Soluble epoxide hydrolase inhibitor and use thereof

Abstract

Disclosed in the present invention are a soluble epoxide hydrolase inhibitor, synthesis therefor and the use thereof. The structure of the soluble epoxide hydrolase inhibitor is shown as general formula (I), the definition of each substituent being as described in the description and the claims. Compounds represented by general formula (I) of the present invention as the soluble epoxide hydrolase inhibitor can be used for preparing drugs for treating sEH-related or mediated diseases.

Description

Soluble epoxide hydrolase inhibitors and their applications Technical Field

[0001] The present application relates to the fields of biomedicine and soluble epoxide hydrolase inhibitors. Specifically, the present application relates to a cyclic imidazole compound, a method for preparing the cyclic imidazole compound, and the use of the cyclic imidazole compound as a soluble epoxide hydrolase inhibitor. Background Art

[0002] Soluble epoxide hydrolases (sEH) play a central role in the metabolism of bioactive lipid signaling molecules. sEH specifically converts the substrate epoxyeicosatrienoic acid (EET) into less biologically active dihydroxyeicosatrienoic acid. These EETs are ubiquitous in endothelial cells, kidneys, and lungs. Compared to many proinflammatory end products of the prostaglandin and leukotriene pathways, EETs possess anti-inflammatory, analgesic, antihypertensive, cardioprotective, and organ-protective properties. Although EETs have significant positive effects on human health, due to the high catalytic activity of sEH in vivo, EETs cannot be effectively accumulated in vivo to more effectively exert their biological effects. Therefore, the development of suitable sEH inhibitors to inhibit the hydrolysis of EETs and promote their accumulation in vivo to enhance their anti-inflammatory and other effects has become a key research area. Studies have shown that sEH inhibition can significantly lower blood pressure in mammals and promote the resolution of inflammation by reducing the production of inflammatory factors (NO), cytokines, and lipid mediators. Several sEH inhibitors have entered the clinical trial stage in the early stage, but no sEH inhibitor drugs have been approved for marketing yet.

[0003] sEH possesses exceptionally high catalytic activity, effectively catalyzing the ring-opening hydrolysis of endogenous epoxides such as EETs. However, active anti-inflammatory substances like EETs are present in very low concentrations in the human body. To fully exploit the anti-inflammatory activity of EETs, highly active sEH enzyme inhibitors are required to comprehensively inhibit sEH hydrolysis of EETs. Therefore, developing drug molecules with superior activity and pharmacokinetic properties has become a pressing challenge in the development of sEH inhibitors. Summary of the Invention

[0004] The purpose of the present application is to provide a novel cyclic imidazole compound. Specifically, the cyclic imidazole compound of the present application has a core structure of benzimidazole or nitrogen-containing heteroaryl imidazole.

[0005] The present application also aims to provide a use of the above-mentioned cyclic imidazole compound as a soluble epoxide hydrolase inhibitor.

[0006] The present application also aims to provide a pharmaceutical composition comprising the above-mentioned cyclic imidazole compound and a pharmaceutically acceptable carrier, adjuvant or excipient.

[0007] The present application also aims to provide a kit comprising the above-mentioned cycloimidazole compound or pharmaceutical composition. The present application also aims to provide a use of the above-mentioned cycloimidazole compound in a drug for treating sEH-related diseases.

[0008] The present application also aims to provide a method for preventing or treating sEH-related diseases.

[0009] In order to solve the above technical problems, this application provides the following technical solutions.

[0010] The first aspect of the present invention provides a compound represented by formula I, its stereoisomers, tautomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs,

[0011] Where X is N or CR 1a 、Y is N or CR 2a 、Z is N or CR 3a ;

[0012] R 1a 、R 2a and R 3a Each independently selected from the group consisting of hydrogen, deuterium, halogen, cyano, nitro, NR a R b , hydroxy, carboxyl, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C3-C10 cycloalkyloxy, substituted or unsubstituted 3-10 membered heterocyclyl, substituted or unsubstituted 3-10 membered heterocyclyloxy, substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted C6-C10 aryloxy, substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted 5-10 membered heteroaryloxy, each of the above groups may be optionally further substituted with one or more halogens;

[0013] Ring A is selected from: C6-C10 aromatic ring, 5-10 membered heteroaromatic ring, C3-C10 carbocyclic ring, 3-10 membered heterocyclic ring;

[0014] Ring B is selected from: C6-C10 aromatic ring, 5-10 membered heteroaromatic ring, C3-C10 carbocyclic ring, 4-10 membered heterocyclic ring;

[0015] Ring C is selected from: C6-C10 aromatic ring, 5-10 membered heteroaromatic ring;

[0016] m is 0, 1, 2, 3 or 4, each R 2 Independently selected from: hydrogen, deuterium, halogen, cyano, nitro, NR a R b , hydroxy, carboxyl, ═O, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C3-C10 cycloalkyloxy, substituted or unsubstituted 4-10 membered heterocyclyl, substituted or unsubstituted 4-10 membered heterocyclyloxy, substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted C6-C10 aryloxy, substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted 5-10 membered heteroaryloxy;

[0017] n is 0, 1, 2, 3 or 4, each R 3 Independently selected from: hydrogen, deuterium, halogen, cyano, nitro, NR a R b , substituted or unsubstituted -(C1-C4 alkylene)NR a R b , hydroxyl, carboxyl, =O, =C(R c )2, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted -COO(C1-C6 alkyl), substituted or unsubstituted -CONR a R b , substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C3-C10 cycloalkyloxy, substituted or unsubstituted 4-10 membered heterocyclyl, substituted or unsubstituted 4-10 membered heterocyclyloxy, substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted C6-C10 aryloxy, substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted 5-10 membered heteroaryloxy, substituted or unsubstituted -(C1-C4 alkylene)COO(C1-C6 alkyl); substituted or unsubstituted -SO2(C1-C6 alkyl), substituted or unsubstituted -S(O)(NR a )(C1-C6 alkyl), substituted or unsubstituted-(C1-C4 alkylene)SO2(C1-C6 alkyl), substituted or unsubstituted-(C1-C4 alkylene)S(O)(NR a )(C1-C6 alkyl), substituted or unsubstituted -SO2NR a R b , substituted or unsubstituted -(C1-C4 alkylene)SO2NR a Rb , substituted or unsubstituted -P(O)(C1-C6 alkyl)2, substituted or unsubstituted -(C1-C4 alkylene)P(O)(C1-C6 alkyl)2, substituted or unsubstituted -(C1-C4 alkylene)CONR a R b , substituted or unsubstituted -NR a CONR a R b , substituted or unsubstituted -(C1-C4 alkylene) 5-10 membered heteroaryl, substituted or unsubstituted -(C1-C4 alkylene) 4-10 membered heterocyclyl;

[0018] Alternatively, two R atoms connected to two adjacent atoms 3 The groups and the atoms connecting them together form a substituted or unsubstituted C4-C10 membered carbocyclic ring, a substituted or unsubstituted 4-10 membered heteroaromatic ring or a substituted or unsubstituted 4-10 membered heterocyclic ring;

[0019] s is 0, 1, 2, 3 or 4, each R is independently selected from: hydrogen, deuterium, halogen, cyano, nitro, NR a R b , substituted or unsubstituted -(C1-C4 alkylene)NR a R b , hydroxyl, carboxyl, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted -COO(C1-C6 alkyl), substituted or unsubstituted -CONR a R b, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C3-C10 cycloalkyloxy, substituted or unsubstituted 4-10 membered heterocyclyl, substituted or unsubstituted -(C1-C4 alkylene)4-10 membered heterocyclyl, substituted or unsubstituted C(O)4-10 membered heterocyclyl, substituted or unsubstituted -(C1-C4 alkylene)C(O)4-10 membered heterocyclyl, substituted or unsubstituted S(O)4-10 membered heterocyclyl, substituted or unsubstituted -(C1-C4 alkylene)S(O)4-10 membered heterocyclyl, substituted or unsubstituted S(O)2 4-10 membered heterocyclyl, substituted or unsubstituted -(C1-C4 alkylene)S(O)2 4-10 membered heterocyclyl, substituted or unsubstituted 4-10 membered heterocyclyloxy, substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted C6-C10 aryloxy, substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted 5-10 membered heteroaryloxy, substituted or unsubstituted -(C1-C4 alkylene)COO(C1-C6 alkyl), substituted or unsubstituted -S(O)2(C1-C6 alkyl), substituted or unsubstituted -S(O)(NR a )(C1-C6 alkyl), substituted or unsubstituted-(C1-C4 alkylene)S(O)2(C1-C6 alkyl), substituted or unsubstituted-(C1-C4 alkylene)S(O)(NR a )(C1-C6 alkyl), substituted or unsubstituted -SO2NR a R b , substituted or unsubstituted -(C1-C4 alkylene)SO2NR a R b , substituted or unsubstituted -(C1-C4 alkylene)CONR a R b , substituted or unsubstituted -NR a CONR a R b , substituted or unsubstituted -(C1-C4 alkylene) 5-10 membered heteroaryl, substituted or unsubstituted -(C1-C4 alkylene) 4-10 membered heterocyclyl;

[0020] Alternatively, two R groups attached to two adjacent atoms together with the atoms to which they are attached form a substituted or unsubstituted 4-10 membered cycloalkylene group or a substituted or unsubstituted 4-10 membered heterocyclylene group;

[0021] L is (L a ) t ; Wherein, t is 1, 2, 3 or 4;

[0022] Each L a Independently selected from: O, CO, S, S(O), S(O)2, NR 4 、C(R5 )2;

[0023] Each R 4 Independently selected from: H, C1-C6 alkyl, -SO2(C1-C6 alkyl), C1-C6 alkylacyl, C3-C10 cycloalkyl, wherein the alkyl, alkylacyl and cycloalkyl may be further substituted with one or more halogens;

[0024] Each R 5 Independently selected from: hydrogen, deuterium, halogen, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy;

[0025] Alternatively, two R attached to the same carbon atom 5 and together with the carbon atoms to which they are attached form a 3-6 membered cycloalkylene or a 4-6 membered heterocyclylene, wherein the cycloalkylene and heterocyclylene are optionally further substituted by one or more groups independently selected from deuterium, halogen, =O, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy;

[0026] Alternatively, two R attached to different carbon atoms 5 Together with all atoms connecting them, they form a 3-6 membered cycloalkylene or a 4-6 membered heterocyclylene, wherein the cycloalkylene and heterocyclylene are optionally further substituted by one or more groups independently selected from deuterium, halogen, =O, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy;

[0027] Or, R 4 and an R 5 and all atoms connecting them together form a 3-6 membered cycloalkylene or a 4-6 membered heterocyclylene, wherein the cycloalkylene and heterocyclylene are optionally further substituted by one or more groups independently selected from deuterium, halogen, =O, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy;

[0028] Each of the above substitutions independently refers to substitution by one or more substituents selected from the group consisting of deuterium, halogen, hydroxy, carboxyl, amino, cyano, nitro, =O, =C(R c )2, benzyl, C1-C6 alkyl, C1-C6 alkyl acyl, -CO(C1-C6 alkoxy), -CONR a R b 、-SO2(C1-C6 alkyl),-SO2(C1-C6 cycloalkyl), SO2NR a R b 、-S(O)(NR a)(C1-C6 alkyl), C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C10 cycloalkyl, C3-C10 cycloalkyloxy, 4-10 membered heterocyclyl, 4-10 membered heterocyclyloxy, C6-C10 aryl, C6-C10 aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, each of which may be optionally further substituted with one or more substituents selected from halogen, =O, CN, hydroxy, amino, carboxyl, C1-C4 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl, C3-C6 cycloalkoxy;

[0029] Each R a , each R b Each of the following is independently selected from H, C1-C6 alkyl, -SO2(C1-C6 alkyl), -CO(C1-C6 alkyl), C1-C6 alkylacyl, C3-C10 cycloalkyl, wherein the alkyl, cycloalkyl, alkylacyl and heterocyclyl groups are optionally further substituted with one or more substituents selected from halogen, =O, CN, hydroxy, amino, carboxyl, C1-C4 alkoxy, C3-C6 cycloalkyl and C3-C6 cycloalkyloxy;

[0030] or R attached to the same nitrogen atom a With R b and the nitrogen atom where they are located together form a substituted or unsubstituted 4-8 membered heterocyclic group, which may be optionally further substituted with one or more substituents selected from halogen, =O, CN, hydroxy, amino, carboxyl, C1-C4 alkyl, C1-C4 haloalkyl;

[0031] Each R c Each is independently selected from: hydrogen, deuterium, halogen, C1-C3 alkyl, C1-C3 haloalkyl;

[0032] Or two R c and the carbon atoms where they are located together form a 3-6 membered cycloalkylene or 4-6 membered heterocyclylene, and the cycloalkylene and heterocyclylene may be optionally further substituted by one or more substituents selected from halogen, C1-C4 alkoxy, and C1-C4 haloalkoxy.

[0033] In another preferred embodiment, X is N or CR 1a 、Y is CR 2a 、Z is CR 3a ;

[0034] R 1a 、R 2a and R 3a Each independently selected from the group consisting of hydrogen, deuterium, halogen, cyano, nitro, NR a R bR , hydroxy, carboxyl, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C2-C4 alkenyl, substituted or unsubstituted C2-C4 alkynyl, substituted or unsubstituted C1-C4 alkoxy, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C3-C6 cycloalkyloxy, substituted or unsubstituted 4-7 membered heterocyclyl, substituted or unsubstituted 4-7 membered heterocyclyloxy, substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted C6-C10 aryloxy, substituted or unsubstituted 5-7 membered heteroaryl, substituted or unsubstituted 5-7 membered heteroaryloxy, each of the above groups may be optionally further substituted with one or more halogens; a and R b The definition of is the same as above.

[0035] In another preferred embodiment, L is selected from: O, CO, S, S(O), S(O)2, NR 4 、C(R 5 )2、-OC(R 5 )2-、-C(R 5 )2-C(R 5 )2-、-NR 4 -C(R 5 )2-、-NR 4 -S(O)2-、-C(R 5 )2-S(O)2-;R 4 and R 5 The definition of is the same as above.

[0036] In another preferred embodiment, L is selected from: O, CO, S, S(O), S(O)2, NR 4 、C(R 5 )2. -OC(R 5 )2-、 -C(R 5 )2-C(R 5 )2-、 -NR 4 -C(R 5 )2-、 -NR 4 -S(O)2-、-C(R 5 )2-S(O)2-, the above groups may be optionally further substituted by one or more substituents selected from halogen, C1-C3 alkyl, C1-C3 alkoxy;

[0037] Each R 4Independently selected from: H, C1-C4 alkyl, -SO2(C1-C3 alkyl), C1-C3 alkylacyl, C3-C5 cycloalkyl, wherein the alkyl, alkylacyl and cycloalkyl groups may be further substituted with one or more halogens;

[0038] Each R 5 Independently selected from the group consisting of: hydrogen, deuterium, halogen, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy.

[0039] In another preferred embodiment, L is selected from: O, C(R 5 )2; each R 5 Independently selected from the group consisting of: hydrogen, deuterium, halogen, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy.

[0040] In another preferred embodiment, L is O or -CH2-.

[0041] In another preferred embodiment, ring A is selected from: benzene ring, pyridine ring, C4-C10 carbon ring, 4-10 membered heterocycle;

[0042] Each R 2 Independently selected from: hydrogen, deuterium, halogen, cyano, NR a R b , =O, C1-C4 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C3-C6 cycloalkyloxy, 3-6 membered heterocyclyl, 3-6 membered heterocyclyloxy, each of the above groups may be optionally further substituted by one or more substituents selected from halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 cycloalkyl, C1-C4 halocycloalkyl, C1-C4 cycloalkoxy, C1-C4 halocycloalkoxy, and cyano; R a and R b The definition of is the same as above.

[0043] In another preferred embodiment, ring A is a benzene ring, a pyridine ring, a C4-C8 carbon ring, or a 6-8 membered heterocycle.

[0044] In another preferred embodiment, ring A is a benzene ring or a pyridine ring;

[0045] The relationship between L and the imidazole ring is para or meta substitution of ring A;

[0046] Each R 2 Independently selected from: hydrogen, deuterium, halogen, cyano, C1-C4 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C3-C6 cycloalkyloxy, each of the above groups may be optionally further substituted by one or more halogens.

[0047] In another preferred embodiment, ring A is selected from: The above structure may optionally further contain one or two intracyclic double bonds;

[0048] Each R 2 Independently selected from: hydrogen, deuterium, halogen, cyano, C1-C4 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C3-C6 cycloalkyloxy, each of the above groups may be optionally further substituted by one or more halogens.

[0049] In another preferred embodiment, ring B is selected from: a benzene ring, a 5-10 membered heteroaromatic ring, a C3-C8 carbocyclic ring, a 4-10 membered heterocyclic ring;

[0050] Each R 3 Independently selected from: hydrogen, deuterium, halogen, cyano, NR a R b , substituted or unsubstituted -(C1-C4 alkylene)NR a R b , hydroxyl, carboxyl, =O, =C(R c )2, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted -COO(C1-C6 alkyl), substituted or unsubstituted -CONR a R b , substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C3-C6 cycloalkyloxy, substituted or unsubstituted 4-8 membered heterocyclyl, substituted or unsubstituted 4-8 membered heterocyclyloxy, substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted C6-C10 aryloxy, substituted or unsubstituted 5-8 membered heteroaryl, substituted or unsubstituted 5-8 membered heteroaryloxy, substituted or unsubstituted -(C1-C4 alkylene)COOH, substituted or unsubstituted -(C1-C4 alkylene)COO(C1-C6 alkyl), substituted or unsubstituted -SO2(C1-C6 alkyl), substituted or unsubstituted -S(O)(NR a )(C1-C6 alkyl), substituted or unsubstituted-(C1-C4 alkylene)SO2(C1-C6 alkyl), substituted or unsubstituted-(C1-C4 alkylene)S(O)(NR a )(C1-C6 alkyl), substituted or unsubstituted -SO2NR a R b , substituted or unsubstituted -(C1-C4 alkylene)SO2NR a R b, substituted or unsubstituted -P(O)(C1-C6 alkyl)2, substituted or unsubstituted -(C1-C4 alkylene)P(O)(C1-C6 alkyl)2, substituted or unsubstituted -(C1-C4 alkylene)CONR a R b , substituted or unsubstituted -NR a CONR a R b , substituted or unsubstituted -(C1-C4 alkylene) 5-10 membered heteroaryl, substituted or unsubstituted -(C1-C4 alkylene) 4-8 membered heterocyclyl;

[0051] Alternatively, two R atoms connected to two adjacent atoms 3 The groups and the atoms connecting them together form a substituted or unsubstituted C5-C8 membered carbocyclic ring, a substituted or unsubstituted 5-8 membered heteroaromatic ring or a substituted or unsubstituted 5-8 membered heterocyclic ring;

[0052] R a 、R b and R c The definition of is the same as above.

[0053] In another preferred embodiment, ring B is selected from: a benzene ring, a 5-10 membered heteroaromatic ring, a C4-C6 carbocyclic ring, and a 4-8 membered heterocyclic ring.

[0054] In another preferred embodiment, each R 3 Independently selected from: hydrogen, deuterium, halogen, cyano, NR a R b 、-(C1-C4 alkylene)NR a R b , hydroxyl, carboxyl, =O, C1-C6 alkyl, C1-C6 alkoxy, -COO(C1-C6 alkyl), -CONR a R b , C3-C6 cycloalkyl, C3-C6 cycloalkyloxy, 4-8 membered heterocyclyl, 4-8 membered heterocyclyloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy, -(C1-C4 alkylene)COOH, -(C1-C4 alkylene)COO(C1-C6 alkyl), -SO2(C1-C6 alkyl), -S(O)(NR a )(C1-C6 alkyl), -(C1-C4 alkylene)SO2(C1-C6 alkyl), -(C1-C4 alkylene)S(O)(NR a )(C1-C6 alkyl), -SO2NR a R b 、-(C1-C4 alkylene)SO2NR a R b、-P(O)(C1-C6 alkyl)2、-(C1-C4 alkylene)P(O)(C1-C6 alkyl)2、-(C1-C4 alkylene)CONR a R b 、-NR a CONR a R b , -(C1-C4 alkylene) 5-10 membered heteroaryl, -(C1-C4 alkylene) 4-8 membered heterocyclyl, each of the above groups may be optionally further replaced by one or more selected from halogen, =O, CN, hydroxyl, amino, carboxyl, C1-C4 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl, C3-C6 cycloalkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, C3-C6 halocycloalkyl, C3-C6 halocycloalkoxy, C1-C6 alkylacyl, C1-C6 alkoxyacyl, -CONR a R b 、-SO2(C1-C6 alkyl),-SO2(C1-C6 cycloalkyl), SO2NR a R b 、-S(O)(NR a )(C1-C6 alkyl) substituent;

[0055] Alternatively, two R atoms connected to two adjacent atoms 3 The groups and the atoms connecting them together form a substituted or unsubstituted C5-C8 membered carbocyclic ring, a substituted or unsubstituted 5-8 membered heteroaromatic ring or a substituted or unsubstituted 5-8 membered heterocyclic ring;

[0056] R a and R b The definition of is the same as above.

[0057] In another preferred embodiment, the two R 3 The groups and the atoms connecting them together form a substituted or unsubstituted 5-6 membered heteroaryl ring or a 5-6 membered heterocyclic ring.

[0058] In another preferred embodiment, ring B is selected from the group consisting of benzene ring, thiophene, pyridine, pyrimidine, indazole, benzo[d][1,2,3]triazole, and [1,2,4]triazolo[4,3-a]pyridine.

[0059] In another preferred embodiment, ring C is a 5-10 membered heteroaromatic ring;

[0060] Each R is independently selected from: hydrogen, deuterium, halogen, cyano, NR a R b, hydroxyl, carboxyl, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted -COO(C1-C6 alkyl), substituted or unsubstituted -CONR a R b , substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C3-C6 cycloalkyloxy, substituted or unsubstituted 4-8 membered heterocyclyl, substituted or unsubstituted -(C1-C4 alkylene)4-8 membered heterocyclyl, substituted or unsubstituted C(O)4-8 membered heterocyclyl, substituted or unsubstituted -(C1-C4 alkylene)C(O)4-8 membered heterocyclyl, substituted or unsubstituted S(O)4-8 membered heterocyclyl, substituted or unsubstituted -(C1-C4 alkylene)S(O)3-8 membered heterocyclyl, substituted or unsubstituted S(O)2 4-10 membered heterocyclyl, substituted or unsubstituted -(C1-C4 alkylene)S(O)2 4-10 membered heterocyclyl, substituted or unsubstituted 4-8 membered heterocyclyloxy, substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted C6-C10 aryloxy, substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted 5-10 membered heteroaryloxy, substituted or unsubstituted -(C1-C4 alkylene)COO(C1-C6 alkyl), substituted or unsubstituted -S(O)2(C1-C6 alkyl), substituted or unsubstituted -S(O)(NR a )(C1-C6 alkyl), substituted or unsubstituted-(C1-C4 alkylene)S(O)2(C1-C6 alkyl), substituted or unsubstituted-(C1-C4 alkylene)S(O)(NR a )(C1-C6 alkyl), substituted or unsubstituted -SO2NR a R b , substituted or unsubstituted -(C1-C4 alkylene)SO2NR a R b , substituted or unsubstituted -(C1-C4 alkylene)CONR a R b , substituted or unsubstituted -NR a CONR a R b , substituted or unsubstituted -(C1-C4 alkylene) 5-10 membered heteroaryl, substituted or unsubstituted -(C1-C4 alkylene) 4-10 membered heterocyclyl; R a and R b The definition of is the same as above.

[0061] In another preferred embodiment, ring C is a 5-6 membered heteroaromatic ring.

[0062] In another preferred embodiment, ring C is a 5-6 membered heteroaromatic ring containing 1 or 2 N atoms.

[0063] In another preferred embodiment, each R is independently selected from: hydrogen, deuterium, halogen, cyano, NR a R b , hydroxyl, carboxyl, C1-C6 alkyl, C1-C6 alkoxy, -COO(C1-C6 alkyl), -CONR a R b , C3-C6 cycloalkyl, C3-C6 cycloalkyloxy, 4-8 membered heterocyclyl, -(C1-C4 alkylene) 4-8 membered heterocyclyl, C(O) 4-8 membered heterocyclyl, -(C1-C4 alkylene) C(O) 4-8 membered heterocyclyl, S(O) 4-8 membered heterocyclyl, -(C1-C4 alkylene) S(O) 4-8 membered heterocyclyl, S(O) 2 4-8 membered heterocyclyl, -(C1-C4 alkylene) S(O) 2 4-8 membered heterocyclyl, 4-8 membered heterocyclyloxy, C6-C10 aryl, C6-C10 aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, -(C1-C4 alkylene) COO(C1-C6 alkyl), -S(O) 2(C1-C6 alkyl), -S(O)(NR a )(C1-C6 alkyl), -(C1-C4 alkylene)S(O)2(C1-C6 alkyl), -(C1-C4 alkylene)S(O)(NR a )(C1-C6 alkyl), -SO2NR a R b 、-(C1-C4 alkylene)SO2NR a R b 、-(C1-C4 alkylene)CONR a R b 、-NR a CONR a R b , -(C1-C4 alkylene) 5-10 membered heteroaryl, -(C1-C4 alkylene) 4-10 membered heterocyclyl, each of the above groups may be optionally further replaced by one or more selected from halogen, =O, CN, hydroxyl, amino, carboxyl, C1-C4 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl, C3-C6 cycloalkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, C3-C6 halocycloalkyl, C3-C6 halocycloalkoxy, C1-C6 alkylacyl, C1-C6 alkoxyacyl, -CONR a R b 、-SO2(C1-C6 alkyl),-SO2(C1-C6 cycloalkyl), SO2NR a R b 、-S(O)(NR a )(C1-C6 alkyl) substituent; R a and Rb The definition of is the same as above.

[0064] In another preferred embodiment, Selected from: wherein R', R", R"', R"" are each independently selected from the group consisting of H, halogen, NR a R b , C1-C4 alkyl, 4-6 membered heterocyclyl, C1-C4 alkoxy, C3-C6 cycloalkyl, cyano, -(C1-C4 alkyl)4-6 membered heterocyclyl,; the above groups are optionally substituted by 1, 2 or 3 substituents selected from the following groups: halogen, C1-C4 alkyl, C1-C4 haloalkyl, carboxyl, -COO(C1-C4 alkyl), -SO2(C1-C4 alkyl), -CONR a R b 、SO2NR a R b ; R a 、R b Each is independently selected from: H, C1-C4 alkyl.

[0065] In another preferred embodiment, the compound is selected from the following group:

[0066] The second aspect of the present invention provides a pharmaceutical composition comprising the compound described in the first aspect, its stereoisomers, tautomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs, and pharmaceutically acceptable carriers, adjuvants or excipients.

[0067] The third aspect of the present invention provides a kit comprising the compound described in the first aspect, its stereoisomers, tautomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs, or the pharmaceutical composition described in the second aspect.

[0068] In a fourth aspect, the present invention provides the use of the compound described in the first aspect, its stereoisomers, tautomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs, or the pharmaceutical composition described in the second aspect, as a soluble epoxide hydrolase inhibitor; or for the preparation of a medicament for treating sEH-related or mediated diseases.

[0069] In another preferred embodiment, the sEH-related or mediated disease is selected from the group consisting of: Alzheimer's disease, Parkinson's disease, Huntington's disease, dementia, cerebral ischemia, epilepsy, traumatic brain injury, stroke, Alexander disease, Alpers disease, amyotrophic lateral sclerosis, ataxia telangiectasia, Batten disease, Canavan disease, Cockayne syndrome, corticobasal degeneration, Creutzfeldt-Jakob disease, Kennedy disease, Krabbe disease, Lewy body dementia, Machado-Johnson disease, Cerf's disease, multiple sclerosis, multiple system atrophy, Pelitzow-Merzbacher disease, Pick's disease, primary lateral sclerosis, Refsum's disease, Sandhoff's disease, Schilder's disease, Tay-Sachs disease, spinocerebellar ataxia, spinal muscular atrophy, progressive supranuclear palsy, transmissible spongiform encephalopathy, tabes dorsalis, peripheral neuropathy, neuroinflammation, asthma, chronic obstructive pulmonary disease, chronic bronchitis, cystic fibrosis, atherosclerosis, blood Restenosis after angioplasty, coronary artery disease, rheumatoid arthritis, osteoarthritis, dermatitis, eczematous dermatitis, psoriasis, late and chronic solid organ rejection after transplantation, systemic lupus erythematosus, dermatomyositis, polymyositis, Sjögren's syndrome, polymyalgia rheumatica, temporal arteritis, Behçet's disease, Guillain-Barré syndrome, Wegener's granulomatosis, polyarteritis nodosa, neuralgia, vasculitis, pancreatitis, ulcerative colitis, Crohn's disease, Kaposi's sarcoma, hypertension, pulmonary hypertension, adult respiratory distress syndrome, end-stage renal disease, heart failure, renal failure, liver failure, cardiac fibrosis, renal fibrosis, pulmonary fibrosis, hepatic fibrosis, non-alcoholic fatty liver disease, ischemic limb disease, intermittent claudication, endothelial dysfunction, male erectile dysfunction, Raynaud's disease, diabetic vasculopathy, herpes zoster, gastrointestinal diseases caused by nonsteroidal anti-inflammatory drugs, hand-foot syndrome caused by chemotherapy, etc.

[0070] Compared with the prior art, the beneficial effect of the present invention lies in that the cyclic imidazole compound described in the present invention has a core structure of a benzene ring imidazole or an azoaromatic ring imidazole, the 2-position of which is a substituted or unsubstituted saturated or aromatic ring system, and the ring substituent at the 2-position is also connected to the new ring system through a suitable connecting group. Therefore, the cyclic imidazole compound in the present invention not only exhibits excellent inhibitory activity at the picomolar level against human sEH, but also has an inhibitory activity against mouse sEH that is comparable to or even stronger than TPPU. The difference in its inhibitory activity among various genera is small, thus having good development potential. DETAILED DESCRIPTION

[0071] Definition of terms

[0072] It is to be understood that the terminology used herein is for the purpose of describing particular embodiments and is not intended to be limiting.

[0073] In the present invention, unless otherwise specified, the terms used have the general meanings commonly known to those skilled in the art.

[0074] In the present invention, the term "C1-C6" refers to a group having 1, 2, 3, 4, 5 or 6 carbon atoms, "C1-C8" refers to a group having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, and so on. "3-8 membered" refers to a group having 3, 4, 5, 6, 7 or 8 ring atoms, and so on.

[0075] As used herein, the term "acyl" represents hydrogen or alkyl as defined herein, attached to the parent molecular group through a carbonyl as defined herein, including but not limited to formyl (i.e., formaldehyde group), acetyl, trifluoroacetyl, propionyl, and butyryl. Exemplary unsubstituted acyl groups include from 1 to 6, from 1 to 11, or from 1 to 21 carbon atoms.

[0076] As used herein, the term "alkyl" refers to a branched or straight-chain monovalent saturated aliphatic hydrocarbon group of 1 to 20 carbon atoms (such as 1 to 16 carbon atoms, 1 to 10 carbon atoms, or 1 to 6 carbon atoms). An alkylene group is a divalent alkyl group.

[0077] The term "alkenyl" as used herein, alone or in combination with other groups, refers to a straight or branched chain hydrocarbon residue having a carbon-carbon double bond and having 2-20 carbon atoms (e.g., 2-16 carbon atoms, 2-10 carbon atoms, 2-6, or 2 carbon atoms).

[0078] The term "alkynyl" as used herein, alone or in combination with other groups, refers to a straight or branched chain hydrocarbon residue having a carbon-carbon triple bond and having 2-20 carbon atoms (e.g., 2-16 carbon atoms, 2-10 carbon atoms, 2-6, or 2 carbon atoms).

[0079] As used herein, the term "amino" represents -N(RN1)2, wherein each RN1 is independently H, N(RN2)2, SO2ORN2, SO2RN2, SORN2, N-protecting group, alkyl, alkoxy, aryl, heteroaryl, arylalkyl, cycloalkyl, heterocycloalkyl, acyl (e.g., acetyl, trifluoroacetyl, or other groups described herein), wherein each of these described RN1 groups may be optionally further substituted; or two RN1s are combined to form an alkylene or heteroalkylene group, and wherein each RN2 is independently H, alkyl, or aryl. The amino groups of the present invention may be unsubstituted amino groups (i.e., -NH2) or substituted amino groups (i.e., -N(RN1)2).

[0080] As used herein, the term "aryl" refers to a monocyclic or polycyclic ring system with aromaticity, wherein all the ring atoms are carbon. For example, phenyl and naphthyl. The hydrogen of the ring-forming carbon atoms may be further substituted by one or more different substituents. Furthermore, two or more adjacent substituents may be linked to each other to form a non-aromatic paracyclic, bridged and / or spirocyclic system, and the paracyclic, bridged and / or spirocyclic system may contain one or more unsaturated structures (including but not limited to alkenes, alkynes, etc.), and one or more carbon atoms constituting the ring system may be optionally replaced by atoms selected from nitrogen, oxygen and sulfur. Examples of such groups include, but are not limited to, 1,2,3,4-tetrahydronaphthyl, 1,2-dihydronaphthyl, indanyl, 1H-indenyl, wait.

[0081] As used herein, the term "aromatic substituent" refers to an unsaturated substituent having aromaticity consisting of 5-14 atoms, and the atoms forming the ring may include one or more of carbon atoms, nitrogen atoms, oxygen atoms and sulfur atoms. The aromatic substituent may be further substituted by different substituents. Furthermore, two or more adjacent substituents may be linked to each other to form a non-aromatic cyclic, bridged and / or spirocyclic system, and the cyclic, bridged and / or spirocyclic system may contain one or more unsaturated structures (including but not limited to alkenes, alkynes, etc.), and one or more carbon atoms constituting the ring system may be optionally replaced by atoms selected from nitrogen, oxygen and sulfur.

[0082] The term "arylalkyl" as used herein represents an alkyl group substituted with an aryl group. Exemplary unsubstituted arylalkyl groups are from 7 to 30 carbon atoms (including, but not limited to, from 7 to 16 or from 7 to 20 carbon atoms, such as C 6-10 Aryl C 1-6 Alkyl, C 6-10 Aryl C 1-10 Alkyl, or C 6-10 Aryl C 1-20 In some embodiments, the alkyl and aryl groups are each further substituted with 1, 2, 3, or 4 substituents as defined herein for the respective groups.

[0083] The term "cyano" as used herein represents a -CN group.

[0084] As used herein, the term "carbocyclyl" refers to a C 3-14 Monocyclic, bicyclic, or tricyclic structures, wherein the ring structure as a whole is not aromatic but may contain one or more unsaturated structures, including but not limited to alkenes, alkynes, etc. The ring may be further substituted with one or more substituents. When there are two or more rings in the carbocyclic group, the rings may further form a cyclic ring, a bridged ring, a spirocyclic ring, or any combination thereof, and heteroatoms (if any) may be located in any suitable position.

[0085] As used herein, the term "cycloalkyl" refers to a saturated, non-aromatic, monovalent monocarbocyclic or polycarbocyclic group (e.g., fused, bridged, spirocyclic, etc.) of 3 to 14 carbon atoms. The term is further exemplified by groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, and adamantyl.

[0086] The term "halogen" as used herein refers to a fluorine (fluoro), chlorine (chloro), bromine (bromo), or iodine (iodo) group.

[0087] As used herein, the term "heteroalkyl" refers to an alkyl group as defined herein, in which one or more of the constituent carbon atoms has been replaced by nitrogen, oxygen, or sulfur. In some embodiments, the heteroalkyl group may be further substituted with one, two, three, or four substituents as described herein for alkyl. "Alkoxy" represents all branched and straight chain isomers of a specified number of carbon atoms, with the terminal hydrogen atoms replaced by oxygen atoms. Representative examples include, but are not limited to, methoxy, ethoxy, propoxy, and isopropoxy.

[0088] As used herein, the term "heteroalkenyl" refers to an alkenyl group as defined herein, wherein one or more non-olefinic carbon atoms have been replaced by nitrogen, oxygen, or sulfur. In some embodiments, the heteroalkenyl group may be further substituted with 1, 2, 3, or 4 substituents as described herein for alkenyl.

[0089] As used herein, the term "heteroalkynyl" refers to an alkynyl group as defined herein in which one or more of the non-alkyne constituent carbon atoms has been replaced by nitrogen, oxygen, or sulfur. In some embodiments, the heteroalkynyl group can be further substituted with 1, 2, 3, or 4 substituents as described herein for alkynyl.

[0090] As used herein, the term "heteroaryl" refers to a monocyclic or polycyclic ring system having aromaticity, wherein the ring atoms (preferably 5-12) contain, in addition to carbon atoms, at least one (such as 1, 2, 3 or 4) atom selected from nitrogen, oxygen, and sulfur, and the nitrogen and sulfur atoms in the ring may also be in the form of suitable oxides, including but not limited to nitrogen oxides, -S(O)-, etc. The hydrogen of the ring atoms may be further substituted by one or more different substituents. Furthermore, two or more adjacent substituents may be linked to each other to form a non-aromatic cyclic, bridged and / or spirocyclic system, and the cyclic, bridged and / or spirocyclic system may contain one or more unsaturated structures (including but not limited to alkenes, alkynes, etc.), and one or more carbon atoms constituting the ring system may be optionally replaced by atoms selected from nitrogen, oxygen and sulfur. Examples of heteroaryl include, but are not limited to, pyridyl, pyrimidinyl, pyrazolyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, pyridoimidazolyl, imidazolyl, oxazolyl, and thiazolyl.

[0091] As used herein, the term "heteroarylalkyl" represents an alkyl group substituted with a heteroaryl group. Exemplary unsubstituted heteroarylalkyl groups include, but are not limited to, groups having from 7 to 30 carbon atoms (e.g., from 7 to 16 or from 7 to 20 carbon atoms, e.g., C 2-9 Heteroaryl C 1-6 Alkyl, C 2-9 Heteroaryl C 1-10 Alkyl, or C 2-9 Heteroaryl C 1-20 In some embodiments, the alkyl and heteroaryl groups can each be further substituted with 1, 2, 3, or 4 substituents as defined herein for the respective groups.

[0092] As used herein, the term "heterocyclic group" refers to a monocyclic or polycyclic non-aromatic system containing at least one (such as 1, 2, 3 or 4) ring heteroatom selected from N, O or S, which may contain one or more unsaturated structures, including but not limited to alkenes, alkynes, etc. The nitrogen atom and sulfur atom in the ring can also be in the form of their suitable oxides, including but not limited to nitrogen oxides, -S(O)-, -S(O)2-, etc. The ring may be further substituted by one or more substituents. When there are two or more rings in the heterocyclic group, the rings can further form a cyclic ring, a bridged ring, a spirocyclic ring or any combination of several forms, and the heteroatom can be in any suitable position therein. Examples of heterocyclic groups include, but are not limited to, morpholinyl, thiomorpholinyl, furanyl, piperazinyl, piperidinyl, pyranyl, pyrrolidinyl, tetrahydropyranyl, tetrahydrofuranyl, 1,3-dioxanyl, decahydroisoquinolinyl,

[0093] As used herein, the term "heterocyclylalkyl" represents an alkyl group substituted with a heterocyclyl group. Exemplary unsubstituted heterocyclylalkyl groups include, but are not limited to, groups with from 7 to 30 carbon atoms (e.g., from 7 to 16 or from 7 to 20 carbon atoms, such as C 2-9 Heterocyclyl C 1-6 Alkyl, C 2-9 Heterocyclyl C 1-10 Alkyl, or C 2-9 Heterocyclyl C 1-20 In some embodiments, the alkyl and heterocyclyl groups can each be further substituted with 1, 2, 3, or 4 substituents as defined herein for the respective groups.

[0094] The term "hydroxy" as used herein refers to an -OH group. The term "thiol" as used herein refers to a -SH group.

[0095] Alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl (such as cycloalkyl), aryl, heteroaryl, and heterocyclyl groups can be substituted or unsubstituted. When substituted, there will generally be 1-4 substituents unless otherwise specified. Substituents include, but are not limited to, aryl (such as substituted and unsubstituted phenyl), carbocyclyl (such as substituted and unsubstituted cycloalkyl), halogen (such as fluoro), hydroxy, heteroalkyl (such as substituted and unsubstituted methoxy, ethoxy, or thioalkoxy), heteroaryl, heterocyclyl, amino (such as NH2 or mono- or dialkylamino), azido, cyano, nitro, sulfhydryl, sulfonyl, sulfone, alkoxycarbonyl, methylene, oxo (=O) and the like. Aryl, carbocyclyl (such as cycloalkyl), heteroaryl, and heterocyclyl can also be substituted with alkyl (unsubstituted and substituted, for example, arylalkyl (such as substituted and unsubstituted benzyl)).

[0096] In practicing the methods of the present invention, an "effective amount" of any one of the compounds of the present invention or any combination of compounds of the present invention or pharmaceutically acceptable salts thereof is administered by any common and acceptable method known in the art (alone or in combination).

[0097] As used herein, the term "epoxyeicosatrienoic acid" refers to a signaling molecule formed by the action of cytochrome P450 epoxygenase on 20-carbon essential fatty acids, such as arachidonic acid. A "dihydroxyeicosatrienoic acid" is the corresponding vicinal diol produced by the hydrolysis of an epoxyeicosatrienoic acid, for example, by a soluble epoxide hydrolase. As used herein, the term "increasing the level of epoxyeicosatrienoic acid" refers to an increase in the total level of epoxyeicosatrienoic acid in a subject following administration of a compound of the present invention, as compared to the total level of epoxyeicosatrienoic acid in the subject prior to administration. As used herein, the term "decreasing the level of dihydroxyeicosatrienoic acid" refers to an increase in the total level of dihydroxyeicosatrienoic acid in a subject following administration of a compound of the present invention, as compared to the total level of dihydroxyeicosatrienoic acid in the subject prior to administration.

[0098] As used herein, the term "inhibit soluble epoxide hydrolase" refers to an agent that inhibits the enzymatic activity of soluble epoxide hydrolase with a half inhibitory concentration (IC) of 50Less than 10 μM (e.g., less than 5 μM, less than 1 μM, less than 500 nM, less than 100 nM, less than 10 nM, etc.). The enzymatic activity of the soluble epoxide hydrolase can be determined using any method known in the art. For example, the activity can be determined using an assay utilizing (3-phenyl-oxiranyl)-acetic acid cyano-(6-methoxy-naphthalen-2-yl)-methyl ester (PHOME) as a substrate (Analytical Biochemistry 2005, 343, 66-75). In this specific assay, the hydrolysis of PHOME by the epoxide hydrolase produces highly fluorescent 6-methoxy-2-naphthaldehyde, the concentration of which can be determined using an excitation wavelength of 330 nm and an emission wavelength of 465 nm.

[0099] As used herein, the term "pharmaceutical composition" refers to a composition containing a compound described herein formulated with a pharmaceutically acceptable excipient and approved for manufacture or sale by a governmental regulatory agency as part of a therapeutic regimen for treating a disease in a mammal. The pharmaceutical composition can be formulated, for example, as a unit dosage form for oral administration (e.g., tablets, capsules, caplets, softgels, or syrups); for topical administration (e.g., as a cream, gel, lotion, or ointment); for intravenous administration (e.g., as a sterile solution in a non-particulate embolus and in a solvent system suitable for intravenous use); or as any other pharmaceutically acceptable formulation. As used herein, a "pharmaceutically acceptable excipient" refers to any ingredient other than a compound described herein (e.g., a vehicle capable of suspending or dissolving an active compound) that has the property of being substantially non-toxic and non-inflammatory in a patient. Excipients may include, for example, anti-adherents, antioxidants, binders, coatings, tableting aids, disintegrants, dyes (colorants), emollients, emulsifiers, fillers (diluents), film formers or coatings, flavorings, fragrances, glidants (flow enhancers), lubricants, preservatives, printing inks, adsorbents, suspending or dispersing agents, sweeteners, and water for hydration. Exemplary excipients include, but are not limited to, butylated hydroxytoluene (BHT), calcium carbonate, calcium phosphate (dibasic), calcium stearate, cross-linked carboxymethylcellulose, cross-linked polyvinyl pyrrolidone, citric acid, crospovidone, cysteine, ethylcellulose, gelatin, hydroxypropyl cellulose, hydroxypropyl methylcellulose, lactose, magnesium stearate, maltitol, mannitol, methionine, methylcellulose, methylparaben, microcrystalline cellulose, polyethylene glycol, polyvinyl pyrrolidone, povidone, pregelatinized starch, propylparaben, retinyl palmitate, shellac, silicon dioxide, sodium carboxymethylcellulose, sodium citrate, sodium starch glycolate, sorbitol, starch (corn), stearic acid, sucrose, talc, titanium dioxide, vitamin A, vitamin E, vitamin C, and xylitol.

[0100] As used herein, the term "stereoisomer" is called stereoisomer in English and refers to the isomers produced by the different spatial arrangements of atoms in a molecule. It can be divided into two types: cis-trans isomers and enantiomers, or into two major categories: enantiomers and diastereomers. Stereoisomers caused by the rotation of single bonds are called conformational stereoisomers, sometimes also referred to as rotamers. Stereoisomers caused by bond length, bond angle, double bonds in molecules, rings, etc. are called configurational stereoisomers, which are further divided into two categories. Among them, isomers caused by the inability of double bonds or single bonds of ring carbon atoms to rotate freely are called geometric isomers, also called cis-trans isomers, and are divided into two configurations: Z and E. For example, cis-2-butene and trans-2-butene are a pair of geometric isomers. Stereoisomers with different optical rotation properties due to the lack of anti-axial symmetry in the molecule are called optical isomers and are classified into R and S configurations. In this invention, "stereoisomers," unless otherwise specified, are understood to include one or more of the aforementioned enantiomers, configurational isomers, and conformational isomers.

[0101] As used herein, the term "tautomer" refers to functional group isomers resulting from the rapid shift of an atom (usually a hydrogen atom) between different positions within a molecule. This interconversion process is known as tautomerism. In compounds exhibiting tautomerism, equilibrium between the tautomers typically exists; the tautomers cannot be separated, and their ratios vary with changing external conditions.

[0102] As used herein, the term "pharmaceutically acceptable salt" means any pharmaceutically acceptable salt of a compound of formula (I). For example, any pharmaceutically acceptable salt of the compound described herein is included within the scope of reasonable medical judgment, suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reaction and commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, pharmaceutically acceptable salts are described in: Berge et al., J. Pharmaceutical Sciences 66: 1-19, 1977 and Pharmaceutical Salts: Properties, Selection, and Use (Eds. P.H. Stahl and C.G. Wermuth), Wiley-VCH, 2008. Salts can be prepared in situ during the final isolation and purification of the compounds described herein or separately by reacting the free base group with a suitable organic acid.

[0103] The compounds of the present invention may have ionizable groups so that they can be prepared as pharmaceutically acceptable salts. These salts may be acid addition salts involving inorganic or organic acids, or salts may be prepared (in the case of the acid form of the compounds of the present invention) from inorganic or organic bases. Frequently, the compounds are prepared or used as pharmaceutically acceptable salts prepared as addition products of pharmaceutically acceptable acids or bases. Suitable pharmaceutically acceptable acids and bases and methods for preparing appropriate salts are well known in the art. Salts may be prepared from pharmaceutically acceptable non-toxic acids and bases (including inorganic and organic acids and bases).

[0104] Representative acid addition salts include acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrobromide, hydrochloride, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, toluenesulfonate, undecanoate, and valerate. Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, and magnesium, as well as non-toxic ammonium, quaternary ammonium, and amine cations, including, but not limited to, ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, and ethylamine.

[0105] As used herein, the term "subject" refers to any organism to which a composition according to the present invention can be administered, e.g., for experimental, diagnostic, prophylactic, and / or therapeutic purposes. Typical subjects include any animal (e.g., mammals such as mice, rats, rabbits, non-human primates, and humans). A subject may be a person or animal seeking or requiring treatment, in need of treatment, currently receiving treatment, to be treated in the future, or under the care of a trained professional for a particular disease or condition.

[0106] As used herein, the terms "treat" or "therapeutic" mean both therapeutic treatment and prophylactic or preventative measures, wherein the goal is to prevent or delay (lessen) an unwanted physiological condition, disorder, or disease, or to obtain a beneficial or desired clinical result. Beneficial or desired clinical results include, but are not limited to, relief of symptoms; a reduction in the extent of the condition, disorder, or disease; stabilization of the condition, disorder, or disease state (i.e., not worsening); a delay or slowing of the onset of the condition, disorder, or disease progression; an improvement or alleviation (whether partial or complete) of the condition, disorder, or disease state, whether detectable or undetectable; an improvement in at least one measurable human physiological parameter, which parameter is not necessarily discernible by the patient; or an amelioration or improvement of the condition, disorder, or disease. Treatment includes causing a clinically significant response without excessive levels of side effects. Treatment also includes prolonging survival compared to the expected survival if not receiving treatment.

[0107] Compound

[0108] The present invention provides a compound represented by formula I, its stereoisomers, tautomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs.

[0109] The substituents are as defined above.

[0110] Pharmaceutical composition

[0111] The cycloimidazole compounds or derivatives thereof, stereoisomers, tautomers, hydrates, solvates, pharmaceutically acceptable salts, or prodrugs described herein can be provided in the form of pharmaceutical compositions. The pharmaceutical compositions can include a therapeutically effective amount of the cycloimidazole compound and a pharmaceutically acceptable adjuvant, carrier, or vehicle. Depending on the intended mode of injection, the pharmaceutical composition can be a solid, semisolid, or liquid formulation. Those skilled in the art can select adjuvants, carriers, or vehicles, as well as the dosage form of the pharmaceutical composition according to actual circumstances, and will not be described in detail here.

[0112] How to use

[0113] The present application also provides a method for treating or preventing a disease associated with or mediated by soluble epoxide hydrolase (sEH) in a subject. The method comprises injecting an effective amount of one or more compounds or pharmaceutical compositions as described herein, or a pharmaceutically acceptable salt or prodrug thereof, into the subject. When used in the methods, the term "effective amount" refers to the amount of the compound that can achieve the desired biological effect. For example, the effective amount can be the concentration of the compound that inhibits sEH in vitro.

[0114] The cycloimidazole compounds or pharmaceutical compositions described herein can be used to treat sEH-related or mediated diseases in humans and animals. sEH-related or mediated diseases include, but are not limited to, neurodegenerative diseases, inflammation, hypertension, etc.

[0115] The method of treating or preventing a sEH-related or mediated disease in a subject may further comprise administering to the subject a second compound, biomolecule, or composition. The additional agents and the cyclic imidazole compounds described herein may be used in combination in any order.

[0116] Reagent test kit

[0117] The present application also provides a kit for treating a disease associated with or mediated by sEH in a subject. The kit may include one or more cycloimidazole compounds or pharmaceutical compositions described herein. The kit may also include one or more other agents, such as anti-inflammatory drugs. The kit may include an oral formulation or an intravenous formulation of the cycloimidazole compounds or pharmaceutical compositions described herein. The kit may also include instructions for use of the kit, a container, a device for injecting the compound or composition, and / or a carrier.

[0118] use

[0119] The present application also relates to the use of the cyclic imidazole compounds described herein, their stereoisomers, tautomers, hydrates, solvates, pharmaceutically acceptable salts, or prodrugs as soluble epoxide hydrolase inhibitors. The present application also relates to the use of the cyclic imidazole compounds described herein, their stereoisomers, tautomers, hydrates, solvates, pharmaceutically acceptable salts, or prodrugs in the preparation of medicaments for treating diseases associated with or mediated by sEH.

[0120] The present invention will be described and illustrated in conjunction with the following examples. Unless otherwise specified, all chemical raw materials used can be purchased from the market. It will be understood by those skilled in the art that the following examples are merely illustrative.

[0121] In the following examples, the characterization methods used are as follows.

[0122] H NMR spectroscopy ( 1H NMR): Nuclear magnetic resonance spectra of reaction products and intermediates ( 1 H NMR spectra were obtained on a Bruker AVANCE III HD 400 / 500 in Germany. Sample preparation is as follows: In a clean, dry glass NMR tube, completely dissolve an appropriate amount of sample in approximately 0.5 mL of a deuterated solvent. Most compounds have good solubility in DMSO-d6, making it the preferred deuterated solvent. DMSO-d6 readily solidifies at relatively low room temperatures and requires a hair dryer to dissolve it before loading. Other suitable deuterated reagents, such as CDCl3 and CD3OD, can also be used depending on testing needs. Tetramethylsilane (TMS) was used as the internal standard for testing at room temperature, with a chemical shift of 0 ppm.

[0123] 1. Preparation of intermediates

[0124] Intermediate 1: Preparation of 5-bromo-3,4-difluorobenzene-1,2-diamine

[0125] Step 1: Dissolve 2,3-difluoro-6-nitroaniline (100 g, 574.38 mmol, 1 eq) in 1 L of DMF. Add N-bromosuccinimide (112.45 g, 631.82 mmol, 1.1 eq). The mixture is stirred at 90°C for 3 hours. Thin-layer chromatography indicates completion of the reaction. Upon addition of the mixture to ice water, a yellow solid precipitates. The solid is collected by filtration, slurried with saturated sodium thiosulfate solution, filtered, washed with water, and then dried under reduced pressure to yield 4-bromo-2,3-difluoro-6-nitroaniline (136 g, yield: 93.59%).

[0126] Step 2: To a solution of 4-bromo-2,3-difluoro-6-nitroaniline (10 g, 39.53 mmol, 1 eq) in ethanol (200 mL) was added tin dichloride (29.98 g, 7.59 mL, 158.10 mmol, 4 eq), heated to 70°C and stirred for 2 hours. Liquid chromatography-mass spectrometry showed that the reaction was complete. The reaction solution was concentrated under reduced pressure, then diluted with water, adjusted to pH 9, filtered, and the filter cake was washed with ethyl acetate. The filtrate was washed with brine, dried over anhydrous sodium sulfate, and concentrated to give 5-bromo-3,4-difluorobenzene-1,2-diamine (7.80 g, yield: 88.49%) as a brown solid.

[0127] Intermediate 2: Preparation of 5-(2-amino-4-methylpyrimidin-5-yl)-3,4-difluorobenzene-1,2-diamine

[0128] Step 1: Add pinacol diboronate (15.20 g, 15.20 mL, 59.86 mmol, 1.1255 eq), 2-amino-5-bromo-4-methylpyrimidine (10 g, 53.18 mmol, 1 eq), potassium acetate (15.66 g, 9.97 mL, 159.55 mmol, 3 eq) and [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium dichloromethane complex (2.50 g, 3.42 mmol, 0.0642 eq) to the reaction flask in sequence, replace the system with nitrogen three times, add 1,4-dioxane (200 mL), heat to 110 ° C for 18 hours, cool the reaction solution to room temperature, filter, wash the filter cake with 1,4-dioxane, and use the filtrate directly in the next step.

[0129] Step 2: 5-bromo-3,4-difluorobenzene-1,2-diamine (9.81 g, 44 mmol, 1 eq), 2-pyrimidinamine, 4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-(10.34 g, 44 mmol, 1 eq) in 1,4-dioxane, potassium phosphate (28.02 g, 10.93 mL, 132 mmol, 3 eq), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (2.50 g, 3.42 mmol, 0.0777 eq) and water (60 mL) were added to the reaction flask. After nitrogen replacement three times, the reaction was carried out at 110 ° C for 6 hours. Liquid chromatography-mass spectrometry showed that the reaction was complete. The reaction solution was diluted with water, extracted three times with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by column chromatography (dichloromethane: ethyl acetate = 1: 1) to give 5-(2-amino-4-methylpyrimidin-5-yl)-3,4-difluorobenzene-1,2-diamine (6.10 g, yield: 55.18%).

[0130] Intermediates 2a and 2b can be prepared by selecting appropriate raw materials according to the synthesis method of intermediate 2, and their structures are shown in Table 1.

[0131] Table 1. Structural formulas and chemical names of intermediates 2a and 2b

[0132] Intermediate 3: Preparation of 5-(2-amino-4-(difluoromethyl)pyrimidin-5-yl)-3,4-difluorobenzene-1,2-diamine

[0133] Step 1: To a solution of ethoxyethylene (5 g, 6.67 mL, 69.34 mmol, 1 eq) and pyridine (6.58 g, 6.73 mL, 83.21 mmol, 1.2 eq) in dichloromethane (5 mL) at -70°C was added difluoroacetic anhydride (14.48 g, 83.21 mmol, 1.2 eq). The reaction mixture was warmed to room temperature and stirred overnight. The reaction mixture was washed with deionized water and extracted with dichloromethane. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The resulting intermediate was added to 20 mL of ethanol, followed by the addition of guanidine hydrochloride (4.80 g, 50.2 mmol, 1.2 eq.). After stirring for one hour, sodium hydroxide (2.00 g, 50.0 mmol, 1.2 eq.) was added and the mixture was stirred overnight at room temperature. The mixture was diluted with dichloromethane (20 mL) and stirred for 2 hours. The solvent was removed by concentration, and deionized water (25 mL) was added. The mixture was vigorously stirred for another 2 hours and filtered. The filter cake was washed with deionized water and heptane to give crude 4-(difluoromethyl)pyrimidin-2-amine (7 g, Yield: 69.6%).

[0134] Step 2: To a solution of 4-(difluoromethyl)pyrimidin-2-amine (10 g, 68.91 mmol, 1 eq) in DMF (20 mL) was added N-bromosuccinimide (12.27 g, 5.85 mL, 68.91 mmol, 1 eq). The mixture was stirred at 25°C for 2 hours. Liquid chromatography-mass spectrometry indicated the reaction was complete. The mixture was diluted with ethyl acetate, washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 4:1) to afford 5-bromo-4-(difluoromethyl)pyrimidin-2-amine (12 g, yield: 77.73%).

[0135] Step 3: 5-Bromo-4-(difluoromethyl)pyrimidin-2-amine (70 mg, 312.49 μmol, 1 eq), 3,4-difluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzene-1,2-diamine (84.40 mg, 312.49 μmol, 1 eq), potassium carbonate (86.38 mg, 35.55 μL, 624.97 μmol, 2 eq), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (22.86 mg, 31.25 μmol, 0.1 eq), 1,4-dioxane (3 mL), and water (300 μL) were added to the reaction flask in sequence. The reaction mixture was purged with nitrogen three times and allowed to react at 80°C for 16 hours. Liquid chromatography-mass spectrometry was performed to determine the completion of the reaction. The reaction mixture was concentrated, and the crude product was purified by column chromatography to give 5-[2-amino-4-(difluoromethyl)pyrimidin-5-yl]-3,4-difluorobenzene-1,2-diamine (30 mg, Yield: 33.43%).

[0136] Intermediate 4: Preparation of (1r,4r)-4-[3-cyano-4-(trifluoromethyl)phenoxy]cyclohexane-1-carboxylic acid

[0137] Step 1: Dissolve 5-bromo-2-(trifluoromethyl)benzonitrile (2.05 g, 8.04 mmol), 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (348 mg, 803.54 μmol), potassium hydroxide (1.25 g, 20.09 mmol), and tris(dibenzylideneacetone)dipalladium (736 mg, 803.54 μmmol) in 1,4-dioxane (30 mL) and water (30 mL). The atmosphere was replaced with nitrogen three times, and the mixture was heated to 80°C and stirred for 16 hours. After completion of the reaction, the mixture was cooled to room temperature and quenched with water. The pH was adjusted to approximately 3 with 1 M hydrochloric acid, and the mixture was extracted three times with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and the crude product was purified by normal phase column chromatography to afford 5-hydroxy-2-(trifluoromethyl)benzonitrile (710 mg, yield: 47.22%) as a yellow solid.

[0138] Step 2: Dissolve 5-hydroxy-2-(trifluoromethyl)benzonitrile (710 mg, 3.79 mmol), methyl (1s,4s)-4-hydroxycyclohexane-1-carboxylate (919 mg, 5.69 mmol), and triphenylphosphine (1.51 g, 5.69 mmol) in tetrahydrofuran (15 mL). Cool to 0°C and add dropwise a solution of diisopropyl azodicarboxylate (1.17 g, 5.69 mmol) in tetrahydrofuran (2 mL). Warm to room temperature and react overnight. The reaction mixture is quenched with saturated aqueous ammonium chloride and extracted three times with ethyl acetate. The organic phase is washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate is concentrated and the crude product is purified on a normal phase silica gel column to afford methyl (1r,4r)-4-[3-cyano-4-(trifluoromethyl)phenoxy]cyclohexane-1-carboxylate as a yellow solid (450 mg, yield: 36.24%).

[0139] Step 3: Methyl (1r,4r)-4-[3-cyano-4-(trifluoromethyl)phenoxy]cyclohexane-1-carboxylate (100 mg, 305.53 μmol) and lithium hydroxide monohydrate (26 mg, 611.06 mol) were dissolved in tetrahydrofuran (3 mL) and water (3 mL) and stirred at room temperature for 1 hour. The reaction system was concentrated and diluted with water. The aqueous phase was adjusted to pH 3 with 1M dilute hydrochloric acid and extracted three times with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound (1r,4r)-4-[3-cyano-4-(trifluoromethyl)phenoxy]cyclohexane-1-carboxylic acid (90 mg, yield: 94.03%).

[0140] Intermediate 5: Preparation of 5-(4,5-diamino-2,3-difluorophenyl)-N2-(4-methoxybenzyl)-N4,N4-dimethylpyrimidine-2,4-diamine

[0141] Step 1: Dissolve 5-bromo-2,4-dichloropyrimidine (5 g, 20.85 mmol) in tetrahydrofuran (60 mL). Add dimethylamine (940 mg, 20.85 mmol, 2 M in THF) at -78°C. Slowly warm the temperature to room temperature and react for 2 hours. After completion of the reaction, dilute with ethyl acetate, wash three times with water and brine, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate. The crude product is purified by normal phase separation to yield 5-bromo-2-chloro-N,N-dimethylpyrimidin-4-amine (2.42 g, yield: 49.09%).

[0142] Step 2: 5-Bromo-2-chloro-N,N-dimethylpyrimidin-4-amine (500 mg, 2.11 mmol) and (4-methoxyphenyl)methanamine (352 mg, 2.54 mmol) were dissolved in N,N-dimethylformamide (10 mL) in sequence. Potassium carbonate (590 mg, 4.23 mmol) was added and the mixture was heated to 100°C and stirred for 16 hours. After completion of the reaction, the mixture was diluted with ethyl acetate, washed three times with water and brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by normal phase separation to afford 5-bromo-N2-(4-methoxybenzyl)-N4,N4-dimethylpyrimidine-2,4-diamine (440 mg, yield: 61.72%).

[0143] Step 3: 5-Bromo-N2-(4-methoxybenzyl)-N4,N4-dimethylpyrimidine-2,4-diamine (220 mg, 0.65 mmol), 3,4-difluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzene-1,2-diamine (352 mg, 1.30 mmol), potassium carbonate (182 mg, 1.30 mmol) and tetrakistriphenylphosphine palladium (75 mg, 0.06 mmol) were dissolved in 1,4-dioxane (5 mL) and water (1 mL). The system was replaced with nitrogen three times and heated to 90 ° C for 3 hours. After the reaction, the system was cooled to room temperature, the reaction solution was filtered, the filtrate was concentrated, and the crude product was purified by normal phase medium pressure separation and reverse phase medium pressure separation to obtain compound 5-(4,5-diamino-2,3-difluorophenyl)-N2-(4-methoxybenzyl)-N4,N4-dimethylpyrimidine-2,4-diamine (139 mg, yield: 27.86%).

[0144] Intermediate: Preparation of (1r,4r)-4-(4-(2H-tetrazol-5-yl)phenoxy)cyclohexane-1-carboxylic acid

[0145] Step 1: Dissolve 4-hydroxybenzonitrile (753 mg, 6.19 mmol), methyl (1s,4s)-4-hydroxycyclohexane-1-carboxylate (1 g, 6.19 mmol), and triphenylphosphine (2.46 g, 9.29 mmol) in tetrahydrofuran (20 mL). Add diisopropyl azodicarboxylate (1.92 g, 9.29 mmol) at 0°C and allow to react overnight at room temperature. After completion, the reaction was quenched with water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and the crude product was purified by normal phase separation to yield methyl (1r,4r)-4-(4-cyanophenoxy)cyclohexane-1-carboxylate (500 mg, yield: 31.13%).

[0146] Step 2: Methyl (1r,4r)-4-(4-cyanophenoxy)cyclohexane-1-carboxylate (450 mg, 1.74 mmol), trimethylsilyl azide (473 mg, 3.82 mmol), and dibutylstannane diacetate (705 mg, 1.91 mmol) were dissolved in toluene (10 mL) and heated to 80°C overnight. After completion of the reaction, the mixture was cooled to room temperature and concentrated. The crude product was purified by normal phase separation to afford methyl (1r,4r)-4-(4-(2H-tetrazol-5-yl)phenoxy)cyclohexane-1-carboxylate (508 mg, yield: 87.23%).

[0147] Step 3: Methyl (1r,4r)-4-(4-(2H-tetrazol-5-yl)phenoxy)cyclohexane-1-carboxylate (458 mg, 1.51 mmol) was dissolved in tetrahydrofuran (10 mL) and water (1 mL). Lithium hydroxide monohydrate (130 mg, 3.03 mmol) was added and allowed to react at room temperature for 10 hours. After completion of the reaction, the system was concentrated to remove the volatile solvent, diluted with water (15 mL), and the pH was adjusted to 5 with saturated aqueous potassium bisulfate. A solid precipitated, which was collected by filtration and dried under vacuum to afford (1r,4r)-4-(4-(2H-tetrazol-5-yl)phenoxy)cyclohexane-1-carboxylic acid (429 mg, yield: 98.22%).

[0148] 2. Preparation of Specific Compounds

[0149] Example 1: Preparation of 4-(4-{6-[2-amino-4-(difluoromethyl)pyrimidin-5-yl]-4,5-difluoro-1H-1,3-benzodiazol-2-yl}phenoxy)benzoic acid

[0150] Step 1: To a reaction flask, add 4-fluorobenzaldehyde (2 g, 1.74 mL, 16.11 mmol), N,N-dimethylformamide (10 mL), methyl 4-hydroxybenzoate (2.45 g, 16.11 mmol), and potassium carbonate (3.34 g, 1.37 mL, 24.17 mmol). Evacuate the system and replace the atmosphere with nitrogen three times. After stirring at 80°C for 16 hours, cool to room temperature, dilute with water, and extract with ethyl acetate. The organic phase is washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate is concentrated and purified using a normal phase column to afford methyl 4-(4-formylphenoxy)benzoate (800 mg, yield: 19.37%). 1 H NMR (400MHz, DMSO-d6) δ9.97(s,1H),8.11-7.95(m,4H),7.33-7.18(m,4H),3.86(s,3H).

[0151] Step 2: To the reaction flask, methyl 4-(4-formylphenoxy)benzoate (89.22 mg, 348.17 μmol), 5-[2-amino-4-(difluoromethyl)pyrimidin-5-yl]-3,4-difluorobenzene-1,2-diamine (100 mg, 348.17 μmol) and sodium metabisulfite (117.76 mg, 696.33 μmol) were added in sequence. The system was evacuated and replaced with nitrogen three times, and ethanol (10 mL) and water (1 mL) were added. The mixture was stirred at 80°C for 16 hours and cooled to room temperature. The reaction mixture was concentrated to remove ethanol and diluted with water. The pH was adjusted to 7 with sodium bicarbonate and extracted with dichloromethane. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and purified using a normal phase column to obtain methyl 4-(4-{6-[2-amino-4-(difluoromethyl)pyrimidin-5-yl]-4,5-difluoro-1H-1,3-benzodiazol-2-yl}phenoxy)benzoate (70 mg, yield: 38.41%). MS [M+H] + :found 524.4.

[0152] Step 3: 4-(4-{6-[2-amino-4-(difluoromethyl)pyrimidin-5-yl]-4,5-difluoro-1H-1,3-benzodiazol-2-yl}phenoxy)benzoic acid methyl ester (60 mg, 114.62 μmol) and lithium hydroxide monohydrate (24.07 mg, 573.12 μmol) were added to the reaction bottle in sequence. The system was evacuated and replaced with nitrogen three times. Tetrahydrofuran (1 mL), methanol (1 mL) and water (1 mL) were added in sequence and heated to 400 °C. The reaction was stirred at 80°C for 4 hours, cooled to room temperature, quenched with water, extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and purified using a normal phase column and then a reverse phase preparative column to obtain 4-(4-{6-[2-amino-4-(difluoromethyl)pyrimidin-5-yl]-4,5-difluoro-1H-1,3-benzodiazol-2-yl}phenoxy)benzoic acid (26.47 mg, yield: 34.87%, purity: 99.75%). MS [M+H] + :found 510.1. 1 H NMR(400MHz,DMSO-d6)δ10.12(s,2H),8.43(s,1H),8.32-8.24(m,2H),8.02-7.94(m,2H),7.3 4(d,J=5.2Hz,1H),7.30(s,2H),7.27-7.21(m,2H),7.14-7.08(m,2H),6.67(t,J=53.2Hz,1H).

[0153] Example 2: Preparation of methyl 4-(4-(6-(2-amino-4-methylpyrimidin-5-yl)-4,5-difluoro-1H-benzo[d]imidazol-2-yl)-2-(trifluoromethyl)phenoxy)benzoate

[0154] Step 1: 3-Bromobenzaldehyde (1.34 g, 7.23 mmol), methyl 3-hydroxybenzoate (1 g, 6.57 mmol), cuprous iodide (62.59 mg, 0.33 mol), potassium phosphate (2.79 g, 13.14 mmol), and o-picolinic acid (8.09 mg, 0.66 mmol) were added to a reaction flask in sequence. Dimethyl sulfoxide (20 ml) was injected into the mixture using a syringe. The system was evacuated and replaced with nitrogen three times. The temperature was raised to 80°C and the reaction was stirred for 16 hours. The reaction solution was cooled to room temperature, diluted with water, and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified using a normal phase column to obtain methyl 4-(3-formylphenoxy)benzoate (437 mg, yield: 95%). MS [M+H] + :found 257.3.

[0155] Step 2: To a reaction flask, methyl 4-(3-formylphenoxy)benzoate (400 mg, 1.56 mmol), 5-(2-amino-4-methylpyrimidin-5-yl)-3,4-difluorobenzene-1,2-diamine (392.17 mg, 1.56 mmol), and sodium metabisulfite (890.25 mg, 4.68 mmol) were added sequentially. Ethanol (3 mL) and water (0.3 mL) were added sequentially. The system was evacuated and replaced with nitrogen three times, heated to 90°C, and stirred for 16 hours. The reaction mixture was filtered, and the filtrate was concentrated and purified by reverse phase preparative purification to afford methyl 4-(4-(6-(2-amino-4-methylpyrimidin-5-yl)-4,5-difluoro-1H-benzo[d]imidazol-2-yl)-2-(trifluoromethyl)phenoxy)benzoate (377.9 mg, yield: 9.66%). MS [M+H] + :found 488.1. 1 H NMR(400MHz,DMSO-d6)δ13.45(s,1H),8.10(s,1H),8.06-8.04(m,1H),7.87-7.86(m 1H),7.80-7.77(m,1H),7.66-7.58(m,2H),7.56-7.55(m,1H),7.46-7.43(m,1H),7.28-7.25(m 2H), 6.75 (s, 2H), 3.84 (s, 3H), 2.16 (d, J = 1.2Hz, 3H).

[0156] Examples 3-52 can be prepared by selecting appropriate raw materials according to the synthesis methods of Examples 1 and 2, and their structures are shown in Table 2.

[0157] Table 2. Structural formula, chemical name and mass spectrometry data of Examples 3-52

[0158] The NMR data of the compound prepared in the above example are as follows:

[0159] Example 53: Preparation of methyl (1r,4r)-4-(4-(6-(2-amino-4-methylpyrimidin-5-yl)-4,5-difluoro-1H-benzo[d]imidazol-2-yl)phenoxy)cyclohexane-1-carboxylate

[0160] Step 1: 4-Hydroxybenzaldehyde (578.95 mg, 4.74 mmol), cis-4-hydroxy-cyclohexanecarboxylic acid methyl ester (500 mg, 3.16 mmol), and triphenylphosphine (2.49 g, 9.48 mmol) were added to the reaction flask in sequence. The system was evacuated and replaced with nitrogen three times. Tetrahydrofuran (20 ml) was added, and diethyl azodicarboxylate (825.62 mg, 4.74 mmol) was added at 0°C. After stirring for 16 hours, water was added to quench the reaction, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified using a normal phase column to obtain methyl (1r, 4r)-4-(4-formylphenoxy)cyclohexane-1-carboxylate (250 mg, yield: 30.16%).

[0161] Step 2: Methyl (1r, 4r)-4-(4-formylphenoxy)cyclohexane-1-carboxylate (104.41 mg, 398.03 μmol), 5-(2-amino-4-methylpyrimidin-5-yl)-3,4-difluorobenzene-1,2-diamine (100 mg, 398.03 μmol), and sodium metabisulfite (151.34 mg, 796.05 μmol) were added to the reaction bottle in sequence. The system was evacuated and the mixture was stirred for 2 h. The atmosphere was replaced with nitrogen three times, and water (0.2 ml) and ethanol (2 ml) were added. After stirring at 80°C for 16 hours, the reaction solution was cooled to room temperature and filtered. The filtrate was concentrated and purified by reverse phase column chromatography to obtain methyl (1r,4r)-4-(4-(6-(2-amino-4-methylpyrimidin-5-yl)-4,5-difluoro-1H-benzo[d]imidazol-2-yl)phenoxy)cyclohexane-1-carboxylate (70.6 g, yield: 35.98%). MS [M+H] + :found 494.2. 1 H NMR (400MHz, DMSO-d6) δ8.37(s,1H),8.14-8.12(m,2H),7.35(dd,J=5.6,1.2Hz,1H),7.16(d,J=8.8Hz,2H),4.51-4.43(m,1H),3. 62(s,3H),2.44-2.37(m,1H),2.29(d,J=1.2Hz,3H),2.13-2.09(m,2H),1.99-1.95(m,2H),1.63-1.53(m,2H),1.50-1.40(m,2H).

[0162] Example 54: Preparation of (1r,4r)-4-{4-[6-(2-amino-4-methylpyrimidin-5-yl)-4,5-difluoro-1H-1,3-benzodiazol-2-yl]phenoxy}cyclohexane-1-carboxylic acid

[0163] (1r,4r)-4-{4-[6-(2-amino-4-methylpyrimidin-5-yl)-4,5-difluoro-1H-1,3-benzodiazole-2-yl]phenoxy}cyclohexane-1-carboxylic acid can be prepared according to the method of the third step of Example 1 using Example 53 methyl (1r,4r)-4-(4-(6-(2-amino-4-methylpyrimidin-5-yl)-4,5-difluoro-1H-benzo[d]imidazol-2-yl)phenoxy)cyclohexane-1-carboxylate as the starting material. MS[M+H] + :found 480.1. 1 H NMR(400MHz,DMSO-d6)δ12.91(s,1H),11.77(s,1H),8.15-8.07(m,3H),7.20(s,1H),7.15-7.09(m,2H),6.44(s,2H),4.40-4.4 7(m,1H),2.26-2.34(m,1H),2.18(d,J=1.2Hz,3H),2.16-2.09(m,2H),2.03-1.95(m,2H),1.64-1.53(m,2H),1.42-1.52(m,2H).

[0164] Examples 55-56 can be prepared by selecting appropriate raw materials by referring to the synthesis methods of Examples 53 and 54, and their structures are shown in Table 3.

[0165] Table 3. Structural formula, chemical name and mass spectrometry data of Examples 55-56

[0166] The NMR data of the compound prepared in the above example are as follows:

[0167] Example 57: Preparation of 1-(4-(6-(2-amino-4-methylpyrimidin-5-yl)-4,5-difluoro-1H-benzo[d]imidazol-2-yl)benzyl)piperidine-4-carboxylic acid

[0168] Step 1: To a reaction flask, add 4-(bromomethyl)benzoic acid (200 mg, 0.93 mmol), methylpiperidine-4-carboxylate (146.48 mg, 1.02 mmol), N,N-diisopropylethylamine (360.60 mg, 2.79 mmol), and acetonitrile (2 ml) in sequence. Stir at room temperature for 1 hour. The reaction mixture is concentrated to yield crude 4-((4-(carbomethoxymethyl)piperidin-1-yl)methyl)benzoic acid (200 mg).

[0169] Step 2: 4-((4-(carbomethoxycarbonyl)piperidin-1-yl)methyl)benzoic acid (200 mg, 0.72 mmol) and 5-(2-amino-4-methylpyrimidin-5-yl)-3,4-difluorobenzene-1,2-diamine (181.19 mg, 0.73 mmol) were dissolved in N,N-dimethylformamide (2 ml), and N,N-diisopropylethylamine (186.41 mg, 1.44 mmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (411.34 mg, 1.08 mmol) were added in sequence. After stirring at room temperature for 16 hours, acetic acid (2 ml) was added to the reaction solution. The system was evacuated and replaced with nitrogen three times, and heated to 100 degrees Celsius and stirred for 16 hours. After cooling to room temperature, water was added to quench the reaction, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to give crude methyl 1-(4-(6-(2-amino-4-methylpyrimidin-5-yl)-4,5-difluoro-1H-benzo[d]imidazol-2-yl)benzyl)piperidine-4-carboxylate (300 mg).

[0170] Step 3: Methyl 1-(4-(6-(2-amino-4-methylpyrimidin-5-yl)-4,5-difluoro-1H-benzo[d]imidazol-2-yl)benzyl)piperidine-4-carboxylate (490 mg, 0.99 mmol) was dissolved in tetrahydrofuran (2 ml) and water (2 ml). Lithium hydroxide monohydrate (125.35 mg, 2.98 mmol) was added and stirred at room temperature for 16 hours. The filtrate was concentrated and purified by reverse phase preparative purification to afford 1-(4-(6-(2-amino-4-methylpyrimidin-5-yl)-4,5-difluoro-1H-benzo[d]imidazol-2-yl)benzyl)piperidine-4-carboxylic acid (22.40 mg, yield: 4.71%). MS [M+H] + :found 479.3. 1 H NMR (400MHz, DMSO-d6) δ8.16(d,J=8.2Hz,2H),8.11(s,1H),7.49(d,J=8.3Hz,2H),7.28(d,J=5.4Hz,1H),6.73(s,2H),3.52(s, 2H),2.78(d,J=10.8Hz,2H),2.20(s,1H),2.17(d,J=1.3Hz,3H),2.03(t,J=10.5Hz,2H),1.85-1.75(m,2H),1.63-1.51(m,2H).

[0171] Example 58: Preparation of 4-{4-[6-(2-amino-4-methylpyrimidin-5-yl)-4,5-difluoro-1H-1,3-benzodiazol-2-yl]phenoxy}benzamide

[0172] Methyl 4-{4-[6-(2-amino-4-methylpyrimidin-5-yl)-4,5-difluoro-1H-1,3-benzodiazol-2-yl]phenoxy}benzoate (140 mg, 0.28 mmol) was added to aqueous ammonia (3 mL) and stirred at 100°C for 20 hours. The reaction mixture was concentrated to obtain a crude product, which was then purified by reverse phase preparative method to give 4-{4-[6-(2-amino-4-methylpyrimidin-5-yl)-4,5-difluoro-1H-1,3-benzodiazol-2-yl]phenoxy}benzamide (6.57 mg, yield: 4.84%). MS [M+H] + :found 473.0. 1 H NMR (400MHz, DMSO-d6) δ8.23(d,J=8.4Hz,2H),8.09(s,1H),7.97-7.92(m,2H),7.26-7.18(m,3H),7.16-7.10(m,2H),6.43(s,2H),2.17(s,3H).

[0173] Examples 59-60 can be prepared by selecting appropriate raw materials according to the synthesis method of Example 58, and their structures are shown in Table 4.

[0174] Table 4. Structural formula, chemical name and mass spectrometry data of Examples 59-60

[0175] The NMR data of the compound prepared in the above example are as follows:

[0176] Example 61: Preparation of 4-(((1r,4r)-4-(6-(2-amino-4-methylpyrimidin-5-yl)-4,5-difluoro-1H-benzo[d]imidazol-2-yl)cyclohexyl)oxy)benzoic acid

[0177] Step 1: Dissolve methyl (1r,4r)-4-(4-formylphenoxy)cyclohexane-1-carboxylate (130 mg, 0.50 mmol) in tetrahydrofuran (1 ml) and water (1 ml). Add lithium hydroxide monohydrate (62.45 mg, 1.49 mmol) and stir at room temperature for 16 hours. The reaction mixture is filtered, the filtrate is concentrated, diluted with water, and extracted with ethyl acetate. The aqueous phase is adjusted to a pH of approximately 1 with 2M HCl solution to precipitate a solid. The mixture is filtered, the filter cake is washed several times with water, and the solid is collected and dried to yield (1r,4r)-4-(4-formylphenoxy)cyclohexane-1-carboxylic acid (71.20 mg, yield: 57.86%).

[0178] Step 2: (1r,4r)-4-(4-formylphenoxy)cyclohexane-1-carboxylic acid (56 mg, 0.23 mmol) and 5-(2-amino-4-methylpyrimidin-5-yl)-3,4-difluorobenzene-1,2-diamine (68 mg, 0.27 mmol) were dissolved in N,N-dimethylformamide (2 ml), and N,N-diisopropylethylamine (87.45 mg, 0.68 mmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (171.53 mg, 0.45 mmol) were added in sequence. After reacting at room temperature for 2 hours, acetic acid (2 ml) was added, the system was evacuated and replaced with nitrogen three times, heated to 100 degrees Celsius and stirred for 16 hours. After cooling to room temperature, the mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified using a normal phase column to obtain 4-(((1r,4r)-4-(6-(2-amino-4-methylpyrimidin-5-yl)-4,5-difluoro-1H-benzo[d]imidazol-2-yl)cyclohexyl)oxy)benzaldehyde (41.30 mg, yield: 39.51%).

[0179] Step 3: Dissolve 4-(((1r,4r)-4-(6-(2-amino-4-methylpyrimidin-5-yl)-4,5-difluoro-1H-benzo[d]imidazol-2-yl)cyclohexyl)oxy)benzaldehyde (41.30 mg, 0.09 mmol) and sodium dihydrogen phosphate (6.41 mg, 0.05 mmol) in tetrahydrofuran (1 ml) and water (1 ml). Stir at room temperature for 10 minutes, then add sodium chlorite (33.65 mg, 0.30 mmol) and hydrogen peroxide (22.22 mg, 0.20 mmol) in turn, and stir at room temperature for 16 hours. The mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by reverse phase preparative purification to give 4-(((1r,4r)-4-(6-(2-amino-4-methylpyrimidin-5-yl)-4,5-difluoro-1H-benzo[d]imidazol-2-yl)cyclohexyl)oxy)benzoic acid (0.5 mg, yield: 1.17%). MS [M+H] + :found 480.2. 1 H NMR (400MHz, DMSO-d6) δ8.10 (s, 1H), 7.92-7.84 (m, 2H), 7.21 (d, J = 5.5Hz, 1H), 7.09-7.03 (m, 2H), 6.88 (s, 2H) ,4.56-4.49(m,1H),3.00-2.93(m,1H),2.29-2.16(m,4H),2.15(s,3H),1.91-1.80(m,2H),1.62-1.53(m,2H).

[0180] Example 62 can be prepared by selecting appropriate raw materials according to the synthesis method of Example 61, and its structure is shown in Table 5.

[0181] Table 5. Structural formula, chemical name and mass spectrometry data of Example 62

[0182] The NMR data of the compound prepared in the above example are as follows:

[0183] Example 63: Preparation of 4-(4-(6-(2-amino-4-methylpyrimidin-5-yl)-4,5-difluoro-1H-benzo[d]imidazol-2-yl)-2-fluorophenoxy)benzamide

[0184] 4-(4-(6-(2-amino-4-methylpyrimidin-5-yl)-4,5-difluoro-1H-benzo[d]imidazol-2-yl)-2-fluorophenoxy)benzoic acid (100 mg, 0.2 mmol) was dissolved in N,N-dimethylformamide (2 ml). Ammonium bicarbonate (48.26 mg, 0.61 mmol), N,N-diisopropylethylamine (78.90 mg, 0.61 mmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (154.75 mg, 0.41 mmol) were added in sequence and the mixture was stirred at room temperature for 16 hours. The reaction mixture was directly concentrated to obtain a crude product, which was then purified by reverse phase purification to yield 4-(4-(6-(2-amino-4-methylpyrimidin-5-yl)-4,5-difluoro-1H-benzo[d]imidazol-2-yl)-2-fluorophenoxy)benzamide (19.9 mg, yield: 19.81%). MS [M+H] + :found 491.5. 1 H NMR(400MHz, DMSO-d6)δ13.39(s,1H),8.21(dd,J=11.7,2.1Hz,1H),8.01-8.08(m,2H),7.96-7.94(m, 2H),7.93-7.92(m,1H),7.43-7.40(m,1H),7.34(s,2H),7.17-7.11(m,2H),6.75(s,2H),2.17(s,3H).

[0185] Examples 64-73 can be prepared by selecting appropriate raw materials according to the synthesis method of Example 63, and their structures are shown in Table 6.

[0186] Table 6. Structural formula, chemical name and mass spectrometry data of Examples 64-73

[0187] The NMR data of the compound prepared in the above example are as follows:

[0188] Examples 74 and 75: Preparation of 4-{[(1s,4s)-4-[6-(2-amino-4-methylpyrimidin-5-yl)-4,5-difluoro-1H-1,3-benzodiazol-2-yl]cyclohexyl]oxy}benzamide and 4-{[(1r,4r)-4-[6-(2-amino-4-methylpyrimidin-5-yl)-4,5-difluoro-1H-1,3-benzodiazol-2-yl]cyclohexyl]oxy}benzamide

[0189] Step 1: 4-Hydroxybenzamide (1 g, 7.29 mmol) and cis-4-hydroxy-cyclohexanecarboxylic acid ethyl ester (1.32 g, 7.66 mmol) were dissolved in tetrahydrofuran (10 mL), and triphenylphosphine (2.49 g, 9.48 mmol) and diisopropyl azodicarboxylate (1.92 g, 9.48 mmol) were added in sequence. The mixture was stirred at room temperature for 16 hours. The reaction system was poured into ice water, extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. After filtration and concentration of the filtrate, the crude product was purified by normal phase purification to obtain ethyl (1r, 4r)-4-(4-carbamoylphenoxy)cyclohexane-1-carboxylate (2.50 g, yield: 117.68%, purity: 30%).

[0190] Step 2: Ethyl (1r,4r)-4-(4-carbamoylphenoxy)cyclohexane-1-carboxylate (500 mg, 1.72 mmol, purity: 30%) was dissolved in methanol (2 mL), tetrahydrofuran (2 mL), and water (1 mL). Lithium hydroxide monohydrate (216 mg, 5.15 mmol) was added and reacted at room temperature for 2 hours. The reaction system was concentrated, diluted with water, and extracted with ethyl acetate to remove impurities. The aqueous phase was adjusted to pH 3 with 1M dilute hydrochloric acid. A solid precipitated and the residue was collected by filtration and dried under vacuum to obtain (1r,4r)-4-(4-carbamoylphenoxy)cyclohexane-1-carboxylic acid (105 mg, yield: 23.24%).

[0191] Step 3: Dissolve (1r,4r)-4-(4-aminoformylphenoxy)cyclohexane-1-carboxylic acid (50 mg, 190 μmol) and 5-(2-amino-4-methylpyrimidin-5-yl)-3,4-difluorobenzene-1,2-diamine (48 mg, 190 μmol) in N,N-dimethylformamide (2 mL). Add N,N-diisopropylethylamine (74 mg, 570 μmol) and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (87 mg, 228 μmol) sequentially. React at room temperature for 1 hour. Then, add acetic acid (2 mL), slowly raise the temperature to 100°C, and stir for 16 hours. After cooling to room temperature, pour the reaction mixture into water, extract with ethyl acetate, wash with saturated brine, and dry over anhydrous sodium sulfate. After filtration, the filtrate was concentrated and the crude product was purified by reverse phase preparation to give 4-{[(1s,4s)-4-[6-(2-amino-4-methylpyrimidin-5-yl)-4,5-difluoro-1H-1,3-benzodiazol-2-yl]cyclohexyl]oxy}benzamide (4.02 mg, yield: 4.42%, purity: 99.65%) and 4-{[(1r,4r)-4-[6-(2-amino-4-methylpyrimidin-5-yl)-4,5-difluoro-1H-1,3-benzodiazol-2-yl]cyclohexyl]oxy}benzamide (8.34 mg, yield: 9.18%, purity: 99.50%).

[0192] 4-{[(1s,4s)-4-[6-(2-amino-4-methylpyrimidin-5-yl)-4,5-difluoro-1H-1,3-benzodiazol-2-yl]cyclohexyl]oxy}benzamide: MS [M+H] + :found 479.6. 1 H NMR(400MHz,DMSO-d6)δ12.69(s,1H),8.06(s,1H),7.85-7.82(m,3H),7.15-7.14(m,2H),7.04-7.02(m,2H),6 .71(s,2H),4.77-4.76(m,1H),3.08-3.03(m,1H),2.14(d,J=1.2Hz,3H),2.10-1.98(m,4H),1.91-1.75(m,4H).

[0193] 4-{[(1r,4r)-4-[6-(2-amino-4-methylpyrimidin-5-yl)-4,5-difluoro-1H-1,3-benzodiazol-2-yl]cyclohexyl]oxy}benzamide: MS [M+H] + :found 479.5. 1H NMR(400MHz,DMSO-d6)δ12.70(s,1H),8.06(s,1H),7.84-7.81(m,3H),7.17(s,2H),7.03-7.00(m,2H),6.71(s,2H),4 .53-4.47(m,1H),2.99-2.91(m,1H),2.23-2.15(m,4H),2.14(d,J=1.2Hz,3H),1.90-1.80(m,2H),1.61-1.52(m,2H).

[0194] Examples 76-79 can be prepared by selecting appropriate raw materials by referring to the synthesis methods of Examples 74 and 75, and their structures are shown in Table 7.

[0195] Table 7. Structural formula, chemical name and mass spectrometry data of Examples 76-79

[0196] The NMR data of the compound prepared in the above example are as follows:

[0197] Example 80: Preparation of 4-{[(1s,4s)-4-[6-(2-amino-4-methylpyrimidin-5-yl)-4,5-difluoro-1H-1,3-benzodiazol-2-yl]-1-(trifluoromethyl)cyclohexyl]oxy}benzamide

[0198] Step 1: To a solution of (1s,4s)-4-hydroxy-4-(trifluoromethyl)cyclohexane-1-carboxylic acid (1 g, 4.71 mmol) in nitrogen-dimethylformamide (20 mL) were added potassium carbonate (1.30 g / L, 9.43 mmol) and benzyl bromide (806.15 mg, 4.71 mmol) in sequence. The mixture was stirred at room temperature for 16 hours. The reaction was quenched by the addition of saturated aqueous ammonium chloride. The mixture was extracted with ethyl acetate, and the organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The filtrate was filtered, concentrated, and the crude product was purified by column chromatography to yield benzyl (1s,4s)-4-hydroxy-4-(trifluoromethyl)cyclohexane-1-carboxylate (1.4 g, 98.26%) as a yellow solid. 1 H NMR (400MHz, MeOH-d4) δ7.42-7.27(m,5H),5.12(s,2H),2.43-2.34(m,1H),1.91-1.72(m,6H),1.67-1.57(m,2H).

[0199] Step 2: To a solution of 1,3,5-trimethoxybenzene (1.11 g, 6.58 mmol) in acetonitrile (20 mL) was added m-chloroperbenzoic acid (1.36 g, 7.89 mmol) portionwise. Trifluoroacetic acid (749.84 mg, 6.58 mmol) was then added dropwise at 60°C. The mixture was stirred for 1 hour. Tert-butyl 4-iodobenzoate (2 g, 6.58 mmol) was then added portionwise. The mixture was stirred for 15 minutes. The mixture was concentrated in vacuo to afford crude (4-(tert-butoxycarbonyl)phenyl)(2,4,6-trimethoxyphenyl)iodide trifluoroacetate (3.10 g, yield: 100.02%). MS[M]: found 471.1.

[0200] Step 3: To a solution of benzyl (1s,4s)-4-hydroxy-4-(trifluoromethyl)cyclohexane-1-carboxylate (800 mg, 2.65 mmol) in methyl tert-butyl ether (30 mL) was added sodium hydride (158.79 mg, 60%, 3.97 mmol). The mixture was stirred at 0°C for 10 minutes, followed by the addition of (4-(tert-butoxycarbonyl)phenyl)(2,4,6-trimethoxyphenyl)iodide trifluoroacetate (1.25 g, 2.65 mmol). The mixture was allowed to warm to room temperature and react for 0.5 hours. The mixture was diluted with ethyl acetate, washed sequentially with water and saturated brine, and dried over anhydrous sodium sulfate. The filtrate was filtered, and the filtrate was concentrated. The crude product was purified by column chromatography to yield tert-butyl 4-(((1s,4s)-4-((benzyloxy)carbonyl)-1-(trifluoromethyl)cyclohexyl)oxy)benzoate (510 mg, yield: 40.27%). MS[M+Na] + :found 501.2.

[0201] Step 4: To a solution of tert-butyl 4-(((1s,4s)-4-((benzyloxy)carbonyl)-1-(trifluoromethyl)cyclohexyl)oxy)phenol (400 mg, 835.93 μmol) in tetrahydrofuran (5 mL) and water (1 mL) was added lithium hydroxide (175.38 mg, 4.18 mmol) and stirred at 25°C for 1 hour. The mixture was diluted with water and the pH was adjusted to 2-3 with 1N HCl. The mixture was extracted with ethyl acetate, and the organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated to give the crude product (1s,4s)-4-(4-(tert-butoxycarbonyl)phenoxy)-4-(trifluoromethyl)cyclohexane-1-carboxylic acid (230 mg, yield: 70.84%). 1H NMR (400MHz, CDCl3) δ7.91-7.85(m,2H),7.12-7.06(m,2H),2.37-2.28(m,1H), 2.24(d,J=12.3Hz,2H),1.91(d,J=13.0Hz,2H),1.74-1.63(m,4H),1.52(s,9H).

[0202] Step 5: 5-(2-amino-4-methylpyrimidin-5-yl)-3,4-difluorobenzene-1,2-diamine (148.79 mg, 592.20 μmol) and (1s,4s)-4-(4-(tert-butoxycarbonyl)phenoxy)-4-(trifluoromethyl)cyclohexane-1-carboxylic acid (230 mg, 592.20 μmol) were dissolved in N,N-dimethylformamide (1 mL). Diisopropylethylamine (153.07 mg, 1.18 mmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (337.77 mg, 888.31 μmol) were added sequentially. The mixture was stirred at room temperature for 1 hour. The mixture was diluted with ethyl acetate, washed sequentially with water and saturated brine, and dried over anhydrous sodium sulfate. The filtrate was filtered and the filtrate was concentrated. The crude product was purified by column chromatography to give tert-butyl 4-(((1s,4s)-4-(6-(2-amino-4-methylpyrimidin-5-yl)-4,5-difluoro-1H-benzo[d]imidazol-2-yl)-1-(trifluoromethyl)cyclohexyl)oxy)benzoate (212 mg, yield: 59.30%)).

[0203] Step 6: Dissolve tert-butyl 4-(((1s,4s)-4-(6-(2-amino-4-methylpyrimidin-5-yl)-4,5-difluoro-1H-benzo[d]imidazol-2-yl)-1-(trifluoromethyl)cyclohexyl)oxy)benzoate (292 mg) in trifluoroacetic acid (3 mL) and stir at 50°C for 1 hour. The mixture was concentrated in vacuo to give crude 4-(((1s,4s)-4-(6-(2-amino-4-methylpyrimidin-5-yl)-4,5-difluoro-1H-benzo[d]imidazol-2-yl)-1-(trifluoromethyl)cyclohexyl)oxy)benzoic acid (190 mg, yield: 99%). MS [M+H] + :found 548.2.

[0204] Step 7: 4-(((1s,4s)-4-(6-(2-amino-4-methylpyrimidin-5-yl)-4,5-difluoro-1H-benzo[d]imidazol-2-yl)-1-(trifluoromethyl)cyclohexyl)oxy)benzoic acid (150 mg, 273.98 μmol) was dissolved in N,N-dimethylformamide (2 mL), and ammonium bicarbonate (64.98 mgL, 821.93 μmol), diisopropylethylamine (106.23 mg, 821.93 μmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (156.27 mg, 410.97 μmol) were added in sequence and reacted at room temperature for 16 hours. The reaction mixture was directly purified by HPLC to give 4-{[(1s,4s)-4-[6-(2-amino-4-methylpyrimidin-5-yl)-4,5-difluoro-1H-1,3-benzodiazol-2-yl]-1-(trifluoromethyl)cyclohexyl]oxy}benzamide (83.11 mg, yield: 55.51%, purity: 97.55%) as a white solid. MS [M+H] + :found 547.1. 1 H NMR (400MHz, DMSO-d6) δ12.74(s,1H),8.06(s,1H),7.95(s,1H),7.91-7.86(m,2H),7.33(s,1H),7.27-7.21(m,2H),7.16(d,J =5.4Hz,1H),6.71(s,2H),3.15-3.05(m,1H),2.31-2.28(m,2H),2.14(d,J=1.2Hz,3H),2.13-2.07(m,2H),2.00-1.89(m,4H).

[0205] Examples 81-83 and 168 can be prepared by selecting appropriate raw materials according to the synthesis method of Example 80, and their structures are shown in Table 8.

[0206] Table 8. Structural formula, chemical name and mass spectrometry data of Examples 81-83

[0207] The NMR data of the compound prepared in the above example are as follows:

[0208] Examples 84 and 85: Preparation of 4-{[(1s,4s)-4-[6-(2-amino-4-methylpyrimidin-5-yl)-4,5-difluoro-1H-1,3-benzodiazol-2-yl]cyclohexyl]oxy}benzene-1-sulfonyl and 4-{[(1r,4r)-4-[6-(2-amino-4-methylpyrimidin-5-yl)-4,5-difluoro-1H-1,3-benzodiazol-2-yl]cyclohexyl]oxy}benzene-1-sulfonyl

[0209] Step 1: Dissolve cis-4-hydroxy-cyclohexanecarboxylic acid ethyl ester (1 g, 5.81 mmol) in dichloromethane (20 mL). Add triethylamine (1.47 g, 14.52 mmol), 4-dimethylaminopyridine (71 mg, 580 μmol), and p-toluenesulfonyl chloride (1.22 g, 6.39 mmol) sequentially. React at room temperature for 16 hours. Pour the reaction mixture into ice water, extract with ethyl acetate, wash with saturated brine, and dry over anhydrous sodium sulfate. Filter, concentrate the filtrate, and purify the crude product using normal phase column chromatography to obtain ethyl (1s,4s)-4-(tosyloxy)cyclohexane-1-carboxylate (1.73 g, yield: 91.28%).

[0210] Step 2: Dissolve p-hydroxybenzenesulfonamide (400 mg, 2.31 mmol) and ethyl (1s,4s)-4-(tosyloxy)cyclohexane-1-carboxylate (980 mg, 3 mmol) in N,N-dimethylformamide (10 mL). Add sodium hydroxide (138 mg, 3.46 mmol). Heat the mixture to 80°C and stir for 16 hours. After cooling to room temperature, pour the reaction mixture into ice water, extract with ethyl acetate, wash with saturated brine, and dry over anhydrous sodium sulfate. Filter, concentrate the filtrate, and purify the crude product using normal phase column chromatography to yield ethyl (1r,4r)-4-(4-sulfamoylphenoxy)cyclohexane-1-carboxylate (450 mg, yield: 59.51%).

[0211] Step 3: Ethyl (1r,4r)-4-(4-sulfamoylphenoxy)cyclohexane-1-carboxylate (120 mg, 366 μmol) was dissolved in methanol (1 mL), tetrahydrofuran (1 mL), and water (0.5 mL). Lithium hydroxide monohydrate (30 mg, 733 μmol) was added and allowed to react at room temperature for 1 hour. The reaction system was concentrated, diluted with water, and extracted with ethyl acetate to remove impurities. The aqueous phase was adjusted to pH 3 with 1 M dilute hydrochloric acid. A solid precipitated and the residue was collected by filtration and dried under vacuum to afford (1r,4r)-4-(4-sulfamoylphenoxy)cyclohexane-1-carboxylic acid (50 mg, yield: 45.57%).

[0212] Step 4: Dissolve (1r,4r)-4-(4-sulfamoylphenoxy)cyclohexane-1-carboxylic acid (44 mg, 147 μmol) and 5-(2-amino-4-methylpyrimidin-5-yl)-3,4-difluorobenzene-1,2-diamine (37 mg, 147 μmol) in N,N-dimethylformamide (2 mL). Add N,N-diisopropylethylamine (57 mg, 441 μmol) and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (84 mg, 221 μmol) sequentially. Heat to 70°C for 2 hours. Then, add acetic acid (2 mL) and slowly raise the temperature to 110°C with stirring for 16 hours. Concentrate the reaction mixture, dilute with water, extract with ethyl acetate, wash with saturated brine, and dry over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated. The crude product was purified by reverse phase preparation to give 4-{[(1s,4s)-4-[6-(2-amino-4-methylpyrimidin-5-yl)-4,5-difluoro-1H-1,3-benzodiazol-2-yl]cyclohexyl]oxy}benzene-1-sulfonyl (5.90 mg, yield: 7.79%) and 4-{[(1r,4r)-4-[6-(2-amino-4-methylpyrimidin-5-yl)-4,5-difluoro-1H-1,3-benzodiazol-2-yl]cyclohexyl]oxy}benzene-1-sulfonyl (10.11 mg, yield: 13.34%).

[0213] 4-{[(1s,4s)-4-[6-(2-amino-4-methylpyrimidin-5-yl)-4,5-difluoro-1H-1,3-benzodiazol-2-yl]cyclohexyl]oxy}benzene-1-sulfonyl: MS [M+H] + :found 515.2. 1 H NMR(400MHz,DMSO-d6)δ12.67(s,1H),8.06(s,1H),7.76-7.73(m,2H),7.20(s,2H),7.17-7.08(m,3H),6.71(s, 2H), 4.78 (s, 1H), 3.06 (s, 1H), 2.14 (d, J = 1.2Hz, 3H), 2.06-1.99 (m, 4H), 1.91-1.88 (m, 2H), 1.84-1.78 (m, 2H).

[0214] 4-{[(1r,4r)-4-[6-(2-amino-4-methylpyrimidin-5-yl)-4,5-difluoro-1H-1,3-benzodiazol-2-yl]cyclohexyl]oxy}benzene-1-sulfonyl: MS [M+H] + :found 515.2. 1H NMR(400MHz,DMSO-d6)δ12.56(s,1H),8.06(s,1H),7.78-7.70(m,2H),7.20(s,2H),7.18-7.07(m,3H),6.72(s,2H),4 .58-4.48(m,1H),3.02-2.91(m,1H),2.23-2.19(m,4H),2.14(d,J=1.2Hz,3H),1.90-1.81(m,2H),1.61-1.53(m,2H).

[0215] Examples 86-163 can be prepared by selecting appropriate raw materials by referring to the synthesis methods of Examples 84 and 85, and their structures are shown in Table 9.

[0216] Table 9. Structural formula, chemical name and mass spectrometry data of Examples 86-163

[0217] The NMR data of the compound prepared in the above example are as follows:

[0218] Example 164: Preparation of 4-({4-[6-(2-amino-4-methylpyrimidin-5-yl)-4,5-difluoro-1H-1,3-benzodiazol-2-yl]bicyclo[2.2.2]octan-1-yl}oxo)-3-fluorobenzamide

[0219] Step 1: Dissolve 4-hydroxybicyclo[2.2.2]octane-1-carboxylic acid (200 mg, 1.18 mmol) in N,N-dimethylformamide (500 μL) and tetrahydrofuran (500 μL). Cool to 0°C, add sodium hydride (141 mg, 60%, 3.53 mmol), and allow to react at room temperature for 10 minutes. Methyl 3,4-difluorobenzoate (404.51 mg, 2.35 mmol) is then added and heated to 50°C for 16 hours. After cooling to room temperature, the mixture is poured into saturated aqueous ammonium chloride, extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. Filter, concentrate the filtrate, and purify the crude product by column chromatography to yield 4-[2-fluoro-4-(methoxycarbonyl)phenoxy]bicyclo[2.2.2]octane-1-carboxylic acid (140 mg, yield: 36.96%). MS [M+H] + :found 323.1. 1 H NMR (400MHz, DMSO-d6) δ12.18(s,1H),7.71(dd,J=8.8,2.1Hz,1H),7.61(dd,J=11.9,2.1Hz,1H),7 .26(t,J=8.6Hz,1H),3.91(s,3H),2.07(dd,J=10.4,5.5Hz,6H),1.89(ddd,J=7.9,5.1,4.1Hz,6H).

[0220] Step 2: To a solution of 5-(2-amino-4-methylpyrimidin-5-yl)-3,4-difluorobenzene-1,2-diamine (109.12 mg, 434.34 μmol) and 4-[2-fluoro-4-(methoxycarbonyl)phenoxy]bicyclo[2.2.2]octane-1-carboxylic acid (140 mg, 434.34 μmol) in N,N-dimethylformamide (3 mL) were added diisopropylethylamine (168.40 mg, 1.30 mmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (181.67 mg, 477.77 μmol) in sequence. The mixture was allowed to react at room temperature for 16 hours. HPLC analysis indicated the reaction was complete. The reaction system was diluted with ethyl acetate, washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by preparative thin-layer chromatography to obtain the pure intermediate. This intermediate was dissolved in trifluoroacetic acid (1 mL) and stirred at 50°C for 2 hours. After cooling to room temperature and concentration, the crude product was purified by preparative thin-layer chromatography to yield methyl 4-((4-(6-(2-amino-4-methylpyrimidin-5-yl)-4,5-difluoro-1H-benzo[d]imidazol-2-yl)bicyclo[2.2.2]octan-1-yl)oxy)-3-fluorobenzoate (120 mg, yield: 51.40%) as a yellow solid. MS [M+H] +:found 538.2.

[0221] Step 3: To a solution of methyl 4-((4-(6-(2-amino-4-methylpyrimidin-5-yl)-4,5-difluoro-1H-benzo[d]imidazol-2-yl)bicyclo[2.2.2]octane-1-yl)oxy)-3-fluorobenzoate (100 mg, 186.03 μmol) in tetrahydrofuran (1 mL) and water (500 μL) was added lithium hydroxide (39.03 mg, 930.16 μmol) and reacted at room temperature for 25 hours. 1N HCl was added to the system to adjust the pH to about 2, and then dichloromethane was added for extraction, washed with saturated brine, and dried over anhydrous sodium sulfate. The mixture was filtered and the filtrate was concentrated to give 4-({4-[6-(2-amino-4-methylpyrimidin-5-yl)-4,5-difluoro-hydrogen-1,3-benzodiazol-2-yl]bicyclo[2.2.2]octan-1-yl})-3-fluorobenzoic acid (80 mg, yield: 82.14%), which was used directly in the next step. MS [M+H] + :found 524.3.

[0222] Step 4: To a solution of 4-({4-[6-(2-amino-4-methylpyrimidin-5-yl)-4,5-difluoro-1h-1,3-benzodiazol-2-yl]bicyclo[2.2.2]octan-1-yl}oxy)-3-fluorobenzoic acid (100 mg, 191.01 μmol) in N,N-dimethylformamide (2 mL) were added ammonium bicarbonate (45.30 mg, 573.04 μmol), diisopropylethylamine (74.06 mg, 573.04 μmol), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (145.26 mg, 382.03 μmol) in N,N-dimethylformamide (2 mL). The mixture was reacted at room temperature for 16 hours. The mixture was diluted with ethyl acetate, washed sequentially with water and saturated brine, and dried over anhydrous sodium sulfate. The mixture was filtered and the filtrate was concentrated to obtain a crude product, which was then purified by high performance liquid chromatography (column model: Welch Xtimate C18 150*30mm*10um, mobile phase: Water (10mM NH4HCO3)-CAN, gradient: (%): 20-50, flow rate: (ml / min): 40) to obtain 4-({4-[6-(2-amino-4-methylpyrimidin-5-yl)-4,5-difluoro-1-1,3-benzodiazol-2-yl]bicyclo[2.2.2]octan-1-yl}oxy)-3-fluorobenzamide (1.03 mg, yield: 1.03%). MS [M+H] + :found 523.2. 1H NMR (400MHz, DMSO-d6) δ12.52(s,1H),8.05(s,1H),7.99(s,1H),7.74(dd,J=11.5,2.2Hz,1H),7.67(d,J=8.5Hz,1 H),7.44(s,1H),7.28(t,J=8.3Hz,1H),7.11(d,J=5.6Hz,1H),6.72(s,2H),2.24-2.03(m,9H),2.01-1.86(m,6H).

[0223] Example 165: Preparation of 4-({1-[6-(2-amino-4-methylpyrimidin-5-yl)-4,5-difluoro-1H-1,3-benzodiazol-2-yl]piperidin-4-yl}oxo)-3-fluorobenzamide

[0224] Step 1: Dissolve 1-tert-Butyloxycarbonyl-4-hydroxypiperidine (1 g, 4.97 mmol) and methyl 3-fluoro-4-hydroxybenzoate (1.01 g, 5.96 mmol) in tetrahydrofuran (15 mL). Cool to 0°C and add triphenylphosphine (1.95 g, 7.45 mmol) sequentially. After stirring for 0.5 hours, add diisopropyl azodicarboxylate (1.51 g, 7.45 mmol). The mixture is then allowed to warm to room temperature and react for 16 hours. After completion of the reaction, the mixture is concentrated to obtain a crude product. The crude product is purified by silica gel chromatography to yield tert-butyl 4-[2-fluoro-4-(carbomethoxy)phenoxy]piperidine-1-carboxylate (1.20 g, 68.34% yield).

[0225] Step 2: tert-Butyl 4-[2-fluoro-4-(carbomethoxy)phenoxy]piperidine-1-carboxylate (1 g, 2.83 mmol) was dissolved in 4 M hydrochloric acid in dioxane (10 mL), and the mixture was stirred at 25°C for 16 hours. After the reaction, the mixture was concentrated to obtain a crude product. The crude product was slurried with 100 mL of 10% ethyl acetate in petroleum ether and filtered. The collected solid was dried under vacuum to yield methyl 3-fluoro-4-(piperidin-4-oxy)benzoate hydrochloride (550 mg, 67.08% yield).

[0226] Step 3: Dissolve 5-bromo-3,4-difluorobenzene-1,2-diamine (5 g, 22.42 mmol) in tetrahydrofuran (60 mL), add N,N'-carbonyldiimidazole (5.45 g, 33.63 mmol), and react at room temperature for 16 hours. Quench with sodium bicarbonate solution, add water, and extract with ethyl acetate. The organic phase is washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate is concentrated and slurried with acetonitrile. After filtration, the solid is collected and dried under vacuum to obtain 5-bromo-6,7-difluoro-1H-benzo[d]imidazol-2-ol (2.14 g, yield: 38.33%). MS [M+H] + :found 249.1.

[0227] Step 4: 5-Bromo-6,7-difluoro-1H-benzo[d]imidazole-2-ol (1.20 g, 4.82 mmol) and phenylphosphine dichloride (50 mL) were added to the reaction flask in sequence and stirred at 120°C for 3 hours. After the reaction, the mixture was cooled to room temperature and poured into ice water. The pH was adjusted to approximately 7 with sodium hydroxide solution. Water was added and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and slurried with acetonitrile. The filtered solid was 5-bromo-2-chloro-6,7-difluoro-1H-benzo[d]imidazole (966 mg, yield: 74.95%). MS [M+H] + :found 267.1 / 269.2.

[0228] Step 5: Dissolve 5-bromo-2-chloro-6,7-difluoro-1H-benzo[d]imidazole (140.80 mg, 0.53 mmol) in N-methylpyrrolidone (3 mL), followed by methyl 3-fluoro-4-(piperidin-4-oxy)benzoate hydrochloride (153.56 mg, 0.53 mmol) and N,N-diisopropylethylamine (0.26 mL). Microwave the mixture at 120°C for 1 hour. Dilute with water and extract with ethyl acetate. The organic phase is washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated and reacted with reverse phase to give methyl 4-((1-(6-bromo-4,5-difluoro-1H-benzo[d]imidazol-2-yl)piperidin-4-yl)oxy)-3-fluorobenzoate (53 mg). MS [M+H] + :found484.1 / 486.1.

[0229] Step 6: Methyl 4-{[1-(5-bromo-6,7-difluoro-1h-1,3-benzodiazol-2-yl)piperidin-4-yl]oxy}-3-fluorobenzoate (43 mg, 88.79 μmol) and 2-pyrimidinamine, 4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-(22.96 mg, 97.67 μmolq) were dissolved in 1,4-dioxane (1 mL) and water (300 μL). Potassium carbonate (24.54 mg, 177.59 μmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (7.25 mg, 8.88 μmol) were added sequentially. The mixture was sparged with nitrogen for 3 minutes and then heated to 100°C under nitrogen with stirring for 2 hours. The reaction mixture was cooled to room temperature and diluted with ethyl acetate. The system was washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give crude methyl 4-((1-(6-bromo-4,5-difluoro-1H-benzo[d]imidazol-2-yl)piperidin-4-yl)oxy)-3-fluorobenzoate (19.70 mg, yield: 43.29%). MS [M+H] + :found 513.2.

[0230] Steps 7 and 8 can be carried out under the same conditions as those in Steps 3 and 4 of Example 164 to obtain Example 165 4-({1-[6-(2-amino-4-methylpyrimidin-5-yl)-4,5-difluoro-1H-1,3-benzodiazol-2-yl]piperidin-4-yl}oxo)-3-fluorobenzamide. MS [M+H] + :found 498.2. 1 H NMR (400MHz, DMSO-d6) δ11.76(s,1H),8.04(s,1H),7.94(s,1H),7.78-7.69(m,2H),7.44-7.30(m,2H),6.84(d,J=5.5Hz,1H),6. 66(s,2H),4.87-4.76(m,1H),3.92-3.89(m,2H),3.49-3.42(m,2H),2.14(d,J=1.2Hz,3H),2.12-2.08(m,2H),1.83-1.67(m,2H).

[0231] Examples 166-167 can be prepared by selecting appropriate raw materials according to the synthesis method of Example 165, and their structures are shown in Table 10.

[0232] Table 10. Structural formula, chemical name and mass spectrometry data of Examples 166-167

[0233] The NMR data of the compound prepared in the above example are as follows:

[0234] Example 169: Preparation of 5-(((1r,4r)-4-(6-(2-amino-4-(difluoromethyl)pyrimidin-5-yl)-4,5-difluoro-1H-benzo[d]imidazol-2-yl)cyclohexyl)oxy)-2-(trifluoromethyl)benzonitrile

[0235] Step 1: (1r,4r)-4-[3-cyano-4-(trifluoromethyl)phenoxy]cyclohexane-1-carboxylic acid (90 mg, 287.28 umol), 5-(2-amino-4-(difluoromethyl)pyrimidin-5-yl)-3,4-difluorobenzene-1,2-diamine (82.5 mg, 287.28 umol) and N,N-diisopropylethylamine (112.5 mg, 861.85 umol) were dissolved in N,N-dimethylformamide (3 mL) in sequence, and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (145 mg, 373.47 umol) was added and the reaction was stirred at room temperature overnight. Saturated aqueous ammonium chloride solution was added to quench the reaction, and the mixture was extracted three times with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give a brown gummy crude compound (1r, 4r)-N-{2-amino-5-[2-amino-4-(difluoromethyl)pyrimidin-5-yl]-3,4-difluorophenyl}-4-[3-cyano-4-(trifluoromethyl)phenoxy]cyclohexane-1-carboxamide (160 mg, yield: 95.62%).

[0236] Step 2: (1r,4r)-N-{2-amino-5-[2-amino-4-(difluoromethyl)pyrimidin-5-yl]-3,4-difluorophenyl}-4-[3-cyano-4-(trifluoromethyl)phenoxy]cyclohexane-1-carboxamide (160 mg, 274.69 μmol) was dissolved in trifluoroacetic acid (2 mL) and stirred at 50°C for 16 hours. After completion of the reaction, the mixture was cooled to room temperature. The reaction solution was concentrated and the crude product was purified by reverse phase high pressure separation to obtain compound 5-{[(1r,4r)-4-{6-[2-amino-4-(difluoromethyl)pyrimidin-5-yl]-4,5-difluoro-1H-1,3-benzodiazol-2-yl}cyclohexyl]oxy}-2-(trifluoromethyl)benzonitrile (119.12 mg, yield: 76.83%, purity: 100%). MS [M+H] + :found 565.2. 1H NMR: (400MHz, DMSO-d6) δ12.70(s,1H),8.38(d,J=2.8Hz,1H),8.10-7.67(m,3H),7.22(dd,J=12.8,2.4Hz,1H),7.05(dd,J=8.8,2.4Hz,1H),6.92(t, J=3.2Hz,1H),4.68-4.56(m,1H),3.27(s,3H),2.98(t,J=11.6Hz,1H),2.2 9-2.09(m,4H),1.87(q,J=12.0,11.6Hz,2H),1.60(q,J=10.8,10.4Hz,2H).

[0237] Examples 170-194 can be prepared by selecting appropriate raw materials according to the synthesis method of Example 169, and their structures are shown in Table 11.

[0238] Table 11. Structural formula, chemical name and mass spectrometry data of Examples 170-194

[0239] The NMR data of the compound prepared in the above example are as follows:

[0240] 3. Biological Testing

[0241] In vitro biochemical activity test:

[0242] This example describes the relationship between the structure and activity of cyclic imidazole compounds. Specifically, the biochemical activity of each example compound as a sEH inhibitor was evaluated using the PHOME assay. The synthesis of the substrate required for this assay and the assay method were based on previously reported literature (Analytical Biochemistry 2005, 343, 66-75).

[0243] sEH enzyme inhibition assays were performed in a low-binding 96-well plate. The reaction system consisted of 100 μL of 25 mM Bis-Tris, pH 7.0, 0.1 mg / mL BSA buffer. The PHOME assay activity assay was performed as follows.

[0244] First, a sEH enzyme solution with a final concentration of 500 pM was mixed with compounds of different concentrations and pre-incubated on a shaker at room temperature for 10 minutes. The reaction was triggered by adding Phome fluorescent substrate at a final concentration of 5 uM and immediately placed in a Perkin Elmer microplate reader. Dynamic monitoring was performed for 1 hour under the conditions of excitation wavelength 330 nm and emission wavelength 465 nm, with fluorescence readings at intervals of 1 minute. Graphpad Prism 9.0 software was used to calculate the slope of the fluorescence value increase in each well within 20 minutes, and the slope was used to calibrate the enzyme activity to calculate the inhibition rate of the compound on sEH enzyme activity under different concentration conditions. Finally, Graphpad Prism 9 was used to plot and calculate the IC 50 Value. Among them, "A" represents IC 50 ≤500pM, “B” means 500pM <IC 50 ≤2nM, “C” means 2nM <IC 50 ≤10nM, “D” means 10nM <IC 50 .

[0245] The inhibitory activity IC values ​​of some compounds against soluble epoxide hydrolases obtained by PHOME assay activity evaluation experiment 50 See Table 12 and Table 13.

[0246] Table 12. Test results of some examples of compounds inhibiting human sEH activity

[0247] Table 13. Test results of some examples of compounds inhibiting mouse sEH activity

[0248] The positive control compound TPPU is N-[1-(1-carbonylpropyl)-4-piperidinyl]-N'-[4-(trifluoromethoxy)phenyl]-urea, which is a known sEH inhibitor.

[0249] These results demonstrate that the cycloimidazole compounds described herein exhibit potent inhibitory activity against human sEH, with some compounds exhibiting activity below 100 pM. Furthermore, the cycloimidazole compounds described herein also exhibit potent inhibitory activity against murine sEH, with inhibitory activity comparable to or superior to that of TPPU. Overall, the cycloimidazole compounds described herein represent a class of highly active, soluble epoxide hydrolase inhibitors with excellent properties and promising development potential.

[0250] The above description of the embodiments is intended to facilitate understanding and application of the present application by those skilled in the art. It will be apparent that those skilled in the art can readily make various modifications to these embodiments and apply the general principles described herein to other embodiments without expending any creative effort. Therefore, the present application is not limited to the embodiments described herein, and improvements and modifications made by those skilled in the art based on the disclosure of this application without departing from the scope and spirit of this application are within the scope of this application.

Claims

1. A compound of formula I, its stereoisomers, tautomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs, Among them, X is N or CR 1a 、Y is N or CR 2a 、Z is N or CR 3a ; R 1a 、 R 2a and R 3a are each independently selected from the group consisting of: hydrogen, deuterium, halogen, cyano, nitro, NR a R b , hydroxy, carboxy, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C3-C10 cycloalkyloxy, substituted or unsubstituted 3-10 membered heterocyclic group, substituted or unsubstituted 3-10 membered heterocyclic group oxy, substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted C6-C10 aryloxy, substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted 5-10 membered heteroaryloxy, and each of the above groups may optionally be further substituted by one or more halogens; Ring A is selected from: a C6-C10 aromatic ring, a 5-10 membered heteroaromatic ring, a C3-C10 carbocyclic ring, a 3-10 membered heterocyclic ring; Ring B is selected from: a C6-C10 aromatic ring, a 5-10 membered heteroaromatic ring, a C3-C10 carbocyclic ring, a 4-10 membered heterocyclic ring; Ring C is selected from: a C6-C10 aromatic ring, a 5-10 membered heteroaromatic ring; m is 0, 1, 2, 3 or 4, and each R 2 is independently selected from: hydrogen, deuterium, halogen, cyano, nitro, NR a R b , hydroxy, carboxy, =O, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C3-C10 cycloalkyloxy, substituted or unsubstituted 4-10 membered heterocyclic group, substituted or unsubstituted 4-10 membered heterocyclic oxy group, substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted C6-C10 aryloxy, substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted 5-10 membered heteroaryloxy; n is 0, 1, 2, 3 or 4, and each R 3 is independently selected from: hydrogen, deuterium, halogen, cyano, nitro, NR a R b , substituted or unsubstituted -(C1-C4 alkylene)NR a R b , hydroxyl, carboxyl, =O, =C(R c )2, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted -COO(C1-C6 alkyl), substituted or unsubstituted -CONR a R b , substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C3-C10 cycloalkyloxy, substituted or unsubstituted 4-10 membered heterocyclic group, substituted or unsubstituted 4-10 membered heterocyclic oxy group, substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted C6-C10 aryloxy, substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted 5-10 membered heteroaryloxy, substituted or unsubstituted -(C1-C4 alkylene)COO(C1-C6 alkyl), substituted or unsubstituted -SO2(C1-C6 alkyl), substituted or unsubstituted -S(O)(NR a )(C1-C6 alkyl), substituted or unsubstituted -(C1-C4 alkylene)SO2(C1-C6 alkyl), substituted or unsubstituted -(C1-C4 alkylene)S(O)(NR a )(C1-C6 alkyl), substituted or unsubstituted -SO2NR a R b , substituted or unsubstituted -(C1-C4 alkylene)SO2NR a R b , substituted or unsubstituted -P(O)(C1-C6 alkyl)2, substituted or unsubstituted -(C1-C4 alkylene)P(O)(C1-C6 alkyl)2, substituted or unsubstituted -(C1-C4 alkylene)CONR a R b , substituted or unsubstituted -NR a CONR a R b , substituted or unsubstituted -(C1-C4 alkylene)5-10 membered heteroaryl, substituted or unsubstituted -(C1-C4 alkylene)4-10 membered heterocyclic group; Alternatively, two Rs attached to two adjacent atoms, together with the atoms connecting them, form a substituted or unsubstituted C4-C10 carbocyclic ring, a substituted or unsubstituted 4-10 membered heteroaromatic ring, or a substituted or unsubstituted 4-10 membered heterocyclic ring; 3 wherein the two Rs attached to two adjacent atoms, together with the atoms connecting them, form a substituted or unsubstituted C4-C10 carbocyclic ring, a substituted or unsubstituted 4-10 membered heteroaromatic ring, or a substituted or unsubstituted 4-10 membered heterocyclic ring; s is 0, 1, 2, 3 or 4, and each R is independently selected from: hydrogen, deuterium, halogen, cyano, nitro, NR a R b 、substituted or unsubstituted -(C1-C4 alkylene)NR a R b 、hydroxy, carboxy, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted -COO(C1-C6 alkyl), substituted or unsubstituted -CONR a R b 、substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C3-C10 cycloalkyloxy, substituted or unsubstituted 4-10 membered heterocyclic group, substituted or unsubstituted -(C1-C4 alkylene)4-10 membered heterocyclic group, substituted or unsubstituted C(O)4-10 membered heterocyclic group, substituted or unsubstituted -(C1-C4 alkylene)C(O)4-10 membered heterocyclic group, substituted or unsubstituted S(O)4-10 membered heterocyclic group, substituted or unsubstituted -(C1-C4 alkylene)S(O)4-10 membered heterocyclic group, substituted or unsubstituted S(O)24-10 membered heterocyclic group, substituted or unsubstituted -(C1-C4 alkylene)S(O)24-10 membered heterocyclic group, substituted or unsubstituted 4-10 membered heterocyclic oxy group, substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted C6-C10 aryloxy, substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted 5-10 membered heteroaryloxy, substituted or unsubstituted -(C1-C4 alkylene)COO(C1-C6 alkyl), substituted or unsubstituted -S(O)2(C1-C6 alkyl), substituted or unsubstituted -S(O)(NR a )(C1-C6 alkyl), substituted or unsubstituted -(C1-C4 alkylene)S(O)2(C1-C6 alkyl), substituted or unsubstituted -(C1-C4 alkylene)S(O)(NR a )(C1-C6 alkyl), substituted or unsubstituted -SO2NR a R b 、substituted or unsubstituted -(C1-C4 alkylene)SO2NR a R b 、substituted or unsubstituted -(C1-C4 alkylene)CONR a R b 、substituted or unsubstituted -NR a CONR a R b 、substituted or unsubstituted -(C1-C4 alkylene)5-10 membered heteroaryl, substituted or unsubstituted -(C1-C4 alkylene)4-10 membered heterocyclic group; Alternatively, two R groups attached to two adjacent atoms and the atoms to which they are attached together form a substituted or unsubstituted 4-10 membered cycloalkylidene or a substituted or unsubstituted 4-10 membered heteroalkylidene; L is (L a ) t ; wherein, t is 1, 2, 3 or 4; Each L a is independently selected from: O, CO, S, S(O), S(O)2, NR 4 , C(R 5 )2; Each R 4 is independently selected from: H, C1-C6 alkyl, -SO2(C1-C6 alkyl), C1-C6 alkyl acyl, C3-C10 cycloalkyl, and the alkyl, alkyl acyl and cycloalkyl may optionally be further substituted by one or more halogens; Each R 5 is independently selected from: hydrogen, deuterium, halogen, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy; Alternatively, two Rs attached to the same carbon atom 5 together with the carbon atom to which they are attached form a 3- to 6-membered cycloalkylidene or 4- to 6-membered heterocycloalkylidene group, and the cycloalkylidene group and the heterocycloalkylidene group are optionally further substituted by one or more groups independently selected from deuterium, halogen, ═O, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, and C1-C3 haloalkoxy; Alternatively, two Rs attached to different carbon atoms 5 together with all the atoms connecting them form a 3- to 6-membered cycloalkylidene or 4- to 6-membered heteroalkylidene group, and the cycloalkylidene and heteroalkylidene groups are optionally further substituted by one or more groups independently selected from deuterium, halogen, ═O, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, and C1-C3 haloalkoxy; Alternatively, R 4 and an R 5 together with all the atoms connecting them form a 3- to 6-membered sub-cycloalkyl group or a 4- to 6-membered hetero-sub-cycloalkyl group, and the sub-cycloalkyl group and the hetero-sub-cycloalkyl group are optionally further substituted by one or more groups independently selected from deuterium, halogen, ═O, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, and C1-C3 haloalkoxy; Each of the above substituents independently refers to being substituted by one or more substituents selected from the group consisting of deuterium, halogen, hydroxyl, carboxyl, amino, cyano, nitro, =O, =C(R c )2, benzyl, C1-C6 alkyl, C1-C6 alkyl acyl, -CO(C1-C6 alkoxy), -CONR a R b , -SO2(C1-C6 alkyl), -SO2(C1-C6 cycloalkyl), SO2NR a R b , -S(O)(NR a )(C1-C6 alkyl), C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C10 cycloalkyl, C3-C10 cycloalkyloxy, 4-10 membered heterocyclic group, 4-10 membered heterocyclic group oxy, C6-C10 aryl, C6-C10 aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, and each of the above groups may optionally be further substituted by one or more substituents selected from halogen, =O, CN, hydroxyl, amino, carboxyl, C1-C4 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl, C3-C6 cycloalkyloxy; Each R a 、each R b is independently selected from H, C1-C6 alkyl, -SO2(C1-C6 alkyl), -CO(C1-C6 alkyl), C1-C6 alkyl acyl, C3-C10 cycloalkyl at the occurrence thereof, and the alkyl, cycloalkyl, alkyl acyl and heterocyclic group may optionally be further substituted by one or more substituents selected from halogen, =O, CN, hydroxyl, amino, carboxyl, C1-C4 alkoxy, C3-C6 cycloalkyl, C3-C6 cycloalkoxy; or R attached to the same nitrogen atom a and R b together with the nitrogen atom to which they are attached form a substituted or unsubstituted 4- to 8-membered heterocyclic group, which heterocyclic group may optionally be further substituted by one or more substituents selected from halogen, ═O, CN, hydroxy, amino, carboxy, C1-C4 alkyl, C1-C4 haloalkyl; Each R c is independently selected from: hydrogen, deuterium, halogen, C1-C3 alkyl, C1-C3 haloalkyl; or two Rs c together with the carbon atoms to which they are attached form a 3- to 6-membered cycloalkylidene or 4- to 6-membered heteroalkylidene group, which may optionally be further substituted by one or more substituents selected from halogen, C1-C4 alkoxy, and C1-C4 haloalkoxy.

2. The compound according to claim 1, characterized in that, X is N or CR 1a , Y is CR 2a , Z is CR 3a ; R 1a 、R 2a and R 3a are each independently selected from the group consisting of: hydrogen, deuterium, halogen, cyano, nitro, NR a R b , hydroxy, carboxy, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C2-C4 alkenyl, substituted or unsubstituted C2-C4 alkynyl, substituted or unsubstituted C1-C4 alkoxy, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C3-C6 cycloalkyloxy, substituted or unsubstituted 4-7 membered heterocyclic group, substituted or unsubstituted 4-7 membered heterocyclic oxy group, substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted C6-C10 aryloxy, substituted or unsubstituted 5-7 membered heteroaryl, substituted or unsubstituted 5-7 membered heteroaryloxy, and each of the above groups may optionally be further substituted by one or more halogens; R a and R b are defined in the same way as in claim 1.

3. The compound according to claim 1 or 2, characterized in that, L is selected from: O, CO, S, S(O), S(O)2, NR 4 , C(R 5 )2, -O-C(R 5 )2-, -C(R 5 )2-C(R 5 )2-, -NR 4 -C(R 5 )2-, -NR 4 -S(O)2-, -C(R 5 )2-S(O)2-; R 4 and R 5 are defined in the same way as in claim 1.

4. The compound according to any one of claims 1-3, characterized in that, L is selected from: O, CO, S, S(O), S(O)2, NR 4 , C(R 5 )2, -O-C(R 5 )2-, C(R 5 )2-C(R 5 )2-, -NR 4 -C(R 5 )2-, -NR 4 -S(O)2-, -C(R 5 )2-S(O)2-, and each of the above groups may optionally be further substituted by one or more substituents selected from halogen, C1-C3 alkyl, and C1-C3 alkoxy; Each R 4 is independently selected from: H, C1-C4 alkyl, -SO2(C1-C3 alkyl), C1-C3 alkyl acyl, C3-C5 cycloalkyl, and the alkyl, alkyl acyl and cycloalkyl may optionally be further substituted by one or more halogens; Each R 5 is independently selected from: hydrogen, deuterium, halogen, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy.

5. The compound according to any one of claims 1-4, characterized in that, L is selected from: O, C(R 5 )2; Each R 5 is independently selected from: hydrogen, deuterium, halogen, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy.

6. The compound according to claim 1, characterized in that, Ring A is selected from: a benzene ring, a pyridine ring, a C4-C10 carbocyclic ring, a 4-10 membered heterocyclic ring; Each R 2 is independently selected from: hydrogen, deuterium, halogen, cyano, NR a R b , =O, C1-C4 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C3-C6 cycloalkyloxy, 3-6 membered heterocyclic group, 3-6 membered heterocyclic group oxy, and each of the above groups may optionally be further substituted by one or more substituents selected from halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 cycloalkyl, C1-C4 halocycloalkyl, C1-C4 cycloalkyloxy, C1-C4 halocycloalkyloxy, cyano; R a and R b are defined in the same way as in claim 1.

7. The compound according to any one of claims 1-6, characterized in that, Ring A is a benzene ring or a pyridine ring; L and the imidazole ring are in a para or meta substitution relationship with respect to Ring A; Each R 2 is independently selected from: hydrogen, deuterium, halogen, cyano, C1-C4 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C3-C6 cycloalkyloxy, and each of the above groups may optionally be further substituted by one or more halogens.

8. The compound according to any one of claims 1-6, characterized in that, Ring A is selected from: Optionally, the above-described structure further contains one or two double bonds substituted within the ring; Each R 2 is independently selected from: hydrogen, deuterium, halogen, cyano, C1-C4 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C3-C6 cycloalkyloxy, and each of the above groups may optionally be further substituted by one or more halogens.

9. The compound according to any one of claims 1-8, characterized in that Ring B is selected from: a benzene ring, a 5-10 membered heteroaromatic ring, a C3-C8 carbocyclic ring, a 4-10 membered heterocyclic ring; Each R 3 is independently selected from: hydrogen, deuterium, halogen, cyano, NR a R b , substituted or unsubstituted -(C1-C4 alkylene)NR a R b , hydroxyl, carboxyl, =O, =C(R c )2, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted -COO(C1-C6 alkyl), substituted or unsubstituted -CONR a R b , substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C3-C6 cycloalkyloxy, substituted or unsubstituted 4-8 membered heterocyclic group, substituted or unsubstituted 4-8 membered heterocyclic oxy group, substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted C6-C10 aryloxy, substituted or unsubstituted 5-8 membered heteroaryl, substituted or unsubstituted 5-8 membered heteroaryloxy, substituted or unsubstituted -(C1-C4 alkylene)COOH, substituted or unsubstituted -(C1-C4 alkylene)COO(C1-C6 alkyl), substituted or unsubstituted -SO2(C1-C6 alkyl), substituted or unsubstituted -S(O)(NR a )(C1-C6 alkyl), substituted or unsubstituted -(C1-C4 alkylene)SO2(C1-C6 alkyl), substituted or unsubstituted -(C1-C4 alkylene)S(O)(NR a )(C1-C6 alkyl), substituted or unsubstituted -SO2NR a R b , substituted or unsubstituted -(C1-C4 alkylene)SO2NR a R b , substituted or unsubstituted -P(O)(C1-C6 alkyl)2, substituted or unsubstituted -(C1-C4 alkylene)P(O)(C1-C6 alkyl)2, substituted or unsubstituted -(C1-C4 alkylene)CONR a R b , substituted or unsubstituted -NR a CONR a R b , substituted or unsubstituted -(C1-C4 alkylene)5-10 membered heteroaryl, substituted or unsubstituted -(C1-C4 alkylene)4-8 membered heterocyclic group; Alternatively, two Rs attached to two adjacent atoms, together with the atoms connecting them, form a substituted or unsubstituted C5-C8 carbocyclic ring, a substituted or unsubstituted 5-8 membered heteroaromatic ring, or a substituted or unsubstituted 5-8 membered heterocyclic ring; 3 wherein the two Rs attached to two adjacent atoms, together with the atoms connecting them, form a substituted or unsubstituted C5-C8 carbocyclic ring, a substituted or unsubstituted 5-8 membered heteroaromatic ring, or a substituted or unsubstituted 5-8 membered heterocyclic ring; R a , R b and R c are defined in the same way as in claim 1.

10. The compound according to any one of claims 1-9, characterized in that, Each R 3 is independently selected from: hydrogen, deuterium, halogen, cyano, NR a R b 、-(C1-C4 alkylene)NR a R b 、hydroxy, carboxy, =O, C1-C6 alkyl, C1-C6 alkoxy, -COO(C1-C6 alkyl), -CONR a R b 、C3-C6 cycloalkyl, C3-C6 cycloalkoxy, 4-8 membered heterocyclic group, 4-8 membered heterocyclic oxy group, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy, -(C1-C4 alkylene)COOH, -(C1-C4 alkylene)COO(C1-C6 alkyl), -SO2(C1-C6 alkyl), -S(O)(NR a )(C1-C6 alkyl), -(C1-C4 alkylene)SO2(C1-C6 alkyl), -(C1-C4 alkylene)S(O)(NR a )(C1-C6 alkyl), -SO2NR a R b 、-(C1-C4 alkylene)SO2NR a R b 、-P(O)(C1-C6 alkyl)2, -(C1-C4 alkylene)P(O)(C1-C6 alkyl)2, -(C1-C4 alkylene)CONR a R b 、-NR a CONR a R b 、-(C1-C4 alkylene)5-10 membered heteroaryl, -(C1-C4 alkylene)4-8 membered heterocyclic group, and each of the above groups may optionally be further substituted by one or more substituents selected from halogen, =O, CN, hydroxy, amino, carboxy, C1-C4 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl, C3-C6 cycloalkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, C3-C6 halocycloalkyl, C3-C6 halocycloalkoxy, C1-C6 alkyl acyl, C1-C6 alkoxy acyl, -CONR a R b 、-SO2(C1-C6 alkyl), -SO2(C1-C6 cycloalkyl), SO2NR a R b 、-S(O)(NR a )(C1-C6 alkyl); Alternatively, two Rs attached to two adjacent atoms, together with the atoms connecting them, form a substituted or unsubstituted C5-C8 carbocyclic ring, a substituted or unsubstituted 5-8 membered heteroaromatic ring or a substituted or unsubstituted 5-8 membered heterocyclic ring; 3 wherein the two Rs attached to two adjacent atoms, together with the atoms connecting them, form a substituted or unsubstituted C5-C8 carbocyclic ring, a substituted or unsubstituted 5-8 membered heteroaromatic ring or a substituted or unsubstituted 5-8 membered heterocyclic ring; R a and R b are defined in the same way as in claim 1.

11. The compound according to any one of claims 1-10, characterized in that, Ring B is selected from: a benzene ring, thiophene, pyridine, pyrimidine, indazole, benzo[d][1,2,3]triazole, [1,2,4]triazolo[4,3-a]pyridine.

12. The compound according to any one of claims 1-11, characterized in that, Ring C is a 5-10 membered heteroaromatic ring; Each R is independently selected from: hydrogen, deuterium, halogen, cyano, NR a R b 、hydroxyl, carboxyl, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted -COO(C1-C6 alkyl), substituted or unsubstituted -CONR a R b 、substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C3-C6 cycloalkyloxy, substituted or unsubstituted 4-8-membered heterocyclic group, substituted or unsubstituted -(C1-C4 alkylene)4-8-membered heterocyclic group, substituted or unsubstituted C(O)4-8-membered heterocyclic group, substituted or unsubstituted -(C1-C4 alkylene)C(O)4-8-membered heterocyclic group, substituted or unsubstituted S(O)4-8-membered heterocyclic group, substituted or unsubstituted -(C1-C4 alkylene)S(O)3-8-membered heterocyclic group, substituted or unsubstituted S(O)24-10-membered heterocyclic group, substituted or unsubstituted -(C1-C4 alkylene)S(O)24-10-membered heterocyclic group, substituted or unsubstituted 4-8-membered heterocyclic group oxy, substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted C6-C10 aryloxy, substituted or unsubstituted 5-10-membered heteroaryl, substituted or unsubstituted 5-10-membered heteroaryloxy, substituted or unsubstituted -(C1-C4 alkylene)COO(C1-C6 alkyl), substituted or unsubstituted -S(O)2(C1-C6 alkyl), substituted or unsubstituted -S(O)(NR a )(C1-C6 alkyl), substituted or unsubstituted -(C1-C4 alkylene)S(O)2(C1-C6 alkyl), substituted or unsubstituted -(C1-C4 alkylene)S(O)(NR a )(C1-C6 alkyl), substituted or unsubstituted -SO2NR a R b 、substituted or unsubstituted -(C1-C4 alkylene)SO2NR a R b 、substituted or unsubstituted -(C1-C4 alkylene)CONR a R b 、substituted or unsubstituted -NR a CONR a R b 、substituted or unsubstituted -(C1-C4 alkylene)5-10-membered heteroaryl, substituted or unsubstituted -(C1-C4 alkylene)4-10-membered heterocyclic group; R a and R b are defined in the same way as in claim 1.

13. The compound according to any one of claims 1-12, characterized in that, Ring C is a 5-6 membered heteroaromatic ring.

14. The compound according to any one of claims 1-13, characterized in that, Each R is independently selected from: hydrogen, deuterium, halogen, cyano, NR a R b , hydroxy, carboxy, C1-C6 alkyl, C1-C6 alkoxy, -COO(C1-C6 alkyl), -CONR a R b , C3-C6 cycloalkyl, C3-C6 cycloalkoxy, 4-8 membered heterocyclic group, -(C1-C4 alkylene)4-8 membered heterocyclic group, C(O)4-8 membered heterocyclic group, -(C1-C4 alkylene)C(O)4-8 membered heterocyclic group, S(O)4-8 membered heterocyclic group, -(C1-C4 alkylene)S(O)4-8 membered heterocyclic group, S(O)24-8 membered heterocyclic group, -(C1-C4 alkylene)S(O)24-8 membered heterocyclic group, 4-8 membered heterocyclic oxy, C6-C10 aryl, C6-C10 aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, -(C1-C4 alkylene)COO(C1-C6 alkyl), -S(O)2(C1-C6 alkyl), -S(O)(NR a )(C1-C6 alkyl), -(C1-C4 alkylene)S(O)2(C1-C6 alkyl), -(C1-C4 alkylene)S(O)(NR a )(C1-C6 alkyl), -SO2NR a R b , -(C1-C4 alkylene)SO2NR a R b , -(C1-C4 alkylene)CONR a R b , -NR a CONR a R b , -(C1-C4 alkylene)5-10 membered heteroaryl, -(C1-C4 alkylene)4-10 membered heterocyclic group, and each of the above groups may optionally be further substituted by one or more substituents selected from halogen, =O, CN, hydroxy, amino, carboxy, C1-C4 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl, C3-C6 cycloalkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, C3-C6 halocycloalkyl, C3-C6 halocycloalkoxy, C1-C6 alkyl acyl, C1-C6 alkoxy acyl, -CONR a R b , -SO2(C1-C6 alkyl), -SO2(C1-C6 cycloalkyl), SO2NR a R b , -S(O)(NR a )(C1-C6 alkyl); R a and R b are defined the same as in claim 1.

15. The compound according to claim 1, characterized in that The said compound is selected from the following group:

16. A pharmaceutical composition comprising a compound as described in any one of claims 1-15, its stereoisomers, tautomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs, and a pharmaceutically acceptable carrier, adjuvant or excipient.

17. A kit comprising a compound as described in any one of claims 1-15, its stereoisomers, tautomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs, or the pharmaceutical composition as described in claim 16.

18. Use of a compound as described in any one of claims 1-15, its stereoisomers, tautomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs or the pharmaceutical composition as described in claim 16, as a soluble epoxide hydrolase inhibitor; or for the preparation of a medicament for the treatment of sEH-related or mediated diseases.

19. The use according to claim 18, wherein The sEH-related or mediated diseases are selected from: Alzheimer's disease, Parkinson's disease, Huntington's disease, dementia, cerebral ischemia, epilepsy, traumatic brain injury, stroke, Alexander disease, Alpers disease, amyotrophic lateral sclerosis, ataxia-telangiectasia, Batten disease, Canavan disease, Cockayne syndrome, corticobasal degeneration, Creutzfeldt-Jakob disease, Kennedy disease, Krabbe disease, Lewy body dementia, Machado-Joseph disease, multiple sclerosis, multiple system atrophy, Pelizaeus-Merzbacher disease, Pick's disease, primary lateral sclerosis, Refsum's disease, Sandhoff disease, Schilder's disease, Tay-Sachs disease, spinocerebellar ataxia, spinal muscular atrophy, progressive supranuclear palsy, transmissible spongiform encephalopathy, tabes dorsalis, peripheral neuralgia, neuroinflammation, asthma, chronic obstructive pulmonary disease (COPD), chronic bronchitis, cystic fibrosis, atherosclerosis, restenosis after angioplasty, coronary artery disease, rheumatoid arthritis, osteoarthritis, dermatitis, eczematous dermatitis, psoriasis, late and chronic solid organ rejection after transplantation, systemic lupus erythematosus, dermatomyositis, polymyositis, Sjogren's syndrome, polymyalgia rheumatica, temporal arteritis, Behcet's disease, Guillain-Barré syndrome, Wegener's granulomatosis, polyarteritis nodosa, neuralgia, vasculitis, pancreatitis, ulcerative colitis, Crohn's disease, Kaposi's sarcoma, hypertension, pulmonary hypertension, adult respiratory distress syndrome, end-stage renal disease, heart failure, renal failure, liver failure, cardiac fibrosis, renal fibrosis, pulmonary fibrosis, liver fibrosis, non-alcoholic fatty liver, ischemic limb disease, intermittent claudication, endothelial dysfunction, male erectile dysfunction, Raynaud's disease, diabetic angiopathy, herpes zoster, gastrointestinal diseases caused by non-steroidal anti-inflammatory drugs, hand-foot syndrome caused by chemotherapy, etc.

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