Compounds and compositions as PDGF receptor kinase inhibitors

Abstract

The object of the present invention is to provide a compound having PDGF receptor kinase inhibitory activity. Examples of the present invention include a compound represented by the following formula [1], a pharmaceutically acceptable salt thereof, or a solvate thereof. The compound of the present invention has PDGF receptor kinase inhibitory activity. Furthermore, in that 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, angioplasty diseases, autoimmune / inflammatory diseases, metabolic diseases, vascular occlusive diseases, etc.

Description

Technology Field

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

[0002] Pulmonary arterial hypertension (PAH) is defined as a condition where the mean PAP (pulmonary arterial pressure) measured by right heart catheterization at rest is 25 mmHg or higher, a definition that was adopted at the 2013 Nice conference, where large-scale symposiums on pulmonary hypertension are held every five years in Europe and America. In the Dana Point classification, pulmonary hypertension is divided into five groups: Group 1: PAH, Group 2: pulmonary hypertension associated with left heart disease, Group 3: pulmonary hypertension associated with lung disease and / or hypoxemia, Group 4: chronic thromboembolic pulmonary hypertension (CTEPH), and Group 5: pulmonary hypertension associated with unspecified multifactorial mechanisms. This basic structure is also maintained in the revised clinical classification of pulmonary hypertension (Nice classification

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

[0003] In addition, the latest definition of pulmonary hypertension was proposed at the 6th World Symposium on Pulmonary Hypertension (NICE Conference 2018). Among the proposals, it is defined that 24 mmHg ≥ mean pulmonary arterial pressure (mPAP) > 20 mmHg is also included in the above definition of pulmonary hypertension.

[0004] Platelet-Derived Growth Factor (PDGF) can stimulate the migration of arterial smooth muscle cells from the medial side of the artery to the intima-thin layer where stem cells can proliferate. Cell proliferation induced by all isoforms of PDGF is mediated by ligands that bind to PDGF receptors.

[0005] PDGF receptors belong to the class III tyrosine kinase family and consist 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.

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

[0007] Imatinib, which acts as a PDGF receptor kinase inhibitor, demonstrated efficacy in the P3 study targeting pulmonary arterial hypertension. However, it did not receive approval due to insufficient tolerability caused by side effects such as bone marrow suppression.

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

[0009] However, until now, the relationship between bone marrow suppression and the inhibitory effect of KIT, a receptor-type tyrosine kinase involved in bone marrow hematopoiesis, has not been known. Prior art literature

[0010] WO2013 / 033620 Public Notice

[0011] Smolich et al., Blood, 97, 1413-1421. The problem to be solved

[0012] The problem that the present invention aims to solve is to provide a preventive and / or therapeutic agent for pulmonary arterial pulmonary hypertension that has an excellent balance of efficacy and safety. means of solving the problem

[0013] The inventors have discovered a correlation between the bone marrow suppression effect and the inhibitory effect of KIT, a receptor-type tyrosine kinase involved in bone marrow hematopoiesis. Specifically, the inventors have discovered that a compound represented by the following general formula [1], which has high inhibitory activity of 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 while simultaneously reducing the inhibitory effect on the formation of erythroblast colonies, thereby completing the present invention.

[0014] That is, the present invention may include the inventions of (Clause 1) to (Clause 8) below.

[0015] (Article 1)

[0016] The following equation [1]

[0017] [Chemical Formula 1]

[0018]

[0019] [During the meal,

[0020] R 1silver, hydrogen atom, 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, and

[0021] R 2 is, coupling loss, -(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- and,

[0022] R 2 R in a is a hydrogen atom, a halogen atom, a C1-C6 alkyl or C1-C6 haloalkyl, and

[0023] R 2 R in b is a hydrogen atom, a halogen atom, a C1-C6 alkyl or C1-C6 haloalkyl, or

[0024] R 2 R in a and R bThey form C=O together with the carbon atoms they bond to, and

[0025] R 2 R in c Each is independently a hydrogen atom, a C1-C6 alkyl or a C1-C6 haloalkyl, and

[0026] m is an integer from 0 to 3, and

[0027] Het is a 5- to 10-membered heteroaryl, and

[0028] L 1 silver, bonding loss, -(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- and,

[0029] Here,

[0030] L 1 R in a is a hydrogen atom, a halogen atom, a C1-C6 alkyl or C1-C6 haloalkyl, and

[0031] L 1 R in b is a hydrogen atom, a halogen atom, a C1-C6 alkyl or C1-C6 haloalkyl, or

[0032] L 1 R in a and R b They form C=O together with the carbon atoms they bond to, and,

[0033] L 1 R in c Each is independently a hydrogen atom, a C1-C6 alkyl or a C1-C6 haloalkyl, and

[0034] L 1 m in is an integer from 0 to 3, and

[0035] X is, N or CR 3 And,

[0036] R 3 is a hydrogen atom, a halogen atom, a C1-C6 alkyl or C1-C6 haloalkyl, and

[0037] R 4 is a hydrogen atom, a halogen atom, and methyl,

[0038] L 2 is, coupling loss, -(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- and, where,

[0039] L 2 R in a is a hydrogen atom, a halogen atom, a C1-C6 alkyl or C1-C6 haloalkyl, and

[0040] L 2 R in b is a hydrogen atom, a halogen atom, a C1-C6 alkyl or C1-C6 haloalkyl, or

[0041] L 2 R in a and R b They form C=O together with the carbon atoms they bond to, and

[0042] L 2 R in c Each is independently a hydrogen atom, a C1-C6 alkyl, or a C1-C6 haloalkyl, and

[0043] L 2 m in is an integer from 0 to 3, and

[0044] R 5 is a hydrogen atom, a halogen atom, a hydroxyl, an amino, a C1-C6 alkyl, a C1-C6 haloalkyl, a C1-C6 alkoxy, or a C1-C6 haloalkoxy, and

[0045] R 6 is a hydrogen atom, a halogen atom, a C1-C6 alkyl, a C1-C6 haloalkyl, or optionally a substituted phenyl, and

[0046] R 7 It is silver, a hydrogen atom, a halogen atom, a C1-C6 alkyl, a C1-C6 haloalkyl, a hydroxyalkyl, optionally a substituted phenyl, or optionally a substituted C3-C6 cycloalkyl, or

[0047] R 6 and R 7 A compound represented by [which, together with the carbon atoms to which they bond, forms a C3-C6 cycloalkyl, optionally a substituted aryl, or optionally a substituted heteroaryl] or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0048] (Article 2)

[0049] R 1This is a hydrogen atom, a halogen atom, a C1-C6 alkyl, a C2-C6 alkenyl, a C1-C6 alkoxy, an amino, a monoalkylamino, a dialkylamino, an aminoalkyl, an alkylcarbonylamino, a C3-C6 cycloalkyl which is optionally substituted, a heterocycloalkyl which is optionally substituted, an aryl which is optionally substituted, or a heteroaryl which is optionally substituted.

[0050] R 2 a, coupling loss, -(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- and,

[0051] L 1 This, combined hand, -(CR a R b ) m -NR c -, -NR c -(CR a R b ) m -, -(CR a R b ) m -O-, -O-(CR a R b ) m -, -(CR a R b ) m -, -NR c -, -CR a =CR b - or -C≡C- and,

[0052] Here,

[0053] L 1 R in ais a hydrogen atom, a halogen atom, or a C1-C6 alkyl, and

[0054] L 1 R in b is a hydrogen atom, a halogen atom, or a C1-C6 alkyl, or

[0055] L 1 R in a and L 1 R in b They form C=O together with the carbon atoms they bond to, and,

[0056] L 1 R in c Each is independently a hydrogen atom, a C1-C6 alkyl or a C1-C6 haloalkyl, and

[0057] L 1 m at is an integer from 0 to 2, and

[0058] X is N or CR 3 is,

[0059] R 3 is a hydrogen atom, a halogen atom, a C1-C6 alkyl or C1-C6 haloalkyl, and

[0060] R 4 is a hydrogen atom, a halogen atom, or methyl,

[0061] L 2 Ga -(CR a R b ) m -NR c - or -NR c -CO-NR c - and, here,

[0062] L 2 R in a and R b They form C=O together with the carbon atoms they bond to, and

[0063] L 2 R in c Each is independently a hydrogen atom, and

[0064] L 2 m at is 1, and

[0065] R 5 ga is hydroxyl, and

[0066] R 6 is a hydrogen atom, a C1-C6 alkyl, or, in some cases, a substituted phenyl, and

[0067] R 7 This hydrogen atom is a C1-C6 alkyl, hydroxyalkyl, or, in some cases, a substituted phenyl, and

[0068] or

[0069] R 6 and R 7 A compound described in claim 1 or a pharmaceutically acceptable salt thereof, or a solvate thereof, which, together with the carbon atoms to which they are bonded, forms a C3-C6 cycloalkyl or, in some cases, a substituted aryl.

[0070] (Article 3)

[0071] R 1 This hydrogen atom is a C1-C6 alkoxy, amino, monoalkylamino, optionally a substituted C3-C6 cycloalkyl, optionally a substituted heterocycloalkyl, optionally a substituted aryl, or optionally a substituted heteroaryl, and

[0072] R 2 a, coupling loss, -(CR a R b ) m -O-, -(CR a R b ) m - or -NR c -is,

[0073] L 1 This, -(CR a R b ) m -NR c -, -NR c -(CR a R b ) m - or -CR a =CR b - and,

[0074] Here,

[0075] L 1 R in a is a hydrogen atom or a halogen atom,

[0076] L 1 R in b is a hydrogen atom, or

[0077] L 1 R in a and R b They form C=O together with the carbon atoms they bond to, and

[0078] L 1 R in c Each is independently a hydrogen atom, and

[0079] L 1 m at is 0 or 1, and

[0080] X is N or CR 3 is,

[0081] Here, R 3 is a hydrogen atom, and

[0082] R 4 ga is a halogen atom or methyl, and

[0083] L 2 Ga -(CR a R b ) m -NR c - and,

[0084] Here L 2 R in a and R b They form C=O together with the carbon atoms they bond to, and,

[0085] L 2 R in c Each is independently a hydrogen atom, and

[0086] L 2 m at is 1, and

[0087] R 5 ga is hydroxyl, and

[0088] R 6 and R 7 A compound described in claim 1, or a pharmaceutically acceptable salt thereof, or a solvate thereof, which, together with the carbon atoms to which they bond, form a C3-C6 cycloalkyl group.

[0089] (Article 4)

[0090] A compound described in claim 1, a pharmaceutically acceptable salt thereof, or a solvate thereof, selected from the group consisting of (1) to (207) below.

[0091] (1) 2-(cyclopropylamino)-N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)-1,3-thiazole-5-carboxamide,

[0092] (2) N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)-5-phenylpyridine-3-carboxamide,

[0093] (3) 2-(cyclopropylmethyl)-N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)-1,3-thiazole-5-carboxamide,

[0094] (4) 5-(cyclopropylamino)-N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)pyridine-3-carboxamide,

[0095] (5) N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)-2-phenyl-1,3-oxazole-5-carboxamide,

[0096] (6) N-(5-{[(1S)-2-hydroxy-1-phenylethyl]carbamoyl}-2-methylphenyl)-5-phenylpyridine-3-carboxamide,

[0097] (7) N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)-5-[(propane-2-yl)oxy]pyridine-3-carboxamide,

[0098] (8) 2-[(cyclopropylmethyl)amino]-N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)-1,3-thiazole-5-carboxamide,

[0099] (9) 5-(4-chlorophenyl)-N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)pyridine-3-carboxamide,

[0100] (10) N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)-2-propyl-1,3-thiazole-5-carboxamide,

[0101] (11) 5-(3-chlorophenyl)-N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)pyridine-3-carboxamide,

[0102] (12) N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)-5-(2-methylphenyl)pyridine-3-carboxamide,

[0103] (13) 5-(2-chlorophenyl)-N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)pyridine-3-carboxamide,

[0104] (14) N-(5-{[(2S)-1-hydroxypentane-2-yl]carbamoyl}-2-methylphenyl)-5-phenylpyridine-3-carboxamide,

[0105] (15) 5-[(E)-2-cyclopropylethenyl]-N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)pyridine-3-carboxamide,

[0106] (16) 5-[(cyclopropylmethyl)amino]-N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)pyridine-3-carboxamide,

[0107] (17) 5-[cyclopropyl(methyl)amino]-N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)pyridine-3-carboxamide,

[0108] (18) N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)-5-(4-methoxyphenyl)pyridine-3-carboxamide,

[0109] (19) 5-(4-fluorophenyl)-N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)pyridine-3-carboxamide,

[0110] (20) 5-(3-fluorophenyl)-N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)pyridine-3-carboxamide,

[0111] (21) N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)-5-[4-(trifluoromethyl)phenyl]pyridine-3-carboxamide,

[0112] (22) N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)-5-[3-(trifluoromethyl)phenyl]pyridine-3-carboxamide,

[0113] (23) N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)-5-(2-methylprop-1-en-1-yl)pyridine-3-carboxamide,

[0114] (24) 5-(cyclopropylmethoxy)-N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)pyridine-3-carboxamide,

[0115] (25) 2-[(3,3-difluorocyclobutyl)amino]-N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)-1,3-thiazole-5-carboxamide,

[0116] (26) 2-[(2-cyclopropylethyl)amino]-N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)-1,3-thiazole-5-carboxamide,

[0117] (27) N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)-2-[(propane-2-yl)amino]-1,3-thiazole-5-carboxamide,

[0118] (28) 5-[(4,4-difluorocyclohexyl)oxy]-N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)pyridine-3-carboxamide,

[0119] (29) 5-(2-fluorophenyl)-N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)pyridine-3-carboxamide,

[0120] (30) 5-(2,3-difluorophenyl)-N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)pyridine-3-carboxamide,

[0121] (31) 5-(2,4-difluorophenyl)-N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)pyridine-3-carboxamide,

[0122] (32) 5-(3,5-difluorophenyl)-N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)pyridine-3-carboxamide,

[0123] (33) 5-(2-fluoro-4-methoxyphenyl)-N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)pyridine-3-carboxamide,

[0124] (34) N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)-5-[3-(trifluoromethoxy)phenyl]pyridine-3-carboxamide,

[0125] (35) N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)-5-[2-(trifluoromethoxy)phenyl]pyridine-3-carboxamide,

[0126] (36) 5-[2-fluoro-4-(trifluoromethyl)phenyl]-N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)pyridine-3-carboxamide,

[0127] (37) 5-(2,6-difluorophenyl)-N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)pyridine-3-carboxamide,

[0128] (38) 2-(tert-butylamino)-N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)-1,3-thiazole-5-carboxamide,

[0129] (39) N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)-2-[(1-methylcyclopropyl)amino]-1,3-thiazole-5-carboxamide,

[0130] (40) N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)-2-[(1-methylcyclobutyl)amino]-1,3-thiazole-5-carboxamide,

[0131] (41) 2-[(2,2-dimethylpropyl)amino]-N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)-1,3-thiazole-5-carboxamide,

[0132] (42) N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)-5-(3,4,5-trifluorophenyl)pyridine-3-carboxamide,

[0133] (43) 5-(4-cyclopropylphenyl)-N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)pyridine-3-carboxamide,

[0134] (44) N-(2-chloro-5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}phenyl)-5-(cyclopropylmethoxy)pyridine-3-carboxamide,

[0135] (45) N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)imidazo[2,1-b][1,3]thiazole-5-carboxamide,

[0136] (46) 5-(cyclopropylmethoxy)-N-(3-fluoro-5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)pyridine-3-carboxamide,

[0137] (47) 5-[(3,3-difluorocyclobutyl)oxy]-N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)pyridine-3-carboxamide,

[0138] (48) 2-(cyclopropylmethyl)-N-(3-fluoro-5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)-1,3-thiazole-5-carboxamide,

[0139] (49) N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)-5-methoxypyridine-3-carboxamide,

[0140] (50) 5-ethoxy-N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)pyridine-3-carboxamide,

[0141] (51) N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)-5-[(pyridine-2-yl)oxy]pyridine-3-carboxamide,

[0142] (52) N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)-5-[(pyrimidine-2-yl)oxy]pyridine-3-carboxamide,

[0143] (53) N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)-5-[(1-methylcyclopropyl)methoxy]pyridine-3-carboxamide,

[0144] (54) 5-[(3,3-difluorocyclobutyl)methoxy]-N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)pyridine-3-carboxamide,

[0145] (55) N-(2-chloro-5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}phenyl)-2-(cyclopropylmethyl)-1,3-thiazole-5-carboxamide,

[0146] (56) 5-(cyclopropylmethoxy)-N-(2-fluoro-5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}phenyl)pyridine-3-carboxamide,

[0147] (57) 3-[(5-bromopyridine-3-yl)ethinyl]-4-chloro-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide,

[0148] (58) 4-chloro-N-[(1S,2S)-2-hydroxycyclohexyl]-3-[(5-phenylpyridine-3-yl)ethinyl]benzamide,

[0149] (59) N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-[(5-methylpyridine-3-yl)ethinyl]benzamide,

[0150] (60) N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-[(5-phenylpyridine-3-yl)ethinyl]benzamide,

[0151] (61) 3-[(5-bromopyridine-3-yl)ethinyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide,

[0152] (62) N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-{[5-(pyrimidine-2-yl)pyridine-3-yl]ethinyl}benzamide,

[0153] (63) N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-{[5-(pyrazine-2-yl)pyridine-3-yl]ethinyl}benzamide,

[0154] (64) 4-chloro-N-[(1S,2S)-2-hydroxycyclohexyl]-3-{[5-(pyrimidine-2-yl)pyridine-3-yl]ethinyl}benzamide,

[0155] (65) 3-[(6-aminopyridine-3-yl)ethinyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide,

[0156] (66) 3-[([2,3'-bipyridine]-5'-yl)ethinyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide,

[0157] (67) 3-[(5-cyclopropylpyridine-3-yl)ethinyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide,

[0158] (68) 3-[(6-cyclopropylpyrazine-2-yl)ethinyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide,

[0159] (69) 3-{[6-(2-fluorophenyl)pyrazine-2-yl]ethinyl}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide,

[0160] (70) 3-{[6-(3-fluorophenyl)pyrazine-2-yl]ethinyl}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide,

[0161] (71) 3-{[6-(4-fluorophenyl)pyrazine-2-yl]ethinyl}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide,

[0162] (72) 3-({6-[(cyclopropylmethyl)amino]pyrazine-2-yl}ethinyl)-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide,

[0163] (73) 5-[(5-cyclopropylpyridine-3-yl)ethinyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-6-methylpyridine-3-carboxamide,

[0164] (74) 3-[(6-bromopyrazine-2-yl)ethinyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide,

[0165] (75) N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-[(6-phenylpyrazine-2-yl)ethinyl]benzamide,

[0166] (76) 3-[(5-bromopyridine-3-yl)ethinyl]-N-[(1S,2S)-1,3-dihydroxy-1-phenylpropane-2-yl]-4-methylbenzamide,

[0167] (77) N 1 -[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-N 3 -(5-phenylpyridine-3-yl)benzene-1,3-dicarboxamide,

[0168] (78) N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-{[2-(pyridine-3-yl)pyrimidine-4-yl]amino}benzamide,

[0169] (79) N-[(1S,2S)-2-hydroxycyclohexyl]-3-{[2-(isoquinoline-4-yl)pyrimidine-4-yl]amino}-4-methylbenzamide,

[0170] (80) N-[(1S,2S)-1,3-dihydroxy-1-phenylpropane-2-yl]-3-{[2-(isoquinoline-4-yl)pyrimidine-4-yl]amino}-4-methylbenzamide,

[0171] (81) 3-[([2,3'-bipyridine]-6-yl)amino]-5-fluoro-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide,

[0172] (82) N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-{[2-(methylamino)quinazolin-5-yl]amino}benzamide,

[0173] (83) 3-(2-amino-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-yl)-N-[(1S,2S)-1,3-dihydroxy-1-phenylpropane-2-yl]-4-methylbenzamide,

[0174] (84) N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-{[(1S)-1-(5-phenylpyridine-3-yl)ethyl]amino}benzamide,

[0175] (85) 3-{[(1S)-1-([3,3'-bipyridine]-5-yl)ethyl]amino}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide,

[0176] (86) N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-({(1S)-1-[5-(phenylethynyl)pyridine-3-yl]ethyl}amino)benzamide,

[0177] (87) 3-{[(1S)-1-([3,4'-bipyridine]-5-yl)ethyl]amino}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide,

[0178] (88) N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-({(1S)-1-[5-(pyrimidine-2-yl)pyridine-3-yl]ethyl}amino)benzamide,

[0179] (89) 3-{[(1S)-1-([2,3'-bipyridine]-5'-yl)ethyl]amino}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide,

[0180] (90) 3-{[(1S)-1-([3,3'-bipyridine]-5-yl)ethyl]amino}-4-chloro-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide,

[0181] (91) 3-{[(5-bromopyridine-3-yl)methyl]amino}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide,

[0182] (92) N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-{[(5-phenylpyridine-3-yl)methyl]amino}benzamide,

[0183] (93) 3-{[([3,3'-bipyridine]-5-yl)methyl]amino}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide,

[0184] (94) 3-({[5-(cyclopropylethinyl)pyridine-3-yl]methyl}amino)-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide,

[0185] (95) N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-({[5-(pyrimidine-2-yl)pyridine-3-yl]methyl}amino)benzamide,

[0186] (96) N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-{[(quinoline-3-yl)methyl]amino}benzamide,

[0187] (97) N-[(1S,2S)-2-hydroxycyclohexyl]-3-[({5-[(1-hydroxycyclopropyl)ethinyl]pyridine-3-yl}methyl)amino]-4-methylbenzamide,

[0188] (98) 3-[({5-[4-(2-aminopropane-2-yl)phenyl]pyridine-3-yl}methyl)amino]-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide,

[0189] (99) 3-({[5-(4-aminophenyl)pyridine-3-yl]methyl}amino)-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide,

[0190] (100) 3-({[5-(3,5-difluorophenyl)pyridine-3-yl]methyl}amino)-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide,

[0191] (101) N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-{[(6-phenylpyrazine-2-yl)methyl]amino}benzamide,

[0192] (102) N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-({[5-(thiophene-2-yl)pyridine-3-yl]methyl}amino)benzamide,

[0193] (103) N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-({[5-(thiophene-3-yl)pyridine-3-yl]methyl}amino)benzamide,

[0194] (104) 4-chloro-N-[(1S,2S)-2-hydroxycyclohexyl]-3-({[5-(pyrimidine-2-yl)pyridine-3-yl]methyl}amino)benzamide,

[0195] (105) N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-{[(pyrazolo[5,1-b][1,3]thiazole-7-yl)methyl]amino}benzamide,

[0196] (106) 3-fluoro-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-5-({[5-(pyrimidine-2-yl)pyridine-3-yl]methyl}amino)benzamide,

[0197] (107) 3-({[5-(5-fluoropyrimidine-2-yl)pyridine-3-yl]methyl}amino)-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide,

[0198] (108) N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-{[(thieno[3,2-b]pyridine-6-yl)methyl]amino}benzamide,

[0199] (109) N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-{[(1H-pyrazolo[3,4-b]pyridin-5-yl)methyl]amino}benzamide,

[0200] (110) N-[(1S,2S)-2-hydroxycyclohexyl]-3-{[(imidazo[1,2-b]pyridazine-3-yl)methyl]amino}-4-methylbenzamide,

[0201] (111) N-[(1S,2S)-2-hydroxycyclohexyl]-3-({[5-(imidazo[1,2-a]pyrazine-6-yl)pyridine-3-yl]methyl}amino)-4-methylbenzamide,

[0202] (112) N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-({[1-(pyridine-2-yl)-1H-pyrazole-4-yl]methyl}amino)benzamide,

[0203] (113) 3-{[(2-aminopyrimidine-5-yl)methyl]amino}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide,

[0204] (114) 3-({[2-(cyclopropylamino)pyrimidine-5-yl]methyl}amino)-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide,

[0205] (115) N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-({[5-(pyrazine-2-yl)pyridine-3-yl]methyl}amino)benzamide,

[0206] (116) 3-{[(6-acetamidopyridine-3-yl)methyl]amino}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide,

[0207] (117) 3-[({6-[(cyclopropylmethyl)amino]pyridine-3-yl}methyl)amino]-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide,

[0208] (118) 3-{[([2,2'-bipyridine]-5-yl)methyl]amino}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide,

[0209] (119) N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-{[(pyrazolo[1,5-a]pyrimidine-3-yl)methyl]amino}benzamide,

[0210] (120) 3-[({6-[(cyclopropanecarbonyl)amino]pyridine-3-yl}methyl)amino]-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide,

[0211] (121) N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-{[(2-phenylpyrimidine-5-yl)methyl]amino}benzamide,

[0212] (122) N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-({[6-(1H-pyrazole-1-yl)pyridin-3-yl]methyl}amino)benzamide,

[0213] (123) N-[(1S,2S)-2-hydroxycyclohexyl]-6-methyl-5-{[(pyrazolo[1,5-a]pyridin-3-yl)methyl]amino}pyridin-3-carboxamide,

[0214] (124) methyl {5-[(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylanilino)methyl]pyridine-2-yl}carbamate,

[0215] (125) N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-[({6-[(oxane-4-yl)amino]pyridine-3-yl}methyl)amino]benzamide,

[0216] (126) N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-[({2-[(pyridine-2-yl)amino]pyrimidine-5-yl}methyl)amino]benzamide,

[0217] (127) N-{5-[(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylanilino)methyl]pyridine-2-yl}morpholine-4-carboxamide,

[0218] (128) N-[(1S,2S)-2-hydroxycyclohexyl]-3-({[2-(4-methoxyphenyl)pyrimidine-5-yl]methyl}amino)-4-methylbenzamide,

[0219] (129) N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-{[(6-{[(pyridin-3-yl)carbamoyl]amino}pyridin-3-yl)methyl]amino}benzamide,

[0220] (130) 3-({[6-(cyclobutylamino)pyridine-3-yl]methyl}amino)-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide,

[0221] (131) 3-{[(5-aminopyrazine-2-yl)methyl]amino}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide,

[0222] (132) N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-[({2-[(oxane-4-yl)amino]pyrimidine-5-yl}methyl)amino]benzamide,

[0223] (133) 3-{[(6-{[cyclopropyl(methyl)carbamoyl]amino}pyridine-3-yl)methyl]amino}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide,

[0224] (134) N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-[({6-[(propane-2-yl)amino]pyridine-3-yl}methyl)amino]benzamide,

[0225] (135) N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-{[(2-{[(3R)-oxolan-3-yl]amino}pyrimidine-5-yl)methyl]amino}benzamide,

[0226] (136) N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-{[(2-{[(3S)-oxolan-3-yl]amino}pyrimidine-5-yl)methyl]amino}benzamide

[0227] (137) N-{5-[(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylanilino)methyl]pyridine-2-yl}oxane-4-carboxamide,

[0228] (138) N-[(1S,2S)-2-hydroxycyclohexyl]-3-{[(6-{[(1r,3r)-3-methoxycyclobutane-1-carbonyl]amino}pyridine-3-yl)methyl]amino}-4-methylbenzamide,

[0229] (139) N-{5-[(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylanilino)methyl]pyridine-2-yl}oxolan-3-carboxamide,

[0230] (140) N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-({[6-(1H-1,2,3-triazole-1-yl)pyridine-3-yl]methyl}amino)benzamide,

[0231] (141) N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-[({6-[(oxetane-3-yl)amino]pyridine-3-yl}methyl)amino]benzamide,

[0232] (142) 3-{[(2-aminopyrimidine-5-yl)methyl]amino}-4-chloro-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide,

[0233] (143) 3-{[(2-aminopyrimidine-5-yl)methyl]amino}-5-fluoro-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide,

[0234] (144) 3-{[(3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-7-yl)methyl]amino}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide,

[0235] (145) N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-({[5-(2H-1,2,3-triazole-2-yl)pyridine-3-yl]methyl}amino)benzamide,

[0236] (146) 3-{[([3,3'-bipyridine]-5-yl)amino]methyl}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide,

[0237] (147) N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-({[5-(pyrimidine-2-yl)pyridine-3-yl]amino}methyl)benzamide,

[0238] (148) 3-{[([2,3'-bipyridine]-5'-yl)amino]methyl}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide,

[0239] (149) N-[(1R,2R)-2-hydroxycyclohexyl]-4-methyl-3-({[5-(pyrimidine-2-yl)pyridine-3-yl]amino}methyl)benzamide,

[0240] (150) N-[(1S,2S)-2-hydroxycyclohexyl]-3-({[5-(pyrimidine-2-yl)pyridine-3-yl]amino}methyl)benzamide,

[0241] (151) 4-fluoro-N-[(1S,2S)-2-hydroxycyclohexyl]-3-({[5-(pyrimidine-2-yl)pyridine-3-yl]amino}methyl)benzamide,

[0242] (152) 3-{[(5-bromopyridine-3-yl)amino]methyl}-N-[(1S,2S)-1,3-dihydroxy-1-phenylpropane-2-yl]-4-methylbenzamide,

[0243] (153) N-[(1S,2S)-1,3-dihydroxy-1-phenylpropane-2-yl]-4-methyl-3-{[(5-phenylpyridine-3-yl)amino]methyl}benzamide,

[0244] (154) 3-{[(5-cyclopropylpyridine-3-yl)amino]methyl}-N-[(1S,2S)-1,3-dihydroxy-1-phenylpropane-2-yl]-4-methylbenzamide,

[0245] (155) 3-{[([2,3'-bipyridine]-5'-yl)amino]methyl}-N-[(1S,2S)-1,3-dihydroxy-1-phenylpropane-2-yl]-4-methylbenzamide,

[0246] (156) N-[(1S,2S)-1,3-dihydroxy-1-phenylpropane-2-yl]-4-methyl-3-{[(6-phenylpyrazine-2-yl)amino]methyl}benzamide,

[0247] (157) 5-({[5-(cyclopropylethinyl)pyridine-3-yl]amino}methyl)-N-[(1S,2S)-2-hydroxycyclohexyl]-6-methylpyridine-3-carboxamide,

[0248] (158) N-[3-({[6-(3,4-dimethoxyphenyl)pyrazine-2-yl]amino}methyl)phenyl]-N'-[(1R,2S)-2-hydroxycyclohexyl]urea,

[0249] (159) N-[(1R,2S)-2-hydroxycyclohexyl]-N'-[3-({[5-(pyrimidine-2-yl)pyridine-3-yl]amino}methyl)phenyl]urea,

[0250] (160) N-[2-fluoro-5-({[5-(pyrimidine-2-yl)pyridine-3-yl]amino}methyl)phenyl]-N'-[(1R,2S)-2-hydroxycyclohexyl]urea,

[0251] (161) N-[4-fluoro-3-({[5-(pyrimidine-2-yl)pyridine-3-yl]amino}methyl)phenyl]-N'-[(1R,2S)-2-hydroxycyclohexyl]urea,

[0252] (162) N-[(1R,2S)-2-hydroxycyclohexyl]-N'-[4-methyl-3-({[5-(pyrimidine-2-yl)pyridine-3-yl]amino}methyl)phenyl]urea,

[0253] (163) N-[(1R,2S)-2-hydroxycyclohexyl]-N'-[2-methyl-5-({[5-(pyrimidine-2-yl)pyridine-3-yl]amino}methyl)phenyl]urea,

[0254] (164) N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-{1-[(6-phenylpyrazine-2-yl)amino]ethyl}benzamide,

[0255] (165) 3-[([3,3'-bipyridine]-5-yl)methoxy]-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide,

[0256] (166) N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-{[5-(pyrimidine-2-yl)pyridine-3-yl]methoxy}benzamide,

[0257] (167) 4-chloro-N-[(1S,2S)-2-hydroxycyclohexyl]-3-{[5-(pyrimidine-2-yl)pyridine-3-yl]methoxy}benzamide,

[0258] (168) 3-{[([3,3'-bipyridine]-5-yl)oxy]methyl}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide,

[0259] (169) N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-({[5-(pyrimidine-2-yl)pyridine-3-yl]oxy}methyl)benzamide,

[0260] (170) 4-chloro-N-[(1S,2S)-2-hydroxycyclohexyl]-3-({[5-(pyrimidine-2-yl)pyridine-3-yl]oxy}methyl)benzamide,

[0261] (171) N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-{1-[5-(pyrimidine-2-yl)pyridine-3-yl]ethoxy}benzamide,

[0262] (172) N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-[1-(5-phenylpyridine-3-yl)ethoxy]benzamide,

[0263] (173) N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-[(E)-2-(5-phenylpyridine-3-yl)ethenyl]benzamide,

[0264] (174) N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-[2-(5-phenylpyridine-3-yl)ethyl]benzamide,

[0265] (175) N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-{[methyl(5-phenylpyridine-3-yl)amino]methyl}benzamide,

[0266] (176) 3-{[ethyl(5-phenylpyridine-3-yl)amino]methyl}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide,

[0267] (177) 3-[(Z)-2-([2,3'-bipyridine]-5'-yl)-2-fluoroethenyl]-4-fluoro-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide,

[0268] (178) 4-fluoro-3-{(Z)-2-fluoro-2-[5-(pyrimidine-2-yl)pyridine-3-yl]ethenyl}-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide,

[0269] (179) 3-[(Z)-2-fluoro-2-(imidazo[1,2-b]pyridazine-3-yl)ethenyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide,

[0270] (180) 5-[(Z)-2-([2,3'-bipyridine]-5'-yl)-2-fluoroethenyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-6-methylpyridine-3-carboxamide,

[0271] (181) 3-[(Z)-2-fluoro-2-{5-[(4-methylpiperazine-1-yl)methyl]pyridine-3-yl}ethenyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide,

[0272] (182) 3-[(Z)-2-fluoro-2-{5-[(morpholine-4-yl)methyl]pyridine-3-yl}ethenyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide,

[0273] (183) 3-[(Z)-2-{6-[(cyclopropylmethyl)amino]pyridine-3-yl}-2-fluoroethenyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide,

[0274] (184) 4-fluoro-3-{(Z)-2-fluoro-2-[5-(morpholine-4-yl)pyridine-3-yl]ethenyl}-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide,

[0275] (185) 4-fluoro-3-[(Z)-2-fluoro-2-{5-[(oxane-4-yl)amino]pyridine-3-yl}ethenyl]-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide,

[0276] (186) 4-fluoro-3-[(Z)-2-fluoro-2-{5-[(4-methylpiperazine-1-yl)methyl]pyridine-3-yl}ethenyl]-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide,

[0277] (187) 5-{(Z)-2-[5-(cyclopropylmethoxy)pyridine-3-yl]-2-fluoroethenyl}-N-[(1S,2S)-2-hydroxycyclohexyl]-6-methylpyridine-3-carboxamide,

[0278] (188) 5-{(Z)-2-fluoro-2-[5-(morpholine-4-yl)pyridine-3-yl]ethenyl}-N-[(1S,2S)-2-hydroxycyclohexyl]-6-methylpyridine-3-carboxamide,

[0279] (189) 5-[(Z)-2-(6-aminopyridine-3-yl)-2-fluoroethenyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-6-methylpyridine-3-carboxamide,

[0280] (190) 5-[(Z)-2-(2-aminopyrimidine-5-yl)-2-fluoroethenyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-6-methylpyridine-3-carboxamide,

[0281] (191) 3-[(Z)-2-(6-aminopyridine-3-yl)-2-fluoroethenyl]-4-fluoro-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide,

[0282] (192) 3-[(Z)-2-(2-aminopyrimidine-5-yl)-2-fluoroethenyl]-4-fluoro-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide,

[0283] (193) 3-[(Z)-2-fluoro-2-{5-[(1-methylpiperidin-4-yl)amino]pyridin-3-yl}ethenyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide,

[0284] (194) 3-[(Z)-2-{5-[(4-ethylpiperazine-1-yl)methyl]pyridine-3-yl}-2-fluoroethenyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide,

[0285] (195) 5-[(Z)-2-fluoro-2-{5-[(oxetane-3-yl)amino]pyridine-3-yl}ethenyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-6-methylpyridine-3-carboxamide,

[0286] (196) 4-fluoro-3-[(Z)-2-fluoro-2-{5-[(oxetane-3-yl)amino]pyridine-3-yl}ethenyl]-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide,

[0287] (197) 3-[(Z)-2-(6-{[2-(dimethylamino)ethyl]amino}pyridine-3-yl)-2-fluoroethenyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide,

[0288] (198) 3-[(Z)-2-(5-{[2-(dimethylamino)ethyl]amino}pyridine-3-yl)-2-fluoroethenyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide,

[0289] (199) 5-[(Z)-2-{6-[(cyclopropylmethyl)amino]pyridine-3-yl}-2-fluoroethenyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-6-methylpyridine-3-carboxamide,

[0290] (200) 3-[(Z)-2-fluoro-2-{5-[(4-methylpiperazine-1-yl)methyl]pyridine-3-yl}ethenyl]-N-[(1S,2S)-2-hydroxy-2,3-dihydro-1H-indene-1-yl]-4-methylbenzamide,

[0291] (201) 3-[(Z)-2-fluoro-2-{5-[(4-methylpiperazine-1-yl)methyl]pyridine-3-yl}ethenyl]-N-(2-hydroxy-3,3-dimethylbutyl)-4-methylbenzamide,

[0292] (202) 3-[(Z)-2-{2-[(cyclopropylmethyl)amino]pyrimidine-5-yl}-2-fluoroethenyl]-4-fluoro-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide,

[0293] (203) 3-{(Z)-2-[2-(cyclopropylamino)pyrimidine-5-yl]-2-fluoroethenyl}-4-fluoro-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide,

[0294] (204) 3-[(Z)-2-(2-amino-4-methylpyrimidine-5-yl)-2-fluoroethenyl]-4-fluoro-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide,

[0295] (205) 4-fluoro-3-{(Z)-2-fluoro-2-[2-(methylamino)pyrimidine-5-yl]ethenyl}-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide,

[0296] (206) 3-[(Z)-2-(5-aminopyrazine-2-yl)-2-fluoroethenyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide,

[0297] (207) 4-fluoro-3-[(Z)-2-fluoro-2-(5-fluoropyridine-3-yl)ethenyl]-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide.

[0298] (Article 5)

[0299] A compound or a pharmaceutically acceptable salt or solvate of the compound described in claim 1, or a pharmaceutically acceptable salt or solvate of the same, selected from the group consisting of (1) to (15) below.

[0300] (1) 2-(cyclopropylmethyl)-N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)-1,3-thiazole-5-carboxamide,

[0301] (2) 5-[cyclopropyl(methyl)amino]-N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)pyridine-3-carboxamide,

[0302] (3) 5-(3-fluorophenyl)-N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)pyridine-3-carboxamide,

[0303] (4) 5-(cyclopropylmethoxy)-N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)pyridine-3-carboxamide,

[0304] (5) 5-ethoxy-N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)pyridine-3-carboxamide,

[0305] (6) 3-{[(2-aminopyrimidine-5-yl)methyl]amino}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide,

[0306] (7) N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-{[(pyrazolo[1,5-a]pyrimidine-3-yl)methyl]amino}benzamide,

[0307] (8) N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-[({2-[(oxane-4-yl)amino]pyrimidine-5-yl}methyl)amino]benzamide,

[0308] (9) N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-({[6-(1H-1,2,3-triazole-1-yl)pyridine-3-yl]methyl}amino)benzamide,

[0309] (10) 3-{[([2,3'-bipyridine]-5'-yl)amino]methyl}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide,

[0310] (11) 5-[(Z)-2-(6-aminopyridine-3-yl)-2-fluoroethenyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-6-methylpyridine-3-carboxamide,

[0311] (12) 3-[(Z)-2-{5-[(4-ethylpiperazine-1-yl)methyl]pyridine-3-yl}-2-fluoroethenyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide,

[0312] (13) 4-fluoro-3-{(Z)-2-fluoro-2-[2-(methylamino)pyrimidine-5-yl]ethenyl}-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide,

[0313] (14) 3-[(Z)-2-(5-aminopyrazine-2-yl)-2-fluoroethenyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide,

[0314] (15) 4-fluoro-3-[(Z)-2-fluoro-2-(5-fluoropyridine-3-yl)ethenyl]-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide.

[0315] (Paragraph 6)

[0316] A pharmaceutical composition containing, as an active ingredient, a compound described in any one of claims 1 to 5, a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0317] (Article 7)

[0318] A PDGF receptor kinase inhibitor containing, as an active ingredient, a compound described in any of claims 1 to 5, a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0319] (Article 8)

[0320] A compound listed in any of claims 1 to 5, or a pharmaceutically acceptable salt thereof, or a solvate thereof, containing as an active ingredient a PDGF receptor kinase-involved pulmonary hypertension, scleroderma, asthma, obstructive bronchiolitis, pulmonary fibrosis, acute myelogenous leukemia (AML), eosinophilic syndrome, T-lymphoblastic leukemia, chronic myelomonocytic leukemia (CMML), chronic myelogenous leukemia (CML), chronic eosinophilic leukemia, cutaneous fibrosarcoma protuberance, glioma, ovarian cancer, vascular restenosis, atherosclerotic / obstructive arteriosclerosis, Moyamoya disease (idiopathic Willis's arterial ring occlusion), leiomyoma, lymphangiomyomatosis, or, for example, age-related macular degeneration ( A treatment for macular degeneration (AMD). Effects of the invention

[0321] Since the compound of the present invention inhibits PDGF receptor kinase, it is useful as a therapeutic agent for diseases involving PDGF receptor kinase (e.g., respiratory diseases, cancer, smooth muscle proliferative diseases, angioplastic diseases, autoimmune / inflammatory diseases, metabolic diseases, vascular occlusive diseases, etc.). Specific details for implementing the invention

[0322] The meaning of each term used in this specification is explained below. Unless otherwise specifically stated, each term is used with the same meaning whether used alone or in combination with other terms.

[0323] "Halogen atoms" refers to fluorine atoms, chlorine atoms, bromine atoms, and iodine atoms.

[0324] Examples of “alkyl” include alkyls having 1 to 6 carbon atoms in a straight or branched chain, preferably 1 to 4 carbon atoms, and more preferably 1 to 3 carbon atoms. Specifically, examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, sec-pentyl, 1-ethylpropyl, 1,2-dimethylpropyl, tert-pentyl, 2-methylbutyl, isopentyl, neopentyl, n-hexyl, sec-hexyl, 1-ethylbutyl, isohexyl, neohexyl, 1,1-dimethylbutyl, 2-ethylbutyl, 1,2,2-trimethylpropyl, 2,2-dimethylbutyl, etc.

[0325] The alkyl portions of “monoalkylamino”, “alkylcarbonyloxy”, “dialkylamino”, “alkylcarbonylamino”, “alkylsulfonyl”, “aminoalkyl”, and “alkylcarbonyl” may include “alkyl” as described above.

[0326] "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 even more preferably 2 to 4 carbon atoms, having one or more double bonds at any position in a straight or branched chain. Specifically, examples include vinyl, allyl, 2-methylpropenyl, propenyl, isopropenyl, butenyl, isobutenyl, prenyl, butadienyl, pentenyl, isopentenyl, pentadienyl, hexenyl, isohexenyl, hexadienyl, etc.

[0327] "Amino" represents -NH2.

[0328] "Aminoalkyl" refers to a group in which an amino group is substituted for a hydrogen atom bonded to a carbon atom of the "alkyl" group. Specifically, examples include aminomethyl, 1-aminoethyl, 2-aminoethyl, 1-aminopropyl, 2-aminopropyl, 2-aminopropane-2-yl, 3-aminopropyl, etc.

[0329] "Monoalkylamino" refers to a group in which the "alkyl" is substituted with one hydrogen atom bonded to the nitrogen atom of the amino group. Specifically, examples include methylamino, ethylamino, isopropylamino, etc.

[0330] "Hydroxyalkyl" refers to a group in which a hydroxyl group is substituted for a hydrogen atom bonded to a carbon atom of the "alkyl" group. Specifically, examples include hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1-hydroxypropyl, 2-hydroxypropyl, etc.

[0331] "Alkyl carbonyl" means a group in which the above "alkyl" is bonded to a carbonyl group. Examples include methyl carbonyl, ethyl carbonyl, propyl carbonyl, isopropyl carbonyl, tert-butyl carbonyl, isobutyl carbonyl, sec-butyl carbonyl, pentyl carbonyl, isopentyl carbonyl, hexyl carbonyl, etc.

[0332] "Haloalkyl" refers to a group in which the "halogen atom" is substituted for a hydrogen atom of the "alkyl". Specifically, examples include fluoromethyl, chloromethyl, fluoroethyl, difluoromethyl, dichloromethyl, difluoroethyl, trifluoromethyl, trichloromethyl, and trifluoroethyl.

[0333] "Alkoxy" refers to a group in which the above "alkyl" is bonded to an oxygen atom. For example, an alkoxy having 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, in a straight or branched chain can be cited. Specifically, examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentyloxy, and n-hexyloxy.

[0334] As for the alkoxy portion of the "haloalkoxy," the same "alkoxy" as above can be cited.

[0335] Examples of "aryl" include monocyclic to tricyclic aromatic hydrocarbon groups having 6 to 14 carbon atoms. Specifically, examples include phenyl, 1-naphthyl, 2-naphthyl, 1-anthryl, 2-anthryl, 9-anthryl, 1-phenanthryl, 2-phenanthryl, 3-phenanthryl, 4-phenanthryl, 10-phenanthryl, etc. Among these, phenyl is preferred.

[0336] "Cycloalkyl" refers to a cyclic non-aromatic hydrocarbon group that is monocyclic to tricyclic. Specifically, examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

[0337] The above "non-aromatic carbon-cyclic group" may be a cross-linked hydrocarbon group. Examples of such cross-linked hydrocarbon groups include,

[0338] · 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),

[0339] · Bicyclo[1.1.1]fentanyl (e.g., bicyclo[1.1.1]pentan-1-yl, bicyclo[1.1.1]pentan-2-yl),

[0340] · 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),

[0341] · Bicyclo[2.2.2]octanil (e.g., bicyclo[2.2.2]octan-1-yl, bicyclo[2.2.2]octan-2-yl),

[0342] · 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

[0343] · Cuban-1- can be cited.

[0344] The above "non-aromatic carbon cyclic group" may be a spirocyclic group. Examples of such spirocyclic groups include,

[0345] · Spiro[3.3]heptanyl (e.g., spiro[3.3]heptan-1-yl, spiro[3.3]heptan-2-yl),

[0346] · Spiro[4.4]nonanyl (e.g., Spiro[4.4]nonan-1-yl, Spiro[4.4]nonan-2-yl),

[0347] · Spiro[5.5]Undecanil (e.g., Spiro[5.5]Undecan-1-yl, Spiro[5.5]Undecan-2-yl, Spiro[5.5]Undecan-3-yl) or

[0348] · 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.

[0349] Examples of "heteroaryls" include aromatic rings that are mono- to tri-ring, have 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur atoms as constituent atoms, and have 6 to 14 carbon atoms. Specifically, for example,

[0350] · Furyl (e.g., 2-furyl, 3-furyl),

[0351] ·Thienyl (e.g., 2-thienyl, 3-thienyl),

[0352] · Pyrrolyl (e.g., 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl),

[0353] ·Imidazolyl (e.g., 1-imidazolyl, 2-imidazolyl, 4-imidazolyl),

[0354] · Pyrazolil (e.g., 1-pyrazolil, 3-pyrazolil, 4-pyrazolil),

[0355] · Triazolyl (e.g., 1,2,4-triazol-1-yl, 1,2,4-triazol-3-yl, 1,2,4-triazol-4-yl),

[0356] · Tetrazolyl (e.g., 1-tetrazolyl, 2-tetrazolyl, 5-tetrazolyl),

[0357] · Oxazolyls (e.g., 2-oxazolyl, 4-oxazolyl, 5-oxazolyl),

[0358] · Isooxazolil (e.g., 3-isooxazolil, 4-isooxazolil, 5-isooxazolil),

[0359] · Oxadiazolyl (e.g., 1,3,4-oxadiazol-2-yl),

[0360] · Thiazolyl (e.g., 2-thiazolyl, 4-thiazolyl, 5-thiazolyl),

[0361] ·Thiadiazolyl (e.g., 1,3,4-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,3-thiadiazolyl),

[0362] · Isothiazolyls (e.g., 3-isothiazolil, 4-isothiazolil, 5-isothiazolil),

[0363] ·Piridil (e.g., 2-Piridil, 3-Piridil, 4-Piridil),

[0364] · Pyridazinil (e.g., 3-pyridazinil, 4-pyridazinil),

[0365] · Pyrimidinyl (e.g., 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl),

[0366] · Pyrazinil (e.g., 2-pyrazinil),

[0367] · Benzothiadiazole (e.g., 1,2,3-benzothiadiazole-4-yl, 1,2,3-benzothiadiazole-5-yl, 2,1,3-benzothiadiazole-4-yl, 2,1,3-benzothiadiazole-5-yl),

[0368] · Benzothiazolyl (e.g., benzothiazol-2-day, benzothiazol-4-day, benzothiazol-5-day, benzothiazol-6-day, benzothiazol-7-day),

[0369] · Indolil (e.g., indol-3-day, indol-4-day, indol-5-day, indol-6-day, indol-7-day,),

[0370] ·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),

[0371] ·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),

[0372] · Quinolyl (quinoline-2-yl, quinoline-3-yl, quinoline-4-yl, quinoline-5-yl, quinoline-6-yl, quinoline-7-yl, quinoline-8-yl) or

[0373] ·1,3-benzoxazole-2-yl can be cited.

[0374] "Heterocycloalkyl" may refer to a cyclic non-aromatic heterocyclic group having one or more identical or different heteroatoms selected from nitrogen, oxygen, and sulfur atoms within the ring, and having a ring of two or more rings. Specifically, for example,

[0375] · Oxetanil (e.g., 2-oxetanil, 3-oxetanil),

[0376] · Azetidinyl (e.g., 2-azetidinyl, 3-azetidinyl),

[0377] · Tetrahydropyranil (e.g., 2-tetrahydropyranil, 3-tetrahydropyranil, 4-tetrahydropyranil),

[0378] ·1,4-dioxanyl (e.g., 1,4-dioxane-2-yl),

[0379] · 1,3-dioxanyl (e.g., 1,3-dioxane-2-yl, 1,3-dioxane-4-yl, 1,3-dioxane-5-yl),

[0380] · Pyrrolidinyl (e.g., 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl),

[0381] · Piperidinyl (e.g., 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl),

[0382] · Piperazinyl (e.g., 1-piperazinyl, 2-piperazinyl, 3-piperazinyl),

[0383] · Azephanil (e.g., 1-azephanil, 2-azephanil, 3-azephanil, 4-azephanil),

[0384] · Azocanil (e.g., 1-azocanil, 2-azocanil, 3-azocanil, 4-azocanil, 5-azocanil),

[0385] · Homopiperidinyl (e.g., 2-homopiperidinyl, 3-homopiperidinyl, 4-homopiperidinyl),

[0386] · Morpholnil (e.g., 2-morpholnil, 3-morpholnil, 4-morpholnil),

[0387] · Thiomorphollinil (e.g., 2-thiomorphollinil, 3-thiomorphollinil, 4-thiomorphollinil) or

[0388] Examples include tetrahydrofuryl (2-tetrahydrofuryl, 3-tetrahydrofuryl).

[0389] The above "heterocycloalkyl" may be an exchange group. Examples of such exchange groups include,

[0390] · 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),

[0391] · Quinuclidinyl (e.g., quinuclidin-2-yl, quinuclidin-3-yl, quinuclidin-4-yl) or

[0392] ·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.

[0393] The above "heterocycloalkyl" may be a spirocyclic group. Examples of such spirocyclic groups include,

[0394] ·6-Azaspiro[2.5]octane-1-yl (e.g., 6-Azaspiro[2.5]octane-1-yl, 6-Azaspiro[2.5]octane-4-yl, 6-Azaspiro[2.5]octane-5-yl),

[0395] ·3,9-diazaspiro[5.5]undecan-1-il(e.g., 3,9-diazaspiro[5.5]undecan-1-il, 3,9-diazaspiro[5.5]undecan-2-il, 3,9-diazaspiro[5.5]undecan-3-il),

[0396] · 2,7-diazaspiro[3.5]nonan-1-il (e.g., 2,7-diazaspiro[3.5]nonan-1-il, 2,7-diazaspiro[3.5]nonan-2-il, 2,7-diazaspiro[3.5]nonan-5-il, 2,7-diazaspiro[3.5]nonan-6-il, 2,7-diazaspiro[3.5]nonan-7-il),

[0397] ·7-Azaspiro[3.5]nonanyl (e.g., 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

[0398] · 2,5-diazabicyclo[2.2.1]heptanyl (e.g., 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.

[0399] Below, each symbol of Equation [1] is explained.

[0400] R in Equation [1] 1 It is silver, hydrogen atom, 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.

[0401] Preferably, a hydrogen atom, a halogen atom, a C1-C6 alkyl, a C2-C6 alkenyl, an amino, a monoalkylamino, a dialkylamino, an alkylcarbonylamino, a C3-C6 cycloalkyl substituted in some cases, a heterocycloalkyl substituted in some cases, an aryl substituted in some cases, or a heteroaryl substituted in some cases.

[0402] In some cases, a heterocycloalkyl substituted, an aryl substituted, or a heteroaryl substituted is more preferable.

[0403] Oxetanil, tetrahydrofuranil, tetrahydropyranil, morpholinil, piperidinil, piperazinil, phenyl, pyridyl, pyrimidinil, pyrazinil, isoquinolinil, thienyl, pyrazolil, imidazo[1,2-a]pyrazinil, 1,2,3-triazolyl, or imidazo[1,2-b]pyridazinil is more preferable.

[0404] R 2 is, coupling loss, -(CR a R b ) m -NR c -, -NR c -(CR a R b ) m -, -(CR a Rb ) 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- is.

[0405] Combined hand, -(CR a R b ) m -NR c -, -(CR a R b ) m -O-, -(CR a R b ) m -, -NR c -, -O-, -NR c -CO-NR c -, -CR a =CR b Or -C≡C- is preferable, and

[0406] Combined hand, -(CR a R b ) m -NR c -, or -NR c - is more desirable.

[0407] R 2 R in a is a hydrogen atom, a halogen atom, a C1-C6 alkyl or C1-C6 haloalkyl.

[0408] Hydrogen atom or R a and R b It is desirable to form C=O together with the carbon atom that bonds.

[0409] R 2 R in b is a hydrogen atom, a halogen atom, a C1-C6 alkyl or C1-C6 haloalkyl.

[0410] Hydrogen atom or Ra and R b It is desirable to form C=O together with the carbon atom that bonds.

[0411] R 2 R in c Each is independently a hydrogen atom, a C1-C6 alkyl, or a C1-C6 haloalkyl.

[0412] Hydrogen atoms are desirable.

[0413] Het is a heteroaryl with a value of 5 to 10 won.

[0414] 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, or pyrazolo[1,5-a]pyridyl is preferred,

[0415] Thiazolyl, pyridyl, or pyrimidinyl is more preferable.

[0416] L 1 silver, bonding loss, -(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- is.

[0417] Combined hand, -(CR a R b ) m -NR c -, -NR c -(CR a R b ) m -, -(CR a R b ) m -O-, -O-(CR a R b ) m -, -(CR a R b ) m -, -NR c -, -CR a =CR b - or -C≡C- is preferable, and

[0418] -(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 desirable.

[0419] L 1 R in a is, a hydrogen atom, a halogen atom, a C1-C6 alkyl, a C1-C6 haloalkyl, or R a and R b It forms C=O together with the carbon atom it bonds with.

[0420] Hydrogen atoms, halogen atoms, C1-C6 alkyl or R a and R b It is desirable to form C=O together with the carbon atom that bonds.

[0421] L 1 R in b is, a hydrogen atom, a halogen atom, a C1-C6 alkyl, a C1-C6 haloalkyl, or R aand R b It forms C=O together with the carbon atom it bonds with.

[0422] Hydrogen atom or R a and R b It is desirable to form C=O together with the carbon atom that bonds.

[0423] L 1 R in c Each is independently a hydrogen atom, a C1-C6 alkyl, or a C1-C6 haloalkyl.

[0424] Hydrogen atoms or C1-C6 alkyls are preferred, and

[0425] Hydrogen atoms are more desirable.

[0426] L 2 ne, -(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- is.

[0427] Combined hand, -(CR a R b ) m -NR c -, or -NR c -CO-NR c - is desirable, bond loss, or -(CR a R b ) m -NR c - is more desirable.

[0428] L 2 R in a is, a hydrogen atom, a halogen atom, a C1-C6 alkyl, a C1-C6 haloalkyl, or R b And, together with the carbon atoms they bond with, they form C=O.

[0429] L 2 R in a Ro, R b And, together with the carbon atoms they bond with, it is desirable to form C=O.

[0430] L 2 R in b is, a hydrogen atom, a halogen atom, a C1-C6 alkyl, a C1-C6 haloalkyl, or R a And, together with the carbon atoms they bond with, they form C=O.

[0431] L 2 R in b Ro, R a And, together with the carbon atoms they bond with, it is desirable to form C=O.

[0432] L 2 R in c is a hydrogen atom, a C1-C6 alkyl or a C1-C6 haloalkyl.

[0433] L 2 R in c Each one is independent, and hydrogen atoms are preferred.

[0434] R 4 is a hydrogen atom, a halogen atom, or methyl.

[0435] Halogen atoms, or methyl, are preferred.

[0436] R 5 is a hydrogen atom, a halogen atom, a hydroxyl, an amino, a C1-C6 alkyl, a C1-C6 haloalkyl, a C1-C6 alkoxy, or a C1-C6 haloalkoxy.

[0437] Hydroxy is desirable.

[0438] R 6is a hydrogen atom, a halogen atom, a C1-C6 alkyl, a C1-C6 haloalkyl, or optionally a substituted phenyl, and

[0439] R 7 Silver, a hydrogen atom, a halogen atom, a C1-C6 alkyl, a C1-C6 haloalkyl, a hydroxyalkyl, optionally a substituted phenyl or C3-C6 cycloalkyl, or

[0440] R 6 and R 7 They form C3-C6 cycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl, together with the carbon atoms they bond to.

[0441] R 6 The phenyl is preferably a hydrogen atom, a C1-C6 alkyl, or, in some cases, a substituted phenyl.

[0442] R 7 Silver, C1-C6 alkyl, hydroxyalkyl, or optionally substituted phenyl is preferred, or,

[0443] R 6 and R 7 It is preferable that they form a C3-C6 cycloalkyl or, in some cases, a substituted aryl, together with the carbon atoms to which they bond, and

[0444] R 6 and R 7 It is more desirable for them to form a C3-C6 cycloalkyl group together with the carbon atoms they bond to.

[0445] More specifically, the compound of the present invention is L 1 Depending on the type, it includes the compounds shown in Table 1 below.

[0446] [Table 1]

[0447]

[0448] (In the table, R 1 , R 2 , R 4 , R 5 , R6 , R 7 , R c , L 1 , L 2 , Het is synonymous with the above.)

[0449] ·1-A: In compound [1], L 1 This -(CR a R b ) m -NR c - and, m is 1 and, R a and R b is a compound in which they form C=O together with the carbon atoms they bond to.

[0450] ·1-B: In compound [1], L 1 Compounds in the case where -C≡C-.

[0451] ·1-C: In compound [1], L 1 This -NR c -(CR a R b ) m - and, m is 1 and, R a and R b is a compound in which they form C=O together with the carbon atoms they bond to.

[0452] ·1-D: In compound [1], L 1 This -NR c -Compound in the case of.

[0453] ·1-E: In compound [1], L 1 This -(CR a R b ) m -NR c - and, m is 1 and, R a and R b A compound in which g is a hydrogen atom.

[0454] ·1-F: In compound [1], L 1 This -NR c -(CR a R b ) m - and, m is 1 and, Ra and R b A compound in which g is a hydrogen atom.

[0455] [Table 2]

[0456]

[0457] (In the table, R 1 , R 2 , R 4 , R 5 , R 6 , R 7 , R c , L 1 , L 2 , Het is synonymous with the above.)

[0458] ·1-G: In compound [1], L 1 This -(CR a R b ) m -O- and, m is 1 and R a and R b A compound in which g is a hydrogen atom.

[0459] ·1-H: In compound [1], L 1 This -O-(CR a R b ) m - and, m is 1 and, R a and R b go Compounds in the case of hydrogen atoms.

[0460] ·1-I: In compound [1], L 1 This -CR a =CR b -is, R a and R b Compound in the case where is H.

[0461] ·1-J: In compound [1], L 1 This -(CR a R b ) m - and, m is 2 and, R a and R b Compound in the case where is H.

[0462] ·1-K: In compound [1], L 1 This -CR a =CR b -is, R a ga halogen atom, R b Compound in the case where is H.

[0463] R in compound 1-A 1 As for the atom, 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 is preferred, and C1-C6 alkyl, C1-C6 alkoxy, optionally substituted C3-C6 cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl is more preferred.

[0464] R in compound 1-A 2 Ro, coupling loss, -(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 desirable, bond loss, -(CR a R b ) m -NR c -, -(CR a R b ) m -O-, -(CR a R b ) m -, -NR c - or -O- is more preferable.

[0465] R in compound 1-A2 As for m, 0, 1, and 2 are preferred, and 0 and 1 are more preferred.

[0466] As for the Het in compound 1-A, thiazolyl, pyridyl, oxazolyl, or imidazothiazolyl is preferred, and thiazolyl or pyridyl is more preferred.

[0467] R in compound 1-A 4 In the case of the rheo, a halogen atom or methyl is preferred, and methyl is more preferred.

[0468] L in compound 1-A 2 로, -(CR a R b ) m -NR c - is desirable.

[0469] L in compound 1-A 2 As for m, 1 is preferable.

[0470] R in compound 1-A 5 Hydroxy is preferred.

[0471] R in compound 1-A 6 Ro is H, C1-C6 alkyl or R 7 And, together with the carbon atoms to which they bond, it is desirable to form a C3-C6 cycloalkyl group, and R 7 And, together with the carbon atoms they bond to, it is more desirable to form a C3-C6 cycloalkyl.

[0472] R in compound 1-A 7 As, C1-C6 alkyl, optionally substituted phenyl or R 6 And, together with the carbon atoms they bond to, it is desirable to form a C3-C6 cycloalkyl, and R 6 And, together with the carbon atoms they bond to, it is more desirable to form a C3-C6 cycloalkyl.

[0473] R in compound 1-B 1As for the halogen atom, H, a halogen atom, a C1-C6 alkyl, an amino, a C3-C6 cycloalkyl substituted in some cases, an aryl substituted in some cases, or a heteroaryl substituted in some cases is preferred, and a halogen atom, a C3-C6 cycloalkyl substituted in some cases, an aryl substituted in some cases, or a heteroaryl substituted in some cases is more preferred.

[0474] R in compound 1-B 2 Ro, coupling loss, -(CR a R b ) m -NR c - is desirable, and bonding is more desirable.

[0475] R in compound 1-B 2 For m, 0 or 1 is preferred.

[0476] For the Het in compound 1-B, pyridyl or pyrazinyl is preferred.

[0477] R in compound 1-B 4 The halogen atom, or methyl is preferred, and methyl is preferred.

[0478] L in compound 1-B 2 로, -(CR a R b ) m -NR c - is desirable.

[0479] L in compound 1-B 2 As for m, 1 is preferable.

[0480] R in compound 1-B 5 Hydroxy is preferred.

[0481] R in compound 1-B 6 Ro is, in some cases, a substituted phenyl or R 7 And, together with the carbon atoms to which they bond, it is desirable to form a C3-C6 cycloalkyl group, and R 7And, together with the carbon atoms they bond to, it is more desirable to form a C3-C6 cycloalkyl.

[0482] R in compound 1-B 7 As for, hydroxyalkyl or R 6 And, together with the carbon atoms they bond to, it is desirable to form a C3-C6 cycloalkyl, and R 6 And, together with the carbon atoms they bond to, it is more desirable to form a C3-C6 cycloalkyl.

[0483] R in compound 1-C 1 As for the, 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 are preferred, and optionally substituted aryl is more preferred.

[0484] R in compound 1-C 2 Ro, coupling loss, -(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 desirable, and bonding is more desirable.

[0485] As for the Het in compound 1-C, thiazolyl, pyridyl, oxazolyl, or imidazothiazolyl is preferred, and pyridyl is more preferred.

[0486] R in compound 1-C 4 In the case of the rheo, a halogen atom or methyl is preferred, and methyl is more preferred.

[0487] R in compound 1-C 5 Hydroxy is preferred.

[0488] R in compound 1-C 6 Ro is H, C1-C6 alkyl or R 7 And, together with the carbon atoms to which they bond, it is desirable to form a C3-C6 cycloalkyl group, and R 7 And, together with the carbon atoms they bond to, it is more desirable to form a C3-C6 cycloalkyl.

[0489] R in compound 1-C 7 As, C1-C6 alkyl, optionally substituted phenyl or R 6 And, together with the carbon atoms they bond to, it is desirable to form a C3-C6 cycloalkyl, and R 6 And, together with the carbon atoms they bond to, it is more desirable to form a C3-C6 cycloalkyl.

[0490] R in compound 1-D 1 As for the, 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 is preferred, and monoalkylamino, optionally substituted heteroaryl is more preferred.

[0491] R in compound 1-D 2 Ro, coupling loss, -(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 desirable, and bonding is more desirable.

[0492] As for the Het in compound 1-D, pyrimidinyl, pyridyl, or kinazolyl are preferred, and pyrimidinyl is more preferred.

[0493] R in compound 1-D 4 In the case of the rheo, a halogen atom or methyl is preferred, and methyl is more preferred.

[0494] R in compound 1-D 5 Hydroxy is preferred.

[0495] R in compound 1-D 6 Rho is, in some cases, a substituted aryl or R 7 And, together with the carbon atoms to which they bond, it is desirable to form a C3-C6 cycloalkyl group, and R 7 And, together with the carbon atoms they bond to, it is more desirable to form a C3-C6 cycloalkyl.

[0496] R in compound 1-D 7 As, hydroxyalkyl, optionally substituted phenyl or R 6 And, together with the carbon atoms they bond to, it is desirable to form a C3-C6 cycloalkyl, and R 6 And, together with the carbon atoms they bond to, it is more desirable to form a C3-C6 cycloalkyl.

[0497] R in compound 1-E 1As for the components, 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, carboxyl, alkylcarbonyloxy, amino, aminoalkyl, monoalkylamino, dialkylamino, alkylcarbonylamino, nitro, optionally substituted C3-C6 cycloalkyl, optionally substituted C3-C6 cycloalkenyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted H, amino, optionally substituted C3-C6 cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl are more preferable.

[0498] R in compound 1-E 2 Ro, coupling loss, -(CR a R b ) m -NR c -, -NR c -, -NR c -CO-NR c - or -C≡C- is preferable, bond loss, -(CR a R b ) m -NR c - or -NR c - is more desirable.

[0499] R in compound 1-E 2 For m, 0 or 1 is preferable.

[0500] As Het in compounds 1-E, thiazolyl, pyridyl, oxazolyl, pyrazinyl, pyrimidinyl, pyrazolyl, imidazothiazolyl, quinazolinyl, quinolinyl, 7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-yl, thieno[3,2-b]pyridinyl, 1H-pyrolo[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, or pyrazolo[1,5-a]pyrimidinyl is more preferred.

[0501] R in compound 1-E 4 H, a halogen atom, or methyl is preferred, and a halogen atom or methyl is more preferred.

[0502] L in compound 1-E 2 로, -(CR a R b ) m -NR c - is desirable.

[0503] L in compound 1-E 2 As for m, 1 is preferable.

[0504] R in compound 1-E 5 Hydroxy is preferred.

[0505] R in compound 1-E 6 Ro, R 7 And, together with the carbon atoms they bond to, it is more desirable to form a C3-C6 cycloalkyl.

[0506] R in compound 1-E 7 As for, R 6 And, together with the carbon atoms they bond to, it is more desirable to form a C3-C6 cycloalkyl.

[0507] R in compound 1-F 1As for the halogen atom, a C3-C6 cycloalkyl substituted in some cases, an aryl substituted in some cases, or a heteroaryl substituted in some cases is preferred, and a C3-C6 cycloalkyl substituted in some cases, an aryl substituted in some cases, or a heteroaryl substituted in some cases is more preferred.

[0508] R in compound 1-F 2 In this case, a bonding hand or -C≡C- is preferred, and a bonding hand is more preferred.

[0509] As for the Het in compound 1-F, pyridyl or pyrazinyl is preferred, and pyridyl is more preferred.

[0510] R in compound 1-F 4 H, a halogen atom, or methyl is preferred, and H or methyl is more preferred.

[0511] L in compound 1-F 2 로, -(CR a R b ) m -NR c -, -NR c -CO-NR c - is desirable.

[0512] L in compound 1-F 2 As for m, 1 is preferable.

[0513] R in compound 1-F 5 Hydroxy is preferred.

[0514] R in compound 1-F 6 Ro is, in some cases, a substituted phenyl or R 7 And, together with the carbon atoms to which they bond, it is desirable to form a C3-C6 cycloalkyl group, and R 7 And, together with the carbon atoms they bond to, it is more desirable to form a C3-C6 cycloalkyl.

[0515] R in compound 1-F 7As for, hydroxyalkyl or R 6 And, together with the carbon atoms they bond to, it is desirable to form a C3-C6 cycloalkyl, and R 6 And, together with the carbon atoms they bond to, it is more desirable to form a C3-C6 cycloalkyl.

[0516] R in compound 1-G 1 In some cases, a substituted aryl or a substituted heteroaryl is preferred, and a substituted heteroaryl is more preferred.

[0517] R in compound 1-G 2 For the joint, a joining hand is desirable.

[0518] Pyridyl is preferred as the Het in compound 1-G.

[0519] R in compound 1-G 4 H, a halogen atom, or methyl is preferred, and a halogen atom or methyl is more preferred.

[0520] R in compound 1-G 5 Hydroxy is preferred.

[0521] R in compound 1-G 6 Ro, R 7 And, together with the carbon atoms they bond to, it is desirable to form a C3-C6 cycloalkyl.

[0522] R in compound 1-G 7 As for, R 6 And, together with the carbon atoms they bond to, it is desirable to form a C3-C6 cycloalkyl.

[0523] R in compound 1-H 1 As for this, a heteroaryl substituted in some cases is preferred.

[0524] R in compound 1-H 2 For the joint, a joining hand is desirable.

[0525] As for the Het in compound 1-H, pyridyl is preferred.

[0526] R in compound 1-H 4 In the case of the rheo, a halogen atom or methyl is preferred, and methyl is more preferred.

[0527] R in compound 1-H 5 Hydroxy is preferred.

[0528] R in compound 1-H 6 Ro, R 7 And, together with the carbon atoms they bond to, it is desirable to form a C3-C6 cycloalkyl.

[0529] R in compound 1-H 7 As for, R 6 And, together with the carbon atoms they bond to, it is desirable to form a C3-C6 cycloalkyl.

[0530] R in compound 1-I 1 In this case, an aryl substituted depending on the case is preferred.

[0531] R in compound 1-I 2 For the joint, a joining hand is desirable.

[0532] Pyridyl is preferred as the Het in compound 1-I.

[0533] R in compound 1-I 4 Methyl is preferred.

[0534] R in compound 1-I 5 Hydroxy is preferred.

[0535] R in compound 1-I 6 Ro, R 7 And, together with the carbon atoms they bond to, it is desirable to form a C3-C6 cycloalkyl.

[0536] R in compound 1-I 7 As for, R 6 And, together with the carbon atoms they bond to, it is desirable to form a C3-C6 cycloalkyl.

[0537] R in compound 1-J 1 In this case, an aryl substituted depending on the case is preferred.

[0538] R in compound 1-J 2 For the joint, a joining hand is desirable.

[0539] Pyridyl is preferred as the Het in compound 1-J.

[0540] R in compound 1-J 4 Methyl is preferred.

[0541] R in compound 1-J 5 Hydroxy is preferred.

[0542] R in compound 1-J 6 Ro, R 7 And, together with the carbon atoms they bond to, it is desirable to form a C3-C6 cycloalkyl.

[0543] R in compound 1-J 7 As for, R 6 And, together with the carbon atoms they bond to, it is desirable to form a C3-C6 cycloalkyl.

[0544] R in compound 1-K 1 As for the, H, a halogen atom, amino, monoalkylamino, dialkylamino, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, or optionally substituted heteroaryl are preferred, and optionally substituted heteroaryl are more preferred.

[0545] R in compound 1-K 2 Ro, coupling loss, -(CR a R b ) m -NR c -, -(CR a R b ) m-O-, -(CR a R b ) m - or -NR c - is desirable, bond loss, -(CR a R b ) m -NR c -, -(CR a R b ) m - or -NR c - is more desirable.

[0546] As for the Het in compound 1-K, pyridyl, pyrimidinyl, pyrazinyl, or imidazo[1,2-b]pyridazinyl is preferred, and pyridyl, pyrimidinyl, or pyrazinyl is more preferred.

[0547] R in compound 1-K 4 In this case, a halogen atom or methyl is preferred.

[0548] L in compound 1-K 2 로, -(CR a R b ) m -NR c - is desirable.

[0549] L in compound 1-K 2 As for m, 1 is preferable.

[0550] R in compound 1-K 5 Hydroxy is preferred.

[0551] R in compound 1-K 6 Ro is a C1-C6 alkyl or R 7 And, together with the carbon atoms to which they bond, it is preferable to form a C3-C6 cycloalkyl, or in some cases a substituted aryl, and R 7 And, together with the carbon atoms they bond to, it is more desirable to form a C3-C6 cycloalkyl.

[0552] R in compound 1-K 7 As for, C1-C6 alkyl or R 6And, together with the carbon atoms to which they bond, it is preferable to form a C3-C6 cycloalkyl, or in some cases a substituted aryl, and R 6 And, together with the carbon atoms they bond to, it is more desirable to form a C3-C6 cycloalkyl.

[0553] The compound of the present invention may be prepared from known compounds or easily synthesizable intermediates, for example, by the method described below, the examples described later, or a known method. In the preparation of the compound of the present invention, if the raw material has a substituent that affects the reaction, it is common practice to protect the raw material with a suitable protecting group by a known method beforehand and then carry out the reaction. The protecting group may be removed by a known method after the reaction.

[0554] The compound represented by Formula [1] can be used as a medicine as is, but it can also be used in the form of a salt, solvate, or solvate of a salt that is pharmaceutically acceptable by known methods. Examples of pharmaceutically acceptable salts include salts of inorganic acids such as hydrochloric acid, hydrobromide, 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 alkali metals such as lithium, potassium, and sodium; salts of alkaline earth metals such as magnesium and calcium; and salts of organic bases such as ammonium salts. These salts can be formed by methods commonly practiced.

[0555] 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 alcohol solution of hydrogen chloride, an ethyl acetate solution of hydrogen chloride, a 1,4-dioxane solution of hydrogen chloride, a cyclopentylmethyl ether solution of hydrogen chloride, or a diethyl ether solution of hydrogen chloride.

[0556] Among the compounds of the present invention having non-uniform carbons, each stereoisomer and mixtures thereof are included in the present invention. Stereoisomers may be prepared, for example, by optically separating from a racemic mixture using an optically active acid (tartaric acid, dibenzoyltranic acid, mandelic acid, 10-campersulfonic acid, etc.) by a known method utilizing its basicity, or by using a pre-prepared optically active compound as a raw material. Alternatively, they may be prepared by optical separating using a chiral column or by non-uniform synthesis.

[0557] The compounds of the present invention are not limited to specific isomers and include all possible isomers or racemic mixtures.

[0558] (Method for preparing the compound of the present invention)

[0559] The compound of the present invention can be prepared from a compound known itself or an intermediate that can be easily prepared from a known compound, for example, by the method below, the examples described below, or a known method.

[0560] If the solvents, reagents, and raw materials used in each process of the manufacturing method described below are commercially available, they may be used as is. Furthermore, the compounds obtained in each process of the manufacturing method described below, or the raw materials used, may form salts, or they may be converted into other types of salts or vitreous bodies by known methods. Conversely, if the compounds obtained in each process of the manufacturing method below, or the raw materials used, are vitreous bodies, they may be converted into the desired salt by known methods. Examples of such salts include those similar to the salts used in the compounds of the present invention described above.

[0561] The compound represented by Formula [1] of the present invention or a salt permitted therefrom may form solvates (e.g., hydrates, etc.) and / or crystal polymorphs, and the present invention includes such various solvates and crystal polymorphs. The "solvates" may coordinate with any number of solvent molecules (e.g., water molecules, etc.) with respect to the compound represented by Formula [1]. By leaving the compound represented by Formula [1] or a salt permitted therefrom in the atmosphere, it may absorb moisture, resulting in the attachment of adsorbed water or the formation of hydrates. Additionally, the compound represented by Formula [1] or a salt permitted therefrom may form their crystal polymorphs by recrystallizing them.

[0562] In the preparation of the compound of the present invention, if the raw material has substituents that may affect the reaction, a protecting group may be introduced to these substituents in advance by a known method, and the target compound may be obtained by removing the protecting group as necessary after the reaction. Such introduction of and removal of protecting groups may be appropriately selected and utilized, for example, the conditions presented in *Greene's Protective Groups in Organic Synthesis*, 4th edition, John Wiley & Sons Inc., 2006, or *Protecting Groups*, 3rd edition, Thieme, 2005, by PJ Kocienski.

[0563] The compounds obtained in each process of the manufacturing method below may be isolated or purified according to standard methods such as solvent extraction, concentration, distillation, sublimation, recrystallization, reprecipitation, or chromatography, or may be used in the following process in the form of a reaction mixture or crude product.

[0564] Unless otherwise specified, the reactions of each process in the following manufacturing method are to be performed by appropriately modifying or combining known methods, such as those described in *Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 2nd Edition* by RC Larock, John Wiley & Sons Inc., 1999; *Lectures on Experimental Chemistry*, 4th edition, compiled by the Nihon Kagakukai, Maruzen, 1992; *Organic Synthesis Strategies Learned from Human Reactions*, supervised and translated by Kiyoshi Tomioka, Kagaku Dojin, 2006; *Latest Organic Synthesis Methods, Design, and Strategies*, translated by Tamejiro Hiyama, Kagaku Dojin, 2009, etc., or the methods described in the Examples. It is carried out.

[0565] The compound of the present invention described above

[0566] (1-A: L 1 This -(CR a R b ) m -NR c - and, R a and R b is a compound that forms C=O together with the carbon atoms they bond to.

[0567] 1-B: L 1 This is a compound where -C≡C-.

[0568] 1-C: L 1 This -NR c -(CR a R b ) m - and, R a and R b is a compound that forms C=O together with the carbon atoms they bond to.

[0569] 1-D: L 1 This -NRc - Phosphorus compound.

[0570] 1-E: L 1 This -(CR a R b ) m -NR c - and, R a and R b are compounds that are each independently H, a halogen atom, a C1-C6 alkyl, or a C1-C6 haloalkyl.

[0571] 1-F: L 1 This NR c -(CR a R b ) m - and, R a and R b are compounds that are each independently H, a halogen atom, a C1-C6 alkyl, or a C1-C6 haloalkyl.

[0572] 1-G: L 1 This -(CR a R b ) m -O- and, R a and R b are compounds that are each independently H, a halogen atom, a C1-C6 alkyl, or a C1-C6 haloalkyl.

[0573] 1-H: L 1 This -O-(CR a R b ) m - and, R a and R b are compounds that are each independently H, a halogen atom, a C1-C6 alkyl, or a C1-C6 haloalkyl.

[0574] 1-I: L 1 This -CR a =CR b - and, R a and R b is a compound that is H.

[0575] 1-J: L 1 This -(CR a R b ) m - and, R aand R b is a compound that is H.

[0576] 1-K: L 1 This -CR a =CR b - and, R a ga halogen atom, R b (Compounds in which is H)

[0577] It can be manufactured, for example, by the general synthesis method shown below. Extraction, purification, etc., can be performed by the same treatments used in ordinary organic chemistry experiments.

[0578] Preparation of Compound 1-A

[0579] [Chemical Formula 2]

[0580]

[0581] (during food, R 1 , R 2 , R 4 , R 5 , R 6 , R 7 , R c , Het, X are synonyms with the above.)

[0582] Step 1

[0583] This process is a process for obtaining compound 1-A by condensing compound 1 or its reactive compound with amine compound 2 in the presence of a condensing agent.

[0584] Examples of reactive compounds of compound 1 include acid halides (e.g., acid chlorides, acid bromides), mixed acid anhydrides, imidazolids, active amides, etc., which are commonly used in amide condensation reactions.

[0585] In this process, the amount of condensing agent and amine compound 2 used is suitable within the range of 1 molar equivalent to 3 molar equivalents each relative to compound 1.

[0586] Examples of condensation agents used in this process 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 cyanophosphonic acid, O-(benzotriazole-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (hereinafter referred to as "HBTU"), and O-(7-azabenzotriazole-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (hereinafter referred to as "HATU").

[0587] In this process, a base may be used as needed. Examples of bases that can be used include organic bases such as TEA, DIPEA, N,N-dimethylaniline, and DBU.

[0588] The amount of such base used is suitable within the range of 1 molar equivalent to 10 molar equivalents for compound 1.

[0589] In this process, additives such as 1-hydroxybenzotriazole (hereinafter referred to as “HOBt”), N-hydroxysuccinate imide, and 1-hydroxy-7-azabenzotriazole (hereinafter referred to as “HOAt”) may be added as needed.

[0590] When using the above additive in this process, the amount of such additive used is suitable in the range of 0.1 molar equivalent to 3 molar equivalents for compound 1.

[0591] The solvents used are not particularly limited as long as they do not participate in the reaction, but 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 mixed solvents thereof.

[0592] The reaction temperature varies depending on the types of raw materials and reagents used, but typically, a range of -20°C to 150°C is suitable. Additionally, a microwave reaction device may be used if necessary.

[0593] The reaction time varies depending on the type of raw material used and the reaction temperature, but typically, a range of 0.1 to 72 hours is suitable.

[0594] Also, in compound [1], L 2 Ga -(CR a R b ) m -NR c -(R a and R b They form C=O together with the carbon atoms they bond to, and m and R c A compound (compound 1-AA) that is in the case of (which is agreed with the above) can also be prepared by the following method.

[0595] Preparation of Compound 1-AA

[0596] [Chemical Formula 3]

[0597]

[0598] (during food, R 1 , R 2 , R 4 , R 5 , R 6 , R 7 , R c , Het, and X are synonymous with the above. R is an alkyl group, for example, methyl, ethyl, and n-butyl.)

[0599] Step 1

[0600] This process is a process for obtaining compound 1-AA by condensing compound 1 or its reactive compound with amine compound 3 in the presence of a condensing agent, and can be prepared by the same method as Step 1 of the preparation of compound 1-A.

[0601] Step 2

[0602] This process is a process for obtaining compound 5 by condensing compound 1 or its reactive compound with amine compound 4 in the presence of a condensing agent, and can be prepared by the same method as Step 1 of the preparation of compound 1-A.

[0603] Step 3

[0604] The present process is a process for obtaining compound 6 by hydrolyzing the ester portion of compound 5 in a suitable solvent in the presence of a suitable acid or base.

[0605] In this process, the acids used may include inorganic acids such as hydrochloric acid and sulfuric acid, and organic acids such as trifluoroacetic acid (hereinafter referred to as “TFA”), methanesulfonic acid, and toluenesulfonic acid. The bases may include inorganic bases such as sodium hydroxide, potassium hydroxide, and lithium hydroxide.

[0606] In this process, the amount of acid or base used is suitable within the range of 1 molar equivalent to 10 molar equivalents relative to compound 5. If necessary, an excess amount of acid or base relative to compound 5 may be used.

[0607] The solvent used is not particularly limited as long as it does not participate in the reaction, but examples include alcohols such as methanol, ethanol, and 2-propanol; ethers such as THF, diethyl ether, 1,4-dioxane, and DME; nitriles such as acetonitrile and propionitrile; ketones such as acetone; water; or a mixture thereof.

[0608] The reaction temperature varies depending on the type of raw materials and reagents used, but typically, it can be carried out within the range of 20°C to 200°C, preferably 20°C to 100°C. In addition, if necessary, a microwave reaction device may be used.

[0609] The reaction time varies depending on the type of raw material used and the reaction temperature, but typically, a range of 0.5 hours to 4 days is suitable.

[0610] Step 4

[0611] This process is a process for obtaining compound 1-AA by condensing compound 6 or its reactive compound with amine compound 7 in the presence of a condensing agent, and can be prepared by the same method as Step 1 of the preparation of compound 1-A.

[0612] Preparation of Compound 1-B

[0613] [Chemical Formula 4]

[0614]

[0615] (during food, R 1 , R 2 , R 4 , R 5 , R 6 , R 7 , R c , Het, X, L 2 ...is consistent with the above. Y is a leaving group, and examples include a bromine atom, an iodine atom, methanesulfonate, and trifluoromethanesulfonate.)

[0616] Step 1

[0617] This process is a process for obtaining compound 1-B by coupling compound 8 and compound 9, respectively, in the presence of a transition metal such as palladium.

[0618] This reaction can be carried out by applying conditions commonly used in coupling reactions using transition metals, specifically the Sonogashira coupling reaction, and by methods described in literature such as Sonogashira et al., J, Organomet. Chem. 2002, 653, 46-49; Negishi et al., Chem. Rev., 2003, 103, 1979-2017.

[0619] The amount of compound 9 used is suitable in the range of 0.5 molar equivalents to 3 molar equivalents relative to compound 8.

[0620] The organometallic catalyst used in this reaction is not particularly limited. As preferred examples of organometallic catalysts, tris(dibenzylideneacetone)bispalladium·chloroform adduct (hereinafter referred to as “Pd2(dba)3·CHCl3”), tris(dibenzylideneacetone)bispalladium (hereinafter referred to as “Pd2(dba)3”), tetracyclotriphenylphosphinepalladium (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, Examples include metal catalysts such as “Pd(dtbpf)Cl2”, bis(tricyclohexylphosphine)palladium(II) dichloride (hereinafter referred to as “PdCl2(PCy3)2”), palladium(II) acetate (hereinafter referred to as “Pd(OAc)2”), and [1,3-bis(diphenylphosphino)propane]nickel(II), and mixtures of these metal catalysts.

[0621] The amount of transition metal used is suitable in the range of, for example, 0.01 molar equivalent to 0.3 molar equivalent for compound 8.

[0622] In this process, a base or salt may be used as needed. Examples of bases or salts to be used include potassium carbonate, cesium carbonate, sodium carbonate, sodium bicarbonate, sodium acetate, potassium acetate, trisodium phosphate, tripotassium phosphate and their solutions, as well as triethylamine (hereinafter referred to as “TEA”), N,N-diisopropylethylamine (hereinafter referred to as “DIPEA”), lithium chloride, and copper(I) iodide.

[0623] The amount of base used is suitable for compound 8, for example, in the range of 1 molar equivalent to 4 molar equivalents.

[0624] In this process, suitable ligands may be used as needed. Examples of ligands that can be used include, for instance, 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'-binafthyl (hereinafter referred to as "BINAP"), 2-dicyclohexylphosphino-2',6'-diisopropylbiphenyl (hereinafter referred to as "RuPhos"), triphenylphosphine (hereinafter referred to as "PPh3"), and tricyclohexylphosphine (hereinafter referred to as "PCy3").

[0625] The amount of ligand used is suitable within the range of 1 molar equivalent to 5 molar equivalents for the transition metal used, for example.

[0626] In the present process, the solvent used is not particularly limited as long as it does not participate in the reaction, but 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 mixture of these solvents.

[0627] The reaction temperature varies depending on the type of raw materials and reagents used, but typically, a range of 20°C to 200°C is suitable. In addition, if necessary, a microwave reaction device may be used.

[0628] The reaction time varies depending on the type of raw material used and the reaction temperature, but typically, a range of 0.1 to 24 hours is suitable.

[0629] L2 Ga -(CR a R b ) m -NR c - and, R a and R b Compounds (compound 1-BB) in which they form C=O together with the carbon atoms they bond to can also be prepared as follows.

[0630] Preparation of Compound 1-BB

[0631] [Chemical Formula 5]

[0632]

[0633] (during food, R 1 , R 2 , R 4 , R 5 , R 6 , R 7 , R c , Het, X, Y, and R are synonymous with the above. Z is a leaving group, and examples include trimethylsilyl and triethylsilyl.)

[0634] Step 1

[0635] This process is a process for obtaining alkyne compound 12 by coupling compound 10 and compound 11, respectively, in the presence of a transition metal such as palladium, and can be prepared by the same method as Step 1 of the preparation of compound 1-B.

[0636] Step 2

[0637] The process is a process of deprotecting Z to obtain compound 13, and can be carried out by referring, for example, to Wuts and Greene, “Greene’s Protective Groups in Organic Synthesis,” 4th edition, John Wiley & Sons Inc., 2006, or to PJ Kocienski, “Protecting Groups,” 3rd edition, Thieme, 2005.

[0638] Step 3

[0639] This process is a process for obtaining compound 15 by coupling compound 13 and compound 14, respectively, in the presence of a transition metal such as palladium, and can be prepared by the same method as Step 1 of the preparation of compound 1-B.

[0640] Step 4

[0641] This process is a process for obtaining compound 16 by hydrolyzing the ester portion of compound 15 in a suitable solvent in the presence of a suitable acid or base, and can be prepared by the same method as Step 3 of the preparation of compound 1-AA.

[0642] Step 5

[0643] This process is a process for obtaining compound 1-BB by condensing compound 16 or its reactive compound with amine compound 17 in the presence of a condensing agent, and can be prepared by the same method as Step 1 of the preparation of compound 1-A.

[0644] Preparation of Compound 1-C

[0645] [Chemical Formula 6]

[0646]

[0647] (during food, R 1 , R 2 , R 4 , R 5 , R 6 , R 7 , R c , Het, X are synonyms with the above.)

[0648] Step 1

[0649] The present process is a process for obtaining compound 1-C by condensing compound 19 or its reactive compound with amine compound 18 in the presence of a condensing agent, and can be prepared by the same method as Step 1 of the preparation of compound 1-A.

[0650] Preparation of Compound 1-D

[0651] [Chemical Formula 7]

[0652]

[0653] (during food, R 1 , R 2 , R 4 , R 5 , R 6 , R 7 , R c , L 2 , Het, and X are synonymous with the above. Y is a leaving group, and examples include a bromine atom, an iodine atom, and trifluoromethanesulfonate.)

[0654] Step 1

[0655] This process is a process for obtaining compound 1-D by coupling compound 20 and compound 21, respectively, in the presence of a transition metal such as palladium.

[0656] This reaction can be carried out under conditions commonly used in coupling reactions using transition metals, specifically the coupling reaction of Buchwald et al., and by methods described in literature such as Buchwald et al., J. Am. Chem. Soc. 1994, 116, 7901-7902., Buchwald et al., Org. Synth. 2002, 78, 23-28., and Hartwig et al., Acc. Chem. Res. 2008, 41, 1534-1544.

[0657] The amount of compound 21 used is suitable in the range of 0.5 molar equivalents to 3 molar equivalents relative to compound 20.

[0658] The organometallic catalyst used in this reaction is not particularly limited. As preferred examples of organometallic catalysts, tris(dibenzylideneacetone)bispalladium·chloroform adduct (hereinafter referred to as “Pd2(dba)3·CHCl3”), tris(dibenzylideneacetone)bispalladium (hereinafter referred to as “Pd2(dba)3”), tetracyclotriphenylphosphinepalladium (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, Examples include metal catalysts such as “Pd(dtbpf)Cl2”, bis(tricyclohexylphosphine)palladium(II) dichloride (hereinafter referred to as “PdCl2(PCy3)2”), palladium(II) acetate (hereinafter referred to as “Pd(OAc)2”), and [1,3-bis(diphenylphosphino)propane]nickel(II), and mixtures of these metal catalysts.

[0659] The amount of transition metal used is suitable, for example, in the range of 0.01 molar equivalent to 0.3 molar equivalent for compound 20.

[0660] In this process, a base or salt may be used as needed. Examples of bases or salts to be used include potassium carbonate, cesium carbonate, sodium carbonate, sodium bicarbonate, sodium acetate, potassium acetate, trisodium phosphate, tripotassium phosphate and their solutions, as well as triethylamine (hereinafter referred to as “TEA”), N,N-diisopropylethylamine (hereinafter referred to as “DIPEA”), lithium chloride, and copper(I) iodide.

[0661] The amount of base used is suitable within the range of, for example, 1 molar equivalent to 4 molar equivalents for compound 20.

[0662] In this process, suitable ligands may be used as needed. Examples of ligands that can be used include, for instance, 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'-binafthyl (hereinafter referred to as "BINAP"), 2-dicyclohexylphosphino-2',6'-diisopropylbiphenyl (hereinafter referred to as "RuPhos"), triphenylphosphine (hereinafter referred to as "PPh3"), and tricyclohexylphosphine (hereinafter referred to as "PCy3").

[0663] The amount of ligand used is suitable within the range of 1 molar equivalent to 5 molar equivalents for the transition metal used, for example.

[0664] In the present process, the solvent used is not particularly limited as long as it does not participate in the reaction, but 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 mixture of these solvents.

[0665] The reaction temperature varies depending on the type of raw materials and reagents used, but typically, a range of 20°C to 200°C is suitable. In addition, if necessary, a microwave reaction device may be used.

[0666] The reaction time varies depending on the type of raw material used and the reaction temperature, but typically, a range of 0.1 to 24 hours is suitable.

[0667] Preparation of Compound 1-E

[0668] [Chemical Formula 8]

[0669]

[0670] (during food, R 1 , R 2 , R 4 , R 5 , R 6 , R 7 , R a , R b , R c , L 2 , Het, X, Y are synonymous with the above.)

[0671] Step 1

[0672] This process is a process for obtaining compound 1-E by coupling compound 22 and compound 23 in the presence of a transition metal such as palladium, and can be prepared by the same method as Step 1 of the preparation of compound 1-D.

[0673] L 1 This -(CR a R b ) m -NR c - and, R a and R b In the case where H is used, it may be manufactured as follows.

[0674] Preparation of Compound 1-EE

[0675] [Chemical Formula 9]

[0676]

[0677] (during food, R 1 , R 2 , R 4 , R 5 , R 6 , R 7 , R c , L 2 , Het, X are synonyms with the above.)

[0678] Step 1

[0679] The present process is a process for obtaining compound 1-EE by a reductive amination reaction between compound 24 and compound 23, and can be carried out in accordance with known methods as a reductive amination reaction. The present process may also be carried out in steps of imine formation (first process) and reduction of the imine portion (second process).

[0680] The amount of compound 23 used is suitable within the range of 1 molar equivalent to 2.5 molar equivalents relative to compound 24.

[0681] In this process, an acid or a suitable Lewis acid may be used as needed. Examples of acids that can be used in the reaction include acetic acid, and examples of Lewis acids that can be used include tetraisopropyl orthotitanoate.

[0682] In this process, when using an acid, the amount of acid used is suitable within the range of 2 molar equivalents to 3 molar equivalents relative to the amount of compound 24.

[0683] In this process, when using a Lewis acid, the amount of Lewis acid used is suitable within the range of 1.5 molar equivalents to 2 molar equivalents relative to the amount of compound 24.

[0684] In this process, the solvent used is not particularly limited as long as it does not participate in the reaction, but examples include hydrocarbons such as toluene and xylene, ethers such as 1,4-dioxane, THF, and DME, halogenated hydrocarbons such as dichloromethane, or a mixture of these solvents.

[0685] In this process, the reaction temperature varies depending on the type of raw materials and reagents used, but typically, a range of 0°C to 100°C is suitable.

[0686] In this process, the reaction time varies depending on the type of raw material used and the reaction temperature, but typically, a range of 0.1 hours to 48 hours is suitable.

[0687] Examples of reducing agents used in this process include sodium triacetoxyborohydride and sodium borohydride.

[0688] The amount of reducing agent used in this process is suitable within the range of 1 molar equivalent to 2 molar equivalents for compound 24.

[0689] The solvent used in this process is not particularly limited as long as it does not participate in the reaction, but examples include hydrocarbons such as toluene and xylene, ethers such as 1,4-dioxane, THF, and DME, halogenated hydrocarbons such as dichloromethane, or a mixture of these solvents.

[0690] Preparation of Compound 1-F

[0691] [Chemical Formula 10]

[0692]

[0693] (during food, R 1 , R 2 , R 4 , R 5 , R 6 , R 7 , R a , R b , R c , L 2 , Het, X, Y are synonymous with the above.)

[0694] Step 1

[0695] This process is a process for obtaining compound 1-F by reacting compound 25 with compound 26 in the presence of a base.

[0696] The amount of compound 26 used is suitable in the range of 0.5 molar equivalents to 3 molar equivalents relative to compound 25.

[0697] The bases used in this reaction include pyridine, TEA, DIPEA, potassium carbonate, and sodium bicarbonate.

[0698] The amount of base used is suitable within the range of 1 molar equivalent to 10 molar equivalents for compound 25.

[0699] The solvent used is not particularly limited as long as it does not participate in the reaction, but examples include alcohols such as isopropanol, 1-butanol, and 2-methoxyethanol; ethers such as THF and 1,4-dioxane; amides such as DMF, DMA, and NMP; hydrocarbons such as benzene and toluene; dimethyl sulfoxide (hereinafter referred to as "DMSO"), acetonitrile, or a mixture of these solvents.

[0700] In this process, the reaction temperature varies depending on the type of raw materials and reagents used, but typically, a range of 20°C to 200°C is suitable. Additionally, if necessary, a microwave reaction device may be used.

[0701] The reaction time varies depending on the type of raw material used and the reaction temperature, but typically, a range of 1 hour to 24 hours is suitable.

[0702] L 1 This -NR c -(CR a R b ) m - and, R a and R b In the case where H is used, it may be manufactured as follows.

[0703] Preparation of Compound 1-FF

[0704] [Chemical Formula 11]

[0705]

[0706] (during food, R 1 , R 2 , R 4 , R 5 , R 6 , R 7 , R c , L 2 , Het, X are synonyms with the above.)

[0707] Step 1

[0708] This process is a process for obtaining compound 1-FF by a reductive amination reaction between compound 27 and compound 28, and can be prepared by the same method as Step 1 of the preparation of compound 1-EE.

[0709] Preparation of Compound 1-G

[0710] [Chemical Formula 12]

[0711]

[0712] (during food, R 1 , R 2 , R 4 , R 5 , R 6 , R 7 , R c , L 2 , Het, X are synonyms with the above.)

[0713] Step 1

[0714] This process is a process for obtaining ether compound 1-G by a Mitsunobu reaction between alcohol compound 29 and alcohol compound 30, and can be carried out in accordance with known methods.

[0715] This process is typically carried out in a suitable solvent in the presence of an azodicarboxylic acid ester reagent and a phosphine reagent.

[0716] The amount of compound 29 used is suitable within the range of 0.5 molar equivalents to 1.5 molar equivalents relative to compound 30.

[0717] Examples of azodicarboxylic acid ester reagents used include, for instance, diethyl azodicarboxylic acid (hereinafter referred to as “DEAD”), diisopropyl azodicarboxylic acid (hereinafter referred to as “DIAD”), bis(2-methoxyethyl)azodicarboxylate (hereinafter referred to as “DMEAD”), etc.

[0718] Examples of phosphine reagents used include, for instance, triphenylphosphine and tributylphosphine.

[0719] The amount of azodicarboxylic acid ester reagent used is suitable in the range of 1 molar equivalent to 2 molar equivalents for compound 29.

[0720] The amount of phosphine reagent used is suitable in the range of 1 molar equivalent to 2 molar equivalents for compound 29.

[0721] The solvent used is not particularly limited as long as it does not participate in the reaction, but examples include hydrocarbons such as toluene and xylene, ethers such as 1,4-dioxane, THF, and DME, or a mixture of these solvents.

[0722] In this process, the reaction temperature varies depending on the type of raw materials and reagents used, but typically, a range of 0°C to 100°C is suitable.

[0723] The reaction time varies depending on the type of raw material used and the reaction temperature, but typically, a range of 0.5 to 24 hours is suitable.

[0724] Preparation of Compound 1-H

[0725] [Chemical Formula 13]

[0726]

[0727] (during food, R 1 , R 2 , R 4 , R 5 , R 6 , R 7 , R c , L 2 , Het, X are synonyms with the above.)

[0728] Step 1

[0729] This process is a process for obtaining ether compound 1-H by a Mitsunobu reaction between alcohol compound 31 and alcohol compound 32, and can be prepared by the same method as Step 1 of the preparation of compound 1-G.

[0730] Preparation of Compound 1-I

[0731] [Chemical Formula 14]

[0732]

[0733] (during food, R 1 , R 2 , R 4 , R 5 , R 6 , R 7 , R c , L 2 , Het, and X are synonymous with the above. Y is a leaving group, examples of which include a bromine atom, an iodine atom, and trifluoromethanesulfonate.)

[0734] Step 1

[0735] This process is a process for obtaining compound 1-I by coupling compound 33 and compound 34, respectively, in the presence of a transition metal such as palladium.

[0736] This reaction can be carried out by applying conditions commonly used in coupling reactions using transition metals, specifically the Heck reaction, and by methods described in literature such as Org. Synth. 2005, 81, 63-76., Heck et al., J. Org. Chem. 1972, 37, 2320-2322., and Beletskaya et al., Chem. Rev., 2000, 100, 3009-3066.

[0737] The amount of compound 33 used is suitable in the range of 0.5 molar equivalents to 3 molar equivalents relative to compound 34.

[0738] The organometallic catalyst used in this reaction is not particularly limited. As preferred examples of organometallic catalysts, tris(dibenzylideneacetone)bispalladium·chloroform adduct (hereinafter referred to as “Pd2(dba)3·CHCl3”), tris(dibenzylideneacetone)bispalladium (hereinafter referred to as “Pd2(dba)3”), tetracyclotriphenylphosphinepalladium (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, Examples include metal catalysts such as “Pd(dtbpf)Cl2”, bis(tricyclohexylphosphine)palladium(II) dichloride (hereinafter referred to as “PdCl2(PCy3)2”), palladium(II) acetate (hereinafter referred to as “Pd(OAc)2”), and [1,3-bis(diphenylphosphino)propane]nickel(II), and mixtures of these metal catalysts.

[0739] The amount of transition metal used is suitable in the range of, for example, 0.01 molar equivalent to 0.3 molar equivalent for compound 33.

[0740] In this process, a base or salt may be used as needed. Examples of bases or salts to be used include potassium carbonate, cesium carbonate, sodium carbonate, sodium bicarbonate, sodium acetate, potassium acetate, trisodium phosphate, tripotassium phosphate and their solutions, as well as triethylamine (hereinafter referred to as “TEA”), N,N-diisopropylethylamine (hereinafter referred to as “DIPEA”), lithium chloride, and copper(I) iodide.

[0741] The amount of base used is suitable for compound 33, for example, in the range of 1 molar equivalent to 4 molar equivalents.

[0742] In this process, suitable ligands may be used as needed. Examples of ligands that can be used include, for instance, 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'-binafthyl (hereinafter referred to as "BINAP"), 2-dicyclohexylphosphino-2',6'-diisopropylbiphenyl (hereinafter referred to as "RuPhos"), triphenylphosphine (hereinafter referred to as "PPh3"), and tricyclohexylphosphine (hereinafter referred to as "PCy3").

[0743] The amount of ligand used is suitable within the range of 1 molar equivalent to 5 molar equivalents for the transition metal used, for example.

[0744] In the present process, the solvent used is not particularly limited as long as it does not participate in the reaction, but 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 mixture of these solvents.

[0745] The reaction temperature varies depending on the type of raw materials and reagents used, but typically, a range of 20°C to 200°C is suitable. In addition, if necessary, a microwave reaction device may be used.

[0746] The reaction time varies depending on the type of raw material used and the reaction temperature, but typically, a range of 0.1 to 24 hours is suitable.

[0747] Preparation of compound 1-K

[0748] [Chemical Formula 15]

[0749]

[0750] (during food, R 1 , R 2 , R 4 , R 5 , R 6 , R 7 , R a , L 2 , Het, and X are synonymous with the above. Y is a leaving group, and examples include a bromine atom, an iodine atom, and trifluoromethanesulfonate. R AA and R BB are all hydroxyl groups, or R AA and R BB Together, it is -OC(CH3)2-C(CH3)2-O-, -O-(CH2)3-O-, or O-CH2-C(CH3)2-CH2-O-.)

[0751] Step 1

[0752] This process is a process for obtaining compound 1-K by coupling compound 35 and compound 36 in the presence of a transition metal such as palladium.

[0753] This reaction can be carried out under conditions commonly used in coupling reactions using transition metals, specifically by applying the Suzuki-Miyaura coupling reaction, and by methods described in literature such as Suzuki et al., Chem. Rev., 1995, 95, 2457-2483.

[0754] The amount of compound 36 used is suitable in the range of 0.5 molar equivalents to 3 molar equivalents relative to compound 35.

[0755] The organometallic catalyst used in this reaction is not particularly limited. As preferred examples of organometallic catalysts, tris(dibenzylideneacetone)bispalladium·chloroform adduct (hereinafter referred to as “Pd2(dba)3·CHCl3”), tris(dibenzylideneacetone)bispalladium (hereinafter referred to as “Pd2(dba)3”), tetracyclotriphenylphosphinepalladium (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, Examples include metal catalysts such as “Pd(dtbpf)Cl2”, bis(tricyclohexylphosphine)palladium(II) dichloride (hereinafter referred to as “PdCl2(PCy3)2”), palladium(II) acetate (hereinafter referred to as “Pd(OAc)2”), and [1,3-bis(diphenylphosphino)propane]nickel(II), and mixtures of these metal catalysts.

[0756] The amount of transition metal used is suitable in the range of, for example, 0.01 molar equivalent to 0.3 molar equivalent for compound 35.

[0757] In this process, a base or salt may be used as needed. Examples of bases or salts to be used include potassium carbonate, cesium carbonate, sodium carbonate, sodium bicarbonate, sodium acetate, potassium acetate, trisodium phosphate, tripotassium phosphate and their solutions, as well as triethylamine (hereinafter referred to as “TEA”), N,N-diisopropylethylamine (hereinafter referred to as “DIPEA”), lithium chloride, and copper(I) iodide.

[0758] The amount of base used is suitable for compound 35, for example, in the range of 1 molar equivalent to 4 molar equivalents.

[0759] In this process, suitable ligands may be used as needed. Examples of ligands that can be used include, for instance, 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'-binafthyl (hereinafter referred to as "BINAP"), 2-dicyclohexylphosphino-2',6'-diisopropylbiphenyl (hereinafter referred to as "RuPhos"), triphenylphosphine (hereinafter referred to as "PPh3"), and tricyclohexylphosphine (hereinafter referred to as "PCy3").

[0760] The amount of ligand used is suitable within the range of 1 molar equivalent to 5 molar equivalents for the transition metal used, for example.

[0761] In the present process, the solvent used is not particularly limited as long as it does not participate in the reaction, but 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 mixture of these solvents.

[0762] The reaction temperature varies depending on the type of raw materials and reagents used, but typically, a range of 20°C to 200°C is suitable. In addition, if necessary, a microwave reaction device may be used.

[0763] The reaction time varies depending on the type of raw material used and the reaction temperature, but typically, a range of 0.1 to 24 hours is suitable.

[0764] The compound of the present invention has PDGF receptor kinase inhibitory activity, as shown in the test examples described below. Furthermore, the compound of the present invention is effective for respiratory diseases, cancer, smooth muscle proliferative diseases, angioplastic diseases, autoimmune / inflammatory diseases, metabolic diseases, and vascular occlusive diseases due to its PDGF receptor kinase inhibitory activity.

[0765] In addition, 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, so the compound of the present invention can be expected to provide a PDGF receptor kinase inhibitor in which undesirable effects such as bone marrow suppression are suppressed.

[0766] Accordingly, the compound of the present invention or its pharmaceutically acceptable salt can be used, for example, as a preventive agent or therapeutic agent for diseases involving PDGF receptor kinase.

[0767] Respiratory diseases to which the compound of the present invention or its pharmaceutically acceptable salt can be applied include lung disease and pulmonary hypertension. Among these, pulmonary hypertension is classified as follows according to etiology and pathological condition.

[0768] · Pulmonary arterial pulmonary hypertension (PAH),

[0769] · Pulmonary hypertension due to left heart disease as described below,

[0770] Left heart failure with maintained rescue rate,

[0771] Left heart failure with reduced rescue rate,

[0772] Valvular disease,

[0773] Congenital / acquired cardiovascular conditions leading to post-capillary pulmonary hypertension

[0774] · Lung disease and / or pulmonary hypertension due to hypoxemia associated with the diseases listed below,

[0775] Chronic obstructive pulmonary disease (COPD),

[0776] Interstitial (constrained) lung disease,

[0777] Other lung diseases accompanied by a mixed disorder of restrictive and obstructive conditions,

[0778] Hypoxic conditions associated with lung disease, or

[0779] developmental disorders

[0780] · Pulmonary hypertension accompanied by pulmonary artery occlusion,

[0781] Chronic thromboembolic pulmonary hypertension (CTEPH),

[0782] 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, pulmonary tumor thrombotic microangiopathy (PTTM)).

[0783] · Pulmonary hypertension associated with a multifactorial mechanism of unspecified type associated with the diseases described below

[0784] Blood diseases (chronic hemolytic anemia, myeloproliferative disorders, etc.),

[0785] Systemic and metabolic diseases (e.g., pulmonary Langerhans cell histiocytosis, Gaucher disease, glycogen storage disease, neurofibroma, sarcoidosis, etc.),

[0786] Others (e.g., chronic renal failure with or without dialysis, fibrosing mediastinitis, etc.),

[0787] Congenital complex heart malformation

[0788] The above-mentioned pulmonary arterial hypertension (PAH) is, for example,

[0789] Idiopathic PAH,

[0790] Hereditary PAH (especially BMPR2, TBX4, ACVRL1, ENG, SMAD9, KCNK3, SMAD1, CAV1, SMAD4, ATP13A3, SOX17, AQP1, GDF2, unknown gene abnormalities),

[0791] Drugs and toxic-inducing PAHs

[0792] PAH associated with disease (where "disease" refers to, for example, connective tissue disease, HIV infection, portal hypertension, congenital shunt heart disease, schistosomiasis),

[0793] PAH long-term responders to calcium channel blockers, pulmonary venous obstructive disease / pulmonary hemangiomatosis (PVOD / PCH) (including PVOD / PCH with EIF2AK4 mutations),

[0794] It includes persistent pulmonary hypertension of the newborn (PPHN).

[0795] Inflammatory and autoimmune diseases to which the compound of the present invention or its pharmaceutically acceptable salt can be applied include scleroderma, asthma, obstructive bronchiolitis, pulmonary fibrosis, systemic lupus erythematosus (SLE), mixed connective tissue disease (MCTD), Sjögren's syndrome, polymyositis / dermatomyositis, Crohn's disease, ulcerative colitis, cytopenia, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), allergic rhinitis, allergic sinusitis, interstitial lung disease, idiopathic interstitial pneumonia, chronic obstructive pulmonary disease (COPD), pulmonary fibrosis combined with emphysema (CPFE), adult respiratory distress syndrome (ARDS), psoriasis, rheumatoid arthritis, mastocytosis, anaphylaxis syndrome, angioedema, erythema nodosum, erythema multifocalis, cutaneous vasculitis, skin inflammation / disease, urticaria, and allergic contact dermatitis.

[0796] Cancers to which the compound of the present invention or its pharmaceutically acceptable salts can be applied include acute myelogenous leukemia (AML), eosinophilic syndrome, T-lymphoblastic leukemia, chronic myelomonocytic leukemia (CMML), chronic myelogenous leukemia (CML), chronic eosinophilic leukemia, myelofibrosis, cutaneous fibrosarcoma protuberance, 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 carcinoma, adenocarcinoma, pancreatic cancer, mastocyte disease, and gastrointestinal stromal tumor (GIST). there is.

[0797] Smooth muscle proliferative diseases to which the compound of the present invention or a pharmaceutically acceptable salt thereof can be applied include restenosis of blood vessels, atherosclerotic / occlusive arteriosclerosis, Moyamoya disease (idiopathic Willis's arterial ring occlusion), leiomyoma, lymphangiomyomatosis, Williams syndrome, tuberous sclerosis, angina pectoris, myocardial infarction, peripheral artery disease, hypertrophic / dilated cardiomyopathy, and restrained / dilated insufficiency cardiomyopathy.

[0798] Angioproliferative diseases to which the compound of the present invention or its pharmaceutically acceptable salt can be applied include, for example, age-related macular degeneration (AMD), Osler disease (hereditary hemorrhagic peripheral vasodilation), hemangioma, tumor angiogenesis, and arteriovenous fistula.

[0799] Metabolic diseases to which the compound of the present invention or its pharmaceutically acceptable salt can be applied include diabetes mellitus (type 1 diabetes or type 2 diabetes).

[0800] The compound of the present invention can be used as a therapeutic agent for various diseases in mammals such as humans, mice, rats, rabbits, dogs, cats, cattle, horses, pigs, and monkeys by making a pharmaceutical composition containing, for example, 0.001% to 99.5%, preferably 0.1% to 90%, either as is or mixed with a pharmacologically acceptable carrier.

[0801] It is preferable to adjust the dosage as a medicine after considering the patient's condition, such as age, weight, type and severity of the disease, route of administration, type of compound of the present invention, whether it is a salt or not, and type of salt; however, generally, for adults, the amount of the active ingredient of the compound of the present invention or its pharmaceutically acceptable salt is appropriate in the range of 0.01 mg to 5 g / adult per day, preferably in the range of 1 mg to 500 mg / adult, in the case of oral administration. In some cases, a dose lower than this may be sufficient, or conversely, a dose higher than this may be required. Typically, it may be administered once a day or divided into several doses, or in the case of intravenous administration, it may be administered rapidly or continuously within 24 hours.

[0802] One or more hydrogen, carbon, and / or other atoms of the compound of the present invention may be substituted with isotopes of hydrogen, carbon, and / or other atoms, respectively. Examples of such isotopes include, respectively 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F, 123 I and 36Cl, that is, hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine are included. Compounds substituted with these isotopes are also useful as pharmaceuticals and include all radioactive labels of the compounds of the present invention.

[0803] The present invention will be described in more detail below with reference to comparative examples, examples, and test examples, but these do not limit the invention.

[0804] In the examples, the following abbreviations are used.

[0805] TFA: Trifluoroacetic acid

[0806] Pd-C: Palladium-Carbon

[0807] Pd2(dba)3: Tris(dibenzylideneacetone)bispalladium

[0808] Pd(PPh3)4: Tetracyclophenylphosphine palladium

[0809] PdCl2(PPh3)2: bis(triphenylphosphine)palladium(II)dichloride

[0810] Pd(OAc)2: Palladium(II) acetate

[0811] Xantphos: 4,5-bis(diphenylphosphino)-9,9-dimethylxanthen

[0812] BINAP: 2,2'-bis(diphenylphosphino)-1,1'-binaphyl

[0813] PPh3: Triphenylphosphine

[0814] Boc2O: di-tert-butyl carbonate

[0815] HATU: O-(7-azabenzotriazole-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate

[0816] HBTU: O-(benzotriazole-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate

[0817] THF: Tetrahydrofuran

[0818] DME: Dimethoxyethane

[0819] DMF: Dimethylformamide

[0820] DMSO: Dimethyl sulfoxide

[0821] NMP: N-methylpyrrolidone

[0822] DIPEA: N,N-Diisopropylethylamine

[0823] TEA: Triethylamine

[0824] BH3-THF: Borane-tetrahydrofuran complex

[0825] CDCl3: Heavy chloroform

[0826] TLC: Thin-layer chromatography

[0827] MS: Mass Spectrometry

[0828] LCMS: High-speed Liquid Chromatography Mass Spectrometry

[0829] ESI: Electron Spray Ionization

[0830] M: Molar concentration (mol / L)

[0831] MS was measured by LCMS. The ESI method was used for ionization. The observed mass spectrometry values ​​are expressed in m / z.

[0832] The measurement conditions of the LCMS are as follows.

[0833] Analysis instrument: ACQUITY UPLC MS / PDA system (manufactured by Waters)

[0834] Mass Spectrometer: Waters 3100 MS Detector

[0835] Photodiode array detector: ACQUITY PDA detector (UV detection wavelength: 210–400 nm)

[0836] Column: Acquity BEH C18, 1.7㎛, 2.1×50㎜

[0837] Flow rate: 0.5 mL / min

[0838] Column temperature: 40℃

[0839] menstruum;

[0840] Solution A: 0.1% formic acid / H2O (v / v; same applies below)

[0841] Solution B: 0.1% formic acid / acetonitrile

[0842] 1 ¹H NMR spectra were measured using a JNM-ECS400 type nuclear magnetic resonance instrument (manufactured by JEOL RESONANCE, Inc.). Observed peaks are denoted by chemical shift values ​​δ (ppm) (s = singlet, d = doublet, t = triplet, q = quartet, brs = broad singlet, m = multiplet, dd = double doublet, ddd = double double doublet, dt = double triplet).

[0843] For the microwave experiment, Initiator 60 (manufactured by Biotage) was used. It can achieve temperatures of 40-250°C and reach pressures of up to 20 bar.

[0844] The compound names in this specification are named using naming software in accordance with the rules of IUPAC, such as ACD / NAME (registered trademark, Advanced Chemistry Development Inc.), ChemBioDraw (version 14.0, manufactured by Cambridge Soft), or in accordance with IUPAC nomenclature.

[0845] The r and s (lowercase) in compound names represent the stereochemistry of a carbon atom similar to the IUPAC rule.

[0846] Reference Example 1 5-[(cyclopropylmethyl)amino]pyridine-3-carboxylic acid

[0847] [Process 1] Preparation of Methyl 5-[(cyclopropylmethyl)amino]pyridine-3-carboxylate

[0848] 1,4-dioxane (139 mL) was added to methyl 5-bromopyridine-3-carboxylate (15.0 g), 1-cyclopropylmethaneamine (9.9 g), BINAP (8.6 g), cesium carbonate (45.2 g), and Pd(OAc)2 (1.6 g). After degassing, the mixture was stirred overnight at 80°C under an argon atmosphere. The insoluble material was filtered and fractionated using Celite (registered trademark), and the solvent was removed by vacuum distillation. The residue was purified by silica gel column chromatography to obtain the title compound (8.4 g). MS (m / z): 207.2 [M+H] +

[0849] [Process 2] Preparation of 5-[(cyclopropylmethyl)amino]pyridine-3-carboxylic acid

[0850] To the THF (81 mL)-methanol (81 mL) solution of methyl 5-[(cyclopropylmethyl)amino]pyridine-3-carboxylate (8.4 g) obtained in Process 1, lithium hydroxide monohydrate (3.4 g) and water (81 mL) were added, and the mixture was stirred overnight at room temperature. The solvent was removed by distillation under reduced pressure, diluted with water, and neutralized by adding 1 M hydrochloric acid. The precipitated precipitate was filtered and collected to obtain the title compound (6.8 g). MS (m / z): 193.2 [M+H] +

[0851] Reference Example 2 5-[cyclopropyl(methyl)amino]pyridine-3-carboxylic acid

[0852] [Process 1] Preparation of Methyl 5-[Cyclopropyl(methyl)amino]pyridine-3-carboxylate

[0853] The title compound (6.6 g) was obtained by using N-methylcyclopropanamine (9.9 g) instead of 1-cyclopropylmethaneamine by a method according to Process 1 of Reference Example 1. MS(m / z): 207.4[M+H] +

[0854] [Process 2] Preparation of 5-[cyclopropyl(methyl)amino]pyridine-3-carboxylic acid

[0855] By a method according to Process 2 of Reference Example 1, the title compound (4.3 g) was obtained using methyl 5-[(cyclopropylmethyl)amino]pyridine-3-carboxylate (6.6 g) obtained in Process 1 instead of methyl 5-[(cyclopropyl(methyl)amino]pyridine-3-carboxylate. MS(m / z): 193.4[M+H] +

[0856] Reference Example 3 5-[(3,3-difluorocyclobutyl)oxy]pyridine-3-carboxylic acid

[0857] [Process 1] Preparation of Methyl 5-[(3,3-Difluorocyclobutyl)oxy]pyridine-3-carboxylate

[0858] Diisopropyl azodicarboxylate (40% toluene solution, 1.12 mL) was added to a THF (4.1 mL) solution of methyl 5-hydroxypyridine-3-carboxylate (250 mg), 3,3-difluorocyclobutan-1-ol (212 mg), and PPh3 (599 mg), and stirred at 60°C for 2 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to obtain the title compound (170 mg). MS (m / z): 244.4 [M+H] +

[0859] [Process 2] Preparation of 5-[(3,3-difluorocyclobutyl)oxy]pyridine-3-carboxylic acid

[0860] By the method according to Process 2 of Reference Example 1, the title compound (84 mg) was obtained using methyl 5-[(3,3-difluorocyclobutyl)oxy]pyridine-3-carboxylate (170 mg) obtained in Process 1 instead of methyl 5-[(cyclopropylmethyl)amino]pyridine-3-carboxylate.

[0861] Reference Example 4 5-[(4,4-difluorocyclohexyl)oxy]pyridine-3-carboxylic acid

[0862] [Process 1] Preparation of Methyl 5-[(4,4-Difluorocyclohexyl)oxy]pyridine-3-carboxylate

[0863] The title compound (450 mg) was obtained by using 4,4-difluorocyclohexan-1-ol instead of 3,3-difluorocyclobutan-1-ol by the method according to Process 1 of Reference Example 3. MS(m / z): 272.2[M+H] +

[0864] [Process 2] Preparation of 5-[(4,4-difluorocyclohexyl)oxy]pyridine-3-carboxylic acid

[0865] By a method according to Process 2 of Reference Example 1, the title compound (350 mg) was obtained using methyl 5-[(4,4-difluorocyclohexyl)oxy]pyridine-3-carboxylate (450 mg) obtained in Process 1 instead of methyl 5-[(cyclopropylmethyl)amino]pyridine-3-carboxylate. MS(m / z): 258.2[M+H] +

[0866] Reference Example 5 5-[(1-methylcyclopropyl)methoxy]pyridine-3-carboxylic acid

[0867] [Process 1] Preparation of Methyl 5-[(1-methylcyclopropyl)methoxy]pyridine-3-carboxylate

[0868] By the method according to Process 1 of Reference Example 3, (1-methylcyclopropyl)methanol (500 mg) was used instead of 3,3-difluorocyclobutan-1-ol to obtain the title compound (540 mg). MS(m / z): 222.1[M+H] +

[0869] [Process 2] Preparation of 5-[(1-methylcyclopropyl)methoxy]pyridine-3-carboxylic acid

[0870] By a method according to Process 2 of Reference Example 1, the title compound (340 mg) was obtained using methyl 5-[(1-methylcyclopropyl)methoxy]pyridine-3-carboxylate (540 mg) obtained in Process 1 instead of methyl 5-[(cyclopropylmethyl)amino]pyridine-3-carboxylate. MS(m / z): 208.2[M+H] +

[0871] Reference Example 6 5-[(3,3-difluorocyclobutyl)methoxy]pyridine-3-carboxylic acid

[0872] [Process 1] Preparation of Methyl 5-[(3,3-Difluorocyclobutyl)methoxy]pyridine-3-carboxylate

[0873] The title compound (1.10 g) was obtained by the method according to Process 1 of Reference Example 3, using (3,3-difluorocyclobutyl)methanol (500 mg) instead of 3,3-difluorocyclobutan-1-ol. MS(m / z): 258.1[M+H] +

[0874] [Process 2] Preparation of 5-[(3,3-difluorocyclobutyl)methoxy]pyridine-3-carboxylic acid

[0875] By a method according to Process 2 of Reference Example 1, the title compound (580 mg) was obtained using methyl 5-[(3,3-difluorocyclobutyl)methoxy]pyridine-3-carboxylate (1.10 g) obtained in Process 1 instead of methyl 5-[(cyclopropylmethyl)amino]pyridine-3-carboxylate. MS(m / z): 244.2[M+H] +

[0876] Reference Example 7 3-amino-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide

[0877] Dipea (17.2 mL) was added to a THF (165 mL) suspension of 3-amino-4-methylbenzoic acid (5.00 g), (1S,2S)-2-aminocyclohexane-1-ol hydrochloride (5.52 g), and HBTU (15.1 g), and stirred at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate, and the organic layer was washed with an aqueous solution of saturated sodium bicarbonate and saturated saline solution. After drying with anhydrous magnesium sulfate, the solvent was removed by vacuum distillation, and the resulting residue was suspended by adding ethyl acetate; the precipitate was filtered and collected to obtain the title compound (6.10 g). MS (m / z): 249.2 [M+H] +

[0878] Reference Example 8 Methyl 4-chloro-3-ethynylbenzoate

[0879] [Process 1] Preparation of Methyl 4-Chloro-3-[(Trimethylsilyl)ethinyl]Benzoate

[0880] THF (27.5 mL) was added to methyl 4-chloro-3-iodobenzoate (8.15 g), ethinyl(trimethyl)silane (2.78 g), copper iodide (570 mg), Pd(PPh3)4 (3.18 g), and TEA (55 mL). After degassing, the mixture was stirred overnight at 45°C under an argon atmosphere. The insoluble material was filtered and fractionated using Celite (registered trademark), and the solvent was removed by vacuum distillation. The residue was purified by silica gel column chromatography to obtain the title compound (6.8 g).

[0881] [Process 2] Preparation of Methyl 4-Chloro-3-Ethinyl Benzoate

[0882] Methyl 4-chloro-3-[(trimethylsilyl)ethynyl]benzoate (6.8 g) obtained in Process 1 was dissolved in THF (85 mL), TBAF (1 M THF solution, 31 mL) was added, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to obtain the title compound (2.6 g).

[0883] Reference Example 9 3-ethynyl-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide

[0884] The title compound (570 mg) was obtained by using 3-ethynyl-4-methylbenzoic acid (500 mg) instead of 3-amino-4-methylbenzoic acid by the method according to Reference Example 7. MS(m / z): 258.2[M+H] +

[0885] Reference Example 10 2-(5-ethynylpyridine-3-yl)pyrimidine

[0886] [Process 1] Preparation of 2-[5-(methoxymethoxy)pyridine-3-yl]pyrimidine

[0887] 1,4-dioxane (73 mL) was added to 3-bromo-5-(methoxymethoxy)pyridine (4.0 g), bis(pinacolato)diborone (5.6 g), potassium acetate (3.6 g), and Pd(dppf)Cl2·CH2Cl2 (1.5 g). After degassing, the mixture was stirred at 80°C for 2.5 hours under an argon atmosphere. Subsequently, 2-bromopyrimidine (3.5 g), potassium carbonate (5.1 g), and water (0.5 mL) were added, and the mixture was stirred overnight at 85°C. The reaction mixture was diluted with ethyl acetate, and the organic layer was washed with water. After drying with anhydrous sodium sulfate, the solvent was removed by vacuum distillation, and the resulting residue was purified by silica gel column chromatography to obtain the title compound (3.6 g). MS(m / z): 218.4[M+H] +

[0888] [Process 2] Preparation of 5-(pyrimidine-2-yl)pyridine-3-ol

[0889] 2-[5-(methoxymethoxy)pyridine-3-yl]pyrimidine (4.11 g) obtained in Process 1 was dissolved in THF (38 mL), 35% hydrochloric acid (1.4 mL) was added, and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, and an aqueous sodium bicarbonate solution was added to the resulting residue to neutralize it. The resulting precipitate was filtered to obtain the title compound (2.51 g). MS (m / z): 174.4 [M+H] +

[0890] [Process 3] Preparation of 5-(pyrimidine-2-yl)pyridine-3-yl trifluoromethanesulfonate

[0891] Trifluoromethanesulfonic acid anhydride (2.27 mL) was added dropwise under ice cooling to the dichloromethane (38 mL) solution of 5-(pyrimidine-2-yl)pyridine-3-ol (2.00 g) and TEA (2.10 mL) obtained in Process 2, and stirred for 1 hour at the same temperature. 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] +

[0892] [Process 4] Preparation of 2-{5-[(trimethylsilyl)ethinyl]pyridine-3-yl}pyrimidine

[0893] The title compound (570 mg) was obtained by using 5-(pyrimidine-2-yl)pyridine-3-yl trifluoromethanesulfonate (770 mg), obtained in Process 3, instead of methyl 4-chloro-3-iodobenzoate by a method according to Process 1 of Reference Example 8. MS(m / z): 254.5[M+H] +

[0894] [Process 5] Preparation of 2-(5-ethynylpyridine-3-yl)pyrimidine

[0895] The title compound (350 mg) was obtained by using 2-{5-[(trimethylsilyl)ethinyl]pyridine-3-yl}pyrimidine (570 mg), obtained in Process 4, instead of methyl 4-chloro-3-[(trimethylsilyl)ethinyl]benzoate by the method according to Process 2 of Reference Example 8. MS(m / z): 182.4[M+H] +

[0896] Reference Example 11 3-Bromo-4-chloro-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide

[0897] The title compound (315 mg) was obtained by using 3-bromo-4-chlorobenzoic acid (250 mg) instead of 3-amino-4-methylbenzoic acid by the method according to Reference Example 7. MS(m / z): 332.4[M+H] +

[0898] Reference Example 12 6-Bromo-N-(cyclopropylmethyl)pyrazine-2-amine

[0899] 1-cyclopropylmethaneamine (449 mg) and potassium carbonate (871 mg) were added to a DMF (1 mL) solution of 2,6-dibromopyrazine (500 mg), sealed using a stainless steel pressure vessel, and stirred at 120°C for 8 hours. The reaction mixture was diluted with ethyl acetate, washed with water and saturated saline solution, and the solvent was removed by vacuum distillation. The resulting residue was purified by silica gel column chromatography to obtain the title compound (400 mg).

[0900] Reference Example 13 5-ethynyl-N-[(1S,2S)-2-hydroxycyclohexyl]-6-methylpyridine-3-carboxamide

[0901] [Process 1] Preparation of 5-Bromo-N-[(1S,2S)-2-hydroxycyclohexyl]-6-methylpyridine-3-carboxamide

[0902] The title compound (380 mg) was obtained by using 5-bromo-6-methylpyridine-3-carboxylic acid (250 mg) instead of 3-amino-4-methylbenzoic acid by the method according to Reference Example 7. MS(m / z): 313.4[M+H] +

[0903] [Process 2] Preparation of N-[(1S,2S)-2-hydroxycyclohexyl]-6-methyl-5-[(trimethylsilyl)ethinyl]pyridine-3-carboxamide

[0904] The title compound (40 mg) was obtained by a method according to Process 1 of Reference Example 8, using 5-bromo-N-[(1S,2S)-2-hydroxycyclohexyl]-6-methylpyridine-3-carboxamide (100 mg) obtained in Process 1 instead of methyl 4-chloro-3-iodobenzoate. MS(m / z): 331.5[M+H] +

[0905] [Process 3] Preparation of 5-ethynyl-N-[(1S,2S)-2-hydroxycyclohexyl]-6-methylpyridine-3-carboxamide

[0906] By a method according to Process 2 of Reference Example 8, the title compound (23 mg) was obtained using N-[(1S,2S)-2-hydroxycyclohexyl]-6-methyl-5-[(trimethylsilyl)ethinyl]pyridine-3-carboxamide (40 mg), obtained in Process 2, instead of methyl 4-chloro-3-[(trimethylsilyl)ethinyl]benzoate. MS(m / z): 259.5[M+H] +

[0907] Reference Example 14 2-(isoquinoline-4-yl)pyrimidine-4-amine

[0908] 1,4-dioxane (5 mL) was added to 2-chloropyrimidine-4-amine (200 mg), isoquinoline-4-ylboronic acid (294 mg), 1 M sodium carbonate aqueous solution (3.1 mL), and Pd(dppf)Cl2·CH2Cl2 (126 mg). After degassing, the mixture was replaced with argon and stirred at 90°C for 2 hours under an argon atmosphere. The residue obtained by concentrating the reaction mixture under reduced pressure was purified by silica gel column chromatography to obtain the title compound (300 mg).

[0909] Reference Example 15 (1S)-1-(5-phenylpyridine-3-yl)ethane-1-amine

[0910] By the method according to Reference Example 14, the title compound (280 mg) was obtained using (1S)-1-(5-bromopyridine-3-yl)ethane-1-amine hydrochloride (300 mg) and phenylboronic acid (185 mg) instead of 2-chloropyrimidine-4-amine and isoquinoline-4-ylboronic acid. MS(m / z): 199.2[M+H] +

[0911] Reference Example 16 (1S)-1-([3,3'-bipyridine]-5-yl)ethane-1-amine

[0912] [Process 1] Preparation of (SS)-N-[(1E)-1-(5-bromopyridine-3-yl)ethylidene]-2-methylpropane-2-sulfinamide

[0913] 1-(5-bromopyridine-3-yl)ethane-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 overnight at 65°C. The reaction mixture was diluted with ethyl acetate, and water was added. The reaction mixture was filtered through Celite (trademark), and the solvent was removed by vacuum distillation. The residue was purified by silica gel column chromatography to obtain the title compound (34 g). MS (m / z): 303.0 [M+H] +

[0914] [Process 2] Preparation of (SS)-N-[(1S)-1-(5-bromopyridine-3-yl)ethyl]-2-methylpropane-2-sulfinamide

[0915] A suspension of 2-propanol (560 mL) 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) was stirred at 80°C for 30 minutes under an argon atmosphere. Subsequently, while stirring the reaction mixture at 50°C, a 2-propanol (9 mL) solution of (SS)-N-[(1E)-1-(5-bromopyridine-3-yl)ethylidene]-2-methylpropane-2-sulfinamide (34 g) obtained in Process 1, potassium tert-butoxide (6.29 g) was added, and the mixture was stirred at the same temperature for 6 hours. The reaction mixture was filtered through Celite (trademark), and the solvent was removed by vacuum distillation. The residue was purified by silica gel column chromatography to obtain the title compound (24.2 g). MS(m / z): 305.1[M+H] +

[0916] [Process 3] Preparation of (SS)-N-[(1S)-1-([3,3'-bipyridine]-5-yl)ethyl]-2-methylpropane-2-sulfinamide

[0917] By the method according to Reference Example 14, the title compound (22.7 g) was obtained using (SS)-N-[(1S)-1-(5-bromopyridine-3-yl)ethyl]-2-methylpropane-2-sulfinamide (23.2 g) and pyridine-3-ylboronic acid (11.2 g), obtained in Process 2, instead of 2-chloropyrimidine-4-amine and isoquinoline-4-ylboronic acid, according to the method according to Reference Example 14. MS(m / z): 304.2[M+H] +

[0918] [Process 4] Preparation of (1S)-1-([3,3'-bipyridine]-5-yl)ethane-1-amine

[0919] Hydrogen chloride (2M methanol solution, 5.46 mL) was added to a methanol (150 mL) solution of (SS)-N-[(1S)-1-([3,3'-bipyridine]-5-yl)ethyl]-2-methylpropane-2-sulfinamide (22.7 g) obtained in Process 3 under ice cooling, and stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by column chromatography using amino-modified spherical silica gel to obtain the title compound (12.9 g). MS(m / z): 200.2[M+H] +

[0920] Reference Example 17 (1S)-1-[5-(phenylethynyl)pyridine-3-yl]ethane-1-amine dihydrochloride

[0921] [Process 1] Preparation of (SS)-2-methyl-N-{(1S)-1-[5-(phenylethynyl)pyridine-3-yl]ethyl}propane-2-sulfinamide

[0922] By a method according to Process 1 of Reference Example 8, the title compound (530 mg) was obtained using (SS)-N-[(1S)-1-(5-bromopyridine-3-yl)ethyl]-2-methylpropane-2-sulfinamide (500 mg) and ethinylbenzene (335 mg), obtained in Process 2 of Reference Example 16, instead of methyl 4-chloro-3-iodobenzoate and ethinyl(trimethyl)silane. MS(m / z): 327.2[M+H] +

[0923] [Process 2] Preparation of (1S)-1-[5-(phenylethynyl)pyridine-3-yl]ethane-1-amine dihydrochloride

[0924] Hydrogen chloride (2M methanol solution, 0.18 mL) was added to an 8.1 mL methanol solution of (SS)-2-methyl-N-{(1S)-1-[5-(phenylethynyl)pyridine-3-yl]ethyl}propane-2-sulfinamide (530 mg) obtained in Process 1 under ice cooling, and stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, and ethyl acetate was added to the resulting residue to suspend it; the precipitate was filtered and collected to obtain the title compound (500 mg). MS(m / z): 223.2[M+H] +

[0925] Reference Example 18 (1S)-1-[5-(pyrimidine-2-yl)pyridine-3-yl]ethane-1-amine

[0926] [Process 1] Preparation of (SS)-2-methyl-N-{(1S)-1-[5-(pyrimidine-2-yl)pyridine-3-yl]ethyl}propane-2-sulfinamide

[0927] The title compound (420 mg) was obtained by using (SS)-N-[(1S)-1-(5-bromopyridine-3-yl)ethyl]-2-methylpropane-2-sulfinamide (600 mg), obtained in Process 2 of Reference Example 16, instead of 3-bromo-5-(methoxymethoxy)pyridine, by a method according to Process 1 of Reference Example 10. MS(m / z): 305.4[M+H] +

[0928] [Process 2] Preparation of (1S)-1-[5-(pyrimidine-2-yl)pyridine-3-yl]ethane-1-amine

[0929] By the method according to Process 4 of Reference Example 16, the title compound (200 mg) was obtained using (SS)-2-methyl-N-{(1S)-1-[5-(pyrimidine-2-yl)pyridine-3-yl]ethyl}propane-2-sulfinamide (420 mg), obtained in Process 1, instead of (SS)-N-[(1S)-1-([3,3'-bipyridine]-5-yl)ethyl]-2-methylpropane-2-sulfinamide. MS(m / z): 201.3[M+H] +

[0930] Reference Example 19 Pyrazolo[5,1-b][1,3]thiazole-7-carvaldehydride

[0931] [Process 1] Preparation of (pyrazolo[5,1-b][1,3]thiazole-7-yl)methanol

[0932] Lithium aluminum hydride (1.5 mL, 1 M hexane solution) was added to a 2 mL THF solution of pyrazolo[5,1-b][1,3]thiazole-7-carboxylic acid (100 mg) and stirred at 50 °C for 5 hours. At 0 °C, methanol and L-(+)-sodium potassium tartrate tetrahydrate were added to the reaction mixture and stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to obtain the title compound (57 mg). MS (m / z): 155.3 [M+H] +

[0933] [Process 2] Preparation of Pyrazolo[5,1-b][1,3]thiazole-7-carbaldehydride

[0934] Manganese dioxide (160 mg) was added to the THF (1.2 mL) solution of (pyrazolo[5,1-b][1,3]thiazole-7-yl)methanol (57 mg) obtained in Process 1, and stirred overnight at room temperature. After filtering the reaction mixture to remove insoluble matter, the filtrate was concentrated under reduced pressure to obtain the title compound (42 mg).

[0935] Reference Example 20 5-amino-N-[(1S,2S)-2-hydroxycyclohexyl]-6-methylpyridine-3-carboxamide

[0936] The title compound (1.17 g) was obtained by the method according to Reference Example 7, using 5-amino-6-methylpyridine-3-carboxylic acid (915 mg) instead of 3-amino-4-methylbenzoic acid. MS(m / z): 250.2[M+H] +

[0937] Reference Example 21 N-(5-formylpyridine-2-yl)morpholine-4-carboxamide

[0938] [Process 1] Preparation of Phenyl(5-Formylpyridine-2-yl)Carbamate

[0939] TEA (0.57 mL) and phenyl chloroformate (304 mg) were added to a THF (5.1 mL) solution of 6-aminopyridine-3-carbaldehydride (250 mg), and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to obtain the title compound (246 mg). MS (m / z): 243.2 [M+H] +

[0940] [Process 2] Preparation of N-(5-formylpyridine-2-yl)morpholine-4-carboxamide

[0941] Morpholine (43 mg) and TEA (0.072 mL) were added to the NMP (0.34 mL) solution of phenyl(5-formylpyridine-2-yl)carbamate (40 mg) obtained in Process 1, and stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to obtain the title compound (246 mg). MS (m / z): 236.1 [M+H] +

[0942] Reference Example 22 N-cyclopropyl-N'-(5-formylpyridine-2-yl)-N-methylurea

[0943] The title compound (21 mg) was obtained by using N-methylcyclopropanamine (94 mg) instead of morpholine by the method according to Process 2 of Reference Example 21. MS(m / z): 220.1[M+H] +

[0944] Reference Example 23 tert-butyl 7-formyl-2,3-dihydro-4H-pyrido[3,2-b][1,4]oxazine-4-carboxylate

[0945] [Process 1] Preparation of tert-butyl 7-bromo-2,3-dihydro-4H-pyrido[3,2-b][1,4]oxazine-4-carboxylate

[0946] TEA (0.01 mL), Boc2O (0.19 mL), and DMAP (4.5 mg) were added to a THF (2.5 mL) solution of 7-bromo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine (160 mg), and the mixture was stirred overnight at room temperature. The residue obtained by concentrating the reaction mixture under reduced pressure was purified by silica gel column chromatography to obtain the title compound (177 mg). MS (m / z): 315.1 [M+H] +

[0947] [Process 2] Preparation of tert-butyl 7-ethenyl-2,3-dihydro-4H-pyrido[3,2-b][1,4]oxazine-4-carboxylate

[0948] By the method according to Reference Example 14, the title compound (118 mg) was obtained using tert-butyl 7-bromo-2,3-dihydro-4H-pyridodo[3,2-b][1,4]oxazine-4-carboxylate (177 mg) and 2-ethenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolan (172 mg), obtained in Process 1, instead of 2-chloropyrimidine-4-amine and isoquinoline-4-ylboronic acid. MS(m / z): 263.2[M+H] +

[0949] [Process 3] Preparation of tert-butyl 7-formyl-2,3-dihydro-4H-pyrido[3,2-b][1,4]oxazine-4-carboxylate

[0950] O3 was bubbled into a dichloromethane (2 mL) solution of tert-butyl 7-ethenyl-2,3-dihydro-4H-pyrido[3,2-b][1,4]oxazine-4-carboxylate (118 mg) obtained in Process 2 for 30 minutes at -78°C. Subsequently, argon gas was bubbled into the solution until it became colorless, triphenylphosphine (142 mg) was added, and the mixture was stirred overnight at room temperature. Water was added to the reaction mixture and extracted with dichloromethane. After drying the organic layer with anhydrous sodium sulfate, the solvent was removed by vacuum distillation, and the title compound was obtained as a crude product.

[0951] Reference Example 24 6-(1H-1,2,3-triazole-1-yl)pyridine-3-carvaldehydride

[0952] [Process 1] Preparation of 5-Ethenyl-2-(1H-1,2,3-Triazole-1-yl)Pyridine

[0953] By the method according to Reference Example 14, the title compound (90 mg) was obtained using 5-bromo-2-(1H-1,2,3-triazole-1-yl)pyridine (142 mg) (synthesized, for example, according to the method described in WO2006 / 038100) and 2-ethenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolan (117 mg) instead of 2-chloropyrimidine-4-amine and isoquinoline-4-ylboronic acid. MS(m / z): 173.1[M+H] +

[0954] [Process 2] Preparation of 6-(1H-1,2,3-triazole-1-yl)pyridine-3-carbaldehydride

[0955] By the method according to Process 3 of Reference Example 23, the title compound (306 mg) was obtained as a crude product using 5-ethenyl-2-(1H-1,2,3-triazole-1-yl)pyridine (90 mg) obtained in Process 1 instead of tert-butyl 7-ethenyl-2,3-dihydro-4H-pyrido[3,2-b][1,4]oxazine-4-carboxylate. MS(m / z): 175.1[M+H] +

[0956] Reference Example 25 5-(2H-1,2,3-triazole-2-yl)pyridine-3-carvaldehydride

[0957] [Process 1] Preparation of [5-(2H-1,2,3-triazole-2-yl)pyridine-3-yl]methanol

[0958] Sodium borohydride (41 mg) was added to a methanol (2.2 mL) solution of methyl 5-(2H-1,2,3-triazole-2-yl)pyridine-3-carboxylate (44 mg) (synthesized, for example, according to the method described in Angew. Chem. Int. Ed. 2011, 50, 8944-8947) and stirred overnight at room temperature. Water was added to the reaction mixture, and the solvent was removed by vacuum distillation. The residue was purified by silica gel column chromatography to obtain the title compound.

[0959] [Process 2] Preparation of 5-(2H-1,2,3-triazole-2-yl)pyridine-3-carbaldehydride

[0960] The title compound (22 mg) was obtained by using [5-(2H-1,2,3-triazole-2-yl)pyridine-3-yl]methanol obtained in Process 1 instead of (pyrazolo[5,1-b][1,3]thiazole-7-yl)methanol by the method according to Process 2 of Reference Example 19.

[0961] Reference Example 26 3-Formyl-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide

[0962] The title compound (134 mg) was obtained by using 3-formyl-4-methylbenzoic acid (100 mg) instead of 3-amino-4-methylbenzoic acid by the method according to Reference Example 7. MS(m / z): 262.5[M+H] +

[0963] Reference Example 27 5-(pyrimidine-2-yl)pyridine-3-amine dihydrochloride

[0964] [Process 1] Preparation of di-tert-butyl(5-bromopyridine-3-yl)-2-imidodicarbonate

[0965] The title compound (40.0 g) was obtained by using 5-bromopyridine-3-amine (25.0 g) instead of 7-bromo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine by a method according to Process 1 of Reference Example 23. MS(m / z): 373.4[M+H] +

[0966] [Process 2] Preparation of di-tert-butyl [5-(pyrimidine-2-yl)pyridine-3-yl]-2-imidodicarbonate

[0967] By a method according to Process 1 of Reference Example 10, the title compound (14.3 g) was obtained using di-tert-butyl (5-bromopyridine-3-yl)-2-imidodicarbonate (30.0 g) obtained in Process 1, instead of 3-bromo-5-(methoxymethoxy)pyridine. MS(m / z): 373.5[M+H] +

[0968] [Process 3] Preparation of 5-(pyrimidine-2-yl)pyridine-3-amine dihydrochloride

[0969] Hydrogen chloride (4M ethyl acetate solution, 14 mL) was added to an ethanol (128 mL) solution of di-tert-butyl [5-(pyrimidine-2-yl)pyridine-3-yl]-2-imidodicarbonate (14.3 g) obtained in Process 2, and the mixture was stirred at 60°C for 3 hours. The reaction mixture was concentrated under reduced pressure, the residue was suspended in ethyl acetate, the precipitate was filtered and collected, washed with ethyl acetate, and dried to obtain the title compound (3.5 g). MS(m / z): 173.4[M+H] +

[0970] Reference Example 28 3-Formyl-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide

[0971] The title compound (590 mg) was obtained by using 3-formylbenzoic acid (500 mg) instead of 3-amino-4-methylbenzoic acid by the method according to Reference Example 7. MS(m / z): 248.5[M+H] +

[0972] Reference Example 29 4-fluoro-3-formyl-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide

[0973] The title compound (300 mg) was obtained by using 4-fluoro-3-formylbenzoic acid (300 mg) instead of 3-amino-4-methylbenzoic acid by the method according to Reference Example 7. MS(m / z): 266.5[M+H] +

[0974] Reference Example 30 5-Formyl-N-[(1S,2S)-2-hydroxycyclohexyl]-6-methylpyridine-3-carboxamide

[0975] [Process 1] Preparation of 5-Ethenyl-N-[(1S,2S)-2-hydroxycyclohexyl]-6-methylpyridine-3-carboxamide

[0976] By the method according to Reference Example 14, the title compound (614 mg) was obtained using 5-bromo-N-[(1S,2S)-2-hydroxycyclohexyl]-6-methylpyridine-3-carboxamide (750 mg) and 2-ethenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolan (479 mg), obtained in Process 1 of Reference Example 13, instead of 2-chloropyrimidine-4-amine and isoquinoline-4-ylboronic acid. MS(m / z): 261.2[M+H] +

[0977] [Process 2] Preparation of 5-Formyl-N-[(1S,2S)-2-hydroxycyclohexyl]-6-methylpyridine-3-carboxamide

[0978] The title compound (360 mg) was obtained by using 5-ethenyl-N-[(1S,2S)-2-hydroxycyclohexyl]-6-methylpyridine-3-carboxamide (614 mg), obtained in Process 1, instead of tert-butyl 7-ethenyl-2,3-dihydro-4H-pyrido[3,2-b][1,4]oxazine-4-carboxylate by a method according to Process 3 of Reference Example 23. MS(m / z): 263.2[M+H] +

[0979] Reference Example 31 Methyl 4-chloro-3-(hydroxymethyl)benzoate

[0980] Sodium borohydride (38 mg) was added to a methanol (3.4 mL)-THF (3.4 mL) solution of methyl 4-chloro-3-formylbenzoate (200 mg) at 0°C and stirred overnight at room temperature. Water was added to the reaction mixture, and the solvent was removed by vacuum distillation. The residue was purified by silica gel column chromatography to obtain the title compound (130 mg).

[0981] Reference Example 32 Methyl 3-[(ethylamino)methyl]-4-methylbenzoate

[0982] Ethylamine (2 M methanol solution, 2.8 mL) was added to a methanol (11 mL) solution of methyl 3-formyl-4-methylbenzoate (500 mg) and stirred at room temperature for 30 minutes. Subsequently, sodium borohydride (159 mg) was added and stirred at room temperature for 2 hours. Water was added to the reaction mixture, and the solvent was removed by vacuum distillation. The residue was purified by silica gel column chromatography to obtain the title compound (423 mg). MS(m / z): 208.2 [M+H] +

[0983] Reference Example 33 Ethyl 5-formyl-6-methylpyridine-3-carboxylate

[0984] [Process 1] Preparation of Ethyl 5-Ethenyl-6-Methylpyridine-3-Carboxylate

[0985] By the method according to Reference Example 14, the title compound (3.0 g) was obtained using ethyl 5-bromo-6-methylpyridine-3-carboxylate (4.2 g) and 2-ethenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolan (3.7 g) instead of 2-chloropyrimidine-4-amine and isoquinoline-4-ylboronic acid. MS(m / z): 192.1[M+H] +

[0986] [Process 2] Preparation of Ethyl 5-Formyl-6-Methylpyridine-3-Carboxylate

[0987] By a method according to Process 3 of Reference Example 23, the title compound (2.7 g) was obtained using ethyl 5-ethenyl-6-methylpyridine-3-carboxylate (3.0 g) obtained in Process 1 instead of tert-butyl 7-ethenyl-2,3-dihydro-4H-pyrido[3,2-b][1,4]oxazine-4-carboxylate. MS(m / z): 194.1[M+H] +

[0988] Reference Example 34 1-[(5-bromopyridine-3-yl)methyl]-4-methylpiperazine

[0989] Acetic acid (0.15 mL) and 1-methylpiperazine (808 mg) were added to a dichloromethane (11 mL) solution of 5-bromopyridine-3-carbaldehydride (500 mg), and stirred at room temperature for 1 hour. Subsequently, sodium triacetoxyborohydride (1.14 g) was added, and stirred at room temperature for 2 hours. Water was added to the reaction mixture, and the solvent was removed by vacuum distillation. The residue was purified by silica gel column chromatography to obtain the title compound (700 mg). MS (m / z): 270.1 [M+H] +

[0990] Reference Example 35 4-[(5-bromopyridine-3-yl)methyl]morpholine

[0991] The title compound (570 mg) was obtained by using morpholine (703 mg) instead of 1-methylpiperazine by the method according to Reference Example 34. MS(m / z): 257.1[M+H] +

[0992] Reference Example 36 5-Bromo-N-(oxane-4-yl)pyridine-3-amine

[0993] The title compound (230 mg) was obtained by a method according to Process 1 of Reference Example 1, using 3,5-dibromopyridine, oxane-4-amine (256 mg) instead of methyl 5-bromopyridine-3-carboxylate, 1-cyclopropylmethaneamine. MS(m / z): 257.0[M+H] +

[0994] Reference Example 37 5-Bromo-N-(1-methylpiperidine-4-yl)pyridine-3-amine

[0995] The title compound (300 mg) was obtained by a method according to Process 1 of Reference Example 1, using 3,5-dibromopyridine, 1-methylpiperidine-4-amine (304 mg) instead of methyl 5-bromopyridine-3-carboxylate, 1-cyclopropylmethaneamine. MS(m / z): 270.1[M+H] +

[0996] Reference Example 38 1-[(5-bromopyridine-3-yl)methyl]-4-ethylpiperazine

[0997] The title compound (680 mg) was obtained by using 1-ethylpiperazine (921 mg) instead of 1-methylpiperazine by the method according to Reference Example 34. MS(m / z): 284.1[M+H] +

[0998] Reference Example 39 5-Bromo-N-(oxetane-3-yl)pyridine-3-amine

[0999] The title compound (410 mg) was obtained by a method according to Process 1 of Reference Example 1, using 3,5-dibromopyridine (1.00 g) and oxetane-3-amine (309 mg) instead of methyl 5-bromopyridine-3-carboxylate and 1-cyclopropylmethaneamine. MS(m / z): 229.3[M+H] +

[1000] Reference Example 40 di-tert-butyl 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2-yl-2-imidodicarbonate

[1001] [Process 1] Preparation of Benzyl 2-[bis(tert-butoxycarbonyl)amino]-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate

[1002] By the method according to Process 1 of Reference Example 23, the title compound (960 mg) was obtained using benzyl 2-amino-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate (600 mg) instead of 7-bromo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine.

[1003] [Process 2] Preparation of di-tert-butyl 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2-yl-2-imidodicarbonate

[1004] To a methanol (100 mL) solution of benzyl 2-[bis(tert-butoxycarbonyl)amino]-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate (960 mg) obtained in Process 1, 5% Pd-C (400 mg) was added while stirring at room temperature under an argon atmosphere after degassing, and stirred for 4 hours at room temperature under a hydrogen atmosphere. After filtering the reaction mixture with Celite (registered trademark), the solvent was removed by vacuum distillation to obtain the title compound (700 mg).

[1005] Reference Example 41 3-amino-N-[(1S,2S)-2-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl]-4-methylbenzamide

[1006] To a dichloromethane (16 mL) solution of 3-amino-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide (800 mg) obtained in Reference Example 7, tert-butyldimethylsilyl trilate (1.11 g) and 2,6-rutidine (690 mg) were added and stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate, washed with water and saturated saline, and the solvent was removed by vacuum distillation. The resulting residue was purified by silica gel column chromatography to obtain the title compound (661 mg). MS (m / z): 363.3 [M+H] +

[1007] Reference Example 42 Methyl 3-(aminomethyl)-4-methylbenzoate

[1008] [Process 1] Preparation of Methyl 3-[(hydroxyimino)methyl]-4-methylbenzoate

[1009] A 50% aqueous hydroxylamine solution (1.32 mL) was added to a methanol (20 mL) solution of methyl 3-formyl-4-methylbenzoate (1.00 g) and stirred at 50°C for 2 hours. The reaction mixture was concentrated under reduced pressure, ethyl acetate was added to the resulting residue, and the organic layer was washed with water and saturated saline solution. After drying with anhydrous magnesium sulfate, the solvent was removed by vacuum distillation to obtain the title compound (1.02 g). MS(m / z): 194.4[M+H] +

[1010] [Process 2] Preparation of Methyl 3-(Aminomethyl)-4-Methylbenzoate

[1011] Hydrogen chloride (2M methanol solution, 15 mL) was added to methyl 3-[(hydroxyimino)methyl]-4-methylbenzoate (1.02 g) obtained in Process 1. 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 mixture was filtered through Celite (registered trademark), and the solvent was removed by vacuum distillation. An aqueous sodium hydroxide solution was added to the resulting residue to make it basic, and then extracted with ethyl acetate. The organic layer was washed with saturated saline solution, dried with anhydrous magnesium sulfate, and the solvent was removed by vacuum distillation to obtain the title compound (820 mg). MS (m / z): 180.4 [M+H] +

[1012] Reference Example 43 3-Bromo-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide

[1013] By the method according to Reference Example 7, the title compound (23.0 g) was obtained using 3-bromo-4-methylbenzoic acid (16.6 g) instead of 3-amino-4-methylbenzoic acid. MS(m / z): 312.0[M+H] +

[1014] Example 1 2-(cyclopropylamino)-N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)-1,3-thiazole-5-carboxamide

[1015] [Process 1] Preparation of Methyl 3-[(2-Bromo-1,3-thiazole-5-carbonyl)amino]-4-methylbenzoate

[1016] Methyl 3-amino-4-methylbenzoate (1.75g), HATU (4.83g), and DIPEA (3.66mL) were added sequentially to a DMF (20mL) solution of 2-bromo-1,3-thiazole-5-carboxylic acid (2.20g), and stirred at room temperature for 6 hours. The reaction mixture was diluted with ethyl acetate, and the organic layer was washed with a saturated sodium bicarbonate aqueous solution and a saturated saline solution. After drying with anhydrous magnesium sulfate, the solvent was removed by vacuum distillation, and the residue was purified by silica gel column chromatography to obtain the title compound (1.02g).

[1017] [Process 2] Preparation of Methyl 3-{[2-(cyclopropylamino)-1,3-thiazole-5-carbonyl]amino}-4-methylbenzoate

[1018] Cyclopropanamine (121 mg) was added to the NMP (0.5 mL) solution of methyl 3-[(2-bromo-1,3-thiazole-5-carbonyl)amino]-4-methylbenzoate (150 mg) obtained in Process 1, and stirred at 80°C for 6 hours. After cooling the reaction mixture, it was purified by silica gel column chromatography to obtain the title compound (105 mg).

[1019] [Process 3] Preparation of 3-{[2-(cyclopropylamino)-1,3-thiazole-5-carbonyl]amino}-4-methylbenzoic acid

[1020] By the method according to Process 2 of Reference Example 1, the title compound (90 mg) was obtained using methyl 3-{[2-(cyclopropylamino)-1,3-thiazole-5-carbonyl]amino}-4-methylbenzoate (103 mg), obtained in Process 2, instead of methyl 5-[(cyclopropylmethyl)amino]pyridine-3-carboxylate.

[1021] [Process 4] Preparation of 2-(cyclopropylamino)-N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)-1,3-thiazole-5-carboxamide

[1022] To the DMF (1 mL) solution of 3-{[2-(cyclopropylamino)-1,3-thiazole-5-carbonyl]amino}-4-methylbenzoic acid (30 mg) obtained in Process 3, HATU (54 mg) and DIPEA (0.065 mL) were added sequentially and stirred at room temperature for 10 minutes. Subsequently, (1S,2S)-2-aminocyclohexane-1-ol hydrochloride (22 mg) was added and stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate, and the organic layer was washed with a saturated sodium bicarbonate aqueous solution and a saturated saline solution. After drying with anhydrous magnesium sulfate, the solvent was removed by vacuum distillation, and the residue was purified by silica gel column chromatography to obtain the title compound (16 mg).

[1023] Example 2 N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)-5-phenylpyridine-3-carboxamide

[1024] [Process 1] Preparation of Methyl 3-[(5-Bromopyridine-3-Carbonyl)amino]-4-Methylbenzoate

[1025] The title compound (1.70 g) was obtained by a method according to Process 1 of Example 1 using 5-bromopyridine-3-carboxylic acid (1.00 g) instead of 2-bromo-1,3-thiazole-5-carboxylic acid. MS(m / z): 349.0[M+H] +

[1026] [Process 2] Preparation of 3-[(5-bromopyridine-3-carbonyl)amino]-4-methylbenzoic acid

[1027] By a method according to Process 2 of Reference Example 1, the title compound (505 mg) was obtained using methyl 3-[(5-bromopyridine-3-carbonyl)amino]-4-methylbenzoate (650 mg) obtained in Process 1 instead of methyl 5-[(cyclopropylmethyl)amino]pyridine-3-carboxylate. MS(m / z): 335.0[M+H] +

[1028] [Process 3] Preparation of 5-Bromo-N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)pyridine-3-carboxamide

[1029] By the method according to Process 4 of Example 1, the title compound (650 mg) was obtained using 3-[(5-bromopyridine-3-carbonyl)amino]-4-methylbenzoic acid (505 mg) obtained in Process 2 instead of 3-{[2-(cyclopropylamino)-1,3-thiazole-5-carbonyl]amino}-4-methylbenzoic acid. MS(m / z): 432.1[M+H] +

[1030] [Process 4] Preparation of N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)-5-phenylpyridine-3-carboxamide

[1031] By the method according to Reference Example 14, the title compound (40 mg) was obtained using 5-bromo-N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)pyridine-3-carboxamide (50 mg) and phenylboronic acid (17 mg), obtained in Process 3, instead of 2-chloropyrimidine-4-amine and isoquinoline-4-ylboronic acid.

[1032] Example 3 2-(cyclopropylmethyl)-N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)-1,3-thiazole-5-carboxamide

[1033] [Process 1] Preparation of Methyl 3-{[2-(cyclopropylmethyl)-1,3-thiazole-5-carbonyl]amino}-4-methylbenzoate

[1034] The title compound (160 mg) was obtained by using 2-(cyclopropylmethyl)-1,3-thiazole-5-carboxylic acid (100 mg) instead of 2-bromo-1,3-thiazole-5-carboxylic acid by a method according to Process 1 of Example 1. MS(m / z): 331.5[M+H] +

[1035] [Process 2] Preparation of 3-{[2-(cyclopropylmethyl)-1,3-thiazole-5-carbonyl]amino}-4-methylbenzoic acid

[1036] By a method according to Process 2 of Reference Example 1, the title compound (145 mg) was obtained using methyl 3-{[2-(cyclopropylmethyl)-1,3-thiazole-5-carbonyl]amino}-4-methylbenzoate (160 mg), obtained in Process 1, instead of methyl 5-[(cyclopropylmethyl)amino]pyridine-3-carboxylate. MS(m / z): 317.4[M+H] +

[1037] [Process 3] Preparation of 2-(cyclopropylmethyl)-N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)-1,3-thiazole-5-carboxamide

[1038] By the method according to Process 4 of Example 1, the title compound (38 mg) was obtained using 3-{[2-(cyclopropylamino)-1,3-thiazole-5-carbonyl]amino}-4-methylbenzoic acid (40 mg) obtained in Process 2 instead of 3-{[2-(cyclopropylmethyl)-1,3-thiazole-5-carbonyl]amino}-4-methylbenzoic acid.

[1039] Example 5 N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)-2-phenyl-1,3-oxazole-5-carboxamide

[1040] By the method according to Process 1 of Example 1, the title compound (53 mg) was obtained using 2-phenyl-1,3-oxazole-5-carboxylic acid (30 mg) and 3-amino-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide (43 mg), obtained in Reference Example 7, instead of 2-bromo-1,3-thiazole-5-carboxylic acid and methyl 3-amino-4-methylbenzoate.

[1041] Example 6 N-(5-{[(1S)-2-hydroxy-1-phenylethyl]carbamoyl}-2-methylphenyl)-5-phenylpyridine-3-carboxamide

[1042] [Process 1] Preparation of Methyl 4-Methyl-3-[(5-Phenylpyridine-3-Carbonyl)amino]Benzoate

[1043] By the method according to Reference Example 14, the title compound (1.00 g) was obtained using methyl 3-[(5-bromopyridine-3-carbonyl)amino]-4-methylbenzoate (1.00 g) and phenylboronic acid (419 mg), obtained in Process 1 of Example 2, instead of 2-chloropyrimidine-4-amine and isoquinoline-4-ylboronic acid. MS(m / z): 347.2[M+H] +

[1044] [Process 2] Preparation of 4-methyl-3-[(5-phenylpyridine-3-carbonyl)amino]benzoic acid

[1045] The title compound (910 mg) was obtained by using methyl 4-methyl-3-[(5-phenylpyridine-3-carbonyl)amino]benzoate (1.00 g) obtained in Process 1 instead of methyl 5-[(cyclopropylmethyl)amino]pyridine-3-carboxylate by a method according to Process 2 of Reference Example 1. MS(m / z): 333.2[M+H] +

[1046] [Process 3] Preparation of N-(5-{[(1S)-2-hydroxy-1-phenylethyl]carbamoyl}-2-methylphenyl)-5-phenylpyridine-3-carboxamide

[1047] By the method according to Process 4 of Example 1, the title compound (38 mg) was obtained using 4-methyl-3-[(5-phenylpyridine-3-carbonyl)amino]benzoic acid (40 mg) and (2S)-2-amino-2-phenylethanol-1-ol (25 mg), obtained in Process 2, instead of 3-{[2-(cyclopropylamino)-1,3-thiazole-5-carbonyl]amino}-4-methylbenzoic acid, (1S,2S)-2-aminocyclohexan-1-ol hydrochloride.

[1048] Example 17 5-[cyclopropyl(methyl)amino]-N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)pyridine-3-carboxamide

[1049] By the method according to Process 1 of Example 1, the title compound (43 mg) was obtained using 5-[cyclopropyl(methyl)amino]pyridine-3-carboxylic acid (70 mg) obtained in Reference Example 2 and 3-amino-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide (90 mg) obtained in Reference Example 7, instead of 2-bromo-1,3-thiazole-5-carboxylic acid and methyl 3-amino-4-methylbenzoate.

[1050] Example 20 5-(3-fluorophenyl)-N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)pyridine-3-carboxamide

[1051] By the method according to Reference Example 14, the title compound (43 mg) was obtained using 5-bromo-N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)pyridine-3-carboxamide (61 mg) and (3-fluorophenyl)boronic acid (28 mg), obtained in Process 3 of Example 2, instead of 2-chloropyrimidine-4-amine and isoquinoline-4-ylboronic acid, according to the method according to Reference Example 14.

[1052] Example 24 5-(cyclopropylmethoxy)-N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)pyridine-3-carboxamide

[1053] By the method according to Process 1 of Example 1, the title compound (58 mg) was obtained using 5-(cyclopropylmethoxy)pyridine-3-carboxylic acid (40 mg) and 3-amino-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide (57 mg), obtained in Reference Example 7, instead of 2-bromo-1,3-thiazole-5-carboxylic acid and methyl 3-amino-4-methylbenzoate.

[1054] Example 26 2-[(2-cyclopropylethyl)amino]-N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)-1,3-thiazole-5-carboxamide

[1055] [Process 1] Preparation of Methyl 3-[(2-chloro-1,3-thiazole-5-carbonyl)amino]-4-methylbenzoate

[1056] To an 80 mL THF solution of 2-chloro-1,3-thiazole-5-carbonyl chloride (8.31 g) was added dropwise under ice-cold stirring to an 80 mL THF solution of methyl 3-amino-4-methylbenzoate (6.89 g), and the mixture was stirred for 30 minutes at the same temperature. The reaction mixture was diluted with ethyl acetate, and the organic layer was washed with an aqueous solution of saturated sodium bicarbonate and saturated saline solution. After drying with anhydrous sodium sulfate, the solvent was removed by vacuum distillation, and the resulting residue was suspended by adding water. The precipitate was filtered and collected to obtain the title compound (12.5 g). MS (m / z): 311.4 [M+H] +

[1057] [Process 2] Preparation of 3-[(2-chloro-1,3-thiazole-5-carbonyl)amino]-4-methylbenzoic acid

[1058] By a method according to Process 2 of Reference Example 1, the title compound (10.4 g) was obtained using methyl 3-[(2-chloro-1,3-thiazole-5-carbonyl)amino]-4-methylbenzoate (12.5 g) obtained in Process 1 instead of methyl 5-[(cyclopropylmethyl)amino]pyridine-3-carboxylate. MS(m / z): 297.4[M+H] +

[1059] [Process 3] Preparation of 2-chloro-N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)-1,3-thiazole-5-carboxamide

[1060] By the method according to Process 4 of Example 1, the title compound (9.8 g) was obtained using 3-[(2-chloro-1,3-thiazole-5-carbonyl)amino]-4-methylbenzoic acid (7.5 g) obtained in Process 2 instead of 3-{[2-(cyclopropylamino)-1,3-thiazole-5-carbonyl]amino}-4-methylbenzoic acid. MS(m / z): 394.2[M+H] +

[1061] [Process 4] Preparation of N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)-5-phenylpyridine-3-carboxamide

[1062] By the method according to Process 2 of Example 1, the title compound (72 mg) was obtained using 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 Process 3, instead of methyl 3-[(2-bromo-1,3-thiazole-5-carbonyl)amino]-4-methylbenzoate and cyclopropanamine.

[1063] Example 57 3-[(5-bromopyridine-3-yl)ethinyl]-4-chloro-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide

[1064] [Process 1] Preparation of Methyl 3-[(5-Bromopyridine-3-yl)ethinyl]-4-chlorobenzoate

[1065] By a method according to Process 1 of Reference Example 8, the title compound (1.60 g) was obtained using methyl 4-chloro-3-ethynylbenzoate (1.01 g) and 3-bromo-5-iodopyridine (1.47 g) obtained in Reference Example 8, instead of ethinyl(trimethyl)silane and methyl 4-chloro-3-iodobenzoate. MS(m / z): 350.0[M+H] +

[1066] [Process 2] Preparation of 3-[(5-bromopyridine-3-yl)ethinyl]-4-chlorobenzoic acid

[1067] The title compound (360 mg) was obtained by using methyl 3-[(5-bromopyridine-3-yl)ethinyl]-4-chlorobenzoate (600 mg), obtained in Process 1, instead of methyl 5-[(cyclopropylmethyl)amino]pyridine-3-carboxylate, by a method according to Process 2 of Reference Example 1. MS(m / z): 335.9[M+H] +

[1068] [Process 3] Preparation of 3-[(5-bromopyridine-3-yl)ethinyl]-4-chloro-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide

[1069] By the method according to Process 4 of Example 1, the title compound (170 mg) was obtained using 3-[(5-bromopyridine-3-yl)ethinyl]-4-chlorobenzoic acid (370 mg), obtained in Process 2, instead of 3-{[2-(cyclopropylamino)-1,3-thiazole-5-carbonyl]amino}-4-methylbenzoic acid.

[1070] Example 58 4-chloro-N-[(1S,2S)-2-hydroxycyclohexyl]-3-[(5-phenylpyridine-3-yl)ethynyl]benzamide

[1071] By the method according to Reference Example 14, the title compound (5 mg) was obtained using 3-[(5-bromopyridine-3-yl)ethinyl]-4-chloro-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide (50 mg) and phenylboronic acid (15 mg), obtained in Example 57, instead of 2-chloropyrimidine-4-amine and isoquinoline-4-ylboronic acid.

[1072] Example 59 N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-[(5-methylpyridine-3-yl)ethynyl]benzamide

[1073] By the method according to Process 1 of Reference Example 8, the title compound (14 mg) was obtained using 3-ethynyl-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide (30 mg) and 3-bromo-5-methylpyridine (30 mg), obtained in Reference Example 9, instead of ethinyl(trimethyl)silane and methyl 4-chloro-3-iodobenzoate.

[1074] Example 61 3-[(5-bromopyridine-3-yl)ethinyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide

[1075] By the method according to Process 1 of Reference Example 8, the title compound (14.5g) was obtained using 3-ethynyl-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide (20.5g) and 3-bromo-5-iodopyridine (24.8g), obtained in Reference Example 9, instead of ethinyl(trimethyl)silane and methyl 4-chloro-3-iodobenzoate.

[1076] Example 62 N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-{[5-(pyrimidine-2-yl)pyridine-3-yl]ethinyl}benzamide

[1077] DMF (0.5 mL) was added to 3-[(5-bromopyridine-3-yl)ethynyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide (30 mg), 2-(tributyltannyl)pyrimidine (54 mg), Pd(PPh3)4 (17 mg), copper iodide (7 mg), and cesium fluoride (22 mg) obtained in Example 61, and the mixture was reacted in a microwave reaction apparatus at 150°C for 30 minutes. After cooling the reaction solution, it was purified by silica gel column chromatography to obtain the title compound (15 mg).

[1078] Example 67 3-[(5-cyclopropylpyridine-3-yl)ethinyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide

[1079] By the method according to Reference Example 14, the title compound (250 mg) was obtained using 3-[(5-bromopyridine-3-yl)ethinyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide (400 mg) and cyclopropylboronic acid (249 mg), obtained in Example 61, instead of 2-chloropyrimidine-4-amine and isoquinoline-4-ylboronic acid, by the method according to Reference Example 14.

[1080] Example 76 3-[(5-bromopyridine-3-yl)ethynyl]-N-[(1S,2S)-1,3-dihydroxy-1-phenylpropane-2-yl]-4-methylbenzamide

[1081] [Process 1] Preparation of 3-[(5-bromopyridine-3-yl)ethynyl]-4-methylbenzoic acid

[1082] By the method according to Process 1 of Reference Example 8, the title compound (47 mg) was obtained using 3-ethynyl-4-methylbenzoic acid (40 mg) and 3-bromo-5-iodopyridine (71 mg) instead of ethinyl(trimethyl)silane and methyl 4-chloro-3-iodobenzoate. MS(m / z): 316.2[M+H] +

[1083] [Process 2] Preparation of 3-[(5-bromopyridine-3-yl)ethynyl]-N-[(1S,2S)-1,3-dihydroxy-1-phenylpropane-2-yl]-4-methylbenzamide

[1084] By the method according to Process 4 of Example 1, the title compound (28 mg) was obtained using 3-[(5-bromopyridine-3-yl)ethynyl]-4-methylbenzoic acid (25 mg) and (1S,2S)-2-amino-1-phenylpropane-1,3-diol (16 mg), obtained in Process 1, instead of 3-{[2-(cyclopropylamino)-1,3-thiazole-5-carbonyl]amino}-4-methylbenzoic acid and (1S,2S)-2-aminocyclohexan-1-ol hydrochloride.

[1085] Example 77 N 1 -[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-N 3 -(5-phenylpyridine-3-yl)benzene-1,3-dicarboxamide

[1086] [Process 1] Preparation of Methyl 5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylbenzoate

[1087] The title compound (600 mg) was obtained by using 3-(methoxycarbonyl)-4-methylbenzoic acid (500 mg) instead of 3-{[2-(cyclopropylamino)-1,3-thiazole-5-carbonyl]amino}-4-methylbenzoic acid by the method according to Process 4 of Example 1. MS(m / z): 292.3[M+H] +

[1088] [Process 2] Preparation of 5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylbenzoic acid

[1089] By a method according to Process 2 of Reference Example 1, the title compound (430 mg) was obtained using methyl 5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylbenzoate (600 mg) obtained in Process 1 instead of methyl 5-[(cyclopropylmethyl)amino]pyridine-3-carboxylate. MS(m / z): 278.3[M+H] +

[1090] [Process 3] N 3 -(5-bromopyridin-3-yl)-N 1 Preparation of -[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzene-1,3-dicarboxamide

[1091] By a method according to Process 1 of Example 1, the title compound (166 mg) was obtained using 5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylbenzoic acid (200 mg) and 5-bromopyridine-3-amine (137 mg), obtained in Process 2, instead of 2-bromo-1,3-thiazole-5-carboxylic acid and methyl 3-amino-4-methylbenzoate. MS(m / z): 432.3[M+H] +

[1092] [Process 4] N 1 -[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-N 3 - Preparation of (5-phenylpyridine-3-yl)benzene-1,3-dicarboxamide

[1093] By the method according to Reference Example 14, instead of 2-chloropyrimidine-4-amine and isoquinoline-4-ylboronic acid, N obtained in Process 3 3 -(5-bromopyridin-3-yl)-N 1 -[(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).

[1094] Example 78 N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-{[2-(pyridine-3-yl)pyrimidine-4-yl]amino}benzamide

[1095] [Process 1] Preparation of methyl 4-methyl-3-{[2-(pyridine-3-yl)pyrimidine-4-yl]amino}benzoate

[1096] By the method according to Process 1 of Reference Example 1, the title compound (280 mg) was obtained using methyl 3-bromo-4-methylbenzoate (350 mg) and 2-(pyridin-3-yl)pyrimidine-4-amine (263 mg) instead of methyl 5-bromopyridine-3-carboxylate and 1-cyclopropylmethaneamine.

[1097] [Process 2] Preparation of 4-methyl-3-{[2-(pyridine-3-yl)pyrimidine-4-yl]amino}benzoic acid

[1098] By the method according to Process 2 of Reference Example 1, the title compound (180 mg) was obtained by using methyl 4-methyl-3-{[2-(pyridin-3-yl)pyrimidin-4-yl]amino}benzoate (280 mg), obtained in Process 1, instead of methyl 5-[(cyclopropylmethyl)amino]pyridin-3-carboxylate.

[1099] [Process 3] Preparation of N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-{[2-(pyridine-3-yl)pyrimidine-4-yl]amino}benzamide

[1100] By the method according to process 4 of Example 1, the title compound (50 mg) was obtained using 4-methyl-3-{[2-(pyridine-3-yl)pyrimidine-4-yl]amino} benzoic acid (50 mg) instead of 3-{[2-(cyclopropylamino)-1,3-thiazole-5-carbonyl]amino}-4-methylbenzoic acid.

[1101] Example 83 3-(2-amino-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-yl)-N-[(1S,2S)-1,3-dihydroxy-1-phenylpropane-2-yl]-4-methylbenzamide

[1102] [Process 1] Preparation of methyl 3-{2-[bis(tert-butoxycarbonyl)amino]-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-yl}-4-methylbenzoate

[1103] The title compound (54 mg) was obtained by a method according to Process 1 of Reference Example 1, using methyl 3-bromo-4-methylbenzoate (84 mg) and di-tert-butyl 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2-yl-2-imidodicarbonate (86 mg), obtained in Reference Example 40, instead of methyl 5-bromopyridine-3-carboxylate and 1-cyclopropylmethaneamine. MS(m / z): 499.6[M+H] +

[1104] [Process 2] Preparation of methyl 3-(2-amino-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-yl)-4-methylbenzoate

[1105] Hydrogen chloride (2 M methanol solution, 2.1 mL) was added to the methyl 3-{2-[bis(tert-butoxycarbonyl)amino]-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-yl}-4-methylbenzoate (70 mg) obtained in Process 1, and the mixture was stirred at 50°C for 5 hours. After cooling the reaction mixture, it was purified by silica gel column chromatography to obtain the title compound (10 mg). MS(m / z): 299.5[M+H] +

[1106] [Process 3] Preparation of 3-(2-amino-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-yl)-4-methylbenzoic acid

[1107] The title compound was obtained by using methyl 3-(2-amino-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-yl)-4-methylbenzoate (10 mg), obtained in Process 2, instead of methyl 5-[(cyclopropylmethyl)amino]pyridine-3-carboxylate, by a method according to Process 2 of Reference Example 1. MS(m / z): 285.3[M+H] +

[1108] [Process 4] Preparation of 3-(2-amino-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-yl)-N-[(1S,2S)-1,3-dihydroxy-1-phenylpropane-2-yl]-4-methylbenzamide

[1109] By the method according to Process 4 of Example 1, the title compound (6 mg) was obtained using 3-{[2-(cyclopropylamino)-1,3-thiazole-5-carbonyl]amino}-4-methylbenzoic acid, (1S,2S)-2-aminocyclohexan-1-ol hydrochloride, (11 mg) obtained in Process 3, instead of 3-{[2-(cyclopropylamino)-1,3-thiazole-5-carbonyl]amino}-4-methylbenzoic acid, (1S,2S)-2-amino-1-phenylpropane-1,3-diol obtained in Process 3.

[1110] Example 84 N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-{[(1S)-1-(5-phenylpyridine-3-yl)ethyl]amino}benzamide

[1111] [Process 1] Preparation of methyl 4-methyl-3-{[(1S)-1-(5-phenylpyridine-3-yl)ethyl]amino}benzoate

[1112] By a method according to Process 1 of Reference Example 1, the title compound (220 mg) was obtained using methyl 3-bromo-4-methylbenzoate (324 mg) and (1S)-1-(5-phenylpyridine-3-yl)ethane-1-amine (280 mg), obtained in Reference Example 15, instead of methyl 5-bromopyridine-3-carboxylate and 1-cyclopropylmethaneamine. MS(m / z): 347.3[M+H] +

[1113] [Process 2] Preparation of 4-methyl-3-{[(1S)-1-(5-phenylpyridine-3-yl)ethyl]amino}benzoic acid

[1114] By a method according to Process 2 of Reference Example 1, the title compound (180 mg) was obtained using methyl 4-methyl-3-{[(1S)-1-(5-phenylpyridine-3-yl)ethyl]amino}benzoate obtained in Process 1 (220 mg) instead of methyl 5-[(cyclopropylmethyl)amino]pyridine-3-carboxylate. MS(m / z): 333.3[M+H] +

[1115] [Process 3] Preparation of N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-{[(1S)-1-(5-phenylpyridine-3-yl)ethyl]amino}benzamide

[1116] By the method according to Process 4 of Example 1, the title compound (60 mg) was obtained using 4-methyl-3-{[(1S)-1-(5-phenylpyridine-3-yl)ethyl]amino} benzoic acid (50 mg) obtained in Process 2 instead of 3-{[2-(cyclopropylamino)-1,3-thiazole-5-carbonyl]amino}-4-methylbenzoic acid.

[1117] Example 85 3-{[(1S)-1-([3,3'-bipyridine]-5-yl)ethyl]amino}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide

[1118] [Process 1] Preparation of methyl 3-{[(1S)-1-([3,3'-bipyridine]-5-yl)ethyl]amino}-4-methylbenzoate

[1119] By a method according to Process 1 of Reference Example 1, the title compound (10.3 g) was obtained using methyl 3-bromo-4-methylbenzoate (13.9 g) and (1S)-1-([3,3'-bipyridine]-5-yl)ethane-1-amine obtained in Reference Example 16 (11.0 g) instead of methyl 5-bromopyridine-3-carboxylate and 1-cyclopropylmethaneamine. MS(m / z): 348.3[M+H] +

[1120] [Process 2] Preparation of 3-{[(1S)-1-([3,3'-bipyridine]-5-yl)ethyl]amino}-4-methylbenzoic acid

[1121] By a method according to Process 2 of Reference Example 1, the title compound (8.7 g) was obtained using methyl 3-{[(1S)-1-([3,3'-bipyridine]-5-yl)ethyl]amino}-4-methylbenzoate (10.3 g) obtained in Process 1, instead of methyl 5-[(cyclopropylmethyl)amino]pyridine-3-carboxylate. MS(m / z): 334.4[M+H] +

[1122] [Process 3] Preparation of 3-{[(1S)-1-([3,3'-bipyridine]-5-yl)ethyl]amino}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide

[1123] By the method according to Process 4 of Example 1, the title compound (9.4g) was obtained using 3-{[(1S)-1-([3,3'-bipyridine]-5-yl)ethyl]amino}-4-methylbenzoic acid (8.7g) obtained in Process 2 instead of 3-{[2-(cyclopropylamino)-1,3-thiazole-5-carbonyl]amino}-4-methylbenzoic acid.

[1124] Example 87 3-{[(1S)-1-([3,4'-bipyridine]-5-yl)ethyl]amino}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide

[1125] [Process 1] Preparation of methyl 3-{[(1R)-1-(5-bromopyridine-3-yl)ethyl]amino}-4-methylbenzoate

[1126] By a method according to Process 1 of Reference Example 1, the title compound (1.80 g) was obtained using methyl 3-iod-4-methylbenzoate (6.49 g) and (1S)-1-(5-bromopyridine-3-yl)ethane-1-amine (3.78 g) instead of methyl 5-bromopyridine-3-carboxylate and 1-cyclopropylmethaneamine. MS(m / z): 349.0[M+H] +

[1127] [Process 2] Preparation of 3-{[(1R)-1-(5-bromopyridine-3-yl)ethyl]amino}-4-methylbenzoic acid

[1128] The title compound (820 mg) was obtained by using methyl 3-{[(1R)-1-(5-bromopyridine-3-yl)ethyl]amino}-4-methylbenzoate (1.00 g) obtained in Process 1, instead of methyl 5-[(cyclopropylmethyl)amino]pyridine-3-carboxylate, by a method according to Process 2 of Reference Example 1. MS(m / z): 335.1[M+H] +

[1129] [Process 3] Preparation of 3-{[(1S)-1-(5-bromopyridine-3-yl)ethyl]amino}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide

[1130] By the method according to Process 4 of Example 1, the title compound (920 mg) was obtained using 3-{[(1R)-1-(5-bromopyridine-3-yl)ethyl]amino}-4-methylbenzoic acid obtained in Process 2 (820 mg) instead of 3-{[2-(cyclopropylamino)-1,3-thiazole-5-carbonyl]amino}-4-methylbenzoic acid. MS(m / z): 432.3[M+H] +

[1131] [Process 4] Preparation of 3-{[(1S)-1-([3,4'-bipyridine]-5-yl)ethyl]amino}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide

[1132] By the method according to Reference Example 14, the title compound (9 mg) was obtained using 3-{[(1S)-1-(5-bromopyridine-3-yl)ethyl]amino}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide (30 mg) and pyridine-4-ylboronic acid (10 mg), obtained in Process 3, instead of 2-chloropyrimidine-4-amine and isoquinoline-4-ylboronic acid.

[1133] Example 89 3-{[(1S)-1-([2,3'-bipyridine]-5'-yl)ethyl]amino}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide

[1134] [Process 1] Preparation of methyl 3-{[(1S)-1-([2,3'-bipyridine]-5'-yl)ethyl]amino}-4-methylbenzoate

[1135] By a method according to Process 1 of Reference Example 10, the title compound (90 mg) was obtained using methyl 3-{[(1R)-1-(5-bromopyridin-3-yl)ethyl]amino}-4-methylbenzoate (150 mg) and 2-bromopyridine (170 mg), obtained in Process 1 of Example 87, instead of 3-bromo-5-(methoxymethoxy)pyridine and 2-bromopyrimidine. MS(m / z): 348.2[M+H]+

[1136] [Process 2] Preparation of 3-{[(1S)-1-([2,3'-bipyridine]-5'-yl)ethyl]amino}-4-methylbenzoic acid

[1137] By a method according to Process 2 of Reference Example 1, the title compound (86 mg) was obtained using methyl 3-{[(1S)-1-([2,3'-bipyridine]-5'-yl)ethyl]amino}-4-methylbenzoate (90 mg), obtained in Process 1, instead of methyl 5-[(cyclopropylmethyl)amino]pyridine-3-carboxylate. MS(m / z): 334.2[M+H] +

[1138] [Process 3] Preparation of 3-{[(1S)-1-([2,3'-bipyridine]-5'-yl)ethyl]amino}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide

[1139] By the method according to Process 4 of Example 1, the title compound (10 mg) was obtained using 3-{[(1S)-1-([2,3'-bipyridine]-5'-yl)ethyl]amino}-4-methylbenzoic acid (70 mg) obtained in Process 2 instead of 3-{[2-(cyclopropylamino)-1,3-thiazole-5-carbonyl]amino}-4-methylbenzoic acid.

[1140] Example 91 3-{[(5-bromopyridine-3-yl)methyl]amino}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide

[1141] By the method according to Reference Example 34, the title compound (2.0g) was obtained using 3-amino-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide (1.6g) obtained in Reference Example 7 instead of 1-methylpiperazine.

[1142] Example 92 N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-{[(5-phenylpyridine-3-yl)methyl]amino}benzamide

[1143] By the method according to Reference Example 14, the title compound (23 mg) was obtained using 3-{[(5-bromopyridine-3-yl)methyl]amino}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide (30 mg) and phenylboronic acid (10 mg), obtained in Example 91, instead of 2-chloropyrimidine-4-amine and isoquinoline-4-ylboronic acid.

[1144] Example 94 3-({[5-(cyclopropylethinyl)pyridine-3-yl]methyl}amino)-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide

[1145] By the method according to Process 1 of Reference Example 8, the title compound (64 mg) was obtained using ethinylcyclopropane (63 mg) instead of methyl 4-chloro-3-iodobenzoate, and 3-{[(5-bromopyridine-3-yl)methyl]amino}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide (100 mg) obtained in Example 91.

[1146] Example 95 N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-({[5-(pyrimidine-2-yl)pyridine-3-yl]methyl}amino)benzamide

[1147] [Process 1] Preparation of methyl 3-{[(5-bromopyridine-3-yl)methyl]amino}-4-methylbenzoate

[1148] The title compound (13.0 g) was obtained by using methyl 3-amino-4-methylbenzoate (9.0 g) instead of 1-methylpiperazine by the method according to Reference Example 34. MS(m / z): 335.3[M+H] +

[1149] [Process 2] Preparation of methyl 4-methyl-3-({[5-(pyrimidine-2-yl)pyridine-3-yl]methyl}amino)benzoate

[1150] By a method according to Process 1 of Reference Example 10, the title compound (9.0 g) was obtained using methyl 3-{[(5-bromopyridine-3-yl)methyl]amino}-4-methylbenzoate obtained in Process 1 (13.0 g) instead of 3-bromo-5-(methoxymethoxy)pyridine. MS(m / z): 335.5[M+H] +

[1151] [Process 3] Preparation of 4-methyl-3-({[5-(pyrimidine-2-yl)pyridine-3-yl]methyl}amino)benzoic acid

[1152] By a method according to Process 2 of Reference Example 1, the title compound (6.6 g) was obtained using methyl 4-methyl-3-({[5-(pyrimidine-2-yl)pyridine-3-yl]methyl}amino)benzoate (9.0 g) obtained in Process 2, instead of methyl 5-[(cyclopropylmethyl)amino]pyridine-3-carboxylate. MS(m / z): 321.5[M+H] +

[1153] [Process 4] Preparation of N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-({[5-(pyrimidine-2-yl)pyridine-3-yl]methyl}amino)benzamide

[1154] By the method according to Process 4 of Example 1, the title compound (5.5g) was obtained using 4-methyl-3-({[5-(pyrimidine-2-yl)pyridine-3-yl]methyl}amino)benzoic acid obtained in Process 3 (6.0g) instead of 3-{[2-(cyclopropylamino)-1,3-thiazole-5-carbonyl]amino}-4-methylbenzoic acid.

[1155] Example 96 N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-{[(quinoline-3-yl)methyl]amino}benzamide

[1156] [Process 1] Preparation of methyl 4-methyl-3-{[(quinoline-3-yl)methyl]amino}benzoate

[1157] By the method according to Reference Example 34, the title compound (230 mg) was obtained using methyl 3-amino-4-methylbenzoate (210 mg) and quinoline-3-carbaldehydride (200 mg) instead of 1-methylpiperazine and 5-bromopyridine-3-carbaldehydride.

[1158] [Process 2] Preparation of 4-methyl-3-{[(quinoline-3-yl)methyl]amino}benzoic acid

[1159] By the method according to Process 2 of Reference Example 1, the title compound (200 mg) was obtained by using methyl 4-methyl-3-{[(quinoline-3-yl)methyl]amino}benzoate (230 mg), obtained in Process 1, instead of methyl 5-[(cyclopropylmethyl)amino]pyridine-3-carboxylate.

[1160] [Process 3] Preparation of N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-{[(quinoline-3-yl)methyl]amino}benzamide

[1161] By the method according to Process 4 of Example 1, the title compound (43 mg) was obtained using 4-methyl-3-{[(quinoline-3-yl)methyl]amino}benzoic acid (40 mg) obtained in Process 2 instead of 3-{[2-(cyclopropylamino)-1,3-thiazole-5-carbonyl]amino}-4-methylbenzoic acid.

[1162] Example 98 3-[({5-[4-(2-aminopropane-2-yl)phenyl]pyridine-3-yl}methyl)amino]-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide

[1163] By the method according to Process 1 of Reference Example 10, the title compound (41 mg) was obtained using 3-{[(5-bromopyridine-3-yl)methyl]amino}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide (80 mg) and 2-(4-bromophenyl)propane-2-amine (49 mg), obtained in Example 91, instead of 3-bromo-5-(methoxymethoxy)pyridine and 2-bromopyrimidine.

[1164] Example 101 N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-{[(6-phenylpyrazine-2-yl)methyl]amino}benzamide

[1165] [Process 1] Preparation of Methyl 3-{[(6-chloropyrazine-2-yl)methyl]amino}-4-methylbenzoate

[1166] By the method according to Reference Example 34, the title compound (150 mg) was obtained using methyl 3-amino-4-methylbenzoate (449 mg) and 6-chloropyrazine-2-carbaldehydride (774 mg) instead of 1-methylpiperazine and 5-bromopyridine-3-carbaldehydride.

[1167] [Process 2] Preparation of methyl 4-methyl-3-{[(6-phenylpyrazine-2-yl)methyl]amino}benzoate

[1168] By the method according to Reference Example 14, the title compound (66 mg) was obtained using methyl 3-{[(6-chloropyrazine-2-yl)methyl]amino}-4-methylbenzoate (70 mg) and phenylboronic acid (35 mg), obtained in Process 1, instead of 2-chloropyrimidine-4-amine and isoquinoline-4-ylboronic acid.

[1169] [Process 3] Preparation of 4-methyl-3-{[(6-phenylpyrazine-2-yl)methyl]amino}benzoic acid

[1170] By the method according to Process 2 of Reference Example 1, the title compound (55 mg) was obtained using methyl 4-methyl-3-{[(6-phenylpyrazine-2-yl)methyl]amino}benzoate (66 mg), obtained in Process 2, instead of methyl 5-[(cyclopropylmethyl)amino]pyridine-3-carboxylate.

[1171] [Process 4] Preparation of N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-{[(6-phenylpyrazine-2-yl)methyl]amino}benzamide

[1172] By the method according to Process 4 of Example 1, the title compound (19 mg) was obtained using 4-methyl-3-{[(6-phenylpyrazine-2-yl)methyl]amino} benzoic acid (25 mg) obtained in Process 3 instead of 3-{[2-(cyclopropylamino)-1,3-thiazole-5-carbonyl]amino}-4-methylbenzoic acid.

[1173] Example 109 N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-{[(1H-pyrazolo[3,4-b]pyridin-5-yl)methyl]amino}benzamide

[1174] By the method according to Reference Example 34, the title compound (84 mg) was obtained using 3-amino-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide (73 mg) and 1H-pyrazolo[3,4-b]pyridine-5-carbaldehydride (43 mg), obtained in Reference Example 7, instead of 1-methylpiperazine and 5-bromopyridine-3-carbaldehydride.

[1175] Example 110 N-[(1S,2S)-2-hydroxycyclohexyl]-3-{[(imidazo[1,2-b]pyridazine-3-yl)methyl]amino}-4-methylbenzamide

[1176] By the method according to Reference Example 34, the title compound (18 mg) was obtained using 3-amino-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide (24 mg) and imidazo[1,2-b]pyridazine-3-carbaldehydride (15 mg), obtained in Reference Example 7, instead of 1-methylpiperazine and 5-bromopyridine-3-carbaldehydride.

[1177] Example 113 3-{[(2-aminopyrimidine-5-yl)methyl]amino}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide

[1178] [Process 1] Preparation of 3-{[(2-chloropyrimidine-5-yl)methyl]amino}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide

[1179] By the method according to Reference Example 34, the title compound (320 mg) was obtained using 3-amino-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide (513 mg) and 2-chloropyrimidine-5-carbaldehydride (310 mg), obtained in Reference Example 7, instead of 1-methylpiperazine and 5-bromopyridine-3-carbaldehydride. MS(m / z): 375.5[M+H] +

[1180] [Process 2] Preparation of 3-{[(2-aminopyrimidine-5-yl)methyl]amino}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide

[1181] To the 3-{[(2-chloropyrimidine-5-yl)methyl]amino}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide (320 mg) obtained in Process 1, 1,4-dioxane (8 mL) and a 28% aqueous ammonia solution (4 mL) were added, sealed using a stainless steel pressure vessel, and stirred at 100°C for 8 hours. After cooling the reaction mixture, it was purified by silica gel column chromatography to obtain the title compound (173 mg).

[1182] Example 116 3-{[(6-acetamidopyridine-3-yl)methyl]amino}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide

[1183] [Process 1] Preparation of 3-{[(6-bromopyridine-3-yl)methyl]amino}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide

[1184] By the method according to Reference Example 34, the title compound (370 mg) was obtained using 3-amino-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide (380 mg) and 6-bromopyridine-3-carbaldehydride (300 mg), obtained in Reference Example 7, instead of 1-methylpiperazine and 5-bromopyridine-3-carbaldehydride. MS(m / z): 418.5[M+H] +

[1185] [Process 2] Preparation of 3-{[(6-acetamidopyridine-3-yl)methyl]amino}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide

[1186] By a method based on Process 1 of Reference Example 1, the title compound (22 mg) was obtained using 3-{[(6-bromopyridine-3-yl)methyl]amino}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide (50 mg) and acetamide (18 mg), obtained in Process 1, instead of methyl 5-bromopyridine-3-carboxylate and 1-cyclopropylmethaneamine.

[1187] Example 118 3-{[([2,2'-bipyridine]-5-yl)methyl]amino}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide

[1188] By the method according to Example 62, the title compound (23 mg) was obtained using 3-{[(6-bromopyridine-3-yl)ethynyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide, obtained in Process 1 of Example 116, instead of 2-(tributyltannyl)pyrimidine, 3-{[(6-bromopyridine-3-yl)methyl]amino}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide (60 mg) and 2-(tributyltannyl)pyridine (79 mg), obtained in Process 1 of Example 116.

[1189] Example 122 N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-({[6-(1H-pyrazole-1-yl)pyridin-3-yl]methyl}amino)benzamide

[1190] A mixture of 3-{[(6-bromopyridine-3-yl)methyl]amino}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide (60 mg), 1H-pyrazole (20 mg), copper iodide (11 mg), potassium phosphate (91 mg), trans-N,N'-dimethylcyclohexane-1,2-diamine (0.014 mL), and DMF (0.36 mL), obtained in Process 1 of Example 116, was reacted in a microwave reaction apparatus at 100°C for 30 minutes. To the reaction mixture, 1H-pyrazole (20 mg), copper iodide (11 mg), and trans-N,N'-dimethylcyclohexane-1,2-diamine (0.014 mL) were added, and the mixture was reacted in a microwave reaction apparatus at 100°C for an additional 30 minutes. After cooling the reaction solution, it was purified by silica gel column chromatography to obtain the title compound (34 mg).

[1191] Example 129 N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-{[(6-{[(pyridin-3-yl)carbamoyl]amino}pyridin-3-yl)methyl]amino}benzamide

[1192] [Process 1] Preparation of 3-{[(6-aminopyridine-3-yl)methyl]amino}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide

[1193] By the method according to Reference Example 34, the title compound (149 mg) was obtained using 3-amino-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide (203 mg) and 6-aminopyridine-3-carbaldehydride (100 mg), obtained in Reference Example 7, instead of 1-methylpiperazine and 5-bromopyridine-3-carbaldehydride. MS(m / z): 355.6[M+H]+

[1194] [Process 2] Preparation of N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-{[(6-{[(pyridine-3-yl)carbamoyl]amino}pyridine-3-yl)methyl]amino}benzamide

[1195] A mixture of 3-{[(6-aminopyridine-3-yl)methyl]amino}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide (35 mg), 3-isocyanate pyridine (14 mg), potassium carbonate (20 mg), and DMF (0.33 mL), obtained in Process 1, was reacted in a microwave reaction apparatus at 80°C for 30 minutes. After cooling the reaction mixture, it was purified by silica gel column chromatography to obtain the title compound (5.8 mg).

[1196] Example 131 3-{[(5-aminopyrazine-2-yl)methyl]amino}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide

[1197] [Process 1] Preparation of methyl 3-[({5-[(tert-butoxycarbonyl)amino]pyrazine-2-yl}methyl)amino]-4-methylbenzoate

[1198] Potassium carbonate (1.76 g) was added to a 12 mL DMF solution of tert-butyl [5-(bromomethyl)pyrazine-2-yl]carbamate (1.44 g) and methyl 3-amino-4-methylbenzoate (561 mg), and stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate, washed with water and saturated saline solution, and the solvent was removed by vacuum distillation. The resulting residue was purified by silica gel column chromatography to obtain the title compound (360 mg). MS (m / z): 373.5 [M+H] +

[1199] [Process 2] Preparation of 3-[({5-[(tert-butoxycarbonyl)amino]pyrazine-2-yl}methyl)amino]-4-methylbenzoic acid

[1200] By a method according to Process 2 of Reference Example 1, the title compound (125 mg) was obtained using methyl 3-[({5-[(tert-butoxycarbonyl)amino]pyrazine-2-yl}methyl)amino]-4-methylbenzoate (160 mg), obtained in Process 1, instead of methyl 5-[(cyclopropylmethyl)amino]pyridine-3-carboxylate. MS(m / z): 359.3[M+H] +

[1201] [Process 3] Preparation of tert-butyl {5-[(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylanilino)methyl]pyrazine-2-yl}carbamate

[1202] By the method according to Process 4 of Example 1, the title compound (105 mg) was obtained using 3-[({5-[(tert-butoxycarbonyl)amino]pyrazine-2-yl}methyl)amino]-4-methylbenzoic acid (125 mg), obtained in Process 2, instead of 3-{[2-(cyclopropylamino)-1,3-thiazole-5-carbonyl]amino}-4-methylbenzoic acid. MS(m / z): 456.6[M+H] +

[1203] [Process 4] Preparation of 3-{[(5-aminopyrazine-2-yl)methyl]amino}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide

[1204] Trifluoroacetic acid (0.16 mL) was added to a dichloromethane (2 mL) solution of tert-butyl {5-[(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylanilino)methyl]pyrazine-2-yl}carbamate (95 mg) obtained in Process 3, and stirred at room temperature for 2 hours. Methanol (2 mL) and a 2 M aqueous sodium hydroxide solution (2 mL) were added to the residue obtained by concentrating the reaction mixture under reduced pressure, and stirred at room temperature for 1 hour. The reaction mixture was diluted with water and extracted with chloroform. The organic layer was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to obtain the title compound (40 mg).

[1205] Example 138 N-[(1S,2S)-2-hydroxycyclohexyl]-3-{[(6-{[(1r,3r)-3-methoxycyclobutane-1-carbonyl]amino}pyridine-3-yl)methyl]amino}-4-methylbenzamide

[1206] [Process 1] Preparation of 3-{[(6-aminopyridine-3-yl)methyl]amino}-N-[(1S,2S)-2-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl]-4-methylbenzamide

[1207] By the method according to Reference Example 34, the title compound (223 mg) was obtained using 3-amino-N-[(1S,2S)-2-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl]-4-methylbenzamide (468 mg) and 6-aminopyridine-3-carbaldehydride (150 mg), obtained in Reference Example 41, instead of 1-methylpiperazine and 5-bromopyridine-3-carbaldehydride. MS(m / z): 469.4[M+H] +

[1208] [Process 2] Preparation of N-[(1S,2S)-2-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl]-3-{[(6-{[(1r,3r)-3-methoxycyclobutane-1-carbonyl]amino}pyridine-3-yl)methyl]amino}-4-methylbenzamide

[1209] By a method according to Process 1 of Example 1, the title compound (60 mg) was obtained using (1r,3r)-3-methoxycyclobutane-1-carboxylic acid (36 mg) and 3-{[(6-aminopyridine-3-yl)methyl]amino}-N-[(1S,2S)-2-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl]-4-methylbenzamide (30 mg), obtained in Process 1, instead of 2-bromo-1,3-thiazole-5-carboxylic acid and methyl 3-amino-4-methylbenzoate.

[1210] [Process 3] Preparation of N-[(1S,2S)-2-hydroxycyclohexyl]-3-{[(6-{[(1r,3r)-3-methoxycyclobutane-1-carbonyl]amino}pyridine-3-yl)methyl]amino}-4-methylbenzamide

[1211] By the method according to Process 2 of Reference Example 8, the title compound (8 mg) was obtained using N-[(1S,2S)-2-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl]-3-{[(6-{[(1r,3r)-3-methoxycyclobutane-1-carbonyl]amino}pyridine-3-yl)methyl]amino}-4-methylbenzamide (60 mg), obtained in Process 2, instead of methyl 4-chloro-3-[(trimethylsilyl)ethynyl]benzoate.

[1212] Example 140 N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-({[6-(1H-1,2,3-triazole-1-yl)pyridine-3-yl]methyl}amino)benzamide

[1213] By the method according to Reference Example 34, the title compound (74 mg) was obtained using 3-amino-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide (136 mg) obtained in Reference Example 7 and 6-(1H-1,2,3-triazole-1-yl)pyridine-3-carbaldehydride (306 mg) obtained in Reference Example 24, instead of 1-methylpiperazine and 5-bromopyridine-3-carbaldehydride.

[1214] Example 142 3-{[(2-aminopyrimidine-5-yl)methyl]amino}-4-chloro-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide

[1215] [Process 1] Preparation of methyl 4-chloro-3-{[(2-chloropyrimidine-5-yl)methyl]amino}benzoate

[1216] By the method according to Reference Example 34, the title compound (376 mg) was obtained using methyl 3-amino-4-chlorobenzoate (1.00 g) and 2-chloropyrimidine-5-carbaldehydride (806 mg) instead of 1-methylpiperazine and 5-bromopyridine-3-carbaldehydride. MS(m / z): 312.3[M+H] +

[1217] [Process 2] Preparation of 3-{[(2-aminopyrimidine-5-yl)methyl]amino}-4-chlorobenzoic acid

[1218] To the methyl 4-chloro-3-{[(2-chloropyrimidine-5-yl)methyl]amino}benzoate (199 mg) obtained in Process 1, 0.86 mL of 1,4-dioxane and 0.86 mL of a 28% aqueous ammonia solution were added, 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, 3.2 mL of ethanol and 3.2 mL of a 2 M aqueous sodium hydroxide solution were added, and the mixture was stirred overnight at 90°C. The solvent was removed by distillation under reduced pressure, diluted with water, and neutralized by adding hydrochloric acid. The precipitated precipitate was filtered to obtain the title compound (102 mg). MS(m / z): 279.4[M+H] +

[1219] [Process 3] Preparation of 3-{[(2-aminopyrimidine-5-yl)methyl]amino}-4-chloro-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide

[1220] By the method according to Process 4 of Example 1, the title compound (36 mg) was obtained using 3-{[(2-aminopyrimidine-5-yl)methyl]amino}-4-chlorobenzoic acid (50 mg), obtained in Process 2, instead of 3-{[2-(cyclopropylamino)-1,3-thiazole-5-carbonyl]amino}-4-methylbenzoic acid.

[1221] Example 144 3-{[(3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-7-yl)methyl]amino}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide

[1222] [Process 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

[1223] By the method according to Reference Example 34, the title compound (124 mg) was obtained using 3-amino-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide (134 mg) obtained in Reference Example 7 and tert-butyl 7-formyl-2,3-dihydro-4H-pyrido[3,2-b][1,4]oxazine-4-carboxylate obtained in Reference Example 23, instead of 1-methylpiperazine and 5-bromopyridine-3-carbaldehydride. MS(m / z): 497.3[M+H] +

[1224] [Process 2] Preparation of 3-{[(3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-7-yl)methyl]amino}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide

[1225] Trifluoroacetic acid (0.7 mL) was added to a dichloromethane (1.4 mL) 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 Process 1, and stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to obtain the title compound (37 mg).

[1226] Example 147 N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-({[5-(pyrimidine-2-yl)pyridine-3-yl]amino}methyl)benzamide

[1227] [Process 1] Preparation of methyl 3-{[(5-bromopyridine-3-yl)amino]methyl}-4-methylbenzoate

[1228] By the method according to Reference Example 34, the title compound (2.3 g) was obtained using 5-bromopyridine-3-amine (1.5 g) and methyl 3-formyl-4-methylbenzoate (1.5 g) instead of 1-methylpiperazine and 5-bromopyridine-3-carbaldehydride. MS(m / z): 335.4[M+H] +

[1229] [Process 2] Preparation of methyl 4-methyl-3-({[5-(pyrimidine-2-yl)pyridine-3-yl]amino}methyl)benzoate

[1230] By a method according to Process 1 of Reference Example 10, the title compound (35 mg) was obtained using methyl 3-{[(5-bromopyridine-3-yl)amino]methyl}-4-methylbenzoate (170 mg) obtained in Process 1, instead of 3-bromo-5-(methoxymethoxy)pyridine. MS(m / z): 335.5[M+H] +

[1231] [Process 3] Preparation of 4-methyl-3-({[5-(pyrimidine-2-yl)pyridine-3-yl]amino}methyl)benzoic acid

[1232] By a method according to Process 2 of Reference Example 1, the title compound (33 mg) was obtained using methyl 4-methyl-3-({[5-(pyrimidine-2-yl)pyridine-3-yl]amino}methyl)benzoate (35 mg), obtained in Process 2, instead of methyl 5-[(cyclopropylmethyl)amino]pyridine-3-carboxylate. MS(m / z): 321.5[M+H] +

[1233] [Process 4] Preparation of N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-({[5-(pyrimidine-2-yl)pyridine-3-yl]amino}methyl)benzamide

[1234] By the method according to Process 4 of Example 1, the title compound (6 mg) was obtained using 4-methyl-3-({[5-(pyrimidine-2-yl)pyridine-3-yl]amino}methyl)benzoic acid (33 mg), obtained in Process 3, instead of 3-{[2-(cyclopropylamino)-1,3-thiazole-5-carbonyl]amino}-4-methylbenzoic acid.

[1235] Example 148 3-{[([2,3'-bipyridine]-5'-yl)amino]methyl}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide

[1236] [Process 1] Preparation of 3-{[(5-bromopyridine-3-yl)amino]methyl}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide

[1237] The title compound (560 mg) was obtained by the method according to Reference Example 34 using 5-bromopyridine-3-amine (437 mg) and 3-formyl-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide (600 mg), obtained in Reference Example 26, instead of 1-methylpiperazine and 5-bromopyridine-3-carbaldehydride. MS(m / z): 418.6[M+H] +

[1238] [Process 2] Preparation of 3-{[([2,3'-bipyridine]-5'-yl)amino]methyl}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide

[1239] By the method according to Process 1 of Reference Example 10, the title compound (10 mg) was obtained using 3-{[(5-bromopyridin-3-yl)amino]methyl}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide (80 mg) and 2-bromopyridine (36 mg), obtained in Process 1, instead of 3-bromo-5-(methoxymethoxy)pyridine and 2-bromopyrimidine.

[1240] Example 152 3-{[(5-bromopyridine-3-yl)amino]methyl}-N-[(1S,2S)-1,3-dihydroxy-1-phenylpropane-2-yl]-4-methylbenzamide

[1241] [Process 1] Preparation of 3-{[(5-bromopyridine-3-yl)amino]methyl}-4-methylbenzoic acid

[1242] The title compound (950 mg) was obtained by using methyl 3-{[(5-bromopyridine-3-yl)amino]methyl}-4-methylbenzoate (1.0 g), obtained in Process 1 of Example 147, instead of methyl 5-[(cyclopropylmethyl)amino]pyridine-3-carboxylate, by a method according to Process 2 of Reference Example 1. MS(m / z): 321.4[M+H] +

[1243] [Process 2] Preparation of 3-{[(5-bromopyridine-3-yl)amino]methyl}-N-[(1S,2S)-1,3-dihydroxy-1-phenylpropane-2-yl]-4-methylbenzamide

[1244] By the method according to Process 4 of Example 1, the title compound (500 mg) was obtained using 3-{[2-(cyclopropylamino)-1,3-thiazole-5-carbonyl]amino}-4-methylbenzoic acid and (1S,2S)-2-aminocyclohexan-1-ol hydrochloride obtained in Process 1, 3-{[(5-bromopyridine-3-yl)amino]methyl}-4-methylbenzoic acid (350 mg) and (1S,2S)-2-amino-1-phenylpropane-1,3-diol (219 mg), instead of 3-{[2-(cyclopropylamino)-1,3-thiazole-5-carbonyl]amino}-4-methylbenzoic acid and (1S,2S)-2-amino-1-phenylpropane-1,3-diol (219 mg), obtained in Process 1.

[1245] Example 153 N-[(1S,2S)-1,3-dihydroxy-1-phenylpropane-2-yl]-4-methyl-3-{[(5-phenylpyridine-3-yl)amino]methyl}benzamide

[1246] By the method according to Reference Example 14, the title compound (29 mg) was obtained using 3-{[(5-bromopyridine-3-yl)amino]methyl}-N-[(1S,2S)-1,3-dihydroxy-1-phenylpropane-2-yl]-4-methylbenzamide (50 mg) and phenylboronic acid (16 mg), obtained in Example 152, instead of 2-chloropyrimidine-4-amine and isoquinoline-4-ylboronic acid.

[1247] Example 155 3-{[([2,3'-bipyridine]-5'-yl)amino]methyl}-N-[(1S,2S)-1,3-dihydroxy-1-phenylpropane-2-yl]-4-methylbenzamide

[1248] By the method according to Example 62, the title compound (20 mg) was obtained using 3-[(5-bromopyridine-3-yl)ethynyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide, 2-(tributyltannyl)pyrimidine obtained in Example 152, instead of 3-[(5-bromopyridine-3-yl)amino]methyl}-N-[(1S,2S)-1,3-dihydroxy-1-phenylpropane-2-yl]-4-methylbenzamide (50 mg) and 2-(tributyltannyl)pyridine (51 mg).

[1249] Example 156 N-[(1S,2S)-1,3-dihydroxy-1-phenylpropane-2-yl]-4-methyl-3-{[(6-phenylpyrazine-2-yl)amino]methyl}benzamide

[1250] [Process 1] Preparation of methyl 3-{[(6-chloropyrazine-2-yl)amino]methyl}-4-methylbenzoate

[1251] A mixture of 2,6-dichloropyrazine (300 mg), methyl 3-(aminomethyl)-4-methylbenzoate (397 mg) obtained in Reference Example 42, NMP (4 mL), and DIPEA (1.05 mL) was stirred at 100°C for 4 hours. The reaction mixture was diluted with ethyl acetate, and the organic layer was washed with water and saturated saline solution. The solvent was removed by vacuum distillation, and the resulting residue was purified by silica gel column chromatography to obtain the title compound (423 mg). MS (m / z): 292.5 [M+H] +

[1252] [Process 2] Preparation of 3-{[(6-chloropyrazine-2-yl)amino]methyl}-4-methylbenzoic acid

[1253] By a method according to Process 2 of Reference Example 1, the title compound (520 mg) was obtained using methyl 3-{[(6-chloropyrazine-2-yl)amino]methyl}-4-methylbenzoate (580 mg), obtained in Process 1, instead of methyl 5-[(cyclopropylmethyl)amino]pyridine-3-carboxylate. MS(m / z): 278.4[M+H] +

[1254] [Process 3] Preparation of 3-{[(6-chloropyrazine-2-yl)amino]methyl}-N-[(1S,2S)-1,3-dihydroxy-1-phenylpropane-2-yl]-4-methylbenzamide

[1255] By a method according to Process 4 of Example 1, the title compound (420 mg) was obtained using 3-{[(6-chloropyrazine-2-yl)amino]methyl}-4-methylbenzoic acid (300 mg) and (1S,2S)-2-amino-1-phenylpropane-1,3-diol (217 mg) obtained in Process 2, instead of 3-{[2-(cyclopropylamino)-1,3-thiazole-5-carbonyl]amino}-4-methylbenzoic acid and (1S,2S)-2-amino-1-phenylpropane-1,3-diol, obtained in Process 2. MS(m / z): 427.6[M+H] +

[1256] [Process 4] Preparation of N-[(1S,2S)-1,3-dihydroxy-1-phenylpropane-2-yl]-4-methyl-3-{[(6-phenylpyrazine-2-yl)amino]methyl}benzamide

[1257] By the method according to Reference Example 14, the title compound (36 mg) was obtained using 3-{[(6-chloropyrazine-2-yl)amino]methyl}-N-[(1S,2S)-1,3-dihydroxy-1-phenylpropane-2-yl]-4-methylbenzamide (50 mg) and phenylboronic acid (17 mg), obtained in Process 3, instead of 2-chloropyrimidine-4-amine and isoquinoline-4-ylboronic acid.

[1258] Example 158 N-[3-({[6-(3,4-dimethoxyphenyl)pyrazine-2-yl]amino}methyl)phenyl]-N'-[(1R,2S)-2-hydroxycyclohexyl]urea

[1259] [Process 1] Preparation of N-[(3-aminophenyl)methyl]-6-chloropyrazine-2-amine

[1260] By the method according to Process 3 of Example 156, 3-(aminomethyl)aniline (1.23g) was used instead of methyl 3-(aminomethyl)-4-methylbenzoate to obtain the title compound (1.22g).

[1261] [Process 2] Preparation of N-[(3-aminophenyl)methyl]-6-(3,4-dimethoxyphenyl)pyrazine-2-amine

[1262] By the method according to Reference Example 14, the title compound (190 mg) was obtained using N-[(3-aminophenyl)methyl]-6-chloropyrazine-2-amine (160 mg) and (3,4-dimethoxyphenyl)boronic acid (149 mg), obtained in Process 1, instead of 2-chloropyrimidine-4-amine and isoquinoline-4-ylboronic acid.

[1263] [Process 3] Preparation of N-[3-({[6-(3,4-dimethoxyphenyl)pyrazine-2-yl]amino}methyl)phenyl]-N'-[(1R,2S)-2-hydroxycyclohexyl]urea

[1264] To N-[(3-aminophenyl)methyl]-6-(3,4-dimethoxyphenyl)pyrazine-2-amine (40 mg) obtained in Process 2, THF (1 mL), TEA (0.20 mL), and triphosgene (18 mg) were added and stirred at room temperature for 10 minutes. Subsequently, (1S,2R)-2-aminocyclohexane-1-ol hydrochloride (180 mg) was added and stirred at the same temperature for 2 hours. The reaction mixture was purified by silica gel column chromatography to obtain the title compound (37 mg).

[1265] Example 159 N-[(1R,2S)-2-hydroxycyclohexyl]-N'-[3-({[5-(pyrimidine-2-yl)pyridine-3-yl]amino}methyl)phenyl]urea

[1266] [Process 1] Preparation of N-[(3-nitrophenyl)methyl]-5-(pyrimidine-2-yl)pyridine-3-amine

[1267] By the method according to Reference Example 34, the title compound (40 mg) was obtained using 5-(pyrimidine-2-yl)pyridine-3-amine (100 mg) and 3-nitrobenzaldehyde (88 mg), obtained in Reference Example 27, instead of 1-methylpiperazine and 5-bromopyridine-3-carbaldehydride.

[1268] [Process 2] Preparation of N-[(3-aminophenyl)methyl]-5-(pyrimidine-2-yl)pyridine-3-amine

[1269] To a methanol (5 mL) and THF (5 mL) solution of N-[(3-nitrophenyl)methyl]-5-(pyrimidine-2-yl)pyridine-3-amine (40 mg) obtained in Process 1, 10% Pd-C (50 mg) was added while stirring at room temperature under an argon atmosphere after degassing, and the mixture was stirred for 4 hours at room temperature under a hydrogen atmosphere. The reaction mixture was filtered through Celite (registered trademark), and the solvent was removed by vacuum distillation. The residue was purified by silica gel column chromatography to obtain the title compound (20 mg).

[1270] [Process 3] Preparation of N-[(1R,2S)-2-hydroxycyclohexyl]-N'-[3-({[5-(pyrimidine-2-yl)pyridine-3-yl]amino}methyl)phenyl]urea

[1271] By the method according to Process 3 of Example 158, the title compound (13 mg) was obtained using N-[(3-aminophenyl)methyl]-5-(pyrimidine-2-yl)pyridine-3-amine (20 mg) obtained in Process 2 instead of N-[(3-aminophenyl)methyl]-6-(3,4-dimethoxyphenyl)pyrazine-2-amine.

[1272] Example 161 N-[4-fluoro-3-({[5-(pyrimidine-2-yl)pyridine-3-yl]amino}methyl)phenyl]-N'-[(1R,2S)-2-hydroxycyclohexyl]urea

[1273] [Process 1] Preparation of N-[(2-fluoro-5-nitrophenyl)methyl]-5-(pyrimidine-2-yl)pyridine-3-amine

[1274] By the method according to Reference Example 34, the title compound (150 mg) was obtained using 5-(pyrimidine-2-yl)pyridine-3-amine (133 mg) and 2-fluoro-5-nitrobenzaldehyde (196 mg), obtained in Reference Example 27, instead of 1-methylpiperazine and 5-bromopyridine-3-carbaldehydride.

[1275] [Process 2] Preparation of tert-butyl [(2-fluoro-5-nitrophenyl)methyl][5-(pyrimidine-2-yl)pyridine-3-yl]carbamate

[1276] By the method according to Process 1 of Reference Example 23, the title compound (105 mg) was obtained using N-[(2-fluoro-5-nitrophenyl)methyl]-5-(pyrimidine-2-yl)pyridine-3-amine (150 mg), obtained in Process 1, instead of 7-bromo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine.

[1277] [Process 3] Preparation of tert-butyl [(5-amino-2-fluorophenyl)methyl][5-(pyrimidine-2-yl)pyridine-3-yl]carbamate

[1278] Tin(II) chloride dihydrate (221 mg) was added to an ethanol (2 mL)-water (0.2 mL) solution of tert-butyl [(2-fluoro-5-nitrophenyl)methyl][5-(pyrimidine-2-yl)pyridine-3-yl]carbamate (104 mg) obtained in Process 2, and stirred at 65°C for 2 hours. An aqueous sodium hydroxide solution was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with saturated saline solution, and the solvent was removed by vacuum distillation. The residue was purified by silica gel column chromatography to obtain the title compound (72 mg).

[1279] [Process 4] Preparation of tert-butyl {[2-fluoro-5-({[(1R,2S)-2-hydroxycyclohexyl]carbamoyl}amino)phenyl]methyl}[5-(pyrimidine-2-yl)pyridine-3-yl]carbamate

[1280] By the method according to Process 3 of Example 158, the title compound (82 mg) was obtained using tert-butyl [(5-amino-2-fluorophenyl)methyl][5-(pyrimidine-2-yl)pyridine-3-yl]carbamate (70 mg), obtained in Process 3, instead of N-[(3-aminophenyl)methyl]-6-(3,4-dimethoxyphenyl)pyrazine-2-amine.

[1281] [Process 5] Preparation of N-[4-fluoro-3-({[5-(pyrimidine-2-yl)pyridine-3-yl]amino}methyl)phenyl]-N'-[(1R,2S)-2-hydroxycyclohexyl]urea

[1282] Hydrogen chloride (4M 1,4-dioxane solution, 1 mL) was added to a methanol (0.3 mL) solution of tert-butyl {[2-fluoro-5-({[(1R,2S)-2-hydroxycyclohexyl]carbamoyl}amino)phenyl]methyl}[5-(pyrimidine-2-yl)pyridine-3-yl]carbamate (80 mg) obtained in Process 4, 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).

[1283] Example 164 N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-{1-[(6-phenylpyrazine-2-yl)amino]ethyl}benzamide

[1284] [Process 1] Preparation of Methyl 3-{1-[(6-chloropyrazine-2-yl)amino]ethyl}-4-methylbenzoate

[1285] By the method according to process 3 of Example 156, the title compound (75 mg) was obtained using methyl 3-(1-aminoethyl)-4-methylbenzoate (218 mg) instead of methyl 3-(aminomethyl)-4-methylbenzoate.

[1286] [Process 2] Preparation of methyl 4-methyl-3-{1-[(6-phenylpyrazine-2-yl)amino]ethyl}benzoate

[1287] By the method according to Reference Example 14, the title compound (80 mg) was obtained using methyl 3-{1-[(6-chloropyrazine-2-yl)amino]ethyl}-4-methylbenzoate (75 mg) and phenylboronic acid (36 mg), obtained in Process 1, instead of 2-chloropyrimidine-4-amine and isoquinoline-4-ylboronic acid.

[1288] [Process 3] Preparation of 4-methyl-3-{1-[(6-phenylpyrazine-2-yl)amino]ethyl}benzoic acid

[1289] By the method according to Process 2 of Reference Example 1, the title compound (67 mg) was obtained using methyl 4-methyl-3-{1-[(6-phenylpyrazine-2-yl)amino]ethyl}benzoate (77 mg), obtained in Process 2, instead of methyl 5-[(cyclopropylmethyl)amino]pyridine-3-carboxylate.

[1290] [Process 4] Preparation of N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-{1-[(6-phenylpyrazine-2-yl)amino]ethyl}benzamide

[1291] By the method according to Process 4 of Example 1, the title compound (17 mg) was obtained using 4-methyl-3-{1-[(6-phenylpyrazine-2-yl)amino]ethyl}benzoic acid (30 mg) obtained in Process 3 instead of 3-{[2-(cyclopropylamino)-1,3-thiazole-5-carbonyl]amino}-4-methylbenzoic acid.

[1292] Example 165 3-[([3,3'-bipyridine]-5-yl)methoxy]-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide

[1293] [Process 1] Preparation of Methyl 3-[(5-bromopyridine-3-yl)methoxy]-4-methylbenzoate

[1294] The title compound (1.16 g) was obtained by a method according to Process 1 of Reference Example 3, using methyl 3-hydroxy-4-methylbenzoate (750 mg) and (5-bromopyridine-3-yl)methanol (933 mg) instead of methyl 5-hydroxypyridine-3-carboxylate and 3,3-difluorocyclobutan-1-ol. MS(m / z): 336.4[M+H] +

[1295] [Process 2] Preparation of Methyl 3-[([3,3'-Bipyridine]-5-yl)methoxy]-4-methylbenzoate

[1296] By the method according to Reference Example 14, the title compound (103 mg) was obtained using methyl 3-[(5-bromopyridine-3-yl)methoxy]-4-methylbenzoate (150 mg) and pyridine-3-ylboronic acid (66 mg), obtained in Process 1, instead of 2-chloropyrimidine-4-amine and isoquinoline-4-ylboronic acid. MS(m / z): 335.5[M+H] +

[1297] [Process 3] Preparation of 3-[([3,3'-bipyridine]-5-yl)methoxy]-4-methylbenzoic acid

[1298] By a method according to Process 2 of Reference Example 1, the title compound (100 mg) was obtained using methyl 3-[([3,3'-bipyridine]-5-yl)methoxy]-4-methylbenzoate (103 mg), obtained in Process 2, instead of methyl 5-[(cyclopropylmethyl)amino]pyridine-3-carboxylate. MS(m / z): 321.6[M+H] +

[1299] [Process 4] Preparation of 3-[([3,3'-bipyridine]-5-yl)methoxy]-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide

[1300] By the method according to process 4 of Example 1, the title compound (47 mg) was obtained using 3-[([3,3'-bipyridine]-5-yl)methoxy]-4-methylbenzoic acid (50 mg) obtained in process 3 instead of 3-{[2-(cyclopropylamino)-1,3-thiazole-5-carbonyl]amino}-4-methylbenzoic acid.

[1301] Example 166 N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-{[5-(pyrimidine-2-yl)pyridine-3-yl]methoxy}benzamide

[1302] [Process 1] Preparation of methyl 4-methyl-3-{[5-(pyrimidine-2-yl)pyridine-3-yl]methoxy}benzoate

[1303] The title compound (127 mg) was obtained by using methyl 3-[(5-bromopyridine-3-yl)methoxy]-4-methylbenzoate (250 mg), obtained in Process 1 of Example 165, instead of 3-bromo-5-(methoxymethoxy)pyridine, by a method according to Process 1 of Reference Example 10. MS(m / z): 336.4[M+H] +

[1304] [Process 2] Preparation of 4-methyl-3-{[5-(pyrimidine-2-yl)pyridine-3-yl]methoxy}benzoic acid

[1305] By the method according to Process 2 of Reference Example 1, the title compound (101 mg) was obtained using methyl 4-methyl-3-{[5-(pyrimidine-2-yl)pyridine-3-yl]methoxy}benzoate (127 mg) obtained in Process 1 instead of methyl 5-[(cyclopropylmethyl)amino]pyridine-3-carboxylate.

[1306] [Process 3] Preparation of N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-{[5-(pyrimidine-2-yl)pyridine-3-yl]methoxy}benzamide

[1307] By the method according to Process 4 of Example 1, the title compound (76 mg) was obtained using 4-methyl-3-{[5-(pyrimidine-2-yl)pyridine-3-yl]methoxy}benzoic acid (60 mg) obtained in Process 2 instead of 3-{[2-(cyclopropylamino)-1,3-thiazole-5-carbonyl]amino}-4-methylbenzoic acid.

[1308] Example 170 4-chloro-N-[(1S,2S)-2-hydroxycyclohexyl]-3-({[5-(pyrimidine-2-yl)pyridine-3-yl]oxy}methyl)benzamide

[1309] [Process 1] Preparation of methyl 4-chloro-3-({[5-(pyrimidine-2-yl)pyridine-3-yl]oxy}methyl)benzoate

[1310] By a method according to Process 1 of Reference Example 3, the title compound (50 mg) was obtained using 5-(pyrimidine-2-yl)pyridine-3-ol (123 mg) obtained in Process 2 of Reference Example 10 and methyl 4-chloro-3-(hydroxymethyl)benzoate (130 mg) obtained in Reference Example 31, instead of methyl 5-hydroxypyridine-3-carboxylate and 3,3-difluorocyclobutan-1-ol. MS(m / z): 356.4[M+H] +

[1311] [Process 2] Preparation of 4-chloro-3-({[5-(pyrimidine-2-yl)pyridine-3-yl]oxy}methyl)benzoic acid

[1312] By a method according to Process 2 of Reference Example 1, the title compound (43 mg) was obtained using methyl 4-chloro-3-({[5-(pyrimidine-2-yl)pyridine-3-yl]oxy}methyl)benzoate (50 mg) obtained in Process 1 instead of methyl 5-[(cyclopropylmethyl)amino]pyridine-3-carboxylate. MS(m / z): 342.4[M+H] +

[1313] [Process 3] Preparation of 4-chloro-N-[(1S,2S)-2-hydroxycyclohexyl]-3-({[5-(pyrimidine-2-yl)pyridine-3-yl]oxy}methyl)benzamide

[1314] By the method according to Process 4 of Example 1, the title compound (39 mg) was obtained using 4-chloro-3-({[5-(pyrimidine-2-yl)pyridine-3-yl]oxy}methyl)benzoic acid (43 mg), obtained in Process 2, instead of 3-{[2-(cyclopropylamino)-1,3-thiazole-5-carbonyl]amino}-4-methylbenzoic acid.

[1315] Example 172 N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-[1-(5-phenylpyridine-3-yl)ethoxy]benzamide

[1316] [Process 1] Preparation of Methyl 3-[1-(5-bromopyridine-3-yl)ethoxy]-4-methylbenzoate

[1317] By the method according to Process 1 of Reference Example 3, the title compound (650 mg) was obtained using methyl 3-hydroxy-4-methylbenzoate (432 mg) and 1-(5-bromopyridine-3-yl)ethanol-1-ol (500 mg) instead of methyl 5-hydroxypyridine-3-carboxylate and 3,3-difluorocyclobutan-1-ol. MS(m / z): 350.3[M+H] +

[1318] [Process 2] Preparation of 3-[1-(5-bromopyridine-3-yl)ethoxy]-4-methylbenzoic acid

[1319] The title compound (350 mg) was obtained by using methyl 3-[1-(5-bromopyridine-3-yl)ethoxy]-4-methylbenzoate (450 mg), obtained in Process 1, instead of methyl 5-[(cyclopropylmethyl)amino]pyridine-3-carboxylate, by a method according to Process 2 of Reference Example 1. MS(m / z): 336.3[M+H] +

[1320] [Process 3] Preparation of 3-[1-(5-bromopyridine-3-yl)ethoxy]-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide

[1321] The title compound (350 mg) was obtained by using 3-[1-(5-bromopyridine-3-yl)ethoxy]-4-methylbenzoic acid (350 mg) obtained in Process 2 instead of 3-{[2-(cyclopropylamino)-1,3-thiazole-5-carbonyl]amino}-4-methylbenzoic acid by a method according to Process 4 of Example 1. MS(m / z): 433.5[M+H] +

[1322] [Process 4] Preparation of N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-[1-(5-phenylpyridine-3-yl)ethoxy]benzamide

[1323] By the method according to Reference Example 14, the title compound (30 mg) was obtained using 3-[1-(5-bromopyridine-3-yl)ethoxy]-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide (50 mg) and phenylboronic acid (17 mg), obtained in Process 3, instead of 2-chloropyrimidine-4-amine and isoquinoline-4-ylboronic acid.

[1324] Example 173 N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-[(E)-2-(5-phenylpyridine-3-yl)ethenyl]benzamide

[1325] [Process 1] Preparation of 3-Ethenyl-N-[(1R,2R)-2-hydroxycyclohexyl]-4-methylbenzamide

[1326] By the method according to Reference Example 14, the title compound (13.0 g) was obtained using 3-bromo-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide (20.0 g) and 2-ethenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolan (11.8 g), obtained in Reference Example 43, instead of 2-chloropyrimidine-4-amine and isoquinoline-4-ylboronic acid. MS(m / z): 260.2[M+H] +

[1327] [Process 2] Preparation of N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-[(E)-2-(5-phenylpyridine-3-yl)ethenyl]benzamide

[1328] A mixture of 3-ethenyl-N-[(1R,2R)-2-hydroxycyclohexyl]-4-methylbenzamide (30 mg), 3-bromo-5-phenylpyridine (27 mg), TEA (0.024 mL), tris(2-methylphenyl)phosphine (11 mg), Pd(OAc)2 (3.9 mg), and acetonitrile (0.58 mL), obtained in Process 1, was reacted in a microwave reaction apparatus at 100°C for 80 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 (24 mg).

[1329] Example 174 N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-[2-(5-phenylpyridine-3-yl)ethyl]benzamide

[1330] To an ethanol (5 mL) solution of N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-[(E)-2-(5-phenylpyridine-3-yl)ethenyl]benzamide (15 mg) obtained in Example 173, 10% Pd-C (7.7 mg) was added while stirring at room temperature under an argon atmosphere after degassing, and stirred overnight at room temperature under a hydrogen atmosphere. The reaction mixture was filtered through Celite (registered trademark), and the solvent was removed by vacuum distillation. The residue was purified by silica gel column chromatography to obtain the title compound (7 mg).

[1331] Example 175 N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-{[methyl(5-phenylpyridine-3-yl)amino]methyl}benzamide

[1332] [Process 1] Preparation of methyl 3-{[(5-bromopyridine-3-yl)(methyl)amino]methyl}-4-methylbenzoate

[1333] To the THF (10 mL) solution of methyl 3-{[(5-bromopyridine-3-yl)amino]methyl}-4-methylbenzoate (850 mg) obtained in Process 1 of Example 147, 60% sodium hydride (79 mg) was added under ice cooling and stirred at room temperature for 20 minutes. Subsequently, iodomethane (720 mg) was added and stirred overnight at the same temperature. Under ice cooling, water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with saturated saline solution, dried with anhydrous sodium sulfate, and the solvent was removed by vacuum distillation. The residue was purified by silica gel column chromatography to obtain the title compound (200 mg). MS(m / z): 349.4[M+H] +

[1334] [Process 2] Preparation of 3-{[(5-bromopyridine-3-yl)(methyl)amino]methyl}-4-methylbenzoic acid

[1335] By a method according to Process 2 of Reference Example 1, the title compound (170 mg) was obtained using methyl 3-{[(5-bromopyridine-3-yl)(methyl)amino]methyl}-4-methylbenzoate (200 mg), obtained in Process 1, instead of methyl 5-[(cyclopropylmethyl)amino]pyridine-3-carboxylate. MS(m / z): 335.4[M+H] +

[1336] [Process 3] Preparation of 3-{[(5-bromopyridine-3-yl)(methyl)amino]methyl}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide

[1337] By the method according to Process 4 of Example 1, the title compound (147 mg) was obtained using 3-{[(5-bromopyridine-3-yl)(methyl)amino]methyl}-4-methylbenzoic acid (170 mg) obtained in Process 2 instead of 3-{[2-(cyclopropylamino)-1,3-thiazole-5-carbonyl]amino}-4-methylbenzoic acid. MS(m / z): 432.6[M+H]+

[1338] [Process 4] Preparation of N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-{[methyl(5-phenylpyridine-3-yl)amino]methyl}benzamide

[1339] By the method according to Reference Example 14, the title compound (24 mg) was obtained using 3-{[(5-bromopyridine-3-yl)(methyl)amino]methyl}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide (30 mg) and phenylboronic acid (9.3 mg), obtained in Process 3, instead of 2-chloropyrimidine-4-amine and isoquinoline-4-ylboronic acid.

[1340] Example 177 3-[(Z)-2-([2,3'-bipyridine]-5'-yl)-2-fluoroethenyl]-4-fluoro-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide

[1341] [Process 1] Preparation of 3-(2,2-difluoroethenyl)-4-fluoro-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide

[1342] To the DMF (3.8 mL) solution of 4-fluoro-3-formyl-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide (500 mg) and triphenylphosphine (593 mg) obtained in Reference Example 29, a DMF (0.94 mL) solution of sodium chlorodifluoroacetate (431 mg) was added dropwise over 30 minutes at 100°C, and stirred for 30 minutes at the same temperature. After cooling to ice, water was added to the reaction mixture, and it was extracted with ethyl acetate. The organic layer was washed with saturated saline solution, dried with anhydrous sodium sulfate, and the solvent was removed by vacuum distillation. The residue was purified by silica gel column chromatography to obtain the title compound (200 mg). MS (m / z): 300.1 [M+H] +

[1343] [Process 2] Preparation of 4-fluoro-3-[(Z)-2-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)ethenyl]-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide

[1344] THF (2.2 mL) was added to 3-(2,2-difluoroethenyl)-4-fluoro-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide (100 mg), bis(pinacolato)diborone (170 mg), potassium acetate (39 mg), tricyclohexylphosphine (19 mg), and copper(I) chloride (3.3 mg) obtained in Process 1, and after degassing, stirred overnight at 40°C under an argon atmosphere. Saturated aqueous ammonium chloride solution was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with saturated saline solution, dried with anhydrous sodium sulfate, and the solvent was removed by vacuum distillation to obtain the title compound (130 mg).

[1345] [Process 3] Preparation of 3-[(Z)-2-([2,3'-bipyridine]-5'-yl)-2-fluoroethenyl]-4-fluoro-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide

[1346] By the method according to Reference Example 14, the title compound (10 mg) was obtained using 5'-bromo-2,3'-bipyridine (45 mg) and 4-fluoro-3-[(Z)-2-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)ethenyl]-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide (65 mg), obtained in Process 2, instead of 2-chloropyrimidine-4-amine and isoquinoline-4-ylboronic acid.

[1347] Example 180 5-[(Z)-2-([2,3'-bipyridine]-5'-yl)-2-fluoroethenyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-6-methylpyridine-3-carboxamide

[1348] [Process 1] Preparation of Ethyl 5-(2,2-Difluoroethenyl)-6-Methylpyridine-3-Carboxylate

[1349] The title compound (2.80 g) was obtained by a method according to Process 1 of Example 177, using ethyl 5-formyl-6-methylpyridine-3-carboxylate (2.65 g) obtained in Reference Example 33 instead of 4-fluoro-3-formyl-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide. MS(m / z): 228.1[M+H] +

[1350] [Process 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

[1351] By the method according to Process 2 of Example 177, the title compound (280 mg) was obtained using ethyl 5-(2,2-difluoroethenyl)-6-methylpyridine-3-carboxylate (200 mg) obtained in Process 1 instead of 3-(2,2-difluoroethenyl)-4-fluoro-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide.

[1352] [Process 3] Preparation of ethyl 5-[(Z)-2-([2,3'-bipyridine]-5'-yl)-2-fluoroethenyl]-6-methylpyridine-3-carboxylate

[1353] By the method according to Reference Example 14, the title compound (230 mg) was obtained using 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 Process 2, instead of 2-chloropyrimidine-4-amine and isoquinoline-4-ylboronic acid. MS(m / z): 364.2[M+H] +

[1354] [Process 4] Preparation of 5-[(Z)-2-([2,3'-bipyridine]-5'-yl)-2-fluoroethenyl]-6-methylpyridine-3-carboxylic acid

[1355] By the method according to Process 2 of Reference Example 1, the title compound (165 mg) was obtained using ethyl 5-[(Z)-2-([2,3'-bipyridine]-5'-yl)-2-fluoroethenyl]-6-methylpyridine-3-carboxylate (230 mg), obtained in Process 3, instead of methyl 5-[(cyclopropylmethyl)amino]pyridine-3-carboxylate, by the method according to Process 2 of Reference Example 1. MS(m / z): 336.1[M+H] +

[1356] [Process 5] Preparation of 5-[(Z)-2-([2,3'-bipyridine]-5'-yl)-2-fluoroethenyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-6-methylpyridine-3-carboxamide

[1357] By the method according to process 4 of Example 1, the title compound (77 mg) was obtained using 5-[(Z)-2-([2,3'-bipyridine]-5'-yl)-2-fluoroethenyl]-6-methylpyridine-3-carboxylic acid (120 mg), obtained in process 4, instead of 3-{[2-(cyclopropylamino)-1,3-thiazole-5-carbonyl]amino}-4-methylbenzoic acid.

[1358] Example 192 3-[(Z)-2-(2-aminopyrimidine-5-yl)-2-fluoroethenyl]-4-fluoro-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide

[1359] [Process 1] Preparation of Methyl 3-(2,2-Difluoroethenyl)-4-Fluorobenzoate

[1360] The title compound (1.30 g) was obtained by using methyl 4-fluoro-3-formylbenzoate (1.27 g) instead of 4-fluoro-3-formylbenzamide by the method according to Process 1 of Example 177.

[1361] [Process 2] Preparation of Methyl 3-[(Z)-2-(2-aminopyrimidine-5-yl)-2-fluoroethenyl]-4-fluorobenzoate

[1362] THF (4 mL) was added to the methyl 3-(2,2-difluoroethenyl)-4-fluorobenzoate (130 mg), bis(pinacolato)diborone (305 mg), potassium acetate (118 mg), tricyclohexylphosphine (34 mg), and copper(I) chloride (22 mg) obtained in Process 1, and after degassing, the mixture was stirred at 40°C for 8 hours under an argon atmosphere. A saturated aqueous ammonium chloride solution was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with saturated saline solution, dried with anhydrous sodium sulfate, and the solvent was removed by vacuum distillation. To the residue obtained, 5-bromopyrimidine-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 overnight at 85°C under an argon atmosphere. The residue obtained by vacuum concentration of the reaction solution was purified by silica gel column chromatography to obtain the title compound (200 mg). MS (m / z): 292.1 [M+H] +

[1363] [Process 3] Preparation of 3-[(Z)-2-(2-aminopyrimidine-5-yl)-2-fluoroethenyl]-4-fluorobenzoic acid

[1364] By a method according to Process 2 of Reference Example 1, the title compound (36 mg) was obtained using methyl 3-[(Z)-2-(2-aminopyrimidine-5-yl)-2-fluoroethenyl]-4-fluorobenzoate (200 mg), obtained in Process 2, instead of methyl 5-[(cyclopropylmethyl)amino]pyridine-3-carboxylate. MS(m / z): 278.1[M+H] +

[1365] [Process 4] Preparation of 3-[(Z)-2-(2-aminopyrimidine-5-yl)-2-fluoroethenyl]-4-fluoro-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide

[1366] By the method according to Process 4 of Example 1, the title compound (4 mg) was obtained using 3-[(Z)-2-(2-aminopyrimidine-5-yl)-2-fluoroethenyl]-4-fluorobenzoic acid (36 mg), obtained in Process 3, instead of 3-{[2-(cyclopropylamino)-1,3-thiazole-5-carbonyl]amino}-4-methylbenzoic acid.

[1367] Example 194 3-[(Z)-2-{5-[(4-ethylpiperazine-1-yl)methyl]pyridine-3-yl}-2-fluoroethenyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide

[1368] [Process 1] Preparation of Methyl 3-(2,2-Difluoroethenyl)-4-Methylbenzoate

[1369] The title compound (15.0 g) was obtained by using methyl 3-formyl-4-methylbenzoate (13.4 g) instead of 4-fluoro-3-formyl-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide by a method according to Process 1 of Example 177. MS(m / z): 213.1[M+H] +

[1370] [Process 2] Preparation of Methyl 3-[(Z)-2-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)ethenyl]-4-methylbenzoate

[1371] By the method according to Process 2 of Example 177, the title compound (8.6 g) was obtained using methyl 3-(2,2-difluoroethenyl)-4-fluoro-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide obtained in Process 1, instead of 3-(2,2-difluoroethenyl)-4-methylbenzoate (6.0 g).

[1372] [Process 3] Preparation of methyl 3-[(Z)-2-fluoro-2-{5-[(4-ethylpiperazine-1-yl)methyl]pyridine-3-yl}ethenyl]-4-methylbenzoate

[1373] By the method according to Reference Example 14, the title compound (7.5 g) was obtained using 1-[(5-bromopyridine-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 Process 2, instead of 2-chloropyrimidine-4-amine and isoquinoline-4-ylboronic acid. MS(m / z): 398.3[M+H] +

[1374] [Process 4] Preparation of 3-[(Z)-2-fluoro-2-{5-[(4-ethylpiperazine-1-yl)methyl]pyridine-3-yl}ethenyl]-4-methylbenzoic acid

[1375] By a method according to Process 2 of Reference Example 1, the title compound (4.7 g) was obtained using methyl 3-[(Z)-2-fluoro-2-{5-[(4-ethylpiperazine-1-yl)methyl]pyridine-3-yl}ethenyl]-4-methylbenzoate (7.5 g), obtained in Process 3, instead of methyl 5-[(cyclopropylmethyl)amino]pyridine-3-carboxylate. MS(m / z): 384.5[M+H] +

[1376] [Process 5] Preparation of 3-[(Z)-2-{5-[(4-ethylpiperazine-1-yl)methyl]pyridine-3-yl}-2-fluoroethenyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide

[1377] By the method according to Process 4 of Example 1, the title compound (3.4g) was obtained using 3-{[2-(cyclopropylamino)-1,3-thiazole-5-carbonyl]amino}-4-methylbenzoic acid (4.7g) obtained in Process 4, instead of 3-{[2-(cyclopropylamino)-1,3-thiazole-5-carbonyl]amino}-4-methylbenzoic acid.

[1378] Example 199 5-[(Z)-2-{6-[(cyclopropylmethyl)amino]pyridine-3-yl}-2-fluoroethenyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-6-methylpyridine-3-carboxamide

[1379] [Process 1] Preparation of ethyl 5-[(Z)-2-(6-aminopyridine-3-yl)-2-fluoroethenyl]-6-methylpyridine-3-carboxylate

[1380] By the method according to Reference Example 14, the title compound (40 mg) was obtained using 5-bromopyridine-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 Process 2 of Example 180, instead of 2-chloropyrimidine-4-amine and isoquinoline-4-ylboronic acid. MS(m / z): 302.1[M+H] +

[1381] [Process 2] Preparation of ethyl 5-[(Z)-2-{6-[(cyclopropylmethyl)amino]pyridine-3-yl}-2-fluoroethenyl]-6-methylpyridine-3-carboxylate

[1382] By the method according to Reference Example 34, the title compound (12 mg) was obtained using ethyl 5-[(Z)-2-(6-aminopyridin-3-yl)-2-fluoroethenyl]-6-methylpyridin-3-carboxylate (60 mg) and cyclopropane carvaldehydride (19 mg), obtained in Process 1, instead of 1-methylpiperazine and 5-bromopyridine-3-carbaldehyde. MS(m / z): 356.5[M+H] +

[1383] [Process 3] Preparation of 5-[(Z)-2-{6-[(cyclopropylmethyl)amino]pyridine-3-yl}-2-fluoroethenyl]-6-methylpyridine-3-carboxylic acid

[1384] By the method according to Process 2 of Reference Example 1, the title compound (11 mg) was obtained using ethyl 5-[(Z)-2-{6-[(cyclopropylmethyl)amino]pyridine-3-yl}-2-fluoroethenyl]-6-methylpyridine-3-carboxylate (12 mg), obtained in Process 2, instead of methyl 5-[(cyclopropylmethyl)amino]pyridine-3-yl]pyridine-3-carboxylate, obtained in Process 2.

[1385] [Process 4] Preparation of 5-[(Z)-2-{6-[(cyclopropylmethyl)amino]pyridine-3-yl}-2-fluoroethenyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-6-methylpyridine-3-carboxamide

[1386] By the method according to Process 4 of Example 1, the title compound (10 mg) was obtained using 5-[(Z)-2-{6-[(cyclopropylmethyl)amino]pyridine-3-yl}-2-fluoroethenyl]-6-methylpyridine-3-carboxylic acid (11 mg) obtained in Process 3 instead of 3-{[2-(cyclopropylamino)-1,3-thiazole-5-carbonyl]amino}-4-methylbenzoic acid.

[1387] Tables 3 to 29 listed below show reference example and example compounds.

[1388] In the table, the reference example indicates that the compound in question is manufactured using the corresponding raw material by a method based on the manufacturing method of the compound of the reference example number corresponding to that number, and for example, the reference example compound with reference example number 1 means that it is manufactured by a method based on reference example 1.

[1389] In the table, a reference example indicates that the compound is prepared using a corresponding raw material by a method based on the preparation method of the compound of the example number corresponding to that number, and for example, the example compound with reference example number 1 means that it is prepared by a method based on Example 1.

[1390] In the table, "Chemical Name" indicates the name of the compound corresponding to the number of the reference example and example, and "Data" indicates instrumental analysis data of such compound, for example, mass spectrometry data (m / z value). 1 This includes H NMR data (peak δ (ppm)), elemental analysis data (composition of C, H, and N (%)), etc.

[1391] [Table 3]

[1392]

[1393] [Table 4]

[1394]

[1395] [Table 5]

[1396]

[1397] [Table 6]

[1398]

[1399] [Table 7]

[1400]

[1401] [Table 8]

[1402]

[1403] [Table 9]

[1404]

[1405] [Table 10]

[1406]

[1407] [Table 11]

[1408]

[1409] [Table 12]

[1410]

[1411] [Table 13]

[1412]

[1413] [Table 14]

[1414]

[1415] [Table 15]

[1416]

[1417] [Table 16]

[1418]

[1419] [Table 17]

[1420]

[1421] [Table 18]

[1422]

[1423] [Table 19]

[1424]

[1425] [Table 20]

[1426]

[1427] [Table 21]

[1428]

[1429] [Table 22]

[1430]

[1431] [Table 23]

[1432]

[1433] [Table 24]

[1434]

[1435] [Table 25]

[1436]

[1437] [Table 26]

[1438]

[1439] [Table 27]

[1440]

[1441] [Table 28]

[1442]

[1443] [Table 29]

[1444]

[1445] The following describes biological test examples of compounds used in the present invention.

[1446] <Test Example 1 PDGFR-β Tyrosine Kinase Inhibitory Effect>

[1447] 1. Preparation of the test substance

[1448] The substance to be tested was prepared at 10 mM in dimethyl sulfoxide (DMSO) and diluted with DMSO to a concentration 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 oxrthovanadate, 1 mM dithiothreitol, 5 mM MgCl2, 1 mM MnCl2) and additionally diluted 5-fold with assay buffer 2 (50 mM HEPES (pH 7.0), 0.02% NaN3, 0.01% bovine serum albumin, 0.1 mM oxrthovanadate, 1 mM dithiothreitol, 5 mM MgCl2, 1 mM MnCl2, 40 nM Supplemented Enzymatic Buffer (cisbio)).

[1449] 2. Measurement of PDGFR-β tyrosine kinase inhibitory activity

[1450] The HTRF KinEASE-TK kit from cisbio was used for the measurement. 4 μL of the test substance solution was added to a 384-well plate, followed by 2 μL of PDGFR-β enzyme solution (final concentration 1 ng / μL, Carna Bioscience) and 4 μL of a substrate solution containing 0.6 μM ATP added to TK substrate-3-biotin (cisbio). The reaction was carried out at 30°C for 30 minutes with the final concentration of the test substance set to 0.01–10000 nM.

[1451] Afterwards, 10 μL of the detection solution (cisbio) was added to each well and reacted at 30°C for 1 hour. Fluorescence intensity was measured using a microplate reader (Spectra Max M5, Molecular device).

[1452] 3. Interpretation of Measurement Results

[1453] Using the ratio of fluorescence intensities for each condition, the inhibition rates were calculated when the values ​​for the positive control (1% DMSO solution) and the negative control (enzyme(-)) were set to 0% and 100%, respectively. Subsequently, using the SAS system (SAS Institute Inc.), non-linear regression analysis based on a two-parameter logistic model was performed on logarithmic concentration and inhibition rate to determine the concentration of the test substance that inhibits PDGFR-β tyrosine kinase activity by 50% (IC10). 50 Estimated the value.

[1454] The results are shown in Tables 30 to 33 below.

[1455] [Table 30]

[1456]

[1457] [Table 31]

[1458]

[1459] [Table 32]

[1460]

[1461] [Table 33]

[1462]

[1463] <Test Example 2: Inhibitory effect on proliferation of TEL-PDGFRβ and TEL-KIT fusion gene-introduced cells>

[1464] 1. Production of TEL-PDGFRβ, TEL-KIT fusion gene-introduced cells

[1465] A gene delivery vector was constructed by inserting a human TEL-PDGFRβ fusion gene (see, e.g., CELL, 1994, 77, 307-316) or a human TEL-KIT fusion gene into the multicloning site of the retroviral expression vector pMYs-IRES-GFP. For the human TEL-KIT fusion gene, the amino acid sequence important for the enzymatic activity of the KIT gene (Accession No. NP_000213.1, amino acids 521–928) was identified and appropriately combined with the amino acid sequence of the TEL gene to construct a sequence that exhibits activation even without a ligand factor. Subsequently, the gene delivery vector was introduced into PLAT-E, a packaged cell line 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 delivery contained virus particles for gene delivery, it was recovered and used as a medium for gene delivery. A plate coated with Retronectin was incubated with gene transfer medium, and virus particles were attached to the plate. Subsequently, mouse pro-B cell line Ba / F3 in the logarithmic growth phase was seeded onto the plate and infected with the virus to produce cells that proliferate in a PDGFRβ or KIT-dependent manner.

[1466] 2. Preparation of the test substance

[1467] The test substance was prepared at 10 mM in dimethyl sulfoxide (DMSO) and diluted with DMSO to concentrations of 0.0001 to 3 mM, respectively. It was also diluted 100 times with distilled water.

[1468] 3. Measurement of the inhibitory effect of TEL-PDGFRβ and TEL-KIT on cell proliferation

[1469] On the day after seeding TEL-PDGFRβ and TEL-KIT expressing cells in a 96-well plate, the prepared test substance solution was added to the cells at a seed concentration of 0.1 to 10,000 nM. After 72 hours, the number of live cells was measured using the amount of forma residue resulting from the reduction of tetrazolium salt compounds by mitochondrial dehydrogenase of live cells as an indicator.

[1470] 4. Interpretation of Measurement Results

[1471] Based on the residual forma content of each condition, the cell proliferation inhibition rates were calculated when the residual forma content of the negative control (0.1% DMSO solution) and the blank (medium only) was set to 0% and 100%, respectively. Subsequently, using the SAS system (SAS Institute Inc.), a non-linear regression analysis based on a two-parameter logistic model was performed on the logarithmic dose and cell proliferation inhibition rates, and the IC50 was calculated. 50 Estimated the value.

[1472] The results are shown in Tables 34 to 38 below.

[1473] [Table 34]

[1474]

[1475] [Table 35]

[1476]

[1477] [Table 36]

[1478]

[1479] [Table 37]

[1480]

[1481] [Table 38]

[1482]

[1483] <Test Example 3: Inhibitory Effect on Proliferation of Pulmonary Artery Smooth Muscle Cells>

[1484] 1. Preparation of the test substance

[1485] The test substance was prepared at 10 mM in dimethyl sulfoxide (DMSO) and diluted with DMSO to concentrations of 0.003 to 3 mM, respectively. It was also diluted 50-fold with distilled water.

[1486] 2. Measurement of proliferation inhibitory effect on pulmonary artery smooth muscle cells

[1487] Pulmonary artery smooth muscle cells derived from healthy individuals were seeded into a 96-well plate using smooth muscle cell proliferation medium. The following day, the proliferation medium was replaced with 0.1% FBS medium, and the cells were cultured for an additional day. The test substance solution was diluted 10-fold in a medium containing BrdU and human PDGF-BB (special concentration 10 ng / mL, SIGMA-Aldrich), and the species concentration was adjusted to 3–10,000 nM by adding an equal amount to the cells. Additionally, BrdU and a 0.1% DMSO solution were added to the human PDGF-BB negative control. After culturing for one day, the amount of BrdU introduced into the proliferating cells was measured using an anti-BrdU antibody.

[1488] 3. Interpretation of Measurement Results

[1489] Based on the BrdU levels of each condition, the cell proliferation inhibition rates were calculated when the BrdU levels of the positive control (human PDGF-BB(+)) and negative control (human PDGF-BB(-)) were set to 0% and 100%, respectively. Subsequently, using the SAS system (SAS Institute Inc.), a non-linear regression analysis based on a two-parameter logistic model was performed on the logarithmic dose and cell proliferation inhibition rates, and the IC 50 Estimated the value.

[1490] The results are shown in Tables 39 to 46 below.

[1491] [Table 39]

[1492]

[1493] [Table 40]

[1494]

[1495] [Table 41]

[1496]

[1497] [Table 42]

[1498]

[1499] [Table 43]

[1500]

[1501] [Table 44]

[1502]

[1503] [Table 45]

[1504]

[1505] [Table 46]

[1506]

[1507] <Test Example 4: Inhibitory effect on erythroblast colony formation>

[1508] 1. Preparation of the test substance

[1509] The test substance was prepared at 10 mM in dimethyl sulfoxide (DMSO), diluted with DMSO to concentrations of 0.1 to 3 mM, and a 1000-fold solution of the test substance was prepared.

[1510] 2. Measurement of the inhibitory effect on the formation of erythroblast colonies

[1511] Human bone marrow CD34-positive hematopoietic stem cells were thawed, suspended in MethoCult medium, and a solution of the test substance was added to achieve a species concentration of 0.1 to 10 μM. Cells were seeded in 35 mm dishes and cultured for 14 days. The number of cell colonies derived from erythroblast progenitor cells was counted under a microscope.

[1512] 3. Interpretation of Measurement Results

[1513] 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 2-parameter logistic model was performed on the logarithmic capacity and colony formation inhibition rate using the SAS system (SAS Institute Inc.), and IC 50 The values ​​were estimated. The results are shown in Table 47 below.

[1514] [Table 47]

[1515]

[1516] Examples of preparations

[1517] The formulation examples presented below are merely illustrative and are not intended to limit the scope of the invention in any way.

[1518] Preparation Example 1 Tablet (Oral Tablet)

[1519] Of the prescribed 1 tablet (80 mg),

[1520] 5.0 mg of the compound of the present invention of Example 1

[1521] Corn starch 46.6 mg

[1522] Crystalline cellulose 24.0 mg

[1523] Methylcellulose 4.0 mg

[1524] Magnesium stearate 0.4 mg

[1525] The mixed powder of this ratio is formed into a tablet by a conventional method to make an oral tablet.

[1526] Industrial applicability

[1527] The compound of the present invention is useful as a therapeutic agent for respiratory diseases, cancer, smooth muscle proliferative diseases, angioplastic diseases, autoimmune / inflammatory diseases, metabolic diseases, vascular occlusive diseases, etc., in that it has PDGF receptor kinase inhibitory activity.

Claims

Claim 1 A compound, a pharmaceutically acceptable salt thereof, or a solvate thereof selected from the group consisting of (1) to (207) below. (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-[(propane-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-hydroxypentane-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-[(propane-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-[(pyridine-2-yl)oxy]pyridine-3-carboxamide,(52) N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)-5-[(pyrimidine-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-bromopyridine-3-yl)ethynyl]-4-chloro-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide,(58) 4-chloro-N-[(1S,2S)-2-hydroxycyclohexyl]-3-[(5-phenylpyridine-3-yl)ethynyl]benzamide,(59) N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-[(5-methylpyridine-3-yl)ethynyl]benzamide,(60) N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-[(5-phenylpyridine-3-yl)ethynyl]benzamide,(61) 3-[(5-bromopyridine-3-yl)ethynyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide,(62) N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-{[5-(pyrimidine-2-yl)pyridine-3-yl]ethynyl}benzamide,(63) N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-{[5-(pyrazine-2-yl)pyridine-3-yl]ethynyl}benzamide,(64) 4-chloro-N-[(1S,2S)-2-hydroxycyclohexyl]-3-{[5-(pyrimidine-2-yl)pyridine-3-yl]ethynyl}benzamide,(65) 3-[(6-aminopyridine-3-yl)ethynyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide,(66) 3-[([2,3'-bipyridine]-5'-yl)ethynyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide,(67) 3-[(5-cyclopropylpyridine-3-yl)ethynyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide,(68) 3-[(6-cyclopropylpyrazine-2-yl)ethynyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide,(69) 3-{[6-(2-fluorophenyl)pyrazine-2-yl]ethynyl}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide,(70) 3-{[6-(3-fluorophenyl)pyrazine-2-yl]ethynyl}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide,(71) 3-{[6-(4-fluorophenyl)pyrazine-2-yl]ethynyl}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide,(72) 3-({6-[(cyclopropylmethyl)amino]pyrazine-2-yl}ethynyl)-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide,(73) 5-[(5-cyclopropylpyridine-3-yl)ethynyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-6-methylpyridine-3-carboxamide,(74) 3-[(6-bromopyrazine-2-yl)ethynyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide,(75) N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-[(6-phenylpyrazine-2-yl)ethynyl]benzamide,(76) 3-[(5-bromopyridine-3-yl)ethynyl]-N-[(1S,2S)-1,3-dihydroxy-1-phenylpropane-2-yl]-4-methylbenzamide,(77) N, 1 -[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-N 3 -(5-phenylpyridine-3-yl)benzene-1,3-dicarboxamide,(78) N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-{[2-(pyridine-3-yl)pyrimidine-4-yl]amino}benzamide,(79) N-[(1S,2S)-2-hydroxycyclohexyl]-3-{[2-(isoquinoline-4-yl)pyrimidine-4-yl]amino}-4-methylbenzamide,(80) N-[(1S,2S)-1,3-dihydroxy-1-phenylpropane-2-yl]-3-{[2-(isoquinoline-4-yl)pyrimidine-4-yl]amino}-4-methylbenzamide,(81) 3-[([2,3'-bipyridine]-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]pyrimidine-6(5H)-yl)-N-[(1S,2S)-1,3-dihydroxy-1-phenylpropane-2-yl]-4-methylbenzamide,(84) N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-{[(1S)-1-(5-phenylpyridine-3-yl)ethyl]amino}benzamide,(85) 3-{[(1S)-1-([3,3'-bipyridine]-5-yl)ethyl]amino}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide,(86) N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-({(1S)-1-[5-(phenylethynyl)pyridine-3-yl]ethyl}amino)benzamide,(87) 3-{[(1S)-1-([3,4'-bipyridine]-5-yl)ethyl]amino}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide,(88) N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-({(1S)-1-[5-(pyrimidine-2-yl)pyridine-3-yl]ethyl}amino)benzamide,(89) 3-{[(1S)-1-([2,3'-bipyridine]-5'-yl)ethyl]amino}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide,(90) 3-{[(1S)-1-([3,3'-bipyridine]-5-yl)ethyl]amino}-4-chloro-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide,(91) 3-{[(5-bromopyridine-3-yl)methyl]amino}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide,(92) N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-{[(5-phenylpyridine-3-yl)methyl]amino}benzamide,(93) 3-{[([3,3'-bipyridine]-5-yl)methyl]amino}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide,(94) 3-({[5-(cyclopropylethinyl)pyridine-3-yl]methyl}amino)-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide,(95) N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-({[5-(pyrimidine-2-yl)pyridine-3-yl]methyl}amino)benzamide,(96) N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-{[(quinoline-3-yl)methyl]amino}benzamide,(97) N-[(1S,2S)-2-hydroxycyclohexyl]-3-[({5-[(1-hydroxycyclopropyl)ethinyl]pyridine-3-yl}methyl)amino]-4-methylbenzamide,(98) 3-[({5-[4-(2-aminopropane-2-yl)phenyl]pyridine-3-yl}methyl)amino]-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide,(99) 3-({[5-(4-aminophenyl)pyridine-3-yl]methyl}amino)-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide,(100) 3-({[5-(3,5-difluorophenyl)pyridine-3-yl]methyl}amino)-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide,(101) N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-{[(6-phenylpyrazine-2-yl)methyl]amino}benzamide,(102) N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-({[5-(thiophene-2-yl)pyridine-3-yl]methyl}amino)benzamide,(103) N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-({[5-(thiophene-3-yl)pyridine-3-yl]methyl}amino)benzamide,(104) 4-chloro-N-[(1S,2S)-2-hydroxycyclohexyl]-3-({[5-(pyrimidine-2-yl)pyridine-3-yl]methyl}amino)benzamide,(105) N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-{[(pyrazolo[5,1-b][1,3]thiazole-7-yl)methyl]amino}benzamide,(106) 3-fluoro-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-5-({[5-(pyrimidine-2-yl)pyridine-3-yl]methyl}amino)benzamide,(107) 3-({[5-(5-fluoropyrimidine-2-yl)pyridine-3-yl]methyl}amino)-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide,(108) N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-{[(thieno[3,2-b]pyridine-6-yl)methyl]amino}benzamide,(109) N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-{[(1H-pyrazolo[3,4-b]pyridine-5-yl)methyl]amino}benzamide,(110) N-[(1S,2S)-2-hydroxycyclohexyl]-3-{[(imidazo[1,2-b]pyridazine-3-yl)methyl]amino}-4-methylbenzamide,(111) N-[(1S,2S)-2-hydroxycyclohexyl]-3-({[5-(imidazo[1,2-a]pyrazine-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-aminopyrimidine-5-yl)methyl]amino}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide,(114) 3-({[2-(cyclopropylamino)pyrimidine-5-yl]methyl}amino)-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide,(115) N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-({[5-(pyrazine-2-yl)pyridine-3-yl]methyl}amino)benzamide,(116) 3-{[(6-acetamidopyridine-3-yl)methyl]amino}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide,(117) 3-[({6-[(cyclopropylmethyl)amino]pyridine-3-yl}methyl)amino]-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide,(118) 3-{[([2,2'-bipyridine]-5-yl)methyl]amino}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide,(119) N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-{[(pyrazolo[1,5-a]pyrimidine-3-yl)methyl]amino}benzamide,(120) 3-[({6-[(cyclopropanecarbonyl)amino]pyridine-3-yl}methyl)amino]-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide,(121) N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-{[(2-phenylpyrimidine-5-yl)methyl]amino}benzamide,(122) N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-({[6-(1H-pyrazol-1-yl)pyridine-3-yl]methyl}amino)benzamide,(123) N-[(1S,2S)-2-hydroxycyclohexyl]-6-methyl-5-{[(pyrazolo[1,5-a]pyridin-3-yl)methyl]amino}pyridin-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-[(oxane-4-yl)amino]pyridin-3-yl}methyl)amino]benzamide,(126) N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-[({2-[(pyridine-2-yl)amino]pyrimidine-5-yl}methyl)amino]benzamide,(127) N-{5-[(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylanilino)methyl]pyridine-2-yl}morpholine-4-carboxamide,(128) N-[(1S,2S)-2-hydroxycyclohexyl]-3-({[2-(4-methoxyphenyl)pyrimidine-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)pyridine-3-yl]methyl}amino)-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide,(131) 3-{[(5-aminopyrazine-2-yl)methyl]amino}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide,(132) N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-[({2-[(oxane-4-yl)amino]pyrimidine-5-yl}methyl)amino]benzamide,(133) 3-{[(6-{[cyclopropyl(methyl)carbamoyl]amino}pyridine-3-yl)methyl]amino}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide,(134) N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-[({6-[(propane-2-yl)amino]pyridine-3-yl}methyl)amino]benzamide,(135) N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-{[(2-{[(3R)-oxolan-3-yl]amino}pyrimidine-5-yl)methyl]amino}benzamide,(136) N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-{[(2-{[(3S)-oxolan-3-yl]amino}pyrimidine-5-yl)methyl]amino}benzamide (137) N-{5-[(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylanilino)methyl]pyridine-2-yl}oxane-4-carboxamide, (138) N-[(1S,2S)-2-hydroxycyclohexyl]-3-{[(6-{[(1r,3r)-3-methoxycyclobutane-1-carbonyl]amino}pyridine-3-yl)methyl]amino}-4-methylbenzamide, (139) N-{5-[(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylanilino)methyl]pyridine-2-yl}oxolan-3-carboxamide,(140) N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-({[6-(1H-1,2,3-triazole-1-yl)pyridine-3-yl]methyl}amino)benzamide,(141) N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-[({6-[(oxetane-3-yl)amino]pyridine-3-yl}methyl)amino]benzamide,(142) 3-{[(2-aminopyrimidine-5-yl)methyl]amino}-4-chloro-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide, (143) 3-{[(2-aminopyrimidine-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]oxazine-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-triazole-2-yl)pyridine-3-yl]methyl}amino)benzamide, (146) 3-{[([3,3'-bipyridine]-5-yl)amino]methyl}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide,(147) N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-({[5-(pyrimidine-2-yl)pyridine-3-yl]amino}methyl)benzamide,(148) 3-{[([2,3'-bipyridine]-5'-yl)amino]methyl}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide,(149) N-[(1R,2R)-2-hydroxycyclohexyl]-4-methyl-3-({[5-(pyrimidine-2-yl)pyridine-3-yl]amino}methyl)benzamide,(150) N-[(1S,2S)-2-hydroxycyclohexyl]-3-({[5-(pyrimidine-2-yl)pyridine-3-yl]amino}methyl)benzamide,(151) 4-fluoro-N-[(1S,2S)-2-hydroxycyclohexyl]-3-({[5-(pyrimidine-2-yl)pyridine-3-yl]amino}methyl)benzamide,(152) 3-{[(5-bromopyridine-3-yl)amino]methyl}-N-[(1S,2S)-1,3-dihydroxy-1-phenylpropane-2-yl]-4-methylbenzamide,(153) N-[(1S,2S)-1,3-dihydroxy-1-phenylpropane-2-yl]-4-methyl-3-{[(5-phenylpyridine-3-yl)amino]methyl}benzamide,(154) 3-{[(5-cyclopropylpyridine-3-yl)amino]methyl}-N-[(1S,2S)-1,3-dihydroxy-1-phenylpropane-2-yl]-4-methylbenzamide,(155) 3-{[([2,3'-bipyridine]-5'-yl)amino]methyl}-N-[(1S,2S)-1,3-dihydroxy-1-phenylpropane-2-yl]-4-methylbenzamide, (156) N-[(1S,2S)-1,3-dihydroxy-1-phenylpropane-2-yl]-4-methyl-3-{[(6-phenylpyrazine-2-yl)amino]methyl}benzamide, (157) 5-({[5-(cyclopropylethinyl)pyridine-3-yl]amino}methyl)-N-[(1S,2S)-2-hydroxycyclohexyl]-6-methylpyridine-3-carboxamide, (158) N-[3-({[6-(3,4-dimethoxyphenyl)pyrazine-2-yl]amino}methyl)phenyl]-N'-[(1R,2S)-2-hydroxycyclohexyl]urea, (159) N-[(1R,2S)-2-hydroxycyclohexyl]-N'-[3-({[5-(pyrimidine-2-yl)pyridine-3-yl]amino}methyl)phenyl]urea,(160) N-[2-fluoro-5-({[5-(pyrimidine-2-yl)pyridine-3-yl]amino}methyl)phenyl]-N'-[(1R,2S)-2-hydroxycyclohexyl]urea,(161) N-[4-fluoro-3-({[5-(pyrimidine-2-yl)pyridine-3-yl]amino}methyl)phenyl]-N'-[(1R,2S)-2-hydroxycyclohexyl]urea,(162) N-[(1R,2S)-2-hydroxycyclohexyl]-N'-[4-methyl-3-({[5-(pyrimidine-2-yl)pyridine-3-yl]amino}methyl)phenyl]urea,(163) N-[(1R,2S)-2-hydroxycyclohexyl]-N'-[2-methyl-5-({[5-(pyrimidine-2-yl)pyridine-3-yl]amino}methyl)phenyl]urea,(164) N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-{1-[(6-phenylpyrazine-2-yl)amino]ethyl}benzamide,(165) 3-[([3,3'-bipyridine]-5-yl)methoxy]-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide,(166) N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-{[5-(pyrimidine-2-yl)pyridine-3-yl]methoxy}benzamide,(167) 4-chloro-N-[(1S,2S)-2-hydroxycyclohexyl]-3-{[5-(pyrimidine-2-yl)pyridine-3-yl]methoxy}benzamide,(168) 3-{[([3,3'-bipyridine]-5-yl)oxy]methyl}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide,(169) N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-({[5-(pyrimidine-2-yl)pyridine-3-yl]oxy}methyl)benzamide,(170) 4-chloro-N-[(1S,2S)-2-hydroxycyclohexyl]-3-({[5-(pyrimidine-2-yl)pyridine-3-yl]oxy}methyl)benzamide,(171) N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-{1-[5-(pyrimidine-2-yl)pyridine-3-yl]ethoxy}benzamide,(172) N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-[1-(5-phenylpyridine-3-yl)ethoxy]benzamide,(173) N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-[(E)-2-(5-phenylpyridine-3-yl)ethenyl]benzamide,(174) N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-[2-(5-phenylpyridine-3-yl)ethyl]benzamide,(175) N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-{[methyl(5-phenylpyridine-3-yl)amino]methyl}benzamide,(176) 3-{[ethyl(5-phenylpyridine-3-yl)amino]methyl}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide,(177) 3-[(Z)-2-([2,3'-bipyridine]-5'-yl)-2-fluoroethenyl]-4-fluoro-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide,(178) 4-fluoro-3-{(Z)-2-fluoro-2-[5-(pyrimidine-2-yl)pyridine-3-yl]ethenyl}-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide,(179) 3-[(Z)-2-fluoro-2-(imidazo[1,2-b]pyridazine-3-yl)ethenyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide,(180) 5-[(Z)-2-([2,3'-bipyridine]-5'-yl)-2-fluoroethenyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-6-methylpyridine-3-carboxamide,(181) 3-[(Z)-2-fluoro-2-{5-[(4-methylpiperazine-1-yl)methyl]pyridine-3-yl}ethenyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide,(182) 3-[(Z)-2-fluoro-2-{5-[(morpholine-4-yl)methyl]pyridine-3-yl}ethenyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide,(183) 3-[(Z)-2-{6-[(cyclopropylmethyl)amino]pyridine-3-yl}-2-fluoroethenyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide,(184) 4-fluoro-3-{(Z)-2-fluoro-2-[5-(morpholine-4-yl)pyridine-3-yl]ethenyl}-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide,(185) 4-fluoro-3-[(Z)-2-fluoro-2-{5-[(oxane-4-yl)amino]pyridine-3-yl}ethenyl]-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide,(186) 4-fluoro-3-[(Z)-2-fluoro-2-{5-[(4-methylpiperazine-1-yl)methyl]pyridine-3-yl}ethenyl]-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide,(187) 5-{(Z)-2-[5-(cyclopropylmethoxy)pyridine-3-yl]-2-fluoroethenyl}-N-[(1S,2S)-2-hydroxycyclohexyl]-6-methylpyridine-3-carboxamide,(188) 5-{(Z)-2-fluoro-2-[5-(morpholine-4-yl)pyridine-3-yl]ethenyl}-N-[(1S,2S)-2-hydroxycyclohexyl]-6-methylpyridine-3-carboxamide,(189) 5-[(Z)-2-(6-aminopyridine-3-yl)-2-fluoroethenyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-6-methylpyridine-3-carboxamide,(190) 5-[(Z)-2-(2-aminopyrimidine-5-yl)-2-fluoroethenyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-6-methylpyridine-3-carboxamide,(191) 3-[(Z)-2-(6-aminopyridine-3-yl)-2-fluoroethenyl]-4-fluoro-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide,(192) 3-[(Z)-2-(2-aminopyrimidine-5-yl)-2-fluoroethenyl]-4-fluoro-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide,(193) 3-[(Z)-2-fluoro-2-{5-[(1-methylpiperidine-4-yl)amino]pyridine-3-yl}ethenyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide,(194) 3-[(Z)-2-{5-[(4-ethylpiperazine-1-yl)methyl]pyridine-3-yl}-2-fluoroethenyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide,(195) 5-[(Z)-2-fluoro-2-{5-[(oxetane-3-yl)amino]pyridine-3-yl}ethenyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-6-methylpyridine-3-carboxamide,(196) 4-fluoro-3-[(Z)-2-fluoro-2-{5-[(oxetane-3-yl)amino]pyridine-3-yl}ethenyl]-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide,(197) 3-[(Z)-2-(6-{[2-(dimethylamino)ethyl]amino}pyridine-3-yl)-2-fluoroethenyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide,(198) 3-[(Z)-2-(5-{[2-(dimethylamino)ethyl]amino}pyridine-3-yl)-2-fluoroethenyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide,(199) 5-[(Z)-2-{6-[(cyclopropylmethyl)amino]pyridine-3-yl}-2-fluoroethenyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-6-methylpyridine-3-carboxamide,(200) 3-[(Z)-2-fluoro-2-{5-[(4-methylpiperazine-1-yl)methyl]pyridine-3-yl}ethenyl]-N-[(1S,2S)-2-hydroxy-2,3-dihydro-1H-indene-1-yl]-4-methylbenzamide,(201) 3-[(Z)-2-fluoro-2-{5-[(4-methylpiperazine-1-yl)methyl]pyridine-3-yl}ethenyl]-N-(2-hydroxy-3,3-dimethylbutyl)-4-methylbenzamide,(202) 3-[(Z)-2-{2-[(cyclopropylmethyl)amino]pyrimidine-5-yl}-2-fluoroethenyl]-4-fluoro-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide,(203) 3-{(Z)-2-[2-(cyclopropylamino)pyrimidine-5-yl]-2-fluoroethenyl}-4-fluoro-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide,(204) 3-[(Z)-2-(2-amino-4-methylpyrimidine-5-yl)-2-fluoroethenyl]-4-fluoro-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide,(205) 4-fluoro-3-{(Z)-2-fluoro-2-[2-(methylamino)pyrimidine-5-yl]ethenyl}-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide,(206) 3-[(Z)-2-(5-aminopyrazine-2-yl)-2-fluoroethenyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide,(207) 4-fluoro-3-[(Z)-2-fluoro-2-(5-fluoropyridine-3-yl)ethenyl]-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide., Claim 2 A compound selected from the group consisting of (1) to (15) below, 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-aminopyrimidine-5-yl)methyl]amino}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide,(7) N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-{[(pyrazolo[1,5-a]pyrimidine-3-yl)methyl]amino}benzamide,(8) N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-[({2-[(oxane-4-yl)amino]pyrimidine-5-yl}methyl)amino]benzamide,(9) N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-({[6-(1H-1,2,3-triazole-1-yl)pyridine-3-yl]methyl}amino)benzamide,(10) 3-{[([2,3'-bipyridine]-5'-yl)amino]methyl}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide,(11) 5-[(Z)-2-(6-aminopyridine-3-yl)-2-fluoroethenyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-6-methylpyridine-3-carboxamide,(12) 3-[(Z)-2-{5-[(4-ethylpiperazine-1-yl)methyl]pyridine-3-yl}-2-fluoroethenyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide,(13) 4-fluoro-3-{(Z)-2-fluoro-2-[2-(methylamino)pyrimidine-5-yl]ethenyl}-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide,(14) 3-[(Z)-2-(5-aminopyrazine-2-yl)-2-fluoroethenyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide,(15) 4-fluoro-3-[(Z)-2-fluoro-2-(5-fluoropyridine-3-yl)ethenyl]-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide., Claim 3 A pharmaceutical composition for the treatment of respiratory diseases, cancer, smooth muscle proliferative diseases, angioplastic diseases, autoimmune diseases, inflammatory diseases, metabolic diseases, or vascular occlusive diseases, comprising as an active ingredient a compound described in claim 1 or 2, a pharmaceutically acceptable salt thereof, or a solvate thereof. Claim 4 A compound described in Claim 1 or 2, or a pharmaceutically acceptable salt thereof, or a solvate thereof, containing as an active ingredient a PDGF receptor kinase-involved pulmonary hypertension, scleroderma, asthma, obstructive bronchiolitis, pulmonary fibrosis, acute myelogenous leukemia (AML), eosinophilic syndrome, T-lymphoblastic leukemia, chronic myelomonocytic leukemia (CMML), chronic myelogenous leukemia (CML), chronic eosinophilic leukemia, cutaneous fibrosarcoma protuberance, glioma, ovarian cancer, vascular restenosis, atherosclerotic / obstructive arteriosclerosis, Moyamoya disease (idiopathic Willis's arterial ring occlusion), leiomyoma, lymphangiomyomatosis, or, for example, age-related macular degeneration (age-related A treatment for macular degeneration (AMD). Claim 5 delete Claim 6 delete Claim 7 delete Claim 8 delete

Images