CN104788412B

CN104788412B - Aromatic polycyclic carboxylic acid derivatives

Info

Publication number: CN104788412B
Application number: CN201410123710.3A
Authority: CN
Inventors: 吴永谦
Original assignee: Shandong Xuanzhu Pharma Co Ltd
Current assignee: BEIJING TIANXINYUAN PHARMACEUTICAL SCIENCE AND TECHNOLOGY DEVELOPMENT Co Ltd; Beijing Sihuan Pharmaceutical Co Ltd; Beijing Ao He Research Institute Co Ltd; Jilin Shengtong Chemical Co Ltd
Priority date: 2014-01-22
Filing date: 2014-03-29
Publication date: 2017-02-15
Anticipated expiration: 2034-03-29
Also published as: CN104788412A

Abstract

The invention specifically relates to aromatic polycyclic carboxylic acid derivative GPR40 receptor agonists as shown in a general formula (I) which is described in the specification, and pharmaceutically acceptable salts, esters or stereoisomers thereof, belonging to the technical field of medicine. R1, R2, R3, R4 and R5 in the general formula (I) are as defined in the specification. The invention also relates to a preparation method, a medicinal preparation and a pharmaceutical composition of the compounds, and application of the compounds and the pharmaceutical composition in preparation of drugs used as GPR40 receptor agonists for prevention and/or treatment of diabetes.

Description

Aromatic polycyclic carboxylic acid derivatives

1. Field of the invention

The invention belongs to the technical field of medicines, and particularly relates to an aromatic polycyclic carboxylic acid derivative GPR40 receptor agonist, pharmaceutically acceptable salts, esters and stereoisomers thereof, a preparation method, a pharmaceutical preparation and a pharmaceutical composition of the compounds, and application of the compounds serving as GPR40 receptor agonist in preparation of medicines for preventing and/or treating diabetes.

2. Background of the invention

Recent studies have shown that GPR40 receptor agonists are a new drug for the treatment of type II diabetes, with an improved glycemic control effect similar to that of glimepiride, but with a significantly lower risk of causing hypoglycemia.

Type II diabetes is the most common type of diabetes. Currently, about 1.5 million people in the united states suffer from diabetes, 90% of which are type II diabetes. The degree of harm to the general health of human populations has been at position 3 of chronic non-infectious diseases. With the rapid development of economy and improvement of material life of people in China, China has become one of the countries with the highest number of patients with diabetes. Diabetes and complications thereof become a major public health problem in the world of the 21 st century, and according to the results of national diabetes epidemiological investigation in 2007-2008, in Chinese people with the age of more than or equal to 20 years, the prevalence rates of diabetes and pre-diabetes are 9.7% and 15.5%, respectively, so that it is estimated that about 9240 ten thousand adults in China currently suffer from diabetes, which is 4 times that in 2003.

The disease is mainly caused by the reduction of the body's response to insulin, resulting in the rise of blood sugar and various chronic diseases. Only about 1/2 in type II diabetics can control blood glucose at a desirable level.

Free fatty acid receptor 1(FFAR1), otherwise known as G protein-coupled receptor 40(GRP40), plays a key role in stimulating and regulating insulin production. The mechanism by which Free Fatty Acids (FFA) cause an increase in intracellular calcium ion concentration via GPR 40: the increase of the glucose concentration accelerates the metabolism of glucose in cells, causes the ATP/ADP level in cytosol to rise, closes ATP-dependent potassium ion channels, causes the depolarization of cell membranes, and activates the opening of L-type calcium ion channels. FFA then stimulates a seven-transmembrane receptor GPR40 on a cell membrane, and the information of circulating phosphatidylinositol is transferred to a path, thereby stimulating calcium ions to be released on an endoplasmic reticulum, further opening an L-type calcium ion channel, causing the calcium ions to flow in the outside of the cell, greatly increasing the calcium ion concentration in the cell, and further leading to the insulin secretion. When postprandial blood glucose and fatty acids rise, FFAR1 lowers blood glucose levels by stimulating the release of insulin from the beta cells of the islets of langerhans. The drug, which is capable of activating FFAR1, effectively controls blood glucose levels by helping the diabetic release more insulin.

GPR40 receptor agonists, which are novel oral drugs that enhance insulin secretion in a glucose-dependent manner, act by stimulating insulin secretion from the beta cells of the islets of langerhans, but only when most needed by the patient, e.g. when glucose and fatty acids rise in the blood after meals, i.e. when blood glucose levels are normal, do not have any effect on insulin secretion. Therefore, GPR40 receptor agonists are both effective in controlling elevated blood glucose and minimizing the risk of hypoglycemia.

Given the frequent hypoglycemia associated with many medications (e.g., glimepiride, etc.) treatment, GPR40 receptor agonist treatment is less at risk of hypoglycemia. This indicates that there is a clear advantage in targeting FFAR1 for the treatment of type II diabetes.

The safety and efficacy of long-term clinical trials will also demonstrate that GPR40 receptor agonists may play a part in drug therapy in type II diabetes.

By using GPR40 receptor agonists, diabetes with the same pathogenesis can be effectively treated, and to date, there are no new drugs formally marketed that target GPR 40. WO2008001931 (published japanese 2008.01.03) discloses the TAK-875 racemate, a drug developed by Takeda in phase III of clinical trials, for the treatment of diabetes, with a definite therapeutic effect. Therefore, the research and development of the GPR40 agonist with stronger pharmacological activity, higher safety and better selectivity has very important significance for treating the type II diabetes mellitus, and has huge market.

Because GPR40 receptor agonist compounds participate in various physiological processes in human bodies, the GPR40 receptor agonist compounds can also be closely related to other various diseases. Therefore, the study of potent and low-toxicity agonists of GPR40 is of great interest for the treatment of diabetes, particularly type II diabetes, and related indications such as obesity, glucose intolerance, insulin resistance, metabolic syndrome X, hyperlipidemia, hypercholesterolemia, atherosclerosis, Alzheimer's disease, parkinson's disease, stroke, and certain cancers (e.g., breast cancer).

3. Summary of the invention

The invention aims to solve the technical problem of providing an aromatic polycyclic carboxylic acid derivative GPR40 receptor agonist for preparing medicaments for preventing and/or treating diabetes and the like.

The technical scheme of the invention is as follows:

a compound of formula (I), pharmaceutically acceptable salts, esters and stereoisomers thereof:

wherein R is₁、R₂、R₃、R₄Each independently selected from hydrogen atom, halogen atom, hydroxyl, amino, cyano, C_1-6Alkyl or C optionally substituted by substituents_3-8Cycloalkyl, said substituents being selected from halogen atoms, hydroxy, amino, cyano, haloC_1-6Alkyl radical, C_1-6Alkylcarbonyl or C_1-6An alkylsulfonyl group;

R₅is a hydrogen atom, C_2-6Alkenyl radical, C_2-6Alkynyl, or C optionally substituted by substituents_1-6Alkyl radical, C_3-8Cycloalkyl, 3-14 membered heterocyclyl, 6-14 membered aryl or 5-14 membered heteroaryl, said substituents being selected from the group consisting of halogen atom, hydroxy, amino, cyano, C_1-6Alkyl radical, C_3-8Cycloalkyl, optionally substituted by C_1-6Alkyl-substituted 3-14 membered heterocyclyl or-NHS (O)_mR₆；

m is 0, 1 or 2;

R₆is a hydrogen atom, C optionally substituted by substituents_1-6Alkyl, amino or 3-14 membered cycloalkyl, said substituents being selected from C_1-6Alkyl, halogen atom, hydroxy, amino or halogeno C_1-6An alkyl group.

wherein R is₁、R₂、R₃、R₄Each independently selected from hydrogen atom, fluorine atom, chlorine atom, hydroxyl group, amino group, cyano group, C_1-4Alkyl or C optionally substituted by substituents_3-6Cycloalkyl, said substituents being selected from fluorine, chlorine, hydroxyl, amino, cyano, halogeno C_1-4Alkyl radical, C_1-4Alkylcarbonyl or C_1-4An alkylsulfonyl group;

R₅is a hydrogen atom, or C optionally substituted by a substituent_1-4Alkyl radical, C_3-6Cycloalkyl group, 3-8 membered heterocyclic group, 6-8 membered aryl group or 5-8 membered heteroaryl group, said substituent being selected from the group consisting of fluorine atom, chlorine atom, methyl group, ethyl group, hydroxyl group, amino group, cyano group, C_1-4Alkyl radical, C_3-6Cycloalkyl, optionally substituted by C_1-4Alkyl-substituted 3-8 membered heterocyclyl or-NHS (O)_mR₆；

m is 0, 1 or 2;

R₆is a hydrogen atom, C optionally substituted by substituents_1-4Alkyl, amino or 3-6 memberedCycloalkyl, said substituents being selected from C_1-4Alkyl, fluorine, chlorine, hydroxy, amino or halogeno C_1-4An alkyl group.

The compound shown in the general formula (I), the pharmaceutically acceptable salt, ester and stereoisomer thereof have the following structure shown in the general formula (II):

m is 0, 1 or 2;

The preferable technical scheme of the compound shown in the general formula (I) and the pharmaceutically acceptable salt, ester and stereoisomer thereof is as follows:

wherein R is₁、R₂Is a hydrogen atom, C_1-4Alkyl or cyclopropyl, cyclopentyl or cyclohexyl optionally substituted by a substituent selected from the group consisting of a fluorine atom, a chlorine atom, a hydroxyl group, an amino group, a cyano group, a halogenated C group_1-4Alkyl radical, C_1-4Alkylcarbonyl or C_1-4An alkylsulfonyl group;

R₃、R₄each independently selected from a hydrogen atom, a fluorine atom, a chlorine atom, a methyl group, an ethyl group, a propyl group or an isopropyl group;

R₅is methyl, ethyl, propyl, isobutyl, cyclopropyl, cyclopentyl, cyclohexyl, aziridinyl, azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, morpholinyl, oxiranyl, dioxalanyl, thienylalkyl, oxetanyl, tetrahydrofuranyl, tetrahydrothienyl, 1, 3-dioxalanyl, tetrahydropyranyl, 1, 4-dioxanyl, tetrahydrothiazolyl, dihydropyrrolyl, 4, 5-dihydroimidazolyl, 4, 5-dihydropyrazolyl, 1,2, 3-triazolyl, 1,2, 4-triazolyl, 2H-pyran-2-one or 2H-1, 3-oxazine, optionally substituted by a substituent selected from amino, cyano, methyl, ethyl, oxazine, and pharmaceutically acceptable salts thereof, Pyrrolidinyl, piperidinyl, oxiranyl, tetrahydrofuranyl, tetrahydrothienyl, 1, 3-dioxolanyl, tetrahydropyranyl, 1-dioxoisothiazolidinyl, 1-dioxo-1, 2, 5-thiadiazolidinyl, methyl-substituted 1, 1-dioxo-1, 2, 5-thiadiazolidinyl, 1, 1-dioxo-1, 2-thiazinoalkyl, 1-dioxo-1, 2, 6-thiadiazinylalkyl, methyl-substituted 1, 1-dioxo-1, 2, 6-thiadiazinylalkyl, tetrahydrooxazolyl, morpholinyl, 1, 2-dioxacyclobutanealkyl, thietane, 1,2, 4-triazolyl, 2-pyridonyl or-NHS (O)._mR₆；

m is 1 or 2;

R₆is methyl, ethyl, propyl, isopropyl, amino, cyclopropyl, cyclopentyl or cyclohexyl optionally substituted by a substituent selected from the group consisting of methyl, ethyl, fluorine atom, chlorine atom, hydroxyl, amino or halogenated C_1-4An alkyl group.

wherein R is₁、R₂Is a hydrogen atom, a methyl group, an ethyl group, or a cyclopropyl group optionally substituted with a substituent selected from a fluorine atom, a chlorine atom, a hydroxyl group, an amino group, a cyano group, a trifluoromethyl group, a formyl group, an acetyl group or a methanesulfonyl group;

R₃、R₄each independently selected from a hydrogen atom, a fluorine atom, a chlorine atom, a methyl group or an ethyl group;

R₅is pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl, tetrahydrothienyl, 1, 3-dioxolanyl or tetrahydropyranyl, optionally substituted with a substituent selected from amino, cyano, methyl or ethyl.

R₅is methyl, ethyl or propyl optionally substituted with a substituent selected from-NHS (O)_mR₆；

m is 2;

R₆is methyl, ethyl, propyl or butyl.

R₅is methyl, ethyl or propyl optionally substituted with a substituent selected from 1, 1-dioxoisothiazolidinyl, 1-dioxo-1, 2, 5-thiadiazolidinyl, methyl-substituted 1, 1-dioxo-1, 2, 5-thiadiazolidinyl, 1-dioxo-1, 2-thiazinanyl, 1-dioxo-1, 2, 6-thiadiazinylalkyl, methyl-substituted 1, 1-dioxo-1, 2, 6-thiadiazinylalkyl, tetrahydrooxazolyl, morpholinyl, 1, 2-dioxacyclobutane, thietanyl, 1,2, 4-triazolyl or 2-pyridonyl.

Particularly preferred compounds include:

the term "halo" as used herein means substituted with a "halogen atom" which means a fluorine atom, chlorine atom, bromine atom, iodine atom or the like.

Said "C" of the present invention_1-6Alkyl "denotes straight-chain or branched alkyl having 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, n-hexyl, isohexyl, 3-methylpentyl, 2-methylpentyl, methyl-ethyl, ethyl-propyl, isopropyl, isobutyl-butyl, tert-butyl, pentyl-, isopentyl-, 2-methylbutyl-, neopentyl-pentyl-, 1,1-methylpentyl, 3-dimethylbutyl, 2-dimethylbutyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 1, 2-dimethylpropyl, etc. "C" according to the invention_1-4The alkyl group "means a specific example containing 1 to 4 carbon atoms among the above examples.

The "halo C" of the present invention_1-6Alkyl "means one or more" halogen atoms "substituted" C_1-6A group derived from one or more hydrogen atoms on an alkyl group, said "halogen atom" and "C_1-6Alkyl "is as defined above. The "halo C" of the present invention_1-4The alkyl group "means a specific example containing 1 to 4 carbon atoms among the above examples.

"C" according to the invention_2-6Alkenyl "means a straight-chain or branched or cyclic alkenyl group having 2 to 6 carbon atoms and containing at least one double bond, such as vinyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 1, 3-butadiene, 1-pentenyl, 2-pentenyl, 3-pentenyl, 1, 3-pentadiene, 1, 4-pentadiene, 1-hexenyl, 2-hexenyl, 3-hexenyl, 1, 4-hexadiene, C_4-6Cycloalkenyl includes cyclopentenyl, 1, 3-cyclopentadienyl, cyclohexenyl, 1, 4-cyclohexadienyl, and the like.

"C" according to the invention_2-6The alkynyl group "means a straight-chain or branched alkynyl group having 2 to 6 carbon atoms and having a triple bond, such as ethynyl, propynyl, 2-butynyl, 2-pentynyl, 3-pentynyl, 4-methyl-2-pentynyl, 2-hexynyl, 3-hexynyl, 5-methyl-2-hexynyl and the like.

"C" according to the invention_1-6Alkylcarbonyl group, C_1-6Alkylsulfonyl "means with C_1-6alkyl-C (O) -, C_1-6alkyl-SO₂A group attached by a formula wherein "C_1-6Alkyl "is as defined above. "C" according to the invention_1-4Alkylcarbonyl group, C_1-4Alkylsulfonyl "means a specific example containing 1 to 4 carbon atoms among the above examples.

The invention isThe above-mentioned "C_3-8Cycloalkyl "means a saturated cyclic alkyl group containing from 3 to 8 carbon atoms, preferably C_3-6Cycloalkyl groups, specific examples include, but are not limited to: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 1-methylcyclopropyl, 1-pentylcyclopropyl, 1, 2-diethylcyclobutyl, 1-methylcyclobutyl, 1-butylcyclobutyl, 1, 3-dimethylcyclobutyl, 1-methylcyclopentyl, 1-butylcyclopentyl, 1-methylcyclohexyl, 1-ethylcyclopentyl, etc.

The term "3-to 14-membered heterocyclic group" as used herein means a cyclic group having 3 to 14 ring atoms (wherein at least one hetero atom is contained) such as nitrogen, oxygen and sulfur, and the like, and includes a 3-to 8-membered heterocyclic group and a 6-to 14-membered fused heterocyclic group, wherein the carbon atom, nitrogen atom and sulfur atom may be oxidized.

The 3-to 8-membered heterocyclic group means a cyclic group having 3 to 8 ring atoms (wherein at least one hetero atom is contained), and specific examples include, but are not limited to, aziridinyl, diazirinyl, azetidinyl, 1, 2-diazetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, oxiranyl, dioxazinyl, thietanyl, oxetanyl, 1, 2-dioxanyl, thietanyl, tetrahydrofuranyl, tetrahydrothienyl, 1, 3-dioxolanyl, 1, 3-dithiolanyl, tetrahydropyranyl, 1, 4-dioxanyl, 1, 3-oxathianyl, oxaziridinyl, tetrahydrooxazolyl, oxazolyl, etc, Tetrahydroisoxazolyl, tetrahydrothiazolyl, 1-dioxoisothiazolinyl, morpholinyl, 2H-aziridinyl, 3H-diazacyclopropenyl, azetidinadienyl, 1, 2-diazacyclobutenyl, dihydropyrrolyl, 4, 5-dihydroimidazolyl, 4, 5-dihydropyrazolyl, 1,2, 3-triazolyl, 1,2, 4-triazolyl, 2-pyridonyl, 4-pyridonyl, 1, 2-diazacycloheptyltrienyl, 1, 3-diazacycloheptyltrienyl, 1, 4-dihydro-1, 4-diazacyclooctrienyl, 1, 2-dithiocyclobutenyl, 2, 5-dihydrothienyl, 1, 2-dithiocyclopentenyl, 2H-aziridinylpropenyl, 3H-diazacyclopropenyl, 3H-diazacyclo-pyrrolyl, 1,2, 4-diazacycloheptyltrienyl, 1, 2-dithio, 1, 3-dithiocyclopentenyl, 2H-pyranyl, 2H-pyran-2-onyl, 3, 4-dihydro-2H-pyranyl, 4H-pyran-4-onyl, 4, 5-dihydrooxazolyl, 4, 5-dihydroisoxazolyl, 2, 3-dihydroisoxazolyl, 4, 5-dihydrothiazolyl, 2H-1, 2-oxazinyl, 4H-1, 2-oxazinyl, 6H-1, 2-oxazinyl, 2H-1, 3-oxazinyl, 4H-1, 3-oxazinyl, 6H-1, 3-oxazinyl, 2H-1, 4-oxazinyl, 4H-1, 4-oxazinyl, 5, 6-dihydro-4H-1, 3-oxazinyl, 2H-1, 3-thiazinyl, 4H-1, 3-thiazinyl, 6H-1, 3-thiazinyl, 2H-1, 4-thiazinyl, 4H-1, 4-thiazinyl, 5, 6-dihydro-4H-1, 3-thiazinyl, and the like.

The 6-to 14-membered fused heterocyclic group means a fused ring structure having 6 to 14 ring atoms (wherein at least one hetero atom is contained) and formed by two or more ring structures sharing two adjacent atoms with each other, and includes carbon atoms, nitrogen atoms and sulfur atoms which may be oxo, and specific examples include, but are not limited to, octahydro-benzo [ d ] imidazole, decahydroquinolyl, octahydrobenzothiophene, octahydrobenzofuran, hexahydrothienoimidazole, hexahydrofuroimidazole, 4H-1, 3-benzoxazine, 4, 6-dihydro-1H-furo [3,4-d ] imidazole, 4, 6-dihydro-1H-thieno [3,4-d ] imidazole, 4, 6-dihydro-1H-pyrrolo [3,4-d ] imidazole, 4,5,6, 7-tetrahydro-1H-benzo [ d ] imidazole, and the like.

The "5-14 membered heteroaryl" of the present invention means an unsaturated aromatic group having 5-14 ring atoms (wherein at least one heteroatom is contained), and includes 5-8 membered heteroaryl, 6-14 membered fused heteroaryl, wherein the heteroatom has nitrogen, oxygen, sulfur, etc., and includes carbon atom, nitrogen atom and sulfur atom which may be oxidized.

The 5-to 8-membered heteroaryl group means a cyclic group having an aromatic ring containing 5 to 8 ring atoms (at least one hetero atom therein), and specific examples include, but are not limited to, furyl, thienyl, pyrrolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, imidazolyl, pyrazolyl, 1,2, 3-triazolyl, 1,2, 4-triazolyl, 1,2, 3-oxadiazolyl, 1,2, 4-oxadiazolyl, 1,2, 5-oxadiazolyl, 1,3, 4-oxadiazolyl, pyridyl, pyrimidinyl, 1, 4-dioxadienyl, 2H-1, 2-oxazinyl, 4H-1, 2-oxazinyl, 6H-1, 2-oxazinyl, 4H-1, 3-oxazinyl, and the like, 6H-1, 3-oxazinyl, 4H-1, 4-oxazinyl, pyridazinyl, pyrazinyl, 1,2, 3-triazinyl, 1,2, 4-triazinyl, 1,3, 5-triazinyl, 1,3, 4-triazinyl, 1,2,4, 5-tetrazinyl, oxepinyl, thiepinyl, azepinyl, 1, 3-diazepinyl, and azepinyl.

The 6-to 14-membered fused heteroaryl group means an unsaturated aromatic fused ring structure having 6 to 14 ring atoms (wherein at least one heteroatom is contained) formed by two or more ring structures sharing two adjacent atoms to each other, and specific examples include, but are not limited to: benzofuranyl, benzoisotropfuranyl, benzothienyl, indolyl, benzoxazolyl, benzimidazolyl, indazolyl, benzotriazolyl, quinolyl, isoquinolyl, acridinyl, phenanthridinyl, pyridazinyl, phthalazinyl, quinazolinyl, quinoxalinyl, phenazinyl, pteridinyl, purinyl, naphthyridinyl, and the like.

The "6-14 membered aryl" as referred to herein means an unsaturated aromatic group having 6 to 14 carbon atoms, and includes 6-8 membered aryl and 8-14 membered condensed ring aryl. The 6-to 8-membered aryl group means a monocyclic aryl group having 6 to 8 carbon atoms, such as phenyl, cyclooctatetraenyl and the like. The 8-14 membered fused ring aryl group means an unsaturated aromatic fused ring group having 8 to 14 ring carbon atoms, formed by two or more ring structures sharing two adjacent carbon atoms with each other, and specific examples include, but are not limited to: naphthalene, anthracene, phenanthrene, and the like. The "6-to 8-membered aryl" means a cyclic structure having 6 to 8 ring atoms in the above examples.

The invention claims "pharmaceutically acceptable salts" of the compounds of formula (I) including alkali metal salts, alkaline earth metal salts, inorganic base salts, organic base salts, inorganic acid salts, organic acid salts, amino acid salts, and the like.

The "ester" of the compound represented by the general formula (I) of the present invention means an ester which can be formed by esterification with an alcohol when a carboxyl group is present in the compound represented by the formula (I), and an ester which can be formed by esterification with an organic acid, an inorganic acid, an organic acid salt or the like when a hydroxyl group is present in the compound represented by the formula (I). The ester can be hydrolyzed in the presence of acid or alkali to generate corresponding acid or alcohol.

Examples of the compound represented by the general formula (I), a pharmaceutically acceptable salt thereof, an ester thereof, or a solvate of a stereoisomer thereof include, but are not limited to, a hydrate.

The "stereoisomers" of the compounds of the general formula (I) of the present invention are classified into conformational isomers and configurational isomers, and configurational isomers are also classified into cis-trans isomers and optical isomers. "stereoisomers" refers to compounds of the invention when they contain one or more asymmetric centers, each of which independently produces two optical isomers, and the scope of the invention includes all possible optical isomers and diastereomeric mixtures and pure or partially pure compounds. The compounds of the present invention, if they contain an olefinic double bond, include both cis-and trans-isomers, unless otherwise specified. The compounds of the present invention may exist in tautomeric forms having different points of attachment of hydrogen through one or more double bond shifts. For example, a ketone and its enol form are keto-enol tautomers. Each tautomer and mixtures thereof are included in the compounds of the invention.

The compound of the present invention may be used in combination with one or more other drugs, which may be a drug for treating diabetes, a drug for treating diabetic complications, a drug for treating hyperlipidemia, an antihypertensive drug, an anti-obesity drug, a diuretic, a chemotherapeutic drug, an immunotherapeutic drug, an anti-inflammatory drug, an antithrombotic drug, a therapeutic drug for osteoporosis, celluloses, an anti-dementia drug, a therapeutic drug for pollakiuria or urinary incontinence, a therapeutic drug for dysuria, or the like.

The compound shown in the formula (I), the pharmaceutically acceptable salt, the ester or the stereoisomer thereof can be combined with two or more than two pharmaceutical active ingredients or one or more than two pharmaceutical carriers to form a pharmaceutical composition. The pharmaceutical composition can be prepared into a conventional pharmaceutical preparation used clinically, and can be used for patients needing the treatment in an oral or parenteral mode. Such as tablet, granule, capsule, powder, injection, inhalant, sublingual preparation, syrup, gel, ointment, suppository, lotion, nasal drop, spray, transdermal preparation, etc. These preparations can be prepared by conventional methods by adding pharmaceutically acceptable carriers such as excipient, binder, moisturizer, disintegrator, thickener, etc. Such as lactose, sucrose, D-mannitol, starch, corn starch, crystalline cellulose, light silica, and the like.

The compounds represented by the general formula (I), pharmaceutically acceptable salts, esters and stereoisomers thereof can be administered to mammals, such as humans, by oral, parenteral (intravenous, intramuscular, subcutaneous or rectal), pulmonary, topical, etc. administration. The amount of the compound of the present invention in the pharmaceutical formulation is from 0.01 to about 100% by weight relative to the actual formulation. The dose varies depending on the administration subject, administration route, disease, disorder and the like, and for example, the compound of the present invention (as an active ingredient) can be orally administered to a diabetic patient (body weight: about 60kg) in the following doses: about 0.01 to 30mg/kg body weight per day, preferably about 0.1 to 20mg/kg body weight per day, more preferably about 1 to 20mg/kg body weight per day. The dose may be administered once a day or divided into several administrations.

The compound represented by the formula (I), a pharmaceutically acceptable salt thereof, an ester thereof or a stereoisomer thereof shows an excellent GPR40 receptor function modulating effect in mammals (including humans), and is useful as a modulator relating to the physiological function of the GPR40 receptor, or as a preventive and/or therapeutic agent for preventing and/or treating the pathology or disease of the GPR40 receptor.

Specifically, the compound represented by the formula (I), a pharmaceutically acceptable salt thereof, an ester thereof or a stereoisomer thereof is useful as an insulin secretion regulator (preferably an insulin secretagogue), a hypoglycemic agent and a pancreatic beta cell protective agent.

In particular, the present invention provides a compound represented by the formula (i), a pharmaceutically acceptable salt thereof, an ester thereof or a stereoisomer thereof, which is useful as an insulin secretagogue depending on blood glucose levels, based on the GPR40 receptor agonist activity thereof. This is different from sulfonylureas, and the compound represented by the formula (I), a pharmaceutically acceptable salt thereof, an ester thereof or a stereoisomer thereof of the present invention is useful as an insulin secretagogue which does not cause hypoglycemia.

The compound represented by the formula (I), a pharmaceutically acceptable salt thereof, an ester thereof or a stereoisomer thereof can be used as a medicament for preventing and/or treating diabetes and related diseases, wherein the related diseases comprise impaired glucose tolerance, ketosis, acidosis, diabetic complications (such as diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, macroangiopathy and diabetic gangrene), macular edema, hyperlipidemia, obesity, hypoglycemia, hypertension, edema, insulin resistance, unstable diabetes mellitus, lipoatrophy insulin allergy, insulinoma, lipotoxicity, hyperinsulinemia, metabolic syndrome, immunological diseases, inflammatory diseases, multiple sclerosis, acute renal failure and the like. In addition, diabetes includes type I diabetes, type II diabetes, gestational diabetes, and obese diabetes. Hyperlipidemia includes hypertriglyceridemia, hypercholesterolemia, hypo-high density lipoproteinemia, postprandial hyperlipidemia, etc.

The compound of formula (i), its pharmaceutically acceptable salt, its ester or its stereoisomer of the present invention can be used as a medicament for the prevention and/or treatment of Diabetes, borderline type, Impaired Glucose tolerance, IFG (Impaired Fasting Glucose), and IFG (Impaired Fasting hyperglycaemia) according to the new diagnostic criteria reported by ADA (American Diabetes Association), WHO and the japan Diabetes Association. In addition, the present invention provides a compound of formula (i), a pharmaceutically acceptable salt thereof, an ester thereof or a stereoisomer thereof, which can prevent the development of borderline type, Impaired Glucose tolerance, IFG (Impaired Fasting Glucose) and IFG (Impaired Fasting hyperglycemia) into diabetes.

The advantageous effects of the compounds of the present invention are further illustrated below by experiments, but this should not be understood as the compounds of the present invention have only the following advantageous effects.

EXAMPLE 1 calcium flux assay of GPR40 transfected cell line with the Compounds of the invention

Purpose of the experiment: the efficacy of the compounds of the invention and LA (linoleic acid) in the activation of hGPR40 was evaluated using a HEK293 cell line stably expressing human hGPR40 to detect calcium flux signals induced by the compounds of the invention using a FLIPR instrument.

And (3) testing the sample: some of the compounds of the invention, prepared according to the methods of the examples of the invention;

comparison products: control LA (linoleic acid); the control TAK-875, whose formula is as described above, was prepared according to the method of patent WO2008001931 (published as 2008.01.03).

Experimental reagent:

the experimental steps are as follows:

(1) cell culture

The day before calcium flux assay, low passage numbers of hGPR40 cells were plated at 8000 cells/well and 50. mu.L/well in 384-well assay plates. At 37 ℃ 5% CO₂The culture was carried out overnight in an incubator.

(2) Gradient dilution of compound

Preparing a dilution buffer solution:

buffer 1: 25mL of HBSS (containing 20mM HEPES) + 250. mu.L of 10% BSA, 0.1% BSA buffer was prepared

Buffer 2: 19.7mL Buffer1+0.3mL DMSO, 1.5% DMSO Buffer was prepared.

Compound dilution:

1) a proper amount of a test sample and a control TAK-875 racemate (3.01mg) are accurately weighed and dissolved in DMSO to prepare a sample with the concentration of 10 mM.

2) Test and control TAK-875 racemates at 10mM were diluted to 3mM with DMSO.

3) Transferring 2.5. mu.L of a sample with a concentration of 3mM, adding 148. mu.L of buffer solution for dilution to prepare a mother solution, transferring 40. mu.L of the mother solution, adding 80. mu.L of buffer solution 2, sequentially diluting according to a gradient of 1:3, and obtaining 10 concentration points with a maximum concentration of 50. mu.M. Dilutions were first performed in 96-well plates and subsequently transferred to 384-well plates, duplicate wells.

4)10 u L LA and 22 u L DMSO make concentration 1mol/L solution, 10 u L solution is added 20 u L DMSO and diluted to 300mM solution, 1 u L300Mm LA/DMSO solution is added 100u L DMSO and diluted to 3mM solution, 2.5 u L3mM LA/DMSO solution, added 148 u L buffer solution 1 solution, made the mother liquor, transfer 40 u L mother liquor, added 80 u L buffer solution 2, in order according to 1:3 gradient dilution, total 10 concentration points, the highest concentration of 50 u M. Dilutions were first performed in 96-well plates and subsequently transferred to 384-well plates, duplicate wells.

(3) FLIPR calcium flux detection

Preparation of calcium dye: 10mL of HBSS (20mM HEPES) +1tube calcium dye + 100. mu.L 10% BSA.

Loading of calcium dye into cells:

1) the 384 well plates plated with cells were removed from the incubator and the medium was discarded.

2) Calcium dye was added to 384-well plates at 40. mu.L/well.

3) The 384 well plates were returned to the incubator and incubated for 1 h.

FLIPR detection:

1) the 384 well plates plated with cells and the 384 well plates with compounds were placed in the corresponding positions in the cabinet above the FLIPR.

2) The FLIPR protocol was set such that the compound was added to the cells in 10. mu.L volumes per well, giving a maximum final concentration of 10. mu.M compound and a final concentration of 0.3% DMSO.

High control: 10 μ M TAK-875 control.

Low control: control without compound.

3) And operating the instrument to obtain a calcium flow detection curve.

Data processing and results

The raw data were fitted with XLFit to give the EC for each compound and control₅₀And efficacy value. Wherein EC₅₀Values are given by fitting curves, efficacy = maximum/(High control-Lowcontrol) × 100% obtained by compound fitting, results are shown in tables 1-4.

EC₅₀The value: half maximal effect concentration, i.e. the concentration that causes 50% of the maximal effect.

TABLE 1 calcium flux assay results for Compound 1 of the present invention

TABLE 2 calcium flux assay results for Compound 3 of the present invention

TABLE 3 calcium flux assay results for Compound 6 of the present invention

TABLE 4 calcium flux assay results for compounds 9 and 12 of the present invention

LA is one of the natural ligands of GPR40, EC acting in vitro₅₀At higher concentrations, the compounds of the invention act on GPR40, compete with LA after entering into the body, and show the binding capacity of the compounds with GPR40 by comparing with the relative activity value of LA. Relative activity value>80, full agonist, relative activity value<80, is a partial agonist.

And (4) experimental conclusion: as is clear from the data in tables 1,2,3 and 4, the compounds EC according to the invention₅₀The value is equivalent to TAK-875, and the compound is a complete agonist, which shows that the compound has obvious effect on GPR 40.

Experimental example 2 detection of GTPgS binding ability of the Compounds of the present invention on GPR40 transfected cell line

And (3) testing the sample: some of the compounds of the invention, each prepared according to the methods of the examples of the invention;

comparison products: the control TAK-875, whose formula is as described above, was prepared according to the method of patent WO2008001931 (published as 2008.01.03).

Experimental reagent:

the experimental steps are as follows:

(1) extraction of cell membranes

1. 100 dishes of cells were collected and digested with PBS-EDTA.

2. The cells were resuspended in 5-fold TE (Tris-EDTA) solution. 1000g, centrifugation at 4 ℃ for 10min, supernatant 26000g, 4 DEG C

Centrifuge for 30 min.

3. The supernatant was discarded, resuspended in 5-fold TE, 26000g, and centrifuged at 4 ℃ for 30 min.

4. The supernatant was discarded, resuspended and diluted to 30mL with 5-fold TE.

5. Protein concentrations were determined by Bradford method and diluted to 1mg/mL and dispensed into l-2mL centrifuge tubes for storage at-80 ℃.

(2) Dilution of Compounds

Compounds were diluted in DMSO in 5-fold gradients to compound stocks.

(3) Cell membrane dilution (1mg/mL to 0.035mg/mL)

1. Preparing a detection solution: 23mL of buffer (50mM Hepes, 160mM NaCl, 10mM MgCl2, 1mM EDTA) + 230. mu.L 10% BSA (without free fatty acids) + 4.6. mu.L saponin (50mg/mL) + 11.5. mu.L GDP (5mM)) was placed in ice water.

2. 0.8mL of the cell membrane solution with a concentration of 1mg/mL was added to 23mL of the detection solution and diluted to a concentration of 0.035 mg/mL.

3. To the above 2.0 cell membrane solution was added 23. mu.L of 100nM³⁵S-GTPgS, final concentration 0.1 nM.

(4) Binding reaction

1. Two Corning96 hole U plates (catalog #3605) were taken and labeled recovery plate1and recovery plate2.

2. Taking 1. mu.L of the compound mother liquor diluted in gradient to corresponding wells of the reaction plate1and 2 (final concentrations of the compounds are 10, 2, 0.4, 0.08, 0.016, 0.003, 0.0006, 0.0001, 0.00003 and 0.000001. mu.M, respectively)

3. Add 1. mu.L 10mM Unlabeled GTPgS to the corresponding wells of the action plate1and the action plate2.

4. 99. mu.L of a 3.3 cell membrane dilution (0.035mg/mL membrane, 0.1nM membrane) was added³⁵S-GTPgS) into corresponding holes of the interaction plate1and the interaction plate2.

5. The reaction plate was sealed with topseal.

6.1000 spin for 1 min, shake for 2 min.

The reaction was carried out at 7.4 ℃ for 1.5h and at room temperature for 1 h.

(5) Termination of the reaction

The Cell membranes were collected by Cell Harvester (Perkin Elmer) using GF/B plates, which were then washed 10 times with buffer and dried by an electric blower (10 min).

(6) Detection of

1. The plate was bottom-sealed and 50. mu.L/well of Microscint40 scanning fluid solution was added and incubated for 2 h.

2. Plates were placed on a TopCount-NXT reading.

Data processing:

IC₅₀fitting with XLFit, Y = (A + ((B-A)/(1+ ((C/X) ^ D)))), Y is the reading of the isotope (cpm), X is the logarithmic value of the compound concentration, A is the lowest value of the curve, B is the highest value of the curve, and C is the IC₅₀The value, D, is hillslope.

Data processing and results:

TABLE 5 binding ability assay results of Compound 6 of the present invention

And (4) conclusion:

binding potency of the compounds of the invention to human GPR40 the assay indicated that Compound 6 binds comparably to the control compound TAK-875.

Experimental example 3 in vivo pharmacokinetic determination of the Compound of the invention

1. Design of experiments

2. Test article

Some of the compounds of the invention, prepared according to the methods of the examples of the invention;

dissolution scheme: dissolving the compound 3 in 10% DMF, 20% PEG400 and 70% sterile water for injection;

compound 6IV dissolved PO in 3% DMSO +25% (40% HP- β -CD) +72% sterile water for injection 2% HPC +0.1% Tween 80.

Preparing concentration: compound 3: 0.5mg/mL (IV: solution; PO: solution)

Compound 6:0.5mg/mL (IV: solution; PO: suspension)

Reference TAK-875 racemate, of the formula:prepared according to the method of patent WO2008001931 (published as 2008.01.03)

Internal standard: TAK-875, the formula of which is as described above, was prepared according to the method of patent WO2008001931 (published as 2008.01.03), dissolved in ethyl acetate.

3. Device

The instrument equipment comprises: API3000LC-MS/MS

A chromatographic column: waters Xbridge^TMC18(2.10×50mm,5μm)

4. Blood collection

Collecting rat blood: fixing animal, heating tail part 10min before each time point with water bath, collecting whole blood about 100 μ L via tail vein, collecting blood, and placing into a container containing EDTA-K₂In an anticoagulation tube. The blood samples were centrifuged at 8000rpm at 4 ℃ for 6min to obtain plasma samples, which had to be prepared within 30min after blood collection. Plasma was stored in a-80 ℃ freezer prior to testing.

5. Experimental methods

(1) Taking out the sample to be tested from the refrigerator, naturally melting at room temperature (-80 ℃), and vortexing for 5 min;

(2) precisely transferring 20 mu L of sample into a 1.5mL centrifuge tube;

(3) adding 600 μ L of internal standard solution;

(4) after vortexing at 1500 rpm for 10min, centrifuging for 5min (12000 rpm);

(5) precisely transferring 400. mu.L of the supernatant to a 96-well plate, N₂Blow-dry, add 200 μ L of reconstituted solution (acetonitrile: water =7:3), vortex and mix well, and analyze by LC-MS/MS.

6. Data processing method

The test substance (plasma sample) concentration was outputted using analyst1.5.1 from AB. Microsoft Excel calculates parameters such as mean value, standard deviation, coefficient of variation and the like (analyst1.5.1 is directly output without calculation), and PK parameters are calculated by adopting Pharsight Phoenix6.2 software. Calculating the formula: f% = AUCinf_-po*Dose_iv/AUCinf_-iv*Dose_po。

Table 6 rat PK assessment results for test compounds following intravenous bolus dosing of compounds

Table 7 rat PK assessment results for test compounds following gavage administration of compounds

Table 8 rat PK assessment results for test compounds following intravenous bolus dosing of compounds

TABLE 9 rat PK evaluation results of test compounds after gastric gavage

Wherein, T_1/2Represents the half-life; AUC_lastArea under curve when representing drug_0→t(ii) a CL represents clearance; vss represents apparent volume of distribution; c_maxRepresents the peak blood drug concentration; t is_maxRepresents the peak time of blood drug; f% represents the absolute bioavailability.

7. Conclusion of the experiment

As can be seen from tables 6,7, 8 and 9, the PK parameters of the compounds of the invention, measured by IV and PO in rats, were comparable to the exposure (AUC) of TAK-875 for IV administration, with compound 3 having a volume of distribution (Vss) superior to that of the TAK-875 racemate; the half-life and Clearance (CL) of the compound 3 are equivalent to those of the TAK-875 racemate; peak concentration of PO administration (C)_max) Is equivalent to the exposure (AUC) which is superior to the TAK-875 racemate, can be used for treating diseases such as diabetes and the like, and has good clinical application prospect.

Experimental example 4 Effect of the Compounds of the present invention on cell proliferation of HepG2

comparison products: positive control sorafenib; reference TAK-875 racemate, of the formula:a control TAK-875, the formula of which is as described above, prepared according to the method of patent WO2008001931 (published as 2008.01.03); compound Q has the structure:prepared according to the method in Journal of Medicinal Chemistry (2012),55(8), 3756-.

Cell line:

experimental reagent:

the instrument comprises the following steps:

an enzyme-labeling instrument: EnVision2104Multilable Reader

The experimental steps are as follows:

(1)37℃，5%CO₂HepG2 cells were cultured in L-glutamine-containing MEM medium containing 10% FBS, 100U/mL penicillin, and 100mg/mL streptomycin under conditions to achieve 80% confluency between cells.

(2) Cells were digested with pancreatin, centrifuged at 1000rpm for 4 minutes, resuspended in fresh medium containing 0.5% FBS, and seeded in 96-well plates at adjusted cell concentrations. A total of 2500 cells per well of 90. mu.L, 3 duplicate wells.

(3) Culturing the cells for 24h, preparing 10 times of compound solution, and adding 10 μ L of 10 times of compound solution (total volume 100 μ L) into each well; the final concentration of the compound was 30. mu.M, and the final concentration of sorafenib was 5. mu.M.

a) Solvent comparison: cells added with 0.3% DMSO.

b) Control of the medium: cells without added compound.

c) Blank control: cells were not added for instrument zeroing.

(4)37℃，5%CO₂The cells were treated with the drug for 72h under the conditions。

(5) The plates were then allowed to equilibrate for 30min at room temperature.

(6) Adding 100 μ L of the solution per well

(7) Shaking and mixing for 2min to dissolve the cells.

(8) The plate was equilibrated at room temperature for 10min to stabilize the signal.

(9) The light absorption was measured using an EnVision2104 multifunctional microplate reader.

Calculating the formula:

cell viability = (mean of compound light absorption-mean of blank)/(mean of medium control-blank control)

Average value) 100

TABLE 10 results of experiments on cell proliferation of HepG2 by the compounds of the present invention

TABLE 11 results of experiment on proliferation of HepG2 cells by the compounds of the present invention

And (4) conclusion: in the experiment of the compound on the strength of the cell activity in the experiment of cell proliferation of HepG2, the strength of the compound 1and the compound 3 on the cell activity is superior to that of the TAK-875 racemate, and the compound has equivalent toxic effect on liver cells.

Experimental example 5 intraperitoneal glucose tolerance test of the Compound of the present invention

The experimental method comprises the following steps:

accurately weighing the sample and a 0.5% methyl cellulose solution as a solvent. All were prepared as 3mg/mL solutions.

11g of glucose was dissolved in 100mL of water for injection, and 4 parts were added.

After 1 week of quarantine, male SD rats are fasted without water supply overnight, and after weighing, the SD rats are randomly divided into a normal control group, a solvent control group, a test article group and a control article group according to the weight, wherein the dosages of the SD rats are 30mg/kg, and the SD rats are divided into 6 groups, and each group comprises 5 rats, which is shown in a table 7. After the compound solution or the solvent is orally taken for 1 hour, 1g/kg of glucose solution is injected into the abdominal cavity, the administration volume is 10mL/kg, the tail vein is punctured by a disposable syringe before (-60min), before (0min) and 10, 20, 30, 60 and 120min after the administration of glucose respectively, blood is taken, 3 mu L of blood is taken by a pipette, the blood is dripped on a test paper of a blood glucose determinator, the concentration of blood glucose is determined, and the reading is recorded.

Grouping and dosing

Individual blood glucose values for each animal were plotted in a scatter plot using Excell. Adopting a WinNonLin software NCA model to calculate AUC, calculating the blood glucose inhibition rate according to the delta AUC, using SPSS13.0 software to carry out One-Way ANOVA test, carrying out statistical analysis between groups on the delta AUC, and considering that P <0.05 has significant difference.

Calculating the formula:

blood glucose inhibition rate = (vehicle control group AUC average value-administration group AUC average value)/(vehicle control group AUC average value-normal control group AUC average value) × 100%.

The experimental results are as follows:

TABLE 12 inhibition of blood glucose in rats by compounds

The value of P is compared with that of a solvent control group, and the value of P is less than 0.05, which has statistical significance.

And (4) conclusion: the blood sugar reducing level of the compound 6 is superior to that of TAK-875, and the compound has a remarkable blood sugar reducing effect. The compound 6 has low AUC value and good drug effect, and shows that the compound 6 has obvious effect of reducing blood sugar.

4. Detailed description of the preferred embodiments

The present invention will be described in further detail with reference to the following examples. It should not be understood that the scope of the above-described subject matter of the present invention is limited to the following examples. All the technologies realized based on the above contents of the present invention belong to the scope of the present invention.

The abbreviations used in the present invention have the following meanings:

the THF is tetrahydrofuran, and the THF is tetrahydrofuran,

ADDP is an azodicarbonyl dipiperidine,

the PE is petroleum ether, and the mixture is,

EA is ethyl acetate and the mixture is reacted with ethyl acetate,

the DCM is the methylene chloride, and the DCM is the methylene chloride,

boc is tert-butyloxycarbonyl, and the Boc is tert-butyloxycarbonyl,

TFA is trifluoroacetic acid.

Example preparation of 12- (6- ((2' -cyclopropyl-4 ' - ((tetrahydrofuran-3-yl) oxy) - [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetic acid (Compound 1)

(1) Preparation of methyl 2- (6- ((3-bromobenzyl) oxy) -2, 3-dihydrobenzofuran-3-yl) acetate

Methyl 2- (6-hydroxy-2, 3-dihydrobenzofuran-3-yl) acetate (1.04g, 5.0mmol), 3-bromobenzyl alcohol (935mg, 5.0mmol) and azobisformyldipiperidine (1.89g, 7.5mmol) were dissolved in anhydrous tetrahydrofuran (30mL) and stirred well for 30 minutes. N-butylphosphine (1.51g, 7.5mmol) was dissolved in anhydrous tetrahydrofuran (30mL), added dropwise to the reaction system using a dropping funnel, stirred well for 2 hours, and the reaction solution was directly concentrated under reduced pressure and separated by silica gel column chromatography (eluent petroleum ether/ethyl acetate =15:1) to obtain 1.1g of a product with a yield of 58%.

(2) Preparation of methyl 2- (6- ((3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzyl) oxy) -2, 3-dihydrobenzofuran-3-yl) acetate

Methyl 2- (6- ((3-bromobenzyl) oxy) -2, 3-dihydrobenzofuran-3-yl) acetate (1.1g, 2.92mmol), pinacol diborate (0.89g, 3.5mmol), Pd (dppf)₂Cl₂(110mg) and potassium carbonate (0.60g, 4.38mmol) were added to 1, 4-dioxane (50mL), oil-bathed at 80 ℃ for 6 hours, the solvent was removed by concentration under reduced pressure, and the silica gel column layerThe separation by chromatography (eluent petroleum ether/ethyl acetate =10:1) gave 0.88g of product, 71% yield.

(3) Preparation of tetrahydrofuran-3-yl methanesulfonate

3-Hydroxytetrahydrofuran (4.4g, 50mmol) was dissolved in dichloromethane (50mL) under ice-bath, triethylamine (7.6g, 75mmol) was added and stirred for 10min, methanesulfonyl chloride (6.3g, 55mmol) was slowly added dropwise, after the addition was completed, the mixture was warmed to room temperature and stirred for 1h, washed with saturated aqueous sodium chloride (50mL), and the organic phase was concentrated under reduced pressure to give 8.8g of a crude product.

(4) Preparation of 2-bromo-5- ((tetrahydrofuran-3-yl) oxy) benzaldehyde

Tetrahydrofuran-3-ylmethanesulfonate (8.8g, 53mmol), 2-bromo-5-hydroxybenzaldehyde (5.3g, 26.5mmol) and potassium carbonate (7.4g, 53mmol) were added to acetonitrile (150mL), heated under reflux for 8 hours, concentrated under reduced pressure to remove the solvent, and separated and purified by column chromatography (eluent petroleum ether/ethyl acetate =10:1) to give 3.5g of the product in 49% yield.

(5) Preparation of 3- (4-bromo-3-vinylphenoxy) tetrahydrofuran

Potassium tert-butoxide (2.5g, 22mmol) and methyltriphenylphosphonium bromide (6.0g, 17mmol) were added to tetrahydrofuran (100mL) under ice-bath stirring for 1 hour, 2-bromo-5- ((tetrahydrofuran-3-yl) oxy) benzaldehyde (3.5g, 13mmol) dissolved in tetrahydrofuran was added dropwise, stirring was continued for 1 hour and warmed to room temperature and stirred for 3 hours, and the product was isolated by column chromatography (eluent petroleum ether/ethyl acetate =10:1) in 3.0g, 85% yield.

(6) Preparation of 3- (4-bromo-3-cyclopropylphenoxy) tetrahydrofuran

Trifluoroacetic acid (3.42g, 30mmol) and diethyl zinc (30mL, 30mmol) were added to dry dichloromethane (100mL) under ice-bath, after stirring for 30 minutes, diiodomethane (8.04g, 30mmol) was added, stirring was carried out for 1 hour, and finally 3- (4-bromo-3-vinylphenoxy) tetrahydrofuran (2.69g, 10mmol) was dissolved in dichloromethane and added to the reaction system, and stirring and warmed to room temperature, washed with a saturated aqueous sodium chloride solution, dried with organic phase, concentrated under reduced pressure, and subjected to column chromatography (petroleum ether: ethyl acetate =10:1) to separate and purify the product 1.2g, yield 43%.

(7) Preparation of methyl 2- (6- ((2' -cyclopropyl-4 ' - ((tetrahydrofuran-3-yl) oxy) - [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate

3- (4-bromo-3-cyclopropylphenoxy) tetrahydrofuran (283mg, 1mmol), methyl 2- (6- ((3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzyl) oxy) -2, 3-dihydrobenzofuran-3-yl) acetate (424mg, 1mmol), Pd (dppf)₂Cl₂(42mg), potassium carbonate (276mg, 2mmol) was added to 1, 4-dioxane (10mL), and reacted in an oil bath at 80 ℃ for 8 hours. The solvent was removed by concentration under reduced pressure and the product was isolated by preparative chromatography in 30% yield at 150 mg.

(8) Preparation of 2- (6- ((2' -cyclopropyl-4 ' - ((tetrahydrofuran-3-yl) oxy) - [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetic acid (Compound 1)

Methyl 2- (6- ((2' -cyclopropyl-4 ' - ((tetrahydrofuran-3-yl) oxy) - [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate (150mg, 0.3mmol) was dissolved in methanol (2mL), sodium hydroxide (18mg, 0.45mmol) was added, stirring was sufficiently for half an hour, potassium hydrogensulfate (61mg, 0.45mmol) was added, after stirring uniformly, water (10mL) was added, extraction was performed with ethyl acetate (20mL), drying was performed, concentration under reduced pressure was performed to obtain 100mg of the product, yield 69%.

The molecular formula is as follows: c₃₀H₃₀O₆Molecular weight: 486 LC-MS (m/z): 487(M +1)

¹H-NMR(400MHz,MeOD):.7.41(m,3H),7.32(m,1H),7.10(m,2H),6.75(d,J=2.8Hz,1H),6.49(d,J=2.8Hz,1H),6.45(m,1H),6.41(m,1H),5.09(s,2H),4.95(m,1H),4.69(m,1H),4.21(m,1H),3.80-4.00(m,4H),3.75(m,1H),2.69(m,1H),2.22(m,1H),2.11(m,1H),1.75(m,1H),0.76(m,2H),0.60(m,2H).

EXAMPLE 22 preparation of (6- ((2' -cyclopropyl-4 ' - (2- (methylsulfonylamino) ethoxy) - [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetic acid (Compound 3)

(1) Preparation of 2- (tert-butoxycarbonylamino) ethyl methanesulfonate

N-tert-Butoxycarbonylethanolamine (6.2g, 38.5mmol) is dissolved in anhydrous tetrahydrofuran (150mL), triethylamine (9.7g, 96mmol) is added, methanesulfonyl chloride (5.3g, 46mmol) is added dropwise in ice bath, after dropwise addition within 20min, the reaction is continued for 12h by warming to room temperature. The reaction system was filtered under reduced pressure, the filtrate was concentrated under reduced pressure, ethyl acetate was added and extracted with aqueous solution, the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 7.7g of the title compound as brown oil in 83.7% yield.

(2) Preparation of tert-butyl 2- (4-bromo-3-formylphenoxy) ethylcarbamate

2- (tert-Butoxycarbonylamino) ethyl methanesulfonate (7.7g, 32mmol) was dissolved in anhydrous dimethylformamide (250mL), and 2-bromo-5-hydroxybenzaldehyde (6.4g, 32mmol) and anhydrous potassium carbonate (13.2g, 96mmol) were added and reacted at 80 ℃ for 12 h. After cooling to room temperature, water and ethyl acetate were added for extraction, the organic phase was washed three times with saturated sodium hydroxide solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure and separated by column chromatography (eluent petroleum ether/ethyl acetate =10:1) to give the title compound as a white solid 6.3g, in 57.2% yield.

(3) Preparation of tert-butyl 2- (4-bromo-3-vinylphenoxy) ethylcarbamate

Methyltriphenylphosphonium bromide (9.8g, 27.5mmol) was dissolved in anhydrous tetrahydrofuran (100mL), potassium tert-butoxide (5.1g, 45.8mmol) was added and the reaction was stirred at room temperature for 1 h. Then, a tetrahydrofuran solution of tert-butyl 2- (4-bromo-3-formylphenoxy) ethylcarbamate (6.3g, 18.3mmol) was added dropwise thereto, and the reaction was continued for 4 hours after the dropwise addition was completed for 5 minutes. The reaction was quenched by addition of saturated sodium chloride solution, extracted with ethyl acetate and water, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure and separated by column chromatography (eluent petroleum ether/ethyl acetate =10:1) to give the title compound 3.2g as an oil in 51.1% yield.

(4) Preparation of 2- (4-bromo-3-vinylphenoxy) ethylamine

Tert-butyl 2- (4-bromo-3-vinylphenoxy) ethylcarbamate (3.2g, 9.4mmol) was dissolved in dichloromethane (20mL), and trifluoroacetic acid (10mL) was added to react at room temperature for 2 h. The reaction was quenched by addition of saturated sodium bicarbonate solution, extracted, and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound as an oil, 2.1g, in 93.3% yield.

(5) Preparation of N- (2- (4-bromo-3-vinylphenoxy) ethyl) methanesulfonamide

2- (4-bromo-3-vinylphenoxy) ethylamine (2.1g, 8.7mmol) was dissolved in anhydrous tetrahydrofuran (100mL), triethylamine (1.75g, 17.3mmol) was added, methanesulfonyl chloride (1.2g, 10.5mmol) was added dropwise over an ice bath, completing the addition within 10 min. The reaction was carried out at room temperature for 12 hours, concentrated under reduced pressure and then isolated by column chromatography (eluent petroleum ether/ethyl acetate =2:1) to obtain 2.2g of the title compound as an oil in 80.5% yield.

(6) Preparation of N- (2- (4-bromo-3-cyclopropylphenoxy) ethyl) methanesulfonamide

To dry dichloromethane (20mL) was added 1.5mol/L diethylzinc n-hexane solution (13.8mL, 20.6mmol) at-78 deg.C under nitrogen, followed by slow addition of trifluoroacetic acid (2.35g, 20.6mmol) and continued stirring for 1 h. Diiodomethane (5.52g, 20.6mmol) was then added to the system and the reaction was continued for 1h, and finally a solution of N- (2- (4-bromo-3-vinylphenoxy) ethyl) methanesulfonamide (2.2g, 6.9mmol) in dichloromethane was added and allowed to slowly warm to room temperature for 4 h. Aqueous sodium chloride solution was added, liquid was separated by extraction, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and subjected to column chromatography (eluent petroleum ether/ethyl acetate =2:1) to obtain 1.8g of the title compound as a pale solid in 78.3% yield.

(7) Preparation of N- (2- (2-cyclopropyl-3 '- (hydroxymethyl) - [1,1' -biphenyl ] -4-yloxy) ethyl) methanesulfonamide

N- (2- (4-bromo-3-cyclopropylphenoxy) ethyl) methanesulfonamide (1.8g, 5.4mmol), 3-hydroxymethylphenylboronic acid (0.98g, 6.5mmol), Pd (dppf) Cl₂(220mg, 0.27mmol) and potassium carbonate (1.49g, 10.8mmol) were added to a mixed solvent of dioxane/water (20:1) (10mL) and reacted with a microwave at 110 ℃ for 2 hours. After concentration under reduced pressure and column chromatography (eluent petroleum ether/ethyl acetate =2:1), the title compound was isolated as a colorless oil 850mg, yield 43.7%.

(8) Preparation of methyl 2- (6- ((2' -cyclopropyl-4 ' - (2- (methylsulfonylamino) ethoxy) - [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate

N- (2- (2-cyclopropyl-3 '- (hydroxymethyl) - [1,1' -biphenyl ] -4-yloxy) ethyl) methanesulfonamide (550mg, 1.52mmol), methyl 2- (6-hydroxy-2, 3-dihydrobenzofuran-3-yl) acetate (349mg, 1.68mmol), azobisformyldipiperidine (689mg, 2.74mmol) were dissolved in anhydrous tetrahydrofuran (20mL), and tri-N-butylphosphine (553mg, 2.74mmol) was added under ice bath to react at room temperature for 4 h. The reaction system was suction-filtered under reduced pressure, and the filtrate was concentrated under reduced pressure and then separated by column chromatography (eluent petroleum ether/ethyl acetate =2:1) to give the title compound 200mg as a colorless oil in 23.8% yield.

(9) Preparation of 2- (6- ((2' -cyclopropyl-4 ' - (2- (methylsulfonylamino) ethoxy) - [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetic acid (Compound 3)

Methyl 2- (6- ((2' -cyclopropyl-4 ' - (2- (methylsulfonylamino) ethoxy) - [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate (200mg, 0.36mmol) was dissolved in a mixed solvent of tetrahydrofuran/methanol (1:1) (6mL), and an aqueous solution (3mL) of lithium hydroxide (39mg,0.93mmol) was slowly added and reacted at room temperature for 3 h. Aqueous hydrochloric acid (0.08mL) was added, pH =3 was adjusted, and after concentration, ethyl acetate (20mL) was added for extraction, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the solvent, and then subjected to column chromatography (eluent dichloromethane/MeOH =50:1) to isolate the title compound as a colorless waxy product 42mg, yield 21.5%.

Molecular formula C₂₉H₃₁NO₇Molecular weight of S537.6 LC-MS (M/z):538.2(M +1)

¹H-NMR(400MHz,CDCl₃):7.47(s,1H),7.42-7.35(m,3H),7.18-7.15(d,J=8.4Hz,1H),7.07-7.04(d,J=8.1Hz,1H),6.75-6.72(dd,J=8.4,2.3Hz,1H),6.52-6.45(m,3H),5.07(s,2H),5.01-4.98(m,1H),4.78-4.73(t,J=9.0Hz,1H),4.31-4.26(m,1H),4.14-4.10(m,2H),3.84-3.77(m,1H),3.58-3.53(m,2H),3.03(s,3H),2.82-2.76(m,1H),2.63-2.56(m,1H),1.75(m,1H),0.84-0.79(m,2H),0.69-0.65(q,J=5.2Hz,2H).

EXAMPLE 3 preparation of (S) -2- (6- ((2' -cyclopropyl-4 ' - (2- (1, 1-dioxoisothiazolidin-2-yl) ethoxy) - [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetic acid (Compound 6)

(1) Preparation of 2- (tert-butoxycarbonylamino) ethyl methanesulfonate

N-tert-Butoxycarbonylethanolamine (15g, 93mmol) was dissolved in anhydrous tetrahydrofuran (400mL) under ice bath, triethylamine (23.5g, 233mmol) was added, methanesulfonyl chloride (12.8g, 111.6mmol) was added dropwise, and after completion of the addition, the mixture was warmed to room temperature to react for 12 hours. Suction filtration was performed, the filtrate was concentrated under reduced pressure, ethyl acetate (300mL) and water (300mL) were added, ethyl acetate (300 mL. times.3) was extracted, the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 18.9g of the title compound as a brown oil in 85% yield.

(2) Preparation of tert-butyl 2- (4-bromo-3-formylphenoxy) ethylcarbamate

2- (tert-Butoxycarbonylamino) ethyl methanesulfonate (18g, 75mmol) was dissolved in anhydrous N, N-dimethylformamide (400mL), and 2-bromo-5-hydroxybenzaldehyde (15.1g, 75mmol) and anhydrous potassium carbonate (31g, 225mmol) were added and reacted at 80 ℃ for 12 hours. After cooling to room temperature, water (1000mL) and ethyl acetate (1000mL) were added for extraction, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure and subjected to column chromatography (eluent petroleum ether/ethyl acetate =10:1) to obtain the title compound 17.8g in 69% yield.

(3) Preparation of tert-butyl 2- (4-bromo-3-vinylphenoxy) ethylcarbamate

Methyltriphenylphosphine bromide (46.8g, 131mmol) was dissolved in anhydrous tetrahydrofuran (100mL), potassium tert-butoxide (14.7g, 131mmol) was added, and the reaction was continued with stirring at room temperature for 1 hour. Then, a tetrahydrofuran solution (100mL) of tert-butyl 2- (4-bromo-3-formylphenoxy) ethylcarbamate (15g, 43.6mmol) was added dropwise thereto, and the reaction was continued for 4 hours after the dropwise addition was completed for 25 min. The reaction was quenched by addition of saturated sodium chloride (200mL), extracted with ethyl acetate (500mL × 3), the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure and separated by column chromatography (eluent petroleum ether/ethyl acetate =10:1) to give the title compound 9.1g in 61% yield.

(4) Preparation of 2- (4-bromo-3-vinylphenoxy) ethylamine

Tert-butyl 2- (4-bromo-3-vinylphenoxy) ethylcarbamate (9g, 26.3mmol) was dissolved in dichloromethane (60mL), and trifluoroacetic acid (25mL) was added to react at room temperature for 2 hours. The solvent was removed by concentration under reduced pressure, saturated sodium bicarbonate was adjusted to pH about 8, ethyl acetate (200 mL. times.3) was extracted, the organic phase was dried over anhydrous sodium sulfate, and concentration under reduced pressure gave 6g of the title compound in 95% yield.

(5) Preparation of N- (2- (4-bromo-3-vinylphenoxy) ethyl) -3-chloropropane-1-sulfonamide

Dissolving 2- (4-bromo-3-vinylphenoxy) ethylamine (5g, 20mmol) in tetrahydrofuran (100mL), adding triethylamine (6.25g, 60mmol), dropwise adding 3-chloropropyl-1-sulfonyl chloride (3.9g, 22mmol) in ice bath, and heating to room temperature for reaction for 16 hours after dropwise addition. Water (200mL) was added, extraction was performed with ethyl acetate (200mL × 3), the organic phases were combined, washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography on crude silica gel (eluent ethyl acetate/petroleum ether =1:10) to obtain 5.5g of the title compound in 70% yield.

(6) Preparation of 2- (2- (4-bromo-3-vinylphenoxy) ethyl) isothiazolidine 1, 1-dioxide

N- (2- (4-bromo-3-vinylphenoxy) ethyl) -3-chloropropane-1-sulfonamide (5.0g, 13mmol) was dissolved in N, N-dimethylformamide (200mL), and sodium hydride (60%) (780mg, 19.6mmol) was added thereto under ice bath, followed by reaction for 1 hour under ice bath, and then warmed to room temperature for 2 hours. Poured into ice water (500mL), extracted with ethyl acetate (200mL × 3), the organic phases combined, washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, concentrated and the crude product isolated by column chromatography (eluent ethyl acetate/petroleum ether =1:5) to yield 3.4g of the title compound in 75% yield.

(7) Preparation of 2- (2- (4-bromo-3-cyclopropylphenoxy) ethyl) isothiazolidine 1, 1-dioxide

To dichloromethane (50mL) was added anhydrous 1.5mol/L diethylzinc n-hexane solution (13.8mL, 20.6mmol) at-78 deg.C under nitrogen, followed by slow addition of trifluoroacetic acid (2.35g, 20.6mmol) and continued stirring for 1 hour. Diiodomethane (5.52g, 20.6mmol) was then added to the system and the reaction was continued for 1 hour, and finally a solution of 2- (2- (4-bromo-3-vinylphenoxy) ethyl) isothiazolidine 1, 1-dioxide (2.4g, 6.9mmol) in dichloromethane was added and the reaction was allowed to slowly warm to room temperature for 4 hours. To the system was added an aqueous sodium chloride solution, followed by extraction with ethyl acetate (50mL × 3), liquid separation, drying of the organic phase over anhydrous sodium sulfate, concentration under reduced pressure, and column chromatography (eluent ethyl acetate/petroleum ether =1:2) to obtain 2g of the title compound in 82% yield.

(8) Preparation of 2- (2- ((2-cyclopropyl-3 '- (hydroxymethyl) - [1,1' -biphenyl ] -4-yl) oxy) ethyl) isothiazolidine 1, 1-dioxide

2- (2- (4-bromo-3-cyclopropylphenoxy) ethyl) isothiazolidine 1, 1-dioxide (1.94g, 5.4mmol), 3-hydroxymethylphenylboronic acid (0.98g, 6.5mmol), Pd (dppf) Cl₂(220mg, 0.27mmol) and potassium carbonate (1.49g, 10.8mmol) were added to a mixed solvent of dioxane/water (20:1) (10mL) and reacted with a microwave at 110 ℃ for 2 hours. Concentration under reduced pressure followed by column chromatography (eluent ethyl acetate, petroleum ether =1:2) gave 1.55g of the title compound in 76% yield.

(9) Preparation of methyl (S) -2- (6- ((2' -cyclopropyl-4 ' - (2- (1, 1-dioxoisothiazolidin-2-yl) ethoxy) - [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate

2- (2- ((2-cyclopropyl-3 '- (hydroxymethyl) - [1,1' -biphenyl ] -4-yl) oxy) ethyl) isothiazolidine 1, 1-dioxide (589mg, 1.52mmol), methyl (S) -2- (6-hydroxy-2, 3-dihydrobenzofuran-3-yl) acetate (349mg, 1.68mmol), azobisformyldipiperidine (689mg, 2.74mmol) were dissolved in anhydrous tetrahydrofuran (20mL), tri-n-butylphosphine (553mg, 2.74mmol) was added under ice bath, and the mixture was allowed to warm to room temperature for 4 hours. The system was suction filtered under reduced pressure, and the filtrate was concentrated under reduced pressure and then separated by column chromatography (eluent ethyl acetate/petroleum ether =1:2) to give the title compound 289mg in 33% yield.

(10) Preparation of (S) -2- (6- ((2' -cyclopropyl-4 ' - (2- (1, 1-dioxoisothiazolidin-2-yl) ethoxy) - [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetic acid (Compound 6)

Methyl (S) -2- (6- ((2' -cyclopropyl-4 ' - (2- (1, 1-dioxoisothiazolidin-2-yl) ethoxy) - [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate (280mg, 0.48mmol) was dissolved in tetrahydrofuran/MeOH =1:1(6mL), and an aqueous solution (3mL) of lithium hydroxide (29mg,1.21mmol) was slowly added and reacted at room temperature for 3 hours. Concentrated hydrochloric acid (80 μ L) was added, pH =3 was adjusted, ethyl acetate was added after concentration for extraction (10mL × 3), the organic phase was dried over anhydrous sodium sulfate, and column chromatography (eluent dichloromethane/methanol =10:1) after concentration under reduced pressure was performed to isolate the title compound 220mg in 81% yield.

Molecular formula C₃₁H₃₃NO₇Molecular weight of S563.66 LC-MS (M/z):564.3(M +1)

¹H-NMR(400MHz,DMSO):12.38(br,1H),7.44-7.42(m,2H),7.37-7.55(m,1H),7.31(m,1H),7.11-7.08(m,2H),6.81-6.79(m,1H),6.47-6.45(m,3H),5.10(m,2H),4.69-4.64(m,1H),4.19-4.11(m,3H),3.67-3.64(m,1H),3.42-3.32(m,2H),3.28-3.16(m,2H),2.71-2.65(m,1H),2.49-2.43(m,1H),2.26-2.19(m,2H),1.76-1.73(m,1H),0.77-0.75(m,2H),0.68-0.67(m,2H).

EXAMPLE 4 preparation of (R) -2- (6- ((2' -cyclopropyl-4 ' - (2- (1, 1-dioxoisothiazolidin-2-yl) ethoxy) - [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetic acid (Compound 7)

(1) Preparation of 2- (tert-butoxycarbonylamino) ethyl methanesulfonate

N-tert-Butoxycarbonylethanolamine (5g, 31mmol) was dissolved in anhydrous tetrahydrofuran (400mL) under ice-bath, triethylamine (7.8g, 76mmol) was added, methanesulfonyl chloride (4.3g, 37mmol) was added dropwise, and after completion of the addition, the reaction was warmed to room temperature for 12 hours. The reaction system was suction-filtered under reduced pressure, the filtrate was concentrated under reduced pressure, ethyl acetate (100mL) and water (100mL) were added, liquid-separation extraction (100 mL. times.3) was performed, the organic phase was dried over anhydrous sodium sulfate, and concentration under reduced pressure gave 6g of the title compound as a brown oil in 81% yield.

(2) Preparation of tert-butyl 2- (4-bromo-3-formylphenoxy) ethylcarbamate

2- (tert-Butoxycarbonylamino) ethyl methanesulfonate (6g, 25mmol) was dissolved in anhydrous N, N-dimethylformamide (100mL), and 2-bromo-5-hydroxybenzaldehyde (5g, 25mmol) and anhydrous potassium carbonate (10g, 75mmol) were added and reacted at 80 ℃ for 12 hours. After cooling to room temperature, water (300mL) and ethyl acetate (300mL) were added for extraction, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure and subjected to column chromatography (eluent petroleum ether: ethyl acetate =10:1) to obtain 5g of the title compound in 69.5% yield. (3) Preparation of tert-butyl 2- (4-bromo-3-vinylphenoxy) ethylcarbamate

Methyltriphenylphosphonium bromide (15.6g, 43.6mmol) was dissolved in anhydrous tetrahydrofuran (40mL), potassium tert-butoxide (4.9g, 43.6mmol) was added and stirring continued at room temperature for 1 hour. A solution of tert-butyl 2- (4-bromo-3-formylphenoxy) ethylcarbamate (5g, 14.5mmol) in tetrahydrofuran (100mL) was then added dropwise over 25 minutes, and the reaction was continued for 4 hours. The reaction was quenched by addition of saturated sodium chloride solution (100mL), extracted with ethyl acetate (100mL × 3), the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure and separated by column chromatography (eluent petroleum ether/ethyl acetate =10:1) to obtain 3g of the title compound in 60% yield.

(4) Preparation of 2- (4-bromo-3-vinylphenoxy) ethylamine

Tert-butyl 2- (4-bromo-3-vinylphenoxy) ethylcarbamate (3g, 8.7mmol) was dissolved in dichloromethane (20mL), and trifluoroacetic acid (15mL) was added to react at room temperature for 2 hours. The solvent was removed by concentration under reduced pressure, extracted with ethyl acetate (100 mL. times.3), and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 2g of the title compound as an oil with a yield of 95%.

2- (4-bromo-3-vinylphenoxy) ethylamine (2g, 8.3mmol) was dissolved in tetrahydrofuran (20mL), triethylamine (2.5g, 24.7mmol) was added, 3-chloropropyl-1-sulfonyl chloride (1.62g, 9.1mmol) was added dropwise in an ice bath, and after the addition was completed, the reaction was warmed to room temperature for 16 hours. Water (100mL) was added, extraction was performed with ethyl acetate (100 mL. times.3), the organic phases were combined, washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, concentrated, and subjected to silica gel column chromatography (eluent ethyl acetate: petroleum ether =1:10) to obtain the title compound 2.2g in 70% yield.

N- (2- (4-bromo-3-vinylphenoxy) ethyl) -3-chloropropane-1-sulfonamide (2.0g, 5.2mmol) was dissolved in N, N-dimethylformamide (50mL), and sodium hydride (60%) (313mg, 7.8mmol) was added thereto under ice bath, followed by reaction for 1 hour under ice bath and warming to room temperature for 2 hours. Poured into ice water (50mL), extracted with ethyl acetate (100mL × 3), the organic phases combined, washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, concentrated and the crude product isolated by column chromatography (eluent ethyl acetate/petroleum ether =1:5) to give the title compound 1.46g, 81% yield.

To dry dichloromethane (50mL) was added 1.5mol/L diethylzinc n-hexane solution (6.9mL, 10.3mmol) at-78 deg.C under nitrogen, followed by slow addition of trifluoroacetic acid (1.17g, 10.3mmol) and continued stirring for 1 hour. Diiodomethane (2.76g, 10.3mmol) was then added to the system and the reaction was continued for 1 hour, and finally a solution of 2- (2- (4-bromo-3-vinylphenoxy) ethyl) isothiazolidine 1, 1-dioxide (1.2g, 3.4mmol) in dichloromethane was added and the reaction was allowed to slowly warm to room temperature for 4 hours. To the system was added an aqueous sodium chloride solution, followed by extraction with ethyl acetate (50mL × 3) and liquid separation, drying of the organic phase over anhydrous sodium sulfate, concentration under reduced pressure, and column chromatography (eluent ethyl acetate/petroleum ether =1:2) to give the title compound 1g in 80% yield.

2- (2- (4-bromo-3-cyclopropylphenoxy) ethyl) isothiazolidine 1, 1-dioxide (1g, 2.78mmol), 3-hydroxymethylphenylboronic acid (0.51g, 3.3mmol), Pd (dppf) Cl₂(22mg, 0.027mmol) and potassium carbonate (0.77g, 5.56mmol) were added to a mixed solvent of dioxane/water (20:1) (10mL), and microwave reaction was carried out at 110 ℃ for 2 hours. After concentration under reduced pressure and column chromatography (eluent ethyl acetate/petroleum ether =1:2), the title compound was isolated as a colorless oil 0.87g with a yield of 81%.

(9) Preparation of methyl (R) -2- (6- ((2' -cyclopropyl-4 ' - (2- (1, 1-dioxoisothiazolidin-2-yl) ethoxy) - [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate

2- (2- ((2-cyclopropyl-3 '- (hydroxymethyl) - [1,1' -biphenyl ] -4-yl) oxy) ethyl) isothiazolidine 1, 1-dioxide (0.8g, 2mmol), (R) -methyl 2- (6-hydroxy-2, 3-dihydrobenzofuran-3-yl) acetate (459mg, 2.2mmol), azobisformyldipiperidine (908mg, 3.6mmol) were added to anhydrous tetrahydrofuran (20mL), tri-n-butylphosphine (727mg, 3.6mmol) was added under ice bath, and the mixture was allowed to warm to room temperature for 4 hours. The system was suction filtered under reduced pressure, and the filtrate was concentrated under reduced pressure and then separated by column chromatography (eluent ethyl acetate/petroleum ether =1:2) to give the title compound 369mg as a colorless oil in 31% yield.

(10) Preparation of (R) -2- (6- ((2' -cyclopropyl-4 ' - (2- (1, 1-dioxoisothiazolidin-2-yl) ethoxy) - [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetic acid (Compound 7)

Methyl (R) -2- (6- ((2' -cyclopropyl-4 ' - (2- (1, 1-dioxoisothiazolidin-2-yl) ethoxy) - [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate (200mg, 0.35mmol) was dissolved in tetrahydrofuran/MeOH =1:1(6mL), and an aqueous solution (3mL) of lithium hydroxide (21mg,0.88mmol) was slowly added and reacted at room temperature for 3 hours. Concentrated hydrochloric acid (0.06mL) was added, pH =3 was adjusted, and after concentration, ethyl acetate (20mL) was added for extraction, the organic phase was dried over anhydrous sodium sulfate, and after concentration under reduced pressure, column chromatography (eluent dichloromethane/methanol =10:1) was performed to isolate the title compound 150mg in 77% yield.

¹H-NMR(400MHz,DMSO):12.7-12.2(br,1H),7.42-7.40(m,2H),7.31-7.29(m,2H),7.10-7.08(m,2H),6.81-6.78(m,1H),6.47-6.44(m,3H),5.10(m,2H),4.68-4.64(m,1H),4.18-4.10(m,3H),3.70-3.60(m,1H),3.34-3.28(m,2H),3.20-3.16(m,2H),2.71-2.65(m,1H),2.49-2.47(m,1H),2.24-2.20(m,2H),1.74(m,1H),0.77-0.75(m,2H),0.69-0.66(m,2H).

EXAMPLE 5 preparation of (R) -2- (6- ((2' -cyclopropyl-4 ' - (2- (1, 1-dioxoisothiazolidin-2-yl) ethoxy) - [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetic acid (Compound 9)

(1) Preparation of 2-benzyl-1, 2, 5-thiadiazolidine 1, 1-dioxide

Will N¹-benzylethane-1, 2-diamine (5.0g,33.28mmmol) was dissolved in pyridine (100mL), sulfuric acid diamide (3.2g,33.28mmol) was added, heated to 80 ℃ for 16 hours, and LC-MS checked that the reaction was completed, the solvent was concentrated, ethyl acetate (100mL) and (50mL) water were added, liquid was separated, the aqueous phase was extracted with ethyl acetate (2 × 50mL), the organic phases were combined, and the title compound was obtained by silica gel column chromatography (petroleum ether: ethyl acetate =3:1) after concentration (4.2g, yield 59.3%).

(2) Preparation of ethyl 2- (benzyl-1, 1-dioxido-1, 2, 5-thiadiazolidin-2-yl) acetate

Dissolving 2-benzyl-1, 2, 5-thiadiazolidine 1, 1-dioxide (4.2g,19.72mmol) in tetrahydrofuran (50mL), adding sodium hydride (60%,1.03g,25.64mmol) in an ice-water bath, continuously stirring for 0.5 h, slowly dropwise adding 2-bromoethyl acetate (3.95g,23.66mmol) into the reaction solution, stirring at room temperature for 3h, and detecting by LC-MS that the reaction is finished. The reaction was quenched by the addition of water (5mL), the solvent was concentrated, ethyl acetate (100mL) and water (50mL) were added, the layers were separated, the aqueous layer was extracted with ethyl acetate (2X 50mL), the organic layers were combined, dried over anhydrous sodium sulfate, filtered, concentrated to dryness, and the residue was used directly in the next step.

(3) Preparation of 2-benzyl-5- (2-hydroxyethyl) 1,2, 5-thiadiazolidine) 1, 1-dioxide

Dissolving ethyl 2- (benzyl-1, 1-dioxo-1, 2, 5-thiadiazolidin-2-yl) acetate (5.88g,19.72mmol) in tetrahydrofuran (50mL), adding lithium borohydride (0.52g,23.66mmol) under an ice-water bath, reacting at room temperature for 3 hours, detecting the reaction completion by LC-MS, adding water (5mL) to quench the reaction, concentrating the solvent, adding ethyl acetate (100mL) and water (50mL), separating the liquid, extracting the aqueous phase with ethyl acetate (2X 50mL), combining the organic phases, drying over anhydrous sodium sulfate, filtering, concentrating to dryness, and using the residue in the next step directly.

(4) Preparation of 2- (5-benzyl-1, 1-dioxo-1, 2, 5-thiadiazolyl-2-yl) ethyl 4-methylbenzenesulfonate

Dissolving 2-benzyl-5- (2-hydroxyethyl) 1,2, 5-thiadiazolidine) 1, 1-dioxide (5.03g,19.72mmol) in tetrahydrofuran (50mL), adding triethylamine (5.98g, 59.16mmol), adding p-toluenesulfonyl chloride (7.52g, 39.44mmol) in portions under ice-water bath, stirring at room temperature for 5 hours, detecting the reaction by LC-MS, concentrating the solvent, adding ethyl acetate (100mL) and water (50mL), separating, extracting the aqueous phase with ethyl acetate (2X 50mL), combining the organic phases, drying with anhydrous sodium sulfate, filtering, concentrating to dryness, and using the residue in the next step.

(5) Preparation of 2- (1, 1-dioxo-1, 2, 5-thiadiazolidin-2-yl) ethyl 4-methylbenzenesulfonate

2- (5-benzyl-1, 1-dioxo-1, 2, 5-thiadiazolyl-2-yl) ethyl 4-methylbenzenesulfonate (4.8g,11.71mmol) was dissolved in ethanol (50mL), ammonium formate (3.69g,58.55mmol) and palladium on charcoal (400mg) were added, the mixture was heated to 60 ℃ and reacted for 6 hours, and the reaction was terminated by LC-MS detection. Filtration and concentration of the solution, addition of ethyl acetate (100mL) and water (50mL), liquid separation, extraction of the aqueous phase with ethyl acetate (50mL), combination of the organic phases, spin drying and column chromatography of the residue on silica gel (petroleum ether: ethyl acetate =2:1) gave the title compound (2.2g, 58.8% yield).

(6) Preparation of 5- (2- (p-toluenesulfonyloxy) ethyl-1, 2, 5-thiadiazolidinyl-2-carboxylic acid tert-butyl ester 1, 1-dioxide

2- (1, 1-dioxo-1, 2, 5-thiadiazolidin-2-yl) ethyl 4-methylbenzenesulfonate (2.2g,6.87mmol) was dissolved in tetrahydrofuran (50mL), di-tert-butyl carbonate (2.25g,10.31mmol), diisopropylethylamine (2.66g,20.61mmol) and 4-dimethylaminopyridine (0.335g,2.75mmol) were added, and the reaction was stirred at room temperature for 5 hours and checked by LC-MS for completion. The solution was concentrated, ethyl acetate (100mL) and water (50mL) were added, the layers were separated, the aqueous layer was extracted with ethyl acetate (50mL), the organic layers were combined, spun-dried, and the residue was subjected to silica gel column chromatography (petroleum ether: ethyl acetate =2:1) to give the title compound (2.0g, two-step yield 69.3%).

(7) Preparation of 4-bromo-3-vinylphenol

2-bromo-5-hydroxybenzaldehyde (5.0g,24.87mmol) was dissolved in tetrahydrofuran (100mL), methyl triphenyl phosphine bromide (26.6g,74.26mmol) and potassium tert-butoxide (9.21g,82.07mmol) were added, the mixture was stirred at room temperature for 3 hours, the solution was concentrated, ethyl acetate (100mL) and water (50mL) were added, the layers were separated, the aqueous phase was extracted with ethyl acetate (2X 50mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated to dryness, and the residue was used directly in the next step.

(8) Preparation of (4-bromo-3-vinylphenoxy) (tert-butyl) dimethylsilane

4-bromo-3-vinylphenol (4.95g,24.87mmol) was dissolved in tetrahydrofuran (100mL), imidazole (2.54g,37.31mmol) was added, tert-butyldimethylsilyl chloride (5.62g,37.31mmol) was added in portions under an ice-water bath, and stirred at room temperature for 5 hours. The solvent was concentrated, ethyl acetate (100mL) and water (50mL) were added, the layers were separated, the aqueous layer was extracted with ethyl acetate (50mL), the organic layers were combined, spun-dried, and the residue was subjected to silica gel column chromatography (petroleum ether: ethyl acetate =10:1) to give the title compound (5.5g, 47.1% yield in two steps).

(9) Preparation of (4-bromo-3-cyclopropylphenoxy) (tert-butyl) dimethylsilane

Diethyl zinc toluene solution (35mL,52.55mmol) was added to dichloromethane (50mL), cooled to-40 deg.C, trifluoroacetic acid (6.0g,52.55mmol) was slowly added dropwise to the solution, stirred for 0.5 h, diiodomethane (14.1g,52.55mmol) was slowly added dropwise, stirring was continued for 0.5 h, (4-bromo-3-vinylphenoxy) (tert-butyl) dimethylsilane (5.5g,17.52mmol) was dissolved in dichloromethane (10mL) and slowly added dropwise to the reaction mixture, warmed to room temperature, and stirring was continued for 16 h. After completion of the reaction, water (50mL) and dichloromethane (100mL) were added, the layers were separated, the aqueous layer was extracted with dichloromethane (50mL), the organic layers were combined, concentrated, and the residue was subjected to silica gel column chromatography (petroleum ether: ethyl acetate =10:1) to give the title compound (3.0g, yield 32.8%).

(10) Preparation of (4 ' ((tert-butyldimethylsilyl) oxy) -2 ' -cyclopropyl [1,1' -biphenyl ] -3-yl) methanol

(4-bromo-3-cyclopropylphenoxy) (tert-butyl) dimethylsilane (2.0g,6.11mmol), 3-hydroxymethylphenylboronic acid (1.11g,7.33mmol) were dissolved in 1, 4-dioxane (50mL), and [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (0.536g,0.73mmol), potassium carbonate (1.7g,12.22mmol) and water (2mL) were added to heat the solution to 100 ℃ for overnight reaction, and LC-MS detected that the reaction was complete. The solvent was concentrated, ethyl acetate (50mL) and water (20mL) were added, liquid separation was performed, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, the solvent was concentrated, and purified by silica gel column chromatography (petroleum ether: ethyl acetate =3:1) to obtain the title compound (1.2g, yield 55.5%).

(11) Preparation of methyl (S) -2- (6- ((4 ' - ((tert-butyldimethylsilyl) oxy) -2 ' -cyclopropyl- [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate

(4 ' ((tert-butyldimethylsilyl) oxy) -2 ' -cyclopropyl [1,1' -biphenyl ] -3-yl) methanol (0.74g,2.09mmol), (S) -methyl 2- (6-hydroxy-2, 3-dihydrobenzofuran-3-yl) acetate (0.435g,2.09mmol), tri-n-butylphosphine (1.27g,6.27mmol) and azobisformyldipiperidine (1.58g,6.27mmol) were dissolved in tetrahydrofuran (20mL), stirred at room temperature for 24h, LC-MS detected the reaction was complete, the solvent was concentrated, ethyl acetate (50mL) and water (30mL) were added, the layers were separated, the aqueous phase was extracted with ethyl acetate (2X 20mL), the organic phases were combined and dried over anhydrous sodium sulfate. Filtration, spin-drying, and column chromatography over silica gel (petroleum ether: ethyl acetate =4:1) gave the title compound (0.5g, 43.9% yield).

(12) Preparation of methyl (S) -2- (6- ((2' -cyclopropyl-4 ' -hydroxy- [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate

Methyl (S) -2- (6- ((4 ' - ((tert-butyldimethylsilyl) oxy) -2 ' -cyclopropyl- [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate (0.50g,0.92mmol) was dissolved in tetrahydrofuran (20mL), tetrabutylammonium fluoride (0.24g,0.92mmol) was added, stirring was carried out at room temperature for 5 hours, LC-MS detection of the completion of the reaction, the solvent was concentrated, ethyl acetate (50mL) and water (30mL) were added, liquid separation was carried out, the aqueous phase was extracted with ethyl acetate (2X 20mL), the organic phases were combined, and anhydrous sodium sulfate was dried. Filtration, spin-drying, and silica gel column chromatography (petroleum ether: ethyl acetate =2:1) gave the title compound (0.32g, yield 81.0%).

(13) Preparation of (S) -5- (2- ((2-cyclopropyl-3 '- (((3- (2-methoxy-2-oxoethyl) -2, 3-dihydrobenzofuran-6-yl) oxy) methyl) - [1,1' -biphenyl ] -4-yl) oxy) ethyl) -1,2, 5-thiadiazolidinyl-2-carboxylic acid tert-butyl ester 1, 1-dioxide

(S) -methyl 2- (6- ((2' -cyclopropyl-4 ' -hydroxy- [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate (90mg,0.21mmol) was dissolved in N, N-dimethylformamide (10mL), sodium hydride (60%, 16.7mg,0.41mmol) was added, stirring was carried out at room temperature for 0.5 hour, tert-butyl 5- (2- (p-toluenesulfonyloxy) ethyl) -1,2, 5-thiadiazolidinyl-2-carboxylate 1, 1-dioxide (100mg,0.21mmol) was added, stirring was continued for 5 hours, LC-MS detection reaction was completed, the solvent was concentrated, ethyl acetate (50mL) and water (30mL) were added, liquid separation was carried out, the aqueous phase was extracted with ethyl acetate (2X 20mL), and the organic phases were combined and dried over anhydrous sodium sulfate. The solvent was concentrated and the residue was used directly in the next step.

(14) Preparation of methyl (S) -2- (6- ((2' -cyclopropyl-4 ' - (2- (1, 1-dioxo-1, 2, 5-thiadiazolidin-2-yl) ethoxy) - [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate

(S) -5- (2- ((2-cyclopropyl-3 '- (((3- (2-methoxy-2-oxoethyl) -2, 3-dihydrobenzofuran-6-yl) oxy) methyl) - [1,1' -biphenyl ] -4-yl) oxy) ethyl) -1,2, 5-thiadiazolidinyl-2-carboxylic acid tert-butyl ester 1, 1-dioxide (142.4mg,0.21mmol) was dissolved in dichloromethane (10mL), trifluoroacetic acid (2mL) was added, stirring at room temperature for 4 hours, LC-MS detection reaction was complete, solvent was concentrated, and the residue was used directly in the next step.

(15) Preparation of (S) -2- (6- ((2' -cyclopropyl-4 ' - (2- (1, 1-dioxo-1, 2, 5-thiadiazolidin-2-yl) ethoxy) - [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetic acid (Compound 9)

Methyl (S) -2- (6- ((2' -cyclopropyl-4 ' - (2- (1, 1-dioxo-1, 2, 5-thiadiazolidin-2-yl) ethoxy) - [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate (121.4mg,0.21mmol) was dissolved in methanol (5mL), a sodium hydroxide (2N) solution (2mL) was added, stirring was carried out at room temperature for 3 hours, LC-MS detection of the completion of the reaction was carried out, the solvent was concentrated, water (50mL) was added, pH =4-5 was adjusted, the aqueous phase was extracted with ethyl acetate (2X 50mL), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and the residue was subjected to silica gel column chromatography (dichloromethane: methanolether =15:1) to obtain the title compound (6.0mg, three step yield 5.1%).

The molecular formula is as follows: c₃₀H₃₂N₂O₇S molecular weight: 564.65 LC-MS (m/z): 565.3(M +1)

¹H-NMR(400MHz,MeOD):7.30-7.41(m,4H),7.06-7.12(m,2H),6.80(dd,J=8.4Hz,2.0Hz,1H),6.47-6.51(m,2H),6.41(d,J=2.0Hz,1H),5.09(s,2H),4.67-4.69(m,1H),4.45-4.54(m,1H),4.18-4.24(m,3H),3.71-3.78(m,1H),3.54-3.62(m,2H),3.31-3.42(m,4H),2.69(dd,J=9.2Hz,5.6Hz,1H),2.53(dd,J=9.2Hz,5.6Hz,1H),1.62-1.65(m,1H),0.74-0.76(m,2H),0.62-0.64(m,2H).

EXAMPLE 6 preparation of (R) -2- (6- ((2' -cyclopropyl-4 ' - (2- (1, 1-dioxoisothiazolidin-2-yl) ethoxy) - [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetic acid (Compound 12)

(1) Preparation of (S) -5- (2- ((2-cyclopropyl-3 '- (((3- (2-methoxy-2-oxoethyl) -2, 3-dihydrobenzofuran-6-yl) oxy) methyl) - [1,1' -biphenyl ] -4-yl) oxy) ethyl) -1,2, 5-thiadiazolidinyl-2-carboxylic acid tert-butyl ester 1, 1-dioxide

Methyl (S) -2- (6- ((2' -cyclopropyl-4 ' -hydroxy- [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate (100mg,0.23mmol) was dissolved in N, N-dimethylformamide (10mL), sodium hydride (60%, 18.6mg,0.464mmol) was added, stirring was carried out at room temperature for 0.5 hour, tert-butyl 5- (2- (p-toluenesulfonyloxy) ethyl) -1,2, 5-thiadiazolidinyl-2-carboxylate 1, 1-dioxide (146mg,0.35mmol) was added, stirring was continued for 5 hours, LC-MS detection reaction was completed, the solvent was concentrated, ethyl acetate (50mL) and water (30mL) were added, liquid separation was carried out, the aqueous phase was extracted with ethyl acetate (2X 50mL), and the organic phases were combined and dried over anhydrous sodium sulfate. The solvent was concentrated and the residue was used directly in the next step.

(2) Preparation of methyl (S) -2- (6- ((2' -cyclopropyl-4 ' - (2- (1, 1-dioxo-1, 2, 5-thiadiazolidin-2-yl) ethoxy) - [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate

(S) -5- (2- ((2-cyclopropyl-3 '- (((3- (2-methoxy-2-oxoethyl) -2, 3-dihydrobenzofuran-6-yl) oxy) methyl) - [1,1' -biphenyl ] -4-yl) oxy) ethyl) -1,2, 5-thiadiazolidinyl-2-carboxylic acid tert-butyl ester 1, 1-dioxide (156.1mg,0.23mmol) was dissolved in dichloromethane (10mL), trifluoroacetic acid (2mL) was added, stirring was carried out at room temperature for 4 hours, the reaction was terminated by LC-MS detection, the solvent was concentrated, and the residue was used directly in the next step.

(3) Preparation of methyl (S) -2- (6- ((2' -cyclopropyl-4 ' - (2- ((5-methyl-1, 1-dioxo-1, 2, 5-thiadiazolidin-2-yl) ethoxy) - [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate

Methyl (S) -2- (6- ((2' -cyclopropyl-4 ' - (2- (1, 1-dioxo-1, 2, 5-thiadiazolidin-2-yl) ethoxy) - [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate (80mg,0.14mmol) was dissolved in N, N-dimethylformamide (10mL), sodium hydride (60%,11mg,0.276mmol) was added, and the mixture was stirred at room temperature for 0.5 hour. Methyl iodide (29.5mg,0.21mmol) was added slowly, stirring was continued for 3 hours, water (10mL) and ethyl acetate (50mL) were added, the layers were separated, the aqueous layer was extracted with ethyl acetate (20mL), the organic layers were combined, dried over anhydrous sodium sulfate, concentrated, and the residue was used directly in the next step.

(4) Preparation of (S)2- (6- ((2' -cyclopropyl-4 ' - (2- (5-methyl-1, 1-dioxo-1, 2, 5-thiadiazolidin-2-yl) ethoxy) - [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetic acid (Compound 12)

Methyl (S) -2- (6- ((2' -cyclopropyl-4 ' - (2- ((5-methyl-1, 1-dioxo-1, 2, 5-thiadiazolidin-2-yl) ethoxy) - [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate (82.9mg,0.14mmol) was dissolved in methanol (5mL), a sodium hydroxide (2N) solution (2mL) was added, stirring was carried out at room temperature for 3 hours, LC-MS detection of reaction completion, the solvent was dried, water (50mL) was added, pH =4-5 was adjusted, the aqueous phase was extracted with ethyl acetate (2X 50mL), the organic phases were combined, dried over anhydrous sodium sulfate, dried, and subjected to silica gel column chromatography (dichloromethane: methanolic ether =15:1) to give the title compound (7.0mg, yield 8.64%).

The molecular formula is as follows: c₃₁H₃₄N₂O₇S molecular weight: 578.68 LC-MS (m/z): 579.3(M +1)

¹H-NMR(400MHz,MeOD):7.36-7.41(m,3H),7.29-7.31(m,1H),7.08(dd,J=14.4Hz,8.4Hz,2H),6.78(dd,J=8.4Hz,2.8Hz,1H),6.46-6.51(m,2H),6.41(d,J=2.4Hz,1H),5.08(s,2H),4.69(t,J=9.2Hz,1H),4.19-4.23(m,1H),4.18(t,J=9.2Hz,2H),3.70-3.77(m,1H),3.50(t,J=6.4Hz,2H),3.43(t,J=5.6Hz,2H),3.31-3.35(m,2H),2.70(s,3H),2.65-2.68(m,1H),2.48-2.54(m,1H),1.75-1.81(m,1H),0.73-0.76(m,2H),0.62-0.64(m,2H).

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof:

wherein,

R₁、R₂each independently selected from a hydrogen atom or a cyclopropyl group;

R₃、R₄each independently selected from a hydrogen atom;

R₅is pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl or methyl, ethyl, propyl substituted with a substituent selected from 1, 1-dioxoisothiazolidinyl, 1-dioxo-1, 2, 5-thiadiazolidinyl, methyl substituted 1, 1-dioxo-1, 2, 5-thiadiazolidinyl, 1-dioxo-1, 2-thiazinoalkyl, 1-dioxo-1, 2, 6-thiadiazinylalkyl, methyl substituted 1, 1-dioxo-1, 2, 6-thiadiazinylalkyl or-NHS (O)_mR₆；

m is 2;

R₆methyl, ethyl and propyl.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, having the structure of formula (II):

R₁、R₂、R₃、R₄、R₅as defined in claim 1.

3. The compound of claim 1, or a pharmaceutically acceptable salt thereof:

wherein,

R₃、R₄each independently selected from a hydrogen atom;

R₅is pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl.

4. A compound according to claim 3, or a pharmaceutically acceptable salt thereof, selected from:

5. the compound of claim 1, or a pharmaceutically acceptable salt thereof:

wherein,

R₃、R₄each independently selected from a hydrogen atom;

R₅is methyl, ethyl or propyl substituted by a substituent taken from-NHS (O)_mR₆；

m is 2;

R₆methyl, ethyl and propyl.

6. A compound as claimed in claim 5, or a pharmaceutically acceptable salt thereof, selected from:

7. the compound of claim 1, or a pharmaceutically acceptable salt thereof:

wherein,

R₃、R₄each independently selected from a hydrogen atom;

R₅is methyl, ethyl or propyl substituted by a substituent selected from the group consisting of 1, 1-dioxoisothiazolidinyl, 1-dioxo-1, 2, 5-thiadiazolidinyl, methyl substituted 1, 1-dioxo-1, 2, 5-thiadiazolidinyl, 1-dioxo-1, 2-thiazinanyl, 1-dioxo-1, 2, 6-thiadiazinylalkyl, methyl substituted 1, 1-dioxo-1, 2, 6-thiadiazinylalkyl.

8. The compound of claim 7, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:

9. a pharmaceutical composition comprising a compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, characterised in that it comprises one or more pharmaceutically acceptable carriers and/or diluents.

10. The compound of claims 1-8, or a pharmaceutically acceptable salt thereof, further comprising one or more additional pharmaceutical agents which may be an agent for treating diabetes, an agent for treating diabetic complications, an agent for treating hyperlipidemia, an antihypertensive agent, an antiobesity agent, a diuretic agent, a chemotherapeutic agent, an immunotherapeutic agent, an anti-inflammatory agent, an antithrombotic agent, an agent for treating osteoporosis, cellulosics, an anti-dementia agent, an agent for treating frequent urination or urinary incontinence.

11. Use of a pharmaceutical composition according to claim 9 for the preparation of a GPR40 receptor agonist for the prophylaxis and/or treatment of diabetes and diabetes-related diseases.

12. Use of a compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment and/or prophylaxis of diabetes and diabetes-related disorders.