Compounds and medicaments as DDR1 kinase inhibitors

Abstract

The present invention provides a compound represented by general formula [1] having DDR1 kinase inhibitory activity, a pharmaceutically acceptable salt thereof, or a solvate thereof (in the formula, R1 represents a hydrogen atom, a halogen atom, or an optionally substituted alkyl group; het is a 5-membered to 10-membered heteroaryl group; l1 is-CO-NH <->, and-CRa is equal to CRb <->; x is C-Rc; r2 is a halogenated alkoxy group with 1 to 6 carbon atoms or a halogenated alkyl group with 1 to 6 carbon atoms; r3 and R4 together with the carbon atoms to which they are bonded form optionally substituted C3-C6 cycloalkyl or optionally substituted heterocycloalkyl). # imgabs0 #

Description

Technical Field

[0001] The present invention relates to compounds and medicaments that are inhibitors of DDR1 kinase. Background Art

[0002] Discoidin domain receptor 1 (DDR1) is a tyrosine kinase receptor belonging to the discoidin domain receptor family, which is involved in cell proliferation and differentiation as well as migration, invasion, and adhesion. It is mainly expressed in epithelial cells of the lung, kidney, breast, digestive tract, etc.

[0003] DDR1 transmits collagen signals into cells by binding to collagen as a ligand using its discoid domain. DDR1 is characterized in that it recognizes basement membrane collagens such as type IV collagen as well as fibrous collagens such as type I collagen as ligands. In DDR1 bound to collagen, specific tyrosine residues in the kinase domain present on the cytoplasmic side of the receptor are phosphorylated, and molecules having Src homology 2 and phosphotyrosine binding domains are bound, thereby activating various downstream signaling pathways.

[0004] Activation of DDR1 is associated with various renal diseases. DDR1 activation is associated with various renal diseases, including Alport syndrome (Non-Patent Documents 1 and 2) caused by type IV collagen gene mutation, IgA nephropathy (Non-Patent Document 3), Goodpasture syndrome (Non-Patent Document 4), lupus nephritis (Non-Patent Document 4), ANCA (anti-neutrophil cytoplasmic antibody)-associated nephritis (Non-Patent Document 5), and diabetic nephropathy (Non-Patent Document 6).

[0005] In addition, there are reports that activation of DDR1 is involved in various fibrotic diseases, such as pulmonary fibrosis (Non-Patent Document 7) and liver cirrhosis (Non-Patent Document 8).

[0006] Furthermore, DDR1 is reported to be involved in the function of Th17 cells involved in autoimmune diseases and allergies (Non-Patent Document 9). Th17 cells are involved in the pathogenesis of diseases such as rheumatoid arthritis, multiple sclerosis, ulcerative colitis, and Crohn's disease.

[0007] It is also reported to be associated with cancer-related pathological formation. For example, acute myeloid leukemia (non-patent document 10), acute lymphocytic leukemia (non-patent document 11), chronic lymphocytic leukemia (non-patent document 12), Hodgkin's lymphoma (non-patent document 13), glioma (non-patent document 14), non-small cell lung cancer (non-patent document 15), breast cancer (non-patent document 16), ovarian cancer (non-patent document 17), prostate cancer (non-patent document 18), colorectal cancer (non-patent document 19), etc. are known.

[0008] In addition, there are reports that DDR1 is also involved in pathological conditions such as systemic lupus erythematosus (Non-Patent Document 5), osteoarthritis (Non-Patent Document 20), heparin-induced thrombocytopenia (Non-Patent Document 21), atherosclerosis (Non-Patent Document 22), and vitiligo vulgaris (Non-Patent Document 23).

[0009] The treatment of these diseases mostly stays at symptomatic treatment, inhibiting the disease from getting worse, and improving the quality of life, and it is extremely difficult to carry out effective treatment. Therefore, it can be considered that: for these DDR1-related diseases, DDR1 inhibitors can provide a new type of treatment method.

[0010] Prior art literature

[0011] Non-patent literature

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[0034] Non-patent literature 1: Almasi-Nasrabadi et al., Gene. 2019 Jun 5; 700: 17-22. Summary of the invention

[0035] Problems to be solved by the invention

[0036] The object of the present invention is to provide a compound having DDR1 kinase inhibitory activity or a pharmaceutically acceptable salt or solvate thereof.

[0037] Means used to solve problems

[0038] The present inventors have found that the following compounds or pharmaceutically acceptable salts or solvates thereof have excellent DDR1 kinase inhibitory activity, thereby completing the present invention.

[0039] That is, the present invention includes the following inventions (Item 1) to (Item 16).

[0040] (Item 1)

[0041] A compound represented by the following formula [1] or a pharmaceutically acceptable salt or solvate thereof,

[0042] [Chemistry 1]

[0043]

[0044] [Wherein,

[0045] R 1 is one or two groups selected from the group consisting of a hydrogen atom, a halogen atom, an optionally substituted alkyl group, an optionally substituted amino group, an optionally substituted alkoxy group, an optionally substituted aryl group, a haloalkyl group, a cycloalkyl group, an optionally substituted sulfonyl group, a cyano group, an optionally substituted carbamoyl group, a heteroaryl group, and a dialkylphosphoryl group;

[0046] Het is a 5- to 10-membered heteroaryl group;

[0047] L 1 For connecting bonds, -CO-NH-, -CR a =CR b -or-C≡C-;

[0048] Here, the carbonyl group (C=O) of -CO-NH- is bonded to Het, -CR a =CR b -of-CR a Bonded to Het;

[0049] R a is a hydrogen atom or a halogen atom;

[0050] R b is a hydrogen atom or a halogen atom;

[0051] X is N or CR c ;

[0052] Here, R c is a hydrogen atom or a halogen atom;

[0053] R 2 is a hydrogen atom, an ethyl group, a C1-C6 haloalkoxy group or a C1-C6 haloalkyl group;

[0054] R 3 is a hydrogen atom;

[0055] R 4 is a hydrogen atom, a phenyl group which may be substituted as appropriate, or an alkyl group which may be substituted as appropriate;

[0056] or,

[0057] R 3 and R 4 Together with the carbon atom to which they are bonded, they form an optionally substituted C3-C8 cycloalkyl group].

[0058] (Item 2)

[0059] The compound according to item 1 or its pharmaceutically acceptable salt or solvate thereof, wherein R 1 is one or two groups selected from the group consisting of a hydrogen atom, a halogen atom, an optionally substituted alkyl group, an optionally substituted amino group, an optionally substituted alkoxy group, an optionally substituted aryl group, a haloalkyl group, and an optionally substituted carbamoyl group;

[0060] Het is a 5- to 10-membered heteroaryl group;

[0061] L 1For the connection key, -CR a =CR b -, -CO-NH- or -C≡C-;

[0062] Here, the carbonyl group (C=O) of -CO-NH- is bonded to Het,

[0063] -CR a =CR b -of-CR a Bonded to Het;

[0064] R a is a hydrogen atom or a halogen atom;

[0065] R b is a hydrogen atom or a halogen atom;

[0066] X is N or CR c , R c is a hydrogen atom or a halogen atom;

[0067] R 2 is ethyl, C1-C6 haloalkoxy or C1-C6 haloalkyl;

[0068] R 3 is a hydrogen atom;

[0069] R 4 is a hydrogen atom, a phenyl group which may be substituted as appropriate, or an alkyl group which may be substituted as appropriate;

[0070] or,

[0071] R 3 and R 4 Together with the carbon atom to which they are bonded, they form a C3-C8 cycloalkyl group which may be substituted.

[0072] (Item 3)

[0073] The compound according to item 1 or its pharmaceutically acceptable salt or solvate thereof, wherein R 1 is one or two groups selected from the group consisting of a hydrogen atom, an optionally substituted alkyl group, an optionally substituted amino group, and an optionally substituted carbamoyl group;

[0074] Het is a 5- to 10-membered heteroaryl group;

[0075] L 1 For the connection key, -CR a =CR b -or-C≡C-;

[0076] Here, -CR a =CR b -of-CRa Bonded to Het;

[0077] R a is a hydrogen atom;

[0078] R b is a halogen atom;

[0079] X is N or CR c , R c is a hydrogen atom;

[0080] R 2 is C1-C6 haloalkoxy or C1-C6 haloalkyl;

[0081] R 3 and R 4 Together with the carbon atom to which they are bonded, they form a C3-C8 cycloalkyl group which may be substituted.

[0082] (Item 4)

[0083] The compound according to (1) or a pharmaceutically acceptable salt or a solvate thereof, wherein R 1 is one or two groups selected from a hydrogen atom, an alkyl group, an amino group, and a carbamoyl group;

[0084] Het is pyrimidinyl, pyridyl, pyrazinyl, pyrazolyl, pyridinyl, imidazo[1,5-a]pyridinyl, oxazolyl, thiazolyl, pyrazyl (pyrazyl, ピラジル);

[0085] L 1 For the connection key, -CR a =CR b -or-C≡C-;

[0086] Here, -CR a =CR b -of-CR a Bonded to Het;

[0087] R a is a hydrogen atom;

[0088] R b is a halogen atom;

[0089] X is N or CR c , R c is a hydrogen atom;

[0090] R 2is C1-C6 fluoroalkoxy, C1-C6 difluoroalkoxy, C1-C6 trifluoroalkoxy, C1-C6 fluoroalkyl, C1-C6 difluoroalkyl or C1-C6 trifluoroalkyl;

[0091] R 3 and R 4 Together with the carbon atoms to which they are bonded, they form optionally substituted cyclopentyl, optionally substituted cyclohexyl, or optionally substituted spiro[2.4]heptyl.

[0092] (Item 5)

[0093] The compound according to (1) or a pharmaceutically acceptable salt or a solvate thereof, wherein R 1 is a group selected from a hydrogen atom, an alkyl group, an amino group, and a carbamoyl group;

[0094] Het is pyrimidinyl, pyridyl, pyrazinyl, pyrazolyl, pyridinyl, imidazo[1,5-a]pyridinyl, oxazolyl, thiazolyl, pyrazyl;

[0095] L 1 For the connection key, -CR a =CR b -or-C≡C-;

[0096] Here, -CR a =CR b -of-CR a Bonded to Het;

[0097] R a is a hydrogen atom;

[0098] R b is a halogen atom;

[0099] X is N or CR c , R c is a hydrogen atom;

[0100] R 2 is C1-C6 fluoroalkoxy, C1-C6 difluoroalkoxy, C1-C6 trifluoroalkoxy, C1-C6 fluoroalkyl, C1-C6 difluoroalkyl or C1-C6 trifluoroalkyl;

[0101] R 3 and R 4 Together with the carbon atoms to which they are bonded, they form a cyclopentyl group substituted with one or two groups selected from halogen and haloalkoxy, a cyclohexyl group substituted with one or two groups selected from halogen and haloalkoxy, or a spiro[2.4]heptyl group substituted with one or two groups selected from halogen and haloalkoxy.

[0102] (Item 6)

[0103] The compound according to (item 1) or a pharmaceutically acceptable salt or a solvate thereof, which is selected from the following compounds (1) to (47).

[0104] (1) 4-(difluoromethoxy)-N-[(1S,2S,4S)-2-hydroxy-4-(trifluoromethoxy)cyclopentyl]-3-[(pyrimidin-5-yl)ethynyl]benzamide,

[0105] (2) 4-(difluoromethoxy)-3-[2-(5-fluoropyridin-3-yl)ethynyl]-N-[(1S,2S,4S)-2-hydroxy-4-(trifluoromethoxy)cyclopentyl]benzamide,

[0106] (3) 3-[2-(2-aminopyrimidin-5-yl)ethynyl]-4-(difluoromethoxy)-N-[(1S,2S,4S)-2-hydroxy-4-(trifluoromethoxy)cyclopentyl]benzamide,

[0107] (4) 3-[2-(5-aminopyrazin-2-yl)ethynyl]-4-(difluoromethoxy)-N-[(1S,2S,4S)-2-hydroxy-4-(trifluoromethoxy)cyclopentyl]benzamide,

[0108] (5) 3-[2-(2-Amino-4-methoxypyrimidin-5-yl)ethynyl]-4-(difluoromethoxy)-N-[(1S,2S,4S)-2-hydroxy-4-(trifluoromethoxy)cyclopentyl]benzamide.

[0109] (6) 4-(difluoromethoxy)-N-[(1S,2S,4S)-2-hydroxy-4-(trifluoromethoxy)cyclopentyl]-3-[2-(1-methyl-1H-pyrazol-4-yl)ethynyl]benzamide,

[0110] (7) 3-[2-(5-aminopyrazin-2-yl)ethynyl]-4-(difluoromethoxy)-N-[(2S)-1-hydroxy-4-(trifluoromethoxy)butane-2-yl]benzamide,

[0111] (8) 3-[2-(2-aminopyrimidin-5-yl)ethynyl]-4-(difluoromethoxy)-N-[(1S)-1-(3-fluorophenyl)-2-hydroxyethyl]benzamide,

[0112] (9) 3-[2-(2-aminopyrimidin-5-yl)ethynyl]-4-(difluoromethoxy)-N-[(2S)-1-hydroxy-3-(4-methoxyphenyl)propan-2-yl]benzamide,

[0113] (10) 3-[(1Z)-2-(5-aminopyrazin-2-yl)-2-fluorovinyl]-4-(difluoromethoxy)-N-[(1S,2S,4S)-2-hydroxy-4-(trifluoromethoxy)cyclopentyl]benzamide,

[0114] (11) 5-[(1Z)-2-(2-aminopyrimidin-5-yl)-2-fluorovinyl]-6-ethyl-N-[(1S,2S,4S)-2-hydroxy-4-(trifluoromethoxy)cyclopentyl]pyridine-3-carboxamide,

[0115] (12) 3-[(1Z)-2-(2-aminopyrimidin-5-yl)-1-fluorovinyl]-4-(difluoromethoxy)-N-[(2S)-1-hydroxy-4-(trifluoromethoxy)butane-2-yl]benzamide,

[0116] (13) 4-(difluoromethoxy)-3-fluoro-5-[(1Z)-1-fluoro-2-(5-methoxypyridin-3-yl)vinyl]-N-[(1S,2S,4S)-2-hydroxy-4-(trifluoromethoxy)cyclopentyl]benzamide,

[0117] (14) 7-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-(trifluoromethyl)phenyl)imidazo[1,5-a]pyridine-3-carboxamide,

[0118] (15) 5-{3-carbamoylimidazo[1,5-a]pyridin-7-yl}-N-[(1S,2S,4S)-2-hydroxy-4-(trifluoromethoxy)cyclopentyl]-6-(trifluoromethyl)pyridine-3-carboxamide,

[0119] (16) N-(2-ethyl-5-{[(1S,2S,4S)-2-hydroxy-4-(trifluoromethoxy)cyclopentyl]carbamoyl}phenyl)-2-phenyl-1,3-oxazole-5-carboxamide,

[0120] (17) 2-(cyclopropylmethyl)-N-(2-ethyl-5-{[(1S,2S,4S)-2-hydroxy-4-(trifluoromethoxy)cyclopentyl]carbamoyl}phenyl)-1,3-thiazole-5-carboxamide,

[0121] (18) 4-(difluoromethoxy)-N-[(5S,6S)-6-hydroxyspiro[2.4]heptane-5-yl]-3-[2-(pyrimidin-5-yl)ethynyl]benzamide,

[0122] (19) 4-(difluoromethoxy)-3-[2-(5-fluoropyridin-3-yl)ethynyl]-N-[(5S,6S)-6-hydroxyspiro[2.4]heptane-5-yl]benzamide,

[0123] (20) 3-[2-(2-aminopyrimidin-5-yl)ethynyl]-N-[(1S,2S)-5,5-difluoro-2-hydroxycyclohexyl]-4-(difluoromethoxy)benzamide,

[0124] (21) 3-[2-(2-aminopyrimidin-5-yl)ethynyl]-4-(difluoromethoxy)-N-[(5S,6S)-6-hydroxyspiro[2.4]heptane-5-yl]benzamide,

[0125] (22) 3-[2-(2-aminopyrimidin-5-yl)ethynyl]-4-(difluoromethoxy)-N-[(2S)-1-hydroxy-4-(trifluoromethoxy)butan-2-yl]benzamide,

[0126] (23) 3-[2-(2-amino-4-methoxypyrimidin-5-yl)ethynyl]-4-(difluoromethoxy)-N-[(5S,6S)-6-hydroxyspiro[2.4]heptane-5-yl]benzamide,

[0127] (24) 4-(difluoromethoxy)-N-[(2S)-1-hydroxy-4-(trifluoromethoxy)butane-2-yl]-3-[2-(1-methyl-1H-pyrazol-4-yl)ethynyl]benzamide,

[0128] (25) 3-[(1Z)-2-(5-aminopyrazin-2-yl)-2-fluorovinyl]-N-[(1S,2S)-5,5-difluoro-2-hydroxycyclohexyl]-4-(difluoromethoxy)benzamide,

[0129] (26) 3-[(1Z)-2-(5-aminopyrazin-2-yl)-2-fluorovinyl]-4-(difluoromethoxy)-N-[(5S,6S)-6-hydroxyspiro[2.4]heptane-5-yl]benzamide,

[0130] (27) 7-(5-{[(1S,2S)-5,5-difluoro-2-hydroxycyclohexyl]carbamoyl}-2-(trifluoromethyl)phenyl)imidazo[1,5-a]pyridine-3-carboxamide,

[0131] (28) 7-(5-{[(5S,6S)-6-hydroxyspiro[2.4]heptane-5-yl]carbamoyl}-2-(trifluoromethyl)phenyl)imidazo[1,5-a]pyridine-3-carboxamide,

[0132] (29) 7-(5-{[(1S,2S,4S)-2-hydroxy-4-(trifluoromethoxy)cyclopentyl]carbamoyl}-2-(trifluoromethyl)phenyl)imidazo[1,5-a]pyridine-3-carboxamide,

[0133] (30) 5-{3-carbamoylimidazo[1,5-a]pyridin-7-yl}-N-[(2S)-1-hydroxy-4-(trifluoromethoxy)butane-2-yl]-6-(trifluoromethyl)pyridine-3-carboxamide,

[0134] (31) 7-(5-{[(2S)-1-hydroxy-4-(trifluoromethoxy)butan-2-yl]carbamoyl}-2-(trifluoromethyl)phenyl)imidazo[1,5-a]pyridine-3-carboxamide,

[0135] (32) N-(2-ethyl-5-{[(2S)-1-hydroxy-4-(trifluoromethoxy)butan-2-yl]carbamoyl}phenyl)-5-(3-fluorophenyl)pyridine-3-carboxamide,

[0136] (33) N-(2-ethyl-5-{[(1S,2S,4S)-2-hydroxy-4-(trifluoromethoxy)cyclopentyl]carbamoyl}phenyl)-5-(3-fluorophenyl)pyridine-3-carboxamide,

[0137] (34) 3-[(1Z)-2-(2-aminopyrimidin-5-yl)-2-fluorovinyl]-4-(difluoromethoxy)-N-[(1S)-1-(3-fluorophenyl)-2-hydroxyethyl]benzamide,

[0138] (35) 3-[2-(2-aminopyrimidin-5-yl)ethynyl]-N-[(2S)-1-(4-chlorophenyl)-3-hydroxypropane-2-yl]-4-(difluoromethoxy)benzamide hydrochloride,

[0139] (36) 3-[2-(2-aminopyrimidin-5-yl)ethynyl]-4-(difluoromethoxy)-N-[(1S)-2-hydroxy-1-phenylethyl]benzamide hydrochloride,

[0140] (37) 3-[(1Z)-2-(2-aminopyrimidin-5-yl)-2-fluorovinyl]-N-[(1S,2S)-5,5-difluoro-2-hydroxycyclohexyl]-4-(difluoromethoxy)benzamide,

[0141] (38) 3-[(1Z)-2-(2-aminopyrimidin-5-yl)-2-fluorovinyl]-4-(difluoromethoxy)-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide,

[0142] (39) 3-[(1Z)-2-(2-aminopyrimidin-5-yl)-1-fluorovinyl]-4-(difluoromethoxy)-N-[(1S,2S,4S)-2-hydroxy-4-(trifluoromethoxy)cyclopentyl]benzamide,

[0143] (40) 3-[(1Z)-2-(2-aminopyrimidin-5-yl)-1-fluorovinyl]-4-(difluoromethoxy)-N-[(5S,6S)-6-hydroxyspiro[2.4]heptane-5-yl]benzamide,

[0144] (41) 5-{3-carbamoylimidazo[1,5-a]pyridin-7-yl}-N-[(1S,2S)-5,5-difluoro-2-hydroxycyclohexyl]-6-(trifluoromethyl)pyridine-3-carboxamide,

[0145] (42) 5-(cyclopropylmethoxy)-N-(2-ethyl-5-{[(1S,2S,4S)-2-hydroxy-4-(trifluoromethoxy)cyclopentyl]carbamoyl}phenyl)pyridine-3-carboxamide,

[0146] (43) 5-(cyclopropylmethoxy)-N-(2-ethyl-5-{[(2S)-1-hydroxy-4-(trifluoromethoxy)butan-2-yl]carbamoyl}phenyl)pyridine-3-carboxamide,

[0147] (44) 2-[(cyclopropylmethyl)amino]-N-(2-ethyl-5-{[(2S)-1-hydroxy-4-(trifluoromethoxy)butan-2-yl]carbamoyl}phenyl)-1,3-thiazole-5-carboxamide,

[0148] (45) 2-[(Cyclopropylmethyl)amino]-N-(2-ethyl-5-{[(1S,2S,4S)-2-hydroxy-4-(trifluoromethoxy)cyclopentyl]carbamoyl}phenyl)-1,3-thiazole-5-carboxamide,

[0149] (46) 2-cyclopropyl-N-(2-ethyl-5-{[(1S,2S,4S)-2-hydroxy-4-(trifluoromethoxy)cyclopentyl]carbamoyl}phenyl)-1,3-thiazole-5-carboxamide,

[0150] (47) 2-(Cyclopropylmethyl)-N-(2-ethyl-5-{[(2S)-1-hydroxy-4-(trifluoromethoxy)butan-2-yl]carbamoyl}phenyl)-1,3-thiazole-5-carboxamide.

[0151] (Item 7)

[0152] A pharmaceutical composition comprising the compound described in (item 1) above or a pharmaceutically acceptable salt or solvate thereof as an active ingredient.

[0153] (Item 8)

[0154] A DDR1 kinase inhibitor comprising the compound described in (Item 1) above or a pharmaceutically acceptable salt or solvate thereof as an active ingredient.

[0155] (Item 9)

[0156] A method for inhibiting DDR1 kinase, comprising: administering the compound described in (1) above or a pharmaceutically acceptable salt or solvate thereof to a subject in need thereof.

[0157] (Item 10)

[0158] The compound according to (Item 1) above or a pharmaceutically acceptable salt thereof, which is used for inhibiting DDR1 kinase.

[0159] (Item 11)

[0160] Use of the compound described in (item 1) above or a pharmaceutically acceptable salt thereof in the manufacture of a DDR1 kinase inhibitor.

[0161] (Item 12)

[0162] A preventive or therapeutic agent for a disease associated with DDR1 kinase, comprising the compound described in (item 1) above or a pharmaceutically acceptable salt or solvate thereof.

[0163] (Item 13)

[0164] A method for preventing or treating a disease associated with DDR1 kinase, comprising: administering the compound described in (1) above or a pharmaceutically acceptable salt or solvate thereof to a subject in need thereof.

[0165] (Item 14)

[0166] The compound of the present invention or a pharmaceutically acceptable salt thereof is used for preventing or treating a disease associated with DDR1 kinase.

[0167] (Item 15)

[0168] Use of the compound of the present invention or a pharmaceutically acceptable salt thereof in the manufacture of a preventive or therapeutic agent for a disease associated with DDR1 kinase.

[0169] (Item 16)

[0170] A therapeutic agent for Alport syndrome, IgA nephropathy, Goodpasture syndrome, anti-glomerular basement membrane nephritis, lupus nephritis, ANCA-associated nephritis, diabetic nephropathy, purpuric nephritis, focal segmental glomerulosclerosis, chronic renal failure, minimal change nephrotic syndrome, mesangial proliferative glomerulonephritis, membranoproliferative glomerulonephritis, crescentic glomerulonephritis, membranous nephropathy, pulmonary fibrosis, myelofibrosis, hepatic fibrosis, acute myeloid leukemia, chronic myeloid leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma, glioma, non-small cell lung cancer, small cell lung cancer, breast cancer, ovarian cancer, prostate cancer, colorectal cancer or osteoarthritis, which contains the compound described in (item 1) or a pharmaceutically acceptable salt or solvate thereof as an active ingredient. DETAILED DESCRIPTION

[0171] The meanings of the terms used in this specification are described below. Unless otherwise specified, each term has the same meaning when used alone or in combination with other terms.

[0172] Examples of the "alkyl group" include, for example, linear or branched alkyl groups having 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, and more preferably 1 to 3 carbon atoms. Specifically, examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, sec-pentyl, 1-ethylpropyl, 1,2-dimethylpropyl, tert-pentyl, 2-methylbutyl, isopentyl, neopentyl, n-hexyl, sec-hexyl, 1-ethylbutyl, isohexyl, neohexyl, 1,1-dimethylbutyl, 2-ethylbutyl, 1,2,2-trimethylpropyl, and 2,2-dimethylbutyl.

[0173] The "halogen atom" means a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.

[0174] "Amino" means -NH2.

[0175] "Alkoxy" means a group in which the above-mentioned "alkyl" is bonded to an oxygen atom. Examples thereof include linear or branched alkoxy groups having 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms. Specifically, examples thereof include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentoxy, and n-hexoxy.

[0176] Examples of the alkoxy moiety of the "haloalkoxy" include the same "alkoxy" as mentioned above.

[0177] Examples of the "aryl group" include monocyclic to tricyclic aromatic hydrocarbon groups having 6 to 14 carbon atoms. Specifically, phenyl, 1-naphthyl, 2-naphthyl, 1-anthryl, 2-anthryl, 9-anthryl, 1-phenanthrenyl, 2-phenanthrenyl, 3-phenanthrenyl, 4-phenanthrenyl, 10-phenanthrenyl, etc. are included. Among them, phenyl is preferred.

[0178] The "haloalkyl group" means a group in which the hydrogen atom of the above-mentioned "alkyl group" is substituted with the above-mentioned "halogen atom". Specific examples thereof include fluoromethyl, chloromethyl, fluoroethyl, difluoromethyl, dichloromethyl, difluoroethyl, trifluoromethyl, trichloromethyl and trifluoroethyl.

[0179] The "cycloalkyl group" refers to a monocyclic to tricyclic cyclic non-aromatic hydrocarbon group, and specific examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

[0180] The above-mentioned "non-aromatic hydrocarbon group" may be a bridged hydrocarbon group. Examples of the bridged hydrocarbon group include:

[0181] - Bicyclo[2.2.1]heptyl (e.g. bicyclo[2.2.1]heptan-1-yl, bicyclo[2.2.1]heptan-2-yl, bicyclo[2.2.1]heptan-7-yl),

[0182] Bicyclo[1.1.1]pentyl (e.g. bicyclo[1.1.1]pentan-1-yl, bicyclo[1.1.1]pentan-2-yl),

[0183] - Bicyclo[4.1.0]heptyl (e.g., bicyclo[4.1.0]heptan-1-yl, bicyclo[4.1.0]heptan-2-yl, bicyclo[4.1.0]heptan-3-yl, bicyclo[4.1.0]heptan-7-yl),

[0184] Bicyclo[2.2.2]octyl (e.g. bicyclo[2.2.2]octan-1-yl, bicyclo[2.2.2]octan-2-yl),

[0185] - bicyclo[3.1.1]heptyl (e.g. bicyclo[3.1.1]heptan-1-yl, bicyclo[3.1.1]heptan-2-yl, bicyclo[3.1.1]heptan-3-yl, bicyclo[3.1.1]heptan-6-yl), or

[0186] ·Cubiman-1-yl.

[0187] The above-mentioned "non-aromatic carbocyclic group" may be a spirocyclic group. Examples of the spirocyclic group include:

[0188] Spiro[3.3]heptyl (e.g., spiro[3.3]heptan-1-yl, spiro[3.3]heptan-2-yl),

[0189] Spiro[2.4]heptyl (e.g., spiro[2.4]heptan-1-yl, spiro[2.4]heptan-4-yl, spiro[2.4]heptan-5-yl),

[0190] Spiro[4.4]nonyl (e.g., spiro[4.4]nonan-1-yl, spiro[4.4]nonan-2-yl),

[0191] Spiro[5.5]undecyl (e.g., spiro[5.5]undec-1-yl, spiro[5.5]undec-2-yl, spiro[5.5]undec-3-yl), or

[0192] - Spiro[2.5]octyl (e.g., spiro[2.5]octane-1-yl, spiro[2.5]octane-4-yl, spiro[2.5]octane-5-yl, spiro[2.5]octane-6-yl).

[0193] "Carbamyl" means -CO-NH2.

[0194] "Carbonyl" means -C(=O)-.

[0195] Examples of the "heteroaryl group" include monocyclic to tricyclic aromatic rings having 1 to 3 heteroatoms selected from nitrogen atoms, oxygen atoms, and sulfur atoms as constituent atoms and having 6 to 14 carbon atoms. Specifically, examples include:

[0196] Furyl (e.g., 2-furyl, 3-furyl),

[0197] · Thienyl (e.g., 2-thienyl, 3-thienyl),

[0198] Pyrrolyl (e.g., 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl),

[0199] Imidazolyl (e.g., 1-imidazolyl, 2-imidazolyl, 4-imidazolyl),

[0200] · pyrazolyl (e.g. 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl),

[0201] · triazolyl (e.g., 1,2,4-triazol-1-yl, 1,2,4-triazol-3-yl, 1,2,4-triazol-4-yl),

[0202] Tetrazolyl (e.g., 1-tetrazolyl, 2-tetrazolyl, 5-tetrazolyl),

[0203] Oxazolyl (e.g., 2-oxazolyl, 4-oxazolyl, 5-oxazolyl),

[0204] ·Isoxazolyl (e.g., 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl),

[0205] Oxadiazolyl (e.g. 1,3,4-oxadiazol-2-yl),

[0206] · thiazolyl (e.g. 2-thiazolyl, 4-thiazolyl, 5-thiazolyl),

[0207] · thiadiazolyl (e.g., 1,3,4-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,3-thiadiazolyl),

[0208] ·Isothiazolyl (e.g. 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl),

[0209] · pyridyl (e.g. 2-pyridyl, 3-pyridyl, 4-pyridyl),

[0210] · pyridazinyl (e.g. 3-pyridazinyl, 4-pyridazinyl),

[0211] · pyrimidinyl (e.g. 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl),

[0212] · pyrazinyl (e.g. 2-pyrazinyl),

[0213] imidazo[1,5-a]pyridinyl (e.g., imidazo[1,5-a]pyridin-1-yl, imidazo[1,5-a]pyridin-3-yl, imidazo[1,5-a]pyridin-5-yl, imidazo[1,5-a]pyridin-6-yl, imidazo[1,5-a]pyridin-7-yl, imidazo[1,5-a]pyridin-8-yl),

[0214] Benzothiadiazole (e.g., 1,2,3-benzothiadiazol-4-yl, 1,2,3-benzothiadiazol-5-yl, 2,1,3-benzothiadiazol-4-yl, 2,1,3-benzothiadiazol-5-yl),

[0215] Benzothiazolyl (e.g., benzothiazol-2-yl, benzothiazol-4-yl, benzothiazol-5-yl, benzothiazol-6-yl, benzothiazol-7-yl),

[0216] Indolyl (e.g., indol-3-yl, indol-4-yl, indol-5-yl, indol-6-yl, indol-7-yl),

[0217] Benzothiophene (e.g., 1-benzothiophene-2-yl, 1-benzothiophene-3-yl, 1-benzothiophene-4-yl, 1-benzothiophene-5-yl, 1-benzothiophene-6-yl, 1-benzothiophene-7-yl),

[0218] 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, 1,1-dioxo-1-benzothiophene-7-yl),

[0219] Quinolinyl (quinolin-2-yl, quinolin-3-yl, quinolin-4-yl, quinolin-5-yl, quinolin-6-yl, quinolin-7-yl, quinolin-8-yl), or

[0220] ·1,3-Benzoxazol-2-yl.

[0221] The following describes each symbol in formula [1].

[0222] R in formula [1] 1 Optionally substituted by one or two groups selected from a hydrogen atom, a halogen atom, an optionally substituted alkyl group, an optionally substituted amino group, an optionally substituted alkoxy group, an optionally substituted aryl group, a haloalkyl group, a cycloalkyl group, an optionally substituted sulfonyl group, a cyano group, an optionally substituted carbamoyl group, a heteroaryl group and a dialkylphosphoryl group.

[0223] It is preferably substituted by one or two groups selected from a hydrogen atom, a halogen atom, an optionally substituted alkyl group, an optionally substituted amino group, an optionally substituted alkoxy group, an optionally substituted aryl group, a haloalkyl group, and an optionally substituted carbamoyl group,

[0224] More preferably, it is substituted by one or two groups selected from the group consisting of a hydrogen atom, an optionally substituted alkyl group, an optionally substituted amino group, and an optionally substituted carbamoyl group,

[0225] It is further preferably substituted by one or two groups selected from a hydrogen atom, an alkyl group, an amino group, and a carbamoyl group,

[0226] Most preferably, it is substituted with one group selected from the group consisting of a hydrogen atom, an alkyl group, an amino group, and a carbamoyl group.

[0227] As the above R 1 The "alkyl group which may be substituted" is preferably an alkyl group substituted with a cycloalkyl group, preferably an alkyl group substituted with a cyclopropyl group, and more preferably a cyclopropylmethyl group.

[0228] As the above R 1 The "aryl group which may be substituted" is preferably an aryl group substituted with halogen, and more preferably an aryl group substituted with fluorine.

[0229] As the above R 1The "alkoxy group which may be substituted" is preferably an alkoxy group substituted with a cycloalkyl group, preferably an alkoxy group substituted with a cyclopropyl group, and more preferably a cyclopropylmethoxy group.

[0230] Het is a 5- to 10-membered heteroaryl group.

[0231] Preferred are pyrimidinyl, pyridyl, pyrazinyl, pyrazolyl, pyridinyl, imidazo[1,5-a]pyridinyl, oxazolyl, thiazolyl, and pyrazyl, and more preferred are pyrimidinyl, pyrazinyl, pyrazolyl, and imidazo[1,5-a]pyridinyl.

[0232] L 1 For connecting bonds, -CO-NH-, -CR a =CR b -or-C≡C-, R a is a hydrogen atom or a halogen atom, R b A hydrogen atom or a halogen atom.

[0233] Preferably, the linking bond, -CR a =CR b -or-C≡C-, where R a Preferably, a hydrogen atom, R b Preferred is a halogen atom.

[0234] More preferably, the linking bond, -CR a =CR b -or-C≡C-, where R a More preferably, it is a hydrogen atom, R b A fluorine atom is more preferred.

[0235] X is N or CR c , R c A hydrogen atom or a halogen atom.

[0236] Preferably N or CR c , R c is a hydrogen atom or a halogen atom, more preferably N or CR c , R c A hydrogen atom.

[0237] R 2 It is a hydrogen atom, an ethyl group, a C1-C6 haloalkoxy group or a C1-C6 haloalkyl group.

[0238] Preferably it is ethyl, C1-C6 haloalkoxy or C1-C6 haloalkyl, more preferably C1-C6 haloalkoxy or C1-C6 haloalkyl,

[0239] More preferably, it is C1-C6 fluoroalkoxy, C1-C6 difluoroalkoxy, C1-C6 trifluoroalkoxy, C1-C6 fluoroalkyl, C1-C6 difluoroalkyl or C1-C6 trifluoroalkyl,

[0240] More preferably, it is a C1-C6 difluoroalkoxy group, a C1-C6 fluoroalkyl group or a C1-C6 trifluoroalkyl group.

[0241] The most preferred group is C1-C6 difluoroalkoxy.

[0242] R 3 is a hydrogen atom or 4 Together with the carbon atom to which they are bonded, they are optionally substituted C3-C8 cycloalkyl.

[0243] R 3 Preferred with R 4 Together with the carbon atom to which they are bonded, they are optionally substituted C3-C8 cycloalkyl, R 3 Preferred with R 4 Together with the carbon atom to which they are bonded, they are optionally substituted cyclopentyl, cyclohexyl or spiro[2.4]heptyl, and more preferably optionally substituted cyclopentyl.

[0244] As the above R 3 The “C3-C8 cycloalkyl group which may be substituted as the case may be” is preferably a C3-C8 cycloalkyl group substituted with one or two groups selected from halogen and haloalkoxy, more preferably a C3-C8 cycloalkyl group substituted with one or two haloalkoxy groups, further preferably a C3-C8 cycloalkyl group substituted with one or two trifluoroalkoxy groups, further preferably a C3-C8 cycloalkyl group substituted with one trifluoroalkoxy group, and most preferably a C3-C8 cycloalkyl group substituted with one trifluoromethoxy group.

[0245] R 4 is optionally substituted phenyl or optionally substituted alkyl, or, R 4 With R 3 Together with the carbon atom to which they are bonded, they are optionally substituted C3-C8 cycloalkyl.

[0246] R 4 is optionally substituted phenyl or optionally substituted alkyl, or, R 4 Preferred with R 3 Together with the carbon atoms to which they are bonded, they are optionally substituted C3-C8 cycloalkyl, more preferably optionally substituted alkyl or R 4 With R 3 Together with the carbon atoms to which they are bonded, they are optionally substituted C3-C8 cycloalkyl, R 4 Further optimization with R 3Together with the carbon atoms to which they are bonded, they are optionally substituted C3-C8 cycloalkyl, R 4 Further optimization with R 3 Together with the carbon atoms to which they are bonded, they are optionally substituted cyclopentyl, cyclohexyl, spiro[2.4]heptyl, R 4 The best choice is R 3 Together with the carbon atom to which they are bonded, they are optionally substituted cyclopentyl.

[0247] As the above R 4 The “C3-C8 cycloalkyl group which may be substituted as the case may be” is preferably a C3-C8 cycloalkyl group substituted with one or two groups selected from halogen and haloalkoxy, more preferably a C3-C8 cycloalkyl group substituted with one or two haloalkoxy groups, further preferably a C3-C8 cycloalkyl group substituted with one or two trifluoroalkoxy groups, further preferably a C3-C8 cycloalkyl group substituted with one trifluoroalkoxy group, and most preferably a C3-C8 cycloalkyl group substituted with one trifluoromethoxy group.

[0248] The compounds of this invention can use known compounds or intermediates that can be easily synthesized by known compounds, and can be manufactured according to, for example, the following method, embodiments described later, or known methods. In the manufacture of the compounds of this invention, when the raw material has a substituent that affects the reaction, the raw material is usually reacted after being protected by a known method and utilizing an appropriate protecting group in advance. The protecting group can be deprotected by a known method after the reaction.

[0249] The compounds of the present invention can be used directly as a drug, or can be used in the form of a pharmaceutically acceptable salt, solvate or solvate of a salt by a known method. As pharmaceutically acceptable salts, for example, salts of inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid; salts of organic acids such as acetic acid, malic acid, lactic acid, citric acid, tartaric acid, maleic acid, succinic acid, fumaric acid, p-toluenesulfonic acid, benzenesulfonic acid, methanesulfonic acid; or salts of alkali metals such as lithium, potassium, sodium; salts of alkaline earth metals such as magnesium and calcium; and salts of organic bases such as ammonium salts. These salts can be formed by commonly used methods.

[0250] For example, when the compound of the present invention is a hydrochloride, the free base of the compound of the present invention can be obtained by dissolving an aqueous solution of hydrogen chloride (hydrochloric acid), an alcohol solution of hydrogen chloride, an ethyl acetate solution of hydrogen chloride, a 1,4-dioxane solution of hydrogen chloride, a cyclopentyl methyl ether solution of hydrogen chloride, or a diethyl ether solution of hydrogen chloride.

[0251] The compounds of the present invention may absorb solvent molecules and form solvates by being placed in the atmosphere or recrystallized, and such solvates are also included in the compounds of the present invention. Such solvates include methanolates, ethanolates, isopropanolates, butanolates, dimethyl sulfoxides, acetonitrile compounds and solvent molecules; as well as monohydrates and dihydrates.

[0252] A part of the compounds of the present invention has an asymmetric carbon, and each optical isomer and a mixture thereof are included in the present invention. Stereoisomers, for example, can also be produced by utilizing their alkalinity and using an optically active acid (tartaric acid, dibenzoyltartaric acid, mandelic acid, 10-camphorsulfonic acid, etc.) to perform optical resolution from a racemate by a known method, or by using a pre-prepared optically active compound as a raw material. In addition, optical resolution using a chiral column and asymmetric synthesis can also be used to produce.

[0253] As shown in the test examples described below, the compounds of the present invention have DDR1 kinase inhibitory activity.

[0254] Therefore, one embodiment of the present invention provides a DDR1 kinase inhibitor comprising the compound of the present invention.

[0255] Furthermore, one embodiment of the present invention provides a method for inhibiting DDR1 kinase, comprising: administering the compound of the present invention to a subject in need thereof.

[0256] Furthermore, one embodiment of the present invention provides the compound of the present invention for use in inhibiting DDR1 kinase.

[0257] Furthermore, one embodiment of the present invention provides use of the compound of the present invention in the manufacture of a DDR1 kinase inhibitor.

[0258] One embodiment of the present invention provides a preventive or therapeutic agent for a disease associated with DDR1 kinase, comprising the compound of the present invention.

[0259] Furthermore, one embodiment of the present invention provides a method for preventing or treating a disease associated with DDR1 kinase, comprising administering the compound of the present invention to a subject in need thereof.

[0260] Furthermore, one embodiment of the present invention provides the compound of the present invention for use in preventing or treating a disease associated with DDR1 kinase.

[0261] Furthermore, one embodiment of the present invention provides use of the compound of the present invention in the manufacture of a preventive or therapeutic agent for a disease associated with DDR1 kinase.

[0262] Examples of diseases to which the compounds of the present invention can be applied include Alport syndrome, IgA nephropathy, Goodpasture syndrome, anti-glomerular basement membrane nephritis, lupus nephritis, ANCA-associated nephritis, diabetic nephropathy, purpuric nephritis, focal segmental glomerulosclerosis, chronic renal failure, minimal change nephrotic syndrome, mesangial proliferative glomerulonephritis, membranoproliferative glomerulonephritis, crescentic glomerulonephritis, membranous nephropathy, pulmonary fibrosis, myelofibrosis, hepatic fibrosis, acute myeloid leukemia, chronic myeloid leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma, glioma, non-small cell lung cancer, small cell lung cancer, breast cancer, ovarian cancer, prostate cancer, colorectal cancer, and osteoarthritis.

[0263] "Subject" refers to a human or non-human animal that has or is suspected of having a disease associated with DDR1. In one embodiment of the present invention, the subject is a mammal. In one embodiment of the present invention, the subject is a human.

[0264] The compounds of the present invention can be used as therapeutic agents for the aforementioned various diseases in mammals such as humans, mice, rats, rabbits, dogs, cats, cows, horses, pigs, monkeys, etc. by directly or mixing with a pharmacologically acceptable carrier to prepare a pharmaceutical composition containing, for example, 0.001% to 99.5%, preferably 0.1% to 90%.

[0265] As a carrier, one or more of a pharmaceutically acceptable and conventional solid, semisolid or liquid diluent, filler and other prescription adjuvant can be used. The pharmaceutical composition of the present invention is expected to be administered in a unit form. The pharmaceutical composition can be administered intra-tissue, orally, intravenously, topically (transdermally, in the eye, intraperitoneally, intrathoracically, etc.) or rectally. The pharmaceutical composition of the present invention is administered in a dosage form suitable for these administration methods.

[0266] The dosage of the drug is expected to be adjusted based on the patient status such as age, weight, disease type, degree, administration route, type of the compound of the present invention, whether it is salt, type of salt, etc., usually for adults, as the active ingredient amount of the compound of the present invention or its pharmaceutically acceptable salt, in the case of oral administration, every 1 day in the range of 0.01mg~5g / adult, preferably in the range of 1mg~500mg / adult is appropriate. Depending on the situation, the amount is also sufficient, and sometimes the amount above the amount is also needed. Usually, in the case of once a day or multiple administration or intravenous administration, it can be quickly administered or continuously administered within 24 hours.

[0267] More than one hydrogen, carbon and / or other atom of the compounds of the present invention may be replaced by isotopes of hydrogen, carbon and / or other atoms, respectively. Examples of such isotopes include 2 H. 3 H. 11 C. 13 C. 14 C. 15 N. 18 O. 17 O. 31 P. 32 P. 35 S. 18 F. 123 I and 36 Cl, i.e. hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine and chlorine. Compounds substituted with the isotopes are also useful as pharmaceuticals, including all radiolabeled compounds of the present invention.

[0268] (Method for producing the compound of the present invention)

[0269] The compounds of the present invention can be produced, for example, according to the following methods, the examples described later, or known methods, from compounds known per se or intermediates that can be easily produced from known compounds.

[0270] When the solvent, reagent and raw material used in each step of the following manufacture method are already sold, commercial products can be directly used. In addition, the compound obtained by each step in the manufacture method described later and the raw material used can form a salt, and can also be converted into other types of salts or free forms by a known method. On the contrary, when the compound obtained by each step in the following manufacture method and the raw material used are free forms, the salt as the target can be converted by a known method. As the example of the salt, the salt identical with the salt used in the aforementioned compounds of the present invention can be listed.

[0271] In the manufacture of the compounds of the present invention, when the raw material has a substituent that can affect the reaction, a protecting group can be introduced into these substituents in advance by a known method, and the target compound can be obtained by removing the protecting group as required after the reaction. As this protecting group, for example, the protecting groups shown in " Greene's Protective Groups in Organic Synthesis ", the 4th edition, John Wiley & Sons Inc., 2006, or " Protecting Groups ", the 3rd edition, Thieme, 2005, written by Wuts and Greene, etc. can be listed, as long as they are appropriately selected and used according to their reaction conditions.

[0272] The compound obtained by each step of the following production method can be isolated or purified by conventional methods using solvent extraction, concentration, distillation, sublimation, recrystallization, reprecipitation, chromatography, etc., or can be used in the following steps in the form of a reaction mixture or a crude product.

[0273] Unless otherwise specified, the reaction of each step in the following production method can be carried out by appropriately modifying or combining known methods, for example, the methods described in "Comprehensive Organic Transformations: A Guide to Functional Group Preparations 2nd Edition" by RC Larock, John Wiley & Sons Inc., 1999, "Experimental Chemistry Lectures" edited by the Chemical Society of Japan, 4th edition, Maruzen, 1992, "Organic Synthesis Strategies Learned from Personal Name Reactions", Chemical Journal, 2006, by L. Kuerti and B. Czako, and translated by Kiyoshi Tomioka, "The Latest Organic Synthesis Methods - Design and Strategies", Chemical Journal, 2009, by GS Zweifel and MH Nantz, and translated by Tamejiro Hiyama, or the methods described in the Examples.

[0274] The compound of the present invention can be produced, for example, by the general synthesis method shown below. For extraction, purification, etc., any treatment performed in ordinary organic chemical experiments may be performed.

[0275] Preparation of Compound 1-A

[0276] [Chemistry 2]

[0277]

[0278] (Where R 1 , R 2 , R 3 , R 4 , Het, and X have the same meanings as above. AA and R BB All represent hydroxyl groups, or R AA and R BB Together they are -OC(CH3)2-C(CH3)2-O-, -O-(CH2)3-O- or -O-CH2-C(CH3)2-CH2-O-. LG is a leaving group, and examples thereof include halogen and trifluoromethanesulfonate. 11 The alkyl group includes, for example, a methyl group and an ethyl group.

[0279] Step 1

[0280] This step is a step of obtaining Compound 3 by coupling reaction of Compound 1 and Compound 2 in the presence of a transition metal such as palladium, and can be carried out according to a known method.

[0281] This reaction can be carried out under conditions generally used in coupling reactions using transition metals. Examples of coupling reactions using transition metals include Suzuki-Miyaura coupling reaction and Heck reaction.

[0282] Examples of the Suzuki-Miyaura coupling reaction include reactions described in Suzuki et al., Chem. Rev., 1995, 95, 2457-2483.

[0283] Examples of the Heck reaction include reactions described in Heck et al., 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.

[0284] The amount of Compound 1 to be used is preferably within a range of 0.5 to 3 molar equivalents relative to Compound 2.

[0285] The organic metal catalyst used in the present reaction is not particularly limited. Preferred examples of the organic metal catalyst include tris(dibenzylideneacetone)palladium-chloroform adduct (hereinafter referred to as "Pd2(dba)3·CHCl3"), tris(dibenzylideneacetone)palladium (hereinafter referred to as "Pd2(dba)3"), tetrakis(triphenylphosphine)palladium (hereinafter referred to as "Pd(PPh3)4"), [1,1'-bis(diphenylphosphino)ferrocene]-dichloropalladium(II)-dichloromethane adduct (hereinafter referred to as "Pd(dppf)Cl2·CH2Cl2"), bis(triphenylphosphine)palladium (hereinafter referred to as "Pd(dppf)Cl2·CH2Cl2"), ) dichloropalladium(II) (hereinafter referred to as "PdCl2(PPh3)2"), [1,1'-bis(di-tert-butylphosphino)ferrocene]-dichloropalladium(II) (hereinafter referred to as "Pd(dtbpf)Cl2"), bis(tricyclohexylphosphine) dichloride palladium(II) (hereinafter referred to as "PdCl2(PCy3)2"), palladium(II) acetate (hereinafter referred to as "Pd(OAc)2") and [1,3-bis(diphenylphosphino)propane]nickel(II) and other metal catalysts, as well as mixtures of these metal catalysts.

[0286] The amount of the transition metal to be used is preferably within a range of 0.01 to 0.3 molar equivalents relative to Compound 1, for example.

[0287] In this step, an alkali or salt may be used as needed. Examples of the alkali or salt used include potassium carbonate, cesium carbonate, sodium carbonate, sodium bicarbonate, sodium acetate, potassium acetate, trisodium phosphate, tripotassium phosphate, and solutions thereof, as well as triethylamine (hereinafter referred to as "TEA"), N,N-diisopropylethylamine (hereinafter referred to as "DIPEA"), lithium chloride, and copper (I) iodide.

[0288] The amount of the base to be used is preferably in the range of 1 to 4 molar equivalents relative to Compound 1, for example.

[0289] This step can use appropriate ligands as needed. Examples of usable ligands include 1,1'-bis(diphenylphosphino)ferrocene (hereinafter referred to as "dppf"), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (hereinafter referred to as "Xantphos"), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (hereinafter referred to as "XPhos"), 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (hereinafter referred to as "BINAP"), 2-dicyclohexylphosphino-2',6'-diisopropylbiphenyl (hereinafter referred to as "RuPhos"), triphenylphosphine (hereinafter referred to as "PPh3"), tricyclohexylphosphine (hereinafter referred to as "PCy3"), etc.

[0290] The amount of the ligand used is preferably within a range of 1 to 5 molar equivalents relative to the transition metal used.

[0291] The solvent used in this process is not particularly limited as long as it does not participate in the reaction, and examples thereof include hydrocarbons such as toluene and xylene; ethers such as 1,4-dioxane, tetrahydrofuran (hereinafter referred to as "THF"), and dimethoxyethane (hereinafter referred to as "DME"); amides such as N,N-dimethylformamide (hereinafter referred to as "DMF"), N,N-dimethylacetamide (hereinafter referred to as "DMA"), and N-methylpyrrolidone (hereinafter referred to as "NMP"); alcohols such as ethanol, 2-propanol, and tert-butanol; and water or a mixed solvent thereof.

[0292] The reaction temperature varies depending on the types of raw materials and reagents used, but is usually appropriately within a range of 20° C. to 200° C. In addition, a microwave reaction apparatus may be used as necessary.

[0293] The reaction time varies depending on the type of raw materials used and the reaction temperature, but is usually appropriately within the range of 0.1 hour to 24 hours.

[0294] Step 2

[0295] This step is a step of obtaining Compound 4 by hydrolyzing the ester moiety in the presence of a suitable acid or base in a suitable solvent.

[0296] Examples of the acid used in this step include inorganic acids such as hydrochloric acid and sulfuric acid, and organic acids such as trifluoroacetic acid (hereinafter referred to as "TFA"), methanesulfonic acid, and toluenesulfonic acid. Examples of the base include inorganic bases such as sodium hydroxide, potassium hydroxide, and lithium hydroxide.

[0297] In this step, the amount of the acid or base used is preferably in the range of 1 to 10 molar equivalents relative to compound 3. If necessary, an excess amount of the acid or base relative to compound 3 may be used, and when an acid is used, hydrolysis can proceed even in a catalytic amount.

[0298] The solvent used is not particularly limited as long as it does not participate in the reaction, and examples thereof include alcohols such as methanol, ethanol, and 2-propanol; ethers such as THF, diethyl ether, 1,4-dioxane, and DME; nitriles such as acetonitrile and propionitrile; ketones such as acetone; water, and mixed solvents thereof.

[0299] The reaction temperature varies depending on the types of raw materials and reagents used, but can generally be carried out in the range of 20° C. to 200° C., preferably 20° C. to 100° C. In addition, a microwave reaction apparatus can be used as necessary.

[0300] The reaction time varies depending on the type of raw materials used and the reaction temperature, but is usually appropriately within the range of 0.5 hour to 4 days.

[0301] Step 3

[0302] This step is a step of obtaining compound 1-A by condensing compound 4 or a reactive derivative thereof with amine compound 5 in the presence of a condensing agent.

[0303] Examples of the reactive derivative of compound 4 include those generally used in amide condensation reactions, such as acid halides (eg, acid chlorides and acid bromides), mixed acid anhydrides, imidazolide, and activated amides.

[0304] The amounts of the condensing agent and the amine compound 5 used in this step are preferably in the range of 1 to 10 molar equivalents relative to the compound 4, respectively.

[0305] Examples of the condensing agent used in this step include 1,1'-carbonyldiimidazole (hereinafter referred to as "CDI"), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (hereinafter referred to as "EDCI"), diisopropylcarbodiimide (hereinafter referred to as "DIC"), diethyl cyanophosphonate, O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (hereinafter referred to as "HBTU"), and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (hereinafter referred to as "HATU").

[0306] In this step, a base may be used as necessary. Examples of the base that can be used include organic bases such as TEA, DIPEA, N,N-dimethylaniline, and DBU.

[0307] The amount of the base used is preferably in the range of 1 to 10 molar equivalents relative to Compound 4.

[0308] In this step, additives such as 1-hydroxybenzotriazole (hereinafter referred to as "HOBt"), N-hydroxysuccinimide, and 1-hydroxy-7-azabenzotriazole (hereinafter referred to as "HOAt") may be added as necessary.

[0309] When the additive is used in this step, the amount of the additive used is preferably in the range of 0.1 to 10 molar equivalents relative to Compound 4.

[0310] The solvent used is not particularly limited as long as it does not participate in the reaction, and examples thereof include hydrocarbons such as toluene and xylene; ethers such as 1,4-dioxane, THF, and DME; amides such as DMF and DMA; halogenated hydrocarbons such as dichloromethane and chloroform; nitriles such as acetonitrile and propionitrile; or mixed solvents thereof.

[0311] The reaction temperature varies depending on the types of raw materials and reagents used, but is usually appropriately within a range of -20°C to 150°C. In addition, a microwave reaction apparatus may be used as necessary.

[0312] The reaction time varies depending on the types of raw materials used and the reaction temperature, but is usually appropriately within the range of 0.1 to 72 hours.

[0313] Preparation of compound 1-B

[0314] [Chemistry 3]

[0315]

[0316] (Where R 1 , R 2 , R 3 , R 4 , Het, and X have the same meanings as above. 11 is an alkyl group, for example, a methyl group, an ethyl group, etc.

[0317] Step 1

[0318] This step is a step of obtaining compound 8 by condensing compound 6 or a reactive derivative thereof with amine compound 7 in the presence of a condensing agent, and can be produced by the same method as step 3 of production method 1.

[0319] Step 2

[0320] This step is a step of obtaining compound 9 by hydrolyzing the ester moiety in the presence of a suitable acid or base in a suitable solvent, and can be produced by the same method as step 2 of production method 1.

[0321] Step 3

[0322] This step is a step of obtaining compound 1-B by condensing compound 9 or a reactive derivative thereof with amine compound 5 in the presence of a condensing agent, and can be produced by the same method as step 3 of production method 1.

[0323] Preparation of compound 1-C

[0324] [Chemistry 4]

[0325]

[0326] (Where R 1 , R 2 , R 3 , R 4 , R a , R b 、Het、R AA , R BB , X, and LG have the same meanings as above.)

[0327] Step 1

[0328] This step is a step of obtaining compound 12 by coupling reaction of compound 10 and compound 11 in the presence of a transition metal such as palladium, and can be produced by the same method as step 1 of production method 1.

[0329] Step 2

[0330] This step is a step of obtaining compound 13 by hydrolyzing the ester portion of compound 12 in the presence of a suitable acid or base in a suitable solvent, and can be produced by the same method as step 2 of production method 1.

[0331] Step 3

[0332] This step is a step of obtaining compound 1-C by condensing compound 13 or a reactive derivative thereof with amine compound 5 in the presence of a condensing agent, and can be produced by the same method as step 3 of production method 1.

[0333] Alternatively, compound 12 can also be produced by the following method.

[0334] [Chemistry 5]

[0335]

[0336] (Where R1 , R 2 , R 3 , R 4 , R a , R b 、Het、R AA , R BB , X, and LG have the same meanings as above.)

[0337] Step 1

[0338] This step is a step of obtaining compound 12 by coupling reaction of compound 10a and compound 11a in the presence of a transition metal such as palladium, and can be produced by the same method as step 1 of production method 1.

[0339] Preparation of compound 1-D

[0340] [Chemistry 6]

[0341]

[0342] (Where R 1 , R 2 , R 3 , R 4 , R 11 , Het, X, and LG have the same meanings as above. Z is a leaving group, and examples thereof include trimethylsilyl and triethylsilyl.

[0343] Step 1

[0344] This step is a step of obtaining compound 16 by coupling reaction of compound 14 and compound 15 in the presence of a transition metal such as palladium.

[0345] This reaction can be applied to conditions commonly used in coupling reactions using transition metals. Specifically, the Sonogashira coupling reaction can be applied and can be carried out by methods described in Sonogashira et al., J. Organomet. Chem. 2002, 653, 46-49., Negishi et al., Chem. Rev., 2003, 103, 1979-2017., etc.

[0346] The amount of Compound 15 to be used is preferably in the range of 0.5 to 3 molar equivalents relative to Compound 14.

[0347] The amount of the transition metal to be used is preferably within a range of 0.01 to 0.3 molar equivalents relative to Compound 14, for example.

[0348] In this step, an alkali or salt may be used as needed. Examples of the alkali or salt used include potassium carbonate, cesium carbonate, sodium carbonate, sodium bicarbonate, sodium acetate, potassium acetate, trisodium phosphate, tripotassium phosphate, and solutions thereof, as well as triethylamine (hereinafter referred to as "TEA"), N,N-diisopropylethylamine (hereinafter referred to as "DIPEA"), lithium chloride, and copper (I) iodide.

[0349] The amount of the base to be used is preferably in the range of 1 to 4 molar equivalents relative to Compound 14, for example.

[0350] This step can use appropriate ligands as needed. Examples of usable ligands include 1,1'-bis(diphenylphosphino)ferrocene (hereinafter referred to as "dppf"), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (hereinafter referred to as "Xantphos"), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (hereinafter referred to as "XPhos"), 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (hereinafter referred to as "BINAP"), 2-dicyclohexylphosphino-2',6'-diisopropylbiphenyl (hereinafter referred to as "RuPhos"), triphenylphosphine (hereinafter referred to as "PPh3"), tricyclohexylphosphine (hereinafter referred to as "PCy3"), etc.

[0351] The amount of the ligand used is preferably within a range of 1 to 5 molar equivalents relative to the transition metal used.

[0352] In this step, the solvent used is not particularly limited as long as it does not participate in the reaction, and examples thereof include hydrocarbons such as toluene and xylene; ethers such as 1,4-dioxane, tetrahydrofuran (hereinafter referred to as "THF"), and dimethoxyethane (hereinafter referred to as "DME"); amides such as N,N-dimethylformamide (hereinafter referred to as "DMF"), N,N-dimethylacetamide (hereinafter referred to as "DMA"), and N-methylpyrrolidone (hereinafter referred to as "NMP"); alcohols such as ethanol, 2-propanol, and tert-butanol, water, or a mixed solvent thereof.

[0353] The reaction temperature varies depending on the types of raw materials and reagents used, but is usually appropriately within a range of 20° C. to 200° C. In addition, a microwave reaction apparatus may be used as necessary.

[0354] The reaction time varies depending on the type of raw materials used and the reaction temperature, but is usually appropriately within the range of 0.1 hour to 24 hours.

[0355] Step 2

[0356] This step is a step of deprotecting Z to obtain compound 17, and can be performed with reference to, for example, "Greene's Protective Groups in Organic Synthesis", 4th edition, John Wiley & Sons Inc., 2006, by Wuts and Greene, or "Protecting Groups", 3rd edition, Thieme, 2005, by PJ Kocienski.

[0357] Step 3

[0358] This step is a step of obtaining compound 19 by coupling compound 17 and compound 18 separately in the presence of a transition metal such as palladium, and can be produced by the same method as the production method of compound 1-D and step 1.

[0359] It should be noted that compound 19 can be directly prepared from compound 16 and compound 18 according to the method of Tolnai et al. (J. Org. Chem., 2018, 83, 8281-8291).

[0360] Step 4

[0361] This step is a step of obtaining compound 20 by hydrolyzing the ester portion of compound 19 in the presence of a suitable acid or base in a suitable solvent, and can be produced by the same method as step 2 of production method 1.

[0362] Step 5

[0363] This step is a step of obtaining compound 1-D by condensing compound 20 or a reactive derivative thereof with amine compound 5 in the presence of a condensing agent, and can be produced by the same method as step 3 of production method 1.

[0364] As shown in the test examples described below, the compounds of the present invention have DDR1 kinase inhibitory activity. In addition, since the compounds of the present invention have DDR1 kinase inhibitory activity, they are effective for Alport syndrome, IgA nephropathy, Goodpasture syndrome, anti-glomerular basement membrane nephritis, lupus nephritis, ANCA-associated nephritis, diabetic nephropathy, purpuric nephritis, focal segmental glomerulosclerosis, chronic renal failure, minimal change nephrotic syndrome, mesangial proliferative glomerulonephritis, membranoproliferative glomerulonephritis, crescentic glomerulonephritis, membranous nephropathy, pulmonary fibrosis, myelofibrosis, hepatic fibrosis, acute myeloid leukemia, chronic myeloid leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma, glioma, non-small cell lung cancer, small cell lung cancer, breast cancer, ovarian cancer, prostate cancer, colorectal cancer or osteoarthritis.

[0365] Therefore, the compound of the present invention or a pharmaceutically acceptable salt thereof can be used as a preventive or therapeutic agent for diseases associated with DDR1 kinase, for example.

[0366] Hereinafter, the present invention will be described in more detail with reference to reference examples, examples and test examples, but the present invention is not limited thereto.

[0367] The abbreviations used in this specification have the following meanings.

[0368] The following abbreviations are used in the examples.

[0369] Pd-C: Palladium-Carbon

[0370] Pd(PPh3)4: Tetrakis(triphenylphosphine)palladium

[0371] PdCl2(PPh3)2: Bis(triphenylphosphine)palladium(II) dichloride

[0372] PPh3: triphenylphosphine

[0373] Boc2O: di-tert-butyl dicarbonate

[0374] HATU: O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate

[0375] HBTU: O-(Benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate

[0376] EDCI: 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide

[0377] HOBt: 1-Hydroxybenzotriazole

[0378] THF: Tetrahydrofuran

[0379] DMF: dimethylformamide

[0380] DMSO: dimethyl sulfoxide

[0381] NMP: N-methylpyrrolidone

[0382] IPA: 2-propanol

[0383] DIPA: diisopropylamine

[0384] DIPEA: N,N-diisopropylethylamine

[0385] TEA: triethylamine

[0386] DBU: 1,8-diazabicyclo[5.4.0]-7-undecene

[0387] MS: mass spectrometry

[0388] LCMS: High Performance Liquid Chromatography Mass Spectrometry

[0389] ESI: Electron Spray Ionization

[0390] M: molar concentration (mol / L)

[0391] MS was measured by LCMS. ESI was used as an ionization method. The observed mass spectrometry value was expressed as m / z.

[0392] The measurement conditions of LCMS are as follows.

[0393] Analytical instrument: ACQUITY UPLC MS / PDA system (manufactured by WATERS)

[0394] Mass spectrometer: ACQUITY QDa detector or Waters 3100MS detector

[0395] Photodiode array detector: ACQUITY PDA detector (UV detection wavelength: 210-400nm)

[0396] Column: Acquity BEH C18, 1.7μm, 2.1×50mm

[0397] Flow rate: 0.5mL / min

[0398] Column temperature: 40°C

[0399] Solvents;

[0400] Solution A: 0.1% formic acid / H2O (v / v; the same below)

[0401] Solution B: 0.1% formic acid / acetonitrile

[0402] The measurement conditions of chiral column chromatography are as follows.

[0403] Method A:

[0404] Analytical instrument: i-Series UHPLC model LC-2060C 3D (PDA model) (manufactured by Shimadzu Corporation)

[0405] Detection wavelength: 220nm

[0406] Column: CHIRALPAK IB, 0.46cmI.D.×25cmL

[0407] Flow rate: 1.0mL / min

[0408] Column temperature: 40°C

[0409] Mobile phase: n-hexane / IPA=92 / 8 (v / v)

[0410] Method B:

[0411] Pump: LC-20AD (manufactured by Shimadzu Corporation)

[0412] Detector: SPD-20A (manufactured by Shimadzu Corporation)

[0413] Detection wavelength: 210nm

[0414] Column: CHIRALPAK AD, 0.46cmI.D.×25cmL

[0415] Flow rate: 1.0mL / min

[0416] Column temperature: 40°C

[0417] Mobile phase: n-hexane / IPA=90 / 10 (v / v)

[0418] 1 H NMR spectra were measured using a JNM-ECS400 nuclear magnetic resonance apparatus (manufactured by JEOL, RESONANCE). Observed peaks are represented by chemical shift values ​​δ (ppm) (s = singlet, d = doublet, t = triplet, q = quartet, brs = broad singlet, m = multiplet, dd = doublet, dt = doublet).

[0419] In the microwave experiment, Initiator 60 (manufactured by Biotage) was used, which can reach a temperature of 40-250° C. and a pressure of 20 bar.

[0420] Specific rotation [α] 589 The measurement conditions are as follows.

[0421] Analytical instrument: Automatic polarimeter SEPA-500 (manufactured by Horiba, Ltd.)

[0422] Determination solvent: methanol

[0423] Optical path length: 50mm

[0424] The compound names in this specification are named using the naming software ACD / NAME (registered trademark, Advanced Chemistry Development Inc.) based on the IUPAC rules, or using ChemBioDraw (version 19.1, manufactured by CambridgeSoft), or according to the IUPAC nomenclature.

[0425] The r and s (lower case letters) in the compound names indicate the stereochemistry of pseudoasymmetric carbon atoms according to IUPAC rules.

[0426] Reference Example 1 Methyl 3-bromo-4-(difluoromethoxy)benzoate

[0427] To a mixture of methyl 3-bromo-4-hydroxybenzoate (10.0 g) and DMF (87 mL) was added sodium difluorochloroacetate (13.2 g) and potassium carbonate (8.97 g) in sequence at room temperature, and stirred at 100° C. for 4 hours. The reaction solution was diluted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (9.5 g).

[0428] Reference Example 2 Methyl 4-(difluoromethoxy)-3-[(trimethylsilyl)ethynyl]benzoate

[0429] To a mixture of methyl 3-bromo-4-(difluoromethoxy)benzoate (4.0 g), DMF (14 mL), and TEA (14 mL) was added ethynyl (trimethyl) silane (3 mL), copper (I) iodide (27 mg), and Pd (dppf) Cl2 · CH2Cl2 (116 mg) in sequence at room temperature, and the mixture was stirred at 80°C for 15 hours. Water was added to the reaction solution, and extraction was performed with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (3.74 g). MS (m / z): 299.0 [M+H] +

[0430] Reference Example 3 4-(Difluoromethoxy)-3-[(pyrimidin-5-yl)ethynyl]benzoic acid

[0431] [Step 1] Production of methyl 4-(difluoromethoxy)-3-[(pyrimidin-5-yl)ethynyl]benzoate

[0432] To a mixture of 4-(difluoromethoxy)-3-[(trimethylsilyl)ethynyl]benzoic acid methyl ester (400 mg), DMF (1.34 mL), DIPEA (1.34 mL), water (0.24 mL), and 5-bromopyridine (320 mg) obtained in Reference Example 2, hexafluorosilicic acid (0.020 mL), copper (I) iodide (13 mg), and PdCl2(PPh3)2 (47 mg) were added in sequence and degassed, and then stirred overnight at 80°C under an argon atmosphere. After filtering the insoluble matter with Celite (registered trademark), the filtrate was washed with saturated brine and the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (283 mg). MS (m / z): 305.0 [M+H] +

[0433] [Step 2] Production of 4-(difluoromethoxy)-3-[(pyrimidin-5-yl)ethynyl]benzoic acid

[0434] To a mixture of methyl 4-(difluoromethoxy)-3-[(pyrimidin-5-yl)ethynyl]benzoate (283 mg), methanol (1.9 mL), and THF (1.9 mL) was added 2M aqueous sodium hydroxide solution (1.4 mL) at room temperature, and stirred overnight. The reaction solution was concentrated under reduced pressure, and acetic acid was added to the residue for neutralization. The precipitate was filtered to obtain the title compound (244 mg). MS (m / z): 291.1 [M+H] +

[0435] Reference Example 4 4-(Difluoromethoxy)-3-[(5-fluoropyridin-3-yl)ethynyl]benzoic acid

[0436] [Step 1] Production of methyl 4-(difluoromethoxy)-3-[(5-fluoropyridin-3-yl)ethynyl]benzoate

[0437] Hexafluorosilicic acid (0.012 mL), copper (I) iodide (8.0 mg), and Pd (PPh3) 4 (48 mg) were added to a mixture of methyl 4-(difluoromethoxy)-3-[(trimethylsilyl)ethynyl]benzoate (250 mg), DMF (0.84 mL), DIPEA (0.84 mL), water (0.15 mL), and 3-bromo-5-fluoropyridine (140 mg) obtained in Reference Example 2, and the mixture was degassed and stirred overnight at 90° C. under an argon atmosphere. The reaction solution was purified by silica gel column chromatography to obtain the title compound (239 mg). MS (m / z): 322.1 [M+H] +

[0438] [Step 2] Production of 4-(difluoromethoxy)-3-[(5-fluoropyridin-3-yl)ethynyl]benzoic acid

[0439] To a mixture of methyl 4-(difluoromethoxy)-3-[(5-fluoropyridin-3-yl)ethynyl]benzoate (239 mg), THF (2.5 mL), and methanol (0.074 mL) was added 2M aqueous sodium hydroxide solution (1.1 mL) at room temperature, and stirred for 5 hours. The reaction solution was concentrated under reduced pressure, diluted with water, and then 1M hydrochloric acid was added to adjust the pH to 4. The precipitate was filtered to obtain the title compound (190 mg). MS (m / z): 308.0 [M+H] +

[0440] Reference Example 5 3-[(2-aminopyrimidin-5-yl)ethynyl]-4-(difluoromethoxy)benzoic acid

[0441] [Step 1] Production of methyl 3-[(2-aminopyrimidin-5-yl)ethynyl]-4-(difluoromethoxy)benzoate

[0442] To a mixture of 4-(difluoromethoxy)-3-[(trimethylsilyl)ethynyl]benzoic acid methyl ester (6.0 g), DMF (20 mL), DIPA (20 mL), water (3.6 mL), and 5-bromopyrimidin-2-amine (4.55 g) obtained in Reference Example 2, hexafluorosilicic acid (0.119 mL), copper (I) iodide (115 mg), and PdCl2(PPh3)2 (423 mg) were added in sequence and degassed, and then stirred at 80°C for 1 hour under an argon atmosphere. Water was added to the reaction solution, the precipitate was filtered out, and purified by silica gel column chromatography. The solvent was distilled off under reduced pressure, ethyl acetate was added to the residue, it was suspended and the precipitate was filtered out to obtain the title compound (4.4 g). MS (m / z): 320.0 [M+H] +

[0443] [Step 2] Production of 3-[(2-aminopyrimidin-5-yl)ethynyl]-4-(difluoromethoxy)benzoic acid

[0444] To a mixture of methyl 3-[(2-aminopyrimidin-5-yl)ethynyl]-4-(difluoromethoxy)benzoate (4.4 g) and methanol (28 mL) was added 2M sodium hydroxide aqueous solution (14 mL) at room temperature, and the mixture was stirred at 80°C for 3 hours. After filtering the insoluble matter with Celite (registered trademark), the filtrate was concentrated under reduced pressure. After dilution with water, concentrated hydrochloric acid was added for neutralization. The precipitate was filtered to obtain the title compound (3.93 g). MS (m / z): 306.0 [M+H] +

[0445] Reference Example 6 3-[(5-aminopyrazin-2-yl)ethynyl]-4-(difluoromethoxy)benzoic acid

[0446] [Step 1] Production of methyl 3-[(5-aminopyrazin-2-yl)ethynyl]-4-(difluoromethoxy)benzoate

[0447] Hexafluorosilicic acid (0.025 mL), copper (I) iodide (16 mg), and Pd (PPh3) 4 (100 mg) were added to a mixture of methyl 4-(difluoromethoxy)-3-[(trimethylsilyl)ethynyl]benzoate (1.12 g), DMF (4.1 mL), DIPA (4.1 mL), water (0.52 mL), and 5-bromopyrazin-2-amine (500 mg) obtained in Reference Example 2, and the mixture was degassed and stirred at 80° C. for 3 hours under an argon atmosphere. Water and ethyl acetate were added to the reaction solution, and the precipitate was filtered to obtain the title compound (600 mg). MS (m / z): 320.1 [M+H] +

[0448] [Step 2] Production of 3-[(5-aminopyrazin-2-yl)ethynyl]-4-(difluoromethoxy)benzoic acid

[0449] 2M sodium hydroxide aqueous solution (2.8 mL) was added to a mixture of methyl 3-[(5-aminopyrazin-2-yl)ethynyl]-4-(difluoromethoxy)benzoate (600 mg) and methanol (3.8 mL) at room temperature, and stirred at 50°C for 2 hours. The reaction solution was concentrated under reduced pressure, diluted with water, and then neutralized by adding concentrated hydrochloric acid under ice cooling. The precipitate was filtered to obtain the title compound (500 mg). MS (m / z): 306.0 [M+H] +

[0450] Reference Example 7 3-[(2-amino-4-methoxypyrimidin-5-yl)ethynyl]-4-(difluoromethoxy)benzoic acid

[0451] [Step 1] Production of methyl 3-[(2-amino-4-methoxypyrimidin-5-yl)ethynyl]-4-(difluoromethoxy)benzoate

[0452] To a mixture of 4-(difluoromethoxy)-3-[(trimethylsilyl)ethynyl]benzoic acid methyl ester (3.22 g), DMF (20 mL), DIPEA (20 mL), water (1.8 mL), and 5-bromo-4-methoxypyrimidine-2-amine (2.00 g) obtained in Reference Example 2, hexafluorosilicic acid (0.14 mL), copper (I) iodide (93 mg), and Pd(PPh3)4 (566 mg) were added in sequence and degassed, and then stirred at 95°C for 15 hours under an argon atmosphere. Water was added to the reaction solution, and the precipitate was filtered out. The obtained solid was suspended in methanol and stirred for 1 hour, and then filtered out to obtain the title compound (1.92 g). MS (m / z): 350.1 [M+H] +

[0453] [Step 2] Production of 3-[(2-amino-4-methoxypyrimidin-5-yl)ethynyl]-4-(difluoromethoxy)benzoic acid

[0454] To a mixture of methyl 3-[(2-amino-4-methoxypyrimidin-5-yl)ethynyl]-4-(difluoromethoxy)benzoate (1.92 g), THF (28 mL), and methanol (5.5 mL) was added 2M aqueous sodium hydroxide solution (8.3 mL) at room temperature, and stirred at 40°C for 2 hours. The reaction solution was concentrated under reduced pressure, and 2M hydrochloric acid was added to adjust the pH to 3. The precipitate was filtered to obtain the title compound (1.78 g). MS (m / z): 336.2 [M+H] +

[0455] Reference Example 8 4-(Difluoromethoxy)-3-[(1-methyl-1H-pyrazol-4-yl)ethynyl]benzoic acid

[0456] [Step 1] Production of methyl 4-(difluoromethoxy)-3-[(1-methyl-1H-pyrazol-4-yl)ethynyl]benzoate

[0457] After degassing methyl 4-(difluoromethoxy)-3-[(trimethylsilyl)ethynyl]benzoate (344 mg), 4-iodo-1-methylpyrazole (200 mg), DMF (3.2 mL), and DIPEA (0.96 mL) obtained in Reference Example 2, Pd(PPh3)4 (56 mg) and copper (I) iodide (9.2 mg) were added under an argon atmosphere and degassed again, and then placed under an argon atmosphere. Next, hexafluorosilicic acid (0.014 mL) and water (0.17 mL) were added in sequence, and the mixture was stirred at 80°C for 11 hours. Ethyl acetate was added to the reaction solution, and Celite (registered trademark) was filtered. After washing the filtrate with saturated brine, the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (234 mg). MS (m / z): 307.1 [M+H] +

[0458] [Step 2] Production of 4-(difluoromethoxy)-3-[(1-methyl-1H-pyrazol-4-yl)ethynyl]benzoic acid

[0459] To a mixture of methyl 4-(difluoromethoxy)-3-[(1-methyl-1H-pyrazol-4-yl)ethynyl]benzoate (234 mg), methanol (2.0 mL), and THF (2.0 mL) was added 2M aqueous sodium hydroxide solution (1.9 mL) at room temperature and stirred for 4 hours. The reaction solution was concentrated under reduced pressure, diluted with water, and then neutralized by adding acetic acid. The precipitate was filtered to obtain the title compound (204 mg). MS (m / z): 293.1 [M+H] +

[0460] Reference Example 9 (1S, 2S, 4S)-2-Amino-4-(trifluoromethoxy)cyclopentan-1-ol hydrochloride

[0461] [Step 1] Production of (1S, 3S, 4S)-3-azido-4-(benzyloxy)cyclopentane-1-ol

[0462] To a mixture of cis-1-acetoxycyclopentane 3,4-epoxide (200 g) (synthesized, for example, by the method described in J. Org. Chem. 1973, 38 (24), 4122-4126.) and azidotrimethylsilane (228 mL) was added (R,R)-(-)-N,N'-bis(3,5-di-tert-butylsalicylidene)-1,2-cyclohexanediaminorhodium chloride (III) (9.9 g) under ice-cooling, and the mixture was stirred at room temperature for 2 days. The reaction solution was concentrated under reduced pressure, hexane (703 mL) and triethylsilane (337 mL) were added, and trimethylsilyl trifluoromethanesulfonate (12.7 mL) was added under ice-cooling, and then benzaldehyde (172 mL) was added dropwise and stirred for 1 hour. Potassium carbonate (292 g) and methanol (352 mL) were then added, and the mixture was stirred at 80°C for 2 hours. The reaction solution was adjusted to room temperature, diluted with ethyl acetate, filtered through silica gel, the silica gel was washed with ethyl acetate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (238 g). 1 H-NMR(400MHz, CDCl3)δ7.40-7.28(m,5H),4.63-4.54(m,2H),4.40-4.31(m,1H) ),4.19-4.12(m,1H),3.92-3.86(m,1H),2.24-2.07(m,3H),1.99-1.83(m,2H).

[0463] [Step 2] Production of ({[(1S,2S,4S)-2-azido-4-(trifluoromethoxy)cyclopentyl]oxy}methyl)benzene

[0464] Silver trifluoromethanesulfonate (220 g), potassium fluoride (54.8 g), and toluene (429 mL) were stirred at room temperature until uniform. 2-Fluoropyridine (111 mL) was added at room temperature. (1S, 3S, 4S)-3-azido-4-(benzyloxy)cyclopentane-1-ol (100 g), Selectfluor (Select Fluor, registered trademark) (227 g), 2,6-di-tert-butyl-4-methylphenol (9.4 g), and dehydrated ethyl acetate (1.43 L) were added at 20°C and degassed. Under an argon atmosphere, (trifluoromethyl)trimethylsilane (127 mL) was added dropwise at 20-23°C for 3 hours and stirred for 2 hours. The reaction solution was diluted with hexane, filtered through silica gel, and the silica gel was washed with hexane / ethyl acetate (1 / 1), and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (95 g). 1H-NMR (400MHz, CDCl3) δ7.41-7.28(m,5H),4.76-4.67(m,1H),4.62-4.52(m,2H),4.12-4 .03(m,1H),3.85-3.79(m,1H),2.52-2.40(m,1H),2.35-2.25(m,1H),2.07-1.94(m,2H).

[0465] [Step 3] Production of tert-butyl [(1S,2S,4S)-2-hydroxy-4-(trifluoromethoxy)cyclopentyl]carbamate

[0466] A mixture of ({[(1S,2S,4S)-2-azido-4-(trifluoromethoxy)cyclopentyl]oxy}methyl)benzene (15.7 g), 5% Pd-C (4.71 g), methanol (52 mL), and concentrated hydrochloric acid (6.51 mL) was stirred at 50°C under a hydrogen atmosphere (0.4 MPa) for 6 hours. The reaction solution was cooled to 0°C, TEA (14.5 mL) and Boc2O (18.0 mL) were added, and stirred at room temperature for 1 hour. The insoluble matter was filtered with Celite (registered trademark), washed with methanol, and the filtrate was concentrated under reduced pressure. Water was added to the residue, extracted with ethyl acetate, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (9.0 g). It should be noted that, for example, by using optical resolution of lipase (a mixture of the title compound, lipase B (supported by acrylic resin) (0.05 g / g) from Candida antarctica, vinylacetic acid, TEA, and 1,4-dioxane was stirred at 40° C. for 19 hours) with reference to Tetrahedron, 2013, 69, 5407-5412. (a mixture of the title compound, 3,5-dinitrochlorobenzene, pyridine, and THF was stirred at 60° C. for 1 hour to prepare a 3,5-dinitrophenyl ester derivative of the title compound, and the optical purity was determined by chiral HPLC). 1 H-NMR (400MHz, CD3OD) δ4.83-4.73 (m, 1H), 3.97-3.88 (m, 1H), 3.88-3.79 (m, 1H), 2.53-2.40 (m, 1H) 2.30-2.17 (m, 1H), 1.95-1.83 (m, 1H), 1.83-1.72 (m, 1H), 1.44 (s, 9H). HPLC analysis: Method A, t (1S, 2S, 4S) isomer = 15.7min.

[0467] [Step 4] Production of (1S,2S,4S)-2-amino-4-(trifluoromethoxy)cyclopentan-1-ol hydrochloride

[0468] Tert-butyl [(1S,2S,4S)-2-hydroxy-4-(trifluoromethoxy)cyclopentyl]carbamate (3.25 g), methanol (11 mL), and hydrogen chloride (4M 1,4-dioxane solution, 1.7 mL) were stirred at 60°C for 30 minutes. The reaction solution was concentrated under reduced pressure, diethyl ether was added to the residue, and the precipitate was filtered to obtain the title compound (2.48 g). MS (m / z): 186.1 [M+H] + , 1 H-NMR(400MHz,D2O)δ4.85-4.77(m,1H),4.18-4.09(m,1H),3.60-3.51(m,1H), 2.53-2.41(m,1H),2.41-2.31(m,1H),2.02-1.91(m,1H),1.89-1.79(m,1H).[α] 589 20 = +24.3° (c = 1.0, MeOH)

[0469] Reference Example 104-(Difluoromethoxy)-3-[(Z)-2-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane [cyclo-2-yl)vinyl]benzoic acid methyl ester

[0470] [Step 1] Production of methyl 4-(difluoromethoxy)-3-vinylbenzoate

[0471] A mixture of methyl 3-bromo-4-(difluoromethoxy)benzoate (10.0 g), 2-vinyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (9.0 mL), tripotassium phosphate (15.1 g), Pd(dppf)Cl2·CH2Cl2 (1.45 g), 1,4-dioxane (71 mL), and water (12 mL) obtained in Reference Example 1 was stirred overnight at 80°C under an argon atmosphere. Water was added to the reaction solution and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (6.84 g). MS (m / z): 299.1 [M+H] +

[0472] [Step 2] Production of methyl 4-(difluoromethoxy)-3-formylbenzoate

[0473] A mixture of methyl 4-(difluoromethoxy)-3-vinylbenzoate (6.84 g), dichloromethane (60 mL) and methanol (60 mL) was cooled to -78°C and stirred for 4 hours while bubbling O3. Then, after bubbling oxygen for 15 minutes, PPh3 (9.43 g) was added at -78°C and stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure and the residue was purified by silica gel column chromatography to obtain the title compound (5.6 g).

[0474] [Step 3] Production of methyl 3-(2,2-difluorovinyl)-4-(difluoromethoxy)benzoate

[0475] To a mixture of methyl 4-(difluoromethoxy)-3-formylbenzoate (5.6 g), PPh3 (7.7 g), and DMF (49 mL) was added a solution of sodium difluorochloroacetate (5.6 g) in DMF (24 mL) using a dropping funnel at 100°C, and stirred at 100°C for 30 minutes. Water was added to the reaction solution, extracted with ethyl acetate, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (5.1 g).

[0476] [Step 4] Production of methyl 4-(difluoromethoxy)-3-[(Z)-2-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)vinyl]benzoate

[0477] THF (12 mL) was added to methyl 3-(2,2-difluorovinyl)-4-(difluoromethoxy)benzoate (1.0 g), bis(pinacolato)diboron (1.44 g), potassium acetate (557 mg), tricyclohexylphosphine (106 mg) and copper (I) chloride (19 mg), and the mixture was stirred at 40°C for 4 hours. A saturated aqueous ammonium chloride solution was added to the reaction solution, and extraction was performed with ethyl acetate. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, hexane / ethyl acetate (1 / 1) was added and filtered, and the filtrate was concentrated under reduced pressure. The precipitate produced by adding hexane to the residue was filtered to obtain the title compound (1.05 g). 1 H-NMR (400MHz, CDCl3) δ8.66(s,1H),7.98(dd,1H),7.17(d,1H),6.69(d,1H),6.60(t,1H),3.91(s,3H),1.35(s,12H).

[0478] Reference Example 11 3-[(Z)-2-(5-aminopyrazin-2-yl)-2-fluorovinyl]-4-(difluoromethoxy)benzoic acid

[0479] [Step 1] Production of methyl 3-[(Z)-2-(5-aminopyrazin-2-yl)-2-fluorovinyl]-4-(difluoromethoxy)benzoate

[0480] A mixture of methyl 4-(difluoromethoxy)-3-[(Z)-2-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)vinyl]benzoate (600 mg), 5-bromopyrazin-2-amine (286 mg), sodium carbonate (513 mg), Pd(dppf)Cl2·CH2Cl2 (66 mg), 1,4-dioxane (2.0 mL), and water (0.54 mL) obtained by [Step 4] of Reference Example 10 was degassed and stirred at 90°C for 4 hours under an argon atmosphere. Water was added to the reaction solution and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (430 mg). MS (m / z): 340.0 [M+H] +

[0481] [Step 2] Production of 3-[(Z)-2-(5-aminopyrazin-2-yl)-2-fluorovinyl]-4-(difluoromethoxy)benzoic acid

[0482] To a mixture of methyl 3-[(Z)-2-(5-aminopyrazin-2-yl)-2-fluorovinyl]-4-(difluoromethoxy)benzoate (430 mg), methanol (1.3 mL), and THF (1.3 mL) was added 2M aqueous sodium hydroxide solution (3.2 mL) at room temperature, and stirred overnight. The reaction solution was concentrated under reduced pressure, and 1M hydrochloric acid was added to adjust the pH to 3. The precipitate was filtered to obtain the title compound (350 mg). MS (m / z): 326.1 [M+H] +

[0483] Reference Example 12 (2S)-2-Amino-4-(trifluoromethoxy)butan-1-ol hydrochloride

[0484] [Step 1] Production of N-[(benzyloxy)carbonyl]-O-(trifluoromethyl)-L-homoserine methyl ester

[0485] Potassium fluoride (6.7 g) in an eggplant-shaped flask was heated with a heat gun under reduced pressure for 1 minute. The mixture was brought to room temperature, and silver trifluoromethanesulfonate (26.9 g), 2-fluoropyridine (13.5 mL), and dehydrated ethyl acetate (262 mL) were added, and stirred at room temperature for 15 minutes. To the reaction solution, 2,6-di-tert-butyl-4-methylphenol (1.15 g), Selectfluor (registered trademark) (27.8 g), and N-[(benzyloxy)carbonyl]-L-homoserine methyl ester (14 g) (synthesized, for example, according to the method described in WO2009127546) in ethyl acetate (52 mL) were added. (Trifluoromethyl)trimethylsilane (13.9 mL) was added using a dropping funnel, and stirred at room temperature for 72 hours under light-shielding conditions. The reaction solution was filtered through silica gel, and the silica gel was washed with ethyl acetate. The filtrate was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (10.5 g). MS (m / z): 336.1 [M+H] +

[0486] [Step 2] Production of benzyl [(2S)-1-hydroxy-4-(trifluoromethoxy)butan-2-yl]carbamate

[0487] Sodium borohydride (3.55 g) was added to a mixture of N-[(benzyloxy)carbonyl]-O-(trifluoromethyl)-L-homoserine methyl ester (10.5 g) and methanol (31 mL) under an ice bath, and the mixture was stirred for 15 minutes and then stirred at room temperature for 5 hours. The reaction solution was concentrated under reduced pressure, water was added and extracted with ethyl acetate. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (9.2 g). MS (m / z): 308.1 [M+H] +

[0488] [Step 3] Production of (2S)-2-amino-4-(trifluoromethoxy)butan-1-ol hydrochloride

[0489] Benzyl [(2S)-1-hydroxy-4-(trifluoromethoxy)butan-2-yl]carbamate (300 mg), methanol (3.9 mL), hydrogen chloride (2M methanol solution, 0.49 mL), 10% Pd—C (100 mg) were added, and the mixture was stirred at room temperature for 4 hours under a hydrogen atmosphere (0.3 MPa). The insoluble matter was filtered through Celite (registered trademark), and the filtrate was concentrated under reduced pressure to obtain the title compound (200 mg). 1 H-NMR (400MHz, CD3OD) δ: 4.25-4.16(m,2H), 3.80(dd,1H), 3.61(dd,1H), 3.41-3.34(m,1H), 2.14-2.00(m,2H).

[0490] Reference Example 13 5-[(Z)-2-(2-aminopyrimidin-5-yl)-2-fluorovinyl]-6-ethylpyridine-3-carboxylic acid

[0491] [Step 1] Production of ethyl 5-vinyl-6-ethylpyridine-3-carboxylate

[0492] A mixture of 5-bromo-6-ethylpyridine-3-carboxylic acid ethyl ester (1.0 g) (synthesized, for example, according to the method described in WO2013164769), 2-vinyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.9 mL), tripotassium phosphate (1.64 g), Pd(dppf)Cl2·CH2Cl2 (158 mg), 1,4-dioxane (13 mL), and water (1.3 mL) was stirred at 80°C for 1 hour. Water was added to the reaction solution, extracted with ethyl acetate, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (180 mg). MS (m / z): 206.1 [M+H] +

[0493] [Step 2] Production of ethyl 6-ethyl-5-formylpyridine-3-carboxylate

[0494] A mixture of ethyl 5-vinyl-6-ethylpyridine-3-carboxylate (350 mg), dichloromethane (5.7 mL), and methanol (5.7 mL) was cooled to -78°C and stirred for 1 hour while bubbling ozone. PPh3 (537 mg) was added at -78°C and stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure and the residue was purified by silica gel column chromatography to obtain the title compound (165 mg). MS (m / z): 208.1 [M+H] +

[0495] [Step 3] Production of ethyl 5-(2,2-difluorovinyl)-6-ethylpyridine-3-carboxylate

[0496] To a mixture of 6-ethyl-5-formylpyridine-3-carboxylic acid ethyl ester (165 mg), PPh3 (251 mg), and DMF (1.6 mL) was added a DMF solution (0.4 mL) of sodium difluorochloroacetate (158 mg) dropwise using a syringe pump at 100°C for 30 minutes, and stirred at 100°C for 30 minutes. Water was added to the reaction solution, extracted with ethyl acetate, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (130 mg). MS (m / z): 242.1 [M+H] +

[0497] [Step 4] Production of ethyl 5-[(Z)-2-(2-aminopyrimidin-5-yl)-2-fluorovinyl]-6-ethylpyridine-3-carboxylate

[0498] THF (4.4 mL) was added to ethyl 5-(2,2-difluorovinyl)-6-ethylpyridine-3-carboxylate (160 mg), bis(pinacolato)diboron (337 mg), potassium acetate (130 mg), tricyclohexylphosphine (74 mg) and copper(I) chloride (13 mg), and the mixture was stirred at 50°C for 3 hours. A saturated aqueous ammonium chloride solution was added to the reaction solution, and extraction was performed with ethyl acetate. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and 5-bromopyrimidin-2-amine (115 mg), Pd(dppf)Cl2·CH2Cl2 (54 mg), potassium carbonate (183 mg), 1,4-dioxane (2.2 mL), and water (0.22 mL) were added to the residue, and the mixture was stirred at 80°C for 3 hours. Water was added to the reaction solution, and extraction was performed with ethyl acetate, and the mixture was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (22 mg). MS (m / z): 317.2 [M+H] +

[0499] [Step 5] Production of 5-[(Z)-2-(2-aminopyrimidin-5-yl)-2-fluorovinyl]-6-ethylpyridine-3-carboxylic acid

[0500] Lithium hydroxide monohydrate (15 mg) was added to a mixture of ethyl 5-[(Z)-2-(2-aminopyrimidin-5-yl)-2-fluorovinyl]-6-ethylpyridine-3-carboxylate (22 mg), methanol (0.070 mL), THF (0.070 mL), and water (0.070 mL) at room temperature, and stirred for 3 hours. The reaction solution was concentrated under reduced pressure, diluted with water, and 1M hydrochloric acid was added. The precipitate was filtered to obtain the title compound (10 mg). MS (m / z): 289.2 [M+H] +

[0501] Reference Example 14 Methyl 3-[(Z)-2-bromo-1-fluorovinyl]-4-(difluoromethoxy)benzoate

[0502] To a mixture of 4-(difluoromethoxy)-3-[(trimethylsilyl)ethynyl]benzoic acid methyl ester (4.9 g), N-bromosuccinimide (3.7 g) and acetone (55 mL) obtained by reference example 2, a solution of silver nitrate (I) (140 mg) in water (1.2 mL) was added, and the mixture was stirred overnight at room temperature. The reaction solution was filtered through amino silica gel, and the silica gel was washed with ethyl acetate. The filtrate was concentrated under reduced pressure, and silver fluoride (I) (6.3 g), acetonitrile (55 mL) and water (3 mL) were added to the residue, and the mixture was stirred overnight at 80 degrees. The insoluble matter was filtered through Celite (registered trademark), and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (2.6 g). 1H-NMR (400MHz, CDCl3) δ8.28(d,1H),8.09(dd,1H),7.25-7.21(m,1H),6.64(t,1H),6.52(d,1H),3.94(s,3H).

[0503] Reference Example 15 3-[(Z)-2-(2-aminopyrimidin-5-yl)-1-fluorovinyl]-4-(difluoromethoxy)benzoic acid

[0504] [Step 1] Production of methyl 3-[(Z)-2-(2-aminopyrimidin-5-yl)-1-fluorovinyl]-4-(difluoromethoxy)benzoate

[0505] A mixture of 3-[(Z)-2-bromo-1-fluorovinyl]-4-(difluoromethoxy)benzoic acid methyl ester (300 mg), (2-aminopyrimidin-5-yl)boric acid (192 mg), potassium carbonate (220 mg), Pd(dppf)Cl2·CH2Cl2 (38 mg), 1,4-dioxane (4.6 mL), and water (0.46 mL) obtained in Reference Example 14 was degassed and stirred at 100° C. for 3 hours under an argon atmosphere. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (270 mg). MS (m / z): 340.0 [M+H] +

[0506] [Step 2] Production of 3-[(Z)-2-(2-aminopyrimidin-5-yl)-1-fluorovinyl]-4-(difluoromethoxy)benzoic acid

[0507] To a mixture of methyl 3-[(Z)-2-(2-aminopyrimidin-5-yl)-1-fluorovinyl]-4-(difluoromethoxy)benzoate (270 mg) and methanol (4 mL) was added 2M sodium hydroxide aqueous solution (1.2 mL) at room temperature, and stirred at 50°C for 2 hours. The reaction solution was concentrated under reduced pressure, diluted with water, and then neutralized by adding acetic acid. The precipitate was filtered to obtain the title compound (238 mg). MS (m / z): 326.0 [M+H] +

[0508] Reference Example 16 Methyl 3-[(Z)-2-bromo-1-fluorovinyl]-4-(difluoromethoxy)-5-fluorobenzoate

[0509] [Step 1] Production of methyl 4-(difluoromethoxy)-3-fluoro-5-[(trimethylsilyl)ethynyl]benzoate

[0510] To a mixture of 3-bromo-4-(difluoromethoxy)-5-fluorobenzoic acid methyl ester (2.48 g) (synthesized, for example, according to the method described in WO2020100959), DMF (8.3 mL), TEA (8.3 mL) was added ethynyl (trimethyl) silane (1.7 mL), copper (I) iodide (15.8 mg), Pd (dppf) Cl2 · CH2Cl2 (67.7 mg) in sequence at room temperature, and stirred at 80 ° C overnight under an argon atmosphere. Water was added to the reaction solution and extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was refined by silica gel column chromatography to obtain the title compound (1.97 g).

[0511] [Step 2] Production of methyl 3-[(Z)-2-bromo-1-fluorovinyl]-4-(difluoromethoxy)-5-fluorobenzoate

[0512] To a mixture of methyl 4-(difluoromethoxy)-3-fluoro-5-[(trimethylsilyl)ethynyl]benzoate (1.00 g), N-bromosuccinimide (703 mg) and acetone (10.5 mL), a solution of silver nitrate (I) (26.8 mg) in water (1.05 mL) was added, and the mixture was stirred overnight at room temperature. The reaction solution was filtered through amino silica gel, and the silica gel was washed with ethyl acetate. The filtrate was concentrated under reduced pressure, and silver fluoride (I) (1.00 g), acetonitrile (10.5 mL) and water (0.57 mL) were added to the residue, and the mixture was stirred at 80 degrees for 4 hours. The reaction solution was filtered through silica gel, and the silica gel was washed with ethyl acetate. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (692 mg). 1 H-NMR (400MHz, CDCl3) δ8.07(t,1H),7.89(dd,1H),6.71(td,1H),6.60(d,1H),3.95(s,3H).

[0513] Reference Example 17 4-(Difluoromethoxy)-3-fluoro-5-[(Z)-1-fluoro-2-(5-methoxypyridin-3-yl)vinyl] benzoic acid

[0514] A mixture of 3-[(Z)-2-bromo-1-fluorovinyl]-4-(difluoromethoxy)-5-fluorobenzoic acid methyl ester (150 mg), (2-aminopyrimidin-5-yl)boric acid (100 mg), sodium carbonate (139 mg), Pd(dppf)Cl2·CH2Cl2 (35.7 mg), 1,4-dioxane (2.0 mL), and water (0.4 mL) obtained by step 2 of reference example 16 was degassed and stirred at 100°C for 3 hours under an argon atmosphere. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 4-(difluoromethoxy)-3-fluoro-5-[(Z)-1-fluoro-2-(5-methoxypyridin-3-yl)vinyl]benzoic acid methyl ester. A 2M sodium hydroxide aqueous solution (0.66 mL) was added to the mixture with methanol (4 mL) at room temperature, and stirred at 50°C for 2 hours. The reaction solution was concentrated under reduced pressure and neutralized by adding 2M hydrochloric acid. The precipitate was collected by filtration to obtain the title compound (125 mg). MS (m / z): 357.9 [M+H] +

[0515] Reference Example 18 7-Bromoimidazo[1,5-a]pyridine-3-carboxylic acid

[0516] [Step 1] Production of 7-bromoimidazo[1,5-a]pyridine-3-carbaldehyde

[0517] Water (7.4 mL) and 4-bromopyridine-2-carboxaldehyde (5.00 g) were added to 2,2-dimethoxyacetaldehyde (45% 2-methoxy-2-methylpropane solution, 11.9 mL), acetic acid (90 mL) and ammonium acetate (5.80 g), and the mixture was stirred at room temperature for 4 hours. Saturated sodium bicarbonate aqueous solution and water were added to the reaction solution, and the mixture was stirred at room temperature for 30 minutes. The precipitate was filtered to obtain the title compound (4.86 g). 1 H-NMR (400MHz, DMSO-D6) δ9.88(s,1H),9.28(d,1H),8.37-8.32(m,1H),7.82(s,1H),7.38(dd,1H).

[0518] [Step 2] Production of 7-bromoimidazo[1,5-a]pyridine-3-carboxylic acid

[0519] To a suspension of 7-bromoimidazo[1,5-a]pyridine-3-carbaldehyde (3.15 g), tert-butyl alcohol (32 mL), THF (64 mL), and 2-methyl-2-butene (15.6 mL), a separately prepared solution of sodium dihydrogen phosphate (5.04 g) in water (10 mL) was added. Sodium chlorite (3.85 g) was added under ice bath, and after stirring for 1 hour, the mixture was brought to room temperature and stirred for 1 hour. Sodium chlorite (385 mg) was added, and the mixture was further stirred at room temperature for 1 hour. 2M hydrochloric acid was added to the reaction solution under ice bath to adjust the pH to 5. The title compound (3.23 g) was obtained by filtering out the precipitate. MS (m / z): 240.9 [M+H] +

[0520] Reference Example 19 3-(3-Carbamoylimidazo[1,5-a]pyridin-7-yl)-4-(trifluoromethyl)benzoic acid

[0521] [Step 1] Production of 7-bromoimidazo[1,5-a]pyridine-3-carboxamide

[0522] To a mixture of 7-bromoimidazo[1,5-a]pyridine-3-carboxylic acid (6.34 g), DIPEA (13.7 mL), and DMF (88 mL) obtained in step 2 of reference example 18 was added HBTU (13.0 g) under ice bath, and stirred at room temperature for 5 minutes. Ammonium chloride (2.81 g) was added, and stirred at room temperature for 2 hours. Saturated sodium bicarbonate aqueous solution and water were added to the reaction solution under ice bath. The title compound (5.02 g) was obtained by filtering the generated precipitate. MS (m / z): 240.0 [M+H] +

[0523] [Step 2] Production of methyl 3-(3-carbamoylimidazo[1,5-a]pyridin-7-yl)-4-(trifluoromethyl)benzoate

[0524] A mixture of 7-bromoimidazo[1,5-a]pyridine-3-carboxamide (3.48 g), methyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)benzoate (5.54 g) (synthesized, for example, according to the method described in WO2016161572), sodium carbonate (4.61 g), Pd(dppf)Cl2·CH2Cl2 (592 mg), 1,4-dioxane (73 mL), and water (7.3 mL) was degassed and stirred at 95°C for 15 hours under an argon atmosphere. The reaction solution was concentrated under reduced pressure, water was added, and the resulting precipitate was filtered out. The obtained solid was suspended in hexane / ethyl acetate (1 / 1) and stirred at room temperature for 1 hour. The precipitate was filtered out to obtain the title compound (4.86 g). MS (m / z): 364.1 [M+H] +

[0525] [Step 3] Production of 3-(3-carbamoylimidazo[1,5-a]pyridin-7-yl)-4-(trifluoromethyl)benzoic acid

[0526] Methyl 3-(3-carbamoylimidazo[1,5-a]pyridin-7-yl)-4-(trifluoromethyl)benzoate (4.86 g), THF (67 mL), methanol (13 mL), and 2M aqueous sodium hydroxide solution (21 mL) were added at room temperature and stirred for 2 hours. The solvent was distilled off under reduced pressure, and 2M hydrochloric acid was added to adjust the pH to 5. The precipitate was filtered out and suspended in ethyl acetate, and the precipitate was filtered out to obtain the title compound (4.35 g). MS (m / z): 350.0 [M+H] +

[0527] Reference Example 20 5-(3-Carbamoylimidazo[1,5-a]pyridin-7-yl)-6-(trifluoromethyl)pyridine-3-carboxylic acid

[0528] [Step 1] Production of methyl 5-(3-carbamoylimidazo[1,5-a]pyridin-7-yl)-6-(trifluoromethyl)pyridine-3-carboxylate

[0529] A mixture of 7-bromoimidazo[1,5-a]pyridine-3-carboxamide (500 mg), bis(pinacolato)diboron (635 mg), potassium acetate (409 mg), Pd(dppf)Cl2·CH2Cl2 (85 mg), and 1,4-dioxane (6.5 mL) obtained in step 1 of Reference Example 19 was degassed and stirred at 100° C. for 16 hours under an argon atmosphere. The mixture was brought to room temperature, and methyl 5-bromo-6-(trifluoromethyl)pyridine-3-carboxylate (550 mg) (synthesized, for example, according to the method described in WO2009141398), sodium carbonate (616 mg), and water (0.97 mL) were added and stirred at 100° C. for 41 hours. The reaction solution was concentrated under reduced pressure, water was added to the residue, and the resulting precipitate was filtered out. The resulting precipitate was purified by silica gel column chromatography to obtain the title compound (211 mg). MS (m / z): 365.3 [M+H] +

[0530] [Step 2] Production of 5-(3-carbamoylimidazo[1,5-a]pyridin-7-yl)-6-(trifluoromethyl)pyridine-3-carboxylic acid

[0531] 2M sodium hydroxide aqueous solution (1.16 mL) was added to a mixture of 5-(3-carbamoylimidazo[1,5-a]pyridin-7-yl)-6-(trifluoromethyl)pyridine-3-carboxylic acid methyl ester (211 mg), THF (5.8 mL), and methanol (0.58 mL) at room temperature, and stirred for 1 hour. The reaction solution was concentrated under reduced pressure, and 2M hydrochloric acid was added to adjust the pH to 4. The precipitate was filtered to obtain the title compound (144 mg). MS (m / z): 351.2 [M+H] +

[0532] Reference Example 21 4-Ethyl-3-[(2-phenyl-1,3-oxazole-5-carbonyl)amino]benzoic acid

[0533] [Step 1] Production of methyl 4-ethyl-3-[(2-phenyl-1,3-oxazole-5-carbonyl)amino]benzoate

[0534] DIPEA (0.13 mL) was added to a mixture of 2-phenyl-1,3-oxazole-5-carboxylic acid (70 mg), methyl 3-amino-4-ethylbenzoate (70 mg), HATU (169 mg), and DMF (0.74 mL), and the mixture was stirred at room temperature for 2 hours. The reaction solution was purified by silica gel column chromatography to obtain the title compound (84 mg). MS (m / z): 351.3 [M+H] +

[0535] [Step 2] Production of 4-ethyl-3-[(2-phenyl-1,3-oxazole-5-carbonyl)amino]benzoic acid

[0536] To a mixture of methyl 4-ethyl-3-[(2-phenyl-1,3-oxazole-5-carbonyl)amino]benzoate (84 mg), methanol (0.24 mL), and THF (0.24 mL) was added 2M aqueous sodium hydroxide solution (0.60 mL) at room temperature, and stirred overnight. The reaction solution was concentrated under reduced pressure, and 1M hydrochloric acid was added for neutralization. The precipitate was filtered to obtain the title compound (75 mg). MS (m / z): 337.2 [M+H] +

[0537] Reference Example 22 3-{[2-(Cyclopropylmethyl)-1,3-thiazole-5-carbonyl]amino]-4-ethylbenzoic acid

[0538] [Step 1] Production of methyl 3-{[2-(cyclopropylmethyl)-1,3-thiazole-5-carbonyl]amino]-4-ethylbenzoate

[0539] DIPEA (0.85 mL) was added to a mixture of 2-(cyclopropylmethyl)-1,3-thiazole-5-carboxylic acid (300 mg), HATU (747 mg), and DMF (3.3 mL), and the mixture was stirred at room temperature for 10 minutes. Methyl 3-amino-4-ethylbenzoate (323 mg) was added, and the mixture was stirred at room temperature for 3 hours. A saturated aqueous sodium bicarbonate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate and dried over anhydrous sodium sulfate. The solvent was distilled off and the mixture was purified by silica gel column chromatography to obtain the title compound (600 mg). MS (m / z) 345.1 [M+H] +

[0540] [Step 2] Production of 3-{[2-(cyclopropylmethyl)-1,3-thiazole-5-carbonyl]amino]-4-ethylbenzoic acid

[0541] Lithium hydroxide monohydrate (200 mg) was added to a mixture of methyl 4-ethyl-3-[(2-phenyl-1,3-oxazole-5-carbonyl)amino]benzoate (600 mg), methanol (5.8 mL), THF (5.8 mL), and water (5.8 mL) at room temperature, and stirred overnight. The reaction solution was concentrated under reduced pressure and neutralized by adding 1M hydrochloric acid. The precipitate was filtered to obtain the title compound (400 mg). MS (m / z) 331.1 [M+H] +

[0542] Reference Example 23 (1S, 2S)-2-Amino-4,4-difluorocyclohexane-1-ol hydrochloride

[0543] [Step 1] Production of (4,4-difluorocyclohexylidene)amino-4-methylbenzene-1-sulfonate

[0544] To a mixture of 4,4-difluorocyclohexanone (20 g) and acetonitrile (75 mL) was added a 50% hydroxylamine aqueous solution (13.2 mL) under ice-cooling, and the mixture was stirred under ice-cooling for 1 hour. The mixture was concentrated under reduced pressure in a 35°C water bath, and water was added to the residue, which was filtered and dried to obtain N-(4,4-difluorocyclohexylidene)hydroxylamine (23.6 g).

[0545] Next, 2M sodium hydroxide aqueous solution (48 mL) and 4-methylbenzenesulfonyl chloride (17.0 g) were added to the mixture of N-(4,4-difluorocyclohexylidene)hydroxylamine (13 g) and acetonitrile (87 mL) obtained above under ice bath, and stirred for 1 hour under ice bath. The mixture was concentrated under reduced pressure in a 30°C water bath, water was added to the residue and the resulting precipitate was filtered out. The obtained solid was slurried and stirred with hexane / ethyl acetate (10 / 1), filtered out and dried to obtain the title compound (22.8 g). MS (m / z): 304.0 [M+H] +

[0546] [Step 2] Production of benzyl N-(5,5-difluoro-2-oxocyclohexyl)carbamate

[0547] To a mixture of (4,4-difluorocyclohexylene)amino-4-methylbenzene-1-sulfonate (29g) and toluene (640mL) was added potassium ethoxide (48mL, 24% w / w ethanol solution) under an ice bath, and stirred for 1 hour under an ice bath. The insoluble matter was filtered and washed with diethyl ether. Sodium bicarbonate (8.0g), water (150mL), and benzyl chloroformate (17.7mL) were added to the filtrate, stirred for 30 minutes under an ice bath, and then stirred overnight at room temperature. The reaction solution was concentrated under reduced pressure, THF (48mL) and concentrated hydrochloric acid (16mL) were added under an ice bath, and stirred at room temperature for 15 hours. Saturated sodium bicarbonate aqueous solution was added to the reaction solution, extracted with ethyl acetate, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (21.4g). 1 H-NMR(400MHz, CDCl3)δ:7.43-7.30(m,5H),5.70-5.51(m,1H),5.11(s,2H),4.64-4.47(m,1H), 3.20-3.03(m,1H),2.80-2.65(m,1H),2.62-2.42(m,2H),2.34-2.08(m,1H),2.08-1.89(m,1H).

[0548] [Step 3] Production of benzyl N-[(1S,2R)-5,5-difluoro-2-hydroxycyclohexyl]carbamate

[0549] Under an argon atmosphere, N-(5,5-difluoro-2-oxocyclohexyl) benzyl carbamate (9.84 g), [(R,R)-N-(2-amino-1,2-diphenylethyl) p-toluenesulfonamide]chloro(p-cymene)ruthenium (II) (111 mg), and a 5:2 formic acid-TEA complex (35 mL) were stirred at 50°C for 6 hours. Saturated sodium bicarbonate aqueous solution was added to the reaction solution, extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (5.78 g, 94% ee). It should be noted that, for the obtained stereochemistry, for example, reference is made to the 2017 Summer Symposium of the Japan Society of Process Chemistry, 2P-06, 2017, 178-179. and Org. Lett., 2006, 8, 1, 127-130. and Tetrahedron, 2007, 63, 6755-6763. MS (m / z): 286.0 [M+H] + ,1 H-NMR (400MHz, CDCl3) δ7.42-7.30 (m, 5H), 5.25-5.02 (m, 3H), 4.13-3.86 (m, 2H), 2.25-1.73 (m, 7H), HPLC analysis: method B, t (1S, 2R) isomer = 8.3min. t (1R, 2S) isomer = 10.2min.

[0550] [Step 4] Production of benzyl N-[(1S,2R)-5,5-difluoro-2-(methylsulfonyloxy)cyclohexyl]carbamate

[0551] Methanesulfonyl chloride (2.6 mL) was added dropwise to a mixture of N-[(1S,2R)-5,5-difluoro-2-hydroxycyclohexyl] benzyl carbamate (5.78 g), toluene (58 mL), trimethylamine hydrochloride (194 mg), and TEA (8.47 mL) under an ice bath, and stirred at room temperature for 3 hours. Water was added to the reaction solution, extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, the residue was slurried with hexane, filtered, and dried to obtain the title compound (7.3 g). MS (m / z): 364.1 [M+H] +

[0552] [Step 5] Production of benzyl N-[(1S,2S)-5,5-difluoro-2-hydroxycyclohexyl]carbamate

[0553] DBU (6 mL) was added to a mixture of acetic acid (4.6 mL) and toluene (20 mL), and the mixture was stirred at room temperature for 5 minutes. N-[(1S, 2R)-5,5-difluoro-2-(methylsulfonyloxy)cyclohexyl] benzyl carbamate (7.3 g) was added thereto, and the mixture was stirred at 100°C for 6 hours, and then at room temperature for 2 days, and then at 120°C for 6 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate and washed with saturated brine. Drying was performed over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain (1S, 2S)-2-{[(benzyloxy)carbonyl]amino}-4,4-difluorocyclohexyl acetate.

[0554] Next, the above-obtained (1S,2S)-2-{[(benzyloxy)carbonyl]amino}-4,4-difluorocyclohexyl acetate, methanol (20 mL), and potassium carbonate (5.55 g) were stirred at room temperature for 15 hours. The reaction solution was filtered, and a saturated aqueous solution of ammonium chloride was added to the filtrate, extracted with ethyl acetate, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and recrystallized using EtOAc / hexane to obtain the title compound (2.53 g, 100% ee). 1H-NMR (400MHz,CDCl3)δ7.41-7.30(m,5H),5.17-4.93(m,3H),3.87-3.74(m,1H),3.74-3.61(m,1H),2.70-2.54(m,1H),2.51-2.37(m,1H),2.22-2.06(m,1H),2.03-1.93(m,1H),1.92-1.66(m,3H),HPLC analysis: Method B, t(1S,2S) isomer = 10.1min.

[0555] [Step 6] (1S,2S)-2-Amino-4,4-difluorocyclohexane-1-ol hydrochloride

[0556] Under a hydrogen atmosphere, benzyl N-[(1S,2S)-5,5-difluoro-2-hydroxycyclohexyl]carbamate (4.2 g), methanol (30 mL), hydrogen chloride (2M methanol solution, 15 mL), and 10% Pd / C (2.1 g) were stirred overnight at room temperature. After filtering the insoluble matter, the filtrate was concentrated to obtain the title compound (2.7 g). MS (m / z): 152.1 [M+H] + , 1 H-NMR(400MHz,D2O)δ3.69-3.57(m,1H),3.23-3.10(m,1H),2.50-2.35(m,1H),2.17-1.73(m,4H),1.59-1.43(m,1H).

[0557] Reference Example 24 (5S, 6S)-6-aminospiro[2.4]heptane-5-ol hydrochloride

[0558] [Step 1] Production of (5S,6S)-6-bromospiro[2.4]heptane-5-ol

[0559] Iodine (37 g) was added to a mixture of cyclopent-3-ene-1,1-diyldimethanol (7.4 g) (synthesized, for example, by the method described in Tetrahedron, 2009, 65, 1162-1170.), PPh3 (38 g), imidazole (12 g), and THF (290 mL), and stirred at 80°C for 2 hours. The reaction solution was diluted with hexane, filtered using silica gel, and then the silica gel was washed with hexane / ethyl acetate (10 / 1). The filtrate was concentrated under reduced pressure to obtain 4,4-bis(iodomethyl)cyclopent-1-ene.

[0560] Next, the above-obtained 4,4-bis(iodomethyl)cyclopent-1-ene, indium (16 g), 1,4-dioxane (118.8 mL), and water (1.2 mL) were stirred overnight at 100° C. After the insoluble matter was filtered out with Celite (registered trademark), the filtrate was concentrated under reduced pressure to obtain spiro[2.4]hept-5-ene.

[0561] Next, N-bromosuccinimide (12 g) was added to the spiro[2.4]hept-5-ene obtained above and water (120 mL), and the mixture was stirred at room temperature for 30 minutes. Sodium sulfite was added to the reaction solution and stirred for 30 minutes. The mixture was extracted with ethyl acetate and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (7.1 g).

[0562] [Step 2] Production of (5S,6S)-6-aminospiro[2.4]heptane-5-ol hydrochloride

[0563] Sodium hydroxide (4.5 g) was added to a mixture of (5S, 6S)-6-bromospiro [2.4] heptane-5-ol (7.1 g) and diethyl ether (74 mL), and the mixture was stirred at room temperature for 1 hour. The reaction solution was filtered using silica gel, and the silica gel was washed with diethyl ether. The filtrate was concentrated under reduced pressure to obtain 6-oxaspiro [bicyclo [3.1.0] hexane -3,1'- cyclopropane].

[0564] Next, (R,R)-(-)-N,N'-bis(3,5-di-tert-butyl salicylidene)-1,2-cyclohexanediaminorhodium chloride (III) (520 mg) was added to the mixture of the above-obtained 6-oxaspiro[bicyclo[3.1.0]hexane-3,1'-cyclopropane] and azidotrimethylsilane (9.8 mL), and stirred overnight at room temperature. The reaction solution was filtered using amino silica gel, and the amino silica gel was washed with hexane / ethyl acetate (10 / 1). The filtrate was concentrated under reduced pressure to obtain {[(5S,6S)-6-azidospiro[2.4]heptane-5-yl]oxy}trimethylsilane.

[0565] Next, the above-obtained {[(5S,6S)-6-azidospiro[2.4]heptane-5-yl]oxy}trimethylsilane, methanol (37 mL), 5% Pd / C (2.1 g), and hydrogen chloride (4M 1,4-dioxane solution, 9.3 mL) were stirred overnight at room temperature under a hydrogen atmosphere. The insoluble matter was filtered through Celite (registered trademark), and the filtrate was concentrated under reduced pressure to obtain the title compound (3.3 g). 1 H-NMR(400MHz,D2O)δ4.29-4.11(m,1H),3.54-3.36(m,1H),1.96(dd,1H),1.87(dd,1H),1.62-1.52(m,2H),0.45-0.32(m,4H).

[0566] Reference Example 25 4-Ethyl-3-[5-(3-fluorophenyl)pyridine-3-amide]benzoic acid

[0567] [Step 1] Production of methyl 4-ethyl-3-[5-(3-fluorophenyl)pyridine-3-amide]benzoate

[0568] DIPEA (0.36 mL) was added to a mixture of 5-(3-fluorophenyl)pyridine-3-carboxylic acid (150 mg), HATU (315 mg), and DMF (1.4 mL), and the mixture was stirred at room temperature for 10 minutes. Methyl 3-amino-4-ethylbenzoate (136 mg) was added, and the mixture was stirred at room temperature for 3 hours. A saturated aqueous sodium bicarbonate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate and dried over anhydrous sodium sulfate. The solvent was distilled off and the mixture was purified by silica gel column chromatography to obtain the title compound (200 mg). MS (m / z): 379.2 [M+H] +

[0569] [Step 2] Production of 4-ethyl-3-[5-(3-fluorophenyl)pyridine-3-amide]benzoic acid

[0570] 2M sodium hydroxide aqueous solution (0.80 mL) was added to a mixture of methyl 4-ethyl-3-[5-(3-fluorophenyl)pyridine-3-amide]benzoate (200 mg), methanol (1.1 mL), and THF (1.1 mL) at room temperature, and stirred overnight. The reaction solution was concentrated under reduced pressure and neutralized by adding 1M hydrochloric acid. The precipitate was filtered to obtain the title compound (160 mg). MS (m / z): 365.1 [M+H] +

[0571] Reference Example 26 3-[(1Z)-2-(2-aminopyrimidin-5-yl)-2-fluorovinyl]-4-(difluoromethoxy)benzoic acid

[0572] [Step 1] Production of methyl 3-[(1Z)-2-(2-aminopyrimidin-5-yl)-2-fluorovinyl]-4-(difluoromethoxy)benzoate

[0573] A mixture of methyl 4-(difluoromethoxy)-3-[(Z)-2-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)vinyl]benzoate (1.50 g), 5-bromopyrimidin-2-amine (700 mg), potassium carbonate (1.10 g), Pd(dppf)Cl2·CH2Cl2 (160 mg), DMF (13 mL), and water (1.3 mL) was degassed and stirred at 85° C. for 4 hours under an argon atmosphere. The reaction solution was purified by silica gel column chromatography to obtain the title compound (820 mg). MS (m / z): 340.0 [M+H] +

[0574] [Process 2] 3-[(1Z)-2-(2-aminopyrimidin-5-yl)-2-fluorovinyl]-4-(difluoromethoxy)benzoic acid Manufacturing

[0575] Lithium hydroxide monohydrate (530 mg) was added to a mixture of methyl 3-[(1Z)-2-(2-aminopyrimidin-5-yl)-2-fluorovinyl]-4-(difluoromethoxy)benzoate (820 mg), methanol (2.4 mL), THF (2.4 mL), and water (2.4 mL) at room temperature, and stirred overnight. The reaction solution was concentrated under reduced pressure and neutralized by adding 1M hydrochloric acid. The precipitate was filtered to obtain the title compound (720 mg). MS (m / z): 326.0 [M+H] +

[0576] Reference Example 27 3-[5-(Cyclopropylmethoxy)pyridine-3-amide]-4-ethylbenzoic acid

[0577] [Step 1] Production of methyl 3-[5-(cyclopropylmethoxy)pyridine-3-amide]-4-ethylbenzoate

[0578] DIPEA (0.81 mL) was added to a mixture of 5-(cyclopropylmethoxy)nicotinic acid (300 mg), HATU (709 mg), and DMF (3.1 mL), and the mixture was stirred at room temperature for 10 minutes. Methyl 3-amino-4-ethylbenzoate (306 mg) was added, and the mixture was stirred at room temperature for 3 hours. A saturated aqueous sodium bicarbonate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate and dried over anhydrous sodium sulfate. The solvent was distilled off, and the mixture was purified by silica gel column chromatography to obtain the title compound (500 mg). MS (m / z): 355.1 [M+H] +

[0579] [Step 2] Production of 3-[5-(cyclopropylmethoxy)pyridine-3-amide]-4-ethylbenzoic acid

[0580] Lithium hydroxide monohydrate (200 mg) was added to a mixture of methyl 3-[5-(cyclopropylmethoxy)pyridine-3-amide]-4-ethylbenzoate (500 mg), methanol (4.7 mL), THF (4.7 mL), and water (4.7 mL) at room temperature, and stirred overnight. The reaction solution was concentrated under reduced pressure and neutralized by adding 1M hydrochloric acid. The precipitate was filtered to obtain the title compound (430 mg). MS (m / z): 341.1 [M+H] +

[0581] Reference Example 28 3-{2-[(Cyclopropylmethyl)amino]-1,3-thiazole-5-amide}-4-ethylbenzoic acid

[0582] [Step 1] Production of methyl 3-(2-bromo-1,3-thiazole-5-carboxamide)-4-ethylbenzoate

[0583] DIPEA (0.83 mL) was added to a mixture of methyl 3-amino-4-ethylbenzoate (431 mg), 2-bromothiazole-5-carboxylic acid (500 mg), HATU (1.10 g), and DMF (20 mL), and the mixture was stirred overnight at room temperature. Saturated aqueous sodium bicarbonate solution was added to the reaction solution, extracted with ethyl acetate, and dried over anhydrous sodium sulfate. The solvent was distilled off, and the mixture was purified by silica gel column chromatography to obtain the title compound (100 mg).

[0584] [Step 2] Production of methyl 3-{2-[(cyclopropylmethyl)amino]-1,3-thiazole-5-amide}-4-ethylbenzoate

[0585] A mixture of methyl 3-(2-bromo-1,3-thiazole-5-carboxamide)-4-ethylbenzoate (100 mg), cyclopropylmethanamine (96 mg), and NMP (0.9 mL) was stirred overnight at 80°C. The reaction solution was purified by silica gel column chromatography to obtain the title compound (65 mg). MS (m / z): 360.3 [M+H] +

[0586] [Step 3] Production of 3-{2-[(cyclopropylmethyl)amino]-1,3-thiazole-5-amide}-4-ethylbenzoic acid

[0587] To a mixture of methyl 3-{2-[(cyclopropylmethyl)amino]-1,3-thiazole-5-amide}-4-ethylbenzoate (65 mg) and methanol (0.72 mL) was added 2M aqueous sodium hydroxide solution (0.27 mL) at room temperature and stirred overnight. The reaction solution was concentrated under reduced pressure and neutralized by adding 1M hydrochloric acid. The precipitate was filtered to obtain the title compound (60 mg). MS (m / z): 346.2 [M+H] +

[0588] Reference Example 29 3-(2-Cyclopropyl-1,3-thiazole-5-carboxamide)-4-ethylbenzoic acid

[0589] [Step 1] Production of methyl 3-(2-cyclopropyl-1,3-thiazole-5-carboxamide)-4-ethylbenzoate

[0590] DIPEA (0.143 mL) was added to a mixture of 2-cyclopropyl-1,3-thiazole-5-carboxylic acid (70 mg), methyl 3-amino-4-ethylbenzoate (78 mg), HATU (189 mg), and DMF (0.83 mL), and the mixture was stirred at room temperature for 2 hours. The reaction solution was purified by silica gel column chromatography to obtain the title compound (120 mg). MS (m / z): 331.1 [M+H] +

[0591] [Step 2] Production of 3-(2-cyclopropyl-1,3-thiazole-5-carboxamide)-4-ethylbenzoic acid

[0592] 2M sodium hydroxide aqueous solution (0.90 mL) was added to a mixture of methyl 3-(2-cyclopropyl-1,3-thiazole-5-amide)-4-ethylbenzoate (120 mg), methanol (0.36 mL), and THF (0.36 mL) at room temperature, and stirred overnight. The reaction solution was concentrated under reduced pressure and neutralized by adding 1M hydrochloric acid. The precipitate was filtered to obtain the title compound (80 mg). MS (m / z): 317.2 [M+H] +

[0593] Example 14-(Difluoromethoxy)-N-[(1S,2S,4S)-2-hydroxy-4-(trifluoromethoxy)cyclopentyl]-3- [(Pyrimidin-5-yl)ethynyl]benzamide

[0594] HATU (47 mg) and DIPEA (0.054 mL) were added to a DMF (0.34 mL) solution of 4-(difluoromethoxy)-3-[(pyrimidin-5-yl)ethynyl]benzoic acid (30 mg) obtained in step 2 of reference example 3, and the mixture was stirred at room temperature for 15 minutes. Next, (1S,2S,4S)-2-amino-4-(trifluoromethoxy)cyclopentane-1-ol hydrochloride (27 mg) was added, and the mixture was stirred overnight at room temperature. The reaction solution was purified by silica gel column chromatography to obtain the title compound (31 mg). MS (m / z): 458.1 [M+H] +

[0595] Example 24-(Difluoromethoxy)-3-[2-(5-fluoropyridin-3-yl)ethynyl]-N-[(1S,2S,4S)-2-hydroxy 4-(trifluoromethoxy)cyclopentyl]benzamide

[0596] The title compound (35 mg) was obtained by the method according to Example 1, using 4-(difluoromethoxy)-3-[(5-fluoropyridin-3-yl)ethynyl]benzoic acid (30 mg) obtained in Step 2 of Reference Example 4 instead of 4-(difluoromethoxy)-3-[(pyrimidin-5-yl)ethynyl]benzoic acid. MS (m / z): 475.1 [M+H] +

[0597] Example 33-[2-(2-aminopyrimidin-5-yl)ethynyl]-4-(difluoromethoxy)-N-[(1S,2S,4S)-2- Hydroxy-4-(trifluoromethoxy)cyclopentyl]benzamide

[0598] The title compound (35 mg) was obtained by the method according to Example 1, using 3-[(2-aminopyrimidin-5-yl)ethynyl]-4-(difluoromethoxy)benzoic acid (30 mg) obtained in step 2 of Reference Example 5 instead of 4-(difluoromethoxy)-3-[(pyrimidin-5-yl)ethynyl]benzoic acid. MS (m / z): 473.1 [M+H] +

[0599] Example 43-[2-(5-aminopyrazin-2-yl)ethynyl]-4-(difluoromethoxy)-N-[(1S,2S,4S)-2- Hydroxy-4-(trifluoromethoxy)cyclopentyl]benzamide

[0600] The title compound (45 mg) was obtained by the method according to Example 1, using 3-[(5-aminopyrazin-2-yl)ethynyl]-4-(difluoromethoxy)benzoic acid (35 mg) obtained in step 2 of Reference Example 6 instead of 4-(difluoromethoxy)-3-[(pyrimidin-5-yl)ethynyl]benzoic acid. MS (m / z): 473.2 [M+H] +

[0601] Example 53-[2-(2-amino-4-methoxypyrimidin-5-yl)ethynyl]-4-(difluoromethoxy)-N-[(1S, 2S,4S)-2-Hydroxy-4-(trifluoromethoxy)cyclopentyl]benzamide

[0602] The title compound (25 mg) was obtained by the method according to Example 1, using 3-[(2-amino-4-methoxypyrimidin-5-yl)ethynyl]-4-(difluoromethoxy)benzoic acid (30 mg) obtained in step 2 of Reference Example 7 instead of 4-(difluoromethoxy)-3-[(pyrimidin-5-yl)ethynyl]benzoic acid. MS (m / z): 503.2 [M+H] +

[0603] Example 64-(Difluoromethoxy)-N-[(1S,2S,4S)-2-hydroxy-4-(trifluoromethoxy)cyclopentyl]-3- [2-(1-Methyl-1H-pyrazol-4-yl)ethynyl]benzamide

[0604] The title compound (27 mg) was obtained by the method according to Example 1, using 4-(difluoromethoxy)-3-[(1-methyl-1H-pyrazol-4-yl)ethynyl]benzoic acid (20 mg) obtained in Step 2 of Reference Example 8 instead of 4-(difluoromethoxy)-3-[(pyrimidin-5-yl)ethynyl]benzoic acid. MS (m / z): 460.2 [M+H] +

[0605] Example 7 3-[2-(5-aminopyrazin-2-yl)ethynyl]-4-(difluoromethoxy)-N-[(2S)-1-hydroxy- 4-(Trifluoromethoxy)butan-2-yl]benzamide

[0606] The title compound (35 mg) was obtained by the method of Example 1, except that 3-[(5-aminopyrazin-2-yl)ethynyl]-4-(difluoromethoxy)benzoic acid (30 mg) obtained in Step 2 of Reference Example 6 and (2S)-2-amino-4-(trifluoromethoxy)butane-1-ol hydrochloride (23 mg) obtained in Step 3 of Reference Example 12 were used instead of 4-(difluoromethoxy)-3-[(pyrimidin-5-yl)ethynyl]benzoic acid and (1S,2S,4S)-2-amino-4-(trifluoromethoxy)cyclopentane-1-ol hydrochloride. MS (m / z): 461.1 [M+H] ++

[0607] Example 8 3-[2-(2-aminopyrimidin-5-yl)ethynyl]-4-(difluoromethoxy)-N-[(1S)-1-(3-fluorophenyl)- [(2-hydroxyethyl)-2-benzamide hydrochloride]

[0608] By the method based on Example 1, instead of 4-(difluoromethoxy)-3-[(pyrimidin-5-yl)ethynyl]benzoic acid and (1S,2S,4S)-2-amino-4-(trifluoromethoxy)cyclopentan-1-ol hydrochloride, 3-[(2-aminopyrimidin-5-yl)ethynyl]-4-(difluoromethoxy)benzoic acid (30 mg) and (2S)-2-amino-2-(3-fluorophenyl)ethanol (18 mg) obtained by Step 2 of Reference Example 5 were used to obtain 3-[2-(2-aminopyrimidin-5-yl)ethynyl]-4-(difluoromethoxy)-N-[(1S)-1-(3-fluorophenyl)-2-hydroxyethyl]benzamide (34 mg). The obtained 3-[2-(2-aminopyrimidin-5-yl)ethynyl]-4-(difluoromethoxy)-N-[(1S)-1-(3-fluorophenyl)-2-hydroxyethyl]benzamide (34 mg) was dissolved in 1,4-dioxane (2 mL), and hydrogen chloride (4M 1,4-dioxane solution, 0.020 mL) was added, and stirred at room temperature for 20 minutes. The solvent was distilled off under reduced pressure to obtain the title compound (25 mg). MS (m / z): 443.1 [M+H] +

[0609] Example 9 3-[2-(2-aminopyrimidin-5-yl)ethynyl]-4-(difluoromethoxy)-N-[(2S)-1-hydroxy- 3-(4-methoxyphenyl)propan-2-yl]benzamide hydrochloride

[0610] By the method based on Example 1, instead of 4-(difluoromethoxy)-3-[(pyrimidin-5-yl)ethynyl]benzoic acid and (1S,2S,4S)-2-amino-4-(trifluoromethoxy)cyclopentan-1-ol hydrochloride, 3-[(2-aminopyrimidin-5-yl)ethynyl]-4-(difluoromethoxy)benzoic acid (30 mg) and (2S)-2-amino-3-(4-methoxyphenyl)propan-1-ol (21 mg) obtained by Step 2 of Reference Example 5 were used to obtain 3-[2-(2-aminopyrimidin-5-yl)ethynyl]-4-(difluoromethoxy)-N-[(2S)-1-hydroxy-3-(4-methoxyphenyl)propan-2-yl]benzamide (41 mg). The obtained 3-[2-(2-aminopyrimidin-5-yl)ethynyl]-4-(difluoromethoxy)-N-[(2S)-1-hydroxy-3-(4-methoxyphenyl)propan-2-yl]benzamide (40 mg) was dissolved in 1,4-dioxane (2 mL), and hydrogen chloride (4M 1,4-dioxane solution, 0.022 mL) was added, and stirred at room temperature for 20 minutes. The solvent was distilled off under reduced pressure to obtain the title compound (25 mg). MS (m / z): 469.1 [M+H] +

[0611] Example 10 3-[(1Z)-2-(5-aminopyrazin-2-yl)-2-fluorovinyl]-4-(difluoromethoxy)-N- [(1S,2S,4S)-2-Hydroxy-4-(trifluoromethoxy)cyclopentyl]benzamide

[0612] The title compound (22 mg) was obtained by the method of Example 1, except that 3-[(Z)-2-(5-aminopyrazin-2-yl)-2-fluorovinyl]-4-(difluoromethoxy)benzoic acid (30 mg) obtained in Step 2 of Reference Example 11 was used instead of 4-(difluoromethoxy)-3-[(pyrimidin-5-yl)ethynyl]benzoic acid. MS (m / z): 493.2 [M+H] +

[0613] Example 11 5-[(1Z)-2-(2-aminopyrimidin-5-yl)-2-fluorovinyl]-6-ethyl-N-[(1S,2S, 4S)-2-Hydroxy-4-(trifluoromethoxy)cyclopentyl]pyridine-3-carboxamide

[0614] The title compound (3 mg) was obtained by the method of Example 1, except that 5-[(Z)-2-(2-aminopyrimidin-5-yl)-2-fluorovinyl]-6-ethylpyridine-3-carboxylic acid (10 mg) obtained in Step 5 of Reference Example 13 was used instead of 4-(difluoromethoxy)-3-[(pyrimidin-5-yl)ethynyl]benzoic acid. MS (m / z): 456.2 [M+H] +

[0615] Example 123-[(1Z)-2-(2-aminopyrimidin-5-yl)-1-fluorovinyl]-4-(difluoromethoxy)-N- [(2S)-1-Hydroxy-4-(trifluoromethoxy)butan-2-yl]benzamide

[0616] The title compound (29 mg) was obtained by the method of Example 1, except that 3-[(Z)-2-(2-aminopyrimidin-5-yl)-1-fluorovinyl]-4-(difluoromethoxy)benzoic acid (30 mg) obtained in Step 2 of Reference Example 15 and (2S)-2-amino-4-(trifluoromethoxy)butane-1-ol hydrochloride (21 mg) obtained in Step 3 of Reference Example 12 were used instead of 4-(difluoromethoxy)-3-[(pyrimidin-5-yl)ethynyl]benzoic acid and (1S,2S,4S)-2-amino-4-(trifluoromethoxy)cyclopentane-1-ol hydrochloride. MS (m / z): 481.2 [M+H] +

[0617] Example 134-(Difluoromethoxy)-3-fluoro-5-[(1Z)-1-fluoro-2-(5-methoxypyridin-3-yl)ethylene [(1S,2S,4S)-2-hydroxy-4-(trifluoromethoxy)cyclopentyl]benzamide

[0618] The title compound (22 mg) was obtained by the method of Example 1, except that 4-(difluoromethoxy)-3-fluoro-5-[(Z)-1-fluoro-2-(5-methoxypyridin-3-yl)vinyl]benzoic acid (30 mg) obtained in Reference Example 17 was used instead of 4-(difluoromethoxy)-3-[(pyrimidin-5-yl)ethynyl]benzoic acid. MS (m / z): 525.2 [M+H] ++

[0619] Example 14 7-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-(trifluoromethyl)phenyl)imidazolyl [1,5-a]Pyridine-3-carboxamide

[0620] DIPEA (0.037 mL) was added to a mixture of 3-(3-carbamoylimidazo[1,5-a]pyridin-7-yl)-4-(trifluoromethyl)benzoic acid (22 mg), (1S,2S)-2-aminocyclohexane-1-ol hydrochloride (14 mg), HATU (35 mg), and DMF (0.5 mL) obtained in step 3 of Reference Example 19, and the mixture was stirred at room temperature for 1 hour. The reaction solution was purified by silica gel column chromatography to obtain the title compound (23 mg). MS (m / z): 447.3 [M+H] +

[0621] Example 155-{3-carbamoylimidazo[1,5-a]pyridin-7-yl}-N-[(1S,2S,4S)-2-hydroxy-4- [(trifluoromethoxy)cyclopentyl]-6-(trifluoromethyl)pyridine-3-carboxamide

[0622] To a mixture of 5-(3-carbamoylimidazo[1,5-a]pyridin-7-yl)-6-(trifluoromethyl)pyridine-3-carboxylic acid (30 mg) obtained by step 2 of Reference Example 20 and dichloromethane (0.29 mL), TEA (0.048 mL), EDCI-HCl (164 mg) and HOBt (12 mg) were added in sequence, and stirred at room temperature for 5 minutes. Next, (1S,2S,4S)-2-amino-4-(trifluoromethoxy)cyclopentane-1-ol hydrochloride (25 mg) was added, and stirred overnight at room temperature. The reaction solution was purified by silica gel column chromatography to obtain the title compound (35 mg). MS (m / z): 518.2 [M+H] +

[0623] Example 16 N-(2-ethyl-5-{[(1S,2S,4S)-2-hydroxy-4-(trifluoromethoxy)cyclopentyl]carbamyl 1,3-oxazole-5-carboxamide

[0624] The title compound (50 mg) was obtained by the method of Example 1, except that 4-ethyl-3-[(2-phenyl-1,3-oxazole-5-carbonyl)amino]benzoic acid (40 mg) obtained in Step 2 of Reference Example 23 was used instead of 4-(difluoromethoxy)-3-[(pyrimidin-5-yl)ethynyl]benzoic acid. MS (m / z): 504.3 [M+H] +

[0625] Example 17 2-(Cyclopropylmethyl)-N-(2-ethyl-5-{[(1S,2S,4S)-2-hydroxy-4-(trifluoromethoxy 1,3-thiazole-5-carboxamide

[0626] The title compound (33 mg) was obtained by the method of Example 1, except that 3-{[2-(cyclopropylmethyl)-1,3-thiazole-5-carbonyl]amino]-4-ethylbenzoic acid (30 mg) obtained in step 2 of Reference Example 22 was used instead of 4-(difluoromethoxy)-3-[(pyrimidin-5-yl)ethynyl]benzoic acid. MS (m / z): 498.2 [M+H] +

[0627] Example 18 4-(Difluoromethoxy)-N-[(5S,6S)-6-hydroxyspiro[2.4]heptane-5-yl]-3-[2-(pyrimidine- 5-yl)ethynyl]benzamide

[0628] The title compound (29 mg) was obtained by the method of Example 1, except that (5S,6S)-6-aminospiro[2.4]heptane-5-ol hydrochloride (20 mg) obtained in step 2 of Reference Example 24 was used instead of (1S,2S,4S)-2-amino-4-(trifluoromethoxy)cyclopentane-1-ol hydrochloride. MS (m / z): 400.1 [M+H] +

[0629] Example 19 4-(Difluoromethoxy)-3-[2-(5-fluoropyridin-3-yl)ethynyl]-N-[(5S,6S)-6-hydroxy Spiro[2.4]heptane-5-yl]benzamide

[0630] The title compound (34 mg) was obtained by the method of Example 1, except that 4-(difluoromethoxy)-3-[(5-fluoropyridin-3-yl)ethynyl]benzoic acid (30 mg) obtained in Step 2 of Reference Example 4 and (5S,6S)-6-aminospiro[2.4]heptan-5-ol hydrochloride (19 mg) obtained in Step 2 of Reference Example 24 were used instead of 4-(difluoromethoxy)-3-[(pyrimidin-5-yl)ethynyl]benzoic acid and (1S,2S,4S)-2-amino-4-(trifluoromethoxy)cyclopentan-1-ol hydrochloride. MS (m / z): 417.1 [M+H] +

[0631] Example 203-[2-(2-aminopyrimidin-5-yl)ethynyl]-N-[(1S,2S)-5,5-difluoro-2-hydroxycyclohexyl [4-(difluoromethoxy)benzamide toluenesulfonate

[0632] 3-[2-(2-aminopyrimidin-5-yl)ethynyl]-N-[(1S,2S)-5,5-difluoro-2-hydroxycyclohexyl]-4-(difluoromethoxy)benzamide was obtained by the method according to Example 1, except that 3-[(2-aminopyrimidin-5-yl)ethynyl]-4-(difluoromethoxy)benzoic acid (30 mg) obtained in Step 2 of Reference Example 5 and (1S,2S)-2-amino-4,4-difluorocyclohexane-1-ol hydrochloride (22 mg) obtained in Step 6 of Reference Example 23 were used instead of 4-(difluoromethoxy)-3-[(pyrimidin-5-yl)ethynyl]benzoic acid and (1S,2S,4S)-2-amino-4-(trifluoromethoxy)cyclopentane-1-ol hydrochloride. The obtained product was dissolved in a small amount of methanol, p-toluenesulfonic acid monohydrate (22 mg) was added, and the solvent was distilled off under reduced pressure. The product was powdered with 2-propanol / ethyl acetate to obtain the title compound (22 mg). MS (m / z): 439.2 [M+H] +

[0633] Example 21 3-[2-(2-aminopyrimidin-5-yl)ethynyl]-4-(difluoromethoxy)-N-[(5S,6S)-6-hydroxy spiro[2.4]heptane-5-yl]benzamide

[0634] The title compound (194 mg) was obtained by the method of Example 1, except that 3-[(2-aminopyrimidin-5-yl)ethynyl]-4-(difluoromethoxy)benzoic acid (200 mg) obtained in Step 2 of Reference Example 5 and (5S,6S)-6-aminospiro[2.4]heptan-5-ol hydrochloride (161 mg) obtained in Step 2 of Reference Example 24 were used instead of 4-(difluoromethoxy)-3-[(pyrimidin-5-yl)ethynyl]benzoic acid and (1S,2S,4S)-2-amino-4-(trifluoromethoxy)cyclopentane-1-ol hydrochloride. MS (m / z): 415.2 [M+H] +

[0635] Example 22 3-[2-(2-aminopyrimidin-5-yl)ethynyl]-4-(difluoromethoxy)-N-[(2S)-1-hydroxy- 4-(Trifluoromethoxy)butan-2-yl]benzamide

[0636] The title compound (25 mg) was obtained by the method of Example 1, except that 3-[(2-aminopyrimidin-5-yl)ethynyl]-4-(difluoromethoxy)benzoic acid (30 mg) obtained in Step 2 of Reference Example 5 and (2S)-2-amino-4-(trifluoromethoxy)butane-1-ol hydrochloride (25 mg) obtained in Step 3 of Reference Example 12 were used instead of 4-(difluoromethoxy)-3-[(pyrimidin-5-yl)ethynyl]benzoic acid and (1S,2S,4S)-2-amino-4-(trifluoromethoxy)cyclopentane-1-ol hydrochloride. MS (m / z): 461.2 [M+H] +

[0637] Example 233-[2-(2-amino-4-methoxypyrimidin-5-yl)ethynyl]-4-(difluoromethoxy)-N-[(5S, 6S)-6-Hydroxyspiro[2.4]heptane-5-yl]benzamide

[0638] The title compound (20 mg) was obtained by the method according to Example 1, except that 3-[(2-amino-4-methoxypyrimidin-5-yl)ethynyl]-4-(difluoromethoxy)benzoic acid (30 mg) obtained in Step 2 of Reference Example 7 and (5S,6S)-6-aminospiro[2.4]heptan-5-ol hydrochloride (18 mg) obtained in Step 2 of Reference Example 24 were used instead of 4-(difluoromethoxy)-3-[(pyrimidin-5-yl)ethynyl]benzoic acid and (1S,2S,4S)-2-amino-4-(trifluoromethoxy)cyclopentane-1-ol hydrochloride. MS (m / z): 445.2 [M+H] +

[0639] Example 24 4-(Difluoromethoxy)-N-[(2S)-1-hydroxy-4-(trifluoromethoxy)butan-2-yl]-3-[2- (1-methyl-1H-pyrazol-4-yl)ethynyl]benzamide

[0640] The title compound (27 mg) was obtained by the method of Example 1, except that 4-(difluoromethoxy)-3-[(1-methyl-1H-pyrazol-4-yl)ethynyl]benzoic acid (30 mg) obtained in Step 2 of Reference Example 8 and (2S)-2-amino-4-(trifluoromethoxy)butane-1-ol hydrochloride (24 mg) obtained in Step 3 of Reference Example 12 were used instead of 4-(difluoromethoxy)-3-[(pyrimidin-5-yl)ethynyl]benzoic acid and (1S,2S,4S)-2-amino-4-(trifluoromethoxy)cyclopentane-1-ol hydrochloride. MS (m / z): 448.2 [M+H] +

[0641] Example 25 3-[(1Z)-2-(5-aminopyrazin-2-yl)-2-fluorovinyl]-N-[(1S,2S)-5,5-difluoro- 2-Hydroxycyclohexyl]-4-(difluoromethoxy)benzamide

[0642] The title compound (19 mg) was obtained by the method of Example 1, except that 3-[(Z)-2-(5-aminopyrazin-2-yl)-2-fluorovinyl]-4-(difluoromethoxy)benzoic acid (30 mg) obtained in Step 2 of Reference Example 11 and (1S,2S)-2-amino-4,4-difluorocyclohexane-1-ol hydrochloride (21 mg) obtained in Step 6 of Reference Example 23 were used instead of 4-(difluoromethoxy)-3-[(pyrimidin-5-yl)ethynyl]benzoic acid and (1S,2S,4S)-2-amino-4-(trifluoromethoxy)cyclopentane-1-ol hydrochloride. MS (m / z): 459.1 [M+H] +

[0643] Example 263-[(1Z)-2-(5-aminopyrazin-2-yl)-2-fluorovinyl]-4-(difluoromethoxy)-N- [(5S,6S)-6-Hydroxyspiro[2.4]heptane-5-yl]benzamide

[0644] The title compound (32 mg) was obtained by the method of Example 1, except that 3-[(Z)-2-(5-aminopyrazin-2-yl)-2-fluorovinyl]-4-(difluoromethoxy)benzoic acid (30 mg) obtained in Step 2 of Reference Example 11 and (5S,6S)-6-aminospiro[2.4]heptan-5-ol hydrochloride (17 mg) obtained in Step 2 of Reference Example 24 were used instead of 4-(difluoromethoxy)-3-[(pyrimidin-5-yl)ethynyl]benzoic acid and (1S,2S,4S)-2-amino-4-(trifluoromethoxy)cyclopentane-1-ol hydrochloride. MS (m / z): 435.2 [M+H] +

[0645] Example 27 7-(5-{[(1S,2S)-5,5-difluoro-2-hydroxycyclohexyl]carbamoyl}-2-(trifluoromethyl)benzene yl)imidazo[1,5-a]pyridine-3-carboxamide

[0646] To a DMF (0.29 mL) solution of 3-(3-carbamoylimidazo[1,5-a]pyridin-7-yl)-4-(trifluoromethyl)benzoic acid (30 mg) obtained by step 3 of reference example 19, DIPEA (0.045 mL) and HBTU (42 mg) were added in sequence, and the mixture was stirred at room temperature for 15 minutes. Next, (1S,2S)-2-amino-4,4-difluorocyclohexane-1-ol hydrochloride (18 mg) obtained by step 6 of reference example 23 was added, and the mixture was stirred at room temperature for 2 hours. The reaction solution was purified by silica gel column chromatography to obtain the title compound (28 mg). MS (m / z): 483.2 [M+H] +

[0647] Example 28 7-(5-{[(5S,6S)-6-hydroxyspiro[2.4]heptane-5-yl]carbamoyl}-2-(trifluoromethyl) Phenyl)imidazo[1,5-a]pyridine-3-carboxamide

[0648] The title compound (26 mg) was obtained by the method of Example 27, except that (5S,6S)-6-aminospiro[2.4]heptane-5-ol hydrochloride (15 mg) obtained in step 2 of Reference Example 24 was used instead of (1S,2S)-2-amino-4,4-difluorocyclohexane-1-ol hydrochloride. MS (m / z): 459.2 [M+H] +

[0649] Example 297-(5-{[(1S,2S,4S)-2-hydroxy-4-(trifluoromethoxy)cyclopentyl]carbamoyl}-2-(trifluoromethoxy)cyclopentyl (fluoromethyl)phenyl)imidazo[1,5-a]pyridine-3-carboxamide

[0650] The title compound (23 mg) was obtained by the method of Example 27, except that (1S,2S,4S)-2-amino-4-(trifluoromethoxy)cyclopentane-1-ol hydrochloride (25 mg) obtained in step 4 of Reference Example 9 was used instead of (1S,2S)-2-amino-4,4-difluorocyclohexane-1-ol hydrochloride. MS (m / z): 517.1 [M+H]+

[0651] Example 305-{3-carbamoylimidazo[1,5-a]pyridin-7-yl}-N-[(2S)-1-hydroxy-4-(trifluoromethyl)- [(2-( ...

[0652] The title compound (31 mg) was obtained by the method of Example 15, except that (2S)-2-amino-4-(trifluoromethoxy)butane-1-ol hydrochloride (23 mg) obtained in step 3 of Reference Example 12 was used instead of (1S,2S,4S)-2-amino-4-(trifluoromethoxy)cyclopentane-1-ol hydrochloride. MS (m / z): 506.3 [M+H] +

[0653] Example 317-(5-{[(2S)-1-hydroxy-4-(trifluoromethoxy)butan-2-yl]carbamoyl}-2-(trifluoromethoxy)butane-2-yl methyl)phenyl)imidazo[1,5-a]pyridine-3-carboxamide

[0654] The title compound (22 mg) was obtained by the method of Example 27, except that (2S)-2-amino-4-(trifluoromethoxy)butane-1-ol hydrochloride (23 mg) obtained in step 3 of Reference Example 12 was used instead of (1S,2S)-2-amino-4,4-difluorocyclohexane-1-ol hydrochloride. MS (m / z): 505.1 [M+H] +

[0655] Example 32 N-(2-ethyl-5-{[(2S)-1-hydroxy-4-(trifluoromethoxy)butan-2-yl]carbamoyl}benzene 1-(4-(4-fluorophenyl)pyridine-3-carboxamide

[0656] The title compound (29 mg) was obtained by the method of Example 1, except that 4-ethyl-3-[5-(3-fluorophenyl)pyridine-3-amide]benzoic acid (30 mg) obtained in step 2 of Reference Example 25 and (2S)-2-amino-4-(trifluoromethoxy)butane-1-ol hydrochloride (19 mg) obtained in step 3 of Reference Example 12 were used instead of 4-(difluoromethoxy)-3-[(pyrimidin-5-yl)ethynyl]benzoic acid and (1S,2S,4S)-2-amino-4-(trifluoromethoxy)cyclopentane-1-ol hydrochloride to obtain the title compound (29 mg). MS (m / z): 520.3 [M+H] +

[0657] Example 33 N-(2-ethyl-5-{[(1S,2S,4S)-2-hydroxy-4-(trifluoromethoxy)cyclopentyl]carbamyl phenyl)-5-(3-fluorophenyl)pyridine-3-carboxamide

[0658] The title compound (26 mg) was obtained by the method of Example 1, except that 4-ethyl-3-[5-(3-fluorophenyl)pyridine-3-amide]benzoic acid (30 mg) obtained in Step 2 of Reference Example 25 was used instead of 4-(difluoromethoxy)-3-[(pyrimidin-5-yl)ethynyl]benzoic acid. MS (m / z): 532.3 [M+H] +

[0659] Example 343-[(1Z)-2-(2-aminopyrimidin-5-yl)-2-fluorovinyl]-4-(difluoromethoxy)-N- [(1S)-1-(3-Fluorophenyl)-2-hydroxyethyl]benzamide

[0660] The title compound (24 mg) was obtained by the method of Example 1, except that 3-[(1Z)-2-(2-aminopyrimidin-5-yl)-2-fluorovinyl]-4-(difluoromethoxy)benzoic acid (30 mg) and (2S)-2-amino-(3-fluorophenyl)ethanol (17 mg) obtained in Step 2 of Reference Example 26 were used instead of 4-(difluoromethoxy)-3-[(pyrimidin-5-yl)ethynyl]benzoic acid and (1S,2S,4S)-2-amino-4-(trifluoromethoxy)cyclopentan-1-ol hydrochloride. MS (m / z): 463.1 [M+H] +

[0661] Example 35 3-[2-(2-aminopyrimidin-5-yl)ethynyl]-N-[(2S)-1-(4-chlorophenyl)-3-hydroxypropane [2-Alkyl]-4-(difluoromethoxy)benzamide hydrochloride

[0662] 3-[2-(2-aminopyrimidin-5-yl)ethynyl]-N-[(2S)-1-(4-chlorophenyl)-3-hydroxypropan-2-yl]-4-(difluoromethoxy)benzamide (43 mg) was obtained by the method based on Example 1, except that 3-[(2-aminopyrimidin-5-yl)ethynyl]-4-(difluoromethoxy)benzoic acid (30 mg) and (3S)-3-amino-3-(4-chlorophenyl)-1-propanol (24 mg) obtained by Step 2 of Reference Example 5 were used instead of 4-(difluoromethoxy)-3-[(pyrimidin-5-yl)ethynyl]benzoic acid and (1S,2S,4S)-2-amino-4-(trifluoromethoxy)cyclopentan-1-ol hydrochloride. The obtained 3-[2-(2-aminopyrimidin-5-yl)ethynyl]-N-[(2S)-1-(4-chlorophenyl)-3-hydroxypropane-2-yl]-4-(difluoromethoxy)benzamide (43 mg) was dissolved in methanol (2 mL), and hydrogen chloride (4M 1,4-dioxane solution, 0.023 mL) was added, and stirred at room temperature for 20 minutes. The solvent was distilled off under reduced pressure to obtain the title compound (34 mg). MS (m / z): 473.4 [M+H] +

[0663] Example 36 3-[2-(2-aminopyrimidin-5-yl)ethynyl]-4-(difluoromethoxy)-N-[(1S)-2-hydroxy- 1-phenylethyl]benzamide hydrochloride

[0664] By the method based on Example 1, instead of 4-(difluoromethoxy)-3-[(pyrimidin-5-yl)ethynyl]benzoic acid and (1S,2S,4S)-2-amino-4-(trifluoromethoxy)cyclopentan-1-ol hydrochloride, 3-[(2-aminopyrimidin-5-yl)ethynyl]-4-(difluoromethoxy)benzoic acid (30 mg) and (2S)-2-amino-2-phenylethanol (16 mg) obtained by Step 2 of Reference Example 5 were used to obtain 3-[2-(2-aminopyrimidin-5-yl)ethynyl]-4-(difluoromethoxy)-N-[(1S)-2-hydroxy-1-phenylethyl]benzamide (33 mg). The obtained 3-[2-(2-aminopyrimidin-5-yl)ethynyl]-N-[(2S)-1-(4-chlorophenyl)-3-hydroxypropane-2-yl]-4-(difluoromethoxy)benzamide (33 mg) was dissolved in 1,4-dioxane (2 mL), and hydrogen chloride (4M 1,4-dioxane solution, 0.020 mL) was added, and stirred at room temperature for 20 minutes. The solvent was distilled off under reduced pressure to obtain the title compound (20 mg). MS (m / z): 425.5 [M+H] +

[0665] Example 373-[(1Z)-2-(2-aminopyrimidin-5-yl)-2-fluorovinyl]-N-[(1S,2S)-5,5-difluoro- 2-Hydroxycyclohexyl]-4-(difluoromethoxy)benzamide

[0666] The title compound (61 mg) was obtained by the method of Example 1, except that 3-[(1Z)-2-(2-aminopyrimidin-5-yl)-2-fluorovinyl]-4-(difluoromethoxy)benzoic acid (60 mg) obtained in Step 2 of Reference Example 26 and (1S,2S)-2-amino-4,4-difluorocyclohexane-1-ol hydrochloride (42 mg) obtained in Step 6 of Reference Example 23 were used instead of 4-(difluoromethoxy)-3-[(pyrimidin-5-yl)ethynyl]benzoic acid and (1S,2S,4S)-2-amino-4-(trifluoromethoxy)cyclopentane-1-ol hydrochloride. MS (m / z): 459.1 [M+H] +

[0667] Example 38 3-[(1Z)-2-(2-aminopyrimidin-5-yl)-2-fluorovinyl]-4-(difluoromethoxy)-N- [(1S,2S)-2-Hydroxycyclohexyl]benzamide

[0668] HATU (28 mg) and DIPEA (0.032 mL) were added to a DMF (0.12 mL) solution of 3-[(1Z)-2-(2-aminopyrimidin-5-yl)-2-fluorovinyl]-4-(difluoromethoxy)benzoic acid (20 mg) obtained by step 2 of reference example 26, and the mixture was stirred at room temperature for 5 minutes. Then, (1S,2S)-2-aminocyclohexanol hydrochloride (11 mg) was added and stirred at room temperature for 1.5 hours. Saturated aqueous sodium bicarbonate solution was added to the reaction solution, and the resulting precipitate was filtered to obtain the title compound (22 mg). MS (m / z): 423.3 [M+H] +

[0669] Example 393-[(1Z)-2-(2-aminopyrimidin-5-yl)-1-fluorovinyl]-4-(difluoromethoxy)-N- [(1S,2S,4S)-2-Hydroxy-4-(trifluoromethoxy)cyclopentyl]benzamide

[0670] The title compound (35 mg) was obtained by the method of Example 27, except that 3-[(Z)-2-(2-aminopyrimidin-5-yl)-1-fluorovinyl]-4-(difluoromethoxy)benzoic acid (30 mg) obtained in Step 2 of Reference Example 15 and (1S,2S,4S)-2-amino-4-(trifluoromethoxy)cyclopentane-1-ol hydrochloride (25 mg) obtained in Step 4 of Reference Example 9 were used instead of 3-(3-carbamoylimidazo[1,5-a]pyridin-7-yl)-4-(trifluoromethyl)benzoic acid and (1S,2S)-2-amino-4,4-difluorocyclohexane-1-ol hydrochloride. MS (m / z): 493.1 [M+H] +

[0671] Example 403-[(1Z)-2-(2-aminopyrimidin-5-yl)-1-fluorovinyl]-4-(difluoromethoxy)-N- [(5S,6S)-6-Hydroxyspiro[2.4]heptane-5-yl]benzamide

[0672] The title compound (25 mg) was obtained by the method of Example 1, except that 3-[(Z)-2-(2-aminopyrimidin-5-yl)-1-fluorovinyl]-4-(difluoromethoxy)benzoic acid (30 mg) obtained in Step 2 of Reference Example 15 and (5S,6S)-6-aminospiro[2.4]heptan-5-ol hydrochloride (18 mg) obtained in Step 2 of Reference Example 24 were used instead of 4-(difluoromethoxy)-3-[(pyrimidin-5-yl)ethynyl]benzoic acid and (1S,2S,4S)-2-amino-4-(trifluoromethoxy)cyclopentan-1-ol hydrochloride. MS (m / z): 435.2 [M+H] +

[0673] Example 415-{3-carbamoylimidazo[1,5-a]pyridin-7-yl}-N-[(1S,2S)-5,5-difluoro-2-hydroxy [[(1-(trifluoromethyl)-cyclohexyl)-6-(trifluoromethyl)pyridine-3-carboxamide]]

[0674] To a mixture of 5-(3-carbamoylimidazo[1,5-a]pyridin-7-yl)-6-(trifluoromethyl)pyridine-3-carboxylic acid (10 mg) obtained by step 2 of reference example 20 and dichloromethane (0.095 mL), TEA (0.016 mL), EDCI-HCl (55 mg) and HOBt (4 mg) were added in sequence, and stirred at room temperature for 5 minutes. Next, (1S,2S)-2-amino-4,4-difluorocyclohexane-1-ol hydrochloride (7 mg) obtained by step 6 of reference example 23 was added, and stirred overnight at room temperature. The reaction solution was purified by silica gel column chromatography to obtain the title compound (12 mg). MS (m / z): 484.3 [M+H] +

[0675] Example 425-(Cyclopropylmethoxy)-N-(2-ethyl-5-{[(1S,2S,4S)-2-hydroxy-4-(trifluoromethoxy)- 1-[(4-(4-yl)cyclopentyl]carbamoyl}phenyl)pyridine-3-carboxamide

[0676] The title compound (35 mg) was obtained by the method of Example 1, except that 3-[5-(cyclopropylmethoxy)pyridine-3-amide]-4-ethylbenzoic acid (30 mg) obtained in Step 2 of Reference Example 27 was used instead of 4-(difluoromethoxy)-3-[(pyrimidin-5-yl)ethynyl]benzoic acid. MS (m / z): 508.3 [M+H] +

[0677] Example 435-(Cyclopropylmethoxy)-N-(2-ethyl-5-{[(2S)-1-hydroxy-4-(trifluoromethoxy)butyl alkyl-2-yl]carbamoyl}phenyl)pyridine-3-carboxamide

[0678] The title compound (29 mg) was obtained by the method of Example 1, except that 3-[5-(cyclopropylmethoxy)pyridine-3-amide]-4-ethylbenzoic acid (30 mg) obtained in Step 2 of Reference Example 27 and (2S)-2-amino-4-(trifluoromethoxy)butane-1-ol hydrochloride (22 mg) obtained in Step 3 of Reference Example 12 were used instead of 4-(difluoromethoxy)-3-[(pyrimidin-5-yl)ethynyl]benzoic acid and (1S,2S,4S)-2-amino-4-(trifluoromethoxy)cyclopentane-1-ol hydrochloride to obtain the title compound (29 mg). MS (m / z): 496.2 [M+H] +

[0679] Example 44 2-[(Cyclopropylmethyl)amino]-N-(2-ethyl-5-{[(2S)-1-hydroxy-4-(trifluoromethoxy) ((2-Butane-2-yl]carbamoyl}phenyl)-1,3-thiazole-5-carboxamide)

[0680] The title compound (17 mg) was obtained by the method according to Example 1, except that 3-{2-[(cyclopropylmethyl)amino]-1,3-thiazole-5-amide}-4-ethylbenzoic acid (20 mg) obtained in Step 3 of Reference Example 28 and (2S)-2-amino-4-(trifluoromethoxy)butane-1-ol hydrochloride (13 mg) obtained in Step 3 of Reference Example 12 were used instead of 4-(difluoromethoxy)-3-[(pyrimidin-5-yl)ethynyl]benzoic acid and (1S,2S,4S)-2-amino-4-(trifluoromethoxy)cyclopentane-1-ol hydrochloride to obtain the title compound (17 mg). MS (m / z): 501.3 [M+H] +

[0681] Example 45 2-[(Cyclopropylmethyl)amino]-N-(2-ethyl-5-{[(1S,2S,4S)-2-hydroxy-4-(trifluoro 1,3-thiazole-5-carboxamide

[0682] The title compound (23 mg) was obtained by the method of Example 1, except that 3-{2-[(cyclopropylmethyl)amino]-1,3-thiazole-5-amide}-4-ethylbenzoic acid (20 mg) obtained in Step 3 of Reference Example 28 was used instead of 4-(difluoromethoxy)-3-[(pyrimidin-5-yl)ethynyl]benzoic acid. MS (m / z): 513.3 [M+H] +

[0683] Example 462-Cyclopropyl-N-(2-ethyl-5-{[(1S,2S,4S)-2-hydroxy-4-(trifluoromethoxy)cyclopentyl 1,3-thiazole-5-carboxamide

[0684] The title compound (29 mg) was obtained by the method of Example 1, except that 3-(2-cyclopropyl-1,3-thiazole-5-amide)-4-ethylbenzoic acid (30 mg) obtained in Step 2 of Reference Example 29 was used instead of 4-(difluoromethoxy)-3-[(pyrimidin-5-yl)ethynyl]benzoic acid. MS (m / z): 484.3 [M+H] +

[0685] Example 47 2-(Cyclopropylmethyl)-N-(2-ethyl-5-{[(2S)-1-hydroxy-4-(trifluoromethoxy)butane- 2-yl]carbamoyl}phenyl)-1,3-thiazole-5-carboxamide

[0686] The title compound (27 mg) was obtained by the method according to Example 1, except that 3-{[2-(cyclopropylmethyl)-1,3-thiazole-5-carbonyl]amino]-4-ethylbenzoic acid (30 mg) obtained in Step 2 of Reference Example 22 and (2S)-2-amino-4-(trifluoromethoxy)butane-1-ol hydrochloride (23 mg) obtained in Step 3 of Reference Example 12 were used instead of 4-(difluoromethoxy)-3-[(pyrimidin-5-yl)ethynyl]benzoic acid and (1S,2S,4S)-2-amino-4-(trifluoromethoxy)cyclopentane-1-ol hydrochloride to obtain the title compound (27 mg). MS (m / z): 486.1 [M+H] +

[0687] The structural formulas of Examples 1 to 47 are shown in Tables 1 to 4.

[0688] [Table 1]

[0689]

[0690] [Table 2]

[0691]

[0692] [Table 3]

[0693]

[0694] [Table 4]

[0695]

[0696] [Table 5]

[0697]

[0698] [Table 6]

[0699]

[0700] [Table 7]

[0701]

[0702] [Table 8]

[0703]

[0704] [Table 9]

[0705]

[0706] [Table 10]

[0707]

[0708] The following are biological test examples of the compounds used in the present invention.

[0709] <Test Example 1 Evaluation of DDR1 kinase inhibitory effect>

[0710] 1. Preparation of test substances

[0711] The test substance was prepared at 10 mM using dimethyl sulfoxide (DMSO, Nacalai Tesque, 13445-74), and 6 concentrations were selected for each compound and diluted with DMSO to give final concentrations of 1000, 100, 10, 1, 0.1, 0.01, and 0.001 μM, respectively. Furthermore, for the solution, 6 concentrations of each compound were selected and diluted in a buffer solution containing 50 mM HEPES (Fujifilm Wako Pure Chemical Industries, Ltd., 340-01371), 1 mM EGTA (DOJINDO, G002), 10 mM magnesium chloride hexahydrate (Nacalai Tesque, 20908-65), 2 mM dithiothreitol (Nacalai Tesque, 14112-52), and 0.01% Tween20 (Tokyo Chemical Industry, T0543) to obtain 330000, 33000, 330, 33, 3, 0.3, and 0.03 nM, to prepare a test substance solution.

[0712] 2. Determination of the Inhibition of Kinase Activity of DDR1 Kinase

[0713] Six concentrations were selected for each compound, and the prepared test substance solution was added to a 384-well plate (Corning, 4512) at 3 μL / well to a final concentration of 10000, 1000, 100, 10, 1, 0.1, and 0.01 nM. DDR1 protein (CarnaBiosciences, 08-113) was added at 2 μL / well to a final concentration of 0.5 nM. LANCE Ultra ULight TM -poly GAT (PerkinElmer, TRF0101) and ATP (SigmaAldrich, A6559) were mixed in a final concentration of 50nM and 100μM, respectively, and added at 5μL / well. After incubation at room temperature for 2 hours, LANCE Detection Buffer (PerkinElmer, CR97-100) containing EDTA (DOJINDO, K001) with a final concentration of 10mM and Europium (PerkinElmer, AD0068) with a final concentration of 1nM was added at 10μL / well. After incubation at room temperature for 1 hour, Envision (PerkinElmer) or SpectraMax iD5 (molecular sieve device) was used to measure the fluorescence intensity at 615nm and 665nm. The experiment was performed in duplicate.

[0714] 3. Analysis of measurement results

[0715] The value obtained by dividing the fluorescence intensity of 665 nM by the fluorescence intensity of 615 nM was calculated, and the inhibition rate of the test substance was calculated by setting the maximum inhibition rate of each test substance as 100% and the minimum inhibition rate as 0%. IC of the test substance 50 The value (50% inhibition concentration) was calculated by logistic regression analysis. The results of each example compound are shown in Table 5 below.

[0716] [Table 11]

[0717]

[0718] <Test Example 2 Evaluation of DDR1 kinase inhibitory effect in DDR1-expressing U2OS cells>

[0719] 1. Preparation of test substances

[0720] The test substance was prepared to 10 mM using DMSO, and diluted with DMSO to a final concentration of 1000, 100, 10, 1, and 0.1 μM. Furthermore, the solution was diluted to 60000, 6000, 600, 60, 6, and 0.6 nM using E-MEM medium (Fujifilm Wako Pure Chemical Industries, Ltd., 051-07615) containing 10% fetal bovine serum (FBS, Gibco, 10270106) to prepare a test substance solution.

[0721] 2. Assay for DDR1 Kinase Inhibition in DDR1-expressing U2OS Cells

[0722] DDR1-expressing U2OS cells (DiscoverX, 93-0894C3) suspended at 2.5×10^5 cells / mL in 10% FBS+E-MEM medium were seeded into 384-well plates (DiscoverX, 92-0013) at 20 μL per well and cultured overnight at 37°C and 5% CO2.

[0723] The next day, the prepared test substance solution was added at 5 μL / well to a final concentration of 10000, 1000, 100, 10, 1, and 0.1 nM, respectively. After culturing at 37°C and 5% CO2 for 1 hour, type I collagen (Nitta gelatin, 631-00771) was added at 5 μL / well to a final concentration of 50 μg / mL, and cultured at 37°C and 5% CO2 overnight.

[0724] The next day, the plate was left at room temperature for 1 hour, and then the detection solution was added at 5 μL / well according to the instructions for the PathHunter (registered trademark) Detection Kit (DiscoverX, 93-0001). After incubation at room temperature for 2 hours, the luminescence intensity was measured using Envision (PerkinElmer). The experiment was performed in duplicate.

[0725] 3. Analysis of measurement results

[0726] The blank (type I collagen stimulation only) was set as 100%, and the negative control group (no type I collagen stimulation) was set as 0%, and the inhibition rate based on the test substance was calculated. IC of the test substance 50 The value (50% inhibition concentration) was calculated by logistic regression analysis. The results of each example compound are shown in Table 6 below.

[0727] [Table 12]

[0728]

[0729] <Test Example 3: Study of in vivo drug efficacy using anti-glomerular basement membrane antibody-induced nephritis model>

[0730] 1. Preparation of test substances

[0731] The test substance was weighed and suspended in 0.5% methylcellulose (Shin-Etsu Chemical Co., Ltd.) + 99.5% Otsuka distilled water (Otsuka Pharmaceutical Co., Ltd.) to prepare a test substance administration solution.

[0732] 2. Preparation of Animal Model

[0733] Phosphate buffered saline (Wako, 045-29795) containing 33.3 μg / mL of anti-glomerular basement membrane antibody (Chondrex, 70221) was administered to WKY / NCrlCrlj rats (7-week-old male) via the tail vein in a dose of 300 μL per rat. The test substance was administered twice a day for 7 days after the administration, and the rats were transferred to the metabolic chamber from the 6th day to the 7th day after the administration. · The urine was collected in a urine collection cage for 24 hours and the weight of the collected urine was measured.

[0734] 3. Determination of albumin in urine

[0735] 150 μL of urine was transferred to a sample cup (650-M, BMBio ST). The concentration of albumin in urine was quantified using a JCA-BM6050 automatic analyzer (JEOL). The measured urine weight was used for correction and the amount of albumin in urine was calculated.

[0736] 4. Analysis of measurement results

[0737] The urinary albumin amounts in the anti-glomerular basement membrane antibody non-administration group and the vehicle-administration group were set to 0% and 100%, respectively, and the ratio of the urinary albumin amount in the test substance-administered group was calculated.

[0738] [Table 13]

[0739]

Claims

1. A compound represented by the following formula [1] or a pharmaceutically acceptable salt or solvate thereof, [Chemistry 1] In formula [1], R 1 is one or two groups selected from a hydrogen atom, a halogen atom, an optionally substituted alkyl group, an optionally substituted amino group, an optionally substituted alkoxy group, an optionally substituted aryl group, a haloalkyl group, a cycloalkyl group, an optionally substituted sulfonyl group, a cyano group, an optionally substituted carbamoyl group, a heteroaryl group and a dialkylphosphoryl group, Het is a 5- to 10-membered heteroaryl group, L 1 For connecting bonds, -CO-NH-, -CR a =CR b -or-C≡C-, Here, the carbonyl group (C=O) of -CO-NH- is bonded to Het, -CR a =CR b -of-CR a Bonded to Het, R a is a hydrogen atom or a halogen atom, R b is a hydrogen atom or a halogen atom, X is N or CR c , Here, R c is a hydrogen atom or a halogen atom, R 2 is a hydrogen atom, an ethyl group, a C1-C6 haloalkoxy group or a C1-C6 haloalkyl group, R 3 is a hydrogen atom, R 4 is a hydrogen atom, optionally substituted phenyl or optionally substituted alkyl, or, R 3 and R 4 Together with the carbon atom to which they are bonded, they form a C3-C8 cycloalkyl group which may be substituted.

2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein: R 1 is one or two groups selected from a hydrogen atom, a halogen atom, an optionally substituted alkyl group, an optionally substituted amino group, an optionally substituted alkoxy group, an optionally substituted aryl group, a haloalkyl group, and an optionally substituted carbamoyl group, Het is a 5- to 10-membered heteroaryl group, L 1 For the connection key, -CR a =CR b -, -CO-NH- or -C≡C-, Here, the carbonyl group (C=O) of -CO-NH- is bonded to Het, -CR a =CR b -of-CR a Bonded to Het, R a is a hydrogen atom or a halogen atom, R b is a hydrogen atom or a halogen atom, X is N or CR c , R c is a hydrogen atom or a halogen atom, R 2 is ethyl, C1-C6 haloalkoxy or C1-C6 haloalkyl, R 3 is a hydrogen atom, R 4 is a hydrogen atom, optionally substituted phenyl or optionally substituted alkyl, R 3 and R 4 Together with the carbon atom to which they are bonded, they form a C3-C8 cycloalkyl group which may be substituted.

3. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein: R 1 is one or two groups selected from the group consisting of a hydrogen atom, an optionally substituted alkyl group, an optionally substituted amino group, and an optionally substituted carbamoyl group, Het is a 5- to 10-membered heteroaryl group, L 1 For the connection key, -CR a =CR b -or-C≡C-, Here, -CR a =CR b -of-CR a Bonded to Het, R a is a hydrogen atom, R b is a halogen atom, X is N or CR c , R c is a hydrogen atom, R 2 is C1-C6 haloalkoxy or C1-C6 haloalkyl, R 3 and R 4 Together with the carbon atom to which they are bonded, they form a C3-C8 cycloalkyl group which may be substituted.

4. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein: R 1 are one or two groups selected from a hydrogen atom, an alkyl group, an amino group, and a carbamoyl group, Het is pyrimidinyl, pyridyl, pyrazinyl, pyrazolyl, pyridinyl, imidazo[1,5-a]pyridinyl, oxazolyl, thiazolyl, pyrazyl, L 1 For the connection key, -CR a =CR b -or-C≡C-, Here, -CR a =CR b -of-CR a Bonded to Het, R a is a hydrogen atom, R b is a halogen atom, X is N or CR c , R c is a hydrogen atom, R 2 is C1-C6 fluoroalkoxy, C1-C6 difluoroalkoxy, C1-C6 trifluoroalkoxy, C1-C6 fluoroalkyl, C1-C6 difluoroalkyl or C1-C6 trifluoroalkyl, R 3 and R 4 Together with the carbon atom to which they are bound, they form an optionally substituted cyclopentyl, an optionally substituted cyclohexyl or an optionally substituted spiro[2.4]heptyl.

5. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein: R 1 is a group selected from a hydrogen atom, an alkyl group, an amino group, and a carbamoyl group, Het is pyrimidinyl, pyridyl, pyrazinyl, pyrazolyl, pyridinyl, imidazo[1,5-a]pyridinyl, oxazolyl, thiazolyl, pyrazyl, L 1 For the connection key, -CR a =CR b -or-C≡C-, Here, -CR a =CR b -of-CR a Bonded to Het, R a is a hydrogen atom, R b is a halogen atom, X is N or CR c , R c is a hydrogen atom, R 2 is C1-C6 fluoroalkoxy, C1-C6 difluoroalkoxy, C1-C6 trifluoroalkoxy, C1-C6 fluoroalkyl, C1-C6 difluoroalkyl or C1-C6 trifluoroalkyl, R 3 and R 4 Together with the carbon atoms to which they are bonded, they form a cyclopentyl group substituted with one or two groups selected from halogen and haloalkoxy, a cyclohexyl group substituted with one or two groups selected from halogen and haloalkoxy, or a spiro[2.4]heptyl group substituted with one or two groups selected from halogen and haloalkoxy.

6. A compound selected from the following compounds (1) to (47) or a pharmaceutically acceptable salt or solvate thereof, (1) 4-(difluoromethoxy)-N-[(1S,2S,4S)-2-hydroxy-4-(trifluoromethoxy)cyclopentyl]-3-[(pyrimidin-5-yl)ethynyl]benzamide, (2) 4-(difluoromethoxy)-3-[2-(5-fluoropyridin-3-yl)ethynyl]-N-[(1S,2S,4S)-2-hydroxy-4-(trifluoromethoxy)cyclopentyl]benzamide, (3) 3-[2-(2-aminopyrimidin-5-yl)ethynyl]-4-(difluoromethoxy)-N-[(1S,2S,4S)-2-hydroxy-4-(trifluoromethoxy)cyclopentyl]benzamide, (4) 3-[2-(5-aminopyrazin-2-yl)ethynyl]-4-(difluoromethoxy)-N-[(1S,2S,4S)-2-hydroxy-4-(trifluoromethoxy)cyclopentyl]benzamide, (5) 3-[2-(2-Amino-4-methoxypyrimidin-5-yl)ethynyl]-4-(difluoromethoxy)-N-[(1S,2S,4S)-2-hydroxy-4-(trifluoromethoxy)cyclopentyl]benzamide. (6) 4-(difluoromethoxy)-N-[(1S,2S,4S)-2-hydroxy-4-(trifluoromethoxy)cyclopentyl]-3-[2-(1-methyl-1H-pyrazol-4-yl)ethynyl]benzamide, (7) 3-[2-(5-aminopyrazin-2-yl)ethynyl]-4-(difluoromethoxy)-N-[(2S)-1-hydroxy-4-(trifluoromethoxy)butane-2-yl]benzamide, (8) 3-[2-(2-aminopyrimidin-5-yl)ethynyl]-4-(difluoromethoxy)-N-[(1S)-1-(3-fluorophenyl)-2-hydroxyethyl]benzamide, (9) 3-[2-(2-aminopyrimidin-5-yl)ethynyl]-4-(difluoromethoxy)-N-[(2S)-1-hydroxy-3-(4-methoxyphenyl)propan-2-yl]benzamide, (10) 3-[(1Z)-2-(5-aminopyrazin-2-yl)-2-fluorovinyl]-4-(difluoromethoxy)-N-[(1S,2S,4S)-2-hydroxy-4-(trifluoromethoxy)cyclopentyl]benzamide, (11) 5-[(1Z)-2-(2-aminopyrimidin-5-yl)-2-fluorovinyl]-6-ethyl-N-[(1S,2S,4S)-2-hydroxy-4-(trifluoromethoxy)cyclopentyl]pyridine-3-carboxamide, (12) 3-[(1Z)-2-(2-aminopyrimidin-5-yl)-1-fluorovinyl]-4-(difluoromethoxy)-N-[(2S)-1-hydroxy-4-(trifluoromethoxy)butane-2-yl]benzamide, (13) 4-(difluoromethoxy)-3-fluoro-5-[(1Z)-1-fluoro-2-(5-methoxypyridin-3-yl)vinyl]-N-[(1S,2S,4S)-2-hydroxy-4-(trifluoromethoxy)cyclopentyl]benzamide, (14) 7-(5-{[(1S,2S)-2-hydroxycyclohexyl]carbamoyl}-2-(trifluoromethyl)phenyl)imidazo[1,5-a]pyridine-3-carboxamide, (15) 5-{3-carbamoylimidazo[1,5-a]pyridin-7-yl}-N-[(1S,2S,4S)-2-hydroxy-4-(trifluoromethoxy)cyclopentyl]-6-(trifluoromethyl)pyridine-3-carboxamide, (16) N-(2-ethyl-5-{[(1S,2S,4S)-2-hydroxy-4-(trifluoromethoxy)cyclopentyl]carbamoyl}phenyl)-2-phenyl-1,3-oxazole-5-carboxamide, (17) 2-(cyclopropylmethyl)-N-(2-ethyl-5-{[(1S,2S,4S)-2-hydroxy-4-(trifluoromethoxy)cyclopentyl]carbamoyl}phenyl)-1,3-thiazole-5-carboxamide, (18) 4-(difluoromethoxy)-N-[(5S,6S)-6-hydroxyspiro[2.4]heptane-5-yl]-3-[2-(pyrimidin-5-yl)ethynyl]benzamide, (19) 4-(difluoromethoxy)-3-[2-(5-fluoropyridin-3-yl)ethynyl]-N-[(5S,6S)-6-hydroxyspiro[2.4]heptane-5-yl]benzamide, (20) 3-[2-(2-aminopyrimidin-5-yl)ethynyl]-N-[(1S,2S)-5,5-difluoro-2-hydroxycyclohexyl]-4-(difluoromethoxy)benzamide, (21) 3-[2-(2-aminopyrimidin-5-yl)ethynyl]-4-(difluoromethoxy)-N-[(5S,6S)-6-hydroxyspiro[2.4]heptane-5-yl]benzamide, (22) 3-[2-(2-aminopyrimidin-5-yl)ethynyl]-4-(difluoromethoxy)-N-[(2S)-1-hydroxy-4-(trifluoromethoxy)butan-2-yl]benzamide, (23) 3-[2-(2-amino-4-methoxypyrimidin-5-yl)ethynyl]-4-(difluoromethoxy)-N-[(5S,6S)-6-hydroxyspiro[2.4]heptane-5-yl]benzamide, (24) 4-(difluoromethoxy)-N-[(2S)-1-hydroxy-4-(trifluoromethoxy)butane-2-yl]-3-[2-(1-methyl-1H-pyrazol-4-yl)ethynyl]benzamide, (25) 3-[(1Z)-2-(5-aminopyrazin-2-yl)-2-fluorovinyl]-N-[(1S,2S)-5,5-difluoro-2-hydroxycyclohexyl]-4-(difluoromethoxy)benzamide, (26) 3-[(1Z)-2-(5-aminopyrazin-2-yl)-2-fluorovinyl]-4-(difluoromethoxy)-N-[(5S,6S)-6-hydroxyspiro[2.4]heptane-5-yl]benzamide, (27) 7-(5-{[(1S,2S)-5,5-difluoro-2-hydroxycyclohexyl]carbamoyl}-2-(trifluoromethyl)phenyl)imidazo[1,5-a]pyridine-3-carboxamide, (28) 7-(5-{[(5S,6S)-6-hydroxyspiro[2.4]heptane-5-yl]carbamoyl}-2-(trifluoromethyl)phenyl)imidazo[1,5-a]pyridine-3-carboxamide, (29) 7-(5-{[(1S,2S,4S)-2-hydroxy-4-(trifluoromethoxy)cyclopentyl]carbamoyl}-2-(trifluoromethyl)phenyl)imidazo[1,5-a]pyridine-3-carboxamide, (30) 5-{3-carbamoylimidazo[1,5-a]pyridin-7-yl}-N-[(2S)-1-hydroxy-4-(trifluoromethoxy)butane-2-yl]-6-(trifluoromethyl)pyridine-3-carboxamide, (31) 7-(5-{[(2S)-1-hydroxy-4-(trifluoromethoxy)butan-2-yl]carbamoyl}-2-(trifluoromethyl)phenyl)imidazo[1,5-a]pyridine-3-carboxamide, (32) N-(2-ethyl-5-{[(2S)-1-hydroxy-4-(trifluoromethoxy)butan-2-yl]carbamoyl}phenyl)-5-(3-fluorophenyl)pyridine-3-carboxamide, (33) N-(2-ethyl-5-{[(1S,2S,4S)-2-hydroxy-4-(trifluoromethoxy)cyclopentyl]carbamoyl}phenyl)-5-(3-fluorophenyl)pyridine-3-carboxamide, (34) 3-[(1Z)-2-(2-aminopyrimidin-5-yl)-2-fluorovinyl]-4-(difluoromethoxy)-N-[(1S)-1-(3-fluorophenyl)-2-hydroxyethyl]benzamide, (35) 3-[2-(2-aminopyrimidin-5-yl)ethynyl]-N-[(2S)-1-(4-chlorophenyl)-3-hydroxypropane-2-yl]-4-(difluoromethoxy)benzamide hydrochloride, (36) 3-[2-(2-aminopyrimidin-5-yl)ethynyl]-4-(difluoromethoxy)-N-[(1S)-2-hydroxy-1-phenylethyl]benzamide hydrochloride, (37) 3-[(1Z)-2-(2-aminopyrimidin-5-yl)-2-fluorovinyl]-N-[(1S,2S)-5,5-difluoro-2-hydroxycyclohexyl]-4-(difluoromethoxy)benzamide, (38) 3-[(1Z)-2-(2-aminopyrimidin-5-yl)-2-fluorovinyl]-4-(difluoromethoxy)-N-[(1S,2S)-2-hydroxycyclohexyl]benzamide, (39) 3-[(1Z)-2-(2-aminopyrimidin-5-yl)-1-fluorovinyl]-4-(difluoromethoxy)-N-[(1S,2S,4S)-2-hydroxy-4-(trifluoromethoxy)cyclopentyl]benzamide, (40) 3-[(1Z)-2-(2-aminopyrimidin-5-yl)-1-fluorovinyl]-4-(difluoromethoxy)-N-[(5S,6S)-6-hydroxyspiro[2.4]heptane-5-yl]benzamide, (41) 5-{3-carbamoylimidazo[1,5-a]pyridin-7-yl}-N-[(1S,2S)-5,5-difluoro-2-hydroxycyclohexyl]-6-(trifluoromethyl)pyridine-3-carboxamide, (42) 5-(cyclopropylmethoxy)-N-(2-ethyl-5-{[(1S,2S,4S)-2-hydroxy-4-(trifluoromethoxy)cyclopentyl]carbamoyl}phenyl)pyridine-3-carboxamide, (43) 5-(cyclopropylmethoxy)-N-(2-ethyl-5-{[(2S)-1-hydroxy-4-(trifluoromethoxy)butan-2-yl]carbamoyl}phenyl)pyridine-3-carboxamide, (44) 2-[(cyclopropylmethyl)amino]-N-(2-ethyl-5-{[(2S)-1-hydroxy-4-(trifluoromethoxy)butan-2-yl]carbamoyl}phenyl)-1,3-thiazole-5-carboxamide, (45) 2-[(Cyclopropylmethyl)amino]-N-(2-ethyl-5-{[(1S,2S,4S)-2-hydroxy-4-(trifluoromethoxy)cyclopentyl]carbamoyl}phenyl)-1,3-thiazole-5-carboxamide, (46) 2-cyclopropyl-N-(2-ethyl-5-{[(1S,2S,4S)-2-hydroxy-4-(trifluoromethoxy)cyclopentyl]carbamoyl}phenyl)-1,3-thiazole-5-carboxamide, (47) 2-(Cyclopropylmethyl)-N-(2-ethyl-5-{[(2S)-1-hydroxy-4-(trifluoromethoxy)butan-2-yl]carbamoyl}phenyl)-1,3-thiazole-5-carboxamide.

7. A pharmaceutical composition comprising the compound according to claim 1 or a pharmaceutically acceptable salt or solvate thereof as an active ingredient.

8. A DDR1 kinase inhibitor comprising the compound according to claim 1 or a pharmaceutically acceptable salt or solvate thereof as an active ingredient.

9. A method for inhibiting DDR1 kinase, comprising administering the compound according to claim 1 or a pharmaceutically acceptable salt or solvate thereof to a subject in need thereof. 10 . A preventive or therapeutic agent for a disease associated with DDR1 kinase, comprising the compound according to claim 1 or a pharmaceutically acceptable salt or solvate thereof.

11. A therapeutic agent for Alport syndrome, IgA nephropathy, Goodpasture syndrome, anti-glomerular basement membrane nephritis, lupus nephritis, ANCA-associated nephritis, diabetic nephropathy, purpuric nephritis, focal segmental glomerulosclerosis, chronic renal failure, minimal change nephrotic syndrome, mesangial proliferative glomerulonephritis, membranoproliferative glomerulonephritis, crescentic glomerulonephritis, membranous nephropathy, pulmonary fibrosis, myelofibrosis, hepatic fibrosis, acute myeloid leukemia, chronic myeloid leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma, glioma, non-small cell lung cancer, small cell lung cancer, breast cancer, ovarian cancer, prostate cancer, colorectal cancer or osteoarthritis, comprising the compound according to claim 1 or a pharmaceutically acceptable salt thereof or a solvate thereof as an active ingredient.

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