Dihydropyrazolopyridinone compound and use thereof

Abstract

Provided in the present invention is a compound as represented by formula I, wherein R1, R2, R3, R4, R5, R6, R7, R8, A and Y are as defined in the description. The compound as represented by formula I of the present invention can effectively inhibit the enzymatic activity of MGAT2, has good metabolic properties, and thus has clinical application prospects.

Description

A dihydropyridone-pyrazole compound and its uses Technical Field

[0001] This invention relates to the pharmaceutical field, and more specifically to dihydropyridonepyrazole compounds and their uses. Background Technology

[0002] The widespread prevalence of obesity has become a major global public health challenge. Driven by people's pursuit of health and beauty, weight loss has become a huge unmet need. Excessive fat intake due to a high-fat diet is a significant cause of obesity. Triglycerides are one of the main forms of energy storage in animals and a major component of the fat we ingest. After eating, triglycerides in food are digested by lipases in the intestines, producing free fatty acids and monoacylglycerols, which are then absorbed by intestinal epithelial cells. The absorbed free fatty acids and monoacylglycerols are regenerated into triglycerides by monoacylglycerol acyltransferases and diacylglycerol acyltransferases on the endoplasmic reticulum membrane. The newly generated triglycerides, apolipoproteins and other lipids are packaged into chylomicrons in the endoplasmic reticulum. The chylomicrons are then secreted into the blood and utilized by other organs (Ko CW et al. Regulation of intestinal lipid metabolism: current concepts and relevance to disease. Nat Rev Gastroenterol Hepatol. 2020 Mar; 17(3):169-183; Mansbach CM et al. The biogenesis of chylomicrons. Annu Rev Physiol. 2010; 72:315-33.).Preventing ingested triglycerides from entering the bloodstream and being absorbed by the body is a promising strategy for treating obesity. The conversion of monoacylglycerols to diacylglycerols is an important step in the resynthesis of triglycerides in small intestinal cells. This step is catalyzed by monoacylglycerol acyltransferases. MOGAT2 is mainly expressed in the small intestine and liver and is a major monoacylglycerol acyltransferase in the small intestine. MOGAT2 knockout mice exhibit a series of beneficial metabolic phenotypic changes, including reduced body weight in mice fed a high-fat diet, reduced rate of triglyceride entry into the bloodstream from the small intestine, reduced triglyceride levels in the liver, and increased energy expenditure (Yen CL et al. Deficiency of the intestinal enzyme acyl-CoA:monoacylglycerol acyltransferase-2 protects mice from metabolic disorders induced by high-fat feeding. Nat Med. 2009 Apr; 15(4):442-6; Nelson DW et al. Intestine-specific deletion of acyl-CoA:monoacylglycerol acyltransferase (MGAT)2). Protects mice from diet-induced obesity and glucose intolerance. J Biol Chem. 2014 Jun 20; 289(25):17338-49.). Therefore, MOGAT2 is a potential target for treating obesity. There are existing reports that MOGAT2 inhibitors can help reduce body weight and treat non-alcoholic fatty liver disease (Cheng D et al. MGAT2 inhibitor decreases liver fibrosis and inflammation in murine NASH models and reduces body weight in human adults with obesity. Cell Metab. 2022 Nov 1; 34(11):1732-1748.e5.).

[0003] Example 14 of patent WO2019013311 discloses compound II-203 (S-309309) with MGAT2 inhibitory activity, the structure of which is as follows. This compound has completed phase 2 clinical trials, but the efficacy of this drug in phase 2 clinical trials is not significant, and it has not yet entered phase 3 clinical trials.

[0004] Patents JP2020111571 and JP2023055851 disclose compounds I-70 and I-171 with MGAT2 inhibitory activity, the structures of which are shown below. Neither of these compounds has been pushed to the clinical stage.

[0005] There remains an urgent need in this field for the development and research of compounds with MGAT2 inhibitory activity that have significant clinical efficacy. Summary of the Invention

[0006] To address the issue of limited clinical efficacy of existing compounds, the present invention aims to provide a dihydropyridinone-pyrazole compound that can effectively inhibit MOGAT2 enzyme activity and has good metabolic properties, exhibiting excellent performance in terms of efficacy, safety, and stability.

[0007] The objective of this invention is achieved through the following technical solution:

[0008] A compound of Formula I or a stereoisomer thereof, a prodrug, a solvate thereof, or a pharmaceutically acceptable salt thereof:

[0009] R1 is selected from H, C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, 5-8 membered heterocycles, C 6-10 aryl or 5-8 membered heteroaryl, wherein C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, 5-8 membered heterocycle, C 6-10 The aryl group and the 5-8 heteroaryl group are optionally substituted by 1 to 3 or fewer substituents: deuterium, halogen, carboxyl, cyano, hydroxyl, amino, C1-C6 alkyl, C1-C6 alkoxy, phenyl;

[0010] R2 is selected from H, halogen, hydroxyl, carboxyl, cyano, pentafluorothio, C1-C6 alkyl or C1-C6 alkoxy, wherein the C1-C6 alkyl or C1-C6 alkoxy is optionally substituted by 1 to 3 or fewer substituents: deuterium, halogen, carboxyl, cyano, hydroxyl, amino, C1-C6 alkyl, C1-C6 alkoxy, phenyl;

[0011] R3 is selected from halogens, hydroxyl groups, carboxyl groups, cyano groups, C1-C6 alkyl groups, C1-C6 alkoxy groups, C3-C8 cycloalkyl groups, 5-8 membered heterocycles, and C 6-10 aryl or 5-8 membered heteroaryl, wherein C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, 5-8 membered heterocycle, C 6-10 The aryl group and the 5-8 heteroaryl group are optionally substituted by 1 to 3 or fewer substituents: deuterium, halogen, carboxyl, cyano, hydroxyl, amino, C1-C6 alkyl, C1-C6 alkoxy, phenyl;

[0012] R4 is selected from H, halogen, hydroxyl, carboxyl, cyano, pentafluorothio, C1-C6 alkyl or C1-C6 alkoxy, wherein the C1-C6 alkyl or C1-C6 alkoxy is optionally substituted by 1 to 3 or fewer substituents: deuterium, halogen, carboxyl, cyano, hydroxyl, amino, C1-C6 alkyl, C1-C6 alkoxy, phenyl;

[0013] R5 is selected from H, halogen, hydroxyl, carboxyl, cyano, pentafluorothio, C1-C6 alkyl or C1-C6 alkoxy, wherein the C1-C6 alkyl or C1-C6 alkoxy is optionally substituted by 1 to 3 or fewer substituents: deuterium, halogen, carboxyl, cyano, hydroxyl, amino, C1-C6 alkyl, C1-C6 alkoxy, phenyl;

[0014] R6 is selected from -NHCO-(CH2). m -R9;

[0015] R7 is selected from H, halogen, hydroxyl, carboxyl, cyano, pentafluorothio, C1-C6 alkyl or C1-C6 alkoxy, wherein the C1-C6 alkyl or C1-C6 alkoxy is optionally substituted by 1 to 3 or fewer substituents: deuterium, halogen, carboxyl, cyano, hydroxyl, amino, C1-C6 alkyl, C1-C6 alkoxy, phenyl;

[0016] R8 is a C3-C8 cycloalkyl, C1-C6 alkyl, C1-C6 alkoxy, or 5-8 heteroaryl group, wherein the C3-C8 cycloalkyl, C1-C6 alkyl, C1-C6 alkoxy, or 5-8 heteroaryl group is optionally substituted by 1 to 3 or fewer substituents: deuterium, halogen, carboxyl, cyano, hydroxyl, amino, C1-C6 alkyl, C1-C6 alkoxy, or phenyl.

[0017] R9 is selected from C1-C6 alkylsulfonyl, C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, 5-8 membered heterocycles, C 6-10 aryl or 5-8 membered heteroaryl, wherein C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, 5-8 membered heterocycle, C 6-10 The aryl group and the 5-8 heteroaryl group are optionally substituted by 1 to 3 or fewer substituents: deuterium, halogen, carboxyl, cyano, hydroxyl, amino, C1-C6 alkyl, C1-C6 alkoxy, phenyl;

[0018] A is -(CH2) n -;

[0019] Y is selected from O, S, NH or CH2;

[0020] m is 0, 1, or 2;

[0021] n can be 0, 1, 2, 3, or 4.

[0022] In some embodiments, the compound represented by Formula I of the present invention is selected from the compounds represented by Formula II:

[0023] R1, R2, R3, R4, R5, R6, R7, R8, and A are defined as above.

[0024] In some embodiments, in the compound represented by Formula II of the present invention,

[0025] R1 is selected from H, C1-C6 alkyl or C1-C6 alkoxy, wherein the C1-C6 alkyl or C1-C6 alkoxy is optionally substituted by 1 to 3 or fewer substituents: deuterium, halogen, carboxyl, cyano, hydroxyl, amino, C1-C6 alkyl, C1-C6 alkoxy, phenyl;

[0026] R2 is selected from H, C1-C6 alkyl or C1-C6 alkoxy, wherein the C1-C6 alkyl or C1-C6 alkoxy is optionally substituted by 1 to 3 or fewer substituents: deuterium, halogen, carboxyl, cyano, hydroxyl, amino, C1-C6 alkyl, C1-C6 alkoxy, phenyl;

[0027] R3 is selected from C1-C6 alkyl or C1-C6 alkoxy, wherein the C1-C6 alkyl or C1-C6 alkoxy is optionally substituted by one to three or fewer substituents: deuterium, halogen, carboxyl, cyano, hydroxyl, amino, C1-C6 alkyl, C1-C6 alkoxy, phenyl;

[0028] R4 is selected from H, C1-C6 alkyl or C1-C6 alkoxy, wherein the C1-C6 alkyl or C1-C6 alkoxy is optionally substituted by 1 to 3 or fewer substituents: deuterium, halogen, carboxyl, cyano, hydroxyl, amino, C1-C6 alkyl, C1-C6 alkoxy, phenyl;

[0029] R5 is selected from H, C1-C6 alkyl or C1-C6 alkoxy, wherein the C1-C6 alkyl or C1-C6 alkoxy is optionally substituted by 1 to 3 or fewer substituents: deuterium, halogen, carboxyl, cyano, hydroxyl, amino, C1-C6 alkyl, C1-C6 alkoxy, phenyl;

[0030] R6 is selected from -NHCO-(CH2). m -R9;

[0031] R7 is selected from H, C1-C6 alkyl or C1-C6 alkoxy, wherein the C1-C6 alkyl or C1-C6 alkoxy is optionally substituted by 1 to 3 or fewer substituents: deuterium, halogen, carboxyl, cyano, hydroxyl, amino, C1-C6 alkyl, C1-C6 alkoxy, phenyl;

[0032] R8 is a C3-C8 cycloalkyl, C1-C6 alkyl, C1-C6 alkoxy, or 5-8 heteroaryl group, wherein the C3-C8 cycloalkyl, C1-C6 alkyl, C1-C6 alkoxy, or 5-8 heteroaryl group is optionally substituted by 1 to 3 or fewer substituents: deuterium, halogen, carboxyl, cyano, hydroxyl, amino, C1-C6 alkyl, C1-C6 alkoxy, or phenyl.

[0033] R9 is selected from C1-C6 alkylsulfonyl groups;

[0034] A is -(CH2) n -;

[0035] m is 0, 1, or 2;

[0036] n can be 0, 1, 2, or 3.

[0037] In some embodiments, the compound represented by Formula I of the present invention is selected from the compounds represented by Formula III:

[0038] Among them, R1, R2, R3, R4, R5, R7, R8, and A are as defined above.

[0039] In some embodiments, in the compound represented by Formula III of the present invention,

[0040] R1 is selected from H, C1-C6 alkyl or C1-C6 alkoxy, wherein the C1-C6 alkyl or C1-C6 alkoxy is optionally substituted by 1 to 3 or fewer substituents: deuterium, halogen, carboxyl, cyano, hydroxyl, amino, C1-C6 alkyl, C1-C6 alkoxy, phenyl;

[0041] R2 is selected from H, C1-C6 alkyl or C1-C6 alkoxy, wherein the C1-C6 alkyl or C1-C6 alkoxy is optionally substituted by 1 to 3 or fewer substituents: deuterium, halogen, carboxyl, cyano, hydroxyl, amino, C1-C6 alkyl, C1-C6 alkoxy, phenyl;

[0042] R3 is selected from C1-C6 alkyl or C1-C6 alkoxy, wherein the C1-C6 alkyl or C1-C6 alkoxy is optionally substituted by one to three or fewer substituents: deuterium, halogen, carboxyl, cyano, hydroxyl, amino, C1-C6 alkyl, C1-C6 alkoxy, phenyl;

[0043] R4 is selected from H, C1-C6 alkyl or C1-C6 alkoxy, wherein the C1-C6 alkyl or C1-C6 alkoxy is optionally substituted by 1 to 3 or fewer substituents: deuterium, halogen, carboxyl, cyano, hydroxyl, amino, C1-C6 alkyl, C1-C6 alkoxy, phenyl;

[0044] R5 is selected from H, C1-C6 alkyl or C1-C6 alkoxy, wherein the C1-C6 alkyl or C1-C6 alkoxy is optionally substituted by 1 to 3 or fewer substituents: deuterium, halogen, carboxyl, cyano, hydroxyl, amino, C1-C6 alkyl, C1-C6 alkoxy, phenyl;

[0045] R7 is selected from H, C1-C6 alkyl or C1-C6 alkoxy, wherein the C1-C6 alkyl or C1-C6 alkoxy is optionally substituted by 1 to 3 or fewer substituents: deuterium, halogen, carboxyl, cyano, hydroxyl, amino, C1-C6 alkyl, C1-C6 alkoxy, phenyl;

[0046] R8 is a C3-C8 cycloalkyl, C1-C6 alkyl, C1-C6 alkoxy, or 5-8 heteroaryl group, wherein the C3-C8 cycloalkyl, C1-C6 alkyl, C1-C6 alkoxy, or 5-8 heteroaryl group is optionally substituted by 1 to 3 or fewer substituents: deuterium, halogen, carboxyl, cyano, hydroxyl, amino, C1-C6 alkyl, C1-C6 alkoxy, or phenyl.

[0047] A is -(CH2) n -;

[0048] n can be 0, 1, 2, or 3.

[0049] In some embodiments, in the compound represented by Formula III of the present invention,

[0050] R1 is selected from H, C1-C6 alkyl or C1-C6 alkoxy, wherein the C1-C6 alkyl or C1-C6 alkoxy is optionally substituted by 1 to 3 or fewer substituents: deuterium, halogen, carboxyl, cyano, hydroxyl, amino, C1-C6 alkyl, C1-C6 alkoxy, phenyl;

[0051] R2 is selected from H;

[0052] R3 is selected from C1-C6 alkyl or C1-C6 alkoxy, wherein the C1-C6 alkyl or C1-C6 alkoxy is optionally substituted by one to three or fewer substituents: deuterium, halogen, carboxyl, cyano, hydroxyl, amino, C1-C6 alkyl, C1-C6 alkoxy, phenyl;

[0053] R4 is selected from H;

[0054] R5 is selected from H or C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted by 1 to 3 or fewer substituents: deuterium, halogen, carboxyl, cyano, hydroxyl, amino, C1-C6 alkyl, C1-C6 alkoxy, phenyl;

[0055] R7 is selected from H;

[0056] R8 is a C3-C8 cycloalkyl, C1-C6 alkyl, C1-C6 alkoxy, or 5-8 heteroaryl group, wherein the C3-C8 cycloalkyl, C1-C6 alkyl, C1-C6 alkoxy, or 5-8 heteroaryl group is optionally substituted by 1 to 3 or fewer substituents: deuterium, halogen, carboxyl, cyano, hydroxyl, amino, C1-C6 alkyl, C1-C6 alkoxy, or phenyl.

[0057] A is -(CH2) n -;

[0058] n is 0, 1, 2, or 3;

[0059] Preferably, R1 is selected from H, C1-C6 alkyl, or C1-C6 alkoxy, wherein the C1-C6 alkyl or C1-C6 alkoxy is optionally substituted by 1 to 3 or fewer substituents: halogen; more preferably, R1 is selected from H, C1-C3 alkyl, or C1-C3 alkoxy, wherein the C1-C3 alkyl or C1-C3 alkoxy is optionally substituted by 3 or fewer substituents: halogen; more preferably, R1 is selected from H, methyl, halomethyl, methoxy, or halomethoxy; more preferably, R1 is selected from H, methyl, trifluoromethyl, methoxy, or trifluoromethoxy;

[0060] Preferably, R3 is selected from C1-C6 alkoxy groups, wherein the C1-C6 alkoxy groups are optionally substituted by 1 to 3 or fewer substituents: halogen; more preferably, R3 is selected from C1-C5 alkoxy groups, wherein the C1-C5 alkoxy groups are optionally substituted by 3 or fewer substituents: halogen; more preferably, R3 is selected from (CF3)O-, (CF3)CH2O-, (CF3)CH2CH2O-,

[0061] (CF3)CH2CH2CH2O- or (CF3)CH2CH2CH2CH2O-;

[0062] Preferably, R5 is selected from H or C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted by 1 to 3 or fewer substituents: halogen; more preferably, R5 is selected from H or C1-C3 alkyl, wherein the C1-C3 alkyl is optionally substituted by 3 or fewer substituents: halogen; more preferably, R5 is selected from H, methyl or halomethyl; more preferably, R5 is selected from H, methyl or trifluoromethyl;

[0063] Preferably, R8 is a C3-C8 cycloalkyl, C1-C6 alkyl, C1-C6 alkoxy, or 5-8 heteroaryl, wherein the C3-C8 cycloalkyl, C1-C6 alkyl, C1-C6 alkoxy, or 5-8 heteroaryl is optionally substituted by 1 to 3 or fewer substituents: halogen, methyl; more preferably, R8 is a cyclopropyl, C1-C3 alkyl, C1-C3 alkoxy, or 6 heteroaryl, wherein the cyclopropyl, C1-C3 alkyl, C1-C3 alkoxy, or 6 heteroaryl is optionally substituted by 1 to 3 or fewer substituents: halogen, methyl; more preferably, R8 is a cyclopropyl, methyl, trifluoromethyl, methoxy, trifluoromethoxy, pyridyl, or 5-methylpyridin-2-yl.

[0064] In some embodiments, the compound represented by Formula III of the present invention is selected from the compounds represented by Formula III-1 or Formula III-2:

[0065] Among them, R1, R2, R3, R4, R5, R7, R8, and A are as defined above.

[0066] In some embodiments, the compound represented by Formula I of the present invention is selected from the compounds represented by Formula IV:

[0067] R1, R3, R5, R8, and A are defined as above.

[0068] In some embodiments, in the compound represented by Formula IV of the present invention,

[0069] R1 is selected from H, C1-C6 alkyl or C1-C6 alkoxy, wherein the C1-C6 alkyl or C1-C6 alkoxy is optionally substituted by 1 to 3 or fewer substituents: deuterium, halogen, carboxyl, cyano, hydroxyl, amino, C1-C6 alkyl, C1-C6 alkoxy, phenyl;

[0070] R3 is selected from C1-C6 alkyl or C1-C6 alkoxy, wherein the C1-C6 alkyl or C1-C6 alkoxy is optionally substituted by one to three or fewer substituents: deuterium, halogen, carboxyl, cyano, hydroxyl, amino, C1-C6 alkyl, C1-C6 alkoxy, phenyl;

[0071] R5 is selected from H or C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted by 1 to 3 or fewer substituents: deuterium, halogen, carboxyl, cyano, hydroxyl, amino, C1-C6 alkyl, C1-C6 alkoxy, phenyl;

[0072] R8 is a C3-C8 cycloalkyl, C1-C6 alkyl, C1-C6 alkoxy, or 5-8 heteroaryl group, wherein the C3-C8 cycloalkyl, C1-C6 alkyl, C1-C6 alkoxy, or 5-8 heteroaryl group is optionally substituted by 1 to 3 or fewer substituents: deuterium, halogen, carboxyl, cyano, hydroxyl, amino, C1-C6 alkyl, C1-C6 alkoxy, or phenyl.

[0073] A is -(CH2) n -;

[0074] n is 0, 1, 2, or 3;

[0075] Preferably, R1 is selected from H, C1-C6 alkyl, or C1-C6 alkoxy, wherein the C1-C6 alkyl or C1-C6 alkoxy is optionally substituted by 1 to 3 or fewer substituents: halogen; more preferably, R1 is selected from H, C1-C3 alkyl, or C1-C3 alkoxy, wherein the C1-C3 alkyl or C1-C3 alkoxy is optionally substituted by 3 or fewer substituents: halogen; more preferably, R1 is selected from H, methyl, halomethyl, methoxy, or halomethoxy; more preferably, R1 is selected from H, methyl, trifluoromethyl, methoxy, or trifluoromethoxy;

[0076] Preferably, R3 is selected from C1-C6 alkoxy groups, wherein the C1-C6 alkoxy groups are optionally substituted by 1 to 3 or fewer substituents: halogen; more preferably, R3 is selected from C1-C5 alkoxy groups, wherein the C1-C5 alkoxy groups are optionally substituted by 3 or fewer substituents: halogen; more preferably, R3 is selected from (CF3)O-, (CF3)CH2O-, (CF3)CH2CH2O-, (CF3)CH2CH2CH2O- or (CF3)CH2CH2CH2CH2O-;

[0077] Preferably, R5 is selected from H or C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted by 1 to 3 or fewer substituents: halogen; more preferably, R5 is selected from H or C1-C3 alkyl, wherein the C1-C3 alkyl is optionally substituted by 3 or fewer substituents: halogen; more preferably, R5 is selected from H, methyl or halomethyl; more preferably, R5 is selected from H, methyl or trifluoromethyl;

[0078] Preferably, R8 is a C3-C8 cycloalkyl, C1-C6 alkyl, C1-C6 alkoxy, or 5-8 heteroaryl, wherein the C3-C8 cycloalkyl, C1-C6 alkyl, C1-C6 alkoxy, or 5-8 heteroaryl is optionally substituted by 1 to 3 or fewer substituents: halogen, methyl; more preferably, R8 is a cyclopropyl, C1-C3 alkyl, C1-C3 alkoxy, or 6 heteroaryl, wherein the cyclopropyl, C1-C3 alkyl, C1-C3 alkoxy, or 6 heteroaryl is optionally substituted by 1 to 3 or fewer substituents: halogen, methyl; more preferably, R8 is a cyclopropyl, methyl, trifluoromethyl, methoxy, trifluoromethoxy, pyridyl, or 5-methylpyridin-2-yl.

[0079] In some embodiments, the compound represented by Formula IV of the present invention is selected from the compounds represented by Formula IV-1 or Formula IV-2:

[0080] R1, R3, R5, R8, and A are defined as above.

[0081] In some embodiments, the compound represented by Formula I of the present invention is selected from the following compounds:

[0082] The present invention also provides a pharmaceutical composition comprising a compound of Formula I or a stereoisomer thereof, a prodrug, a solvate or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0083] The present invention also provides the use of the compound of Formula I described above, or its stereoisomer, prodrug, solvate, or pharmaceutically acceptable salt thereof, or the aforementioned pharmaceutical composition, in the preparation of an MGAT2 inhibitor medicament.

[0084] In some embodiments, the MGAT2 inhibitor drug is a drug for treating and / or preventing obesity, metabolic syndrome, hyperlipidemia, hypertriglyceridemia, hyperVLDLemia, hyperfatty acidemia, diabetes, or arteriosclerosis.

[0085] The present invention also provides a method for treating and / or preventing MGAT2-mediated related diseases, comprising administering to a subject in need a therapeutically effective amount of a compound of Formula I above or a stereoisomer thereof, a prodrug, a solvate thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0086] In some embodiments, the MGAT2-mediated related diseases are selected from obesity, metabolic syndrome, hyperlipidemia, hypertriglyceridemia, hyperVLDLemia, hyperfatty acidemia, diabetes, or arteriosclerosis.

[0087] The present invention also provides a compound, stereoisomer thereof, prodrug, solvate thereof, or pharmaceutically acceptable salt thereof as shown in Formula I above, for use as a drug.

[0088] This invention also provides a compound, stereoisomer thereof, prodrug, solvate thereof, or pharmaceutically acceptable salt thereof, as shown in Formula I above, for the treatment and / or prevention of MGAT2-mediated diseases. The MGAT2-mediated diseases are as defined above.

[0089] Definitions and general terminology:

[0090] The following terms, etc., are used to describe the present invention. It should be understood that, as those skilled in the art will recognize, terms without a specific definition are given the same meaning as used in the context of the present invention.

[0091] As used in this invention, the term "alkyl" refers to a saturated aliphatic hydrocarbon group, including both straight-chain and branched hydrocarbon groups. Examples include C1-C6 alkyl groups. "C1-C6 alkyl" refers to alkyl groups having 1 to 6 carbon atoms, such as alkyl groups having 1, 2, 3, 4, 5, or 6 carbon atoms, including but not limited to methyl, ethyl, propyl (e.g., n-propyl, isopropyl), butyl (e.g., n-butyl, isobutyl, tert-butyl), pentyl (e.g., n-pentyl, isopentyl, neopentyl), hexyl (e.g., n-hexyl), etc. The alkyl group may optionally be further substituted with one or more substituents.

[0092] The term "halogen" as used in this invention refers to fluorine, chlorine, bromine or iodine; preferably fluorine or chlorine.

[0093] As used in this invention, the term "C3-C8 cycloalkyl" refers to a cycloalkyl group having 3 to 8 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl; preferably cyclopropyl. The cycloalkyl group may optionally be further substituted with one or more substituents.

[0094] The term "C1-C6 alkoxy" as used in this invention refers to a group formed by the linkage of a C1-C6 alkyl group with an oxygen atom, i.e., a "C1-C6 alkyl-O-" group, wherein C1-C6 alkyl is the same as the "C1-C6 alkyl" defined above. This includes, but is not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, and tert-butoxy; preferably methoxy and ethoxy. The alkoxy group may optionally be further substituted by one or more substituents.

[0095] "Heterocyclic" or "heterocyclic group" refers to a substituted or unsubstituted saturated or partially unsaturated non-aromatic cyclic group, which can be a 3- to 8-membered (e.g., 3, 4, 5, 6, 7, 8-membered) monocyclic, a 6- to 12-membered (e.g., 6, 7, 8, 9, 10, 11, 12-membered) bicyclic, or a 10- to 15-membered (e.g., 10, 11, 12, 13, 14, 15-membered) tricyclic system, and contains 1, 2, or 3 heteroatoms selected from N, O, or S, preferably a 3- to 8-membered heterocyclic group. The "heterocyclic group" can be attached to a heteroatom or a carbon atom; the "heterocyclic group" can be a bridged ring or a spirocyclic ring. Non-limiting examples of "heterocyclic groups" include epoxyethyl, aziridinepropyl, oxacyclobutyl, aziridinebutyl, 1,3-dioxopentyl, 1,4-dioxopentyl, 1,3-dioxahexacycloyl, aziridineheptyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, pyran, 1,3-dithiaalkyl, tetrahydrofuranyl, tetrahydropyrroleyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyranyl, aziridine[3.2.1]octyl, aziridine[5.2.0]nonyl, oxacyclo[5.3.1.1]dodecyl, aziridine, and oxaspiro[3.3]heptyl, etc. The heterocyclic group may optionally be further substituted with one or more substituents.

[0096] "Aromatic ring" or "aryl" refers to a substituted or unsubstituted aromatic ring, which can be a 6- to 8-membered monocyclic ring (e.g., 6, 7, 8-membered), a 6- to 12-membered (e.g., 6, 7, 8, 9, 10, 11, 12-membered) bicyclic ring, or a 10- to 15-membered (e.g., 10, 11, 12, 13, 14, 15-membered) tricyclic system. It can be a bridged ring or a spirocyclic ring. Non-limiting examples include phenyl, naphthyl, etc. The aromatic ring may optionally be further substituted by one or more substituents.

[0097] "Heteroaromatic ring" or "heteroaryl" refers to an aromatic ring having a conjugated planar ring system and containing heteroatoms. It can be a 5- to 8-membered (e.g., 5, 6, 7, 8-membered) monocyclic ring, an 8- to 12-membered (e.g., 8, 9, 10, 11, 12-membered) bicyclic ring, or a 10- to 15-membered (e.g., 10, 11, 12, 13, 14, 15-membered) tricyclic system, and contains 1 to 6 (e.g., 1, 2, 3, 4, 5, 6) heteroatoms selected from N, O, or S. Examples include 5-8-membered nitrogen-containing heteroaromatic rings, 5-8-membered oxygen-containing heteroaromatic rings, and 5-8-membered sulfur-containing heteroaromatic rings. Non-limiting examples of heteroaryl groups include oxazolyl, triazolyl, pyridyl, furanyl, thiophenyl, pyrroloyl, pyrazolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, benzimidazolyl, benzopyridyl, pyrrolopyridyl, etc. The heterocyclic ring may optionally be further substituted by one or more substituents.

[0098] The term "pharmaceutically acceptable salt" as used in this invention refers to a salt of a compound of the invention, prepared by combining a compound of the invention having specific substituents with a pharmaceutically acceptable acid or base.

[0099] As used in this invention, the term "stereoisomer" refers to compounds that have the same chemical composition but differ in the spatial arrangement of atoms and groups. These include enantiomers, diastereomers, geometric isomers, transisomers, or conformational isomers.

[0100] The term "solvent" as used in this invention describes a molecular complex comprising a compound having any of the above chemical formulas or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable solvent molecules (e.g., ethanol). When the solvent is water, the term "hydrate" is used.

[0101] The "prodrug" used in this invention, also known as a precursor drug, drug precursor, or predrug, refers to a compound obtained by chemically modifying a drug, which has no or low activity in vitro, but releases an active drug in vivo through enzymatic or non-enzymatic conversion to exert its therapeutic effect.

[0102] The compounds of the present invention may also contain atomic isotopes in non-natural proportions at one or more atoms constituting such compounds. For example, the compounds may be radiolabeled with radioactive isotopes such as deuterium (D), tritium (D), etc. 3 H), Iodine-125 ( 125 I) or carbon-14 ( 14 C). All isotopic variations of the compounds of this invention, whether radioactive or not, are covered within the scope of this invention. Beneficial effects

[0103] The compounds of this invention effectively inhibit MOGAT2 enzyme activity and possess favorable metabolic properties, exhibiting excellent performance in terms of efficacy, safety, and stability. Specifically, according to the experimental results of this application, the compounds of this invention demonstrate excellent inhibitory activity against MOGAT2, showing significant inhibition of MOGAT2 activity in cells, good plasma stability, stability in various liver microsomes, and good CYP properties. The tested compounds showed significant weight-loss effects, good lipid absorption inhibition, and good PK properties, with high distribution in the jejunum. Therefore, the compounds of this invention have promising clinical application prospects. Detailed Implementation

[0104] The structure of the compound was determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS).

[0105] NMR testing instruments and conditions:

[0106] NMR measurements were performed using a Bruker Avance III 400 NMR spectrometer. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6) and deuterated chloroform (CDCl3), with tetramethylsilane (TMS) as the internal standard.

[0107] MS testing instruments and conditions:

[0108] MS was determined using (Waters Arc+QDA(ESI)) and (Waters H-Class+SQD2(ESI)).

[0109] All chemical reagents used are commercially available chemically pure or analytically pure products, and are generally used directly without purification.

[0110] Unless otherwise specified in the examples, "solution" refers to an aqueous solution.

[0111] Unless otherwise specified in the examples, the room temperature is 20℃~30℃.

[0112] Preferred embodiments of the present invention will now be described in more detail. While preferred embodiments of the present invention are described below, it should be understood that one should not be limited to the embodiments set forth herein. The described embodiments are merely some, not all, of the embodiments of the present invention. All other embodiments obtained by those skilled in the art based on the embodiments of the present invention are within the scope of protection of the present invention.

[0113] Synthesis of Intermediate 1

[0114] Step 1:

[0115] At room temperature, N′-BOC-N,N-aminophthalic acid (25 g, 95.52 mmol) and cyclopropane ethanol (8.22 g, 95.52 mmol) were dissolved in anhydrous dichloromethane (200 mL). The solution was purged with nitrogen three times, cooled in an ice bath, and after the temperature stabilized, triphenylphosphine (25.02 g, 95.52 mmol) was quickly added, followed by slow addition of diisopropyl azodicarbonate (19.29 g, 95.52 mmol). After the addition was complete, the mixture was stirred at low temperature for 5 minutes, the ice bath was removed, and the mixture was allowed to rise to room temperature and stirred overnight. The reaction was monitored by TLC and LCMS to indicate the end of the reaction. The reaction solution was directly concentrated, and petroleum ether (100 mL) was added to slurry the mixture. Most of the triphenylphosphine oxide was removed by filtration. The filtrate was evaporated to dryness and allowed to stand in a refrigerator for 16 hours. A solid precipitated out. This solid was diluted with petroleum ether (100 mL) and filtered to obtain a white solid, which was the desired product (most of the product). The filtrate was evaporated to dryness and then subjected to rapid column chromatography (PE:EA = 9:1) to give a transparent oily substance, which turned into a white solid upon prolonged standing. A total of compound B was obtained (29.6 g, 89.69 mmol, yield: 93.9%). LCMS (ESI): m / z = 275.08 [M+H-56]. + .

[0116] Step 2:

[0117] Compound B (29.6 g, 89.69 mmol) was placed in a reaction flask at room temperature, and a mixed solution of ethanol / hydrazine hydrate (3:1, 100 mL, v / v) was added. The mixture was stirred for 12 hours. After TLC detection, the reaction was completed. The mixture was diluted with water, extracted four times with DCM, and the organic phases were combined, dried, filtered, and concentrated to dryness. The crude product was purified by rapid column chromatography (DCM) to give a clear liquid intermediate 1 (15.5 g, 77.51 mmol, yield: 86.4%). 1 H NMR(400MHz,DMSO-d6)δ4.36(s,2H),3.36-3.23(m,2H),1.40(s,9H),1.38-1.32(m,1H),1.22-1.11 (m,1H),0.65-0.54(m,1H),0.41-0.32(m,2H),0.03-0.00(m,2H), LCMS(ESI):m / z=145.17[M+H-56] + .

[0118] Example

[0119] Example 1: EVO38094

[0120] Step 1:

[0121] 4-Hydroxy-2-trifluoromethylbenzaldehyde (25 g, 131.49 mmol), 4,4,4-trifluorobutanol (16.85 g, 131.49 mmol), and dichloromethane (200 mL) were added to the reaction flask. The mixture was purged with nitrogen three times. Triphenylphosphine (34.50 g, 131.49 mmol) was added under ice bath conditions, followed by slow addition of diisopropyl azodicarbonate (26.60 g, 131.49 mmol, 25.9 mL), avoiding exothermic boiling. After the addition was complete, the mixture was brought to room temperature and stirred overnight. TLC (PE:EA = 8:1) showed the reaction was complete. The reaction solution was washed twice with water and concentrated. Rapid column chromatography (PE:EA = 10:1) purified the solution to give a yellow solid EVO38094-A1 (30 g, yield: 76.1%). 1 H NMR (400MHz, CDCl3) δ10.26(dd,J=2.2,0.8Hz,1H),8.13(d,J=8.7Hz,1H),7.25(d,J=2.6Hz,1 H), 7.13 (dd, J=8.7, 2.5Hz, 1H), 4.15 (t, J=6.0Hz, 2H), 2.42-2.27 (m, 2H), 2.18-2.07 (m, 2H).

[0122] Step 2:

[0123] Compound EVO38094-A1 (30 g, 99.9 mmol), tert-butylsulfinamide (12.15 g, 99.9 mmol), and anhydrous THF (200 mL) were added to the reaction flask. Tetraisopropyl titanate (42.60 g, 149.9 mmol, 44.61 mL) was added at room temperature. The mixture was purged with nitrogen three times and stirred overnight at room temperature. TLC (PE:EA = 5:1) showed the reaction was complete. Water (40 mL) was added to the reaction solution, resulting in the precipitation of a large amount of solid. The reaction solution was diluted with ethyl acetate (300 mL), the solid was removed by filtration, and the crude product was concentrated. Rapid column chromatography (PE:EA = 6:1) purified the crude product to a white solid EVO38094-A2 (30 g, yield: 74.5%), LCMS (ESI): m / z = 403.99 [M+H]. + .

[0124] Step 3:

[0125] Methyl acetate (8.27 g, 111.66 mmol, 8.85 mL) and anhydrous THF (30 mL) were added to a nitrogen-filled reaction flask. The mixture was cooled in an ethanol / dry ice bath. After the temperature stabilized, potassium bis(trimethylsilyl)amino (111.7 mL, 1 N) was slowly added. After stirring at low temperature for 1 hour, an anhydrous THF solution of EVO38094-A2 (30 g, 74.44 mmol) (70 mL) was slowly added dropwise, and stirring was continued for 1 hour. The mixture was quenched with saturated ammonium chloride aqueous solution, diluted with water, extracted with ethyl acetate, and the organic phase was concentrated to obtain the crude product. The crude product was then subjected to rapid column chromatography (PE:EA = 1:1) to obtain a pale yellow oily substance, EVO38094-A3 (38 g, yield: 90.7%), LCMS (ESI): m / z = 478.42 [M+H]. + .

[0126] Step 4:

[0127] Compound EVO38094-A3 (38 g, 79.66 mmol) was placed in a reaction flask, dissolved in dichloromethane (50 mL), and stirred until homogeneous. Then, hydrochloric acid / dioxane solution (50 mL, 4 M) was added, and the mixture was stirred at room temperature for 1 hour. The reaction was confirmed by LCMS. The reaction solution was directly concentrated to obtain a yellow crude product EVO38094-A4 (38.5 g, yield: >99%).

[0128] Step 5:

[0129] The crude compound EVO38094-A4 (38.5 g, 103.22 mmol) was placed in a reaction flask and dissolved in dichloromethane (200 mL). Then, N,N-diisopropylethylamine (26.63 g, 206.44 mmol) was added. After stirring the mixture at room temperature for 10 minutes, cyanoacetic acid (13.315 g, 154.83 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (29.73 g, 154.83 mmol) and 1-hydroxybenzotriazole (20.9 g, 154.83 mmol) were added. The mixture was stirred at room temperature for 12 hours. After the LCMS reaction was completed, the reaction solution was diluted with DCM (300 mL), the organic phase was washed with water (*2), dried over anhydrous sodium sulfate, filtered and concentrated to dryness. The crude product was subjected to rapid column chromatography (PE:EA = 1:1) to obtain a yellow oily substance EVO38094-A5 (29.1 g, 66.13 mmol, yield: 78.3%), LCMS (ESI): m / z = 439.10 [MH]. - .

[0130] Step 6:

[0131] Compound EVO38094-A5 (29.1 g, 66.13 mmol) was added to a reaction flask, dissolved in methanol (150 mL), and then a methanol solution of sodium methoxide (10 eq., 5.4 M) was slowly added. The mixture was heated to 50 °C and stirred for 1 hour. The reaction was monitored by LCMS until completion. The reaction solution was concentrated under reduced pressure to remove most of the methanol, then water (400 mL) was added, and the pH was adjusted to 3 with 1 N hydrochloric acid aqueous solution. The mixture was extracted with ethyl acetate (*4), approximately 1.5 L. The organic phase was concentrated, and the crude product was purified by reverse column chromatography (mobile phase A: water (0.225 wt% FA), mobile phase B: CAN) to obtain a white solid EVO38094-A6 (16.1 g, 39.46 mmol, yield: 69%), LCMS (ESI): m / z = 407.16 [MH]. - .

[0132] Step 7:

[0133] Compound EVO38094-A6 (16.1 g, 39.46 mmol) was added to a reaction flask and dissolved in 1,2-dichloroethane (200 mL). Phosphorus oxychloride (30.25 g, 197.30 mmol) was slowly added under ice bath conditions, followed by DMF (2.88 g, 39.46 mmol). After the addition was complete, the ice bath was removed, and the mixture was heated to 50 °C and stirred for 3 hours. The reaction was monitored by TLC until complete. The reaction solution was slowly poured into ice water to quench the reaction mixture while stirring rapidly. After quenching, the mixture was extracted with ethyl acetate (*3), approximately 1.5 L. The organic phase was dried and concentrated, and then subjected to rapid column chromatography to obtain a yellow oily compound EVO38094-A7 (13.2 g, 30.98 mmol, yield: 78.5%), LCMS (ESI): m / z = 425.1, 427.1 [MH]. - .

[0134] Step 8:

[0135] Compound EVO38094-A7 (13.2 g, 30.98 mmol) was added to the reaction flask and dissolved in ethanol (130 mL). NaHCO3 (7.8 g, 92.94 mmol) and intermediate 1 (7.45 g, 37.18 mmol) were added to the reaction system. After the addition was complete, the mixture was stirred at room temperature for 5 hours. The reaction was monitored by LCMS to ensure completeness. The reaction solution was directly concentrated, and the crude product was subjected to rapid column chromatography to obtain a yellow oily substance EVO38094-A8 (12.2 g, 20.67 mmol, yield: 66.7%), LCMS (ESI): m / z = 589.23 [MH]. - .

[0136] Step 9:

[0137] Compound EVO38094-A8 (12.2 g, 20.67 mmol) was placed in a reaction flask, and hydrochloric acid / dioxane solution (50 mL, 4 N) was added. The mixture was stirred at room temperature for 2 hours. The reaction was monitored by LCMS until complete. The reaction solution was directly concentrated to obtain a yellow crude product EVO38094-A9 (12.8 g, yield: >99%), a mixture of solids and oil. LCMS (ESI): m / z = 491.49 [M+H] + .

[0138] Step 10:

[0139] Compound EVO38094-A9 (12.8 g) was added to a reaction flask and dissolved in DMF (100 mL). Then, methanesulfonylacetic acid (3.61 g, 26.12 mmol), N,N'-diisopropylcarbodiimide (6.59 g, 52.24 mmol), and 4-dimethylaminopyridine (3.19 g, 26.12 mmol) were added. LC-MS analysis showed that approximately 5% of the starting material remained unreacted. The reaction solution was quenched with water (300 mL), extracted with ethyl acetate (*5), approximately 2 L. The organic phase was dried and concentrated. The crude product was subjected to rapid column chromatography (EA:PE = 2:1) to give a yellow solid EVO38094 (7.8 g, yield: 61.8%), LC-MS (ESI): m / z = 611.54 [M+H]. + HPLC purity: 97.57% 1 H NMR (400MHz, DMSO-d6) δ10.63(s,1H),7.73(s,1H),7.68(d,J=8.7Hz,1H),7.26(dd,J=8.7,2. 7Hz,1H),7.22(d,J=2.6Hz,1H),4.97(t,J=7.6Hz,1H),4.39(s,2H),4.13(t,J=6.2Hz,2H),3.9 5(t,J=7.2Hz,2H),3.21(s,3H),3.02-2.94(m,1H),2.91-2.81(m,1H),2.46-2.40(m,2H),1.9 9-1.90(m,2H),1.65-1.56(m,2H),0.65-0.54(m,1H),0.37-0.31(m,2H),-0.01--0.08(m,2H).

[0140] Example 2 EVO38024-B

[0141] Starting with 4-hydroxybenzaldehyde, and following the preparation method of compound EVO38094 in Example 1, the obtained product was separated by high-performance liquid chromatography (HPLC) column chromatography (column: YMC Triart C18 12nm 10um, 30*250mm; mobile phase A: water (10mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 40mL / min; gradient: 30%B to 80%B over 30min; wavelength: 200-400nm). The product was then freeze-dried to obtain a white solid EVO38024-B (11mg, yield: 14.3%), LCMS (ESI) m / z = 543.33 [M+H). + HPLC purity: 99.93% 1H NMR(400MHz, CDCl3) δ7.27(d,J=8.4Hz,2H),6.88(d,J=8.3Hz,2H),5.89(s,1H), 4.82(dd,J=11.2,5.1Hz,1H),4.26(q,J=14.4Hz,2H),4.09(t,J=7.2Hz,2H),3.9 9(t,J=6.0Hz,2H),3.24(s,3H),3.08-2.92(m,2H),2.39-2.22(m,2H),2.10-1.9 9(m,2H),1.81-1.73(m,2H),0.63(m,1H),0.47-0.37(m,2H),0.06--0.03(m,2H).

[0142] Example 3 EVO38027

[0143] Starting with 4-hydroxy-2-trifluoromethylbenzaldehyde, and following the preparation method of compound EVO38094 in Example 1, the product was purified by silica gel column chromatography (mobile phase A: EtOAc, mobile phase B: EtOAc / MeOH = 9 / 1; gradient: 0% B to 10% B over 15 min), followed by freeze-drying to obtain a white solid EVO38027 (24.6 mg, yield: 21%), LCMS (ESI) m / z = 583.2 [M+H]. + HPLC purity: 97.08% 1 H NMR (400MHz, DMSO-d6) δ10.65(s,1H),7.79(s,1H),7.72(d,J=8.4Hz,1H),7.40-7.36(m,2H),5.01-4.97(m,1H),4.91(q,J=8.8Hz,2H),4.40( s,2H),3.96(t,J=7.2Hz,2H),3.21(s,3H),3.01-2.83(m,2H),1.62-1. 57(m,2H),0.65-0.55(m,1H),0.38-0.31(m,2H),-0.01--0.08(m,2H).

[0144] Example 4 EVO38093

[0145] Starting with 4-hydroxy-2,6-dimethylbenzaldehyde, and following the preparation method of compound EVO38094 in Example 1, the product was separated by high-performance liquid chromatography (HPLC) column chromatography (column: Sunfire-C18, 19*250mm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 20 mL / min; gradient: 45% B to 60% B over 15 min; wavelength: 200-400 nm), followed by freeze-drying to obtain a white solid EVO38093 (4.6 mg, yield: 10%), LCMS (ESI) m / z = 571.4 [M+H). + HPLC purity: 98.96% 1 H NMR (400MHz, DMSO-d6) δ10.55(s,1H),7.41(s,1H),6.62(s,2H),5.15(dd,J= 13.7,5.2Hz,1H),4.39(s,2H),4.03-3.92(m,4H),3.21(s,3H),3.07-2.93(m ,1H),2.85-2.74(m,1H),2.45-2.39(m,2H),2.35(s,6H),1.95-1.87(m,2H), 1.66-1.59(m,2H),0.68-0.59(m,1H),0.41-0.34(m,2H),0.04--0.03(m,2H).

[0146] Example 5: EVO38094-P1 and EVO38094-P2

[0147] The preparation method of the compound in Example 1 was repeated to obtain racemic EVO38094 (4.2 g), which was separated by supercritical fluid chromatography (column: DAICEL). OD-3, 25*250mm 10μm; mobile phase A: Supercritical CO2, mobile phase B: MeOH + 0.05% NH3·MeOH; flow rate: 90mL / min; gradient: A:B = 70:30; wavelength: 214 / 254nm), EVO38094-P1 (1398.42mg, yield: 33.1%) was obtained at a retention time of 3.05min, LCMS (ESI) m / z = 611.3 [M+H] + HPLC purity: 97.05% 1H NMR (400MHz, DMSO-d6) δ10.63(s,1H),7.75(s,1H),7.68(d,J=8.7Hz,1H),7.26(dd,J=8. 7,2.7Hz,1H),7.22(d,J=2.7Hz,1H),4.97(t,J=7.5Hz,1H),4.39(s,2H),4.12(t,J=6.2H The concentrations of EVO38094-P2 (1390.8 mg, yield: 33.1%) were obtained at a retention time of 4.08 min. The LCMS (ESI) m / z = 611.3 [M+H] 3.96 (t, J = 7.2 Hz, 2H), 3.21 (s, 3H), 3.02–2.80 (m, 2H), 2.48–2.37 (m, 2H), 1.99–1.89 (m, 2H), 1.64–1.56 (m, 2H), 0.66–0.52 (m, 1H), 0.38–0.30 (m, 2H), and 0.06–0.03 (m, 2H). + HPLC purity: 95.14% 1 H NMR (400MHz, DMSO-d6) δ10.65(s,1H),7.75(s,1H),7.68(d,J=8.7Hz,1H),7.25(d,J=9 .0Hz,1H),7.22(d,J=2.7Hz,1H),4.97(t,J=7.4Hz,1H),4.39(s,2H),4.12(t,J=6.2Hz, 2H),3.95(t,J=7.2Hz,2H),3.21(s,3H),3.03-2.81(m,2H),2.47-2.36(m,2H),2.00-1. 88(m,2H),1.67-1.55(m,2H),0.66-0.52(m,1H),0.39-0.30(m,2H),0.06-0.03(m,2H).

[0148] Example 6 EVO38094-A

[0149] Starting with 4-hydroxy-2-trifluoromethylbenzaldehyde, and following the preparation method of compound EVO38094 in Example 1, the obtained product was separated by high-performance liquid chromatography (HPLC) column chromatography (column: Sunfire-C18, 19*250 mm; mobile phase A: water (0.225 wt% FA), mobile phase B: ACN; flow rate: 20 mL / min; gradient: 44% B to 68% B within 15 min; wavelength: 200-400 nm), followed by freeze-drying to obtain a white solid EVO38094-A (3.3 mg, yield: 1.5%), LCMS (ESI) m / z = 634.3 [M+H].+ HPLC purity: 95.73% 1 H NMR (400MHz, DMSO-d6) δ10.86 (s, 1H), 8.29 (d, J = 2.2Hz, 1H), 7.93 (s, 1H), 7.83-7.76 (m ,1H),7.74(d,J=8.7Hz,1H),7.61(d,J=8.3Hz,1H),7.29(dd,J=8.8,2.7Hz,1H),7.24(d, J=2.7Hz,1H),5.06(t,J=7.3Hz,1H),4.33(s,2H),4.13(t,J=6.2Hz,2H),3.15(s,3H),3 .14-3.06(m,1H),3.02-2.92(m,1H),2.46-2.39(m,2H),2.34(s,3H),2.00-1.94(m,2H).

[0150] Example 7 EVO38094-C

[0151] Starting with 4-hydroxy-2-trifluoromethylbenzaldehyde, and following the preparation method of compound EVO38094 in Example 1, the product was separated by high-performance liquid chromatography (HPLC) column (column: Sunfire-C18, 19*250 mm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 20 mL / min; gradient: 40% B to 80% B over 15 min; wavelength: 200-400 nm), and then freeze-dried to obtain a white solid EVO38094-C (1.4 mg, yield: 12%), LCMS (ESI) m / z = 669.3 [M+H]. + HPLC purity: 96.58% 1 H NMR (400MHz, DMSO-d6) δ10.67(s,1H),7.77(s,1H),7.68(d,J=8.8Hz,1H),7.30-7.22(m ,1H),7.21(d,J=2.6Hz,1H),4.98(t,J=7.5Hz,1H),4.38(s,2H),4.12(t,J=6.2Hz,2H), 4.07(t,J=6.4Hz,2H),4.00(t,J=7.0Hz,2H),3.20(s,3H),2.98(dd,J=15.8,5.3Hz,1H) ,2.87(dd,J=15.8,9.7Hz,1H),2.46-2.38(m,2H),2.16-2.09(m,2H),2.00-1.90(m,2H).

[0152] Example 8 EVO38114

[0153] Using 4-hydroxy-2-methoxybenzaldehyde as the starting material, and following the preparation method of compound EVO38094 in Example 1, the obtained product was separated by high-performance liquid chromatography (HPLC) column chromatography (column: Sunfire-C18, 19*250mm; mobile phase A: water (0.1% NH4+)). 3· H2O), mobile phase B: ACN; flow rate: 20 mL / min; gradient: 30% B to 60% B over 15 min; wavelength: 200-400 nm), followed by freeze-drying to obtain a white solid EVO38114 (11.1 mg, yield: 43%), LCMS (ESI) m / z = 545.0 [M+H). + HPLC purity: 95.71% 1 H NMR (400MHz, DMSO-d6) δ10.62(s,1H),7.56(d,J=3.2Hz,1H),7.03(d,J=8.5Hz,1H),6.71(d,J= 2.4Hz,1H),6.55(dd,J=8.5,2.4Hz,1H),4.99-4.93(m,1H),4.73(q,J=8.9Hz,2H),4.38(s,2H) ,3.90(t,J=7.2Hz,2H),3.84(s,3H),3.20(s,3H),3.09(dd,J=15.8,6.2Hz,1H),2.80(dd,J=15 .8,5.4Hz,1H),1.61-1.50(m,2H),0.62-0.48(m,1H),0.36-0.24(m,2H),-0.02--0.18(m,2H).

[0154] Experimental Section

[0155] Experiment 1. MOGAT2 enzyme activity inhibition experiment

[0156] The monoacylglycerol acyltransferase MOGAT2 catalyzes the transfer of the fatty acyl group of fatty acyl-CoA to monoacylglycerol to generate diacylglycerol. The content of the reaction product diacylglycerol can be quantitatively detected by liquid chromatography-tandem mass spectrometry (LC-MS / MS). First, wild-type hMOGAT2 (NM_025098) was cloned into the pFastBac expression vector, and a tev restriction site and a 6xHis tag were added to the C-terminus. Protein expression was performed using SF9 cells. SF9 cells expressing hMOGAT2 were collected by centrifugation, and the cells were resuspended in homogenization buffer (20mM Tris-HCl, pH 7.6, 250mM sucrose, proteinase inhibitor). The cells were lysed using a Dounce homogenizer, and the cell homogenate was centrifuged at 1,000g for 10 minutes. The supernatant was collected, and then centrifuged at 100,000g for 60 minutes using an ultracentrifuge. The supernatant was discarded, and the pellet was resuspended in buffer (20mM Tris-HCl, pH 7.6, 250mM sucrose). The enzyme activity of the prepared MOGAT2-expressing microsomes was tested. The reaction buffer consisted of 100 mM Tris-HCl, pH 7.6, 250 mM sucrose, and 0.01% BSA. The reaction volume was 20 μL. MOGAT2 microsomes, the analyte, and the substrate were added sequentially to a final concentration of 0.01 mg / mL MOGAT2 microsomes, 100 μM lithium oleoyl-CoA, and 200 μM 2-oleoylglycerol. The reaction was carried out at room temperature for 60 minutes, and then terminated with 180 μL of methanol. After centrifugation at 13,000 rpm for 15 minutes, 150 μL of the supernatant was collected and the dioleoylglycerol content was determined by LC-MS / MS. The product concentrations with and without substrate were defined as DAG concentrations. (对照+) / DAG concentration (对照-) The formula for calculating the compound inhibition rate is as follows: Compound inhibition rate = (DAG concentration) / (DAG concentration) (对照+) -DAG concentration (试验化合物) )*100% / (DAG concentration) (对 照+) -DAG concentration (对照-) Based on the inhibition rates of compounds at different concentrations, GraphPad Prism 9.0 software was used to plot concentration-effect curves using a four-parameter fitting equation and to calculate the IC50 of the compounds. 50 The values ​​and experimental results are shown in Table 1.

[0157] Table 1. Inhibitory activity of compounds against MOGAT2

[0158] Where A represents IC 50 ≤100nM; B indicates 100nM < IC 50≤500nM; C indicates 500nM < IC 50 ≤1000nM; D indicates 1000nM < IC 50 ≤5000nM.

[0159] Experiment 2. Inhibition of MOGAT2 activity in cells

[0160] Caco-2 cells lack endogenous monoacylglycerol acyltransferase activity. Therefore, a Caco-2 cell line stably expressing hMOGAT2 (human monoacylglycerol acyltransferase 2) was first established to make it a cell line with monoacylglycerol acyltransferase activity. Then, 2-O-hexadecylglycerol (HDG), an analog of MAG (monoacylglycerol), was added exogenously and packaged into liposomes with DOPC (dioleoyl lecithin) for delivery into the cells. HDG can serve as a substrate for MOGAT2. The product catalyzed by HDG and MOGAT2 is relatively stable and can be distinguished from endogenous DAG. Mass spectrometry detection of the product catalyzed by HDG and MOGAT2 can reflect the cellular MOGAT2 activity.

[0161] In a glass tube, mix 10 mM HDG (2-O-hexadecylglycerol) chloroform solution and 100 mM DOPC chloroform solution at a volume ratio of 1:2. Dry the mixture under nitrogen (N2) and then vacuum dry for 30 minutes. Add buffer (100 mM Tris-Cl pH 7.4, 250 mM sucrose, 1 mM EDTA) to the dried HDG / DOPC mixture to a final HDG concentration of 10 mM. Seed hMOGAT2-Caco2 cells at 40,000 cells per well in a 96-well plate and incubate overnight. Remove the growth medium and pretreat cells for 30 minutes with a DMEM / F12 mixed medium (DMEM and F12 mixed at a 3:1 ratio) containing the corresponding concentration of the test compound and 2% BSA. Then, treat cells for 4 hours with a DMEM / F12 mixed medium containing oleic acid, HDG / DOPC liposomes, the corresponding concentration of the test compound, and 2% BSA (final oleic acid concentration 1200 μM, final HDG concentration 400 μM). Discard the medium, centrifuge at 1000 rpm for 1 min, aspirate the residual liquid, wash with 160 μL of methanol and scrape cells from each well. Repeat the washing of each well with 160 μL of methanol, combine the two methanol solutions, centrifuge at 12000 rpm for 15 min, aspirate the supernatant, and detect the content of HDG products and trioleoylglycerol (TAG) by LC-MS / MS. The inhibition rate of the compound was calculated using the following formula: Inhibition rate = (HDG product / TAG concentration (blank control) - HDG product / TAG concentration (test compound)) * 100% / HDG product / TAG concentration (blank control). Based on the inhibition rates of different compound concentrations, a concentration-effect curve was plotted using a four-parameter fitting equation and the IC50 of the compound was calculated using GraphPad Prism 9.0 software. 50 Values. The experimental results are shown in Table 2. The results indicate that the tested compounds significantly inhibited cell activity.

[0162] Table 2. Inhibition of MOGAT2 activity by compounds in cells.

[0163] Where A represents IC 50 ≤100nM; B indicates 100nM < IC 50 ≤500nM; C indicates 500nM < IC 50 ≤1000nM; D indicates 1000nM < IC 50 ≤5000nM.

[0164] Note: "-" indicates that it has not been tested.

[0165] Experiment 3. Plasma stability test

[0166] Blank plasma samples (from C57 mice, SD rats, and humans, sourced from Shanghai WuXi AppTec Co., Ltd.) were thawed, centrifuged at 3220g for 5 minutes to remove flocculent material, and then the test compound was added. The reaction was initiated by incubation at 37℃ in a water bath, with samples taken at 0, 30, 60, and 120 minutes. 500 μL of stop solution was added to each sample, and the mixture was centrifuged at 3220g for 20 minutes. After centrifugation, 150 μL of the supernatant was collected, and the compound was determined by LC-MS / MS. The remaining amount of the compound was calculated. The experimental results are shown in Table 3. The results indicate that the compound of this invention has good plasma stability.

[0167] Table 3

[0168] Note: "-" indicates that it has not been tested.

[0169] Experiment 4. Liver microsomal stability experiment

[0170] The reaction system was prepared with the following final concentrations: 0.5 mg / mL for CD-1 mice, SD rats, and human liver microsomes (from Kanglong Pharmaceutical (Beijing) New Drug Technology Co., Ltd.); 100 mM phosphate buffer; 5 mM magnesium chloride; 25 μg / mL promethazine; 1 mM NADPH; 2 mM UDPGA; and 1 μM of the analyte. The reaction was started by incubation at 37°C, with 10 μL samples taken at 0, 15, 30, 45, and 60 minutes. All samples were mixed with 120 μL of stop solution and centrifuged at 3220 g for 45 minutes. After centrifugation, 40 μL of the supernatant was collected, diluted with 40 μL of water, and the concentration of the compound was determined by LC-MS / MS. The in vitro Tg was calculated. 1 / 2 Clearance rate CL int The experimental results are shown in Table 4. The results indicate that the compounds of this invention are relatively stable in various liver microsomes.

[0171] Table 4

[0172] Experiment 5. CYP Enzyme Inhibition Assay

[0173] The specific probe substrate for the P450 isoenzyme and human liver microsomes (from Shanghai Runno Biotechnology Co., Ltd.) were preheated at 38°C for 7 minutes. Then, the test compound was added, and the mixture was vortexed at 1000 rpm for 10 seconds. 60 μL of NADPH was added to initiate the reaction, and the mixture was incubated at 38°C and 300 rpm for 10 minutes. After the reaction, 500 μL of stop solution was added to all samples, and the mixture was mixed at 1000 rpm for 90 seconds and centrifuged at 4000 rpm for 15 minutes. After centrifugation, 300 μL of the supernatant was collected, and the concentration of the compound was determined by LC-MS / MS. The inhibition rates of the compound against CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2D6, and CYP3A were calculated.

[0174] The experimental results are shown in Table 5. The results indicate that the compound of the present invention has good CYP properties and no significant inhibitory effect on any CYP isoform.

[0175] Table 5

[0176] Experiment 6. Weight loss experiment using a DIO mouse in vivo pharmacodynamic model

[0177] The weight-loss effect of the compound on obese mice was tested in a high-fat diet-induced obesity (DIO) mouse model. Male SPF-grade DIO mice aged 16–17 weeks were purchased from Shanghai Southern Model Biotechnology Co., Ltd. They were fed a 60 kcal high-fat diet. After one week of acclimatization, the weight of each mouse was measured, and they were grouped according to weight before administration. The solvent was a 0.5% hydroxypropyl methylcellulose (HPMC) + 0.1% Tween-80 aqueous solution. The test compound was dissolved in the solvent, and the dosage volume was calculated at 10 μL / g mouse body weight. Mouse weight was recorded daily during the experiment. The weight reduction in the compound-treated group relative to the solvent control group reflected the weight-loss efficacy of the compound in obese mice. The dosage, administration method, and experimental results are shown in Table 6. The experimental results indicate that the compound of this invention has a significant weight-loss effect.

[0178] Table 6. Weight loss effects of the compounds in the DIO mouse model. Note: "-" indicates that no test drug was given.

[0179] Experiment 7. Corn Oil Absorption Inhibition Experiment

[0180] C57BL / 6 mice under starvation were administered compounds and corn oil orally. The inhibitory effect of the compounds on MGAT2 in mice was evaluated by detecting triglycerides (TG) in the blood. Male C57BL / 6 mice aged 6–8 weeks were purchased from Changzhou Cavens Laboratory Animal Co., Ltd. The solvent was 0.5% hydroxypropyl methylcellulose (HPMC) + 0.1% Tween-80 aqueous solution. The test compound was dissolved in the solvent, and the dosage volume was calculated at 10 μL / g mouse body weight. After one week of acclimatization, C57BL / 6 mice were grouped and starved. The starvation time point was defined as -17h. Mice in each group were administered the compound at -1h. At -0.25h, all mice were injected intravenously with 100 μL of tetrabutylphenol aldehyde solution (prepared with physiological saline, concentration 5%). At 0h, all mice were orally administered 200 μL of corn oil. Blood was collected from mice at 4h, plasma was separated, and TG content was detected using a kit. The reduction in TG in the compound-treated group relative to the solvent control group reflects the inhibitory effect of the compound on MGAT2 in mice. The formula for calculating TG absorption inhibition is (plasma TG in the treated group / plasma TG in the control group) x 100%. The experimental results are shown in Table 7, indicating that the compound of this invention has a good inhibitory effect on corn oil absorption.

[0181] Table 7 Effects of compounds on mouse plasma TG Note: "-" indicates that no test drug was given.

[0182] Experiment 8. Mouse Pharmacokinetic Experiment

[0183] Male C57 mice (6-8 weeks old) (from Medicilon Pharmaceuticals (Shanghai) Co., Ltd.) were administered intravenously (IV) at a dose of 1 mg / kg via tail vein bolus or orally (PO) at a dose of 5 mg / kg via gavage. The compound was prepared in 5% DMSO + 10% Solutol HS15 + 85% physiological saline (IV) or 0.5% MC water containing 0.1% Tween 80 (PO). All animals had free access to food and water during the experiment. Blood samples (n=3) were collected intravenously at 0.083, 0.25, 0.5, 1, 2, 4, 8, and 24 hours after administration and placed in tubes containing EDTA-K2 as an anticoagulant. Blood samples were centrifuged at 6800g, 2-8℃ for 6 minutes. The resulting plasma was analyzed by LC-MS / MS, and p-kJ parameters were analyzed using WinNonlin software. Version 8.5) was calculated using a non-compartmental model analysis method. The experimental results are shown in Table 8, indicating that the compound PK of this invention exhibits good properties.

[0184] Table 8 Note: "-" indicates that it is not applicable.

[0185] Experiment 9. Rat Pharmacokinetic Experiment

[0186] Male SD rats (6-8 weeks old) (from Medicilon Pharmaceuticals (Shanghai) Co., Ltd.) were administered the compound via intravenous injection (IV) at a dose of 1 mg / kg via tail vein bolus or oral administration (PO) at a dose of 10 mg / kg via gavage. The compound was prepared in 5% DMSO + 10% Solutol HS15 + 85% physiological saline (IV) or 0.5% MC water containing 0.1% Tween 80 (PO). All animals had free access to food and water during the experiment. Blood samples (n=3) were collected intravenously at 0.083, 0.25, 0.5, 1, 2, 4, 8, and 24 hours post-administration and placed in tubes containing EDTA-K2 as an anticoagulant. Blood samples were centrifuged at 6800g, 2-8℃ for 6 minutes. The resulting plasma was analyzed by LC-MS / MS, and p-kJ parameters were analyzed using WinNonlin software. Version 8.5) was calculated using a non-compartmental model analysis method. The experimental results are shown in Table 9, indicating that the compound PK of this invention exhibits good properties.

[0187] Table 9 Note: "-" indicates that it is not applicable.

[0188] Experiment 10. Canine Pharmacokinetics Experiment

[0189] Male beagle dogs (Mediasys Pharmaceuticals (Shanghai) Co., Ltd.) were administered intravenously (IV) at a dose of 1 mg / kg via tail vein bolus or orally (PO) at a dose of 5 mg / kg via gavage. The compound was prepared in 5% DMSO + 10% Solutol HS15 + 85% physiological saline (IV) or 0.5% MC water containing 0.1% Tween 80 (PO). All animals had free access to food and water during the experiment. Blood samples (n=2) were collected intravenously at 0.083, 0.25, 0.5, 1, 2, 4, 8, 24, and 48 hours after administration and placed in tubes containing EDTA-K2 as an anticoagulant. Blood samples were centrifuged at 2200g, 2-8℃ for 10 minutes. The resulting plasma was analyzed by LC-MS / MS, and p-pharmaceutical parameters were analyzed using WinNonlin software. Version 8.5) was calculated using a non-compartmental model analysis method. The experimental results are shown in Table 10, indicating that the compound PK of this invention exhibits good properties.

[0190] Table 10 Note: "-" indicates that it is not applicable.

[0191] Experiment 11. Rat Tissue Distribution Experiment

[0192] Male SD rats (6-8 weeks old) (from Suzhou Fangda New Drug Development Co., Ltd.) were administered the compound orally (PO) at a dose of 10 mg / kg via gavage. The compound was prepared in a solvent containing 0.1% Tween 80 in 0.5% MC water (PO). All animals had free access to food and water during the experiment. Euthanasia was performed at 0.25, 1, 4, 6, 8, and 24 hours after administration via carbon dioxide inhalation. Blood was collected via cardiac puncture before sacrifice and placed in tubes containing EDTA-K2 as an anticoagulant. The animals were then dissected, and liver and jejunal tissues were collected (n=3). Blood samples were centrifuged at 3500g, 4℃ for 5 minutes to obtain plasma. Tissue samples were washed with physiological saline, dried with filter paper, and homogenized with 10 times their volume of homogenate to obtain tissue homogenate samples. The obtained plasma and tissue homogenate samples were analyzed by LC-MS / MS. PK parameters were analyzed using WinNonlin software. Version 8.3 was calculated using a non-compartmental model analysis method. The experimental results are shown in Table 11, indicating that the compound of this invention has a high distribution in the jejunum.

[0193] Table 11

[0194] Experiment 12. 3D Hepatotoxicity Detection Experiment of Human Primary Hepatocytes

[0195] Human primary hepatocytes (from Shanghai Hepo Biotechnology Co., Ltd.) were seeded into cell culture plates and incubated at 37°C in a 5% CO2 incubator until the cells grew to form 3D spheroids. When the cell spheroids were sufficiently compact and reached a diameter of approximately 150 μm, the culture medium was replaced with serum-free medium. Drug treatment was then initiated and continued for 2 weeks (with medium changes every 48 hours). On day 14 after drug treatment, cell viability was quantitatively assessed and EC50 was calculated using the CellTiter-Glo luminescence cell viability assay. 20 Value (the test drug concentration corresponding to a cell viability inhibition rate of 20%). The experimental results are shown in Table 12. The experimental results indicate that EVO38094-P1 has a low risk of hepatotoxicity.

[0196] Table 12

Claims

A compound of Formula I or a stereoisomer thereof, a prodrug, a solvate thereof, or a pharmaceutically acceptable salt thereof: in, R1 is selected from H, C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, 5-8 membered heterocycles, C 6-10 aryl or 5-8 membered heteroaryl, wherein C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, 5-8 membered heterocycle, C 6-10 The aryl group and the 5-8 heteroaryl group are optionally substituted by 1 to 3 or fewer substituents: deuterium, halogen, carboxyl, cyano, hydroxyl, amino, C1-C6 alkyl, C1-C6 alkoxy, phenyl; R2 is selected from H, halogen, hydroxyl, carboxyl, cyano, pentafluorothio, C1-C6 alkyl or C1-C6 alkoxy, wherein the C1-C6 alkyl or C1-C6 alkoxy is optionally substituted by 1 to 3 or fewer substituents: deuterium, halogen, carboxyl, cyano, hydroxyl, amino, C1-C6 alkyl, C1-C6 alkoxy, phenyl; R3 is selected from halogens, hydroxyl groups, carboxyl groups, cyano groups, C1-C6 alkyl groups, C1-C6 alkoxy groups, C3-C8 cycloalkyl groups, 5-8 membered heterocycles, and C 6-10 aryl or 5-8 membered heteroaryl, wherein C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, 5-8 membered heterocycle, C 6-10 The aryl group and the 5-8 heteroaryl group are optionally substituted by 1 to 3 or fewer substituents: deuterium, halogen, carboxyl, cyano, hydroxyl, amino, C1-C6 alkyl, C1-C6 alkoxy, phenyl; R4 is selected from H, halogen, hydroxyl, carboxyl, cyano, pentafluorothio, C1-C6 alkyl or C1-C6 alkoxy, wherein the C1-C6 alkyl or C1-C6 alkoxy is optionally substituted by 1 to 3 or fewer substituents: deuterium, halogen, carboxyl, cyano, hydroxyl, amino, C1-C6 alkyl, C1-C6 alkoxy, phenyl; R5 is selected from H, halogen, hydroxyl, carboxyl, cyano, pentafluorothio, C1-C6 alkyl or C1-C6 alkoxy, wherein the C1-C6 alkyl or C1-C6 alkoxy is optionally substituted by 1 to 3 or fewer substituents: deuterium, halogen, carboxyl, cyano, hydroxyl, amino, C1-C6 alkyl, C1-C6 alkoxy, phenyl; R6 is selected from -NHCO-(CH2). m -R9; R7 is selected from H, halogen, hydroxyl, carboxyl, cyano, pentafluorothio, C1-C6 alkyl or C1-C6 alkoxy, wherein the C1-C6 alkyl or C1-C6 alkoxy is optionally substituted by 1 to 3 or fewer substituents: deuterium, halogen, carboxyl, cyano, hydroxyl, amino, C1-C6 alkyl, C1-C6 alkoxy, phenyl; R8 is a C3-C8 cycloalkyl, C1-C6 alkyl, C1-C6 alkoxy, or 5-8 heteroaryl group, wherein the C3-C8 cycloalkyl, C1-C6 alkyl, C1-C6 alkoxy, or 5-8 heteroaryl group is optionally substituted by 1 to 3 or fewer substituents: deuterium, halogen, carboxyl, cyano, hydroxyl, amino, C1-C6 alkyl, C1-C6 alkoxy, or phenyl. R9 is selected from C1-C6 alkylsulfonyl, C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, 5-8 membered heterocycles, C 6-10 aryl or 5-8 membered heteroaryl, wherein C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, 5-8 membered heterocycle, C 6-10 The aryl group and the 5-8 heteroaryl group are optionally substituted by 1 to 3 or fewer substituents: deuterium, halogen, carboxyl, cyano, hydroxyl, amino, C1-C6 alkyl, C1-C6 alkoxy, phenyl; A is -(CH2) n -; Y is selected from O, S, NH or CH2; m is 0, 1, or 2; n can be 0, 1, 2, 3, or 4. According to claim 1, the compound of formula I or its stereoisomers, prodrugs, solvates or pharmaceutically acceptable salts thereof, wherein, The compound represented by Formula I is selected from the compounds represented by Formula II: R1, R2, R3, R4, R5, R6, R7, R8, and A are defined as in claim 1. According to claim 2, the compound of formula I or its stereoisomers, prodrugs, solvates or pharmaceutically acceptable salts thereof, wherein, In the compound represented by Formula II R1 is selected from H, C1-C6 alkyl or C1-C6 alkoxy, wherein the C1-C6 alkyl or C1-C6 alkoxy is optionally substituted by 1 to 3 or fewer substituents: deuterium, halogen, carboxyl, cyano, hydroxyl, amino, C1-C6 alkyl, C1-C6 alkoxy, phenyl; R2 is selected from H, C1-C6 alkyl or C1-C6 alkoxy, wherein the C1-C6 alkyl or C1-C6 alkoxy is optionally substituted by 1 to 3 or fewer substituents: deuterium, halogen, carboxyl, cyano, hydroxyl, amino, C1-C6 alkyl, C1-C6 alkoxy, phenyl; R3 is selected from C1-C6 alkyl or C1-C6 alkoxy, wherein the C1-C6 alkyl or C1-C6 alkoxy is optionally substituted by one to three or fewer substituents: deuterium, halogen, carboxyl, cyano, hydroxyl, amino, C1-C6 alkyl, C1-C6 alkoxy, phenyl; R4 is selected from H, C1-C6 alkyl or C1-C6 alkoxy, wherein the C1-C6 alkyl or C1-C6 alkoxy is optionally substituted by 1 to 3 or fewer substituents: deuterium, halogen, carboxyl, cyano, hydroxyl, amino, C1-C6 alkyl, C1-C6 alkoxy, phenyl; R5 is selected from H, C1-C6 alkyl or C1-C6 alkoxy, wherein the C1-C6 alkyl or C1-C6 alkoxy is optionally substituted by 1 to 3 or fewer substituents: deuterium, halogen, carboxyl, cyano, hydroxyl, amino, C1-C6 alkyl, C1-C6 alkoxy, phenyl; R6 is selected from -NHCO-(CH2). m -R9; R7 is selected from H, C1-C6 alkyl or C1-C6 alkoxy, wherein the C1-C6 alkyl or C1-C6 alkoxy is optionally substituted by 1 to 3 or fewer substituents: deuterium, halogen, carboxyl, cyano, hydroxyl, amino, C1-C6 alkyl, C1-C6 alkoxy, phenyl; R8 is a C3-C8 cycloalkyl, C1-C6 alkyl, C1-C6 alkoxy, or 5-8 heteroaryl group, wherein the C3-C8 cycloalkyl, C1-C6 alkyl, C1-C6 alkoxy, or 5-8 heteroaryl group is optionally substituted by 1 to 3 or fewer substituents: deuterium, halogen, carboxyl, cyano, hydroxyl, amino, C1-C6 alkyl, C1-C6 alkoxy, or phenyl. R9 is selected from C1-C6 alkylsulfonyl groups; A is -(CH2) n -; m is 0, 1, or 2; n can be 0, 1, 2, or 3. According to claim 1, the compound of formula I or its stereoisomers, prodrugs, solvates or pharmaceutically acceptable salts thereof, wherein, The compound represented by Formula I is selected from the compounds represented by Formula III: R1, R2, R3, R4, R5, R7, R8, and A are defined as in claim 1. According to claim 4, the compound of formula I or its stereoisomers, prodrugs, solvates or pharmaceutically acceptable salts thereof, wherein, In the compound represented by Formula III, R1 is selected from H, C1-C6 alkyl or C1-C6 alkoxy, wherein the C1-C6 alkyl or C1-C6 alkoxy is optionally substituted by 1 to 3 or fewer substituents: deuterium, halogen, carboxyl, cyano, hydroxyl, amino, C1-C6 alkyl, C1-C6 alkoxy, phenyl; R2 is selected from H, C1-C6 alkyl or C1-C6 alkoxy, wherein the C1-C6 alkyl or C1-C6 alkoxy is optionally substituted by 1 to 3 or fewer substituents: deuterium, halogen, carboxyl, cyano, hydroxyl, amino, C1-C6 alkyl, C1-C6 alkoxy, phenyl; R3 is selected from C1-C6 alkyl or C1-C6 alkoxy, wherein the C1-C6 alkyl or C1-C6 alkoxy is optionally substituted by one to three or fewer substituents: deuterium, halogen, carboxyl, cyano, hydroxyl, amino, C1-C6 alkyl, C1-C6 alkoxy, phenyl; R4 is selected from H, C1-C6 alkyl or C1-C6 alkoxy, wherein the C1-C6 alkyl or C1-C6 alkoxy is optionally substituted by 1 to 3 or fewer substituents: deuterium, halogen, carboxyl, cyano, hydroxyl, amino, C1-C6 alkyl, C1-C6 alkoxy, phenyl; R5 is selected from H, C1-C6 alkyl or C1-C6 alkoxy, wherein the C1-C6 alkyl or C1-C6 alkoxy is optionally substituted by 1 to 3 or fewer substituents: deuterium, halogen, carboxyl, cyano, hydroxyl, amino, C1-C6 alkyl, C1-C6 alkoxy, phenyl; R7 is selected from H, C1-C6 alkyl or C1-C6 alkoxy, wherein the C1-C6 alkyl or C1-C6 alkoxy is optionally substituted by 1 to 3 or fewer substituents: deuterium, halogen, carboxyl, cyano, hydroxyl, amino, C1-C6 alkyl, C1-C6 alkoxy, phenyl; R8 is a C3-C8 cycloalkyl, C1-C6 alkyl, C1-C6 alkoxy, or 5-8 heteroaryl group, wherein the C3-C8 cycloalkyl, C1-C6 alkyl, C1-C6 alkoxy, or 5-8 heteroaryl group is optionally substituted by 1 to 3 or fewer substituents: deuterium, halogen, carboxyl, cyano, hydroxyl, amino, C1-C6 alkyl, C1-C6 alkoxy, or phenyl. A is -(CH2) n -; n can be 0, 1, 2, or 3. The compound of formula I according to claim 4 or 5, or its stereoisomer, prodrug, solvate, or pharmaceutically acceptable salt thereof, wherein, In the compound represented by Formula III, R1 is selected from H, C1-C6 alkyl or C1-C6 alkoxy, wherein the C1-C6 alkyl or C1-C6 alkoxy is optionally substituted by 1 to 3 or fewer substituents: deuterium, halogen, carboxyl, cyano, hydroxyl, amino, C1-C6 alkyl, C1-C6 alkoxy, phenyl; R2 is selected from H; R3 is selected from C1-C6 alkyl or C1-C6 alkoxy, wherein the C1-C6 alkyl or C1-C6 alkoxy is optionally substituted by one to three or fewer substituents: deuterium, halogen, carboxyl, cyano, hydroxyl, amino, C1-C6 alkyl, C1-C6 alkoxy, phenyl; R4 is selected from H; R5 is selected from H or C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted by 1 to 3 or fewer substituents: deuterium, halogen, carboxyl, cyano, hydroxyl, amino, C1-C6 alkyl, C1-C6 alkoxy, phenyl; R7 is selected from H; R8 is a C3-C8 cycloalkyl, C1-C6 alkyl, C1-C6 alkoxy, or 5-8 heteroaryl group, wherein the C3-C8 cycloalkyl, C1-C6 alkyl, C1-C6 alkoxy, or 5-8 heteroaryl group is optionally substituted by 1 to 3 or fewer substituents: deuterium, halogen, carboxyl, cyano, hydroxyl, amino, C1-C6 alkyl, C1-C6 alkoxy, or phenyl. A is -(CH2) n -; n can be 0, 1, 2, or 3. According to claim 6, the compound of formula I or its stereoisomers, prodrugs, solvates or pharmaceutically acceptable salts thereof, wherein, In the compound represented by Formula III, R1 is selected from H, C1-C6 alkyl or C1-C6 alkoxy, wherein the C1-C6 alkyl or C1-C6 alkoxy is optionally substituted by 1 to 3 or fewer substituents: halogen; R3 is selected from C1-C6 alkoxy groups, wherein the C1-C6 alkoxy groups are optionally substituted by 1 to 3 or fewer substituents: halogen; R5 is selected from H or C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted by 1 to 3 or fewer substituents: halogen; R8 is a C3-C8 cycloalkyl, C1-C6 alkyl, C1-C6 alkoxy, or 5-8 heteroaryl group, wherein the C3-C8 cycloalkyl, C1-C6 alkyl, C1-C6 alkoxy, or 5-8 heteroaryl group is optionally substituted by 1 to 3 or fewer substituents: halogen, methyl. According to claim 7, the compound of formula I or its stereoisomers, prodrugs, solvates or pharmaceutically acceptable salts thereof, wherein, In the compound represented by Formula III, R1 is selected from H, methyl, halomethyl, methoxy or halomethoxy; R3 is selected from (CF3)O-, (CF3)CH2O-, (CF3)CH2CH2O-, (CF3)CH2CH2CH2O-, or (CF3)CH2CH2CH2CH2O-; R5 is selected from H, methyl, or halomethyl; R8 is cyclopropyl, methyl, trifluoromethyl, methoxy, trifluoromethoxy, pyridyl, or 5-methylpyridin-2-yl. According to claim 8, the compound of formula I or its stereoisomers, prodrugs, solvates or pharmaceutically acceptable salts thereof, wherein, In the compound represented by Formula III, R1 is selected from H, methyl, trifluoromethyl, methoxy, or trifluoromethoxy; R3 is selected from (CF3)O-, (CF3)CH2O-, (CF3)CH2CH2O-, (CF3)CH2CH2CH2O-, or (CF3)CH2CH2CH2CH2O-; R5 is selected from H, methyl, or trifluoromethyl; R8 is cyclopropyl. The compound of formula I according to any one of claims 4-9, or a stereoisomer thereof, prodrug, solvate thereof, or a pharmaceutically acceptable salt thereof, wherein, The compound represented by Formula III is selected from the compounds represented by Formula III-1 or Formula III-2: According to claim 1, the compound of formula I or its stereoisomers, prodrugs, solvates or pharmaceutically acceptable salts thereof, wherein, The compound represented by Formula I is selected from the compounds represented by Formula IV: R1, R3, R5, R8, and A are as defined in claim 1. According to claim 11, the compound of formula I or its stereoisomers, prodrugs, solvates or pharmaceutically acceptable salts thereof, wherein, In the compound represented by Formula IV, R1 is selected from H, C1-C6 alkyl or C1-C6 alkoxy, wherein the C1-C6 alkyl or C1-C6 alkoxy is optionally substituted by 1 to 3 or fewer substituents: deuterium, halogen, carboxyl, cyano, hydroxyl, amino, C1-C6 alkyl, C1-C6 alkoxy, phenyl; R3 is selected from C1-C6 alkyl or C1-C6 alkoxy, wherein the C1-C6 alkyl or C1-C6 alkoxy is optionally substituted by one to three or fewer substituents: deuterium, halogen, carboxyl, cyano, hydroxyl, amino, C1-C6 alkyl, C1-C6 alkoxy, phenyl; R5 is selected from H or C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted by 1 to 3 or fewer substituents: deuterium, halogen, carboxyl, cyano, hydroxyl, amino, C1-C6 alkyl, C1-C6 alkoxy, phenyl; R8 is a C3-C8 cycloalkyl, C1-C6 alkyl, C1-C6 alkoxy, or 5-8 heteroaryl group, wherein the C3-C8 cycloalkyl, C1-C6 alkyl, C1-C6 alkoxy, or 5-8 heteroaryl group is optionally substituted by 1 to 3 or fewer substituents: deuterium, halogen, carboxyl, cyano, hydroxyl, amino, C1-C6 alkyl, C1-C6 alkoxy, or phenyl. A is -(CH2) n -; n can be 0, 1, 2, or 3. According to claim 12, the compound of formula I or its stereoisomers, prodrugs, solvates or pharmaceutically acceptable salts thereof, wherein, In the compound represented by Formula IV, R1 is selected from H, C1-C6 alkyl or C1-C6 alkoxy, wherein the C1-C6 alkyl or C1-C6 alkoxy is optionally substituted by 1 to 3 or fewer substituents: halogen; R3 is selected from C1-C6 alkoxy groups, wherein the C1-C6 alkoxy groups are optionally substituted by 1 to 3 or fewer substituents: halogen; R5 is selected from H or C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted by 1 to 3 or fewer substituents: halogen; R8 is a C3-C8 cycloalkyl, C1-C6 alkyl, C1-C6 alkoxy, or 5-8 heteroaryl group, wherein the C3-C8 cycloalkyl, C1-C6 alkyl, C1-C6 alkoxy, or 5-8 heteroaryl group is optionally substituted by 1 to 3 or fewer substituents: halogen, methyl. According to claim 13, the compound of formula I or its stereoisomers, prodrugs, solvates or pharmaceutically acceptable salts thereof, wherein, In the compound represented by Formula III, R1 is selected from H, methyl, halomethyl, methoxy or halomethoxy; R3 is selected from (CF3)O-, (CF3)CH2O-, (CF3)CH2CH2O-, (CF3)CH2CH2CH2O-, or (CF3)CH2CH2CH2CH2O-; R5 is selected from H, methyl, or halomethyl; R8 is cyclopropyl, methyl, trifluoromethyl, methoxy, trifluoromethoxy, pyridyl, or 5-methylpyridin-2-yl. According to claim 14, the compound of formula I or its stereoisomers, prodrugs, solvates or pharmaceutically acceptable salts thereof, wherein, In the compound represented by Formula III, R1 is selected from H, methyl, trifluoromethyl, methoxy, or trifluoromethoxy; R3 is selected from (CF3)O-, (CF3)CH2O-, (CF3)CH2CH2O-, (CF3)CH2CH2CH2O-, or (CF3)CH2CH2CH2CH2O-; R5 is selected from H, methyl, or trifluoromethyl; R8 is cyclopropyl. The compound of formula I according to any one of claims 11-15, or a stereoisomer thereof, prodrug, solvate thereof, or a pharmaceutically acceptable salt thereof, wherein, The compound represented by Formula IV is selected from the compounds represented by Formula IV-1 or Formula IV-2: The compound of formula I according to any one of claims 1-16, or a stereoisomer thereof, prodrug, solvate thereof, or a pharmaceutically acceptable salt thereof, wherein, The compound represented by Formula I is selected from the following compounds: A pharmaceutical composition comprising a compound of formula I according to any one of claims 1-17 or a stereoisomer thereof, a prodrug, a solvate or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. Use of the compound of Formula I according to any one of claims 1-17, its stereoisomer, prodrug, solvate, or pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 18, in the preparation of an MGAT2 inhibitor medicament. The use according to claim 19, wherein, The MGAT2 inhibitor is a drug for the treatment and / or prevention of obesity, metabolic syndrome, hyperlipidemia, hypertriglyceridemia, hyperVLDLemia, hyperfatty acidemia, diabetes, or arteriosclerosis.

Images