl)-1,3-thiazole-5-carboxamide, (56) 5-(cyclopropylmethoxy)-N-(2-fluoro-5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}phenyl)pyridine-3-carboxamide, (57) 3-[(5-bromopyridin-3-yl)ethynyl]-4-chloro-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide, (58) 4-chloro-N-[(1S,2S)-2-hydroxycyclohexyl]-3-[(5-phenylpyridin-3-yl)ethynyl]benzamide, (59) N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-[(5-methylpyridin-3-yl)ethynyl]benzamide, (60) N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-[(5-phenylpyridin-3-yl)ethynyl]benzamide, (61) 3-[(5-bromopyridin-3-yl)ethynyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide, (62) N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-{[5-(pyrimidin-2-yl)pyridin-3-yl]ethynyl}benzamide, (63) N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-{[5-(pyrazin-2-yl)pyridin-3-yl]ethynyl}benzamide, (64) 4-chloro-N-[(1S,2S)-2-hydroxycyclohexyl]-3-{[5-(pyrimidin-2-yl)pyridin-3-yl]ethynyl}benzamide, (65) 3-[(6-aminopyridin-3-yl)ethynyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide, (66) 3-[([2,3'-bipyridyl]-5'-yl)ethynyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide, (67) 3-[(5-cyclopropylpyridin-3-yl)ethynyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide, (68) 3-[(6-cyclopropylpyrazin-2-yl)ethynyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide, (69) 3-{[6-(2-fluorophenyl)pyrazin-2-yl]ethynyl}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide, (70) 3-{[6-(3-fluorophenyl)pyrazin-2-yl]ethynyl}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide, (71) 3-{[6-(4-fluorophenyl)pyrazin-2-yl]ethynyl}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide, (72) 3-({6-[(cyclopropylmethyl)amino]pyrazin-2-yl}ethynyl)-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide, (73) 5-[(5-cyclopropylpyridin-3-yl)ethynyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-6-methylpyridine-3-carboxamide, (74) 3-[(6-bromopyrazin-2-yl)ethynyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide, (75) N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-[(6-phenylpyrazin-2-yl)ethynyl]benzamide, (76) 3-[(5-bromopyridin-3-yl)ethynyl]-N-[(1S,2S)-1,3-dihydroxy-1-phenylpropan-2-yl]-4-methylbenzamide, (77)N 1 -[(1S,2S)-2-Hydroxycyclohexyl]-4-methyl-N 3 -(5-phenylpyridin-3-yl)benzene-1,3-dicarboxamide, (78) N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-{[2-(pyridin-3-yl)pyrimidin-4-yl]amino}benzamide, (79) N-[(1S,2S)-2-hydroxycyclohexyl]-3-{[2-(isoquinolin-4-yl)pyrimidin-4-yl]amino}-4-methylbenzamide, (80) N-[(1S,2S)-1,3-dihydroxy-1-phenylpropan-2-yl]-3-{[2-(isoquinolin-4-yl)pyrimidin-4-yl]amino}-4-methylbenzamide, (81) 3-[([2,3'-bipyridyl]-6-yl)amino]-5-fluoro-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide, (82) N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-{[2-(methylamino)quinazolin-5-yl]amino}benzamide, (83) 3-(2-amino-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-N-[(1S,2S)-1,3-dihydroxy-1-phenylpropan-2-yl]-4-methylbenzamide, (84) N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-{[(1S)-1-(5-phenylpyridin-3-yl)ethyl]amino}benzamide, (85) 3-{[(1S)-1-([3,3'-bipyridinyl]-5-yl)ethyl]amino}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide, (86) N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-({(1S)-1-[5-(phenylethynyl)pyridin-3-yl]ethyl}amino)benzamide, (87) 3-{[(1S)-1-([3,4'-bipyridyl]-5-yl)ethyl]amino}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide, (88) N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-({(1S)-1-[5-(pyrimidin-2-yl)pyridin-3-yl]ethyl}amino)benzamide, (89) 3-{[(1S)-1-([2,3'-bipyridyl]-5'-yl)ethyl]amino}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide, (90) 3-{[(1S)-1-([3,3'-bipyridyl]-5-yl)ethyl]amino}-4-chloro-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide, (91) 3-{[(5-bromopyridin-3-yl)methyl]amino}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide, (92) N-[(1S,2S)-2-Hydroxycyclohexyl]-4-methyl-3-{[(5-phenylpyridin-3-yl)methyl]amino}benzamide, (93) 3-{[([3,3'-bipyridyl]-5-yl)methyl]amino}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide, (94) 3-({[5-(cyclopropylethynyl)pyridin-3-yl]methyl}amino)-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide, (95) N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-({[5-(pyrimidin-2-yl)pyridin-3-yl]methyl}amino)benzamide, (96) N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-{[(quinolin-3-yl)methyl]amino}benzamide, (97) N-[(1S,2S)-2-hydroxycyclohexyl]-3-[({5-[(1-hydroxycyclopropyl)ethynyl]pyridin-3-yl}methyl)amino]-4-methylbenzamide, (98) 3-[({5-[4-(2-aminopropan-2-yl)phenyl]pyridin-3-yl}methyl)amino]-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide, (99) 3-({[5-(4-aminophenyl)pyridin-3-yl]methyl}amino)-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide, (100) 3-({[5-(3,5-difluorophenyl)pyridin-3-yl]methyl}amino)-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide, (101) N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-{[(6-phenylpyrazin-2-yl)methyl]amino}benzamide, (102) N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-({[5-(thiophen-2-yl)pyridin-3-yl]methyl}amino)benzamide, (103) N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-({[5-(thiophen-3-yl)pyridin-3-yl]methyl}amino)benzamide, (104) 4-chloro-N-[(1S,2S)-2-hydroxycyclohexyl]-3-({[5-(pyrimidin-2-yl)pyridin-3-yl]methyl}amino)benzamide, (105) N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-{[(pyrazolo[5,1-b][1,3]thiazol-7-yl)methyl]amino}benzamide, (106) 3-fluoro-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-5-({[5-(pyrimidin-2-yl)pyridin-3-yl]methyl}amino)benzamide, (107) 3-({[5-(5-fluoropyrimidin-2-yl)pyridin-3-yl]methyl}amino)-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide, (108) N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-{[(thieno[3,2-b]pyridin-6-yl)methyl]amino}benzamide, (109) N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-{[(1H-pyrazolo[3,4-b]pyridin-5-yl)methyl]amino}benzamide, (110) N-[(1S,2S)-2-hydroxycyclohexyl]-3-{[(imidazo[1,2-b]pyridazin-3-yl)methyl]amino}-4-methylbenzamide, (111) N-[(1S,2S)-2-hydroxycyclohexyl]-3-({[5-(imidazo[1,2-a]pyrazin-6-yl)pyridin-3-yl]methyl}amino)-4-methylbenzamide, (112) N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-({[1-(pyridin-2-yl)-1H-pyrazol-4-yl]methyl}amino)benzamide, (113) 3-{[(2-aminopyrimidin-5-yl)methyl]amino}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide, (114) 3-({[2-(cyclopropylamino)pyrimidin-5-yl]methyl}amino)-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide, (115) N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-({[5-(pyrazin-2-yl)pyridin-3-yl]methyl}amino)benzamide, (116) 3-{[(6-acetylaminopyridin-3-yl)methyl]amino}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide, (117) 3-[({6-[(cyclopropylmethyl)amino]pyridin-3-yl}methyl)amino]-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide, (118) 3-{[([2,2'-bipyridyl]-5-yl)methyl]amino}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide, (119) N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-{[(pyrazolo[1,5-a]pyrimidin-3-yl)methyl]amino}benzamide, (120) 3-[({6-[(cyclopropanecarbonyl)amino]pyridin-3-yl}methyl)amino]-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide, (121) N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-{[(2-phenylpyrimidin-5-yl)methyl]amino}benzamide, (122) N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-({[6-(1H-pyrazol-1-yl)pyridin-3-yl]methyl}amino)benzamide, (123) N-[(1S,2S)-2-hydroxycyclohexyl]-6-methyl-5-{[(pyrazolo[1,5-a]pyridin-3-yl)methyl]amino}pyridine-3-carboxamide, (124) methyl {5-[(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylanilino)methyl]pyridin-2-yl}carbamate, (125) N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-[({6-[(oxan-4-yl)amino]pyridin-3-yl}methyl)amino]benzamide, (126) N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-[({2-[(pyridin-2-yl)amino]pyrimidin-5-yl}methyl)amino]benzamide, (127) N-{5-[(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylanilino)methyl]pyridin-2-yl}morpholine-4-carboxamide, (128) N-[(1S,2S)-2-hydroxycyclohexyl]-3-({[2-(4-methoxyphenyl)pyrimidin-5-yl]methyl}amino)-4-methylbenzamide, (129) N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-{[(6-{[(pyridin-3-yl)carbamoyl]amino}pyridin-3-yl)methyl]amino}benzamide, (130) 3-({[6-(cyclobutylamino)pyridin-3-yl]methyl}amino)-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide (131) 3-{[(5-aminopyrazin-2-yl)methyl]amino}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide, (132) N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-[({2-[(oxan-4-yl)amino]pyrimidin-5-yl}methyl)amino]benzamide, (133) 3-{[(6-{[cyclopropyl(methyl)carbamoyl]amino}pyridin-3-yl)methyl]amino}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide, (134) N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-[({6-[(propan-2-yl)amino]pyridin-3-yl}methyl)amino]benzamide, (135) N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-{[(2-{[(3R)-oxolan-3-yl]amino}pyrimidin-5-yl)methyl]amino}benzamide, (136) N-[(1S,2S)-2-Hydroxycyclohexyl]-4-methyl-3-{[(2-{[(3S)-oxolan-3-yl]amino}pyrimidin-5-yl)methyl]amino}benzamide (137) N-{5-[(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylanilino)methyl]pyridin-2-yl}oxane-4-carboxamide, (138) N-[(1S,2S)-2-hydroxycyclohexyl]-3-{[(6-{[(1r,3r)-3-methoxycyclobutane-1-carbonyl]amino}pyridin-3-yl)methyl]amino}-4-methylbenzamide, (139) N-{5-[(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylanilino)methyl]pyridin-2-yl}oxolane-3-carboxamide, (140) N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-({[6-(1H-1,2,3-triazol-1-yl)pyridin-3-yl]methyl}amino)benzamide, (141) N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-[({6-[(oxetan-3-yl)amino]pyridin-3-yl}methyl)amino]benzamide, (142) 3-{[(2-aminopyrimidin-5-yl)methyl]amino}-4-chloro-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide, (143) 3-{[(2-aminopyrimidin-5-yl)methyl]amino}-5-fluoro-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide, (144) 3-{[(3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)methyl]amino}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide, (145) N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-({[5-(2H-1,2,3-triazol-2-yl)pyridin-3-yl]methyl}amino)benzamide, (146) 3-{[([3,3'-bipyridyl]-5-yl)amino]methyl}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide, (147) N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-({[5-(pyrimidin-2-yl)pyridin-3-yl]amino}methyl)benzamide, (148) 3-{[([2,3'-bipyridyl]-5'-yl)amino]methyl}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide, (149) N-[(1R,2R)-2-hydroxycyclohexyl]-4-methyl-3-({[5-(pyrimidin-2-yl)pyridin-3-yl]amino}methyl)benzamide, (150) N-[(1S,2S)-2-hydroxycyclohexyl]-3-({[5-(pyrimidin-2-yl)pyridin-3-yl]amino}methyl)benzamide, (151) 4-fluoro-N-[(1S,2S)-2-hydroxycyclohexyl]-3-({[5-(pyrimidin-2-yl)pyridin-3-yl]amino}methyl)benzamide, (152) 3-{[(5-bromopyridin-3-yl)amino]methyl}-N-[(1S,2S)-1,3-dihydroxy-1-phenylpropan-2-yl]-4-methylbenzamide, (153) N-[(1S,2S)-1,3-dihydroxy-1-phenylpropan-2-yl]-4-methyl-3-{[(5-phenylpyridin-3-yl)amino]methyl}benzamide, (154) 3-{[(5-cyclopropylpyridin-3-yl)amino]methyl}-N-[(1S,2S)-1,3-dihydroxy-1-phenylpropan-2-yl]-4-methylbenzamide, (155) 3-{[([2,3'-bipyridyl]-5'-yl)amino]methyl}-N-[(1S,2S)-1,3-dihydroxy-1-phenylpropan-2-yl]-4-methylbenzamide, (156) N-[(1S,2S)-1,3-dihydroxy-1-phenylpropan-2-yl]-4-methyl-3-{[(6-phenylpyrazin-2-yl)amino]methyl}benzamide, (157) 5-({[5-(cyclopropylethynyl)pyridin-3-yl]amino}methyl)-N-[(1S,2S)-2-hydroxycyclohexyl]-6-methylpyridine-3-carboxamide, (158) N-[3-({[6-(3,4-dimethoxyphenyl)pyrazin-2-yl]amino}methyl)phenyl]-N'-[(1R,2S)-2-hydroxycyclohexyl]urea, (159) N-[(1R,2S)-2-hydroxycyclohexyl]-N'-[3-({[5-(pyrimidin-2-yl)pyridin-3-yl]amino}methyl)phenyl]urea, (160) N-[2-fluoro-5-({[5-(pyrimidin-2-yl)pyridin-3-yl]amino}methyl)phenyl]-N'-[(1R,2S)-2-hydroxycyclohexyl]urea, (161) N-[4-fluoro-3-({[5-(pyrimidin-2-yl)pyridin-3-yl]amino}methyl)phenyl]-N'-[(1R,2S)-2-hydroxycyclohexyl]urea, (162) N-[(1R,2S)-2-hydroxycyclohexyl]-N'-[4-methyl-3-({[5-(pyrimidin-2-yl)pyridin-3-yl]amino}methyl)phenyl]urea, (163) N-[(1R,2S)-2-hydroxycyclohexyl]-N'-[2-methyl-5-({[5-(pyrimidin-2-yl)pyridin-3-yl]amino}methyl)phenyl]urea, (164) N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-{1-[(6-phenylpyrazin-2-yl)amino]ethyl}benzamide, (165) 3-[([3,3'-bipyridyl]-5-yl)methoxy]-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide, (166) N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-{[5-(pyrimidin-2-yl)pyridin-3-yl]methoxy}benzamide, (167) 4-chloro-N-[(1S,2S)-2-hydroxycyclohexyl]-3-{[5-(pyrimidin-2-yl)pyridin-3-yl]methoxy}benzamide, (168) 3-{[([3,3'-bipyridyl]-5-yl)oxy]methyl}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide, (169) N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-({[5-(pyrimidin-2-yl)pyridin-3-yl]oxy}methyl)benzamide, (170) 4-chloro-N-[(1S,2S)-2-hydroxycyclohexyl]-3-({[5-(pyrimidin-2-yl)pyridin-3-yl]oxy}methyl)benzamide, (171) N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-{1-[5-(pyrimidin-2-yl)pyridin-3-yl]ethoxy}benzamide, (172) N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-[1-(5-phenylpyridin-3-yl)ethoxy]benzamide, (173) N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-[(E)-2-(5-phenylpyridin-3-yl)vinyl]benzamide, (174) N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-[2-(5-phenylpyridin-3-yl)ethyl]benzamide, (175) N-[(1S,2S)-2-Hydroxycyclohexyl]-4-methyl-3-{[methyl(5-phenylpyridin-3-yl)amino]methyl}benzamide, (176) 3-{[ethyl(5-phenylpyridin-3-yl)amino]methyl}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide, (177) 3-[(Z)-2-([2,3'-bipyridyl]-5'-yl)-2-fluorovinyl]-4-fluoro-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide, (178) 4-fluoro-3-{(Z)-2-fluoro-2-[5-(pyrimidin-2-yl)pyridin-3-yl]vinyl}-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide, (179) 3-[(Z)-2-fluoro-2-(imidazo[1,2-b]pyridazin-3-yl)vinyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide, (180) 5-[(Z)-2-([2,3'-bipyridyl]-5'-yl)-2-fluorovinyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-6-methylpyridine-3-carboxamide, (181) 3-[(Z)-2-fluoro-2-{5-[(4-methylpiperazin-1-yl)methyl]pyridin-3-yl}vinyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide, (182) 3-[(Z)-2-fluoro-2-{5-[(morpholin-4-yl)methyl]pyridin-3-yl}vinyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide, (183) 3-[(Z)-2-{6-[(cyclopropylmethyl)amino]pyridin-3-yl}-2-fluorovinyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide, (184) 4-fluoro-3-{(Z)-2-fluoro-2-[5-(morpholin-4-yl)pyridin-3-yl]vinyl}-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide, (185) 4-fluoro-3-[(Z)-2-fluoro-2-{5-[(oxan-4-yl)amino]pyridin-3-yl}vinyl]-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide, (186) 4-fluoro-3-[(Z)-2-fluoro-2-{5-[(4-methylpiperazin-1-yl)methyl]pyridin-3-yl}vinyl]-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide, (187) 5-{(Z)-2-[5-(cyclopropylmethoxy)pyridin-3-yl]-2-fluorovinyl}-N-[(1S,2S)-2-hydroxycyclohexyl]-6-methylpyridine-3-carboxamide, (188) 5-{(Z)-2-fluoro-2-[5-(morpholin-4-yl)pyridin-3-yl]vinyl}-N-[(1S,2S)-2-hydroxycyclohexyl]-6-methylpyridine-3-carboxamide, (189) 5-[(Z)-2-(6-aminopyridin-3-yl)-2-fluorovinyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-6-methylpyridine-3-carboxamide, (190) 5-[(Z)-2-(2-aminopyrimidin-5-yl)-2-fluorovinyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-6-methylpyridine-3-carboxamide, (191) 3-[(Z)-2-(6-aminopyridin-3-yl)-2-fluorovinyl]-4-fluoro-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide, (192) 3-[(Z)-2-(2-aminopyrimidin-5-yl)-2-fluorovinyl]-4-fluoro-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide, (193) 3-[(Z)-2-fluoro-2-{5-[(1-methylpiperidin-4-yl)amino]pyridin-3-yl}vinyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide, (194) 3-[(Z)-2-{5-[(4-ethylpiperazin-1-yl)methyl]pyridin-3-yl}-2-fluorovinyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide, (195) 5-[(Z)-2-fluoro-2-{5-[(oxetan-3-yl)amino]pyridin-3-yl}vinyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-6-methylpyridine-3-carboxamide, (196) 4-fluoro-3-[(Z)-2-fluoro-2-{5-[(oxetan-3-yl)amino]pyridin-3-yl}vinyl]-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide, (197) 3-[(Z)-2-(6-{[2-(dimethylamino)ethyl]amino}pyridin-3-yl)-2-fluorovinyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide, (198) 3-[(Z)-2-(5-{[2-(dimethylamino)ethyl]amino}pyridin-3-yl)-2-fluorovinyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide, (199) 5-[(Z)-2-{6-[(cyclopropylmethyl)amino]pyridin-3-yl}-2-fluorovinyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-6-methylpyridine-3-carboxamide, (200) 3-[(Z)-2-fluoro-2-{5-[(4-methylpiperazin-1-yl)methyl]pyridin-3-yl}vinyl]-N-[(1S,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]-4-methylbenzamide, (201) 3-[(Z)-2-fluoro-2-{5-[(4-methylpiperazin-1-yl)methyl]pyridin-3-yl}vinyl]-N-(2-hydroxy-3,3-dimethylbutyl)-4-methylbenzamide, (202) 3-[(Z)-2-{2-[(cyclopropylmethyl)amino]pyrimidin-5-yl}-2-fluorovinyl]-4-fluoro-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide, (203) 3-{(Z)-2-[2-(cyclopropylamino)pyrimidin-5-yl]-2-fluorovinyl}-4-fluoro-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide, (204) 3-[(Z)-2-(2-amino-4-methylpyrimidin-5-yl)-2-fluorovinyl]-4-fluoro-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide, (205) 4-fluoro-3-{(Z)-2-fluoro-2-[2-(methylamino)pyrimidin-5-yl]vinyl}-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide, (206) 3-[(Z)-2-(5-aminopyrazin-2-yl)-2-fluorovinyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide, and (207) 4-fluoro-3-[(Z)-2-fluoro-2-(5-fluoropyridin-3-yl)vinyl]-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide or a pharmaceutically acceptable salt or solvate thereof.

5. The compound according to claim 1, which is selected from the following (1) to (15): (1) 2-(cyclopropylmethyl)-N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)-1,3-thiazole-5-carboxamide, (2) 5-[cyclopropyl(methyl)amino]-N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)pyridine-3-carboxamide, (3) 5-(3-fluorophenyl)-N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)pyridine-3-carboxamide, (4) 5-(cyclopropylmethoxy)-N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)pyridine-3-carboxamide, (5) 5-ethoxy-N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)pyridine-3-carboxamide, (6) 3-{[(2-aminopyrimidin-5-yl)methyl]amino}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide, (7) N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-{[(pyrazolo[1,5-a]pyrimidin-3-yl)methyl]amino}benzamide, (8) N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-[({2-[(oxan-4-yl)amino]pyrimidin-5-yl}methyl)amino]benzamide, (9) N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-({[6-(1H-1,2,3-triazol-1-yl)pyridin-3-yl]methyl}amino)benzamide, (10) 3-{[([2,3'-bipyridyl]-5'-yl)amino]methyl}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide, (11) 5-[(Z)-2-(6-aminopyridin-3-yl)-2-fluorovinyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-6-methylpyridine-3-carboxamide, (12) 3-[(Z)-2-{5-[(4-ethylpiperazin-1-yl)methyl]pyridin-3-yl}-2-fluorovinyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide, (13) 4-fluoro-3-{(Z)-2-fluoro-2-[2-(methylamino)pyrimidin-5-yl]vinyl}-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide, (14) 3-[(Z)-2-(5-aminopyrazin-2-yl)-2-fluorovinyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide, and (15) 4-fluoro-3-[(Z)-2-fluoro-2-(5-fluoropyridin-3-yl)vinyl]-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide or a pharmaceutically acceptable salt or solvate thereof.

6. A pharmaceutical composition comprising the compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt or solvate thereof as an active ingredient.

7. A PDGF receptor kinase inhibitor comprising the compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt or solvate thereof as an active ingredient.

8. A therapeutic agent for pulmonary hypertension, scleroderma, asthma, bronchiolitis obliterans, pulmonary fibrosis, acute myeloid leukemia (AML), hypereosinophilic syndrome, T-lymphocytic leukemia, chronic myelomonocytic leukemia (CMML), chronic myeloid leukemia (CML), chronic eosinophilic leukemia, dermatofibrosarcoma protuberans, glioma, ovarian cancer, vascular restenosis, atherosclerosis / arteriosclerosis obliterans, moyamoya disease (idiopathic Willis circle occlusion), leiomyoma, lymphangioleiomyomatosis or age-related macular degeneration (AMD), wherein PDGF receptor kinase is involved, and the therapeutic agent comprises a compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof or a solvate thereof as an active ingredient.

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