Novel tetrahydroisoquinoline compound, preparation method therefor, pharmaceutical composition comprising compound, and use thereof

Abstract

The present invention provides a novel tetrahydroisoquinoline compound, a preparation method therefor, a pharmaceutical composition comprising the compound, and a use thereof. Specifically, the present invention provides a nitrogen-containing heterocyclic compound as shown in Formula (I), or a pharmaceutically acceptable salt, enantiomer, diastereomer, or racemate thereof. The compound of the present invention is capable of effectively reducing the synthesis of fatty acids and cholesterol esters, thereby alleviating the development and deterioration of metabolic diseases.

Description

Novel tetrahydroisoquinoline compounds, their preparation methods, pharmaceutical compositions containing such compounds, and their uses. Technical Field

[0001] This invention relates to novel nitrogen-containing heterocyclic compounds, their preparation methods, pharmaceutical compositions comprising such compounds, and their uses, belonging to the field of pharmaceutical technology. It relates to novel nitrogen-containing heterocyclic compounds of general formula (I), pharmaceutically acceptable salts, isomers, solvates, metabolites, and metabolic precursors, pharmaceutical compositions containing them, and the use of such compounds in the prevention and / or treatment of metabolic diseases such as obesity, diabetes, hyperlipidemia, and non-alcoholic fatty liver disease. Background Technology

[0002] Metabolic diseases, including diabetes, hyperlipidemia, obesity, non-alcoholic fatty liver disease (NAFLD), cardiovascular disease, and gout, have become major global public health problems. Precise regulation of glucose and lipid metabolism plays a crucial role in maintaining energy homeostasis. With socioeconomic development, various metabolic diseases caused by imbalances in glucose and lipid metabolism, such as obesity, diabetes, NAFLD, and hyperlipidemia, have become serious threats to human health. The liver is the regulatory center of energy metabolism, and its lipid metabolism homeostasis plays a vital role in maintaining energy balance. Increased fatty acid intake and de novo lipid synthesis can lead to ectopic lipid accumulation in the liver, inducing insulin resistance and hepatocyte damage, thereby causing or accelerating the development of metabolic diseases such as NAFLD, diabetes, obesity, and hyperlipidemia.

[0003] Diabetes mellitus is a complex metabolic disorder primarily caused by insufficient insulin secretion or decreased sensitivity of target tissue cells to insulin, with hyperglycemia as its main characteristic. Diabetes also frequently leads to hyperlipidemia, thereby increasing the risk of atherosclerotic vascular disease. In diabetic patients, insulin resistance promotes obesity; increased fat promotes the production of various cytokines, thus accelerating muscle breakdown. Conversely, decreased muscle mass leads to a reduction in insulin-responsive target tissues, resulting in severe insulin resistance. This vicious cycle continues, causing even more serious consequences for the patient's health.

[0004] Obesity is a chronic disease based on excessive fat accumulation, caused by multiple factors, and usually associated with lipid metabolism disorders. Various factors lead to energy expenditure being less than energy intake, causing excess energy to be converted into fat and stored in fat cells, which is the pathophysiological mechanism of obesity. Obesity increases the risk of cardiovascular disease, diabetes, and hypertension, and is one of the top five risk factors for death globally. China has become the country with the largest obese population in the world. Obesity is a global health problem. Although intensive lifestyle interventions can lead to an average weight loss of 7-10% within 52 weeks, maintaining weight loss long-term is a challenge. Therefore, clinical practice guidelines recommend a multimodal treatment approach, such as medication and surgery, to achieve weight loss goals. The development of obesity treatment drugs has always been a hot topic in new drug research. The FDA approved many weight-loss drugs in the early stages, but most had insufficient efficacy or significant side effects, and several were even withdrawn from the market due to safety concerns.

[0005] In recent years, GLP-1-based single-receptor or multi-receptor combination agonist therapies (such as smegglutide and telpolide) have opened up new avenues for the development of new drugs for obesity. However, these drugs also face a series of challenges: such as a high incidence of adverse reactions, with more than half of patients using the medication continuously for less than one year; about one-third of the weight loss is fat-free mass, meaning a significant loss of muscle tissue; and rapid weight regain after discontinuation of the medication. Current research on new weight-loss drugs mainly focuses on regulating the central nervous system and suppressing appetite; or acting on GLP-1 receptors and inhibiting the digestion and absorption of fat in the intestines. Furthermore, how to prevent muscle loss after using GLP-1 receptor drugs has become a potential direction for research into novel weight-loss drugs. For example, activin type II receptor (ActRII) monoclonal antibodies or antagonists, and apelin receptor agonists have become hot topics in the development of anti-obesity drugs. The liver, as the central hub for the regulation of glucose and lipid metabolism in the body, plays a crucial role in the development of various metabolic diseases such as obesity, diabetes, and fatty liver due to its lipid metabolism disorders. Hepatic lipid metabolism homeostasis plays a vital role in the balance of systemic energy metabolism.

[0006] With increasing life expectancy and changing lifestyles, the incidence of sarcopenic obesity, a condition characterized by the coexistence of excessive obesity and sarcopenia, is rising and has become a significant global public health problem. Statistics show that the global prevalence of sarcopenic obesity is approximately 11% and continues to rise, but treatment measures, especially drug interventions, still need improvement. The causes of sarcopenic obesity are complex, including aging, unhealthy lifestyle habits, and inflammation. The dual pressures of muscle loss and fat accumulation can further lead to complications such as weakness, disability, fractures, metabolic diseases, and cancer, thus contributing to a continuously increasing mortality rate.

[0007] Hyperlipidemia is a condition characterized by abnormal lipid metabolism and elevated levels of lipids in the blood plasma. It has numerous causes and can trigger various high-risk diseases. With societal progress and rising living standards, the incidence of hyperlipidemia is gradually increasing.

[0008] Lipid metabolism disorders are the pathological basis of atherosclerosis. Because the lipids accumulated in the arterial intima appear as a yellowish, porridge-like substance, it is called atherosclerosis. Atherosclerosis is caused by the combined effects of multiple factors, and its pathogenesis is complex. Major risk factors include hypertension, hyperlipidemia, diabetes, obesity, and genetic factors.

[0009] Nonalcoholic fatty liver disease (NAFLD) is a chronic, progressive disease closely associated with obesity and type 2 diabetes, affecting approximately 25% of the global population. In China, it is the second most common liver disease after viral hepatitis. Nonalcoholic steatohepatitis (NASH) is a more severe form of NAFLD, characterized by hepatic steatosis, intralobular inflammation, hepatocellular ballooning lesions, and fibrosis. In the development of NAFLD, approximately 5% to 20% of patients with simple hepatic steatosis will progress to NASH. As the disease progresses, about 25% of NASH patients will develop liver fibrosis. Without medical intervention, this can easily lead to cirrhosis and hepatocellular carcinoma, ultimately threatening life.

[0010] Chronic kidney diseases such as diabetic nephropathy and nephrotic syndrome are accompanied by lipid metabolism disorders. Abnormal blood lipids can also accelerate the occurrence and development of kidney diseases. This abnormal blood lipid is also related to kidney lesions and abnormal glucose metabolism in patients with diabetic nephropathy.

[0011] Lipid metabolism is also related to tumor development. Tumor tissues can synthesize fatty acids and phospholipids de novo, rather than relying solely on lipid uptake from the environment, providing the necessary material support for the excessive growth and proliferation of tumor cells. Tumor cells have a much higher energy demand than normal cells, and fatty acids within the cells can be oxidized to produce ATP for energy. Meanwhile, lipid production plays a crucial role in membrane synthesis, cell signal transduction, cell polarization, and migration; therefore, disrupting or blocking lipid metabolism pathways could serve as potential targets for tumor therapy.

[0012] In summary, developing highly effective drugs for the treatment of metabolic diseases has significant research implications and clinical value. Summary of the Invention

[0013] The purpose of this invention is to provide a novel therapeutic drug for metabolic diseases.

[0014] In a first aspect, the present invention provides a nitrogen-containing heterocyclic compound of formula (I), or a pharmaceutically acceptable salt thereof, an enantiomer, a diastereomer, or a racemic mixture thereof:

[0015] in,

[0016] The chiral carbon atom C* can be independently of the S-type, R-type, racemic, or a combination thereof;

[0017] Ring A is selected from the group consisting of phenyl, 5-10-membered heteroaryl; and ring A optionally has one or more R4 substituents:

[0018] n = 0 or 1;

[0019] R1 is an unsubstituted or substituted group with 1-3 substituents of the following groups: C1-C7 alkyl, C2-C7 alkenyl, C2-C7 ynyl, -(CH2). p C3-C7 cycloalkyl groups, -(CH2) p 3- to 12-membered heterocyclic groups, -(CH2) p C6~C12 aryl, -(CH2) p 5- to 12-membered heteroaryl groups (such as benzo5- to 7-membered heteroaryl groups); wherein each of the said heterocyclic or heteroaryl groups contains 1 to 3 heteroatoms selected from oxygen, sulfur, and nitrogen; wherein p is 0, 1, 2, 3, or 4;

[0020] R2 and R3 are each independently selected from the group consisting of: hydrogen, deuterium, tritium, halogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted 3-7 membered heterocycle, substituted or unsubstituted C1-C6 alkylphenyl, substituted or unsubstituted C1-C6 alkyl 5-7 membered heteroaryl, substituted or unsubstituted C3-C12 cycloalkyl, substituted or unsubstituted C2-C10 acyl, substituted or unsubstituted C2-C10 ester, amino, substituted or unsubstituted C1-C6 amide, -SOR5, -OSOR5, -OCOR; and R2 and R3 are not both hydrogen.

[0021] Or, as mentioned above, R2 and R3 and the adjacent (CH2). n O and C=C together constitute a substituted or unsubstituted 5-7 membered heterocycle, wherein the heterocycle is a partially unsaturated heterocycle or an aromatic heterocycle;

[0022] R4 is selected from hydrogen, deuterium, tritium, halogen, hydroxyl, or unsubstituted or substituted with 1-3 halogens from the group consisting of: C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C2-C6 alkenyloxy, C2-C6 alkynyloxy, -(CH2). pC3-C6 cycloalkyl groups, -(CH2) p C6~C10 aryl, -(CH2) p 5-7 quinone heteroaryl groups, -O(CH2) p C3-C6 cycloalkyl groups, -O(CH2) p C6~C10 aryl, -O(CH2) p -3-7 membered heteroaryl;

[0023] The substitution refers to the substitution of a hydrogen atom on a group by one or more substituents, and the substituents are selected from the group consisting of: halogen, cyano, nitro, hydroxyl, amino, carboxyl, mercapto, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkoxy, C1-C6 alkyl-OC(O)-, C1-C6 alkyl-C(O)O-, hydroxy-substituted C1-C6 alkyl, C1-C6 haloalkyl, NH2-NHC(O)-, C1-C6 alkyl-C(O)-, C1-C6 alkyl-NHC(O)-, C1-C6 alkyl-C(O)NH-, C1-C6 alkyl-S(O)2-, C1-C6 alkyl-NHS(O)2-, C1-C6 alkyl-S(O)2-, or two substituents located on adjacent atoms together with the carbon atom attached thereto form a 5-7 membered carbon ring or heterocycle;

[0024] In the above formulas, the heterocyclic or heteroaromatic ring may arbitrarily have 1 to 3 heteroatoms selected from N, O or S.

[0025] In another preferred embodiment, ring A is selected from the group consisting of:

[0026] In another preferred embodiment, the compound of formula I has a structure selected from the group consisting of:

[0027] R2 and R3 are each independently selected from the following group: substituted or unsubstituted C6-C10 aryl groups, substituted or unsubstituted 5-7 membered heterocycles.

[0028] In another preferred embodiment, R1 is an unsubstituted or halogenated group selected from the group consisting of: C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, -(CH2)C3-C7 cycloalkyl, -(CH2)3-12 heterocyclic, benzyl, -CH2C(O)NHNH2, -CH2C(O)OH, -CH2C(O)OCH3.

[0029] In another preferred embodiment, R4 is an unsubstituted or halogenated group selected from the group consisting of: C1-C6 alkoxy, C2-C6 alkenoxy, C2-C6 alkynoxy, -O(CH2)phenyl, -O(CH2) p5-7-membered heteroaryl, -O(CH2)C3-C6 cycloalkyl, -O(CH2)-3-7-membered heteroaryl.

[0030] In another preferred embodiment, the compound has a structure selected from the group consisting of:

[0031] Where q is 0, 1, 2, 3 or 4.

[0032] In another preferred embodiment, the compound has a structure selected from the group consisting of:

[0033] In another preferred embodiment, the compound is the compound described in the examples.

[0034] A second aspect of the present invention provides a pharmaceutical composition comprising: (A) a therapeutically effective amount of the compound as described in the first aspect of the present invention, its enantiomers, diastereomers, racemates and mixtures thereof, and one or more of its pharmaceutically acceptable salts, hydrates and solvates; and (B) a pharmaceutically acceptable carrier.

[0035] In another preferred embodiment, the pharmaceutical composition is used to treat metabolic diseases; preferably, the metabolic diseases are selected from the group consisting of diabetes, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, fatty liver deformity, atherosclerosis, obesity, non-alcoholic fatty liver disease, cardiovascular disease, and gout.

[0036] A third aspect of the invention provides the use of the compounds described in the first aspect of the invention, their enantiomers, diastereomers, racemates and mixtures thereof, as well as pharmaceutically acceptable salts, hydrates and solvates thereof, for the preparation of pharmaceutical compositions for the prevention or treatment of metabolic diseases.

[0037] In another preferred embodiment, the metabolic disease is selected from the group consisting of: diabetes, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, fatty liver deformity, atherosclerosis, obesity, non-alcoholic fatty liver disease, cardiovascular disease, and gout.

[0038] It should be understood that, within the scope of this invention, the above-described technical features of this invention and the technical features specifically described below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be described in detail here. Attached Figure Description

[0039] Figure 1 shows the effect of the compound on LPS-induced BMDM IL-1β gene expression;

[0040] Figure 2 shows the effect of A5 on the differentiation of iWAT-SVF into mature adipocytes;

[0041] Figure 3 shows the effect of A5 on blood glucose after glucose load in normal mice;

[0042] Figure 4 shows the effects of A5 on body weight and food intake in NASH mice induced by a high-fat diet combined with carbon tetrachloride;

[0043] Figure 5 shows the effect of A5 on the weight of epididymal and inguinal fat in NASH mice induced by a high-fat diet combined with carbon tetrachloride.

[0044] Figure 6 shows the effects of A5 on fasting blood glucose and serum TG in NASH mice induced by a high-fat diet combined with carbon tetrachloride.

[0045] Figure 7 shows the HE staining and NAS score results of livers in NASH mice induced by a high-fat diet combined with carbon tetrachloride.

[0046] Figure 8 shows the expression of the Col-1α1 gene in the liver of NASH mice induced by a high-fat diet combined with carbon tetrachloride.

[0047] Figure 9 shows the effects of oral administration of A66 for 6 weeks on hepatic steatosis, liver triglyceride and cholesterol levels in NASH mice induced by a high-fat diet combined with carbon tetrachloride.

[0048] Figure 10 shows that A66 significantly reduced random and fasting blood glucose in type 2 diabetic db / db mice;

[0049] Figure 11 shows that oral administration of A66 at 5 and 15 mg / kg significantly reduced the body weight of DIO mice. Detailed Implementation

[0050] Through long-term and in-depth research, the inventors have developed a novel therapeutic compound for metabolic diseases. This compound effectively reduces the synthesis of fatty acids and cholesterol esters, thereby mitigating the progression and exacerbation of metabolic diseases. Based on these findings, the inventors have completed this invention.

[0051] the term

[0052] As used herein, the term "alkyl" refers to a straight-chain (i.e., unbranched) or branched saturated hydrocarbon group containing only carbon atoms, either alone or as part of other substituents, or a combination of straight and branched groups. When an alkyl group is preceded by a carbon number definiteness (e.g., C...), it is used to indicate a carbon atom number. 1-10 When ), it refers to the alkyl group containing 1-10 carbon atoms. For example, C 1-8Alkyl refers to an alkyl group containing 1 to 8 carbon atoms, including methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, or similar groups. Unless otherwise specified, the alkyl group refers to an alkyl group containing 1 to 10 carbon atoms.

[0053] As used herein, the term "alkenyl," whether alone or as part of other substituents, refers to a straight-chain or branched carbon chain group having at least one carbon-carbon double bond. Alkenyl groups can be substituted or unsubstituted. When an alkenyl group is preceded by a carbon number definiteness (e.g., C...), it signifies a carbon chain group. 2-8 When ), it refers to the alkenyl group containing 2-8 carbon atoms. For example, C 2-8 Alkenyl refers to an alkenyl group containing 2-8 carbon atoms, including vinyl, propenyl, 1,2-butenyl, 2,3-butenyl, butadienyl, or similar groups. Unless otherwise specified, the alkenyl group refers to an alkenyl group containing 2-10 carbon atoms.

[0054] As used herein, the term "alkynyl" refers to an aliphatic hydrocarbon group having at least one carbon-carbon triple bond, either alone or as part of other substituents. The alkynyl group can be straight-chain or branched, or a combination thereof. When the alkynyl group is preceded by a carbon number definiteness (e.g., C...), it is considered a alkynyl group. 2-8 When alkynyl is used, it means that the alkynyl group contains 2-8 carbon atoms. For example, the term "C 2-8 "Alynyl" refers to a straight-chain or branched alkynyl group having 2-8 carbon atoms, including ethynyl, propynyl, isopropynyl, butynyl, isobutynyl, sec-butynyl, tert-butynyl, or similar groups. Unless otherwise specified, the alkynyl group refers to an alkynyl group containing 2-10 carbon atoms.

[0055] As used herein, the term "cycloalkyl" refers to a cyclic group having a saturated or partially saturated monocyclic ring, bicyclic or polycyclic (fused, bridged or spirocyclic) ring. When a cycloalkyl group is preceded by a carbon number determination (e.g., C...), it is used to indicate a cyclic group having a saturated or partially saturated monocyclic ring, bicyclic or polycyclic (fused, bridged or spirocyclic). 3-10 When ), it refers to the cycloalkyl group containing 3-10 carbon atoms. In some preferred embodiments, the term "C" is used. 3-8"Cycloalkyl" refers to a saturated or partially saturated monocyclic or bicyclic alkyl group having 3-8 carbon atoms, including cyclopropyl, cyclobutyl, cyclopentyl, cycloheptyl, or similar groups. "Spirocycloalkyl" refers to a bicyclic or polycyclic group in which monocyclic rings share a single carbon atom (called a spiro atom). These may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. "Fused cycloalkyl" refers to a fully carbon bicyclic or polycyclic group in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system. One or more rings may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. "Bridged cycloalkyl" refers to a fully carbon polycyclic group in which any two rings share two non-directly connected carbon atoms. These may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. All atoms in the cycloalkyl group are carbon atoms. Unless otherwise specified, the cycloalkyl group refers to a cycloalkyl group containing 3-10 carbon atoms. The following are some examples of cycloalkyl groups; the present invention is not limited to the cycloalkyl groups described below.

[0056] Unless otherwise stated, the terms used in the specification and claims have the following meanings. "Aryl" refers to a monocyclic or fused polycyclic (i.e., a ring sharing adjacent carbon atom pairs) group having a conjugated π-electron system, such as phenyl and naphthyl. The aryl ring may be fused to other cyclic groups (including saturated and unsaturated rings), but cannot contain heteroatoms such as nitrogen, oxygen, or sulfur, and the point of attachment to the parent group must be on a carbon atom of a ring having a conjugated π-electron system. The aryl group may be substituted or unsubstituted; unless otherwise specified, the aryl group is an aryl group containing 6-10 carbon atoms. Some examples of aryl groups are given below; the invention is not limited to the aryl groups described below.

[0057] "Heteroaryl" refers to a heteroaryl group containing one or more heteroatoms, possessing a fully conjugated π-electron system. The heteroatoms referred to here include oxygen, sulfur, and nitrogen, such as furanyl, thiophene, pyridinyl, pyrazolyl, pyrroleyl, N-alkylpyrroleyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, etc. When the heteroaryl group is a fused structure, the heteroaryl ring can be fused to an aryl or heteroaryl ring. The heteroaryl group can be optionally substituted or unsubstituted. Some examples of heteroaryl groups are given below; the present invention is not limited to the heteroaryl groups described below. Preferably, the heteroatom in the heteroaryl group can be N, O, or S. Unless otherwise specified, the heteroaryl group is a 5-10 member heteroaryl group.

[0058] "Heterocyclic group" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, wherein one or more ring atoms are selected from nitrogen, oxygen, or sulfur, and the remaining ring atoms are carbon. Non-limiting examples of monocyclic heterocyclic groups include pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, and homopiperazinyl. Polycyclic heterocyclic groups refer to heterocyclic groups including spirocyclic, fused-ring, and bridged-ring groups. "Spirocyclic heterocyclic group" refers to a polycyclic heterocyclic group in which each ring in the system shares an atom (called a spiro atom) with other rings in the system, wherein one or more ring atoms are selected from nitrogen, oxygen, or sulfur, and the remaining ring atoms are carbon. "Fused-ring heterocyclic group" refers to a polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with other rings in the system, one or more rings may contain one or more double bonds, but at least one ring does not have a fully conjugated π-electron system, and one or more ring atoms are selected from nitrogen, oxygen, or sulfur, and the remaining ring atoms are carbon. "Bridged heterocyclic group" refers to a polycyclic heterocyclic group in which any two rings share two non-directly connected atoms. These groups may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. Furthermore, one or more ring atoms are selected from nitrogen, oxygen, or sulfur, while the remaining ring atoms are carbon. Preferably, the heteroatom of the heterocyclic group can be N, O, or S. Unless otherwise specified, the heterocyclic group is a 5-10 member heterocyclic group. The following are some examples of heterocyclic groups; however, this invention is not limited to the heterocyclic groups described below.

[0059] As used herein, the term "halogen" refers to F, Cl, Br, and I, either alone or as part of other substituents.

[0060] As used herein, the term "substitution" (with or without the "arbitrarily" modified) refers to the substitution of one or more hydrogen atoms on a particular group by a particular substituent. The particular substituent is the substituent described accordingly above, or the substituent appearing in the various embodiments. Unless otherwise specified, an arbitrarily substituted group may have a substituent selected from a particular group at any substituted site of that group, and the substituents may be the same or different at each position. Cyclic substituents, such as heterocyclic groups, may be attached to another ring, such as a cycloalkyl group, thereby forming a spirobicyclic system, i.e., two rings sharing a common carbon atom. Those skilled in the art will understand that the combinations of substituents contemplated in this invention are those that are stable or chemically feasible. The substituents include, for example (but are not limited to): C 1-8 Alkyl, C 2-8 alkenyl, C 2-8 alkynyl group, C 3- 8-cycloalkyl, 3- to 12-membered heterocyclic groups, aryl, heteroaryl, halogen, hydroxyl, carboxyl (-COOH), C 1-8 Aldehyde group, C 2-10 Acyl group, C 2-10 Ester group, amino group.

[0061] Unless otherwise specified, all compounds mentioned in this invention are intended to include all possible optical isomers, such as compounds with a single chirality, or mixtures of various chiral compounds (i.e., racemates). In all compounds of this invention, each chiral carbon atom may optionally be in the R configuration or the S configuration, or a mixture of the R and S configurations.

[0062] As used herein, the term "compound of the invention" refers to a compound of Formula I. The term also includes various crystalline forms, pharmaceutically acceptable salts, hydrates, or solvates of compounds of Formula I.

[0063] As used herein, the term "pharmaceutically acceptable salt" refers to a salt formed by the compounds of the present invention with an acid or base that is suitable for use as a medicine. Pharmaceutically acceptable salts include both inorganic and organic salts. A preferred class of salts are those formed by the compounds of the present invention with an acid. Suitable acids for forming salts include, but are not limited to: inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, and phosphoric acid; organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, benzenesulfonic acid, and benzenesulfonic acid; and acidic amino acids such as aspartic acid and glutamic acid.

[0064] The tetrahydroisoquinoline compound represented by formula (I)

[0065] This invention provides a tetrahydroisoquinoline compound represented by general formula (I), its enantiomers, diastereomers, racemates, mixtures thereof, or pharmaceutically acceptable salts thereof.

[0066] The definitions of each group are as described above.

[0067] In particular, the tetrahydroisoquinoline compounds of the present invention are preferably selected from the compounds shown in Table A below:

[0068] Preparation of compound (I)

[0069] The present invention also provides a method for synthesizing a compound having general formula I, specifically, the compound of formula I is prepared by the following process:

[0070] Step a: Dissolve compound II in a solvent and react it with sodium borohydride to obtain compound III; the solvent is methanol;

[0071] Step b: Dissolve III in a solvent, add sodium iodide and excess allyl bromide, reflux and stir to obtain compound IV; the solvent is anhydrous acetonitrile;

[0072] Step c: Dissolve IV in a solvent, add excess sodium borohydride, and stir until the reaction is complete to obtain compound V; the solvent is anhydrous ethanol;

[0073] n, R1, R2, R3, and A are defined in the aforementioned requirements.

[0074] Specifically, the method includes the following steps:

[0075] (1) In an inert solvent, in the presence of a base, the compound of formula II is reduced to obtain the compound of formula III; preferably, the reduction reaction is carried out using a borohydride as a reducing agent.

[0076] (2) The compound of formula III is reacted with the halogenated product in an inert solvent to obtain the compound of formula IV; preferably, the halogenated product is a brominated product;

[0077] (3) In an inert solvent, the compound of formula IV is reacted with a reducing agent to obtain the compound of formula V; preferably, the reduction reaction uses a borohydride as a reducing agent;

[0078] In another preferred embodiment, the compound of formula V is prepared by the following method:

[0079] (4) In an inert solvent, in the presence of a condensing agent, the compound of formula VI and the compound of formula VII react to obtain the compound of formula VIII; preferably, the condensing agent is HATU (N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea);

[0080] (5) In an inert solvent, the compound of formula VIII is subjected to a Bischler–Napieralski cyclization reaction to obtain the compound of formula IX; preferably, the cyclization reaction is performed using phosphorus oxychloride as a Lewis acid;

[0081] (6) In an inert solvent, a reduction reaction is carried out with a compound of formula IX to obtain a compound of formula X; preferably, the reduction reaction uses a borohydride as a reducing agent;

[0082] (7) In an inert solvent, the compound of formula X is subjected to a Pictet–Spengler reaction to obtain the compound of formula V; preferably, formic acid is used as the acid in the cyclization reaction.

[0083] In another preferred embodiment, the compound of formula VII is prepared by the following method:

[0084] (8) In an inert solvent, the compound of formula XII is subjected to a hydrolysis reaction to obtain the compound of formula VII; preferably, sodium hydroxide is used as a base for the hydrolysis reaction.

[0085] In another preferred embodiment, the compound of formula V is prepared by the following method:

[0086] (9) In an inert solvent, the compound of formula VII was subjected to a cyclization reaction with phenylboronic acid and paraformaldehyde to obtain the compound of formula XIII;

[0087] (10) In an inert solvent, the compound of formula XIII is subjected to an aminolysis reaction with the compound of formula VI to obtain the compound of formula XIV; preferably, the aminolysis reaction is carried out using triethylamine as a base;

[0088] (11) In an inert solvent, a compound of formula XIV is reacted with acetyl chloride to give a compound of formula XV; preferably, the substitution reaction is carried out using pyridine as a base.

[0089] (12) In an inert solvent, the compound of formula XV is subjected to a Bischler–Napieralski cyclization reaction to obtain the compound of formula XVI; preferably, the cyclization reaction is performed using phosphorus oxychloride as a Lewis acid.

[0090] (13) In an inert solvent, a compound of formula XVI is used for reduction to obtain a compound of formula XVII; preferably, the reduction reaction is carried out using a borohydride as a reducing agent.

[0091] (14) The compound of formula XVII is hydrolyzed in an inert solvent to obtain the compound of formula XVIII; preferably, sodium hydroxide is used as a base for the hydrolysis reaction.

[0092] (15) In an inert solvent, a cyclization reaction is carried out with a compound of formula XVIII to obtain a compound of formula V; preferably, sodium bicarbonate is used as a base for the cyclization reaction.

[0093] In another preferred embodiment, the preparation method further includes the step of:

[0094] (16) In an inert solvent, the compound of formula XX is subjected to an oxidation reaction to obtain the compound of formula II; preferably, the oxidation reaction is carried out using elemental iodine as an oxidant;

[0095] In the above formulas, the definitions of each group are as described in any one of the claims.

[0096] Pharmaceutical compositions containing a compound of formula (I)

[0097] The pharmaceutical compositions of the present invention comprise, within a safe and effective range, the compound of the present invention or a pharmacologically acceptable salt thereof, and a pharmacologically acceptable excipient or carrier. "Safe and effective range" refers to an amount of the compound sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical composition contains 1-2000 mg of the compound of the present invention per dose, more preferably, 5-200 mg of the compound of the present invention per dose. Preferably, "one dose" is one capsule or tablet.

[0098] "Pharmaceutically acceptable carriers" refers to one or more compatible solid or liquid fillers or gelling substances that are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility" here means that the components in the composition can be mixed with and with the compounds of the present invention without significantly reducing the efficacy of the compounds. Examples of pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as... Wetting agents (such as sodium dodecyl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0099] There are no particular limitations on the administration of the compounds or pharmaceutical compositions of the present invention. Representative administration methods include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous) and local administration.

[0100] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following components: (a) fillers or compatibilizers, such as starch, lactose, sucrose, glucose, mannitol, and silica; (b) binders, such as hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic; (c) humectants, such as glycerin; (d) disintegrants, such as agar, calcium carbonate, potato starch or cassava starch, alginate, certain complex silicates, and sodium carbonate; (e) slowing agents, such as paraffin wax; (f) absorption accelerators, such as quaternary ammonium compounds; (g) wetting agents, such as cetyl alcohol and glyceryl monostearate; (h) adsorbents, such as kaolin; and (i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium dodecyl sulfate, or mixtures thereof. Buffers may also be included in capsules, tablets, and pills.

[0101] Solid dosage forms such as tablets, sugar pills, capsules, pellets, and granules can be prepared using coatings and shells, such as casings and other materials known in the art. They may contain opacifying agents, and the release of the active compound or compound from such compositions can be delayed in a portion of the digestive tract. Examples of encapsulating components that can be used are polymeric substances and waxes. If necessary, the active compound may also be formed into microcapsules with one or more of the excipients described above.

[0102] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, or tinctures. In addition to the active compound, liquid dosage forms may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, e.g., ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butanediol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, and sesame oil, or mixtures of these substances.

[0103] In addition to these inert diluents, the composition may also contain auxiliaries such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents and fragrances.

[0104] In addition to the active compound, the suspension may contain suspending agents, such as ethoxylated isooctadecyl alcohol, polyoxyethylene sorbitol and dehydrated sorbitol esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances.

[0105] Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions, or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents, or excipients include water, ethanol, polyols, and suitable mixtures thereof.

[0106] Dosage forms of the compounds of the present invention for topical administration include ointments, powders, patches, sprays, and inhalers. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be necessary.

[0107] The compounds of this invention can be administered alone or in combination with other pharmaceutically acceptable compounds.

[0108] The compounds according to the present invention, as described above, are suitable for clinical use in mammals, including humans and animals, and can be administered via oral, nasal, skin, lung, or gastrointestinal routes, more preferably orally. The preferred daily dose is 0.01–200 mg / kg body weight, administered as a single dose, or 0.01–100 mg / kg body weight, administered in divided doses. Regardless of the method of administration, the optimal dose for an individual should be determined based on the specific treatment. Generally, a low dose is started, and the dose is gradually increased until the most suitable dose is found. Of course, the specific dose should also consider factors such as the route of administration and the patient's health condition, which are within the scope of a skilled physician's expertise.

[0109] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental methods in the following embodiments, unless otherwise specified, are generally performed under conventional conditions or as recommended by the manufacturer. Percentages and parts are by weight unless otherwise stated.

[0110] The invention will be further illustrated by examples in the following embodiments. These embodiments are for illustrative purposes only and are not intended to limit the invention in any way. All parameters and other descriptions in the embodiments, unless otherwise stated, are for illustrative purposes only.

[0111] The analytical data of the samples were determined by the following instruments: nuclear magnetic resonance (NMR) was measured by a GEMINI-300, Bruker AMX-400, and INVOA-600 NMR spectrometer, with TMS (tetramethylsilane) as an internal standard. Chemical shifts were measured in ppm, and coupling constants were measured in Hz. Mass spectrometry (MS) was measured by a Finnigan MAT-711, MAT-95, and LCQ-DECA mass spectrometer, as well as an IonSpec 4.7 Tesla mass spectrometer.

[0112] Column chromatography used 200-300 mesh silica gel (produced by Qingdao Ocean Chemical Plant); TLC silica gel plates were HSGF-254 type thin-layer chromatography pre-prepared plates produced by Yantai Chemical Plant; petroleum ether had a boiling range of 60-90℃; ultraviolet light and an iodine tank were used for color development. Unless otherwise specified, all conventional reagents and chemicals used in the following examples were purchased from Sinopharm Group. Reagents and solvents used in the experiments were handled according to the specific reaction conditions.

[0113] Example A1: Synthesis of Compound A1

[0114] Synthesis route:

[0115] Synthesis of compounds 1-2:

[0116] 1-1 and potassium carbonate were dispersed in methanol. Sodium borohydride was dissolved in 5% sodium hydroxide solution and added dropwise to the reaction solution. After reacting at room temperature for two hours, the mixture was filtered. The filter cake was washed successively with water, 30% ethanol, and anhydrous ethanol to obtain yellow solid 1-2, which was directly used in the next reaction. 1 H NMR (400MHz, DMSO-d6) δ7.30(s,1H),6.82(d,J=8.3Hz,1H),6.76(s,1H),6.69(d,J=8.3Hz,1H),6.05(s,1H ),6.00(s,2H),4.21(s,2H),3.76(s,3H),3.71(s,3H),3.06(t,J=5.9Hz,2H),2.80(t,J=5.9Hz,2H).ESI-MS m / z337.3[M+H] + .

[0117] Synthesis of compounds 1-3:

[0118] Dissolve 1-2 and sodium iodide in acetonitrile, add iodomethane, and reflux at 80°C for 16 hours under argon protection. Cool the reaction solution to room temperature and remove acetonitrile by rotary evaporation. Add water to the residue, sonicate, filter, and dry the filter cake to obtain intermediate 1-3. ESI-MS m / z 353.4 [M] + .

[0119] Synthesis of compound A1:

[0120] Disperse 1-3 in anhydrous ethanol, add sodium borohydride in portions under ice bath conditions, and react at room temperature for 1 hour. After the reaction is complete as monitored by TLC, quench the reaction with saturated ammonium chloride solution, extract with ethyl acetate, combine the organic phases, wash with saturated sodium chloride solution, dry with anhydrous sodium sulfate, evaporate to dryness, and perform column chromatography (petroleum ether:ethyl acetate 10:1) to give a pale yellow solid. The overall yield of the three steps is 35%. 1H NMR(500MHz,Chloroform-d)δ7.03(d,J=8.2Hz,1H),6.81(d,J=0.6Hz,1H),6.70(d,J=8.1Hz,1H),6.53(t,J=1.0Hz,1H),6.01(s,2H),4.38–4.32(m ,1H),4.25(s,1H),4.15(s,1H),3.83(d,J=2.0Hz,6H),3.77–3.68(m,1H), 3.16–3.07(m,2H),2.90–2.81(m,2H),1.48(dd,J=6.2,1.5Hz,3H).ESI-MS m / z354.2[M+H] + .

[0121] Example A2: Synthesis of Compound A2

[0122] By replacing the iodomethane in Example A1 with bromoethane, and following the same synthesis method as compound A1, compound A2 was obtained. 1 HNMR(500MHz,Chloroform-d)δ7.01(d,J=8.7Hz,1H),6.81(d,J=0.6Hz,1H),6.69(d,J=8 .6Hz,1H),6.53(t,J=1.0Hz,1H),6.00(d,J=4.8Hz,2H),4.39(d,J=8.1Hz,1H),4.25(s,1H ),4.15(s,1H),3.83(d,J=0.7Hz,6H),3.54–3.45(m,1H),3.14(dd,J=9.0,6.2Hz,1H),3.0 7(dd,J=9.1,6.3Hz,1H),2.90–2.83(m,2H),1.91–1.79(m,2H),1.00–0.94(m,3H).ESI-MS m / z 368.1[M+H] + .

[0123] Example A3: Synthesis of Compound A3

[0124] By replacing iodomethane in Example A1 with 1-bromopropane, and following the synthesis method of compound A1, compound A3 was obtained. 1H NMR(400MHz,DMSO-d6)δ6.95–6.79(m,3H),6.68(s,1H),5.98(d,J=1.0Hz,1H), 5.94(d,J=1.0Hz,1H),4.08(s,J=16.1Hz,1H),3.78(s,3H),3.72(s,3H),3.54(d ,J=2.3Hz,1H),3.39(s,1H),3.13–2.95(m,2H),2.92–2.82(m,1H),2.54(d,J=1 5.9Hz,1H),2.43–2.35(m,1H),1.36–0.94(m,4H),0.67(t,J=6.9Hz,3H).ESI-MS m / z382.0[M+H] + .

[0125] Example A4: Synthesis of Compound A4

[0126] By replacing iodomethane in Example A1 with 1-bromobutane, and following the synthesis method of compound A1, compound A4 was obtained. 1 H NMR(500MHz,Chloroform-d)δ6.99(dd,J=8.6,0.7Hz,1H),6.79(d,J=0.6Hz,1H),6.69(d,J=8.6Hz,1 H),6.53(t,J=1.0Hz,1H),5.99(d,J=4.6Hz,2H),4.32(d,J=8.2Hz,1H),4.25(s,1H),4.15(s,1H),3.8 4(d,J=4.4Hz,6H),3.59–3.50(m,1H),3.14(dd,J=9.1,6.3Hz,1H),3.07(dd,J=9.0,6.2Hz,1H),2.91 –2.83(m,2H),1.96–1.85(m,2H),1.62–1.51(m,2H),1.42–1.32(m,2H),0.91(t,J=5.5Hz,3H).ESI-MS m / z396.4[M+H] + .

[0127] Example A5: Synthesis of Compound A5

[0128] By replacing iodomethane in Example A1 with 3-bromopropene, and following the synthesis method of compound A1, compound A5 was obtained. 1H NMR(400MHz,DMSO-d6)δ6.90(s,1H),6.89–6.77(m,2H),6.69(s,1H),5.96(dd,J=11.7,1.1 Hz,2H),5.75–5.62(m,1H),4.82–4.76(m,1H),4.69–4.61(m,1H),4.08(d,J=16.0Hz,1H),3. 78(s,3H),3.73(s,3H),3.60(s,1H),3.39(d,J=16.0Hz,1H),3.24–3.16(m,1H),3.12–3.05 (m,1H),2.95–2.82(m,1H),2.60–2.52(m,1H),2.47–2.38(m,1H),2.10–1.92(m,2H).ESI-MS m / z 380.0[M+H] + .

[0129] Example A6: Synthesis of Compound A6

[0130] By replacing iodomethane in Example A1 with 3-bromo-3,3-difluoropropene, and following the synthesis method of compound A1, compound A6 was obtained. 1 H NMR(400MHz, DMSO-d6)δ6.94–6.83(m,3H),6.69(s,1H),5.96(d,J=9.0Hz,2H),4.30( dtd,J=26.9,8.5,2.9Hz,1H),4.09(d,J=16.0Hz,1H),3.78(s,3H),3.73(s,3H),3.61 (s,1H),3.39(d,J=16.0Hz,1H),3.24–3.15(m,1H),3.12–3.05(m,1H),2.96–2.82(m, 1H),2.56(d,J=15.6Hz,1H),2.42(td,J=11.6,2.8Hz,1H),2.04–1.84(m,2H).ESI-MS m / z 416.2[M+H] + .

[0131] Example A7: Synthesis of Compound A7

[0132] By replacing iodomethane in Example A1 with 3-bromo-2-methylpropene, and following the synthesis method of compound A1, compound A7 was obtained. 1H NMR(500MHz,DMSO-d6)δ6.94(s,1H),6.83(d,J=8.4Hz,1H),6.68(d,J=9.1Hz,2H),5.98(d,J=1.1Hz,1H), 5.94(d,J=1.1Hz,1H),4.61(t,J=2.1Hz,1H),4.32–4.26(m,1H),4.08(d,J=16.0Hz,1H),3.77(s,3H),3.7 3(s,3H),3.61(s,1H),3.40(d,J=15.9Hz,1H),3.32–3.20(m,1H),3.10–3.04(m,1H),2.94–2.83(m,1H),2 .61–2.52(m,1H),2.45–2.38(m,1H),1.96(dd,J=13.6,9.7Hz,1H),1.87–1.81(m,1H),1.60(s,3H).ESI-MS m / z 394.2[M+H] + .

[0133] Example A8: Synthesis of Compound A8

[0134] By replacing iodomethane in Example A1 with 3-bromopropyne, and following the synthesis method of compound A1, compound A8 was obtained. 1 H NMR (500MHz, CDCl3) δ7.23(d,J=8.5Hz,1H),6.82(d,J=8.4Hz,1H),6.70(s,1H),6.58(s,1 H),5.93(s,1H),5.92(s,1H),4.18(d,J=16.0Hz,1H),3.87(s,3H),3.85(s,3H),3.72(s,1H ),3.53(d,J=16.0Hz,1H),3.21–3.13(m,1H),3.11–3.06(m,1H),3.04–2.93(m,1H),2.63–2 .50(m,2H),2.49–2.34(m,1H),2.11(dt,J=17.1,3.1Hz,1H),1.95(t,J=2.7Hz,1H).ESI-MS m / z 378.1[M+H] + .

[0135] Example A9: Synthesis of Compound 9

[0136] By replacing iodomethane in Example A1 with benzyl bromide, and following the synthesis method of compound A1, compound A9 was obtained. 1H NMR(600MHz,DMSO-d6)δ7.20–7.13(m,2H),7.13–7.09(m,1H),7.01(s,1H),6.88-6.8 4(m,2H),6.69(s,1H),6.60(d,J=8.4Hz,1H),5.98(d,J=8.5Hz,1H),5.95(s,2H),4.14 (d,J=16.0Hz,1H),3.73(s,3H),3.71(s,3H),3.65(s,1H),3.48–3.37(m,2H),3.12(dd ,J=11.5,4.6Hz,1H),2.99–2.91(m,1H),2.66–2.52(m,2H),2.48–2.41(m,2H).ESI-MS m / z 430.2[M+H] + .

[0137] Example A10: Synthesis of compound A10

[0138] By replacing iodomethane in Example A1 with bromomethylcyclopropane, and following the synthesis method of compound A1, compound A10 was obtained. 1 H NMR(500MHz,Chloroform-d)δ6.97(d,J=8.7Hz,1H),6.79(d,J=0.6Hz,1H),6.69(d,J=8.6Hz,1H), 6.53(t,J=1.0Hz,1H),5.99(d,J=3.5Hz,2H),4.32(dd,J=8.1,0.7Hz,1H),4.25(s,1H),4.15(s,1H) ,3.84(d,J=5.3Hz,6H),3.40(td,J=9.4,7.9Hz,1H),3.14(dd,J=9.1,6.3Hz,1H),3.07(dd,J=9.0, 6.2Hz,1H),2.91–2.83(m,2H),2.11(t,J=9.2Hz,2H),1.82–1.72(m,1H),1.56–1.46(m,5H).ESI-MS m / z 394.2[M+H] + .

[0139] Example A11: Synthesis of compound A11

[0140] By replacing iodomethane in Example A1 with bromomethylcyclobutane, and following the same synthesis method as compound A1, compound A11 was obtained. 1H NMR (500MHz, Chloroform-d) δ6.97 (dd, J=8.6, 0.7Hz, 1H), 6.78 (d, J=0.6Hz, 1H), 6.70 (d, J=8. 6Hz,1H),6.53(t,J=1.1Hz,1H),6.00(d,J=7.1Hz,2H),4.33(d,J=8.1Hz,1H),4.25(s,1H),4.15 (s,1H),3.84(d,J=4.0Hz,6H),3.38–3.29(m,1H),3.14(dd,J=9.0,6.4Hz,1H),3.08(dd,J=9.0, 6.2Hz,1H),2.91–2.83(m,2H),2.30–2.21(m,2H),1.83–1.72(m,1H),1.75–1.57(m,7H).ESI-MS m / z 408.1[M+H] + .

[0141] Example A12: Synthesis of compound A12

[0142] By replacing iodomethane in Example A1 with bromomethylcyclopentane, and following the same synthesis method as compound A1, compound A12 was obtained. 1 H NMR(500MHz,Chloroform-d)δ6.94(d,J=8.7Hz,1H),6.78(d,J=0.6Hz,1H),6.69(d,J=8.6Hz,1H), 6.53(t,J=1.0Hz,1H),6.01(d,J=5.9Hz,2H),4.33(d,J=8.1Hz,1H),4.25(s,1H),4.15(s,1H),3.84 (d,J=3.1Hz,6H),3.38–3.29(m,1H),3.14(dd,J=9.0,6.4Hz,1H),3.08(dd,J=9.0,6.2Hz,1H),2.9 3–2.84(m,2H),2.26–2.16(m,2H),1.83–1.71(m,1H),1.65–1.53(m,5H),1.56–1.41(m,4H).ESI-MS m / z 422.4[M+H] + .

[0143] Example A13: Synthesis of compound A13

[0144] By replacing iodomethane in Example A1 with bromomethylcyclohexane, and following the synthesis method of compound A1, compound A13 was obtained. 1H NMR(500MHz,Chloroform-d)δ6.94(d,J=8.7Hz,1H),6.76(s,1H),6.69(d,J=8.6Hz,1H),6.53(t,J=1.0Hz ,1H),6.01(d,J=3.7Hz,2H),4.33(d,J=8.1Hz,1H),4.25(s,1H),4.17(s,1H),3.84(d,J=1.8Hz,6H),3.38– 3.29(m,1H),3.14(dd,J=9.0,6.4Hz,1H),3.08(dd,J=9.0,6.2Hz,1H),2.93–2.84(m,2H),2.26–2.16(m,2 H),1.67–1.58(m,1H),1.61–1.52(m,3H),1.55–1.49(m,3H),1.52–1.42(m,4H),1.44–1.33(m,1H).ESI-MS m / z 435.9[M+H] + .

[0145] Example A14: Synthesis of compound A14

[0146] By replacing iodomethane in Example A1 with epoxybromopropane, and following the synthesis method of compound A1, compound A14 was obtained. 1 H NMR(500MHz,Chloroform-d)δ6.91(dd,J=8.6,0.7Hz,1H),6.78(s,1H),6.71(d,J=8.4Hz,1 H),6.53(t,J=1.0Hz,1H),5.99(d,J=3.5Hz,2H),4.39–4.34(m,1H),4.24(d,J=4.9Hz,2H), 3.84(d,J=3.8Hz,6H),3.80–3.71(m,1H),3.62–3.55(m,2H),3.51–3.42(m,1H),3.14(dd,J =9.1,6.3Hz,1H),3.07(dd,J=9.0,6.2Hz,1H),2.92–2.84(m,2H),2.63–2.49(m,2H).ESI-MS m / z 396.4[M+H] + .

[0147] Example A15: Synthesis of Compound A15

[0148] By replacing iodomethane in Example A1 with 4-(bromomethyl)morpholine, and following the synthetic method of compound A1, compound A15 was obtained. 1H NMR(500MHz,Chloroform-d)δ6.99(d,J=8.7Hz,1H),6.76(s,1H),6.69(d,J=8.6Hz ,1H),6.53(t,J=1.0Hz,1H),6.01(d,J=3.7Hz,2H),4.39(d,J=8.1Hz,1H),4.25(s, 1H),4.17(s,1H),3.84(d,J=3.8Hz,7H),3.84–3.76(m,1H),3.73–3.64(m,5H),3.3 4(dd,J=9.0,1.8Hz,2H),3.17–3.05(m,2H),2.92–2.83(m,6H),2.84(s,1H).ESI-MS m / z 439.1 [M+H] + .

[0149] Example A16: Synthesis of Compound A16

[0150] By replacing iodomethane in Example A1 with 4-bromomethylpiperidine, and following the synthetic method of compound A1, compound A16 was obtained. 1 H NMR(500MHz,Chloroform-d)δ6.94(d,J=8.7Hz,1H),6.76(s,1H),6.69(d,J=8.6Hz,1H),6. 53(t,J=1.0Hz,1H),6.01(d,J=3.7Hz,2H),4.33(d,J=8.1Hz,1H),4.25(s,1H),4.17(s,1H), 3.84(d,J=0.7Hz,7H),3.38–3.29(m,1H),3.17–3.05(m,2H),2.97–2.89(m,5H),2.91–2.84 (m,2H),2.34–2.26(m,1H),2.26–2.17(m,2H),1.89–1.77(m,1H),1.72–1.59(m,5H).ESI-MS m / z 437.3[M+H] + .

[0151] Example A17: Synthesis of Compound A17

[0152] By replacing iodomethane in Example A1 with methyl bromoacetate, and following the synthesis method of compound A1, compound A17 was obtained. 1H NMR(500MHz,Chloroform-d)δ6.98(d,J=8.7Hz,1H),6.81(d,J=0.6Hz,1H),6.70(d,J=8.6Hz,1H),6.46(t,J=0.9Hz,1H),5.99(d,J=3.3Hz,2H ),4.57–4.51(m,1H),4.32–4.22(m,3H),3.84(d,J=2.9Hz,6H),3.67(s,2H),3.17–3.10(m,2H),3.14–3.07(m,2H),2.93–2.84(m,2H).ESI-MS m / z 412.1[M+H] + .

[0153] Example A18: Synthesis of Compound A18

[0154] Compound A17 was dissolved in a 1:2 mixture of methanol and tetrahydrofuran, and 1M sodium hydroxide solution was added. The mixture was reacted at room temperature for 2 hours. After the reaction was complete, methanol and tetrahydrofuran were removed by rotary evaporation. The pH of the remaining liquid was adjusted to 4-5 with dilute hydrochloric acid, and the mixture was extracted three times with ethyl acetate. The combined organic phases were dried and then evaporated to dryness. Column chromatography (petroleum ether:ethyl acetate 5:1) gave a pale yellow solid, A18, in 87% yield. 1 H NMR (500MHz, DMSO-d6) δ12.51(s,1H),6.99(d,J=8.7Hz,1H),6.86(d,J=0.7Hz,1H),6.67(d,J=8.6Hz,1H),6.49(t,J=0.9Hz,1H),6.02(d,J=4 .6Hz,2H),4.58–4.53(m,1H),4.41–4.30(m,1H),4.24(d,J=4.6Hz,2H),3.83(d,J=10.3Hz,6H),3.28–3.12(m,4H),2.94–2.86(m,2H).ESI-MS m / z 397.9[M+H] + .

[0155] Example A19: Synthesis of Compound A19

[0156] Compound A17 was dissolved in anhydrous ethanol, and hydrazine hydrate was added. The mixture was refluxed at 75°C for 12 hours. After the reaction was completed by TLC monitoring, it was cooled to room temperature, the solvent was removed by rotary evaporation, anhydrous ethanol was added, the mixture was sonicated, filtered, and the filter cake was washed with water and dried to give a white solid A19, with a yield of 52%. 1H NMR(500MHz,DMSO-d6)δ9.03(t,J=5.1Hz,1H),6.94(d,J=8.7Hz,1H),6.83(d,J=0.7H z,1H),6.67(d,J=8.6Hz,1H),6.49(t,J=1.0Hz,1H),6.02(d,J=7.1Hz,2H),4.55–4.50 (m,1H),4.36–4.26(m,1H),4.24(d,J=4.6Hz,2H),4.08(d,J=5.1Hz,2H),3.83(d,J=1 1.3Hz,5H),3.24(dd,J=9.0,6.2Hz,1H),3.16–3.07(m,3H),2.93–2.86(m,2H).ESI-MS m / z 412.1[M+H] + .

[0157] Example A20: Synthesis of compound A20

[0158] Compound A2 was dissolved in toluene under argon protection. 3.5 M aluminum hydroxide was added in an ice bath, and the reaction was carried out at 0°C for 1.5 hours. After further addition of aluminum hydroxide in an ice bath, the reaction was transferred to 80°C and continued for 2 hours. After the reaction was complete, the mixture was cooled to room temperature, and the reaction was quenched with saturated ammonium chloride solution. The mixture was filtered through diatomaceous earth, and the filtrate was evaporated to dryness. Column chromatography (petroleum ether:ethyl acetate 10:1) yielded a pale yellow solid, A20, in 47% yield. 1 H NMR(400MHz, DMSO-d6)δ6.95–6.76(m,3H),6.69(s,1H),6.33(dd,J=86.9,11.0Hz,1H)6.50(dd,J=86.9,4 .6Hz,1H),5.97(d,J=1.1Hz,1H),5.95(d,J=1.1Hz,1H),5.31–5.13(m,1H)4.86–4.67(m,1H),4.07(d,J=1 5.9Hz,1H),3.78(s,3H),3.72(s,3H),3.60(d,J=2.7Hz,1H),3.39(d,J=16.2Hz,1H),3.21–3.14(m,1H),3 .11–3.02(m,1H),2.94–2.82(m,1H),2.56(d,J=15.2Hz,1H),2.52–2.32(m,1H),1.96–1.75(m,2H).ESI-MS m / z 398.0[M+H] + .

[0159] Example A21: Synthesis of Compound A21

[0160] By replacing 1-1 in Example A3 with berberine, and referring to the synthesis method of compound A1, compound A21 was obtained. 1 H NMR(500MHz,DMSO-d6)δ6.96–6.90(m,1H),6.79(d,J=0.6Hz,1H),6.67(d,J=8 .6Hz,1H),6.60–6.56(m,1H),4.34–4.29(m,1H),4.25(s,1H),4.15(s,1H),3. 86–3.80(m,9H),3.78(s,2H),3.66–3.57(m,1H),3.20–3.11(m,2H),2.89–2.8 1(m,2H),1.93–1.84(m,2H),1.56–1.46(m,2H),0.97(t,J=5.7Hz,3H).ESI-MS m / z 398.3 [M+H] + .

[0161] Example A22: Synthesis of compound A22

[0162] By replacing 1-1 in Example A5 with berberine, and referring to the synthesis method of compound A1, compound A22 was obtained. 1 H NMR(500MHz, DMSO-d6)δ6.97–6.92(m,1H),6.79(d,J=0.6Hz,1H),6.68(d,J=8.6Hz,1H),6.60–6.56(m,1H),5.81–5.70(m,1H),5.14–5.07(m,2H), 4.32(d,J=8.6Hz,1H),4.25(s,1H),4.15(s,1H),3.86–3.78(m,10H),3.7 8(s,3H),3.20–3.11(m,2H),2.86–2.78(m,2H),2.77–2.70(m,2H).ESI-MS m / z 396.4[M+H] + .

[0163] Example A23: Synthesis of compound A23

[0164] By replacing 1-1 in Example A10 with berberine, and referring to the synthesis method of compound A1, compound A23 was obtained. 1HNMR(500MHz,DMSO-d6)δ6.95(dd,J=8.6,0.7Hz,1H),6.79(d,J=0.6Hz,1H),6 .69(d,J=8.6Hz,1H),6.60–6.55(m,1H),4.34(d,J=8.1Hz,1H),4.25(s,1H),4. 15(s,1H),3.86–3.80(m,12H),3.57–3.48(m,1H),3.21–3.12(m,2H),2.89–2. 81(m,2H),2.11(t,J=9.1Hz,2H),1.82–1.72(m,1H),1.53–1.46(m,4H).ESI-MS m / z 410.1[M+H] + .

[0165] Example A24: Synthesis of compound A24

[0166] Synthesis route:

[0167] Synthesis of compound 2-2:

[0168] Anhydrous tetrahydrofuran was added to a two-necked flask. Sodium hydride (60% by mass, dispersed in kerosene) was added in portions under argon protection in an ice bath. A 2:1 solution of tetrahydrofuran was then injected. After reacting at room temperature for 30 minutes, iodomethane was added, and the reaction continued at room temperature for 3 hours. The reaction was quenched with saturated ammonium chloride solution, extracted with ethyl acetate, and the combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation. Column chromatography (petroleum ether:ethyl acetate 10:1) yielded a colorless oily product in 85% yield. 1 H NMR (500MHz, DMSO-d6) δ7.07–7.01(m,1H),6.95(dd,J=2.0,0.7Hz,1H),6.88(d,J=8.3Hz,1H),5.89–5.75(m ,1H),5.19–5.10(m,2H),3.82(d,J=17.4Hz,6H),3.80–3.75(m,0H),3.75(s,2H),2.76–2.66(m,2H).ESI-MS m / z 225.0[M+H] + .

[0169] Synthesis of compounds 2-3:

[0170] Dissolve 2-2 in methanol, add 1M sodium hydroxide solution, and react at room temperature for 2 hours. After the reaction is complete as monitored by TLC, most of the methanol is removed by rotary evaporation. The residue is diluted with water, and the pH is adjusted to 1-2 with 1M hydrochloric acid. Extraction is performed with ethyl acetate. The combined organic phases are dried over anhydrous sodium sulfate, and the solvent is removed by rotary evaporation to obtain a colorless oil, which is used directly in the next reaction. ESI-MS m / z 209.2 [MH] - .

[0171] Synthesis of compound 4-1:

[0172] Dissolve 2-3 in dichloromethane, then add HATU and triethylamine sequentially. Stir at room temperature for 20 minutes, then add 3-1 and continue the reaction at room temperature for 3 hours. Wash the reaction solution sequentially with saturated ammonium chloride solution, saturated sodium bicarbonate solution, and saturated sodium chloride solution. Dry the organic phase with anhydrous sodium sulfate, then remove the solvent by rotary evaporation. Column chromatography (petroleum ether: ethyl acetate 2:1) gives a white solid in 63% yield. 1 H NMR (600MHz, DMSO-d6) δ7.96–7.92(m,1H),6.89(d,J=2.1Hz,1H),6.85(d,J=8.3H z,1H),6.79(dd,J=8.3,2.0Hz,1H),6.73(d,J=7.9Hz,1H),6.68(d,J=1.7Hz,1H),6 .52(dd,J=7.9,1.7Hz,1H),5.93(d,J=3.8Hz,2H),4.35–4.28(m,1H),3.87(s,3H) ,3.81(s,3H),3.41–3.26(m,2H),2.86–2.73(m,2H),1.43(d,J=5.9Hz,3H).ESI-MS m / z 358.3 [M+H] + .

[0173] Synthesis of compound 4-2:

[0174] Compound 4-1 was placed in a two-necked flask and dissolved in ultra-dry acetonitrile. Phosphorus oxychloride was added under argon protection, and the mixture was refluxed at 80°C for 2 hours. After the reaction, the reaction solution was cooled to room temperature, and the acetonitrile was removed by rotary evaporation. The residue was diluted with dichloromethane, and the pH was adjusted to approximately 9 with saturated sodium bicarbonate solution. The mixture was extracted with dichloromethane, and the organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation to obtain an orange solid, which was then directly used for the next reaction. ESI-MS m / z 340.1 [M+H] + .

[0175] Synthesis of compound 4-3:

[0176] Compound 4-2 was dissolved in methanol, and sodium borohydride was added under ice bath conditions. The reaction was carried out at room temperature for 3 hours. After the reaction was completed by TLC monitoring, a saturated ammonium chloride solution was added to quench the reaction. The mixture was extracted with dichloromethane, and the combined organic phases were dried over anhydrous sodium sulfate and then evaporated to dryness. The residue was purified by column chromatography (dichloromethane:methanol 20:1) to give a pale yellow solid in 52% yield. 1 H NMR(500MHz,DMSO-d6)δ6.99–6.94(m,1H),6.88–6.83(m,2H),6.77(dd,J=1.9,1.0Hz,1H),6.60–6.56(m,1H),6.07(s,1H),6.02(s,1H) ,5.09–5.01(m,1H),3.81(d,J=2.7Hz,6H),3.75–3.65(m,1H),3.17–3.05(m,3H),2.97–2.88(m,2H),1.43(dd,J=5.5,1.5Hz,3H).ESI-MS m / z 342.1[M+H] + .

[0177] Synthesis of compound A24:

[0178] Dissolve 4-3 in a mixed solution of 98% formic acid and 37% formaldehyde (formic acid:formaldehyde 3:2), and react at 90°C for 2 hours under argon protection. Remove most of the solvent by rotary evaporation, neutralize the remaining formic acid with sodium bicarbonate solution, extract with dichloromethane, combine the organic phases, dry to anhydrous sodium sulfate, and evaporate the solvent. Purify by column chromatography (petroleum ether:ethyl acetate 4:1) to give a white solid in 73% yield. 1 H NMR(500MHz,DMSO-d6)δ6.89(d,J=0.6Hz,1H),6.83(t,J=1.0Hz,1H),6.77( d,J=0.7Hz,1H),6.55(t,J=1.0Hz,1H),6.06(s,1H),6.02(s,1H),4.40–4.34 (m,1H),4.10(dd,J=3.1,0.9Hz,2H),3.82(d,J=6.4Hz,6H),3.77–3.68(m,1H ),3.15–3.05(m,2H),2.92–2.85(m,2H),1.49(dd,J=6.2,1.5Hz,3H).ESI-MS m / z 354.1[M+H] + .

[0179] Example A25: Synthesis of Compound A25

[0180] By replacing the iodomethane in Example A24 with iodomethane, and following the same synthesis method as compound A24, compound A25 was obtained.1 H NMR(500MHz,DMSO-d6)δ6.90(d,J=0.6Hz,1H),6.84(t,J=1.0Hz,1H),6.73(s ,1H),6.50(d,J=1.0Hz,1H),6.04(d,J=17.0Hz,2H),4.41(d,J=8.1Hz,1H),4 .08(dd,J=3.7,1.0Hz,2H),3.81(d,J=3.5Hz,6H),3.59–3.50(m,1H),3.11–3 .02(m,2H),2.92–2.85(m,2H),1.89–1.80(m,2H),1.00–0.94(m,3H).ESI-MS m / z 367.9[M+H] + .

[0181] Example A26: Synthesis of Compound A26

[0182] By replacing iodomethane in Example A24 with 1-bromopropane, and following the synthetic method of compound A24, compound A26 was obtained. 1 H NMR(500MHz,DMSO-d6)δ6.89–6.82(m,2H),6.76(s,1H),6.50(t,J=1.0Hz,1H), 6.03(d,J=15.4Hz,2H),4.33(d,J=8.2Hz,1H),4.07(d,J=0.9Hz,1H),4.02(d,J= 1.1Hz,1H),3.82(d,J=5.7Hz,6H),3.57–3.48(m,1H),3.11–3.02(m,2H),2.92–2 .85(m,2H),1.88(q,J=8.7Hz,2H),1.56–1.45(m,2H),1.00–0.94(m,3H).ESI-MS m / z382.1[M+H] + .

[0183] Example A27: Synthesis of Compound A27

[0184] By replacing iodomethane in Example A24 with 1-bromobutane, and following the synthetic method of compound A24, compound A27 was obtained. 1H NMR (500MHz, DMSO-d6) δ6.89–6.82(m,2H),6.73(d,J=0.6Hz,1H),6.55(t,J=1.0Hz,1 H),6.02(d,J=5.5Hz,2H),4.37–4.31(m,1H),4.07(d,J=0.9Hz,1H),4.02(d,J=1.0Hz, 1H),3.82(d,J=6.0Hz,6H),3.62–3.53(m,1H),3.11–3.02(m,2H),2.92–2.85(m,2H),1 .96–1.86(m,2H),1.62–1.51(m,2H),1.41–1.31(m,2H),0.90(t,J=5.6Hz,3H).ESI-MS m / z 396.2[M+H] + .

[0185] Example A28: Synthesis of Compound A28

[0186] By replacing iodomethane in Example A24 with isobutyl bromide, and following the same synthesis method as compound A24, compound A28 was obtained. 1 H NMR(500MHz,DMSO-d6)δ6.89–6.82(m,2H),6.76(d,J=0.6Hz,1H),6.55(t,J=1.0Hz,1H), 6.02(d,J=5.5Hz,2H),4.35–4.30(m,1H),4.07(d,J=0.9Hz,1H),4.02(d,J=0.9Hz,1H),3. 82(d,J=6.0Hz,6H),3.51–3.42(m,1H),3.10–3.00(m,2H),2.92–2.85(m,2H),2.04(dd,J =9.8,7.0Hz,2H),1.91–1.81(m,1H),0.99(d,J=4.9Hz,3H),0.94(d,J=4.9Hz,3H).ESI-MS m / z 396.2[M+H] + .

[0187] Example A29: Synthesis of Compound A29

[0188] By replacing iodomethane in Example A24 with 3-bromopropene, and following the synthetic method of compound A24, compound A29 was obtained. 1H NMR (500MHz, CDCl3) δ6.73(s,1H),6.70(s,1H),6.58(s,1H),6.50(s,1H),5.89(d,J=1.5H z,1H),5.88(d,J=1.4Hz,1H),5.77–5.67(m,1H),5.14(dd,J=17.1,1.8Hz,1H),5.11–5.02 (m,1H),3.98–3.92(m,2H),3.85(s,3H),3.83(s,3H),3.66(d,J=15.2Hz,1H),3.18–3.12( m,1H),3.11–3.02(m,1H),2.97–2.88(m,2H),2.86–2.73(m,2H),2.62–2.54(m,1H).ESI-MS m / z 380.1[M+H] + .

[0189] Example A30: Synthesis of compound A30

[0190] By replacing iodomethane in Example A24 with 3-bromo-3,3-difluoropropene, and following the synthesis method of compound A24, compound A30 was obtained. 1 H NMR (500MHz, DMSO-d6) δ6.85–6.78(m,3H),6.55(t,J=1.0Hz,1H),6.02(d,J=13.7Hz,2H),5.36–5.29(m,1H),4.43(d,J=8.2Hz,1H),4.07(dd,J =3.7,1.1Hz,2H),3.82(d,J=7.7Hz,7H),3.21–3.11(m,1H),3.10–3.02(m,2H),2.93–2.85(m,2H),2.66(ddd,J=14.8,10.4,8.0Hz,1H).ESI-MS m / z 416.3[M+H] + .

[0191] Example A31: Synthesis of Compound A31

[0192] By replacing the iodomethane in Example A24 with 3-bromopropyne, and following the synthetic method of compound A24, compound A31 was obtained. 1H NMR(500MHz,DMSO-d6)δ6.89(d,J=0.6Hz,1H),6.85(t,J=1.0Hz,1H),6.78(s,1H ),6.50(d,J=1.0Hz,1H),6.03(d,J=15.4Hz,2H),4.48(dd,J=7.1,0.7Hz,1H),4.0 7(d,J=0.9Hz,1H),4.02(d,J=1.1Hz,1H),3.82(d,J=5.5Hz,6H),3.66–3.58(m,1 H),3.15–3.07(m,2H),3.09–3.02(m,2H),2.93–2.85(m,2H),2.68(s,1H).ESI-MS m / z378.2[M+H] + .

[0193] Example A32: Synthesis of compound A32

[0194] By replacing the iodomethane in Example A24 with bromomethylcyclopropane, and following the synthesis method of compound A24, compound A32 was obtained. 1 H NMR (500MHz, DMSO-d6) δ6.89–6.82(m,2H),6.80(d,J=0.7Hz,1H),6.55(t,J=1.0H z,1H),6.01(d,J=12.1Hz,2H),4.34(d,J=8.1Hz,1H),4.07(d,J=0.9Hz,1H),4.02( d,J=0.9Hz,1H),3.82(d,J=7.7Hz,6H),3.53–3.44(m,1H),3.10–3.00(m,2H),2.93 –2.85(m,2H),2.11(t,J=9.2Hz,2H),1.82–1.72(m,1H),1.53–1.46(m,4H).ESI-MS m / z 394.0 [M+H] + .

[0195] Example A33: Synthesis of compound A33

[0196] By replacing 2-1 in Example A29 with methyl p-methoxyphenylacetate, and referring to the synthesis method of compound A24, compound A33 was obtained. 1H NMR(500MHz,DMSO-d6)δ7.05(dd,J=8.6,0.6Hz,1H),6.91(d,J=0.6Hz,1H),6.80–6.75(m,1H ),6.65(dd,J=8.8,2.0Hz,1H),6.60–6.56(m,1H),6.06(s,1H),6.02(s,1H),5.80–5.66(m,1H ),5.16–5.05(m,2H),4.39(d,J=8.4Hz,1H),4.04(d,J=1.1Hz,1H),3.99(d,J=0.9Hz,1H),3.8 0(s,3H),3.56–3.47(m,1H),3.15–3.06(m,2H),2.94–2.84(m,2H),2.77–2.64(m,2H).ESI-MS m / z 350.2[M+H] + .

[0197] Example A34: Synthesis of compound A34

[0198] By replacing 2-1 in Example A29 with methyl 3,4,5-trimethoxyphenylacetate, and referring to the synthesis method of compound A24, compound A34 was obtained. 1 H NMR(500MHz,DMSO-d6)δ6.81(d,J=0.6Hz,1H),6.68(s,1H),6.57–6.53(m,1 H),6.02(d,J=13.7Hz,2H),5.80–5.66(m,1H),5.15–5.04(m,2H),4.39–4.34 (m,1H),4.27(d,J=10.6Hz,2H),3.88(s,3H),3.82(d,J=11.3Hz,6H),3.77–3 .68(m,1H),3.20–3.11(m,2H),2.94–2.84(m,2H),2.79–2.73(m,2H).ESI-MS m / z410.2[M+H] + .

[0199] Example A35: Synthesis of Compound A35

[0200] 2-(5-methoxybenzo[b]thiophene-3-yl)acetic acid and anhydrous potassium carbonate were dissolved in ultra-dry DMF. Iodomethane was slowly added dropwise under ice bath conditions. After stirring for 10 minutes, the mixture was moved to room temperature and reacted for 3 hours. After the reaction was completed by TLC monitoring, saturated sodium thiosulfate solution was slowly added under ice bath conditions to quench the reaction. The reaction solution was diluted with water and extracted three times with ethyl acetate. The combined organic phases were washed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the ethyl acetate was removed by rotary evaporation. The purified solution was purified by column chromatography (petroleum ether:ethyl acetate 4:1) to give a yellow oily liquid 2-1a.

[0201] By replacing 2-1 in Example A24 with 2-1a, and referring to the synthesis method of compound A24, compound A35 was obtained. 1 H NMR(500MHz,DMSO-d6)δ7.72(d,J=8.0Hz,1H),7.37(d,J=2.2Hz,1H),6.94(dd, J=8.0,1.9Hz,1H),6.88(d,J=0.6Hz,1H),6.50(t,J=1.0Hz,1H),6.03(d,J=15.4 Hz,2H),4.40–4.34(m,1H),3.98(s,1H),4.02–3.95(m,1H),3.94(s,1H),3.81(s ,2H),3.11–3.03(m,2H),2.96–2.84(m,2H),1.50(dd,J=6.0,1.5Hz,3H).ESI-MS m / z 380.3 [M+H] + .

[0202] Example A36: Synthesis of Compound A36

[0203] By replacing 2-1 in Example A25 with 2-1a, and referring to the synthesis method of compound A24, compound A36 was obtained. 1H NMR (500MHz, DMSO-d6) δ7.71(d,J=8.2Hz,1H),7.37(d,J=2.2Hz,1H),6.93(dd,J=8.1,2 .0Hz,1H),6.89(d,J=0.6Hz,1H),6.55(t,J=1.0Hz,1H),6.04(s,1H),6.00(s,1H),4.45 (d,J=7.7Hz,1H),4.32–4.23(m,1H),4.02(d,J=4.6Hz,2H),3.81(s,2H),3.16–3.05(m, 2H),2.95–2.86(m,2H),2.20–2.09(m,1H),1.70–1.58(m,1H),0.99–0.93(m,3H).ESI-MS m / z 394.0[M+H] + .

[0204] Example A37: Synthesis of Compound A37

[0205] By replacing 2-1 in Example A26 with 2-1a, and referring to the synthesis method of compound A24, compound A37 was obtained. 1 H NMR (500MHz, DMSO-d6) δ7.71(d,J=8.2Hz,1H),7.39(d,J=2.0Hz,1H),6.94(dd,J=8. 0,1.9Hz,1H),6.87(s,1H),6.55(t,J=1.0Hz,1H),6.02(d,J=13.7Hz,2H),4.46–4.40 (m,1H),4.21–4.12(m,1H),4.02(d,J=4.6Hz,2H),3.82(s,2H),3.15–3.05(m,2H),2. 95–2.85(m,2H),1.96–1.87(m,2H),1.54–1.43(m,2H),0.96(t,J=5.7Hz,3H).ESI-MS m / z 407.9[M+H] + .

[0206] Example A38: Synthesis of compound A38

[0207] By replacing 2-1 in Example A27 with 2-1a, and referring to the synthesis method of compound A24, compound A38 was obtained. 1H NMR (500MHz, DMSO-d6) δ7.71(d,J=8.2Hz,1H),7.37(d,J=1.9Hz,1H),6.92(dd,J=8.0,1.9H z,1H),6.83(d,J=0.6Hz,1H),6.57–6.53(m,1H),6.04(d,J=17.4Hz,2H),4.41(d,J=7.9Hz,1 H),4.21–4.12(m,1H),4.02(d,J=4.6Hz,2H),3.82(s,2H),3.16–3.05(m,2H),2.94–2.85(m, 2H),1.96–1.86(m,2H),1.56–1.40(m,2H),1.39–1.29(m,2H),0.90(t,J=5.5Hz,3H).ESI-MS m / z 422.4[M+H] + .

[0208] Example A39: Synthesis of Compound A39

[0209] By replacing 2-1 in Example A28 with 2-1a, and referring to the synthesis method of compound A24, compound A39 was obtained. 1 H NMR (500MHz, DMSO-d6) δ7.71(d,J=8.2Hz,1H),7.37(d,J=2.0Hz,1H),6.92(dd,J=8.0,1.9H z,1H),6.87(s,1H),6.57–6.53(m,1H),6.04(d,J=17.4Hz,2H),4.44(dd,J=8.1,0.7Hz,1H), 4.02(d,J=4.6Hz,2H),4.00–3.92(m,1H),3.82(s,2H),3.15–3.05(m,2H),2.93–2.84(m,2H) ,2.11–1.97(m,2H),1.92–1.82(m,1H),0.98(d,J=4.9Hz,3H),0.93(d,J=4.9Hz,3H).ESI-MS m / z 422.4[M+H] + .

[0210] Example A40: Synthesis of Compound A40

[0211] By replacing 2-1 in Example A29 with 2-1a, and referring to the synthesis method of compound A24, compound A40 is obtained. 1H NMR(500MHz,DMSO-d6)δ7.71(d,J=8.2Hz,1H),7.39(d,J=2.0Hz,1H),6.94(dd,J=8.0,1 .9Hz,1H),6.87(s,1H),6.57–6.53(m,1H),6.02(d,J=7.1Hz,2H),5.82–5.70(m,1H),5.1 3–5.06(m,2H),4.45(d,J=8.4Hz,1H),4.37–4.29(m,1H),4.02(d,J=4.6Hz,2H),3.82(s, 2H),3.15–3.05(m,2H),2.94–2.86(m,2H),2.80–2.71(m,1H),2.74–2.65(m,1H).ESI-MS m / z 406.1[M+H] + .

[0212] Example A41: Synthesis of Compound A41

[0213] By replacing 2-1 in Example A32 with 2-1a, and referring to the synthesis method of compound A24, compound A41 is obtained. 1 H NMR(500MHz,DMSO-d6)δ7.71(d,J=8.2Hz,1H),7.37(d,J=1.9Hz,1H),6.92(dd,J=8 .0,1.9Hz,1H),6.87(s,1H),6.57–6.53(m,1H),6.04(d,J=17.4Hz,2H),4.47–4.42 (m,1H),4.02(d,J=4.6Hz,2H),3.82(s,2H),3.67–3.59(m,1H),3.15–3.05(m,2H), 2.94–2.84(m,2H),2.13–2.04(m,2H),1.88–1.76(m,1H),1.50–1.42(m,4H).ESI-MS m / z 420.0[M+H] + .

[0214] Example A42: Synthesis of compound A42

[0215] Synthesis of compound 2-1b:

[0216] By replacing 2-(5-methoxy-1H-indol-3-yl)acetic acid in Example A35 with 2-(5-methoxybenzo[b]thiophen-3-yl)acetic acid, and referring to the synthesis method of compound 2-1a, compound 2-1b was obtained.

[0217] Synthesis of compound 3-1a:

[0218] Dissolve 5-1 in acetone, add anhydrous potassium carbonate and 4-trifluoromethylbenzyl bromide, and react at 60°C for 12 hours. After the reaction is complete, cool to room temperature, filter, wash the filter cake several times with dichloromethane, concentrate the filtrate, add petroleum ether:ethyl acetate 10:1, sonicate to precipitate the solid, filter, and dry the filter cake to give white solid 5-2, yield 91%.

[0219] 5-2 was dissolved in nitromethane, and ammonium acetate and acetic acid were added sequentially. The reaction was carried out under argon protection at 80°C for 2 hours. After the reaction was completed, the reaction solution was cooled and allowed to stand. A large amount of solid precipitated and was then filtered. The filter cake was washed sequentially with saturated sodium bicarbonate solution, water, and isopropanol, and then dried to give a yellow solid 5-3, with a yield of 69%.

[0220] Dissolve 5-3 in ultra-dry tetrahydrofuran, and slowly add lithium aluminum hydride in batches under ice bath conditions. After stirring for 30 minutes, heat to 60°C and react for 2 hours. After the reaction is complete as monitored by TLC, place the reaction solution in an ice bath, dilute with diethyl ether, and quench the reaction dropwise with water under ice bath conditions until no bubbles are generated. Filter through diatomaceous earth, wash the filter cake repeatedly with ethyl acetate, and evaporate the filtrate to dryness to obtain a yellow oily solid 3-1a.

[0221] Synthesis of compound A42:

[0222] Replace 2-1 and 3-1 in Example A24 with 2-1b and 3-1a respectively, and synthesize according to the method of compound A24 to obtain compound A42. 1 H NMR (500MHz, DMSO-d6) δ7.67–7.61(m,2H),7.52–7.45(m,2H),7.26(d,J=7.4Hz,1H),7.20(d,J=1. 8Hz,1H),7.04(dd,J=7.4,1.9Hz,1H),6.86(d,J=0.6Hz,1H),6.66–6.62(m,1H),5.15–5.11(m,2H) ,4.54–4.48(m,1H),4.30–4.22(m,1H),3.92(d,J=2.4Hz,2H),3.80(d,J=2.7Hz,6H),3.33(dd,J=9 .1,6.3Hz,1H),3.28(dd,J=9.1,6.3Hz,1H),2.90–2.82(m,2H),1.68(dd,J=6.2,1.5Hz,3H).ESI-MS m / z523.1[M+H] + .

[0223] Example A43: Synthesis of compound A43

[0224] By replacing 2-1 and 3-1 in Example A25 with 2-1b and 3-1a respectively, and referring to the synthesis method of compound A24, compound A43 was obtained. 1 H NMR(500MHz,DMSO-d6)δ7.67–7.61(m,2H),7.52–7.45(m,2H),7.26(d,J=7.5Hz,1H),7.15(d ,J=2.0Hz,1H),7.04(dd,J=7.4,1.9Hz,1H),6.82(d,J=0.7Hz,1H),6.65(d,J=1.1Hz,1H),5.1 3(t,J=1.0Hz,2H),4.79–4.69(m,1H),4.58–4.53(m,1H),3.92(d,J=2.4Hz,2H),3.80(d,J=1. 1Hz,6H),3.36–3.25(m,2H),2.90–2.82(m,2H),2.07–1.98(m,2H),1.03–0.97(m,3H).ESI-MS m / z 537.2[M+H] + .

[0225] Example A44: Synthesis of Compound A44

[0226] Replace 2-1 and 3-1 in Example A26 with 2-1b and 3-1a respectively, and synthesize according to the method of compound A24 to obtain compound A44. 1H NMR (600MHz, DMSO-d6) δ10.48(s,1H),7.76(d,J=8.0Hz,2H),7.65(d,J=8.0Hz,2H),7.14(d,J=8.7Hz,1H),6.96(d,J=2.4Hz,1H ),6.81(s,1H),6.72(s,1H),6.65(dd,J=8.7,2.4Hz,1H),5.15(q,J=12.8Hz,2H),4.05(d,J=16.0Hz,1H),3.91(d,J=4.9Hz,1H) ,3.73(s,3H),3.70(s,3H),3.63(d,J=16.0Hz,1H),3.27-3.21(m,1H),3.18-3.09(m,1H),3.01-2.92(m,1H),2.91-2.83(m,1H) ,2.80-2.70(m,1H),2.09-2.01(m,1H),1.85-1.76(m,1H),1.55-1.42(m,1H),1.23-1.15(m,1H),0.91(t,J=7.3Hz,3H).ESI-MS m / z 551.3[M+H] + .

[0227] Example A45: Synthesis of Compound A45

[0228] By replacing 2-1 and 3-1 in Example A29 with 2-1b and 3-1a respectively, and referring to the synthesis method of compound A24, compound A45 was obtained. 1 H NMR (600MHz, DMSO-d6) δ10.55(s,1H),7.76(d,J=8.0Hz,2H),7.66(d,J=8.0Hz,2H),7.16(d,J=8.7Hz,1H),6. 99(d,J=2.4Hz,1H),6.83(s,1H),6.76(s,1H),6.66(dd,J=8.7,2.4Hz,1H),5.81-5.69(m,1H),5.20-5.12(m, 3H),5.04(d,=10.3Hz,1H),4.07(d,J=16.0Hz,1H),3.88(s,1H),3.73(s,3H),3.72(s,3H),3.67(d,J=16.0Hz ,1H),3.20-3.04(m,1H),3.01-2.89(m,2H),2.89-2.72(m,2H),2.64-2.56(m,1H),2.52-2.51(m,1H).ESI-MS m / z 549.1[M+H] + .

[0229] Example A46: Synthesis of Compound A46

[0230] By replacing 2-1 and 3-1 in Example A32 with 2-1b and 3-1a respectively, and referring to the synthesis method of compound A24, compound A46 was obtained. 1 H NMR (500MHz, DMSO-d6) δ7.67–7.61(m,2H),7.51–7.45(m,2H),7.26(d,J=7.6Hz,1H),7.14(d,J=1.8Hz,1H),7. 04(dd,J=7.4,1.9Hz,1H),6.84(d,J=0.7Hz,1H),6.65(t,J=1.0Hz,1H),5.13(t,J=1.0Hz,2H),4.50(d,J=7.7Hz ,1H),4.20–4.11(m,1H),3.92(d,J=5.7Hz,2H),3.79(s,6H),3.36–3.25(m,2H),2.90–2.82(m,2H),2.54–2.44 (m,1H),2.04–1.94(m,1H),1.87–1.76(m,1H),1.48(dd,J=8.9,5.0Hz,2H),1.40(dd,J=8.9,5.0Hz,2H).ESI-MS m / z 563.1[M+H] + .

[0231] Example A47: Synthesis of Compound A47

[0232] Synthesis of compound 3-1b:

[0233] Compound 3-1b was synthesized by replacing 3-hydroxy-4-methoxybenzaldehyde in Example A39 with 3-methoxy-4-hydroxybenzaldehyde.

[0234] Synthesis of compound A47

[0235] Replace 2-1 and 3-1 in Example A24 with 2-1b and 3-1b respectively, and synthesize according to the method of compound A24 to obtain compound A47. 1H NMR (500MHz, DMSO-d6) δ7.67–7.61(m,2H),7.52–7.45(m,2H),7.26(d,J=7.4Hz,1H),7.20(d,J=1 .8Hz,1H),7.04(dd,J=7.4,1.9Hz,1H),6.81(s,1H),6.57(t,J=1.0Hz,1H),5.13(t,J=1.0Hz,2H), 4.54–4.48(m,1H),4.30–4.22(m,1H),3.92(d,J=2.4Hz,2H),3.80(d,J=8.8Hz,6H),3.33(dd,J=9. 1,6.3Hz,1H),3.28(dd,J=9.1,6.3Hz,1H),2.90–2.82(m,2H),1.68(dd,J=6.2,1.5Hz,3H).ESI-MS m / z 523.1[M+H] + .

[0236] Example A48: Synthesis of Compound A48

[0237] By replacing 2-1 and 3-1 in Example A25 with 2-1b and 3-1b respectively, and referring to the synthesis method of compound A24, compound A48 was obtained. 1 H NMR(500MHz,DMSO-d6)δ7.67–7.61(m,2H),7.52–7.45(m,2H),7.26(d,J=7.5Hz,1H),7.15 (d,J=2.0Hz,1H),7.04(dd,J=7.4,1.9Hz,1H),6.81(s,1H),6.57(t,J=1.1Hz,1H),5.15–5 .11(m,2H),4.78–4.69(m,1H),4.58–4.53(m,1H),3.92(d,J=2.4Hz,2H),3.80(d,J=5.3Hz ,6H),3.36–3.25(m,2H),2.90–2.82(m,2H),2.07–1.98(m,2H),1.03–0.97(m,3H).ESI-MS m / z 537.2[M+H] + .

[0238] Example A49: Synthesis of Compound A49

[0239] By replacing 2-1 and 3-1 in Example A26 with 2-1b and 3-1b respectively, and referring to the synthesis method of compound A24, compound A49 was obtained. 1H NMR (500MHz, DMSO-d6) δ7.65–7.59(m,2H),7.52–7.45(m,2H),7.26(d,J=7.5Hz,1H),7.15(d,J=2 .0Hz,1H),7.04(dd,J=7.4,1.9Hz,1H),6.82(d,J=0.6Hz,1H),6.59–6.55(m,1H),5.15–5.11(m,2H ),4.50(d,J=7.9Hz,1H),4.08–3.99(m,1H),3.92(d,J=2.4Hz,2H),3.80(d,J=3.8Hz,6H),3.36–3. 25(m,2H),2.90–2.82(m,2H),2.09–1.98(m,2H),1.53–1.43(m,2H),0.96(t,J=5.7Hz,3H).ESI-MS m / z 551.3[M+H] + .

[0240] Example A50: Synthesis of Compound A50

[0241] Replace 2-1 and 3-1 in Example A29 with 2-1b and 3-1b respectively, and synthesize according to the method of compound A24 to obtain compound A50. 1 H NMR (500MHz, DMSO-d6) δ7.65–7.59(m,2H),7.52–7.45(m,2H),7.26(d,J=7.5Hz,1H),7.17(d,J=1.8Hz,1H) ,7.04(dd,J=7.4,1.9Hz,1H),6.82(d,J=0.6Hz,1H),6.59–6.55(m,1H),5.83–5.69(m,1H),5.13(d,J=1.2H z,2H),5.14–5.03(m,2H),4.60–4.52(m,1H),4.50(dd,J=8.2,0.7Hz,1H),3.92(d,J=2.4Hz,2H),3.80(d,J =3.8Hz,6H),3.27(dd,J=9.1,6.3Hz,1H),3.24–3.14(m,2H),2.90–2.82(m,2H),2.73–2.63(m,1H).ESI-MS m / z 549.1[M+H] + .

[0242] Example A51: Synthesis of Compound A51

[0243] Replace 2-1 and 3-1 in Example A32 with 2-1b and 3-1b respectively, and synthesize according to the method of compound A24 to obtain compound A51. 1 H NMR (500MHz, DMSO-d6) δ7.67–7.61(m,2H),7.51–7.45(m,2H),7.26(d,J=7.6Hz,1H),7.14(d,J=1.8Hz,1H),7.04 (dd,J=7.4,1.9Hz,1H),6.82(d,J=0.6Hz,1H),6.57(t,J=1.0Hz,1H),5.13(d,J=1.1Hz,2H),4.52(d,J=7.7Hz,1H) ,4.20–4.11(m,1H),3.92(d,J=5.7Hz,2H),3.79(d,J=3.7Hz,6H),3.36–3.25(m,2H),2.90–2.82(m,2H),2.54–2. 44(m,1H),2.04–1.94(m,1H),1.87–1.76(m,1H),1.47(dd,J=8.8,5.0Hz,2H),1.40(dd,J=8.9,5.0Hz,2H).ESI-MS m / z 563.1[M+H] + .

[0244] Example A52: Synthesis of compound A52

[0245] Synthetic route

[0246] Synthesis of compound 6-2:

[0247] Dissolve 6-1 in acetic acid, and separately dissolve liquid bromine in acetic acid, and slowly add the solutions dropwise to the reaction flask. After reacting at room temperature for 2 hours, quench the reaction with saturated sodium bisulfite solution. Dilute with ethyl acetate, wash with water to remove acetic acid, dry the ethyl acetate layer with anhydrous sodium sulfate, evaporate to dryness, and then perform column chromatography (petroleum ether:ethyl acetate 5:1) to give a colorless oily substance in 83% yield. 1 H NMR(400MHz,Chloroform-d)δ7.39(d,J=2.1Hz,1H),7.12(dd,J=8.3,2.1Hz,1H),6.95(d,J=8.3Hz,1H),3.70(s,3H),3.54(s,2H).ESI-MS m / z 246.0[M+H] + .

[0248] Synthesis of compound 6-3:

[0249] Potassium carbonate was suspended in acetone, and 6-2 and benzyl bromide were added. The reaction was carried out at 60°C for 4 hours under argon protection. After cooling, the acetone was removed by rotary evaporation, and the residue was diluted with ethyl acetate. The potassium carbonate was washed away with water, and the aqueous phase was extracted with ethyl acetate. The ethyl acetate phases were combined and dried over anhydrous sodium sulfate. The solvent was removed by rotary evaporation, and column chromatography (petroleum ether:ethyl acetate 15:1) yielded a colorless oil in 77% yield. ESI-MS m / z 335.9 [M+H] + .

[0250] Synthesis of compound 6-4:

[0251] Anhydrous tetrahydrofuran was added to a two-necked flask. Sodium hydride (60% by mass, dispersed in kerosene) was added in portions under argon protection in an ice bath. A 6:3 tetrahydrofuran solution was then injected. After reacting at room temperature for 30 minutes, allyl bromide was added, and the reaction was continued at room temperature for 3 hours. The reaction was quenched with saturated ammonium chloride solution, extracted with ethyl acetate, and the combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation. Column chromatography (petroleum ether:ethyl acetate 10:1) yielded a colorless oily product in 53% yield. ESI-MS m / z 375.0 [M+H] + .

[0252] Synthesis of compound 6-5:

[0253] Dissolve 6-4 in a mixed solvent of dimethyl sulfoxide, water, and tert-butanol (V:V:V = 1:1:1). Add potassium hydroxide, cuprous iodide, and 2-(2,6-dimethylphenylamino)-2-oxoacetic acid. React at 120°C for 48 hours under argon protection. After the reaction is complete, cool to room temperature, filter to remove insoluble matter, add 1M dilute hydrochloric acid to adjust the pH to 1-2, extract with ethyl acetate, combine the organic phases, wash with water, dry with anhydrous sodium sulfate, remove solvent by rotary evaporation, and then perform column chromatography (dichloromethane:methanol 20:1) to give a brown oily substance in 43% yield. ESI-MS m / z 297.1 [MH] - .

[0254] Synthesis of compound 6-6:

[0255] 6-5 and phenylboronic acid were dissolved in toluene and reacted at 110°C for 2 hours under argon protection. The reaction solution was then poured into a sealed tube, and paraformaldehyde and... Molecular sieves were reacted at 100°C for 48 hours. The molecular sieves were removed by hot filtration, and the filtrate was evaporated to dryness and subjected to column chromatography (dichloromethane:methanol 100:1) to give a white solid in 37% yield. ESI-MS m / z 309.0 [MH] - .

[0256] Synthesis of compounds 6-7:

[0257] 6-6 and potassium carbonate were suspended in acetone, and iodomethane was added. The reaction was carried out at 60°C for 6 hours under argon protection. After cooling to room temperature, most of the acetone was removed by rotary evaporation. The mixture was diluted with ethyl acetate, and the potassium carbonate was washed away with water. The aqueous phase was extracted with ethyl acetate. The combined ethyl acetate phases were dried over anhydrous sodium sulfate. The solvent was removed by rotary evaporation, and the solution was purified by column chromatography (petroleum ether:ethyl acetate 3:1) to give a white solid in 72% yield. ESI-MS m / z 325.1 [M+H] + .

[0258] Synthesis of compound 7-1:

[0259] Dissolve 6-7 and 3-1 in anhydrous ethanol, then add triethylamine and react at 80°C for 16 hours. Adjust the solution to acidic pH with 1M hydrochloric acid, extract with dichloromethane, dry, and evaporate the solvent to obtain a pale yellow solid, which can be used directly in the next reaction. ESI-MS m / z 490.2 [M+H] + .

[0260] Synthesis of compound 7-2:

[0261] Dissolve 7-1, DMAP, and pyridine in 10 mL of dichloromethane, and add acetyl chloride under ice bath conditions. After reacting at room temperature for 2 hours, quench the reaction with saturated ammonium chloride solution. Extract with dichloromethane, dry to anhydrous sodium sulfate, evaporate the solvent, and purify by column chromatography (dichloromethane:methanol 50:1) to give a white solid in 92% yield. 1 H NMR (400MHz, DMSO-d6) δ7.90(t,J=5.6Hz,1H),7.45–7.30(m,5H),7.06(d,J=8.4Hz,1H),6.98(d,J=8.4Hz,1H),6.79(d,J=7.9Hz,1H),6.75(s,1H),6 .61(d,J=7.9Hz,1H),5.95(s,2H),5.08(s,2H),4.93(s,2H),3.85(s,3H), 3.41(s,2H),3.26–3.16(m,2H),2.60(t,J=7.2Hz,2H),1.91(s,3H).ESI-MS m / z 532.1[M+H] + .

[0262] Synthesis of compound 7-3:

[0263] Compound 7-2 was placed in a two-necked flask and dissolved in ultra-dry acetonitrile. Phosphorus oxychloride was added under argon protection, and the mixture was refluxed at 80°C for 2 hours. After the reaction was complete, the reaction solution was cooled to room temperature, and the acetonitrile was removed by rotary evaporation. The residue was diluted with dichloromethane, and the pH was adjusted to approximately 9 with saturated sodium bicarbonate solution. The mixture was extracted with dichloromethane, and the organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation to obtain an orange solid, which was then directly used for the next reaction. ESI-MS m / z 514.3 [M+H] + .

[0264] Synthesis of compound 7-4:

[0265] Compound 7-3 was dissolved in methanol, and sodium borohydride was added under ice bath conditions. The reaction was carried out at room temperature for 3 hours. After the reaction was complete as monitored by TLC, a saturated ammonium chloride solution was added to quench the reaction. The mixture was extracted with dichloromethane, and the combined organic phases were dried over anhydrous sodium sulfate and then evaporated to dryness. The residue was purified by column chromatography (dichloromethane:methanol 20:1) to give a pale brown solid. The overall yield of the two steps was 37%. ESI-MS m / z 516.3 [M+H] + .

[0266] Synthesis of compound 7-5:

[0267] Compound 7-4 was dissolved in ethanol, and an equal volume of 1M sodium hydroxide solution was added dropwise. The mixture was allowed to react at room temperature for 2 hours. A white solid precipitated in the reaction system. The solid was filtered, and the filter cake was washed successively with water and anhydrous ethanol. After drying, the cake was used directly in the next reaction step.

[0268] Synthesis of compound A52:

[0269] Compound 7-5 was placed in a two-necked flask and dissolved in dichloromethane. Under ice bath and argon protection, thionyl chloride was slowly added. After reacting at room temperature for 2 hours, the mixture was again placed in an ice bath, and saturated sodium bicarbonate solution was added until the pH was greater than 9. The reaction was then brought to room temperature and reacted for another 2 hours. The organic phase was separated, the aqueous layer was washed with dichloromethane, and the combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and then subjected to column chromatography (petroleum ether:ethyl acetate 10:1) to give a white solid in 87% yield. 1H NMR (500MHz, DMSO-d6) δ7.45–7.39(m,2H),7.39–7.27(m,3H),6.93(d,J=8.5Hz,1H),6.86(d, J=0.6Hz,1H),6.70(d,J=8.6Hz,1H),6.56(t,J=1.0Hz,1H),6.06(s,1H),6.02(s,1H),5.81–5 .67(m,1H),5.16–5.04(m,4H),4.32(d,J=8.6Hz,1H),4.25(s,1H),4.18(s,1H),3.80(s,2H), 3.64–3.55(m,1H),3.20–3.11(m,2H),2.93–2.85(m,2H),2.74(dd,J=8.3,7.3Hz,2H).ESI-MS m / z 456.2[M+H] + .

[0270] Example A53: Synthesis of compound A53

[0271] Compound A52 was dissolved in trifluoroacetic acid under ice bath conditions, and the reaction was allowed to proceed to room temperature for 6 hours. After the reaction was completed by TLC monitoring, the pH was adjusted to neutral with saturated sodium bicarbonate solution, and the mixture was extracted with dichloromethane. The extracts were combined, evaporated to dryness, and then subjected to column chromatography (dichloromethane:methanol 20:1) to give a white solid in 62% yield. 1 H NMR(500MHz,DMSO-d6)δ8.13(s,1H),7.01–6.96(m,1H),6.89(d,J=0.6Hz,1H),6.70 (d,J=9.0Hz,1H),6.52–6.48(m,1H),6.04(d,J=17.0Hz,2H),5.83–5.69(m,1H),5.16 –5.05(m,2H),4.36(d,J=8.6Hz,1H),4.20(s,1H),4.11(s,1H),3.85(s,2H),3.64–3. 55(m,1H),3.19–3.11(m,2H),2.93–2.85(m,2H),2.74(dd,J=8.3,7.3Hz,2H).ESI-MS m / z 366.2[M+H] + .

[0272] Example A54: Synthesis of Compound A54

[0273] A53 was dissolved in N,N-dimethylformamide, and sodium hydride (60% by mass, dispersed in kerosene) was added. The mixture was reacted at room temperature for 30 minutes. Iodoethane was added, and the mixture was heated to 80°C and reacted for 3 hours. After the reaction was completed, the mixture was cooled to room temperature, quenched with water, extracted with ethyl acetate, washed with water, dried over anhydrous sodium sulfate, and then subjected to column chromatography (petroleum ether:ethyl acetate 10:1) to give a white solid in 55% yield. 1 H NMR (500MHz, DMSO-d6) δ6.94(d,J=8.4Hz,1H),6.87(s,1H),6.73(d,J=8.6Hz,1H),6.55(t,J =1.0Hz,1H),6.02(d,J=11.4Hz,2H),5.83–5.69(m,1H),5.16–5.05(m,2H),4.33(dd,J=8.6,0 .7Hz,1H),4.25(s,1H),4.15(s,1H),4.13–4.07(m,2H),3.82(s,2H),3.64–3.55(m,1H),3.1 9–3.11(m,2H),2.94–2.85(m,2H),2.74(dd,J=8.3,7.3Hz,2H),1.40(t,J=4.7Hz,3H).ESI-MS m / z 394.1[M+H] + .

[0274] Example A55: Synthesis of compound A55

[0275] By replacing the iodoethane in Example A54 with 1-bromopropane, and following the synthetic method of compound A54, compound A55 was obtained. 1 H NMR(500MHz,DMSO-d6)δ6.97–6.92(m,1H),6.80(d,J=0.6Hz,1H),6.67(d,J=8.4Hz,1H),6.57– 6.53(m,1H),6.02(d,J=13.7Hz,2H),5.83–5.69(m,1H),5.16–5.05(m,2H),4.33(dd,J=8.6,0. 8Hz,1H),4.25(s,1H),4.15(s,1H),4.07–3.92(m,2H),3.81(s,2H),3.55–3.47(m,1H),3.20–3 .11(m,2H),2.93–2.85(m,2H),2.77–2.70(m,2H),1.87–1.77(m,2H),1.05–0.99(m,3H).ESI-MS m / z 408.2[M+H] + .

[0276] Example A56: Synthesis of Compound A56

[0277] By replacing the iodoethane in Example A54 with allyl bromide, and following the same synthesis method as compound A54, compound A56 was obtained. 1 H NMR(500MHz,DMSO-d6)δ6.97–6.92(m,1H),6.80(d,J=0.6Hz,1H),6.68(d,J=8.6Hz,1H),6.57–6.53(m ,1H),6.10–5.96(m,3H),5.83–5.69(m,1H),5.39(dd,J=17.0,2.4Hz,1H),5.28(dd,J=17.0,2.4Hz,1H) ,5.16–5.05(m,2H),4.60(d,J=6.9Hz,2H),4.33(dd,J=8.6,0.8Hz,1H),4.25(s,1H),4.15(s,1H),3.8 1(s,2H),3.55–3.47(m,1H),3.20–3.11(m,2H),2.93–2.85(m,2H),2.74(dd,J=8.3,7.3Hz,2H).ESI-MS m / z406.3[M+H] + .

[0278] Example A57: Synthesis of Compound A57

[0279] By replacing the iodoethane in Example A54 with bromomethylcyclopropane, and following the same synthesis method as compound A54, compound A57 was obtained. 1 H NMR (500MHz, DMSO-d6) δ6.94(dd,J=8.4,0.7Hz,1H),6.80(d,J=0.6Hz,1H),6.66(d,J=8.4Hz,1H),6. 57–6.53(m,1H),6.04(d,J=17.4Hz,2H),5.83–5.69(m,1H),5.15–5.04(m,2H),4.33(dd,J=8.6,0.7H z,1H),4.25(s,1H),4.15(s,1H),3.94(d,J=7.3Hz,2H),3.81(s,2H),3.55–3.47(m,1H),3.20–3.11( m,2H),2.94–2.84(m,2H),2.74(dd,J=8.3,7.3Hz,2H),1.46–1.33(m,1H),1.27–1.21(m,4H).ESI-MS m / z 420.0[M+H] + .

[0280] Example A58: Synthesis of Compound A58

[0281] By replacing the iodoethane in Example A54 with fluorobromomethane, and following the same synthesis method as compound A54, compound A58 was obtained. 1 H NMR(500MHz,DMSO-d6)δ6.95–6.89(m,1H),6.87(s,1H),6.75(d,J=8.6Hz,1H), 6.57–6.53(m,1H),6.02(d,J=5.5Hz,2H),5.83–5.69(m,3H),5.16–5.05(m,2H) ,4.33(dd,J=8.6,0.7Hz,1H),4.24(d,J=4.9Hz,2H),3.84(s,2H),3.64–3.55(m ,1H),3.19–3.11(m,2H),2.94–2.85(m,2H),2.74(dd,J=8.3,7.3Hz,2H).ESI-MS m / z398.2[M+H] + .

[0282] Example A59: Synthesis of Compound A59

[0283] Synthesis of compound 8-1:

[0284] Difluoromethylphenyl sulfone and N-chlorosuccinimide were dissolved in ultra-dry tetrahydrofuran under argon protection and cooled to -78°C. Bistrimethylsilylaminolithium was added dropwise, and the reaction was carried out at -78°C for 2 hours after the addition was complete. After the reaction was complete, a saturated ammonium chloride solution was added to quench the reaction. The mixture was extracted with ethyl acetate, and the combined organic phases were washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, and then evaporated to dryness. Column chromatography (petroleum ether:ethyl acetate 30:1) yielded a colorless oily liquid 8-1, with a yield of 49%.

[0285] Synthesis of compound A59:

[0286] Compound A53 was dissolved in a mixed solvent of water and acetonitrile (V:V = 2:7), and 8-1 and potassium hydroxide were added. The reaction was carried out under argon protection at 50°C for 5 hours. After the reaction was completed, the mixture was cooled to room temperature, and the acetonitrile was removed by rotary evaporation. The aqueous phase was extracted with ethyl acetate, and the combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and then evaporated to dryness. Column chromatography (petroleum ether:ethyl acetate 15:1) gave a pale yellow solid A59 in 62% yield. 1H NMR(500MHz,DMSO-d6)δ6.98(d,J=9.0Hz,1H),6.96–6.91(m,1H),6.84–6.79(m, 2H),6.57–6.53(m,1H),6.02(d,J=13.7Hz,2H),5.83–5.69(m,1H),5.16–5.05(m, 2H),4.33(dd,J=8.6,0.7Hz,1H),4.24(d,J=4.6Hz,2H),3.84(s,3H),3.55–3.47( m,1H),3.20–3.11(m,2H),2.93–2.85(m,2H),2.74(dd,J=8.3,7.3Hz,2H).ESI-MS m / z 416.1 [M+H] + .

[0287] Example A60: Synthesis of compound A60

[0288] Synthetic route

[0289] Synthesis of compound 9-2:

[0290] 9-1 and phenylboronic acid were suspended in toluene and refluxed at 110°C for 2 hours under argon protection. The mixture was then transferred to a sealed tube and paraformaldehyde and... Molecular sieves were used, and the reaction was carried out at 100°C for 48 hours. After the reaction was completed, the mixture was filtered while hot, and toluene was removed by rotary evaporation of the filtrate. Water was then added, and the mixture was refluxed at 100°C for 2 hours under argon protection. The reaction solution was cooled to room temperature, extracted with dichloromethane, and the organic phases were combined and evaporated to dryness. Anhydrous diethyl ether was added, and the mixture was stirred at room temperature until the solid completely precipitated. The mixture was filtered to obtain a white solid filter cake with a yield of 52%. 1 H NMR (400MHz, DMSO-d6) δ9.18(s,1H),6.92(d,J=8.1Hz,1H),6.70(d,J=8.1Hz,1H),5.31(s,2H),3.79(s,3H),3.65(s,2H).ESI-MS m / z 195.0[M+H] + .

[0291] Synthesis of compound 9-3:

[0292] Potassium carbonate was suspended in acetone, and 9-2 and benzyl bromide were added. The reaction was carried out at 60°C for 4 hours under argon protection. After cooling, the acetone was removed by rotary evaporation, and the residue was diluted with ethyl acetate. The potassium carbonate was washed away with water, and the aqueous phase was extracted with ethyl acetate. The ethyl acetate phases were combined and dried over anhydrous sodium sulfate. The solvent was removed by rotary evaporation, and the product was subjected to column chromatography (petroleum ether:ethyl acetate 15:1) to give a white solid in 79% yield. ESI-MS m / z 285.3 [M+H]+ .

[0293] Synthesis of compound 10-1:

[0294] Dissolve 9-3 and 3-1 in ethanol, then add triethylamine and react at 80°C for 16 hours. Adjust the solution to acidic with 1M hydrochloric acid, extract with dichloromethane, dry, and evaporate the solvent to obtain a pale yellow solid, which can be used directly in the next reaction. ESI-MS m / z 450.1 [M+H] + .

[0295] Synthesis of compound 10-2:

[0296] 10⁻¹, DMAP, and pyridine were dissolved in dichloromethane, and acetyl chloride was added under ice bath conditions. After reacting at room temperature for 2 hours, the reaction was quenched with saturated ammonium chloride solution. The mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, and the solvent was evaporated. The resulting product was purified by column chromatography (dichloromethane:methanol 50:1) to give a white solid. The overall yield of the two steps was 68%. 1 H NMR(400MHz, DMSO-d6)δ7.90(t,J=5.6Hz,1H),7.45–7.30(m,5H),7.06(d,J=8 .5Hz,1H),6.97(d,J=8.5Hz,1H),6.79(d,J=7.9Hz,1H),6.75(d,J=1.6Hz,1H), 6.61(dd,J=8.0,1.7Hz,1H),5.95(s,2H),5.08(s,2H),4.93(s,2H),3.85(s,3 H),3.41(s,2H),3.25–3.18(m,2H),2.60(t,J=7.2Hz,2H),1.92(s,3H).ESI-MS m / z 492.2[M+H] + .

[0297] Synthesis of compound 10⁻³:

[0298] Compound 10-2 was placed in a two-necked flask and dissolved in ultra-dry acetonitrile. Phosphorus oxychloride was added under argon protection, and the mixture was refluxed at 80°C for 2 hours. After the reaction was complete, the reaction solution was cooled to room temperature, and the acetonitrile was removed by rotary evaporation. The residue was diluted with dichloromethane, and the pH was adjusted to approximately 9 with saturated sodium bicarbonate solution. The mixture was extracted with dichloromethane, and the organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation to obtain an orange solid, which was then directly used for the next reaction. ESI-MS m / z 474.1 [M+H] + .

[0299] Synthesis of compound 10⁻⁴:

[0300] Compound 10⁻³ was dissolved in methanol, and sodium borohydride was added under ice bath conditions. The reaction was carried out at room temperature for 3 hours. After the reaction was complete as monitored by TLC, a saturated ammonium chloride solution was added to quench the reaction. The mixture was extracted with dichloromethane, and the combined organic phases were dried over anhydrous sodium sulfate and then evaporated to dryness. The residue was purified by column chromatography (dichloromethane:methanol 20:1) to give a pale brown solid. The overall yield of the two steps was 54%. ESI-MS m / z 476.1 [M+H] + .

[0301] Synthesis of compound 10-5:

[0302] Compound 10⁻⁴ was dissolved in methanol, and an equal volume of 1M sodium hydroxide solution was added dropwise. The mixture was reacted at room temperature for 2 hours. A white solid precipitated in the reaction system. The solid was filtered, and the filter cake was washed successively with water and anhydrous ethanol. After drying, the cake was used directly in the next reaction step. 1 H NMR(400MHz,DMSO-d6)δ7.50(d,J=7.4Hz,2H),7.44–7.31(m,3H),7.10(d,J=8.4Hz,1H),6 .99(d,J=8.4Hz,1H),6.92(s,1H),6.63(s,1H),5.94(d,J=3.8Hz,2H),4.99–4.88(m,2H),4 .60(d,J=11.1Hz,1H),4.43(d,J=11.1Hz,1H),3.93–3.87(m,1H),3.82(s,3H),3.10–3.02( m,1H),3.00–2.91(m,1H),2.90–2.82(m,1H),2.81–2.72(m,1H),2.59–2.53(m,2H).ESI-MS m / z 434.0[M+H] + .

[0303] Synthesis of compound 10⁻⁶:

[0304] Compound 10⁻⁵ was placed in a two-necked flask, dissolved in dichloromethane, and slowly added under argon protection in an ice bath. After reacting at room temperature for 2 hours, it was again placed in an ice bath, and saturated sodium bicarbonate solution was added until the pH was greater than 9. The reaction was then brought to room temperature for another 2 hours. The organic phase was separated, the aqueous layer was washed with dichloromethane, and the combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and then subjected to column chromatography (petroleum ether:ethyl acetate 10:1) to give a white solid. The overall yield of the two steps was 63%. ESI-MS m / z 416.2 [M+H] + .

[0305] Synthesis of compound 10-7:

[0306] Compound 10⁻⁶ was dissolved in anhydrous ethanol, potassium acetate was added, and the mixture was heated at 80°C for about 10 minutes under argon protection until the solution became clear. Elemental iodine was dissolved in anhydrous ethanol and slowly added dropwise to the reaction system, and the reaction was continued at 80°C for 3 hours. After the reaction was completed, the mixture was cooled to room temperature, filtered, and the filter cake was washed successively with water and anhydrous ethanol and dried to give a yellow solid with a yield of 71%. 1 H NMR(600MHz, DMSO-d6)δ9.74(s,1H),8.92(s,1H),8.22(d,J=9.1Hz,1H),8.00(d,J=9.1Hz,1H),7.79(s,1H),7.62–7.56(m,2H),7.43–7 .39(m,2H),7.38–7.34(m,1H),7.09(s,1H),6.18(s,2H),5.36(s,2H),4.91(t,J=6.4Hz,2H),4.09(s,3H),3.19(t,J=6.4Hz,2H).ESI-MS m / z 412.2[M] + .

[0307] Synthesis of compound 10-8:

[0308] Compound 10-7 and potassium carbonate were dispersed in methanol. Sodium borohydride was dissolved in 5% sodium hydroxide solution and added dropwise to the reaction solution. After reacting at room temperature for two hours, the mixture was filtered. The filter cake was washed successively with water, 30% ethanol, and anhydrous ethanol to obtain a yellow solid 10-8, which was directly used in the next reaction with a yield of 55%.

[0309] Synthesis of compound 10-9:

[0310] 10⁻⁸ and sodium iodide were dissolved in acetonitrile, and allyl bromide was added. The mixture was refluxed at 80 °C for 16 hours under argon protection. The reaction solution was cooled to room temperature, and the acetonitrile was removed by rotary evaporation. The residue was added to water, sonicated, and filtered. The filter cake was dried to give intermediate 10⁻⁹. ESI-MS m / z 454.1 [M] + .

[0311] Synthesis of compound A60:

[0312] 10⁻⁹ was dispersed in anhydrous ethanol, and sodium borohydride was added in portions under ice bath conditions. The reaction was then allowed to proceed at room temperature for 1 hour. After the reaction was completed by TLC monitoring, the reaction was quenched with saturated ammonium chloride solution, extracted with ethyl acetate, and the combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and then evaporated to dryness. Column chromatography (petroleum ether:ethyl acetate 10:1) yielded a pale yellow solid, A60, with an overall yield of 39% for both steps. 1H NMR(500MHz,DMSO-d6)δ7.45–7.39(m,2H),7.39–7.27(m,3H),7.01–6.95(m,1H),6.86(d,J =0.6Hz,1H),6.69(d,J=8.6Hz,1H),6.58–6.54(m,1H),6.06(s,1H),6.02(s,1H),5.81–5.67 (m,1H),5.15–5.04(m,4H),4.32(d,J=8.6Hz,1H),4.25(s,1H),4.18(s,1H),3.80(s,2H),3 .64–3.55(m,1H),3.20–3.11(m,2H),2.93–2.85(m,2H),2.74(dd,J=8.3,7.3Hz,2H).ESI-MS m / z 456.1[M+H] + .

[0313] Example A61: Synthesis of Compound A61

[0314] By replacing compound A52 in Example A53 with compound A60, and following the same synthesis method as compound A53, compound A61 was obtained. 1 H NMR(500MHz,DMSO-d6)δ9.24(s,1H),7.06(d,J=9.1Hz,1H),6.89(d,J=0.6Hz,1H), 6.69(d,J=9.0Hz,1H),6.52–6.48(m,1H),6.04(d,J=17.0Hz,2H),5.83–5.69(m,1H) ,5.16–5.05(m,2H),4.36(d,J=8.6Hz,1H),4.13(s,1H),4.08(s,1H),3.78(s,2H), 3.62–3.53(m,1H),3.19–3.11(m,2H),2.93–2.85(m,2H),2.79–2.65(m,2H).ESI-MS m / z 366.1[M+H] + .

[0315] Example A62: Synthesis of compound A62

[0316] By replacing compound A53 in Example A54 with compound A61, and following the same synthesis method as compound A54, compound A62 was obtained. 1H NMR(500MHz,DMSO-d6)δ6.97–6.91(m,1H),6.87(s,1H),6.69(d,J=8.6Hz,1H),6.57–6. 53(m,1H),6.02(d,J=11.4Hz,2H),5.83–5.69(m,1H),5.16–5.05(m,2H),4.33(dd,J=8. 6,0.7Hz,1H),4.25(s,1H),4.18–4.06(m,3H),3.83(s,2H),3.64–3.55(m,1H),3.19–3. 11(m,2H),2.94–2.85(m,2H),2.74(dd,J=8.3,7.3Hz,2H),1.43(t,J=4.7Hz,3H).ESI-MS m / z 394.1[M+H] + .

[0317] Example A63: Synthesis of compound A63

[0318] By replacing compound A53 in Example A55 with compound A61, and following the same synthesis method as compound A55, compound A63 was obtained. 1 H NMR(500MHz,DMSO-d6)δ6.97–6.92(m,1H),6.80(d,J=0.6Hz,1H),6.69(d,J=8.6Hz,1H),6.57–6.5 3(m,1H),6.02(d,J=13.7Hz,2H),5.83–5.69(m,1H),5.16–5.05(m,2H),4.33(dd,J=8.6,0.7Hz,1H) ,4.25(s,1H),4.15(s,1H),3.99(t,J=7.6Hz,2H),3.83(s,2H),3.55–3.47(m,1H),3.20–3.11(m,2H ),2.93–2.85(m,2H),2.74(dd,J=8.3,7.3Hz,2H),1.87–1.77(m,2H),1.02(t,J=6.0Hz,3H).ESI-MS m / z408.2[M+H] + .

[0319] Example A64: Synthesis of Compound A64

[0320] By replacing compound A53 in Example A56 with compound A61, and following the same synthesis method as compound A56, compound A64 was obtained. 1H NMR (500MHz, DMSO-d6) δ6.94(d,J=8.7Hz,1H),6.80(d,J=0.6Hz,1H),6.69(d,J=8.6Hz,1H),6. 57–6.53(m,1H),6.11–6.01(m,2H),6.00(s,1H),5.83–5.69(m,1H),5.35(d,J=11.4Hz,2H),5.1 6–5.05(m,2H),4.66(d,J=7.0Hz,2H),4.33(dd,J=8.6,0.7Hz,1H),4.25(s,1H),4.15(s,1H),3 .82(s,2H),3.55–3.47(m,1H),3.20–3.11(m,2H),2.93–2.85(m,2H),2.77–2.70(m,2H).ESI-MS m / z 406.3[M+H] + .

[0321] Example A65: Synthesis of Compound A65

[0322] By replacing compound A53 in Example A57 with compound A61, and following the same synthesis method as compound A57, compound A65 was obtained. 1 H NMR(500MHz,DMSO-d6)δ6.94(d,J=8.7Hz,1H),6.80(d,J=0.6Hz,1H),6.69(d,J=8.6Hz,1H),6.5 7–6.53(m,1H),6.04(d,J=17.4Hz,2H),5.82–5.70(m,1H),5.13–5.06(m,2H),4.35–4.30(m,1H), 4.25(s,1H),4.15(s,1H),3.92(d,J=7.5Hz,2H),3.83(s,2H),3.55–3.47(m,1H),3.20–3.11(m,2 H),2.94–2.84(m,2H),2.74(dd,J=8.3,7.3Hz,2H),1.63–1.50(m,1H),1.27–1.18(m,4H).ESI-MS m / z 420.0[M+H] + .

[0323] Example A66: Synthesis of Compound A66

[0324] By replacing compound A53 in Example A58 with compound A61, and following the same synthesis method as compound A58, compound A66 was obtained. 1H NMR(600MHz,DMSO-d6)δ6.96(d,J=8.5Hz,1H),6.91(d,J=8.6Hz,2H),6.69(s,1H),5.96(dd, J=17.1,1.1Hz,2H),5.76–5.61(m,3H),4.82–4.76(m,1H),4.68–4.62(m,1H),4.12(d,J=16.1 Hz,1H),3.79(s,3H),3.60(s,1H),3.41(d,J=16.0Hz,1H),3.26–3.21(m,1H),3.11–3.03(m, 1H),2.93–2.84(m,1H),2.56(d,J=15.6Hz,1H),2.45–2.39(m,1H),2.08–1.95(m,2H).ESI-MS m / z 398.2[M+H] + .

[0325] Example A67: Synthesis of Compound A67

[0326] By replacing compound A53 in Example A59 with compound A61, and following the same synthesis method as compound A59, compound A67 was obtained. 1 H NMR(400MHz,DMSO-d6)δ7.03–6.98(m,2H),6.90(s,1H),7.18–6.75(m,1H),6.69(s,1H),5.96(dd,J =10.9,1.0Hz,2H),5.75–5.61(m,1H),4.79(dd,J=10.1,2.3Hz,1H),4.70–4.61(m,1H),4.09(d,J=1 6.2Hz,1H),3.81(s,3H),3.61(d,J=3.0Hz,1H),3.42(d,J=16.1Hz,1H),3.29–3.23(m,1H),3.12–3. 04(m,1H),2.95–2.82(m,1H),2.56(d,J=15.7Hz,1H),2.47–2.38(m,1H),2.09–1.94(m,2H).ESI-MS m / z 416.1[M+H] + .

[0327] Example A68: Synthesis of compound A68

[0328] By replacing 3-1 in Example A60 with 2-(2,3-dihydro-1,4-benzodioxin-6-yl)ethyl-1-amine, and referring to the synthesis method of compound A60, compound A68 was obtained.1 H NMR (500MHz, DMSO-d6) δ6.97–6.91(m,1H),6.86(d,J=0.6Hz,1H),6.68(d,J=8.6Hz,1H),6.66–6.63(m,1H),5.83–5.69(m,1H),5.16–5.05 (m,2H),4.35–4.27(m,5H),4.25(s,1H),4.15(s,1H),3.85–3.76(m,7H),3.20–3.11(m,2H),2.90–2.82(m,2H),2.77–2.70(m,2H).ESI-MS m / z 394.3[M+H] + .

[0329] Example A69: Synthesis of Compound A69

[0330] By replacing 3-1 in Example A60 with 3-ethoxy-4-methoxyphenethylamine, and following the synthetic method of compound A60, compound A69 was obtained. 1 H NMR (500MHz, DMSO-d6) δ6.96 (dd, J=8.6, 0.7Hz, 1H), 6.79 (d, J=0.6Hz, 1H), 6.69 (d, J= 8.6Hz,1H),6.61–6.57(m,1H),5.81–5.70(m,1H),5.14–5.07(m,2H),4.34–4.29(m,1H) ),4.25(s,1H),4.15(s,1H),4.13–4.07(m,2H),3.86–3.80(m,9H),3.77–3.68(m,1H), 3.21–3.12(m,2H),2.91–2.81(m,2H),2.77–2.70(m,2H),1.41(t,J=4.6Hz,3H).ESI-MS m / z 410.2[M+H] + .

[0331] Example A70: Synthesis of Compound A70

[0332] By replacing 3-1 in Example A60 with 3-(cyclopropylmethoxy)-4-methoxyphenethylamine, and referring to the synthesis method of compound A60, compound A70 was obtained. 1H NMR(500MHz,DMSO-d6)δ6.94(d,J=8.7Hz,1H),6.77(d,J=0.6Hz,1H),6.69(d,J=8.6Hz,1H), 6.61–6.57(m,1H),5.82–5.70(m,1H),5.13–5.06(m,2H),4.34–4.29(m,1H),4.25(s,1H),4. 17(s,1H),3.94(d,J=7.4Hz,2H),3.86–3.81(m,9H),3.77–3.68(m,1H),3.21–3.13(m,2H),2 .90–2.82(m,2H),2.74(dd,J=8.3,7.4Hz,2H),1.46–1.33(m,1H),1.27–1.21(m,4H).ESI-MS m / z 436.1[M+H] + .

[0333] Example A71: Synthesis of Compound A71

[0334] By replacing 3-1 in Example A60 with 3-benzyloxy-4-methoxyphenethylamine, and referring to the synthesis method of compound A60, compound A71 was obtained. 1 H NMR(500MHz,DMSO-d6)δ7.45–7.39(m,2H),7.39–7.32(m,2H),7.35–7.27(m,1H),6 .96–6.90(m,1H),6.78(d,J=0.6Hz,1H),6.69(d,J=8.6Hz,1H),6.66–6.62(m,1H),5 .80–5.68(m,1H),5.15–5.06(m,4H),4.33–4.27(m,1H),4.25(s,1H),4.18(s,1H),3 .85–3.76(m,10H),3.23–3.13(m,2H),2.90–2.81(m,2H),2.77–2.70(m,2H).ESI-MS m / z 472.2[M+H] + .

[0335] Example A72: Synthesis of Compound A72

[0336] By replacing 3-1 in Example A60 with 3-(4-fluorobenzyloxy)-4-methoxyphenethylamine, and referring to the synthesis method of compound A60, compound A72 was obtained. 1H NMR (500MHz, DMSO-d6) δ7.52–7.46(m,2H),7.18–7.12(m,2H),6.98(d,J=8.7Hz,1H),6.78( d,J=0.6Hz,1H),6.69(d,J=8.6Hz,1H),6.66–6.62(m,1H),5.83–5.71(m,1H),5.16–5.06(m ,4H),4.30(dd,J=8.6,0.7Hz,1H),4.25(s,1H),4.18(s,1H),4.03–3.95(m,1H),3.86–3.78 (m,9H),3.23–3.13(m,2H),3.03–2.94(m,1H),2.90–2.81(m,2H),2.53–2.44(m,1H).ESI-MS m / z 490.0[M+H] + .

[0337] Example A73: Synthesis of Compound A73

[0338] By replacing 3-1 in Example A60 with 3-(4-trifluoromethylbenzyloxy)-4-methoxyphenethylamine, and referring to the synthesis method of compound A60, compound A73 was obtained. 1 H NMR(500MHz,DMSO-d6)δ7.65–7.59(m,2H),7.52–7.45(m,2H),6.98(d,J=8.7Hz,1H ),6.78(s,1H),6.71–6.63(m,2H),5.83–5.71(m,1H),5.15–5.06(m,4H),4.30(dd,J =8.6,0.7Hz,1H),4.25(s,1H),4.18(s,1H),4.03–3.95(m,1H),3.81–3.77(m,9H), 3.21–3.13(m,2H),3.03–2.94(m,1H),2.88–2.81(m,2H),2.53–2.44(m,1H).ESI-MS m / z 540.1[M+H] + .

[0339] Example A74: Synthesis of Compound A74

[0340] By replacing 3-1 in Example A60 with 4-ethoxy-3-methoxyphenethylamine, and following the synthetic method of compound A60, compound A74 was obtained. 1H NMR (500MHz, DMSO-d6) δ6.96 (dd, J=8.6, 0.7Hz, 1H), 6.80 (d, J=0.6Hz, 1H), 6.69 (d, J=8. 6Hz,1H),6.60–6.56(m,1H),5.81–5.70(m,1H),5.14–5.07(m,2H),4.34–4.29(m,1H),4. 25(s,1H),4.15(s,1H),4.14–4.02(m,2H),3.86–3.80(m,9H),3.77–3.68(m,1H),3.21–3 .12(m,2H),2.91–2.81(m,2H),2.74(dd,J=8.3,7.3Hz,2H),1.40(t,J=4.6Hz,3H).ESI-MS m / z 410.2[M+H] + .

[0341] Example A75: Synthesis of Compound A75

[0342] By replacing 3-1 in Example A60 with 4-(cyclopropylmethoxy)-3-methoxyphenethylamine, and referring to the synthesis method of compound A60, compound A75 was obtained. 1 H NMR(500MHz,DMSO-d6)δ6.94(d,J=8.7Hz,1H),6.78(s,1H),6.69(d,J=8.6Hz,1H),6.59–6 .55(m,1H),5.82–5.70(m,1H),5.13–5.06(m,2H),4.34–4.29(m,1H),4.25(s,1H),4.17(s ,1H),3.95(d,J=7.3Hz,2H),3.86–3.81(m,9H),3.77–3.68(m,1H),3.21–3.13(m,2H),2.8 7–2.79(m,2H),2.74(dd,J=8.4,7.3Hz,2H),1.46–1.33(m,1H),1.27–1.21(m,4H).ESI-MS m / z 436.1[M+H] + .

[0343] Example A76: Synthesis of Compound A76

[0344] By replacing 3-1 in Example A60 with 4-benzyloxy-3-methoxyphenethylamine, and referring to the synthesis method of compound A60, compound A76 was obtained. 1H NMR(500MHz,DMSO-d6)δ7.45–7.39(m,2H),7.39–7.33(m,2H),7.33–7.27(m,1H),6.93(d d,J=8.6,0.7Hz,1H),6.81(d,J=0.6Hz,1H),6.69(d,J=8.6Hz,1H),6.58(d,J=1.0Hz,1H), 5.80–5.68(m,1H),5.14–5.06(m,4H),4.33–4.27(m,1H),4.25(s,1H),4.18(s,1H),3.85 –3.76(m,10H),3.23–3.13(m,2H),2.90–2.81(m,2H),2.74(dd,J=8.3,7.3Hz,2H).ESI-MS m / z 472.2[M+H] + .

[0345] Example A77: Synthesis of Compound A77

[0346] By replacing 3-1 in Example A60 with 4-(4-fluorobenzyloxy)-3-methoxyphenethylamine, and referring to the synthesis method of compound A60, compound A77 was obtained. 1 H NMR (500MHz, DMSO-d6) δ7.53–7.47(m,2H),7.18–7.12(m,2H),6.98(d,J=8.7Hz,1H),6.81(d, J=0.6Hz,1H),6.69(d,J=8.6Hz,1H),6.59–6.55(m,1H),5.83–5.71(m,1H),5.15–5.09(m,2H) ,5.12–5.06(m,2H),4.33–4.27(m,1H),4.25(s,1H),4.18(s,1H),4.03–3.95(m,1H),3.86–3. 78(m,9H),3.23–3.13(m,2H),3.03–2.94(m,1H),2.90–2.81(m,2H),2.53–2.44(m,1H).ESI-MS m / z 490.0[M+H] + .

[0347] Example A78: Synthesis of Compound A78

[0348] By replacing 3-1 in Example A60 with 4-(4-trifluoromethylbenzyloxy)-3-methoxyphenethylamine, and referring to the synthesis method of compound A60, compound A78 was obtained. 1H NMR (500MHz, DMSO-d6) δ7.65–7.59(m,2H),7.52–7.45(m,2H),6.98(d,J=8.7Hz,1H),6.81(d,J=0 .6Hz,1H),6.68(d,J=8.6Hz,1H),6.58(d,J=1.0Hz,1H),5.83–5.71(m,1H),5.13(d,J=1.1Hz,2H), 5.13–5.06(m,2H),4.30(dd,J=8.6,0.7Hz,1H),4.25(s,1H),4.18(s,1H),4.03–3.95(m,1H),3.82 –3.77(m,9H),3.21–3.13(m,2H),3.03–2.94(m,1H),2.88–2.81(m,2H),2.53–2.44(m,1H).ESI-MS m / z 540.1[M+H] + .

[0349] Example A79: Synthesis of Compound A79

[0350] Compound A79 was obtained by chiral resolution of compound A66. 1 H NMR(600MHz,DMSO-d6)δ6.96(d,J=8.5Hz,1H),6.91(d,J=8.6Hz,2H),6.69(s,1H),5.96(dd, J=17.1,1.1Hz,2H),5.76–5.61(m,3H),4.82–4.76(m,1H),4.68–4.62(m,1H),4.12(d,J=16.1 Hz,1H),3.79(s,3H),3.60(s,1H),3.41(d,J=16.0Hz,1H),3.26–3.21(m,1H),3.11–3.03(m, 1H),2.93–2.84(m,1H),2.56(d,J=15.6Hz,1H),2.45–2.39(m,1H),2.08–1.95(m,2H).ESI-MS m / z 398.2[M+H] + .

[0351] Example A80: Synthesis of Compound A80

[0352] Compound A80 was obtained by chiral resolution of compound A66. 1H NMR(600MHz,DMSO-d6)δ6.96(d,J=8.5Hz,1H),6.91(d,J=8.6Hz,2H),6.69(s,1H),5.96(dd, J=17.1,1.1Hz,2H),5.76–5.61(m,3H),4.82–4.76(m,1H),4.68–4.62(m,1H),4.12(d,J=16.1 Hz,1H),3.79(s,3H),3.60(s,1H),3.41(d,J=16.0Hz,1H),3.26–3.21(m,1H),3.11–3.03(m, 1H),2.93–2.84(m,1H),2.56(d,J=15.6Hz,1H),2.45–2.39(m,1H),2.08–1.95(m,2H).ESI-MS m / z 398.2[M+H] + .

[0353] Example A81: Synthesis of Compound A81

[0354] The synthesis method is the same as A54, yielding compound A81. 1 H NMR(500MHz,DMSO-d6)δ7.59–7.53(m,1H),7.45–7.37(m,1H),7.30–7.18(m,2H),7.00–6.93(m ,2H),6.72(s,1H),6.64(s,1H),5.90(s,1H),5.87(s,1H),5.86–5.76(m,1H),5.16–4.99(m,4H ),3.85(d,J=4.2Hz,1H),3.70(d,J=16.3Hz,1H),3.66(s,3H),3.59(d,J=16.3Hz,1H),3.31–3. 25(m,1H),3.13–3.01(m,1H),3.01–2.87(m,2H),2.75–2.56(m,2H),2.43–2.35(m,1H).ESI-MS m / z 474.3[M+H] + .

[0355] Example A82: Synthesis of compound A82

[0356] The synthesis method is the same as A54, yielding compound A82. 1H NMR (500MHz, CDCl3) δ7.39–7.33(m,1H),7.25–7.15(m,2H),7.05–7.00(m,1H),6.91(d,J =8.4Hz,1H),6.81(d,J=8.4Hz,1H),6.73(s,1H),6.59(s,1H),5.98–5.76(m,2H),5.80–5. 62(m,1H),5.21–5.10(m,2H),5.09(s,2H),4.04–3.89(m,3H),3.87(s,3H),3.25–3.19(m ,1H),3.18–3.08(m,1H),3.04–2.94(m,2H),2.90–2.71(m,2H),2.61–2.54(m,1H).ESI-MS m / z 474.2[M+H] + .

[0357] Example A83: Synthesis of compound A83

[0358] The synthesis method is the same as A54, yielding compound A83. 1 H NMR(400MHz,DMSO-d6)δ7.50(dd,J=8.6,5.7Hz,2H),7.27–7.19(m,2H),6.95(s,2H),6.72 (s,1H),6.65(s,1H),5.91(d,J=1.0Hz,1H),5.87(d,J=1.0Hz,1H),5.87–5.70(m,1H),5.24 –4.97(m,4H),3.84(d,J=4.2Hz,1H),3.71(d,J=16.4Hz,1H),3.67(s,3H),3.57(d,J=16.4H z,1H),3.32–3.24(m,1H),3.15–2.86(m,3H),2.75–2.55(m,2H),2.44–2.32(m,1H).ESI-MS m / z474.3[M+H] + .

[0359] Example A84: Synthesis of Compound A84

[0360] The synthesis method is the same as A54, yielding compound A84. 1H NMR (500MHz, CDCl3) δ7.28–7.15(m,2H),7.11–7.06(m,1H),6.78(d,J=8.6Hz,1H),6.74–6. 69(m,2H),6.61(t,J=1.0Hz,1H),5.94(s,2H),5.78–5.68(m,1H),5.15–5.02(m,4H),4.12(d ,J=12.4Hz,1H),3.95(d,J=6.7Hz,1H),3.89(s,3H),3.72(d,J=12.3Hz,1H),3.27–3.22(m, 1H),3.12(t,J=5.2Hz,2H),2.99–2.95(m,1H),2.81–2.73(m,1H),2.59–2.40(m,2H).ESI-MS m / z492.2[M+H] + .

[0361] Example A85: Synthesis of Compound A85

[0362] The synthesis method is the same as A54, yielding compound A85. 1 H NMR(500MHz, CDCl3)δ7.16–7.13(m,2H),6.78(d,J=8.6Hz,1H),6.74–6.69(m,2H),6.6 1(t,J=1.0Hz,1H),5.94(s,2H),5.78–5.68(m,1H),5.17–5.02(m,4H),4.12(d,J=12.4H z,1H),3.95(d,J=6.8Hz,1H),3.89(s,3H),3.72(d,J=12.3Hz,1H),3.27–3.22(m,1H), 3.12(t,J=5.2Hz,2H),2.99–2.95(m,1H),2.81–2.73(m,1H),2.59–2.49(m,2H).ESI-MS m / z 510.2[M+H] + .

[0363] Example A86: Synthesis of Compound A86

[0364] The synthesis method is the same as A54, yielding compound A86. 1H NMR(DMSO-d6,600MHz)δ7.77(d,J=8.1Hz,2H),7.67(d,J=8.0Hz,2H),6.98–6.8 9(m,2H),6.72(s,1H),6.65(s,1H),5.94–5.74(m,3H),5.19(s,2H),5.13–4.98 (m,2H),3.85(d,J=4.2Hz,1H),3.73–3.69(m,4H),3.59(d,J=16.4Hz,1H),3.30 –3.27(m,1H),3.10–2.90(m,3H),2.68–2.58(m,2H),2.42–2.36(m,1H).ESI-MS m / z 509.2[M+H] + .

[0365] Example A87: Synthesis of Compound A87

[0366] The synthesis method is the same as A54, yielding compound A87. 1 H NMR (400MHz, DMSO-d6) δ7.51(d,J=8.4Hz,2H),7.24(t,J=72.0Hz,1H),7.20(d,J=8.4 Hz,2H),6.95(s,2H),6.72(s,1H),6.65(s,1H),5.89(d,J=14.4Hz,2H),5.85–5.75(m ,1H),5.08–5.03(m,4H),3.85(d,J=4.2Hz,1H),3.73–3.68(m,4H),3.61–3.57(m,1H) ,3.30–3.27(m,1H),3.10–2.90(m,3H),2.68–2.58(m,2H),2.42–2.36(m,1H).ESI-MS m / z 522.2[M+H] + .

[0367] Example A88: Synthesis of Compound A88

[0368] The synthesis method is the same as A54, yielding compound A88. 1H NMR(500MHz, CDCl3)δ7.25(dd,J=8.4,7.7Hz,1H),7.14–7.10(m,1H),7.10–7.08(m,1H),7.06–7.02(m,1H),6.82( t,J=55.0Hz,1H),6.78(d,J=8.6Hz,1H),6.74–6.68(m,2H),6.61(t,J=1.0Hz,1H),5.94(s,2H),5.78–5.68(m,1H), 5.15–5.07(m,3H),5.06–5.04(m,1H),4.12(d,J=12.4Hz,1H),3.95(d,J=6.8Hz,1H),3.89(s,3H),3.72(d,J=12.3 Hz,1H),3.29–3.20(m,1H),3.12(t,J=5.2Hz,2H),2.99–2.95(m,1H),2.81–2.73(m,1H),2.59–2.49(m,2H).ESI-MS m / z 522.1[M+H] + .

[0369] Example A89: Synthesis of Compound A89

[0370] The synthesis method is the same as A54, yielding compound A89. 1 H NMR (400MHz, DMSO-d6) δ7.57–7.43(m,3H),7.35–7.30(m,1H),6.99–6.91(m,2H),6.72( s,1H),6.65(s,1H),5.89(dd,J=15.9,1.0Hz,2H),5.85–5.74(m,1H),5.13(d,J=2.1Hz,2 H),5.10–5.00(m,2H),3.84(d,J=4.2Hz,1H),3.69(d,J=3.9Hz,4H),3.58(d,J=16.3Hz, 1H),3.31–3.27(m,1H),3.11–2.88(m,3H),2.68–2.58(m,2H),2.42–2.35(m,1H).ESI-MS m / z 540.2[M+H] + .

[0371] Example A90: Synthesis of Compound A90

[0372] The synthesis method is the same as A54, yielding compound A90. 1H NMR (400MHz, DMSO-d6) δ7.36(d,J=7.9Hz,2H),7.26(d,J=7.9Hz,2H),6.94(s,2H),6. 71(s,1H),6.65(s,1H),5.89(dd,J=15.3,1.0Hz,2H),5.86–5.75(m,1H),5.09–4.97(m ,4H),3.84(d,J=4.2Hz,1H),3.68(s,4H),3.58(d,J=16.3Hz,1H),3.30–3.26(m,1H),3 .10–2.84(m,4H),2.68–2.58(m,2H),2.42–2.35(m,1H),1.20(d,J=6.9Hz,6H).ESI-MS m / z 498.3[M+H] + .

[0373] Example A91: Synthesis of Compound A91

[0374] The synthesis method is referenced in A54, yielding compound A91. 1 H NMR(500MHz, CDCl3)δ7.37(dt,J=8.1,1.1Hz,2H),7.16–7.10(m,2H),6.78(d,J=8.6Hz,1H),6.74–6.69(m,2 H),6.61(t,J=1.0Hz,1H),5.94(s,2H),5.78–5.68(m,1H),5.13(t,J=1.2Hz,2H),5.14–5.07(m,1H),5.04(dd t,J=16.1,2.0,0.9Hz,1H),4.12(d,J=12.4Hz,1H),3.95(d,J=6.8Hz,1H),3.89(s,3H),3.72(d,J=12.3Hz,1H ),3.27–3.22(m,1H),3.12(t,J=5.2Hz,2H),2.99–2.95(m,1H),2.79–2.75(m,1H),2.59–2.49(m,2H).ESI-MS m / z 540.2[M+H] + .

[0375] Example A92: Synthesis of Compound A92

[0376] The synthesis method is the same as A54, yielding compound A92. 1H NMR (500MHz, CDCl3) δ7.35(ddt,J=7.5,1.8,1.0Hz,1H),7.29(td,J=7.3,1.6Hz,1H),7.16(dd,J=7.1,1.2Hz,1H),7.02 (td,J=7.7,1.3Hz,1H),6.78(dd,J=8.6,0.7Hz,1H),6.74–6.67(m,2H),6.61(t,J=1.0Hz,1H),5.94(s,2H),5.78–5.68 (m,1H),5.16–5.07(m,3H),5.06–5.02(m,1H),4.12(d,J=12.4Hz,1H),3.95(d,J=6.8Hz,1H),3.89(s,3H),3.72(d,J=1 2.3Hz,1H),3.29–3.20(m,1H),3.12(t,J=5.2Hz,2H),2.99–2.95(m,1H),2.79–2.75(m,1H),2.59–2.49(m,2H).ESI-MS m / z 540.3[M+H] + .

[0377] Example A93: Synthesis of Compound A93

[0378] The synthesis method is the same as A54, yielding compound A93. 1 H NMR (500MHz, CDCl3) δ6.78(dd,J=8.6,0.7Hz,1H),6.72(d,J=0.7Hz,1H),6.67(d,J=8.6Hz,1H),6.61(t,J=1.0 Hz,1H),5.94(s,2H),5.78–5.68(m,1H),5.13–5.09(m,1H),5.06–5.02(m,1H),4.11(d,J=12.5Hz,1H),4.00(d ,J=4.6Hz,2H),3.95(d,J=6.8Hz,1H),3.89(s,3H),3.71(d,J=12.5Hz,1H),3.29–3.20(m,1H),3.12(t,J=5.2H z,2H),2.99–2.95(m,1H),2.79–2.75(m,1H),2.59–2.49(m,2H),2.10–1.82(m,5H),1.72–1.53(m,4H).ESI-MS m / z 498.3[M+H] + .

[0379] Example A94: Synthesis of Compound A94

[0380] The synthesis method is the same as A54, yielding compound A94. 1 H NMR (500MHz, CDCl3) δ6.78(dd,J=8.6,0.7Hz,1H),6.72(d,J=0.7Hz,1H),6.67(d,J=8.6Hz,1H),6.61(t,J=1.0Hz,1H),5.94(s,2H),5 .78–5.68(m,1H),5.13–5.09(m,1H),5.06–5.02(m,1H),4.11(d,J=12.5Hz,1H),4.02(d,J=4.9Hz,2H),3.95(d,J=6.8Hz,1H),3.89(s ,3H),3.71(d,J=12.5Hz,1H),3.64(ddd,J=12.3,5.8,3.2Hz,2H),3.57(ddd,J=12.4,5.8,3.2Hz,2H),3.29–3.20(m,1H),3.12(t,J=5 .2Hz,2H),2.99–2.95(m,1H),2.79–2.75(m,1H),2.59–2.49(m,2H),2.15–2.08(m,1H),1.86–1.80(m,2H),1.67–1.61(m,2H).ESI-MS m / z464.2[M+H] + .

[0381] Example A95: Synthesis of Compound A95

[0382] The synthesis method is the same as A54, yielding compound A95. 1H NMR (500MHz, CDCl3) δ6.78(dd,J=8.6,0.7Hz,1H),6.72(d,J=0.6Hz,1H),6.67(d,J=8.7Hz,1H),6.61(t,J=1.0Hz ,1H),5.94(s,2H),5.78–5.68(m,1H),5.13–5.09(m,1H),5.06–5.02(m,1H),4.15–4.08(m,3H),3.95(d,J=6.8Hz, 1H),3.89(s,3H),3.77(dd,J=12.5,4.6Hz,2H),3.71(d,J=12.4Hz,1H),3.61(dd,J=12.4,4.5Hz,2H),3.29–3.20( m,1H),3.12(t,J=5.2Hz,2H),2.99–2.96(m,1H),2.79–2.75(m,1H),2.72–2.66(m,1H),2.59–2.49(m,2H).ESI-MS m / z436.2[M+H] + .

[0383] Example A96: Synthesis of Compound A96

[0384] The synthesis method is referenced in A54, yielding compound A96. 1 H NMR (500MHz, CDCl3) δ6.78(dd,J=8.6,0.7Hz,1H),6.72(d,J=0.7Hz,1H),6.67(d,J=8.6Hz,1H),6. 61(t,J=1.0Hz,1H),5.94(s,2H),5.78–5.68(m,1H),5.13–5.09(m,1H),5.06–5.02(m,1H),4.14–4 .06(m,3H),3.95(d,J=6.8Hz,1H),3.89(s,3H),3.71(d,J=12.4Hz,1H),3.29–3.20(m,1H),3.12(t ,J=5.2Hz,2H),2.99–2.95(m,1H),2.79–2.75(m,1H),2.59–2.49(m,2H),2.42–2.16(m,5H).ESI-MS m / z 470.2[M+H] + .

[0385] Example A97: Synthesis of Compound A97

[0386] The synthesis method is the same as A54, yielding compound A97. 1H NMR(500MHz, CDCl3) δ7.52(ddd,J=11.7,5.0,1.2Hz,1H),7.36–7.33(m,1H),7.23(dd,J=11.7,8.5Hz,1H),6.78( d,J=8.7Hz,1H),6.74–6.68(m,2H),6.61(t,J=1.0Hz,1H),5.94(s,2H),5.78–5.68(m,1H),5.24–5.14(m,2H),5. 13–5.09(m,1H),5.06–5.02(m,1H),4.12(d,J=12.5Hz,1H),3.95(d,J=6.8Hz,1H),3.89(s,3H),3.72(d,J=12.3H z,1H),3.29–3.20(m,1H),3.12(t,J=5.2Hz,2H),2.99–2.95(m,1H),2.79–2.75(m,1H),2.59–2.49(m,2H).ESI-MS m / z542.2[M+H] + .

[0387] Example A98: Synthesis of Compound A98

[0388] The synthesis method is referenced in A54, yielding compound A98. 1 H NMR (500MHz, CDCl3) δ8.54(dd,J=2.3,1.6Hz,1H),8.48(dt,J=4.0,1.9Hz,1H),7.78(dt,J=7.7,2.2Hz,1H),7.55(dd,J=7 .6,4.3Hz,1H),6.78(d,J=8.7Hz,1H),6.74–6.69(m,2H),6.61(t,J=1.0Hz,1H),5.94(s,2H),5.78–5.68(m,1H),5.20(d, J=0.7Hz,2H),5.13–5.09(m,1H),5.06–5.02(m,1H),4.12(d,J=12.4Hz,1H),3.95(d,J=6.8Hz,1H),3.89(s,3H),3.72(d, J=12.3Hz,1H),3.29–3.20(m,1H),3.12(t,J=5.2Hz,2H),2.99–2.95(m,1H),2.79–2.75(m,1H),2.59–2.49(m,2H).ESI-MS m / z 457.2[M+H] + .

[0389] Example A99: Synthesis of Compound A99

[0390] The synthesis method is referenced in A54, yielding compound A99. 1 H NMR(500MHz, CDCl3)δ8.61–8.56(m,2H),7.37–7.33(m,2H),6.78(d,J=8.6Hz,1H),6.74–6.69(m,2H), 6.61(t,J=1.0Hz,1H),5.94(s,2H),5.78–5.68(m,1H),5.17(d,J=1.8Hz,2H),5.15–5.07(m,1H),5.06 –5.02(m,1H),4.12(d,J=12.4Hz,1H),3.95(d,J=6.8Hz,1H),3.89(s,3H),3.72(d,J=12.3Hz,1H),3.2 9–3.20(m,1H),3.12(t,J=5.2Hz,2H),2.99–2.95(m,1H),2.79–2.75(m,1H),2.59–2.49(m,2H).ESI-MS m / z 457.2[M+H] + .

[0391] Example A100: Synthesis of compound A100

[0392] The synthesis method is referenced in A54, yielding compound A100. 1 H NMR(500MHz, CDCl3)δ8.00(d,J=7.9Hz,1H),7.83(dt,J=7.7,1.7Hz,1H),7.79–7.73(m,2H),7.55–7.43(m,3H),6.78(d ,J=8.7Hz,1H),6.74–6.69(m,2H),6.61(t,J=1.0Hz,1H),5.94(s,2H),5.78–5.68(m,1H),5.17(d,J=11.7Hz,1H),5.15 (s,1H),5.13–5.07(m,1H),5.06–5.02(m,1H),4.12(d,J=12.4Hz,1H),3.95(d,J=6.8Hz,1H),3.89(s,3H),3.72(d,J=1 2.3Hz,1H),3.29–3.20(m,1H),3.12(t,J=5.2Hz,2H),2.99–2.95(m,1H),2.79–2.75(m,1H),2.59–2.49(m,2H).ESI-MS m / z 506.2[M+H] + .

[0393] Example A101: Synthesis of compound A101

[0394] The synthesis method is the same as A54, yielding compound A101. 1 H NMR (500MHz, CDCl3) δ7.23–7.17(m,1H),7.13(td,J=8.8,4.9Hz,1H),7.01–6.97(m,1H),6.78(d,J=8.7Hz,1 H),6.74–6.68(m,2H),6.61(t,J=1.0Hz,1H),5.94(s,2H),5.78–5.68(m,1H),5.22–5.12(m,2H),5.14–5.09( m,1H),5.06–5.02(m,1H),4.12(d,J=12.5Hz,1H),3.95(d,J=6.8Hz,1H),3.89(s,3H),3.72(d,J=12.3Hz,1H ),3.29–3.20(m,1H),3.12(t,J=5.2Hz,2H),2.99–2.95(m,1H),2.79–2.75(m,1H),2.59–2.49(m,2H).ESI-MS m / z 492.1[M+H] + .

[0395] Example A102: Synthesis of compound A102

[0396] The synthesis method is referenced in A54, yielding compound A102. 1 H NMR (500MHz, CDCl3) δ6.81–6.73(m,1H),6.72(d,J=0.7Hz,1H),6.69(d,J=8.6Hz,1H),6.61(t,J =1.0Hz,1H),5.94(s,2H),5.78–5.68(m,1H),5.29(s,2H),5.14–5.09(m,1H),5.06–5.02(m,1H) ,4.12(d,J=12.5Hz,1H),3.95(d,J=6.8Hz,1H),3.89(s,3H),3.72(d,J=12.3Hz,1H),3.29–3.20 (m,1H),3.12(t,J=5.2Hz,2H),2.99–2.95(m,1H),2.79–2.75(m,1H),2.59–2.49(m,2H).ESI-MS m / z 546.2[M+H] + .

[0397] Example A103: Synthesis of compound A103

[0398] The synthesis method is the same as A54, yielding compound A103. 1 H NMR(500MHz, CDCl3)δ7.20–7.18(m,1H),7.10(t,J=7.9Hz,1H),7.10–7.03(m,1H),6.78(d,J=8.6Hz,1H),6 .74–6.69(m,2H),6.61(t,J=1.0Hz,1H),5.94(s,2H),5.78–5.68(m,1H),5.14–5.09(m,1H),5.10–5.07(m, 2H),5.06–5.02(m,1H),4.12(d,J=12.4Hz,1H),3.95(d,J=6.8Hz,1H),3.89(s,3H),3.72(d,J=12.3Hz,1H) ,3.27–3.22(m,1H),3.12(t,J=5.2Hz,2H),2.99–2.95(m,1H),2.79–2.75(m,1H),2.59–2.49(m,2H).ESI-MS m / z 558.2[M+H] + .

[0399] Example A104: Synthesis of compound A104

[0400] The synthesis method is referenced in A54, yielding compound A104. 1 H NMR (400MHz, DMSO-d6) δ7.96–7.86(m,2H),7.51–7.40(m,2H),7.03(d,J=8.5Hz,1H),6.92(d, J=8.5Hz,1H),6.76(s,1H),6.66(s,1H),5.91(dd,J=8.2,1.0Hz,2H),5.84–5.70(m,1H),5.06( s,1H),5.04–5.00(m,1H),3.85(d,J=4.3Hz,1H),3.63(d,J=16.4Hz,1H),3.56(s,3H),3.51(d ,J=16.4Hz,1H),3.35(s,1H),3.01–2.83(m,3H),2.70–2.55(m,2H),2.44–2.37(m,1H).ESI-MS m / z 524.2[M+H] + .

[0401] Example A105: Synthesis of compound A105

[0402] The synthesis method is the same as A54, yielding compound A105. 1 H NMR (400MHz, DMSO-d6) δ8.05(d,J=8.3Hz,2H),7.99(d,J=8.4Hz,2H),7.06(d,J=8.5Hz,1H),6.97(d ,J=8.5Hz,1H),6.76(s,1H),6.65(s,1H),5.91(dd,J=9.1,1.1Hz,2H),5.85–5.69(m,1H),5.05(s,1 H),5.02(d,J=4.2Hz,1H),3.85(d,J=4.3Hz,1H),3.62(d,J=16.5Hz,1H),3.54(s,3H),3.48(d,J=16 .4Hz,1H),3.37(d,J=14.7Hz,1H),3.01–2.80(m,3H),2.73–2.54(m,2H),2.44–2.37(m,1H).ESI-MS m / z 574.2[M+H] + .

[0403] Example A106: Synthesis of compound A106

[0404] The synthesis method is the same as A54, yielding compound A106. 1 H NMR (500MHz, CDCl3) δ6.98–6.90(m,2H),6.72(d,J=0.6Hz,1H),6.61(t,J=1.0Hz,1H),5.94(s,2 H),5.78–5.68(m,1H),5.13–5.09(m,1H),5.06–5.04(m,1H),4.10(d,J=12.5Hz,1H),3.95(d,J=6 .8Hz,1H),3.89(s,3H),3.72(d,J=12.5Hz,1H),3.61–3.55(m,1H),3.26–3.22(m,1H),3.12(t,J =5.2Hz,2H),2.99–2.95(m,1H),2.79–2.75(m,1H),2.59–2.49(m,2H),1.85–1.63(m,4H).ESI-MS m / z 470.1[M+H] + .

[0405] Example A107: Synthesis of compound A107

[0406] The synthesis method is the same as A54, yielding compound A107.1 H NMR (500MHz, CDCl3) δ6.93 (s, 2H), 6.72 (d, J = 0.6Hz, 1H), 6.61 (t, J = 1.0Hz, 1H), 5.94 (s, 2H),5.78–5.68(m,1H),5.13–5.09(m,1H),5.06–5.04(m,1H),4.10(d,J=12.5Hz,1H),3. 95(d,J=6.8Hz,1H),3.89(s,3H),3.72(d,J=12.5Hz,1H),3.30(s,3H),3.28–3.20(m,1H) ,3.12(t,J=5.2Hz,2H),2.99–2.95(m,1H),2.79–2.75(m,1H),2.59–2.49(m,2H).ESI-MS m / z 444.1[M+H] + .

[0407] Example A108: Synthesis of compound A108

[0408] The synthesis method is the same as A54, yielding compound A108. 1 H NMR (500MHz, CDCl3) δ6.94(d,J=1.8Hz,2H),6.72(d,J=0.6Hz,1H),6.60(d,J=1.0Hz,1H),5.94(s,2H) ,5.78–5.68(m,1H),5.13–5.09(m,1H),5.06–5.04(m,1H),4.10(d,J=12.5Hz,1H),3.95(d,J=6.8Hz,1 H),3.89(s,3H),3.72(d,J=12.5Hz,1H),3.43–3.34(m,1H),3.26–3.22(m,1H),3.19–3.11(m,1H),3.1 4–3.07(m,3H),2.99–2.95(m,1H),2.79–2.75(m,1H),2.59–2.49(m,2H),1.39(t,J=9.4Hz,2H).ESI-MS m / z 458.2[M+H] + .

[0409] Example A109: Synthesis of compound A109

[0410] The synthesis method is the same as A52, yielding compound A109. 1H NMR(400MHz,DMSO-d6)δ7.80–7.63(m,4H),7.10–7.00(m,2H),6.73(s,1H),6.65(s,1H),5.92–5.70(m,4H),5.61(s,1H),5.20(s,2H),5.10–5.0 1(m,2H),3.86(d,J=4.3Hz,1H),3.71(q,J=16.5Hz,2H),3.30(s,1H),3.11–2.86(m,3H),2.67(dd,J=13.9,7.4Hz,2H),2.43–2.37(m,1H).ESI-MS m / z 542.2[M+H] + .

[0411] Example A110: Synthesis of compound A110

[0412] The synthesis method is the same as A52, yielding compound A110. 1 H NMR (400MHz, DMSO-d6) δ7.44(td,J=8.1,6.0Hz,1H),7.29(d,J=8.2Hz,2H),7.17(td,J=9 .0,2.1Hz,1H),7.11–7.00(m,2H),6.74(s,1H),6.66(s,1H),5.90(d,J=12.3Hz,2H),5.8 6–5.78(m,1H),5.75–5.58(m,2H),5.13–5.02(m,4H),3.87(d,J=4.3Hz,1H),3.71(q,J=1 6.5Hz,2H),3.31(s,1H),3.07–2.88(m,3H),2.70–2.60(m,2H),2.43–2.37(m,1H).ESI-MS m / z 492.2[M+H] + .

[0413] Example A111: Synthesis of compound A111

[0414] The synthesis method is the same as A52, yielding compound A111. 1H NMR (400MHz, DMSO-d6) δ7.82–7.74(m,2H),7.73–7.61(m,2H),7.10(d,J=8.6Hz,1H),7.04(d ,J=8.6Hz,1H),6.74(s,1H),6.65(s,1H),5.90(dd,J=13.0,1.0Hz,2H),5.86–5.76(m,1H),5 .66(d,J=54.9Hz,2H),5.19(s,2H),5.10–5.01(m,2H),3.86(d,J=4.4Hz,1H),3.70(q,J=16. 5Hz,2H),3.30–3.27(m,1H),3.06–2.87(m,3H),2.70–2.59(m,2H),2.44–2.37(m,1H).ESI-MS m / z 542.2[M+H] + .

[0415] Example A112: Synthesis of compound A112

[0416] The synthesis method is the same as A52, yielding compound A112. 1 H NMR(400MHz,DMSO-d6)δ7.56(td,J=7.5,1.7Hz,1H),7.45–7.40(m,1H),7.29–7.21(m,2H),7.09 (s,2H),6.74(s,1H),6.65(s,1H),5.90(dd,J=13.2,1.0Hz,2H),5.87–5.77(m,1H),5.76(s,1H), 5.62(dd,J=55.1,2.9Hz,2H),5.13(s,2H),5.11–5.01(m,2H),3.86(d,J=4.3Hz,1H),3.70(q,J= 16.5Hz,2H),3.30–3.27(m,1H),3.07–2.84(m,3H),2.70–2.59(m,2H),2.44–2.37(m,1H).ESI-MS m / z 492.2[M+H] + .

[0417] Example A113: Synthesis of compound A113

[0418] The synthesis method is the same as A52, yielding compound A113. 1H NMR(500MHz, CDCl3)δ7.30–7.23(m,1H),7.18–7.10(m,2H),7.10–7.08(m,1H),6.79(s,1H),6.74–6.6 8(m,2H),6.60(d,J=1.1Hz,1H),5.98–5.88(m,3H),5.82(d,J=0.7Hz,1H),5.78–5.68(m,1H),5.15–5.0 7(m,3H),5.06–5.02(m,1H),4.11(d,J=12.3Hz,1H),3.95(d,J=6.7Hz,1H),3.73(d,J=12.3Hz,1H),3.2 6–3.22(m,1H),3.12(t,J=5.2Hz,2H),2.99–2.95(m,1H),2.79–2.75(m,1H),2.59–2.49(m,2H).ESI-MS m / z 558.2[M+H] + .

[0419] Example A114: Synthesis of compound A114

[0420] The synthesis method is the same as A52, yielding compound A114. 1 H NMR(500MHz, CDCl3)δ7.64(dd,J=10.5,1.3Hz,1H),7.47–7.45(m,1H),7.45–7.39(m,1H),7.28(td,J=7.0,1.3Hz,1H) ,6.79(s,1H),6.74–6.68(m,2H),6.60(d,J=1.1Hz,1H),5.98–5.88(m,3H),5.82(d,J=0.7Hz,1H),5.78–5.68(m,1H),5 .25(t,J=0.9Hz,2H),5.15–5.07(m,1H),5.06–5.02(m,1H),4.11(d,J=12.3Hz,1H),3.95(d,J=6.7Hz,1H),3.73(d,J=1 2.3Hz,1H),3.26–3.22(m,1H),3.12(t,J=5.2Hz,2H),2.99–2.95(m,1H),2.79–2.75(m,1H),2.59–2.49(m,2H).ESI-MS m / z 542.2[M+H] + .

[0421] Example A115: Synthesis of compound A115

[0422] The synthesis method is the same as A52, yielding compound A115. 1 H NMR (500MHz, CDCl3) δ7.69–7.64(m,2H),7.36(dt,J=7.1,1.0Hz,2H),6.80(dd,J=8.6,0.7Hz,1H),6.74–6.69(m ,2H),6.60(d,J=1.1Hz,1H),5.94(s,2H),5.78–5.68(m,1H),5.17–5.07(m,3H),5.06–5.02(m,1H),4.12(d,J=12 .4Hz,1H),4.00(d,J=4.4Hz,2H),3.95(d,J=6.8Hz,1H),3.72(d,J=12.4Hz,1H),3.29–3.20(m,1H),3.12(t,J=5. 2Hz,2H),2.99–2.95(m,1H),2.79–2.75(m,1H),2.59–2.49(m,2H),1.41–1.31(m,1H),0.63–0.46(m,4H).ESI-MS m / z564.2[M+H] + .

[0423] Example A116: Synthesis of compound A116

[0424] The synthesis method is the same as A52, yielding compound A116. 1 H NMR (500MHz, CDCl3) δ7.43–7.41(m,2H),7.39–7.32(m,2H),7.32–7.25(m,1H),6.80(dd,J=8.6,0.7Hz,1H),6.74–6.69( m,2H),6.60(d,J=1.1Hz,1H),5.94(s,2H),5.78–5.68(m,1H),5.14(q,J=0.9Hz,2H),5.13–5.09(m,1H),5.06–5.02(m,1H ),4.12(d,J=12.4Hz,1H),4.00(d,J=4.4Hz,2H),3.95(d,J=6.8Hz,1H),3.72(d,J=12.4Hz,1H),3.29–3.20(m,1H),3.12 (t,J=5.2Hz,2H),2.99–2.95(m,1H),2.79–2.75(m,1H),2.59–2.49(m,2H),1.41–1.31(m,1H),0.63–0.46(m,4H).ESI-MS m / z 496.2[M+H] + .

[0425] Example A117: Synthesis of compound A117

[0426] The synthesis method is the same as A52, yielding compound A117. 1 H NMR (500MHz, CDCl3) δ7.43–7.41(m,2H),7.39–7.32(m,2H),7.32–7.25(m,1H),6.75(s,1H),6.74–6.67(m,2H),6.60( d,J=1.1Hz,1H),6.06–5.99(m,1H),5.94(s,2H),5.78–5.68(m,1H),5.36–5.32(m,2H),5.14(q,J=1.0Hz,2H),5.13–5. 09(m,1H),5.06–5.02(m,1H),4.67(dt,J=5.7,1.1Hz,2H),4.12(d,J=12.4Hz,1H),3.95(d,J=6.7Hz,1H),3.71(d,J=1 2.3Hz,1H),3.29–3.20(m,1H),3.12(t,J=5.2Hz,2H),2.99–2.95(m,1H),2.79–2.75(m,1H),2.59–2.49(m,2H).ESI-MS m / z 482.2[M+H] + .

[0427] Example A118: Synthesis of compound A118

[0428] The synthesis method is the same as A52, yielding compound A118. 1 H NMR(500MHz,DMSO-d6)δ7.45–7.31(m,5H),7.06(q,J=8.5Hz,2H),6.73(s, 1H),6.65(s,1H),5.90(d,J=12.6Hz,2H),5.86–5.76(m,1H),5.66(d,J=55 .0Hz,2H),5.06(d,J=19.5Hz,4H),3.86(s,1H),3.70(q,J=16.4Hz,2H),3. 30(s,1H),3.08–2.86(m,3H),2.73–2.57(m,2H),2.46–2.35(m,1H).ESI-MS m / z 474.2[M+H] + .

[0429] Example A119: Synthesis of compound A119

[0430] The synthesis method is the same as A52, yielding compound A119. 1 H NMR (500MHz, CDCl3) δ7.53–7.50(m,1H),7.36–7.33(m,1H),7.23(dd,J=11.7,8.5Hz,1H),6.80(d,J=8.8Hz,1H), 6.74–6.67(m,2H),6.60(d,J=1.1Hz,1H),5.98–5.88(m,3H),5.82(d,J=0.7Hz,1H),5.78–5.68(m,1H),5.24–5.1 4(m,2H),5.13–5.09(m,1H),5.06–5.02(m,1H),4.11(d,J=12.3Hz,1H),3.95(d,J=6.7Hz,1H),3.73(d,J=12.3Hz ,1H),3.29–3.20(m,1H),3.12(t,J=5.2Hz,2H),2.99–2.95(m,1H),2.79–2.75(m,1H),2.59–2.49(m,2H).ESI-MS m / z 560.2[M+H] + .

[0431] Example A120: Synthesis of compound A120

[0432] The synthesis method is the same as A52, yielding compound A120. 1 H NMR (500MHz, CDCl3) δ6.82–6.77(m,1H),6.72(d,J=0.6Hz,1H),6.67(d,J=8.6Hz,1H),6.61(t,J=1.0Hz,1H), 5.93–5.92(m,3H),5.82(s,1H),5.78–5.68(m,1H),5.13–5.09(m,1H),5.06–5.02(m,1H),4.11(d,J=12.4Hz, 1H),4.00(d,J=4.6Hz,2H),3.95(d,J=6.8Hz,1H),3.73(d,J=12.3Hz,1H),3.26–3.22(m,1H),3.12(t,J=5.2H z,2H),2.99–2.95(m,1H),2.79–2.75(m,1H),2.59–2.49(m,2H),1.38–1.31(m,1H),0.63–0.46(m,4H).ESI-MS m / z 438.2[M+H] + .

[0433] Example A121: Synthesis of compound A121

[0434] The synthesis method is the same as A52, yielding compound A121. 1 H NMR (500MHz, CDCl3) δ6.82–6.77(m,1H),6.72(d,J=0.6Hz,1H),6.67(d,J=8.6Hz,1H),6.61(t,J=1.0Hz,1H), 5.93–5.92(m,3H),5.82(s,1H),5.78–5.68(m,1H),5.13–5.09(m,1H),5.06–5.02(m,1H),4.11(d,J=12.4Hz, 1H),4.03(d,J=4.4Hz,2H),3.95(d,J=6.7Hz,1H),3.73(d,J=12.3Hz,1H),3.26–3.22(m,1H),3.12(t,J=5.2H z,2H),2.99–2.95(m,1H),2.79–2.75(m,1H),2.59–2.49(m,2H),2.05–1.95(m,1H),1.86–1.63(m,6H).ESI-MS m / z 452.2[M+H] + .

[0435] Example A122: Synthesis of compound A122

[0436] The synthesis method is the same as A52, yielding compound A122. 1H NMR (500MHz, CDCl3) δ6.82–6.77(m,1H),6.72(d,J=0.6Hz,1H),6.67(d,J=8.6Hz,1H),6.60(d,J=1.1Hz,1H),5.93–5. 92(m,3H),5.82(s,1H),5.78–5.68(m,1H),5.13–5.09(m,1H),5.06–5.02(m,1H),4.11(d,J=12.4Hz,1H),4.01(d,J=4 .4Hz,2H),3.95(d,J=6.8Hz,1H),3.73(d,J=12.3Hz,1H),3.26–3.22(m,1H),3.12(t,J=5.2Hz,2H),2.99–2.95(m,1H) ,2.79–2.75(m,1H),2.59–2.49(m,2H),2.03–1.94(m,1H),1.78–1.57(m,5H),1.56–1.47(m,1H),1.48(s,1H).ESI-MS m / z 466.1[M+H] + .

[0437] Example A123: Synthesis of compound A123

[0438] The synthesis method is the same as A52, yielding compound A123. 1 H NMR (500MHz, CDCl3) δ6.82–6.77(m,1H),6.72(d,J=0.6Hz,1H),6.67(d,J=8.6Hz,1H),6.60(d,J=1.1Hz,1H), 5.93–5.92(m,3H),5.82(s,1H),5.78–5.68(m,1H),5.13–5.09(m,1H),5.06–5.04(m,1H),4.11(d,J=12.4Hz,1 H),4.01(d,J=5.1Hz,2H),3.95(d,J=6.7Hz,1H),3.73(d,J=12.3Hz,1H),3.26–3.22(m,1H),3.12(t,J=5.2Hz ,2H),2.99–2.95(m,1H),2.79–2.75(m,1H),2.59–2.49(m,2H),1.97–1.90(m,1H),1.69–1.36(m,10H).ESI-MS m / z 480.2[M+H] + .

[0439] Example A124: Synthesis of compound A124

[0440] The synthesis method is referenced in A54, yielding compound A124. 1 H NMR (500MHz, CDCl3) δ7.30–7.23(m,1H),7.18–7.10(m,2H),7.10–7.08(m,1H),6.78(d,J=8.7Hz,1H ),6.75–6.69(m,2H),6.59(t,J=1.0Hz,1H),5.78–5.68(m,1H),5.15–5.07(m,3H),5.06–5.02(m,1H) ,4.12(d,J=12.5Hz,1H),3.97–3.95(m,1H),3.89(s,3H),3.81(s,6H),3.71(d,J=12.5Hz,1H),3.29– 3.20(m,1H),3.12(t,J=5.2Hz,2H),2.96–2.91(m,1H),2.78–2.73(m,1H),2.59–2.49(m,2H).ESI-MS m / z 556.2[M+H] + .

[0441] Example A125: Synthesis of compound A125

[0442] The synthesis method is referenced in A54, yielding compound A125. 1 H NMR (500MHz, CDCl3) δ7.51–7.47(m,1H),7.33–7.24(m,1H),7.19–7.08(m,2H),6.78(d,J=8.6Hz,1H),6.74(d,J =0.6Hz,1H),6.71(d,J=8.6Hz,1H),6.59(t,J=1.0Hz,1H),5.78–5.68(m,1H),5.22–5.12(m,2H),5.15–5.07(m, 1H),5.06–5.02(m,1H),4.12(d,J=12.5Hz,1H),3.98–3.93(m,1H),3.89(s,3H),3.81(s,6H),3.71(d,J=12.5Hz ,1H),3.29–3.20(m,1H),3.12(t,J=5.2Hz,2H),2.96–2.91(m,1H),2.78–2.83(m,1H),2.59–2.49(m,2H).ESI-MS m / z490.2[M+H] + .

[0443] Example A126: Synthesis of compound A126

[0444] The synthesis method is referenced in A54, yielding compound A126. 1 H NMR (500MHz, CDCl3) δ7.53–7.46(m,1H),7.33–7.24(m,1H),7.19–7.08(m,2H),6.78(d,J=8.8Hz,1H),6.73–6.66(m,2H) ,6.59(t,J=1.0Hz,1H),5.78–5.68(m,1H),5.22–5.12(m,2H),5.15–5.07(m,1H),5.06–5.02(m,1H),4.12(d,J=12.5Hz,1 H),3.99(d,J=4.6Hz,2H),3.97–3.93(m,1H),3.89(s,3H),3.85(s,3H),3.71(d,J=12.5Hz,1H),3.29–3.20(m,1H),3.12 (t,J=5.2Hz,2H),2.96–2.91(m,1H),2.80–2.71(m,1H),2.59–2.49(m,2H),1.39–1.30(m,1H),0.63–0.46(m,4H).ESI-MS m / z 530.3[M+H] + .

[0445] Example A127: Synthesis of compound A127

[0446] The synthesis method is referenced in A54, yielding compound A127. 1 H NMR (500MHz, CDCl3) δ7.69–7.64(m,2H),7.37–7.35(m,2H),6.78(d,J=8.8Hz,1H),6.74–6.66(m,2H),6.59(t, J=1.0Hz,1H),5.78–5.68(m,1H),5.15–5.09(m,3H),5.06–5.02(m,1H),4.12(d,J=12.5Hz,1H),3.99(d,J=4.6H z,2H),3.97–3.93(m,1H),3.89(s,3H),3.85(s,3H),3.71(d,J=12.5Hz,1H),3.29–3.20(m,1H),3.12(t,J=5.2 Hz,2H),2.96–2.91(m,1H),2.78–2.73(m,1H),2.59–2.49(m,2H),1.39–1.30(m,1H),0.63–0.46(m,4H).ESI-MS m / z 580.2[M+H]+ .

[0447] Example A128: Synthesis of compound A128

[0448] The synthesis method is referenced in A54, yielding compound A128. 1 H NMR (500MHz, CDCl3) δ7.30–7.23(m,1H),7.18–7.10(m,2H),7.09(ddd,J=7.1,2.2,1.2Hz,1H),6.78(d,J=8 .8Hz,1H),6.74–6.67(m,2H),6.59(t,J=1.0Hz,1H),5.78–5.68(m,1H),5.15–5.07(m,3H),5.06–5.02(m,1H ),4.27(d,J=0.6Hz,4H),4.12(d,J=12.4Hz,1H),3.95(d,J=6.7Hz,1H),3.89(s,3H),3.72(d,J=12.3Hz,1H) ,3.27–3.22(m,1H),3.12(t,J=5.2Hz,2H),2.99–2.94(m,1H),2.79–2.74(m,1H),2.59–2.49(m,2H).ESI-MS m / z 554.2[M+H] + .

[0449] Example A129: Synthesis of compound A129

[0450] The synthesis method is referenced in A54, yielding compound A129. 1 H NMR(500MHz, CDCl3)δ7.26(t,J=7.4Hz,1H),7.20(dd,J=8.5,0.7Hz,1H),7.17–7.10(m,2H),7.09(ddd,J =7.1,2.2,1.2Hz,1H),6.84–6.76(m,2H),6.74–6.67(m,2H),5.78–5.68(m,1H),5.15–5.09(m,2H),5.12– 5.07(m,1H),5.06–5.02(m,1H),4.12(d,J=12.5Hz,1H),4.02–3.96(m,1H),3.89(s,3H),3.81(s,3H),3. 71(d,J=12.3Hz,1H),3.24–3.19(m,1H),3.15–3.09(m,2H),2.87–2.85(m,2H),2.59–2.49(m,2H).ESI-MS m / z 526.2[M+H]+ .

[0451] Example A130: Synthesis of compound A130

[0452] The synthesis method is referenced in A54, yielding compound A130. 1 H NMR (400MHz, DMSO-d6) δ7.72(d,J=8.1Hz,2H),7.60(d,J=8.0Hz,2H),6.99(d,J=8 .5Hz,1H),6.91(d,J=8.5Hz,1H),6.70(s,1H),6.62(s,1H),5.89(dd,J=13.8,1.1H z,2H),5.79–5.68(m,1H),5.09–4.97(m,4H),3.79(s,4H),3.62–3.49(m,2H),3.23 (q,J=5.6Hz,1H),2.94–2.76(m,3H),2.68–2.56(m,2H),2.43–2.36(m,1H).ESI-MS m / z 524.2 [M+H] + .

[0453] Bioactivity testing

[0454] 1. Effects of the compound on de novo lipid synthesis (DNL) in primary mouse hepatocytes

[0455] 1.1 Test Methods:

[0456] Primary mouse hepatocytes were isolated and cultured in MEM medium containing 10% FBS for 6 hours. The medium was then replaced with MEM medium containing 0.1% BSA, and pretreated with different concentrations of compounds or positive control compounds for 18 hours. The medium was then replaced with MEM medium containing 0.1 μCi / ml 14C-acetate sodium for 6 hours. At the end of the experiment, the cells were washed three times with ice-cold PBS, and lysed with 400 μl of 0.5M KOH. The cell lysate was collected on ice. Subsequently, 320 μl of the cell lysate was mixed with 20% KOH (dissolved in methanol) and subjected to saponification. Lipids that have not undergone saponification, i.e. sterol lipids, were extracted with petroleum ether. The saponified products were acidified by adding 5N H2SO4, and then fatty acids were extracted with petroleum ether. The extracted solution was dried under vacuum and then scintillation fluid was added. The CPM value was read using a liquid scintillation analyzer. The production of sterol lipids and fatty acids in primary mouse hepatocytes was calculated. The experimental results were expressed as folds vs. control. When the fold was <0.005, it was recorded as 0.00 in the table.

[0457] 1.2 Test Results:

[0458] Table 1. Effects of compounds on de novo fatty acid synthesis.

[0459] Table 2. Effects of compounds on de novo synthesis of sterol esters

[0460] The results showed that the compounds of this invention can effectively reduce the synthesis of fatty acids and cholesterol esters.

[0461] 2. Effects of the compound on gluconeogenesis in primary mouse hepatocytes

[0462] 2.1 Test Methods:

[0463] Primary hepatocytes from fasted mice were isolated and placed in an incubator. After 4 hours of cell adhesion, the culture medium was replaced with sugar-free DMEM containing 0.1% BSA, and a concentration gradient of compounds, a positive control metformin (500 μM), or a solvent control was added. Incubation was continued for 1.5 hours. The culture medium was discarded, and the medium was replaced with 0.1% BSA-free DMEM containing or without gluconeogenic substrates (20 mM sodium lactate and 2 mM sodium pyruvate). 10 nM glucagon was added, followed by further incubation for 4 hours. After drug treatment, the culture medium was collected, and glucose content was measured using a kit. Simultaneously, 300 μl / well of 0.5 M KOH solution was added to cell culture plates, and cells were lysed by shaking at room temperature for 5 hours. Cell protein concentration was measured, and the glucose production per unit cell protein was calculated after protein content correction. Gluconeogenesis was represented by the difference between the groups with and without gluconeogenic substrates. The experimental results are expressed as a fold vs. control. When the fold is less than 0.005, it is recorded as 0.00 in the table.

[0464] 2.2 Test Results:

[0465] Table 3. Effects of compound gluconeogenesis

[0466] 3. Effects of the compound on IL-1β gene expression in LPS-induced mouse bone marrow-derived macrophages (BMDM)

[0467] Mice were euthanized by cervical insemination, and leg bones were harvested. A needle was inserted into the bone marrow cavity, and the bone marrow was repeatedly flushed until it turned white. The flushing fluid was added to a 50 mL centrifuge tube and centrifuged at 1000 rpm for 5 min. The centrifuged bone marrow cells were resuspended in 10 mL of 1640 medium containing MCSF (50 ng / mL) and serum, and cultured for 3 days in an incubator at 37°C with a suitable 5% CO2 gas concentration. The supernatant was discarded, and the cells were cultured in 5 mL of 1640 medium containing MCSF (50 ng / mL) and serum for another 4 days. LPS and a compound were added to treat the cells for 24 h. After terminating the reaction, RNA was extracted, and the effect of the compound on LPS-induced IL-1β gene expression was detected.

[0468] Table 4. Primer Sequences for Real-Time Quantitative PCR

[0469] The experimental results are shown in Figure 1. The results show that all the compounds of the present invention can successfully downregulate LPS-induced IL-1β gene expression.

[0470] 4. Effects of A5 on the differentiation of stromal vascular fraction derived from inguinal adipose tissue into mature adipocytes.

[0471] 4.1 Test Methods:

[0472] Six- to eight-week-old C57 mice were euthanized by cervical insemination, and iWAT cells were isolated. Adipose tissue was minced and placed in 1*PBS containing collagenase IV (1 mg / mL) after filtration and sterilization. Digestion was performed at 37°C for 1 hour until the solution was milky white and free of large adipose tissue fragments. The digest was filtered through a 70 μm membrane, centrifuged at 1300 rpm for 3 minutes, and the supernatant was discarded. The cells were resuspended in 10% FBSDMEM and seeded into culture dishes. After confluence, the cells were digested with trypsin. At confluence (D0), the cells were cultured in 10% FBSDMEM containing insulin, IBMX, and dexamethasone for 2 days (D0-D2), in 10% FBSDMEM containing insulin for 2 days (D3-D4), and in 10% FBSDMEM for 4 days (D5-D8). A5 treatment was added starting from the first day of differentiation (D0). On D8, the cells were collected, RNA was extracted, and the effect of A5 on differentiation-related genes of iWAT-derived SVF cells was detected.

[0473] Table 5 Primer sequences for real-time quantitative PCR

[0474] 4.2 Test Results

[0475] Adipose tissue-derived stem cell (SVF) is a cell population containing various cell types, among which adipose-derived mesenchymal stem cells (ADSCs) are one of the important cell types in SVF. Inducing SVF into mature adipocytes in vitro can mimic the in vivo adipogenesis process. The results are shown in Figure 2. After 8 days of induction and drug administration, microscopic observation revealed fewer adipocytes and smaller lipid droplets in the drug-treated group compared to the control group. qPCR results showed that A5 administration significantly downregulated the expression levels of adipogenesis-related genes, suggesting that A5 can inhibit the differentiation of adipose-derived mesenchymal stem cells into adipocytes. Fatty acid stem cells (FAS) are responsible for fatty acid synthesis, and A5 significantly downregulated the gene expression level of FAS, suggesting that A5 can inhibit fat synthesis.

[0476] 5. Preliminary pharmacokinetic parameters of A5 in mice

[0477] 5.1 Test Methods:

[0478] Male C57BL / 6 mice were fasted overnight and then administered A5 (20 mg / kg) by gavage. Blood samples were collected at 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 8 h, and 24 h after administration. The liver, brain, and paragonial fat of the mice were collected at 0.5, 2, 8, and 24 h to test the drug concentration.

[0479] 5.2 Test Results:

[0480] Table 6. Pharmacokinetic parameters of A5 in plasma and tissues of male C57 mice after oral administration.

[0481] The results showed that A5 has good pharmacokinetic properties.

[0482] 6. Efficacy study of A5 on glucose tolerance in normal mice

[0483] Male ICR mice were divided into groups according to body weight and administered 0.25% CMC-Na and 142-40 mg / kg, respectively, once daily for 4 days. The mice were fasted overnight on the third day, and on the morning of the fourth day, 4 g / kg glucose was administered orally 1 hour after administration. Blood glucose levels were measured at -60, 0, 15, 30, 60, and 120 minutes, and the area under the blood glucose curve (AUC0-120min Glu) was calculated. The results are shown in Figure 3. The results showed that the blood glucose level in the A5 group was significantly lower than that in the control group 30 minutes after the glucose load.

[0484] 7. Pharmacodynamic evaluation of A5 in a mouse model of non-alcoholic steatohepatitis (NASH) induced by a high-fat diet combined with carbon tetrachloride.

[0485] 7.1 Test Methods:

[0486] Male C57 mice, 5-6 weeks old, were used in this experiment. They were fed a high-fat diet and a control diet, respectively. After 12 weeks of induction, they were intraperitoneally injected with CCl4 (0.05 μl / g) twice a week. Carbon tetrachloride injection was administered for 6 weeks as the experimental endpoint. Starting in the same week as the CCl4 injection, mice were administered A5 (20 mg / kg) and a solvent control (0.25% CMC-Na) by gavage once daily until the end of the experiment. During the experiment, mouse weight and food intake were recorded daily. Fasting blood glucose was measured at the end of the experiment, and blood samples were collected and serum was separated for serum biochemical analysis. The liver was isolated, fixed, and embedded in the primary lobe, sectioned, stained with hematoxylin and eosin (H&E), and pathologically scored. Epididymal and inguinal fat were isolated and weighed. Real-time quantitative PCR was used to detect the gene expression level of type I collagen α1 (COL1a1) and the level of fibrosis in the liver.

[0487] 7.2 Experimental Results:

[0488] Compared with the model control group, mice in the A5 group had significantly lower body weight, with no significant change in food intake; A5 administration significantly reduced the weight of epididymal fat (eWAT) and inguinal fat (iWAT) in mice; fasting blood glucose and serum triglyceride levels were significantly reduced in mice in the A5 group; HE staining of liver sections showed that, compared with the model control group, A5 significantly improved hepatic steatosis, and also showed a downregulation trend in hepatic ballooning degeneration and inflammation, with a significant decrease in NAS score; the expression of COL1a1 in the liver of mice in the A5 group was significantly downregulated, suggesting an ameliorative effect on fibrosis.

[0489] 8. Preliminary pharmacokinetic parameters of A66 in mice

[0490] 8.1 Test Methods:

[0491] Diet-induced obesity (DIO) mice were fasted overnight and then administered A66 (20 mg / kg) by gavage. Blood samples were collected at 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 8 h, and 24 h after administration. The drug concentration was tested in the liver, brain, and paragonial fat of the mice at 0.5, 2, 8, and 24 h.

[0492] 8.2 Test Results:

[0493] Table 7. Pharmacokinetic parameters of A66 in plasma and tissues of DIO mice after oral administration.

[0494] The results showed that A66 possessed favorable pharmacokinetic properties. 9. Pharmacodynamic evaluation of A66 in a mouse model of non-alcoholic steatohepatitis induced by a high-fat diet combined with carbon tetrachloride.

[0495] 9.1 Test Methods:

[0496] Male C57 mice, 5-6 weeks old, were used in this experiment. They were fed a high-fat diet and a control diet, respectively. After 12 weeks of induction, they were intraperitoneally injected with CCl4 (0.05 μl / g) twice a week. Carbon tetrachloride injection was administered for 6 weeks as the experimental endpoint. In the same week that CCl4 injection began, A66 (15 mg / kg) was administered by gavage once daily until the end of the experiment. After the experiment, blood samples were collected, the liver was separated, the primary lobe of the liver was fixed and embedded, sections were prepared, and hematoxylin-eosin (H&E) staining was performed for pathological scoring. The levels of triglycerides and total cholesterol in the liver were measured to comprehensively evaluate the effect of the compounds in improving non-alcoholic steatohepatitis.

[0497] 9.2 Experimental Results:

[0498] The experimental results are shown in Figure 9. The results of HE staining of liver sections showed that, compared with the model control group, A66 significantly reduced hepatic steatosis in NASH mice after 6 weeks of oral administration and significantly reduced the content of liver triglycerides and cholesterol, indicating that A66 has a significant ameliorative effect on NASH pathology.

[0499] 10. Pharmacodynamic evaluation of the hypoglycemic activity of A66 in type 2 diabetic db / db mice

[0500] 10.1 Experimental Methods:

[0501] Male db / db mice were housed individually after weaning and fed a high-fat diet; other age-matched wild-type male mice were fed a normal diet. Random blood glucose and body weight were measured in db / db male mice at 7-8 weeks of age. Based on these indicators, the db / db mice were divided into three groups of eight mice each: a model control group, a group receiving 15 mg / kg A66, and a group receiving a 30 nmol / kg positive control sema (sema). A separate group of wild-type mice served as a normal control. Animals in the model control group and the A66 administration group were administered the solvent control (0.25% CMC-Na) and A66 by gavage between 8:30 and 9:00 AM on the day of administration, respectively. The positive control group received a subcutaneous injection of 30 nmol / kg sema every three days. Random and fasting blood glucose levels were measured regularly to evaluate the effect of A66 in improving hyperglycemia.

[0502] 10.2 Experimental Results:

[0503] The experimental results are shown in Figure 10. Oral administration of A66 at 15 mg / kg significantly reduced random and fasting blood glucose in db / db mice, demonstrating a good hypoglycemic effect.

[0504] 11. Pharmacodynamic evaluation of the weight loss activity of A66 in diet-induced obesity (DIO) mice.

[0505] 11.1 Experimental Methods:

[0506] Four-week-old C57BL / 6J mice were induced into DIO mice by feeding them a high-fat diet (60% cal / fat) for 13.5 weeks. DIO mice were divided into four groups of eight mice each based on body weight: a model control group, a 5 mg / kg A66 group, a 15 mg / kg A66 group, and a 30 nmol / kg positive control sema group. A separate group of age-matched mice fed a normal diet served as a control group. On the day of administration, the model control group and the A66 administration groups were administered the solvent control (0.25% CMC-Na) and A66 (5 mg / kg and 15 mg / kg) by gavage between 8:30 and 9:00 AM, respectively. The positive control group received a subcutaneous injection of 30 nmol / kg sema every three days. Mouse body weight and weight loss were measured daily to evaluate the weight-loss effect of A66 on obese mice.

[0507] 11.2 Experimental Results:

[0508] The experimental results are shown in Figure 11. Oral administration of A66 at doses of 5 and 15 mg / kg significantly reduced the weight of DIO mice in a dose-dependent manner. After continuous administration of 15 mg / kg for 16 days, the weight-loss effect was comparable to that of subcutaneous injection of 30 nmol / kg smegglutide, showing a significant weight-loss effect.

[0509] All documents mentioned in this invention are incorporated herein by reference as if each document were individually incorporated by reference. Furthermore, it should be understood that after reading the foregoing teachings of this invention, those skilled in the art can make various alterations or modifications to this invention, and these equivalent forms also fall within the scope defined by the appended claims.

Claims

1. A nitrogen-containing heterocyclic compound of formula (I), or a pharmaceutically acceptable salt thereof, enantiomer, diastereomer, or racemate thereof: in, The chiral carbon atom C* can be independently of the S-type, R-type, racemic, or a combination thereof; Ring A is selected from the group consisting of phenyl, 5-10-membered heteroaryl; and ring A optionally has one or more R4 substituents: n = 0 or 1; R1 is an unsubstituted or substituted group with 1-3 substituents of the following groups: C1-C7 alkyl, C2-C7 alkenyl, C2-C7 ynyl, -(CH2). p C3-C7 cycloalkyl groups, -(CH2) p 3- to 12-membered heterocyclic groups, -(CH2) p C6~C12 aryl, -(CH2) p 5- to 12-membered heteroaryl groups (such as benzo5- to 7-membered heteroaryl groups); wherein each of the said heterocyclic or heteroaryl groups contains 1 to 3 heteroatoms selected from oxygen, sulfur, and nitrogen; wherein p is 0, 1, 2, 3, or 4; R2 and R3 are each independently selected from the group consisting of: hydrogen, deuterium, tritium, halogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted 3-7 membered heterocycle, substituted or unsubstituted C1-C6 alkylphenyl, substituted or unsubstituted C1-C6 alkyl 5-7 membered heteroaryl, substituted or unsubstituted C3-C12 cycloalkyl, substituted or unsubstituted C2-C10 acyl, substituted or unsubstituted C2-C10 ester, amino, substituted or unsubstituted C1-C6 amide, -SOR5, -OSOR5, -OCOR; and R2 and R3 are not both hydrogen. Or, as mentioned above, R2 and R3 and the adjacent (CH2). n O and C=C together constitute a substituted or unsubstituted 5-7 membered heterocycle, wherein the heterocycle is a partially unsaturated heterocycle or an aromatic heterocycle; R4 is selected from hydrogen, deuterium, tritium, halogen, hydroxyl, or unsubstituted or substituted with 1-3 halogens from the group consisting of: C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C2-C6 alkenyloxy, C2-C6 alkynyloxy, -(CH2). p C3-C6 cycloalkyl groups, -(CH2) p C6~C10 aryl, -(CH2) p 5-7 quinone heteroaryl groups, -O(CH2) p C3-C6 cycloalkyl groups, -O(CH2) p C6~C10 aryl, -O(CH2) p -3-7 membered heteroaryl; The substitution refers to the substitution of a hydrogen atom on a group by one or more substituents, and the substituents are selected from the group consisting of: halogen, cyano, nitro, hydroxyl, amino, carboxyl, mercapto, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkoxy, C1-C6 alkyl-OC(O)-, C1-C6 alkyl-C(O)O-, hydroxy-substituted C1-C6 alkyl, C1-C6 haloalkyl, NH2-NHC(O)-, C1-C6 alkyl-C(O)-, C1-C6 alkyl-NHC(O)-, C1-C6 alkyl-C(O)NH-, C1-C6 alkyl-S(O)2-, C1-C6 alkyl-NHS(O)2-, C1-C6 alkyl-S(O)2-, or two substituents located on adjacent atoms together with the carbon atom attached thereto form a 5-7 membered carbon ring or heterocycle; In the above formulas, the heterocyclic or heteroaromatic ring may arbitrarily have 1 to 3 heteroatoms selected from N, O or S.

2. The compound of claim 1, or a pharmaceutically acceptable salt, enantiomer, diastereomer, or racemate thereof, characterized in that, The ring A is selected from the following group:

3. The compound of claim 1, or a pharmaceutically acceptable salt, enantiomer, diastereomer, or racemate thereof, characterized in that, The compound of formula I has a structure selected from the group consisting of: R2 and R3 are each independently selected from the following group: substituted or unsubstituted C6-C10 aryl groups, substituted or unsubstituted 5-7 membered heterocycles.

4. The compound of claim 1, or a pharmaceutically acceptable salt, enantiomer, diastereomer, or racemate thereof, characterized in that, R1 is an unsubstituted or halogenated group selected from the group consisting of: C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, -(CH2)C3-C7 cycloalkyl, -(CH2)3-12 heterocyclic, benzyl, -CH2C(O)NHNH2, -CH2C(O)OH, -CH2C(O)OCH3.

5. The compound of claim 1, or a pharmaceutically acceptable salt, enantiomer, diastereomer, or racemate thereof, characterized in that, R4 is an unsubstituted or halogenated group selected from the group consisting of: C1-C6 alkoxy, C2-C6 alkenoxy, C2-C6 alkynoxy, -O(CH2)phenyl, -O(CH2) p 5-7-membered heteroaryl, -O(CH2)C3-C6 cycloalkyl, -O(CH2)-3-7-membered heteroaryl.

6. The compound of claim 1, or a pharmaceutically acceptable salt, enantiomer, diastereomer, or racemate thereof, characterized in that, The compound has a structure selected from the group consisting of: Where q is 0, 1, 2, 3 or 4.

7. The compound of claim 1, or a pharmaceutically acceptable salt, enantiomer, diastereomer, or racemate thereof, characterized in that, The compounds are selected from the following group:

8. A pharmaceutical composition, characterized in that, include: (A) a therapeutically effective amount of the compound of claim 1, its enantiomers, diastereomers, racemates and mixtures thereof, and one or more of its pharmaceutically acceptable salts, hydrates and solvates; and (B) a pharmaceutically acceptable carrier.

9. Use of the compound as claimed in claim 1, its enantiomers, diastereomers, racemates and mixtures thereof, and pharmaceutically acceptable salts, hydrates and solvates thereof, characterized in that, Used to prepare pharmaceutical compositions for the prevention or treatment of metabolic diseases.

10. The use as described in claim 9, characterized in that, The metabolic diseases mentioned are selected from the following group: diabetes, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, fatty liver deformity, atherosclerosis, obesity, non-alcoholic fatty liver disease, cardiovascular disease, and gout.

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