Compound as pdgf receptor kinase inhibitor, and composition

Abstract

To provide a medicine for preventing and / or treating pulmonary arterial pulmonary hypertension.SOLUTION: Provided is a compound represented by formula [1], or a pharmaceutically acceptable salt, or a solvate thereof. (R1, R5, R6, and R7 are halogen, C1-C6 alkyl and the like. R4 is H, a halogen, or methyl. R2, L1, L2 are bonds, (CRaRb)m, NRc and the like. (Ra and Rb are halogen, C1-C6 alkyl and the like. Rc is H, C1-C6 alkyl and the like. m is 0 to 3.) X is N or CR3. (R3 is H, halogen, C1-C6 alkyl and the like. Het is 5 through 10 membered heteroaryl.)SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to a preventive and / or therapeutic agent for pulmonary hypertension, which contains a novel heterocyclic derivative as an active ingredient. [Background technology]

[0002] In Europe and the United States, large-scale symposiums on pulmonary hypertension (PAH) are held every five years. At the 2008 Dana Point Conference, pulmonary hypertension was defined as a mean pulmonary artery pressure (PAP) of 25 mmHg or greater measured by right heart catheterization at rest. This definition was also adopted at the 2013 Nice Conference. The Dana Point Classification classifies pulmonary hypertension into five groups: Group 1: PAH; Group 2: pulmonary hypertension associated with left heart disease; Group 3: pulmonary hypertension associated with lung disease and / or hypoxemia; Group 4: chronic thromboembolic pulmonary hypertension (CTEPH); and Group 5: pulmonary hypertension associated with an unspecified multifactorial mechanism. This basic structure has been maintained in the revised Clinical Classification of Pulmonary Hypertension (Nice Classification

[2013] ) (Non-Patent Document 1). Furthermore, an updated definition of pulmonary hypertension was proposed at the 6th World Symposium on Pulmonary Hypertension (Nice Conference 2018), which defined a mean pulmonary artery pressure (mPAP) of 24 mmHg or greater as >20 mmHg as being included in the above definition.

[0003] Platelet-derived growth factor (PDGF) can stimulate the migration of arterial smooth muscle cells from the inside of the artery to the intimal layer where muscle cells can proliferate. Cell proliferation induced by all PDGF isoforms is mediated by ligand binding to the PDGF receptor. The PDGF receptor belongs to the class III tyrosine kinase family and consists of two receptor subtypes, termed type A (or type alpha) and type B (or type beta). Other members of the PDGF receptor family include colony stimulating factor 1 receptor (CSF1R), KIT, and FLT3. KIT is another receptor tyrosine kinase that belongs to the PDGF receptor family and is normally expressed in hematopoietic progenitor cells, mast cells, and germ cells. KIT expression is known to be involved in several cancers, including mast cell leukemia, germ cell tumors, small cell lung cancer, gastrointestinal stromal tumors (GISTs), acute myeloid leukemia (AML), neuroblastoma, melanoma, ovarian cancer, and breast cancer (Non-Patent Document 1).

[0004] Imatinib inhibits PDGF receptor kinase and showed efficacy in Phase 3 trials for pulmonary arterial hypertension. However, it was not approved due to poor tolerability caused by side effects such as bone marrow suppression.

[0005] Patent Document 1 describes that the compound of general formula [1] or a pharmaceutically acceptable salt thereof is an inhibitor of PDGF receptor kinase or PDGF receptor kinase and KIT.

[0006] However, the relationship between the bone marrow suppression effect and the inhibitory effect of KIT, a receptor tyrosine kinase involved in myelopoiesis, was unknown until now. [Prior art documents] [Patent documents]

[0007] [Patent Document 1] WO2013 / 033620 issue [Non-patent literature]

[0008] [Non-Patent Document 1] Smolich et al., Blood, 97, 1413-1421. Summary of the Invention [Problem to be solved by the invention]

[0009] The problem to be solved by the present invention is to provide an agent for preventing and / or treating pulmonary arterial hypertension that has an excellent balance between efficacy and safety. [Means for solving the problem]

[0010] The present inventors have found a correlation between myelosuppressive activity and inhibitory activity against KIT, a receptor tyrosine kinase involved in myelopoiesis. Specifically, the present inventors have found that a compound represented by the following general formula [1] or a pharmaceutically acceptable salt or solvate thereof (hereinafter sometimes referred to as the "compound of the present invention"), which has a higher inhibitory activity against PDGF receptor kinase than against KIT kinase, exhibits an inhibitory effect on proliferation of pulmonary artery smooth muscle cells and a reduced inhibitory effect on erythroid colony formation, thereby completing the present invention.

[0011] That is, the present invention can include the following (Item 1) to (Item 8). (Section 1) The following formula [1] [ka] [In the formula, R 1is a hydrogen atom, a halogen atom, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkynyl, C2-C6 haloalkynyl, C1-C6 alkoxy, hydroxy, carboxy, alkylcarbonyloxy, amino, monoalkylamino, dialkylamino, aminoalkyl, alkylcarbonylamino, nitro, optionally substituted C3-C6 cycloalkyl, optionally substituted C3-C6 cycloalkenyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; R 2 is a bond, -(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-, R 2 R in a is a hydrogen atom, a halogen atom, C1-C6 alkyl, or C1-C6 haloalkyl, R 2 R in b is a hydrogen atom, a halogen atom, C1-C6 alkyl, or C1-C6 haloalkyl, or R 2 R in a and R b together with the carbon atom to which they are attached to form C=O, R 2 R inc are each independently a hydrogen atom, C1-C6 alkyl, or C1-C6 haloalkyl; m is an integer from 0 to 3; Het is a 5- to 10-membered heteroaryl; L 1 is a bond, -(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 in a is a hydrogen atom, a halogen atom, C1-C6 alkyl, or C1-C6 haloalkyl, L 1 R in b is a hydrogen atom, a halogen atom, C1-C6 alkyl, or C1-C6 haloalkyl, or L 1 R in a and R b together with the carbon atom to which they are attached to form C=O, and L 1 R in c are each independently a hydrogen atom, C1-C6 alkyl, or C1-C6 haloalkyl; L 1 where m is an integer from 0 to 3, X is N or CR 3 and R 3 is a hydrogen atom, a halogen atom, C1-C6 alkyl, or C1-C6 haloalkyl, R 4 is a hydrogen atom, a halogen atom, or a methyl atom, L 2 is a bond, -(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 in a is a hydrogen atom, a halogen atom, C1-C6 alkyl, or C1-C6 haloalkyl, L 2 R in b is a hydrogen atom, a halogen atom, C1-C6 alkyl, or C1-C6 haloalkyl, or L 2 R in a and R b together with the carbon atom to which they are attached to form C=O, L 2 R in c are each independently a hydrogen atom, a C1-C6 alkyl, or a C1-C6 haloalkyl; L 2 where m is an integer from 0 to 3, R 5is a hydrogen atom, a halogen atom, hydroxy, amino, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 haloalkoxy; R 6 is a hydrogen atom, a halogen atom, C1-C6 alkyl, C1-C6 haloalkyl, or optionally substituted phenyl; R 7 is a hydrogen atom, a halogen atom, C1-C6 alkyl, C1-C6 haloalkyl, hydroxyalkyl, optionally substituted phenyl, or optionally substituted C3-C6 cycloalkyl; or R 6 and R 7 together with the carbon atom to which they are attached form a C3-C6 cycloalkyl, an optionally substituted aryl, or an optionally substituted heteroaryl, or a pharmaceutically acceptable salt thereof, or a solvate thereof. (Section 2) R 1 is a hydrogen atom, a halogen atom, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, amino, monoalkylamino, dialkylamino, aminoalkyl, alkylcarbonylamino, optionally substituted C3-C6 cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; R 2 is a bond, -(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 1is a bond, -(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 in a is a hydrogen atom, a halogen atom, or a C1-C6 alkyl; L 1 R in b is a hydrogen atom, a halogen atom, or a C1-C6 alkyl, or L 1 R in a and L 1 R in b together with the carbon atom to which they are attached to form C=O, and L 1 R in c are each independently a hydrogen atom, C1-C6 alkyl, or C1-C6 haloalkyl; L 1 where m is an integer from 0 to 2, X is N or CR 3 and R 3 is a hydrogen atom, a halogen atom, C1-C6 alkyl, or C1-C6 haloalkyl, R 4 is a hydrogen atom, a halogen atom, or methyl, L 2 -(CR a R b ) m -NRc -, or -NR c -CO-NR c -where: L 2 R in a and R b together with the carbon atom to which they are attached to form C=O, L 2 R in c are each independently a hydrogen atom, L 2 m in is 1, R 5 is hydroxy, R 6 is a hydrogen atom, C1-C6 alkyl, or optionally substituted phenyl; R 7 is a hydrogen atom, C1-C6 alkyl, hydroxyalkyl, or optionally substituted phenyl; or R 6 and R 7 are taken together with the carbon atom to which they are attached to form a C3-C6 cycloalkyl, or an optionally substituted aryl, or a pharmaceutically acceptable salt thereof, or a solvate thereof, according to item 1. (Section 3) R 1 is a hydrogen atom, C1-C6 alkoxy, amino, monoalkylamino, optionally substituted C3-C6 cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; R 2 is a bond, -(CR a R b ) m -O-, -(CR a R b ) m -, or -NR c - and L 1 But, -(CR a R b ) m -NR c -, -NRc -(CR a R b ) m - or -CR a =CR b - and where: L 1 R in a is a hydrogen atom or a halogen atom, L 1 R in b is a hydrogen atom, or L 1 R in a and R b together with the carbon atom to which they are attached to form C=O, L 1 R in c are each independently a hydrogen atom, L 1 where m is 0 or 1, X is N or CR 3 and where R 3 is a hydrogen atom, R 4 is a halogen atom or methyl, L 2 -(CR a R b ) m -NR c - and Here, L 2 R in a and R b together with the carbon atom to which they are attached to form C=O, and L 2 R in c are each independently a hydrogen atom, L 2 m in is 1, R 5 is hydroxy, R 6 and R 7and R 1 and R 2 are taken together with the carbon atom to which they are attached to form a C3-C6 cycloalkyl, or a pharmaceutically acceptable salt thereof, or a solvate thereof. (Section 4) Item 1. The compound according to item 1, selected from the group consisting of the following (1) to (207), or a pharmaceutically acceptable salt thereof, or a solvate thereof: (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-cyclopropylethenyl]-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′-bipyridin]-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) N1-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-N3-(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′-bipyridin]-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′-bipyridin]-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′-bipyridin]-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′-bipyridin]-5′-yl)ethyl]amino}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide, (90) 3-{[(1S)-1-([3,3′-bipyridin]-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′-bipyridin]-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-acetamidopyridin-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'-bipyridin]-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'-bipyridin]-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'-bipyridin]-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'-bipyridin]-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'-bipyridin]-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'-bipyridin]-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)ethenyl]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′-bipyridin]-5′-yl)-2-fluoroethenyl]-4-fluoro-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide (178) 4-fluoro-3-{(Z)-2-fluoro-2-[5-(pyrimidin-2-yl)pyridin-3-yl]ethenyl}-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide (179) 3-[(Z)-2-fluoro-2-(imidazo[1,2-b]pyridazin-3-yl)ethenyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide, (180) 5-[(Z)-2-([2,3'-bipyridin]-5'-yl)-2-fluoroethenyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-6-methylpyridine-3-carboxamide, (181) 3-[(Z)-2-fluoro-2-{5-[(4-methylpiperazin-1-yl)methyl]pyridin-3-yl}ethenyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide, (182) 3-[(Z)-2-fluoro-2-{5-[(morpholin-4-yl)methyl]pyridin-3-yl}ethenyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide, (183) 3-[(Z)-2-{6-[(cyclopropylmethyl)amino]pyridin-3-yl}-2-fluoroethenyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide, (184) 4-fluoro-3-{(Z)-2-fluoro-2-[5-(morpholin-4-yl)pyridin-3-yl]ethenyl}-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide (185) 4-fluoro-3-[(Z)-2-fluoro-2-{5-[(oxan-4-yl)amino]pyridin-3-yl}ethenyl]-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide, (186) 4-fluoro-3-[(Z)-2-fluoro-2-{5-[(4-methylpiperazin-1-yl)methyl]pyridin-3-yl}ethenyl]-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide (187) 5-{(Z)-2-[5-(cyclopropylmethoxy)pyridin-3-yl]-2-fluoroethenyl}-N-[(1S,2S)-2-hydroxycyclohexyl]-6-methylpyridine-3-carboxamide, (188) 5-{(Z)-2-fluoro-2-[5-(morpholin-4-yl)pyridin-3-yl]ethenyl}-N-[(1S,2S)-2-hydroxycyclohexyl]-6-methylpyridine-3-carboxamide, (189) 5-[(Z)-2-(6-aminopyridin-3-yl)-2-fluoroethenyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-6-methylpyridine-3-carboxamide, (190) 5-[(Z)-2-(2-aminopyrimidin-5-yl)-2-fluoroethenyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-6-methylpyridine-3-carboxamide, (191) 3-[(Z)-2-(6-aminopyridin-3-yl)-2-fluoroethenyl]-4-fluoro-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide, (192) 3-[(Z)-2-(2-aminopyrimidin-5-yl)-2-fluoroethenyl]-4-fluoro-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide, (193) 3-[(Z)-2-fluoro-2-{5-[(1-methylpiperidin-4-yl)amino]pyridin-3-yl}ethenyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide, (194) 3-[(Z)-2-{5-[(4-ethylpiperazin-1-yl)methyl]pyridin-3-yl}-2-fluoroethenyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide, (195) 5-[(Z)-2-fluoro-2-{5-[(oxetan-3-yl)amino]pyridin-3-yl}ethenyl]-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}ethenyl]-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide (197) 3-[(Z)-2-(6-{[2-(dimethylamino)ethyl]amino}pyridin-3-yl)-2-fluoroethenyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide, (198) 3-[(Z)-2-(5-{[2-(dimethylamino)ethyl]amino}pyridin-3-yl)-2-fluoroethenyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide, (199) 5-[(Z)-2-{6-[(cyclopropylmethyl)amino]pyridin-3-yl}-2-fluoroethenyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-6-methylpyridine-3-carboxamide, (200) 3-[(Z)-2-fluoro-2-{5-[(4-methylpiperazin-1-yl)methyl]pyridin-3-yl}ethenyl]-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}ethenyl]-N-(2-hydroxy-3,3-dimethylbutyl)-4-methylbenzamide, (202) 3-[(Z)-2-{2-[(cyclopropylmethyl)amino]pyrimidin-5-yl}-2-fluoroethenyl]-4-fluoro-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide, (203) 3-{(Z)-2-[2-(cyclopropylamino)pyrimidin-5-yl]-2-fluoroethenyl}-4-fluoro-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide, (204) 3-[(Z)-2-(2-amino-4-methylpyrimidin-5-yl)-2-fluoroethenyl]-4-fluoro-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide (205) 4-fluoro-3-{(Z)-2-fluoro-2-[2-(methylamino)pyrimidin-5-yl]ethenyl}-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide (206) 3-[(Z)-2-(5-aminopyrazin-2-yl)-2-fluoroethenyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide, (207) 4-Fluoro-3-[(Z)-2-fluoro-2-(5-fluoropyridin-3-yl)ethenyl]-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide. (Section 5) Item 1, a compound or a pharmaceutically acceptable salt thereof, or a solvate thereof, which is a compound or a pharmaceutically acceptable salt thereof selected from the group consisting of 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'-bipyridin]-5'-yl)amino]methyl}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide, (11) 5-[(Z)-2-(6-aminopyridin-3-yl)-2-fluoroethenyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-6-methylpyridine-3-carboxamide, (12) 3-[(Z)-2-{5-[(4-ethylpiperazin-1-yl)methyl]pyridin-3-yl}-2-fluoroethenyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide, (13) 4-fluoro-3-{(Z)-2-fluoro-2-[2-(methylamino)pyrimidin-5-yl]ethenyl}-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide, (14) 3-[(Z)-2-(5-aminopyrazin-2-yl)-2-fluoroethenyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide, (15) 4-fluoro-3-[(Z)-2-fluoro-2-(5-fluoropyridin-3-yl)ethenyl]-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide. (Section 6) Item 6. A pharmaceutical composition comprising the compound according to any one of Items 1 to 5, or a pharmaceutically acceptable salt thereof, or a solvate thereof, as an active ingredient. (Section 7) Item 6. A PDGF receptor kinase inhibitor comprising the compound according to any one of Items 1 to 5, or a pharmaceutically acceptable salt thereof, or a solvate thereof, as an active ingredient. (Section 8) Item 6. A therapeutic agent for treating PDGF receptor kinase-associated diseases such as pulmonary hypertension, scleroderma, asthma, bronchiolitis obliterans, pulmonary fibrosis, acute myelogenous leukemia (AML), hypereosinophilic syndrome, T-lymphoblastic leukemia, chronic myelomonocytic leukemia (CMML), chronic myelogenous 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), comprising the compound according to any one of Items 1 to 5 or a pharmaceutically acceptable salt thereof, or a solvate thereof as an active ingredient. [Effects of the Invention]

[0012] The compound of the present invention inhibits PDGF receptor kinase and is therefore useful as a therapeutic agent 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 OF THE INVENTION

[0013] The meaning of each term used in this specification is explained below. Unless otherwise specified, each term has the same meaning whether used alone or in combination with other terms.

[0014] The term "halogen atom" refers to a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.

[0015] Examples of "alkyl" include straight-chain or branched-chain alkyls having 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, and more preferably 1 to 3 carbon atoms. Specific examples 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, and 2,2-dimethylbutyl.

[0016] The alkyl portion of "monoalkylamino," "alkylcarbonyloxy," "monoalkylamino," "dialkylamino," "alkylcarbonylamino," "alkylsulfonyl," "aminoalkyl," and "alkylcarbonyl" can be the same as "alkyl" as defined above.

[0017] The term "alkenyl" refers to a linear 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 even more preferably 2 to 4 carbon atoms. Specific examples include vinyl, allyl, 2-methylpropenyl, propenyl, isopropenyl, butenyl, isobutenyl, prenyl, butadienyl, pentenyl, isopentenyl, pentadienyl, hexenyl, isohexenyl, and hexadienyl.

[0018] "Amino" refers to -NH2.

[0019] The term "aminoalkyl" refers to a group in which an amino group replaces a hydrogen atom bonded to a carbon atom of the above-mentioned "alkyl." Specific examples include aminomethyl, 1-aminoethyl, 2-aminoethyl, 1-aminopropyl, 2-aminopropyl, 2-aminopropan-2-yl, and 3-aminopropyl.

[0020] "Monoalkylamino" refers to a group in which the above-mentioned "alkyl" replaces one hydrogen atom bonded to the nitrogen atom of an amino group. Specific examples include methylamino, ethylamino, and isopropylamino.

[0021] "Hydroxyalkyl" refers to a group in which a hydroxy group replaces a hydrogen atom bonded to a carbon atom of the above-mentioned "alkyl." Specific examples include hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1-hydroxypropyl, and 2-hydroxypropyl.

[0022] The term "alkylcarbonyl" refers to a group in which the above-mentioned "alkyl" is bonded to a carbonyl group. Examples include methylcarbonyl, ethylcarbonyl, propylcarbonyl, isopropylcarbonyl, tert-butylcarbonyl, isobutylcarbonyl, sec-butylcarbonyl, pentylcarbonyl, isopentylcarbonyl, and hexylcarbonyl.

[0023] The term "haloalkyl" refers to a group in which the hydrogen atom of the above-mentioned "alkyl" is replaced by the above-mentioned "halogen atom." Specific examples include fluoromethyl, chloromethyl, fluoroethyl, difluoromethyl, dichloromethyl, difluoroethyl, trifluoromethyl, trichloromethyl, and trifluoroethyl.

[0024] "Alkoxy" refers to a group in which the above-mentioned "alkyl" is bonded to an oxygen atom. For example, a straight-chain or branched alkoxy having 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, can be mentioned. Specific examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentyloxy, and n-hexyloxy.

[0025] The alkoxy moiety of "haloalkoxy" can be the same as "alkoxy" as defined above.

[0026] Examples of "aryl" include monocyclic to tricyclic aromatic hydrocarbon groups having 6 to 14 carbon atoms. Specific examples include phenyl, 1-naphthyl, 2-naphthyl, 1-anthryl, 2-anthryl, 9-anthryl, 1-phenanthryl, 2-phenanthryl, 3-phenanthryl, 4-phenanthryl, and 10-phenanthryl. Of these, phenyl is preferred.

[0027] The term "cycloalkyl" refers to a monocyclic to tricyclic non-aromatic hydrocarbon group, specifically cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

[0028] The above-mentioned "non-aromatic carbocyclic group" may be a bridged hydrocarbon group. Examples of such a bridged hydrocarbon group include: bicyclo[2.2.1]heptanyl (e.g., bicyclo[2.2.1]heptan-1-yl, bicyclo[2.2.1]heptan-2-yl, bicyclo[2.2.1]heptan-7-yl), bicyclo[1.1.1]pentanyl (e.g., bicyclo[1.1.1]pentan-1-yl, bicyclo[1.1.1]pentan-2-yl), bicyclo[4.1.0]heptanyl (e.g., bicyclo[4.1.0]heptan-1-yl, bicyclo[4.1.0]heptan-2-yl, bicyclo[4.1.0]heptan-3-yl, bicyclo[4.1.0]heptan-7-yl), Bicyclo[2.2.2]octanyl (e.g., bicyclo[2.2.2]octan-1-yl, bicyclo[2.2.2]octan-2-yl), bicyclo[3.1.1]heptanyl (e.g., bicyclo[3.1.1]heptan-1-yl, bicyclo[3.1.1]heptan-2-yl, bicyclo[3.1.1]heptan-3-yl, bicyclo[3.1.1]heptan-6-yl), or Cuban-1-yl is an example.

[0029] The above-mentioned "non-aromatic carbocyclic group" may be a spirocyclic group. Examples of such a spirocyclic group include: spiro[3.3]heptanyl (e.g., spiro[3.3]heptan-1-yl, spiro[3.3]heptan-2-yl), spiro[4.4]nonanyl (e.g., spiro[4.4]nonan-1-yl, spiro[4.4]nonan-2-yl), spiro[5.5]undecanyl (e.g., spiro[5.5]undecan-1-yl, spiro[5.5]undecan-2-yl, spiro[5.5]undecan-3-yl), or Mention may be made of spiro[2.5]octanyl (for example, spiro[2.5]octan-1-yl, spiro[2.5]octan-4-yl, spiro[2.5]octan-5-yl, spiro[2.5]octan-6-yl).

[0030] Examples of "heteroaryl" include monocyclic to tricyclic aromatic rings having 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur atoms and having 6 to 14 carbon atoms. Frills (e.g., 2-frills, 3-frills), thienyl (e.g., 2-thienyl, 3-thienyl), pyrrolyl (e.g., 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), Imidazolyl (e.g., 1-imidazolyl, 2-imidazolyl, 4-imidazolyl), pyrazolyl (e.g., 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl), triazolyl (e.g. 1,2,4-triazol-1-yl, 1,2,4-triazol-3-yl, 1,2,4-triazol-4-yl), tetrazolyl (e.g., 1-tetrazolyl, 2-tetrazolyl, 5-tetrazolyl), oxazolyl (e.g., 2-oxazolyl, 4-oxazolyl, 5-oxazolyl), Isoxazolyl (e.g., 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl), oxadiazolyl (e.g., 1,3,4-oxadiazol-2-yl), Thiazolyl (e.g., 2-thiazolyl, 4-thiazolyl, 5-thiazolyl), Thiadiazolyl (e.g., 1,3,4-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,3-thiadiazolyl), isothiazolyl (e.g., 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl), pyridyl (e.g., 2-pyridyl, 3-pyridyl, 4-pyridyl), pyridazinyl (e.g., 3-pyridazinyl, 4-pyridazinyl), pyrimidinyl (e.g., 2-pyrimidinyl, 4-pyrimidinyl, 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, 2,1,3-benzothiadiazol-5-yl), benzothiazolyl (e.g., benzothiazol-2-yl, benzothiazol-4-yl, benzothiazol-5-yl, benzothiazol-6-yl, benzothiazol-7-yl), Indolyls (e.g., indol-3-yl, indol-4-yl, indol-5-yl, indol-6-yl, indol-7-yl), Benzothiophenyl (e.g., 1-benzothiophen-2-yl, 1-benzothiophen-3-yl, 1-benzothiophen-4-yl, 1-benzothiophen-5-yl, 1-benzothiophen-6-yl, 1-benzothiophen-7-yl), 1,1-dioxo-1-benzothiophenyl (e.g., 1,1-dioxo-1-benzothiophen-2-yl, 1,1-dioxo-1-benzothiophen-3-yl, 1,1-dioxo-1-benzothiophen-4-yl, 1,1-dioxo-1-benzothiophen-5-yl, 1,1-dioxo-1-benzothiophen-6-yl, 1,1-dioxo-1-benzothiophen-7-yl), quinolyl (quinolin-2-yl, quinolin-3-yl, quinolin-4-yl, quinolin-5-yl, quinolin-6-yl, quinolin-7-yl, quinolin-8-yl), or 1,3-benzoxazol-2-yl may be mentioned.

[0031] The term "heterocycloalkyl" refers to a monocyclic or bicyclic or more cyclic non-aromatic heterocyclic group having one or more identical or different heteroatoms selected from nitrogen atoms, oxygen atoms, and sulfur atoms in the ring. Specific examples include: Oxetanyl (e.g., 2-oxetanyl, 3-oxetanyl), Azetidinyl (e.g., 2-azetidinyl, 3-azetidinyl), tetrahydropyranyl (e.g., 2-tetrahydropyranyl, 3-tetrahydropyranyl, 4-tetrahydropyranyl), 1,4-dioxanyl (e.g., 1,4-dioxan-2-yl), 1,3-dioxanyl (e.g. 1,3-dioxan-2-yl, 1,3-dioxan-4-yl, 1,3-dioxan-5-yl), pyrrolidinyl (e.g., 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl), piperidinyl (e.g., 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl), piperazinyl (e.g., 1-piperazinyl, 2-piperazinyl, 3-piperazinyl), Azepanil (e.g., 1-azepanil, 2-azepanil, 3-azepanil, 4-azepanil), Azocanyl (e.g., 1-azocanyl, 2-azocanyl, 3-azocanyl, 4-azocanyl, 5-azocanyl), Homopiperidinyl (e.g., 2-homopiperidinyl, 3-homopiperidinyl, 4-homopiperidinyl), morpholinyl (e.g., 2-morpholinyl, 3-morpholinyl, 4-morpholinyl), thiomorpholinyl (e.g., 2-thiomorpholinyl, 3-thiomorpholinyl, 4-thiomorpholinyl), or Tetrahydrofuryl (2-tetrahydrofuryl, 3-tetrahydrofuryl) can be mentioned.

[0032] The above "heterocycloalkyl" may be a bridged cyclic group. Examples of such a bridged cyclic group include: 3-azabicyclo[3.2.1]octanyl (e.g., 3-azabicyclo[3.2.1]octan-1-yl, 3-azabicyclo[3.2.1]octan-2-yl, 3-azabicyclo[3.2.1]octan-3-yl, 3-azabicyclo[3.2.1]octan-6-yl, 3-azabicyclo[3.2.1]octan-8-yl), quinuclidinyl (e.g., quinuclidin-2-yl, quinuclidin-3-yl, quinuclidin-4-yl), or 6-oxa-3-azabicyclo[3.1.1]heptanyl (for example, 6-oxa-3-azabicyclo[3.1.1]heptan-1-yl, 6-oxa-3-azabicyclo[3.1.1]heptan-2-yl, 6-oxa-3-azabicyclo[3.1.1]heptan-3-yl, 6-oxa-3-azabicyclo[3.1.1]heptan-7-yl) may be mentioned.

[0033] The above "heterocycloalkyl" may be a spirocyclic group. Examples of such a spirocyclic group include: 6-Azaspiro[2.5]octan-1-yl (e.g., 6-azaspiro[2.5]octan-1-yl, 6-azaspiro[2.5]octan-4-yl, 6-azaspiro[2.5]octan-5-yl), 3,9-diazaspiro[5.5]undecan-1-yl (e.g., 3,9-diazaspiro[5.5]undecan-1-yl, 3,9-diazaspiro[5.5]undecan-2-yl, 3,9-diazaspiro[5.5]undecan-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, 2,7-diazaspiro[3.5]nonan-7-yl), 7-Azaspiro[3.5]nonanyl, (7-azaspiro[3.5]nonan-1-yl, 7-azaspiro[3.5]nonan-2-yl, 7-azaspiro[3.5]nonan-5-yl, 7-azaspiro[3.5]nonan-6-yl), or Mention may be made of 2,5-diazabicyclo[2.2.1]heptanyl (2,5-diazabicyclo[2.2.1]heptan-1-yl, 2,5-diazabicyclo[2.2.1]heptan-2-yl, 2,5-diazabicyclo[2.2.1]heptan-3-yl, 2,5-diazabicyclo[2.2.1]heptan-7-yl).

[0034] Each symbol in formula [1] will be explained below.

[0035] R in Equation [1] 1is a hydrogen atom, a halogen atom, C-C alkyl, C-C haloalkyl, C-C alkenyl, C-C haloalkenyl, C-C alkynyl, C-C haloalkynyl, C-C alkoxy, hydroxy, carboxy, alkylcarbonyloxy, amino, monoalkylamino, dialkylamino, alkylcarbonylamino, nitro, optionally substituted C-C cycloalkyl, optionally substituted C-C cycloalkenyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl. Preferred are a hydrogen atom, a halogen atom, C1-C6 alkyl, C2-C6 alkenyl, amino, monoalkylamino, dialkylamino, alkylcarbonylamino, optionally substituted C3-C6 cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; Optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl are more preferred; Oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, piperidinyl, piperazinyl, phenyl, pyridyl, pyrimidinyl, pyrazinyl, isoquinolinyl, thienyl, pyrazolyl, imidazo[1,2-a]pyrazinyl, 1,2,3-triazolyl, imidazo[1,2-b]pyridazinyl are more preferred.

[0036] R 2 is a bond, -(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-. Bond, -(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- is preferred, Bond, -(CR a R b ) m -NR c -, -NR c - is more preferred.

[0037] R 2 R in a is a hydrogen atom, a halogen atom, C1-C6 alkyl, or C1-C6 haloalkyl. Hydrogen atom or R a and R b together with the carbon atom to which it is attached to form C=O.

[0038] R 2 R in b is a hydrogen atom, a halogen atom, C1-C6 alkyl, or C1-C6 haloalkyl. Hydrogen atom or R a and R b together with the carbon atom to which it is attached to form C=O.

[0039] R 2 R in care each independently a hydrogen atom, a C1-C6 alkyl, or a C1-C6 haloalkyl. A hydrogen atom is preferred.

[0040] Het is a 5- to 10-membered heteroaryl. 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]pyridyl, pyrazolo[1,5-a]pyridyl are preferred; Thiazolyl, pyridyl and pyrimidinyl are more preferred.

[0041] L 1 is a bond, -(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-. Bond, -(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- is preferred, -(CR a R b ) m -NR c -, -NR c -(CR a R b ) m -, -NR c -, -CR a =CR b - or -C≡C- is more preferred.

[0042] L 1 R in a is a hydrogen atom, a halogen atom, a C1-C6 alkyl, a C1-C6 haloalkyl, or R a and R b together with the carbon atom to which it is attached to form C=O. Hydrogen atom, halogen atom, C1-C6 alkyl, or R a and R b together with the carbon atom to which it is attached to form C=O.

[0043] L 1 R in b is a hydrogen atom, a halogen atom, a C1-C6 alkyl, a C1-C6 haloalkyl, or R a and R b together with the carbon atom to which it is attached to form C=O. Hydrogen atom or R a and R b together with the carbon atom to which it is attached to form C=O.

[0044] L 1R in c are each independently a hydrogen atom, a C1-C6 alkyl, or a C1-C6 haloalkyl. A hydrogen atom or C1-C6 alkyl is preferred, A hydrogen atom is more preferred.

[0045] L 2 is -(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-. Bond, -(CR a R b ) m -NR c -, -NR c -CO-NR c - is preferred, Bond, -(CR a R b ) m -NR c - is more preferable.

[0046] L 2 R in a is a hydrogen atom, a halogen atom, a C1-C6 alkyl, a C1-C6 haloalkyl, or R b and together with the carbon atom to which they are attached form C=O.

[0047] L 2 R in a As for Rb and together with the carbon atom to which they are attached preferably form C=O.

[0048] L 2 R in b is a hydrogen atom, a halogen atom, a C1-C6 alkyl, a C1-C6 haloalkyl, or R a and together with the carbon atom to which they are attached form C=O.

[0049] L 2 R in b As for R a and together with the carbon atom to which they are attached preferably form C=O.

[0050] L 2 R in c is a hydrogen atom, C1-C6 alkyl, or C1-C6 haloalkyl. L 2 R in c are each independently preferably a hydrogen atom.

[0051] R 4 is a hydrogen atom, a halogen atom, or methyl. A halogen atom or methyl is preferred.

[0052] R 5 is a hydrogen atom, a halogen atom, hydroxy, amino, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 haloalkoxy. Hydroxy is preferred.

[0053] R 6 is a hydrogen atom, a halogen atom, C1-C6 alkyl, C1-C6 haloalkyl, or optionally substituted phenyl; R 7 is a hydrogen atom, a halogen atom, C1-C6 alkyl, C1-C6 haloalkyl, hydroxyalkyl, optionally substituted phenyl, or C3-C6 cycloalkyl, or R6 and R 7 together with the carbon atom to which they are attached form a C3-C6 cycloalkyl, an optionally substituted aryl, or an optionally substituted heteroaryl.

[0054] R 6 is preferably a hydrogen atom, C1-C6 alkyl, or optionally substituted phenyl; R 7 is preferably C1-C6 alkyl, hydroxyalkyl, or optionally substituted phenyl, or R 6 and R 7 preferably, taken together with the carbon atom to which they are attached, form a C3-C6 cycloalkyl, or an optionally substituted aryl; R 6 and R 7 more preferably, taken together with the carbon atom to which they are attached form a C3-C6 cycloalkyl.

[0055] More specifically, the compound of the present invention is L 1 Depending on the type, the compounds include those shown in Table 1 below.

[0056] [Table 1] (In the table, R 1 , R 2 , R 4 , R 5 , R 6 , R 7 , R c , L 1 , L 2 , Het has the same meaning as above.) 1-A: In compound [1], L 1 -(CR a R b ) m -NR c -, m is 1, and R a and R bare compounds when they are joined together with the carbon atom to which they are attached to form C=O. 1-B: In compound [1], L 1 Compounds where -C≡C-. 1-C: In compound [1], L 1 Ga-NR c -(CR a R b ) m -, m is 1, and R a and R b are compounds when they are joined together with the carbon atom to which they are attached to form C=O. 1-D: In compound [1], L 1 Ga-NR c -Compounds where: 1-E: In compound [1], L 1 -(CR a R b ) m -NR c -, m is 1, and R a and R b is a hydrogen atom. 1-F: In compound [1], L 1 Ga-NR c -(CR a R b ) m -, m is 1, and R a and R b is a hydrogen atom.

[0057] [Table 2] (In the table, R 1 , R 2 , R 4 , R 5 , R 6 , R 7 , R c , L 1 , L 2 , Het has the same meaning as above.) 1-G: In compound [1], L 1 -(CR a R b )m -O-, m is 1, and R a and R b is a hydrogen atom. 1-H: In compound [1], L 1 -O-(CR a R b ) m -, m is 1, and R a and R b is a hydrogen atom. 1-I: In compound [1], L 1 Ga-CR a =CR b - and R a and R b Compounds where is H. 1-J: In compound [1], L 1 -(CR a R b ) m -, m is 2, and R a and R b Compounds where is H. 1-K: In compound [1], L 1 Ga-CR a =CR b - and R a is a halogen atom, R b Compounds where is H.

[0058] R in Compound 1-A 1 is preferably H, a halogen atom, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, amino, alkylcarbonylamino, optionally substituted C3-C6 cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl, and more preferably C1-C6 alkyl, C1-C6 alkoxy, optionally substituted C3-C6 cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl. R in Compound 1-A 2As the bond, -(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 - is preferred, and a bond, -(CR a R b ) m -NR c -,-(CR a R b ) m -O-, -(CR a R b ) m -, -NR c - or -O- is more preferred. R in Compound 1-A 2 As m, 0, 1 and 2 are preferred, and 0 and 1 are more preferred. Het in compound 1-A is preferably thiazolyl, pyridyl, oxazolyl, or imidazothiazolyl, and more preferably thiazolyl or pyridyl. R in Compound 1-A 4 is preferably a halogen atom or methyl, more preferably methyl. L in Compound 1-A 2 As for -(CR a R b )m-NRc- is preferred. L in compound 1-A 2 As m, 1 is preferred. R in Compound 1-A 5 As the hydroxyl group, hydroxyl is preferred. R in Compound 1-A 6 is H, C1-C6 alkyl, or R 7 and together with the carbon atom to which they are attached preferably form a C3-C6 cycloalkyl, and R 7and more preferably, together with the carbon atom to which they are attached form a C3-C6 cycloalkyl. R in Compound 1-A 7 is C1-C6 alkyl, optionally substituted phenyl, or R 6 and together with the carbon atom to which they are attached preferably form a C3-C6 cycloalkyl, and R 6 and more preferably, together with the carbon atom to which they are attached form a C3-C6 cycloalkyl.

[0059] R in Compound 1-B 1 is preferably H, a halogen atom, C1-C6 alkyl, amino, optionally substituted C3-C6 cycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl, and more preferably a halogen atom, optionally substituted C3-C6 cycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl. R in Compound 1-B 2 As the bond, -(CR a R b ) m -NR c - is preferred, and a bond is more preferred. R in Compound 1-B 2 As m, 0 or 1 is preferred. Het in compound 1-B is preferably pyridyl or pyrazinyl. R in Compound 1-B 4 As the aryl group, a halogen atom or methyl is preferred, and methyl is more preferred. L in Compound 1-B 2 As for -(CR a R b )m-NRc- is preferred. L in Compound 1-B 2 As m, 1 is preferred. R in Compound 1-B 5 As the hydroxyl group, hydroxyl is preferred. R in Compound 1-B6 as an optionally substituted phenyl, or R 7 and together with the carbon atom to which they are attached preferably form a C3-C6 cycloalkyl, and R 7 and more preferably, together with the carbon atom to which they are attached form a C3-C6 cycloalkyl. R in Compound 1-B 7 The group may be hydroxyalkyl or R 6 and together with the carbon atom to which they are attached preferably form a C3-C6 cycloalkyl, and R 6 and more preferably, together with the carbon atom to which they are attached form a C3-C6 cycloalkyl.

[0060] R in compound 1-C 1 is preferably H, a halogen atom, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, amino, alkylcarbonylamino, optionally substituted C3-C6 cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl, and more preferably optionally substituted aryl. R in compound 1-C 2 As the bond, -(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 - is preferred, and a bond is more preferred. In compound 1-C, Het is preferably thiazolyl, pyridyl, oxazolyl, or imidazothiazolyl, and more preferably pyridyl. R in compound 1-C 4is preferably a halogen atom or methyl, more preferably methyl. R in compound 1-C 5 As the hydroxyl group, hydroxyl is preferred. R in compound 1-C 6 is H, C1-C6 alkyl, or R 7 and together with the carbon atom to which they are attached preferably form a C3-C6 cycloalkyl, and R 7 and more preferably, together with the carbon atom to which they are attached form a C3-C6 cycloalkyl. R in compound 1-C 7 is C1-C6 alkyl, optionally substituted phenyl, or R 6 and together with the carbon atom to which they are attached preferably form a C3-C6 cycloalkyl, and R 6 and more preferably, together with the carbon atom to which they are attached form a C3-C6 cycloalkyl.

[0061] R in compound 1-D 1 is preferably H, a halogen atom, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, monoalkylamino, optionally substituted C3-C6 cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl, more preferably monoalkylamino or optionally substituted heteroaryl. R in compound 1-D 2 As the bond, -(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 - is preferred, and a bond is more preferred. Het in compound 1-D is preferably pyrimidinyl, pyridyl, or quinazolyl, more preferably pyrimidinyl. R in compound 1-D 4 is preferably a halogen atom or methyl, more preferably methyl. R in compound 1-D 5 As the hydroxyl group, hydroxyl is preferred. R in compound 1-D 6 is an optionally substituted aryl, or R 7 and together with the carbon atom to which they are attached preferably form a C3-C6 cycloalkyl, and R 7 and more preferably, together with the carbon atom to which they are attached form a C3-C6 cycloalkyl. R in compound 1-D 7 hydroxyalkyl, optionally substituted phenyl, or R 6 and together with the carbon atom to which they are attached preferably form a C3-C6 cycloalkyl, and R 6 and more preferably, together with the carbon atom to which they are attached form a C3-C6 cycloalkyl.

[0062] R in compound 1-E 1is preferably H, a halogen atom, C-C alkyl, C-C haloalkyl, C-C alkenyl, C-C haloalkenyl, C-C alkynyl, C-C haloalkynyl, C-C alkoxy, hydroxy, carboxy, alkylcarbonyloxy, amino, aminoalkyl, monoalkylamino, dialkylamino, alkylcarbonylamino, nitro, optionally substituted C-C cycloalkyl, optionally substituted C-C cycloalkenyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl, more preferably H, amino, optionally substituted C-C cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl. R in compound 1-E 2 As the bond, -(CR a R b ) m -NR c -, -NR c -, -NR c -CO-NR c - or -C≡C- is preferred, and a bond, -(CR a R b ) m -NR c -, or -NR c - is more preferable. R in compound 1-E 2 As m, 0 or 1 is preferred. Het in compound 1-E includes 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, imidazo[1,2-b]pyridazinyl, and imidazo[1,2-b]pyridazinyl. Preferred are pyrazolo[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]pyridyl, or pyrazolo[1,5-a]pyridyl, and more preferred are pyridyl, pyrazinyl, pyrimidinyl, and pyrazolo[1,5-a]pyrimidinyl. R in compound 1-E 4 is preferably H, a halogen atom, or methyl, more preferably a halogen atom or methyl. L in compound 1-E 2 As for -(CR a R b )m-NRc- is preferred. L in compound 1-E 2 As m, 1 is preferred. R in compound 1-E 5 As the hydroxyl group, hydroxyl is preferred. R in compound 1-E 6 As for R 7 and more preferably, together with the carbon atom to which they are attached form a C3-C6 cycloalkyl. R in compound 1-E 7 As for R 6 and more preferably, together with the carbon atom to which they are attached form a C3-C6 cycloalkyl.

[0063] R in compound 1-F 1is preferably a halogen atom, optionally substituted C3-C6 cycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl, and more preferably optionally substituted C3-C6 cycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl. R in compound 1-F 2 is preferably a bond or -C≡C-, and more preferably a bond. Het in compound 1-F is preferably pyridyl or pyrazinyl, more preferably pyridyl. R in compound 1-F 4 is preferably H, a halogen atom, or methyl, more preferably H or methyl. L in compound 1-F 2 As for -(CR a R b )m-NRc-, -NRc-CO-NRc- are preferred. L in compound 1-F 2 As m, 1 is preferred. R in compound 1-F 5 As the hydroxyl group, hydroxyl is preferred. R in compound 1-F 6 as an optionally substituted phenyl, or R 7 and together with the carbon atom to which they are attached preferably form a C3-C6 cycloalkyl, and R 7 and more preferably, together with the carbon atom to which they are attached form a C3-C6 cycloalkyl. R in compound 1-F 7 The group may be hydroxyalkyl or R 6 and together with the carbon atom to which they are attached preferably form a C3-C6 cycloalkyl, and R 6 and more preferably, together with the carbon atom to which they are attached form a C3-C6 cycloalkyl.

[0064] R in compound 1-G 1As the group, optionally substituted aryl or optionally substituted heteroaryl is preferred, and optionally substituted heteroaryl is more preferred. R in compound 1-G 2 is preferably a bond. Het in compound 1-G is preferably pyridyl. R in compound 1-G 4 is preferably H, a halogen atom, or methyl, more preferably a halogen atom or methyl. R in compound 1-G 5 As the hydroxyl group, hydroxyl is preferred. R in compound 1-G 6 As for R 7 together with the carbon atom to which they are attached form a C3-C6 cycloalkyl. R in compound 1-G 7 As for R 6 together with the carbon atom to which they are attached form a C3-C6 cycloalkyl.

[0065] R in compound 1-H 1 As the group, optionally substituted heteroaryl is preferred. R in compound 1-H 2 is preferably a bond. Het in compound 1-H is preferably pyridyl. R in compound 1-H 4 is preferably a halogen atom or methyl, more preferably methyl. R in compound 1-H 5 As the hydroxyl group, hydroxyl is preferred. R in compound 1-H 6 As for R 7 together with the carbon atom to which they are attached form a C3-C6 cycloalkyl. R in compound 1-H 7 As for R 6together with the carbon atom to which they are attached form a C3-C6 cycloalkyl.

[0066] R in Compound 1-I 1 As the aryl group, optionally substituted aryl is preferred. R in Compound 1-I 2 is preferably a bond. Het in compound 1-I is preferably pyridyl. R in Compound 1-I 4 As the alkyl group, methyl is preferred. R in Compound 1-I 5 As the hydroxyl group, hydroxyl is preferred. R in Compound 1-I 6 As for R 7 together with the carbon atom to which they are attached form a C3-C6 cycloalkyl. R in Compound 1-I 7 As for R 6 together with the carbon atom to which they are attached form a C3-C6 cycloalkyl.

[0067] R in compound 1-J 1 As the aryl group, optionally substituted aryl is preferred. R in compound 1-J 2 is preferably a bond. Het in compound 1-J is preferably pyridyl. R in compound 1-J 4 As the alkyl group, methyl is preferred. R in compound 1-J 5 As the hydroxyl group, hydroxyl is preferred. R in compound 1-J 6 As for R 7 together with the carbon atom to which they are attached form a C3-C6 cycloalkyl. R in compound 1-J 7 As for R 6together with the carbon atom to which they are attached form a C3-C6 cycloalkyl.

[0068] R in Compound 1-K 1 is preferably H, a halogen atom, amino, monoalkylamino, dialkylamino, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, or optionally substituted heteroaryl, and more preferably a halogen atom, amino, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, or optionally substituted heteroaryl. R in Compound 1-K 2 As a bond, -(CR a R b )m-NR c -, -(CR a R b ) m -O-, -(CR a R b ) m -, or -NR c - is preferred, and a bond, -(CR a R b ) m -NR c -, -(CR a R b ) m -, or -NR c - is more preferred. Het in compound 1-K is preferably pyridyl, pyrimidinyl, pyrazinyl, or imidazo[1,2-b]pyridazinyl, and more preferably pyridyl, pyrimidinyl, or pyrazinyl. R in Compound 1-K 4 is preferably a halogen atom or methyl. L in compound 1-K 2 As for -(CR a R b )m-NRc- is preferred. L in compound 1-K 2 As m, 1 is preferred. R in Compound 1-K 5As the hydroxyl group, hydroxyl is preferred. R in Compound 1-K 6 is C1-C6 alkyl, or R 7 and together with the carbon atom to which they are attached preferably form a C3-C6 cycloalkyl, optionally substituted aryl, and R 7 and more preferably, together with the carbon atom to which they are attached form a C3-C6 cycloalkyl. R in Compound 1-K 7 is C1-C6 alkyl, or R 6 and together with the carbon atom to which they are attached preferably form a C3-C6 cycloalkyl, optionally substituted aryl, and R 6 and more preferably, together with the carbon atom to which they are attached form a C3-C6 cycloalkyl.

[0069] The compound of the present invention can be produced from a known compound or an easily synthesized intermediate, for example, by the method described below, the Examples described later, or a known method. In producing the compound of the present invention, if the raw material has a substituent that affects the reaction, the raw material is generally protected with an appropriate protecting group by a known method beforehand, and then the reaction is carried out. The protecting group can be removed by a known method after the reaction.

[0070] The compound represented by formula [1] can be used as a pharmaceutical directly, or can be used in the form of a pharmaceutically acceptable salt, solvate, or solvate of a salt by known methods. Examples of pharmaceutically acceptable salts include salts of mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid; salts of organic acids such as 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 of alkali metals such as lithium, potassium, and sodium; salts of alkaline earth metals such as magnesium and calcium; and salts of organic bases such as ammonium salts. These salts can be formed by commonly used methods.

[0071] 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 an alcohol solution of hydrogen chloride, an ethyl acetate solution of hydrogen chloride, a 1,4-dioxane solution of hydrogen chloride, a cyclopentyl methyl ether solution of hydrogen chloride, or a diethyl ether solution of hydrogen chloride.

[0072] Of the compounds of the present invention, those having an asymmetric carbon atom include all stereoisomers and mixtures thereof. Stereoisomers can be produced, for example, by optical resolution of a racemate using an optically active acid (tartaric acid, dibenzoyltartaric acid, mandelic acid, 10-camphorsulfonic acid, etc.) by a known method, taking advantage of its basicity, or by using a pre-prepared optically active compound as a starting material. Alternatively, stereoisomers can be produced by optical resolution using a chiral column or asymmetric synthesis.

[0073] The compound of the present invention is not limited to a specific isomer, but includes all possible isomers and racemates. (Method for producing the compound of the present invention)

[0074] The compounds of the present invention can be produced from known compounds or intermediates that can be easily prepared from known compounds, for example, by the following methods, the Examples described below, or known methods.

[0075] When the solvents, reagents, and raw materials used in each step in the following production methods are commercially available, the commercially available products can be used as they are. Furthermore, the compounds obtained in each step in the production methods described below and the raw materials used may form salts, which can be converted into other types of salts or free forms by known methods. Conversely, when the compounds obtained in each step in the following production methods and the raw materials used are in free forms, they can be converted into the desired salts by known methods. Examples of such salts include the same salts as those used for the compounds of the present invention described above.

[0076] The compound represented by formula [1] of the present invention or a pharmaceutically acceptable salt thereof may form a solvate (e.g., hydrate, etc.) and / or crystalline polymorphism, and the present invention also encompasses such various solvates and crystalline polymorphisms. A "solvate" may be coordinated with the compound represented by formula [1] with any number of solvent molecules (e.g., water molecules, etc.). When the compound represented by formula [1] or a pharmaceutically acceptable salt thereof is left in the atmosphere, it may absorb moisture, resulting in the adsorbed water adsorbing thereon or forming a hydrate. Furthermore, when the compound represented by formula [1] or a pharmaceutically acceptable salt thereof is recrystallized, these crystalline polymorphisms may be formed.

[0077] In the production of the compound of the present invention, when the starting materials have substituents that may affect the reaction, protecting groups may be introduced into these substituents in advance by a known method, and the target compound can be obtained by removing the protecting groups as necessary after the reaction. The introduction and removal of such protecting groups can be carried out by appropriately selecting and using conditions described in, for example, Wuts and Greene, "Greene's Protective Groups in Organic Synthesis," 4th Edition, John Wiley & Sons Inc., 2006, or P.J. Kocienski, "Protecting Groups," 3rd Edition, Thieme, 2005.

[0078] The compounds obtained in each step of the following production methods can be isolated or purified in accordance with conventional methods, such as solvent extraction, concentration, distillation, sublimation, recrystallization, reprecipitation, and chromatography, or can be used in the next step in the form of a reaction mixture or a crude product.

[0079] Unless otherwise specified, the reactions in each step in the following production methods are carried out by known methods, such as those described in "Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 2nd Edition" by R.C. Larock, John Wiley & Sons Inc., 1999; "Experimental Chemistry Lectures" edited by the Chemical Society of Japan, 4th Edition, Maruzen, 1992; "Organic Synthesis Strategies Learned from Named Reactions" by L. Kuerti and B. Czako, translated and supervised by Kiyoshi Tomioka, Kagaku Dojin, 2006; and "Latest Organic Synthesis Methods: Design and Strategy" by G.S. Zweifel and M.H. Nantz, translated by Tamejiro Hiyama, Kagaku Dojin, 2009, or methods described in the Examples, which may be suitably modified or combined.

[0080] The compound of the present invention shown above (1-A:L 1 -(CR a R b )m-NR c - and R a and R b are compounds that, together with the carbon atoms to which they are attached, form C=O. 1-B:L 1 A compound where -C≡C-. 1-C:L 1 Ga-NR c -(CR a R b ) m - and R a and R b are compounds that, together with the carbon atoms to which they are attached, form C=O. 1-D:L 1 Ga-NR c -A compound. 1-E:L 1 -(CR a R b ) m -NR c - and R a and R bare each independently H, a halogen atom, C1-C6 alkyl, or C1-C6 haloalkyl. 1-F:L 1 NR c -(CR a R b ) m - and R a and R b are each independently H, a halogen atom, C1-C6 alkyl, or C 1- A compound that is a C6 haloalkyl. 1-G:L 1 -(CR a R b ) m -O- and R a and R b are each independently H, a halogen atom, C1-C6 alkyl, or C1-C6 haloalkyl. 1-H:L 1 -O-(CR a R b ) m - and R a and R b are each independently H, a halogen atom, C1-C6 alkyl, or C1-C6 haloalkyl. 1-I:L 1 Ga-CR a =CR b - and R a and R b is a compound where H. 1-J:L 1 -(CR a R b ) m - and R a and R b is a compound where H. 1-K:L 1 Ga-CR a =CR b - and R a is a halogen atom, R b is H) can be produced, for example, by the general synthesis method shown below. Extraction, purification, etc. may be carried out by treatments typically performed in organic chemistry experiments.

[0081] Preparation of Compound 1-A [ka] (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 In this step, compound 1 or a reactive compound thereof is condensed with amine compound 2 in the presence of a condensing agent to obtain compound 1-A.

[0082] Examples of reactive compounds of compound 1 include those commonly used in amide condensation reactions, such as acid halides (eg, acid chlorides, acid bromides), mixed acid anhydrides, imidazolides, and activated amides.

[0083] The amounts of the condensing agent and amine compound 2 used in this step are each suitably within the range of 1 to 3 molar equivalents relative to compound 1.

[0084] Examples of condensing agents used in this step include 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 cyanophosphonate, O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (hereinafter referred to as "HBTU"), and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (hereinafter referred to as "HATU").

[0085] In this step, a base can be used as needed, and examples of the base that can be used include organic bases such as TEA, DIPEA, N,N-dimethylaniline, and DBU.

[0086] The amount of the base used is suitably within the range of 1 to 10 molar equivalents relative to Compound 1.

[0087] In this step, additives such as 1-hydroxybenzotriazole (hereinafter referred to as "HOBt"), N-hydroxysuccinimide, 1-hydroxy-7-azabenzotriazole (hereinafter referred to as "HOAt"), etc. may be added as needed.

[0088] When the additive is used in this step, the amount of the additive used is suitably within the range of 0.1 to 3 molar equivalents relative to Compound 1.

[0089] The solvent to be used is not particularly limited as long as it is not involved in the reaction, and examples thereof include 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.

[0090] The reaction temperature varies depending on the types of raw materials and reagents used, but is usually within the range of −20° C. to 150° C. If necessary, a microwave reaction apparatus may be used.

[0091] The reaction time varies depending on the types of raw materials used and the reaction temperature, but is usually within the range of 0.1 to 72 hours.

[0092] In addition, in compound [1], L 2 -(CR a R b ) m -NR c -(R a and R btogether with the carbon atom to which they are attached to form C=O, m, and R c has the same meaning as above), the compound (compound 1-AA) can also be produced by the following method.

[0093] Preparation of Compound 1-AA [ka] (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 alkyl, examples of which include methyl, ethyl, and n-butyl.

[0094] Step 1 In this step, compound 1 or a reactive compound thereof is condensed with amine compound 3 in the presence of a condensing agent to obtain compound 1-AA. Compound 1-AA can be produced by the same method as in Step 1 for producing compound 1-A.

[0095] Step 2 In this step, compound 1 or a reactive compound thereof is condensed with amine compound 4 in the presence of a condensing agent to obtain compound 5. Compound 5 can be produced by the same method as in Step 1 of the above-mentioned method for producing compound 1-A.

[0096] Step 3 In this step, the ester moiety of compound 5 is hydrolyzed in the presence of an appropriate acid or base in an appropriate solvent to obtain compound 6.

[0097] In this step, examples of the acid used 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 used include inorganic bases such as sodium hydroxide, potassium hydroxide, and lithium hydroxide.

[0098] In this step, the amount of acid or base used is suitably within the range of 1 to 10 molar equivalents relative to compound 5. If necessary, an excess amount of acid or base relative to compound 5 may be used.

[0099] The solvent to be used is not particularly limited as long as it is not involved in the reaction, and examples thereof include 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.

[0100] The reaction temperature varies depending on the types of raw materials and reagents used, but is usually within the range of 20° C. to 200° C., preferably 20° C. to 100° C. If necessary, a microwave reaction apparatus may be used.

[0101] The reaction time varies depending on the types of raw materials used and the reaction temperature, but is usually within the range of 0.5 hours to 4 days.

[0102] Step 4 In this step, compound 6 or a reactive compound thereof is condensed with amine compound 7 in the presence of a condensing agent to obtain compound 1-AA, which can be produced by a method similar to that of Step 1 for producing compound 1-A.

[0103] Preparation of Compound 1-B [ka] (In the formula, R 1 , R 2 , R 4 , R 5 , R 6 , R 7 , R c , Het, X, and L2 are as defined above. Y is a leaving group, and examples thereof include a bromine atom, an iodine atom, methanesulfonate, and trifluoromethanesulfonate. Step 1 In this step, compound 1-B is obtained by coupling reaction of compound 8 with compound 9 in the presence of a transition metal such as palladium.

[0104] This reaction can be carried out under conditions typically used in coupling reactions using transition metals, specifically the Sonogashira coupling reaction, and can be carried out by methods described in literature such as Sonogashira et al., J. Organomet. Chem. 2002, 653, 46-49. and Negishi et al., Chem. Rev., 2003, 103, 1979-2017.

[0105] The amount of compound 9 used is suitably within the range of 0.5 to 3 molar equivalents relative to compound 8.

[0106] The organometallic catalyst used in this reaction is not particularly limited. Preferred examples of the organometallic catalyst include tris(dibenzylideneacetone)bispalladium·chloroform adduct (hereinafter referred to as "Pd2(dba)3·CHCl3"), tris(dibenzylideneacetone)bispalladium (hereinafter referred to as "Pd2(dba)3"), tetrakistriphenylphosphinepalladium (hereinafter referred to as "Pd(PPh3)4"), [1,1'-bis(diphenylphosphino)ferrocene]-dichloropalladium(II)·dichloromethane adduct (hereinafter referred to as "Pd(dppf)Cl2·CH2Cl2"), and bis(triphenylphosphine)palladium. Examples of suitable metal catalysts include 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), as well as mixtures of these metal catalysts.

[0107] The amount of the transition metal used is suitably within the range of 0.01 to 0.3 molar equivalents relative to the compound 8, for example.

[0108] In this step, a base or a salt may be used as needed. Examples of the base or salt to be used include potassium carbonate, cesium carbonate, sodium carbonate, sodium bicarbonate, sodium acetate, potassium acetate, trisodium phosphate, tripotassium phosphate, and solutions thereof, as well as triethylamine (hereinafter referred to as "TEA"), N,N-diisopropylethylamine (hereinafter referred to as "DIPEA"), lithium chloride, and copper(I) iodide.

[0109] The amount of the base used is suitably within the range of, for example, 1 to 4 molar equivalents relative to compound 8.

[0110] In this step, an appropriate ligand may be used as needed. Examples of the ligand that can be used include 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"), and tricyclohexylphosphine (hereinafter referred to as "PCy3").

[0111] The amount of the ligand used is suitably within the range of, for example, 1 to 5 molar equivalents relative to the transition metal used.

[0112] The solvent used in this step is not particularly limited as long as it is not involved in the reaction, and examples thereof include 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.

[0113] The reaction temperature varies depending on the types of raw materials and reagents used, but is usually within the range of 20° C. to 200° C. If necessary, a microwave reaction apparatus may be used.

[0114] The reaction time varies depending on the types of raw materials used and the reaction temperature, but is usually within the range of 0.1 to 24 hours.

[0115] L 2 -(CR a R b ) m -NR c - and R a and R b When these are taken together with the carbon atom to which they are attached to form C═O (compound 1-BB), it is also possible to prepare the compound as follows.

[0116] Preparation of Compound 1-BB [ka] (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, examples of which include trimethylsilyl and triethylsilyl.

[0117] Step 1 In this step, compound 10 and compound 11 are coupled in the presence of a transition metal such as palladium to obtain alkyne compound 12, which can be produced by a method similar to Step 1 in the production method for compound 1-B.

[0118] Step 2 This step involves deprotecting Z to obtain compound 13, and can be performed by referring 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.

[0119] Step 3 In this step, compound 13 and compound 14 are coupled in the presence of a transition metal such as palladium to obtain compound 15, which can be produced by a method similar to Step 1 in the production method for compound 1-B.

[0120] Step 4 In this step, the ester moiety of compound 15 is hydrolyzed in the presence of an appropriate acid or base in an appropriate solvent to obtain compound 16, which can be produced by a method similar to Step 3 in the production method for compound 1-AA.

[0121] Step 5 In this step, compound 16 or a reactive compound thereof is condensed with amine compound 17 in the presence of a condensing agent to obtain compound 1-BB, which can be produced by a method similar to that used in Step 1 of the above-mentioned method for producing compound 1-A.

[0122] Preparation of Compound 1-C [ka] (In the formula, R 1 , R 2 , R 4 , R 5 , R 6 , R 7 , R c , Het, and X are as defined above.)

[0123] Step 1 In this step, compound 19 or a reactive compound thereof is condensed with amine compound 18 in the presence of a condensing agent to obtain compound 1-C, which can be produced by a method similar to that used in Step 1 of the above-mentioned method for producing compound 1-A.

[0124] Preparation of Compound 1-D [ka] (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, examples of which include a bromine atom, an iodine atom, and trifluoromethanesulfonate. Step 1 In this step, compound 1-D is obtained by coupling reaction of compound 20 with compound 21 in the presence of a transition metal such as palladium.

[0125] This reaction can be carried out under conditions typically used in coupling reactions using transition metals, specifically the coupling reaction of Buchwald et al., and can be carried out by methods described in literature such as 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.

[0126] The amount of compound 21 used is suitably within the range of 0.5 to 3 molar equivalents relative to compound 20.

[0127] The organometallic catalyst used in this reaction is not particularly limited. Preferred examples of the organometallic catalyst include tris(dibenzylideneacetone)bispalladium·chloroform adduct (hereinafter referred to as "Pd2(dba)3·CHCl3"), tris(dibenzylideneacetone)bispalladium (hereinafter referred to as "Pd2(dba)3"), tetrakistriphenylphosphinepalladium (hereinafter referred to as "Pd(PPh3)4"), [1,1'-bis(diphenylphosphino)ferrocene]-dichloropalladium(II)·dichloromethane adduct (hereinafter referred to as "Pd(dppf)Cl2·CH2Cl2"), and bis(triphenylphosphine)palladium. Examples of suitable metal catalysts include 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), as well as mixtures of these metal catalysts.

[0128] The amount of the transition metal used is suitably within the range of 0.01 to 0.3 molar equivalents relative to compound 20, for example.

[0129] In this step, a base or a salt may be used as needed. Examples of the base or salt to be used include potassium carbonate, cesium carbonate, sodium carbonate, sodium bicarbonate, sodium acetate, potassium acetate, trisodium phosphate, tripotassium phosphate, and solutions thereof, as well as triethylamine (hereinafter referred to as "TEA"), N,N-diisopropylethylamine (hereinafter referred to as "DIPEA"), lithium chloride, and copper(I) iodide.

[0130] The amount of base used is suitably within the range of, for example, 1 to 4 molar equivalents relative to compound 20.

[0131] In this step, an appropriate ligand may be used as needed. Examples of the ligand that can be used include 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"), and tricyclohexylphosphine (hereinafter referred to as "PCy3").

[0132] The amount of the ligand used is suitably within the range of, for example, 1 to 5 molar equivalents relative to the transition metal used.

[0133] The solvent used in this step is not particularly limited as long as it is not involved in the reaction, and examples thereof include 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.

[0134] The reaction temperature varies depending on the types of raw materials and reagents used, but is usually within the range of 20° C. to 200° C. If necessary, a microwave reaction apparatus may be used.

[0135] The reaction time varies depending on the types of raw materials used and the reaction temperature, but is usually within the range of 0.1 to 24 hours.

[0136] Preparation of Compound 1-E [ka] (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 In this step, compound 22 and compound 23 are coupled in the presence of a transition metal such as palladium to obtain compound 1-E, which can be produced by a method similar to that used in Step 1 of the production method for compound 1-D.

[0137] L 1 -(CR a R b ) m -NR c - and R a and R b When is H, it can also be prepared as follows.

[0138] Preparation of Compound 1-EE [ka] (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

[0139] Step 1 This step is a step of obtaining compound 1-EE by reductive amination of compound 24 and compound 23, and can be carried out in accordance with a known method for reductive amination. This step can also be carried out stepwise by forming an imine (step 1) and reducing the imine moiety (step 2).

[0140] The amount of compound 23 used is suitably within the range of 1 to 2.5 molar equivalents relative to compound 24.

[0141] In this step, an acid or a suitable Lewis acid can be used as needed. Examples of acids that can be used in the reaction include acetic acid, and examples of Lewis acids that can be used include tetraisopropyl orthotitanate.

[0142] When an acid is used in this step, the amount of the acid used is suitably within the range of 2 to 3 molar equivalents relative to the amount of compound 24.

[0143] When a Lewis acid is used in this step, the amount of Lewis acid used is suitably within the range of 1.5 to 2 molar equivalents relative to the amount of compound 24.

[0144] The solvent used in this step is not particularly limited as long as it is not involved in the reaction, and examples thereof include hydrocarbons such as toluene and xylene, ethers such as 1,4-dioxane, THF, and DME, halogenated hydrocarbons such as dichloromethane, and mixed solvents thereof.

[0145] In this step, the reaction temperature varies depending on the types of raw materials and reagents used, but is usually within the range of 0°C to 100°C.

[0146] In this step, the reaction time varies depending on the types of raw materials used and the reaction temperature, but is usually within the range of 0.1 to 48 hours.

[0147] The reducing agent used in this step includes, for example, sodium triacetoxyborohydride, sodium cyanoborohydride, and the like.

[0148] The amount of the reducing agent used in this step is suitably within the range of 1 to 2 molar equivalents relative to compound 24.

[0149] The solvent used in this step is not particularly limited as long as it is not involved in the reaction, and examples thereof include hydrocarbons such as toluene and xylene, ethers such as 1,4-dioxane, THF, and DME, halogenated hydrocarbons such as dichloromethane, and mixed solvents thereof.

[0150] Preparation of Compound 1-F [ka] (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 In this step, compound 25 is reacted with compound 26 in the presence of a base to obtain compound 1-F.

[0151] The amount of compound 26 used is suitably within the range of 0.5 to 3 molar equivalents relative to compound 25.

[0152] Examples of the base used in this reaction include pyridine, TEA, DIPEA, potassium carbonate, and sodium hydrogen carbonate.

[0153] The amount of the base used is suitably within the range of 1 to 10 molar equivalents relative to compound 25.

[0154] The solvent to be used is not particularly limited as long as it is not involved in the reaction, and examples thereof include 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, or mixed solvents thereof.

[0155] In this step, the reaction temperature varies depending on the types of raw materials and reagents used, but is usually within the range of 20° C. to 200° C. If necessary, a microwave reaction apparatus may be used.

[0156] The reaction time varies depending on the types of raw materials used and the reaction temperature, but is usually within the range of 1 hour to 24 hours.

[0157] L 1 Ga-NR c -(CR a R b ) m - and R a and R b When is H, it can also be prepared as follows.

[0158] Preparation of Compound 1-FF [ka] (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.)

[0159] Step 1 This step is a step of obtaining compound 1-FF by reductive amination of compound 27 and compound 28, and can be produced by a method similar to Step 1 of the above-mentioned method for producing compound 1-EE.

[0160] Preparation of Compound 1-G [ka] (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.)

[0161] Step 1 This step is a step of obtaining ether compound 1-G by Mitsunobu reaction between alcohol compound 29 and alcohol compound 30, and can be carried out according to known methods.

[0162] This step is usually carried out in a suitable solvent in the presence of an azodicarboxylic acid ester reagent and a phosphine reagent.

[0163] The amount of compound 29 used is suitably within the range of 0.5 to 1.5 molar equivalents relative to compound 30.

[0164] Examples of the azodicarboxylate reagent to be used include diethyl azodicarboxylate (hereinafter referred to as "DEAD"), diisopropyl azodicarboxylate (hereinafter referred to as "DIAD"), and bis(2-methoxyethyl)azodicarboxylate (hereinafter referred to as "DMEAD").

[0165] Examples of the phosphine reagent to be used include triphenylphosphine and tributylphosphine.

[0166] The amount of the azodicarboxylic acid ester reagent used is suitably within the range of 1 to 2 molar equivalents relative to compound 29.

[0167] The amount of the phosphine reagent used is preferably in the range of 1 to 2 molar equivalents relative to compound 29.

[0168] The solvent to be used is not particularly limited as long as it is not involved in the reaction, and examples thereof include hydrocarbons such as toluene and xylene, ethers such as 1,4-dioxane, THF and DME, and mixed solvents thereof.

[0169] In this step, the reaction temperature varies depending on the types of raw materials and reagents used, but is usually within the range of 0°C to 100°C.

[0170] The reaction time varies depending on the types of raw materials used and the reaction temperature, but is usually within the range of 0.5 to 24 hours.

[0171] Preparation of Compound 1-H [ka] (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.)

[0172] Step 1 This step is a step of obtaining ether compound 1-H by Mitsunobu reaction between alcohol compound 31 and alcohol compound 32, and can be produced by a method similar to Step 1 of the production method for compound 1-G above.

[0173] Preparation of Compound 1-I [ka] (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, examples of which include a bromine atom, an iodine atom, and trifluoromethanesulfonate. Step 1 In this step, compound 33 and compound 34 are each subjected to a coupling reaction in the presence of a transition metal such as palladium to obtain compound 1-I.

[0174] This reaction can be carried out under conditions typically used in coupling reactions using transition metals, specifically the Heck reaction, and can be carried out by methods described in literature such as Org. Synth. 2005, 81, 63-76., Heck et al., J. Org. Chem. 1972, 37, 2320-2322. Beletskaya et al., Chem. Rev. 2000, 100, 3009-3066.

[0175] The amount of compound 33 used is suitably within the range of 0.5 to 3 molar equivalents relative to compound 34.

[0176] The organometallic catalyst used in this reaction is not particularly limited. Preferred examples of the organometallic catalyst include tris(dibenzylideneacetone)bispalladium·chloroform adduct (hereinafter referred to as "Pd2(dba)3·CHCl3"), tris(dibenzylideneacetone)bispalladium (hereinafter referred to as "Pd2(dba)3"), tetrakistriphenylphosphinepalladium (hereinafter referred to as "Pd(PPh3)4"), [1,1'-bis(diphenylphosphino)ferrocene]-dichloropalladium(II)·dichloromethane adduct (hereinafter referred to as "Pd(dppf)Cl2·CH2Cl2"), and bis(triphenylphosphine)palladium. Examples of suitable metal catalysts include 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), as well as mixtures of these metal catalysts.

[0177] The amount of the transition metal used is suitably within the range of 0.01 to 0.3 molar equivalents relative to compound 33, for example.

[0178] In this step, a base or a salt may be used as needed. Examples of the base or salt to be used include potassium carbonate, cesium carbonate, sodium carbonate, sodium bicarbonate, sodium acetate, potassium acetate, trisodium phosphate, tripotassium phosphate, and solutions thereof, as well as triethylamine (hereinafter referred to as "TEA"), N,N-diisopropylethylamine (hereinafter referred to as "DIPEA"), lithium chloride, and copper(I) iodide.

[0179] The amount of the base used is suitably within the range of, for example, 1 to 4 molar equivalents relative to compound 33.

[0180] In this step, an appropriate ligand may be used as needed. Examples of the ligand that can be used include 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"), and tricyclohexylphosphine (hereinafter referred to as "PCy3").

[0181] The amount of the ligand used is suitably within the range of, for example, 1 to 5 molar equivalents relative to the transition metal used.

[0182] The solvent used in this step is not particularly limited as long as it is not involved in the reaction, and examples thereof include 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.

[0183] The reaction temperature varies depending on the types of raw materials and reagents used, but is usually within the range of 20° C. to 200° C. If necessary, a microwave reaction apparatus may be used.

[0184] The reaction time varies depending on the types of raw materials used and the reaction temperature, but is usually within the range of 0.1 to 24 hours.

[0185] Preparation of Compound 1-K [ka] (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 include a bromine atom, an iodine atom, and trifluoromethanesulfonate. R AA , and R BB represents a hydroxy group, or R AA and R BB together form -OC(CH3)2-C(CH3)2-O-, -O-(CH2)3-O-, or O-CH2-C(CH3)2-CH2-O-. Step 1 In this step, compound 35 and compound 36 are each subjected to a coupling reaction in the presence of a transition metal such as palladium to obtain compound 1-K.

[0186] This reaction can be carried out under conditions typically used in coupling reactions using transition metals, specifically the Suzuki-Miyaura coupling reaction, by methods described in literature such as Suzuki et al., Chem. Rev., 1995, 95, 2457-2483.

[0187] The amount of compound 36 used is suitably within the range of 0.5 to 3 molar equivalents relative to compound 35.

[0188] The organometallic catalyst used in this reaction is not particularly limited. Preferred examples of the organometallic catalyst include tris(dibenzylideneacetone)bispalladium·chloroform adduct (hereinafter referred to as "Pd2(dba)3·CHCl3"), tris(dibenzylideneacetone)bispalladium (hereinafter referred to as "Pd2(dba)3"), tetrakistriphenylphosphinepalladium (hereinafter referred to as "Pd(PPh3)4"), [1,1'-bis(diphenylphosphino)ferrocene]-dichloropalladium(II)·dichloromethane adduct (hereinafter referred to as "Pd(dppf)Cl2·CH2Cl2"), and bis(triphenylphosphine)palladium. Examples of suitable metal catalysts include 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), as well as mixtures of these metal catalysts.

[0189] The amount of the transition metal used is suitably within the range of 0.01 to 0.3 molar equivalents relative to compound 35, for example.

[0190] In this step, a base or a salt may be used as needed. Examples of the base or salt to be used include potassium carbonate, cesium carbonate, sodium carbonate, sodium bicarbonate, sodium acetate, potassium acetate, trisodium phosphate, tripotassium phosphate, and solutions thereof, as well as triethylamine (hereinafter referred to as "TEA"), N,N-diisopropylethylamine (hereinafter referred to as "DIPEA"), lithium chloride, and copper(I) iodide.

[0191] The amount of the base used is suitably within the range of, for example, 1 to 4 molar equivalents relative to compound 35.

[0192] In this step, an appropriate ligand may be used as needed. Examples of the ligand that can be used include 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"), and tricyclohexylphosphine (hereinafter referred to as "PCy3").

[0193] The amount of the ligand used is suitably within the range of, for example, 1 to 5 molar equivalents relative to the transition metal used.

[0194] The solvent used in this step is not particularly limited as long as it is not involved in the reaction, and examples thereof include 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.

[0195] The reaction temperature varies depending on the types of raw materials and reagents used, but is usually within the range of 20° C. to 200° C. If necessary, a microwave reaction apparatus may be used.

[0196] The reaction time varies depending on the types of raw materials used and the reaction temperature, but is usually within the range of 0.1 to 24 hours.

[0197] As shown in the test examples described later, the compound of the present invention has PDGF receptor kinase inhibitory activity. Furthermore, since the compound of the present invention has PDGF receptor kinase inhibitory activity, it is effective for respiratory diseases, cancer, smooth muscle proliferative diseases, vascular proliferative diseases, autoimmune / inflammatory diseases, metabolic diseases, and vascular obstructive diseases.

[0198] Furthermore, as shown in the test examples described below, the PDGF receptor kinase inhibitory activity of the compounds of the present invention is highly selective for the inhibitory activity against KIT kinase, and therefore the compounds of the present invention are expected to provide PDGF receptor kinase inhibitors that are suppressed in terms of undesirable effects such as bone marrow suppression.

[0199] Therefore, the compound of the present invention or a pharmaceutically acceptable salt thereof can be used, for example, as a preventive or therapeutic agent for diseases involving PDGF receptor kinase.

[0200] Respiratory diseases to which the compound of the present invention or a pharmaceutically acceptable salt thereof can be applied include lung diseases and pulmonary hypertension. Among these, pulmonary hypertension is classified as follows depending on the etiology and pathology: Pulmonary arterial hypertension (PAH), Pulmonary hypertension due to the following left heart disease: Left heart failure with preserved ejection fraction, Left heart failure with reduced ejection fraction, valvular disease, Congenital / acquired cardiovascular conditions leading to post-capillary pulmonary hypertension Pulmonary hypertension due to lung disease and / or hypoxemia associated with the following conditions: chronic obstructive pulmonary disease (COPD), interstitial (restrictive) lung disease, Other lung diseases with mixed restrictive and obstructive disorders, Hypoxia associated with lung disease, or Developmental disorders Pulmonary hypertension due to pulmonary artery obstruction: chronic thromboembolic pulmonary hypertension (CTEPH)], Pulmonary hypertension caused by the following diseases (sarcoma, angiosarcoma, malignant tumor, non-malignant tumor, vasculitis associated with connective tissue disease, congenital pulmonary artery stenosis, parasites, etc., pulmonary tumor thrombotic microangiopathy (PTTM)) Pulmonary hypertension due to an unknown multifactorial mechanism associated with the following diseases: Blood diseases (chronic hemolytic anemia, myeloproliferative disorders, etc.), Systemic and metabolic diseases (e.g., pulmonary Langerhans cell histiocytosis, Gaucher disease, glycogen storage disease, neurofibroma, sarcoidosis, etc.), Others (e.g., chronic renal failure with or without dialysis, fibrosing mediastinitis, etc.), Complex congenital heart defects

[0201] The above-mentioned pulmonary arterial hypertension (PAH) can be, for example, Idiopathic PAH, Hereditary PAH (especially BMPR2, TBX4, ACVRL1, ENG, SMAD9, KCNK3, SMAD1, CAV1, SMAD4, ATP13A3, SOX17, AQP1, GDF2, and unknown gene abnormalities), Drug- and toxin-induced PAHs, PAH associated with a disease (where "disease" refers to, for example, connective tissue disease, HIV infection, portal hypertension, congenital shunt heart disease, or schistosomiasis); PAH long-term responders to calcium channel blockers, pulmonary veno-occlusive disease / pulmonary capillary hemangiomatosis (PVOD / PCH) (including PVOD / PCH with EIF2AK4 mutations), This includes persistent pulmonary hypertension of the newborn (PPHN).

[0202] Inflammatory diseases and autoimmune diseases to which the compound of the present invention or a pharmaceutically acceptable salt thereof can be applied 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, cytopenia, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), allergic rhinitis, allergic sinusitis, interstitial lung disease, idiopathic interstitial pneumonia, chronic obstructive pulmonary disease (COPD), pulmonary fibrosis with emphysema (CPFE), adult respiratory distress syndrome (ARDS), psoriasis, rheumatoid arthritis, mastocytosis, anaphylactic syndrome, angioedema, erythema nodosum, erythema multiplex, cutaneous vasculitis, skin inflammation / disease, urticaria, and allergic contact dermatitis.

[0203] Cancers to which the compound of the present invention or a pharmaceutically acceptable salt thereof can be applied include acute myeloid leukemia (AML), hypereosinophilic syndrome, T-lymphoblastic leukemia, chronic myelomonocytic leukemia (CMML), chronic myelogenous leukemia (CML), chronic eosinophilic leukemia, myelofibrosis, dermatofibrosarcoma protuberans, glioma, ovarian cancer, endometrial tumor, hepatocellular carcinoma, thyroid cancer, small cell lung cancer, non-small cell lung cancer, renal cancer, soft tissue sarcoma, neuroendocrine tumor, skin cancer, mesothelioma, bile duct cancer, squamous cell carcinoma of the head and neck, colorectal cancer, mesenchymal cell carcinoma, adenocarcinoma, pancreatic cancer, mastocytosis, and gastrointestinal stromal tumor (GIST).

[0204] Examples of smooth muscle proliferative diseases to which the compound of the present invention or a pharmaceutically acceptable salt thereof can be applied include vascular restenosis, atherosclerotic / obstructive arteriosclerosis, Moyamoya disease (idiopathic circle of Willis occlusion), leiomyoma, lymphangioleiomyomatosis, Williams syndrome, tuberous sclerosis, angina pectoris, myocardial infarction, peripheral arterial disease, hypertrophic / dilated cardiomyopathy, and restrictive / dysplastic cardiomyopathy.

[0205] Examples of vascular proliferative diseases to which the compound of the present invention or a pharmaceutically acceptable salt thereof can be applied include age-related macular degeneration (AMD), Osler's disease (hereditary hemorrhagic telangiectasia), hemangioma, tumor angiogenesis, and arteriovenous fistula.

[0206] The metabolic disease to which the compound of the present invention or a pharmaceutically acceptable salt thereof can be applied includes diabetes (type 1 diabetes or type 2 diabetes).

[0207] The compound of the present invention can be used as a therapeutic agent for the above-mentioned various diseases in mammals such as humans, mice, rats, rabbits, dogs, cats, cows, horses, pigs, and monkeys, either as such or by mixing with a pharmacologically acceptable carrier or the like to prepare a pharmaceutical composition containing, for example, 0.001% to 99.5%, preferably 0.1% to 90%.

[0208] The pharmaceutical dosage is preferably adjusted taking into consideration the patient's condition, such as age, body weight, type and severity of disease, the route of administration, the type of compound of the present invention, whether or not it is a salt, and the type of salt. However, the amount of the active ingredient of the compound of the present invention or a pharmaceutically acceptable salt thereof for an adult is usually within the range of 0.01 mg to 5 g per adult, preferably 1 mg to 500 mg per adult, when administered orally. In some cases, a lower dose may be sufficient, or conversely, a higher dose may be required. Usually, the compound is administered once a day or in divided doses, or in the case of intravenous administration, it can be administered as a rapid administration or continuously for up to 24 hours.

[0209] One or more hydrogen, carbon and / or other atoms of the compounds of the present invention may be replaced with an isotope of the hydrogen, carbon and / or other atom, respectively. Examples of such isotopes include, but are not limited to, 2 H, 3 H, 11 C. 13 C. 14 C. 15 N, 18 O. 17 O. 31P, 32 P, 35 S, 18 F, 123 I and 36 The isotope-substituted compounds are useful as pharmaceuticals and include all radiolabeled compounds of the present invention.

[0210] The present invention will be explained in more detail below with reference to comparative examples, examples and test examples, but the present invention is not limited thereto.

[0211] The following abbreviations are used in the examples: TFA: Trifluoroacetic acid Pd-C: Palladium-carbon Pd2(dba)3: Tris(dibenzylideneacetone)bispalladium 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)

[0212] MS was measured by LCMS. ESI was used as the ionization method. The observed mass spectrometry values ​​are expressed as m / z.

[0213] The LCMS measurement conditions are as follows. Analytical equipment: ACQUITY UPLC MS / PDA system (Waters) Mass spectrometer: Waters 3100 MS detector Photodiode array detector: ACQUITY PDA detector (UV detection wavelength: 210-400 nm) Column: Acquity BEH C18, 1.7 μm, 2.1 × 50 mm Flow rate: 0.5mL / min Column temperature: 40℃ solvent; Solution A: 0.1% formic acid / H2O (v / v; hereinafter the same) Solution B: 0.1% formic acid / acetonitrile

[0214] 1 H NMR spectra were measured using a JNM-ECS400 nuclear magnetic resonance spectrometer (manufactured by JEOL RESONANCE Co., Ltd.). The 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 doublet, ddd = double double doublet, dt = double triplet).

[0215] For microwave experiments, an Initiator 60 (Biotage) was used, which can achieve temperatures of 40-250°C and pressures up to 20 bar.

[0216] The compound names in this specification were determined using naming software conforming to IUPAC rules, ACD / NAME (registered trademark, Advanced Chemistry Development Inc.), or ChemBioDraw (version 14.0, Cambridge Soft), or were determined according to IUPAC nomenclature.

[0217] The r and s (lower case) in the compound names indicate the stereochemistry of the pseudo-asymmetric carbon atom according to IUPAC rules.

[0218] Reference Example 1 5-[(cyclopropylmethyl)amino]pyridine-3-carboxylic acid [Step 1] Preparation of methyl 5-[(cyclopropylmethyl)amino]pyridine-3-carboxylate Methyl 5-bromopyridine-3-carboxylate (15.0 g), 1-cyclopropylmethanamine (9.9 g), BINAP (8.6 g), cesium carbonate (45.2 g), and Pd(OAc) (1.6 g) were added to 1,4-dioxane (139 mL) and degassed. The mixture was then stirred overnight at 80°C under an argon atmosphere. Insoluble matter was removed by filtration through Celite (registered trademark), and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (8.4 g). MS (m / z): 207.2 [M+H] + [Step 2] Preparation 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)-methanol (81 mL), lithium hydroxide monohydrate (3.4 g) and water (81 mL) were added and stirred at room temperature overnight. The solvent was evaporated under reduced pressure, diluted with water, and then neutralized with 1 M hydrochloric acid. The precipitate was collected by filtration to give 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] Preparation of methyl 5-[cyclopropyl(methyl)amino]pyridine-3-carboxylate The procedure of Step 1 of Reference Example 1 was repeated except that N-methylcyclopropanamine (9.9 g) was used instead of 1-cyclopropylmethanamine to give the title compound (6.6 g). MS (m / z): 207.4 [M+H] + [Step 2] Preparation of 5-[cyclopropyl(methyl)amino]pyridine-3-carboxylic acid The procedure of Step 2 of Reference Example 1 was repeated, except that methyl 5-[cyclopropyl(methyl)amino]pyridine-3-carboxylate (6.6 g) obtained in Step 1 was used instead of methyl 5-[(cyclopropylmethyl)amino]pyridine-3-carboxylate, to give the title compound (4.3 g). MS (m / z): 193.4 [M+H] + Reference Example 3 5-[(3,3-difluorocyclobutyl)oxy]pyridine-3-carboxylic acid [Step 1] Preparation of methyl 5-[(3,3-difluorocyclobutyl)oxy]pyridine-3-carboxylate To a solution of methyl 5-hydroxypyridine-3-carboxylate (250 mg), 3,3-difluorocyclobutan-1-ol (212 mg), and PPh3 (599 mg) in THF (4.1 mL), diisopropyl azodicarboxylate (40% toluene solution, 1.12 mL) was added and stirred at 60°C for 2 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to give the title compound (170 mg). MS (m / z): 244.4 [M+H] + [Step 2] Preparation of 5-[(3,3-difluorocyclobutyl)oxy]pyridine-3-carboxylic acid The title compound (84 mg) was obtained by a method similar to that in Step 2 of Reference Example 1, except that methyl 5-[(3,3-difluorocyclobutyl)oxy]pyridine-3-carboxylate (170 mg) obtained in Step 1 was used instead of methyl 5-[(cyclopropylmethyl)amino]pyridine-3-carboxylate. Reference Example 4 5-[(4,4-difluorocyclohexyl)oxy]pyridine-3-carboxylic acid [Step 1] Preparation of methyl 5-[(4,4-difluorocyclohexyl)oxy]pyridine-3-carboxylate The procedure of Step 1 of Reference Example 3 was repeated except that 4,4-difluorocyclohexane-1-ol was used instead of 3,3-difluorocyclobutan-1-ol to give the title compound (450 mg). MS (m / z): 272.2 [M+H] + [Step 2] Preparation of 5-[(4,4-difluorocyclohexyl)oxy]pyridine-3-carboxylic acid The procedure of Step 2 of Reference Example 1 was repeated, except that methyl 5-[(4,4-difluorocyclohexyl)oxy]pyridine-3-carboxylate (450 mg) obtained in Step 1 was used instead of methyl 5-[(cyclopropylmethyl)amino]pyridine-3-carboxylate, to give the title compound (350 mg). MS (m / z): 258.2 [M+H] + Reference Example 5 5-[(1-methylcyclopropyl)methoxy]pyridine-3-carboxylic acid [Step 1] Preparation of methyl 5-[(1-methylcyclopropyl)methoxy]pyridine-3-carboxylate The procedure of Step 1 of Reference Example 3 was repeated except that 3,3-difluorocyclobutan-1-ol was replaced with (1-methylcyclopropyl)methanol (500 mg), to give the title compound (540 mg). MS (m / z): 222.1 [M+H] + [Step 2] Preparation of 5-[(1-methylcyclopropyl)methoxy]pyridine-3-carboxylic acid The procedure described in Step 2 of Reference Example 1 was repeated, except that methyl 5-[(1-methylcyclopropyl)methoxy]pyridine-3-carboxylate (540 mg) obtained in Step 1 was used instead of methyl 5-[(cyclopropylmethyl)amino]pyridine-3-carboxylate, to give the title compound (340 mg). MS (m / z): 208.2 [M+H] +

[0219] Reference Example 6 5-[(3,3-difluorocyclobutyl)methoxy]pyridine-3-carboxylic acid [Step 1] Preparation of methyl 5-[(3,3-difluorocyclobutyl)methoxy]pyridine-3-carboxylate The procedure of Step 1 of Reference Example 3 was repeated except that 3,3-difluorocyclobutan-1-ol was replaced with (3,3-difluorocyclobutyl)methanol (500 mg) to give the title compound (1.10 g). MS (m / z): 258.1 [M+H] + [Step 2] Preparation of 5-[(3,3-difluorocyclobutyl)methoxy]pyridine-3-carboxylic acid The procedure of Step 2 of Reference Example 1 was repeated, except that methyl 5-[(3,3-difluorocyclobutyl)methoxy]pyridine-3-carboxylate (1.10 g) obtained in Step 1 was used instead of methyl 5-[(cyclopropylmethyl)amino]pyridine-3-carboxylate, to give the title compound (580 mg). 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 stirred at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate, and the organic layer was washed with saturated aqueous sodium bicarbonate and saturated brine. After drying over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure. The resulting residue was suspended in ethyl acetate and the precipitate was collected by filtration to give the title compound (6.10 g). MS (m / z): 249.2 [M+H] + Reference Example 8 Methyl 4-chloro-3-ethynylbenzoate [Step 1] Preparation of methyl 4-chloro-3-[(trimethylsilyl)ethynyl]benzoate Methyl 4-chloro-3-iodobenzoate (8.15 g), ethynyl(trimethyl)silane (2.78 g), copper iodide (570 mg), Pd(PPh3)4 (3.18 g), and TEA (55 mL) were added to THF (27.5 mL) and degassed. The mixture was stirred overnight at 45°C under an argon atmosphere. Insoluble matter was filtered off through Celite®, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (6.8 g). [Step 2] Preparation of methyl 4-chloro-3-ethynylbenzoate Methyl 4-chloro-3-[(trimethylsilyl)ethynyl]benzoate (6.8 g) obtained in Step 1 was dissolved in THF (85 mL), and TBAF (1 M THF solution, 31 mL) was added and stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to give the title compound (2.6 g). Reference Example 9 3-ethynyl-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide The procedure of Reference Example 7 was repeated except that 3-ethynyl-4-methylbenzoic acid (500 mg) was used instead of 3-amino-4-methylbenzoic acid to give the title compound (570 mg). MS (m / z): 258.2 [M+H] + Reference Example 10 2-(5-ethynylpyridin-3-yl)pyrimidine [Step 1] Preparation of 2-[5-(methoxymethoxy)pyridin-3-yl]pyrimidine 3-Bromo-5-(methoxymethoxy)pyridine (4.0 g), bis(pinacolato)diboron (5.6 g), potassium acetate (3.6 g), and Pd(dppf)Cl2·CHCl2 (1.5 g) were added to 1,4-dioxane (73 mL) and degassed. The mixture was stirred at 80°C for 2.5 hours under an argon atmosphere. 2-Bromopyrimidine (3.5 g), potassium carbonate (5.1 g), and water (0.5 mL) were then added, and the mixture was stirred overnight at 85°C. The reaction mixture was diluted with ethyl acetate, and the organic layer was washed with water. After drying over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give the title compound (3.6 g). MS (m / z): 218.4 [M+H] + [Step 2] Preparation 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, and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, and the resulting residue was neutralized with aqueous sodium bicarbonate solution. The resulting precipitate was collected by filtration to give the title compound (2.51 g). MS (m / z): 174.4 [M+H] + [Step 3] Preparation of 5-(pyrimidin-2-yl)pyridin-3-yl trifluoromethanesulfonate To a solution of 5-(pyrimidin-2-yl)pyridin-3-ol (2.00 g) obtained in Step 2 and TEA (2.10 mL) in dichloromethane (38 mL), trifluoromethanesulfonic anhydride (2.27 mL) was added dropwise under ice cooling, and the mixture was stirred at the same temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to give the title compound (770 mg). MS (m / z): 306.4 [M+H] + [Step 4] Preparation of 2-{5-[(trimethylsilyl)ethynyl]pyridin-3-yl}pyrimidine The procedure of Step 1 of Reference Example 8 was repeated, except that 5-(pyrimidin-2-yl)pyridin-3-yl trifluoromethanesulfonate (770 mg) obtained in Step 3 was used instead of methyl 4-chloro-3-iodobenzoate to give the title compound (570 mg). MS (m / z): 254.5 [M+H] + [Step 5] Preparation of 2-(5-ethynylpyridin-3-yl)pyrimidine The procedure of Step 2 of Reference Example 8 was repeated, except that 2-{5-[(trimethylsilyl)ethynyl]pyridin-3-yl}pyrimidine (570 mg) obtained in Step 4 was used instead of methyl 4-chloro-3-[(trimethylsilyl)ethynyl]benzoate to give the title compound (350 mg). MS (m / z): 182.4 [M+H] +

[0220] Reference Example 11 3-bromo-4-chloro-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide The procedure of Reference Example 7 was repeated except that 3-bromo-4-chlorobenzoic acid (250 mg) was used instead of 3-amino-4-methylbenzoic acid to give the title compound (315 mg). MS (m / z): 332.4 [M+H] + Reference Example 12 6-Bromo-N-(cyclopropylmethyl)pyrazin-2-amine To a solution of 2,6-dibromopyrazine (500 mg) in DMF (1 mL), 1-cyclopropylmethanamine (449 mg) and potassium carbonate (871 mg) were added, the mixture was sealed in a stainless steel pressure vessel, and stirred at 120°C for 8 hours. The reaction mixture was diluted with ethyl acetate and washed with water and saturated brine, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give the title compound (400 mg). Reference Example 13 5-ethynyl-N-[(1S,2S)-2-hydroxycyclohexyl]-6-methylpyridine-3-carboxamide [Step 1] Preparation of 5-bromo-N-[(1S,2S)-2-hydroxycyclohexyl]-6-methylpyridine-3-carboxamide The title compound (380 mg) was obtained by a method similar to that of Reference Example 7, 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] Preparation of N-[(1S,2S)-2-hydroxycyclohexyl]-6-methyl-5-[(trimethylsilyl)ethynyl]pyridine-3-carboxamide The procedure described in Step 1 of Reference Example 8 was repeated, except that 5-bromo-N-[(1S,2S)-2-hydroxycyclohexyl]-6-methylpyridine-3-carboxamide (100 mg) obtained in Step 1 was used instead of methyl 4-chloro-3-iodobenzoate to give the title compound (40 mg). MS (m / z): 331.5 [M+H] + [Step 3] Preparation of 5-ethynyl-N-[(1S,2S)-2-hydroxycyclohexyl]-6-methylpyridine-3-carboxamide The procedure of Step 2 of Reference Example 8 was repeated, except that N-[(1S,2S)-2-hydroxycyclohexyl]-6-methyl-5-[(trimethylsilyl)ethynyl]pyridine-3-carboxamide (40 mg) obtained in Step 2 was used instead of methyl 4-chloro-3-[(trimethylsilyl)ethynyl]benzoate to give the title compound (23 mg). MS (m / z): 259.5 [M+H] + Reference Example 14 2-(isoquinolin-4-yl)pyrimidin-4-amine 2-Chloropyrimidin-4-amine (200 mg), isoquinolin-4-ylboronic acid (294 mg), 1M aqueous sodium carbonate (3.1 mL), and Pd(dppf)Cl.CHCl (126 mg) were added to 1,4-dioxane (5 mL), degassed, and then purged with argon. The mixture was stirred under an argon atmosphere at 90°C for 2 hours. The residue obtained by concentrating the reaction mixture under reduced pressure was purified by silica gel column chromatography to give the title compound (300 mg). Reference Example 15 (1S)-1-(5-phenylpyridin-3-yl)ethan-1-amine The procedure of Reference Example 14 was repeated except that 2-chloropyrimidin-4-amine and isoquinolin-4-ylboronic acid were replaced with (1S)-1-(5-bromopyridin-3-yl)ethan-1-amine hydrochloride (300 mg) and phenylboronic acid (185 mg) to give the title compound (280 mg). MS (m / z): 199.2 [M+H] +

[0221] Reference Example 16 (1S)-1-([3,3'-bipyridin]-5-yl)ethan-1-amine [Step 1] Preparation of (SS)-N-[(1E)-1-(5-bromopyridin-3-yl)ethylidene]-2-methylpropane-2-sulfinamide 1-(5-Bromopyridin-3-yl)ethan-1-one (25 g) and (SS)-2-methylpropane-2-sulfinamide (18.2 g) were dissolved in THF (500 mL), and tetraethyl orthotitanate (57 g) was added, followed by stirring at 65° C. overnight. The reaction mixture was diluted with ethyl acetate, and water was added. The reaction mixture was filtered through Celite (registered trademark), 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] Preparation of (SS)-N-[(1S)-1-(5-bromopyridin-3-yl)ethyl]-2-methylpropane-2-sulfinamide A suspension of dichloro(p-cymene)ruthenium(II) dimer (6.86 g), 2-amino-2-methyl-1-propanol (2.14 mL), and molecular sieves 4A (34 g) in 2-propanol (560 mL) was stirred at 80°C for 30 minutes under an argon atmosphere. Next, while stirring the reaction mixture 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, and the mixture was stirred at the same temperature for 6 hours. The reaction mixture was filtered through Celite®, and the solvent was evaporated 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] Preparation of (SS)-N-[(1S)-1-([3,3'-bipyridin]-5-yl)ethyl]-2-methylpropane-2-sulfinamide The title compound (22.7 g) was obtained by a method similar to Reference Example 14, except that (SS)—N-[(1S)-1-(5-bromopyridin-3-yl)ethyl]-2-methylpropane-2-sulfinamide (23.2 g) and pyridin-3-ylboronic acid (11.2 g) obtained in Step 2 were used instead of 2-chloropyrimidin-4-amine and isoquinolin-4-ylboronic acid. MS (m / z): 304.2 [M+H] + [Step 4] Preparation of (1S)-1-([3,3'-bipyridin]-5-yl)ethan-1-amine To a solution of (SS)-N-[(1S)-1-([3,3'-bipyridin]-5-yl)ethyl]-2-methylpropane-2-sulfinamide (22.7 g) obtained in Step 3 in methanol (150 mL), hydrogen chloride (2 M methanol solution, 5.46 mL) was added under ice cooling and stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by column chromatography using amino-modified spherical silica gel to give 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] Preparation of (SS)-2-methyl-N-{(1S)-1-[5-(phenylethynyl)pyridin-3-yl]ethyl}propane-2-sulfinamide The procedure of Step 1 of Reference Example 8 was repeated, except that, instead of methyl 4-chloro-3-iodobenzoate and ethynyl(trimethyl)silane, (SS)—N-[(1S)-1-(5-bromopyridin-3-yl)ethyl]-2-methylpropane-2-sulfinamide (500 mg) and ethynylbenzene (335 mg) obtained in Step 2 of Reference Example 16 were used to obtain the title compound (530 mg). MS (m / z): 327.2 [M+H] + [Step 2] Preparation 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-sulfinamide (530 mg) obtained in step 1 in methanol (8.1 mL), hydrogen chloride (2 M methanol solution, 0.18 mL) was added under ice cooling and stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure, and the resulting residue was suspended in ethyl acetate. The precipitate was collected by filtration to give 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] Preparation of (SS)-2-methyl-N-{(1S)-1-[5-(pyrimidin-2-yl)pyridin-3-yl]ethyl}propane-2-sulfinamide The procedure of Step 1 of Reference Example 10 was repeated, except that (SS)—N-[(1S)-1-(5-bromopyridin-3-yl)ethyl]-2-methylpropane-2-sulfinamide (600 mg) obtained in Step 2 of Reference Example 16 was used instead of 3-bromo-5-(methoxymethoxy)pyridine to give the title compound (420 mg). MS (m / z): 305.4 [M+H] + [Step 2] Preparation of (1S)-1-[5-(pyrimidin-2-yl)pyridin-3-yl]ethan-1-amine The procedure of Step 4 of Reference Example 16 was repeated, except that (SS)-2-methyl-N-{(1S)-1-[5-(pyrimidin-2-yl)pyridin-3-yl]ethyl}propane-2-sulfinamide (420 mg) obtained in Step 1 was used instead of (SS)-N-[(1S)-1-([3,3'-bipyridin]-5-yl)ethyl]-2-methylpropane-2-sulfinamide to give the title compound (200 mg). MS (m / z): 201.3 [M+H] + Reference Example 19 Pyrazolo[5,1-b][1,3]thiazole-7-carbaldehyde [Step 1] Preparation of (pyrazolo[5,1-b][1,3]thiazol-7-yl)methanol Lithium aluminum hydride (1M hexane solution, 1.5 mL) was added to a solution of pyrazolo[5,1-b][1,3]thiazole-7-carboxylic acid (100 mg) in THF (2 mL) and stirred at 50°C for 5 hours. Methanol and potassium sodium L-(+)-tartrate tetrahydrate were added to the reaction mixture at 0°C and stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to give the title compound (57 mg). MS (m / z): 155.3 [M+H] + [Step 2] Preparation of pyrazolo[5,1-b][1,3]thiazole-7-carbaldehyde Manganese dioxide (160 mg) was added 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), and the mixture was stirred at room temperature overnight. The reaction mixture was filtered to remove insoluble matter, and the filtrate was concentrated under reduced pressure to give the title compound (42 mg). Reference Example 20 5-amino-N-[(1S,2S)-2-hydroxycyclohexyl]-6-methylpyridine-3-carboxamide The procedure described in Reference Example 7 was repeated except that 5-amino-6-methylpyridine-3-carboxylic acid (915 mg) was used instead of 3-amino-4-methylbenzoic acid to give the title compound (1.17 g). MS (m / z): 250.2 [M+H] +

[0222] Reference Example 21 N-(5-formylpyridin-2-yl)morpholine-4-carboxamide [Step 1] Preparation of phenyl (5-formylpyridin-2-yl)carbamate To a solution of 6-aminopyridine-3-carbaldehyde (250 mg) in THF (5.1 mL), TEA (0.57 mL) and phenyl chloroformate (304 mg) were added and stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to give the title compound (246 mg). MS (m / z): 243.2 [M+H] + [Step 2] Preparation 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), morpholine (43 mg) and TEA (0.072 mL) were added and stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to give 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 a method similar to that of Step 2 of Reference Example 21, except that N-methylcyclopropanamine (94 mg) was used 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] Preparation 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), TEA (0.01 mL), BocO (0.19 mL), and DMAP (4.5 mg) were added and stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to give the title compound (177 mg). MS (m / z): 315.1 [M+H] + [Step 2] Preparation of tert-butyl 7-ethenyl-2,3-dihydro-4H-pyrido[3,2-b][1,4]oxazine-4-carboxylate The procedure of Reference Example 14 was repeated except that, instead of 2-chloropyrimidin-4-amine and isoquinolin-4-ylboronic acid, tert-butyl 7-bromo-2,3-dihydro-4H-pyrido[3,2-b][1,4]oxazine-4-carboxylate (177 mg) and 2-ethenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (172 mg) obtained in Step 1 were used to obtain the title compound (118 mg). MS (m / z): 263.2 [M+H] + [Step 3] Preparation of tert-butyl 7-formyl-2,3-dihydro-4H-pyrido[3,2-b][1,4]oxazine-4-carboxylate To a solution of tert-butyl 7-ethenyl-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 through at -78 °C for 30 minutes. Argon gas was then bubbled through the solution until it became colorless, and triphenylphosphine (142 mg) was added and stirred at room temperature overnight. Water was added to the reaction solution, which was then extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain the title compound as a crude product. Reference Example 24 6-(1H-1,2,3-triazol-1-yl)pyridine-3-carbaldehyde [Step 1] Preparation of 5-ethenyl-2-(1H-1,2,3-triazol-1-yl)pyridine The title compound (90 mg) was obtained by a method similar to that described in Reference Example 14, except that 5-bromo-2-(1H-1,2,3-triazol-1-yl)pyridine (142 mg) (synthesized, for example, according to the method described in WO2006038100) and 2-ethenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (117 mg) were used instead of 2-chloropyrimidin-4-amine and isoquinolin-4-ylboronic acid. MS (m / z): 173.1 [M+H] + [Step 2] Preparation of 6-(1H-1,2,3-triazol-1-yl)pyridine-3-carbaldehyde The title compound (306 mg) was obtained as a crude product by a method similar to that of Step 3 of Reference Example 23, except that 5-ethenyl-2-(1H-1,2,3-triazol-1-yl)pyridine (90 mg) obtained in Step 1 was used instead of tert-butyl 7-ethenyl-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-carbaldehyde [Step 1] Preparation of [5-(2H-1,2,3-triazol-2-yl)pyridin-3-yl]methanol Sodium borohydride (41 mg) was added to a solution of methyl 5-(2H-1,2,3-triazol-2-yl)pyridine-3-carboxylate (44 mg) (synthesized, for example, according to the method described in Angew. Chem. Int. Ed. 2011, 50, 8944-8947.) in methanol (2.2 mL), and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound. [Step 2] Preparation of 5-(2H-1,2,3-triazol-2-yl)pyridine-3-carbaldehyde The title compound (22 mg) was obtained by a method similar to that of Step 2 of Reference Example 19, 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.

[0223] Reference Example 26 3-formyl-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide The procedure of Reference Example 7 was repeated except that 3-formyl-4-methylbenzoic acid (100 mg) was used instead of 3-amino-4-methylbenzoic acid to give the title compound (134 mg). MS (m / z): 262.5 [M+H] + Reference Example 27 5-(pyrimidin-2-yl)pyridin-3-amine dihydrochloride [Step 1] Preparation of di-tert-butyl (5-bromopyridin-3-yl)-2-imidodicarbonate The procedure of Step 1 of Reference Example 23 was repeated except that 5-bromopyridin-3-amine (25.0 g) was used instead of 7-bromo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine to give the title compound (40.0 g). MS (m / z): 373.4 [M+H] + [Step 2] Preparation of di-tert-butyl [5-(pyrimidin-2-yl)pyridin-3-yl]-2-imidodicarbonate The procedure of Step 1 of Reference Example 10 was repeated, except that di-tert-butyl (5-bromopyridin-3-yl)-2-imidodicarbonate (30.0 g) obtained in Step 1 was used instead of 3-bromo-5-(methoxymethoxy)pyridine to give the title compound (14.3 g). MS (m / z): 373.5 [M+H] + [Step 3] Preparation of 5-(pyrimidin-2-yl)pyridin-3-amine dihydrochloride To a solution of di-tert-butyl [5-(pyrimidin-2-yl)pyridin-3-yl]-2-imidodicarbonate (14.3 g) obtained in Step 2 in ethanol (128 mL), hydrogen chloride (4 M ethyl acetate solution, 14 mL) was added and stirred at 60 ° C. for 3 hours. The reaction solution was concentrated under reduced pressure, the residue was suspended in ethyl acetate, and the precipitate was collected by filtration, washed with ethyl acetate, and dried to give the title compound (3.5 g). MS (m / z): 173.4 [M + H] + Reference Example 28 3-formyl-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide The procedure of Reference Example 7 was repeated except that 3-formylbenzoic acid (500 mg) was used instead of 3-amino-4-methylbenzoic acid to give the title compound (590 mg). 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 a method similar to that of Reference Example 7, except that 4-fluoro-3-formylbenzoic acid (300 mg) was used 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] Preparation of 5-ethenyl-N-[(1S,2S)-2-hydroxycyclohexyl]-6-methylpyridine-3-carboxamide The procedure of Reference Example 14 was repeated, except that 5-bromo-N-[(1S,2S)-2-hydroxycyclohexyl]-6-methylpyridine-3-carboxamide (750 mg) and 2-ethenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (479 mg) obtained in Step 1 of Reference Example 13 were used instead of 2-chloropyrimidin-4-amine and isoquinolin-4-ylboronic acid to give the title compound (614 mg). MS (m / z): 261.2 [M+H] + [Step 2] Preparation of 5-formyl-N-[(1S,2S)-2-hydroxycyclohexyl]-6-methylpyridine-3-carboxamide The procedure of Step 3 of Reference Example 23 was repeated, except that 5-ethenyl-N-[(1S,2S)-2-hydroxycyclohexyl]-6-methylpyridine-3-carboxamide (614 mg) obtained in Step 1 was used instead of tert-butyl 7-ethenyl-2,3-dihydro-4H-pyrido[3,2-b][1,4]oxazine-4-carboxylate to give the title compound (360 mg). MS (m / z): 263.2 [M+H] +

[0224] Reference Example 31 Methyl 4-chloro-3-(hydroxymethyl)benzoate To a solution of methyl 4-chloro-3-formylbenzoate (200 mg) in methanol (3.4 mL)-THF (3.4 mL), sodium borohydride (38 mg) was added at 0°C and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (130 mg). Reference Example 32 Methyl 3-[(ethylamino)methyl]-4-methylbenzoate To a solution of methyl 3-formyl-4-methylbenzoate (500 mg) in methanol (11 mL), ethylamine (2 M methanol solution, 2.8 mL) was added and stirred at room temperature for 30 minutes. Sodium borohydride (159 mg) was then added and stirred at room temperature for 2 hours. Water was added to the reaction mixture, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (423 mg). MS (m / z): 208.2 [M+H] + Reference Example 33 Ethyl 5-formyl-6-methylpyridine-3-carboxylate [Step 1] Preparation of ethyl 5-ethenyl-6-methylpyridine-3-carboxylate The procedure of Reference Example 14 was repeated except that ethyl 5-bromo-6-methylpyridine-3-carboxylate (4.2 g) and 2-ethenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (3.7 g) were used instead of 2-chloropyrimidin-4-amine and isoquinolin-4-ylboronic acid to give the title compound (3.0 g). MS (m / z): 192.1 [M+H] + [Step 2] Preparation of ethyl 5-formyl-6-methylpyridine-3-carboxylate The procedure of Step 3 of Reference Example 23 was repeated, except that ethyl 5-ethenyl-6-methylpyridine-3-carboxylate (3.0 g) obtained in Step 1 was used instead of tert-butyl 7-ethenyl-2,3-dihydro-4H-pyrido[3,2-b][1,4]oxazine-4-carboxylate, to give the title compound (2.7 g). 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-carbaldehyde (500 mg) in dichloromethane (11 mL), acetic acid (0.15 mL) and 1-methylpiperazine (808 mg) were added and stirred at room temperature for 1 hour. Sodium triacetoxyborohydride (1.14 g) was then added and 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 procedure of Reference Example 34 was repeated except that morpholine (703 mg) was used instead of 1-methylpiperazine to give the title compound (570 mg). MS (m / z): 257.1 [M+H] +

[0225] Reference Example 36 5-bromo-N-(oxan-4-yl)pyridin-3-amine The procedure of Step 1 of Reference Example 1 was repeated except that 3,5-dibromopyridine and oxan-4-amine (256 mg) were used instead of methyl 5-bromopyridine-3-carboxylate and 1-cyclopropylmethanamine to give the title compound (230 mg). MS (m / z): 257.0 [M+H] + Reference Example 37 5-bromo-N-(1-methylpiperidin-4-yl)pyridin-3-amine The procedure of Step 1 of Reference Example 1 was repeated except that 3,5-dibromopyridine and 1-methylpiperidin-4-amine (304 mg) were used instead of methyl 5-bromopyridine-3-carboxylate and 1-cyclopropylmethanamine to give the title compound (300 mg). MS (m / z): 270.1 [M+H] + Reference Example 38 1-[(5-bromopyridin-3-yl)methyl]-4-ethylpiperazine The procedure described in Reference Example 34 was repeated except that 1-ethylpiperazine (921 mg) was used instead of 1-methylpiperazine to give the title compound (680 mg). MS (m / z): 284.1 [M+H] + Reference Example 39 5-bromo-N-(oxetan-3-yl)pyridin-3-amine The procedure described in Step 1 of Reference Example 1 was repeated except that 3,5-dibromopyridine (1.00 g) and oxetan-3-amine (309 mg) were used instead of methyl 5-bromopyridine-3-carboxylate and 1-cyclopropylmethanamine to give the title compound (410 mg). 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-imidodicarbonate [Step 1] Preparation of benzyl 2-[bis(tert-butoxycarbonyl)amino]-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate The title compound (960 mg) was obtained by a method similar to that of Step 1 of Reference Example 23, except that benzyl 2-amino-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate (600 mg) was used instead of 7-bromo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine. [Step 2] Preparation of di-tert-butyl 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl-2-imidodicarbonate To a solution of benzyl 2-[bis(tert-butoxycarbonyl)amino]-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate (960 mg) in methanol (100 mL), the mixture was degassed and stirred at room temperature under an argon atmosphere. 5% Pd-C (400 mg) was added, and the mixture was stirred at room temperature under a hydrogen atmosphere for 4 hours. The reaction mixture was filtered through Celite (registered trademark), and the solvent was evaporated under reduced pressure to give the title compound (700 mg).

[0226] 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), tert-butyldimethylsilyl triflate (1.11 g) and 2,6-lutidine (690 mg) were added and stirred at room temperature overnight. The reaction solution was diluted with ethyl acetate, washed with water and saturated brine, and the solvent was evaporated under reduced pressure. The resulting 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] Preparation of methyl 3-[(hydroxyimino)methyl]-4-methylbenzoate To a solution of methyl 3-formyl-4-methylbenzoate (1.00 g) in methanol (20 mL), 50% aqueous hydroxylamine solution (1.32 mL) was added and stirred at 50°C for 2 hours. The reaction mixture was concentrated under reduced pressure, and ethyl acetate was added to the resulting residue. The organic layer was washed with water and saturated brine. After drying over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure to give the title compound (1.02 g). MS (m / z): 194.4 [M+H] + [Step 2] Preparation of methyl 3-(aminomethyl)-4-methylbenzoate Hydrogen chloride (2M methanol solution, 15 mL) was added to methyl 3-[(hydroxyimino)methyl]-4-methylbenzoate (1.02 g) obtained in Step 1. After degassing, 5% Pd-C (500 mg) was added while stirring at room temperature under an argon atmosphere, and the mixture was stirred at room temperature under a hydrogen atmosphere for 3 hours. The reaction mixture was filtered through Celite®, and the solvent was evaporated under reduced pressure. The resulting residue was made basic with aqueous sodium hydroxide solution and then extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give 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 procedure of Reference Example 7 was repeated except that 3-bromo-4-methylbenzoic acid (16.6 g) was used instead of 3-amino-4-methylbenzoic acid to give the title compound (23.0 g). MS (m / z): 312.0 [M+H] +

[0227] Example 1 2-(cyclopropylamino)-N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)-1,3-thiazole-5-carboxamide [Step 1] Preparation 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), methyl 3-amino-4-methylbenzoate (1.75 g), HATU (4.83 g), and DIPEA (3.66 mL) were added sequentially and stirred at room temperature for 6 hours. The reaction mixture was diluted with ethyl acetate, and the organic layer was washed with saturated aqueous sodium bicarbonate and saturated brine. After drying over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (1.02 g). [Step 2] Preparation 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 cyclopropanamine (121 mg), and the mixture was stirred for 6 hours at 80° C. After allowing the reaction solution to cool, it was purified by silica gel column chromatography to obtain the title compound (105 mg). [Step 3] Preparation of 3-{[2-(cyclopropylamino)-1,3-thiazole-5-carbonyl]amino}-4-methylbenzoic acid The title compound (90 mg) was obtained by a method similar to that in Step 2 of Reference Example 1, except that methyl 3-{[2-(cyclopropylamino)-1,3-thiazole-5-carbonyl]amino}-4-methylbenzoate (103 mg) obtained in Step 2 was used instead of methyl 5-[(cyclopropylmethyl)amino]pyridine-3-carboxylate. [Step 4] Preparation 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), HATU (54 mg) and DIPEA (0.065 mL) were added sequentially and stirred at room temperature for 10 minutes. Next, (1S,2S)-2-aminocyclohexan-1-ol hydrochloride (22 mg) was added and stirred at room temperature for 1 hour. The reaction solution was diluted with ethyl acetate, and the organic layer was washed with saturated aqueous sodium bicarbonate and saturated brine. After drying over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (16 mg). Example 2 N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)-5-phenylpyridine-3-carboxamide [Step 1] Preparation of methyl 3-[(5-bromopyridine-3-carbonyl)amino]-4-methylbenzoate The same procedure as in Step 1 of Example 1 was repeated except that 5-bromopyridine-3-carboxylic acid (1.00 g) was used instead of 2-bromo-1,3-thiazole-5-carboxylic acid to give the title compound (1.70 g). MS (m / z): 349.0 [M+H] + [Step 2] Preparation of 3-[(5-bromopyridine-3-carbonyl)amino]-4-methylbenzoic acid The procedure of Step 2 of Reference Example 1 was repeated, except that methyl 3-[(5-bromopyridine-3-carbonyl)amino]-4-methylbenzoate (650 mg) obtained in Step 1 was used instead of methyl 5-[(cyclopropylmethyl)amino]pyridine-3-carboxylate to give the title compound (505 mg). MS (m / z): 335.0 [M+H] + [Step 3] Preparation of 5-bromo-N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)pyridine-3-carboxamide The same procedure as in Step 4 of Example 1 was repeated, except that 3-[(5-bromopyridine-3-carbonyl)amino]-4-methylbenzoic acid (505 mg) obtained in Step 2 was used instead of 3-{[2-(cyclopropylamino)-1,3-thiazole-5-carbonyl]amino}-4-methylbenzoic acid to give the title compound (650 mg). MS (m / z): 432.1 [M+H] + [Step 4] Preparation of N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)-5-phenylpyridine-3-carboxamide The title compound (40 mg) was obtained by a method similar to Reference Example 14, using 5-bromo-N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)pyridine-3-carboxamide (50 mg) and phenylboronic acid (17 mg) obtained in Step 3 instead of 2-chloropyrimidin-4-amine and isoquinolin-4-ylboronic acid. Example 3 2-(cyclopropylmethyl)-N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)-1,3-thiazole-5-carboxamide [Step 1] Preparation of methyl 3-{[2-(cyclopropylmethyl)-1,3-thiazole-5-carbonyl]amino}-4-methylbenzoate The same procedure as in Step 1 of Example 1 was repeated except that 2-(cyclopropylmethyl)-1,3-thiazole-5-carboxylic acid (100 mg) was used instead of 2-bromo-1,3-thiazole-5-carboxylic acid to give the title compound (160 mg). MS (m / z): 331.5 [M+H] + [Step 2] Preparation of 3-{[2-(cyclopropylmethyl)-1,3-thiazole-5-carbonyl]amino}-4-methylbenzoic acid The procedure of Step 2 of Reference Example 1 was repeated, except that methyl 3-{[2-(cyclopropylmethyl)-1,3-thiazole-5-carbonyl]amino}-4-methylbenzoate (160 mg) obtained in Step 1 was used instead of methyl 5-[(cyclopropylmethyl)amino]pyridine-3-carboxylate to give the title compound (145 mg). MS (m / z): 317.4 [M+H] + [Step 3] Preparation of 2-(cyclopropylmethyl)-N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)-1,3-thiazole-5-carboxamide The procedure of Step 4 of Example 1 was repeated, except that 3-{[2-(cyclopropylmethyl)-1,3-thiazole-5-carbonyl]amino}-4-methylbenzoic acid (40 mg) obtained in Step 2 was used instead of 3-{[2-(cyclopropylamino)-1,3-thiazole-5-carbonyl]amino}-4-methylbenzoic acid, to obtain the title compound (38 mg). 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 a method similar to that of Step 1 of Example 1, except that 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 were used instead of 2-bromo-1,3-thiazole-5-carboxylic acid and methyl 3-amino-4-methylbenzoate.

[0228] Example 6 N-(5-{[(1S)-2-hydroxy-1-phenylethyl]carbamoyl}-2-methylphenyl)-5-phenylpyridine-3-carboxamide [Step 1] Preparation of methyl 4-methyl-3-[(5-phenylpyridine-3-carbonyl)amino]benzoate The procedure described in Reference Example 14 was repeated except that methyl 3-[(5-bromopyridine-3-carbonyl)amino]-4-methylbenzoate (1.00 g) and phenylboronic acid (419 mg) obtained in Step 1 of Example 2 were used instead of 2-chloropyrimidin-4-amine and isoquinolin-4-ylboronic acid to give the title compound (1.00 g). MS (m / z): 347.2 [M+H] + [Step 2] Preparation of 4-methyl-3-[(5-phenylpyridine-3-carbonyl)amino]benzoic acid The procedure of Step 2 of Reference Example 1 was repeated, except that methyl 4-methyl-3-[(5-phenylpyridine-3-carbonyl)amino]benzoate (1.00 g) obtained in Step 1 was used instead of methyl 5-[(cyclopropylmethyl)amino]pyridine-3-carboxylate to give the title compound (910 mg). MS (m / z): 333.2 [M+H] + [Step 3] Preparation of N-(5-{[(1S)-2-hydroxy-1-phenylethyl]carbamoyl}-2-methylphenyl)-5-phenylpyridine-3-carboxamide The same procedure as in Step 4 of Example 1 was repeated, except that 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 were used instead of 3-{[2-(cyclopropylamino)-1,3-thiazole-5-carbonyl]amino}-4-methylbenzoic acid and (1S,2S)-2-aminocyclohexan-1-ol hydrochloride, to obtain the title compound (38 mg). Example 17 5-[cyclopropyl(methyl)amino]-N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)pyridine-3-carboxamide The same procedure as in Step 1 of Example 1 was repeated, except that 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 were used instead of 2-bromo-1,3-thiazole-5-carboxylic acid and methyl 3-amino-4-methylbenzoate, to give the title compound (43 mg). 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 a method similar to Reference Example 14, using 5-bromo-N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)pyridine-3-carboxamide (61 mg) and (3-fluorophenyl)boronic acid (28 mg) obtained in Step 3 of Example 2 instead of 2-chloropyrimidin-4-amine and isoquinolin-4-ylboronic acid. Example 24 5-(cyclopropylmethoxy)-N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)pyridine-3-carboxamide The title compound (58 mg) was obtained by a method similar to that in Step 1 of Example 1, except that 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 were used instead of 2-bromo-1,3-thiazole-5-carboxylic acid and methyl 3-amino-4-methylbenzoate. Example 26 2-[(2-cyclopropylethyl)amino]-N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)-1,3-thiazole-5-carboxamide [Step 1] Preparation of methyl 3-[(2-chloro-1,3-thiazole-5-carbonyl)amino]-4-methylbenzoate A solution of 2-chloro-1,3-thiazole-5-carbonyl chloride (8.31 g) in THF (80 mL) was added dropwise to a solution of methyl 3-amino-4-methylbenzoate (6.89 g) in THF (80 mL) under ice-cooling and stirring, and the mixture was stirred at the same temperature for 30 minutes. The reaction mixture was diluted with ethyl acetate, and the organic layer was washed with saturated aqueous sodium bicarbonate and saturated brine. After drying over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure. The resulting residue was suspended in water and the precipitate was collected by filtration to give the title compound (12.5 g). MS (m / z): 311.4 [M+H] + [Step 2] Preparation of 3-[(2-chloro-1,3-thiazole-5-carbonyl)amino]-4-methylbenzoic acid The procedure of Step 2 of Reference Example 1 was repeated, except that methyl 3-[(2-chloro-1,3-thiazole-5-carbonyl)amino]-4-methylbenzoate (12.5 g) obtained in Step 1 was used instead of methyl 5-[(cyclopropylmethyl)amino]pyridine-3-carboxylate to give the title compound (10.4 g). MS (m / z): 297.4 [M+H] + [Step 3] Preparation of 2-chloro-N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)-1,3-thiazole-5-carboxamide The same procedure as in Step 4 of Example 1 was repeated, except that 3-[(2-chloro-1,3-thiazole-5-carbonyl)amino]-4-methylbenzoic acid (7.5 g) obtained in Step 2 was used instead of 3-{[2-(cyclopropylamino)-1,3-thiazole-5-carbonyl]amino}-4-methylbenzoic acid to give the title compound (9.8 g). MS (m / z): 394.2 [M+H] + [Step 4] Preparation of N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)-5-phenylpyridine-3-carboxamide The same procedure as in Step 2 of Example 1 was repeated, except that 2-chloro-N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)-1,3-thiazole-5-carboxamide (90 mg) and 2-cyclopropylethan-1-amine (249 mg) obtained in Step 3 were used instead of methyl 3-[(2-bromo-1,3-thiazole-5-carbonyl)amino]-4-methylbenzoate and cyclopropanamine, to obtain the title compound (72 mg).

[0229] Example 57 3-[(5-bromopyridin-3-yl)ethynyl]-4-chloro-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide [Step 1] Preparation of methyl 3-[(5-bromopyridin-3-yl)ethynyl]-4-chlorobenzoate The procedure of Step 1 of Reference Example 8 was repeated, except that methyl 4-chloro-3-ethynylbenzoate (1.01 g) and 3-bromo-5-iodopyridine (1.47 g) obtained in Reference Example 8 were used instead of ethynyl(trimethyl)silane and methyl 4-chloro-3-iodobenzoate to give the title compound (1.60 g). MS (m / z): 350.0 [M+H] + [Step 2] Preparation of 3-[(5-bromopyridin-3-yl)ethynyl]-4-chlorobenzoic acid The procedure of Step 2 of Reference Example 1 was repeated, except that methyl 3-[(5-bromopyridin-3-yl)ethynyl]-4-chlorobenzoate (600 mg) obtained in Step 1 was used instead of methyl 5-[(cyclopropylmethyl)amino]pyridine-3-carboxylate to give the title compound (360 mg). MS (m / z): 335.9 [M+H] + [Step 3] Preparation of 3-[(5-bromopyridin-3-yl)ethynyl]-4-chloro-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide The procedure of Step 4 of Example 1 was repeated, except that 3-[(5-bromopyridin-3-yl)ethynyl]-4-chlorobenzoic acid (370 mg) obtained in Step 2 was used instead of 3-{[2-(cyclopropylamino)-1,3-thiazole-5-carbonyl]amino}-4-methylbenzoic acid, to obtain the title compound (170 mg). Example 58 4-chloro-N-[(1S,2S)-2-hydroxycyclohexyl]-3-[(5-phenylpyridin-3-yl)ethynyl]benzamide The title compound (5 mg) was obtained by a method similar to Reference Example 14, using 3-[(5-bromopyridin-3-yl)ethynyl]-4-chloro-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide (50 mg) and phenylboronic acid (15 mg) obtained in Example 57 instead of 2-chloropyrimidin-4-amine and isoquinolin-4-ylboronic acid. Example 59 N-[(1S,2S)-2-Hydroxycyclohexyl]-4-methyl-3-[(5-methylpyridin-3-yl)ethynyl]benzamide The title compound (14 mg) was obtained by a method similar to that in Step 1 of Reference Example 8, except that 3-ethynyl-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide (30 mg) and 3-bromo-5-methylpyridine (30 mg) obtained in Reference Example 9 were used instead of ethynyl(trimethyl)silane and methyl 4-chloro-3-iodobenzoate. Example 61 3-[(5-bromopyridin-3-yl)ethynyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide The title compound (14.5 g) was obtained by a method similar to that of Step 1 of Reference Example 8, except that 3-ethynyl-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide (20.5 g) and 3-bromo-5-iodopyridine (24.8 g) obtained in Reference Example 9 were used instead of ethynyl(trimethyl)silane and methyl 4-chloro-3-iodobenzoate. Example 62 N-[(1S,2S)-2-Hydroxycyclohexyl]-4-methyl-3-{[5-(pyrimidin-2-yl)pyridin-3-yl]ethynyl}benzamide DMF (0.5 mL) was added 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), and the mixture was reacted in a microwave reactor at 150 °C for 30 minutes. After cooling, the reaction mixture was purified by silica gel column chromatography to give the title compound (15 mg).

[0230] Example 67 3-[(5-cyclopropylpyridin-3-yl)ethynyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide The title compound (250 mg) was obtained by a method similar to Reference Example 14, using 3-[(5-bromopyridin-3-yl)ethynyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide (400 mg) and cyclopropylboronic acid (249 mg) obtained in Example 61 instead of 2-chloropyrimidin-4-amine and isoquinolin-4-ylboronic acid. Example 76 3-[(5-bromopyridin-3-yl)ethynyl]-N-[(1S,2S)-1,3-dihydroxy-1-phenylpropan-2-yl]-4-methylbenzamide [Step 1] Preparation of 3-[(5-bromopyridin-3-yl)ethynyl]-4-methylbenzoic acid The procedure of Step 1 of Reference Example 8 was repeated except that 3-ethynyl-4-methylbenzoic acid (40 mg) and 3-bromo-5-iodopyridine (71 mg) were used instead of ethynyl(trimethyl)silane and methyl 4-chloro-3-iodobenzoate to give the title compound (47 mg). MS (m / z): 316.2 [M+H] + [Step 2] Preparation of 3-[(5-bromopyridin-3-yl)ethynyl]-N-[(1S,2S)-1,3-dihydroxy-1-phenylpropan-2-yl]-4-methylbenzamide The title compound (28 mg) was obtained by a method similar to that of Step 4 of Example 1, 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. Example 77 N 1 -[(1S,2S)-2-Hydroxycyclohexyl]-4-methyl-N3-(5-phenylpyridin-3-yl)benzene-1,3-dicarboxamide [Step 1] Preparation of methyl 5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylbenzoate The same procedure as in Step 4 of Example 1 was repeated except that 3-(methoxycarbonyl)-4-methylbenzoic acid (500 mg) was used instead of 3-{[2-(cyclopropylamino)-1,3-thiazole-5-carbonyl]amino}-4-methylbenzoic acid to give the title compound (600 mg). MS (m / z): 292.3 [M+H] + [Step 2] Preparation of 5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylbenzoic acid The procedure of Step 2 of Reference Example 1 was repeated, except that methyl 5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylbenzoate (600 mg) obtained in Step 1 was used instead of methyl 5-[(cyclopropylmethyl)amino]pyridine-3-carboxylate to give the title compound (430 mg). MS (m / z): 278.3 [M+H] + [Step 3] N 3 Preparation of -(5-bromopyridin-3-yl)-N1-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzene-1,3-dicarboxamide The same procedure as in Step 1 of Example 1 was repeated except that 2-bromo-1,3-thiazole-5-carboxylic acid and methyl 3-amino-4-methylbenzoate were replaced with 5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylbenzoic acid (200 mg) and 5-bromopyridin-3-amine (137 mg) obtained in Step 2 to give the title compound (166 mg). MS (m / z): 432.3 [M+H] + [Step 4] N 1 Preparation of -[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-N3-(5-phenylpyridin-3-yl)benzene-1,3-dicarboxamide In a similar manner to Reference Example 14, N-chloropyrimidin-4-amine obtained in Step 3 was used in place of 2-chloropyrimidin-4-amine and isoquinolin-4-ylboronic acid. 3 Using -(5-bromopyridin-3-yl)-N1-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzene-1,3-dicarboxamide (50 mg) and phenylboronic acid (17 mg), the title compound (40 mg) was obtained. Example 78 N-[(1S,2S)-2-Hydroxycyclohexyl]-4-methyl-3-{[2-(pyridin-3-yl)pyrimidin-4-yl]amino}benzamide [Step 1] Preparation of methyl 4-methyl-3-{[2-(pyridin-3-yl)pyrimidin-4-yl]amino}benzoate The procedure of Reference Example 1, Step 1 was repeated, except that methyl 3-bromo-4-methylbenzoate (350 mg) and 2-(pyridin-3-yl)pyrimidin-4-amine (263 mg) were used instead of methyl 5-bromopyridine-3-carboxylate and 1-cyclopropylmethanamine, to give the title compound (280 mg). [Step 2] Preparation of 4-methyl-3-{[2-(pyridin-3-yl)pyrimidin-4-yl]amino}benzoic acid The title compound (180 mg) was obtained by a method similar to that of Step 2 of Reference Example 1, 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. [Step 3] Preparation of N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-{[2-(pyridin-3-yl)pyrimidin-4-yl]amino}benzamide The procedure of Example 1, step 4 was repeated, except that 4-methyl-3-{[2-(pyridin-3-yl)pyrimidin-4-yl]amino}benzoic acid (50 mg) was used instead of 3-{[2-(cyclopropylamino)-1,3-thiazole-5-carbonyl]amino}-4-methylbenzoic acid, to obtain the title compound (50 mg). 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] Preparation of methyl 3-{2-[bis(tert-butoxycarbonyl)amino]-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl}-4-methylbenzoate The procedure of Step 1 of Reference Example 1 was repeated, except that methyl 3-bromo-4-methylbenzoate (84 mg) and di-tert-butyl 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl-2-imidodicarbonate (86 mg) obtained in Reference Example 40 were used instead of methyl 5-bromopyridine-3-carboxylate and 1-cyclopropylmethanamine to give the title compound (54 mg). MS (m / z): 499.6 [M+H] + [Step 2] Preparation of methyl 3-(2-amino-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-4-methylbenzoate To the 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, hydrogen chloride (2 M methanol solution, 2.1 mL) was added and stirred at 50 ° C. for 5 hours. After cooling, the reaction mixture was purified by silica gel column chromatography to obtain the title compound (10 mg). MS (m / z): 299.5 [M + H] + [Step 3] Preparation of 3-(2-amino-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-4-methylbenzoic acid The title compound was obtained by a method similar to that of Step 2 of Reference Example 1, except that methyl 3-(2-amino-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-4-methylbenzoate (10 mg) obtained in Step 2 was used instead of methyl 5-[(cyclopropylmethyl)amino]pyridine-3-carboxylate. MS (m / z): 285.3 [M+H] + [Step 4] Preparation 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 The same procedure as in step 4 of Example 1 was repeated, except that 3-{[2-(cyclopropylamino)-1,3-thiazole-5-carbonyl]amino}-4-methylbenzoic acid, (1S,2S)-2-aminocyclohexan-1-ol hydrochloride was replaced with 3-(2-amino-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-4-methylbenzoic acid, (1S,2S)-2-amino-1-phenylpropane-1,3-diol (11 mg) obtained in step 3, to obtain the title compound (6 mg).

[0231] Example 84 N-[(1S,2S)-2-Hydroxycyclohexyl]-4-methyl-3-{[(1S)-1-(5-phenylpyridin-3-yl)ethyl]amino}benzamide [Step 1] Preparation of methyl 4-methyl-3-{[(1S)-1-(5-phenylpyridin-3-yl)ethyl]amino}benzoate The procedure of Step 1 of Reference Example 1 was repeated, except that methyl 3-bromo-4-methylbenzoate (324 mg) and (1S)-1-(5-phenylpyridin-3-yl)ethan-1-amine (280 mg) obtained in Reference Example 15 were used instead of methyl 5-bromopyridine-3-carboxylate and 1-cyclopropylmethanamine to give the title compound (220 mg). MS (m / z): 347.3 [M+H] + [Step 2] Preparation of 4-methyl-3-{[(1S)-1-(5-phenylpyridin-3-yl)ethyl]amino}benzoic acid The procedure of Step 2 of Reference Example 1 was repeated, except that methyl 4-methyl-3-{[(1S)-1-(5-phenylpyridin-3-yl)ethyl]amino}benzoate (220 mg) obtained in Step 1 was used instead of methyl 5-[(cyclopropylmethyl)amino]pyridine-3-carboxylate to give the title compound (180 mg). MS (m / z): 333.3 [M+H] + [Step 3] Preparation of N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-{[(1S)-1-(5-phenylpyridin-3-yl)ethyl]amino}benzamide The procedure of Example 1, step 4 was repeated, except that 4-methyl-3-{[(1S)-1-(5-phenylpyridin-3-yl)ethyl]amino}benzoic acid (50 mg) obtained in step 2 was used instead of 3-{[2-(cyclopropylamino)-1,3-thiazole-5-carbonyl]amino}-4-methylbenzoic acid, to obtain the title compound (60 mg). Example 85 3-{[(1S)-1-([3,3'-bipyridin]-5-yl)ethyl]amino}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide [Step 1] Preparation of methyl 3-{[(1S)-1-([3,3'-bipyridin]-5-yl)ethyl]amino}-4-methylbenzoate The procedure of Step 1 of Reference Example 1 was repeated, except that methyl 3-bromo-4-methylbenzoate (13.9 g) and (1S)-1-([3,3'-bipyridin]-5-yl)ethan-1-amine (11.0 g) obtained in Reference Example 16 were used instead of methyl 5-bromopyridine-3-carboxylate and 1-cyclopropylmethanamine to give the title compound (10.3 g). MS (m / z): 348.3 [M+H] + [Step 2] Preparation of 3-{[(1S)-1-([3,3'-bipyridin]-5-yl)ethyl]amino}-4-methylbenzoic acid The procedure of Step 2 of Reference Example 1 was repeated, except that methyl 3-{[(1S)-1-([3,3'-bipyridin]-5-yl)ethyl]amino}-4-methylbenzoate (10.3 g) obtained in Step 1 was used instead of methyl 5-[(cyclopropylmethyl)amino]pyridine-3-carboxylate to give the title compound (8.7 g). MS (m / z): 334.4 [M+H] + [Step 3] Preparation of 3-{[(1S)-1-([3,3'-bipyridin]-5-yl)ethyl]amino}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide The procedure of Step 4 of Example 1 was repeated, except that 3-{[(1S)-1-([3,3'-bipyridin]-5-yl)ethyl]amino}-4-methylbenzoic acid (8.7 g) obtained in Step 2 was used instead of 3-{[2-(cyclopropylamino)-1,3-thiazole-5-carbonyl]amino}-4-methylbenzoic acid, to obtain the title compound (9.4 g). Example 87 3-{[(1S)-1-([3,4'-bipyridin]-5-yl)ethyl]amino}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide [Step 1] Preparation of methyl 3-{[(1R)-1-(5-bromopyridin-3-yl)ethyl]amino}-4-methylbenzoate The procedure of Step 1 of Reference Example 1 was repeated except that methyl 3-iodo-4-methylbenzoate (6.49 g) and (1S)-1-(5-bromopyridin-3-yl)ethan-1-amine (3.78 g) were used instead of methyl 5-bromopyridine-3-carboxylate and 1-cyclopropylmethanamine to give the title compound (1.80 g). MS (m / z): 349.0 [M+H] + [Step 2] Preparation of 3-{[(1R)-1-(5-bromopyridin-3-yl)ethyl]amino}-4-methylbenzoic acid The procedure of Step 2 of Reference Example 1 was repeated, except that methyl 3-{[(1R)-1-(5-bromopyridin-3-yl)ethyl]amino}-4-methylbenzoate (1.00 g) obtained in Step 1 was used instead of methyl 5-[(cyclopropylmethyl)amino]pyridine-3-carboxylate to give the title compound (820 mg). MS (m / z): 335.1 [M+H] + [Step 3] Preparation of 3-{[(1S)-1-(5-bromopyridin-3-yl)ethyl]amino}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide The procedure of Step 4 of Example 1 was repeated except that 3-{[(1R)-1-(5-bromopyridin-3-yl)ethyl]amino}-4-methylbenzoic acid (820 mg) obtained in Step 2 was used instead of 3-{[2-(cyclopropylamino)-1,3-thiazole-5-carbonyl]amino}-4-methylbenzoic acid to give the title compound (920 mg). MS (m / z): 432.3 [M+H] + [Step 4] Preparation of 3-{[(1S)-1-([3,4'-bipyridin]-5-yl)ethyl]amino}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide The title compound (9 mg) was obtained by a method similar to Reference Example 14, using 3-{[(1S)-1-(5-bromopyridin-3-yl)ethyl]amino}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide (30 mg) and pyridin-4-ylboronic acid (10 mg) obtained in Step 3 instead of 2-chloropyrimidin-4-amine and isoquinolin-4-ylboronic acid. Example 89 3-{[(1S)-1-([2,3'-bipyridin]-5'-yl)ethyl]amino}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide [Step 1] Preparation of methyl 3-{[(1S)-1-([2,3'-bipyridin]-5'-yl)ethyl]amino}-4-methylbenzoate The procedure of Step 1 of Reference Example 10 was repeated, except that methyl 3-{[(1R)-1-(5-bromopyridin-3-yl)ethyl]amino}-4-methylbenzoate (150 mg) and 2-bromopyridine (170 mg) obtained in Step 1 of Example 87 were used instead of 3-bromo-5-(methoxymethoxy)pyridine and 2-bromopyrimidine to give the title compound (90 mg). MS (m / z): 348.2 [M+H] + [Step 2] Preparation of 3-{[(1S)-1-([2,3'-bipyridin]-5'-yl)ethyl]amino}-4-methylbenzoic acid The procedure of Step 2 of Reference Example 1 was repeated, except that methyl 3-{[(1S)-1-([2,3'-bipyridine]-5'-yl)ethyl]amino}-4-methylbenzoate (90 mg) obtained in Step 1 was used instead of methyl 5-[(cyclopropylmethyl)amino]pyridine-3-carboxylate to give the title compound (86 mg). MS (m / z): 334.2 [M+H] + [Step 3] Preparation of 3-{[(1S)-1-([2,3'-bipyridin]-5'-yl)ethyl]amino}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide The title compound (10 mg) was obtained by a method similar to that of Step 4 of Example 1, using 3-{[(1S)-1-([2,3'-bipyridine]-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. 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 a method similar to that of Reference Example 34, except that 3-amino-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide (1.6 g) obtained in Reference Example 7 was used instead of 1-methylpiperazine.

[0232] 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 a method similar to Reference Example 14, 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. 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 a method similar to that of Step 1 of Reference Example 8, except that ethynylcyclopropane (63 mg) and 3-{[(5-bromopyridin-3-yl)methyl]amino}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide (100 mg) obtained in Example 91 were used instead of ethynyl(trimethyl)silane and methyl 4-chloro-3-iodobenzoate. Example 95 N-[(1S,2S)-2-Hydroxycyclohexyl]-4-methyl-3-({[5-(pyrimidin-2-yl)pyridin-3-yl]methyl}amino)benzamide [Step 1] Preparation of methyl 3-{[(5-bromopyridin-3-yl)methyl]amino}-4-methylbenzoate The procedure of Reference Example 34 was repeated except that methyl 3-amino-4-methylbenzoate (9.0 g) was used instead of 1-methylpiperazine to give the title compound (13.0 g). MS (m / z): 335.3 [M+H] + [Step 2] Preparation of methyl 4-methyl-3-({[5-(pyrimidin-2-yl)pyridin-3-yl]methyl}amino)benzoate The procedure of Step 1 of Reference Example 10 was repeated, except that methyl 3-{[(5-bromopyridin-3-yl)methyl]amino}-4-methylbenzoate (13.0 g) obtained in Step 1 was used instead of 3-bromo-5-(methoxymethoxy)pyridine to give the title compound (9.0 g). MS (m / z): 335.5 [M+H] + [Step 3] Preparation of 4-methyl-3-({[5-(pyrimidin-2-yl)pyridin-3-yl]methyl}amino)benzoic acid The procedure of Step 2 of Reference Example 1 was repeated, except that methyl 4-methyl-3-({[5-(pyrimidin-2-yl)pyridin-3-yl]methyl}amino)benzoate (9.0 g) obtained in Step 2 was used instead of methyl 5-[(cyclopropylmethyl)amino]pyridine-3-carboxylate to give the title compound (6.6 g). MS (m / z): 321.5 [M+H] + [Step 4] Preparation of N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-({[5-(pyrimidin-2-yl)pyridin-3-yl]methyl}amino)benzamide The procedure of Step 4 of Example 1 was repeated, except that 4-methyl-3-({[5-(pyrimidin-2-yl)pyridin-3-yl]methyl}amino)benzoic acid (6.0 g) obtained in Step 3 was used instead of 3-{[2-(cyclopropylamino)-1,3-thiazole-5-carbonyl]amino}-4-methylbenzoic acid, to obtain the title compound (5.5 g). Example 96 N-[(1S,2S)-2-Hydroxycyclohexyl]-4-methyl-3-{[(quinolin-3-yl)methyl]amino}benzamide [Step 1] Preparation of methyl 4-methyl-3-{[(quinolin-3-yl)methyl]amino}benzoate The procedure of Reference Example 34 was repeated except that methyl 3-amino-4-methylbenzoate (210 mg) and quinoline-3-carbaldehyde (200 mg) were used instead of 1-methylpiperazine and 5-bromopyridine-3-carbaldehyde to give the title compound (230 mg). [Step 2] Preparation of 4-methyl-3-{[(quinolin-3-yl)methyl]amino}benzoic acid The title compound (200 mg) was obtained by a method similar to that in Step 2 of Reference Example 1, except that methyl 4-methyl-3-{[(quinolin-3-yl)methyl]amino}benzoate (230 mg) obtained in Step 1 was used instead of methyl 5-[(cyclopropylmethyl)amino]pyridine-3-carboxylate. [Step 3] Preparation of N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-{[(quinolin-3-yl)methyl]amino}benzamide The procedure of Example 1, step 4 was repeated, except that 4-methyl-3-{[(quinolin-3-yl)methyl]amino}benzoic acid (40 mg) obtained in step 2 was used instead of 3-{[2-(cyclopropylamino)-1,3-thiazole-5-carbonyl]amino}-4-methylbenzoic acid, to obtain the title compound (43 mg). Example 98 3-[({5-[4-(2-aminopropan-2-yl)phenyl]pyridin-3-yl}methyl)amino]-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide By a method similar to Step 1 of Reference Example 10, using 3-{[(5-bromopyridin-3-yl)methyl]amino}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide (80 mg) and 2-(4-bromophenyl)propan-2-amine (49 mg) obtained in Example 91 instead of 3-bromo-5-(methoxymethoxy)pyridine and 2-bromopyrimidine, the title compound (41 mg) was obtained.

[0233] Example 101 N-[(1S,2S)-2-Hydroxycyclohexyl]-4-methyl-3-{[(6-phenylpyrazin-2-yl)methyl]amino}benzamide [Step 1] Preparation of methyl 3-{[(6-chloropyrazin-2-yl)methyl]amino}-4-methylbenzoate The procedure of Reference Example 34 was repeated except that methyl 3-amino-4-methylbenzoate (449 mg) and 6-chloropyrazine-2-carbaldehyde (774 mg) were used instead of 1-methylpiperazine and 5-bromopyridine-3-carbaldehyde to give the title compound (150 mg). [Step 2] Preparation of methyl 4-methyl-3-{[(6-phenylpyrazin-2-yl)methyl]amino}benzoate The title compound (66 mg) was obtained by a method similar to Reference Example 14, using methyl 3-{[(6-chloropyrazin-2-yl)methyl]amino}-4-methylbenzoate (70 mg) and phenylboronic acid (35 mg) obtained in Step 1 instead of 2-chloropyrimidin-4-amine and isoquinolin-4-ylboronic acid. [Step 3] Preparation of 4-methyl-3-{[(6-phenylpyrazin-2-yl)methyl]amino}benzoic acid The title compound (55 mg) was obtained by a method similar to that in Step 2 of Reference Example 1, except that methyl 4-methyl-3-{[(6-phenylpyrazin-2-yl)methyl]amino}benzoate (66 mg) obtained in Step 2 was used instead of methyl 5-[(cyclopropylmethyl)amino]pyridine-3-carboxylate. [Step 4] Preparation of N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-{[(6-phenylpyrazin-2-yl)methyl]amino}benzamide The procedure of Example 1, step 4 was repeated, except that 4-methyl-3-{[(6-phenylpyrazin-2-yl)methyl]amino}benzoic acid (25 mg) obtained in step 3 was used instead of 3-{[2-(cyclopropylamino)-1,3-thiazole-5-carbonyl]amino}-4-methylbenzoic acid, to obtain the title compound (19 mg). 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 a method similar to Reference Example 34, using 3-amino-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide (73 mg) and 1H-pyrazolo[3,4-b]pyridine-5-carbaldehyde (43 mg) obtained in Reference Example 7 instead of 1-methylpiperazine and 5-bromopyridine-3-carbaldehyde. 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 a method similar to Reference Example 34, using 3-amino-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide (24 mg) and imidazo[1,2-b]pyridazine-3-carbaldehyde (15 mg) obtained in Reference Example 7 instead of 1-methylpiperazine and 5-bromopyridine-3-carbaldehyde. Example 113 3-{[(2-aminopyrimidin-5-yl)methyl]amino}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide [Step 1] Preparation of 3-{[(2-chloropyrimidin-5-yl)methyl]amino}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide The procedure of Reference Example 34 was repeated except that 3-amino-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide (513 mg) and 2-chloropyrimidine-5-carbaldehyde (310 mg) obtained in Reference Example 7 were used instead of 1-methylpiperazine and 5-bromopyridine-3-carbaldehyde to give the title compound (320 mg). MS (m / z): 375.5 [M+H] + [Step 2] Preparation of 3-{[(2-aminopyrimidin-5-yl)methyl]amino}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide 1,4-Dioxane (8 mL) and 28% aqueous ammonia solution (4 mL) were added to 3-{[(2-chloropyrimidin-5-yl)methyl]amino}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide (320 mg) obtained in Step 1, and the mixture was sealed in a stainless steel pressure vessel and stirred for 8 hours at 100° C. The reaction solution was allowed to cool and then purified by silica gel column chromatography to give the title compound (173 mg). Example 116 3-{[(6-acetamidopyridin-3-yl)methyl]amino}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide [Step 1] Preparation of 3-{[(6-bromopyridin-3-yl)methyl]amino}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide The procedure of Reference Example 34 was repeated except that 3-amino-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide (380 mg) and 6-bromopyridine-3-carbaldehyde (300 mg) obtained in Reference Example 7 were used instead of 1-methylpiperazine and 5-bromopyridine-3-carbaldehyde to give the title compound (370 mg). MS (m / z): 418.5 [M+H] + [Step 2] Preparation of 3-{[(6-acetamidopyridin-3-yl)methyl]amino}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide The title compound (22 mg) was obtained by a method similar to that in Step 1 of Reference Example 1, using 3-{[(6-bromopyridin-3-yl)methyl]amino}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide (50 mg) and acetamide (18 mg) obtained in Step 1 instead of methyl 5-bromopyridine-3-carboxylate and 1-cyclopropylmethanamine.

[0234] Example 118 3-{[([2,2'-bipyridin]-5-yl)methyl]amino}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide The procedure of Example 62 was repeated, except that 3-{[(6-bromopyridin-3-yl)methyl]amino}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide (60 mg) and 2-(tributylstannyl)pyridine (79 mg) obtained in Step 1 of Example 116 were used in place of 3-[(5-bromopyridin-3-yl)ethynyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide and 2-(tributylstannyl)pyrimidine, to obtain the title compound (23 mg). Example 122 N-[(1S,2S)-2-Hydroxycyclohexyl]-4-methyl-3-({[6-(1H-pyrazol-1-yl)pyridin-3-yl]methyl}amino)benzamide 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 in a microwave reactor 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 mixture, and the mixture was reacted in a microwave reactor at 100 °C for an additional 30 minutes. The reaction mixture was allowed to cool and then purified by silica gel column chromatography to obtain the title compound (34 mg). Example 129 N-[(1S,2S)-2-Hydroxycyclohexyl]-4-methyl-3-{[(6-{[(pyridin-3-yl)carbamoyl]amino}pyridin-3-yl)methyl]amino}benzamide [Step 1] Preparation of 3-{[(6-aminopyridin-3-yl)methyl]amino}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide The procedure of Reference Example 34 was repeated except that 3-amino-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide (203 mg) and 6-aminopyridine-3-carbaldehyde (100 mg) obtained in Reference Example 7 were used instead of 1-methylpiperazine and 5-bromopyridine-3-carbaldehyde to give the title compound (149 mg). MS (m / z): 355.6 [M+H] + [Step 2] Preparation 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 in a microwave reactor at 80° C. for 30 minutes. The reaction mixture was allowed to cool and then purified by silica gel column chromatography to give the title compound (5.8 mg). Example 131 3-{[(5-aminopyrazin-2-yl)methyl]amino}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide [Step 1] Preparation of methyl 3-[({5-[(tert-butoxycarbonyl)amino]pyrazin-2-yl}methyl)amino]-4-methylbenzoate Potassium carbonate (1.76 g) was added 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), and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give the title compound (360 mg). MS (m / z): 373.5 [M+H] + [Step 2] Preparation of 3-[({5-[(tert-butoxycarbonyl)amino]pyrazin-2-yl}methyl)amino]-4-methylbenzoic acid The procedure of Step 2 of Reference Example 1 was repeated, except that methyl 3-[({5-[(tert-butoxycarbonyl)amino]pyrazin-2-yl}methyl)amino]-4-methylbenzoate (160 mg) obtained in Step 1 was used instead of methyl 5-[(cyclopropylmethyl)amino]pyridine-3-carboxylate to give the title compound (125 mg). MS (m / z): 359.3 [M+H] + [Step 3] Preparation of tert-butyl {5-[(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylanilino)methyl]pyrazin-2-yl}carbamate The procedure of Step 4 of Example 1 was repeated, except that 3-[({5-[(tert-butoxycarbonyl)amino]pyrazin-2-yl}methyl)amino]-4-methylbenzoic acid (125 mg) obtained in Step 2 was used instead of 3-{[2-(cyclopropylamino)-1,3-thiazole-5-carbonyl]amino}-4-methylbenzoic acid to give the title compound (105 mg). MS (m / z): 456.6 [M+H] + [Step 4] Preparation of 3-{[(5-aminopyrazin-2-yl)methyl]amino}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide Trifluoroacetic acid (0.16 mL) was added to a dichloromethane (2 mL) solution of tert-butyl {5-[(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylanilino)methyl]pyrazin-2-yl}carbamate (95 mg) obtained in Step 3, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and to the resulting residue, methanol (2 mL) and a 2 M aqueous sodium hydroxide solution (2 mL) were added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with water and extracted with chloroform. The organic layer was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to give the title compound (40 mg). 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] Preparation of 3-{[(6-aminopyridin-3-yl)methyl]amino}-N-[(1S,2S)-2-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl]-4-methylbenzamide The procedure of Reference Example 34 was repeated except that 3-amino-N-[(1S,2S)-2-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl]-4-methylbenzamide (468 mg) and 6-aminopyridine-3-carbaldehyde (150 mg) obtained in Reference Example 41 were used instead of 1-methylpiperazine and 5-bromopyridine-3-carbaldehyde to give the title compound (223 mg). MS (m / z): 469.4 [M+H] + [Step 2] Preparation 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 same procedure as in Step 1 of Example 1 was repeated, except that 2-bromo-1,3-thiazole-5-carboxylic acid and methyl 3-amino-4-methylbenzoate were replaced with (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, to give the title compound (60 mg). [Step 3] Preparation 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 a method similar to that 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.

[0235] 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 a method similar to Reference Example 34, 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. Example 142 3-{[(2-aminopyrimidin-5-yl)methyl]amino}-4-chloro-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide [Step 1] Preparation of methyl 4-chloro-3-{[(2-chloropyrimidin-5-yl)methyl]amino}benzoate The procedure described in Reference Example 34 was repeated except that methyl 3-amino-4-chlorobenzoate (1.00 g) and 2-chloropyrimidine-5-carbaldehyde (806 mg) were used instead of 1-methylpiperazine and 5-bromopyridine-3-carbaldehyde to give the title compound (376 mg). MS (m / z): 312.3 [M+H] + [Step 2] Preparation of 3-{[(2-aminopyrimidin-5-yl)methyl]amino}-4-chlorobenzoic acid To the methyl 4-chloro-3-{[(2-chloropyrimidin-5-yl)methyl]amino}benzoate (199 mg) obtained in Step 1, 1,4-dioxane (0.86 mL) and 28% aqueous ammonia (0.86 mL) were added, and the mixture was sealed in a stainless steel pressure vessel and stirred at 100°C for 2 days. The reaction mixture was concentrated under reduced pressure, and to the resulting residue, ethanol (3.2 mL) and 2M aqueous sodium hydroxide (3.2 mL) were added, and the mixture was stirred overnight at 90°C. The solvent was evaporated under reduced pressure, and the mixture was diluted with water and neutralized with hydrochloric acid. The precipitate was collected by filtration to give the title compound (102 mg). MS (m / z): 279.4 [M+H] + [Step 3] Preparation of 3-{[(2-aminopyrimidin-5-yl)methyl]amino}-4-chloro-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide The procedure of Step 4 of Example 1 was repeated, except that 3-{[(2-aminopyrimidin-5-yl)methyl]amino}-4-chlorobenzoic acid (50 mg) obtained in Step 2 was used instead of 3-{[2-(cyclopropylamino)-1,3-thiazole-5-carbonyl]amino}-4-methylbenzoic acid, to obtain the title compound (36 mg). 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] Preparation 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 The procedure of Reference Example 34 was repeated, except that 1-methylpiperazine and 5-bromopyridine-3-carbaldehyde were replaced with 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 to give the title compound (124 mg). MS (m / z): 497.3 [M+H] + [Step 2] Preparation 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), trifluoroacetic acid (0.7 mL) was added and the mixture was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to give the title compound (37 mg). Example 147 N-[(1S,2S)-2-Hydroxycyclohexyl]-4-methyl-3-({[5-(pyrimidin-2-yl)pyridin-3-yl]amino}methyl)benzamide [Step 1] Preparation of methyl 3-{[(5-bromopyridin-3-yl)amino]methyl}-4-methylbenzoate The procedure described in Reference Example 34 was repeated except that 5-bromopyridin-3-amine (1.5 g) and methyl 3-formyl-4-methylbenzoate (1.5 g) were used instead of 1-methylpiperazine and 5-bromopyridine-3-carbaldehyde to give the title compound (2.3 g). MS (m / z): 335.4 [M+H] + [Step 2] Preparation of methyl 4-methyl-3-({[5-(pyrimidin-2-yl)pyridin-3-yl]amino}methyl)benzoate The procedure of Step 1 of Reference Example 10 was repeated, except that methyl 3-{[(5-bromopyridin-3-yl)amino]methyl}-4-methylbenzoate (170 mg) obtained in Step 1 was used instead of 3-bromo-5-(methoxymethoxy)pyridine to give the title compound (35 mg). MS (m / z): 335.5 [M+H] + [Step 3] Preparation of 4-methyl-3-({[5-(pyrimidin-2-yl)pyridin-3-yl]amino}methyl)benzoic acid The procedure described in Step 2 of Reference Example 1 was repeated, except that methyl 4-methyl-3-({[5-(pyrimidin-2-yl)pyridin-3-yl]amino}methyl)benzoate (35 mg) obtained in Step 2 was used instead of methyl 5-[(cyclopropylmethyl)amino]pyridine-3-carboxylate to give the title compound (33 mg). MS (m / z): 321.5 [M+H] + [Step 4] Preparation of N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-({[5-(pyrimidin-2-yl)pyridin-3-yl]amino}methyl)benzamide The procedure of Example 1, step 4 was repeated, except that 3-{[2-(cyclopropylamino)-1,3-thiazole-5-carbonyl]amino}-4-methylbenzoic acid was replaced with 4-methyl-3-({[5-(pyrimidin-2-yl)pyridin-3-yl]amino}methyl)benzoic acid (33 mg) obtained in step 3, to give the title compound (6 mg). Example 148 3-{[([2,3'-bipyridin]-5'-yl)amino]methyl}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide [Step 1] Preparation of 3-{[(5-bromopyridin-3-yl)amino]methyl}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide The procedure described in Reference Example 34 was repeated except that 5-bromopyridin-3-amine (437 mg) and 3-formyl-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide (600 mg) obtained in Reference Example 26 were used instead of 1-methylpiperazine and 5-bromopyridine-3-carbaldehyde to give the title compound (560 mg). MS (m / z): 418.6 [M+H] + [Step 2] Preparation of 3-{[([2,3'-bipyridin]-5'-yl)amino]methyl}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide The title compound (10 mg) was obtained by a method similar to that of Step 1 of Reference Example 10, using 3-{[(5-bromopyridin-3-yl)amino]methyl}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide (80 mg) and 2-bromopyridine (36 mg) obtained in Step 1 instead of 3-bromo-5-(methoxymethoxy)pyridine and 2-bromopyrimidine.

[0236] Example 152 3-{[(5-bromopyridin-3-yl)amino]methyl}-N-[(1S,2S)-1,3-dihydroxy-1-phenylpropan-2-yl]-4-methylbenzamide [Step 1] Preparation of 3-{[(5-bromopyridin-3-yl)amino]methyl}-4-methylbenzoic acid The procedure of Step 2 of Reference Example 1 was repeated, except that methyl 3-{[(5-bromopyridin-3-yl)amino]methyl}-4-methylbenzoate (1.0 g) obtained in Step 1 of Example 147 was used instead of methyl 5-[(cyclopropylmethyl)amino]pyridine-3-carboxylate to give the title compound (950 mg). MS (m / z): 321.4 [M+H] + [Step 2] Preparation 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 a method similar to that of 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. 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 a method similar to Reference Example 14, using 3-{[(5-bromopyridin-3-yl)amino]methyl}-N-[(1S,2S)-1,3-dihydroxy-1-phenylpropan-2-yl]-4-methylbenzamide (50 mg) and phenylboronic acid (16 mg) obtained in Example 152 instead of 2-chloropyrimidin-4-amine and isoquinolin-4-ylboronic acid. Example 155 3-{[([2,3'-bipyridin]-5'-yl)amino]methyl}-N-[(1S,2S)-1,3-dihydroxy-1-phenylpropan-2-yl]-4-methylbenzamide By a method similar to Example 62, 3-[(5-bromopyridin-3-yl)ethynyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide, instead of 2-(tributylstannyl)pyrimidine, 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 were used to obtain the title compound (20 mg). Example 156 N-[(1S,2S)-1,3-dihydroxy-1-phenylpropan-2-yl]-4-methyl-3-{[(6-phenylpyrazin-2-yl)amino]methyl}benzamide [Step 1] Preparation 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 mixture was diluted with ethyl acetate, and the organic layer was washed with water and saturated brine. The solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to give the title compound (423 mg). MS (m / z): 292.5 [M+H] + [Step 2] Preparation of 3-{[(6-chloropyrazin-2-yl)amino]methyl}-4-methylbenzoic acid The procedure of Step 2 of Reference Example 1 was repeated, except that methyl 3-{[(6-chloropyrazin-2-yl)amino]methyl}-4-methylbenzoate (580 mg) obtained in Step 1 was used instead of methyl 5-[(cyclopropylmethyl)amino]pyridine-3-carboxylate to give the title compound (520 mg). MS (m / z): 278.4 [M+H] + [Step 3] Preparation of 3-{[(6-chloropyrazin-2-yl)amino]methyl}-N-[(1S,2S)-1,3-dihydroxy-1-phenylpropan-2-yl]-4-methylbenzamide The same procedure as in Step 4 of Example 1 was repeated except that 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 were used instead of 3-{[2-(cyclopropylamino)-1,3-thiazole-5-carbonyl]amino}-4-methylbenzoic acid and (1S,2S)-2-aminocyclohexan-1-ol hydrochloride to give the title compound (420 mg). MS (m / z): 427.6 [M+H] + [Step 4] Preparation of N-[(1S,2S)-1,3-dihydroxy-1-phenylpropan-2-yl]-4-methyl-3-{[(6-phenylpyrazin-2-yl)amino]methyl}benzamide The title compound (36 mg) was obtained by a method similar to Reference Example 14, using 3-{[(6-chloropyrazin-2-yl)amino]methyl}-N-[(1S,2S)-1,3-dihydroxy-1-phenylpropan-2-yl]-4-methylbenzamide (50 mg) and phenylboronic acid (17 mg) obtained in Step 3 instead of 2-chloropyrimidin-4-amine and isoquinolin-4-ylboronic acid. Example 158 N-[3-({[6-(3,4-dimethoxyphenyl)pyrazin-2-yl]amino}methyl)phenyl]-N'-[(1R,2S)-2-hydroxycyclohexyl]urea [Step 1] Preparation of N-[(3-aminophenyl)methyl]-6-chloropyrazin-2-amine The procedure of Step 3 of Example 156 was repeated, except that 3-(aminomethyl)aniline (1.23 g) was used instead of methyl 3-(aminomethyl)-4-methylbenzoate, to give the title compound (1.22 g). [Step 2] Preparation of N-[(3-aminophenyl)methyl]-6-(3,4-dimethoxyphenyl)pyrazin-2-amine The title compound (190 mg) was obtained by a method similar to Reference Example 14, using N-[(3-aminophenyl)methyl]-6-chloropyrazin-2-amine (160 mg) and (3,4-dimethoxyphenyl)boronic acid (149 mg) obtained in Step 1 instead of 2-chloropyrimidin-4-amine and isoquinolin-4-ylboronic acid. [Step 3] Preparation of N-[3-({[6-(3,4-dimethoxyphenyl)pyrazin-2-yl]amino}methyl)phenyl]-N'-[(1R,2S)-2-hydroxycyclohexyl]urea To the N-[(3-aminophenyl)methyl]-6-(3,4-dimethoxyphenyl)pyrazin-2-amine (40 mg) obtained in Step 2, THF (1 mL), TEA (0.20 mL), and triphosgene (18 mg) were added and stirred at room temperature for 10 minutes. Next, (1S,2R)-2-aminocyclohexan-1-ol hydrochloride (180 mg) was added and 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).

[0237] Example 159 N-[(1R,2S)-2-Hydroxycyclohexyl]-N'-[3-({[5-(pyrimidin-2-yl)pyridin-3-yl]amino}methyl)phenyl]urea [Step 1] Preparation of N-[(3-nitrophenyl)methyl]-5-(pyrimidin-2-yl)pyridin-3-amine The title compound (40 mg) was obtained by a method similar to that of Reference Example 34, 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. [Step 2] Preparation of N-[(3-aminophenyl)methyl]-5-(pyrimidin-2-yl)pyridin-3-amine 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), degassing was performed, and then 10% Pd-C (50 mg) was added under argon atmosphere while stirring at room temperature, and the mixture was stirred at room temperature under hydrogen atmosphere for 4 hours. The reaction solution was filtered through Celite (registered trademark), and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (20 mg). [Step 3] Preparation of N-[(1R,2S)-2-hydroxycyclohexyl]-N'-[3-({[5-(pyrimidin-2-yl)pyridin-3-yl]amino}methyl)phenyl]urea The procedure of Example 158, Step 3 was repeated, except that N-[(3-aminophenyl)methyl]-5-(pyrimidin-2-yl)pyridin-3-amine (20 mg) obtained in Step 2 was used instead of N-[(3-aminophenyl)methyl]-6-(3,4-dimethoxyphenyl)pyrazin-2-amine, to obtain the title compound (13 mg). Example 161 N-[4-fluoro-3-({[5-(pyrimidin-2-yl)pyridin-3-yl]amino}methyl)phenyl]-N'-[(1R,2S)-2-hydroxycyclohexyl]urea [Step 1] Preparation of N-[(2-fluoro-5-nitrophenyl)methyl]-5-(pyrimidin-2-yl)pyridin-3-amine The title compound (150 mg) was obtained by a method similar to that of Reference Example 34, 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. [Step 2] Preparation of tert-butyl [(2-fluoro-5-nitrophenyl)methyl][5-(pyrimidin-2-yl)pyridin-3-yl]carbamate The title compound (105 mg) was obtained by a method similar to that of 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. [Step 3] Preparation 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)-water (0.2 mL), tin(II) chloride dihydrate (221 mg) was added and 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 saturated brine, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (72 mg). [Step 4] Preparation of tert-butyl {[2-fluoro-5-({[(1R,2S)-2-hydroxycyclohexyl]carbamoyl}amino)phenyl]methyl}[5-(pyrimidin-2-yl)pyridin-3-yl]carbamate The procedure similar to that of Step 3 of Example 158 was repeated, except that, instead of N-[(3-aminophenyl)methyl]-6-(3,4-dimethoxyphenyl)pyrazin-2-amine, tert-butyl [(5-amino-2-fluorophenyl)methyl][5-(pyrimidin-2-yl)pyridin-3-yl]carbamate (70 mg) obtained in Step 3 was used, to obtain the title compound (82 mg). [Step 5] Preparation 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), hydrogen chloride (4 M 1,4-dioxane solution, 1 mL) was added and stirred at room temperature for 2 hours. The reaction solution was purified by silica gel column chromatography to obtain the title compound (50 mg). Example 164 N-[(1S,2S)-2-Hydroxycyclohexyl]-4-methyl-3-{1-[(6-phenylpyrazin-2-yl)amino]ethyl}benzamide [Step 1] Preparation of methyl 3-{1-[(6-chloropyrazin-2-yl)amino]ethyl}-4-methylbenzoate The procedure similar to that of Step 3 of Example 156 was repeated except that methyl 3-(1-aminoethyl)-4-methylbenzoate (218 mg) was used instead of methyl 3-(aminomethyl)-4-methylbenzoate to give the title compound (75 mg). [Step 2] Preparation of methyl 4-methyl-3-{1-[(6-phenylpyrazin-2-yl)amino]ethyl}benzoate The title compound (80 mg) was obtained by a method similar to Reference Example 14, using methyl 3-{1-[(6-chloropyrazin-2-yl)amino]ethyl}-4-methylbenzoate (75 mg) and phenylboronic acid (36 mg) obtained in Step 1 instead of 2-chloropyrimidin-4-amine and isoquinolin-4-ylboronic acid. [Step 3] Preparation of 4-methyl-3-{1-[(6-phenylpyrazin-2-yl)amino]ethyl}benzoic acid The title compound (67 mg) was obtained by a method similar to that in Step 2 of Reference Example 1, except that methyl 4-methyl-3-{1-[(6-phenylpyrazin-2-yl)amino]ethyl}benzoate (77 mg) obtained in Step 2 was used instead of methyl 5-[(cyclopropylmethyl)amino]pyridine-3-carboxylate. [Step 4] Preparation of N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-{1-[(6-phenylpyrazin-2-yl)amino]ethyl}benzamide The same procedure as in Step 4 of Example 1 was repeated, except that 3-{[2-(cyclopropylamino)-1,3-thiazole-5-carbonyl]amino}-4-methylbenzoic acid was replaced with 4-methyl-3-{1-[(6-phenylpyrazin-2-yl)amino]ethyl}benzoic acid (30 mg) obtained in Step 3, to give the title compound (17 mg). Example 165 3-[([3,3'-bipyridin]-5-yl)methoxy]-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide [Step 1] Preparation of methyl 3-[(5-bromopyridin-3-yl)methoxy]-4-methylbenzoate The procedure of Step 1 of Reference Example 3 was repeated except that methyl 3-hydroxy-4-methylbenzoate (750 mg) and (5-bromopyridin-3-yl)methanol (933 mg) were used instead of methyl 5-hydroxypyridine-3-carboxylate and 3,3-difluorocyclobutan-1-ol to give the title compound (1.16 g). MS (m / z): 336.4 [M+H] + [Step 2] Preparation of methyl 3-[([3,3'-bipyridin]-5-yl)methoxy]-4-methylbenzoate The title compound (103 mg) was obtained by a method similar to Reference Example 14, except that methyl 3-[(5-bromopyridin-3-yl)methoxy]-4-methylbenzoate (150 mg) and pyridin-3-ylboronic acid (66 mg) obtained in Step 1 were used instead of 2-chloropyrimidin-4-amine and isoquinolin-4-ylboronic acid. MS (m / z): 335.5 [M+H] + [Step 3] Preparation of 3-[([3,3'-bipyridin]-5-yl)methoxy]-4-methylbenzoic acid The procedure of Step 2 of Reference Example 1 was repeated, except that methyl 3-[([3,3'-bipyridin]-5-yl)methoxy]-4-methylbenzoate (103 mg) obtained in Step 2 was used instead of methyl 5-[(cyclopropylmethyl)amino]pyridine-3-carboxylate to give the title compound (100 mg). MS (m / z): 321.6 [M+H] + [Step 4] Preparation of 3-[([3,3'-bipyridin]-5-yl)methoxy]-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide The procedure of Step 4 of Example 1 was repeated, except that 3-[([3,3'-bipyridin]-5-yl)methoxy]-4-methylbenzoic acid (50 mg) obtained in Step 3 was used instead of 3-{[2-(cyclopropylamino)-1,3-thiazole-5-carbonyl]amino}-4-methylbenzoic acid, to obtain the title compound (47 mg).

[0238] Example 166 N-[(1S,2S)-2-Hydroxycyclohexyl]-4-methyl-3-{[5-(pyrimidin-2-yl)pyridin-3-yl]methoxy}benzamide [Step 1] Preparation of methyl 4-methyl-3-{[5-(pyrimidin-2-yl)pyridin-3-yl]methoxy}benzoate The procedure of Step 1 of Reference Example 10 was repeated, except that methyl 3-[(5-bromopyridin-3-yl)methoxy]-4-methylbenzoate (250 mg) obtained in Step 1 of Example 165 was used instead of 3-bromo-5-(methoxymethoxy)pyridine to give the title compound (127 mg). MS (m / z): 336.4 [M+H] + [Step 2] Preparation of 4-methyl-3-{[5-(pyrimidin-2-yl)pyridin-3-yl]methoxy}benzoic acid The title compound (101 mg) was obtained by a method similar to that of Step 2 of Reference Example 1, 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. [Step 3] Preparation of N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-{[5-(pyrimidin-2-yl)pyridin-3-yl]methoxy}benzamide The procedure of Example 1, step 4 was repeated, except that 4-methyl-3-{[5-(pyrimidin-2-yl)pyridin-3-yl]methoxy}benzoic acid (60 mg) obtained in step 2 was used instead of 3-{[2-(cyclopropylamino)-1,3-thiazole-5-carbonyl]amino}-4-methylbenzoic acid, to obtain the title compound (76 mg). Example 170 4-chloro-N-[(1S,2S)-2-hydroxycyclohexyl]-3-({[5-(pyrimidin-2-yl)pyridin-3-yl]oxy}methyl)benzamide [Step 1] Preparation of methyl 4-chloro-3-({[5-(pyrimidin-2-yl)pyridin-3-yl]oxy}methyl)benzoate The procedure of Step 1 of Reference Example 3 was repeated, except that 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 were used instead of methyl 5-hydroxypyridine-3-carboxylate and 3,3-difluorocyclobutan-1-ol to give the title compound (50 mg). MS (m / z): 356.4 [M+H] + [Step 2] Preparation of 4-chloro-3-({[5-(pyrimidin-2-yl)pyridin-3-yl]oxy}methyl)benzoic acid The procedure described in Step 2 of Reference Example 1 was repeated, except that methyl 4-chloro-3-({[5-(pyrimidin-2-yl)pyridin-3-yl]oxy}methyl)benzoate (50 mg) obtained in Step 1 was used instead of methyl 5-[(cyclopropylmethyl)amino]pyridine-3-carboxylate to give the title compound (43 mg). MS (m / z): 342.4 [M+H] + [Step 3] Preparation of 4-chloro-N-[(1S,2S)-2-hydroxycyclohexyl]-3-({[5-(pyrimidin-2-yl)pyridin-3-yl]oxy}methyl)benzamide The procedure of Example 1, step 4 was repeated, except that 4-chloro-3-({[5-(pyrimidin-2-yl)pyridin-3-yl]oxy}methyl)benzoic acid (43 mg) obtained in step 2 was used instead of 3-{[2-(cyclopropylamino)-1,3-thiazole-5-carbonyl]amino}-4-methylbenzoic acid, to obtain the title compound (39 mg). Example 172 N-[(1S,2S)-2-Hydroxycyclohexyl]-4-methyl-3-[1-(5-phenylpyridin-3-yl)ethoxy]benzamide [Step 1] Preparation of methyl 3-[1-(5-bromopyridin-3-yl)ethoxy]-4-methylbenzoate The procedure of Step 1 of Reference Example 3 was repeated except that methyl 3-hydroxy-4-methylbenzoate (432 mg) and 1-(5-bromopyridin-3-yl)ethan-1-ol (500 mg) were used instead of methyl 5-hydroxypyridine-3-carboxylate and 3,3-difluorocyclobutan-1-ol to give the title compound (650 mg). MS (m / z): 350.3 [M+H] + [Step 2] Preparation of 3-[1-(5-bromopyridin-3-yl)ethoxy]-4-methylbenzoic acid The procedure of Step 2 of Reference Example 1 was repeated, except that methyl 3-[1-(5-bromopyridin-3-yl)ethoxy]-4-methylbenzoate (450 mg) obtained in Step 1 was used instead of methyl 5-[(cyclopropylmethyl)amino]pyridine-3-carboxylate to give the title compound (350 mg). MS (m / z): 336.3 [M+H] + [Step 3] Preparation of 3-[1-(5-bromopyridin-3-yl)ethoxy]-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide The same procedure as in Step 4 of Example 1 was repeated, except that 3-[1-(5-bromopyridin-3-yl)ethoxy]-4-methylbenzoic acid (350 mg) obtained in Step 2 was used instead of 3-{[2-(cyclopropylamino)-1,3-thiazole-5-carbonyl]amino}-4-methylbenzoic acid to give the title compound (350 mg). MS (m / z): 433.5 [M+H] + [Step 4] Preparation of N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-[1-(5-phenylpyridin-3-yl)ethoxy]benzamide The title compound (30 mg) was obtained by a method similar to Reference Example 14, using 3-[1-(5-bromopyridin-3-yl)ethoxy]-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide (50 mg) and phenylboronic acid (17 mg) obtained in Step 3 instead of 2-chloropyrimidin-4-amine and isoquinolin-4-ylboronic acid. Example 173 N-[(1S,2S)-2-Hydroxycyclohexyl]-4-methyl-3-[(E)-2-(5-phenylpyridin-3-yl)ethenyl]benzamide [Step 1] Preparation of 3-ethenyl-N-[(1R,2R)-2-hydroxycyclohexyl]-4-methylbenzamide The procedure of Reference Example 14 was repeated, except that 2-chloropyrimidin-4-amine and isoquinolin-4-ylboronic acid were replaced with 3-bromo-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide (20.0 g) and 2-ethenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (11.8 g) obtained in Reference Example 43 to give the title compound (13.0 g). MS (m / z): 260.2 [M+H] + [Step 2] Preparation of N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-[(E)-2-(5-phenylpyridin-3-yl)ethenyl]benzamide A mixture of 3-ethenyl-N-[(1R,2R)-2-hydroxycyclohexyl]-4-methylbenzamide (30 mg) obtained in Step 1, 3-bromo-5-phenylpyridine (27 mg), TEA (0.024 mL), tris(2-methylphenyl)phosphine (11 mg), Pd(OAc) (3.9 mg), and acetonitrile (0.58 mL) was reacted in a microwave reactor at 100° C. for 80 minutes. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to give the title compound (24 mg). Example 174 N-[(1S,2S)-2-Hydroxycyclohexyl]-4-methyl-3-[2-(5-phenylpyridin-3-yl)ethyl]benzamide To a solution of N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-[(E)-2-(5-phenylpyridin-3-yl)ethenyl]benzamide (15 mg) obtained in Example 173 in ethanol (5 mL), the mixture was degassed and stirred at room temperature under an argon atmosphere. 10% Pd-C (7.7 mg) was added, and the mixture was stirred overnight at room temperature under a hydrogen atmosphere. The reaction mixture was filtered through Celite®, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (7 mg).

[0239] Example 175 N-[(1S,2S)-2-Hydroxycyclohexyl]-4-methyl-3-{[methyl(5-phenylpyridin-3-yl)amino]methyl}benzamide [Step 1] Preparation of methyl 3-{[(5-bromopyridin-3-yl)(methyl)amino]methyl}-4-methylbenzoate 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) under ice-cooling and stirred at room temperature for 20 minutes. Next, iodomethane (720 mg) was added, and the mixture was stirred overnight at the same temperature. Water was added to the reaction mixture under ice-cooling, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was then evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (200 mg). MS (m / z): 349.4 [M+H] + [Step 2] Preparation of 3-{[(5-bromopyridin-3-yl)(methyl)amino]methyl}-4-methylbenzoic acid The procedure of Step 2 of Reference Example 1 was repeated, except that methyl 3-{[(5-bromopyridin-3-yl)(methyl)amino]methyl}-4-methylbenzoate (200 mg) obtained in Step 1 was used instead of methyl 5-[(cyclopropylmethyl)amino]pyridine-3-carboxylate to give the title compound (170 mg). MS (m / z): 335.4 [M+H] + [Step 3] Preparation of 3-{[(5-bromopyridin-3-yl)(methyl)amino]methyl}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide The same procedure as in Step 4 of Example 1 was repeated except that 3-{[(5-bromopyridin-3-yl)(methyl)amino]methyl}-4-methylbenzoic acid (170 mg) obtained in Step 2 was used instead of 3-{[2-(cyclopropylamino)-1,3-thiazole-5-carbonyl]amino}-4-methylbenzoic acid to give the title compound (147 mg). MS (m / z): 432.6 [M+H] + [Step 4] Preparation of N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-{[methyl(5-phenylpyridin-3-yl)amino]methyl}benzamide The title compound (24 mg) was obtained by a method similar to Reference Example 14, using 3-{[(5-bromopyridin-3-yl)(methyl)amino]methyl}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide (30 mg) and phenylboronic acid (9.3 mg) obtained in Step 3 instead of 2-chloropyrimidin-4-amine and isoquinolin-4-ylboronic acid. Example 177 3-[(Z)-2-([2,3'-bipyridin]-5'-yl)-2-fluoroethenyl]-4-fluoro-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide [Step 1] Preparation of 3-(2,2-difluoroethenyl)-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), a solution of sodium chlorodifluoroacetate (431 mg) in DMF (0.94 mL) was added dropwise over 30 minutes at 100°C, and the mixture was stirred at the same temperature for 30 minutes. Water was added to the reaction mixture under ice cooling, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (200 mg). MS (m / z): 300.1 [M+H] + [Step 2] Preparation of 4-fluoro-3-[(Z)-2-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)ethenyl]-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide THF (2.2 mL) was added to 3-(2,2-difluoroethenyl)-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), and the mixture was degassed and stirred overnight at 40°C under an argon atmosphere. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was then evaporated under reduced pressure to give the title compound (130 mg). [Step 3] Preparation of 3-[(Z)-2-([2,3'-bipyridin]-5'-yl)-2-fluoroethenyl]-4-fluoro-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide By a method similar to Reference Example 14, instead of 2-chloropyrimidin-4-amine, isoquinolin-4-ylboronic acid, 5'-bromo-2,3'-bipyridine (45 mg), 4-fluoro-3-[(Z)-2-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)ethenyl]-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide (65 mg) obtained in step 2, the title compound (10 mg) was obtained. Example 180 5-[(Z)-2-([2,3'-bipyridin]-5'-yl)-2-fluoroethenyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-6-methylpyridine-3-carboxamide [Step 1] Preparation of ethyl 5-(2,2-difluoroethenyl)-6-methylpyridine-3-carboxylate The procedure of Step 1 of Example 177 was repeated, except that ethyl 5-formyl-6-methylpyridine-3-carboxylate (2.65 g) obtained in Reference Example 33 was used instead of 4-fluoro-3-formyl-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide to give the title compound (2.80 g). MS (m / z): 228.1 [M+H] + [Step 2] Preparation of ethyl 5-[(Z)-2-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)ethenyl]-6-methylpyridine-3-carboxylate The procedure similar to that of Step 2 of Example 177 was repeated, except that ethyl 5-(2,2-difluoroethenyl)-6-methylpyridine-3-carboxylate (200 mg) obtained in Step 1 was used instead of 3-(2,2-difluoroethenyl)-4-fluoro-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide, to obtain the title compound (280 mg). [Step 3] Preparation of ethyl 5-[(Z)-2-([2,3'-bipyridine]-5'-yl)-2-fluoroethenyl]-6-methylpyridine-3-carboxylate The procedure of Reference Example 14 was repeated except that, instead of 2-chloropyrimidin-4-amine and isoquinolin-4-ylboronic acid, 5'-bromo-2,3'-bipyridine (196 mg) and ethyl 5-[(Z)-2-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)ethenyl]-6-methylpyridine-3-carboxylate (280 mg) obtained in Step 2 were used to obtain the title compound (230 mg). MS (m / z): 364.2 [M+H] + [Step 4] Preparation of 5-[(Z)-2-([2,3'-bipyridine]-5'-yl)-2-fluoroethenyl]-6-methylpyridine-3-carboxylic acid The procedure of Step 2 of Reference Example 1 was repeated, except that ethyl 5-[(Z)-2-([2,3'-bipyridine]-5'-yl)-2-fluoroethenyl]-6-methylpyridine-3-carboxylate (230 mg) obtained in Step 3 was used instead of methyl 5-[(cyclopropylmethyl)amino]pyridine-3-carboxylate to give the title compound (165 mg). MS (m / z): 336.1 [M+H] + [Step 5] Preparation of 5-[(Z)-2-([2,3'-bipyridine]-5'-yl)-2-fluoroethenyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-6-methylpyridine-3-carboxamide The procedure of Example 1, step 4 was repeated, except that 5-[(Z)-2-([2,3'-bipyridine]-5'-yl)-2-fluoroethenyl]-6-methylpyridine-3-carboxylic acid (120 mg) obtained in step 4 was used instead of 3-{[2-(cyclopropylamino)-1,3-thiazole-5-carbonyl]amino}-4-methylbenzoic acid, to obtain the title compound (77 mg). Example 192 3-[(Z)-2-(2-aminopyrimidin-5-yl)-2-fluoroethenyl]-4-fluoro-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide [Step 1] Preparation of methyl 3-(2,2-difluoroethenyl)-4-fluorobenzoate The procedure of Example 177, Step 1 was repeated, except that methyl 4-fluoro-3-formylbenzoate (1.27 g) was used instead of 4-fluoro-3-formyl-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide, to give the title compound (1.30 g). [Step 2] Preparation of methyl 3-[(Z)-2-(2-aminopyrimidin-5-yl)-2-fluoroethenyl]-4-fluorobenzoate Methyl 3-(2,2-difluoroethenyl)-4-fluorobenzoate (130 mg), bis(pinacolato)diboron (305 mg), potassium acetate (118 mg), tricyclohexylphosphine (34 mg), and copper(I) chloride (22 mg) obtained in Step 1 were added to THF (4 mL) and degassed. The mixture was then stirred at 40°C under an argon atmosphere for 8 hours. Saturated aqueous ammonium chloride was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was then evaporated under reduced pressure. The resulting residue was mixed with 5-bromopyrimidin-2-amine (105 mg), potassium carbonate (166 mg), Pd(dppf)Cl2·CHCl2 (49 mg), 1,4-dioxane (2 mL), and water (0.2 mL). The mixture was degassed and stirred overnight at 85°C under an argon atmosphere. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to give the title compound (200 mg). MS (m / z): 292.1 [M+H] + [Step 3] Preparation of 3-[(Z)-2-(2-aminopyrimidin-5-yl)-2-fluoroethenyl]-4-fluorobenzoic acid The procedure of Step 2 of Reference Example 1 was repeated, except that methyl 3-[(Z)-2-(2-aminopyrimidin-5-yl)-2-fluoroethenyl]-4-fluorobenzoate (200 mg) obtained in Step 2 was used instead of methyl 5-[(cyclopropylmethyl)amino]pyridine-3-carboxylate to give the title compound (36 mg). MS (m / z): 278.1 [M+H] + [Step 4] Preparation of 3-[(Z)-2-(2-aminopyrimidin-5-yl)-2-fluoroethenyl]-4-fluoro-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide The procedure of Example 1, step 4 was repeated, except that 3-[(Z)-2-(2-aminopyrimidin-5-yl)-2-fluoroethenyl]-4-fluorobenzoic acid (36 mg) obtained in step 3 was used instead of 3-{[2-(cyclopropylamino)-1,3-thiazole-5-carbonyl]amino}-4-methylbenzoic acid, to obtain the title compound (4 mg). Example 194 3-[(Z)-2-{5-[(4-ethylpiperazin-1-yl)methyl]pyridin-3-yl}-2-fluoroethenyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide [Step 1] Preparation of methyl 3-(2,2-difluoroethenyl)-4-methylbenzoate The procedure of Step 1 of Example 177 was repeated except that methyl 3-formyl-4-methylbenzoate (13.4 g) was used instead of 4-fluoro-3-formyl-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide to give the title compound (15.0 g). MS (m / z): 213.1 [M+H] + [Step 2] Preparation of methyl 3-[(Z)-2-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)ethenyl]-4-methylbenzoate The procedure similar to that of Step 2 of Example 177 was repeated, except that methyl 3-(2,2-difluoroethenyl)-4-methylbenzoate (6.0 g) obtained in Step 1 was used instead of 3-(2,2-difluoroethenyl)-4-fluoro-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide, to obtain the title compound (8.6 g). [Step 3] Preparation of methyl 3-[(Z)-2-fluoro-2-{5-[(4-ethylpiperazin-1-yl)methyl]pyridin-3-yl}ethenyl]-4-methylbenzoate The procedure of Reference Example 14 was repeated, except that 2-chloropyrimidin-4-amine and isoquinolin-4-ylboronic acid were replaced with 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)ethenyl]-4-methylbenzoate (8.5 g) obtained in Step 2 to give the title compound (7.5 g). MS (m / z): 398.3 [M+H] + [Step 4] Preparation of 3-[(Z)-2-fluoro-2-{5-[(4-ethylpiperazin-1-yl)methyl]pyridin-3-yl}ethenyl]-4-methylbenzoic acid The procedure of Step 2 of Reference Example 1 was repeated, except that methyl 3-[(Z)-2-fluoro-2-{5-[(4-ethylpiperazin-1-yl)methyl]pyridin-3-yl}ethenyl]-4-methylbenzoate (7.5 g) obtained in Step 3 was used instead of methyl 5-[(cyclopropylmethyl)amino]pyridine-3-carboxylate to give the title compound (4.7 g). MS (m / z): 384.5 [M+H] + [Step 5] Preparation of 3-[(Z)-2-{5-[(4-ethylpiperazin-1-yl)methyl]pyridin-3-yl}-2-fluoroethenyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide The procedure of Example 1, step 4 was repeated, but instead of 3-{[2-(cyclopropylamino)-1,3-thiazole-5-carbonyl]amino}-4-methylbenzoic acid, 3-[(Z)-2-fluoro-2-{5-[(4-ethylpiperazin-1-yl)methyl]pyridin-3-yl}ethenyl]-4-methylbenzoic acid (4.7 g) obtained in step 4 was used to obtain the title compound (3.4 g).

[0240] Example 199 5-[(Z)-2-{6-[(cyclopropylmethyl)amino]pyridin-3-yl}-2-fluoroethenyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-6-methylpyridine-3-carboxamide [Step 1] Preparation of ethyl 5-[(Z)-2-(6-aminopyridin-3-yl)-2-fluoroethenyl]-6-methylpyridine-3-carboxylate The procedure of Reference Example 14 was repeated except that, instead of 2-chloropyrimidin-4-amine and isoquinolin-4-ylboronic acid, 5-bromopyridin-2-amine (114 mg) and ethyl 5-[(Z)-2-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)ethenyl]-6-methylpyridine-3-carboxylate obtained in Step 2 of Example 180 was used to obtain the title compound (40 mg). MS (m / z): 302.1 [M+H] + [Step 2] Preparation of ethyl 5-[(Z)-2-{6-[(cyclopropylmethyl)amino]pyridin-3-yl}-2-fluoroethenyl]-6-methylpyridine-3-carboxylate The procedure of Reference Example 34 was repeated except that, instead of 1-methylpiperazine and 5-bromopyridine-3-carbaldehyde, ethyl 5-[(Z)-2-(6-aminopyridin-3-yl)-2-fluoroethenyl]-6-methylpyridine-3-carboxylate (60 mg) and cyclopropanecarbaldehyde (19 mg) obtained in Step 1 were used to obtain the title compound (12 mg). MS (m / z): 356.5 [M+H] + [Step 3] Preparation of 5-[(Z)-2-{6-[(cyclopropylmethyl)amino]pyridin-3-yl}-2-fluoroethenyl]-6-methylpyridine-3-carboxylic acid The title compound (11 mg) was obtained by a method similar to that in Step 2 of Reference Example 1, using ethyl 5-[(Z)-2-{6-[(cyclopropylmethyl)amino]pyridin-3-yl}-2-fluoroethenyl]-6-methylpyridine-3-carboxylate (12 mg) obtained in Step 2 instead of methyl 5-[(cyclopropylmethyl)amino]pyridine-3-carboxylate. [Step 4] Preparation of 5-[(Z)-2-{6-[(cyclopropylmethyl)amino]pyridin-3-yl}-2-fluoroethenyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-6-methylpyridine-3-carboxamide The same procedure as in step 4 of Example 1 was repeated, except that 5-[(Z)-2-{6-[(cyclopropylmethyl)amino]pyridin-3-yl}-2-fluoroethenyl]-6-methylpyridine-3-carboxylic acid (11 mg) obtained in step 3 was used instead of 3-{[2-(cyclopropylamino)-1,3-thiazole-5-carbonyl]amino}-4-methylbenzoic acid, to obtain the title compound (10 mg).

[0241] Tables 3 to 29 below show compounds of Reference Examples and Examples.

[0242] In the table, "Reference Example" indicates that the compound was produced using the corresponding raw materials by a method similar to the production method of the compound with the corresponding Reference Example number. For example, the Reference Example compound with Reference Example number 1 means that it was produced by a method similar to Reference Example 1.

[0243] In the table, Reference Example indicates that the compound was produced using the corresponding raw materials by a method similar to the production method of the compound with the Example number corresponding to that number. For example, the Example compound with Reference Example number 1 means that it was produced by a method similar to Example 1.

[0244] In the table, the chemical name indicates the name of the compound corresponding to the number of the reference example or example, and the data indicates the instrumental analysis data of the compound, such as mass spectrometry data (m / z value), H NMR data (peak δ (ppm)), elemental analysis data (composition (%) of C, H, and N), etc.

[0245] [Table 3]

[0246] [Table 4]

[0247] [Table 5]

[0248]

Table 6

[0249]

Table 7

[0250]

Table 8

[0251]

Table 9

[0252]

Table 10

[0253]

Table 11

[0254]

Table 12

[0255]

Table 13

[0256]

Table 14

[0257]

Table 15

[0258] Table 16

[0259]

Table 17

[0260] Table 18

[0261]

Table 19

[0262] Table 20

[0263] Table 21

[0264] Table 22

[0265] Table 23

[0266] Table 24

[0267] Table 25

[0268] [Table 26]

[0269] [Table 27]

[0270] [Table 28]

[0271] [Table 29]

[0272] The following are examples of biological tests of the compounds used in the present invention.

[0273] <Test Example 1: PDGFR-β tyrosine kinase inhibitory effect> 1. Preparation of Test Substances Test substances were prepared at 10 mM in dimethyl sulfoxide (DMSO) and diluted with DMSO to concentrations ranging from 0.001 to 1000 μM. These DMSO solutions were 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, 1 mM MnCl2) and then 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, 40 nM Supplemented Enzymatic Buffer (cisbio)).

[0274] 2. Measurement of PDGFR-β tyrosine kinase inhibitory activity Measurements were performed using the HTRF KinEASE-TK kit from cisbio. 4 μL of the test substance solution was added to a 384-well plate, followed by 2 μL of PDGFR-β enzyme solution (final concentration 1 ng / μL, Carna Biosciences) and 4 μL of a substrate solution (TK substrate-3-biotin (cisbio) with 0.6 μM ATP). The final test substance concentrations were adjusted to 0.01–10,000 nM, and the reaction was carried out at 30°C for 30 minutes. Then, 10 μL of detection solution (cisbio) was added to each well and reacted for 1 hour at 30° C. The fluorescence intensity was measured using a microplate reader (Spectra Max M5, Molecular Device).

[0275] 3. Analysis of measurement results The ratio of fluorescence intensity under each condition was used to calculate the inhibition rate, with the values ​​of the positive control (1% DMSO solution) and the negative control (enzyme (-)) set as 0% and 100%, respectively. Then, using the SAS system (SAS Institute Inc.), nonlinear regression analysis was performed using a two-parameter logistic model for the logarithmic concentration and inhibition rate to determine the concentration of the test substance that inhibits PDGFR-β tyrosine kinase activity by 50% (IC 50 values) were estimated. The results are shown in Tables 30 to 33 below.

[0276] [Table 30]

[0277] [Table 31]

[0278] [Table 32]

[0279] [Table 33]

[0280] <Test Example 2: Growth inhibitory effect on TEL-PDGFRβ and TEL-KIT fusion gene-transfected cells>

[0281] 1. Preparation of TEL-PDGFRβ and TEL-KIT fusion gene transfected cells A human TEL-PDGFRβ fusion gene (see, for example, CELL, 1994, 77, 307-316) or a human TEL-KIT fusion gene was inserted into the multiple cloning site of the retroviral expression vector pMYs-IRES-GFP to construct a gene transfer vector. The amino acid sequence critical for the enzymatic activity of the KIT gene (Accession No. NP_000213.1, amino acids 521-928) was identified for the human TEL-KIT fusion gene, and by appropriately combining it with the amino acid sequence of the TEL gene, a sequence was created that exhibited activation even in the absence of ligand. The gene transfer vector was then introduced into logarithmically growing human embryonic kidney cell line-derived packaging cells, PLAT-E, using a transfection reagent (FuGENE6, Promega). After gene transfer, the PLAT-E culture supernatant, which contained viral particles for gene transfer, was harvested and used as the medium for gene transfer. The medium for gene transfer was added to RetroNectin-coated plates and incubated to allow the viral particles to adhere to the plate. Then, the mouse pro-B cell line Ba / F3 in the logarithmic growth phase was plated and infected with the virus to generate cells that proliferate in a PDGFRβ- or KIT-dependent manner.

[0282] 2. Preparation of Test Substances The test substance was prepared at 10 mM in dimethyl sulfoxide (DMSO), diluted with DMSO to concentrations of 0.0001 to 3 mM, and then further diluted 100-fold with distilled water.

[0283] 3. Measurement of the inhibitory effect on proliferation of TEL-PDGFRβ and TEL-KIT expressing cells The day after seeding TEL-PDGFRβ and TEL-KIT expressing cells onto a 96-well plate, the prepared test substance solution was added to a final concentration of 0.1 to 10,000 nM. After 72 hours, the number of viable cells was measured using the amount of formazan produced by the reduction of a tetrazolium salt compound by mitochondrial dehydrogenase in viable cells as an indicator.

[0284] 4. Analysis of Measurement Results Based on the amount of formazan under each condition, the cell growth inhibition rate was calculated when the amounts of formazan in the negative control (0.1% DMSO solution) and blank (medium only) were set at 0% and 100%, respectively. Then, using the SAS system (SAS Institute Inc.), nonlinear regression analysis was performed using a two-parameter logistic model to determine the logarithmic dose and cell growth inhibition rate, and the IC 50 The value was estimated. The results are shown in Tables 34 to 38 below.

[0285] [Table 34]

[0286] [Table 35]

[0287] [Table 36]

[0288] [Table 37]

[0289] [Table 38]

[0290] <Test Example 3: Inhibitory effect on proliferation of pulmonary artery smooth muscle cells>

[0291] 1. Preparation of Test Substances The test substance was prepared at 10 mM in dimethyl sulfoxide (DMSO), diluted with DMSO to concentrations of 0.003 to 3 mM, and then further diluted 50-fold with distilled water.

[0292] 2. Measurement of the antiproliferative effect on pulmonary artery smooth muscle cells Pulmonary artery smooth muscle cells derived from healthy donors were seeded onto 96-well plates using smooth muscle cell growth medium. The following day, the growth medium was replaced with 0.1% FBS medium and cultured for an additional day. The test substance solution was diluted 10-fold with medium containing BrdU and human PDGF-BB (final concentration 10 ng / mL, SIGMA-Aldrich) and added to the cells in equal volumes to achieve final concentrations of 3–10,000 nM. A human PDGF-BB negative control was prepared by adding BrdU and 0.1% DMSO solution. After one day of culture, the amount of BrdU incorporated into the proliferating cells was measured using an anti-BrdU antibody.

[0293] 3. Analysis of measurement results Based on the BrdU levels under each condition, the cell proliferation inhibition rate was calculated when the BrdU levels of the positive control (human PDGF-BB (+)) and negative control (human PDGF-BB (-)) were set at 0% and 100%, respectively. Then, using the SAS system (SAS Institute Inc.), nonlinear regression analysis was performed using a two-parameter logistic model to determine the logarithmic dose and cell proliferation inhibition rate, and the IC 50 The value was estimated. The results are shown in Tables 39 to 46 below.

[0294] [Table 39]

[0295] [Table 40]

[0296] [Table 41]

[0297] [Table 42]

[0298] [Table 43]

[0299] [Table 44]

[0300] [Table 45]

[0301] [Table 46]

[0302] <Test Example 4: Erythroid colony formation inhibitory effect>

[0303] 1. Preparation of Test Substances The test substance was prepared at 10 mM with dimethyl sulfoxide (DMSO) and diluted with DMSO to concentrations of 0.1 to 3 mM to prepare test substance solutions at 1000 times the final concentration.

[0304] 2. Measurement of erythroid colony formation inhibitory effect Human bone marrow CD34-positive hematopoietic stem cells were thawed and suspended in MethoCult medium. Test substance solution was added to a final concentration of 0.1-10 μM. Cells were seeded onto 35 mm dishes and cultured for 14 days. The number of erythroid progenitor cell-derived cell colonies was counted under a microscope.

[0305] 3. Analysis of measurement results Based on the number of colonies under each condition, the colony formation inhibition rate was calculated, with the negative control (0.1% DMSO solution) taken as 100%. Using the SAS system (SAS Institute Inc.), nonlinear regression analysis was performed using a two-parameter logistic model to determine the logarithmic dose and colony formation inhibition rate, and the IC 50 The values ​​were estimated and the results are shown in Table 47 below.

[0306] [Table 47]

[0307] Formulation example The formulation examples shown below are merely illustrative and are not intended to limit the scope of the invention in any way. It is not something to do. Formulation Example 1 Tablets (oral tablets) Prescription per tablet 80mg Compound of the present invention of Example 1 5.0 mg Corn starch 46.6mg Crystalline cellulose 24.0mg Methylcellulose 4.0mg Magnesium stearate 0.4mg The mixed powder in this ratio is tableted by a conventional method to form oral tablets. [Industrial Applicability]

[0308] The compound of the present invention has PDGF receptor kinase inhibitory activity and is therefore useful as a therapeutic agent for respiratory diseases, cancer, smooth muscle proliferative diseases, vascular proliferative diseases, autoimmune / inflammatory diseases, metabolic diseases, vascular occlusive diseases, etc.

Claims

[Claim 1] The following formula [1]: 【Chemical 1】 [In the formula, R １ represents a hydrogen atom, a halogen atom, or C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Haloalkenyl, C ２ -C ６ Alkynyl, C ２ -C ６ Haloalkynyl, C １ -C ６ Alkoxy, hydroxy, carboxy, alkylcarbonyloxy, amino, monoalkylamino, dialkylamino, aminoalkyl, alkylcarbonylamino, nitro, optionally substituted C ３ -C ６ Cycloalkyl, optionally substituted C ３ -C ６ cycloalkenyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; R ２ is a bond, -(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-, R ２ R in ａ represents a hydrogen atom, a halogen atom, or C １ -C ６ Alkyl, or C １ -C ６ is haloalkyl, R ２ R in ｂ represents a hydrogen atom, a halogen atom, or C １ -C ６ Alkyl, or C １ -C ６ haloalkyl, or R ２ R in ａ and R ｂ together with the carbon atom to which they are attached to form C=O, R ２ R in ｃ are each independently a hydrogen atom, C １ -C ６ Alkyl, or C １ -C ６ is haloalkyl, m is an integer from 0 to 3; and Het is a 5- to 10-membered heteroaryl; L １ is a bond, -(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 in ａ represents a hydrogen atom, a halogen atom, or C １ -C ６ Alkyl, or C １ -C ６ is haloalkyl, L １ R in ｂ represents a hydrogen atom, a halogen atom, or C １ -C ６ Alkyl, or C １ -C ６ haloalkyl, or L １ R in ａ and R ｂ together with the carbon atom to which they are attached to form C=O, and L １ R in ｃ are each independently a hydrogen atom, C １ -C ６ Alkyl, or C １ -C ６ is haloalkyl, L １ In the formula, m is an integer from 0 to 3; X is N or C-R ３ and R ３ represents a hydrogen atom, a halogen atom, or C １ -C ６ Alkyl, or C １ -C ６ is haloalkyl, R ４ is a hydrogen atom, a halogen atom, or a methyl atom, L ２ is a bond, -(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 in ａ represents a hydrogen atom, a halogen atom, or C １ -C ６ Alkyl, or C １ -C ６ is haloalkyl, L ２ R in ｂ represents a hydrogen atom, a halogen atom, or C １ -C ６ Alkyl, or C １ -C ６ haloalkyl, or L ２ R in ａ and R ｂ together with the carbon atom to which they are attached to form C=O, L ２ R in ｃ are each independently a hydrogen atom, C １ -C ６ Alkyl, or C １ -C ６ is haloalkyl, L ２ In the formula, m is an integer from 0 to 3; R ５ is a hydrogen atom, a halogen atom, hydroxy, amino, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Alkoxy, or C １ -C ６ haloalkoxy, R ６ represents a hydrogen atom, a halogen atom, or C １ -C ６ Alkyl, C １ -C ６ haloalkyl, or optionally substituted phenyl; R ７ represents a hydrogen atom, a halogen atom, or C １ -C ６ Alkyl, C １ -C ６ haloalkyl, hydroxyalkyl, optionally substituted phenyl, or optionally substituted C ３ -C ６ cycloalkyl, or R ６ and R ７ together with the carbon atoms to which they are attached, form C ３ -C ６ forming a cycloalkyl, an optionally substituted aryl, or an optionally substituted heteroaryl; or a pharmaceutically acceptable salt thereof, or a solvate thereof.

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