aryl or heteroaryl derivatives

Abstract

As a compound that can be used as a therapeutic or preventative agent for diseases involving TRPC6, such as nephrotic syndrome, membranous nephropathy, acute renal failure, sepsis, chronic renal failure, diabetic nephropathy, pulmonary hypertension, acute lung injury, heart failure, malignant tumors, and muscular dystrophy, a compound of formula (I) or a pharmaceutically acceptable salt thereof is provided (where Ar... 1 Ar 2 X 1 ~X 3 R 1 R 3 R 7 R 8 and L 1 L 2 (As defined in the instruction manual).

Description

Technical Field

[0001] This invention relates to aryl or heteroaryl derivatives useful as pharmaceuticals. More specifically, it relates to aryl or heteroaryl derivatives or pharmaceutically acceptable salts thereof useful for the treatment or prevention of diseases in which TRPC6 inhibitors may be involved, such as nephrotic syndrome, membranous nephropathy, acute renal failure, sepsis, chronic renal failure, diabetic nephropathy, pulmonary hypertension, acute lung injury, heart failure, malignancy, or muscular dystrophy. Background Technology

[0002] TRPC6 channels, members of the transient receptor potential (TRP) family of non-selective cation permeation channels, are activated by diacylglycerols produced by phospholipase C activation, exerting physiological and pathophysiological functions. TRPC6 plays a role in pathological hypertrophy and fibrosis of the heart, progression of myocardial dysfunction in muscular dystrophy, acute pulmonary vasoconstriction, progression of chronic hypoxia-induced pulmonary hypertension, allergic immune responses, cell migration of neutrophils, increased permeability during endothelial cell inflammation, pathological flattening of podocytes and progression of glomerular dysfunction, and growth or infiltration of malignant tumors. It is distributed in various locations including the brain, heart, lungs, kidneys, placenta, ovaries, and spleen (Non-Patent Literature 1-13). In familial focal segmental glomerulosclerosis (FSGS), gain-of-function variants of TRPC6 have been identified. In patients with idiopathic nephrotic syndrome or idiopathic pulmonary artery hypertension, promoter region variants that increase TRPC6 mRNA expression have been identified. Therefore, it is believed that hyperfunction or elevated expression of TRPC6 contributes to the progression of nephrotic syndrome, pulmonary hypertension, etc. (Non-Patent Literature 14–22). Furthermore, elevated TRPC6 expression has been reported in minimal change nephrotic syndrome, membranous nephropathy, and diabetic nephropathy (Non-Patent Literature 23–24). Therefore, TRPC6 inhibitors that inhibit ion influx via the TRPC6 channel are expected to be useful for the prevention and / or treatment of nephrotic syndrome, membranous nephropathy, acute renal failure, sepsis, chronic renal failure, diabetic nephropathy, pulmonary hypertension, acute lung injury, heart failure, malignancies, and muscular dystrophy.

[0003] Compounds that inhibit TRPC6 are described in patent documents 1 to 11.

[0004] Existing technical documents

[0005] Patent documents

[0006] Patent Document 1: International Publication No. 2011 / 107474;

[0007] Patent Document 2: International Publication No. 2012 / 037349;

[0008] Patent Document 3: International Publication No. 2012 / 037351;

[0009] Patent document 4: International Publication No. 2014 / 016766;

[0010] Patent document 5: Chinese application publication No. 104292233;

[0011] Patent document 6: Chinese application publication No. 106317050;

[0012] Patent document 7: Chinese application publication No. 107253952;

[0013] Patent document 8: International Publication No. 2019 / 079578;

[0014] Patent document 9: International Publication No. 2019 / 081637;

[0015] Patent Document 10: International Publication No. 2019 / 158572;

[0016] Patent Document 11: International Publication No. 2019 / 161010;

[0017] Non-patent literature

[0018] Non-patent literature 1: J. Clin. Invest. 116:3114-3126, 2006;

[0019] Non-patent literature 2: Dev.Cell.23:705-715,2012;

[0020] Non-patent literature 3: Circ.Res.114:823-832,2014;

[0021] Non-patent literature 4: Proc.Natl.Acd.Sci.USA 103:19093-19098,2006;

[0022] Non-patent literature 5: J. Cardiovasc. Pharmacol. 57:140-147, 2011;

[0023] Non-patent literature 6: Hypertension 63:173-80, 2014;

[0024] Non-patent literature 7: Clin. Exp. Allergy 38:1548-1558, 2008;

[0025] Non-patent literature 8: Acta. Physiol. 195:3-11, 2009;

[0026] Non-patent literature 9: J.Exp.Med.209:1953-1968,2011;

[0027] Non-patent literature 10: Arterioscler. Thromb. Vasc. Biol. 33: 2121-2129, 2013;

[0028] Non-patent literature 11: PLoS ONE 5:e12859,2010;

[0029] Non-patent literature 12: Expert. Opin. Ther. Targets. 14:513-27, 2010;

[0030] Non-patent literature 13: BMC Cancer 13:116,2013;

[0031] Non-patent literature 14: Science 308:1801-1804, 2005;

[0032] Non-patent literature 15: Nat. Genet. 37:739-744, 2005;

[0033] Non-patent literature 16: PLoS One 4: e7771, 2009;

[0034] Non-patent literature 17: Clin. J. Am. Soc. Nephrol. 6: 1139-1148, 2011;

[0035] Non-patent literature 18: Mol. Biol. Cell. 22: 1824-1835, 2011;

[0036] Non-patent literature 19: BMC Nephrol. 14:104, 2013;

[0037] Non-patent literature 20: Pediatr.Res.74:511-516,2013;

[0038] Non-patent literature 21: Nephrol. Dial. Transplant. 28:1830-1838, 2013;

[0039] Non-patent literature 22: Circulation 119:2313-2322, 2009;

[0040] Non-patent literature 23: J.Am.Soc.Nephrol.18:29-36,2007;

[0041] Non-patent literature 24: Mol Immunol. Feb; 94:75-81, 2018. Summary of the Invention

[0042] The problem that the invention aims to solve

[0043] The subject of this invention is to provide novel compounds having TRPC6 inhibitory activity or pharmaceutically acceptable salts thereof, as well as pharmaceutical compositions comprising them and therapeutic or preventative agents for diseases in which TRPC6 is involved.

[0044] Methods for solving problems

[0045] The inventors conducted in-depth research for the above-mentioned purposes and as a result completed the following invention.

[0046] [1] The compound represented by formula (I) or its pharmaceutically acceptable salt:

[0047] [Chemical Formula 1]

[0048]

[0049] In the formula,

[0050] X 1 X 2 and X 3 Independently CH, N, or CY;

[0051] X 1 X 2 and X 3 At least one of them is CH or CY;

[0052] Y is a halogen atom, or C can be replaced by 1 to 3 halogen atoms. 1-3 alkyl;

[0053] R 1 It consists of a cyano group, a fluorine atom, or a chlorine atom;

[0054] L 1 is -O-, -S-, -SO-, -CH(R 11 -, -C(=CH2)-, -CO-, 1,1-cyclopropylene, or -NR 12 -;

[0055] R 11 A carbon atom consisting of a hydrogen atom, a hydroxyl group, and a carbon atom that can be substituted by 1 to 3 halogen atoms. 1-3 Alkyl groups, or C groups that can be substituted with 1 to 2 cyano groups. 1-3 Alkoxy;

[0056] R 12 C is a hydrogen atom, or a carbon atom that can be replaced by 1 to 3 halogen atoms. 1-3 alkyl;

[0057] Ar 1 R can be 1 to 3 2 Substituted nitrogen-containing heteroaromatic rings;

[0058] R 2 C that is independently a halogen atom, a cyano group, or a C that can be substituted by 1 to 3 halogen atoms. 1-4 alkyl;

[0059] R 3 It consists of hydrogen atoms, halogen atoms, amino groups, cyano groups, carboxyl groups, and (C) 1-3 alkylcarbonyl)amino, (C 1-6 alkylamino)carbonyl, di(C 1-3 alkyl)aminocarbonyl, (C 1-3 alkoxy)carbonyl, (C 3-8 cycloalkyl)amino, (C 3-8 Heterocyclic alkyl)amino, C 3-8 Cycloalkyl, 3- to 8-membered heterocyclic alkyloxy groups, can be substituted by 1 to 6 R groups. 31 Replacement C 3-8 Cycloalkyloxy groups, which can be oxidized by 1 to 6 R groups 31 Replacement C 1-6 Alkyl groups, which can be 1 to 6 R groups 31 Replacement C 1-6 Alkyl groups can be oxidized by 1 to 6 R groups. 31 Replaced by two (C) 1-6 Alkyl)amino, can be 1-6 R 31 Replacement (C) 1-6 Alkyl)amino, can be 1 to 4 R 32 Substituted 3- to 8-membered heterocyclic alkyl groups, which can be substituted with 1 to 4 R groups. 32 Substituted aryl groups, or those with 1 to 4 R groups. 32 Substituted heteroaryl groups;

[0060] R 31 Independently, a halogen atom, hydroxyl group, cyclopropylidene group, or a C group that can be substituted by 1 to 3 halogen atoms. 3-8 Cycloalkyl, 3-8 membered heterocyclic alkyl, oxobutanediyl, C 1-4 Alkyloxy or 3- to 8-membered cycloalkyloxy groups;

[0061] R 32 C atoms that are independently halogen atoms, hydroxyl groups, acetylamino groups, or C atoms that can be substituted by 1 to 3 halogen atoms. 1-3 Alkyl groups, C atoms that can be substituted with 1 to 3 halogen atoms 1-3Alkoxy, oxo, cyano, carboxyl, (C 1-3 alkoxy)carbonyl, (C 1-3 Alkyl)sulfonyl, carboxamide, or benzyloxy;

[0062] In R 2 and R 3 with Ar 1 In the case of neighboring atomic bonding, R 2 and R 3 Ar can be bonded to them via single bonds or -O- bonds. 1 The atoms together form 5- to 7-membered rings;

[0063] Ar 2 R can be 1 to 4 4 Substituted aromatic rings, or those that can be replaced by 1–4 R 4 Substituted heterocyclic aromatic rings;

[0064] R 4 Independently, it can be a halogen atom, hydroxyl group, carboxyl group, cyano group, cyanomethyl group, amino group, or di(C) group. 1-3 Alkyl)amino, C atoms that can be substituted with 1 to 3 halogen atoms 1-3 Alkyl, or C 1-3 Alkoxy;

[0065] L 2 It is a single bond, which can be bound by 1 to 3 Rs. 21 Replacement C 1-6 Alkylene, which can be denoted by 1 to 3 R 21 Replacement C 3-8 Cycloalkylene, or can be 1 to 3 R 21 Substituted 4- to 8-membered heterocyclic alkylene groups;

[0066] L 2 Ar can be placed at any position and at both ends of it. 2 and -NR 7 R 8 Bonding;

[0067] Located in L 2 one sp at any position 3 Carbon atoms can be -O- or -NR 22 -Structural substitution;

[0068] R 21 Independently representing halogen atoms, hydroxyl groups, oxo groups, cyano groups, 1,1-cyclopropylene, oxetanediol, carboxyl groups, carboxamide groups, and C groups that can be substituted by 1 to 3 halogen atoms. 1-6 Alkyl, C 3-8 cycloalkyl, C 1-6 Alkoxy, (C 1-3 Alkoxy)C1-3 Alkyl, (C 1-3 Alkoxy)C 1-3 Alkyl, (hydroxy) C 1-6 Alkyl, (carboxyl) C 1-3 Alkyl, (carboxyl) C 1-3 Alkoxy, (C 1-3 alkoxy)carbonyl, (C 1-3 alkoxycarbonyl)C 1-3 Alkyl, (C 1-6 alkylamino)carbonyl, di(C 1-3 Alkyl)aminocarbonyl, phenyl that can be substituted with 1 to 3 halogen atoms, heteroaryl that can be substituted with 1 to 3 halogen atoms, or phenoxy that can be substituted with 1 to 3 halogen atoms;

[0069] R 22 It is a hydrogen atom or a carbon atom. 1-3 alkyl;

[0070] L 2 and R 7 It can be achieved via single bonds, -O-, or -S (=O). n - or -NR 23 - Bonded together to form L 2 and R 7 The bonded nitrogen atom is a 4- to 8-membered ring, and this ring can be replaced by 1 to 3 halogen atoms or 1 to 2 hydroxyl groups;

[0071] n represents an integer from 0 to 2;

[0072] R 23 It is a hydrogen atom or a carbon atom. 1-3 alkyl;

[0073] In L 2 and R 4 with Ar 2 In the case of adjacent atoms bonded together, Ar atoms that are bonded to them can... 2 Atoms together form 5- to 8-membered rings via single bonds or -O-;

[0074] R 7 It is a hydrogen atom or a C atom 1-3 alkyl;

[0075] R 7 and Ar 2 The atoms can form 5- to 8-membered rings through single bond bonding;

[0076] R 8 For hydrogen atoms, C 1-6 Alkyl, adamantyl, C 1-6 Cycloalkyl, cyanomethyl, oxetane, (C 1-3alkylamino)carbonylmethyl, di(C 1-3 alkyl)aminocarbonylmethyl, (C 1-3 (alkylamino)C 1-8 Alkyl, di(C) 1-3 alkyl)aminoC 1-8 Alkyl, (hydroxy) C 1-8 Alkyl, (carboxyl) C 1-3 Alkyl, (C 1-3 alkoxycarbonyl)C 1-3 Alkyl, or (C 1-3 Alkoxy)C 1-3 alkyl;

[0077] R 7 and R 8 They can be connected via single bonds, -O-, or -S (=O). m - or -NR 41 - Bonding forms a 3- to 8-membered ring, and this ring can be formed by amino groups, oxo groups, or C groups. 1-3 Alkyl substitution;

[0078] m represents an integer from 0 to 2;

[0079] R 41 It is a hydrogen atom or a C atom 1-3 alkyl.

[0080] [2][1] The compound or a pharmaceutically acceptable salt thereof, wherein X 1 X 2 and X 3 For CH.

[0081] The compound described in [3][1] or [2] or a pharmaceutically acceptable salt thereof, wherein R 1 It is a cyano group.

[0082] The compound described in [4][1] or [2] or a pharmaceutically acceptable salt thereof, wherein R 1 It is a fluorine atom.

[0083] The compound or a pharmaceutically acceptable salt thereof described in any one of [5][1] to [4], wherein Ar 1 The nitrogen-containing heteroaryl ring is:

[0084] [Chemical Formula 2]

[0085]

[0086] The compound or a pharmaceutically acceptable salt thereof as described in any one of [6][1] to [5], wherein L 1 It is -O-.

[0087] The compound or a pharmaceutically acceptable salt thereof described in any one of [7][1] to [5], wherein L 1 It is -CO-.

[0088] The compound or a pharmaceutically acceptable salt thereof described in any one of [8][1] to [5], wherein L 1 It is -CH2-.

[0089] The compound or a pharmaceutically acceptable salt thereof as described in any one of [9][1] to [8], wherein R 2 It is a methyl group.

[0090] The compound or a pharmaceutically acceptable salt thereof as described in any one of

[10] [1] to [9], wherein R 3 C 3-8 Cycloalkyl, 3- to 8-membered heterocyclic alkyloxy groups, can be substituted by 1 to 6 R groups. 31 Replacement C 3-8 Cycloalkyloxy groups, which can be oxidized by 1 to 6 R groups 31 Replacement C 1-6 Alkyl groups, which can be 1 to 6 R groups 31 Replacement C 1-6 Alkyl groups can be oxidized by 1 to 6 R groups. 31 Replaced by two (C) 1-6 Alkyl)amino, can be 1-6 R 31 Replacement (C) 1-6 Alkyl)amino, can be 1 to 4 R 32 Substituted 3- to 8-membered heterocyclic alkyl groups, which can be substituted with 1 to 4 R groups. 32 Substituted aryl groups, or those with 1 to 4 R groups. 32 Substituted heteroaryl groups.

[0091] The compound or a pharmaceutically acceptable salt thereof as described in any one of

[11] [1] to

[10] , wherein R 31 Halogen atom, cyclopropylidene, C 1-4 Alkyl group.

[0092] The compound or a pharmaceutically acceptable salt thereof as described in any one of

[12] [1] to

[11] , wherein R 32 C is a halogen atom that can be replaced by 1 to 3 halogen atoms. 1-3 Alkyl groups, C atoms that can be substituted with 1 to 3 halogen atoms 1-3 Alkoxy, oxo, cyano.

[0093] The compound or a pharmaceutically acceptable salt thereof, as described in any one of

[13] [1] to

[12] , wherein Ar 2 The heterocyclic aromatic rings are:

[0094] [Chemical Formula 3]

[0095]

[0096] The compound or a pharmaceutically acceptable salt thereof as described in any one of

[14] [1] to

[13] , wherein L 2 It can be 1 to 2 R 21 Replacement C 1-3 Alkylene.

[0097] The compound or a pharmaceutically acceptable salt thereof as described in any one of

[15] [1] to

[13] , wherein L 2 It is -CH2-.

[0098] The compound or a pharmaceutically acceptable salt thereof as described in any one of

[16] [1] to

[13] , wherein L 2 It is -CH2CH2-.

[0099] The compound or a pharmaceutically acceptable salt thereof as described in any one of

[17] [1] to

[16] , wherein R 7 It is a hydrogen atom.

[0100] The compound or a pharmaceutically acceptable salt thereof as described in any one of

[18] [1] to

[17] , wherein R 8 It is a hydrogen atom.

[0101]

[19] [1] The compound or a pharmaceutically acceptable salt thereof, wherein the compound represented by formula (I) is selected from (1) to (150):

[0102] (1) 4-[5-(2-aminoethyl)pyridin-2-yl]-3-(2-methyl-6-morpholin-4-ylpyridin-4-yl)oxybenzonitrile;

[0103] (2) 4-[5-(2-aminoethyl)pyridin-2-yl]-3-(2-methyl-5-phenylpyrazol-3-yl)oxybenzonitrile;

[0104] (3) 4-[5-(2-aminoethyl)pyridin-2-yl]-3-(2-methyl-5-pyridin-2-ylpyrazol-3-yl)oxybenzonitrile;

[0105] (4) 4-[5-(2-aminoethyl)pyridin-2-yl]-3-[2-methyl-5-(5-methylpyridin-2-yl)pyrazol-3-yl]oxybenzonitrile;

[0106] (5) 4-[5-(2-aminoethyl)pyridin-2-yl]-3-[5-(4-fluorophenyl)-2-methylpyrazol-3-yl]oxybenzonitrile;

[0107] (6) 4-[5-(2-aminoethyl)pyridin-2-yl]-3-[5-(3-fluorophenyl)-2-methylpyrazol-3-yl]oxybenzonitrile;

[0108] (7) 4-[5-(2-aminoethyl)pyridin-2-yl]-3-(5-cyclopropyl-2-methylpyrazol-3-yl)oxybenzonitrile;

[0109] (8) 4-[5-(2-aminoethyl)pyridin-2-yl]-3-[2-methyl-5-(2-methylpropyl)pyrazol-3-yl]oxybenzonitrile;

[0110] (9) 4-[5-(2-aminoethyl)pyridin-2-yl]-3-(2-methyl-5-propane-2-ylpyrazol-3-yl)oxybenzonitrile;

[0111] (10) 4-[5-(2-aminoethyl)pyridin-2-yl]-3-(2-methyl-5-propylpyrazole-3-yl)oxybenzonitrile;

[0112] (11) 4-[5-(2-aminoethyl)pyridin-2-yl]-3-(5-cyclobutyl-2-methylpyrazol-3-yl)oxybenzonitrile;

[0113] (12) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-(2-methyl-6-morpholin-4-ylpyridin-4-yl)oxybenzonitrile;

[0114] (13) 4-[5-(2-aminoethyl)pyridin-2-yl]-3-(2-methyl-6-pyrrolidone-1-ylpyridin-4-yl)oxybenzonitrile;

[0115] (14) 4-[5-(2-aminoethyl)pyridin-2-yl]-3-(2-methyl-6-pyridin-2-ylpyridin-4-yl)oxybenzonitrile;

[0116] (15) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-(2-methyl-5-propylpyrazole-3-yl)oxybenzonitrile;

[0117] (16) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-(2-methyl-5-propane-2-ylpyrazol-3-yl)oxybenzonitrile;

[0118] (17) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-(2-methyl-6-pyrrolidone-1-ylpyridin-4-yl)oxybenzonitrile;

[0119] (18) 4-[5-(2-aminoethyl)pyridin-2-yl]-3-[2-methyl-5-(trifluoromethyl)pyrazol-3-yl]oxybenzonitrile;

[0120] (19) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-(5-cyclobutyl-2-methylpyrazol-3-yl)oxybenzonitrile;

[0121] (20) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-(2-methyl-5-phenylpyrazol-3-yl)oxybenzonitrile;

[0122] (21) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-(2-methyl-6-phenylpyrimidin-4-yl)oxybenzonitrile;

[0123] (22) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-(6-phenylpyridazin-4-yl)oxybenzonitrile;

[0124] (23) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-(2-methyl-5-pyridin-2-ylpyrazol-3-yl)oxybenzonitrile;

[0125] (24) 4-[5-(2-aminoethyl)pyridin-2-yl]-3-(5-ethyl-2-methylpyrazol-3-yl)oxybenzonitrile;

[0126] (25) 4-[5-(aminomethyl)pyridin-2-yl]-3-(2-methyl-5-phenylpyrazol-3-yl)oxybenzonitrile;

[0127] (26) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-(5-ethyl-2-methylpyrazol-3-yl)oxybenzonitrile;

[0128] (27) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[6-(2-cyanophenyl)-2-methylpyrimidin-4-yl]oxybenzonitrile;

[0129] (28) 4-[5-(2-aminoethyl)pyridin-2-yl]-3-(2,5-dimethylpyrazol-3-yl)oxybenzonitrile;

[0130] (29) 4-[5-(aminomethyl)pyrimidin-2-yl]-3-(2-methyl-5-phenylpyrazol-3-yl)oxybenzonitrile;

[0131] (30) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-(5-cyclopropyl-2-methylpyrazol-3-yl)oxybenzonitrile;

[0132] (31) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-(5-butyl-2-methylpyrazol-3-yl)oxybenzonitrile;

[0133] (32) 4-[5-(aminomethyl)pyrimidin-2-yl]-3-(5-ethyl-2-methylpyrazol-3-yl)oxybenzonitrile;

[0134] (33) 4-[5-(aminomethyl)pyrimidin-2-yl]-3-(5-cyclopropyl-2-methylpyrazol-3-yl)oxybenzonitrile;

[0135] (34) 4-[5-(aminomethyl)pyridin-2-yl]-3-(5-ethyl-2-methylpyrazol-3-yl)oxybenzonitrile;

[0136] (35) 4-[5-(aminomethyl)pyridin-2-yl]-3-(5-cyclopropyl-2-methylpyrazol-3-yl)oxybenzonitrile;

[0137] (36) 4-[5-(aminomethyl)pyrimidin-2-yl]-3-(2-methyl-6-morpholin-4-ylpyridin-4-yl)oxybenzonitrile;

[0138] (37) 4-[5-(aminomethyl)pyridin-2-yl]-3-(2-methyl-6-morpholin-4-ylpyridin-4-yl)oxybenzonitrile;

[0139] (38) 4-[5-(aminomethyl)pyridin-2-yl]-3-(2-methyl-5-propylpyrazole-3-yl)oxybenzonitrile;

[0140] (39) 4-[5-(aminomethyl)pyridin-2-yl]-3-(2-methyl-5-propane-2-ylpyrazol-3-yl)oxybenzonitrile;

[0141] (40) 4-[5-(aminomethyl)pyrimidin-2-yl]-3-(2-methyl-5-propylpyrazole-3-yl)oxybenzonitrile;

[0142] (41) 4-[5-(aminomethyl)pyrimidin-2-yl]-3-(2-methyl-5-propane-2-ylpyrazol-3-yl)oxybenzonitrile;

[0143] (42) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-(5-tert-butyl-2-methylpyrazol-3-yl)oxybenzonitrile;

[0144] (43) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-(2-methyl-6-pyridin-2-ylpyridin-4-yl)oxybenzonitrile;

[0145] (44) 4-[5-(2-aminoethyl)pyridin-2-yl]-3-[2-methyl-5-(1,3-thiazo-2-yl)pyrazol-3-yl]oxybenzonitrile;

[0146] (45) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[2-methyl-5-(1,3-thiazo-2-yl)pyrazol-3-yl]oxybenzonitrile;

[0147] (46) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-(5-cyclopentyl-2-methylpyrazol-3-yl)oxybenzonitrile;

[0148] (47) 4-[5-(aminomethyl)pyrimidin-2-yl]-3-(2-methyl-5-pyridin-2-ylpyrazol-3-yl)oxybenzonitrile;

[0149] (48) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[5-(3-fluorophenyl)-2-methylpyrazol-3-yl]oxybenzonitrile;

[0150] (49) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[2-[(2S)-2-(difluoromethyl)morpholin-4-yl]-6-methylpyridin-4-yl]oxybenzonitrile;

[0151] (50) 4-[5-(aminomethyl)pyridin-2-yl]-3-[2-methyl-5-(oxan-4-yl)pyrazol-3-yl]oxybenzonitrile;

[0152] (51) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[2-[(2R)-2-(difluoromethyl)morpholin-4-yl]-6-methylpyridin-4-yl]oxybenzonitrile;

[0153] (52) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[2-methyl-6-(3-oxa-8-azabicyclo[3.2.1]octane-8-yl)pyridin-4-yl]oxybenzonitrile;

[0154] (53) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-(2-methyl-6-piperidin-1-ylpyrimidin-4-yl)oxybenzonitrile;

[0155] (54) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-(2-methyl-6-pyrrolidone-1-ylpyrimidin-4-yl)oxybenzonitrile;

[0156] (55) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[2-methyl-6-(8-oxa-3-azabicyclo[3.2.1]octane-3-yl)pyridin-4-yl]oxybenzonitrile;

[0157] (56) 4-[5-(2-aminoethyl)pyridin-2-yl]-3-[2-[2-methoxyethyl(methyl)amino]-6-methylpyridin-4-yl]oxybenzonitrile;

[0158] (57) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[2-methyl-6-(propane-2-ylamino)pyridin-4-yl]oxybenzonitrile;

[0159] (58) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[2-methyl-6-[(3R)-3-methylmorpholin-4-yl]pyridin-4-yl]oxybenzonitrile;

[0160] (59) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[2-methyl-6-[(3S)-3-methylmorpholin-4-yl]pyridin-4-yl]oxybenzonitrile;

[0161] (60) 4-[5-(2-aminoethyl)pyridin-2-yl]-3-(2-methyl-5-piperidin-1-ylpyrazol-3-yl)oxybenzonitrile;

[0162] (61) 4-[5-(2-aminoethyl)pyridin-2-yl]-3-(2-methyl-5-pyrrolidone-1-ylpyrazole-3-yl)oxybenzonitrile;

[0163] (62) 4-[5-(2-aminoethyl)pyridin-2-yl]-3-[5-(dimethylamino)-2-methylpyrazol-3-yl]oxybenzonitrile;

[0164] (63) 4-[5-(aminomethyl)pyrimidin-2-yl]-3-[2-methyl-5-(1,3-thiazo-2-yl)pyrazol-3-yl]oxybenzonitrile;

[0165] (64) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-(2-methyl-6-pyridin-2-ylpyrimidin-4-yl)oxybenzonitrile;

[0166] (65) 4-[5-(aminomethyl)pyridin-2-yl]-3-(2-methyl-5-pyridin-2-ylpyrazol-3-yl)oxybenzonitrile;

[0167] (66) 4-[5-(aminomethyl)pyridin-2-yl]-3-(2-methyl-5-piperidin-1-ylpyrazol-3-yl)oxybenzonitrile;

[0168] (67) 4-[5-(aminomethyl)pyridin-2-yl]-3-(2-methyl-5-pyrrolidone-1-ylpyrazole-3-yl)oxybenzonitrile;

[0169] (68) 4-[5-(aminomethyl)pyridin-2-yl]-3-[5-(dimethylamino)-2-methylpyrazol-3-yl]oxybenzonitrile;

[0170] (69) 4-[5-(aminomethyl)pyrimidin-2-yl]-3-[2-methyl-5-(4-methylpyridin-2-yl)pyrazol-3-yl]oxybenzonitrile;

[0171] (70) 4-[5-(aminomethyl)pyrimidin-2-yl]-3-[5-(diethylamino)-2-methylpyrazol-3-yl]oxybenzonitrile;

[0172] (71) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[5-(diethylamino)-2-methylpyrazol-3-yl]oxybenzonitrile;

[0173] (72) 4-[5-(aminomethyl)pyridin-2-yl]-3-(2-methyl-6-pyrrolidone-1-ylpyrimidin-4-yl)oxybenzonitrile;

[0174] (73) 4-[5-(aminoethyl)pyrimidin-2-yl]-3-[2-methyl-6-pyrrolidone-1-ylpyrimidin-4-yl]oxybenzonitrile;

[0175] (74) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[6-(7-azabicyclo[2.2.1]heptane-7-yl)-2-methylpyrimidin-4-yl]oxybenzonitrile;

[0176] (75) 4-[5-(aminomethyl)pyrimidin-2-yl]-3-[6-(7-azabicyclo[2.2.1]heptane-7-yl)-2-methylpyrimidin-4-yl]oxybenzonitrile;

[0177] (76) 4-[5-(aminomethyl)pyridin-2-yl]-3-(6-piperidin-1-ylpyridazin-4-yl)oxybenzonitrile;

[0178] (77) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[(5-phenyl-1,3,4-thiadiazol-2-yl)oxy]benzonitrile;

[0179] (78) 4-[5-(2-aminoethyl)pyridin-2-yl]-3-[5-(diethylamino)-2-methylpyrazol-3-yl]oxybenzonitrile;

[0180] (79) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[2-methyl-5-[methyl(2-methylpropyl)amino]pyrazol-3-yl]oxybenzonitrile;

[0181] (80) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[5-[cyclopropylmethyl(methyl)amino]-2-methylpyrazol-3-yl]oxybenzonitrile;

[0182] (81) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[2-methyl-5-[methyl(propyl)amino]pyrazol-3-yl]oxybenzonitrile;

[0183] (82) 4-[5-(aminomethyl)pyridin-2-yl]-3-(2-methyl-5-morpholin-4-ylpyrazol-3-yl)oxybenzonitrile;

[0184] (83) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[2-methyl-5-[methyl(propane-2-yl)amino]pyrazol-3-yl]oxybenzonitrile;

[0185] (84) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[5-[2,2-difluoroethyl(methyl)amino]-2-methylpyrazol-3-yl]oxybenzonitrile;

[0186] (85) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[2-methyl-5-[methyl(2,2,2-trifluoroethyl)amino]pyrazol-3-yl]oxybenzonitrile;

[0187] (86) 4-[5-(aminomethyl)pyrimidin-2-yl]-3-[2-methyl-6-[(2S)-2-methylpyrrolidin-1-yl]pyrimidin-4-yl]oxybenzonitrile;

[0188] (87) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[3-methyl-1-(2-methylpropyl)pyrazol-4-yl]oxybenzonitrile;

[0189] (88) 4-[5-(aminomethyl)pyrimidin-2-yl]-3-[3-methyl-1-(2-methylpropyl)pyrazol-4-yl]oxybenzonitrile;

[0190] (89) 4-[5-(aminomethyl)pyridin-2-yl]-3-[2-methyl-5-(trifluoromethyl)pyrazol-3-yl]oxybenzonitrile;

[0191] (90) 4-[5-(aminomethyl)pyrimidin-2-yl]-3-[2-methyl-5-(trifluoromethyl)pyrazol-3-yl]oxybenzonitrile;

[0192] (91) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[2-methyl-5-(trifluoromethyl)pyrazol-3-yl]oxybenzonitrile;

[0193] (92) 4-[5-(aminomethyl)pyrimidin-2-yl]-3-[2-(7-azabicyclo[2.2.1]heptane-7-yl)-6-methylpyridin-4-yl]oxybenzonitrile;

[0194] (93) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[2-(7-azabicyclo[2.2.1]heptane-7-yl)-6-methylpyridin-4-yl]oxybenzonitrile;

[0195] (94) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-(3-methyl-1-pyridin-2-ylpyrazol-4-yl)oxybenzonitrile;

[0196] (95) 4-[5-(aminomethyl)pyrimidin-2-yl]-3-(3-methyl-1-pyridin-2-ylpyrazol-4-yl)oxybenzonitrile;

[0197] (96) 4-[5-(aminomethyl)pyrimidin-2-yl]-3-[3-methyl-1-(2,2,2-trifluoroethyl)pyrazol-4-yl]oxybenzonitrile;

[0198] (97) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[5-[ethyl(propane-2-yl)amino]-2-methylpyrazol-3-yl]oxybenzonitrile;

[0199] (98) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[2-methyl-6-(2-methylpropoxy)pyrimidin-4-yl]oxybenzonitrile;

[0200] (99)4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[6-(diethylamino)-2-methylpyrimidin-4-yl]oxybenzonitrile;

[0201] (100)4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[2-methyl-6-[methyl(propane-2-yl)amino]pyrimidin-4-yl]oxybenzonitrile;

[0202] (101)4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[2-methyl-6-[(2R)-2-methylpyrrolidin-1-yl]pyrimidin-4-yl]oxybenzonitrile;

[0203] (102)4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[2-methyl-6-[(2S)-2-methylpyrrolidin-1-yl]pyrimidin-4-yl]oxybenzonitrile;

[0204] (103)4-[5-(aminomethyl)pyrimidin-2-yl]-3-[2-methyl-5-(3,3,4,4-tetrafluoropyrrolidone-1-yl)pyrazol-3-yl]oxybenzonitrile;

[0205] (104)4-[5-(aminomethyl)pyrimidin-2-yl]-3-[5-[2,2-difluoroethyl(ethyl)amino]-2-methylpyrazol-3-yl]oxybenzonitrile;

[0206] (105)4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[5-[2,2-difluoroethyl(ethyl)amino]-2-methylpyrazol-3-yl]oxybenzonitrile;

[0207] (106)4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[2-methyl-5-(3,3,4,4-tetrafluoropyrrolidone-1-yl)pyrazol-3-yl]oxybenzonitrile;

[0208] (107)4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[1-(2-methylpropyl)pyrazol-4-yl]oxybenzonitrile;

[0209] (108)4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-(1-pyridin-2-ylpyrazol-4-yl)oxybenzonitrile;

[0210] (109)4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[1-(2,2-dimethylpropyl)-3-methylpyrazol-4-yl]oxybenzonitrile;

[0211] (110)4-[5-(aminomethyl)pyrimidin-2-yl]-3-[2-methyl-5-(1,3-thiazo-4-yl)pyrazol-3-yl]oxybenzonitrile;

[0212] (111)4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[3-ethyl-1-(2-methylpropyl)pyrazol-4-yl]oxybenzonitrile;

[0213] (112) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[1-(2-methylpropyl)-3-(trifluoromethyl)pyrazol-4-yl]oxybenzonitrile;

[0214] (113) 4-[5-(aminomethyl)pyrimidin-2-yl]-3-[2-methyl-5-(4-methyl-1,3-thiazo-5-yl)pyrazol-3-yl]oxybenzonitrile;

[0215] (114) 4-[5-(aminomethyl)pyrimidin-2-yl]-3-[2-methyl-5-(5-methyl-1,3-thiazo-4-yl)pyrazol-3-yl]oxybenzonitrile;

[0216] (115)2-[2-[4-fluoro-2-[3-methyl-1-(2-methylpropyl)pyrazol-4-yl]oxyphenyl]pyrimidin-5-yl]ethylamine;

[0217] (116) 5-[2-[5-(2-aminoethyl)pyrimidin-2-yl]-5-fluorophenoxy]-N,N-diethyl-1-methylpyrazol-3-amine;

[0218] (117)2-[6-[4-fluoro-2-(2-methyl-5-morpholin-4-ylpyrazol-3-yl)oxyphenyl]pyridin-3-yl]ethylamine;

[0219] (118)2-[2-[4-fluoro-2-(2-methyl-5-pyridin-2-ylpyrazol-3-yl)oxyphenyl]pyrimidin-5-yl]ethylamine;

[0220] (119)2-[2-[4-fluoro-2-(2-methyl-5-pyrrolidone-1-ylpyrazole-3-yl)oxyphenyl]pyrimidin-5-yl]ethylamine;

[0221] (120)2-[6-[4-fluoro-2-(2-methyl-5-pyrrolidone-1-ylpyrazole-3-yl)oxyphenyl]pyridin-3-yl]ethylamine;

[0222] (121)5-[2-[5-(2-aminoethyl)pyrimidin-2-yl]-5-fluorophenoxy]-N-(2,2-difluoroethyl)-N,1-dimethylpyrazol-3-amine;

[0223] (122)5-[2-[5-(2-aminoethyl)pyridin-2-yl]-5-fluorophenoxy]-N-(2,2-difluoroethyl)-N,1-dimethylpyrazol-3-amine;

[0224] (123) 5-[2-[5-(2-aminoethyl)pyrimidin-2-yl]-5-fluorophenoxy]-N-(2,2-difluoroethyl)-N-ethyl-1-methylpyrazol-3-amine;

[0225] (124) 5-[2-[5-(2-aminoethyl)pyridin-2-yl]-5-fluorophenoxy]-N-(2,2-difluoroethyl)-N-ethyl-1-methylpyrazol-3-amine;

[0226] (125) 5-[2-[5-(2-aminoethyl)pyridin-2-yl]-5-fluorophenoxy]-N,N-diethyl-1-methylpyrazol-3-amine;

[0227] (126) 5-[2-[5-(2-aminoethyl)pyridin-2-yl]-5-fluorophenoxy]-N,N,1-trimethylpyrazole-3-amine;

[0228] (127)2-[6-[4-fluoro-2-[2-methyl-5-(oxan-4-yl)pyrazol-3-yl]oxyphenyl]pyridin-3-yl]ethylamine;

[0229] (128)[2-[4-fluoro-2-(2-methyl-5-propane-2-ylpyrazol-3-yl)oxyphenyl]pyrimidin-5-yl]methylamine;

[0230] (129)2-[2-[4-fluoro-2-(2-methyl-5-propane-2-ylpyrazol-3-yl)oxyphenyl]pyrimidin-5-yl]ethylamine;

[0231] (130)2-[6-[4-fluoro-2-(2-methyl-5-propane-2-ylpyrazol-3-yl)oxyphenyl]pyridin-3-yl]ethylamine;

[0232] (131)2-[6-[2-(5-cyclopropyl-2-methylpyrazol-3-yl)oxy-4-fluorophenyl]pyridin-3-yl]ethylamine;

[0233] (132) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-(5-ethyl-2-methylpyrazole-3-carbonyl)benzonitrile;

[0234] (133)4-[5-(aminomethyl)pyrimidin-2-yl]-3-(5-ethyl-2-methylpyrazol-3-carbonyl)benzonitrile;

[0235] (134)4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-(2-methyl-5-morpholin-4-ylpyrazole-3-carbonyl)benzonitrile;

[0236] (135)4-[5-(aminomethyl)pyrimidin-2-yl]-3-(2-methyl-5-morpholin-4-ylpyrazole-3-carbonyl)benzonitrile;

[0237] (136) 4-[5-(aminomethyl)pyridin-2-yl]-3-(2-methyl-5-morpholin-4-ylpyrazole-3-carbonyl)benzonitrile;

[0238] (137) 4-[5-(aminomethyl)pyrimidin-2-yl]-3-(5-tert-butyl-2-methylpyrazole-3-carbonyl)benzonitrile;

[0239] (138)4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-(5-tert-butyl-2-methylpyrazole-3-carbonyl)benzonitrile;

[0240] (139)4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[5-(diethylamino)-2-methylpyrazole-3-carbonyl]benzonitrile;

[0241] (140)4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-(1-pyridin-2-ylpyrazole-4-carbonyl)benzonitrile;

[0242] (141) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-(2-methyl-6-morpholin-4-ylpyridin-4-carbonyl)benzonitrile;

[0243] (142) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[5-(dimethylamino)-2-methylpyrazole-3-carbonyl]benzonitrile;

[0244] (143) 4-[5-(aminomethyl)pyrimidin-2-yl]-3-[5-(dimethylamino)-2-methylpyrazol-3-carbonyl]benzonitrile;

[0245] (144)4-[5-(aminomethyl)pyrimidin-2-yl]-3-[5-(diethylamino)-2-methylpyrazole-3-carbonyl]benzonitrile;

[0246] (145) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-(2-methyl-5-piperidin-1-ylpyrazole-3-carbonyl)benzonitrile;

[0247] (146) 4-[5-(aminomethyl)pyrimidin-2-yl]-3-(2-methyl-5-piperidin-1-ylpyrazole-3-carbonyl)benzonitrile;

[0248] (147) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-(2-methyl-5-pyrrolidine-1-ylpyrazole-3-carbonyl)benzonitrile;

[0249] (148) 4-[5-(aminomethyl)pyrimidin-2-yl]-3-(2-methyl-5-pyrrolidine-1-ylpyrazole-3-carbonyl)benzonitrile;

[0250] (149) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[5-[2,2-difluoroethyl(ethyl)amino]-2-methylpyrazole-3-carbonyl]benzonitrile;

[0251] (150)4-[5-(aminomethyl)pyrimidin-2-yl]-3-[5-[2,2-difluoroethyl(ethyl)amino]-2-methylpyrazole-3-carbonyl]benzonitrile.

[0252]

[20] A pharmaceutical composition comprising any one of the compounds of claims 1 to 19 or a pharmaceutically acceptable salt thereof.

[0253]

[21] A pharmaceutical composition having TRPC6 channel inhibitory activity, comprising any one of claims 1 to 19 or a pharmaceutically acceptable salt thereof.

[0254]

[22] A treatment or preventive medicine for nephrotic syndrome, membranous nephropathy, acute renal failure, sepsis, chronic renal failure, diabetic nephropathy, pulmonary hypertension, acute lung injury, heart failure, malignancy, or muscular dystrophy, comprising any compound of claims 1 to 19 or a pharmaceutically acceptable salt thereof.

[0255] Invention Effects

[0256] According to the present invention, novel compounds having TRPC6 inhibitory activity or pharmaceutically acceptable salts thereof are provided, as well as pharmaceutical compositions comprising them and therapeutic or preventive agents for diseases in which TRPC6 is involved. Detailed Implementation

[0257] The following describes the terms used individually or in combination in this specification. Unless otherwise specified, the descriptions of substituents are generally applicable to all parts of the compound. Furthermore, combinations of substituents and variables are permitted only if such combinations produce chemically stable compounds. When a substituent is replaced by more than two groups, many of these groups may be located on the same or different carbons, provided that a stable structure is produced.

[0258] In this invention, the number to the right of a carbon atom indicates the number of carbon atoms. For example, if it is "C 1-6 This indicates a carbon number of 1 to 6. For example, "C 1-4 "Alkyl" refers to alkyl groups with 1 to 4 carbon atoms. The treatment of carbon numbers in other groups is the same. It should be noted that, for example, in "(C 1-3 In the description of "alkyl)carbonyl", etc., C 1-3 The number of carbons represents the C in brackets 1-3 The number of carbon atoms in alkyl groups is not considered, excluding the carbon atoms in carbonyl groups. The calculation method for the number of carbon atoms in similar statements is the same. Furthermore, unless otherwise specified, substituents are named starting from the terminal portion of the functional group, and then moving towards the bond site to the adjacent functional groups.

[0259] In this invention, "halogen atom" refers to fluorine atom, chlorine atom, bromine atom, and iodine atom.

[0260] In this invention, "alkyl" refers to a saturated straight-chain or branched aliphatic hydrocarbon group. Examples include: methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 3-methylbutyl, 1-ethylpropyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, neopentyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 1-ethylbutyl, and 2-ethylbutyl, etc.

[0261] In this invention, "cycloalkyl" refers to a monocyclic or polycyclic hydrocarbon group that is saturated or partially unsaturated. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

[0262] In this invention, "heterocyclic alkyl" refers to a group in which one or more carbon atoms in a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon ring are replaced by heteroatoms selected from O, S, and N. Examples of heterocyclic alkyl groups include: azirropropyl, acridine, oxadicyclic butyl, morpholino, thiomorpholino, pyrrolidinyl, piperidinyl, piperazinyl, imidazoalkyl, pyrazolyl, tetrahydrofuranyl, tetrahydropyranyl, etc.

[0263] In this invention, "alkoxy", "cycloalkyloxy", and "heterocyclic alkyloxy" refer to oxygen groups that are substituted by alkyl, cycloalkyl, or heterocyclic alkyl groups.

[0264] In this invention, "(alkoxy)alkoxy" and "(carboxyl)alkoxy" refer to alkoxy groups substituted with alkoxy or carboxyl groups. For example, "(C 1-3 Alkoxy)C 1-3 "Alkoxy group" refers to an alkoxy group with 1 to 3 carbon atoms that has been replaced by an alkoxy group with 1 to 3 carbon atoms.

[0265] In this invention, "(alkoxy)carbonyl" refers to a carbonyl group substituted with an alkoxy group. For example, "(C 1-3 "Alkoxy)carbonyl" refers to a carbonyl group that has been substituted by an alkoxy group having 1 to 3 carbon atoms.

[0266] In this invention, "(alkyl)amino", "(cycloalkyl)amino", and "(heterocyclic)amino" refer to amino groups substituted with one alkyl, cycloalkyl, or heterocyclic alkyl group, respectively. For example, "(C 3-8 "Heterocyclic alkyl)amino" refers to an amino group that has been substituted by a 3- to 8-membered heterocyclic alkyl group.

[0267] In this invention, "di(alkyl)amino" refers to an amino group substituted with two identical or different alkyl groups. For example, "di(C... 1-6"alkyl)amino" refers to an amino group that is replaced by two identical or different alkyl groups having 1 to 6 carbon atoms.

[0268] In this invention, "(alkylcarbonyl)amino" refers to an amino group substituted with one alkyl carbonyl group. For example, "(C 1-3 "alkyl)carbonylamino" refers to an amino group composed of one (C) group. 1-3 Alkyl)carbonyl-substituted amino groups.

[0269] In this invention, "(alkylamino)carbonyl" refers to a carbonyl group substituted with an alkylamino group. Similarly, "di(alkyl)aminocarbonyl" refers to a carbonyl group substituted with a di(alkyl)amino group.

[0270] In this invention, "alkoxyalkyl", "alkoxycarbonylalkyl", "di(alkyl)aminoalkyl", "hydroxyalkyl", and "carboxylalkyl" refer to alkyl groups substituted with alkoxy, alkoxycarbonyl, di(alkyl)amino, hydroxy, and carboxyl groups. Additionally, "di(alkyl)aminocarbonylmethyl" refers to a methyl group substituted with a di(alkyl)aminocarbonyl group.

[0271] In this invention, "alkylene" refers to a divalent group derived by further removing one hydrogen atom at any position from the aforementioned "alkyl". Examples include: methylene, ethylene, n-propylene, isopropylene, n-butylene, isobutylene, n-pentylene, n-hexylene, etc.

[0272] In this invention, "cycloalkylene" refers to a divalent group derived from the above-mentioned "cycloalkyl" by further removing one hydrogen atom at any position. Examples include cyclopropylene, cyclobutylene, and cyclohexylene.

[0273] In this invention, "heterocyclic alkylene" refers to a divalent group derived from the above-mentioned "heterocyclic alkyl" by further removing one hydrogen atom at an arbitrary position.

[0274] In this invention, "replaceable C" 1-3 "Alkyl" refers to an alkyl group having 1 to 3 carbon atoms, which may have one or more substituents at the substituted positions. In the presence of multiple substituents, the substituents may be the same or different. The same meaning is expressed in similar expressions.

[0275] In this invention, "aryl" refers to a monocyclic or bicyclic aromatic hydrocarbon group having 6 to 10 carbon atoms. Examples include phenyl, naphthyl, indene, and azulel. "Aromatic ring" refers to the ring portion of the aryl group.

[0276] In this invention, "heteroaryl" refers to a 5- to 10-membered monocyclic or bicyclic aromatic heterocyclic group having 1 to 5 heteroatoms selected from O, S, and N. Examples of heteroaryl groups include: pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, furanyl, thiopheneyl, isoxazolyl, isothiazolyl, benzofuranyl, benzothiopheneyl, benzothiazolyl, benzimidazolyl, benzoxazolyl, pyranyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, triazinyl, triazolyl, benzoxazolyl, and benziisoxazolyl. "Heteroaromatic ring" refers to the ring portion of the heteroaryl group. "Nitrogen-containing heteroaromatic ring" refers to a heteroaromatic ring containing one or more nitrogen atoms on the ring.

[0277] In formula (I), X 1 X 2 and X 3 Independently CH, N or CY, X 1 X 2 and X 3 At least one of them is CH or CY. X is preferred. 1 X 2 and X 3 For CH.

[0278] Y is a halogen atom or a methyl atom.

[0279] In equation (I), R 1 It can be a cyano group, a fluorine atom, or a chlorine atom. Preferably, it is a cyano group or a fluorine atom.

[0280] In equation (I), the connecting base L 1 is -O-, -S-, -SO-, -CH(R 11 -, -C(=CH2)-, -CO-, 1,1-cyclopropylene, or -NR 12 -. Preferably -O-, -S-, or -CH(R) 11 -, -CO-, or -NR 12 -, more preferably -O-, -CO-, or -CH2-.

[0281] R 11 A carbon atom consisting of a hydrogen atom, a hydroxyl group, and a carbon atom that can be substituted by 1 to 3 halogen atoms. 1-3 Alkyl groups, or C groups that can be substituted with 1 to 2 cyano groups. 1-3 Alkyl group.

[0282] R 12 C is a hydrogen atom, or a carbon atom that can be replaced by 1 to 3 halogen atoms. 1-3 alkyl.

[0283] In formula (I), Ar 1 R can be 1 to 3 2 A substituted nitrogen-containing heteroaryl ring. Preferably, the following structure is used.

[0284] [Chemical Formula 4]

[0285]

[0286] R 2 C that is independently a halogen atom, a cyano group, or a C that can be substituted by 1 to 3 halogen atoms. 1-4 Alkyl group. Preferably, C atoms can be substituted with 1 to 3 halogen atoms. 1-4 Alkyl, more preferably methyl. In R 2 and R 3 with Ar 1 In the case of neighboring atomic bonding, R 2 and R 3 Ar can be bonded to them via single bonds or -O- bonds. 1 The atoms together form 5- to 7-membered rings.

[0287] In equation (I), R 3 It consists of hydrogen atoms, halogen atoms, amino groups, cyano groups, carboxyl groups, and (C) 1-3 alkylcarbonyl)amino, (C 1-6 alkylamino)carbonyl, di(C 1-3 alkyl)aminocarbonyl, (C 1-3 alkoxy)carbonyl, (C 3-8 cycloalkyl)amino, (C 3-8 Heterocyclic alkyl)amino, C 3-8 Cycloalkyl, 3- to 8-membered heterocyclic alkyloxy groups, can be substituted by 1 to 6 R groups. 31 Replacement C 3-8 Cycloalkyloxy groups, which can be oxidized by 1 to 6 R groups 31 Replacement C 1-6 Alkyl groups, which can be 1 to 6 R groups 31 Replacement C 1-6 Alkyl groups can be oxidized by 1 to 6 R groups. 31 Replaced by two (C) 1-6 Alkyl)amino, can be 1-6 R 31 Replacement (C) 1-6 Alkyl)amino, can be 1 to 4 R 32 Substituted 3- to 8-membered heterocyclic alkyl groups, which can be substituted with 1 to 4 R groups. 32 Substituted aryl groups, or those with 1 to 4 R groups. 32 Substituted heteroaryl groups.

[0288] R 31 Independently, a halogen atom, hydroxyl group, cyclopropylidene group, or a C group that can be substituted by 1 to 3 halogen atoms. 3-8 Cycloalkyl, 3-8 membered heterocyclic alkyl, oxobutanediyl, C 1-4 Alkyloxy or 3- to 8-membered cycloalkyloxy.

[0289] R32 C atoms that are independently halogen atoms, hydroxyl groups, acetylamino groups, or C atoms that can be substituted by 1 to 3 halogen atoms. 1-3 Alkyl groups, C atoms that can be substituted with 1 to 3 halogen atoms 1-3 Alkoxy, oxo, cyano, carboxyl, (C 1-3 alkoxy)carbonyl, (C 1-3 Alkyl) sulfonyl, carboxamide, or benzyloxy.

[0290] In formula (I), the preferred R 3 C 3-8 Cycloalkyl, 3- to 8-membered heterocyclic alkyloxy groups, can be substituted by 1 to 6 R groups. 31 Replacement C 3-8 Cycloalkyloxy groups, which can be oxidized by 1 to 6 R groups 31 Replacement C 1-6 Alkyl groups, which can be 1 to 6 R groups 31 Replacement C 1-6 Alkyl groups can be oxidized by 1 to 6 R groups. 31 Replaced by two (C) 1-6 Alkyl)amino, can be 1-6 R 31 Replacement (C) 1-6 Alkyl)amino, can be 1 to 4 R 32 Substituted 3- to 8-membered heterocyclic alkyl groups, which can be substituted with 1 to 4 R groups. 32 Substituted aryl groups, or those with 1 to 4 R groups. 32 Substituted heteroaryl groups.

[0291] Preferred R 31 Halogen atom, cyclopropylidene, C 1-4 Alkyl group.

[0292] Preferred R 32 C is a halogen atom that can be replaced by 1 to 3 halogen atoms. 1-3 Alkyl groups, C atoms that can be substituted with 1 to 3 halogen atoms 1-3 Alkoxy, oxo, or cyano groups.

[0293] In formula (I), Ar 2 R can be 1 to 4 4 Substituted aromatic rings, or those that can be replaced by 1–4 R 4 Substituted heterocyclic aromatic rings. Preferably, they can be replaced by 1 to 4 R... 4 The substituted heteroaromatic ring is more preferably a pyridine or pyrimidine ring with the following substituted structure.

[0294] [Chemical Formula 5]

[0295]

[0296] R 4Independently, it can be a halogen atom, hydroxyl group, carboxyl group, cyano group, cyanomethyl group, amino group, or di(C) group. 1-3 Alkyl)amino, C atoms that can be substituted with 1 to 3 halogen atoms 1-3 Alkyl, or C 1-3 Alkyl group.

[0297] In formula (I), L 2 It is a single bond, which can be bound by 1 to 3 Rs. 21 Replacement C 1-6 Alkylene, which can be denoted by 1 to 3 R 21 Replacement C 3-8 Cycloalkylene, or can be 1 to 3 R 21 Substituted 4- to 8-membered heterocyclic alkylene groups. L 2 Ar can be placed at any position and at both ends of it. 2 and -NR 7 R 8 Bonding. Additionally, in L... 2 one sp at any position 3 Carbon atoms can be -O- or -NR 22 -Structural substitution. Preferred L 2 It can be 1 to 2 R 21 Replacement C 1-3 Alkylene, more preferably -CH2- or -CH2CH2-.

[0298] R 21 Independently, a halogen atom, hydroxyl group, oxo group, cyano group, 1,1-cyclopropylidene group, oxetanediyl group, carboxyl group, carboxamide group, or a C group that can be substituted by 1 to 3 halogen atoms. 1-6 Alkyl, C 3-8 cycloalkyl, C 1-6 Alkoxy, (C 1-3 Alkoxy)C 1-3 Alkyl, (C 1-3 Alkoxy)C 1-3 Alkyl, (hydroxy) C 1-6 Alkyl, (carboxyl) C 1-3 Alkyl, (carboxyl) C 1-3 Alkoxy, (C 1-3 alkoxy)carbonyl, (C 1-3 alkoxycarbonyl)C 1-3 Alkyl, (C 1-6 alkylamino)carbonyl, di(C 1-3 Alkyl)aminocarbonyl, phenyl group substituted with 1 to 3 halogen atoms, heteroaryl group substituted with 1 to 3 halogen atoms, or phenoxy group substituted with 1 to 3 halogen atoms. Preferred R 21 It is a C-aryl group consisting of a halogen atom, hydroxyl group, oxo group, oxetane subunit, or a C-aryl group that can be substituted by 1 to 3 halogen atoms. 1-6Alkyl, more preferably halogen atom or hydroxyl.

[0299] R 22 It is a hydrogen atom or a carbon atom. 1-3 alkyl.

[0300] L 2 and R 7 It can be achieved via single bonds, -O-, or -S (=O). n - or -NR 23 - Bonded together to form L 2 and R 7 The bonded nitrogen atom is a 4- to 8-membered ring, and this ring can be substituted by 1 to 3 halogen atoms or 1 to 2 hydroxyl groups. Here, n represents an integer from 0 to 2.

[0301] R 23 It is a hydrogen atom or a C atom 1-3 alkyl.

[0302] In L 2 and R 4 with Ar 2 In the case of adjacent atoms bonded together, Ar atoms that are bonded to them can... 2 The atoms together form 5- to 8-membered rings via single bonds or -O-.

[0303] In equation (I), R 7 It is a hydrogen atom or a C atom 1-3 Alkyl group, more preferably hydrogen atom. R 7 and Ar 2 The atoms can form 5- to 8-membered rings through single bond bonding.

[0304] In equation (I), R 8 For hydrogen atoms, C 1-6 Alkyl, adamantyl, C 1-6 Cycloalkyl, cyanomethyl, oxetane, (C 1-3 alkylamino)carbonylmethyl, di(C 1-3 alkyl)aminocarbonylmethyl, (C 1-3 (alkylamino)C 1-8 Alkyl, di(C) 1-3 alkyl)aminoC 1-8 Alkyl, (hydroxy) C 1-8 Alkyl, (carboxyl) C 1-3 Alkyl, (C 1-3 alkoxycarbonyl)C 1-3 Alkyl, or (C 1-3 Alkoxy)C 1-3 Alkyl group. More preferably, R 8 It is a hydrogen atom.

[0305] R 7 and R8 They can be connected via single bonds, -O-, or -S (=O). m - or -NR 41 - Bonding forms a 3- to 8-membered ring, and this ring can be formed by amino groups, oxo groups, or C groups. 1-3 Alkyl substitution. Here, m represents an integer from 0 to 2.

[0306] R 41 It is a hydrogen atom or a C atom 1-3 alkyl.

[0307] The following group of compounds is preferred in the compounds of this invention.

[0308] That is, the following group of compounds:

[0309] In formula (I),

[0310] X 1 X 2 and X 3 For CH,

[0311] R 1 It is a cyano group or a fluorine atom.

[0312] Connecting base L 1 It can be -O-, -CO-, or -CH2-.

[0313] Ar 1 The structure is as follows:

[0314] [Chemical Formula 6]

[0315]

[0316] R 2 It is methyl.

[0317] R 3 C 3-8 Cycloalkyl, 3- to 8-membered heterocyclic alkyloxy groups, can be substituted by 1 to 6 R groups. 31 Replacement C 3-8 Cycloalkyloxy groups, which can be oxidized by 1 to 6 R groups 31 Replacement C 1-6 Alkyl groups, which can be 1 to 6 R groups 31 Replacement C 1-6 Alkyl groups can be oxidized by 1 to 6 R groups. 31 Replaced by two (C) 1-6 Alkyl)amino, can be 1-6 R 31 Replacement (C) 1-6 Alkyl)amino, can be 1 to 4 R 32 Substituted 3- to 8-membered heterocyclic alkyl groups, which can be substituted with 1 to 4 R groups. 32 Substituted aryl groups, or those with 1 to 4 R groups. 32Substituted heteroaryl groups,

[0318] R 31 Halogen atom, cyclopropylidene, C 1-4 Alkoxy

[0319] R 32 C is a halogen atom that can be replaced by 1 to 3 halogen atoms. 1-3 Alkyl groups, C atoms that can be substituted with 1 to 3 halogen atoms 1-3 Alkoxy, oxo, cyano

[0320] Ar 2 The pyridine or pyrimidine ring is substituted in the manner shown in the following structures.

[0321] [Chemical Formula 7]

[0322]

[0323] L 2 It is -CH2- or -CH2CH2-.

[0324] R 7 It is a hydrogen atom.

[0325] R 8 It is a hydrogen atom.

[0326] Specific examples of compounds of formula (I) can be found in the compounds shown in Table 1 below.

[0327] [Table 1-1]

[0328]

[0329]

[0330] [Table 1-2]

[0331]

[0332]

[0333] [Table 1-3]

[0334]

[0335] [Table 1-4]

[0336]

[0337] [Table 1-5]

[0338]

[0339]

[0340] [Table 1-6]

[0341]

[0342]

[0343] [Table 1-7]

[0344]

[0345]

[0346] [Table 1-8]

[0347]

[0348]

[0349] [Table 1-9]

[0350]

[0351]

[0352] [Table 1-10]

[0353]

[0354]

[0355] [Table 1-11]

[0356]

[0357]

[0358] [Table 1-12]

[0359]

[0360]

[0361] [Table 1-13]

[0362]

[0363] [Table 1-14]

[0364]

[0365] [Table 1-15]

[0366]

[0367]

[0368] [Table 1-16]

[0369]

[0370]

[0371] [Table 1-17]

[0372]

[0373]

[0374] [Table 1-18]

[0375]

[0376]

[0377] [Table 1-19]

[0378]

[0379]

[0380] [Table 1-20]

[0381]

[0382]

[0383] [Table 1-21]

[0384]

[0385]

[0386] [Table 1-22]

[0387]

[0388]

[0389] [Table 1-23]

[0390]

[0391] [Table 1-24]

[0392]

[0393] [Table 1-25]

[0394]

[0395]

[0396] [Table 1-26]

[0397]

[0398]

[0399] [Table 1-27]

[0400]

[0401]

[0402] [Table 1-28]

[0403]

[0404]

[0405] [Table 1-29]

[0406]

[0407]

[0408] [Table 1-30]

[0409]

[0410]

[0411] [Table 1-31]

[0412]

[0413]

[0414] [Table 1-32]

[0415]

[0416]

[0417] [Table 1-33]

[0418]

[0419] [Table 1-34]

[0420]

[0421] [Table 1-35]

[0422]

[0423]

[0424] [Table 1-36]

[0425]

[0426]

[0427] [Table 1-37]

[0428]

[0429]

[0430] [Table 1-38]

[0431]

[0432]

[0433] [Table 1-39]

[0434]

[0435]

[0436] [Table 1-40]

[0437]

[0438]

[0439] [Table 1-41]

[0440]

[0441]

[0442] [Table 1-42]

[0443]

[0444]

[0445] [Table 1-43]

[0446]

[0447] [Table 1-44]

[0448]

[0449] [Table 1-45]

[0450]

[0451]

[0452] [Table 1-46]

[0453]

[0454]

[0455] [Table 1-47]

[0456]

[0457]

[0458] [Table 1-48]

[0459]

[0460]

[0461] [Table 1-49]

[0462]

[0463]

[0464] [Table 1-50]

[0465]

[0466]

[0467] [Table 1-51]

[0468]

[0469]

[0470] [Table 1-52]

[0471]

[0472]

[0473] [Table 1-53]

[0474]

[0475] [Table 1-54]

[0476]

[0477] [Table 1-55]

[0478]

[0479]

[0480] [Table 1-56]

[0481]

[0482]

[0483] [Table 1-57]

[0484]

[0485]

[0486] [Table 1-58]

[0487]

[0488]

[0489] [Table 1-59]

[0490]

[0491]

[0492] [Table 1-60]

[0493]

[0494]

[0495] [Table 1-61]

[0496]

[0497]

[0498] [Table 1-62]

[0499]

[0500]

[0501] [Table 1-63]

[0502]

[0503] [Table 1-64]

[0504]

[0505] [Table 1-65]

[0506]

[0507]

[0508] [Table 1-66]

[0509]

[0510]

[0511] [Table 1-67]

[0512]

[0513]

[0514] [Table 1-68]

[0515]

[0516]

[0517] [Table 1-69]

[0518]

[0519]

[0520] [Table 1-70]

[0521]

[0522]

[0523] [Table 1-71]

[0524]

[0525]

[0526] [Table 1-72]

[0527]

[0528]

[0529] [Table 1-73]

[0530]

[0531] [Table 1-74]

[0532]

[0533] [Table 1-75]

[0534]

[0535]

[0536] [Table 1-76]

[0537]

[0538]

[0539] [Table 1-77]

[0540]

[0541]

[0542] [Table 1-78]

[0543]

[0544]

[0545] [Table 1-79]

[0546]

[0547]

[0548] [Table 1-80]

[0549]

[0550]

[0551] [Table 1-81]

[0552]

[0553]

[0554] [Table 1-82]

[0555]

[0556]

[0557] [Table 1-83]

[0558]

[0559] [Table 1-84]

[0560]

[0561] [Table 1-85]

[0562]

[0563]

[0564] [Table 1-86]

[0565]

[0566]

[0567] [Table 1-87]

[0568]

[0569]

[0570] [Table 1-88]

[0571]

[0572]

[0573] [Table 1-89]

[0574]

[0575]

[0576] [Table 1-90]

[0577]

[0578]

[0579] [Table 1-91]

[0580]

[0581]

[0582] [Table 1-92]

[0583]

[0584]

[0585] [Table 1-93]

[0586]

[0587] [Table 1-94]

[0588]

[0589] [Table 1-95]

[0590]

[0591]

[0592] [Table 1-96]

[0593]

[0594]

[0595] [Table 1-97]

[0596]

[0597]

[0598] [Table 1-98]

[0599]

[0600]

[0601] [Table 1-99]

[0602]

[0603]

[0604] [Table 1-100]

[0605]

[0606]

[0607] [Table 1-101]

[0608]

[0609]

[0610] [Table 1-102]

[0611]

[0612]

[0613] [Table 1-103]

[0614]

[0615] [Table 1-104]

[0616]

[0617] [Table 1-105]

[0618]

[0619]

[0620] [Table 1-106]

[0621]

[0622]

[0623] [Table 1-107]

[0624]

[0625]

[0626] [Table 1-108]

[0627]

[0628]

[0629] [Table 1-109]

[0630]

[0631]

[0632] [Table 1-110]

[0633]

[0634]

[0635] [Table 1-111]

[0636]

[0637]

[0638] [Table 1-112]

[0639]

[0640]

[0641] [Table 1-113]

[0642]

[0643] [Table 1-114]

[0644]

[0645] [Table 1-115]

[0646]

[0647]

[0648] [Table 1-116]

[0649]

[0650]

[0651] [Table 1-117]

[0652]

[0653]

[0654] [Table 1-118]

[0655]

[0656]

[0657] [Table 1-119]

[0658]

[0659]

[0660] [Table 1-120]

[0661]

[0662]

[0663] [Table 1-121]

[0664]

[0665]

[0666] [Table 1-122]

[0667]

[0668]

[0669] [Table 1-123]

[0670]

[0671] [Table 1-124]

[0672]

[0673] [Table 1-125]

[0674]

[0675]

[0676] [Table 1-126]

[0677]

[0678]

[0679] [Table 1-127]

[0680]

[0681]

[0682] [Table 1-128]

[0683]

[0684]

[0685] [Table 1-129]

[0686]

[0687]

[0688] [Table 1-130]

[0689]

[0690]

[0691] [Table 1-131]

[0692]

[0693]

[0694] [Table 1-132]

[0695]

[0696]

[0697] [Table 1-133]

[0698]

[0699] [Table 1-134]

[0700]

[0701] [Table 1-135]

[0702]

[0703]

[0704] [Table 1-136]

[0705]

[0706]

[0707] [Table 1-137]

[0708]

[0709]

[0710] [Table 1-138]

[0711]

[0712]

[0713] [Table 1-139]

[0714]

[0715]

[0716] [Table 1-140]

[0717]

[0718]

[0719] [Table 1-141]

[0720]

[0721]

[0722] [Table 1-142]

[0723]

[0724]

[0725] [Table 1-143]

[0726]

[0727] [Table 1-144]

[0728]

[0729] [Table 1-145]

[0730]

[0731]

[0732] [Table 1-146]

[0733]

[0734]

[0735] [Table 1-147]

[0736]

[0737]

[0738] [Table 1-148]

[0739]

[0740]

[0741] [Table 1-149]

[0742]

[0743]

[0744] [Table 1-150]

[0745]

[0746]

[0747] [Table 1-151]

[0748]

[0749]

[0750] [Table 1-152]

[0751]

[0752]

[0753] [Table 1-153]

[0754]

[0755] [Table 1-154]

[0756]

[0757] [Table 1-155]

[0758]

[0759]

[0760] [Table 1-156]

[0761]

[0762]

[0763] [Table 1-157]

[0764]

[0765]

[0766] [Table 1-158]

[0767]

[0768]

[0769] [Table 1-159]

[0770]

[0771]

[0772] [Table 1-160]

[0773]

[0774]

[0775] [Table 1-161]

[0776]

[0777]

[0778] [Table 1-162]

[0779]

[0780]

[0781] [Table 1-163]

[0782]

[0783] [Table 1-164]

[0784]

[0785] [Table 1-165]

[0786]

[0787]

[0788] [Table 1-166]

[0789]

[0790]

[0791] [Table 1-167]

[0792]

[0793]

[0794] [Table 1-168]

[0795]

[0796]

[0797] [Table 1-169]

[0798]

[0799]

[0800] [Table 1-170]

[0801]

[0802]

[0803] [Table 1-171]

[0804]

[0805]

[0806] [Table 1-172]

[0807]

[0808]

[0809] [Table 1-173]

[0810]

[0811] [Table 1-174]

[0812]

[0813] [Table 1-175]

[0814]

[0815]

[0816] [Table 1-176]

[0817]

[0818]

[0819] Among these, the preferred compounds are compounds numbered 2, 6, 7, 9, 11, 17, 21, 25, 26, 30, 32, 33, 46, 50, 62, 65, 66, 69, 70, 82, 93, 100, 101, 112, 113, 115, 120, 130, 133, 137, 138, 149, 150, 153, 157, 159–162, 164, 170–177, 179, 180, 182, 183, 185–187, 197–199, 202, 204–206, 211–213, 215, 225–233, 237, 238, 241, 246–250, 253, 254, 258, and 26. 0~262, 264, 266, 267, 272~278, 285, 287~289, 293~296, 299, 301, 306, 310, 312~315, 317~321, 324~329, 333~338, 341, 344, 346, 348, 360~367, 370~376 378, 379, 381~384, 388, 390~394, 396, 398, 399, 401~407, 413, 426, 429, 430, 432, 434, 439~441, 444~448, 454, 458, 459, 461, 467, 469~471, 477, 482~ 485, 493, 496, 498~503, 505~510, 517, 521, 522, 525~527, 529~532, 536, 541~544, 550, 562, 575, 587, 592, 599, 604, 609, 610, 619, 621~629, 634, 637, 6 42, 644, 651, 652, 655~657, 668, 670~672, 691, 695~697, 701, 702, 704, 706, 708, 711, 714, 715, 718, 724, 734, 735, 737, 742, 743, 748, 754, 758~760, 76 5. 767~770, 772~775, 786, 787, 795, 799, 801~803, 808~812, 822, 823, 826~828, 832~835, 842, 848~850, 854, 856, 857, 859~861, 866, 872~878, 900, 903 ~910, 912~916, 932, 935, 937, 945, 948~953, 955, 957, 958, 963, 966, 968, 969, 972, 975, 977~980, 983, 985, 987~992, 996, 1000, 1001, 1010~1014, 1017,1018, 1025~1033, 1035, 1037, 1042~1049, 1051, 1054, 1057~1063, 1065, 1066, 1071~1080, 1086, 1087, 1097, 1106, 1107, 1110, 1120, 1129~1131, 113 5, 1137, 1143~1145, 1147~1156, 1167, 1173, 1184~1187, 1195, 1199, 1202, 1203, 1205~1208, 1210~1212, 1214, 1215, 1217~1219, 1233, 1234, 1237, 1 Compounds 239–1241, 1243, 1244, 1249, 1255, 1258, 1259, 1279, 1280, 1295, 1296, 1299–1302, 1304, 1306, 1312, 1316, 1317, 1322–1325, 1330, 1334, 1335, 1337–1340, 1346, 1348, 1350, 1354, 1357, 1360, 1361, 1366–1369, 1371, 1373, 1380, 1387, 1395, 1398, and 1404, more preferably compounds numbered 173, 175, 176, 182, 185, 199, and 2. 02, 228~230, 237, 250, 254, 258, 260~262, 264, 272, 274, 275, 277, 285, 288, 289, 293, 295, 299, 310, 317, 319, 324~329, 361~364, 367, 371, 390, 391 393, 394, 402, 439, 440, 444, 445, 447, 448, 454, 459, 461, 470, 471, 541~543, 592, 599, 609, 621~623, 652, 655~658, 671, 672, 697, 706, 754, 758, 769 770, 773, 775, 786, 787, 795, 801, 802, 810, 811, 812, 826, 827, 832, 833, 835, 842, 849, 856, 857, 859, 860, 866, 874, 875, 877, 907, 912, 937, 948, 953 Compounds of the following order: 955, 958, 963, 966, 972, 975, 977, 979, 980, 987–991, 1000, 1010, 1012–1014, 1018, 1025–1032, 1037, 1042, 1043, 1051, 1061–1063, 1071–1074.

[0820] <General Synthesis Method>

[0821] The compounds represented by formula (I) of the present invention and their pharmaceutically acceptable salts (hereinafter collectively referred to as the compounds of the present invention) can be synthesized by a combination of methods known in the art, including the synthetic methods described below. As also described herein, the reagents or solvents used as conditions described in the chemical formulas are merely exemplary. Substituents may be protected with appropriate protecting groups as needed, or protected or deprotected at appropriate stages. It should be noted that appropriate protecting groups and their removal methods may employ protecting groups of substituents commonly used in the art and known methods, for example, as described in PROTECTIVE GROUPS in ORGANIC SYNTHESIS, THIRD EDITION, John Wiley & Sons, Inc. Furthermore, intermediates generated in the following synthetic methods may be separated and purified by methods such as column chromatography, recrystallization, or distillation, or may be used directly in the next step without separation.

[0822] The following describes representative synthetic methods for the compounds of the present invention represented by general formula (I). It should be noted that the synthetic methods for the compounds of the present invention are not limited to these methods. It should be noted that the symbols in each formula are as defined in formula (I).

[0823] The compounds of this invention can be prepared by several synthetic methods. Hereinafter, L of formula (I) will be described. 1 For each structure, describe its representative synthetic method.

[0824] When L in equation (I) 1 For -NR 12 When using compounds of the present invention, for example, as shown in the reaction formula below, Ar can be constructed... 2 Following the ring and biaryl structure, with Ar 1 The method involves ring linkage for synthesis. Specifically, (AI) is converted to a borate ester (A-II), followed by a Suzuki-Miyaura coupling reaction (A-III), and then amination via a Buchwald-Hartwig reaction to obtain (A-IV). Deprotection of this ester yields the target compound. Modification with amino groups after deprotection also yields the target compound.

[0825] In the following reaction formulas, PG is the protecting group of the amino group (the same applies below).

[0826] [Chemical Formula 8]

[0827]

[0828] Step 1: The preferred borate is bis(pinacolyl)diboron, and the preferred palladium catalyst is tris(dibenzylacetone)dipalladium, palladium acetate, tetra(triphenylphosphine)palladium, bis(triphenylphosphine)dichloride, [1,1'-bis(diphenylphosphine)ferrocene]dichloride, etc. Where necessary, tricyclohexylphosphine, tricyclohexylphosphine tetrafluoroborate, 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthracene, etc., can be used as ligands. Potassium acetate is preferred as the base used. The solvent is not particularly limited, and examples include ethers such as tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane; N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, or mixtures thereof. The preferred reaction temperature is 50°C to 150°C, particularly preferably 70°C to 120°C.

[0829] Step 2: As a palladium catalyst, tetra(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride are preferred. As a base, examples include inorganic salts such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, and tripotassium phosphate. The solvent is not particularly limited, and examples include aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, and 1,2-diethoxyethane; alcohols such as methanol, ethanol, 2-propanol, and butanol; and solvents such as N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, water, or mixtures thereof. The reaction temperature is preferably 50°C to 150°C, and particularly preferably 80°C to 120°C.

[0830] Step 3: As a palladium catalyst, tris(dibenzylacetone)dipalladium, palladium acetate, etc., are preferred. As a ligand, 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthracene, 2-dicyclohexylphosphine-2',6'-dimethoxybiphenyl, 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl, etc., are preferred. As a base, examples include: inorganic salts such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, and tripotassium phosphate; potassium tert-butoxide, sodium tert-butoxide, etc. Here, there are no particular limitations on the solvent, for example: aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, and 1,2-diethoxyethane; N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, etc. The reaction temperature is preferably 50℃~150℃, and particularly preferably 80℃~150℃.

[0831] Step 4: The removal of the protecting group can be achieved using known methods commonly used in this field. For example, when the protecting group is a Boc group, strong acids such as trifluoroacetic acid, hydrochloric acid, and sulfuric acid are preferred; when the protecting group is phthalimide, hydrazine or ethylenediamine are preferred. The solvent is not particularly limited, and examples include: aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, and 1,2-diethoxyethane; halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, and chloroform; alcohols such as methanol, ethanol, 2-propanol, and butanol; and N,N-dimethylformamide, N-methylpyrrolidone, and dimethyl sulfoxide. The reaction temperature is preferably 0℃ to 100℃.

[0832] Step 5: As a reaction reagent with a leaving group, alkyl halides or the like can be used for the reaction. Examples of bases include organic bases such as triethylamine or N,N-diisopropylethylamine; and inorganic bases such as potassium carbonate or cesium carbonate. The preferred solvents are tetrahydrofuran, N,N-dimethylformamide, and dimethyl sulfoxide. The preferred reaction temperature is 0°C to 120°C, particularly preferably 0°C to room temperature. It should be noted that X in formula (I) can be used as an example in the above reaction formula. 1 X 2 and X 3 For the case of CH, but even if X 1 X 2 and X 3 If at least one of the atoms is N or CY (where Y is a halogen atom or a methyl atom), the same method can also be used for synthesis.

[0833] When L in equation (I) 1 For -NR 12 When reacting with the compounds of the present invention, as shown in the reaction formula below, it is also possible to react with Ar having an amino group. 1 L is constructed by reacting the ring. 1 After the connection point, through Ar 2 Synthesized by forming biaryl bonds through ring formation.

[0834] [Chemical Formula 9]

[0835]

[0836] Step 1: As a palladium catalyst, tris(dibenzylacetone)dipalladium, palladium acetate, etc., are preferred. As a ligand, 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthracene, 2-dicyclohexylphosphine-2',6'-dimethoxybiphenyl, 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl, etc., are preferred. As a base, examples include: inorganic salts such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, tripotassium phosphate, etc.; potassium tert-butoxide, sodium tert-butoxide, etc. Here, there are no particular limitations on the solvent, for example: aromatic hydrocarbons such as benzene, toluene, xylene, etc.; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, etc.; N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, etc. The reaction temperature is preferably 50℃~150℃, and particularly preferably 80℃~150℃.

[0837] Step 2: As the borizing agent, bis(pinacolyl)diboron is preferred; as the palladium catalyst, tris(dibenzylacetone)dipalladium, palladium acetate, tetra(triphenylphosphine)palladium, bis(triphenylphosphine)dichloride palladium, [1,1'-bis(diphenylphosphine)ferrocene]dichloride palladium, etc., are preferred. Where necessary, tricyclohexylphosphine, tricyclohexylphosphine tetrafluoroborate, or 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthracene, etc., are used as ligands. Potassium acetate is an example of the base used. The solvent is not particularly limited, and examples include ethers such as tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, and 1,2-diethoxyethane; N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, or mixtures thereof. The reaction temperature is preferably 50°C to 150°C, and particularly preferably 70°C to 120°C.

[0838] Step 3: As a palladium catalyst, tetra(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride are preferred. As a base, examples include inorganic salts such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, and tripotassium phosphate. The solvent is not particularly limited, and examples include aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, and 1,2-diethoxyethane; alcohols such as methanol, ethanol, 2-propanol, and butanol; and solvents such as N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, water, or mixtures thereof. The reaction temperature is preferably 50°C to 150°C, and particularly preferably 80°C to 120°C.

[0839] Step 4: Preferred reagents include strong acids such as trifluoroacetic acid, hydrochloric acid, and sulfuric acid; preferred solvents include dichloromethane, tetrahydrofuran, and ethyl acetate. The reaction temperature is preferably 0℃~50℃, and particularly preferably 0℃~room temperature.

[0840] When L in equation (I) 1 When the compound of the present invention is -O-, it can be synthesized using several synthetic methods shown below.

[0841] For example, it can be synthesized by the method shown in the following reaction formula. That is, by an aromatic nucleosubstitution reaction, it yields a product obtained via an oxygen atom reacting with Ar. 1 After the (C-II) ring is connected, the (C-II) is converted into boron compounds or tin compounds, etc., by reacting with the corresponding Ar. 2 The cyclic compound undergoes a cross-coupling reaction to synthesize a biaryl matrix (C-IV). Subsequently, with the amino group protected, its protection is carried out; if desired, the target compound can be synthesized by modifying the free amino group. It should be noted that step 2 is omitted, and Ar with appropriately reactive substituents is used instead. 2 Cyclic compounds can also be directly used for cross-coupling reactions such as (C-II). Additionally, the substituent R... 3 The conversion can be performed at the appropriate time in the following reaction formula, according to the target structure, using methods known to those skilled in the art.

[0842] [Chemical Formula 10]

[0843]

[0844] Step 1: Potassium carbonate, sodium carbonate, cesium carbonate, potassium tert-butoxide, sodium tert-butoxide, etc., are preferred as the alkali used. Preferred solvents include N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, etc. The reaction temperature is preferably room temperature to 150°C.

[0845] Step 2: Examples of borizing agents used include bis(pinacolyl)diboron, and examples of tin-oxidizing agents include hexamethyldistin. Preferred palladium catalysts include tris(dibenzylacetone)dipalladium, palladium acetate, tetra(triphenylphosphine)palladium, bis(triphenylphosphine)dichloride, and [1,1'-bis(diphenylphosphine)ferrocene]dichloride. Where necessary, tricyclohexylphosphine, tricyclohexylphosphine tetrafluoroborate, or 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthracene may be used as ligands. Preferred bases used during borination include potassium acetate. Here, the solvent is not particularly limited, and examples include: aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, and 1,2-diethoxyethane; alcohols such as methanol, ethanol, 2-propanol, and butanol; and N,N-dimethylformamide, N-methylpyrrolidone, and dimethyl sulfoxide. The reaction temperature is preferably 50℃ to 150℃, and particularly preferably 70℃ to 120℃.

[0846] Step 3: As a palladium catalyst, tetratetra(triphenylphosphine)palladium(0), bis(triphenylphosphine)palladium(II) dichloride, and [1,1'-bis(diphenylphosphine)ferrocene]palladium(II) dichloride are preferred. As a base, examples include inorganic salts such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, and tripotassium phosphate. As a solvent, there are no particular limitations; examples include aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, and 1,2-diethoxyethane; alcohols such as methanol, ethanol, 2-propanol, and butanol; and solvents such as N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, water, or mixtures thereof. The reaction temperature is preferably 50°C to 150°C, and particularly preferably 80°C to 120°C.

[0847] Step 4: The removal of the protecting group can be achieved using known methods commonly used in this field. For example, when the protecting group is a Boc group, strong acids such as trifluoroacetic acid, hydrochloric acid, and sulfuric acid are preferred; when the protecting group is phthalimide, hydrazine or ethylenediamine are preferred. The solvent is not particularly limited, and examples include: aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, and 1,2-diethoxyethane; halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, and chloroform; alcohols such as methanol, ethanol, 2-propanol, and butanol; and N,N-dimethylformamide, N-methylpyrrolidone, and dimethyl sulfoxide. The reaction temperature is preferably 0℃ to 100℃.

[0848] Step 5: As a reaction reagent with a leaving group, alkyl halides or the like can be used for the reaction. Examples of bases include organic bases such as triethylamine or N,N-diisopropylethylamine; and inorganic bases such as potassium carbonate or cesium carbonate. Preferred solvents include tetrahydrofuran, N,N-dimethylformamide, N-methylpyrrolidone, and dimethyl sulfoxide. The preferred reaction temperature is 0°C to 120°C.

[0849] When L in equation (I) 1 When the compound of the present invention is -O-, as shown in the reaction formula below, there is also a method for synthesizing the target compound using the intermediate pyrazole (DI). That is, after obtaining (D-II) by modifying the amino group by reacting a reagent having a leaving group with (DI), the target compound can be synthesized by the same method as described above.

[0850] [Chemical Formula 11]

[0851]

[0852] In the formula, R D 1 R D2Is as -NR D 1 R D2 R that satisfies equation (I) 3 Substituents.

[0853] Step 1: Examples of reaction reagents with leaving groups include alkyl halides or alkyl trifluoromethanesulfonates. Preferred bases are organic bases such as triethylamine or N,N-diisopropylethylamine; and inorganic bases such as potassium carbonate or cesium carbonate. Potassium iodide or other additives may be added if necessary. Preferred solvents include 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, and N-methylpyrrolidone. The preferred reaction temperature is room temperature to 150°C, particularly preferably 50°C to 120°C.

[0854] Step 2: Examples of boronizing agents include bis(pinacolyl)diboron. Preferred palladium catalysts include tris(dibenzylacetone)dipalladium, palladium acetate, tetra(triphenylphosphine)palladium, bis(triphenylphosphine)dichloride, and [1,1'-bis(diphenylphosphine)ferrocene]dichloride. Where necessary, tricyclohexylphosphine, tricyclohexylphosphine tetrafluoroborate, or 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthracene may be used as ligands. Potassium acetate is preferred as the base used. The solvent is not particularly limited, and examples include ethers such as tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, and 1,2-diethoxyethane; N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, or mixtures thereof. The reaction temperature is preferably 50°C to 150°C, and particularly preferably 70°C to 120°C.

[0855] Step 3: As a palladium catalyst, tetra(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride are preferred. As a base, examples include inorganic salts such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, and tripotassium phosphate. The solvent is not particularly limited, and examples include aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, and 1,2-diethoxyethane; alcohols such as methanol, ethanol, 2-propanol, and butanol; and solvents such as N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, water, or mixtures thereof. The reaction temperature is preferably 50°C to 150°C, and particularly preferably 80°C to 120°C.

[0856] Step 4: The removal of the protecting group can be achieved using known methods commonly used in this field. For example, when the protecting group is a Boc group, strong acids such as trifluoroacetic acid, hydrochloric acid, and sulfuric acid are preferred; when the protecting group is phthalimide, hydrazine or ethylenediamine are preferred. The solvent is not particularly limited, and examples include: aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, and 1,2-diethoxyethane; halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, and chloroform; alcohols such as methanol, ethanol, 2-propanol, and butanol; and N,N-dimethylformamide, N-methylpyrrolidone, and dimethyl sulfoxide. The reaction temperature is preferably 0℃ to 100℃.

[0857] When L in equation (I) 1 When the compound of the present invention is -O-, as shown in the following reaction formula, the following method is also used: in constructing the compound with Ar 2 Following the biaryl bond of the ring, the (E-III) amino group is converted to a bromine atom, and R is introduced through cross-coupling reactions, etc. 3 Substituents are used to synthesize the target compound.

[0858] [Chemical Formula 12]

[0859]

[0860] Step 1: As the borizing agent, bis(pinacolyl)diboron is preferred; as the palladium catalyst, tris(dibenzylacetone)dipalladium, palladium acetate, tetra(triphenylphosphine)palladium, bis(triphenylphosphine)dichloride palladium, [1,1'-bis(diphenylphosphine)ferrocene]dichloride palladium, etc., are preferred. Where necessary, tricyclohexylphosphine, tricyclohexylphosphine tetrafluoroborate, or 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthracene, etc., are used as ligands. Potassium acetate, etc., is preferred as the base used. The solvent is not particularly limited, and examples include ethers such as tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane; N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, or mixtures thereof. The reaction temperature is preferably 50°C to 150°C, and particularly preferably 70°C to 120°C.

[0861] Step 2: As a palladium catalyst, tetra(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride are preferred. As a base, examples include inorganic salts such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, and tripotassium phosphate. The solvent is not particularly limited, and examples include aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, and 1,2-diethoxyethane; alcohols such as methanol, ethanol, 2-propanol, and butanol; and solvents such as N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, water, or mixtures thereof. The reaction temperature is preferably 50°C to 150°C, and particularly preferably 80°C to 120°C.

[0862] Step 3: Isoamyl nitrite is preferably used as the reagent, and copper bromide is preferably used as the brominating agent. Preferred solvents include acetonitrile and toluene. The reaction temperature is preferably 0℃~50℃.

[0863] Step 4: As a palladium catalyst, tetra(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride are preferred. As a base, examples include inorganic salts such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, and tripotassium phosphate. The solvent is not particularly limited, and examples include aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, and 1,2-diethoxyethane; alcohols such as methanol, ethanol, 2-propanol, and butanol; and solvents such as N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, water, or mixtures thereof. The reaction temperature is preferably 50°C to 150°C, and particularly preferably 80°C to 120°C.

[0864] Step 5: The method for removing the protecting group can be any known method commonly used in this field. For example, when the protecting group is a Boc group, strong acids such as trifluoroacetic acid, hydrochloric acid, and sulfuric acid are preferred; when the protecting group is phthalimide, hydrazine or ethylenediamine are preferred. Here, the solvent is not particularly limited, and examples include: aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, and 1,2-diethoxyethane; halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, and chloroform; alcohols such as methanol, ethanol, 2-propanol, and butanol; and N,N-dimethylformamide, N-methylpyrrolidone, and dimethyl sulfoxide. The reaction temperature is preferably 0℃ to 100℃.

[0865] When L in equation (I) 1When the compound of the present invention is -O-, as shown in the reaction formula below, there is also a method as follows: after performing an aromatic nucleosubstitution reaction using a starting material (FI) having a nitro group, a functional group conversion of the nitro group is carried out, and Ar is reacted with... 2 The target compound is synthesized by forming a biaryl bond around the ring.

[0866] [Chemical Formula 13]

[0867]

[0868] Step 1: Potassium carbonate, sodium carbonate, cesium carbonate, potassium tert-butoxide, sodium tert-butoxide, etc., are preferred as the alkali used. Preferred solvents include N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, etc. The reaction temperature is preferably room temperature to 100°C.

[0869] Step 2: The preferred metal reagent is iron or zinc, preferably in combination with reagents such as ammonium chloride or acetic acid. Preferred solvents include organic solvents such as ethanol, methanol, and tetrahydrofuran, as well as mixed solvents obtained by adding water to them. The preferred reaction temperature is room temperature to 100°C.

[0870] Step 3: Isoamyl nitrite is preferably used as the reagent, and copper bromide is preferably used as the brominating agent. Preferred solvents include acetonitrile and toluene. The reaction temperature is preferably 0℃~50℃.

[0871] Step 4: As the borizing agent, bis(pinacolyl)diboron is preferred; as the palladium catalyst, tris(dibenzylacetone)dipalladium, palladium acetate, tetra(triphenylphosphine)palladium, bis(triphenylphosphine)dichloride, [1,1'-bis(diphenylphosphine)ferrocene]dichloride, etc., are preferred. Where necessary, tricyclohexylphosphine, tricyclohexylphosphine tetrafluoroborate, or 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthracene, etc., are used as ligands. Potassium acetate, etc., is preferred as the base used. The solvent is not particularly limited, and examples include ethers such as tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane; N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, or mixtures thereof. The reaction temperature is preferably 50°C to 150°C, and particularly preferably 70°C to 120°C.

[0872] Step 5: As a palladium catalyst, tetra(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride are preferred. As a base, examples include inorganic salts such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, and tripotassium phosphate. As a solvent, there are no particular limitations; examples include aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, and 1,2-diethoxyethane; alcohols such as methanol, ethanol, 2-propanol, and butanol; and solvents such as N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, water, or mixtures thereof. The reaction temperature is preferably 50°C to 150°C, and particularly preferably 80°C to 120°C.

[0873] Step 6: The method for removing the protecting group can be any known method commonly used in this field. For example, when the protecting group is a Boc group, strong acids such as trifluoroacetic acid, hydrochloric acid, and sulfuric acid are preferred; when the protecting group is phthalimide, hydrazine or ethylenediamine are preferred. Here, the solvent is not particularly limited, and examples include: aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, and 1,2-diethoxyethane; halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, and chloroform; alcohols such as methanol, ethanol, 2-propanol, and butanol; and N,N-dimethylformamide, N-methylpyrrolidone, and dimethyl sulfoxide. The reaction temperature is preferably 0℃ to 100℃.

[0874] When L in equation (I) 1 When the compound of the present invention is -O-, as shown in the reaction formula below, there is also a method for synthesizing the target compound using the intermediate pyrazole (G-IV) obtained through a cyclization reaction. That is, R can be introduced by reacting a reagent having a leaving group with pyrazole (G-IV) obtained from the starting material (GI) in three steps. 3 After the substituents are added, the target compound is synthesized using the same procedure as described above.

[0875] [Chemical Formula 14]

[0876]

[0877] Step 1: Potassium carbonate, sodium carbonate, cesium carbonate, potassium tert-butoxide, sodium tert-butoxide, etc., are preferred as the alkali used. Preferred solvents include N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, etc. The reaction temperature is preferably room temperature to 100°C.

[0878] Step 2: This reaction is preferably carried out in a solvent-free environment. The preferred reaction temperature is 50℃~100℃.

[0879] Step 3: The reaction is carried out using hydrazine monohydrate as a reagent. Acetic acid is preferred as a solvent. The preferred reaction temperature is 70℃~120℃.

[0880] Step 4: Examples of reagents with leaving groups include alkyl halides and aryl halides. Preferred bases are organic bases such as triethylamine or N,N-diisopropylethylamine; and inorganic bases such as potassium carbonate and cesium carbonate. Solvents are not particularly limited; examples include ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, and 1,2-diethoxyethane; and N,N-dimethylformamide, N-methylpyrrolidone, and dimethyl sulfoxide. The preferred reaction temperature is room temperature to 150°C.

[0881] Step 5: As the borizing agent, bis(pinacolyl)diboron is preferred; as the palladium catalyst, tris(dibenzylacetone)dipalladium, palladium acetate, tetra(triphenylphosphine)palladium, bis(triphenylphosphine)dichloride palladium, [1,1'-bis(diphenylphosphine)ferrocene]dichloride palladium, etc., are preferred. Where necessary, tricyclohexylphosphine, tricyclohexylphosphine tetrafluoroborate, or 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthracene, etc., are used as ligands. Potassium acetate, etc., is preferred as the base used. Here, the solvent is not particularly limited; examples include ethers such as tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane; N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, or mixtures thereof. The reaction temperature is preferably 50°C to 150°C, particularly preferably 70°C to 120°C.

[0882] Step 6: As a palladium catalyst, tetra(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride are preferred. As a base, examples include inorganic salts such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, and tripotassium phosphate. The solvent is not particularly limited, and examples include aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, and 1,2-diethoxyethane; alcohols such as methanol, ethanol, 2-propanol, and butanol; and solvents such as N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, water, or mixtures thereof. The reaction temperature is preferably 50°C to 150°C, and particularly preferably 80°C to 120°C.

[0883] Step 7: The method for removing the protecting group can be any known method commonly used in this field. For example, when the protecting group is a Boc group, strong acids such as trifluoroacetic acid, hydrochloric acid, and sulfuric acid are preferred; when the protecting group is phthalimide, hydrazine or ethylenediamine are preferred. Here, the solvent is not particularly limited, and examples include: aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, and 1,2-diethoxyethane; halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, and chloroform; alcohols such as methanol, ethanol, 2-propanol, and butanol; and N,N-dimethylformamide, N-methylpyrrolidone, and dimethyl sulfoxide. The reaction temperature is preferably 0℃ to 100℃.

[0884] When L in equation (I) 1 When the compound of the present invention is -O-, it can also be used in Ar as shown in the following reaction formula. 1 Aromatic nucleophilic substitution reactions can be carried out on a matrix with a leaving group on the ring, etc. Alternatively, step 2 can be omitted by using Ar with appropriate reactive substituents. 2 Cyclic compounds can be synthesized by directly using (H-II) in the reaction to synthesize (H-IV). It should be noted that the substituent R... 3 (For example, halogen atoms) can be converted into the target structure at the appropriate time in the following reaction using methods known to those skilled in the art.

[0885] [Chemical Formula 15]

[0886]

[0887] Step 1: Potassium carbonate, sodium carbonate, cesium carbonate, potassium tert-butoxide, sodium tert-butoxide, etc., are preferred as the alkali used. Preferred solvents include N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, etc. The reaction temperature is preferably room temperature to 150°C.

[0888] Step 2: As the borizing agent, bis(pinacolyl)diboron is preferred; as the palladium catalyst, tris(dibenzylacetone)dipalladium, palladium acetate, tetra(triphenylphosphine)palladium, bis(triphenylphosphine)dichloride palladium, [1,1'-bis(diphenylphosphine)ferrocene]dichloride palladium, etc., are preferred. Where necessary, tricyclohexylphosphine, tricyclohexylphosphine tetrafluoroborate, or 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthracene, etc., are used as ligands. Potassium acetate, etc., is preferred as the base used. Here, the solvent is not particularly limited; examples include ethers such as tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane; N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, or mixtures thereof. The reaction temperature is preferably 50°C to 150°C, and particularly preferably 70°C to 120°C.

[0889] Step 3: As a palladium catalyst, tetra(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride are preferred. As a base, examples include inorganic salts such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, and tripotassium phosphate. The solvent is not particularly limited, and examples include aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, and 1,2-diethoxyethane; alcohols such as methanol, ethanol, 2-propanol, and butanol; and solvents such as N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, water, or mixtures thereof. The reaction temperature is preferably 50°C to 150°C, and particularly preferably 80°C to 120°C.

[0890] Step 4: The removal of the protecting group can be achieved using known methods commonly used in this field. For example, when the protecting group is a Boc group, strong acids such as trifluoroacetic acid, hydrochloric acid, and sulfuric acid are preferred; when the protecting group is phthalimide, hydrazine or ethylenediamine are preferred. The solvent is not particularly limited, and examples include: aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, and 1,2-diethoxyethane; halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, and chloroform; alcohols such as methanol, ethanol, 2-propanol, and butanol; and N,N-dimethylformamide, N-methylpyrrolidone, and dimethyl sulfoxide. The reaction temperature is preferably 0℃ to 100℃.

[0891] Step 5: Examples of reagents with leaving groups include alkyl halides or aryl trifluoromethanesulfonates. Examples of bases include organic bases such as triethylamine or N,N-diisopropylethylamine; and inorganic bases such as potassium carbonate and cesium carbonate. Preferred solvents include tetrahydrofuran, N,N-dimethylformamide, N-methylpyrrolidone, and dimethyl sulfoxide. The preferred reaction temperature is 0℃ to 120℃.

[0892] When L in equation (I) 1 When the compound of the present invention is -O-, the target compound can be synthesized by modifying the compound (II) containing an alcohol, as shown in the following reaction formula.

[0893] [Chemical Formula 16]

[0894]

[0895] In the formula, R I R is a function that satisfies equation (I). 21 As -OR I Substituents.

[0896] Step 1: Examples of reagents with leaving groups include alkyl halides and alkyl trifluoromethanesulfonates. Preferred bases include sodium hydride, potassium carbonate, and cesium carbonate. Solvents are not particularly limited; examples include ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, and 1,2-diethoxyethane; and N,N-dimethylformamide, N-methylpyrrolidone, and dimethyl sulfoxide. The preferred reaction temperature is 0°C to 120°C.

[0897] Step 2: The strong acid used is preferably trifluoroacetic acid, hydrochloric acid, sulfuric acid, etc., and the solvent is preferably dichloromethane, tetrahydrofuran, ethyl acetate, etc. The reaction temperature is preferably 0℃~50℃, and particularly preferably 0℃~room temperature.

[0898] When L in equation (I) 1 When the compound of the present invention is -O-, as shown in the following reaction formula, the target compound can also be synthesized by the same method as the above-described synthesis method after converting the alcohol of (JI) into a leaving group and introducing an alkoxy group.

[0899] [Chemical Formula 17]

[0900]

[0901] In the formula,

[0902] Ms represents methanesulfonyl group;

[0903] R J R is a function that satisfies equation (I). 21 As -OR J Substituents.

[0904] Step 1: Methanesulfonyl chloride can be used as the methanesulfonylating agent for the reaction. Triethylamine, potassium carbonate, cesium carbonate, etc., are preferred as the base. There are no particular limitations on the solvent in this reaction; for example, organic solvents such as tetrahydrofuran or dichloromethane can be used. This reaction is preferably carried out at 0°C to 60°C, and particularly preferably at 0°C to room temperature.

[0905] Step 2: An alcohol (R) corresponding to the target compound can be used. J The reaction proceeds with the reaction proceeding from -OH). Preferred bases include inorganic bases such as sodium hydride, potassium carbonate, and cesium carbonate. Solvents used in this reaction include, for example, organic solvents such as tetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide, or N-methylpyrrolidone, or mixtures thereof. This reaction is preferably carried out at room temperature to 150°C, and particularly preferably at room temperature to 100°C.

[0906] Step 3: The strong acid used is preferably trifluoroacetic acid, hydrochloric acid, sulfuric acid, etc., and the solvent is preferably dichloromethane, tetrahydrofuran, ethyl acetate, etc. The reaction temperature is preferably 0℃~50℃, and particularly preferably 0℃~room temperature.

[0907] When L in equation (I) 1 When the compound of the present invention is -O-, as shown in the following reaction formula, it can also be synthesized by the same method as described above after introducing the target substituent via toluenehydrazone (K-II).

[0908] [Chemical Formula 18]

[0909]

[0910] In the formula,

[0911] Ts represents p-toluenesulfonyl group;

[0912] R K C 1-3 Alkoxy-C 1-3 Alkyl, hydroxyl (C 1-6 alkyl group, hydroxycarbonyl group (C 1-3 alkyl) group, (C 1-3 alkoxy)carbonyl-(C 1-3 Alkyl groups, or phenyl groups that can be replaced by 1 to 3 halogen atoms.

[0913] Step 1: In this reaction, toluenehydrazine is used as a reagent. Preferred solvents include toluene, methanol, and ethanol. The reaction temperature is preferably room temperature to 120°C, and particularly preferably 50°C to 120°C.

[0914] Step 2: Potassium carbonate, cesium carbonate, or cesium fluoride are preferred as the alkali used. The solvent is not particularly limited, and examples include ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, and 1,2-diethoxyethane. The reaction temperature is preferably room temperature to 150°C, and particularly preferably 80°C to 120°C.

[0915] Step 3: The strong acid used is preferably trifluoroacetic acid, hydrochloric acid, sulfuric acid, etc., and the solvent is preferably dichloromethane, tetrahydrofuran, ethyl acetate, etc. The reaction temperature is preferably 0℃~50℃, and particularly preferably 0℃~room temperature.

[0916] When L in equation (I) 1 When the compound of the present invention is -O-, it can also be synthesized by the method described in the following reaction formula. That is, p-methoxybenzyl alcohol is reacted with the starting material (LI) to obtain compound (L-II). Then, after functional group conversion of the bromine atom of (L-II) to obtain the biaryl compound (L-IV), the PMB group is deprotected to introduce phenol (LV). This phenol (LV) can be reacted with Ar having a reactive substituent by appropriate reaction. 1 After the compounds are linked, the amino groups are deprotected to synthesize the target compound.

[0917] [Chemical Formula 19]

[0918]

[0919] Step 1: Potassium carbonate, sodium carbonate, cesium carbonate, potassium tert-butoxide, sodium tert-butoxide, etc., are preferred as the alkali used. Preferred solvents include N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, etc. The reaction temperature is preferably room temperature to 100°C.

[0920] Step 2: The preferred borate is bis(pinacolyl)diboron, and the preferred palladium catalyst is tris(dibenzylacetone)dipalladium, palladium acetate, tetra(triphenylphosphine)palladium, bis(triphenylphosphine)dichloride, [1,1'-bis(diphenylphosphine)ferrocene]dichloride, etc. Where necessary, tricyclohexylphosphine, tricyclohexylphosphine tetrafluoroborate, or 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthracene, etc., can be used as ligands. Potassium acetate is preferred as the base. The solvent is not particularly limited, and examples include: aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, and 1,2-diethoxyethane; alcohols such as methanol, ethanol, 2-propanol, and butanol; and N,N-dimethylformamide, N-methylpyrrolidone, and dimethyl sulfoxide, etc. The reaction temperature is preferably 50℃~150℃, and particularly preferably 70℃~120℃.

[0921] Step 3: The preferred palladium catalysts are tetra(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride. The preferred bases are inorganic salts such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, and tripotassium phosphate. The solvent is not particularly limited; examples include aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, and 1,2-diethoxyethane; alcohols such as methanol, ethanol, 2-propanol, and butanol; and solvents such as N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, water, or mixtures thereof. The reaction temperature is preferably 50°C to 150°C, and particularly preferably 80°C to 120°C.

[0922] Step 4: The removal of the methoxybenzyl group can be achieved using known methods. Examples of solvents include strong acids such as trifluoroacetic acid, hydrochloric acid, and sulfuric acid. There are no particular limitations; examples include tetrahydrofuran, 1,4-dioxane, and dichloromethane. The preferred reaction temperature is 0℃ to 100℃.

[0923] Step 5: Potassium carbonate, sodium carbonate, cesium carbonate, potassium tert-butoxide, sodium tert-butoxide, etc., are preferred as the alkali used. Preferred solvents include N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, etc. The reaction temperature is preferably room temperature to 150°C.

[0924] Step 6: The method for removing the protecting group can be any known method commonly used in this field. For example, when the protecting group is a Boc group, strong acids such as trifluoroacetic acid, hydrochloric acid, and sulfuric acid are preferred; when the protecting group is phthalimide, hydrazine or ethylenediamine are preferred. Here, the solvent is not particularly limited, and examples include: aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, and 1,2-diethoxyethane; halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, and chloroform; alcohols such as methanol, ethanol, 2-propanol, and butanol; and N,N-dimethylformamide, N-methylpyrrolidone, and dimethyl sulfoxide. The reaction temperature is preferably 0℃ to 100℃.

[0925] When L in equation (I) 1 When the compound of the present invention is -O-, it can also be synthesized by the method described in the following reaction formula. That is, 2,4-dihydroxy-6-methylpyridine is reacted with the starting material (MI) to obtain compound (M-II). Then, (M-II) is trifluoromethanesulfonated and introduced into the target R. 3Substituents are added to obtain (M-IV). Then, after functional group conversion of the bromine atom in (M-IV) to obtain the biaryl compound (M-VI), the amino group is deprotected to synthesize the target compound.

[0926] [Chemical Formula 20]

[0927]

[0928] Step 1: Potassium carbonate, sodium carbonate, cesium carbonate, potassium tert-butoxide, sodium tert-butoxide, etc., are preferred as the alkali used. Preferred solvents include N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, etc. The reaction temperature is preferably room temperature to 160°C.

[0929] Step 2: Examples of trifluoromethanesulfonylating agents used include trifluoromethanesulfonic anhydride (Tf₂O), and preferred bases include pyridine, triethylamine, and N,N-diisopropylethylamine. Preferred solvents include tetrahydrofuran, dichloromethane, and 1,2-dichloroethane. The reaction temperature is preferably 0°C to 100°C.

[0930] Process 3: R 3 The introduction of substituents can employ known methods commonly used in this field. For example, when introducing R using boric acid derivatives... 3 In the case of substituents, tetra(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride are preferred as palladium catalysts. Examples of bases include inorganic salts such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, and tripotassium phosphate. The solvent is not particularly limited, and examples include aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, and 1,2-diethoxyethane; alcohols such as methanol, ethanol, 2-propanol, and butanol; and solvents such as N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, water, or mixtures thereof. The reaction temperature is preferably 50°C to 150°C, and particularly preferably 80°C to 120°C.

[0931] Additionally, for example, in relation to R 3 When reacting with alcohols or amines corresponding to the substituents, preferred bases include organic bases such as triethylamine or N,N-diisopropylethylamine; and inorganic bases such as potassium carbonate and cesium carbonate. Solvents are not particularly limited, and examples include ethers such as tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, and 1,2-diethoxyethane; and N,N-dimethylformamide, N-methylpyrrolidone, and dimethyl sulfoxide. The preferred reaction temperature is room temperature to 150°C.

[0932] Step 4: The preferred borate is bis(pinacolyl)diboron, and the preferred palladium catalyst is tris(dibenzylacetone)dipalladium, palladium acetate, tetra(triphenylphosphine)palladium, bis(triphenylphosphine)dichloride, [1,1'-bis(diphenylphosphine)ferrocene]dichloride, etc. Where necessary, tricyclohexylphosphine, tricyclohexylphosphine tetrafluoroborate, or 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthracene, etc., can be used as ligands. Potassium acetate is an example of a base used. The solvent is not particularly limited, and examples include aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, and 1,2-diethoxyethane; alcohols such as methanol, ethanol, 2-propanol, and butanol; and N,N-dimethylformamide, N-methylpyrrolidone, and dimethyl sulfoxide, etc. The reaction temperature is preferably 50℃~150℃, and particularly preferably 70℃~120℃.

[0933] Step 5: As a palladium catalyst, tetra(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride are preferred. As a base, examples include inorganic salts such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, and tripotassium phosphate. As a solvent, there are no particular limitations; examples include aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, and 1,2-diethoxyethane; alcohols such as methanol, ethanol, 2-propanol, and butanol; and solvents such as N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, water, or mixtures thereof. The reaction temperature is preferably 50°C to 150°C, and particularly preferably 80°C to 120°C.

[0934] Step 6: The method for removing the protecting group can be any known method commonly used in this field. For example, when the protecting group is a Boc group, strong acids such as trifluoroacetic acid, hydrochloric acid, and sulfuric acid are preferred; when the protecting group is phthalimide, hydrazine or ethylenediamine are preferred. Here, the solvent is not particularly limited, and examples include: aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, and 1,2-diethoxyethane; halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, and chloroform; alcohols such as methanol, ethanol, 2-propanol, and butanol; and N,N-dimethylformamide, N-methylpyrrolidone, and dimethyl sulfoxide. The reaction temperature is preferably 0℃ to 100℃.

[0935] When L in equation (I) 1 When the compound of the present invention is -CO-, it can be synthesized using several synthetic methods shown below.

[0936] For example, it can be synthesized by the method shown in the following reaction formula. That is, by making Ar with aldehyde... 1 The cyclic compound reacts with an anionic reagent modulated by compound (NI) to synthesize the corresponding alcohol (N-II), which is further oxidized to form a ketone (N-III), followed by the formation of a biaryl bond, to synthesize (NV). Additionally, the substituent R... 3 The conversion can be performed at the appropriate time in the following reaction formula, according to the target structure, using methods known to those skilled in the art.

[0937] [Chemical Formula 21]

[0938]

[0939] Step 1: As a reagent used to modulate the anion in the reaction with (NI), examples include: n-butyllithium, isopropyl magnesium chloride-lithium chloride complex solution, etc. Here, the solvent is not particularly limited, and examples include: aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, and 1,2-diethoxyethane; and halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, and chloroform, etc. The reaction temperature is preferably -78°C to 50°C, and particularly preferably -40°C to room temperature.

[0940] Step 2: The preferred oxidant is Dysmartin periodoalkane, 2-iodobenzoic acid, or pyridinium chlorochromate. The solvent is not particularly limited; examples include aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, and 1,2-diethoxyethane; and halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, and chloroform. The preferred reaction temperature is 0°C to 100°C.

[0941] Step 3: Examples of borizing agents used include bis(pinacolyl)diboron, and examples of tin-oxidizing agents include hexamethyldistin. Preferred palladium catalysts include tris(dibenzylacetone)dipalladium, palladium acetate, tetra(triphenylphosphine)palladium, bis(triphenylphosphine)dichloride, and [1,1'-bis(diphenylphosphine)ferrocene]dichloride. Where necessary, tricyclohexylphosphine, tricyclohexylphosphine tetrafluoroborate, or 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthracene may be used as ligands. Examples of bases used during borination include potassium acetate. Here, the solvent is not particularly limited, and examples include: aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, and 1,2-diethoxyethane; alcohols such as methanol, ethanol, 2-propanol, and butanol; and N,N-dimethylformamide, N-methylpyrrolidone, and dimethyl sulfoxide. The reaction temperature is preferably 50℃ to 150℃, and particularly preferably 70℃ to 120℃.

[0942] Step 4: As a palladium catalyst, tetra(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride are preferred. As a base, examples include inorganic salts such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, and tripotassium phosphate. The solvent is not particularly limited, and examples include aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, and 1,2-diethoxyethane; alcohols such as methanol, ethanol, 2-propanol, and butanol; and solvents such as N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, water, or mixtures thereof. The reaction temperature is preferably 50°C to 150°C, and particularly preferably 80°C to 120°C.

[0943] Step 5: The method for removing the protecting group can be any known method commonly used in this field. For example, when the protecting group is a Boc group, strong acids such as trifluoroacetic acid, hydrochloric acid, and sulfuric acid are preferred; when the protecting group is phthalimide, hydrazine or ethylenediamine are preferred. Here, the solvent is not particularly limited, and examples include: aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, and 1,2-diethoxyethane; halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, and chloroform; alcohols such as methanol, ethanol, 2-propanol, and butanol; and N,N-dimethylformamide, N-methylpyrrolidone, and dimethyl sulfoxide. The reaction temperature is preferably 0℃ to 100℃.

[0944] When L in equation (I) 1When the compound of the present invention is -CO-, as shown in the reaction formula below, there is also a method to synthesize the target compound using the intermediate pyrazole (O-II). That is, after obtaining (O-III) by modifying the amino group by reacting a reagent having a leaving group with (O-II) obtained by reduction (OI), the target compound can be synthesized by the same method as described above.

[0945] [Chemical Formula 22]

[0946]

[0947] In the formula, R O 1 R O2 Yes -NR O 1 R O2 R can be included in equation (I) 3 Substituents in.

[0948] Step 1: The preferred metallic reagent is iron or zinc, preferably in combination with reagents such as ammonium chloride or acetic acid. Preferred solvents include organic solvents such as ethanol, methanol, and tetrahydrofuran, as well as mixed solvents containing water. The preferred reaction temperature is room temperature to 100°C.

[0949] Step 2: Examples of reagents with leaving groups include alkyl halides or alkyl trifluoromethanesulfonates. Preferred bases are organic bases such as triethylamine or N,N-diisopropylethylamine; and inorganic bases such as potassium carbonate or cesium carbonate. Preferred solvents include 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, and dimethyl sulfoxide. The preferred reaction temperature is room temperature to 150°C.

[0950] Step 3: Examples of borizing agents used include bis(pinacolyl)diboron, and examples of tin-oxidizing agents include hexamethyldistin. Preferred palladium catalysts include tris(dibenzylacetone)dipalladium, palladium acetate, tetra(triphenylphosphine)palladium, bis(triphenylphosphine)dichloride, and [1,1'-bis(diphenylphosphine)ferrocene]dichloride. Where necessary, tricyclohexylphosphine, tricyclohexylphosphine tetrafluoroborate, or 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthracene may be used as ligands. Examples of bases used during borination include potassium acetate. Here, the solvent is not particularly limited, and examples include: aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, and 1,2-diethoxyethane; alcohols such as methanol, ethanol, 2-propanol, and butanol; and N,N-dimethylformamide, N-methylpyrrolidone, and dimethyl sulfoxide. The reaction temperature is preferably 50℃ to 150℃, and particularly preferably 70℃ to 120℃.

[0951] Step 4: As a palladium catalyst, tetra(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride are preferred. As a base, examples include inorganic salts such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, and tripotassium phosphate. The solvent is not particularly limited, and examples include aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, and 1,2-diethoxyethane; alcohols such as methanol, ethanol, 2-propanol, and butanol; and solvents such as N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, water, or mixtures thereof. The reaction temperature is preferably 50°C to 150°C, and particularly preferably 80°C to 120°C.

[0952] Step 5: The method for removing the protecting group can be any known method commonly used in this field. For example, when the protecting group is a Boc group, strong acids such as trifluoroacetic acid, hydrochloric acid, and sulfuric acid are preferred; when the protecting group is phthalimide, hydrazine or ethylenediamine are preferred. Here, the solvent is not particularly limited, and examples include: aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, and 1,2-diethoxyethane; halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, and chloroform; alcohols such as methanol, ethanol, 2-propanol, and butanol; and N,N-dimethylformamide, N-methylpyrrolidone, and dimethyl sulfoxide. The reaction temperature is preferably 0℃ to 100℃.

[0953] When L in equation (I) 1 When the compound of the present invention is -CO-, as shown in the reaction formula below, it can also be produced by using Ar. 1 After the ring-modified anionic reagent reacts with an aldehyde (PI) to obtain the corresponding alcohol (P-II), it is synthesized by the same method as described above.

[0954] [Chemical Formula 23]

[0955]

[0956] In the formula, X P It is an H or halogen atom.

[0957] Step 1: As a reagent for modulating the anion in the reaction system, examples include: n-butyllithium, isopropyl magnesium chloride-lithium chloride complex solution, etc. Here, the solvent is not particularly limited, and examples include: aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, and 1,2-diethoxyethane; and halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, and chloroform, etc. The reaction temperature is preferably -78℃ to 50℃, and particularly preferably -40℃ to room temperature.

[0958] Step 2: The preferred oxidant is Dysmartin periodoalkane, 2-iodobenzoic acid, or pyridinium chlorochromate. The solvent is not particularly limited; examples include aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, and 1,2-diethoxyethane; and halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, and chloroform. The preferred reaction temperature is 0°C to 100°C.

[0959] Step 3: Examples of borizing agents used include bis(pinacolyl)diboron, and examples of tin-oxidizing agents include hexamethyldistin. Preferred palladium catalysts include tris(dibenzylacetone)dipalladium, palladium acetate, tetra(triphenylphosphine)palladium, bis(triphenylphosphine)dichloride, and [1,1'-bis(diphenylphosphine)ferrocene]dichloride. Where necessary, tricyclohexylphosphine, tricyclohexylphosphine tetrafluoroborate, or 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthracene can be used as ligands. Examples of bases used in borination include potassium acetate. Here, the solvent is not particularly limited, and examples include: aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, and 1,2-diethoxyethane; alcohols such as methanol, ethanol, 2-propanol, and butanol; and N,N-dimethylformamide, N-methylpyrrolidone, and dimethyl sulfoxide. The reaction temperature is preferably 50℃ to 150℃, and particularly preferably 70℃ to 120℃.

[0960] Step 4: As a palladium catalyst, tetra(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride are preferred. As a base, examples include inorganic salts such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, and tripotassium phosphate. The solvent is not particularly limited, and examples include aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, and 1,2-diethoxyethane; alcohols such as methanol, ethanol, 2-propanol, and butanol; and solvents such as N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, water, or mixtures thereof. The reaction temperature is preferably 50°C to 150°C, and particularly preferably 80°C to 120°C.

[0961] Step 5: The method for removing the protecting group can be any known method commonly used in this field. For example, when the protecting group is a Boc group, strong acids such as trifluoroacetic acid, hydrochloric acid, and sulfuric acid are preferred; when the protecting group is phthalimide, hydrazine or ethylenediamine are preferred. Here, the solvent is not particularly limited, and examples include: aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, and 1,2-diethoxyethane; halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, and chloroform; alcohols such as methanol, ethanol, 2-propanol, and butanol; and N,N-dimethylformamide, N-methylpyrrolidone, and dimethyl sulfoxide. The reaction temperature is preferably 0℃ to 100℃.

[0962] When L in equation (I) 1 When the compound of the present invention is -CO-, as shown in the reaction formula below, it can also be used with Ar having Weinreb amide (Q-II). 1 After the corresponding ketone (Q-III) is synthesized from the ring, it is synthesized using the same method as described above.

[0963] [Chemical Formula 24]

[0964]

[0965] Step 1: As a reagent for modulating the anion in the reaction system, examples include: n-butyllithium, isopropyl magnesium chloride-lithium chloride complex solution, etc. Here, the solvent is not particularly limited, and examples include: aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, and 1,2-diethoxyethane; and halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, and chloroform, etc. The reaction temperature is preferably -78℃ to 50℃, and particularly preferably -40℃ to room temperature.

[0966] Step 2: Examples of borizing agents used include bis(pinacolyl)diboron, and examples of tin-oxidizing agents include hexamethyldistin. Preferred palladium catalysts include tris(dibenzylacetone)dipalladium, palladium acetate, tetra(triphenylphosphine)palladium, bis(triphenylphosphine)dichloride, and [1,1'-bis(diphenylphosphine)ferrocene]dichloride. Where necessary, tricyclohexylphosphine, tricyclohexylphosphine tetrafluoroborate, or 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthracene may be used as ligands. Examples of bases used during borination include potassium acetate. Here, the solvent is not particularly limited, and examples include: aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, and 1,2-diethoxyethane; alcohols such as methanol, ethanol, 2-propanol, and butanol; and N,N-dimethylformamide, N-methylpyrrolidone, and dimethyl sulfoxide. The reaction temperature is preferably 50℃ to 150℃, and particularly preferably 70℃ to 120℃.

[0967] Step 3: As a palladium catalyst, tetra(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride are preferred. As a base, examples include inorganic salts such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, and tripotassium phosphate. The solvent is not particularly limited, and examples include aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, and 1,2-diethoxyethane; alcohols such as methanol, ethanol, 2-propanol, and butanol; and solvents such as N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, water, or mixtures thereof. The reaction temperature is preferably 50°C to 150°C, and particularly preferably 80°C to 120°C.

[0968] Step 4: The removal of the protecting group can be achieved using known methods commonly used in this field. For example, when the protecting group is a Boc group, strong acids such as trifluoroacetic acid, hydrochloric acid, and sulfuric acid are preferred; when the protecting group is phthalimide, hydrazine or ethylenediamine are preferred. The solvent is not particularly limited, and examples include: aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, and 1,2-diethoxyethane; halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, and chloroform; alcohols such as methanol, ethanol, 2-propanol, and butanol; and N,N-dimethylformamide, N-methylpyrrolidone, and dimethyl sulfoxide. The reaction temperature is preferably 0℃ to 100℃.

[0969] When L in equation (I) 1 When the compound of the present invention is -CH2-, it can be synthesized using several synthetic methods shown below.

[0970] For example, it can be synthesized as shown in the reaction formula below. That is, it can be synthesized by introducing reactive substituents into Ar such as boric acid derivatives. 1 After the cyclic compound (R-II) is linked to benzyl bromide (RI) via a cross-coupling reaction, (R-III) is converted into a boron compound or a tin compound, etc., which then reacts with the corresponding Ar. 2 Synthesization is achieved through cross-coupling reactions of cyclic compounds, thereby forming biaryl bonds. Alternatively, step 2 can be omitted, using Ar with appropriately reactive substituents. 2 Cyclic compounds, thus allowing (R-III) to be used directly in cross-coupling reactions, etc.

[0971] [Chemical Formula 25]

[0972]

[0973] Step 1: As a palladium catalyst, tetra(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride are preferred. As a base, examples include inorganic salts such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, and tripotassium phosphate. As a solvent, there are no particular limitations; examples include aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, and 1,2-diethoxyethane; alcohols such as methanol, ethanol, 2-propanol, and butanol; and solvents such as N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, water, or mixtures thereof. The reaction temperature is preferably 50°C to 150°C, and particularly preferably 80°C to 120°C.

[0974] Step 2: Examples of borizing agents used include bis(pinacolyl)diboron, and examples of tin-oxidizing agents include hexamethyldistin. Preferred palladium catalysts include tris(dibenzylacetone)dipalladium, palladium acetate, tetra(triphenylphosphine)palladium, bis(triphenylphosphine)dichloride, and [1,1'-bis(diphenylphosphine)ferrocene]dichloride. Where necessary, tricyclohexylphosphine, tricyclohexylphosphine tetrafluoroborate, or 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthracene may be used as ligands. Examples of bases used during borination include potassium acetate. Here, the solvent is not particularly limited, and examples include: aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, and 1,2-diethoxyethane; alcohols such as methanol, ethanol, 2-propanol, and butanol; and N,N-dimethylformamide, N-methylpyrrolidone, and dimethyl sulfoxide. The reaction temperature is preferably 50℃ to 150℃, and particularly preferably 70℃ to 120℃.

[0975] Step 3: As a palladium catalyst, tetra(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride are preferred. As a base, examples include inorganic salts such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, and tripotassium phosphate. The solvent is not particularly limited, and examples include aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, and 1,2-diethoxyethane; alcohols such as methanol, ethanol, 2-propanol, and butanol; and solvents such as N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, water, or mixtures thereof. The reaction temperature is preferably 50°C to 150°C, and particularly preferably 80°C to 120°C.

[0976] Step 4: The removal of the protecting group can be achieved using known methods commonly used in this field. For example, when the protecting group is a Boc group, strong acids such as trifluoroacetic acid, hydrochloric acid, and sulfuric acid are preferred; when the protecting group is phthalimide, hydrazine or ethylenediamine are preferred. The solvent is not particularly limited, and examples include: aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, and 1,2-diethoxyethane; halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, and chloroform; alcohols such as methanol, ethanol, 2-propanol, and butanol; and N,N-dimethylformamide, N-methylpyrrolidone, and dimethyl sulfoxide. The reaction temperature is preferably 0℃ to 100℃.

[0977] When L in equation (I) 1 When the compound of the present invention is -CH2-, as shown in the following reaction formula, it can also be produced by utilizing the presence of Ar 1 The alkylation reaction of nitrogen atoms on the ring, with Ar 1 After obtaining (S-II) by ring connection, it is synthesized using the same method as the above synthesis method.

[0978] [Chemical Formula 26]

[0979]

[0980] Step 1: The preferred base is triethylamine, N,N-diisopropylethylamine, potassium carbonate, cesium carbonate, etc. The solvent is not particularly limited; for example, ethers such as tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, and 1,2-diethoxyethane are preferred; as are N,N-dimethylformamide, N-methylpyrrolidone, and dimethyl sulfoxide. The reaction temperature is preferably room temperature to 120°C, and particularly preferably 40°C to 100°C.

[0981] Step 2: As a palladium catalyst, tetra(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride are preferred. As a base, examples include inorganic salts such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, and tripotassium phosphate. The solvent is not particularly limited, and examples include aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, and 1,2-diethoxyethane; alcohols such as methanol, ethanol, 2-propanol, and butanol; and solvents such as N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, water, or mixtures thereof. The reaction temperature is preferably 50°C to 150°C, and particularly preferably 80°C to 120°C.

[0982] Step 3: The removal of the protecting group can be achieved using known methods commonly used in this field. For example, when the protecting group is a Boc group, strong acids such as trifluoroacetic acid, hydrochloric acid, and sulfuric acid are preferred; when the protecting group is phthalimide, hydrazine or ethylenediamine are preferred. The solvent is not particularly limited, and examples include: aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, and 1,2-diethoxyethane; halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, and chloroform; alcohols such as methanol, ethanol, 2-propanol, and butanol; and N,N-dimethylformamide, N-methylpyrrolidone, and dimethyl sulfoxide. The reaction temperature is preferably 0℃ to 100℃.

[0983] When L in equation (I) 1 When the compound of the present invention is -CH2-, as shown in the reaction formula below, there is a method for synthesizing a compound with the target amino or alkoxy group introduced from the aldehyde of the intermediate (TI).

[0984] [Chemical Formula 27]

[0985]

[0986] In the formula, R T 1 R T2 R T3 H atom or C 1-6 alkyl.

[0987] Step 1: A reducing amination reaction is carried out using an amine corresponding to the target compound. Examples of imine reducing agents include sodium triacetoxyborohydride and sodium cyanoborohydride. Preferred solvents include toluene, dichloromethane, and dichloroethane. The preferred reaction temperature is room temperature to 80°C.

[0988] Step 2: The strong acid used is preferably trifluoroacetic acid, hydrochloric acid, sulfuric acid, etc., and the solvent is preferably dichloromethane, tetrahydrofuran, ethyl acetate, etc. The reaction temperature is preferably 0℃~50℃, and particularly preferably 0℃~room temperature.

[0989] Step 3: Examples of reducing agents used include sodium borohydride and lithium borohydride. Preferred solvents include tetrahydrofuran, methanol, or mixtures thereof. The reaction is preferably carried out at 0°C to room temperature.

[0990] Step 4: As a reagent with a leaving group, alkyl halides, alkyl trifluoromethanesulfonates, etc., are used. Examples of bases include sodium hydride, potassium carbonate, cesium carbonate, etc. The preferred solvents are tetrahydrofuran, N,N-dimethylformamide, dimethyl sulfoxide, etc. The preferred reaction temperature is 0℃~80℃.

[0991] Step 5: The strong acid used is preferably trifluoroacetic acid, hydrochloric acid, sulfuric acid, etc., and the solvent is preferably dichloromethane, tetrahydrofuran, ethyl acetate, etc. The reaction temperature is preferably 0℃~50℃, and particularly preferably 0℃~room temperature.

[0992] When L in equation (I) 1 When the compound of the present invention is -CH2-, as shown in the reaction formula below, there is also a method to synthesize a compound having the target amide group by functional group conversion of the ester group present in the intermediate (UI).

[0993] [Chemical Formula 28]

[0994]

[0995] In the formula, R U C 1-6 alkyl.

[0996] Step 1: Examples of suitable bases include inorganic salts such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, and potassium carbonate; metal alkoxides such as sodium ethoxide and sodium methoxide; or solutions obtained by diluting these bases with water, etc. The solvent is not particularly limited; examples include tetrahydrofuran, methanol, ethanol, water, or mixtures thereof. The preferred reaction temperature is 0°C to 60°C.

[0997] Step 2: Examples of condensing agents used include HATU, HOBt, HOAt, and EDCI. The reaction is carried out in the absence of an alkali or in the presence of triethylamine, N,N-diisopropylethylamine, etc., as an alkali. Tetrahydrofuran, dichloromethane, N,N-dimethylformamide, etc., are preferred solvents. The reaction temperature is preferably between 0°C and 100°C.

[0998] Step 3: The strong acid used is preferably trifluoroacetic acid, hydrochloric acid, sulfuric acid, etc., and the solvent is preferably dichloromethane, tetrahydrofuran, ethyl acetate, etc. The reaction temperature is preferably 0℃~50℃, and particularly preferably 0℃~room temperature.

[0999] When L in equation (I) 1 When the compound of the present invention is -CH2-, it can also be synthesized by the method shown in the reaction formula below. That is, it can be synthesized by the same method as described above after reacting an acetylene compound (V-III) with (V-II) which has been introduced with an azide group to obtain a triazole (V-IV).

[1000] [Chemical Formula 29]

[1001]

[1002] Step 1: This reaction involves introducing an azide group using sodium azide. Examples of solvents include N,N-dimethylformamide, N-methylpyrrolidone, and dimethyl sulfoxide. The preferred reaction temperature is room temperature to 100°C.

[1003] Step 2: This reaction involves the synthesis of a triazole ring using an alkyne compound corresponding to the target compound. Copper iodide (I) and copper bromide (I) are preferred metal reagents; ligands such as tris[(1-benzyl-1H-1,2,3-triazol-4-yl)methyl]amine (TBTA) may be added if necessary. The solvent is not particularly limited, and examples include: aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, and 1,2-diethoxyethane; halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, and chloroform; alcohols such as methanol, ethanol, 2-propanol, and butanol; and N,N-dimethylformamide, N-methylpyrrolidone, and dimethyl sulfoxide. The reaction is preferably carried out at room temperature to 80°C.

[1004] Step 3: As a palladium catalyst, tetra(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride are preferred. As a base, examples include inorganic salts such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, and tripotassium phosphate. The solvent is not particularly limited, and examples include aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, and 1,2-diethoxyethane; alcohols such as methanol, ethanol, 2-propanol, and butanol; and solvents such as N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, water, or mixtures thereof. The reaction temperature is preferably 50°C to 150°C, and particularly preferably 80°C to 120°C.

[1005] Step 4: The removal of the protecting group can be achieved using known methods commonly used in this field. For example, when the protecting group is a Boc group, strong acids such as trifluoroacetic acid, hydrochloric acid, and sulfuric acid are preferred; when the protecting group is phthalimide, hydrazine or ethylenediamine are preferred. The solvent is not particularly limited, and examples include: aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, and 1,2-diethoxyethane; halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, and chloroform; alcohols such as methanol, ethanol, 2-propanol, and butanol; and N,N-dimethylformamide, N-methylpyrrolidone, and dimethyl sulfoxide. The reaction temperature is preferably 0℃ to 100℃.

[1006] When L in equation (I) 1 When the compound of the present invention is -CH2-, it can also be synthesized by the method shown in the reaction formula below. That is, after obtaining (WV) by coupling reaction of boric acid (WI) with nitropyrazole ring (W-II), reduction of nitro group, and modification of amino group, the target compound can be synthesized by the same method as described above.

[1007] [Chemical Formula 30]

[1008]

[1009] In the formula, R W1 R W2 Yes -NR W1 R W2 R can be included in equation (I) 3 Substituents in.

[1010] Step 1: As a palladium catalyst, tetra(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride are preferred. As a base, examples include inorganic salts such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, and tripotassium phosphate. As a solvent, there are no particular limitations; examples include aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, and 1,2-diethoxyethane; alcohols such as methanol, ethanol, 2-propanol, and butanol; and solvents such as N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, water, or mixtures thereof. The reaction temperature is preferably 50°C to 150°C, and particularly preferably 80°C to 120°C.

[1011] Step 2: The preferred metal reagent is iron or zinc, preferably in combination with reagents such as ammonium chloride or acetic acid. Preferred solvents include organic solvents such as ethanol, methanol, and tetrahydrofuran, as well as mixed solvents obtained by adding water to them. The preferred reaction temperature is room temperature to 100°C.

[1012] Step 3: Examples of reagents with leaving groups include alkyl halides or alkyl trifluoromethanesulfonates. Preferred bases are organic bases such as triethylamine or N,N-diisopropylethylamine; and inorganic bases such as potassium carbonate or cesium carbonate. Preferred solvents include 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, and dimethyl sulfoxide. The preferred reaction temperature is room temperature to 150°C.

[1013] Step 4: Examples of boryling agents include bis(pinacolyl)diboron. Preferred catalysts include tetra(triphenylphosphine)palladium, bis(triphenylphosphine)dichloride palladium, [1,1'-bis(diphenylphosphine)ferrocene]dichloride palladium, tris(dibenzylacetone)dipalladium, palladium acetate, and XPhos-Pd-G2. Where necessary, ligands such as tricyclohexylphosphine, 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl, and 2-dicyclohexylphosphine-2',6'-dimethoxybiphenyl can also be used. Potassium acetate is preferred as a base. Preferred solvents include 1,4-dioxane and dimethyl sulfoxide. The reaction temperature is preferably 50°C to 150°C, and particularly preferably 70°C to 120°C.

[1014] Step 5: As a palladium catalyst, tetra(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride are preferred. As a base, examples include inorganic salts such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, and tripotassium phosphate. As a solvent, there are no particular limitations; examples include aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, and 1,2-diethoxyethane; alcohols such as methanol, ethanol, 2-propanol, and butanol; and solvents such as N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, water, or mixtures thereof. The reaction temperature is preferably 50°C to 150°C, and particularly preferably 80°C to 120°C.

[1015] Step 6: The method for removing the protecting group can be any known method commonly used in this field. For example, when the protecting group is a Boc group, strong acids such as trifluoroacetic acid, hydrochloric acid, and sulfuric acid are preferred; when the protecting group is phthalimide, hydrazine or ethylenediamine are preferred. Here, the solvent is not particularly limited, and examples include: aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, and 1,2-diethoxyethane; halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, and chloroform; alcohols such as methanol, ethanol, 2-propanol, and butanol; and N,N-dimethylformamide, N-methylpyrrolidone, and dimethyl sulfoxide. The reaction temperature is preferably 0℃ to 100℃.

[1016] When L in equation (I) 1 When the compounds of the present invention are -CHMe-, -C(=CH2)-, 1,1-cyclopropylidene, they can be synthesized using the method shown below. That is, by reacting toluenehydrazone (X-III) with Ar having a halogen atom... 1 After reacting the cyclic compound to obtain the exo-olefin (X-IV), the olefin is reduced or cyclopropanized and deprotected to synthesize the target compound. 1 Compounds with the form -C(=CH2)- can be synthesized by deprotecting (X-IV).

[1017] [Chemical Formula 31]

[1018]

[1019] Step 1: As a palladium catalyst, tetra(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride are preferred. As a base, examples include inorganic salts such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, and tripotassium phosphate. As a solvent, there are no particular limitations; examples include aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, and 1,2-diethoxyethane; alcohols such as methanol, ethanol, 2-propanol, and butanol; and solvents such as N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, water, or mixtures thereof. The reaction temperature is preferably 50°C to 150°C, and particularly preferably 80°C to 120°C.

[1020] Step 2: This reaction uses toluidine hydrazide as a reagent to form toluene hydrazone. Preferred solvents include toluene, methanol, and ethanol. The preferred reaction temperature is room temperature to 120°C.

[1021] Step 3: This reaction involves the coupling reaction of toluenehydrazone with aryl halides to synthesize foreign olefins. Preferred catalysts include tetra(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride, tris(dibenzylacetone)palladium, and palladium acetate. Where necessary, ligands such as 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthracene, 2-(dicyclohexylphosphine)-2',4',6'-triisopropyl-1,1'-biphenyl, and 2-dicyclohexylphosphine-2',6'-dimethoxybiphenyl are also used. Preferred bases include cesium carbonate, lithium tert-butoxide, and tripotassium phosphate. Preferred solvents include 1,4-dioxane, toluene, and fluorobenzene. The preferred reaction temperature is 50°C to 150°C.

[1022] Step 4: This reaction involves the reduction of olefins by combining a metallic reagent such as palladium on carbon (Pd / C) with a hydrogen source such as hydrogen gas. Ethanol, methanol, or ethyl acetate are preferred solvents. The reaction is preferably carried out at a temperature between 0°C and 100°C.

[1023] Step 5: The strong acid used is preferably trifluoroacetic acid, hydrochloric acid, sulfuric acid, etc., and the solvent is preferably dichloromethane, tetrahydrofuran, ethyl acetate, etc. The reaction temperature is preferably 0℃~50℃, and particularly preferably 0℃~room temperature.

[1024] Step 6: This reaction converts an olefin into a cyclopropane using trimethyl sulfoxide. Preferred bases include sodium hydride and potassium tert-butoxide. The preferred solvent is dimethyl sulfoxide or tetrahydrofuran. The preferred reaction temperature is 0°C to 100°C.

[1025] Step 7: The strong acid used is preferably trifluoroacetic acid, hydrochloric acid, sulfuric acid, etc., and the solvent is preferably dichloromethane, tetrahydrofuran, ethyl acetate, etc. The reaction temperature is preferably 0℃~50℃, and particularly preferably 0℃~room temperature.

[1026] When L in equation (I) 1 It is -CH(R) 11 When synthesizing the compounds of the present invention, various methods as shown below can be used.

[1027] For example, the synthesis can be carried out as shown in the reaction formula below. That is, there is a method to synthesize the target compound by reducing the ketone of (YI) prepared in the above synthesis method and then deprotecting the amino group. Alternatively, the hydroxyl group of the intermediate (Y-II) can be modified by alkylation or the like.

[1028] [Chemical Formula 32]

[1029]

[1030] In the formula, R YR is a function that satisfies equation (I). 11 As -OR Y Substituents.

[1031] Step 1: Examples of reducing agents include sodium borohydride and lithium borohydride. Preferred solvents include tetrahydrofuran, methanol, ethanol, or mixtures thereof. The reaction is preferably carried out at a temperature between 0°C and 50°C.

[1032] Step 2: The removal of the protecting group can be achieved using known methods commonly used in this field. For example, when the protecting group is a Boc group, strong acids such as trifluoroacetic acid, hydrochloric acid, and sulfuric acid are preferred; when the protecting group is phthalimide, hydrazine or ethylenediamine are preferred. The solvent is not particularly limited, and examples include: aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, and 1,2-diethoxyethane; halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, and chloroform; alcohols such as methanol, ethanol, 2-propanol, and butanol; and N,N-dimethylformamide, N-methylpyrrolidone, and dimethyl sulfoxide. The reaction temperature is preferably 0℃ to 100℃.

[1033] Step 3: As a reagent with a leaving group, alkyl halides, alkyl trifluoromethanesulfonates, etc., are used. Examples of bases include sodium hydride, potassium carbonate, cesium carbonate, etc. The preferred solvents are tetrahydrofuran, N,N-dimethylformamide, dimethyl sulfoxide, etc. The preferred reaction temperature is 0℃~80℃.

[1034] Step 4: The removal of the protecting group can be achieved using known methods commonly used in this field. For example, when the protecting group is a Boc group, strong acids such as trifluoroacetic acid, hydrochloric acid, and sulfuric acid are preferred; when the protecting group is phthalimide, hydrazine or ethylenediamine are preferred. The solvent is not particularly limited, and examples include: aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, and 1,2-diethoxyethane; halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, and chloroform; alcohols such as methanol, ethanol, 2-propanol, and butanol; and N,N-dimethylformamide, N-methylpyrrolidone, and dimethyl sulfoxide. The reaction temperature is preferably 0℃ to 100℃.

[1035] When L in equation (I) 1 -CH(R) 11 When synthesizing the compounds of the present invention, the reaction can also be carried out as follows: That is, after adding an acetylenic group to the aldehyde (ZI) of the starting material, a cyclization reaction is performed using (Z-IV) to obtain the compound having the target R. 3Substituent isoxazoles (ZVs). The target compound can be synthesized by deprotecting the amino group after modifying the hydroxyl group of the (ZV) through alkylation or other reactions.

[1036] [Chemical Formula 33]

[1037]

[1038] In the formula, R Z R is a function that satisfies equation (I). 11 As -OR Z Substituents.

[1039] Step 1: This reaction is an addition reaction between acetylenyl magnesium bromide (Z-II) and an aldehyde (ZI). Tetrahydrofuran, dichloromethane, etc., are preferred solvents. The reaction is preferably carried out at a temperature of -78°C to room temperature.

[1040] Step 2: This reaction involves constructing an isoxazole ring using an oxime reagent (Z-IV) corresponding to the target compound. Potassium carbonate, sodium carbonate, cesium carbonate, etc., are preferred as a base, and 1,4-dioxane, toluene, etc., are preferred as a solvent. The reaction temperature is preferably 50℃~120℃.

[1041] Step 3: As a reagent with a leaving group, alkyl halides, alkyl trifluoromethanesulfonates, etc., are used. Examples of bases include sodium hydride, potassium carbonate, cesium carbonate, etc. The preferred solvents are tetrahydrofuran, N,N-dimethylformamide, dimethyl sulfoxide, etc. The preferred reaction temperature is 0℃~80℃.

[1042] Step 4: As a palladium catalyst, tetra(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride are preferred. As a base, examples include inorganic salts such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, and tripotassium phosphate. The solvent is not particularly limited, and examples include aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, and 1,2-diethoxyethane; alcohols such as methanol, ethanol, 2-propanol, and butanol; and solvents such as N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, water, or mixtures thereof. The reaction temperature is preferably 50°C to 150°C, and particularly preferably 80°C to 120°C.

[1043] Step 5: The strong acid used is preferably trifluoroacetic acid, hydrochloric acid, sulfuric acid, etc., and the solvent is preferably dichloromethane, tetrahydrofuran, ethyl acetate, etc. The reaction temperature is preferably 0℃~50℃, and particularly preferably 0℃~room temperature.

[1044] When L in equation (I) 1When the compound of the present invention is -S- or -SO-, it can be synthesized using a variety of methods shown below.

[1045] For example, the synthesis can be carried out as shown in the following reaction formula. That is, after converting the intermediate (A'-I) obtained in the above synthesis into trifluoromethanesulfonate (A'-II), a thiol side chain can be introduced in a coupling reaction, and the compound (A'-III) can be treated with a suitable base to carry out an aromatic nucleosubstitution reaction, thereby reacting with Ar 1 Ring connection. If needed, it can then be connected via Ar. 1 Using the halogen atom as a starting point, target side chain substituents are introduced to synthesize the target compound. It should be noted that the Ar used in step 3... 1 The compound has been R 3 In cases of modification, step 4 can be omitted.

[1046] [Chemical Formula 34]

[1047]

[1048] Step 1: Examples of trifluoromethanesulfonylating agents used include trifluoromethanesulfonic anhydride (Tf₂O), and preferred bases include pyridine, triethylamine, and N,N-diisopropylethylamine. Preferred solvents include tetrahydrofuran, dichloromethane, and 1,2-dichloroethane. The preferred reaction temperature is -20°C to 50°C.

[1049] Step 2: As a catalyst, tetra(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride, tris(dibenzylacetone)palladium, palladium acetate, etc., are preferred. Where necessary, ligands such as 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthracene, 2-(dicyclohexylphosphine)-2',4',6'-triisopropyl-1,1'-biphenyl, and 2-dicyclohexylphosphine-2',6'-dimethoxybiphenyl can also be used. Preferred bases include N,N-diisopropylethylamine or triethylamine, potassium carbonate, cesium carbonate, etc. Solvents include 1,4-dioxane, tetrahydrofuran, N,N-dimethylformamide, etc. The preferred reaction temperature is 50°C to 150°C.

[1050] Step 3: Potassium carbonate, cesium carbonate, and 1,8-diazabicyclo[5.4.0]-7-undecene (DBU) are preferred as the base. Preferred solvents include 1,4-dioxane, tetrahydrofuran, N,N-dimethylformamide, N-methylpyrrolidone, and dimethyl sulfoxide. The reaction temperature is preferably 0°C to 150°C.

[1051] Process 4: R 3The introduction of substituents can be achieved using known methods common in the field. For example, when introducing R using boric acid derivatives... 3 In the case of substituents, tetra(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride are preferred as palladium catalysts. Examples of bases include inorganic salts such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, and tripotassium phosphate. The solvent is not particularly limited, and examples include aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, and 1,2-diethoxyethane; alcohols such as methanol, ethanol, 2-propanol, and butanol; and solvents such as N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, water, or mixtures thereof. The reaction temperature is preferably 50°C to 150°C, and particularly preferably 80°C to 120°C.

[1052] Additionally, for example, in relation to R 3 When reacting with alcohols or amines corresponding to the substituents, preferred bases include organic bases such as triethylamine or N,N-diisopropylethylamine; and inorganic bases such as potassium carbonate and cesium carbonate. Solvents are not particularly limited, and examples include ethers such as tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, and 1,2-diethoxyethane; and N,N-dimethylformamide, N-methylpyrrolidone, and dimethyl sulfoxide. The preferred reaction temperature is room temperature to 150°C.

[1053] Step 5: The strong acid used is preferably trifluoroacetic acid, hydrochloric acid, sulfuric acid, etc., and the solvent is preferably dichloromethane, tetrahydrofuran, ethyl acetate, etc. The reaction temperature is preferably 0℃~50℃, and particularly preferably 0℃~room temperature.

[1054] When L in equation (I) 1 When the compound of the present invention is -S-, it can also be synthesized as shown in the following reaction formula. That is, as an Ar-like compound such as pyrazole. 2 The ring-linking method can utilize aromatic nucleosubstitution reactions, and the synthesis method after the formation of biaryl bonds can be carried out in the same way as the above process.

[1055] [Chemical Formula 35]

[1056]

[1057] Step 1: The preferred base used is triethylamine, N,N-diisopropylethylamine, potassium carbonate, cesium carbonate, etc. Preferred solvents include 1,4-dioxane, tetrahydrofuran, N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, etc. The preferred reaction temperature is room temperature to 150°C.

[1058] Step 2: As a catalyst, tetra(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride, tris(dibenzylacetone)palladium, palladium acetate, etc., are preferred. Where necessary, ligands such as 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthracene, 2-(dicyclohexylphosphine)-2',4',6'-triisopropyl-1,1'-biphenyl, and 2-dicyclohexylphosphine-2',6'-dimethoxybiphenyl are also used. Preferred bases include N,N-diisopropylethylamine or triethylamine, potassium carbonate, cesium carbonate, etc. Recommended solvents include 1,4-dioxane, tetrahydrofuran, N,N-dimethylformamide, etc. The reaction temperature is preferably 50°C to 150°C.

[1059] Step 3: Potassium carbonate, cesium carbonate, and 1,8-diazabicyclo[5.4.0]-7-undecene (DBU) are preferred as the base. Preferred solvents include 1,4-dioxane, tetrahydrofuran, N,N-dimethylformamide, N-methylpyrrolidone, and dimethyl sulfoxide. The reaction temperature is preferably 0°C to 150°C.

[1060] Step 4: The strong acid used is preferably trifluoroacetic acid, hydrochloric acid, sulfuric acid, etc., and the solvent is preferably dichloromethane, tetrahydrofuran, ethyl acetate, etc. The reaction temperature is preferably 0℃~50℃, and particularly preferably 0℃~room temperature.

[1061] When L in equation (I) 1 When the compound of the present invention is -SO-, the sulfide (C'-I) can be oxidized to sulfoxide (C'-II) as shown in the following reaction formula, thereby deprotecting and synthesizing the target compound.

[1062] [Chemical Formula 36]

[1063]

[1064] Step 1: Examples of oxidants used include 3-chloroperbenzoic acid. Examples of solvents include 1,4-dioxane, tetrahydrofuran, N,N-dimethylformamide, and dimethyl sulfoxide. The preferred reaction temperature is 0°C to 100°C.

[1065] Step 2: The strong acid used is preferably trifluoroacetic acid, hydrochloric acid, sulfuric acid, etc., and the solvent is preferably dichloromethane, tetrahydrofuran, ethyl acetate, etc. The reaction temperature is preferably 0℃~50℃, and particularly preferably 0℃~room temperature.

[1066] As a pharmaceutically acceptable salt of a compound of formula (I), there are no particular limitations as long as it is a pharmaceutically acceptable salt. Examples of salts that may be considered include: salts with inorganic acids such as hydrogen chloride, hydrogen bromide, sulfuric acid, nitric acid, phosphoric acid, and carbonic acid; salts with organic acids such as maleic acid, fumaric acid, citric acid, malic acid, tartaric acid, lactic acid, succinic acid, benzoic acid, oxalic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, acetic acid, trifluoroacetic acid, and formic acid; salts with amino acids such as glycine, lysine, arginine, histidine, ornithine, glutamic acid, and aspartic acid; salts with alkali metals such as sodium, potassium, and lithium; salts with alkaline earth metals such as calcium and magnesium; and salts with aluminum. Salts of metals such as zinc and iron; salts of organic onions such as tetramethylammonium and choline; and salts of organic bases such as ammonia, propylenediamine, pyrrolidine, piperidine, pyridine, ethanolamine, N,N-dimethylethanolamine, 4-hydroxypiperidine, tert-octylamine, dibenzylamine, morpholine, dextran, phenyl glycidyl ester, ethylenediamine, N-methylglucamine, guanidine, diethylamine, triethylamine, dicyclohexylamine, N,N'-dibenzylethylenediamine, chloroprocaine, procaine, diethanolamine, N-benzylaniline, piperazine, and tris(hydroxymethyl)aminomethane.

[1067] Furthermore, the compounds of formula (I) or their pharmaceutically acceptable salts contain various hydrates or solvates. Solvents for solvates are not particularly limited, but examples include: methanol, ethanol, 1-propanol, 2-propanol, butanol, tert-butanol, acetonitrile, acetone, methyl ethyl ketone, chloroform, ethyl acetate, diethyl ether, tert-butyl methyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, benzene, toluene, N,N-dimethylformamide, dimethyl sulfoxide, etc.

[1068] Pharmaceutically acceptable salts of compounds of formula (I) can be appropriately manufactured based on conventional knowledge in this technical field.

[1069] The compounds of formula (I) or their pharmaceutically acceptable salts also include stereoisomers, racemates, and all possible optically active forms.

[1070] The compounds of formula (I) of the present invention or their pharmaceutically acceptable salts may be used in any dosage form, such as solid dosage forms, semi-solid dosage forms, and liquid dosage forms, and in any applicable formulations, such as oral dosage forms and parenteral dosage forms (injections, transdermal dosage forms, eye drops, suppositories, nasal dosage forms, and inhalers, etc.).

[1071] Common additives are used to formulate pharmaceutical compositions containing compounds of formula (I) of the present invention or pharmaceutically acceptable salts thereof. Examples of these additives, in the case of solid dosage forms, include: excipients such as lactose, white sugar, glucose, corn starch, potato starch, crystalline cellulose, light silicic anhydride, synthetic aluminum silicate, magnesium aluminum metasilicate, and calcium hydrogen phosphate; binders such as crystalline cellulose, carboxymethyl cellulose, hydroxypropyl cellulose, sodium carboxymethyl cellulose, and polyvinylpyrrolidone; disintegrants such as starch, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, cross-linked sodium carboxymethyl cellulose, and sodium carboxymethyl starch; lubricants such as talc and stearic acids; coating agents such as hydroxymethylpropyl cellulose, hydroxypropyl methyl cellulose phthalates, and ethyl cellulose; and colorants. In the case of semi-solid dosage forms, examples include: bases such as white petrolatum. In the case of liquid dosage forms, examples include: solvents such as ethanol, co-solvents such as ethanol, preservatives such as parabens, isotonic agents such as glucose, buffers such as citric acid, antioxidants such as L-ascorbic acid, chelating agents such as EDTA, suspending agents such as polysorbate 80, and emulsifiers.

[1072] The therapeutically effective dose of the active ingredient in the therapeutic or preventive medicine of the present invention varies depending on the route of administration, the patient's age, gender, and the severity of the disease, and is usually around 0.1 to 1000 mg / day. The frequency of administration is usually 1 to 3 times / day to 1 to 7 times / week. The formulation is preferably prepared in a manner that satisfies these conditions.

[1073] In this invention, "prevention" means preventing the onset of disease or illness in individuals who have not yet developed the disease or illness, while "treatment" means curing, suppressing, or improving the disease or symptoms in individuals who have already developed the disease or illness.

[1074] Example

[1075] The present invention will now be described in more detail through examples, but the invention is not limited thereto. Additionally, the abbreviations used in this invention are as follows.

[1076] BINAP = 2,2'-bis(diphenylphosphine)-1,1'-binaphthylene;

[1077] DBU = 1,8-diazabicyclo[5.4.0]-7-undecene;

[1078] DMA = N,N-dimethylacetamide;

[1079] DMF = N,N-dimethylformamide;

[1080] DMSO = dimethyl sulfoxide;

[1081] HATU = 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate;

[1082] NMP = 1-methyl-2-pyrrolidone;

[1083] TFA = trifluoroacetic acid;

[1084] THF = Tetrahydrofuran.

[1085] The structure of the isolated novel compound was obtained by using a method possessing 1 Confirmation was performed using mass spectrometry with 1H NMR and / or a single quadrupole instrumentation source via electron spray, or other appropriate analytical methods.

[1086] For the determination 1 The material was analyzed by 1H NMR spectroscopy (400 MHz, DMSO-d6, CDCl3, or CD3 OD), showing its chemical shift (δ: ppm) and coupling constant (J: Hz). The results of the mass spectrometry analysis show that the material was analyzed as a mass spectrometer in M... + +H, which is the addition of a proton (H) to the molecular mass (M) of the compound. + The measured value obtained from the observed value. It should be noted that the following abbreviations represent the following:

[1087] s = singlet, d = doublet, t = triplet, q = quartet, quin = quintet, brs = broad singlet, m = multiplet.

[1088] [Reference Example 1] Tert-butyl (2-hydroxy-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)ethyl)carbamate

[1089] [Chemical Formula 37]

[1090]

[1091] (2-(4-bromophenyl)-2-hydroxyethyl)carbamate tert-butyl ester (503 mg, 1.59 mmol) was dissolved in 1,4-dioxane (10 mL), and bis(pinacol)diboron (404 mg, 1.59 mmol), [1,1'-bis(diphenylphosphine)ferrocene]dichloropalladium (61 mg, 0.084 mmol), and potassium acetate (469 mg, 4.78 mmol) were added. The mixture was stirred at 90 °C for 15 hours. The reaction solution was cooled to room temperature, filtered through diatomaceous earth, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to give the title compound (412 mg, 71%).

[1092] 1 H-NMR(CDCl3)δ:7.81(2H,d,J=7.8Hz),7.38(2H,d,J=7.8Hz),4.90-4.86(2H,m),3.53-3.45(1H,m),3.27-3.20(1H,m),1.45(9H,s),1.34(12H,s).

[1093] [Reference Example 2] N-[3,3-difluoro-2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)phenyl]propyl] tert-butyl carbamate

[1094] [Chemical Formula 38]

[1095]

[1096] Step 1: 1-Bromo-4-(1,1-difluoro-3-nitropropane-2-yl)benzene

[1097] 1-Bromo-4-[(E)-2-nitrovinyl]benzene (1 g) was dissolved in acetonitrile (4.4 mL), cooled to 0 °C, and (bromodifluoromethyl)trimethylsilane (1.03 mL), triphenylphosphine (1.38 g), and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (1.06 mL) were added. The mixture was stirred at room temperature for 30 minutes. The reaction solution was cooled to -20 °C, and chlorotrimethylsilane (0.11 mL) and methanol (0.89 mL) were added. The mixture was stirred at the same temperature for 15 minutes, and then heated to room temperature. Water (4 mL) and pyridine (0.42 mL) were added to the reaction solution, and the mixture was stirred at 80 °C for 1.5 hours. The mixture was extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate. The solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to give 785 mg of the target compound.

[1098] 1H-NMR (CDCl3) δ: 7.54 (2H, d, J = 9.0Hz), 7.18 (2H, d, J = 8.2Hz), 6.01 (1H, td, J = 55.3, 2.7H z),4.94(1H,dd,J=13.7,5.5Hz),4.83(1H,ddd,J=71.4,13.7,7.3Hz),4.06-3.93(1H,m).

[1099] Step 2: N-[2-(4-bromophenyl)-3,3-difluoropropyl] tert-butyl carbamate

[1100] 1-Bromo-4-(1,1-difluoro-3-nitropropane-2-yl)benzene (785 mg) was suspended in a mixed solvent of ethanol (7 mL) and water (2 mL). Iron powder (470 mg) and ammonium chloride (450 mg) were added, and the mixture was stirred at 80 °C for 2 hours. The reaction solution was cooled to room temperature, filtered through diatomaceous earth, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The crude product was dissolved in dichloromethane (14 mL), and di-tert-butyl dicarbonate (612 mg) and N,N-diisopropylethylamine (0.39 mL) were added. The mixture was stirred at room temperature for 1 hour. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the mixture was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the target compound (667 mg).

[1101] MS:m / z 294.1(M-tBu+H) + .

[1102] Step 3: N-[3,3-difluoro-2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)benzene] [3]propyl] tert-butyl carbamate

[1103] N-[2-(4-bromophenyl)-3,3-difluoropropyl]tert-butyl carbamate (667 mg) was dissolved in 1,4-dioxane (19 mL), and bis(pinacol)diboron (629 mg), [1,1'-bis(diphenylphosphine)ferrocene]dichloropalladium (139 mg), and potassium acetate (561 mg) were added. The mixture was stirred at 100 °C for 3 hours. The reaction solution was cooled to room temperature, filtered through diatomaceous earth, and concentrated under reduced pressure to obtain the crude product of the title compound.

[1104] [Reference Example 3] N-[2-(6-chloropyridin-3-yl)-2-hydroxyethyl]tert-butyl carbamate

[1105] [Chemical Formula 39]

[1106]

[1107] Step 1: 1-(6-chloropyridin-3-yl)-2-nitroethanol

[1108] Add nitromethane (3 mL) and triethylamine (3 mL) to 6-chloropyridine-3-carboxaldehyde (1 g) and stir for 1 hour at room temperature. Concentrate the reaction solution under reduced pressure and use the crude product directly in the next reaction.

[1109] Step 2: N-[2-(6-chloropyridin-3-yl)-2-hydroxyethyl] tert-butyl carbamate

[1110] The crude product obtained in step 1 was dissolved in THF (10 mL), and zinc powder (2.31 g) and acetic acid (3 mL) were added. The mixture was stirred at room temperature for 1 hour. The reaction solution was filtered through diatomaceous earth and then concentrated under reduced pressure. The crude product was then dissolved in dichloromethane (14 mL), and di-tert-butyl dicarbonate (1.54 g) and N,N-diisopropylethylamine (2 mL) were added. The mixture was stirred at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to obtain the title compound (651 mg).

[1111] MS:m / z 273.2(M+H) + .

[1112] [Reference Example 4] N-[2-(2-chloropyrimidin-5-yl)-2-hydroxyethyl]tert-butyl carbamate

[1113] [Chemical Formula 40]

[1114]

[1115] Step 1: 1-(2-chloropyrimidin-5-yl)-2-nitroethanol

[1116] Add nitromethane (1 mL) and triethylamine (2 mL) to 428 mg of 2-chloropyrimidine-5-carboxaldehyde, and stir for 2 hours at room temperature. Concentrate the reaction solution under reduced pressure, and use the crude product directly in the next reaction.

[1117] Step 2: N-[2-(2-chloropyrimidin-5-yl)-2-hydroxyethyl] tert-butyl carbamate

[1118] The crude product obtained in step 1 was dissolved in THF (5 mL), and zinc powder (981 mg) and acetic acid (0.86 mL) were added. The mixture was stirred at room temperature for 2 hours. The reaction solution was filtered through diatomaceous earth and concentrated under reduced pressure. The crude product was then dissolved in dichloromethane (5 mL), and di-tert-butyl dicarbonate (1.31 g) and N,N-diisopropylethylamine (1.6 mL) were added. The mixture was stirred at room temperature for 2 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to give the title compound (208 mg).

[1119] MS:m / z 274.1(M+H) + .

[1120] 1 H-NMR(CDCl3)δ:8.64(2H,s),4.96-4.94(2H,m),3.55-3.51(1H,m),3.34-3.27(1H,m),1.45(9H,s).

[1121] [Reference Example 5] N-[2-(5-chloropyrazin-2-yl)-2-hydroxyethyl]tert-butyl carbamate

[1122] [Chemical Formula 41]

[1123]

[1124] Step 1: 1-(5-chloropyrazine-2-yl)-2-nitroethanol

[1125] Add nitromethane (1 mL) and triethylamine (1 mL) to 5-chloropyrazine-2-carboxaldehyde (826 mg) and stir at room temperature for 1 hour. Concentrate the reaction solution under reduced pressure and use the crude product directly in the next reaction.

[1126] Step 2: N-[2-(5-chloropyrazin-2-yl)-2-hydroxyethyl] tert-butyl carbamate

[1127] The crude product obtained in step 1 was dissolved in THF (5 mL), cooled to 0 °C, and then di-tert-butyl dicarbonate (1.06 g), zinc powder (792 mg), and acetic acid (0.7 mL) were added. The mixture was stirred at room temperature for 16 hours. The reaction solution was filtered through diatomaceous earth, water was added, and the solution was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to give the title compound (57.5 mg).

[1128] MS:m / z 218.1(M-tBu+H) + .

[1129] [Reference Example 6] 3-(6-chloropyridin-3-yl)-3-fluorozacrito-1-carboxylic acid tert-butyl ester

[1130] [Chemical Formula 42]

[1131]

[1132] Step 1: tert-butyl 3-(6-chloropyridin-3-yl)-3-hydroxyazine-1-carboxylate

[1133] 5-Bromo-2-chloropyridine (385 mg) was dissolved in THF (10 mL), cooled to -78 °C, and 1.2 mL of n-butyllithium was added dropwise. After stirring at the same temperature for 1 hour, 2 mL of a THF solution of 1-(tert-butoxycarbonyl)-3-azacyclobutanone (342 mg) was added, and the mixture was heated to room temperature over 4 hours. A saturated aqueous solution of ammonium chloride was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to give the target compound (209 mg).

[1134] MS:m / z 285.0(M+H) + .

[1135] Step 2: tert-butyl 3-(6-chloropyridin-3-yl)-3-fluorozahexacyclobutane-1-carboxylate

[1136] 100 mg of tert-butyl 3-(6-chloropyridin-3-yl)-3-hydroxyazacyclobutane-1-carboxylate was dissolved in 1.8 mL of dichloromethane and cooled to -78 °C. 0.078 mL of bis(2-methoxyethyl)aminosulfur trifluoride was added, and the mixture was stirred at the same temperature for 2 hours. The reaction solution was then heated to room temperature, and a saturated aqueous solution of sodium bicarbonate was added. The solution was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solution was concentrated under reduced pressure to give 40 mg of the crude title compound.

[1137] MS:m / z 287.0(M+H) + .

[1138] [Reference Example 7] N-[3-[(6-chloropyridin-3-yl)methyl]oxetane-3-yl]-2-methylpropane-2-sulfinamide

[1139] [Chemical Formula 43]

[1140]

[1141] 2-Chloro-5-iodopyridine (479 mg) was dissolved in THF (10 mL), and magnesium isopropyl bromide (1 M THF solution, 2.0 mL) was added dropwise at 0 °C. After stirring for 1 hour at the same temperature, copper iodide (I) (38.1 mg) was added, and the mixture was cooled to -30 °C. A THF solution of 1-tert-butylthionyl-5-oxa-1-azaspiro[2.3]hexane (189 mg) (2 mL) was added dropwise to the reaction mixture, and the mixture was heated to room temperature and stirred for 2 hours. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to give the title compound (108 mg).

[1142] MS:m / z 303.1(M+H)+ .

[1143] 1 H-NMR(CDCl3)δ:8.33(1H,s),7.71(1H,d,J=7.3Hz),7.30(1H,d,J=8.2Hz),4.83(1H ,d,J=6.4Hz),4.66-4.56(3H,m),3.59(1H,s),3.41(2H,q,J=14.5Hz),1.22(9H,s).

[1144] [Reference Example 8] N-[(2R)-2-(6-chloropyridin-3-yl)-2-fluoroethyl] tert-butyl carbamate

[1145] [Chemical Formula 44]

[1146]

[1147] N-[(2S)-2-(6-chloropyridin-3-yl)-2-hydroxyethyl] tert-butyl carbamate (164 mg), obtained by chiral separation of the racemic compound of Reference Example 3, was dissolved in dichloromethane (3 mL), and bis(2-methoxyethyl)aminosulfur trifluoride (0.13 mL) was added dropwise at 0 °C. After stirring at the same temperature for 1 hour, the reaction solution was purified directly by silica gel column chromatography to give the title compound (37.5 mg).

[1148] MS:m / z 275.1(M+H) + .

[1149] [Reference Example 9] N-[(2R)-2-(2-chloropyrimidin-5-yl)-2-fluoroethyl] tert-butyl carbamate

[1150] [Chemical Formula 45]

[1151]

[1152] N-[(2S)-2-(2-chloropyrimidin-5-yl)-2-hydroxyethyl] tert-butyl carbamate (547 mg), obtained by chiral separation of the racemic compound from Example 4, was dissolved in dichloromethane (10 mL), and bis(2-methoxyethyl)aminosulfur trifluoride (0.44 mL) was added dropwise at 0 °C. After stirring at the same temperature for 1 hour, the reaction solution was directly purified by silica gel column chromatography to give the title compound (83.3 mg). MS: m / z 276.2 (M+H) + .

[1153] [Reference Example 10] 2-[2-(6-chloropyridin-3-yl)-2,2-difluoroethyl]isoindole-1,3-dione

[1154] [Chemical Formula 46]

[1155]

[1156] Step 1: Ethyl 2-(6-chloropyridin-3-yl)-2,2-difluoroacetate

[1157] 2-Chloro-5-iodopyridine (2 g) was dissolved in DMSO (33 mL), and ethyl bromodifluoroacetate (1.87 g) and copper powder (1.33 g) were added. The mixture was stirred at 80 °C for 16 hours. The reaction solution was cooled to room temperature, and an aqueous solution of disodium hydrogen phosphate was added. The mixture was extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate. The solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to give the target compound (958 mg). MS: m / z 236.1 (M+H) + .

[1158] Step 2: 2-(6-chloropyridin-3-yl)-2,2-difluoroethanol

[1159] Ethyl 2-(6-chloropyridin-3-yl)-2,2-difluoroacetate (958 mg) was dissolved in methanol (20 mL), cooled to 0 °C, and sodium borohydride (308 mg) was added. The mixture was stirred at room temperature for 1 hour. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to give the target compound (493 mg).

[1160] MS:m / z 194.1(M+H) + .

[1161] Step 3: 2-[2-(6-chloropyridin-3-yl)-2,2-difluoroethyl]isoindole-1,3-dione

[1162] 2-(6-chloropyridin-3-yl)-2,2-difluoroethanol (493 mg), phthalimide (487 mg), and triphenylphosphine (1 g) were suspended in THF (5 mL), and diisopropyl azodicarbonate (0.74 mL) was added dropwise. The mixture was stirred at room temperature for 16 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to give the title compound (395 mg).

[1163] MS:m / z 323.1(M+H) + .

[1164] [Example 1] 4-[4-(2-aminoacetyl)phenyl]-3-[(2-methyl-6-morpholin-4-ylpyrimidin-4-yl)amino]benzonitrile (Compound No. 4)

[1165] [Chemical Formula 47]

[1166]

[1167] Step 1: 3-Amino-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)benzonitrile

[1168] 3-Amino-4-chlorobenzonitrile (700 mg, 4.59 mmol) was dissolved in 1,4-dioxane (23 mL), and bis(pinacol)diboron (1.28 g, 5.05 mmol), tris(dibenzylacetone)dipalladium (126 mg, 0.14 mmol), tricyclohexylphosphine tetrafluoroborate (101 mg, 0.28 mmol), and potassium acetate (1.35 g, 13.8 mmol) were added. The mixture was stirred at 100 °C for 15 hours. The reaction solution was cooled to room temperature, filtered through diatomaceous earth, and the mother liquor was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the target compound (541 mg, 48%).

[1169] 1 H-NMR(CDCl3)δ:7.65((1H,d,J=7.3Hz), 6.89(1H,d,J=7.8Hz), 6.81(1H,s), 4.93(2H,br s), 1.35(12H,s).

[1170] Step 2: (2-(2'-amino-4'-cyano-[1,1'-biphenyl]-4-yl)-2-oxoethyl)tert-butyl carbamate

[1171] To a 4 / 1 mixture (5 mL) of 3-amino-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboron-2-yl)benzonitrile (245 mg, 1.00 mmol) in toluene / water, N-[2-(4-bromophenyl)-2-oxo-ethyl]carbamate tert-butyl ester (315 mg, 1.00 mmol), tetrakis(triphenylphosphine)palladium (57.9 mg, 0.050 mmol), and potassium carbonate (416 mg, 3.00 mmol) were added, and the mixture was stirred at 80 °C for 2 hours. The reaction solution was cooled to room temperature and filtered through diatomaceous earth. Water was added to the mother liquor, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the target compound (280 mg, 80%).

[1172] MS:m / z 296.1(M-tBu+H) + .

[1173] Step 3: (2-(4'-cyano-2'-((2-methyl-6-morpholinopyrimidin-4-yl)amino)-[1,1'-biphenyl]-4- tert-butyl 2-oxoethyl carbamate

[1174] Dissolve tert-butyl (2-(2'-amino-4'-cyano-[1,1'-biphenyl]-4-yl)-2-oxoethyl)carbamate (50.8 mg, 0.145 mmol) in toluene (2 mL), and add 4-(6-chloro-2-methylpyrimidin-4-yl)morpholine (30.9 mg, 0.145 mmol), tris(dibenzylacetone)dipalladium (6.6 mg, 0.072 mmol), 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthracene (8.4 mg, 0.015 mmol), and sodium tert-butoxide (27.8 mg, 0.289 mmol). Stir at 150 °C for 1.5 hours under microwave irradiation. Cool the reaction solution to room temperature, filter through diatomaceous earth, and concentrate the solution under reduced pressure. Use the crude product directly in the next reaction.

[1175] Step 4: 4-[4-(2-aminoacetyl)phenyl]-3-[(2-methyl-6-morpholin-4-ylpyrimidin-4-yl)amino] Benzonitrile

[1176] Dichloromethane (2 mL) and TFA (0.5 mL) were added to the crude product obtained in step 3, and the mixture was stirred at room temperature for 30 minutes. The reaction solution was concentrated under reduced pressure, and the crude product was purified by HPLC to obtain the target compound (2.09 mg).

[1177] Exact MS: 428.2

[1178] Obs.MS(M+H) + 429.4

[1179] [Example 2] 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[methyl-(2-methyl-5-phenylpyrazole-3-yl)amino]benzonitrile (Compound No. 6)

[1180] [Chemical Formula 48]

[1181]

[1182] Step 1: 4-Chloro-3-[methyl-(2-methyl-5-phenylpyrazol-3-yl)amino]benzonitrile

[1183] 1,4-Dioxane (6.7 mL) was added to 3-bromo-4-chlorobenzonitrile (578 mg, 2.67 mmol), N,2-dimethyl-5-phenylpyrazole-3-amine (500 mg, 2.67 mmol), followed by tris(dibenzylacetone)dipalladium (122 mg, 0.134 mmol), 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthracene (232 mg, 0.401 mmol), and cesium carbonate (2.18 g, 6.68 mmol). The mixture was stirred at 100 °C for 16 hours. The reaction solution was cooled to room temperature, filtered through diatomaceous earth, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the target compound (512 mg, 59%).

[1184] MS:m / z 323.1(M+H) + .

[1185] Step 2: 3-[methyl-(2-methyl-5-phenylpyrazol-3-yl)amino]-4-(4,4,5,5-tetramethyl-1,3,2- Dioxaborane-2-yl)benzonitrile

[1186] 4-Chloro-3-[methyl-(2-methyl-5-phenylpyrazol-3-yl)amino]benzonitrile (256 mg, 0.792 mmol) was dissolved in 1,4-dioxane (2.6 mL), and bis(pinacol)diboron (302 mg, 1.19 mmol), bis(tricyclohexylphosphine)palladium dichloride (58.5 mg, 0.0792 mmol), and potassium acetate (233 mg, 2.38 mmol) were added. The mixture was stirred at 100 °C for 2 hours. The reaction solution was cooled to room temperature, filtered through diatomaceous earth, and concentrated under reduced pressure. The crude product was used directly in the next reaction.

[1187] MS:m / z 415.0(M+H) + .

[1188] Step 3: N-[2-[2-[4-cyano-2-[methyl-(2-methyl-5-phenylpyrazol-3-yl)amino]phenyl]pyrimidine- 5-yl]ethyl] tert-butyl carbamate

[1189] The crude product obtained in step 2 was dissolved in 1,4-dioxane (2.6 mL), and N-[2-(2-chloropyrimidin-5-yl)ethyl]carbamate tert-butyl ester (50.0 mg, 0.194 mmol), tetrakis(triphenylphosphine)palladium (22.4 mg, 0.0194 mmol), potassium carbonate (80.4 mg, 0.582 mmol), and water (0.1 mL) were added. The mixture was stirred at 100 °C for 1 hour. After cooling the reaction solution to room temperature, ethyl acetate and water were added for extraction. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solution was concentrated under reduced pressure. The crude product was used directly in the next reaction.

[1190] MS:m / z 510.0(M+H) + .

[1191] Step 4: 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[methyl-(2-methyl-5-phenylpyrazol-3-yl)amino] Benzonitrile

[1192] Add dichloromethane (1 mL) and TFA (0.5 mL) to the crude product obtained in step 3, and stir at room temperature for 30 minutes. Concentrate the reaction solution under reduced pressure, and purify the crude product by HPLC to obtain the target compound (48.3 mg).

[1193] Exact MS: 409.2

[1194] Obs.MS(M+H) + 410.4

[1195] [Example 3] 4-[4-(2-aminoethyl)phenyl]-3-(2-methyl-6-morpholin-4-ylpyrimidin-4-yl)oxybenzonitrile (Compound No. 7)

[1196] [Chemical Formula 49]

[1197]

[1198] Step 1: 4-Bromo-3-((2-methyl-6-morpholinopyrimidin-4-yl)oxy)benzonitrile

[1199] 4-Bromo-3-hydroxybenzonitrile (1.19 g, 6.0 mmol) was dissolved in DMF (10 mL), and 4-(6-chloro-2-methylpyrimidin-4-yl)morpholine (1.28 g, 6.0 mmol) and potassium carbonate (2.49 g, 18 mmol) were added. The mixture was stirred at 150 °C for 23 hours. The reaction solution was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to give the target compound (1.23 g, 54%).

[1200] Step 2: (2-(4'-cyano-2'-((2-methyl-6-morpholinopyrimidin-4-yl)oxy)-[1,1'-biphenyl]-4- tert-butyl carbamate (ethyl)

[1201] 4-Bromo-3-((2-methyl-6-morpholinopyrimidin-4-yl)oxy)benzonitrile (110 mg, 0.29 mmol) was dissolved in a 4 / 1 toluene / water mixture (2.5 mL). 4-(4,4,5,5-tetramethyl-1,3,2-dioxaboron-2-yl)phenethylcarbamate tert-butyl ester (132 mg, 0.38 mmol), tetrakis(triphenylphosphine)palladium (16.9 mg, 0.015 mmol), and potassium carbonate (121 mg, 0.88 mmol) were added, and the mixture was stirred at 110 °C for 10 hours. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to give the target compound (140 mg, 93%).

[1202] MS: m / z 516.3 (M+H) + .

[1203] Step 3: 4-[4-(2-aminoethyl)phenyl]-3-(2-methyl-6-morpholin-4-ylpyrimidin-4-yl)oxybenzonitrile

[1204] (2-(4'-cyano-2'-((2-methyl-6-morpholinopyrimidin-4-yl)oxy)-[1,1'-biphenyl]-4-yl)ethyl)tert-butyl carbamate (140 mg, 0.27 mmol) was dissolved in 1,4-dioxane (2 mL), and 4M (=mol / L) hydrochloric acid / 1,4-dioxane solution (2 mL) was added dropwise. The mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the crude product was dissolved in a mixture of ethyl acetate (50 mL) and 2M hydrochloric acid (20 mL). The target compound was back-extracted to the aqueous layer, and then a methanol / dichloromethane (1 / 4) mixture (50 mL) and 2M sodium hydroxide aqueous solution (22 mL) were added to extract into the organic phase. The organic layer was dried over anhydrous sodium sulfate, and the solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the target compound (84.1 mg).

[1205] Exact MS: 415.2

[1206] Obs.MS(M+H) + 416.2

[1207] [Example 4] 4-[4-(2-amino-1-methoxyethyl)phenyl]-3-(2-methyl-6-morpholin-4-ylpyrimidin-4-yl)oxybenzonitrile (Compound No. 11)

[1208] [Chemical Formula 50]

[1209]

[1210] Step 1: (2-(4'-cyano-2'-((2-methyl-6-morpholinopyrimidin-4-yl)oxy)-[1,1'-biphenyl]-4- 2-Methoxyethyl(tert-butyl)carbamate

[1211] (29 mg, 0.055 mmol) tert-butyl carbamate, synthesized by the same method as in Example 3, was dissolved in DMF (1 mL), and sodium hydride (2.7 mg) was added. The mixture was stirred at room temperature for 5 minutes. Iodimethane (4.2 μL, 0.066 mmol) was added to the reaction mixture, and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture, and the mixture was stirred and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solution was concentrated under reduced pressure. The crude product was used directly in the next reaction.

[1212] Step 2: 4-[4-(2-amino-1-methoxyethyl)phenyl]-3-(2-methyl-6-morpholin-4-ylpyrimidin-4-yl)oxy Benzonitrile

[1213] The crude product obtained in step 1 was dissolved in dichloromethane (2 mL), and TFA (0.5 mL) was added. The mixture was stirred at room temperature for 30 minutes. The reaction solution was concentrated under reduced pressure, and the crude product was purified by HPLC to obtain the target compound (8.7 mg).

[1214] Exact MS: 445.2

[1215] Obs.MS(M+H) + 446.2

[1216] [Example 5] 4-[4-(2-amino-1-phenoxyethyl)phenyl]-3-(2-methyl-6-morpholin-4-ylpyrimidin-4-yl)oxybenzonitrile (Compound No. 13)

[1217] [Chemical Formula 51]

[1218]

[1219] Step 1: 2-((tert-butoxycarbonyl)amino)-1-(4'-cyano-2'-((2-methyl-6-morpholinopyrimidine-4- (1,1'-biphenyl)-4-yl)ethyl methanesulfonate

[1220] (2-(4'-cyano-2'-((2-methyl-6-morpholinopyrimidin-4-yl)oxy)-[1,1'-biphenyl]-4-yl)-2-hydroxyethyl)tert-butyl carbamate (60.9 g, 0.115 mmol), synthesized by the same method as in Example 3, was dissolved in THF (2 mL). Triethylamine (48 μL, 0.34 mmol) and methanesulfonyl chloride (11 μL, 0.14 mmol) were added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with water and ethyl acetate and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The crude product was used directly in the next reaction.

[1221] MS:m / z 610.3(M+H) + .

[1222] Step 2: (2-(4'-cyano-2'-((2-methyl-6-morpholinopyrimidin-4-yl)oxy)-[1,1'-biphenyl]-4- 2-Phenoxyethyl) tert-butyl carbamate

[1223] The crude product obtained in step 1 was dissolved in DMF (2 mL), and phenol (10.8 mg, 0.115 mmol) and potassium carbonate (47.5 mg, 0.34 mmol) were added. The mixture was stirred at 100 °C for 16 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The crude product was used directly in the next reaction.

[1224] MS:m / z 608.3(M+H) + .

[1225] Step 3: 4-[4-(2-amino-1-phenoxyethyl)phenyl]-3-(2-methyl-6-morpholin-4-ylpyrimidin-4-yl)oxy Benzonitrile

[1226] The crude product obtained in step 2 was dissolved in dichloromethane (2 mL), and TFA (0.5 mL) was added. The mixture was stirred at room temperature for 30 minutes. The reaction solution was concentrated under reduced pressure, and the crude product was purified by HPLC to obtain the target compound (5.5 mg).

[1227] Exact MS: 507.2

[1228] Obs.MS(M+H) + 508.2

[1229] [Example 6] 4-[4-(2-aminoethyl)phenyl]-3-(2-methyl-6-piperidin-1-ylpyrimidin-4-yl)oxybenzonitrile (Compound No. 17)

[1230] [Chemical Formula 52]

[1231]

[1232] Step 1: (2-(4'-cyano-2'-hydroxy-[1,1'-biphenyl]-4-yl)ethyl)tert-butyl carbamate

[1233] To a 50 mL mixture of 4-bromo-3-hydroxybenzonitrile (8.6 g, 43.4 mmol) and toluene / water (9 / 1), 22.7 g (65.1 mmol), 5.0 g (4.34 mmol), and 11.9 g (86.1 mmol) of tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaboron-2-yl)phenethylcarbamate were added, and the mixture was stirred at 90 °C for 16 hours. The reaction mixture was cooled to room temperature, filtered through diatomaceous earth, and the mother liquor was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the target compound (5.0 g, 35%).

[1234] Step 2: (2-(2'-((6-chloro-2-methylpyrimidin-4-yl)oxy)-4'-cyano-[1,1'-biphenyl]-4-yl)ethyl tert-butyl carbamate

[1235] To a DMF (15 mL) solution of (2.8 g, 8.3 mmol) tert-butyl carbamate (2.8 g, 8.3 mmol), 4,6-dichloro-2-methylpyrimidine (1.35 g, 8.28 mmol) and cesium carbonate (5.38 g, 16.6 mmol) were added, and the mixture was stirred overnight at room temperature. Water and ethyl acetate were added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to give the target compound (1.8 g, 46%).

[1236] MS:m / z 464.8(M+H) + .

[1237] Step 3: (2-(4'-cyano-2'-((2-methyl-6-(piperidin-1-yl)pyrimidin-4-yl)oxy)-[1,1'-bin 4-yl)ethyl)tert-butyl carbamate

[1238] Dissolve tert-butyl (2-(2'-(((6-chloro-2-methylpyrimidin-4-yl)oxy)-4'-cyano-[1,1'-biphenyl]-4-yl)ethyl)carbamate (100 mg, 0.216 mmol) in DMF (3 mL), add piperidine (0.043 mL, 0.432 mmol) and cesium carbonate (140 mg, 0.431 mmol), and stir at room temperature for 16 hours. Add water to the reaction solution, extract with dichloromethane, dry the organic layer with anhydrous sodium sulfate, and concentrate the solution under reduced pressure. Use the crude product directly in the next reaction.

[1239] MS:m / z 514.3(M+H) + .

[1240] Step 4: 4-[4-(2-aminoethyl)phenyl]-3-(2-methyl-6-piperidin-1-ylpyrimidin-4-yl)oxybenzonitrile

[1241] TFA (0.5 mL) was added to a 2 mL solution of the crude product obtained in step 3 in dichloromethane, and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and the crude product was purified by HPLC to obtain the target compound (57.2 mg).

[1242] Exact MS: 413.2

[1243] Obs.MS(M+H) + 414.0

[1244] 1 H-NMR(DMSO-d6)δ:7.73(1H,d,J=8.4Hz),7.68(1H,s),7.61(1H,d,J=8.0Hz),7.35(2H,d,J=7.6Hz),7.21(2H,d ,J=7.6Hz),6.03(1H,s),3.52(4H,bs),2.75-2.78(2H,m),2.64(2H,s),2.15(3H,s),1.59(2H,s),1.45(4H,bs).

[1245] [Example 7] 4-[4-(2-aminoethyl)phenyl]-3-[6-(2-cyanophenyl)-2-methylpyrimidin-4-yl]oxybenzonitrile (Compound No. 21)

[1246] [Chemical Formula 53]

[1247]

[1248] Step 1: (2-(4'-cyano-2'-((6-(2-cyanophenyl)-2-methylpyrimidin-4-yl)oxy)-[1,1'-bin 4-yl)ethyl)tert-butyl carbamate

[1249] The intermediate (2-(2'-(((6-chloro-2-methylpyrimidin-4-yl)oxy)-4'-cyano-[1,1'-biphenyl]-4-yl)ethyl)tert-butyl carbamate (100 mg, 0.215 mmol) obtained in Example 6 was dissolved in 1,4-dioxane (2 mL), and potassium carbonate (59 mg, 0.43 mmol), 2-cyanophenylboronic acid (47 mg, 0.32 mmol), and tetrakis(triphenylphosphine)palladium (20 mg, 0.017 mmol) were added. The mixture was stirred overnight at 100 °C under a nitrogen atmosphere. The reaction solution was cooled to room temperature, filtered through diatomaceous earth, and then extracted with ethyl acetate after adding water. The organic layer was dried over anhydrous sodium sulfate, and the solution was concentrated under reduced pressure. The crude product was used directly in the next reaction.

[1250] Step 2: 4-[4-(2-aminoethyl)phenyl]-3-[6-(2-cyanophenyl)-2-methylpyrimidin-4-yl]oxybenzyl nitrile

[1251] The crude product obtained in step 1 was dissolved in dichloromethane (2 mL), and TFA (0.5 mL) was added. The mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and the crude product was purified by HPLC to obtain the target compound (15.4 mg).

[1252] Exact MS: 431.2

[1253] Obs.MS(M+H) + 431.9

[1254] 1 H-NMR(DMSO-d6)δ:8.01-7.99(2H,m),7.95-7.93(1H,m),7.89-7.82(2H,m),7.74-7.7 0(2H,m),7.44-7.39(3H,m),7.28-7.23(2H,m),3.23(2H,s),1.90(3H,s),1.23(2H,s).

[1255] [Example 8] 4-[4-(2-aminoethyl)phenyl]-3-[6-(2,2-dimethylpropoxy)-2-methylpyrimidin-4-yl]oxybenzonitrile (Compound No. 47)

[1256] [Chemical Formula 54]

[1257]

[1258] Step 1: 4-Chloro-2-methyl-6-(neopentoxy)pyrimidine

[1259] To a stirred solution containing 323 mg, 3.68 mmol, sodium hydride suspended in 4 mL of THF, 2,2-dimethylprop-1-ol in 0.5 mL of THF was added dropwise, and the mixture was stirred for 15 minutes at the same temperature. After cooling the reaction solution to 0 °C, 4,6-dichloro-2-methylpyrimidine in 0.5 mL of THF was added dropwise, and the mixture was stirred at 0 °C for 4 hours. A saturated aqueous solution of ammonium chloride was added to the reaction solution, and the mixture was extracted with diethyl ether. The organic layer was dried over anhydrous sodium sulfate, and the solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to give the target compound (245 mg, 47%).

[1260] Step 2: (2-(4'-cyano-2'-((2-methyl-6-(neopentoxy)pyrimidin-4-yl)oxy)-[1,1'-bin 4-yl)ethyl)tert-butyl carbamate

[1261] Dissolve tert-butyl (2-(4'-cyano-2'-hydroxy-[1,1'-biphenyl]-4-yl)ethyl)carbamate (50 mg, 0.148 mmol) in DMF (1 mL), add 4-chloro-2-methyl-6-(neopentoxy)pyrimidine (63.5 mg, 0.296 mmol) and cesium carbonate (96.4 mg, 0.296 mmol), and stir overnight at 70 °C. Add water to the reaction solution, extract with ethyl acetate, dry the organic layer with anhydrous sodium sulfate, and concentrate the solution under reduced pressure. Use the crude product directly in the next reaction.

[1262] MS:m / z 517.0(M+H) + .

[1263] Step 3: 4-[4-(2-aminoethyl)phenyl]-3-[6-(2,2-dimethylpropoxy)-2-methylpyrimidin-4-yl]oxy Benzonitrile

[1264] Dichloromethane (2 mL) and TFA (0.5 mL) were added to the crude product obtained in step 2, and the mixture was stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure, and the crude product was purified by HPLC to obtain the target compound (21.4 mg).

[1265] Exact MS: 416.2

[1266] Obs.MS(M+H) + 417.3

[1267] [Example 9] 4-[4-[2-(3-hydroxypropylamino)ethyl]phenyl]-3-(2-methyl-6-morpholin-4-ylpyrimidin-4-yl)oxybenzonitrile (Compound No. 58)

[1268] [Chemical Formula 55]

[1269]

[1270] Step 1: 4-[4-[2-(3-hydroxypropylamino)ethyl]phenyl]-3-(2-methyl-6-morpholin-4-ylpyrimidine-4-) 2-(2-)-oxybenzonitrile

[1271] The 4-[4-(2-aminoethyl)phenyl]-3-(2-methyl-6-morpholin-4-ylpyrimidin-4-yl)oxybenzonitrile (54 mg, 0.13 mmol) obtained in Example 3 was dissolved in DMF (1 mL), and 3-bromopropane-1-ol (0.014 mL, 0.16 mmol) and triethylamine (0.055 mL, 0.39 mmol) were added. The mixture was stirred at 60 °C for 3 hours. The reaction solution was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solution was concentrated under reduced pressure. The crude product was purified by HPLC to obtain the target compound (11.3 mg).

[1272] Exact MS: 473.2

[1273] Obs.MS(M+H) + 474.5

[1274] [Example 10] 4-[4-(2-amino-1-phenylethyl)phenyl]-3-(2-methyl-6-morpholin-4-ylpyrimidin-4-yl)oxybenzonitrile (Compound No. 59)

[1275] [Chemical Formula 56]

[1276]

[1277] Step 1: (2-(4'-cyano-2'-((2-methyl-6-morpholinopyrimidin-4-yl)oxy)-[1,1'-biphenyl]-4- tert-butyl carbamate (2-(2-toluenesulfonylhydrazine)ethyl)carbamate

[1278] (2-(4'-cyano-2'-((2-methyl-6-morpholinopyrimidin-4-yl)oxy)-[1,1'-biphenyl]-4-yl)-2-oxoethyl)tert-butyl carbamate (855.8 mg, 1.62 mmol), synthesized by the same method as in Example 3, was dissolved in toluene (8 mL). p-Toluenesulfonyl hydrazine (301 mg, 1.62 mmol) was added, and the mixture was stirred at 110 °C for 4 hours. The reaction solution was concentrated under reduced pressure, and the crude product was used directly in the next reaction. MS: m / z 698.2 (M+H) + .

[1279] Step 2: (2-(4'-cyano-2'-((2-methyl-6-morpholinopyrimidin-4-yl)oxy)-[1,1'-biphenyl]-4- 2-Phenylacetyl 2-phenylethyl)carbamate tert-butyl

[1280] A portion (30 mg) of the crude product obtained in step 1 was dissolved in 1,4-dioxane (1 mL), and phenylboronic acid (11 mg, 0.086 mmol) and potassium carbonate (24 mg, 0.17 mmol) were added. The mixture was stirred at 110 °C for 15 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solution was concentrated under reduced pressure. The crude product was used directly in the next reaction.

[1281] MS: m / z 592.3 (M+H) + .

[1282] Step 3: 4-[4-(2-amino-1-phenylethyl)phenyl]-3-(2-methyl-6-morpholin-4-ylpyrimidin-4-yl)oxy Benzonitrile

[1283] The crude product obtained in step 2 was dissolved in dichloromethane (2 mL), and TFA (0.5 mL) was added. The mixture was stirred at room temperature for 30 minutes. The reaction solution was concentrated under reduced pressure, and the crude product was purified by HPLC to obtain the target compound (3.1 mg).

[1284] Exact MS: 491.2

[1285] Obs.MS(M+H) + 492.5

[1286] [Example 11] 4-(2-amino-1-oxo-2,3-dihydroinden-5-yl)-3-(2-methyl-6-morpholin-4-ylpyrimidin-4-yl)oxybenzonitrile (Compound No. 131)

[1287] [Chemical Formula 57]

[1288]

[1289] Step 1: 3-(2-methyl-6-morpholin-4-ylpyrimidin-4-yl)oxy-4-(1-oxo-2,3-dihydroindene-5-yl) Benzonitrile

[1290] 4-Bromo-3-(2-methyl-6-morpholin-4-ylpyrimidin-4-yl)oxybenzonitrile (300 mg, 0.800 mmol) was dissolved in 1,4-dioxane (2 mL), and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborpine-2-yl)-2,3-dihydroindene-1-one (289 mg, 1.12 mmol), tetrakis(triphenylphosphine)palladium (46.2 mg, 0.0400 mmol), potassium carbonate (332 mg, 2.40 mmol), and water (0.5 mL) were added. The mixture was stirred at 100 °C for 4 hours. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to give the target compound (290 mg, 85%).

[1291] MS: m / z 427.2 (M+H) + .

[1292] Step 2: 4-(2-bromo-1-oxo-2,3-dihydroinden-5-yl)-3-(2-methyl-6-morpholin-4-ylpyrimidin-4-yl) oxybenzonitrile

[1293] 3-(2-methyl-6-morpholin-4-ylpyrimidin-4-yl)oxy-4-(1-oxo-2,3-dihydroindene-5-yl)benzonitrile (290 mg, 0.680 mmol) was dissolved in a 1 / 1 mixture of chloroform and ethyl acetate (6 mL). Copper(II) bromide (304 mg, 1.36 mmol) was added, and the mixture was stirred at 90 °C for 7 hours. The reaction solution was cooled to room temperature, filtered through diatomaceous earth, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to give the target compound (26.0 mg, 8%).

[1294] MS:m / z 505.1(M+H) + .

[1295] Step 3: 4-[2-[(2,4-dimethoxyphenyl)methylamino]-1-oxo-2,3-dihydroindene-5-yl]-3-(2- Methyl-6-morpholino-4-ylpyrimidin-4-yl)oxybenzonitrile

[1296] Dissolve 26.0 mg (0.0514 mmol) of 4-(2-bromo-1-oxo-2,3-dihydroinden-5-yl)-3-(2-methyl-6-morpholin-4-ylpyrimidin-4-yl)oxybenzonitrile in DMF (1 mL), add 12.9 mg (0.0772 mmol) and 0.022 mL (0.154 mmol) of triethylamine, and stir at room temperature for 1 hour. Add water to the reaction mixture and extract with ethyl acetate. Wash the organic layer with saturated brine, dry with anhydrous magnesium sulfate, and concentrate the solution under reduced pressure. Use the crude product directly in the next reaction.

[1297] Step 4: 4-(2-amino-1-oxo-2,3-dihydroinden-5-yl)-3-(2-methyl-6-morpholin-4-ylpyrimidine-4-) 2-(2-)-oxybenzonitrile

[1298] Add 1 mL of TFA to the crude product obtained in step 3 and stir at 120 °C for 10 minutes. Concentrate the reaction solution under reduced pressure and purify the crude product by HPLC to obtain the target compound (6.00 mg).

[1299] Exact MS: 441.2

[1300] Obs.MS(M+H) + 442.2

[1301] [Example 12] 4-[4-(2-amino-1-hydroxyethyl)-3-fluorophenyl]-3-(2-methyl-6-morpholin-4-ylpyrimidin-4-yl)oxybenzonitrile (Compound No. 149)

[1302] [Chemical Formula 58]

[1303]

[1304] Step 1: 4-(3-fluoro-4-formylphenyl)-3-(2-methyl-6-morpholin-4-ylpyrimidin-4-yl)oxybenzonitrile

[1305] 4-Bromo-3-(2-methyl-6-morpholin-4-ylpyrimidin-4-yl)oxybenzonitrile (188 mg, 0.500 mmol) was dissolved in 1,4-dioxane (4 mL), and 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)benzaldehyde (250 mg, 1.00 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (36.6 mg, 0.0500 mmol), potassium carbonate (415 mg, 3.00 mmol), and water (1 mL) were added. The mixture was stirred at 100 °C for 30 minutes. The reaction solution was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to give the target compound (174 mg, 83%).

[1306] MS:m / z 419.2(M+H) + .

[1307] Step 2: 4-[3-fluoro-4-(1-hydroxy-2-nitroethyl)phenyl]-3-(2-methyl-6-morpholin-4-ylpyrimidine-4-) 2-(2-)-oxybenzonitrile

[1308] Dissolve 4-(3-fluoro-4-formylphenyl)-3-(2-methyl-6-morpholin-4-ylpyrimidin-4-yl)oxybenzonitrile (174 mg, 0.416 mmol) in THF (4 mL), add nitromethane (0.5 mL) and triethylamine (1 mL), and stir at room temperature for 2 hours. Concentrate the reaction solution under reduced pressure, and use the crude product directly in the next reaction.

[1309] MS:m / z 480.2(M+H) + .

[1310] Step 3: 4-[4-(2-amino-1-hydroxyethyl)-3-fluorophenyl]-3-(2-methyl-6-morpholino-4-pyrimidine-4-) 2-(2-)-oxybenzonitrile

[1311] Add zinc powder (500 mg, 7.64 mmol) and acetic acid (4 mL) to the crude product obtained in step 2, and stir for 30 minutes. After filtering the reaction solution through diatomaceous earth, concentrate it under reduced pressure, and purify the crude product by HPLC to obtain the target compound (15.7 mg).

[1312] Exact MS: 449.2

[1313] Obs.MS(M+H) + 450.2

[1314] [Example 13] 4-[4-[(1R)-2-amino-1-hydroxyethyl]pyrazol-1-yl]-3-(2-methyl-6-phenylpyrimidin-4-yl)oxybenzonitrile (Compound No. 170)

[1315] [Chemical Formula 59]

[1316]

[1317] Step 1: Ethyl 1-(4-cyano-2-methoxyphenyl)pyrazole-4-carboxylate

[1318] DMSO (120 mL) was added to a mixture of 4-fluoro-3-methoxybenzonitrile (15.1 g, 100 mmol), ethyl 1H-pyrazole-4-carboxylate (15.4 g, 110 mmol), and potassium carbonate (27.6 g, 200 mmol), and the mixture was stirred at 60 °C for 3 hours. The reaction mixture was cooled to room temperature, water was added, and the mixture was stirred. The precipitated solid was collected by filtration through a glass filter and dried to give the target compound (22.8 g, 84%). MS: m / z 272.0 (M+H) + .

[1319] Step 2: 1-(4-cyano-2-methoxyphenyl)pyrazole-4-carboxylic acid

[1320] 1-(4-cyano-2-methoxyphenyl)pyrazole-4-carboxylic acid ethyl ester (11.0 g, 40.5 mmol) was dissolved in a mixed solvent of THF (40 mL) / methanol (40 mL), and 2M sodium hydroxide aqueous solution (40.5 mL, 81.1 mmol) was added. The mixture was stirred at room temperature for 2 hours. 2M hydrochloric acid was added to the reaction solution and stirred, followed by the addition of water to precipitate the target compound. The precipitate was collected by filtration through a glass filter and dried to obtain the target compound (7.38 g, 75%).

[1321] MS:m / z 244.0(M+H) + .

[1322] Step 3: 3-Methoxy-4-[4-(2-nitroacetyl)pyrazol-1-yl]benzonitrile

[1323] DMF (40 mL) and 1,1'-carbonyldiimidazole (5.90 g, 36.4 mmol) were added to 1-(4-cyano-2-methoxyphenyl)pyrazole-4-carboxylic acid (7.38 g, 30.3 mmol) and stirred for 2 hours (reaction solution A). Nitromethane (2.78 g, 45.5 mmol), DMF (40 mL), and sodium hydride (1.59 g, 36.4 mmol) were added to a separate reaction vessel and stirred for 2 hours to prepare another solution (reaction solution B). Reaction solution B was cooled to 0 °C, and after adding reaction solution A dropwise, the temperature was increased to 100 °C and stirred for 3 hours. The reaction solution was cooled to room temperature, and water was added to precipitate the target compound. The precipitate was collected by filtration through a glass filter and dried to obtain the target compound (8.70 g, quantitative).

[1324] MS:m / z 287.0(M+H) + .

[1325] Step 4: 3-Hydroxy-4-[4-(2-nitroacetyl)pyrazol-1-yl]benzonitrile

[1326] 3-Methoxy-4-[4-(2-nitroacetyl)pyrazol-1-yl]benzonitrile (4.50 g, 15.7 mmol) was dissolved in DMF (40 mL), and lithium chloride (6.67 g, 157 mmol) was added. The mixture was stirred overnight at 150 °C. The reaction solution was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solution was concentrated under reduced pressure. The crude product was used directly in the next reaction.

[1327] MS:m / z 273.0(M+H) + .

[1328] Step 5: 3-(2-methyl-6-phenylpyrimidin-4-yl)oxy-4-[4-(2-nitroacetyl)pyrazol-1-yl]benzene Formonitrile

[1329] The crude product obtained in step 4 was dissolved in DMF (40 mL), and 4-chloro-2-methyl-6-phenylpyrimidine (3.54 g, 17.3 mmol) and potassium carbonate (4.35 g, 31.4 mmol) were added. The mixture was stirred overnight at 100 °C. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solution was concentrated under reduced pressure to give the target compound (2.69 g, 39%). MS: m / z 441.1 (M+H) + .

[1330] Step 6: N-[2-[1-[4-cyano-2-(2-methyl-6-phenylpyrimidin-4-yl)oxyphenyl]pyrazol-4-yl]- 2-Oxoethyl]tert-butyl carbamate

[1331] THF (40 mL) and acetic acid (1.83 g, 30.5 mmol) were added to 3-(2-methyl-6-phenylpyrimidin-4-yl)oxy-4-[4-(2-nitroacetyl)pyrazol-1-yl]benzonitrile (2.69 g, 6.11 mmol), di-tert-butyl dicarbonate (4.00 g, 18.3 mmol), and zinc powder (2.00 g, 30.5 mmol). The mixture was stirred overnight at room temperature. The reaction solution was filtered through diatomaceous earth, and water was added. The solution was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to give the target compound (540 mg, 17%).

[1332] MS:m / z 511.2(M+H) + .

[1333] Step 7: N-[(2R)-2-[1-[4-cyano-2-(2-methyl-6-phenylpyrimidin-4-yl)oxyphenyl]pyrazole-4- tert-butyl carbamate (2-hydroxyethyl)

[1334] N-[2-[1-[4-cyano-2-(2-methyl-6-phenylpyrimidin-4-yl)oxyphenyl]pyrazol-4-yl]-2-oxoethyl]tert-butyl carbamate (106 mg, 0.208 mmol) and (S)-5,5-biphenyl-2-methyl-3,4-propanol-1,3,2-oxazaborolidine (5.8 mg, 0.021 mmol) were dissolved in dichloromethane (1 mL) and cooled to 0 °C. Dimethyl sulfoxide borane (47.3 mg, 0.633 mmol) was added to the reaction solution, and the mixture was stirred at the same temperature for 10 hours. Methanol and water were added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was used directly in the next reaction.

[1335] MS: m / z 513.2 (M+H) + .

[1336] Step 8: 4-[4-[(1R)-2-amino-1-hydroxyethyl]pyrazol-1-yl]-3-(2-methyl-6-phenylpyrimidine-4-yl) 2-(2-)-oxybenzonitrile

[1337] The crude product obtained in step 7 was dissolved in dichloromethane (1 mL), and TFA (1 mL) was added. The mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the crude product was purified by HPLC to obtain the target compound (18.6 mg).

[1338] Exact MS: 412.2

[1339] Obs.MS(M+H) + 413.2

[1340] [Example 14] 3-(6-cyclopentyl-2-methylpyrimidin-4-yl)oxy-4-[4-(2-oxopiperazin-1-yl)pyrazol-1-yl]benzonitrile (Compound No. 208)

[1341] [Chemical Formula 60]

[1342]

[1343] Step 1: 3-(6-chloro-2-methylpyrimidin-4-yl)oxy-4-fluorobenzonitrile

[1344] 4-Fluoro-3-hydroxybenzonitrile (3.7 g, 27 mmol) was dissolved in DMF (90 mL), and 4,6-dichloro-2-methylpyrimidine (6.6 g, 40 mmol) and potassium carbonate (7.5 g, 54 mmol) were added. The mixture was stirred at 100 °C for 2 hours. The reaction solution was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to give the target compound (6.5 g).

[1345] MS:m / z 264.1(M+H) + .

[1346] 1 H-NMR (CDCl3) δ: 7.61 (1H, dq, J=8.7, 2.1Hz), 7.56 (1H, dd, J=7.1, 2.2Hz), 7.32 (1H, dd, J=9.5, 8.5Hz), 6.90 (1H, s), 2.51 (3H, s).

[1347] Step 2: 3-(6-cyclopentyl-2-methylpyrimidin-4-yl)oxy-4-fluorobenzonitrile

[1348] THF (12.6 mL) was added to 3-(6-chloro-2-methylpyrimidin-4-yl)oxy-4-fluorobenzonitrile (1.0 g, 3.79 mmol) and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (557 mg, 0.759 mmol), followed by dropwise addition of cyclopentylzinc bromide (1.22 g, 5.69 mmol). The mixture was stirred at 70 °C for 1 hour. The reaction solution was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to give the target compound (888 mg).

[1349] MS:m / z 298.1(M+H) + .

[1350] Step 3: 3-(6-cyclopentyl-2-methylpyrimidin-4-yl)oxy-4-(4-iodopyrazol-1-yl)benzonitrile

[1351] 3-(6-cyclopentyl-2-methylpyrimidin-4-yl)oxy-4-fluorobenzonitrile (100 mg, 0.336 mmol) was dissolved in DMSO (0.5 mL), and 4-iodo-1H-pyrazole (65.2 mg, 0.336 mmol) and potassium carbonate (93.0 mg, 0.673 mmol) were added. The mixture was stirred at 120 °C for 2 hours. The reaction solution was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to give the target compound (78.9 mg). MS: m / z 472.1 (M+H) + .

[1352] Step 4: 3-(6-cyclopentyl-2-methylpyrimidin-4-yl)oxy-4-(4-iodopyrazol-1-yl)benzonitrile

[1353] 3-(6-cyclopentyl-2-methylpyrimidin-4-yl)oxy-4-(4-iodopyrazol-1-yl)benzonitrile (34.2 mg, 0.0726 mmol) was dissolved in 1,4-dioxane (0.4 mL), and tert-butyl 3-oxopiperazine-1-carboxylate (16 mg, 0.080 mmol), copper iodide (I) (2.8 mg, 0.015 mmol), trans-1,2-cyclohexanediamine (1.7 mg, 0.015 mmol), and tripotassium phosphate (46.2 mg, 0.218 mmol) were added. The mixture was stirred at 110 °C for 2 hours. After cooling to room temperature, the reaction solution was filtered through diatomaceous earth, water was added, and the solution was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solution was concentrated under reduced pressure. The crude product was used directly in the next reaction.

[1354] Step 5: 3-(6-cyclopentyl-2-methylpyrimidin-4-yl)oxy-4-[4-(2-oxopiperazin-1-yl)pyrazole-1- [Benzonitrile]

[1355] Dichloromethane (1 mL) and TFA (1 mL) were added to the crude product obtained in step 4, and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the crude product was purified by HPLC to obtain the target compound (7.3 mg).

[1356] Exact MS: 443.2

[1357] Obs.MS(M+H) + 444.3

[1358] [Example 15] 3-(2-methyl-5-phenylpyrazol-3-yl)oxy-4-[4-(7-oxo-1,4-diazacycloheptane-1-yl)pyrazol-1-yl]benzonitrile (Compound No. 219)

[1359] [Chemical Formula 61]

[1360]

[1361] Step 1: 3-Fluoro-4-(4-iodopyrazole-1-yl)benzonitrile

[1362] DMF (8.6 mL) was added to a mixture of 3,4-difluorobenzonitrile (430 mg, 3.09 mmol), 4-iodo-1H-pyrazole (500 mg, 2.58 mmol), and cesium carbonate (1.68 g, 5.16 mmol), and the mixture was stirred at 120 °C for 3 hours. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to give the target compound (428 mg, 53%).

[1363] 1H-NMR (CDCl3) δ: 8.18 (1H, d, J = 2.7Hz), 8.15 (1H, t, J = 8.2Hz), 7.79 (1H, s), 7.60-7.55 (2H, m).

[1364] Step 2: 4-(4-iodopyrazol-1-yl)-3-(2-methyl-5-phenylpyrazol-3-yl)oxybenzonitrile

[1365] NMP (2.6 mL) was added to 3-fluoro-4-(4-iodopyrazol-1-yl)benzonitrile (201 mg, 0.642 mmol), 2-methyl-5-phenyl-4H-pyrazol-3-one (123 mg, 0.706 mmol), and potassium carbonate (177 mg, 1.28 mmol), and the mixture was stirred overnight at 120 °C. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to give the target compound (198 mg, 66%).

[1366] MS:m / z 468.1(M+H) + .

[1367] Step 3: 4-[1-[4-cyano-2-(2-methyl-5-phenylpyrazol-3-yl)oxyphenyl]pyrazol-4-yl]-5-oxo tert-butyl 1,4-diazacycloheptan-1-carboxylate

[1368] To a 1,4-dioxane solution (0.5 mL) of 4-(4-iodopyrazol-1-yl)-3-(2-methyl-5-phenylpyrazol-3-yl)oxybenzonitrile (46 mg, 0.098 mmol), tert-butyl 5-oxo-1,4-diazacycloheptane-1-carboxylate (24 mg, 0.11 mmol), copper iodide (I) (3.7 mg, 0.020 mmol), trans-1,2-cyclohexanediamine (2.2 mg, 0.020 mmol), and tripotassium phosphate (62.7 mg, 0.295 mmol) were added, and the mixture was stirred overnight at 100 °C. The reaction mixture was cooled to room temperature, and water was added. The mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was used directly in the next reaction.

[1369] Step 4: 3-(2-methyl-5-phenylpyrazol-3-yl)oxy-4-[4-(7-oxo-1,4-diazacycloheptane-1- [1-yl]pyrazole-1-yl]benzonitrile

[1370] The crude product obtained in step 3 was dissolved in dichloromethane (1 mL), and TFA (1 mL) was added. The mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and the crude product was purified by HPLC to obtain the target compound (15.7 mg).

[1371] Exact MS: 453.2

[1372] Obs.MS(M+H) + 454.3

[1373] [Example 16] 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-(2-methyl-6-morpholin-4-ylpyridin-4-yl)oxybenzonitrile (Compound No. 250)

[1374] [Chemical Formula 62]

[1375]

[1376] Step 1: 4-Bromo-3-(2-hydroxy-6-methylpyridin-4-yl)oxybenzonitrile

[1377] NMP (400 mL) was added to 4-bromo-3-fluorobenzonitrile (40.0 g, 200 mmol), 6-methylpyridin-2,4-diol (30.0 g, 240 mmol), and sodium carbonate (53.0 g, 500 mmol), and the mixture was stirred at 160 °C for 5 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solution was concentrated under reduced pressure. Ethyl acetate was added to the concentrated crude product to suspend it, and heptane was added further. The precipitate was collected by filtration through a glass filter. The solid was dried under vacuum to give the target compound (20.3 g, 33%).

[1378] MS:m / z 305.0(M+H) + .

[1379] 1 H-NMR (DMSO-d6) δ: 11.47 (1H, s), 8.00 (1H, d, J = 8.2Hz), 7.92 (1H, d, J = 1.8Hz), 7.7 3 (1H, dd, J = 8.2, 2.3Hz), 5.89 (1H, d, J = 1.8Hz), 5.15 (1H, d, J = 2.7Hz), 2.15 (3H, s).

[1380] Step 2: [4-(2-bromo-5-cyanophenoxy)-6-methylpyridin-2-yl]trifluoromethanesulfonate

[1381] Dichloromethane (22 mL) was added to 4-bromo-3-(2-hydroxy-6-methylpyridin-4-yl)oxybenzonitrile (2.7 g, 8.85 mmol), and after cooling to 0 °C, trifluoromethanesulfonic anhydride (3.25 g, 11.5 mmol) was added. Pyridine (2.1 mL, 26.5 mmol) was added dropwise to the reaction mixture at the same temperature, and the mixture was heated to room temperature and stirred for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solution was concentrated under reduced pressure. The crude product was used directly in the next reaction.

[1382] MS: m / z 436.9 (M+H) + .

[1383] Step 3: 4-Bromo-3-(2-methyl-6-morpholin-4-ylpyridin-4-yl)oxybenzonitrile

[1384] The crude product obtained in step 2 was dissolved in DMSO (18 mL), and morpholine (1.16 g, 13.3 mmol) and N,N-diisopropylethylamine (4.73 mL, 26.5 mmol) were added. The mixture was stirred at 70 °C for 2 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solution was concentrated under reduced pressure. Ethanol was added to the concentrated crude product, and the mixture was dried overnight. The precipitate of the target compound was collected by filtration through a glass filter and dried to obtain the target compound (1.87 g, 57%).

[1385] MS:m / z 374.0(M+H) + .

[1386] 1H-NMR (CDCl3) δ: 7.77 (1H, d, J = 8.2Hz), 7.35 (1H, dd, J = 8.2, 1.8Hz), 7.29 (1H, d, J = 1.8Hz), 6.02 ( 1H, d, J=1.4Hz), 6.00 (1H, d, J=1.4Hz), 3.80 (4H, t, J=5.0Hz), 3.48 (4H, t, J=4.8Hz), 2.36 (3H, s).

[1387] Step 4: 3-(2-methyl-6-morpholin-4-ylpyridin-4-yl)oxy-4-(4,4,5,5-tetramethyl-1,3,2-di) oxaborane-2-yl)benzonitrile

[1388] 4-Bromo-3-(2-methyl-6-morpholin-4-ylpyridin-4-yl)oxybenzonitrile (790 mg, 2.11 mmol) was dissolved in 1,4-dioxane (11 mL), and bis(pinacol)diboron (804 mg, 3.17 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (76.4 mg, 0.106 mmol), and potassium acetate (415 mg, 4.22 mmol) were added. The mixture was stirred overnight at 90 °C. The reaction solution was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to give the target compound (567 mg). MS: m / z 422.3 (M+H) + .

[1389] Step 5: N-[2-[2-[4-cyano-2-(2-methyl-6-morpholin-4-ylpyridin-4-yl)oxyphenyl]pyrimidine-5- [B-ethyl] tert-butyl carbamate

[1390] 3-(2-methyl-6-morpholin-4-ylpyridin-4-yl)oxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)benzonitrile (222 mg, 0.527 mmol) was dissolved in 1,4-dioxane (1.8 mL). N-[2-(2-chloropyrimidin-5-yl)ethyl]carbamate tert-butyl ester (90.5 mg, 0.351 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (12.8 mg, 0.0176 mmol), potassium carbonate (97.1 mg, 0.702 mmol), and water (0.4 mL) were added, and the mixture was stirred overnight at 90 °C. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the target compound (71.9 mg, 40%).

[1391] MS:m / z 517.3(M+H) + .

[1392] 1 H-NMR (CDCl3) δ: 8.61 (2H, s), 8.05 (1H, d, J = 8.2Hz), 7.61 (1H, dd, J = 8.2, 1.4Hz), 7.44 (1H, d, J = 1.4Hz), 6.01 (1H, d, J = 1.4Hz), 5.94 (1H, d, J = 1.8Hz), 4.70 (1H, brs), 3.78 (4H, t, J = 4.8Hz), 3.41 (4H, t, J = 4.8Hz), 3.36 (2H, q, J = 6.6Hz), 2.82 (2H, t, J = 6.6Hz), 2.29 (3H, s), 1.43 (9H, s).

[1393] Step 6: 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-(2-methyl-6-morpholin-4-ylpyridin-4-yl)oxybenzene Formonitrile

[1394] N-[2-[2-[4-cyano-2-(2-methyl-6-morpholin-4-ylpyridin-4-yl)oxyphenyl]pyrimidin-5-yl]ethyl]tert-butyl carbamate (71.9 mg, 0.139 mmol) was dissolved in dichloromethane (1 mL), and TFA (1 mL) was added. The mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the crude product was purified by HPLC to obtain the target compound (63.62 mg).

[1395] Exact MS: 416.2

[1396] Obs.MS(M+H) + 417.4

[1397] 1 H-NMR (CD3OD) δ: 8.79 (2H, s), 8.33 (1H, d, J = 8.2Hz), 7.90 (1H, dd, J = 8.0, 1.6Hz), 7.79 (1H, d, J = 1.4Hz), 6.46 (1H, d, J = 1.8Hz), 6.39 (1H, d, J = 1.8Hz), 3.79 (4H, t, J = 5.0Hz), 3.55 (4H, t, J = 5.0Hz), 3.25 (2H, t, J = 7.8Hz), 3.04 (2H, t, J = 7.8Hz), 2.50 (3H, s).

[1398] [Example 17] 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-(2-methyl-5-propane-2-ylpyrazol-3-yl)oxybenzonitrile (Compound No. 261)

[1399] [Chemical Formula 63]

[1400]

[1401] Step 1: 4-Bromo-3-(2-methyl-5-propane-2-ylpyrazole-3-yl)oxybenzonitrile

[1402] 4-Bromo-3-fluorobenzonitrile (2.14 g, 10.7 mmol) and 2-methyl-5-propane-2-ylpyrazole-3-ol (1.50 g, 10.7 mmol) were dissolved in DMA (21 mL), and potassium carbonate (4.44 g, 32.1 mmol) was added. The mixture was stirred at 130 °C for 3 hours. The reaction solution was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to give the target compound (1.06 g, 31%).

[1403] MS:m / z 322.1(M+H) + .

[1404] 1 H-NMR (CDCl3) δ: 7.77 (1H, d, J = 8.2Hz), 7.34-7.32 (2H, m), 5.52 (1H, s), 3.70 (3H, s), 2.94-2.87 (1H, m), 1.25 (6H, d, J = 6.9Hz).

[1405] Step 2: 3-(2-methyl-5-propane-2-ylpyrazole-3-yl)oxy-4-(4,4,5,5-tetramethyl-1,3,2-di) oxaborane-2-yl)benzonitrile

[1406] 4-Bromo-3-(2-methyl-5-propane-2-ylpyrazol-3-yl)oxybenzonitrile (646 mg, 2.02 mmol) was dissolved in 1,4-dioxane (10 mL), and bis(pinacol)diboron (615 mg, 2.42 mmol), bis(triphenylphosphine)palladium dichloride (70.8 mg, 0.101 mmol), and potassium acetate (396 mg, 4.03 mmol) were added. The mixture was stirred at 100 °C for 2 hours. The reaction solution was cooled to room temperature, filtered through diatomaceous earth, and concentrated under reduced pressure. The crude product was used directly in the next reaction.

[1407] MS:m / z 368.2(M+H) + .

[1408] Step 3: N-[2-[2-[4-cyano-2-(2-methyl-5-propane-2-ylpyrazol-3-yl)oxyphenyl]pyrimidine-5- [B-ethyl] tert-butyl carbamate

[1409] To a 1,4-dioxane (13.5 mL) solution of the crude product obtained in step 2, N-[2-(2-chloropyrimidin-5-yl)ethyl]carbamate tert-butyl ester (520 mg, 2.02 mmol), tetrakis(triphenylphosphine)palladium (117 mg, 0.101 mmol), potassium carbonate (697 mg, 5.04 mmol), and water (3.4 mL) were added, and the mixture was stirred at 100 °C for 2 hours. The reaction solution was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the target compound (946 mg, including impurities).

[1410] MS:m / z 463.2(M+H) + .

[1411] Step 4: 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-(2-methyl-5-propane-2-ylpyrazol-3-yl)oxybenzene Formonitrile

[1412] N-[2-[2-[4-cyano-2-(2-methyl-5-propane-2-ylpyrazol-3-yl)oxyphenyl]pyrimidin-5-yl]ethyl]tert-butyl carbamate (946 mg, 1.23 mmol) was dissolved in 1,4-dioxane (5.1 mL). A 4M hydrochloric acid / 1,4-dioxane solution (5.1 mL) was added dropwise at 0 °C, followed by heating to room temperature and stirring for 5 hours. The reaction solution was concentrated under reduced pressure, and ethyl acetate was added to the concentrated crude product, followed by further concentration under reduced pressure. The product was then dried under vacuum to obtain the hydrochloride salt of the target compound (681 mg, 76%).

[1413] Exact MS: 362.2

[1414] Obs.MS(M+H) + 363.3

[1415] [Example 18] 4-[4-(2-aminoethyl)pyrazol-1-yl]-3-(6-pyrrolidone-1-ylpyridazin-4-yl)oxybenzonitrile (Compound No. 284)

[1416] [Chemical Formula 64]

[1417]

[1418] Step 1: N-[2-[1-(4-cyano-2-phenylmethoxyphenyl)pyrazole-4-yl]ethyl]tert-butyl carbamate

[1419] DMA (2 mL) was added to 4-fluoro-3-phenylmethoxybenzonitrile (307 mg, 1.35 mmol), N-[2-(1H-pyrazol-4-yl)ethyl]carbamate tert-butyl ester (190 mg, 0.900 mmol), and potassium carbonate (373 mg, 2.70 mmol), and the mixture was stirred at 150 °C for 2 hours. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to give the target compound (263 mg, 70%).

[1420] MS:m / z 419.2(M+H) + .

[1421] Step 2: N-[2-[1-(4-cyano-2-hydroxyphenyl)pyrazole-4-yl]ethyl]tert-butyl carbamate

[1422] N-[2-[1-(4-cyano-2-phenylmethoxyphenyl)pyrazol-4-yl]ethyl]tert-butyl carbamate (263 mg, 0.628 mmol) was dissolved in methanol (5 mL) / ethyl acetate (5 mL), and palladium-activated carbon (100 mg) was added under a nitrogen atmosphere. A hydrogen balloon was installed inside the reaction vessel, and the vessel was replaced with hydrogen gas. The mixture was stirred at room temperature for 30 minutes. The reaction solution was filtered through diatomaceous earth, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to obtain the target compound (172 mg, 83%).

[1423] MS:m / z 273.0(M-tBu+H) + .

[1424] Step 3: N-[2-[1-[2-(6-chloropyridazin-4-yl)oxy-4-cyanophenyl]pyrazol-4-yl]ethyl]aminomethyl tert-butyl ester

[1425] DMF (1.3 mL) was added to N-[2-[1-(4-cyano-2-hydroxyphenyl)pyrazol-4-yl]ethyl]carbamate tert-butyl ester (172 mg, 0.524 mmol), 3,5-dichloropyridazine (101 mg, 0.681 mmol), and potassium carbonate (217 mg, 1.57 mmol), and the mixture was stirred at 100 °C for 1 hour. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to give the target compound (218 mg, 94%).

[1426] MS:m / z 385.0(M-tBu+H) + .

[1427] Step 4: N-[2-[1-[4-cyano-2-(6-pyrrolidone-1-ylpyridazin-4-yl)oxyphenyl]pyrazole-4-yl]ethyl [B] tert-butyl carbamate

[1428] N-[2-[1-[2-(6-chloropyridazin-4-yl)oxy-4-cyanophenyl]pyrazol-4-yl]ethyl]tert-butyl carbamate (70.0 mg, 0.159 mmol) was dissolved in toluene (0.8 mL), and pyrrolidine (33.9 mg, 0.476 mmol), tris(dibenzylacetone)dipalladium (7.3 mg, 7.9 μmol), (±)-BINAP (9.9 mg, 16 μmol), and cesium carbonate (220 mg, 2.25 mmol) were added. The mixture was stirred at 100 °C for 1 hour. The reaction solution was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to give the target compound (51.0 mg, 68%).

[1429] Step 5: 4-[4-(2-aminoethyl)pyrazol-1-yl]-3-(6-pyrrolidine-1-ylpyridazin-4-yl)oxybenzonitrile

[1430] N-[2-[1-[4-cyano-2-(6-pyrrolidone-1-ylpyridazin-4-yl)oxyphenyl]pyrazol-4-yl]ethyl]tert-butyl carbamate (51.0 mg, 0.107 mmol) was dissolved in dichloromethane (2 mL), and TFA (0.5 mL) was added. The mixture was stirred at room temperature for 30 minutes. The reaction solution was concentrated under reduced pressure, and the crude product was purified by HPLC to obtain the target compound (9.71 mg).

[1431] Exact MS: 375.2

[1432] Obs.MS(M+H) + 376.2

[1433] [Example 19] 4-[5-(1-amino-2-morpholin-4-yl-2-oxoethyl)pyridin-2-yl]-3-(5-cyclopropyl-2-methylpyrazol-3-yl)oxybenzonitrile (Compound No. 487)

[1434] [Chemical Formula 65]

[1435]

[1436] Step 1: 2-[6-[4-cyano-2-(5-cyclopropyl-2-methylpyrazol-3-yl)oxyphenyl]pyridin-3-yl]-2- Methyl acetate [(2-methylpropane-2-yl)oxycarbonylamino]acetate

[1437] 3-(5-cyclopropyl-2-methylpyrazol-3-yl)oxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)benzonitrile (881 mg, 2.41 mmol) synthesized by the same method as in Example 17 was dissolved in 1,4-dioxane (12 mL). Methyl 2-(6-chloropyridin-3-yl)-2-[(2-methylpropane-2-yl)oxycarbonylamino]acetate (725 mg, 2.41 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (176.5 mg, 0.241 mmol), potassium carbonate (1.00 g, 7.24 mmol), and water (3 mL) were added, and the mixture was stirred at 100 °C for 2 hours. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the target compound (976 mg, 80%).

[1438] MS:m / z 504.4(M+H) + .

[1439] Step 2: 2-[6-[4-cyano-2-(5-cyclopropyl-2-methylpyrazol-3-yl)oxyphenyl]pyridin-3-yl]-2- [(2-Methylpropane-2-yl)oxycarbonylamino]acetic acid

[1440] Methyl 2-[6-[4-cyano-2-(5-cyclopropyl-2-methylpyrazol-3-yl)oxyphenyl]pyridin-3-yl]-2-[(2-methylpropane-2-yl)oxycarbonylamino]acetate (976 mg, 1.94 mmol) was dissolved in methanol (10 mL), and 2 M sodium hydroxide aqueous solution (2 mL) was added. The mixture was stirred at room temperature for 15 minutes. 1 M hydrochloric acid (4 mL) was added to the reaction mixture, and after stirring, ethyl acetate was added and the mixture was extracted. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The crude product was used directly in the next reaction.

[1441] MS: m / z 490.3 (M+H) + .

[1442] Step 3: N-[1-[6-[4-cyano-2-(5-cyclopropyl-2-methylpyrazol-3-yl)oxyphenyl]pyridine-3- tert-butyl carbamate [2-morpholino-4-yl-2-oxoethyl]carbamate

[1443] A portion of the crude product obtained in step 2 (160 mg, 0.320 mmol) was dissolved in DMF (1 mL), and morpholine (0.041 mL, 0.48 mmol), HATU (160 mg, 0.420 mmol), and triethylamine (0.130 mL, 0.960 mmol) were added. The mixture was stirred at room temperature for 3 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solution was concentrated under reduced pressure. The crude product was used directly in the next reaction.

[1444] MS: m / z 559.4 (M+H) + .

[1445] Step 4: 4-[5-(1-amino-2-morpholin-4-yl-2-oxoethyl)pyridin-2-yl]-3-(5-cyclopropyl-2-methyl) pyrazole-3-yl)oxybenzonitrile

[1446] The crude product obtained in step 3 was dissolved in dichloromethane (1 mL), and TFA (0.5 mL) was added. The mixture was stirred at room temperature for 30 minutes. The reaction solution was concentrated under reduced pressure, and the crude product was purified by HPLC to obtain the target compound (39.7 mg).

[1447] Exact MS: 458.2

[1448] Obs.MS(M+H) + 459.3

[1449] [Example 20] 4-[5-[(3-aminooxetane-3-yl)methyl]pyridin-2-yl]-3-[6-(7-azabicyclo[2.2.1]heptane-7-yl)-2-methylpyrimidin-4-yl]oxybenzonitrile (Compound No. 670)

[1450] [Chemical Formula 66]

[1451]

[1452] Step 1: 4-Bromo-3-(6-chloro-2-methylpyrimidin-4-yl)oxybenzonitrile

[1453] 4-Bromo-3-hydroxybenzonitrile (1.78 g, 9.00 mmol) was dissolved in DMSO (30 mL), and 4,6-dichloro-2-methylpyrimidine (1.28 g, 6.0 mmol) and potassium carbonate (2.49 g, 18.0 mmol) were added. The mixture was stirred overnight at 80 °C. The reaction solution was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to give the target compound (1.16 g, 60%).

[1454] MS:m / z 324.0(M+H) + .

[1455] Step 2: 3-[6-(7-azabicyclo[2.2.1]heptane-7-yl)-2-methylpyrimidin-4-yl]oxy-4-bromobenzyl nitrile

[1456] 4-Bromo-3-(6-chloro-2-methylpyrimidin-4-yl)oxybenzonitrile (325 mg, 1.00 mmol) was dissolved in DMF (5 mL), and 7-azabicyclo[2.2.1]heptane hydrochloride (200 mg, 1.50 mmol) and potassium carbonate (415 mg, 3.00 mmol) were added. The mixture was stirred overnight at 80 °C. The reaction solution was cooled to room temperature, water was added, and the mixture was extracted with a 1 / 1 mixture of ethyl acetate and heptane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to give the target compound (235 mg, 61%).

[1457] MS:m / z 385.1(M+H) + .

[1458] 1 H-NMR (CDCl3) δ: 7.73 (1H, d, J = 8.2Hz), 7.47 (1H, d, J = 2.3Hz), 7.36 (1H, dd, J = 8.2, 1.8Hz), 5.89 (1H, s), 4.51 (2H, br s), 2.36 (3H, s), 1.82-1.80 (4H, m), 1.57-1.50 (4H, m).

[1459] Step 3: 3-[6-(7-azabicyclo[2.2.1]heptane-7-yl)-2-methylpyrimidin-4-yl]oxy-4-(4,4, 5,5-Tetramethyl-1,3,2-dioxaborane-2-yl)benzonitrile

[1460] 3-[6-(7-azabicyclo[2.2.1]heptane-7-yl)-2-methylpyrimidin-4-yl]oxy-4-bromobenzonitrile (231 mg, 0.600 mmol) was dissolved in 1,4-dioxane (3 mL), and bis(pinacol)diboron (305 mg, 1.20 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (43.9 mg, 0.0600 mmol), and potassium acetate (177 mg, 1.80 mmol) were added. The mixture was stirred overnight at 100 °C. The reaction solution was cooled to room temperature, filtered through diatomaceous earth, and concentrated under reduced pressure. The concentrated crude product was used directly in the next reaction.

[1461] Step 4: N-[3-[[6-[2-[6-(7-azabicyclo[2.2.1]heptane-7-yl)-2-methylpyrimidin-4-yl]oxy [4-cyanophenyl]pyridin-3-yl]methyl]oxetane-3-yl]-2-methylpropane-2-sulfinamide

[1462] A portion (64.8 mg) of the crude product obtained in step 3 was dissolved in 1,4-dioxane (1 mL), and N-[3-[(6-chloropyridin-3-yl)methyl]oxetane-3-yl]-2-methylpropane-2-sulfinamide (30.3 mg, 0.100 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (7.3 mg, 0.010 mmol), potassium carbonate (41.5 mg, 0.300 mmol), and water (0.2 mL) were added. The mixture was stirred overnight at 100 °C. The reaction solution was cooled to room temperature, filtered through diatomaceous earth, and then concentrated under reduced pressure. The concentrated crude product was used directly in the next reaction.

[1463] Step 5: 4-[5-[(3-aminooxetane-3-yl)methyl]pyridin-2-yl]-3-[6-(7-azabicyclo] [2.2.1]Heptane-7-yl)-2-methylpyrimidin-4-yl]oxybenzonitrile

[1464] The crude product obtained in step 4 was dissolved in methanol (1 mL), and 0.15 mL of 4 M hydrochloric acid / 1,4-dioxane solution was added at 0 °C. The mixture was stirred at the same temperature for 2 hours. A saturated sodium bicarbonate aqueous solution (5 mL) was added to the reaction mixture, and the solution was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, and the solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to give the target compound (8.2 mg). Exact MS: 468.2

[1465] Obs.MS(M+H) + 469.2

[1466] [Example 21] 4-[5-(2-aminoethyl)pyridin-2-yl]-3-[[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]oxy]benzonitrile (Compound No. 712)

[1467] [Chemical Formula 67]

[1468]

[1469] Step 1: 4-Bromo-3-[(4-methoxyphenyl)methoxy]benzonitrile

[1470] 4-Bromo-3-fluorobenzonitrile (6.00 g, 30.0 mmol) was added to a DMF (100 mL) solution of 4-methoxybenzyl alcohol (4.97 g, 36.0 mmol) and potassium tert-butoxide (4.04 g, 36.0 mmol), and the mixture was stirred at room temperature for 2.5 hours. Water was added to the reaction solution and the mixture was stirred. The precipitated solid was collected by filtration through a glass filter. The solid was dried under vacuum to give the target compound (8.04 g, 84%).

[1471] 1H-NMR (CDCl3) δ: 7.65 (1H, d, J = 7.8Hz), 7.37 (2H, d, J = 8.7Hz), 7.13 (2H, dd, J = 9.8, 1.1Hz), 6.93 (2H, d, J = 8.2Hz), 5.11 (2H, s), 3.83 (3H, s).

[1472] Step 2: 3-[(4-methoxyphenyl)methoxy]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboranecyclopentane) Alkyl-2-yl)benzonitrile

[1473] 4-Bromo-3-[(4-methoxyphenyl)methoxy]benzonitrile (1.0 g, 3.14 mmol) was dissolved in 1,4-dioxane (16 mL), and bis(pinacol)diboron (1.20 g, 4.71 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (115 mg, 0.157 mmol), and potassium acetate (617 mg, 6.29 mmol) were added. The mixture was stirred at 100 °C for 2 hours. The reaction solution was cooled to room temperature, filtered through diatomaceous earth, and then concentrated under reduced pressure. The concentrated crude product was used directly in the next reaction.

[1474] MS:m / z 433.2(M+H) + .

[1475] Step 3: N-[2-[6-[4-cyano-2-[(4-methoxyphenyl)methoxy]phenyl]pyridin-3-yl]ethyl]amino tert-butyl carbamate

[1476] To a 6 mL solution of the crude product obtained in step 2, containing 1,4-dioxane, N-[2-(6-chloropyridin-3-yl)ethyl] tert-butyl carbamate (807 mg, 3.14 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (231 mg, 0.314 mmol), potassium carbonate (2.05 g, 6.29 mmol), and water (1 mL) were added, and the mixture was stirred at 100 °C for 4 hours. The reaction solution was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the target compound (1.17 g, 81%).

[1477] MS:m / z 460.2(M+H) + .

[1478] Step 4: 4-[5-(2-aminoethyl)pyridin-2-yl]-3-hydroxybenzonitrile

[1479] Dissolve tert-butyl N-[2-[6-[4-cyano-2-[(4-methoxyphenyl)methoxy]phenyl]pyridin-3-yl]ethyl]carbamate (1.05 g, 1.60 mmol) in dichloromethane (10 mL), add TFA (2 mL), and stir at room temperature for 2 hours. Concentrate the reaction solution under reduced pressure, and use the concentrated crude product directly in the next reaction.

[1480] Step 5: N-[2-[6-(4-cyano-2-hydroxyphenyl)pyridin-3-yl]ethyl]tert-butyl carbamate

[1481] The crude product obtained in step 4 was dissolved in dichloromethane (5 mL), and di-tert-butyl dicarbonate (698 mg, 3.20 mmol) and triethylamine (1.00 mL) were added. The mixture was stirred at room temperature for 1 hour. Water was added to the reaction solution, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to give the target compound (526 mg, 97%).

[1482] MS:m / z 340.1(M+H) + .

[1483] Step 6: N-[2-[6-[4-cyano-2-[[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]oxy]phenyl]pyridine [Pyridine-3-yl]ethyl]tert-butyl carbamate

[1484] N-[2-[6-(4-cyano-2-hydroxyphenyl)pyridin-3-yl]ethyl]carbamate tert-butyl ester (30 mg, 0.088 mmol) was dissolved in NMP (1 mL), and 2-bromo-5-(trifluoromethyl)-1,3,4-thiadiazole (24.7 mg, 0.106 mmol) and potassium carbonate (36.7 mg, 0.265 mmol) were added. The mixture was stirred at 80 °C for 1 hour. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solution was concentrated under reduced pressure. The crude product was used directly in the next reaction.

[1485] MS:m / z 492.1(M+H) + .

[1486] Step 7: 4-[5-(2-aminoethyl)pyridin-2-yl]-3-[[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]oxy [Benzonitrile]

[1487] The crude product obtained in step 6 was dissolved in dichloromethane (1 mL), and TFA (0.5 mL) was added. The mixture was stirred at room temperature for 30 minutes. The reaction solution was concentrated under reduced pressure, and the crude product was purified by HPLC to obtain the target compound (35.9 mg).

[1488] Exact MS: 391.1

[1489] Obs.MS(M+H) +392.2

[1490] [Example 22] 4-[5-(aminomethyl)pyrimidin-2-yl]-3-[2-methyl-5-(trifluoromethyl)pyrazol-3-yl]oxybenzonitrile (Compound No. 811)

[1491] [Chemical Formula 68]

[1492]

[1493] Step 1: 3-[2-methyl-5-(trifluoromethyl)pyrazol-3-yl]oxy-4-nitrobenzene

[1494] 3-Fluoro-4-nitrobenzene (664 mg, 4.00 mmol) and 2-methyl-5-(trifluoromethyl)-4H-pyrazole-3-one (731 mg, 4.40 mmol) were dissolved in DMF (6 mL), and potassium carbonate (663 mg, 4.80 mmol) was added. The mixture was stirred at room temperature for 5 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solution was concentrated under reduced pressure. The resulting solid was washed with a small amount of ethyl acetate to give the target compound (417 mg).

[1495] MS:m / z 313.1(M+H) + .

[1496] Step 2: 4-Amino-3-[2-methyl-5-(trifluoromethyl)pyrazol-3-yl]oxybenzonitrile

[1497] Iron powder (224 mg, 4.01 mmol), ammonium chloride (214 mg, 4.01 mmol), ethanol (1.3 mL), and water (1.3 mL) were added to 3-[2-methyl-5-(trifluoromethyl)pyrazol-3-yl]oxy-4-nitrobenzene (417 mg, 1.34 mmol), and the mixture was stirred at 70 °C for 1.5 hours. The reaction solution was cooled to room temperature, filtered through diatomaceous earth, and the mother liquor was extracted with ethyl acetate and water. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The concentrated crude product was used directly in the next reaction.

[1498] MS:m / z 283.1(M+H) + .

[1499] Step 3: 4-Bromo-3-[2-methyl-5-(trifluoromethyl)pyrazol-3-yl]oxybenzonitrile

[1500] The crude product obtained in step 2 was dissolved in acetonitrile (6.5 mL), and isoamyl nitrite (224 mg, 1.92 mmol) and copper(II) bromide (341 mg, 1.53 mmol) were added. The mixture was stirred at 65 °C for 16 hours. The reaction solution was cooled to room temperature, and 20% hydrochloric acid was added. The solution was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the target compound (389 mg).

[1501] MS:m / z 346.0(M+H) + .

[1502] Step 4: 3-[2-methyl-5-(trifluoromethyl)pyrazol-3-yl]oxy-4-(4,4,5,5-tetramethyl-1,3,2-di- oxaborane-2-yl)benzonitrile

[1503] Dissolve 4-bromo-3-[2-methyl-5-(trifluoromethyl)pyrazol-3-yl]oxybenzonitrile (389 mg, 1.12 mmol) in 1,4-dioxane (5.6 mL), add bis(pinacol)diboron (428 mg, 1.68 mmol), bis(triphenylphosphine)palladium dichloride (78.8 mg, 0.112 mmol), and potassium acetate (220 mg, 2.25 mmol), and stir at 110 °C for 1 hour. Cool the reaction solution to room temperature and use it directly in the next reaction.

[1504] MS: m / z 394.2 (M+H) + .

[1505] Step 5: N-[[2-[4-cyano-2-[2-methyl-5-(trifluoromethyl)pyrazol-3-yl]oxyphenyl]pyrimidine-5- [2-methyl]-N-[(2-methylpropane-2-yl)oxycarbonyl]tert-butyl carbamate

[1506] To a portion (1.2 mL) of the reaction solution obtained in step 4, add N-[(2-chloropyrimidin-5-yl)methyl]-N-[(2-methylpropane-2-yl)oxycarbonyl]tert-butyl carbamate (107 mg, 0.31 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (21 mg, 0.028 mmol), potassium carbonate (120 mg, 0.840 mmol), and water (0.3 mL), and stir at 100 °C for 1 hour. Cool the reaction solution to room temperature, add water, and extract with ethyl acetate. Wash the organic layer with saturated brine, dry with anhydrous sodium sulfate, and concentrate the solution under reduced pressure. Use the concentrated crude product directly in the next reaction.

[1507] Step 6: 4-[5-(aminomethyl)pyrimidin-2-yl]-3-[2-methyl-5-(trifluoromethyl)pyrazol-3-yl]oxybenzene Formonitrile

[1508] Dichloromethane (0.5 mL) and TFA (0.5 mL) were added to the crude product obtained in step 5, and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the crude product was purified by HPLC to obtain the target compound (88.7 mg).

[1509] Exact MS: 374.1

[1510] Obs.MS(M+H) + 375.3

[1511] [Example 23] 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[5-[2,2-difluoroethyl(ethyl)amino]-2-methylpyrazol-3-yl]oxybenzonitrile (Compound No. 875)

[1512] [Chemical Formula 69]

[1513]

[1514] Step 1: 3-(5-amino-2-methylpyrazol-3-yl)oxy-4-bromobenzonitrile

[1515] 4-Bromo-3-fluorobenzonitrile (3.0 g, 15 mmol) and 5-amino-2-methyl-4H-pyrazole-3-one (1.7 g, 15 mmol) were dissolved in DMA (40 mL), and potassium carbonate (4.14 g, 30.0 mmol) was added. The mixture was stirred at 120 °C for 2 hours. The reaction solution was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to give the target compound (444 mg, 10%).

[1516] MS: m / z 292.9 (M+H) + .

[1517] 1 H-NMR (CDCl3) δ: 7.76 (1H, d, J = 8.2Hz), 7.36 (1H, d, J = 1.8Hz), 7.32 (1H, dd, J = 8.0, 1.6Hz), 5.11 (1H, s), 3.63 (2H, br s), 3.57 (3H, s).

[1518] Step 2: 4-Bromo-3-[5-(2,2-difluoroethylamino)-2-methylpyrazol-3-yl]oxybenzonitrile

[1519] 3-(5-amino-2-methylpyrazol-3-yl)oxy-4-bromobenzonitrile (1.47 g, 5.00 mmol) was dissolved in DMA (10 mL), and 1,1-difluoro-2-iodoethane (1.44 g, 7.50 mmol) and N,N-diisopropylethylamine (1.74 mL, 10.0 mmol) were added. The mixture was stirred overnight at 140 °C. The reaction solution was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to give the target compound (1.10 g, 62%).

[1520] MS:m / z 359.0(M+H) + .

[1521] Step 3: 4-Bromo-3-[5-[2,2-difluoroethyl(ethyl)amino]-2-methylpyrazol-3-yl]oxybenzonitrile

[1522] 4-Bromo-3-[5-(2,2-difluoroethylamino)-2-methylpyrazol-3-yl]oxybenzonitrile (1.10 g, 3.09 mmol) was dissolved in DMA (10 mL), and iodoethane (963 mg, 6.17 mmol) and N,N-diisopropylethylamine (1.08 mL, 6.17 mmol) were added. The mixture was stirred overnight at 120 °C. The reaction solution was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to give the target compound (766 mg, 64%).

[1523] MS:m / z 385.0(M+H) + .

[1524] Step 4: 3-[5-[2,2-difluoroethyl(ethyl)amino]-2-methylpyrazol-3-yl]oxy-4-(4,4,5,5- Tetramethyl-1,3,2-dioxaborane-2-yl)benzonitrile

[1525] 4-Bromo-3-[5-[2,2-difluoroethyl(ethyl)amino]-2-methylpyrazol-3-yl]oxybenzonitrile (766 mg, 1.99 mmol) was dissolved in 1,4-dioxane (10 mL), and bis(pinacol)diboron (758 mg, 2.98 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (72.8 mg, 0.0995 mmol), and potassium acetate (391 mg, 3.98 mmol) were added. The mixture was stirred at 100 °C for 2 hours. The reaction solution was cooled to room temperature, filtered through diatomaceous earth, and concentrated under reduced pressure. The crude product was used directly in the next reaction.

[1526] MS:m / z 433.2(M+H) + .

[1527] Step 5: N-[2-[2-[4-cyano-2-[5-[2,2-difluoroethyl(ethyl)amino]-2-methylpyrazol-3-yl] [Oxyphenyl]pyrimidin-5-yl]ethyl]tert-butyl carbamate

[1528] The crude product obtained in step 4 was dissolved in 1,4-dioxane (10 mL), and N-[2-(2-chloropyrimidin-5-yl)ethyl]carbamate tert-butyl ester (462 mg, 1.79 mmol), tetrakis(triphenylphosphine)palladium (115 mg, 0.0995 mmol), potassium carbonate (550 mg, 3.98 mmol), and water (3 mL) were added. The mixture was stirred at 100 °C for 1 hour. The reaction solution was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to give the target compound (648 mg, 62%).

[1529] MS: m / z 528.2 (M+H) + .

[1530] Step 6: 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[5-[2,2-difluoroethyl(ethyl)amino]-2-methyl Pyrazol-3-yl]oxybenzonitrile

[1531] N-[2-[2-[4-cyano-2-[5-[2,2-difluoroethyl(ethyl)amino]-2-methylpyrazol-3-yl]oxyphenyl]pyrimidin-5-yl]ethyl]carbamate tert-butyl ester (648 mg, 1.23 mmol) was dissolved in 1,4-dioxane (4 mL). A 4M hydrochloric acid / 1,4-dioxane solution (2 mL) was added dropwise at 0 °C, followed by heating to room temperature and stirring for 2 hours. The reaction solution was concentrated under reduced pressure, and the resulting solid was dried under vacuum to obtain the hydrochloride salt of the target compound (642 mg).

[1532] Exact MS: 427.2

[1533] Obs.MS(M+H) + 428.3

[1534] [Example 24] 4-[5-(aminomethyl)pyrimidin-2-yl]-3-(2-methyl-5-pyrazin-2-ylpyrazol-3-yl)oxybenzonitrile (Compound No. 931)

[1535] [Chemical Formula 70]

[1536]

[1537] Step 1: 3-(5-amino-2-methylpyrazol-3-yl)oxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboron) Heterocyclopentan-2-yl)benzonitrile

[1538] The intermediate 3-(5-amino-2-methylpyrazol-3-yl)oxy-4-bromobenzonitrile (879 mg, 3.00 mmol) obtained in Example 23 was dissolved in 1,4-dioxane (7.5 mL), and bis(pinacol)diboron (1.52 g, 6.00 mmol), bis(triphenylphosphine)palladium dichloride (211 mg, 0.300 mmol), and potassium acetate (589 mg, 6.00 mmol) were added. The mixture was stirred at 110 °C for 2 hours. The reaction solution was cooled to room temperature, filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure. The concentrated crude product was used directly in the next reaction.

[1539] Step 2: N-[[2-[2-(5-amino-2-methylpyrazol-3-yl)oxy-4-cyanophenyl]pyrimidin-5-yl]methyl tert-butyl carbamate [N-(2-methylpropane-2-yl)oxycarbonyl]carbamate

[1540] To a 1,4-dioxane (15 mL) solution of the crude product obtained in step 1, N-[(2-chloropyrimidin-5-yl)methyl]-N-[(2-methylpropane-2-yl)oxycarbonyl]tert-butyl carbamate (1.03 g, 3.00 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (220 mg, 0.300 mmol), potassium carbonate (1.24 g, 9.00 mmol), and water (3 mL) were added, and the mixture was stirred at 100 °C for 1 hour. The reaction solution was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the target compound (1.48 g, including impurities).

[1541] MS:m / z 522.3(M+H) + .

[1542] Step 3: N-[[2-[2-(5-bromo-2-methylpyrazol-3-yl)oxy-4-cyanophenyl]pyrimidin-5-yl]methyl]- N-[(2-methylpropane-2-yl)oxycarbonyl]tert-butyl carbamate

[1543] N-[[2-[2-(5-amino-2-methylpyrazol-3-yl)oxy-4-cyanophenyl]pyrimidin-5-yl]methyl]-N-[(2-methylpropane-2-yl)oxycarbonyl]carbamate tert-butyl ester (1.48 g, 2.83 mmol) was dissolved in acetonitrile (28 mL), and isoamyl nitrite (488 mg, 4.17 mmol) and copper bromide (I) (476 mg, 3.32 mmol) were added. The mixture was stirred overnight at room temperature. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to give the target compound (289 mg).

[1544] MS: m / z 585.2 (M+H) + .

[1545] Step 4: N-[[2-[4-cyano-2-[2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaboranecyclopentane) [Alkyl-2-yl]pyrazol-3-yl]oxyphenyl]pyrimidin-5-yl]methyl]-N-[(2-methylpropane-2-yl)oxycarbonyl]amino tert-butyl formate

[1546] N-[[2-[2-(5-bromo-2-methylpyrazol-3-yl)oxy-4-cyanophenyl]pyrimidin-5-yl]methyl]-N-[(2-methylpropane-2-yl)oxycarbonyl]tert-butyl carbamate (40 mg, 0.068 mmol) was dissolved in 1,4-dioxane (0.2 mL), and bis(pinacol)diboron (26.0 mg, 0.102 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (5.0 mg, 6.8 μmol), and potassium acetate (20.1 mg, 0.205 mmol) were added. The mixture was stirred at 110 °C for 2 hours. The reaction solution was cooled to room temperature, filtered through diatomaceous earth, and concentrated under reduced pressure. The crude product was used directly in the next reaction.

[1547] Step 5: N-[[2-[4-cyano-2-(2-methyl-5-pyrazin-2-ylpyrazol-3-yl)oxyphenyl]pyrimidine-5- [2-methyl]-N-[(2-methylpropane-2-yl)oxycarbonyl]tert-butyl carbamate

[1548] A portion (24 mg) of the crude product obtained in step 4 was dissolved in 1,4-dioxane (0.19 mL), and 2-chloropyrazine (25.7 mg, 0.076 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (2.8 mg, 3.8 μmol), potassium carbonate (16 mg, 0.11 mmol), and water (0.038 mL) were added. The mixture was stirred at 100 °C for 1 hour. The reaction solution was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solution was concentrated under reduced pressure. The crude product was used directly in the next reaction.

[1549] Step 6: 4-[5-(aminomethyl)pyrimidin-2-yl]-3-(2-methyl-5-pyrazin-2-ylpyrazol-3-yl)oxybenzyl nitrile

[1550] Add 0.5 mL of TFA to the crude product obtained in step 5 and stir at room temperature for 1 hour. Concentrate the reaction solution under reduced pressure and purify the crude product by HPLC to obtain the target compound (5.25 mg).

[1551] Exact MS: 384.1

[1552] Obs.MS(M+H) + 385.2

[1553] [Example 25] 2-[2-[4-fluoro-2-[3-methyl-1-(2-methylpropyl)pyrazol-4-yl]oxyphenyl]pyrimidin-5-yl]ethylamine (Compound No. 966) (Target compound)And 2-[2-[4-fluoro-2-[5-methyl-1-(2-methylpropyl)pyrazol-4-yl]oxyphenyl]pyrimidin-5-yl]ethylamine (compound number 967) (Positional isomers)

[1554] [Chemical Formula 71]

[1555]

[1556] Step 1: 1-(2-bromo-5-fluorophenoxy)propane-2-one

[1557] 2-Bromo-5-fluorophenol (2.29 g, 12.0 mmol) and 1-bromopropane-2-one (1.97 g, 14.4 mmol) were dissolved in DMF (20 mL), and potassium carbonate (3.32 g, 24.0 mmol) was added. The mixture was heated and stirred at 100 °C. After the reaction was complete, the reaction solution was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to give the target compound (2.51 g, 85%).

[1558] Step 2: 3-(2-bromo-5-fluorophenoxy)-4-(dimethylamino)but-3-en-2-one

[1559] N,N-dimethylformamide dimethylacetal (1.58 g, 13.2 mmol) was added to 1-(2-bromo-5-fluorophenoxy)propane-2-one (2.73 g, 11.0 mmol), and the mixture was stirred overnight at 80 °C. After cooling the reaction mixture to room temperature, acetic acid (20 mL) and hydrazine monohydrate (826 mg, 16.5 mmol) were added, and the mixture was stirred at 100 °C for 3 hours. After cooling the reaction mixture to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to give the target compound (2.41 g, 81%).

[1560] MS:m / z 271.0(M+H) + .

[1561] Step 3: 4-(2-bromo-5-fluorophenoxy)-3-methyl-1-(2-methylpropyl)pyrazole

[1562] To 4-(2-bromo-5-fluorophenoxy)-3-methyl-1H-pyrazole (270 mg, 1.0 mmol), DMSO (2 mL), 1-bromo-2-methylpropane (160 mg, 1.2 mmol), and potassium carbonate (280 mg, 2.0 mmol) were added, and the mixture was stirred at 100 °C for 5 hours. The reaction solution was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain a mixture (185 mg) of the target compound and its positional isomers. The positional isomers were separated by HPLC purification following the final step.

[1563] MS:m / z 327.1(M+H) + .

[1564] 1 H-NMR (DMSO-d6) δ: 7.80 (1H, s), 7.72 (1H, dd, J=9.2, 2.8Hz), 6.93-6.88 (1H, m), 6.60 (1H, dd, J=10.4, 2.8Hz), 3.81 (1H, d, J=7.2Hz), 2.14-2.07 (1H, m), 1.98 (3H, s), 0.85 (6H, d, J=6.8Hz).

[1565] Step 4: 4-[5-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)phenoxy]- 3-Methyl-1-(2-methylpropyl)pyrazole

[1566] The isomer mixture obtained in step 3 (185 mg, 0.565 mmol) was dissolved in 1,4-dioxane (1.1 mL), and bis(pinacol)diboron (215 mg, 0.848 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (20.7 mg, 0.0283 mmol), and potassium acetate (111 mg, 1.13 mmol) were added. The mixture was stirred at 100 °C for 2 hours. The reaction solution was cooled to room temperature, filtered through diatomaceous earth, and concentrated under reduced pressure. The crude product was used directly in the next reaction.

[1567] Step 5: N-[2-[2-[4-fluoro-2-[3-methyl-1-(2-methylpropyl)pyrazol-4-yl]oxyphenyl]pyrimidine- 5-yl]ethyl] tert-butyl carbamate

[1568] A portion (106 mg) of the crude product obtained in step 4 was dissolved in 1,4-dioxane (1 mL), and N-[2-(2-chloropyrimidin-5-yl)ethyl]carbamate tert-butyl ester (87.6 mg, 0.340 mmol), tetrakis(triphenylphosphine)palladium (16.4 mg, 0.0142 mmol), potassium carbonate (78.3 mg, 0.566 mmol), and water (0.3 mL) were added. The mixture was stirred at 100 °C for 2 hours. The reaction solution was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solution was concentrated under reduced pressure. The crude product was used directly in the next reaction.

[1569] Step 6: 2-[2-[4-fluoro-2-[3-methyl-1-(2-methylpropyl)pyrazol-4-yl]oxyphenyl]pyrimidine-5- [2-[4-fluoro-2-[5-methyl-1-(2-methylpropyl)pyrazol-4-yl]oxyphenyl]pyrimidine (target compound) [Pyridine-5-yl]ethylamine (positional isomer)

[1570] The crude product obtained in step 5 was dissolved in dichloromethane (1 mL), and TFA (0.5 mL) was added. The mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the crude product was purified by HPLC to obtain the target compound (11.82 mg) and its positional isomer (10.77 mg).

[1571] Exact MS: 369.2

[1572] Obs.MS(M+H) + Compounds 370.4 (compound number 966) and 370.3 (compound number 967) are listed.

[1573] [Example 26] 4-[5-(aminomethyl)pyrimidin-2-yl]-3-(2-methyl-5-morpholin-4-ylpyrazole-3-carbonyl)benzonitrile (Compound No. 1028)

[1574] [Chemical Formula 72]

[1575]

[1576] Step 1: 4-Chloro-3-[hydroxy-(2-methyl-5-nitropyrazole-3-yl)methyl]benzonitrile

[1577] 3-Bromo-4-chlorobenzonitrile (5.69 g, 26.3 mmol) was dissolved in THF (50 mL), and isopropyl magnesium chloride-lithium chloride complex (14% THF solution, 20 mL, 26.27 mmol) was added dropwise at 0 °C, with stirring for 30 min at the same temperature. Then, a THF solution (5 mL) of 2-methyl-5-nitropyrazole-3-carboxaldehyde (3.13 g, 20.2 mmol) was added dropwise to the reaction mixture, and the mixture was heated to room temperature and stirred for 1 h. After adding 1 M hydrochloric acid and stirring, the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to give the target compound (4.85 g, 82%).

[1578] MS:m / z 293.1(M+H) + .

[1579] 1 H-NMR (CDCl3) δ: 8.06 (1H, s), 7.67 (1H, dd, J=8.2, 1.8Hz), 7.56 (1H, d, J=8.2Hz), 6.39 (1H, s), 6.23 (1H, s), 4.10 (3H, s), 2.97 (1H, s).

[1580] Step 2: 4-Chloro-3-(2-methyl-5-nitropyrazole-3-carbonyl)benzonitrile

[1581] Add Dysmann reagent (7.73 g, 18.2 mmol) to a dichloromethane solution (4.85 g, 16.6 mmol) of 4-chloro-3-[hydroxy-(2-methyl-5-nitropyrazol-3-yl)methyl]benzonitrile (4.85 g, 16.6 mmol) and stir for 2 hours at room temperature. Add saturated aqueous solutions of sodium thiosulfate and sodium bicarbonate to the reaction mixture, stir, and extract with dichloromethane. Wash the organic layer with saturated brine, dry with anhydrous magnesium sulfate, and concentrate the solution under reduced pressure. Use the crude product directly in the next reaction. MS: m / z 291.0 (M+H) + .

[1582] 1 H-NMR (DMSO-d6) δ: 8.21 (1H, d, J = 2.3Hz), 8.11 (1H, dd, J = 8.5, 2.1Hz), 7.88 (1H, d, J = 8.2Hz), 7.58 (1H, s), 4.27 (3H, s).

[1583] Step 3: 3-(5-amino-2-methylpyrazole-3-carbonyl)-4-chlorobenzonitrile

[1584] The crude product obtained in step 2 was suspended in a 1 / 1 mixture of ethanol and water (66 mL), and iron powder (2.78 g, 49.7 mmol) and ammonium chloride (2.66 g, 49.74 mol) were added. The mixture was stirred at 80 °C for 2 hours. The reaction solution was cooled to room temperature, filtered through diatomaceous earth, and most of the ethanol was distilled off under reduced pressure. Ethyl acetate was added to the residue for extraction. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the target compound (3.76 g, 87%).

[1585] MS:m / z 261.1(M+H) + .

[1586] 1 H-NMR (CDCl3) δ: 7.72-7.70 (2H, m), 7.60 (1H, d, J=9.1Hz), 5.67 (1H, s), 4.11 (3H, s), 3.73 (2H, br s).

[1587] Step 4: 4-Chloro-3-(2-methyl-5-morpholin-4-ylpyrazole-3-carbonyl)benzonitrile

[1588] 3-(5-amino-2-methylpyrazole-3-carbonyl)-4-chlorobenzonitrile (449 mg, 1.72 mmol) was dissolved in NMP (4.3 mL), and bis(2-bromoethyl) ether (439 mg, 1.89 mmol) and potassium iodide (28.6 mg, 0.172 mmol) were added. The mixture was stirred at 110 °C for 16 hours. After cooling the reaction solution to room temperature, ethyl acetate and water were added for extraction. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to give the target compound (391 mg, 69%).

[1589] MS:m / z 331.1(M+H) + .

[1590] 1 H-NMR (CDCl3) δ: 7.73-7.71 (2H, m), 7.61 (1H, dd, J=7.5, 1.6Hz), 5.68 (1H, s), 4.15 (3H, s), 3.80 (4H, t, J=4.8Hz), 3.14 (4H, t, J=4.8Hz).

[1591] Step 5: 3-(2-methyl-5-morpholino-4-ylpyrazole-3-carbonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxane) (heteroborane-2-yl)benzonitrile

[1592] 4-Chloro-3-(2-methyl-5-morpholin-4-ylpyrazole-3-carbonyl)benzonitrile (391 mg, 1.18 mmol) was dissolved in 1,4-dioxane (4 mL), and bis(pinacol)diboron (451 mg, 1.78 mmol), bis(tricyclohexylphosphine)palladium dichloride (87.3 mg, 0.118 mmol), and potassium acetate (348 mg, 3.55 mmol) were added. The mixture was stirred at 110 °C for 2 hours. The reaction solution was cooled to room temperature, filtered through diatomaceous earth, and concentrated under reduced pressure. The crude product was used directly in the next reaction.

[1593] MS:m / z 423.2(M+H) + .

[1594] Step 6: N-[[2-[4-cyano-2-(2-methyl-5-morpholin-4-ylpyrazole-3-carbonyl)phenyl]pyrimidin-5-yl] tert-butyl carbamate [methyl]-N-[(2-methylpropane-2-yl)oxycarbonyl]carbamate

[1595] A portion (166 mg) of the crude product obtained in step 5 was dissolved in 1,4-dioxane (1 mL), and N-[(2-chloropyrimidin-5-yl)methyl]-N-[(2-methylpropane-2-yl)oxycarbonyl] tert-butyl carbamate (50.0 mg, 0.145 mmol), tetrakis(triphenylphosphine)palladium (16.8 mg, 0.0145 mmol), potassium carbonate (60.3 mg, 0.436 mmol), and water (0.1 mL) were added. The mixture was stirred at 100 °C for 1 hour. The reaction solution was cooled to room temperature, filtered through diatomaceous earth, and concentrated under reduced pressure. The crude product was used directly in the next reaction.

[1596] MS:m / z 604.3(M+H) + .

[1597] 1 H-NMR (CDCl3) δ: 8.70 (2H, s), 8.51 (1H, d, J = 8.2Hz), 7.90 (1H, d, J = 8.2Hz), 7.79 (1H, s), 5.38 (1H, S), 4.73 (2H, s), 4.14 (3H, s), 3.72 (4H, t, J = 4.8Hz), 3.00 (4H, t, J = 4.8Hz), 1.48 (18H, s).

[1598] Step 7: 4-[5-(aminomethyl)pyrimidin-2-yl]-3-(2-methyl-5-morpholin-4-ylpyrazole-3-carbonyl)benzonitrile

[1599] Add dichloromethane (1 mL) and TFA (0.5 mL) to the crude product obtained in step 6, and stir at room temperature for 30 minutes. Concentrate the reaction solution under reduced pressure, and purify the crude product by HPLC to obtain the target compound (34.2 mg).

[1600] Exact MS: 403.2

[1601] Obs.MS(M+H) + 404.3

[1602] 1 H-NMR (DMSO-d6) δ: 8.93 (2H, s), 8.49 (1H, d, J = 7.8Hz), 8.32 (3H, br s), 8.18 (1H, dd, J = 8.2, 1.8Hz), 8.10 (1H, d, J = 1.8H), 5.72 (1H, S), 4.10 (2 H, d, J = 5.9Hz), 4.02 (3H, S), 3.57 (4H, t, J = 4.8Hz), 2.92 (4H, t, J = 4.6Hz).

[1603] [Example 27] 4-[5-(aminomethyl)pyrimidin-2-yl]-3-(5-tert-butyl-2-methylpyrazole-3-carbonyl)benzonitrile (Compound No. 1030)

[1604] [Chemical Formula 73]

[1605]

[1606] Step 1: 3-[(5-tert-butyl-2-methylpyrazol-3-yl)-hydroxymethyl]-4-chlorobenzonitrile

[1607] 3-Bromo-4-chlorobenzonitrile (3.28 g, 15.2 mmol) was dissolved in THF (50 mL), and isopropyl magnesium chloride-lithium chloride complex (14% THF solution, 13 mL, 16.7 mmol) was added dropwise at 0 °C, with stirring at the same temperature for 15 minutes. A THF solution (5 mL) of 5-tert-butyl-2-methylpyrazole-3-carboxaldehyde (2.52 g, 15.2 mmol) was added dropwise to this reaction solution, and the mixture was heated to room temperature and stirred for 1.5 hours. After adding 1 M hydrochloric acid and stirring, the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Ethanol was added to the crude product and stirred, and the precipitate was collected by filtration through a glass filter. The precipitate was dried under vacuum to give the target compound (2.22 g, 48%).

[1608] MS:m / z 304.2(M+H) + .

[1609] 1H-NMR (CDCl3) δ: 8.02 ((1H, d, J = 1.8Hz), 7.60 (1H, dd, J = 8.2, 1.8Hz), 7.49 (1H, d, J = 8.2H z), 6.15 (1H, d, J = 5.0Hz), 5.62 (1H, s), 3.90 (3H, s), 2.49 (1H, d, J = 5.0Hz), 1.23 (9H, s).

[1610] Step 2: 3-(5-tert-butyl-2-methylpyrazole-3-carbonyl)-4-chlorobenzonitrile

[1611] Add Dys-Martin reagent (768 mg, 1.81 mmol) to a 16 mL solution of 3-[(5-tert-butyl-2-methylpyrazol-3-yl)-hydroxymethyl]-4-chlorobenzonitrile (500 mg, 1.65 mmol) in dichloromethane, and stir for 1.5 h at room temperature. Add saturated aqueous solutions of sodium thiosulfate and sodium bicarbonate to the reaction mixture, stir, and extract with ethyl acetate. Wash the organic layer with saturated brine, dry with anhydrous magnesium sulfate, and concentrate the solution under reduced pressure. Purify the crude product by silica gel column chromatography to give the target compound (440 mg, 89%).

[1612] MS:m / z 302.1(M+H) + .

[1613] Step 3: 3-(5-tert-butyl-2-methylpyrazole-3-carbonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboron) Heterocyclopentan-2-yl)benzonitrile

[1614] 3-(5-tert-butyl-2-methylpyrazole-3-carbonyl)-4-chlorobenzonitrile (440 mg, 1.46 mmol) was dissolved in 1,4-dioxane (4.9 mL), and bis(pinacol)diboron (556 mg, 2.19 mmol), bis(tricyclohexylphosphine)palladium dichloride (53.9 mg, 0.073 mmol), and potassium acetate (430 mg, 4.38 mmol) were added. The mixture was stirred at 110 °C for 3 hours. The reaction solution was cooled to room temperature, filtered through diatomaceous earth, and concentrated under reduced pressure. The crude product was used directly in the next reaction.

[1615] MS: m / z 394.3 (M+H) + .

[1616] Step 4: N-[[2-[2-(5-tert-butyl-2-methylpyrazole-3-carbonyl)-4-cyanophenyl]pyrimidin-5-yl]methyl tert-butyl carbamate [N-(2-methylpropane-2-yl)oxycarbonyl]carbamate

[1617] A portion (115 mg) of the crude product obtained in step 3 was dissolved in 1,4-dioxane (1 mL), and N-[(2-chloropyrimidin-5-yl)methyl]-N-[(2-methylpropane-2-yl)oxycarbonyl] tert-butyl carbamate (50.0 mg, 0.145 mmol), tetrakis(triphenylphosphine)palladium (16.8 mg, 0.0145 mmol), potassium carbonate (60.3 mg, 0.436 mmol), and water (0.1 mL) were added. The mixture was stirred at 100 °C for 1 hour. The reaction solution was cooled to room temperature, filtered through diatomaceous earth, and concentrated under reduced pressure. The crude product was used directly in the next reaction.

[1618] MS: m / z 575.4 (M+H) + .

[1619] Step 5: 4-[5-(aminomethyl)pyrimidin-2-yl]-3-(5-tert-butyl-2-methylpyrazole-3-carbonyl)benzonitrile

[1620] Add dichloromethane (1 mL) and TFA (0.5 mL) to the crude product obtained in step 4, and stir at room temperature for 30 minutes. Concentrate the reaction solution under reduced pressure, and purify the crude product by HPLC to obtain the target compound (9.7 mg).

[1621] Exact MS: 374.2

[1622] Obs.MS(M+H) + 375.4

[1623] [Example 28] 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-(2-methyl-6-morpholin-4-ylpyridin-4-carbonyl)benzonitrile (Compound No. 1042)

[1624] [Chemical Formula 74]

[1625]

[1626] Step 1: N-methoxy-N,2-dimethyl-6-morpholino-4-ylpyridine-4-carboxamide

[1627] 2-Methyl-6-morpholino-4-ylpyridin-4-carboxylic acid (235 mg, 1.43 mmol) was dissolved in DMF (5.3 mL), and N,O-dimethylhydroxylamine hydrochloride (124 mg, 1.27 mmol), HATU (524 mg, 1.38 mmol), and triethylamine (0.45 mL, 3.18 mmol) were added. The mixture was stirred at room temperature for 1 hour. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solution was concentrated under reduced pressure. The crude product was then purified by silica gel column chromatography to give the target compound (174 mg, 62%).

[1628] MS:m / z 266.1(M+H)+ .

[1629] Step 2: 4-Chloro-3-(2-methyl-6-morpholin-4-ylpyridin-4-carbonyl)benzonitrile

[1630] 3-Bromo-4-chlorobenzonitrile (284 g, 1.31 mmol) was dissolved in THF (3.3 mL), and isopropyl magnesium chloride-lithium chloride complex (14% THF solution, 1.0 mL, 1.31 mmol) was added dropwise at 0 °C, with the mixture stirred for 30 min at the same temperature. Then, a THF solution (1 mL) of N-methoxy-N,2-dimethyl-6-morpholino-4-ylpyridin-4-carboxamide (174 mg, 0.656 mmol) was added dropwise to the reaction mixture, which was then heated to room temperature and stirred for 1.5 h. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and after stirring, the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to give the target compound (67.1 mg, 30%).

[1631] MS:m / z 342.1(M+H) + .

[1632] Step 3: 3-(2-methyl-6-morpholino-4-ylpyridin-4-carbonyl)-4-trimethyltinylbenzonitrile

[1633] 4-Chloro-3-(2-methyl-6-morpholin-4-ylpyridin-4-carbonyl)benzonitrile (67.1 mg, 0.196 mmol) was dissolved in 1,4-dioxane (1 mL), and hexamethyldistin (96.5 mg, 0.294 mmol) and tetrakis(triphenylphosphine)palladium (22.7 mg, 0.0196 mmol) were added. The mixture was stirred at 110 °C for 3 hours. The reaction solution was cooled to room temperature, filtered through diatomaceous earth, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the target compound (21.3 mg, 23%).

[1634] MS:m / z 472.1(M+H) + .

[1635] Step 4: N-[2-[2-[4-cyano-2-(2-methyl-6-morpholin-4-ylpyridin-4-carbonyl)phenyl]pyrimidine-5- [B-ethyl] tert-butyl carbamate

[1636] 3-(2-methyl-6-morpholino-4-ylpyridin-4-carbonyl)-4-trimethyltinylbenzonitrile (21.3 mg, 0.0453 mmol) was dissolved in 1,4-dioxane (1 mL), and N-[2-(2-chloropyrimidin-5-yl)ethyl]carbamate tert-butyl ester (30.0 mg, 0.116 mmol), tetrakis(triphenylphosphine)palladium (5.2 mg, 4.53 μmol), and copper iodide (I) (1.7 mg, 9.06 μmol) were added. The mixture was stirred at 110 °C for 2 hours. The reaction solution was cooled to room temperature, filtered through diatomaceous earth, and concentrated under reduced pressure. The crude product was used directly in the next reaction.

[1637] MS: m / z 529.3 (M+H) + .

[1638] Step 5: 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-(2-methyl-6-morpholin-4-ylpyridin-4-carbonyl)benzyl nitrile

[1639] Add dichloromethane (1.0 mL) and TFA (0.5 mL) to the crude product obtained in step 4, and stir at room temperature for 30 minutes. Concentrate the reaction solution under reduced pressure, and purify the crude product by HPLC to obtain the target compound (5.0 mg, 26%).

[1640] Exact MS: 428.2

[1641] Obs.MS((M+H) + 429.3

[1642] [Example 29] 4-[5-(aminomethyl)pyrimidin-2-yl]-3-(4-methyl-2-morpholin-4-yl-1,3-thiazolyl-5-carbonyl)benzonitrile (Compound No. 1064)

[1643] [Chemical Formula 75]

[1644]

[1645] Step 1: 4-Chloro-3-[hydroxy-(4-methyl-2-morpholin-4-yl-1,3-thiazolyl-5-yl)methyl]benzonitrile

[1646] 4-(4-methyl-1,3-thiazolyl-2-yl)morpholine (1.25 g, 6.78 mmol) was dissolved in THF (34 mL). A solution of n-butyllithium hexane (2.76 M, 2.7 mL, 7.46 mmol) was added dropwise to the solution cooled to -78 °C, and the mixture was stirred at the same temperature for 30 minutes. 4-chloro-3-carboxybenzonitrile (1.24 g, 7.46 mmol) was added to the reaction mixture, and the mixture was stirred at -78 °C for 1 hour. Subsequently, the mixture was heated to room temperature, and a saturated aqueous solution of ammonium chloride was added and stirred. The mixture was then extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to give the target compound (1.30 g, 55%).

[1647] MS:m / z 350.0(M+H) + .

[1648] Step 2: 4-Chloro-3-(4-methyl-2-morpholin-4-yl-1,3-thiazolyl-5-carbonyl)benzonitrile

[1649] 4-Chloro-3-[hydroxy-(4-methyl-2-morpholin-4-yl-1,3-thiazo-5-yl)methyl]benzonitrile (500 mg, 1.43 mmol) was dissolved in THF (15 mL), and 2-iodooxybenzoic acid (801 mg, 2.86 mmol) was added. The mixture was stirred at 50 °C for 2 hours. The reaction solution was cooled to room temperature, and a saturated aqueous solution of sodium thiosulfate was added. The solution was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solution was concentrated under reduced pressure. The crude product was then purified by silica gel column chromatography to give the target compound (310 mg, 62%). MS: m / z 348.0 (M+H) + .

[1650] Step 3: 3-(4-methyl-2-morpholin-4-yl-1,3-thiazolyl-5-carbonyl)-4-trimethyltinylbenzonitrile

[1651] 4-Chloro-3-(4-methyl-2-morpholin-4-yl-1,3-thiazolyl-5-carbonyl)benzonitrile (170 mg, 0.489 mmol) was dissolved in 1,4-dioxane (1.2 mL), and hexamethyldistin (240 mg, 0.733 mmol) and tetrakis(triphenylphosphine)palladium (56.5 mg, 0.0489 mmol) were added. The mixture was stirred at 110 °C for 4 hours. The reaction solution was cooled to room temperature and purified directly by silica gel column chromatography to obtain the target compound (138 mg, 59%).

[1652] MS:m / z 478.0(M+H) + .

[1653] Step 4: N-[[2-[4-cyano-2-(4-methyl-2-morpholin-4-yl-1,3-thiazolyl-5-carbonyl)phenyl]pyrimidine- 5-yl]methyl]-N-[(2-methylpropane-2-yl)oxycarbonyl]tert-butyl carbamate

[1654] 3-(4-methyl-2-morpholin-4-yl-1,3-thiazolyl-5-carbonyl)-4-trimethylsterylbenzonitrile (46.0 mg, 0.0966 mmol) was dissolved in 1,4-dioxane (1 mL), and N-[(2-chloropyrimidin-5-yl)methyl]-N-[(2-methylpropane-2-yl)oxycarbonyl] tert-butyl carbamate (66.0 mg, 0.193 mmol), tetrakis(triphenylphosphine)palladium (11.2 mg, 9.66 μmol), and copper iodide (I) (3.68 mg, 0.0193 mmol) were added. The mixture was stirred at 110 °C for 16 hours. The reaction solution was concentrated under reduced pressure, and the crude product was used directly in the next reaction.

[1655] Step 5: 4-[5-(aminomethyl)pyrimidin-2-yl]-3-(4-methyl-2-morpholin-4-yl-1,3-thiazolyl-5-carbonyl) Benzonitrile

[1656] Dichloromethane (0.5 mL) and TFA (0.5 mL) were added to the crude product obtained in step 4, and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and the crude product was purified by HPLC to obtain the target compound (10.8 mg).

[1657] Exact MS: 420.1

[1658] Obs.MS(M+H) + 421.2

[1659] [Example 30] 4-[5-(2-aminoethyl)pyridin-2-yl]-3-[(4-phenylimidazol-1-yl)methyl]benzonitrile (Compound No. 1131)

[1660] [Chemical Formula 76]

[1661]

[1662] Step 1: 3-[(4-phenylimidazol-1-yl)methyl]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane heterocycle) Pentane-2-yl)benzonitrile

[1663] 3-(bromomethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)benzonitrile (6.00 g, 18.6 mmol) was dissolved in DMF (80 mL), and 4-phenyl-1H-imidazolium (2.69 g, 18.6 mmol) and potassium carbonate (5.15 g, 37.3 mmol) were added. The mixture was stirred at 80 °C for 3 hours. The reaction solution was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was used directly in the next reaction.

[1664] MS: m / z 386.2 (M+H) + .

[1665] Step 2: N-[2-[6-[4-cyano-2-[(4-phenylimidazol-1-yl)methyl]phenyl]pyridin-3-yl]ethyl]amino tert-butyl carbamate

[1666] The crude product obtained in step 1 was dissolved in 1,4-dioxane (80 mL), and N-[2-(6-chloropyridin-3-yl)ethyl]carbamate tert-butyl ester (3.87 g, 15.1 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (552 mg, 0.754 mmol), potassium carbonate (4.17 g, 30.2 mmol), and water (20 mL) were added. The mixture was stirred at 100 °C for 2 hours. The reaction solution was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The solution was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to give the target compound (1.41 g, 20%).

[1667] MS:m / z 480.2(M+H) + .

[1668] Step 3: 4-[5-(2-aminoethyl)pyridin-2-yl]-3-[(4-phenylimidazol-1-yl)methyl]benzonitrile

[1669] 1,4-Dioxane (20 mL) was added to N-[2-[6-[4-cyano-2-[(4-phenylimidazol-1-yl)methyl]phenyl]pyridin-3-yl]ethyl]tert-butyl carbamate (1.19 g, 2.49 mmol). After adding 20 mL of 4 M hydrochloric acid / dioxane solution dropwise at 0 °C, the mixture was heated to room temperature and stirred for 3 hours. The reaction solution was concentrated under reduced pressure, and the crude product was purified by HPLC to obtain the target compound (678 mg, 72%). Exact MS: 379.2

[1670] Obs.MS(M+H) + 380.3

[1671] [Example 31] 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[[2-methyl-4-(piperidin-1-ylmethyl)imidazol-1-yl]methyl]benzonitrile (Compound No. 1179)

[1672] [Chemical Formula 77]

[1673]

[1674] Step 1: 3-[(4-formyl-2-methylimidazol-1-yl)methyl]-4-(4,4,5,5-tetramethyl-1,3,2-dioxane) Boronylcyclopentan-2-yl)benzonitrile

[1675] 3-(bromomethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborphane-2-yl)benzonitrile (354 mg, 1.10 mmol) was dissolved in acetonitrile (5 mL), and 2-methyl-1H-imidazolium-4-carboxaldehyde (110 mg, 1.00 mmol) and triethylamine (0.356 mL, 2.00 mmol) were added. The mixture was stirred at 80 °C for 1 hour. The reaction solution was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solution was concentrated under reduced pressure. The crude product was used directly in the next reaction.

[1676] Step 2: N-[2-[2-[4-cyano-2-[(4-formyl-2-methylimidazol-1-yl)methyl]phenyl]pyrimidin-5-yl] [Ethyl] tert-butyl carbamate

[1677] The crude product obtained in step 1 was dissolved in 1,4-dioxane (5 mL), and N-[2-(2-chloropyrimidin-5-yl)ethyl]carbamate tert-butyl ester (283 mg, 1.10 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (73.4 mg, 0.100 mmol), potassium carbonate (415 mg, 3.00 mmol), and water (1 mL) were added. The mixture was stirred at 100 °C for 1 hour. The reaction solution was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The solution was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the target compound (446 mg, quantitative).

[1678] MS:m / z 447.3(M+H) + .

[1679] Step 3: N-[2-[2-[4-cyano-2-[[2-methyl-4-(piperidin-1-ylmethyl)imidazol-1-yl]methyl]benzene [5-yl]pyrimidin-5-yl]ethyl]tert-butyl carbamate

[1680] N-[2-[2-[4-cyano-2-[(4-formyl-2-methylimidazol-1-yl)methyl]phenyl]pyrimidin-5-yl]ethyl]tert-butyl carbamate (31.0 mg, 0.070 mmol) was dissolved in dichloromethane (0.7 mL), and piperidine (7.2 mg, 0.084 mmol) and sodium triacetoxyborohydride (37.0 mg, 0.180 mmol) were added. The mixture was stirred at room temperature for 5 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solution was concentrated under reduced pressure. The crude product was used directly in the next reaction.

[1681] Step 4: 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[[2-methyl-4-(piperidin-1-ylmethyl)imidazol-1-] [Methyl]benzonitrile

[1682] Dichloromethane (0.5 mL) and TFA (0.5 mL) were added to the crude product obtained in step 3, and the mixture was stirred at room temperature for 1 hour. The crude product was then concentrated under reduced pressure and purified by HPLC to obtain the target compound (12.2 mg).

[1683] Exact MS: 415.3

[1684] Obs.MS(M+H) + 416.4

[1685] [Example 32] 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[(4-cyclopropyltriazol-1-yl)methyl]benzonitrile (Compound No. 1187)

[1686] [Chemical Formula 78]

[1687]

[1688] Step 1: 3-(azidomethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)benzyl nitrile

[1689] 3-(bromomethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)benzonitrile (3.50 g, 10.9 mmol) was dissolved in DMSO (22 mL), and sodium azide (777 mg, 12.0 mmol) was added. The mixture was stirred at 70 °C for 3 hours. The reaction solution was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to give the target compound (2.80 g, 91%).

[1690] Step 2: 3-[(4-cyclopropyltriazol-1-yl)methyl]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane) Cyclopentan-2-yl)benzonitrile

[1691] 3-(azidomethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)benzonitrile (1.10 g, 3.87 mmol) was dissolved in DMSO (10 mL), and ethynylcyclopropane (307 mg, 4.65 mmol), copper iodide (I) (36.9 mg, 0.194 mmol), and TBTA (103 mg, 0.194 mmol) were added. The mixture was stirred overnight at room temperature. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to give the target compound (416 mg, 31%).

[1692] Step 3: N-[2-[2-[4-cyano-2-[(4-cyclopropyltriazol-1-yl)methyl]phenyl]pyrimidin-5-yl]ethyl] tert-butyl carbamate

[1693] 3-[(4-cyclopropyltriazol-1-yl)methyl]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)benzonitrile (208 mg, 0.594 mmol) was dissolved in 1,4-dioxane (3 mL), and N-[2-(2-chloropyrimidin-5-yl)ethyl]carbamate tert-butyl ester (168 mg, 0.653 mmol), tetrakis(triphenylphosphine)palladium (34 mg, 0.030 mmol), sodium carbonate (126 mg, 1.19 mmol), and water (1 mL) were added. The mixture was stirred overnight at 80 °C. The reaction solution was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to give the target compound (120 mg, 45%).

[1694] Step 4: 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[(4-cyclopropyltriazol-1-yl)methyl]benzonitrile

[1695] Dichloromethane (1 mL) and TFA (0.5 mL) were added to N-[2-[2-[4-cyano-2-[(4-cyclopropyltriazol-1-yl)methyl]phenyl]pyrimidin-5-yl]ethyl]tert-butyl carbamate (120 mg, 0.269 mmol), and the mixture was stirred at room temperature for 1 hour. The mixture was then concentrated under reduced pressure, and the crude product was purified by HPLC to obtain the target compound (12.8 mg).

[1696] Exact MS: 345.2

[1697] Obs.MS(M+H) + 346.2

[1698] [Example 33] 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[[1-(2-methylpropyl)pyrazol-4-yl]methyl]benzonitrile (Compound No. 1195)

[1699] [Chemical Formula 79]

[1700]

[1701] Step 1: 1-(2-methylpropyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)pyridine azole

[1702] 4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborphanecyclopentan-2-yl)-1H-pyrazole (1.94 g, 10.0 mmol) was dissolved in DMF (10 mL), and 1-bromo-2-methylpropane (1.64 g, 12.0 mmol) and potassium carbonate (4.14 g, 30.0 mmol) were added. The mixture was stirred at 100 °C for 2 hours. The reaction solution was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solution was concentrated under reduced pressure. The crude product was used directly in the next reaction.

[1703] MS:m / z 251.2(M+H) + .

[1704] Step 2: 4-Chloro-3-[[1-(2-methylpropyl)pyrazol-4-yl]methyl]benzonitrile

[1705] A portion (500 mg, 2.00 mmol) of the crude product obtained in step 1 was dissolved in 1,4-dioxane (10 mL), and 3-(bromomethyl)-4-chlorobenzonitrile (461 mg, 2.00 mmol), tetrakis(triphenylphosphine)palladium (162 mg, 0.140 mmol), cesium carbonate (1.95 g, 6.00 mmol), and water (2 mL) were added. The mixture was stirred overnight at 100 °C. The reaction solution was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the target compound (548 mg, including impurities).

[1706] MS:m / z 274.1(M+H) + .

[1707] Step 3: 3-[[1-(2-methylpropyl)pyrazol-4-yl]methyl]-4-(4,4,5,5-tetramethyl-1,3,2-dioxane) (heteroborane-2-yl)benzonitrile

[1708] 4-Chloro-3-[[1-(2-methylpropyl)pyrazol-4-yl]methyl]benzonitrile (274 mg, 1.00 mmol) was dissolved in 1,4-dioxane (3.3 mL), and bis(pinacol)diboron (381 mg, 1.50 mmol), bis(tricyclohexylphosphine)palladium dichloride (73.8 mg, 0.100 mmol), and potassium acetate (294 mg, 3.00 mmol) were added. The mixture was stirred at 110 °C for 2 hours. The reaction solution was cooled to room temperature, filtered through diatomaceous earth, and concentrated under reduced pressure. The crude product was used directly in the next reaction.

[1709] MS:m / z 366.3(M+H) + .

[1710] Step 4: N-[2-[2-[4-cyano-2-[[1-(2-methylpropyl)pyrazol-4-yl]methyl]phenyl]pyrimidine-5- [B-ethyl] tert-butyl carbamate

[1711] A portion (37 mg) of the crude product obtained in step 3 was dissolved in 1,4-dioxane (0.5 mL), and N-[2-(2-chloropyrimidin-5-yl)ethyl]carbamate tert-butyl ester (25.8 mg, 0.100 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (7.3 mg, 0.01 mmol), potassium carbonate (41.0 mg, 0.300 mmol), and water (0.1 mL) were added. The mixture was stirred at 100 °C for 1 hour. The reaction solution was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The solution was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was used directly in the next reaction.

[1712] Step 5: 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[[1-(2-methylpropyl)pyrazol-4-yl]methyl]benzyl nitrile

[1713] Add 0.5 mL of TFA to the crude product obtained in step 4 and stir at room temperature for 1 hour. Concentrate the reaction solution under reduced pressure and purify the crude product by HPLC to obtain the target compound (26.0 mg).

[1714] Exact MS: 360.2

[1715] Obs.MS(M+H) + 361.0

[1716] [Example 34] 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[(4-pyrrolidine-1-ylpyrazole-1-yl)methyl]benzonitrile (Compound No. 1198)

[1717] [Chemical Formula 80]

[1718]

[1719] Step 1: 3-[(4-nitropyra...

Claims

1. The compound represented by formula (I) or a pharmaceutically acceptable salt thereof: [Chemical Formula 1] In the formula, X 1 X 2 and X 3 Each is CH; R 1 It consists of a cyano group, a fluorine atom, or a chlorine atom; L 1 -O-, -S-, -CH(R) 11 -, -C(=CH2)-, -CO-, 1,1-cyclopropylidene, or -NR 12 -; R 11 A carbon atom consisting of a hydrogen atom, a hydroxyl group, and a carbon atom that can be substituted by 1 to 3 halogen atoms. 1-3 Alkyl groups, or C groups that can be substituted with 1 to 2 cyano groups. 1-3 Alkoxy; R 12 It is a hydrogen atom, or a carbon atom that can be replaced by 1 to 3 halogen atoms. 1-3 alkyl; Ar 1 As shown in one of the following formulas: [Chemical Formula 2] R 2 C that is independently a cyano group, or that can be substituted by 1 to 3 halogen atoms. 1-4 alkyl; R 3 For hydrogen atoms, amino groups, (C 1-3 alkylcarbonyl)amino, (C 1-3 alkoxy)carbonyl, (C 3-8 Cycloalkyl)amino, C 3-8 Cycloalkyl groups, 3- to 8-membered heterocyclic alkyloxy groups having 1 to 5 heteroatoms selected from O, S, and N, and can be substituted by 1 to 6 R groups. 31 Replacement C 3-8 Cycloalkyloxy groups, which can be oxidized by 1 to 6 R groups 31 Replacement C 1-6 Alkyl groups, which can be 1 to 6 R groups 31 Replacement C 1-6 Alkyl groups can be oxidized by 1 to 6 R groups. 31 Replaced by two (C) 1-6 Alkyl)amino, can be 1-6 R 31 Replacement (C) 1-6 Alkyl)amino, having 1 to 5 heteroatoms selected from O, S, and N, and can be converted by 1 to 4 R... 32 Substituted 3- to 8-membered heterocyclic alkyl groups, which can be substituted with 1 to 4 R groups. 32 Replacement C 6-10 Aryl group, or having 1 to 5 heteroatoms selected from O, S, and N, and being soluble in 1 to 4 R groups. 32 Substituted 5- to 10-membered heteroaryl groups; R 31 Independently, it consists of a halogen atom, a hydroxyl group, a cyclopropylidene group, or a C group that can be substituted by 1 to 3 halogen atoms. 3-8 Cycloalkyl groups, 3- to 8-membered heterocycloalkyl groups having 1 to 5 heteroatoms selected from O, S, and N, C 1-4 Alkyloxy or 3- to 8-membered cycloalkyloxy groups; R 32 Independently, a halogen atom, a hydroxyl group, or a C atom that can be substituted by 1 to 3 halogen atoms. 1-3 Alkyl groups, C atoms that can be substituted with 1 to 3 halogen atoms 1-3 Alkyl, oxo, cyano, or benzyloxy groups; Ar 2 It can be 1 to 4 R 4 Replacement C 6-10 Aromatic ring, or having 1 to 5 heteroatoms selected from O, S, and N, and being capable of being bonded by 1 to 4 R atoms. 4 Replaced 5- to 10-membered heterocyclic aromatic rings; R 4 Independently, a halogen atom, hydroxyl group, carboxyl group, cyanomethyl group, or a C group that can be substituted by 1 to 3 halogen atoms. 1-3 Alkyl, or C 1-3 Alkoxy; L 2 It can be 1 to 3 R 21 Replacement C 1-6 Alkylene, or having 1 to 5 heteroatoms selected from O, S, and N and being capable of being substituted by 1 to 3 R atoms. 21 Substituted 4- to 8-membered heterocyclic alkylene groups; L 2 Ar can be placed at any position and at both ends of it. 2 and -NR 7 R 8 Bonding; Located in L 2 one sp at any position 3 Carbon atoms can be -O- or -NR 22 -Structural substitution; R 21 Independently representing halogen atoms, hydroxyl groups, oxo groups, cyano groups, 1,1-cyclopropylidene groups, oxetanediene groups, carboxyl groups, carboxamide groups, and C groups that can be substituted by 1 to 3 halogen atoms. 1-6 Alkyl, C 1-6 Alkoxy, (hydroxy) C 1-6 Alkyl, (carboxyl) C 1-3 Alkyl, (carboxyl) C 1-3 Alkoxy, (C 1-3 alkoxy)carbonyl, (C 1-6 Alkylamino)carbonyl, phenyl that can be substituted with 1 to 3 halogen atoms, 5 to 10 heteroaryl groups having 1 to 5 heteroatoms selected from O, S, and N and substituted with 1 to 3 halogen atoms, or phenoxy that can be substituted with 1 to 3 halogen atoms; R 22 It is a hydrogen atom or a carbon atom. 1-3 alkyl; L 2 and R 7 It can form L through single bond bonding 2 and R 7 The bonded nitrogen atom is a 4- to 8-membered ring, and this ring can be replaced by 1 to 3 halogen atoms or 1 to 2 hydroxyl groups; In L 2 and R 4 with Ar 2 In the case of adjacent atoms bonded together, Ar atoms that are bonded to them can... 2 Atoms together form 5- to 8-membered rings via single bonds or -O- bonds; R 7 It is a hydrogen atom or a C atom 1-3 alkyl; R 7 and Ar 2 The atoms can form 5- to 8-membered rings through single bond bonding; R 8 For hydrogen atoms, C 1-6 Alkyl, C 3-6 Cycloalkyl, cyanomethyl, oxetane, (C 1-3 (alkylamino)C 1-8 Alkyl or (hydroxy) C 1-8 alkyl; R 7 and R 8 They can form 3- to 8-membered rings through single bond bonding, and these rings can be formed by amino groups, oxo groups, or C groups. 1-3 Alkyl substitution.

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein, R 1 It is a cyano group.

3. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein, R 1 It is a fluorine atom.

4. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein, L 1 It is -O-.

5. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein, L 1 It is -CO-.

6. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein, L 1 It is -CH2-.

7. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein, R 2 It is a methyl group.

8. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein, R 3 C 3-8 Cycloalkyl groups, 3- to 8-membered heterocyclic alkyloxy groups having 1 to 5 heteroatoms selected from O, S, and N, and can be substituted by 1 to 6 R groups. 31 Replacement C 3-8 Cycloalkyloxy groups, which can be oxidized by 1 to 6 R groups 31 Replacement C 1-6 Alkyl groups, which can be 1 to 6 R groups 31 Replacement C 1-6 Alkyl groups can be oxidized by 1 to 6 R groups. 31 Replaced by two (C) 1-6 Alkyl)amino, can be 1-6 R 31 Replacement (C) 1-6 Alkyl)amino, having 1 to 5 heteroatoms selected from O, S, and N, and can be converted by 1 to 4 R... 32 Substituted 3- to 8-membered heterocyclic alkyl groups, which can be substituted with 1 to 4 R groups. 32 Replacement C 6-10 Aryl group, or having 1 to 5 heteroatoms selected from O, S, and N, and being capable of being bonded by 1 to 4 R groups. 32 Substituted 5- to 10-membered heteroaryl groups.

9. The compound according to any one of claims 1-8, or a pharmaceutically acceptable salt thereof, wherein, R 31 Halogen atom, cyclopropyl subunit, C 1-4 Alkyl group.

10. The compound of any one of claims 1-8 or a pharmaceutically acceptable salt thereof, wherein, R 32 C is a halogen atom that can be replaced by 1 to 3 halogen atoms. 1-3 Alkyl groups, C atoms that can be substituted with 1 to 3 halogen atoms 1-3 Alkoxy, oxo, or cyano groups.

11. The compound of any one of claims 1-8 or a pharmaceutically acceptable salt thereof, wherein, Ar 2 The heterocyclic aromatic rings are: [Chemical Formula 3] 。 12. The compound of any one of claims 1-8 or a pharmaceutically acceptable salt thereof, wherein, L 2 It can be 1 to 2 R 21 Replacement C 1-3 Alkylene.

13. The compound of claim 12 or a pharmaceutically acceptable salt thereof, wherein, L 2 It is -CH2-.

14. The compound of claim 12 or a pharmaceutically acceptable salt thereof, wherein, L 2 It is -CH2CH2-.

15. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-8, 13 and 14, wherein, R 7 It is a hydrogen atom.

16. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-8, 13 and 14, wherein, R 8 It is a hydrogen atom.

17. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein, The compounds represented by formula (I) are selected from the following (1) to (150): (1) 4-[5-(2-aminoethyl)pyridin-2-yl]-3-(2-methyl-6-morpholin-4-ylpyridin-4-yl)oxybenzonitrile; (2) 4-[5-(2-aminoethyl)pyridin-2-yl]-3-(2-methyl-5-phenylpyrazol-3-yl)oxybenzonitrile; (3) 4-[5-(2-aminoethyl)pyridin-2-yl]-3-(2-methyl-5-pyridin-2-ylpyrazol-3-yl)oxybenzonitrile; (4) 4-[5-(2-aminoethyl)pyridin-2-yl]-3-[2-methyl-5-(5-methylpyridin-2-yl)pyrazol-3-yl]oxybenzonitrile; (5) 4-[5-(2-aminoethyl)pyridin-2-yl]-3-[5-(4-fluorophenyl)-2-methylpyrazol-3-yl]oxybenzonitrile; (6) 4-[5-(2-aminoethyl)pyridin-2-yl]-3-[5-(3-fluorophenyl)-2-methylpyrazol-3-yl]oxybenzonitrile; (7) 4-[5-(2-aminoethyl)pyridin-2-yl]-3-(5-cyclopropyl-2-methylpyrazol-3-yl)oxybenzonitrile; (8) 4-[5-(2-aminoethyl)pyridin-2-yl]-3-[2-methyl-5-(2-methylpropyl)pyrazol-3-yl]oxybenzonitrile; (9) 4-[5-(2-aminoethyl)pyridin-2-yl]-3-(2-methyl-5-propane-2-ylpyrazol-3-yl)oxybenzonitrile; (10) 4-[5-(2-aminoethyl)pyridin-2-yl]-3-(2-methyl-5-propylpyrazole-3-yl)oxybenzonitrile; (11) 4-[5-(2-aminoethyl)pyridin-2-yl]-3-(5-cyclobutyl-2-methylpyrazol-3-yl)oxybenzonitrile; (12) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-(2-methyl-6-morpholin-4-ylpyridin-4-yl)oxybenzonitrile; (13) 4-[5-(2-aminoethyl)pyridin-2-yl]-3-(2-methyl-6-pyrrolidine-1-ylpyridin-4-yl)oxybenzonitrile; (14) 4-[5-(2-aminoethyl)pyridin-2-yl]-3-(2-methyl-6-pyridin-2-ylpyridin-4-yl)oxybenzonitrile; (15) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-(2-methyl-5-propylpyrazole-3-yl)oxybenzonitrile; (16) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-(2-methyl-5-propane-2-ylpyrazol-3-yl)oxybenzonitrile; (17) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-(2-methyl-6-pyrrolidine-1-ylpyridin-4-yl)oxybenzonitrile; (18) 4-[5-(2-aminoethyl)pyridin-2-yl]-3-[2-methyl-5-(trifluoromethyl)pyrazol-3-yl]oxybenzonitrile; (19) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-(5-cyclobutyl-2-methylpyrazol-3-yl)oxybenzonitrile; (20) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-(2-methyl-5-phenylpyrazol-3-yl)oxybenzonitrile; (21) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-(2-methyl-6-phenylpyrimidin-4-yl)oxybenzonitrile; (22) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-(6-phenylpyridazin-4-yl)oxybenzonitrile; (23) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-(2-methyl-5-pyridin-2-ylpyrazol-3-yl)oxybenzonitrile; (24) 4-[5-(2-aminoethyl)pyridin-2-yl]-3-(5-ethyl-2-methylpyrazol-3-yl)oxybenzonitrile; (25) 4-[5-(aminomethyl)pyridin-2-yl]-3-(2-methyl-5-phenylpyrazol-3-yl)oxybenzonitrile; (26) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-(5-ethyl-2-methylpyrazol-3-yl)oxybenzonitrile; (27) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[6-(2-cyanophenyl)-2-methylpyrimidin-4-yl]oxybenzonitrile; (28) 4-[5-(2-aminoethyl)pyridin-2-yl]-3-(2,5-dimethylpyrazol-3-yl)oxybenzonitrile; (29) 4-[5-(aminomethyl)pyrimidin-2-yl]-3-(2-methyl-5-phenylpyrazol-3-yl)oxybenzonitrile; (30) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-(5-cyclopropyl-2-methylpyrazol-3-yl)oxybenzonitrile; (31) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-(5-butyl-2-methylpyrazol-3-yl)oxybenzonitrile; (32) 4-[5-(aminomethyl)pyrimidin-2-yl]-3-(5-ethyl-2-methylpyrazol-3-yl)oxybenzonitrile; (33) 4-[5-(aminomethyl)pyrimidin-2-yl]-3-(5-cyclopropyl-2-methylpyrazol-3-yl)oxybenzonitrile; (34) 4-[5-(aminomethyl)pyridin-2-yl]-3-(5-ethyl-2-methylpyrazol-3-yl)oxybenzonitrile; (35) 4-[5-(aminomethyl)pyridin-2-yl]-3-(5-cyclopropyl-2-methylpyrazol-3-yl)oxybenzonitrile; (36) 4-[5-(aminomethyl)pyrimidin-2-yl]-3-(2-methyl-6-morpholin-4-ylpyridin-4-yl)oxybenzonitrile; (37) 4-[5-(aminomethyl)pyridin-2-yl]-3-(2-methyl-6-morpholin-4-ylpyridin-4-yl)oxybenzonitrile; (38) 4-[5-(aminomethyl)pyridin-2-yl]-3-(2-methyl-5-propylpyrazole-3-yl)oxybenzonitrile; (39) 4-[5-(aminomethyl)pyridin-2-yl]-3-(2-methyl-5-propane-2-ylpyrazol-3-yl)oxybenzonitrile; (40) 4-[5-(aminomethyl)pyrimidin-2-yl]-3-(2-methyl-5-propylpyrazole-3-yl)oxybenzonitrile; (41) 4-[5-(aminomethyl)pyrimidin-2-yl]-3-(2-methyl-5-propane-2-ylpyrazol-3-yl)oxybenzonitrile; (42) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-(5-tert-butyl-2-methylpyrazol-3-yl)oxybenzonitrile; (43) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-(2-methyl-6-pyridin-2-ylpyridin-4-yl)oxybenzonitrile; (44) 4-[5-(2-aminoethyl)pyridin-2-yl]-3-[2-methyl-5-(1,3-thiazolyl-2-yl)pyrazol-3-yl]oxybenzonitrile; (45) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[2-methyl-5-(1,3-thiazolyl-2-yl)pyrazol-3-yl]oxybenzonitrile; (46) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-(5-cyclopentyl-2-methylpyrazol-3-yl)oxybenzonitrile; (47) 4-[5-(aminomethyl)pyrimidin-2-yl]-3-(2-methyl-5-pyridin-2-ylpyrazol-3-yl)oxybenzonitrile; (48) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[5-(3-fluorophenyl)-2-methylpyrazol-3-yl]oxybenzonitrile; (49) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[2-[(2S)-2-(difluoromethyl)morpholin-4-yl]-6-methylpyridin-4-yl]oxybenzonitrile; (50) 4-[5-(aminomethyl)pyridin-2-yl]-3-[2-methyl-5-(oxan-4-yl)pyrazol-3-yl]oxybenzonitrile; (51) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[2-[(2R)-2-(difluoromethyl)morpholin-4-yl]-6-methylpyridin-4-yl]oxybenzonitrile; (52) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[2-methyl-6-(3-oxa-8-azabicyclo[3.2.1]octane-8-yl)pyridin-4-yl]oxybenzonitrile; (53) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-(2-methyl-6-piperidin-1-ylpyrimidin-4-yl)oxybenzonitrile; (54) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-(2-methyl-6-pyrrolidine-1-ylpyrimidin-4-yl)oxybenzonitrile; (55) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[2-methyl-6-(8-oxa-3-azabicyclo[3.2.1]octane-3-yl)pyridin-4-yl]oxybenzonitrile; (56) 4-[5-(2-aminoethyl)pyridin-2-yl]-3-[2-[2-methoxyethyl(methyl)amino]-6-methylpyridin-4-yl]oxybenzonitrile; (57) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[2-methyl-6-(propane-2-ylamino)pyridin-4-yl]oxybenzonitrile; (58) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[2-methyl-6-[(3R)-3-methylmorpholin-4-yl]pyridin-4-yl]oxybenzonitrile; (59) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[2-methyl-6-[(3S)-3-methylmorpholin-4-yl]pyridin-4-yl]oxybenzonitrile; (60) 4-[5-(2-aminoethyl)pyridin-2-yl]-3-(2-methyl-5-piperidin-1-ylpyrazol-3-yl)oxybenzonitrile; (61) 4-[5-(2-aminoethyl)pyridin-2-yl]-3-(2-methyl-5-pyrrolidine-1-ylpyrazol-3-yl)oxybenzonitrile; (62) 4-[5-(2-aminoethyl)pyridin-2-yl]-3-[5-(dimethylamino)-2-methylpyrazol-3-yl]oxybenzonitrile; (63) 4-[5-(aminomethyl)pyrimidin-2-yl]-3-[2-methyl-5-(1,3-thiazolyl-2-yl)pyrazol-3-yl]oxybenzonitrile; (64) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-(2-methyl-6-pyridin-2-ylpyrimidin-4-yl)oxybenzonitrile; (65) 4-[5-(aminomethyl)pyridin-2-yl]-3-(2-methyl-5-pyridin-2-ylpyrazol-3-yl)oxybenzonitrile; (66) 4-[5-(aminomethyl)pyridin-2-yl]-3-(2-methyl-5-piperidin-1-ylpyrazol-3-yl)oxybenzonitrile; (67) 4-[5-(aminomethyl)pyridin-2-yl]-3-(2-methyl-5-pyrrolidine-1-ylpyrazol-3-yl)oxybenzonitrile; (68) 4-[5-(aminomethyl)pyridin-2-yl]-3-[5-(dimethylamino)-2-methylpyrazol-3-yl]oxybenzonitrile; (69) 4-[5-(aminomethyl)pyrimidin-2-yl]-3-[2-methyl-5-(4-methylpyridin-2-yl)pyrazol-3-yl]oxybenzonitrile; (70) 4-[5-(aminomethyl)pyrimidin-2-yl]-3-[5-(diethylamino)-2-methylpyrazol-3-yl]oxybenzonitrile; (71) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[5-(diethylamino)-2-methylpyrazol-3-yl]oxybenzonitrile; (72) 4-[5-(aminomethyl)pyridin-2-yl]-3-(2-methyl-6-pyrrolidine-1-ylpyrimidin-4-yl)oxybenzonitrile; (73) 4-[5-(aminoethyl)pyrimidin-2-yl]-3-[2-methyl-6-pyrrolidine-1-ylpyrimidin-4-yl]oxybenzonitrile; (74) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[6-(7-azabicyclo[2.2.1]heptane-7-yl)-2-methylpyrimidin-4-yl]oxybenzonitrile; (75) 4-[5-(aminomethyl)pyrimidin-2-yl]-3-[6-(7-azabicyclo[2.2.1]heptane-7-yl)-2-methylpyrimidin-4-yl]oxybenzonitrile; (76) 4-[5-(aminomethyl)pyridin-2-yl]-3-(6-piperidin-1-ylpyridazin-4-yl)oxybenzonitrile; (77) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[(5-phenyl-1,3,4-thiadiazol-2-yl)oxy]benzonitrile; (78) 4-[5-(2-aminoethyl)pyridin-2-yl]-3-[5-(diethylamino)-2-methylpyrazol-3-yl]oxybenzonitrile; (79) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[2-methyl-5-[methyl(2-methylpropyl)amino]pyrazol-3-yl]oxybenzonitrile; (80) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[5-[cyclopropylmethyl(methyl)amino]-2-methylpyrazol-3-yl]oxybenzonitrile; (81) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[2-methyl-5-[methyl(propyl)amino]pyrazol-3-yl]oxybenzonitrile; (82) 4-[5-(aminomethyl)pyridin-2-yl]-3-(2-methyl-5-morpholin-4-ylpyrazol-3-yl)oxybenzonitrile; (83) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[2-methyl-5-[methyl(propane-2-yl)amino]pyrazol-3-yl]oxybenzonitrile; (84) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[5-[2,2-difluoroethyl(methyl)amino]-2-methylpyrazol-3-yl]oxybenzonitrile; (85) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[2-methyl-5-[methyl(2,2,2-trifluoroethyl)amino]pyrazol-3-yl]oxybenzonitrile; (86) 4-[5-(aminomethyl)pyrimidin-2-yl]-3-[2-methyl-6-[(2S)-2-methylpyrrolidin-1-yl]pyrimidin-4-yl]oxybenzonitrile; (87) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[3-methyl-1-(2-methylpropyl)pyrazol-4-yl]oxybenzonitrile; (88) 4-[5-(aminomethyl)pyrimidin-2-yl]-3-[3-methyl-1-(2-methylpropyl)pyrazol-4-yl]oxybenzonitrile; (89) 4-[5-(aminomethyl)pyridin-2-yl]-3-[2-methyl-5-(trifluoromethyl)pyrazol-3-yl]oxybenzonitrile; (90) 4-[5-(aminomethyl)pyrimidin-2-yl]-3-[2-methyl-5-(trifluoromethyl)pyrazol-3-yl]oxybenzonitrile; (91) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[2-methyl-5-(trifluoromethyl)pyrazol-3-yl]oxybenzonitrile; (92) 4-[5-(aminomethyl)pyrimidin-2-yl]-3-[2-(7-azabicyclo[2.2.1]heptane-7-yl)-6-methylpyridin-4-yl]oxybenzonitrile; (93) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[2-(7-azabicyclo[2.2.1]heptane-7-yl)-6-methylpyridin-4-yl]oxybenzonitrile; (94) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-(3-methyl-1-pyridin-2-ylpyrazol-4-yl)oxybenzonitrile; (95) 4-[5-(aminomethyl)pyrimidin-2-yl]-3-(3-methyl-1-pyridin-2-ylpyrazol-4-yl)oxybenzonitrile; (96) 4-[5-(aminomethyl)pyrimidin-2-yl]-3-[3-methyl-1-(2,2,2-trifluoroethyl)pyrazol-4-yl]oxybenzonitrile; (97) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[5-[ethyl(propane-2-yl)amino]-2-methylpyrazol-3-yl]oxybenzonitrile; (98) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[2-methyl-6-(2-methylpropoxy)pyrimidin-4-yl]oxybenzonitrile; (99) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[6-(diethylamino)-2-methylpyrimidin-4-yl]oxybenzonitrile; (100) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[2-methyl-6-[methyl(propane-2-yl)amino]pyrimidin-4-yl]oxybenzonitrile; (101) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[2-methyl-6-[(2R)-2-methylpyrrolidin-1-yl]pyrimidin-4-yl]oxybenzonitrile; (102) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[2-methyl-6-[(2S)-2-methylpyrrolidin-1-yl]pyrimidin-4-yl]oxybenzonitrile; (103) 4-[5-(aminomethyl)pyrimidin-2-yl]-3-[2-methyl-5-(3,3,4,4-tetrafluoropyrrolidone-1-yl)pyrazol-3-yl]oxybenzonitrile; (104) 4-[5-(aminomethyl)pyrimidin-2-yl]-3-[5-[2,2-difluoroethyl(ethyl)amino]-2-methylpyrazol-3-yl]oxybenzonitrile; (105) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[5-[2,2-difluoroethyl(ethyl)amino]-2-methylpyrazol-3-yl]oxybenzonitrile; (106) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[2-methyl-5-(3,3,4,4-tetrafluoropyrrolidone-1-yl)pyrazol-3-yl]oxybenzonitrile; (107) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[1-(2-methylpropyl)pyrazol-4-yl]oxybenzonitrile; (108) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-(1-pyridin-2-ylpyrazol-4-yl)oxybenzonitrile; (109) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[1-(2,2-dimethylpropyl)-3-methylpyrazol-4-yl]oxybenzonitrile; (110) 4-[5-(aminomethyl)pyrimidin-2-yl]-3-[2-methyl-5-(1,3-thiazolyl-4-yl)pyrazol-3-yl]oxybenzonitrile; (111) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[3-ethyl-1-(2-methylpropyl)pyrazol-4-yl]oxybenzonitrile; (112) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[1-(2-methylpropyl)-3-(trifluoromethyl)pyrazol-4-yl]oxybenzonitrile; (113) 4-[5-(aminomethyl)pyrimidin-2-yl]-3-[2-methyl-5-(4-methyl-1,3-thiazolyl-5-yl)pyrazol-3-yl]oxybenzonitrile; (114) 4-[5-(aminomethyl)pyrimidin-2-yl]-3-[2-methyl-5-(5-methyl-1,3-thiazolyl-4-yl)pyrazol-3-yl]oxybenzonitrile; (115) 2-[2-[4-fluoro-2-[3-methyl-1-(2-methylpropyl)pyrazol-4-yl]oxyphenyl]pyrimidin-5-yl]ethylamine; (116) 5-[2-[5-(2-aminoethyl)pyrimidin-2-yl]-5-fluorophenoxy]-N,N-diethyl-1-methylpyrazol-3-amine; (117) 2-[6-[4-fluoro-2-(2-methyl-5-morpholin-4-ylpyrazol-3-yl)oxyphenyl]pyridin-3-yl]ethylamine; (118) 2-[2-[4-fluoro-2-(2-methyl-5-pyridin-2-ylpyrazol-3-yl)oxyphenyl]pyrimidin-5-yl]ethylamine; (119) 2-[2-[4-fluoro-2-(2-methyl-5-pyrrolidone-1-ylpyrazol-3-yl)oxyphenyl]pyrimidin-5-yl]ethylamine; (120) 2-[6-[4-fluoro-2-(2-methyl-5-pyrrolidone-1-ylpyrazol-3-yl)oxyphenyl]pyridin-3-yl]ethylamine; (121) 5-[2-[5-(2-aminoethyl)pyrimidin-2-yl]-5-fluorophenoxy]-N-(2,2-difluoroethyl)-N,1-dimethylpyrazol-3-amine; (122) 5-[2-[5-(2-aminoethyl)pyridin-2-yl]-5-fluorophenoxy]-N-(2,2-difluoroethyl)-N,1-dimethylpyrazol-3-amine; (123) 5-[2-[5-(2-aminoethyl)pyrimidin-2-yl]-5-fluorophenoxy]-N-(2,2-difluoroethyl)-N-ethyl-1-methylpyrazol-3-amine; (124) 5-[2-[5-(2-aminoethyl)pyridin-2-yl]-5-fluorophenoxy]-N-(2,2-difluoroethyl)-N-ethyl-1-methylpyrazol-3-amine; (125) 5-[2-[5-(2-aminoethyl)pyridin-2-yl]-5-fluorophenoxy]-N,N-diethyl-1-methylpyrazol-3-amine; (126) 5-[2-[5-(2-aminoethyl)pyridin-2-yl]-5-fluorophenoxy]-N,N,1-trimethylpyrazol-3-amine; (127) 2-[6-[4-fluoro-2-[2-methyl-5-(oxan-4-yl)pyrazol-3-yl]oxyphenyl]pyridin-3-yl]ethylamine; (128) [2-[4-fluoro-2-(2-methyl-5-propane-2-ylpyrazol-3-yl)oxyphenyl]pyrimidin-5-yl]methylamine; (129) 2-[2-[4-fluoro-2-(2-methyl-5-propane-2-ylpyrazol-3-yl)oxyphenyl]pyrimidin-5-yl]ethylamine; (130) 2-[6-[4-fluoro-2-(2-methyl-5-propane-2-ylpyrazol-3-yl)oxyphenyl]pyridin-3-yl]ethylamine; (131) 2-[6-[2-(5-cyclopropyl-2-methylpyrazol-3-yl)oxy-4-fluorophenyl]pyridin-3-yl]ethylamine; (132) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-(5-ethyl-2-methylpyrazol-3-carbonyl)benzonitrile; (133) 4-[5-(aminomethyl)pyrimidin-2-yl]-3-(5-ethyl-2-methylpyrazol-3-carbonyl)benzonitrile; (134) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-(2-methyl-5-morpholin-4-ylpyrazole-3-carbonyl)benzonitrile; (135) 4-[5-(aminomethyl)pyrimidin-2-yl]-3-(2-methyl-5-morpholin-4-ylpyrazole-3-carbonyl)benzonitrile; (136) 4-[5-(aminomethyl)pyridin-2-yl]-3-(2-methyl-5-morpholin-4-ylpyrazole-3-carbonyl)benzonitrile; (137) 4-[5-(aminomethyl)pyrimidin-2-yl]-3-(5-tert-butyl-2-methylpyrazol-3-carbonyl)benzonitrile; (138) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-(5-tert-butyl-2-methylpyrazole-3-carbonyl)benzonitrile; (139) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[5-(diethylamino)-2-methylpyrazole-3-carbonyl]benzonitrile; (140) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-(1-pyridin-2-ylpyrazole-4-carbonyl)benzonitrile; (141) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-(2-methyl-6-morpholin-4-ylpyridin-4-carbonyl)benzonitrile; (142) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[5-(dimethylamino)-2-methylpyrazol-3-carbonyl]benzonitrile; (143) 4-[5-(aminomethyl)pyrimidin-2-yl]-3-[5-(dimethylamino)-2-methylpyrazol-3-carbonyl]benzonitrile; (144) 4-[5-(aminomethyl)pyrimidin-2-yl]-3-[5-(diethylamino)-2-methylpyrazol-3-carbonyl]benzonitrile; (145) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-(2-methyl-5-piperidin-1-ylpyrazole-3-carbonyl)benzonitrile; (146) 4-[5-(aminomethyl)pyrimidin-2-yl]-3-(2-methyl-5-piperidin-1-ylpyrazole-3-carbonyl)benzonitrile; (147) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-(2-methyl-5-pyrrolidine-1-ylpyrazole-3-carbonyl)benzonitrile; (148) 4-[5-(aminomethyl)pyrimidin-2-yl]-3-(2-methyl-5-pyrrolidine-1-ylpyrazole-3-carbonyl)benzonitrile; (149) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[5-[2,2-difluoroethyl(ethyl)amino]-2-methylpyrazol-3-carbonyl]benzonitrile; (150) 4-[5-(aminomethyl)pyrimidin-2-yl]-3-[5-[2,2-difluoroethyl(ethyl)amino]-2-methylpyrazole-3-carbonyl]benzonitrile.

18. A pharmaceutical composition comprising any one of the compounds of claims 1 to 17 or a pharmaceutically acceptable salt thereof.

19. A pharmaceutical composition having TRPC6 channel inhibitory activity, comprising any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof.

20. Use of any compound of claims 1 to 17 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment or prevention of nephrotic syndrome, membranous nephropathy, acute renal failure, sepsis, chronic renal failure, diabetic nephropathy, pulmonary hypertension, acute lung injury, heart failure, malignancy, or muscular dystrophy.

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