Spiro compound containing alkynyl group and use thereof

Abstract

Provided is a compound as shown in formula I, wherein R1, R2, R3, R4, R5, R6, R8, X, Y, a ring A, and n are as defined in the description. The compound as shown in formula (I) can effectively inhibit the enzymatic activity of MOGAT2, has good metabolic properties, and has clinical application prospects.

Description

Spirane compounds containing alkynyl groups and uses thereof TECHNICAL FIELD

[0001] The present invention relates to the field of medicine, in particular to spirane compounds containing alkynyl groups and uses thereof. BACKGROUND

[0002] Obesity has become a major challenge to global public health due to its widespread prevalence in the population. Based on the pursuit of health and beauty, weight loss has become a huge unmet demand. Excessive intake of fat caused by high-fat diet is an important reason for obesity. Triglyceride is one of the main forms of energy storage in animals and the main component of fat in food we intake. After eating, triglyceride in food is digested by lipase in the intestinal tract to produce free fatty acids and monoacylglycerol, which are then absorbed by intestinal epithelial cells. The absorbed free fatty acids and monoacylglycerol are regenerated into triglyceride under the catalysis of monoacylglycerol acyltransferase and diacylglycerol acyltransferase on the endoplasmic reticulum membrane. The newly generated triglyceride, apolipoprotein and other lipids are packaged into chylomicrons in the endoplasmic reticulum, and then the chylomicrons are secreted into the blood to be used 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 the uptake of dietary triglycerides into the blood is a promising strategy for the treatment of obesity. Monoacylglycerol acyltransferase 2 (MOGAT2) is a key enzyme in the re-synthesis of triglycerides in the small intestine. MOGAT2 knockout mice exhibit a series of beneficial metabolic phenotypes, including reduced body weight, reduced triglyceride absorption from the small intestine into the blood, reduced liver triglyceride levels, and increased energy expenditure. Therefore, MOGAT2 is a potential target for the treatment of obesity. Inhibitors of MOGAT2 have been reported to 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 2-1 in Example 2 of patent WO2013082345 discloses a compound (BMS-963272) with MGAT2 inhibitory activity, the structure of which is as follows, and the compound has completed clinical phase 1 experiment. Example 14 in patent WO2019013311 discloses a compound II-203 (S-309309) with MGAT2 inhibitory activity, the structure of which is as follows, and the compound has currently completed clinical phase 2 experiment, but the clinical phase 2 efficacy of the drug treatment is not significant, and currently it does not enter clinical phase 3.

[0004] There is still an urgent need in the art for the development and research of compounds with MGAT2 inhibitory activity and significant clinical efficacy. SUMMARY

[0005] In view of the problem of the prior art compound with insignificant clinical efficacy, the purpose of the present application is to provide a spiro compound containing an alkynyl group, which can effectively inhibit the activity of MOGAT2 enzyme and has good metabolic properties, and has excellent performance in effectiveness, safety and stability and the like.

[0006] The purpose of the present application is achieved by the following technical solutions.

[0007] A compound shown in formula I or a stereoisomer, a prodrug, a solvate or a pharmaceutically acceptable salt thereof:

[0008] wherein,

[0009] R1 is selected from H, halogen, hydroxyl, carboxyl, cyano, pentafluorothio group, C1-C6 alkyl or C1-C6 alkoxy, wherein C1-C6 alkyl, C1-C6 alkoxy is optionally substituted with 1 to 3 of the following substituents: deuterium, halogen, carboxyl, cyano, hydroxyl, amino, C1-C6 alkyl, C1-C6 alkoxy, phenyl;

[0010] R2 is selected from halogen, hydroxyl, carboxyl, cyano, C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, 5-8 membered heterocyclic ring, C6-10 aryl or C6-10 heteroaryl, wherein C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, 5-8 membered heterocyclic ring, C6-10 aryl, C6-10 heteroaryl is optionally substituted with 1 to 3 of the following substituents: deuterium, halogen, carboxyl, cyano, hydroxyl, amino, C1-C6 alkyl, C1-C6 alkoxy, phenyl;

[0011] R3is selected from H, halogen, hydroxyl, carboxyl, cyano, pentafluorosulfanyl, C1-C6alkyl, or C1-C6alkoxy, wherein C1-C6alkyl, C1-C6alkoxy are optionally substituted with one to three of deuterium, halogen, carboxyl, cyano, hydroxyl, amino, C1-C6alkyl, C1-C6alkoxy, phenyl;

[0012] R4is selected from H, halogen, hydroxyl, carboxyl, cyano, pentafluorosulfanyl, C1-C6alkyl, or C1-C6alkoxy, wherein C1-C6alkyl, C1-C6alkoxy are optionally substituted with one to three of deuterium, halogen, carboxyl, cyano, hydroxyl, amino, C1-C6alkyl, C1-C6alkoxy, phenyl;

[0013] R5is selected from H, halogen, hydroxyl, carboxyl, cyano, C1-C6alkyl, C1-C6alkoxy, C3-C8cycloalkyl, 4-8 membered heterocyclyl, C6-10 aryl, or C6-10 heteroaryl, wherein C1-C6alkyl, C1-C6alkoxy, C3-C8cycloalkyl, 4-8 membered heterocyclyl, C6-10 aryl, C6-10 heteroaryl are optionally substituted with one to three of deuterium, halogen, carboxyl, cyano, hydroxyl, amino, C1-C6alkyl, C1-C6alkoxy, phenyl;

[0014] R6is selected from; -NHCO-(CH2)m-R7;

[0015] wherein R7is selected from C1-C6alkylsulfonyl, C1-C6alkyl, C1-C6alkoxy, C3-C8cycloalkyl, 5-8 membered heterocycle, C6-10 aryl, or C6-10 heteroaryl, wherein C1-C6alkyl, C1-C6alkoxy, C3-C8cycloalkyl, 5-8 membered heterocycle, C6-10 aryl, C6-10 heteroaryl are optionally substituted with one to three of deuterium, halogen, carboxyl, cyano, hydroxyl, amino, C1-C6alkyl, C1-C6alkoxy, phenyl;

[0016] R8is selected from H;

[0017] X is selected from O, S, or NH;

[0018] Y is selected from O, S, NH, or CH2;

[0019] A ring is selected from a 5-6 membered heteroaromatic ring containing one or two heteroatoms, or a saturated or unsaturated 4-6 membered heterocyclic ring containing one or two heteroatoms;

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

[0021] m is 0, 1, or 2.

[0022] In some embodiments, the A ring is a 5-6 membered heteroaromatic ring containing one or two heteroatoms selected from: pyrazole, imidazole, pyrrole, furan, thiophene, thiazole, oxazole, pyridine, pyrimidine, or pyrazine, preferably pyrazole.

[0023] In some embodiments, the A ring is a saturated or partially unsaturated 4-6 membered heterocyclic ring containing one or two heteroatoms selected from: oxetane, tetrahydrofuran, piperidine, piperazine, or pyran.

[0024] In some embodiments, the compound of formula I of the present application is selected from the following compounds of formula II:

[0025] wherein R1, R2, R3, R4, R5, R6, R7, R8, m, n are as defined above.

[0026] In some embodiments, in the compound of formula II of the present application,

[0027] R1is selected from H, hydroxyl, pentafluorosulfanyl, C1-C6alkyl, or C1-C6alkoxy, wherein C1-C6alkyl, C1-C6alkoxy is optionally substituted with one to three of deuterium, halogen, carboxyl, cyano, hydroxyl, amino, C1-C6alkyl, C1-C6alkoxy, phenyl;

[0028] R2is selected from halogen, hydroxyl, C1-C6alkyl, or C1-C6alkoxy, wherein C1-C6alkyl, C1-C6alkoxy is optionally substituted with one to three of deuterium, halogen, carboxyl, cyano, hydroxyl, amino, C1-C6alkyl, C1-C6alkoxy, phenyl;

[0029] R3is selected from H, hydroxyl, pentafluorosulfanyl, C1-C6alkyl, or C1-C6alkoxy, wherein C1-C6alkyl, C1-C6alkoxy is optionally substituted with one to three of deuterium, halogen, carboxyl, cyano, hydroxyl, amino, C1-C6alkyl, C1-C6alkoxy, phenyl;

[0030] R4is selected from H, halogen, hydroxyl, pentafluorosulfanyl, C1-C6alkyl, or C1-C6alkoxy, wherein C1-C6alkyl, C1-C6alkoxy is optionally substituted with one to three of deuterium, halogen, carboxyl, cyano, hydroxyl, amino, C1-C6alkyl, C1-C6alkoxy, phenyl;

[0031] R5is selected from H, hydroxyl, C1-C6alkyl, C3-C6cycloalkyl, 4-6 membered heterocyclyl, or C6-8aryl, wherein C1-C6alkyl, C3-C6cycloalkyl, 4-6 membered heterocyclyl, C6-8aryl are optionally substituted with 1 to 3 of deuterium, halogen, carboxyl, cyano, hydroxyl, amino, C1-C6alkyl, C1-C6alkoxyl, phenyl;

[0032] R6is selected from; -NHCO-(CH2)m-R7;

[0033] wherein R7is selected from C1-C6alkylsulfonyl or C1-C6alkyl, wherein C1-C6alkyl is optionally substituted with 1 to 3 of deuterium, halogen, carboxyl, cyano, hydroxyl, amino, C1-C6alkyl, C1-C6alkoxyl, phenyl;

[0034] R8is selected from H;

[0035] X is selected from O or S;

[0036] Y is selected from O, S or NH;

[0037] n is 0, 1 or 2;

[0038] m is 1 or 2.

[0039] In some embodiments, the compound of Formula I of the present application is selected from the following compounds of Formula III:

[0040] wherein,

[0041] R2is selected from halogen or C1-C6alkoxyl, wherein C1-C6alkoxyl is optionally substituted with 1 to 3 of deuterium, halogen;

[0042] R4is selected from H or halogen;

[0043] R5is selected from H, C1-C4alkyl, C3-C6cycloalkyl, 4-6 membered heterocyclyl, or phenyl, wherein C1-C4alkyl, C3-C6cycloalkyl, 4-6 membered heterocyclyl, phenyl are optionally substituted with 1 to 3 of deuterium, halogen, hydroxyl.

[0044] In some embodiments, the compound of Formula III of the present application is selected from the following compounds of Formula III-1 or Formula III-2:

[0045] wherein, R2, R4and R5are defined as in the compounds of Formula III above.

[0046] In some embodiments, in the compound of Formula III of the present application,

[0047] R2is selected from halogen or ethoxy, wherein ethoxy is optionally substituted with 1 to 3 of deuterium, halogen;

[0048] R4is selected from H or halogen;

[0049] R5is selected from H, methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, i-butyl, cyclopropyl, cyclobutyl, cyclopentyl, phenyl or oxetanyl, wherein methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, i-butyl, cyclopropyl, cyclobutyl, cyclopentyl, phenyl, oxetanyl is optionally substituted with 1 to 3 of deuterium, halogen, hydroxyl.

[0050] In some embodiments, in the compound of Formula III of the present application,

[0051] R2is F or -OCH2CF3;

[0052] R4is H or F.

[0053] In some embodiments, the compound of Formula I of the present application is selected from the following compounds:

[0054] The present application also provides a pharmaceutical composition comprising a compound of Formula I as described above, or a stereoisomer, a prodrug, a solvate thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0055] The present application also provides use of a compound of Formula I as described above, or a stereoisomer, a prodrug, a solvate thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the foregoing, in the manufacture of an MGAT2 inhibitor medicament.

[0056] In some embodiments, the MGAT2 inhibitor medicament is a medicament for treating and / or preventing obesity, metabolic syndrome, hyperlipidemia, hypertriglyceridemia, high VLDL, high fatty acid, diabetes, or arteriosclerosis.

[0057] The present application also provides a method for treating and / or preventing an MGAT2-mediated related disease, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I as described above, or a stereoisomer, a prodrug, a solvate thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the foregoing.

[0058] In some embodiments, the MGAT2-mediated related disease is selected from obesity, metabolic syndrome, hyperlipidemia, hypertriglyceridemia, high VLDL, high fatty acid, diabetes, or arteriosclerosis.

[0059] The present application also provides a compound as illustrated in Formula I above, or a stereoisomer, a prodrug, a solvate, or a pharmaceutically acceptable salt thereof, for use as a medicament.

[0060] The present application also provides a compound as illustrated in Formula I above, or a stereoisomer, a prodrug, a solvate, or a pharmaceutically acceptable salt thereof, for use in the treatment and / or prevention of a MGAT2-mediated related disease. The MGAT2-mediated related disease is as defined above.

[0061] Definitions and general terms:

[0062] The following terms and the like are used to describe the present application. It should be understood that terms not specifically defined herein are given the meaning commonly understood by those of ordinary skill in the art to which the present application pertains.

[0063] The term "alkyl" as used herein refers to saturated aliphatic hydrocarbon groups, including straight chain and branched chain hydrocarbons. For example, C1-C6alkyl. "C1-C6alkyl" refers to alkyl groups having from 1 to 6 carbon atoms, for example, alkyl groups having 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, 6 carbon atoms, including but not limited to methyl, ethyl, propyl (e.g., n-propyl, i-propyl), butyl (e.g., n-butyl, i-butyl, t-butyl), pentyl (e.g., n-pentyl, i-pentyl, neopentyl), hexyl (e.g., n-hexyl), and the like. The alkyl group can be optionally further substituted with one or more substituents.

[0064] The term "halogen" as used herein refers to fluorine, chlorine, bromine, or iodine; preferably fluorine, chlorine.

[0065] The term "C3-C8cycloalkyl" as used herein refers to cycloalkyl groups having from 3 to 8 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl; preferably cyclopropyl. The cycloalkyl group can be optionally further substituted with one or more substituents.

[0066] The term "C1-C6alkoxy" as used herein refers to a group formed by a C1-C6alkyl group linked to an oxygen atom, i.e., a "C1-C6alkyl-O-" group, wherein the C1-C6alkyl group is as defined above. This includes but is not limited to methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, sec-butoxy, t-butoxy; preferably methoxy, ethoxy. The alkoxy group can be optionally further substituted with one or more substituents.

[0067] "Heterocyclo" or "heterocyclyl" refers to a substituted or unsubstituted saturated or partially unsaturated nonaromatic ring group, which can be a 3 to 8 membered (e.g., 3, 4, 5, 6, 7, 8 membered) monocyclic, 6 to 12 membered (e.g., 6, 7, 8, 9, 10, 11, 12 membered) bicyclic, or 10 to 15 membered (e.g., 10, 11, 12, 13, 14, 15 membered) tricyclic ring system, and contains 1, 2, or 3 heteroatoms selected from N, O, or S, preferably 3 to 8 membered heterocyclyl. "Heterocyclyl" can be attached at a heteroatom or carbon atom; "heterocyclyl" can be bridged or spirocyclic. Non-limiting examples of "heterocyclyl" include oxiranyl, aziridinyl, oxetanyl, azetidinyl, 1,3-dioxolanyl, 1,4-dioxolanyl, 1,3-dioxananyl, azepanyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, pyranyl, 1,3-dithianyl, tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyranyl, azabicyclo[3.2.1]octanyl, azabicyclo[5.2.0]nonanyl, oxatricyclo[5.3.1.1]dodecanyl, azadamantyl, and oxaspiro[3.3]heptanyl, and the like. The heterocyclyl group can be optionally further substituted with one or more substituents.

[0068] "Arylo" or "aryl" refers to a substituted or unsubstituted aromatic ring, which can be a 6 to 8 membered monocyclic (e.g., 6, 7, 8 membered), 6 to 12 membered (e.g., 6, 7, 8, 9, 10, 11, 12 membered) bicyclic, or 10 to 15 membered (e.g., 10, 11, 12, 13, 14, 15 membered) tricyclic ring system, which can be bridged or spirocyclic, non-limiting examples of which include phenyl, naphthyl, and the like. The aryl ring can be optionally further substituted with one or more substituents.

[0069] "Heteroarylo" or "heteroaryl" refers to an aromatic ring having a conjugated planar ring system and containing heteroatoms, which can be a 5 to 8 membered (e.g., 5, 6, 7, 8 membered) monocyclic, 8 to 12 membered (e.g., 8, 9, 10, 11, 12 membered) bicyclic, or 10 to 15 membered (e.g., 10, 11, 12, 13, 14, 15 membered) tricyclic ring system, and contains 1 to 6 (e.g., 1, 2, 3, 4, 5, 6) heteroatoms selected from N, O, or S, for example, 5-8 membered nitrogen-containing heteroaryl ring, 5-8 membered oxygen-containing heteroaryl ring, 5-8 membered sulfur-containing heteroaryl ring. Non-limiting examples of heteroaryl include oxazolyl, triazolyl, pyridyl, furanyl, thienyl, pyrrolyl, pyrazolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, benzimidazolyl, benzopyridyl, pyrrolopyridyl, and the like. The heteroaryl ring can be optionally further substituted with one or more substituents.

[0070] The term "pharmaceutically acceptable salt" as used herein refers to a salt of a compound of the present application, prepared from a compound of the present application having a particular substituent with a pharmaceutically acceptable acid or base.

[0071] The term "stereoisomers" as used herein refers to compounds which have identical chemical constitution, but differ with regard to the arrangement of the atoms and groups in space. These include enantiomers, diastereomers, geometric isomers, atropisomers or conformers.

[0072] "Solvate" as used herein describes a molecular complex comprising a compound of any of the above formulae or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable solvent molecules (e.g. ethanol).

[0073] "Prodrug" as used herein also known as a precursor drug, drug precursor or drug pioneer, refers to a compound which is chemically modified to be inactive or less active in vitro, but is converted by enzymatic or non-enzymatic transformation in vivo to release the active drug to exert its pharmacological effect.

[0074] The compounds of the present application can also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds can be radiolabeled with radioactive isotopes, such as deuterium ( 3 H), iodine-125 ( 125 I) or carbon-14 ( 14 C). All isotopic variations of the compounds of the present application, whether radioactive or not, are encompassed within the scope of the present application. Beneficial effects

[0075] The compounds of the present application can effectively inhibit the activity of MOGAT2 enzyme, and have good metabolic properties, and have excellent performance in effectiveness, safety and stability. Specifically, according to the experimental results of the present application, the compounds of the present application have excellent inhibitory activity on MOGAT2, the inhibition of MOGAT2 activity in cells is obvious, the plasma stability is good, the stability in liver microsomes is good, the PPB result is good and there is a high proportion of free compounds to exert the pharmacological effect, the CYP properties are good and there is no inhibition on each CYP subtype, the permeability is low and the efflux rate is large, which is beneficial to the enrichment of the compound in the intestinal tract, the weight loss effect is obvious, the oil absorption inhibition effect is good, the PK properties are good and the bioavailability and apparent volume of distribution are good, the distribution in the jejunum is high and the distribution in the liver is relatively low. Therefore, the compounds of the present application have clinical application prospects. DETAILED DESCRIPTION

[0076] The structure of the compounds is determined by nuclear magnetic resonance (NMR) or / and mass spectrometry (MS).

[0077] NMR test instrument and conditions:

[0078] NMR was measured by Bruker Avance III 400 nuclear magnetic instrument, the solvent was deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and the internal standard was tetramethylsilane (TMS).

[0079] MS testing instrument and conditions:

[0080] MS was measured by (Waters Arc+QDA (ESI) and (Waters H-Class+SQD2 (ESI).

[0081] The chemical reagents used are commercially available chemical pure or analytical pure products, which are generally used directly without purification treatment.

[0082] In the examples, the solution refers to an aqueous solution unless otherwise specified.

[0083] In the examples, room temperature refers to 20-30°C unless otherwise specified.

[0084] The preferred embodiments of the present application will be described in more detail below. Although the preferred embodiments of the present application are described below, it should be understood that they should not be limited by the embodiments set forth herein. The described examples are only a part of the embodiments of the present application, not all. All other embodiments obtained by those skilled in the art based on the examples in the present application are within the scope of protection of the present application.

[0085] Examples

[0086] Example 1 EVO38054

[0087] Step 1:

[0088] EVO38054-A0 (1.2 g, 5.45 mmol, refer to patent WO2016126935 synthesis) and cyclopropyl acetylene (1.8 g, 27.27 mmol) were dissolved in anhydrous 1,4-dioxane (6 mL), and triethylamine (1.66 g, 16.36 mmol), CuI (103.87 mg, 0.54 mmol) and Pd(dppf)Cl2 (400 mg, 0.54 mmol) were added in turn, and the reaction was stirred in an oil bath at 80°C for 3 hours. Liquid chromatography-mass spectrometry showed that the ratio of raw material to product was 4:1. The reaction liquid was extracted with water (20 mL) and ethyl acetate (10 mL), and the aqueous phase was extracted with ethyl acetate (10 mL*2), and the organic phase was washed with saturated sodium chloride solution (*2), dried and rotary evaporated, and then purified by flash silica gel column chromatography (PE:EA=3:1) to obtain yellow solid EVO38054-A1 (250 mg, yield: 22.3%).

[0089] Step 2:

[0090] EVO38054-A1 (50 mg, 0.24 mmol) and EVO38028-A1 (92 mg, 0.24 mmol, refer to patent WO2019122129 for synthesis) were added to anhydrous DMF (6 mL), potassium carbonate (50 mg, 0.36 mmol) was added, and the reaction was heated to 100 °C for 5 hours. The disappearance of the raw material was monitored by liquid chromatography-mass spectrometry, the reaction liquid was poured into water (20 mL), extracted with ethyl acetate (10 mL*3), the organic phase was combined and washed with saturated sodium chloride solution (*2), dried and rotary evaporated, and purified by flash silica gel column chromatography (PE:EA = 2:1) to obtain colorless oil EVO38054-A2 (80 mg, yield: 65.3%).

[0091] Step 3:

[0092] EVO38054-A2 (80 mg, 0.16 mmol) was dissolved in hydrochloric acid dioxane solution (6 mL) at room temperature and stirred for 2 hours. The disappearance of the raw material was monitored by liquid chromatography-mass spectrometry, and the reaction liquid was directly concentrated to obtain yellow oil EVO38054-A3 (64 mg, yield: 100%).

[0093] Step 4:

[0094] EVO38054-A3 (64 mg, 0.16 mmol) was dissolved in anhydrous ethanol (6 mL), sodium ethoxide solution (5 M, 1.2 mL) was added, and the reaction was carried out at 100 °C for 2 hours. The disappearance of the raw material was monitored by liquid chromatography-mass spectrometry, the reaction liquid was adjusted to neutral pH with 4N dilute hydrochloric acid solution, extracted with ethyl acetate (10 mL*3), the organic phase was combined and washed with saturated sodium chloride solution (*2), dried and rotary evaporated, and purified by flash silica gel column chromatography (PE:EA = 1:1) to obtain brown oil EVO38054-A4 (15 mg, yield: 25.5%).

[0095] Step 5:

[0096] EVO38054-A4 (15 mg, 0.04 mmol) and 2-(methylsulfonyl)acetic acid (12 mg, 0.08 mmol) were dissolved in anhydrous tetrahydrofuran (4 mL) at room temperature, HATU (30.8 mg, 0.08 mmol) and triethylamine (16.4 mg, 0.16 mmol) were added, and the reaction was allowed to proceed for 4 hours. The disappearance of the starting material was monitored by LCMS, the reaction solution was partitioned with water (10 mL) and ethyl acetate (10 mL), the aqueous phase was extracted with ethyl acetate (10 mL*2), the organic phase was combined and washed with saturated sodium chloride solution (*2), dried, and the solvent was removed by rotary evaporation, then high performance liquid chromatography preparation (column: YMC Triart C18 12nm 10um, 30*250mm; mobile phase A: 10 mM NH4HCO3 solution, mobile phase B: ACN; flow rate: 40 mL / min; gradient: 30% B to 80% B in 30 min; wavelength: 200-400 nm) was performed, and then freeze-drying was performed to obtain white solid EVO38054 (2 mg, yield: 10.0%), LCMS (ESI) m / z = 491.22 [M+H] + , Rt = 2.978 min, HPLC purity: 99.94%, 1 H NMR (400 MHz, CDCl3) δ 8.42 (s, 1H), 6.58-6.47 (m, 2H), 6.07 (s, 1H), 4.82 (d, J = 13.4 Hz, 1H), 4.32 (d, J = 13.4 Hz, 1H), 4.24-4.14 (m, 2H), 4.11 (s, 2H), 3.23 (s, 3H), 2.22 (t, J = 5.4 Hz, 2H), 1.50-1.42 (m, 1H), 0.93-0.83 (m, 4H).

[0097] Example 2 EVO38023

[0098] Referring to the preparation method of compound EVO38054 of Example 1, high performance liquid chromatography preparation column separation (column: YMC-Actus Triart C18 ExRS 8nm S-5um, 30*250mm; mobile phase A: 0.1% aqueous ammonia solution, mobile phase B: ACN; flow rate: 40 mL / min; gradient: 35% B to 80% B in 15 min; wavelength: 200-400 nm) was performed, and then freeze-drying was performed to obtain white solid EVO38023 (7 mg, yield: 24%), LCMS (ESI) m / z = 553.39 [M+H] + , HPLC purity: 98.2%, 1H NMR (400 MHz, CDC13) δ 8.70 (s, 1H), 7.37 (d, J = 8.8 Hz, 1H), 6.63 (dd, J = 8.8, 2.6 Hz, 1H), 6.45 (d, J = 2.5 Hz, 1H), 6.33 (s, 1H), 4.44 - 4.16 (m, 8H), 3.21 (s, 3H), 2.21 - 2.13 (m, 2H), 1.49 - 1.42 (m, 1H), 0.98 - 0.73 (m, 4H).

[0099] Example 3 EVO38023-R

[0100] Referring to the preparation method of compound EVO38054 in Example 1, a high performance liquid preparation column was separated (column: YMC-Actus Triart C18 ExRS 8nm S-5um, 30*250mm; mobile phase A: 10mM NH4HC03solution, mobile phase B: ACN; flow rate: 30mL / min; gradient: 40% B to 75% B in 20min; wavelength: 200-400nm), and then freeze-dried to obtain white solid EVO38023-R (30mg, yield: 32.7%), LCMS (ESI) m / z = 553.37 [M+H] + , HPLC purity: 98.0%, 1 H NMR (400 MHz, CDC13) δ 8.70 (s, 1H), 7.37 (d, J = 8.8 Hz, 1H), 6.63 (dd, J = 8.8, 2.6 Hz, 1H), 6.45 (d, J = 2.5 Hz, 1H), 6.33 (s, 1H), 4.44 - 4.16 (m, 8H), 3.21 (s, 3H), 2.21 - 2.13 (m, 2H), 1.49 - 1.42 (m, 1H), 0.98 - 0.73 (m, 4H).

[0101] Example 4 EVO38023-D

[0102] Following the procedure for the preparation of compound EVO38054 of Example 1, preparative high performance liquid chromatography (column: YMC-Actus Triart C18 12 nm S-5 um, 30*250 mm; mobile phase A: 10 mM NH4HC03solution, mobile phase B: ACN; flow rate: 40 mL / min; gradient: 30% B to 80% B in 25 min; wavelength: 200-400 nm) separation and lyophilization afforded EVO38023-D as a white solid (1.5 mg, yield: 11.1%), LCMS (ESI) m / z = 554.43 [M+H] + HPLC purity: 97.9%, 1 H NMR (400 MHz, CDC13) δ 8.49 (s, 1H), 7.38 (d, J = 8.8 Hz, 1H), 6.65-6.62 (m, 1H), 6.45 (d, J = 2.6 Hz, 1H), 6.06 (s, 1H), 4.48-4.13 (m, 8H), 3.23 (s, 3H), 2.20-2.17 (m, 2H), 0.88-0.85 (m, 4H).

[0103] Example 5 EVO38023-RD

[0104] Following the procedure for the preparation of compound EVO38054 of Example 1, preparative high performance liquid chromatography (column: YMC-Actus Triart C18 12 nm S-5 um, 30*250 mm; mobile phase A: 10 mM NH4HC03solution, mobile phase B: ACN; flow rate: 40 mL / min; gradient: 30% B to 80% B in 25 min; wavelength: 200-400 nm) separation and lyophilization afforded EVO38023-RD as a white solid (6 mg, yield: 22.2%), LCMS (ESI) m / z = 554.39 [M+H] + HPLC purity: 98.1%, 1 H NMR (400 MHz, CDC13) δ 8.49 (s, 1H), 7.38 (d, J = 8.8 Hz, 1H), 6.65-6.62 (m, 1H), 6.45 (d, J = 2.6 Hz, 1H), 6.06 (s, 1H), 4.48-4.13 (m, 8H), 3.23 (s, 3H), 2.20-2.17 (m, 2H), 0.88-0.85 (m, 4H).

[0105] Example 6 EVO38025

[0106] Following the procedure for the preparation of compound EVO38054 of Example 1, preparative high performance liquid chromatography (column: YMC-Actus Triart C18 ExRS 8 nm S-5 um, 30*250 mm; mobile phase A: 10 mM NH4HC03solution, mobile phase B: ACN; flow rate: 30 mL / min; gradient: 5% B to 35% B in 30 min; wavelength: 200-400 nm) separation and lyophilization afforded EVO38025 as a white solid (12 mg, yield: 45.63%), LCMS (ESI) m / z = 513.05 [M+H] + HPLC purity: 99.6%, 1 H NMR (400 MHz, CDC13) δ 8.80 (s, 1H), 7.38 (d, J = 8.8 Hz, 1H), 6.65 (dd, J = 8.8, 2.7 Hz, 1H), 6.46 (d, J = 2.7 Hz, 1H), 6.23 (s, 1H), 4.47 (d, J = 2.6 Hz, 2H), 4.39 - 4.10 (m, 6H), 3.37 (s, 1H), 3.20 (s, 3H), 2.21 (t, J = 5.5 Hz, 2H).

[0107] Example 7 EVO38026

[0108] Following the procedure for the preparation of compound EVO38054 of Example 1, preparative high performance liquid chromatography (column: YMC-Actus Triart C18 ExRS 8 nm S-5 um, 30*250 mm; mobile phase A: 10 mM NH4HC03solution, mobile phase B: ACN; flow rate: 30 mL / min; gradient: 5% B to 35% B in 30 min; wavelength: 200-400 nm) separation and lyophilization afforded EVO38025 as a white solid (12 mg, yield: 45.63%), LCMS (ESI) m / z = 513.05 [M+H] + HPLC purity: 99.6%, 1 H NMR (400 MHz, CDC13) δ 8.80 (s, 1H), 7.38 (d, J = 8.8 Hz, 1H), 6.65 (dd, J = 8.8, 2.7 Hz, 1H), 6.46 (d, J = 2.7 Hz, 1H), 6.23 (s, 1H), 4.47 (d, J = 2.6 Hz, 2H), 4.39 - 4.10 (m, 6H), 3.37 (s, 1H), 3.20 (s, 3H), 2.21 (t, J = 5.5 Hz, 2H).

[0109] Example 8 EVO38038

[0110] Referring to the preparation method of compound EVO38054 of Example 1, preparative high performance liquid chromatography separation (column: YMC-Actus Triart C18 ExRS 8 nm S-5 um, 30*250 mm; mobile phase A: 10 mM NH4HCO3 solution, mobile phase B: ACN; flow rate: 30 mL / min; gradient: 5% B to 35% B in 30 min; wavelength: 200-400 nm) and then freeze-drying, a white solid EVO38038 (0.92 mg, yield: 5.1%) was obtained, LCMS (ESI) m / z = 555.41 [M+H] + HPLC purity: 86.7%, 1 H NMR (400 MHz, CDCl3) δ 7.43 (d, J = 8.8 Hz, 1H), 6.69 (dd, J = 8.8, 2.4 Hz, 1H), 6.50 (d, J = 2.4 Hz, 1H), 5.96 (s, 1H), 4.56-4.45 (m, 2H), 4.37 (q, J = 8.0 Hz, 2H), 4.33-4.20 (m, 2H), 4.15 (s, 2H), 3.27 (s, 3H), 2.88-2.81 (m, 1H), 2.25-2.22 (m, 2H), 1.32 (d, J = 6.8 Hz, 6H).

[0111] Example 9 EVO38041

[0112] Referring to the preparation method of compound EVO38054 of Example 1, preparative high performance liquid chromatography separation (column: YMC-Actus Triart C18 ExRS 8 nm S-5 um, 30*250 mm; mobile phase A: 10 mM NH4HCO3 solution, mobile phase B: ACN; flow rate: 30 mL / min; gradient: 15% B to 65% B in 30 min; wavelength: 200-400 nm) and then freeze-drying, a white solid EVO38041 (7 mg, yield: 37.82%) was obtained, LCMS (ESI) m / z = 569.43 [M+H] + HPLC purity: 94.9%, 1 H NMR (400 MHz, CDCl3) δ 8.43 (s, 1H), 7.39 (d, J = 8.8 Hz, 1H), 6.64 (dd, J = 8.8, 2.7 Hz, 1H), 6.46 (d, J = 2.6 Hz, 1H), 6.02 (s, 1H), 4.49-4.41 (m, 2H), 4.36-4.08 (m, 6H), 3.21 (s, 3H), 2.18 (t, J = 5.5 Hz, 2H), 1.33 (s, 9H).

[0113] Example 10 EVO38048

[0114] Referring to the preparation method of compound EVO38054 of Example 1, the white solid EVO38048 (7 mg, yield: 41.56%) was obtained by high performance liquid preparation column separation (column: YMC-Actus Triart C18 ExRS 8 nm S-5 um, 30*250 mm; mobile phase A: 10 mM NH4HCO3 solution, mobile phase B: ACN; flow rate: 40 mL / min; gradient: 5% B to 35% B in 30 min; wavelength: 200-400 nm) and freeze-drying, LCMS (ESI) m / z = 527.32 [M+H] + , HPLC purity: 99.87%, 1 H NMR (400 MHz, CDCl3) δ 9.16 (s, 1H), 7.59-7.51 (m, 2H), 7.38-7.31 (m, 3H), 6.84 (d, J = 3.1 Hz, 1H), 6.53-6.47 (m, 2H), 4.83 (d, J = 13.4 Hz, 1H), 4.37 (d, J = 13.4 Hz, 1H), 4.30-4.13 (m, 4H), 3.11 (s, 3H), 2.24 (q, J = 4.6, 4.0 Hz, 2H).

[0115] Example 11 EVO38054-P1 and EVO38054-P2

[0116] Referring to the preparation method of compound of Example 1, the racemate EVO38054 (29 mg) was obtained by supercritical fluid chromatography separation (column: DAICEL AS-10, 25*250 mm 10 um; mobile phase A: Supercritical CO2, mobile phase B: MeOH + 0.05% NH3·MeOH; flow rate: 60 mL / min; gradient: A:B = 70:30; wavelength: 214 / 254 nm), EVO38054-P2 (8.4 mg, yield: 11.82%) was obtained at retention time 5.49 min, LCMS (ESI) m / z = 491.3 [M+H] + , HPLC purity: 98.47%, 1HNMR (400 MHz, DMSO-d6) δ 10.03 (s, 1H), 8.99 (s, 1H), 6.96-6.90 (m, 1H), 6.76-6.72 (m, 1H), 4.66 (s, 2H), 4.43-4.18 (m, 4H), 3.22 (s, 3H), 2.23-2.13 (m, 1H), 2.11-1.99 (m, 1H), 1.59-1.52 (m, 1H), 0.96-0.88 (m, 2H), 0.81-0.77 (m, 2H). EVO38054-P1 (10.4 mg, yield: 14.64%) was obtained at the retention time 12.14 min, LCMS (ESI) m / z = 491.3 [M+H] + HPLC purity: 99.56%, 1 HNMR (400 MHz, DMSO-d6) δ 10.03 (s, 1H), 8.99 (s, 1H), 6.96-6.90 (m, 1H), 6.76-6.72 (m, 1H), 4.66 (s, 2H), 4.43-4.18 (m, 4H), 3.22 (s, 3H), 2.23-2.13 (m, 1H), 2.11-1.99 (m, 1H), 1.59-1.52 (m, 1H), 0.96-0.88 (m, 2H), 0.81-0.77 (m, 2H).

[0117] Example 12 EVO38054-D

[0118] Referring to the preparation method of compound EVO38054 of Example 1, a high performance liquid preparative column was separated (column: YMC-Actus Triart C18 12 nm S-5um, 30*250mm; mobile phase A: 10 mM NH4HCO3 solution, mobile phase B: ACN; flow rate: 30 mL / min; gradient: 30% B to 80% B in 30 min; wavelength: 200-400 nm), and then freeze-dried to obtain white solid EVO38054-D (1.62 mg, yield: 6.07%), LCMS (ESI) m / z = 492.28 [M+H] + HPLC purity: 98.3%, 1H NMR (400 MHz, CDC13) δ 8.52 (s, 1H), 6.59-6.44 (m, 2H), 6.22 (s, 1H), 4.81 (d, J = 13.2 Hz, 1H), 4.32 (d, J = 13.2 Hz, 1H), 4.24-4.16 (m, 2H), 3.49 (s, 2H), 3.23 (s, 3H), 2.22 (t, J = 5.6 Hz, 2H), 0.88-0.85 (m, 4H).

[0119] Example 13 EVO38088-A

[0120] Following the procedure for the preparation of compound EVO38054 of Example 1, preparative high performance liquid chromatography separation (column: YMC-Actus Triart C18 ExRS 8 nm S-5 um, 30*250 mm; mobile phase A: 0.1% aqueous ammonia, mobile phase B: ACN; flow rate: 40 mL / min; gradient: 50% B to 80% B in 15 min; wavelength: 200-400 nm) and lyophilization afforded EVO38088-A as a white solid (7 mg, yield: 51.79%), LCMS (ESI) m / z = 553.39 [M-OH] + HPLC purity: 98.3%, 1 H NMR (400 MHz, CDC13) δ 8.66 (s, 1H), 7.40 (d, J = 8.8 Hz, 1H), 6.65 (dd, J = 8.8, 2.6 Hz, 1H), 6.46 (d, J = 2.6 Hz, 1H), 6.17 (s, 1H), 4.53-4.38 (m, 2H), 4.37-4.10 (m, 6H), 3.22 (s, 3H), 2.97 (s, 1H), 2.18 (t, J = 5.5 Hz, 2H), 1.59 (d, J = 2.5 Hz, 6H).

[0121] Example 14 EVO38095

[0122] Following the procedure for the preparation of compound EVO38054 of Example 1, preparative high performance liquid chromatography separation (column: YMC-Actus Triart C18 ExRS 8 nm S-5 um, 30*250 mm; mobile phase A: 10 mM NH4HCO3solution, mobile phase B: ACN; flow rate: 30 mL / min; gradient: 10% B to 50% B in 30 min; wavelength: 200-400 nm) and lyophilization afforded EVO38095 as a white solid (7 mg, yield: 25.83%), LCMS (ESI) m / z = 559.39 [M+H]+ HPLC purity: 99.48%, 1 H NMR (400 MHz, CDC13) δ 8.96 (s, 1H), 7.37 (d, J = 8.8 Hz, 1H), 6.64 (dd, J = 8.8, 2.7 Hz, 1H), 6.49 - 6.43 (m, 2H), 5.44 (dq, J = 48.1, 6.6 Hz, 1H), 4.53 - 4.40 (m, 2H), 4.37 - 4.12 (m, 6H), 3.18 (s, 3H), 2.19 (q, J = 4.1 Hz, 2H), 1.68 (dd, J = 22.6, 6.6 Hz, 3H).

[0123] Example 15 EVO38097

[0124] Referring to the preparation method of compound EVO38054 of Example 1, separation was performed by high performance liquid preparative column (column: YMC-Actus Triart C18 ExRS 8 nm S-5 um, 30*250 mm; mobile phase A: 10 mM NH4HC03solution, mobile phase B: ACN; flow rate: 30 mL / min; gradient: 10% B to 50% B in 30 min; wavelength: 200-400 nm), and then freeze-drying to obtain white solid EVO38097 (3 mg, yield: 30.59%), LCMS (ESI) m / z = 603.37 [M+H] + HPLC purity: 99.79%, 1 H NMR (400 MHz, CDC13) δ 8.61 (s, 1H), 7.38 (d, J = 8.8 Hz, 1H), 6.65 (dd, J = 8.8, 2.6 Hz, 1H), 6.46 (d, J = 2.6 Hz, 1H), 6.12 (s, 1H), 4.52 - 4.40 (m, 2H), 4.38 - 4.08 (m, 6H), 3.20 (s, 3H), 3.17 - 3.07 (m, 1H), 3.05 - 2.90 (m, 2H), 2.90 - 2.73 (m, 2H), 2.19 (t, J = 5.4 Hz, 2H).

[0125] Example 16 EVO38116

[0126] Following the procedure for the preparation of compound EVO38054 of Example 1, preparative high performance liquid chromatography (column: YMC-Actus Triart C18 12 nm S-5 um, 30*250 mm; mobile phase A: 10 mM NH4HC03solution, mobile phase B: ACN; flow rate: 40 mL / min; gradient: 30% B to 70% B in 20 min; 70% B to 80% B in 10 min wavelength: 200-400 nm) separation and lyophilization afforded EVO38116 as a white solid (3.2 mg, yield: 9.3%), LCMS (ESI) m / z = 543.38 [M+H] + HPLC purity: 98.7%, 1 H NMR (400 MHz, CDC13) δ 7.93 (s, 1H), 7.42 (d, J = 8.8 Hz, 1H), 6.69 (dd, J = 8.8, 2.6 Hz, 1H), 6.50 (d, J = 2.6 Hz, 1H), 5.98 (s, 1H), 4.51 - 4.42 (m, 2H), 4.37 (q, J = 8.0 Hz, 2H), 4.33 - 4.18 (m, 2H), 3.32 (q, J = 10.3 Hz, 2H), 2.32 - 2.16 (m, 2H), 1.56 - 1.46 (m, 1H), 0.97 - 0.85 (m, 4H).

[0127] Example 17 EVO38119

[0128] Following the procedure for the preparation of compound EVO38054 of Example 1, preparative high performance liquid chromatography (column: YMC-Actus Triart C18 12 nm S-5 um, 30*250 mm; mobile phase A: 10 mM NH4HC03solution, mobile phase B: ACN; flow rate: 40 mL / min; gradient: 30% B to 70% B in 20 min; 70% B to 80% B in 10 min wavelength: 200-400 nm) separation and lyophilization afforded EVO38119 as a white solid (15.21 mg, yield: 30.01%), LCMS (ESI) m / z = 569.44 [M+H] + HPLC purity: 99.8%, 1H NMR (400 MHz, CDC13) δ 8.75 (s, 1H), 7.41 (d, J = 8.8 Hz, 1H), 6.67 (dd, J = 8.8, 2.7 Hz, 1H), 6.49 (d, J = 2.6 Hz, 1H), 6.45 (s, 1H), 4.53 - 4.43 (m, 2H), 4.40 - 4.16 (m, 6H), 3.23 (s, 3H), 2.37 (d, J = 6.6 Hz, 2H), 2.23 (t, J = 5.4 Hz, 2H), 2.03 - 1.89 (m, 1H), 1.09 (s, 3H), 1.07 (s, 3H).

[0129] Example 18 EVO38120

[0130] Referring to the preparation method of compound EVO38054 of Example 1, a high performance liquid preparation column was separated (column: YMC-Actus Triart C18 12nm 10um, 30*250mm; mobile phase A: 0.1% ammonia solution, mobile phase B: ACN; flow rate: 30 mL / min; gradient: 30% B to 80% B in 40 min; wavelength: 200-400 nm), and then freeze-dried to obtain a white solid EVO38120 (27 mg, yield: 47.62%), LCMS (ESI) m / z = 581.42 [M+H] + , HPLC purity: 98.4%, 1 H NMR (400 MHz, CDC13) δ 8.54 (s, 1H), 7.38 (d, J = 8.7 Hz, 1H), 6.64 (dd, J = 8.8, 2.6 Hz, 1H), 6.45 (d, J = 2.5 Hz, 1H), 6.18 (s, 1H), 4.54 - 4.05 (m, 8H), 3.21 (s, 3H), 2.85 (q, J = 7.5 Hz, 1H), 2.18 (t, J = 5.4 Hz, 2H), 2.02 - 1.95 (m, 2H), 1.80 - 1.65 (m, 4H).

[0131] Example 19 EVO38121

[0132] Following the procedure for the preparation of compound EVO38054 of Example 1, preparative high performance liquid chromatography (column: YMC-Actus Triart C18 12nm 10um, 30*250mm; mobile phase A: 0.1% ammonia in water, mobile phase B: ACN; flow rate: 30 mL / min; gradient: 30% B to 80% B in 40 min; wavelength: 200-400 nm) separation and lyophilization afforded EVO38121 as a white solid (28 mg, yield: 60.72%), LCMS (ESI) m / z = 567.41 [M+H] + HPLC purity: 99.9%, 1 H NMR (400 MHz, CDC13) δ 8.62 (s, 1H), 7.37 (dd, J = 8.8, 2.4 Hz, 1H), 6.67-6.59 (m, 1H), 6.51-6.40 (m, 1H), 6.31-6.19 (m, 1H), 4.53-4.09 (m, 8H), 3.21 (s, 3H), 2.25-2.10 (m, 2H), 1.29-1.19 (m, 2H), 1.17-1.12 (m, 1H), 1.10 (d, J = 6.0 Hz, 2H), 1.02-0.98 (m, 1H), 0.72-0.45 (m, 1H).

[0133] Example 20 EVO38122

[0134] Following the procedure for the preparation of compound EVO38054 of Example 1, preparative high performance liquid chromatography (column: YMC-Actus Triart C18 12nm S-5um, 30*250mm; mobile phase A: 10 mM NH4HCO3 solution, mobile phase B: ACN; flow rate: 30 mL / min; gradient: 30% B to 80% B in 50 min; wavelength: 200-400 nm) separation and lyophilization afforded EVO38122 as a white solid (32 mg, yield: 66.81%), LCMS (ESI) m / z = 589.39 [M+H] + HPLC purity: 96.8%, 1 H NMR (400 MHz, CDC13) δ 8.62 (s, 1H), 7.37 (dd, J = 8.8, 2.4 Hz, 1H), 6.67-6.59 (m, 1H), 6.51-6.40 (m, 1H), 6.31-6.19 (m, 1H), 4.53-4.09 (m, 8H), 3.21 (s, 3H), 2.25-2.10 (m, 2H), 1.29-1.19 (m, 2H), 1.17-1.12 (m, 1H), 1.10 (d, J = 6.0 Hz, 2H), 1.02-0.98 (m, 1H), 0.72-0.45 (m, 1H).

[0135] Example 21 EVO38123

[0136] Following the procedure for the preparation of compound EVO38054 of Example 1, preparative high performance liquid chromatography column separation (column: YMC-Actus Triart C18 12nm S-5um, 30*250mm; mobile phase A: 10mM NH4HCO3 solution, mobile phase B: ACN; flow rate: 30 mL / min; gradient: 15% B to 45% B in 30 min; 45% B to 80% B in 10 min wavelength: 200-400 nm) and lyophilization afforded EVO38123 as a white solid (10.51 mg, yield: 25.4%), LCMS (ESI) m / z = 569.40 [M+H] + HPLC purity: 96.2%, 1 H NMR (400 MHz, CDC13) δ 8.84 (s, 1H), 7.42 (d, J = 8.7 Hz, 1H), 6.72 - 6.65 (m, 1H), 6.50 (d, J = 2.5 Hz, 1H), 6.42 (s, 1H), 4.96 - 4.79 (m, 4H), 4.57 - 4.45 (m, 2H), 4.42 - 4.05 (m, 7H), 3.25 (s, 3H), 2.31 - 2.17 (m, 2H).

[0137] Experimental Section

[0138] Experiment 1. MOGAT2 enzyme activity inhibition experiment

[0139] The monoacylglycerol acyltransferase MOGAT2 catalyzes the fatty acyl group transfer 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) technology. First, the wild-type hMOGAT2 (NM_025098) was cloned into the pFastBac expression vector, a tev enzyme cleavage site and a 6xHis tag were added at the C-terminus, and protein expression was performed using SF9 cells. The SF9 cells expressing hMOGAT2 were collected by centrifugation, resuspended with homogenate buffer (20 mM Tris-HCl, pH 7.6, 250 mM sucrose, proteinase inhibitor), and the cells were broken by a Dounce homogenizer. The cell homogenate was centrifuged at 1,000 g for 10 minutes, and the supernatant was collected. Then, the supernatant was centrifuged at 100,000 g for 60 minutes using an ultracentrifuge, and the precipitate was resuspended with buffer (20 mM Tris-HCl, pH 7.6, 250 mM sucrose). The prepared microsomes expressing MOGAT2 were used for enzyme activity testing. The reaction buffer was 100 mM Tris-HCl, pH 7.6, 250 mM sucrose, 0.01% BSA, and the reaction system was 20 μL. The MOGAT2 microsomes, the test compound, and the substrate were added in turn, and the final concentration was MOGAT2 microsomes 0.01 mg / mL, oleoyl-CoA lithium salt 100 μM, and 2-oleoylglycerol 200 μM. The reaction was carried out at room temperature for 60 minutes, 180 μL of methanol was added to terminate the reaction, and the mixture was centrifuged at 13,000 rpm for 15 min. The content of dioleoylglycerol in 150 μL of the supernatant was detected by LC-MS / MS. The product concentration with / without substrate was defined as DAG concentration (对照+) / DAG concentration (对照-) , and the compound inhibition rate was calculated according to the following formula: compound inhibition rate = (DAG concentration (对照+) -DAG concentration (试验化合物) )*100% / (DAG concentration (对照+) -DAG concentration (对照-) ). According to the inhibition rates of compounds at different concentrations, the concentration-effect curve was drawn and the IC 50 value of the compound was calculated using the four-parameter fitting equation by GraphPad Prism 9.0 software. The experimental results are shown in Table 1.

[0140] Table 1 Inhibition activity of compounds on MOGAT2

[0141] wherein, A represents IC 50 ≤100 nM; B represents 100 nM < IC 50 ≤500 nM; C represents 500 nM < IC50 ≤ 1000 nM; D indicates 1000 nM < IC 50 ≤ 5000 nM.

[0142] Experiment 2. Inhibition of MOGAT2 activity in cells

[0143] Caco-2 cells lack endogenous monoacylglycerol acyltransferase activity, so first a Caco-2 cell line stably expressing hMOGAT2 (human monoacylglycerol acyltransferase 2) was established to make a cell with monoacylglycerol acyltransferase activity. Then the MAG (monoacylglycerol) analogue 2-O-hexadecylglycerol (HDG) was added exogenously, delivered into the cells by packaging with DOPC (dioleoylphosphatidylcholine) into liposomes, HDG can be a substrate for MOGAT2, the product generated by HDG catalyzed by MOGAT2 is stable and can be distinguished from endogenous DAG, and the detection of the product generated by HDG catalyzed by MOGAT2 by mass spectrometry can reflect the activity of MOGAT2 in cells.

[0144] In a glass test tube, 10 mM HDG (2-O-hexadecylglycerol) chloroform solution and 100 mM DOPC chloroform solution were mixed at a volume ratio of 1:2, and the mixed solution was blown dry with N2, and then vacuum dried for 30 minutes. Buffer (100 mM Tris-Cl pH 7.4, 250 mM sucrose, 1 mM EDTA) was added to the dried HDG / DOPC mixture to a final concentration of 10 mM HDG. The hMOGAT2-Caco2 cells were seeded in a 96-well plate at 40000 cells per well and cultured overnight. The growth medium was removed, and the cells were pretreated with DMEM / F12 mixed medium (DMEM and F12 were mixed at a ratio of 3:1) containing the corresponding concentration of test compound and 2% BSA for 30 minutes, and then treated with DMEM / F12 mixed medium containing oleic acid, HDG / DOPC liposomes, the corresponding concentration of test compound and 2% BSA (the final concentration of oleic acid was 1200 μΜ, and the final concentration of HDG was 400 μΜ) for 4 hours. The culture medium was discarded, centrifuged at 1000 rpm for 1 min, the residual liquid was aspirated, the cells in each well were washed with 160 μL of methanol and scraped, the cells in each well were washed with 160 μL of methanol again, the two methanol solutions were combined, centrifuged at 12000 rpm for 15 min, the supernatant was aspirated, and the content of HDG product and triolein (TAG) was detected by LC-MS / MS. The compound inhibition rate calculation formula is as follows: Compound inhibition rate = (HDG product / TAG concentration (blank control) - HDG product / TAG concentration (test compound)) * 100% / HDG product / TAG concentration (blank control). According to the inhibition rates of compounds at different concentrations, GraphPad Prism 9.0 software was used to draw the concentration-effect curve and calculate the IC 50 values of the compounds using a four-parameter fitting equation. The experimental results are shown in Table 2, and the experimental results show that the tested compounds have obvious inhibition of cell activity.

[0145] Table 2 Inhibition of MOGAT2 activity of compounds in cells

[0146] wherein, A represents IC 50 ≤ 100 nM; B represents 100 nM < IC 50 ≤ 500 nM; C represents 500 nM < IC 50 ≤ 1000 nM; D represents 1000 nM < IC 50 ≤ 5000 nM.

[0147] Experiment 3. Plasma stability experiment

[0148] C57 mice, SD rats and human blank plasma (from Shanghai Sunny Biotechnological Co., Ltd.) were thawed and preheated at 37°C for 15 minutes. After adding the test compound, the sample was incubated at 37°C, 5% CO2, 100 rpm. The samples were taken at 0 minutes, 5 minutes, 15 minutes, 30 minutes, 60 minutes and 120 minutes, respectively. All samples were added with 300 μL of termination solution and mixed, centrifuged at 4000 rpm for 15 minutes. After centrifugation, 100 μL of supernatant was taken and diluted with 100 μL of water. The concentration of the compound was determined by LC-MS / MS method, and the remaining amount of the compound was calculated. The experimental results are shown in Table 3, and the experimental results show that the plasma stability of the test compound is good.

[0149] Table 3

[0150] Note: “-” means not tested.

[0151] Experiment 4. Liver microsomal stability experiment

[0152] The reaction system was prepared, and the final concentrations of each component were as follows: CD-1 mice, SD rats, beagle dogs, cynomolgus monkeys, and human liver microsomes (from Kanglong Huazheng (Beijing) New Drug Technology Co., Ltd.) were 0.5 mg / mL, phosphate buffer 100 mM, magnesium chloride 5 mM, propiomidine 25 μg / mL, 1 mM NADPH and 2 mM UDPGA, and 1 μM test compound. Incubate at 37°C to start the reaction, and take 10 μL samples at 0 minutes, 15 minutes, 30 minutes, 45 minutes and 60 minutes, respectively. All samples were added with 120 μL of termination solution and mixed, and centrifuged at 3220 g for 45 minutes. After centrifugation, 40 μL of supernatant was taken and diluted with 40 μL of water. The concentration of the compound was determined by LC-MS / MS method, and the in vitro T 1 / 2 , clearance CL int The experimental results are shown in Table 4, and the experimental results show that the test compound is relatively stable in liver microsomes of various species.

[0153] Table 4 Note: “-” means not tested.

[0154] Experiment 5. Plasma protein binding rate (PPB) experiment

[0155] The protein binding rate of the compound in C57 mice, Sprague-Dawley (SD) rats and human plasma (from Kanglong Huazheng (Beijing) New Drug Technology Co., Ltd.) was determined by equilibrium dialysis method. After dialysis, 20 μL of the dialyzed drug end plasma sample was removed to the sample receiving plate, and 80 μL of PBS was added. 20 μL of PBS sample at the receiving end after dialysis was removed to the sample receiving plate, and 80 μL of blank plasma was added. All samples were added with 480 μL of termination solution and mixed, and centrifuged at 3220 g at 4°C for 30 minutes. After centrifugation, 100 μL of supernatant was aspirated, diluted with 100 μL of water, and the concentration of the compound in the plasma and PBS was determined by LC-MS / MS method, and the free rate and binding rate were calculated. The experimental results are shown in Table 5, and the experimental results show that the tested compound PPB results are good, and there is a higher proportion of free compounds to exert pharmacological effects.

[0156] Table 5

[0157] Experiment 6. CYP enzyme inhibition experiment

[0158] EVO38023-R scheme: specific probe substrate of P450 isozyme and human liver microsomes (from Shanghai Runuo Biological Technology Co., Ltd.) were preheated at 38°C for 7 minutes, then the tested compound was added, vortexed at 1000 rpm for 10 seconds, 60 μL of NADPH was added to start the reaction, and incubated at 38°C at 300 rpm for 10 minutes. After the reaction was completed, all samples were added with 500 μL of termination solution and mixed at 1000 rpm for 90 seconds, and centrifuged at 4000 rpm for 15 minutes. After centrifugation, 300 μL of supernatant was aspirated, and the concentration of the compound was determined by LC-MS / MS method, and the inhibition rate of the compound on CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP3A was calculated.

[0159] EVO38054-P2 scheme: specific probe substrate of P450 isozyme (from Nanjing Yaoke New Drug Development Co., Ltd.) was preheated with human liver microsomes (from Nanjing Yaoke New Drug Development Co., Ltd.) and the tested compound at 37°C for 10 minutes, then 20 μL of NADPH was added to start the reaction, and incubated at 37°C in a water bath for 10 minutes. After the reaction was completed, all samples were added with 400 μL of termination solution and mixed, and centrifuged at 3220 g for 20 minutes. After centrifugation, 200 μL of supernatant was aspirated, diluted with 100 μL of water, and the concentration of the compound was determined by LC-MS / MS method, and the inhibition rate of the compound on CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP3A was calculated.

[0160] The experimental results are shown in Table 6, and the experimental results show that the tested compounds have good CYP properties and have no inhibitory effect on each CYP subtype.

[0161] Table 6

[0162] Experiment 7. Permeability and efflux transport experiment

[0163] The Caco-2 monolayer cell model (from Kanglong Huazheng (Beijing) New Drug Technology Co., Ltd.) was used to determine the bidirectional permeability of the compound, and the efflux transport of the compound without inhibitors. After removing the culture medium of Caco-2 cells, the cells were rinsed with preheated transport buffer, 75 μL of HEPES drug solution containing 5 uM of the test compound was added into the top and base end holes, respectively, and 235 μL of HEPES receiving solution was added, and the cell plate was incubated at 37°C for 120 minutes. After incubation, the final samples were collected from the drug end and the receiving end, mixed with transport buffer and termination solution in a certain proportion, all samples were vortexed for 5 minutes, then centrifuged at 3220g for 30 minutes. After centrifugation, 100 μL of supernatant was aspirated, diluted with 100 μL of water, and the concentration of the compound was determined by LC-MS / MS method, and the apparent permeability coefficient and efflux rate were calculated. The experimental results are shown in Table 7, and the experimental results show that the tested compounds have low permeability and high efflux rate, which is beneficial to the enrichment of the compound in the intestine.

[0164] Table 7

[0165] Experiment 8. DIO mouse in vivo pharmacodynamic model weight loss experiment

[0166] The weight loss effect of the compound on obese mice was tested on a high-fat diet-induced obese (DIO) mouse model. SPF DIO mice (male) aged 16-17 weeks were purchased from Shanghai South Model Organism Technology Co., Ltd., and the feed was 60kcal% high-fat feed. After 1 week of adaptive feeding, the body weight of each mouse was detected, and the mice were grouped according to the body weight and the drug administration was started. The solvent was 0.5% hydroxypropyl methylcellulose (HPMC) + 0.1% Tween-80 aqueous solution. The test compound was dissolved in the solvent, and the drug volume was calculated according to 10 μL / g of mouse body weight. The body weight of the mice was recorded every day during the test period. The weight loss amount of the compound treatment group relative to the solvent control group reflects the weight loss effect of the compound on obese mice. The drug dose, administration method and experimental results are shown in Tables 8 and 9, and the experimental results show that the tested compounds have obvious weight loss effect.

[0167] Table 8 Weight loss effect of the compound on DIO mouse model Note: "-" indicates no test drug.

[0168] Table 9 Weight loss effect of the compound on DIO mouse model Note: "-" means no test drug.

[0169] Experiment 9. Corn oil absorption inhibition experiment

[0170] C57BL / 6 mice in fasted state were orally gavaged with compounds and corn oil, and the inhibition of compounds on mouse MGAT2 was evaluated by detecting triglyceride (TG) in blood. 6-8 weeks old C57BL / 6 mice (male) were purchased from Changzhou Cavens Experimental Animal Co., Ltd. The vehicle was 0.5% hydroxypropyl methylcellulose (HPMC) + 0.1% Tween-80 aqueous solution. Test compounds were dissolved in the vehicle, and the administration volume was calculated at 10 μL / g of mouse body weight. After 1 week of adaptive feeding, C57BL / 6 mice were grouped and fasted, and the time point of fasted treatment was defined as -17 h. At the time point of -1 h, each group of mice was administered, and at the time point of -0.25 h, all mice were injected with 100 μL of tetrabutyl glycidol solution (prepared with normal saline, concentration of 5%) via the tail vein. At the time point of 0 h, all mice were orally gavaged with 200 μL of corn oil, and at the time point of 4 h, mouse blood was collected, plasma was separated, and the TG content was detected using a kit. The TG reduction of the compound treatment group relative to the vehicle control group reflects the inhibition of the compound on mouse MGAT2. The calculation formula of TG absorption inhibition is (plasma TG of administration group / plasma TG of control group - 1) x 100%. The experimental results are shown in Table 10, and the experimental results show that the test compounds have good corn oil absorption inhibition effect.

[0171] Table 10. Effect of compounds on plasma TG of mice Note: "-" means no test drug.

[0172] Experiment 10. Mouse pharmacokinetic experiment

[0173] Male C57 mice (6-8 weeks old) (from Medisipu Asia Pharmaceutical Technology (Shanghai) Co., Ltd.) were administered intravenously (IV) at a dose of 1 mg / kg by tail vein bolus or orally (PO) at a dose of 5 mg / kg by gavage. The compounds were prepared in a vehicle of 5% DMSO + 10% Solutol HS15 + 85% normal saline (IV) or 0.5% MC water containing 0.1% Tween 80 (PO). During the experiment, all animals could freely eat and drink water. At 0.083, 0.25, 0.5, 1, 2, 4, 8, and 24 hours after administration, blood was collected by vein (n = 3) and placed in a tube containing EDTA-K2 as an anticoagulant. The blood sample was centrifuged at 6800g, 2-8°C for 6 minutes, and the obtained plasma was analyzed by LC-MS / MS method, and the PK parameters were calculated using WinNonlin software (Pharsight Corporation, CA, USA). ​8.5 edition) by non-compartmental analysis method. The experimental results are shown in Table 11, which indicates that the tested compounds have good PK properties, with good bioavailability and apparent volume of distribution.

[0174] Table 11 Note: “-” means not tested.

[0175] Experiment 11. Rat pharmacokinetic experiment

[0176] Male SD rats (6-8 weeks old) (from Medisi Puaya Pharmaceutical Technology (Shanghai) Co., Ltd.) were intravenously (IV) administered by tail vein bolus at a dose of 1 mg / kg or orally (PO) administered by gavage at a dose of 10 mg / kg. The compounds were formulated in a solvent of 5% DMSO + 10% Solutol HS15 + 85% normal saline (IV) or 0.5% MC water containing 0.1% Tween 80 (PO). All animals could freely eat and drink during the experiment. Blood was collected by vein at 0.083, 0.25, 0.5, 1, 2, 4, 8 and 24 hours after administration (n = 3) and placed in tubes containing EDTA-K2 as an anticoagulant. The blood samples were centrifuged at 6800g, 2-8°C for 6 minutes, and the resulting plasma was analyzed by LC-MS / MS method, and the PK parameters were calculated using WinNonlin software (version 8.5) by non-compartmental analysis method. 8.5 edition) by non-compartmental analysis method. The experimental results are shown in Table 12, which indicates that the tested compounds have good PK properties, with good bioavailability and apparent volume of distribution.

[0177] Table 12 Note: “-” means not tested.

[0178] Experiment 12. Dog pharmacokinetic experiment

[0179] Male beagle dogs (6-24 months old) (Suzhou Fangda New Drug Development Co., Ltd.) were intravenously (IV) administered by tail vein bolus at a dose of 1 mg / kg or orally (PO) administered by gavage at a dose of 5 mg / kg. The compounds were formulated in a solvent of 5% DMSO + 10% Solutol HS15 + 85% normal saline (IV) or 0.5% MC water containing 0.1% Tween 80 (PO). All animals could freely eat and drink during the experiment. Blood was collected by vein at 0.083, 0.25, 0.5, 1, 2, 4, 8 and 24 hours after administration (n = 2) and placed in tubes containing EDTA-K2 as an anticoagulant. The blood samples were centrifuged at 3500g, 4°C for 5 minutes, and the resulting plasma was analyzed by LC-MS / MS method, and the PK parameters were calculated using WinNonlin software (version 8.5) by non-compartmental analysis method. 8.3) by non-compartmental analysis method. The experimental results are shown in Table 13, which indicates that the test compound has good PK properties, good bioavailability and apparent volume of distribution.

[0180] Table 13 Note: "-" means not tested.

[0181] Experiment 13. Rat tissue distribution experiment

[0182] Male SD rats (6-8 weeks old) (from Suzhou Fengda New Drug Development Co., Ltd.) were orally (PO) administered at a dose of 10 mg / kg by gavage. The compound was prepared in a solvent containing 0.1% Tween 80 in 0.5% MC water (PO). All animals were allowed free access to food and water during the experiment. At 0.25, 1, 4, 6, 8 and 24 hours after administration, the animals were euthanized by inhalation of carbon dioxide, and blood was collected by cardiac puncture before sacrifice and placed in tubes containing EDTA-K2 as an anticoagulant, and then the animals were dissected and liver and jejunum tissues were collected (n=3). The blood samples were centrifuged at 3500g at 4°C for 5 minutes to obtain plasma, and the tissue samples were rinsed with normal saline and then wiped dry with filter paper, and homogenized with 10 volumes of homogenate to obtain tissue homogenate samples. The obtained plasma and tissue homogenate samples were analyzed by LC-MS / MS method, and the PK parameters were calculated using WinNonlin software (version 8.3) by non-compartmental analysis method. The experimental results are shown in Table 13, which indicates that the test compound has good PK properties, good bioavailability and apparent volume of distribution. 8.3) by non-compartmental analysis method. The experimental results are shown in Table 13, which indicates that the test compound has good PK properties, good bioavailability and apparent volume of distribution.

[0183] Table 14

Claims

1. A compound of Formula I: ###00001### or a stereoisomer, prodrug, solvate, or pharmaceutically acceptable salt thereof. ​ wherein R1is selected from H, halogen, hydroxyl, carboxyl, cyano, pentafluorosulfanyl, C1-C6alkyl, or C1-C6alkoxy, wherein C1-C6alkyl, C1-C6alkoxy are optionally substituted with one to three of deuterium, halogen, carboxyl, cyano, hydroxyl, amino, C1-C6alkyl, C1-C6alkoxy, phenyl; R2is selected from halogen, hydroxyl, carboxyl, cyano, C1-C6alkyl, C1-C6alkoxy, C3-C8cycloalkyl, 5-8 membered heterocyclic ring, C6-10aryl, or C6-10heteroaryl, wherein C1-C6alkyl, C1-C6alkoxy, C3-C8cycloalkyl, 5-8 membered heterocyclic ring, C6-10aryl, C6-10heteroaryl are optionally substituted with one to three of deuterium, halogen, carboxyl, cyano, hydroxyl, amino, C1-C6alkyl, C1-C6alkoxy, phenyl; R3is selected from H, halogen, hydroxyl, carboxyl, cyano, pentafluorosulfanyl, C1-C6alkyl, or C1-C6alkoxy, wherein C1-C6alkyl, C1-C6alkoxy are optionally substituted with one to three of deuterium, halogen, carboxyl, cyano, hydroxyl, amino, C1-C6alkyl, C1-C6alkoxy, phenyl; R4is selected from H, halogen, hydroxyl, carboxyl, cyano, pentafluorosulfanyl, C1-C6alkyl, or C1-C6alkoxy, wherein C1-C6alkyl, C1-C6alkoxy are optionally substituted with one to three of deuterium, halogen, carboxyl, cyano, hydroxyl, amino, C1-C6alkyl, C1-C6alkoxy, phenyl; R5is selected from H, halogen, hydroxyl, carboxyl, cyano, C1-C6alkyl, C1-C6alkoxy, C3-C8cycloalkyl, 4-8 membered heterocyclyl, C6-10aryl, or C6-10heteroaryl, wherein C1-C6alkyl, C1-C6alkoxy, C3-C8cycloalkyl, 4-8 membered heterocyclyl, C6-10aryl, C6-10heteroaryl are optionally substituted with one to three of deuterium, halogen, carboxyl, cyano, hydroxyl, amino, C1-C6alkyl, C1-C6alkoxy, phenyl; R6is selected from; -NHCO-(CH2)m-R7; wherein R7is selected from C1-C6alkylsulfonyl, C1-C6alkyl, C1-C6alkoxy, C3-C8cycloalkyl, 5-8 membered heterocyclic ring, C6-10aryl, or C6-10heteroaryl, wherein C1-C6alkyl, C1-C6alkoxy, C3-C8cycloalkyl, 5-8 membered heterocyclic ring, C6-10aryl, C6-10heteroaryl are optionally substituted with one to three of deuterium, halogen, carboxyl, cyano, hydroxyl, amino, C1-C6alkyl, C1-C6alkoxy, phenyl; R8is selected from H; X is selected from O, S, or NH; Y is selected from O, S, NH, or CH2; A ring is selected from a 5-6 membered heteroaromatic ring containing one or two heteroatoms, or a saturated or unsaturated 4-6 membered heterocyclic ring containing one or two heteroatoms; n is 0, 1, or 2; m is 0, 1, or 2.

2. The compound of claim 1, or a stereoisomer, prodrug, solvate, or pharmaceutically acceptable salt thereof, wherein, A ring is a 5-6 membered heteroaromatic ring containing one or two heteroatoms selected from: pyrazole, imidazole, pyrrole, furan, thiophene, thiazole, oxazole, pyridine, pyrimidine or pyrazine, preferably pyrazole.

3. The compound of claim 1, or a stereoisomer, prodrug, solvate, or pharmaceutically acceptable salt thereof, wherein, A ring is a saturated or partially unsaturated 4-6 membered heterocyclic ring containing one or two heteroatoms selected from: oxetane, tetrahydrofuran, piperidine, piperazine or pyran.

4. The compound of Formula I according to claim 1 or 2, or a stereoisomer, prodrug, solvate, or pharmaceutically acceptable salt thereof, wherein, The compound of Formula I is selected from the group consisting of the following compounds of Formula II: wherein R1, R2, R3, R4, R5, R6, R7, R8, m, n are as defined in claim 1.

5. The compound of claim 4, or a stereoisomer, prodrug, solvate, or pharmaceutically acceptable salt thereof, wherein, in the compound of formula II, R1is selected from H, hydroxyl, pentafluorosulfanyl, C1-C6alkyl or C1-C6alkoxy, wherein C1-C6alkyl, C1-C6alkoxy is optionally substituted with one to three of deuterium, halogen, carboxyl, cyano, hydroxyl, amino, C1-C6alkyl, C1-C6alkoxy, phenyl; R2is selected from halogen, hydroxyl, C1-C6alkyl or C1-C6alkoxy, wherein C1-C6alkyl, C1-C6alkoxy is optionally substituted with one to three of deuterium, halogen, carboxyl, cyano, hydroxyl, amino, C1-C6alkyl, C1-C6alkoxy, phenyl; R3is selected from H, hydroxyl, pentafluorosulfanyl, C1-C6alkyl or C1-C6alkoxy, wherein C1-C6alkyl, C1-C6alkoxy is optionally substituted with one to three of deuterium, halogen, carboxyl, cyano, hydroxyl, amino, C1-C6alkyl, C1-C6alkoxy, phenyl; R4is selected from H, halogen, hydroxyl, pentafluorosulfanyl, C1-C6alkyl or C1-C6alkoxy, wherein C1-C6alkyl, C1-C6alkoxy is optionally substituted with one to three of deuterium, halogen, carboxyl, cyano, hydroxyl, amino, C1-C6alkyl, C1-C6alkoxy, phenyl; R5is selected from H, hydroxyl, C1-C6alkyl, C3-C6cycloalkyl, 4-6 membered heterocyclyl or C6-8aryl, wherein C1-C6alkyl, C3-C6cycloalkyl, 4-6 membered heterocyclyl, C6-8aryl is optionally substituted with one to three of deuterium, halogen, carboxyl, cyano, hydroxyl, amino, C1-C6alkyl, C1-C6alkoxy, phenyl; R6is selected from; -NHCO-(CH2)m-R7; wherein R7is selected from C1-C6alkylsulfonyl or C1-C6alkyl, wherein C1-C6alkyl is optionally substituted with one to three of deuterium, halogen, carboxyl, cyano, hydroxyl, amino, C1-C6alkyl, C1-C6alkoxy, phenyl; R8is selected from H; X is selected from O or S; Y is selected from O, S or NH; n is 0, 1 or 2; m is 1 or 2.

6. The compound of any one of claims 1, 2, 4, 5, or a stereoisomer, prodrug, solvate, or pharmaceutically acceptable salt thereof, wherein, The compound of Formula I is selected from the group consisting of the following compounds of Formula III: wherein, R2is selected from halogen or C1-C6alkoxy, wherein C1-C6alkoxy is optionally substituted with one to three of deuterium, halogen; R4is selected from H or halogen; R5is selected from H, C1-C4alkyl, C3-C6cycloalkyl, 4-6 membered heterocyclyl or phenyl, wherein C1-C4alkyl, C3-C6cycloalkyl, 4-6 membered heterocyclyl, phenyl is optionally substituted with one to three of deuterium, halogen, hydroxyl.

7. The compound of claim 6, or a stereoisomer, prodrug, solvate, or pharmaceutically acceptable salt thereof, wherein, The compound of Formula III is selected from a compound of Formula III-1 or Formula III-2: wherein R2, R4and R5are as defined in claim 6.

8. The compound of Formula I according to claim 6 or 7, or a stereoisomer, prodrug, solvate, or pharmaceutically acceptable salt thereof, wherein, In the compound of formula III, R2is selected from halogen or ethoxy, wherein ethoxy is optionally substituted with 1 to 3 of deuterium, halogen; R4is selected from H or halogen; R5is as defined in claim 6.

9. The compound of Formula I according to claim 6 or 7, or a stereoisomer, prodrug, solvate, or pharmaceutically acceptable salt thereof, wherein, In the compound of formula III, R4is selected from H or halogen; R5is selected from H, methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, i-butyl, cyclopropyl, cyclobutyl, cyclopentyl, phenyl or oxetanyl, wherein methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, i-butyl, cyclopropyl, cyclobutyl, cyclopentyl, phenyl, oxetanyl is optionally substituted with 1 to 3 of deuterium, halogen, hydroxyl; R4is as defined in claim 6.

10. The compound of Formula I according to claim 6 or 7, or a stereoisomer, prodrug, solvate, or pharmaceutically acceptable salt thereof, wherein, In the compound of formula III, R2is selected from halogen or ethoxy, wherein ethoxy is optionally substituted with 1 to 3 of deuterium, halogen; R5is selected from H, methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, i-butyl, cyclopropyl, cyclobutyl, cyclopentyl, phenyl or oxetanyl, wherein methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, i-butyl, cyclopropyl, cyclobutyl, cyclopentyl, phenyl, oxetanyl is optionally substituted with 1 to 3 of deuterium, halogen, hydroxyl; R4is as defined in claim 6.

11. The compound of Formula I according to claim 6 or 7, or a stereoisomer, prodrug, solvate, or pharmaceutically acceptable salt thereof, wherein, In the compound of formula III, R2is F or -OCH2CF3; R4is H or F; R5is as defined in claim 6, preferably R5is selected from H, methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, i-butyl, cyclopropyl, cyclobutyl, cyclopentyl, phenyl or oxetanyl, wherein methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, i-butyl, cyclopropyl, cyclobutyl, cyclopentyl, phenyl, oxetanyl is optionally substituted with 1 to 3 of deuterium, halogen, hydroxyl.

12. The compound of Formula I according to any one of claims 1-11, or a stereoisomer, prodrug, solvate, or pharmaceutically acceptable salt thereof, wherein, The compound of Formula I is selected from the following compounds:

13. A pharmaceutical composition comprising a compound of formula I as defined in any one of claims 1-12, or a stereoisomer, prodrug, solvate, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

14. Use of a compound of formula I as defined in any one of claims 1-12, or a stereoisomer, prodrug, solvate, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 13, for the manufacture of a medicament for inhibiting MGAT2.

15. Use according to claim 14, wherein, The medicament for inhibiting MGAT2 is a medicament for treating and / or preventing obesity, metabolic syndrome, hyperlipidemia, hypertriglyceridemia, hyper-VLDL, hyper-fatty acid, diabetes, or arteriosclerosis.

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