Long-chain compounds that act on ACLY, their preparation methods, and their applications.

Abstract

The present invention discloses a long-chain compound, its preparation method and its use, the structure of which is as shown in formula I, and in the formula, the definition of each substituent is as described in the specification and claims. The compound of the present invention can directly inhibit ACLY, inhibit lipid synthesis in primary hepatocytes, inhibit the de novo synthesis of lipids in various cancer cells such as H358, acetylation of histones, inhibit the proliferation of cancer cells, and can be used to prepare drugs for treating metabolic diseases such as hyperlipidemia, atherosclerosis, or various cancers such as lung cancer, pancreatic cancer, breast cancer, ovarian cancer, liver cancer, intestinal cancer, brain cancer, acute myeloid leukemia, etc. [Formula 1] JPEG2024534605000043.jpg1559

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical chemistry and relates to novel ACLY inhibitors or pharmaceutically acceptable salts thereof, a method for preparing the same, and a pharmaceutical composition containing an inhibitor of this type. The inhibitor of this type can directly inhibit ACLY, inhibit lipid synthesis in primary hepatocytes, inhibit the de novo synthesis of lipids and histone acetylation in various cancer cells such as H358, and can inhibit its proliferation. It can be used for the preparation of drugs for treating metabolic diseases such as hyperlipidemia, atherosclerosis, non-alcoholic steatohepatitis, or various cancer diseases such as lung cancer, pancreatic cancer, breast cancer, ovarian cancer, liver cancer, intestinal cancer, brain cancer, acute myeloid leukemia, etc.

Background Art

[0002] ATP citrate lyase (ACLY) plays a crucial role in glucose and lipid metabolism. Acetyl coenzyme A (Ac-CoA), produced in mitochondria, cannot directly cross the mitochondrial membrane to reach the cytoplasm. However, AC-CoA can enter the tricarboxylic acid cycle, and the citrate produced by this cycle is transported to the cytoplasm via citrate transporters on the mitochondrial membrane. In the cytoplasm, citrate and coenzyme A (CoA) are catalyzed by ACLY to produce acetyl coenzyme A and oxaloacetate, consuming one molecule of ATP. The biological functions of acetyl coenzyme A in the body can be summarized into three categories: In the fatty acid synthesis pathway, acetylcoenzyme A is carboxylated by acetylcoenzyme A carboxylase (ACC) to form malonyl coenzyme A, which is then mediated by related fatty acid synthases to ultimately produce fatty acids. Acetylcoenzyme A is also a precursor to the mevalonate pathway, which can synthesize farnesyl pyrophosphate (FPP), and FPP is involved in cholesterol synthesis. Furthermore, acetylcoenzyme A is a raw material for acetylation reactions and is involved in the acetylation of various proteins, including histones. ACLY is involved in lipid synthesis and epigenetic regulation in the body by regulating acetylcoenzyme A.

[0003] Various metabolic diseases, including hyperlipidemia, atherosclerosis, and non-alcoholic fatty liver disease, are all related to increased levels of lipid synthesis. ACLY, as the main enzyme that produces Ac-CoA in the cytoplasm, provides raw materials for lipid synthesis and plays a crucial role in this process. Bempedoic acid, a drug that acts on ACLY, can significantly reduce lipid synthesis levels in the liver. Furthermore, the lipid-lowering effects of ACLY inhibitors such as benzenesulfonamides have also been verified at the cellular level.

[0004] Metabolic recombination is the most common and primary characteristic of cancer cells, because rapid proliferation of cancer cells requires large amounts of energy and macromolecules, and their metabolism undergoes significant changes to meet these "demands." As cancerous tissue often grows into irregularly shaped masses, cancer cells find it very difficult to obtain lipids from surrounding blood vessels, and their own novel lipid synthesis is usually at high levels, being the main source of lipids necessary for their proliferation. Abnormal epigenetic regulation is another major characteristic of cancer cells, functioning as a crucial part of epigenetic regulation, with histone acetylation playing a very important role. When histone acetylation levels increase, chromatin structure relaxes and transcription becomes activated; conversely, when histone acetylation levels are low, chromatin structure becomes rigid and transcription is inhibited. Studies have shown that the development of many cancers is closely associated with increased histone acetylation levels. Acetyl coenzyme A, catalyzed and produced by ACLY, is involved not only as a raw material for lipid synthesis but also in histone acetylation. Studies have shown that ACLY is highly expressed in various cancers, including non-small cell lung cancer, breast cancer, and liver cancer, and that high ACLY expression is closely associated with poor prognosis in these cancers.

[0005] In summary, the development of ACLY inhibitors is expected to be used in the clinical treatment of metabolic diseases and cancer. [Overview of the Initiative] [Problems that the invention aims to solve]

[0006] The object of the present invention is to provide novel compounds having ACLY inhibitory activity or pharmaceutically acceptable salts thereof, the “pharmaceutically acceptable salts” include, but are not limited to, sodium salts, potassium salts, magnesium salts, calcium salts formed by the carboxylic acid group in the compound, or inorganic salts formed when the compounds in the series contain nitrogen. [Means for solving the problem]

[0007] A first aspect of the present invention provides a compound represented by general formula (I), or its stereoisomers, enantiomers, diastereomers, racemates, or pharmaceutically acceptable salts thereof. [ka] In the formula, [ka] This represents a double bond or a single bond. R1 and R2 are independently H, C1-C4 alkyl group, C2-C4 alkenyl group, C2-C4 alkynyl group, C3-C7 cycloalkyl group, C3-C7 cycloalkenyl group, or C6-C10 aryl group, or R1 and R2 together with the bonded carbon to form a saturated 3-7 membered ring, or a 3-7 membered ring containing an unsaturated double bond. R3 and R4 are independently H, C1-C4 alkyl group, C2-C4 alkenyl group, C2-C4 alkynyl group, C3-C7 cycloalkyl group, C3-C7 cycloalkenyl group, or C6-C10 aryl group, or R3 and R4 together with the bonded carbon to form a saturated 3-7 membered ring or a 3-7 membered ring containing an unsaturated double bond. R5 and R6 are independently H, C1-C4 alkyl group, C2-C4 alkenyl group, C2-C4 alkynyl group, C3-C7 cycloalkyl group, C3-C7 cycloalkenyl group, or C6-C10 aryl group, or R5 and R6 together with the bonded carbon to form a saturated 3-7 membered ring or a 3-7 membered ring containing an unsaturated double bond. m, n, and q are independently 0, 1, 2, 3, 4, 5, or 6, respectively. Z is -OH, -COOH, -COOR7, -SO3H, or -CONHR7, where R7 is a C1-C4 alkyl group. X is -CO-, -O-, -NH-, -S-, -CH2-, [ka] And, Y is H, a C6-C10 aryl group, a C1-C4 alkyl group or an adamantyl group (Ad-), or Y is

Chemical formula

[0008] In another preferred example,

Chemical formula

[0009] In another preferred example, the compound has the structure shown in Formula II.

Chemical formula

[0010] In another preferred example, the compound has the structure shown in Formula III.

Chemical formula

[0011] In another preferred example, the compound has the structure shown in Formula IV,

Chemical formula

[0012] In another preferred example, R1 and R2 are each independently H, a C1-C4 alkyl group, a C2-C4 alkenyl group, a C2-C4 alkynyl group, a C3-C7 cycloalkyl group, a C3-C7 cycloalkenyl group or a C6-C10 aryl group, the above C1-C4 alkyl group, C2-C4 alkenyl group, C2-C4 alkynyl group, C3-C7 cycloalkyl group, C3-C7 cycloalkenyl group or C6-C10 aryl group is unsubstituted or substituted, where the substitution means being substituted by 1, 2, 3, 4 or 5 substituents selected from the group consisting of halogen, a C1-C4 alkyl group, a C1-C4 alkoxy group, a C3-C7 cycloalkyl group, a C3-C7 cycloalkenyl group, a C6-C10 aryl group, -CO-(5- to 7-membered heterocyclyl)-(5- to 7-membered heteroaryl group), and the above groups are optionally further substituted by substituents selected from the group consisting of a C6-C10 aryl group, a halogenated C6-C10 aryl group, a carboxy-substituted C6-C10 aryl group, a C1-C4 alkyl-substituted C6-C10 aryl group, a C1-C4 halogenated alkyl-substituted C6-C10 aryl group.

[0013] In another preferred example, R1 and R2 are independently H, a C1-C4 alkyl group, a C6-C7 cycloalkenyl group, or a C6-C10 aryl group, where the C1-C4 alkyl group, C6-C7 cycloalkenyl group, or C6-C10 aryl group is either unsubstituted or substituted, where the substitution refers to halogen, C1-C4 alkyl group, C1-C4 alkoxy group, C5-C6 cycloalkyl group, C6-C7 cycloalkenyl group, or C6-C10 aryl group. This refers to substitution with one, two, or three substituents selected from the group consisting of a reel group and -CO-(6-membered nitrogen-containing heterocyclyl)-(6-membered heteroaryl group), wherein the above group may be further optionally substituted with substituents selected from the group consisting of a C6-C10 aryl group, a halogenated C6-C10 aryl group, a carboxylated C6-C10 aryl group, a C1-C4 alkyl-substituted C6-C10 aryl group, and a C1-C4 halogenated alkyl-substituted C6-C10 aryl group.

[0014] In another preferred example, R3 and R4 are independently H, a methyl group, an ethyl group, a propyl group, a vinyl group, a propenyl group, an ethynyl group, a propynyl group, a C3-C6 cycloalkyl group, a C3-C6 cycloalkenyl group, or a C6-C10 aryl group, or R3 and R4 together with the bonded carbon to form a saturated 3- to 6-membered ring, or a 3- to 6-membered ring containing one unsaturated double bond.

[0015] In another preferred example, R5 and R6 are independently H, a methyl group, an ethyl group, a propyl group, a vinyl group, a propenyl group, an ethynyl group, a propynyl group, a C3-C6 cycloalkyl group, a C3-C6 cycloalkenyl group, or a C6-C10 aryl group, or R5 and R6 together with the bonded carbon to form a saturated 3- to 6-membered ring, or a 3- to 6-membered ring containing one unsaturated double bond.

[0016] In another preferred example, m and n are independently 1, 2, 3, 4, or 5. In another preferred example, q is 0, 1, 2, 3, or 4.

[0017] In another preferred example, R1 and R2, together with the bonded carbon, form a saturated four-membered ring, a saturated five-membered ring, a saturated six-membered ring, a four-membered ring containing one unsaturated double bond, a five-membered ring containing one unsaturated double bond, or a six-membered ring containing one unsaturated double bond.

[0018] In another preferred example, R3 and R3, together with the bonded carbon, form a saturated four-membered ring, a saturated five-membered ring, a saturated six-membered ring, a four-membered ring containing one unsaturated double bond, a five-membered ring containing one unsaturated double bond, or a six-membered ring containing one unsaturated double bond.

[0019] In another preferred example, R5 and R6, together with the bonded carbon, form a saturated four-membered ring, a saturated five-membered ring, a saturated six-membered ring, a four-membered ring containing one unsaturated double bond, a five-membered ring containing one unsaturated double bond, or a six-membered ring containing one unsaturated double bond.

[0020] In another preferred example, Y is H, a methyl group, an ethyl group, a propyl group, a benzene ring, a naphthalene ring, a methoxy group, an ethoxy group, an adamantyl group, or an aromatic ring (benzene ring or naphthalene ring) having p halogen substitutions, where p is 1, 2, 3, 4, 5, preferably 1 or 2, and the halogen is F, Cl, Br, or I, or Y is a structural fragment having acetyl coenzyme A synthase 2 (ACSS2) inhibitory activity. [ka] Alternatively, Y is a structural fragment having the following histone methyltransferase EZH2 inhibitory activity, and currently, the compound has both ACLY and EZH2 inhibitory activity. [ka] Alternatively, Y is a structure containing an E3 ligase ligand. [ka]

[0021] In another preferred example, the compound is selected from the group consisting of M1 to M40.

[0022] A second aspect of the present invention provides a pharmaceutical composition of a compound having ACLY activity, the composition comprising a compound represented by general formula (I) as described in the first aspect, or its stereoisomers, enantiomers, diastereomers, racemates or pharmaceutically acceptable salts thereof, and pharmaceutically acceptable carriers.

[0023] The drug combination dosage forms described in the present invention include, but are not limited to, tablets, capsules, granules, syrups, solutions, suspensions, or aerosols, and may be a variety of other dosage forms.

[0024] A "pharmaceutically acceptable carrier" refers to one or more compatible solid or liquid fillers or gels that are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatible" here means that each component in the composition can be blended with and among the compounds of the present invention without significantly reducing the potency of the active ingredient. Some examples of pharmaceutically acceptable carriers include cellulose and its derivatives (e.g., sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (e.g., stearic acid, magnesium stearate), calcium sulfate, vegetable oils (e.g., soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (e.g., propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (e.g., tween®), wetting agents (e.g., sodium lauryl sulfate), colorants, fragrances, stabilizers, anti-acidifying agents, preservatives, pyrogen-free water, etc.

[0025] A third aspect of the present invention provides uses for the compound represented by general formula (I) as described in the first aspect, or its stereoisomers, enantiomers, diastereomers, racemates or pharmaceutically acceptable salts thereof, or the pharmaceutical composition as described in the second aspect, for use as an ACLY inhibitor, for preparing an ACLY inhibitor, or for preparing a drug for preventing and / or treating a metabolic disease or cancer.

[0026] In another preferred example, the metabolic disease is selected from the group consisting of hyperlipidemia, atherosclerosis, non-alcoholic fatty liver disease, and diabetes mellitus. In another preferred example, the cancer is selected from the group consisting of lung cancer, pancreatic cancer, breast cancer, ovarian cancer, liver cancer, colon cancer, brain cancer, and acute myeloid leukemia.

[0027] A fourth aspect of the present invention provides a therapeutic method that involves using a compound having ACLY inhibitory activity in combination with other anticancer drugs (treatments). [Effects of the Invention]

[0028] Within the scope of the present invention, it should be understood that new or preferred technical solutions can be constructed by combining the above-described technical features of the present invention with the technical features specifically described below (e.g., Examples). Each feature disclosed in the specification can be replaced by any substitutable feature that serves the same, equivalent, or similar purpose. Due to space limitations, this will not be repeated here. [Modes for carrying out the invention]

[0029] The inventors of this application have developed long-chain compounds after extensive and thorough research. These compounds possess ACLY inhibitory activity and exhibit excellent ACLY inhibitory activity in various cancer cells such as A549, H358, ASPC-1, MIA-PACA, and MCF-7. They reduce histone acetylation levels, inhibit cancer cell proliferation, and are expected to be developed as therapeutic drugs for cancer or metabolic diseases. Based on this, the present invention has been completed.

[0030] term In this invention, unless otherwise specified, terms used have the ordinary meanings known to those skilled in the art. In this invention, the term "C1-C4" refers to having one, two, three, or four carbon atoms. The term "C3-C7" refers to having three, four, five, six, or seven carbon atoms. By analogy, the above applies.

[0031] In the present invention, the term "alkyl group" refers to a saturated linear or branched hydrocarbon group, for example, the term "C1-C4 alkyl group" refers to a linear or branched alkyl group having 1 to 4 carbon atoms, and non-limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, and t-butyl groups.

[0032] In the present invention, the term "alkenyl group" refers to a linear or branched hydrocarbon group portion containing at least one double bond. For example, the term "C2-C4 alkenyl group" refers to a linear or branched alkenyl group containing one double bond having 2 to 4 carbon atoms, and non-limiting examples include vinyl groups, propenyl groups, butenyl groups, and isobutenyl groups.

[0033] In the present invention, the term "alkynyl group" refers to a linear or branched alkynyl group containing one triple bond, and non-limitedly includes ethynyl groups, propynyl groups, butynyl groups, isobutynyl groups, etc.

[0034] In the present invention, the term "cycloalkyl group" refers to a saturated cyclic hydrocarbon group portion. For example, the term "C3-C7 cycloalkyl group" refers to a cyclic alkyl group having 3 to 7 carbon atoms on the ring, and non-limitingly includes cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl groups.

[0035] In the present invention, the term "cycloalkenyl group" refers to a cyclic hydrocarbon group portion containing at least one double bond. For example, the term "C3-C7 cycloalkenyl group" refers to a cyclic alkyl group having 3 to 7 carbon atoms on the ring, and non-limitingly includes cyclopropenyl, cyclobutenyl, cyclopentenyl, and cyclohexenyl groups.

[0036] In this invention, the term "aryl group" refers to a hydrocarbon group portion containing one or more aromatic rings. For example, the term "C6-C10 aryl group" refers to an aromatic ring group having 6 to 10 carbon atoms that does not contain heteroatoms on the ring, such as a phenyl group or a naphthyl group.

[0037] In the present invention, the term "heterocyclyl group" refers to a saturated or unsaturated non-aromatic cyclic group containing at least one (e.g., 1, 2, 3, or 4) ring heteroatoms (e.g., N, O, or S), such as a tetrahydropyridyl group, piperazinyl group, pyrrolinyl group, dihydropyridyl group, dihydrofuryl group, dihydrothienyl group, or morpholinyl group.

[0038] In the present invention, the term "heteroaryl group" refers to an aromatic cyclic group containing at least one (e.g., 1, 2, 3, or 4) cyclic heteroatoms (e.g., N, O, or S), such as a furyl group, pyrrolyl group, thienyl group, oxazolyl group, imidazolyl group, thiazolyl group, pyridyl group, quinolyl group, isoquinolyl group, indolyl group, pyrimidinyl group, or pyranyl group.

[0039] The pharmaceutically acceptable salts described in the present invention may be salts formed by an anion and a positively charged group on a compound of formula I. Suitable anions include chloride ions, bromide ions, iodide ions, sulfate ions, nitrate ions, phosphate ions, citrate ions, methanesulfonate ions, trifluoroacetate ions, acetate ions, malate ions, tosylate ions, tartrate ions, fumarate ions, glutamate ions, glucuronate ions, lactate ions, glutarate ions, or maleate ions. Similarly, salts can be formed by cations and negatively charged groups on a compound of formula I. Suitable cations include sodium ions, potassium ions, magnesium ions, calcium ions, and ammonium ions such as tetramethylammonium ions.

[0040] Preparation method The compounds of general formulas I, II, III, and IV described in the present invention can be prepared and synthesized through the following routes. Route 1 [ka]

[0041] (1) Intermediate A3 is produced from 1-alkynyl alcohol compound A1 and excess 3,4-dihydro-2H-pyran (DHP) under the catalysis of p-toluenesulfonic acid (TsOH), and intermediate A4 is produced from 1-hydroxybromide and excess 3,4-dihydro-2H-pyran (DHP) under the catalysis of p-toluenesulfonic acid (TsOH). (2) A3 and A4 are converted into intermediate A5 under the conditions of n-butyllithium (n-BuLi) and hexamethylphosphate triamide (HMPA).

[0042] (3) Intermediate A5 is deprotected in methanol under the catalysis of TsOH to produce intermediate A6. (4) Intermediate A6 is subjected to an Appel reaction with carbon tetrabromide and triphenylphosphine (PPh3) to produce intermediate A7. (5) Convert A7 to A8 under hydrogen gas conditions using nickel acetate, sodium borohydride, and ethylenediamine.

[0043] (6) A8 and an ester having an active hydrogen at the α-position are used to produce A9 under lithium diisopropylamide (LDA) conditions. (7) A9 is hydrolyzed in the presence of potassium hydroxide and then acidified to obtain A10. R3, R4, R5, R6, m, and n are as described in General Formula I, and R7 and R8 are independently either a methyl group or an ethyl group.

[0044] Route 2 [ka]

[0045] (1) Intermediate A15 is reduced to intermediate A11 containing a trans double bond by lithium aluminum tetrahydrogen (LiAlH4) at 180°C. (2) Intermediate A11 is deprotected in methanol under the catalysis of TsOH to produce intermediate A12. (3) Intermediate A12 is subjected to an Appel reaction with carbon tetrabromide and triphenylphosphine (PPh3) to produce intermediate A13. (4) Intermediate A13 and an ester having an active hydrogen at the α-position are used to produce A14 under lithium diisopropylamide conditions. (5) A14 is hydrolyzed in the presence of potassium hydroxide and then acidified to obtain A15.

[0046] Route 3 [ka]

[0047] (1) Intermediate A15 is reduced to intermediate A11 containing a trans double bond by lithium aluminum tetrahydrogen (LiAlH4) at 140°C. (2) Compound A17 is produced by condensing compound A10 and compound A16 under the conditions of dicyclohexylcarbodiimide (DCC) and 4-dimethylaminopyridine (DMAP), or by condensing them under the conditions of the condensing agent N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorourea phosphate (HATU), or by converting A10 to an acid chloride with oxalyl chloride and then converting it together with A16 to A17, or by using A10 and A16 as bases in potassium carbonate to produce A17 Compound A18 is produced by generating a compound A15 and compound A16, and then condensing them under the conditions of dicyclohexylcarbodiimide (DCC) and 4-dimethylaminopyridine (DMAP), or by condensing them under the conditions of the condensing agent N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorourea phosphate (HATU), or by converting A15 to an acid chloride via oxalyl chloride, which is then converted to A16 and A18, or by acting A15 and A16 with potassium carbonate as a base to produce A18.

[0048] R3, R4, R5, R6, m, n, Y, and W are as described in General Formula IV, R7 and R8 are independently a methyl group or an ethyl group, and Z in A16 is a hydroxyl group or a halogen.

[0049] Route 4 [ka]

[0050] (1) Intermediate A117 and an ester having an active hydrogen at the α-position are used to produce intermediate A19 under lithium diisopropylamide (LDA) conditions. (2) A19 is reacted with pinacol diborate under the catalysis of tetrakistriphenylphosphoplatinum, or with pinacolborane under the catalysis of tris(acetonitrile)cyclopentadienylruthenium hexafluorophosphate to produce A20. (3) Compound A21 is obtained by coupling A20 with R1L1 or R2L2 under the catalysis of tetrakistriphenylphosphopalladium. (4) Hydrolyze A21 under basic conditions and acidify it to obtain compound A22.

[0051] R3, R4, R5, R6, m, and n are as described in general formula I, R7 and R8 are independently a methyl group or an ethyl group, and L1 and L2 are independently a halogen, i.e., F, Cl, Br, or I.

[0052] Intermediate A7 in route 1 can also be synthesized by the following route 5. Route 5 [ka]

[0053] (1) Sodium acetylide suspended in xylene and dihalide A34 are reacted in DMF to produce intermediate A35. (2) A35 is dehydrogenated with n-butyllithium in the solvent tetrahydrofuran (THF) in the presence of hexamethyltriamide phosphate (HMPA) and reacted with dihalide A36 to produce dichloride A37. (3) Intermediate A37 and lithium bisulfide are refluxed in an organic solvent to produce A7.

[0054] The present invention will be further described below in conjunction with specific examples. These examples are used solely to illustrate the present invention and should not be used to limit its scope. In the following examples, experimental methods that do not specify conditions typically follow conventional conditions, such as those described in Sambrook et al., Molecular Cloning: An Experimental Manual (New York: Cold Spring Harbor Laboratory Press, 1989), or conditions proposed by the manufacturer. Unless otherwise specified, percentages and quantities refer to percentages and quantities by weight.

[0055] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those well known to those skilled in the art. Furthermore, any methods and materials similar or equivalent to those described herein can all be applied to the methods of the present invention. Preferred methods and materials described herein are for demonstration purposes only.

[0056] In the examples described in this invention, NMR was measured using a Bruker 400M instrument, with NMR calibration: δH 7.26 ppm (CDC13), 2.50 ppm (DMSO-d6), 2.05 ppm (Acetone-d6). Mass spectrometry was performed using an Agilent 1200 Quadrupole LC / MS. The TLC thin-layer chromatography silica gel plates were manufactured by Shandong Yantai Huiyou Silica Gel Development Co., Ltd., model HSGF254. The normal-phase column chromatography silica gel used for compound purification was manufactured by Shandong Qingdao Marine Chemical Plant Branch, model zcx-11, 200-300 mesh. Other commonly used commercial reagents were supplied by Shanghai Reagents Company.

[0057] Example 1. Synthesis of M1 [ka]

[0058] (1) Preparation of compounds B3 and B4 Under nitrogen gas protection, 4.6 g of compound B1 (36.0 mmol) was dissolved in 40 ml of dichloromethane (DCM), 1.2 g of p-toluenesulfonic acid TSOH (7.2 mmol) was added, the mixture was cooled in an ice bath, and 6.1 g of 3,4-dihydro-2H-pyran was added dropwise. The mixture was allowed to react overnight at room temperature. The reaction was monitored by TLC, diluted with 80 ml of DCM, washed twice with water, washed once with saturated brine, dried over anhydrous sodium sulfate, concentrated, and passed through a column at PE:EA = 50:1 to obtain 7.1 g of product B3, with a yield of 95%.

[0059] Under nitrogen gas protection, 5.0 g of compound B2 (27.6 mmol) was dissolved in 40 ml of dichloromethane, 951 mg of p-toluenesulfonic acid TSOH (5.5 mmol) was added, the mixture was cooled in an ice bath, and 4.6 g of 3,4-dihydro-2H-pyran was added dropwise. The mixture was allowed to react overnight at room temperature. The reaction was monitored by TLC, diluted with 80 ml of DCM, washed twice with water, washed once with saturated brine, dried over anhydrous sodium sulfate, concentrated, and passed through a column at PE:EA = 50:1 to obtain 5.9 g of a colorless oily product B4, with a yield of 69%.

[0060] (2) Preparation of compound B5 2.0 g of compound B3 (9.4 mmol) was dissolved in 20 ml of dry tetrahydrofuran (THF), protected with nitrogen gas, ventilated three times, cooled to -78°C, 4.7 ml of n-butyllithium (2.4 M 11.3 mmol) was added dropwise, and 4.0 ml of hexamethyltriamide phosphate (HMPA) was added. The mixture was reacted at -78°C for 30 minutes. 3.0 g of compound B4 (11.3 mmol) was dissolved in 8 ml of dry tetrahydrofuran, then added dropwise to the reaction bottle. The mixture was reacted overnight at -78°C to room temperature, and the completion of the reaction was monitored by TLC. 80 ml of saturated ammonium chloride solution was added, and the mixture was extracted three times with ethyl acetate to combine the organic phases. The mixture was washed once with saturated brine, dried over anhydrous sodium sulfate, concentrated, and passed through a column at PE:EA = 10:1 to obtain 3.2 g of a colorless oily product B5, with a yield of 84%.

[0061] (3) Preparation of compound B6 3.2 g of compound B5 (7.9 mmol) was dissolved in 30 ml of methanol, 136 mg of p-toluenesulfonic acid TsOH (0.79 mmol) was added, and the mixture was reacted at room temperature for 4 hours. The completion of the reaction was monitored by TLC, the methanol was centrifuged, 60 ml of ethyl acetate was added, the mixture was washed three times with water, washed once with saturated brine, dried over anhydrous sodium sulfate, concentrated, and passed through a column with PE:EA = 3:1 to obtain 1.3 g of product B6 as a white solid, with a yield of 73%.

[0062] (4) Preparation of compound B7 1.9 g of B6 (8.4 mmol) and 5.6 g of carbon tetrabromide (16.8 mmol) were dissolved in 20 ml of dry methyl chloride, protected with nitrogen gas, and cooled to 0°C. 4.4 g of triphenylphosphine (16.8 mmol) was dissolved in dry dichloromethane and added dropwise to the reaction bottle. The mixture was heated to room temperature and reacted for 2 hours. The completion of the reaction was monitored by TLC, most of the solvent was centrifuged, and 80 ml of ethyl ether was slowly added dropwise. A large amount of solid precipitated, which was removed by diatomaceous earth filtration. The solid was washed with ethyl ether, the filtrate was concentrated, and passed through a column with PE:EA = 50:1 to obtain 2.8 g of colorless oily product B7, with a yield of 95%.

[0063] (5) Preparation of compound B8 477 mg of nickel acetate (1.9 mmol) was suspended in 10 ml of ethanol, and 72 mg of sodium borohydride (1.9 mmol) was added. The solution changed from light green to black, a hydrogen balloon was added, the mixture was ventilated several times, 0.58 ml of ethylenediamine was added, and 1.4 g of B7 ethanol solution was added dropwise. The mixture was allowed to react at room temperature for 3 hours, and the completion of the reaction was monitored by TLC. The mixture was diluted with 40 ml of ethyl acetate, the solid was removed by diatomaceous earth filtration, the filtrate was concentrated and passed through a column with a PE:EA ratio of 50:1 to obtain 900 mg of a colorless oily product, with a yield of 67%.

[0064] (6) Preparation of compound B10 150 mg of B8 (0.4 mmol) and 453 mg of B9 (2.5 mmol) were dissolved in 8 ml of dry tetrahydrofuran, protected with nitrogen gas, ventilated, cooled to -78°C, and 1.3 ml of lithium diisopropylamide LDA (2.0 M 2.6 mmol) was added dropwise. The solution changed from colorless to orange, and the reaction was allowed to proceed overnight at -78°C to room temperature. The completion of the reaction was monitored by TLC, 40 ml of saturated ammonium chloride solution was added, and the mixture was extracted three times with ethyl acetate to combine the organic phases. The mixture was washed once with saturated brine, dried over anhydrous sodium sulfate, concentrated, and passed through a column with PE:EA = 20:1 to obtain 200 mg of colorless oily product B10, with a yield of 77%.

[0065] (7) Preparation of compound M1 180 mg of B10 (0.28 mmol) was dissolved in 8 ml of ethanol, and 180 mg of potassium hydroxide was dissolved in 2 ml of water. These were added to the reaction bottle and refluxed overnight. The reaction was monitored by TLC to confirm completion. The ethanol was centrifuged, diluted with 16 ml of water, and the pH was adjusted to approximately 2 with 1 M hydrochloric acid. A solid precipitated, which was extracted three times with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and passed through a column with PE:EA = 2:1 to obtain 110 mg of pale yellow solid product M1, with a yield of 80%. 1H NMR(400MHz,CDCl3)δ 7.42-7.28(m,8H),7.27-7.19(m,2H),5.41-5.25(m,2H),2.21-2.05(m,2H),2.0 5-1.95(m,4H),1.92-1.80(m,2H),1.54(s,3H),1.51(s,3H),1.42-1.02(m,16H).

[0066] By replacing the substrates and using a synthetic route similar to that of M1, the following compounds are obtained. [ka]

[0067] Compound M2: ¹H NMR (400MHz, CDCl₃) δ 5.63–5.58 (m, 4H), 5.36–5.30 (m, 2H), 2.92 (d, J = 15.1 Hz, 4H), 2.29 (d, J = 15.1 Hz, 4H), 2.06–1.96 (m, 4H), 1.75–1.65 (m, 4H), 1.31–1.21 (m, 16H).

[0068] Compound M3: ¹H NMR (400MHz, CDCl₃) δ 5.66–5.55 (m, 4H), 5.39–5.26 (m, 2H), 2.91 (d, J = 16.1 Hz, 4H), 2.30 (d, J = 16.1 Hz, 4H), 2.08–1.93 (m, 4H), 1.75–1.64 (m, 4H), 1.35–1.22 (m, 18H).

[0069] Compound M4: 1H NMR (400MHz, CDCl3) δ 5.40-5.25 (m, 2H), 2.22-2.07 (m, 4H), 2.07-1.95 (m, 4H), 1.70-1.53 ​​(m, 13H), 1.51-1.41 (m, 4H), 1.37-1.14 (m, 17H).

[0070] Compound M5: ¹H NMR (400MHz, CDCl₃) δ 5.85–5.78 (m, 2H), 5.77–5.70 (m, 2H), 5.39–5.27 (m, 2H), 2.46–2.30 (m, 6H), 2.07–1.95 (m, 4H), 1.76 (dt, J = 17.4, 6.1 Hz, 4H), 1.64–1.47 (m, 2H), 1.29 (d, J = 21.1 Hz, 16H).

[0071] Compound M6: ¹H NMR (400MHz, CDCl₃) δ 5.73–5.55 (m, 4H), 5.39–5.21 (m, 2H), 2.54 (d, J = 16.9 Hz, 2H), 2.21–2.09 (m, 2H), 2.09–1.95 (m, 8H), 1.95–1.85 (m, 2H), 1.68–1.55 (m, 4H), 1.54–1.45 (m, 2H), 1.37–1.28 (m, 4H), 1.28–1.15 (m, 12H).

[0072] Compound M7: ¹H NMR (400 MHz, CDCl₃) δ 6.14–6.01 (m, 2H), 5.39–5.28 (m, 2H), 5.18–5.08 (m, 4H), 2.08–1.94 (m, 4H), 1.84–1.68 (m, 2H), 1.58–1.44 (m, 2H), 1.39–1.11 (m, 22H).

[0073] Compound M8: ¹H NMR (400 MHz, CDCl₃) δ 5.70–5.58 (m, 4H), 5.37–5.27 (m, 2H), 2.54 (d, J = 16.9 Hz, 2H), 2.23–2.09 (m, 2H), 2.08–1.95 (m, 8H), 1.94–1.84 (m, 2H), 1.71–1.54 (m, 4H), 1.54–1.43 (m, 2H), 1.38–1.13 (m, 17H).

[0074] Compound M9: 1H NMR (400MHz, CDCl3) δ 7.39-7.31 (m, 10H), 5.44-5.31 (m, 2H), 2.14-1.89 (m, 8H), 1.55-1.50 (m, 6H), 1.40-1.15 (m, 10H).

[0075] Compound M10: ¹H NMR (400MHz, CDCl₃) δ 6.10–5.97 (m, 2H), 5.41–5.27 (m, 2H), 5.12 (d, J = 13.9 Hz, 4H), 2.07–1.92 (m, 4H), 1.80–1.66 (m, 2H), 1.64–1.49 (m, 2H), 1.35–1.23 (m, 24H).

[0076] Compound M11: ¹H NMR (400MHz, CDCl₃) δ 7.40–7.31 (m, 8H), 7.27–7.21 (m, 2H), 5.41–5.23 (m, 2H), 2.10–1.85 (m, 8H), 1.55 (s, 6H), 1.33–1.18 (m, 18H).

[0077] Compound M12: ¹H NMR (400MHz, CDCl₃) δ 5.75–5.56 (m, 4H), 5.41–5.24 (m, 2H), 2.53 (d, J = 17.3 Hz, 2H), 2.21–2.08 (m, 2H), 2.05–1.97 (m, 6H), 1.95–1.87 (m, 2H), 1.67–1.48 (m, 6H), 1.33–1.23 (m, 22H).

[0078] Compound M13: ¹H NMR (400MHz, CDCl₃) δ 5.85–5.78 (m, 2H), 5.78–5.69 (m, 2H), 5.40–5.24 (m, 2H), 2.48–2.29 (m, 6H), 2.09–1.89 (m, 5H), 1.87–1.67 (m, 4H), 1.66–1.52 (m, 2H), 1.43–1.13 (m, 18H).

[0079] Compound M14: ¹H NMR (400MHz, CDCl₃) δ 5.86–5.78 (m, 2H), 5.77–5.69 (m, 2H), 5.39–5.28 (m, 2H), 2.46–2.32 (m, 6H), 2.06–1.93 (m, 4H), 1.83–1.71 (m, 4H), 1.64–1.55 (m, 2H), 1.32–1.24 (m, 14H).

[0080] Example 2. Synthesis of Compound M15

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[0081] (1) Preparation of compound B13 and B14 Under nitrogen gas protection, 4.1 g of compound B11 (41.2 mmol) was dissolved in 30 ml of dichloromethane (DCM), 1.5 g of p-toluenesulfonic acid TSOH (8.2 mmol) was added, the mixture was cooled in an ice bath, and 7.4 ml of 3,4-dihydro-2H-pyran was added dropwise. The mixture was allowed to react overnight at room temperature. The reaction was monitored by TLC, diluted with 80 ml of DCM, washed twice with water, washed once with saturated saline, dried over anhydrous sodium sulfate, concentrated, and passed through a column with PE:EA = 50:1 to obtain 5.5 g of colorless oily product B13, with a yield of 39%.

[0082] Under nitrogen gas protection, 3.5 g of compound B12 (20.9 mmol) was dissolved in 30 ml of dichloromethane, 794 mg of p-toluenesulfonic acid TSOH (4.2 mmol) was added, the mixture was cooled in an ice bath, and 3.9 ml of 3,4-dihydro-2H-pyran was added dropwise. The mixture was allowed to react overnight at room temperature. The reaction was monitored by TLC, diluted with 80 ml of DCM, washed twice with water, washed once with saturated brine, dried over anhydrous sodium sulfate, concentrated, and passed through a column at PE:EA = 50:1 to obtain 6.3 g of a colorless oily product B14, with a yield of 75%.

[0083] (2) Preparation of compound B15 1.8 g of compound B13 (9.9 mmol) was dissolved in 20 ml of dry tetrahydrofuran (THF), protected with nitrogen gas, ventilated three times, cooled to -78°C, 7.4 ml of n-butyllithium (1.6 M 11.9 mmol) was added dropwise, and 3.0 ml of hexamethyltriamide phosphate (HMPA) was added. The mixture was reacted at -78°C for 30 minutes. 2.5 g of compound B14 (11.3 mmol) was dissolved in 6 ml of dry tetrahydrofuran, then added dropwise to the reaction bottle. The mixture was reacted overnight at -78°C to room temperature, and the completion of the reaction was monitored by TLC. 50 ml of saturated ammonium chloride solution was added, and the mixture was extracted three times with ethyl acetate. The organic phase was combined, washed once with saturated brine, dried over anhydrous sodium sulfate, concentrated, and passed through a column with PE:EA = 10:1 to obtain 1.9 g of colorless oily product B15, with a yield of 55%.

[0084] (3) Preparation of compound B16 Under nitrogen gas protection, 726 mg of lithium aluminum tetrahydrogen (18.2 mmol) was dissolved in 10 ml of diethylene glycol dimethyl ether, and 800 mg of B15 (2.3 mmol) was dissolved in 4 ml of diethylene glycol dimethyl ether. The reaction solution was added dropwise, and the mixture was reacted at 140°C for 28 hours. The completion of the reaction was monitored by TLC, and the mixture was diluted with 40 ml of ethyl ether. Under ice water cooling conditions, sodium sulfate decahydrate was added in batches until the foaming subsided. The solid was removed by diatomaceous earth filtration, washed with anhydrous ethyl ether, dried over anhydrous sodium sulfate, concentrated, and passed through a column with PE:EA = 20:1 to obtain 487 mg of colorless liquid product B16, with a yield of 61%.

[0085] (4) Preparation of compound B17 Dissolve 1 g of B16 (2.8 mmol) in 20 ml of methanol, add 100 mg of p-toluenesulfonic acid, stir at room temperature for 3 hours, monitor for completion of the reaction by TLC, centrifuge the methanol, add 80 ml of water, extract three times with ethyl acetate, wash with saturated brine, dry over anhydrous sodium sulfate, concentrate, and pass through a column with PE:EA = 3:1 to obtain 470 mg of colorless oily product B17, with a yield of 90%.

[0086] (5) Preparation of compound B18 Under nitrogen gas protection, 470 mg of B18 (2.5 mmol) and 2.5 g of carbon tetrabromide (7.5 mmol) were dissolved in 10 ml of dry dichloromethane, cooled to 0°C, and 1.9 g of triphenylphosphine (7.5 mmol) was dissolved in dry dichloromethane. This was added dropwise to the reaction bottle, the temperature was raised to room temperature, and the reaction was allowed to proceed for 2 hours. The completion of the reaction was monitored by TLC, and 40 ml of ethyl ether was slowly added dropwise. A large amount of solid precipitated, the solid was removed by diatomaceous earth filtration, the solid was washed with ethyl ether, the filtrate was concentrated, and passed through a column with PE:EA = 50:1 to obtain 740 mg of a colorless oily product with a yield of 95%.

[0087] (6) Preparation of compound B19 Under nitrogen gas protection, 150 mg of B18 (0.48 mmol) and 510 mg of B9 (2.9 mmol) were dissolved in dry tetrahydrofuran, ventilated with nitrogen gas, cooled to -78°C, and 1.5 ml of lithium diisopropylamide LDA (2.0 M 3.0 mmol) was slowly added dropwise. The solution changed from colorless to orange, and the reaction was allowed to proceed overnight at room temperature from -78°C. The completion of the reaction was monitored by TLC, 40 ml of saturated ammonium chloride solution was added, and the mixture was extracted three times with ethyl acetate to combine the organic phases. The mixture was washed once with saturated brine, dried over anhydrous sodium sulfate, concentrated, and passed through a column at PE:EA = 20:1 to obtain 130 mg of the yellow oily product B19, with a yield of 54%.

[0088] (7) Preparation of compound M15 130 mg of B19 (0.26 mmol) was dissolved in 8 ml of ethanol, and 130 mg of potassium hydroxide was dissolved in 2 ml of water. These were added to a reaction bottle and refluxed overnight. The reaction was monitored by TLC to ensure completion. The ethanol was centrifuged, diluted with 20 ml of water, and the pH was adjusted to 2 with 1 M HCl. A solid precipitate was formed, and the mixture was extracted three times with ethyl acetate. The organic phase was combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and passed through a column with PE:EA = 2:1 to obtain 80 mg of a yellow oily product M23, with a yield of 69%. 1H NMR(400MHz,CDCl3)δ 7.39-7.30(m,8H),7.25-7.20(m,2H),5.36-5.27(m,2H),2.08-2.02(m,2H),2.00-1.87(m,6H),1.55(s,6H),1.33-1.18(m,10H).

[0089] Using the same synthetic route as M15, but with different substrates, the following compounds can be obtained. [ka] Compound M16: ¹H NMR (400MHz, CDCl₃) δ 7.42–7.28 (m, 8H), 7.26–7.23 (m, 2H), 5.42–5.23 (m, 2H), 2.31–2.16 (m, 2H), 2.08–1.71 (m, 6H), 1.52 (s, 3H), 1.46 (s, 3H), 1.34–1.24 (m, 16H). Compound M17: ¹H NMR (400MHz, CDCl₃) δ 5.66–5.55 (m, 4H), 5.33–5.23 (m, 2H), 2.93 (d, J = 15.7 Hz, 4H), 2.29 (d, J = 15.7 Hz, 4H), 2.03–1.91 (m, 4H), 1.76–1.64 (m, 4H), 1.33–1.19 (m, 16H). Compound M18: ¹H NMR (400MHz, CDCl₃) δ 5.34–5.21 (m, 2H), 2.15–2.03 (m, 4H), 2.02–1.90 (m, 4H), 1.64–1.53 (m, 6H), 1.51–1.44 (m, 4H), 1.45–1.34 (m, 4H), 1.34–1.11 (m, 22H).

[0090] Example 3. Synthesis of Compound M19

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[0091] By substituting different B20 analogs and using a similar synthesis method to M19, the following compounds can be obtained: [ka]

[0092] Compound M20:1H NMR(400MHz,CDCl3)δ 5.86-5.81(m,1H),5.81-5.76(m,1H),5.74-5.68(m,2H),5.38-5.29(m,2H),4.13(t,J=7.1 ,3.0Hz,2H),2.46-2.29(m,7H),2.07-1.93(m,4H),1.77-1.60(m,6H),1.28-1.24(m,16H).

[0093] Compound M21: ¹H NMR (400MHz, CDCl₃) δ 5.85–5.77 (m, 2H), 5.75–5.67 (m, 2H), 5.38–5.30 (m, 2H), 3.67 (s, 3H), 2.48–2.30 (m, 6H), 2.05–1.93 (m, 4H), 1.81–1.55 (m, 6H), 1.34–1.23 (m, 16H).

[0094] Compound M22: 1H NMR (400MHz, CDCl3) δ 5.87-5.80 (m, 1H), 5.80-5.74 (m, 1H), 5.73-5.65 (m, 2H), 5.39-5.26 (m, 2H), 4.12 (td, J=7.4, 1.7Hz, 2H), 2.46-2.30 (m, 6H), 2.02-1.93 (m, 6H), 1.84-1.56 (m, 12H), 1.52 (d, J=2.0Hz, 6H), 1.41 (t, J=7.2Hz, 2H), 1.27 (d, J=10.4Hz, 16H).

[0095] Compound M23: 1H NMR (400MHz, CDCl3) δ 7.24-7.16 (m, 2H), 7.09-6.98 (m, 2H), 5.86-5.80 (m, 1H), 5.78-5.73 (m, 1H), 5.73-5.68 (m, 1H), 5.66-5.61 (m, 1H), 5.39-5.28 (m, 2H), 4.29 (td, J=6.7, 1.8Hz, 2H), 2.98 (t, J=6.7Hz, 2H), 2.48-2.26 (m, 6H), 2.05-1.93 (m, 4H), 1.82-1.47 (m, 6H), 1.32-1.10 (m, 16H).

[0096] Compound M24:1H NMR(400MHz, CDCl3)δ 7.40(d,J=1.9Hz,1H),7.33(d,J=8.3Hz,1H),7.24(dd,J=8.3,1.9Hz,1H),5.85-5.77(m,2H),5.75-5.66(m,2H),5.39-5.26(m ,2H),5.16(d,J=2.7Hz,2H),2.50-2.27(m,7H),2.04-1.95(m,4H),1.84-1.70(m,5H),1.63-1.55(m,2H),1.30-1.19(m,16H).

[0097] Compound M25: ¹H NMR (400MHz, CDCl3) δ 7.21-7.12 (m, 2H), 7.03-6.91 (m, 2H), 5.87-5.80 (m, 1H), 5.80-5.73 (m, 1H), 5.73-5.67 (m, 1H), 5.67-5.61 (m, 1H), 5.40-5.28 (m, 2H), 4.26 (t, J = 6.4 Hz, 2H), 2.90 (t, J = 6.5 Hz, 2H), 2.48-2.25 (m, 6H), 2.06-1.93 (m, 4H), 1.84-1.46 (m, 6H), 1.32-1.18 (m, 16H).

[0098] Compound M26: 1H NMR (400MHz, CDCl3) δ 7.34 (d, J=7.8Hz, 2H), 7.25-7.17 (m, 1H), 5.86-5.80 (m, 1H), 5.79-5.73 (m, 1H), 5.73-5.66 (m, 2H), 5.40-5.26 (m, 4H), 2.47-2.29 (m, 6H), 2.03-1.91 (m, 4H), 1.81-1.66 (m, 4H), 1.65-1.50 (m, 3H), 1.32-1.22 (m, 16H).

[0099] Compound M27: ¹H NMR (400MHz, CDCl3) δ 7.33–7.26 (m, 2H), 7.25–7.18 (m, 3H), 5.85–5.80 (m, 1H), 5.79–5.74 (m, 1H), 5.73–5.68 (m, 1H), 5.68–5.63 (m, 1H), 5.39–5.28 (m, 2H), 4.29 (td, J = 6.9, 2.9 Hz, 2H), 2.93 (t, J = 6.9 Hz, 2H), 2.50–2.26 (m, 6H), 2.07–1.92 (m, 4H), 1.80–1.50 (m, 6H), 1.32–1.19 (m, 16H).

[0100] Compound M28: ¹H NMR (400MHz, CDCl3) δ 7.36 (d, J=1.9Hz, ¹H), 7.20–7.10 (m, 2H), 5.86–5.77 (m, 2H), 5.74–5.67 (m, 2H), 5.38–5.27 (m, 2H), 4.10 (t, J=6.2Hz, 2H), 2.82–2.72 (m, 2H), 2.49–2.31 (m, 6H), 2.05–1.89 (m, 6H), 1.84–1.68 (m, 4H), 1.60 (dd, J=11.9, 3.5Hz, 2H), 1.32–1.23 (m, 16H).

[0101] Compound M29: 1H NMR (400MHz, CDCl3) δ 7.83-7.74(m,3H),7.65(s,1H),7.48-7.40(m,2H),7.35(dd,J=8.4,1.5Hz,1H ),5.84-5.79(m,1H),5.78-5.73(m,1H),5.73-5.68(m,1H),5.67-5.63(m,1H), 5.36-5.27(m,2H),4.44-4.31(m,2H),3.09(t,J=6.8Hz,2H),2.43-2.28(m,6H) ,2.04-1.91(m,5H),1.81-1.66(m,4H),1.62-1.49(m,2H),1.29-1.11(m,16H).

[0102] Compound M30: ¹H NMR (400MHz, CDCl₃) δ 7.25 (d, J = 5.2 Hz, 2H), 7.14 (d, J = 8.3 Hz, 2H), 5.87–5.80 (m, 1H), 5.80–5.75 (m, 1H), 5.73–5.68 (m, 1H), 5.66–5.61 (m, 1H), 5.38–5.28 (m, 2H), 4.30–4.19 (m, 2H), 2.90 (t, J = 6.7 Hz, 2H), 2.46–2.24 (m, 6H), 2.06–1.94 (m, 4H), 1.80–1.52 (m, 6H), 1.32–1.19 (m, 16H).

[0103] Compound M31: ¹H NMR (400MHz, CDCl₃) δ 7.37–7.33 (m, ¹H), 7.25–7.22 (m, ¹H), 7.21–7.14 (m, 2H), 5.86–5.80 (m, ¹H), 5.79–5.74 (m, ¹H), 5.73–5.68 (m, ¹H), 5.67–5.62 (m, ¹H), 5.38–5.28 (m, 2H), 4.31 (td, J = 6.8, 2.1 Hz, 2H), 3.08 (t, J = 6.8 Hz, 2H), 2.44–2.29 (m, 6H), 2.04–1.94 (m, 4H), 1.79–1.51 (m, 6H), 1.31–1.22 (m, 16H).

[0104] Compound M32:1H NMR(400MHz, CDCl3)δ 7.13(d,J=8.6Hz,2H),6.83(d,J=8.6Hz,2H),5.85-5.80(m,1H),5.79- 5.75(m,1H),5.73-5.68(m,1H),5.68-5.64(m,1H),5.38-5.28(m,2H), 4.24(td,J=7.0,2.7Hz,2H),3.78(s,3H),2.87(t,J=6.9Hz,2H),2.44- 2.26(m,6H),2.05-1.94(m,4H),1.80-1.53(m,6H),1.32-1.18(m,16H).

[0105] Example 4. Synthesis of Compound M33

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[0106] (1) Preparation of compound B23 Under nitrogen gas protection, 600 mg of compound B21 (1.1 mmol) and 599 mg of compound B22 (1.7 mmol) were dissolved in 26 ml of dry DMF (N,N-dimethylformamide). 646 mg of N,N,N′,N′-tetramethyl-O-(7-azabenzotriazole-1-yl)hexafluorourea phosphate HATU (1.7 mmol) and 4.8 ml of N,N-diisopropylethylamine DIPEA were added, and the mixture was allowed to react overnight at room temperature. The completion of the reaction was monitored by TCL, the DMF was centrifuged, 60 ml of ethyl acetate was added, the mixture was washed three times with water, and once with saturated saline solution. The mixture was dried over anhydrous sodium sulfate, concentrated, and passed through a column with DCM:MeOH = 20:1 to obtain 900 mg of product B23 as an orange powdery solid, with a yield of 94%.

[0107] (2) Preparation of compound B24 Under nitrogen gas protection, 900 mg of B23 was dissolved in 8 ml of dichloromethane, 2.0 ml of trifluoroacetic acid was added, and the mixture was reacted at room temperature for 1 hour. The completion of the reaction was monitored by TLC, 50 ml of saturated sodium bicarbonate was added to quench the reaction, and the mixture was extracted multiple times with dichloromethane, concentrated, and passed through a column with DCM:MeOH = 10:1 to obtain 513 mg of the white solid product B24, with a yield of 82%.

[0108] (3) Preparation of compound M33 Under nitrogen gas protection, 512 mg of B24 (0.8 mmol) and 514 mg of M18 (1.5 mmol) were dissolved in 16 ml of dry dichloromethane, cooled to 0°C, and 309 mg of DCC (1.5 mmol) and 98 mg (0.8 mmol) of DMAP were added. The mixture was reacted overnight at 0°C to room temperature, and the completion of the reaction was monitored by TLC. The solid was removed by filtration, 80 ml of water was added, and the mixture was extracted three times with DCM. The mixture was washed with saturated brine, dried over anhydrous sodium sulfate, and passed through a column with DCM:MeOH = 20:1 to obtain 318 mg of a white powdery solid, with a yield of 42%. 1H NMR(400MHz,CDCl3)δ 8.47(d,J=2.4Hz,1H),7.80(dd,J=7.7,5.6Hz,1H),7.47(s,1H),7.02(s,1H),6.96(d,J=5.5Hz,1H),6.76-6.68(m,1H),6.15(d,J=7. 2Hz,1H),5.35-5.26(m,3H),4.60(d,J=2.5Hz,2H),4.39(dd,J=13.2,6.5Hz,1H),3.77(d,J=3.1Hz,2H),0.83(dd,J=8.2,6.3Hz,3H). The above compound B22 can be synthesized by conventional chemical methods.

[0109] By changing the substrate and using the same synthesis method as described above, as well as the synthesis method of route 3, the following compounds are synthesized. [ka] Compound M34:1H NMR(400MHz,CDCl3)δ 8.70(d,J=4.3Hz,1H),8.67(s,1H),8.40(d,J=8.2Hz,1H),7.41-7.35(m,4H),6.28(d,J=7.8Hz,1H),5.32 (d,J=16.1Hz,2H),5.11-5.03(m,1H),4.75(t,J=7.9Hz,1H),4.50(d,J=7.4Hz,2H),4.22(d,J=11.1Hz,1H ),3.55(d,J=9.6Hz,1H),2.53(s,3H),2.07-1.97(m,4H),1.86-1.80(m,2H),1.63-1.61(m,5H),1.51-1.4 9(m,6H),1.49-1.46(m,4H),1.39-1.36(m,4H),1.28-1.23(m,6H),1.18-1.15(m,6H),1.06-1.01(m,9H).

[0110] Example 5. Synthesis of Compound M35 [ka]

[0111] (1) Preparation of compound B26 Under nitrogen gas protection, 3.0 g of B7 (8.5 mmol) was dissolved in 30 ml of dry tetrahydrofuran, 5.9 ml of hexamethylphosphate triamide HMPA (34 mmol) was added, the mixture was cooled to -78°C, ventilated multiple times with nitrogen gas, and 17 ml of lithium diisopropylamide LDA (2.0 M 34 mmol) was slowly added dropwise. The solution changed from colorless to orange, and after 30 minutes, 4.3 g of B25 (34.0 mmol) was added dropwise. The mixture was allowed to react overnight at -78°C to room temperature, monitoring the completion of the reaction by TLC. 80 ml of saturated ammonium chloride was added, and the mixture was extracted three times with ethyl acetate to combine the organic phases. The mixture was washed once with saturated brine, dried over anhydrous sodium sulfate, concentrated, and passed through a column with PE:EA = 10:1 to obtain 2.3 g of a colorless oily product, with a yield of 61%.

[0112] (2) Preparation of compound B27 400 mg of B26 (0.93 mmol) and 474 mg of pinacol diborate (1.8 mmol) were dissolved in 6 ml of dioxane, and 111 mg of the catalyst tetrakistriphenylphosphine platinum (0.09 mmol) was added. The reaction was carried out at 110°C under microwave conditions for 1 hour until the solution changed from yellow to reddish-brown. The completion of the reaction was monitored by TLC, the solid was removed by filtration, the solvent was spin-dried, and the mixture was passed through a column with a PE:EA ratio of 10:1 to obtain 338 mg of a colorless oily product, with a yield of 52%.

[0113] (3) Preparation of compound B28 338 mg of B27 (0.48 mmol), 228 mg of bromobenzene (1.45 mmol), and 402 mg of potassium carbonate (2.91 mmol) were dissolved in 12 ml of toluene and 1.5 ml of water, and the mixture was ventilated multiple times with nitrogen gas. 58 mg of the catalyst tetrakistriphenylphosphine palladium (0.05 mmol) was added, and the mixture was reacted overnight at 90°C. The solution changed from yellow to pale green, and the completion of the reaction was monitored by TLC. The solid was removed by filtration, the mixture was diluted with 60 ml of water, extracted three times with ethyl acetate, the organic phase was combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated by passing through a column to obtain 188 mg of a colorless oily product, with a yield of 66%.

[0114] (4) Preparation of compound M35 142 mg of B28 (0.24 mmol) was dissolved in 16 ml of ethanol and 2 ml of water, 284 mg of potassium hydroxide was added, and the mixture was reacted overnight at 60°C. The completion of the reaction was monitored by TLC, the ethanol was centrifuged, diluted with 30 ml of water, acidified with 1 M HCl, extracted three times with ethyl acetate, the organic phase was combined, washed with saturated brine, dried over anhydrous sulfuric acid, concentrated, and passed through a column to obtain 69 mg of a pale yellow powdery solid product, with a yield of 51%. 1H NMR(400MHz,CDCl3)δ 7.07-6.90(m,10H),5.86-5.78(m,2H),5.77-5.70(m,2H),2.56-2.46(m,4H), 2.46-2.30(m,7H),1.81-1.69(m,4H),1.64-1.52(m,2H),1.35-1.25(m,16H).

[0115] Example 6. Preparation of compound M36 [ka]

[0116] 1) Preparation of compound B30 Under nitrogen gas protection, 1.6 g of B7 (5 mmol) and 2.04 g of B29 (20 mmol) were dissolved in dry tetrahydrofuran, ventilated multiple times with nitrogen gas, cooled to -78°C, and 10 ml of LDA (20 mmol) was slowly added dropwise. The reaction mixture changed from colorless to orange. The reaction was allowed to proceed overnight at -78°C to room temperature, and the completion of the reaction was monitored by TLC. 80 ml of saturated ammonium chloride was added, and the mixture was extracted three times with ethyl acetate to combine the organic phases. The mixture was washed once with saturated brine, dried over anhydrous sodium sulfate, concentrated, and passed through a column with PE:EA = 20:1 to obtain 1.2 g of a colorless oily product with a yield of 61%.

[0117] 2) Preparation of Compound B31 and Compound B32 Under nitrogen gas protection, 1.2 g of B30 (3 mmol) and 768 mg of pinacorborane (6 mmol) were dissolved in 50 ml of dichloromethane, ventilated multiple times with nitrogen gas, and 257 mg of tris(acetonitrile)cyclopentadienylruthenium hexafluorophosphate (0.6 mmol) was added under an ice bath at 0°C. The solution changed from colorless to brown, and the reaction was allowed to proceed at room temperature for 3 hours. The completion of the reaction was monitored by TLC, the magnet was removed, 1.5 g of silica gel was added, and the mixture was mixed uniformly. The sample was loaded by dry method and passed through a column with PE:EA = 30:1 to obtain 501 mg of compound B31 and 520 mg of compound B32, all of which were colorless oily compounds, with a yield of 33%.

[0118] 3) Preparation of compound B33 520 mg of B32 (1 mmol) and 514 mg of t-butyl 4-bromobenzoate (2 mmol) were dissolved in 10 ml of 1,4-dioxane and 2 ml of water. The mixture was ventilated multiple times with nitrogen gas, and 828 mg of potassium carbonate (6 mmol) and 231 mg of tetrakis(triphenylphosphine)palladium (0.2 mmol) were added sequentially. The solution changed from colorless to brown, and the reaction was allowed to proceed overnight at 80°C. The completion of the reaction was monitored by TLC, and after cooling to room temperature, the solution was diluted with 60 ml of ethyl acetate, washed three times with water, washed once with saturated brine, dried over anhydrous sodium sulfate, concentrated, and passed through a column at PE:EA = 20:1 to obtain 497 mg of product, with a yield of 87%.

[0119] 4) Preparation of compound B34 497 mg of compound (0.8 mmol) B34 was dissolved in 10 ml of dichloromethane, 2 ml of trifluoroacetic acid was added dropwise under an ice bath, and the reaction was allowed to proceed at room temperature for 3 hours. The completion of the reaction was monitored by TLC, and after concentration, the solution was diluted with 60 ml of ethyl acetate, washed three times with water, washed three times with saturated saline solution, dried over anhydrous sodium sulfate, concentrated, and passed through a column with DCM:MeOH = 30:1 to obtain 422 mg of product, with a yield of 90%.

[0120] 5) Preparation of compound B36 54 mg of B34 (0.1 mmol), 20 mg of B35 (0.12 mmol), and 58 mg of HATU (0.15 mmol) were dissolved in 5 ml of dry DMF, ventilated with nitrogen gas, 0.2 ml of DIPEA was added, and the mixture was reacted at 60°C for 4 hours. The completion of the reaction was monitored by TLC, and after cooling to room temperature, the mixture was diluted with 60 ml of water. The mixture was extracted three times with EA, the organic phase was combined, washed once with saturated brine, dried over anhydrous sodium sulfate, concentrated, and passed through a column with PE:EA = 5:1 to obtain 51 mg of product, with a yield of 77%.

[0121] 6) Preparation of compound M36 51 mg of compound M36 (0.07 mmol) was dissolved in 10 ml of methanol and 1 ml of water, 51 mg of NaOH was added, and the mixture was reacted overnight at 60°C. The completion of the reaction was monitored by TLC, the methanol was centrifuged, diluted with 30 ml of water, acidified with 1 M HCl, extracted three times with ethyl acetate, the organic phase was combined, washed with saturated brine, dried over anhydrous sulfuric acid, concentrated, and passed through a column to obtain 23 mg of a colorless oily product, with a yield of 47%. 1H NMR(400MHz,CDCl3)δ 10.27(s,2H),8.19(d,J=3.0Hz,1H),7.51(dd,J=11.3,4.3Hz,1H),7.37(s,4H),6.66(d,J=7.6Hz,2H),5.67(t,J=7.0Hz, 1H),3.73(d,J=122.7Hz,8H),2.48(s,2H),2.17(d,J=9.0Hz,2H),1.47(d,J=35.6Hz,6H),1.21(dd,J=47.1,14.9Hz,26H).

[0122] Using B7 and B26 as starting materials, and by changing the substrate B35, the following compounds can be synthesized using the same route as described above. [ka]

[0123] Compound M37: ¹H NMR (400MHz, CDCl₃) δ 8.20 (d, J = 2.7 Hz, ¹H), 7.52 (t, J = 7.3 Hz, ¹H), 7.41 (d, J = 7.4 Hz, 2H), 7.16 (d, J = 7.5 Hz, 2H), 6.68 (d, J = 8.4 Hz, 2H), 5.43 (d, J = 6.9 Hz, 1H), 3.75 (d, J = 122.3 Hz, 8H), 2.31 (s, 2H), 1.88 (d, J = 6.1 Hz, 2H), 1.46 (s, 4H), 1.35–1.10 (m, 28H).

[0124] Compound M38: 1H NMR (400MHz, CDCl3) δ 8.20 (d, J=3.8Hz, 1H), 7.56-7.48 (m, 1H), 7.42-7.32 (m, 4H), 6.67 (t, J=6.9Hz, 2H), 5.69 (dd, J=18.2, 10.7Hz, 5H), 3.64 (t, J=81.7Hz, 9H), 2.29 (dd, J=91.6, 33.5Hz, 11H), 1.82-1.07 (m, 25H).

[0125] Compound M39:1H NMR(400MHz, CDCl3)δ 8.44(s,1H),8.01(d,J=8.1Hz,2H),7.90(d,J=6.8Hz,1H),7.58(d,J=8.0Hz,2H),7.44(d,J=3.1Hz,4H),6.95(d,J=8.9Hz,1H),5.71(s,5H ),3.76(d,J=93.9Hz,8H),2.54(s,2H),2.34(s,6H),2.22(d,J=7.2Hz,2H),1.73(d,J=12.1Hz,6H),1.47(s,2H),1.28(d,J=25.8Hz,14H). Compound M40: ¹H NMR (400 MHz, CDCl₃) δ 7.37 (s, 4H), 7.13–7.01 (m, 2H), 7.01–6.90 (m, 2H), 5.85–5.63 (m, 5H), 3.69 (s, 4H), 3.06 (s, 5H), 2.49 (s, 2H), 2.33 (s, 6H), 2.18 (s, 2H), 1.78–1.48 (m, 7H), 1.43 (s, 2H), 1.32–1.17 (m, 14H).

[0126] Example 7. Biological test 7.1. ACLY Enzyme Activity Test Equipment: Envision (PerkinElmer, USA) Materials: ACL----Human ACLY / acly / ATP citrate lyase protein (His tag) purchased from Sino Biological Company, kinase detection kit ADP-GLO (Promega Company #V9102).

[0127] Experimental Principle: In this experiment, ATP-dependent citrate lyase ACL catalyzes the conversion of citrate to acetyl coenzyme A, thereby producing malonyl A, a precursor molecule for fatty acid synthesis. Since this reaction involves the consumption of ATP, the ADP-Glo ​​Kinase Assay (#V9102) can be used. The kinase detection kit detects the change in ATP, indirectly reflecting the inhibitory effect of the reaction compound on the enzymatic activity of ACL. This kinase detection kit can provide a precise measurement of the amount of ADP produced catalyzed by ACLY enzyme activity. (First, incubate the compound, enzyme, and substrate at 37°C for 30 minutes, add ADP-Glo ​​(#V9102), incubate with the reagent for 30 minutes to stop the reaction and completely consume the remaining ATP, add the kinase detection reagent (which converts ADP to ATP while simultaneously detecting newly synthesized ATP using the coupled luciferase / luciferin reaction), incubate for 30 minutes, and read the value using Envision).

[0128] Experimental Method: Measurement is performed using the ADP-Glo ​​luminescence method. The activity of the ACLY enzyme is reflected by quantitatively detecting the amount of ADP, and the enzymatic reaction catalyzed by ACLY is proportional to the amount of ADP detected by the luminescence signal. First, the compound is diluted with 10% DMSO, and 1 μl of the diluted compound is added to 5 μl of the reaction system so that the DMSO content in the final reaction system is 2%. The enzymatic reaction catalyzed by ACLY is carried out at 37°C for 30 minutes, and the 5 μl reaction mixture contains the following components (40 mM Tris, pH 8.0, 10 mM MgCl2, 5 mM DTT, ATP, CoA, sodium citrate, and ACLY). After the enzymatic reaction, 2.5 μl of ADP-Glo ​​reagent is added to the reaction system and incubated at room temperature for 1 hour. Then, 5 μl of kinase detection reagent is added and incubated at room temperature for 30 minutes. The luminescence signal is detected by Envision (PerkinElmer, USA).

[0129] Data processing: For dose-dependent compound activity, see IC. 50 The values ​​are obtained by nonlinear fitting of sample activity to sample concentration. The software used for calculations was Graphpad Prism 7, and the model used for fitting was sigmoidal dose-response (variable slope). For most inhibitor screening models, the bottom and top of the fitting curve are set to 0 and 100. Generally, each sample sets duplicate wells (n≧2) during the test, and the results are expressed as standard deviation (SD) or standard error (SE).

[0130] The experimental results are shown in Table 1 below. NDI-091143 is a reported ACLY inhibitor and serves as a positive control. [Table 1]

[0131] NDI-091143 is a reported ACLY inhibitor that functions as a positive control, and its structure is as follows: [ka]

[0132] 7.2. MTS Experiment Experimental equipment: Molecular Device VersaMax Experimental materials: NCI-H358 cells (H358, human non-small cell lung cancer cells) were purchased from the Chinese Academy of Sciences Cell Bank / Stem Cell Bank. Culture medium RPMI-1640 (GIBCO, catalog number 3180002), human tumor cells, and human non-small cell lung cancer cells A549 were donated by researcher Li Jia of the Shanghai Institute of Materia Medica, Chinese Academy of Sciences. CellTiter 96R AQueous One Solution Cell Proliferation Assay (MTS) was purchased from promega #G3581.

[0133] Experimental Principle: Cell proliferation is detected using the CellTiter 96R AQueous One Solution Cell Proliferation Assay (MTS) colorimetric method. This analytical method is based on the tetrazole compound [3-(4,5-dimethylthiazole-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, internal salt, MTS]. The conversion from yellow MTS to blue-violet water-soluble formazan is catalyzed by dehydrogenase present in metabolically active living cells, while dead cells can complete the conversion from MTS to formazan. The amount of formazan, determined by the absorbance at 490 nm, is directly proportional to the number of living cells in culture.

[0134] Experimental method: Sample preparation: Dissolve the sample in DMSO and store at a low temperature. The concentration of DMSO in the final system is controlled to a range that does not affect the detection activity. Using the MTS method, cell viability was detected. For cells growing in the logarithmic growth phase, adherent cells were digested with 0.025% trypsin, counted, and inoculated into 80 ul 96-well plates at densities of 3000 A549 cells / well and 5000 H358 cells / well (both plated under 1% FBS conditions) and incubated overnight in a 5% CO2, 37°C incubator. Each test compound was diluted in a 3x concentration gradient to test eight concentrations, and three duplicate wells were set up for each concentration. 20 ul of the diluted compound was added to the corresponding cell wells, and adherent cells A549 and H358 were cultured for 72 hours in a 5% CO2, 37°C incubator. 20 ul of MTS was added to each, and the cells were incubated for 2 hours in a 5% CO2, 37°C incubator. Using the Molecular Device VersaMax, absorbance values ​​at 490 nm (L1) were tested, referenced to wavelength 690 nm (L2), and the (L1-L2) values ​​were plotted for various concentrations of the inhibitor. The equation was then fitted to determine IC. 50 To obtain.

[0135] Data processing: Using Graphpad Prism 7, experimental results are obtained via IC. 50 The model fitted to the model is log(inhibitor)vs.Response---variable slop, and to ensure experimental accuracy, three replicate wells are provided for each test result, and the results are expressed as standard deviation (SD) or standard error (SE). Similarly, the antiproliferative experiments of compounds against the pancreatic cancer cell line ASPC-1, human pancreatic cancer cells MIA-PACA, and breast cancer cells MCF-7 are basically the same as described above.

[0136] Experimental results: The inhibitory activity of compounds M5, M19, M25, and M29 against the proliferation of various cancer cells is shown in Table 2 below, where * indicates that it has not yet been tested, and NDI-091143 is a reported ACLY inhibitor and is used as a positive control. [Table 2]

[0137] The compounds described in this invention exhibit inhibitory activity against ACLY, and their cellular activity is superior to that of NDI-091143. This is because the compounds of this invention have hydrophobic long chains and exhibit superior membrane permeability compared to the benzenesulfonamide inhibitor NDI-091143. The compounds described in this invention possess excellent drug-like properties and have the potential to serve as ACLY-targeting inhibitors in the preparation of therapeutic agents for metabolic diseases or cancer.

[0138] All documents referenced in this invention are cited as references in this application, as if each document were cited individually. Furthermore, after reading the above teachings of this invention, persons skilled in the art can make various changes or modifications to the invention, and these equivalent forms are also included within the scope defined by the claims appended to this application.

Claims

1. A compound represented by general formula (I), or its stereoisomer, enantiomer, diastereomer, racemate, or pharmaceutically acceptable salt thereof, 【Chemistry 1】 In the formula, 【Chemistry 2】 This represents a double bond, R １ , R ２ Each of these is independently H or a C1-C4 alkyl group. R ３ , R ４ Each of these is independently either a C1-C4 alkyl group or R ３ and R ４ Together with the bonded carbon, it forms a saturated 3-7 membered ring, or a 3-7 membered ring containing an unsaturated double bond. R ５ 、 R ６ is each independently a C1-C4 alkyl group, or R ５ and R ６ together with the carbon to which they are attached form a saturated 3- to 7-membered ring or a 3- to 7-membered ring containing an unsaturated double bond, m and n are independently 2, 3, 4, or 5. q is 0, 1, 2, 3, or 4. Z is -COOH, X is -CO-, 【Transformation 3】 And, Y is a C6-C10 aryl group, a C1-C4 alkyl group, an adamantyl group (Ad-), 【Chemistry 4】 And, Here, The C6-C10 aryl group is either unsubstituted or substituted, wherein the substitution refers to substitution by one, two, or three substituents selected from the group consisting of halogens, C1-C4 alkyl groups, and C1-C4 alkoxy groups. The compound represented by the general formula (I) above, or its stereoisomers, enantiomers, diastereomers, racemates, or pharmaceutically acceptable salts thereof.

2. The compound has the structure shown in formula IV, 【Transformation 5】 W is characterized by being -O- or -S-. The compound described in claim 1, or its stereoisomer, enantiomer, diastereomer, racemate, or pharmaceutically acceptable salt thereof.

3. R １ , R ２ These are, independently, H or a methyl group. R ３ , R ４ Each of these is independently a methyl group, an ethyl group, or a propyl group, or R ３ and R ４ Together with the bonded carbon, it forms a saturated 3-6 membered ring, or a 3-6 membered ring containing one unsaturated double bond. R ５ , R ６ Each of these is independently either H, a methyl group, an ethyl group, or a propyl group, or R ５ and R ６ It is characterized by forming a saturated 3-6 membered ring, or a 3-6 membered ring containing one unsaturated double bond, together with the bonded carbon. The compound described in claim 1, or its stereoisomer, enantiomer, diastereomer, racemate, or pharmaceutically acceptable salt thereof.

4. m and n are independently 3 or 4, and / or q is characterized by being 0, 1, 2, or 3. The compound described in claim 1, or its stereoisomer, enantiomer, diastereomer, racemate, or pharmaceutically acceptable salt thereof.

5. A compound represented by general formula (I), or its stereoisomer, enantiomer, diastereomer, racemate, or pharmaceutically acceptable salt thereof, 【Transformation 6】 In the formula, 【Transformation 7】 This represents a double bond, R １ , R ２ Each of these is independently a C6-C10 aryl group, The C6-C10 aryl group is substituted, where substitution means substitution by one or two substituents selected from the group consisting of -CO-(5-7 membered heterocyclyl)-(5-7 membered heteroaryl group), and the group may be further optionally substituted by substituents selected from the group consisting of C6-C10 aryl group, halogenated C6-C10 aryl group, carboxysubstituted C6-C10 aryl group, C1-C4 alkyl substituted C6-C10 aryl group, and C1-C4 halogenated alkyl substituted C6-C10 aryl group. R ３ , R ４ Each of these is independently either a C1-C4 alkyl group or R ３ and R ４ Together with the bonded carbon, it forms a saturated 3-7 membered ring, or a 3-7 membered ring containing an unsaturated double bond. R ５ , R ６ Each of them is independently a C1-C4 alkyl group, or R5 and R6, together with the bonded carbon, form a saturated 3-7 membered ring or a 3-7 membered ring containing an unsaturated double bond. m and n are independently 3, 4, or 5. q is 0, Z is -COOH, X is, 【Transformation 8】 And, Y is characterized by being H. The compound represented by the general formula (I) above, or its stereoisomers, enantiomers, diastereomers, racemates, or pharmaceutically acceptable salts thereof.

6. The compound has the structure shown in formula II, 【Chemistry 9】 In the formula, 【Chemistry 10】 This represents a double bond, R １ , R ２ Each of these is independently a C6 aryl group, The C6 aryl group is substituted, where substitution means substitution by one substituent selected from the group consisting of -CO-(5-7 membered heterocyclyl)-(5-7 membered heteroaryl group), and the group may be further optionally substituted by substituents selected from the group consisting of C6 aryl groups, halogenated C6 aryl groups, and carboxysubstituted C6 aryl groups. R ３ , R ４ Each of these is independently either a C1-C4 alkyl group or R ３ and R ４ Together with the bonded carbon, it forms a saturated 3-7 membered ring, or a 3-7 membered ring containing an unsaturated double bond. R ５ , R ６ Each of these is independently either a C1-C4 alkyl group or R ５ and R ６ Together with the bonded carbon, it forms a saturated 3-7 membered ring, or a 3-7 membered ring containing an unsaturated double bond. m and n are each independently 3, 4, or 5. The compound according to claim 5.

7. R ３ , R ４ Each of these is independently either H, a methyl group, an ethyl group, or a propyl group, or R3 and R ４ Together with the bonded carbon, it forms a saturated 3-6 membered ring, or a 3-6 membered ring containing one unsaturated double bond. R ５ , R ６ Each of these is independently either H, a methyl group, an ethyl group, or a propyl group, or R ５ and R ６ Together with the bonded carbon, it forms a saturated 3-6 membered ring, or a 3-6 membered ring containing one unsaturated double bond. The compound according to claim 5.

8. Characterized by being selected from the following group Compounds, or their stereoisomers, enantiomers, diastereomers, racemates, or pharmaceutically acceptable salts thereof. 【Chemistry 11】 【Chemistry 12】 【Chemistry 13】 【Chemistry 14】

9. A pharmaceutical composition, The pharmaceutical composition is characterized by comprising a compound represented by general formula (I) as described in any one of claims 1 to 8, or a stereoisomer, enantiomer, diastereomer, racemate or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

10. The use of a compound represented by general formula (I) as described in any one of claims 1 to 8, or a stereoisomer, enantiomer, diastereomer, racemate thereof, or a pharmaceutically acceptable salt thereof, The use is characterized by being used in the preparation of ACLY inhibitors, or in the preparation of drugs for the prevention and / or treatment of metabolic diseases or cancer.

11. The aforementioned metabolic diseases are selected from the group consisting of hyperlipidemia, atherosclerosis, non-alcoholic fatty liver disease, and diabetes mellitus. The aforementioned cancer is characterized by being selected from the group consisting of lung cancer, pancreatic cancer, breast cancer, ovarian cancer, liver cancer, intestinal cancer, brain cancer, and acute myeloid leukemia. The use described in claim 10.

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