Platelet aggregation inhibitors, processes for their preparation and use

Abstract

This invention belongs to the field of pharmaceutical technology and relates to platelet aggregation inhibitors, their preparation methods, and applications. This invention provides compounds of general formula I and their pharmaceutically usable salts, tautomers, and pharmaceutically usable solvates, wherein R1, R2, and n are as described in the claims and specification. This invention also provides intermediates for preparing compounds of general formula I and their pharmaceutically usable salts, tautomers, and pharmaceutically usable solvates. The compounds of general formula I of this invention, their pharmaceutically usable salts, tautomers, pharmaceutically usable solvates, or pharmaceutical compositions thereof have platelet-inhibiting activity and can be used to prepare platelet aggregation inhibitors, which can be used to treat thromboembolic diseases, especially cerebral infarction.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology and relates to platelet aggregation inhibitors, their preparation methods, and applications. Background Technology

[0002] Thromboembolic diseases, such as acute myocardial infarction and stroke, remain the most common causes of death and morbidity in developing countries. It is a pathological process caused by various intrinsic and extrinsic factors leading to the formation of thrombi or embolisms within arteries and veins, further resulting in damage to tissue and organ function. It is one of the most common cardiovascular and cerebrovascular diseases clinically, and is also a cause and complication of many other cardiovascular and cerebrovascular diseases. Once a thrombus forms, it often causes irreversible and serious consequences.

[0003] The formation of a stable platelet embolus involves three distinct stages: platelet adhesion, platelet activation and expansion, and platelet aggregation. Numerous strategies have been developed to reduce the risk of pathological thrombosis by interfering with platelet adhesion, activation, or aggregation. Platelet activation plays a crucial role in thrombotic complications. Therefore, antiplatelet therapy remains an important means of preventing and treating thrombotic diseases in clinical practice.

[0004] Currently available drugs that inhibit platelet aggregation include clopidogrel and ticagrelor, but the variety is very limited and they all have certain bleeding side effects. Therefore, the development of highly effective platelet aggregation inhibitors with low bleeding side effects has good application prospects. Summary of the Invention

[0005] The purpose of this invention is to provide a compound represented by general formula I, which has platelet aggregation inhibition activity and can be used to prepare a drug for the prevention and / or treatment of thrombotic diseases.

[0006] Compounds represented by general formula I and their pharmaceutically usable salts, tautomers, and pharmaceutically usable solvates:

[0007]

[0008] Wherein, R1 is a C1-C6 alkyl, C1-C6 alkoxy, -CH2OCH3, C3-C6 cycloalkyl, 5-6 aryl or heteroaryl; the heteroaryl contains 1-3 N, O or S heteroatoms;

[0009] The R1 is substituted by one or more of the following substituents: H, halogen, deuterium, C1-C6 alkyl, C1-C6 alkoxy;

[0010] R2 is a 5-10 aryl or heteroaryl group, wherein the heteroaryl group contains 1-3 heteroatoms of N, O or S;

[0011] The R2 is substituted by one or more of the following substituents: H, cyano, halogen, halo-C1-C6 alkyl, halo-C1-C6 alkoxy, amino, C1-C6 alkyl-substituted amino, C1-C6 alkoxy-substituted amino, morpholino.

[0012] n = 1 - 3.

[0013] The present invention preferably includes compounds represented by general formula I and their pharmaceutically usable salts, tautomers, and pharmaceutically usable solvates:

[0014] Wherein, R1 is C1-C4 alkyl, C1-C4 alkoxy, -CH2OCH3, C3-C6 cycloalkyl, phenyl, pyridyl, pyrazinyl, thiophenyl, furanyl, or thiazolyl;

[0015] The R1 is substituted by one or more of the following substituents: H, halogen, deuterium, C1-C4 alkyl, C1-C4 alkoxy;

[0016] R2 is a substituted or unsubstituted phenyl, pyridinyl, morpholinyl, thiazolyl, oxazole, or benzo[d][1,3]dioxacyclopenten-5-yl;

[0017] The substituents are halogen, cyano, halo-C1-C4 alkyl, halo-C1-C4 alkoxy, amino, C1-C4 alkyl-substituted amino, C1-C4 alkoxy-substituted amino, and morpholino.

[0018] n = 1.

[0019] The present invention preferably includes compounds represented by general formula I and their pharmaceutically usable salts, tautomers, and pharmaceutically usable solvates:

[0020] R1 is ethyl, isopropyl, isobutyl, cyclopropyl, 1-methylcyclopropyl, cyclobutyl, 1-methylcyclobutyl, cyclopentyl, cyclohexyl, methoxymethyl, difluoromethyl, trifluoromethyl, methyl-D3, 2,2-difluorocyclopropyl, 3,3-difluorocyclobutyl, phenyl, pyridin-4-yl, pyridin-3-yl, pyridin-2-yl, pyrazin-2-yl, thiophene-2-yl, thiophene-3-yl, furan-2-yl, furan-3-yl, thiazolyl-2-yl, thiazolyl-5-yl, thiazolyl-4-yl;

[0021] R2 is 4-fluorophenyl, 3-fluorophenyl, 2-fluorophenyl, (4-trifluoromethyl)phenyl, (3-trifluoromethyl)phenyl, (2-trifluoromethyl)phenyl, (4-trifluoromethoxy)phenyl, (3-trifluoromethoxy)phenyl, (2-trifluoromethoxy)phenyl, thiazolyl-5-yl, thiazolyl-2-yl, thiazolyl-4-yl, 2-(dimethylamino)thiazolyl-4-yl, 2-(diethylamino)thiazolyl -4-yl, 2-morpholinothiazol-4-yl, 5-methyl-2-morpholinothiazol-4-yl, 2-aminothiazol-4-yl, oxazol-5-yl, oxazol-2-yl, oxazol-4-yl, pyridin-4-yl, pyridin-3-yl, pyridin-2-yl, 2-morpholinoethoxy, benzo[d][1,3]dioxacyclopenten-5-yl, 6-bromopyridin-3-yl, 5-bromopyridin-2-yl;

[0022] n = 1.

[0023] The pharmaceutical salts of this invention are defined as follows, but are not limited thereto: Salts containing the formic acid moiety can be alkali metal salts such as Li, Na, and K salts; alkaline earth metal salts such as Ca and Mg salts; organic base salts such as various amino acids, guanidine, diethanolamine, choline, etc.; ammonium salts or substituted ammonium salts and aluminum salts. Salts can be acid addition salts, including but not limited to hydrochlorides, sulfates, nitrates, phosphates, perchlorates, borates, tartrates, maleates, citrates, succinates, palmitates, methanesulfonates, benzoates, benzenesulfonates, salicylates, glycerophosphates, ketoglutarate, ascorbic acid salts, etc.

[0024] Pharmaceutical solvates can be hydrates or contain other crystalline solvents such as alcohols.

[0025] Specifically, the compound or pharmaceutically acceptable salt with platelet-inhibiting activity provided by the present invention is any one of the following compounds (1) to (54):

[0026] (1) 1-[(4-cyanobenzyl)oxy]-2-(3-cyanophenyl)-4-ethyl-1H-imidazol-5-carboxylic acid (6a)

[0027] (2) 1-[(4-cyanobenzyl)oxy]-2-(3-cyanophenyl)-4-isopropyl-1H-imidazol-5-carboxylic acid (6b)

[0028] (3) 1-[(4-cyanobenzyl)oxy]-2-(3-cyanophenyl)-4-isobutyl-1H-imidazol-5-carboxylic acid (6c)

[0029] (4) 1-[(4-cyanobenzyl)oxy]-2-(3-cyanophenyl)-4-cyclopropyl-1H-imidazol-5-carboxylic acid (6d)

[0030] (5) 1-[(4-cyanobenzyl)oxy]-2-(3-cyanophenyl)-4-(1-methylcyclopropyl)-1H-imidazol-5-carboxylic acid (6e)

[0031] (6) 1-[(4-cyanobenzyl)oxy]-2-(3-cyanophenyl)-4-cyclobutyl-1H-imidazol-5-carboxylic acid (6f)

[0032] (7) 1-[(4-cyanobenzyl)oxy]-2-(3-cyanophenyl)-4-(1-methylcyclobutyl)-1H-imidazol-5-carboxylic acid (6g)

[0033] (8) 1-[(4-cyanobenzyl)oxy]-2-(3-cyanophenyl)-4-cyclopentyl-1H-imidazol-5-carboxylic acid (6h)

[0034] (9) 1-[(4-cyanobenzyl)oxy]-2-(3-cyanophenyl)-4-cyclohexyl-1H-imidazol-5-carboxylic acid (6i)

[0035] (10) 1-[(4-cyanobenzyl)oxy]-2-(3-cyanophenyl)-4-(methoxymethyl)-1H-imidazol-5-carboxylic acid (6j)

[0036] (11) 1-[(4-cyanobenzyl)oxy]-2-(3-cyanophenyl)-4-(difluoromethyl)-1H-imidazol-5-carboxylic acid (6k)

[0037] (12) 1-[(4-cyanobenzyl)oxy]-2-(3-cyanophenyl)-4-(trifluoromethyl)-1H-imidazol-5-carboxylic acid (6l)

[0038] (13) 1-[(4-cyanobenzyl)oxy]-2-(3-cyanophenyl)-4-(methyl-D3)-1H-imidazol-5-carboxylic acid (6m)

[0039] (14) 1-[(4-cyanobenzyl)oxy]-2-(3-cyanophenyl)-4-(2,2-difluorocyclopropyl)-1H-imidazol-5-carboxylic acid (6n)

[0040] (15) 1-[(4-cyanobenzyl)oxy]-2-(3-cyanophenyl)-4-(3,3-difluorocyclobutyl)-1H-imidazol-5-carboxylic acid (6o)

[0041] (16) 1-[(4-cyanobenzyl)oxy]-2-(3-cyanophenyl)-4-phenyl-1H-imidazol-5-carboxylic acid (6p)

[0042] (17) 1-[(4-cyanobenzyl)oxy]-2-(3-cyanophenyl)-4-(pyridin-4-yl)-1H-imidazol-5-carboxylic acid (6q)

[0043] (18) 1-[(4-cyanobenzyl)oxy]-2-(3-cyanophenyl)-4-(pyridin-3-yl)-1H-imidazol-5-carboxylic acid (6r)

[0044] (19) 1-[(4-cyanobenzyl)oxy]-2-(3-cyanophenyl)-4-(pyridin-2-yl)-1H-imidazol-5-carboxylic acid (6s)

[0045] (20) 1-[(4-cyanobenzyl)oxy]-2-(3-cyanophenyl)-4-(pyrazin-2-yl)-1H-imidazol-5-carboxylic acid (6t)

[0046] (21) 1-[(4-cyanobenzyl)oxy]-2-(3-cyanophenyl)-4-(thiophen-2-yl)-1H-imidazol-5-carboxylic acid (6u)

[0047] (22) 1-[(4-cyanobenzyl)oxy]-2-(3-cyanophenyl)-4-(thiophen-3-yl)-1H-imidazol-5-carboxylic acid (6v)

[0048] (23) 1-[(4-cyanobenzyl)oxy]-2-(3-cyanophenyl)-4-(furan-2-yl)-1H-imidazol-5-carboxylic acid (6w)

[0049] (24) 1-[(4-cyanobenzyl)oxy]-2-(3-cyanophenyl)-4-(furan-3-yl)-1H-imidazol-5-carboxylic acid (6x)

[0050] (25) 1-[(4-cyanobenzyl)oxy]-2-(3-cyanophenyl)-4-(thiazolyl-2-yl)-1H-imidazol-5-carboxylic acid (6y)

[0051] (26) 1-[(4-cyanobenzyl)oxy]-2-(3-cyanophenyl)-4-(thiazolyl-5-yl)-1H-imidazol-5-carboxylic acid (6z)

[0052] (27) 1-[(4-cyanobenzyl)oxy]-2-(3-cyanophenyl)-4-(thiazolyl-4-yl)-1H-imidazol-5-carboxylic acid (6z1)

[0053] (28) 1-[(4-fluorobenzyl)oxy]-2-(3-cyanophenyl)-4-(difluoromethyl)-1H-imidazol-5-carboxylic acid (6K-1)

[0054] (29) 1-[(3-fluorobenzyl)oxy]-2-(3-cyanophenyl)-4-(difluoromethyl)-1H-imidazol-5-carboxylic acid (6K-2)

[0055] (30) 1-[(2-fluorobenzyl)oxy]-2-(3-cyanophenyl)-4-(difluoromethyl)-1H-imidazol-5-carboxylic acid (6K-3)

[0056] (31) 1-{[(4-trifluoromethyl)benzyl]oxy}-2-(3-cyanophenyl)-4-(difluoromethyl)-1H-imidazol-5-carboxylic acid (6K-4)

[0057] (32) 1-{[(3-trifluoromethyl)benzyl]oxy}-2-(3-cyanophenyl)-4-(difluoromethyl)-1H-imidazol-5-carboxylic acid (6K-5)

[0058] (33) 1-{[(2-trifluoromethyl)benzyl]oxy}-2-(3-cyanophenyl)-4-(difluoromethyl)-1H-imidazol-5-carboxylic acid (6K-6)

[0059] (34) 1-{[(4-trifluoromethoxy)benzyl]oxy}-2-(3-cyanophenyl)-4-(difluoromethyl)-1H-imidazol-5-carboxylic acid (6K-7)

[0060] (35) 1-{[(3-trifluoromethoxy)benzyl]oxy}-2-(3-cyanophenyl)-4-(difluoromethyl)-1H-imidazol-5-carboxylic acid (6K-8)

[0061] (36) 1-{[(2-trifluoromethoxy)benzyl]oxy}-2-(3-cyanophenyl)-4-(difluoromethyl)-1H-imidazol-5-carboxylic acid (6K-9)

[0062] (37) 1-(pyridin-4-ylmethoxy)-2-(3-cyanophenyl)-4-(difluoromethyl)-1H-imidazol-5-carboxylic acid (6K-10)

[0063] (38) 1-(pyridin-3-ylmethoxy)-2-(3-cyanophenyl)-4-(difluoromethyl)-1H-imidazol-5-carboxylic acid (6K-11)

[0064] (39) 1-(pyridin-2-ylmethoxy)-2-(3-cyanophenyl)-4-(difluoromethyl)-1H-imidazol-5-carboxylic acid (6K-12)

[0065] (40) 1-(2-morpholinoethoxy)-2-(3-cyanophenyl)-4-(difluoromethyl)-1H-imidazol-5-carboxylic acid (6K-13)

[0066] (41) 1-[(benzo[d][1,3]dioxacyclopenten-5-yl)methoxy]-2-(3-cyanophenyl)-4-(difluoromethyl)-1H-imidazol-5-carboxylic acid (6K-14)

[0067] (42) 1-[(6-bromopyridin-3-yl)methoxy]-2-(3-cyanophenyl)-4-(difluoromethyl)-1H-imidazol-5-carboxylic acid (6K-15)

[0068] (43) 1-[(5-bromopyridin-2-yl)methoxy]--2-(3-cyanophenyl)-4-(difluoromethyl)-1H-imidazol-5-carboxylic acid (6K-16)

[0069] (44) 1-(thiazol-5-ylmethoxy)-2-(3-cyanophenyl)-4-(difluoromethyl)-1H-imidazol-5-carboxylic acid (6K-17)

[0070] (45) 1-(thiazol-2-ylmethoxy)-2-(3-cyanophenyl)-4-(difluoromethyl)-1H-imidazol-5-carboxylic acid (6K-18)

[0071] (46) 1-(thiazol-4-ylmethoxy)-2-(3-cyanophenyl)-4-(difluoromethyl)-1H-imidazol-5-carboxylic acid (6K-19)

[0072] (47) 1-(oxazol-5-ylmethoxy)-2-(3-cyanophenyl)-4-(difluoromethyl)-1H-imidazol-5-carboxylic acid (6K-20)

[0073] (48) 1-(oxazol-2-ylmethoxy)-2-(3-cyanophenyl)-4-(difluoromethyl)-1H-imidazol-5-carboxylic acid (6K-21)

[0074] (49) 1-(oxazol-4-ylmethoxy)-2-(3-cyanophenyl)-4-(difluoromethyl)-1H-imidazol-5-carboxylic acid (6K-22)

[0075] (50) 1-[(2-aminothiazol-4-yl)methoxy]-2-(3-cyanophenyl)-4-(difluoromethyl)-1H-imidazol-5-carboxylic acid (6K-23)

[0076] (51) 1-{[2-(dimethylamino)thiazolyl-4-yl]methoxy}-2-(3-cyanophenyl)-4-(difluoromethyl)-1H-imidazol-5-carboxylic acid (6K-24)

[0077] (52) 1-{[2-(diethylamino)thiazolyl-4-yl]methoxy}-2-(3-cyanophenyl)-4-(difluoromethyl)-1H-imidazol-5-carboxylic acid (6K-25)

[0078] (53) 1-[(2-morpholinothiazolyl-4-yl)methoxy]-2-(3-cyanophenyl)-4-(difluoromethyl)-1H-imidazol-5-carboxylic acid (6K-26)

[0079] (54) 1-[(5-methyl-2-morpholinothiazolyl-4-yl)methoxy]-2-(3-cyanophenyl)-4-(difluoromethyl)-1H-imidazol-5-carboxylic acid (6K-27)

[0080]

[0081]

[0082]

[0083] This invention also provides intermediates for the preparation of compounds of general formula I and their pharmaceutically usable salts, tautomers, and pharmaceutically usable solvates:

[0084] (1) Ethyl 2-(3-cyanophenyl)-4-ethyl-1-hydroxy-1H-imidazolium-5-carboxylate (4a)

[0085] (2) Ethyl 2-(3-cyanophenyl)-1-hydroxy-4-isopropyl-1H-imidazolium-5-carboxylate (4b)

[0086] (3) 2-(3-cyanophenyl)-1-hydroxy-4-isobutyl-1H-imidazolium-5-carboxylic acid ethyl ester (4c)

[0087] (4) Ethyl 2-(3-cyanophenyl)-4-cyclopropyl-1-hydroxy-1H-imidazolium-5-carboxylate (4d)

[0088] (5) 2-(3-cyanophenyl)-1-hydroxy-4-(1-methylcyclopropyl)-1H-imidazolium-5-carboxylic acid ethyl ester (4e):

[0089] (6) ethyl 2-(3-cyanophenyl)-4-cyclobutyl-1-hydroxy-1H-imidazolium-5-carboxylate (4f):

[0090] (7) 2-(3-cyanophenyl)-1-hydroxy-4-(1-methylcyclobutyl)-1H-imidazolium-5-carboxylic acid ethyl ester (4g)

[0091] (8) Ethyl 2-(3-cyanophenyl)-4-cyclopentyl-1-hydroxy-1H-imidazolium-5-carboxylate (4h)

[0092] (9) Ethyl 2-(3-cyanophenyl)-4-cyclohexyl-1-hydroxy-1H-imidazolium-5-carboxylate (4i)

[0093] (10) 2-(3-cyanophenyl)-1-hydroxy-4-(methoxymethyl)-1H-imidazol-5-carboxylic acid ethyl ester (4j)

[0094] (11) Ethyl 2-(3-cyanophenyl)-4-(difluoromethyl)-1-hydroxy-1H-imidazolium-5-carboxylate (4k)

[0095] (12) Ethyl 2-(3-cyanophenyl)-4-(trifluoromethyl)-1-hydroxy-1H-imidazolium-5-carboxylate (4l)

[0096] (13) 2-(3-cyanophenyl)-1-hydroxy-4-(methyl-D3)-1H-imidazolium-5-carboxylic acid ethyl ester (4m)

[0097] (14) 2-(3-Cyanophenyl)-4-(2,2-Difluorocyclopropyl)-1-hydroxy-1H-imidazolium-5-carboxylic acid ethyl ester (4n)

[0098] (15) 2-(3-Cyanophenyl)-4-(3,3-difluorocyclobutyl)-1-hydroxy-1H-imidazolium-5-carboxylic acid ethyl ester (4o)

[0099] (16) 2-(3-cyanophenyl)-1-hydroxy-4-phenyl-1H-imidazolium-5-carboxylic acid ethyl ester (4p)

[0100] (17) 2-(3-cyanophenyl)-1-hydroxy-4-(pyridin-4-yl)-1H-imidazol-5-carboxylic acid ethyl ester (4q)

[0101] (18) 2-(3-cyanophenyl)-1-hydroxy-4-(pyridin-3-yl)-1H-imidazol-5-carboxylic acid ethyl ester (4r)

[0102] (19) 2-(3-cyanophenyl)-1-hydroxy-4-(pyridin-2-yl)-1H-imidazol-5-carboxylic acid ethyl ester (4s)

[0103] (20) ethyl 2-(3-cyanophenyl)-1-hydroxy-4-(pyrazin-2-yl)-1H-imidazol-5-carboxylate (4t)

[0104] (21) Ethyl 2-(3-cyanophenyl)-1-hydroxy-4-(thiophen-2-yl)-1H-imidazolium-5-carboxylate (4u)

[0105] (22) ethyl 2-(3-cyanophenyl)-1-hydroxy-4-(thiophen-3-yl)-1H-imidazolium-5-carboxylate (4v)

[0106] (23) 2-(3-cyanophenyl)-4-(furan-2-yl)-1-hydroxy-1H-imidazol-5-carboxylic acid ethyl ester (4w)

[0107] (24) ethyl 2-(3-cyanophenyl)-4-(furan-3-yl)-1-hydroxy-1H-imidazolium-5-carboxylate (4x)

[0108] (25) ethyl 2-(3-cyanophenyl)-1-hydroxy-4-(thiazolyl-2-yl)-1H-imidazolium-5-carboxylate (4y)

[0109] (26) 2-(3-cyanophenyl)-1-hydroxy-4-(thiazolyl-5-yl)-1H-imidazol-5-carboxylic acid ethyl ester (4z)

[0110] (27) 2-(3-cyanophenyl)-1-hydroxy-4-(thiazolyl-4-yl)-1H-imidazol-5-carboxylic acid ethyl ester (4z1)

[0111] (28) 1-[(4-cyanobenzyl)oxy]-2-(3-cyanophenyl)-4-ethyl-1H-imidazolium-5-carboxylic acid ethyl ester (5a)

[0112] (29) 1-[(4-cyanobenzyl)oxy]-2-(3-cyanophenyl)-4-isopropyl-1H-imidazol-5-carboxylic acid ethyl ester (5b)

[0113] (30) 1-[(4-cyanobenzyl)oxy]-2-(3-cyanophenyl)-4-isobutyl-1H-imidazol-5-carboxylic acid ethyl ester (5c)

[0114] (31) 1-[(4-cyanobenzyl)oxy]-2-(3-cyanophenyl)-4-cyclopropyl-1H-imidazol-5-carboxylic acid ethyl ester (5d)

[0115] (32) 1-[(4-cyanobenzyl)oxy]-2-(3-cyanophenyl)-4-(1-methylcyclopropyl)-1H-imidazolium-5-carboxylic acid ethyl ester (5e)

[0116] (33) 1-[(4-cyanobenzyl)oxy]-2-(3-cyanophenyl)-4-cyclobutyl-1H-imidazolium-5-carboxylic acid ethyl ester (5f)

[0117] (34) 1-[(4-cyanobenzyl)oxy]-2-(3-cyanophenyl)-4-(1-methylcyclobutyl)-1H-imidazolium-5-carboxylic acid ethyl ester (5g)

[0118] (35) 1-[(4-cyanobenzyl)oxy]-2-(3-cyanophenyl)-4-cyclopentyl-1H-imidazolium-5-carboxylic acid ethyl ester (5h)

[0119] (36) 1-[(4-cyanobenzyl)oxy]-2-(3-cyanophenyl)-4-cyclohexyl-1H-imidazolium-5-carboxylic acid ethyl ester (5i)

[0120] (37) 1-[(4-cyanobenzyl)oxy]-2-(3-cyanophenyl)-4-(methoxymethyl)-1H-imidazol-5-carboxylic acid ethyl ester (5j)

[0121] (38) 1-[(4-cyanobenzyl)oxy]-2-(3-cyanophenyl)-4-(difluoromethyl)-1H-imidazol-5-carboxylic acid ethyl ester (5k)

[0122] (39) 1-[(4-cyanobenzyl)oxy]-2-(3-cyanophenyl)-4-(trifluoromethyl)-1H-imidazol-5-carboxylic acid ethyl ester (5l)

[0123] (40) 1-[(4-cyanobenzyl)oxy]-2-(3-cyanophenyl)-4-(methyl-D3)-1H-imidazol-5-carboxylic acid ethyl ester (5m)

[0124] (41) 1-[(4-cyanobenzyl)oxy]-2-(3-cyanophenyl)-4-(2,2-difluorocyclopropyl)-1H-imidazol-5-carboxylic acid ethyl ester (5n)

[0125] (42) 1-[(4-cyanobenzyl)oxy]-2-(3-cyanophenyl)-4-(3,3-difluorocyclobutyl)-1H-imidazolium-5-carboxylic acid ethyl ester (5o)

[0126] (43) 1-[(4-cyanobenzyl)oxy]-2-(3-cyanophenyl)-4-phenyl-1H-imidazol-5-carboxylic acid ethyl ester (5p)

[0127] (44) 1-[(4-cyanobenzyl)oxy]-2-(3-cyanophenyl)-4-(pyridin-4-yl)-1H-imidazol-5-carboxylic acid ethyl ester (5q)

[0128] (45) 1-[(4-cyanobenzyl)oxy]-2-(3-cyanophenyl)-4-(pyridin-3-yl)-1H-imidazol-5-carboxylic acid ethyl ester (5r)

[0129] (46) 1-[(4-cyanobenzyl)oxy]-2-(3-cyanophenyl)-4-(pyridin-2-yl)-1H-imidazol-5-carboxylic acid ethyl ester (5s)

[0130] (47) 1-[(4-cyanobenzyl)oxy]-2-(3-cyanophenyl)-4-(pyrazin-2-yl)-1H-imidazol-5-carboxylic acid ethyl ester (5t)

[0131] (48) 1-[(4-cyanobenzyl)oxy]-2-(3-cyanophenyl)-4-(thiophen-2-yl)-1H-imidazol-5-carboxylic acid ethyl ester (5u)

[0132] (49) 1-[(4-cyanobenzyl)oxy]-2-(3-cyanophenyl)-4-(thiophen-3-yl)-1H-imidazol-5-carboxylic acid ethyl ester (5v)

[0133] (50) 1-[(4-cyanobenzyl)oxy]-2-(3-cyanophenyl)-4-(furan-2-yl)-1H-imidazol-5-carboxylic acid ethyl ester (5w)

[0134] (51) 1-[(4-cyanobenzyl)oxy]-2-(3-cyanophenyl)-4-(furan-3-yl)-1H-imidazol-5-carboxylic acid ethyl ester (5x)

[0135] (52) 1-[(4-cyanobenzyl)oxy]-2-(3-cyanophenyl)-4-(thiazolyl-2-yl)-1H-imidazol-5-carboxylic acid ethyl ester (5y)

[0136] (53) 1-[(4-cyanobenzyl)oxy]-2-(3-cyanophenyl)-4-(thiazolyl-5-yl)-1H-imidazol-5-carboxylic acid ethyl ester (5z)

[0137] (54) 1-[(4-cyanobenzyl)oxy]-2-(3-cyanophenyl)-4-(thiazolyl-4-yl)-1H-imidazol-5-carboxylic acid ethyl ester (5z1)

[0138] (55) 2-(3-cyanophenyl)-4-(difluoromethyl)-1-[(4-fluorobenzyl)oxy]-1H-imidazol-5-carboxylic acid ethyl ester (5K-1)

[0139] (56) 2-(3-cyanophenyl)-4-(difluoromethyl)-1-[(3-fluorobenzyl)oxy]-1H-imidazol-5-carboxylic acid ethyl ester (5K-2)

[0140] (57) 2-(3-cyanophenyl)-4-(difluoromethyl)-1-[(2-fluorobenzyl)oxy]-1H-imidazol-5-carboxylic acid ethyl ester (5K-3)

[0141] (58) 2-(3-cyanophenyl)-4-(difluoromethyl)-1-{[(4-trifluoromethyl)benzyl]oxy}-1H-imidazolium-5-carboxylic acid ethyl ester (5K-4)

[0142] (59) 2-(3-cyanophenyl)-4-(difluoromethyl)-1-{[3-(trifluoromethyl)benzyl]oxy}-1H-imidazol-5-carboxylate (5K-5)

[0143] (60) 2-(3-cyanophenyl)-4-(difluoromethyl)-1-{[2-(trifluoromethyl)benzyl]oxy}-1H-imidazol-5-carboxylate (5K-6)

[0144] (61) 2-(3-cyanophenyl)-4-(difluoromethyl)-1-{[4-(trifluoromethoxy)benzyl]oxy}-1H-imidazol-5-carboxylic acid ethyl ester (5K-7)

[0145] (62) 2-(3-cyanophenyl)-4-(difluoromethyl)-1-{[3-(trifluoromethoxy)benzyl]oxy}-1H-imidazol-5-carboxylic acid ethyl ester (5K-8)

[0146] (63) 2-(3-cyanophenyl)-4-(difluoromethyl)-1-{[2-(trifluoromethoxy)benzyl]oxy}-1H-imidazol-5-carboxylic acid ethyl ester (5K-9)

[0147] (64) 2-(3-Cyanophane)-4-(difluoromethyl)-1-(pyridine-4-methoxy)-1H-imidazol-5-carboxylic acid ethyl ester (5K-10)

[0148] (65) 2-(3-cyanophenyl)-4-(difluoromethyl)-1-(pyridine-3-methoxy)-1H-imidazolium-5-carboxylic acid ethyl ester (5K-11)

[0149] (66) 2-(3-cyanophenyl)-4-(difluoromethyl)-1-(pyridin-2-ylmethoxy)-1H-imidazol-5-carboxylic acid ethyl ester (5K-12)

[0150] (67) 2-(3-Cyanophane)-4-(difluoromethyl)-1-(2-morpholinoethoxy)-1H-imidazol-5-carboxylic acid ethyl ester (5K-13)

[0151] (68) 1-(benzo[d][1,3]dioxacyclopenten-5-ylmethoxy)-2-(3-cyanophenyl)-4-(difluoromethyl)-1H-imidazol-5-carboxylic acid ethyl ester (5K-14)

[0152] (69) 1-[(6-bromopyridin-3-yl)methoxy]-2-(3-cyanophenyl)-4-(difluoromethyl)-1H-imidazol-5-carboxylic acid ethyl ester (5K-15)

[0153] (70) 1-[(5-bromopyridin-2-yl)methoxy]-2-(3-cyanophenyl)-4-(difluoromethyl)-1H-imidazol-5-carboxylic acid ethyl ester (5K-16)

[0154] (71) 2-(3-cyanophenyl)-4-(difluoromethyl)-1-(thiazol-5-methoxy)-1H-imidazol-5-carboxylic acid ethyl ester (5K-17)

[0155] (72) 2-(3-cyanophenyl)-4-(difluoromethyl)-1-(thiazol-2-ylmethoxy)-1H-imidazol-5-carboxylic acid ethyl ester (5K-18)

[0156] (73) 2-(3-cyanophenyl)-4-(difluoromethyl)-1-(thiazol-4-ylmethoxy)-1H-imidazol-5-carboxylic acid ethyl ester (5K-19)

[0157] (74) 2-(3-Cyanophane)-4-(difluoromethyl)-1-(oxazol-5-methoxy)-1H-imidazol-5-carboxylic acid ethyl ester (5K-20)

[0158] (75) 2-(3-cyanophenyl)-4-(difluoromethyl)-1-(oxazol-2-ylmethoxy)-1H-imidazol-5-carboxylic acid ethyl ester (5K-21)

[0159] (76) 2-(3-cyanophenyl)-4-(difluoromethyl)-1-(oxazol-4-methoxy)-1H-imidazol-5-carboxylic acid ethyl ester (5K-22)

[0160] (77) 2-(3-cyanophenyl)-4-(difluoromethyl)-1-[(2-aminothiazol-4-yl)methoxy]-1H-imidazol-5-carboxylic acid ethyl ester (5K-23)

[0161] (78) 2-(3-cyanophenyl)-4-(difluoromethyl)-1-{[2-(dimethylamino)thiazolyl-4-yl]methoxy}-1H-imidazol-5-carboxylic acid ethyl ester (5K-24)

[0162] (79) 2-(3-cyanophenyl)-1-{[2-(diethylamino)thiazolyl-4-yl]methoxy}-4-(difluoromethyl)-1H-imidazol-5-carboxylic acid ethyl ester (5K-25)

[0163] (80) 2-(3-cyanophenyl)-4-(difluoromethyl)-1-[(2-morpholinothiazolyl-4-yl)methoxy]-1H-imidazol-5-carboxylic acid ethyl ester (5K-26)

[0164] (81) 2-(3-cyanophenyl)-4-(difluoromethyl)-1-[(5-methyl-2-morpholinothiazolyl-4-yl)methoxy]-1H-imidazolium-5-carboxylic acid ethyl ester (5K-27)

[0165] (82) 1-{{2-[(tert-butoxycarbonyl)amino]thiazol-4-yl}methoxy}-2-(3-cyanophenyl)-4-(difluoromethyl)-1H-imidazol-5-carboxylic acid ethyl ester (C-6a)

[0166]

[0167]

[0168]

[0169]

[0170] The present invention also provides a method for preparing compounds of general formula I or pharmaceutically acceptable salts thereof, the preparation steps of which are as follows:

[0171] (1) β-keto esters are prepared by carbonylation reaction of diethyl carbonate with acetone derivatives; or β-keto esters are prepared by condensation reaction of potassium monoethyl malonate with carboxylic acid derivatives.

[0172] (2) The intermediate was prepared by nitrosation of β-keto ester derivatives with sodium nitrite in water and glacial acetic acid solvent;

[0173] (3) The intermediate in step (2) is cyclized with m-cyanobenzaldehyde and ammonium acetate in acetic acid solvent to prepare a 5-hydroxyimidazole derivative, which is then hydrolyzed under lithium hydroxide conditions to obtain the target compound.

[0174] The present invention also provides pharmaceutical compositions comprising the compound of general formula I and its pharmaceutically acceptable salts, tautomers, and pharmaceutically acceptable solvates.

[0175] This invention provides the use of the compound of general formula I and its pharmaceutically usable salts, tautomers, pharmaceutically usable solvates or pharmaceutical compositions thereof in the preparation of platelet aggregation inhibitors.

[0176] This invention provides the use of the compound of general formula I and its pharmaceutically usable salts, tautomers, pharmaceutically usable solvates or pharmaceutical compositions thereof in the preparation of a medicament for treating thromboembolic diseases, wherein the thromboembolic disease is preferably cerebral infarction. Attached Figure Description

[0177] Figure 1 This is a diagram illustrating the efficacy of drugs in treating acute cerebral infarction in rats.

[0178] Figure 2 This represents the volume of bleeding. Detailed Implementation

[0179] The following embodiments will further illustrate the present invention, but are not intended to limit the invention.

[0180] Prepare according to the following procedure:

[0181] Route 1:

[0182]

[0183] Route 1: a. Acetone derivative, sodium hydride, toluene, nitrogen, reflux; b. Carboxylic acid derivative, N,N'-carbonyldiimidazole, anhydrous magnesium chloride, anhydrous tetrahydrofuran, 40℃, nitrogen; c. Sodium nitrite, glacial acetic acid, water, 0℃; d. Ammonium acetate, glacial acetic acid, 50℃, nitrogen; e. Potassium carbonate, potassium iodide, N,N-dimethylformamide, 40℃; f. Lithium hydroxide, water / tetrahydrofuran, 35-40℃.

[0184] Route 2:

[0185] Starting with intermediate 4k from route 1, intermediates 5k-1 to 5k-14 were prepared by alkylation with benzyl chloride or benzyl bromide derivatives under potassium carbonate catalysis. These intermediates were then hydrolyzed to yield the target compounds 6k-1 to 6k-14.

[0186] Starting with (6-bromopyridin-3-yl)methanol (A-1a) or (5-bromopyridin-2-yl)methanol (A-1b), methanesulfonate derivatives A-2a to A-2b were prepared by sulfonation with methanesulfonyl chloride under triethylamine catalysis. Then, they were alkylated with intermediate 4k under potassium carbonate to obtain intermediates 5k-15 to 5k-16, which were subsequently hydrolyzed to obtain the target compounds 6k-15 to 6k-16.

[0187] Starting with thiazocarboxylic acid derivatives B-1a to B-1c or oxazolicarboxylic acid derivatives B-1d to B-1f, the carboxyl groups were reduced with lithium aluminum hydride to obtain hydroxymethyl-substituted thiazolic acid or hydroxymethyl-substituted oxazolicarboxylic acid derivatives B-2a to B-2f. Subsequently, these were sulfonated with methanesulfonyl chloride under triethylamine catalysis to prepare methanesulfonate intermediates B-3a to B-3f. Then, they were alkylated with intermediate 4k to obtain intermediates 5k-17 to 5k-22, which were subsequently hydrolyzed to obtain the target compounds 6k-17 to 6k-22.

[0188]

[0189]

[0190] Route 2: a. R-Cl or R-Br, potassium carbonate, potassium iodide, N,N-dimethylformamide, 40℃, nitrogen; b. lithium hydroxide, water / tetrahydrofuran.

[0191] 35-40℃; c. Methanesulfonyl chloride, triethylamine, anhydrous tetrahydrofuran, 25℃; d. Lithium aluminum hydride, anhydrous tetrahydrofuran, 0℃.

[0192] Route 3:

[0193] Starting with thiourea, ethyl 3-bromo-2-oxopropionate (C-1a) or ethyl 3-bromo-2-oxobutyrate (D-1a) under ethanol reflux were cyclized to yield intermediates C-2a to D-2a. Intermediate C-2a underwent a condensation reaction with Boc anhydride to yield intermediate C-3a, followed by reduction of the ester group under lithium aluminum hydride conditions to obtain intermediate C-4a. Intermediate C-4a underwent a condensation reaction with methanesulfonyl chloride under triethylamine conditions to prepare methanesulfonate intermediate C-5a, which was then alkylated with intermediate 4k to yield intermediate C-6a. Deprotection of intermediate C-6a was then carried out under trifluoroacetic acid conditions using acetonitrile as a solvent to obtain intermediate 5k-23, which was subsequently hydrolyzed to yield the target compound 6k-23. Intermediates C-2a to D-2a undergo a Sandmeier reaction, where the amino group is converted to a bromine substituent by tert-butyl nitrite and cuprous bromide to prepare intermediates D-3a to D-3b. These intermediates are then alkylated with amine derivatives to give intermediates D-4a to D-4d. Subsequent reduction with lithium aluminum hydride yields intermediates D-5a to D-5d, which are then condensed with methanesulfonyl chloride under triethylamine conditions to prepare methanesulfonate intermediates D-6a to D-6d. These intermediates are then alkylated with intermediate 4k to give intermediates 5k-24 to 5k-27. Intermediates 5k-24 to 5k-27 are hydrolyzed under lithium hydroxide conditions to give the target compounds 6k-24 to 6k-27.

[0194]

[0195] Route 3: a. Ethanol, reflux; b. Di-tert-butyl dicarbonate, triethylamine, 4-dimethylaminopyridine, dichloromethane / tetrahydrofuran, 25°C; c. Lithium aluminum hydride, anhydrous tetrahydrofuran, 0°C; d. Methanesulfonyl chloride, triethylamine, anhydrous tetrahydrofuran, 25°C;

[0196] e. Potassium carbonate, N,N-dimethylformamide, 40°C; f. Trifluoroacetic acid, acetonitrile, 60°C; g. Lithium hydroxide, water / tetrahydrofuran, 35°C; h. Tert-butyl nitrite, cuprous bromide, acetonitrile, reflux; i. Amine derivative, triethylamine, tetrahydrofuran, 40°C.

[0197] Example 1. Synthesis of ethyl 3-oxovalerate (2a)

[0198] Propionic acid (1 g, 13.50 mmol) was dissolved in 20 mL of anhydrous tetrahydrofuran solution. N,N'-carbonyldiimidazole (2.63 g, 16.20 mmol, 1.2 times the volume) was added in portions, and the mixture was heated to reflux until the reaction was complete. Separately, potassium monoethyl malonate (2.53 g, 14.85 mmol, 1.1 times the volume) was weighed into 30 mL of anhydrous tetrahydrofuran solution, and anhydrous magnesium chloride (1.41 g, 14.85 mmol, 1.1 times the volume) was added. The first reaction solution was then slowly added dropwise to the second reaction solution under nitrogen protection at 40 °C. After the reaction was complete, the mixture was rotary evaporated under reduced pressure. The reaction solution was then cooled to room temperature. 5 mL of 1M dilute hydrochloric acid and 20 mL of water were added and stirred for 5 minutes. Then, ethyl acetate (30 mL × 2) was added for extraction. The organic layer was collected, washed once with water and once with saturated brine, and the organic layer was collected and dried with anhydrous sodium sulfate. The mixture was then rotary evaporated under reduced pressure and dried to obtain 1.61 g of a transparent oily substance, yield: 83%. The product was directly used for the next step without purification.

[0199] Example 2. Synthesis of ethyl 4-methyl-3-oxovalerate (2b)

[0200] 3-Methylbut-2-one (1.5 g, 17.43 mmol), diethyl carbonate (2.06 g, 17.43 mmol, 1 fold volume), and sodium hydride (767 mg, 19.17 mmol, 1.1 fold volume) were dissolved in 20 mL of toluene solution. The reaction solution was then heated to reflux until the reaction was complete. The toluene solvent was removed by rotary evaporation under reduced pressure. The solution was then cooled to 0 °C, and 5 mL of 1 M dilute hydrochloric acid solution was slowly added dropwise to quench the reaction. 20 mL of water was then added, and the solution was extracted twice with ethyl acetate (30 mL). The organic phase was collected, washed once with water and once with saturated brine, and the organic layer was collected and dried over anhydrous sodium sulfate. Column chromatography yielded a clear oily substance with a yield of 55%.

[0201] Example 3. Synthesis of ethyl 5-methyl-3-oxohexanoate (2c)

[0202] Starting with isobutyric acid, intermediate 5-methyl-3-oxohexanoic acid ethyl ester 2c was prepared by referring to the synthesis method of ethyl 3-oxopentanoate (2a). It was a transparent oily substance and was directly used in the next step without purification.

[0203] Example 4. Synthesis of ethyl 3-cyclopropyl-3-oxopropionate (2d)

[0204] Using 1-cyclopropyl-1-one as a starting material, intermediate 3-cyclopropyl-3-oxopropionic acid ethyl ester 2d was prepared by referring to the synthesis method of 4-methyl-3-oxovalerate ethyl ester (2b). It was a transparent oil with a yield of 61%.

[0205] 2d:1 H NMR(400MHz,Chloroform-d)δ8.09(dd,J=2.9,1.3Hz,1H),7.52(dd,J=5.1,1.3Hz,1H), 7.31(dd,J=5.1,2.8Hz,1H),4.18(q,J=7.1Hz,2H),3.86(s,2H),1.23(t,J=7.1Hz,3H).

[0206] Example 5. Synthesis of intermediates 2e, 2f, 2g, 2h, 2i, 2j, 2m, 2n, 2o

[0207] Intermediates 2e, 2f, 2g, 2h, 2i, 2j, 2m, 2n, and 2o were prepared from 1-methylcyclopropane-1-carboxylic acid, cyclobutylcarboxylic acid, 1-methylcyclobutane-1-carboxylic acid, cyclopentylcarboxylic acid, cyclohexylcarboxylic acid, 2-methoxyacetic acid, acetic acid-2,2,2-D3, 2,2-difluorocyclopropane-1-carboxylic acid, and 3,3-difluorocyclobutyl-1-carboxylic acid, respectively, following the synthesis method of ethyl 3-oxopentanoate (2a). All of them were transparent oily substances and were directly used in the next step without purification.

[0208] Example 6. Synthesis of intermediates 2p, 2q, 2r, and 2s

[0209] Intermediates 2p, 2q, 2r, and 2s were prepared using acetophenone, 4-acetylpyridine, 3-acetylpyridine, and 2-acetylpyridine as raw materials, respectively, following the synthesis method of ethyl 4-methyl-3-oxovalerate (2b). All of them were transparent oily substances and were directly used in the next step without purification.

[0210] 2s: Yield: 56%. 1 H NMR(400MHz,Chloroform-d)δ8.67–8.62(m,1H),8.05(dt,J=7.9,1.1Hz,1H),7.83(t d,J=7.7,1.7Hz,1H),7.49–7.44(m,1H),4.18(d,J=6.9Hz,4H),1.22(t,J=7.1Hz,3H).

[0211] Example 7. Synthesis of ethyl 3-oxo-3-(pyrazin-2-yl)propionate (2t)

[0212] Using pyrazin-2-carboxylic acid as a raw material, intermediate ethyl 3-oxo-3-(pyrazin-2-yl)propionate 2t was prepared by referring to the synthesis method of ethyl 3-oxopentanoate (2a). It was a white solid and was directly used in the next step without purification.

[0213] Example 8. Synthesis of intermediates 2u, 2v, 2w, 2x, 2y, 2z, 2z1

[0214] Intermediates 2u, 2v, 2w, 2x, 2y, 2z, and 2z1 were prepared from thiophene-2-carboxylic acid, thiophene-3-carboxylic acid, furan-2-carboxylic acid, furan-3-carboxylic acid, (thiazol-2-yl)carboxylic acid, (thiazol-5-yl)carboxylic acid, and (thiazol-4-yl)carboxylic acid, respectively, following the synthesis method of ethyl 4-methyl-3-oxovalerate (2b). All were white solids and proceeded directly to the next step without purification.

[0215] 2w: 1 H NMR(400MHz,Chloroform-d)δ7.72(dd,J=3.9,1.1Hz,1H),7.68(dd,J=5.0,1.1Hz,1H), 7.13(dd,J=4.9,3.8Hz,1H),4.19(q,J=7.1Hz,2H),3.90(s,2H),1.24(t,J=7.1Hz,3H).

[0216] Example 9. Synthesis of (Z)-2-(hydroxyimino)-3-oxovalerate ethyl ester (3a)

[0217] Ethyl 3-oxovalerate 2a (1.5 g, 8.67 mmol) was dissolved in 10 mL of glacial acetic acid and 5 mL of water, and stirred in an ice-water bath. Sodium nitrite (718 mg, 10.40 mmol, 1.2 times the amount) was accurately weighed and dissolved in 5 mL of water, and then slowly added dropwise to the above reaction solution. After the reaction was complete, 20 mL of water and ethyl acetate (30 mL × 2) were added for extraction twice. The organic phase was collected, washed twice with 60 mL of water, and once with 30 mL of saturated brine. The mixture was dried over anhydrous sodium sulfate and rotary evaporated under reduced pressure to obtain a transparent oily substance with a yield of 76%. This product was directly used for the next step without purification.

[0218] Example 10. Synthesis of (Z)-2-(hydroxyimino)-4-methyl-3-oxovalerate ethyl ester (3b)

[0219] Starting from ethyl 4-methyl-3-oxovalerate 2b, intermediate (Z)-2-(hydroxyimino)-4-methyl-3-oxovalerate 3b was prepared following the synthetic method of (Z)-2-(hydroxyimino)-3-oxovalerate 3a. The intermediate was a clear oil, yield: 85%. ESI-MS m / z: 185.7 [MH] - . 1H NMR (400MHz, Chloroform-d) δ9.61 (s, 1H), 4.37 (q, J = 7.1Hz, 2H), 3.40 (hept, J = 6.9Hz, 1H), 1.34 (t, J = 7.2Hz, 3H), 1.14 (d, J = 6.9Hz, 6H).

[0220] Example 11. Synthesis of intermediate 3c-3z1

[0221] Intermediates 3c-3z1 were prepared using 2c, 2d, 2e, 2f, 2g, 2h, 2i, 2j, 2k, 2l, 2m, 2n, 2o, 2p, 2q, 2r, 2s, 2t, 2u, 2v, 2w, 2x, 2y, 2z, and 2zl as starting materials, respectively, following the synthesis method of (Z)-2-(hydroxyimino)-3-oxovalerate ethyl ester (3a). All of them were transparent oily substances.

[0222] 3c: Yield: 79%.

[0223] (Z)-3-cyclopropyl-2-(hydroxyimino)-3-oxopropionic acid ethyl ester (3d): Yield: 76%. ESI-MS m / z: 186.1 [M+H] + ;208.1[M+Na] + . 1 H NMR(400MHz,Chloroform-d)δ10.04(s,1H),4.36(q,J=7.1Hz,2H),2.74(tt,J =7.9,4.6Hz,1H),1.33(t,J=7.1Hz,3H),1.22–1.17(m,2H),1.06–0.99(m,2H).

[0224] (Z)-2-(hydroxyimino)-3-(1-methylcyclopropyl)-3-oxopropionic acid ethyl ester (3e): Yield: 82%.

[0225] (Z)-3-cyclobutyl-2-(hydroxyimino)-3-oxopropionic acid ethyl ester (3f): Yield: 78%. 1 H NMR(400MHz,Chloroform-d)δ9.74(s,1H),4.36(q,J=7.1Hz,2H),3.87(pd,J=8.5,1.0Hz,1H),2. 37–2.25(m,2H),2.23–2.10(m,2H),2.04–1.93(m,1H),1.93–1.78(m,1H),1.34(t,J=7.1Hz,3H).

[0226] (Z)-2-(hydroxyimino)-3-(1-methylcyclobutyl)-3-oxopropionic acid ethyl ester (3g): Yield: 83%.

[0227] (Z)-3-cyclopentyl-2-(hydroxyimino)-3-oxopropionic acid ethyl ester (3h): Yield: 75%. ESI-MS m / z: 211.5 [MH] - . 1 H NMR(400MHz,Chloroform-d)δ9.34(s,1H),4.37(q,J=7.2Hz,2H),3.61–3.51(m,1H ),1.88–1.78(m,4H),1.72–1.65(m,2H),1.63–1.56(m,2H),1.35(t,J=7.1Hz,3H).

[0228] (Z)-3-cyclohexyl-2-(hydroxyimino)-3-oxopropionic acid ethyl ester (3i): Yield: 82%. ESI-MS m / z: 250.1 [M+Na] + . 1 H NMR (400MHz, Chloroform-d) δ9.14(s,1H),4.37(q,J=7.1Hz,2H),3.15(tt,J=11.5,3.3Hz,1H),1.90–1.75(m,4H),1.72–1.65(m,1H),1.46–1.24(m,8H).

[0229] (Z)-2-(hydroxyimino)-4-methoxy-3-oxobutyrate ethyl ester (3j): Yield: 86%. Mp 119.2-120.3℃. ESI-MS m / z: 187.6 [MH] - . 1 H NMR (400MHz, Chloroform-d) δ10.00 (s, 1H), 4.54 (s, 2H), 4.39 (q, J = 7.2Hz, 2H), 3.47 (s, 3H), 1.35 (t, J = 7.1Hz, 3H).

[0230] (Z)-4,4-difluoro-2-(hydroxyimino)-3-oxobutyrate ethyl ester (3k): Yield: 85%. ESI-MS m / z: 193.6 [MH] - .

[0231] (Z)-4,4,4-trifluoro-2-(hydroxyimino)-3-oxobutyrate ethyl ester (3l): Yield: 85%. ESI-MS m / z: 212.4 [MH] - .

[0232] (Z)-2-(hydroxyimino)-3-oxobutyrate ethyl ester-4,4,4-D3(3m): Yield: 74%.

[0233] 3n: Yield: 80%.

[0234] (Z)-3-(3,3-difluorocyclobutyl)-2-(hydroxyimino)-3-oxopropionic acid ethyl ester (3o): Yield: 78%.

[0235] (Z)-2-(hydroxyimino)-3-oxo-3-phenylpropionic acid ethyl ester (3p): Yield: 78%. Mp 118.0-119.2℃. ESI-MS (m / z) = 220.1 [MH] - . 1 H NMR (400MHz, DMSO-d6) δ13.05(s,1H),7.84–7.79(m,2H),7.76–7.70(m,1H),7.59(t,J=7.7Hz,2H),4.25(q,J=7.1Hz,2H),1.20(t,J=7.1Hz,3H).

[0236] Ethyl (Z)-2-(hydroxyimino)-3-oxo-3-(pyridin-4-yl)propionate (3q): Yield: 62%. Mp 153.4-153.6℃. ESI-MS m / z: 223.1 [M+H] + 245.1 [M+Na] + . 1 H NMR (400MHz, DMSO-d6) δ13.32(s,1H),9.03–8.79(m,2H),7.79–7.66(m,2H),4.26(q,J=7.1Hz,2H),1.20(t,J=7.1Hz,3H).

[0237] Ethyl (Z)-2-(hydroxyimino)-3-oxo-3-(pyridin-3-yl)propionate (3r): Yield: 65%. Mp 132.5-136.1℃. ESI-MS m / z: 223.1 [M+H] + 245.1 [M+Na] + . 1 H NMR(400MHz,Chloroform-d)δ9.64(d,J=1.8Hz,1H),8.71(dd,J=5.0,1.7Hz,1H),8.41(dd,J=8 .1,1.9Hz,1H),7.59(ddd,J=8.1,5.0,0.8Hz,1H),4.48(q,J=7.2Hz,2H),1.43(t,J=7.1Hz,3H).

[0238] (Z)-2-(hydroxyimino)-3-oxo-3-(pyridin-2-yl)propionate ethyl ester (3s): Yield: 56%.

[0239] Ethyl (Z)-2-(hydroxyimino)-3-oxo-3-(pyrazin-2-yl)propionate (3t): Yield: 66%. Mp 216.2-231.6℃. ESI-MS m / z: 224.1 [M+H] + 246.1 [M+Na] + . 1 H NMR(400MHz,Chloroform-d)δ10.44(s,1H),9.28(d,J=1.5Hz,1H),8.81(d,J=2.5 Hz, 1H), 8.69 (dd, J=2.5, 1.5Hz, 1H), 4.31 (q, J=7.1Hz, 2H), 1.26 (t, J=7.1Hz, 3H).

[0240] Ethyl (Z)-2-(hydroxyimino)-3-oxo-3-(thiophen-2-yl)propionate (3u): Yield: 86%. Mp 118.2-119.7℃. ESI-MS m / z: 250.0 [M+Na] + . 1 H NMR(400MHz,Chloroform-d)δ9.62(s,1H),7.80(dt,J=4.9,0.9Hz,1H),7.63(dt,J =3.9,0.9Hz,1H),7.20–7.15(m,1H),4.32(q,J=7.1Hz,2H),1.27(t,J=7.1Hz,3H).

[0241] Ethyl (Z)-2-(hydroxyimino)-3-oxo-3-(thiophen-3-yl)propionate (3v): Yield: 81%. Mp 117.6-117.9℃. ESI-MS m / z: 250.0 [M+Na] + . 1 H NMR(400MHz,Chloroform-d)δ9.63(s,1H),8.07(dd,J=2.9,1.2Hz,1H),7.54(dd,J=5.1 ,1.2Hz,1H),7.37(dd,J=5.2,2.9Hz,1H),4.31(q,J=7.1Hz,2H),1.26(t,J=7.1Hz,3H).

[0242] Ethyl (Z)-3-(furan-2-yl)-2-(hydroxyimino)-3-oxopropionic acid (3w): Yield: 76%. Mp 122.7-126.2℃. ESI-MS m / z: 212.0 [M+H] + ;234.1[M+Na] + .

[0243] (Z)-3-(furan-3-yl)-2-(hydroxyimino)-3-oxopropionic acid ethyl ester (3x): Yield: 78%. Mp 118.0-120.0℃. ESI-MS m / z: 234.0 [M+Na] + . 1 H NMR (400MHz, DMSO-d6) δ9.83(s,1H),8.30(t,J=1.1Hz,1H),7.42(t,J=1.7Hz,1H),6.88(d,J=2.0Hz,1H),4.42(q,J=7.1Hz,2H),1.37(t,J=7.1Hz,3H).

[0244] (Z)-2-(hydroxyimino)-3-oxo-3-(thiazolyl-2-yl)propionate ethyl ester (3y): Yield: 75%.

[0245] Ethyl (Z)-2-(hydroxyimino)-3-oxo-3-(thiazolyl-5-yl)propionate (3z): Yield: 77%.

[0246] Ethyl (Z)-2-(hydroxyimino)-3-oxo-3-(thiazol-4-yl)propionate (3z1): Yield: 72%. Mp 139.8-140.1℃. ESI-MS m / z: 229.0 [M+H] + ; 251.0 [M+Na] + .

[0247] Example 12. Synthesis of ethyl 2-(3-cyanophenyl)-4-ethyl-1-hydroxy-1H-imidazolium-5-carboxylate (4a)

[0248] Ethyl (Z)-2-(hydroxyimino)-3-oxovalerate 3a (1 g, 5.78 mmol) and 3-cyanobenzaldehyde (757 mg, 5.78 mmol, 1 fold volume) were dissolved in 8 mL of glacial acetic acid solution. Then, ammonium acetate (4.46 g, 57.80 mmol, 10 fold volume) was added. The reaction mixture was then protected with nitrogen and heated to 50 °C. After the reaction was complete, the mixture was cooled to room temperature, and 16 mL of water was slowly added. The mixture was stirred at room temperature for 5 hours until a white solid precipitated. The precipitate was filtered, washed twice with water, dried, and then recrystallized from ethanol / water (6:1) to obtain a white solid (1.1 g), yield: 67%.

[0249] Example 13. Synthesis of ethyl 2-(3-cyanophenyl)-1-hydroxy-4-isopropyl-1H-imidazolium-5-carboxylate (4b)

[0250] Starting from (Z)-2-(hydroxyimino)-4-methyl-3-oxovalerate ethyl ester (3b), intermediate 2-(3-cyanophenyl)-1-hydroxy-4-isopropyl-1H-imidazolium-5-carboxylate ethyl ester 4b was prepared following the synthetic method of 2-(3-cyanophenyl)-4-ethyl-1-hydroxy-1H-imidazolium-5-carboxylate (4a). The product was a white solid, yield: 59%. Mp 110.1-110.6℃. ESI-MS m / z: 300.1 [M+H] + 322.1[M+Na] + . 1 H NMR (400MHz, DMSO-d6) δ8.39(t,J=1.6Hz,1H),8.35(dt,J=8.1,1.4Hz,1H),7.92(dt,J=7.8,1.4Hz,1H),7.72(td, J=7.9,0.6Hz,1H),4.31(q,J=7.1Hz,2H),3.48(hept,J=6.8Hz,1H),1.32(t,J=7.1Hz,3H),1.23(d,J=6.8Hz,6H).

[0251] Example 14. Synthesis of intermediate 4c-4z1

[0252] Intermediates 4c-4z1 were prepared using 3c, 3d, 3e, 3f, 3g, 3h, 3i, 3j, 3k, 3l, 3m, 3n, 3o, 3p, 3q, 3r, 3s, 3t, 3u, 3v, 3w, 3x, 3y, 3z, and 3zl as starting materials, respectively, following the synthetic method of ethyl 2-(3-cyanophenyl)-4-ethyl-1-hydroxy-1H-imidazolium-5-carboxylate (4a).

[0253] 2-(3-Cyanophenyl)-1-hydroxy-4-isobutyl-1H-imidazolium-5-carboxylic acid ethyl ester 4c: white solid, yield: 76%. Mp 105.9-107.2℃. ESI-MS m / z: 314.2 [M+H] + 336.2 [M+Na] + . 1H NMR (400MHz, DMSO-d6) δ12.23(s,1H),8.38(t,J=1.7Hz,1H),8.35(dt,J=8.0,1.4Hz,1H),7.92(dt,J=7.7,1.4Hz,1H),7.72(t,J=7 .9Hz,1H),4.30(q,J=7.1Hz,2H),2.67(d,J=7.1Hz,2H),2.08–1.90(m,J=6.7Hz,1H),1.32(t,J=7.1Hz,3H),0.90(d,J=6.6Hz,6H).

[0254] 2-(3-Cyanophenyl)-4-cyclopropyl-1-hydroxy-1H-imidazolium-5-carboxylic acid ethyl ester (4d): white solid, yield: 72%. Mp 200.8-202.5℃. ESI-MS m / z: 298.1 [M+H] + 320.0 [M+Na] + . 1 H NMR (400MHz, DMSO-d6) δ12.21(s,1H),8.41–8.32(m,1H),8.30(dt,J=8.0,1.4Hz,1H),7.91(dt,J=7.8,1.4Hz ,1H),7.75–7.66(m,1H),4.33(q,J=7.1Hz,2H),2.55–2.51(m,1H),1.33(t,J=7.1Hz,3H),0.98–0.89(m,4H).

[0255] 2-(3-Cyanophenyl)-1-hydroxy-4-(1-methylcyclopropyl)-1H-imidazolium-5-carboxylic acid ethyl ester (4e): white solid, yield: 78%. ESI-MS m / z: 312.2 [M+H] + 334.2 [M+Na] + . 1 H NMR (400MHz, DMSO-d6) δ12.23(s,1H),8.37(t,J=1.7Hz,1H),8.33(dt,J=8.0,1.4Hz,1H),7.91(dt,J=7.8,1.4 Hz,1H),7.71(t,J=7.9Hz,1H),4.33(q,J=7.1Hz,2H),1.41–1.28(m,6H),0.96–0.83(m,2H),0.72–0.62(m,2H).

[0256] 2-(3-Cyanophenyl)-4-cyclobutyl-1-hydroxy-1H-imidazolium-5-carboxylic acid ethyl ester (4f): white solid, yield: 81%. Mp 130.7-132.0℃. ESI-MS m / z: 312.1 [M+H] + 334.1 [M+Na] + . 1 H NMR (400MHz, DMSO-d6) δ8.44–8.34(m,2H),7.93(dt,J=7.7,1.4Hz,1H),7.74(t,J=7.9Hz,1H),4.30(q,J=7.1Hz,2H),3.95(p ,J=8.1Hz,1H),2.44–2.28(m,2H),2.21(qt,J=8.6,2.8Hz,2H),2.06–1.92(m,1H),1.91–1.77(m,1H),1.32(t,J=7.1Hz,3H).

[0257] 2-(3-Cyanophenyl)-1-hydroxy-4-(1-methylcyclobutyl)-1H-imidazolium-5-carboxylic acid ethyl ester (4 g): white solid, yield: 52%. Mp 117.1-117.1℃. ESI-MS m / z: 326.2 [M+H] + 348.2 [M+Na] + . 1 H NMR (400MHz, DMSO-d6) δ12.21(s,1H),8.38(t,J=1.7Hz,1H),8.35(dt,J=8.1,1.4Hz,1H),7.92(dt,J=7.7,1.4Hz,1H),7.72(t,J =7.9Hz,1H),4.28(q,J=7.1Hz,2H),2.58–2.51(m,2H),2.09–1.96(m,3H),1.78–1.64(m,1H),1.47(s,3H),1.31(t,J=7.1Hz,3H).

[0258] Ethyl 2-(3-cyanophenyl)-4-cyclopentyl-1-hydroxy-1H-imidazolium-5-carboxylate (4h): white solid, yield: 72%. Mp 127.1-129.7℃. ESI-MS m / z: 326.1 [M+H] + 348.1 [M+Na] + . 1H NMR (400MHz, Chloroform-d) δ12.44(s,1H),8.52(td,J=1.7,0.6Hz,1H),8.44(ddd,J=8.0,1.8,1.2Hz,1H),7.66(dt,J=7.7,1.4Hz,1H ),7.56(td,J=7.9,0.6Hz,1H),4.48(q,J=7.1Hz,2H),3.57–3.44(m,1H),2.02–1.83(m,6H),1.72–1.64(m,2H),1.45(t,J=7.1Hz,3H).

[0259] 2-(3-Cyanophenyl)-4-cyclohexyl-1-hydroxy-1H-imidazolium-5-carboxylic acid ethyl ester (4i): white solid, yield: 75%. Mp 138.1-138.3℃. ESI-MS m / z: 340.0 [M+H] + 362.1 [M+Na] + . 1 H NMR(400MHz,Chloroform-d)δ12.40(s,1H),8.52(dt,J=1.6,0.8Hz,1H),8.48–8.41(m,1H),7.66(dt,J=7.7,1.4Hz,1H),7.56(td,J=7.8,0.6 Hz,1H),4.48(q,J=7.1Hz,2H),3.06(tt,J=11.8,3.3Hz,1H),1.92–1.81(m,4H),1.78–1.66(m,3H),1.46(t,J=7.1Hz,3H),1.41–1.31(m,3H).

[0260] 2-(3-Cyanophenyl)-1-hydroxy-4-(methoxymethyl)-1H-imidazolium-5-carboxylic acid ethyl ester (4j): white solid, yield: 69%. ESI-MS m / z: 302.06 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ12.44(s,1H),8.44–8.39(m,1H),8.39–8.33(m,1H),7.94(dt,J=7.7,1.4Hz,1H ),7.74(td,J=7.9,0.6Hz,1H),4.52(s,2H),4.33(q,J=7.1Hz,2H),3.30(s,3H),1.33(t,J=7.1Hz,3H).

[0261] 2-(3-cyanophenyl)-4-(difluoromethyl)-1-hydroxy-1H-imidazolium-5-carboxylic acid ethyl ester (4k): white solid, yield: 73%. Mp 149.3-152.4℃. ESI-MS m / z: 305.9 [MH] - . 1 H NMR (400MHz, DMSO-d6) δ12.86(s,1H),8.42(d,J=1.7Hz,1H),8.37(dt,J=8.0,1.4Hz,1H),7.99(dt,J=7.8,1.4H z,1H),7.76(t,J=7.9Hz,1H),7.19(t,J=53.8Hz,1H),4.36(q,J=7.1Hz,2H),2.12(s,1H),1.34(t,J=7.1Hz,3H).

[0262] 2-(3-cyanophenyl)-4-(trifluoromethyl)-1-hydroxy-1H-imidazolium-5-carboxylic acid ethyl ester (4l): white solid, proceeded directly to the next step without purification.

[0263] 2-(3-cyanophenyl)-1-hydroxy-4-(methyl-D3)-1H-imidazolium-5-carboxylic acid ethyl ester (4m): white solid, yield: 82%. Mp 164.5-164.9℃. ESI-MS m / z: 275.2 [M+H] + 297.1 [M+Na] + . 1 H NMR (400MHz, DMSO-d6) δ12.28(s,1H),8.39(t,J=1.7Hz,1H),8.35(dt,J=8.1,1.4Hz,1H),7.9 2(dt,J=7.7,1.4Hz,1H),7.71(t,J=7.9Hz,1H),4.30(q,J=7.1Hz,2H),1.32(t,J=7.1Hz,3H).

[0264] 2-(3-Cyanophynyl)-4-(2,2-difluorocyclopropyl)-1-hydroxy-1H-imidazolium-5-carboxylic acid ethyl ester (4n): white solid, yield: 62%. Mp 145.0-146.9℃. ESI-MS m / z: 334.2 [M+H] + 356.1 [M+Na] + . 1H NMR (400MHz, DMSO-d6) δ12.50(s,1H),8.42–8.36(m,1H),8.35(dt,J=8.0,1.4Hz,1H),7.94(dt,J=7.7,1.4Hz,1H),7.73(t, J=7.9Hz,1H),4.44–4.24(m,2H),3.23(td,J=11.9,8.1Hz,1H),2.27–2.12(m,1H),2.06–1.91(m,1H),1.33(t,J=7.1Hz,3H).

[0265] 2-(3-Cyanophynyl)-4-(3,3-difluorocyclobutyl)-1-hydroxy-1H-imidazolium-5-carboxylic acid ethyl ester (4o): white solid, yield: 61%. Mp 155.5-157.1℃. ESI-MS m / z: 348.2 [M+H] + 370.1 [M+Na] + . 1 H NMR (400MHz, DMSO-d6) δ12.42(s,1H),8.44–8.41(m,1H),8.38(dt,J=8.1,1.5Hz,1H),7.94(dt,J=7.8,1.4Hz,1H),7.7 4(td,J=7.9,0.6Hz,1H),4.32(q,J=7.1Hz,2H),3.77(pd,J=8.5,2.9Hz,1H),3.03–2.83(m,4H),1.33(t,J=7.1Hz,3H).

[0266] 2-(3-cyanophenyl)-1-hydroxy-4-phenyl-1H-imidazolium-5-carboxylic acid ethyl ester (4p): white solid, yield: 86%. Mp 124.6-124.9℃. ESI-MS m / z: 334.1 [M+H] + 356.0 [M+Na] + . 1 H NMR (400MHz, DMSO-d6) δ12.52(s,1H),8.47(d,J=1.7Hz,1H),8.42(dt,J=8.1,1.4Hz,1H),7.96(dt,J =7.8,1.4Hz,1H),7.79–7.71(m,3H),7.46–7.35(m,3H),4.29(q,J=7.1Hz,2H),1.22(t,J=7.1Hz,3H).

[0267] 2-(3-cyanophenyl)-1-hydroxy-4-(pyridin-4-yl)-1H-imidazolium-5-carboxylic acid ethyl ester (4q): white solid, yield: 59%. Mp 172.1-176.9℃. ESI-MS m / z: 335.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ13.32(s,1H),8.64–8.58(m,2H),8.48(t,J=1.6Hz,1H),8.39(dt,J=8.1,1.4Hz,1H),7.8 8(dt,J=7.8,1.4Hz,1H),7.76–7.70(m,2H),7.69(t,J=7.9Hz,1H),4.31(q,J=7.1Hz,2H),1.25(t,J=7.1Hz,3H).

[0268] 2-(3-cyanophenyl)-1-hydroxy-4-(pyridin-3-yl)-1H-imidazolium-5-carboxylic acid ethyl ester (4r): white solid, yield: 51%. Mp 156.5-157.6℃. ESI-MS m / z: 335.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.92(s,1H),8.58(s,1H),8.48(t,J=1.7Hz,1H),8.43(dt,J=8.0,1.4Hz,1H),8.13(dt,J=7.9,1.7Hz,1H),8.0 1–7.95(m,1H),7.77(t,J=7.9Hz,1H),7.48(dd,J=7.9,4.8Hz,1H),4.29(q,J=7.1Hz,2H),1.21(t,J=7.1Hz,3H),1.05(t,J=7.0Hz,1H).

[0269] 2-(3-Cyanophane)-1-hydroxy-4-(pyridin-2-yl)-1H-imidazolium-5-carboxylic acid ethyl ester (4s): white solid, yield: 63%. Mp 145.0-146.9℃. ESI-MS m / z: 334.2 [M+H] + 356.1 [M+Na] + . 1H NMR (400MHz, DMSO-d6) δ12.50(s,1H),8.42–8.36(m,1H),8.35(dt,J=8.0,1.4Hz,1H),7.94(dt,J=7.7,1.4Hz,1H),7.73(t, J=7.9Hz,1H),4.44–4.24(m,2H),3.23(td,J=11.9,8.1Hz,1H),2.27–2.12(m,1H),2.06–1.91(m,1H),1.33(t,J=7.1Hz,3H).

[0270] 2-(3-Cyanophane)-1-hydroxy-4-(pyrazin-2-yl)-1H-imidazolium-5-carboxylic acid ethyl ester (4t): white solid, yield: 66%. ESI-MS m / z: 336.0 [M+H] + 358.1 [M+Na] + . 1 H NMR (400MHz, DMSO-d6) δ9.09(d,J=1.5Hz,1H),8.66(dd,J=2.6,1.5Hz,1H),8.62(d,J=2.6Hz,1H),8.47(t,J=1.7Hz,1H),8. 42(dt,J=8.0,1.4Hz,1H),7.98(dt,J=7.7,1.4Hz,1H),7.77(t,J=7.9Hz,1H),4.30(q,J=7.1Hz,2H),1.20(t,J=7.1Hz,3H).

[0271] 2-(3-cyanophenyl)-1-hydroxy-4-(thiophen-2-yl)-1H-imidazolium-5-carboxylic acid ethyl ester (4u): white solid, yield: 69%. Mp 154.3-155.0℃. ESI-MS m / z: 340.1 [M+H] + 362.1 [M+Na] + . 1 H NMR (400MHz, DMSO-d6) δ12.53(s,1H),8.44(t,J=1.7Hz,1H),8.39(dt,J=8.0,1.4Hz,1H),7.98(dt,J=7.8,1.4Hz,1H),7.84(dd,J=3.7,1 .2Hz,1H),7.77(t,J=7.9Hz,1H),7.60(dd,J=5.1,1.2Hz,1H),7.13(dd,J=5.1,3.7Hz,1H),4.40(q,J=7.1Hz,2H),1.35(t,J=7.1Hz,3H).

[0272] 2-(3-cyanophenyl)-1-hydroxy-4-(thiophen-3-yl)-1H-imidazolium-5-carboxylic acid ethyl ester (4v): white solid, yield: 61%. Mp 163.9-164.5℃. ESI-MS m / z: 340.1 [M+H] + 362.0 [M+Na] + . 1 H NMR (400MHz, DMSO-d6) δ12.46(s,1H),8.47(d,J=1.7Hz,1H),8.44–8.38(m,1H),8.03(dd,J=3.0,1.3Hz,1H),7.96(dd,J=7.8,1.4Hz ,1H),7.76(t,J=7.9Hz,1H),7.63(dd,J=5.0,1.3Hz,1H),7.57(dd,J=5.1,3.0Hz,1H),4.35(q,J=7.1Hz,2H),1.31(t,J=7.1Hz,3H).

[0273] 2-(3-cyanophenyl)-4-(furan-2-yl)-1-hydroxy-1H-imidazolium-5-carboxylic acid ethyl ester (4w): white solid, yield: 68%. Mp 158.1-162.0℃. ESI-MS m / z: 324.1 [M+H] + 346.0 [M+Na] +

[0274] 2-(3-cyanophenyl)-4-(furan-3-yl)-1-hydroxy-1H-imidazol-5-carboxylic acid ethyl ester (4x): white solid, yield: 76%. 1 H NMR(400MHz, DMSO-d6)δ8.46(t,J=1.7Hz,1H),8.41(dt,J=8.0,1.5Hz,1H),8.28–8.21(m,1H),7.97(dt ,J=7.8,1.4Hz,1H),7.79–7.72(m,2H),7.03–7.01(m,1H),4.38(q,J=7.1Hz,2H),1.34(t,J=7.1Hz,3H)

[0275] 2-(3-Cyanophynyl)-1-hydroxy-4-(thiazolyl-2-yl)-1H-imidazolium-5-carboxylic acid ethyl ester (4y): white solid, yield: 71%. ESI-MS m / z: 341.1 [M+H] + 363.1 [M+Na] + . 1H NMR (400MHz, DMSO-d6) δ12.88(s,1H),8.43(t,J=1.7Hz,1H),8.38(dt,J=8.0,1.4Hz,1H),7.98(dt,J=7.8,1.4Hz,1H ),7.90(d,J=3.3Hz,1H),7.80(d,J=3.2Hz,1H),7.77(t,J=8.0Hz,1H),4.36(q,J=7.1Hz,2H),1.29(t,J=7.1Hz,3H).

[0276] 2-(3-cyanophenyl)-1-hydroxy-4-(thiazolyl-5-yl)-1H-imidazolium-5-carboxylic acid ethyl ester (4z): white solid, yield: 68%. Mp 112.3-113.0℃. ESI-MS m / z: 341.1 [M+H] + 363.1 [M+Na] + . 1 H NMR (400MHz, DMSO-d6) δ12.68(s,1H),9.13(s,1H),8.54(s,1H),8.45(t,J=1.7Hz,1H),8.39(dt,J=8.0,1. 5Hz,1H),7.99(dt,J=7.7,1.4Hz,1H),7.77(t,J=7.9Hz,1H),4.41(q,J=7.1Hz,2H),1.36(t,J=7.1Hz,3H).

[0277] 2-(3-cyanophenyl)-1-hydroxy-4-(thiazolyl-4-yl)-1H-imidazolium-5-carboxylic acid ethyl ester (4z1): white solid, yield: 79%. Mp 183.1-184.2℃. ESI-MS m / z: 341.1 [M+H] + 363.1 [M+Na] + . 1 H NMR (400MHz, DMSO-d6) δ12.62(s,1H),9.14(d,J=2.0Hz,1H),8.45(t,J=1.7Hz,1H),8.40(dt,J=8.1,1.4Hz,1H),8.0 3(d,J=2.0Hz,1H),7.96(dt,J=7.7,1.4Hz,1H),7.76(t,J=7.9Hz,1H),4.29(q,J=7.1Hz,2H),1.23(t,J=7.1Hz,3H).

[0278] Example 15. Synthesis of methyl (6-bromopyridin-3-yl)methanesulfonate (A-2a)

[0279] (6-Bromopyridin-3-yl)methanol (A-1a) was dissolved in anhydrous tetrahydrofuran, and 2.5 times the amount of triethylamine was added, while the temperature was lowered to 0°C. Then, methanesulfonyl chloride (1.05 times the amount) was dissolved in anhydrous tetrahydrofuran and slowly added dropwise to the above reaction solution. After 5 minutes of addition, the mixture was transferred to room temperature and stirred. The reaction was monitored by TLC until complete. The pH was adjusted to approximately 7 with 0.5M hydrochloric acid, followed by extraction with ethyl acetate / water. The mixture was washed twice with saturated brine, and the organic layer was collected and dried over anhydrous sodium sulfate. The residue was then evaporated under reduced pressure to obtain a clear oil, which was proceeded directly to the next step without purification.

[0280] Example 16. Synthesis of methyl (5-bromopyridin-2-yl)methanesulfonate (A-2b)

[0281] Starting with (5-bromopyridin-2-yl)methanol (A-1b), the procedure was the same as that for the synthesis of A-2a. The resulting oily, transparent substance was proceeded directly to the next step without purification.

[0282] Example 17. Synthesis of thiazol-2-ylmethanol (B-2b)

[0283] Thiazole-2-carboxylic acid B-1b (500 mg, 3.88 mmol) was dissolved in anhydrous tetrahydrofuran and stirred at 0 °C. Then, lithium aluminum hydride (2 times the amount, 294 mg, 7.75 mmol) was added in batches. The mixture was then transferred to room temperature and stirred for another 1 h. After the reaction was confirmed to be complete by TLC, water was slowly added dropwise to quench the reaction. The mixture was then filtered, and the filtrate was collected and extracted with ethyl acetate (25 mL × 2) and saturated brine. The organic phase was collected and dried with anhydrous sodium sulfate. The product was then evaporated under reduced pressure to obtain a transparent oily substance, 350 mg, yield: 78%. This product was used directly in the next step without purification.

[0284] Example 18. Synthesis of thiazol-4-ylmethanol (B-2c)

[0285] Using thiazol-4-carboxylic acid as the starting material, the preparation method was the same as that for the synthesis of thiazol-2-ylmethanol (B-2b), resulting in a transparent oily substance, which was then directly proceeded to the next step without purification.

[0286] Example 19. Synthesis of thiazol-5-ylmethylmethanesulfonate (B-3a)

[0287] Thiazole-5-methanol (560 mg, 4.87 mmol) was dissolved in 15 mL of anhydrous tetrahydrofuran and placed in an ice-water bath. Triethylamine (2.5 times the volume) was added, followed by the weighing of methanesulfonyl chloride (1.5 times the volume) dissolved in 3 mL of anhydrous tetrahydrofuran. The mixture was thoroughly mixed and then slowly added dropwise to the above solution. After the addition was complete, the mixture was transferred to room temperature and stirred until the reaction was complete. 5 mL of 0.5 M dilute hydrochloric acid was added to quench the reaction, followed by the addition of 10 mL of water and 25 mL of ethyl acetate. The mixture was extracted twice, and the organic layer was collected, dried over anhydrous sodium sulfate, and evaporated under reduced pressure to obtain 706 mg of a pale yellow oil (yield: 75%). This oil was proceeded directly to the next step without purification.

[0288] Example 20. Synthesis of intermediates B-3b to B-3f

[0289] Using thiazole-2-methanol, thiazole-4-methanol, oxazole-5-methanol, thiazole-2-methanol, and oxazole-4-methanol as starting materials, respectively, and following the synthesis method of thiazole-5-ylmethylmethanesulfonate (B-3a), pale yellow oily substances B-3b to B-3f were obtained, which were then directly proceeded to the next step without purification.

[0290] Example 21. Synthesis of 2-aminothiazole-4-carboxylic acid ethyl ester (C-2a)

[0291] Thiourea and ethyl 3-bromo-2-oxopropionate were dissolved in anhydrous ethanol and refluxed overnight. After the reaction was complete, the reaction solution was rotary evaporated under reduced pressure until a solid precipitated. Water was then slowly added to the solid at room temperature with stirring. The mixture was then filtered, the filter cake was washed twice with water, and dried to obtain a yellow solid. ESI-MS m / z: 173.1 [M+H] + 195.0 [M+Na] + .

[0292] Example 22. Synthesis of 2-amino-5-methylthiazol-4-carboxylic acid ethyl ester (D-2a)

[0293] Starting with thiourea (4.31 g, 56.72 mmol) and ethyl 3-bromo-2-oxobutyrate (10 g, 51.56 mmol), the synthesis method was the same as that for ethyl 2-aminothiazole-4-carboxylate (C-2a), yielding 7.18 g of a yellow solid, with a yield of 81%. 1 HNMR (400MHz, Chloroform-d) δ5.53 (s, 2H), 4.32 (q, J = 7.1Hz, 2H), 2.57 (s, 3H), 1.36 (t, J = 7.1Hz, 3H).

[0294] Example 23.2 - Synthesis of ethyl [(tert-butoxycarbonyl)amino]thiazole-4-carboxylate (C-3a)

[0295] Ethyl 2-amino-5-methylthiazolyl-4-carboxylate D-2a (2 g, 11.63 mmol) was dissolved in 30 mL of dichloromethane and 30 mL of tetrahydrofuran. Triethylamine (2.35 g, 23.26 mmol, twice the volume) and 4-dimethylaminopyridine (1.42 g, 11.63 mmol, once the volume) were then added. The mixture was stirred at room temperature for 1 minute, followed by the addition of Boc anhydride (3.05 g, 13.96 mmol, 1.2 times the volume). After the reaction was complete, the solvent was removed by rotary evaporation under reduced pressure. Extraction was then performed using ethyl acetate (50 mL × 2) and 1 M citric acid aqueous solution (50 mL). The ethyl acetate layer was collected, washed once with water and once with saturated brine, and the organic layer was collected. The organic layer was dried over anhydrous sodium sulfate and then rotary evaporated under reduced pressure to obtain a yellow solid, which was proceeded directly to the next step without purification.

[0296] Example 24. Synthesis of tert-butyl [4-(hydroxymethyl)thiazolyl]carbamate (C-4a)

[0297] The crude product obtained in the previous step, ethyl 2-[(tert-butoxycarbonyl)amino]thiazole-4-carboxylate C-3a (1.5 g, 5.51 mmol), was dissolved in 20 mL of anhydrous tetrahydrofuran solution and stirred in an ice-water bath. Lithium aluminum hydride (419 mg, 11.03 mmol, twice the amount) was then added in batches. After the reaction was complete, water was slowly added dropwise to quench the reaction. The mixture was then filtered, and the filtrate was collected. Ethyl acetate (30 mL × 2) and water (20 mL) were added to the filtrate for extraction. The ethyl acetate layer was collected, washed once with saturated brine, and the organic layer was collected. The organic layer was then dried over anhydrous sodium sulfate and distilled under reduced pressure to give 532 mg of a pale yellow solid, yield: 42%. 1 HNMR(400MHz,Chloroform-d)δ6.73(s,1H),4.56(s,2H),1.56(s,9H).

[0298] Example 25. Synthesis of methyl 2-[(tert-butoxycarbonyl)amino]thiazol-4-yl}methanesulfonate (C-5a)

[0299] Starting with [4-(hydroxymethyl)thiazol-2-yl]tert-butyl carbamate C-4a, and following the synthesis method of thiazol-5-ylmethylmethanesulfonate (B-3a), a pale yellow oil was obtained, which was then directly proceeded to the next step without purification.

[0300] Example 26.2 Synthesis of ethyl bromothiazole-4-carboxylate (D-3a)

[0301] Ethyl 2-aminothiazolyl-4-carboxylate C-2a (5 g, 29.07 mmol) was dissolved in 30 mL of acetonitrile, and then tert-butyl nitrite (4.49 g, 43.61 mmol, 1.5 times the volume) and cuprous bromide (4.59 g, 31.98 mmol, 1.1 times the volume) were added. The reaction solution was then refluxed for 2 hours until the reaction was complete. The solution was filtered while hot, and the filtrate was collected. The filtrate was then evaporated under reduced pressure to obtain a white solid, which was directly used for the next step without purification.

[0302] Example 27. Synthesis of ethyl 2-bromo-5-methylthiazol-4-carboxylate (D-3b)

[0303] Using ethyl 2-amino-5-methylthiazol-4-carboxylate D-2a as a starting material, intermediate ethyl 2-bromo-5-methylthiazol-4-carboxylate D-3b was prepared by referring to the synthesis method of ethyl 2-bromothiazol-4-carboxylate D-3a. It was a white solid with a yield of 82%. 1 H NMR (400MHz, Chloroform-d) δ4.40 (q, J = 7.1Hz, 2H), 2.72 (s, 3H), 1.39 (t, J = 7.1Hz, 3H).

[0304] Example 28. Synthesis of ethyl 2-(dimethylamino)thiazole-4-carboxylate (D-4a)

[0305] The synthesis of ethyl 2-bromothiazol-4-carboxylate D-3a (1.2 g, 5.11 mmol) was dissolved in 25 mL of anhydrous tetrahydrofuran. Triethylamine (1.03 g, 10.21 mmol, twice the amount) was then added dropwise to the solution. The reaction mixture was placed in an ice-water bath. Dimethylamine (276 mg, 6.13 mmol, 1.2 times the amount) was weighed into 4 mL of anhydrous tetrahydrofuran solution and then slowly added dropwise to the reaction mixture. After the addition was complete, the reaction mixture was heated to 40 °C and the reaction continued. After the reaction was complete, the mixture was rotary evaporated under reduced pressure. 2 mL of 0.5 M dilute hydrochloric acid and 20 mL of water were added, and the mixture was extracted twice with ethyl acetate (25 mL × 2). The ethyl acetate was collected, washed once with water, and once with saturated brine. The organic layer was collected, dried over anhydrous sodium sulfate, and then rotary evaporated under reduced pressure to obtain 869 mg of a white solid, yield: 85%. 1 H NMR (400MHz, Chloroform-d) δ7.37 (s, 1H), 4.34 (q, J = 7.1Hz, 2H), 3.12 (s, 6H), 1.36 (t, J = 7.1Hz, 3H).

[0306] Example 29. Synthesis of ethyl (diethylamino)thiazole-4-carboxylate (D-4b)

[0307] Starting with diethylamine, and referring to the synthesis method of ethyl 2-(diethylamino)thiazole-4-carboxylate D-4a, intermediate ethyl 2-(diethylamino)thiazole-4-carboxylate D-4b was prepared. It was a white solid with a yield of 76%.

[0308] Example 30.2 Synthesis of ethyl morpholinothiazol-4-carboxylate (D-4c)

[0309] Starting with morpholine, and following the synthetic method for ethyl 2-(dimethylamino)thiazolium-4-carboxylate D-4a, the intermediate ethyl 2-morpholinothiazolium-4-carboxylate D-4c was prepared as a white solid in 91% yield. ESI-MS m / z: 243.1 [M+H] + 265.1 [M+Na] + . 1 H NMR (400MHz, Chloroform-d) δ7.47 (s, 1H), 4.35 (q, J = 7.2Hz, 2H), 3.80 (t, J = 4.9Hz, 4H), 3.51 (t, J = 4.9Hz, 4H), 1.36 (t, J = 7.2Hz, 3H).

[0310] Example 31. Synthesis of ethyl 1,5-methyl-2-morpholinothiazolyl-4-carboxylate (D-4d)

[0311] Starting with morpholine and ethyl 2-bromo-5-methylthiazol-4-carboxylate D-3b, and following the synthetic method of ethyl 2-(dimethylamino)thiazol-4-carboxylate D-4a, intermediate ethyl 5-methyl-2-morpholinothiazol-4-carboxylate D-4d was prepared as a white solid in 85% yield. It was proceeded directly to the next step without purification.

[0312] Example 32. Synthesis of [2-(dimethylamino)thiazol-4-yl]methanol (D-5a)

[0313] Starting from ethyl 2-(dimethylamino)thiazol-4-carboxylate D-4a, intermediate [2-(dimethylamino)thiazol-4-yl]methanol D-5a was prepared by referring to the synthesis method of [4-(hydroxymethyl)thiazol-2-yl]carbamate tert-butyl ester (C-4a). The intermediate was a white solid with a yield of 56%. 1 H NMR(400MHz,Chloroform-d)δ6.34(s,1H),4.52(s,2H),3.07(s,6H).

[0314] Example 33. Synthesis of [2-(diethylamino)thiazol-4-yl]methanol (D-5b)

[0315] Starting with ethyl 2-(diethylamino)thiazol-4-carboxylate D-4b, intermediate [2-(diethylamino)thiazol-4-yl]methanol D-5b was prepared using the same method as for [4-(hydroxymethyl)thiazol-2-yl]carbamate tert-butyl ester (C-4a). The resulting white solid was produced in 65% yield. It was then directly proceeded to the next step without purification.

[0316] Example 34. Synthesis of (2-morpholinothiazo-4-yl)methanol (D-5c)

[0317] Starting from ethyl 2-morpholinothiazol-4-carboxylate D-4c, intermediate (2-morpholinothiazol-4-yl)methanol D-5c was prepared following the synthetic method for [4-(hydroxymethyl)thiazol-2-yl]tert-butyl carbamate (C-4a). The resulting product was a white solid, yield: 63%. ESI-MS m / z: 201.1 [M+H] + 223.0[M+Na] + . 1 H NMR (400MHz, Chloroform-d) δ6.45 (s, 1H), 4.54 (d, J = 1.0Hz, 2H), 3.83–3.77 (m, 4H), 3.48–3.41 (m, 4H).

[0318] Example 35. Synthesis of (5-methyl-2-morpholinothiazo-4-yl)methanol (D-5d)

[0319] Starting from ethyl 5-methyl-2-morpholinothiazolyl-4-carboxylate D-4d, and following the synthetic method of ethyl 2-(dimethylamino)thiazolyl-4-carboxylate D-4a, intermediate (5-methyl-2-morpholinothiazolyl-4-yl)methanol D-5d was prepared as a white solid with a yield of 57%. 1 H NMR(400MHz,Chloroform-d)δ4.45(s,2H),3.78–3.74(m,4H),3.38–3.34(m,4H),2.25(s,3H).

[0320] Example 36. Synthesis of intermediates D-6a to D-6d

[0321] Intermediates D-6a to D-6d were prepared using D-5a, D-5b, D-5c, and D-5d as starting materials, respectively, following the synthesis method of thiazol-5-ylmethylmethanesulfonate (B-3a). All of them were oily substances and were directly used in the next step without purification.

[0322] Example 37.1 Synthesis of ethyl 5-(5a)-[(4-cyanobenzyl)oxy]-2-(3-cyanophenyl)-4-ethyl-1H-imidazolium-5-carboxylate

[0323] Ethyl 2-(3-cyanophenyl)-4-ethyl-1-hydroxy-1H-imidazolium-5-carboxylate 4a (500 mg, 1.75 mmol) was dissolved in 10 mL of N,N-dimethylformamide solution. Then, potassium carbonate (726 mg, 5.26 mmol, 3 times the volume) and potassium iodide (29 mg, 0.18 mmol, 0.1 times the volume) were weighed into the reaction solution and stirred at room temperature for 5 minutes. Next, p-cyanobenzyl chloride (319 mg, 2.1 mmol, 1.2 times the volume) was accurately weighed and added to the above reaction solution. The reaction solution was then heated to 50 °C under nitrogen protection. After the reaction was complete, the reaction solution was cooled to room temperature, and then 20 mL of ice water was slowly added dropwise. The mixture was stirred at room temperature until a solid precipitated. The solid was filtered, the filter cake was washed twice with water and twice with petroleum ether, dried, and the crude product was recrystallized from ethanol / water (10:1) to give 637 mg of a white solid, with a yield of 91%.

[0324] Mp 149.7-150.2℃.ESI-MS m / z:401.2[M+H] + 423.1[M+Na] + . 1 H NMR (400MHz, DMSO-d6) δ8.12–8.03(m,2H),7.91(d,J=7.8Hz,1H),7.73(d,J=8.1Hz,2H),7.65(t,J=7.8Hz,1H),7.40(d ,J=8.2Hz,2H),5.24(s,2H),4.35(q,J=7.1Hz,2H),2.85(q,J=7.5Hz,2H),1.33(t,J=7.1Hz,3H),1.21(t,J=7.5Hz,3H)

[0325] Example 38. Synthesis of intermediates 5b-5z1

[0326] Intermediates 5b to 5z1 were prepared using one of the following starting materials: 4b, 4c, 4d, 4e, 4f, 4g, 4h, 4i, 4j, 4k, 4l, 4m, 4n, 4o, 4p, 4q, 4r, 4s, 4t, 4u, 4v, 4w, 4x, 4y, 4z, 4z1, and p-cyanobenzyl chloride, respectively, with reference to the synthesis method of 1-[(4-cyanobenzyl)oxy]-2-(3-cyanophenyl)-4-ethyl-1H-imidazolium-5-carboxylic acid ethyl ester (5a).

[0327] 1-[(4-cyanobenzyl)oxy]-2-(3-cyanophenyl)-4-isopropyl-1H-imidazolium-5-carboxylic acid ethyl ester 5b: white solid, yield 88%. ESI-MS (m / z) = 415.1 [M+H] + 437.1 [M+Na]+ . 1 H NMR (400MHz, DMSO-d6) δ8.13–8.05(m,2H),7.92(dt,J=7.8,1.4Hz,1H),7.74(d,J=8.2Hz,2H),7.66(td,J=7.8,0.9Hz,1H),7.3 9(d,J=8.3Hz,2H),5.23(s,2H),4.35(q,J=7.1Hz,2H),3.56(hept,J=6.9Hz,1H),1.33(t,J=7.1Hz,3H),1.24(d,J=6.9Hz,7H).

[0328] 1-[(4-cyanobenzyl)oxy]-2-(3-cyanophenyl)-4-isobutyl-1H-imidazolium-5-carboxylic acid ethyl ester (5c): white solid, 92% yield. Mp 113.9-114.2℃. ESI-MS m / z: 429.2 [M+H] + 451.2 [M+Na] + . 1 H NMR(400MHz,Chloroform-d)δ8.26(t,J=1.7Hz,1H),8.13(dt,J=8.0,1.5Hz,1H),7.69(dt,J=7.8,1.4Hz,1H),7.60(d,J=8.3Hz,2H),7.53(t,J=7.9Hz,1 H),7.44–7.36(m,2H),5.14(s,2H),4.42(q,J=7.1Hz,2H),2.78(d,J=7.2Hz, 2H), 2.08(hept,J=6.8Hz,1H), 1.43(t,J=7.1Hz,3H), 0.97(d,J=6.6Hz,6H).

[0329] 1-[(4-cyanobenzyl)oxy]-2-(3-cyanophenyl)-4-cyclopropyl-1H-imidazolium-5-carboxylic acid ethyl ester (5d): white solid, yield 86%. Mp 128.3-128.9℃. ESI-MS (m / z) = 413.1 [M+H] + 435.0 [M+Na] + . 1H NMR (400MHz, DMSO-d6) δ8.04(td,J=1.8,0.7Hz,1H),8.03–7.98(m,1H),7.90(dt,J=7.8,1.4Hz,1H),7.77–7.69(m,2H),7.63(td,J=7.8,0 .7Hz,1H),7.46–7.36(m,2H),5.23(s,2H),4.37(q,J=7.1Hz,2H),2.61(p,J=6.6Hz,1H),1.34(t,J=7.1Hz,3H),1.01–0.93(m,4H).ESI-MS m / z:413.1[M+H] + 435.0 [M+Na] + .

[0330] 1-[(4-cyanobenzyl)oxy]-2-(3-cyanophenyl)-4-(1-methylcyclopropyl)-1H-imidazolium-5-carboxylic acid ethyl ester (5e): white solid, yield 79%. Proceeded directly to the next step without purification.

[0331] 1-[(4-cyanobenzyl)oxy]-2-(3-cyanophenyl)-4-cyclobutyl-1H-imidazolium-5-carboxylic acid ethyl ester (5f): white solid, yield 79%. Mp 161.2-161.4℃. ESI-MS (m / z) = 427.1 [M+H] + 449.2 [M+Na] + . 1 H NMR (400MHz, DMSO-d6) δ8.17–8.08(m,2H),7.92(d,J=7.8Hz,1H),7.74(d,J=8.1Hz,2H),7.67(t,J=7.8Hz,1H),7.41(d,J=8.2Hz,2H),5.23(s,2H),4. 34(q,J=7.1Hz,2H),4.02(p,J=8.6Hz,1H),2.44–2.31(m,2H),2.29–2.17( m,2H),2.07–1.92(m,1H),1.91–1.80(m,1H),1.33(t,J=7.1Hz,3H).ESI-MS m / z:427.1[M+H] + 449.2 [M+Na] + .

[0332] 1-[(4-cyanobenzyl)oxy]-2-(3-cyanophenyl)-4-(1-methylcyclobutyl)-1H-imidazolium-5-carboxylic acid ethyl ester (5 g): white solid, yield 83%. Mp 134.4-134.9℃. ESI-MS (m / z) = 441.3 [M+H]+ 463.2 [M+Na] + . 1 H NMR (400MHz, DMSO-d6) δ8.15–8.07(m,2H),7.92(dt,J=7.8,1.4Hz,1H),7.78–7.73(m,2H),7.67(td,J=7.8,0.8Hz,1H),7.43–7.36(m, 2H),5.23(s,2H),4.31(q,J=7.1Hz,2H),2.61–2.53(m,2H),2.16–1.98(m,3H),1.84–1.65(m,1H),1.49(s,3H),1.32(t,J=7.1Hz,3H).

[0333] 1-[(4-cyanobenzyl)oxy]-2-(3-cyanophenyl)-4-cyclopentyl-1H-imidazolium-5-carboxylic acid ethyl ester (5h): white solid, yield 83%. Mp 132.9-133.3℃. ESI-MS (m / z) = 441.1 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ8.14–8.05(m,2H),7.92(dt,J=7.8,1.4Hz,1H),7.7 9–7.71(m,2H),7.66(td,J=7.8,0.8Hz,1H),7.44–7.36(m,2H),5.23(s,2H) ,4.35(q,J=7.1Hz,2H),3.65(p,J=8.1Hz,1H),1.93(dt,J=10.5,2.9Hz,2H) ,1.86–1.73(m,4H),1.64(tt,J=8.1,6.5,2.9Hz,2H),1.32(t,J=7.1Hz,3H).

[0334] 1-[(4-cyanobenzyl)oxy]-2-(3-cyanophenyl)-4-cyclohexyl-1H-imidazolium-5-carboxylic acid ethyl ester (5i): white solid, yield 83%. Mp 138.4-139.5℃. ESI-MS (m / z) = 455.2 [M+H] + 477.2 [M+Na] + . 1H NMR(400MHz,DMSO-d6)δ8.13–8.04(m,2H),7.91(dt,J=7.8,1.4Hz,1H),7.7 7–7.70(m,2H),7.65(td,J=7.8,0.9Hz,1H),7.43–7.34(m,2H),5.28–5.18( m,4H),4.34(q,J=7.1Hz,2H),3.20(tt,J=11.7,3.2Hz,1H),1.85–1.75(m,4 H),1.70(d,J=12.0Hz,1H),1.59(dd,J=12.1,3.2Hz,2H),1.41–1.21(m,6H).

[0335] 1-[(4-cyanobenzyl)oxy]-2-(3-cyanophenyl)-4-(methoxymethyl)-1H-imidazolium-5-carboxylic acid ethyl ester (5j): white solid, 92% yield. Mp 105.0-106.8℃. ESI-MS (m / z) = 417.1 [M+H] + 439.1 [M+Na] + . 1 H NMR (400MHz, DMSO-d6) δ8.09(td,J=1.7,0.7Hz,1H),8.09–8.05(m,1H),7.93(dt,J=7.8,1.3Hz,1H),7.77–7.70(m,2H),7.66( td,J=7.9,0.7Hz,1H),7.44–7.36(m,2H),5.27(s,2H),4.57(s,2H),4.36(q,J=7.1Hz,2H),3.32(s,3H),1.34(t,J=7.1Hz,3H).

[0336] 1-[(4-cyanobenzyl)oxy]-2-(3-cyanophenyl)-4-(difluoromethyl)-1H-imidazolium-5-carboxylic acid ethyl ester (5k): white solid, 92% yield. Mp 153.3-156.3℃. ESI-MS (m / z) = 423.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.11(t,J=1.6Hz,1H),8.07(dt,J=8.0,1.4Hz,1H),7.97(dt,J=7.8,1.4Hz,1H),7.74(d,J= 8.3Hz,2H),7.68(t,J=7.9Hz,1H),7.41(d,J=8.2Hz,2H),5.33(s,2H),4.40(q,J=7.1Hz,2H),1.35(t,J=7.1Hz,3H).

[0337] 1-[(4-cyanobenzyl)oxy]-2-(3-cyanophenyl)-4-(trifluoromethyl)-1H-imidazolium-5-carboxylic acid ethyl ester (5l): white solid, yield 85%. Proceeded directly to the next step without purification.

[0338] 1-[(4-cyanobenzyl)oxy]-2-(3-cyanophenyl)-4-(methyl-D3)-1H-imidazolium-5-carboxylic acid ethyl ester (5m): white solid, 85% yield. ESI-MS (m / z) = 390.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.10–8.01(m,2H),7.90(dt,J=7.8,1.4Hz,1H),7.73(d,J=8.1Hz,2H),7.64 (t,J=7.8Hz,1H),7.41(d,J=8.1Hz,2H),5.24(s,2H),4.35(q,J=7.1Hz,2H),1.34(t,J=7.1Hz,3H).

[0339] 1-[(4-cyanobenzyl)oxy]-2-(3-cyanophenyl)-4-(2,2-difluorocyclopropyl)-1H-imidazolium-5-carboxylic acid ethyl ester (5n): white solid, yield 76%. Mp 146.5-147.7℃. ESI-MS m / z: 449.1 [M+H] + 471.1 [M+Na] + . 1 HNMR(400MHz,DMSO-d6)δ8.07(dt,J=1.8,1.0Hz,1H),8.04(dt,J=8.0,1.5 Hz,1H),7.93(dt,J=7.8,1.4Hz,1H),7.76–7.68(m,2H),7.65(td,J=7.9,0. 6Hz,1H),7.43–7.34(m,2H),5.30(q,J=8.4Hz,2H),4.46–4.30(m,2H),3.31 –3.26(m,1H),2.28–2.15(m,1H),2.11–1.96(m,1H),1.35(t,J=7.1Hz,3H).

[0340] 1-[(4-cyanobenzyl)oxy]-2-(3-cyanophenyl)-4-(3,3-difluorocyclobutyl)-1H-imidazolium-5-carboxylic acid ethyl ester (5°): white solid, 80% yield. Mp 159.5-162.0℃. ESI-MS (m / z) = 463.2 [M+H] + 485.1 [M+Na] +. 1 H NMR (400MHz, DMSO-d6) δ8.12(td,J=1.7,0.6Hz,1H),8.11–8.06(m,1H),7.93(dt,J=7.8,1.3Hz,1H),7.77–7.70(m,2H),7.66(td,J=7.9, 0.6Hz,1H),7.44–7.38(m,2H),5.25(s,2H),4.36(q,J=7.1Hz,2H),3.84(pd,J=8.7,3.1Hz,1H),3.06–2.84(m,4H),1.34(t,J=7.1Hz,3H).

[0341] 1-[(4-cyanobenzyl)oxy]-2-(3-cyanophenyl)-4-phenyl-1H-imidazolium-5-carboxylic acid ethyl ester (5p): white solid, 92% yield. ESI-MS m / z: 449.1 [M+H] + ; 471.1 [M+Na] + . 1 H NMR (400MHz, DMSO-d6) δ8.17(t,J=1.6Hz,1H),8.13(dt,J=8.0,1.5Hz,1H),7.95(dt,J=7.8,1.4Hz,1H),7.78–7 .72(m,4H),7.68(t,J=7.9Hz,1H),7.47–7.41(m,5H),5.33(s,2H),4.28(q,J=7.1Hz,2H),1.20(t,J=7.1Hz,3H).

[0342] 1-[(4-cyanobenzyl)oxy]-2-(3-cyanophenyl)-4-(pyridin-4-yl)-1H-imidazol-5-carboxylic acid ethyl ester (5q): white solid, yield 68%. Mp 109.1-111.0℃. ESI-MS m / z: 450.1 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ8.66(d,J=6.1Hz,2H),8.21–8.15(m,1H),8.13(dt,J=8.0,1.3Hz,2H),7.97(dt,J=7.8,1.2Hz,2H), 7.81–7.72(m,4H),7.69(t,J=7.9Hz,1H),7.44(d,J=8.2Hz,2H),5.35(s,2H),4.33(q,J=7.1Hz,2H),1.23(t,J=7.1Hz,3H).

[0343] 1-[(4-cyanobenzyl)oxy]-2-(3-cyanophenyl)-4-(pyridin-3-yl)-1H-imidazolium-5-carboxylic acid ethyl ester (5r): white solid, yield 76%. Mp 158.3-159.0℃. ESI-MS (m / z) = 450.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.93(d,J=2.2Hz,1H),8.61(dd,J=4.8,1.7Hz,1H),8.17(s,1H),8.13(dt,J=8.2,1.6Hz,2H),7.96(dt,J=7.8,1.2Hz,1H),7.75 (d,J=8.2Hz,2H),7.69(t,J=7.9Hz,1H),7.49(dd,J=7.7,4.6Hz,1H),7.44( d,J=8.2Hz,2H),5.35(s,2H),4.30(q,J=7.1Hz,2H),1.20(t,J=7.1Hz,3H).

[0344] 1-[(4-cyanobenzyl)oxy]-2-(3-cyanophenyl)-4-(pyridin-2-yl)-1H-imidazolium-5-carboxylic acid ethyl ester (5s): white solid, yield 76%. Mp 143.6-145.8℃. ESI-MS (m / z) = 450.1 [M+H] + . 1 H NMR(400MHz, DMSO-d6)δ8.63–8.56(m,1H),8.18(d,J=1.7Hz,1H),8.15(dt, J=8.0,1.4Hz,1H),7.96(dt,J=7.8,1.4Hz,1H),7.92–7.82(m,2H),7.77(d,J =8.3Hz,2H),7.71(d,J=7.9Hz,1H),7.43(d,J=8.3Hz,2H),7.39(ddd,J=7.3 ,4.8,1.5Hz,1H),5.36(s,2H),4.28(q,J=7.1Hz,2H),1.18(t,J=7.1Hz,3H).

[0345] 1-[(4-cyanobenzyl)oxy]-2-(3-cyanophenyl)-4-(pyrazin-2-yl)-1H-imidazol-5-carboxylic acid ethyl ester (5t): white solid, yield 81%. Mp 136.2-136.9℃. ESI-MS (m / z) = 473.1 [M+Na] + . 1H NMR (400MHz, DMSO-d6) δ9.06(d,J=1.5Hz,1H),8.71(dd,J=2.6,1.5Hz,1H),8.67(d,J=2.5Hz,1H),8.18(t,J=1.6Hz,1H),8.15(dt,J=8.1,1.4Hz,1H),7. 97(dt,J=7.8,1.3Hz,1H),7.76(d,J=8.2Hz,2H),7.70(t,J=7.9Hz,1H),7.45 (d,J=8.2Hz,2H),5.38(s,2H),4.27(q,J=7.1Hz,2H),1.16(t,J=7.1Hz,3H).

[0346] 1-[(4-cyanobenzyl)oxy]-2-(3-cyanophenyl)-4-(thiophen-2-yl)-1H-imidazol-5-carboxylic acid ethyl ester (5u): white solid, 88% yield. Mp 138.0-138.3℃. ESI-MS (m / z) = 455.2 [M+H] + 477.1 [M+Na] + . 1 HNMR(400MHz, DMSO-d6)δ8.12(t,J=1.5Hz,1H),8.09(dt,J=8.0,1.4Hz,1H),8.00–7.92(m,2H),7.77–7.70(m,2H),7.73 –7.62(m,2H),7.43–7.36(m,2H),7.16(dd,J=5.1,3.7Hz,1H),5.29(s,2H),4.41(q,J=7.1Hz,2H),1.34(t,J=7.1Hz,3H).

[0347] 5v1-[(4-cyanobenzyl)oxy]-2-(3-cyanophenyl)-4-(thiophen-3-yl)-1H-imidazolium-5-carboxylic acid ethyl ester (5v): white solid, 89% yield. Mp 148.9-149.5℃. ESI-MS m / z: 455.1 [M+H] + 477.1 [M+Na] + . 1HNMR(400MHz, DMSO-d6)δ8.15(t,J=1.7Hz,1H),8.13–8.09(m,2H),7.95(dt,J=7.8,1.3Hz,1H),7.78–7.71(m,2H),7.69(d,J=7.9Hz,1H), 7.65(dd,J=5.1,1.4Hz,1H),7.59(dd,J=5.1,3.0Hz,1H),7.41(d,J=8.2Hz,2H),5.29(s,2H),4.36(q,J=7.1Hz,2H),1.29(t,J=7.1Hz,3H).

[0348] 1-[(4-cyanobenzyl)oxy]-2-(3-cyanophenyl)-4-(furan-2-yl)-1H-imidazol-5-carboxylic acid ethyl ester (5w): white solid, yield 85%. Mp 137.7-140℃. ESI-MS (m / z) = 439.2 [M+H] + 461.2 [M+Na] + . 1 HNMR (600MHz, DMSO-d6) δ8.14–8.10(m,1H),8.09(dt,J=8.0,1.5Hz,1H),7.95(dt,J=7.8,1.4Hz,1H),7.82(d,J=1.5Hz,1H),7.75–7.70(m,2H),7.6 7(t,J=7.9Hz,1H),7.41–7.37(m,2H),7.16(d,J=3.2Hz,1H),6.65(dd,J=3 .4,1.8Hz,1H),5.30(s,2H),4.38(q,J=7.1Hz,2H),1.32(t,J=7.1Hz,3H).

[0349] 1-[(4-cyanobenzyl)oxy]-2-(3-cyanophenyl)-4-(furan-3-yl)-1H-imidazol-5-carboxylic acid ethyl ester (5x): white solid, yield 81%. Mp 142.9-144.7℃. ESI-MS m / z: 439.1 [M+H] + 461.1 [M+Na] + . 1HNMR (400MHz, DMSO-d6) δ8.35–8.29(m,1H),8.17–8.13(m,1H),8.11(dt,J=8.0,1.4Hz,1H),7.94(dt,J=7.8,1.4Hz,1H),7.79–7.70( m,3H),7.67(t,J=7.9Hz,1H),7.40(d,J=8.0Hz,2H),7.05(d,J=1.8Hz,1H),5.28(s,2H),4.40(q,J=7.1Hz,2H),1.33(t,J=7.1Hz,3H).

[0350] 1-[(4-cyanobenzyl)oxy]-2-(3-cyanophenyl)-4-(thiazolyl-2-yl)-1H-imidazolium-5-carboxylic acid ethyl ester (5y): white solid, 75% yield. Mp 153.3-156.3℃. ESI-MS m / z: 456.1 [M+H] + 478.1 [M+Na] + . 1 H NMR (400MHz, DMSO-d6) δ8.16(t,J=1.5Hz,1H),8.12(dt,J=7.9,1.4Hz,1H),7.98(dt,J=7.7,1.3Hz,1H),7.96(d,J=3.2Hz,1H),7.87(d ,J=3.2Hz,1H),7.79–7.74(m,2H),7.71(t,J=7.9Hz,1H),7.46–7.39(m,2H),5.36(s,2H),4.34(q,J=7.1Hz,2H),1.27(t,J=7.1Hz,3H).

[0351] 1-[(4-cyanobenzyl)oxy]-2-(3-cyanophenyl)-4-(thiazolyl-5-yl)-1H-imidazol-5-carboxylic acid ethyl ester (5z): white solid, yield 79%. Mp 153.7-156.9℃. ESI-MS (m / z) = 456.2 [M+H] + 478.1 [M+Na] + . 1HNMR (400MHz, DMSO-d6) δ9.17(s,1H),8.62(d,J=0.7Hz,1H),8.12(t,J=1.7Hz,1H),8.08(dt,J=7.9,1.4Hz,1H),7.97(dt,J=7.8,1.4H z,1H),7.73(d,J=8.2Hz,2H),7.68(t,J=7.9Hz,1H),7.40(d,J=8.2Hz,2H),5.31(s,2H),4.43(q,J=7.1Hz,2H),1.35(t,J=7.1Hz,3H).

[0352] 1-[(4-cyanobenzyl)oxy]-2-(3-cyanophenyl)-4-(thiazolyl-4-yl)-1H-imidazolium-5-carboxylic acid ethyl ester (5z1): white solid, yield 75%. Mp 150.9-153.7℃. 1 H NMR (400MHz, DMSO-d6) δ9.16(d,J=2.0Hz,1H),8.16(t,J=1.6Hz,1H),8.13(dt,J=8.0,1.5Hz,1H),8.09(d,J=2.0Hz,1H),7.95(dt,J=7 .7,1.4Hz,1H),7.79–7.73(m,2H),7.69(t,J=7.9Hz,1H),7.46–7.40(m,2H),5.34(s,2H),4.29(q,J=7.1Hz,2H),1.21(t,J=7.1Hz,3H).

[0353] Example 39. Synthesis of intermediates 5K-1 to 5K-12

[0354] Intermediates 5K-1 to 5K-12 were prepared using one of the following: 4-fluorobenzyl chloride, 3-fluorobenzyl chloride, 2-fluorobenzyl chloride, (4-trifluoromethyl)bromobenzyl chloride, (3-trifluoromethyl)bromobenzyl chloride, (2-trifluoromethyl)bromobenzyl chloride, (4-trifluoromethoxy)bromobenzyl chloride, (3-trifluoromethoxy)bromobenzyl chloride, (2-trifluoromethoxy)bromobenzyl chloride, 4-chloromethylpyridine, 3-chloromethylpyridine, 2-chloromethylpyridine, and 2-(3-cyanophenyl)-4-(difluoromethyl)-1-hydroxy-1H-imidazolium-5-carboxylate 4k, respectively, with reference to the synthesis method of 1-[(4-cyanobenzyl)oxy]-2-(3-cyanophenyl)-4-ethyl-1H-imidazolium-5-carboxylate (5a).

[0355] 2-(3-cyanophenyl)-4-(difluoromethyl)-1-[(4-fluorobenzyl)oxy]-1H-imidazol-5-carboxylic acid ethyl ester (5K-1): white solid, yield 82%. 1H NMR(400MHz,Chloroform-d)δ8.29(t,J=1.7Hz,1H),8.19(dt,J=8.1,1.5Hz,1H),7.73(dt,J=7.7,1.4Hz,1H),7.55 (t,J=7.9Hz,1H),7.24–7.08(m,3H),7.02–6.93(m,2H),5.12(s,2H),4.49(q,J=7.2Hz,2H),1.46(t,J=7.1Hz,3H).

[0356] 2-(3-cyanophenyl)-4-(difluoromethyl)-1-[(3-fluorobenzyl)oxy]-1H-imidazol-5-carboxylic acid ethyl ester (5K-2), white solid, yield 61%. 1 H NMR(400MHz,Chloroform-d)δ8.25(t,J=1.7Hz,1H),8.19(dt,J=8.0,1.4Hz,1H),7.73(dt,J=7.8,1.4Hz,1H),7.56(t,J=7.9 Hz,1H),7.32–7.27(m,1H),7.24–7.03(m,2H),7.01–6.95(m,2H),5.13(s,2H),4.50(q,J=7.2Hz,2H),1.46(t,J=7.1Hz,3H).

[0357] 2-(3-cyanophenyl)-4-(difluoromethyl)-1-[(2-fluorobenzyl)oxy]-1H-imidazol-5-carboxylic acid ethyl ester (5K-3): white solid, yield 69%. 1 H NMR(400MHz,Chloroform-d)δ8.16(t,J=1.7Hz,1H),8.13(dt,J=8.0,1.5Hz,1H),7.67(dt,J=7.8,1.4Hz,1H),7.50(t,J=7.8 Hz,1H),7.35–7.28(m,1H),7.18–6.95(m,3H),6.90–6.83(m,1H),5.25(s,2H),4.49(q,J=7.2Hz,2H),1.46(t,J=7.1Hz,3H).

[0358] 2-(3-cyanophenyl)-4-(difluoromethyl)-1-{[(4-trifluoromethyl)benzyl]oxy}-1H-imidazolium-5-carboxylic acid ethyl ester (5K-4): white solid, yield 82%. Mp 105.5-106.0℃. ESI-MS (m / z) = 466.2 [M+H] + 488.0 [M+Na] + .1 H NMR(400MHz, DMSO-d6)δ8.10–8.01(m,2H),7.93(dt,J=7.7,1.4Hz,1H),7.64(td,J=7.6,1.3Hz,1H), 7.59(d,J=8.0Hz,2H),7.44–7.08(m,3H),5.34(s,2H),4.41(q,J=7.1Hz,2H),1.36(t,J=7.1Hz,3H).

[0359] 2-(3-cyanophenyl)-4-(difluoromethyl)-1-{[3-(trifluoromethyl)benzyl]oxy}-1H-imidazolium-5-carboxylate (5K-5): white solid, yield 66%. Mp 129.6-133.2℃. ESI-MS (m / z) = 466.2 [M+H] + 488.1 [M+Na] + . 1 H NMR(400MHz, DMSO-d6)δ8.08–7.99(m,2H),7.92(dt,J=7.7,1.4Hz,1H),7.72–7.59(m,2H),7.54 –7.42(m,3H),7.28(t,J=53.7Hz,1H),5.36(s,2H),4.42(q,J=7.1Hz,2H),1.37(t,J=7.1Hz,3H).

[0360] 2-(3-cyanophenyl)-4-(difluoromethyl)-1-{[2-(trifluoromethyl)benzyl]oxy}-1H-imidazolium-5-carboxylate (5K-6): White solid, 75% yield. Mp 88.2-88.3℃. ESI-MS (m / z) = 466.2 [M+H] + 488.2 [M+Na] + . 1 H NMR(400MHz,DMSO-d6)δ7.94(t,J=1.7Hz,1H),7.92–7.84(m,2H),7.61–7.45(m,4 H),7.44–7.13(m,2H),5.38(s,2H),4.41(q,J=7.1Hz,2H),1.36(t,J=7.1Hz,3H).

[0361] 2-(3-cyanophenyl)-4-(difluoromethyl)-1-{[4-(trifluoromethoxy)benzyl]oxy}-1H-imidazolium-5-carboxylic acid ethyl ester (5K-7), white solid, 89% yield. Mp 102.4-103.7℃. ESI-MS (m / z) = 482.1 [M+H] +504.1 [M+Na] + . 1 H NMR (400MHz, DMSO-d6) δ8.13–8.09(m,1H),8.07(dt,J=8.0,1.3Hz,1H),7.94(dt,J=7.8,1.4Hz,1H),7. 66(td,J=7.9,0.7Hz,1H),7.44–7.08(m,5H),5.27(s,2H),4.41(q,J=7.1Hz,2H),1.37(t,J=7.1Hz,3H).

[0362] 2-(3-cyanophenyl)-4-(difluoromethyl)-1-{[3-(trifluoromethoxy)benzyl]oxy}-1H-imidazolium-5-carboxylic acid ethyl ester (5K-8), white solid, 86% yield. Mp 89.1-89.2℃. ESI-MS (m / z) = 482.2 [M+H] + 504.2[M+Na] + . 1 H NMR(400MHz, DMSO-d6)δ8.12–8.04(m,2H),7.95(dt,J=7.8,1.4Hz,1H),7.70–7.60( m,1H),7.43–7.11(m,5H),5.30(s,2H),4.41(q,J=7.1Hz,2H),1.36(t,J=7.1Hz,3H).

[0363] 2-(3-cyanophenyl)-4-(difluoromethyl)-1-{[2-(trifluoromethoxy)benzyl]oxy}-1H-imidazolium-5-carboxylic acid ethyl ester (5K-9), white solid, yield 76%. Mp 98.9-99.0℃. ESI-MS (m / z) = 482.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.05–7.99(m,1H),7.96(dt,J=8.0,1.5Hz,1H),7.91(dt,J=7.8,1.3Hz,1H),7.61(td,J=8.0,0.6Hz,1H ),7.46–7.37(m,1H),7.33(dd,J=7.7,1.8Hz,1H),7.28–7.09(m,3H),5.33(s,2H),4.41(q,J=7.1Hz,2H),1.36(t,J=7.1Hz,3H).

[0364] 2-(3-Cyanophenyl)-4-(difluoromethyl)-1-(pyridine-4-methoxy)-1H-imidazol-5-carboxylic acid ethyl ester (5K-10), white solid, yield 78%. 1 H NMR (400MHz, DMSO-d6) δ8.55–8.47(m,2H),8.19(t,J=1.7Hz,1H),8.14(dt,J=8.1,1.4Hz,1H),7.99(dt,J=7.8, 1.4Hz,1H),7.71(t,J=7.9Hz,1H),7.44–7.11(m,3H),5.29(s,2H),4.40(q,J=7.1Hz,2H),1.34(t,J=7.1Hz,3H)

[0365] 2-(3-Cyanophynol)-4-(difluoromethyl)-1-(pyridine-3-methoxy)-1H-imidazol-5-carboxylic acid ethyl ester (5K-11), white solid, yield 73%. 1 H NMR (400MHz, DMSO-d6) δ8.50(dd,J=4.8,1.7Hz,1H),8.40–8.30(m,1H),8.11(t,J=1.7Hz,1H),8.08(dt,J=8.1,1.4Hz,1H),7.97(dt,J=7.8, 1.5Hz,1H),7.69(t,J=7.9Hz,1H),7.61(dt,J=7.8,2.0Hz,1H),7.46–7.09(m,2H),5.30(s,2H),4.41(q,J=7.1Hz,2H),1.37(t,J=7.1Hz,3H).

[0366] 2-(3-cyanophenyl)-4-(difluoromethyl)-1-(pyridin-2-ylmethoxy)-1H-imidazol-5-carboxylic acid ethyl ester (5K-12), white solid, yield 76%. 1 H NMR (400MHz, DMSO-d6) δ8.45(ddd,J=4.8,1.8,0.9Hz,1H),8.36(t,J=1.7Hz,1H),8.18(dt,J=8.2,1.4Hz,1H),7.94(dt,J=7.8,1.4Hz, 1H),7.72(td,J=7.7,1.8Hz,1H),7.66(t,J=7.9Hz,1H),7.43–7.13(m,3H),5.33(s,2H),4.40(q,J=7.1Hz,2H),1.36(t,J=7.1Hz,3H).

[0367] Example 40. Synthesis of ethyl 2-(3-cyanophenyl)-4-(difluoromethyl)-1-(2-morpholinethoxy)-1H-imidazolium-5-carboxylate (5K-13)

[0368] Starting from ethyl 2-(3-cyanophenyl)-4-(difluoromethyl)-1-hydroxy-1H-imidazolium-5-carboxylate 4K and N-(2-chloroethyl)morpholine hydrochloride, intermediate ethyl 2-(3-cyanophenyl)-4-ethyl-1H-imidazolium-5-carboxylate 5K-13 was prepared according to the synthetic method of ethyl 1-[(4-cyanobenzyl)oxy]-2-(3-cyanophenyl)-4-ethyl-1H-imidazolium-5-carboxylate (5a). The product was a white solid in 61% yield. Mp 106.8-107.8℃. ESI-MS (m / z) = 421.2 [M+H]. + 443.2[M+Na] + . 1 H NMR(400MHz,Chloroform-d)δ8.50(td,J=1.7,0.6Hz,1H),8.47–8.43(m,1H),7.77(dt,J=7.8,1.4Hz,1H),7.63(td,J=7.8,0.7Hz,1H),7.07(t, J=54.1Hz,1H),4.45(q,J=7.2Hz,2H),4.31(t,J=5.2Hz,2H),3.73–3.66(m,4H),2.73(t,J=5.2Hz,2H),2.47–2.38(m,4H),1.44(t,J=7.1Hz,3H).

[0369] Example 41.1 Synthesis of ethyl 5-(benzo[d][1,3]dioxacyclopenten-5-ylmethoxy)-2-(3-cyanophenyl)-4-(difluoromethyl)-1H-imidazolium-5-carboxylate (5K-14)

[0370] Starting with ethyl 2-(3-cyanophenyl)-4-(difluoromethyl)-1-hydroxy-1H-imidazol-5-carboxylate 4K and piperonyl chloride, intermediate 1-(benzo[d][1,3]dioxacyclopenten-5-ylmethoxy)-2-(3-cyanophenyl)-4-ethyl-1H-imidazol-5-carboxylate 5K-14 was prepared as a white solid in 93% yield, following the same method used to synthesize 1-[(4-cyanobenyl)oxy]-2-(3-cyanophenyl)-4-ethyl-1H-imidazol-5-carboxylate (5a). 1H NMR (400MHz, DMSO-d6) δ8.06(t,1H),8.03(dt,J=8.0,1.5Hz,1H),7.94(dt,J=7.8,1.4Hz,1H),7.67(t,J=7.9Hz,1H),7.26(t,J=53.7Hz,1H),6. 71(d,J=7.9Hz,1H),6.63(d,J=1.6Hz,1H),6.56(dd,J=7.9,1.7Hz,1H),5.98(s,2H),5.11(s,2H),4.41(q,J=7.1Hz,2H),1.38(t,J=7.1Hz,3H).

[0371] Example 42.1 Synthesis of ethyl 5-(6-bromopyridin-3-yl)methoxy]-2-(3-cyanophenyl)-4-(difluoromethyl)-1H-imidazolium-5-carboxylate (5K-15)

[0372] Ethyl 2-(3-cyanophenyl)-4-(difluoromethyl)-1-hydroxy-1H-imidazolium-5-carboxylate 4k (500 mg, 1.63 mmol) and potassium carbonate (674 mg, 4.89 mmol, 3 times the volume) were dissolved in 10 mL of N,N-dimethylformamide solution. Then, methyl 6-bromopyridin-3-yl)methanesulfonate A-2a (518 mg, 1.96 mmol, 1.2 times the volume) was weighed into the reaction solution. The reaction solution was then heated to 50 °C under nitrogen protection. After the reaction was complete, the reaction solution was cooled to room temperature, and then 20 mL of ice water was slowly added dropwise. The mixture was stirred at room temperature until a solid precipitated. The solid was filtered, and the filter cake was washed twice with water and twice with petroleum ether. The cake was dried, and the crude product was recrystallized from ethanol / water (10:1) to give 637 mg of white solid, with a yield of 86%. Mp 137.8-138.8℃.ESI-MS(m / z)=477.1[M+H] + 499.1 [M+Na] + . 1 H NMR(400MHz, DMSO-d6)δ8.11(dd,J=2.4,0.8Hz,1H),8.04(t,J=1.7Hz,1H),8.03–7.93(m,2H),7.68(t,J=7.9 Hz,1H),7.55–7.46(m,2H),7.27(t,J=53.6Hz,1H),5.30(s,2H),4.41(q,J=7.1Hz,2H),1.37(t,J=7.1Hz,3H).

[0373] Example 43.1 Synthesis of ethyl 5-(5-bromopyridin-2-yl)methoxy]-2-(3-cyanophenyl)-4-(difluoromethyl)-1H-imidazolium-5-carboxylate (5K-16)

[0374] Starting with ethyl 2-(3-cyanophenyl)-4-(difluoromethyl)-1-hydroxy-1H-imidazolium-5-carboxylate 4k and methyl (5-bromopyridin-2-yl)methanesulfonate A-2b, intermediate 1-[(6-bromopyridin-3-yl)methoxy]-2-(3-cyanophenyl)-4-(difluoromethyl)-1H-imidazolium-5-carboxylate 5K-16 was prepared according to the synthetic method of 1-[(6-bromopyridin-3-yl)methoxy]-2-(3-cyanophenyl)-4-(difluoromethyl)-1H-imidazolium-5-carboxylate (5K-15). The result was a white solid in 83% yield. Mp 167.8-170.0℃. ESI-MS (m / z) = 477.1 [M+H]. + . 1 H NMR(400MHz, DMSO-d6)δ8.48(dd,J=2.4,0.7Hz,1H),8.19(t,J=1.6Hz,1H),8.12–8.03(m,1H),7.96–7.90( m,2H),7.64(t,J=7.9Hz,1H),7.43–7.09(m,2H),5.31(s,2H),4.40(q,J=7.1Hz,2H),1.36(t,J=7.1Hz,3H).

[0375] Example 44. Synthesis of intermediates 5K-17 to 5K-22

[0376] Intermediates 5K-17 to 5K-22 were prepared using one of B-3a, B-3b, B-3c, B-3d, B-3e, B-3f and ethyl 2-(3-cyanophenyl)-4-(difluoromethyl)-1-hydroxy-1H-imidazolium-5-carboxylate 4k as starting materials, respectively, following the synthetic method of ethyl 1-[(6-bromopyridin-3-yl)methoxy]-2-(3-cyanophenyl)-4-(difluoromethyl)-1H-imidazolium-5-carboxylate (5K-13).

[0377] 2-(3-cyanophenyl)-4-(difluoromethyl)-1-(thiazol-5-methoxy)-1H-imidazol-5-carboxylic acid ethyl ester (5K-17): white solid, yield 81%. Mp 165.2-165.7℃. ESI-MS (m / z) = 405.2 [M+H] + 427.1 [M+Na] + . 1H NMR (400MHz, DMSO-d6) δ9.07(d,J=0.8Hz,1H),8.19–8.14(m,1H),8.09(ddd,J=8.0,1.8,1.2Hz,1H),7.98(dt,J=7.8,1.4Hz,1H),7. 73(d,J=0.8Hz,1H),7.70(td,J=8.1,0.7Hz,1H),7.27(t,J=53.7Hz,1H),5.58(s,2H),4.42(q,J=7.1Hz,2H),1.38(t,J=7.1Hz,3H).

[0378] 2-(3-cyanophenyl)-4-(difluoromethyl)-1-(thiazol-2-ylmethoxy)-1H-imidazol-5-carboxylic acid ethyl ester (5K-18), white solid, 73% yield. Mp 124.5-128.4℃. ESI-MS (m / z) = 405.1 [M+H] + 427.1 [M+Na] + . 1 H NMR (400MHz, DMSO-d6) δ8.19(t,J=1.7Hz,1H),8.15–8.07(m,1H),7.94(dt,J=7.8,1.4Hz,1H),7.76(d,J=3.2Hz,1H),7.7 2(d,J=3.2Hz,1H),7.71–7.62(m,1H),7.28(t,J=53.6Hz,1H),5.60(s,2H),4.41(q,J=7.1Hz,2H),1.38(t,J=7.1Hz,3H).

[0379] 2-(3-cyanophenyl)-4-(difluoromethyl)-1-(thiazol-4-ylmethoxy)-1H-imidazol-5-carboxylic acid ethyl ester (5K-19), white solid, yield 76%. Mp 117.2-118.0℃. ESI-MS m / z: 405.0 [M+H] + 427.1 [M+Na] + . 1 HNMR (400MHz, DMSO-d6) δ8.86(d,J=1.9Hz,1H),8.23(t,J=1.8Hz,1H),8.12(dt,J=8.1,1.4Hz,1H),7.92(dt,J=7.7,1.4Hz,1H), 7.69(d,J=1.9Hz,1H),7.65(t,J=7.9Hz,1H),7.26(t,J=53.7Hz,1H),5.41(s,2H),4.41(q,J=7.1Hz,2H),1.38(t,J=7.1Hz,3H).

[0380] 2-(3-Cyanophane)-4-(difluoromethyl)-1-(oxazol-5-methoxy)-1H-imidazol-5-carboxylic acid ethyl ester (5K-20), white solid, 82% yield. Mp 149.5-153.9. ESI-MS m / z: 389.1 [M+H] + 411.0[M+Na] + . 1 HNMR(400MHz,DMSO-d6)δ8.16(t,J=1.6Hz,1H),8.13(s,1H),8.09(dt,J=8.0,1.5Hz,1H),7.96(dt,J=7.8,1.4Hz,1H), 7.70(t,J=7.9Hz,1H),7.26(t,J=53.6Hz,1H),7.08(s,1H),5.42(s,2H),4.40(q,J=7.1Hz,2H),1.38(t,J=7.1Hz,3H).

[0381] 2-(3-cyanophenyl)-4-(difluoromethyl)-1-(oxazol-2-ylmethoxy)-1H-imidazol-5-carboxylic acid ethyl ester (5K-21), white solid, 85% yield. ESI-MS m / z: 389.1 [M+H] + 411.0[M+Na] + . 1 H NMR (400MHz, DMSO-d6) δ8.19(t,J=1.6Hz,1H),8.13(dt,J=8.2,1.6Hz,1H),7.95(dt,J=7.8,1.4Hz,1H),7.91(d,J=0.8Hz,1H), 7.69(t,J=7.9Hz,1H),7.27(t,J=53.6Hz,1H),7.06(d,J=0.8Hz,1H),5.42(s,2H),4.39(q,J=7.1Hz,2H),1.37(t,J=7.1Hz,3H).

[0382] 2-(3-cyanophenyl)-4-(difluoromethyl)-1-(oxazol-4-methoxy)-1H-imidazol-5-carboxylic acid ethyl ester (5K-22), white solid, 81% yield. ESI-MS m / z: 389.1 [M+H] + 411.1[M+Na] + . 1H NMR (400MHz, DMSO-d6) δ8.27(t,J=1.7Hz,1H),8.21(d,J=0.9Hz,1H),8.17(dt,J=8.0,1.4Hz,1H),8.05(d,J=1.0Hz,1H),7.97( dt,J=7.7,1.4Hz,1H),7.70(t,J=7.9Hz,1H),7.26(t,J=53.7Hz,1H),5.24(s,2H),4.40(q,J=7.1Hz,2H),1.37(t,J=7.1Hz,3H).

[0383] Example 45.1 Synthesis of ethyl 2-[(tert-butoxycarbonyl)amino]thiazol-4-yl}methoxy}-2-(3-cyanophenyl)-4-(difluoromethyl)-1H-imidazol-5-carboxylate (C-6a)

[0384] Starting with ethyl 2-(3-cyanophenyl)-4-(difluoromethyl)-1-hydroxy-1H-imidazol-5-carboxylate 4k and methyl {2-[(tert-butoxycarbonyl)amino]thiazol-4-yl}methanesulfonate C-5a, intermediate 1-{{2-[(tert-butoxycarbonyl)amino]thiazol-4-yl}methoxy}-2-(3-cyanophenyl)-4-(difluoromethyl)-1H-imidazol-5-carboxylate (5K-13) was prepared as an intermediate, a white solid, in 68% yield. 1 H NMR (400MHz, DMSO-d6) δ11.16(s,1H),8.12–8.06(m,1H),8.04(dt,J=1.8,1.0Hz,1H),7.84(dt,J=7.8,1.4Hz,1H),7.61(td,J =7.9,0.6Hz,1H),7.25(t,J=53.7Hz,1H),7.00(s,1H),5.14(s,2H),4.40(q,J=7.1Hz,2H),1.50(s,9H),1.37(t,J=7.1Hz,3H).

[0385] Example 46. Synthesis of ethyl 2-(3-cyanophenyl)-4-(difluoromethyl)-1-[(2-aminothiazol-4-yl)methoxy]-1H-imidazol-5-carboxylate (5K-23)

[0386] Ethyl 1-{{2-[(tert-butoxycarbonyl)amino]thiazol-4-yl}methoxy}-2-(3-cyanophenyl)-4-(difluoromethyl)-1H-imidazol-5-carboxylate C-6a (450 mg) was dissolved in 2 mL of trifluoroacetic acid and 10 mL of acetonitrile. The reaction solution was then heated to 60 °C. After the reaction was complete, column chromatography (dichloromethane and methanol) was performed to prepare the intermediate ethyl 2-(3-cyanophenyl)-4-(difluoromethyl)-1-[(2-aminothiazol-4-yl)methoxy]-1H-imidazol-5-carboxylate 5K-23, a white solid in 52% yield. ESI-MS (m / z) = 420.1 [M+H] + 442.1[M+Na] + . 1 H NMR(400MHz,Chloroform-d)δ8.36–8.11(m,4H),7.76(dt,J=7.8,1.4Hz,1H),7.64–7.55(m,1H) ,7.15(t,J=54.0Hz,1H),6.38(s,1H),5.12(s,2H),4.48(q,J=7.1Hz,2H),1.46(t,J=7.1Hz,3H).

[0387] Example 47. Synthesis of intermediates 5K-24 to 5K-27

[0388] Intermediates 5K-24 to 5K-27 were prepared using one of D-6a, D-6b, D-6c, and D-6d and ethyl 2-(3-cyanophenyl)-4-(difluoromethyl)-1-hydroxy-1H-imidazolium-5-carboxylate 4k as starting materials, respectively, following the synthetic method of ethyl 1-[(6-bromopyridin-3-yl)methoxy]-2-(3-cyanophenyl)-4-(difluoromethyl)-1H-imidazolium-5-carboxylate (5K-13).

[0389] 2-(3-cyanophenyl)-4-(difluoromethyl)-1-{[2-(dimethylamino)thiazol-4-yl]methoxy}-1H-imidazol-5-carboxylic acid ethyl ester (5K-24): white solid, yield 76%. Mp 112.7-115.3℃. ESI-MS m / z: 448.1 [M+H] + 470.1 [M+Na] + . 1H NMR (400MHz, DMSO-d6) δ8.14–8.02(m,2H),7.90(dt,J=7.9,1.4Hz,1H),7.64(t,J=7.8Hz,1H),7.26(t ,J=53.7Hz,1H),6.56(s,1H),5.03(s,2H),4.40(q,J=7.1Hz,2H),2.85(s,6H),1.38(t,J=7.1Hz,3H).

[0390] 2-(3-cyanophenyl)-1-{[2-(diethylamino)thiazol-4-yl]methoxy}-4-(difluoromethyl)-1H-imidazol-5-carboxylic acid ethyl ester (5K-25): white solid, 82% yield. Mp 116.9-116.9℃. ESI-MS m / z: 450.1 [M+H] + 472.1 [M+Na] + . 1 H NMR (400MHz, DMSO-d6) δ8.12–8.06(m,2H),7.94(dt,J=7.7,1.4Hz,1H),7.64(td,J=7.7,1.2Hz,1H),7.26(t,J=53.7Hz ,1H),6.61(s,1H),5.03(s,2H),4.40(q,J=7.1Hz,2H),3.18(t,J=5.3Hz,4H),1.59–1.49(m,6H),1.37(t,J=7.1Hz,3H).

[0391] 2-(3-cyanophenyl)-4-(difluoromethyl)-1-[(2-morpholinothiazolyl-4-yl)methoxy]-1H-imidazolium-5-carboxylic acid ethyl ester (5K-26), white solid, 82% yield. Mp 165.2-165.7℃. ESI-MS (m / z) = 490.0 [M+H] + . 1 HNMR (400MHz, DMSO-d6) δ8.11(s,2H),7.96(d,J=7.8Hz,1H),7.65(t,J=8.0Hz,1H),7.26(t,J=53.7Hz,1H),6.72 (s,1H),5.06(s,2H),4.40(q,J=7.1Hz,2H),3.67(t,J=4.4Hz,4H),3.15(t,J=4.8Hz,4H),1.37(t,J=7.0Hz,3H).

[0392] 2-(3-cyanophenyl)-4-(difluoromethyl)-1-[(5-methyl-2-morpholinothiazolyl-4-yl)methoxy]-1H-imidazolium-5-carboxylic acid ethyl ester (5K-27), white solid, yield 67%. Mp 157.9-161.1℃. ESI-MS m / z: 504.2 [M+H] + 526.1 [M+Na] + . 1 H NMR (400MHz, DMSO-d6) δ8.11–8.06(m,2H),7.95(dt,J=7.8,1.4Hz,1H),7.66(dd,J=8.5,7.8Hz,1H),7.25(t,J=53.7Hz,1 H), 5.05 (s, 2H), 4.41 (q, J = 7.1Hz, 2H), 3.65 (t, J = 4.9Hz, 4H), 3.08 (t, J = 4.9Hz, 4H), 1.87 (s, 3H), 1.38 (t, J = 7.1Hz, 3H).

[0393] Example 48. Synthesis of 1-[(4-cyanobenzyl)oxy]-2-(3-cyanophenyl)-4-ethyl-1H-imidazol-5-carboxylic acid (6a)

[0394] Ethyl 1-[(4-cyanobenzyl)oxy]-2-(3-cyanophenyl)-4-ethyl-1H-imidazolium-5-carboxylic acid 5a (300 mg, 0.75 mmol) was dissolved in 20 mL of tetrahydrofuran solution. Then, 5 mL of saturated lithium hydroxide aqueous solution was added to the reaction solution, and the temperature of the reaction solution was raised to 30 °C. After the reaction was complete, the tetrahydrofuran was removed by rotary evaporation under reduced pressure. Then, the pH of the reaction solution was adjusted to 1-2 with 1M dilute hydrochloric acid, and 10 mL of water was added. After stirring at room temperature for 30 minutes, the mixture was filtered, the filter cake was washed twice with water, dried, and column chromatography (dichloromethane and methanol) was used to prepare the final product 1-[(4-cyanobenzyl)oxy]-2-(3-cyanophenyl)-4-ethyl-1H-imidazolium-5-carboxylic acid 6a (226 mg), a white solid, with a yield of 81%. Purity(HPLC):97.3%.Mp 191.6-192.2℃.ESI-MSm / z:373.1[M+H] + 395.0 [M+Na] + . 1H NMR(400MHz, DMSO-d6)δ13.26(s,1H),8.10–8.03(m,2H),7.90(dt,J=7.8,1.4Hz,1H),7.73(dd,J=6.4,1.8Hz,2H), 7.64(td,J=7.8,0.8Hz,1H),7.40(dd,J=6.4,1.8Hz,2H),5.23(s,2H),2.85(q,J=7.5Hz,2H),1.20(t,J=7.5Hz,3H). 13 CNMR(100MHz,DMSO-d6)δ160.26,149.07,141.40,138.47,133.40,132.69,132.52,131.2 9,131.10,130.36,129.32,118.80,118.61,116.78,112.47,112.24,80.57,22.80,13.83.

[0395] Example 49. Synthesis of compounds 6b-6z1

[0396] Compounds 6b to 6z1 were prepared using 5b, 5c, 5d, 5e, 5f, 5g, 5h, 5i, 5j, 5k, 5l, 5m, 5n, 5o, 5p, 5q, 5r, 5s, 5t, 5u, 5v, 5w, 5x, 5y, 5z, and 5z1 as starting materials, respectively, following the synthetic method for 1-[(4-cyanobenzyl)oxy]-2-(3-cyanophenyl)-4-ethyl-1H-imidazol-5-carboxylic acid (6a).

[0397] 1-[(4-cyanobenzyl)oxy]-2-(3-cyanophenyl)-4-isopropyl-1H-imidazol-5-carboxylic acid (6b), white solid, yield: 73%. Purity (HPLC): 97.9%. ESI-HRMS m / z calculated for C 22 H 19 N4O3 + [M+H] + 387.1452, found 387.1447. 1 H NMR(400MHz, DMSO-d6)δ8.12–8.04(m,2H),7.90(dt,J=7.7,1.4Hz,1H),7.76–7.69(m,2H),7.65 (t,J=8.2Hz,1H),7.42–7.35(m,2H),5.22(s,2H),3.60(q,J=6.9Hz,1H),1.23(d,J=6.8Hz,6H). 13C NMR(100MHz,DMSO-d6)δ160.35,152.64,141.29,138.47,133.36,132.67,132.50,131.26 ,131.01,130.36,129.38,118.78,118.61,116.11,112.43,112.22,80.48,27.20,22.31.

[0398] 1-[(4-cyanobenzyl)oxy]-2-(3-cyanophenyl)-4-isobutyl-1H-imidazol-5-carboxylic acid (6c): white solid, yield: 61%. Purity (HPLC): 97.1%. MPa: 160.5-162.5℃. ESI-MS m / z: 401.1 [M+H] + 423.1[M+Na] + . 1 H NMR (400MHz, DMSO-d6) δ13.24(s,1H),8.08–7.98(m,2H),7.89(dt,J=7.8,1.4Hz,1H),7.70(dd,2H),7.63(td,J=7 .7,0.9Hz,1H),7.37(dd,2H),5.23(s,2H),2.72(d,J=7.1Hz,2H),2.05(hept,J=6.8Hz,1H),0.91(d,J=6.7Hz,6H). 13 C NMR(100MHz,DMSO-d6)δ160.35,147.05,141.50,138.40,133.37,132.62,132.54,131.31,13 1.14,130.33,129.33,118.77,118.60,117.71,112.48,112.22,80.49,37.97,28.61,22.80.

[0399] 1-[(4-cyanobenzyl)oxy]-2-(3-cyanophenyl)-4-cyclopropyl-1H-imidazol-5-carboxylic acid (6d): white solid, yield: 68%. Purity (HPLC): 97.8%. MPa: 170.1-189.3℃. ESI-MS m / z: 385.1 [M+H] + 407.0 [M+Na] + . 1H NMR(400MHz, DMSO-d6)δ8.06–7.98(m,3H),7.89(dt,J=7.7,1.4Hz,1H),7.73(d,J=8.2Hz,2H),7 .63(t,J=7.9Hz,1H),7.41(d,J=8.2Hz,2H),5.23(s,2H),2.69–2.64(m,1H),0.98–0.92(m,4H). 13 C NMR(150MHz,DMSO-d6)δ160.59,148.79,141.87,138.54,133.46,132.70,132.58,131.3 9,131.08,130.35,129.23,118.82,118.61,117.26,112.42,112.20,80.55,9.67,8.88.

[0400] 1-[(4-cyanobenzyl)oxy]-2-(3-cyanophenyl)-4-(1-methylcyclopropyl)-1H-imidazolium-5-carboxylic acid (6e): white solid, yield: 68%. Purity (HPLC): 97.9%. MPa 170.1-170.9℃. ESI-MS m / z: 399.2 [M+H] + 421.1[M+Na] + . 1 H NMR (400MHz, DMSO-d6) δ13.24(s,1H),8.12–8.02(m,2H),7.90(d,J=7.7Hz,1H),7.75(d,J=7.9Hz,2H),7.6 5(t,J=7.8Hz,1H),7.40(d,J=7.9Hz,2H),5.23(s,2H),1.38(s,3H),1.00–0.85(m,2H),0.73–0.61(m,2H). 13 C NMR(100MHz,DMSO-d6)δ160.08,150.24,140.24,138.48,133.38,132.73,132.51,131.29,1 31.02,130.40,129.34,118.81,118.69,118.62,112.48,112.27,80.58,24.86,16.78,14.32

[0401] 1-[(4-cyanobenzyl)oxy]-2-(3-cyanophenyl)-4-cyclobutyl-1H-imidazolium-5-carboxylic acid (6f): white solid, yield: 62%. Purity (HPLC): 98.1%. MPa: 176.4-176.7℃. ESI-MS m / z: 399.1 [M+H] + 421.1[M+Na] + . 1 H NMR (400MHz, DMSO-d6) δ8.15–8.07(m,2H),7.92(dt,J=7.8,1.4Hz,1H),7.74(d,J=8.2Hz,2H),7.71–7.62(m,1H),7.41(d,J= 8.2Hz,2H),5.23(s,2H),4.09(p,J=8.6Hz,1H),2.43–2.30(m,2H),2.27–2.14(m,2H),2.07–1.92(m,1H),1.90–1.79(m,1H). 13 C NMR(100MHz,DMSO-d6)δ160.18,149.69,141.52,138.54,133.43,132.72,132.60,131.37,13 1.05,130.41,129.42,118.81,118.63,116.15,112.46,112.27,80.61,33.76,27.75,18.37.

[0402] 1-[(4-cyanobenzyl)oxy]-2-(3-cyanophenyl)-4-(1-methylcyclobutyl)-1H-imidazolium-5-carboxylic acid (6 g): white solid, yield: 66%. Purity (HPLC): 98.3%. MPa 165.2-166.3℃. ESI-MS m / z: 413.2 [M+H] + 435.2 [M+Na] + . 1 H NMR (400MHz, DMSO-d6) δ13.15(s,1H),8.11–8.06(m,2H),7.91(dt,J=7.7,1.4Hz,1H),7.75(dd,J=6.3,1.7Hz,2H),7.66(t,J =7.8Hz,1H),7.40(dd,J=6.3,1.7Hz,2H),5.23(s,2H),2.60–2.52(m,2H),2.09–1.95(m,3H),1.76–1.67(m,1H),1.49(s,3H). 13C NMR(100MHz,DMSO-d6)δ160.02,154.80,140.13,138.51,133.36,132.73,132.53,131.29,13 1.02,130.42,129.40,118.82,118.65,116.07,112.47,112.26,80.56,33.71,27.37,15.81.

[0403] 1-[(4-cyanobenzyl)oxy]-2-(3-cyanophenyl)-4-cyclopentyl-1H-imidazol-5-carboxylic acid (6h): white solid, yield: 61%. Purity (HPLC): 99.1%. MPa 168.5-169.7℃. ESI-HRMS m / z calculated for C 24 H 21 N4O3 + [M+H] + 413.1608, found 413.1606. 1 H NMR (400MHz, DMSO-d6) δ8.12–8.05(m,2H),7.91(dt,J=7.7,1.3Hz,1H),7.74(d,J=8.3Hz,2H),7.65(td,J=7.6,1.0Hz,1 H),7.41(d,J=8.2Hz,2H),5.23(s,2H),3.71(p,J=8.1Hz,1H),1.99–1.86(m,2H),1.86–1.73(m,4H),1.68–1.56(m,2H). 13 CNMR(100MHz,DMSO-d6)δ160.36,150.97,141.36,138.54,133.40,132.71,132.54,131.31,1 31.02,130.40,129.42,118.80,118.63,116.79,112.46,112.27,80.54,38.39,32.57,25.87.

[0404] 1-[(4-cyanobenzyl)oxy]-2-(3-cyanophenyl)-4-cyclohexyl-1H-imidazol-5-carboxylic acid (6i): white solid, yield: 52%. Purity (HPLC): 98.8%. MPa: 169.1-170.0℃. ESI-HRMS m / z calculated for C 24 H 21 N4O3 + [M+H]+ 427.1765, found 427.1758. 1 H NMR (400MHz, DMSO-d6) δ8.11–8.04(m,2H),7.90(dt,J=7.7,1.3Hz,1H),7.73(d,J=8.3Hz,2H),7.65(td,J=7.6,1.5Hz ,1H),7.39(d,J=8.2Hz,2H),5.22(s,2H),3.28–3.23(m,1H),1.83–1.74(m,4H),1.67–1.54(m,2H),1.37–1.26(m,2H). 13 C NMR(100MHz,DMSO-d6)δ160.30,152.08,141.35,138.49,133.37,132.69,132.51,131.28,131.0 3,130.39,129.42,118.79,118.62,116.23,112.47,112.25,80.51,37.06,32.13,26.53,26.13.

[0405] 1-[(4-cyanobenzyl)oxy]-2-(3-cyanophenyl)-4-(methoxymethyl)-1H-imidazol-5-carboxylic acid (6j): white solid, yield: 62%. Purity (HPLC): 98.7%. MPa: 166.5-167.7℃. ESI-HRMS m / z calculated for C 21 H 17 N4O4+[M+H] + 389.1244, found 389.1245. 1 H NMR (400MHz, DMSO-d6) δ8.11–8.04(m,2H),7.91(dt,J=7.7,1.3Hz,2H),7.73(d,J=8.2Hz, 2H),7.65(t,J=7.8Hz,1H),7.41(d,J=8.2Hz,2H),5.28(s,2H),4.59(s,2H),3.31(s,3H). 13 C NMR(100MHz,DMSO-d6)δ159.92,142.39,141.58,138.42,133.51,132.69,132.59,13 1.36,131.16,130.41,129.26,118.78,118.57,112.51,112.29,80.76,67.43,58.03.

[0406] 1-[(4-cyanobenzyl)oxy]-2-(3-cyanophenyl)-4-(difluoromethyl)-1H-imidazol-5-carboxylic acid (6k): white solid, yield: 61%. Purity (HPLC): 99.4%. MPa: 166.9-167.3℃. ESI-HRMS m / z calculated for C 13 H 15 N7O2 - [M+H] + 395.0950, found 395.0942. 1 H NMR (400MHz, DMSO-d6) δ14.26(s,1H),8.09(t,J=1.8Hz,1H),8.06(dt,J=7.9,1.5Hz,1H),7.96( dt,J=7.8,1.4Hz,1H),7.76–7.70(m,2H),7.67(t,J=7.9Hz,1H),7.45–7.14(m,3H),5.32(s,2H). 13 C NMR(100MHz,DMSO-d6)δ158.79,142.77,138.11,136.69,134.06,132.92,132.75,131 .68,131.27,130.48,128.61,121.03,118.76,118.47,112.63,112.33,109.61,81.26.

[0407] 1-[(4-cyanobenzyl)oxy]-2-(3-cyanophenyl)-4-(trifluoromethyl)-1H-imidazol-5-carboxylic acid (6l): white solid, yield: 59%. Purity (HPLC): 98.6%. MPa 126.1-127.6℃. ESI-HRMS m / z calculated for: C 20 H 12 F3N4O3 + [M+H] + 413.0856, found 413.0848. 1 H NMR(400MHz,DMSO-d6)δ8.09–8.01(m,2H),7.92(dt,J=7.8,1.5Hz,1H),7.74 (d,J=8.1Hz,2H),7.66(t,J=7.8Hz,1H),7.45(d,J=8.2Hz,2H),5.42(s,2H). 13C NMR(150MHz,DMSO-d6)δ158.87,138.51,133.46,132.83,132.74,132.39,131.20, 131.11,130.48,129.06,122.86,118.83,118.72,118.59,112.48,112.30,80.86.

[0408] 1-[(4-cyanobenzyl)oxy]-2-(3-cyanophenyl)-4-(methyl-D3)-1H-imidazol-5-carboxylic acid (6m): white solid, yield: 79%. Purity (HPLC): 97.3%. MPa 192.4-193.8℃. ESI-MS m / z: 362.2 [M+H] + 384.1 [M+Na] + . 1 H NMR(400MHz,DMSO-d6)δ13.24(s,1H),8.09–8.01(m,2H),7.89(dt,J=7.8,1.4Hz,1H),7.7 2(dd,J=6.4,1.8Hz,2H),7.63(t,J=7.8Hz,1H),7.40(dd,J=6.4,1.9Hz,2H),5.24(s,2H). 13 C NMR(100MHz,DMSO-d6)δ160.37,143.69,141.31,138.48,133.38,132.68,132.49,131 .27,131.13,130.36,129.29,118.78,118.58,117.58,112.47,112.25,80.61,55.36.

[0409] 1-[(4-cyanobenzyl)oxy]-2-(3-cyanophenyl)-4-(2,2-difluorocyclopropyl)-1H-imidazol-5-carboxylic acid (6n): white solid, yield: 65%. Purity (HPLC): 98.8%. MPa 191.5-191.9℃. ESI-MS m / z: 421.1 [M+H] + 443.1 [M+Na] + . 1H NMR (400MHz, DMSO-d6) δ13.59(s,1H),8.06(t,J=1.8Hz,1H),8.03(dt,J=8.0,1.5Hz,1H),7.91(dt,J=7.8,1.4Hz,1H),7.71(dd,J=6.3,1.8Hz,2H ),7.64(t,J=7.9Hz,1H),7.39(dd,J=6.4,1.9Hz,2H),5.28(q,J=10.7Hz, 2H),3.37(td,J=11.9,8.1Hz,1H),2.28–2.16(m,1H),2.08–1.95(m,1H). 13 C NMR(100MHz,DMSO-d6)δ159.87,141.79,138.48,138.29,133.65,132.68,132.62,131.46,13 1.18,130.39,128.94,119.77,118.76,118.55,112.55,112.28,80.83,55.36,22.44,14.93.

[0410] 1-[(4-cyanobenzyl)oxy]-2-(3-cyanophenyl)-4-(3,3-difluorocyclobutyl)-1H-imidazol-5-carboxylic acid (6o): white solid, yield: 61%. Purity (HPLC): 99.2%. MPa: 189.3-190.4℃. ESI-MS m / z: 435.1 [M+H] + 457.2 [M+Na] + . 1 H NMR (400MHz, DMSO-d6) δ8.13–8.10(m,1H),8.09(dt,J=7.9,1.5Hz,1H),7.92(dt,J=7.8,1.4Hz,1H),7.73(dd ,2H),7.66(t,J=7.8Hz,1H),7.41(dd,J=6.4,1.8Hz,2H),5.25(s,2H),3.97–3.83(m,1H),3.04–2.82(m,4H). 13 C NMR(100MHz,DMSO-d6)δ159.90,146.75,141.66,138.38,133.59,132.71,132.63,131.44,13 1.12,130.42,129.15,123.59,118.77,118.57,117.52,112.53,112.32,80.78,22.07,21.90.

[0411] 1-[(4-cyanobenzyl)oxy]-2-(3-cyanophenyl)-4-phenyl-1H-imidazol-5-carboxylic acid (6p): white solid, yield: 76%. Purity (HPLC): 95.4%. MPa: 167.3-167.9℃. ESI-HRMS m / z calculated for C 25 H 17 N4O3 + [M+H] + 421.1295, found 421.1286. 1 H NMR (400MHz, DMSO-d6) δ13.47(s,1H),8.16(t,J=1.6Hz,1H),8.13(dt,J=8.0,1.4Hz,1H),7.94(dt,J=7.8,1.4Hz,1 H),7.81–7.77(m,2H),7.77–7.73(m,2H),7.68(t,J=7.9Hz,1H),7.47–7.42(m,3H),7.42–7.38(m,2H),5.33(s,2H). 13 C NMR(100MHz,DMSO-d6)δ160.28,143.54,141.85,138.41,134.09,133.65,132.76,132.71,131.56, 131.17,130.45,129.57,129.18,128.73,128.20,118.81,118.61,118.09,112.55,112.33,80.94.

[0412] 1-[(4-cyanobenzyl)oxy]-2-(3-cyanophenyl)-4-(pyridin-4-yl)-1H-imidazol-5-carboxylic acid (6q): white solid, yield: 69%. Purity (HPLC): 98.4%. MPa: 182.4-183.4℃. ESI-MS m / z: 422.2 [M+H] + 444.1[M+Na] + . 1 H NMR (400MHz, DMSO-d6) δ8.64(d,J=5.0Hz,2H),8.16(t,J=1.6Hz,1H),8.12(dt,J=7.9,1.4Hz,1H),7.95(dt,J=7 .8,1.4Hz,1H),7.89–7.81(m,2H),7.78–7.71(m,2H),7.68(t,J=7.9Hz,1H),7.44(d,J=8.1Hz,2H),5.36(s,2H). 13C NMR(100MHz,DMSO-d6)δ160.12,149.64,141.95,141.57,138.32,133.75,132.77,132 .71,131.58,131.22,130.48,129.01,123.55,118.80,118.58,112.58,112.35,81.09.

[0413] 1-[(4-cyanobenzyl)oxy]-2-(3-cyanophenyl)-4-(pyridin-3-yl)-1H-imidazol-5-carboxylic acid (6r): white solid, yield: 72%. Purity (HPLC): 98.2%. MPa: 172.8-173.1℃. ESI-MS m / z: 422.1 [M+H] + 444.1[M+Na] + . 1 H NMR(400MHz, DMSO-d6)δ8.99(d,J=2.2Hz,1H),8.57(dd,J=4.8,1.7Hz,1H),8.24–8.09(m,3H),7.94(dt ,J=7.7,1.4Hz,1H),7.74(dd,J=6.3,1.8Hz,2H),7.68(t,J=7.9Hz,1H),7.51–7.40(m,3H),5.36(s,2H). 13 C NMR(100MHz,DMSO-d6)δ160.24,150.06,149.27,141.91,138.42,136.64,133.63,132.75,132 .67,131.52,131.24,130.44,130.21,129.15,123.39,118.81,118.60,112.54,112.33,80.93.

[0414] 1-[(4-cyanobenzyl)oxy]-2-(3-cyanophenyl)-4-(pyridin-2-yl)-1H-imidazol-5-carboxylic acid (6s): white solid, yield: 61%. Purity (HPLC): 97.7%. MPa: 190.7-191.2℃. ESI-MS m / z: 422.1 [M+H] + 444.1[M+Na] + . 1H NMR (400MHz, DMSO-d6) δ8.75(d,J=5.1Hz,1H),8.49(d,J=8.1Hz,1H),8.27(td,J=7.9,1.6Hz,1H),8.18(t,J=1.8Hz, 1H), 8.14 (dt, J=8.0, 1.4Hz, 1H), 7.96 (dt, J=7.8, 1.4Hz, 1H), 7.76–7.66 (m, 4H), 7.48 (d, J=8.0Hz, 2H), 5.33 (s, 2H). 13 C NMR(100MHz,DMSO-d6)δ158.26,149.33,145.19,142.86,141.80,138.35,136.25,134.00,132.87,132 .71,131.87,131.35,130.45,128.70,125.34,122.62,122.22,118.81,118.52,112.53,112.36,80.86.

[0415] 1-[(4-cyanobenzyl)oxy]-2-(3-cyanophenyl)-4-(pyrazin-2-yl)-1H-imidazol-5-carboxylic acid (6t): white solid, yield: 69%. Purity (HPLC): 99.2%. MPa: 183.2-184.2℃. ESI-MS m / z: 423.1 [M+H] + 445.1 [M+Na] + . 1 H NMR (400MHz, DMSO-d6) δ9.41(d,J=1.4Hz,1H),8.81(d,J=2.7Hz,1H),8.81–8.75(m,1H),8.20(t,J=1.7Hz,1H),8.15(d ,J=8.0Hz,1H),7.98(d,J=7.8Hz,1H),7.74(d,J=8.1Hz,2H),7.69(d,J=7.9Hz,1H),7.47(d,J=8.0Hz,2H),5.36(s,2H). 13 C NMR(150MHz,DMSO-d6)δ158.48,146.38,145.28,144.87,142.86,142.17,138.15,137.08,134.05, 132.89,132.77,131.84,131.39,130.49,128.64,121.61,118.79,118.54,112.63,112.38,81.20.

[0416] 1-[(4-cyanobenzyl)oxy]-2-(3-cyanophenyl)-4-(thiophen-2-yl)-1H-imidazol-5-carboxylic acid (6u): white solid, yield: 59%. Purity (HPLC): 98.9%. MPa. Degraded at 153.7℃. ESI-MS m / z: 427.1 [M+H] + 449.1 [M+Na] + . 1 H NMR (400MHz, DMSO-d6) δ13.76(s,1H),8.14–8.07(m,2H),8.01(dd,J=3.7,1.2Hz,1H),7.95(dt,J=7.8,1.4Hz,1H),7.73(d,J =8.1Hz,2H),7.68(t,J=7.9Hz,1H),7.62(dd,J=5.1,1.2Hz,1H),7.44–7.38(m,2H),7.15(dd,J=5.1,3.7Hz,1H),5.29(s,2H). 13 C NMR(100MHz,DMSO-d6)δ160.13,142.02,138.36,138.23,136.79,133.83,132.86,132.75,131.66, 131.16,130.46,128.81,128.48,128.10,128.07,118.79,118.57,116.44,112.55,112.32,81.00.

[0417] 61-[(4-cyanobenzyl)oxy]-2-(3-cyanophenyl)-4-(thiophen-3-yl)-1H-imidazol-5-carboxylic acid (6v), white solid, yield: 89%. Purity (HPLC): 98.8%. Degraded at 161℃. ESI-MS m / z: 427.1 [M+H] + 449.1 [M+Na] + . 1 H NMR (400MHz, DMSO-d6) δ8.16–8.14(m,2H),8.12(dt,J=8.0,1.4Hz,1H),7.94(dt,J=7.8,1.4Hz,1H),7. 74(d,J=8.3Hz,2H),7.71–7.65(m,2H),7.57(dd,J=5.0,3.0Hz,1H),7.42(d,J=8.2Hz,2H),5.30(s,2H). 13C NMR(150MHz,DMSO-d6)δ160.21,141.90,139.48,138.39,134.89,133.69,132.77,132.75,131.65, 131.17,130.43,129.10,129.00,126.15,125.63,118.81,118.61,117.18,112.52,112.29,80.92.

[0418] 1-[(4-cyanobenzyl)oxy]-2-(3-cyanophenyl)-4-(furan-2-yl)-1H-imidazol-5-carboxylic acid (6w): white solid, yield: 86%. Purity (HPLC): 97.8%. MPa. Degraded at 172.5℃. ESI-MS m / z: 411.1 [M+H] + 433.1[M+Na] + . 1 H NMR (400MHz, DMSO-d6) δ13.71(s,1H),8.11(t,1H),8.09(dt,J=8.0,1.5Hz,1H),7.94(dt,J=7.8,1.4Hz,1H),7.80(d,J=1.7Hz,1H),7.73(dd, J=6.3,1.8Hz,2H),7.67(t,J=7.9Hz,1H),7.40(dd,J=6.4,1.9Hz,2H),7.20(dd,J=3.5,0.8Hz,1H),6.63(dd,J=3.4,1.8Hz,1H),5.30(s,2H). 13 C NMR(100MHz,DMSO-d6)δ159.80,147.34,143.77,142.19,138.30,134.74,133.76,132.81,132.73, 131.60,131.20,130.43,128.98,118.78,118.55,117.35,112.57,112.30,112.08,112.00,81.05.

[0419] 1-[(4-cyanobenzyl)oxy]-2-(3-cyanophenyl)-4-(furan-3-yl)-1H-imidazol-5-carboxylic acid (6x), white solid, yield: 84%. Purity (HPLC): 98.8%. Decomposes at 167.5 MPa. ESI-MS m / z: 411.1 [M+H] + 433.0 [M+Na] + . 1H NMR (400MHz, DMSO-d6) δ13.67(s,1H),8.35(d,J=1.5Hz,1H),8.14(t,J=1.8Hz,1H),8.11(dt,J=8.2,1.4Hz,1H),7.9 8–7.92(m,1H),7.79–7.71(m,3H),7.67(t,J=7.9Hz,1H),7.41(d,J=7.9Hz,2H),7.08(d,J=1.8Hz,1H),5.28(s,2H). 13 C NMR(100MHz,DMSO-d6)δ160.17,143.38,142.11,138.39,137.07,133.66,132.72,131.62,131 .12,130.39,129.06,119.98,118.78,118.58,116.94,112.48,112.26,111.07,111.06,80.88.

[0420] 1-[(4-cyanobenzyl)oxy]-2-(3-cyanophenyl)-4-(thiazolyl-2-yl)-1H-imidazol-5-carboxylic acid (6y), white solid, yield: 74%. Purity (HPLC): 96.8%. MPa: 195.5-196.6℃. ESI-MS m / z: 428.0 [M+H] + 450.1 [M+Na] + . 1 H NMR(400MHz, DMSO-d6)δ8.17(d,J=3.4Hz,1H),8.09(t,J=1.7Hz,1H),8.08–8.04(m,2H), 7.99(dt,J=7.8,1.4Hz,1H),7.73–7.66(m,3H),7.45(dd,J=6.4,1.8Hz,2H),5.34(s,2H). 13 C NMR(100MHz,DMSO-d6)δ164.05,157.32,143.83,141.72,138.13,134.27,133.96,133.14,132 .72,131.93,131.48,130.49,128.21,123.23,119.16,118.77,118.46,112.63,112.36,81.17.

[0421] 1-[(4-cyanobenzyl)oxy]-2-(3-cyanophenyl)-4-(thiazolyl-5-yl)-1H-imidazol-5-carboxylic acid (6z), white solid, yield: 78%. Purity (HPLC): 95.1%. MPa: 172.0-175.3℃. ESI-MS m / z: 428.1 [M+H] + 450.1 [M+Na] + . 1 H NMR (400MHz, DMSO-d6) δ13.98(s,1H),9.14(d,J=0.7Hz,1H),8.67(d,J=0.7Hz,1H),8.15–8.09(m,1H),8.13–8.05(m,1H),7. 96(dt,J=7.8,1.4Hz,1H),7.73(dd,J=6.4,1.8Hz,2H),7.69(td,J=7.9,0.6Hz,1H),7.41(dd,J=6.4,1.8Hz,2H),5.32(s,2H). 13 C NMR(100MHz,DMSO-d6)δ159.87,155.75,143.62,142.54,138.28,135.69,133.97,132.93,132 .75,132.10,131.74,131.23,130.47,128.64,118.78,118.54,117.48,112.58,112.34,81.14.

[0422] 1-[(4-cyanobenzyl)oxy]-2-(3-cyanophenyl)-4-(thiazolyl-4-yl)-1H-imidazol-5-carboxylic acid (6z1), white solid, yield: 69%. Purity (HPLC): 99.4%. MPa: 190.9-192.4℃. ESI-MS m / z: 428.1 [M+H] + 450.1 [M+Na] + . 1 H NMR (400MHz, DMSO-d6) δ9.51(d,J=2.1Hz,1H),8.37(d,J=2.1Hz,1H),8.14(t,J=1.7Hz,1H),8.10(dt, J=8.0,1.4Hz,1H),7.96(dt,J=7.8,1.4Hz,1H),7.75–7.65(m,3H),7.45(d,J=8.3Hz,2H),5.31(s,2H). 13C NMR(100MHz,DMSO-d6)δ158.11,156.59,147.95,143.19,138.32,135.62,133.94,132.91,132 .71,131.83,131.35,130.44,128.78,119.93,118.79,118.53,118.13,112.54,112.31,80.84.

[0423] Example 50. Synthesis of compounds 6K-1 to 6K-27

[0424] Compounds 6K-1 to 6K-27 were prepared using 5K-1 to 5K-27 as starting materials, following the synthetic method for 1-[(4-cyanobenzyl)oxy]-2-(3-cyanophenyl)-4-ethyl-1H-imidazol-5-carboxylic acid (6a).

[0425] 2-(3-cyanophenyl)-4-(difluoromethyl)-1-[(4-fluorobenzyl)oxy]-1H-imidazol-5-carboxylic acid (6K-1): white solid, yield: 79%. Purity (HPLC): 99.2%. MPa 159.9-161.1℃. ESI-MS m / z: 388.1 [M+H] + 410.0 [M+Na] + . 1 H NMR (400MHz, DMSO-d6) δ8.14–8.04(m,2H),7.95(dt,J=7.7,1.4Hz,1H),7.67(t,J=7.9Hz,1H),7.47–7.14(m,3H),7.06(t,J=8.9Hz,2H),5.22(s,2H). 13 C NMR(100MHz,DMSO-d6)δ164.50,162.04,158.80,142.85,133.93,133.21,133.13, 132.86,131.59,130.39,128.74,118.53,115.88,115.66,112.26,109.65,81.50.

[0426] 2-(3-cyanophenyl)-4-(difluoromethyl)-1-[(3-fluorobenzyl)oxy]-1H-imidazol-5-carboxylic acid (6K⁻²): white solid, yield: 71%. Purity (HPLC): 99.6%. MPa: 160.4–160.6 °C. ESI-MS m / z: 388.1 [M + H⁺] + 410.0 [M+Na] + . 1H NMR (400MHz, DMSO-d6) δ8.15–8.05(m,2H),7.95(dt,J=7.7,1.4Hz,1H),7.68(t,J= 7.8Hz,1H),7.47–7.25(m,2H),7.19–7.11(m,1H),7.08–6.99(m,2H),5.23(s,2H). 13 C NMR(100MHz,DMSO-d6)δ163.49,158.79,142.83,135.37,133.99,132.91,131.61,130.98,130 .45,128.62,126.69,126.66,118.50,117.47,117.25,116.98,116.77,112.32,109.62,81.42.

[0427] 2-(3-cyanophenyl)-4-(difluoromethyl)-1-[(2-fluorobenzyl)oxy]-1H-imidazol-5-carboxylic acid (6K-3): white solid, yield: 86%. Purity (HPLC): 99.6%. MPa: 170.3-170.5℃. ESI-MS m / z: 388.1 [M+H] + 410.1[M+Na] + . 1 H NMR (400MHz, DMSO-d6) δ8.04(t,J=1.7Hz,1H),7.99(dt,J=8.0,1.5Hz,1H),7.91(dt,J=7.8,1.4Hz,1H),7.62(t, J=7.9Hz,1H),7.45–7.25(m,2H),7.21–7.11(m,1H),7.04(td,J=7.5,1.1Hz,1H),7.00–6.92(m,1H),5.30(s,2H). 13 C NMR(100MHz,DMSO-d6)δ162.81,160.33,158.78,143.13,133.86,133.43,132.92,131.58, 130.27,128.53,124.87,120.96,120.03,119.88,118.53,115.75,112.17,109.62,75.71.

[0428] 2-(3-cyanophenyl)-4-(difluoromethyl)-1-{[4-(trifluoromethyl)benzyl]oxy}-1H-imidazolium-5-carboxylic acid (6K-4): white solid, yield: 82%. Purity (HPLC): 96.4%. MPa: 168.0-168.6℃. ESI-MS m / z: 438.1 [M+H] + 460.1 [M+Na] + . 1 H NMR(400MHz,DMSO-d6)δ14.25(s,1H),8.07–8.00(m,2H),7.92(dt,J=7.8,1.4Hz ,1H),7.67–7.61(m,1H),7.58(d,J=8.0Hz,2H),7.46–7.15(m,3H),5.33(s,2H). 13 C NMR(100MHz,DMSO-d6)δ158.66,142.72,137.10,136.59,133.75,132.68,131.42,131 .21,130.22,129.95,128.46,125.50,122.82,120.82,118.24,112.12,109.46,81.20.

[0429] 2-(3-cyanophenyl)-4-(difluoromethyl)-1-{[3-(trifluoromethyl)benzyl]oxy}-1H-imidazol-5-carboxylic acid (6K-5): white solid, yield: 75%. Purity (HPLC): 96.7%. MPa: 161.8-162.4℃. ESI-MS m / z: 438.0 [M+H] + 460.0 [M+Na] + . 1 H NMR(400MHz,DMSO-d6)δ14.23(s,1H),8.06–7.99(m,2H),7.90(dt,J=7.8,1.4 Hz,1H),7.67–7.58(m,2H),7.54(s,1H),7.49–7.43(m,2H),7.43–7.15(m,1H). 13 C NMR(100MHz,DMSO-d6)δ158.82,142.97,136.78,134.70,134.00,132.85,131.50,130.32,129 .98,129.60,128.57,127.45,126.66,125.55,122.84,120.93,118.41,112.24,109.57,81.29.

[0430] 2-(3-cyanophenyl)-4-(difluoromethyl)-1-{[2-(trifluoromethyl)benzyl]oxy}-1H-imidazolium-5-carboxylic acid (6K-6): white solid, yield: 78%. Purity (HPLC): 96.6%. MPa: 153.7-154.2℃. ESI-MS m / z: 438.0 [M+H] + 460.0 [M+Na] + . 1 H NMR (400MHz, DMSO-d6) δ14.25(s,1H),7.95–7.91(m,1H),7.88(ddt,J=10.5,7.8,1.4Hz,2H),7.61–7.46(m,4H),7.45–7.16(m,2H),5.38(s,2H). 13 CNMR(100MHz,DMSO-d6)δ158.71,143.20,136.66,133.59,133.22,133.01,132.74,131.75,130 .61,130.46,129.97,128.29,126.22,125.35,122.63,120.69,118.19,111.86,109.46,78.41.

[0431] 2-(3-cyanophenyl)-4-(difluoromethyl)-1-{[4-(trifluoromethoxy)benzyl]oxy}-1H-imidazol-5-carboxylic acid (6K-7): white solid, yield: 74%. Purity (HPLC): 99.2%. MPa: 162.4-163.0℃. ESI-MS m / z: 454.0 [M+H] + 476.0 [M+Na] + . 1 H NMR(600MHz,DMSO-d6)δ8.08(d,J=1.8Hz,1H),8.06(dt,J=8.0,1.5Hz,1H),7.9 3(dt,J=7.8,1.4Hz,1H),7.65(t,J=7.9Hz,1H),7.43–7.17(m,5H),5.27(s,2H). 13 C NMR(100MHz,DMSO-d6)δ158.82,149.52,142.78,136.64,133.87,132.83,132.74,132 .14,131.50,130.34,128.66,121.63,121.18,119.08,118.45,112.23,109.63,81.24.

[0432] 2-(3-cyanophenyl)-4-(difluoromethyl)-1-{[3-(trifluoromethoxy)benzyl]oxy}-1H-imidazol-5-carboxylic acid (6K-8): white solid, yield: 87%. Purity (HPLC): 97.9%. MPa 149.8-151.1℃. ESI-MS m / z: 454.1 [M+H] + 476.1 [M+Na] + . 1 H NMR (400MHz, DMSO-d6) δ14.24(s,1H),8.11–8.05(m,2H),7.94(dt,J=7.8,1.4Hz,1H),7.66(t,J=7.8Hz,1H),7.45–7.14(m,5H),5.29(s,2H). 13 CNMR(100MHz,DMSO-d6)δ158.83,148.64,142.88,136.76,135.29,133.98,132.87,131.56,130 .91,130.40,129.72,128.61,122.98,122.44,121.67,120.98,118.45,112.34,109.60,81.23.

[0433] 2-(3-cyanophenyl)-4-(difluoromethyl)-1-{[2-(trifluoromethoxy)benzyl]oxy}-1H-imidazol-5-carboxylic acid (6K-9): white solid, yield: 81%. Purity (HPLC): 98.5%. MPa: 158.8-159.2℃. ESI-MS m / z: 454.1 [M+H] + 476.1 [M+Na] + . 1 H NMR (600MHz, DMSO-d6) δ8.00(s,1H),7.94(d,J=8.0Hz,1H),7.90(d,J=7.8Hz,1H),7.60(t,J=7 .8Hz,1H),7.41(td,J=7.9,1.8Hz,1H),7.38–7.18(m,3H),7.16(d,J=8.4Hz,1H),5.33(s,2H). 13C NMR(100MHz,DMSO-d6)δ158.87,147.99,143.15,136.78,133.90,133.83,132.98,132.50,131 .73,130.26,128.52,127.54,124.93,121.47,121.10,119.96,118.47,112.15,109.62,76.14.

[0434] 2-(3-cyanophenyl)-4-(difluoromethyl)-1-(pyridin-4-ylmethoxy)-1H-imidazol-5-carboxylic acid (6K-10): white solid, yield: 73%. Mp 154.6-155.3℃. ESI-MS m / z: 371.1 [M+H] + 393.0 [M+Na] + . 1 HNMR (400MHz, DMSO-d6) δ8.71(d,J=5.6Hz,2H),8.22(t,J=1.7Hz,1H),8.17(dt,J=8.0,1.4Hz,1H),7.99(dt ,J=7.8,1.3Hz,1H),7.72(td,J=7.9,2.5Hz,1H),7.62(d,J=5.3Hz,2H),7.31(t,J=53.8Hz,1H),5.44(s,2H).

[0435] 2-(3-Cyanophenyl)-4-(difluoromethyl)-1-(pyridin-3-ylmethoxy)-1H-imidazol-5-carboxylic acid (6K-11): white solid, yield: 64%. Purity (HPLC): 98.0%. MPa. Degraded at 155.7℃. ESI-MS m / z: 371.1 [M+H] + 393.1 [M+Na] + . 1 H NMR (400MHz, DMSO-d6) δ8.50 (d, J=4.8Hz, 1H), 8.37 (s, 1H), 8.17–8.04 (m, 2H), 7.96 (d, J= 7.7Hz,1H),7.68(t,J=7.9Hz,1H),7.62(d,J=7.9Hz,1H),7.47–7.15(m,2H),5.30(s,2H). 13C NMR(100MHz,DMSO-d6)δ158.82,151.35,150.91,142.80,138.42,136.73,136.48,134 .09,132.87,131.61,130.55,128.62,123.99,121.09,118.53,112.38,109.62,79.80.

[0436] 2-(3-cyanophenyl)-4-(difluoromethyl)-1-(pyridin-2-ylmethoxy)-1H-imidazol-5-carboxylic acid (6K-12): white solid, yield: 80%. Purity (HPLC): 99.5%. MPa. Degraded at 167.2℃. ESI-MS m / z: 371.1 [M+H] + 393.1 [M+Na] + . 1 H NMR (400MHz, DMSO-d6) δ14.24(s,1H),8.44(d,J=4.8Hz,1H),8.33(s,1H),8.15(d,J=8.0Hz ,1H),7.92(d,J=7.7Hz,1H),7.67(dt,J=24.5,7.8Hz,2H),7.46–7.13(m,3H),5.33(s,2H). 13 C NMR(100MHz,DMSO-d6)δ158.84,152.50,149.88,142.63,137.34,136.67,133.94,132 .92,131.71,130.31,128.50,125.43,124.73,121.15,118.62,112.30,109.65,83.03.

[0437] 2-(3-Cyanophenyl)-4-(difluoromethyl)-1-(2-morpholinoethoxy)-1H-imidazol-5-carboxylic acid (6K-13), white solid, yield: 52%. Purity (HPLC): 98.8%. MPa: 149.0-150.4℃. ESI-MS m / z: 393.2 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ8.41–8.31(m,2H),7.99(d,J=7.7Hz,1H),7.76(t,J=7.8Hz,1H),7.45(t,J=54 .5Hz,1H),4.50(t,J=4.7Hz,2H),3.78(t,J=4.7Hz,4H),3.19(t,J=4.6Hz,2H),3.04(t,J=4.5Hz,4H). 13 C NMR(100MHz,DMSO-d6)δ167.58,158.70,142.19,136.43,134.59,132.98,13 1.70,131.05,128.30,120.84,118.56,112.82,74.92,63.55,53.83,51.56.

[0438] 1-(benzo[d][1,3]dioxacyclopenten-5-ylmethoxy)-2-(3-cyanophenyl)-4-(difluoromethyl)-1H-imidazol-5-carboxylic acid (6K-14), white solid, yield: 82%. Purity (HPLC): 95.5%. MPa 150.9-151.0℃. ESI-MS m / z: 414.0 [M+H] + 436.1 [M+Na] + . 1 H NMR (400MHz, DMSO-d6) δ8.05(t,J=1.7Hz,1H),8.03(dt,J=7.9,1.4Hz,1H),7.93(dt,J=7.8,1.4Hz,1H),7.67(t,J=7.9Hz,1H) ,7.28(t,J=53.9Hz,1H),6.72(d,J=7.8Hz,1H),6.64(d,J=1.6Hz,1H),6.56(dd,J=7.9,1.7Hz,1H),5.98(s,2H),5.11(s,2H). 13 C NMR(100MHz,DMSO-d6)δ158.79,148.87,147.58,143.27,136.82,133.83,132.99,131.67,130 .22,128.74,126.30,125.18,120.87,118.58,112.09,110.96,109.66,108.37,101.79,82.45.

[0439] 1-[(6-bromopyridin-3-yl)methoxy]-2-(3-cyanophenyl)-4-(difluoromethyl)-1H-imidazol-5-carboxylic acid (6K-15): white solid, yield: 69%. Purity (HPLC): 99.1%. MPa: 191.3-194.6℃. ESI-MS m / z: 451.0 [M+H] + 473.0 [M+Na] + . 1 H NMR (400MHz, DMSO-d6) δ8.12(d,J=2.3Hz,1H),8.03(t,J=1.7Hz,1H),8.00(dt,J=8.0,1.5Hz,1H),7.96 (dt,J=7.8,1.4Hz,1H),7.67(t,J=7.9Hz,1H),7.55–7.46(m,2H),7.30(t,J=53.8Hz,1H),5.29(s,2H). 13 C NMR(100MHz,DMSO-d6)δ158.80,152.13,143.14,142.93,141.50,136.81,134.02,132 .85,131.62,130.44,128.59,128.49,128.28,121.01,118.49,112.35,109.60,78.82.

[0440] 1-[(5-bromopyridin-2-yl)methoxy]-2-(3-cyanophenyl)-4-(difluoromethyl)-1H-imidazol-5-carboxylic acid (6K-16): white solid, yield: 71%. Purity (HPLC): 97.3%. MPa: 140.9-141.3℃. ESI-MS m / z: 449.0 [M+H] + . 1 H NMR(400MHz, DMSO-d6)δ8.46(d,J=2.4Hz,1H),8.16(t,J=1.7Hz,1H),8.05(dt,J=8.0, 1.4Hz,1H),7.94–7.87(m,2H),7.63(t,J=7.9Hz,1H),7.47–7.13(m,2H),5.31(s,2H). 13 C NMR(100MHz,DMSO-d6)δ158.83,151.42,150.54,142.81,139.83,136.70,133.81,132 .95,131.70,130.19,128.48,127.30,121.65,121.08,118.56,112.17,109.63,82.26.

[0441] 2-(3-Cyanophenyl)-4-(difluoromethyl)-1-(thiazol-5-ylmethoxy)-1H-imidazol-5-carboxylic acid (6K-17): white solid, yield: 68%. Purity (HPLC): 98.7%. MPa: 171.1-172.1℃. ESI-MS m / z: 377.1 [M+H] + 399.0 [M+Na] + . 1 H NMR (600MHz, DMSO-d6) δ9.06 (s, 1H), 8.14 (t, J = 1.7Hz, 1H), 8.09 (dt, J = 7.9, 1.5Hz, 1H), 7.95 ( dt,J=7.8,1.4Hz,1H),7.72(s,1H),7.69(t,J=7.9Hz,1H),7.42(t,J=54.1Hz,1H),5.62(s,2H). 13 C NMR (100MHz, DMSO-d6) δ159.21,158.05,146.39,142.03,133.74,132.79,131.42,130.47,129.68,128.91,118.61,112.29,109.86,72.59.

[0442] 2-(3-Cyanophenyl)-4-(difluoromethyl)-1-(thiazol-2-ylmethoxy)-1H-imidazol-5-carboxylic acid (6K-18): white solid, yield: 65%. Purity (HPLC): 97.7%. MPa: 150.1-150.2℃. ESI-MS m / z: 377.0 [M+H] + 398.9 [M+Na] + . 1 H NMR (400MHz, DMSO-d6) δ14.32(s,1H),8.17(t,J=1.7Hz,1H),8.09(dt,J=8.0,1.4Hz,1H),7.94(dt,J=7.8,1.4H z,1H),7.75(d,J=3.2Hz,1H),7.71(d,J=3.2Hz,1H),7.66(t,J=7.9Hz,1H),7.31(t,J=53.8Hz,1H),5.59(s,2H). 13C NMR(100MHz,DMSO-d6)δ159.94,158.86,143.76,143.00,136.73,134.01,133 .04,131.67,130.38,128.43,124.55,120.97,118.58,112.26,109.61,76.46.

[0443] 2-(3-Cyanophenyl)-4-(difluoromethyl)-1-(thiazol-4-ylmethoxy)-1H-imidazol-5-carboxylic acid (6K-19): white solid, yield: 63%. Purity (HPLC): 98.8%. MPa: 179.4-182.9℃. ESI-MS m / z: 377.1 [M+H] + 399.1 [M+Na] + . 1 H NMR (400MHz, DMSO-d6) δ14.19(s,1H),8.83(d,J=1.9Hz,1H),8.18(t,J=1.7Hz,1H),8.08(dt,J=7. 8,1.3Hz,1H),7.90(dt,J=7.8,1.4Hz,1H),7.66–7.60(m,2H),7.29(t,J=53.9Hz,1H),5.41(s,2H). 13 C NMR(100MHz,DMSO-d6)δ158.87,155.20,148.88,142.97,136.74,133.77,132 .85,131.61,130.19,128.50,123.72,121.18,118.66,112.13,109.66,76.33.

[0444] 2-(3-Cyanophenyl)-4-(difluoromethyl)-1-(oxazol-5-ylmethoxy)-1H-imidazol-5-carboxylic acid (6K-20): white solid, yield: 59%. Purity (HPLC): 97.9%. MPa 169.1-171.0℃. ESI-MS m / z: 361.1 [M+H] + 383.0 [M+Na] + . 1H NMR(400MHz,DMSO-d6)δ14.26(s,1H),8.12(d,J=1.7Hz,1H),8.09(s,1H),8.09–8.02(m,1H),7 .95(d,J=7.8Hz,1H),7.69(t,J=7.9Hz,1H),7.29(t,J=53.8Hz,1H),7.05(s,1H),5.41(s,2H). 13 C NMR(100MHz,DMSO-d6)δ159.04,152.83,142.63,141.08,136.24,133.83,132 .84,132.75,131.64,130.33,128.77,121.99,118.65,112.27,109.74,73.05.

[0445] 2-(3-Cyanophenyl)-4-(difluoromethyl)-1-(oxazol-2-ylmethoxy)-1H-imidazol-5-carboxylic acid (6K-21): white solid, yield: 65%. Purity (HPLC): 96.8%. MPa. Degraded at 162.2℃. ESI-MS m / z: 361.0 [M+H] + 383.1 [M+Na] + .

[0446] 2-(3-Cyanophenyl)-4-(difluoromethyl)-1-(oxazol-4-ylmethoxy)-1H-imidazol-5-carboxylic acid (6K-22): white solid, yield: 69%. Purity (HPLC): 98.3%. MPa: 166.3-168.1℃. ESI-MS m / z: 361.1 [M+H] + 383.0 [M+Na] + . 1 H NMR (400MHz, DMSO-d6) δ8.24(t,J=1.8Hz,1H),8.17(s,1H),8.14(dt,J=8.0,1.5Hz,1H),8.01( s,1H),7.93(dt,J=7.8,1.4Hz,1H),7.67(t,J=7.9Hz,1H),7.32(t,J=53.9Hz,1H),5.26(s,2H). 13 C NMR(100MHz,DMSO-d6)δ159.04,152.83,142.63,141.08,136.24,133.83,132 .84,132.75,131.64,130.33,128.77,121.99,118.65,112.27,109.74,73.05.

[0447] 2-(3-Cyanophenyl)-4-(difluoromethyl)-1-[(2-aminothiazol-4-yl)methoxy]-1H-imidazol-5-carboxylic acid (6K-23): white solid, yield: 56%. Purity (HPLC): 96.6%. 1 H NMR (400MHz, DMSO-d6) δ8.29(t,J=1.7Hz,1H),8.21(dt,J=8.1,1.4Hz,1H),7.91(dt,J=7.8,1. 4Hz,1H),7.66(t,J=7.9Hz,1H),7.28(t,J=53.9Hz,1H),6.82(s,2H),6.48(s,1H),5.02(s,2H). 13 C NMR(100MHz,DMSO-d6)δ169.03,158.90,143.79,143.15,136.62,133.64,132 .86,131.66,130.15,128.51,121.13,118.92,112.12,110.72,109.71,77.39.

[0448] 2-(3-Cyanophenyl)-4-(difluoromethyl)-1-{[2-(dimethylamino)thiazolyl-4-yl]methoxy}-1H-imidazol-5-carboxylic acid (6K-24): white solid, yield: 69%. Purity (HPLC): 98.3%. MPa. Degraded at 152.5℃. ESI-MS m / z: 420.1 [M+H] + 442.1[M+Na] + . 1 H NMR(400MHz,DMSO-d6)δ14.10(s,1H),8.09–7.99(m,2H),7.88(dt,J=7.8,1.4Hz,1H), 7.62(t,J=7.8Hz,1H),7.28(t,J=53.9Hz,1H),6.51(s,1H),5.03(s,2H),2.83(s,6H). 13 C NMR(100MHz,DMSO-d6)δ170.56,158.96,144.98,143.92,136.90,133.40,133.14 ,131.69,129.82,128.57,120.79,118.82,111.76,111.38,109.68,77.29,40.00.

[0449] 2-(3-cyanophenyl)-1-{[2-(diethylamino)thiazol-4-yl]methoxy}-4-(difluoromethyl)-1H-imidazol-5-carboxylic acid (6K-25), white solid, yield: 64%. Purity (HPLC): 97.7%. MPa. Degraded at 152.4℃. ESI-MS m / z: 448.1 [M+H] + 470.1 [M+Na] + . 1 H NMR (400MHz, DMSO-d6) δ14.13(s,1H),8.11(dt,J=8.0,1.4Hz,1H),8.07(dt,J=1.7,1.0Hz,1H),7.89(dt,J=7.8,1.4Hz,1 H),7.61(t,J=7.8Hz,1H),7.29(t,J=53.9Hz,1H),6.48(s,1H),5.04(s,2H),3.23(q,J=7.1Hz,4H),1.05(t,J=7.1Hz,6H). 13 C NMR(100MHz,DMSO-d6)δ169.03,158.96,144.80,143.76,136.90,133.50,132.97,13 1.57,129.94,128.60,120.81,118.75,111.85,110.19,109.67,77.24,45.03,12.74.

[0450] 2-(3-Cyanophenyl)-4-(difluoromethyl)-1-[(2-morpholinothiazolyl-4-yl)methoxy]-1H-imidazol-5-carboxylic acid (6K-26): white solid, yield: 82%. Purity (HPLC): 98.1%. MPa. Degraded at 154.9℃. ESI-MS m / z: 462.1 [M+H] + 484.1 [M+Na] + . 1 H NMR(400MHz,DMSO-d6)δ8.13–8.06(m,2H),7.88(dt,J=7.7,1.4Hz,1H),7.68–7 .35(m,2H),6.61(s,1H),5.15(s,2H),3.66(t,J=4.9Hz,4H),3.20–3.10(m,4H). 13C NMR(100MHz,DMSO-d6)δ171.19,158.94,144.67,143.75,136.85,133.62,133.14,13 1.65,129.99,128.50,120.90,118.83,112.45,111.88,109.67,77.11,65.76,48.16.

[0451] 2-(3-Cyanophenyl)-4-(difluoromethyl)-1-[(5-methyl-2-morpholinothiazolyl-4-yl)methoxy]-1H-imidazolium-5-carboxylic acid (6K-27): white solid, yield: 74%. Purity (HPLC): 97.7%. MPa. Degraded at 175.4℃. ESI-MS m / z: 476.2 [M+H] + 498.1 [M+Na] + . 1 H NMR(400MHz, DMSO-d6)δ14.22(s,1H),8.13–8.06(m,2H),7.95(dt,J=7.8,1.4Hz,1H),7.70–7.62( m,1H),7.29(t,J=53.9Hz,1H),5.05(s,2H),3.65(t,J=4.9Hz,4H),3.13–3.05(m,4H),1.88(s,3H). 13 C NMR(100MHz,DMSO-d6)δ167.62,158.95,143.73,139.88,136.99,133.64,133.00 ,131.50,130.01,128.46,125.84,121.09,118.82,111.92,109.64,74.39,65.70.

[0452] Example 51. Preparation of tablets containing compound 1-[(2-aminothiazol-4-yl)methoxy]-2-(3-cyanophenyl)-4-(difluoromethyl)-1H-imidazol-5-carboxylic acid (6k-23)

[0453] Prescription composition and content:

[0454]

[0455]

[0456] Coating solution prescription:

[0457] Opadai (03B26796) 21g 95% ethanol (appropriate amount)

[0458] Makes approximately 430ml

[0459] Process:

[0460] The excipients that have passed through a 100-mesh sieve are mixed with the active pharmaceutical ingredient that has passed through a 60-mesh sieve. The mixture is then prepared into a soft mass with 95% ethanol, granulated with an 18-mesh sieve, dried in a ventilated environment at 60°C, granulated again with a 16-mesh sieve, and then mixed evenly with magnesium stearate. Finally, it is tableted using a shallow concave punch with a diameter of 6mm.

[0461] Preparation of coating solution: Add an appropriate amount of 95% ethanol to a container, turn on the stirrer, and evenly add the prescribed amount of Opadry (03B26796) solid powder into the vortex, while trying to avoid any powder floating on the liquid surface. If necessary, the speed can be increased to maintain a proper vortex. After all the Opadry has been added, reduce the stirring speed until the vortex disappears, and continue stirring for 45 minutes to obtain the coating solution.

[0462] Preparation of film-coated tablets: Place the tablet core in a coating pan and maintain the temperature at 60℃±5℃ for coating to obtain the final product.

[0463] Example 52. Preparation of capsules containing compound 1-[(2-aminothiazol-4-yl)methoxy]-2-(3-cyanophenyl)-4-(difluoromethyl)-1H-imidazol-5-carboxylic acid (6k-23)

[0464] Prescription composition and content:

[0465]

[0466] Process:

[0467] Take the prescribed amount of 1-[(2-aminothiazol-4-yl)methoxy]-2-(3-cyanophenyl)-4-(difluoromethyl)-1H-imidazol-5-carboxylic acid (6k-23), add PEG-400, 1,2-propanediol and Tween-80, stir at about 40°C to completely dissolve the drug, and process into soft capsules after cooling to room temperature.

[0468] Example 53. ADP-induced inhibition of rabbit platelet aggregation

[0469] 1. Plasma preparation

[0470] Blood was collected from the marginal ear vein of healthy male rabbits and anticoagulated with 3.8% sodium citrate. Platelet-rich plasma (PRP) and platelet-poor plasma (PPP) were prepared by centrifugation (800 rpm, 10 minutes) (3000 rpm, 10 minutes). The prepared plasma was used within 0.5-3 hours after preparation.

[0471] 2. Determination of platelet aggregation using the microplate assay

[0472] Weigh the test drug and add an appropriate amount of DMSO to prepare a 10mM stock solution, then dilute with physiological saline to prepare a 10× stock solution. Add 135 μL of PRP to each well of the ELISA plate, followed by 15 μL of each concentration of 10× drug stock solution. For the solvent control group, add 15 μL of physiological saline to the PRP solution; for the blank control group, add 15 μL of physiological saline to the 135 μL PPP solution. All experimental groups are replicates. After vortexing, incubate the ELISA plate at 37°C for 5 minutes and measure the A0 value at 655 nm. Add 15 μL of the inducer bisphosphononucleotide (ADP) working solution (25 μmol / L) to each well and incubate with vortexing at 37°C. Measure the A1 value at 655 nm based on the maximum aggregation time determined in the preliminary experiment. Calculate the platelet aggregation rate (AR) and platelet aggregation inhibition rate (AIR) using the following formulas.

[0473] AR = (A0 – A1) / (A0 – Appp)

[0474] AIR = (1 – AR sample / AR control)

[0475] Calculate IC based on AIR values ​​at different concentrations. 50 value.

[0476] Example 54. Evaluation of the neuroprotective activity of hydrogen peroxide-induced hippocampal neurons (HT22)

[0477] Experimental procedure: 5000 HT22 cells in logarithmic growth phase were seeded into 96-well plates, with a volume of 100 μL per well. The cells were incubated in a CO2 incubator for 24 h. Then, 10 μL of the compound (final concentration 10 μM) was added to the 96-well plates and incubated for 2 h. Then, 10 μL of hydrogen peroxide (final concentration 500 μM) was added and incubated for 24 h. Finally, the cell viability was tested using the MTT assay.

[0478] Table 1. IC50 of the target compound 50 Value (Mean + SD)

[0479]

[0480] a The inhibition rate of the target compound on platelet aggregation at 20 μM;

[0481] b Cell viability of HT22 cells in the blank group after injury induced by 500 μM H2O2: 47.8% ± 7.5%.

[0482] Example 55. Evaluation of drug efficacy in acute cerebral infarction

[0483] 1. Reagents

[0484] 20% urethane, positive control: edaravone and BPTU, test compound 6k-23, triphenyltetrazolium chloride (TTC)

[0485] 2. Instruments

[0486] Curved needle holder, micro forceps, artery clamp, 7-0 needle-with-suture suture, water bath, etc.

[0487] 3. Laboratory animals

[0488] Fifty-six male SD rats were used in the experiment, divided into a model group, a blank group, a positive control group (6 mg / kg: edaravone, 10 mg / kg: BPTU), and compound 6k-23 groups (low dose: 2.5 mg / kg, medium dose: 5 mg / kg, high dose: 10 mg / kg). Animals were acclimatized for 7 days before the start of the experiment until they reached a suitable weight (250-280 g). The animal room temperature was maintained at 22±3℃, and the humidity at 45%±10%.

[0489] 4. Experimental Procedure

[0490] Rats were anesthetized by intraperitoneal injection of 20% urethane. The rats were then placed gently on a warming pad and maintained at 37°C. The right common carotid artery, external carotid artery, and internal carotid artery were exposed using ophthalmic scissors and forceps. The right middle cerebral artery was then permanently occluded using silicone-coated fishing line in the model group, positive control group, and compound group. Immediately afterward, the positive control group and compound group received tail vein injection; the model group and control group received tail vein injection of saline. Neurological function scores were assessed in all rats 24 hours later.

[0491] 5. TTC staining - infarct area assessment

[0492] After assessment of neurological dysfunction, rats were euthanized, and the brain, with the cerebellum and olfactory bulb removed, was coronally sectioned into 2.0 mm thick sections. All sections were immersed in 2% TTC at 37°C for 20 minutes; infarcted brain tissue appeared white, while non-infarcted areas appeared red. Coronal sections were photographed with a mobile phone and analyzed using image processing software (ImageJ). The infarct volume of the entire brain was calculated according to the following formula:

[0493] Corrected infarct area = (contralateral area × 2 + ipsilateral non-infarct area - total brain area) / 2 × contralateral area × 100%.

[0494] like Figure 2 As shown, compound 6k-23 can significantly improve the infarct area of ​​brain tissue caused by acute cerebral infarction in rats in a dose-dependent manner.

[0495] Example 56. Bleeding Risk Assessment

[0496] 1. Reagents

[0497] 20% urethane, saline, positive control: edaravone and BPTU, test compound 18b.

[0498] 2. Instruments

[0499] Scalpel, 15mL syringe, timer, water bath, vernier calipers.

[0500] 3. Laboratory animals

[0501] Twenty-four male SD rats were used: a control group, a positive control group (6 mg / kg: edaravone, 10 mg / kg: BPTU), and a compound 18b group (10 mg / kg). Animals were acclimatized for 7 days before the experiment until they reached a suitable weight (250-280 g). The animal room temperature was maintained at 22±3℃, and the humidity at 45%±10%.

[0502] 4. Experimental Procedure

[0503] Rats were anesthetized by intraperitoneal injection of 20% urethane. The rats were then placed stably on a warming mat and maintained at 37°C. The treated group and the control group were administered the drug via tail vein injection, while the control group received saline. Immediately afterward, the tail was cut 3 mm from the tip, and the severed tail was placed in a centrifuge tube containing 8 mL of saline. A 15-minute timer was started. The blood loss volume was calculated after 15 minutes. Figure 2 As shown, the bleeding volume of compound 6k-23 was lower than that of the positive control drugs ticagrelor and BPTU, indicating that compound 6k-23 has a correspondingly lower bleeding risk.

Claims

1. Compounds represented by general formula I and their pharmaceutically usable salts, tautomers, and pharmaceutically usable solvates: in, R1 is a C1-C6 alkyl, C1-C6 alkoxy, -CH2OCH3, C3-C6 cycloalkyl, 5-6 aryl or heteroaryl; The heteroaryl group contains 1-3 heteroatoms of N, O or S; The R1 is substituted by one or more of the following substituents: H, halogen, deuterium, C1-C6 alkyl, C1-C6 alkoxy; R2 is a 5-10 aryl or heteroaryl group, wherein the heteroaryl group contains 1-3 heteroatoms of N, O or S; The R2 is substituted by one or more of the following substituents: H, cyano, halogen, halo-C1-C6 alkyl, halo-C1-C6 alkoxy, amino, C1-C6 alkyl-substituted amino, C1-C6 alkoxy-substituted amino, morpholino. n＝1-3。 2. The compound of general formula I according to claim 1, and its pharmaceutically usable salts, tautomers, and pharmaceutically usable solvates: in, R1 can be C1-C4 alkyl, C1-C4 alkoxy, -CH2OCH3, C3-C6 cycloalkyl, phenyl, pyridyl, pyrazinyl, thiophenyl, furanyl, or thiazolyl. The R1 is substituted by one or more of the following substituents: H, halogen, deuterium, C1-C4 alkyl, C1-C4 alkoxy; R2 is a substituted or unsubstituted phenyl, pyridinyl, morpholinyl, thiazolyl, oxazole, or benzo[d][1,3]dioxacyclopenten-5-yl; The substituents are halogen, cyano, halo-C1-C4 alkyl, halo-C1-C4 alkoxy, amino, C1-C4 alkyl-substituted amino, C1-C4 alkoxy-substituted amino, and morpholino. n＝1； Preferably, R1 is ethyl, isopropyl, isobutyl, cyclopropyl, 1-methylcyclopropyl, cyclobutyl, 1-methylcyclobutyl, cyclopentyl, cyclohexyl, methoxymethyl, difluoromethyl, trifluoromethyl, methyl-D3, 2,2-difluorocyclopropyl, 3,3-difluorocyclobutyl, phenyl, pyridin-4-yl, pyridin-3-yl, pyridin-2-yl, pyrazin-2-yl, thiophene-2-yl, thiophene-3-yl, furan-2-yl, furan-3-yl, thiazolyl-2-yl, thiazolyl-5-yl, thiazolyl-4-yl; R2 is 4-fluorophenyl, 3-fluorophenyl, 2-fluorophenyl, (4-trifluoromethyl)phenyl, (3-trifluoromethyl)phenyl, (2-trifluoromethyl)phenyl, (4-trifluoromethoxy)phenyl, (3-trifluoromethoxy)phenyl, (2-trifluoromethoxy)phenyl, thiazolyl-5-yl, thiazolyl-2-yl, thiazolyl-4-yl, 2-(dimethylamino)thiazolyl-4-yl, 2-(diethylamino)thiazolyl -4-yl, 2-morpholinothiazol-4-yl, 5-methyl-2-morpholinothiazol-4-yl, 2-aminothiazol-4-yl, oxazol-5-yl, oxazol-2-yl, oxazol-4-yl, pyridin-4-yl, pyridin-3-yl, pyridin-2-yl, 2-morpholinoethoxy, benzo[d][1,3]dioxacyclopenten-5-yl, 6-bromopyridin-3-yl, 5-bromopyridin-2-yl.

3. The following compounds or pharmaceutically acceptable salts:

4. An intermediate for preparing the compound or pharmaceutically acceptable salt according to any one of claims 1-4:

5. The method for preparing the compound of general formula I according to claim 1 and its pharmaceutically usable salt, characterized in that, (1) β-keto esters are prepared by carbonylation reaction of diethyl carbonate with acetone derivatives; or β-keto esters are prepared by condensation reaction of potassium monoethyl malonate with carboxylic acid derivatives. (2) The intermediate was prepared by nitrosation of β-keto ester derivatives with sodium nitrite in water and glacial acetic acid solvent; (3) The intermediate in step (2) is cyclized with m-cyanobenzaldehyde and ammonium acetate in acetic acid solvent to prepare a 5-hydroxyimidazole derivative, which is then hydrolyzed under lithium hydroxide conditions to obtain the target compound.

6. A pharmaceutical composition comprising the compound of any one of claims 1-4 and its pharmaceutically acceptable salt, tautomer, or pharmaceutically acceptable solvate.

7. The use of the compound of any one of claims 1-4, its pharmaceutically usable salt, tautomer, pharmaceutically usable solvate, or the pharmaceutical composition of claim 7 in the preparation of a platelet aggregation inhibitor.

8. The use of the compound of any one of claims 1-4, its pharmaceutically usable salt, tautomer, pharmaceutically usable solvate, or the pharmaceutical composition of claim 7 in the preparation of a medicament for treating thromboembolic diseases.

9. Use of the compound of any one of claims 1-4, its pharmaceutically usable salt, tautomer, pharmaceutically usable solvate, or the pharmaceutical composition of claim 7 in the preparation of a neuroprotective medicament.

10. Use of the intermediate of claim 5 in the preparation of the compound of general formula I of claim 1 and its pharmaceutically usable salts, tautomers, and pharmaceutically usable solvates.

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