HK40082889B - Compound and composition as pdgf receptor kinase inhibitor - Google Patents

Description

Compounds and compositions as PDGF receptor kinase inhibitors

Technical Field

This invention relates to preventive and/or therapeutic agents for pulmonary hypertension that contain novel heterocyclic derivatives as active ingredients.

Background Technology

Regarding pulmonary hypertension (PAH), large-scale workshops on pulmonary hypertension are held every five years in Western countries. At the 2008 Dana Point Conference, pulmonary hypertension was defined as a mean pulmonary artery pressure (PAP) of 25 mmHg or higher, measured using a resting right heart catheterization test. This definition was continued at the 2013 Nice Conference. In the Dana Point classification, pulmonary hypertension is divided into five groups: Group 1: PAH; Group 2: pulmonary hypertension caused by left ventricular disease; Group 3: pulmonary hypertension and/or hypoxemia caused by lung disease; Group 4: chronic thromboembolic pulmonary hypertension (CTEPH); and Group 5: pulmonary hypertension caused by multifactorial mechanisms of unknown origin. This basic structure is maintained in the revised clinical classification of pulmonary hypertension (Nice classification [2013]) (Non-Patent Literature 1).

Furthermore, an updated definition of pulmonary hypertension was proposed at the 6th World Conference on Pulmonary Hypertension (Nice Conference 2018). In this proposal, a mean pulmonary artery pressure (mPAP) of 24 mmHg ≥ 20 mmHg was also defined as including pulmonary hypertension as described above.

Platelet-derived growth factor (PDGF) may stimulate arterial smooth muscle cells to migrate from the arterial interior to the intima, where the muscle cells can proliferate. Cell proliferation induced by all isotypes of PDGF is mediated by ligands that bind to the PDGF receptor.

PDGF receptors belong to the class III tyrosine kinase family and consist of two receptor subtypes, called type A (or α) and type B (or β). Other members of the PDGF receptor family include colony-stimulating factor 1 receptor (CSF1R), KIT, and FLT3.

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

Imatinib has inhibitory activity against PDGF receptor kinase and has shown efficacy in the P3 study of pulmonary hypertension. However, it is not well tolerated due to side effects such as myelosuppression and has therefore not been approved.

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

However, the relationship between myelosuppression and inhibition of KIT, a receptor tyrosine kinase involved in bone marrow hematopoiesis, remains unknown to date.

Reference List

Patent documents

PTL 8: WO 2013/033620

Non-patent literature

NPL 1: Smolich et al., Blood, 97, 1413-1421.

Summary of the Invention

Technical issues

The problem this invention seeks to solve is to provide a preventive and/or therapeutic agent for pulmonary hypertension that has an excellent balance between effectiveness and safety.

Solution to the problem

The inventors have discovered a relationship between myelosuppression and inhibition of KIT, a receptor tyrosine kinase involved in bone marrow hematopoiesis. Specifically, the inventors have discovered that compounds represented by the following general formula [1], or pharmaceutically acceptable salts or solvates thereof (which may be referred to as compounds of the present invention in this specification) exhibit inhibitory activity against PDGF receptor kinase in KIT kinase inhibition, and that their inhibitory activity against erythrocyte colony formation is reduced, thereby completing the present invention.

That is, the following (Item 1) to (Item 8) are disclosed in this document.

(Project 1)

Compounds represented by the following formula [1]:

[Formula 1]

in

^R1 is a hydrogen atom, a halogen atom, a _C1 - _C6 alkyl, a _C1 - _C6 haloalkyl, a _C2 - _C6 alkenyl, a _C2 - _C6 haloalkenyl, a _C2 - _C6 alkynyl, a _C2 - _C6 haloalkynyl, a _C1 - _C6 alkoxy, a hydroxyl group, a carboxyl group, an alkylcarbonyloxy group, an amino group, a monoalkylamino group, a dialkylamino group, an aminoalkyl group, an alkylcarbonylamino group, a nitro group, an optionally substituted _C3 - _C6 cycloalkyl group, an optionally substituted _C3 - _C6 cycloalkenyl group, an optionally substituted heterocycloalkyl group, an optionally substituted aryl group, or an optionally substituted heteroaryl group.

R ² is a bonding hand, -(CR ^a R ^b ) _m -NR ^c -, -NR ^c -(CR ^a R ^b ) _m -, -(CR ^a R ^b ) _m -O-, -O-(CR ^a R ^b ) _m -, -(CR ^a R ^b ) _m -, -NR ^c -, -O-, -NR ^c -CO-NR ^c -, -CR ^a =CR ^b - or -C≡C-, where

In ^R2 , ^Ra is a hydrogen atom, a halogen atom, a _C1 - _C6 alkyl group, or a _C1 - _C6 haloalkyl group.

^Rb in ^R2 is a hydrogen atom, a halogen atom, a _C1 - _C6 alkyl group, or a _C1 - _C6 haloalkyl group, or

In ^R2 , ^Ra and ^Rb together with their bonded carbon atoms form C=O.

Each ^Rc in ^R2 is independently a hydrogen atom, a _C1 - _C6 alkyl group, or a _C1 - _C6 haloalkyl group, and

m is an integer between 0 and 3;

Het is a 5-10 quinone heteroaryl group;

L ¹ is the bonding hand, -(CR ^a R ^b ) _m -NR ^c -, -NR ^c -(CR ^a R ^b ) _m -, -(CR ^a R ^b ) _m -O-, -O-(CR ^a R ^b ) _m -, -(CR ^a R ^b ) _m -, -NR ^c -, -O-, -NR ^c -CO-NR ^c -, -CR ^a =CR ^b - or -C≡C-, where

In ^{L1, Ra} can be a hydrogen atom, a halogen atom, a _C1 - _C6 alkyl group, or a _C1 - _C6 haloalkyl group.

In ^L1 , ^Rb is a hydrogen atom, a halogen atom, a _C1 - _C6 alkyl group, or a _C1 - _C6 haloalkyl group, or

In ^L1 , ^Ra and ^Rb together with their bonded carbon atoms form C=O.

Each ^Rc in ^L1 is independently a hydrogen atom, a _C1 - _C6 alkyl group, or a _C1 - _C6 haloalkyl group, and

In ^L1 , m is an integer between 0 and 3;

X is N or CR ³ , where

^R3 is a hydrogen atom, a halogen atom, a _C1 - _C6 alkyl group, or a _C1 - _C6 haloalkyl group;

^R4 is a hydrogen atom, a halogen atom, or a methyl group;

L ² is the bonding hand, -(CR ^a R ^b ) _m -NR ^c -, -NR ^c -(CR ^a R ^b ) _m -, -(CR ^a R ^b ) _m -O-, -O-(CR ^a R ^b ) _m -, -(CR ^a R ^b ) _m -, -NR ^c -, -O-, -NR ^c -CO-NR ^c -, -CR ^a =CR ^b - or -C≡C-, where

In ^L2 , ^Ra can be a hydrogen atom, a halogen atom, a _C1 - _C6 alkyl group, or a _C1 - _C6 haloalkyl group.

In ^L2 , ^Rb is a hydrogen atom, a halogen atom, a _C1 - _C6 alkyl group, or a _C1 - _C6 haloalkyl group.

In ^L2 , ^Ra and ^Rb together with their bonded carbon atoms form C=O.

Each ^Rc in ^L2 is independently a hydrogen atom, a _C1 - _C6 alkyl group, or a _C1 - _C6 haloalkyl group, and

In ^L2 , m is an integer between 0 and 3;

^R5 is a hydrogen atom, a halogen atom, a hydroxyl group, an amino group, a _C1 - _C6 alkyl group, a _C1 - _C6 haloalkyl group, a _C1 - _C6 alkoxy group, or a _C1 - _C6 haloalkoxy group; and

^R6 is a hydrogen atom, a halogen atom, a _C1 - _C6 alkyl group, a _C1 - _C6 haloalkyl group, or an optionally substituted phenyl group, and

R ⁷ is a hydrogen atom, a halogen atom, a _C1 - _C6 alkyl group, a _C1 - _C6 haloalkyl group, a hydroxyalkyl group, an optionally substituted phenyl group, or an optionally substituted _C3 - _C6 cycloalkyl group, or

^R6 and ^R7, together with the carbon atoms they are bonded to, form _C3 - _C6 cycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl.

Or its pharmaceutically acceptable salt or its solvate.

(Project 2)

According to the compound described in Project 1, wherein:

^R1 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, an optionally substituted _C3 - _C6 cycloalkyl, an optionally substituted heterocycloalkyl, an optionally substituted aryl, or an optionally substituted heteroaryl.

R ² is the bonding hand, -(CR ^a R ^b ) _m -NR ^c -, -(CR ^a R ^b ) _m -O-, -(CR ^a R ^b ) _m -, -NR ^c -, -O-, -NR ^c -CO-NR ^c -, -CR ^a =CR ^b - or -C≡C-;

L ¹ is the bonding hand, -(CR ^a R ^b ) _m -NR ^c -, -NR ^c -(CR ^a R ^b ) _m -, -(CR ^a R ^b ) _m -O-, -O-(CR ^a R ^b ) _m -, -(CR ^a R ^b ) _m -, -NR ^c -, -CR ^a =CR ^b - or -C≡C-, where

In ^{L1, Ra} is a hydrogen atom, a halogen atom, or a _C1 - _C6 alkyl group, and

In ^L1 , ^Rb is a hydrogen atom, a halogen atom, or a _C1 - _C6 alkyl group, or

^Ra and ^{Rb in L1} , together with their bonded carbon atoms, form C=O.

Each ^Rc in ^L1 is independently a hydrogen atom, a _C1 - _C6 alkyl group, or a _C1 - _C6 haloalkyl group, and

In ^L1 , m is an integer between 0 and 2;

X is N or CR ³ , where

^R3 is a hydrogen atom, a halogen atom, a _C1 - _C6 alkyl group, or a _C1 - _C6 haloalkyl group;

^R4 is a hydrogen atom, a halogen atom, or a methyl group;

^L2 is -(CR ^a R ^b ) _m -NR ^c - or -NR ^c -CO-NR ^c -, where

In ^L2 , ^Ra and ^Rb together with their bonded carbon atoms form C=O.

Each ^Rc in ^L2 is independently a hydrogen atom, and

In ^L2 , m is 1;

^R5 is a hydroxyl group; and

^R6 is a hydrogen atom, a _C1 - _C6 alkyl group, or an optionally substituted phenyl group, and

^R7 is a hydrogen atom, a _C1 - _C6 alkyl group, a hydroxyalkyl group, or an optionally substituted phenyl group, or

^R6 and ^R7, together with the carbon atoms they are bonded to, form a _C3 - _C6 cycloalkyl group or an optionally substituted aryl group.

Or its pharmaceutically acceptable salt or its solvate.

(Project 3)

According to the compound described in Project 1, wherein:

^R1 is a hydrogen atom, a _C1 - _C6 alkoxy group, an amino group, a monoalkylamino group, an optionally substituted _C3 - _C6 cycloalkyl group, an optionally substituted heterocycloalkyl group, an optionally substituted aryl group, or an optionally substituted heteroaryl group.

^R2 is a bonding agent, -(CR ^a R ^b ) _m -O-, -(CR ^a R ^b ) _m - or -NR ^c -;

L ¹ is -(CR ^a R ^b ) _m -NR ^c -, -NR ^c -(CR ^a R ^b ) _m - or -CR ^a =CR ^b -, where

In ^L1 , ^Ra is a hydrogen atom or a halogen atom, and

In ^L1 , ^Rb is a hydrogen atom, or

In ^L1 , ^Ra and ^Rb together with their bonded carbon atoms form C=O.

Each ^Rc in ^L1 is independently a hydrogen atom, and

In ^L1 , m is either 0 or 1;

X is N or CR ³ , where

^R3 is a hydrogen atom;

^R4 is a halogen atom or a methyl group;

^L2 is -(CR ^a R ^b ) _m -NR ^c -, where

In ^L2 , ^Ra and ^Rb together with their bonded carbon atoms form C=O.

Each ^Rc in ^L2 is independently a hydrogen atom, and

In ^L2 , m is 1;

^R5 is a hydroxyl group; and

^R6 and ^R7, together with the carbon atoms they are bonded to, form _C3 - _C6 cycloalkyl groups.

Or its pharmaceutically acceptable salt or its solvate.

(Project 3)

The compounds according to Item 1 are selected from the following (1) to (207):

(1) 2-(cyclopropylamino)-N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)-1,3-thiazolyl-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-thiazolyl-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-oxazol-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-[(prop-2-yl)oxy]pyridine-3-carboxamide,

(8) 2-[(cyclopropylmethyl)amino]-N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)-1,3-thiazolyl-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-thiazolyl-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-hydroxypent-2-yl]carbamoyl}-2-methylphenyl)-5-phenylpyridine-3-carboxamide,

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

(57) 3-[(5-bromopyridin-3-yl)ethynyl]-4-chloro-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide,

(58) 4-Chloro-N-[(1S,2S)-2-hydroxycyclohexyl]-3-[(5-phenylpyridin-3-yl)ethynyl]benzamide,

(59) N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-[(5-methylpyridin-3-yl)ethynyl]benzamide,

(60) N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-[(5-phenylpyridin-3-yl)ethynyl]benzamide,

(61) 3-[(5-bromopyridin-3-yl)ethynyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide,

(62) N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-{[5-(pyrimidin-2-yl)pyridin-3-yl]ethynyl}benzamide,

(63) N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-{[5-(pyrazin-2-yl)pyridin-3-yl]ethynyl}benzamide,

(64) 4-Chloro-N-[(1S,2S)-2-hydroxycyclohexyl]-3-{[5-(pyrimidin-2-yl)pyridin-3-yl]ethynyl}benzamide,

(65) 3-[(6-aminopyridin-3-yl)ethynyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide,

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

(67) 3-[(5-cyclopropylpyridin-3-yl)ethynyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide,

(68) 3-[(6-cyclopropylpyrazin-2-yl)ethynyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide,

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

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

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

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

(73) 5-[(5-cyclopropylpyridin-3-yl)ethynyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-6-methylpyridin-3-carboxamide,

(74) 3-[(6-bromopyrazin-2-yl)ethynyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide,

(75) N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-[(6-phenylpyrazin-2-yl)ethynyl]benzamide,

(76) 3-[(5-bromopyridin-3-yl)ethynyl]-N-[(1S,2S)-1,3-dihydroxy-1-phenylprop-2-yl]-4-methylbenzamide,

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

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

(79) N-[(1S,2S)-2-hydroxycyclohexyl]-3-{[2-(isoquinolin-4-yl)pyrimidin-4-yl]amino}-4-methylbenzamide,

(80) N-[(1S,2S)-1,3-dihydroxy-1-phenylprop-2-yl]-3-{[2-(isoquinolin-4-yl)pyrimidin-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]pyrimidin-6(5H)-yl)-N-[(1S,2S)-1,3-dihydroxy-1-phenylprop-2-yl]-4-methylbenzamide,

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

(104) 4-Chloro-N-[(1S,2S)-2-hydroxycyclohexyl]-3-({[5-(pyrimidin-2-yl)pyridin-3-yl]methyl}amino)benzamide,

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

(106) 3-Fluoro-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-5-({[5-(pyrimidin-2-yl)pyridin-3-yl]methyl}amino)benzamide,

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

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

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

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

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

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

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

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

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

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

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

(118) 3-{[([2,2'-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]pyrimidin-3-yl)methyl]amino}benzamide,

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

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

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

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

(124) methyl 5-[(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylaniline)methyl]pyridin-2-yl}carbamate,

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

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

(127) N-{5-[(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylaniline)methyl]pyridin-2-yl}morpholin-4-carboxamide,

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

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

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

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

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

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

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

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

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

(137) N-{5-[(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylaniline)methyl]pyridin-2-yl}oxacyclohexane-4-carboxamide,

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

(139) N-{5-[(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylaniline)methyl]pyridin-2-yl}oxacyclopentane-3-carboxamide,

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

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

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

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

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

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

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

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

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

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

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

(151) 4-Fluoro-N-[(1S,2S)-2-hydroxycyclohexyl]-3-({[5-(pyrimidin-2-yl)pyridin-3-yl]amino}methyl)benzamide,

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

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

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

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

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

(157) 5-({[5-(cyclopropylethynyl)pyridin-3-yl]amino}methyl)-N-[(1S,2S)-2-hydroxycyclohexyl]-6-methylpyridin-3-carboxamide,

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

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

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

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

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

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

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

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

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

(167) 4-Chloro-N-[(1S,2S)-2-hydroxycyclohexyl]-3-{[5-(pyrimidin-2-yl)pyridin-3-yl]methoxy}benzamide,

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

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

(170) 4-Chloro-N-[(1S,2S)-2-hydroxycyclohexyl]-3-({[5-(pyrimidin-2-yl)pyridin-3-yl]oxy}methyl)benzamide,

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

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

(173) N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-[(E)-2-(5-phenylpyridin-3-yl)vinyl]benzamide,

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

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

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

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

(178) 4-Fluoro-3-{(Z)-2-fluoro-2-[5-(pyrimidin-2-yl)pyridin-3-yl]vinyl}-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide,

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

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

(181) 3-[(Z)-2-fluoro-2-{5-[(4-methylpiperazin-1-yl)methyl]pyridin-3-yl}vinyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide,

(182) 3-[(Z)-2-fluoro-2-{5-[(morpholin-4-yl)methyl]pyridin-3-yl}vinyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide,

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

(184) 4-Fluoro-3-{(Z)-2-fluoro-2-[5-(morpholino-4-yl)pyridin-3-yl]vinyl}-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide,

(185) 4-Fluoro-3-[(Z)-2-Fluoro-2-{5-[(oxacyclohexane-4-yl)amino]pyridin-3-yl}vinyl]-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide,

(186) 4-Fluoro-3-[(Z)-2-Fluoro-2-{5-[(4-methylpiperazin-1-yl)methyl]pyridin-3-yl}vinyl]-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide,

(187) 5-{(Z)-2-[5-(cyclopropylmethoxy)pyridin-3-yl]-2-fluorovinyl}-N-[(1S,2S)-2-hydroxycyclohexyl]-6-methylpyridin-3-carboxamide,

(188) 5-{(Z)-2-fluoro-2-[5-(morpholin-4-yl)pyridin-3-yl]vinyl}-N-[(1S,2S)-2-hydroxycyclohexyl]-6-methylpyridin-3-carboxamide,

(189) 5-[(Z)-2-(6-aminopyridin-3-yl)-2-fluorovinyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-6-methylpyridin-3-carboxamide,

(190) 5-[(Z)-2-(2-aminopyrimidin-5-yl)-2-fluorovinyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-6-methylpyridine-3-carboxamide,

(191) 3-[(Z)-2-(6-aminopyridin-3-yl)-2-fluorovinyl]-4-fluoro-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide,

(192) 3-[(Z)-2-(2-aminopyrimidin-5-yl)-2-fluorovinyl]-4-fluoro-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide,

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

(194) 3-[(Z)-2-{5-[(4-ethylpiperazin-1-yl)methyl]pyridin-3-yl}-2-fluorovinyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide,

(195) 5-[(Z)-2-fluoro-2-{5-[(oxecyclobutan-3-yl)amino]pyridin-3-yl}vinyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-6-methylpyridin-3-carboxamide,

(196) 4-Fluoro-3-[(Z)-2-Fluoro-2-{5-[(oxecyclobutan-3-yl)amino]pyridin-3-yl}vinyl]-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide,

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

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

(199) 5-[(Z)-2-{6-[(cyclopropylmethyl)amino]pyridin-3-yl}-2-fluorovinyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-6-methylpyridin-3-carboxamide,

(200) 3-[(Z)-2-fluoro-2-{5-[(4-methylpiperazin-1-yl)methyl]pyridin-3-yl}vinyl]-N-[(1S,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]-4-methylbenzamide,

(201) 3-[(Z)-2-fluoro-2-{5-[(4-methylpiperazin-1-yl)methyl]pyridin-3-yl}vinyl]-N-(2-hydroxy-3,3-dimethylbutyl)-4-methylbenzamide,

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

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

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

(205) 4-Fluoro-3-{(Z)-2-fluoro-2-[2-(methylamino)pyrimidin-5-yl]vinyl}-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide,

(206) 3-[(Z)-2-(5-aminopyrazin-2-yl)-2-fluorovinyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide, and

(207) 4-Fluoro-3-[(Z)-2-fluoro-2-(5-fluoropyridin-3-yl)vinyl]-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide

Or its pharmaceutically acceptable salt or its solvate.

(Project 5)

The compounds described in Item 1 are selected from the following (1) to (15):

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

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

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

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

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

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

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

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

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

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

(11) 5-[(Z)-2-(6-aminopyridin-3-yl)-2-fluorovinyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-6-methylpyridin-3-carboxamide,

(12) 3-[(Z)-2-{5-[(4-ethylpiperazin-1-yl)methyl]pyridin-3-yl}-2-fluorovinyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide,

(13) 4-Fluoro-3-{(Z)-2-fluoro-2-[2-(methylamino)pyrimidin-5-yl]vinyl}-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide,

(14) 3-[(Z)-2-(5-aminopyrazin-2-yl)-2-fluorovinyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide, and

(15) 4-Fluoro-3-[(Z)-2-fluoro-2-(5-fluoropyridin-3-yl)vinyl]-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide

Or its pharmaceutically acceptable salt or its solvate.

(Project 6)

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

(Project 7)

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

(Project 8)

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

Beneficial effects of the invention

Since the compounds of the present invention inhibit PDGF receptor kinase, they can be used as therapeutic agents for diseases involving PDGF receptor kinase, such as respiratory diseases, cancer, smooth muscle proliferative disorders, angiogenesis disorders, autoimmune/inflammatory diseases, metabolic diseases, vascular occlusive diseases, etc.

Detailed Implementation

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

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

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

As for the alkyl portion of "monoalkylamino", "alkylcarbonyloxy", "monoalkylamino", "dialkylamino", "alkylcarbonylamino", "alkylsulfonyl", "aminoalkyl" and "alkylcarbonyl", the same "alkyl" as above may be mentioned.

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

The term "amino" refers to _-NH₂ .

The term "aminoalkyl" refers to a group in which the hydrogen atom of the carbon atom bonded to the aforementioned "alkyl" is replaced by an amino group. Specific examples may include, for example, aminomethyl, 1-aminoethyl, 2-aminoethyl, 1-aminopropyl, 2-aminopropyl, 2-aminopropyl-2-yl, 3-aminopropyl, etc.

The term "monoalkylamino" refers to a group in which one hydrogen atom of the nitrogen atom bonded to the amino group is replaced by the term "alkyl". Specific examples may include methylamino, ethylamino, isopropylamino, etc.

The term "hydroxyalkyl" refers to a group in which the hydrogen atom of the carbon atom bonded to the alkyl group is replaced by a hydroxyl group. Specific examples may include, for example, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1-hydroxypropyl, 2-hydroxypropyl, etc.

The term "alkyl carbonyl" refers to a group in which the aforementioned "alkyl" group is bonded to a carbonyl group. Examples of such groups include, for instance, methyl carbonyl, ethyl carbonyl, propyl carbonyl, isopropyl carbonyl, tert-butyl carbonyl, isobutyl carbonyl, sec-butyl carbonyl, pentyl carbonyl, isopentyl carbonyl, hexyl carbonyl, etc.

The term "halogenated alkyl" refers to a group in which the hydrogen atom of the alkyl group is replaced by a halogen atom. Specific examples may include, for example, fluoromethyl, chloromethyl, fluoroethyl, difluoromethyl, dichloromethyl, difluoroethyl, trifluoromethyl, trichloromethyl, trifluoroethyl, etc.

The term "alkoxy" refers to a group in which the aforementioned "alkyl" is bonded to an oxygen atom. Examples may include, for instance, straight-chain or branched alkoxy groups having 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms. Specific examples may include, for instance, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentoxy, n-hexoxy, etc.

As for the alkoxy portion of "haloalkoxy", the same "alkoxy" as mentioned above can be referred to.

Examples of "aryl" can include, for example, monocyclic to tricyclic aromatic hydrocarbon groups having 6-14 carbon atoms. Specific examples can include phenyl, 1-naphthyl, 2-naphthyl, 1-anthrayl, 2-anthrayl, 9-anthrayl, 1-phenanthyl, 2-phenanthyl, 3-phenanthyl, 4-phenanthyl, 10-phenanthyl, etc. Among them, phenyl is preferred.

Examples of "cycloalkyl" can include monocyclic to tricyclic cyclic non-aromatic hydrocarbon groups. Specific examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

The aforementioned "non-aromatic carbocyclic group" can be a bridged hydrocarbon group. Examples of such bridged hydrocarbon groups may include, for example, the following:

• Bicyclo[2.2.1]heptyl (e.g., bicyclo[2.2.1]hept-1-yl, bicyclo[2.2.1]hept-2-yl and bicyclo[2.2.1]hept-7-yl);

• Bicyclo[1.1.1]pentyl (e.g., bicyclo[1.1.1]pent-1-yl and bicyclo[1.1.1]pent-2-yl);

• Bicyclo[4.1.0]heptyl (e.g., bicyclo[4.1.0]hept-1-yl, bicyclo[4.1.0]hept-2-yl, bicyclo[4.1.0]hept-3-yl and bicyclo[4.1.0]hept-7-yl);

• Bicyclic [2.2.2]octyl (e.g., bicyclic [2.2.2]oct-1-yl and bicyclic [2.2.2]oct-2-yl);

• Bicyclo[3.1.1]heptyl (e.g., bicyclo[3.1.1]hept-1-yl, bicyclo[3.1.1]hept-2-yl, bicyclo[3.1.1]hept-3-yl and bicyclo[3.1.1]hept-6-yl); and

• Cuboalkyl-1-yl.

The aforementioned "non-aromatic carbocyclic group" can be a spirocyclic group. Examples of such spirocyclic groups may include, for example, the following:

• Spiro[3.3]heptyl (e.g., spiro[3.3]hept-1-yl and spiro[3.3]hept-2-yl);

• Spiro[4.4]nonyl (e.g., spiro[4.4]non-1-yl and spiro[4.4]non-2-yl);

• Spiro[5.5]undecyl (e.g., spiro[5.5]undec-1-yl, spiro[5.5]undec-2-yl, and spiro[5.5]undec-3-yl); and

• Spiro[2.5]octyl (e.g., spiro[2.5]oct-1-yl, spiro[2.5]oct-4-yl, spiro[2.5]oct-5-yl and spiro[2.5]oct-6-yl).

Examples of "heteroaryl" can include, for example, monocyclic to tricyclic aromatic rings having 6-14 carbon atoms and 1-3 heteroatoms selected from nitrogen, oxygen, and sulfur atoms as constituent atoms. Specific examples can include, for example, the following:

• Furanyl (e.g., 2-furanyl and 3-furanyl);

• Thiophene group (e.g., 2-thienyl and 3-thienyl);

• Pyrrole (e.g., 1-pyrrole, 2-pyrrole, and 3-pyrrole);

• Imidazolyl (e.g., 1-imidazolyl, 2-imidazolyl, and 4-imidazolyl);

• Pyrazolyl group (e.g., 1-pyrazolyl, 3-pyrazolyl, and 4-pyrazolyl);

• Triazolyl (e.g., 1,2,4-triazol-1-yl, 1,2,4-triazol-3-yl, and 1,2,4-triazol-4-yl);

• Tetrazolyl (e.g., 1-tetrazolyl, 2-tetrazolyl, and 5-tetrazolyl);

• Oxazolyl (e.g., 2-oxazolyl, 4-oxazolyl, and 5-oxazolyl);

• Isoxazolyl (e.g., 3-isooxazolyl, 4-isooxazolyl, and 5-isooxazolyl);

• Oxadiazolyl (e.g., 1,3,4-oxadiazol-2-yl);

• Thiazolyl (e.g., 2-thiazolyl, 4-thiazolyl, and 5-thiazolyl);

• Thiadiazolyl (e.g., 1,3,4-thiadiazolyl, 1,2,4-thiadiazolyl, and 1,2,3-thiadiazolyl);

• Isothiazolyl (e.g., 3-isothiazolyl, 4-isothiazolyl, and 5-isothiazolyl);

• Pyridyl (e.g., 2-pyridyl, 3-pyridyl, and 4-pyridyl);

• Pyridazinyl (e.g., 3-pyridazinyl and 4-pyridazinyl);

• Pyrimidinyl (e.g., 2-pyrimidinyl, 4-pyrimidinyl, and 5-pyrimidinyl);

• Pyrazinyl (e.g., 2-pyrazinyl);

• Benzothiadiazole group (e.g., 1,2,3-benzothiadiazole-4-yl, 1,2,3-benzothiadiazole-5-yl, 2,1,3-benzothiadiazole-4-yl and 2,1,3-benzothiadiazole-5-yl);

• Benzothiazolyl (e.g., benzothiazolyl-2-yl, benzothiazolyl-4-yl, benzothiazolyl-5-yl, benzothiazolyl-6-yl, and benzothiazolyl-7-yl);

• Indole (e.g., indole-3-yl, indole-4-yl, indole-5-yl, indole-6-yl, and indole-7-yl);

• Benzothiophene group (e.g., 1-benzothiophene-2-yl, 1-benzothiophene-3-yl, 1-benzothiophene-4-yl, 1-benzothiophene-5-yl, 1-benzothiophene-6-yl and 1-benzothiophene-7-yl);

• 1,1-Dioxo-1-benzothiophene (e.g., 1,1-dioxo-1-benzothiophene-2-yl, 1,1-dioxo-1-benzothiophene-3-yl, 1,1-dioxo-1-benzothiophene-4-yl, 1,1-dioxo-1-benzothiophene-5-yl, 1,1-dioxo-1-benzothiophene-6-yl and 1,1-dioxo-1-benzothiophene-7-yl);

• Quinolinyl (quinolin-2-yl, quinolin-3-yl, quinolin-4-yl, quinolin-5-yl, quinolin-6-yl, quinolin-7-yl, and quinolin-8-yl); and

· 1,3-Benzoxazol-2-yl.

Examples of "heterocyclic alkyl" can include cyclic non-aromatic heterocyclic groups having one or more rings and having one or more heteroatoms selected from nitrogen, oxygen, and sulfur atoms in the rings, wherein the heteroatoms may be the same or different from each other. Specific examples may include, for example, the following:

• Oxycyclic butyl groups (e.g., 2-oxycyclic butyl and 3-oxycyclic butyl groups);

• Azacyclic butyl groups (e.g., 2-azacyclic butyl and 3-azacyclic butyl);

• Tetrahydropyranyl (e.g., 2-tetrahydropyranyl, 3-tetrahydropyranyl, and 4-tetrahydropyranyl);

• 1,4-Dioxacyclohexyl (e.g., 1,4-dioxacyclohexane-2-yl);

• 1,3-Dioxanehexyl groups (e.g., 1,3-dioxane-2-yl, 1,3-dioxane-4-yl, and 1,3-dioxane-5-yl);

• Pyrrolidinyl (e.g., 1-pyrrolidinyl, 2-pyrrolidinyl, and 3-pyrrolidinyl);

• Piperidinyl (e.g., 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, and 4-piperidinyl);

• Piperazinyl (e.g., 1-piperazinyl, 2-piperazinyl, and 3-piperazinyl);

• Azaheptanyl groups (e.g., 1-azaheptanyl, 2-azaheptanyl, 3-azaheptanyl, and 4-azaheptanyl);

• Azacyclic octyl groups (e.g., 1-azacyclic octyl, 2-azacyclic octyl, 3-azacyclic octyl, 4-azacyclic octyl, and 5-azacyclic octyl);

• High-piperidinyl groups (e.g., 2-high-piperidinyl, 3-high-piperidinyl, and 4-high-piperidinyl);

• Morpholinyl (e.g., 2-morpholinyl, 3-morpholinyl, and 4-morpholinyl);

• Thiomorpholino (e.g., 2-thiomorpholino, 3-thiomorpholino, and 4-thiomorpholino); and

Tetrahydrofuranyl (2-tetrahydrofuranyl and 3-tetrahydrofuranyl).

The aforementioned "heterocyclic alkyl" can be a bridged cyclic group. Examples of such bridged cyclic groups may include, for example, the following:

• 3-azabicyclo[3.2.1]octyl (e.g., 3-azabicyclo[3.2.1]oct-1-yl, 3-azabicyclo[3.2.1]oct-2-yl, 3-azabicyclo[3.2.1]oct-3-yl, 3-azabicyclo[3.2.1]oct-6-yl and 3-azabicyclo[3.2.1]oct-8-yl);

• Quinine cycloyl groups (e.g., quinine cyclo-2-yl, quinine cyclo-3-yl, and quinine cyclo-4-yl); and

• 6-oxa-3-azabicyclo[3.1.1]heptyl (e.g., 6-oxa-3-azabicyclo[3.1.1]hept-1-yl, 6-oxa-3-azabicyclo[3.1.1]hept-2-yl, 6-oxa-3-azabicyclo[3.1.1]hept-3-yl and 6-oxa-3-azabicyclo[3.1.1]hept-7-yl).

The aforementioned "heterocyclic alkyl" can be a spirocyclic group. Examples of such spirocyclic groups may include, for example, the following:

• 6-azaspiro[2.5]oct-1-yl (e.g., 6-azaspiro[2.5]oct-1-yl, 6-azaspiro[2.5]oct-4-yl and 6-azaspiro[2.5]oct-5-yl);

• 3,9-diazaspiro[5.5]undecane-1-yl (e.g., 3,9-diazaspiro[5.5]undecane-1-yl, 3,9-diazaspiro[5.5]undecane-2-yl and 3,9-diazaspiro[5.5]undecane-3-yl);

• 2,7-diazaspiro[3.5]non-1-yl (e.g., 2,7-diazaspiro[3.5]non-1-yl, 2,7-diazaspiro[3.5]non-2-yl, 2,7-diazaspiro[3.5]non-5-yl, 2,7-diazaspiro[3.5]non-6-yl and 2,7-diazaspiro[3.5]non-7-yl);

• 7-azaspiro[3.5]nonyl (7-azaspiro[3.5]non-1-yl, 7-azaspiro[3.5]non-2-yl, 7-azaspiro[3.5]non-5-yl and 7-azaspiro[3.5]non-6-yl); and

• 2,5-diazabicyclo[2.2.1]heptyl (2,5-diazabicyclo[2.2.1]hept-1-yl, 2,5-diazabicyclo[2.2.1]hept-2-yl, 2,5-diazabicyclo[2.2.1]hept-3-yl and 2,5-diazabicyclo[2.2.1]hept-7-yl).

The following will describe each symbol in expression [1].

In formula [1], ^R1 is a hydrogen atom, a halogen atom, a _C1 - _C6 alkyl, a _C1 - _C6 haloalkyl, a _C2 - _C6 alkenyl, a _C2 - _C6 haloalkenyl, a _C2 - _C6 alkynyl, a _C2 - _C6 haloalkynyl, a _C1 - _C6 alkoxy, a hydroxyl group, a carboxyl group, an alkyl carbonyloxy group, an amino group, a monoalkylamino group, a dialkylamino group, an alkyl carbonylamino group, a nitro group, an optionally substituted _C3 - _C6 cycloalkyl, an optionally substituted _C3 - _C6 cycloalkenyl, an optionally substituted heterocyclic alkyl, an optionally substituted aryl, or an optionally substituted heteroaryl.

It is preferably a hydrogen atom, a halogen atom, a _C1 - _C6 alkyl, a _C2 - _C6 alkenyl, an amino, a monoalkylamino, a dialkylamino, an alkylcarbonylamino, an optionally substituted _C3 - _C6 cycloalkyl, an optionally substituted heterocycloalkyl, an optionally substituted aryl, or an optionally substituted heteroaryl.

More preferably, it is a optionally substituted heterocyclic alkyl, optionally substituted aryl, or optionally substituted heteroaryl.

It is further preferably oxacyclobutyl, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, piperidinyl, piperazineyl, phenyl, pyridinyl, pyrimidinyl, pyrazineyl, isoquinolinyl, thiophenyl, pyrazolyl, imidazo[1,2-a]pyrazineyl, 1,2,3-triazolyl or imidazo[1,2-b]pyridazineyl.

R ² is a bonding hand, -(CR ^a R ^b ) _m -NR ^c -, -NR ^c -(CR ^a R ^b ) _m -, -(CR ^a R ^b ) _m -O-, -O-(CR ^a R ^b ) _m -, -(CR ^a R ^b ) _m -, -NR ^c -, -O-, -NR ^c -CO-NR ^c -, -CR ^a =CR ^b - or -C≡C-.

The preferred bonding elements are -(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-.

More preferably, it is a bonding hand, -(CR ^a R ^b ) _m -NR ^c - or -NR ^c -.

^Ra in ^R2 is a hydrogen atom, a halogen atom, a _C1 - _C6 alkyl group, or a _C1 - _C6 haloalkyl group.

It is preferably a hydrogen atom, or a carbon atom bonded to ^Ra and ^Rb to form C=O.

^Rb in ^R2 is a hydrogen atom, a halogen atom, a _C1 - _C6 alkyl group, or a _C1 - _C6 haloalkyl group.

It is preferably a hydrogen atom, or a carbon atom bonded to ^Ra and ^Rb to form C=O.

Each ^Rc in ^R2 is independently a hydrogen atom, a _C1 - _C6 alkyl group, or a _C1 - _C6 haloalkyl group.

It is preferably composed of hydrogen atoms.

Het consists of 5 to 10 heteroaryl groups.

It is preferably thiazolyl, pyridinyl, 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, pyrazo[1,5-a]pyrimidinyl, 3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazinyl, pyrazo[5,1-b]thiazolyl, pyrazo[3,4-b]pyridinyl, or pyrazo[1,5-a]pyridinyl.

More preferably, it is thiazolyl, pyridinyl, or pyrimidinyl.

L ¹ is the bonding hand, -(CR ^a R ^b ) _m -NR ^c -, -NR ^c -(CR ^a R ^b ) _m -, -(CR ^a R ^b ) _m -O-, -O-(CR ^a R ^b ) _m -, -(CR ^a R ^b ) _m -, -NR ^c -, -O-, -NR ^c -CO-NR ^c -, -CR ^a =CR ^b - or -C≡C-.

It is preferably a bonding hand, -(CR ^a R ^b ) _m -NR ^c -, -NR ^c -(CR ^a R ^b ) _m -, -(CR ^a R ^b ) _m -O-, -O-(CR ^a R ^b ) _m -, -(CR ^a R ^b ) _m -, -NR ^c -, -CR ^a =CR ^b - or -C≡C-.

It is further preferred to be -(CR ^a R ^b ) _m -NR ^c -, -NR ^c -(CR ^a R ^b ) _m -, -NR ^c -, -CR ^a =CR ^b - or -C≡C-.

In ^L1 , ^Ra is a hydrogen atom, a halogen atom, a _C1 - _C6 alkyl or _C1 - _C6 haloalkyl, or a carbon atom bonded to ^Ra and ^Rb to form C=O.

It is preferably a hydrogen atom, a halogen atom, or a _C1 - _C6 alkyl group, or it can form C=O together with carbon atoms bonded to ^Ra and ^Rb .

In ^L1 , ^Rb is a hydrogen atom, a halogen atom, a _C1 - _C6 alkyl or _C1 - _C6 haloalkyl, or a carbon atom bonded to ^Ra and ^Rb to form C=O.

It is preferably a hydrogen atom, or a carbon atom bonded to ^Ra and ^Rb to form C=O.

Each ^Rc in ^L1 is independently a hydrogen atom, a _C1 - _C6 alkyl group, or a _C1 - _C6 haloalkyl group.

It is preferably a hydrogen atom or a _C1 - _C6 alkyl group.

A hydrogen atom is preferred.

L ² is -(CR ^a R ^b ) _m -NR ^c -, -NR ^c -(CR ^a R ^b ) _m -, -(CR ^a R ^b ) _m -O-, -O-(CR ^a R ^b ) _m -, -(CR ^a R ^b ) _m -, -NR ^c -, -O-, -NR ^c -CO-NR ^c -, -CR ^a =CR ^b - or -C≡C-.

It is preferably a bonding agent, -(CR ^a R ^b ) _m -NR ^c - or -NR ^c -CO-NR ^c -.

More preferably, it is a bonding hand or -(CR ^a R ^b ) _m -NR ^c -.

In ^L2 , ^Ra is a hydrogen atom, a halogen atom, a _C1 - _C6 alkyl or _C1 - _C6 haloalkyl, or forms C=O together with ^Rb and the carbon atoms they are bonded to.

In ^L2 , ^Ra preferably forms C=O together with ^Rb and the carbon atoms they are bonded to.

^Rb in ^L2 is a hydrogen atom, a halogen atom, a _C1 - _C6 alkyl or _C1 - _C6 haloalkyl, or forms C=O together with ^Ra and the carbon atoms they are bonded to.

In ^L2 , ^Rb preferably forms C=O together with ^Ra and the carbon atoms they are bonded to.

^Rc in ^L2 is a hydrogen atom, a _C1 - _C6 alkyl group, or a _C1 - _C6 haloalkyl group.

Preferably, each ^Rc in ^L2 is an independent hydrogen atom.

^R4 is a hydrogen atom, a halogen atom, or a methyl group.

It is preferably a halogen atom or a methyl group.

^R5 is a hydrogen atom, a halogen atom, a hydroxyl group, an amino group, a _C1 - _C6 alkyl group, a _C1 - _C6 haloalkyl group, a _C1 - _C6 alkoxy group, or a _C1 - _C6 haloalkoxy group.

It is preferably hydroxyl.

^R6 is a hydrogen atom, a halogen atom, a _C1 - _C6 alkyl group, a _C1 - _C6 haloalkyl group, or an optionally substituted phenyl group.

^R7 is a hydrogen atom, a halogen atom, a _C1 - _C6 alkyl group, a _C1 - _C6 haloalkyl group, a hydroxyalkyl group, an optionally substituted phenyl group, or a _C3 - _C6 cycloalkyl group.

Alternatively, ^R6 and ^R7 together with the carbon atoms they are bonded to form _C3 - _C6 cycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl.

^R6 is preferably a hydrogen atom, a _C1 - _C6 alkyl group, or an optionally substituted phenyl group.

^R7 is preferably a _C1 - _C6 alkyl, hydroxyalkyl, or optionally substituted phenyl.

Alternatively, ^R6 and ^R7 preferably form a _C3 - _C6 cycloalkyl or optionally substituted aryl group together with the carbon atoms they are bonded to.

^R6 and ^R7 are further preferred to form _C3 - _C6 cycloalkyl groups together with the carbon atoms they are bonded to.

More specifically, the compounds of the present invention include those shown in Table 1 below, depending on the type of ^L1 .

[Table 1]

(In the table, ^R1 , ^R2 , ^R4 , ^R5 , ^R6 , ^R7 , ^Rc , ^L1 , ^L2 , and Het are defined as above.)

· 1-A: compound [1], wherein L ¹ is -(CR ^a R ^b ) _m -NR ^c -, m is 1, and ^Ra and R ^b together with the carbon atoms they are bonded to form C=O.

· 1-B: compound [1], where L ¹ is -C≡C-.

· 1-C: compound [1], wherein L ¹ is -NR ^c -(CR ^a R ^b ) _m -, m is 1, and ^Ra and R ^b together with the carbon atoms they are bonded to form C=O.

· 1-D: compound [1], where L ¹ is -NR ^c -.

· 1-E: compound [1], wherein L ¹ is -(CR ^a R ^b ) _m -NR ^c -, m is 1, and ^Ra and R ^b are each hydrogen atoms.

· 1-F: compound [1], wherein L ¹ is -NR ^c -(CR ^a R ^b ) _m -, m is 1, and ^Ra and R ^b are each hydrogen atoms.

[Table 2]

(In the table, ^R1 , ^R2 , ^R4 , ^R5 , ^R6 , ^R7 , ^Rc , ^L1 , ^L2 , and Het are defined as above.)

· 1-G: compound[1], wherein L ¹ is -(CR ^a R ^b ) _m -O-, m is 1, and ^Ra and R ^b are each hydrogen atoms.

· 1-H: compound[1], wherein L ¹ is -O-(CR ^a R ^b ) _m -, m is 1, and ^Ra and R ^b are each hydrogen atoms.

· 1-I: compound [1], wherein L ¹ is -CR ^a =CR ^b - and ^Ra and R ^b are each H.

· 1-J: compound [1], wherein L ¹ is -(CR ^a R ^b ) _m -, m is 2, and ^Ra and R ^b are each H.

· 1-K: compound[1], where L ¹ is -CR ^a =CR ^b -, ^Ra is a halogen atom, and R ^b is H.

^R1 in compound 1-A is preferably H, a halogen atom, _C1 - _C6 alkyl, _C2 - _C6 alkenyl, _C1 - _C6 alkoxy, amino, alkylcarbonylamino, optionally substituted _C3 - _C6 cycloalkyl, optionally substituted heterocyclic alkyl, optionally substituted aryl or optionally substituted heteroaryl, and more preferably _C1 - _C6 alkyl, _C1 - _C6 alkoxy, optionally substituted _C3 - _C6 cycloalkyl, optionally substituted heterocyclic alkyl, optionally substituted aryl or optionally substituted heteroaryl.

In compound 1-A, ^R2 is preferably a bonding member, -(CR ^a R ^b ) _m -NR ^c -, -(CR ^a R ^b ) _m -O-, -(CR ^a R ^b ) _m -, -NR ^c -, -O- or -CR ^a =CR ^b -, and more preferably a bonding member, -(CR ^a R ^b ) _m -NR ^c -, -(CR ^a R ^b ) _m -O-, -(CR ^a R ^b ) _m -, -NR ^c - or -O-.

In compound 1-A, the m of R ² is preferably 0, 1 or 2, and more preferably 0 or 1.

The Het in compound 1-A is preferably thiazolyl, pyridinyl, oxazolyl or imidazothiazolyl, and more preferably thiazolyl or pyridinyl.

In compound 1-A, ^R4 is preferably a halogen atom or a methyl group, and more preferably a methyl group.

In compound 1-A ^{, L2} is preferably -(CR ^a R ^b ) _m -NR ^c -.

In compound 1-A, the m of L ² is preferably 1.

^R5 in compound 1-A is preferably a hydroxyl group.

In compound 1-A, ^R6 is preferably H or _C1 - _C6 alkyl, or together with ^R7 and the carbon atoms bonded thereto form _C3 - _C6 cycloalkyl, and more preferably together with ^R7 and the carbon atoms bonded thereto form _C3 - _C6 cycloalkyl.

In compound 1-A, ^R7 is preferably a _C1 - _C6 alkyl or optionally substituted phenyl, or forms a _C3 - _C6 cycloalkyl with ^R6 and the carbon atoms thereto, and more preferably forms a _C3 - _C6 cycloalkyl with ^R6 and the carbon atoms thereto.

^R1 in compound 1-B is preferably H, a halogen atom, a _C1 - _C6 alkyl, an amino, an optionally substituted _C3 - _C6 cycloalkyl, an optionally substituted aryl or an optionally substituted heteroaryl, and more preferably a halogen atom, an optionally substituted _C3 - _C6 cycloalkyl, an optionally substituted aryl or an optionally substituted heteroaryl.

In compound 1-B ^{, R2} is preferably a bonding chirp or -(CR ^a R ^b ) _m -NR ^c -, and more preferably a bonding chirp.

In compound 1-B, the m of R ² is preferably 0 or 1.

The Het in compound 1-B is preferably pyridyl or pyrazinyl.

In compound 1-B, ^R4 is preferably a halogen atom or a methyl group, and more preferably a methyl group.

In compound 1-B ^{, L2} is preferably -(CR ^a R ^b ) _m -NR ^c -.

In compound 1-B, the m of L ² is preferably 1.

In compound 1-B, ^R5 is preferably a hydroxyl group.

In compound 1-B, ^R6 is preferably an optionally substituted phenyl group, or together with ^R7 and the carbon atoms bonded thereto form a _C3 - _C6 cycloalkyl group, and more preferably together with ^R7 and the carbon atoms bonded thereto form a _C3 - _C6 cycloalkyl group.

In compound 1-B, ^R7 is preferably a hydroxyalkyl group, or together with ^R6 and the carbon atoms bonded thereto form a _C3 - _C6 cycloalkyl group, and more preferably together with ^R6 and the carbon atoms bonded thereto form a _C3 - _C6 cycloalkyl group.

^R1 in compound 1-C is preferably H, a halogen atom, a _C1 - _C6 alkyl, a _C2 - _C6 alkenyl, a _C1 - _C6 alkoxy, an amino, an alkylcarbonylamino, an optionally substituted _C3 - _C6 cycloalkyl, an optionally substituted heterocyclic alkyl, an optionally substituted aryl or an optionally substituted heteroaryl, and more preferably an optionally substituted aryl.

^R2 in compound 1-C is preferably a bonding member, -(CR ^a R ^b ) _m -NR ^c -, -(CR ^a R ^b ) _m -O-, -(CR ^a R ^b ) _m -, -NR ^c -, -O- or -CR ^a =CR ^b -, and more preferably a bonding member.

The Het in compound 1-C is preferably thiazolyl, pyridinyl, oxazolyl or imidazothiazolyl, and more preferably pyridinyl.

In compound 1-C, R ⁴ is preferably a halogen atom or a methyl group, and more preferably a methyl group.

^R5 in compound 1-C is preferably a hydroxyl group.

^R6 in compound 1-C is preferably H or _C1 - _C6 alkyl, or together with ^R7 and the carbon atoms bonded thereto form _C3 - _C6 cycloalkyl, and more preferably together with ^R7 and the carbon atoms bonded thereto form _C3 - _C6 cycloalkyl.

^R7 in compound 1-C is preferably a _C1 - _C6 alkyl or optionally substituted phenyl, or forms a _C3 - _C6 cycloalkyl with ^R6 and the carbon atoms thereto, and more preferably forms a _C3 - _C6 cycloalkyl with ^R6 and the carbon atoms thereto.

^R1 in compound 1-D is preferably H, a halogen atom, a _C1 - _C6 alkyl, a _C2 - _C6 alkenyl, a _C1 - _C6 alkoxy, a monoalkylamino, an optionally substituted _C3 - _C6 cycloalkyl, an optionally substituted heterocycloalkyl, an optionally substituted aryl or an optionally substituted heteroaryl, and more preferably a monoalkylamino or an optionally substituted heteroaryl.

^R2 in compound 1-D is preferably a bonding member, -(CR ^a R ^b ) _m -NR ^c -, -(CR ^a R ^b ) _m -O-, -(CR ^a R ^b ) _m -, -NR ^c -, -O- or -CR ^a =CR ^b -, and more preferably a bonding member.

The Het in compound 1-D is preferably pyrimidinyl, pyridinyl, or quinazolinyl, and more preferably pyrimidinyl.

In compound 1-D, R ⁴ is preferably a halogen atom or a methyl group, and more preferably a methyl group.

^R5 in compound 1-D is preferably a hydroxyl group.

In compound 1-D ^{, R6} is preferably an optionally substituted aryl group, or together with ^R7 and the carbon atoms bonded thereto form a _C3 - _C6 cycloalkyl group, and more preferably together with ^R7 and the carbon atoms bonded thereto form a _C3 - _C6 cycloalkyl group.

In compound 1-D ^{, R7} is preferably a hydroxyalkyl or optionally substituted phenyl, or forms a _C3 - _C6 cycloalkyl group together with ^R6 and the carbon atoms bonded thereto, and more preferably forms a _C3 - _C6 cycloalkyl group together with ^R6 and the carbon atoms bonded thereto.

^R1 in compounds 1-E is preferably 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, hydroxyl, carboxyl, alkylcarbonyloxy, amino, aminoalkyl, monoalkylamino, dialkylamino _, alkylcarbonylamino, nitro, optionally substituted _C3 - _C6 cycloalkyl, optionally substituted _C3 - _C6 cycloalkenyl, optionally substituted heterocyclic alkyl, optionally substituted aryl or optionally substituted heteroaryl, and more preferably H, amino, optionally substituted _C3 - _C6 cycloalkyl, optionally substituted heterocyclic alkyl, optionally substituted aryl or optionally substituted heteroaryl.

In compound 1-E ^{, R2} is preferably a bonding chirp, -(CR ^a R ^b ) _m -NR ^c -, -NR ^c -, -NR ^c -CO-NR ^c - or -C≡C-, and more preferably a bonding chirp, -(CR ^a R ^b ) _m -NR ^c - or -NR ^c -.

In compound 1-E, the m of R ² is preferably 0 or 1.

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

In compound 1-E, R ⁴ is preferably H, a halogen atom, or a methyl group, and more preferably a halogen atom or a methyl group.

In compound 1-E, ^L2 is preferably -(CR ^a R ^b ) _m -NR ^c -.

In compound 1-E, the m of L ² is preferably 1.

In compound 1-E, ^R5 is preferably a hydroxyl group.

In compound 1-E, ^R6 more preferably forms a _C3 - _C6 cycloalkyl group together with ^R7 and the carbon atoms they are bonded to.

In compound 1-E, ^R7 more preferably forms a _C3 - _C6 cycloalkyl group together with ^R6 and the carbon atoms they are bonded to.

^R1 in compounds 1-F is preferably a halogen atom, an optionally substituted _C3 - _C6 cycloalkyl group, an optionally substituted aryl group, or an optionally substituted heteroaryl group, and more preferably an optionally substituted _C3 - _C6 cycloalkyl group, an optionally substituted aryl group, or an optionally substituted heteroaryl group.

In compound 1-F, ^R2 is preferably a bonding chiral or -C≡C-, and is more preferably a bonding chiral.

In compound 1-F, Het is preferably pyridyl or pyrazinyl, and more preferably pyridyl.

In compound 1-F, ^R4 is preferably H, a halogen atom, or a methyl group, and more preferably H or a methyl group.

In compound 1-F, ^L2 is preferably -(CR ^a R ^b ) _m -NR ^c - or -NR ^c -CO-NR ^c -.

In compound 1-F, the m of L ² is preferably 1.

In compound 1-F, ^R5 is preferably a hydroxyl group.

In compounds 1-F, ^R6 is preferably an optionally substituted phenyl group, or forms a _C3 - _C6 cycloalkyl group together with ^R7 and the carbon atoms bonded thereto, and more preferably forms a _{C3-C6 cycloalkyl group together with R7 and} ^the carbon atoms bonded thereto.

In compounds 1-F, ^R7 is preferably a hydroxyalkyl group, or together with ^R6 and the carbon atoms bonded thereto form a _C3 - _C6 cycloalkyl group, and more preferably together with ^R6 and the carbon atoms bonded thereto form a _C3 - _C6 cycloalkyl group.

In compound 1-G ^{, R1} is preferably an optionally substituted aryl or optionally substituted heteroaryl, and more preferably an optionally substituted heteroaryl.

^R2 in compound 1-G is preferably a bonding member.

In compound 1-G, Het is preferably a pyridyl group.

In compound 1-G, ^R4 is preferably H, a halogen atom, or a methyl group, and more preferably a halogen atom or a methyl group.

In compound 1-G, ^R5 is preferably a hydroxyl group.

In compound 1-G ^{, R6} preferably forms a _C3 - _C6 cycloalkyl group together with ^R7 and the carbon atoms they are bonded to.

In compound 1-G ^{, R7} preferably forms a _C3 - _C6 cycloalkyl group together with ^R6 and the carbon atoms they are bonded to.

^R1 in compound 1-H is preferably an optionally substituted heteroaryl group.

^R2 in compound 1-H is preferably a bonding member.

The Het in compound 1-H is preferably a pyridinyl group.

^R4 in compound 1-H is preferably a halogen atom or a methyl group, and more preferably a methyl group.

^R5 in compound 1-H is preferably a hydroxyl group.

In compound 1-H ^{, R6} preferably forms a _C3 - _C6 cycloalkyl group together with ^R7 and the carbon atoms they are bonded to.

In compound 1-H ^{, R7} preferably forms a _C3 - _C6 cycloalkyl group together with ^R6 and the carbon atoms they are bonded to.

In compound 1-I, ^R1 is preferably an aryl group with optional substitution.

^R2 in compound 1-I is preferably a bonding member.

In compound 1-I, Het is preferably pyridyl.

^R4 in compound 1-I is preferably methyl.

In compound 1-I, R ⁵ is preferably a hydroxyl group.

In compound 1-I ^{, R6} preferably forms a _C3 - _C6 cycloalkyl group together with ^R7 and the carbon atoms they are bonded to.

In compound 1-I ^{, R7} preferably forms a _C3 - _C6 cycloalkyl group together with ^R6 and the carbon atoms they are bonded to.

^R1 in compound 1-J is preferably an aryl group with optional substitution.

^R2 in compound 1-J is preferably a bonding member.

In compound 1-J, Het is preferably pyridinyl.

^R4 in compound 1-J is preferably methyl.

^R5 in compound 1-J is preferably a hydroxyl group.

In compounds 1-J ^{, R6} preferably forms a _C3 - _C6 cycloalkyl group together with ^R7 and the carbon atoms they are bonded to.

In compounds 1-J ^{, R7} preferably forms a _C3 - _C6 cycloalkyl group together with ^R6 and the carbon atoms they are bonded to.

^R1 in compound 1-K is preferably H, a halogen atom, an amino group, a monoalkylamino group, a dialkylamino group, an optionally substituted cycloalkyl group, an optionally substituted heterocycloalkyl group, or an optionally substituted heteroaryl group, and more preferably a halogen atom, an amino group, an optionally substituted cycloalkyl group, an optionally substituted heterocycloalkyl group, or an optionally substituted heteroaryl group.

^R2 in compound 1-K is preferably a bonding chirp, -(CR ^a R ^b ) _m -NR ^c -, -(CR ^a R ^b ) _m -O-, -(CR ^a R ^b ) _m - or -NR ^c -, and more preferably a bonding chirp, -(CR ^a R ^b ) _m -NR ^c -, -(CR ^a R ^b ) _m - or -NR ^c -.

The Het in compound 1-K is preferably pyridinyl, pyrimidinyl, pyrazinyl or imidazo[1,2-b]pyridazinyl, and more preferably pyridinyl, pyrimidinyl or pyrazinyl.

^R4 in compound 1-K is preferably a halogen atom or a methyl group.

In compound 1-K ^{, L2} is preferably -(CR ^a R ^b ) _m -NR ^c -.

In compound 1-K, the m of L ² is preferably 1.

^R5 in compound 1-K is preferably a hydroxyl group.

In compound 1-K ^{, R6} is preferably a _C1 - _C6 alkyl group, or together with ^R7 and the carbon atoms bonded thereto, it forms a _C3 - _C6 cycloalkyl group or an optionally substituted aryl group, and more preferably together with ^R7 and the carbon atoms bonded thereto, it forms a _C3 - _C6 cycloalkyl group.

^R7 in compound 1-K is preferably a _C1 - _C6 alkyl group, or a _C3 - _C6 cycloalkyl group or optionally substituted aryl group together with ^R6 and the carbon atoms bonded thereto, and more preferably a _C3 - _C6 cycloalkyl group together with ^R6 and the carbon atoms bonded thereto.

The compounds of the present invention can be produced, for example, from known compounds or readily synthesizable intermediates, according to the methods described below, the examples described later, or known methods. In the production of the compounds of the present invention, when the starting material has substituents that affect the reaction, the reaction is typically carried out after the starting material has been protected with a suitable protecting group by a known method. After the reaction, the protecting group can be removed by a known method.

Compounds represented by formula [1] can be used as pharmaceuticals, but can also be prepared by known methods into pharmaceutically acceptable salts, solvates, or salts of solvates. Examples of pharmaceutically acceptable salts include, for example, salts formed with inorganic acids (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid); salts formed with organic acids (e.g., acetic acid, malic acid, lactic acid, citric acid, tartaric acid, maleic acid, succinic acid, fumaric acid, p-toluenesulfonic acid, benzenesulfonic acid, and methanesulfonic acid); salts formed with alkali metals (e.g., lithium, potassium, and sodium); salts formed with alkaline earth metals (e.g., magnesium and calcium); and salts formed with organic bases (e.g., ammonium salts). These salts can be formed by methods of common practice.

For example, when the compound of the present invention is a hydrochloride, it can be obtained by dissolving the compound represented by formula [1] in an alcoholic 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 an ether solution of hydrogen chloride.

In the compounds of this invention, for those having asymmetric carbons, their respective stereoisomers and mixtures thereof are included in this invention. For example, stereoisomers can be produced by optically resolving them from the racemic mixture using an optically active acid (tartaric acid, dibenzoyltartaric acid, mandelic acid, 10-camphorsulfonic acid, etc.) according to known methods, utilizing their basicity, or by using a pre-prepared optically active compound as a starting material. Furthermore, stereoisomers can also be produced by optical resolution using chiral columns or by asymmetric synthesis.

The compounds of this invention are not limited to specific isomers, but include all possible isomers and racemates.

(Method for producing the compounds of the present invention)

For example, the compounds of the present invention can be produced from compounds known per se or intermediates readily prepared from known compounds, according to the methods described below, the examples described later, or known methods.

If the solvents, reagents, and raw materials used in the steps of the following production methods are commercially available, such commercially available products can be used as is. Additionally, the obtained compound and the raw materials used in the steps of the following production methods can form a salt, and can be converted to another type of salt or a free form by known methods. Alternatively, when the obtained compound or the raw materials used in the steps of the following production methods are in a free form, they can be converted to the desired salt by known methods. Examples of such salts may include salts similar to those used in the compounds of the present invention described above.

The compounds of the present invention represented by formula [1] or their pharmaceutically acceptable salts can form solvates (e.g., hydrates, etc.) and/or crystalline polymorphs, and the present invention also includes various types of such solvates and crystalline polymorphs. For “solvate,” the compound represented by formula [1] can be coordinated with any number of solvent molecules (e.g., water molecules, etc.). By keeping the compound represented by formula [1] or its pharmaceutically acceptable salt in the atmosphere, it absorbs water, and the adsorbed water can adhere to it or can form hydrates. Additionally, its crystalline polymorphs can be formed by recrystallizing the compound represented by formula [1] or its pharmaceutically acceptable salts.

In the production of the compounds of the present invention, where the starting material has substituents that can affect the reaction, a protecting group can be introduced into the substituents beforehand by known methods, and the target compound can be obtained by removing the protecting group as needed after the reaction. To introduce and remove such a protecting group, suitable conditions can be selected, for example, as shown in Wuts and Greene, "Greene's Protective Groups in Organic Synthesis", 4th edition, John Wiley & Sons Inc., 2006; or P. J. Kocienski, "Protecting Groups", 3rd edition, Thieme, 2005.

The compounds obtained in the steps of the following production methods can be separated or purified using conventional methods (e.g., solvent extraction, concentration, distillation, sublimation, recrystallization, reprecipitation, and chromatography). Alternatively, the compounds can be used as a reaction mixture or crude product in subsequent steps.

Unless otherwise stated, the reactions in the following production methods are based on, for example, R. C. Larock, "Comprehensive Organic Transformations: A Guide to Functional Group Preparations", 2nd ed., John Wiley & Sons, Inc., 1999; The Chemical Society of Japan, "Experimental Chemistry", 4th ed., Maruzen, 1992; L. Kuerti and B. Czako, "Strategic Applications". The well-known methods described in "Of Named Reactions in Organic Synthesis", translated by Kiyoshi Tomioka, Kagaku-Dojin Publishing Company, Inc., 2006; and G. S. Zweifel and M.H. Nantz, "Modern Organic Synthesis: An Introduction", translated by Tamejiro Hiyama, Kagaku-Dojin Publishing Company, Inc., 2009, or methods that are similar in manner to those described in the embodiments, may be modified or combined as appropriate.

The compounds of the present invention described above

(1-A: where L ¹ is -(CR ^a R ^b ) _m -NR ^c - and ^Ra and R ^b together with the carbon atoms they are bonded to form a C=O compound;

1-B: where ^L1 is a compound of -C≡C-.

1-C: where L ¹ is -NR ^c -(CR ^a R ^b ) _m - and ^Ra and R ^b together with the carbon atoms they are bonded to form a C=O compound;

1-D: where ^L1 is a compound of -NR ^c- ;

1-E: Where ^L1 is -( ^CRaRb ) _m - ^NRc- and ^Ra and ^Rb are each independently H, halogen atom ^, _C1 - _C6 alkyl or _C1 - _C6 haloalkyl;

1-F: where ^L1 is a compound in ^{which NRc-} ( ^CRaRb ) _m- and ^Ra and ^Rb are each independently H, halogen atom, _C1 - _C6 alkyl or C1 _{- C6} haloalkyl;

1-G: Compounds in which ^L1 is -( ^CRaRb ) _m - ^O- and ^Ra and ^Rb are each independently H, halogen atom, _C1 - _C6 alkyl or _C1 - _C6 haloalkyl;

¹ -H: Compounds in which ^L1 is -O-( ^CRaRb ) _m- and ^Ra and ^Rb are each independently H, halogen atom, _C1 - _C6 alkyl or _C1 - _C6 haloalkyl;

1-I: where L ¹ is a compound of -CR ^a =CR ^b - and ^Ra and R ^b are each H;

¹ -J: where ^L1 is a compound of -( ^CRaRb ) _m- and ^Ra and ^Rb are each H; and

1-K: where ^L1 is a compound of ^-CRa = ^CRb- , ^Ra is a halogen atom and ^Rb is H.

For example, it can be produced using the general synthetic methods shown below. Extraction, purification, and other processes can be performed in routine organic chemistry experiments.

Method for producing compound [1-A]

[Equation 2]

(In the formula, ^R1 , ^R2 , ^R4 , ^R5 , ^R6 , ^R7 , ^Rc , Het, and X are defined as above.)

Step 1

This step is a process of obtaining compound 1-A by condensing compound 1 or its reactive compound and amine compound 2 in the presence of a condensing agent.

Examples of reactive compounds of compound 1 may include those commonly used in amide condensation reactions, such as acyl halides (e.g., acyl chlorides and acyl bromides), mixed acid anhydrides, imidazoles, and active amides.

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

Examples of condensing agents used in this step include, for example, 1,1'-carbonyldiimidazole (hereinafter “CDI”), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (hereinafter “EDCI”), diisopropylcarbodiimide (hereinafter “DIC”), diethyl cyanophosphate, O-(benzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate (hereinafter “HBTU”), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate (hereinafter “HATU”), etc.

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

Appropriately, the amount of such a base relative to compound 1 should be in the range of 1 to 10 molar equivalents.

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

When using the above-mentioned additive in this step, it is appropriate that the amount of such additive relative to compound 1 be in the range of 0.1 molar equivalents to 3 molar equivalents.

Although there are no particular restrictions on the solvents used, as long as they do not participate in the reaction, examples may include, for example, hydrocarbons such as toluene and xylene; ethers such as 1,4-dioxane, THF and DME; amides such as DMF and DMA; halogenated hydrocarbons such as dichloromethane and chloroform; nitriles such as acetonitrile and propionitrile; and mixtures thereof.

Ideally, the reaction temperature should generally be in the range of -20°C to 150°C, although this varies depending on the type of raw materials and reagents used. Alternatively, microwave reaction equipment can be used if necessary.

Appropriately, the reaction time should generally be in the range of 0.1 hours to 72 hours, although it varies depending on the type of raw materials used and the reaction temperature.

In addition, a compound [1] (compound 1-AA) in which L ² is -(CR ^a R ^b ) _m -NR ^c (where ^Ra and R ^b together with the carbon atoms they are bonded to form C=O and m and R ^c are as defined above) can also be produced by the following method.

Method for producing compound [1-AA]

[Formula 3]

(In the formula, ^R1 , ^R2 , ^R4 , ^R5 , ^R6 , ^R7 , ^Rc , Het, and X are as defined above. R is an alkyl group, and examples of it may include, for example, methyl, ethyl, and n-butyl.)

Step 1

This step is a step in obtaining compound 1-AA by condensing compound 1 or its reactive compound and amine compound 3 in the presence of a condensing agent. Compound 1-AA can be produced by the same method as step 1 of the method used to produce compound 1-A described above.

Step 2

This step is a step in which compound 5 is obtained by condensing compound 1 or its reactive compound and amine compound 4 in the presence of a condensing agent. Compound 5 can be produced by the same method as step 1 of the method used to produce compound 1-A described above.

Step 3

This step involves obtaining compound 6 by hydrolyzing the ester portion of compound 5 in a suitable solvent and in the presence of a suitable acid or base.

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

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

Although there are no restrictions on the solvents used, as long as they do not participate in the reaction, examples may include, for example, alcohols such as methanol, ethanol and 2-propanol; ethers such as THF, diethyl ether, 1,4-dioxane and DME; nitriles such as acetonitrile and propionitrile; ketones such as acetone; water; and mixtures thereof.

Although the reaction temperature varies depending on the type of raw materials and reagents used, the reaction can generally be carried out in the range of 20°C to 200°C, preferably 20°C to 100°C. Alternatively, microwave reaction equipment can be used if necessary.

Appropriately, the reaction time should generally be in the range of 0.5 hours to 4 days, although it varies depending on the type of raw materials used and the reaction temperature.

Step 4

This step is a step of obtaining compound 1-AA by condensing compound 6 or its reactive compound and amine compound 7 in the presence of a condensing agent, and compound 1-AA can be produced by the same method as step 1 of the method used to produce the above-described compound 1-A.

Method for producing compound [1-B]

[Formula 4]

(In the formula, ^R1 , ^R2 , ^R4 , ^R5 , ^R6 , ^R7 , ^Rc , Het, X, and ^L2 are as defined above. Y is a leaving group, and examples of it may include, for example, bromine, iodine, methanesulfonate, and trifluoromethanesulfonate.)

Step 1

This step is a process of obtaining compound 1-B by subjecting compounds 8 and 9 to a coupling reaction in the presence of a transition metal (e.g., palladium).

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

Appropriately, the amount of compound 9 should be in the range of 0.5 molar equivalents to 3 molar equivalents relative to compound 8.

There are no particular limitations on the organometallic catalysts used in this reaction. Preferred examples of organometallic catalysts may include metal catalysts, such as tris(dibenzylacetone)bispalladium-chloroform adduct (hereinafter referred to as " _Pd₂ (dba) _{₃ ·} CHCl₃"), tris(dibenzylacetone)bispalladium (hereinafter referred to as " _Pd₂ (dba) _₃ "), tetra(triphenylphosphine)palladium (hereinafter referred to as "Pd( _PPh₃ ) _₄ "), [1,1'-bis(diphenylphosphine)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-butylphosphine)ferrocene]-dichloropalladium(II) (hereinafter referred to as "Pd(dtbpf)Cl₂ _") The mixture of these metal catalysts includes bis(tricyclohexylphosphine)palladium(II) dichloride (hereinafter referred to as " _PdCl2 ( _PCy3 ) ₂ "), palladium(II) acetate (hereinafter referred to as "Pd(OAc) ₂ "), and nickel(II) [1,3-bis(diphenylphosphine)propane] and these metal catalysts.

Suitablely, the amount of transition metal relative to compound 8 should be, for example, in the range of 0.01 molar equivalents to 0.3 molar equivalents.

In this step, alkalis or salts may be used as needed. Examples of alkalis or salts used may include, for example, potassium carbonate, cesium carbonate, sodium carbonate, sodium bicarbonate, sodium acetate, potassium acetate, trisodium phosphate, tripotassium phosphate and solutions thereof; as well as triethylamine (hereinafter “TEA”), N,N-diisopropylethylamine (hereinafter “DIPEA”), lithium chloride and copper iodide (I).

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

In this step, appropriate ligands may be used as needed. Examples of ligands that may be used include, for example, 1,1'-bis(diphenylphosphino)ferrocene (hereinafter referred to as "dppf"), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthophenone (hereinafter referred to as "Xantphos"), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (hereinafter referred to as "XPhos"), 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (hereinafter referred to as "BINAP"), 2-dicyclohexylphosphino-2',6'-diisopropylbiphenyl (hereinafter referred to as "RuPhos"), triphenylphosphine (hereinafter referred to as "PPh ₃ "), tricyclohexylphosphine (hereinafter referred to as "PCy ₃ "), etc.

Appropriately, the amount of ligand used should be, for example, in the range of 1 to 5 molar equivalents relative to the transition metal used.

Although there are no particular restrictions on the solvents used in this step, as long as they do not participate in the reaction, examples may include, for example, hydrocarbons such as toluene and xylene; ethers such as 1,4-dioxane, tetrahydrofuran (hereinafter “THF”) and dimethoxyethane (hereinafter “DME”); amides such as N,N-dimethylformamide (hereinafter “DMF”), N,N-dimethylacetamide (hereinafter “DMA”) and N-methylpyrrolidone (hereinafter “NMP”); alcohols such as ethanol, 2-propanol and tert-butanol; water; and mixtures thereof.

Ideally, the reaction temperature should generally be in the range of 20°C to 200°C, although this varies depending on the type of raw materials and reagents used. Alternatively, microwave reaction equipment may be used if necessary.

Appropriately, the reaction time should generally be in the range of 0.1 hours to 24 hours, although it varies depending on the type of raw materials used and the reaction temperature.

The compound ^L2, which is -(CR ^a R ^b ) _m -NR ^c - (where ^Ra and R ^b together with their bonded carbon atoms form C=O) (compound 1-BB), can also be produced as follows.

Method for producing compound [1-BB]

[Formula 5]

(In the formula, ^R1 , ^R2 , ^R4 , ^R5 , ^R6 , ^R7 , ^Rc , Het, X, Y, and R are as defined above. Z is a leaving group, and examples of it may include, for example, trimethylsilyl and triethylsilyl.)

Step 1

This step is a step of obtaining alkyne compound 12 by coupling compound 10 and compound 11 in the presence of a transition metal (e.g., palladium), and alkyne compound 12 can be produced by the same method as step 1 of the method for producing compound 1-B.

Step 2

This step is to deprotect Z to obtain compound 13, and can be performed by referring to, for example, Wuts and Greene, "Greene's Protective Groups in Organic Synthesis", 4th edition, John Wiley & Sons Inc., 2006; or P. J. Kocienski, "Protecting Groups", 3rd edition, Thieme, 2005.

Step 3

This step is a step of obtaining compound 15 by coupling compound 13 and compound 14 in the presence of a transition metal (e.g., palladium), and compound 15 can be produced by the same method as step 1 of the method for producing compound 1-B.

Step 4

This step involves obtaining compound 16 by hydrolyzing the ester portion of compound 15 in a suitable solvent and in the presence of a suitable acid or base, and compound 16 can be produced by the same method as step 3 of the method used to produce compound 1-AA.

Step 5

This step is a step of obtaining compound 1-BB by condensing compound 16 or its reactive compound and amine compound 17 in the presence of a condensing agent, and compound 1-BB can be produced by the same method as step 1 of the method used to produce compound 1-A described above.

Method for producing compound [1-C]

[Formula 6]

(In the formula, ^R1 , ^R2 , ^R4 , ^R5 , ^R6 , ^R7 , ^Rc , Het, and X are defined as above.)

Step 1

This step is a step of obtaining compound 1-C by condensing compound 19 or its reactive compound and amine compound 18 in the presence of a condensing agent, and compound 1-C can be produced by the same method as step 1 of the method used to produce compound 1-A described above.

Methods for producing compound [1-D]

[Formula 7]

(In the formula, ^R1 , ^R2 , ^R4 , ^R5 , ^R6 , ^R7 , ^Rc , ^L2 , Het, and X are as defined above. Y is a leaving group, and examples of it may include, for example, bromine, iodine, and trifluoromethanesulfonate.)

Step 1

This step is a process of obtaining compound 1-D by subjecting compound 20 and compound 21 to a coupling reaction in the presence of a transition metal (e.g., palladium).

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

Appropriately, the amount of compound 21 relative to compound 20 should be in the range of 0.5 molar equivalents to 3 molar equivalents.

There are no particular limitations on the organometallic catalysts used in this reaction. Preferred examples of organometallic catalysts may include metal catalysts, such as tris(dibenzylacetone)bispalladium-chloroform adduct (hereinafter referred to as " _Pd₂ (dba) _{₃ ·} CHCl₃"), tris(dibenzylacetone)bispalladium (hereinafter referred to as " _Pd₂ (dba) _₃ "), tetra(triphenylphosphine)palladium (hereinafter referred to as "Pd( _PPh₃ ) _₄ "), [1,1'-bis(diphenylphosphine)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-butylphosphine)ferrocene]-dichloropalladium(II) (hereinafter referred to as "Pd(dtbpf)Cl₂ _") The mixture of these metal catalysts includes bis(tricyclohexylphosphine)palladium(II) dichloride (hereinafter referred to as " _PdCl2 ( _PCy3 ) ₂ "), palladium(II) acetate (hereinafter referred to as "Pd(OAc) ₂ "), and nickel(II) [1,3-bis(diphenylphosphine)propane] and these metal catalysts.

Suitablely, the amount of transition metal relative to compound 20 should be, for example, in the range of 0.01 molar equivalents to 0.3 molar equivalents.

In this step, alkalis or salts may be used as needed. Examples of alkalis or salts used may include, for example, potassium carbonate, cesium carbonate, sodium carbonate, sodium bicarbonate, sodium acetate, potassium acetate, trisodium phosphate, tripotassium phosphate and solutions thereof; as well as triethylamine (hereinafter “TEA”), N,N-diisopropylethylamine (hereinafter “DIPEA”), lithium chloride and copper iodide (I).

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

In this step, appropriate ligands may be used as needed. Examples of ligands that may be used include, for example, 1,1'-bis(diphenylphosphino)ferrocene (hereinafter referred to as "dppf"), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthophenone (hereinafter referred to as "Xantphos"), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (hereinafter referred to as "XPhos"), 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (hereinafter referred to as "BINAP"), 2-dicyclohexylphosphino-2',6'-diisopropylbiphenyl (hereinafter referred to as "RuPhos"), triphenylphosphine (hereinafter referred to as "PPh ₃ "), tricyclohexylphosphine (hereinafter referred to as "PCy ₃ "), etc.

Appropriately, the amount of ligand used should be, for example, in the range of 1 to 5 molar equivalents relative to the transition metal used.

Although there are no particular restrictions on the solvents used in this step, as long as they do not participate in the reaction, examples may include, for example, hydrocarbons such as toluene and xylene; ethers such as 1,4-dioxane, tetrahydrofuran (hereinafter “THF”) and dimethoxyethane (hereinafter “DME”); amides such as N,N-dimethylformamide (hereinafter “DMF”), N,N-dimethylacetamide (hereinafter “DMA”) and N-methylpyrrolidone (hereinafter “NMP”); alcohols such as ethanol, 2-propanol and tert-butanol; water; and mixtures thereof.

Ideally, the reaction temperature should generally be in the range of 20°C to 200°C, although this varies depending on the type of raw materials and reagents used. Alternatively, microwave reaction equipment may be used if necessary.

Appropriately, the reaction time should generally be in the range of 0.1 hours to 24 hours, although it varies depending on the type of raw materials used and the reaction temperature.

Method for producing compound [1-E]

[Formula 8]

(In the formula, ^R1 , ^R2 , ^R4 , ^R5 , ^R6 , ^R7 , ^Ra , ^Rb , ^Rc , ^L2 , Het, X, and Y are defined as above.)

Step 1

This step is a step of obtaining compound 1-E by subjecting compound 22 and compound 23 to a coupling reaction in the presence of a transition metal (e.g., palladium), and compound 1-E can be produced by the same method as step 1 of the method used to produce compound 1-D described above.

Compounds in which ^L1 is -(CR ^a R ^b ) _m -NR ^c - and ^Ra and R ^b are each H can also be produced as follows.

Method for producing compound [1-EE]

[Formula 9]

(In the formula, ^R1 , ^R2 , ^R4 , ^R5 , ^R6 , ^R7 , ^Rc , ^L2 , Het, and X are defined as above.)

Step 1

Step 1

This step is the process of obtaining compound 1-EE through the reductive amination reaction of compounds 24 and 23, and can be carried out according to a known reductive amination method. In this step, imine formation (step one) and reduction of the imine moiety (step two) can be carried out sequentially.

Appropriately, the amount of compound 23 relative to compound 24 should be in the range of 1 molar equivalent to 2.5 molar equivalents.

In this step, an acid or a suitable Lewis acid may be used as needed. Examples of acids that can be used in the reaction may include, for example, acetic acid, and examples of Lewis acids that can be used may include, for example, tetraisopropyl titanate.

When using acid in this step, it is appropriate that the amount of acid used be in the range of 2 to 3 molar equivalents relative to the amount of compound 24.

When using Lewis acids in this step, it is appropriate that the amount of Lewis acid used is in the range of 1.5 molar equivalents to 2 molar equivalents relative to the amount of compound 24.

Although there are no particular restrictions on the solvents used in this step, as long as they do not participate in the reaction, examples may include, for example, hydrocarbons such as toluene and xylene; ethers such as 1,4-dioxane, THF and DME; halogenated hydrocarbons such as dichloromethane; and mixtures thereof.

In this step, it is appropriate that the reaction temperature is generally in the range of 0°C to 100°C, although it varies depending on the type of raw materials and reagents used.

In this step, it is appropriate that the reaction time is generally in the range of 0.1 hours to 48 hours, although it varies depending on the type of raw materials used and the reaction temperature.

Examples of reducing agents used in this step may include, for example, sodium triacetoxyborohydride, sodium cyanoborohydride, etc.

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

Although there are no particular restrictions on the solvents used in this step, as long as they do not participate in the reaction, examples may include, for example, hydrocarbons such as toluene and xylene; ethers such as 1,4-dioxane, THF and DME; halogenated hydrocarbons such as dichloromethane; and mixtures thereof.

Method for producing compound [1-F]

[Formula 10]

(In the formula, ^R1 , ^R2 , ^R4 , ^R5 , ^R6 , ^R7 , ^Ra , ^Rb , ^Rc , ^L2 , Het, X, and Y are defined as above.)

Step 1

This step involves reacting compound 25 with compound 26 in the presence of a base to obtain compound 1-F.

Appropriately, the amount of compound 26 relative to compound 25 should be in the range of 0.5 molar equivalents to 3 molar equivalents.

Examples of bases that can be used in this reaction include pyridine, TEA, DIPEA, potassium carbonate, and sodium bicarbonate.

Appropriately, the amount of base used relative to compound 25 should be in the range of 1 to 10 molar equivalents.

Although there are no particular restrictions on the solvents used, as long as they do not participate in the reaction, examples may include, for example, alcohols such as isopropanol, 1-butanol and 2-methoxyethanol; ethers such as THF and 1,4-dioxane; amides such as DMF, DMA and NMP; hydrocarbons such as benzene and toluene; dimethyl sulfoxide (hereinafter referred to as "DMSO"); acetonitrile; and mixtures thereof.

In this step, it is appropriate that the reaction temperature is generally in the range of 20°C to 200°C, although this varies depending on the type of raw materials and reagents used. Alternatively, a microwave reaction apparatus may be used if necessary.

Appropriately, the reaction time should generally be in the range of 1 hour to 24 hours, although it varies depending on the type of raw materials used and the reaction temperature.

Compounds in which ^L1 is ^-NRc- ( ^CRaRb ) _m- and ^Ra and ^{Rb are} each H can also be produced as follows.

Method for producing compound [1-FF]

[Equation 11]

(In the formula, ^R1 , ^R2 , ^R4 , ^R5 , ^R6 , ^R7 , ^Rc , ^L2 , Het, and X are defined as above.)

Step 1

This step is the step of obtaining compound 1-FF by the reductive amination reaction of compounds 27 and 28, and compound 1-FF can be produced by the same method as step 1 of the method used to produce the above-mentioned compound 1-EE.

Method for producing compound [1-G]

[Equation 12]

(In the formula, ^R1 , ^R2 , ^R4 , ^R5 , ^R6 , ^R7 , ^Rc , ^L2 , Het, and X are defined as above.)

Step 1

This step is the process of obtaining ether compound 1-G by the Mitsunobu reaction of alcohol compound 29 and alcohol compound 30, and can be carried out according to known methods.

This step is typically carried out in a suitable solvent in the presence of azodicarbonate and phosphine reagents.

Appropriately, the amount of compound 29 relative to compound 30 should be in the range of 0.5 molar equivalents to 1.5 molar equivalents.

Examples of azodicarbonate reagents that may be used include, for example, diethyl azodicarbonate (hereinafter referred to as “DEAD”), diisopropyl azodicarbonate (hereinafter referred to as “DIAD”), bis(2-methoxyethyl) azodicarbonate (hereinafter referred to as “DMEAD”), etc.

Examples of phosphine reagents that can be used include, for example, triphenylphosphine, tributylphosphine, etc.

Appropriately, the amount of azodicarbonate reagent should be in the range of 1 to 2 molar equivalents relative to compound 29.

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

Although there are no particular restrictions on the solvents used, as long as they do not participate in the reaction, examples may include, for example, hydrocarbons such as toluene and xylene; ethers such as 1,4-dioxane, THF and DME; and mixtures thereof.

In this step, it is appropriate that the reaction temperature is generally in the range of 0°C to 100°C, although it varies depending on the type of raw materials and reagents used.

Appropriately, the reaction time should generally be in the range of 0.5 hours to 24 hours, although it varies depending on the type of raw materials used and the reaction temperature.

Method for producing compound [1-H]

[Equation 13]

(In the formula, ^R1 , ^R2 , ^R4 , ^R5 , ^R6 , ^R7 , ^Rc , ^L2 , Het, and X are defined as above.)

Step 1

This step is the step of obtaining ether compound 1-H by the Mitsunobu reaction of alcohol compound 31 and alcohol compound 32, and compound 1-H can be produced by the same method as step 1 of the method used to produce the above-mentioned compound 1-G.

Method for producing compound [1-I]

[Formula 14]

(In the formula, ^R1 , ^R2 , ^R4 , ^R5 , ^R6 , ^R7 , ^Rc , ^L2 , Het, and X are as defined above. Y is a leaving group, and examples of it may include, for example, bromine, iodine, and trifluoromethanesulfonate.)

Step 1

This step is a process of obtaining compound 1-I by subjecting compounds 33 and 34 to a coupling reaction in the presence of a transition metal (e.g., palladium).

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

Appropriately, the amount of compound 33 should be in the range of 0.5 molar equivalents to 3 molar equivalents relative to compound 34.

There are no particular limitations on the organometallic catalysts used in this reaction. Preferred examples of organometallic catalysts may include metal catalysts, such as tris(dibenzylacetone)bispalladium-chloroform adduct (hereinafter referred to as " _Pd₂ (dba) _{₃ ·} CHCl₃"), tris(dibenzylacetone)bispalladium (hereinafter referred to as " _Pd₂ (dba) _₃ "), tetra(triphenylphosphine)palladium (hereinafter referred to as "Pd( _PPh₃ ) _₄ "), [1,1'-bis(diphenylphosphine)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-butylphosphine)ferrocene]-dichloropalladium(II) (hereinafter referred to as "Pd(dtbpf)Cl₂ _") The mixture of these metal catalysts includes bis(tricyclohexylphosphine)palladium(II) dichloride (hereinafter referred to as " _PdCl2 ( _PCy3 ) ₂ "), palladium(II) acetate (hereinafter referred to as "Pd(OAc) ₂ "), and nickel(II) [1,3-bis(diphenylphosphine)propane] and these metal catalysts.

Suitablely, the amount of transition metal relative to compound 33 should be, for example, in the range of 0.01 molar equivalent to 0.3 molar equivalent.

In this step, alkalis or salts may be used as needed. Examples of alkalis or salts used may include, for example, potassium carbonate, cesium carbonate, sodium carbonate, sodium bicarbonate, sodium acetate, potassium acetate, trisodium phosphate, tripotassium phosphate and solutions thereof; as well as triethylamine (hereinafter “TEA”), N,N-diisopropylethylamine (hereinafter “DIPEA”), lithium chloride and copper iodide (I).

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

In this step, appropriate ligands may be used as needed. Examples of ligands that may be used include, for example, 1,1'-bis(diphenylphosphino)ferrocene (hereinafter referred to as "dppf"), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthophenone (hereinafter referred to as "Xantphos"), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (hereinafter referred to as "XPhos"), 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (hereinafter referred to as "BINAP"), 2-dicyclohexylphosphino-2',6'-diisopropylbiphenyl (hereinafter referred to as "RuPhos"), triphenylphosphine (hereinafter referred to as "PPh ₃ "), tricyclohexylphosphine (hereinafter referred to as "PCy ₃ "), etc.

Appropriately, the amount of ligand used should be, for example, in the range of 1 to 5 molar equivalents relative to the transition metal used.

Although there are no particular restrictions on the solvents used in this step, as long as they do not participate in the reaction, examples may include, for example, hydrocarbons such as toluene and xylene; ethers such as 1,4-dioxane, tetrahydrofuran (hereinafter “THF”) and dimethoxyethane (hereinafter “DME”); amides such as N,N-dimethylformamide (hereinafter “DMF”), N,N-dimethylacetamide (hereinafter “DMA”) and N-methylpyrrolidone (hereinafter “NMP”); alcohols such as ethanol, 2-propanol and tert-butanol; water; and mixtures thereof.

Ideally, the reaction temperature should generally be in the range of 20°C to 200°C, although this varies depending on the type of raw materials and reagents used. Alternatively, microwave reaction equipment may be used if necessary.

Appropriately, the reaction time should generally be in the range of 0.1 hours to 24 hours, although it varies depending on the type of raw materials used and the reaction temperature.

Methods for producing compound [1-K]

[Formula 15]

(In the formula, ^R1 , ^R2 , ^R4 , ^R5 , ^R6 , ^R7 , ^Ra , ^L2 , Het, and X are as defined above. Y is a leaving group, and examples of it may include, for example, bromine, iodine, and trifluoromethanesulfonate. ^RAA and ^RBB each represent a hydroxyl group, or ^RAA and ^RBB together represent -OC( _CH3 ) ₂ -C( _CH3 ) ₂ -O-, -O-( _CH2 ) ₃ -O-, or O- _CH2 -C( _CH3 ) ₂ - _CH2 -O-.)

Step 1

This step is a process of obtaining compound 1-K by subjecting compounds 35 and 36 to a coupling reaction in the presence of a transition metal (e.g., palladium).

For this reaction, the conditions typically used for coupling reactions involving transition metals (especially the Suzuki-Miyaura coupling reaction) can be applied, and it can be carried out by the method described in the literature (e.g., Suzuki et al., Chem. Rev., 1995, 95, 2457-2483).

Appropriately, the amount of compound 36 relative to compound 35 should be in the range of 0.5 molar equivalents to 3 molar equivalents.

There are no particular limitations on the organometallic catalysts used in this reaction. Preferred examples of organometallic catalysts may include metal catalysts, such as tris(dibenzylacetone)bispalladium-chloroform adduct (hereinafter referred to as " _Pd₂ (dba) _{₃ ·} CHCl₃"), tris(dibenzylacetone)bispalladium (hereinafter referred to as " _Pd₂ (dba) _₃ "), tetra(triphenylphosphine)palladium (hereinafter referred to as "Pd( _PPh₃ ) _₄ "), [1,1'-bis(diphenylphosphine)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-butylphosphine)ferrocene]-dichloropalladium(II) (hereinafter referred to as "Pd(dtbpf)Cl₂ _") The mixture of these metal catalysts includes bis(tricyclohexylphosphine)palladium(II) dichloride (hereinafter referred to as " _PdCl2 ( _PCy3 ) ₂ "), palladium(II) acetate (hereinafter referred to as "Pd(OAc) ₂ "), and nickel(II) [1,3-bis(diphenylphosphine)propane] and these metal catalysts.

Suitablely, the amount of transition metal relative to compound 35 should be, for example, in the range of 0.01 molar equivalents to 0.3 molar equivalents.

In this step, alkalis or salts may be used as needed. Examples of alkalis or salts used may include, for example, potassium carbonate, cesium carbonate, sodium carbonate, sodium bicarbonate, sodium acetate, potassium acetate, trisodium phosphate, tripotassium phosphate and solutions thereof; as well as triethylamine (hereinafter “TEA”), N,N-diisopropylethylamine (hereinafter “DIPEA”), lithium chloride and copper iodide (I).

Appropriately, the amount of base used relative to compound 35 should be, for example, in the range of 1 to 4 molar equivalents.

In this step, appropriate ligands may be used as needed. Examples of ligands that may be used include, for example, 1,1'-bis(diphenylphosphino)ferrocene (hereinafter referred to as "dppf"), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthophenone (hereinafter referred to as "Xantphos"), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (hereinafter referred to as "XPhos"), 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (hereinafter referred to as "BINAP"), 2-dicyclohexylphosphino-2',6'-diisopropylbiphenyl (hereinafter referred to as "RuPhos"), triphenylphosphine (hereinafter referred to as "PPh ₃ "), tricyclohexylphosphine (hereinafter referred to as "PCy ₃ "), etc.

Appropriately, the amount of ligand used should be, for example, in the range of 1 to 5 molar equivalents relative to the transition metal used.

Although there are no particular restrictions on the solvents used in this step, as long as they do not participate in the reaction, examples may include, for example, hydrocarbons such as toluene and xylene; ethers such as 1,4-dioxane, tetrahydrofuran (hereinafter “THF”) and dimethoxyethane (hereinafter “DME”); amides such as N,N-dimethylformamide (hereinafter “DMF”), N,N-dimethylacetamide (hereinafter “DMA”) and N-methylpyrrolidone (hereinafter “NMP”); alcohols such as ethanol, 2-propanol and tert-butanol; water; and mixtures thereof.

Ideally, the reaction temperature should generally be in the range of 20°C to 200°C, although this varies depending on the type of raw materials and reagents used. Alternatively, microwave reaction equipment may be used if necessary.

Appropriately, the reaction time should generally be in the range of 0.1 hours to 24 hours, although it varies depending on the type of raw materials used and the reaction temperature.

The compounds of the present invention possess inhibitory activity against PDGF receptor kinase, as demonstrated in the test examples below. Furthermore, due to their inhibitory activity against PDGF receptor kinase, the compounds of the present invention are effective for respiratory diseases, cancer, smooth muscle proliferative disorders, angiogenic disorders, autoimmune/inflammatory diseases, metabolic diseases, and vascular occlusive diseases.

Furthermore, the inhibitory activity of the compounds of the present invention against PDGF receptor kinase is highly selective against KIT kinase, as demonstrated in the test examples below, and thus it is expected that the compounds of the present invention will provide PDGF receptor kinase inhibitors with undesirable inhibitory effects, such as myelosuppression.

Therefore, the compounds of the present invention or their pharmaceutically acceptable salts can be used as preventive or therapeutic agents for diseases, for example, involving PDGF receptor kinase.

Examples of respiratory diseases to which the compounds of the present invention or their pharmaceutically acceptable salts can be applied include lung diseases and pulmonary hypertension. First, pulmonary hypertension is classified according to etiology and pathology as follows.

• Pulmonary hypertension (PAH);

Pulmonary hypertension caused by the following left ventricular diseases

Left ventricular failure with maintained ejection fraction,

Left ventricular failure with reduced ejection fraction,

Valvular heart disease, and

Congenital/acquired cardiovascular conditions leading to postcapillary PH;

• Pulmonary hypertension due to lung disease and/or hypoxemia due to the following conditions

Chronic obstructive pulmonary disease (COPD)

Interstitial (restrictive) lung disease,

Other lung diseases involving mixed symptoms of both restrictive and obstructive conditions.

Hypoxia caused by lung disease, and

Developmental disorders;

• The following types of pulmonary hypertension caused by pulmonary artery occlusion

Chronic thromboembolic pulmonary hypertension (CTEPH), and

Pulmonary hypertension due to the following conditions (sarcoma, angiosarcoma, malignant tumors, non-malignant tumors, vasculitis caused by connective tissue diseases, congenital pulmonary artery stenosis, parasites, etc., and thrombotic microangiopathy (PTTM) of lung tumors); and

• Pulmonary hypertension caused by diseases described below, with unknown multifactorial mechanisms.

Blood disorders (chronic hemolytic anemia, myeloproliferative disorders, etc.),

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

Other (e.g., chronic renal failure with/without dialysis, fibrotic mediastinitis, etc.) and

Complex congenital heart malformation.

For example, the above-mentioned pulmonary arterial hypertension (PAH) includes the following:

Idiopathic PAH;

Hereditary PAH (especially abnormalities in BMPR2, TBX4, ACVRL1, ENG, SMAD9, KCNK3, SMAD1, CAV1, SMAD4, ATP13A3, SOX17, AQP1, GDF2 or unknown genes);

Drug- and toxin-induced PAH;

PAH caused by disease (here, "disease" includes, for example, connective tissue diseases, HIV infection, portal hypertension, congenital shunt heart disease and schistosomiasis);

Long-term PAH responders to calcium channel blockers, pulmonary venous occlusive disease/pulmonary capillary angiomatous hyperplasia (PVOD/PCH) (including PVOD/PCH with EIF2AK4 mutation); and

Persistent pulmonary hypertension in newborns (PPHN).

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

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

Examples of smooth muscle proliferative diseases to which the compounds of the present invention or their pharmaceutically acceptable salts can be applied may include restenosis, atherosclerosis/occlusive arteriosclerosis, moyamoya disease (idiopathic Willis ring occlusion), leiomyomas, lymphangioleiomyomatosis, Williams syndrome, tuberous sclerosis, angina pectoris, myocardial infarction, peripheral artery disease, hypertrophic/dilated cardiomyopathy, and systolic/diastolic cardiomyopathy.

Examples of angiogenic diseases to which the compounds of the present invention or their pharmaceutically acceptable salts can be applied may include age-related macular degeneration (AMD), Osler's disease (hereditary hemorrhagic telangiectasia), hemangioma, tumor angiogenesis, and arteriovenous fistula.

Examples of metabolic diseases to which the compounds of the present invention or their pharmaceutically acceptable salts can be applied may include diabetes (type 1 or type 2 diabetes).

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

Although it is desirable to adjust the dosage as a medicine taking into account the patient's condition (e.g., age, weight, type and severity of disease, route of administration) and the type of compound of the invention (whether it is a salt and the type of salt), it is generally suitable that, for adults, in the case of oral administration, the effective amount of the compound of the invention or a pharmaceutically acceptable salt thereof should be in the range of 0.01 mg to 5 g/ad per adult, preferably in the range of 1 mg to 500 mg/adult per day. In some cases, a smaller amount may be sufficient, or a larger amount may be required. Generally, the dosage may be administered once a day, or may be divided into several doses per day, or, in the case of intravenous administration, the dosage may be administered rapidly or continuously over 24 hours.

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

The present invention will be further described in detail below with reference to comparative embodiments, embodiments and test embodiments; however, the present invention is not limited to those embodiments.

Example

In this embodiment, the following abbreviations will be used.

TFA: Trifluoroacetic acid

Pd-C: Palladium-Carbon

_Pd2 (dba) ₃ : Tris(dibenzylacetone)bispalladium

Pd( _PPh3 ) ₄ : Tetraphenylphosphine palladium

_PdCl₂ ( _PPh₃ ) _₂ : Bis(triphenylphosphine)palladium(II) dichloride

Pd(OAc) _₂ : Palladium(II) acetate

Xantphos: 4,5-bis(diphenylphosphino)-9,9-dimethylxanthanium

BINAP: 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl

PPh ₃ : Triphenylphosphine

Boc ₂ O: Ditert-butyl dicarbonate

HATU: O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate

HBTU: O-(benzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate

THF: Tetrahydrofuran

DME: Dimethoxyethane

DMF: Dimethylformamide

DMSO: Dimethyl sulfoxide

NMP: N-methylpyrrolidone

DIPEA: N,N-Diisopropylethylamine

TEA: Triethylamine

BH ₃ -THF: Borane-tetrahydrofuran complex

CDCl ₃ : Deuterated chloroform

TLC: Thin-layer chromatography

MS: Mass spectrometry

LCMS: High Performance Liquid Chromatography-Mass Spectrometry

ESI: Electrospray Ionization

M: Molar concentration (mol/L)

MS is measured using LCMS. ESI is used as a method for ionization. Mass spectrometry observations are expressed as m/z.

The measurement conditions for LCMS are as follows:

Analytical instrument: ACQUITY UPLC MS/PDA system (manufactured by Waters Corporation);

Mass spectrometer: Waters 3100 MS detector;

Photodiode array detector: ACQUITY PDA detector (UV detection wavelength: 210-400 nm);

Column: Acquity BEH C18, 1.7 μm, 2.1×50 mm;

Flow rate: 0.5 mL/min;

Column temperature: 40℃;

Solvent;

Solution A: 0.1% formic acid/ _H₂O (v/v; same below)

Solution B: 0.1% formic acid/acetonitrile.

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

In microwave experiments, initiator 60 (manufactured by Biotage AB) is used. This allows for temperatures ranging from 40°C to 250°C and pressures up to 20 bar.

In this specification, the names of compounds are given using the naming software ACD/NAME (registered trademark, Advanced Chemistry Development Inc.) conforming to IUPAC rules, using ChemBioDraw (version 14.0, manufactured by Cambridge Soft Corporation), or in accordance with IUPAC naming rules.

In the name of a compound, the descriptors “r” and “s” (lowercase) refer to the stereochemistry of the pseudo-asymmetric carbon atom according to IUPAC rules.

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

[Step 1] Production of methyl 5-[(cyclopropylmethyl)amino]pyridine-3-carboxylate

1,4-Dioxane (139 mL) was added to methyl 5-bromopyridine-3-carboxylate (15.0 g), 1-cyclopropylmethylamine (9.9 g), BINAP (8.6 g), cesium carbonate (45.2 g), and Pd(OAc) _₂ (1.6 g). After degassing, the reaction mixture was stirred overnight at 80 °C under an argon atmosphere. The insoluble matter was filtered off with celite (R), and the solvent was then removed by vacuum distillation. The residue was purified by silica gel column chromatography to give the title compound (8.4 g). MS (m/z): 207.2 [M+H] ^⁺

[Step 2] Production of 5-[(cyclopropylmethyl)amino]pyridine-3-carboxylic acid

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

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

[Step 1] Production of methyl 5-[cyclopropyl(methyl)amino]pyridine-3-carboxylate

The title compound (6.6 g) was obtained by using N-methylcyclopropylamine (9.9 g) instead of 1-cyclopropylmethylamine, via the method described in step 1 of Reference Example 1. MS (m/z): 207.4 [M+H] ⁺

[Step 2] Production of 5-[cyclopropyl(methyl)amino]pyridine-3-carboxylic acid

The title compound (4.3 g) was obtained by replacing methyl 5-[(cyclopropylmethyl)amino]pyridine-3-carboxylate (6.6 g) obtained in step 1 with methyl 5-[(cyclopropylmethyl)amino]pyridine-3-carboxylate, as described in step 2 of Reference Example 1. MS (m/z): 193.4 [M+H] ⁺

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

[Step 1] Production of methyl 5-[(3,3-difluorocyclobutyl)oxy]pyridine-3-carboxylate

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

[Step 2] Production of 5-[(3,3-difluorocyclobutyl)oxy]pyridine-3-carboxylic acid

The title compound (84 mg) was obtained by using methyl 5-[(3,3-difluorocyclobutyl)oxy]pyridine-3-carboxylate (170 mg) instead of methyl 5-[(cyclopropylmethyl)amino]pyridine-3-carboxylate, as described in step 2 of Reference Example 1.

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

[Step 1] Production of methyl 5-[(4,4-difluorocyclohexyl)oxy]pyridine-3-carboxylate

The title compound (450 mg) was obtained by using 4,4-difluorocyclohexane-1-ol instead of 3,3-difluorocyclobutane-1-ol, as described in step 1 of Reference Example 3. MS (m/z): 272.2 [M+H] ⁺

[Step 2] Production of 5-[(4,4-difluorocyclohexyl)oxy]pyridine-3-carboxylic acid

The title compound (350 mg) was obtained by replacing methyl 5-[(4,4-difluorocyclohexyl)oxy]pyridine-3-carboxylate (450 mg) with methyl 5-[(cyclopropylmethyl)amino]pyridine-3-carboxylate as described in step 2 of Reference Example 1. MS (m/z): 258.2 [M+H] ⁺

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

[Step 1] Production of methyl 5-[(1-methylcyclopropyl)methoxy]pyridine-3-carboxylate

The title compound (540 mg) was obtained by using (1-methylcyclopropyl)methanol (500 mg) instead of 3,3-difluorocyclobut-1-ol, as described in step 1 of Reference Example 3. MS (m/z): 222.1 [M+H] ⁺

[Step 2] Production of 5-[(1-methylcyclopropyl)methoxy]pyridine-3-carboxylic acid

The title compound (340 mg) was obtained by replacing methyl 5-[(1-methylcyclopropyl)methoxy]pyridine-3-carboxylate (540 mg) with methyl 5-[(cyclopropylmethyl)amino]pyridine-3-carboxylate as described in step 2 of Reference Example 1. MS (m/z): 208.2 [M+H] ⁺

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

[Step 1] Production of methyl 5-[(3,3-difluorocyclobutyl)methoxy]pyridine-3-carboxylate

The title compound (1.10 g) was obtained by using (3,3-difluorocyclobutyl)methanol (500 mg) instead of 3,3-difluorocyclobut-1-ol, as described in step 1 of Reference Example 3. MS (m/z): 258.1 [M+H] ⁺

[Step 2] Production of 5-[(3,3-difluorocyclobutyl)methoxy]pyridine-3-carboxylic acid

The title compound (580 mg) was obtained by replacing methyl 5-[(3,3-difluorocyclobutyl)methoxy]pyridine-3-carboxylate (1.10 g) obtained in step 1 with methyl 5-[(cyclopropylmethyl)amino]pyridine-3-carboxylate, as described in step 2 of Reference Example 1. MS (m/z): 244.2 [M+H] ⁺

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

DIPEA (17.2 mL) was added to a suspension of 3-amino-4-methylbenzoic acid (5.00 g), (1S,2S)-2-aminocyclohexyl-1-ol hydrochloride (5.52 g), and HBTU (15.1 g) in THF (165 mL), and the reaction mixture was stirred at room temperature for 2 hours. The reaction solution was diluted with ethyl acetate, and the organic layer was washed with saturated aqueous sodium bicarbonate solution and saturated salt solution. The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. Ethyl acetate was added to the obtained residue to suspend it, and the precipitate was collected by filtration to give the title compound (6.10 g). MS (m/z): 249.2 [M+H] ⁺

Reference Example 8: Methyl 4-chloro-3-ethynylbenzoate

[Step 1] Production of methyl 4-chloro-3-[(trimethylsilyl)ethynyl]benzoate

THF (27.5 mL) was added to methyl 4-chloro-3-iodobenzoate (8.15 g), ethynyl(trimethyl)silane (2.78 g), copper iodide (570 mg), Pd( _PPh3 ) ₄ (3.18 g), and TEA (55 mL). After degassing, the reaction mixture was stirred overnight at 45 °C under an argon atmosphere. Insoluble matter was filtered off with celite (R), and the solvent was then removed by vacuum distillation. The residue was purified by silica gel column chromatography to give the title compound (6.8 g).

[Step 2] Production of methyl 4-chloro-3-ethynylbenzoate

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

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

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

Reference Example 10: 2-(5-ethynylpyridin-3-yl)pyrimidine

[Step 1] Production of 2-[5-(methoxymethoxy)pyridin-3-yl]pyrimidine

1,4-Dioxane (73 mL) was added to 3-bromo-5-(methoxymethoxy)pyridine (4.0 g), bis(pinacol)diboron (5.6 g), potassium acetate (3.6 g), and Pd(dppf) _Cl₂ · _CH₂Cl₂ ( _1.5 g). After degassing, the reaction mixture was stirred at 80 °C for 2.5 h under an argon atmosphere. Then, 2-bromopyrimidine (3.5 g), potassium carbonate (5.1 g), and water (0.5 mL) were added, and the reaction mixture was stirred overnight at 85 °C. The reaction solution was diluted with ethyl acetate, and the organic layer was washed with water. The organic layer was dried over anhydrous sodium sulfate, and then the solvent was removed by vacuum distillation. The residue obtained was purified by silica gel column chromatography to give the title compound (3.6 g). MS (m/z): 218.4 [M+H] ^⁺

[Step 2] Production of 5-(pyrimidin-2-yl)pyridin-3-ol

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

[Step 3] Production of 5-(pyrimidin-2-yl)pyridin-3-yl trifluoromethanesulfonic acid ester

Under ice-cooled conditions, trifluoromethanesulfonic anhydride (2.27 mL) was added dropwise to a solution of 5-(pyrimidin-2-yl)pyridin-3-ol (2.00 g) and TEA (2.10 mL) obtained in step 2 in dichloromethane (38 mL), and the reaction mixture was stirred at the same temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to give the title compound (770 mg). MS (m/z): 306.4 [M+H] ⁺

[Step 4] Production of 2-{5-[(trimethylsilyl)ethynyl]pyridin-3-yl}pyrimidine

The title compound (570 mg) was obtained by replacing methyl 4-chloro-3-iodobenzoate with 5-(pyrimidin-2-yl)pyridin-3-yl trifluoromethanesulfonate (770 mg) obtained in step 3, as described in step 1 of Reference Example 8. MS (m/z): 254.5 [M+H] ⁺

[Step 5] Production of 2-(5-ethynylpyridin-3-yl)pyrimidine

The title compound (350 mg) was obtained by replacing methyl 4-chloro-3-[(trimethylsilyl)ethynyl]pyridin-3-yl}pyrimidine (570 mg) obtained in step 4 with methyl 4-chloro-3-[(trimethylsilyl)ethynyl]benzoate, as described in step 2 of Reference Example 8. MS (m/z): 182.4 [M+H] ⁺

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

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

Reference Example 12: 6-Bromo-N-(cyclopropylmethyl)pyrazine-2-amine

To a solution of 2,6-dibromopyrazine (500 mg) in DMF (1 mL), 1-cyclopropylmethylamine (449 mg) and potassium carbonate (871 mg) were added, and the reaction mixture was sealed in a pressure-resistant stainless steel container and stirred at 120 °C for 8 hours. The reaction solution was diluted with ethyl acetate. After washing with water and saturated salt solution, the solvent was removed by vacuum distillation. The residue obtained was purified by silica gel column chromatography to give the title compound (400 mg).

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

[Step 1] Production of 5-bromo-N-[(1S,2S)-2-hydroxycyclohexyl]-6-methylpyridine-3-carboxamide

The title compound (380 mg) was obtained by using 5-bromo-6-methylpyridin-3-carboxylic acid (250 mg) instead of 3-amino-4-methylbenzoic acid, as described in Reference Example 7. MS (m/z): 313.4 [M+H] ⁺

[Step 2] Production of N-[(1S,2S)-2-hydroxycyclohexyl]-6-methyl-5-[(trimethylsilyl)ethynyl]pyridine-3-carboxamide

The title compound (40 mg) was obtained by replacing methyl 4-chloro-3-iodobenzoate with 100 mg of 5-bromo-N-[(1S,2S)-2-hydroxycyclohexyl]-6-methylpyridine-3-carboxamide obtained in step 1, as described in step 1 of Reference Example 8. MS (m/z): 331.5 [M+H] ⁺

[Step 3] Production of 5-ethynyl-N-[(1S,2S)-2-hydroxycyclohexyl]-6-methylpyridine-3-carboxamide

The title compound (23 mg) was obtained by replacing methyl 4-chloro-3-[(trimethylsilyl)ethynyl]pyridine-3-carboxamide (40 mg) obtained in step 2 with N-[(trimethylsilyl)ethynyl]benzoate, as described in step 2 of Reference Example 8. MS (m/z): 259.5 [M+H] ⁺

Reference Example 14: 2-(isoquinoline-4-yl)pyrimidin-4-amine

_1,4 -Dioxane (5 mL) was added to 2-chloropyrimidin-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 and replacing with argon, the reaction mixture was stirred at 90 °C for 2 hours under an argon atmosphere. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to give the title compound (300 mg).

Reference Example 15: (1S)-1-(5-phenylpyridin-3-yl)ethyl-1-amine

The title compound (280 mg) was obtained by using (1S)-1-(5-bromopyridin-3-yl)ethyl-1-amine hydrochloride (300 mg) and phenylboronic acid (185 mg) instead of 2-chloropyrimidin-4-amine and isoquinoline-4-ylboronic acid, as described in Reference Example 14. MS (m/z): 199.2 [M+H] ⁺

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

[Step 1] Production of (SS)-N-[(1E)-1-(5-bromopyridin-3-yl)ethylene]-2-methylpropane-2-sulfinamide

1-(5-bromopyridin-3-yl)ethyl-1-one (25 g) and (SS)-2-methylpropane-2-sulfinamide (18.2 g) were dissolved in THF (500 mL), and tetraethyl orthotitanate (57 g) was added. The reaction mixture was stirred overnight at 65 °C. The reaction solution was diluted with ethyl acetate and water was added. The reaction solution was filtered through celite® and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (34 g). MS (m/z): 303.0 [M+H] ⁺

[Step 2] Production of (SS)-N-[(1S)-1-(5-bromopyridin-3-yl)ethyl]-2-methylpropane-2-sulfinamide

A suspension of dichloro(p-isopropyltoluene)ruthenium(II) dimer (6.86 g), 2-amino-2-methyl-1-propanol (2.14 mL), and 4A molecular sieve (34 g) in 2-propanol (560 mL) was stirred at 80 °C for 30 min under an argon atmosphere. Then, while stirring the reaction solution at 50 °C, a solution of (SS)-N-[(1E)-1-(5-bromopyridin-3-yl)ethylene]-2-methylpropane-2-sulfinamide (34 g) obtained in step 1 in 2-propanol (9 mL) and potassium tert-butoxide (6.29 g) were added, and the reaction mixture was stirred at the same temperature for 6 h. The reaction solution was filtered through celite (R) and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (24.2 g). MS (m/z): 305.1 [M+H] ⁺

[Step 3] Production of (SS)-N-[(1S)-1-([3,3'-bipyridin]-5-yl)ethyl]-2-methylpropane-2-sulfinamide

The title compound (22.7 g) was obtained by replacing 2-chloropyrimidin-4-amine and isoquinoline-4-ylboronic acid with (SS)-N-[(1S)-1-(5-bromopyridin-3-yl)ethyl]-2-methylpropane-2-sulfinamide (23.2 g) and pyridin-3-ylboronic acid (11.2 g) obtained in step 2, as described in Reference Example 14. MS (m/z): 304.2 [M+H] ⁺

[Step 4] Production of (1S)-1-([3,3'-bipyridin]-5-yl)ethyl-1-amine

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

Reference Example 17: (1S)-1-[5-(phenylethynyl)pyridin-3-yl]ethyl-1-amine dihydrochloride

[Step 1] Production of (SS)-2-methyl-N-{(1S)-1-[5-(phenylethynyl)pyridin-3-yl]ethyl}propane-2-sulfinamide

The title compound (530 mg) was obtained by replacing methyl 4-chloro-3-iodobenzoate and ethynyl(trimethyl)silane with (SS)-N-[(1S)-1-(5-bromopyridin-3-yl)ethyl]-2-methylpropane-2-sulfinamide (500 mg) and ethynylbenzene (335 mg) obtained in step 2 of Reference Example 16, as described in step 1 of Reference Example 8. MS (m/z): 327.2 [M+H] ⁺

[Step 2]: Production of (1S)-1-[5-(phenylethynyl)pyridin-3-yl]ethyl-1-amine dihydrochloride

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

Reference Example 18: (1S)-1-[5-(pyrimidin-2-yl)pyridin-3-yl]ethyl-1-amine

[Step 1] Production of (SS)-2-methyl-N-{(1S)-1-[5-(pyrimidin-2-yl)pyridin-3-yl]ethyl}propane-2-sulfinamide

The title compound (420 mg) was obtained by replacing 3-bromo-5-(methoxymethoxy)pyridine with (SS)-N-[(1S)-1-(5-bromopyridin-3-yl)ethyl]-2-methylpropane-2-sulfinamide (600 mg) obtained in step 2 of Reference Example 16, by the method described in step 1 of Reference Example 10. MS (m/z): 305.4 [M+H] ⁺

[Step 2]: Production of (1S)-1-[5-(pyrimidin-2-yl)pyridin-3-yl]ethyl-1-amine

The title compound (200 mg) was obtained by replacing (SS)-N-[(1S)-1-[5-(pyrimidin-2-yl)pyridin-3-yl]ethyl}propane-2-sulfinamide (420 mg) with (SS)-N-[(1S)-1-([3,3'-bipyridin]-5-yl)ethyl]-2-methylpropane-2-sulfinamide as described in step 4 of Reference Example 16. MS (m/z): 201.3 [M+H] ⁺

Reference Example 19: Pyrazolo[5,1-b][1,3]thiazole-7-carboxaldehyde

[Step 1] Production of (pyrazolo[5,1-b][1,3]thiazo-7-yl)methanol

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

[Step 2] Production of pyrazolo[5,1-b][1,3]thiazole-7-carboxaldehyde

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

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

The title compound (1.17 g) was obtained by using 5-amino-6-methylpyridin-3-carboxylic acid (915 mg) instead of 3-amino-4-methylbenzoic acid, as described in Reference Example 7. MS (m/z): 250.2 [M+H] ⁺

Reference Example 21: N-(5-formylpyridin-2-yl)morpholine-4-carboxamide

[Step 1] Production of (5-formylpyridin-2-yl)carbamate

TEA (0.57 mL) and phenyl chloroformate (304 mg) were added to a solution of 6-aminopyridine-3-carboxaldehyde (250 mg) in THF (5.1 mL), and the reaction mixture was stirred overnight at room temperature. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to give the title compound (246 mg). MS (m/z): 243.2 [M+H] ⁺

[Step 2] Production of N-(5-formylpyridin-2-yl)morpholin-4-carboxamide

Morpholine (43 mg) and TEA (0.072 mL) were added to a solution of (5-formylpyridin-2-yl)carbamate (40 mg) obtained in step 1 in NMP (0.34 mL), and the reaction mixture was stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to give the title compound (246 mg). MS (m/z): 236.1 [M+H] ⁺

Reference Example 22: N-cyclopropyl-N'-(5-formylpyridin-2-yl)-N-methylurea

The title compound (21 mg) was obtained by using N-methylcyclopropylamine (94 mg) instead of morpholine, as described in step 2 of Reference Example 21. MS (m/z): 220.1 [M+H] ⁺

Reference Example 23: 7-Formyl-2,3-dihydro-4H-pyrido[3,2-b][1,4]oxazine-4-carboxylic acid tert-butyl ester

[Step 1] Production of 7-bromo-2,3-dihydro-4H-pyrido[3,2-b][1,4]oxazine-4-carboxylic acid tert-butyl ester

To a solution of 7-bromo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine (160 mg) in THF (2.5 mL), TEA (0.01 mL), _Boc₂O (0.19 mL), and DMAP (4.5 mg) were added, and the reaction mixture was stirred overnight at room temperature. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to give the title compound (177 mg). MS (m/z): 315.1 [M+H] ^⁺

[Step 2] Production of 7-vinyl-2,3-dihydro-4H-pyrido[3,2-b][1,4]oxazine-4-carboxylic acid tert-butyl ester

The title compound (118 mg) was obtained by using tert-butyl 7-bromo-2,3-dihydro-4H-pyrido[3,2-b][1,4]oxazine-4-carboxylate (177 mg) and 2-vinyl-4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane (172 mg) instead of 2-chloropyrimidin-4-amine and isoquinoline-4-ylboronic acid, as described in Reference Example 14. MS (m/z): 263.2 [M+H] ⁺

[Step 3] Production of 7-formyl-2,3-dihydro-4H-pyrido[3,2-b][1,4]oxazine-4-carboxylic acid tert-butyl ester

The tert-butyl 7-vinyl-2,3-dihydro-4H-pyrido[3,2-b][1,4]oxazine-4-carboxylate (118 mg) obtained in step ₂ was bubbled in dichloromethane (2 mL) at -78 °C for 30 minutes. Argon was then bubbled into the solution until it became colorless. Triphenylphosphine (142 mg) was added, and the reaction mixture was stirred overnight at room temperature. Water was added to the reaction solution, and the reaction mixture was extracted with dichloromethane. After drying the organic layer with anhydrous sodium sulfate, the solvent was removed under reduced pressure to give the title compound as the crude product.

Reference Example 24: 6-(1H-1,2,3-triazol-1-yl)pyridine-3-carboxaldehyde

[Step 1] Production of 5-vinyl-2-(1H-1,2,3-triazol-1-yl)pyridine

The title compound (90 mg) was obtained by using 5-bromo-2-(1H-1,2,3-triazol-1-yl)pyridine (142 mg) (e.g., synthesized by the method described in WO2006/038100) and 2-vinyl-4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane (117 mg) instead of 2-chloropyrimidin-4-amine and isoquinoline-4-ylboronic acid, by the method described in Reference Example 14. MS (m/z): 173.1 [M+H] ⁺

[Step 2] Production of 6-(1H-1,2,3-triazol-1-yl)pyridine-3-carboxaldehyde

The title compound (306 mg) was obtained as a crude product by replacing 7-vinyl-2-(1H-1,2,3-triazol-1-yl)pyridine (90 mg) obtained in step 1 with 7-vinyl-2,3-dihydro-4H-pyrido[3,2-b][1,4]oxazine-4-carboxylic acid tert-butyl ester, as described in step 3 of Reference Example 23. MS (m/z): 175.1 [M+H] ⁺

Reference Example 25: 5-(2H-1,2,3-triazol-2-yl)pyridine-3-carboxaldehyde

[Step 1] Production of [5-(2H-1,2,3-triazol-2-yl)pyridin-3-yl]methanol

To a solution of methyl 5-(2H-1,2,3-triazol-2-yl)pyridine-3-carboxylate (44 mg) (e.g., synthesized by the method described in Angew. Chem. Int. Ed. 2011, 50, 8944-8947) in methanol (2.2 mL), sodium borohydride (41 mg) was added, and the reaction mixture was stirred overnight at room temperature. Water was added to the reaction solution, and the solvent was removed by vacuum distillation. The residue was purified by silica gel column chromatography to give the title compound.

[Step 2] Production of 5-(2H-1,2,3-triazol-2-yl)pyridine-3-carboxaldehyde

The title compound (22 mg) was obtained by replacing pyrazolo[5,1-b][1,3]thiazolyl-7-yl]methanol with [5-(2H-1,2,3-triazol-2-yl)pyridin-3-yl]methanol obtained in step 1, as described in step 2 of Reference Example 19.

Reference Example 26: 3-Formyl-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide

The title compound (134 mg) was obtained by using 3-formyl-4-methylbenzoic acid (100 mg) instead of 3-amino-4-methylbenzoic acid, as described in Reference Example 7. MS (m/z): 262.5 [M+H] ⁺

Reference Example 27: 5-(pyrimidin-2-yl)pyridine-3-amine dihydrochloride

[Step 1] Production of (5-bromopyridin-3-yl)-2-iminodicarbonate ditert-butyl ester

The title compound (40.0 g) was obtained by using 5-bromopyridin-3-amine (25.0 g) instead of 7-bromo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine, as described in step 1 of Reference Example 23. MS (m/z): 373.4 [M+H] ⁺

[Step 2] Production of [5-(pyrimidin-2-yl)pyridin-3-yl]-2-iminodicarbonate ditert-butyl ester

The title compound (14.3 g) was obtained by replacing 3-bromo-5-(methoxymethoxy)pyridine with (5-bromopyridin-3-yl)-2-iminodiacetic acid ditert-butyl ester (30.0 g) obtained in step 1, as described in step 1 of Reference Example 10. MS (m/z): 373.5 [M+H] ⁺

[Step 3] Production of 5-(pyrimidin-2-yl)pyridine-3-amine dihydrochloride

Hydrogen chloride (4M ethyl acetate solution, 14 mL) was added to a solution of [5-(pyrimidin-2-yl)pyridin-3-yl]-2-iminodicarbonate ditert-butyl ester (14.3 g) obtained in step 2 in ethanol (128 mL), and the reaction mixture was stirred at 60 °C for 3 h. The reaction solution was concentrated under reduced pressure, and the residue was suspended in ethyl acetate to collect the precipitate by filtration. The precipitate was washed with ethyl acetate and then dried to give the title compound (3.5 g). MS (m/z): 173.4 [M+H] ⁺

Reference Example 28: 3-Formyl-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide

The title compound (590 mg) was obtained by using 3-formylbenzoic acid (500 mg) instead of 3-amino-4-methylbenzoic acid, as described in Reference Example 7. MS (m/z): 248.5 [M+H] ⁺

Reference Example 29: 4-Fluoro-3-formyl-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide

The title compound (300 mg) was obtained by using 4-fluoro-3-carboxybenzoic acid (300 mg) instead of 3-amino-4-methylbenzoic acid, as described in Reference Example 7. MS (m/z): 266.5 [M+H] ⁺

Reference Example 30: 5-Formyl-N-[(1S,2S)-2-hydroxycyclohexyl]-6-methylpyridine-3-carboxamide

[Step 1] Production of 5-vinyl-N-[(1S,2S)-2-hydroxycyclohexyl]-6-methylpyridine-3-carboxamide

The title compound (614 mg) was obtained by using 5-bromo-N-[(1S,2S)-2-hydroxycyclohexyl]-6-methylpyridine-3-carboxamide (750 mg) and 2-vinyl-4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane (479 mg) instead of 2-chloropyrimidin-4-amine and isoquinoline-4-ylboronic acid, as described in Reference Example 14. MS (m/z): 261.2 [M+H] ⁺

[Step 2] Production of 5-formyl-N-[(1S,2S)-2-hydroxycyclohexyl]-6-methylpyridine-3-carboxamide

The title compound (360 mg) was obtained by replacing 7-vinyl-N-[(1S,2S)-2-hydroxycyclohexyl]-6-methylpyridine-3-carboxamide (614 mg) obtained in step 1 with 7-vinyl-2,3-dihydro-4H-pyrido[3,2-b][1,4]oxazine-4-carboxylic acid tert-butyl ester, as described in step 3 of Reference Example 23. MS (m/z): 263.2 [M+H] ⁺

Reference Example 31: Methyl 4-chloro-3-(hydroxymethyl)benzoate

Sodium borohydride (38 mg) was added to a solution of methyl 4-chloro-3-carboxybenzoate (200 mg) in methanol (3.4 mL) and THF (3.4 mL) at 0 °C, and the reaction mixture was stirred overnight at room temperature. Water was added to the reaction solution, and the solvent was removed by vacuum distillation. The residue was purified by silica gel column chromatography to give the title compound (130 mg).

Reference Example 32: Methyl 3-[(ethylamino)methyl]-4-methylbenzoate

Ethylamine (2M methanol solution, 2.8 mL) was added to a solution of methyl 3-formyl-4-methylbenzoate (500 mg) in methanol (11 mL), and the reaction mixture was stirred at room temperature for 30 min. Then, sodium borohydride (159 mg) was added, and the reaction mixture was stirred at room temperature for 2 h. Water was added to the reaction solution, and the solvent was removed by vacuum distillation. The residue was purified by silica gel column chromatography to give the title compound (423 mg). MS (m/z): 208.2 [M+H] ⁺

Reference Example 33: Ethyl 5-formyl-6-methylpyridine-3-carboxylate

[Step 1] Production of ethyl 5-vinyl-6-methylpyridine-3-carboxylate

The title compound (3.0 g) was obtained by using ethyl 5-bromo-6-methylpyridine-3-carboxylate (4.2 g) and 2-vinyl-4,4,5,5-tetramethyl-1,3,2-dioxane-pentaborane (3.7 g) instead of 2-chloropyrimidin-4-amine and isoquinoline-4-ylboronic acid, as described in Reference Example 14. MS (m/z): 192.1 [M+H] ⁺

[Step 2] Production of ethyl 5-formyl-6-methylpyridine-3-carboxylate

The title compound (2.7 g) was obtained by replacing 7-vinyl-2,3-dihydro-4H-pyrido[3,2-b][1,4]oxazine-4-carboxylate tert-butyl ester with ethyl 5-vinyl-6-methylpyridinium-3-carboxylate (3.0 g) obtained in step 1, as described in step 3 of Reference Example 23. MS (m/z): 194.1 [M+H] ⁺

Reference Example 34: 1-[(5-bromopyridin-3-yl)methyl]-4-methylpiperazine

Acetic acid (0.15 mL) and 1-methylpiperazine (808 mg) were added to a solution of 5-bromopyridine-3-carboxaldehyde (500 mg) in dichloromethane (11 mL), and the reaction mixture was stirred at room temperature for 1 hour. Then, sodium triacetoxyborohydride (1.14 g) was added, and the reaction mixture was stirred at room temperature for 2 hours. Water was added to the reaction solution, and the solvent was removed by vacuum distillation. The residue was purified by silica gel column chromatography to give the title compound (700 mg). MS (m/z): 270.1 [M+H] ⁺

Reference Example 35: 4-[(5-bromopyridin-3-yl)methyl]morpholine

The title compound (570 mg) was obtained by using morpholine (703 mg) instead of 1-methylpiperazine, as described in Reference Example 34. MS (m/z): 257.1 [M+H] ⁺

Reference Example 36: 5-Bromo-N-(oxacyclohexane-4-yl)pyridine-3-amine

The title compound (230 mg) was obtained by using methyl 5-bromopyridine and oxacyclohexane-4-amine (256 mg) instead of methyl 5-bromopyridine-3-carboxylate and 1-cyclopropylmethylamine, as described in step 1 of Reference Example 1. MS (m/z): 257.0 [M+H] ⁺

Reference Example 37: 5-Bromo-N-(1-methylpiperidin-4-yl)pyridine-3-amine

The title compound (300 mg) was obtained by using methyl 5-bromopyridine and 1-methylpiperidin-4-amine (304 mg) instead of methyl 5-bromopyridine-3-carboxylate and 1-cyclopropylmethylamine, as described in step 1 of Reference Example 1. MS (m/z): 270.1 [M+H] ⁺

Reference Example 38: 1-[(5-bromopyridin-3-yl)methyl]-4-ethylpiperazine

The title compound (680 mg) was obtained by using 1-ethylpiperazine (921 mg) instead of 1-methylpiperazine, as described in Reference Example 34. MS (m/z): 284.1 [M+H] ⁺

Reference Example 39: 5-Bromo-N-(oxetane-3-yl)pyridine-3-amine

The title compound (410 mg) was obtained by using methyl 5-bromopyridine (1.00 g) and oxetane-3-amine (309 mg) instead of methyl 5-bromopyridine-3-carboxylate and 1-cyclopropylmethylamine, as described in step 1 of Reference Example 1. MS (m/z): 229.3 [M+H] ⁺

Reference Example 40: 5,6,7,8-Tetrahydropyrido[4,3-d]pyrimidin-2-yl-2-iminodicarbonate ditert-butyl ester

[Step 1] Production of 2-[bis(tert-butoxycarbonyl)amino]-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-carboxylic acid benzyl ester

The title compound (960 mg) was obtained by using 2-amino-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-formate benzyl ester (600 mg) instead of 7-bromo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine, as described in step 1 of Reference Example 23.

[Step 2] Production of 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl-2-iminodicarbonate ditert-butyl ester

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

Reference Example 41: 3-Amino-N-[(1S,2S)-2-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl]-4-methylbenzamide

To a solution of 3-amino-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide (800 mg) obtained in Reference Example 7 in dichloromethane (16 mL), tert-butyl dimethylsilyl trifluoromethanesulfonate (1.11 g) and 2,6-dimethylpyridine (690 mg) were added, and the reaction mixture was stirred overnight at room temperature. The reaction solution was diluted with ethyl acetate. After washing with water and saturated salt solution, the solvent was removed by vacuum distillation. The residue obtained was purified by silica gel column chromatography to give the title compound (661 mg). MS (m/z): 363.3 [M+H] ⁺

Reference Example 42: Methyl 3-(aminomethyl)-4-methylbenzoate

[Step 1] Production of methyl 3-[(hydroxyimino)methyl]-4-methylbenzoate

A solution of methyl 3-formyl-4-methylbenzoate (1.00 g) in methanol (20 mL) was added to a 50% aqueous solution of hydroxylamine (1.32 mL), and the reaction mixture was stirred at 50 °C for 2 hours. The reaction solution was concentrated under reduced pressure, and ethyl acetate was added to the resulting residue. The organic layer was washed with water and a saturated salt solution. The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure to give the title compound (1.02 g). MS (m/z): 194.4 [M+H] ⁺

[Step 2] Production of methyl 3-(aminomethyl)-4-methylbenzoate

Hydrogen chloride (2M methanol solution, 15 mL) was added to methyl 3-[(hydroxyimino)methyl]-4-methylbenzoate (1.02 g) obtained in step 1. After degassing, 5% Pd-C (500 mg) was added under an argon atmosphere while stirring the reaction mixture at room temperature. The reaction mixture was stirred at room temperature for 3 hours under a hydrogen atmosphere. The reaction solution was filtered through celite (R) and then the solvent was removed under reduced pressure. The residue was alkalized by adding an aqueous sodium hydroxide solution and then extracted with ethyl acetate. The organic layer was washed with a saturated salt solution and dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure to give the title compound (820 mg). MS (m/z): 180.4 [M+H] ⁺

Reference Example 43: 3-Bromo-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide

The title compound (23.0 g) was obtained by using 3-bromo-4-methylbenzoic acid (16.6 g) instead of 3-amino-4-methylbenzoic acid, as described in Reference Example 7. MS (m/z): 312.0 [M+H] ⁺

Example 1: 2-(cyclopropylamino)-N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)-1,3-thiazolyl-5-carboxamide

[Step 1] Production of methyl 3-[(2-bromo-1,3-thiazo-5-carbonyl)amino]-4-methylbenzoate

To a solution of 2-bromo-1,3-thiazolyl-5-carboxylic acid (2.20 g) in DMF (20 mL), methyl 3-amino-4-methylbenzoate (1.75 g), HATU (4.83 g), and DIPEA (3.66 mL) were added sequentially, and the reaction mixture was stirred at room temperature for 6 hours. The reaction solution was diluted with ethyl acetate, and the organic layer was washed with saturated aqueous sodium bicarbonate solution and saturated salt solution. The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was removed by vacuum distillation. The residue was purified by silica gel column chromatography to give the title compound (1.02 g).

[Step 2] Production of methyl 3-{[2-(cyclopropylamino)-1,3-thiazolyl-5-carbonyl]amino}-4-methylbenzoate

Cyclopropylamine (121 mg) was added to a solution of methyl 3-[(2-bromo-1,3-thiazolyl-5-carbonyl)amino]-4-methylbenzoate (150 mg) obtained in step 1 in NMP (0.5 mL), and the reaction mixture was stirred at 80 °C for 6 hours. After cooling, the reaction solution was purified by silica gel column chromatography to give the title compound (105 mg).

[Step 3] Production of 3-{[2-(cyclopropylamino)-1,3-thiazolyl-5-carbonyl]amino}-4-methylbenzoic acid

The title compound (90 mg) was obtained by replacing methyl 3-{[2-(cyclopropylamino)-1,3-thiazolyl-5-carbonyl]amino}-4-methylbenzoate (103 mg) with methyl 5-[(cyclopropylmethyl)amino]pyridine-3-carboxylate as described in step 2 of Reference Example 1.

[Step 4] Production of 2-(cyclopropylamino)-N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)-1,3-thiazolyl-5-carboxamide

To a solution of 3-{[2-(cyclopropylamino)-1,3-thiazolyl-5-carbonyl]amino}-4-methylbenzoic acid (30 mg) obtained in step 3 in DMF (1 mL), HATU (54 mg) and DIPEA (0.065 mL) were added sequentially, and the reaction mixture was stirred at room temperature for 10 min. Then, (1S,2S)-2-aminocyclohexyl-1-ol hydrochloride (22 mg) was added, and the reaction mixture was stirred at room temperature for 1 h. The reaction solution was diluted with ethyl acetate, and the organic layer was washed with saturated aqueous sodium bicarbonate solution and saturated salt solution. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was removed by vacuum distillation. The residue was purified by silica gel column chromatography to give the title compound (16 mg).

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

[Step 1] Production of methyl 3-[(5-bromopyridine-3-carbonyl)amino]-4-methylbenzoate

The title compound (1.70 g) was obtained by using 5-bromopyridine-3-carboxylic acid (1.00 g) instead of 2-bromo-1,3-thiazolyl-5-carboxylic acid, via the method described in step 1 of Example 1. MS (m/z): 349.0 [M+H] ⁺

[Step 2] Production of 3-[(5-bromopyridin-3-carbonyl)amino]-4-methylbenzoic acid

The title compound (505 mg) was obtained by replacing methyl 3-[(5-bromopyridin-3-carbonyl)amino]-4-methylbenzoate (650 mg) with methyl 5-[(cyclopropylmethyl)amino]pyridin-3-carboxylate as described in step 2 of Reference Example 1. MS (m/z): 335.0 [M+H] ⁺

[Step 3] Production of 5-bromo-N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)pyridine-3-carboxamide

The title compound (650 mg) was obtained by replacing 3-{[2-(cyclopropylamino)-1,3-thiazolyl-5-carbonyl]amino}-4-methylbenzoic acid with 3-[(5-bromopyridin-3-carbonyl)amino]-4-methylbenzoic acid (505 mg) obtained in step 2, as described in step 4 of Example 1. MS (m/z): 432.1 [M+H] ⁺

[Step 4] Production of N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)-5-phenylpyridine-3-carboxamide

The title compound (40 mg) was obtained by replacing 2-chloropyrimidin-4-amine and isoquinoline-4-ylboronic acid with 5-bromo-N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)pyridine-3-carboxamide (50 mg) and phenylboronic acid (17 mg) obtained in step 3, by the method described in Reference Example 14.

Example 3: 2-(cyclopropylmethyl)-N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)-1,3-thiazolyl-5-carboxamide

[Step 1] Production of methyl 3-{[2-(cyclopropylmethyl)-1,3-thiazolyl-5-carbonyl]amino}-4-methylbenzoate

The title compound (160 mg) was obtained by using 2-(cyclopropylmethyl)-1,3-thiazolyl-5-carboxylic acid (100 mg) instead of 2-bromo-1,3-thiazolyl-5-carboxylic acid, as described in step 1 of Example 1. MS (m/z): 331.5 [M+H] ⁺

[Step 2] Production of 3-{[2-(cyclopropylmethyl)-1,3-thiazolyl-5-carbonyl]amino}-4-methylbenzoic acid

The title compound (145 mg) was obtained by replacing methyl 3-{[2-(cyclopropylmethyl)-1,3-thiazolyl-5-carbonyl]amino}-4-methylbenzoate (160 mg) with methyl 5-[(cyclopropylmethyl)amino]pyridine-3-carboxylate as described in step 2 of Reference Example 1. MS (m/z): 317.4 [M+H] ⁺

[Step 3] Production of 2-(cyclopropylmethyl)-N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)-1,3-thiazolyl-5-carboxamide

The title compound (38 mg) was obtained by replacing 3-{[2-(cyclopropylmethyl)-1,3-thiazol-5-carbonyl]amino}-4-methylbenzoic acid with 3-{[2-(cyclopropylamino)-1,3-thiazol-5-carbonyl]amino}-4-methylbenzoic acid as described in step 4 of Example 1.

Example 5: N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)-2-phenyl-1,3-oxazol-5-carboxamide

The title compound (53 mg) was obtained by using 2-phenyl-1,3-oxazol-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-thiazolyl-5-carboxylic acid and methyl 3-amino-4-methylbenzoate, by the method described in step 1 of Example 1.

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

[Step 1] Production of methyl 4-methyl-3-[(5-phenylpyridine-3-carbonyl)amino]benzoate

The title compound (1.00 g) was obtained by replacing 2-chloropyrimidin-4-amine and isoquinoline-4-ylboronic acid with methyl 3-[(5-bromopyridin-3-carbonyl)amino]-4-methylbenzoate (1.00 g) and phenylboronic acid (419 mg) obtained in step 1 of Example 2, as described in Reference Example 14. MS (m/z): 347.2 [M+H] ⁺

[Step 2] Production of 4-methyl-3-[(5-phenylpyridine-3-carbonyl)amino]benzoic acid

The title compound (910 mg) was obtained by replacing methyl 4-methyl-3-[(5-phenylpyridin-3-carbonyl)amino]benzoate (1.00 g) obtained in step 1 with methyl 5-[(cyclopropylmethyl)amino]pyridin-3-carboxylate, as described in step 2 of Reference Example 1. MS (m/z): 333.2 [M+H] ⁺

[Step 3] Production of N-(5-{[(1S)-2-hydroxy-1-phenylethyl]carbamoyl}-2-methylphenyl)-5-phenylpyridine-3-carboxamide

The title compound (38 mg) was obtained by replacing 3-{[2-(cyclopropylamino)-1,3-thiazolyl-5-carbonyl]amino}-4-methylbenzoic acid and (1S,2S)-2-aminocyclohexyl-1-ol hydrochloride with 4-methyl-3-[(5-phenylpyridin-3-carbonyl)amino]amino (40 mg) and (2S)-2-amino-2-phenylethyl-1-ol hydrochloride as described in step 4 of Example 1.

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

The title compound (43 mg) was obtained by 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-thiazolyl-5-carboxylic acid and methyl 3-amino-4-methylbenzoate, as described in step 1 of Example 1.

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

The title compound (43 mg) was obtained by replacing 2-chloropyrimidin-4-amine and isoquinoline-4-ylboronic acid with 5-bromo-N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)pyridine-3-carboxamide (61 mg) and (3-fluorophenyl)boronic acid (28 mg) obtained in step 3 of Example 2, by the method described in Reference Example 14.

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

The title compound (58 mg) was obtained by 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-thiazolyl-5-carboxylic acid and methyl 3-amino-4-methylbenzoate, as described in step 1 of Example 1.

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

[Step 1] Production of methyl 3-[(2-chloro-1,3-thiazo-5-carbonyl)amino]-4-methylbenzoate

Under ice-cooled conditions, a solution of 2-chloro-1,3-thiazolyl-5-carbonyl chloride (8.31 g) in THF (80 mL) was added dropwise to a stirred solution of methyl 3-amino-4-methylbenzoate (6.89 g) in THF (80 mL), and the reaction mixture was stirred at the same temperature for 30 min. The reaction solution was diluted with ethyl acetate, and the organic layer was washed with saturated aqueous sodium bicarbonate solution and saturated salt solution. The organic layer was dried over anhydrous sodium sulfate, and the solvent was then removed by vacuum distillation. Water was added to the obtained residue to suspend it, and the precipitate was collected by filtration to give the title compound (12.5 g). MS (m/z): 311.4 [M+H] ⁺

[Step 2] Production of 3-[(2-chloro-1,3-thiazo-5-carbonyl)amino]-4-methylbenzoic acid

The title compound (10.4 g) was obtained by replacing methyl 3-[(2-chloro-1,3-thiazolyl-5-carbonyl)amino]-4-methylbenzoate (12.5 g) with methyl 5-[(cyclopropylmethyl)amino]pyridine-3-carboxylate as described in step 2 of Reference Example 1. MS (m/z): 297.4 [M+H] ⁺

[Step 3] Production of 2-chloro-N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)-1,3-thiazolyl-5-carboxamide

The title compound (9.8 g) was obtained by replacing 3-{[2-(cyclopropylamino)-1,3-thiazol-5-carbonyl)amino]-4-methylbenzoic acid (7.5 g) obtained in step 2 with 3-[2-(cyclopropylamino)-1,3-thiazol-5-carbonyl]amino}-4-methylbenzoic acid as described in step 4 of Example 1. MS (m/z): 394.2 [M+H] ⁺

[Step 4] Production of N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)-5-phenylpyridine-3-carboxamide

The title compound (72 mg) was obtained by using 2-chloro-N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)-1,3-thiazol-5-carboxamide (90 mg) and 2-cyclopropylethyl-1-amine (249 mg) obtained in step 3 instead of methyl 3-[(2-bromo-1,3-thiazol-5-carbonyl)amino]-4-methylbenzoate and cyclopropylamine, as described in step 2 of Example 1.

Example 57: 3-[(5-bromopyridin-3-yl)ethynyl]-4-chloro-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide

[Step 1] Production of methyl 3-[(5-bromopyridin-3-yl)ethynyl]-4-chlorobenzoate

The title compound (1.60 g) was obtained by replacing methyl 4-chloro-3-ethynylbenzoate (1.01 g) and 3-bromo-5-iodopyridine (1.47 g) obtained in Reference Example 8 with ethynyl(trimethyl)silane and methyl 4-chloro-3-iodobenzoate, as described in step 1 of Reference Example 8. MS (m/z): 350.0 [M+H] ⁺

[Step 2] Production of 3-[(5-bromopyridin-3-yl)ethynyl]-4-chlorobenzoic acid

The title compound (360 mg) was obtained by replacing methyl 3-[(5-bromopyridin-3-yl)ethynyl]-4-chlorobenzoate (600 mg) obtained in step 1 with methyl 5-[(cyclopropylmethyl)amino]pyridin-3-carboxylate, as described in step 2 of Reference Example 1. MS (m/z): 335.9 [M+H] ⁺

[Step 3] Production of 3-[(5-bromopyridin-3-yl)ethynyl]-4-chloro-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide

The title compound (170 mg) was obtained by replacing 3-{[2-(cyclopropylamino)-1,3-thiazolyl-5-carbonyl]amino}-4-methylbenzoic acid with 3-[(5-bromopyridin-3-yl)ethynyl]-4-chlorobenzoic acid (370 mg) obtained in step 2, by the method described in step 4 of Example 1.

Example 58: 4-Chloro-N-[(1S,2S)-2-hydroxycyclohexyl]-3-[(5-phenylpyridin-3-yl)ethynyl]benzamide

The title compound (5 mg) was obtained by replacing 2-chloropyrimidin-4-amine and isoquinoline-4-ylboronic acid with 3-[(1S,2S)-2-hydroxycyclohexyl]benzamide (50 mg) and phenylboronic acid (15 mg) obtained in Example 57, as described in Reference Example 14.

Example 59: N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-[(5-methylpyridin-3-yl)ethynyl]benzamide

The title compound (14 mg) was obtained by using 3-ethynyl-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide (30 mg) and 3-bromo-5-methylpyridine (30 mg) instead of ethynyl(trimethyl)silane and methyl 4-chloro-3-iodobenzoate, as described in step 1 of Reference Example 8.

Example 61: 3-[(5-bromopyridin-3-yl)ethynyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide

The title compound (14.5 g) was obtained by replacing ethynyl(trimethyl)silane and methyl 4-chloro-3-iodobenzoate with 3-ethynyl-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide (20.5 g) and 3-bromo-5-iodopyridine (24.8 g) obtained in Reference Example 9, via step 1 of Reference Example 8.

Example 62: N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-{[5-(pyrimidin-2-yl)pyridin-3-yl]ethynyl}benzamide

DMF (0.5 mL) was added to 3-[(5-bromopyridin-3-yl)ethynyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide (30 mg), 2-(tributylmethylstannyl)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 stirred at 150 °C for 30 minutes using a microwave reaction apparatus. After cooling the reaction solution, it was purified by silica gel column chromatography to give the title compound (15 mg).

Example 67: 3-[(5-cyclopropylpyridin-3-yl)ethynyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide

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

Example 76: 3-[(5-bromopyridin-3-yl)ethynyl]-N-[(1S,2S)-1,3-dihydroxy-1-phenylprop-2-yl]-4-methylbenzamide

[Step 1] Production of 3-[(5-bromopyridin-3-yl)ethynyl]-4-methylbenzoic acid

The title compound (47 mg) was obtained by using 3-ethynyl-4-methylbenzoic acid (40 mg) and 3-bromo-5-iodopyridine (71 mg) instead of ethynyl(trimethyl)silane and methyl 4-chloro-3-iodobenzoate, via step 1 of Reference Example 8. MS (m/z): 316.2 [M+H] ⁺

[Step 2] Production of 3-[(5-bromopyridin-3-yl)ethynyl]-N-[(1S,2S)-1,3-dihydroxy-1-phenylprop-2-yl]-4-methylbenzamide

The title compound (28 mg) was obtained by replacing 3-{[2-(cyclopropylamino)-1,3-thiazolyl-5-carbonyl]amino}-4-methylbenzoic acid (25 mg) and (1S,2S)-2-amino-1-phenylprop-1,3-diol (16 mg) obtained in step 1 with the same compounds as described in step 4 of Example 1.

Example 77: ^N1 -[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-N3-(5-phenylpyridin-3-yl)benzene-1,3-dicarboxamide

[Step 1] Production of methyl 5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylbenzoate

The title compound (600 mg) was obtained by replacing 3-{[2-(cyclopropylamino)-1,3-thiazolyl-5-carbonyl]amino}-4-methylbenzoic acid with 3-(methoxycarbonyl)-4-methylbenzoic acid (500 mg) as described in step 4 of Example 1. MS (m/z): 292.3 [M+H] ⁺

[Step 2] Production of 5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylbenzoic acid

The title compound (430 mg) was obtained by replacing methyl 5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylbenzoate (600 mg) with methyl 5-[(cyclopropylmethyl)amino]pyridine-3-carboxylate as described in step 2 of Reference Example 1. MS (m/z): 278.3 [M+H] ⁺

[Step 3] Production of ^N3- (5-bromopyridin-3-yl)-N1-[(1S,2S)-2-hydroxycyclohexyl]-4-methylphenyl-1,3-dicarboxamide

The title compound (166 mg) was obtained by replacing 2-bromo-1,3-thiazolyl-5-carboxylic acid and methyl 3-amino-4-methylbenzoate with 5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylbenzoic acid (200 mg) and 5-bromopyridin-3-amine (137 mg) obtained in step 2, as described in step 1 of Example 1. MS (m/z): 432.3 [M+H] ⁺

[Step 4] Production of ^N1 -[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-N3-(5-phenylpyridin-3-yl)benzene-1,3-dicarboxamide

The title compound (40 mg) was obtained by replacing 2-chloropyrimidin-4-amine and isoquinoline-4-ylboronic acid with ^N3- (5-bromopyridin-3-yl)-N1-[(1S,2S)-2-hydroxycyclohexyl]-4-methylphenyl-1,3-dicarboxamide (50 mg) and phenylboronic acid (17 mg) obtained in step 3, by the method described in Reference Example 14.

Example 78: N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-{[2-(pyridin-3-yl)pyrimidin-4-yl]amino}benzamide

[Step 1] Production of methyl 4-methyl-3-{[2-(pyridin-3-yl)pyrimidin-4-yl]amino}benzoate

The title compound (280 mg) was obtained by using methyl 3-bromo-4-methylbenzoate (350 mg) and 2-(pyridin-3-yl)pyrimidin-4-amine (263 mg) instead of methyl 5-bromopyridin-3-carboxylate and 1-cyclopropylmethylamine, as described in step 1 of Reference Example 1.

[Step 2] Production of 4-methyl-3-{[2-(pyridin-3-yl)pyrimidin-4-yl]amino}benzoic acid

The title compound (180 mg) was obtained by using methyl 4-methyl-3-{[2-(pyridin-3-yl)pyrimidin-4-yl]amino}benzoate (280 mg) instead of methyl 5-[(cyclopropylmethyl)amino]pyridin-3-carboxylate, as described in step 2 of Reference Example 1.

[Step 3] Production of N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-{[2-(pyridin-3-yl)pyrimidin-4-yl]amino}benzamide

The title compound (50 mg) was obtained by using 4-methyl-3-{[2-(pyridin-3-yl)pyrimidin-4-yl]amino}benzoic acid (50 mg) instead of 3-{[2-(cyclopropylamino)-1,3-thiazolyl-5-carbonyl]amino}-4-methylbenzoic acid, as described in step 4 of Example 1.

Example 83: 3-(2-amino-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-N-[(1S,2S)-1,3-dihydroxy-1-phenylprop-2-yl]-4-methylbenzamide

[Step 1] Production of methyl 3-{2-[bis(tert-butoxycarbonyl)amino]-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl}-4-methylbenzoate

The title compound (54 mg) was obtained by using methyl 3-bromo-4-methylbenzoate (84 mg) and 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl-2-iminodicarbonate ditert-butyl ester (86 mg) instead of methyl 5-bromopyridin-3-carboxylate and 1-cyclopropylmethylamine, as described in step 1 of Reference Example 1. MS (m/z): 499.6 [M+H] ⁺

[Step 2] Production of methyl 3-(2-amino-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-4-methylbenzoate

Hydrogen chloride (2 M methanol solution, 2.1 mL) was added to methyl 3-{2-[bis(tert-butoxycarbonyl)amino]-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl}-4-methylbenzoate (70 mg) obtained in step 1, and the reaction mixture was stirred at 50 °C for 5 hours. After cooling, the reaction solution was purified by silica gel column chromatography to give the title compound (10 mg). MS (m/z): 299.5 [M+H] ⁺

[Step 3] Production of 3-(2-amino-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-4-methylbenzoic acid

The title compound was obtained by using methyl 3-(2-amino-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-4-methylbenzoate (10 mg) instead of methyl 5-[(cyclopropylmethyl)amino]pyridin-3-carboxylate, as described in step 2 of Reference Example 1. MS (m/z): 285.3 [M+H] ⁺

[Step 4] Production of 3-(2-amino-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-N-[(1S,2S)-1,3-dihydroxy-1-phenylprop-2-yl]-4-methylbenzamide

The title compound (6 mg) was obtained by replacing 3-{[2-(cyclopropylamino)-1,3-thiazolyl-5-carbonyl]amino}-4-methylbenzoic acid and (1S,2S)-2-amino-1-phenylprop-1,3-diol (11 mg) obtained in step 3 with 3-{[2-(cyclopropylamino)-1,3-thiazolyl-5-carbonyl]amino}-4-methylbenzoic acid and (1S,2S)-2-aminocyclohexyl-1-ol hydrochloride as described in step 4 of Example 1.

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

[Step 1] Production of methyl 4-methyl-3-{[(1S)-1-(5-phenylpyridin-3-yl)ethyl]amino}benzoate

The title compound (220 mg) was obtained by using methyl 3-bromo-4-methylbenzoate (324 mg) and (1S)-1-(5-phenylpyridin-3-yl)ethyl-1-amine (280 mg) instead of methyl 5-bromopyridin-3-carboxylate and 1-cyclopropylmethylamine, as described in step 1 of Reference Example 1. MS (m/z): 347.3 [M+H] ⁺

[Step 2] Production of 4-methyl-3-{[(1S)-1-(5-phenylpyridin-3-yl)ethyl]amino}benzoic acid

The title compound (180 mg) was obtained by replacing methyl 4-methyl-3-{[(1S)-1-(5-phenylpyridin-3-yl)ethyl]amino}benzoate (220 mg) with methyl 5-[(cyclopropylmethyl)amino]pyridin-3-carboxylate as described in step 2 of Reference Example 1. MS (m/z): 333.3 [M+H] ⁺

[Step 3] Production of N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-{[(1S)-1-(5-phenylpyridin-3-yl)ethyl]amino}benzamide

The title compound (60 mg) was obtained by replacing 3-{[2-(cyclopropylamino)-1,3-thiazolyl-5-carbonyl]amino}-4-methylbenzoic acid with 4-methyl-3-{[(1S)-1-(5-phenylpyridin-3-yl)ethyl]amino}benzoic acid obtained in step 2, by the method described in step 4 of Example 1.

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

[Step 1] Production of methyl 3-{[(1S)-1-([3,3’-bipyridin]-5-yl)ethyl]amino}-4-methylbenzoate

The title compound (10.3 g) was obtained by using methyl 3-bromo-4-methylbenzoate (13.9 g) and (1S)-1-([3,3'-bipyridin]-5-yl)ethyl-1-amine (11.0 g) instead of methyl 5-bromopyridin-3-carboxylate and 1-cyclopropylmethylamine, as described in step 1 of Reference Example 1. MS (m/z): 348.3 [M+H] ⁺

[Step 2] Production of 3-{[(1S)-1-([3,3'-bipyridin]-5-yl)ethyl]amino}-4-methylbenzoic acid

The title compound (8.7 g) was obtained by replacing methyl 5-[(cyclopropylmethyl)amino]pyridine-3-carboxylate with methyl 3-{[(1S)-1-([3,3'-bipyridinyl]-5-yl)ethyl]amino}-4-methylbenzoate (10.3 g) obtained in step 1, as described in step 2 of Reference Example 1. MS (m/z): 334.4 [M+H] ⁺

[Step 3] Production of 3-{[(1S)-1-([3,3'-bipyridin]-5-yl)ethyl]amino}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide

The title compound (9.4 g) was obtained by replacing 3-{[2-(cyclopropylamino)-1,3-thiazolyl-5-carbonyl]amino}-4-methylbenzoic acid with 3-{[1S)-1-([3,3'-bipyridinyl]-5-yl)ethyl]amino}-4-methylbenzoic acid obtained in step 2, by the method described in step 4 of Example 1.

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

[Step 1] Production of methyl 3-{[(1R)-1-(5-bromopyridin-3-yl)ethyl]amino}-4-methylbenzoate

The title compound (1.80 g) was obtained by using methyl 3-iodo-4-methylbenzoate (6.49 g) and (1S)-1-(5-bromopyridin-3-yl)ethyl-1-amine (3.78 g) instead of methyl 5-bromopyridin-3-carboxylate and 1-cyclopropylmethylamine, as described in step 1 of Reference Example 1. MS (m/z): 349.0 [M+H] ⁺

[Step 2] Production of 3-{[(1R)-1-(5-bromopyridin-3-yl)ethyl]amino}-4-methylbenzoic acid

The title compound (820 mg) was obtained by replacing methyl 5-[(cyclopropylmethyl)amino]pyridine-3-carboxylate with methyl 3-{[(1R)-1-(5-bromopyridin-3-yl)ethyl]amino}-4-methylbenzoate (1.00 g) obtained in step 1, as described in step 2 of Reference Example 1. MS (m/z): 335.1 [M+H] ⁺

[Step 3] Production of 3-{[(1S)-1-(5-bromopyridin-3-yl)ethyl]amino}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide

The title compound (920 mg) was obtained by replacing 3-{[2-(cyclopropylamino)-1,3-thiazolyl-5-carbonyl]amino}-4-methylbenzoic acid with 3-{[1R)-1-(5-bromopyridin-3-yl)ethyl]amino}-4-methylbenzoic acid obtained in step 2, as described in step 4 of Example 1. MS (m/z): 432.3 [M+H] ⁺

[Step 4] Production of 3-{[(1S)-1-([3,4'-bipyridin]-5-yl)ethyl]amino}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide

The title compound (9 mg) was obtained by replacing 2-chloropyrimidin-4-amine and isoquinoline-4-ylboronic acid with 3-{[(1S)-1-(5-bromopyridin-3-yl)ethyl]amino}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide (30 mg) and pyridin-4-ylboronic acid (10 mg) obtained in step 3, by the method described in Reference Example 14.

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

[Step 1] Production of methyl 3-{[(1S)-1-([2,3’-bipyridine]-5’-yl)ethyl]amino}-4-methylbenzoate

The title compound (90 mg) was obtained by using methyl 3-{[(1R)-1-(5-bromopyridin-3-yl)ethyl]amino}-4-methylbenzoate (150 mg) and 2-bromopyridine (170 mg) instead of 3-bromo-5-(methoxymethoxy)pyridine and 2-bromopyrimidine, as described in step 1 of Reference Example 10. MS (m/z): 348.2 [M+H] ⁺

[Step 2] Production of 3-{[(1S)-1-([2,3'-bipyridin]-5'-yl)ethyl]amino}-4-methylbenzoic acid

The title compound (86 mg) was obtained by replacing methyl 3-{[(1S)-1-([2,3'-bipyridinyl]-5'-yl)ethyl]amino}-4-methylbenzoate (90 mg) with methyl 5-[(cyclopropylmethyl)amino]pyridin-3-carboxylate as described in step 2 of Reference Example 1. MS (m/z): 334.2 [M+H] ⁺

[Step 3] Production of 3-{[(1S)-1-([2,3'-bipyridin]-5'-yl)ethyl]amino}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide

The title compound (10 mg) was obtained by replacing 3-{[2-(cyclopropylamino)-1,3-thiazolyl-5-carbonyl]amino}-4-methylbenzoic acid with 3-{[1S)-1-([2,3'-bipyridine]-5'-yl)ethyl]amino}-4-methylbenzoic acid obtained in step 2 with 3-{[1S)-1-([2,3'-bipyridine]-5'-yl)ethyl]amino}-4-methylbenzoic acid with the method described in step 4 of Example 1.

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

The title compound (2.0 g) was obtained by using 3-amino-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide (1.6 g) obtained in Reference Example 7 instead of 1-methylpiperazine, by means of the method described in Reference Example 34.

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

The title compound (23 mg) was obtained by replacing 2-chloropyrimidin-4-amine and isoquinoline-4-ylboronic acid with 3-{[(5-bromopyridin-3-yl)methyl]amino}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide (30 mg) and phenylboronic acid (10 mg) obtained in Example 91, by the method described in Reference Example 14.

Example 94: 3-({[5-(cyclopropylethynyl)pyridin-3-yl]methyl}amino)-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide

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

Example 95: N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-({[5-(pyrimidin-2-yl)pyridin-3-yl]methyl}amino)benzamide

[Step 1] Production of methyl 3-{[(5-bromopyridin-3-yl)methyl]amino}-4-methylbenzoate

The title compound (13.0 g) was obtained by using methyl 3-amino-4-methylbenzoate (9.0 g) instead of 1-methylpiperazine, as described in Reference Example 34. MS (m/z): 335.3 [M+H] ⁺

[Step 2] Production of methyl 4-methyl-3-({[5-(pyrimidin-2-yl)pyridin-3-yl]methyl}amino)benzoate

The title compound (9.0 g) was obtained by replacing 3-bromo-5-(methoxymethoxy)pyridine with methyl 3-{[(5-bromopyridin-3-yl)methyl]amino}-4-methylbenzoate (13.0 g) obtained in step 1, as described in step 1 of Reference Example 10. MS (m/z): 335.5 [M+H] ⁺

[Step 3] Production of 4-methyl-3-({[5-(pyrimidin-2-yl)pyridin-3-yl]methyl}amino)benzoic acid

The title compound (6.6 g) was obtained by replacing methyl 5-[(cyclopropylmethyl)amino]pyridine-3-carboxylate with methyl 4-methyl-3-({[5-(pyrimidin-2-yl)pyridin-3-yl]methyl}amino)benzoate (9.0 g) obtained in step 2, as described in step 2 of Reference Example 1. MS (m/z): 321.5 [M+H] ⁺

[Step 4] Production of N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-({[5-(pyrimidin-2-yl)pyridin-3-yl]methyl}amino)benzamide

The title compound (5.5 g) was obtained by replacing 3-{[2-(cyclopropylamino)-1,3-thiazolyl-5-carbonyl]amino}-4-methylbenzoic acid with 4-methyl-3-({[5-(pyrimidin-2-yl)pyridin-3-yl]methyl}amino)benzoic acid obtained in step 3, by the method described in step 4 of Example 1.

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

[Step 1] Production of methyl 4-methyl-3-{[(quinolin-3-yl)methyl]amino}benzoate

The title compound (230 mg) was obtained by using methyl 3-amino-4-methylbenzoate (210 mg) and quinoline-3-carboxaldehyde (200 mg) instead of 1-methylpiperazine and 5-bromopyridine-3-carboxaldehyde, as described in Reference Example 34.

[Step 2] Production of 4-methyl-3-{[(quinolin-3-yl)methyl]amino}benzoic acid

The title compound (200 mg) was obtained by using methyl 4-methyl-3-{[(quinolin-3-yl)methyl]amino}benzoate (230 mg) obtained in step 1 instead of methyl 5-[(cyclopropylmethyl)amino]pyridine-3-carboxylate, as described in step 2 of Reference Example 1.

[Step 3] Production of N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-{[(quinolin-3-yl)methyl]amino}benzamide

The title compound (43 mg) was obtained by replacing 3-{[2-(cyclopropylamino)-1,3-thiazolyl-5-carbonyl]amino}-4-methylbenzoic acid with 4-methyl-3-{[(quinolin-3-yl)methyl]amino}benzoic acid obtained in step 2, by the method described in step 4 of Example 1.

Example 98: 3-[({5-[4-(2-aminopropyl-2-yl)phenyl]pyridin-3-yl}methyl)amino]-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide

The title compound (41 mg) was obtained by using 3-{[(5-bromopyridin-3-yl)methyl]amino}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide (80 mg) and 2-(4-bromophenyl)prop-2-amine (49 mg) instead of 3-bromo-5-(methoxymethoxy)pyridine and 2-bromopyrimidine, as described in step 1 of Reference Example 10.

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

[Step 1] Production of methyl 3-{[(6-chloropyrazin-2-yl)methyl]amino}-4-methylbenzoate

The title compound (150 mg) was obtained by using methyl 3-amino-4-methylbenzoate (449 mg) and 6-chloropyrazine-2-carboxaldehyde (774 mg) instead of 1-methylpiperazine and 5-bromopyridine-3-carboxaldehyde, as described in Reference Example 34.

[Step 2] Production of methyl 4-methyl-3-{[(6-phenylpyrazin-2-yl)methyl]amino}benzoate

The title compound (66 mg) was obtained by using methyl 3-{[(6-chloropyrazine-2-yl)methyl]amino}-4-methylbenzoate (70 mg) and phenylboronic acid (35 mg) obtained in step 1 instead of 2-chloropyrimidin-4-amine and isoquinoline-4-ylboronic acid, as described in Reference Example 14.

[Step 3] Production of 4-methyl-3-{[(6-phenylpyrazin-2-yl)methyl]amino}benzoic acid

The title compound (55 mg) was obtained by replacing methyl 4-methyl-3-{[(6-phenylpyrazin-2-yl)methyl]amino}benzoate (66 mg) with methyl 5-[(cyclopropylmethyl)amino]pyridine-3-carboxylate as described in step 2 of Reference Example 1.

[Step 4] Production of N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-{[(6-phenylpyrazin-2-yl)methyl]amino}benzamide

The title compound (19 mg) was obtained by replacing 3-{[2-(cyclopropylamino)-1,3-thiazolyl-5-carbonyl]amino}-4-methylbenzoic acid with 4-methyl-3-{[(6-phenylpyrazin-2-yl)methyl]amino}benzoic acid obtained in step 3, by the method described in step 4 of Example 1.

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

The title compound (84 mg) was obtained by using 3-amino-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide (73 mg) and 1H-pyrazolo[3,4-b]pyridine-5-carboxaldehyde (43 mg) instead of 1-methylpiperazine and 5-bromopyridine-3-carboxaldehyde, as described in Reference Example 34.

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

The title compound (18 mg) was obtained by using 3-amino-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide (24 mg) and imidazo[1,2-b]pyridazine-3-carboxaldehyde (15 mg) instead of 1-methylpiperazine and 5-bromopyridine-3-carboxaldehyde, as described in Reference Example 34.

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

[Step 1] Production of 3-{[(2-chloropyrimidin-5-yl)methyl]amino}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide

The title compound (320 mg) was obtained by using 3-amino-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide (513 mg) and 2-chloropyrimidine-5-carboxaldehyde (310 mg) obtained in Reference Example 7 instead of 1-methylpiperazine and 5-bromopyridin-3-carboxaldehyde, as described in Reference Example 34. MS (m/z): 375.5 [M+H] ⁺

[Step 2] Production of 3-{[(2-aminopyrimidin-5-yl)methyl]amino}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide

To the 3-{[(2-chloropyrimidin-5-yl)methyl]amino}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide (320 mg) obtained in step 1, 1,4-dioxane (8 mL) and 28% ammonia solution (4 mL) were added, and the reaction mixture was sealed in a pressure-resistant stainless steel container and stirred at 100 °C for 8 hours. After cooling the reaction solution, it was purified by silica gel column chromatography to give the title compound (173 mg).

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

[Step 1] Production of 3-{[(6-bromopyridin-3-yl)methyl]amino}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide

The title compound (370 mg) was obtained by using 3-amino-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide (380 mg) and 6-bromopyridin-3-carboxaldehyde (300 mg) obtained in Reference Example 7 instead of 1-methylpiperazine and 5-bromopyridin-3-carboxaldehyde, as described in Reference Example 34. MS (m/z): 418.5 [M+H] ⁺

[Step 2] Production of 3-{[(6-acetamidopyridin-3-yl)methyl]amino}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide

The title compound (22 mg) was obtained by replacing methyl 5-bromopyridin-3-carboxylate and 1-cyclopropylmethylamine with 3-{[(6-bromopyridin-3-yl)methyl]amino}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide (50 mg) and acetamide (18 mg) obtained in step 1, as described in step 1 of Reference Example 1.

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

The title compound (23 mg) was obtained by replacing 3-[(6-bromopyridin-3-yl)methyl]amino}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide (60 mg) and 2-(tributyltinyl)pyridine (79 mg) with 3-[(5-bromopyridin-3-yl)ethynyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide and 2-(tributyltinyl)pyrimidine as described in Example 62.

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

Using a microwave reaction apparatus, a mixture of 3-{[(6-bromopyridin-3-yl)methyl]amino}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide (60 mg), 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 step 1 of Example 116 was reacted at 100°C for 30 minutes. Then, 1H-pyrazole (20 mg), copper iodide (11 mg), and trans-N,N'-dimethylcyclohexane-1,2-diamine (0.014 mL) were added to the reaction solution, and the reaction mixture was reacted at 100°C for an additional 30 minutes using a microwave reaction apparatus. After cooling the reaction solution, it was purified by silica gel column chromatography to obtain the title compound (34 mg).

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

[Step 1] Production of 3-{[(6-aminopyridin-3-yl)methyl]amino}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide

The title compound (149 mg) was obtained by using 3-amino-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide (203 mg) and 6-aminopyridine-3-carboxaldehyde (100 mg) obtained in Reference Example 7 instead of 1-methylpiperazine and 5-bromopyridine-3-carboxaldehyde, as described in Reference Example 34. MS (m/z): 355.6 [M+H] ⁺

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

Using a microwave reaction apparatus, a mixture of 3-{[(6-aminopyridin-3-yl)methyl]amino}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide (35 mg), 3-isocyanopyridine (14 mg), potassium carbonate (20 mg), and DMF (0.33 mL) obtained in step 1 was reacted at 80 °C for 30 min. After cooling the reaction solution, it was purified by silica gel column chromatography to give the title compound (5.8 mg).

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

[Step 1] Production of methyl 3-[({5-[(tert-butoxycarbonyl)amino]pyrazin-2-yl}methyl)amino]-4-methylbenzoate

Potassium carbonate (1.76 g) was added to a solution of [5-(bromomethyl)pyrazin-2-yl]carbamate tert-butyl ester (1.44 g) and methyl 3-amino-4-methylbenzoate (561 mg) in DMF (12 mL), and the reaction mixture was stirred overnight at room temperature. The reaction solution was diluted with ethyl acetate. After washing with water and saturated salt solution, the solvent was removed by vacuum distillation. The residue obtained was purified by silica gel column chromatography to give the title compound (360 mg). MS (m/z): 373.5 [M+H] ⁺

[Step 2] Production of 3-[({5-[(tert-butoxycarbonyl)amino]pyrazin-2-yl}methyl)amino]-4-methylbenzoic acid

The title compound (125 mg) was obtained by replacing methyl 5-[(cyclopropylmethyl)amino]pyridine-3-carboxylate with methyl 3-[(tert-butoxycarbonyl)amino]pyrazin-2-yl}methyl)amino]-4-methylbenzoate (160 mg) obtained in step 1, as described in step 2 of Reference Example 1. MS (m/z): 359.3 [M+H] ⁺

[Step 3] Production of tert-butyl carbamate {5-[(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylaniline)methyl]pyrazin-2-yl}carbamate

The title compound (105 mg) was obtained by replacing 3-{[2-(cyclopropylamino)-1,3-thiazolyl-5-carbonyl]amino}-4-methylbenzoic acid with 3-[({5-[(tert-butoxycarbonyl)amino]pyrazin-2-yl}methyl)amino]-4-methylbenzoic acid (125 mg) obtained in step 2, as described in step 4 of Example 1. MS (m/z): 456.6 [M+H] ⁺

[Step 4] Production of 3-{[(5-aminopyrazin-2-yl)methyl]amino}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide

Trifluoroacetic acid (0.16 mL) was added to a solution of {5-[(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylaniline)methyl]pyrazin-2-yl} tert-butyl carbamate (95 mg) obtained in step 3 in dichloromethane (2 mL), and the reaction mixture was stirred at room temperature for 2 hours. Methanol (2 mL) and 2M aqueous sodium hydroxide solution (2 mL) were added to the residue obtained by concentrating the reaction solution under reduced pressure, and the reaction mixture was stirred at room temperature for 1 hour. The reaction solution was diluted with water, and the reaction mixture was extracted with chloroform. The organic layer was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to give the title compound (40 mg).

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

[Step 1] Production of 3-{[(6-aminopyridin-3-yl)methyl]amino}-N-[(1S,2S)-2-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl]-4-methylbenzamide

The title compound (223 mg) was obtained by using 3-amino-N-[(1S,2S)-2-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl]-4-methylbenzamide (468 mg) and 6-aminopyridine-3-carboxaldehyde (150 mg) instead of 1-methylpiperazine and 5-bromopyridine-3-carboxaldehyde, as described in Reference Example 34. MS (m/z): 469.4 [M+H] ⁺

[Step 2] Production of N-[(1S,2S)-2-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl]-3-{[(6-{[(1r,3r)-3-methoxycyclobutane-1-carbonyl]amino}pyridin-3-yl)methyl]amino}-4-methylbenzamide

The title compound (60 mg) was obtained by using (1r,3r)-3-methoxycyclobutane-1-carboxylic acid (36 mg) and 3-{[(6-aminopyridin-3-yl)methyl]amino}-N-[(1S,2S)-2-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl]-4-methylbenzamide (30 mg) obtained in step 1 instead of 2-bromo-1,3-thiazolyl-5-carboxylic acid and methyl 3-amino-4-methylbenzoate, by the method described in step 1 of Example 1.

[Step 3] Production of N-[(1S,2S)-2-hydroxycyclohexyl]-3-{[(6-{[(1r,3r)-3-methoxycyclobutane-1-carbonyl]amino}pyridin-3-yl)methyl]amino}-4-methylbenzamide

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

Example 140: N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-({[6-(1H-1,2,3-triazol-1-yl)pyridin-3-yl]methyl}amino)benzamide

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

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

[Step 1] Production of methyl 4-chloro-3-{[(2-chloropyrimidin-5-yl)methyl]amino}benzoate

The title compound (376 mg) was obtained by using methyl 3-amino-4-chlorobenzoate (1.00 g) and 2-chloropyrimidin-5-carboxaldehyde (806 mg) instead of 1-methylpiperazine and 5-bromopyridin-3-carboxaldehyde, as described in Reference Example 34. MS (m/z): 312.3 [M+H] ⁺

[Step 2] Production of 3-{[(2-aminopyrimidin-5-yl)methyl]amino}-4-chlorobenzoic acid

To the methyl 4-chloro-3-{[(2-chloropyrimidin-5-yl)methyl]amino}benzoate (199 mg) obtained in step 1, 0.86 mL of 1,4-dioxane and 0.86 mL of 28% ammonia solution were added, and the reaction mixture was sealed in a pressure-resistant stainless steel container and stirred at 100 °C for 2 days. To the residue obtained by concentrating the reaction solution under reduced pressure, 3.2 mL of ethanol and 3.2 mL of 2M sodium hydroxide solution were added, and the reaction mixture was stirred overnight at 90 °C. The solvent was removed by vacuum distillation. The reaction mixture was diluted with water and then neutralized by adding hydrochloric acid. The precipitate was collected by filtration to give the title compound (102 mg). MS (m/z): 279.4 [M+H] ⁺

[Step 3] Production of 3-{[(2-aminopyrimidin-5-yl)methyl]amino}-4-chloro-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide

The title compound (36 mg) was obtained by replacing 3-{[2-aminopyrimidin-5-yl)methyl]amino}-4-chlorobenzoic acid (50 mg) obtained in step 2 with 3-{[2-(cyclopropylamino)-1,3-thiazolyl-5-carbonyl]amino}-4-methylbenzoic acid as described in step 4 of Example 1.

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

[Step 1] Production of 7-[(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylaniline)methyl]-2,3-dihydro-4H-pyrido[3,2-b][1,4]oxazine-4-carboxylic acid tert-butyl ester

The title compound (124 mg) was obtained by using 3-amino-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide (134 mg) obtained in Reference Example 7 and 7-formyl-2,3-dihydro-4H-pyrido[3,2-b][1,4]oxazine-4-carboxylate tert-butyl ester obtained in Reference Example 23 instead of 1-methylpiperazine and 5-bromopyridin-3-carboxaldehyde, by the method described in Reference Example 34. MS (m/z): 497.3 [M+H] ⁺

[Step 2] Production of 3-{[(3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)methyl]amino}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide

To a solution of 7-[(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylaniline)methyl]-2,3-dihydro-4H-pyrido[3,2-b][1,4]oxazine-4-carboxylic acid tert-butyl ester (59 mg) obtained in step 1 in dichloromethane (1.4 mL), trifluoroacetic acid (0.7 mL) was added, and the reaction mixture was stirred overnight at room temperature. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to give the title compound (37 mg).

Example 147: N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-({[5-(pyrimidin-2-yl)pyridin-3-yl]amino}methyl)benzamide

[Step 1] Production of methyl 3-{[(5-bromopyridin-3-yl)amino]methyl}-4-methylbenzoate

The title compound (2.3 g) was obtained by using 5-bromopyridin-3-amine (1.5 g) and methyl 3-formyl-4-methylbenzoate (1.5 g) instead of 1-methylpiperazine and 5-bromopyridin-3-carboxaldehyde, as described in Reference Example 34. MS (m/z): 335.4 [M+H] ⁺

[Step 2] Production of methyl 4-methyl-3-({[5-(pyrimidin-2-yl)pyridin-3-yl]amino}methyl)benzoate

The title compound (35 mg) was obtained by replacing 3-bromo-5-(methoxymethoxy)pyridine with methyl 3-{[(5-bromopyridin-3-yl)amino]methyl}-4-methylbenzoate (170 mg) obtained in step 1, as described in step 1 of Reference Example 10. MS (m/z): 335.5 [M+H] ⁺

[Step 3] Production of 4-methyl-3-({[5-(pyrimidin-2-yl)pyridin-3-yl]amino}methyl)benzoic acid

The title compound (33 mg) was obtained by replacing methyl 5-[(cyclopropylmethyl)amino]pyridine-3-carboxylate with methyl 4-methyl-3-({[5-(pyrimidin-2-yl)pyridin-3-yl]amino}methyl)benzoate (35 mg) obtained in step 2, as described in step 2 of Reference Example 1. MS (m/z): 321.5 [M+H] ⁺

[Step 4] Production of N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-({[5-(pyrimidin-2-yl)pyridin-3-yl]amino}methyl)benzamide

The title compound (6 mg) was obtained by replacing 3-{[2-(cyclopropylamino)-1,3-thiazolyl-5-carbonyl]amino}-4-methylbenzoic acid with 4-methyl-3-({[5-(pyrimidin-2-yl)pyridin-3-yl]amino}methyl)benzoic acid obtained in step 3, by the method described in step 4 of Example 1.

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

[Step 1] Production of 3-{[(5-bromopyridin-3-yl)amino]methyl}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide

The title compound (560 mg) was obtained by using 5-bromopyridin-3-amine (437 mg) and 3-formyl-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide (600 mg) instead of 1-methylpiperazine and 5-bromopyridin-3-carboxaldehyde, as described in Reference Example 34. MS (m/z): 418.6 [M+H] ⁺

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

The title compound (10 mg) was obtained by using 3-{[(5-bromopyridin-3-yl)amino]methyl}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide (80 mg) and 2-bromopyridine (36 mg) obtained in step 1 instead of 3-bromo-5-(methoxymethoxy)pyridine and 2-bromopyrimidine, as described in step 1 of Reference Example 10.

Example 152: 3-{[(5-bromopyridin-3-yl)amino]methyl}-N-[(1S,2S)-1,3-dihydroxy-1-phenylprop-2-yl]-4-methylbenzamide

[Step 1] Production of 3-{[(5-bromopyridin-3-yl)amino]methyl}-4-methylbenzoic acid

The title compound (950 mg) was obtained by using methyl 3-{[(5-bromopyridin-3-yl)amino]methyl}-4-methylbenzoate (1.0 g) instead of methyl 5-[(cyclopropylmethyl)amino]pyridin-3-carboxylate, obtained in step 1 of Example 147, by the method described in step 2 of Reference Example 1. MS (m/z): 321.4 [M+H] ⁺

[Step 2] Production of 3-{[(5-bromopyridin-3-yl)amino]methyl}-N-[(1S,2S)-1,3-dihydroxy-1-phenylprop-2-yl]-4-methylbenzamide

The title compound (500 mg) was obtained by replacing 3-{[(5-bromopyridin-3-yl)amino]methyl}-4-methylbenzoic acid (350 mg) and (1S,2S)-2-amino-1-phenylprop-1,3-diol (219 mg) with 3-{[2-(cyclopropylamino)-1,3-thiazolyl-5-carbonyl]amino}-4-methylbenzoic acid and (1S,2S)-2-aminocyclohexyl-1-ol hydrochloride as described in step 4 of Example 1.

Example 153: N-[(1S,2S)-1,3-dihydroxy-1-phenylprop-2-yl]-4-methyl-3-{[(5-phenylpyridin-3-yl)amino]methyl}benzamide

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

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

The title compound (20 mg) was obtained by using 3-{[(5-bromopyridin-3-yl)amino]methyl}-N-[(1S,2S)-1,3-dihydroxy-1-phenylprop-2-yl]-4-methylbenzamide (50 mg) and 2-(tributylmethyltinyl)pyridine (51 mg) instead of 3-[(5-bromopyridin-3-yl)ethynyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide and 2-(tributylmethyltinyl)pyrimidine, as described in Example 62.

Example 156: N-[(1S,2S)-1,3-dihydroxy-1-phenylprop-2-yl]-4-methyl-3-{[(6-phenylpyrazin-2-yl)amino]methyl}benzamide

[Step 1] Production of methyl 3-{[(6-chloropyrazin-2-yl)amino]methyl}-4-methylbenzoate

A mixture of 2,6-dichloropyrazine (300 mg), methyl 3-(aminomethyl)-4-methylbenzoate (397 mg) obtained in Reference Example 42, NMP (4 mL), and DIPEA (1.05 mL) was stirred at 100 °C for 4 hours. The reaction solution was diluted with ethyl acetate, and the organic layer was washed with water and a saturated salt solution. The solvent was removed under reduced pressure, and the residue obtained was purified by silica gel column chromatography to give the title compound (423 mg). MS (m/z): 292.5 [M+H] ⁺

[Step 2] Production of 3-{[(6-chloropyrazin-2-yl)amino]methyl}-4-methylbenzoic acid

The title compound (520 mg) was obtained by replacing methyl 3-{[(6-chloropyrazin-2-yl)amino]methyl}-4-methylbenzoate (580 mg) with methyl 5-[(cyclopropylmethyl)amino]pyridine-3-carboxylate as described in step 2 of Reference Example 1. MS (m/z): 278.4 [M+H] ⁺

[Step 3] Production of 3-{[(6-chloropyrazin-2-yl)amino]methyl}-N-[(1S,2S)-1,3-dihydroxy-1-phenylprop-2-yl]-4-methylbenzamide

The title compound (420 mg) was obtained by replacing 3-{[(6-chloropyrazin-2-yl)amino]methyl}-4-methylbenzoic acid (300 mg) and (1S,2S)-2-amino-1-phenylprop-1,3-diol (217 mg) with 3-{[2-(cyclopropylamino)-1,3-thiazolyl-5-carbonyl]amino}-4-methylbenzoic acid and (1S,2S)-2-aminocyclohexyl-1-ol hydrochloride as described in step 4 of Example 1. MS (m/z): 427.6 [M+H] ⁺

[Step 4] Production of N-[(1S,2S)-1,3-dihydroxy-1-phenylprop-2-yl]-4-methyl-3-{[(6-phenylpyrazin-2-yl)amino]methyl}benzamide

The title compound (36 mg) was obtained by replacing 2-chloropyrimidin-4-amine and isoquinoline-4-ylboronic acid with 3-{[(6-chloropyrazin-2-yl)amino]methyl}-N-[(1S,2S)-1,3-dihydroxy-1-phenylprop-2-yl]-4-methylbenzamide (50 mg) and phenylboronic acid (17 mg) obtained in step 3, by the method described in Reference Example 14.

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

[Step 1] Production of N-[(3-aminophenyl)methyl]-6-chloropyrazine-2-amine

The title compound (1.22 g) was obtained by using methyl 3-(aminomethyl)aniline (1.23 g) instead of methyl 3-(aminomethyl)-4-methylbenzoate, as described in step 3 of Example 156.

[Step 2] Production of N-[(3-aminophenyl)methyl]-6-(3,4-dimethoxyphenyl)pyrazine-2-amine

The title compound (190 mg) was obtained by using N-[(3-aminophenyl)methyl]-6-chloropyrazine-2-amine (160 mg) and (3,4-dimethoxyphenyl)boronic acid (149 mg) obtained in step 1 instead of 2-chloropyrimidin-4-amine and isoquinoline-4-ylboronic acid, as described in Reference Example 14.

[Step 3] Production of N-[3-({[6-(3,4-dimethoxyphenyl)pyrazin-2-yl]amino}methyl)phenyl]-N'-[(1R,2S)-2-hydroxycyclohexyl]urea

THF (1 mL), TEA (0.20 mL), and triphosgene (18 mg) were added to N-[(3-aminophenyl)methyl]-6-(3,4-dimethoxyphenyl)pyrazine-2-amine (40 mg) obtained in step 2, and the reaction mixture was stirred at room temperature for 10 minutes. Then, (1S,2R)-2-aminocyclohexyl-1-ol hydrochloride (180 mg) was added, and the reaction mixture was stirred at the same temperature for 2 hours. The reaction solution was purified by silica gel column chromatography to give the title compound (37 mg).

Example 159: N-[(1R,2S)-2-hydroxycyclohexyl]-N'-[3-({[5-(pyrimidin-2-yl)pyridin-3-yl]amino}methyl)phenyl]urea

[Step 1] Production of N-[(3-nitrophenyl)methyl]-5-(pyrimidin-2-yl)pyridine-3-amine

The title compound (40 mg) was obtained by using 5-(pyrimidin-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-carboxaldehyde, as described in Reference Example 34.

[Step 2] Production of N-[(3-aminophenyl)methyl]-5-(pyrimidin-2-yl)pyridine-3-amine

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

[Step 3] Production of N-[(1R,2S)-2-hydroxycyclohexyl]-N'-[3-({[5-(pyrimidin-2-yl)pyridin-3-yl]amino}methyl)phenyl]urea

The title compound (13 mg) was obtained by replacing N-[(3-aminophenyl)methyl]-5-(pyrimidin-2-yl)pyridine-3-amine (20 mg) obtained in step 2 with N-[(3-aminophenyl)methyl]-6-(3,4-dimethoxyphenyl)pyrazine-2-amine as described in step 3 of Example 158.

Example 161: N-[4-fluoro-3-({[5-(pyrimidin-2-yl)pyridin-3-yl]amino}methyl)phenyl]-N'-[(1R,2S)-2-hydroxycyclohexyl]urea

[Step 1] Production of N-[(2-fluoro-5-nitrophenyl)methyl]-5-(pyrimidin-2-yl)pyridine-3-amine

The title compound (150 mg) was obtained by using 5-(pyrimidin-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-carboxaldehyde, as described in Reference Example 34.

[Step 2] Production of [(2-fluoro-5-nitrophenyl)methyl][5-(pyrimidin-2-yl)pyridin-3-yl]tert-butyl carbamate

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

[Step 3] Production of [(5-amino-2-fluorophenyl)methyl][5-(pyrimidin-2-yl)pyridin-3-yl]tert-butyl carbamate

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

[Step 4] Production of {[2-fluoro-5-({[(1R,2S)-2-hydroxycyclohexyl]carbamoyl}amino)phenyl]methyl}[5-(pyrimidin-2-yl)pyridin-3-yl]tert-butyl carbamate

The title compound (82 mg) was obtained by replacing N-[(3-aminophenyl)methyl]-6-(3,4-dimethoxyphenyl)pyrazine-2-amine with [(5-amino-2-fluorophenyl)methyl][5-(pyrimidin-2-yl)pyridin-3-yl]carbamate tert-butyl ester (70 mg) obtained in step 3, as described in step 3 of Example 158.

[Step 5] Production of N-[4-fluoro-3-({[5-(pyrimidin-2-yl)pyridin-3-yl]amino}methyl)phenyl]-N'-[(1R,2S)-2-hydroxycyclohexyl]urea

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

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

[Step 1] Production of methyl 3-{1-[(6-chloropyrazin-2-yl)amino]ethyl}-4-methylbenzoate

The title compound (75 mg) was obtained by using methyl 3-(1-aminoethyl)-4-methylbenzoate (218 mg) instead of methyl 3-(aminomethyl)-4-methylbenzoate, as described in step 3 of Example 156.

[Step 2] Production of methyl 4-methyl-3-{1-[(6-phenylpyrazin-2-yl)amino]ethyl}benzoate

The title compound (80 mg) was obtained by using methyl 3-{1-[(6-chloropyrazin-2-yl)amino]ethyl}-4-methylbenzoate (75 mg) and phenylboronic acid (36 mg) obtained in step 1 in place of 2-chloropyrimidin-4-amine and isoquinoline-4-ylboronic acid, as described in Reference Example 14.

[Step 3] Production of 4-methyl-3-{1-[(6-phenylpyrazin-2-yl)amino]ethyl}benzoic acid

The title compound (67 mg) was obtained by replacing methyl 4-methyl-3-{1-[(6-phenylpyrazin-2-yl)amino]ethyl}benzoate (77 mg) with methyl 5-[(cyclopropylmethyl)amino]pyridine-3-carboxylate as described in step 2 of Reference Example 1.

[Step 4] Production of N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-{1-[(6-phenylpyrazin-2-yl)amino]ethyl}benzamide

The title compound (17 mg) was obtained by replacing 3-{[2-(cyclopropylamino)-1,3-thiazolyl-5-carbonyl]amino}-4-methylbenzoic acid with 4-methyl-3-{1-[(6-phenylpyrazin-2-yl)amino]ethyl}benzoic acid obtained in step 3, by the method described in step 4 of Example 1.

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

[Step 1] Production of methyl 3-[(5-bromopyridin-3-yl)methoxy]-4-methylbenzoate

The title compound (1.16 g) was obtained by using methyl 3-hydroxy-4-methylbenzoate (750 mg) and (5-bromopyridin-3-yl)methanol (933 mg) instead of methyl 5-hydroxypyridin-3-carboxylate and 3,3-difluorocyclobutan-1-ol, as described in step 1 of Reference Example 3. MS (m/z): 336.4 [M+H] ⁺

[Step 2] Production of methyl 3-[([3,3’-bipyridine]-5-yl)methoxy]-4-methylbenzoate

The title compound (103 mg) was obtained by replacing 2-chloropyrimidin-4-amine and isoquinoline-4-ylboronic acid with methyl 3-[(5-bromopyridin-3-yl)methoxy]-4-methylbenzoate (150 mg) and pyridin-3-ylboronic acid (66 mg) obtained in step 1, as described in Reference Example 14. MS (m/z): 335.5 [M+H] ⁺

[Step 3] Production of 3-[([3,3'-bipyridin]-5-yl)methoxy]-4-methylbenzoic acid

The title compound (100 mg) was obtained by replacing methyl 3-[([3,3'-bipyridinyl]-5-yl)methoxy]-4-methylbenzoate (103 mg) with methyl 5-[(cyclopropylmethyl)amino]pyridin-3-carboxylate as described in step 2 of Reference Example 1. MS (m/z): 321.6 [M+H] ⁺

[Step 4] Production of 3-[([3,3'-bipyridine]-5-yl)methoxy]-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide

The title compound (47 mg) was obtained by replacing 3-{[2-(cyclopropylamino)-1,3-thiazolyl-5-carbonyl]amino}-4-methylbenzoic acid with 3-[([3,3'-bipyridine]-5-yl)methoxy]-4-methylbenzoic acid (50 mg) obtained in step 3, by the method described in step 4 of Example 1.

Example 166: N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-{[5-(pyrimidin-2-yl)pyridin-3-yl]methoxy}benzamide

[Step 1] Production of methyl 4-methyl-3-{[5-(pyrimidin-2-yl)pyridin-3-yl]methoxy}benzoate

The title compound (127 mg) was obtained by replacing 3-bromo-5-(methoxymethoxy)pyridine with methyl 3-[(5-bromopyridin-3-yl)methoxy]-4-methylbenzoate (250 mg) obtained in step 1 of Example 165, by the method described in step 1 of Reference Example 10. MS (m/z): 336.4 [M+H] ⁺

[Step 2] Production of 4-methyl-3-{[5-(pyrimidin-2-yl)pyridin-3-yl]methoxy}benzoic acid

The title compound (101 mg) was obtained by replacing methyl 4-methyl-3-{[5-(pyrimidin-2-yl)pyridin-3-yl]methoxy}benzoate (127 mg) with methyl 5-[(cyclopropylmethyl)amino]pyridin-3-carboxylate as described in step 2 of Reference Example 1.

[Step 3] Production of N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-{[5-(pyrimidin-2-yl)pyridin-3-yl]methoxy}benzamide

The title compound (76 mg) was obtained by replacing 3-{[2-(cyclopropylamino)-1,3-thiazolyl-5-carbonyl]amino}-4-methylbenzoic acid with 4-methyl-3-{[5-(pyrimidin-2-yl)pyridin-3-yl]methoxy}benzoic acid obtained in step 2, by the method described in step 4 of Example 1.

Example 170: 4-Chloro-N-[(1S,2S)-2-hydroxycyclohexyl]-3-({[5-(pyrimidin-2-yl)pyridin-3-yl]oxy}methyl)benzamide

[Step 1] Production of methyl 4-chloro-3-({[5-(pyrimidin-2-yl)pyridin-3-yl]oxy}methyl)benzoate

The title compound (50 mg) was obtained by replacing methyl 5-hydroxypyridine-3-carboxylate and 3,3-difluorocyclobutanol with 5-(pyrimidin-2-yl)pyridin-3-ol (123 mg) obtained in step 2 of Reference Example 10 and methyl 4-chloro-3-(hydroxymethyl)benzoate (130 mg) obtained in Reference Example 31, as described in step 1 of Reference Example 3. MS (m/z): 356.4 [M+H] ⁺

[Step 2] Production of 4-chloro-3-({[5-(pyrimidin-2-yl)pyridin-3-yl]oxy}methyl)benzoic acid

The title compound (43 mg) was obtained by replacing methyl 5-[(cyclopropylmethyl)amino]pyridine-3-carboxylate with methyl 4-chloro-3-({[5-(pyrimidin-2-yl)pyridin-3-yl]oxy}methyl)benzoate (50 mg) obtained in step 1, as described in step 2 of Reference Example 1. MS (m/z): 342.4 [M+H] ⁺

[Step 3] Production of 4-chloro-N-[(1S,2S)-2-hydroxycyclohexyl]-3-({[5-(pyrimidin-2-yl)pyridin-3-yl]oxy}methyl)benzamide

The title compound (39 mg) was obtained by replacing 3-{[2-(cyclopropylamino)-1,3-thiazolyl-5-carbonyl]amino}-4-methylbenzoic acid with 4-chloro-3-({[5-(pyrimidin-2-yl)pyridin-3-yl]oxy}methyl)benzoic acid obtained in step 2, by the method described in step 4 of Example 1.

Example 172: N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-[1-(5-phenylpyridin-3-yl)ethoxy]benzamide

[Step 1] Production of methyl 3-[1-(5-bromopyridin-3-yl)ethoxy]-4-methylbenzoate

The title compound (650 mg) was obtained by using methyl 3-hydroxy-4-methylbenzoate (432 mg) and 1-(5-bromopyridin-3-yl)ethanol-1-ol (500 mg) instead of methyl 5-hydroxypyridin-3-carboxylate and 3,3-difluorocyclobutanol, as described in step 1 of Reference Example 3. MS (m/z): 350.3 [M+H] ⁺

[Step 2] Production of 3-[1-(5-bromopyridin-3-yl)ethoxy]-4-methylbenzoic acid

The title compound (350 mg) was obtained by replacing methyl 3-[1-(5-bromopyridin-3-yl)ethoxy]-4-methylbenzoate (450 mg) obtained in step 1 with methyl 5-[(cyclopropylmethyl)amino]pyridin-3-carboxylate, as described in step 2 of Reference Example 1. MS (m/z): 336.3 [M+H] ⁺

[Step 3] Production of 3-[1-(5-bromopyridin-3-yl)ethoxy]-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide

The title compound (350 mg) was obtained by replacing 3-{[2-(cyclopropylamino)-1,3-thiazolyl-5-carbonyl]amino}-4-methylbenzoic acid with 3-[1-(5-bromopyridin-3-yl)ethoxy]-4-methylbenzoic acid (350 mg) obtained in step 2, as described in step 4 of Example 1. MS (m/z): 433.5 [M+H] ⁺

[Step 4] Production of N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-[1-(5-phenylpyridin-3-yl)ethoxy]benzamide

The title compound (30 mg) was obtained by replacing 2-chloropyrimidin-4-amine and isoquinoline-4-ylboronic acid with 3-[1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide (50 mg) and phenylboronic acid (17 mg) obtained in step 3, by the method described in Reference Example 14.

Example 173: N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-[(E)-2-(5-phenylpyridin-3-yl)vinyl]benzamide

[Step 1] Production of 3-vinyl-N-[(1R,2R)-2-hydroxycyclohexyl]-4-methylbenzamide

The title compound (13.0 g) was obtained by using 2-bromo-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide (20.0 g) and 2-vinyl-4,4,5,5-tetramethyl-1,3,2-dioxaneborane (11.8 g) instead of 2-chloropyrimidine-4-amine and isoquinoline-4-ylboronic acid, as described in Reference Example 14. MS (m/z): 260.2 [M+H] ⁺

[Step 2] Production of N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-[(E)-2-(5-phenylpyridin-3-yl)vinyl]benzamide

Using a microwave reaction apparatus, a mixture of 3-vinyl-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 step 1 was reacted at 100 °C for 80 min. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to give the title compound (24 mg).

Example 174: N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-[2-(5-phenylpyridin-3-yl)ethyl]benzamide

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

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

[Step 1] Production of methyl 3-{[(5-bromopyridin-3-yl)(methyl)amino]methyl}-4-methylbenzoate

Under ice-cooling, 60% sodium hydride (79 mg) was added to a solution of methyl 3-{[(5-bromopyridin-3-yl)amino]methyl}-4-methylbenzoate (850 mg) obtained in step 1 of Example 147 in THF (10 mL), and the reaction mixture was stirred at room temperature for 20 minutes. Iodimethane (720 mg) was then added, and the reaction mixture was stirred overnight at the same temperature. Under ice-cooling, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated brine solution, dried over anhydrous sodium sulfate, and then the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (200 mg). MS (m/z): 349.4 [M+H] ⁺

[Step 2] Production of 3-{[(5-bromopyridin-3-yl)(methyl)amino]methyl}-4-methylbenzoic acid

The title compound (170 mg) was obtained by replacing methyl 3-{[(5-bromopyridin-3-yl)(methyl)amino]methyl}-4-methylbenzoate (200 mg) with methyl 5-[(cyclopropylmethyl)amino]pyridin-3-carboxylate as described in step 2 of Reference Example 1. MS (m/z): 335.4 [M+H] ⁺

[Step 3] Production of 3-{[(5-bromopyridin-3-yl)(methyl)amino]methyl}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide

The title compound (147 mg) was obtained by replacing 3-{[(5-bromopyridin-3-yl)(methyl)amino]methyl}-4-methylbenzoic acid (170 mg) with 3-{[2-(cyclopropylamino)-1,3-thiazolyl-5-carbonyl]amino}-4-methylbenzoic acid as described in step 4 of Example 1. MS (m/z): 432.6 [M+H] ⁺

[Step 4] Production of N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-{[methyl(5-phenylpyridin-3-yl)amino]methyl}benzamide

The title compound (24 mg) was obtained by replacing 2-chloropyrimidin-4-amine and isoquinoline-4-ylboronic acid with 3-{[(5-bromopyridin-3-yl)(methyl)amino]methyl}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide (30 mg) and phenylboronic acid (9.3 mg) obtained in step 3, by the method described in Reference Example 14.

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

[Step 1] Production of 3-(2,2-difluorovinyl)-4-fluoro-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide

At 100 °C, for 30 minutes, a solution of sodium dichlorofluoroacetate (431 mg) in DMF (0.94 mL) was added dropwise to a solution of 4-fluoro-3-formyl-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide (500 mg) and triphenylphosphine (593 mg) obtained in Reference Example 29 in DMF (3.8 mL), and the reaction mixture was stirred at the same temperature for 30 minutes. Water was added to the reaction solution under ice cooling, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated brine solution and dried over anhydrous sodium sulfate, and then the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (200 mg). MS (m/z): 300.1 [M+H] ⁺

[Step 2] Production of 4-fluoro-3-[(Z)-2-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)vinyl]-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide

THF (2.2 mL) was added to the mixture obtained in step 1, consisting of 3-(2,2-difluorovinyl)-4-fluoro-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide (100 mg), bis(pinacol)diboron (170 mg), potassium acetate (39 mg), tricyclohexylphosphine (19 mg), and copper chloride (I) (3.3 mg). After degassing, the reaction mixture was stirred overnight at 40 °C under an argon atmosphere. A saturated aqueous solution of ammonium chloride was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous salt solution, dried over anhydrous sodium sulfate, and then the solvent was removed under reduced pressure to give the title compound (130 mg).

[Step 3] Production of 3-[(Z)-2-([2,3'-bipyridin]-5'-yl)-2-fluorovinyl]-4-fluoro-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide

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

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

[Step 1] Production of ethyl 5-(2,2-difluorovinyl)-6-methylpyridine-3-carboxylate

The title compound (2.80 g) was obtained by 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, as described in step 1 of Example 177. MS (m/z): 228.1 [M+H] ⁺

[Step 2] Production of ethyl 5-[(Z)-2-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)vinyl]-6-methylpyridine-3-carboxylate

The title compound (280 mg) was obtained by using ethyl 5-(2,2-difluorovinyl)-6-methylpyridine-3-carboxylate (200 mg) obtained in step 1 instead of 3-(2,2-difluorovinyl)-4-fluoro-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide, as described in step 2 of Example 177.

[Step 3] Production of ethyl 5-[(Z)-2-([2,3’-bipyridine]-5’-yl)-2-fluorovinyl]-6-methylpyridine-3-carboxylate

The title compound (230 mg) was obtained by using ethyl 5'-bromo-2,3'-bipyridine (196 mg) and 5-[(Z)-2-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)vinyl]-6-methylpyridin-3-carboxylate (280 mg) obtained in step 2 instead of 2-chloropyrimidin-4-amine and isoquinoline-4-ylboronic acid, as described in Reference Example 14. MS (m/z): 364.2 [M+H] ⁺

[Step 4] Production of 5-[(Z)-2-([2,3'-bipyridin]-5'-yl)-2-fluorovinyl]-6-methylpyridin-3-carboxylic acid

The title compound (165 mg) was obtained by replacing methyl 5-[(Z)-2-([2,3'-bipyridinyl]-5'-yl)-2-fluorovinyl]-6-methylpyridine-3-carboxylate (230 mg) with methyl 5-[(cyclopropylmethyl)amino]pyridine-3-carboxylate as described in step 2 of Reference Example 1. MS (m/z): 336.1 [M+H] ⁺

[Step 5] Production of 5-[(Z)-2-([2,3'-bipyridine]-5'-yl)-2-fluorovinyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-6-methylpyridine-3-carboxamide

The title compound (77 mg) was obtained by replacing 3-{[2-[2-(2,3'-bipyridine]-5'-yl)-2-fluorovinyl]-6-methylpyridine-3-carboxylic acid with 5-[(Z)-2-([2,3'-bipyridine]-5'-yl)-2-fluorovinyl]-6-methylpyridine-3-carboxylic acid in step 4 of Example 1.

Example 192: 3-[(Z)-2-(2-aminopyrimidin-5-yl)-2-fluorovinyl]-4-fluoro-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide

[Step 1] Production of methyl 3-(2,2-difluorovinyl)-4-fluorobenzoate

The title compound (1.30 g) was obtained by using methyl 4-fluoro-3-carboxybenzoate (1.27 g) instead of 4-fluoro-3-carboxy-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide, as described in step 1 of Example 177.

[Step 2] Production of methyl 3-[(Z)-2-(2-aminopyrimidin-5-yl)-2-fluorovinyl]-4-fluorobenzoate

THF (4 mL) was added to the methyl 3-(2,2-difluorovinyl)-4-fluorobenzoate (130 mg), bis(pinacol)diboron (305 mg), potassium acetate (118 mg), tricyclohexylphosphine (34 mg), and copper chloride (I) (22 mg) obtained in step 1, and after degassing, the reaction mixture was stirred at 40 °C for 8 hours under an argon atmosphere. A saturated aqueous solution of ammonium chloride was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated brine solution, dried over anhydrous sodium sulfate, and then the solvent was removed under reduced pressure. 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 to the obtained residue, and after degassing, the reaction mixture was stirred overnight at 85 °C under an argon atmosphere. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to give the title compound (200 mg). MS (m/z): 292.1 [M+H] ⁺

[Step 3] Production of 3-[(Z)-2-(2-aminopyrimidin-5-yl)-2-fluorovinyl]-4-fluorobenzoic acid

The title compound (36 mg) was obtained by replacing methyl 3-[(Z)-2-(2-aminopyrimidin-5-yl)-2-fluorovinyl]-4-fluorobenzoate (200 mg) with methyl 5-[(cyclopropylmethyl)amino]pyridine-3-carboxylate as described in step 2 of Reference Example 1. MS (m/z): 278.1 [M+H] ⁺

[Step 4] Production of 3-[(Z)-2-(2-aminopyrimidin-5-yl)-2-fluorovinyl]-4-fluoro-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide

The title compound (4 mg) was obtained by replacing 3-{[2-(cyclopropylamino)-1,3-thiazolyl-5-carbonyl]amino}-4-methylbenzoic acid with 3-[(Z)-2-(2-aminopyrimidin-5-yl)-2-fluorovinyl]-4-fluorobenzoic acid (36 mg) obtained in step 3, by the method described in step 4 of Example 1.

Example 194: 3-[(Z)-2-{5-[(4-ethylpiperazin-1-yl)methyl]pyridin-3-yl}-2-fluorovinyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide

[Step 1] Production of methyl 3-(2,2-difluorovinyl)-4-methylbenzoate

The title compound (15.0 g) was obtained by using methyl 3-formyl-4-methylbenzoate (13.4 g) instead of 4-fluoro-3-formyl-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide, as described in step 1 of Example 177. MS (m/z): 213.1 [M+H] ⁺

[Step 2] Production of methyl 3-[(Z)-2-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)vinyl]-4-methylbenzoate

The title compound (8.6 g) was obtained by using methyl 3-(2,2-difluorovinyl)-4-methylbenzoate (6.0 g) obtained in step 1 instead of 3-(2,2-difluorovinyl)-4-fluoro-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide, as described in step 2 of Example 177.

[Step 3] Production of methyl 3-[(Z)-2-fluoro-2-{5-[(4-ethylpiperazin-1-yl)methyl]pyridin-3-yl}vinyl]-4-methylbenzoate

The title compound (7.5 g) was obtained by using 1-[(5-bromopyridin-3-yl)methyl]-4-ethylpiperazine (6.3 g) obtained in Reference Example 38 and methyl 3-[(Z)-2-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)vinyl]-4-methylbenzoate (8.5 g) obtained in step 2 instead of 2-chloropyrimidin-4-amine and isoquinoline-4-ylboronic acid, by the method described in Reference Example 14. MS (m/z): 398.3 [M+H] ⁺

[Step 4] Production of 3-[(Z)-2-fluoro-2-{5-[(4-ethylpiperazin-1-yl)methyl]pyridin-3-yl}vinyl]-4-methylbenzoic acid

The title compound (4.7 g) was obtained by replacing methyl 5-[(cyclopropylmethyl)amino]pyridin-3-carboxylate with methyl 3-[(Z)-2-fluoro-2-{5-[(4-ethylpiperazin-1-yl)methyl]pyridin-3-yl}vinyl]-4-methylbenzoate (7.5 g) in step 3, as described in step 2 of Reference Example 1. MS (m/z): 384.5 [M+H] ⁺

[Step 5] Production of 3-[(Z)-2-{5-[(4-ethylpiperazin-1-yl)methyl]pyridin-3-yl}-2-fluorovinyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide

The title compound (3.4 g) was obtained by replacing 3-{[2-(cyclopropylamino)-1,3-thiazolyl-5-carbonyl]amino}-4-methylbenzoic acid with 3-[(Z)-2-fluoro-2-{5-[(4-ethylpiperazin-1-yl)methyl]pyridin-3-yl}vinyl]-4-methylbenzoic acid in step 4 of Example 1.

Example 199: 5-[(Z)-2-{6-[(cyclopropylmethyl)amino]pyridin-3-yl}-2-fluorovinyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-6-methylpyridin-3-carboxamide

[Step 1] Production of ethyl 5-[(Z)-2-(6-aminopyridin-3-yl)-2-fluorovinyl]-6-methylpyridin-3-carboxylate

The title compound (40 mg) was obtained by using 5-bromopyridin-2-amine (114 mg) obtained in step 2 of Example 180 and ethyl 5-[(Z)-2-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)vinyl]-6-methylpyridin-3-carboxylate instead of 2-chloropyrimidin-4-amine and isoquinoline-4-ylboronic acid, by the method described in Reference Example 14. MS (m/z): 302.1 [M+H] ⁺

[Step 2] Produce ethyl 5-[(Z)-2-{6-[(cyclopropylmethyl)amino]pyridin-3-yl}-2-fluorovinyl]-6-methylpyridin-3-carboxylate

The title compound (12 mg) was obtained by using ethyl 5-[(Z)-2-(6-aminopyridin-3-yl)-2-fluorovinyl]-6-methylpyridin-3-carboxylate (60 mg) and cyclopropanecarboxaldehyde (19 mg) instead of 1-methylpiperazine and 5-bromopyridin-3-carboxaldehyde, as described in Reference Example 34. MS (m/z): 356.5 [M+H] ⁺

[Step 3] Production of 5-[(Z)-2-{6-[(cyclopropylmethyl)amino]pyridin-3-yl}-2-fluorovinyl]-6-methylpyridin-3-carboxylic acid

The title compound (11 mg) was obtained by replacing methyl 5-[(Z)-2-{6-[(cyclopropylmethyl)amino]pyridin-3-yl}-2-fluorovinyl]-6-methylpyridin-3-carboxylate (12 mg) with methyl 5-[(cyclopropylmethyl)amino]pyridin-3-carboxylate as described in step 2 of Reference Example 1.

[Step 4] Production of 5-[(Z)-2-{6-[(cyclopropylmethyl)amino]pyridin-3-yl}-2-fluorovinyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-6-methylpyridin-3-carboxamide

The title compound (10 mg) was obtained by replacing 3-{[2-[2-[2-(cyclopropylamino)-1,3-thiazolyl-5-carbonyl]amino}-4-methylbenzoic acid with 5-[(Z)-2-{6-[(cyclopropylmethyl)amino]pyridin-3-yl}-2-fluorovinyl]-6-methylpyridin-3-carboxylic acid (11 mg) obtained in step 3, by the method described in step 4 of Example 1.

The reference examples and the compounds of the examples are shown in Tables 3 to 29 described below.

In the table, a reference example refers to a compound discussed that is produced using the corresponding raw materials as described in the method for producing a compound having a reference example number corresponding to that number, and for example, a reference example compound having reference example number 1 refers to one that is produced by the method described in reference example 1.

In the table, the referenced examples refer to compounds discussed that are produced using the corresponding raw materials as described in the method for producing compounds having example numbers corresponding to that number, and for example, the example compound having reference example number 1 refers to one produced as described in Example 1.

In the table, chemical names refer to the names of compounds corresponding to the reference example number and example number. Furthermore, data refer to instrumental analysis data, such as mass spectrometry data (m/z values), 1H NMR data (δ values of peaks (ppm)), and elemental analysis data (composition of C, H, and N (%)).

[Table 3]

Example Referenced embodiments Chemical name 1 1 2-(cyclopropylamino)-N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)-1,3-thiazolyl-5-carboxamide 2 2 N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)-5-phenylpyridine-3-carboxamide 3 3 2-(cyclopropylmethyl)-N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)-1,3-thiazolyl-5-carboxamide 4 3 5-(cyclopropylamino)-N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)pyridine-3-carboxamide 5 5 N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)-2-phenyl-1,3-oxazol-5-carboxamide 6 6 N-(5-{[(1S)-2-hydroxy-1-phenylethyl]carbamoyl}-2-methylphenyl)-5-phenylpyridine-3-carboxamide 7 5 N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)-5-[(propyl-2-yl)oxy]pyridine-3-carboxamide 8 1 2-[(cyclopropylmethyl)amino]-N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)-1,3-thiazolyl-5-carboxamide 9 2 5-(4-Chlorophenyl)-N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)pyridine-3-carboxamide 10 5 N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)-2-propyl-1,3-thiazolyl-5-carboxamide 11 2 5-(3-Chlorophenyl)-N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)pyridine-3-carboxamide 12 2 N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)-5-(2-methylphenyl)pyridine-3-carboxamide 13 2 5-(2-Chlorophenyl)-N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)pyridine-3-carboxamide

[Table 4]

Example Referenced embodiments Chemical name 14 6 N-(5-{[(2S)-1-hydroxypentan-2-yl]carbamoyl}-2-methylphenyl)-5-phenylpyridine-3-carboxamide 15 2 5-[(E)-2-cyclopropylvinyl]-N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)pyridine-3-carboxamide 16 3 5-[(cyclopropylmethyl)amino]-N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)pyridine-3-carboxamide 17 17 5-[cyclopropyl(methyl)amino]-N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)pyridine-3-carboxamide 18 2 N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)-5-(4-methoxyphenyl)pyridine-3-carboxamide 19 2 5-(4-Fluorophenyl)-N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)pyridine-3-carboxamide 20 20 5-(3-Fluorophenyl)-N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)pyridine-3-carboxamide twenty one 2 N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)-5-[4-(trifluoromethyl)phenyl]pyridine-3-carboxamide twenty two 2 N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)-5-[3-(trifluoromethyl)phenyl]pyridine-3-carboxamide twenty three 2 N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)-5-(2-methylprop-1-en-1-yl)pyridine-3-carboxamide twenty four twenty four 5-(cyclopropylmethoxy)-N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)pyridine-3-carboxamide 25 1 2-[(3,3-difluorocyclobutyl)amino]-N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)-1,3-thiazolyl-5-carboxamide

[Table 5]

Example Referenced embodiments Chemical name 26 26 2-[(2-cyclopropylethyl)amino]-N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)-1,3-thiazolyl-5-carboxamide 27 26 N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)-2-[(propyl-2-yl)amino]-1,3-thiazolyl-5-carboxamide 28 3 5-[(4,4-difluorocyclohexyl)oxy]-N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)pyridine-3-carboxamide 29 2 5-(2-Fluorophenyl)-N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)pyridine-3-carboxamide 30 2 5-(2,3-Difluorophenyl)-N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)pyridine-3-carboxamide 31 2 5-(2,4-Difluorophenyl)-N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)pyridine-3-carboxamide 32 2 5-(3,5-Difluorophenyl)-N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)pyridine-3-carboxamide 33 2 5-(2-fluoro-4-methoxyphenyl)-N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)pyridine-3-carboxamide 34 2 N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)-5-[3-(trifluoromethoxy)phenyl]pyridine-3-carboxamide 35 2 N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)-5-[2-(trifluoromethoxy)phenyl]pyridine-3-carboxamide 36 2 5-[2-fluoro-4-(trifluoromethyl)phenyl]-N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)pyridine-3-carboxamide

[Table 6]

Example Referenced embodiments Chemical name 37 2 5-(2,6-Difluorophenyl)-N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)pyridine-3-carboxamide 38 26 2-(tert-butylamino)-N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)-1,3-thiazolyl-5-carboxamide 39 26 N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)-2-[(1-methylcyclopropyl)amino]-1,3-thiazolyl-5-carboxamide 40 26 N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)-2-[(1-methylcyclobutyl)amino]-1,3-thiazolyl-5-carboxamide 41 26 2-[(2,2-dimethylpropyl)amino]-N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)-1,3-thiazolyl-5-carboxamide 42 2 N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)-5-(3,4,5-trifluorophenyl)pyridine-3-carboxamide 43 2 5-(4-Cyclopropylphenyl)-N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)pyridine-3-carboxamide 44 3 N-(2-chloro-5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}phenyl)-5-(cyclopropylmethoxy)pyridine-3-carboxamide 45 5 N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)imidazo[2,1-b][1,3]thiazolyl-5-carboxamide 46 3 5-(cyclopropylmethoxy)-N-(3-fluoro-5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)pyridine-3-carboxamide 47 5 5-[(3,3-difluorocyclobutyl)oxy]-N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)pyridine-3-carboxamide

[Table 7]

Example Referenced embodiments Chemical name 48 3 2-(cyclopropylmethyl)-N-(3-fluoro-5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)-1,3-thiazolyl-5-carboxamide 49 5 N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)-5-methoxypyridine-3-carboxamide 50 5 5-Ethoxy-N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)pyridine-3-carboxamide 51 5 N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)-5-[(pyridin-2-yl)oxy]pyridine-3-carboxamide 52 5 N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)-5-[(pyrimidin-2-yl)oxy]pyridine-3-carboxamide 53 5 N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)-5-[(1-methylcyclopropyl)methoxy]pyridine-3-carboxamide 54 5 5-[(3,3-difluorocyclobutyl)methoxy]-N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)pyridine-3-carboxamide 55 3 N-(2-chloro-5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}phenyl)-2-(cyclopropylmethyl)-1,3-thiazolyl-5-carboxamide 56 3 5-(cyclopropylmethoxy)-N-(2-fluoro-5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}phenyl)pyridine-3-carboxamide 57 57 3-[(5-bromopyridin-3-yl)ethynyl]-4-chloro-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide 58 58 4-Chloro-N-[(1S,2S)-2-hydroxycyclohexyl]-3-[(5-phenylpyridin-3-yl)ethynyl]benzamide 59 59 N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-[(5-methylpyridin-3-yl)ethynyl]benzamide

[Table 8]

Example Referenced embodiments Chemical name 60 59 N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-[(5-phenylpyridin-3-yl)ethynyl]benzamide 61 61 3-[(5-bromopyridin-3-yl)ethynyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide 62 62 N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-{[5-(pyrimidin-2-yl)pyridin-3-yl]ethynyl}benzamide 63 62 N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-{[5-(pyrazin-2-yl)pyridin-3-yl]ethynyl}benzamide 64 59 4-Chloro-N-[(1S,2S)-2-hydroxycyclohexyl]-3-{[5-(pyrimidin-2-yl)pyridin-3-yl]ethynyl}benzamide 65 59 3-[(6-aminopyridin-3-yl)ethynyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide 66 62 3-[([2,3'-bipyridine]-5'-yl)ethynyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide 67 67 3-[(5-Cyclopropylpyridin-3-yl)ethynyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide 68 67 3-[(6-Cyclopropylpyrazin-2-yl)ethynyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide 69 67 3-{[6-(2-fluorophenyl)pyrazin-2-yl]ethynyl}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide 70 67 3-{[6-(3-fluorophenyl)pyrazin-2-yl]ethynyl}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide 71 67 3-{[6-(4-fluorophenyl)pyrazin-2-yl]ethynyl}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide 72 59 3-({6-[(cyclopropylmethyl)amino]pyrazin-2-yl}ethynyl)-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide

[Table 9]

Example Referenced embodiments Chemical name 73 59 5-[(5-cyclopropylpyridin-3-yl)ethynyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-6-methylpyridin-3-carboxamide 74 59 3-[(6-bromopyrazin-2-yl)ethynyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide 75 67 N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-[(6-phenylpyrazin-2-yl)ethynyl]benzamide 76 76 3-[(5-bromopyridin-3-yl)ethynyl]-N-[(1S,2S)-1,3-dihydroxy-1-phenylprop-2-yl]-4-methylbenzamide 77 77 N1-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-N3-(5-phenylpyridin-3-yl)benzene-1,3-dicarboxamide 78 78 N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-{[2-(pyridin-3-yl)pyrimidin-4-yl]amino}benzamide 79 78 N-[(1S,2S)-2-hydroxycyclohexyl]-3-{[2-(isoquinolin-4-yl)pyrimidin-4-yl]amino}-4-methylbenzamide 80 78 N-[(1S,2S)-1,3-dihydroxy-1-phenylprop-2-yl]-3-{[2-(isoquinolin-4-yl)pyrimidin-4-yl]amino}-4-methylbenzamide 81 78 3-[([2,3'-bipyridine]-6-yl)amino]-5-fluoro-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide 82 78 N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-{[2-(methylamino)quinazolin-5-yl]amino}benzamide 83 83 3-(2-amino-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-N-[(1S,2S)-1,3-dihydroxy-1-phenylprop-2-yl]-4-methylbenzamide 84 84 N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-{[(1S)-1-(5-phenylpyridin-3-yl)ethyl]amino}benzamide

[Table 10]

Example Referenced embodiments Chemical name 85 85 3-{[(1S)-1-([3,3'-bipyridinyl]-5-yl)ethyl]amino}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide 86 84 N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-({(1S)-1-[5-(phenylethynyl)pyridin-3-yl]ethyl}amino)benzamide 87 87 3-{[(1S)-1-([3,4'-bipyridinyl]-5-yl)ethyl]amino}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide 88 84 N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-({(1S)-1-[5-(pyrimidin-2-yl)pyridin-3-yl]ethyl}amino)benzamide 89 89 3-{[(1S)-1-([2,3'-bipyridine]-5'-yl)ethyl]amino}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide 90 84 3-{[(1S)-1-([3,3'-bipyridin]-5-yl)ethyl]amino}-4-chloro-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide 91 91 3-{[(5-bromopyridin-3-yl)methyl]amino}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide 92 92 N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-{[(5-phenylpyridin-3-yl)methyl]amino}benzamide 93 92 3-{[([2,2'-bipyridine]-5-yl)methyl]amino}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide 94 94 3-({[5-(cyclopropylethynyl)pyridin-3-yl]methyl}amino)-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide 95 95 N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-({[5-(pyrimidin-2-yl)pyridin-3-yl]methyl}amino)benzamide 96 96 N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-{[(quinolin-3-yl)methyl]amino}benzamide

[Table 11]

Example Referenced embodiments Chemical name 97 94 N-[(1S,2S)-2-hydroxycyclohexyl]-3-[({5-[(1-hydroxycyclopropyl)ethynyl]pyridin-3-yl}methyl)amino]-4-methylbenzamide 98 98 3-[({5-[4-(2-aminopropyl-2-yl)phenyl]pyridin-3-yl}methyl)amino]-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide 99 92 3-({[5-(4-aminophenyl)pyridin-3-yl]methyl}amino)-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide 100 92 3-({[5-(3,5-difluorophenyl)pyridin-3-yl]methyl}amino)-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide 101 101 N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-{[(6-phenylpyrazin-2-yl)methyl]amino}benzamide 102 92 N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-({[5-(thien-2-yl)pyridin-3-yl]methyl}amino)benzamide 103 92 N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-({[5-(thien-3-yl)pyridin-3-yl]methyl}amino)benzamide 104 95 4-Chloro-N-[(1S,2S)-2-hydroxycyclohexyl]-3-({[5-(pyrimidin-2-yl)pyridin-3-yl]methyl}amino)benzamide 105 91 N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-{[(pyrazolo[5,1-b][1,3]thiazolyl-7-yl)methyl]amino}benzamide 106 95 3-Fluoro-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-5-({[5-(pyrimidin-2-yl)pyridin-3-yl]methyl}amino)benzamide 107 98 3-({[5-(5-fluoropyrimidin-2-yl)pyridin-3-yl]methyl}amino)-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide

[Table 12]

Example Referenced embodiments Chemical name 108 91 N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-{[(thieno[3,2-b]pyridin-6-yl)methyl]amino}benzamide 109 109 N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-{[(1H-pyrazolo[3,4-b]pyridin-5-yl)methyl]amino}benzamide 110 110 N-[(1S,2S)-2-hydroxycyclohexyl]-3-{[(imidazo[1,2-b]pyridazin-3-yl)methyl]amino}-4-methylbenzamide 111 98 N-[(1S,2S)-2-hydroxycyclohexyl]-3-({[5-(imidazo[1,2-a]pyrazin-6-yl)pyridin-3-yl]methyl}amino)-4-methylbenzamide 112 91 N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-({[1-(pyridin-2-yl)-1H-pyrazol-4-yl]methyl}amino)benzamide 113 113 3-{[(2-aminopyrimidin-5-yl)methyl]amino}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide 114 113 3-({[2-(cyclopropylamino)pyrimidin-5-yl]methyl}amino)-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide 115 98 N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-({[5-(pyrazin-2-yl)pyridin-3-yl]methyl}amino)benzamide 116 116 3-{[(6-acetamidopyridin-3-yl)methyl]amino}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide 117 113 3-[({6-[(cyclopropylmethyl)amino]pyridin-3-yl}methyl)amino]-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide 118 118 3-{[([2,2'-bipyridine]-5-yl)methyl]amino}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide 119 91 N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-{[(pyrazolo[1,5-a]pyrimidin-3-yl)methyl]amino}benzamide

[Table 13]

Example Referenced embodiments Chemical name 120 116 3-[({6-[(cyclopropanecarbonyl)amino]pyridin-3-yl}methyl)amino]-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide 121 92 N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-{[(2-phenylpyrimidin-5-yl)methyl]amino}benzamide 122 122 N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-({[6-(1H-pyrazol-1-yl)pyridin-3-yl]methyl}amino)benzamide 123 91 N-[(1S,2S)-2-hydroxycyclohexyl]-6-methyl-5-{[(pyrazolo[1,5-a]pyridin-3-yl)methyl]amino}pyridine-3-carboxamide 124 116 methyl carbamate {5-[(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylaniline)methyl]pyridin-2-yl}carbamate 125 116 N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-[({6-[(oxecyclohexane-4-yl)amino]pyridin-3-yl}methyl)amino]benzamide 126 116 N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-[({2-[(pyridin-2-yl)amino]pyrimidin-5-yl}methyl)amino]benzamide 127 91 N-{5-[(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylaniline)methyl]pyridin-2-yl}morpholin-4-carboxamide 128 92 N-[(1S,2S)-2-hydroxycyclohexyl]-3-({[2-(4-methoxyphenyl)pyrimidin-5-yl]methyl}amino)-4-methylbenzamide 129 129 N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-{[(6-{[(pyridin-3-yl)carbamoyl]amino}pyridin-3-yl)methyl]amino}benzamide 130 116 3-({[6-(cyclobutylamino)pyridin-3-yl]methyl}amino)-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide 131 131 3-{[(5-aminopyrazin-2-yl)methyl]amino}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide

[Table 14]

Example Referenced embodiments Chemical name 132 113 N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-[({2-[(oxecyclohexane-4-yl)amino]pyrimidin-5-yl}methyl)amino]benzamide 133 91 3-{[(6-{[cyclopropyl(methyl)carbamoyl]amino}pyridin-3-yl)methyl]amino}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide 134 116 N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-[({6-[(propyl-2-yl)amino]pyridin-3-yl}methyl)amino]benzamide 135 113 N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-{[(2-{[(3R)-oxacyclopentan-3-yl]amino}pyrimidin-5-yl)methyl]amino}benzamide 136 113 N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-{[(2-{[(3S)-oxacyclopentan-3-yl]amino}pyrimidin-5-yl)methyl]amino}benzamide 137 116 N-{5-[(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylaniline)methyl]pyridin-2-yl}oxacyclohexane-4-carboxamide 138 138 N-[(1S,2S)-2-hydroxycyclohexyl]-3-{[(6-{[(1r,3r)-3-methoxycyclobutane-1-carbonyl]amino}pyridin-3-yl)methyl]amino}-4-methylbenzamide 139 138 N-{5-[(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylaniline)methyl]pyridin-2-yl}oxepane-3-carboxamide 140 140 N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-({[6-(1H-1,2,3-triazol-1-yl)pyridin-3-yl]methyl}amino)benzamide 141 116 N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-[({6-[(oxecyclobutan-3-yl)amino]pyridin-3-yl}methyl)amino]benzamide 142 142 3-{[(2-aminopyrimidin-5-yl)methyl]amino}-4-chloro-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide

[Table 15]

Example Referenced embodiments Chemical name 143 142 3-{[(2-aminopyrimidin-5-yl)methyl]amino}-5-fluoro-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide 144 144 3-{[(3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)methyl]amino}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide 145 91 N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-({[5-(2H-1,2,3-triazol-2-yl)pyridin-3-yl]methyl}amino)benzamide 146 101 3-{[([3,3'-bipyridine]-5-yl)amino]methyl}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide 147 147 N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-({[5-(pyrimidin-2-yl)pyridin-3-yl]amino}methyl)benzamide 148 148 3-{[([2,3'-bipyridine]-5'-yl)amino]methyl}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide 149 95 N-[(1R,2R)-2-hydroxycyclohexyl]-4-methyl-3-({[5-(pyrimidin-2-yl)pyridin-3-yl]amino}methyl)benzamide 150 91 N-[(1S,2S)-2-hydroxycyclohexyl]-3-({[5-(pyrimidin-2-yl)pyridin-3-yl]amino}methyl)benzamide 151 91 4-Fluoro-N-[(1S,2S)-2-hydroxycyclohexyl]-3-({[5-(pyrimidin-2-yl)pyridin-3-yl]amino}methyl)benzamide 152 152 3-{[(5-bromopyridin-3-yl)amino]methyl}-N-[(1S,2S)-1,3-dihydroxy-1-phenylprop-2-yl]-4-methylbenzamide 153 153 N-[(1S,2S)-1,3-dihydroxy-1-phenylprop-2-yl]-4-methyl-3-{[(5-phenylpyridin-3-yl)amino]methyl}benzamide 154 153 3-{[(5-cyclopropylpyridin-3-yl)amino]methyl}-N-[(1S,2S)-1,3-dihydroxy-1-phenylprop-2-yl]-4-methylbenzamide

[Table 16]

Example Referenced embodiments Chemical name 155 155 3-{[([2,3'-bipyridine]-5'-yl)amino]methyl}-N-[(1S,2S)-1,3-dihydroxy-1-phenylprop-2-yl]-4-methylbenzamide 156 156 N-[(1S,2S)-1,3-dihydroxy-1-phenylprop-2-yl]-4-methyl-3-{[(6-phenylpyrazin-2-yl)amino]methyl}benzamide 157 94 5-({[5-(cyclopropylethynyl)pyridin-3-yl]amino}methyl)-N-[(1S,2S)-2-hydroxycyclohexyl]-6-methylpyridin-3-carboxamide 158 158 N-[3-({[6-(3,4-dimethoxyphenyl)pyrazin-2-yl]amino}methyl)phenyl]-N'-[(1R,2S)-2-hydroxycyclohexyl]urea 159 159 N-[(1R,2S)-2-hydroxycyclohexyl]-N'-[3-({[5-(pyrimidin-2-yl)pyridin-3-yl]amino}methyl)phenyl]urea] 160 159 N-[2-fluoro-5-({[5-(pyrimidin-2-yl)pyridin-3-yl]amino}methyl)phenyl]-N'-[(1R,2S)-2-hydroxycyclohexyl]urea 161 161 N-[4-fluoro-3-({[5-(pyrimidin-2-yl)pyridin-3-yl]amino}methyl)phenyl]-N'-[(1R,2S)-2-hydroxycyclohexyl]urea 162 161 N-[(1R,2S)-2-hydroxycyclohexyl]-N'-[4-methyl-3-({[5-(pyrimidin-2-yl)pyridin-3-yl]amino}methyl)phenyl]urea] 163 161 N-[(1R,2S)-2-hydroxycyclohexyl]-N'-[2-methyl-5-({[5-(pyrimidin-2-yl)pyridin-3-yl]amino}methyl)phenyl]urea] 164 164 N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-{1-[(6-phenylpyrazin-2-yl)amino]ethyl}benzamide 165 165 3-[([3,3'-bipyridine]-5-yl)methoxy]-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide 166 166 N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-{[5-(pyrimidin-2-yl)pyridin-3-yl]methoxy}benzamide

[Table 17]

Example Referenced embodiments Chemical name 167 166 4-Chloro-N-[(1S,2S)-2-hydroxycyclohexyl]-3-{[5-(pyrimidin-2-yl)pyridin-3-yl]methoxy}benzamide 168 165 3-{[([3,3'-bipyridine]-5-yl)oxy]methyl}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide 169 166 N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-({[5-(pyrimidin-2-yl)pyridin-3-yl]oxy}methyl)benzamide 170 170 4-Chloro-N-[(1S,2S)-2-hydroxycyclohexyl]-3-({[5-(pyrimidin-2-yl)pyridin-3-yl]oxy}methyl)benzamide 171 166 N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-{1-[5-(pyrimidin-2-yl)pyridin-3-yl]ethoxy}benzamide 172 172 N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-[1-(5-phenylpyridin-3-yl)ethoxy]benzamide 173 173 N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-[(E)-2-(5-phenylpyridin-3-yl)vinyl]benzamide 174 174 N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-[2-(5-phenylpyridin-3-yl)ethyl]benzamide 175 175 N-[(1S,2S)-2-hydroxycyclohexyl]-4-methyl-3-{[methyl(5-phenylpyridin-3-yl)amino]methyl}benzamide 176 84 3-{[ethyl(5-phenylpyridin-3-yl)amino]methyl}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide 177 177 3-[(Z)-2-([2,3'-bipyridine]-5'-yl)-2-fluorovinyl]-4-fluoro-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide 178 177 4-Fluoro-3-{(Z)-2-fluoro-2-[5-(pyrimidin-2-yl)pyridin-3-yl]vinyl}-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide

[Table 18]

Example Referenced embodiments Chemical name 179 177 3-[(Z)-2-fluoro-2-(imidazo[1,2-b]pyridazin-3-yl)vinyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide 180 180 5-[(Z)-2-([2,3'-bipyridine]-5'-yl)-2-fluorovinyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-6-methylpyridine-3-carboxamide 181 177 3-[(Z)-2-fluoro-2-{5-[(4-methylpiperazin-1-yl)methyl]pyridin-3-yl}vinyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide 182 177 3-[(Z)-2-fluoro-2-{5-[(morpholin-4-yl)methyl]pyridin-3-yl}vinyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide 183 177 3-[(Z)-2-{6-[(cyclopropylmethyl)amino]pyridin-3-yl}-2-fluorovinyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide 184 180 4-Fluoro-3-{(Z)-2-fluoro-2-[5-(morpholino-4-yl)pyridin-3-yl]vinyl}-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide 185 180 4-Fluoro-3-[(Z)-2-Fluoro-2-{5-[(oxacyclohexane-4-yl)amino]pyridin-3-yl}vinyl]-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide 186 180 4-Fluoro-3-[(Z)-2-Fluoro-2-{5-[(4-methylpiperazin-1-yl)methyl]pyridin-3-yl}vinyl]-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide 187 180 5-{(Z)-2-[5-(cyclopropylmethoxy)pyridin-3-yl]-2-fluorovinyl}-N-[(1S,2S)-2-hydroxycyclohexyl]-6-methylpyridin-3-carboxamide 188 180 5-{(Z)-2-fluoro-2-[5-(morpholin-4-yl)pyridin-3-yl]vinyl}-N-[(1S,2S)-2-hydroxycyclohexyl]-6-methylpyridin-3-carboxamide

[Table 19]

Example Referenced embodiments Chemical name 189 180 5-[(Z)-2-(6-aminopyridin-3-yl)-2-fluorovinyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-6-methylpyridin-3-carboxamide 190 180 5-[(Z)-2-(2-aminopyrimidin-5-yl)-2-fluorovinyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-6-methylpyridine-3-carboxamide 191 180 3-[(Z)-2-(6-aminopyridin-3-yl)-2-fluorovinyl]-4-fluoro-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide 192 192 3-[(Z)-2-(2-aminopyrimidin-5-yl)-2-fluorovinyl]-4-fluoro-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide 193 177 3-[(Z)-2-fluoro-2-{5-[(1-methylpiperidin-4-yl)amino]pyridin-3-yl}vinyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide 194 194 3-[(Z)-2-{5-[(4-ethylpiperazin-1-yl)methyl]pyridin-3-yl}-2-fluorovinyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide 195 180 5-[(Z)-2-fluoro-2-{5-[(oxocyclobutan-3-yl)amino]pyridin-3-yl}vinyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-6-methylpyridin-3-carboxamide 196 180 4-Fluoro-3-[(Z)-2-Fluoro-2-{5-[(oxecyclobutan-3-yl)amino]pyridin-3-yl}vinyl]-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide 197 177 3-[(Z)-2-(6-{[2-(dimethylamino)ethyl]amino}pyridin-3-yl)-2-fluorovinyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide 198 177 3-[(Z)-2-(5-{[2-(dimethylamino)ethyl]amino}pyridin-3-yl)-2-fluorovinyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide

[Table 20]

Example Referenced embodiments Chemical name 199 199 5-[(Z)-2-{6-[(cyclopropylmethyl)amino]pyridin-3-yl}-2-fluorovinyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-6-methylpyridin-3-carboxamide 200 180 3-[(Z)-2-fluoro-2-{5-[(4-methylpiperazin-1-yl)methyl]pyridin-3-yl}vinyl]-N-[(1S,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]-4-methylbenzamide 201 180 3-[(Z)-2-fluoro-2-{5-[(4-methylpiperazin-1-yl)methyl]pyridin-3-yl}vinyl]-N-(2-hydroxy-3,3-dimethylbutyl)-4-methylbenzamide 202 180 3-[(Z)-2-{2-[(cyclopropylmethyl)amino]pyrimidin-5-yl}-2-fluorovinyl]-4-fluoro-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide 203 180 3-{(Z)-2-[2-(cyclopropylamino)pyrimidin-5-yl]-2-fluorovinyl}-4-fluoro-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide 204 180 3-[(Z)-2-(2-amino-4-methylpyrimidin-5-yl)-2-fluorovinyl]-4-fluoro-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide 205 180 4-Fluoro-3-{(Z)-2-fluoro-2-[2-(methylamino)pyrimidin-5-yl]vinyl}-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide 206 177 3-[(Z)-2-(5-aminopyrazin-2-yl)-2-fluorovinyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide 207 177 4-Fluoro-3-[(Z)-2-fluoro-2-(5-fluoropyridin-3-yl)vinyl]-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide

[Table 21]

[Table 22]

[Table 23]

[Table 24]

[Table 25]

[Table 26]

[Table 27]

[Table 28]

[Table 29]

Below, examples of biological testing of the compounds used in this invention will be shown.

<Test Example 1: Inhibition of PDGFR-β Tyrosine Kinase>

1. Preparation of test substances

The test substance was prepared to 10 mM using dimethyl sulfoxide (DMSO) and diluted with DMSO to achieve concentrations of 0.001–1000 μM. This DMSO solution was diluted 8-fold with assay buffer 1 (50 mM HEPES (pH 7.0), 0.02% _NaN3 , 0.01% bovine serum albumin, 0.1 mM orthovanadate, 1 mM dithiothreitol, 5 mM _MgCl2 , and 1 mM _MnCl2 ), and further diluted 5-fold with assay buffer 2 (50 mM HEPES (pH 7.0), 0.02% _NaN3 , 0.01% bovine serum albumin, 0.1 mM orthovanadate, 1 mM dithiothreitol, 5 mM MgCl2, ₁ mM _MnCl2 , and 40 nM supplemental enzyme buffer (cisbio)).

2. Measurement of PDGFR-β tyrosine kinase inhibition

For measurements, the HTRF KinEASE-TK kit from Cisbio Bioassays SAS was used. 4 μL of the test substance solution was added to each well of a 384-well plate, followed by 2 μL of PDGFR-β enzyme solution (final concentration 1 ng/L, CarnaBiosciences, Inc.), and then 4 μL of substrate solution obtained by adding 0.6 μM ATP to the TK substrate-3-biotin (cisbio). The solution was incubated at 30°C for 30 minutes. The final concentration of the test substance ranged from 0.01 to 10,000 nM.

Subsequently, 10 μL of detection solution (cisbio) was added to each well, and the mixture was allowed to react at 30°C for 1 hour. Fluorescence intensity was measured using a microplate reader (Spectra Max M5, Molecular device).

3. Analysis of Measurement Results

Using the fluorescence intensity ratio for each condition, the inhibition rate was calculated when the values for the positive control (1% DMSO solution) and the negative control (enzyme (-)) were defined as 0% and 100%, respectively. Subsequently, a nonlinear regression analysis of a two-parameter logistic model of logarithmic concentration and inhibition rate was performed using the SAS system (SAS Institute Inc.) to estimate the concentration ( _IC50 value) of the test substance that inhibited 50% of PDGFR-β tyrosine kinase activity.

The results are shown in Tables 30 to 33 below.

[Table 30]

[Table 31]

[Table 32]

[Table 33]

<Test Example 2: Inhibitory effect on the proliferation of cells transfected with TEL-PDGFRβ and TEL-KIT fusion genes>

1. Manufacturing of cells transfected with the TEL-PDGFRβ and TEL-KIT fusion genes

The human TEL-PDGFRβ fusion gene (see, for example, CELL, 1994, 77, 307-316) or the human TEL-KIT fusion gene was inserted into the multiple cloning site of the retroviral expression vector pMYs-IRES-GFP to create a vector for gene transfection. For the human TEL-KIT fusion gene, an amino acid sequence important for the enzymatic activity of the KIT gene (accession number NP_000213.1, amino acids 521-928) was identified and appropriately combined with the amino acid sequence of the TEL gene to produce a sequence that exhibits activation in the absence of ligand factors. Subsequently, the vector for gene transfection was introduced into packaging cells derived from the logarithmically growing human fetal kidney cell line PLAT-E using a transfection reagent (FuGENE6, Promega Corporation). Since the culture supernatant of PLAT-E after gene transfection contained viral particles for gene transfection, it was collected and used as the culture medium for gene transfection. The culture medium for gene transfection was added to a RetroNectin-coated plate and incubated to allow viral particles to adhere to the plate. Then, logarithmically growing mouse pre-B cell line Ba/F3 was seeded onto the plate and infected with the virus to produce cells that proliferate in a PDGFRβ or KIT-dependent manner.

2. Preparation of test substances

The test substance was prepared to 10 mM using dimethyl sulfoxide (DMSO) and then diluted with DMSO to achieve a concentration of 0.0001–3 mM. It was then diluted 100-fold with distilled water.

3. Measurement of the inhibitory effect on the proliferation of cells expressing TEL-PDGFRβ or TEL-KIT

On the day after TEL-PDGFRβ and TEL-KIT expressing cells were seeded into 96-well plates, the prepared test substance solution was added to the plates, with a final concentration of 0.1–10,000 nM. After 72 hours, the live cell count was measured using the amount of formazan produced by the reduction of the tetrazolium salt compound by mitochondrial dehydrogenases in live cells as an indicator.

4. Analysis of Measurement Results

Based on the amount of methylphenidate under each condition, the inhibition rate against cell proliferation was calculated when the amount of methylphenidate in the negative control (0.1% DMSO solution) and the blank (culture medium only) was defined as 0% and 100%, respectively. Subsequently, nonlinear regression analysis of a two-parameter logistic model of logarithmic dose and inhibition rate against cell proliferation was performed using the SAS system (SAS Institute Inc.) to estimate the _IC50 value.

The results are shown in Tables 34 to 38 below.

[Table 34]

[Table 35]

[Table 36]

[Table 37]

[Table 38]

<Test Example 3: Inhibitory Effect on the Proliferation of Pulmonary Artery Smooth Muscle Cells>

1. Preparation of test substances

The test substance was prepared to 10 mM using dimethyl sulfoxide (DMSO) and then diluted with DMSO to achieve a concentration of 0.003–3 mM. It was then diluted 50-fold with distilled water.

2. Measurement of the inhibitory effect on the proliferation of pulmonary artery smooth muscle cells

On the day after seeding healthy human-derived pulmonary artery smooth muscle cells into 96-well plates using smooth muscle cell proliferation medium, the proliferation medium was replaced with 0.1% FBS, and the cells were cultured for another day. The test substance solution was diluted 10-fold with medium containing BrdU and human PDGF-BB (final concentration 10 ng/mL, Sigma-Aldrich) and added to the cells in equal volumes to achieve a final concentration of 3–10,000 nM. Additionally, BrdU and 0.1% DMSO solution were added to the human PDGF-BB negative control. After one day of culture, the amount of BrdU absorbed by the proliferating cells was measured using an anti-BrdU antibody.

3. Analysis of Measurement Results

Based on the amount of BrdU under each condition, the inhibition rate against cell proliferation was calculated when the amount of BrdU in the positive control (human PDGF-BB (+)) and the negative control (human PDGF-BB (-)) was defined as 0% and 100%, respectively. Subsequently, a nonlinear regression analysis of a two-parameter logistic model of logarithmic dose and inhibition rate against cell proliferation was performed using the SAS system (SAS Institute Inc.) to estimate the _IC50 value.

The results are shown in Tables 39 to 46 below.

[Table 39]

[Table 40]

[Table 41]

[Table 42]

[Table 43]

[Table 44]

[Table 45]

[Table 46]

<Test Example 4: Inhibitory Effect on Erythrocyte Colony Formation>

1. Preparation of test substances

The test substance was prepared to 10 mM using dimethyl sulfoxide (DMSO) and then diluted with DMSO to achieve a concentration of 0.1-3 mM, thus preparing a test substance solution with a final concentration of 1000 times.

2. Measurement of the inhibitory effect on erythrocyte colony formation

Human bone marrow CD34-positive hematopoietic stem cells were thawed and suspended in MethodCult medium. Test substance solutions were then added to achieve a final concentration of 0.1–10 μM. Cells were seeded onto 35 mm plates and cultured for 14 days. The number of erythrocyte progenitor-derived cell colonies was measured under a microscope.

3. Analysis of Measurement Results

Based on the number of colonies under each condition, the inhibition rate against colony formation was calculated when the negative control (0.1% DMSO solution) was defined as 100%. A nonlinear regression analysis of a two-parameter logistic model of the logarithmic dose and the inhibition rate against colony formation was performed using the SAS system (SAS Institute Inc.) to estimate the _IC50 value. The results are shown in Table 47 below.

[Table 47]

Formulation Examples

The following formulation examples are illustrative only and are not intended to limit the scope of the invention in any way.

Formulation Example 1: Tablets (oral)

In a formulation of 80 mg tablets

The powder mixture of the above-mentioned components is compressed into oral tablets using conventional methods.

Industrial applicability

Because the compounds of the present invention have inhibitory activity against PDGF receptor kinase, they can be used as therapeutic agents for respiratory diseases, cancer, smooth muscle proliferative disorders, angiogenesis disorders, autoimmune/inflammatory diseases, metabolic diseases, vascular occlusive diseases, etc.

Claims (3)

1. Compounds selected from the following (3), (17), (20), (24), (113) and (148): (3) 2-(cyclopropylmethyl)-N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)-1,3-thiazolyl-5-carboxamide, (17) 5-[cyclopropyl(methyl)amino]-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, (24) 5-(cyclopropylmethoxy)-N-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-methylphenyl)pyridine-3-carboxamide, (113) 3-{[(2-aminopyrimidin-5-yl)methyl]amino}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide, and (148) 3-{[([2,3'-bipyridine]-5'-yl)amino]methyl}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-methylbenzamide or a pharmaceutically acceptable salt thereof. 2. A pharmaceutical composition comprising, as an active ingredient, the compound of claim 1 or a pharmaceutically acceptable salt thereof. 3. A therapeutic agent for pulmonary hypertension, scleroderma, asthma, bronchiolitis obliterans, pulmonary fibrosis, acute myeloid leukemia (AML), eosinophilic syndrome, T-lymphocytic leukemia, chronic myelomonocytic leukemia (CMML), chronic myeloid leukemia (CML), chronic eosinophilic leukemia, dermatofibrosarcoma protuberans, glioma, ovarian cancer, restenosis, atherosclerosis/occlusive arteriosclerosis, moyamoya disease (idiopathic Willis ring occlusion), leiomyoma, lymphangioleiomyomatosis, or age-related macular degeneration (AMD), said therapeutic agent comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient.