Compounds and Compositions as PDGF Receptor Kinase Inhibitors

Abstract

The purpose of the present invention is to provide a compound having an inhibitory activity against a PDGF receptor kinase.　The present invention includes, for example, a compound represented by formula [1] or a pharmaceutically acceptable salt of the compound, or a solvate of the compound. The compound of the present invention has an inhibitory activity against a PDGF receptor kinase. Due to the inhibitory activity thereof against a PDGF receptor kinase, the compound of the present invention is useful as a therapeutic agent for respiratory diseases, cancer, smooth muscle proliferative diseases, vascular proliferative diseases, autoimmune / inflammatory diseases, metabolic diseases, vascular obstructive diseases and the like.

Description

Technical Field

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

Background Art

[0002] In Western countries, large-scale symposia on pulmonary hypertension are held every five years for pulmonary arterial hypertension (PAH). At the Dana Point Conference in 2008, pulmonary hypertension was defined as the mean pulmonary artery pressure (mean PAP) measured by right heart catheterization at rest being 25 mmHg or higher, and this definition was continued to be adopted at the Nice Conference in 2013. In the Dana Point classification, pulmonary hypertension is classified into five groups, namely 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 a multifactorial mechanism of unknown details. This basic structure is also maintained in the revised clinical classification of pulmonary hypertension (Nice classification

[2013] ) (Non-Patent Document 1). Furthermore, at the 6th World Symposium on Pulmonary Hypertension (Nice Conference 2018), the latest definition of pulmonary hypertension was proposed. Among the proposals, it is defined that 24 mmHg ≥ mean pulmonary artery pressure (mPAP) > 20 mmHg is also included in the above pulmonary hypertension.

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

[0004] Imatinib has a PDGF receptor kinase inhibitory effect and showed efficacy in a P3 trial for pulmonary arterial hypertension. However, it did not obtain approval because of insufficient tolerance due to side effects such as myelosuppression.

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

[0006] However, the relationship between the myelosuppressive effect and the inhibitory effect on KIT, a receptor-type tyrosine kinase involved in bone marrow hematopoiesis, has not been known until now.

Prior Art Documents

Patent Documents

[0007]

Patent Document 1

Non-Patent Documents

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

[0009] The problem to be solved by the present invention is to provide a prophylactic and / or therapeutic agent for pulmonary arterial hypertension having an excellent balance between efficacy and safety. [Means for Solving the Problems]

[0010] The present inventors found the relationship between the myelosuppressive effect and the inhibitory effect on KIT, a receptor tyrosine kinase involved in bone marrow hematopoiesis. That is, the present inventors found that a compound represented by the following general formula [1] having a high inhibitory activity on PDGF receptor kinase with respect to the inhibitory activity of KIT kinase, or a pharmaceutically acceptable salt thereof, or a solvate thereof (which may be referred to as the compound of the present invention in the specification) exhibits an inhibitory effect on the proliferation of pulmonary artery smooth muscle cells and reduces the inhibitory effect on the formation of erythroid colonies, and completed the present invention.

[0011] That is, the present invention can include the inventions of the following (Item 1) to (Item 8). (Item 1) The following formula [1] [Chemical Formula] [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 (CR c -CO-NR c -, -CR a =CR b -, or -C≡C-, and R 2 in R a is a hydrogen atom, a halogen atom, C1-C6 alkyl, or C1-C6 haloalkyl, R 2 in R b is a hydrogen atom, a halogen atom, C1-C6 alkyl, or C1-C6 haloalkyl, or R 2 in R a and R b together with the carbon atom to which they are attached form C=O, R 2 in Rc Each is 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-, wherein, R 1 in L a is a hydrogen atom, a halogen atom, C1-C6 alkyl, or C1-C6 haloalkyl, R 1 in L b is a hydrogen atom, a halogen atom, C1-C6 alkyl, or C1-C6 haloalkyl, or R 1 in L a and R b together with the carbon atom to which they are attached form C=O, and R 1 in L c are each independently a hydrogen atom, C1-C6 alkyl, or C1-C6 haloalkyl, m 1 in L X is N, or C-R 3 is, 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 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 the R in a is a hydrogen atom, a halogen atom, C1-C6 alkyl, or C1-C6 haloalkyl, L 2 the R in b is a hydrogen atom, a halogen atom, C1-C6 alkyl, or C1-C6 haloalkyl, or L 2 the R in a and R b together with the carbon atom to which they are attached form C=O, L 2 the R in c are each independently a hydrogen atom, C1-C6 alkyl, or C1-C6 haloalkyl, L 2 the m in 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, optionally substituted aryl, or optionally substituted heteroaryl, a compound represented thereby or a pharmaceutically acceptable salt thereof, or a solvate thereof. (Item 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 linker, -(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-, and herein, L 1 the R in a is a hydrogen atom, a halogen atom, or C1-C6 alkyl, L 1 the R in b is a hydrogen atom, a halogen atom, or C1-C6 alkyl, or L 1 the R in a and the R in 1 L b together with the carbon atom to which they are attached form C=O, and L 1 the R in c are each independently a hydrogen atom, C1-C6 alkyl, or C1-C6 haloalkyl, L 1 the m in is an integer from 0 to 2, X is N, or C-R 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 is -(CR a R b ) m -NRc - or -NR c -CO-NR c - and, where L 2 R in a and R b together with the carbon atom to which they are attached 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 together with the carbon atom to which they are attached form C3-C6 cycloalkyl, or optionally substituted aryl, the compound according to claim 1 or a pharmaceutically acceptable salt thereof, or a solvate thereof. (Claim 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 is -(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 form C=O, L 1 R in c are each independently a hydrogen atom, L 1 m in is 0 or 1, X is N, or C-R 3 and where R 3 is a hydrogen atom, R 4 is a halogen atom or methyl, L 2 is -(CR a R b ) m -NR c -, and where L 2 R in a and R b together with the carbon atom to which they are attached 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 7The compound according to item 1, or a pharmaceutically acceptable salt thereof, or a solvate thereof, which together with the carbon atom to which they are attached forms a C3-C6 cycloalkyl. (Item 4) The compound according to item 1, or a pharmaceutically acceptable salt thereof, or a solvate thereof, selected from the group consisting of the following (1) to (207). (1) 2-(Cyclopropylamino)-N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)-1,3-thiazole-5-carboxamide, (2) N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)-5-phenylpyridine-3-carboxamide, (3) 2-(Cyclopropylmethyl)-N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)-1,3-thiazole-5-carboxamide, (4) 5-(Cyclopropylamino)-N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)pyridine-3-carboxamide, (5) N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)-2-phenyl-1,3-oxazole-5-carboxamide, (6) N-(5-{[(1S)-2-hydroxy-1-phenylethyl]carbamoyl}-2-methylphenyl)-5-phenylpyridine-3-carboxamide, (7) N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)-5-[(propan-2-yl)oxy]pyridine-3-carboxamide, (8) 2-[(Cyclopropylmethyl)amino]-N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)-1,3-thiazole-5-carboxamide, (9) 5-(4-Chlorophenyl)-N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)pyridine-3-carboxamide, (10) N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)-2-propyl-1,3-thiazole-5-carboxamide, (11) 5-(3-Chlorophenyl)-N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)pyridine-3-carboxamide, (12) N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)-5-(2-methylphenyl)pyridine-3-carboxamide, (13) 5-(2-Chlorophenyl)-N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)pyridine-3-carboxamide, (14) N-(5-{[(2S)-1-hydroxypentan-2-yl]carbamoyl}-2-methylphenyl)-5-phenylpyridine-3-carboxamide, (15) 5-[(E)-2-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}oxane-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. (Item 5) The compound according to Item 1 or a pharmaceutically acceptable salt thereof, or a solvate thereof, which is a compound selected from the group consisting of the following (1) to (15) or a pharmaceutically acceptable salt thereof, or a solvate thereof. (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. (Item 6) A pharmaceutical composition containing, as an active ingredient, the compound according to any one of Items 1 to 5 or a pharmaceutically acceptable salt thereof, or a solvate thereof. (Item 7) A PDGF receptor kinase inhibitor containing, as an active ingredient, the compound according to any one of Items 1 to 5 or a pharmaceutically acceptable salt thereof, or a solvate thereof. (Item 8) A therapeutic agent for pulmonary hypertension, scleroderma, asthma, obstructive bronchiolitis, 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, atherosclerotic / obstructive arteriosclerosis, moyamoya disease (idiopathic occlusion of the circle of Willis), leiomyoma, lymphangioleiomyomatosis, or age-related macular degeneration (AMD), which contains, as an active ingredient, a compound according to any one of Items 1 to 5 or a pharmaceutically acceptable salt thereof, or a solvate thereof, and in which a PDGF receptor kinase is involved.

Advantages of the Invention

[0012] Since the compound of the present invention inhibits a PDGF receptor kinase, it is useful as a therapeutic agent for diseases in which a PDGF receptor kinase is involved (for example, respiratory diseases, cancers, smooth muscle proliferative diseases, vascular proliferative diseases, autoimmune / inflammatory diseases, metabolic diseases, vascular obstructive diseases, etc.).

Modes for Carrying Out the Invention

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

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

[0015] Examples of "alkyl" include alkyl groups having 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, more preferably 1 to 3 carbon atoms, which may be linear or branched. Specifically, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, sec-pentyl, 1-ethylpropyl, 1,2-dimethylpropyl, tert-pentyl, 2-methylbutyl, isopentyl, neopentyl, n-hexyl, sec-hexyl, 1-ethylbutyl, isohexyl, neohexyl, 1,1-dimethylbutyl, 2-ethylbutyl, 1,2,2-trimethylpropyl, 2,2-dimethylbutyl, etc. can be mentioned.

[0016] Examples of the alkyl moieties of "monoalkylamino", "alkylcarbonyloxy", "monoalkylamino", "dialkylamino", "alkylcarbonylamino", "alkylsulfonyl", "aminoalkyl" and "alkylcarbonyl" include the same "alkyl" as described above.

[0017] "Alkenyl" represents a hydrocarbon group having 2 to 10 carbon atoms, preferably 2 to 8 carbon atoms, more preferably 2 to 6 carbon atoms, and still more preferably 2 to 4 carbon atoms, which may be linear or branched and has one or more double bonds at any position. Specifically, vinyl, allyl, 2-methylpropenyl, propenyl, isopropenyl, butenyl, isobutenyl, prenyl, butadienyl, pentenyl, isopentenyl, pentadienyl, hexenyl, isohexenyl, hexadienyl, etc. can be mentioned.

[0018] "Amino" represents -NH2.

[0019] "Aminoalkyl" represents a group in which the amino group has replaced the hydrogen atom bonded to the carbon atom of the above "alkyl". For example, specifically, aminomethyl, 1-aminoethyl, 2-aminoethyl, 1-aminopropyl, 2-aminopropyl, 2-aminopropan-2-yl, 3-aminopropyl, etc. can be mentioned.

[0020] "Monoalkylamino" represents a group in which the above "alkyl" replaces one hydrogen atom bonded to the nitrogen atom of the amino group. Specifically, examples thereof include methylamino, ethylamino, isopropylamino and the like.

[0021] "Hydroxyalkyl" represents a group in which a hydroxy group replaces a hydrogen atom bonded to a carbon atom of the above "alkyl". For example, specifically, examples thereof include hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1-hydroxypropyl, 2-hydroxypropyl and the like.

[0022] "Alkylcarbonyl" means a group in which the above "alkyl" is bonded to a carbonyl group. For example, examples thereof include methylcarbonyl, ethylcarbonyl, propylcarbonyl, isopropylcarbonyl, tert-butylcarbonyl, isobutylcarbonyl, sec-butylcarbonyl, pentylcarbonyl, isopentylcarbonyl, hexylcarbonyl and the like.

[0023] "Haloalkyl" indicates a group in which the above "halogen atom" replaces a hydrogen atom of the above "alkyl". Specifically, for example, examples thereof include fluoromethyl, chloromethyl, fluoroethyl, difluoromethyl, dichloromethyl, difluoroethyl, trifluoromethyl, trichloromethyl, and trifluoroethyl and the like.

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

[0025] As the alkoxy moiety of "haloalkoxy", the same "alkoxy" as described above can be mentioned.

[0026] Examples of "aryl" include aromatic hydrocarbon groups having 6 to 14 carbon atoms and being monocyclic to tricyclic. Specifically, phenyl, 1-naphthyl, 2-naphthyl, 1-anthryl, 2-anthryl, 9-anthryl, 1-phenanthryl, 2-phenanthryl, 3-phenanthryl, 4-phenanthryl, 10-phenanthryl, etc. can be mentioned. Among them, phenyl is preferable.

[0027] "Cycloalkyl" refers to cyclic non-aromatic hydrocarbon groups that are monocyclic to tricyclic. Specifically, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl can be mentioned.

[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 can be mentioned.

[0029] The above-mentioned "non-aromatic carbocyclic group" may be a spiro cyclic group. Examples of such a spiro cyclic 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 · spiro[2.5]octanyl (e.g., spiro[2.5]octan-1-yl, spiro[2.5]octan-4-yl, spiro[2.5]octan-5-yl, spiro[2.5]octan-6-yl) can be mentioned.

[0030] Examples of "heteroaryl" include monocyclic to tricyclic ones having 1 to 3 heteroatoms selected from the group consisting of nitrogen atom, oxygen atom, and sulfur atom as constituent atoms and having an aromatic ring with 6 to 14 carbon atoms. Specifically, for example, · furyl (e.g., 2-furyl, 3-furyl), · 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), · Indolyl (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 can be mentioned.

[0031] "Heterocycloalkyl" can refer to a monocyclic or polycyclic, cyclic non-aromatic heterocyclic group having one or more identical or different heteroatoms selected from nitrogen, oxygen, and sulfur atoms in the ring. Specifically, for example, · 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), · Azepanyl (e.g., 1-azepanyl, 2-azepanyl, 3-azepanyl, 4-azepanyl), · 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-mentioned "heterocycloalkyl" may be a bridged cyclic group. Such bridged cyclic groups include, for example, · 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 (e.g., 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) can be mentioned.

[0033] The above-mentioned "heterocycloalkyl" may be a spiro cyclic group. Such spiro cyclic groups include, for example, ·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 ·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) can be mentioned.

[0034] Hereinafter, each symbol of formula [1] will be described.

[0035] R in formula [1] 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, alkylcarbonylamino, nitro, optionally substituted C3-C6 cycloalkyl, optionally substituted C3-C6 cycloalkenyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl. 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, or optionally substituted heteroaryl are preferred. Optionally substituted heterocycloalkyl, optionally substituted aryl, or 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, or imidazo[1,2-b]pyridazinyl are even 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 In R a is a hydrogen atom, a halogen atom, C1-C6 alkyl, or C1-C6 haloalkyl. A hydrogen atom, or R a and R b together with the carbon atom to which it is attached form C=O is preferred.

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

[0039] R 2 In R cEach is independently a hydrogen atom, C1-C6 alkyl, or 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, 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-. 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- 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 In R of a is a hydrogen atom, a halogen atom, C1-C6 alkyl, C1-C6 haloalkyl, or R a and R b together with the carbon atom to which it is attached forms C=O. A hydrogen atom, a halogen atom, C1-C6 alkyl, or R a and R b together with the carbon atom to which it is attached preferably forms C=O.

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

[0044] L 1R in c is, independently of one another, a hydrogen atom, C1-C6 alkyl, or C1-C6 haloalkyl. A hydrogen atom or C1-C6 alkyl is preferred, and 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-. A bond, -(CR a R b ) m -NR c -, -NR c -CO-NR c - are preferred, and a bond, -(CR a R b ) m -NR c - is more preferred.

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

[0047] L 2 The R in a As R,b 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, C1-C6 alkyl, 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 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 is preferably a hydrogen atom, each independently.

[0051] R 4 is a hydrogen atom, a halogen atom, methyl. A halogen atom and methyl are 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, optionally substituted aryl, or 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 together with the carbon atom to which they are attached form a C3-C6 cycloalkyl, or optionally substituted aryl, R 6 and R 7 more preferably together with the carbon atom to which they are attached form a C3-C6 cycloalkyl.

[0055] More specifically, the compounds of the present invention include the compounds shown in Table 1 below depending on the type of L 1

Table 1

[0056]

Table 1

[0057]

Table 2

[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, 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, linking group, -(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 linking group, -(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. For m of R in Compound 1-A 2 , 0, 1, 2 are preferred, and 0 and 1 are more preferred. For Het in Compound 1-A, thiazolyl, pyridyl, oxazolyl, or imidazothiazolyl is preferred, and thiazolyl or pyridyl is more preferred. For R in Compound 1-A 4 , a halogen atom or methyl is preferred, and methyl is more preferred. For L in Compound 1-A 2 , -(CR a R b )m-NRc- is preferred. For m of L in Compound 1-A 2 , 1 is preferred. For R in Compound 1-A 5 , hydroxy is preferred. For R in Compound 1-A 6 , H, C1-C6 alkyl, or R 7 together with the carbon atom to which they are attached form C3-C6 cycloalkyl, and R 7It is more preferable that, together with the carbon atom to which they are attached, they form a C3-C6 cycloalkyl. R in Compound 1-A 7 Examples include C1-C6 alkyl, optionally substituted phenyl, or R 6 It is preferable that, together with the carbon atom to which they are attached, they form a C3-C6 cycloalkyl, and R 6 It is more preferable that, together with the carbon atom to which they are attached, they form a C3-C6 cycloalkyl.

[0059] R in Compound 1-B 1 Examples include H, a halogen atom, C1-C6 alkyl, amino, optionally substituted C3-C6 cycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl, and a halogen atom, optionally substituted C3-C6 cycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl are more preferable. R in Compound 1-B 2 Examples include a bond, -(CR a R b ) m -NR c - is preferable, and a bond is more preferable. R in Compound 1-B 2 m of R is preferably 0 or 1. Het in Compound 1-B is preferably pyridyl or pyrazinyl. R in Compound 1-B 4 Examples include a halogen atom and methyl, and methyl is preferable. L in Compound 1-B 2 Examples include -(CR a R b )m-NRc- is preferable. L in Compound 1-B 2 m of L is preferably 1. R in Compound 1-B 5 Examples include hydroxy, which is preferable. R in Compound 1-B6 is phenyl which may be substituted, or R 7 and together with the carbon atom to which they are attached preferably form C3-C6 cycloalkyl, R 7 and together with the carbon atom to which they are attached more preferably form C3-C6 cycloalkyl. R in Compound 1-B 7 is hydroxyalkyl, or R 6 and together with the carbon atom to which they are attached preferably form C3-C6 cycloalkyl, R 6 and together with the carbon atom to which they are attached more preferably form 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, C3-C6 cycloalkyl which may be substituted, heterocycloalkyl which may be substituted, aryl which may be substituted, or heteroaryl which may be substituted, and more preferably aryl which may be substituted. R in Compound 1-C 2 is preferably a 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-C 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 is preferably hydroxy. R in Compound 1-C 6 is preferably H, C1-C6 alkyl, or R 7 which, together with the carbon atom to which they are attached, preferably forms C3-C6 cycloalkyl, more preferably R 7 which, together with the carbon atom to which they are attached, forms C3-C6 cycloalkyl. R in Compound 1-C 7 is preferably C1-C6 alkyl, optionally substituted phenyl, or R 6 which, together with the carbon atom to which they are attached, preferably forms C3-C6 cycloalkyl, more preferably R 6 which, together with the carbon atom to which they are attached, forms 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 is preferably a 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 -, more preferably a bond. As Het in Compound 1-D, pyrimidinyl, pyridyl, or quinazolyl is preferred, and pyrimidinyl is more preferred. R in Compound 1-D 4 is preferably a halogen atom or methyl, and more preferably methyl. R in Compound 1-D 5 is preferably hydroxy. R in Compound 1-D 6 is preferably optionally substituted aryl, or R 7 together with the carbon atom to which they are attached forms C3-C6 cycloalkyl, and more preferably R 7 together with the carbon atom to which they are attached forms C3-C6 cycloalkyl. R in Compound 1-D 7 is preferably hydroxyalkyl, optionally substituted phenyl, or R 6 together with the carbon atom to which they are attached forms C3-C6 cycloalkyl, and more preferably R 6 together with the carbon atom to which they are attached forms C3-C6 cycloalkyl.

[0062] R in Compound 1-E 1Examples include H, 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, aminoalkyl, monoalkylamino, dialkylamino, alkylcarbonylamino, nitro, optionally substituted C3-C6 cycloalkyl, optionally substituted C3-C6 cycloalkenyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl, with H, amino, optionally substituted C3-C6 cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl being more preferred. R in Compound 1-E 2 Examples include a 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 preferred. R in Compound 1-E 2 m is preferably 0 or 1. As Het in Compound 1-E, 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-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 is preferred, and pyridyl, pyrazinyl, pyrimidinyl, pyrazolo[1,5-a]pyrimidinyl are more preferred. R in Compound 1-E 4 is preferably H, a halogen atom, or methyl, and more preferably a halogen atom or methyl. L in Compound 1-E 2 is preferably -(CR a R b )m-NRc-. L in Compound 1-E 2 m is preferably 1. R in Compound 1-E 5 is preferably hydroxy. R in Compound 1-E 6 is preferably R 7 which, together with the carbon atom to which they are attached, forms C3-C6 cycloalkyl. R in Compound 1-E 7 is preferably R 6 which, together with the carbon atom to which they are attached, forms C3-C6 cycloalkyl.

[0063] R in Compound 1-F 1Examples thereof preferably include a halogen atom, optionally substituted C3-C6 cycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl, and more preferably include optionally substituted C3-C6 cycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl. R in Compound 1-F 2 Examples thereof preferably include a bond or -C≡C-, and more preferably include a bond. Examples of Het in Compound 1-F preferably include pyridyl or pyrazinyl, and more preferably include pyridyl. R in Compound 1-F 4 Examples thereof preferably include H, a halogen atom, or methyl, and more preferably include H or methyl. L in Compound 1-F 2 Examples thereof preferably include -(CR a R b )m-NRc-, -NRc-CO-NRc-. L in Compound 1-F 2 m in thereof is preferably 1. R in Compound 1-F 5 Examples thereof preferably include hydroxy. R in Compound 1-F 6 Examples thereof preferably include optionally substituted phenyl, or R 7 which, together with the carbon atom to which they are attached, preferably forms C3-C6 cycloalkyl, and more preferably forms C3-C6 cycloalkyl together with the carbon atom to which they are attached. 7 which, together with the carbon atom to which they are attached, preferably forms C3-C6 cycloalkyl, and more preferably forms C3-C6 cycloalkyl together with the carbon atom to which they are attached. R in Compound 1-F 7 Examples thereof preferably include hydroxyalkyl, or R 6 which, together with the carbon atom to which they are attached, preferably forms C3-C6 cycloalkyl, and more preferably forms C3-C6 cycloalkyl together with the carbon atom to which they are attached. 6 which, together with the carbon atom to which they are attached, preferably forms C3-C6 cycloalkyl, and more preferably forms C3-C6 cycloalkyl together with the carbon atom to which they are attached.

[0064] R in Compound 1-G 1Preferably, it is aryl which may be substituted, or heteroaryl which may be substituted, and more preferably heteroaryl which may be substituted. R in Compound 1-G 2 Preferably, it is a bond. As Het in Compound 1-G, pyridyl is preferable. R in Compound 1-G 4 Preferably, it is H, a halogen atom, or methyl, and more preferably a halogen atom or methyl. R in Compound 1-G 5 Preferably, it is hydroxy. R in Compound 1-G 6 As 7 it and the carbon atom to which they are attached, it preferably forms C3-C6 cycloalkyl. R in Compound 1-G 7 As 6 it and the carbon atom to which they are attached, it preferably forms C3-C6 cycloalkyl.

[0065] R in Compound 1-H 1 Preferably, it is heteroaryl which may be substituted. R in Compound 1-H 2 Preferably, it is a bond. As Het in Compound 1-H, pyridyl is preferable. R in Compound 1-H 4 Preferably, it is a halogen atom or methyl, and more preferably methyl. R in Compound 1-H 5 Preferably, it is hydroxy. R in Compound 1-H 6 As 7 it and the carbon atom to which they are attached, it preferably forms C3-C6 cycloalkyl. R in Compound 1-H 7 As 6and, together with the carbon atom to which they are attached, preferably form a C3-C6 cycloalkyl.

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

[0067] R in Compound 1-J 1 is preferably optionally substituted aryl. R in Compound 1-J 2 is preferably a bond. Het in Compound 1-J is preferably pyridyl. R in Compound 1-J 4 is preferably methyl. R in Compound 1-J 5 is preferably hydroxy. R in Compound 1-J 6 is R 7 and, together with the carbon atom to which they are attached, preferably form a C3-C6 cycloalkyl. R in Compound 1-J 7 is R 6and, together with the carbon atom to which they are attached, preferably 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, more preferably a halogen atom, amino, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, or optionally substituted heteroaryl. R in Compound 1-K 2 is preferably a bond, -(CR a R b )m-NR c -, -(CR a R b ) m -O-, -(CR a R b ) m -, or -NR c -, more preferably a bond, -(CR a R b ) m -NR c -, -(CR a R b ) m -, or -NR c -. Het in Compound 1-K is preferably pyridyl, pyrimidinyl, pyrazinyl, or imidazo[1,2-b]pyridazinyl, 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 is preferably -(CR a R b )m-NRc-. L in Compound 1-K 2 m is preferably 1. R in Compound 1-K 5Preferably, it is hydroxy. R in Compound 1-K 6 is C1-C6 alkyl, or R 7 together with the carbon atom to which they are attached preferably forms C3-C6 cycloalkyl, optionally substituted aryl, and R 7 together with the carbon atom to which they are attached more preferably forms C3-C6 cycloalkyl. R in Compound 1-K 7 is C1-C6 alkyl, or R 6 together with the carbon atom to which they are attached preferably forms C3-C6 cycloalkyl, optionally substituted aryl, and R 6 together with the carbon atom to which they are attached more preferably forms C3-C6 cycloalkyl.

[0069] The compounds of the present invention can be produced from known compounds or easily synthesizable intermediates, for example, according to the methods described below, the examples described later, or known methods. In the production of the compounds of the present invention, when the raw material has a substituent that affects the reaction, it is common to protect the raw material with an appropriate protecting group by a known method before carrying out the reaction. 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 medicine as it is, or can also be used in the form of a pharmaceutically acceptable salt, solvate, or solvate of a salt by a known method. 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, or salts of organic bases such as salts of alkali metals such as lithium, potassium, and sodium, salts of alkaline earth metals such as magnesium and calcium, and ammonium salts. These salts can be formed by commonly practiced methods.

[0071] For example, when the compound of the present invention is a hydrochloride, the compound represented by formula [1] can be obtained by dissolving it in an alcoholic 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] Among the compounds of the present invention, those having an asymmetric carbon include all stereoisomers and mixtures thereof within the scope of the present invention. Stereoisomers can be resolved optically, for example, from a racemate by a known method using an optically active acid (such as tartaric acid, dibenzoyl tartaric acid, mandelic acid, 10-camphorsulfonic acid, etc.) utilizing its basicity, or can be produced using a previously prepared optically active compound as a raw material. In addition, they can also be produced by optical resolution using a chiral column or asymmetric synthesis.

[0073] The compounds of the present invention are not limited to specific isomers, but include 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 per se or intermediates that can be easily prepared from known compounds, for example, according to the following methods, the examples described later, or known methods.

[0075] When the solvents, reagents, and raw materials used in each step of the following production methods are commercially available, the commercial products can be used as they are. Also, the compounds obtained in each step of the production methods described later and the raw materials used may form salts and can be converted into other types of salts or free forms by known methods. Conversely, when the compounds obtained in each step of the following production methods and the raw materials used are in free form, 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 solvates (e.g., hydrates, etc.) and / or crystal polymorphs, and the present invention also includes such various solvates and crystal polymorphs. A "solvate" may be coordinated with any number of solvent molecules (e.g., water molecules, etc.) with respect to the compound represented by formula [1]. When the compound represented by formula [1] or a pharmaceutically acceptable salt thereof is left in the atmosphere, it may absorb moisture and adsorbed water may adhere, or a hydrate may be formed. Further, the compound represented by formula [1] or a pharmaceutically acceptable salt thereof may form their crystal polymorphs by recrystallization.

[0077] In the production of the compound of the present invention, when the starting materials have substituents that can affect the reaction, protecting groups may be introduced into these substituents in advance by known methods, and the protecting groups may be removed as necessary after the reaction to obtain the target compound. The introduction of such protecting groups and the removal of protecting groups may be appropriately selected and used according to the conditions shown, for example, in "Greene’s Protective Groups in Organic Synthesis", 4th edition, John Wiley & Sons Inc., 2006, written by Wuts and Greene, or in "Protecting Groups", 3rd edition, Thieme, 2005, written by P.J. Kocienski.

[0078] The compounds obtained in each step of the following production methods can be isolated or purified by methods such as solvent extraction, concentration, distillation, sublimation, recrystallization, reprecipitation, chromatography, etc. according to conventional methods, or can be used in the next step in the state of the reaction mixture or the crude product.

[0079] The reactions in each step in the following production methods are carried out, unless otherwise specified, by known methods, for example, methods 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 appropriately 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 which, together with the carbon atom 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 which, together with the carbon atom to which they are attached, form C=O. 1-D:L 1 Ga-NR c A compound which is 1-E:L 1 -(CR a R b ) m -NR c - and R a and R bA compound that is independently H, a halogen atom, C1-C6 alkyl, or C1-C6 haloalkyl for each. 1-F:L 1 is NR c -(CR a R b ) m - and R a and R b are independently H, a halogen atom, C1-C6 alkyl, or C 1- C6 haloalkyl for each. 1-G:L 1 is -(CR a R b ) m -O- and R a and R b are independently H, a halogen atom, C1-C6 alkyl, or C1-C6 haloalkyl for each. 1-H:L 1 is -O-(CR a R b ) m - and R a and R b are independently H, a halogen atom, C1-C6 alkyl, or C1-C6 haloalkyl for each. 1-I:L 1 is -CR a =CR b - and R a and R b are H. 1-J:L 1 is -(CR a R b ) m - and R a and R b are H. 1-K:L 1 is -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 performed by the processes carried out in ordinary organic chemistry experiments.

[0081] Process for Preparing Compound 1-A

Chemical formula

[0082] Examples of the reactive compound of Compound 1 include those commonly used in amide condensation reactions, such as acid halides (e.g., acid chlorides, acid bromides), mixed acid anhydrides, imidazolides, and active amides.

[0083] The amount of the condensing agent and Amine Compound 2 used in this step is appropriately in the range of 1 to 3 molar equivalents with respect to Compound 1.

[0084] Examples of the condensing agent 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"), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (hereinafter referred to as "HATU"), and the like.

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

[0086] The appropriate amount of such base to use is in the range of 1 molar equivalent to 10 molar equivalents relative to Compound 1.

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

[0088] When using the above additives in this process, the appropriate amount of such additives to use is in the range of 0.1 molar equivalent to 3 molar equivalents relative to Compound 1.

[0089] The solvent to be used is not particularly limited as long as it does not participate in the reaction. Examples 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, or a mixed solvent thereof.

[0090] The reaction temperature varies depending on the types of raw materials and reagents used, but usually, it is appropriately in the range of -20°C to 150°C. Also, if necessary, a microwave reactor may be used.

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

[0092] Also in Compound [1], L 2 is -(CR a R b ) m -NR c -(R a and R bTogether with the carbon atoms to which they are attached, they form C=O, m, and R c When (compound 1-AA) is as defined above), the compound can also be produced by the following method.

[0093] Production method of compound 1-AA

Chemical formula

[0094] Step1 This step is a step of obtaining compound 1-AA by condensing compound 1 or its reactive compound with amine compound 3 in the presence of a condensing agent. It can be produced by the same method as Step 1 of the above production method of compound 1-A.

[0095] Step2 This step is a step of obtaining compound 5 by condensing compound 1 or its reactive compound with amine compound 4 in the presence of a condensing agent. It can be produced by the same method as Step 1 of the above production method of compound 1-A.

[0096] Step3 This step is a step of obtaining compound 6 by hydrolyzing the ester part of the above compound 5 in a suitable solvent in the presence of a suitable acid or base.

[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 include inorganic bases such as sodium hydroxide, potassium hydroxide, and lithium hydroxide.

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

[0099] The solvent to be used is not particularly limited as long as it does not participate in the reaction. For example, alcohols such as methanol, ethanol, 2-propanol, ethers such as THF, diethyl ether, 1,4-dioxane, DME, nitriles such as acetonitrile, propionitrile, ketones such as acetone, water, or a mixed solvent thereof can be mentioned.

[0100] The reaction temperature varies depending on the types of raw materials and reagents used, but usually, it can be carried out within the range of 20°C to 200°C, preferably 20°C to 100°C. Further, if necessary, a microwave reactor may be used.

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

[0102] Step4 This step is a step of obtaining Compound 1-AA by condensing Compound 6 or its reactive compound with amine Compound 7 in the presence of a condensing agent, and it can be produced by the same method as in the production method of Compound 1-A, Step 1.

[0103] Production method of Compound 1-B

Chemical formula

[0104] This reaction is a coupling reaction using a transition metal, and the conditions commonly used in such reactions can be applied. Specifically, the Sonogashira coupling reaction can be used, and it can be carried out by the methods described in the literature such as Sonogashira et al., J. Organomet. Chem. 2002, 653, 46 - 49., Negishi et al., Chem. Rev., 2003, 103, 1979 - 2017., etc.

[0105] The amount of Compound 9 used is appropriately within the range of 0.5 molar equivalent 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) dipalladium chloroform adduct (hereinafter referred to as "Pd2(dba)3·CHCl3"), tris(dibenzylideneacetone) dipalladium (hereinafter referred to as "Pd2(dba)3"), tetrakis(triphenylphosphine) palladium (hereinafter referred to as "Pd(PPh3)4"), [1,1'-bis(diphenylphosphino) ferrocene]-dichloropalladium(II) dichloromethane adduct (hereinafter referred to as "Pd(dppf)Cl2·CH2Cl2"), bis(triphenylphosphine) palladium(II) dichloride (hereinafter referred to as "PdCl2(PPh3)2"), [1,1'-bis(di-tert-butylphosphino) ferrocene]-dichloropalladium(II) (hereinafter referred to as "Pd(dtbpf)Cl2"), bis(tricyclohexylphosphine) palladium(II) dichloride (hereinafter referred to as "PdCl2(PCy3)2"), palladium(II) acetate (hereinafter referred to as "Pd(OAc)2"), and metal catalysts such as [1,3-bis(diphenylphosphino) propane] nickel(II), and mixtures of these metal catalysts can be mentioned.

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

[0108] In this step, a base or a salt may be used as necessary. Examples of the base or salt to be used include, for example, potassium carbonate, cesium carbonate, sodium carbonate, sodium hydrogen carbonate, sodium acetate, potassium acetate, trisodium phosphate, tripotassium phosphate and their solutions, and bases or salts such 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 in the range of, for example, 1 to 4 molar equivalents relative to Compound 8.

[0110] In this step, a suitable ligand may be used as necessary. Examples of ligands that can be used include, for example, 1,1'-bis(diphenylphosphino)ferrocene (hereinafter referred to as "dppf"), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (hereinafter referred to as "Xantphos"), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (hereinafter referred to as "XPhos"), 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (hereinafter referred to as "BINAP"), 2-dicyclohexylphosphino-2',6'-diisopropylbiphenyl (hereinafter referred to as "RuPhos"), triphenylphosphine (hereinafter referred to as "PPh3"), tricyclohexylphosphine (hereinafter referred to as "PCy3"), and the like.

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

[0112] In this process, the solvent to be used is not particularly limited as long as it does not participate in the reaction. For example, hydrocarbons such as toluene and xylene, ethers such as 1,4-dioxane, tetrahydrofuran (hereinafter referred to as "THF"), and dimethoxyethane (hereinafter referred to as "DME"), amides such as N,N-dimethylformamide (hereinafter referred to as "DMF"), N,N-dimethylacetamide (hereinafter referred to as "DMA"), and N-methylpyrrolidone (hereinafter referred to as "NMP"), alcohols such as ethanol, 2-propanol, and tert-butanol, water, or a mixed solvent thereof can be mentioned.

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

[0114] The reaction time varies depending on the type of raw material and the reaction temperature, but usually, a range of 0.1 hour to 24 hours is appropriate.

[0115] L 2 is -(CR a R b ) m -NR c -, and when R a and R b together with the carbon atom to which they are attached form C=O, the compound (Compound 1-BB) can also be produced as follows.

[0116] Production method of Compound 1-BB

Chemical formula

[0117] Step1 This step is to obtain the alkyne compound 12 by coupling compound 10 and compound 11 in the presence of a transition metal such as palladium, and it can be produced by the same method as in the preparation method of compound 1-B, Step1.

[0118] Step2 This step is to obtain compound 13 by deprotecting Z, and it can be carried out by referring to, for example, "Greene’s Protective Groups in Organic Synthesis" by Wuts and Greene, 4th Edition, John Wiley & Sons Inc., 2006, or "Protecting Groups" by P.J. Kocienski, 3rd Edition, Thieme, 2005.

[0119] Step3 This step is to obtain compound 15 by coupling compound 13 and compound 14 in the presence of a transition metal such as palladium, and it can be produced by the same method as in the preparation method of compound 1-B, Step1.

[0120] Step4 This step is to obtain compound 16 by hydrolyzing the ester part of compound 15 in the presence of a suitable acid or base in a suitable solvent, and it can be produced by the same method as in the preparation method of compound 1-AA, Step3.

[0121] Step5 This step is to obtain compound 1-BB by condensing compound 16, or its reactive compound, and amine compound 17 in the presence of a condensing agent, and it can be produced by the same method as in the preparation method of compound 1-A, Step1.

[0122] Preparation method of compound 1-C

Chemical formula

[0123] Step1 This step is a step of obtaining Compound 1-C by condensing Compound 19, or a reactive compound thereof, and Amine Compound 18 in the presence of a condensing agent, and it can be produced by the same method as Step 1 of the method for producing the above Compound 1-A.

[0124] Method for Producing Compound 1-D

Chemical Structure

[0125] This reaction can be carried out under the conditions usually used in coupling reactions using transition metals. Specifically, the coupling reaction of Buchwald et al. can be applied. It can be carried out by the methods described in the literature such as Buchwald et al., J. Am. Chem. Soc. 1994, 116, 7901 - 7902., Buchwald et al., Org. Synth. 2002, 78, 23 - 28., Hartwig et al., Acc. Chem. Res. 2008, 41, 1534 - 1544., etc.

[0126] The amount of Compound 21 to be used is suitably in 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)bis palladium chloroform adduct (hereinafter referred to as "Pd2(dba)3·CHCl3"), tris(dibenzylideneacetone)bis palladium (hereinafter referred to as "Pd2(dba)3"), tetrakis triphenylphosphine palladium (hereinafter referred to as "Pd(PPh3)4"), [1,1'-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) dichloromethane adduct (hereinafter referred to as "Pd(dppf)Cl2·CH2Cl2"), bis(triphenylphosphine)palladium(II) dichloride (hereinafter referred to as "PdCl2(PPh3)2"), [1,1'-bis(di-tert-butylphosphino)ferrocene]-dichloropalladium(II) (hereinafter referred to as "Pd(dtbpf)Cl2"), bis(tricyclohexylphosphine)palladium(II) dichloride (hereinafter referred to as "PdCl2(PCy3)2"), palladium(II) acetate (hereinafter referred to as "Pd(OAc)2"), and metal catalysts such as [1,3-bis(diphenylphosphino)propane]nickel(II), and mixtures of these metal catalysts can be mentioned.

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

[0129] In this step, a base or a salt may be used if necessary. Examples of the base or salt to be used include potassium carbonate, cesium carbonate, sodium carbonate, sodium hydrogen carbonate, sodium acetate, potassium acetate, trisodium phosphate, tripotassium phosphate and their solutions, and bases or salts such 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 the base used is suitably in 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 necessary. Examples of ligands that can be used include, for example, 1,1'-bis(diphenylphosphino)ferrocene (hereinafter referred to as "dppf"), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (hereinafter referred to as "Xantphos"), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (hereinafter referred to as "XPhos"), 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (hereinafter referred to as "BINAP"), 2-dicyclohexylphosphino-2',6'-diisopropylbiphenyl (hereinafter referred to as "RuPhos"), triphenylphosphine (hereinafter referred to as "PPh3"), tricyclohexylphosphine (hereinafter referred to as "PCy3"), and the like.

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

[0133] In this step, the solvent used is not particularly limited as long as it does not participate in the reaction. Examples 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, or a mixed solvent thereof.

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

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

[0136] Method for producing Compound 1-E

Chemical formula

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

[0138] Method for producing Compound 1-EE

Chemical formula

[0139] Step1 This step is to obtain Compound 1-EE through the reductive amination reaction of Compound 24 and Compound 23, and it can be carried out according to a method known as the reductive amination reaction. This step can also be carried out stepwise with imine formation (the first step) and reduction of the imine moiety (the second step).

[0140] The amount of Compound 23 to be used is suitably in the range of 1 molar equivalent to 2.5 molar equivalents relative to Compound 24.

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

[0142] In this step, when an acid is used, the amount of the acid to be used is suitably in the range of 2 molar equivalents to 3 molar equivalents relative to the amount of Compound 24.

[0143] In this step, when a Lewis acid is used, the amount of the Lewis acid to be used is suitably in the range of 1.5 molar equivalents to 2 molar equivalents relative to the amount of Compound 24.

[0144] In this step, the solvent to be used is not particularly limited as long as it does not participate in the reaction. Examples include hydrocarbons such as toluene and xylene, ethers such as 1,4-dioxane, THF, and DME, halogenated hydrocarbons such as dichloromethane, or a mixed solvent thereof.

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

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

[0147] Examples of the reducing agent used in this step include sodium triacetoxyborohydride and sodium cyanoborohydride.

[0148] The amount of the reducing agent used in this step is appropriately in 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 does not participate in the reaction. Examples thereof include hydrocarbons such as toluene and xylene, ethers such as 1,4-dioxane, THF, and DME, halogenated hydrocarbons such as dichloromethane, or a mixed solvent thereof.

[0150] Process for Preparing Compound 1-F

Chemical Formula

[0151] The amount of Compound 26 used is appropriately in 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 bicarbonate.

[0153] The amount of the base used is appropriately in 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 does not participate in the reaction. For example, alcohols such as isopropanol, 1-butanol, and 2-methoxyethanol, ethers such as THF and 1,4-dioxane, amides such as DMF, DMA, and NMP, hydrocarbons such as benzene and toluene, dimethyl sulfoxide (hereinafter referred to as "DMSO"), acetonitrile, or a mixed solvent thereof can be mentioned.

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

[0156] The reaction time varies depending on the type of raw material used and the reaction temperature, but usually, a range of 1 hour to 24 hours is appropriate.

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

[0158] Production method of compound 1-FF

Chemical formula

[0159] Step1 This step is a step of obtaining compound 1-FF by the reductive amination reaction of compound 27 and compound 28, and it can be produced by the same method as Step1 of the production method of the above compound 1-EE.

[0160] Process for Preparing Compound 1-G

Chemical Formula

[0161] Step1 This step is a step of obtaining ether compound 1-G by Mitsunobu reaction of alcohol compound 29 and alcohol compound 30, and can be carried out according to a known method.

[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 in the range of 0.5 to 1.5 molar equivalents relative to compound 30.

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

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

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

[0167] The amount of the phosphine reagent to be used is suitably 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 does not participate in the reaction. For example, hydrocarbons such as toluene and xylene, ethers such as 1,4-dioxane, THF, and DME, or a mixed solvent thereof can be mentioned.

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

[0170] The reaction time varies depending on the type of raw material and the reaction temperature, but usually, a range of 0.5 hours to 24 hours is appropriate.

[0171] Process for preparing compound 1-H

Chemical formula

[0172] Step1 This step is a step of obtaining ether compound 1-H by Mitsunobu reaction of alcohol compound 31 and alcohol compound 32, and it can be produced by the same method as Step1 in the process for preparing the above compound 1-G.

[0173] Process for preparing compound 1-I

Chemical formula

[0174] This reaction can be carried out under the conditions usually used in coupling reactions using transition metals, specifically, the Heck reaction can be applied, and it can be carried out by methods described in the 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., etc.)

[0175] The amount of Compound 33 to be used is suitably in the range of 0.5 molar equivalent to 3 molar equivalents with respect to Compound 34.)

[0176] The organometallic catalyst used in this reaction is not particularly limited. Preferred examples of the organometallic catalyst include tris(dibenzylideneacetone)bis palladium chloroform adduct (hereinafter referred to as "Pd2(dba)3·CHCl3"), tris(dibenzylideneacetone)bis palladium (hereinafter referred to as "Pd2(dba)3"), tetrakis triphenylphosphine palladium (hereinafter referred to as "Pd(PPh3)4"), [1,1'-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) dichloromethane adduct (hereinafter referred to as "Pd(dppf)Cl2·CH2Cl2"), bis(triphenylphosphine)palladium(II) dichloride (hereinafter referred to as "PdCl2(PPh3)2"), [1,1'-bis(di-tert-butylphosphino)ferrocene]-dichloropalladium(II) (hereinafter referred to as "Pd(dtbpf)Cl2"), bis(tricyclohexylphosphine)palladium(II) dichloride (hereinafter referred to as "PdCl2(PCy3)2"), palladium(II) acetate (hereinafter referred to as "Pd(OAc)2"), and metal catalysts such as [1,3-bis(diphenylphosphino)propane]nickel(II), and mixtures of these metal catalysts can be mentioned.

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

[0178] In this step, a base or a salt may be used as necessary. Examples of the base or salt to be used include potassium carbonate, cesium carbonate, sodium carbonate, sodium hydrogen carbonate, sodium acetate, potassium acetate, trisodium phosphate, tripotassium phosphate and their solutions, and bases or salts such 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 in the range of, for example, 1 to 4 molar equivalents relative to Compound 33.

[0180] In this step, appropriate ligands may be used as needed. Examples of ligands that can be used include, for example, 1,1'-bis(diphenylphosphino)ferrocene (hereinafter referred to as "dppf"), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (hereinafter referred to as "Xantphos"), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (hereinafter referred to as "XPhos"), 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (hereinafter referred to as "BINAP"), 2-dicyclohexylphosphino-2',6'-diisopropylbiphenyl (hereinafter referred to as "RuPhos"), triphenylphosphine (hereinafter referred to as "PPh3"), tricyclohexylphosphine (hereinafter referred to as "PCy3"), and the like.

[0181] The amount of the ligand to be used is, for example, appropriately in the range of 1 molar equivalent to 5 molar equivalents relative to the transition metal to be used.

[0182] In this step, the solvent to be used is not particularly limited as long as it does not participate in the reaction. 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, or a mixed solvent thereof.

[0183] The reaction temperature varies depending on the types of raw materials and reagents to be used, but is usually appropriately in the range of 20°C to 200°C. Further, a microwave reactor may be used as needed.

[0184] The reaction time varies depending on the type of raw material and the reaction temperature, but is usually appropriately in the range of 0.1 hour to 24 hours.

[0185] Process for Preparing Compound 1-K [Chemical Formula] (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 each represent a hydroxy group, or R AA and R BB together form -O-C(CH3)2-C(CH3)2-O-, -O-(CH2)3-O-, or O-CH2-C(CH3)2-CH2-O-.) Step1 This step is a process for obtaining Compound 1-K by subjecting Compound 35 and Compound 36 to a coupling reaction in the presence of a transition metal such as palladium.

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

[0187] The amount of Compound 36 used is suitably in the range of 0.5 molar equivalent 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)bis palladium chloroform adduct (hereinafter referred to as "Pd2(dba)3·CHCl3"), tris(dibenzylideneacetone)bis palladium (hereinafter referred to as "Pd2(dba)3"), tetrakis triphenylphosphine palladium (hereinafter referred to as "Pd(PPh3)4"), [1,1'-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) dichloromethane adduct (hereinafter referred to as "Pd(dppf)Cl2·CH2Cl2"), bis(triphenylphosphine)palladium(II) dichloride (hereinafter referred to as "PdCl2(PPh3)2"), [1,1'-bis(di-tert-butylphosphino)ferrocene]-dichloropalladium(II) (hereinafter referred to as "Pd(dtbpf)Cl2"), bis(tricyclohexylphosphine)palladium(II) dichloride (hereinafter referred to as "PdCl2(PCy3)2"), palladium(II) acetate (hereinafter referred to as "Pd(OAc)2"), and metal catalysts such as [1,3-bis(diphenylphosphino)propane]nickel(II), and mixtures of these metal catalysts.

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

[0190] In this step, a base or a salt may be used as necessary. Examples of the base or salt to be used include potassium carbonate, cesium carbonate, sodium carbonate, sodium hydrogen carbonate, sodium acetate, potassium acetate, trisodium phosphate, tripotassium phosphate and their solutions, and bases or salts such 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, for example, in the range of 1 to 4 molar equivalents relative to Compound 35.

[0192] In this process, appropriate ligands may be used as needed. Examples of ligands that can be used include, for example, 1,1'-bis(diphenylphosphino)ferrocene (hereinafter referred to as "dppf"), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (hereinafter referred to as "Xantphos"), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (hereinafter referred to as "XPhos"), 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (hereinafter referred to as "BINAP"), 2-dicyclohexylphosphino-2',6'-diisopropylbiphenyl (hereinafter referred to as "RuPhos"), triphenylphosphine (hereinafter referred to as "PPh3"), tricyclohexylphosphine (hereinafter referred to as "PCy3"), and the like.

[0193] The amount of the ligand to be used is suitably, for example, in the range of 1 molar equivalent to 5 molar equivalents with respect to the transition metal to be used.

[0194] In this process, the solvent to be used is not particularly limited as long as it does not participate in the reaction. 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, or a mixed solvent thereof.

[0195] The reaction temperature varies depending on the types of raw materials and reagents to be used, but is usually suitably in the range of 20°C to 200°C. Further, a microwave reactor may be used as needed.

[0196] The reaction time varies depending on the type of raw material and the reaction temperature, but is usually suitably in the range of 0.1 hour to 24 hours.

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

[0198] Also, as shown in the test examples described below, the PDGF receptor kinase inhibitory activity of the compound of the present invention has high selectivity for the inhibitory activity of KIT kinase. Therefore, it is expected that the compound of the present invention can provide a PDGF receptor kinase inhibitor with reduced 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 prophylactic or therapeutic agent for diseases involving PDGF receptor kinase.

[0200] Examples of 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 them, pulmonary hypertension is classified as follows according to its etiology and pathological condition. · Pulmonary arterial hypertension (PAH), · Pulmonary hypertension due to the following left heart diseases, Left heart failure with maintained ejection fraction, Left heart failure with reduced ejection fraction, Valvular disease, Congenital / acquired cardiovascular conditions leading to post-capillary PH · Pulmonary hypertension due to lung diseases and / or hypoxemia associated with the following diseases, Chronic obstructive pulmonary disease (COPD), Interstitial (restrictive) lung disease, Other lung diseases with a mixed disorder of restrictive and obstructive, Hypoxic state associated with lung diseases, or Growth disorder · Pulmonary hypertension associated with pulmonary artery occlusion, 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 associated with a multi-factorial mechanism of unknown details associated with the following diseases blood diseases (chronic hemolytic anemia, myeloproliferative diseases, etc.), systemic and metabolic diseases (e.g., pulmonary Langerhans cell histiocytosis, Gaucher disease, glycogenosis, neurofibromatosis, sarcoidosis, etc.), others (e.g., chronic renal failure with / without dialysis, Fibrosing mediastinitis, etc.), congenital complex heart malformations

[0201] The above-mentioned pulmonary arterial hypertension (PAH) includes, for example, idiopathic PAH, hereditary (especially, BMPR2, TBX4, ACVRL1, ENG, SMAD9, KCNK3, SMAD1, CAV1, SMAD4, ATP13A3, SOX17, AQP1, GDF2, unknown gene abnormalities) PAH, drug and toxin-induced PAH, PAH associated with diseases (here, "diseases" include, for example, connective tissue disease, HIV infection, portal hypertension, congenital shunt heart disease, schistosomiasis), PAH showing long-term response to calcium channel blockers (PAH long-term responders to calcium channel blockers), pulmonary veno-occlusive disease / pulmonary capillary hemangiomatosis (PVOD / PCH) (including PVOD / PCH with EIF2AK4 mutation), neonatal persistent pulmonary hypertension (PPHN).

[0202] Inflammatory 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), combined pulmonary fibrosis and emphysema (CPFE), adult respiratory distress syndrome (ARDS), psoriasis, rheumatoid arthritis, mastocytosis, anaphylactic syndrome, angioedema, erythema nodosum, erythema multiforme, cutaneous vasculitis, skin inflammation / disease, urticaria, allergic contact dermatitis.

[0203] Cancers to which the compound of the present invention or a pharmaceutically acceptable salt thereof can be applied include acute myelogenous 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, cholangiocarcinoma, head and neck squamous cell carcinoma, colorectal cancer, mesenchymal cell tumor, adenocarcinoma, pancreatic cancer, mastocytosis, gastrointestinal stromal tumor (GIST).

[0204] 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 occlusion of the circle of Willis), leiomyoma, lymphangioleiomyomatosis, Williams syndrome, tuberous sclerosis, angina pectoris, myocardial infarction, peripheral arterial disease, hypertrophic / dilated cardiomyopathy, restrictive / diastolic heart failure.

[0205] Examples of 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] Examples of metabolic diseases to which the compound of the present invention or a pharmaceutically acceptable salt thereof can be applied include diabetes (type 1 diabetes or type 2 diabetes).

[0207] The compound of the present invention, either as it is or mixed with a pharmacologically acceptable carrier or the like, can be made into a pharmaceutical composition containing, for example, 0.001% to 99.5%, preferably 0.1% to 90%. Thus, it can be used as a therapeutic agent for various diseases in mammals such as humans, mice, rats, rabbits, dogs, cats, cows, horses, pigs, monkeys, etc.

[0208] The dosage as a medicine is preferably adjusted in consideration of the patient's condition such as age, weight, type and degree of the disease, administration route, type of the compound of the present invention, whether it is a salt or not, type of the salt, etc. Usually, for adults, as the effective ingredient amount of the compound of the present invention or a pharmaceutically acceptable salt thereof, in the case of oral administration, it is appropriate within the range of 0.01 mg to 5 g / adult per day, preferably within the range of 1 mg to 500 mg / adult per day. In some cases, a lower dose may be sufficient, or conversely, a higher dose may be required. Usually, it can be administered once a day or divided into several times a day, or in the case of intravenous administration, it can be administered rapidly or continuously within 24 hours.

[0209] One or more hydrogens, carbons, and / or other atoms of the compound of the present invention can be replaced with isotopes of hydrogen, carbon, and / or other atoms, respectively. Examples of such isotopes are 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 Cl, namely hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine and chlorine are included. Compounds substituted with such isotopes are also useful as pharmaceuticals and include all radiolabeled forms of the compounds of the present invention.

[0210] The present invention will be described in more detail below by way of comparative examples, examples, and test examples, which, however, do not limit the present invention thereto.

[0211] In the examples, the following abbreviations are used. TFA: Trifluoroacetic acid Pd-C: Palladium-carbon Pd2(dba)3: Tris(dibenzylideneacetone)bis palladium Pd(PPh3)4: Tetrakis(triphenylphosphine)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: Deuterochloroform TLC: Thin layer chromatography MS: Mass spectrometry LCMS: Liquid chromatography-mass spectrometry ESI: Electron Spray Ionization M: Molarity (mol / L)

[0212] MS was measured by LCMS. As the ionization method, the ESI method was used. The observed mass spectrometry values are represented by m / z.

[0213] The measurement conditions of LCMS are as follows. Analytical instrument: ACQUITY UPLC MS / PDA system (manufactured by 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: 0.5 mL / min Column temperature: 40 °C Solvent; Solution A: 0.1% formic acid / H2O (v / v; the same hereinafter) Solution B: 0.1% formic acid / acetonitrile

[0214] 1 The 1H NMR spectrum was measured using a JNM-ECS400 nuclear magnetic resonance apparatus (manufactured by JEOL RESONANCE). The observed peaks are represented by the chemical shift value 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] The microwave experiment used Initiator 60 (manufactured by Biotage). A temperature of 40 - 250 °C can be achieved, and a pressure up to 20 bar can be reached.

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

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

[0218] Reference Example 1 5-[(Cyclopropylmethyl)amino]pyridine-3-carboxylic acid [Step 1] Preparation of methyl 5-[(cyclopropylmethyl)amino]pyridine-3-carboxylate To 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)2 (1.6 g) in 1,4-dioxane (139 mL), after degassing, it was stirred at 80 °C overnight under an argon atmosphere. The insoluble matter was filtered off with Celite (registered trademark), and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (8.4 g). MS (m / z): 207.2 [M + H] + [Step 2] Preparation of 5-[(cyclopropylmethyl)amino]pyridine-3-carboxylic acid To a solution of methyl 5-[(cyclopropylmethyl)amino]pyridine-3-carboxylate (8.4 g) in THF (81 mL) - methanol (81 mL) obtained in Step 1, lithium hydroxide monohydrate (3.4 g) and water (81 mL) were added, and the mixture was stirred at room temperature overnight. The solvent was distilled off under reduced pressure, diluted with water, and neutralized by adding 1 M hydrochloric acid. The precipitated precipitate was collected by filtration to obtain the title compound (6.8 g). MS (m / z): 193.2 [M+H] + Reference Example 2 5-[Cyclopropyl(methyl)amino]pyridine-3-carboxylic acid [Step 1] Production of methyl 5-[cyclopropyl(methyl)amino]pyridine-3-carboxylate According to the method according to Step 1 of Reference Example 1, N-methylcyclopropaneamine (9.9 g) was used instead of 1-cyclopropylmethanamine to obtain the title compound (6.6 g). MS (m / z): 207.4 [M+H] + [Step 2] Production of 5-[cyclopropyl(methyl)amino]pyridine-3-carboxylic acid According to the method according to Step 2 of Reference Example 1, 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 obtain 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] Production 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 the mixture was stirred at 60 °C for 2 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography to obtain the title compound (170 mg). MS (m / z): 244.4 [M+H] + Production of 5-[(3,3-difluorocyclobutyl)oxy]pyridine-3-carboxylic acid According to the method according to Step 2 of Reference Example 1, instead of methyl 5-[(cyclopropylmethyl)amino]pyridine-3-carboxylate, methyl 5-[(3,3-difluorocyclobutyl)oxy]pyridine-3-carboxylate (170 mg) obtained in Step 1 was used to obtain the title compound (84 mg). Reference Example 4 5-[(4,4-Difluorocyclohexyl)oxy]pyridine-3-carboxylic acid Production of methyl 5-[(4,4-difluorocyclohexyl)oxy]pyridine-3-carboxylate According to the method according to Step 1 of Reference Example 3, instead of 3,3-difluorocyclobutan-1-ol, 4,4-difluorocyclohexan-1-ol was used to obtain the title compound (450 mg). MS (m / z): 272.2 [M+H] + Production of 5-[(4,4-difluorocyclohexyl)oxy]pyridine-3-carboxylic acid According to the method according to Step 2 of Reference Example 1, instead of methyl 5-[(cyclopropylmethyl)amino]pyridine-3-carboxylate, methyl 5-[(4,4-difluorocyclohexyl)oxy]pyridine-3-carboxylate (450 mg) obtained in Step 1 was used to obtain the title compound (350 mg). MS (m / z): 258.2 [M+H] + Reference Example 5 5-[(1-Methylcyclopropyl)methoxy]pyridine-3-carboxylic acid Production of methyl 5-[(1-methylcyclopropyl)methoxy]pyridine-3-carboxylate According to the method according to Step 1 of Reference Example 3, instead of 3,3-difluorocyclobutan-1-ol, (1-methylcyclopropyl)methanol (500 mg) was used to obtain the title compound (540 mg). MS (m / z): 222.1 [M+H] + Production of 5-[(1-methylcyclopropyl)methoxy]pyridine-3-carboxylic acid According to the method according to Step 2 of Reference Example 1, instead of methyl 5-[(cyclopropylmethyl)amino]pyridine-3-carboxylate, methyl 5-[(1-methylcyclopropyl)methoxy]pyridine-3-carboxylate (540 mg) obtained in Step 1 was used to obtain 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 According to the method according to Step 1 of Reference Example 3, instead of 3,3-difluorocyclobutan-1-ol, (3,3-difluorocyclobutyl)methanol (500 mg) was used to obtain 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 According to the method according to Step 2 of Reference Example 1, instead of methyl 5-[(cyclopropylmethyl)amino]pyridine-3-carboxylate, methyl 5-[(3,3-difluorocyclobutyl)methoxy]pyridine-3-carboxylate (1.10 g) obtained in Step 1 was used to obtain 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 the mixture was stirred at room temperature for 2 hours. The reaction solution was diluted with ethyl acetate, and the organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. Ethyl acetate was added to the obtained residue to suspend it, and the precipitate was collected by filtration to obtain the title compound (6.10 g). MS (m / z): 249.2 [M+H] + Reference Example 8 Methyl 4-chloro-3-ethynylbenzoate [Step 1] Production of Methyl 4-chloro-3-[(trimethylsilyl)ethynyl]benzoate To methyl 4-chloro-3-iodobenzoate (8.15 g), ethynyl(trimethyl)silane (2.78 g), copper(I) iodide (570 mg), Pd(PPh3)4 (3.18 g) and TEA (55 mL) was added THF (27.5 mL). After degassing, the mixture was stirred at 45 °C overnight under an argon atmosphere. The insoluble material was filtered off through Celite®, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (6.8 g). [Step 2] Production 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. The mixture was stirred at room temperature for 30 minutes. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to obtain the title compound (2.6 g). Reference Example 9 3-Ethynyl-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide According to the method according to Reference Example 7, instead of 3-amino-4-methylbenzoic acid, 3-ethynyl-4-methylbenzoic acid (500 mg) was used to obtain the title compound (570 mg). MS (m / z): 258.2 [M+H] + Reference Example 10 2-(5-Ethynylpyridin-3-yl)pyrimidine [Step 1] Production of 2-[5-(methoxymethoxy)pyridin-3-yl]pyrimidine 3-Bromo-5-(methoxymethoxy)pyridine (4.0 g), bis(pinacolato)diboron (5.6 g), potassium acetate (3.6 g) and Pd(dppf)Cl2·CH2Cl2 (1.5 g) were added to 1,4-dioxane (73 mL). After degassing, the mixture was stirred at 80 °C for 2.5 h under an argon atmosphere. Then, 2-bromopyrimidine (3.5 g), potassium carbonate (5.1 g) and water (0.5 mL) were added, and the mixture was stirred at 85 °C overnight. The reaction solution was diluted with ethyl acetate, and the organic layer was washed with water. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography to obtain the title compound (3.6 g). MS (m / z): 218.4 [M+H] + [Step 2] Production of 5-(pyrimidin-2-yl)pyridin-3-ol 2-[5-(Methoxymethoxy)pyridin-3-yl]pyrimidine (4.11 g) obtained in Step 1 was dissolved in THF (38 mL), 35% hydrochloric acid (1.4 mL) was added, and the mixture was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure, an aqueous sodium hydrogen carbonate solution was added to the obtained residue for neutralization. The resulting precipitate was collected by filtration to obtain the title compound (2.51 g). MS (m / z): 174.4 [M+H] + [Step 3] Production of 5-(pyrimidin-2-yl)pyridin-3-yl trifluoromethanesulfonate To a solution of 5-(pyrimidin-2-yl)pyridin-3-ol (2.00 g) and TEA (2.10 mL) in dichloromethane (38 mL) obtained in Step 2, trifluoromethanesulfonic anhydride (2.27 mL) was added dropwise under ice-cooling, and the mixture was stirred at the same temperature for 1 h. The residue obtained by concentrating the reaction solution under reduced pressure was purified by silica gel column chromatography to obtain the title compound (770 mg). MS (m / z): 306.4 [M+H] + [Step 4] Production of 2-{5-[(trimethylsilyl)ethynyl]pyridin-3-yl}pyrimidine According to the method according to Step 1 of Reference Example 8, instead of methyl 4-chloro-3-iodobenzoate, 5-(pyrimidin-2-yl)pyridin-3-yl trifluoromethanesulfonate (770 mg) obtained in Step 3 was used to obtain the title compound (570 mg). MS (m / z): 254.5 [M+H] + [Step 5] Production of 2-(5-ethynylpyridin-3-yl)pyrimidine According to the method according to Step 2 of Reference Example 8, instead of methyl 4-chloro-3-[(trimethylsilyl)ethynyl]benzoate, 2-{5-[(trimethylsilyl)ethynyl]pyridin-3-yl}pyrimidine (570 mg) obtained in Step 4 was used to obtain 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 According to the method according to Reference Example 7, instead of 3-amino-4-methylbenzoic acid, 3-bromo-4-chlorobenzoic acid (250 mg) was used to obtain 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, sealed using a stainless steel pressure-resistant container, and stirred at 120 °C for 8 hours. The reaction solution was diluted with ethyl acetate, washed with water and saturated brine, and then the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain the title compound (400 mg). Reference Example 13 5-Ethynyl-N-[(1S,2S)-2-hydroxycyclohexyl]-6-methylpyridine-3-carboxamide [Step 1] Production of 5-bromo-N-[(1S,2S)-2-hydroxycyclohexyl]-6-methylpyridine-3-carboxamide According to the method according to Reference Example 7, instead of 3-amino-4-methylbenzoic acid, 5-bromo-6-methylpyridine-3-carboxylic acid (250 mg) was used to obtain the title compound (380 mg). MS (m / z): 313.4 [M+H] + [Step 2] Preparation of N-[(1S,2S)-2-hydroxycyclohexyl]-6-methyl-5-[(trimethylsilyl)ethynyl]pyridine-3-carboxamide According to the method similar to Step 1 of Reference Example 8, instead of methyl 4-chloro-3-iodobenzoate, 5-bromo-N-[(1S,2S)-2-hydroxycyclohexyl]-6-methylpyridine-3-carboxamide (100 mg) obtained in Step 1 was used to obtain 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 According to the method similar to Step 2 of Reference Example 8, instead of methyl 4-chloro-3-[(trimethylsilyl)ethynyl]benzoate, N-[(1S,2S)-2-hydroxycyclohexyl]-6-methyl-5-[(trimethylsilyl)ethynyl]pyridine-3-carboxamide (40 mg) obtained in Step 2 was used to obtain the title compound (23 mg). MS (m / z): 259.5 [M+H] + Reference Example 14 2-(Isoquinolin-4-yl)pyrimidin-4-amine To 2-chloropyrimidin-4-amine (200 mg), isoquinolin-4-ylboronic acid (294 mg), 1M aqueous sodium carbonate solution (3.1 mL) and Pd(dppf)Cl2·CH2Cl2 (126 mg), 1,4-dioxane (5 mL) was added. After degassing, it was replaced with argon and stirred at 90 °C for 2 hours under an argon atmosphere. The residue obtained by concentrating the reaction solution under reduced pressure was purified by silica gel column chromatography to obtain the title compound (300 mg). Reference Example 15 (1S)-1-(5-Phenylpyridin-3-yl)ethan-1-amine According to the method similar to Reference Example 14, instead of 2-chloropyrimidin-4-amine and isoquinolin-4-ylboronic acid, (1S)-1-(5-bromopyridin-3-yl)ethane-1-amine hydrochloride (300 mg) and phenylboronic acid (185 mg) were used to obtain 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] Production 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), tetraethyl orthotitanate (57 g) was added, and the mixture was stirred at 65 °C overnight. The reaction solution was diluted with ethyl acetate and water was added. The reaction solution was filtered through Celite (registered trademark), and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (34 g). MS (m / z): 303.0 [M+H] + [Step 2] Production of (SS)-N-[(1S)-1-(5-bromopyridin-3-yl)ethyl]-2-methylpropane-2-sulfinamide A suspension of dichloro(p-cymene)ruthenium(II), dimer (6.86 g), 2-amino-2-methyl-1-propanol (2.14 mL), and molecular sieve 4A (34 g) in 2-propanol (560 mL) was stirred at 80 °C for 30 minutes under an argon atmosphere. Then, while stirring the reaction solution 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 solution was filtered through Celite (registered trademark), and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (24.2 g). MS (m / z): 305.1 [M+H] + [Step 3] Production of (SS)-N-[(1S)-1-([3,3'-bipyridin]-5-yl)ethyl]-2-methylpropane-2-sulfinamide According to the method according to Reference Example 14, instead of 2-chloropyrimidin-4-amine and isoquinolin-4-ylboronic acid, (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 to obtain the title compound (22.7 g). MS (m / z): 304.2 [M+H] + [Step 4] Production 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 (2M methanol solution, 5.46 mL) was added under ice-cooling, and the mixture was stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by column chromatography using amino-modified spherical silica gel to obtain the title compound (12.9 g). MS (m / z): 200.2 [M+H] + Reference Example 17 (1S)-1-[5-(Phenylethynyl)pyridin-3-yl]ethan-1-amine dihydrochloride [Step 1] Production of (SS)-2-methyl-N-{(1S)-1-[5-(phenylethynyl)pyridin-3-yl]ethyl}propane-2-sulfinamide According to the method according to Step 1 of Reference Example 8, 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] Production of (1S)-1-[5-(phenylethynyl)pyridin-3-yl]ethan-1-amine dihydrochloride To a solution of (SS)-2-methyl-N-{(1S)-1-[5-(phenylethynyl)pyridin-3-yl]ethyl}propan-2-sulfinamide (530 mg) in methanol (8.1 mL) obtained in Step 1, hydrogen chloride (2 M methanol solution, 0.18 mL) was added under ice-cooling, and the mixture was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure, ethyl acetate was added to the obtained residue to suspend it, and the precipitate was collected by filtration to obtain the title compound (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}propan-2-sulfinamide According to the method according to Step 1 of Reference Example 10, instead of 3-bromo-5-(methoxymethoxy)pyridine, (SS)-N-[(1S)-1-(5-bromopyridin-3-yl)ethyl]-2-methylpropan-2-sulfinamide (600 mg) obtained in Step 2 of Reference Example 16 was used to obtain 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 According to the method according to Step 4 of Reference Example 16, instead of (SS)-N-[(1S)-1-([3,3'-bipyridin]-5-yl)ethyl]-2-methylpropan-2-sulfinamide, (SS)-2-methyl-N-{(1S)-1-[5-(pyrimidin-2-yl)pyridin-3-yl]ethyl}propan-2-sulfinamide (420 mg) obtained in Step 1 was used to obtain 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 To a solution of pyrazolo[5,1-b][1,3]thiazole-7-carboxylic acid (100 mg) in THF (2 mL) was added lithium aluminum hydride (1 M hexane solution, 1.5 mL), and the mixture was stirred at 50 °C for 5 hours. At 0 °C, methanol and sodium potassium L-(+)-tartrate tetrahydrate were added to the reaction mixture, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography to obtain the title compound (57 mg). MS (m / z): 155.3 [M+H] + [Step 2] Production of pyrazolo[5,1-b][1,3]thiazole-7-carbaldehyde To a solution of (pyrazolo[5,1-b][1,3]thiazol-7-yl)methanol (57 mg), obtained in Step 1, in THF (1.2 mL) was added manganese dioxide (160 mg), and the mixture was stirred at room temperature overnight. The reaction mixture was filtered to remove insoluble materials, and then the filtrate was concentrated under reduced pressure to obtain the title compound (42 mg). Reference Example 20 5-Amino-N-[(1S,2S)-2-hydroxycyclohexyl]-6-methylpyridine-3-carboxamide According to the method according to Reference Example 7, 5-amino-6-methylpyridine-3-carboxylic acid (915 mg) was used instead of 3-amino-4-methylbenzoic acid to obtain 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] Production of phenyl (5-formylpyridin-2-yl)carbamate To a solution of 6-aminopyridine-3-carbaldehyde (250 mg) in THF (5.1 mL) were added TEA (0.57 mL) and phenyl chloroformate (304 mg), and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography to obtain the title compound (246 mg). MS (m / z): 243.2 [M+H] + [Step 2] Production of N-(5-formylpyridin-2-yl)morpholine-4-carboxamide To a solution of phenyl (5-formylpyridin-2-yl)carbamate (40 mg) in NMP (0.34 mL) obtained in Step 1, morpholine (43 mg) and TEA (0.072 mL) were added, and the mixture was stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography to obtain the title compound (246 mg). MS (m / z): 236.1 [M+H] + Reference Example 22 N-Cyclopropyl-N'-(5-formylpyridin-2-yl)-N-methylurea According to the method according to Step 2 of Reference Example 21, N-methylcyclopropanamine (94 mg) was used instead of morpholine to obtain the title compound (21 mg). 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), Boc2O (0.19 mL) and DMAP (4.5 mg) were added, and the mixture was stirred at room temperature overnight. The residue obtained by concentrating the reaction solution under reduced pressure was purified by silica gel column chromatography to obtain 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 According to the method according to Reference Example 14, using 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 instead of 2-chloropyrimidin-4-amine and isoquinolin-4-ylboronic acid, the title compound (118 mg) was obtained. MS (m / z): 263.2 [M+H] + [Process 3] Production 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) in dichloromethane (2 mL) obtained in Process 2, O3 was bubbled at -78 °C over 30 minutes. Then, argon gas was bubbled into the solution until it became colorless, triphenylphosphine (142 mg) was added, and the mixture was stirred at room temperature overnight. Water was added to the reaction solution, and the mixture was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off 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 [Process 1] Production of 5-Ethenyl-2-(1H-1,2,3-triazol-1-yl)Pyridine According to the method according to Reference Example 14, instead of 2-chloropyrimidin-4-amine and isoquinolin-4-ylboronic acid, 5-bromo-2-(1H-1,2,3-triazol-1-yl)pyridine (142 mg) (synthesized according to the method described in, for example, WO2006038100) and 2-ethenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (117 mg) were used to obtain the title compound (90 mg). MS (m / z): 173.1 [M+H] + [Process 2] Production of 6-(1H-1,2,3-triazol-1-yl)Pyridine-3-Carbaldehyde According to the method according to Step 3 of Reference Example 23, instead of tert-butyl 7-ethenyl-2,3-dihydro-4H-pyrido[3,2-b][1,4]oxazine-4-carboxylate, 5-ethenyl-2-(1H-1,2,3-triazol-1-yl)pyridine (90 mg) obtained in Process 1 was used to obtain the title compound (306 mg) as a crude product. MS (m / z): 175.1 [M+H] + Reference Example 25 5-(2H-1,2,3-Triazol-2-yl)pyridine-3-carbaldehyde [Process 1] Production of [5-(2H-1,2,3-triazol-2-yl)Pyridin-3-yl]Methanol To a solution of methyl 5-(2H-1,2,3-triazol-2-yl)pyridine-3-carboxylate (44 mg) (synthesized according to the method described in, for example, Angew. Chem. Int. Ed. 2011, 50, 8944 - 8947) in methanol (2.2 mL) was added sodium borohydride (41 mg), and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound. [Step 2] Production of 5-(2H-1,2,3-triazol-2-yl)pyridine-3-carbaldehyde According to the method similar to that in Step 2 of Reference Example 19, instead of (pyrazolo[5,1-b][1,3]thiazol-7-yl)methanol, [5-(2H-1,2,3-triazol-2-yl)pyridin-3-yl]methanol obtained in Step 1 was used to obtain the title compound (22 mg).

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

[0224] Reference Example 31 Methyl 4-chloro-3-(hydroxymethyl)benzoate Sodium borohydride (38 mg) was added to a solution of methyl 4-chloro-3-formylbenzoate (200 mg) in methanol (3.4 mL) - THF (3.4 mL) at 0 °C, and the mixture was stirred at room temperature overnight. Water was added to the reaction solution, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (130 mg). Reference Example 32 Methyl 3-[(ethylamino)methyl]-4-methylbenzoate Ethylamine (2M methanol solution, 2.8 mL) was added to a solution of methyl 3-formyl-4-methylbenzoate (500 mg) in methanol (11 mL), and the mixture was stirred at room temperature for 30 minutes. Then, sodium borohydride (159 mg) was added, and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction solution, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (423 mg). MS (m / z): 208.2 [M+H] + Reference Example 33 Ethyl 5-formyl-6-methylpyridine-3-carboxylate [Step 1] Preparation of Ethyl 5-ethenyl-6-methylpyridine-3-carboxylate According to the method similar to Reference Example 14, instead of 2-chloropyrimidin-4-amine and isoquinolin-4-ylboronic acid, 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 to obtain the title compound (3.0 g). MS (m / z): 192.1 [M+H] + [Step 2] Preparation of Ethyl 5-formyl-6-methylpyridine-3-carboxylate According to the method similar to Step 3 of Reference Example 23, instead of tert-butyl 7-ethenyl-2,3-dihydro-4H-pyrido[3,2-b][1,4]oxazine-4-carboxylate, ethyl 5-ethenyl-6-methylpyridine-3-carboxylate (3.0 g) obtained in Step 1 was used to obtain 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) were added acetic acid (0.15 mL) and 1-methylpiperazine (808 mg), and the mixture was stirred at room temperature for 1 hour. Then, sodium triacetoxyborohydride (1.14 g) was added, and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction solution, and the solvent was distilled off 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 According to the method similar to Reference Example 34, instead of 1-methylpiperazine, morpholine (703 mg) was used to obtain 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 According to the method according to Step 1 of Reference Example 1, instead of methyl 5-bromopyridine-3-carboxylate and 1-cyclopropylmethanamine, 3,5-dibromopyridine and oxan-4-amine (256 mg) were used to obtain 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 According to the method according to Step 1 of Reference Example 1, instead of methyl 5-bromopyridine-3-carboxylate and 1-cyclopropylmethanamine, 3,5-dibromopyridine and 1-methylpiperidin-4-amine (304 mg) were used to obtain the title compound (300 mg). MS (m / z): 270.1 [M+H] + Reference Example 38 1-[(5-Bromopyridin-3-yl)methyl]-4-ethylpiperazine According to the method according to Reference Example 34, instead of 1-methylpiperazine, 1-ethylpiperazine (921 mg) was used to obtain the title compound (680 mg). MS (m / z): 284.1 [M+H] + Reference Example 39 5-Bromo-N-(oxetan-3-yl)pyridin-3-amine According to the method according to Step 1 of Reference Example 1, instead of methyl 5-bromopyridine-3-carboxylate and 1-cyclopropylmethanamine, 3,5-dibromopyridine (1.00 g) and oxetan-3-amine (309 mg) were used to obtain 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] Production of benzyl 2-[bis(tert-butoxycarbonyl)amino]-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate According to the method according to Step 1 of Reference Example 23, instead of 7-bromo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine, benzyl 2-amino-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate (600 mg) was used to obtain the title compound (960 mg). [Process 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) obtained in Process 1, after degassing, 5% Pd-C (400 mg) was added while stirring at room temperature under an argon atmosphere, and the mixture was stirred for 4 hours at room temperature under a hydrogen atmosphere. After filtering the reaction solution through Celite (registered trademark), the solvent was distilled off under reduced pressure to obtain 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 the mixture was stirred overnight at room temperature. The reaction solution was diluted with ethyl acetate, washed with water and saturated brine, and then the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain the title compound (661 mg). MS (m / z): 363.3 [M+H] + Reference Example 42 Methyl 3-(aminomethyl)-4-methylbenzoate [Process 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 the mixture was stirred at 50 °C for 2 hours. The reaction solution was concentrated under reduced pressure, ethyl acetate was added to the obtained residue, and the organic layer was washed with water and saturated brine. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain the title compound (1.02 g). MS (m / z): 194.4 [M+H] + [Process 2] Preparation of Methyl 3-(aminomethyl)-4-methylbenzoate To methyl 3-[(hydroxyimino)methyl]-4-methylbenzoate (1.02 g) obtained in Step 1, hydrogen chloride (2 M methanol solution, 15 mL) was added. After degassing, 5% Pd-C (500 mg) was added while stirring at room temperature under an argon atmosphere, and the mixture was stirred for 3 hours at room temperature under a hydrogen atmosphere. The reaction solution was filtered through Celite (registered trademark), and then the solvent was distilled off under reduced pressure. An aqueous sodium hydroxide solution was added to the obtained residue to make it basic, and then it was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure to obtain the title compound (820 mg). MS (m / z): 180.4 [M+H] + Reference Example 43 3-Bromo-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide According to the method according to Reference Example 7, 3-bromo-4-methylbenzoic acid (16.6 g) was used instead of 3-amino-4-methylbenzoic acid to obtain 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] Production of methyl 3-[(2-bromo-1,3-thiazole-5-carbonyl)amino]-4-methylbenzoate To a solution of 2-bromo-1,3-thiazole-5-carboxylic acid (2.20 g) in DMF (20 mL), methyl 3-amino-4-methylbenzoate (1.75 g), HATU (4.83 g), and DIPEA (3.66 mL) were sequentially added, and the mixture was stirred at room temperature for 6 hours. The reaction solution was diluted with ethyl acetate, and the organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and saturated brine. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (1.02 g). [Step 2] Production of methyl 3-{[2-(cyclopropylamino)-1,3-thiazole-5-carbonyl]amino}-4-methylbenzoate To a solution of methyl 3-[(2-bromo-1,3-thiazole-5-carbonyl)amino]-4-methylbenzoate (150 mg) in NMP (0.5 mL) obtained in Step 1, cyclopropanamine (121 mg) was added, and the mixture was stirred at 80 °C for 6 hours. After allowing the reaction solution to cool, it was purified by silica gel column chromatography to obtain the title compound (105 mg). [Step 3] Production of 3-{[2-(cyclopropylamino)-1,3-thiazole-5-carbonyl]amino}-4-methylbenzoic acid According to the method according to Step 2 of Reference Example 1, instead of methyl 5-[(cyclopropylmethyl)amino]pyridine-3-carboxylate, methyl 3-{[2-(cyclopropylamino)-1,3-thiazole-5-carbonyl]amino}-4-methylbenzoate (103 mg) obtained in Step 2 was used to obtain the title compound (90 mg). [Step 4] Production of 2-(cyclopropylamino)-N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)-1,3-thiazole-5-carboxamide To a solution of 3-{[2-(cyclopropylamino)-1,3-thiazole-5-carbonyl]amino}-4-methylbenzoic acid (30 mg) obtained in Step 3 in DMF (1 mL), HATU (54 mg) and DIPEA (0.065 mL) were sequentially added, and the mixture was stirred at room temperature for 10 minutes. Then, (1S,2S)-2-aminocyclohexan-1-ol hydrochloride (22 mg) was added, and the mixture was stirred at room temperature for 1 hour. The reaction solution was diluted with ethyl acetate, and the organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and saturated brine. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (16 mg). Example 2 N-(5-{[(1S,2S)-2-Hydroxycyclohexyl]carbamoyl}-2-methylphenyl)-5-phenylpyridine-3-carboxamide [Step 1] Production of methyl 3-[(5-bromopyridine-3-carbonyl)amino]-4-methylbenzoate According to the method according to Step 1 of Example 1, instead of 2-bromo-1,3-thiazole-5-carboxylic acid, 5-bromopyridine-3-carboxylic acid (1.00 g) was used to obtain the title compound (1.70 g). MS (m / z): 349.0 [M+H] + [Step 2] Production of 3-[(5-bromopyridine-3-carbonyl)amino]-4-methylbenzoic acid According to the method according to Step 2 of Reference Example 1, instead of methyl 5-[(cyclopropylmethyl)amino]pyridine-3-carboxylate, methyl 3-[(5-bromopyridine-3-carbonyl)amino]-4-methylbenzoate (650 mg) obtained in Step 1 was used to obtain the title compound (505 mg). MS (m / z): 335.0 [M+H] + [Step 3] Production of 5-bromo-N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)pyridine-3-carboxamide According to the method according to Step 4 of Example 1, instead of 3-{[2-(cyclopropylamino)-1,3-thiazole-5-carbonyl]amino}-4-methylbenzoic acid, 3-[(5-bromopyridine-3-carbonyl)amino]-4-methylbenzoic acid (505 mg) obtained in Step 2 was used to obtain the title compound (650 mg). MS (m / z): 432.1 [M+H] + [Step 4] Production of N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)-5-phenylpyridine-3-carboxamide According to the method according to Reference Example 14, instead of 2-chloropyrimidin-4-amine and isoquinolin-4-ylboronic acid, 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 were used to obtain the title compound (40 mg). 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 According to the method according to Step 1 of Example 1, instead of 2-bromo-1,3-thiazole-5-carboxylic acid, 2-(Cyclopropylmethyl)-1,3-thiazole-5-carboxylic acid (100 mg) was used to obtain 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 According to the method according to Step 2 of Reference Example 1, instead of Methyl 5-[(Cyclopropylmethyl)amino]pyridine-3-carboxylate, Methyl 3-{[2-(Cyclopropylmethyl)-1,3-thiazole-5-carbonyl]amino}-4-methylbenzoate (160 mg) obtained in Step 1 was used to obtain 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 According to the method according to Step 4 of Example 1, instead of 3-{[2-(Cyclopropylamino)-1,3-thiazole-5-carbonyl]amino}-4-methylbenzoic acid, 3-{[2-(Cyclopropylmethyl)-1,3-thiazole-5-carbonyl]amino}-4-methylbenzoic acid (40 mg) obtained in Step 2 was used 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 According to the method according to Step 1 of Example 1, instead of 2-bromo-1,3-thiazole-5-carboxylic acid and Methyl 3-amino-4-methylbenzoate, 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 to obtain the title compound (53 mg).

[0228] Example 6 N-(5-{[(1S)-2-Hydroxy-1-phenylethyl]carbamoyl}-2-methylphenyl)-5-phenylpyridine-3-carboxamide [Step 1] Production of Methyl 4-Methyl-3-[(5-phenylpyridine-3-carbonyl)amino]benzoate According to the method according to Reference Example 14, instead of 2-chloropyrimidin-4-amine and isoquinolin-4-ylboronic acid, 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 to obtain the title compound (1.00 g). MS (m / z): 347.2 [M+H] + [Step 2] Production of 4-Methyl-3-[(5-phenylpyridine-3-carbonyl)amino]benzoic Acid According to the method according to Step 2 of Reference Example 1, instead of methyl 5-[(cyclopropylmethyl)amino]pyridine-3-carboxylate, methyl 4-methyl-3-[(5-phenylpyridine-3-carbonyl)amino]benzoate (1.00 g) obtained in Step 1 was used to obtain the title compound (910 mg). MS (m / z): 333.2 [M+H] + [Step 3] Production of N-(5-{[(1S)-2-Hydroxy-1-phenylethyl]carbamoyl}-2-methylphenyl)-5-phenylpyridine-3-carboxamide According to the method according to Step 4 of Example 1, instead of 3-{[2-(cyclopropylamino)-1,3-thiazole-5-carbonyl]amino}-4-methylbenzoic acid and (1S,2S)-2-aminocyclohexan-1-ol hydrochloride, 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 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 According to the method according to Step 1 of Example 1, instead of 2-bromo-1,3-thiazole-5-carboxylic acid and methyl 3-amino-4-methylbenzoate, 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 to obtain the title compound (43 mg). Example 20 5-(3-Fluorophenyl)-N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)pyridine-3-carboxamide According to the method according to Reference Example 14, instead of 2-chloropyrimidin-4-amine and isoquinolin-4-ylboronic acid, 5-bromo-N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)pyridine-3-carboxamide (61 mg) obtained in Step 3 of Example 2 and (3-fluorophenyl)boronic acid (28 mg) were used to obtain the title compound (43 mg). Example 24 5-(Cyclopropylmethoxy)-N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)pyridine-3-carboxamide According to the method according to Step 1 of Example 1, instead of 2-bromo-1,3-thiazole-5-carboxylic acid and methyl 3-amino-4-methylbenzoate, 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 to obtain the title compound (58 mg). Example 26 2-[(2-Cyclopropylethyl)amino]-N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)-1,3-thiazole-5-carboxamide [Step 1] Production of methyl 3-[(2-chloro-1,3-thiazole-5-carbonyl)amino]-4-methylbenzoate To a solution of methyl 3-amino-4-methylbenzoate (6.89 g) in THF (80 mL), a solution of 2-chloro-1,3-thiazole-5-carbonyl chloride (8.31 g) in THF (80 mL) was added dropwise under ice-cooling and stirring, and the mixture was stirred at the same temperature for 30 minutes. The reaction solution was diluted with ethyl acetate, and the organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and saturated brine. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. Water was added to the obtained residue to suspend it, and the precipitate was collected by filtration to obtain 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 According to the method similar to Step 2 of Reference Example 1, instead of methyl 5-[(cyclopropylmethyl)amino]pyridine-3-carboxylate, methyl 3-[(2-chloro-1,3-thiazole-5-carbonyl)amino]-4-methylbenzoate (12.5 g) obtained in Step 1 was used to obtain 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 According to the method similar to Step 4 of Example 1, instead of 3-{[2-(cyclopropylamino)-1,3-thiazole-5-carbonyl]amino}-4-methylbenzoic acid, 3-[(2-chloro-1,3-thiazole-5-carbonyl)amino]-4-methylbenzoic acid (7.5 g) obtained in Step 2 was used to obtain 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 According to the method similar to Step 2 of Example 1, instead of methyl 3-[(2-bromo-1,3-thiazole-5-carbonyl)amino]-4-methylbenzoate and cyclopropanamine, 2-chloro-N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)-1,3-thiazole-5-carboxamide (90 mg) and 2-cyclopropylethane-1-amine (249 mg) obtained in Step 3 were used 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 According to the method according to Step 1 of Reference Example 8, instead of ethynyl(trimethyl)silane and methyl 4-chloro-3-iodobenzoate, methyl 4-chloro-3-ethynylbenzoate (1.01 g) obtained in Reference Example 8 and 3-bromo-5-iodopyridine (1.47 g) were used to obtain the title compound (1.60 g). MS(m / z): 350.0 [M+H] + [Step 2] Production of 3-[(5-bromopyridin-3-yl)ethynyl]-4-chlorobenzoic acid According to the method according to Step 2 of Reference Example 1, instead of methyl 5-[(cyclopropylmethyl)amino]pyridine-3-carboxylate, methyl 3-[(5-bromopyridin-3-yl)ethynyl]-4-chlorobenzoate (600 mg) obtained in Step 1 was used to obtain the title compound (360 mg). MS(m / z): 335.9 [M+H] + [Step 3] Production of 3-[(5-bromopyridin-3-yl)ethynyl]-4-chloro-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide According to the method according to Step 4 of Example 1, instead of 3-{[2-(cyclopropylamino)-1,3-thiazole-5-carbonyl]amino}-4-methylbenzoic acid, 3-[(5-bromopyridin-3-yl)ethynyl]-4-chlorobenzoic acid (370 mg) obtained in Step 2 was used to obtain the title compound (170 mg). Example 58 4-Chloro-N-[(1S,2S)-2-hydroxycyclohexyl]-3-[(5-phenylpyridin-3-yl)ethynyl]benzamide According to the method according to Reference Example 14, instead of 2-chloropyrimidin-4-amine and isoquinolin-4-ylboronic acid, 3-[(5-bromopyridin-3-yl)ethynyl]-4-chloro-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide (50 mg) obtained in Example 57 and phenylboronic acid (15 mg) were used to obtain the title compound (5 mg). Example 59 N-[(1S,2S)-2-Hydroxycyclohexyl]-4-methyl-3-[(5-methylpyridin-3-yl)ethynyl]benzamide According to the method according to Step 1 of Reference Example 8, instead of ethynyl(trimethyl)silane and methyl 4-chloro-3-iodobenzoate, 3-ethynyl-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide (30 mg) obtained in Reference Example 9 and 3-bromo-5-methylpyridine (30 mg) were used to obtain the title compound (14 mg). Example 61 3-[(5-Bromopyridin-3-yl)ethynyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide According to the method according to Step 1 of Reference Example 8, instead of ethynyl(trimethyl)silane and methyl 4-chloro-3-iodobenzoate, 3-ethynyl-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide (20.5 g) obtained in Reference Example 9 and 3-bromo-5-iodopyridine (24.8 g) were used to obtain the title compound (14.5 g). Example 62 N-[(1S,2S)-2-Hydroxycyclohexyl]-4-methyl-3-{[5-(pyrimidin-2-yl)pyridin-3-yl]ethynyl}benzamide To 3-[(5-bromopyridin-3-yl)ethynyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide (30 mg) obtained in Example 61, 2-(tributylstannyl)pyrimidine (54 mg), Pd(PPh3)4 (17 mg), copper(I) iodide (7 mg), and cesium fluoride (22 mg) in DMF (0.5 mL) was added, and the mixture was reacted at 150 °C for 30 minutes in a microwave reactor. After allowing the reaction solution to cool, it was purified by silica gel column chromatography to obtain the title compound (15 mg).

[0230] Example 67 3-[(5-Cyclopropylpyridin-3-yl)ethynyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide According to the method according to Reference Example 14, instead of 2-chloropyrimidin-4-amine and isoquinolin-4-ylboronic acid, 3-[(5-bromopyridin-3-yl)ethynyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide (400 mg) obtained in Example 61 and cyclopropylboronic acid (249 mg) were used to obtain the title compound (250 mg). Example 76 3-[(5-Bromopyridin-3-yl)ethynyl]-N-[(1S,2S)-1,3-dihydroxy-1-phenylpropan-2-yl]-4-methylbenzamide [Step 1] Production of 3-[(5-bromopyridin-3-yl)ethynyl]-4-methylbenzoic acid According to the method according to Step 1 of Reference Example 8, instead of ethynyl(trimethyl)silane and methyl 4-chloro-3-iodobenzoate, 3-ethynyl-4-methylbenzoic acid (40 mg) and 3-bromo-5-iodopyridine (71 mg) were used to obtain the title compound (47 mg). MS(m / z): 316.2 [M+H] + [Step 2] Production of 3-[(5-bromopyridin-3-yl)ethynyl]-N-[(1S,2S)-1,3-dihydroxy-1-phenylpropan-2-yl]-4-methylbenzamide According to the method according to Step 4 of Example 1, instead of 3-{[2-(cyclopropylamino)-1,3-thiazole-5-carbonyl]amino}-4-methylbenzoic acid and (1S,2S)-2-aminocyclohexan-1-ol hydrochloride, 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 were used to obtain the title compound (28 mg). Example 77 N 1 -[(1S,2S)-2-Hydroxycyclohexyl]-4-methyl-N3-(5-phenylpyridin-3-yl)benzene-1,3-dicarboxamide [Step 1] Production of methyl 5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylbenzoate According to the method according to Step 4 of Example 1, instead of 3-{[2-(cyclopropylamino)-1,3-thiazole-5-carbonyl]amino}-4-methylbenzoic acid, 3-(methoxycarbonyl)-4-methylbenzoic acid (500 mg) was used to obtain the title compound (600 mg). MS(m / z): 292.3 [M+H] + [Step 2] Production of 5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylbenzoic acid According to the method according to Step 2 of Reference Example 1, instead of methyl 5-[(cyclopropylmethyl)amino]pyridine-3-carboxylate, methyl 5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylbenzoate (600 mg) obtained in Step 1 was used to obtain the title compound (430 mg). MS (m / z): 278.3 [M+H] + [Step 3] N 3 - (5-Bromopyridin-3-yl)-N1-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzene-1,3-dicarboxamide Production According to the method according to Step 1 of Example 1, instead of 2-bromo-1,3-thiazole-5-carboxylic acid and methyl 3-amino-4-methylbenzoate, 5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylbenzoic acid (200 mg) and 5-bromopyridin-3-amine (137 mg) obtained in Step 2 were used to obtain the title compound (166 mg). MS (m / z): 432.3 [M+H] + [Step 4] N 1 -[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-N3-(5-phenylpyridin-3-yl)benzene-1,3-dicarboxamide Production According to the method according to Reference Example 14, instead of 2-chloropyrimidin-4-amine and isoquinolin-4-ylboronic acid, N 3 -(5-Bromopyridin-3-yl)-N1-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzene-1,3-dicarboxamide (50 mg) and phenylboronic acid (17 mg) were used to obtain the title compound (40 mg). Example 78 N-[(1S,2S)-2-Hydroxycyclohexyl]-4-methyl-3-{[2-(pyridin-3-yl)pyrimidin-4-yl]amino}benzamide [Step 1] Production of methyl 4-methyl-3-{[2-(pyridin-3-yl)pyrimidin-4-yl]amino}benzoate According to the method according to Step 1 of Reference Example 1, instead of methyl 5-bromopyridine-3-carboxylate and 1-cyclopropylmethanamine, methyl 3-bromo-4-methylbenzoate (350 mg) and 2-(pyridin-3-yl)pyrimidin-4-amine (263 mg) were used to obtain the title compound (280 mg). [Step 2] Production of 4-methyl-3-{[2-(pyridin-3-yl)pyrimidin-4-yl]amino}benzoic acid According to the method according to Step 2 of Reference Example 1, instead of methyl 5-[(cyclopropylmethyl)amino]pyridine-3-carboxylate, methyl 4-methyl-3-{[2-(pyridin-3-yl)pyrimidin-4-yl]amino}benzoate (280 mg) obtained in Step 1 was used to obtain the title compound (180 mg). [Step 3] Production of N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-{[2-(pyridin-3-yl)pyrimidin-4-yl]amino}benzamide According to the method according to Step 4 of Example 1, instead of 3-{[2-(cyclopropylamino)-1,3-thiazole-5-carbonyl]amino}-4-methylbenzoic acid, 4-methyl-3-{[2-(pyridin-3-yl)pyrimidin-4-yl]amino}benzoic acid (50 mg) was used 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] Production of methyl 3-{2-[bis(tert-butoxycarbonyl)amino]-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl}-4-methylbenzoate According to the method according to Step 1 of Reference Example 1, instead of methyl 5-bromopyridine-3-carboxylate and 1-cyclopropylmethanamine, 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 to obtain the title compound (54 mg). MS (m / z): 499.6 [M+H] + [Process 2] Preparation of Methyl 3-(2-Amino-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-4-methylbenzoate To methyl 3-{2-[bis(tert-butoxycarbonyl)amino]-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl}-4-methylbenzoate (70 mg) obtained in Process 1 was added hydrogen chloride (2 M methanol solution, 2.1 mL), and the mixture was stirred at 50 °C for 5 hours. After allowing the reaction solution to cool, it was purified by silica gel column chromatography to obtain the title compound (10 mg). MS (m / z): 299.5 [M+H] + [Process 3] Preparation of 3-(2-Amino-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-4-methylbenzoic Acid According to the method analogous to Process 2 of Reference Example 1, methyl 3-(2-amino-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-4-methylbenzoate (10 mg) obtained in Process 2 was used instead of methyl 5-[(cyclopropylmethyl)amino]pyridine-3-carboxylate to obtain the title compound. MS (m / z): 285.3 [M+H] + [Process 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 According to the method analogous to Process 4 of Example 1, 3-(2-amino-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-4-methylbenzoic acid obtained in Process 3 and (1S,2S)-2-amino-1-phenylpropane-1,3-diol (11 mg) 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 (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 According to the method analogous to Step 1 of Reference Example 1, instead of methyl 5-bromopyridine-3-carboxylate and 1-cyclopropylmethanamine, 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 to obtain 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 According to the method analogous to Step 2 of Reference Example 1, instead of methyl 5-[(cyclopropylmethyl)amino]pyridine-3-carboxylate, methyl 4-methyl-3-{[(1S)-1-(5-phenylpyridin-3-yl)ethyl]amino}benzoate (220 mg) obtained in Step 1 was used to obtain 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 According to the method analogous to Step 4 of Example 1, instead of 3-{[2-(cyclopropylamino)-1,3-thiazole-5-carbonyl]amino}-4-methylbenzoic acid, 4-methyl-3-{[(1S)-1-(5-phenylpyridin-3-yl)ethyl]amino}benzoic acid (50 mg) obtained in Step 2 was used 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 According to the method according to Step 1 of Reference Example 1, instead of methyl 5-bromopyridine-3-carboxylate and 1-cyclopropylmethanamine, methyl 3-bromo-4-methylbenzoate (13.9 g) and (1S)-1-([3,3'-bipyridin]-5-yl)ethane-1-amine (11.0 g) obtained in Reference Example 16 were used to obtain the title compound (10.3 g). MS (m / z): 348.3 [M+H] + [Step 2] Production of 3-{[(1S)-1-([3,3'-bipyridin]-5-yl)ethyl]amino}-4-methylbenzoic acid According to the method according to Step 2 of Reference Example 1, instead of methyl 5-[(cyclopropylmethyl)amino]pyridine-3-carboxylate, methyl 3-{[(1S)-1-([3,3'-bipyridin]-5-yl)ethyl]amino}-4-methylbenzoate (10.3 g) obtained in Step 1 was used to obtain the title compound (8.7 g). MS (m / z): 334.4 [M+H] + [Step 3] Production of 3-{[(1S)-1-([3,3'-bipyridin]-5-yl)ethyl]amino}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide According to the method according to Step 4 of Example 1, instead of 3-{[2-(cyclopropylamino)-1,3-thiazole-5-carbonyl]amino}-4-methylbenzoic acid, 3-{[(1S)-1-([3,3'-bipyridin]-5-yl)ethyl]amino}-4-methylbenzoic acid (8.7 g) obtained in Step 2 was used 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] Production of methyl 3-{[(1R)-1-(5-bromopyridin-3-yl)ethyl]amino}-4-methylbenzoate According to the method according to Step 1 of Reference Example 1, instead of methyl 5-bromopyridine-3-carboxylate and 1-cyclopropylmethanamine, methyl 3-iodo-4-methylbenzoate (6.49 g) and (1S)-1-(5-bromopyridine-3-yl)ethane-1-amine (3.78 g) were used to obtain the title compound (1.80 g). MS (m / z): 349.0 [M+H] + [Step 2] Production of 3-{[(1R)-1-(5-bromopyridine-3-yl)ethyl]amino}-4-methylbenzoic acid According to the method according to Step 2 of Reference Example 1, instead of methyl 5-[(cyclopropylmethyl)amino]pyridine-3-carboxylate, methyl 3-{[(1R)-1-(5-bromopyridine-3-yl)ethyl]amino}-4-methylbenzoate (1.00 g) obtained in Step 1 was used to obtain the title compound (820 mg). MS (m / z): 335.1 [M+H] + [Step 3] Production of 3-{[(1S)-1-(5-bromopyridine-3-yl)ethyl]amino}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide According to the method according to Step 4 of Example 1, instead of 3-{[2-(cyclopropylamino)-1,3-thiazole-5-carbonyl]amino}-4-methylbenzoic acid, 3-{[(1R)-1-(5-bromopyridine-3-yl)ethyl]amino}-4-methylbenzoic acid (820 mg) obtained in Step 2 was used to obtain the title compound (920 mg). MS (m / z): 432.3 [M+H] + [Step 4] Production of 3-{[(1S)-1-([3,4'-bipyridine]-5-yl)ethyl]amino}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide According to the method according to Reference Example 14, instead of 2-chloropyrimidin-4-amine and isoquinolin-4-ylboronic acid, 3-{[(1S)-1-(5-bromopyridin-3-yl)ethyl]amino}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide (30 mg) obtained in Step 3 and pyridin-4-ylboronic acid (10 mg) were used to obtain the title compound (9 mg). 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 According to the method according to Step 1 of Reference Example 10, instead of 3-bromo-5-(methoxymethoxy)pyridine and 2-bromopyrimidine, methyl 3-{[(1R)-1-(5-bromopyridin-3-yl)ethyl]amino}-4-methylbenzoate (150 mg) obtained in Step 1 of Example 87 and 2-bromopyridine (170 mg) were used to obtain 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 According to the method according to Step 2 of Reference Example 1, instead of methyl 5-[(cyclopropylmethyl)amino]pyridine-3-carboxylate, methyl 3-{[(1S)-1-([2,3'-bipyridin]-5'-yl)ethyl]amino}-4-methylbenzoate (90 mg) obtained in Step 1 was used to obtain 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 According to the method according to Step 4 of Example 1, instead of 3-{[2-(cyclopropylamino)-1,3-thiazole-5-carbonyl]amino}-4-methylbenzoic acid, 3-{[(1S)-1-([2,3'-bipyridin]-5'-yl)ethyl]amino}-4-methylbenzoic acid (70 mg) obtained in Step 2 was used to obtain the title compound (10 mg). Example 91 3-{[(5-Bromopyridin-3-yl)methyl]amino}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide According to the method according to Reference Example 34, instead of 1-methylpiperazine, 3-amino-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide (1.6 g) obtained in Reference Example 7 was used to obtain the title compound (2.0 g).

[0232] Example 92 N-[(1S,2S)-2-Hydroxycyclohexyl]-4-methyl-3-{[(5-phenylpyridin-3-yl)methyl]amino}benzamide According to the method according to Reference Example 14, instead of 2-chloropyrimidin-4-amine and isoquinolin-4-ylboronic acid, 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 were used to obtain the title compound (23 mg). Example 94 3-({[5-(Cyclopropylethynyl)pyridin-3-yl]methyl}amino)-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide According to the method according to Step 1 of Reference Example 8, instead of ethynyl(trimethyl)silane and methyl 4-chloro-3-iodobenzoate, 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 to obtain the title compound (64 mg). Example 95 N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-({[5-(pyrimidin-2-yl)pyridin-3-yl]methyl}amino)benzamide [Step 1] Production of methyl 3-{[(5-bromopyridin-3-yl)methyl]amino}-4-methylbenzoate According to the method according to Reference Example 34, instead of 1-methylpiperazine, methyl 3-amino-4-methylbenzoate (9.0 g) was used to obtain the title compound (13.0 g). MS (m / z): 335.3 [M+H] + [Process 2] Preparation of methyl 4-methyl-3-({[5-(pyrimidin-2-yl)pyridin-3-yl]methyl}amino)benzoate According to the method similar to Step 1 of Reference Example 10, instead of 3-bromo-5-(methoxymethoxy)pyridine, methyl 3-{[(5-bromopyridin-3-yl)methyl]amino}-4-methylbenzoate (13.0 g) obtained in Step 1 was used to obtain the title compound (9.0 g). MS (m / z): 335.5 [M+H] + [Process 3] Preparation of 4-methyl-3-({[5-(pyrimidin-2-yl)pyridin-3-yl]methyl}amino)benzoic acid According to the method similar to Step 2 of Reference Example 1, instead of methyl 5-[(cyclopropylmethyl)amino]pyridine-3-carboxylate, methyl 4-methyl-3-({[5-(pyrimidin-2-yl)pyridin-3-yl]methyl}amino)benzoate (9.0 g) obtained in Step 2 was used to obtain the title compound (6.6 g). MS (m / z): 321.5 [M+H] + [Process 4] Preparation of N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-({[5-(pyrimidin-2-yl)pyridin-3-yl]methyl}amino)benzamide According to the method similar to Step 4 of Example 1, instead of 3-{[2-(cyclopropylamino)-1,3-thiazole-5-carbonyl]amino}-4-methylbenzoic acid, 4-methyl-3-({[5-(pyrimidin-2-yl)pyridin-3-yl]methyl}amino)benzoic acid (6.0 g) obtained in Step 3 was used to obtain the title compound (5.5 g). Example 96 N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-{[(quinolin-3-yl)methyl]amino}benzamide [Process 1] Preparation of methyl 4-methyl-3-{[(quinolin-3-yl)methyl]amino}benzoate According to the method similar to Reference Example 34, instead of 1-methylpiperazine and 5-bromopyridine-3-carbaldehyde, methyl 3-amino-4-methylbenzoate (210 mg) and quinoline-3-carbaldehyde (200 mg) were used to obtain the title compound (230 mg). [Step 2] Production of 4-Methyl-3-{[(quinolin-3-yl)methyl]amino}benzoic Acid According to the method analogous to Step 2 of Reference Example 1, instead of methyl 5-[(cyclopropylmethyl)amino]pyridine-3-carboxylate, methyl 4-methyl-3-{[(quinolin-3-yl)methyl]amino}benzoate (230 mg) obtained in Step 1 was used to obtain the title compound (200 mg). [Step 3] Production of N-[(1S,2S)-2-Hydroxycyclohexyl]-4-methyl-3-{[(quinolin-3-yl)methyl]amino}benzamide According to the method analogous to Step 4 of Example 1, instead of 3-{[2-(cyclopropylamino)-1,3-thiazole-5-carbonyl]amino}-4-methylbenzoic acid, 4-methyl-3-{[(quinolin-3-yl)methyl]amino}benzoic acid (40 mg) obtained in Step 2 was used 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 According to the method analogous to Step 1 of Reference Example 10, instead of 3-bromo-5-(methoxymethoxy)pyridine and 2-bromopyrimidine, 3-{[(5-bromopyridin-3-yl)methyl]amino}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide (80 mg) obtained in Example 91 and 2-(4-bromophenyl)propan-2-amine (49 mg) were used to obtain the title compound (41 mg).

[0233] Example 101 N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-{[(6-phenylpyrazin-2-yl)methyl]amino}benzamide [Step 1] Production of Methyl 3-{[(6-chloropyrazin-2-yl)methyl]amino}-4-methylbenzoate According to the method analogous to Reference Example 34, instead of 1-methylpiperazine and 5-bromopyridine-3-carbaldehyde, methyl 3-amino-4-methylbenzoate (449 mg) and 6-chloropyrazine-2-carbaldehyde (774 mg) were used to obtain the title compound (150 mg). [Step 2] Production of Methyl 4-Methyl-3-{[(6-phenylpyrazin-2-yl)methyl]amino}benzoate According to the method according to Reference Example 14, instead of 2-chloropyrimidin-4-amine and isoquinolin-4-ylboronic acid, methyl 3-{[(6-chloropyrazin-2-yl)methyl]amino}-4-methylbenzoate (70 mg) obtained in Step 1 and phenylboronic acid (35 mg) were used to obtain the title compound (66 mg). [Step 3] Production of 4-methyl-3-{[(6-phenylpyrazin-2-yl)methyl]amino}benzoic acid According to the method according to Step 2 of Reference Example 1, instead of methyl 5-[(cyclopropylmethyl)amino]pyridine-3-carboxylate, methyl 4-methyl-3-{[(6-phenylpyrazin-2-yl)methyl]amino}benzoate (66 mg) obtained in Step 2 was used to obtain the title compound (55 mg). [Step 4] Production of N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-{[(6-phenylpyrazin-2-yl)methyl]amino}benzamide According to the method according to Step 4 of Example 1, instead of 3-{[2-(cyclopropylamino)-1,3-thiazole-5-carbonyl]amino}-4-methylbenzoic acid, 4-methyl-3-{[(6-phenylpyrazin-2-yl)methyl]amino}benzoic acid (25 mg) obtained in Step 3 was used 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 According to the method according to Reference Example 34, instead of 1-methylpiperazine and 5-bromopyridine-3-carbaldehyde, 3-amino-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide (73 mg) obtained in Reference Example 7 and 1H-pyrazolo[3,4-b]pyridine-5-carbaldehyde (43 mg) were used to obtain the title compound (84 mg). Example 110 N-[(1S,2S)-2-hydroxycyclohexyl]-3-{[(imidazo[1,2-b]pyridazin-3-yl)methyl]amino}-4-methylbenzamide According to the method according to Reference Example 34, instead of 1-methylpiperazine and 5-bromopyridine-3-carbaldehyde, 3-amino-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide (24 mg) obtained in Reference Example 7 and imidazo[1,2-b]pyridazine-3-carbaldehyde (15 mg) were used to obtain the title compound (18 mg). 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 According to the method according to Reference Example 34, instead of 1-methylpiperazine and 5-bromopyridine-3-carbaldehyde, 3-amino-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide (513 mg) obtained in Reference Example 7 and 2-chloropyrimidine-5-carbaldehyde (310 mg) were used to obtain 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 To 3-{[(2-chloropyrimidin-5-yl)methyl]amino}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide (320 mg) obtained in Step 1, 1,4-dioxane (8 mL) and 28% aqueous ammonia solution (4 mL) were added, sealed in a stainless steel pressure vessel, and stirred at 100 °C for 8 hours. After allowing the reaction solution to cool, it was purified by silica gel column chromatography to obtain 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 According to the method according to Reference Example 34, instead of 1-methylpiperazine and 5-bromopyridine-3-carbaldehyde, 3-amino-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide (380 mg) obtained in Reference Example 7 and 6-bromopyridine-3-carbaldehyde (300 mg) were used to obtain the title compound (370 mg). MS (m / z): 418.5 [M+H] + [Step 2] Production of 3-{[(6-acetamidopyridin-3-yl)methyl]amino}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide According to the method according to Step 1 of Reference Example 1, instead of methyl 5-bromopyridine-3-carboxylate and 1-cyclopropylmethanamine, 3-{[(6-bromopyridin-3-yl)methyl]amino}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide (50 mg) obtained in Step 1 and acetamide (18 mg) were used to obtain the title compound (22 mg).

[0234] Example 118 3-{[([2,2’-Bipyridin]-5-yl)methyl]amino}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide According to the method according to Example 62, instead of 3-[(5-bromopyridin-3-yl)ethynyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide and 2-(tributylstannyl)pyrimidine, 3-{[(6-bromopyridin-3-yl)methyl]amino}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide (60 mg) obtained in Step 1 of Example 116 and 2-(tributylstannyl)pyridine (79 mg) were used 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), 1H-pyrazole (20 mg), copper(I) iodide (11 mg), potassium phosphate (91 mg), trans-N,N'-dimethylcyclohexane-1,2-diamine (0.014 mL) and DMF (0.36 mL), obtained in Step 1 of Example 116, was reacted in a microwave reactor at 100 °C for 30 minutes. To the reaction solution were added 1H-pyrazole (20 mg), copper(I) iodide (11 mg) and trans-N,N'-dimethylcyclohexane-1,2-diamine (0.014 mL), and the mixture was further reacted in a microwave reactor at 100 °C for 30 minutes. After allowing the reaction solution to cool, it was 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 According to the method according to Reference Example 34, using 3-amino-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide (203 mg) and 6-aminopyridin-3-carbaldehyde (100 mg), obtained in Reference Example 7, instead of 1-methylpiperazine and 5-bromopyridine-3-carbaldehyde, the title compound (149 mg) was obtained. 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), 3-isocyanatopyridine (14 mg), potassium carbonate (20 mg) and DMF (0.33 mL) obtained in Step 1 was reacted in a microwave reactor at 80 °C for 30 minutes. After allowing the reaction solution to cool, it was purified by silica gel column chromatography to obtain 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 To a solution of tert-butyl [5-(bromomethyl)pyrazin-2-yl]carbamate (1.44 g) and methyl 3-amino-4-methylbenzoate (561 mg) in DMF (12 mL) was added potassium carbonate (1.76 g), and the mixture was stirred at room temperature overnight. The reaction solution was diluted with ethyl acetate, washed with water and saturated brine, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain the title compound (360 mg). MS (m / z): 373.5 [M+H] + [Step 2] Preparation of 3-[({5-[(tert-butoxycarbonyl)amino]pyrazin-2-yl}methyl)amino]-4-methylbenzoic acid According to the method according to Step 2 of Reference Example 1, instead of methyl 5-[(cyclopropylmethyl)amino]pyridine-3-carboxylate, methyl 3-[({5-[(tert-butoxycarbonyl)amino]pyrazin-2-yl}methyl)amino]-4-methylbenzoate (160 mg) obtained in Step 1 was used to obtain 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 According to the method according to Step 4 of Example 1, instead of 3-{[2-(cyclopropylamino)-1,3-thiazole-5-carbonyl]amino}-4-methylbenzoic acid, 3-[({5-[(tert-butoxycarbonyl)amino]pyrazin-2-yl}methyl)amino]-4-methylbenzoic acid (125 mg) obtained in Step 2 was used to obtain 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 To a solution of tert-butyl {5-[(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylanilino)methyl]pyrazin-2-yl}carbamate (95 mg) obtained in Step 3 in dichloromethane (2 mL) was added trifluoroacetic acid (0.16 mL), and the mixture was stirred at room temperature for 2 hours. To the residue obtained by concentrating the reaction solution under reduced pressure were added methanol (2 mL) and 2M aqueous sodium hydroxide solution (2 mL), and the mixture was stirred at room temperature for 1 hour. The reaction solution was diluted with water and extracted with chloroform. The organic layer was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography to obtain the title compound (40 mg). 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 According to the method according to Reference Example 34, instead of 1-methylpiperazine and 5-bromopyridine-3-carbaldehyde, 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 to obtain the title compound (223 mg). MS (m / z): 469.4 [M+H] + [Process 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 By the method according to Step 1 of Example 1, instead of 2-bromo-1,3-thiazole-5-carboxylic acid and methyl 3-amino-4-methylbenzoate, (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 were used to obtain the title compound (60 mg). [Process 3] Preparation of N-[(1S,2S)-2-hydroxycyclohexyl]-3-{[(6-{[(1r,3r)-3-methoxycyclobutane-1-carbonyl]amino}pyridin-3-yl)methyl]amino}-4-methylbenzamide By the method according to Step 2 of Reference Example 8, instead of methyl 4-chloro-3-[(trimethylsilyl)ethynyl]benzoate, 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 was used to obtain the title compound (8 mg).

[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 By the method according to Reference Example 34, instead of 1-methylpiperazine and 5-bromopyridine-3-carbaldehyde, 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 were used to obtain the title compound (74 mg). 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 By the method according to Reference Example 34, using methyl 3-amino-4-chlorobenzoate (1.00 g) and 2-chloropyrimidine-5-carbaldehyde (806 mg) instead of 1-methylpiperazine and 5-bromopyridine-3-carbaldehyde, the title compound (376 mg) was obtained. MS (m / z): 312.3 [M+H] + [Step 2] Preparation of 3-{[(2-aminopyrimidin-5-yl)methyl]amino}-4-chlorobenzoic Acid To 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 solution (0.86 mL) were added, and the mixture was sealed in a stainless steel pressure vessel and stirred at 100 °C for 2 days. To the residue obtained by concentrating the reaction mixture under reduced pressure, ethanol (3.2 mL) and 2M aqueous sodium hydroxide solution (3.2 mL) were added, and the mixture was stirred at 90 °C overnight. The solvent was distilled off under reduced pressure, diluted with water, and neutralized by adding hydrochloric acid. The precipitated precipitate was collected by filtration to obtain 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 By the method according to Step 4 of Example 1, using 3-{[(2-aminopyrimidin-5-yl)methyl]amino}-4-chlorobenzoic acid (50 mg) obtained in Step 2 instead of 3-{[2-(cyclopropylamino)-1,3-thiazole-5-carbonyl]amino}-4-methylbenzoic acid, the title compound (36 mg) was obtained. 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 According to the method according to Reference Example 34, instead of 1-methylpiperazine and 5-bromopyridine-3-carbaldehyde, 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 were used to obtain 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) was added trifluoroacetic acid (0.7 mL), and the mixture was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography to obtain the title compound (37 mg). 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 According to the method according to Reference Example 34, instead of 1-methylpiperazine and 5-bromopyridine-3-carbaldehyde, 5-bromopyridin-3-amine (1.5 g) and methyl 3-formyl-4-methylbenzoate (1.5 g) were used to obtain 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 According to the method according to Step 1 of Reference Example 10, instead of 3-bromo-5-(methoxymethoxy)pyridine, methyl 3-{[(5-bromopyridin-3-yl)amino]methyl}-4-methylbenzoate (170 mg) obtained in Step 1 was used to obtain the title compound (35 mg). MS (m / z): 335.5 [M+H] + [Step 3] Production of 4-methyl-3-({[5-(pyrimidin-2-yl)pyridin-3-yl]amino}methyl)benzoic acid According to the method according to Step 2 of Reference Example 1, instead of methyl 5-[(cyclopropylmethyl)amino]pyridine-3-carboxylate, methyl 4-methyl-3-({[5-(pyrimidin-2-yl)pyridin-3-yl]amino}methyl)benzoate (35 mg) obtained in Step 2 was used to obtain the title compound (33 mg). MS (m / z): 321.5 [M+H] + [Step 4] Production of N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-({[5-(pyrimidin-2-yl)pyridin-3-yl]amino}methyl)benzamide According to the method according to Step 4 of Example 1, instead of 3-{[2-(cyclopropylamino)-1,3-thiazole-5-carbonyl]amino}-4-methylbenzoic acid, 4-methyl-3-({[5-(pyrimidin-2-yl)pyridin-3-yl]amino}methyl)benzoic acid (33 mg) obtained in Step 3 was used to obtain the title compound (6 mg). Example 148 3-{[([2,3’-Bipyridin]-5’-yl)amino]methyl}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide [Step 1] Production of 3-{[(5-bromopyridin-3-yl)amino]methyl}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide According to the method according to Reference Example 34, instead of 1-methylpiperazine and 5-bromopyridine-3-carbaldehyde, 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 to obtain 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 According to the method analogous to Step 1 of Reference Example 10, instead of 3-bromo-5-(methoxymethoxy)pyridine and 2-bromopyrimidine, 3-{[(5-bromopyridin-3-yl)amino]methyl}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide (80 mg) obtained in Step 1 and 2-bromopyridine (36 mg) were used to obtain the title compound (10 mg).

[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 According to the method analogous to Step 2 of Reference Example 1, instead of methyl 5-[(cyclopropylmethyl)amino]pyridine-3-carboxylate, methyl 3-{[(5-bromopyridin-3-yl)amino]methyl}-4-methylbenzoate (1.0 g) obtained in Step 1 of Example 147 was used to obtain 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 According to the method analogous to Step 4 of Example 1, instead of 3-{[2-(cyclopropylamino)-1,3-thiazole-5-carbonyl]amino}-4-methylbenzoic acid and (1S,2S)-2-aminocyclohexan-1-ol hydrochloride, 3-{[(5-bromopyridin-3-yl)amino]methyl}-4-methylbenzoic acid (350 mg) obtained in Step 1 and (1S,2S)-2-amino-1-phenylpropane-1,3-diol (219 mg) were used to obtain the title compound (500 mg). Example 153 N-[(1S,2S)-1,3-dihydroxy-1-phenylpropan-2-yl]-4-methyl-3-{[(5-phenylpyridin-3-yl)amino]methyl}benzamide According to the method according to Reference Example 14, instead of 2-chloropyrimidin-4-amine and isoquinolin-4-ylboronic acid, 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 were used to obtain the title compound (29 mg). Example 155 3-{[([2,3’-Bipyridin]-5’-yl)amino]methyl}-N-[(1S,2S)-1,3-dihydroxy-1-phenylpropan-2-yl]-4-methylbenzamide According to the method according to Example 62, instead of 3-[(5-bromopyridin-3-yl)ethynyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide and 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] Production of methyl 3-{[(6-chloropyrazin-2-yl)amino]methyl}-4-methylbenzoate A mixture of 2,6-dichloropyrazine (300 mg), methyl 3-(aminomethyl)-4-methylbenzoate (397 mg) obtained in Reference Example 42, NMP (4 mL) and DIPEA (1.05 mL) was stirred at 100 °C for 4 hours. The reaction solution was diluted with ethyl acetate, and the organic layer was washed with water and saturated brine. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography to obtain the title compound (423 mg). MS (m / z): 292.5 [M+H] + [Step 2] Production of 3-{[(6-chloropyrazin-2-yl)amino]methyl}-4-methylbenzoic acid According to the method according to Step 2 of Reference Example 1, instead of methyl 5-[(cyclopropylmethyl)amino]pyridine-3-carboxylate, methyl 3-{[(6-chloropyrazin-2-yl)amino]methyl}-4-methylbenzoate (580 mg) obtained in Step 1 was used to obtain 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 According to the method according to Step 4 of Example 1, instead of 3-{[2-(cyclopropylamino)-1,3-thiazole-5-carbonyl]amino}-4-methylbenzoic acid and (1S,2S)-2-aminocyclohexan-1-ol hydrochloride, 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 to obtain 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 According to the method according to Reference Example 14, instead of 2-chloropyrimidin-4-amine and isoquinolin-4-ylboronic acid, 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 were used to obtain the title compound (36 mg). 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 According to the method according to Step 3 of Example 156, 3-(aminomethyl)aniline (1.23 g) was used instead of methyl 3-(aminomethyl)-4-methylbenzoate to obtain the title compound (1.22 g). [Step 2] Production of N-[(3-aminophenyl)methyl]-6-(3,4-dimethoxyphenyl)pyrazine-2-amine According to the method according to Reference Example 14, N-[(3-aminophenyl)methyl]-6-chloropyrazine-2-amine (160 mg) and (3,4-dimethoxyphenyl)boronic acid (149 mg) obtained in Step 1 were used instead of 2-chloropyrimidin-4-amine and isoquinolin-4-ylboronic acid to obtain the title compound (190 mg). [Step 3] Production of N-[3-({[6-(3,4-dimethoxyphenyl)pyrazin-2-yl]amino}methyl)phenyl]-N'-[(1R,2S)-2-hydroxycyclohexyl]urea To N-[(3-aminophenyl)methyl]-6-(3,4-dimethoxyphenyl)pyrazine-2-amine (40 mg) obtained in Step 2, THF (1 mL), TEA (0.20 mL), and triphosgene (18 mg) were added, and the mixture was stirred at room temperature for 10 minutes. Then, (1S,2R)-2-aminocyclohexan-1-ol hydrochloride (180 mg) was added, and the mixture was stirred at the same temperature for 2 hours. The reaction solution was purified by silica gel column chromatography to obtain the title compound (37 mg).

[0237] Example 159 N-[(1R,2S)-2-hydroxycyclohexyl]-N’-[3-({[5-(pyrimidin-2-yl)pyridin-3-yl]amino}methyl)phenyl]urea [Step 1] Production of N-[(3-nitrophenyl)methyl]-5-(pyrimidin-2-yl)pyridin-3-amine According to the method according to Reference Example 34, 5-(pyrimidin-2-yl)pyridin-3-amine (100 mg) and 3-nitrobenzaldehyde (88 mg) obtained in Reference Example 27 were used instead of 1-methylpiperazine and 5-bromopyridine-3-carbaldehyde to obtain the title compound (40 mg). [Step 2] Production 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) in methanol (5 mL) and THF (5 mL) obtained in Step 1, after degassing, 10% Pd-C (50 mg) was added under an argon atmosphere while stirring at room temperature, and the mixture was stirred for 4 hours at room temperature under a hydrogen atmosphere. The reaction solution was filtered through Celite (registered trademark), and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (20 mg). [Step 3] Production of N-[(1R,2S)-2-hydroxycyclohexyl]-N’-[3-({[5-(pyrimidin-2-yl)pyridin-3-yl]amino}methyl)phenyl]urea According to the method according to Step 3 of Example 158, instead of N-[(3-aminophenyl)methyl]-6-(3,4-dimethoxyphenyl)pyrazin-2-amine, N-[(3-aminophenyl)methyl]-5-(pyrimidin-2-yl)pyridin-3-amine (20 mg) obtained in Step 2 was used 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] Production of N-[(2-fluoro-5-nitrophenyl)methyl]-5-(pyrimidin-2-yl)pyridin-3-amine According to the method according to Reference Example 34, instead of 1-methylpiperazine and 5-bromopyridine-3-carbaldehyde, 5-(pyrimidin-2-yl)pyridin-3-amine (133 mg) and 2-fluoro-5-nitrobenzaldehyde (196 mg) obtained in Reference Example 27 were used to obtain the title compound (150 mg). [Step 2] Production of tert-butyl [(2-fluoro-5-nitrophenyl)methyl][5-(pyrimidin-2-yl)pyridin-3-yl]carbamate According to the method according to Step 1 of Reference Example 23, instead of 7-bromo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine, N-[(2-fluoro-5-nitrophenyl)methyl]-5-(pyrimidin-2-yl)pyridin-3-amine (150 mg) obtained in Step 1 was used to obtain the title compound (105 mg). [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) in ethanol (2 mL) - water (0.2 mL) obtained in Step 2 was added stannous(II) chloride dihydrate (221 mg), and the mixture was stirred at 65 °C for 2 hours. An aqueous sodium hydroxide solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain 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 According to the method according to Step 3 of Example 158, tert-butyl [(5-amino-2-fluorophenyl)methyl][5-(pyrimidin-2-yl)pyridin-3-yl]carbamate (70 mg) obtained in Step 3 was used instead of N-[(3-aminophenyl)methyl]-6-(3,4-dimethoxyphenyl)pyrazine-2-amine 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) in methanol (0.3 mL) was added hydrogen chloride (4M 1,4-dioxane solution, 1 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture 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 [Process 1] Preparation of methyl 3-{1-[(6-chloropyrazin-2-yl)amino]ethyl}-4-methylbenzoate By the method according to Step 3 of Example 156, instead of methyl 3-(aminomethyl)-4-methylbenzoate, methyl 3-(1-aminoethyl)-4-methylbenzoate (218 mg) was used to obtain the title compound (75 mg). [Process 2] Preparation of methyl 4-methyl-3-{1-[(6-phenylpyrazin-2-yl)amino]ethyl}benzoate By the method according to Reference Example 14, instead of 2-chloropyrimidin-4-amine and isoquinolin-4-ylboronic acid, methyl 3-{1-[(6-chloropyrazin-2-yl)amino]ethyl}-4-methylbenzoate (75 mg) and phenylboronic acid (36 mg) obtained in Step 1 were used to obtain the title compound (80 mg). [Process 3] Preparation of 4-methyl-3-{1-[(6-phenylpyrazin-2-yl)amino]ethyl}benzoic acid By the method according to Step 2 of Reference Example 1, instead of methyl 5-[(cyclopropylmethyl)amino]pyridine-3-carboxylate, methyl 4-methyl-3-{1-[(6-phenylpyrazin-2-yl)amino]ethyl}benzoate (77 mg) obtained in Step 2 was used to obtain the title compound (67 mg). [Process 4] Preparation of N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-{1-[(6-phenylpyrazin-2-yl)amino]ethyl}benzamide By the method according to Step 4 of Example 1, instead of 3-{[2-(cyclopropylamino)-1,3-thiazole-5-carbonyl]amino}-4-methylbenzoic acid, 4-methyl-3-{1-[(6-phenylpyrazin-2-yl)amino]ethyl}benzoic acid (30 mg) obtained in Step 3 was used to obtain the title compound (17 mg). Example 165 3-[([3,3’-Bipyridin]-5-yl)methoxy]-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide [Process 1] Preparation of methyl 3-[(5-bromopyridin-3-yl)methoxy]-4-methylbenzoate By the method according to Step 1 of Reference Example 3, instead of methyl 5-hydroxypyridine-3-carboxylate and 3,3-difluorocyclobutan-1-ol, methyl 3-hydroxy-4-methylbenzoate (750 mg) and (5-bromopyridin-3-yl)methanol (933 mg) were used to obtain the title compound (1.16 g). MS (m / z): 336.4 [M+H] + [Step 2] Production of methyl 3-[([3,3'-bipyridin]-5-yl)methoxy]-4-methylbenzoate By the method according to Reference Example 14, instead of 2-chloropyrimidin-4-amine and isoquinolin-4-ylboronic acid, methyl 3-[(5-bromopyridin-3-yl)methoxy]-4-methylbenzoate (150 mg) and pyridin-3-ylboronic acid (66 mg) obtained in Step 1 were used to obtain the title compound (103 mg). MS (m / z): 335.5 [M+H] + [Step 3] Production of 3-[([3,3'-bipyridin]-5-yl)methoxy]-4-methylbenzoic acid By the method according to Step 2 of Reference Example 1, instead of methyl 5-[(cyclopropylmethyl)amino]pyridine-3-carboxylate, methyl 3-[([3,3'-bipyridin]-5-yl)methoxy]-4-methylbenzoate (103 mg) obtained in Step 2 was used to obtain the title compound (100 mg). MS (m / z): 321.6 [M+H] + [Step 4] Production of 3-[([3,3'-bipyridin]-5-yl)methoxy]-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide By the method according to Step 4 of Example 1, instead of 3-{[2-(cyclopropylamino)-1,3-thiazole-5-carbonyl]amino}-4-methylbenzoic acid, 3-[([3,3'-bipyridin]-5-yl)methoxy]-4-methylbenzoic acid (50 mg) obtained in Step 3 was used 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 According to the method analogous to Step 1 of Reference Example 10, instead of 3-Bromo-5-(methoxymethoxy)pyridine, Methyl 3-[(5-bromopyridin-3-yl)methoxy]-4-methylbenzoate (250 mg) obtained in Step 1 of Example 165 was used to obtain 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 According to the method analogous to Step 2 of Reference Example 1, instead of Methyl 5-[(cyclopropylmethyl)amino]pyridine-3-carboxylate, Methyl 4-Methyl-3-{[5-(pyrimidin-2-yl)pyridin-3-yl]methoxy}benzoate (127 mg) obtained in Step 1 was used to obtain the title compound (101 mg). [Step 3] Preparation of N-[(1S,2S)-2-Hydroxycyclohexyl]-4-methyl-3-{[5-(pyrimidin-2-yl)pyridin-3-yl]methoxy}benzamide According to the method analogous to Step 4 of Example 1, instead of 3-{[2-(Cyclopropylamino)-1,3-thiazole-5-carbonyl]amino}-4-methylbenzoic acid, 4-Methyl-3-{[5-(pyrimidin-2-yl)pyridin-3-yl]methoxy}benzoic acid (60 mg) obtained in Step 2 was used 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 According to the method according to Step 1 of Reference Example 3, instead of methyl 5-hydroxypyridine-3-carboxylate and 3,3-difluorocyclobutan-1-ol, 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 to obtain the title compound (50 mg). MS (m / z): 356.4 [M+H] + [Step 2] Production of 4-chloro-3-({[5-(pyrimidin-2-yl)pyridin-3-yl]oxy}methyl)benzoic acid According to the method according to Step 2 of Reference Example 1, instead of methyl 5-[(cyclopropylmethyl)amino]pyridine-3-carboxylate, methyl 4-chloro-3-({[5-(pyrimidin-2-yl)pyridin-3-yl]oxy}methyl)benzoate (50 mg) obtained in Step 1 was used to obtain the title compound (43 mg). MS (m / z): 342.4 [M+H] + [Step 3] Production of 4-chloro-N-[(1S,2S)-2-hydroxycyclohexyl]-3-({[5-(pyrimidin-2-yl)pyridin-3-yl]oxy}methyl)benzamide According to the method according to Step 4 of Example 1, instead of 3-{[2-(cyclopropylamino)-1,3-thiazole-5-carbonyl]amino}-4-methylbenzoic acid, 4-chloro-3-({[5-(pyrimidin-2-yl)pyridin-3-yl]oxy}methyl)benzoic acid (43 mg) obtained in Step 2 was used 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] Production of methyl 3-[1-(5-bromopyridin-3-yl)ethoxy]-4-methylbenzoate By the method according to Step 1 of Reference Example 3, instead of methyl 5-hydroxypyridine-3-carboxylate and 3,3-difluorocyclobutan-1-ol, methyl 3-hydroxy-4-methylbenzoate (432 mg) and 1-(5-bromopyridin-3-yl)ethan-1-ol (500 mg) were used to obtain the title compound (650 mg). MS (m / z): 350.3 [M+H] + [Step 2] Production of 3-[1-(5-bromopyridin-3-yl)ethoxy]-4-methylbenzoic acid By the method according to Step 2 of Reference Example 1, instead of methyl 5-[(cyclopropylmethyl)amino]pyridine-3-carboxylate, methyl 3-[1-(5-bromopyridin-3-yl)ethoxy]-4-methylbenzoate (450 mg) obtained in Step 1 was used to obtain the title compound (350 mg). MS (m / z): 336.3 [M+H] + [Step 3] Production of 3-[1-(5-bromopyridin-3-yl)ethoxy]-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide By the method according to Step 4 of Example 1, instead of 3-{[2-(cyclopropylamino)-1,3-thiazole-5-carbonyl]amino}-4-methylbenzoic acid, 3-[1-(5-bromopyridin-3-yl)ethoxy]-4-methylbenzoic acid (350 mg) obtained in Step 2 was used to obtain the title compound (350 mg). MS (m / z): 433.5 [M+H] + [Step 4] Production of N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-[1-(5-phenylpyridin-3-yl)ethoxy]benzamide By the method according to Reference Example 14, instead of 2-chloropyrimidin-4-amine and isoquinolin-4-ylboronic acid, 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 were used to obtain the title compound (30 mg). Example 173 N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-[(E)-2-(5-phenylpyridin-3-yl)ethenyl]benzamide [Process 1] Production of 3-ethenyl-N-[(1R,2R)-2-hydroxycyclohexyl]-4-methylbenzamide According to the method according to Reference Example 14, instead of 2-chloropyrimidin-4-amine and isoquinolin-4-ylboronic acid, 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 were used to obtain the title compound (13.0 g). MS (m / z): 260.2 [M+H] + [Process 2] Production 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 Process 1, 3-bromo-5-phenylpyridine (27 mg), TEA (0.024 mL), tris(2-methylphenyl)phosphine (11 mg), and Pd(OAc)2 (3.9 mg), and acetonitrile (0.58 mL) was reacted in a microwave reactor at 100 °C for 80 minutes. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography to obtain the title compound (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), after degassing, 10% Pd-C (7.7 mg) was added while stirring at room temperature under an argon atmosphere, and the mixture was stirred overnight at room temperature under a hydrogen atmosphere. The reaction solution was filtered through Celite (registered trademark), and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain 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) in THF (10 mL), which was obtained in Step 1 of Example 147, was added 60% sodium hydride (79 mg) under ice-cooling, and the mixture was stirred at room temperature for 20 minutes. Then, iodomethane (720 mg) was added, and the mixture was stirred at the same temperature overnight. Under ice-cooling, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (200 mg). MS (m / z): 349.4 [M+H] + [Step 2] Preparation of 3-{[(5-Bromopyridin-3-yl)(methyl)amino]methyl}-4-methylbenzoic Acid According to the method analogous to Step 2 of Reference Example 1, using methyl 3-{[(5-bromopyridin-3-yl)(methyl)amino]methyl}-4-methylbenzoate (200 mg) obtained in Step 1 instead of methyl 5-[(cyclopropylmethyl)amino]pyridine-3-carboxylate, the title compound (170 mg) was obtained. 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 According to the method analogous to Step 4 of Example 1, using 3-{[(5-bromopyridin-3-yl)(methyl)amino]methyl}-4-methylbenzoic acid (170 mg) obtained in Step 2 instead of 3-{[2-(cyclopropylamino)-1,3-thiazole-5-carbonyl]amino}-4-methylbenzoic acid, the title compound (147 mg) was obtained. 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 According to the method according to Reference Example 14, instead of 2-chloropyrimidin-4-amine and isoquinolin-4-ylboronic acid, 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 were used to obtain the title compound (24 mg). Example 177 3-[(Z)-2-([2,3’-Bipyridin]-5’-yl)-2-fluoroethenyl]-4-fluoro-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide [Step 1] Production 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) and triphenylphosphine (593 mg) in DMF (3.8 mL) obtained in Reference Example 29, a solution of sodium chlorodifluoroacetate (431 mg) in DMF (0.94 mL) was added dropwise at 100°C over 30 minutes, and the mixture was stirred at the same temperature for 30 minutes. Under ice-cooling, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (200 mg). MS (m / z): 300.1 [M+H] + [Step 2] Production of 4-fluoro-3-[(Z)-2-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)ethenyl]-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide To 3-(2,2-difluoroethenyl)-4-fluoro-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide (100 mg), bis(pinacolato)diboron (170 mg), potassium acetate (39 mg), tricyclohexylphosphine (19 mg), and copper(I) chloride (3.3 mg) obtained in Step 1, THF (2.2 mL) was added and degassed, and then the mixture was stirred at 40°C overnight under an argon atmosphere. A saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 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 According to the method according to Reference Example 14, instead of 2-chloropyrimidin-4-amine and isoquinolin-4-ylboronic acid, 5'-bromo-2,3'-bipyridine (45 mg) and 4-fluoro-3-[(Z)-2-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)ethenyl]-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide (65 mg) obtained in Step 2 were used to obtain the title compound (10 mg). 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 According to the method according to Step 1 of Example 177, instead of 4-fluoro-3-formyl-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide, ethyl 5-formyl-6-methylpyridine-3-carboxylate (2.65 g) obtained in Reference Example 33 was used to obtain 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 According to the method according to Step 2 of Example 177, instead of 3-(2,2-difluoroethenyl)-4-fluoro-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide, ethyl 5-(2,2-difluoroethenyl)-6-methylpyridine-3-carboxylate (200 mg) obtained in Step 1 was used to obtain the title compound (280 mg). [Step 3] Preparation of Ethyl 5-[(Z)-2-([2,3'-Bipyridin]-5'-yl)-2-fluoroethenyl]-6-methylpyridine-3-carboxylate According to the method according to Reference Example 14, 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'-bipyridin]-5'-yl)-2-fluoroethenyl]-6-methylpyridine-3-carboxylic acid According to the method according to Step 2 of Reference Example 1, instead of methyl 5-[(cyclopropylmethyl)amino]pyridine-3-carboxylate, ethyl 5-[(Z)-2-([2,3'-bipyridin]-5'-yl)-2-fluoroethenyl]-6-methylpyridine-3-carboxylate (230 mg) obtained in Step 3 was used to obtain the title compound (165 mg). MS (m / z): 336.1 [M+H] + [Step 5] Preparation of 5-[(Z)-2-([2,3'-bipyridin]-5'-yl)-2-fluoroethenyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-6-methylpyridine-3-carboxamide According to the method according to Step 4 of Example 1, instead of 3-{[2-(cyclopropylamino)-1,3-thiazole-5-carbonyl]amino}-4-methylbenzoic acid, 5-[(Z)-2-([2,3'-bipyridin]-5'-yl)-2-fluoroethenyl]-6-methylpyridine-3-carboxylic acid (120 mg) obtained in Step 4 was used 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 By the method according to Step 1 of Example 177, instead of 4-fluoro-3-formyl-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide, methyl 4-fluoro-3-formylbenzoate (1.27 g) was used to obtain the title compound (1.30 g). [Step 2] Preparation of methyl 3-[(Z)-2-(2-aminopyrimidin-5-yl)-2-fluoroethenyl]-4-fluorobenzoate To 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) in THF (4 mL), after degassing, the mixture was stirred at 40 °C for 8 hours under an argon atmosphere. An aqueous saturated 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, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. To the residue obtained, 5-bromopyrimidin-2-amine (105 mg), potassium carbonate (166 mg), Pd(dppf)Cl2·CH2Cl2 (49 mg), 1,4-dioxane (2 mL), and water (0.2 mL) were added. After degassing, the mixture was stirred at 85 °C overnight under an argon atmosphere. The reaction mixture was concentrated under reduced pressure, and the residue obtained was purified by silica gel column chromatography to obtain 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 By the method according to Step 2 of Reference Example 1, instead of methyl 5-[(cyclopropylmethyl)amino]pyridine-3-carboxylate, methyl 3-[(Z)-2-(2-aminopyrimidin-5-yl)-2-fluoroethenyl]-4-fluorobenzoate (200 mg) obtained in Step 2 was used to obtain the title compound (36 mg). MS (m / z): 278.1 [M+H] + [Process 4] Preparation of 3-[(Z)-2-(2-aminopyrimidin-5-yl)-2-fluoroethenyl]-4-fluoro-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide According to the method analogous to that of Step 4 of Example 1, instead of 3-{[2-(cyclopropylamino)-1,3-thiazole-5-carbonyl]amino}-4-methylbenzoic acid, 3-[(Z)-2-(2-aminopyrimidin-5-yl)-2-fluoroethenyl]-4-fluorobenzoic acid (36 mg) obtained in Step 3 was used 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 [Process 1] Preparation of methyl 3-(2,2-difluoroethenyl)-4-methylbenzoate According to the method analogous to that of Step 1 of Example 177, instead of 4-fluoro-3-formyl-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide, methyl 3-formyl-4-methylbenzoate (13.4 g) was used to obtain the title compound (15.0 g). MS (m / z): 213.1 [M+H] + [Process 2] Preparation of methyl 3-[(Z)-2-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)ethenyl]-4-methylbenzoate According to the method analogous to that of Step 2 of Example 177, instead of 3-(2,2-difluoroethenyl)-4-fluoro-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide, methyl 3-(2,2-difluoroethenyl)-4-methylbenzoate (6.0 g) obtained in Step 1 was used to obtain the title compound (8.6 g). [Process 3] Preparation of methyl 3-[(Z)-2-fluoro-2-{5-[(4-ethylpiperazin-1-yl)methyl]pyridin-3-yl}ethenyl]-4-methylbenzoate According to the method according to Reference Example 14, instead of 2-chloropyrimidin-4-amine and isoquinolin-4-ylboronic acid, 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 were used to obtain 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 According to the method according to Step 2 of Reference Example 1, instead of methyl 5-[(cyclopropylmethyl)amino]pyridine-3-carboxylate, 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 to obtain 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 According to the method according to Step 4 of Example 1, 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 According to the method according to Reference Example 14, 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 were used to obtain the title compound (40 mg). MS (m / z): 302.1 [M+H] + [Step 2] Production of ethyl 5-[(Z)-2-{6-[(cyclopropylmethyl)amino]pyridin-3-yl}-2-fluoroethenyl]-6-methylpyridine-3-carboxylate According to the method according to Reference Example 34, 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) obtained in Step 1 and cyclopropanecarbaldehyde (19 mg) were used to obtain the title compound (12 mg). MS (m / z): 356.5 [M+H] + [Step 3] Production of 5-[(Z)-2-{6-[(cyclopropylmethyl)amino]pyridin-3-yl}-2-fluoroethenyl]-6-methylpyridine-3-carboxylic acid According to the method according to Step 2 of Reference Example 1, instead of methyl 5-[(cyclopropylmethyl)amino]pyridine-3-carboxylate, ethyl 5-[(Z)-2-{6-[(cyclopropylmethyl)amino]pyridin-3-yl}-2-fluoroethenyl]-6-methylpyridine-3-carboxylate (12 mg) obtained in Step 2 was used to obtain the title compound (11 mg). [Step 4] Production of 5-[(Z)-2-{6-[(cyclopropylmethyl)amino]pyridin-3-yl}-2-fluoroethenyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-6-methylpyridine-3-carboxamide According to the method according to Step 4 of Example 1, instead of 3-{[2-(cyclopropylamino)-1,3-thiazole-5-carbonyl]amino}-4-methylbenzoic acid, 5-[(Z)-2-{6-[(cyclopropylmethyl)amino]pyridin-3-yl}-2-fluoroethenyl]-6-methylpyridine-3-carboxylic acid (11 mg) obtained in Step 3 was used to obtain the title compound (10 mg).

[0241] Tables 3 to 29 described below show the reference examples and the compounds of the examples.

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

[0243] In the table, "reference example" indicates that the compound was produced using the corresponding raw material by a method according to the production method of the compound of the example number corresponding to the number. For example, an example compound with a reference example number of 1 means that it was produced by a method according to Example 1.

[0244] In the table, "chemical name" represents the name of the compound corresponding to the reference example and example numbers, and "data" represents the instrumental analysis data of such a compound. For example, mass spectrometry data (m / z value), 1H NMR data (δ (ppm) of the peak), elemental analysis data (composition of C, H, N (%)) and the like are applicable.

[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 shows biological test examples of the compounds used in the present invention.

[0273] <Test Example 1 PDGFR-β Tyrosine Kinase Inhibitory Activity> 1. Preparation of the test substance The test substance was prepared to 10 mM with dimethyl sulfoxide (DMSO) and diluted with DMSO to concentrations of 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 further diluted 5-fold with assay buffer 2 (50 mM HEPES (pH 7.0), 0.02% NaN3, 0.01% Bovine Serum Albumin, 0.1 mM orthovanadate, 1 mM Dithiothreitol, 5 mM MgCl2, 1 mM MnCl2, 40 nM Supplemented Enzymatic Buffer (cisbio)).

[0274] 2. Measurement of the PDGFR-β tyrosine kinase inhibitory effect For the measurement, the HTRF KinEASE-TK kit from Cisbio was used. 4 μL of the test substance solution was added to each well of a 384-well plate. Next, 2 μL of the PDGFR-β enzyme solution (final concentration 1 ng / μL, Carna Biosciences) and 4 μL of the substrate solution in which 0.6 μM ATP was added to TK substrate-3-biotin (Cisbio) were added, and the reaction was carried out at 30 °C for 30 minutes with the final concentration of the test substance being 0.01 - 10,000 nM. Thereafter, 10 μL of the detection solution (Cisbio) was added to each well and the reaction was carried out at 30 °C for 1 hour. The fluorescence intensity was measured using a microplate reader (Spectra Max M5, Molecular device).

[0275] 3. Analysis of the measurement results Using the ratio of the fluorescence intensities under each condition, the inhibition rates were calculated when the values of the positive control (1% DMSO solution) and the negative control (enzyme (-)) were set to 0% and 100% respectively. Thereafter, using the SAS system (SAS Institute Inc.), a non-linear regression analysis was performed on the logarithmic concentration and the inhibition rate using a two-parameter logistic model, and the concentration (IC 50 value) of the test substance that inhibits 50% of the PDGFR-β tyrosine kinase activity was 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 Cells Transduced with TEL-PDGFRβ and TEL-KIT Fusion Genes>

[0281] 1. Preparation of cells transfected with the TEL-PDGFRβ and TEL-KIT fusion genes The human TEL-PDGFRβ fusion gene (see, for example, CELL, 1994, 77, 307-316) or the human TEL-KIT fusion gene was inserted into the multiple cloning site of the retroviral expression vector pMYs-IRES-GFP to prepare a gene transfer vector. The human TEL-KIT fusion gene was identified for the amino acid sequence (Accession No. NP_000213.1, amino acids 521-928) important for the enzymatic activity of the KIT gene, and a sequence showing activation even in the absence of a ligand factor was created by appropriately binding it to the amino acid sequence of the TEL gene. Thereafter, the gene transfer vector was introduced into the packaging cell PLAT-E derived from a human fetal kidney cell line in the logarithmic growth phase using a transfection reagent (FuGENE6, Promega). Since the culture supernatant of PLAT-E after gene transfer contains gene transfer virus particles, it was collected and used as the gene transfer medium. The gene transfer medium was added to a plate coated with RetroNectin and incubated to attach the virus particles to the plate. Thereafter, the mouse pro-B cell line Ba / F3 in the logarithmic growth phase was seeded on the plate and infected with the virus to prepare cells that proliferate in a PDGFRβ- or KIT-dependent manner.

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

[0283] 3. Measurement of the inhibitory effect on the growth of cells expressing TEL-PDGFRβ and TEL-KIT On the day after seeding TEL-PDGFRβ- and TEL-KIT-expressing cells in a 96-well plate, the prepared test substance solution was added so that the final concentration became 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 of viable cells as an index.

[0284] 4. Analysis of the measurement results Based on the amount of formazan for each condition, the cell growth inhibition rate was calculated when the amount of formazan in the negative control (0.1% DMSO solution) and Blank (medium only) was set to 0% and 100%, respectively. Thereafter, using the SAS system (SAS Institute Inc.), non-linear regression analysis was performed on the logarithmic dose and the cell growth inhibition rate using a two-parameter logistic model, and the IC 50 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 Proliferation Inhibitory Effect on Pulmonary Artery Smooth Muscle Cells>

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

[0292] 2. Measurement of the inhibitory effect on the growth of pulmonary artery smooth muscle cells On the day after seeding normal human pulmonary artery smooth muscle cells into 96-well plates using smooth muscle cell growth medium, the growth medium was replaced with 0.1% FBS medium and cultured for another day. The test substance solution was diluted 10-fold with a medium containing BrdU and human PDGF-BB (final concentration 10 ng / mL, SIGMA-Aldrich), and an equal volume was added to the cells to make the final concentration 3 - 10,000 nM. Also, a BrdU and 0.1% DMSO solution was added to the human PDGF-BB negative control. After culturing for 1 day, the amount of BrdU incorporated into proliferating cells was measured using an anti-BrdU antibody.

[0293] 3. Analysis of the measurement results Based on the amount of BrdU under each condition, the cell growth inhibition rate was calculated when the amount of BrdU in the positive control (human PDGF-BB (+)) and negative control (human PDGF-BB (-)) was set to 0% and 100%, respectively. Then, using the SAS system (SAS Institute Inc.), non-linear regression analysis of the logarithmic dose and cell growth inhibition rate was performed using a two-parameter logistic model to estimate the IC 50 value. The results are shown in Tables 39 - 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 Inhibitory Effect on the Formation of Erythroblast Colony>

[0303] 1. Preparation of the test substance The test substance was prepared to 10 mM with dimethyl sulfoxide (DMSO) and diluted with DMSO to concentrations of 0.1 - 3 mM, respectively, to prepare a test substance solution 1000 times the final concentration.

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

[0305] 3. Analysis of the 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) set to 100%, and a non-linear regression analysis using a two-parameter logistic model was performed on the logarithmic dose and the colony formation inhibition rate using the SAS system (SAS Institute Inc.) to estimate the IC 50 value. The results are shown in Table 47 below.

[0306]

Table 47

[0307] Formulation Example The following formulation examples are merely illustrative and are not intended to limit the scope of the invention in any way. Formulation Example 1 Tablet (Oral Tablet) In a prescription of 80 mg per tablet The compound of the present invention in Example 1 5.0 mg Corn starch 46.6 mg Crystalline cellulose 24.0 mg Methylcellulose 4.0 mg Magnesium stearate 0.4 mg The mixed powder in this ratio is tableted by a conventional method to obtain an oral tablet.

Industrial Applicability

[0308] Since the compound of the present invention has PDGF receptor kinase inhibitory activity, it is useful as a therapeutic agent for respiratory diseases, cancer, smooth muscle proliferative diseases, vascular proliferative diseases, autoimmune / inflammatory diseases, metabolic diseases, vascular obstructive diseases, and the like.​

Claims

1. A compound selected from the group consisting of the following (1) to (207), 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, N-(5-{[(1S,2S)-2-Hydroxycyclohexyl]carbamoyl}-2-methylphenyl)-5-[3-(trifluoromethoxy)phenyl]pyridine-3-carboxamide, N-(5-{[(1S,2S)-2-Hydroxycyclohexyl]carbamoyl}-2-methylphenyl)-5-[2-(trifluoromethoxy)phenyl]pyridine-3-carboxamide, 5-[2-Fluoro-4-(trifluoromethyl)phenyl]-N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)pyridine-3-carboxamide, 5-(2,6-Difluorophenyl)-N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)pyridine-3-carboxamide, 2-(tert-Butylamino)-N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)-1,3-thiazole-5-carboxamide, N-(5-{[(1S,2S)-2-Hydroxycyclohexyl]carbamoyl}-2-methylphenyl)-2-[(1-methylcyclopropyl)amino]-1,3-thiazole-5-carboxamide, N-(5-{[(1S,2S)-2-Hydroxycyclohexyl]carbamoyl}-2-methylphenyl)-2-[(1-methylcyclobutyl)amino]-1,3-thiazole-5-carboxamide, 2-[(2,2-Dimethylpropyl)amino]-N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)-1,3-thiazole-5-carboxamide, N-(5-{[(1S,2S)-2-Hydroxycyclohexyl]carbamoyl}-2-methylphenyl)-5-(3,4,5-trifluorophenyl)pyridine-3-carboxamide, 5-(4-Cyclopropylphenyl)-N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)pyridine-3-carboxamide, N-(2-Chloro-5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}phenyl)-5-(cyclopropylmethoxy)pyridine-3-carboxamide, N-(5-{[(1S,2S)-2-Hydroxycyclohexyl]carbamoyl}-2-methylphenyl)imidazo[2,1-b][1,3]thiazole-5-carboxamide, 5-(Cyclopropylmethoxy)-N-(3-fluoro-5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)pyridine-3-carboxamide, 5-[(3,3-Difluorocyclobutyl)oxy]-N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)pyridine-3-carboxamide, 2-(Cyclopropylmethyl)-N-(3-fluoro-5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)-1,3-thiazole-5-carboxamide, N-(5-{[(1S,2S)-2-Hydroxycyclohexyl]carbamoyl}-2-methylphenyl)-5-methoxypyridine-3-carboxamide, 5-Ethoxy-N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)pyridine-3-carboxamide, N-(5-{[(1S,2S)-2-Hydroxycyclohexyl]carbamoyl}-2-methylphenyl)-5-[(pyridin-2-yl)oxy]pyridine-3-carboxamide, N-(5-{[(1S,2S)-2-Hydroxycyclohexyl]carbamoyl}-2-methylphenyl)-5-[(pyrimidin-2-yl)oxy]pyridine-3-carboxamide, N-(5-{[(1S,2S)-2-Hydroxycyclohexyl]carbamoyl}-2-methylphenyl)-5-[(1-methylcyclopropyl)methoxy]pyridine-3-carboxamide, 5-[(3,3-Difluorocyclobutyl)methoxy]-N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)pyridine-3-carboxamide, 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, N-[(1S,2S)-2-Hydroxycyclohexyl]-4-methyl-3-{[(pyrazolo[5,1-b][1,3]thiazol-7-yl)methyl]amino}benzamide, 3-Fluoro-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-5-({[5-(pyrimidin-2-yl)pyridin-3-yl]methyl}amino)benzamide, 3-({[5-(5-Fluoropyrimidin-2-yl)pyridin-3-yl]methyl}amino)-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide, N-[(1S,2S)-2-Hydroxycyclohexyl]-4-methyl-3-{[(thieno[3,2-b]pyridin-6-yl)methyl]amino}benzamide, N-[(1S,2S)-2-Hydroxycyclohexyl]-4-methyl-3-{[(1H-pyrazolo[3,4-b]pyridin-5-yl)methyl]amino}benzamide, N-[(1S,2S)-2-Hydroxycyclohexyl]-3-{[(imidazo[1,2-b]pyridazin-3-yl)methyl]amino}-4-methylbenzamide, N-[(1S,2S)-2-Hydroxycyclohexyl]-3-({[5-(imidazo[1,2-a]pyrazin-6-yl)pyridin-3-yl]methyl}amino)-4-methylbenzamide, N-[(1S,2S)-2-Hydroxycyclohexyl]-4-methyl-3-({[1-(pyridin-2-yl)-1H-pyrazol-4-yl]methyl}amino)benzamide, 3-{[(2-Aminopyrimidin-5-yl)methyl]amino}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide, 3-({[2-(Cyclopropylamino)pyrimidin-5-yl]methyl}amino)-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide, N-[(1S,2S)-2-Hydroxycyclohexyl]-4-methyl-3-({[5-(pyrazin-2-yl)pyridin-3-yl]methyl}amino)benzamide, 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-Cyclobutylaminopyridin-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, N-{5-[(5-{[(1S,2S)-2-Hydroxycyclohexyl]carbamoyl}-2-methylanilino)methyl]pyridin-2-yl}oxolane-3-carboxamide, N-[(1S,2S)-2-Hydroxycyclohexyl]-4-methyl-3-({[6-(1H-1,2,3-triazol-1-yl)pyridin-3-yl]methyl}amino)benzamide, N-[(1S,2S)-2-Hydroxycyclohexyl]-4-methyl-3-[({6-[(oxetan-3-yl)amino]pyridin-3-yl}methyl)amino]benzamide, 3-{[(2-Aminopyrimidin-5-yl)methyl]amino}-4-chloro-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide, 3-{[(2-Aminopyrimidin-5-yl)methyl]amino}-5-fluoro-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide, 3-{[(3,4-Dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)methyl]amino}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide, N-[(1S,2S)-2-Hydroxycyclohexyl]-4-methyl-3-({[5-(2H-1,2,3-triazol-2-yl)pyridin-3-yl]methyl}amino)benzamide, 3-{[([3,3'-Bipyridin]-5-yl)amino]methyl}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide, N-[(1S,2S)-2-Hydroxycyclohexyl]-4-methyl-3-({[5-(pyrimidin-2-yl)pyridin-3-yl]amino}methyl)benzamide, 3-{[([2,3'-Bipyridin]-5'-yl)amino]methyl}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide, N-[(1R,2R)-2-Hydroxycyclohexyl]-4-methyl-3-({[5-(pyrimidin-2-yl)pyridin-3-yl]amino}methyl)benzamide, N-[(1S,2S)-2-Hydroxycyclohexyl]-3-({[5-(pyrimidin-2-yl)pyridin-3-yl]amino}methyl)benzamide, 4-Fluoro-N-[(1S,2S)-2-hydroxycyclohexyl]-3-({[5-(pyrimidin-2-yl)pyridin-3-yl]amino}methyl)benzamide, 3-{[(5-Bromopyridin-3-yl)amino]methyl}-N-[(1S,2S)-1,3-dihydroxy-1-phenylpropan-2-yl]-4-methylbenzamide, N-[(1S,2S)-1,3-Dihydroxy-1-phenylpropan-2-yl]-4-methyl-3-{[(5-phenylpyridin-3-yl)amino]methyl}benzamide, 3-{[(5-Cyclopropylpyridin-3-yl)amino]methyl}-N-[(1S,2S)-1,3-dihydroxy-1-phenylpropan-2-yl]-4-methylbenzamide, 3-{[([2,3'-Bipyridin]-5'-yl)amino]methyl}-N-[(1S,2S)-1,3-dihydroxy-1-phenylpropan-2-yl]-4-methylbenzamide, N-[(1S,2S)-1,3-Dihydroxy-1-phenylpropan-2-yl]-4-methyl-3-{[(6-phenylpyrazin-2-yl)amino]methyl}benzamide, 5-({[5-(Cyclopropylethynyl)pyridin-3-yl]amino}methyl)-N-[(1S,2S)-2-hydroxycyclohexyl]-6-methylpyridine-3-carboxamide, N-[3-({[6-(3,4-Dimethoxyphenyl)pyrazin-2-yl]amino}methyl)phenyl]-N'-[(1R,2S)-2-hydroxycyclohexyl]urea, N-[(1R,2S)-2-Hydroxycyclohexyl]-N'-[3-({[5-(pyrimidin-2-yl)pyridin-3-yl]amino}methyl)phenyl]urea 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. (Claim 2) A compound selected from the group consisting of the following (1) to (15), or a pharmaceutically acceptable salt thereof, or a solvate thereof. (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.

3. A pharmaceutical composition comprising, as an active ingredient, at least one compound according to Claim 1 or 2, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

4. A PDGF receptor kinase inhibitor comprising, as an active ingredient, at least one compound according to Claim 1 or 2, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

5. A therapeutic agent for pulmonary hypertension, scleroderma, asthma, obstructive bronchiolitis, pulmonary fibrosis, acute myelogenous leukemia (AML), hypereosinophilic syndrome, T-lymphoblastic leukemia, chronic myelomonocytic leukemia (CMMML), chronic myelogenous leukemia (CML), chronic eosinophilic leukemia, dermatofibrosarcoma protuberans, glioma, ovarian cancer, vascular restenosis, atherosclerotic / obstructive arteriosclerosis, moyamoya disease (idiopathic occlusion of the circle of Willis), leiomyoma, lymphangioleiomyomatosis, or age-related macular degeneration (AMD), which contains as an active ingredient at least one compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, or a solvate thereof, and in which a PDGF receptor kinase is involved.

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