Aryl or heteroaryl derivative

Abstract

A compound indicated by formula (I) or a pharmacologically acceptable salt thereof is provided as a compound that can be a therapeutic or prophylactic drug for TRPC6-related diseases, such as nephrotic syndrome, membranous nephropathy, acute renal failure, septicemia, chronic renal failure, diabetic nephropathy, pulmonary hypertension, acute lung injury, heart failure, malignant tumor, and muscular dystrophy. (In the formula, Ar1, Ar2, X1–X3, R1, R3, R7, R8, L1, and L2 are as defined in the specifications.)

Description

Aryl or heteroaryl derivatives

[0001] The present invention relates to an aryl or heteroaryl derivative useful as a pharmaceutical. More specifically, the present invention relates to an aryl or heteroaryl derivative or a pharmaceutically acceptable salt thereof useful for the treatment or prevention of diseases in which a TRPC6 inhibitor 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, malignant tumor, or muscular dystrophy.

[0002] The TRPC6 channel, a member of the transient receptor potential (TRP) family of nonselective cation-permeable channels, is activated by diacylglycerol produced by the activation of phospholipase C and exerts physiological and pathophysiological effects. TRPC6 plays a role in pathological cardiac hypertrophy and fibrosis, progression of myocardial damage in muscular dystrophy, acute pulmonary vasoconstriction, the pathological progression of chronic hypoxia-induced pulmonary hypertension, allergic immune responses, cell migration such as neutrophils, increased permeability of endothelial cells during inflammation, pathological flattening of podocytes and progression of glomerular damage, and the growth or infiltration of malignant tumors. TRPC6 is widely distributed in various tissues, including the brain, heart, lungs, kidneys, placenta, ovaries, and spleen (Non-Patent Documents 1 to 13). Gain-of-function mutations in TRPC6 have been identified in familial focal segmental glomerulosclerosis (FSGS), and promoter mutations that increase TRPC6 mRNA expression have been identified in patients with idiopathic nephrotic syndrome or idiopathic pulmonary arterial hypertension. Therefore, enhanced function or elevated expression of TRPC6 is thought to contribute to the progression of pathologies such as nephrotic syndrome and pulmonary hypertension (Non-Patent Documents 14 to 22). Furthermore, elevated TRPC6 expression has been reported in minimal change nephrotic syndrome, membranous nephropathy, and diabetic nephropathy (Non-Patent Documents 23 to 24). Therefore, TRPC6 inhibitors that inhibit ion influx through 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, malignant tumors, and muscular dystrophy. Patent Documents 1 to 11 describe compounds that inhibit TRPC6.

[0003] International Publication No. WO 2011 / 107474 International Publication No. WO 2012 / 037349 International Publication No. WO 2012 / 037351 International Publication No. WO 2014 / 016766 Chinese Application Publication No. 104292233 Chinese Application Publication No. 106317050 Chinese Application Publication No. 107253952 International Publication No. WO 2019 / 079578 International Publication No. 2019 / 081637 International Publication No. 2019 / 158572 International Publication No. 2019 / 161010

[0004] J. Clin. Invest. 116:3114-3126, 2006Dev. Cell. 23:705-715, 2012Circ. Res. 114:823-832, 2014Proc. Natl. Acd. Sci. USA 103:19093-19098, 2006J. Cardiovasc. Pharmacol. 57:140-147, 2011Hypertension 63:173-80, 2014Clin. Exp. Allergy 38:1548-1558, 2008Acta. Physiol. 195:3-11, 2009J. Exp. Med. 209:1953-1968, 2011Arterioscler. Thromb. Vasc. Biol. 33:2121-2129, 2013PLoS ONE 5: e12859, 2010Expert. Opin. Ther. Targets. 14:513-27, 2010BMC Cancer 13:116, 2013Science 308:1801-1804, 2005Nat. Genet. 37:739-744, 2005PLoS One 4: e7771, 2009Clin. J. Am. Soc. Nephrol. 6:1139-1148, 2011Mol. Biol. Cell. 22:1824-1835, 2011BMC Nephrol. 14:104, 2013Pediatr. Res. 74:511-516, 2013Nephrol. Dial. Transplant. 28:1830-1838, 2013Circulation 119:2313-2322, 2009J. Am. Soc. Nephrol. 18:29-36, 2007Mol Immunol. Feb;94:75-81, 2018.

[0005] An object of the present invention is to provide a novel compound having a TRPC6 inhibitory activity or a pharmaceutically acceptable salt thereof, a pharmaceutical composition containing the compound, and a therapeutic or preventive agent for a disease involving TRPC6.

[0006] As a result of intensive research aimed at the above object, the present inventors have arrived at the following invention: [1] A compound represented by formula (I) or a pharmaceutically acceptable salt thereof. [In the formula, X 1 , X 2 , and X 3 is independently CH, N, or CY; X 1 , X 2 , and X 3 at least one of the groups is CH or CY; Y is a halogen atom or a C group optionally substituted with 1 to 3 halogen atoms; 1-3 is an alkyl group; 1 is a cyano group, a fluorine atom, or a chlorine atom; 1 is -O-, -S-, -SO-, -CH(R 11 )-, -C(=CH2)-, -CO-, a 1,1-cyclopropylidene group, or -NR 12 - is; R 11 is a C optionally substituted with a hydrogen atom, a hydroxy group, or 1 to 3 halogen atoms 1-3 C optionally substituted with an alkyl group or 1 to 2 cyano groups 1-3 R is an alkoxy group; 12 is a hydrogen atom or a C optionally substituted with 1 to 3 halogen atoms 1-3 Ar is an alkyl group; 1 is R 1 to 3 2 is a nitrogen-containing heteroaryl ring optionally substituted with R 2 are independently a halogen atom, a cyano group, or a C optionally substituted with 1 to 3 halogen atoms. 1-4 is an alkyl group; 3 represents a hydrogen atom, a halogen atom, an amino group, a cyano group, a carboxy group, (C 1-3 alkylcarbonyl)amino group, (C 1-6 alkylamino)carbonyl group, di(C 1-3 alkyl)aminocarbonyl group, (C 1-3 alkoxy)carbonyl group, (C 3-8 cycloalkyl)amino group, (C 3-8 heterocycloalkyl)amino group, C 3-8a cycloalkyl group, a 3- to 8-membered heterocycloalkyloxy group, 1 to 6 R 31 C optionally substituted with 3-8 a cycloalkyloxy group, 1 to 6 R 31 C optionally substituted with 1-6 alkyl group, 1 to 6 R 31 C optionally substituted with 1-6 an alkoxy group, 1 to 6 R 31 optionally substituted di(C 1-6 alkyl)amino group, 1 to 6 R 31 (C 1-6 alkyl)amino group, 1 to 4 R 32 a 3- to 8-membered heterocycloalkyl group optionally substituted with one to four R 32 an aryl group optionally substituted with 1 to 4 R 32 R is a heteroaryl group optionally substituted with 31 are independently a halogen atom, a hydroxy group, a cyclopropylidene group, a C optionally substituted with 1 to 3 halogen atoms, 3-8 Cycloalkyl groups, 3- to 8-membered heterocycloalkyl groups, oxetanylidene groups, C 1-4 an alkoxy group or a 3- to 8-membered cycloalkyloxy group; 32 are independently selected from a halogen atom, a hydroxy group, an acetylamino group, and C optionally substituted with 1 to 3 halogen atoms. 1-3 an alkyl group, a C group optionally substituted with 1 to 3 halogen atoms; 1-3 Alkoxy group, oxo group, cyano group, carboxy group, (C 1-3 alkoxy)carbonyl group, (C 1-3 R is a hydroxyl group, ... 2 and R 3 Ar 1 When bonded to adjacent atoms on the 2 and R 3 are bonded to each other, and the Ar 1 may form a 5- to 7-membered ring together with the atoms of Ar 2 is R 1 to 4 4an aryl ring optionally substituted with 1 to 4 R 4 a heteroaryl ring optionally substituted with R 4 are independently a halogen atom, a hydroxy group, a carboxy group, a cyano group, a cyanomethyl group, an amino group, a di(C 1-3 alkyl)amino group, C optionally substituted with 1 to 3 halogen atoms 1-3 alkyl group, or C 1-3 an alkoxy group; 2 is a single bond, 1 to 3 R 21 C optionally substituted with 1-6 an alkylene group, 1 to 3 R 21 C optionally substituted with 3-8 a cycloalkylene group, or 1 to 3 R 21 is a 4- to 8-membered heterocycloalkylene group optionally substituted by 2 is the Ar at both ends 2 or -NR 7 R 8 and L may be bonded at any position; 2 One sp at any position of 3 The carbon atom is —O— or —NR 22 - may be replaced by the structure of R 21 are independently selected from the group consisting of a halogen atom, a hydroxy group, an oxo group, a cyano group, a 1,1-cyclopropylidene group, an oxetanylidene group, a carboxy group, a carboxamide group, and C optionally substituted with 1 to 3 halogen atoms. 1-6 Alkyl group, C 3-8 Cycloalkyl group, C 1-6 Alkoxy group, (C 1-3 Alkoxy)C 1-3 alkyl group, (C 1-3 Alkoxy)C 1-3 Alkoxy group, (hydroxy)C 1-6 Alkyl group, (carboxy)C 1-3 Alkyl group, (carboxy)C 1-3 Alkoxy group, (C 1-3 alkoxy)carbonyl group, (C 1-3 Alkoxycarbonyl)C 1-3 alkyl group, (C 1-6alkylamino)carbonyl group, di(C 1-3 R represents a phenyl group optionally substituted with 1 to 3 halogen atoms, a heteroaryl group optionally substituted with 1 to 3 halogen atoms, or a phenoxy group optionally substituted with 1 to 3 halogen atoms; 22 is a hydrogen atom or C 1-3 is an alkyl group; 2 and R 7 is a single bond, -O-, -S(=O) n - or -NR 23 - and L 2 and R 7 may form a 4- to 8-membered ring containing the nitrogen atom to which R is bonded, and the ring may be further substituted with 1 to 3 halogen atoms or 1 to 2 hydroxy groups; n represents an integer of 0 to 2; R 23 is a hydrogen atom or C 1-3 is an alkyl group; 2 and R 4 Ar 2 If they are bonded to adjacent atoms on the Ar 2 may form a 5- to 8-membered ring together with the atom of R via a single bond or —O—; 7 is a hydrogen atom or C 1-3 is an alkyl group; 7 and Ar 2 The atoms of may be linked via single bonds to form a 5- to 8-membered ring; 8 is a hydrogen atom, C 1-6 Alkyl group, adamantyl group, C 1-6 a cycloalkyl group, a cyanomethyl group, an oxetanyl group, (C 1-3 alkylamino)carbonylmethyl group, di(C 1-3 alkyl)aminocarbonylmethyl group, (C 1-3 alkylamino)C 1-8 Alkyl group, di(C 1-3 Alkyl)amino C 1-8 Alkyl group, (hydroxy) C 1-8 Alkyl group, (carboxy)C 1-3 alkyl group, (C 1-3Alkoxycarbonyl)C 1-3 an alkyl group, or (C 1-3 Alkoxy)C 1-3 is an alkyl group; 7 and R 8 are mutually single bonds, -O-, -S(=O) m - or -NR 41 - to form a 3- to 8-membered ring, which may further include an amino group, an oxo group, or a C 1-3 may be substituted with an alkyl group; m represents an integer of 0 to 2; R 41 is a hydrogen atom or C 1-3 is an alkyl group.] [2] X 1 , X 2 , and X 3 [3] The compound according to [1], or a pharmaceutically acceptable salt thereof, wherein R is CH. 1 [4] The compound according to [1] or [2], or a pharmaceutically acceptable salt thereof, wherein R 1 [5] The compound according to [1] or [2], or a pharmaceutically acceptable salt thereof, wherein Ar is a fluorine atom. 1 The nitrogen-containing heteroaryl ring is [6] The compound according to any one of [1] to [4], or a pharmaceutically acceptable salt thereof, wherein L 1 [7] The compound according to any one of [1] to [5], wherein L is —O—, or a pharmaceutically acceptable salt thereof. 1 [8] The compound according to any one of [1] to [5], wherein L is —CO—, or a pharmaceutically acceptable salt thereof. 1 [9] The compound according to any one of [1] to [5], or a pharmaceutically acceptable salt thereof, wherein R is —CH—. 2

[10] The compound according to any one of [1] to [8], or a pharmaceutically acceptable salt thereof, wherein R is a methyl group. 3 But C 3-8 a cycloalkyl group, a 3- to 8-membered heterocycloalkyloxy group, 1 to 6 R 31 C optionally substituted with 3-8 a cycloalkyloxy group, 1 to 6 R 31 C optionally substituted with1-6 alkyl group, 1 to 6 R 31 C optionally substituted with 1-6 an alkoxy group, 1 to 6 R 31 optionally substituted di(C 1-6 alkyl)amino group, 1 to 6 R 31 (C 1-6 alkyl)amino group, 1 to 4 R 32 a 3- to 8-membered heterocycloalkyl group optionally substituted with one to four R 32 an aryl group optionally substituted with 1 to 4 R 32

[11] The compound according to any one of [1] to [9], or a pharmaceutically acceptable salt thereof, wherein R is a heteroaryl group optionally substituted by 31 is a halogen atom, a cyclopropylidene group, C 1-4

[12] The compound according to any one of [1] to

[10] , or a pharmaceutically acceptable salt thereof, wherein R is an alkoxy group. 32 C optionally substituted with a halogen atom, 1 to 3 halogen atoms 1-3 an alkyl group, a C group optionally substituted with 1 to 3 halogen atoms; 1-3

[13] The compound according to any one of [1] to

[11] , wherein Ar is an alkoxy group, an oxo group, or a cyano group, or a pharmaceutically acceptable salt thereof. 2 The heteroaryl ring of

[14] The compound according to any one of [1] to

[12] , or a pharmaceutically acceptable salt thereof, wherein L 2 But one or two R 21 C optionally substituted with 1-3

[15] The compound according to any one of [1] to

[13] , or a pharmaceutically acceptable salt thereof, wherein L is an alkylene group. 2

[16] The compound according to any one of [1] to

[13] , or a pharmaceutically acceptable salt thereof, wherein L is —CH—. 2

[17] The compound according to any one of [1] to

[13] , or a pharmaceutically acceptable salt thereof, wherein R is —CHCH—. 7

[18] The compound according to any one of [1] to

[16] , or a pharmaceutically acceptable salt thereof, wherein R is a hydrogen atom. 8

[19] The compound according to [1], wherein the compound represented by formula (I) is selected from the following (1) to (150), or a pharmaceutically acceptable salt thereof. (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-propan-2-ylpyrazol-3-yl)oxybenzonitrile (10) 4-[5-(2-aminoethyl)pyridin-2-yl]-3-(2-methyl-5-propylpyrazol-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-pyrrolidin-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-propylpyrazol-3-yl)oxybenzonitrile (16) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-(2-methyl-5-propan-2-ylpyrazol-3-yl)oxybenzonitrile (17) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-(2-methyl-6-pyrrolidin-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-propylpyrazol-3-yl)oxybenzonitrile (39) 4-[5-(aminomethyl)pyridin-2-yl]-3-(2-methyl-5-propan-2-ylpyrazol-3-yl)oxybenzonitrile (40) 4-[5-(aminomethyl)pyrimidin-2-yl]-3-(2-methyl-5-propylpyrazol-3-yl)oxybenzonitrile (41)4-[5-(aminomethyl)pyrimidin-2-yl]-3-(2-methyl-5-propan-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-thiazol-2-yl)pyrazol-3-yl]oxybenzonitrile (45) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[2-methyl-5-(1,3-thiazol-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]octan-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-pyrrolidin-1-ylpyrimidin-4-yl)oxybenzonitrile (55) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[2-methyl-6-(8-oxa-3-azabicyclo[3.2.1]octan-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-(propan-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-pyrrolidin-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-thiazol-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-pyrrolidin-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-pyrrolidin-1-ylpyrimidin-4-yl)oxybenzonitrile (73) 4-[5-(aminoethyl)pyrimidin-2-yl]-3-[2-methyl-6-pyrrolidin-1-ylpyrimidin-4-yl]oxybenzonitrile (74) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[6-(7-azabicyclo[2.2.1]heptan-7-yl)-2-methylpyrimidin-4-yl]oxybenzonitrile (75) 4-[5-(aminomethyl)pyrimidin-2-yl]-3-[6-(7-azabicyclo[2.2.1]heptan-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(propan-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]heptan-7-yl)-6-methylpyridin-4-yl]oxybenzonitrile (93) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[2-(7-azabicyclo[2.2.1]heptan-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(propan-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(propan-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-tetrafluoropyrrolidin-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-tetrafluoropyrrolidin-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-thiazol-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-thiazol-5-yl)pyrazol-3-yl]oxybenzonitrile (114)4-[5-(aminomethyl)pyrimidin-2-yl]-3-[2-methyl-5-(5-methyl-1,3-thiazol-4-yl)pyrazol-3-yl]oxybenzonitrile (115) 2-[2-[4-fluoro-2-[3-methyl-1-(2-methylpropyl)pyrazol-4-yl]oxyphenyl]pyrimidin-5-yl]ethanamine (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]ethanamine (118) 2-[2-[4-fluoro-2-(2-methyl-5-pyridin-2-ylpyrazol-3-yl)oxyphenyl]pyrimidin-5-yl]ethanamine (119) 2-[2-[4-fluoro-2-(2-methyl-5-pyrrolidin-1-ylpyrazol-3-yl)oxyphenyl]pyrimidin-5-yl]ethanamine (120) 2-[6-[4-fluoro-2-(2-methyl-5-pyrrolidin-1-ylpyrazol-3-yl)oxyphenyl]pyridin-3-yl]ethanamine (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]ethanamine (128) [2-[4-fluoro-2-(2-methyl-5-propan-2-ylpyrazol-3-yl)oxyphenyl]pyrimidin-5-yl]methanamine (129) 2-[2-[4-fluoro-2-(2-methyl-5-propan-2-ylpyrazol-3-yl)oxyphenyl]pyrimidin-5-yl]ethanamine (130) 2-[6-[4-fluoro-2-(2-methyl-5-propan-2-ylpyrazol-3-yl)oxyphenyl]pyridin-3-yl]ethanamine (131) 2-[6-[2-(5-cyclopropyl-2-methylpyrazol-3-yl)oxy-4-fluorophenyl]pyridin-3-yl]ethanamine (132) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-(5-ethyl-2-methylpyrazole-3-carbonyl)benzonitrile (133) 4-[5-(aminomethyl)pyrimidin-2-yl]-3-(5-ethyl-2-methylpyrazole-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-methylpyrazole-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-ylpyridine-4-carbonyl)benzonitrile (142) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[5-(dimethylamino)-2-methylpyrazole-3-carbonyl]benzonitrile (143) 4-[5-(aminomethyl)pyrimidin-2-yl]-3-[5-(dimethylamino)-2-methylpyrazole-3-carbonyl]benzonitrile (144) 4-[5-(aminomethyl)pyrimidin-2-yl]-3-[5-(diethylamino)-2-methylpyrazole-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-pyrrolidin-1-ylpyrazole-3-carbonyl)benzonitrile (148) 4-[5-(aminomethyl)pyrimidin-2-yl]-3-(2-methyl-5-pyrrolidin-1-ylpyrazole-3-carbonyl)benzonitrile (149) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[5-[2,2-difluoroethyl(ethyl)amino]-2-methylpyrazole-3-carbonyl]benzonitrile (150) 4-[5-(aminomethyl)pyrimidin-2-yl]-3-[5-[2,2-difluoroethyl(ethyl)amino]-2-methylpyrazole-3-carbonyl]benzonitrile

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

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

[22] A therapeutic or preventive agent for nephrotic syndrome, membranous nephropathy, acute renal failure, sepsis, chronic renal failure, diabetic nephropathy, pulmonary hypertension, acute lung injury, heart failure, malignant tumor, or muscular dystrophy, comprising the compound according to any one of claims 1 to 19 or a pharmaceutically acceptable salt thereof.

[0007] According to the present invention, there are provided novel compounds having a TRPC6 inhibitory activity or pharmaceutically acceptable salts thereof, as well as pharmaceutical compositions containing them and therapeutic or preventive agents for diseases involving TRPC6.

[0008] Terms used alone or in combination in this specification are explained below. Unless otherwise specified, the description of each substituent is the same for each site. Furthermore, combinations of substituents and variables are permitted only if such combinations result in chemically stable compounds. When a substituent itself is substituted with two or more groups, these multiple groups may be present on the same carbon or different carbons as long as a stable structure is produced.

[0009] In the present invention, the number to the right of the carbon atom indicates the number of carbon atoms, for example, "C 1-6 " indicates "1 to 6 carbon atoms." For example, "C 1-4 The term "alkyl group" means an alkyl group having 1 to 4 carbon atoms. The same applies to the number of carbon atoms in other groups. For example, "(C 1-3 In the description of "alkyl)carbonyl group" and the like, 1-3 The number of carbon atoms in 1-3 The number of carbon atoms in the alkyl is shown, and the carbon atom in the carbonyl is not taken into account. The method for calculating the number of carbon atoms in similar expressions is the same. Unless otherwise specified, the naming of substituents is performed by naming the terminal portion of the functional group, and then naming the adjacent functional group toward the attachment point.

[0010] In the present invention, the term "halogen atom" means a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.

[0011] In the present invention, the term "alkyl group" refers to a saturated, linear or branched aliphatic hydrocarbon group. Examples thereof include a methyl group, an ethyl group, an n-propyl group, an n-butyl group, an n-pentyl group, an n-hexyl group, an isopropyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, an isopentyl group, a 2-methylbutyl group, a 3-methylbutyl group, a 1-ethylpropyl group, a 1,1-dimethylpropyl group, a 1,2-dimethylpropyl group, a neopentyl group, a 4-methylpentyl group, a 3-methylpentyl group, a 2-methylpentyl group, a 1-methylpentyl group, a 3,3-dimethylbutyl group, a 2,2-dimethylbutyl group, a 1,1-dimethylbutyl group, a 1,2-dimethylbutyl group, a 1,3-dimethylbutyl group, a 2,3-dimethylbutyl group, a 1-ethylbutyl group, and a 2-ethylbutyl group.

[0012] In the present invention, the term "cycloalkyl group" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon group, such as a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, and a cyclooctyl group.

[0013] In the present invention, the term "heterocycloalkyl group" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon ring in which one or more carbon atoms are replaced by a heteroatom selected from O, S, and N. Examples of heterocycloalkyl groups include an aziridino group, an azetidino group, an oxetanyl group, a morpholino group, a thiomorpholino group, a pyrrolidinyl group, a piperidinyl group, a piperazinyl group, an imidazolidinyl group, a pyrazolidinyl group, a tetrahydrofuranyl group, and a tetrahydropyranyl group.

[0014] In the present invention, the terms "alkoxy group," "cycloalkyloxy group," and "heterocycloalkyloxy group" mean an oxy group substituted with an alkyl group, a cycloalkyl group, or a heterocycloalkyl group.

[0015] In the present invention, the terms "(alkoxy)alkoxy group" and "(carboxy)alkoxy group" refer to an alkoxy group or an alkoxy group substituted with a carboxy group. For example, "(C 1-3Alkoxy)C 1-3 The term "alkoxy group" means an alkoxy group having 1 to 3 carbon atoms substituted with an alkoxy group having 1 to 3 carbon atoms.

[0016] In the present invention, the term "(alkoxy)carbonyl group" refers to a carbonyl group substituted with an alkoxy group. For example, "(C 1-3 The term "alkoxy)carbonyl group" means a carbonyl group substituted with an alkoxy group having 1 to 3 carbon atoms.

[0017] In the present invention, the terms "(alkyl)amino group", "(cycloalkyl)amino group", and "(heterocycloalkyl)amino group" respectively refer to an amino group substituted with one alkyl group, cycloalkyl group, or heterocycloalkyl group. For example, "(C 3-8 The term "heterocycloalkyl)amino group" refers to an amino group substituted with a 3- to 8-membered heterocycloalkyl group.

[0018] In the present invention, the term "di(alkyl)amino group" refers to an amino group substituted with two alkyl groups, which may be the same or different. For example, "di(C 1-6 The term "(alkyl)amino group" means an amino group substituted with two identical or different alkyl groups having 1 to 6 carbon atoms.

[0019] In the present invention, the term "(alkylcarbonyl)amino group" refers to an amino group substituted with one alkylcarbonyl group. For example, "(C 1-3 The "carbonylamino group" is a group having one (C 1-3 The term "amino group substituted with an alkyl)carbonyl group" refers to an amino group substituted with an alkylcarbonyl group.

[0020] In the present invention, the term "(alkylamino)carbonyl group" refers to a carbonyl group substituted with an alkylamino group. Similarly, the term "di(alkyl)aminocarbonyl group" refers to a carbonyl group substituted with a di(alkyl)amino group.

[0021] In the present invention, the terms "alkoxyalkyl group," "alkoxycarbonylalkyl group," "di(alkyl)aminoalkyl group," "hydroxyalkyl group," and "carboxyalkyl group" refer to alkyl groups substituted with an alkoxy group, an alkoxycarbonyl group, a di(alkyl)amino group, a hydroxy group, and a carboxy group. The term "di(alkyl)aminocarbonylmethyl group" refers to a methyl group substituted with a di(alkyl)aminocarbonyl group.

[0022] In the present invention, the term "alkylene group" refers to a divalent group derived by removing one more hydrogen atom at any position from the above-mentioned "alkyl group." Examples include a methylene group, ethylene group, n-propylene group, isopropylene group, n-butylene group, isobutylene group, n-pentylene group, and n-hexylene group.

[0023] In the present invention, the term "cycloalkylene group" refers to a divalent group derived by removing one more hydrogen atom at any position from the above-mentioned "cycloalkyl group." Examples include a cyclopropylene group, a cyclobutylene group, and a cyclohexylene group.

[0024] In the present invention, the term "heterocycloalkylene group" refers to a divalent group derived by further removing one hydrogen atom at any position from the above-mentioned "heterocycloalkyl group".

[0025] In the present invention, "optionally substituted C 1-3 The term "alkyl group" refers to an alkyl group having 1 to 3 carbon atoms which may have one or more substituents at substitutable positions. When multiple substituents are present, the respective substituents may be the same or different. Similar expressions also have the same meaning.

[0026] In the present invention, an "aryl group" refers to a monocyclic or bicyclic aromatic hydrocarbon group having 6 to 10 carbon atoms. Examples include a phenyl group, a naphthyl group, an indenyl group, and an azulenyl group. An "aryl ring" refers to the ring portion of an aryl group.

[0027] In the present invention, the term "heteroaryl group" 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, pyrazyl, pyrimidyl, pyridazyl, furyl, thienyl, isoxazolyl, isothiazolyl, benzofuranyl, benzothienyl, benzothiazolyl, benzimidazolyl, benzoxazolyl, pyranyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, triazinyl, triazolyl, benzoxazolyl, and benzisoxazolyl groups. The term "heteroaryl ring" refers to the ring portion of a heteroaryl group. The term "nitrogen-containing heteroaryl ring" refers to a heteroaryl ring containing one or more N atoms on the ring.

[0028] In formula (I), X 1 , X 2 , and X 3 are independently CH, N or CY, and X 1 , X 2 and X 3 At least one of X is CH or CY. 1 , X 2 , and X 3 is CH. Y is a halogen atom or a methyl group.

[0029] In formula (I), R 1 is a cyano group, a fluorine atom, or a chlorine atom, preferably a cyano group or a fluorine atom.

[0030] In formula (I), the linker L 1 is -O-, -S-, -SO-, -CH(R 11 )-, -C(=CH2)-, -CO-, a 1,1-cyclopropylidene group, or -NR 12 -. Preferably, -O-, -S-, -CH(R 11 )-, -CO-, or -NR 12 -, and more preferably -O-, -CO-, or -CH2-.

[0031] R 11is a C optionally substituted with a hydrogen atom, a hydroxy group, or 1 to 3 halogen atoms 1-3 C optionally substituted with an alkyl group or 1 to 2 cyano groups 1-3 It is an alkoxy group.

[0032] R 12 is a hydrogen atom or a C optionally substituted with 1 to 3 halogen atoms 1-3 It is an alkyl group.

[0033] In formula (I), Ar 1 is R 1 to 3 2 Preferably, the ring has the following structure:

[0034]

[0035] R 2 are independently a halogen atom, a cyano group, or a C optionally substituted with 1 to 3 halogen atoms. 1-4 Preferably, the alkyl group is a C alkyl group optionally substituted with 1 to 3 halogen atoms. 1-4 R is an alkyl group, and more preferably a methyl group. 2 and R 3 But Ar 1 When bonded to adjacent atoms on the 2 and R 3 are bonded to each other, and the Ar 1 may be taken together with the atoms to form a 5- to 7-membered ring.

[0036] In formula (I), R 3 represents a hydrogen atom, a halogen atom, an amino group, a cyano group, a carboxy group, (C 1-3 alkylcarbonyl)amino group, (C 1-6 alkylamino)carbonyl group, di(C 1-3 alkyl)aminocarbonyl group, (C 1-3 alkoxy)carbonyl group, (C 3-8 cycloalkyl)amino group, (C 3-8 heterocycloalkyl)amino group, C 3-8 a cycloalkyl group, a 3- to 8-membered heterocycloalkyloxy group, 1 to 6 R31 C optionally substituted with 3-8 a cycloalkyloxy group, 1 to 6 R 31 C optionally substituted with 1-6 alkyl group, 1 to 6 R 31 C optionally substituted with 1-6 an alkoxy group, 1 to 6 R 31 optionally substituted di(C 1-6 alkyl)amino group, 1 to 6 R 31 (C 1-6 alkyl)amino group, 1 to 4 R 32 a 3- to 8-membered heterocycloalkyl group optionally substituted with one to four R 32 an aryl group optionally substituted with 1 to 4 R 32 is an optionally substituted heteroaryl group.

[0037] R 31 are independently a halogen atom, a hydroxy group, a cyclopropylidene group, a C optionally substituted with 1 to 3 halogen atoms, 3-8 Cycloalkyl groups, 3- to 8-membered heterocycloalkyl groups, oxetanylidene groups, C 1-4 It is an alkoxy group, or a 3- to 8-membered cycloalkyloxy group.

[0038] R 32 are independently selected from a halogen atom, a hydroxy group, an acetylamino group, and C optionally substituted with 1 to 3 halogen atoms. 1-3 an alkyl group, a C group optionally substituted with 1 to 3 halogen atoms; 1-3 Alkoxy group, oxo group, cyano group, carboxy group, (C 1-3 alkoxy)carbonyl group, (C 1-3 alkyl)sulfonyl group, carboxamide group, or benzyloxy group.

[0039] In formula (I), preferred R 3 is C 3-8 a cycloalkyl group, a 3- to 8-membered heterocycloalkyloxy group, 1 to 6 R 31 C optionally substituted with 3-8 a cycloalkyloxy group, 1 to 6 R 31C optionally substituted with 1-6 alkyl group, 1 to 6 R 31 C optionally substituted with 1-6 an alkoxy group, 1 to 6 R 31 optionally substituted di(C 1-6 alkyl)amino group, 1 to 6 R 31 (C 1-6 alkyl)amino group, 1 to 4 R 32 a 3- to 8-membered heterocycloalkyl group optionally substituted with one to four R 32 an aryl group optionally substituted with 1 to 4 R 32 is an optionally substituted heteroaryl group.

[0040] Preferred R 31 represents a halogen atom, a cyclopropylidene group, C 1-4 It is an alkoxy group.

[0041] Preferred R 32 is a halogen atom, C optionally substituted with 1 to 3 halogen atoms 1-3 an alkyl group, a C group optionally substituted with 1 to 3 halogen atoms; 1-3 It is an alkoxy group, an oxo group, or a cyano group.

[0042] In formula (I), Ar 2 is R 1 to 4 4 an aryl ring optionally substituted with 1 to 4 R 4 Preferably, the heteroaryl ring is a heteroaryl ring optionally substituted with 1 to 4 R 4 and more preferably a pyridine ring or pyrimidine ring substituted in the manner shown in the following structure.

[0043] R 4 are independently a halogen atom, a hydroxy group, a carboxy group, a cyano group, a cyanomethyl group, an amino group, a di(C 1-3 alkyl)amino group, C optionally substituted with 1 to 3 halogen atoms 1-3 alkyl group, or C 1-3 It is an alkoxy group.

[0044] In formula (I), L 2 is a single bond, 1 to 3 R 21 C optionally substituted with 1-6 an alkylene group, 1 to 3 R 21 C optionally substituted with 3-8 a cycloalkylene group, or 1 to 3 R 21 L is a 4- to 8-membered heterocycloalkylene group optionally substituted with 2 is the Ar at both ends 2 and -NR 7 R 8 and may be bonded at any position. 2 One sp at any position of 3 The carbon atom is —O— or —NR 22 - may be replaced by the structure of 2 is 1 to 2 R 21 C optionally substituted with 1-3 It is an alkylene group, more preferably —CH2— or —CH2CH2—.

[0045] R 21 are independently selected from the group consisting of a halogen atom, a hydroxy group, an oxo group, a cyano group, a 1,1-cyclopropylidene group, an oxetanylidene group, a carboxy group, a carboxamide group, and C optionally substituted with 1 to 3 halogen atoms. 1-6 Alkyl group, C 3-8 Cycloalkyl group, C 1-6 Alkoxy group, (C 1-3 Alkoxy)C 1-3 alkyl group, (C 1-3 Alkoxy)C 1-3 Alkoxy group, (hydroxy)C 1-6 Alkyl group, (carboxy)C 1-3 Alkyl group, (carboxy)C 1-3 Alkoxy group, (C 1-3 alkoxy)carbonyl group, (C 1-3 Alkoxycarbonyl)C 1-3 alkyl group, (C 1-6 alkylamino)carbonyl group, di(C 1-3A preferred R is a phenyl group optionally substituted with 1 to 3 halogen atoms, a heteroaryl group optionally substituted with 1 to 3 halogen atoms, or a phenoxy group optionally substituted with 1 to 3 halogen atoms. 21 is a C optionally substituted with a halogen atom, a hydroxy group, an oxo group, an oxetanylidene group, or 1 to 3 halogen atoms. 1-6 It is an alkyl group, and more preferably a halogen atom or a hydroxy group.

[0046] R 22 is a hydrogen atom or C 1-3 It is an alkyl group.

[0047] L 2 and R 7 is a single bond, -O-, -S(=O) n - or -NR 23 - and L 2 and R 7 may form a 4- to 8-membered ring containing the nitrogen atom to which is bonded, and the ring may be further substituted with 1 to 3 halogen atoms or 1 to 2 hydroxy groups, where n is an integer of 0 to 2.

[0048] R 23 is a hydrogen atom or C 1-3 It is an alkyl group.

[0049] L 2 and R 4 Ar 2 If they are bonded to adjacent atoms on the Ar 2 may form a 5- to 8-membered ring together with the atom via a single bond or —O—.

[0050] In formula (I), R 7 is a hydrogen atom or C 1-3 R is an alkyl group, and more preferably a hydrogen atom. 7 and Ar 2 The atoms may be joined via single bonds to form a 5- to 8-membered ring.

[0051] In formula (I), R 8 is a hydrogen atom, C1-6 Alkyl group, adamantyl group, C 1-6 a cycloalkyl group, a cyanomethyl group, an oxetanyl group, (C 1-3 alkylamino)carbonylmethyl group, di(C 1-3 alkyl)aminocarbonylmethyl group, (C 1-3 alkylamino)C 1-8 Alkyl group, di(C 1-3 Alkyl)amino C 1-8 Alkyl group, (hydroxy) C 1-8 Alkyl group, (carboxy)C 1-3 alkyl group, (C 1-3 Alkoxycarbonyl)C 1-3 an alkyl group, or (C 1-3 Alkoxy)C 1-3 It is an alkyl group. More preferred R 8 is a hydrogen atom.

[0052] R 7 and R 8 are mutually single bonds, -O-, -S(=O) m - or -NR 41 - to form a 3- to 8-membered ring, which may further include an amino group, an oxo group, or a C 1-3 It may be substituted with an alkyl group, where m is an integer of 0 to 2.

[0053] R 41 is a hydrogen atom or C 1-3 It is an alkyl group.

[0054] Among the compounds of the present invention, the following compound group is preferred: 1 , X 2 , and X 3 is CH, and R 1 is a cyano group or a fluorine atom, and the linker L 1 is —O—, —CO—, or —CH—, and Ar 1 is the following structure: R 2 is a methyl group, R 3 is C 3-8 a cycloalkyl group, a 3- to 8-membered heterocycloalkyloxy group, 1 to 6 R31 C optionally substituted with 3-8 a cycloalkyloxy group, 1 to 6 R 31 C optionally substituted with 1-6 alkyl group, 1 to 6 R 31 C optionally substituted with 1-6 an alkoxy group, 1 to 6 R 31 optionally substituted di(C 1-6 alkyl)amino group, 1 to 6 R 31 (C 1-6 alkyl)amino group, 1 to 4 R 32 a 3- to 8-membered heterocycloalkyl group optionally substituted with one to four R 32 an aryl group optionally substituted with 1 to 4 R 32 is a heteroaryl group optionally substituted with R 31 represents a halogen atom, a cyclopropylidene group, C 1-4 is an alkoxy group, R 32 is a halogen atom, C optionally substituted with 1 to 3 halogen atoms 1-3 an alkyl group, a C group optionally substituted with 1 to 3 halogen atoms; 1-3 an alkoxy group, an oxo group, or a cyano group; Ar 2 is a pyridine or pyrimidine ring with the substitution pattern shown in the structure below, L 2 is —CH— or —CHCH—, R 7 is a hydrogen atom, and R 8 is a group of compounds in which the hydrogen atom is

[0055] Specific examples of the compound of formula (I) include the compounds shown in Table 1 below.

[0056]

[0057] Among these, preferred compounds are compound numbers 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 to 162, 164, 170 to 177, 179, 180, 182, 183, 185 to 187, 197 to 199, 202, 204 to 206, 211 to 213, 215, 225 to 233, 237, 238, 241, 246 to 250, 253, and 254. , 258, 260-262, 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, 621-62 9, 634, 637, 642, 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, 75 4, 758-760, 765, 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, 87 2 to 878, 900, 903 to 910, 912 to 916, 932, 935, 937, 945, 948 to 953, 955, 957, 958, 963, 966, 968, 969, 972, 975, 977 to 980, 983, 985, 987 to 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, 1135, 1137, 1143-1145, 1147-1156, 1167, 1173, 1184-1187, 1195, 1199, 1202, 1203, 1205-1208, 1210-1212, 1214, 1215, 1217-1219, 1233 , 1234, 1237, 1239 to 1241, 1243, 1244, 1249, 1255, 1258, 1259, 1279, 1280, 1295, 1296, 1299 to 1302, 1304, 1306, 1312, 1316, 1317, 1322 to 1325, 1330, 1334, 1335, 1337 to 1340, 1346, 1348, 1350, 1354, 1357, 1360, 1361, 1366 to 1369, 1371, 1373, 1380, 1387, 1395, 1398 and 1404, and more preferably, compound numbers 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 1950, 1951, 1952, 1953, 1954, 1955, 1956, 1957, 1960, 1961, 1962, 1963, 1964, 1965, 1966, 1967, 1968, 1969, 1970, 1971, 197 5, 176, 182, 185, 199, 202, 228-230, 237, 250, 254, 258, 260-262, 264, 272, 274, 275, 277, 285, 288, 289, 293, 295, 299, 310, 317, 319, 324-329, 361-36 4, 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, 955, 958, 963, 966, 972, 975, 977, 979, 980, 987 to 991, 1000, 1010, 1012 to 1014, 1018, 1025 to 1032, 1037, 1042, 1043, 1051, 1061 to 1063,The compounds are 1071 to 1074.

[0058] <General Synthesis Method> The compounds of the present invention represented by formula (I) and pharmaceutically acceptable salts thereof (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 synthesis methods described below. Reagents, solvents, and other conditions described in the chemical formulas are merely examples, as described herein. Each substituent may be protected with an appropriate protecting group, as necessary, and protection or deprotection may be performed at an appropriate stage. Suitable protecting groups and methods for their removal can be those commonly used in the field and known methods, as described, for example, in "PROTECTIVE GROUPS IN ORGANIC SYNTHESIS, THIRD EDITION," John Wiley & Sons, Inc. The intermediates produced in the following synthesis methods may be isolated and purified using methods such as column chromatography, recrystallization, or distillation, or may be used directly in the next step without isolation.

[0059] Representative methods for synthesizing the compounds of the present invention represented by general formula (I) are described below. However, the methods for synthesizing the compounds of the present invention are not limited to these. The symbols in each formula are defined as in formula (I).

[0060] The compounds of the present invention can be prepared by several synthetic methods. 1 Representative synthesis methods for each structure will be explained.

[0061] In formula (I), L 1 Ga-NR 12 When the compound of the present invention is represented by the formula -, for example, as shown in the following reaction formula, 2 After constructing the ring and biaryl structure, Ar 1The compound can be synthesized by linking the ring. That is, (A-I) is converted to a boronic acid ester (A-II), which is then subjected to a Suzuki-Miyaura coupling reaction to give (A-III), and then a Buchwald-Hartwig amination reaction to give (A-IV). This can be deprotected to synthesize the target compound. The target compound can also be synthesized by modifying the amino group after deprotection. In the reaction scheme below, PG is a protecting group for the amino group (same below).

[0062]

[0063] Step 1: The boronation reagent is preferably bis(pinacolato)diboron, and the palladium catalyst is preferably tris(dibenzylideneacetone)dipalladium, palladium acetate, tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride, or the like. If necessary, tricyclohexylphosphine, tricyclohexylphosphonium tetrafluoroborate, 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, or the like is used as a ligand. Potassium acetate or the like is preferred as the base used. The solvent is not particularly limited, but examples include ethers such as tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, and 1,2-diethoxyethane, N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, and mixtures thereof. The reaction temperature is preferably from 50 to 150°C, particularly preferably from 70 to 120°C.

[0064] Step 2: Preferred palladium catalysts include tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride. 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, but 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; N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, water, and mixtures thereof. The reaction temperature is preferably 50°C to 150°C, and more preferably 80°C to 120°C.

[0065] Step 3: Preferred palladium catalysts include tris(dibenzylideneacetone)dipalladium and palladium acetate. Preferred ligands include 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl, and 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl. Examples of bases include inorganic salts such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, and tripotassium phosphate; potassium tert-butoxide; and sodium tert-butoxide. The solvent is not particularly limited, but 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; N,N-dimethylformamide, N-methylpyrrolidone, and dimethyl sulfoxide. The reaction temperature is preferably from 50 to 150°C, particularly preferably from 80 to 150°C.

[0066] Step 4: The method for removing the protecting group can be a 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, and when the protecting group is a phthalimide group, hydrazine and ethylenediamine are preferred. The solvent is not particularly limited, but 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; N,N-dimethylformamide, N-methylpyrrolidone, and dimethyl sulfoxide. The reaction temperature is preferably 0° C. to 100° C.

[0067] Step 5: The reaction can be carried out using an alkyl halide or the like as a reaction reagent having a leaving group. Examples of the base include organic bases such as triethylamine and N,N-diisopropylethylamine, and inorganic bases such as potassium carbonate and cesium carbonate. The solvent is preferably tetrahydrofuran, N,N-dimethylformamide, dimethyl sulfoxide, or the like. The reaction temperature is preferably 0°C to 120°C, and particularly preferably 0°C to room temperature. In the above reaction scheme, X in formula (I) 1 , X 2 and X 3 Although the case of CH was mentioned, X 1 , X 2 and X 3 In the case where at least one of the groups is N or CY (where Y is a halogen atom or a methyl group), the compound can be synthesized in a similar manner.

[0068] In formula (I), L 1 Ga-NR 12 When the compound of the present invention is a compound of the formula (I), the compound of the present invention can be prepared by reacting Ar with an amino group as shown in the following reaction formula. 1 React with the ring, L 1 After constructing the linker moiety, Ar 2 It can also be synthesized by forming a biaryl bond with the ring.

[0069]

[0070] Step 1: Preferred palladium catalysts include tris(dibenzylideneacetone)dipalladium and palladium acetate. Preferred ligands include 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl, and 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl. Examples of bases include inorganic salts such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, and tripotassium phosphate; potassium tert-butoxide; and sodium tert-butoxide. The solvent is not particularly limited, but 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; N,N-dimethylformamide, N-methylpyrrolidone, and dimethyl sulfoxide. The reaction temperature is preferably from 50 to 150°C, particularly preferably from 80 to 150°C.

[0071] Step 2: The boronation reagent is preferably bis(pinacolato)diboron, and the palladium catalyst is preferably tris(dibenzylideneacetone)dipalladium, palladium acetate, tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, or [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride. If necessary, tricyclohexylphosphine, tricyclohexylphosphonium tetrafluoroborate, 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, or the like is used as a ligand. Potassium acetate and the like can be used as the base. The solvent is not particularly limited, but examples include ethers such as tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, and 1,2-diethoxyethane, N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, and mixtures thereof. The reaction temperature is preferably from 50 to 150°C, particularly preferably from 70 to 120°C.

[0072] Step 3: Preferred palladium catalysts include tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride. 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, but 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; N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, water, and mixtures thereof. The reaction temperature is preferably 50°C to 150°C, and more preferably 80°C to 120°C.

[0073] Step 4: Preferred reagents are strong acids such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, etc. Preferred solvents are dichloromethane, tetrahydrofuran, ethyl acetate, etc. The reaction temperature is preferably 0° C. to 50° C., particularly preferably 0° C. to room temperature.

[0074] In formula (I), L 1 When the compound of the present invention is —O—, it can be synthesized by the following synthetic methods.

[0075] For example, it can be synthesized by the method shown in the following reaction formula: 1 After obtaining (C-II) linked to the ring, (C-II) is converted into a boron compound or a tin compound, etc., and the corresponding Ar 2 The biaryl compound (C-IV) is synthesized by a cross-coupling reaction with a cyclic compound. If the amino group is protected, it is then deprotected, and if necessary, the free amino group is modified to synthesize the target compound. Note that the operation of step 2 can be omitted and a compound having an appropriate reactive substituent, such as Ar 2By using a ring compound, it is also possible to directly use (C-II) to carry out a cross-coupling reaction or the like. 3 can be converted into the desired structure at an appropriate timing in the following reaction scheme using a method known to those skilled in the art.

[0076]

[0077] Step 1: The base used is preferably potassium carbonate, sodium carbonate, cesium carbonate, potassium tert-butoxide, sodium tert-butoxide, etc. Preferred solvents include N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, etc. The reaction temperature is preferably room temperature to 150°C.

[0078] Step 2: Examples of the boronation reagent include bis(pinacolato)diboron, and examples of the stannation reagent include hexamethylditin. Preferred palladium catalysts include tris(dibenzylideneacetone)dipalladium, palladium acetate, tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride. If necessary, tricyclohexylphosphine, tricyclohexylphosphonium tetrafluoroborate, 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, or the like is used as a ligand. Preferred bases used during boronation include potassium acetate, etc. The solvent is not particularly limited, but examples thereof include aromatic hydrocarbons such as benzene, toluene, xylene, etc., ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, etc., alcohols such as methanol, ethanol, 2-propanol, butanol, etc., N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, etc. The reaction temperature is preferably 50°C to 150°C, and particularly preferably 70°C to 120°C.

[0079] Step 3: Preferred palladium catalysts include tetrakis(triphenylphosphine)palladium(0), bis(triphenylphosphine)palladium(II) dichloride, and [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride. 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, but 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; N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, water, and mixtures thereof. The reaction temperature is preferably 50°C to 150°C, and more preferably 80°C to 120°C.

[0080] Step 4: The method for removing the protecting group can be a 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, and when the protecting group is a phthalimide group, hydrazine and ethylenediamine are preferred. The solvent is not particularly limited, but 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; N,N-dimethylformamide, N-methylpyrrolidone, and dimethyl sulfoxide. The reaction temperature is preferably 0° C. to 100° C.

[0081] Step 5: The reaction can be carried out using an alkyl halide or the like as a reaction reagent having a leaving group. Examples of the base include organic bases such as triethylamine and 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 reaction temperature is preferably 0°C to 120°C.

[0082] In formula (I), L 1 When the compound of the present invention is —O—, there is also a method for synthesizing the target compound using an intermediate pyrazole (DI), as shown in the following reaction formula: That is, (DI) is reacted with a reagent having a leaving group to modify the amino group to obtain (D-II), and then the target compound can be synthesized by a method similar to the method described above.

[0083] (In the formula, R D1 , R D2 is -NR D1 R D2 as R of formula (I) 3 is a substituent that satisfies the following:

[0084] Step 1: Examples of reaction reagents having a leaving group include alkyl halides and alkyl triflates. Preferred bases include organic bases such as triethylamine and N,N-diisopropylethylamine, and inorganic bases such as potassium carbonate and cesium carbonate. If necessary, an additive such as potassium iodide may be added. Preferred solvents include 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, and N-methylpyrrolidone. The reaction temperature is preferably room temperature to 150°C, and particularly preferably 50°C to 120°C.

[0085] Step 2: Examples of boronation reagents include bis(pinacolato)diboron and the like. Preferred palladium catalysts include tris(dibenzylideneacetone)dipalladium, palladium acetate, tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride. If necessary, tricyclohexylphosphine, tricyclohexylphosphonium tetrafluoroborate, 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, and the like are used as ligands. Preferred bases include potassium acetate and the like. The solvent used here is not particularly limited, but examples include ethers such as tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, and 1,2-diethoxyethane, N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, and mixtures thereof. The reaction temperature is preferably from 50 to 150°C, particularly preferably from 70 to 120°C.

[0086] Step 3: Preferred palladium catalysts include tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride. 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, but 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; N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, water, and mixtures thereof. The reaction temperature is preferably 50°C to 150°C, and more preferably 80°C to 120°C.

[0087] Step 4: The method for removing the protecting group can be a 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, and when the protecting group is a phthalimide group, hydrazine and ethylenediamine are preferred. The solvent is not particularly limited, but 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; N,N-dimethylformamide, N-methylpyrrolidone, and dimethyl sulfoxide. The reaction temperature is preferably 0° C. to 100° C.

[0088] In formula (I), L 1 When the compound of the present invention is —O—, Ar 2 After constructing the ring and biaryl bond, the amino group of (E-III) is converted to a bromine atom, and R 3 There is also a method for synthesizing the desired compound by introducing a substituent.

[0089] Step 1: The boronation reagent is preferably bis(pinacolato)diboron, and the palladium catalyst is preferably tris(dibenzylideneacetone)dipalladium, palladium acetate, tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride, or the like. If necessary, tricyclohexylphosphine, tricyclohexylphosphonium tetrafluoroborate, 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, or the like is used as a ligand. Potassium acetate or the like is preferred as the base used. The solvent is not particularly limited, but examples include ethers such as tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, and 1,2-diethoxyethane, N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, and mixtures thereof. The reaction temperature is preferably from 50 to 150°C, particularly preferably from 70 to 120°C.

[0090] Step 2: Preferred palladium catalysts include tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride. 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, but 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; N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, water, and mixtures thereof. The reaction temperature is preferably 50°C to 150°C, and more preferably 80°C to 120°C.

[0091] Step 3: The reagent used is preferably isoamyl nitrite, and the brominating reagent is preferably copper bromide. Preferred solvents include acetonitrile, toluene, etc. The reaction temperature is preferably 0°C to 50°C.

[0092] Step 4: Preferred palladium catalysts include tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride. 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, but 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; N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, water, and mixtures thereof. The reaction temperature is preferably 50°C to 150°C, and particularly preferably 80°C to 120°C.

[0093] Step 5: For the removal of the protecting group, a known method commonly used in this field can be employed. For example, when the protecting group is a Boc group, strong acids such as trifluoroacetic acid, hydrochloric acid, and sulfuric acid are preferred, and when the protecting group is a phthalimide group, hydrazine, ethylenediamine, and the like are preferred. The solvent is not particularly limited, but examples thereof 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; N,N-dimethylformamide, N-methylpyrrolidone, and dimethyl sulfoxide. The reaction temperature is preferably 0° C. to 100° C.

[0094] In formula (I), L 1is —O—, as shown in the following reaction formula, a raw material (FI) having a nitro group is used to carry out an aromatic nucleophilic substitution reaction, and then a functional group transformation of the nitro group is carried out to give Ar 2 Another method is to form a biaryl bond with the ring to synthesize the desired compound.

[0095]

[0096] Step 1: The base used is preferably potassium carbonate, sodium carbonate, cesium carbonate, potassium tert-butoxide, sodium tert-butoxide, etc. Preferred solvents include N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, etc. The reaction temperature is preferably room temperature to 100°C.

[0097] Step 2: The metal reagent used is preferably iron or zinc, and is preferably a combination with a reagent such as ammonium chloride or acetic acid. Preferred solvents include organic solvents such as ethanol, methanol, and tetrahydrofuran, and mixed solvents of these with water. The reaction temperature is preferably room temperature to 100°C.

[0098] Step 3: The reagent used is preferably isoamyl nitrite, and the brominating reagent is preferably copper bromide. Preferred solvents include acetonitrile, toluene, etc. The reaction temperature is preferably 0°C to 50°C.

[0099] Step 4: The boronation reagent is preferably bis(pinacolato)diboron, and the palladium catalyst is preferably tris(dibenzylideneacetone)dipalladium, palladium acetate, tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride, or the like. If necessary, tricyclohexylphosphine, tricyclohexylphosphonium tetrafluoroborate, 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, or the like is used as a ligand. Potassium acetate or the like is preferred as the base used. The solvent is not particularly limited, but examples include ethers such as tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, and 1,2-diethoxyethane, N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, and mixtures thereof. The reaction temperature is preferably from 50 to 150°C, particularly preferably from 70 to 120°C.

[0100] Step 5: Preferred palladium catalysts include tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride. 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, but 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; N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, water, and mixtures thereof. The reaction temperature is preferably 50°C to 150°C, and more preferably 80°C to 120°C.

[0101] Step 6: The method for removing the protecting group can be a 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, and when the protecting group is phthalimide, hydrazine and ethylenediamine are preferred. The solvent is not particularly limited, but 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; N,N-dimethylformamide, N-methylpyrrolidone, and dimethyl sulfoxide. The reaction temperature is preferably 0° C. to 100° C.

[0102] In formula (I), L 1 When the compound of the present invention is -O-, there is also a method for synthesizing the target compound using an intermediate pyrazole (G-IV) obtained through a cyclization reaction, as shown in the following reaction formula. That is, pyrazole (G-IV) obtained in three steps from raw material (GI) is reacted with a reagent having a leaving group to form R 3 After the introduction of the substituent, the target compound can be synthesized by the same procedure as described above.

[0103]

[0104] Step 1: The base used is preferably potassium carbonate, sodium carbonate, cesium carbonate, potassium tert-butoxide, sodium tert-butoxide, etc. Preferred solvents include N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, etc. The reaction temperature is preferably room temperature to 100°C.

[0105] Step 2: This reaction is preferably carried out without a solvent, and the reaction temperature is preferably 50°C to 100°C.

[0106] Step 3: The reaction is carried out using hydrazine monohydrate as a reagent. The solvent is preferably acetic acid or the like. The reaction temperature is preferably 70°C to 120°C.

[0107] Step 4: Examples of reaction reagents having a leaving group include alkyl halides and aryl halides. Preferred bases include organic bases such as triethylamine and N,N-diisopropylethylamine, and inorganic bases such as potassium carbonate and cesium carbonate. The solvent is not particularly limited, but examples include ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, and 1,2-diethoxyethane, N,N-dimethylformamide, N-methylpyrrolidone, and dimethyl sulfoxide. The reaction temperature is preferably from room temperature to 150°C.

[0108] Step 5: The boronation reagent is preferably bis(pinacolato)diboron, and the palladium catalyst is preferably tris(dibenzylideneacetone)dipalladium, palladium acetate, tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride, or the like. If necessary, tricyclohexylphosphine, tricyclohexylphosphonium tetrafluoroborate, 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, or the like is used as a ligand. Potassium acetate or the like is preferred as the base used. The solvent is not particularly limited, but examples include ethers such as tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, and 1,2-diethoxyethane, N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, and mixtures thereof. The reaction temperature is preferably from 50 to 150°C, particularly preferably from 70 to 120°C.

[0109] Step 6: Preferred palladium catalysts include tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride. 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, but 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; N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, water, and mixtures thereof. The reaction temperature is preferably 50°C to 150°C, and more preferably 80°C to 120°C.

[0110] Step 7: The method for removing the protecting group can be a 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, and when the protecting group is phthalimide, hydrazine and ethylenediamine are preferred. The solvent is not particularly limited, but 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; N,N-dimethylformamide, N-methylpyrrolidone, and dimethyl sulfoxide. The reaction temperature is preferably 0° C. to 100° C.

[0111] In formula (I), L 1 When the compound of the present invention is —O—, Ar 1 Aromatic nucleophilic substitution reactions can also be carried out using a substrate having a leaving group on the ring. Alternatively, the procedure of step 2 can be omitted and a suitable reactive substituent can be used. 2By using a ring compound, (H-II) can be directly used in the reaction to synthesize (H-IV). 3 (e.g., a halogen atom) can be converted to the desired structure at an appropriate time in the following reaction scheme using a method known to those skilled in the art.

[0112]

[0113] Step 1: The base used is preferably potassium carbonate, sodium carbonate, cesium carbonate, potassium tert-butoxide, sodium tert-butoxide, etc. Preferred solvents include N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, etc. The reaction temperature is preferably room temperature to 150°C.

[0114] Step 2: The boronation reagent is preferably bis(pinacolato)diboron, and the palladium catalyst is preferably tris(dibenzylideneacetone)dipalladium, palladium acetate, tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride, or the like. If necessary, tricyclohexylphosphine, tricyclohexylphosphonium tetrafluoroborate, 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, or the like is used as a ligand. Potassium acetate or the like is preferred as the base used. The solvent is not particularly limited, but examples include ethers such as tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, and 1,2-diethoxyethane, N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, and mixtures thereof. The reaction temperature is preferably from 50 to 150°C, particularly preferably from 70 to 120°C.

[0115] Step 3: Preferred palladium catalysts include tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride. 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, but 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; N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, water, and mixtures thereof. The reaction temperature is preferably 50°C to 150°C, and more preferably 80°C to 120°C.

[0116] Step 4: The method for removing the protecting group can be a 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, and when the protecting group is a phthalimide group, hydrazine and ethylenediamine are preferred. The solvent is not particularly limited, but 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; N,N-dimethylformamide, N-methylpyrrolidone, and dimethyl sulfoxide. The reaction temperature is preferably 0° C. to 100° C.

[0117] Step 5: Examples of reaction reagents having a leaving group include alkyl halides and aryl triflates. Examples of bases include organic bases such as triethylamine and 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 reaction temperature is preferably 0°C to 120°C.

[0118] In formula (I), L 1 When the compound of the present invention is —O—, the target compound can be synthesized by modifying the compound (II) having an alcohol, as shown in the following reaction formula.

[0119] (In the formula, R I is -OR I as R of formula (I) 21 is a substituent that satisfies the following:

[0120] Step 1: Examples of reaction reagents having a leaving group include alkyl halides and alkyl triflates. Preferred bases include sodium hydride, potassium carbonate, and cesium carbonate. The solvent is not particularly limited, but examples include ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, and 1,2-diethoxyethane, as well as N,N-dimethylformamide, N-methylpyrrolidone, and dimethyl sulfoxide. The reaction temperature is preferably 0°C to 120°C.

[0121] 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° C. to 50° C., particularly preferably 0° C. to room temperature.

[0122] In formula (I), L 1 is the compound of the present invention in which —O—, the alcohol of (J-I) can be converted into a leaving group, an alkoxy group can be introduced, and then the target compound can be synthesized by a method similar to the above-mentioned synthesis method, as shown in the following reaction formula:

[0123] (Wherein, Ms is a methanesulfonyl group; R J is -OR J as R of formula (I) 21 is a substituent that satisfies the following:

[0124] Step 1: The reaction can be carried out using methanesulfonyl chloride as the mesylation reagent. Preferred bases include triethylamine, potassium carbonate, and cesium carbonate. The solvent used in this reaction is not particularly limited, but examples include organic solvents such as tetrahydrofuran and dichloromethane. This reaction is preferably carried out at a temperature between 0°C and 60°C, and particularly preferably between 0°C and room temperature.

[0125] Step 2: The alcohol (R J The reaction can be carried out using a base such as tetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide, or N-methylpyrrolidone, or a mixture thereof. The reaction is preferably carried out at a temperature between room temperature and 150°C, and particularly preferably between room temperature and 100°C.

[0126] 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° C. to 50° C., particularly preferably 0° C. to room temperature.

[0127] In formula (I), L 1 When the compound of the present invention is —O—, as shown in the following reaction formula, a method for synthesizing the compound may be carried out by introducing a desired substituent via tosylhydrazone (K-II) and then using the same synthesis method as described above.

[0128] (Wherein, Ts is a p-toluenesulfonyl group; R K is C 1-3 Alkoxy-C 1-3 Alkyl group, hydroxyl (C 1-6 alkyl) group, hydroxycarbonyl-(C 1-3alkyl) group, (C 1-3 alkoxy)carbonyl-(C 1-3 alkyl) group, or a phenyl group optionally substituted with 1 to 3 halogen atoms.

[0129] Step 1: This reaction uses tosylhydrazine as a reagent. Preferred solvents include toluene, methanol, ethanol, etc. The reaction temperature is preferably room temperature to 120°C, particularly preferably 50°C to 120°C.

[0130] Step 2: The base used is preferably potassium carbonate, cesium carbonate, cesium fluoride, etc. The solvent is not particularly limited, but examples thereof 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.

[0131] 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° C. to 50° C., particularly preferably 0° C. to room temperature.

[0132] In formula (I), L 1 When the compound of the present invention is -O-, it can also be synthesized by the method shown in the following reaction formula. That is, the raw material (LI) is reacted with para-methoxybenzyl alcohol to obtain compound (L-II). Then, the functional group of the bromine atom of (L-II) is converted to obtain biaryl compound (L-IV), and the PMB group is deprotected to obtain phenol (LV). This phenol (LV) is then reacted with Ar having a reactive substituent. 1 After the compounds are linked by an appropriate reaction, the amino group is deprotected to synthesize the desired compound.

[0133]

[0134] Step 1: The base used is preferably potassium carbonate, sodium carbonate, cesium carbonate, potassium tert-butoxide, sodium tert-butoxide, etc. Preferred solvents include N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, etc. The reaction temperature is preferably room temperature to 100°C.

[0135] Step 2: The boronation reagent used is preferably bis(pinacolato)diboron, and the palladium catalyst is preferably tris(dibenzylideneacetone)dipalladium, palladium acetate, tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride, or the like. If necessary, tricyclohexylphosphine, tricyclohexylphosphonium tetrafluoroborate, 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, or the like is used as a ligand. The base used is preferably potassium acetate, or the like. The solvent is not particularly limited, but examples thereof include aromatic hydrocarbons such as benzene, toluene, xylene, etc., ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, etc., alcohols such as methanol, ethanol, 2-propanol, butanol, etc., N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, etc. The reaction temperature is preferably 50°C to 150°C, and particularly preferably 70°C to 120°C.

[0136] Step 3: Preferred palladium catalysts include tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride. 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, but 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; N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, water, and mixtures thereof. The reaction temperature is preferably 50°C to 150°C, and more preferably 80°C to 120°C.

[0137] Step 4: A known method can be used to remove the paramethoxybenzyl group. Examples include strong acids such as trifluoroacetic acid, hydrochloric acid, and sulfuric acid. The solvent is not particularly limited, but examples include tetrahydrofuran, 1,4-dioxane, and dichloromethane. The reaction temperature is preferably 0°C to 100°C.

[0138] Step 5: The base used is preferably potassium carbonate, sodium carbonate, cesium carbonate, potassium tert-butoxide, sodium tert-butoxide, etc. Preferred solvents include N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, etc. The reaction temperature is preferably room temperature to 150°C.

[0139] Step 6: The method for removing the protecting group can be a 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, and when the protecting group is phthalimide, hydrazine and ethylenediamine are preferred. The solvent is not particularly limited, but 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; N,N-dimethylformamide, N-methylpyrrolidone, and dimethyl sulfoxide. The reaction temperature is preferably 0° C. to 100° C.

[0140] In formula (I), L 1 When the compound of the present invention is -O-, it can also be synthesized by the method shown in the following reaction formula. That is, the raw material (M-I) is reacted with 2,4-dihydroxy-6-methylpyridine to obtain the compound (M-II). Then, (M-II) is triflated, and the desired R 3 Substituents are introduced to obtain (M-IV). Subsequently, functional group conversion of the bromine atom of (M-IV) is performed to obtain biaryl compound (M-VI), after which the amino group is deprotected to synthesize the target compound.

[0141]

[0142] Step 1: The base used is preferably potassium carbonate, sodium carbonate, cesium carbonate, potassium tert-butoxide, sodium tert-butoxide, etc. Preferred solvents include N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, etc. The reaction temperature is preferably room temperature to 160°C.

[0143] Step 2: The triflation agent used may be trifluoromethanesulfonic anhydride (TfO), etc., and the base may preferably be pyridine, triethylamine, N,N-diisopropylethylamine, etc. Preferred solvents include tetrahydrofuran, dichloromethane, 1,2-dichloroethane, etc. The reaction temperature is preferably 0°C to 100°C.

[0144] Step 3: R 3 The method for introducing a substituent can be a known method widely used in this field. For example, a boronic acid derivative can be used to introduce R 3 When introducing a substituent, preferred palladium catalysts include tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride. 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, but 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; N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, water, and mixtures thereof. The reaction temperature is preferably 50°C to 150°C, and more preferably 80°C to 120°C.

[0145] Also, for example, R 3 When reacting with an alcohol or amine corresponding to the substituent, preferred bases include organic bases such as triethylamine and N,N-diisopropylethylamine, and inorganic bases such as potassium carbonate and cesium carbonate. The solvent is not particularly limited, but examples include ethers such as tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, and 1,2-diethoxyethane, N,N-dimethylformamide, N-methylpyrrolidone, and dimethyl sulfoxide. The reaction temperature is preferably from room temperature to 150°C.

[0146] Step 4: The boronation reagent used is preferably bis(pinacolato)diboron, and the palladium catalyst is preferably tris(dibenzylideneacetone)dipalladium, palladium acetate, tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride, or the like. If necessary, tricyclohexylphosphine, tricyclohexylphosphonium tetrafluoroborate, 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, or the like is used as a ligand. Potassium acetate, or the like can be used as a base. The solvent is not particularly limited, but examples thereof include aromatic hydrocarbons such as benzene, toluene, xylene, etc., ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, etc., alcohols such as methanol, ethanol, 2-propanol, butanol, etc., N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, etc. The reaction temperature is preferably 50°C to 150°C, and particularly preferably 70°C to 120°C.

[0147] Step 5: Preferred palladium catalysts include tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride. 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, but 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; N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, water, and mixtures thereof. The reaction temperature is preferably 50°C to 150°C, and more preferably 80°C to 120°C.

[0148] Step 6: The method for removing the protecting group can be a 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, and when the protecting group is phthalimide, hydrazine and ethylenediamine are preferred. The solvent is not particularly limited, but 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; N,N-dimethylformamide, N-methylpyrrolidone, and dimethyl sulfoxide. The reaction temperature is preferably 0° C. to 100° C.

[0149] In formula (I), L 1 When the compound of the present invention is —CO—, it can be synthesized using the following synthetic methods.

[0150] For example, it can be synthesized by the method shown in the following reaction formula: 1 The ring compound can be reacted with an anion reagent prepared from compound (NI) to synthesize the corresponding alcohol (N-II), which can then be oxidized to form a ketone (N-III), followed by the formation of a biaryl bond to synthesize (NV). 3 can be converted into the desired structure at an appropriate timing in the following reaction scheme using a method known to those skilled in the art.

[0151]

[0152] Step 1: Examples of reagents for preparing an anion by reacting with (N-I) include n-butyllithium and isopropylmagnesium chloride-lithium chloride complex solution. The solvent is not particularly limited, but 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 reaction temperature is preferably −78° C. to 50° C., and particularly preferably −40° C. to room temperature.

[0153] Step 2: The oxidizing agent used is preferably Dess-Martin periodinane, 2-iodoxybenzoic acid, pyridinium chlorochromate, etc. The solvent is not particularly limited, but examples thereof 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 reaction temperature is preferably 0°C to 100°C.

[0154] Step 3: Examples of the boronation reagent used include bis(pinacolato)diboron, and examples of the stannation reagent include hexamethylditin. Preferred palladium catalysts include tris(dibenzylideneacetone)dipalladium, palladium acetate, tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride. If necessary, tricyclohexylphosphine, tricyclohexylphosphonium tetrafluoroborate, 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, or the like is used as a ligand. Examples of the base used during boronation include potassium acetate. The solvent is not particularly limited, but examples thereof include aromatic hydrocarbons such as benzene, toluene, xylene, etc., ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, etc., alcohols such as methanol, ethanol, 2-propanol, butanol, etc., N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, etc. The reaction temperature is preferably 50°C to 150°C, and particularly preferably 70°C to 120°C.

[0155] Step 4: Preferred palladium catalysts include tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride. 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, but 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; N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, water, and mixtures thereof. The reaction temperature is preferably 50°C to 150°C, and particularly preferably 80°C to 120°C.

[0156] Step 5: For the removal of the protecting group, a known method commonly used in this field can be employed. For example, when the protecting group is a Boc group, strong acids such as trifluoroacetic acid, hydrochloric acid, and sulfuric acid are preferred, and when the protecting group is a phthalimide group, hydrazine, ethylenediamine, and the like are preferred. The solvent is not particularly limited, but examples thereof 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; N,N-dimethylformamide, N-methylpyrrolidone, and dimethyl sulfoxide. The reaction temperature is preferably 0° C. to 100° C.

[0157] In formula (I), L 1When the compound of the present invention is —CO—, there is also a method for synthesizing the target compound using an intermediate pyrazole (O-II), as shown in the following reaction formula: That is, (O-I) is reduced to obtain (O-II), and the amino group is modified by reacting the obtained compound with a reagent having a leaving group to obtain (O-III), and then the target compound can be synthesized by a method similar to the above-mentioned method.

[0158] (In the formula, R O1 , R O2 is -NR O1 R O2 is R of formula (I) 3 is a substituent that can be included in

[0159] Step 1: The metal reagent used is preferably iron or zinc, and is preferably a combination with a reagent such as ammonium chloride or acetic acid. Preferred solvents include organic solvents such as ethanol, methanol, and tetrahydrofuran, and mixed solvents of these with water. The reaction temperature is preferably room temperature to 100°C.

[0160] Step 2: Examples of reaction reagents having a leaving group include alkyl halides and alkyl triflates. Preferred bases include organic bases such as triethylamine and N,N-diisopropylethylamine, and inorganic bases such as potassium carbonate and cesium carbonate. Preferred solvents include 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, and dimethyl sulfoxide. The reaction temperature is preferably room temperature to 150°C.

[0161] Step 3: Examples of the boronation reagent used include bis(pinacolato)diboron, and examples of the stannation reagent include hexamethylditin. Preferred palladium catalysts include tris(dibenzylideneacetone)dipalladium, palladium acetate, tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride. If necessary, tricyclohexylphosphine, tricyclohexylphosphonium tetrafluoroborate, 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, or the like is used as a ligand. Examples of the base used during boronation include potassium acetate. The solvent is not particularly limited, but examples thereof include aromatic hydrocarbons such as benzene, toluene, xylene, etc., ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, etc., alcohols such as methanol, ethanol, 2-propanol, butanol, etc., N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, etc. The reaction temperature is preferably 50°C to 150°C, and particularly preferably 70°C to 120°C.

[0162] Step 4: Preferred palladium catalysts include tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride. 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, but 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; N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, water, and mixtures thereof. The reaction temperature is preferably 50°C to 150°C, and particularly preferably 80°C to 120°C.

[0163] Step 5: For the removal of the protecting group, a known method commonly used in this field can be employed. For example, when the protecting group is a Boc group, strong acids such as trifluoroacetic acid, hydrochloric acid, and sulfuric acid are preferred, and when the protecting group is a phthalimide group, hydrazine, ethylenediamine, and the like are preferred. The solvent is not particularly limited, but examples thereof 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; N,N-dimethylformamide, N-methylpyrrolidone, and dimethyl sulfoxide. The reaction temperature is preferably 0° C. to 100° C.

[0164] In formula (I), L 1 is —CO—, as shown in the following reaction formula, 1Alternatively, the corresponding alcohol (P-II) can be obtained by reacting the aldehyde (PI) with an anion reagent prepared from the ring, and then the resulting product can be synthesized by the same synthesis method as described above.

[0165] (In the formula, X P is H or a halogen atom.

[0166] Step 1: Examples of reagents for preparing anions in the reaction system include n-butyllithium and isopropylmagnesium chloride-lithium chloride complex solutions. The solvent is not particularly limited, but 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 reaction temperature is preferably −78° C. to 50° C., and particularly preferably −40° C. to room temperature.

[0167] Step 2: The oxidizing agent used is preferably Dess-Martin periodinane, 2-iodoxybenzoic acid, pyridinium chlorochromate, etc. The solvent is not particularly limited, but examples thereof 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 reaction temperature is preferably 0°C to 100°C.

[0168] Step 3: Examples of the boronation reagent used include bis(pinacolato)diboron, and examples of the stannation reagent include hexamethylditin. Preferred palladium catalysts include tris(dibenzylideneacetone)dipalladium, palladium acetate, tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride. If necessary, tricyclohexylphosphine, tricyclohexylphosphonium tetrafluoroborate, 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, or the like is used as a ligand. Examples of the base used during boronation include potassium acetate. The solvent is not particularly limited, but examples thereof include aromatic hydrocarbons such as benzene, toluene, xylene, etc., ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, etc., alcohols such as methanol, ethanol, 2-propanol, butanol, etc., N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, etc. The reaction temperature is preferably 50°C to 150°C, and particularly preferably 70°C to 120°C.

[0169] Step 4: Preferred palladium catalysts include tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride. 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, but 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; N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, water, and mixtures thereof. The reaction temperature is preferably 50°C to 150°C, and particularly preferably 80°C to 120°C.

[0170] Step 5: For the removal of the protecting group, a known method commonly used in this field can be employed. For example, when the protecting group is a Boc group, strong acids such as trifluoroacetic acid, hydrochloric acid, and sulfuric acid are preferred, and when the protecting group is a phthalimide group, hydrazine, ethylenediamine, and the like are preferred. The solvent is not particularly limited, but examples thereof 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; N,N-dimethylformamide, N-methylpyrrolidone, and dimethyl sulfoxide. The reaction temperature is preferably 0° C. to 100° C.

[0171] In formula (I), L 1 is —CO—, as shown in the following reaction scheme, 1 The corresponding ketone (Q-III) can be synthesized using the ring, and then the compound can be synthesized by the same synthesis method as described above.

[0172]

[0173] Step 1: Examples of reagents for preparing anions in the reaction system include n-butyllithium and isopropylmagnesium chloride-lithium chloride complex solutions. The solvent is not particularly limited, but 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 reaction temperature is preferably −78° C. to 50° C., and particularly preferably −40° C. to room temperature.

[0174] Step 2: Examples of the boronation reagent used include bis(pinacolato)diboron, and examples of the stannation reagent include hexamethylditin. Preferred palladium catalysts include tris(dibenzylideneacetone)dipalladium, palladium acetate, tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride. If necessary, tricyclohexylphosphine, tricyclohexylphosphonium tetrafluoroborate, 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, or the like is used as a ligand. Examples of the base used during boronation include potassium acetate. The solvent is not particularly limited, but examples thereof include aromatic hydrocarbons such as benzene, toluene, xylene, etc., ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, etc., alcohols such as methanol, ethanol, 2-propanol, butanol, etc., N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, etc. The reaction temperature is preferably 50°C to 150°C, and particularly preferably 70°C to 120°C.

[0175] Step 3: Preferred palladium catalysts include tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride. 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, but 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; N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, water, and mixtures thereof. The reaction temperature is preferably 50°C to 150°C, and more preferably 80°C to 120°C.

[0176] Step 4: The method for removing the protecting group can be a 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, and when the protecting group is a phthalimide group, hydrazine and ethylenediamine are preferred. The solvent is not particularly limited, but 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; N,N-dimethylformamide, N-methylpyrrolidone, and dimethyl sulfoxide. The reaction temperature is preferably 0° C. to 100° C.

[0177] In formula (I), L 1 When the compound of the present invention is —CH2—, it can be synthesized using the following synthetic methods.

[0178] For example, it can be synthesized as shown in the following reaction formula:1 After linking the cyclic compound (R-II) and benzyl bromide (R-I) by a cross-coupling reaction, (R-III) is converted into a boron compound or a tin compound, etc., to give the corresponding Ar 2 It is possible to synthesize the compound by forming a biaryl bond by performing a cross-coupling reaction with a cyclic compound. 2 By using the ring compound, (R-III) can be directly used in a cross-coupling reaction or the like.

[0179]

[0180] Step 1: Preferred palladium catalysts include tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride. 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, but 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; N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, water, and mixtures thereof. The reaction temperature is preferably 50°C to 150°C, and particularly preferably 80°C to 120°C.

[0181] Step 2: Examples of the boronation reagent used include bis(pinacolato)diboron, and examples of the stannation reagent include hexamethylditin. Preferred palladium catalysts include tris(dibenzylideneacetone)dipalladium, palladium acetate, tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride. If necessary, tricyclohexylphosphine, tricyclohexylphosphonium tetrafluoroborate, 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, or the like is used as a ligand. Examples of the base used during boronation include potassium acetate. The solvent is not particularly limited, but examples thereof include aromatic hydrocarbons such as benzene, toluene, xylene, etc., ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, etc., alcohols such as methanol, ethanol, 2-propanol, butanol, etc., N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, etc. The reaction temperature is preferably 50°C to 150°C, and particularly preferably 70°C to 120°C.

[0182] Step 3: Preferred palladium catalysts include tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride. 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, but 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; N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, water, and mixtures thereof. The reaction temperature is preferably 50°C to 150°C, and more preferably 80°C to 120°C.

[0183] Step 4: The method for removing the protecting group can be a 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, and when the protecting group is a phthalimide group, hydrazine and ethylenediamine are preferred. The solvent is not particularly limited, but 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; N,N-dimethylformamide, N-methylpyrrolidone, and dimethyl sulfoxide. The reaction temperature is preferably 0° C. to 100° C.

[0184] In formula (I), L 1 When the compound of the present invention is —CH—, Ar 1 Ar is obtained by alkylation using the nitrogen atom present on the ring. 1After linking with the ring to obtain (S-II), it can be synthesized by the same synthesis method as described above.

[0185]

[0186] Step 1: The base is preferably triethylamine, N,N-diisopropylethylamine, potassium carbonate, cesium carbonate, etc. The solvent is not particularly limited, but examples thereof include ethers such as tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, and 1,2-diethoxyethane, N,N-dimethylformamide, N-methylpyrrolidone, and dimethyl sulfoxide. The reaction temperature is preferably room temperature to 120°C, and more preferably 40°C to 100°C.

[0187] Step 2: Preferred palladium catalysts include tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride. 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, but 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; N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, water, and mixtures thereof. The reaction temperature is preferably 50°C to 150°C, and more preferably 80°C to 120°C.

[0188] Step 3: For the removal of the protecting group, a known method commonly used in this field can be employed. For example, when the protecting group is a Boc group, strong acids such as trifluoroacetic acid, hydrochloric acid, and sulfuric acid are preferred, and when the protecting group is a phthalimide group, hydrazine and ethylenediamine are preferred. The solvent is not particularly limited, but 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; N,N-dimethylformamide, N-methylpyrrolidone, and dimethyl sulfoxide. The reaction temperature is preferably 0° C. to 100° C.

[0189] In formula (I), L 1 is the compound of the present invention having —CH—, there is a method for synthesizing a compound having the desired amino group or alkoxy group introduced therein, using the aldehyde of intermediate (TI) as a foothold, as shown in the following reaction formula.

[0190] (In the formula, R T1 , R T2 , R T3 is a H atom or C 1-6 is an alkyl group.)

[0191] Step 1: A reductive amination reaction is carried out using an amine appropriate for the target compound. Examples of imine reducing agents include sodium triacetoxyborohydride and sodium cyanoborohydride. Preferred solvents include toluene, dichloromethane, and dichloroethane. The reaction temperature is preferably room temperature to 80°C.

[0192] 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° C. to 50° C., particularly preferably 0° C. to room temperature.

[0193] Step 3: The reducing agent used may be sodium borohydride, lithium borohydride, etc. Preferred solvents include tetrahydrofuran, methanol, or a mixture thereof, etc. The reaction is preferably carried out at a temperature of 0° C. to room temperature.

[0194] Step 4: An alkyl halide, alkyl triflate, or the like is used as a reagent having a leaving group. Examples of the base include sodium hydride, potassium carbonate, and cesium carbonate. Preferred solvents include tetrahydrofuran, N,N-dimethylformamide, and dimethyl sulfoxide. The reaction temperature is preferably 0°C to 80°C.

[0195] 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° C. to 50° C., particularly preferably 0° C. to room temperature.

[0196] In formula (I), L 1 is —CH—, there is also a method for synthesizing the target compound having an amide group via functional group conversion of the ester group present in intermediate (UI), as shown in the following reaction formula.

[0197] (In the formula, R U is C 1-6 is an alkyl group.)

[0198] Step 1: Examples of 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, and solutions of these bases diluted with water. The solvent is not particularly limited, but examples include tetrahydrofuran, methanol, ethanol, water, and mixed solvents thereof. The reaction temperature is preferably 0°C to 60°C.

[0199] Step 2: Examples of condensing agents used include HATU, HOBt, HOAt, and EDCI. The reaction is carried out in the absence of a base or in the presence of a base such as triethylamine or N,N-diisopropylethylamine. Preferred solvents include tetrahydrofuran, dichloromethane, and N,N-dimethylformamide. The reaction is preferably carried out at a temperature of 0°C to 100°C.

[0200] 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° C. to 50° C., particularly preferably 0° C. to room temperature.

[0201] In formula (I), L 1 When the compound of the present invention is —CH—, it can also be synthesized by the method shown in the following reaction formula: That is, the triazole (V-IV) is obtained by reacting the azido group-introduced compound (V-II) with the acetylene compound (V-III), and then the triazole (V-IV) can be synthesized by the same method as the above-mentioned synthesis method.

[0202]

[0203] Step 1: This reaction introduces an azide group using sodium azide. Examples of solvents include N,N-dimethylformamide, N-methylpyrrolidone, and dimethyl sulfoxide. The reaction temperature is preferably from room temperature to 100°C.

[0204] Step 2: This reaction synthesizes a triazole ring using an alkyne compound corresponding to the target compound. Preferred metal reagents include copper(I) iodide and copper(I) bromide. If necessary, a ligand such as tris[(1-benzyl-1H-1,2,3-triazol-4-yl)methyl]amine (TBTA) may also be added. The solvent used here is not particularly limited, but 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; N,N-dimethylformamide, N-methylpyrrolidone, and dimethyl sulfoxide. The reaction is preferably carried out at room temperature to 80°C.

[0205] Step 3: Preferred palladium catalysts include tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride. 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, but 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; N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, water, and mixtures thereof. The reaction temperature is preferably 50°C to 150°C, and more preferably 80°C to 120°C.

[0206] Step 4: The method for removing the protecting group can be a 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, and when the protecting group is a phthalimide group, hydrazine and ethylenediamine are preferred. The solvent is not particularly limited, but 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; N,N-dimethylformamide, N-methylpyrrolidone, and dimethyl sulfoxide. The reaction temperature is preferably 0° C. to 100° C.

[0207] In formula (I), L 1 When the compound of the present invention is —CH—, it can also be synthesized by the method shown in the following reaction scheme: That is, after obtaining (W-V) by coupling reaction of boronic acid (W-I) with nitropyrazole ring (W-II), reduction of the nitro group, and modification of the amino group, the target compound can be synthesized by the same method as the above-mentioned synthesis method.

[0208] (In the formula, R W1 , R W2 is -NR W1 R W2 is R of formula (I) 3 is a substituent that can be included in

[0209] Step 1: Preferred palladium catalysts include tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride. 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, but 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; N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, water, and mixtures thereof. The reaction temperature is preferably 50°C to 150°C, and particularly preferably 80°C to 120°C.

[0210] Step 2: The metal reagent used is preferably iron or zinc, and is preferably a combination with a reagent such as ammonium chloride or acetic acid. Preferred solvents include organic solvents such as ethanol, methanol, and tetrahydrofuran, and mixed solvents of these with water. The reaction temperature is preferably room temperature to 100°C.

[0211] Step 3: Examples of reaction reagents having a leaving group include alkyl halides and alkyl triflates. Preferred bases include organic bases such as triethylamine and N,N-diisopropylethylamine, and inorganic bases such as potassium carbonate and cesium carbonate. Preferred solvents include 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, and dimethyl sulfoxide. The reaction temperature is preferably room temperature to 150°C.

[0212] Step 4: Examples of boronation reagents include bis(pinacolato)diboron and the like. Preferred catalysts include tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride, tris(dibenzylideneacetone)dipalladium, palladium acetate, and XPhos-Pd-G2. If necessary, ligands such as tricyclohexylphosphine, 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, and 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl may also be used. Preferred bases include potassium acetate and the like. Preferred solvents include 1,4-dioxane and dimethyl sulfoxide. The reaction temperature is preferably 50°C to 150°C, particularly 70°C to 120°C.

[0213] Step 5: Preferred palladium catalysts include tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride. 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, but 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; N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, water, and mixtures thereof. The reaction temperature is preferably 50°C to 150°C, and more preferably 80°C to 120°C.

[0214] Step 6: The method for removing the protecting group can be a 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, and when the protecting group is phthalimide, hydrazine and ethylenediamine are preferred. The solvent is not particularly limited, but 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; N,N-dimethylformamide, N-methylpyrrolidone, and dimethyl sulfoxide. The reaction temperature is preferably 0° C. to 100° C.

[0215] In formula (I), L 1 When the compound of the present invention is a -CHMe-, -C(=CH)-, or 1,1-cyclopropylidene group, it can be synthesized by the following method. 1 After the cyclic compound is reacted to obtain the exo-olefin (X-IV), the target compound can be synthesized by reduction or cyclopropanation of the olefin and deprotection. 1 The compound having —C(═CH2)— can be synthesized by deprotecting (X-IV).

[0216]

[0217] Step 1: Preferred palladium catalysts include tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride. 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, but 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; N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, water, and mixtures thereof. The reaction temperature is preferably 50°C to 150°C, and particularly preferably 80°C to 120°C.

[0218] Step 2: This reaction is a reaction to form tosylhydrazone using tosylhydrazine as a reagent. Preferred solvents include toluene, methanol, ethanol, etc. The reaction temperature is preferably room temperature to 120°C.

[0219] Step 3: This reaction involves coupling tosylhydrazone with an aryl halide to synthesize an exo-olefin. Preferred catalysts include tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride, tris(dibenzylideneacetone)dipalladium, and palladium acetate. If necessary, ligands such as 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, 2-(dicyclohexylphosphino)-2',4',6'-tri-isopropyl-1,1'-biphenyl, and 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl may also be used. Preferred bases include cesium carbonate, tert-butoxylithium, and tripotassium phosphate. Preferred solvents include 1,4-dioxane, toluene, and fluorobenzene. The reaction temperature is preferably from 50°C to 150°C.

[0220] Step 4: This reaction involves the reduction of an olefin using a metal reagent such as palladium on carbon (Pd / C) in combination with a hydrogen source such as hydrogen gas. Ethanol, methanol, ethyl acetate, etc. are preferred solvents. The reaction temperature is preferably between 0°C and 100°C.

[0221] 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° C. to 50° C., particularly preferably 0° C. to room temperature.

[0222] Step 6: This reaction converts an olefin to a cyclopropane using trimethylsulfoxonium iodide. Preferred bases include sodium hydride and potassium tert-butoxide. Preferred solvents include dimethyl sulfoxide and tetrahydrofuran. The reaction temperature is preferably 0°C to 100°C.

[0223] 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° C. to 50° C., particularly preferably 0° C. to room temperature.

[0224] In formula (I), L 1 -CH(R 11 )--, can be synthesized using the following methods.

[0225] For example, the compound can be synthesized as shown in the following reaction scheme. Specifically, the ketone (Y-I) prepared by the aforementioned synthesis method can be reduced, followed by deprotection of the amino group to synthesize the target compound. Alternatively, the hydroxyl group of intermediate (Y-II) can be modified by alkylation or other methods.

[0226] (In the formula, R Y is -OR Y as R of formula (I) 11 is a substituent that satisfies the following:

[0227] Step 1: Examples of reducing reagents include sodium borohydride and lithium borohydride. Preferred solvents include tetrahydrofuran, methanol, ethanol, or a mixture thereof. The reaction temperature is preferably 0°C to 50°C.

[0228] Step 2: For the removal of the protecting group, a known method commonly used in this field can be employed. For example, when the protecting group is a Boc group, strong acids such as trifluoroacetic acid, hydrochloric acid, and sulfuric acid are preferred, and when the protecting group is a phthalimide group, hydrazine and ethylenediamine are preferred. The solvent is not particularly limited, but 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; N,N-dimethylformamide, N-methylpyrrolidone, and dimethyl sulfoxide. The reaction temperature is preferably 0° C. to 100° C.

[0229] Step 3: An alkyl halide, alkyl triflate, or the like is used as a reagent having a leaving group. Examples of the base include sodium hydride, potassium carbonate, and cesium carbonate. Preferred solvents include tetrahydrofuran, N,N-dimethylformamide, and dimethyl sulfoxide. The reaction temperature is preferably 0°C to 80°C.

[0230] Step 4: The method for removing the protecting group can be a 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, and when the protecting group is a phthalimide group, hydrazine and ethylenediamine are preferred. The solvent is not particularly limited, but 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; N,N-dimethylformamide, N-methylpyrrolidone, and dimethyl sulfoxide. The reaction temperature is preferably 0° C. to 100° C.

[0231] In formula (I), L 1 -CH(R11 )-, the compound of the present invention can also be synthesized as shown in the following reaction formula: That is, after adding an ethynyl group to the raw material aldehyde (Z-I), a cyclization reaction is carried out using (Z-IV) to obtain the target R 3 Substituted isoxazole (ZV) is obtained. The hydroxy group of (ZV) is modified by alkylation or the like, and then the amino group is deprotected to synthesize the target compound.

[0232] (In the formula, R Z is -OR Z as R of formula (I) 11 is a substituent that satisfies the following:

[0233] Step 1: This reaction is an addition reaction of ethynylmagnesium bromide (Z-II) to aldehyde (Z-I). The solvent used is preferably tetrahydrofuran, dichloromethane, etc. The reaction temperature is preferably from -78°C to room temperature.

[0234] Step 2: This reaction is a reaction to construct an isoxazole ring using an oxime reagent (Z-IV) corresponding to the target compound. Potassium carbonate, sodium carbonate, cesium carbonate, etc. are preferred as the base, and 1,4-dioxane, toluene, etc. are preferred as the solvent. The reaction temperature is preferably 50°C to 120°C.

[0235] Step 3: An alkyl halide, alkyl triflate, or the like is used as a reagent having a leaving group. Examples of the base include sodium hydride, potassium carbonate, and cesium carbonate. Preferred solvents include tetrahydrofuran, N,N-dimethylformamide, and dimethyl sulfoxide. The reaction temperature is preferably 0°C to 80°C.

[0236] Step 4: Preferred palladium catalysts include tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride. 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, but 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; N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, water, and mixtures thereof. The reaction temperature is preferably 50°C to 150°C, and particularly preferably 80°C to 120°C.

[0237] 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° C. to 50° C., particularly preferably 0° C. to room temperature.

[0238] In formula (I), L 1 When the compound of the present invention is -S- or -SO-, it can be synthesized by the following methods.

[0239] For example, it can be synthesized as shown in the following reaction scheme: After converting the intermediate (A'-I) obtained by the above-mentioned synthesis method into a triflate (A'-II), a thiol side chain is introduced by a coupling reaction, and this compound (A'-III) is treated with an appropriate base to carry out an aromatic nucleophilic substitution reaction, thereby obtaining Ar 1 If necessary, Ar can be connected to the ring. 1 Using the halogen atom as a starting point, it is possible to introduce the desired side chain substituent and synthesize the target compound. 1 If the compound is already R 3 When the compound is modified with, step 4 can be omitted.

[0240]

[0241] Step 1: The triflation agent used may be trifluoromethanesulfonic anhydride (TfO), etc., and the base may preferably be pyridine, triethylamine, N,N-diisopropylethylamine, etc. Preferred solvents include tetrahydrofuran, dichloromethane, 1,2-dichloroethane, etc. The reaction temperature is preferably −20° C. to 50° C.

[0242] Step 2: Preferred catalysts include tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride, tris(dibenzylideneacetone)dipalladium, and palladium acetate. If necessary, ligands such as 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, 2-(dicyclohexylphosphino)-2',4',6'-tri-isopropyl-1,1'-biphenyl, and 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl may also be used. Preferred bases include N,N-diisopropylethylamine, triethylamine, potassium carbonate, and cesium carbonate. Preferred solvents include 1,4-dioxane, tetrahydrofuran, and N,N-dimethylformamide. The reaction temperature is preferably 50°C to 150°C.

[0243] Step 3: The base is preferably potassium carbonate, cesium carbonate, 1,8-diazabicyclo[5.4.0]-7-undecene (DBU), etc. Preferred solvents include 1,4-dioxane, tetrahydrofuran, N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, etc. The reaction temperature is preferably 0°C to 150°C.

[0244] Step 4: R 3 The method for introducing a substituent can be a known method widely used in this field. For example, a boronic acid derivative can be used to introduce R 3When introducing a substituent, preferred palladium catalysts include tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride. 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, but 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; N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, water, and mixtures thereof. The reaction temperature is preferably 50°C to 150°C, and particularly preferably 80°C to 120°C. Furthermore, for example, R 3 When reacting with an alcohol or amine corresponding to the substituent, preferred bases include organic bases such as triethylamine and N,N-diisopropylethylamine, and inorganic bases such as potassium carbonate and cesium carbonate. The solvent is not particularly limited, but examples include ethers such as tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, and 1,2-diethoxyethane, N,N-dimethylformamide, N-methylpyrrolidone, and dimethyl sulfoxide. The reaction temperature is preferably from room temperature to 150°C.

[0245] 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° C. to 50° C., particularly preferably 0° C. to room temperature.

[0246] In formula (I), L 1 When the compound of the present invention is -S-, it can also be synthesized as shown in the following reaction formula. 2 Aromatic nucleophilic substitution can be used as a method for linking to the ring, and the synthesis method after biaryl bond formation can be similar to the above scheme.

[0247]

[0248] Step 1: The base used is preferably triethylamine, N,N-diisopropylethylamine, potassium carbonate, cesium carbonate, etc. Preferable solvents include 1,4-dioxane, tetrahydrofuran, N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, etc. The reaction temperature is preferably room temperature to 150°C.

[0249] Step 2: Preferred catalysts include tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride, tris(dibenzylideneacetone)dipalladium, and palladium acetate. If necessary, ligands such as 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, 2-(dicyclohexylphosphino)-2',4',6'-tri-isopropyl-1,1'-biphenyl, and 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl may also be used. Preferred bases include N,N-diisopropylethylamine, triethylamine, potassium carbonate, and cesium carbonate. Preferred solvents include 1,4-dioxane, tetrahydrofuran, and N,N-dimethylformamide. The reaction temperature is preferably 50°C to 150°C.

[0250] Step 3: The base is preferably potassium carbonate, cesium carbonate, 1,8-diazabicyclo[5.4.0]-7-undecene (DBU), etc. Preferred solvents include 1,4-dioxane, tetrahydrofuran, N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, etc. The reaction temperature is preferably 0°C to 150°C.

[0251] 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° C. to 50° C., particularly preferably 0° C. to room temperature.

[0252] In formula (I), L1 is the compound of the present invention in which the group is —SO—, the sulfide (C′-I) is oxidized to convert it to a sulfoxide (C′-II), and then deprotected, as shown in the following reaction formula, to thereby synthesize the target compound.

[0253]

[0254] Step 1: Examples of the oxidizing agent used include 3-chloroperbenzoic acid, etc. Examples of the solvent used include 1,4-dioxane, tetrahydrofuran, N,N-dimethylformamide, dimethyl sulfoxide, etc. The reaction temperature is preferably 0°C to 100°C.

[0255] 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° C. to 50° C., particularly preferably 0° C. to room temperature.

[0256] The pharmaceutically acceptable salt of the compound of formula (I) is not particularly limited as long as it is a pharmaceutically acceptable salt. Examples of such salts 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; salts with metals such as aluminum, zinc, and iron; salts with tetramethylammonium, choline, etc. and salts with organic bases such as ammonia, propanediamine, pyrrolidine, piperidine, pyridine, ethanolamine, N,N-dimethylethanolamine, 4-hydroxypiperidine, t-octylamine, dibenzylamine, morpholine, glucosamine, phenylglycyl alkyl ester, ethylenediamine, N-methylglucamine, guanidine, diethylamine, triethylamine, dicyclohexylamine, N,N'-dibenzylethylenediamine, chloroprocaine, procaine, diethanolamine, N-benzylphenylamine, piperazine, and tris(hydroxymethyl)aminomethane.

[0257] Furthermore, the compound of formula (I) or a pharmaceutically acceptable salt thereof includes various hydrates and solvates. Examples of solvents for solvates include, but are not limited to, methanol, ethanol, 1-propanol, 2-propanol, butanol, t-butanol, acetonitrile, acetone, methyl ethyl ketone, chloroform, ethyl acetate, diethyl ether, t-butyl methyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, benzene, toluene, N,N-dimethylformamide, and dimethyl sulfoxide.

[0258] Pharmaceutically acceptable salts of the compounds of formula (I) can be prepared appropriately based on ordinary knowledge in the art. The compounds of formula (I) or pharmaceutically acceptable salts thereof also include stereoisomers, racemates, and all possible optically active substances.

[0259] The compound of formula (I) of the present invention or a pharmaceutically acceptable salt thereof can be used in any dosage form such as a solid preparation, a semi-solid preparation, or a liquid preparation, and in any application preparation such as an oral preparation or a parenteral preparation (such as an injection, a transdermal preparation, an eye drop, a suppository, a nasal preparation, or an inhalant).

[0260] The pharmaceutical composition containing the compound of formula (I) of the present invention or a pharmaceutically acceptable salt thereof is prepared using commonly used additives. In the case of solid preparations, these additives include excipients such as lactose, sucrose, glucose, corn starch, potato starch, crystalline cellulose, light anhydrous silicic acid, synthetic aluminum silicate, magnesium aluminometasilicate, and calcium hydrogen phosphate; binders such as crystalline cellulose, carboxymethylcellulose, hydroxypropyl cellulose, sodium carboxymethylcellulose, and polyvinylpyrrolidone; starch, sodium carboxymethylcellulose, calcium carboxymethylcellulose, croscarmellose sodium, and carboxymethylcellulose; Examples of the additives include disintegrants such as sodium ethyl starch; lubricants such as talc and stearic acids; coating agents such as hydroxymethylpropylcellulose, hydroxypropylmethylcellulose phthalate, and ethylcellulose; colorants; in the case of semi-solid preparations, bases such as white petrolatum; and in the case of liquid preparations, solvents such as ethanol, solubilizing agents such as ethanol, preservatives such as parahydroxybenzoates, isotonic agents such as glucose, buffers such as citric acids, antioxidants such as L-ascorbic acid, chelating agents such as EDTA, and suspending agents / emulsifiers such as polysorbate 80.

[0261] The therapeutically effective amount of the active ingredient in the therapeutic or prophylactic agent of the present invention varies depending on the route of administration, the age and sex of the patient, and the severity of the disease, but is usually about 0.1 to 1000 mg / day, and the frequency of administration is usually 1 to 3 times / day or 1 to 7 times / week. It is preferable to prepare a formulation that satisfies these conditions.

[0262] In the present invention, "prevention" refers to preventing an individual who has not yet contracted or developed a disease from contracting or developing the disease, and "treatment" refers to curing, suppressing, or ameliorating a disease or symptom in an individual who has already contracted or developed the disease or symptom.

[0263] The present invention will be described in more detail below with reference to examples, but the present invention is not limited thereto. Abbreviations used in the present invention are as follows: BINAP = 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl, DBU = 1,8-diazabicyclo[5.4.0]-7-undecene, DMA = N,N-dimethylacetamide, DMF = N,N-dimethylformamide, DMSO = dimethyl sulfoxide, HATU = 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate, NMP = 1-methyl-2-pyrrolidone, TFA = trifluoroacetic acid, THF = tetrahydrofuran.

[0264] The structure of the isolated novel compound is: 1 Confirmation was by 1 H NMR and / or mass spectrometry using single quadrupole instrumentation equipped with an electrospray source, or other appropriate analytical method.

[0265] 1 For H NMR spectra (400 MHz, DMSO-d, CDCl, or CDOD), the chemical shifts (δ: ppm) and coupling constants (J: Hz) are shown. + +H, that is, the compound molecular mass (M) plus a proton (H + ​The following abbreviations stand for: s = singlet, d = doublet, t = triplet, q = quartet, quin = quintet, brs = broad singlet, m = multiplet.

[0266] Reference Example 1 tert-butyl(2-hydroxy-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)phenyl)ethyl)carbamate

[0267] tert-Butyl (2-(4-bromophenyl)-2-hydroxyethyl)carbamate (503 mg, 1.59 mmol) was dissolved in 1,4-dioxane (10 mL), and bis(pinacolato)diboron (404 mg, 1.59 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (61 mg, 0.084 mmol), and potassium acetate (469 mg, 4.78 mmol) were added, followed by stirring at 90°C for 15 hours. The reaction solution was cooled to room temperature, filtered through Celite, and then concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the title compound (412 mg, 71%). 1 H-NMR(CDCl3)δ: 7.81(2H, d, J=7.8 Hz), 7.38 (2H, d, J=7.8 Hz), 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).

[0268] [Reference Example 2] tert-butyl N-[3,3-difluoro-2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propyl]carbamate

[0269] Step 1: 1-Bromo-4-(1,1-difluoro-3-nitropropan-2-yl)benzene 1-Bromo-4-[(E)-2-nitroethenyl]benzene (1 g) was dissolved in acetonitrile (4.4 mL), cooled to 0 ° C., (bromodifluoromethyl)trimethylsilane (1.03 mL), triphenylphosphine (1.38 g), 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (1.06 mL) was added, and the mixture was stirred at room temperature for 30 minutes. The reaction solution was cooled to -20 ° C., chlorotrimethylsilane (0.11 mL), methanol (0.89 mL) were added, and the mixture was stirred at the same temperature for 15 minutes, and then the mixture was warmed 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 then 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 (785 mg). 1 H-NMR(CDCl3)δ: 7.54(2H, d, J=9.0Hz), 7.18 (2H, d, J=8.2 Hz),6.01 (1H, td, J = 55.3, 2.7 Hz), 4.94 (1H, dd, J= 13.7, 5.5 Hz), 4.83 (1H, ddd, J = 71.4, 13.7, 7.3 Hz), 4.06-3.93 (1H, m).

[0270] Step 2: tert-Butyl N-[2-(4-bromophenyl)-3,3-difluoropropyl]carbamate 1-Bromo-4-(1,1-difluoro-3-nitropropan-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 and filtered through Celite. The mother liquor was then dried over anhydrous magnesium sulfate, and the solution was concentrated under reduced pressure. This crude product was dissolved in dichloromethane (14 mL), and di-tert-butyl dicarbonate (612 mg) and N,N-diisopropylethylamine (0.39 mL) were added, followed by stirring at room temperature for 1 hour. Water was added to the reaction solution, followed by extraction 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 (667 mg). MS: m / z 294.1 (M-tBu+H) + .

[0271] Step 3: tert-Butyl N-[3,3-difluoro-2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propyl]carbamate tert-Butyl N-[2-(4-bromophenyl)-3,3-difluoropropyl]carbamate (667 mg) was dissolved in 1,4-dioxane (19 mL), and bis(pinacolato)diboron (629 mg), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (139 mg), and potassium acetate (561 mg) were added, followed by stirring for 3 hours at 100° C. The reaction solution was cooled to room temperature, filtered through Celite, and then concentrated under reduced pressure to obtain the title compound in crude form.

[0272] [Reference Example 3] tert-Butyl N-[2-(6-chloropyridin-3-yl)-2-hydroxyethyl]carbamate

[0273] Step 1: 1-(6-chloropyridin-3-yl)-2-nitroethanol. Nitromethane (3 mL) and triethylamine (3 mL) were added to 6-chloropyridine-3-carbaldehyde (1 g), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the crude product was used directly in the next reaction.

[0274] Step 2: tert-Butyl N-[2-(6-chloropyridin-3-yl)-2-hydroxyethyl]carbamate 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, followed by stirring at room temperature for 1 hour. The reaction solution was filtered through Celite and then concentrated under reduced pressure. This crude product was dissolved in dichloromethane (14 mL), and di-tert-butyl dicarbonate (1.54 g) and N,N-diisopropylethylamine (2 mL) were added, followed by stirring 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). MS: m / z 273.2 (M+H) + .

[0275] [Reference Example 4] tert-Butyl N-[2-(2-chloropyrimidin-5-yl)-2-hydroxyethyl]carbamate

[0276] Step 1: 1-(2-chloropyrimidine-5-yl)-2-nitroethanol. Nitromethane (1 mL) and triethylamine (2 mL) were added to 2-chloropyrimidine-5-carbaldehyde (428 mg), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the crude product was used directly in the next reaction.

[0277] Step 2: tert-Butyl N-[2-(2-chloropyrimidin-5-yl)-2-hydroxyethyl]carbamate 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, followed by stirring at room temperature for 2 hours. The reaction solution was filtered through Celite and then concentrated under reduced pressure. This crude product was dissolved in dichloromethane (5 mL), and di-tert-butyl dicarbonate (1.31 g) and N,N-diisopropylethylamine (1.6 mL) were added, followed by stirring at room temperature for 2 hours. Water was added to the reaction solution, followed by extraction 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). MS: m / z 274.1 (M+H) + . 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).

[0278] [Reference Example 5] tert-Butyl N-[2-(5-chloropyrazin-2-yl)-2-hydroxyethyl]carbamate

[0279] Step 1: 1-(5-chloropyrazine-2-yl)-2-nitroethanol. Nitromethane (1 mL) and triethylamine (1 mL) were added to 5-chloropyrazine-2-carbaldehyde (826 mg), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the crude product was used in the next reaction as it was.

[0280] Step 2: tert-Butyl N-[2-(5-chloropyrazin-2-yl)-2-hydroxyethyl]carbamate The crude product obtained in Step 1 was dissolved in THF (5 mL), cooled to 0°C, and di-tert-butyl dicarbonate (1.06 g), zinc powder (792 mg), and acetic acid (0.7 mL) were added, followed by stirring at room temperature for 16 hours. The reaction solution was filtered through Celite, followed by addition of water and extraction 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 title compound (57.5 mg). MS: m / z 218.1 (M-tBu+H) + .

[0281] [Reference Example 6] tert-Butyl 3-(6-chloropyridin-3-yl)-3-fluoroazetidine-1-carboxylate

[0282] Step 1: tert-Butyl 3-(6-chloropyridin-3-yl)-3-hydroxyazetidine-1-carboxylate 5-Bromo-2-chloropyridine (385 mg) was dissolved in THF (10 mL) and cooled to -78°C, and n-butyllithium (1.2 mL) was added dropwise. After stirring at the same temperature for 1 hour, a THF solution (2 mL) of 1-(tert-butoxycarbonyl)-3-azetidinone (342 mg) was added, and the mixture was warmed to room temperature over 4 hours. A saturated aqueous ammonium chloride solution was added to the reaction solution, followed by extraction 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 (209 mg). MS: m / z 285.0 (M+H) + .

[0283] Step 2: tert-Butyl 3-(6-chloropyridin-3-yl)-3-fluoroazetidine-1-carboxylate tert-Butyl 3-(6-chloropyridin-3-yl)-3-hydroxyazetidine-1-carboxylate (100 mg) was dissolved in dichloromethane (1.8 mL) and cooled to -78°C. Bis(2-methoxyethyl)aminosulfur trifluoride (0.078 mL) was added and stirred at the same temperature for 2 hours. After warming the reaction solution to room temperature, saturated aqueous sodium bicarbonate 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 to give the crude title compound (40 mg). MS: m / z 287.0 (M+H) + .

[0284] [Reference Example 7] N-[3-[(6-chloropyridin-3-yl)methyl]oxetan-3-yl]-2-methylpropane-2-sulfinamide

[0285] 2-Chloro-5-iodopyridine (479 mg) was dissolved in THF (10 mL), and isopropylmagnesium bromide (1 M THF solution, 2.0 mL) was added dropwise at 0°C. After stirring at the same temperature for 1 hour, copper(I) iodide (38.1 mg) was added, and the mixture was cooled to -30°C. A THF solution (2 mL) of 1-tert-butylsulfinyl-5-oxa-1-azaspiro[2.3]hexane (189 mg) was added dropwise to the reaction mixture, and the mixture was warmed to room temperature and stirred for 2 hours. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, which was then 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 title compound (108 mg). MS: m / z 303.1 (M+H) + . 1 H-NMR(CDCl3)δ: 8.33 (1H, s), 7.71 (1H, d, J=7.3 Hz), 7.30 (1H, d, J = 8.2 Hz), 4.83 (1H, d, J = 6.4 Hz), 4.66-4.56(3H, m), 3.59 (1H, s), 3.41 (2H, q, J = 14.5 Hz), 1.22 (9H, s).

[0286] [Reference Example 8] tert-Butyl N-[(2R)-2-(6-chloropyridin-3-yl)-2-fluoroethyl]carbamate

[0287] Tert-butyl N-[(2S)-2-(6-chloropyridin-3-yl)-2-hydroxyethyl]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 mixture was directly purified by silica gel column chromatography to give the title compound (37.5 mg). MS: m / z 275.1 (M+H) + .

[0288] [Reference Example 9] tert-Butyl N-[(2R)-2-(2-chloropyrimidin-5-yl)-2-fluoroethyl]carbamate

[0289] Tert-butyl N-[(2S)-2-(2-chloropyrimidin-5-yl)-2-hydroxyethyl]carbamate (547 mg), obtained by chiral separation of the racemic compound of 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 mixture was directly purified by silica gel column chromatography to obtain the title compound (83.3 mg). MS: m / z 276.2 (M+H) + .

[0290] [Reference Example 10] 2-[2-(6-chloropyridin-3-yl)-2,2-difluoroethyl]isoindole-1,3-dione

[0291] Step 1: Ethyl 2-(6-chloropyridin-3-yl)-2,2-difluoroacetate 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, followed by stirring 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, 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 (958 mg). MS: m / z 236.1 (M+H) + .

[0292] Step 2: 2-(6-chloropyridin-3-yl)-2,2-difluoroethanol 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. Stirring was carried out at room temperature for 1 hour. Water was added to the reaction solution, followed by extraction 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 (493 mg). MS: m / z 194.1 (M+H) + .

[0293] Step 3: 2-[2-(6-chloropyridin-3-yl)-2,2-difluoroethyl]isoindole-1,3-dione 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 azodicarboxylate (0.74 mL) was added dropwise, followed by stirring at room temperature for 16 hours. Water was added to the reaction solution, followed by extraction 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 title compound (395 mg). MS: m / z 323.1 (M+H) + .

[0294] Example 1: 4-[4-(2-aminoacetyl)phenyl]-3-[(2-methyl-6-morpholin-4-ylpyrimidin-4-yl)amino]benzonitrile (Compound No. 4)

[0295] Step 1: 3-amino-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)benzonitrile. 3-Amino-4-chlorobenzonitrile (700 mg, 4.59 mmol) was dissolved in 1,4-dioxane (23 mL), and bis(pinacolato)diboron (1.28 g, 5.05 mmol), tris(dibenzylideneacetone)dipalladium (126 mg, 0.14 mmol), tricyclohexylphosphonium tetrafluoroborate (101 mg, 0.28 mmol), and potassium acetate (1.35 g, 13.8 mmol) were added, followed by stirring at 100°C for 15 hours. The reaction mixture was cooled to room temperature and filtered through Celite. 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%). 1 H-NMR (CDCl3) δ: 7.65 ((1H, d, J = 7.3 Hz), 6.89 (1H, d, J = 7.8 Hz), 6.81 (1H, s), 4.93 (2H, br s), 1.35 (12H, s).

[0296] Step 2: tert-Butyl (2-(2'-amino-4'-cyano-[1,1'-biphenyl]-4-yl)-2-oxoethyl)carbamate To a solution (5 mL) of 3-amino-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)benzonitrile (245 mg, 1.00 mmol) in a toluene / water = 4 / 1 mixture, tert-butyl N-[2-(4-bromophenyl)-2-oxo-ethyl]carbamate (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 Celite. Water was added to the mother liquor, which was then extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the target compound (280 mg, 80%). MS: m / z 296.1 (M-tBu+H). + .

[0297] Step 3: tert-butyl (2-(4'-cyano-2'-((2-methyl-6-morpholinopyrimidin-4-yl)amino)-[1,1'-biphenyl]-4-yl)-2-oxoethyl)carbamate tert-Butyl (2-(2'-amino-4'-cyano-[1,1'-biphenyl]-4-yl)-2-oxoethyl)carbamate (50.8 mg, 0.145 mmol) was dissolved in toluene (2 mL), and 4-(6-chloro-2-methylpyrimidin-4-yl)morpholine (30.9 mg, 0.145 mmol), tris(dibenzylideneacetone)dipalladium (6.6 mg, 0.072 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (8.4 mg, 0.015 mmol), and sodium tert-butoxide (27.8 mg, 0.289 mmol) were added, followed by stirring at 150°C for 1.5 hours under microwave irradiation. The reaction solution was cooled to room temperature and filtered through Celite, and then the solution was concentrated under reduced pressure. The crude product was used directly in the next reaction.

[0298] Step 4: 4-[4-(2-aminoacetyl)phenyl]-3-[(2-methyl-6-morpholin-4-ylpyrimidin-4-yl)amino]benzonitrile. 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 mixture was concentrated under reduced pressure, and the crude product was purified by HPLC to obtain the target compound (2.09 mg). Exact MS: 428.2 Obs. MS(M+H) + : 429.4

[0299] [Example 2] 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[methyl-(2-methyl-5-phenylpyrazol-3-yl)amino]benzonitrile (Compound No. 6)

[0300] Step 1: 4-chloro-3-[methyl-(2-methyl-5-phenylpyrazol-3-yl)amino]benzonitrile. 1,4-Dioxane (6.7 mL) was added to 3-bromo-4-chlorobenzonitrile (578 mg, 2.67 mmol) and N,2-dimethyl-5-phenylpyrazol-3-amine (500 mg, 2.67 mmol), and tris(dibenzylideneacetone)dipalladium (122 mg, 0.134 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (232 mg, 0.401 mmol), and cesium carbonate (2.18 g, 6.68 mmol) were added, followed by stirring at 100°C for 16 hours. The reaction mixture was cooled to room temperature and filtered through Celite. The solution was then concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the target compound (512 mg, 59%). MS: m / z 323.1(M+H) + .

[0301] Step 2: 3-[methyl-(2-methyl-5-phenylpyrazol-3-yl)amino]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile 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(pinacolato)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, followed by stirring at 100°C for 2 hours. The reaction solution was cooled to room temperature and filtered through Celite, and then the solution was concentrated under reduced pressure. The resulting crude product was used as is in the next reaction. MS: m / z 415.0(M+H) + .

[0302] Step 3: tert-butyl N-[2-[2-[4-cyano-2-[methyl-(2-methyl-5-phenylpyrazol-3-yl)amino]phenyl]pyrimidin-5-yl]ethyl]carbamate The crude product obtained in Step 2 was dissolved in 1,4-dioxane (2.6 mL), and tert-butyl N-[2-(2-chloropyrimidin-5-yl)ethyl]carbamate (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, followed by stirring at 100°C for 1 hour. The reaction solution was cooled to room temperature, and then extracted with ethyl acetate and water. 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. MS: m / z 510.0(M+H) + .

[0303] Step 4: 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[methyl-(2-methyl-5-phenylpyrazol-3-yl)amino]benzonitrile Dichloromethane (1 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 mixture was concentrated under reduced pressure, and the crude product was purified by HPLC to obtain the target compound (48.3 mg). Exact MS: 409.2 Obs. MS(M+H) + : 410.4

[0304] [Example 3] 4-[4-(2-aminoethyl)phenyl]-3-(2-methyl-6-morpholin-4-ylpyrimidin-4-yl)oxybenzonitrile (Compound No. 7)

[0305] Step 1: 4-Bromo-3-((2-methyl-6-morpholinopyrimidin-4-yl)oxy)benzonitrile 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, followed by stirring 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 using a silica gel column to obtain the target compound (1.23 g, 54%).

[0306] Step 2: tert-butyl (2-(4'-cyano-2'-((2-methyl-6-morpholinopyrimidin-4-yl)oxy)-[1,1'-biphenyl]-4-yl)ethyl)carbamate 4-Bromo-3-((2-methyl-6-morpholinopyrimidin-4-yl)oxy)benzonitrile (110 mg, 0.29 mmol) was dissolved in a toluene / water = 4 / 1 mixed solution (2.5 mL), and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)phenethylcarbamate (132 mg, 0.38 mmol), tetrakistriphenylphosphine palladium (16.9 mg, 0.015 mmol), and potassium carbonate (121 mg, 0.88 mmol) were added, followed by stirring 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 obtain the target compound (140 mg, 93%). MS: m / z 516.3 (M+H) + .

[0307] Step 3: 4-[4-(2-aminoethyl)phenyl]-3-(2-methyl-6-morpholin-4-ylpyrimidin-4-yl)oxybenzonitrile tert-Butyl (2-(4'-cyano-2'-((2-methyl-6-morpholinopyrimidin-4-yl)oxy)-[1,1'-biphenyl]-4-yl)ethyl)carbamate (140 mg, 0.27 mmol) was dissolved in 1,4-dioxane (2 mL), and a 4 M (=mol / L) hydrochloric acid / 1,4-dioxane solution (2 mL) was added dropwise thereto, followed by stirring at room temperature for 1 hour. The reaction mixture 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 into the aqueous layer, and then a 1 / 4 mixture of methanol / dichloromethane (50 mL) and 2M aqueous sodium hydroxide (22 mL) were added, followed by extraction 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). Exact MS: 415.2 Obs. MS (M+H) + : 416.2

[0308] [Example 4] 4-[4-(2-amino-1-methoxyethyl)phenyl]-3-(2-methyl-6-morpholin-4-ylpyrimidin-4-yl)oxybenzonitrile (Compound No. 11)

[0309] Step 1: tert-butyl (2-(4'-cyano-2'-((2-methyl-6-morpholinopyrimidin-4-yl)oxy)-[1,1'-biphenyl]-4-yl)-2-methoxyethyl)carbamate tert-Butyl (2-(4'-cyano-2'-((2-methyl-6-morpholinopyrimidin-4-yl)oxy)-[1,1'-biphenyl]-4-yl)-2-hydroxyethyl)carbamate (29 mg, 0.055 mmol), synthesized in the same manner as in Example 3, was dissolved in DMF (1 mL), and sodium hydride (2.7 mg) was added and stirred at room temperature for 5 minutes. To this reaction solution, iodomethane (4.2 μL, 0.066 mmol) was added and stirred at room temperature for 1 hour. Water was added to the reaction solution, and the mixture was stirred, followed by extraction 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.

[0310] Step 2: 4-[4-(2-amino-1-methoxyethyl)phenyl]-3-(2-methyl-6-morpholin-4-ylpyrimidin-4-yl)oxybenzonitrile The crude product obtained in Step 1 was dissolved in dichloromethane (2 mL), and TFA (0.5 mL) was added and stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by HPLC to obtain the target compound (8.7 mg). Exact MS: 445.2 Obs. MS(M+H) + : 446.2

[0311] [Example 5] 4-[4-(2-amino-1-phenoxyethyl)phenyl]-3-(2-methyl-6-morpholin-4-ylpyrimidin-4-yl)oxybenzonitrile (Compound No. 13)

[0312] Step 1: 2-((tert-butoxycarbonyl)amino)-1-(4'-cyano-2'-((2-methyl-6-morpholinopyrimidin-4-yl)oxy)-[1,1'-biphenyl]-4-yl)ethyl methanesulfonate tert-Butyl (2-(4'-cyano-2'-((2-methyl-6-morpholinopyrimidin-4-yl)oxy)-[1,1'-biphenyl]-4-yl)-2-hydroxyethyl)carbamate (60.9 g, 0.115 mmol), synthesized in a manner similar to that in Example 3, was dissolved in THF (2 mL), and triethylamine (48 μL, 0.34 mmol) and methanesulfonyl chloride (11 μL, 0.14 mmol) were added, followed by stirring at room temperature for 1 hour. The reaction solution 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. MS: m / z 610.3 (M+H) + .

[0313] Step 2: tert-butyl (2-(4'-cyano-2'-((2-methyl-6-morpholinopyrimidin-4-yl)oxy)-[1,1'-biphenyl]-4-yl)-2-phenoxyethyl)carbamate 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, followed by stirring at 100°C for 16 hours. Water was added to the reaction solution, which was then 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. MS: m / z 608.3 (M+H) + .

[0314] Step 3: 4-[4-(2-amino-1-phenoxyethyl)phenyl]-3-(2-methyl-6-morpholin-4-ylpyrimidin-4-yl)oxybenzonitrile. The crude product obtained in Step 2 was dissolved in dichloromethane (2 mL), and TFA (0.5 mL) was added, followed by stirring at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by HPLC to obtain the target compound (5.5 mg). Exact MS: 507.2 Obs. MS(M+H) +: 508.2

[0315] [Example 6] 4-[4-(2-aminoethyl)phenyl]-3-(2-methyl-6-piperidin-1-ylpyrimidin-4-yl)oxybenzonitrile (Compound No. 17)

[0316] Step 1: tert-butyl (2-(4'-cyano-2'-hydroxy-[1,1'-biphenyl]-4-yl)ethyl)carbamate To a toluene / water (9 / 1) mixed solution (50 mL) of 4-bromo-3-hydroxybenzonitrile (8.6 g, 43.4 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)phenethylcarbamate (22.7 g, 65.1 mmol), tetrakistriphenylphosphine palladium (5.0 g, 4.34 mmol), and potassium carbonate (11.9 g, 86.1 mmol) were added, and the mixture was stirred at 90°C for 16 hours. The reaction solution was cooled to room temperature and filtered through Celite. 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%).

[0317] Step 2: tert-Butyl (2-(2'-((6-chloro-2-methylpyrimidin-4-yl)oxy)-4'-cyano-[1,1'-biphenyl]-4-yl)ethyl)carbamate 4,6-Dichloro-2-methylpyrimidine (1.35 g, 8.28 mmol) and cesium carbonate (5.38 g, 16.6 mmol) were added to a solution of tert-butyl (2-(4'-cyano-2'-hydroxy-[1,1'-biphenyl]-4-yl)ethyl)carbamate (2.8 g, 8.3 mmol) in DMF (15 mL), and the mixture was stirred at room temperature overnight. Water and ethyl acetate were added to the reaction mixture, which was then 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 (1.8 g, 46%). MS: m / z 464.8 (M+H) + .

[0318] Step 3: tert-butyl (2-(4'-cyano-2'-((2-methyl-6-(piperidin-1-yl)pyrimidin-4-yl)oxy)-[1,1'-biphenyl]-4-yl)ethyl)carbamate 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) was dissolved in DMF (3 mL), piperidine (0.043 mL, 0.432 mmol) and cesium carbonate (140 mg, 0.431 mmol) were added, and the mixture was stirred at room temperature for 16 hours. Water was added to the reaction solution, which was then extracted with dichloromethane. 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. MS: m / z 514.3(M+H) + .

[0319] Step 4: 4-[4-(2-aminoethyl)phenyl]-3-(2-methyl-6-piperidin-1-ylpyrimidin-4-yl)oxybenzonitrile. TFA (0.5 mL) was added to a dichloromethane (2 mL) solution of the crude product obtained in Step 3, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by HPLC to obtain the target compound (57.2 mg). Exact MS: 413.2 Obs. MS(M+H) + : 414.0 1 H-NMR (DMSO-d6) δ: 7.73 (1H, d, J = 8.4 Hz), 7.68 (1H, s), 7.61 (1H, d, J = 8.0 Hz), 7.35 (2H, d, J = 7.6 Hz), 7.21 (2H, d, J = 7.6 Hz), 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).

[0320] [Example 7] 4-[4-(2-aminoethyl)phenyl]-3-[6-(2-cyanophenyl)-2-methylpyrimidin-4-yl]oxybenzonitrile (Compound No. 21)

[0321] Step 1: tert-butyl(2-(4'-cyano-2'-((6-(2-cyanophenyl)-2-methylpyrimidin-4-yl)oxy)-[1,1'-biphenyl]-4-yl)ethyl)carbamate The intermediate tert-butyl(2-(2'-((6-chloro-2-methylpyrimidin-4-yl)oxy)-4'-cyano-[1,1'-biphenyl]-4-yl)ethyl)carbamate (100 mg, 0.215 mmol) obtained in Example 6 was dissolved in 1,4-dioxane (2 mL), potassium carbonate (59 mg, 0.43 mmol), 2-cyanophenylboronic acid (47 mg, 0.32 mmol), and tetrakistriphenylphosphine palladium (20 mg, 0.017 mmol) were added, and the mixture was stirred overnight at 100°C under a nitrogen atmosphere. The reaction mixture was cooled to room temperature and filtered through Celite. Water was added 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 used directly in the next reaction.

[0322] Step 2: 4-[4-(2-aminoethyl)phenyl]-3-[6-(2-cyanophenyl)-2-methylpyrimidin-4-yl]oxybenzonitrile The crude product obtained in Step 1 was dissolved in dichloromethane (2 mL), TFA (0.5 mL) was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by HPLC to obtain the target compound (15.4 mg). Exact MS: 431.2 Obs. MS(M+H) + : 431.9 1 H-NMR (DMSO-d6)δ: 8.01-7.99 (2H, m), 7.95-7.93 (1H, m), 7.89-7.82 (2H, m), 7.74-7.70 (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).

[0323] [Example 8] 4-[4-(2-aminoethyl)phenyl]-3-[6-(2,2-dimethylpropoxy)-2-methylpyrimidin-4-yl]oxybenzonitrile (Compound No. 47)

[0324] Step 1: 4-chloro-2-methyl-6-(neopentyloxy)pyrimidine To a stirred suspension of sodium hydride (82 mg, 3.4 mmol) in THF (4 mL), a solution of 2,2-dimethylpropan-1-ol (323 mg, 3.68 mmol) in THF (0.5 mL) was added dropwise at room temperature and stirred at the same temperature for 15 minutes. After cooling the reaction solution to 0°C, a solution of 4,6-dichloro-2-methylpyrimidine (400 mg, 2.45 mmol) in THF (0.5 mL) was added dropwise and 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 using a silica gel column to obtain the target compound (245 mg, 47%).

[0325] Step 2: tert-Butyl (2-(4'-cyano-2'-((2-methyl-6-(neopentyloxy)pyrimidin-4-yl)oxy)-[1,1'-biphenyl]-4-yl)ethyl)carbamate tert-Butyl (2-(4'-cyano-2'-hydroxy-[1,1'-biphenyl]-4-yl)ethyl)carbamate (50 mg, 0.148 mmol) was dissolved in DMF (1 mL), 4-chloro-2-methyl-6-(neopentyloxy)pyrimidine (63.5 mg, 0.296 mmol) and cesium carbonate (96.4 mg, 0.296 mmol) were added, and the mixture was stirred at 70°C overnight. Water was added to the reaction solution, which was then 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 used directly in the next reaction. MS: m / z 517.0 (M+H) + .

[0326] Step 3: 4-[4-(2-aminoethyl)phenyl]-3-[6-(2,2-dimethylpropoxy)-2-methylpyrimidin-4-yl]oxybenzonitrile. 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 mixture was concentrated under reduced pressure, and the crude product was purified by HPLC to obtain the target compound (21.4 mg). Exact MS: 416.2 Obs. MS(M+H)+ : 417.3

[0327] [Example 9] 4-[4-[2-(3-hydroxypropylamino)ethyl]phenyl]-3-(2-methyl-6-morpholin-4-ylpyrimidin-4-yl)oxybenzonitrile (Compound No. 58)

[0328] Step 1: 4-[4-[2-(3-hydroxypropylamino)ethyl]phenyl]-3-(2-methyl-6-morpholin-4-ylpyrimidin-4-yl)oxybenzonitrile 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), 3-bromopropan-1-ol (0.014 ml, 0.16 mmol) and triethylamine (0.055 mL, 0.39 mmol) were added, and 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). Exact MS: 473.2 Obs. MS(M+H) + :474.5

[0329] [Example 10] 4-[4-(2-amino-1-phenylethyl)phenyl]-3-(2-methyl-6-morpholin-4-ylpyrimidin-4-yl)oxybenzonitrile (Compound No. 59)

[0330] Step 1: tert-butyl (2-(4'-cyano-2'-((2-methyl-6-morpholinopyrimidin-4-yl)oxy)-[1,1'-biphenyl]-4-yl)-2-(2-tosylhydrazono)ethyl)carbamate. tert-Butyl (2-(4'-cyano-2'-((2-methyl-6-morpholinopyrimidin-4-yl)oxy)-[1,1'-biphenyl]-4-yl)-2-oxoethyl)carbamate (855.8 mg, 1.62 mmol), synthesized in the same manner as in Example 3, was dissolved in toluene (8 mL), and p-toluenesulfonylhydrazide (301 mg, 1.62 mmol) was added, followed by stirring 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) + .

[0331] Step 2: tert-butyl (2-(4'-cyano-2'-((2-methyl-6-morpholinopyrimidin-4-yl)oxy)-[1,1'-biphenyl]-4-yl)-2-phenylethyl)carbamate 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, followed by stirring at 110°C for 15 hours. Water was added to the reaction solution, which was then 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. MS: m / z 592.3 (M+H) + .

[0332] Step 3: 4-[4-(2-amino-1-phenylethyl)phenyl]-3-(2-methyl-6-morpholin-4-ylpyrimidin-4-yl)oxybenzonitrile. The crude product obtained in Step 2 was dissolved in dichloromethane (2 mL), and TFA (0.5 mL) was added, followed by stirring at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by HPLC to obtain the target compound (3.1 mg). Exact MS: 491.2 Obs. MS (M+H) + :492.5

[0333] [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)

[0334] Step 1: 3-(2-methyl-6-morpholin-4-ylpyrimidin-4-yl)oxy-4-(1-oxo-2,3-dihydroinden-5-yl)benzonitrile 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-dioxaborolan-2-yl)-2,3-dihydroinden-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, followed by stirring 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 obtain the target compound (290 mg, 85%). MS: m / z 427.2 (M+H) + .

[0335] Step 2: 4-(2-bromo-1-oxo-2,3-dihydroinden-5-yl)-3-(2-methyl-6-morpholin-4-ylpyrimidin-4-yl)oxybenzonitrile. 3-(2-methyl-6-morpholin-4-ylpyrimidin-4-yl)oxy-4-(1-oxo-2,3-dihydroinden-5-yl)benzonitrile (290 mg, 0.680 mmol) was dissolved in a chloroform / ethyl acetate = 1 / 1 mixed solvent (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 Celite, and then the solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the target compound (26.0 mg, 8%). MS: m / z 505.1 (M+H) + .

[0336] Step 3: 4-[2-[(2,4-dimethoxyphenyl)methylamino]-1-oxo-2,3-dihydroinden-5-yl]-3-(2-methyl-6-morpholin-4-ylpyrimidin-4-yl)oxybenzonitrile 4-(2-bromo-1-oxo-2,3-dihydroinden-5-yl)-3-(2-methyl-6-morpholin-4-ylpyrimidin-4-yl)oxybenzonitrile (26.0 mg, 0.0514 mmol) was dissolved in DMF (1 mL), 2,4-dimethoxybenzenemethanamine (12.9 mg, 0.0772 mmol) and triethylamine (0.022 mL, 0.154 mmol) were added, and 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 washed with saturated brine, dried over anhydrous magnesium sulfate, and the solution was concentrated under reduced pressure. The crude product was used as is in the next reaction.

[0337] Step 4: 4-(2-amino-1-oxo-2,3-dihydroinden-5-yl)-3-(2-methyl-6-morpholin-4-ylpyrimidin-4-yl)oxybenzonitrile. TFA (1 mL) was added to the crude product obtained in Step 3, and the mixture was stirred at 120°C for 10 minutes. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by HPLC to obtain the target compound (6.00 mg). Exact MS: 441.2 Obs. MS (M+H) + :442.2

[0338] [Example 12] 4-[4-(2-amino-1-hydroxyethyl)-3-fluorophenyl]-3-(2-methyl-6-morpholin-4-ylpyrimidin-4-yl)oxybenzonitrile (Compound No. 149)

[0339] Step 1: 4-(3-fluoro-4-formylphenyl)-3-(2-methyl-6-morpholin-4-ylpyrimidin-4-yl)oxybenzonitrile 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), 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (250 mg, 1.00 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (36.6 mg, 0.0500 mmol), potassium carbonate (415 mg, 3.00 mmol), water (1 mL) was added, and the mixture was stirred at 100 ° C. for 30 minutes. 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 (174 mg, 83%). MS: m / z 419.2 (M+H) + .

[0340] Step 2: 4-[3-fluoro-4-(1-hydroxy-2-nitroethyl)phenyl]-3-(2-methyl-6-morpholin-4-ylpyrimidin-4-yl)oxybenzonitrile 4-(3-fluoro-4-formylphenyl)-3-(2-methyl-6-morpholin-4-ylpyrimidin-4-yl)oxybenzonitrile (174 mg, 0.416 mmol) was dissolved in THF (4 mL), and nitromethane (0.5 mL) and triethylamine (1 mL) were added and stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the crude product was used directly in the next reaction. MS: m / z 480.2 (M+H) + .

[0341] Step 3: 4-[4-(2-amino-1-hydroxyethyl)-3-fluorophenyl]-3-(2-methyl-6-morpholin-4-ylpyrimidin-4-yl)oxybenzonitrile. Zinc powder (500 mg, 7.64 mmol) and acetic acid (4 mL) were added to the crude product obtained in Step 2, and the mixture was stirred for 30 minutes. The reaction mixture was filtered through Celite and then concentrated under reduced pressure. The crude product was purified by HPLC to obtain the target compound (15.7 mg). Exact MS: 449.2 Obs. MS (M+H) + :450.2

[0342] [Example 13] 4-[4-[(1R)-2-amino-1-hydroxyethyl]pyrazol-1-yl]-3-(2-methyl-6-phenylpyrimidin-4-yl)oxybenzonitrile (Compound No. 170)

[0343] Step 1: Ethyl 1-(4-cyano-2-methoxyphenyl)pyrazole-4-carboxylate DMSO (120 mL) was added to 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, and water was added and the mixture was stirred. The precipitated solid was collected by filtration using a glass filter and dried to obtain the target compound (22.8 g, 84%). MS: m / z 272.0 (M+H) + .

[0344] Step 2: 1-(4-cyano-2-methoxyphenyl)pyrazole-4-carboxylate Ethyl 1-(4-cyano-2-methoxyphenyl)pyrazole-4-carboxylate (11.0 g, 40.5 mmol) was dissolved in a mixed solvent of THF (40 mL) and methanol (40 mL), and 2 M aqueous sodium hydroxide solution (40.5 mL, 81.1 mmol) was added and stirred at room temperature for 2 hours. 2 M hydrochloric acid was added to the reaction solution and stirred, and then water was added to precipitate the target compound. This was collected by filtration through a glass filter and dried to obtain the target compound (7.38 g, 75%). MS: m / z 244.0 (M+H) + .

[0345] Step 3: 3-Methoxy-4-[4-(2-nitroacetyl)pyrazol-1-yl]benzonitrile. 1-(4-cyano-2-methoxyphenyl)pyrazole-4-carboxylic acid (7.38 g, 30.3 mmol) was added with DMF (40 mL) and 1,1'-carbonyldiimidazole (5.90 g, 36.4 mmol) and stirred for 2 hours (Reaction Solution A). A separate reaction vessel was charged with nitromethane (2.78 g, 45.5 mmol), DMF (40 mL), and sodium hydride (1.59 g, 36.4 mmol). This solution was stirred for 2 hours to prepare a separate solution (Reaction Solution B). This Reaction Solution B was cooled to 0 °C, and Reaction Solution A was added dropwise. The mixture was then heated 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. This was collected by filtration through a glass filter and dried to obtain the target compound (8.70 g, quant.). MS: m / z 287.0 (M+H) + .

[0346] Step 4: 3-hydroxy-4-[4-(2-nitroacetyl)pyrazol-1-yl]benzonitrile 3-Methoxy-4-[4-(2-nitroacetyl)pyrazol-1-yl]benzonitrile (4.50 g, 15.7 mmol) was dissolved in DMF (40 mL), lithium chloride (6.67 g, 157 mmol) was added, and the mixture was stirred at 150°C overnight. 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 used directly in the next reaction. MS: m / z 273.0 (M+H) + .

[0347] Step 5: 3-(2-methyl-6-phenylpyrimidin-4-yl)oxy-4-[4-(2-nitroacetyl)pyrazol-1-yl]benzonitrile 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, followed by stirring at 100°C overnight. Water was added to the reaction solution, which was then 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 obtain the target compound (2.69 g, 39%). MS: m / z 441.1 (M+H) + .

[0348] Step 6: tert-Butyl N-[2-[1-[4-cyano-2-(2-methyl-6-phenylpyrimidin-4-yl)oxyphenyl]pyrazol-4-yl]-2-oxoethyl]carbamate. 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) were added to THF (40 mL) and acetic acid (1.83 g, 30.5 mmol), and the mixture was stirred at room temperature overnight. The reaction mixture was filtered through Celite, 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 (540 mg, 17%). MS: m / z 511.2 (M+H) + .

[0349] Step 7: tert-Butyl N-[(2R)-2-[1-[4-cyano-2-(2-methyl-6-phenylpyrimidin-4-yl)oxyphenyl]pyrazol-4-yl]-2-hydroxyethyl]carbamate tert-Butyl N-[2-[1-[4-cyano-2-(2-methyl-6-phenylpyrimidin-4-yl)oxyphenyl]pyrazol-4-yl]-2-oxoethyl]carbamate (106 mg, 0.208 mmol) and (S)-5,5-diphenyl-2-methyl-3,4-propano-1,3,2-oxazaborolidine (5.8 mg, 0.021 mmol) were dissolved in dichloromethane (1 mL) and cooled to 0 ° C. Dimethylsulfide borane (47.3 mg, 0.633 mmol) was added to this 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 the solution was concentrated under reduced pressure. The crude product was used directly in the next reaction. MS: m / z 513.2 (M+H) + .

[0350] Step 8: 4-[4-[(1R)-2-amino-1-hydroxyethyl]pyrazol-1-yl]-3-(2-methyl-6-phenylpyrimidin-4-yl)oxybenzonitrile. The crude product obtained in Step 7 was dissolved in dichloromethane (1 mL), and TFA (1 mL) was added and stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by HPLC to obtain the target compound (18.6 mg). Exact MS: 412.2 Obs. MS (M+H) + :413.2

[0351] [Example 14] 3-(6-cyclopentyl-2-methylpyrimidin-4-yl)oxy-4-[4-(2-oxopiperazin-1-yl)pyrazol-1-yl]benzonitrile (Compound No. 208)

[0352] Step 1: 3-(6-chloro-2-methylpyrimidin-4-yl)oxy-4-fluorobenzonitrile 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, followed by stirring 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 sodium sulfate, and the solution was concentrated under reduced pressure. The crude product was purified using a silica gel column to obtain the target compound (6.5 g). MS: m / z 264.1 (M+H) + . 1 H-NMR (CDCl3)δ:7.61 (1H, dq, J = 8.7, 2.1 Hz), 7.56 (1H, dd, J = 7.1, 2.2 Hz), 7.32 (1H, dd, J = 9.5, 8.5 Hz), 6.90 (1H, s), 2.51 (3H, s).

[0353] Step 2: 3-(6-cyclopentyl-2-methylpyrimidin-4-yl)oxy-4-fluorobenzonitrile. 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(diphenylphosphino)ferrocene]palladium dichloride (557 mg, 0.759 mmol), and cyclopentylzinc bromide (1.22 g, 5.69 mmol) was added dropwise and stirred at 70°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 using a silica gel column to obtain the target compound (888 mg). MS: m / z 298.1 (M+H) + .

[0354] Step 3: 3-(6-cyclopentyl-2-methylpyrimidin-4-yl)oxy-4-(4-iodopyrazol-1-yl)benzonitrile 3-(6-cyclopentyl-2-methylpyrimidin-4-yl)oxy-4-fluorobenzonitrile (100 mg, 0.336 mmol) was dissolved in DMSO (0.5 mL), 4-iodo-1H-pyrazole (65.2 mg, 0.336 mmol) and potassium carbonate (93.0 mg, 0.673 mmol) were added, and the mixture was stirred at 120°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 using a silica gel column to obtain the target compound (78.9 mg). MS: m / z 472.1 (M+H) + .

[0355] Step 4: 3-(6-cyclopentyl-2-methylpyrimidin-4-yl)oxy-4-(4-iodopyrazol-1-yl)benzonitrile 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(I) iodide (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, followed by stirring at 110° C. for 2 hours. The reaction mixture was cooled to room temperature, filtered through Celite, 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.

[0356] Step 5: 3-(6-cyclopentyl-2-methylpyrimidin-4-yl)oxy-4-[4-(2-oxopiperazin-1-yl)pyrazol-1-yl]benzonitrile. 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 mixture was concentrated under reduced pressure, and the crude product was purified by HPLC to obtain the target compound (7.3 mg). Exact MS: 443.2 Obs. MS (M+H) + :444.3

[0357] [Example 15] 3-(2-methyl-5-phenylpyrazol-3-yl)oxy-4-[4-(7-oxo-1,4-diazepan-1-yl)pyrazol-1-yl]benzonitrile (Compound No. 219)

[0358] Step 1: 3-Fluoro-4-(4-iodopyrazol-1-yl)benzonitrile. 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) were added to DMF (8.6 mL) and 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 obtain the target compound (428 mg, 53%). 1H-NMR (CDCl3) δ: 8.18 (1H, d, J = 2.7 Hz), 8.15 (1H, t, J = 8.2 Hz), 7.79 (1H, s), 7.60-7.55 (2H, m).

[0359] Step 2: 4-(4-iodopyrazol-1-yl)-3-(2-methyl-5-phenylpyrazol-3-yl)oxybenzonitrile. 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 at 120°C overnight. 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 (198 mg, 66%). MS: m / z 468.1 (M+H) + .

[0360] Step 3: tert-butyl 4-[1-[4-cyano-2-(2-methyl-5-phenylpyrazol-3-yl)oxyphenyl]pyrazol-4-yl]-5-oxo-1,4-diazepane-1-carboxylate 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-diazepane-1-carboxylate (24 mg, 0.11 mmol), copper(I) iodide (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 at 100° C. overnight. 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 used directly in the next reaction.

[0361] Step 4: 3-(2-methyl-5-phenylpyrazol-3-yl)oxy-4-[4-(7-oxo-1,4-diazepan-1-yl)pyrazol-1-yl]benzonitrile. The crude product obtained in Step 3 was dissolved in dichloromethane (1 mL), and TFA (1 mL) was added and stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by HPLC to obtain the target compound (15.7 mg). Exact MS: 453.2 Obs. MS (M+H) + :454.3

[0362] [Example 16] 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-(2-methyl-6-morpholin-4-ylpyridin-4-yl)oxybenzonitrile (Compound No. 250)

[0363] Step 1: 4-Bromo-3-(2-hydroxy-6-methylpyridin-4-yl)oxybenzonitrile. NMP (400 mL) was added to 4-bromo-3-fluorobenzonitrile (40.0 g, 200 mmol), 6-methylpyridine-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 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. Ethyl acetate was added to the concentrated crude product, and the suspension was formed. Heptane was then added, and the precipitated solid was collected by filtration using a glass filter. The product was dried in vacuo to obtain the target compound (20.3 g, 33%). MS: m / z 305.0 (M+H) + . 1 H-NMR (DMSO-d6)δ: 11.47 (1H, s), 8.00 (1H, d, J = 8.2 Hz), 7.92 (1H, d, J = 1.8 Hz), 7.73 (1H, dd, J = 8.2, 2.3 Hz), 5.89 (1H, d, J = 1.8 Hz), 5.15 (1H, d, J = 2.7 Hz), 2.15 (3H, s).

[0364] Step 2: [4-(2-bromo-5-cyanophenoxy)-6-methylpyridin-2-yl]trifluoromethanesulfonate Dichloromethane (22 mL) was added to 4-bromo-3-(2-hydroxy-6-methylpyridin-4-yl)oxybenzonitrile (2.7 g, 8.85 mmol), and the mixture was cooled to 0°C. Trifluoromethanesulfonic anhydride (3.25 g, 11.5 mmol) was then added. Pyridine (2.1 mL, 26.5 mmol) was added dropwise to the reaction mixture at the same temperature, and the mixture was then warmed to room temperature and stirred for 2 hours. Water was added to the reaction mixture, which was then 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. MS: m / z 436.9 (M+H) + .

[0365] Step 3: 4-Bromo-3-(2-methyl-6-morpholin-4-ylpyridin-4-yl)oxybenzonitrile. 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, followed by stirring 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 precipitated target compound was collected by filtration using a glass filter and dried to obtain the target compound (1.87 g, 57%). MS: m / z 374.0 (M+H) + . 1 H-NMR (CDCl3)δ:7.77 (1H, d, J = 8.2 Hz), 7.35 (1H, dd, J = 8.2, 1.8 Hz), 7.29 (1H, d, J = 1.8 Hz), 6.02 (1H, d, J = 1.4 Hz), 6.00 (1H, d, J = 1.4 Hz), 3.80 (4H, t, J = 5.0 Hz), 3.48 (4H, t, J = 4.8 Hz), 2.36 (3H, s).

[0366] Step 4: 3-(2-methyl-6-morpholin-4-ylpyridin-4-yl)oxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile 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(pinacolato)diboron (804 mg, 3.17 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (76.4 mg, 0.106 mmol), and potassium acetate (415 mg, 4.22 mmol) were added, followed by stirring at 90°C overnight. 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 (567 mg). MS: m / z 422.3 (M+H) + .

[0367] Step 5: tert-butyl N-[2-[2-[4-cyano-2-(2-methyl-6-morpholin-4-ylpyridin-4-yl)oxyphenyl]pyrimidin-5-yl]ethyl]carbamate 3-(2-methyl-6-morpholin-4-ylpyridin-4-yl)oxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (222 mg, 0.527 mmol) was dissolved in 1,4-dioxane (1.8 mL), and tert-butyl N-[2-(2-chloropyrimidin-5-yl)ethyl]carbamate (90.5 mg, 0.351 mmol), [1,1'-bis(diphenylphosphino)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 at 90°C overnight. 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%). MS: m / z 517.3 (M+H) + .1 H-NMR (CDCl3)δ:8.61 (2H, s), 8.05 (1H, d, J = 8.2 Hz), 7.61 (1H, dd, J = 8.2, 1.4 Hz), 7.44 (1H, d, J = 1.4 Hz), 6.01 (1H, d, J = 1.4 Hz), 5.94 (1H, d, J = 1.8 Hz), 4.70 (1H, br s), 3.78 (4H, t, J = 4.8 Hz), 3.41 (4H, t, J = 4.8 Hz), 3.36 (2H, q, J = 6.6 Hz), 2.82 (2H, t, J = 6.6 Hz), 2.29 (3H, s), 1.43 (9H, s).

[0368] Step 6: 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-(2-methyl-6-morpholin-4-ylpyridin-4-yl)oxybenzonitrile tert-butyl N-[2-[2-[4-cyano-2-(2-methyl-6-morpholin-4-ylpyridin-4-yl)oxyphenyl]pyrimidin-5-yl]ethyl]carbamate (71.9 mg, 0.139 mmol) was dissolved in dichloromethane (1 mL), TFA (1 mL) was added, 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 (63.62 mg). Exact MS: 416.2 Obs. MS (M+H) + :417.4 1 H-NMR (CD3OD)δ:8.79 (2H, s), 8.33 (1H, d, J = 8.2 Hz), 7.90 (1H, dd, J = 8.0, 1.6 Hz), 7.79 (1H, d, J = 1.4 Hz), 6.46 (1H, d, J = 1.8 Hz), 6.39 (1H, d, J = 1.8 Hz), 3.79 (4H, t, J = 5.0 Hz), 3.55 (4H, t, J = 5.0 Hz), 3.25 (2H, t, J = 7.8 Hz), 3.04 (2H, t, J = 7.8 Hz), 2.50 (3H, s).

[0369] [Example 17] 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-(2-methyl-5-propan-2-ylpyrazol-3-yl)oxybenzonitrile (Compound No. 261)

[0370] Step 1: 4-Bromo-3-(2-methyl-5-propan-2-ylpyrazol-3-yl)oxybenzonitrile 4-Bromo-3-fluorobenzonitrile (2.14 g, 10.7 mmol) and 2-methyl-5-propan-2-ylpyrazol-3-ol (1.50 g, 10.7 mmol) were dissolved in DMA (21 mL), potassium carbonate (4.44 g, 32.1 mmol) was added, and the mixture was stirred at 130°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 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 (1.06 g, 31%). MS: m / z 322.1 (M+H) + . 1 H-NMR (CDCl3)δ:7.77 (1H, d, J = 8.2 Hz), 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 = 6.9 Hz).

[0371] Step 2: 3-(2-methyl-5-propan-2-ylpyrazol-3-yl)oxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile 4-Bromo-3-(2-methyl-5-propan-2-ylpyrazol-3-yl)oxybenzonitrile (646 mg, 2.02 mmol) was dissolved in 1,4-dioxane (10 mL), and bis(pinacolato)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, followed by stirring at 100°C for 2 hours. The reaction mixture was cooled to room temperature, filtered through Celite, and then concentrated under reduced pressure. The crude product was used directly in the next reaction. MS: m / z 368.2 (M+H) + .

[0372] Step 3: tert-Butyl N-[2-[2-[4-cyano-2-(2-methyl-5-propan-2-ylpyrazol-3-yl)oxyphenyl]pyrimidin-5-yl]ethyl]carbamate To a solution of the crude product obtained in Step 2 in 1,4-dioxane (13.5 mL), tert-butyl N-[2-(2-chloropyrimidin-5-yl)ethyl]carbamate (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 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 (946 mg, containing impurities). MS: m / z 463.2 (M+H) + .

[0373] Step 4: 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-(2-methyl-5-propan-2-ylpyrazol-3-yl)oxybenzonitrile tert-butyl N-[2-[2-[4-cyano-2-(2-methyl-5-propan-2-ylpyrazol-3-yl)oxyphenyl]pyrimidin-5-yl]ethyl]carbamate (946 mg, 1.23 mmol) was dissolved in 1,4-dioxane (5.1 mL), and 4 M hydrochloric acid / 1,4-dioxane solution (5.1 mL) was added dropwise at 0°C. The mixture was then warmed to room temperature and stirred for 5 hours. The reaction mixture was concentrated under reduced pressure, and ethyl acetate was added to the crude product after concentration, followed by further concentration under reduced pressure. This was dried in vacuo to give the hydrochloride salt of the target compound (681 mg, 76%). Exact MS: 362.2 Obs. MS (M+H) + :363.3

[0374] [Example 18] 4-[4-(2-aminoethyl)pyrazol-1-yl]-3-(6-pyrrolidin-1-ylpyridazin-4-yl)oxybenzonitrile (Compound No. 284)

[0375] Step 1: tert-Butyl N-[2-[1-(4-cyano-2-phenylmethoxyphenyl)pyrazol-4-yl]ethyl]carbamate 4-Fluoro-3-phenylmethoxybenzonitrile (307 mg, 1.35 mmol), tert-butyl N-[2-(1H-pyrazol-4-yl)ethyl]carbamate (190 mg, 0.900 mmol), potassium carbonate (373 mg, 2.70 mmol), and DMA (2 mL) were added and 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 obtain the target compound (263 mg, 70%). MS: m / z 419.2 (M+H) + .

[0376] Step 2: tert-Butyl N-[2-[1-(4-cyano-2-hydroxyphenyl)pyrazol-4-yl]ethyl]carbamate. tert-Butyl N-[2-[1-(4-cyano-2-phenylmethoxyphenyl)pyrazol-4-yl]ethyl]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 gas balloon was attached to the reaction vessel, and the atmosphere inside the vessel was replaced with hydrogen gas. The mixture was then stirred at room temperature for 30 minutes. The reaction solution was filtered through Celite, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to obtain the target compound (172 mg, 83%). MS: m / z 273.0 (M-tBu+H) + .

[0377] Step 3: tert-Butyl N-[2-[1-[2-(6-chloropyridazin-4-yl)oxy-4-cyanophenyl]pyrazol-4-yl]ethyl]carbamate. DMF (1.3 mL) was added to tert-butyl N-[2-[1-(4-cyano-2-hydroxyphenyl)pyrazol-4-yl]ethyl]carbamate (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 obtain the target compound (218 mg, 94%). MS: m / z 385.0 (M-tBu+H) + .

[0378] Step 4: tert-Butyl N-[2-[1-[4-cyano-2-(6-pyrrolidin-1-ylpyridazin-4-yl)oxyphenyl]pyrazol-4-yl]ethyl]carbamate tert-Butyl N-[2-[1-[2-(6-chloropyridazin-4-yl)oxy-4-cyanophenyl]pyrazol-4-yl]ethyl]carbamate (70.0 mg, 0.159 mmol) was dissolved in toluene (0.8 mL), pyrrolidine (33.9 mg, 0.476 mmol), tris(dibenzylideneacetone)dipalladium (7.3 mg, 7.9 μmol), (±)-BINAP (9.9 mg, 16 μmol), and cesium carbonate (220 mg, 2.25 mmol) were added, 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 concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the target compound (51.0 mg, 68%).

[0379] Step 5: 4-[4-(2-aminoethyl)pyrazol-1-yl]-3-(6-pyrrolidin-1-ylpyridazin-4-yl)oxybenzonitrile tert-butyl N-[2-[1-[4-cyano-2-(6-pyrrolidin-1-ylpyridazin-4-yl)oxyphenyl]pyrazol-4-yl]ethyl]carbamate (51.0 mg, 0.107 mmol) was dissolved in dichloromethane (2 mL), TFA (0.5 mL) was added, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by HPLC to obtain the target compound (9.71 mg). Exact MS: 375.2 Obs. MS (M+H) + :376.2

[0380] [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)

[0381] Step 1: Methyl 2-[6-[4-cyano-2-(5-cyclopropyl-2-methylpyrazol-3-yl)oxyphenyl]pyridin-3-yl]-2-[(2-methylpropan-2-yl)oxycarbonylamino]acetate 3-(5-cyclopropyl-2-methylpyrazol-3-yl)oxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (881 mg, 2.41 mmol), synthesized in the same manner as in Example 17, was dissolved in 1,4-dioxane (12 mL), and methyl 2-(6-chloropyridin-3-yl)-2-[(2-methylpropan-2-yl)oxycarbonylamino]acetate (725 mg, 2.41 mmol), [1,1'-bis(diphenylphosphino)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%). MS: m / z 504.4 (M+H) + .

[0382] Step 2: 2-[6-[4-cyano-2-(5-cyclopropyl-2-methylpyrazol-3-yl)oxyphenyl]pyridin-3-yl]-2-[(2-methylpropan-2-yl)oxycarbonylamino]acetic acid Methyl 2-[6-[4-cyano-2-(5-cyclopropyl-2-methylpyrazol-3-yl)oxyphenyl]pyridin-3-yl]-2-[(2-methylpropan-2-yl)oxycarbonylamino]acetate (976 mg, 1.94 mmol) was dissolved in methanol (10 mL), 2 M aqueous sodium hydroxide solution (2 mL) was added, and the mixture was stirred at room temperature for 15 minutes. 1 M hydrochloric acid (4 mL) was added to the reaction mixture, and the mixture was stirred, followed by extraction 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. MS: m / z 490.3 (M+H) + .

[0383] Step 3: tert-Butyl N-[1-[6-[4-cyano-2-(5-cyclopropyl-2-methylpyrazol-3-yl)oxyphenyl]pyridin-3-yl]-2-morpholin-4-yl-2-oxoethyl]carbamate. 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, followed by stirring at room temperature for 3 hours. Water was added to the reaction solution, which was then 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. MS: m / z 559.4 (M+H) + .

[0384] Step 4: 4-[5-(1-amino-2-morpholin-4-yl-2-oxoethyl)pyridin-2-yl]-3-(5-cyclopropyl-2-methylpyrazol-3-yl)oxybenzonitrile. The crude product obtained in Step 3 was dissolved in dichloromethane (1 mL), and TFA (0.5 mL) was added, followed by stirring at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by HPLC to obtain the target compound (39.7 mg). Exact MS: 458.2 Obs. MS (M+H) + :459.3

[0385] [Example 20] 4-[5-[(3-aminooxetan-3-yl)methyl]pyridin-2-yl]-3-[6-(7-azabicyclo[2.2.1]heptan-7-yl)-2-methylpyrimidin-4-yl]oxybenzonitrile (Compound No. 670)

[0386] Step 1: 4-Bromo-3-(6-chloro-2-methylpyrimidin-4-yl)oxybenzonitrile 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, followed by stirring at 80°C overnight. 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 (1.16 g, 60%). MS: m / z 324.0 (M+H) + .

[0387] Step 2: 3-[6-(7-azabicyclo[2.2.1]heptan-7-yl)-2-methylpyrimidin-4-yl]oxy-4-bromobenzonitrile. 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 at 80°C overnight. The reaction mixture 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 the solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the target compound (235 mg, 61%). MS: m / z 385.1 (M+H) + . 1 H-NMR (CDCl3)δ:7.73 (1H, d, J = 8.2 Hz), 7.47 (1H, d, J = 2.3 Hz), 7.36 (1H, dd, J = 8.2, 1.8 Hz), 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).

[0388] Step 3: 3-[6-(7-Azabicyclo[2.2.1]heptan-7-yl)-2-methylpyrimidin-4-yl]oxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile 3-[6-(7-Azabicyclo[2.2.1]heptan-7-yl)-2-methylpyrimidin-4-yl]oxy-4-bromobenzonitrile (231 mg, 0.600 mmol) was dissolved in 1,4-dioxane (3 mL), and bis(pinacolato)diboron (305 mg, 1.20 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (43.9 mg, 0.0600 mmol), and potassium acetate (177 mg, 1.80 mmol) were added, and the mixture was stirred at 100°C overnight. The reaction mixture was cooled to room temperature, filtered through Celite, and then concentrated under reduced pressure. The crude product was used directly in the next reaction.

[0389] Step 4: N-[3-[[6-[2-[6-(7-azabicyclo[2.2.1]heptan-7-yl)-2-methylpyrimidin-4-yl]oxy-4-cyanophenyl]pyridin-3-yl]methyl]oxetan-3-yl]-2-methylpropane-2-sulfinamide 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]oxetan-3-yl]-2-methylpropane-2-sulfinamide (30.3 mg, 0.100 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (7.3 mg, 0.010 mmol), potassium carbonate (41.5 mg, 0.300 mmol), and water (0.2 mL) were added, followed by stirring overnight at 100°C. The reaction solution was cooled to room temperature and filtered through Celite, after which the solution was concentrated under reduced pressure. The crude product after concentration was used as is in the next reaction.

[0390] Step 5: 4-[5-[(3-aminooxetan-3-yl)methyl]pyridin-2-yl]-3-[6-(7-azabicyclo[2.2.1]heptan-7-yl)-2-methylpyrimidin-4-yl]oxybenzonitrile. The crude product obtained in Step 4 was dissolved in methanol (1 mL), and 4 M hydrochloric acid / 1.4-dioxane solution (0.15 mL) was added at 0°C, followed by stirring at the same temperature for 2 hours. Saturated aqueous sodium bicarbonate (5 mL) was added to the reaction solution, and the mixture 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 obtain the target compound (8.2 mg). Exact MS: 468.2 Obs. MS (M+H) + :469.2

[0391] [Example 21] 4-[5-(2-aminoethyl)pyridin-2-yl]-3-[[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]oxy]benzonitrile (Compound No. 712)

[0392] Step 1: 4-Bromo-3-[(4-methoxyphenyl)methoxy]benzonitrile 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 mixture, and the mixture was stirred. The precipitated solid was collected by filtration using a glass filter. This was dried under vacuum to obtain the target compound (8.04 g, 84%). 1 H-NMR (CDCl3)δ:7.65 (1H, d, J = 7.8 Hz), 7.37 (2H, d, J = 8.7 Hz), 7.13 (2H, dd, J = 9.8, 1.1 Hz), 6.93 (2H, d, J = 8.2 Hz), 5.11 (2H, s), 3.83 (3H, s).

[0393] Step 2: 3-[(4-methoxyphenyl)methoxy]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile 4-Bromo-3-[(4-methoxyphenyl)methoxy]benzonitrile (1.0 g, 3.14 mmol) was dissolved in 1,4-dioxane (16 mL), and bis(pinacolato)diboron (1.20 g, 4.71 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (115 mg, 0.157 mmol), and potassium acetate (617 mg, 6.29 mmol) were added, followed by stirring at 100°C for 2 hours. The reaction solution was cooled to room temperature, filtered through Celite, and then concentrated under reduced pressure. The crude product after concentration was used directly in the next reaction. MS: m / z 433.2 (M+H) + .

[0394] Step 3: tert-Butyl N-[2-[6-[4-cyano-2-[(4-methoxyphenyl)methoxy]phenyl]pyridin-3-yl]ethyl]carbamate To a solution of the crude product obtained in Step 2 in 1,4-dioxane (6 mL), tert-butyl N-[2-(6-chloropyridin-3-yl)ethyl]carbamate (807 mg, 3.14 mmol), [1,1'-bis(diphenylphosphino)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 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 (1.17 g, 81%). MS: m / z 460.2 (M+H) + .

[0395] Step 4: 4-[5-(2-aminoethyl)pyridin-2-yl]-3-hydroxybenzonitrile tert-butyl N-[2-[6-[4-cyano-2-[(4-methoxyphenyl)methoxy]phenyl]pyridin-3-yl]ethyl]carbamate (1.05 g, 1.60 mmol) was dissolved in dichloromethane (10 mL), TFA (2 mL) was added, and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and the crude product after concentration was used as is in the next reaction.

[0396] Step 5: tert-Butyl N-[2-[6-(4-cyano-2-hydroxyphenyl)pyridin-3-yl]ethyl]carbamate 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, followed by stirring 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 obtain the target compound (526 mg, 97%). MS: m / z 340.1 (M+H) + .

[0397] Step 6: tert-Butyl N-[2-[6-[4-cyano-2-[[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]oxy]phenyl]pyridin-3-yl]ethyl]carbamate tert-Butyl N-[2-[6-(4-cyano-2-hydroxyphenyl)pyridin-3-yl]ethyl]carbamate (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, followed by stirring 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 obtained crude product was used as is in the next reaction. MS: m / z 492.1 (M+H) + .

[0398] Step 7: 4-[5-(2-aminoethyl)pyridin-2-yl]-3-[[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]oxy]benzonitrile The crude product obtained in Step 6 was dissolved in dichloromethane (1 mL), TFA (0.5 mL) was added, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by HPLC to obtain the target compound (35.9 mg). Exact MS: 391.1 Obs. MS (M+H) + :392.2

[0399] [Example 22] 4-[5-(aminomethyl)pyrimidin-2-yl]-3-[2-methyl-5-(trifluoromethyl)pyrazol-3-yl]oxybenzonitrile (Compound No. 811)

[0400] Step 1: 3-[2-methyl-5-(trifluoromethyl)pyrazol-3-yl]oxy-4-nitrobenzonitrile 3-Fluoro-4-nitrobenzonitrile (664 mg, 4.00 mmol) and 2-methyl-5-(trifluoromethyl)-4H-pyrazol-3-one (731 mg, 4.40 mmol) were dissolved in DMF (6 mL), potassium carbonate (663 mg, 4.80 mmol) was added, and the mixture was stirred at room temperature 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 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). MS: m / z 313.1 (M+H) + .

[0401] Step 2: 4-amino-3-[2-methyl-5-(trifluoromethyl)pyrazol-3-yl]oxybenzonitrile. To 3-[2-methyl-5-(trifluoromethyl)pyrazol-3-yl]oxy-4-nitrobenzonitrile (417 mg, 1.34 mmol), 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, and the mixture was stirred at 70°C for 1.5 hours. The reaction mixture was cooled to room temperature and filtered through Celite. The mother liquor was then 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 crude product after concentration was used directly in the next reaction. MS: m / z 283.1 (M+H) + .

[0402] Step 3: 4-Bromo-3-[2-methyl-5-(trifluoromethyl)pyrazol-3-yl]oxybenzonitrile. 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, followed by stirring at 65°C for 16 hours. The reaction mixture was cooled to room temperature, 20% hydrochloric acid 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 (389 mg). MS: m / z 346.0 (M+H) + .

[0403] Step 4: 3-[2-methyl-5-(trifluoromethyl)pyrazol-3-yl]oxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile 4-Bromo-3-[2-methyl-5-(trifluoromethyl)pyrazol-3-yl]oxybenzonitrile (389 mg, 1.12 mmol) was dissolved in 1,4-dioxane (5.6 mL), and bis(pinacolato)diboron (428 mg, 1.68 mmol), bis(triphenylphosphine)palladium dichloride (78.8 mg, 0.112 mmol), and potassium acetate (220 mg, 2.25 mmol) were added, followed by stirring at 110°C for 1 hour. The reaction mixture was cooled to room temperature and used directly in the next reaction. MS: m / z 394.2 (M+H) + .

[0404] Step 5: tert-butyl N-[[2-[4-cyano-2-[2-methyl-5-(trifluoromethyl)pyrazol-3-yl]oxyphenyl]pyrimidin-5-yl]methyl]-N-[(2-methylpropan-2-yl)oxycarbonyl]carbamate To a portion (1.2 mL) of the reaction solution obtained in Step 4, tert-butyl N-[(2-chloropyrimidin-5-yl)methyl]-N-[(2-methylpropan-2-yl)oxycarbonyl]carbamate (107 mg, 0.31 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (21 mg, 0.028 mmol), potassium carbonate (120 mg, 0.840 mmol), and water (0.3 mL) were added, 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 concentrated under reduced pressure. The crude product was used directly in the next reaction.

[0405] Step 6: 4-[5-(aminomethyl)pyrimidin-2-yl]-3-[2-methyl-5-(trifluoromethyl)pyrazol-3-yl]oxybenzonitrile. 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 mixture was concentrated under reduced pressure, and the crude product was purified by HPLC to obtain the target compound (88.7 mg). Exact MS: 374.1 Obs. MS (M+H) + :375.3

[0406] [Example 23] 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[5-[2,2-difluoroethyl(ethyl)amino]-2-methylpyrazol-3-yl]oxybenzonitrile (Compound No. 875)

[0407] Step 1: 3-(5-amino-2-methylpyrazol-3-yl)oxy-4-bromobenzonitrile 4-Bromo-3-fluorobenzonitrile (3.0 g, 15 mmol) and 5-amino-2-methyl-4H-pyrazol-3-one (1.7 g, 15 mmol) were dissolved in DMA (40 mL), potassium carbonate (4.14 g, 30.0 mmol) was added, and the mixture was stirred at 120°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 obtain the target compound (444 mg, 10%). MS: m / z 292.9 (M+H) + . 1 H-NMR (CDCl3)δ:7.76 (1H, d, J = 8.2 Hz), 7.36 (1H, d, J = 1.8 Hz), 7.32 (1H, dd, J = 8.0, 1.6 Hz), 5.11 (1H, s), 3.63 (2H, br s), 3.57 (3H, s).

[0408] Step 2: 4-Bromo-3-[5-(2,2-difluoroethylamino)-2-methylpyrazol-3-yl]oxybenzonitrile 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, followed by stirring at 140°C overnight. 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 (1.10 g, 62%). MS: m / z 359.0 (M+H) + .

[0409] Step 3: 4-Bromo-3-[5-[2,2-difluoroethyl(ethyl)amino]-2-methylpyrazol-3-yl]oxybenzonitrile 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, followed by stirring at 120°C overnight. 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 (766 mg, 64%). MS: m / z 385.0 (M+H) + .

[0410] Step 4: 3-[5-[2,2-difluoroethyl(ethyl)amino]-2-methylpyrazol-3-yl]oxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile 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), bis(pinacolato)diboron (758 mg, 2.98 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (72.8 mg, 0.0995 mmol), and potassium acetate (391 mg, 3.98 mmol) were added, and the mixture was stirred at 100°C for 2 hours. The reaction solution was cooled to room temperature and filtered through Celite, and then the solution was concentrated under reduced pressure. The crude product was used directly in the next reaction. MS: m / z 433.2 (M+H) + .

[0411] Step 5: tert-butyl N-[2-[2-[4-cyano-2-[5-[2,2-difluoroethyl(ethyl)amino]-2-methylpyrazol-3-yl]oxyphenyl]pyrimidin-5-yl]ethyl]carbamate The crude product obtained in Step 4 was dissolved in 1,4-dioxane (10 mL), and tert-butyl N-[2-(2-chloropyrimidin-5-yl)ethyl]carbamate (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, followed by stirring 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 (648 mg, 62%). MS: m / z 528.2 (M+H) + .

[0412] Step 6: 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[5-[2,2-difluoroethyl(ethyl)amino]-2-methylpyrazol-3-yl]oxybenzonitrile tert-butyl N-[2-[2-[4-cyano-2-[5-[2,2-difluoroethyl(ethyl)amino]-2-methylpyrazol-3-yl]oxyphenyl]pyrimidin-5-yl]ethyl]carbamate (648 mg, 1.23 mmol) was dissolved in 1,4-dioxane (4 mL), and 4M hydrochloric acid / 1,4-dioxane solution (2 mL) was added dropwise at 0 ° C., and the mixture was then warmed to room temperature and stirred for 2 hours. The reaction solution was concentrated under reduced pressure, and the resulting solid was dried in vacuo to obtain the hydrochloride salt (642 mg) of the target compound. Exact MS: 427.2 Obs. MS (M + H) + :428.3

[0413] [Example 24] 4-[5-(aminomethyl)pyrimidin-2-yl]-3-(2-methyl-5-pyrazin-2-ylpyrazol-3-yl)oxybenzonitrile (Compound No. 931)

[0414] Step 1: 3-(5-amino-2-methylpyrazol-3-yl)oxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile 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(pinacolato)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, followed by stirring at 110°C for 2 hours. The reaction solution was cooled to room temperature and filtered through Celite, and the filtrate was concentrated under reduced pressure. The crude product after concentration was used as is in the next reaction.

[0415] Step 2: tert-butyl N-[[2-[2-(5-amino-2-methylpyrazol-3-yl)oxy-4-cyanophenyl]pyrimidin-5-yl]methyl]-N-[(2-methylpropan-2-yl)oxycarbonyl]carbamate To a solution of the crude product obtained in Step 1 in 1,4-dioxane (15 mL), tert-butyl N-[(2-chloropyrimidin-5-yl)methyl]-N-[(2-methylpropan-2-yl)oxycarbonyl]carbamate (1.03 g, 3.00 mmol), [1,1'-bis(diphenylphosphino)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 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 (1.48 g, containing impurities). MS: m / z 522.3 (M+H) + .

[0416] Step 3: tert-Butyl N-[[2-[2-(5-bromo-2-methylpyrazol-3-yl)oxy-4-cyanophenyl]pyrimidin-5-yl]methyl]-N-[(2-methylpropan-2-yl)oxycarbonyl]carbamate tert-Butyl N-[[2-[2-(5-amino-2-methylpyrazol-3-yl)oxy-4-cyanophenyl]pyrimidin-5-yl]methyl]-N-[(2-methylpropan-2-yl)oxycarbonyl]carbamate (1.48 g, 2.83 mmol) was dissolved in acetonitrile (28 mL), and isoamyl nitrite (488 mg, 4.17 mmol) and copper(I) bromide (476 mg, 3.32 mmol) were added, followed by stirring at room temperature overnight. Water was added to the reaction mixture, which 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 obtain the target compound (289 mg). MS: m / z 585.2 (M+H). + .

[0417] Step 4: tert-butyl N-[[2-[4-cyano-2-[2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-3-yl]oxyphenyl]pyrimidin-5-yl]methyl]-N-[(2-methylpropan-2-yl)oxycarbonyl]carbamate tert-butyl N-[[2-[2-(5-bromo-2-methylpyrazol-3-yl)oxy-4-cyanophenyl]pyrimidin-5-yl]methyl]-N-[(2-methylpropan-2-yl)oxycarbonyl]carbamate (40 mg, 0.068 mmol) was dissolved in 1,4-dioxane (0.2 mL), and bis(pinacolato)diboron (26.0 mg, 0.102 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (5.0 mg, 6.8 μmol), and potassium acetate (20.1 mg, 0.205 mmol) were added, followed by stirring at 110°C for 2 hours. The reaction solution was cooled to room temperature, filtered through Celite, and then concentrated under reduced pressure. The resulting crude product was used directly in the next reaction.

[0418] Step 5: tert-butyl N-[[2-[4-cyano-2-(2-methyl-5-pyrazin-2-ylpyrazol-3-yl)oxyphenyl]pyrimidin-5-yl]methyl]-N-[(2-methylpropan-2-yl)oxycarbonyl]carbamate. 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(diphenylphosphino)ferrocene]palladium dichloride (2.8 mg, 3.8 μmol), potassium carbonate (16 mg, 0.11 mmol), and water (0.038 mL) were added, followed by stirring 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 as is in the next reaction.

[0419] Step 6: 4-[5-(aminomethyl)pyrimidin-2-yl]-3-(2-methyl-5-pyrazin-2-ylpyrazol-3-yl)oxybenzonitrile. TFA (0.5 mL) was added to the crude product obtained in Step 5, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by HPLC to obtain the target compound (5.25 mg). Exact MS: 384.1 Obs. MS (M+H) + :385.2

[0420] [Example 25] 2-[2-[4-fluoro-2-[3-methyl-1-(2-methylpropyl)pyrazol-4-yl]oxyphenyl]pyrimidin-5-yl]ethanamine (Compound Number 966) (target compound) and 2-[2-[4-fluoro-2-[5-methyl-1-(2-methylpropyl)pyrazol-4-yl]oxyphenyl]pyrimidin-5-yl]ethanamine (Compound Number 967) (regioisomer)

[0421] Step 1: 1-(2-bromo-5-fluorophenoxy)propan-2-one 2-Bromo-5-fluorophenol (2.29 g, 12.0 mmol) and 1-bromopropan-2-one (1.97 g, 14.4 mmol) were dissolved in DMF (20 mL), potassium carbonate (3.32 g, 24.0 mmol) was added, and the mixture was heated and stirred at 100°C. After completion of the reaction, 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 (2.51 g, 85%).

[0422] Step 2: 3-(2-bromo-5-fluorophenoxy)-4-(dimethylamino)but-3-en-2-one. N,N-Dimethylformamide dimethyl acetal (1.58 g, 13.2 mmol) was added to 1-(2-bromo-5-fluorophenoxy)propan-2-one (2.73 g, 11.0 mmol), and the mixture was stirred at 80°C overnight. After the reaction mixture was cooled 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. 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 aqueous sodium bicarbonate and 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 (2.41 g, 81%). MS: m / z 271.0 (M+H) + .

[0423] Step 3: 4-(2-Bromo-5-fluorophenoxy)-3-methyl-1-(2-methylpropyl)pyrazole 4-(2-Bromo-5-fluorophenoxy)-3-methyl-1H-pyrazole (270 mg, 1.0 mmol) was added with DMSO (2 mL), 1-bromo-2-methylpropane (160 mg, 1.2 mmol), and potassium carbonate (280 mg, 2.0 mmol), and the mixture was stirred at 100°C for 5 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 obtain a mixture of the target compound and its regioisomer (185 mg). The regioisomers were separated by HPLC purification after the final step. MS: m / z 327.1 (M+H) + . 1 H-NMR (DMSO-d6)δ:7.80 (1H, s), 7.72 (1H, dd, J = 9.2, 2.8 Hz), 6.93-6.88 (1H, m), 6.60 (1H, dd, J = 10.4, 2.8 Hz), 3.81 (1H, d, J = 7.2 Hz), 2.14-2.07 (1H, m), 1.98 (3H, s), 0.85 (6H, d, J = 6.8 Hz).

[0424] Step 4: 4-[5-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]-3-methyl-1-(2-methylpropyl)pyrazole The isomer mixture obtained in Step 3 (185 mg, 0.565 mmol) was dissolved in 1,4-dioxane (1.1 mL), and bis(pinacolato)diboron (215 mg, 0.848 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (20.7 mg, 0.0283 mmol), and potassium acetate (111 mg, 1.13 mmol) were added, followed by stirring at 100°C for 2 hours. The reaction solution was cooled to room temperature, filtered through Celite, and then concentrated under reduced pressure. The crude product was used as is in the next reaction.

[0425] Step 5: tert-butyl N-[2-[2-[4-fluoro-2-[3-methyl-1-(2-methylpropyl)pyrazol-4-yl]oxyphenyl]pyrimidin-5-yl]ethyl]carbamate A portion (106 mg) of the crude product obtained in Step 4 was dissolved in 1,4-dioxane (1 mL), and tert-butyl N-[2-(2-chloropyrimidin-5-yl)ethyl]carbamate (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, followed by stirring 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.

[0426] Step 6: 2-[2-[4-fluoro-2-[3-methyl-1-(2-methylpropyl)pyrazol-4-yl]oxyphenyl]pyrimidin-5-yl]ethanamine (target compound) and 2-[2-[4-fluoro-2-[5-methyl-1-(2-methylpropyl)pyrazol-4-yl]oxyphenyl]pyrimidin-5-yl]ethanamine (regioisomer). The crude product obtained in Step 5 was dissolved in dichloromethane (1 mL), TFA (0.5 mL) was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by HPLC to obtain the target compound (11.82 mg) and its regioisomer (10.77 mg). Exact MS: 369.2 Obs. MS (M+H) + : 370.4 (compound number 966), 370.3 (compound number 967)

[0427] [Example 26] 4-[5-(aminomethyl)pyrimidin-2-yl]-3-(2-methyl-5-morpholin-4-ylpyrazole-3-carbonyl)benzonitrile (Compound No. 1028)

[0428] Step 1: 4-chloro-3-[hydroxy-(2-methyl-5-nitropyrazol-3-yl)methyl]benzonitrile 3-Bromo-4-chlorobenzonitrile (5.69 g, 26.3 mmol) was dissolved in THF (50 mL), and isopropylmagnesium chloride lithium chloride complex (14% THF solution, 20 mL, 26.27 mmol) was added dropwise at 0°C, followed by stirring at the same temperature for 30 minutes. To this reaction solution, a THF solution (5 mL) of 2-methyl-5-nitropyrazole-3-carbaldehyde (3.13 g, 20.2 mmol) was added dropwise, and the mixture was then warmed to room temperature and stirred for 1 hour. 1 M hydrochloric acid was added to the reaction solution, followed by stirring, and then extraction 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 (4.85 g, 82%). MS: m / z 293.1 (M+H) + . 1H-NMR (CDCl3)δ: 8.06 (1H, s), 7.67 (1H, dd, J = 8.2, 1.8 Hz), 7.56 (1H, d, J = 8.2 Hz), 6.39 (1H, s), 6.23 (1H, s), 4.10 (3H, s), 2.97 (1H, s).

[0429] Step 2: 4-chloro-3-(2-methyl-5-nitropyrazole-3-carbonyl)benzonitrile. Dess-Martin reagent (7.73 g, 18.2 mmol) was added to a dichloromethane solution (83 mL) of 4-chloro-3-[hydroxy-(2-methyl-5-nitropyrazol-3-yl)methyl]benzonitrile (4.85 g, 16.6 mmol), and the mixture was stirred at room temperature for 2 hours. A saturated aqueous solution of sodium thiosulfate and a saturated aqueous solution of sodium bicarbonate were added to the reaction mixture, and the mixture was stirred, followed by extraction 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. MS: m / z 291.0 (M+H) + . 1 H-NMR (DMSO-d6)δ: 8.21 (1H, d, J = 2.3 Hz), 8.11 (1H, dd, J = 8.5, 2.1 Hz), 7.88 (1H, d, J = 8.2 Hz), 7.58 (1H, s), 4.27 (3H, s).

[0430] Step 3: 3-(5-amino-2-methylpyrazole-3-carbonyl)-4-chlorobenzonitrile. The crude product obtained in Step 2 was suspended in a 1:1 mixed solvent 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, followed by stirring at 80°C for 2 hours. The reaction mixture was cooled to room temperature and filtered through Celite. Most of the ethanol was then distilled off under reduced pressure. Ethyl acetate was added to the residue for extraction, and 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%). MS: m / z 261.1 (M+H) + . 1H-NMR (CDCl3)δ:7.72-7.70 (2H, m), 7.60 (1H, d, J = 9.1 Hz), 5.67 (1H, s), 4.11 (3H, s), 3.73 (2H, br s).

[0431] Step 4: 4-chloro-3-(2-methyl-5-morpholin-4-ylpyrazole-3-carbonyl)benzonitrile 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, followed by stirring at 110°C for 16 hours. The reaction mixture was cooled to room temperature, and then extracted with ethyl acetate and water. 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 (391 mg, 69%). MS: m / z 331.1 (M+H) + . 1 H-NMR (CDCl3)δ:7.73-7.71 (2H, m), 7.61 (1H, dd, J = 7.5, 1.6 Hz), 5.68 (1H, s), 4.15 (3H, s), 3.80 (4H, t, J = 4.8 Hz), 3.14 (4H, t, J = 4.8 Hz).

[0432] Step 5: 3-(2-methyl-5-morpholin-4-ylpyrazole-3-carbonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile 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(pinacolato)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, followed by stirring at 110°C for 2 hours. The reaction solution was cooled to room temperature and filtered through Celite, and then the solution was concentrated under reduced pressure. The crude product was used as is in the next reaction. MS: m / z 423.2 (M+H) + .

[0433] Step 6: tert-butyl N-[[2-[4-cyano-2-(2-methyl-5-morpholin-4-ylpyrazole-3-carbonyl)phenyl]pyrimidin-5-yl]methyl]-N-[(2-methylpropan-2-yl)oxycarbonyl]carbamate A portion (166 mg) of the crude product obtained in Step 5 was dissolved in 1,4-dioxane (1 mL), and tert-butyl N-[(2-chloropyrimidin-5-yl)methyl]-N-[(2-methylpropan-2-yl)oxycarbonyl]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, followed by stirring at 100° C. for 1 hour. The reaction mixture was cooled to room temperature, filtered through Celite, and then concentrated under reduced pressure. The crude product was used directly in the next reaction. MS: m / z 604.3 (M+H) + . 1H-NMR (CDCl3)δ:8.70 (2H, s), 8.51 (1H, d, J = 8.2 Hz), 7.90 (1H, d, J = 8.2 Hz), 7.79 (1H, s), 5.38 (1H, S), 4.73 (2H, s), 4.14 (3H, s), 3.72 (4H, t, J = 4.8 Hz), 3.00 (4H, t, J = 4.8 Hz), 1.48 (18H, s).

[0434] Step 7: 4-[5-(aminomethyl)pyrimidin-2-yl]-3-(2-methyl-5-morpholin-4-ylpyrazole-3-carbonyl)benzonitrile. Dichloromethane (1 mL) and TFA (0.5 mL) were added to the crude product obtained in Step 6, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by HPLC to obtain the target compound (34.2 mg). Exact MS: 403.2 Obs. MS (M+H) + :404.3 1 H-NMR (DMSO-d6)δ:8.93 (2H, s), 8.49 (1H, d, J = 7.8 Hz), 8.32 (3H, br s), 8.18 (1H, dd, J = 8.2, 1.8 Hz), 8.10 (1H, d, J = 1.8 H), 5.72 (1H, S), 4.10 (2H, d, J = 5.9 Hz), 4.02 (3H, S), 3.57 (4H, t, J = 4.8 Hz), 2.92 (4H, t, J = 4.6 Hz).

[0435] [Example 27] 4-[5-(aminomethyl)pyrimidin-2-yl]-3-(5-tert-butyl-2-methylpyrazole-3-carbonyl)benzonitrile (Compound No. 1030)

[0436] Step 1: 3-[(5-tert-butyl-2-methylpyrazol-3-yl)-hydroxymethyl]-4-chlorobenzonitrile 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, followed by stirring at the same temperature for 15 minutes. To this reaction solution, a THF solution (5 mL) of 5-tert-butyl-2-methylpyrazole-3-carbaldehyde (2.52 g, 15.2 mmol) was added dropwise, and the mixture was then warmed to room temperature and stirred for 1.5 hours. 1 M hydrochloric acid was added to the reaction solution, followed by stirring, and then extraction 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 crude product and stirred, and the precipitated solid was collected by filtration using a glass filter. This was dried in vacuo to give the target compound (2.22 g, 48%). MS: m / z 304.2 (M+H) + . 1 H-NMR (CDCl3) δ:8.02 ((1H, d, J = 1.8 Hz), 7.60 (1H, dd, J = 8.2, 1.8 Hz), 7.49 (1H, d, J = 8.2 Hz), 6.15 (1H, d, J = 5.0 Hz), 5.62 (1H, s), 3.90 (3H, s), 2.49 (1H, d, J = 5.0 Hz), 1.23 (9H, s).

[0437] Step 2: 3-(5-tert-butyl-2-methylpyrazole-3-carbonyl)-4-chlorobenzonitrile. To a dichloromethane solution (16 mL) of 3-[(5-tert-butyl-2-methylpyrazol-3-yl)-hydroxymethyl]-4-chlorobenzonitrile (500 mg, 1.65 mmol), Dess-Martin reagent (768 mg, 1.81 mmol) was added and stirred at room temperature for 1.5 hours. Saturated aqueous sodium thiosulfate and saturated aqueous sodium bicarbonate were added to the reaction mixture, followed by stirring, and then extraction 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 (440 mg, 89%). MS: m / z 302.1 (M+H)+ .

[0438] Step 3: 3-(5-tert-butyl-2-methylpyrazole-3-carbonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile 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(pinacolato)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, followed by stirring at 110°C for 3 hours. The reaction mixture was cooled to room temperature and filtered through Celite, and then the solution was concentrated under reduced pressure. The crude product was used directly in the next reaction. MS: m / z 394.3 (M+H) + .

[0439] Step 4: tert-butyl N-[[2-[2-(5-tert-butyl-2-methylpyrazole-3-carbonyl)-4-cyanophenyl]pyrimidin-5-yl]methyl]-N-[(2-methylpropan-2-yl)oxycarbonyl]carbamate A portion (115 mg) of the crude product obtained in Step 3 was dissolved in 1,4-dioxane (1 mL), and tert-butyl N-[(2-chloropyrimidin-5-yl)methyl]-N-[(2-methylpropan-2-yl)oxycarbonyl]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, followed by stirring at 100° C. for 1 hour. The reaction mixture was cooled to room temperature, filtered through Celite, and then concentrated under reduced pressure. The crude product was used directly in the next reaction. MS: m / z 575.4 (M+H) + .

[0440] Step 5: 4-[5-(aminomethyl)pyrimidin-2-yl]-3-(5-tert-butyl-2-methylpyrazole-3-carbonyl)benzonitrile Dichloromethane (1 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 30 minutes. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by HPLC to obtain the target compound (9.7 mg). Exact MS: 374.2 Obs. MS (M+H) + :375.4

[0441] [Example 28] 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-(2-methyl-6-morpholin-4-ylpyridine-4-carbonyl)benzonitrile (Compound No. 1042)

[0442] Step 1: N-Methoxy-N,2-dimethyl-6-morpholin-4-ylpyridine-4-carboxamide 2-Methyl-6-morpholin-4-ylpyridine-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, followed by stirring at room temperature for 1 hour. Water was added to the reaction solution, which was then 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 obtain the target compound (174 mg, 62%). MS: m / z 266.1 (M+H) + .

[0443] Step 2: 4-chloro-3-(2-methyl-6-morpholin-4-ylpyridine-4-carbonyl)benzonitrile 3-Bromo-4-chlorobenzonitrile (284 g, 1.31 mmol) was dissolved in THF (3.3 mL), and isopropylmagnesium chloride lithium chloride complex (14% THF solution, 1.0 mL, 1.31 mmol) was added dropwise at 0°C, followed by stirring at the same temperature for 30 minutes. To this reaction solution, a THF solution (1 mL) of N-methoxy-N,2-dimethyl-6-morpholin-4-ylpyridine-4-carboxamide (174 mg, 0.656 mmol) was added dropwise, and the mixture was then warmed to room temperature and stirred for 1.5 hours. A saturated aqueous ammonium chloride solution was added to the reaction solution, followed by stirring, and then extraction 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 (67.1 mg, 30%). MS: m / z 342.1 (M+H) + .

[0444] Step 3: 3-(2-methyl-6-morpholin-4-ylpyridine-4-carbonyl)-4-trimethylstannylbenzonitrile 4-Chloro-3-(2-methyl-6-morpholin-4-ylpyridine-4-carbonyl)benzonitrile (67.1 mg, 0.196 mmol) was dissolved in 1,4-dioxane (1 mL), hexamethylditin (96.5 mg, 0.294 mmol) and tetrakis(triphenylphosphine)palladium (22.7 mg, 0.0196 mmol) were added, and the mixture was stirred at 110°C for 3 hours. The reaction mixture was cooled to room temperature and filtered through Celite. The solution was then concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the target compound (21.3 mg, 23%). MS: m / z 472.1 (M+H) + .

[0445] Step 4: tert-butyl N-[2-[2-[4-cyano-2-(2-methyl-6-morpholin-4-ylpyridine-4-carbonyl)phenyl]pyrimidin-5-yl]ethyl]carbamate 3-(2-methyl-6-morpholin-4-ylpyridine-4-carbonyl)-4-trimethylstannylbenzonitrile (21.3 mg, 0.0453 mmol) was dissolved in 1,4-dioxane (1 mL), and tert-butyl N-[2-(2-chloropyrimidin-5-yl)ethyl]carbamate (30.0 mg, 0.116 mmol), tetrakis(triphenylphosphine)palladium (5.2 mg, 4.53 μmol), and copper(I) iodide (1.7 mg, 9.06 μmol) were added, followed by stirring at 110° C. for 2 hours. The reaction mixture was cooled to room temperature, filtered through Celite, and then concentrated under reduced pressure. The crude product was used directly in the next reaction. MS: m / z 529.3 (M+H) + .

[0446] Step 5: 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-(2-methyl-6-morpholin-4-ylpyridine-4-carbonyl)benzonitrile. Dichloromethane (1.0 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 30 minutes. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by HPLC to obtain the target compound (5.0 mg, 26%). Exact MS: 428.2 Obs. MS((M+H) + :429.3

[0447] [Example 29] 4-[5-(aminomethyl)pyrimidin-2-yl]-3-(4-methyl-2-morpholin-4-yl-1,3-thiazole-5-carbonyl)benzonitrile (Compound No. 1064)

[0448] Step 1: 4-chloro-3-[hydroxy-(4-methyl-2-morpholin-4-yl-1,3-thiazol-5-yl)methyl]benzonitrile. 4-(4-methyl-1,3-thiazol-2-yl)morpholine (1.25 g, 6.78 mmol) was dissolved in THF (34 mL) and cooled to -78°C. To this solution, n-butyllithium hexane solution (2.76 M, 2.7 mL, 7.46 mmol) was added dropwise and stirred at the same temperature for 30 minutes. 4-Chloro-3-formylbenzonitrile (1.24 g, 7.46 mmol) was added to this reaction solution and stirred at -78°C for 1 hour. The mixture was then warmed to room temperature, saturated aqueous ammonium chloride solution was added, and the mixture was stirred. Then, 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 (1.30 g, 55%). MS: m / z 350.0 (M+H) + .

[0449] Step 2: 4-chloro-3-(4-methyl-2-morpholin-4-yl-1,3-thiazole-5-carbonyl)benzonitrile 4-Chloro-3-[hydroxy-(4-methyl-2-morpholin-4-yl-1,3-thiazol-5-yl)methyl]benzonitrile (500 mg, 1.43 mmol) was dissolved in THF (15 mL), and 2-iodoxybenzoic acid (801 mg, 2.86 mmol) was added, followed by stirring at 50°C for 2 hours. The reaction mixture was cooled to room temperature, saturated aqueous sodium thiosulfate solution was added, 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 then purified by silica gel column chromatography to obtain the target compound (310 mg, 62%). MS: m / z 348.0 (M+H) + .

[0450] Step 3: 3-(4-methyl-2-morpholin-4-yl-1,3-thiazole-5-carbonyl)-4-trimethylstannylbenzonitrile 4-Chloro-3-(4-methyl-2-morpholin-4-yl-1,3-thiazole-5-carbonyl)benzonitrile (170 mg, 0.489 mmol) was dissolved in 1,4-dioxane (1.2 mL), hexamethylditin (240 mg, 0.733 mmol) and tetrakis(triphenylphosphine)palladium (56.5 mg, 0.0489 mmol) were added, and the mixture was stirred at 110°C for 4 hours. The reaction mixture was cooled to room temperature and directly purified by silica gel column chromatography to obtain the target compound (138 mg, 59%). MS: m / z 478.0 (M+H) + .

[0451] Step 4: tert-butyl N-[[2-[4-cyano-2-(4-methyl-2-morpholin-4-yl-1,3-thiazole-5-carbonyl)phenyl]pyrimidin-5-yl]methyl]-N-[(2-methylpropan-2-yl)oxycarbonyl]carbamate 3-(4-methyl-2-morpholin-4-yl-1,3-thiazole-5-carbonyl)-4-trimethylstannylbenzonitrile (46.0 mg, 0.0966 mmol) was dissolved in 1,4-dioxane (1 mL), and tert-butyl N-[(2-chloropyrimidin-5-yl)methyl]-N-[(2-methylpropan-2-yl)oxycarbonyl]carbamate (66.0 mg, 0.193 mmol), tetrakis(triphenylphosphine)palladium (11.2 mg, 9.66 μmol), and copper(I) iodide (3.68 mg, 0.0193 mmol) were added, and the mixture was stirred for 16 hours at 110° C. The reaction solution was concentrated under reduced pressure, and the crude product was used directly in the next reaction.

[0452] Step 5: 4-[5-(aminomethyl)pyrimidin-2-yl]-3-(4-methyl-2-morpholin-4-yl-1,3-thiazole-5-carbonyl)benzonitrile. 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 mixture was concentrated under reduced pressure, and the crude product was purified by HPLC to obtain the target compound (10.8 mg). Exact MS: 420.1 Obs. MS (M+H) + :421.2

[0453] [Example 30] 4-[5-(2-aminoethyl)pyridin-2-yl]-3-[(4-phenylimidazol-1-yl)methyl]benzonitrile (Compound No. 1131)

[0454] Step 1: 3-[(4-phenylimidazol-1-yl)methyl]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile 3-(bromomethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (6.00 g, 18.6 mmol) was dissolved in DMF (80 mL), and 4-phenyl-1H-imidazole (2.69 g, 18.6 mmol) and potassium carbonate (5.15 g, 37.3 mmol) were added, followed by stirring at 80°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 resulting crude product was used directly in the next reaction. MS: m / z 386.2 (M+H) + .

[0455] Step 2: tert-butyl N-[2-[6-[4-cyano-2-[(4-phenylimidazol-1-yl)methyl]phenyl]pyridin-3-yl]ethyl]carbamate The crude product obtained in Step 1 was dissolved in 1,4-dioxane (80 mL), and tert-butyl N-[2-(6-chloropyridin-3-yl)ethyl]carbamate (3.87 g, 15.1 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (552 mg, 0.754 mmol), potassium carbonate (4.17 g, 30.2 mmol), and water (20 mL) were added, followed by stirring 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 mixture 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 (1.41 g, 20%). MS: m / z 480.2 (M+H) + .

[0456] Step 3: 4-[5-(2-aminoethyl)pyridin-2-yl]-3-[(4-phenylimidazol-1-yl)methyl]benzonitrile tert-butyl N-[2-[6-[4-cyano-2-[(4-phenylimidazol-1-yl)methyl]phenyl]pyridin-3-yl]ethyl]carbamate (1.19 g, 2.49 mmol) was added to 1,4-dioxane (20 mL), and 4M hydrochloric acid / dioxane solution (20 mL) was added dropwise at 0 °C. The mixture was then warmed 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 Obs. MS (M+H) + :380.3

[0457] [Example 31] 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[[2-methyl-4-(piperidin-1-ylmethyl)imidazol-1-yl]methyl]benzonitrile (Compound No. 1179)

[0458] Step 1: 3-[(4-formyl-2-methylimidazol-1-yl)methyl]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile 3-(bromomethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (354 mg, 1.10 mmol) was dissolved in acetonitrile (5 mL), and 2-methyl-1H-imidazole-4-carbaldehyde (110 mg, 1.00 mmol) and triethylamine (0.356 mL, 2.00 mmol) were added, followed by stirring 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 resulting crude product was used directly in the next reaction.

[0459] Step 2: tert-butyl N-[2-[2-[4-cyano-2-[(4-formyl-2-methylimidazol-1-yl)methyl]phenyl]pyrimidin-5-yl]ethyl]carbamate. The crude product obtained in Step 1 was dissolved in 1,4-dioxane (5 mL), and tert-butyl N-[2-(2-chloropyrimidin-5-yl)ethyl]carbamate (283 mg, 1.10 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (73.4 mg, 0.100 mmol), potassium carbonate (415 mg, 3.00 mmol), and water (1 mL) were added, followed by stirring 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 mixture 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, quant.). MS: m / z 447.3 (M+H) + .

[0460] Step 3: tert-Butyl N-[2-[2-[4-cyano-2-[[2-methyl-4-(piperidin-1-ylmethyl)imidazol-1-yl]methyl]phenyl]pyrimidin-5-yl]ethyl]carbamate tert-Butyl N-[2-[2-[4-cyano-2-[(4-formyl-2-methylimidazol-1-yl)methyl]phenyl]pyrimidin-5-yl]ethyl]carbamate (31.0 mg, 0.070 mmol) was dissolved in dichloromethane (0.7 mL), piperidine (7.2 mg, 0.084 mmol) and sodium triacetoxyborohydride (37.0 mg, 0.180 mmol) were added, and the mixture was stirred at room temperature for 5 hours. Water was added to the reaction mixture, which was then 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 crude product was used as is in the next reaction.

[0461] Step 4: 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[[2-methyl-4-(piperidin-1-ylmethyl)imidazol-1-yl]methyl]benzonitrile 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. After concentration under reduced pressure, the crude product was purified by HPLC to obtain the target compound (12.2 mg). Exact MS: 415.3 Obs. MS (M+H) + :416.4

[0462] [Example 32] 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[(4-cyclopropyltriazol-1-yl)methyl]benzonitrile (Compound No. 1187)

[0463] Step 1: 3-(azidomethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile 3-(Bromomethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-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, followed by stirring 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 obtain the target compound (2.80 g, 91%).

[0464] Step 2: 3-[(4-cyclopropyltriazol-1-yl)methyl]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile 3-(azidomethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (1.10 g, 3.87 mmol) was dissolved in DMSO (10 mL), and ethynylcyclopropane (307 mg, 4.65 mmol), copper(I) iodide (36.9 mg, 0.194 mmol), and TBTA (103 mg, 0.194 mmol) were added, followed by stirring at room temperature overnight. Water was added to the reaction solution, which was then 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 (416 mg, 31%).

[0465] Step 3: tert-butyl N-[2-[2-[4-cyano-2-[(4-cyclopropyltriazol-1-yl)methyl]phenyl]pyrimidin-5-yl]ethyl]carbamate 3-[(4-cyclopropyltriazol-1-yl)methyl]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (208 mg, 0.594 mmol) was dissolved in 1,4-dioxane (3 mL), and tert-butyl N-[2-(2-chloropyrimidin-5-yl)ethyl]carbamate (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, and the mixture was stirred at 80° C. overnight. 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 obtain the target compound (120 mg, 45%).

[0466] Step 4: 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[(4-cyclopropyltriazol-1-yl)methyl]benzonitrile tert-butyl N-[2-[2-[4-cyano-2-[(4-cyclopropyltriazol-1-yl)methyl]phenyl]pyrimidin-5-yl]ethyl]carbamate (120 mg, 0.269 mmol) was added to dichloromethane (1 mL) and TFA (0.5 mL) and stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure, and the crude product was purified by HPLC to obtain the target compound (12.8 mg). Exact MS: 345.2 Obs. MS (M+H) + :346.2

[0467] [Example 33] 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[[1-(2-methylpropyl)pyrazol-4-yl]methyl]benzonitrile (Compound No. 1195)

[0468] Step 1: 1-(2-methylpropyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-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, followed by stirring 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 sodium sulfate, and the solution was concentrated under reduced pressure. The resulting crude product was used directly in the next reaction. MS: m / z 251.2 (M+H) + .

[0469] Step 2: 4-chloro-3-[[1-(2-methylpropyl)pyrazol-4-yl]methyl]benzonitrile A portion of the crude product obtained in Step 1 (500 mg, 2.00 mmol) 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, followed by stirring at 100°C overnight. 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 (548 mg, containing impurities). MS: m / z 274.1 (M+H) + .

[0470] Step 3: 3-[[1-(2-methylpropyl)pyrazol-4-yl]methyl]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile 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(pinacolato)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, followed by stirring at 110°C for 2 hours. The reaction mixture was cooled to room temperature, filtered through Celite, and then concentrated under reduced pressure. The crude product was used directly in the next reaction. MS: m / z 366.3 (M+H) + .

[0471] Step 4: tert-butyl N-[2-[2-[4-cyano-2-[[1-(2-methylpropyl)pyrazol-4-yl]methyl]phenyl]pyrimidin-5-yl]ethyl]carbamate A portion (37 mg) of the crude product obtained in Step 3 was dissolved in 1,4-dioxane (0.5 mL), and tert-butyl N-[2-(2-chloropyrimidin-5-yl)ethyl]carbamate (25.8 mg, 0.100 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (7.3 mg, 0.01 mmol), potassium carbonate (41.0 mg, 0.300 mmol), and water (0.1 mL) were added, followed by stirring 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. After drying over anhydrous sodium sulfate, the solution was concentrated under reduced pressure and the crude product was used directly in the next reaction.

[0472] Step 5: 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[[1-(2-methylpropyl)pyrazol-4-yl]methyl]benzonitrile. TFA (0.5 mL) was added to the crude product obtained in Step 4, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by HPLC to obtain the target compound (26.0 mg). Exact MS: 360.2 Obs. MS (M+H) + :361.0

[0473] [Example 34] 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[(4-pyrrolidin-1-ylpyrazol-1-yl)methyl]benzonitrile (Compound No. 1198)

[0474] Step 1: 3-[(4-nitropyrazol-1-yl)methyl]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile. 3-(Bromomethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (230 mg, 0.700 mmol) was dissolved in DMF (0.7 mL), and 4-nitro-1H-pyrazole (95 mg, 0.84 mmol) and potassium carbonate (190 mg, 1.40 mmol) were added. The mixture was stirred at room temperature for 2 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 sodium sulfate, and the solvent was evaporated under reduced pressure. The crude product was used directly in the next reaction. MS: m / z 355.2 (M+H) + .

[0475] Step 2: tert-butyl N-[2-[2-[4-cyano-2-[(4-nitropyrazol-1-yl)methyl]phenyl]pyrimidin-5-yl]ethyl]carbamate The crude product obtained in Step 1 was dissolved in 1,4-dioxane (3.5 mL), and tert-butyl N-[2-(2-chloropyrimidin-5-yl)ethyl]carbamate (180 mg, 0.700 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (51.2 mg, 0.0700 mmol), potassium carbonate (290 mg, 2.10 mmol), and water (0.7 mL) were added, followed by stirring 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 mixture 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 (310 mg, 99%). MS: m / z 450.2 (M+H) + .

[0476] Step 3: tert-Butyl N-[2-[2-[2-[(4-aminopyrazol-1-yl)methyl]-4-cyanophenyl]pyrimidin-5-yl]ethyl]carbamate. tert-Butyl N-[2-[2-[4-cyano-2-[(4-nitropyrazol-1-yl)methyl]phenyl]pyrimidin-5-yl]ethyl]carbamate (310 mg, 0.690 mmol) was dissolved in methanol (0.7 mL), and palladium-activated carbon ethylenediamine complex (50 mg) was added. A hydrogen gas balloon was attached to the reaction vessel, and the atmosphere in the vessel was replaced with hydrogen gas. The mixture was then stirred overnight at room temperature. The reaction vessel was filtered through Celite, and the solution was concentrated under reduced pressure. The crude product was used directly in the next reaction. MS: m / z 420.3 (M+H) + .

[0477] Step 4: tert-Butyl N-[2-[2-[4-cyano-2-[(4-pyrrolidin-1-ylpyrazol-1-yl)methyl]phenyl]pyrimidin-5-yl]ethyl]carbamate. A portion (45.2 mg) of the crude product obtained in Step 3 was dissolved in DMA (0.5 mL), and 1,4-dibromobutane (25.6 mg, 0.119 mmol) and N,N-diisopropylethylamine (0.054 mL, 0.323 mmol) were added, followed by stirring at 110°C overnight. 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 used directly in the next reaction. MS: m / z 474.3 (M+H) + .

[0478] Step 5: 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[(4-pyrrolidin-1-ylpyrazol-1-yl)methyl]benzonitrile. TFA (0.5 mL) was added to the crude product obtained in Step 4, and the mixture was stirred at room temperature for 1 hour. After concentration under reduced pressure, the crude product was purified by HPLC to obtain the target compound (7.4 mg). Exact MS: 373.2 Obs. MS (M+H) + :374.2

[0479] [Example 35] 4-[4-(2-aminoethyl)phenyl]-3-[1-(2-methyl-6-morpholin-4-ylpyrimidin-4-yl)ethyl]benzonitrile (Compound No. 1226)

[0480] Step 1: tert-butyl (2-(2'-acetyl-4'-cyano-[1,1'-biphenyl]-4-yl)ethyl)carbamate To a solution (5 mL) of 2-acetyl-4-cyanophenyl trifluoromethanesulfonate (250 mg, 0.85 mmol) in a toluene / water = 4 / 1 mixture, tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)phenethylcarbamate (355 mg, 1.02 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (62.4 mg, 0.085 mmol), and potassium carbonate (354 mg, 2.56 mmol) were added, and the mixture was stirred at 110°C for 30 minutes. The reaction solution was cooled to room temperature, and water and ethyl acetate were added. After extraction 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 (328 mg, quant.). MS: m / z 309.1 (M+H-tBu). + .

[0481] Step 2: tert-Butyl (2-(4'-cyano-2'-(1-(2-tosylhydrazono)ethyl)-[1,1'-biphenyl]-4-yl)ethyl)carbamate. To a toluene solution (3 mL) of tert-butyl (2-(2'-acetyl-4'-cyano-[1,1'-biphenyl]-4-yl)ethyl)carbamate (328 mg, 0.899 mmol), p-toluenesulfonylhydrazide (167 mg, 0.899 mmol) was added, and the mixture was stirred at 110°C for 3 hours. The reaction mixture was concentrated under reduced pressure, and the crude product was used directly in the next reaction. MS: m / z 477.2 (M+H-tBu) + .

[0482] Step 3: tert-butyl (2-(4'-cyano-2'-(1-(2-methyl-6-morpholinopyrimidin-4-yl)vinyl)-[1,1'-biphenyl]-4-yl)ethyl)carbamate The crude product obtained in Step 2 was dissolved in 1,4-dioxane (4.5 mL), and 4-(6-chloro-2-methylpyrimidin-4-yl)morpholine (192 mg, 0.899 mmol), tris(dibenzylideneacetone)dipalladium (32.9 mg, 0.036 mmol), 2-(dicyclohexylphosphino)-2',4',6'-tri-i-propyl-1,1'-biphenyl (68.6 mg, 0.14 mmol), and lithium tert-butoxide (166 mg, 2.07 mmol) were added, followed by stirring at 110°C for 3 hours. The reaction mixture was cooled to room temperature, filtered through Celite, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the target compound (96.1 mg, 20%). MS: m / z 526.3 (M+H). + .

[0483] Step 4: tert-butyl(2-(4'-cyano-2'-(1-(2-methyl-6-morpholinopyrimidin-4-yl)ethyl)-[1,1'-biphenyl]-4-yl)ethyl)carbamate Ethyl acetate (4 mL) was added to tert-butyl(2-(4'-cyano-2'-(1-(2-methyl-6-morpholinopyrimidin-4-yl)vinyl)-[1,1'-biphenyl]-4-yl)ethyl)carbamate (79 mg, 0.15 mmol), and 10% palladium-activated carbon (20 mg) was added under a nitrogen atmosphere. A hydrogen balloon was attached to the reaction vessel, and the atmosphere inside the vessel was purged with hydrogen gas. The mixture was stirred at room temperature for 1 hour. After purging the reaction system with nitrogen, the reaction solution was filtered through Celite and concentrated under reduced pressure. The obtained crude product was used directly in the next reaction. MS: m / z 528.3 (M+H) + .

[0484] Step 5: 4-[4-(2-aminoethyl)phenyl]-3-[1-(2-methyl-6-morpholin-4-ylpyrimidin-4-yl)ethyl]benzonitrile The crude product obtained in Step 4 was dissolved in dichloromethane (1 mL), TFA (0.5 mL) was added, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by HPLC to obtain the target compound (30.8 mg). Exact MS: 427.2 Obs. MS (M+H) + :428.5

[0485] [Example 36] 4-[4-(2-aminoethyl)phenyl]-3-[1-(2-methyl-6-morpholin-4-ylpyrimidin-4-yl)cyclopropyl]benzonitrile (Compound No. 1227)

[0486] Step 1: tert-butyl (2-(4'-cyano-2'-(1-(2-methyl-6-morpholinopyrimidin-4-yl)cyclopropyl)-[1,1'-biphenyl]-4-yl)ethyl)carbamate. DMSO (0.5 mL) and sodium hydride (1.3 mg) were added to trimethylsulfoxonium iodide (7.1 mg, 0.032 mmol) and the mixture was stirred at room temperature for 40 minutes. After that, a DMSO solution (0.5 mL) of tert-butyl (2-(4'-cyano-2'-(1-(2-methyl-6-morpholinopyrimidin-4-yl)vinyl)-[1,1'-biphenyl]-4-yl)ethyl)carbamate (16.9 mg, 0.032 mmol) obtained in Example 35 was added, and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction solution, which was then extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The crude product was used directly in the next reaction. MS: m / z 540.3 (M+H) + .

[0487] Step 2: 4-[4-(2-aminoethyl)phenyl]-3-[1-(2-methyl-6-morpholin-4-ylpyrimidin-4-yl)cyclopropyl]benzonitrile The crude product obtained in Step 1 was dissolved in dichloromethane (1 mL), TFA (0.5 mL) was added, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to obtain the target compound (11.6 mg). Exact MS: 439.2 Obs. MS (M+H) + :440.5

[0488] [Example 37] 4-[4-(2-aminoethyl)phenyl]-3-[methoxy-[3-(1,3-thiazol-2-yl)-1,2-oxazol-5-yl]methyl]benzonitrile (Compound No. 1232)

[0489] Step 1: 4-Bromo-3-(1-hydroxyprop-2-ynyl)benzonitrile THF (40 mL) was added to 4-bromo-3-formylbenzonitrile (1.38 g, 6.57 mmol), and 0.5 M ethynylmagnesium bromide-THF solution (14.5 mL, 7.23 mmol) was added dropwise at 0°C, followed by stirring at the same temperature for 1 hour. After completion of the reaction, 2 M hydrochloric acid 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 obtained crude product was used in the next reaction.

[0490] Step 2: 4-Bromo-3-[hydroxy-[3-(1,3-thiazol-2-yl)-1,2-oxazol-5-yl]methyl]benzonitrile. To a portion (283 mg) of the crude product obtained in Step 1, (2Z)-N-hydroxy-1,3-thiazole-2-carboximidoyl chloride (163 mg, 1.00 mmol), potassium carbonate (276 mg, 2.00 mmol), and toluene (1 mL) were added, and the mixture was stirred at 100°C overnight. 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 (65.6 mg, 18%). MS: m / z 362.0 (M+H)+ .

[0491] Step 3: 4-Bromo-3-[methoxy-[3-(1,3-thiazol-2-yl)-1,2-oxazol-5-yl]methyl]benzonitrile 4-Bromo-3-[hydroxy-[3-(1,3-thiazol-2-yl)-1,2-oxazol-5-yl]methyl]benzonitrile (65.6 mg, 0.181 mmol) was dissolved in DMF (1 mL), sodium hydride (9.5 mg, 0.217 mmol) was added, and the mixture was stirred at room temperature for 10 minutes. To this reaction solution, iodomethane (38.8 mg, 0.272 mmol) was added, and the mixture was stirred at room temperature overnight. After completion of the reaction, 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 obtained crude product was used in the next reaction. MS: m / z 377.9 (M+H) + .

[0492] Step 4: tert-butyl N-[2-[4-[4-cyano-2-[methoxy-[3-(1,3-thiazol-2-yl)-1,2-oxazol-5-yl]methyl]phenyl]phenyl]ethyl]carbamate The crude product obtained in Step 3 was dissolved in 1,4-dioxane (0.8 mL), and tert-butyl N-[2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethyl]carbamate (75.4 mg, 0.217 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (6.6 mg, 9.0 μmol), potassium carbonate (50.0 mg, 0.362 mmol), and water (0.2 mL) were added, followed by stirring 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 mixture was dried over anhydrous sodium sulfate, and the solution was concentrated under reduced pressure. The crude product was used directly in the next reaction. MS: m / z 517.2 (M+H) + .

[0493] Step 5: 4-[4-(2-aminoethyl)phenyl]-3-[methoxy-[3-(1,3-thiazol-2-yl)-1,2-oxazol-5-yl]methyl]benzonitrile Dichloromethane (1 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 30 minutes. After concentration under reduced pressure, the crude product was purified by HPLC to obtain the target compound (48.3 mg). Exact MS: 416.1 Obs. MS (M+H) + :417.2

[0494] [Example 38] 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[(5-tert-butyl-2-methylpyrazol-3-yl)-(cyanomethoxy)methyl]benzonitrile (Compound No. 1237)

[0495] Step 1: tert-Butyl N-[2-[2-[2-[(5-tert-butyl-2-methylpyrazol-3-yl)-hydroxymethyl]-4-cyanophenyl]pyrimidin-5-yl]ethyl]carbamate. To tert-butyl N-[2-[2-[2-(5-tert-butyl-2-methylpyrazole-3-carbonyl)-4-cyanophenyl]pyrimidin-5-yl]ethyl]carbamate (379 mg, 0.776 mmol), which can be synthesized by a method similar to that of Example 27, was added THF (7.8 mL), and a 4 M solution of lithium borohydride in THF (0.776 mL, 2.33 mmol) was added dropwise. After stirring at room temperature for 1 hour, water was added to the reaction mixture, which was then 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 resulting crude product was used in the next reaction. MS: m / z 491.3 (M+H) + .

[0496] Step 2: tert-Butyl N-[2-[2-[2-[(5-tert-butyl-2-methylpyrazol-3-yl)-(cyanomethoxy)methyl]-4-cyanophenyl]pyrimidin-5-yl]ethyl]carbamate. A portion (127 mg) of the crude product obtained in Step 1 was dissolved in DMF (1 mL), and chloroacetonitrile (23.4 mg, 0.310 mmol) and cesium carbonate (169 mg, 0.517 mmol) were added, followed by stirring at 60°C for 16 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 obtained was used in the next reaction. MS: m / z 530.3 (M+H) + .

[0497] Step 3: 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[(5-tert-butyl-2-methylpyrazol-3-yl)-(cyanomethoxy)methyl]benzonitrile Dichloromethane (1 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 30 minutes. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by HPLC to obtain the target compound (10.2 mg). Exact MS: 429.2 Obs. MS (M+H) + :430.2

[0498] [Example 39] 4-[4-(2-aminoethyl)phenyl]-3-(6-piperidin-1-ylpyridazin-4-yl)sulfanylbenzonitrile (Compound No. 1240)

[0499] Step 1: [5-cyano-2-[5-[2-[(2-methylpropan-2-yl)oxycarbonylamino]ethyl]pyridin-2-yl]phenyl]trifluoromethanesulfonate. Dichloromethane (5 mL) and pyridine (172 mg, 2.17 mmol) were added to the intermediate tert-butyl N-[2-[4-(4-cyano-2-hydroxyphenyl)phenyl]ethyl]carbamate (245 mg, 0.724 mmol) obtained in Example 6, and the mixture was cooled to 0°C. Trifluoromethanesulfonic anhydride (306 mg, 1.09 mmol) was added dropwise. After stirring at the same temperature for 30 minutes, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the target compound (301 mg, 88%). MS: m / z 415.0 (M-tBu+H) + .

[0500] Step 2: 2-Ethylhexyl 3-[5-cyano-2-[4-[2-[(2-methylpropan-2-yl)oxycarbonylamino]ethyl]phenyl]phenyl]sulfanylpropanoate [5-cyano-2-[5-[2-[(2-methylpropan-2-yl)oxycarbonylamino]ethyl]pyridin-2-yl]phenyl]trifluoromethanesulfonate (301 mg, 0.640 mmol) was dissolved in 1,4-dioxane (2.6 mL), and 2-ethylhexyl 3-mercaptopropionate (168 mg, 0.768 mmol), tris(dibenzylideneacetone)dipalladium (29 mg, 0.032 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (37 mg, 0.064 mmol), and N,N-diisopropylethylamine (0.223 mL, 1.28 mmol) were added, followed by stirring at 100°C for 2 hours. The reaction mixture was cooled to room temperature, filtered through Celite, and then concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the target compound (479 mg, containing impurities). MS: m / z 439.2 (M-Boc+H) + .

[0501] Step 3: tert-Butyl N-[2-[4-[2-(6-chloropyridazin-4-yl)sulfanyl-4-cyanophenyl]phenyl]ethyl]carbamate 2-Ethylhexyl 3-[5-cyano-2-[4-[2-[(2-methylpropan-2-yl)oxycarbonylamino]ethyl]phenyl]phenyl]sulfanylpropanoate (479 mg) was dissolved in DMF (5 mL), 3,5-dichloropyridazine (265 mg, 1.78 mmol) and DBU (0.5 mL) were added, and the mixture was stirred at 50°C for 30 minutes. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The mixture 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 (340 mg). MS: m / z 411.0 (M-tBu+H) + . 1 H-NMR (CDCl3)δ:8.58 (1H, d, J=2.3 Hz), 7.98 (1H, d, J = 1.4 Hz), 7.86 (1H, dd, J = 8.0, 1.6 Hz), 7.61 (1H, d, J = 7.8 Hz), 7.22-7.17 (4H, m), 6.83 (1H, d, J = 2.3 Hz), 4.65 (1H, br s), 3.36 (2H, q, J = 6.6 Hz), 2.80 (2H, t, J = 6.9 Hz), 1.45 (9H, s).

[0502] Step 4: tert-Butyl N-[2-[4-[4-cyano-2-(6-piperidin-1-ylpyridazin-4-yl)sulfanylphenyl]phenyl]ethyl]carbamate DMF (1 mL) was added to tert-butyl N-[2-[4-[2-(6-chloropyridazin-4-yl)sulfanyl-4-cyanophenyl]phenyl]ethyl]carbamate (50.0 mg, 0.107 mmol), piperidine (27.4 mg, 0.321 mmol), and N,N-diisopropylethylamine (0.15 mL) were added, and the mixture was stirred at 100°C overnight. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The mixture was dried over anhydrous sodium sulfate, and the solution was concentrated under reduced pressu...

Claims

1. A compound represented by formula (I) or a pharma- ceutically acceptable salt thereof. [In the formula, X 1 , X 2 , and X 3 is independently CH, N, or CY; X 1 , X 2 , and X 3 At least one of the groups is CH or CY; Y is a halogen atom or a C group optionally substituted with 1 to 3 halogen atoms. 1-3 R is an alkyl group; 1 is a cyano group, a fluorine atom, or a chlorine atom; L 1 is -O-, -S-, -SO-, -CH(R 11 ) -, -C(=CH 2 )-, -CO-, a 1,1-cyclopropylidene group, or -NR 12 - is; R 11 is a C group optionally substituted with a hydrogen atom, a hydroxyl group, or 1 to 3 halogen atoms. 1-3 C optionally substituted with an alkyl group or 1 to 2 cyano groups 1-3 R is an alkoxy group; 12 is a hydrogen atom or a C optionally substituted with 1 to 3 halogen atoms. 1-3 Ar is an alkyl group; 1 is R 1 to 3 2 is a nitrogen-containing heteroaryl ring optionally substituted with 2 each independently represents a halogen atom, a cyano group, or a C optionally substituted with 1 to 3 halogen atoms; 1-4 R is an alkyl group; 3 represents a hydrogen atom, a halogen atom, an amino group, a cyano group, a carboxy group, (C 1-3 alkylcarbonyl)amino group, (C 1-6 alkylamino)carbonyl group, di(C 1-3 alkyl)aminocarbonyl group, (C 1-3 alkoxy)carbonyl group, (C 3-8 cycloalkyl)amino group, (C 3-8 heterocycloalkyl)amino group, C 3-8 Cycloalkyl group, 3-8 membered heterocycloalkyloxy group, 1-6 R 31 C optionally substituted with 3-8 Cycloalkyloxy group, 1 to 6 R 31 C optionally substituted with 1-6 an alkyl group, 1 to 6 R 31 C optionally substituted with 1-6 an alkoxy group, 1 to 6 R 31 Di(C 1-6 alkyl)amino group, 1 to 6 R 31 (C 1-6 alkyl)amino group, 1 to 4 R 32 a 3- to 8-membered heterocycloalkyl group optionally substituted with 1 to 4 R 32 an aryl group optionally substituted with 1 to 4 R 32 R is a heteroaryl group optionally substituted with 31 are each independently a halogen atom, a hydroxyl group, a cyclopropylidene group, or a C optionally substituted with 1 to 3 halogen atoms. 3-8 Cycloalkyl groups, 3- to 8-membered heterocycloalkyl groups, oxetanylidene groups, C 1-4 an alkoxy group, or a 3- to 8-membered cycloalkyloxy group; 32 are each independently a halogen atom, a hydroxyl group, an acetylamino group, or a C optionally substituted with 1 to 3 halogen atoms. 1-3 an alkyl group, optionally substituted with 1 to 3 halogen atoms; 1-3 Alkoxy group, oxo group, cyano group, carboxy group, (C 1-3 alkoxy)carbonyl group, (C 1-3 R is a )sulfonyl group, a carboxamide group, or a benzyloxy group; 2 and R 3 Ar 1 When bonded to adjacent atoms on the 2 and R 3 are bonded via a single bond or -O-, and Ar 1 may form a 5- to 7-membered ring together with the atoms of Ar 2 is R 1 to 4 4 an aryl ring optionally substituted with, or 1 to 4 R 4 R is a heteroaryl ring optionally substituted with 4 are independently a halogen atom, a hydroxy group, a carboxy group, a cyano group, a cyanomethyl group, an amino group, a di(C 1-3 C optionally substituted with 1 to 3 halogen atoms 1-3 Alkyl group, or C 1-3 L is an alkoxy group; 2 is a single bond, 1 to 3 R 21 C optionally substituted with 1-6 an alkylene group, 1 to 3 R 21 C optionally substituted with 3-8 A cycloalkylene group or 1 to 3 R 21 is a 4- to 8-membered heterocycloalkylene group optionally substituted with 2 is the Ar at both ends 2 and -NR 7 R 8 and L may be bonded at any position; 2 One sp at any position of 3 The carbon atom is -O- or -NR 22 - may be replaced by the structure of R 21 are each independently a halogen atom, a hydroxy group, an oxo group, a cyano group, a 1,1-cyclopropylidene group, an oxetanylidene group, a carboxy group, a carboxamide group, or a C optionally substituted with 1 to 3 halogen atoms. 1-6 Alkyl group, C 3-8 Cycloalkyl group, C 1-6 Alkoxy group, (C 1-3 Alkoxy)C 1-3 Alkyl group, (C 1-3 Alkoxy)C 1-3 Alkoxy group, (hydroxy)C 1-6 Alkyl group, (carboxy)C 1-3 Alkyl group, (carboxy)C 1-3 Alkoxy group, (C 1-3 alkoxy)carbonyl group, (C 1-3 Alkoxycarbonyl) C 1-3 Alkyl group, (C 1-6 alkylamino)carbonyl group, di(C 1-3 R represents an alkyl)aminocarbonyl group, a phenyl group which may be substituted with 1 to 3 halogen atoms, a heteroaryl group which may be substituted with 1 to 3 halogen atoms, or a phenoxy group which may be substituted with 1 to 3 halogen atoms; 22 is a hydrogen atom or C 1-3 is an alkyl group; 2 and R 7 is a single bond, -O-, -S(=O) n - or -NR 23 - is bonded to L 2 and R 7 may form a 4- to 8-membered ring containing the nitrogen atom to which R is bonded, and the ring may be further substituted with 1 to 3 halogen atoms or 1 to 2 hydroxy groups; n represents an integer of 0 to 2; R 23 is a hydrogen atom or C 1-3 is an alkyl group; 2 and R 4 Ar 2 If they are bonded to adjacent atoms on the Ar 2 may form a 5- to 8-membered ring together with the atom of R via a single bond or —O—; 7 is a hydrogen atom or C 1-3 R is an alkyl group; 7 and Ar 2 The atoms of may be linked via single bonds to form a 5- to 8-membered ring; 8 is a hydrogen atom, C 1-6 Alkyl group, adamantyl group, C 1-6 Cycloalkyl group, cyanomethyl group, oxetanyl group, (C 1-3 alkylamino)carbonylmethyl group, di(C 1-3 alkyl)aminocarbonylmethyl group, (C 1-3 Alkylamino)C 1-8 Alkyl group, di(C 1-3 Alkyl)amino C 1-8 Alkyl group, (hydroxy)C 1-8 Alkyl group, (carboxy)C 1-3 Alkyl group, (C 1-3 Alkoxycarbonyl) C 1-3 an alkyl group, or (C 1-3 Alkoxy)C 1-3 R is an alkyl group; 7 and R 8 are mutually single bonds, -O-, -S(=O) m - or -NR 41 - to form a 3- to 8-membered ring, which may further include an amino group, an oxo group, or a C 1-3 may be substituted with an alkyl group; m represents an integer of 0 to 2; R 41 is a hydrogen atom or C 1-3 is an alkyl group.

2. X 1 , X 2 , and X 3 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof, wherein is CH.

3. R 1 The compound according to claim 1 or 2, or a pharma- ceutically acceptable salt thereof, wherein is a cyano group.

4. R 1 The compound according to claim 1 or 2, or a pharma- ceutically acceptable salt thereof, wherein is a fluorine atom.

5. Ar 1 The nitrogen-containing heteroaryl ring is 5. The compound according to any one of claims 1 to 4, wherein:

6. L 1 The compound according to any one of claims 1 to 5, or a pharma- ceutically acceptable salt thereof, wherein: is -O-.

7. L 1 The compound according to any one of claims 1 to 5, or a pharma- ceutically acceptable salt thereof, wherein is -CO-.

8. L 1 But -CH 2 6. The compound according to any one of claims 1 to 5, wherein R is -, or a pharma- ceutically acceptable salt thereof.

9. R 2 The compound according to any one of claims 1 to 8, or a pharma- ceutically acceptable salt thereof, wherein is a methyl group.

10. R 3 But, C 3-8 Cycloalkyl group, 3-8 membered heterocycloalkyloxy group, 1-6 R 31 C optionally substituted with 3-8 Cycloalkyloxy group, 1 to 6 R 31 C optionally substituted with 1-6 an alkyl group, 1 to 6 R 31 C optionally substituted with 1-6 an alkoxy group, 1 to 6 R 31 Di(C 1-6 alkyl)amino group, 1 to 6 R 31 (C 1-6 alkyl)amino group, 1 to 4 R 32 a 3- to 8-membered heterocycloalkyl group optionally substituted with 1 to 4 R 32 an aryl group optionally substituted with 1 to 4 R 32 10. The compound according to any one of claims 1 to 9, wherein R is an optionally substituted heteroaryl group, or a pharma- ceutically acceptable salt thereof.

11. R 31 is a halogen atom, a cyclopropylidene group, C 1-4 The compound according to any one of claims 1 to 10, or a pharma- ceutically acceptable salt thereof, which is an alkoxy group.

12. R 32 C optionally substituted with a halogen atom or 1 to 3 halogen atoms 1-3 an alkyl group, optionally substituted with 1 to 3 halogen atoms; 1-3 The compound according to any one of claims 1 to 11, wherein R is an alkoxy group, an oxo group, or a cyano group, or a pharma- ceutically acceptable salt thereof.

13. Ar 2 The heteroaryl ring of 13. The compound according to any one of claims 1 to 12, wherein:

14. L 2 But, 1 to 2 R 21 C optionally substituted with 1-3 The compound according to any one of claims 1 to 13, wherein the R is an alkylene group, or a pharma- ceutically acceptable salt thereof.

15. L 2 But -CH 2 14. The compound according to any one of claims 1 to 13, wherein R is -, or a pharma- ceutically acceptable salt thereof.

16. L 2 But -CH 2 CH 2 14. The compound according to any one of claims 1 to 13, wherein R is -, or a pharma- ceutically acceptable salt thereof.

17. R 7 The compound according to any one of claims 1 to 16, or a pharma- ceutically acceptable salt thereof, wherein is a hydrogen atom.

18. R 8 The compound according to any one of claims 1 to 17, or a pharma- ceutically acceptable salt thereof, wherein is a hydrogen atom.

19. The compound according to claim 1, wherein the compound represented by formula (I) is selected from the following (1) to (150), or a pharma- ceutically acceptable salt thereof. (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-propan-2-ylpyrazol-3-yl)oxybenzonitrile (10) 4-[5-(2-aminoethyl)pyridin-2-yl]-3-(2-methyl-5-propylpyrazol-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-pyrrolidin-1-ylpyridin-4-yl)oxybenzonitrile(14) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-(2-methyl-6-pyridin-2-ylpyridin-4-yl)oxybenzonitrile (15) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-(2-methyl-5-propylpyrazol-3-yl)oxybenzonitrile (16) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-(2-methyl-5-propan-2-ylpyrazol-3-yl)oxybenzonitrile (17) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-(2-methyl-6-pyrrolidin-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-propylpyrazol-3-yl)oxybenzonitrile (39) 4-[5-(aminomethyl)pyridin-2-yl]-3-(2-methyl-5-propan-2-ylpyrazol-3-yl)oxybenzonitrile (40) 4-[5-(aminomethyl)pyrimidin-2-yl]-3-(2-methyl-5-propylpyrazol-3-yl)oxybenzonitrile (41) 4-[5-(aminomethyl)pyrimidin-2-yl]-3-(2-methyl-5-propan-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-thiazol-2-yl)pyrazol-3-yl]oxybenzonitrile (45) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[2-methyl-5-(1,3-thiazol-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]octan-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-pyrrolidin-1-ylpyrimidin-4-yl)oxybenzonitrile (55) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[2-methyl-6-(8-oxa-3-azabicyclo[3.2.1]octan-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-(propan-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-pyrrolidin-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-thiazol-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-pyrrolidin-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-pyrrolidin-1-ylpyrimidin-4-yl)oxybenzonitrile (73) 4-[5-(aminoethyl)pyrimidin-2-yl]-3-[2-methyl-6-pyrrolidin-1-ylpyrimidin-4-yl]oxybenzonitrile (74) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[6-(7-azabicyclo[2.2.1]heptan-7-yl)-2-methylpyrimidin-4-yl]oxybenzonitrile (75) 4-[5-(aminomethyl)pyrimidin-2-yl]-3-[6-(7-azabicyclo[2.2.1]heptan-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(propan-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]heptan-7-yl)-6-methylpyridin-4-yl]oxybenzonitrile (93) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[2-(7-azabicyclo[2.2.1]heptan-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(propan-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(propan-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-tetrafluoropyrrolidin-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-tetrafluoropyrrolidin-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-thiazol-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-thiazol-5-yl)pyrazol-3-yl]oxybenzonitrile (114) 4-[5-(aminomethyl)pyrimidin-2-yl]-3-[2-methyl-5-(5-methyl-1,3-thiazol-4-yl)pyrazol-3-yl]oxybenzonitrile (115)2-[2-[4-fluoro-2-[3-methyl-1-(2-methylpropyl)pyrazol-4-yl]oxyphenyl]pyrimidin-5-yl]ethanamine (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]ethanamine (118) 2-[2-[4-fluoro-2-(2-methyl-5-pyridin-2-ylpyrazol-3-yl)oxyphenyl]pyrimidin-5-yl]ethanamine (119) 2-[2-[4-fluoro-2-(2-methyl-5-pyrrolidin-1-ylpyrazol-3-yl)oxyphenyl]pyridin-5-yl]ethanamine (120) 2-[6-[4-fluoro-2-(2-methyl-5-pyrrolidin-1-ylpyrazol-3-yl)oxyphenyl]pyridin-3-yl]ethanamine (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]ethanamine (128) [2-[4-fluoro-2-(2-methyl-5-propan-2-ylpyrazol-3-yl)oxyphenyl]pyrimidin-5-yl]methanamine (129) 2-[2-[4-fluoro-2-(2-methyl-5-propan-2-ylpyrazol-3-yl)oxyphenyl]pyrimidin-5-yl]ethanamine (130) 2-[6-[4-fluoro-2-(2-methyl-5-propan-2-ylpyrazol-3-yl)oxyphenyl]pyridin-3-yl]ethanamine (131) 2-[6-[2-(5-cyclopropyl-2-methylpyrazol-3-yl)oxy-4-fluorophenyl]pyridin-3-yl]ethanamine (132) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-(5-ethyl-2-methylpyrazole-3-carbonyl)benzonitrile (133) 4-[5-(aminomethyl)pyrimidin-2-yl]-3-(5-ethyl-2-methylpyrazole-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-methylpyrazole-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-ylpyridine-4-carbonyl)benzonitrile (142) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[5-(dimethylamino)-2-methylpyrazole-3-carbonyl]benzonitrile (143) 4-[5-(aminomethyl)pyrimidin-2-yl]-3-[5-(dimethylamino)-2-methylpyrazole-3-carbonyl]benzonitrile (144) 4-[5-(aminomethyl)pyrimidin-2-yl]-3-[5-(diethylamino)-2-methylpyrazole-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-pyrrolidin-1-ylpyrazole-3-carbonyl)benzonitrile (148) 4-[5-(aminomethyl)pyrimidin-2-yl]-3-(2-methyl-5-pyrrolidin-1-ylpyrazole-3-carbonyl)benzonitrile (149) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[5-[2,2-difluoroethyl(ethyl)amino]-2-methylpyrazole-3-carbonyl]benzonitrile (150) 4-[5-(aminomethyl)pyrimidin-2-yl]-3-[5-[2,2-difluoroethyl(ethyl)amino]-2-methylpyrazole-3-carbonyl]benzonitrile 20. A pharmaceutical composition comprising a compound according to any one of claims 1 to 19, or a pharma- ceutically acceptable salt thereof.

21. A pharmaceutical composition having a TRPC6 channel inhibitory activity, comprising the compound according to any one of claims 1 to 19 or a pharma- ceutically acceptable salt thereof.

22. A therapeutic or prophylactic agent for nephrotic syndrome, membranous nephropathy, acute renal failure, sepsis, chronic renal failure, diabetic nephropathy, pulmonary hypertension, acute lung disorder, heart failure, malignant tumors, or muscular dystrophy, comprising the compound according to any one of claims 1 to 19 or a medicament for preventing or preventing the same.