1 -difluoromethyl-3-(3-cyanophenyl)imidazo[1,5-a]pyrazin-8(7H)-one compounds and uses thereof

Abstract

This invention belongs to the field of pharmaceutical and chemical technology, and relates to 1-difluoromethyl-3-(3-cyanophenyl)imidazo[1,5-a]pyrazine-8(7H)-one compounds and their uses. The 1-difluoromethyl-3-(3-cyanophenyl)imidazo[1,5-a]pyrazine-8(7H)-one compounds and their pharmaceutically usable salts, tautomers, and pharmaceutically usable solvates of this invention are shown in general formula I or II. Wherein, R1 and X are as described in the claims and specification. The 1-difluoromethyl-3-(3-cyanophenyl)imidazo[1,5-a]pyrazine-8(7H)-one compounds and their pharmaceutically usable salts, tautomers, and pharmaceutically usable solvates of this invention can be used to prepare platelet aggregation inhibitors or neuroprotective agents, and to prepare drugs for the prevention and treatment of thrombotic diseases.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical and chemical technology, and relates to 1-difluoromethyl-3-(3-cyanophenyl)imidazo[1,5-a]pyrazine-8(7H)-one compounds and their uses. Background Technology

[0002] Thromboembolic diseases, such as acute myocardial infarction and stroke, are pathological processes 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, and 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 or II, and its pharmaceutically usable salts, tautomers, and pharmaceutically usable solvates, which have platelet aggregation inhibition and neuroprotective activity and can be used to prepare drugs for the prevention and treatment of thrombotic diseases.

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

[0007]

[0008] R1 is The substituted or unsubstituted phenyl group; the substituent is hydroxyl, nitro, cyano, halogen, amino, C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkyl, halo-C1-C6 alkoxy, thienyl, furanyl;

[0009] Preferably, R1 is The substituted or unsubstituted phenyl group; the substituent is hydroxyl, nitro, cyano, halogen, amino, C1-C4 alkyl, C1-C4 alkoxy, halo-C1-C4 alkyl, halo-C1-C4 alkoxy, thienyl, furanyl;

[0010] X is CH2 or NH.

[0011] Specifically,

[0012] R1 is 4-fluorophenyl, 3-fluorophenyl, 2-fluorophenyl, 4-trifluoromethylphenyl, 3-trifluoromethylphenyl, 2-trifluoromethylphenyl, 4-trifluoromethoxyphenyl, 3-trifluoromethoxyphenyl, 2-trifluoromethoxyphenyl, 4-cyanophenyl, 3-cyanophenyl, 4-nitrophenyl, 3-nitrophenyl, 2-nitrophenyl, 4-chlorophenyl, 3-chlorophenyl, 2-chlorophenyl, 4-bromophenyl, 3-bromophenyl, 2-bromophenyl, 4-methylphenyl, 3- Methylphenyl, 3-bromo-4-fluorophenyl, 3-methyl-4-nitrophenyl, 2-fluoro-4-nitrophenyl, 3-chloro-4-nitrophenyl, 2-bromo-4-nitrophenyl, 4-methoxyphenyl, 2-methoxyphenyl, 3,5-dichloro-4-methoxyphenyl, 3,5-dichloro-4-hydroxyphenyl, 3,5-dichloro-4-aminophenyl, benzo[d][1,3]dioxacyclopenten-5-yl, thiophene-3-yl, thiophene-2-yl, furan-2-yl;

[0013] X is CH2 or NH.

[0014] 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. Pharmaceutically usable solvates can be hydrates or contain other crystalline solvents such as alcohols.

[0015] Specifically, the compound or pharmaceutically acceptable salt having platelet-inhibiting and neuroprotective activities provided by the present invention is any one of the following compounds (1) to (67):

[0016] (1) 2-(3-cyanophenyl)-4-(difluoromethyl)-1-[2-(4-fluorophenyl)-2-oxoethyl]-1H-imidazol-5-carboxylic acid (7ka2)

[0017] (2) 2-(3-cyanophenyl)-4-(difluoromethyl)-1-[2-(3-fluorophenyl)-2-oxoethyl]-1H-imidazol-5-carboxylic acid (7ka3)

[0018] (3) 2-(3-cyanophenyl)-4-(difluoromethyl)-1-[2-(2-fluorophenyl)-2-oxoethyl]-1H-imidazol-5-carboxylic acid (7ka4)

[0019] (4) 2-(3-cyanophenyl)-4-(difluoromethyl)-1-{2-[4-(trifluoromethyl)phenyl]-2-oxoethyl}-1H-imidazol-5-carboxylic acid (7ka5)

[0020] (5) 2-(3-cyanophenyl)-4-(difluoromethyl)-1-{2-[3-(trifluoromethyl)phenyl]-2-oxoethyl}-1H-imidazol-5-carboxylic acid (7ka6)

[0021] (6) 2-(3-cyanophenyl)-4-(difluoromethyl)-1-{2-[2-(trifluoromethyl)phenyl]-2-oxoethyl}-1H-imidazol-5-carboxylic acid (7ka7)

[0022] (7) 2-(3-cyanophenyl)-4-(difluoromethyl)-1-{2-[4-(trifluoromethoxy)phenyl]-2-oxoethyl}-1H-imidazol-5-carboxylic acid (7ka8)

[0023] (8) 2-(3-cyanophenyl)-4-(difluoromethyl)-1-{2-[3-(trifluoromethoxy)phenyl]-2-oxoethyl}-1H-imidazol-5-carboxylic acid (7ka9)

[0024] (9) 2-(3-cyanophenyl)-4-(difluoromethyl)-1-{2-[2-(trifluoromethoxy)phenyl]-2-oxoethyl}-1H-imidazol-5-carboxylic acid (7ka10)

[0025] (10) 2-(3-cyanophenyl)-4-(difluoromethyl)-1-[2-(4-cyanophenyl)-2-oxoethyl]-1H-imidazol-5-carboxylic acid (7ka17)

[0026] (11) 2-(3-cyanophenyl)-4-(difluoromethyl)-1-[2-(3-cyanophenyl)-2-oxoethyl]-1H-imidazol-5-carboxylic acid (7ka18)

[0027] (12) 2-(3-cyanophenyl)-4-(difluoromethyl)-1-(4-fluorobenzamido)-1H-imidazol-5-carboxylic acid (8kn1)

[0028] (13) 2-(3-cyanophenyl)-4-(difluoromethyl)-1-(3-fluorobenzamido)-1H-imidazol-5-carboxylic acid (8kn2)

[0029] (14) 2-(3-cyanophenyl)-4-(difluoromethyl)-1-(2-fluorobenzamido)-1H-imidazol-5-carboxylic acid (8kn3)

[0030] (15) 2-(3-cyanophenyl)-4-(difluoromethyl)-1-[4-(trifluoromethyl)benzamido]-1H-imidazol-5-carboxylic acid (8kn4)

[0031] (16) 2-(3-cyanophenyl)-4-(difluoromethyl)-1-[3-(trifluoromethyl)benzamido]-1H-imidazol-5-carboxylic acid (8kn5)

[0032] (17) 2-(3-cyanophenyl)-4-(difluoromethyl)-1-[2-(trifluoromethyl)benzamido]-1H-imidazol-5-carboxylic acid (8kn6)

[0033] (18) 2-(3-cyanophenyl)-4-(difluoromethyl)-1-[4-(trifluoromethoxy)benzamido]-1H-imidazol-5-carboxylic acid (8kn7)

[0034] (19) 2-(3-cyanophenyl)-4-(difluoromethyl)-1-[3-(trifluoromethoxy)benzamido]-1H-imidazol-5-carboxylic acid (8kn8)

[0035] (20) 2-(3-cyanophenyl)-4-(difluoromethyl)-1-[2-(trifluoromethoxy)benzamido]-1H-imidazol-5-carboxylic acid (8kn9)

[0036] (21) 2-(3-cyanophenyl)-4-(difluoromethyl)-1-(4-cyanobenzamido)-1H-imidazol-5-carboxylic acid (8kn10)

[0037] (22) 2-(3-cyanophenyl)-4-(difluoromethyl)-1-(3-cyanobenzamido)-1H-imidazol-5-carboxylic acid (8kn11)

[0038] (23) 2-(3-cyanophenyl)-4-(difluoromethyl)-1-(4-nitrobenzamido)-1H-imidazol-5-carboxylic acid (8kn12)

[0039] (24) 2-(3-cyanophenyl)-4-(difluoromethyl)-1-(3-nitrobenzamido)-1H-imidazol-5-carboxylic acid (8kn13)

[0040] (25) 2-(3-cyanophenyl)-4-(difluoromethyl)-1-(2-nitrobenzamido)-1H-imidazol-5-carboxylic acid (8kn14)

[0041] (26) 2-(3-cyanophenyl)-4-(difluoromethyl)-1-(4-chlorobenzamido)-1H-imidazol-5-carboxylic acid (8kn15)

[0042] (27) 2-(3-cyanophenyl)-4-(difluoromethyl)-1-(2-chlorobenzamido)-1H-imidazol-5-carboxylic acid (8kn16)

[0043] (28) 2-(3-cyanophenyl)-4-(difluoromethyl)-1-(4-bromobenzamido)-1H-imidazol-5-carboxylic acid (8kn17)

[0044] (29) 2-(3-cyanophenyl)-4-(difluoromethyl)-1-(3-bromobenzamido)-1H-imidazol-5-carboxylic acid (8kn18)

[0045] (30) 2-(3-cyanophenyl)-4-(difluoromethyl)-1-(4-methylbenzamido)-1H-imidazol-5-carboxylic acid (8kn19)

[0046] (31) 2-(3-cyanophenyl)-4-(difluoromethyl)-1-(3-methylbenzamido)-1H-imidazol-5-carboxylic acid (8kn20)

[0047] (32) 2-(3-cyanophenyl)-4-(difluoromethyl)-1-(3-bromo-4-fluorobenzamido)-1H-imidazol-5-carboxylic acid (8kn21)

[0048] (33) 2-(3-cyanophenyl)-4-(difluoromethyl)-1-(3-methyl-4-nitrobenzamido)-1H-imidazol-5-carboxylic acid (8kn22)

[0049] (34) 2-(3-cyanophenyl)-4-(difluoromethyl)-1-(2-fluoro-4-nitrobenzamido)-1H-imidazol-5-carboxylic acid (8kn23)

[0050] (35) 2-(3-cyanophenyl)-4-(difluoromethyl)-1-(2-chloro-4-nitrobenzamido)-1H-imidazol-5-carboxylic acid (8kn24)

[0051] (36) 2-(3-cyanophenyl)-4-(difluoromethyl)-1-(3-chloro-4-nitrobenzamido)-1H-imidazol-5-carboxylic acid (8kn25)

[0052] (37) 2-(3-cyanophenyl)-4-(difluoromethyl)-1-(2-bromo-4-nitrobenzamido)-1H-imidazol-5-carboxylic acid (8kn26)

[0053] (38) 2-(3-cyanophenyl)-4-(difluoromethyl)-1-(4-methoxybenzamido)-1H-imidazol-5-carboxylic acid (8kn27)

[0054] (39) 2-(3-cyanophenyl)-4-(difluoromethyl)-1-(3,5-dichloro-4-methoxybenzamido)-1H-imidazol-5-carboxylic acid (8kn28)

[0055] (40) 2-(3-cyanophenyl)-4-(difluoromethyl)-1-(3,5-dichloro-4-hydroxybenzamido)-1H-imidazol-5-carboxylic acid (8kn29)

[0056] (41) 2-(3-cyanophenyl)-4-(difluoromethyl)-1-(3,5-dichloro-4-aminobenzamido)-1H-imidazol-5-carboxylic acid (8kn30)

[0057] (42) 1-Difluoromethyl-3-(3-cyanophenyl)-6-phenylimidazo[1,5-a]pyrazine-8(7H)-one (7kab1)

[0058] (43) 1-Difluoromethyl-3-(3-cyanophenyl)-6-(4-fluorophenyl)imidazo[1,5-a]pyrazine-8(7H)-one (7kab2)

[0059] (44) 1-Difluoromethyl-3-(3-cyanophenyl)-6-(3-fluorophenyl)imidazo[1,5-a]pyrazine-8(7H)-one (7kab3)

[0060] (45) 1-Difluoromethyl-3-(3-cyanophenyl)-6-(2-fluorophenyl)imidazo[1,5-a]pyrazin-8(7H)-one (7kab4)

[0061] (46) 1-Difluoromethyl-3-(3-cyanophenyl)-6-[4-(trifluoromethyl)phenyl]imidazo[1,5-a]pyrazin-8(7H)-one (7kab5)

[0062] (47) 1-Difluoromethyl-3-(3-cyanophenyl)-6-[3-(trifluoromethyl)phenyl]imidazo[1,5-a]pyrazine-8(7H)-one (7kab6)

[0063] (48) 1-Difluoromethyl-3-(3-cyanophenyl)-6-[2-(trifluoromethyl)phenyl]imidazo[1,5-a]pyrazin-8(7H)-one (7kab7)

[0064] (49) 1-Difluoromethyl-3-(3-cyanophenyl)-6-[4-(trifluoromethoxy)phenyl]imidazo[1,5-a]pyrazin-8(7H)-one (7kab8)

[0065] (50) 1-Difluoromethyl-3-(3-cyanophenyl)-6-[3-(trifluoromethoxy)phenyl]imidazo[1,5-a]pyrazin-8(7H)-one (7kab9)

[0066] (51) 1-Difluoromethyl-3-(3-cyanophenyl)-6-[2-(trifluoromethoxy)phenyl]imidazo[1,5-a]pyrazin-8(7H)-one

[0067] (7kab10)

[0068] (52) 1-Difluoromethyl-3-(3-cyanophenyl)-6-(4-chlorophenyl)imidazo[1,5-a]pyrazine-8(7H)-one (7kab11)

[0069] (53) 1-Difluoromethyl-3-(3-cyanophenyl)-6-(3-chlorophenyl)imidazo[1,5-a]pyrazin-8(7H)-one (7kab12)

[0070] (54) 1-Difluoromethyl-3-(3-cyanophenyl)-6-(2-chlorophenyl)imidazo[1,5-a]pyrazin-8(7H)-one (7kab13)

[0071] (55) 1-Difluoromethyl-3-(3-cyanophenyl)-6-(4-bromophenyl)imidazo[1,5-a]pyrazin-8(7H)-one (7kab14)

[0072] (56) 1-Difluoromethyl-3-(3-cyanophenyl)-6-(3-bromophenyl)imidazo[1,5-a]pyrazin-8(7H)-one (7kab15)

[0073] (57) 1-Difluoromethyl-3-(3-cyanophenyl)-6-(2-bromophenyl)imidazo[1,5-a]pyrazin-8(7H)-one (7kab16)

[0074] (58) 1-Difluoromethyl-3-(3-cyanophenyl)-6-(4-cyanophenyl)imidazo[1,5-a]pyrazine-8(7H)-one (7kab17)

[0075] (59) 1-Difluoromethyl-3-(3-cyanophenyl)-6-(3-cyanophenyl)imidazo[1,5-a]pyrazin-8(7H)-one (7kab18)

[0076] (60) 1-Difluoromethyl-3-(3-cyanophenyl)-6-(4-methoxyphenyl)imidazo[1,5-a]pyrazin-8(7H)-one (7kab19)

[0077] (61) 1-Difluoromethyl-3-(3-cyanophenyl)-6-(2-methoxyphenyl)imidazo[1,5-a]pyrazin-8(7H)-one (7kab20)

[0078] (62) 1-Difluoromethyl-3-(3-cyanophenyl)-6-(4-methylphenylimidazolium)[1,5-a]pyrazin-8(7H)-one (7kab21)

[0079] (63) 1-Difluoromethyl-3-(3-cyanophenyl)-6-(3-methylphenyl)imidazo[1,5-a]pyrazin-8(7H)-one (7kab22)

[0080] (64) 1-Difluoromethyl-3-(3-cyanophenyl)-6-(benzo[d][1,3]dioxacyclopenten-5-yl)imidazo[1,5-a]pyrazin-8(7H)-one (7kab23)

[0081] (65) 1-Difluoromethyl-3-(3-cyanophenyl)-6-(thiophen-3-yl)imidazo[1,5-a]pyrazin-8(7H)-one (7kab24)

[0082] (66) 1-Difluoromethyl-3-(3-cyanophenyl)-6-(thiophen-2-yl)imidazo[1,5-a]pyrazin-8(7H)-one (7kab25)

[0083] (67) 1-Difluoromethyl-3-(3-cyanophenyl)-6-(furan-2-yl)imidazo[1,5-a]pyrazin-8(7H)-one (7kab26)

[0084]

[0085]

[0086]

[0087]

[0088] This invention also provides intermediates for the preparation of compounds of general formula I or II and their pharmaceutically usable salts, tautomers, and pharmaceutically usable solvates:

[0089] (1) 2-(3-cyanophenyl)-4-(difluoromethyl)-1-(2-phenyl-2-oxoethyl)-1H-imidazolium-5-carboxylic acid ethyl ester (6 kb1)

[0090] (2) 2-(3-cyanophenyl)-4-(difluoromethyl)-1-(2-(4-fluorophenyl)-2-oxoethyl)-1H-imidazolium-5-carboxylic acid ethyl ester (6kab2)

[0091] (3) 2-(3-cyanophenyl)-4-(difluoromethyl)-1-(2-(3-fluorophenyl)-2-oxoethyl)-1H-imidazolium-5-carboxylic acid ethyl ester (6kab3)

[0092] (4) 2-(3-cyanophenyl)-4-(difluoromethyl)-1-(2-(2-fluorophenyl)-2-oxoethyl)-1H-imidazolium-5-carboxylic acid ethyl ester (6kab4)

[0093] (5) 2-(3-cyanophenyl)-4-(difluoromethyl)-1-{2-[4-(trifluoromethyl)phenyl]-2-oxoethyl}-1H-imidazolium-5-carboxylic acid ethyl ester (6kab5)

[0094] (6) 2-(3-cyanophenyl)-4-(difluoromethyl)-1-{2-[3-(trifluoromethyl)phenyl]-2-oxoethyl}-1H-imidazolium-5-carboxylic acid ethyl ester (6kab6)

[0095] (7) 2-(3-cyanophenyl)-4-(difluoromethyl)-1-{2-[2-(trifluoromethyl)phenyl]-2-oxoethyl}-1H-imidazolium-5-carboxylic acid ethyl ester (6kab7)

[0096] (8) 2-(3-cyanophenyl)-4-(difluoromethyl)-1-{2-[4-(trifluoromethoxy)phenyl]-2-oxoethyl}-1H-imidazolium-5-carboxylic acid ethyl ester (6kab8)

[0097] (9) 2-(3-cyanophenyl)-4-(difluoromethyl)-1-{2-[3-(trifluoromethoxy)phenyl]-2-oxoethyl}-1H-imidazolium-5-carboxylic acid ethyl ester (6kab9)

[0098] (10) 2-(3-cyanophenyl)-4-(difluoromethyl)-1-{2-[2-(trifluoromethoxy)phenyl]-2-oxoethyl}-1H-imidazolium-5-carboxylic acid ethyl ester (6kab10)

[0099] (11) 2-(3-cyanophenyl)-4-(difluoromethyl)-1-[2-(4-chlorophenyl)-2-oxoethyl]-1H-imidazolium-5-carboxylic acid ethyl ester (6kab11)

[0100] (12) 2-(3-cyanophenyl)-4-(difluoromethyl)-1-[2-(3-chlorophenyl)-2-oxoethyl]-1H-imidazolium-5-carboxylic acid ethyl ester (6kab12)

[0101] (13) 2-(3-cyanophenyl)-4-(difluoromethyl)-1-[2-(2-chlorophenyl)-2-oxoethyl]-1H-imidazolium-5-carboxylic acid ethyl ester (6kab13)

[0102] (14) 2-(3-cyanophenyl)-4-(difluoromethyl)-1-[2-(4-bromophenyl)-2-oxoethyl]-1H-imidazolium-5-carboxylic acid ethyl ester (6kab14)

[0103] (15) 2-(3-cyanophenyl)-4-(difluoromethyl)-1-[2-(3-bromophenyl)-2-oxoethyl]-1H-imidazolium-5-carboxylic acid ethyl ester (6kab15)

[0104] (16) 2-(3-cyanophenyl)-4-(difluoromethyl)-1-[2-(2-bromophenyl)-2-oxoethyl]-1H-imidazolium-5-carboxylic acid ethyl ester (6kab16)

[0105] (17) 2-(3-cyanophenyl)-4-(difluoromethyl)-1-[2-(4-cyanophenyl)-2-oxoethyl]-1H-imidazolium-5-carboxylic acid ethyl ester (6kab17)

[0106] (18) 2-(3-cyanophenyl)-4-(difluoromethyl)-1-[2-(3-cyanophenyl)-2-oxoethyl]-1H-imidazolium-5-carboxylic acid ethyl ester (6kab18)

[0107] (19) 2-(3-cyanophenyl)-4-(difluoromethyl)-1-[2-(4-methoxyphenyl)-2-oxoethyl]-1H-imidazolium-5-carboxylic acid ethyl ester (6kab19)

[0108] (20) 2-(3-cyanophenyl)-4-(difluoromethyl)-1-[2-(2-methoxyphenyl)-2-oxoethyl]-1H-imidazolium-5-carboxylic acid ethyl ester (6kab20)

[0109] (21) 2-(3-cyanophenyl)-4-(difluoromethyl)-1-[2-(4-methylphenyl)-2-oxoethyl]-1H-imidazolium-5-carboxylic acid ethyl ester (6kab21)

[0110] (22) 2-(3-cyanophenyl)-4-(difluoromethyl)-1-[2-(3-methylphenyl)-2-oxoethyl]-1H-imidazolium-5-carboxylic acid ethyl ester (6kab22)

[0111] (23) 2-(3-cyanophenyl)-4-(difluoromethyl)-1-[2-(benzo[d][1,3]dioxacyclopenten-5-yl)-2-oxoethyl]-1H-imidazol-5-carboxylic acid ethyl ester (6kab23)

[0112] (24) 2-(3-cyanophenyl)-4-(difluoromethyl)-1-[2-(thiophen-3-yl)-2-oxoethyl]-1H-imidazol-5-carboxylic acid ethyl ester (6kab24)

[0113] (25) 2-(3-cyanophenyl)-4-(difluoromethyl)-1-[2-(thiophen-2-yl)-2-oxoethyl]-1H-imidazol-5-carboxylic acid ethyl ester (6kab25)

[0114] (26) 2-(3-cyanophenyl)-4-(difluoromethyl)-1-[2-(furan-2-yl)-2-oxoethyl]-1H-imidazol-5-carboxylic acid ethyl ester (6kab26)

[0115] (27) 2-(3-cyanophenyl)-4-(difluoromethyl)-1-(4-fluorobenzamido)-1H-imidazol-5-carboxylic acid ethyl ester (7kn1)

[0116] (28) 2-(3-cyanophenyl)-4-(difluoromethyl)-1-(3-fluorobenzamido)-1H-imidazol-5-carboxylic acid ethyl ester (7kn2)

[0117] (29) 2-(3-cyanophenyl)-4-(difluoromethyl)-1-(2-fluorobenzamido)-1H-imidazol-5-carboxylic acid ethyl ester (7kn3)

[0118] (30) 2-(3-cyanophenyl)-4-(difluoromethyl)-1-[4-(trifluoromethyl)benzamido]-1H-imidazol-5-carboxylic acid ethyl ester (7kn4)

[0119] (31) 2-(3-cyanophenyl)-4-(difluoromethyl)-1-[3-(trifluoromethyl)benzamido]-1H-imidazol-5-carboxylic acid ethyl ester (7kn5)

[0120] (32) 2-(3-cyanophenyl)-4-(difluoromethyl)-1-[2-(trifluoromethyl)benzamido]-1H-imidazol-5-carboxylic acid ethyl ester (7kn6)

[0121] (33) 2-(3-cyanophenyl)-4-(difluoromethyl)-1-[4-(trifluoromethoxy)benzamido]-1H-imidazol-5-carboxylic acid ethyl ester (7kn7)

[0122] (34) 2-(3-cyanophenyl)-4-(difluoromethyl)-1-[3-(trifluoromethoxy)benzamido]-1H-imidazol-5-carboxylic acid ethyl ester (7kn8)

[0123] (35) 2-(3-cyanophenyl)-4-(difluoromethyl)-1-[2-(trifluoromethoxy)benzamido]-1H-imidazol-5-carboxylic acid ethyl ester (7kn9)

[0124] (36) 2-(3-cyanophenyl)-4-(difluoromethyl)-1-(4-cyanobenzamido)-1H-imidazol-5-carboxylic acid ethyl ester (7kn10)

[0125] (37) 2-(3-cyanophenyl)-4-(difluoromethyl)-1-(3-cyanobenzamido)-1H-imidazol-5-carboxylic acid ethyl ester (7kn11)

[0126] (38) 2-(3-cyanophenyl)-4-(difluoromethyl)-1-(4-nitrobenzamido)-1H-imidazol-5-carboxylic acid ethyl ester (7kn12)

[0127] (39) 2-(3-cyanophenyl)-4-(difluoromethyl)-1-(3-nitrobenzamido)-1H-imidazol-5-carboxylic acid ethyl ester (7kn13)

[0128] (40) 2-(3-cyanophenyl)-4-(difluoromethyl)-1-(2-nitrobenzamido)-1H-imidazol-5-carboxylic acid ethyl ester (7kn14)

[0129] (41) 2-(3-cyanophenyl)-4-(difluoromethyl)-1-(4-chlorobenzamido)-1H-imidazol-5-carboxylic acid ethyl ester (7kn15)

[0130] (42) 2-(3-cyanophenyl)-4-(difluoromethyl)-1-(2-chlorobenzamido)-1H-imidazol-5-carboxylic acid ethyl ester (7kn16)

[0131] (43) 2-(3-cyanophenyl)-4-(difluoromethyl)-1-(4-bromobenzamido)-1H-imidazol-5-carboxylic acid ethyl ester (7kn17)

[0132] (44) 2-(3-cyanophenyl)-4-(difluoromethyl)-1-(3-bromobenzamido)-1H-imidazol-5-carboxylic acid ethyl ester (7kn18)

[0133] (45) 2-(3-cyanophenyl)-4-(difluoromethyl)-1-(4-methylbenzamido)-1H-imidazol-5-carboxylic acid ethyl ester (7kn19)

[0134] (46) 2-(3-cyanophenyl)-4-(difluoromethyl)-1-(3-methylbenzamido)-1H-imidazol-5-carboxylic acid ethyl ester (7kn20)

[0135] (47) 2-(3-cyanophenyl)-4-(difluoromethyl)-1-(3-bromo-4-fluorobenzamido)-1H-imidazol-5-carboxylic acid ethyl ester (7kn21)

[0136] (48) 2-(3-cyanophenyl)-4-(difluoromethyl)-1-(3-methyl-4-nitrobenzamido)-1H-imidazol-5-carboxylic acid ethyl ester (7kn22)

[0137] (49) 2-(3-cyanophenyl)-4-(difluoromethyl)-1-(2-fluoro-4-nitrobenzamido)-1H-imidazol-5-carboxylic acid ethyl ester (7kn23)

[0138] (50) 2-(3-cyanophenyl)-4-(difluoromethyl)-1-(2-chloro-4-nitrobenzamido)-1H-imidazol-5-carboxylic acid ethyl ester (7kn24)

[0139] (51) 2-(3-cyanophenyl)-4-(difluoromethyl)-1-(3-chloro-4-nitrobenzamido)-1H-imidazol-5-carboxylic acid ethyl ester (7kn25)

[0140] (52) 2-(3-cyanophenyl)-4-(difluoromethyl)-1-(2-bromo-4-nitrobenzamido)-1H-imidazol-5-carboxylic acid ethyl ester (7kn26)

[0141] (53) 2-(3-cyanophenyl)-4-(difluoromethyl)-1-(4-methoxybenzamido)-1H-imidazol-5-carboxylic acid ethyl ester (7kn27)

[0142] (54) 2-(3-cyanophenyl)-4-(difluoromethyl)-1-(3,5-dichloro-4-methoxybenzamido)-1H-imidazol-5-carboxylic acid ethyl ester (7kn28)

[0143] (55) 2-(3-cyanophenyl)-4-(difluoromethyl)-1-(3,5-dichloro-4-hydroxybenzamido)-1H-imidazol-5-carboxylic acid ethyl ester (7kn29)

[0144] (56) 2-(3-cyanophenyl)-4-(difluoromethyl)-1-(3,5-dichloro-4-aminobenzamido)-1H-imidazol-5-carboxylic acid ethyl ester (7kn30)

[0145] (57) ethyl 2-(3-cyanophenyl)-4-(difluoromethyl)-1H-imidazolium-5-carboxylate (5ka)

[0146] (58) Ethyl 1-amino-2-(3-cyanophenyl)-4-(difluoromethyl)-1H-imidazolium-5-carboxylate (6k-N)

[0147]

[0148]

[0149]

[0150]

[0151] This invention also provides a method for preparing the compound or pharmaceutically acceptable salt having the aforementioned antiplatelet aggregation and neuroprotective activities, wherein the preparation steps of general formulas I and II are as follows:

[0152] Starting with ethyl 4,4-difluoroacetoacetate 2k, it undergoes a nitrosation reaction with sodium nitrite to obtain intermediate (Z)-4,4-difluoro-2-(hydroxyimino)-3-oxobutyrate ethyl ester 3k. Subsequently, it undergoes a cyclization reaction with m-cyanobenzaldehyde B3 and ammonium acetate in acetic acid solvent to prepare intermediate 2-(3-cyanophenyl)-4-(difluoromethyl)-1-hydroxy-1H-imidazolium-5-carboxylate ethyl ester 4k. Acetone derivatives A1-1 to A1-26 are then brominated... Bromination under copper catalysis yields intermediates A2-1 to A2-26. Intermediate 4k undergoes reduction in zinc powder and glacial acetic acid to prepare intermediate 5ka. A2-1 to A2-26 then undergo alkylation with 5ka to prepare intermediates 6ka1 to 6ka26. Intermediates 6ka2 to 6ka10, 6ka17, and 6ka18 are hydrolyzed under lithium hydroxide conditions to yield the target compounds 7ka2 to 7ka10, 7ka17, and 7ka18. Additionally, intermediates 6ka1 to 6ka26 undergo cyclization with ammonium acetate in methanol to yield the target compounds 7kab1 to 7kab26. Intermediate 5ka undergoes alkylation with diphenylphosphohydroxylamine under potassium carbonate catalysis to prepare intermediate 6k-N. Intermediate 6k-N undergoes a condensation reaction with a benzoic acid derivative to yield intermediates 7kn1–7kn28 and 7kn30, which are then hydrolyzed under lithium hydroxide conditions to obtain the target compounds 8kn1–8kn28 and 8kn30. Intermediate 7kn28 is demethylated by lithium chloride to prepare intermediate 7kn29, which is then hydrolyzed to obtain the target compound 8kn29.

[0153]

[0154]

[0155] Route: a. Sodium nitrite, glacial acetic acid, water, 0℃; b. Ammonium acetate, glacial acetic acid, 50℃, nitrogen; c. Zinc powder, glacial acetic acid, 60℃; d. Copper bromide, chloroform / ethyl acetate, reflux; e. Anhydrous potassium carbonate, acetonitrile, reflux; f. Lithium hydroxide, water / tetrahydrofuran, 35-40℃; g. Anhydrous potassium carbonate, diphenylphosphonohydroxylamine, N,N-dimethylformamide, 25℃; h. Phosphorus oxychloride, pyridine, 0-25℃; i. Ammonium acetate, methanol, 90℃; j. Lithium chloride, N,N-dimethylformamide, 110℃. Attached Figure Description

[0156] Figure 1 The efficacy of compound 7kab8 in acute cerebral infarction in rats was investigated.

[0157] Figure 2 The efficacy of compound 7kab8 in acute myocardial infarction in mice was investigated.

[0158] Figure 3 The bleeding volume of compound 7kab8. Detailed Implementation

[0159] Example 1: Synthesis of (Z)-4,4-difluoro-2-(hydroxyimino)-3-oxobutyrate ethyl ester (3k)

[0160] Ethyl 3-oxovalerate 2kJ (1.5g, 9.03mmol) was dissolved in 10mL glacial acetic acid and 5mL water, and stirred in an ice-water bath. Sodium nitrite (748mg, 10.83mmol, 1.2 times the recommended volume) was accurately weighed and dissolved in 5mL water. This solution was then slowly added dropwise to the reaction mixture. After the reaction was complete, 20mL water and ethyl acetate (30mL x 2) were added for extraction twice. The organic phase was collected, washed twice with 60mL water, and once with 30mL saturated brine. The mixture was dried over anhydrous sodium sulfate and rotary evaporated under reduced pressure to obtain a clear oily substance with a yield of 85%. This was proceeded directly to the next step without purification. ESI-MS m / z: 193.6 [MH] - .

[0161] Example 2 Synthesis of ethyl 2-(3-cyanophenyl)-4-(difluoromethyl)-1-hydroxy-1H-imidazolium-5-carboxylate (4k)

[0162] Ammonium acetate (25.1 g, 326 mmol, 10 g) was added to a mixture of ethyl (Z)-4,4-difluoro-2-(hydroxyimino)-3-oxobutyrate 3kJ (10 g, 32.6 mmol) and 3-cyanobenzaldehyde (4.3 mg, 32.6 mmol, 1 mmol) in 20 mL of glacial acetic acid solution (2 mmol). The reaction mixture was then heated to 50 °C under nitrogen. After the 3-cyanobenzaldehyde was consumed as monitored by TLC, the reaction mixture was cooled to room temperature and ice water (120 mL, 12 mmol) was added. The resulting mixture was stirred at room temperature until a white solid precipitate formed. The precipitate was then filtered, washed with water, and recrystallized from ethanol and water to give a white solid (yield: 82%). Mp 149.3–152.4 °C. 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).

[0163] Example 3 Synthesis of ethyl 2-(3-cyanophenyl)-4-(difluoromethyl)-1H-imidazolium-5-carboxylate (5 kJ)

[0164] 4kJ of ethyl 2-(3-cyanophenyl)-4-(difluoromethyl)-1-hydroxy-1H-imidazolium-5-carboxylate (5g, 17.2mmol) was dissolved in 10mL of acetic acid solution (twice the volume). Four times the volume of zinc powder (4.5g, 68.7mmol, four times the volume) was added. The reaction mixture was heated to 60℃ and reacted for 0.5 hours. The reaction solution was then cooled to room temperature, and 6M dilute hydrochloric acid was slowly added. The mixture was stirred at room temperature until the zinc powder was completely consumed, resulting in the precipitation of a white solid. The solid was filtered, the filter cake was washed twice with water, and dried to obtain 4.3g of a white solid (yield: 86%). Temperature: 207.7-208.8℃. ESI-MS m / z: 292.1 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ13.92(s,1H),8.54(s,1H),8.40(d,J=8.0Hz,1H),7.90(d,J=7.7Hz,1H ),7.69(t,J=7.9Hz,1H),7.29(t,J=53.7Hz,1H),4.36(q,J=7.1Hz,2H),1.34(t,J=7.1Hz,3H).

[0165] Synthesis of Examples 4A2-1 to A2-22

[0166] Acetophenone A1-1 (2.0 g, 16.6 mmol) and copper bromide (4.1 g, 18.3 mmol, 1.2 times the volume) were dissolved in a mixed solution of chloroform (10 mL, 2.5 times the volume) and ethyl acetate (10 mL, 2.5 times the volume). The mixture was then heated to reflux until the reaction was complete. The mixture was filtered, and the filtrate was collected and evaporated under reduced pressure to obtain a pale yellow oily substance A2-1. The product was not purified and proceeded directly to the next step.

[0167] The following are listed: 4-fluoroacetophenone A1-2, 3-fluoroacetophenone A1-3, 2-fluoroacetophenone A1-4, 4-(trifluoromethyl)acetophenone A1-5, 3-(trifluoromethyl)acetophenone A1-6, 2-(trifluoromethyl)acetophenone A1-7, 2-(trifluoromethoxy)acetophenone A1-8, 3-(trifluoromethoxy)acetophenone A1-9, 2-(trifluoromethoxy)acetophenone A1-10, 4-chloroacetophenone A1-11, 3-chloroacetophenone A1-12, 2-chloroacetophenone A1-13, 4-bromoacetophenone A1-14, 3-bromoacetophenone A1-15, 2-bromoacetophenone A1-16, and 4-cyanoacetophenone A1-17. Starting from 3-cyanoacetophenone A1-18, 4-methoxyacetophenone A1-19, 2-methoxyacetophenone A1-20, 4-methylacetophenone A1-21, 3-methylacetophenone A1-22, 3-(2-(benzo[d][1,3]dioxacyclopenten-5-yl)acetophenone A1-23, 3-(thiophen-3-yl)acetophenone A1-24, 3-(thiophen-2-yl)acetophenone A1-25, and 3-(furan-2-yl)acetophenone A1-26, A2-2 to A2-26 were prepared following the synthetic method of 2-bromoacetophenone (A2-1). A pale yellow oily substance was obtained, and the product was directly used for the next step without purification.

[0168] Example 5 Synthesis of ethyl 2-(3-cyanophenyl)-4-(difluoromethyl)-1-(2-phenyl-2-oxoethyl)-1H-imidazolium-5-carboxylate (6ka1)

[0169] Ethyl 2-(3-cyanophenyl)-4-(difluoromethyl)-1H-imidazolium-5-carboxylate 5 kJ (500 mg, 1.2 mmol), bromoacetophenone A2-1 (263 mg, 1.32 mmol, 1.1 times the volume), and potassium carbonate (497 mg, 3.6 mmol, 3 times the volume) were dissolved in 10 mL of acetonitrile solution (20 times the volume). The reaction solution was heated to 80 °C. After the reaction was complete, ethyl acetate and saturated brine were added for extraction. The organic layer was collected, dried over anhydrous sodium sulfate, and rotary evaporated under reduced pressure to give the crude product. Recrystallization from ethyl acetate:petroleum ether = 2:1 gave 339 mg of white solid, yield: 69%. Mp 135.6-135.7 °C. ESI-MS (m / z) 410.2 [M+H] + 432.2[M+Na] + . 1 HNMR(400MHz,DMSO-d6)δ8.06(d,J=7.8Hz,2H),8.03–7.96(m,2H),7.88(d,J=7.9Hz,1H),7.73(t,J=7.4Hz,2 H),7.60(t,J=7.6Hz,2H),7.34(t,J=53.8Hz,1H),5.96(s,2H),4.20(q,J=7.1Hz,2H),1.15(t,J=7.1Hz,3H).

[0170] Example 6 Synthesis of ethyl 2-(3-cyanophenyl)-4-(difluoromethyl)-1-[2-(4-fluorophenyl)-2-oxoethyl]-1H-imidazolium-5-carboxylate (6ka2)

[0171] Starting with ethyl 2-(3-cyanophenyl)-4-(difluoromethyl)-1H-imidazolium-5-carboxylate (5 kDa) and 2-bromo-4'-fluoroacetophenone (A2-2), 6 kDa was prepared as a white solid, yield: 81%, following the synthesis method in Example 5. Mp 173.6-174.1 °C. ESI-MS (m / z) = 428.2 [M+H] + 450.2 [M+Na] + . 1 H NMR (400MHz, DMSO-d6) δ8.19–8.09(m,2H),8.01(dt,J=7.7,1.4Hz,1H),7.98(t,J=1.7Hz,1H),7.86(dt,J=7.9, 1.5Hz,1H),7.73(t,J=7.8Hz,1H),7.49–7.17(m,3H),5.93(s,2H),4.19(q,J=7.1Hz,2H),1.14(t,J=7.1Hz,3H).

[0172] Example 7 Synthesis of ethyl 2-(3-cyanophenyl)-4-(difluoromethyl)-1-[2-(3-fluorophenyl)-2-oxoethyl]-1H-imidazolium-5-carboxylate (6ka3)

[0173] Starting with ethyl 2-(3-cyanophenyl)-4-(difluoromethyl)-1H-imidazolium-5-carboxylate (5 kDa) and 2-bromo-3'-fluoroacetophenone (A2-3), 6 kDa was prepared as a white solid, yield: 91%, following the synthesis method in Example 5. Mp 155.8-157.9 °C. ESI-MS (m / z) = 428.1 [M+H] + 450.1 [M+Na] + . 1 H NMR (400MHz, DMSO-d6) δ8.02(dt,J=7.7,1.4Hz,1H),7.98(t,J=1.8Hz,1H),7.89(dt,J=7.6,1.3Hz,1H),7.87–7.81(m,2H), 7.73(t,J=7.8Hz,1H),7.70–7.56(m,2H),7.32(t,J=53.8Hz,1H),5.93(s,2H),4.19(q,J=7.1Hz,2H),1.14(t,J=7.1Hz,3H).

[0174] Example 8 Synthesis of ethyl 2-(3-cyanophenyl)-4-(difluoromethyl)-1-[2-(2-fluorophenyl)-2-oxoethyl]-1H-imidazolium-5-carboxylate (6ka4)

[0175] Starting with ethyl 2-(3-cyanophenyl)-4-(difluoromethyl)-1H-imidazolium-5-carboxylate (5 kDa) and 2-bromo-2'-fluoroacetophenone (A2-4), 6 kDa was prepared as a white solid, yield: 86%, following the synthesis method in Example 5. Mp 147.0-147.9 °C. ESI-MS (m / z) = 428.2 [M+H] + 450.2 [M+Na] + . 1 H NMR (400MHz, DMSO-d6) δ8.06–7.97(m,2H),7.93(td,J=7.6,1.9Hz,1H),7.88(dt,J=8.0,1.5Hz,1H ),7.81–7.70(m,2H),7.49–7.16(m,3H),5.77(s,2H),4.21(q,J=7.1Hz,2H),1.17(t,J=7.1Hz,3H).

[0176] Example 9 Synthesis of ethyl 2-(3-cyanophenyl)-4-(difluoromethyl)-1-{2-[4-(trifluoromethyl)phenyl]-2-oxoethyl}-1H-imidazolium-5-carboxylate (6ka5)

[0177] Starting with ethyl 2-(3-cyanophenyl)-4-(difluoromethyl)-1H-imidazolium-5-carboxylate (5 kDa) and 2-bromo-4'-(trifluoromethyl)acetophenone (A2-5), a white solid (6 kDa) was prepared according to the synthesis method in Example 5, with a yield of 78%. Mp 143.1-145.5 °C. ESI-MS (m / z) = 478.2 [M+H] + 500.1 [M+Na] + . 1 H NMR (400MHz, DMSO-d6) δ8.24(d,J=8.0Hz,2H),8.00(t,J=11.2Hz,4H),7.88(d,J=7.9Hz,1H),7.73( t,J=7.8Hz,1H),7.33(t,J=53.7Hz,1H),5.99(s,2H),4.19(q,J=7.1Hz,2H),1.15(t,J=7.1Hz,3H).

[0178] Example 10 Synthesis of ethyl 2-(3-cyanophenyl)-4-(difluoromethyl)-1-{2-[3-(trifluoromethyl)phenyl]-2-oxoethyl}-1H-imidazolium-5-carboxylate (6ka6)

[0179] Starting with ethyl 2-(3-cyanophenyl)-4-(difluoromethyl)-1H-imidazolium-5-carboxylate (5 kDa) and 2-bromo-3'-(trifluoromethyl)acetophenone (A2-6), 6 kDa was prepared as a white solid, yield: 82%, following the synthetic method described in Example 5. Mp: 183.2-184.4 °C. ESI-MS (m / z): 478.2 [M+H] + 500.2 [M+Na] + . 1 H NMR (400MHz, DMSO-d6) δ8.38–8.30(m,2H),8.11(d,J=7.9Hz,1H),8.05–8.01(m,1H),8.00(d,J=1.5Hz,1H),7.91–7. 83(m,2H),7.73(t,J=7.8Hz,1H),7.32(t,J=53.8Hz,1H),6.01(s,2H),4.18(q,J=7.1Hz,2H),1.14(t,J=7.1Hz,3H).

[0180] Example 11 Synthesis of ethyl 2-(3-cyanophenyl)-4-(difluoromethyl)-1-{2-[2-(trifluoromethyl)phenyl]-2-oxoethyl}-1H-imidazolium-5-carboxylate (6ka7)

[0181] Starting with ethyl 2-(3-cyanophenyl)-4-(difluoromethyl)-1H-imidazolium-5-carboxylate (5 kDa) and 2-bromo-2'-(trifluoromethyl)acetophenone (A2-7), 6 kDa was prepared as a white solid, yield: 80%, following the synthetic method described in Example 5. Mp: 151.9-152.5 °C. ESI-MS (m / z): 478.2 [M+H] + 500.1 [M+Na] + . 1 H NMR (400MHz, DMSO-d6) δ8.12–8.02(m,2H),7.96–7.80(m,5H),7.75(t,J=7.8Hz,1H) ,7.35(t,J=53.7Hz,1H),5.84(s,2H),4.32(q,J=7.1Hz,2H),1.28(t,J=7.1Hz,3H).

[0182] Example 12 Synthesis of ethyl 2-(3-cyanophenyl)-4-(difluoromethyl)-1-{2-[4-(trifluoromethoxy)phenyl]-2-oxoethyl}-1H-imidazolium-5-carboxylate (6ka8)

[0183] Starting with ethyl 2-(3-cyanophenyl)-4-(difluoromethyl)-1H-imidazolium-5-carboxylate (5 kDa) and 2-bromo-4'-(trifluoromethoxy)acetophenone (A2-8), 6 kDa was prepared as a white solid, yield: 69%, following the synthetic method described in Example 5. Mp: 128.3-128.4 °C. ESI-MS (m / z): 494.1 [M+H] + 516.1 [M+Na] + . 1 H NMR (400MHz, DMSO-d6) δ8.18(dd,J=6.7,2.1Hz,2H),8.02(dt,J=7.7,1.4Hz,1H),7.99(t,J=1.7Hz,1H),7.87(dt,J=7.8,1.5H z,1H),7.73(t,J=7.8Hz,1H),7.60(m,2H),7.32(t,J=53.8Hz,1H),5.94(s,2H),4.19(q,J=7.1Hz,2H),1.15(t,J=7.1Hz,3H).

[0184] Example 13 Synthesis of ethyl 2-(3-cyanophenyl)-4-(difluoromethyl)-1-{2-[3-(trifluoromethoxy)phenyl]-2-oxoethyl}-1H-imidazolium-5-carboxylate (6ka9)

[0185] Starting with ethyl 2-(3-cyanophenyl)-4-(difluoromethyl)-1H-imidazolium-5-carboxylate (5 kDa) and 2-bromo-3'-(trifluoromethoxy)acetophenone (A2-9), 6 kDa was prepared as a white solid, yield: 74%, following the synthetic method described in Example 5. Mp: 156.8-157.6 °C. ESI-MS (m / z): 494.2 [M+H] + 516.2 [M+Na] + . 1 H NMR (400MHz, DMSO-d6) δ8.13–8.06(m,1H),8.02(dt,J=7.7,1.3Hz,1H),8.00(t,J=1.6Hz,1H),7.96(t,J=1.2Hz,1H),7.88( dt,J=8.0,1.4Hz,1H),7.79–7.69(m,3H),7.32(t,J=53.8Hz,1H),5.96(s,2H),4.19(q,J=7.1Hz,2H),1.13(t,J=7.1Hz,3H).

[0186] Example 14 Synthesis of ethyl 2-(3-cyanophenyl)-4-(difluoromethyl)-1-{2-[2-(trifluoromethoxy)phenyl]-2-oxoethyl}-1H-imidazolium-5-carboxylate (6ka10)

[0187] Starting with ethyl 2-(3-cyanophenyl)-4-(difluoromethyl)-1H-imidazolium-5-carboxylate (5 kDa) and 2-bromo-2'-(trifluoromethoxy)acetophenone (A2-10), 6 kDa was prepared as a white solid, yield: 81%, following the synthetic method described in Example 5. Mp: 135.7-135.8 °C. ESI-MS (m / z): 494.2 [M+H] + 516.1 [M+Na] + . 1 H NMR (400MHz, DMSO-d6) δ8.12–8.01(m,2H),7.97–7.80(m,5H),7.75(t,J=7.8Hz,1H) ,7.35(t,J=53.7Hz,1H),5.83(s,2H),4.33(q,J=7.1Hz,2H),1.28(t,J=7.1Hz,3H).

[0188] Example 15 Synthesis of ethyl 2-(3-cyanophenyl)-4-(difluoromethyl)-1-[2-(4-chlorophenyl)-2-oxoethyl]-1H-imidazolium-5-carboxylate (6ka11)

[0189] Starting with ethyl 2-(3-cyanophenyl)-4-(difluoromethyl)-1H-imidazolium-5-carboxylate (5 kDa) and 2-bromo-4'-chloroacetophenone (A2-11), 6 kDa was prepared according to the synthesis method in Example 5. The product was a white solid with a yield of 85%. Mp: 185.9-157.9 °C.

[0190] Example 16 Synthesis of ethyl 2-(3-cyanophenyl)-4-(difluoromethyl)-1-[2-(3-chlorophenyl)-2-oxoethyl]-1H-imidazolium-5-carboxylate (6ka12)

[0191] Starting with ethyl 2-(3-cyanophenyl)-4-(difluoromethyl)-1H-imidazolium-5-carboxylate (5 kDa) and 2-bromo-3'-chloroacetophenone A2-12, 6 kDa was prepared according to the synthesis method in Example 5. The result was a white solid with a yield of 87%. Mp 168.3-169.2 °C. ESI-MS (m / z) = 444.1 [M+H] + 466.1 [M+Na] + . 1 H NMR (400MHz, DMSO-d6) δ8.07(t,J=1.9Hz,1H),8.02(dt,J=7.8,1.4Hz,1H),8.00–7.96(m,2H),7.86(dt,J=8.0,1.5Hz,1H),7.83–7.77( m,1H),7.73(t,J=7.8Hz,1H),7.64(t,J=7.9Hz,1H),7.32(t,J=53.8Hz,1H),5.94(s,2H),4.19(q,J=7.1Hz,2H),1.15(t,J=7.1Hz,3H).

[0192] Example 17 Synthesis of ethyl 2-(3-cyanophenyl)-4-(difluoromethyl)-1-[2-(2-chlorophenyl)-2-oxoethyl]-1H-imidazolium-5-carboxylate (6ka13)

[0193] Starting with ethyl 2-(3-cyanophenyl)-4-(difluoromethyl)-1H-imidazolium-5-carboxylate (5 kDa) and 2-bromo-2'-chloroacetophenone A2-13, 6 kDa was prepared as a white solid, yield: 81%, following the synthesis method in Example 5. Mp 131.5-132.2 °C. ESI-MS (m / z) = 444.1 [M+H] + 466.1 [M+Na]+ . 1 H NMR (400MHz, DMSO-d6) δ8.05(dt,J=7.8,1.4Hz,1H),7.97(t,J=1.6Hz,1H),7.94–7.86(m,2H),7.77(t,J=7.8Hz,1H),7.63(dd,J=4. 8,1.6Hz,2H),7.55(ddd,J=8.3,5.1,3.7Hz,1H),7.34(t,J=53.7Hz,1H),5.80(s,2H),4.30(q,J=7.1Hz,2H),1.26(t,J=7.1Hz,3H).

[0194] Example 18 Synthesis of ethyl 2-(3-cyanophenyl)-4-(difluoromethyl)-1-[2-(4-bromophenyl)-2-oxoethyl]-1H-imidazolium-5-carboxylate (6ka14)

[0195] Starting with ethyl 2-(3-cyanophenyl)-4-(difluoromethyl)-1H-imidazolium-5-carboxylate (5 kDa) and 2-bromo-4'-bromoacetophenone A2-14, 6 kDa was prepared according to the synthesis method in Example 5. The result was a white solid with a yield of 82%. Mp 158.0-160.2 °C. ESI-MS (m / z) = 490.1 [M+H] + 510.1[M+Na] + . 1 H NMR (400MHz, DMSO-d6) δ8.05–7.99(m,1H),7.99–7.95(m,3H),7.86(dt,J=8.0,1.4Hz,1H),7.82(d,J=8.4Hz, 2H),7.73(t,J=7.8Hz,1H),7.32(t,J=53.8Hz,1H),5.92(s,2H),4.19(q,J=7.1Hz,2H),1.15(t,J=7.1Hz,3H).

[0196] Example 19 Synthesis of ethyl 2-(3-cyanophenyl)-4-(difluoromethyl)-1-[2-(3-bromophenyl)-2-oxoethyl]-1H-imidazolium-5-carboxylate (6ka15)

[0197] Starting with ethyl 2-(3-cyanophenyl)-4-(difluoromethyl)-1H-imidazolium-5-carboxylate (5 kDa) and 2-bromo-3'-bromoacetophenone A2-15, 6 kDa was prepared according to the synthesis method in Example 5. The result was a white solid with a yield of 85%. Mp 183.7-185.1 °C. ESI-MS (m / z) = 490.1 [M+H] +510.1[M+Na] + . 1 H NMR (400MHz, DMSO-d6) δ8.20(t,J=1.9Hz,1H),8.05–8.00(m,2H),7.98(t,J=1.8Hz,1H),7.94(dt,J=8.0,1.4Hz,1H),7.86(dt,J=8.0,1. 5Hz,1H),7.73(t,J=7.8Hz,1H),7.57(t,J=7.9Hz,1H),7.32(t,J=53.8Hz,1H),5.94(s,2H),4.19(q,J=7.1Hz,2H),1.15(t,J=7.1Hz,3H).

[0198] Example 20 Synthesis of ethyl 2-(3-cyanophenyl)-4-(difluoromethyl)-1-[2-(2-bromophenyl)-2-oxoethyl]-1H-imidazolium-5-carboxylate (6ka16)

[0199] Starting with ethyl 2-(3-cyanophenyl)-4-(difluoromethyl)-1H-imidazolium-5-carboxylate (5 kDa) and 2-bromo-2'-bromoacetophenone A2-16, 6 kDa was prepared according to the synthesis method in Example 5. The result was a white solid with a yield of 81%. Mp 120.3-122.1 °C. ESI-MS (m / z) = 490.1 [M+H] + 510.1[M+Na] + . 1 H NMR (400MHz, DMSO-d6) δ8.06(dt,J=7.7,1.4Hz,1H),7.99(t,J=1.6Hz,1H),7.92(dt,J=7.9,1.4Hz,1H),7.87(dd,J=7.7,1.7Hz,1H),7.83–7.73(m ,2H),7.61(td,J=7.5,1.2Hz,1H),7.54(td,J=7.7,1.7Hz,1H),7.34(t,J =53.7Hz,1H),5.78(s,2H),4.31(q,J=7.1Hz,2H),1.27(t,J=7.1Hz,3H).

[0200] Example 21 Synthesis of ethyl 2-(3-cyanophenyl)-4-(difluoromethyl)-1-[2-(4-cyanophenyl)-2-oxoethyl]-1H-imidazolium-5-carboxylate (6ka17)

[0201] Starting with ethyl 2-(3-cyanophenyl)-4-(difluoromethyl)-1H-imidazolium-5-carboxylate (5 kDa) and 2-bromo-4'-cyanoacetophenone A2-17, 6 kDa 17 was prepared according to the synthesis method in Example 5. The result was a white solid with a yield of 72%. Mp 200.5–202.4 °C. ESI-MS (m / z) = 435.2 [M+H] + 457.2 [M+Na] + . 1 H NMR (400MHz, DMSO-d6) δ8.19(d,J=8.2Hz,2H),8.09(d,J=8.2Hz,2H),8.05–8.01(m,1H),7.99(t,J=1.9Hz,1H),7.88(dd,J =7.9,1.5Hz,1H),7.73(t,J=7.8Hz,1H),7.32(t,J=53.8Hz,1H),5.96(s,2H),4.18(q,J=7.1Hz,2H),1.15(t,J=7.1Hz,3H).

[0202] Example 22 Synthesis of ethyl 2-(3-cyanophenyl)-4-(difluoromethyl)-1-[2-(3-cyanophenyl)-2-oxoethyl]-1H-imidazolium-5-carboxylate (6ka18)

[0203] Using ethyl 2-(3-cyanophenyl)-4-(difluoromethyl)-1H-imidazolium-5-carboxylate (5 kDa) and 2-bromo-3'-cyanoacetophenone (A2-18) as starting materials, 6 kDa was prepared as a white solid, yield: 79%. Mp: 167.9-169.8 °C. 1 H NMR (400MHz, DMSO-d6) δ8.54(s,1H),8.31(d,J=8.0Hz,1H),8.20(d,J=7.7Hz,1H),8.03(d,J=7.9Hz,1H),7.99(s,1H),7.87(d,J=8.0H z,1H),7.82(t,J=7.9Hz,1H),7.73(t,J=7.8Hz,1H),7.32(t,J=53.8Hz,1H),5.98(s,2H),4.19(q,J=7.1Hz,2H),1.15(t,J=7.1Hz,3H).

[0204] Example 23 Synthesis of ethyl 2-(3-cyanophenyl)-4-(difluoromethyl)-1-[2-(4-methoxyphenyl)-2-oxoethyl]-1H-imidazolium-5-carboxylate (6ka19)

[0205] Starting with ethyl 2-(3-cyanophenyl)-4-(difluoromethyl)-1H-imidazolium-5-carboxylate (5 kDa) and 2-bromo-4'-methoxyacetophenone (A2-19), 6 kDa was prepared according to the synthesis method in Example 5. The result was a white solid with a yield of 75%. Mp: 118.4-118.6 °C. ESI-MS (m / z): 440.2 [M+H] + 462.2[M+Na] + . 1 H NMR (400MHz, DMSO-d6) δ8.05–7.99(m,3H),7.98(t,J=1.7Hz,1H),7.84(dt,J=7.9,1.5Hz,1H),7.72(t,J=7.8Hz,1H),7.3 2(t,J=53.8Hz,1H),7.10(dd,J=6.9,2.0Hz,2H),5.87(s,2H),4.19(q,J=7.1Hz,2H),3.87(s,3H),1.14(t,J=7.1Hz,3H).

[0206] Example 24 Synthesis of ethyl 2-(3-cyanophenyl)-4-(difluoromethyl)-1-[2-(2-methoxyphenyl)-2-oxoethyl]-1H-imidazolium-5-carboxylate (6ka20)

[0207] Starting with ethyl 2-(3-cyanophenyl)-4-(difluoromethyl)-1H-imidazolium-5-carboxylate (5 kDa) and 2-bromo-2'-methoxyacetophenone (A2-20), 6 kDa was prepared as a white solid, yield: 82%, following the synthetic method described in Example 5. Mp degraded at 174.1 °C. ESI-MS (m / z) = 440.2 [M+H] + 462.2[M+Na] + . 1 H NMR(400MHz, DMSO-d6)δ8.07–7.98(m,2H),7.86(dt,J=8.1,1.4Hz,1H),7.80–7.70(m,2H),7.69–7.61(m,1H),7.48 –7.17(m,2H),7.10(td,J=7.5,1.0Hz,1H),5.72(s,2H),4.22(q,J=7.1Hz,2H),3.89(s,3H),1.17(t,J=7.1Hz,3H).

[0208] Example 25 Synthesis of ethyl 2-(3-cyanophenyl)-4-(difluoromethyl)-1-[2-(4-methylphenyl)-2-oxoethyl]-1H-imidazolium-5-carboxylate (6ka21)

[0209] Starting with ethyl 2-(3-cyanophenyl)-4-(difluoromethyl)-1H-imidazolium-5-carboxylate (5 kDa) and 2-bromo-4'-methylacetophenone (A2-21), 6 kDa was prepared according to the synthesis method in Example 5. The product was a white solid, yield: 88%. Mp 153.2-154.8℃. ESI-MS m / z: 424.1 [M+H] + 446.1 [M+Na] + . 1 H NMR (400MHz, DMSO-d6) δ8.01(d,J=7.8Hz,1H),7.99–7.97(m,1H),7.94(d,J=7.9Hz,2H),7.85(d,J=8.1Hz,1H),7 .72(t,J=7.8Hz,1H),7.48–7.18(m,3H),5.90(s,2H),4.18(q,J=7.1Hz,2H),2.41(s,3H),1.13(t,J=7.1Hz,3H).

[0210] Example 26 Synthesis of ethyl 2-(3-cyanophenyl)-4-(difluoromethyl)-1-[2-(3-methylphenyl)-2-oxoethyl]-1H-imidazolium-5-carboxylate (6ka22)

[0211] Using ethyl 2-(3-cyanophenyl)-4-(difluoromethyl)-1H-imidazolium-5-carboxylate (5 kDa) and 2-bromo-3'-methylacetophenone (A2-22) as starting materials, 6 kDa was prepared as a white solid with a yield of 73%, following the synthesis method described in Example 5.

[0212] Example 27 Synthesis of ethyl 2-(3-cyanophenyl)-4-(difluoromethyl)-1-[2-(benzo[d][1,3]dioxacyclopenten-5-yl)-2-oxoethyl]-1H-imidazolium-5-carboxylate (6ka23)

[0213] Starting with ethyl 2-(3-cyanophenyl)-4-(difluoromethyl)-1H-imidazolium-5-carboxylate (5 kDa) and 2-bromo-2'-(benzo[d][1,3]dioxane-5-yl)acetophenone A2-23, 6 kDa was prepared as a white solid, yield: 91%, following the synthesis method in Example 5. Mp Degraded at 186.4 °C. ESI-MS (m / z) = 454.2 [M+H] + 476.1 [M+Na] + .

[0214] Example 28 Synthesis of ethyl 2-(3-cyanophenyl)-4-(difluoromethyl)-1-[2-(thiophen-3-yl)-2-oxoethyl]-1H-imidazolium-5-carboxylate (6ka24)

[0215] Starting with ethyl 2-(3-cyanophenyl)-4-(difluoromethyl)-1H-imidazolium-5-carboxylate (5 kDa) and 2-bromo-3'-(thiophene-3-yl)acetophenone (A2-24), 6 kDa was prepared as a white solid, yield: 74%, following the synthetic method described in Example 5. Mp: 181.6-182.4 °C. ESI-MS (m / z): 416.1 [M+H] + 438.1 [M+Na] + . 1 H NMR (400MHz, DMSO-d6) δ8.14(dd,J=5.0,1.1Hz,1H),8.11(dd,J=3.9,1.2Hz,1H),8.02(dt,J=7.7,1.4Hz,1H),7.99(t,J=1.7Hz,1H ),7.86(dt,J=7.9,1.5Hz,1H),7.74(t,J=7.8Hz,1H),7.48–7.16(m,2H),5.85(s,2H),4.21(q,J=7.1Hz,2H),1.15(t,J=7.1Hz,3H).

[0216] Example 29 Synthesis of ethyl 2-(3-cyanophenyl)-4-(difluoromethyl)-1-[2-(thiophen-2-yl)-2-oxoethyl]-1H-imidazolium-5-carboxylate (6ka25)

[0217] Starting with ethyl 2-(3-cyanophenyl)-4-(difluoromethyl)-1H-imidazolium-5-carboxylate (5 kDa) and 2-bromo-3'-(thiophene-2-yl)acetophenone (A2-25), 6 kDa was prepared as a white solid, yield: 76%, following the synthetic method described in Example 5. Mp: 137.8-138.9 °C. ESI-MS (m / z): 416.1 [M+H] + 438.2 [M+Na] + . 1H NMR (400MHz, DMSO-d6) δ8.66(dd,J=2.8,1.3Hz,1H),8.02(dt,J=7.8,1.4Hz,1H),7.98(td,J=1.7,0.6Hz,1H),7.85(dt,J=7.9,1.4Hz, 1H),7.76–7.70(m,2H),7.58(dd,J=5.1,1.3Hz,1H),7.32(t,J=53.8Hz,1H),5.81(s,2H),4.21(q,J=7.1Hz,2H),1.15(t,J=7.1Hz,3H).

[0218] Example 30 Synthesis of ethyl 2-(3-cyanophenyl)-4-(difluoromethyl)-1-[2-(furan-2-yl)-2-oxoethyl]-1H-imidazolium-5-carboxylate (6ka26)

[0219] Starting with ethyl 2-(3-cyanophenyl)-4-(difluoromethyl)-1H-imidazolium-5-carboxylate (5 kDa) and 2-bromo-3'-(furan-2-yl)acetophenone (A2-26), 6 kDa was prepared according to the synthesis method in Example 5. The result was a white solid with a yield of 81%. Mp: 163.5-163.8 °C. ESI-MS (m / z): 400.2 [M+H] + 422.2[M+Na] + . 1 H NMR (400MHz, DMSO-d6) δ8.11 (dd, J=1.7, 0.7Hz, 1H), 8.02 (dt, J=7.7, 1.3Hz, 1H),7.99(td,J=1.8,0.6Hz,1H),7.87(dt,J=8.0,1.3Hz,1H),7.74(td,J=7. 8,0.7Hz,1H),7.60(dd,J=3.7,0.7Hz,1H),7.32(t,J=53.8Hz,1H),6.81(dd, J=3.7,1.7Hz,1H),5.70(s,2H),4.22(q,J=7.1Hz,2H),1.16(t,J=7.1Hz,3H).

[0220] Example 31 Synthesis of ethyl 1-amino-2-(3-cyanophenyl)-4-(difluoromethyl)-1H-imidazolium-5-carboxylate (6k-N)

[0221] Ethyl 2-(3-cyanophenyl)-4-(difluoromethyl)-1H-imidazolium-5-carboxylate (5 kJ, 3 g, 9.8 mmol) and potassium carbonate (4.06 g, 29.4 mmol, 3 times the volume) were dissolved in 5 mL of N,N-dimethylformamide solution (1.7 times the volume). Then, diphenylphosphonohydroxylamine (2.5 g, 10.8 mmol, 1.2 times the volume) was added to the reaction solution. The reaction mixture was stirred at room temperature for 2 hours. After the starting materials had reacted completely, 15 mL of water was added to the reaction solution, and the mixture was stirred at room temperature for half an hour. A pale yellow solid precipitated out. The solid was filtered and dried to obtain 2.1 g of a pale yellow solid, yield: 71%. It decomposed at 153.0 °C. ESI-MS m / z: 307.1 [M+H] + 329.1 [M+Na] + . 1 HNMR(400MHz,Chloroform-d)δ8.62(t,J=1.7Hz,1H),8.49(dd,J=8.1,1.5Hz,1H),7.71(dt,J=7.8,1.4Hz,1 H),7.57(t,J=7.9Hz,1H),7.04(t,J=54.1Hz,1H),5.65(s,2H),4.46(q,J=7.1Hz,2H),1.44(t,J=7.1Hz,3H).

[0222] Example 32 Synthesis of ethyl 2-(3-cyanophenyl)-4-(difluoromethyl)-1-(4-fluorobenzamido)-1H-imidazolium-5-carboxylate (7kn1)

[0223] Ethyl 1-amino-2-(3-cyanophenyl)-4-(difluoromethyl)-1H-imidazolium-5-carboxylate 6k-N (300 mg, 0.98 mmol) and 4-fluorobenzoic acid (137 mg, 0.98 mmol, 1 part) were dissolved in 5 mL of pyridine solution (16.7 parts). The mixture was stirred in an ice-water bath for 10 minutes. Then, 0.3 mL of phosphorus oxychloride (10 parts) was slowly added dropwise to the reaction mixture. After 5 minutes, the mixture was transferred to room temperature and stirred for another 30 minutes. After the reaction was complete, the mixture was rotary evaporated under reduced pressure. Then, 4 mL of ice water was slowly added dropwise, and the mixture was stirred at room temperature for 10 minutes. The mixture was then filtered, the filter cake was washed twice with water, and dried to obtain a white solid. The crude product was used directly for the next step without purification.

[0224] Example 33 Synthesis of ethyl 2-(3-cyanophenyl)-4-(difluoromethyl)-1-(3-fluorobenzamido)-1H-imidazolium-5-carboxylate (7kn2)

[0225] 7kn2, a white solid, was prepared using 6k-N and 3-fluorobenzoic acid as starting materials, following the synthesis method described in Example 32. ESI-MS m / z: 429.1 [M+H] + 451.1[M+Na] + .

[0226] Example 34 Synthesis of ethyl 2-(3-cyanophenyl)-4-(difluoromethyl)-1-(2-fluorobenzamido)-1H-imidazolium-5-carboxylate (7kn3)

[0227] 7kn3, a white solid, was prepared using 6k-N and 2-fluorobenzoic acid as starting materials, following the synthesis method described in Example 32. ESI-MS m / z: 429.2 [M+H] + 451.1[M+Na] + .

[0228] Example 35 Synthesis of ethyl 2-(3-cyanophenyl)-4-(difluoromethyl)-1-[4-(trifluoromethyl)benzamido]-1H-imidazolium-5-carboxylate (7kn4)

[0229] 7kn4, a white solid, was prepared using 6k-N and 4-trifluoromethylbenzoic acid as starting materials, following the synthesis method described in Example 32. ESI-MS m / z: 479.1 [M+H] + 501.1[M+Na] + .

[0230] Example 36 Synthesis of ethyl 2-(3-cyanophenyl)-4-(difluoromethyl)-1-[3-(trifluoromethyl)benzamido]-1H-imidazolium-5-carboxylate (7kn5)

[0231] 7kn5, a white solid, was prepared using 6k-N and 3-trifluoromethylbenzoic acid as starting materials, following the synthesis method described in Example 32. ESI-MS m / z: 479.1 [M+H] + 501.1[M+Na] + .

[0232] Example 37 Synthesis of ethyl 2-(3-cyanophenyl)-4-(difluoromethyl)-1-[2-(trifluoromethyl)benzamido]-1H-imidazolium-5-carboxylate (7kn6)

[0233] 7kn6, a white solid, was prepared using 6k-N and 2-trifluoromethylbenzoic acid as starting materials, following the synthesis method described in Example 32.

[0234] Example 38 Synthesis of ethyl 2-(3-cyanophenyl)-4-(difluoromethyl)-1-[4-(trifluoromethoxy)benzamido]-1H-imidazolium-5-carboxylate (7kn7)

[0235] 7kn7, a white solid, was prepared using 6k-N and 4-trifluoromethoxybenzoic acid as starting materials, following the synthesis method described in Example 32.

[0236] Example 39 Synthesis of ethyl 2-(3-cyanophenyl)-4-(difluoromethyl)-1-[3-(trifluoromethoxy)benzamido]-1H-imidazolium-5-carboxylate (7kn8)

[0237] 7kn8, a white solid, was prepared using 6k-N and 3-trifluoromethoxybenzoic acid as starting materials, following the synthesis method described in Example 32. ESI-MS m / z: 495.1 [M+H] + 517.1 [M+Na] + .

[0238] Example 40 Synthesis of ethyl 2-(3-cyanophenyl)-4-(difluoromethyl)-1-[2-(trifluoromethoxy)benzamido]-1H-imidazolium-5-carboxylate (7kn9)

[0239] 7KN9 was prepared as a white solid using 6k-N and 2-trifluoromethoxybenzoic acid as starting materials, following the synthesis method described in Example 32. ESI-MS m / z: 495.2 [M+H] + 517.1 [M+Na] + .

[0240] Example 41 Synthesis of ethyl 2-(3-cyanophenyl)-4-(difluoromethyl)-1-(4-cyanobenzamido)-1H-imidazolium-5-carboxylate (7kn10)

[0241] 7kn10 was prepared as a white solid with a yield of 86%, using 6k-N and 4-cyanobenzoic acid as starting materials, following the synthesis method described in Example 32. ESI-MS m / z: 436.2 [M+H] + 458.2 [M+Na] + . 1H NMR (400MHz, DMSO-d6) δ12.60(s,1H),8.23(t,J=1.7Hz,1H),8.15(dt,J=8.1,1.4Hz,1H),8.10(dd,J=8.5,1.6Hz,2H),8.05(dd,J=8 .4Hz,2H),8.02(dt,J=7.8,1.4Hz,1H),7.76(t,J=7.9Hz,1H),7.33(t,J=53.5Hz,1H),4.29(q,J=6.6Hz,2H),1.19(t,J=7.1Hz,3H).

[0242] Example 42 Synthesis of ethyl 2-(3-cyanophenyl)-4-(difluoromethyl)-1-(3-cyanobenzamido)-1H-imidazolium-5-carboxylate (7kn11)

[0243] 7kn11, a white solid, was prepared using 6k-N and 3-cyanobenzoic acid as starting materials, following the synthesis method described in Example 32.

[0244] Example 43 Synthesis of ethyl 2-(3-cyanophenyl)-4-(difluoromethyl)-1-(4-nitrobenzamido)-1H-imidazolium-5-carboxylate (7kn12)

[0245] 7kn12, a white solid, was prepared using 6k-N and 4-nitrobenzoic acid as starting materials, following the synthesis method described in Example 32. ESI-MS m / z: 456.1 [M+H] + 478.1 [M+Na] + .

[0246] Example 44 Synthesis of ethyl 2-(3-cyanophenyl)-4-(difluoromethyl)-1-(3-nitrobenzamido)-1H-imidazolium-5-carboxylate (7kn13)

[0247] 7kn13 was prepared as a white solid, yield 78%, using 6k-N and 3-nitrobenzoic acid as starting materials, following the synthesis method described in Example 32. ESI-MS m / z: 456.1 [M+H] + 478.1 [M+Na] + .

[0248] Example 45 Synthesis of ethyl 2-(3-cyanophenyl)-4-(difluoromethyl)-1-(2-nitrobenzamido)-1H-imidazolium-5-carboxylate (7kn14)

[0249] 7kn14 was prepared as a white solid, yielding 52%, using 6k-N and 2-nitrobenzoic acid as starting materials, following the synthesis method described in Example 32. ESI-MS m / z: 456.2 [M+H] + 478.1 [M+Na] + .

[0250] Example 46 Synthesis of ethyl 2-(3-cyanophenyl)-4-(difluoromethyl)-1-(4-chlorobenzamido)-1H-imidazolium-5-carboxylate (7kn15)

[0251] 7kn15 was prepared as a white solid, yielding 82%, using 6k-N and 4-chlorobenzoic acid as starting materials, following the synthesis method described in Example 32. ESI-MS m / z: 445.2 [M+H] + 467.2 [M+Na] + . 1 H NMR (400MHz, DMSO-d6) δ8.31–8.24(m,2H),8.22(t,J=1.6Hz,1H),8.14(dt,J=8.1,1.5Hz,1H),7.97(dt,J=7.9,1.3Hz, 1H),7.72(t,J=7.9Hz,1H),7.53(t,J=8.8Hz,2H),7.48(t,J=53.6Hz,1H),4.27(q,J=7.1Hz,2H),1.17(t,J=7.1Hz,3H).

[0252] Example 47 Synthesis of ethyl 2-(3-cyanophenyl)-4-(difluoromethyl)-1-(2-chlorobenzamido)-1H-imidazolium-5-carboxylate (7kn16)

[0253] 7kn16 was prepared as a white solid, yielding 62%, using 6k-N and 2-chlorobenzoic acid as starting materials, following the synthesis method described in Example 32. ESI-MS m / z: 445.1 [M+H] + 467.1 [M+Na] + .

[0254] Example 48 Synthesis of ethyl 2-(3-cyanophenyl)-4-(difluoromethyl)-1-(4-bromobenzamido)-1H-imidazolium-5-carboxylate (7kn17)

[0255] 7kn17 was prepared as a white solid, yield 76%, using 6k-N and 4-bromobenzoic acid as starting materials, following the synthesis method described in Example 32. ESI-MS m / z: 489.0 [M+H] + 511.0[M+Na] + .

[0256] Example 49 Synthesis of ethyl 2-(3-cyanophenyl)-4-(difluoromethyl)-1-(3-bromobenzamido)-1H-imidazolium-5-carboxylate (7kn18)

[0257] 7kn18 was prepared as a white solid with a yield of 79%, using 6k-N and 3-bromobenzoic acid as starting materials, following the synthesis method of Example 32.

[0258] Example 50 Synthesis of ethyl 2-(3-cyanophenyl)-4-(difluoromethyl)-1-(4-methylbenzamido)-1H-imidazolium-5-carboxylate (7kn19)

[0259] 7kn19 was prepared as a white solid, yield 85%, using 6k-N and 4-methylbenzoic acid as starting materials, following the synthesis method described in Example 32. ESI-MS m / z: 425.1 [M+H] + 447.1 [M+Na] + .

[0260] Example 51 Synthesis of ethyl 2-(3-cyanophenyl)-4-(difluoromethyl)-1-(3-methylbenzamido)-1H-imidazolium-5-carboxylate (7kn20)

[0261] 7kn20 was prepared as a white solid, yield 69%, using 6k-N and 3-methylbenzoic acid as starting materials, following the synthesis method described in Example 32. ESI-MS m / z: 425.2 [M+H] + 447.1 [M+Na] + .

[0262] Example 52 Synthesis of ethyl 2-(3-cyanophenyl)-4-(difluoromethyl)-1-(3-bromo-4-fluorobenzamido)-1H-imidazolium-5-carboxylate (7kn21)

[0263] 7kn21 was prepared as a white solid using 6k-N and 3-bromo-4-fluorobenzoic acid as starting materials, following the synthesis method described in Example 32. ESI-MS m / z: 509.0 [M+H] + 531.1[M+Na] + . 1H NMR (400MHz, DMSO-d6) δ12.46(s,1H),8.27–8.21(m,2H),8.14(dt,J=8.1,1.4Hz,1H),8.01(dt,J=7.9,1.3Hz,1H),7.97(dq,J=6. 9,2.3Hz,1H),7.76(t,J=7.9Hz,1H),7.63(t,J=8.6Hz,1H),7.33(t,J=53.6Hz,1H),4.28(q,J=7.0Hz,2H),1.20(t,J=7.1Hz,3H).

[0264] Example 53 Synthesis of ethyl 2-(3-cyanophenyl)-4-(difluoromethyl)-1-(3-methyl-4-nitrobenzamido)-1H-imidazolium-5-carboxylate (7kn22)

[0265] 7kn22 was prepared as a white solid using 6k-N and 3-methyl-4-nitrobenzoic acid as starting materials, following the synthesis method described in Example 32. ESI-MS m / z: 470.1 [M+H] + 492.0 [M+Na] + .

[0266] Example 54 Synthesis of ethyl 2-(3-cyanophenyl)-4-(difluoromethyl)-1-(2-fluoro-4-nitrobenzamido)-1H-imidazolium-5-carboxylate (7kn23)

[0267] 7kn23, a white solid, was prepared using 6k-N and 2-fluoro-4-nitrobenzoic acid as starting materials, following the synthesis method described in Example 32.

[0268] Example 55 Synthesis of ethyl 2-(3-cyanophenyl)-4-(difluoromethyl)-1-(2-chloro-4-nitrobenzamido)-1H-imidazolium-5-carboxylate (7kn24)

[0269] 7kn24, a white solid, was prepared using 6k-N and 2-chloro-4-nitrobenzoic acid as starting materials, following the synthesis method described in Example 32. ESI-MS m / z: 490.1 [M+H] + 512.1[M+Na] + .

[0270] Example 56 Synthesis of ethyl 2-(3-cyanophenyl)-4-(difluoromethyl)-1-(3-chloro-4-nitrobenzamido)-1H-imidazolium-5-carboxylate (7kn25)

[0271] 7kn25, a white solid, was prepared using 6k-N and 3-chloro-4-nitrobenzoic acid as starting materials, following the synthesis method described in Example 32. ESI-MS m / z: 490.1 [M+H] + 512.1[M+Na] + .

[0272] Example 57 Synthesis of ethyl 2-(3-cyanophenyl)-4-(difluoromethyl)-1-(2-bromo-4-nitrobenzamido)-1H-imidazolium-5-carboxylate (7kn26)

[0273] 7kn26, a white solid, was prepared using 6k-N and 2-bromo-4-nitrobenzoic acid as starting materials, following the synthesis method described in Example 32.

[0274] Example 58 Synthesis of ethyl 2-(3-cyanophenyl)-4-(difluoromethyl)-1-(4-methoxybenzamido)-1H-imidazolium-5-carboxylate (7kn27)

[0275] 7kn27 was prepared as a white solid using 6k-N and 4-methoxybenzoic acid as starting materials, following the synthesis method described in Example 32. ESI-MS m / z: 441.1 [M+H] + 463.1 [M+Na] + .

[0276] Example 59 Synthesis of 2-(3-cyanophenyl)-4-(difluoromethyl)-1-(3,5-dichloro-4-methoxybenzamido)-1H-imidazolium-5-carboxylic acid ethyl ester (7kn28)

[0277] 7kn28, a white solid, was prepared using 6k-N and 3,5-dichloro-4-methoxybenzoic acid as starting materials, following the synthesis method described in Example 32. ESI-MS m / z: 509.1 [M+H] + 531.1[M+Na] + .

[0278] Example 60 Synthesis of ethyl 2-(3-cyanophenyl)-4-(difluoromethyl)-1-(3,5-dichloro-4-hydroxybenzamido)-1H-imidazolium-5-carboxylate (7kn29)

[0279] Intermediate ethyl 2-(3-cyanophenyl)-4-(difluoromethyl)-1-(3,5-dichloro-4-hydroxybenzamido)-1H-imidazolium-5-carboxylate 7kn28 (200 mg, 0.394 mmol) was dissolved in 2 mL of N,N-dimethylformamide solution, followed by the addition of lithium chloride (167 mg, 3.94 mmol, 10 times the amount), and the temperature was raised to 110 °C. After the reaction was complete, the reaction solution was cooled to room temperature, 4 mL of water was added, and the pH of the reaction solution was adjusted to 2–3 with 1 M dilute hydrochloric acid. The solution was then filtered, the filter cake was washed twice with water, collected, and dried to obtain ethyl 2-(3-cyanophenyl)-4-(difluoromethyl)-1-(3,5-dichloro-4-hydroxybenzamido)-1H-imidazolium-5-carboxylate 7kn29, a white solid, yield: 62%.

[0280] Example 61 Synthesis of 2-(3-cyanophenyl)-4-(difluoromethyl)-1-(3,5-dichloro-4-aminobenzamido)-1H-imidazolium-5-carboxylic acid ethyl ester (7kn30)

[0281] 7kn30, a white solid, was prepared using 6k-N and 3,5-dichloro-4-aminobenzoic acid as starting materials, following the synthesis method described in Example 32.

[0282] Example 62 Synthesis of 2-(3-cyanophenyl)-4-(difluoromethyl)-1-[2-(4-fluorophenyl)-2-oxoethyl]-1H-imidazolium-5-carboxylic acid (7ka2)

[0283] 6 kJ (150 mg, 0.35 mmol) of 2-(3-cyanophenyl)-4-(difluoromethyl)-1-[2-(4-fluorophenyl)-2-oxoethyl]-1H-imidazolium-5-carboxylic acid ethyl ester was dissolved in 5 mL of tetrahydrofuran solution (33 times the volume), and then 1 mL of saturated sodium hydroxide aqueous solution was added dropwise. The mixture was stirred at 30 °C. After the reaction was complete, the mixture was rotary evaporated under reduced pressure at room temperature, and then the pH of the reaction solution was adjusted to 1-2 with 3M dilute hydrochloric acid solution. A white solid precipitated, which was then filtered, washed twice with water, and dried to obtain a crude product. Thin-layer chromatography was used to prepare a white solid with a yield of 75%. The product was degraded at 200 °C. ESI-HRMS m / z calculated for C 20 H 12 F3N3NaO3 + [M+Na] + 422.0723, found 422.0738. 1H NMR(400MHz, DMSO-d6)δ8.08(dd,J=8.8,5.5Hz,2H),7.97–7.90(m,2H),7.83( dt,J=7.6,1.3Hz,1H),7.78–7.47(m,2H),7.39(t,J=8.8Hz,2H),6.02(s,2H). 13 C NMR(100MHz,DMSO-d6)δ192.92,167.00,164.49,162.01,147.35,133.95,133.39,132 .62,132.04,131.64,131.59,131.55,130.51,118.72,116.41,116.19,112.40,52.80.

[0284] Example 63 Synthesis of 2-(3-cyanophenyl)-4-(difluoromethyl)-1-[2-(3-fluorophenyl)-2-oxoethyl]-1H-imidazol-5-carboxylic acid (7ka3)

[0285] Starting from ethyl 2-(3-cyanophenyl)-4-(difluoromethyl)-1-[2-(3-fluorophenyl)-2-oxoethyl]-1H-imidazolium-5-carboxylate 6ka3, 7ka3 was prepared according to the preparation method in Example 62. White solid, yield: 79%. Mp 192.3-193.4℃. ESI-HRMS m / z calculated for C 20 H 11 F3N3O3 - [MH] - 398.0758,found398.0745.ESI-MS m / z:400.1[M+H] + 422.1[M+Na] + . 1 H NMR (400MHz, DMSO-d6) δ8.00(dt,J=7.7,1.4Hz,1H),7.98(t,J=1.7Hz,1H),7.90–7.79(m,3H),7.72(t,J=7.8Hz,1H),7.68–7.25(m,3H),5.93(s,2H). 13C NMR(100MHz,DMSO-d6)δ193.00,161.37,160.84,149.77,137.03,136.96,134.25,134.12,132 .98,131.53,130.71,130.35,124.85,121.48,121.27,118.63,115.39,115.17,112.63,53.65.

[0286] Example 64 Synthesis of 2-(3-cyanophenyl)-4-(difluoromethyl)-1-(2-(2-fluorophenyl)-2-oxoethyl)-1H-imidazol-5-carboxylic acid (7ka4)

[0287] Starting from ethyl 2-(3-cyanophenyl)-4-(difluoromethyl)-1-[2-(2-fluorophenyl)-2-oxoethyl]-1H-imidazolium-5-carboxylate 6ka4, 7ka4 was prepared according to the preparation method in Example 62. White solid, yield: 86%. Mp 189.5-191.9℃. ESI-HRMS m / z calculated for C 20 H 12 F3N3NaO3 + [M+Na] + 422.0723, found 422.0719. 1 H NMR (400MHz, DMSO-d6) δ14.03(s,1H),8.04–7.98(m,2H),7.94–7.86(m,2H),7.78–7.70(m,2H),7.51–7.21(m,3H),5.75(s,2H). 13 C NMR (100MHz, DMSO-d6) δ191.65,163.08,160.75,149.97,139.89,136.60,134.29,134.19,133. 02,130.85,130.71,130.33,125.49,123.44,123.32,118.61,117.53,117.30,112.63,110.05.

[0288] Example 65 Synthesis of 2-(3-cyanophenyl)-4-(difluoromethyl)-1-{2-[4-(trifluoromethyl)phenyl]-2-oxoethyl}-1H-imidazol-5-carboxylic acid (7ka5)

[0289] Starting from ethyl 2-(3-cyanophenyl)-4-(difluoromethyl)-1-{2-[4-(trifluoromethyl)phenyl]-2-oxoethyl}-1H-imidazolium-5-carboxylate 6ka5, 7ka5 was prepared according to the preparation method in Example 62. White solid, yield: 88%. Mp 134.3-135.7℃. ESI-HRMS m / z calculated for C 21 H 11 F5N3O3 - [MH] - 448.0726, found 448.0765. 1 H NMR(400MHz,DMSO-d6)δ13.99(s,1H),8.22(d,J=8.0Hz,2H),8.05–7.92(m,4H),7 .88(d,J=8.1Hz,1H),7.73(t,J=7.8Hz,1H),7.36(t,J=54.0Hz,1H),5.95(s,2H). 13 C NMR(100MHz,DMSO-d6)δ193.51,160.67,150.12,140.01,138.15,134.34,134.21,133.78, 133.46,133.03,130.72,130.16,129.53,126.30,125.48,122.77,118.62,112.64,53.78.

[0290] Example 66 Synthesis of 2-(3-cyanophenyl)-4-(difluoromethyl)-1-{2-[3-(trifluoromethyl)phenyl]-2-oxoethyl}-1H-imidazolium-5-carboxylic acid (7ka6)

[0291] Starting from ethyl 2-(3-cyanophenyl)-4-(difluoromethyl)-1-{2-[3-(trifluoromethyl)phenyl]-2-oxoethyl}-1H-imidazolium-5-carboxylate 6ka6, 7ka6 was prepared according to the preparation method in Example 62. White solid, yield: 76%. Mp 134.3-135.7℃. ESI-HRMS m / z calculated for C 21 H 11 F5N3O3 - [MH] - 448.0726, found 448.0725. 1H NMR (400MHz, DMSO-d6) δ14.01(s,1H),8.35–8.25(m,2H),8.10(dd,J=7.9,1.7Hz,1H),8.04–7.98(m,2H),7. 88(dt,J=8.0,1.5Hz,1H),7.84(t,J=8.0Hz,1H),7.73(t,J=7.8Hz,1H),7.36(t,J=54.0Hz,1H),5.97(s,2H). 13 C NMR(100MHz,DMSO-d6)δ193.25,160.71,150.12,135.80,134.36,134.20,133.04,132.66, 130.73,130.69,130.19,129.88,125.57,125.13,125.09,122.86,118.64,112.64,53.68.

[0292] Example 67 Synthesis of 2-(3-cyanophenyl)-4-(difluoromethyl)-1-{2-[2-(trifluoromethyl)phenyl]-2-oxoethyl}-1H-imidazolium-5-carboxylic acid (7ka7)

[0293] Starting from ethyl 2-(3-cyanophenyl)-4-(difluoromethyl)-1-{2-[2-(trifluoromethyl)phenyl]-2-oxoethyl}-1H-imidazolium-5-carboxylate 6ka7, 7ka7 was prepared according to the preparation method in Example 62. White solid, yield: 78%. Mp 199.8-201.0℃. ESI-HRMS m / z calculated for C 21 H 11 F5N3O3 - [MH] - 448.0726, found 448.0739. 1 H NMR(400MHz,DMSO-d6)δ8.09(d,J=7.6Hz,1H),8.04(dt,J=7.8,1.4Hz,1H),7.94–7.84 (m,4H),7.84–7.77(m,1H),7.74(t,J=7.8Hz,1H),7.43(t,J=54.1Hz,1H),5.80(s,2H). 13C NMR(100MHz,DMSO-d6)δ196.68,161.07,149.81,139.56,136.03,134.39,134.31,133.20, 132.63,130.68,130.31,129.49,127.62,127.01,126.69,125.11,118.43,112.58,55.93.

[0294] Example 68 Synthesis of 2-(3-cyanophenyl)-4-(difluoromethyl)-1-{2-[4-(trifluoromethoxy)phenyl]-2-oxoethyl}-1H-imidazolium-5-carboxylic acid (7ka8)

[0295] Starting from ethyl 2-(3-cyanophenyl)-4-(difluoromethyl)-1-{2-[4-(trifluoromethoxy)phenyl]-2-oxoethyl}-1H-imidazolium-5-carboxylate 6ka8, 7ka8 was prepared according to the preparation method in Example 62. White solid, yield: 72%. Mp 180.3-180.5℃. ESI-HRMS m / z calculated for C 21 H 11 F5N3O4 - [MH] - 464.0675, found 464.0784. 1 H NMR(400MHz, DMSO-d6)δ14.04(s,1H),8.16(dd,J=8.0,1.4Hz,2H),8.03–7.95(m,2H),7.86(dt,J =6.7,2.0Hz,1H),7.72(t,J=7.8Hz,1H),7.61–7.54(m,2H),7.38(t,J=54.1Hz,1H),5.92(s,2H). 13 C NMR(100MHz,DMSO-d6)δ192.81,160.78,152.50,149.87,139.71,134.31,134.27,134 .12,133.79,132.99,131.25,130.69,130.32,121.39,118.62,112.62,110.11,53.54.

[0296] Example 69 Synthesis of 2-(3-cyanophenyl)-4-(difluoromethyl)-1-{2-[3-(trifluoromethoxy)phenyl]-2-oxoethyl}-1H-imidazol-5-carboxylic acid (7ka9)

[0297] Starting from ethyl 2-(3-cyanophenyl)-4-(difluoromethyl)-1-{2-[3-(trifluoromethoxy)phenyl]-2-oxoethyl}-1H-imidazolium-5-carboxylate 6ka9, 7ka9 was prepared according to the preparation method in Example 62. White solid, yield: 86%. Mp 185.2-186.1℃. ESI-HRMS m / z calculated for C 21 H 11 F5N3O4 - [MH] - 464.0675, found 464.0749. 1 H NMR(400MHz, DMSO-d6)δ14.02(s,1H),8.10–8.05(m,1H),8.03–7.97(m,2H),7.95–7. 91(m,1H),7.87(dt,J=7.9,1.5Hz,1H),7.76–7.69(m,3H),7.36(s,1H),5.93(s,2H). 13 C NMR(100MHz,DMSO-d6)δ192.97,160.74,150.03,149.02,139.87,136.99,134.34,134.18,133.03, 131.63,130.72,130.23,127.89,126.80,121.75,120.84,119.20,118.63,112.64,110.06,53.65.

[0298] Example 70 Synthesis of 2-(3-cyanophenyl)-4-(difluoromethyl)-1-{2-[2-(trifluoromethoxy)phenyl]-2-oxoethyl}-1H-imidazolium-5-carboxylic acid (7ka10)

[0299] Starting from ethyl 2-(3-cyanophenyl)-4-(difluoromethyl)-1-{2-[2-(trifluoromethoxy)phenyl]-2-oxoethyl}-1H-imidazolium-5-carboxylate 6ka10, 7ka10 was prepared according to the method described in Example 62. White solid, yield: 69%. Mp 183.4-185.6℃. ESI-HRMS m / z calculated for C 21 H 11 F5N3O4 - [MH] - 464.0675, found 464.0711. 1H NMR (400MHz, DMSO-d6) δ14.17(s,1H),8.04(dt,J=7.8,1.4Hz,1H),7.99(t,J=1.8Hz,1H),7.94(dd,J=7.8,1.8Hz,1H),7.89(dt,J= 7.9,1.4Hz,1H),7.82–7.71(m,2H),7.59(td,J=7.6,1.0Hz,1H),7.54(dt,J=8.3,1.5Hz,1H),7.37(t,J=53.9Hz,1H),5.75(s,2H). 13 C NMR(100MHz,DMSO-d6)δ193.25,160.80,150.03,146.26,139.94,135.22,134.33,134.30,132 .78,131.14,130.75,130.24,129.72,128.43,122.26,121.55,118.98,118.42,112.65,55.78.

[0300] Example 71 Synthesis of 2-(3-cyanophenyl)-4-(difluoromethyl)-1-[2-(4-cyanophenyl)-2-oxoethyl]-1H-imidazolium-5-carboxylic acid (7ka17)

[0301] 7ka17 was prepared from 2-(3-cyanophenyl)-4-(difluoromethyl)-1-[2-(4-cyanophenyl)-2-oxoethyl]-1H-imidazolium-5-carboxylic acid 6ka17 as the starting material, following the preparation method described in Example 62. White solid, yield: 73%. Mp 197.0-198.6℃. ESI-HRMS m / z calculated for C 21 H 11 F2N4O3 - [MH] - 405.0805, found 405.0841. 1 H NMR(400MHz, DMSO-d6)δ8.18(d,J=8.4Hz,2H),8.08(d,J=8.4Hz,2H),8.05–7.96(m,2H), 7.88(dt,J=7.9,1.5Hz,1H),7.73(t,J=7.8Hz,1H),7.36(t,J=54.0Hz,1H),5.94(s,2H). 13C NMR(100MHz,DMSO-d6)δ193.34,160.57,149.95,138.05,134.22,134.08,133.17, 132.89,130.59,130.02,129.17,118.50,118.36,116.11,112.51,109.88,53.61N.

[0302] Example 72 Synthesis of 2-(3-cyanophenyl)-4-(difluoromethyl)-1-[2-(3-cyanophenyl)-2-oxoethyl]-1H-imidazol-5-carboxylic acid (7ka18)

[0303] 7ka18 was prepared from 2-(3-cyanophenyl)-4-(difluoromethyl)-1-[2-(3-cyanophenyl)-2-oxoethyl]-1H-imidazolium-5-carboxylic acid 6ka18 as the starting material, following the preparation method described in Example 62. White solid, yield: 79%. Mp 220.8-221.2℃. ESI-HRMS m / z calculated for C 21 H 11 F2N4O3 - [MH] - 405.0805, found 405.0828. 1 H NMR (400MHz, DMSO-d6) δ14.00(s,1H),8.53(t,J=1.8Hz,1H),8.29(dt,J=7.9,1.5Hz,1H),8.18(dt,J=7.7,1.4Hz,1H),8.02(dt,J=7.7,1.5H z,1H),7.99(t,J=1.7Hz,1H),7.87(dt,J=7.8,1.5Hz,1H),7.80(t,J=7.8Hz,1H),7.73(t,J=7.8Hz,1H),7.35(t,J=53.9Hz,1H),5.94(s,2H). 13 C NMR(100MHz,DMSO-d6)δ192.82,160.64,150.14,140.07,137.55,135.68,134.36,134.24, 133.04,132.91,132.68,130.72,130.67,130.10,118.62,118.42,112.64,112.50,53.64.

[0304] Example 73 Synthesis of 2-(3-cyanophenyl)-4-(difluoromethyl)-1-(4-fluorobenzamido)-1H-imidazol-5-carboxylic acid (8kn1)

[0305] Starting from ethyl 2-(3-cyanophenyl)-4-(difluoromethyl)-1-(4-fluorobenzamido)-1H-imidazolium-5-carboxylate 7kn1, 8kn1 was prepared according to the preparation method in Example 62. White solid, yield: 62%. Mp 180.7-182.5℃. ESI-HRMS m / z calculated for C 19 H 10 F3N4O3 - [MH] - 399.0710, found 399.0779. 1 H NMR (400MHz, DMSO-d6) δ12.79(s,1H),8.32(t,J=1.7Hz,1H),8.22(dt,J=8.4,1.4Hz, 1H),8.13–8.04(m,2H),8.02–7.94(m,1H),7.73(t,J=7.9Hz,1H),7.52–7.19(m,3H). 13 C NMR (100MHz, DMSO-d6) δ166.47,165.75,163.98,159.17,148.15,138.25,134. 33,133.25,132.09,131.22,130.67,129.10,127.88,118.45,116.47,116.25,

[0306] Example 74 Synthesis of 2-(3-cyanophenyl)-4-(difluoromethyl)-1-(3-fluorobenzamido)-1H-imidazol-5-carboxylic acid (8kn2)

[0307] 8kn2 was prepared from ethyl 2-(3-cyanophenyl)-4-(difluoromethyl)-1-(3-fluorobenzamido)-1H-imidazolium-5-carboxylate 7kn2 as the starting material, following the preparation method in Example 62. White solid, yield: 59%. Mp 185.6-187.0℃. ESI-HRMS m / z calculated for C 19 H 10 F3N4O3 - [MH] - 399.0710, found 399.0751. 1H NMR (400MHz, DMSO-d6) δ12.35(s,1H),8.23(t,J=1.8Hz,1H),8.15(dt,J=8.0,1.4Hz,1H),8.00(dt,J= 7.8,1.4Hz,1H),7.76(t,J=7.8Hz,2H),7.71–7.63(m,2H),7.59–7.52(m,1H),7.36(t,J=53.8Hz,1H). 13 C NMR(100MHz,DMSO-d6)δ165.83,163.66,159.28,148.05,138.50,134.43,133.60,133.05, 131.99,131.80,130.83,128.95,124.35,120.60,120.39,118.43,114.93,112.57,109.69.

[0308] Example 75 Synthesis of 2-(3-cyanophenyl)-4-(difluoromethyl)-1-(2-fluorobenzamido)-1H-imidazol-5-carboxylic acid (8kn3)

[0309] 8kn3 was prepared from ethyl 2-(3-cyanophenyl)-4-(difluoromethyl)-1-(2-fluorobenzamido)-1H-imidazolium-5-carboxylate 7kn3 as the starting material, following the preparation method in Example 62. White solid, yield: 66%. Mp 179.1-181.5℃. ESI-HRMS m / z calculated for C 19 H 10 F3N4O3 - [MH] - 399.0710, found 399.0731. 1 H NMR (400MHz, DMSO-d6) δ14.21(s,1H),12.18(s,1H),8.26(s,1H),8.19(d,J=8.1Hz,1H ),8.03(d,J=7.6Hz,1H),7.79(d,J=8.5Hz,1H),7.73–7.60(m,2H),7.55–7.20(m,3H). 13 C NMR(100MHz,DMSO-d6)δ164.45,161.09,159.25,158.58,147.78,134.71,134.42,133.34, 131.89,130.71,130.49,128.86,125.41,120.90,120.76,118.42,117.14,116.92,112.46.

[0310] Example 76 Synthesis of 2-(3-cyanophenyl)-4-(difluoromethyl)-1-[4-(trifluoromethyl)benzamido]-1H-imidazol-5-carboxylic acid (8kn4)

[0311] 8kn4 was prepared from ethyl 2-(3-cyanophenyl)-4-(difluoromethyl)-1-[4-(trifluoromethyl)benzamido]-1H-imidazolium-5-carboxylate 7kn4 as the starting material, following the preparation method in Example 62. White solid, yield: 69%. Mp 188.9-190.6℃. ESI-HRMS m / z calculated for C 20 H 10 F5N4O3 - [MH] - 449.0679, found 449.0676. 1 H NMR (400MHz, DMSO-d6) δ14.21(s,1H),12.51(s,1H),8.22(t,J=1.7Hz,1H),8.15(dt,J=8.1,1.4 Hz,1H),8.09(d,J=8.2Hz,2H),8.05–7.95(m,3H),7.75(t,J=7.9Hz,1H),7.36(t,J=53.7Hz,1H). 13 C NMR (100MHz, DMSO-d6) δ166.04,159.28,148.06,135.10,135.05,134.47,133.24,133. 03,132.92,132.01,130.82,129.07,128.92,126.52,126.49,118.42,112.61,107.37.

[0312] Example 77 Synthesis of 2-(3-cyanophenyl)-4-(difluoromethyl)-1-[3-(trifluoromethyl)benzamido]-1H-imidazol-5-carboxylic acid (8kn5)

[0313] 8kn5 was prepared from ethyl 2-(3-cyanophenyl)-4-(difluoromethyl)-1-[3-(trifluoromethyl)benzamido]-1H-imidazolium-5-carboxylate 7kn5 as the starting material, following the preparation method described in Example 62. White solid, yield: 56%. Mp 188.3-190.4℃. ESI-HRMS m / z calculated for C 20 H 10 F5N4O3 - [MH] -449.0679, found 449.0675. 1 H NMR (400MHz, DMSO-d6) δ14.22(s,1H),12.53(s,1H),8.24(t,J=1.8Hz,1H),8.22–8.12(m,3H),8.08(d,J=7. 9Hz, 1H), 8.00 (dt, J = 7.8, 1.4Hz, 1H), 7.86 (t, J = 7.8Hz, 1H), 7.75 (t, J = 7.9Hz, 1H), 7.36 (t, J = 53.7Hz, 1H). 13 C NMR (100MHz, DMSO-d6) δ165.89,159.32,148.10,134.47,133.09,132.36,132.29,131.99,130. 94,130.85,130.25,130.08,130.05,129.93,128.89,125.50,124.66,124.65,118.39,112.59.

[0314] Example 78 Synthesis of 2-(3-cyanophenyl)-4-(difluoromethyl)-1-[2-(trifluoromethyl)benzamido]-1H-imidazol-5-carboxylic acid (8kn6)

[0315] 8kn6 was prepared from ethyl 2-(3-cyanophenyl)-4-(difluoromethyl)-1-[2-(trifluoromethyl)benzamido]-1H-imidazolium-5-carboxylate 7kn6 as the starting material, following the preparation method described in Example 62. White solid, yield: 66%. Mp 186.9-188.6℃. ESI-HRMS m / z calculated for C 20 H 10 F5N4O3 - [MH] - 449.0679, found 449.0700. 1 H NMR (400MHz, DMSO-d6) δ14.29(s,1H),12.34(s,1H),8.19(t,J=1.7Hz,1H),8.14(dt,J=7.9,1.5Hz,1H),8. 04(dt,J=7.8,1.4Hz,1H),7.79–7.71(m,3H),7.66–7.58(m,1H),7.56–7.53(m,1H),7.36(t,J=53.7Hz,1H). 13C NMR(100MHz,DMSO-d6)δ164.74,159.35,148.35,145.82,134.41,133.78,133.49,131.91, 130.64,130.18,128.87,128.19,127.21,122.05,122.02,121.43,118.87,118.41,112.47.

[0316] Example 79 Synthesis of 2-(3-cyanophenyl)-4-(difluoromethyl)-1-[4-(trifluoromethoxy)benzamido]-1H-imidazol-5-carboxylic acid (8kn7)

[0317] 8kn7 was prepared from ethyl 2-(3-cyanophenyl)-4-(difluoromethyl)-1-[4-(trifluoromethoxy)benzamido]-1H-imidazolium-5-carboxylate 7kn7 as the starting material, following the preparation method described in Example 62. White solid, yield: 54%. Mp 187.8-188.3℃. ESI-HRMS m / z calculated for C 20 H 10 F5N4O4 - [MH] - 465.0628, found 465.0687. 1 H NMR (400MHz, DMSO-d6) δ14.17(s,1H),12.37(s,1H),8.22(t,J=1.7Hz,1H),8.14(dt,J=8.0,1.4Hz, 1H),8.06–7.96(m,3H),7.75(t,J=7.9Hz,1H),7.61(dd,J=8.9,1.4Hz,2H),7.36(t,J=53.7Hz,1H). 13 C NMR (100MHz, DMSO-d6) δ165.93,159.28,151.87,148.10,138.54,134.43,133.04,132. 02,130.81,130.62,130.38,128.97,123.97,121.68,119.08,118.43,112.59,109.68.

[0318] Example 80 Synthesis of 2-(3-cyanophenyl)-4-(difluoromethyl)-1-[3-(trifluoromethoxy)benzamido]-1H-imidazol-5-carboxylic acid (8kn8)

[0319] 8kn8 was prepared from ethyl 2-(3-cyanophenyl)-4-(difluoromethyl)-1-[3-(trifluoromethoxy)benzamido]-1H-imidazolium-5-carboxylate 7kn8 as the starting material, following the preparation method in Example 62. It was a white solid, yield: 62%. Mp 183.6-185.4℃. ESI-HRMS m / z calculated for C 20 H 10 F5N4O4 - [MH] - 465.0628, found 465.0710. 1 H NMR (400MHz, DMSO-d6) δ8.24(t,J=1.8Hz,1H),8.17(dt,J=8.0,1.5Hz,1H),8.01(dt,J=7.6,1 .5Hz,1H),7.92(dt,J=7.8,1.4Hz,1H),7.88(s,1H),7.75–7.66(m,3H),7.54(t,J=54.6,1H). 13 C NMR(100MHz,DMSO-d6)δ165.72,160.38,148.83,134.30,133.63,132.90,131.64,131.52, 130.57,130.09,127.45,125.56,121.77,120.79,119.21,118.60,112.30,110.52,108.22.

[0320] Example 81 Synthesis of 2-(3-cyanophenyl)-4-(difluoromethyl)-1-[2-(trifluoromethoxy)benzamido]-1H-imidazol-5-carboxylic acid (8kn9)

[0321] 8kn9 was prepared from ethyl 2-(3-cyanophenyl)-4-(difluoromethyl)-1-[2-(trifluoromethoxy)benzamido]-1H-imidazolium-5-carboxylate 7kn9 as the starting material, following the preparation method described in Example 62. White solid, yield: 58%. Mp 202.9-203.4℃. ESI-HRMS m / z calculated for C 20 H 10 F5N4O4 - [MH] - 465.0628, found 465.0695. 1H NMR (400MHz, DMSO-d6) δ14.31(s,1H),12.36(s,1H),8.20(s,1H),8.15(d,J=8.1Hz,1H),8.05(d,J= 7.8Hz,1H),7.83–7.69(m,3H),7.62(t,J=7.6Hz,1H),7.54(d,J=8.4Hz,1H),7.38(t,J=53.8Hz,1H). 13 C NMR (100MHz, DMSO-d6) δ164.60,159.20,148.24,145.69,138.41,134.26,133.62,133.34,131. 77,130.48,130.03,128.72,128.03,127.06,123.55,121.89,118.72,118.26,112.34,109.55.

[0322] Example 82 Synthesis of 2-(3-cyanophenyl)-4-(difluoromethyl)-1-(4-cyanobenzamido)-1H-imidazol-5-carboxylic acid (8kn10)

[0323] 8kn10 was prepared using ethyl 2-(3-cyanophenyl)-4-(difluoromethyl)-1-(4-cyanobenzamido)-1H-imidazolium-5-carboxylate 7kn10 as the starting material, following the preparation method described in Example 62. It was a white solid, yield: 63%. Mp 198.6-201.3℃. ESI-HRMS m / z calculated for C 20 H 10 F2N5O3 - [MH] - 406.0757, found 406.0783. 1 H NMR (400MHz, DMSO-d6) δ12.53(s,1H),8.22(s,1H),8.14(d,J=8.0Hz,1H),8.08(d,J=8.1Hz,2H ),8.03(d,J=8.2Hz,2H),8.00(d,J=7.7Hz,1H),7.75(t,J=7.9Hz,1H),7.36(t,J=53.8Hz,1H). 13C NMR(100MHz,DMSO-d6)δ165.92,159.28,148.03,138.82,138.58,135.25,134.49, 133.50,133.03,132.01,130.84,128.89,123.86,118.42,115.74,112.61,109.67.

[0324] Example 83 Synthesis of 2-(3-cyanophenyl)-4-(difluoromethyl)-1-(3-cyanobenzamido)-1H-imidazol-5-carboxylic acid (8kn11)

[0325] 8kn11 was prepared using ethyl 2-(3-cyanophenyl)-4-(difluoromethyl)-1-(3-cyanobenzamido)-1H-imidazolium-5-carboxylate 7kn11 as the starting material, following the preparation method described in Example 62. It was a white solid, yield: 69%. Mp 234.0-235.2℃. ESI-HRMS m / z calculated for C 20 H 10 F2N5O3 - [MH] - 406.0757, found 406.0818. 1 H NMR (400MHz, DMSO-d6) δ12.70(s,1H),8.36(t,J=1.8Hz,1H),8.27(t,J=1.8Hz,1H),8.23(dt,J=7.9,1.5Hz,1H),8.18(t d,J=7.8,1.5Hz,2H),8.01(dt,J=7.7,1.4Hz,1H),7.83(t,J=7.8Hz,1H),7.76(t,J=7.9Hz,1H),7.37(t,J=53.8Hz,1H). 13 C NMR(100MHz,DMSO-d6)δ165.44,159.22,148.09,138.58,136.84,134.44,133.07,132.83, 132.45,132.06,131.82,130.86,130.81,128.89,123.80,118.42,118.34,112.58,109.66.

[0326] Example 84 Synthesis of 2-(3-cyanophenyl)-4-(difluoromethyl)-1-(4-nitrobenzamido)-1H-imidazol-5-carboxylic acid (8kn12)

[0327] 8kn12 was prepared from ethyl 2-(3-cyanophenyl)-4-(difluoromethyl)-1-(4-nitrobenzamido)-1H-imidazolium-5-carboxylate 7kn12 as the starting material, following the preparation method in Example 62. It was a white solid, yield: 73%. Mp 181.2-182.9℃. ESI-HRMS m / z calculated for C 19 H 10 F2N5O5 - [MH] - 426.0655, found 426.0722. 1 H NMR(400MHz,DMSO-d6)δ14.25(s,1H),12.64(s,1H),8.50–8.37(m,2H),8.24(t,J=1.7Hz,1H), 8.21–8.10(m,3H),8.02(dt,J=7.8,1.4Hz,1H),7.77(t,J=7.9Hz,1H),7.37(t,J=53.7Hz,1H). 13 C NMR(100MHz,DMSO-d6)δ165.71,159.29,150.51,148.06,138.63,136.76,134.51, 133.04,132.02,130.84,129.68,128.88,124.62,123.78,118.42,112.64,109.68.

[0328] Example 85 Synthesis of 2-(3-cyanophenyl)-4-(difluoromethyl)-1-(3-nitrobenzamido)-1H-imidazol-5-carboxylic acid (8kn13)

[0329] 8kn13 was prepared from ethyl 2-(3-cyanophenyl)-4-(difluoromethyl)-1-(3-nitrobenzamido)-1H-imidazolium-5-carboxylate 7kn13 as the starting material, following the preparation method in Example 62. White solid, yield: 59%. Mp 187.8-187.9℃. ESI-HRMS m / z calculated for C 19 H 10 F2N5O5 - [MH] - 426.0655, found 426.0731. 1H NMR (400MHz, DMSO-d6) δ12.75(s,1H),8.73(t,J=2.0Hz,1H),8.53(ddd,J=8.3,2.3,1.0Hz,1H),8.34(dt,J=7.8,1.3Hz,1H),8.26(t,J=1 .7Hz,1H),8.17(dt,J=8.0,1.4Hz,1H),8.01(dt,J=7.8,1.4Hz,1H),7.91(t,J=8.0Hz,1H),7.75(t,J=7.9Hz,1H),7.37(t,J=53.7Hz,1H). 13 C NMR (100MHz, DMSO-d6) δ165.30,159.30,148.41,148.13,138.61,134.49,133.07,132. 72,132.06,131.39,130.83,128.89,128.03,123.78,122.86,118.41,112.63,109.67.

[0330] Example 86 Synthesis of 2-(3-cyanophenyl)-4-(difluoromethyl)-1-(2-nitrobenzamido)-1H-imidazol-5-carboxylic acid (8kn14)

[0331] 8kn14 was prepared from ethyl 2-(3-cyanophenyl)-4-(difluoromethyl)-1-(2-nitrobenzamido)-1H-imidazolium-5-carboxylate 7kn14 as the starting material, following the preparation method in Example 62. It was a white solid, yield: 63%. Mp 212.6-212.9℃. ESI-HRMS m / z calculated for C 19 H 10 F2N5O5 - [MH] - 426.0655, found 426.0734. 1 H NMR (400MHz, DMSO-d6) δ14.36(s,1H),12.63(s,1H),8.24(t,J=1.8Hz,1H),8.18(dt,J=8.0,1.5Hz,1H),8.14(dd,J=8.1,1.1Hz,1H),8.06(dt,J=7. 8,1.4Hz,1H),7.97(td,J=7.5,1.2Hz,1H),7.89(dd,J=7.7,1.5Hz,1H),7 .85(td,J=7.8,1.6Hz,1H),7.78(t,J=7.9Hz,1H),7.36(t,J=53.7Hz,1H). 13C NMR(100MHz,DMSO-d6)δ165.01,159.37,148.38,147.75,138.55,134.53,134.41,133.67, 132.97,132.07,130.61,129.66,128.75,128.70,125.21,123.75,118.55,112.49,109.70.

[0332] Example 87 Synthesis of 2-(3-cyanophenyl)-4-(difluoromethyl)-1-(4-chlorobenzamido)-1H-imidazol-5-carboxylic acid (8kn15)

[0333] 8kn15 was prepared from ethyl 2-(3-cyanophenyl)-4-(difluoromethyl)-1-(4-chlorobenzamido)-1H-imidazolium-5-carboxylate 7kn15 as the starting material, following the preparation method in Example 62. White solid, yield: 67%. Mp 192.3-192.7℃. ESI-HRMS m / z calculated for C 19 H 10 ClF2N4O3 - [MH] - 415.0415, found 415.0483. 1 H NMR (400MHz, DMSO-d6) δ12.34(s,1H),8.22(t,J=1.8Hz,1H),8.15(dt,J=7.9,1.6Hz,1H),8.00(dt,J= 7.7,1.4Hz,1H),7.95–7.88(m,2H),7.75(t,J=7.9Hz,1H),7.72–7.64(m,2H),7.36(t,J=53.8Hz,1H). 13 C NMR(100MHz,DMSO-d6)δ166.15,159.32,148.13,138.55,138.45,134.45,133.08, 132.00,130.82,130.10,130.05,129.61,129.00,124.02,118.46,112.60,109.72.

[0334] Example 88 Synthesis of 2-(3-cyanophenyl)-4-(difluoromethyl)-1-(2-chlorobenzamido)-1H-imidazol-5-carboxylic acid (8kn16)

[0335] 8KN16 was prepared using ethyl 2-(3-cyanophenyl)-4-(difluoromethyl)-1-(2-chlorobenzamido)-1H-imidazolium-5-carboxylate 7KN16 as the starting material, following the preparation method described in Example 62. It was a white solid, yield: 64%. Mp 201.8-202.1℃. ESI-HRMS m / z calculated for C 19 H 10 ClF2N4O3 - [MH] - 415.0415, found 415.0417. 1 H NMR (400MHz, DMSO-d6) δ14.34(s,1H),12.34(s,1H),8.25(t,J=1.8Hz,1H),8.18(dt,J=8.0,1.5Hz,1H),8.06(dt, J=7.8,1.4Hz,1H),7.79(t,J=7.9Hz,1H),7.67(dd,J=7.2,1.7Hz,1H),7.64–7.52(m,3H),7.37(t,J=53.7Hz,1H). 13 C NMR(100MHz,DMSO-d6)δ166.24,159.35,148.19,138.54,134.55,133.81,133.15,132.91, 132.02,130.88,130.72,130.60,129.60,128.77,127.85,123.70,118.48,112.39,109.69.

[0336] Example 89 Synthesis of 2-(3-cyanophenyl)-4-(difluoromethyl)-1-(4-bromobenzamido)-1H-imidazol-5-carboxylic acid (8kn17)

[0337] 8KN17 was prepared using ethyl 2-(3-cyanophenyl)-4-(difluoromethyl)-1-(4-bromobenzamido)-1H-imidazolium-5-carboxylate 7KN17 as the starting material, following the preparation method described in Example 62. It was a white solid with a yield of 62%. Mp 196.2-197.5℃. ESI-HRMS m / z calculated for C 19 H 10 BrF2N4O3 - [MH] - 458.9910, found 458.9955. 1H NMR (400MHz, DMSO-d6) δ14.17(s,1H),12.34(s,1H),8.22(t,J=1.8Hz,1H),8.15(dt,J=8.0,1.5 Hz,1H),8.01(dt,J=7.8,1.4Hz,1H),7.84(s,4H),7.75(t,J=7.9Hz,1H),7.36(t,J=53.7Hz,1H). 13 C NMR(100MHz,DMSO-d6)δ166.24,159.28,148.10,138.55,134.43,133.05,132.53, 131.98,130.80,130.43,130.13,128.97,127.44,123.95,118.43,112.58,109.68.

[0338] Example 90 Synthesis of 2-(3-cyanophenyl)-4-(difluoromethyl)-1-(3-bromobenzamido)-1H-imidazol-5-carboxylic acid (8kn18)

[0339] 8kn18 was prepared using ethyl 2-(3-cyanophenyl)-4-(difluoromethyl)-1-(3-bromobenzamido)-1H-imidazolium-5-carboxylate 7kn18 as the starting material, following the preparation method in Example 62. It was a white solid with a yield of 66%. It decomposed at 200°C (MP). 1 H NMR (400MHz, DMSO-d6) δ14.20(s,1H),12.38(s,1H),8.23(t,J=1.8Hz,1H),8.14(dt,J=8.0,1.4Hz,1H),8.06(t,J=1.9Hz, 1H),8.00(dt,J=7.8,1.4Hz,1H),7.94–7.85(m,2H),7.76(t,J=7.9Hz,1H),7.56(t,J=7.9Hz,1H),7.36(t,J=53.7Hz,1H). 13 C NMR(100MHz,DMSO-d6)δ165.76,159.31,148.12,138.58,136.25,134.48,133.54,133.08, 132.03,131.75,130.85,130.70,128.95,127.29,123.93,122.54,118.46,112.61,109.71.

[0340] Example 91 Synthesis of 2-(3-cyanophenyl)-4-(difluoromethyl)-1-(4-methylbenzamido)-1H-imidazol-5-carboxylic acid (8kn19)

[0341] 8kn19 was prepared using ethyl 2-(3-cyanophenyl)-4-(difluoromethyl)-1-(4-methylbenzamido)-1H-imidazolium-5-carboxylate 7kn19 as the starting material, following the preparation method described in Example 62. It was a white solid, yield: 56%. Mp 183.0-184.6℃. ESI-HRMS m / z calculated for C 20 H 13 F2N4O3 - [MH] - 395.0961, found 395.0972. 1 H NMR (400MHz, DMSO-d6) δ14.11(s,1H),12.13(s,1H),8.23(t,J=1.8Hz,1H),8.15(dt,J=8.0,1.4Hz,1H),7.9 9(dt,J=7.9,1.4Hz,1H),7.80(dd,J=8.2,1.9Hz,2H),7.74(t,J=7.9Hz,1H),7.51–7.21(m,3H),2.39(s,3H). 13 C NMR(100MHz,DMSO-d6)δ166.79,159.30,148.11,143.78,138.42,134.34,133.11,131 .93,130.75,129.87,129.09,128.56,128.12,124.22,118.45,112.49,109.71,21.56.

[0342] Example 92 Synthesis of 2-(3-cyanophenyl)-4-(difluoromethyl)-1-(3-methylbenzamido)-1H-imidazol-5-carboxylic acid (8kn20)

[0343] 8kn20 was prepared using ethyl 2-(3-cyanophenyl)-4-(difluoromethyl)-1-(3-methylbenzamido)-1H-imidazolium-5-carboxylate 7kn20 as the starting material, following the preparation method in Example 62. It was a white solid, yield: 63%. Mp 186.3-186.7℃. ESI-HRMS m / z calculated for C 20 H 13 F2N4O3 - [MH] - 395.0961, found 395.1001. 1H NMR (400MHz, DMSO-d6) δ14.11(s,1H),12.18(s,1H),8.24(t,J=1.7Hz,1H),8.16(dt,J=8.0,1.4Hz,1H),8.00(dt,J =7.8,1.4Hz,1H),7.76(t,J=7.9Hz,1H),7.72–7.66(m,2H),7.53–7.46(m,2H),7.29(t,J=53.7Hz,1H),2.40(s,3H). 13 C NMR(100MHz,DMSO-d6)δ167.03,159.28,148.12,138.82,138.45,134.37,134.02,133.12,131 .96,131.42,130.79,129.26,129.05,128.57,125.20,124.16,118.45,112.50,109.72,21.35.

[0344] Example 93 Synthesis of 2-(3-cyanophenyl)-4-(difluoromethyl)-1-(3-bromo-4-fluorobenzamido)-1H-imidazol-5-carboxylic acid (8kn21)

[0345] 8kn21 was prepared using ethyl 2-(3-cyanophenyl)-4-(difluoromethyl)-1-(3-bromo-4-fluorobenzamido)-1H-imidazolium-5-carboxylate 7kn21 as the starting material, following the preparation method described in Example 62. It was a white solid, yield: 69%. Mp 182.9-184.3℃. ESI-HRMS m / z calculated for C 19 H9BrF3N4O3 - [MH] - 478.9795, found 478.9804. 1 H NMR (400MHz, DMSO-d6) δ14.20(s,1H),12.39(s,1H),8.26–8.19(m,2H),8.13(dt,J=8.0,1.4Hz,1H),8.00(dt,J=7.8 ,1.4Hz,1H),7.96(ddd,J=8.6,4.7,2.2Hz,1H),7.75(t,J=7.9Hz,1H),7.63(t,J=8.6Hz,1H),7.35(t,J=53.7Hz,1H). 13C NMR(100MHz,DMSO-d6)δ164.95,159.28,148.10,138.55,134.46,133.56,133.04,132.01, 130.84,130.30,130.21,129.35,129.31,128.91,118.43,118.16,117.93,112.60,109.16.

[0346] Example 94 Synthesis of 2-(3-cyanophenyl)-4-(difluoromethyl)-1-(3-methyl-4-nitrobenzamido)-1H-imidazol-5-carboxylic acid (8kn22)

[0347] 8kn22 was prepared using ethyl 2-(3-cyanophenyl)-4-(difluoromethyl)-1-(3-methyl-4-nitrobenzamido)-1H-imidazolium-5-carboxylate 7kn22 as the starting material, following the preparation method described in Example 62. It was a white solid with a yield of 65%. Mp 196.5-198.1℃. ESI-HRMS m / z calculated for C 20 H 12 F2N5O5 - [MH] - 440.0812, found 440.0832. 1 H NMR (400MHz, DMSO-d6) δ14.28(s,1H),12.53(s,1H),8.23(s,1H),8.18(d,J=8.5Hz,1H),8.14(d,J=7.9Hz,1H),8.0 1(d,J=7.8Hz,1H),7.97(s,1H),7.92(d,J=8.5Hz,1H),7.76(t,J=7.9Hz,1H),7.36(t,J=53.7Hz,1H),2.57(s,3H). 13 C NMR(100MHz,DMSO-d6)δ165.60,159.24,151.85,148.00,135.01,134.45,133.72,132.99, 132.51,131.98,130.86,130.82,128.84,126.90,125.44,123.81,118.40,112.58,19.63.

[0348] Example 95 Synthesis of 2-(3-cyanophenyl)-4-(difluoromethyl)-1-(2-fluoro-4-nitrobenzamido)-1H-imidazol-5-carboxylic acid (8kn23)

[0349] 8kn23 was prepared from ethyl 2-(3-cyanophenyl)-4-(difluoromethyl)-1-(2-fluoro-4-nitrobenzamido)-1H-imidazolium-5-carboxylate 7kn23 as the starting material, following the preparation method in Example 62. It was a white solid with a yield of 60%. It decomposed at 200°C. ESI-HRMS m / z calculated for C 19 H9F3N5O5 - [MH] - 444.0561, found 444.0558. 1 H NMR (400MHz, DMSO-d6) δ14.35(s,1H),12.60(s,1H),8.35(dd,J=9.8,2.2Hz,1H),8.27(dd,J=8.5,2.2Hz,1H),8.24(t,J=1.8H z,1H),8.18(dt,J=8.0,1.4Hz,1H),8.05(dt,1H),7.91(dd,J=8.5,6.8Hz,1H),7.79(t,J=7.9Hz,1H),7.37(t,J=53.7Hz,1H).

[0350] Example 96 Synthesis of 2-(3-cyanophenyl)-4-(difluoromethyl)-1-(2-chloro-4-nitrobenzamido)-1H-imidazol-5-carboxylic acid (8kn24)

[0351] 8kn24 was prepared from ethyl 2-(3-cyanophenyl)-4-(difluoromethyl)-1-(2-chloro-4-nitrobenzamido)-1H-imidazolium-5-carboxylate 7kn24 as the starting material, following the preparation method in Example 62. White solid, yield: 67%. Mp 200.5-200.7℃. ESI-HRMS m / z calculated for C 19 H9ClF2N5O5 - [MH] - 460.0266,found460.0263.ESI-MS m / z:462.0[M+H] + . 1H NMR (400MHz, DMSO-d6) δ12.70(s,1H),8.46(d,J=2.1Hz,1H),8.44(dd,J=8.3,2.2Hz,1H),8.24(t,J=1.7Hz,1H),8.19(d t,J=8.0,1.4Hz,1H),8.08(dt,J=7.8,1.4Hz,1H),7.92(d,J=8.3Hz,1H),7.81(t,J=7.9Hz,1H),7.39(t,J=53.7Hz,1H). 13 C NMR (100MHz, DMSO-d6) δ165.09,159.40,149.69,148.19,138.69,138.61,134.65,133. 80,132.08,131.97,130.77,128.63,125.55,123.43,123.23,118.46,112.44,109.68.

[0352] Example 97 Synthesis of 2-(3-cyanophenyl)-4-(difluoromethyl)-1-(3-chloro-4-nitrobenzamido)-1H-imidazol-5-carboxylic acid (8kn25)

[0353] 8kn25 was prepared from ethyl 2-(3-cyanophenyl)-4-(difluoromethyl)-1-(3-chloro-4-nitrobenzamido)-1H-imidazolium-5-carboxylate 7kn25 as the starting material, following the preparation method in Example 62. White solid, yield: 60%. Mp 195.1-197.4℃. ESI-HRMS m / z calculated for C 19 H9ClF2N5O5 - [MH] - 460.0266, found 460.0319. 1 H NMR (400MHz, DMSO-d6) δ12.67(s,1H),8.31(d,J=8.4Hz,1H),8.23(t,J=1.7Hz,1H),8.20(d,J=1.8Hz,1H),8.15(dt,J=8 .1,1.4Hz,1H),8.05(dd,J=8.4,1.8Hz,1H),8.01(dt,J=7.8,1.4Hz,1H),7.75(t,J=7.9Hz,1H),7.37(t,J=53.7Hz,1H). 13C NMR(100MHz,DMSO-d6)δ164.63,159.32,150.35,147.93,138.55,135.86,134.50,133.00, 132.04,131.14,130.87,128.81,128.46,126.89,126.06,123.80,118.43,112.66,109.66.

[0354] Example 98 Synthesis of 2-(3-cyanophenyl)-4-(difluoromethyl)-1-(2-bromo-4-nitrobenzamido)-1H-imidazol-5-carboxylic acid (8kn26)

[0355] 8kn26 was prepared from ethyl 2-(3-cyanophenyl)-4-(difluoromethyl)-1-(2-bromo-4-nitrobenzamido)-1H-imidazolium-5-carboxylate 7kn26 as the starting material, following the preparation method in Example 62. It was a white solid with a yield of 50%. It decomposed at 200°C. ESI-HRMS m / z calculated for C 19 H9BrF2N5O5 - [MH] - 505.9740, found 505.9748. 1 H NMR (400MHz, DMSO-d6) δ12.65(s,1H),8.55(d,J=2.2Hz,1H),8.47(dd,J=8.5,2.1Hz,1H),8.24(t,J=1.7Hz,1H),8.18(d t,J=8.0,1.4Hz,1H),8.06(dt,J=7.8,1.4Hz,1H),7.92(d,J=8.4Hz,1H),7.80(t,J=7.9Hz,1H),7.38(t,J=53.7Hz,1H). 13 C NMR (150MHz, DMSO-d6) δ165.77,159.47,149.60,148.26,140.74,138.57,134.70,133. 84,132.21,130.82,130.77,128.65,128.53,123.64,120.20,118.58,112.54,109.73.

[0356] Example 99 Synthesis of 2-(3-cyanophenyl)-4-(difluoromethyl)-1-(4-methoxybenzamido)-1H-imidazol-5-carboxylic acid (8kn27)

[0357] 8KN27 was prepared using ethyl 2-(3-cyanophenyl)-4-(difluoromethyl)-1-(4-methoxybenzamido)-1H-imidazolium-5-carboxylate 7KN27 as the starting material, following the preparation method described in Example 62. It was a white solid, yield: 59%. Mp 188.2-188.5℃. ESI-HRMS m / z calculated for C 20 H 13 F2N4O4 - [MH] - 411.0910, found 411.0906. 1 H NMR (400MHz, DMSO-d6) δ14.09(s,1H),12.05(s,1H),8.23(s,1H),8.16(d,J=8.0Hz,1H),7.99(d,J=7.8 Hz,1H),7.89(d,J=8.4Hz,2H),7.75(s,1H),7.36(t,J=53.8Hz,1H),7.12(d,J=8.4Hz,2H),3.85(s,3H). 13 C NMR(100MHz,DMSO-d6)δ166.37,163.38,159.33,148.17,138.39,134.32,133.12,131 .95,130.74,130.18,129.15,124.30,123.40,118.47,114.65,112.48,109.74,56.03.

[0358] Example 100 Synthesis of 2-(3-cyanophenyl)-4-(difluoromethyl)-1-(3,5-dichloro-4-methoxybenzamido)-1H-imidazol-5-carboxylic acid (8kn28)

[0359] 8kn28 was prepared from ethyl 2-(3-cyanophenyl)-4-(difluoromethyl)-1-(3,5-dichloro-4-methoxybenzamido)-1H-imidazolium-5-carboxylate 7kn28 as the starting material, following the preparation method in Example 62. It was a white solid, yield: 68%. Mp 188.8-189.9℃. ESI-HRMS m / z calculated for C 20 H 11 Cl2F2N4O4 - [MH] - 479.0131, found 479.0169. 1H NMR (400MHz, DMSO-d6) δ12.43(s,1H),8.24(t,J=1.6Hz,1H),8.14(dt,J=8.2,1.3Hz ,1H),8.05–7.97(m,3H),7.76(t,J=7.9Hz,1H),7.36(t,J=53.8Hz,1H),3.93(s,3H). 13 C NMR(100MHz,DMSO-d6)δ164.39,159.27,155.72,148.09,138.55,134.46,133.01,132 .05,130.85,129.54,129.12,128.86,128.73,123.81,118.44,112.61,109.66,61.46.

[0360] Example 101 Synthesis of 2-(3-cyanophenyl)-4-(difluoromethyl)-1-(3,5-dichloro-4-hydroxybenzamido)-1H-imidazol-5-carboxylic acid (8kn29)

[0361] 8kn29 was prepared using ethyl 2-(3-cyanophenyl)-4-(difluoromethyl)-1-(3,5-dichloro-4-hydroxybenzamido)-1H-imidazolium-5-carboxylate 7kn29 as the starting material, following the preparation method described in Example 62. It was a white solid, yield: 62%. Mp 244.0-245.3℃. ESI-HRMS m / z calculated for C 19 H9Cl2F2N4O4 - [MH] - 464.9974, found 465.0010. 1 H NMR(400MHz,DMSO-d6)δ12.20(s,1H),8.21(s,1H),8.12(d,J=8.0Hz,1H),7.9 9(d,J=7.6Hz,1H),7.90(s,2H),7.74(t,J=7.9Hz,1H),7.36(t,J=53.8Hz,1H). 13 CNMR(150MHz,DMSO-d6)δ164.67,159.35,153.89,148.04,138.37,134.40,133.03, 132.02,130.84,129.01,128.76,124.19,123.30,122.85,118.47,112.58,109.73.

[0362] Example 102 Synthesis of 2-(3-cyanophenyl)-4-(difluoromethyl)-1-(3,5-dichloro-4-aminobenzamido)-1H-imidazol-5-carboxylic acid (8kn30)

[0363] Starting with ethyl 2-(3-cyanophenyl)-4-(difluoromethyl)-1-(3,5-dichloro-4-aminobenzamido)-1H-imidazolium-5-carboxylate 7kn30, 8kn30 was prepared according to the preparation method in Example 62. White solid, yield: 69%. Decomposed at 200°C. ESI-HRMS m / z calculated for C 19 H 10 Cl2F2N5O3 - [MH] - 464.0134, found 464.0152. 1 H NMR (400MHz, DMSO-d6) δ14.10(s,1H),11.99(s,1H),8.21(t,J=1.8Hz,1H),8.11(dt,J=8.0,1.5Hz,1H) ,7.99(dt,J=7.8,1.4Hz,1H),7.80(s,2H),7.74(t,J=7.9Hz,1H),7.34(t,J=53.8Hz,1H),6.45(s,2H). 13 C NMR(150MHz,DMSO-d6)δ164.85,159.30,148.19,145.87,138.34,134.38,133.05, 132.02,130.81,129.07,128.31,124.11,118.53,118.48,117.83,112.54,109.72.

[0364] Example 103 Synthesis of 1-difluoromethyl-3-(3-cyanophenyl)-6-phenylimidazo[1,5-a]pyrazine-8(7H)-one (7kab1)

[0365] 6 kJ of ethyl 2-(3-cyanophenyl)-4-(difluoromethyl)-1-(2-phenyl-2-oxoethyl)-1H-imidazolium-5-carboxylate (120 mg, 0.29 mmol) was dissolved in a sealed tube containing 3 mL of methanol (25 times the volume). Ammonium acetate (226 mg, 2.9 mmol, 10 times the volume) was then added, and the mixture was heated to 95 °C. After the reaction was complete, the reaction solution was cooled to room temperature, and then 9 mL of ice water was added. The mixture was stirred at room temperature for 30 minutes, then filtered. The filter cake was washed twice with water, dried, and the crude product was subjected to hot methanol slurrying. The resulting final product, 7 kJ, was obtained as a white solid, after filtration and drying. Yield: 80%. Mp > 300 °C. ESI-HRMS m / z calculated for C 20 H 11 F2N4O - [MH] - 361.0906, found 361.0923. 1 H NMR (400MHz, DMSO-d6) δ11.62(s,1H),8.33(t,J=1.8Hz,1H),8.21(dt,J=8.0,1.4Hz,1H), 8.04(dt,J=7.8,1.3Hz,1H),7.79(t,J=7.9Hz,1H),7.76–7.70(m,2H),7.67–7.36(m,5H). 13 C NMR(150MHz,DMSO-d6)δ155.96,141.55,134.08,134.02,132.71,131.62,131.10,130 .87,130.09,129.91,129.19,127.73,122.47,118.80,112.86,109.67,102.41,70.25.

[0366] Example 104 Synthesis of 1-difluoromethyl-3-(3-cyanophenyl)-6-(4-fluorophenyl)imidazo[1,5-a]pyrazine-8(7H)-one (7kab2)

[0367] Starting from ethyl 2-(3-cyanophenyl)-4-(difluoromethyl)-1-[2-(4-fluorophenyl)-2-oxoethyl]-1H-imidazolium-5-carboxylate 6ka2, 7kab2 was prepared according to the synthesis method in Example 103. White solid, yield: 52%. Mp > 300℃. ESI-HRMS m / z calculated for C 20 H 10 F3N4O - [MH] -379.0812, found 379.0806. 1 HNMR (400MHz, DMSO-d6) δ11.64(s,1H),8.33(t,J=1.7Hz,1H),8.21(dt,J=8.0,1.4Hz,1H),8.04( dt,J=7.8,1.3Hz,1H),7.85–7.72(m,3H),7.66(s,1H),7.51(t,J=54.0Hz,1H),7.37–7.31(m,2H). 13 C NMR (150MHz, DMSO-d6) δ164.15,162.51,155.89,141.56,134.10,134.03,132.69,130. 86,130.26,130.20,129.88,128.10,118.80,116.18,116.03,112.85,109.65,102.51.

[0368] Example 105 Synthesis of 1-difluoromethyl-3-(3-cyanophenyl)-6-(3-fluorophenyl)imidazo[1,5-a]pyrazine-8(7H)-one (7kab3)

[0369] Starting from ethyl 2-(3-cyanophenyl)-4-(difluoromethyl)-1-[2-(3-fluorophenyl)-2-oxoethyl]-1H-imidazolium-5-carboxylate 6ka3, 7kab3 was prepared according to the synthesis method in Example 103. White solid, yield: 62%. Mp > 300℃. ESI-HRMS m / z calculated for C 20 H 10 F3N4O - [MH] - 379.0812, found 379.0810. 1 HNMR (400MHz, DMSO-d6) δ11.65(s,1H),8.34(t,J=1.7Hz,1H),8.21(d,J=7.9Hz,1H),8.05(d ,J=7.8Hz,1H),7.80(t,J=7.8Hz,1H),7.76(s,1H),7.68–7.36(m,4H),7.32(t,J=8.1Hz,1H). 13C NMR (150MHz, DMSO-d6) δ163.34,161.72,155.84,141.77,134.14,133.78,132.75,131.25,131. 19,130.85,129.80,123.90,122.47,118.81,116.93,114.85,114.69,112.85,109.62,103.21.

[0370] Example 106 Synthesis of 1-difluoromethyl-3-(3-cyanophenyl)-6-(2-fluorophenyl)imidazo[1,5-a]pyrazine-8(7H)-one (7kab4)

[0371] Starting from ethyl 2-(3-cyanophenyl)-4-(difluoromethyl)-1-[2-(2-fluorophenyl)-2-oxoethyl]-1H-imidazolium-5-carboxylate 6ka4, 7kab4 was prepared according to the synthesis method in Example 103. White solid, yield: 43%. Mp > 300℃. ESI-HRMS m / z calculated for C 20 H 10 F3N4O - [MH] - 379.0812, found 379.0806. 1 HNMR (400MHz, DMSO-d6) δ11.66(s,1H),8.29(s,1H),8.18(d,J=8.8Hz,1H),8.02(d,J=8.4Hz,1H),7.83–7.46(m,5H),7.41–7.24(m,2H). 13 C NMR (100MHz, DMSO-d6) δ158.87,155.42,141.53,134.00,132.58,131.65,130.78,129.71,125. 86,125.10,125.07,122.46,119.97,119.83,118.69,116.51,116.30,112.77,109.58,104.51.

[0372] Example 107 Synthesis of 1-difluoromethyl-3-(3-cyanophenyl)-6-[4-(trifluoromethyl)phenyl]imidazo[1,5-a]pyrazin-8(7H)-one (7kab5)

[0373] Starting from ethyl 2-(3-cyanophenyl)-4-(difluoromethyl)-1-{2-[4-(trifluoromethyl)phenyl]-2-oxoethyl}-1H-imidazolium-5-carboxylate 6ka5, 7kab5 was prepared according to the synthesis method in Example 103. White solid, yield: 56%. Mp > 300℃. ESI-HRMS m / z calculated for C 21 H 10 F5N4O - [MH] - 429.0780, found 429.0762. 1 H NMR (400MHz, DMSO-d6) δ11.77(s,1H),8.34(t,J=1.8Hz,1H),8.21(dt,J=8.0,1.4Hz,1H),8.05(dt,J=7 .8,1.3Hz,1H),7.95(d,J=8.2Hz,2H),7.86(d,J=8.3Hz,2H),7.83–7.76(m,2H),7.52(t,J=53.8Hz,1H). 13 C NMR(100MHz,DMSO-d6)δ155.72,141.70,135.52,134.88,133.98,133.93,132.54,130.68, 130.10,129.78,129.61,129.56,128.58,125.82,125.79,122.32,118.61,112.69,103.67.

[0374] Example 108 Synthesis of 1-difluoromethyl-3-(3-cyanophenyl)-6-[3-(trifluoromethyl)phenyl]imidazo[1,5-a]pyrazin-8(7H)-one (7kab6)

[0375] 7kab6 was prepared from ethyl 2-(3-cyanophenyl)-4-(difluoromethyl)-1-{2-[3-(trifluoromethyl)phenyl]-2-oxoethyl}-1H-imidazolium-5-carboxylate 6ka6 as the starting material, following the synthetic method described in Example 103. White solid, yield: 63%. Mp > 300℃. ESI-HRMS m / z calculated for C 21 H 10 F5N4O - [MH] - 429.0780, found 429.0766. 1H NMR (400MHz, DMSO-d6) δ11.77(s,1H),8.34(t,J=1.7Hz,1H),8.21(dt,J=8.1,1.4Hz,1H),8.0 9(s,1H),8.07–8.00(m,2H),7.87–7.76(m,3H),7.73(t,J=7.8Hz,1H),7.52(t,J=53.8Hz,1H). 13 C NMR(100MHz,DMSO-d6)δ155.84,141.80,134.11,134.05,132.69,132.64,132.01,132.00, 130.83,130.22,130.00,129.81,129.67,126.58,124.70,118.76,112.83,109.62,103.59.

[0376] Example 109 Synthesis of 1-difluoromethyl-3-(3-cyanophenyl)-6-[2-(trifluoromethyl)phenyl]imidazo[1,5-a]pyrazin-8(7H)-one (7kab7)

[0377] Starting from ethyl 2-(3-cyanophenyl)-4-(difluoromethyl)-1-{2-[2-(trifluoromethyl)phenyl]-2-oxoethyl}-1H-imidazolium-5-carboxylate 6ka7, 7kab7 was prepared according to the synthesis method in Example 103. White solid, yield: 45%. Mp > 300℃. ESI-HRMS m / z calculated for C 21 H 10 F5N4O - [MH] - 429.0780, found 429.0744. 1 H NMR (400MHz, DMSO-d6) δ11.66(s,1H),8.18(t,J=1.6Hz,1H),8.12(dt,J=7.9,1.6Hz,1H ),8.00(dt,J=7.8,1.3Hz,1H),7.92–7.87(m,1H),7.84–7.69(m,4H),7.67–7.35(m,2H). 13 C NMR (100MHz, DMSO-d6) δ155.08,141.34,135.11,135.08,134.05,133.81,133.31,132. 94,132.34,130.90,130.11,130.06,129.38,128.15,126.71,126.60,118.65,112.72.

[0378] Example 110 Synthesis of 1-difluoromethyl-3-(3-cyanophenyl)-6-[4-(trifluoromethoxy)phenyl]imidazo[1,5-a]pyrazin-8(7H)-one (7kab8)

[0379] Starting from ethyl 2-(3-cyanophenyl)-4-(difluoromethyl)-1-{2-[4-(trifluoromethoxy)phenyl]-2-oxoethyl}-1H-imidazolium-5-carboxylate 6ka8, 7kab8 was prepared according to the synthesis method in Example 103. White solid, yield: 51%. Mp > 300℃. ESI-HRMS m / z calculated for C 21 H 10 F5N4O2 - [MH] - 445.0729, found 445.0721. 1 H NMR (400MHz, DMSO-d6) δ11.67(s,1H),8.33(t,J=1.7Hz,1H),8.20(dt,J=8.0,1.4Hz,1H),8.03(dt,J =7.7,1.4Hz,1H),7.85(dd,J=6.6,2.1Hz,2H),7.78(t,J=7.9Hz,1H),7.72(s,1H),7.67–7.32(m,3H). 13 C NMR(100MHz,DMSO-d6)δ155.83,149.51,141.65,134.96,134.07,134.01,132.64,130.93, 130.80,130.04,129.81,129.78,122.41,121.63,119.19,118.75,112.82,109.59,103.10.

[0380] Example 111 Synthesis of 1-difluoromethyl-3-(3-cyanophenyl)-6-[3-(trifluoromethoxy)phenyl]imidazo[1,5-a]pyrazin-8(7H)-one (7kab9)

[0381] Starting from ethyl 2-(3-cyanophenyl)-4-(difluoromethyl)-1-{2-[3-(trifluoromethoxy)phenyl]-2-oxoethyl}-1H-imidazolium-5-carboxylate 6ka9, 7kab9 was prepared according to the synthesis method in Example 103. White solid, yield: 58%. Mp > 300℃. ESI-HRMS m / z calculated for C 21 H 10 F5N4O2- [MH] - 445.0729, found 445.0712. 1 H NMR (400MHz, DMSO-d6) δ11.71 (s, 1H), 8.34 (t, J = 1.7Hz, 1H), 8.24–8.19 (m, 1H), 8. 04(dt,J=7.8,1.3Hz,1H),7.82–7.75(m,4H),7.66–7.62(m,1H),7.62–7.36(m,2H). 13 C NMR(100MHz,DMSO-d6)δ155.83,148.89,141.79,134.99,134.12,134.05,133.85,132.69,131.16, 130.83,129.79,129.46,126.99,122.36,121.79,120.65,120.40,119.24,118.76,112.82,103.51.

[0382] Example 112 Synthesis of 1-difluoromethyl-3-(3-cyanophenyl)-6-[2-(trifluoromethoxy)phenyl]imidazo[1,5-a]pyrazin-8(7H)-one (7kab10)

[0383] Starting from ethyl 2-(3-cyanophenyl)-4-(difluoromethyl)-1-{2-[2-(trifluoromethoxy)phenyl]-2-oxoethyl}-1H-imidazolium-5-carboxylate 6ka10, 7kab10 was prepared according to the synthesis method in Example 103. White solid, yield: 46%. Mp > 300℃. ESI-HRMS m / z calculated for C 21 H 10 F5N4O2 - [MH] - 445.0729, found 445.0716. 1 H NMR (400MHz, DMSO-d6) δ11.67(s,1H),8.25(t,J=1.7Hz,1H),8.16(dt,J=8.0,1.5Hz,1H),8.02(dt,J =7.8,1.4Hz,1H),7.77(t,J=7.9Hz,1H),7.71(dd,J=7.8,1.8Hz,1H),7.68(s,1H),7.66–7.37(m,4H). 13C NMR(100MHz,DMSO-d6)δ155.28,146.68,141.53,135.05,134.01,133.96,132.63,132.50,132.13, 130.77,129.60,127.91,126.55,125.31,122.44,121.26,119.08,118.66,112.77,109.58,104.61.

[0384] Example 113 Synthesis of 1-difluoromethyl-3-(3-cyanophenyl)-6-(4-chlorophenyl)imidazo[1,5-a]pyrazine-8(7H)-one (7kab11)

[0385] Starting from ethyl 2-(3-cyanophenyl)-4-(difluoromethyl)-1-[2-(4-chlorophenyl)-2-oxoethyl]-1H-imidazolium-5-carboxylate 6ka11, 7kab11 was prepared according to the synthesis method in Example 103. White solid, yield: 76%. Mp > 300℃. ESI-HRMS m / z calculated for C 20 H 10 ClF2N4O - [MH] - 395.0517, found 395.0502. 1 H NMR (400MHz, DMSO-d6) δ11.64(s,1H),8.32(t,J=2.0Hz,1H),8.20(dt,J=8.1,1.6Hz,1H),8.03( dt,J=8.1,1.4Hz,1H),7.79(t,J=7.7Hz,1H),7.77–7.72(m,2H),7.69(s,1H),7.65–7.35(m,3H). 13 C NMR (100MHz, DMSO-d6) δ155.86,141.64,134.77,134.08,134.03,132.69,132. 67,130.83,130.45,129.97,129.81,129.63,129.11,118.76,112.82,102.84.

[0386] Example 114 Synthesis of 1-difluoromethyl-3-(3-cyanophenyl)-6-(3-chlorophenyl)imidazo[1,5-a]pyrazine-8(7H)-one (7kab12)

[0387] Starting from ethyl 2-(3-cyanophenyl)-4-(difluoromethyl)-1-[2-(3-chlorophenyl)-2-oxoethyl]-1H-imidazolium-5-carboxylate 6ka12, 7kab12 was prepared according to the synthesis method in Example 103. White solid, yield: 54%. Mp > 300℃. ESI-HRMS m / z calculated for C 20 H 10 ClF2N4O - [MH] - 395.0517, found 395.0515. 1 H NMR (400MHz, DMSO-d6) δ11.65(s,1H),8.34(t,J=1.7Hz,1H),8.21(dt,J=7.9,1.4Hz,1H),8.04(dt,J=7.7,1.3Hz ,1H),7.84(t,J=2.0Hz,1H),7.80(t,J=7.8Hz,1H),7.76(s,1H),7.70(dt,J=6.8,1.9Hz,1H),7.66–7.36(m,3H). 13 C NMR (100MHz, DMSO-d6) δ155.82,141.78,135.01,134.15,134.06,133.87,133.67,132.74,130. 96,130.85,129.89,129.83,129.69,127.65,126.57,122.48,118.81,112.85,109.63,103.31.

[0388] Example 115 Synthesis of 1-difluoromethyl-3-(3-cyanophenyl)-6-(2-chlorophenyl)imidazo[1,5-a]pyrazine-8(7H)-one (7kab13)

[0389] Starting from ethyl 2-(3-cyanophenyl)-4-(difluoromethyl)-1-[2-(2-chlorophenyl)-2-oxoethyl]-1H-imidazolium-5-carboxylate 6ka13, 7kab13 was prepared according to the synthesis method in Example 103. White solid, yield: 21%. Mp > 300℃. ESI-HRMS m / z calculated for C 20 H 10 ClF2N4O - [MH] - 395.0517, found 395.0526.

[0390] Example 116 Synthesis of 1-difluoromethyl-3-(3-cyanophenyl)-6-(4-bromophenyl)imidazo[1,5-a]pyrazine-8(7H)-one (7kab14)

[0391] 7kab14 was prepared from ethyl 2-(3-cyanophenyl)-4-(difluoromethyl)-1-[2-(4-bromophenyl)-2-oxoethyl]-1H-imidazolium-5-carboxylate 6ka14 as the starting material, following the synthetic method described in Example 103. White solid, yield: 55%. Mp > 300℃. ESI-HRMS m / z calculated for C 20 H 10 BrF2N4O - [MH] - 440.9991, found 440.9990. 1 H NMR (400MHz, DMSO-d6) δ11.66(s,1H),8.33(s,1H),8.20(d,J=7.9Hz,1H),8.04(d ,J=7.8Hz,1H),7.79(t,J=7.9Hz,1H),7.75–7.65(m,5H),7.51(t,J=53.8Hz,1H). 13 C NMR(100MHz,DMSO-d6)δ155.84,141.62,134.05,134.00,132.64,132.01, 130.80,130.02,129.84,129.79,123.42,122.38,118.73,112.80,102.7.

[0392] Example 117 Synthesis of 1-difluoromethyl-3-(3-cyanophenyl)-6-(3-bromophenyl)imidazo[1,5-a]pyrazine-8(7H)-one (7kab15)

[0393] Starting from ethyl 2-(3-cyanophenyl)-4-(difluoromethyl)-1-[2-(3-bromophenyl)-2-oxoethyl]-1H-imidazolium-5-carboxylate 6ka15, 7kab15 was prepared according to the synthesis method in Example 103. White solid, yield: 50%. Mp > 300℃. ESI-HRMS m / z calculated for C 20 H 10 BrF2N4O - [MH] - 440.9991, found 440.9992. 1H NMR (400MHz, DMSO-d6) δ11.65(s,1H),8.34(t,J=1.7Hz,1H),8.21(dt,J=8.1,1.4Hz,1H),8.04(dt,J=7.8,1.3Hz,1H),7.96(t, J=1.9Hz,1H),7.80(t,J=7.9Hz,1H),7.76(s,1H),7.73(dt,J=8.0,1.3Hz,1H),7.68(dt,J=8.2,1.1Hz,1H),7.65–7.36(m,2H). 13 C NMR (100MHz, DMSO-d6) δ155.81,141.78,135.00,134.15,134.06,133.90,132.79,132.73,131. 18,130.86,130.42,129.84,129.61,126.97,122.48,122.38,118.81,112.85,109.63,103.32.

[0394] Example 118 Synthesis of 1-difluoromethyl-3-(3-cyanophenyl)-6-(2-bromophenyl)imidazo[1,5-a]pyrazine-8(7H)-one (7kab16)

[0395] 7kab16 was prepared from ethyl 2-(3-cyanophenyl)-4-(difluoromethyl)-1-[2-(2-bromophenyl)-2-oxoethyl]-1H-imidazolium-5-carboxylate 6ka16 as the starting material, following the synthetic method described in Example 103. White solid, yield: 50%. Mp > 300℃. ESI-HRMS m / z calculated for C 20 H 10 BrF2N4O - [MH] - 440.9991, found 440.9996. 1 H NMR (400MHz, DMSO-d6) δ11.62(s,1H),8.26(s,1H),8.16(s,1H),8.01(s,1H),7.83–7.36(m,7H). 13 C NMR (100MHz, DMSO-d6) δ155.22,141.46,135.01,133.94,133.16,133.09,132.79,132. 50,132.02,132.00,130.74,130.22,129.57,128.19,123.75,118.69,112.77,104.35.

[0396] Example 119 Synthesis of 1-difluoromethyl-3-(3-cyanophenyl)-6-(4-cyanophenyl)imidazo[1,5-a]pyrazine-8(7H)-one (7kab17)

[0397] 7kab17 was prepared from ethyl 2-(3-cyanophenyl)-4-(difluoromethyl)-1-[2-(4-cyanophenyl)-2-oxoethyl]-1H-imidazolium-5-carboxylate 6ka17 as the starting material, following the synthetic method described in Example 103. White solid, yield: 59%. Mp > 300℃. ESI-HRMS m / z calculated for C 21 H 10 F2N5O - [MH] - 386.0859, found 386.0864. 1 H NMR (400MHz, DMSO-d6) δ11.75(s,1H),8.34(t,J=1.6Hz,1H),8.21(dt,J=7.9,1.5Hz,1H),8.05(dt ,J=7.8,1.3Hz,1H),8.00–7.91(m,4H),7.83(s,1H),7.80(t,J=7.9Hz,1H),7.51(t,J=53.8Hz,1H). 13 C NMR(100MHz,DMSO-d6)δ155.85,142.00,136.08,134.19,134.12,132.99,132.76,130.86, 129.74,129.48,128.63,122.47,118.92,118.79,112.87,112.40,109.60,107.29,104.23.

[0398] Example 120 Synthesis of 1-difluoromethyl-3-(3-cyanophenyl)-6-(3-cyanophenyl)imidazo[1,5-a]pyrazine-8(7H)-one (7kab18)

[0399] 7kab18 was prepared from ethyl 2-(3-cyanophenyl)-4-(difluoromethyl)-1-[2-(3-cyanophenyl)-2-oxoethyl]-1H-imidazolium-5-carboxylate 6ka18 as the starting material, following the synthetic method described in Example 103. White solid, yield: 52%. Mp > 300℃. ESI-HRMS m / z calculated for C 21 H 10 F2N5O - [MH] -386.0859, found 386.0866. 1 H NMR (400MHz, DMSO-d6) δ11.70(s,1H),8.34(s,1H),8.25(s,1H),8.21(d,J=7.9Hz,1H),8.10–8.01(m,2H) ,7.94(d,J=8.2Hz,1H),7.84(s,1H),7.80(t,J=7.9Hz,1H),7.70(t,J=7.9Hz,1H),7.51(t,J=53.8Hz,1H). 13 C NMR(100MHz,DMSO-d6)δ161.69,154.72,140.80,134.01,133.10,133.02,132.38,131.70,131.66, 131.52,130.55,129.77,129.22,128.68,128.17,117.79,117.73,111.78,111.17,108.54,102.65.

[0400] Example 121 Synthesis of 1-difluoromethyl-3-(3-cyanophenyl)-6-(4-methoxyphenyl)imidazo[1,5-a]pyrazine-8(7H)-one (7kab19)

[0401] Starting from ethyl 2-(3-cyanophenyl)-4-(difluoromethyl)-1-[2-(4-methoxyphenyl)-2-oxoethyl]-1H-imidazolium-5-carboxylate 6ka19, 7kab19 was prepared according to the synthesis method in Example 103. White solid, yield: 73%. Mp > 300℃. ESI-HRMS m / z calculated for C 21 H 13 F2N4O2 - [MH] - 391.1012, found 391.1022. 1 H NMR (400MHz, DMSO-d6) δ11.55(s,1H),8.33(t,J=1.7Hz,1H),8.20(dt,J=7.9,1.5Hz,1H),8.03(dt,J=7.8,1.4Hz,1 H),7.79(t,J=7.9Hz,1H),7.67(dd,J=6.7,2.2Hz,2H),7.65–7.35(m,2H),7.04(dd,J=6.8,2.2Hz,2H),3.81(s,3H). 13C NMR(100MHz,DMSO-d6)δ160.85,155.96,141.30,134.85,134.01,133.95,132.64,130.95, 130.86,130.00,129.12,123.80,122.38,118.79,114.60,112.86,109.69,101.38,55.85.

[0402] Example 122 Synthesis of 1-difluoromethyl-3-(3-cyanophenyl)-6-(2-methoxyphenyl)imidazo[1,5-a]pyrazin-8(7H)-one (7kab20)

[0403] Starting from ethyl 2-(3-cyanophenyl)-4-(difluoromethyl)-1-[2-(2-methoxyphenyl)-2-oxoethyl]-1H-imidazolium-5-carboxylate 6ka20, 7kab20 was prepared according to the synthesis method in Example 103. White solid, yield: 49%. Mp > 300℃. ESI-HRMS m / z calculated for C 21 H 13 F2N4O2 - [MH] - 391.1012, found 391.1026. 1 H NMR (400MHz, DMSO-d6) δ11.38(s,1H),8.28(s,1H),8.17(d,J=7.9Hz,1H),8.01(d,J=7.6Hz,1H),7 .77(t,J=7.9Hz,1H),7.68–7.33(m,4H),7.14(d,J=8.2Hz,1H),7.03(t,J=7.5Hz,1H),3.83(s,3H). 13 C NMR(100MHz,DMSO-d6)δ157.69,155.31,141.19,133.90,132.51,131.74,131.10,130.78,12 9.8,128.86,120.78,120.59,119.44,118.70,112.75,111.96,103.60,103.58,97.80,56.04.

[0404] Example 123 Synthesis of 1-difluoromethyl-3-(3-cyanophenyl)-6-(4-methylphenyl)imidazo[1,5-a]pyrazine-8(7H)-one (7kab21)

[0405] Starting from ethyl 2-(3-cyanophenyl)-4-(difluoromethyl)-1-[2-(4-methylphenyl)-2-oxoethyl]-1H-imidazolium-5-carboxylate 6ka21, 7kab21 was prepared according to the synthesis method in Example 103. White solid, yield: 76%. Mp > 300℃. ESI-HRMS m / z calculated for C 21 H 13 F2N4O - [MH] - 375.1063, found 375.1053. 1 H NMR (400MHz, DMSO-d6) δ11.59(s,1H),8.33(t,J=1.7Hz,1H),8.20(dt,J=7.9,1.4Hz,1H),8.04(dt ,J=7.9,1.4Hz,1H),7.79(t,J=7.8Hz,1H),7.67–7.35(m,4H),7.30(d,J=7.9Hz,2H),2.36(s,3H).

[0406] Example 124 Synthesis of 1-difluoromethyl-3-(3-cyanophenyl)-6-(3-methylphenyl)imidazo[1,5-a]pyrazin-8(7H)-one (7kab22)

[0407] 7kab22 was prepared from ethyl 2-(3-cyanophenyl)-4-(difluoromethyl)-1-[2-(3-methylphenyl)-2-oxoethyl]-1H-imidazolium-5-carboxylate 6ka22 as the starting material, following the synthetic method of Example 103. It was a white solid, yield: 43%. Mp > 300 °C. 1 H NMR (400MHz, DMSO-d6) δ11.57(s,1H),8.33(t,J=1.8Hz,1H),8.20(dt,J=8.1,1.4Hz,1 H),8.04(dt,J=7.8,1.4Hz,1H),7.80(t,J=7.9Hz,1H),7.66–7.27(m,6H),2.37(s,3H).

[0408] Example 125 Synthesis of 1-difluoromethyl-3-(3-cyanophenyl)-6-(benzo[d][1,3]dioxacyclopenten-5-yl)imidazo[1,5-a]pyrazin-8(7H)-one (7kab23)

[0409] 7kab23 was prepared from ethyl 2-(3-cyanophenyl)-4-(difluoromethyl)-1-[2-(benzo[d][1,3]dioxacyclopenten-5-yl)-2-oxoethyl]-1H-imidazolium-5-carboxylate 6ka23 as the starting material, following the synthetic method described in Example 103. White solid, yield: 83%. Mp > 300℃. ESI-HRMS m / z calculated for C 21 H 11 F2N4O3 - [MH] - 405.0805, found 405.0781. 1 H NMR (400MHz, DMSO-d6) δ11.51(s,1H),8.33(s,1H),8.20(d,J=8.0Hz,1H),8.03(d,J=7.8Hz,1 H),7.97–7.46(m,3H),7.34(s,1H),7.24(d,J=8.3Hz,1H),7.03(d,J=8.1Hz,1H),6.09(s,2H). 13 C NMR(100MHz,DMSO-d6)δ155.85,148.92,148.03,134.05,133.97,132.67,130.86,130.29, 129.93,129.16,125.39,121.97,118.81,117.71,112.85,108.91,108.16,102.06,101.83.

[0410] Example 126 Synthesis of 1-difluoromethyl-3-(3-cyanophenyl)-6-(thiophen-3-yl)imidazo[1,5-a]pyrazin-8(7H)-one (7kab24)

[0411] Starting from ethyl 2-(3-cyanophenyl)-4-(difluoromethyl)-1-[2-(thiophen-3-yl)-2-oxoethyl]-1H-imidazolium-5-carboxylate 6ka24, 7kab24 was prepared according to the synthesis method in Example 103. White solid, yield: 55%. Mp > 300℃. ESI-HRMS m / z calculated for C 18 H9F2N4OS - [MH] - 367.0471, found 367.0467. 1HNMR (400MHz, DMSO-d6) δ11.71(s,1H),8.32(s,1H),8.18(d,J=8.0Hz,1H),8.05(d,J=8. 0Hz,1H),7.85–7.79(m,1H),7.74–7.66(m,2H),7.65–7.34(m,2H),7.18(t,J=4.5Hz,1H). 13 C NMR(100MHz,DMSO-d6)δ155.53,141.41,134.17,134.01,133.93,133.80,132.97, 132.75,132.50,130.77,129.70,128.40,128.04,125.42,118.54,112.69,101.35.

[0412] Example 127 Synthesis of 1-difluoromethyl-3-(3-cyanophenyl)-6-(thiophen-2-yl)imidazo[1,5-a]pyrazin-8(7H)-one (7kab25)

[0413] Starting from ethyl 2-(3-cyanophenyl)-4-(difluoromethyl)-1-[2-(thiophen-2-yl)-2-oxoethyl]-1H-imidazolium-5-carboxylate 6ka25, 7kab25 was prepared according to the synthesis method in Example 103. White solid, yield: 36%. Mp > 300℃. ESI-HRMS m / z calculated for C 18 H9F2N4OS - [MH] - 367.0471, found 367.0482. 1 HNMR(400MHz,DMSO-d6)δ11.38(s,1H),8.32(t,J=1.7Hz,1H),8.24–8.16(m,2H),8.05 (dt,J=7.8,1.4Hz,1H),7.85–7.76(m,2H),7.72–7.66(m,2H),7.50(t,J=53.9Hz,1H). 13 C NMR (100MHz, DMSO-d6) δ155.89,141.62,134.10,133.99,132.79,132.42,130.87,129. 89,127.91,126.60,126.56,124.65,122.37,118.81,112.88,111.96,109.65,101.90.

[0414] Example 128 Synthesis of 1-difluoromethyl-3-(3-cyanophenyl)-6-(furan-2-yl)imidazo[1,5-a]pyrazin-8(7H)-one (7kab26)

[0415] Starting from ethyl 2-(3-cyanophenyl)-4-(difluoromethyl)-1-[2-(furan-2-yl)-2-oxoethyl]-1H-imidazolium-5-carboxylate 6ka26, 7kab26 was prepared according to the synthesis method in Example 103. White solid, yield: 56%. Mp > 300℃. ESI-HRMS m / z calculated for C 18 H9F2N4O2 - [MH] - 351.0699, found 351.0713. 1 HNMR (400MHz, DMSO-d6) δ11.68(s,1H),8.31(s,1H),8.18(d,J=7.9Hz,1H),8.07(d,J=7.8H z,1H),7.91–7.76(m,2H),7.68–7.33(m,2H),7.30(d,J=3.5Hz,1H),6.66(t,J=2.8Hz,1H). 13 C NMR(100MHz,DMSO-d6)δ155.64,144.96,144.83,141.73,134.16,133.89,132.64,130 .98,129.84,122.29,118.65,112.88,112.61,110.58,110.45,109.54,100.00,39.64.

[0416] Example 129 Preparation of 1-difluoromethyl-3-(3-cyanophenyl)-6-[4-(trifluoromethoxy)phenyl]imidazo[1,5-a]pyrazin-8(7H)-one (7kab8) tablets

[0417] Prescription composition and content:

[0418]

[0419] Coating solution prescription:

[0420] Opadai (03B26796) 21g 95% ethanol (appropriate amount)

[0421] Makes approximately 430ml

[0422] Process: 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 softened with 95% ethanol, granulated with an 18-mesh sieve, dried in a ventilated environment at 60°C, granulated 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.

[0423] 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.

[0424] 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.

[0425] Example 130 Preparation of capsules of compound 1-difluoromethyl-3-(3-cyanophenyl)-6-[4-(trifluoromethoxy)phenyl]imidazo[1,5-a]pyrazin-8(7H)-one (7kab8)

[0426] Prescription composition and content:

[0427]

[0428] Process: Take the prescribed amount of 1-difluoromethyl-3-(3-cyanophenyl)-6-[4-(trifluoromethoxy)phenyl]imidazo[1,5-a]pyrazin-8(7H)-one (7kab8), 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.

[0429] Example 131: ADP-induced inhibition experiment on rabbit platelet aggregation

[0430] 1. Plasma preparation

[0431] 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.

[0432] 2. Determination of platelet aggregation using the microplate assay

[0433] 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 (27.5 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.

[0434] AR = (A0 – A1) / (A0 – Appp)

[0435] AIR = (1 – AR sample / AR control)

[0436] Calculate IC based on AIR values ​​at different concentrations. 50 value.

[0437] Example 132 Evaluation of the neuroprotective activity of hydrogen peroxide-induced hippocampal neurons (HT22)

[0438] 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.

[0439] Table 1. IC50 of the target compound 50 Value (Mean±SD)

[0440]

[0441]

[0442] a The inhibitory rate of the target compound on platelet aggregation at 10 μM;

[0443] b Cell viability of HT22 cells in the blank group after injury induced by 500 μM H2O2: 50.5% ± 8.4%.

[0444] Example 133: Evaluation of the efficacy of drugs for acute cerebral infarction

[0445] 1. Reagents: 20% urethane, positive control: edaravone and BPTU, compound 7kab8, triphenyltetrazolium chloride (TTC)

[0446] 2. Instruments: curved needle holder, micro forceps, artery clamp, 7-0 needle-with sutures, water bath, etc.

[0447] 3. Laboratory animals

[0448] Fifty-six male SD rats were used in the experiment, which included a model group, a blank control group, a positive control group (6 mg / kg: edaravone, 10 mg / kg: BPTU), and compound 7kab8 groups at low, medium, and high doses (2.5 mg / kg, 5 mg / kg, and 10 mg / kg respectively). 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%.

[0449] 4. Experimental Procedure

[0450] 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 for all rats 24 hours later.

[0451] 5. TTC staining - infarct area assessment

[0452] 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:

[0453] Corrected infarct area = (contralateral area × 2 + ipsilateral non-infarct area - total brain area) / 2 × contralateral area × 100%.

[0454] like Figure 1 As shown, compound 7kab8 can significantly improve the infarct area of ​​brain tissue caused by acute cerebral infarction in rats in a dose-dependent manner.

[0455] Example 134: Drug Efficacy Experiment for Acute Myocardial Infarction

[0456] 1. Reagents

[0457] 4% chloral hydrate, positive control (BPTU, ticagrelor), test compound 7kab8, triphenyltetrazolium chloride (TTC) 2. Instruments: curved needle holder, micro forceps, arterial clamp, 7-0 needle-supported suture

[0458] 3. Laboratory animals

[0459] One hundred and five male, SPF-grade, 6-week-old C57BL / 6 mice were purchased from Liaoning Changsheng Biotechnology Co., Ltd. Animals were acclimatized for 7 days before the start of the experiment until they reached an appropriate weight (25±2g). The animal room temperature was maintained at 22±3℃ and the humidity at 45%±10%.

[0460] 4. Grouping and administration

[0461] One hundred and five mice were randomly divided into seven groups: model group, blank group, positive drug BPTU group (10 mg / kg), positive drug ticagrelor group (10 mg / kg), high-dose compound 7kab8 group (20 mg / kg), medium-dose compound 7kab8 group (10 mg / kg), and low-dose compound 7kab8 group (5 mg / kg). After successful modeling, the mice were administered the drug via tail vein injection immediately.

[0462] 5. Experimental Methods

[0463] 5.1. Establishment of a mouse model of myocardial infarction

[0464] Before surgery, anesthesia was administered using 4% chloral hydrate. After successful anesthesia, the chest was prepared with a razor and depilatory cream, and the surgical area was disinfected with 75% ethanol. A 1.2cm incision was made at a 30° angle to the right from the junction of the xiphoid process and costal arch. The pectoralis major muscle was bluntly dissected using curved forceps and curved hemostats to expose the pectoralis minor muscle beneath it. When the mouse's breathing was stable, the intercostal muscle was gently punctured at 3 / 4 (later 4 / 5 of the ribs in experiments) with curved hemostats. The forceps were rotated counterclockwise and slightly opened, while simultaneously squeezing with fingers to expel the heart from the thoracic cavity using the heartbeat. The heart was then rotated to locate the left atrial appendage, and 2mm below it, a pre-prepared 7- The left anterior descending coronary artery was ligated with needle and suture. The heart was expelled from the thoracic cavity and remained outside the body for no more than 1 minute before being quickly returned to the thoracic cavity. The thoracic cavity was gently expelled. In the model group, the thoracic cavity and skin were closed with purse-string sutures, and the mice were placed on a temperature-controlled mat to await awakening. In the drug-treated group, the thoracic cavity was first clamped with an arterial clamp, and the mice's limbs were immediately fixed with adhesive tape. The tape was then removed, and the drug was immediately administered via tail vein injection. After administration, the arterial clamp was removed, the skin was sutured, and the mice were placed on a temperature-controlled mat to maintain warmth until awakening. After awakening, the mice were placed in cages and fed with water and food for 24 hours before sample testing.

[0465] 5.2 Sample Detection Indicators - TTC Staining Analysis

[0466] 24 hours post-surgery, mice were anesthetized with 4% chloral hydrate. Their limbs were fixed to a foam board used for perfusion. The chest cavity was reopened along the previous surgical site, and the heart was perfused with physiological saline until the saline flowing from the right atrial appendage became clear and the liver turned a yellowish-brown color. The heart was removed and placed in a glass dish containing physiological saline to clean any bloodstains from the surface (to prevent contamination of the TTC staining solution). After cleaning, the heart was placed on an ice box and stored at -20°C until it hardened (approximately 1 hour). 2% TTC staining solution was prepared using sterile PBS, taking care to avoid light during the process. The staining solution was preheated to 37°C. The frozen heart was removed from the -20°C freezer, and the section below the ligation suture was quickly sliced ​​into 1mm thick slices. These slices were then immersed in 2% TTC staining solution and stained at 37°C for 20-30 minutes. After staining, the heart slices were removed from the TTC staining solution, washed twice with PBS buffer, and then scanned and photographed. The infarct area of ​​the entire heart was calculated using the following formula:

[0467] Infarct area (%) = Infarct area / Total cardiac area × 100%.

[0468] like Figure 2 As shown, compound 7kab8 significantly improved the infarct area caused by acute myocardial infarction in mice in a dose-dependent manner.

[0469] Example 135 Bleeding Risk Assessment

[0470] 1. Reagents: 20% urethane, physiological saline, positive control drugs: edaravone, BPTU and ticagrelor, compound 7kab8.

[0471] 2. Instruments: scalpel, 15mL graduated cylinder, timer, water bath, vernier caliper.

[0472] 3. Laboratory animals

[0473] Twenty-four male SD rats were used: a control group, a positive control group (6 mg / kg: edaravone, 10 mg / kg: BPTU and ticagrelor), and a compound 7kab8 group (10 mg / kg). Animals were acclimatized for 7 days before the start of the experiment until they reached an appropriate weight (250-280 g). The animal room temperature was maintained at 22±3℃, and the humidity at 45%±10%.

[0474] 4. Experimental Procedure

[0475] 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 centrifuge tube readings were taken after 15 minutes to calculate the blood loss volume.

[0476] like Figure 3 As shown, the bleeding volume of compound 7kab8 was lower than that of the positive control drugs ticagrelor and BPTU, indicating that compound 7kab8 has a correspondingly lower bleeding risk.

Claims

1. Compounds represented by general formula I or II and their pharmaceutically usable salts, tautomers, and pharmaceutically usable solvates: in, R1 is The substituted or unsubstituted phenyl group; the substituent is hydroxyl, nitro, cyano, halogen, amino, C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkyl, halo-C1-C6 alkoxy, thienyl, furanyl; Preferably, R1 is The substituted or unsubstituted phenyl group; the substituent is hydroxyl, nitro, cyano, halogen, amino, C1-C4 alkyl, C1-C4 alkoxy, halo-C1-C4 alkyl, halo-C1-C4 alkoxy, thienyl, furanyl; X is CH2 or NH.

2. The compound of claim 1 and its pharmaceutically usable salts, tautomers, and pharmaceutically usable solvates: in, R1 is The substituted or unsubstituted phenyl group; the substituent is hydroxyl, nitro, cyano, halogen, amino, C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkyl, halo-C1-C6 alkoxy, thienyl, furanyl; Preferably, R1 is The substituted or unsubstituted phenyl group; the substituent is hydroxyl, nitro, cyano, halogen, amino, C1-C4 alkyl, C1-C4 alkoxy, halo-C1-C4 alkyl, halo-C1-C4 alkoxy, thienyl, furanyl; X is CH2 or NH.

3. The compound of claim 1 or 2 and its pharmaceutically acceptable salt, tautomer, or pharmaceutically acceptable solvate: in, R1 is 4-fluorophenyl, 3-fluorophenyl, 2-fluorophenyl, 4-trifluoromethylphenyl, 3-trifluoromethylphenyl, 2-trifluoromethylphenyl, 4-trifluoromethoxyphenyl, 3-trifluoromethoxyphenyl, 2-trifluoromethoxyphenyl, 4-cyanophenyl, 3-cyanophenyl, 4-nitrophenyl, 3-nitrophenyl, 2-nitrophenyl, 4-chlorophenyl, 3-chlorophenyl, 2-chlorophenyl, 4-bromophenyl, 3-bromophenyl, 2-bromophenyl, 4-methylphenyl, 3- Methylphenyl, 3-bromo-4-fluorophenyl, 3-methyl-4-nitrophenyl, 2-fluoro-4-nitrophenyl, 3-chloro-4-nitrophenyl, 2-bromo-4-nitrophenyl, 4-methoxyphenyl, 2-methoxyphenyl, 3,5-dichloro-4-methoxyphenyl, 3,5-dichloro-4-hydroxyphenyl, 3,5-dichloro-4-aminophenyl, benzo[d][1,3]dioxacyclopenten-5-yl, thiophene-3-yl, thiophene-2-yl, furan-2-yl; X is CH2 or NH.

4. The following compounds and their pharmaceutically acceptable salts, tautomers, and pharmaceutically acceptable solvates: (1) 2-(3-cyanophenyl)-4-(difluoromethyl)-1-[2-(4-fluorophenyl)-2-oxoethyl]-1H-imidazol-5-carboxylic acid (2) 2-(3-cyanophenyl)-4-(difluoromethyl)-1-[2-(3-fluorophenyl)-2-oxoethyl]-1H-imidazol-5-carboxylic acid (3) 2-(3-cyanophenyl)-4-(difluoromethyl)-1-[2-(2-fluorophenyl)-2-oxoethyl]-1H-imidazol-5-carboxylic acid (4) 2-(3-cyanophenyl)-4-(difluoromethyl)-1-{2-[4-(trifluoromethyl)phenyl]-2-oxoethyl}-1H-imidazol-5-carboxylic acid (5) 2-(3-cyanophenyl)-4-(difluoromethyl)-1-{2-[3-(trifluoromethyl)phenyl]-2-oxoethyl}-1H-imidazol-5-carboxylic acid (6) 2-(3-cyanophenyl)-4-(difluoromethyl)-1-{2-[2-(trifluoromethyl)phenyl]-2-oxoethyl}-1H-imidazol-5-carboxylic acid (7) 2-(3-cyanophenyl)-4-(difluoromethyl)-1-{2-[4-(trifluoromethoxy)phenyl]-2-oxoethyl}-1H-imidazol-5-carboxylic acid (8) 2-(3-cyanophenyl)-4-(difluoromethyl)-1-{2-[3-(trifluoromethoxy)phenyl]-2-oxoethyl}-1H-imidazol-5-carboxylic acid (9) 2-(3-cyanophenyl)-4-(difluoromethyl)-1-{2-[2-(trifluoromethoxy)phenyl]-2-oxoethyl}-1H-imidazol-5-carboxylic acid (10) 2-(3-cyanophenyl)-4-(difluoromethyl)-1-[2-(4-cyanophenyl)-2-oxoethyl]-1H-imidazol-5-carboxylic acid (11) 2-(3-cyanophenyl)-4-(difluoromethyl)-1-[2-(3-cyanophenyl)-2-oxoethyl]-1H-imidazol-5-carboxylic acid (12) 2-(3-cyanophenyl)-4-(difluoromethyl)-1-(4-fluorobenzamido)-1H-imidazol-5-carboxylic acid (13) 2-(3-cyanophenyl)-4-(difluoromethyl)-1-(3-fluorobenzamido)-1H-imidazol-5-carboxylic acid (14) 2-(3-cyanophenyl)-4-(difluoromethyl)-1-(2-fluorobenzamido)-1H-imidazol-5-carboxylic acid (15) 2-(3-cyanophenyl)-4-(difluoromethyl)-1-[4-(trifluoromethyl)benzamido]-1H-imidazol-5-carboxylic acid (16) 2-(3-cyanophenyl)-4-(difluoromethyl)-1-[3-(trifluoromethyl)benzamido]-1H-imidazol-5-carboxylic acid (17) 2-(3-cyanophenyl)-4-(difluoromethyl)-1-[2-(trifluoromethyl)benzamido]-1H-imidazol-5-carboxylic acid (18) 2-(3-cyanophenyl)-4-(difluoromethyl)-1-[4-(trifluoromethoxy)benzamido]-1H-imidazol-5-carboxylic acid (19) 2-(3-cyanophenyl)-4-(difluoromethyl)-1-[3-(trifluoromethoxy)benzamido]-1H-imidazol-5-carboxylic acid (20) 2-(3-cyanophenyl)-4-(difluoromethyl)-1-[2-(trifluoromethoxy)benzamido]-1H-imidazol-5-carboxylic acid (21) 2-(3-cyanophenyl)-4-(difluoromethyl)-1-(4-cyanobenzamido)-1H-imidazol-5-carboxylic acid (22) 2-(3-cyanophenyl)-4-(difluoromethyl)-1-(3-cyanobenzamido)-1H-imidazol-5-carboxylic acid (23) 2-(3-cyanophenyl)-4-(difluoromethyl)-1-(4-nitrobenzamido)-1H-imidazol-5-carboxylic acid (24) 2-(3-cyanophenyl)-4-(difluoromethyl)-1-(3-nitrobenzamido)-1H-imidazol-5-carboxylic acid (25) 2-(3-cyanophenyl)-4-(difluoromethyl)-1-(2-nitrobenzamido)-1H-imidazol-5-carboxylic acid (26) 2-(3-cyanophenyl)-4-(difluoromethyl)-1-(4-chlorobenzamido)-1H-imidazol-5-carboxylic acid (27) 2-(3-cyanophenyl)-4-(difluoromethyl)-1-(2-chlorobenzamido)-1H-imidazol-5-carboxylic acid (28) 2-(3-cyanophenyl)-4-(difluoromethyl)-1-(4-bromobenzamido)-1H-imidazol-5-carboxylic acid (29) 2-(3-cyanophenyl)-4-(difluoromethyl)-1-(3-bromobenzoamide)-1H-imidazol-5-carboxylic acid (30) 2-(3-cyanophenyl)-4-(difluoromethyl)-1-(4-methylbenzamido)-1H-imidazol-5-carboxylic acid (31) 2-(3-cyanophenyl)-4-(difluoromethyl)-1-(3-methylbenzamido)-1H-imidazol-5-carboxylic acid (32) 2-(3-cyanophenyl)-4-(difluoromethyl)-1-(3-bromo-4-fluorobenzamido)-1H-imidazol-5-carboxylic acid (33) 2-(3-cyanophenyl)-4-(difluoromethyl)-1-(3-methyl-4-nitrobenzamido)-1H-imidazol-5-carboxylic acid (34) 2-(3-cyanophenyl)-4-(difluoromethyl)-1-(2-fluoro-4-nitrobenzamido)-1H-imidazol-5-carboxylic acid (35) 2-(3-cyanophenyl)-4-(difluoromethyl)-1-(2-chloro-4-nitrobenzamido)-1H-imidazol-5-carboxylic acid (36) 2-(3-cyanophenyl)-4-(difluoromethyl)-1-(3-chloro-4-nitrobenzamido)-1H-imidazol-5-carboxylic acid (37) 2-(3-cyanophenyl)-4-(difluoromethyl)-1-(2-bromo-4-nitrobenzamido)-1H-imidazol-5-carboxylic acid (38) 2-(3-cyanophenyl)-4-(difluoromethyl)-1-(4-methoxybenzamido)-1H-imidazol-5-carboxylic acid (39) 2-(3-cyanophenyl)-4-(difluoromethyl)-1-(3,5-dichloro-4-methoxybenzamido)-1H-imidazol-5-carboxylic acid (40) 2-(3-cyanophenyl)-4-(difluoromethyl)-1-(3,5-dichloro-4-hydroxybenzamido)-1H-imidazol-5-carboxylic acid (41) 2-(3-cyanophenyl)-4-(difluoromethyl)-1-(3,5-dichloro-4-aminobenzamido)-1H-imidazol-5-carboxylic acid (42) 1-Difluoromethyl-3-(3-cyanophenyl)-6-phenylimidazo[1,5-a]pyrazin-8(7H)-one (43) 1-Difluoromethyl-3-(3-cyanophenyl)-6-(4-fluorophenyl)imidazo[1,5-a]pyrazin-8(7H)-one (44) 1-Difluoromethyl-3-(3-cyanophenyl)-6-(3-fluorophenyl)imidazo[1,5-a]pyrazin-8(7H)-one (45) 1-Difluoromethyl-3-(3-cyanophenyl)-6-(2-fluorophenyl)imidazo[1,5-a]pyrazin-8(7H)-one (46) 1-Difluoromethyl-3-(3-cyanophenyl)-6-[4-(trifluoromethyl)phenyl]imidazo[1,5-a]pyrazin-8(7H)-one (47) 1-Difluoromethyl-3-(3-cyanophenyl)-6-[3-(trifluoromethyl)phenyl]imidazo[1,5-a]pyrazin-8(7H)-one (48) 1-Difluoromethyl-3-(3-cyanophenyl)-6-[2-(trifluoromethyl)phenyl]imidazo[1,5-a]pyrazin-8(7H)-one (49) 1-Difluoromethyl-3-(3-cyanophenyl)-6-[4-(trifluoromethoxy)phenyl]imidazo[1,5-a]pyrazin-8(7H)-one (50) 1-Difluoromethyl-3-(3-cyanophenyl)-6-[3-(trifluoromethoxy)phenyl]imidazo[1,5-a]pyrazin-8(7H)-one (51) 1-Difluoromethyl-3-(3-cyanophenyl)-6-[2-(trifluoromethoxy)phenyl]imidazo[1,5-a]pyrazin-8(7H)-one (52) 1-Difluoromethyl-3-(3-cyanophenyl)-6-(4-chlorophenyl)imidazo[1,5-a]pyrazin-8(7H)-one (53) 1-Difluoromethyl-3-(3-cyanophenyl)-6-(3-chlorophenyl)imidazo[1,5-a]pyrazin-8(7H)-one (54) 1-Difluoromethyl-3-(3-cyanophenyl)-6-(2-chlorophenyl)imidazo[1,5-a]pyrazin-8(7H)-one (55) 1-Difluoromethyl-3-(3-cyanophenyl)-6-(4-bromophenyl)imidazo[1,5-a]pyrazin-8(7H)-one (56) 1-Difluoromethyl-3-(3-cyanophenyl)-6-(3-bromophenyl)imidazo[1,5-a]pyrazin-8(7H)-one (57) 1-Difluoromethyl-3-(3-cyanophenyl)-6-(2-bromophenyl)imidazo[1,5-a]pyrazin-8(7H)-one (58) 1-Difluoromethyl-3-(3-cyanophenyl)-6-(4-cyanophenyl)imidazo[1,5-a]pyrazin-8(7H)-one (59) 1-Difluoromethyl-3-(3-cyanophenyl)-6-(3-cyanophenyl)imidazo[1,5-a]pyrazin-8(7H)-one (60) 1-Difluoromethyl-3-(3-cyanophenyl)-6-(4-methoxyphenyl)imidazo[1,5-a]pyrazin-8(7H)-one (61) 1-Difluoromethyl-3-(3-cyanophenyl)-6-(2-methoxyphenyl)imidazo[1,5-a]pyrazin-8(7H)-one (62) 1-Difluoromethyl-3-(3-cyanophenyl)-6-(4-methylphenyl)imidazo[1,5-a]pyrazin-8(7H)-one (63) 1-Difluoromethyl-3-(3-cyanophenyl)-6-(3-methylphenyl)imidazo[1,5-a]pyrazin-8(7H)-one (64) 1-Difluoromethyl-3-(3-cyanophenyl)-6-(benzo[d][1,3]dioxacyclopenten-5-yl)imidazo[1,5-a]pyrazin-8(7H)-one (65) 1-Difluoromethyl-3-(3-cyanophenyl)-6-(thien-3-yl)imidazo[1,5-a]pyrazin-8(7H)-one (66) 1-Difluoromethyl-3-(3-cyanophenyl)-6-(thien-2-yl)imidazo[1,5-a]pyrazin-8(7H)-one (67) 1-Difluoromethyl-3-(3-cyanophenyl)-6-(furan-2-yl)imidazo[1,5-a]pyrazin-8(7H)-one.

5. Preparation of intermediates of compounds of general formula I or II in claim 1 and their pharmaceutically usable salts, tautomers, and pharmaceutically usable solvates: (1) Ethyl 2-(3-cyanophenyl)-4-(difluoromethyl)-1-(2-phenyl-2-oxoethyl)-1H-imidazol-5-carboxylate (2) Ethyl 2-(3-cyanophenyl)-4-(difluoromethyl)-1-(2-(4-fluorophenyl)-2-oxoethyl)-1H-imidazol-5-carboxylate (3) Ethyl 2-(3-cyanophenyl)-4-(difluoromethyl)-1-(2-(3-fluorophenyl)-2-oxoethyl)-1H-imidazol-5-carboxylate (4) Ethyl 2-(3-cyanophenyl)-4-(difluoromethyl)-1-(2-(2-fluorophenyl)-2-oxoethyl)-1H-imidazol-5-carboxylate (5) 2-(3-cyanophenyl)-4-(difluoromethyl)-1-{2-[4-(trifluoromethyl)phenyl]-2-oxoethyl}-1H-imidazol-5-carboxylic acid ethyl ester (6) 2-(3-cyanophenyl)-4-(difluoromethyl)-1-{2-[3-(trifluoromethyl)phenyl]-2-oxoethyl}-1H-imidazol-5-carboxylic acid ethyl ester (7) 2-(3-cyanophenyl)-4-(difluoromethyl)-1-{2-[2-(trifluoromethyl)phenyl]-2-oxoethyl}-1H-imidazol-5-carboxylic acid ethyl ester (8) 2-(3-cyanophenyl)-4-(difluoromethyl)-1-{2-[4-(trifluoromethoxy)phenyl]-2-oxoethyl}-1H-imidazol-5-carboxylic acid ethyl ester (9) 2-(3-cyanophenyl)-4-(difluoromethyl)-1-{2-[3-(trifluoromethoxy)phenyl]-2-oxoethyl}-1H-imidazol-5-carboxylic acid ethyl ester (10) 2-(3-cyanophenyl)-4-(difluoromethyl)-1-{2-[2-(trifluoromethoxy)phenyl]-2-oxoethyl}-1H-imidazol-5-carboxylic acid ethyl ester (11) 2-(3-cyanophenyl)-4-(difluoromethyl)-1-[2-(4-chlorophenyl)-2-oxoethyl]-1H-imidazol-5-carboxylic acid ethyl ester (12) Ethyl 2-(3-cyanophenyl)-4-(difluoromethyl)-1-[2-(3-chlorophenyl)-2-oxoethyl]-1H-imidazol-5-carboxylate (13) 2-(3-cyanophenyl)-4-(difluoromethyl)-1-[2-(2-chlorophenyl)-2-oxoethyl]-1H-imidazol-5-carboxylic acid ethyl ester (14) 2-(3-cyanophenyl)-4-(difluoromethyl)-1-[2-(4-bromophenyl)-2-oxoethyl]-1H-imidazol-5-carboxylic acid ethyl ester (15) ethyl 2-(3-cyanophenyl)-4-(difluoromethyl)-1-[2-(3-bromophenyl)-2-oxoethyl]-1H-imidazol-5-carboxylate (16) ethyl 2-(3-cyanophenyl)-4-(difluoromethyl)-1-[2-(2-bromophenyl)-2-oxoethyl]-1H-imidazol-5-carboxylate (17) 2-(3-cyanophenyl)-4-(difluoromethyl)-1-[2-(4-cyanophenyl)-2-oxoethyl]-1H-imidazol-5-carboxylic acid ethyl ester (18) 2-(3-cyanophenyl)-4-(difluoromethyl)-1-[2-(3-cyanophenyl)-2-oxoethyl]-1H-imidazol-5-carboxylic acid ethyl ester (19) 2-(3-cyanophenyl)-4-(difluoromethyl)-1-[2-(4-methoxyphenyl)-2-oxoethyl]-1H-imidazol-5-carboxylic acid ethyl ester (20) 2-(3-cyanophenyl)-4-(difluoromethyl)-1-[2-(2-methoxyphenyl)-2-oxoethyl]-1H-imidazol-5-carboxylic acid ethyl ester (21) Ethyl 2-(3-cyanophenyl)-4-(difluoromethyl)-1-[2-(4-methylphenyl)-2-oxoethyl]-1H-imidazol-5-carboxylate (22) Ethyl 2-(3-cyanophenyl)-4-(difluoromethyl)-1-[2-(3-methylphenyl)-2-oxoethyl]-1H-imidazol-5-carboxylate (23) 2-(3-cyanophenyl)-4-(difluoromethyl)-1-[2-(benzo[d][1,3]dioxacyclopenten-5-yl)-2-oxoethyl]-1H-imidazol-5-carboxylic acid ethyl ester (24) 2-(3-cyanophenyl)-4-(difluoromethyl)-1-[2-(thien-3-yl)-2-oxoethyl]-1H-imidazol-5-carboxylic acid ethyl ester (25) 2-(3-cyanophenyl)-4-(difluoromethyl)-1-[2-(thien-2-yl)-2-oxoethyl]-1H-imidazol-5-carboxylic acid ethyl ester (26) 2-(3-cyanophenyl)-4-(difluoromethyl)-1-[2-(furan-2-yl)-2-oxoethyl]-1H-imidazol-5-carboxylic acid ethyl ester (27) 2-(3-cyanophenyl)-4-(difluoromethyl)-1-(4-fluorobenzamido)-1H-imidazol-5-carboxylic acid ethyl ester (28) ethyl 2-(3-cyanophenyl)-4-(difluoromethyl)-1-(3-fluorobenzamido)-1H-imidazol-5-carboxylate (29) Ethyl 2-(3-cyanophenyl)-4-(difluoromethyl)-1-(2-fluorobenzamido)-1H-imidazol-5-carboxylate (30) 2-(3-cyanophenyl)-4-(difluoromethyl)-1-[4-(trifluoromethyl)benzamido]-1H-imidazol-5-carboxylic acid ethyl ester (31) 2-(3-cyanophenyl)-4-(difluoromethyl)-1-[3-(trifluoromethyl)benzamido]-1H-imidazol-5-carboxylic acid ethyl ester (32) 2-(3-cyanophenyl)-4-(difluoromethyl)-1-[2-(trifluoromethyl)benzamido]-1H-imidazol-5-carboxylic acid ethyl ester (33) 2-(3-cyanophenyl)-4-(difluoromethyl)-1-[4-(trifluoromethoxy)benzamido]-1H-imidazol-5-carboxylic acid ethyl ester (34) 2-(3-cyanophenyl)-4-(difluoromethyl)-1-[3-(trifluoromethoxy)benzamido]-1H-imidazol-5-carboxylic acid ethyl ester (35) 2-(3-cyanophenyl)-4-(difluoromethyl)-1-[2-(trifluoromethoxy)benzamido]-1H-imidazol-5-carboxylic acid ethyl ester (36) 2-(3-cyanophenyl)-4-(difluoromethyl)-1-(4-cyanobenzamido)-1H-imidazol-5-carboxylic acid ethyl ester (37) 2-(3-cyanophenyl)-4-(difluoromethyl)-1-(3-cyanobenzamido)-1H-imidazol-5-carboxylic acid ethyl ester (38) 2-(3-cyanophenyl)-4-(difluoromethyl)-1-(4-nitrobenzamido)-1H-imidazol-5-carboxylic acid ethyl ester (39) 2-(3-cyanophenyl)-4-(difluoromethyl)-1-(3-nitrobenzamido)-1H-imidazol-5-carboxylic acid ethyl ester (40) 2-(3-cyanophenyl)-4-(difluoromethyl)-1-(2-nitrobenzamido)-1H-imidazol-5-carboxylic acid ethyl ester (41) Ethyl 2-(3-cyanophenyl)-4-(difluoromethyl)-1-(4-chlorobenzamido)-1H-imidazol-5-carboxylate (42) Ethyl 2-(3-cyanophenyl)-4-(difluoromethyl)-1-(2-chlorobenzamido)-1H-imidazol-5-carboxylate (43) 2-(3-cyanophenyl)-4-(difluoromethyl)-1-(4-bromobenzamido)-1H-imidazol-5-carboxylic acid ethyl ester (44) 2-(3-cyanophenyl)-4-(difluoromethyl)-1-(3-bromobenzamido)-1H-imidazol-5-carboxylic acid ethyl ester (45) 2-(3-cyanophenyl)-4-(difluoromethyl)-1-(4-methylbenzamido)-1H-imidazol-5-carboxylic acid ethyl ester (46) 2-(3-cyanophenyl)-4-(difluoromethyl)-1-(3-methylbenzamido)-1H-imidazol-5-carboxylic acid ethyl ester (47) 2-(3-cyanophenyl)-4-(difluoromethyl)-1-(3-bromo-4-fluorobenzamido)-1H-imidazol-5-carboxylic acid ethyl ester (48) Ethyl 2-(3-cyanophenyl)-4-(difluoromethyl)-1-(3-methyl-4-nitrobenzamido)-1H-imidazol-5-carboxylate (49) Ethyl 2-(3-cyanophenyl)-4-(difluoromethyl)-1-(2-fluoro-4-nitrobenzamido)-1H-imidazol-5-carboxylate (50) ethyl 2-(3-cyanophenyl)-4-(difluoromethyl)-1-(2-chloro-4-nitrobenzamido)-1H-imidazol-5-carboxylate (51) 2-(3-cyanophenyl)-4-(difluoromethyl)-1-(3-chloro-4-nitrobenzamido)-1H-imidazol-5-carboxylic acid ethyl ester (52) Ethyl 2-(3-cyanophenyl)-4-(difluoromethyl)-1-(2-bromo-4-nitrobenzamido)-1H-imidazol-5-carboxylate (53) 2-(3-cyanophenyl)-4-(difluoromethyl)-1-(4-methoxybenzamido)-1H-imidazol-5-carboxylic acid ethyl ester (54) 2-(3-cyanophenyl)-4-(difluoromethyl)-1-(3,5-dichloro-4-methoxybenzamido)-1H-imidazol-5-carboxylic acid ethyl ester (55) 2-(3-cyanophenyl)-4-(difluoromethyl)-1-(3,5-dichloro-4-hydroxybenzamido)-1H-imidazol-5-carboxylic acid ethyl ester (56) 2-(3-cyanophenyl)-4-(difluoromethyl)-1-(3,5-dichloro-4-aminobenzamido)-1H-imidazol-5-carboxylic acid ethyl ester (57) Ethyl 2-(3-cyanophenyl)-4-(difluoromethyl)-1H-imidazol-5-carboxylate (58) ethyl 1-amino-2-(3-cyanophenyl)-4-(difluoromethyl)-1H-imidazol-5-carboxylate.

6. The method for preparing the compound of general formula I or II according to claim 1 and its pharmaceutically usable salt, characterized in that, Wherein, R1 is as described in claim 1.

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

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 platelet aggregation inhibitor.

9. 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 neuroprotective agent.

10. 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 the prevention or treatment of thrombotic diseases.

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