MGAT2 inhibitor, and preparation method therefor and use thereof

Abstract

The present invention relates to a compound as shown in formula (I), and a preparation method therefor and the use thereof. The present invention further relates to a pharmaceutical composition containing the compound as an active ingredient, and the use of the compound or pharmaceutical composition in the treatment and / or prevention of diseases associated with MGAT2 expression.

Description

MGAT2 inhibitors, their preparation methods and uses Technical Field

[0001] This invention relates to the field of medicinal chemistry, specifically to an MGAT2 inhibitor with a specific structure, its preparation method, and its uses. Background Technology

[0002] Triglycerides are an important form of energy storage in the human body, and their synthesis mainly includes the glycerol-3-phosphate (G3P) pathway and the monoacylglycerol (MAG) pathway [Diseases, 2015.3(3):p.176-192.]. The former mainly utilizes G3P to synthesize triglycerides in the liver, while the latter participates in the uptake and synthesis of dietary fat in the small intestine. In the gastrointestinal tract, dietary fat is digested and broken down into glycerol and fatty acids, which are then absorbed by the epithelial cells of the small intestine and resynthesized into triglycerides within the cells. The synthesized triglycerides are packaged into chylomicrons, enter the bloodstream, and are transported to various tissues throughout the body for energy. However, excessive energy intake can disrupt the balance between fat synthesis and breakdown in the body, leading to obesity.

[0003] Currently, drugs for treating obesity include fat absorption inhibitors such as orlistat, sibutramine, semaglutide, and telpoxetine. However, the safety of these drugs still presents certain concerns. Orlistat, as a fat absorption inhibitor, has side effects including severe gastrointestinal side effects such as steatorrhea; sibutramine was withdrawn from the market due to cardiovascular side effects; and GLP-1 drugs, represented by semaglutide, can lead to severe muscle loss [N Engl J Med, 2021. 384(11): p. 989-1002.]. Therefore, developing a drug for treating obesity that is both effective and safe remains a pressing clinical challenge.

[0004] Monoacylglycerol O-acyltransferase 2 (MGAT2) is a key enzyme in the MAG pathway, responsible for transferring fatty acids to monoacylglycerol to generate diacylglycerol. High expression of MGAT2 in the small intestine is closely related to dietary fat absorption. Studies have found that a high-fat diet increases MGAT2 expression in the small intestine, and compared with the control group, the expression of MGAT2 and its family member MGAT3 was significantly increased in the liver of NAFLD patients. Furthermore, obese patients undergoing Roux-en-Y gastric bypass surgery showed a significant decrease in MGAT2 expression one year post-surgery [J Lipid Res, 2012.53(5):p.990-999.]. This evidence suggests that MGAT2 may play an important role in the development and progression of obesity. In mouse experiments, MGAT2 knockout mice showed normal growth and development, but under high-fat diet conditions, they exhibited changes in fat absorption and distribution, effectively inhibiting weight gain and blood glucose abnormalities induced by the high-fat diet [Nat Med, 2009.15(4):p.442-6.]. Meanwhile, MGAT2 knockout did not significantly affect lean mass in mice. These studies indicate that MGAT2 is a key regulatory molecule in small intestinal fat synthesis, and inhibiting MGAT2 may be an effective strategy for treating obesity and related metabolic diseases. Therefore, developing MGAT2 inhibitors has the potential to inhibit triglyceride synthesis, thereby delaying or reducing dietary fat absorption, and thus has potential clinical application value in the treatment of obesity and related metabolic diseases. Summary of the Invention

[0005] The purpose of this invention is to provide a class of compounds that can be used to treat diseases related to MGAT2 regulation.

[0006] To achieve the above-mentioned objectives, the present invention provides the following technical solution:

[0007] The compound of formula (I), or its pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, eutectic, hydrate, solvate, metabolite, prodrug, or deuterated compound:

[0008] in,

[0009] R 1 Selected from C 1-8 Alkyl, C 3-8 cycloalkyl, C 1-6 Halogenated alkyl groups, -SF5, -SCF3; the C 1-8 Alkyl, C 3-8 cycloalkyl, C 1-6Each haloalkyl group is independently unsubstituted or converted by one or more identical or different R groups. a replace;

[0010] Ring A and ring B are each independently selected from phenyl, 5-10-membered heteroaryl, and 5-10-membered heterocyclic group; each of the 5-10-membered heteroaryl and 5-10-membered heterocyclic group independently contains 1, 2, or 3 heteroatoms selected from N, O, or S;

[0011] Each R 2 and R 5 Each is independently selected from halogens, oxo groups (O=), hydroxyl groups, cyano groups, and C. 1-8 Alkyl, C 2-8 alkenyl, C 2-8 alkynyl group, C 1-8 Alkoxy, C 3-8 cycloalkyl, C 3-8 Cycloalkenyl, 6-10 aryl, 5-10 heteroaryl, 5-10 heterocyclic, -SO2R b -SR d -NR i R j C 1-8 Alkyl-C(O)-; each of the 5-10 membered heteroaryl and 5-10 membered heterocyclic groups independently contains 1, 2, or 3 heteroatoms selected from N, O, and S; the C 1-8 Alkyl, C 2-8 alkenyl, C 2-8 alkynyl group, C 1-8 Alkoxy, C 3-8 cycloalkyl, C 3-8 Cycloalkenyl, 6-10 aryl, 5-10 heteroaryl, and 5-10 heterocyclic groups are each independently unsubstituted or converted by one or more identical or different R groups. a replace;

[0012] R 3 R 4 Each is independently selected from hydrogen, halogen, cyano, C 1-8 Alkyl; and R 3 R 4 It can form C together with the carbon atoms it is attached to. 3-8 Cycloalkyl or 4-7 membered heterocycloalkyl; wherein the 4-7 membered heterocycloalkyl contains 1, 2 or 3 heteroatoms selected from N, O or S; the C 1-8 Alkyl, C 3-8 Cycloalkyl groups and 4-7 membered heterocyclic alkyl groups are each independently unsubstituted or converted by one or more identical or different R groups. b replace;

[0013] R 6 Selected from cyano, amino, R c-(CH2) o -X-(CH2) p R c -CONH(C 1-8 Alkyl), -NHCO-Y-SO2R b X is selected from O, S, NH, CONH, NHCO, and Y is selected from C. 1-8 Alkyl, C 3-8 Cycloalkyl; wherein o and p are each independently 0, 1, 2, 3, 4, 5 or 6;

[0014] Each R a Each is independently selected from halogen, cyano, hydroxyl, -SR d -SF5, -SCF3, -S(O)2R b C 1-8 Alkyl, C 1-8 Alkoxy, C 3-8 cycloalkyl, C 1-8 Haloalkyl, C 2-8 alkenyl, C 2-8 alkynyl group, C 3-6 Cycloalkenyl, unsubstituted, or with one or more identical or different R aa Substituted 5-6 aryl groups, -NR i R j -C(O)NR i R j ; or two adjacent R a Combined with atoms on ring A to form unsubstituted or altered compounds by one or more identical or different R atoms. bb Substituted 4-7-membered heterocyclic alkyl groups; wherein each of the 5-6-membered heteroaryl group and the 4-7-membered heterocyclic alkyl group independently contains 1 to 3 heteroatoms selected from N, O, and S; each R aa R bb Each is independently selected from halogens, C 1-4 alkyl;

[0015] Each R i R j Each was independently selected from C 1-8 Alkyl, C 3-8 cycloalkyl, C 1-8 Halogenated alkyl; or R i R j The bonded N atom forms an unsubstituted or substituted atom with one or more identical or different R atoms. aa Substituted 4-7-membered heterocyclic alkyl groups; wherein the 4-7-membered heterocyclic alkyl group contains 1, 2 or 3 heteroatoms selected from N, O or S;

[0016] Each R b R dEach was independently selected from C 1-8 Alkyl, C 3-8 cycloalkyl, C 1-8 Haloalkyl, C 1-8 Alkoxy;

[0017] Each R c Each was independently selected from C 3-8 Cycloalkyl, phenyl, 5-10 membered heterocyclic, 5-10 membered heteroaryl; wherein each of the 5-10 membered heteroaryl and 5-10 membered heterocyclic groups independently contains 1, 2, 3, or 4 heteroatoms selected from N, O, or S; each of the phenyl, 5-10 membered heteroaryl, and 5-10 membered heterocyclic groups is independently unsubstituted or converted by one or more identical or different R atoms. b replace;

[0018] m and n are each independently 1, 2, 3, 4, 5 or 6.

[0019] In some specific implementation schemes, R 1 Selected from -SF5, -SCF3, C 1-6 Halogenated alkyl groups.

[0020] In some specific implementation schemes, R 1 Selected from -SF5, -SCF3, C 1-4 Halogenated alkyl groups.

[0021] In some specific implementation schemes, R 1 Selected from -SF5, -SCF3, -CF3.

[0022] In some specific implementation schemes, R 1 Selected from -SF5 and -SCF3.

[0023] In some specific implementation schemes, R 3 R 4 Both are hydrogen.

[0024] In some specific embodiments, ring A is selected from phenyl, 8-10 membered bicyclic heteroaryl, and 5-6 membered monocyclic heterocyclic group; each of the 8-10 membered bicyclic heteroaryl and 5-6 membered monocyclic heterocyclic group independently contains 1, 2 or 3 heteroatoms selected from N, O and S.

[0025] In some specific embodiments, ring A is selected from phenyl, 8-10 membered bicyclic heteroaryl, or pyridone group; the 8-10 membered bicyclic heteroaryl contains 1, 2, or 3 N heteroatoms.

[0026] In some specific embodiments, ring A is selected from phenyl, 5-6-membered heteroarylphenyl, pyridone; the 5-6-membered bicyclic heteroaryl contains 1, 2 or 3 N heteroatoms.

[0027] In some specific embodiments, ring A is selected from phenyl, pyrrolophenyl, pyrazolophenyl, and pyridone.

[0028] In some specific embodiments, ring A is selected from 8-10-membered bicyclic heteroaryl groups and 5-6-membered monocyclic heterocyclic groups; each of the 8-10-membered bicyclic heteroaryl groups and 5-6-membered monocyclic heterocyclic groups independently contains 1, 2 or 3 heteroatoms selected from N, O and S.

[0029] In some specific embodiments, ring A is selected from 8-10 membered bicyclic heteroaryl groups and pyridinone groups; the 8-10 membered bicyclic heteroaryl group contains 1, 2 or 3 N heteroatoms.

[0030] In some specific embodiments, ring A is selected from 5-6-membered heteroarylphenyl or pyridinone groups; the 5-6-membered bicyclic heteroaryl group contains 1, 2 or 3 N heteroatoms.

[0031] In some specific embodiments, ring A is selected from pyrrolophenyl, pyrazolophenyl, and pyridone.

[0032] In some specific implementations, ring A is a phenyl group.

[0033] In some specific implementation schemes, ring A is selected from... Among them, site 1 and R 2 Connection, site 2 and R 1 The carbon atoms that are connected are linked.

[0034] In some specific implementation schemes, each R 2 Each independently selected C 2-8 alkenyl, C 2-8 Alkyne, halogen, C 1-8 Alkyl, C 1-8 Haloalkoxy, oxo (O=), where Z is O, methylene, vinylene or ethynylene; s and q are 1, 2, 3, 4, 5 or 6 respectively.

[0035] In some specific implementations, at least one R 2 Selected from C 2-8 alkenyl, C 2-8 Alkyne group, wherein Z is O, methylene, vinylene, or ethynylene; s and q are 1, 2, 3, 4, 5, or 6, respectively.

[0036] In some specific implementation schemes, each R 2 Each independently selected C 2-4 alkenyl, C 2-4 Alkyne, halogen, C 1-4 Alkyl, C 1-4Haloalkoxy, oxo (O=), where Z is O, methylene, vinylene or ethynylene; s and q are 1, 2, 3, 4, 5 or 6 respectively.

[0037] In some specific implementation schemes, each R 2 Each independently selected C 2-4 alkenyl, C 2-4 alkynyl group, F, Cl, C 1-4 Alkyl, C 1-4 Haloalkoxy or oxo (O=), where Z is O; s and q are 1, 2, 3 or 4 respectively.

[0038] In some specific implementations, at least one R 2 Selected from C 2-4 alkenyl, C 2-4 Alkyne group, wherein Z is O, methylene, vinylene or ethynylene; s and q are 1, 2, 3 or 4 respectively.

[0039] In some specific implementations, at least one R 2 Selected from C 2-4 alkenyl, C 2-4 Alkyne group, where Z is O; s and q are 1, 2, 3 or 4 respectively.

[0040] In some specific implementations, at least one R 2 Selected from Where Z is O, methylene, vinylene, or ethynylene; s is 1, 2, 3, 4, 5, or 6.

[0041] In some specific implementations, at least one R 2 Selected from q can be 1, 2, 3, 4, 5 or 6.

[0042] In some specific implementations, at least one R 2 Each was independently selected from C 2-8 Alkenyl group.

[0043] In some specific implementations, at least one R 2 Each was independently selected from C 2-8 Alkyne group.

[0044] In some specific implementation schemes, each R 2 Each independently selected Ethylene, acetylene, F, Cl, methyl, oxo group (O=).

[0045] In some specific implementations, at least one R 2 Selected from Ethylene, acetylene.

[0046] In some specific implementation schemes, each R 2 Each independently selected

[0047] In some specific implementation plans, Selected from

[0048] In some specific implementation plans, Selected from

[0049] In some specific implementation plans, Selected from

[0050] In some specific embodiments, ring B is selected from phenyl, 5-6 heteroaryl; the 5-6 heteroaryl contains 1, 2 or 3 heteroatoms selected from N, O or S.

[0051] In some specific embodiments, ring B is selected from phenyl, pyrazolyl, thiophenyl, thiazolyl, pyridyl, and pyrimidinyl.

[0052] In some specific implementation schemes, ring B is selected from phenyl,

[0053] In some specific implementation schemes, each R 5 Each is independently selected from halogens, C 1-8 Alkyl, C 1-8 Alkoxy, C 3-8 Cycloalkyl-(CH2) r -、C 3-8 Cycloalkenyl-(CH2) r -、C 2-8 Alkenyl-(CH2) r -、C 2-8 Alkyne group -(CH2) r -、C 1-8 Alkyl-C(O)-, SO2R b -(CH2) r -、SR d -(CH2) r -、-NR i R j , where R i R j Each was independently selected from C 1-8 Alkyl groups, each r independently being 0, 1, 2, 3, 4, 5, or 6; the C 1- 8-alkyl, C 1-8 Alkoxy, C 3-8cycloalkyl, C 3-8 Cycloalkenyl, C 2-8 alkenyl, C 2-8 Each alkynyl group is independently unsubstituted or surrounded by 1, 2, 3, or 4 groups selected from hydroxyl, cyano, halogen, C. 1-4 Alkyl, C 1-4 Substitution of alkoxy groups.

[0054] In some specific implementations, at least one R 5 Selected from C 1-8 Alkyl, C 2-8 Alkenyl-(CH2) r -、C 2-8 Alkyne group -(CH2) r -、SO2R b -(CH2) r -、SR d -(CH2) r - where each r is independently 0, 1, 2, 3, 4, 5, or 6; the C 1-8 The alkyl group is selected from cyano, C 2-4 alkenyl, C 2- 4Alkynyl, -SO2R b -SR d C 3-8 Substitution of cycloalkenyl groups.

[0055] In some specific implementation schemes, each R 5 Each is independently selected from halogens, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl-(CH2) r -、C 3-6 Cycloalkenyl-(CH2) r -、C 2-4 Alkenyl-(CH2) r -、C 2-4 Alkyne group -(CH2) r -、C 1-4 Alkyl-C(O)-, SO2R b -(CH2) r -、SR d -(CH2) r -、-NR i R j , where R i R j Each r is independently selected from methyl, ethyl, propyl, isopropyl, and C4 alkyl, and each r is independently 0, 1, 2, 3, 4, 5, or 6; the C 1-4 Alkyl, C 1-4 Alkoxy, C3-6 cycloalkyl, C 3-6 Cycloalkenyl, C 2-4 alkenyl, C 2-4 Each alkynyl group is independently unsubstituted or surrounded by 1, 2, 3, or 4 groups selected from hydroxyl, cyano, halogen, C. 1-4 Alkyl, C 1-4 Substitution of alkoxy groups.

[0056] In some specific implementations, at least one R 5 Selected from C 1-4 Alkyl, C 2-4 Alkenyl-(CH2) r -、C 2-4 Alkyne group -(CH2) r -、SO2R b -(CH2) r -、SR d -(CH2) r - where each r is independently 0, 1, 2, 3, 4, 5, or 6; the C 1-4 The alkyl group is selected from cyano, C 2-4 alkenyl, C 2- 4Alkynyl, -SO2R b -SR d C 3-6 Substitution of cycloalkenyl groups.

[0057] In some specific implementation schemes, each R b R d Each is independently selected from methyl, ethyl, propyl, isopropyl, and C4 alkyl, and each is unsubstituted or substituted with 1, 2, 3, or 4 halogens.

[0058] In some specific implementation schemes, each R 5 Each is independently selected from F, Cl, methyl, ethyl, isopropyl, isobutyl, methoxy, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclobutylmethyl, vinyl, hydroxyethyl, cyanomethyl,

[0059] In some specific implementations, at least one R 5 Selected from vinyl, cyanomethyl,

[0060] In some specific implementation plans, Selected from

[0061] In some specific implementation plans, Selected from

[0062] In some specific implementation plans, Selected from

[0063] In some specific implementation schemes, R 6 Selected from cyano, R c -(CH2) o -X-(CH2) p R c -NHCO-Y-SO2R b X is selected from O, S, NH, CONH, NHCO, and Y is selected from C. 1-8 Alkyl, C 3-8 Cycloalkyl.

[0064] In some specific implementations, Y is selected from methylene.

[0065] In some specific implementation schemes, -(CH2) o -X-(CH2) p R c For -CONH-R c .

[0066] In some specific implementation schemes, each R c Each is independently selected from phenyl, 5-6 membered heterocyclic group, and 5-6 membered heteroaryl group; wherein each of the 5-6 membered heterocyclic group and 5-6 membered heteroaryl group independently contains 1, 2, 3, or 4 heteroatoms selected from N, O, or S; wherein each of the phenyl, 5-6 membered heterocyclic group, and 5-6 membered heteroaryl group is independently unsubstituted or converted by one or more identical or different R atoms. b replace.

[0067] In some specific implementation schemes, each R c Each is independently selected from phenyl, Wherein, the phenyl, Each independently is either unsubstituted or by one or more identical or different Rs. b replace.

[0068] In some specific implementation schemes, R c Selected from phenyl, wherein the phenyl group is unsubstituted or converted by one or more identical or different R groups. b replace.

[0069] In some specific implementation schemes, each R b Each is independently selected from oxygen groups (O=) and C. 1-8 Alkyl, C 1-8 Alkoxy, the C 1-8 Alkyl, C 1-8 The alkoxy group can be substituted or unsubstituted.

[0070] In some specific implementation schemes, each R b Each is independently selected from oxygen groups (O=) and C. 1-4 Alkyl, C 1-4 Alkoxy, the C 1-4 Alkyl, C 1-4 The alkoxy group can be substituted or unsubstituted.

[0071] In some specific implementation schemes, each R b Each is independently selected from oxo (O=), methyl, and methoxy groups.

[0072] In some specific implementation schemes, R 6 Selected from CN

[0073] In some specific implementation schemes, R 6 Selected from

[0074] In some specific implementations, Equation I has the structure shown in Equation II. In the formula R 2 R 5 The definitions of m, n, ring A, and ring B are as described in this article.

[0075] In some specific embodiments, the compounds described herein are selected from the following specific compounds:

[0076] The term "pharmaceutically acceptable salt" refers to the salt of the compounds of this invention, prepared by reacting a compound having specific substituents discovered in this invention with a relatively non-toxic acid or base. When the compounds of this invention contain relatively acidic functional groups, base addition salts can be obtained by contacting such compounds with a sufficient amount of base in a pure solution or a suitable inert solvent. When the compounds of this invention contain relatively basic functional groups, acid addition salts can be obtained by contacting such compounds with a sufficient amount of acid in a pure solution or a suitable inert solvent.

[0077] The term "deuterated compound" refers to a compound of the present invention comprising at least one deuterium atom, specifically meaning that one or more hydrogen atoms in the compound of the present invention can be replaced or substituted by a deuterium atom. In some embodiments, the compound comprises two or more deuterium atoms. In some embodiments, the compound comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 deuterium atoms. Methods for synthesizing isotopes into organic compounds are known in the art.

[0078] Preparation method:

[0079] This invention also provides a method for preparing the compound. The preparation of the compound of formula (I) can be accomplished by the following exemplary methods and examples, but these methods and examples should not be considered in any way as limiting the scope of the invention. The compound of this invention can also be synthesized by synthetic techniques known to those skilled in the art, or by combining synthetic methods known in the art with the method described in this invention. The product obtained from each reaction step is obtained using separation techniques known in the art, including but not limited to extraction, filtration, distillation, crystallization, chromatographic separation, etc. The starting materials and chemical reagents required for synthesis can be conventionally synthesized according to literature (such as those provided by Scifinder) or purchased.

[0080] Synthesis process route:

[0081] Method 1:

[0082] The method for preparing the compound shown in formula (II) includes the following steps:

[0083] 1) The compound shown in II-1 reacts with the compound shown in II-2 to form the compound shown in II-3;

[0084] 2) The compound shown in II-3 is deprosthetically removed to generate the compound shown in II-4;

[0085] 3) The compound shown in II-4 and the compound shown in II-5 undergo a condensation reaction to produce the compound shown in II-6;

[0086] 4) The compound shown in II-6 undergoes a cyclization reaction to form the compound shown in II-7;

[0087] 5) The compound shown in II-7 is deprotected to form the compound shown in formula II;

[0088] Where: R 2 R 5 m, n, ring A, and ring B are defined as described in Formula I; PG is an abbreviation for protecting group, selected from common nitrogen atom protecting groups such as Boc, Cbz, PMB, Bn, SEM, and MOM, with PMB and SEM being preferred protecting groups.

[0089] Pharmaceutical composition:

[0090] The present invention also provides a pharmaceutical composition comprising a therapeutically and / or preventively effective amount of the compound as described above or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, polymorph, cocrystal, hydrate, solvate, metabolite, prodrug, deuterated compound, and optionally a pharmaceutical excipient.

[0091] Methods for preparing various pharmaceutical compositions containing a certain amount of active ingredient are known, or will be obvious to those skilled in the art according to the disclosure of the present invention. As described in REMINGTON'S PHARMACEUTICAL SCIENCES, Martin, EW, ed., Mack Publishing Company, 19th ed. (1995), the method for preparing the pharmaceutical composition includes incorporating appropriate pharmaceutical excipients, carriers, diluents, etc.

[0092] Medical uses:

[0093] The present invention also provides the use of the compounds as described above, or pharmaceutically acceptable salts, stereoisomers, tautomers, polymorphs, cocrystals, hydrates, solvates, metabolites, prodrugs, deuterated compounds, or pharmaceutical compositions as described above, in the preparation of medicaments for the treatment and / or prevention of diseases related to MGAT2 regulation.

[0094] The present invention also provides the use of the compounds as described above or pharmaceutically acceptable salts, stereoisomers, tautomers, polymorphs, cocrystals, hydrates, solvates, metabolites, prodrugs, deuterated compounds, or pharmaceutical compositions as described above, in the treatment and / or prevention of diseases related to MGAT2 regulation.

[0095] The present invention also provides the compounds as described above or pharmaceutically acceptable salts, stereoisomers, tautomers, polymorphs, cocrystals, hydrates, solvates, metabolites, prodrugs, deuterated compounds, or pharmaceutical compositions as described above for the treatment and / or prevention of diseases associated with MGAT2 regulation.

[0096] The present invention also provides a method for treating and / or preventing diseases associated with MGAT2 regulation, comprising administering to an individual in need a therapeutically and / or preventively effective amount of the compound as described above, or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, cocrystal, hydrate, solvate, metabolite, prodrug, deuterated compound, or pharmaceutical composition as described above.

[0097] Preferably, the diseases related to MGAT2 regulation described herein are metabolic disorders or metabolic abnormalities; the metabolic disorders or metabolic abnormalities are preferably obesity.

[0098] In this invention, "treatment" generally refers to achieving the desired pharmacological and / or physiological effect. This effect may be preventative based on the complete or partial prevention of the disease or its symptoms; and / or therapeutic based on the partial or complete stabilization or cure of the disease and / or side effects resulting from the disease. As used herein, "treatment" encompasses any treatment of a patient's disease, including: (a) preventing the disease or symptoms occurring in a patient who has not yet been diagnosed with the disease; (b) suppressing the symptoms of the disease, i.e., preventing its progression; or (c) alleviating the symptoms of the disease, i.e., causing the disease or symptoms to regress.

[0099] In this invention, "subject" and "individual in need" refer to vertebrates. In some embodiments, vertebrates refer to mammals. Mammals include, but are not limited to, livestock (such as cattle), pets (such as cats, dogs, and horses), primates, mice, and rats. In some embodiments, mammals refer to humans.

[0100] In this invention, "effective amount" refers to the amount that effectively achieves the desired therapeutic or preventative effect at the necessary dose and time. The "therapeutic effective amount" of the substance / molecule of this invention may vary depending on factors such as an individual's disease state, age, sex, weight, and the substance / molecule's ability to elicit the desired response in the individual. Therapeutic effective amount also encompasses the amount in which the beneficial therapeutic effect of the substance / molecule outweighs any toxic or harmful consequences. "Preventative effective amount" refers to the amount that effectively achieves the desired preventative effect at the necessary dose and time. Typically, but not necessarily, the preventative effective amount will be lower than the therapeutic effective amount because the preventative dose is administered to the subject before the onset of the disease or in its early stages. In the case of cancer, the therapeutically effective amount of the drug may reduce the number of cancer cells; shrink the tumor volume; inhibit (i.e., slow down, preferably stop) the infiltration of cancer cells into surrounding organs; inhibit (i.e., slow down, preferably stop) tumor metastasis; inhibit tumor growth to some extent; and / or alleviate one or more symptoms associated with cancer to some extent.

[0101] Terminology definition:

[0102] According to the conventions of the art, In the structural formula of this paper, the bond is used to describe the connection point between the part or substituent and the parent nucleus or main structure.

[0103] The hyphen "-" that does not appear between two letters or symbols is used to indicate the connection point of a substituent. For example, C 3-6 cycloalkyl-(C 1-6 alkyl) r -meaning through (C) 1-6 alkyl) r - Connected to the rest of the molecule.

[0104] As used in this article, “substituted” or “replaced by one or more” means that any one or more hydrogen atoms on a specified atom or group are selectively replaced by a specified group, provided that the replacement does not exceed the normal valence state of the specified atom.

[0105] In various parts of this specification, the substituents of the compounds disclosed herein are disclosed according to the type or scope of the groups. In particular, the invention includes every independent secondary combination of the various members of these group types and scopes. For example, the term "C..." 1-6 "alkyl" specifically refers to independently disclosed methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl, or independently disclosed "C 1-4 "alkyl", or independently disclosed "C 1-3 alkyl".

[0106] The term "alkyl" refers to both branched and straight-chain saturated aliphatic hydrocarbon groups having a specified number of carbon atoms. For example, "C 1-6 "Alkyl" refers to an alkyl group having 1 to 6 carbon atoms. An alkyl group can be unsubstituted or substituted, whereby one or more of its hydrogen atoms are replaced by another chemical group. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, tert-butyl), pentyl (e.g., n-pentyl, isopentyl, neopentyl), etc. Those skilled in the art will understand that C is used herein. 1-6 Alkyl groups contain monovalent C 1-6 Alkyl, divalent C 1-6 Alkylenes, such as C3-C6 cycloalkyl-(C1-C6 alkyl) r The C1-C6 alkyl in - refers to C1-C6 alkylene.

[0107] The term "alkoxy" refers to any of the above-mentioned alkyl groups (e.g., C10, C20, C30, C40, C50, C6 ... 1-6 Alkyl, C 1-4 Alkyl, C 1-3 Alkyl groups, etc., which are attached to the rest of the molecule by oxygen atoms (-O-).

[0108] Term "C" 1-6 "Halogenated alkyl" or "C" 1-6 "Haloalkoxy" refers to an alkyl or alkoxy group in which one or more (e.g., two or three) hydrogen atoms are replaced by a halogen atom, such as fluorine, chlorine, or bromine. The definition of the alkyl or alkoxy group is as described above. In some embodiments, the term "C" is used... 1-6 The "haloalkyl" is preferably fluorinated, and can be, for example, -CF3, -CHF2, -CH2F, -CH2CH2F, -CH2CHF2, -CH2CF3, etc. In some embodiments, the term "C" is used... 1-6The "haloalkoxy" is preferably fluorinated, for example, it can be -OCF3, -OCHF2, -OCH2F, -OCH2CH2F, -OCH2CHF2, -OCH2CF3, etc.

[0109] The term "hydroxy-substituted C" 1-6 "Alkyl" refers to an alkyl group in which one hydrogen atom is replaced by a hydroxyl group, as defined above. As an example, the "hydroxyl-substituted C..." 1-6 "alkyl" can be hydroxymethyl.

[0110] The term "cycloalkyl" refers to a cyclic alkyl group, including monocyclic, bicyclic, or polycyclic systems. When a cycloalkyl group is bicyclic or polycyclic, each ring should be a saturated carbocyclic ring or carbocyclic residue. The possible connections between two rings in a bicyclic or polycyclic cycloalkyl group include bridging, fusion, or helicaling. For example, C 3-10 Cycloalkyl refers to compounds including C3, C4, C5, C6, C7, C8, C9, and C6. 10 Cycloalkyl groups. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0111] The term "cycloalkenyl" refers to a cycloalkyl group as defined above, which has at least one carbon-carbon double bond, for example...

[0112] The term "cycloalkoxy" refers to any of the above-mentioned cycloalkyl groups (e.g., C10, C20, C30, C40, C50, C60, C7 ... 3-6 Cycloalkyl groups are alkyl groups that are attached to the rest of the molecule by an oxygen atom (-O-).

[0113] The term "carbocyclic ring" or "carbocyclic residue" refers to any stable 3-, 4-, 5-, 6-, or 7-membered monocyclic ring or 5-, 6-, 7-, 8-, 9-, 10-, 11-, 12-, 13-, or 14-membered bicyclic or polycyclic ring, wherein any ring can be saturated, partially saturated, unsaturated, or aromatic. The connection between each pair of bicyclic or polycyclic carbocyclic rings can include bridging, fusion, or helicaling. Examples of such carbocyclic rings include, but are not limited to, cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptenyl, cycloheptyl, adamantyl, cyclooctyl, phenyl, naphthyl, [2,2,2]bicyclooctane, etc. wait.

[0114] The term "aryl" refers to a monocyclic, bicyclic, or tricyclic aromatic hydrocarbon group having 5 to 14 carbon atoms in its ring moiety. When an aryl group is bicyclic or tricyclic, at least one ring is an aromatic ring. The two rings of a bicyclic or tricyclic aryl group can be linked in various ways, including bridging, fusion, and helicaling. Examples include phenyl and naphthyl groups, each of which can be substituted.

[0115] The terms "heterocyclic," "heterocyclic," or "heterocyclic group" are used interchangeably and refer to substituted and unsubstituted 4-8 membered monocyclic or bicyclic groups, 8-10 membered bicyclic or tricyclic groups, and 10-14 membered tricyclic or polycyclic groups, wherein at least one ring has at least one heteroatom (O, S, or N), preferably having one, two, or three heteroatoms selected from O, S, and N. Each heteroatom-containing ring in the group may contain one or two oxygen or sulfur atoms and / or one to four nitrogen atoms, limited by the total number of heteroatoms in each ring being four or less, and further limited by the ring containing at least one carbon atom. In some preferred embodiments, the heteroatom refers only to N or O, and the total number of these does not exceed three, preferably only one or two heteroatoms. Carbon and sulfur atoms may optionally be oxidized, nitrogen atoms may optionally be quaternized, and ring atoms on the heterocycle may optionally be substituted with =O (oxo) when the valence allows. (e.g.: The fused rings completing the bicyclic and tricyclic groups may contain only carbon atoms and may be saturated, partially saturated, or completely unsaturated, aromatic or non-aromatic. Heterocyclic groups may be attached to any available nitrogen or carbon atom. As previously mentioned, heterocyclic groups include “spiroheterocyclic,” “heterobridged,” and “heterocyclic alkenyl,” etc., as described below. Exemplary heterocyclic groups include, but are not limited to, azirrobutyl, oxacyclobutyl, pyrrolidinyl, imidazolinyl, oxazolidinyl, isoxazolinyl, thiazolinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, 2-oxopiperidinyl, 2-oxopiperidinyl, 2-oxopiperidinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxaazirroheptatrienyl, 1-pyridoneyl, 4-piperidinoneyl, tetrahydropyranyl, morpholinyl, 1,3-dioxacyclopentyl, quininecycloyl, etc.

[0116] The terms "saturated heterocyclic group" and "heterocyclic alkyl group" refer to the aforementioned "heterocyclic group" in which each ring of the monocyclic, bicyclic, or tricyclic group is in a fully saturated state. The "heterocyclic group" is as described above. As an example, the saturated heterocyclic group can be a morpholino group (e.g., ...). ), piperidinyl (e.g.) ), piperazine group etc.

[0117] The term "heterocyclic alkenyl" refers to a heterocyclic group that has at least one carbon-carbon double bond in a heterocycle as defined above, for example...

[0118] The term "heteroaryl" refers to the aforementioned aryl groups, both substituted and unsubstituted, having at least one heteroatom (O, N, or S) in at least one ring. These include aromatic 5-8 membered monocyclic groups, 8-10 membered bicyclic groups, and 10-14 membered tricyclic groups. The heteroatom-containing ring preferably has one, two, or three heterocyclic atoms selected from O, N, or S. Each heteroatom-containing ring of the heteroaryl group may contain one or two oxygen or sulfur atoms and / or one to four nitrogen atoms, with the limitation that the total number of heteroatoms in each ring is four or less and each ring has at least one carbon atom. For bicyclic or tricyclic heteroaryl groups, each ring is an aromatic ring.

[0119] The term "spirocyclic" refers to a bicyclic structure having a common ring atom, where each monocyclic ring is a saturated or unsaturated, aromatic or non-aromatic carbon ring having 3-7 carbon atoms. Exemplary spirocyclic alkyl groups include, but are not limited to: spirocyclic[4.5]decane, spirocyclic[3.4]octane, spirocyclic[2.3]hexane, etc. Etc. In this document, the spirocyclic group does not include the aryl group as defined above.

[0120] The terms "saturated spirocyclic" and "spirocyclic alkyl" refer to a "spirocyclic group" as defined above, in which each monocycle is fully saturated. Exemplary spirocyclic alkyl groups include, but are not limited to: spirocyclic[4.5]decane, spirocyclic[3.4]octane, and spirocyclic[2.3]hexane.

[0121] The term "spiroheterocyclic group" refers to a bicyclic structure having one shared ring atom or a tricyclic structure having two independent shared ring atoms, wherein each monocyclic ring is a saturated or unsaturated monocyclic group having 3-8 ring atoms, wherein at least one ring has 1 or 2 ring atoms selected from N, O or S(O). n The heteroatom is a carbon atom, where n is an integer from 0 to 2, and the remaining ring atoms are carbon atoms. Additionally, one or two ring carbon atoms in the heterocyclic group are optionally replaced by a -CO- group. Exemplary spiroheterocyclic groups include, but are not limited to, 5-azaspiro[2.3]hexane and 6-oxaspiro[3.4]-7-octanone. In this document, the spiroheterocyclic groups do not include heteroaryl groups as defined above.

[0122] The terms "saturated spiroheterocyclic" and "spiroheterocyclic alkyl" refer to a "spiroheterocyclic group" as defined above, where each monocycle is fully saturated. Exemplary spirocyclic alkyl groups include, but are not limited to:

[0123] The term "bridged ring group" refers to a 3- to 8-membered monocyclic carbocyclic group, whether saturated or unsaturated, aromatic or non-aromatic, in which two non-adjacent ring atoms are connected by a cross ring (CRR). n Group, C 2-6 alkenyl, C 2-6Alkyne groups or bonds are linked, where n is an integer from 1 to 3, and each R is independently H or methyl (where (CRR) n Group, C 2-6 alkenyl, C 2-6 The alkynyl group or bond is also referred to herein as a bridging group. The bridging group is optionally substituted by one or two substituents independently selected from alkyl, halogen, alkoxy, hydroxy, or cyano groups, wherein the alkyl, alkoxy, alkenyl, and alkynyl groups are each defined as described above. Examples of bridging groups include, but are not limited to, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, etc. It should be understood herein that when two non-adjacent ring atoms of a monocyclic 4- to 7-membered hydrocarbon group are connected by a bond, the “bridging group” may be referred to as a “fused ring group” or “fused ring group.” In this document, the bridging group does not include aryl groups as defined above.

[0124] The terms "saturated bridged cycloalkanes" and "bridged cycloalkyl groups" refer to "bridged cycloalkanes" as defined above, where each ring is in a saturated state. Here, "saturated" should be understood as each carbon atom in the bridged cycloalkanes being in a saturated state (including the carbon atoms in the bridging groups).

[0125] The term "heterobridged cyclogroup" refers to a "bridged cyclogroup" as defined above, having one, two, three, or four cyclic carbon atoms (including carbon atoms in the bridging group) replaced by heteroatoms selected from N, O, or S(O)n, where n is an integer from 0 to 2. Examples of "heterobridged cyclogroups" include, but are not limited to, 2-azabicyclo[2.2.2]octane, quinine ring, 7-oxabicyclo[2.2.1]heptane, etc. In this document, the heterobridged cyclogroups do not include heteroaryl groups as defined above.

[0126] The terms "saturated heterobridged cyclogroup" and "heterobridged cycloalkyl" refer to "heterobridged cyclogroups" as defined above, where each ring is in a saturated state. Here, "saturated" should be understood as each ring atom in the bridged cyclogroup being in a saturated state (including carbon / heteroatoms in the bridging group).

[0127] Unless otherwise specified, when referring to a clearly named aryl (e.g., phenyl), cycloalkyl (e.g., cyclohexyl), heterocyclic (e.g., pyrrolidinyl, piperidinyl, morpholinyl) or heteroaryl (e.g., imidazolyl, pyrazolyl, triazolyl), the reference means a ring having 0 to 3, preferably 0 to 2, substituents selected as needed from the substituents described above for aryl, cycloalkyl, heterocyclic and / or heteroaryl.

[0128] The term "heteroatoms" should include oxygen, sulfur, and nitrogen.

[0129] The term "halogen" should include "F, Cl, Br, I".

[0130] When the term "unsaturated" is used in the text to refer to a ring or group, the ring or group may be completely unsaturated or partially unsaturated.

[0131] When the term "saturation" is used in the text to refer to a ring or group, unless otherwise specified, the ring or group should be completely saturated.

[0132] Throughout the specification, groups and their substituents may be selected by those skilled in the art to provide stable moieties and compounds and compounds that can be used as pharmaceutically acceptable compounds and / or intermediate compounds that can be used to prepare pharmaceutically acceptable compounds.

[0133] In this document, unless otherwise explicitly stated, the descriptive phrase “…each independently selected” used throughout the document can mean either that the specific options expressed by the same or different symbols in different groups do not affect each other, or that the specific options expressed by the same or different symbols in the same group do not affect each other.

[0134] In this article, when the structure and chemical name are inconsistent, the structure shall prevail.

[0135] Invention effects:

[0136] The compound represented by formula (I) of the present invention exhibits good MGAT2 inhibitory activity and can be used as a drug for the treatment and / or prevention of diseases related to this activity. Detailed Implementation

[0137] The invention is further illustrated below with specific examples, but the scope of protection of the invention is not limited to these examples. Unless otherwise specified, all percentages mentioned in this invention are weight percentages. The numerical ranges described in the specification, such as units of measurement, reaction conditions, physical states of compounds, or percentages, are provided for clear and unambiguous written reference. Those skilled in the art may still obtain the desired results when practicing this invention using temperatures, concentrations, quantities, carbon numbers, etc., outside these ranges or different from individual values.

[0138] The structure of the compound was determined by nuclear magnetic resonance (NMR) or mass spectrometry (MS). NMR measurements were performed using a Bruker Avance II-400MHz NMR spectrometer (BBFO probe) or a Bruker Avance II-600MHz NMR spectrometer (BBO probe). The solvents used were deuterated solvents such as deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), deuterated methanol (CD3OD), and heavy water (D2O). Tetramethylsilane (TMS) was used as the internal standard. Chemical shifts were expressed in 10⁻¹⁰ increments. -6 (ppm) is given as the unit.

[0139] Reaction monitoring and MS measurements were performed using a Thermo Scientific ISQ EC single quadrupole mass spectrometer (Philomon Titank C18 3um 4.6*50mm).

[0140] The HPLC determination was performed using a Thermo Ultimate 3000 high-performance liquid chromatograph (GL Sciences ODS-HL HP 3um 3.0*100mm).

[0141] Thin-layer chromatography (TLC) used Qingdao Ocean GF254 silica gel plates. The silica gel plates used in TLC had a diameter of 0.15–0.2 mm, while the purified products were separated using high-performance thin-layer chromatography (HPLC) preparative plates with a diameter of 0.9–1.0 mm. Column chromatography used Qingdao Ocean 200–300 mesh silica gel as the carrier. The developing solvent systems included dichloromethane and methanol, and petroleum ether and ethyl acetate, with the volume ratio adjusted according to the polarity of the compounds. For MPLC purification using medium-pressure preparative liquid chromatography, a Biotage Isera One preparative liquid chromatography system was used.

[0142] In the following examples, unless otherwise specified, all reaction materials can be purchased from suppliers in the SciFinder database. For example, some reagents in the various embodiments of this invention were purchased from manufacturers such as Saen Chemical Technology (Shanghai) Co., Ltd., Shanghai Shaoyuan Reagent Co., Ltd., Nanjing Yaoshi Technology Co., Ltd., Jiangsu Aikon Biomedical R&D Co., Ltd., and Shanghai Bid Pharmaceutical Technology Co., Ltd. Furthermore, unless otherwise specified, all raw materials used in the various embodiments of this invention are of analytical grade.

[0143] intermediate int.-1:

[0144] Step 1: Int.-1a (5 g, 35.69 mmol), 1,2-dibromoethane (67.1 g, 356.89 mmol), and potassium carbonate (9 g, 64.95 mmol) were placed in a 500 mL single-necked flask, and acetonitrile (250 mL) was added. The reaction was carried out at 70 °C for 6 hours. The reaction was monitored by LC-MS until complete. The reaction solution was concentrated, the residue was dissolved in ethyl acetate, the organic phase was washed with water, dried over anhydrous sodium sulfate, and the residue was purified by column chromatography to obtain int.-1b (6.8 g, 27.52 mmol, 77.1% yield). MS Calcd: 245.97; MS Found: 247.05 ([M+H] + ).

[0145] Step 2: Int.-1b (6.8 g, 27.52 mmol) and sodium thiocyanate (3.1 g, 38.53 mmol) were placed in a 250 mL single-necked flask, and acetonitrile (100 mL) was added. The mixture was reacted at 100 °C for 7 hours. The reaction was monitored by LC-MS until complete. The reaction solution was concentrated, and the residue was purified by column chromatography to obtain int.-1c (6 g, 26.64 mmol, 96.8% yield). MS Calcd: 225.03; MS Found: 226.19 ([M+H] + ).

[0146] Step 3: Weigh int.-1c (3g, 13.32mmol) and TMSCF3 (2.8g, 19.98mmol) into a 250mL two-necked flask, and add THF (60mL). Add tetrabutylammonium fluoride (tetrahydrofuran solution, 19.98mL, 19.98mmol) to the system under ice bath conditions, and stir at room temperature for 8 hours. Monitor the reaction for completeness using LCMS. Concentrate the reaction solution, dissolve the residue in ethyl acetate, wash the organic phase with water, dry to anhydrous sodium sulfate, and purify the residue by column chromatography to obtain int.-1d (1.1g, 4.10mmol, 30.8% yield). MS Calcd: 268.02; MS Found: 269.12 ([M+H] + ).

[0147] Step 4: Weigh int.-1d (700 mg, 2.61 mmol) and TMSCF3 (557 mg, 3.91 mmol) into a 50 mL single-necked flask, add ethylene glycol dimethyl ether (15 mL), and add cesium fluoride (39 mg, 0.26 mmol) to the system. Stir at room temperature for 3 hours, then add 0.5 mL of hydrochloric acid (4N) and continue stirring for 1 hour. Monitor the reaction for completeness by TLC. Add ethyl acetate, wash the organic phase with water, dry it with anhydrous sodium sulfate, concentrate the residue, and purify it by column chromatography to obtain int.-1e (820 mg, 2.42 mmol, 92.9% yield).

[0148] Step 5: Weigh int.-1e (800 mg, 2.37 mmol) and active manganese dioxide (3.08 g, 35.48 mmol) into a 50 mL single-necked flask, add 1,2-dichloroethane (15 mL), and react at 85 °C for 24 hours. Monitor the reaction by TLC until complete. After filtration, concentrate the reaction solution to obtain int.-1f (740 mg, 2.20 mmol, 93.1% yield).

[0149] Step Six: Weigh int.-1f (740 mg, 2.20 mmol), S-tert-butylsulfinamide (540 mg, 4.43 mmol), and tetraethyl titanate (2.03 g, 8.92 mmol) into a 50 mL two-necked flask. Add THF (12 mL) and react at 80 °C for 5 hours. Monitor the reaction for completeness using LC-MS. Concentrate the reaction solution, dissolve the residue in ethyl acetate, quench the reaction with 1 N citric acid, and a white solid precipitates. Filter and wash the solid with ethyl acetate. Concentrate the organic phase and purify the residue by column chromatography to obtain int.-1 (480 mg, 1.09 mmol, 49.0% yield). MS Calcd: 439.05; MS Found: 440.07 ([M+H]) + ).

[0150] intermediate int.-2:

[0151] Step 1: Add int.-2a (10g, 59.45mmol), NBS (11.6g, 65.40mmol), AIBN (1g, 5.95mmol), and acetonitrile (130mL) to a 100mL two-necked flask, then heat to 80℃ and react for 2 hours. TLC analysis showed the reaction was complete. The crude product was purified by column chromatography to obtain int.-2b (12g, 48.56mmol, 81.7% yield).

[0152] Step 2: Add int.-2b (5 g, 20.23 mmol) and triethyl phosphite (10 mL) to a 100 mL round-bottom flask; heat to 110 °C and react for 3 hours. TLC analysis showed the reaction was complete. The crude product was purified by column chromatography to give int.-2c (5 g, 16.43 mmol, 81.2% yield). MS Calcd: 304.09; MS Found: 305.11 ([M+H] + ).

[0153] Step 3: Add int.-2c (1 g, 3.29 mmol) and DMF (10 mL) to a 100 mL round-bottom flask; then add potassium tert-butoxide (737.4 mg, 6.57 mmol) and react at room temperature for 30 minutes. Add 4,4,4-trifluorobutanal (828.8 mg, 6.57 mmol) and stir at room temperature for 1 hour. TLC analysis showed the reaction was complete. Dilute with EA (30 mL), wash the organic phase with saturated brine, dry to anhydrous sodium sulfate, concentrate under reduced pressure, and purify the crude product by column chromatography to obtain int.-2d (500 mg, 1.81 mmol, 55.1% yield). MS Calcd: 276.08; MS Found: 277.17 ([M+H)+ ).

[0154] Step 4: Add morpholine (711.1 mg, 8.16 mol) and THF solvent (10 mL) to a 50 mL double-necked flask. Add DIBAL-H (5.31 mL, 7.97 mmol) under ice bath conditions and react at this temperature for 30 minutes. Then add int.-2d (500 mg, 1.81 mmol) and continue stirring for another 30 minutes. LCMS analysis confirmed the reaction was complete. Quench with 1 N dilute hydrochloric acid, extract with EA (50 mL * 3), wash the organic phase with saturated brine, dry to anhydrous sodium sulfate, concentrate under reduced pressure, and purify the crude product by column chromatography to obtain int.-2e (280 mg, 1.14 mmol, 57.1% yield). MS Calcd: 246.07; MS Found: 247.12 ([M+H]) + ).

[0155] Step 5: Add int.-2e (300 mg, 1.22 mmol), cesium fluoride (18.5 mg, 0.12 mmol), and ethylene glycol dimethyl ether (5 mL) to a 25 mL round-bottom flask; add compound TMSCF3 (433.2 mg, 3.05 mmol), and react at room temperature for 30 minutes. After TLC detection confirms the reaction is complete, quench with saturated ammonium chloride solution, extract with EA (30 mL * 3), wash the organic phase with saturated brine, dry with anhydrous sodium sulfate, and concentrate under reduced pressure to obtain crude int.-2f (380 mg), which is directly added to the next step without purification.

[0156] Step Six: Add int.-2f (380 mg, 1.20 mmol) and 1,2-dichloroethane (10 mL) to a 25 mL round-bottom flask; then add active manganese dioxide (1500 mg, 17.26 mmol), and heat to 80 °C overnight. TLC analysis showed the reaction was complete. The reaction solution was filtered and concentrated to obtain crude int.-2g (280 mg), which was directly added to the next step without purification.

[0157] Step 7: Add int.-2 g (550 mg, 1.75 mmol), S-tert-butylsulfinamide (424.3 mg, 3.50 mmol), and THF solvent (15 mL) to a 50 mL round-bottom flask; add tetraethyl titanate (1597.2 mg, 7.00 mmol), and then heat to 80 °C for 3 hours. After the reaction is complete, citric acid is added to the reaction solution for acidification. Extraction is performed using EA (50 mL * 3). The organic phase is washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product is purified by silica gel column chromatography (EA:PE = 10%) to obtain compound int.-2 (440 mg, 1.05 mmol, 60.2% yield). MS Calcd: 217.10; MS Found: 418.12 ([M+H) + ).

[0158] intermediate int.-3:

[0159] Following the preparation method of int.-1, 1,3-dibromopropane was replaced with 1,2-dibromoethane to prepare int.-3.

[0160] intermediate int.-4:

[0161] Step 1: Weigh int.-4a (500 mg, 1.98 mmol), vinylboronic acid pinacol ester (616 mg, 4 mmol), potassium carbonate (830 mg, 6 mmol), and Pd(dppf)Cl2 (146 mg, 0.2 mmol) into a 25 mL two-necked flask. Add dioxane (10 mL) and water (2.5 mL), purge with nitrogen for 2 minutes, raise the temperature to 100 °C, and stir for 5 hours. Monitor the reaction for completeness using LC-MS. Concentrate under reduced pressure, and purify the residue by column chromatography (EA:PE = 1:5) to obtain int.-4b (260 mg). MS Calcd: 199.07; MS Found: 200.09 ([M+H] + )

[0162] Step 2: Weigh int.-4b (260 mg, 1.3 mmol) into a 25 mL two-necked flask, add dichloromethane (5 mL), then add trifluoroacetic acid (3 mL) and water (0.2 mL), stir at room temperature for 2 hours, and monitor the reaction until complete using LCMS. Concentrate under reduced pressure, adjust the pH of the residue to 7 with saturated sodium bicarbonate solution, then extract with EA (5 mL x 2), combine the organic layers, dry over anhydrous sodium sulfate, filter, and concentrate to obtain int.-4c (200 mg). MS Calcd: 153.02; MS Found: 154.05 ([M+H] + )

[0163] Step 3: Weigh int.-4c (200 mg, 1.3 mmol) into a 25 mL two-necked flask, add methanol (5 mL), then add palladium on carbon (20 mg, 10%). Stir for 3 hours under a hydrogen atmosphere, monitoring the reaction until complete via LC-MS. Filter, concentrate the filtrate under reduced pressure, and purify the residue by column chromatography (EA:PE = 1:10) to obtain int.-4 (180 mg). MS Calcd: 155.04; MS Found: 156.06 ([M+H] + )

[0164] intermediate int.-5: The synthetic method is referenced in J. Med. Chem. 2023, 66, 13135-13147.

[0165] intermediate int.-6:

[0166] Referring to the preparation method of int.-1, int.-6a is replaced with int.-1a to obtain int.-6.

[0167] intermediate int.-7:

[0168] Step 1: Weigh int.-7a (1 g, 4.85 mmol), 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborane (1.6 g, 9.7 mmol), potassium carbonate (2.1 g, 15 mmol), and Pd(dppf)Cl2 (365 mg, 0.5 mmol) into a 50 mL two-necked flask. Add dioxane (10 mL) and water (2.5 mL), purge with nitrogen for 2 minutes, raise the temperature to 100 °C, and stir for 3 hours. Monitor the reaction for completeness using LC-MS. Concentrate under reduced pressure, and purify the residue by column chromatography (EA:PE = 1:30) to obtain int.-7b (700 mg). MS Calcd: 167.04; MS Found: 168.07 ([M+H] + )

[0169] Step 2: Weigh int.-7b (700 mg, 4.2 mmol) into a 25 mL two-necked flask, add methanol (5 mL), then add palladium on carbon (70 mg, 10%). Stir for 2 hours under a hydrogen atmosphere, monitoring the reaction until complete via LCMS. Filter, concentrate the filtrate under reduced pressure, and purify the residue by column chromatography (EA:PE = 1:10) to obtain int.-7 (600 mg). MS Calcd: 169.06; MS Found: 170.09 ([M+H] + )

[0170] intermediate int.-8:

[0171] Referring to the preparation method of int.-1, int.-8a is used to replace int.-1a to prepare int.-8.

[0172] Example 1: Preparation of Compound 1

[0173] Step 1: Weigh 1a (187 mg, 1.20 mmol, synthesis method referred to J. Med. Chem. 2023, 66, 13135-13147) into a 25 mL two-necked flask, and add tetrahydrofuran (5 mL). Add KHMDS (1.64 mL, 1.64 mmol) to the system at -78 °C and stir for 20 minutes. Then add int.-1 (480 mg, 1.09 mmol) and continue stirring at this temperature for 1 hour. Monitor the reaction for completeness using LC-MS. Add saturated ammonium chloride solution, extract with ethyl acetate, wash the organic phase with water, dry to anhydrous sodium sulfate, concentrate, and purify the residue by column chromatography to obtain 1b (350 mg, 0.58 mmol, 53.1% yield). MS Calcd: 603.15; MS Found: 604.93 ([M+H] + ).

[0174] Step 2: Weigh 1b (350 mg, 0.58 mmol) into a 25 mL single-necked flask, then add methanol (4 mL) and hydrochloric acid-dioxane solution (0.85 mL, 4 mmol / L), and react at room temperature for 1 hour. Monitor the reaction for completeness using LC-MS. Concentrate the reaction solution, dissolve the residue in dichloromethane, wash the organic phase with saturated sodium bicarbonate solution, dry to anhydrous sodium sulfate, and concentrate to obtain 1c (280 mg, 0.56 mmol, 96.7% yield). MS Calcd: 499.12; MS Found: 499.95 ([M+H] + ).

[0175] Step 3: Weigh 1d (187 mg, 0.55 mmol, synthetic method referred to J. Med. Chem. 2023, 66, 13135-13147) and (1-chloro-2-methylprop-1-enyl)dimethylamine (80 mg, 0.60 mmol) into a 25 mL two-necked flask, add dichloromethane (6 mL), and stir at room temperature for 1 hour. Then add compound 1c (230 mg, 0.46 mmol) and 2-(dimethylamino)pyridine (73 mg, 0.60 mmol) to the system, heat to 50 °C and stir for 3 hours. Monitor the reaction for completeness by LCMS. Dilute with dichloromethane, wash the organic phase with water, dry with anhydrous sodium sulfate, concentrate, and purify the residue by column chromatography to obtain 1e (300 mg, 0.40 mmol, 87.4% yield). MS Calcd: 745.19; MS Found: 745.99 ([M+H) + ).

[0176] Step 4: Weigh 1e (270 mg, 0.36 mmol) into a 25 mL single-necked flask, then add methanol (3 mL) and sodium methoxide (78 mg, 1.45 mmol). React at 55 °C for 1 hour. Monitor the reaction for completeness using LC-MS. Adjust the pH to approximately 1 with 1 N hydrochloric acid, dilute with ethyl acetate, wash the organic phase with water, dry to anhydrous sodium sulfate, and purify the residue by column chromatography to obtain 1f (220 mg, 0.30 mmol, 83.5% yield). MS Calcd: 727.18; MS Found: 727.93 ([M+H]) + ).

[0177] Step 5: Weigh 1 part (250 mg, 0.34 mmol) and cerium ammonium nitrate (1.8 g, 3.44 mmol) into a 25 mL single-necked flask, then add acetonitrile (9 mL) and water (3 mL), and react at room temperature for 3 hours. The reaction was monitored by LCMS to ensure completion. After concentrating the reaction solution, the residue was purified by Pre-HPCL to obtain target compound 1 (64.3 mg, 0.11 mmol, 93.7% yield). MS Calcd: 607.12; MS Found: 608.18 ([M+H] + ).

[0178] 1 H NMR (400MHz, DMSO-d6) 1H NMR (400MHz, DMSO-d6) δ14.49(s,1H),9.58(d,J=24Hz,1H),7.88(d,J=2.4H z,1H),7.57(t,J=9.1Hz,1H),6.98–6.89(m,2H),6.01(dd,J=26.6,2.5Hz,1H ),4.31-4.27(m,3H),4.08-3.96(m,2H),3.73(dd,J=23.8,17.6Hz,1H),3.4 2(t,J=5.9Hz,2H),1.27–1.16(m,1H),0.57-0.51(m,2H),0.40-0.35(m,2H).

[0179] Example 2: Preparation of Compound 2

[0180] Step 1: Add 1a (179.4 mg, 1.09 mmol) and solvent THF (8 mL) to a 50 mL double-necked flask; under N2 protection at -78 °C, add compound KHMDS (1.37 mL, 1 mol / L), react at this temperature for 30 minutes, then add int.-2 (380 mg, 0.91 mmol), and continue stirring for 1 hour. LCMS analysis showed the reaction was complete. Saturated ammonium chloride solution was added to the reaction solution, and extraction was performed using EA (20 mL * 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography to obtain 2a (350 mg, 0.60 mmol, 66.1% yield). MS Calcd: 581.19; MS Found: 582.18 ([M+H) + );

[0181] Step 2: Add 2a (200 mg, 0.34 mmol) and methanol (6 mL) to a 25 mL round-bottom flask; add hydrochloric acid-dioxane solution (2 mL, 4 mmol / L) and react at room temperature for 1 hour. After LCMS detection, the reaction proceeded. Add saturated sodium bicarbonate solution to adjust the alkali, extract with EA (20 mL * 3), wash the organic phase with saturated brine, dry with anhydrous sodium sulfate, and concentrate under reduced pressure to obtain crude product 2b (160 mg), which was directly added to the next step without purification. MS Calcd: 477.17; MS Found: 478.18 ([M+H) + ).

[0182] Step 3: Add 1d (132.8 mg, 0.50 mmol) and DCM (5 mL) to a 25 mL round-bottom flask, then add (1-chloro-2-methylprop-1-enyl)dimethylamine (67.2 mg, 0.50 mmol) and react at room temperature for 20 minutes. Then add the reaction solution to a DCM (5 mL) solution containing 2b (160 mg, 0.34 mmol) and 2-(dimethylamino)pyridine (81.9 mg, 0.67 mmol) and continue reacting for 1 hour. After the starting material reaction was complete, add DCM (20 mL) to dilute the solution. Wash the organic phase with saturated brine, dry with anhydrous sodium sulfate, concentrate the organic phase under reduced pressure, and purify the crude product by column chromatography to obtain 2c (230 mg, 0.32 mmol, 94.8% yield). MS Calcd: 723.24; MS Found: 724.27 ([M+H) + );

[0183] Step 4: Add 2c (230 mg, 0.32 mmol) and methanol (5 mL) to a 25 mL round-bottom flask; then add sodium methoxide (85.8 mg, 1.59 mmol), and heat to 55 °C for 1 hour. After the reaction is complete as determined by LC-MS, adjust the acidity with 1N dilute hydrochloric acid, extract with EA (20 mL * 3), wash the organic phase with saturated brine, dry with anhydrous sodium sulfate, and concentrate under reduced pressure to obtain 2d (190 mg) of crude product, which was directly added to the next step without purification. MS Calcd: 705.23; MS Found: 706.33 ([M+H) + );

[0184] Step 5: Add 2d (190mg, 0.27mmol) and solvent acetonitrile (6mL), H2O (2mL) to a 25mL round-bottom flask; then add cerium ammonium nitrate (856.6mg, 1.62mmol), and react at room temperature for 2 hours. After the reaction is complete as determined by LCMS, dilute with EA (20mL*3), wash the organic phase with saturated brine, dry to anhydrous sodium sulfate, concentrate the organic phase under reduced pressure, and purify the residue with Pre-HPCL to obtain target compound 2 (35mg, 0.06mmol, 22.0% yield). MS Calcd: 585.17; MS Found: 586.21 ([M+H) + ). 1H NMR (400MHz, DMSO-d6) δ14.48(s,1H),9.58(d,J=23.9Hz,1H),7.85(d,J=2.4Hz ,1H),7.57(t,J=8.0Hz,1H),7.37–7.25(m,2H),6.54–6.38(m,2H),5.98(dd,J=2 4.9,2.4Hz,1H),4.32(d,J=17.8Hz,1H),4.07–3.91(m,2H),3.74(t,J=18.8Hz,1 H),2.46–2.35(m,4H),1.28–1.12(m,1H),0.55–0.48(m,2H),0.39–0.30(m,2H).

[0185] Example 3: Preparation of Compound 3

[0186] Following the preparation process of compound 1, intermediate 1a was replaced with intermediate 3a to prepare compound 3. 1 H NMR(400MHz,DMSO-d6)δ7.62–7.51(m,1H),7.19–7.05(m,4H),6.97–6.86(m,2H) ,4.27(t,J=6.0Hz,2H),3.90–3.74(m,2H),3.38(t,J=5.8Hz,2H),2.26(s,3H).MS Calcd:577.10;MS Found:578.05([M+H] + ).

[0187] The following compounds were prepared using a similar method to that used for compound 1 or compound 2. Other required raw materials can be purchased commercially or synthesized by organic synthesizers using conventional reactions with commercially available reagents.

[0188] Reference Example 1

[0189] The preparation process of Example 1 is referenced in J. Med. Chem. 2023, 66, 13135-1314.

[0190] Experimental Example 1: Evaluation of In Vitro Enzyme Activity

[0191] By measuring IC 50 The values ​​were used to evaluate the inhibitory activity of the compounds in the examples against human MGAT2 enzyme.

[0192] Human MGAT2 protein was expressed in Sf9 cells (Gibco, A35243) using the Bac-to-Bac baculovirus expression system. Protein preparation was performed at 4°C. Sf9 cells expressing (His)6MGAT2 were resuspended in buffer (1 mM EDTA: E9884, Sigma; 200 mM Source: V900116, Sigma; 100 mM Tris-HCl pH 7.4: T0497, Sigma), sonicated, and centrifuged at 4000 rpm for 30 min. The supernatant was collected as the MGAT2 protein for subsequent enzymatic activity evaluation.

[0193] The compounds in the examples were serially diluted with DMSO (Sigma, D5879), followed by a second dilution with Assay buffer (100 mM Tris-HCl pH 7.5; 5 mM MgCl2: 63068, Sigma; 100 mM Source), starting at a concentration of 100.0 μM and diluting 4X, for a total of 10 concentration points. 20 μL of the diluted compound solutions were added to each well of a 96-well test plate (Corning, 3916) using a 12-channel pipette (Rainin: Pipet-Lite XLS+). Add 20 μL of recombinant human MGAT2 protein (final concentration 2.5 μg / ml) to a 96-well plate, centrifuge at 1000 rpm (Eppendorf, 5840R) for 1 min, then add 60 μL of substrate [5.3 μM oleoyl-CoA: O1012, Sigma; 7.8 μM 2-oleoylglycerol: T37526, TagertMol; 7.5 μM phosphatidylcholine: P3556, Sigma] to the 96-well plate, centrifuge at 1000 rpm for 1 min, and incubate at room temperature for 20 min. After incubation, add 20 μL of fluorescent probe (Invitrogen, D346) with a final concentration of 5 μM CPM to the 96-well plate, centrifuge at 1000 rpm for 1 min, and incubate at room temperature for 20 min. Subsequently, the fluorescence signals of the reaction system (excitation light 380 nM, emission light 460 nM) were read using a high-throughput drug screening multi-functional microplate reader (TECAN Spark). The inhibition percentage (%) of each concentration compound was calculated based on the signals of the minimum and maximum luminescence signal groups contained in each detection plate. The minimum luminescence signal group contained no added substrate or compound, and was otherwise consistent with the compound group, with the lowest luminescence signal, set as 100% inhibition. The maximum luminescence signal group also contained no added compound, and was otherwise consistent with the compound group, with the highest luminescence signal, set as 0% inhibition.

[0194] The inhibition rate of each compound concentration is calculated as follows: Inhibition rate % = {1 - [(maximum luminescence signal group - compound group luminescence signal) / (maximum luminescence signal group - minimum luminescence signal group)]} * 100%. Finally, the compound concentration required for 50% inhibition, i.e., IC50, is determined using the four-parameter logistic dose-response equation. 50 Values. See Table 1 for the results.

[0195] Table 1 Inhibitory activity of the compound MGAT2 of the present invention.

[0196] The results in Table 1 show that the compounds of the present invention have a significantly better inhibitory effect on the activity of MGAT2 enzyme than existing compounds, as shown in Reference Example 1.

[0197] Experimental Example 2: MGAT2 Inhibitor Cellular LC-MS Detection Experiment

[0198] The inhibitory level on the target protein was evaluated by detecting the amount of product generated in HIEC6 MGAT2 overexpressing cell lines. On day 0, HIEC6 MGAT2 overexpressing cells (Xinyuan Biotechnology, HIEC-6) in logarithmic growth phase were collected and diluted to 1.8 × 10⁻⁶ cells with the appropriate culture medium: DMEM + 10% FBS + 1% PS + 10 mM GlutaMAX + 10 ng / mL EGF (DMEM: 11965092, Gbico; FBS: A5669701, Gbico; PS: 15140122, Gbico; GlutaMAX: 35050061, Gbico; EGF: PMG8045, Gbico). ^5 / mL, then add 100μL of the diluted cell suspension to a 96-well plate (Corning, 3599), and incubate overnight in a CO2 incubator (37℃, 5% CO2). Dissolve the test compound in DMSO to prepare a 10mM stock solution, and then use an automated microplate pipetting system (Biotek, Precision) to perform 5-fold serial dilutions of the compound 10mM in DMSO in a V-bottom 96-well plate (Nest, 701211), diluting 7 times for a total of 8 concentration points. Then, dilute the different concentrations of the compound 1000-fold with DMEM to a DMSO concentration of 0.1%, remove the original cell culture medium from the 96-well plate, and add 100μL of DMEM containing different concentrations of the compound to the corresponding 96-well plate. The blank control group (containing cells and DMEM, 0.1% DMSO) and the DMSO control group (containing cells and DMEM, 0.1% DMSO) are operated on in the same way.

[0199] Cell culture plates were incubated in a CO2 incubator (37℃, 5% CO2) for 1 hour. The original solution was aspirated, and DMEM solutions containing 0.14 mM sodium cholate (Sigma, C1254-25G), 0.15 mM sodium deoxycholate (Sigma, D6750-10G), 0.19 mM 1-Monopalmitin (MCE, HY-W009141), 1.2 mM Palmitic acid-d31 (MACKLIN, P990048-100 mg), and different concentrations of these compounds were added to the corresponding 96-well plates. The DMSO control group cells were treated using the same method, while the blank control group cells were treated with the corresponding solvent. The cell culture plates were then incubated in a CO2 incubator (37℃, 5% CO2) for 1 hour. Incubate with CO2 for 1.5 h; remove the 96-well plate, wash each well twice with PBS, and add 100 μL of lysis buffer (methanol:isopropanol:chloroform = 9.5:9.5:1). Then place the 96-well plate on a microplate shaker (Wiggens, WS-350P) and shake at 400 rpm for 30 min. Transfer the liquid from the 96-well plate to a 96-well deep-well plate (Thermo Scientific, 260251), add 100 μL of lysis buffer to each well of the 96-well deep-well plate, vortex for 10 min, and finally centrifuge at 4000 rpm for 5 min. Detect the target product using LC-MS / MS (mass spectrometer, TQ4500; liquid chromatograph, 30AD).

[0200] The inhibition percentage (%) for each compound concentration was calculated based on the signal values ​​of the minimum signal group (blank group) and the maximum signal group (DMSO control group) included in each test plate. The inhibition rate for each compound concentration was calculated as follows:

[0201] Inhibition rate % = {1 - [(signal value of compound group - signal value of minimum signal group) / (signal value of maximum signal group - signal value of minimum signal group)]} * 100%.

[0202] Then, using GraphPad Prism software, nonlinear regression curve fitting was performed using the log(inhibitor) vs. response-variable slope (four parameters) analysis method to obtain the IC. 50 Values ​​are shown in Table 2.

[0203] Table 2

[0204] The results in Table 2 show that the compounds of the present invention have excellent inhibitory effects on the MGAT2 target protein in cells, and their activity is significantly better than that of Reference Example 1.

[0205] Experimental Example 3: In vivo PK experiment in mice

[0206] Experimental materials and methods:

[0207] The experimental animals were healthy adult male C57 mice (provided by Sichuan Vital River Laboratory Animal Technology Co., Ltd.); the C57 male mice were administered a single dose by gavage (2 mg / kg, 5% DMSO + 5% Solutol + 90% saline) (DMSO: AR 500 mL, Cologne; Solutol: 42966-1 KG, BASF; saline: 100 mL / bag, Sichuan Meida Kangjiale Pharmaceutical Co., Ltd.), and plasma was collected from the mice at different time points of 0.25, 0.5, 1, 2, 4, 6, and 8 h after administration.

[0208] Sample analysis:

[0209] Take 10 μL of mouse plasma, add 110 μL of acetonitrile solution containing internal standard to precipitate proteins, vortex for 10 min, then centrifuge at 4000 rpm for 10 min. Take 80 μL of the supernatant into a 96-well plate, add 80 μL of pure water for dilution, vortex for 10 min, and finally centrifuge at 4000 rpm for 5 min. Analyze using LC-MS / MS (Shimadzu LC-30A, AB API 4500).

[0210] The drug concentration in the plasma of mice after gavage administration of the compound of the present invention was determined by LC-MS / MS at different time points, and the relevant pharmacokinetic parameters were calculated to study the pharmacokinetic behavior of the compound in mice and evaluate its pharmacokinetic characteristics, as shown in Table 3.

[0211] Table 3 Note: 1. The solvent is 5% DMSO+5% Solutol+90% Saline

[0212] The compounds of this invention exhibit AUC, Cmax, or T 1 / 2 The compounds of the present invention are superior to those of Reference Example 1 to varying degrees, indicating that the compounds of the present invention have better pharmacokinetic properties.

[0213] Experiment 4: In vivo pharmacodynamics experiment in diet-induced obese mice

[0214] Experimental protocol: Male C57BL / 6J mice (from Sichuan Vital River Laboratory Animal Technology Co., Ltd.) were fed a high-fat diet (60% kcal fat diet XTHF60) until their weight reached over 40g. Compounds 1 (Reference Example 1) and 21 were dissolved in 5% DMSO + 5% Solutol + 90% Saline (DMSO: AR 500mL, Cologne; Solutol: 42966-1KG, BASF; Saline: 100mL / bag, Sichuan Meida Kangjiale Pharmaceutical Co., Ltd.). The medication was administered once daily for 27 days. Mice were weighed at fixed times daily during the treatment period until the end of the experiment. The experimental protocol is shown in Table 4.

[0215] Table 4 Note: 1. The Vehicle group is the model group (DIO obese mice), and the other groups are the drug administration groups.

[0216] Statistical analysis: Experimental results are expressed as mean ± standard error (Mean ± SEM). One-way ANOVA was used for comparisons among multiple groups. Data were analyzed using Graphpad Prism 8.0, and P < 0.05 was considered statistically significant. The statistical results are shown in Figure 1. The results indicate that the compound of this invention significantly reduces weight gain in diet-induced obese mice, and the weight loss effect is superior to that of Reference Example 1.

Claims

1. The compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, eutectic, hydrate, solvate, metabolite, prodrug, or deuterated compound thereof: in, R 1 Selected from C 1-8 Alkyl, C 3-8 cycloalkyl, C 1-6 Halogenated alkyl groups, -SF5, -SCF3; the C 1-8 Alkyl, C 3-8 cycloalkyl, C 1-6 Each haloalkyl group is independently unsubstituted or converted by one or more identical or different R groups. a replace; Ring A and ring B are each independently selected from phenyl, 5-10-membered heteroaryl, and 5-10-membered heterocyclic group; each of the 5-10-membered heteroaryl and 5-10-membered heterocyclic group independently contains 1, 2, or 3 heteroatoms selected from N, O, or S; Each R 2 and R 5 Each is independently selected from halogen, oxo group (O=), hydroxyl group, cyano group, C 1-8 Alkyl, C 2-8 alkenyl, C 2-8 alkynyl group, C 1-8 Alkoxy, C 3-8 cycloalkyl, C 3-8 Cycloalkenyl, 6-10 aryl, 5-10 heteroaryl, 5-10 heterocyclic, -SO2R b -SR d -NR i R j C 1-8 Alkyl-C(O)-; each of the 5-10 membered heteroaryl and 5-10 membered heterocyclic groups independently contains 1, 2, or 3 heteroatoms selected from N, O, and S; the C 1-8 Alkyl, C 2-8 alkenyl, C 2-8 alkynyl group, C 1-8 Alkoxy, C 3-8 cycloalkyl, C 3-8 Cycloalkenyl, 6-10 aryl, 5-10 heteroaryl, and 5-10 heterocyclic groups are each independently unsubstituted or substituted by one or more identical or different R groups. a Replacement; wherein at least one R 2 Selected from C 2-8 alkenyl, C 2-8 Alkyne group, wherein Z is O, methylene, vinylene, or ethynylene; s and q are 1, 2, 3, 4, 5, or 6, respectively; R 3 R 4 Each is independently selected from hydrogen, halogen, cyano, C 1-8 Alkyl; and R 3 R 4 It can form C together with the carbon atoms it is attached to. 3-8 Cycloalkyl or 4-7 membered heterocycloalkyl; wherein the 4-7 membered heterocycloalkyl contains 1, 2 or 3 heteroatoms selected from N, O or S; the C 1-8 Alkyl, C 3-8 Cycloalkyl groups and 4-7 membered heterocyclic alkyl groups are each independently unsubstituted or converted by one or more identical or different R groups. b replace; R 6 Selected from cyano, amino, R c -(CH2) o -X-(CH2) p R c -CONH(C 1-8 Alkyl), -NHCO-Y-SO2R b X is selected from O, S, NH, CONH, NHCO, and Y is selected from C. 1-8 Alkyl, C 3-8 Cycloalkyl; wherein o and p are each independently 0, 1, 2, 3, 4, 5 or 6; Each R a Each is independently selected from halogen, cyano, hydroxyl, -SR d -SF5, -SCF3, -S(O)2R b C 1-8 Alkyl, C 1-8 Alkoxy, C 3-8 cycloalkyl, C 1-8 Haloalkyl, C 2-8 alkenyl, C 2-8 alkynyl group, C 3-6 Cycloalkenyl, unsubstituted, or with one or more identical or different R aa Substituted 5-6 aryl groups, -NR i R j -C(O)NR i R j ; or two adjacent R a Combined with atoms on ring A to form unsubstituted or altered compounds by one or more identical or different R atoms. bb Substituted 4-7-membered heterocyclic alkyl groups; wherein each of the 5-6-membered heteroaryl group and the 4-7-membered heterocyclic alkyl group independently contains 1 to 3 heteroatoms selected from N, O, and S; each R aa R bb Each is independently selected from halogens, C 1-4 alkyl; Each R i R j Each was independently selected from C 1-8 Alkyl, C 3-8 cycloalkyl, C 1-8 Halogenated alkyl; or R i R j The bonded N atom forms an unsubstituted or substituted atom with one or more identical or different R atoms. aa Substituted 4-7-membered heterocyclic alkyl groups; wherein the 4-7-membered heterocyclic alkyl group contains 1, 2 or 3 heteroatoms selected from N, O or S; Each R b R d Each was independently selected from C 1-8 Alkyl, C 3-8 cycloalkyl, C 1-8 Haloalkyl, C 1-8 Alkoxy; Each R c Each was independently selected from C 3-8 Cycloalkyl, phenyl, 5-10 membered heterocyclic, 5-10 membered heteroaryl; wherein each of the 5-10 membered heteroaryl and 5-10 membered heterocyclic groups independently contains 1, 2, 3, or 4 heteroatoms selected from N, O, or S; each of the phenyl, 5-10 membered heteroaryl, and 5-10 membered heterocyclic groups is independently unsubstituted or converted by one or more identical or different R atoms. b replace; m and n are each independently 1, 2, 3, 4, 5 or 6; Preferred, R 1 Selected from -SF5, -SCF3, C 1-6 Halogenated alkyl groups; Preferred, R 1 Selected from -SF5, -SCF3, C 1-4 Halogenated alkyl groups; Preferred, R 1 Selected from -SF5, -SCF3, -CF3; Preferred, R 3 R 4 All are hydrogen; Preferably, ring A is selected from phenyl, 8-10 membered bicyclic heteroaryl, and 5-6 membered monocyclic heterocyclic group; each of the 8-10 membered bicyclic heteroaryl and 5-6 membered monocyclic heterocyclic group independently contains 1, 2 or 3 heteroatoms selected from N, O and S; Preferably, ring A is selected from phenyl, 8-10 membered bicyclic heteroaryl, or pyridinone group; the 8-10 membered bicyclic heteroaryl contains 1, 2, or 3 N heteroatoms; Preferably, ring A is selected from phenyl, 5-6-membered heteroarylphenyl, or pyridone; the 5-6-membered bicyclic heteroaryl contains 1, 2, or 3 N heteroatoms; Preferably, ring A is selected from phenyl, pyrrolophenyl, pyrazolophenyl, and pyridone group; Preferably, each R 2 Each independently selected C 2-4 alkenyl, C 2-4 Alkyne, halogen, C 1-4 Alkyl, C 1-4 Haloalkoxy or oxo (O=), wherein Z is O, methylene, vinylene, or ethynylene; s and q are 1, 2, 3, 4, 5, or 6, respectively; wherein at least one R 2 Selected from C 2-4 alkenyl, C 2-4 Alkyne group, wherein Z is O, methylene, vinylene, or ethynylene; s and q are 1, 2, 3, or 4, respectively; Preferably, each R 2 Each independently selected Ethylene, acetylene, F, Cl, methyl, oxo group (O=), wherein at least one R 2 Selected from Ethylene, acetylene; Preferred, Selected from Preferably, ring B is selected from phenyl or 5-6-membered heteroaryl; the 5-6-membered heteroaryl contains 1, 2 or 3 heteroatoms selected from N, O or S; Preferably, ring B is selected from phenyl, pyrazolyl, thiophenyl, thiazolyl, pyridyl, and pyrimidinyl. Preferably, ring B is selected from phenyl, Preferably, each R 5 Each is independently selected from halogens, C 1-8 Alkyl, C 1-8 Alkoxy, C 3-8 Cycloalkyl-(CH2) r -、C 3-8 Cycloalkenyl-(CH2) r -、C 2-8 Alkenyl-(CH2) r -、C 2-8 Alkyne group -(CH2) r -、C 1-8 Alkyl-C(O)-, SO2R b -(CH2) r -、SR d -(CH2) r -、-NR i R j , where R i R j Each was independently selected from C 1-8 Alkyl groups, each r independently being 0, 1, 2, 3, 4, 5, or 6; the C 1-8 Alkyl, C 1-8 Alkoxy, C 3-8 cycloalkyl, C 3-8 Cycloalkenyl, C 2-8 alkenyl, C 2-8 Each alkynyl group is independently unsubstituted or surrounded by 1, 2, 3, or 4 groups selected from hydroxyl, cyano, halogen, C. 1-4 Alkyl, C 1-4 Substitution of alkoxy groups; Preferably, each R 5 Each is independently selected from halogens, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl-(CH2) r -、C 3-6 Cycloalkenyl-(CH2) r -、C 2-4 Alkenyl-(CH2) r -、C 2-4 Alkyne group -(CH2) r -、C 1-4 Alkyl-C(O)-, SO2R b -(CH2) r -、SR d -(CH2) r -、-NR i R j , where R i R j Each r is independently selected from methyl, ethyl, propyl, isopropyl, and C4 alkyl, and each r is independently 0, 1, 2, 3, 4, 5, or 6; the C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 cycloalkyl, C 3-6 Cycloalkenyl, C 2-4 alkenyl, C 2-4 Each alkynyl group is independently unsubstituted or surrounded by 1, 2, 3, or 4 groups selected from hydroxyl, cyano, halogen, C. 1-4 Alkyl, C 1-4 Substitution of alkoxy groups; Preferably, each R b R d Each is independently selected from methyl, ethyl, propyl, isopropyl, C4 alkyl, which is unsubstituted or independently substituted by 1, 2, 3 or 4 halogens; Preferably, each R 5 Each is independently selected from F, Cl, methyl, ethyl, isopropyl, isobutyl, methoxy, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclobutylmethyl, vinyl, hydroxyethyl, cyanomethyl, Preferred, Selected from Preferred, Selected from Preferred, R 6 Selected from cyano, R c -(CH2) o -X-(CH2) p R c -NHCO-Y-SO2R b X is selected from O, S, NH, CONH, NHCO, and Y is selected from C. 1-8 Alkyl, C 3-8 cycloalkyl; Preferably, Y is selected from methylene; Preferably, -(CH2) o -X-(CH2) p R c For -CONH-R c ; Preferably, each R c Each is independently selected from phenyl, 5-6 membered heterocyclic group, and 5-6 membered heteroaryl group; wherein each of the 5-6 membered heterocyclic group and 5-6 membered heteroaryl group independently contains 1, 2, 3, or 4 heteroatoms selected from N, O, or S; wherein each of the phenyl, 5-6 membered heterocyclic group, and 5-6 membered heteroaryl group is independently unsubstituted or converted by one or more identical or different R atoms. b replace; Preferably, each R c Each is independently selected from phenyl, Wherein, the phenyl, Each independently is either unsubstituted or by one or more identical or different Rs. b replace; Preferred, R c Selected from phenyl, wherein the phenyl group is unsubstituted or converted by one or more identical or different R groups. b replace; Preferably, each R b Each is independently selected from oxygen groups (O=) and C. 1-8 Alkyl, C 1-8 Alkoxy, the C 1-8 Alkyl, C 1-8 The alkoxy group can be substituted or unsubstituted; Preferably, each R b Each is independently selected from oxygen groups (O=) and C. 1-4 Alkyl, C 1-4 Alkoxy, the C 1-4 Alkyl, C 1-4 The alkoxy group can be substituted or unsubstituted; Preferably, each R b Each is independently selected from oxo (O=), methyl, and methoxy groups; Preferred, R 6 Selected from CN 2. The compound according to claim 1, or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, cocrystal, hydrate, solvate, metabolite, prodrug, or deuterated compound thereof, wherein the compound is selected from the following structures:

3. A pharmaceutical composition, characterized in that: The pharmaceutical composition comprises a therapeutically and / or preventively effective amount of the compound as described in any one of claims 1-2 or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, polymorph, eutectic, hydrate, solvate, metabolite, prodrug, deuterated compound, and optionally a pharmaceutical excipient.

4. The use of the compound of any one of claims 1-2 or its pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, cocrystal, hydrate, solvate, metabolite, prodrug, deuterated compound, or the pharmaceutical composition of claim 3 in the preparation of a medicament for treating and / or preventing diseases related to MGAT2 regulation, and / or in the treatment and / or prevention of diseases related to MGAT2 regulation; Preferably, the diseases associated with MGAT2 regulation are metabolic disorders or metabolic abnormalities. Preferably, the metabolic disorder or metabolic abnormality-related disease is obesity.

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