Aryl urea derivative, and pharmaceutical composition containing same and use thereof

Abstract

The present invention relates to the field of pharmaceutical chemistry, and in particular to a new aryl urea derivative, namely a compound of general formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof, a pharmaceutical composition comprising the compound, and the use thereof, wherein substituents R1, R2, R3 and R4, X, Y, Z, m and n have the significances given in the description. The present invention further relates to the use of the compound of general formula I in the preparation of a drug for treating and / or preventing sEH-mediated diseases, and in particular in the preparation of a drug for treating inflammatory diseases, cardiovascular and cerebrovascular diseases, pain, diabetes, complications of diabetes, diabetes-related diseases, fibrotic diseases, neurological and psychiatric diseases, ulcerative diseases, etc.

Description

Aryl urea derivatives, pharmaceutical compositions containing the same and their uses Technical Field

[0001] The present invention relates to the field of medicinal chemistry, and in particular to a series of novel aryl urea derivatives and pharmaceutically acceptable salts, solvates or prodrugs thereof, methods for preparing the same, pharmaceutical compositions containing the same, and their use in preparing medicaments for treating and / or preventing sEH-mediated diseases, particularly in preparing medicaments for treating inflammatory diseases, cardiovascular and cerebrovascular diseases, diabetes, diabetic complications, diabetes-related diseases, fibrotic diseases, neurological and psychiatric diseases, pain, ulcerative diseases, and the like. Background Art

[0002] Epoxide hydrolases (EHs) convert epoxides into their corresponding vicinal diols. Multiple epoxide hydrolases exist in mammals, including eight subtypes: leukotriene A4 hydrolase (LTA4H), cholesterol 5,6-oxide hydrolase (ChEH), microsomal epoxide hydrolase (mEH), heparin A3 hydrolase (hepoxilin A3 hydrolase), and soluble spoxide hydrolase (sEH). Numerous studies in recent years have demonstrated that soluble spoxide hydrolases are potential therapeutic targets for a wide range of diseases, including hypertension, lung disease, diabetes, pain, inflammation, and other immune system disorders.

[0003] The human soluble epoxide hydrolase (sEH) gene is approximately 45 kb in length, consisting of 18 introns and 19 exons ranging from 27 to 265 bp, encoding over 500 amino acids. It is encoded by the EPHX2 gene, located in the P21-P12 region of chromosome 8. sEH is a member of the α / β hydrolase family. In humans, sEH can be detected in the cytoplasm of many tissues and in peroxisomes, with the highest levels detected in the liver, kidney, intestine, and vascular system. Recently, sEH has also been found in the brain cortex, hippocampus, amygdala, and striatum.

[0004] Arachidonic acid (AA) is an unsaturated fatty acid that is primarily metabolized by cyclooxygenase (COX), lipoxygenase (LOX), and cytochrome P450 (CYP450) enzymes, converting it into various inflammatory mediators, such as prostaglandins, lipoxins, and leukotrienes. Cytochrome P450 enzymes can convert AA into biologically active epoxyeicosatrienoic acids (EETs). Studies have shown that EETs possess anti-inflammatory activity and play a key role in anti-inflammatory responses. Furthermore, EETs regulate ion transport, gene expression, and vasodilation.

[0005] EETs can be converted by sEH into low-activity dihydroxyeicosatrienoic acids (DHETs), which in turn lose their anti-inflammatory activity. Inhibiting sEH activity can increase EET levels, which not only enhances anti-inflammatory effects but also inhibits metabolic pathways such as COX-2 and 5-LOX in the arachidonic acid cascade, thereby reducing the production of inflammatory mediators. Therefore, sEH inhibitors can increase the levels of anti-inflammatory substances in the body, thereby alleviating inflammatory responses and achieving the goal of treating inflammatory diseases.

[0006] Dicyclohexylcarbodiimide (DCC) exhibits strong inhibitory activity against sEH. However, it was later discovered that it hydrolyzes in buffer to form a urea-containing product, N,N-dicyclohexylurea (DCU), which is the molecule truly responsible for sEH inhibition. Among sEH, glutathione transferase, carboxylesterase, cytochrome P450 enzymes, and coenzyme A oxidase, DCU inhibits only sEH, indicating that urea compounds possess good selectivity for sEH. Consequently, urea molecules have become a hot topic of research in subsequent sEH inhibitor research.

[0007] Summary of the invention:

[0008] The present invention aims to provide a series of novel aryl urea derivatives and pharmaceutically acceptable salts, solvates or prodrugs thereof, methods for their preparation and pharmaceutical compositions containing the compounds, as well as the use of the compounds in preparing medicaments for treating and / or preventing sEH-mediated diseases, particularly in preparing medicaments for treating inflammatory diseases, cardiovascular and cerebrovascular diseases, diabetes, diabetic complications, diabetes-related diseases, fibrotic diseases, neurological and psychiatric diseases, pain, ulcerative diseases, etc.

[0009] To achieve the above objectives, the present inventors have discovered a series of aryl urea derivatives, which were tested for sEH kinase inhibitory activity in vitro, and the results showed that all of them have inhibitory activity.

[0010] The technical solution adopted in the present invention is:

[0011] An aryl urea derivative, namely a compound of formula I or a stereoisomer, a pharmaceutically acceptable salt, a solvate or a prodrug thereof,

[0012] in,

[0013] X is N or CR 5 , where R 5 is hydrogen, halogen, (C1-C4)alkyl or (C1-C4)alkoxy;

[0014] Y and Z are independently selected from N or S, and Y and Z are different; when Y is N, the double bond in the heteroaryl group in which Y and Z are located is located between the C atom between Y and Z and Y; when Y is S, the double bond in the heteroaryl group in which Y and Z are located is located between the C atom between Y and Z and Z;

[0015] R 3 (C6-C 10 ) aryl, 5-10 membered heteroaryl or adamantyl, wherein the heteroaryl contains 1-3 heteroatoms selected from N, O or S, and the aryl or heteroaryl is optionally substituted by 1-3 identical or different R 8 replace;

[0016] R 4 is hydrogen, -C(O)(CH2) q R 6 、-(CH2) q C(O)OR 6 or -C(O)NH(CH2) q R 6 , where q is 0, 1, 2, 3, or 4, and R 6 (C1-C6) alkyl, (C3-C7) cycloalkyl, (C6-C 10 ) aryl or 5-10 membered heteroaryl, said aryl or heteroaryl being optionally substituted by 1-3 identical or different R 7 replace;

[0017] m is 0 or 1;

[0018] n is 1, 2, or 3;

[0019] R 7 and R 8are the same or different and are independently selected from hydroxy, halogen, nitro, amino, cyano, azido, mercapto, carbamoyl, (C1-C6) alkylthiol, (C2-C6) alkenyl, (C1-C6) alkylamido, (C1-C6) alkylsulfinyl, (C1-C6) alkylsulfonyl, (C1-C6) alkylacyl, free, salified, esterified and amidated carboxyl, (C1-C6) alkyl which is unsubstituted or substituted with at least one of hydroxy, amino or halogen, (C1-C6) alkoxy which is unsubstituted or substituted with at least one of hydroxy, amino or halogen, amino substituted with one or two (C1-C6 alkyl) groups, or carbamoyl substituted with one or two (C1-C6 alkyl) groups;

[0020] When X is CH (i.e. R 5 When Y is N and Z is S, R 1 and R 2 Together with the nitrogen atom to which they are attached, they are unsubstituted or replaced by at least one identical or different R 9 A substituted 4-10 membered heterocyclic group, wherein the heterocyclic group is 1 and R 2 In addition to the nitrogen atom to which it is attached, it optionally contains 1-3 heteroatoms selected from N, O or S, and the ring carbon atoms of the heterocyclic group are 1-3 oxo-substituted (i.e., forming an endocyclic carbonyl group);

[0021] When X is CH, Y is S and Z is N, R 1 and R 2 are the same or different and are each independently selected from hydrogen, (C1-C6)alkyl, (C3-C7)cycloalkyl, (C1-C6)alkylacyl, (C2-C6)alkenyl or (C2-C6)alkynyl; or R 1 and R 2 Together with the nitrogen atom to which they are attached, they are unsubstituted or replaced by at least one identical or different R 9 a substituted 4-10 membered heterocyclic group, wherein the heterocyclic group, in addition to the nitrogen atom to which R1 and R2 are attached, optionally contains 1-3 heteroatoms selected from N, O or S, optionally includes 1-2 carbon-carbon double bonds, and the ring carbon atoms of the heterocyclic group are substituted with 0-3 oxo groups;

[0022] When X is N or CR 5 , and R 5 When it is not hydrogen, R 1 and R 2 are the same or different and are each independently selected from hydrogen, (C1-C6)alkyl, (C3-C7)cycloalkyl, (C1-C6)alkylacyl, (C2-C6)alkenyl or (C2-C6)alkynyl; or R 1 and R 2Together with the nitrogen atom to which they are attached, they are unsubstituted or replaced by at least one identical or different R 9 a substituted 4-10 membered heterocyclic group, wherein the heterocyclic group, in addition to the nitrogen atom to which R1 and R2 are attached, optionally contains 1-3 heteroatoms selected from N, O or S, optionally includes 1-2 carbon-carbon double bonds, and the ring carbon atoms of the heterocyclic group are substituted with 0-3 oxo groups;

[0023] R 9 is hydroxy, amino, halogen, carboxyl, cyano, nitro, (C1-C6) alkyl, (C1-C6) alkoxy, (C3-C7) cycloalkyl, (C1-C6) alkylsulfinyl, (C1-C6) alkylsulfonyl, (C1-C6) alkylacyl, (C1-C6) alkyl optionally substituted by hydroxy, amino or halogen, (C1-C6) alkoxy optionally substituted by hydroxy, amino or halogen, or amino substituted by one or two (C1-C6 alkyl) groups.

[0024] Preferably, in the compound of formula I or its stereoisomer, pharmaceutically acceptable salt, solvate or prodrug,

[0025] X is N or CR 5 , where R 5 is hydrogen, halogen, (C1-C4)alkyl, (C1-C4)alkoxy;

[0026] Y and Z are each independently selected from N or S, and Y and Z are different;

[0027] R 3 is phenyl, 5-10 membered heteroaryl or adamantyl, wherein the phenyl or heteroaryl is optionally substituted by 1-3 identical or different R 8 replace;

[0028] R 4 is hydrogen, -C(O)(CH2) q R 6 or -C(O)NH(CH2) q R 6 , where q is 0, 1, or 2, and R 6 is (C1-C4) alkyl, (C3-C6) cycloalkyl, phenyl or 5-6 membered heteroaryl, wherein the phenyl or heteroaryl is optionally substituted by 1-3 identical or different R 7 replace;

[0029] m is 0 or 1;

[0030] n is 1 or 2;

[0031] R 7 and R 8are the same or different and are each independently selected from hydroxy, halogen, nitro, amino, cyano, (C1-C4) alkyl, (C1-C4) alkoxy, carbamoyl, (C2-C4) alkenyl, (C1-C4) alkylsulfinyl, (C1-C4) alkylsulfonyl, (C1-C4) alkylacyl, (C1-C4) alkylamido, free, salified, esterified and amidated carboxyl, (C1-C4) alkyl which is unsubstituted or substituted with at least one of hydroxy, amino or halogen, (C1-C4) alkoxy which is unsubstituted or substituted with at least one of hydroxy, amino or halogen, amino substituted with one or two (C1-C4) alkyl groups, or carbamoyl substituted with one or two (C1-C4 alkyl) groups;

[0032] When X is CH, Y is N, and Z is S, R 1 and R 2 Together with the nitrogen atom to which they are attached, they are unsubstituted or replaced by at least one identical or different R 9 A substituted 4-10 membered heterocyclic group, wherein the heterocyclic group is 1 and R 2 In addition to the nitrogen atom to which it is attached, it optionally contains 1 to 3 heteroatoms selected from N, O or S, and the ring carbon atoms of the heterocyclic group are substituted with 1 to 3 oxo groups;

[0033] When X is CH, Y is S and Z is N, R 1 and R 2 are the same or different and are each independently selected from hydrogen, (C1-C6)alkyl, (C3-C7)cycloalkyl, (C1-C6)alkylacyl, (C2-C6)alkenyl or (C2-C6)alkynyl; or R 1 and R 2 Together with the nitrogen atom to which they are attached, they are unsubstituted or replaced by at least one identical or different R 9 a substituted 4-10 membered heterocyclic group, wherein the heterocyclic group, in addition to the nitrogen atom to which R1 and R2 are attached, optionally contains 1-3 heteroatoms selected from N, O or S, optionally includes 1-2 carbon-carbon double bonds, and the ring carbon atoms of the heterocyclic group are substituted with 0-3 oxo groups;

[0034] When X is N or CR 5 , and R 5 When it is not hydrogen, R 1 and R 2 are the same or different and are each independently selected from hydrogen, (C1-C6)alkyl, (C3-C7)cycloalkyl, (C1-C6)alkylacyl, (C2-C6)alkenyl or (C2-C6)alkynyl; or R 1 and R 2 Together with the nitrogen atom to which they are attached, they are unsubstituted or replaced by at least one identical or different R 9a substituted 4-10 membered heterocyclic group, wherein the heterocyclic group, in addition to the nitrogen atom to which R1 and R2 are attached, optionally contains 1-3 heteroatoms selected from N, O or S, optionally includes 1-2 carbon-carbon double bonds, and the ring carbon atoms of the heterocyclic group are substituted with 0-3 oxo groups;

[0035] R 9 is hydroxy, amino, halogen, carboxyl, cyano, nitro, (C1-C6) alkyl, (C1-C6) alkoxy, (C3-C7) cycloalkyl, (C1-C6) alkylsulfinyl, (C1-C6) alkylsulfonyl, (C1-C6) alkylacyl, (C1-C6) alkyl optionally substituted by hydroxy, amino or halogen, (C1-C6) alkoxy optionally substituted by hydroxy, amino or halogen, or amino substituted by one or two (C1-C6 alkyl) groups.

[0036] Further preferably, in the compound of the general formula I or its stereoisomers, pharmaceutically acceptable salts, solvates or prodrugs,

[0037] X is N or CR 5 , where R 5 is hydrogen, halogen, (C1-C4)alkyl or (C1-C4)alkoxy;

[0038] Y and Z are each independently selected from N or S, and Y and Z are different;

[0039] R 3 is phenyl, 5-10 membered heteroaryl or adamantyl, wherein the phenyl or heteroaryl is optionally substituted by 1-3 identical or different R 8 replace;

[0040] R 4 is hydrogen, -C(O)(CH2) q R 6 or -C(O)NH(CH2) q R 6 , where q is 0, 1, or 2, and R 6 is (C1-C4) alkyl, (C3-C6) cycloalkyl, phenyl or 5-6 membered heteroaryl, wherein the phenyl or heteroaryl is optionally substituted by 1-3 identical or different R 7 replace;

[0041] m is 0 or 1;

[0042] n is 1 or 2;

[0043] R 7 and R 8are the same or different and are each independently selected from hydroxy, halogen, nitro, amino, cyano, (C1-C4) alkyl, (C1-C4) alkoxy, carbamoyl, (C2-C4) alkenyl, (C1-C4) alkylsulfinyl, (C1-C4) alkylsulfonyl, (C1-C4) alkylacyl, (C1-C4) alkylamido, free, salified, esterified and amidated carboxyl, (C1-C4) alkyl which is unsubstituted or substituted with at least one of hydroxy, amino or halogen, (C1-C4) alkoxy which is unsubstituted or substituted with at least one of hydroxy, amino or halogen, amino substituted with one or two (C1-C4) alkyl groups, or carbamoyl substituted with one or two (C1-C4 alkyl) groups;

[0044] When X is CH, Y is N, and Z is S, R 1 and R 2 Together with the nitrogen atom to which they are attached, they are unsubstituted or replaced by at least one identical or different R 9 Substituted 4-6 membered heterocyclic group, the heterocyclic group except R 1 and R 2 In addition to the nitrogen atom to which it is attached, it optionally contains 1 to 3 heteroatoms selected from N, O or S, and the ring carbon atoms of the heterocyclic group are substituted with 1 to 3 oxo groups;

[0045] When X is CH, Y is S and Z is N, R 1 and R 2 are the same or different and are independently selected from hydrogen, (C1-C4) alkyl, (C3-C6) cycloalkyl, (C1-C4) alkylacyl, (C2-C4) alkenyl or (C2-C4) alkynyl; or R1 and R2 together with the nitrogen atom to which they are attached form an unsubstituted or substituted group with at least one identical or different R 9 a substituted 4-6 membered heterocyclic group, wherein the heterocyclic group, in addition to the nitrogen atom to which R1 and R2 are attached, optionally contains 1-3 heteroatoms selected from N, O or S, optionally includes 1-2 carbon-carbon double bonds, and the ring carbon atoms of the heterocyclic group are substituted with 0-3 oxo groups;

[0046] When X is N or CR 5 , and R 5 When it is not hydrogen, R 1 and R 2 are the same or different and are each independently selected from hydrogen, (C1-C4)alkyl, (C3-C6)cycloalkyl, (C1-C4)alkylacyl, (C2-C4)alkenyl or (C2-C4)alkynyl; or R 1 and R 2 Together with the nitrogen atom to which they are attached, they are unsubstituted or replaced by at least one identical or different R 9a substituted 4-6 membered heterocyclic group, wherein the heterocyclic group, in addition to the nitrogen atom to which R1 and R2 are attached, optionally contains 1-3 heteroatoms selected from N, O and / or S, optionally includes 1-2 carbon-carbon double bonds, and the ring carbon atoms of the heterocyclic group are substituted with 0-3 oxo groups;

[0047] R 9 is hydroxy, amino, halogen, carboxyl, cyano, nitro, (C1-C4) alkyl, (C1-C4) alkoxy, (C3-C6) cycloalkyl, (C1-C4) alkylsulfinyl, (C1-C4) alkylsulfonyl, (C1-C4) alkylacyl, (C1-C4) alkyl optionally substituted by hydroxy, amino or halogen, (C1-C4) alkoxy optionally substituted by hydroxy, amino or halogen, or amino substituted by one or two (C1-C4 alkyl) groups.

[0048] More preferably, in the compound of the general formula I or its stereoisomers, pharmaceutically acceptable salts, solvates or prodrugs,

[0049] X is N or CR 5 , where R 5 is hydrogen, halogen, (C1-C4)alkyl or (C1-C4)alkoxy;

[0050] Y and Z are each independently selected from N or S, and Y and Z are different;

[0051] R 3 is phenyl or 5-8 membered heteroaryl, wherein the phenyl or heteroaryl is optionally substituted by 1-3 identical or different R 8 replace;

[0052] R 4 is hydrogen, -C(O)(CH2) q R 6 or -C(O)NH(CH2) q R 6 , where q is 0, 1, or 2, and R 6 is (C1-C4)alkyl, (C3-C6)cycloalkyl or phenyl, the phenyl group is optionally substituted by 1-3 identical or different R 7 replace;

[0053] m is 0 or 1;

[0054] n is 2;

[0055] R 7 and R 8are the same or different and are each independently selected from hydroxy, halogen, nitro, amino, cyano, (C1-C4) alkyl, (C1-C4) alkoxy, carbamoyl, (C2-C4) alkenyl, (C1-C4) alkylsulfinyl, (C1-C4) alkylsulfonyl, (C1-C4) alkylacyl, (C1-C4) alkylamido, free, salified, esterified and amidated carboxyl, (C1-C4) alkyl which is unsubstituted or substituted with at least one of hydroxy, amino or halogen, (C1-C4) alkoxy which is unsubstituted or substituted with at least one of hydroxy, amino or halogen, amino substituted with one or two (C1-C4) alkyl groups, or carbamoyl substituted with one or two (C1-C4 alkyl) groups;

[0056] When X is CH, Y is N, and Z is S, R 1 and R 2 Together with the nitrogen atom to which they are attached, they form a heterocyclic group selected from: in Indicates the site of attachment to the rest of the compound;

[0057] When X is CH, Y is S and Z is N, R 1 and R 2 are the same or different and are each independently selected from hydrogen, (C1-C4)alkyl, (C3-C6)cycloalkyl or (C1-C4)alkylacyl; or R 1 and R 2 Together with the nitrogen atom to which they are attached, they form a heterocyclic group selected from:

[0058] When X is N or CR 5 , and R 5 When it is not hydrogen, R 1 and R 2 are the same or different and are each independently selected from hydrogen, (C1-C4)alkyl, (C3-C6)cycloalkyl or (C1-C4)alkylacyl; or R 1 and R 2 Together with the nitrogen atom to which they are attached, they form a heterocyclic group selected from:

[0059] Still further preferably, in the compound of formula I or its stereoisomers, pharmaceutically acceptable salts, solvates or prodrugs,

[0060] X is CR 5 , where R 5 is hydrogen, fluorine or chlorine;

[0061] Y and Z are each independently selected from N or S, and Y and Z are different;

[0062] R 3 is phenyl, the phenyl group is optionally substituted by 1-3 identical or different R 8 replace;

[0063] R 4 is hydrogen, -C(O)(CH2) q R 6 or -C(O)NH(CH2) q R 6 , where q is 0, 1, or 2, and R 6 is (C1-C4)alkyl, (C3-C6)cycloalkyl or phenyl, the phenyl group is optionally substituted by 1-3 identical or different R 7 replace;

[0064] m is 0 or 1;

[0065] n is 2;

[0066] R 7 is hydroxy, halogen, nitro, amino, cyano, (C1-C4)alkyl, (C1-C4)alkoxy, carbamoyl, (C2-C4)alkenyl, (C1-C4)alkylsulfinyl, (C1-C4)alkylsulfonyl, (C1-C4)alkylacyl, (C1-C4)alkylamido, free, salified, esterified and amidated carboxyl, (C1-C4)alkyl which is unsubstituted or substituted with at least one of hydroxy, amino or halogen, (C1-C4)alkoxy which is unsubstituted or substituted with at least one of hydroxy, amino or halogen, amino which is substituted with one or two (C1-C4)alkyl groups, or carbamoyl which is substituted with one or two (C1-C4)alkyl groups;

[0067] R 8 is chlorine, fluorine, bromine, trifluoromethyl or trifluoromethoxy;

[0068] When X is CH, Y is N, and Z is S, R 1 and R 2 Together with the nitrogen atom to which they are attached, they form a heterocyclic group selected from:

[0069] When X is CH, Y is S and Z is N, R 1 and R 2 are the same or different and are each independently selected from hydrogen, (C1-C4)alkyl, (C3-C6)cycloalkyl or (C1-C4)alkylacyl;

[0070] or R 1 and R 2 Together with the nitrogen atom to which they are attached, they form a heterocyclic group selected from:

[0071] When X is N or CR 5 , and R 5 When it is not hydrogen, R 1 and R 2 are the same or different and are each independently selected from hydrogen, (C1-C4)alkyl, (C3-C6)cycloalkyl or (C1-C4)alkylacyl;

[0072] or R 1 and R 2 Together with the nitrogen atom to which they are attached, they form a heterocyclic group selected from:

[0073] More preferably, the compound of formula I is the following compound:

[0074] 1-(2-aminobenzo[d]thiazol-6-yl)-3-(4-chlorophenyl)-1-[2-(3-oxomorpholin-4-yl)ethyl]urea;

[0075] 1-(2-aminobenzo[d]thiazol-6-yl)-3-(4-chlorophenyl)-1-[2-(2-oxopyrrolidin-1-yl)ethyl]urea;

[0076] 1-(2-aminobenzo[d]thiazol-6-yl)-3-(4-chlorophenyl)-1-[2-(2-oxopiperidin-1-yl)ethyl]urea;

[0077] 1-(2-aminobenzo[d]thiazol-6-yl)-3-(3-bromo-4-fluorophenyl)-1-[2-(2-oxopyrrolidin-1-yl)ethyl]urea;

[0078] 1-(2-aminobenzo[d]thiazol-6-yl)-3-(3-bromo-4-fluorophenyl)-1-[2-(3-oxomorpholin-4-yl)ethyl]urea;

[0079] 1-(2-aminobenzo[d]thiazol-5-yl)-3-(4-chlorophenyl)-1-[2-(3-oxomorpholin-4-yl)ethyl]urea;

[0080] 1-(2-aminobenzo[d]thiazol-5-yl)-3-(4-chlorophenyl)-1-[2-(2-oxopiperidin-1-yl)ethyl]urea;

[0081] 1-(2-Acetylaminobenzo[d]thiazol-6-yl)-1-[2-(3-oxomorpholin-4-yl)ethyl]-3-(4-chlorophenyl)urea;

[0082] 1-{2-[3-(4-chlorophenyl)ureido]benzo[d]thiazol-6-yl}-1-[2-(3-oxomorpholin-4-yl)ethyl]-3-(4-chlorophenyl)urea;

[0083] 1-(2-aminobenzo[d]thiazol-5-yl)-3-(4-chloro-3-fluorophenyl)-1-[2-(3-oxomorpholin-4-yl)ethyl]urea;

[0084] 1-(2-amino-5-chlorobenzo[d]thiazol-6-yl)-3-(4-chlorophenyl)-1-[2-(4-morpholinyl)ethyl]urea;

[0085] 1-(2-amino-5-chlorobenzo[d]thiazol-6-yl)-1-(2-aminoethyl)-3-(4-chlorophenyl)urea;

[0086] 1-(2-amino-5-chlorobenzo[d]thiazol-6-yl)-1-(2-acetylaminoethyl)-3-(4-chlorophenyl)urea;

[0087] 1-(2-amino-5-chlorobenzo[d]thiazol-6-yl)-3-(4-chlorophenyl)-1-[2-(2-oxopyrrolidin-1-yl)ethyl]urea;

[0088] 1-(2-amino-5-chlorobenzo[d]thiazol-6-yl)-3-(4-chlorophenyl)-1-[2-(3-oxomorpholin-4-yl)ethyl]urea;

[0089] 1-(2-amino-5-chlorobenzo[d]thiazol-6-yl)-3-(4-chlorophenyl)-1-{2-[4-(1-thiomorpholinothioate)]ethyl}urea;

[0090] 1-(2-amino-5-chlorobenzo[d]thiazol-6-yl)-3-(4-chlorophenyl)-1-[2-(2-oxopiperidin-1-yl)ethyl]urea;

[0091] 1-(2-amino-5-fluorobenzo[d]thiazol-6-yl)-3-(4-chlorophenyl)-1-[2-(4-morpholinyl)ethyl]urea;

[0092] 1-(2-amino-5-fluorobenzo[d]thiazol-6-yl)-3-(4-chlorophenyl)-1-[2-(3-oxomorpholin-4-yl)ethyl]urea;

[0093] 1-(2-amino-5-fluorobenzo[d]thiazol-6-yl)-3-(4-chlorophenyl)-1-[2-(2-oxopyrrolidin-1-yl)ethyl]urea;

[0094] 1-(2-aminobenzo[d]thiazol-5-yl)-3-(4-chlorophenyl)-1-[2-(piperidin-1-yl)ethyl]urea;

[0095] 1-(2-aminobenzo[d]thiazol-5-yl)-3-(4-chlorophenyl)-1-[2-(2-oxopyrrolidin-1-yl)ethyl]urea; or

[0096] 1-(2-Aminobenzo[d]thiazol-5-yl)-3-(4-chlorophenyl)-1-[2-(4-morpholinyl)ethyl]urea.

[0097] The pharmaceutically acceptable salt of the compound of general formula I is a salt formed with an acid, wherein the acid is selected from: hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, phosphoric acid, nitric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalenesulfonic acid, trifluoroacetic acid or aspartic acid.

[0098] The present invention also includes prodrugs of the compounds. Prodrugs of the compounds are derivatives of the compounds of general formula (I) that may themselves have weak activity or even no activity, but after administration, are converted into the corresponding biologically active form under physiological conditions (e.g., by metabolism, solvolysis or other means).

[0099] Unless otherwise indicated, the term "halogen" as used herein refers to fluorine, chlorine, bromine or iodine; "alkyl" refers to a straight or branched saturated hydrocarbon group such as (C1-C6) alkyl; "cycloalkyl" refers to a substituted or unsubstituted cyclic alkyl group such as (C3-C7) cycloalkyl; "alkoxy" refers to -O-alkyl such as (C1-C6) alkoxy; "alkenyl" refers to a straight or branched hydrocarbon group containing one or more double bonds such as (C2-C6) alkenyl; "alkynyl" refers to a straight or branched hydrocarbon group containing one or more triple bonds such as (C2-C6) alkynyl; "aryl" refers to a monocyclic or polycyclic aromatic hydrocarbon group such as (C6-C 10) aryl, such as phenyl or naphthyl; "heteroaryl" refers to a monocyclic or polycyclic ring system containing one or more heteroatoms selected from N, O, and S, wherein at least one ring system is aromatic, such as a 5-10 membered heteroaryl, such as imidazolyl, pyridyl, pyrazolyl, furyl, thienyl, pyrrolyl, thiazolyl, benzothiazolyl, oxazolyl, isoxazolyl, quinolyl, isoquinolyl, benzimidazolyl, benzoxazolyl, etc.; "saturated or partially saturated heterocyclic group" refers to a monocyclic or polycyclic ring system containing one or more heteroatoms selected from N, O, and S, such as pyrrolidinyl, morpholinyl, piperazinyl, piperidinyl, pyrazolidinyl, imidazolidinyl, thiazolinyl, etc. In addition, regarding "free, salified, esterified and amidated carboxyl groups", free carboxyl groups refer to carboxyl groups (-COOH); salified carboxyl groups are carboxylate groups such as sodium carboxylate and potassium carboxylate; esterified carboxyl groups refer to ester groups; and amidated carboxyl groups are groups -CONHR (wherein R is (C1-C6) alkyl). Other terms or groups have the usual meanings understood by those of ordinary skill in the art.

[0100] The present invention also provides a pharmaceutical composition comprising one or more compounds of Formula I or stereoisomers, pharmaceutically acceptable salts, solvates or prodrugs thereof and a pharmaceutically acceptable carrier.

[0101] The present invention also includes pharmaceutical compositions comprising compounds of formula I or pharmaceutically acceptable salts and / or solvates thereof as active ingredients and pharmaceutically acceptable carriers; the compounds of the present invention may be used in combination with other active ingredients as long as they do not produce other adverse effects, such as allergic reactions.

[0102] The carriers used in the pharmaceutical compositions of the present invention are common types available in the pharmaceutical field, including: binders, lubricants, disintegrants, solubilizers, diluents, stabilizers, suspending agents, pigments, flavoring agents, etc. for oral preparations; pH adjusters, osmotic pressure regulators, solubilizers, stabilizers, etc. for injectable preparations; and bases, diluents, lubricants, preservatives, etc. for topical preparations. Pharmaceutical preparations can be administered orally, parenterally (e.g., intravenously, subcutaneously, intraperitoneally, etc.), or topically (e.g., ophthalmically, nasally, sublingually, dermally, etc.). If certain drugs are unstable under gastric conditions, they can be formulated into enteric-coated tablets.

[0103] In vitro and in vivo inhibitory activity tests revealed that the compounds of this invention exhibit significant inhibitory activity against sEH and stabilize EET levels in vivo. Pharmacodynamic studies have shown that the compounds of this invention can inhibit carrageenan-induced paw swelling, protect against ischemic brain damage, maintain blood glucose homeostasis, alleviate neuropathic pain, counteract tissue fibrosis, and alleviate depression. These compounds are potentially useful in treating sEH-mediated inflammatory diseases, cardiovascular and cerebrovascular diseases, diabetes and its complications, fibrotic diseases, neurological and psychiatric disorders, pain, and ulcerative diseases.

[0104] The exact amount of a compound of the invention required to treat a condition mediated by sEH will vary from subject to subject, depending on the species, age and general condition of the subject, the severity of the disease being treated, the specific compound used, and the mode of administration, such as the route and frequency of administration, etc. An appropriate effective amount can be determined by one of ordinary skill in the art using only routine experimentation.

[0105] The compound can be administered in an amount of about 0.1 to 100 mg / kg body weight / day, preferably 1 to 50 mg / kg body weight / day. It is understood that the dosage can vary depending on the patient's needs, the severity of the hypertensive disease, cardiovascular disease, inflammatory disease, and diabetes-related disease being treated, and the specific compound used. Moreover, it is understood that the initial dose administered can be increased beyond the upper limit in order to quickly reach the desired blood level, or the initial dose can be less than the optimal value, and the daily dose can be gradually increased during treatment, depending on the specific circumstances. If necessary, the daily dose can also be divided into multiple doses, for example, 2-4 times a day.

[0106] The animal used in the present invention generally refers to humans or other mammals.

[0107] The amount of active ingredient, i.e., the compound according to the present invention, in the pharmaceutical composition and unit dosage form thereof may vary, depending on the specific application, the potency of the specific compound, the desired concentration, etc. Generally speaking, the active ingredient will be present in an amount between 0.5% and 90% by weight of the total weight of the composition or unit dosage form.

[0108] In combination therapy, the compound of the present invention and other active compounds may be administered simultaneously or intermittently. When administered simultaneously, the compound of the present invention and other active compounds may be combined in a single pharmaceutical composition or in separate compositions.

[0109] The present invention also relates to the use of the compound of formula I or its stereoisomers, pharmaceutically acceptable salts, solvates or prodrugs or the pharmaceutical composition in the preparation of drugs for treating and / or preventing sEH-mediated diseases.

[0110] The diseases include inflammatory diseases, cardiovascular and cerebrovascular diseases, diabetes, diabetic complications, diabetes-related diseases, fibrotic diseases, neurological and mental diseases, pain or ulcerative diseases, etc.

[0111] The inflammatory diseases include: inflammatory liver disease, inflammatory kidney disease, inflammatory lung disease, inflammatory brain disease, pancreatitis, arthritis, soft tissue inflammation, bone tissue inflammation and vascular inflammation; the cardiovascular and cerebrovascular diseases include: hypertension, myocardial infarction, heart failure, coronary heart disease, cardiovascular arteriosclerosis, ischemic stroke, hemorrhagic stroke, etc.; the diabetes includes: type 1 diabetes, type 2 diabetes, etc.; the diabetic complications include: diabetic retinopathy, diabetic uveitis, diabetic cataract, diabetic nephropathy, diabetic skin disease, diabetic peripheral neuropathy, Neuropathy, etc.; the diabetes-related diseases include: hyperlipidemia, hyperuricemia and gout, obesity, metabolic syndrome, etc.; the fibrotic diseases include: pulmonary fibrosis, liver fibrosis, myocardial fibrosis, renal fibrosis, etc.; the neurological and psychiatric diseases include: Alzheimer's disease, epilepsy, Parkinson's disease, schizophrenia, mental disorders, depression, neurasthenia, etc.; the pain diseases include: neuropathic pain, inflammatory pain, tumor pain and mixed pain, etc.; the ulcerative diseases include: gastric ulcer, duodenal ulcer, ulcerative colitis, corneal ulcer, oral ulcer, etc.

[0112] The following examples and preparations are provided to further illustrate and illustrate the compounds of the present invention and their preparation methods. It should be understood that the scope of the following examples and preparations does not limit the scope of the present invention in any way.

[0113] The following synthetic routes 1, 2, 3, 4, 5, and 6 describe the preparation of compounds of formula I used in the present invention. All starting materials are prepared by the methods described in these synthetic routes, by methods well known to those skilled in the art of organic chemistry, or are commercially available. All final compounds of the present invention are prepared by the methods described in these synthetic routes or by methods analogous thereto, which are well known to those skilled in the art of organic chemistry. All variables used in these synthetic routes are as defined below or in the claims.

[0114] According to the compound of formula I of the present invention, in routes 1, 2, 3, 4, 5 and 6, the following compound is taken as an example: R 1 、R 2 、R 3 、R 4 The definitions of X, Y, Z, m, and n are the same as those given above.

[0115] In route 1, 2-amino-6-nitrobenzothiazole is used as the starting material, and a Boc protection reaction is carried out with DMAP as a base and Boc anhydride to obtain intermediate A, which is then reduced under ferric acid (i.e., elemental Fe + NH4Cl) conditions to obtain intermediate B. Intermediate B undergoes a nucleophilic substitution reaction to obtain intermediate C, which is then reacted with R under triethylamine (TEA) as a base. 3 The substituted phenyl carbamate is converted into urea to obtain intermediate D, which is oxidized by iodine under sodium bicarbonate to obtain intermediate E (the oxidation reaction makes R 1 and R 2 The ring carbon atom of the heterocyclic group formed together with the nitrogen atom to which they are connected is oxidized to form an oxo or an intracyclic carbonyl group), followed by a Boc protection removal reaction with trifluoroacetic acid to produce compound Ii of general formula I.

[0116] Route 1: Synthesis of Compound Ii

[0117] In route 2, 2-amino-5-nitrobenzothiazole is used as the starting material, and a Boc protection reaction is carried out with DMAP as a base and Boc anhydride to obtain intermediate F. Intermediate F is reduced under ferric acid conditions to obtain intermediate G, which is then subjected to a nucleophilic substitution reaction to obtain intermediate H. Intermediate H reacts with R under triethylamine as a base. 3 The substituted phenyl carbamate is converted into urea to obtain intermediate J, which is then subjected to a Boc protection removal reaction with trifluoroacetic acid to produce compound I-ii of general formula I.

[0118] Route 2 Synthesis of Compound I-ii

[0119] In route 3, intermediate J is oxidized by iodine under sodium bicarbonate to obtain intermediate K (the oxidation reaction makes R 1 and R 2 The ring carbon atom of the heterocyclic group formed together with the nitrogen atom to which they are connected is oxidized to form an oxo or an intracyclic carbonyl group), followed by a Boc protection removal reaction with trifluoroacetic acid to produce compound I-iii of general formula I.

[0120] Route 3 Synthesis of Compound I-iii

[0121] In route 4, 2-amino-5-chlorobenzothiazole or 2-amino-5-fluorobenzothiazole or 2-amino-5-methylbenzothiazole is used as the starting material, and intermediate L is obtained by nitration. Boc protection reaction is carried out with DMAP as a base and Boc anhydride to obtain intermediate M, which is then reduced under ferric acid conditions to obtain intermediate N. Intermediate N undergoes nucleophilic substitution reaction to obtain intermediate O, which is then reacted with R under triethylamine as a base. 3The substituted carbamate is converted into urea to obtain intermediate P, which is then subjected to a Boc protection removal reaction with trifluoroacetic acid to generate compound I-iv (R 5 is chlorine, fluorine or methyl).

[0122] Route 4: Synthesis of Compounds I-iv

[0123] In route 5, intermediate P is oxidized by iodine under sodium bicarbonate conditions to obtain intermediate Q (the oxidation reaction makes R 1 and R 2 The ring carbon atom of the heterocyclic group formed together with the nitrogen atom to which they are connected is oxidized to form an oxo or an intracyclic carbonyl), followed by a Boc protection reaction with trifluoroacetic acid to generate compound Iv (R 5 is chlorine, fluorine or methyl).

[0124] Route 5 Synthesis of Compound Iv

[0125] In route 6, compound Ii is reacted with an alkylating agent (R 4 -Cl)- in the presence of triethylamine as an acid-binding agent to prepare compound I-vi of general formula I; or with R 4 Substituted phenyl carbamate is converted into urea in the presence of DIPEA as a base to prepare compound I-vii of general formula I.

[0126] Route 6 Synthesis of Compounds I-vi and I-vii BRIEF DESCRIPTION OF THE DRAWINGS

[0127] FIG1 is a diagram showing the anti-inflammatory effect of the compounds of the present invention.

[0128] FIG2 is a diagram showing the anti-stroke effect of the compounds of the present invention.

[0129] FIG3 is a graph showing the hypoglycemic effect of the compounds of the present invention.

[0130] FIG4 is a graph showing the anti-fibrosis effect of the compounds of the present invention.

[0131] FIG5 is a graph showing the analgesic effect of the compounds of the present invention on sciatica.

[0132] FIG6 is a graph showing the analgesic effect of the compounds of the present invention on diabetic pathological neuropathic pain.

[0133] FIG7 is a graph showing the antidepressant effect of the compounds of the present invention. DETAILED DESCRIPTION

[0134] In the following examples, methods for preparing some of the compounds are described. It should be understood that the following methods and other methods known to those of ordinary skill in the art can be applied to the preparation of all compounds described in the present invention. The examples are intended to illustrate but not to limit the scope of the invention. The H NMR spectra of the compounds were measured using a Bruker ARX-400 or Bruker ARX-600, and the mass spectra were measured using an Agilent 1100 LC / MSD; all reagents used were analytically pure or chemically pure and commercially available, for example, from Anhui Zesheng Technology Co., Ltd., Shanghai Bid Pharmaceutical Technology Co., Ltd., Beijing Coupling Technology Co., Ltd., Shenyang Aike Tongsheng Chemical Reagent Co., Ltd., etc.

[0135] The dotted double bond in the general formula compound of the present invention is transformed according to different substituents. When Y is N, the double bond in the heteroaryl group where Y and Z are located is located between the C atom between Y and Z and Y; when Y is S, the double bond in the heteroaryl group where Y and Z are located is located between the C atom between Y and Z and Z.

[0136] Example 1

[0137] Preparation of 1-(2-aminobenzo[d]thiazol-6-yl)-3-(4-chlorophenyl)-1-[2-(3-oxomorpholin-4-yl)ethyl]urea

[0138] 1.1 Preparation of tert-butyl (6-nitrobenzo[d]thiazol-2-yl)carbamate (A)

[0139] At room temperature, 20.0 g (102.6 mmol) of 2-amino-6-nitrobenzothiazole and 6.26 g (51.6 mmol) of 4-dimethylaminopyridine were added to 200 mL of dichloromethane. 33.6 g (154.0 mmol) of di-tert-butyl dicarbonate was slowly added dropwise to the reaction solution. After completion of the dropwise addition, the temperature was raised to 40°C and the reaction was allowed to react for 2 h. After completion of the reaction, the reaction solution was concentrated, 200 mL of 5% aqueous citric acid solution was added, and the mixture was filtered. The filter cake was washed with water (100 mL), collected, and dried to obtain 27.5 g of a light yellow solid, with a yield of 90.9%. ESI-MS m / z: 295.9 [M+H] + .

[0140] 1.2 Synthesis of tert-butyl (6-aminobenzo[d]thiazol-2-yl)carbamate (B)

[0141] At room temperature, 9.5 g (169.5 mmol) of reduced iron powder and 18.1 g (339.0 mmol) of ammonium chloride were added to a 100 mL mixture of methanol and water (MeOH:H2O = 4:1). The mixture was stirred at 45°C for 20 min. 10.0 g (33.9 mmol) of Intermediate A was added to the reaction solution, and the temperature was raised to 80°C for 4 h. After completion of the reaction, the mixture was filtered while hot through a pad of celite. The filter cake was washed with 500 mL of hot methanol. The filtrate was collected and concentrated under reduced pressure, slurried with water, and filtered. The filter cake was washed with water (100 mL) and dried to obtain 6.4 g of a light yellow solid with a yield of 71.2%. ESI-MS m / z: 266.0 [M+H] + .

[0142] 1. Preparation of tert-butyl 3-(6-{[2-(4-morpholinyl)ethyl]amino}benzo[d]thiazol-2-yl)carbamate (C)

[0143] At room temperature, 1.0 g (3.8 mmol) of Intermediate B and 1.0 g (7.5 mmol) of anhydrous potassium carbonate were added to 10 mL of acetonitrile, followed by 0.85 g (5.7 mmol) of chloroethylmorpholine. The temperature was raised to 80°C and the reaction was allowed to react for 4 h. After completion of the reaction, the reaction solution was concentrated under reduced pressure, 20 mL of water was added, and the mixture was extracted with ethyl acetate (20 mL x 3). The organic layer was collected and the solvent was evaporated to obtain 1.1 g of a light yellow solid with a yield of 76.9%.

[0144] 1. Preparation of tert-butyl 4-(6-{3-(4-chlorophenyl)-1-[2-(4-morpholinyl)ethyl]ureido}benzo[d]thiazol-2-yl)carbamate (D)

[0145] At room temperature, 1.0 g (2.6 mmol) of Intermediate C and 0.29 g (2.9 mmol) of triethylamine were added to 3 mL of anhydrous 1,4-dioxane. The temperature was raised to 60°C, and 0.48 g (1.94 mmol) of phenyl N-(4-chlorophenyl)carbamate was added. After reacting for 4 hours, 0.24 g (0.97 mmol) of phenyl N-(4-chlorophenyl)carbamate was added and reacted for 8 hours. After completion of the reaction, the reaction solution was cooled to room temperature, filtered, and washed with a small amount of 1,4-dioxane. The filter cake was collected and dried to obtain 1.1 g of a white solid with a yield of 78.6%.

[0146] 1. Preparation of tert-butyl 6-{3-(4-chlorophenyl)-1-[2-(3-oxomorpholin-4-yl)ethyl]ureido}benzo[d]thiazol-2-yl)carbamate (E)

[0147] At room temperature, 0.5 g (0.94 mmol) of intermediate D and 0.79 g (9.4 mmol) of sodium bicarbonate were added to a 5 mL mixture of tetrahydrofuran and water (THF / H2O = 4:1), followed by the addition of 1.7 g (6.6 mmol) of elemental iodine. The mixture was allowed to react at room temperature for 4 h. After completion of the reaction, the mixture was quenched with 10 mL of saturated aqueous sodium sulfite solution, the organic solvent was evaporated, and the mixture was extracted with dichloromethane (30 mL). The organic layer was collected, washed with saturated brine, the solvent was evaporated, and the mixture was purified by column chromatography to obtain 0.27 g of a white solid in a yield of 52.6%.

[0148] 1.6 Preparation of 1-(2-aminobenzo[d]thiazol-6-yl)-3-(4-chlorophenyl)-1-[2-(3-oxomorpholin-4-yl)ethyl]urea

[0149] At room temperature, 0.2 g (0.37 mmol) of intermediate E was added to 2 mL of dichloromethane, followed by 2 mL of trifluoroacetic acid. The mixture was allowed to react at room temperature for 6 h. After completion of the reaction, the reaction solution was concentrated and 20% aqueous sodium hydroxide solution was added. A solid precipitated, which was filtered and dried to obtain 0.12 g of a white solid (yield: 73.6%).

[0150] Example 2 Preparation of 1-(2-aminobenzo[d]thiazol-6-yl)-3-(4-chlorophenyl)-1-[2-(2-oxopyrrolidin-1-yl)ethyl]urea

[0151] Using 2-amino-6-nitrobenzothiazole as the starting material, key intermediate B was synthesized according to the method described in step 1.2 of Example 1. 1-(2-aminobenzo[d]thiazol-6-yl)-3-(4-chlorophenyl)-1-[2-(2-oxopyrrolidin-1-yl)ethyl]urea was then synthesized according to the method described in step 1.6 of Example 1. The yield was 74.1%.

[0152] Example 3 Preparation of 1-(2-aminobenzo[d]thiazol-6-yl)-3-(4-chlorophenyl)-1-[2-(2-oxopiperidin-1-yl)ethyl]urea

[0153] Using 2-amino-6-nitrobenzothiazole as the starting material, key intermediate B was synthesized according to the synthetic method of step 1.2 in Example 1. 1-(2-aminobenzo[d]thiazol-6-yl)-3-(4-chlorophenyl)-1-[2-(2-oxopiperidin-1-yl)ethyl]urea was then synthesized according to the synthetic method of step 1.6 in Example 1. The yield was 68.9%.

[0154] Example 4 Preparation of 1-(2-aminobenzo[d]thiazol-6-yl)-3-(3-bromo-4-fluorophenyl)-1-[2-(2-oxopyrrolidin-1-yl)ethyl]urea

[0155] Using 2-amino-6-nitrobenzothiazole as the starting material, key intermediate B was synthesized according to the method described in step 1.2 of Example 1. 1-(2-aminobenzo[d]thiazol-6-yl)-3-(3-bromo-4-fluorophenyl)-1-[2-(2-oxopyrrolidin-1-yl)ethyl]urea was then synthesized according to the method described in step 1.6 of Example 1. The yield was 73.9%.

[0156] Example 5 Preparation of 1-(2-aminobenzo[d]thiazol-6-yl)-3-(3-bromo-4-fluorophenyl)-1-[2-(3-oxomorpholin-4-yl)ethyl]urea

[0157] Using 2-amino-6-nitrobenzothiazole as the starting material, key intermediate B was synthesized according to the method described in step 1.2 of Example 1. 1-(2-aminobenzo[d]thiazol-6-yl)-3-(3-bromo-4-fluorophenyl)-1-[2-(3-oxomorpholin-4-yl)ethyl]urea was then synthesized according to the method described in step 1.6 of Example 1. The yield was 76.3%.

[0158] Example 6 Preparation of 1-(2-aminobenzo[d]thiazol-5-yl)-3-(4-chlorophenyl)-1-[2-(3-oxomorpholin-4-yl)ethyl]urea

[0159] Using 2-amino-5-nitrobenzothiazole as the starting material, key intermediate G was synthesized according to the synthesis method of 1.2 in Example 1. Tert-butyl (5-{3-(4-chlorophenyl)-1-[2-(3-oxomorpholin-4-yl)ethyl]ureido}benzo[d]thiazol-2-yl)carbamate (K) was synthesized according to the synthesis method of 1.5 in Example 1. 1-(2-aminobenzo[d]thiazol-5-yl)-3-(4-chlorophenyl)-1-[2-(3-oxomorpholin-4-yl)ethyl]urea was synthesized according to the synthesis method of 1.6 in Example 1. The yield was 85.3%.

[0160] Example 7 Preparation of 1-(2-aminobenzo[d]thiazol-5-yl)-3-(4-chlorophenyl)-1-[2-(2-oxopiperidin-1-yl)ethyl]urea

[0161] Using 2-amino-5-nitrobenzothiazole as the starting material, key intermediate G was synthesized according to the synthesis method of 1.2 in Example 1. Tert-butyl (5-{3-(4-chlorophenyl)-1-[2-(2-oxopiperidin-1-yl)ethyl]ureido}benzo[d]thiazol-2-yl)carbamate (K) was synthesized according to the synthesis method of 1.5 in Example 1. 1-(2-aminobenzo[d]thiazol-5-yl)-3-(4-chlorophenyl)-1-[2-(2-oxopiperidin-1-yl)ethyl]urea was synthesized according to the synthesis method of 1.6 in Example 1. The yield was 79.5%.

[0162] Example 8 Preparation of 1-(2-acetylaminobenzo[d]thiazol-6-yl)-1-[2-(3-oxomorpholin-4-yl)ethyl]-3-(4-chlorophenyl)urea

[0163] Using 2-amino-6-nitrobenzothiazole as the starting material, key intermediate B was synthesized according to the synthetic method of 1.2 in Example 1. 1-(2-aminobenzo[d]thiazol-6-yl)-3-(4-chlorophenyl)-1-[2-(3-oxomorpholin-4-yl)ethyl]urea was then synthesized according to the synthetic method of 1.6 in Example 1. The yield was 73.6%.

[0164] 8.1 Synthesis of 1-(2-acetylaminobenzo[d]thiazol-6-yl)-1-[2-(3-oxomorpholin-4-yl)ethyl]-3-(4-chlorophenyl)urea

[0165] Dissolve 0.2 g (0.4 mmol) of 1-(2-aminobenzo[d]thiazol-6-yl)-3-(4-chlorophenyl)-1-[2-(3-oxomorpholin-4-yl)ethyl]urea in ethyl acetate (3 mL). Add 0.1 g (0.7 mmol) of potassium carbonate. Add 0.1 g (0.4 mmol) of acetyl chloride dropwise to the solution at room temperature and stir overnight. After completion of the reaction, add water (5 mL) and extract with ethyl acetate (2 x 10 mL). The organic layer is concentrated under reduced pressure and purified by column chromatography to afford 0.08 g of a white solid. Yield: 76%.

[0166] Example 9 Preparation of 1-{2-[3-(4-chlorophenyl)ureido]benzo[d]thiazol-6-yl}-1-[2-(3-oxomorpholin-4-yl)ethyl]-3-(4-chlorophenyl)urea

[0167] Using 2-amino-6-nitrobenzothiazole as the starting material, key intermediate B was synthesized according to the synthesis method of 1.2 in Example 1, and then 1-(2-aminobenzo[d]thiazol-6-yl)-3-(4-chlorophenyl)-1-[2-(3-oxomorpholin-4-yl)ethyl]urea was synthesized according to the synthesis method of 1.6 in Example 1. 1-{2-[3-(4-chlorophenyl)ureido]benzo[d]thiazol-6-yl}-1-[2-(3-oxomorpholin-4-yl)ethyl]-3-(4-chlorophenyl)urea was synthesized according to the synthesis method of 8.1 in Example 8 in a yield of 75.4%.

[0168] Example 10 Preparation of 1-(2-aminobenzo[d]thiazol-5-yl)-3-(4-chloro-3-fluorophenyl)-1-[2-(3-oxomorpholin-4-yl)ethyl]urea

[0169] Using 2-amino-5-nitrobenzothiazole as the starting material, key intermediate G was synthesized according to the synthesis method of 1.2 in Example 1. Tert-butyl (5-{3-(4-chloro-3-fluorophenyl)-1-[2-(3-oxomorpholin-4-yl)ethyl]ureido}benzo[d]thiazol-2-yl)carbamate (K) was synthesized according to the synthesis method of 1.5 in Example 1. 1-(2-aminobenzo[d]thiazol-5-yl)-3-(4-chloro-3-fluorophenyl)-1-[2-(3-oxomorpholin-4-yl)ethyl]urea was synthesized according to the synthesis method of 1.6 in Example 1. The yield was 83.3%.

[0170] Example 11 Preparation of 1-(2-amino-5-chlorobenzo[d]thiazol-6-yl)-3-(4-chlorophenyl)-1-[2-(4-morpholinyl)ethyl]urea

[0171] 11.1 Preparation of 2-amino-5-chloro-6-nitrobenzo[d]thiazole (L)

[0172] Under ice, 20.0 g (108.1 mmol) of 2-amino-5-chlorobenzothiazole was dissolved in 120 mL of concentrated sulfuric acid and stirred until clear. 6 mL (128.0 mmol) of fuming nitric acid was slowly added dropwise and allowed to react at room temperature for 2 h. After completion of the reaction, the reaction solution was slowly poured into 100 mL of ice water and the pH was adjusted to 8-10 with 30% aqueous sodium hydroxide solution. A solid precipitated and was filtered. The filter cake was washed with water (100 mL) and dried to obtain 20.0 g of a yellow solid with a yield of 80.8%.

[0173] 11.2 Preparation of tert-butyl (5-chloro-6-nitrobenzo[d]thiazol-2-yl)carbamate (M)

[0174] At room temperature, 20.0 g (87.3 mmol) of intermediate L and 5.3 g (43.7 mmol) of 4-dimethylaminopyridine were added to 200 mL of dichloromethane. 22.8 g (104.8 mmol) of di-tert-butyl dicarbonate was slowly added dropwise to the reaction solution. After completion of the dropwise addition, the temperature was raised to 40°C and the reaction was allowed to proceed for 2 h. After completion of the reaction, the reaction solution was concentrated, 200 mL of 5% aqueous citric acid solution was added, and the mixture was filtered. The filter cake was washed with water (100 mL), collected, and dried to obtain 24.5 g of a light yellow solid with a yield of 85.4%.

[0175] 11.3 Preparation of tert-butyl (5-chloro-6-aminobenzo[d]thiazol-2-yl)carbamate (N)

[0176] At room temperature, 8.5 g (152.0 mmol) of reduced iron powder and 16.4 g (304.0 mmol) of ammonium chloride were added to a 100 mL mixed solvent of methanol and water (MeOH:H2O=4:1), stirred at 45°C for 20 min, and 10.0 g (30.4 mmol) of intermediate M was added to the reaction solution. The temperature was raised to 80°C and the reaction was allowed to proceed for 4 h. After the reaction was completed, the mixture was filtered while hot through a pad of diatomaceous earth, the filter cake was washed with 500 mL of hot methanol, the filtrate was collected, concentrated under reduced pressure, slurried with water, filtered, and the filter cake was washed with water (100 mL) and dried to obtain 6.83 g of a brown solid with a yield of 75.2%.

[0177] 11.4 Preparation of tert-butyl (5-chloro-6-{[2-(4-morpholinyl)ethyl]amino}benzo[d]thiazol-2-yl)carbamate (O)

[0178] At room temperature, 1.0 g (3.3 mmol) of Intermediate N and 1.85 g (13.4 mmol) of anhydrous potassium carbonate were added to 10 mL of acetonitrile. Then, 0.75 g (5.0 mmol) of chloroethylmorpholine was added. The temperature was raised to 80°C and the reaction was allowed to react for 4 h. After completion of the reaction, the reaction solution was concentrated under reduced pressure, 20 mL of water was added, and the mixture was extracted with ethyl acetate (20 mL x 3). The organic layer was collected and the solvent was evaporated to obtain 1.05 g of a light yellow solid, with a yield of 76.2%.

[0179] 11.5 Preparation of tert-butyl (5-chloro-6-{3-(4-chlorophenyl)-1-[2-(4-morpholinyl)ethyl]ureido}benzo[d]thiazol-2-yl)carbamate (P)

[0180] At room temperature, 1.0 g (2.4 mmol) of Intermediate O and 0.27 g (2.7 mmol) of triethylamine were added to 3 mL of anhydrous 1,4-dioxane. The temperature was raised to 60°C, and 0.44 g (1.8 mmol) of phenyl N-(4-chlorophenyl)carbamate was added. After reacting for 4 hours, 0.22 g (0.9 mmol) of phenyl N-(4-chlorophenyl)carbamate was added and reacted for 8 hours. After completion of the reaction, the reaction solution was cooled to room temperature, filtered, and washed with a small amount of 1,4-dioxane. The filter cake was collected and dried to obtain 1.1 g of a white solid with a yield of 78.6%.

[0181] 11.6 Preparation of 1-(2-amino-5-chlorobenzo[d]thiazol-6-yl)-3-(4-chlorophenyl)-1-[2-(4-morpholinyl)ethyl]urea

[0182] At room temperature, 0.2 g (0.35 mmol) of intermediate P was added to 2 mL of dichloromethane, followed by 2 mL of trifluoroacetic acid. The mixture was allowed to react at room temperature for 6 h. After completion of the reaction, the reaction solution was concentrated and 20% aqueous sodium hydroxide solution was added. A solid precipitated, which was filtered and dried to obtain 0.13 g of a white solid (yield: 79.0%).

[0183] Example 12 1-(2-amino-5-chlorobenzo[d]thiazol-6-yl)-1-(2-aminoethyl)-3-(4-chlorophenyl)urea

[0184] Using 2-amino-5-chlorobenzothiazole as the starting material, the key intermediate N was synthesized according to the method described in step 11.3 of Example 11. 1-(2-amino-5-chlorobenzo[d]thiazol-6-yl)-1-(2-aminoethyl)-3-(4-chlorophenyl)urea was then synthesized according to the method described in step 11.6 of Example 11 in a yield of 78.8%.

[0185] Example 13 N-{2-[1-(2-amino-5-chlorobenzo[d]thiazol-6-yl)-3-(4-chlorophenyl)ureido]ethyl}acetamide

[0186] Using 2-amino-5-chlorobenzothiazole as the starting material, the key intermediate N was synthesized according to the synthesis method of 11.3 in Example 11, and then 1-(2-amino-5-chlorobenzo[d]thiazol-6-yl)-1-(2-aminoethyl)-3-(4-chlorophenyl)urea was synthesized according to the synthesis method of 11.6 in Example 11. Then, N-{2-[1-(2-amino-5-chlorobenzo[d]thiazol-6-yl)-3-(4-chlorophenyl)urea-yl]ethyl}acetamide was synthesized according to the synthesis method of 8.1 in Example 8, with a yield of 74.4%.

[0187] Example 14 Preparation of 1-(2-amino-5-chlorobenzo[d]thiazol-6-yl)-3-(4-chlorophenyl)-1-[2-(2-oxopyrrolidin-1-yl)ethyl]urea

[0188] Using 2-amino-5-chlorobenzothiazole as the starting material, the key intermediate N was synthesized according to the synthetic method of 11.3 in Example 11, and then tert-butyl (5-chloro-6-{3-(4-chlorophenyl)-1-[2-(2-pyrrolidin-1-yl)ethyl]ureido}benzo[d]thiazol-2-yl)carbamate (P) was synthesized according to the synthetic method of 11.5 in Example 11.

[0189] 14. Preparation of tert-butyl (5-chloro-6-{3-(4-chlorophenyl)-1-[2-(2-oxopyrrolidin-1-yl)ethyl]ureido}benzo[d]thiazol-2-yl)carbamate (Q)

[0190] At room temperature, 0.5 g (0.91 mmol) of intermediate P and 0.77 g (9.1 mmol) of sodium bicarbonate were added to 5 mL of a mixed solvent of tetrahydrofuran and water (THF / H2O = 4:1), followed by the addition of 1.62 g (6.4 mmol) of elemental iodine. The mixture was allowed to react at room temperature for 4 h. After completion of the reaction, the mixture was quenched with 10 mL of saturated aqueous sodium sulfite solution, the organic solvent was evaporated, and the mixture was extracted with dichloromethane (30 mL). The organic layer was collected, washed with saturated brine, the solvent was evaporated, and the mixture was purified by column chromatography to obtain 0.28 g of a white solid in a yield of 54.6%.

[0191] 14.2 Preparation of 1-(2-amino-5-chlorobenzo[d]thiazol-6-yl)-3-(4-chlorophenyl)-1-[2-(2-oxopyrrolidin-1-yl)ethyl]urea

[0192] At room temperature, 0.2 g (0.36 mmol) of intermediate Q was added to 2 mL of dichloromethane, followed by 2 mL of trifluoroacetic acid. The mixture was allowed to react at room temperature for 6 h. After completion of the reaction, the reaction solution was concentrated and 20% aqueous sodium hydroxide solution was added. A solid precipitated, which was filtered and dried to obtain 0.13 g of a white solid (yield: 79.0%).

[0193] Example 15 Preparation of 1-(2-amino-5-chlorobenzo[d]thiazol-6-yl)-3-(4-chlorophenyl)-1-[2-(3-oxomorpholin-4-yl)ethyl]urea

[0194] Using 2-amino-5-chlorobenzothiazole as the starting material, key intermediate N was synthesized according to the method described in step 11.3 of Example 11. 1-(2-amino-5-chlorobenzo[d]thiazol-6-yl)-3-(4-chlorophenyl)-1-[2-(3-oxomorpholin-4-yl)ethyl]urea was then synthesized according to the method described in step 14.2 of Example 14. The yield was 78.1%.

[0195] Example 16 Preparation of 1-(2-amino-5-chlorobenzo[d]thiazol-6-yl)-3-(4-chlorophenyl)-1-{2-[4-(1-thiomorpholinothioate)]ethyl}urea

[0196] Using 2-amino-5-chlorobenzothiazole as the starting material, the key intermediate N was synthesized according to the synthetic method of 11.3 in Example 11, and then tert-butyl (5-chloro-6-{3-(4-chlorophenyl)-1-[2-(4-thiomorpholinyl)ethyl]ureido}benzo[d]thiazol-2-yl)carbamate (P) was synthesized according to the synthetic method of 11.5 in Example 11.

[0197] 16. Preparation of tert-butyl [5-chloro-6-(3-(4-chlorophenyl)-1-{2-[4-(1-thiomorpholinoxigenin)]ethyl}ureido)benzo[d]thiazol-2-yl]carbamate (Q)

[0198] At room temperature, 0.5 g (0.86 mmol) of intermediate P was added to 3 mL of glacial acetic acid, followed by 0.63 g (4.3 mmol) of 30% hydrogen peroxide solution. The reaction was allowed to react at room temperature for 10 min. After completion, the reaction was quenched with 5 mL of saturated aqueous sodium sulfite solution, and the pH was adjusted to 8-10 with saturated aqueous sodium bicarbonate solution. The product was extracted with ethyl acetate (30 mL). The organic layer was collected and washed with saturated brine. The solvent was evaporated and purified by column chromatography to obtain 0.29 g of a white solid in a yield of 56.5%.

[0199] 1-(2-amino-5-chlorobenzo[d]thiazol-6-yl)-3-(4-chlorophenyl)-1-{2-[4-(1-oxothiomorpholinyl)]ethyl}urea was synthesized according to the synthesis method of 14.2 in Example 14. The yield was 77.2%. Example 17 Preparation of 1-(2-amino-5-chlorobenzo[d]thiazol-6-yl)-3-(4-chlorophenyl)-1-{2-[4-(1-oxothiomorpholinyl)]ethyl}urea

[0200] Using 2-amino-5-chlorobenzothiazole as the starting material, key intermediate N was synthesized according to the method described in step 11.3 of Example 11. 1-(2-amino-5-chlorobenzo[d]thiazol-6-yl)-3-(4-chlorophenyl)-1-[2-(2-oxopiperidin-1-yl)ethyl]urea was then synthesized according to the method described in step 14.2 of Example 14. The yield was 79.3%.

[0201] Example 18 Preparation of 1-(2-amino-5-fluorobenzo[d]thiazol-6-yl)-3-(4-chlorophenyl)-1-[2-(4-morpholinyl)ethyl]urea

[0202] Using 2-amino-5-fluorobenzothiazole as the starting material, key intermediate N was synthesized according to the method described in step 11.3 of Example 11. 1-(2-amino-5-fluorobenzo[d]thiazol-6-yl)-3-(4-chlorophenyl)-1-[2-(4-morpholinyl)ethyl]urea was then synthesized according to the method described in step 11.6 of Example 11. The yield was 75.7%.

[0203] Example 19 Preparation of 1-(2-amino-5-fluorobenzo[d]thiazol-6-yl)-3-(4-chlorophenyl)-1-[2-(3-oxomorpholin-4-yl)ethyl]urea

[0204] Using 2-amino-5-fluorobenzothiazole as the starting material, key intermediate N was synthesized according to the method described in step 11.3 of Example 11. 1-(2-amino-5-fluorobenzo[d]thiazol-6-yl)-3-(4-chlorophenyl)-1-[2-(3-oxomorpholin-4-yl)ethyl]urea was then synthesized according to the method described in step 14.2 of Example 14. The yield was 83.9%.

[0205] Example 20 Preparation of 1-(2-amino-5-fluorobenzo[d]thiazol-6-yl)-3-(4-chlorophenyl)-1-[2-(2-oxopyrrolidin-1-yl)ethyl]urea

[0206] Using 2-amino-5-fluorobenzothiazole as the starting material, key intermediate N was synthesized according to the method described in step 11.3 of Example 11. 1-(2-amino-5-fluorobenzo[d]thiazol-6-yl)-3-(4-chlorophenyl)-1-[2-(2-oxopyrrolidin-1-yl)ethyl]urea was then synthesized according to the method described in step 14.2 of Example 14. The yield was 79.7%.

[0207] Example 21 Preparation of 1-(2-aminobenzo[d]thiazol-5-yl)-3-(4-chlorophenyl)-1-[2-(piperidin-1-yl)ethyl]urea

[0208] Using 2-amino-5-nitrobenzothiazole as the starting material, key intermediate G was synthesized according to the synthesis method of 1.2 in Example 1. Tert-butyl (5-{3-(4-chlorophenyl)-1-[2-(piperidin-1-yl)ethyl]ureido}benzo[d]thiazol-2-yl)carbamate (J) was synthesized according to the synthesis method of 1.4 in Example 1. 1-(2-aminobenzo[d]thiazol-5-yl)-3-(4-chlorophenyl)-1-[2-(piperidin-1-yl)ethyl]urea was synthesized according to the synthesis method of 1.6 in Example 1. The yield was 85.2%.

[0209] Example 22 Preparation of 1-(2-aminobenzo[d]thiazol-5-yl)-3-(4-chlorophenyl)-1-[2-(2-oxopyrrolidin-1-yl)ethyl]urea

[0210] Using 2-amino-5-nitrobenzothiazole as the starting material, key intermediate G was synthesized according to the synthesis method of 1.2 in Example 1. Tert-butyl (5-{3-(4-chlorophenyl)-1-[2-(2-oxopyrrolidin-1-yl)ethyl]ureido}benzo[d]thiazol-2-yl)carbamate (K) was synthesized according to the synthesis method of 1.5 in Example 1. 1-(2-aminobenzo[d]thiazol-5-yl)-3-(4-chlorophenyl)-1-[2-(2-oxopyrrolidin-1-yl)ethyl]urea was synthesized according to the synthesis method of 1.6 in Example 1. The yield was 83.4%.

[0211] Example 23 Preparation of 1-(2-aminobenzo[d]thiazol-5-yl)-3-(4-chlorophenyl)-1-[2-(4-morpholinyl)ethyl]urea

[0212] Using 2-amino-5-nitrobenzothiazole as the starting material, key intermediate G was synthesized according to the synthesis method of 1.2 in Example 1. Tert-butyl (5-{3-(4-chlorophenyl)-1-[2-(4-morpholinyl)ethyl]ureido}benzo[d]thiazol-2-yl)carbamate (J) was synthesized according to the synthesis method of 1.4 in Example 1. 1-(2-aminobenzo[d]thiazol-5-yl)-3-(4-chlorophenyl)-1-[2-(4-morpholinyl)ethyl]urea was synthesized according to the synthesis method of 1.6 in Example 1. The yield was 82.2%.

[0213] The example compounds prepared above are shown in Table 1 below.

[0214] Table 1

[0215] Some of the compounds of the present invention were subjected to in vitro soluble epoxide hydrolase (sEH) enzyme IC 50 The test results are as follows

[0216] The aryl urea compounds of formula I according to the present invention were tested for sEH enzyme activity in vitro using a fluorescence assay. The reference substance t-AUCB was prepared by our research group.

[0217] sEH enzyme buffer is prepared with 25 mM Bis-Tris (pH 7.0). Fluorescent substrate PHOME ((3-phenyl-oxacyclopropyl)-acetic acid cyano-(6-methoxy-naphthalen-2-yl)-methyl ester) buffer is prepared with 25 mM Bis-Tris (pH 7.0). Test compounds are diluted with 100% DMSO to the appropriate 5-7 test concentrations. 100 μL of Bis-Tris (pH 7.0) buffer is added to the blank wells. 100 μL of enzyme buffer is added to the full activity wells, positive control wells, and test sample wells. 5 μL of DMSO is then added to the blank and full activity wells. 5 μL of control and test compound are added to the positive control wells and test sample wells, respectively. Incubate at 37°C for 5 minutes. Then, 95 μL of substrate buffer is added sequentially, and the mixture is incubated at 37°C for 15 minutes. The fluorescence intensity was measured at an excitation wavelength of 330 nm and an emission wavelength of 465 nm. IC was calculated using SPSS software. 50 value.

[0218] sEH enzyme IC of some example compounds 50 Activity data are shown in Table 2.

[0219] Table 2

[0220] Preliminary in vitro sEH enzyme activity test results indicate that the compounds of Formula I, as claimed herein, possess excellent sEH inhibitory activity, with some compounds showing comparable or significantly superior activity to the positive control drug, t-AUCB. The inhibitory activity of the compound of Comparative Example 12, which exhibits superior activity in the inventor's previous comparative application (CN 113831301, "Benzothiazole Derivatives and Their Uses,") against sEH was also tested. The experimental results demonstrate that the majority of the compounds in the examples herein exhibit significantly superior sEH inhibitory activity compared to the compound of Example 12 in the comparative application, achieving unexpected results.

[0221] Anti-inflammatory effects of the compounds of Examples 15, 18, 20 and 23

[0222] KM mice foot plantar subcutaneous injection λ-carrageenan preparation inflammation swelling model, 1h mice intraperitoneal injection compound solution (100mg / kg) or blank solvent (10%PEG 400, 10%Tween 80) in advance, with the initial paw thickness of mice before modeling as 100%, measure the mice paw thickness change situation.Result shows, compound can significantly suppress the mouse paw swelling of carrageenan induction, and is better than celecoxib (Celecoxib, a kind of typical anti-inflammatory drug).Result shows, embodiment 15, embodiment 18, embodiment 20 and embodiment 23 compounds can significantly suppress the mouse paw swelling of carrageenan induction, and is better than celecoxib, and the anti-inflammatory action of wherein embodiment 18, embodiment 20 and embodiment 23 compounds is better than comparative example 12 compounds (Fig. 1) in CN 113831301.

[0223] Anti-stroke effects of the compounds of Examples 15, 18, 20 and 23

[0224] A middle cerebral artery occlusion (MCAO) reperfusion model was established in male SD rats using a suture embolization method. After two hours of ischemia, the suture was removed and perfusion resumed. Immediately after the onset of reperfusion, a compound solution (0.5 mg / kg, 1.0 mg / kg, 3.0 mg / kg) or a blank solvent (10% PEG 400, 10% Tween 80) was injected into the tail vein. Twenty-four hours later, the rats were anesthetized with 10% chloral hydrate and sacrificed. The brain tissue was then cut into 4-5 consecutive equidistant coronal sections. The brain sections were completely immersed in TTC solution, stained, and photographed. The infarct size was calculated. The results showed that the compounds of Examples 15, 18, 20, and 23 significantly reduced the infarct size in rats, demonstrating superior efficacy to edaravone (a typical anti-stroke drug) and the compound of Comparative Example 12 in CN 113831301 (Figure 2, *p<0.05 compared to the solvent group).

[0225] Hypoglycemic effects of the compounds of Examples 15, 18, 20 and 23

[0226] Male BALB / c mice (6-8 weeks old) were intraperitoneally injected with streptozotocin (STZ) at 50 mg / kg once daily for 5 consecutive days to establish a diabetic model. Following modeling, solutions of the example compounds (30 mg / kg) or a blank solvent (10% PEG 400, 10% Tween 80) were intraperitoneally injected daily. Blood glucose levels were measured two weeks later. Results showed that blood glucose levels in the treated groups were significantly lower than those in the blank solvent group. The compounds of Examples 15, 18, and 20 demonstrated superior blood glucose-lowering effects compared to the compound of Comparative Example 12 in CN 113831301 (Figure 3, *p<0.05 compared to the solvent group).

[0227] Anti-fibrotic effects of the compounds of Examples 15, 18, 20 and 23

[0228] After anesthesia, male C57BL / 6J mice (6-8 weeks old) were ligated and cut off the left ureter to prepare a unilateral ureteral obstruction (UUO) model. The experimental animals were intraperitoneally injected with compound solution (30 mg / kg) or blank solvent (10% PEG400, 10% Tween 80) once a day starting 3 days before modeling. The animals were killed 7 days after modeling, and the kidneys were removed and Masson staining was used to detect histopathological changes. The results showed that the compounds of Example 15, Example 18, Example 20 and Example 23 were able to significantly reduce the fibrosis area in the renal tissue of mice (Figure 4, compared with the sham group #p<0.05, compared with the solvent group *p<0.05).

[0229] Analgesic effects of the compounds of Examples 15, 18, 20 and 23

[0230] Male Sprague-Dawley rats (200-250 g) were anesthetized and subjected to a longitudinal skin incision on the left femur. The muscles were bluntly dissected to expose the sciatic nerve trunk and its distal branches. Surrounding adhesions and the three branches of the sciatic nerve (tibial, common peroneal, and sural) were separated. The tibial and common peroneal nerves were tightly ligated with silk sutures, and approximately 2-4 mm of nerve was cut distally to the ligature, preserving and avoiding the sural nerve. This was to establish a selective sciatic nerve branch injury (SNI) pain model. One week after surgery, the MWT was measured to confirm the SNI model.

[0231] Another group of SD rats (180-220 g) were intraperitoneally injected with STZ (60 mg / kg) to establish a diabetic model. Blood glucose was measured one week later to confirm the diabetic model, and MWT was measured two weeks later to confirm the diabetic neuropathic pain (DNP) model.

[0232] After the model was successfully established, rats were gavage-administered with a compound solution (10 mg / kg) or a blank solvent. The changes in MWT at different time points after administration were measured, with the pre-dose MWT as 100%. MWT%-time curves were plotted, and the area under the curve (AUC) was calculated. The results showed that the compounds of Examples 15, 18, 20, and 23 significantly increased the MWT of SNI and DNP rats, alleviating neuropathic pain induced by nerve injury (Figure 5, *p<0.05 compared to the solvent group) and diabetes (Figure 6, *p<0.05 compared to the solvent group).

[0233] Antidepressant effects of the compounds of Examples 15, 18, 20 and 23

[0234] Kunming mice were pre-swimmed for 10 minutes before being injected with lipopolysaccharide (0.5 mg / kg). 23 hours later, compound solution or blank solvent was subcutaneously injected. One hour later, a forced swim test was performed for 6 minutes, and the immobility time (s) of each group of mice was recorded for the following 4 minutes. The results showed that the compounds of Examples 15, 18, 20, and 23 were able to significantly reduce the immobility time of mice during forced swim (Figure 7, #p<0.05 compared with the normal group, *p<0.05 compared with the solvent group).

[0235] In summary, the compound of general formula I of the present invention can better bind to the sEH protein, thereby significantly improving its inhibitory effect on the sEH enzyme, achieving an unexpected effect.

[0236] Those skilled in the art will appreciate that, although the present invention has been specifically described with reference to the above embodiments, the present invention is not limited to these specific embodiments. Based on the content taught by the present invention, without departing from the spirit and scope of the present invention, those skilled in the art can make appropriate modifications or improvements, and the equivalent embodiments thus obtained are all encompassed within the scope of the present invention.

Claims

1. A compound of formula I or a stereoisomer, a pharmaceutically acceptable salt, a solvate or a prodrug thereof, in, X is N or CR 5 , where R 5 is hydrogen, halogen, (C1-C4)alkyl or (C1-C4)alkoxy; Y and Z are each independently selected from N or S, and Y and Z are different; R 3 (C6-C 10 ) aryl, 5-10 membered heteroaryl or adamantyl, wherein the heteroaryl contains 1-3 heteroatoms selected from N, O or S, and the aryl or heteroaryl is optionally substituted by 1-3 identical or different R 8 replace; R 4 Hydrogen, -C(O)(CH2) q R 6 、-(CH2) q C(O)OR 6 or -C(O)NH(CH2) q R 6 , where q is 0, 1, 2, 3, or 4, and R 6 is (C1-C6) alkyl, (C3-C7) cycloalkyl, (C6-C 10 ) aryl or 5-10 membered heteroaryl, the aryl or heteroaryl is optionally substituted by 1-3 identical or different R 7 replace; m is 0 or 1; n is 1, 2 or 3; R 7 and R 8 are the same or different and are independently selected from hydroxy, halogen, nitro, amino, cyano, azido, mercapto, carbamoyl, (C1-C6) alkylthiol, (C2-C6) alkenyl, (C1-C6) alkylamido, (C1-C6) alkylsulfinyl, (C1-C6) alkylsulfonyl, (C1-C6) alkylacyl, free, salified, esterified and amidated carboxyl, (C1-C6) alkyl which is unsubstituted or substituted with at least one of hydroxy, amino or halogen, (C1-C6) alkoxy which is unsubstituted or substituted with at least one of hydroxy, amino or halogen, amino substituted with one or two (C1-C6 alkyl) groups, or carbamoyl substituted with one or two (C1-C6 alkyl) groups; When X is CH, Y is N and Z is S, R 1 and R 2 Together with the nitrogen atom to which they are attached, they are unsubstituted or replaced by at least one identical or different R 9 A substituted 4-10 membered heterocyclic group, wherein the heterocyclic group is 1 and R 2 In addition to the nitrogen atom connected, it optionally contains 1 to 3 atoms selected from N, O or S The heteroatom of the heterocyclic group is substituted with 1 to 3 oxo groups; When X is CH, Y is S and Z is N, R 1 and R 2 are the same or different and are each independently selected from hydrogen, (C1-C6)alkyl, (C3-C7)cycloalkyl, (C1-C6)alkylacyl, (C2-C6)alkenyl or (C2-C6)alkynyl; or R 1 and R 2 Together with the nitrogen atom to which they are attached, they are unsubstituted or replaced by at least one identical or different R 9 a substituted 4-10 membered heterocyclic group, which, in addition to the nitrogen atom to which R1 and R2 are attached, optionally contains 1-3 heteroatoms selected from N, O or S, optionally includes 1-2 carbon-carbon double bonds, and the ring carbon atoms of the heterocyclic group are replaced by 0-3 oxo groups; or When X is N or CR 5 , and R 5 When it is not hydrogen, R 1 and R 2 are the same or different and are each independently selected from hydrogen, (C1-C6)alkyl, (C3-C7)cycloalkyl, (C1-C6)alkylacyl, (C2-C6)alkenyl or (C2-C6)alkynyl; or R 1 and R 2 Together with the nitrogen atom to which they are attached, they are unsubstituted or replaced by at least one identical or different R 9 A substituted 4-10 membered heterocyclic group, which, in addition to the nitrogen atom to which R1 and R2 are attached, optionally contains 1-3 heteroatoms selected from N, O or S, optionally includes 1-2 carbon-carbon double bonds, and the ring carbon atoms of the heterocyclic group are substituted with 0-3 oxo groups; and R 9 is hydroxy, amino, halogen, carboxyl, cyano, nitro, (C1-C6) alkyl, (C1-C6) alkoxy, (C3-C7) cycloalkyl, (C1-C6) alkylsulfinyl, (C1-C6) alkylsulfonyl, (C1-C6) alkylacyl, (C1-C6) alkyl optionally substituted by hydroxy, amino or halogen, (C1-C6) alkoxy optionally substituted by hydroxy, amino or halogen, or amino substituted by one or two (C1-C6 alkyl) groups.

2. The compound of formula I according to claim 1 or its stereoisomer, pharmaceutically acceptable salt, solvate or prodrug thereof, wherein R 3 is phenyl, 5-10 membered heteroaryl or adamantyl; the phenyl or heteroaryl is optionally substituted by 1-3 identical or different R 8 replace; R 4 Hydrogen, -C(O)(CH2) q R 6 or -C(O)NH(CH2) q R 6 , where q is 0, 1, or 2, and R 6 is (C1-C4) alkyl, (C3-C6) cycloalkyl, phenyl or 5-6 membered heteroaryl, wherein the phenyl or heteroaryl is optionally substituted by 1-3 identical or different R 7 replace; n is 1 or 2; and R 7 and R 8 are the same or different and are independently selected from hydroxy, halogen, nitro, amino, cyano, (C1-C4) alkyl, (C1-C4) alkoxy, carbamoyl, (C2-C4) alkenyl, (C1-C4) alkylsulfinyl, (C1-C4) alkylsulfonyl, (C1-C4) alkylacyl, (C1-C4) alkylamido, Free, salified, esterified and amidated carboxyl, (C1-C4)alkyl which is unsubstituted or substituted by at least one of hydroxy, amino or halogen, (C1-C4)alkoxy which is unsubstituted or substituted by at least one of hydroxy, amino or halogen, amino which is substituted by one or two (C1-C4 alkyl) groups, or carbamoyl which is substituted by one or two (C1-C4 alkyl) groups.

3. The compound of formula I according to claim 2, or its stereoisomer, pharmaceutically acceptable salt, solvate or prodrug thereof, wherein When X is CH, Y is N and Z is S, R 1 and R 2 Together with the nitrogen atom to which they are attached, they are unsubstituted or replaced by at least one identical or different R 9 A substituted 4-6 membered heterocyclic group, wherein the heterocyclic group is 1 and R 2 In addition to the nitrogen atom to which it is attached, it optionally contains 1 to 3 heteroatoms selected from N, O or S, and the ring carbon atoms of the heterocyclic group are substituted with 1 to 3 oxo groups; When X is CH, Y is S and Z is N, R 1 and R 2 are the same or different and are independently selected from hydrogen, (C1-C4) alkyl, (C3-C6) cycloalkyl, (C1-C4) alkylacyl, (C2-C4) alkenyl or (C2-C4) alkynyl; or R1 and R2 together with the nitrogen atom to which they are attached form an unsubstituted or substituted group with at least one identical or different R 9 A substituted 4-6 membered heterocyclic group, which, in addition to the nitrogen atom to which R1 and R2 are attached, optionally contains 1-3 heteroatoms selected from N, O or S, optionally includes 1-2 carbon-carbon double bonds, and the ring carbon atoms of the heterocyclic group are replaced by 0-3 oxo groups; or When X is N or CR 5 , and R 5 When it is not hydrogen, R 1 and R 2 are the same or different and are independently selected from hydrogen, (C1-C4)alkyl, (C3-C6)cycloalkyl, (C1-C4)alkylacyl, (C2-C4)alkenyl or (C2-C4)alkynyl; or R 1 and R 2 Together with the nitrogen atom to which they are attached, they are unsubstituted or replaced by at least one identical or different R 9 A substituted 4-6 membered heterocyclic group, which, in addition to the nitrogen atom connected to R1 and R2, optionally contains 1-3 heteroatoms selected from N, O and / or S, optionally includes 1-2 carbon-carbon double bonds, and the ring carbon atoms of the heterocyclic group are substituted with 0-3 oxo groups.

4. The compound of formula I according to claim 3, or its stereoisomer, pharmaceutically acceptable salt, solvate or prodrug thereof, wherein R 3 is phenyl or 5-8 membered heteroaryl; the phenyl or heteroaryl is optionally substituted by 1-3 identical or different R 8 replace; R 4 Hydrogen, -C(O)(CH2) q R 6 or -C(O)NH(CH2) q R 6 , where q is 0, 1, or 2, and R 6 is (C1-C4) alkyl, (C3-C6) cycloalkyl or phenyl, the phenyl group is optionally substituted by 1-3 identical or different R 7 replace; n is 2; and When X is CH, Y is N and Z is S, R 1 and R 2 Together with the nitrogen atom to which they are attached, they form a heterocyclic group selected from: in represents the site of attachment to the rest of the compound; When X is CH, Y is S and Z is N, R 1 and R 2 are the same or different and are each independently selected from hydrogen, (C1-C4)alkyl, (C3-C6)cycloalkyl or (C1-C4)alkylacyl; or R 1 and R 2 Together with the nitrogen atom to which they are attached, they form a heterocyclic group selected from: or When X is N or CR 5 , and R 5 When it is not hydrogen, R 1 and R 2 are the same or different and are each independently selected from hydrogen, (C1-C4)alkyl, (C3-C6)cycloalkyl or (C1-C4)alkylacyl; or R 1 and R 2 Together with the nitrogen atom to which they are attached, they form a heterocyclic group selected from:

5. The compound of general formula I according to claim 4, or its stereoisomer, pharmaceutically acceptable salt, solvate or prodrug thereof, wherein X is CR 5 , where R 5 is hydrogen, fluorine or chlorine; R 3 is phenyl; the phenyl group is optionally substituted by 1-3 identical or different R 8 replace; R 4 Hydrogen, -C(O)(CH2) q R 6 or -C(O)NH(CH2) q R 6 , where q is 0, 1, or 2, and R 6 is (C1-C4) alkyl, (C3-C6) cycloalkyl or phenyl, the phenyl group is optionally substituted by 1-3 identical or different R 7 replace; R 7 is hydroxy, halogen, nitro, amino, cyano, (C1-C4) alkyl, (C1-C4) alkoxy, carbamoyl, (C2-C4) alkenyl, (C1-C4) alkylsulfinyl, (C1-C4) alkylsulfonyl, (C1-C4) alkylacyl, (C1-C4) alkylamido, free, salified, esterified and amidated carboxyl, (C1-C4) alkyl which is unsubstituted or substituted with at least one of hydroxy, amino or halogen, (C1-C4) alkoxy which is unsubstituted or substituted with at least one of hydroxy, amino or halogen, amino which is substituted with one or two (C1-C4 alkyl) groups, or carbamoyl which is substituted with one or two (C1-C4 alkyl) groups; and R 8 is chlorine, fluorine, bromine, trifluoromethyl or trifluoromethoxy.

6. The compound of formula I according to claim 1 or its stereoisomer, pharmaceutically acceptable salt, solvate or prodrug thereof, which is selected from: 1-(2-aminobenzo[d]thiazol-6-yl)-3-(4-chlorophenyl)-1-[2-(3-oxomorpholin-4-yl)ethyl]urea; 1-(2-aminobenzo[d]thiazol-6-yl)-3-(4-chlorophenyl)-1-[2-(2-oxopyrrolidin-1-yl)ethyl]urea; 1-(2-aminobenzo[d]thiazol-6-yl)-3-(4-chlorophenyl)-1-[2-(2-oxopiperidin-1-yl)ethyl]urea; 1-(2-aminobenzo[d]thiazol-6-yl)-3-(3-bromo-4-fluorophenyl)-1-[2-(2-oxopyrrolidin-1-yl)ethyl]urea; 1-(2-aminobenzo[d]thiazol-6-yl)-3-(3-bromo-4-fluorophenyl)-1-[2-(3-oxomorpholin-4-yl)ethyl]urea; 1-(2-aminobenzo[d]thiazol-5-yl)-3-(4-chlorophenyl)-1-[2-(3-oxomorpholin-4-yl)ethyl]urea; 1-(2-aminobenzo[d]thiazol-5-yl)-3-(4-chlorophenyl)-1-[2-(2-oxopiperidin-1-yl)ethyl]urea; 1-(2-Acetylaminobenzo[d]thiazol-6-yl)-1-[2-(3-oxomorpholin-4-yl)ethyl]-3-(4-chlorophenyl)urea; 1-{2-[3-(4-chlorophenyl)ureido]benzo[d]thiazol-6-yl}-1-[2-(3-oxomorpholin-4-yl)ethyl]-3-(4-chlorophenyl)urea; 1-(2-aminobenzo[d]thiazol-5-yl)-3-(4-chloro-3-fluorophenyl)-1-[2-(3-oxomorpholin-4-yl)ethyl]urea; 1-(2-amino-5-chlorobenzo[d]thiazol-6-yl)-3-(4-chlorophenyl)-1-[2-(4-morpholinyl)ethyl]urea; 1-(2-amino-5-chlorobenzo[d]thiazol-6-yl)-1-(2-aminoethyl)-3-(4-chlorophenyl)urea; 1-(2-amino-5-chlorobenzo[d]thiazol-6-yl)-1-(2-acetylaminoethyl)-3-(4-chlorophenyl)urea; 1-(2-amino-5-chlorobenzo[d]thiazol-6-yl)-3-(4-chlorophenyl)-1-[2-(2-oxopyrrolidin-1-yl)ethyl]urea; 1-(2-amino-5-chlorobenzo[d]thiazol-6-yl)-3-(4-chlorophenyl)-1-[2-(3-oxomorpholin-4-yl)ethyl]urea; 1-(2-amino-5-chlorobenzo[d]thiazol-6-yl)-3-(4-chlorophenyl)-1-{2-[4-(1-thiomorpholine oxide)]ethyl}urea; 1-(2-amino-5-chlorobenzo[d]thiazol-6-yl)-3-(4-chlorophenyl)-1-[2-(2-oxopiperidin-1-yl)ethyl]urea; 1-(2-amino-5-fluorobenzo[d]thiazol-6-yl)-3-(4-chlorophenyl)-1-[2-(4-morpholinyl)ethyl]urea; 1-(2-amino-5-fluorobenzo[d]thiazol-6-yl)-3-(4-chlorophenyl)-1-[2-(3-oxomorpholin-4-yl)ethyl]urea; 1-(2-amino-5-fluorobenzo[d]thiazol-6-yl)-3-(4-chlorophenyl)-1-[2-(2-oxopyrrolidin-1-yl)ethyl]urea; 1-(2-aminobenzo[d]thiazol-5-yl)-3-(4-chlorophenyl)-1-[2-(piperidin-1-yl)ethyl]urea; 1-(2-aminobenzo[d]thiazol-5-yl)-3-(4-chlorophenyl)-1-[2-(2-oxopyrrolidin-1-yl)ethyl]urea; or 1-(2-Aminobenzo[d]thiazol-5-yl)-3-(4-chlorophenyl)-1-[2-(4-morpholinyl)ethyl]urea.

7. A compound of formula I according to any one of claims 1 to 6, or a stereoisomer, a pharmaceutically acceptable salt, a solvate or a prodrug thereof, wherein the pharmaceutically acceptable salt is a salt formed with an acid selected from the group consisting of hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, phosphoric acid, nitric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalenesulfonic acid, trifluoroacetic acid or aspartic acid.

8. A pharmaceutical composition comprising one or more compounds of general formula I according to any one of claims 1 to 7 or their stereoisomers, pharmaceutically acceptable salts, solvates or prodrugs thereof and a pharmaceutically acceptable carrier.

9. Use of a compound of formula I according to any one of claims 1 to 7 or a stereoisomer, a pharmaceutically acceptable salt, a solvate or a prodrug thereof, or a pharmaceutical composition according to claim 8 in the preparation of a medicament for treating and / or preventing sEH-mediated diseases.

10. The use according to claim 9, wherein the disease comprises inflammatory diseases, cardiovascular and cerebrovascular diseases, diabetes, diabetic complications, diabetes-related diseases, fibrotic diseases, neurological and psychiatric diseases, pain or ulcerative diseases.

11. The use according to claim 10, wherein The inflammatory disease includes inflammatory liver disease, inflammatory kidney disease, inflammatory lung disease, inflammatory brain disease, pancreatitis, arthritis, soft tissue inflammation, bone tissue inflammation or vascular inflammation; The cardiovascular and cerebrovascular diseases include hypertension, myocardial infarction, heart failure, coronary heart disease, cardiovascular arteriosclerosis, ischemic stroke or hemorrhagic stroke; The diabetes mellitus includes type I diabetes mellitus or type II diabetes mellitus; The diabetic complications include diabetic retinopathy, diabetic uveitis, diabetic cataracts, diabetic nephropathy, diabetic skin disease or diabetic peripheral neuropathy; The diabetes-related diseases include hyperlipidemia, hyperuricemia, gout, obesity or metabolic syndrome; The fibrotic disease includes pulmonary fibrosis, liver fibrosis, myocardial fibrosis or renal fibrosis; The neurological and psychiatric diseases include Alzheimer's disease, epilepsy, Parkinson's disease, schizophrenia, mental disorders, depression or neurasthenia; The pain disease includes neuropathic pain, inflammatory pain, tumor pain or mixed pain; The ulcerative disease includes gastric ulcer, duodenal ulcer, ulcerative colitis, corneal ulcer or oral ulcer.

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