CN104250239B - The polycyclic carboxylic acid derivates of fragrance - Google Patents

Abstract

The invention belongs to pharmaceutical technology field, be specifically related to fragrance polycyclic carboxylic acid derivates class GPR40 receptor stimulating agent, its pharmaceutically acceptable salt, its ester or its stereoisomer, the wherein R shown in formula (I)₁、R₂、R₃、R₄、R₅It is defined as in the description with X；The invention still further relates to the preparation method of these compounds, pharmaceutical preparation and pharmaceutical composition, and described compound and pharmaceutical composition in preparation as GPR40 receptor stimulating agent for preventing and/or treating the application in the medicine of diabetes.

Description

The polycyclic carboxylic acid derivates of fragrance

1, technical field

The invention belongs to pharmaceutical technology field, be specifically related to fragrant polycyclic carboxylic acid derivates class GPR40 receptor stimulating agent, its Pharmaceutically acceptable salt, its ester and their stereoisomer, the preparation method of these compounds, pharmaceutical preparation and medicine Composition, and these compounds as GPR40 receptor stimulating agent for prepare prevention and/or treatment diabetes medicine in Application.

2, background technology

Current research shows, GPR40 receptor stimulating agent compounds is a kind of novel drugs for the treatment of type ii diabetes, and it changes Kind glycemic control effect is similar to Glimepiride, but causes hypoglycemic risk significantly lower than the latter.

Type ii diabetes is modal diabetes type.At present the U.S. there are about 1.5 hundred million people and suffers from diabetes, and wherein 90% It it is type ii diabetes.The extent of injury that general population is healthy has been occupied the 3rd of Chronic Non-Communicable Diseases.Along with China's economy Fast development and the improvement of people's material life, China has become one of the highest country of diabetes number of patients.Diabetes And complication has become 21 century global great public health problem, according to national diabetes epidemic disease in 2007～2008 Learning investigation result, in the Chinese population of age >=20 year old, diabetes and prediabetes illness rate are respectively 9.7% He 15.5%, at present China there are about 92,400,000 adults and suffers from diabetes in prediction on such basis, is 4 times in 2003.

The reaction of insulin is reduced by this disease mainly due to body, thus causes blood sugar to raise and various chronic diseases. Only about 1/2 can be by glycemic control in desirable level in type ii diabetes patient.

Free-fat acid acceptor 1 (FFAR1), or referred to as g protein coupled receptor 40 (GRP40) is stimulating and regulation insulin Play a crucial role during generation.Free fatty (FFA) causes, via GPR40, the mechanism that intracellular calcium concentration raises: Concentration of glucose raises the metabolism accelerating glucose inside cells, causes ATP/ADP level in cytosol to rise, closes what ATP relied on Potassium-channel, causes membrane depolarization, activates L-type calcium channel and opens.Then FFA stimulates seven cross-films on cell membrane Acceptor GPR40, follows phosphatidylinositols information and forwards approach to, on stimulating er discharge calcium ion, and open further L-type calcium from Subchannel, causes stream in extracellular calcium, significantly raises intracellular calcium concentration, thus cause insulin secretion.Work as meal When in rear blood, glucose and aliphatic acid raise, FFAR1 reduces blood sugar level by stimulating beta Cell of islet uelralante.Cause This can activate the medicine of FFAR1, by helping diabetic discharge more insulin and then efficiently control blood sugar level.

GPR40 receptor stimulating agent, is to strengthen the new oral medicine of insulin secretion with glucose-dependent manner, passes through Stimulate islet β cell insulin to play a role, but only just work patient needs most when, as in blood after the meal When glucose and aliphatic acid rise, i.e. when blood sugar level is normal, this activator to insulin secretion without any effect.Therefore, GPR40 receptor stimulating agent both can effectively control blood sugar and raise, and hypoglycemic occurrence risk can be made again to minimize.

Take place frequently after treating in view of a lot of medicines (such as Glimepiride etc.) hypoglycemia, and GPR40 receptor agonist treatment Rear risk of hypoglycemia is relatively low.This shows there is obvious advantage with FFAR1 for target treatment type ii diabetes.

Security and the validity of Long-term clinical experiment also will demonstrate that GPR40 receptor stimulating agent can be in type ii diabetes Drug therapy in occupy a tiny space.

By using GPR40 receptor stimulating agent, can effectively treat and there are identical pathogenetic diabetes, be so far Only, also there is no the official listing new drug with GPR40 as target.WO2008001931 (publication date 2008.01.03) discloses by The medicine TAK-875 raceme of the clinical trial III phase that is in of Takeda company exploitation, is used for treating diabetes, has been achieved with Clear and definite curative effect.Therefore, research and development have higher pharmacologically active, higher security, and the most selective GPR40 is exciting Agent, has very important significance for treatment type ii diabetes, and market is huge.

Owing to GPR40 receptor stimulating agent compounds participates in various physiological processes in human body, it is also possible to multiple with other Disease has close being correlated with.So the activator of the high-efficiency low-toxicity of research GPR40, for treatment diabetes (especially II type sugar Urine disease) and relevant indication such as obesity, GI, insulin resistance, Metabolic syndrome X, high fat of blood, high courage Sterol mass formed by blood stasis, atherosclerotic, Alzheimer disease, parkinsonism, apoplexy and some cancer (such as breast cancer) etc., be respectively provided with Very important meaning.

3, summary of the invention

The technical problem to be solved in the present invention is to provide a kind of fragrant polycyclic carboxylic acid derivates class GPR40 receptor stimulating agent, For preparing the application in the medicine such as prevention and/or treatment diabetes.

Technical scheme is as follows:

Logical compound shown in formula (I), its pharmaceutically acceptable salt, ester and stereoisomer thereof:

Wherein, R₁For hydrogen atom, the C being optionally substituted with a substituent_1-6Alkyl, amino or 3-14 unit cycloalkyl, described replacement Base is selected from C_1-6Alkyl, halogen atom, hydroxyl, amino or halo C_1-6Alkyl；

X is key or-NH-, or R₁-the S (O) being connected with them with X₂-form the 3-14 ring being optionally substituted with a substituent Shape structure, described substituent is selected from halogen atom, hydroxyl, amino, C_1-6Alkyl, halo C_1-6Alkyl, C_1-6Alkoxyl or C_1-6Alkane Base carbonyl；

R₂、R₃、R₄、R₅Separately selected from hydrogen atom, halogen atom, hydroxyl or the C being optionally substituted with a substituent_1-6Alkane Base, described substituent is selected from halogen atom, hydroxyl, amino, halo C_1-6Alkyl, C_1-6Alkyl-carbonyl or C_1-6Alkyl sulphonyl.

Logical compound shown in formula (I), its pharmaceutically acceptable salt, ester and the optimization technique side of stereoisomer thereof Case, has a structure shown in below formula (II):

Wherein, R₁For hydrogen atom, the C being optionally substituted with a substituent_1-6Alkyl, amino or 3-14 unit cycloalkyl, described replacement Base is selected from C_1-6Alkyl, halogen atom, hydroxyl, amino or halo C_1-6Alkyl；

X is key or-NH-, or R₁-the S (O) being connected with them with X₂-form the 3-14 ring being optionally substituted with a substituent Shape structure, described substituent is selected from halogen atom, hydroxyl, amino, C_1-6Alkyl, halo C_1-6Alkyl, C_1-6Alkoxyl or C_1-6Alkane Base carbonyl；

R₂、R₃、R₄、R₅Separately selected from hydrogen atom, halogen atom, hydroxyl or the C being optionally substituted with a substituent_1-6Alkane Base, described substituent is selected from halogen atom, hydroxyl, amino, halo C_1-6Alkyl, C_1-6Alkyl-carbonyl or C_1-6Alkyl sulphonyl.

Logical compound shown in formula (I), the optimal technical scheme of its pharmaceutically acceptable salt, ester and stereoisomer thereof For:

Wherein, R₁For the C being optionally substituted with a substituent_1-4Alkyl, amino or 3-7 unit cycloalkyl, described substituent is selected from C_1-4Alkyl, fluorine atom, chlorine atom, hydroxyl, amino or halo C_1-4Alkyl；

X is-NH-, or R₁-the S (O) being connected with them with X₂-form the ring-type knot of 5-8 unit being optionally substituted with a substituent Structure, described substituent is selected from halogen atom, hydroxyl, amino, C_1-4Alkyl, halo C_1-4Alkyl or C_1-4Alkoxyl；

R₂、R₃、R₄、R₅Separately selected from hydrogen atom, halogen atom or C_1-4Alkyl.

Logical compound shown in formula (I), the optimal technical scheme of its pharmaceutically acceptable salt, ester and stereoisomer thereof For:

Wherein, R₁For the C being optionally substituted with a substituent_1-4Alkyl, amino or 3-7 unit cycloalkyl, described substituent is selected from first Base, ethyl, fluorine atom, chlorine atom, hydroxyl or amino；

X is-NH-, or R₁-the S (O) being connected with them with X₂-form the ring-type knot of 5-6 unit being optionally substituted with a substituent Structure, described substituent is selected from fluorine atom, chlorine atom, methyl, ethyl, hydroxyl, amino, trifluoromethyl, methoxy or ethoxy；

R₂、R₃、R₄、R₅Separately selected from hydrogen atom or C_1-4Alkyl.

Logical compound shown in formula (I), the optimal technical scheme of its pharmaceutically acceptable salt, ester and stereoisomer thereof For:

Wherein, R₁For methyl, ethyl, methylamino, dimethylamino, cyclopropyl, cyclobutyl, cyclopenta or cyclohexyl；

X is-NH-, or R₁-the S (O) being connected with them with X₂The 1,1-dioxo that-formation is optionally substituted with a substituent is different Thiazolidine, 1,1-dioxo-1,2,5-thiadiazolidine, 1,1-dioxo-1,2,3-thiadiazolidine or 1,1-dioxo-1,2,4- Thiadiazolidine, described substituent is selected from fluorine atom, chlorine atom, methyl, ethyl, trifluoromethyl or methoxyl group；

R₂、R₃For methyl；R₄、R₅For hydrogen atom.

Particularly preferred compound includes:

" halo " of the present invention refers to be replaced by " halogen atom ", and " halogen atom " refers to that fluorine atom, chlorine atom, bromine are former Son, atomic iodine etc..

" C of the present invention_1-6Alkyl " represent straight or branched the alkyl containing 1-6 carbon atom, as methyl, ethyl, N-pro-pyl, isopropyl, normal-butyl, isobutyl group, sec-butyl, the tert-butyl group, n-pentyl, isopentyl, 2-methyl butyl, neopentyl, 1- Ethyl propyl, n-hexyl, isohesyl, 3-methyl amyl, 2-methyl amyl, 1-methyl amyl, 3,3-dimethylbutyl, 2,2-bis- Methyl butyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethyl fourth Base, 1,2-dimethyl propyl etc.." C of the present invention_1-4Alkyl " refer to concrete containing 1-4 carbon atom in examples detailed above Example.

" halo C of the present invention_1-6Alkyl " refer to one or more " halogen atom " replacement " C_1-6Alkyl " on one or The group that multiple hydrogen atoms are derived, described " halogen atom " and " C_1-6Alkyl " as defined hereinabove." halogen of the present invention For C_1-4Alkyl " refer to the instantiation containing 1-4 carbon atom in examples detailed above.

" C of the present invention_1-6Alkoxyl, C_1-6Alkyl-carbonyl, C_1-6Alkyl sulphonyl " refer to C_1-6Alkyl-O-, C_1-6 Alkyl-C (O)-, C_1-6Alkyl-SO₂The group that-mode connects, wherein " C_1-6Alkyl " as defined hereinabove.Of the present invention “C_1-4Alkoxyl, C_1-4Alkyl-carbonyl, C_1-4Alkyl sulphonyl " refer to the instantiation containing 1-4 carbon atom in examples detailed above.

" 3-14 unit cycloalkyl " of the present invention refers to the 3-14 cyclic group of all carbon atoms of annular atoms, including 3-8 unit cycloalkyl and 8-14 unit cycloalkyl；" 3-7 unit cycloalkyl " of the present invention refers to contain in " 3-14 unit cycloalkyl " The instantiation of 3-7 annular atoms；

3-8 unit cycloalkyl, refers to the saturated cyclic alkyl containing 3-8 carbon atom, and instantiation includes but not limited to: Cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, suberyl, ring octyl group, 1-methylcyclopropyl groups, 1-pentylcyclopropyl, 1,2-diethyl Tetramethylcyclobutyl, 1-methyl-cyclobutyl, 1-butyl cyclobutyl, 1,3-dimethylcyclobutyl, 1-methylcyclopentyl, 1-butyl ring penta Base, 1-methylcyclohexyl, 1-ethylcyclopentyl etc..

8-14 unit cycloalkyl, refers to be shared two containing 8-14 annular atoms each other by two or more circuluses Adjacent atom couple together formed saturated condensed cyclic structure, instantiation includes but not limited to: Deng.

" 3-14 membered cyclic structure " of the present invention refer to containing 3-14 annular atoms (at least a part of which contain one miscellaneous former Son) cyclic group, described hetero atom has nitrogen, oxygen and sulphur etc., includes that carbon atom, nitrogen-atoms and sulphur atom can be by oxygen simultaneously In generation, including 3-8 unit heterocyclic radical, 6-14 unit condensed hetero ring base, 5-8 unit heteroaryl, the thick heteroaryl of 6-14 unit." 5-8 of the present invention Membered cyclic structure " refer to the instantiation containing 5-8 annular atoms in " 3-14 membered cyclic structure "." 5-6 unit of the present invention Circulus " refer to the instantiation containing 5-6 annular atoms in " 3-14 membered cyclic structure ".

3-8 unit heterocyclic radical refers to the cyclic group containing 3-8 annular atoms (at least a part of which contains a hetero atom), specifically Example include but are not limited to aziridine, diazacyclo propane, azetidine, 1,2-diazetidine, pyrrolidines, Imidazolidine, pyrazolidine, piperidines, piperazine, oxirane, dioxirane, thiirane, oxetanes, 1,2-dioxa Cyclobutane, Thietane, oxolane, thiophane, 1,3-dioxolane, 1,3-dithiolane, tetrahydrochysene pyrrole Mutter, 1,4-dioxane, 1,3-dioxane, 1,3-thioxane, oxaza propane, tetrahydrochysene azoles, Tetrahydrochysene isoxazole, tetrahydro-thiazoles, isothiazolidine, 1,2,3-thiadiazolidine, 1,2,4-thiadiazolidine, 1,2,5-thiadiazolidine, Quinoline, 2H-aziridine, 3H-diazacyclo propylene, diazete, 1,2-diazetine, pyrrolin, 4,5- Glyoxalidine, 4,5-pyrazoline, 1,2,3-triazole, 1,2,4-triazole, 2-pyridone, 4-pyridone, 1,2-diaza cycloheptyl Triolefin, 1,3-diazacyclo heptantriene, 1,4-diazacyclo heptantriene, 1,4-dihydro-1,4-diazacyclo sarohornene, 1,2-bis- Thia cyclobutane, 2,5-dihydro-thiophene, 1,2-dithiole, 1,3-dithiole, 2H-pyrans, 2H-pyrans-2- Ketone, 3,4-dihydro-2H-pyrans, 4H-pyrans, 4H-pyrans-4-ketone, 4,5-dihydro azoles, 4,5-dihydro isoxazole, 2,3-dihydro Isoxazole, 4,5-thiazoline, 2H-1,2-piperazine, 4H-1,2-piperazine, 6H-1,2-piperazine, 2H-1,3-piperazine, 4H-1,3- Piperazine, 6H-1,3-piperazine, 2H-1,4-piperazine, 4H-1,4-piperazine, 5,6-dihydro-4H-1,3-piperazine, 2H-1,3-thiazine, 4H-1, 3-thiazine, 6H-1,3-thiazine, 2H-1,4-thiazine, 4H-1,4-thiazine, 5,6-dihydro-4H-1,3-thiazine etc..

6-14 unit condensed hetero ring base refers to containing 6-14 annular atoms (at least a part of which contains a hetero atom) by two or two Individual above circulus share each other two adjacent atoms couple together formed condensed cyclic structure, include carbon atom, nitrogen simultaneously Atom and sulphur atom can be by oxos, and instantiation includes but are not limited to octahydro-benzo [d] imidazoles, decahydroquinolyl, octahydro Benzothiophene, octahydro benzofuran, hexahydro Thienoimidazole, hexahydro furyl imidazoles, 4H-1,3-Benzoxazine, 4,6-dihydro- 1H-furans also [3,4-d] imidazoles, 4,6-dihydro-1H-thieno [3,4-d] imidazoles, 4,6-dihydro-1H-pyrrolo-[3,4-d] Imidazoles, 4,5,6,7-tetrahydrochysene-1H-benzo [d] imidazoles etc..

5-8 unit heteroaryl refers to have armaticity ring containing 5-8 annular atoms (at least a part of which contains a hetero atom) Shape group, instantiation include but are not limited to furyl, thienyl, pyrrole radicals, thiazolyl, isothiazolyl, thiadiazolyl group, Oxazolyl, isoxazolyl, di azoly, imidazole radicals, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,3-diazole Base, 1,2,4-di azoly, 1,2,5-di azoly, 1,3,4-di azoly, pyridine radicals, pyrimidine radicals, 1,4-dioxa hexamethylene Dialkylene, 2H-1,2-piperazine base, 4H-1,2-piperazine base, 6H-1,2-piperazine base, 4H-1,3-piperazine base, 6H-1,3-piperazine base, 4H-1,4-piperazine base, pyridazinyl, pyrazinyl, 1,2,3-triazine radical, 1,2,4-triazine radical, cyanuro 1,3,5,1,3,4-triazine Base, 1,2,4,5-tetrazine base, oxepin base, thia cycloheptatriene base, azacyclo-heptantriene base, 1,3-diaza cycloheptyl Trialkenyl, azepine cyclooctatetraenyl etc..

The thick heteroaryl of 6-14 unit refers to containing 6-14 annular atoms (at least a part of which contains a hetero atom) by two or two Individual above circulus shares two adjacent atoms each other and couples together the undersaturated condensed ring knot with armaticity formed Structure, instantiation includes but not limited to: benzofuranyl, benzisoxa furyl, benzothienyl, indyl, benzoxazolyl group, Benzimidazolyl, indazolyl, BTA base, quinolyl, isoquinolyl, acridinyl, phenanthridinyl, benzo pyridazinyl, phthalazinyl, Quinazolyl, quinoxalinyl, phenol piperazine base, pteridine radicals, purine radicals, naphthyridines base etc..

Above-claimed cpd of the present invention can use the method described in following flow process and/or those of ordinary skill in the art Other technology known synthesizes, but is not limited only to following methods:

In the present invention, the implication representated by abbreviation is as follows:

THF is oxolane,

ADDP is azo diformyl two piperidines,

PE is petroleum ether,

EA is ethyl acetate,

DCM is dichloromethane,

Boc is tertbutyloxycarbonyl,

TFA is trifluoroacetic acid.

Reaction equation:

Reactions steps:

Step 1: the synthesis of intermediate 1

The ADDP of raw material 2 and 1.5 equivalent of raw material 1 and equivalent is joined in appropriate oxolane, under ice bath Adding 1.5 equivalent three normal-butyl phosphorus, drip complete, be warmed to room temperature, and continue to react after a period of time, separating-purifying obtains intermediate 1。

Step 2: the synthesis of intermediate 2

Intermediate 1 is dissolved in appropriate solvent, sloughs protection group, obtain intermediate 2.

Step 3: the synthesis of intermediate 3

Intermediate 2 is dissolved in appropriate solvent, adds excess of triethylamine, drip 1.1 under ice bath when content of starting materials 3, short time Inside drip off, be warmed to room temperature, after sustained response a period of time.Separating-purifying obtains intermediate 3.

Step 4: the synthesis of intermediate 4

By intermediate 3, the raw material 4 of equivalent, palladium, triphenyl phosphorus, TBAB, the potassium phosphate of excess, add Enter in appropriate oxolane, under nitrogen protection, after back flow reaction a period of time.Separating-purifying obtains intermediate 4.

Step 5: the synthesis of intermediate 5

Intermediate 4 and raw material 5 are joined in appropriate solvent with ADDP, under ice bath, adds three normal-butyl phosphorus, drip Finish, be warmed to room temperature.After sustained response a period of time, separating-purifying obtains intermediate 5.

Step 6: the synthesis of compound shown in logical formula (I)

Intermediate 5 is dissolved in appropriate THF/MeOH mixed solvent, is slowly added to the aqueous solution of alkali compounds, necessarily Under temperature conditions, after stirring a period of time.Separating-purifying obtains the compounds of this invention.

Wherein, the R in above-mentioned reaction equation¹、R²、R³、R⁴、R⁵With X as defined hereinabove.

" pharmaceutically acceptable salt " of claimed formula (I) compound, including alkali metal salt, alkaline-earth metal Salt, inorganic base salts, organic alkali salt, inorganic acid salt, acylate, amino-acid salt etc..

The present invention is led to " ester " of compound shown in formula (I) and is represented when compound shown in formula (I) exists carboxyl, can send out with alcohol The ester giving birth to esterification and formed, when there is hydroxyl in compound shown in formula (I), can be with organic acid, inorganic acid, acylate etc. There is esterification and the ester that formed.Ester under conditions of acid or alkali exist, can occur hydrolysis generate corresponding acid or Alcohol.

As compound, its pharmaceutically acceptable salt, its ester or its stereoisomer molten represented shown in logical formula (I) Agent compound, can enumerate hydrate etc., but be not limited to this.

The present invention is led to " stereoisomer " of compound shown in formula (I) and is divided into rotamer and configurational isomer, and structure Type isomers is also divided into cis-trans-isomer and optical isomer." stereoisomer ", refer to when the compounds of this invention contain one or Multiple asymmetric centers, this kind of asymmetric center respectively will produce two optical isomers independently, and the scope of the present invention includes All possible optical isomer and non-enantiomer mixture and pure or partial-purified compound.Of the present inventionization If compound contains olefinic double bonds, unless stated otherwise, the present invention includes cis-isomer and transisomer.Of the present invention Compound can exist with tautomeric forms, and it has the connection of different hydrogen by one or more double-bond shifts Point.Such as, ketone and its Enol forms are ketoenol tautomerization bodies.Each dynamic isomer and mixture thereof are included in this In the compound of invention.

The compound of the present invention can be combined using with one or more other drugs, and described other drug can be to control Treat the medicine of diabetes, the medicine for the treatment of diabetic complication, the treatment medicine of hyperlipidemia, drug for hypertension, anti-obesity Medicine, diuretics, chemotherapeutics, immunotherapy medicaments, anti-inflammatory drug, antithrombotic reagent, for osteoporotic medicine, Cellulose family, antidementia agent, for the medicine of frequent micturition or the urinary incontinence, for dysuric medicine etc..

Compound, its pharmaceutically acceptable salt, its ester or its stereoisomer shown in formula (I) can be with two kinds Or the active constituents of medicine of two or more compound composition or the pharmaceutical composition that forms with one or more pharmaceutical carriers. Described pharmaceutical composition can make the traditional drug formulations used clinically, can be used in modes such as oral and parenteral administrations Need the patient of this treatment.Such as tablet, particle, capsule, powder, injection, inhalant, sublingual administration preparation, syrup, coagulate Glue, ointment, suppository, lotion, nasal cavity drop, spray, preparation capable of permeating skin etc..These preparations can pass through conventional method, adds medicine It is prepared from carrier such as excipient, binder, humidizer, disintegrant, thickener etc..Described excipient such as lactose, sucrose, D- Mannitol, starch, cornstarch, avicel cellulose, light silicon dioxide etc..

The present invention leads to compound shown in formula (I), its pharmaceutically acceptable salt, its ester and their stereoisomer, Lactation can be applied to administering modes such as oral administration, parenteral (intravenous, muscle interior, subcutaneous or rectum etc.), transpulmonary, local move Thing, such as people.In pharmaceutical preparation, the content of the compound of the present invention is relative to the weight that preparation really is 0.01 to about 100%. Dosage changes, the compound (as active component) of the such as present invention according to being administered object, method of administration, disease, illness etc. Can be with following dosage in diabetic (body weight about 60kg): about 0.01～30mg/kg body weight every day, preferably from about 0.1～20mg/kg body weight every day, more preferably from about 1～20mg/kg body weight every day.This dosage can give once a day or divide Become to give several times.

Shown in formula (I), compound, its pharmaceutically acceptable salt, its ester or its stereoisomer are mammal The GPR40 function of receptors regulation effect that middle display is excellent, the conditioning agent as the physiological function relating to GPR40 acceptor is useful , or be useful as prevention and/or the treatment pathology of GPR40 acceptor or the prevention of disease and/or medicine.

Specifically, compound shown in formula (I), its pharmaceutically acceptable salt, its ester or its stereoisomer are made For insulin secretion modulators (preferably insulin secretagogue), medicine and the beta Cell of islet protective agent of hypoglycemia are useful 's.

Especially, compound, its pharmaceutically acceptable salt, its ester or its stereoisomer shown in formula (I) based on Its GPR40 receptor agonist activity, is useful as the insulin secretagogue depending on blood sugar level.This and sulfonylurea Difference, shown in formula (I), compound, its pharmaceutically acceptable salt, its ester or its stereoisomer are low as not causing The insulin secretagogue of blood sugar is useful.

Shown in formula (I), compound, its pharmaceutically acceptable salt, its ester or its stereoisomer can be as in advance Preventing and/or treat diabetes and the medicine of relevant disease, described relevant disease includes impaired glucose tolerance, ketoacidosis, acid poisoning, glycosuria Sick complication (such as, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, macroangiopathy, glycosuria Characteristic of disease gangrene), macular edema, hyperlipidemia, obesity, hypoglycemia, hypertension, oedema, insulin resistance, instability mode glycosuria Disease, adipositas ex vacuo insulin allergy, insulinoma, Fatty toxicity, hyperinsulinemia, metabolic syndrome, immunity disease, inflammation Property disease, multiple sclerosis, acute renal failure etc..Additionally, diabetes include IDDM, type II diabetes, gestational diabetes mellitus And fat diabetes.Hyperlipidemia include HTC, hypercholesterolemia, low-high density lipoprotein mass formed by blood stasis, Postprandial hyperlipemia etc..

According to ADA (ADA American Diabetes Association), WHO and Japan's glycosuria The new diagnostic criteria of the diabetes of sick association report, formula (I) compound, its pharmaceutically acceptable salt, its ester or Its stereoisomer may be used for prevention and/or treatment diabetes, peripheral type, impaired glucose tolerance, IFG (impaired taboo Food glucose, Impaired Fasting Glucose) and the medicine of IFG (impaired fasting serum glucose is too much).Additionally, the present invention Formula (I) compound, its pharmaceutically acceptable salt, its ester or its stereoisomer can prevent peripheral type, impaired glucose Tolerance, IFG (impaired fasting glucose, Impaired Fasting Glucose) and IFG (impaired fasting serum glucose is too much) Develop into diabetes.

The beneficial effect of the compounds of this invention is expanded on further below by way of experiment, but this should be interpreted as of the present inventionization Compound only has following beneficial effect.

Experimental example 1 the compounds of this invention calcium current test experience to GPR40 transfection cell strain

Experiment purpose: utilize the HEK293 clone stably expressing people hGPR40, uses FLIPR instrument detection of the present inventionization The calcium current signal that compound causes, evaluates the compounds of this invention and the LA (linoleic acid) the activation effect to hGPR40.

Test sample: part of compounds of the present invention, prepares according to the method in the embodiment of the present invention respectively；

Reference substance: tester LA (linoleic acid)；Tester TAK-875 raceme, its structural formula isTester TAK-875, its structural formula is as it was noted above, according to patent Prepared by WO2008001931 (publication date 2008.01.03) method.

Experiment reagent:

Experimental procedure:

(1) cell is cultivated

Calcium current detects the previous day, is layered on by the hGPR40 cell of low algebraically on 384 hole detection plates, and cell density is 8000 Individual/hole, 50 μ L/ holes.At 37 DEG C, 5% CO₂Overnight incubation in incubator.

(2) compound gradient dilution

Dilution buffer is prepared:

Buffer solution 1:25 mL HBSS (containing 20 mM HEPES)+250 μ L 10% BSA, prepares 0.1% BSA buffer solution

Buffer solution 2:19.7 mL Buffer1+0.3 mL DMSO, prepares 1.5% DMSO buffer solution.

Diluted chemical compound:

1) accurately weigh that test sample is appropriate, reference substance TAK-875 raceme (3.01 mg), dissolve with DMSO be configured to dense Degree is the sample of 10 mM.

2) test sample and the reference substance TAK-875 raceme DMSO of 10 mM are diluted to 3 mM.

3) test sample from 3 mM pipettes 2.5 μ L, adds 148 μ L buffer solution dilutions, is configured to mother liquor, pipettes 40 μ L Mother liquor, adds 80 μ L buffer solutions 2, presses 1:3 gradient dilution, totally 10 concentration point, maximum concentration 50 μMs successively.First at 96 orifice plates Middle dilution, then continues in 384 orifice plates, duplicate hole.

4) 10 μ L LA add 22 μ L DMSO and are made into the solution that concentration is 1 mol/L, take 10 μ L solution and add 20 μ L DMSO is diluted to the solution of 300 mM, takes 1 μ L 300 Mm LA/DMSO solution and adds 100 μ L DMSO and be diluted to the molten of 3 mM Liquid, takes 2.5 μ L 3 mM LA/DMSO solution, adds 148 μ L buffer solution 1 solution, is configured to mother liquor, pipettes 40 μ L mother liquors, Add 80 μ L buffer solutions 2, press 1:3 gradient dilution, totally 10 concentration point, maximum concentration 50 μMs successively.The dilutest in 96 orifice plates Release, then continue in 384 orifice plates, duplicate hole.

(3) FLIPR calcium current detection

The preparation of calcium dyestuff: 10 mL HBSS (20 mM HEPES)+1 tube calcium dyestuff+100 μ L 10% BSA.

Calcium dye load is in cell:

1) 384 orifice plates being covered with cell are taken out from incubator, discard culture medium.

2) 384 orifice plates add calcium dyestuff, 40 μ L/ holes.

3) 384 orifice plates are put back in incubator, hatch 1 h.

FLIPR detects:

1) 384 orifice plates of cell will be covered with and be placed with 384 orifice plates of compound and be placed in above FLIPR in cabinet corresponding Position.

2) FLIPR experimental arrangement is set so that the compound volume added in every porocyte is 10 μ L, such compound The highest final concentration of 10 μMs, final concentration of 0.3 % of DMSO.

Control:10 μM of TAK-875 comparison of High.

Low control: be not added with the comparison of compound.

3) run instrument, obtain calcium current detection curve.

Data process and result

Initial data XLfit is fitted, and obtains the EC of each compound and reference substance₅₀And efficacy value.Wherein EC₅₀Value is given by matched curve, the maximum of efficacy=compound matching gained/(High control-Low control)×100%.Result such as table 1-3.

EC₅₀Value: half-maximal effect concentration, i.e. causes the concentration of 50 % ceiling effects.

Table 1 the compounds of this invention 1 calcium current testing result

LA is one of native ligand of GPR40, the EC worked in vitro₅₀Concentration is higher, and the compounds of this invention acts on GPR40, is entered internal rear and LA competition, is compared by the relative activity value with LA, embody it big with the binding ability of GPR40 Little.Relative activity value>80, for full agonist, relative activity value<80, for partial agonist.

Experiment conclusion: from the data in table 1,2,3,4 and 5, the compounds of this invention EC₅₀Value and TAK-875 raceme Quite, relative activity value is suitable with TAK-875 raceme, and the compounds of this invention is full agonist, shows the compounds of this invention Obvious to the agonism of GPR40.

Experimental example 2 the compounds of this invention GTPgS binding ability test experience to GPR40 transfection cell strain

Test sample: part of compounds of the present invention, prepares according to the method in the embodiment of the present invention respectively；

Reference substance: tester TAK-875, its structural formula is as it was noted above, according to patent WO2008001931(publication date 2008.01.03) prepared by method.

Experiment reagent:

Experimental procedure:

(1) cell membrane is extracted

1. collect 100 ware cells, digest with PBS-EDTA.

2. with 5 times of TE(Tris-EDTA) solution re-suspended cell.1000g, 4 DEG C of centrifugal 10min, supernatant 26000g, 4 DEG C Centrifugal 30min.

3. abandoning supernatant, resuspended with 5 times of TE, 26000g, 4 DEG C of centrifugal 30min.

4. abandoning supernatant, resuspended and be diluted to 30mL with 5 times of TE.

5. measure protein concentration by Bradford method and be diluted to 1mg/mL, being dispensed in l-2mL centrifuge tube ,-80 DEG C Store.

(2) diluted chemical compound

Compound DMSO carries out 5 times of gradient dilutions and becomes compound stock solutions.

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

1. preparation detection solution: 23mL buffer solution (50mM Hepes, 160mM NaCl, 10mMMgCl2,1mM EDTA)+ 230 μ L10%BSA (without free fatty)+4.6 μ L saponin (50mg/mL)+11.5 μ LGDP (5mM)) it is placed in frozen water.

2. take the cell membrane solution 0.8mL that concentration is 1mg/mL, addition detection solution 23mL to be diluted to concentration and be The solution of 0.035mg/mL.

3. in the cell membrane solution of above-mentioned 2.0, add 23 μ L100nM³⁵S-GTPgS, final concentration of 0.1nM.

(4) association reaction

1. take two pieces of Corning96 holes U base plate (catalog#3605), be designated as reaction plate1, reaction plate2.

2. take compound stock solutions 1 μ L to reaction plate1 and the corresponding hole of reaction plate2 of gradient dilution (final concentration of compound is respectively 10,2,0.4,0.08,0.016,0.003,0.0006,0.0001,0.00003,0.000001 μM)

3. add 1 μ L10mM Unlabeled GTPgS to reaction plate1and reaction plate2 corresponding Hole.

4. add cell membrane dilute solution (0.035mg/mL film, the 0.1nM in the 3.3 of 99 μ L³⁵S-GTPgS) arrive In the corresponding hole of reaction plate 1and reaction plate2.

5. reaction plate is used topseal sealer.

6.1000 leave the heart 1 minute, vibrate 2 minutes.

7.4 DEG C of reactions 1.5h, room temperature reaction 1h.

(5) reaction terminating

By instrument Cell Harvester(Perkin Elmer), collect cell membrane with GF/B plate, then use buffer solution Being cleaned 10 times by GF/B plate, GF/B plate hair drier dries up (10 minutes).

(6) detection

1. by sealer bottom plate, and add the Microscint40scintillation fluid solution in 50 μ L/ holes, incubate Educate 2h.

2. plate is placed in TopCount-NXT reading.

Data process:

IC₅₀Using XLfit matching, Y=(A+ ((B-A)/(1+ ((C/x) ^D)))), Y is isotopic reading (cpm), being of X The logarithm value of compound concentration, A is curve minimum, and B is curve peak, and C is IC₅₀Value, D is hillslope.

Data process and result:

The binding ability testing result of table 5 the compounds of this invention 5,6

Conclusion:

With the combination potency test of people GPR40, the compounds of this invention shows that the binding ability of compound 5 is better than compareing chemical combination Thing TAK-875, the binding ability of compound 6 is suitable with control compound TAK-875.

The internal pharmacokinetics of experimental example 3 the compounds of this invention measures

1. experimental design

2. test sample

Part of compounds of the present invention, prepares according to the method in the embodiment of the present invention respectively;

Dissolving scheme: compound 1-4 20%DMF+20%PEG400+60% sterilized water for injection dissolves；

Compound 5IV 2%DMSO+20% (40%HP-β-CD)+78% sterilized water for injection PO 2%klucel LF+0.1% Tween；

Compound 6IV 5%DMSO+20% (40%HP-β-CD)+75% sterilized water for injection PO 2%klucel LF+0.1% Tween。

Compound concentration: 0.5 mg/mL (IV: solution；PO: suspension compound 1,2,3,4 is solution, and compound 5,6 is mixed Suspension)

Internal standard 1: Da Gelie clean (Dapagliflozin) used by compound 1, structure isPress Prepare according to the method in patent WO03099836A1 (publication date 2003.12.04), dissolve with MTBE.

Internal standard 2:TAK-875 raceme used by compound 2,3,4,5,6, according to patent WO2008001931 (publication date 2008.01.03 prepared by the method in).Internal standard MTBE used by compound 2,3,4 is dissolved；Internal standard used by compound 5,6 is used Acetic acid ethyl dissolution.

3. equipment

Instrument and equipment: compound 1,2,3,4 uses API4000 LC-MS/MS；Compound 5,6 uses API3000 LC-MS/MS

Chromatographic column: Waters XBridge^TM C18 (2.10×50 mm,5 μm)

4. blood collection

Rat blood gathers: fixing animal, before each time point, 10 min water-baths heat afterbody, are adopted by tail vein Collect the whole blood of 100 μ about L, be placed into after blood collection containing in liquaemin anticoagulant tube.Blood sample is under the conditions of 4 DEG C 8000 Rpm is centrifuged 6 min and obtains plasma sample, and blood plasma must be prepared in 30 min after blood collection.Leave in before blood plasma test- In 80 DEG C of refrigerators.

5. experimental technique

(1) from refrigerator take out testing sample (-80 DEG C), room temperature naturally melt after vortex 5 min；

(2) precision pipettes 20 μ L sample in 1.5mL EP pipe；

(3) 600 μ L inner mark solutions (containing the internal standard TAK-875 raceme 25ng/mL) are added；

After (4) 1500 revs/min of vortex 10 min, centrifugal 5 min (12000 revs/min)；

(5) during precision pipettes 400 μ L of supernatant liquid to 96 orifice plates, N₂Dry up, add 200 μ L redissolve liquid (acetonitrile: water=1: 1), vortex mixes, and LC-MS/MS analyzes.

6. data processing method

Tested material (plasma sample) concentration uses the Analyst 1.5.1 of AB company to export result.Microsoft Excel Calculating the parameter such as average, standard deviation, the coefficient of variation (Analyst 1.5.1 directly export need not calculate), PK parameter uses Pharsight Phoenix 6.2 software calculates.Computing formula: F%=AUCinf_-po*Dose_iv/AUCinf_-iv*Dose_po。

Table 6 compound is quiet is pushed to the P of Rats K evaluation result of detection compound after medicine

The P of Rats K evaluation result of detection compound after table 7 compound gastric infusion

Table 8 compound is quiet is pushed to the P of Rats K evaluation result of detection compound after medicine

The P of Rats K evaluation result of detection compound after table 9 compound gastric infusion

Wherein, T_1/2Represent the half-life；AUC_lastRepresent area under the drug-time curve_0→t；CL represents clearance rate；Vss represents table See distribution volume；C_maxRepresent blood peak concentration of drug；T_maxRepresent blood medicine peak time；F% represents absolute bioavailability.

7. experiment conclusion

From table 6,7,8 and 9, the PK parameter of the compounds of this invention measured by the way of IV and PO in rat body Compared with TAK-875 raceme or TAK-875, the exposed amount (AUC) that IV is administered is suitable, the wherein distribution body of compound 1,3,4 Long-pending (Vss) is better than TAK-875 raceme；The half-life of compound 5,6 is better than TAK-875, clearance rate (CL) quite；PO is administered Peak concentration (C_max) and exposed amount (AUC) and TAK-875 raceme or TAK-875 suitable, the wherein biological utilisation of compound 5 Degree is better than TAK-875, may be used for the treatment of the diseases such as diabetes, and the compounds of this invention oral administration biaavailability compares TAK- 875 preferably, have more preferable potential applicability in clinical practice.

HepG2 cells apoptosis is studied by experimental example 4 the compounds of this invention

Test sample: part of compounds of the present invention, prepares according to the method in the embodiment of the present invention respectively；

Reference substance: positive control staurosporine (commercial)；Tester TAK-875 raceme, its structural formula isTester TAK-875, its structural formula is as it was noted above, according to patent WO200800 Prepared by 1931 (publication date 2008.01.03) method；AMG-837, structural formula is:Compound Q structure is:According to periodical literature Journal of Medicinal Chemistry (2012), 55 (8), prepared by the method in 3756-3776.

Clone:

Experiment reagent:

Instrument:

ELIASA: Perkin Elmer Envision Multilabel Reader

Experimental procedure:

(1) 37 DEG C, 5% CO₂Under the conditions of with containing 10%FBS, 100U/mL penicillin, 100 mg/mL streptomysins containing L-paddy Glutamine MEM medium culture HepG2 cell, reaches the degrees of fusion of 80% to iuntercellular.

(2) with trypsin digestion cell, 1000rpm is centrifuged 4 minutes, with the fresh culture re-suspended cell containing 0.5%FBS, adjusts Whole cell concentration is seeded to 384 planks.Every hole 22.5 μ L totally 1000 cells, 3 multiple holes.

(3) cell cultivates 24h, prepares 10 times of compound solutions, and every hole adds 10 times of compound solution (cumulative volumes 25 of 2.5 μ L μ L), final concentration of 30 μMs of compound, each compound does 1 concentration, 3 multiple holes.

A) solvent control: add the cell of 0.3% DMSO.

B) culture medium comparison: be not added with the cell of compound.

C) blank: be not added with cell and return to zero for instrument.

(4) 37 DEG C, 5% CO₂Under the conditions of drug-treated cell 24h.

(5) every hole adds 25 μ L Caspase-GloR 3/7 reagent, the mixing gently of microwell plate oscillator.

(6) plank sealer is sealed, lucifuge, incubated at room 30min.

(7) absorbance value is measured with ELIASA.

Computing formula:

Caspase activity=(compound light absorption value mean value-average mean value of blank)/(culture medium compares The average mean value of mean value-blank)

Statistical analysis: p value represents the difference of T inspection between medium group and compound group.

Table 10 the compounds of this invention experimental result apoptotic to HepG2

5,6 pairs of apoptotic experimental results of HepG2 of table 10-1 the compounds of this invention

Conclusion: GPR40 its structure unmodified of series of positive control compound Q of document report, has cytotoxicity.

1,2,3,4 couples of HepG2 of the compounds of this invention apoptotic effect power and marketed drug TAK-875 raceme Or TAK-875 is suitable, suitable to hepatocellular toxic action.

HepG2 cel l proliferation is affected by experimental example 5 the compounds of this invention

Test sample: part of compounds of the present invention, prepares according to the method in the embodiment of the present invention respectively；

Reference substance: positive control Sorafenib (commercial)；Tester TAK-875 raceme, its structural formula isTester TAK-875, its structural formula is as it was noted above, according to patent WO20080 Prepared by 01931 (publication date 2008.01.03) method；AMG-837, structural formula is:Chemical combination Thing Q structure is:According to periodical literature Journal of Medicinal Chemistry (2012), 55 (8), prepared by the method in 3756-3776.

Clone

Experiment reagent:

Instrument:

ELIASA: EnVision 2104 Multilable Reader

Experimental procedure:

(1) 37 DEG C, 5% CO₂Under the conditions of with containing 10%FBS, 100U/mL penicillin, 100 mg/mL streptomysins containing L-paddy Glutamine MEM medium culture HepG2 cell, reaches the degrees of fusion of 80% to iuntercellular.

(2) with trypsin digestion cell, 1000rpm is centrifuged 4 minutes, with the fresh culture re-suspended cell containing 0.5% FBS, Adjust cell concentration and be seeded to 96 orifice plates.Every hole 90uL totally 2500 cells, 3 multiple holes.

(3) cell cultivates 24h, prepares 10 times of compound solutions, and every hole adds 10 times of compound solution (cumulative volumes 100 of 10 μ L μL)；Final concentration of 30 μMs of finalization compound, final concentration of 5 μMs of Sorafenib.

A) solvent control: add the cell of 0.3% DMSO.

B) culture medium comparison: be not added with the cell of compound.

C) blank: be not added with cell and return to zero for instrument.

(4) 37 DEG C, 5% CO₂Under the conditions of drug-treated cell 72h.

(5) then plank is placed equilibrium at room temperature 30min.

(6) every hole adds 100 μ L CellTiter-Reagent。

(7) oscillator concussion mixing 2min, makes cell fully dissolve.

(8) equilibrium at room temperature plank 10min makes signal stabilization.

(9) absorbance value is measured with the multi-functional ELIASA of EnVision2104.

Computing formula:

Cell viability=(compound absorbance value mean value-average mean value of blank)/(culture medium comparison mean value- The average mean value of blank) * 100

Table 11 the compounds of this invention result to HepG2 cell proliferation experiment

The result of 5,6 pairs of HepG2 cell proliferation experiment of table 11-1 the compounds of this invention

Conclusion: the compounds of this invention 1,2,3,4 in HepG2 cell proliferation experiment to cell viability effect strong and weak with TAK-875 raceme is suitable, and 5,6 pairs of cell viability effects of the compounds of this invention are strong and weak suitable, to hepatocellular poison with TAK-875 Property effect is suitable.

Experimental example 6 the compounds of this invention lumbar injection dextrose tolerance test

Test sample: part of compounds of the present invention, prepares according to the method in the embodiment of the present invention respectively；

Reference substance: tester TAK-875 raceme, its structural formula is Tester TAK-875, its structural formula is as it was noted above, according to patent WO2008001931 (publication date 2008.01.03) method system Standby.

Experimental technique:

Accurately weigh test sample, solvent 0.5% methocel solution.All it is formulated as the solution of 3mg/mL.

2.750g glucose water for injection is settled to 25mL, 4 parts.

Male SD rat, after quarantining 1 week, fasting can't help water overnight, after weighing, is randomly divided into normal control by body weight Group, solvent control group, test sample group, reference substance group, dosage is 30mg/kg, totally 6 groups, and often 5 rats of group, see table.Gavage Oral administration of compound solution or solvent be after 1 hour, lumbar injection 1g/kg glucose solution, is administered volume 10mL/kg, is giving respectively Before medicine (-60min), to (0min) before glucose, to after glucose 10,20,30,60,120min disposable syringe punctures Tail venous blood sampling, pipettor takes blood 3 μ L, drops on the test paper of Instrument for Measuring Blood Sugar, measures blood sugar concentration, records reading.

Packet and dosage

The individual blood glucose value Excell of every animal does scatter diagram.WinNonLin software NCA model is used to calculate AUC, Calculate blood sugar inhibiting rate according to △ AUC, carry out One-Way ANOVA inspection with SPSS13.0 software, unite between △ AUC group Meter credit analysis, P < 0.05 thinks there is significant difference.

Computing formula:

Blood sugar inhibiting rate=(solvent control group AUC mean value-administration group AUC mean value)/(solvent control group AUC is average Value-Normal group AUC mean value) * 100%.

Experimental result:

Table 12 compound inhibitory action to rat blood sugar

P value is for compare with solvent control group, and P ＜ 0.05 is statistically significant.

Table 13 compound inhibitory action to rat blood sugar

Table 14 compound inhibitory action to rat blood sugar

P value is for compare with solvent control group, and P ＜ 0.05 is statistically significant.

Conclusion: the hypoglycemic level of the compounds of this invention 3 and 4 is better than TAK-875 raceme, the hypoglycemic level of compound 1 with TAK-875 raceme is suitable, and the hypoglycemic level of compound 5 is better than TAK-875, and the compounds of this invention drops hypoglycemic effect and shows Write.

4, detailed description of the invention

The detailed description of the invention of form by the following examples, makees the most specifically the foregoing of the present invention Bright.But this should not being interpreted as, the scope of the above-mentioned theme of the present invention is only limitted to following example.All based on foregoing of the present invention The technology realized belongs to the scope of the present invention.

Embodiment 12-(6-((2', 6'-dimethyl-4'-(2-(methanesulfonamido) ethyoxyl)-[1,1'-xenyl]-3- Base) methoxyl group)-2,3-Dihydrobenzofuranes-3-base) preparation of synthesis (compound 1) of acetic acid

(1) preparation of 4-(chloromethyl)-7-hydroxyl-2H-chromen-2-one

Resorcino (27.5g, 250mmol) is placed in acetic acid (60mL), and to be heated to 50 DEG C of dissolvings stand-by, 4-chloracetyl acetic acid Ethyl ester (20.5g, 125mmol) is dissolved in the cooling of acetic acid (20mL) ice-water bath, is slowly added to the concentrated sulfuric acid (10mL), then keeps frozen water Bath adds the acetum of Resorcino, stirs 1h, react 3 hours at 60 DEG C under room temperature.React complete, add water (300mL), being stirred at room temperature 1h, reduce pressure suction filtration, and gained white solid water (100mL) washs three times, dried product (17.6g, productivity 67%).

(2) preparation of 2-(6-hydroxyl benzofuran-3-base) acetic acid

NaOH (1.35g, 34mmol) is dissolved in water (8mL), be slowly added under ice bath dissolved with 4-(chloromethyl)- 7-hydroxyl-2H-chromen-2-one (2.5g, the 12mmol) aqueous solution (6mL), is stirred at room temperature 1 hour, then anti-at 60 DEG C Answer 4 hours.At 35 DEG C, add concentrated hydrochloric acid (2.8mL, 34mmol), keep temperature 1 hour, then be stirred at room temperature 1 hour.Institute Obtain solid suction filtration, and wash three times with water.Solid obtains white solid product (1.2g, productivity 52%) after drying.

(3) preparation of 2-(6-hydroxyl-2,3-Dihydrobenzofuranes-3-base) acetic acid

2-(6-hydroxyl benzofuran-3-base) acetic acid (1.2g, 6.3mmol) is joined in HOAc (20mL), adds Pd/ C (0.12g), is passed through hydrogen and reacts 24 hours at 40 DEG C.Diatomite decompression suction filtration, filter cake methyl alcohol washs, and filtrate rotation is evaporated off White solid product (1.1g, productivity 90%) is obtained after solvent.

(4) preparation of 2-(6-hydroxyl-2,3-Dihydrobenzofuranes-3-base) methyl acetate

2-(6-hydroxyl-2,3-Dihydrobenzofuranes-3-base) acetic acid (1.1g, 5.7mmol) is dissolved in methyl alcohol (20mL), Drip thionyl chloride (0.67g, 5.7mmol) under ice bath, drip complete in 10 minutes.It is stirred at room temperature 2 hours.Rotation is evaporated off molten Agent, adds toluene rotation and unnecessary thionyl chloride is evaporated off, obtain brown solid (1.1g, productivity 93%).

(5) preparation of (2-(4-bromo-3,5-3,5-dimethylphenyl oxygen) ethyl) t-butyl carbamate

By N-Boc monoethanolamine (2.1g, 10.4mmol), to bromine xylenol (2.08g, 10.4mmol), with azo two Formoxyl two piperidines (3.9g, 15.5mmol) joins THF (100mL), add under ice bath three normal-butyl phosphorus (3.1g, 15.5mmol), drip complete, be warmed to room temperature, and continue to react 4 hours, add petroleum ether (100mL), stir 20min, then Suction filtration, filtrate is spin-dried for rear column chromatography for separation, eluant, eluent (PE/EA=20:1), obtains oil product (2.7g, productivity 75%).

(6) preparation of 2-(4-bromo-3,5-dimethyl phenoxy) ethamine

(2-(4-bromo-3,5-3,5-dimethylphenyl oxygen) ethyl) t-butyl carbamate (2.7g, 7.8mmol) is dissolved in DCM (15mL), in, add TFA (10mL), be stirred at room temperature 2 hours.Rotation is evaporated off solvent, and washs with saturated sodium bicarbonate solution, adds Entering dichloromethane extraction, organic phase anhydrous sodium sulfate is dried, and oil product (1.8g, productivity 94%) is distilled to obtain in decompression.

(7) preparation of N-(2-(4-bromo-3,5-dimethyl phenoxy) ethyl) Methanesulfomide

2-(4-bromo-3,5-dimethyl phenoxy) ethamine (1.8g, 7.4mmol) is dissolved in THF (40mL), adds three second Amine (1.5g), drips mesyl chloride (1.0g, 8.9mmol), drips complete, be warmed to room temperature in 10 minutes under ice bath, sustained response 3 Hour.The cancellation that adds water is reacted, and is extracted with ethyl acetate, and organic phase anhydrous sodium sulfate is dried, and is spin-dried for rear column chromatography for separation, washes De-agent (petrol ether/ethyl acetate=5:1), obtains oil product (2.3g, productivity 96%).

(8) system of N-(2-((3'-(methylol)-26-dimethyl-[11'-biphenyl]-4-base) oxygen) ethyl) Methanesulfomide Standby

By N-(2-(4-bromo-3,5-dimethyl phenoxy) ethyl) Methanesulfomide (1.2g, 3.7mmol), a methylol benzene Boric acid (0.57g, 3.8mmol), palladium (25mg, 0.1mmol), triphenyl phosphorus (77mg, 0.3mmol), TBAB (120mg, 0.3mmol), potassium phosphate (3.0g, 11.3mmol), join in THF (40mL), under nitrogen protection, back flow reaction 12h.System is spin-dried for carrying out column chromatography, eluant, eluent (petrol ether/ethyl acetate=3:1), obtains oil product (410mg, productivity 32%)。

(9) 2-(6-((2', 6'-dimethyl-4'-(2-(methanesulfonamido) ethyoxyl)-[1,1'-xenyl]-3-base) Methoxyl group)-2,3-Dihydrobenzofuranes-3-base) preparation of methyl acetate

By N-(2-((3'-(methylol)-2,6-dimethyl-[1,1'-biphenyl]-4-base) oxygen) ethyl) Methanesulfomide (410mg, 1.2mmol), 2-(6-hydroxyl-2,3-Dihydrobenzofuranes-3-base) methyl acetate (245mg, 1.2mmol), with ADDP (454mg, 1.8mmol) joins THF (40mL), adds three normal-butyl phosphorus (364mg, 1.8mmol) under ice bath, dropping Complete, it is warmed to room temperature.Sustained response 4 hours, adds petroleum ether (40mL), stirs 20min, then suction filtration, and filtrate is spin-dried for rear pillar Chromatography, eluant, eluent (petrol ether/ethyl acetate=2:1), obtain oil product (410mg, productivity 63%).

(10) 2-(6-((2', 6'-dimethyl-4'-(2-(methanesulfonamido) ethyoxyl)-[1,1'-xenyl]-3-base) Methoxyl group)-2,3-Dihydrobenzofuranes-3-base) preparation of acetic acid (compound 1)

By 2-(6-((2', 6'-dimethyl-4'-(2-(methanesulfonamido) ethyoxyl)-[1,1'-xenyl]-3-base) first Epoxide)-2,3-Dihydrobenzofuranes-3-base) methyl acetate (410mg, 0.76mmol) is dissolved in THF/MeO H=1:1 (10mL) In, and it is slowly added into water (5mL) solution of lithium hydroxide sulfuric monohydrate (96mg, 2.3mmol), stir 2 hours at 30 DEG C.Rotation Dry organic solvent, ethyl acetate extracts, and adds aqueous hydrochloric acid solution, regulate pH=3 in aqueous phase.Ethyl acetate extracts, organic phase nothing Aqueous sodium persulfate is dried, and is spin-dried for column chromatography for separation after solvent, eluant, eluent (petrol ether/ethyl acetate=1:1), obtains crude product (100mg), With recrystallisation from isopropanol, obtain white solid product compound 1 (18mg).

Molecular formula: C₂₈H₃₁NO₇S molecular weight: 525.6 mass spectrums (m/z): 526.2 (M+1)

¹H-NMR(400MHz,DMSO-d₆)δ:7.40-7.48(m,1H),7.34-7.39(m,1H),7.27(t,J= 5.9Hz,1H),7.13(s,1H),7.06(dd,J=16.3,7.8Hz,2H),6.70(s,2H),6.40-6.49(m,2H),5.08 (s,2H),4.66(t,J=9.0Hz,1H),4.17(dd,J=8.9,6.9Hz,1H),4.02(t,J=5.5Hz,2H),3.59- 3.71(m,1H),2.95(s,3H),2.63-2.74(m,1H),2.41-2.46(m,1H),1.90(s,6H).

Embodiment 22-(6-((4'-(2-(cyclopropyl sulfonyl amino) ethyoxyl)-2', 6'-dimethyl-[1,1'-biphenyl Base]-3-base) methoxyl group)-2,3-Dihydrobenzofuranes-3-base) preparation of acetic acid (compound 2)

(1) preparation of 2-(4-bromo-3,5-dimethyl phenoxy) ethamine

2-(4-bromo-3,5-dimethyl phenoxy) ethylcarbamate (2.0g, 5.8mmol) is dissolved in dichloromethane In alkane (20mL), add trifluoroacetic acid (10mL), 2h is stirred at room temperature.Decompression is distilled off solvent, adds saturated sodium bicarbonate molten Liquid, ethyl acetate extraction (100mL × 3), organic phase merges, and saturated sodium-chloride water solution washs, and anhydrous sodium sulfate is dried, decompression Solvent is distilled off and obtains oil product (1.36g, productivity 96%).

(2) preparation of N-(2-(4-bromo-3,5-dimethyl phenoxy) ethyl) cyclopropylsulfonamide

2-(4-bromo-3,5-dimethyl phenoxy) ethamine (1.36g, 5.6mmol) is dissolved in oxolane (50mL), adds Enter triethylamine (1.69g, 16.7mmol), drip cyclopropyl sulfonyl chloride (1.1g, 7.8mmol) under ice bath, rise to after dropping Room temperature reaction 16h.Add water (100mL), ethyl acetate extraction (100mL × 3), and organic phase merges, and saturated aqueous common salt washs, anhydrous Sodium sulphate is dried, and concentrates, and crude product silica gel column chromatography (ethyl acetate/petroleum ether=0～1/5) obtains product (1.5g, productivity 77%).

(3) N-(2-(3'-((methylol)-2,6-dimethyl-[1,1'-xenyl]-4-base) epoxide) ethyl) cyclopropyl The preparation of sulfonamide

By N-(2-(4-bromo-3,5-dimethyl phenoxy) ethyl) cyclopropylsulfonamide (1.5g, 4.3mmol), a hydroxyl first Base phenyl boric acid (851mg, 5.6mmol) and four (triphenyl phosphorus) palladium (150mg, 0.13mmol) join dioxane (50mL) In, add potassium carbonate (1.19g, the 8.6mmol) aqueous solution (10mL), under nitrogen protection, back flow reaction 12h.It is cooled to room temperature, dense Contracting, adds 100mL water, ethyl acetate extraction (100mL × 3), and organic phase merges, and saturated sodium-chloride water solution washs, anhydrous slufuric acid Sodium is dried, and concentrates, and crude product is through silica gel column chromatography (ethyl acetate/petroleum ether=0～1/3) isolated product (1.2g, productivity 74%)。

(4) 2-(6-((4'-(2-(cyclopropyl sulfonyl amino) ethyoxyl)-2', 6'-dimethyl-[1,1'-xenyl]-3- Base) methoxyl group)-2,3-Dihydrobenzofuranes-3-base) preparation of methyl acetate

By N-(2-(3'-((methylol)-2,6-dimethyl-[1,1'-xenyl]-4-base) epoxide) ethyl) cyclopropyl sulphur Acid amides (1.2g, 3.2mmol), 2-(6-hydroxyl-2,3-Dihydrobenzofuranes-3-base) methyl acetate (874mg, 4.2mmol) and Azo diformyl two piperidines (1.21g, 4.8mmol) is dissolved in oxolane (100mL), adds three normal-butyl phosphorus under ice bath (970mg, 4.8mmol), is warmed to room temperature after dropping, reacts 16h, adds petroleum ether (50mL), suction filtration, and gained filtrate is revolved Dry, crude product is through silica gel column chromatography (ethyl acetate/petroleum ether=0～1/2) isolated colorless oil as product (1.3g, productivity 72%)。

(5) 2-(6-((4'-(2-(cyclopropyl sulfonyl amino) ethyoxyl)-2', 6'-dimethyl-[1,1'-xenyl]-3- Base) methoxyl group)-2,3-Dihydrobenzofuranes-3-base) preparation of acetic acid (compound 2)

By 2-(6-((4'-(2-(cyclopropyl sulfonyl amino) ethyoxyl)-2', 6'-dimethyl-[1,1'-xenyl]-3- Base) methoxyl group)-2,3-Dihydrobenzofuranes-3-base) methyl acetate (1.3g, 2.3mmol) is dissolved in oxolane (30mL) and first In alcohol (30mL), add the aqueous solution (30mL) of lithium hydroxide monohydrate (290mg, 6.9mmol), under room temperature, react 4h.Dense Being reduced to about 30mL, add water (100mL), regulates pH=3, ethyl acetate extraction (150mL × 3) with 1mol/L watery hydrochloric acid, organic is harmonious And, saturated sodium-chloride water solution wash, anhydrous sodium sulfate is dried, concentrate, crude product through silica gel column chromatography (ethyl acetate/petroleum ether= 0～1/1) isolated product Compound 2 (1.0g, productivity 26%).

Molecular formula: C₃₀H₃₃NO₇S molecular weight: 551.6 mass spectrums (m/z): 552.2 (M+1)

¹H-NMR(400MHz,CDCl₃-d)δ:7.36-7.47(m,2H),7.16(s,1H),7.02-7.09(m,2H), 6.65(s,2H),6.44-6.53(m,2H),5.06(s,2H),4.82(m,1H),4.76(t,J=9.0Hz,1H),4.29(dd,J =9.2,6.1Hz,1H),4.14(t,J=5.0Hz,2H),3.75-3.86(m,1H),3.58(q,J=5.4Hz,2H),2.81(dd, J=16.9,5.4Hz,1H),2.62(dd,J=16.8,9.3Hz,1H),2.44-2.53(m,1H),2.00(s,6H),1.19- 1.25(m,2H),1.00-1.07(m,2H).

Embodiment 32-(6-((4'-(2-((N, N-dimethylaminosulfonyl) amino) ethyoxyl)-2', 6'-dimethyl- [1,1'-xenyl]-3-base) methoxyl group)-2,3-Dihydrobenzofuranes-3-base) preparation of acetic acid (compound 3)

(1) preparation of 2-(4-bromo-3,5-dimethyl phenoxy) ethylcarbamate

By N-Boc monoethanolamine (5.8g, 36mmol), the bromo-MX of 4-(6.03g, 30mmol), with azo two Formoxyl two piperidines (11.34g, 45mmol) is dissolved in oxolane (300mL), add under ice bath three normal-butyl phosphorus (9.1g, 45mmol), being warmed to room temperature after dropping, react 16h, add petroleum ether (200mL), suction filtration, filtrate is spin-dried for, and crude product is through silica gel Column chromatography (ethyl acetate/petroleum ether=0～1/20) isolated colorless oil as product (8.0g, productivity 77%).

(2) preparation of 2-(4-bromo-3,5-dimethyl phenoxy) ethamine

2-(4-bromo-3,5-dimethyl phenoxy) ethylcarbamate (2.5g, 7.8mmol) is dissolved in dichloromethane In alkane (20mL), add trifluoroacetic acid (10mL), 2h is stirred at room temperature.Decompression is distilled off solvent, adds saturated sodium bicarbonate molten Liquid, ethyl acetate extraction (100mL × 3), organic phase merges, and saturated sodium-chloride water solution washs, and anhydrous sodium sulfate is dried, decompression Solvent is distilled off and obtains oil product (1.7g, productivity 89%).

(3) preparation of N-(2-(4-bromo-3,5-dimethyl phenoxy) ethyl) dimethylamino sulfonamide

2-(4-bromo-3,5-dimethyl phenoxy) ethamine (1.7g, 7.0mmol) is dissolved in oxolane (50mL), adds Enter triethylamine (2.1g, 21mmol), drip dimethylaminosulfonyl chloride (1.44g, 10mmol) under ice bath, be warmed to room temperature after dripping Reaction 16h.Add water (100mL), ethyl acetate extraction (100mL × 3), and organic phase merges, and saturated sodium-chloride water solution washs, nothing Aqueous sodium persulfate is dried, concentrate, crude product through silica gel column chromatography (ethyl acetate/petroleum ether=0～1/5) isolated product (1.6g, Productivity 65%).

(4) N-(2-(3'-(methylol)-2,6-dimethyl-[1,1'-xenyl]-4-epoxide) ethyl) dimethylamino sulphur The preparation of acid amides

By N-(2-(4-bromo-3,5-dimethyl phenoxy) ethyl) dimethylamino sulfonamide (1.6g, 4.5mmol), a hydroxyl Methylphenylboronic acid (900mg, 5.9mmol), four (triphenyl phosphorus) palladium (160mg, 0.14mmol), potassium carbonate (1.25g, 9.0mmol) join in dioxane (40mL) and water (6mL), under nitrogen protection, back flow reaction 12h.It is cooled to room temperature, dense Contracting, add water (100mL), ethyl acetate extraction (100mL × 3), and organic phase merges, and saturated sodium-chloride water solution washs, anhydrous sulphur Acid sodium is dried, and concentrates, and crude product is through silica gel column chromatography (ethyl acetate/petroleum ether=0～1/3) isolated product (1.2g, productivity 70%)。

(5) (((4'-(2-((N, N-dimethylamino sulphonyl) amino) ethyoxyl)-2', 6'-dimethyl-[1,1'-joins 6-2- Phenyl]-3-base) methoxyl group)-2,3-Dihydrobenzofuranes-3-base) preparation of methyl acetate

By N-(2-(3'-(methylol)-2,6-dimethyl-[1,1'-xenyl]-4-epoxide) ethyl) dimethylamino sulphonyl Amine (1.2g, 3.2mmol), 2-(6-hydroxyl-2,3-Dihydrobenzofuranes-3-base) methyl acetate (858mg, 4.1mmol), and even Nitrogen diformyl two piperidines (1.29g, 5.1mmol) is dissolved in oxolane (80mL), adds three normal-butyl phosphorus under ice bath (1.0g, 5.1mmol), is warmed to room temperature after dropping, reacts 16h, adds petroleum ether (50mL), and suction filtration, filtrate is spin-dried for, crude product Through silica gel column chromatography (ethyl acetate/petroleum ether=0～1/2) isolated colorless oil as product (600mg, productivity 33%).

(6) (((4'-(2-((N, N-dimethylamino sulphonyl) amino) ethyoxyl)-2', 6'-dimethyl-[1,1'-joins 6-2- Phenyl]-3-base) methoxyl group)-2,3-Dihydrobenzofuranes-3-base) preparation of acetic acid (compound 3)

By 2-, (((4'-(2-((N, N-dimethylamino sulphonyl) amino) ethyoxyl)-2', 6'-dimethyl-[1,1'-joins 6- Phenyl]-3-base) methoxyl group)-2,3-Dihydrobenzofuranes-3-base) methyl acetate (600mg, 1.05mmol) is dissolved in oxolane (10mL) with in methyl alcohol (10mL), the aqueous solution (10mL) of lithium hydroxide monohydrate (130mg, 3.1mmol) is added, under room temperature Reaction 4h.Being concentrated into about 10mL, regulate pH=3 with 1mol/L watery hydrochloric acid, add water (100mL), ethyl acetate extraction (100mL × 3), organic phase merges, and saturated sodium-chloride water solution washs, and anhydrous sodium sulfate is dried, and concentrates, and crude product is through silica gel column chromatography (acetic acid Ethyl ester/petroleum ether=0～1/1) isolated product Compound 3 (100mg, productivity 17%).

Molecular formula: C₂₉H₃₄N₂O₇S molecular weight: 554.6 mass spectrums (m/z): 555.2 (M+1)

¹H-NMR(400MHz,CDCl₃-d)δ:7.37-7.47(m,2H),7.16(s,1H),7.06(t,J=8.7Hz,2H), 6.65(s,2H),6.42-6.54(m,2H),5.06(s,2H),4.76(t,J=9.0Hz,1H),4.69(br.s.,1H),4.23- 4.39(m,1H),4.06-4.19(m,2H),3.69-3.87(m,1H),3.47(q,J=5.3Hz,2H),2.75-2.90(m, 7H),2.61(dd,J=16.8,9.3Hz,1H),1.99(s,6H).

Embodiment 42-(6-((4'-(2-(1,1-dioxo isothiazolidine-2-base) ethyoxyl)-2', 6'-dimethyl-[1, 1'-xenyl]-3-base) methoxyl group)-2,3-Dihydrobenzofuranes-3-base) preparation of acetic acid (compound 4)

(1) preparation of 2-(4-bromo-3,5-dimethyl phenoxy) ethamine

2-(4-bromo-3,5-dimethyl phenoxy) ethylcarbamate (2.5g, 7.8mmol) is dissolved in dichloromethane In alkane (20mL), add trifluoroacetic acid (10mL), 2h is stirred at room temperature.Decompression is distilled off solvent, adds saturated sodium bicarbonate, second Acetoacetic ester extraction (100mL × 3), organic phase merges, and saturated sodium-chloride water solution washs, and anhydrous sodium sulfate is dried, decompression distillation Remove solvent and obtain oil product (1.7g, productivity 89%).

(2) preparation of N-(2-(4-bromo-3,5-dimethyl phenoxy) ethyl)-3-chloropropyl-1-sulfonamide

2-(4-bromo-3,5-dimethyl phenoxy) ethamine (1.7g, 7.0mmol) is dissolved in oxolane (50mL), adds Enter triethylamine (2.1g, 21mmol), drip 3-chloropropyl-1-sulfonic acid chloride (1.77g, 10mmol) under ice bath, rise to after dripping Room temperature reaction 16h.Add water (100mL), ethyl acetate extraction (100mL × 3), and organic phase merges, and saturated sodium-chloride water solution is washed Washing, anhydrous sodium sulfate is dried, and concentrates, and crude product is through silica gel column chromatography (ethyl acetate/petroleum ether=0～1/5) isolated product (2.0g, productivity 74%).

(3) preparation of 2-(2-(4-bromo-3,5-dimethyl phenoxy) ethyl) isothiazolidine 1,1-dioxide

By molten for N-(2-(4-bromo-3,5-dimethyl phenoxy) ethyl)-3-chloropropyl-1-sulfonamide (2.0g, 5.2mmol) In DMF (100mL), under ice bath, add sodium hydride (310mg, 7.8mmol), add reaction 1h under rear ice bath, be warmed to room temperature anti- Answer 2h.Pouring in frozen water (500mL), ethyl acetate extraction (200mL × 3), organic phase merges, and saturated sodium-chloride water solution is washed Washing, anhydrous sodium sulfate is dried, and concentrates, and crude product is through silica gel column chromatography (ethyl acetate/petroleum ether=0～1/4) isolated product (1.6g, productivity 88%).

(4) 2-(2-((3'-(methylol)-2,6-dimethyl-[1,1'-xenyl]-4-base) epoxide) ethyl) isothiazole The preparation of alkane 1,1-dioxide

By 2-(2-(4-bromo-3,5-dimethyl phenoxy) ethyl) isothiazoline 1,1-dioxide (1.6g, 4.6mmol), a methylol phenyl boric acid (908mg, 6.0mmol) and four (triphenyl phosphorus) palladium (160mg, 0.14mmol) join In dioxane (50mL), add potassium carbonate (1.27g, the 9.2mmol) aqueous solution (10mL), under nitrogen protection, back flow reaction 12h.Being cooled to room temperature, concentrate, add water (100mL), ethyl acetate extraction (100mL × 3), and organic phase merges, saturated sodium-chloride Solution washing, anhydrous sodium sulfate is dried, and concentrates, and crude product separates through silica gel column chromatography (ethyl acetate/petroleum ether=0～1/3) To product (1.5g, productivity 86%).

(5) 2-(6-((4'-(2-(1,1-dioxo isothiazolidine-2-base) ethyoxyl)-2', 6'-dimethyl-[1,1'- Xenyl]-3-base) methoxyl group)-2,3-Dihydrobenzofuranes-3-base) preparation of methyl acetate

By 2-(2-((3'-(methylol)-2,6-dimethyl-[1,1'-xenyl]-4-base) epoxide) ethyl) isothiazolidine 1,1-dioxide (1.5g, 4.0mmol), 2-(6-hydroxyl-2,3-Dihydrobenzofuranes-3-base) methyl acetate (1.08g, 5.2mmol), and azo diformyl two piperidines (1.51g, 6.0mmol) is dissolved in oxolane (100mL), adds under ice bath Enter three normal-butyl phosphorus (1.21g, 6.0mmol), be warmed to room temperature after dropping, reaction 16h, addition petroleum ether (50mL), suction filtration, Filtrate is spin-dried for, and through silica gel column chromatography (ethyl acetate/petroleum ether=0～1/2) isolated colorless oil as product, (1.6g produces crude product Rate 71%).

6) (((4'-(2-(1,1-dioxo isothiazolidine-2-base) ethyoxyl)-2', 6'-dimethyl-[1,1'-joins 6-2- Phenyl]-3-base) methoxyl group)-2,3-Dihydrobenzofuranes-3-base) preparation of acetic acid

By 2-, (((4'-(2-(1,1-dioxo isothiazolidine-2-base) ethyoxyl)-2', 6'-dimethyl-[1,1'-joins 6- Phenyl]-3-base) methoxyl group)-2,3-Dihydrobenzofuranes-3-base) methyl acetate (1.6g, 2.8mmol) is dissolved in oxolane (30mL) with in methyl alcohol (30mL), the aqueous solution (30mL) of lithium hydroxide monohydrate (353mg, 8.4mmol) is added, under room temperature Reaction 4h.Being concentrated into about 30mL, add water (100mL), with 1mol/L watery hydrochloric acid regulate pH=3, ethyl acetate extraction (150mL × 3), organic phase merges, and saturated sodium-chloride water solution washs, and anhydrous sodium sulfate is dried, and concentrates, and crude product is through silica gel column chromatography (acetic acid Ethyl ester/petroleum ether=0～1/1) isolated product (1.2g, productivity 78%).

Molecular formula: C₃₀H₃₃NO₇S molecular weight: 551.6 mass spectrums (m/z): 552.2 (M+1)

¹H-NMR(400MHz,CDCl₃-d)δ:7.37-7.41(m,2H),7.16(s,1H),7.07(t,J=8.4Hz,2H), 6.66(s,2H),6.46-6.51(m,2H),5.06(s,2H),4.76(t,J=9.0Hz,1H),4.29(dd,J=9.3,6.0Hz, 1H),4.20(t,J=5.1Hz,2H),3.77-3.87(m,1H),3.43-3.56(m,4H),3.16(t,J=7.7Hz,2H), 2.81(dd,J=16.8,5.3Hz,1H),2.62(dd,J=16.8,9.3Hz,1H),2.38(quin,J=7.3Hz,2H),1.99 (s,6H).

Embodiment 5 (S)-2-(6-((4'-(2-(1,1-dioxo isothiazolidine-2-base) ethyoxyl)-2', 6'-diformazan Base-[1,1'-xenyl]-3-base) methoxyl group)-2,3-Dihydrobenzofuranes-3-base) preparation of acetic acid (compound 5)

(1) (S)-2-(6-((4'-(2-(1,1-dioxo isothiazolidine-2-base) ethyoxyl)-2', 6'-dimethyl-[1, 1'-xenyl]-3-base) methoxyl group)-2,3-Dihydrobenzofuranes-3-base) preparation of methyl acetate

By 2-(2-((3'-(methylol)-2,6-dimethyl-[1,1'-xenyl]-4-base) epoxide) ethyl) isothiazolidine 1,1-dioxide (2.20g, 5.87mmol), (S)-2-(6-hydroxyl-2,3-Dihydrobenzofuranes-3-base) methyl acetate (1.34g, 6.45mmol), and azo diformyl two piperidines (2.37g, 9.39mmol) is dissolved in oxolane (150mL), Add tri-n-butyl phosphine (1.90g, 9.39mmol) under ice bath, be warmed to room temperature reaction 16h after dropping, add petroleum ether (100mL), suction filtration, gained filtrate reduced in volume, crude product silica gel column chromatography (ethyl acetate/petroleum ether=0～1/2), obtain colourless Title compound as oil (2.8g, productivity 84%).

(2) (S)-2-(6-((4'-(2-(1,1-dioxo isothiazolidine-2-base) ethyoxyl)-2', 6'-dimethyl-[1, 1'-xenyl]-3-base) methoxyl group)-2,3-Dihydrobenzofuranes-3-base) preparation of acetic acid

By (S)-2-(6-((4'-(2-(1,1-dioxo isothiazolidine-2-base) ethyoxyl)-2', 6'-dimethyl-[1, 1'-xenyl]-3-base) methoxyl group)-2,3-Dihydrobenzofuranes-3-base) methyl acetate (2.8g, 4.9mmol) is dissolved in tetrahydrochysene In furans (30mL) and methyl alcohol (30mL), add LiOH H₂The aqueous solution (30mL) of O (617mg, 14.7mmol), anti-under room temperature Answer 4h.Being concentrated into about 30mL, add water (100mL), regulates pH to 3 with 1mol/L watery hydrochloric acid, and ethyl acetate extracts (150mL × 3), Organic phase merges, and saturated aqueous common salt washs, and anhydrous sodium sulfate is dried, and concentrates, crude product silica gel column chromatography (ethanol/methylene=0 ～1/15) obtain white solid title compound (2.2g, productivity 81%).

Molecular formula: C₃₀H₃₃NO₇S molecular weight: 551.65 LC-MS (m/z): 552.3 (M+1)

¹H-NMR(400MHz,CDCl₃-d)δ:7.35-7.45(m,2H),7.16(s,1H),7.04-7.09(m,2H), 6.66(s,2H),6.46-6.51(m,2H),5.06(s,2H),4.74-4.79(m,1H),4.27-4.31(m,1H),4.18- 4.21(m,2H),3.79-3.84(m,1H),3.47-3.53(m,4H),3.14-3.18(m,2H),2.79-2.84(m,1H), 2.59-2.65(m,1H),2.34-2.42(m,2H),1.99(s,6H).

Embodiment 6 (R)-2-(6-((4'-(2-(1,1-dioxo isothiazolidine-2-base) ethyoxyl)-2', 6'-diformazan Base-[1,1'-xenyl]-3-base) methoxyl group)-2,3-Dihydrobenzofuranes-3-base) preparation of acetic acid (compound 6)

(1) (R)-2-(6-((4'-(2-(1,1-dioxo isothiazolidine-2-base) ethyoxyl)-2', 6'-dimethyl-[1, 1'-xenyl]-3-base) methoxyl group)-2,3-Dihydrobenzofuranes-3-base) preparation of methyl acetate

By 2-(2-((3'-(methylol)-2,6-dimethyl-[1,1'-xenyl]-4-base) epoxide) ethyl) isothiazolidine 1,1-dioxide (1.79g, 4.77mmol), (R)-2-(6-hydroxyl-2,3-Dihydrobenzofuranes-3-base) methyl acetate (990mg, 4.76mmol), and azo diformyl two piperidines (1.92g, 7.62mmol) is dissolved in oxolane (150mL), Add tri-n-butyl phosphine (1.54g, 7.62mmol) under ice bath, be warmed to room temperature reaction 16h after dropping, add petroleum ether (100mL), suction filtration, gained filtrate reduced in volume, crude product silica gel column chromatography (ethyl acetate/petroleum ether=0～1/2), obtain colourless Title compound as oil (2.4g, productivity 89%).

(2) (R)-2-(6-((4'-(2-(1,1-dioxo isothiazolidine-2-base) ethyoxyl)-2', 6'-dimethyl-[1, 1'-xenyl]-3-base) methoxyl group)-2,3-Dihydrobenzofuranes-3-base) preparation of acetic acid

By (R)-2-(6-((4'-(2-(1,1-dioxo isothiazolidine-2-base) ethyoxyl)-2', 6'-dimethyl-[1, 1'-xenyl]-3-base) methoxyl group)-2,3-Dihydrobenzofuranes-3-base) methyl acetate (2.4g, 4.2mmol) is dissolved in tetrahydrochysene In furans (30mL) and methyl alcohol (30mL), add LiOH H₂The aqueous solution (30mL) of O (529mg, 12.6mmol), anti-under room temperature Answer 4h.Being concentrated into about 30mL, add water (100mL), regulates pH=3 with 1mol/L watery hydrochloric acid, and ethyl acetate extracts (150mL × 3), Organic phase merge, saturated aqueous common salt wash, anhydrous sodium sulfate is dried, concentrate, crude product through silica gel column chromatography (ethanol/methylene= 0～1/15) white solid title compound (1.9g, productivity 81%) is obtained.

Molecular formula: C₃₀H₃₃NO₇S molecular weight: 551.65 LC-MS (m/z): 552.3 (M+1)

¹H-NMR(400MHz,CDCl₃-d)δ:7.37-7 .45(m,2H),7.16(s,1H),7.05-7.09(m,2H), 6.66(s,2H),6.47-6.52(m,2H),5.07(s,2H),4.74-4.79(m,1H),4.27-4.31(m,1H),4.19- 4.21(m,2H),3.79-3.84(m,1H),3.47-3.53(m,4H),3.14-3.18(m,2H),2.79-2.85(m,1H), 2.59-2.66(m,1H),2.38-2.42(m,2H),1.99(s,6H).

Embodiment 72-(6-((4'-(2-(1,1-dioxo-1,2,5-thiadiazolidine-2-base) ethyoxyl)-2', 6'-bis- Methyl-[1,1'-xenyl]-3 bases) methoxyl group)-2,3-Dihydrobenzofuranes-3-base) preparation of acetic acid (compound 7)

(1) preparation of 2-(6-((3-bromobenzyl) epoxide)-2,3-Dihydrobenzofuranes-3-base) methyl acetate

3-bromobenzene methyl alcohol (694mg, 3.71mmol) is dissolved in oxolane (6mL), adds 2-(6-hydroxyl-2,3-bis- Hydrogen benzofuran-3-base) methyl acetate (772mg, 3.71mmol), tributylphosphine (1.5g, 7.42mmol) and azo two formyl Two piperidines (1.87g, 7.42mmol), stirred overnight at room temperature, decompression removes excess of solvent, adds water (10mL), ethyl acetate (10mL × 3) extract, and anhydrous sodium sulfate is dried, and filter, and separate through silica gel column chromatography (petroleum ether: ethyl acetate=5:1) after concentration Purifying obtains title compound (960mg, productivity 68.5%).

(2) 2-(6-((3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan alkane-2-base) benzyl) epoxide)-2, 3-Dihydrobenzofuranes-3-base) preparation of methyl acetate

By 2-(6-((3-bromobenzyl) epoxide)-2,3-Dihydrobenzofuranes-3-base) methyl acetate (0.5g, 1.33mmol) Being dissolved in dimethyl sulfoxide (DMSO) (5mL), add 4,4,4', 4', 5,5,5', 5'-prestox-2,2'-is double, and (1,3,2-dioxa boron is miscellaneous Pentamethylene) (0.41g, 1.6mmol), [1,1'-double (diphenylphosphine) ferrocene] palladium chloride (97mg, 0.133mmol) and second Acid potassium (0.39g, 3.99mmol), nitrogen is protected lower 80 DEG C and is stirred overnight, and is cooled to room temperature, adds water (5mL), ethyl acetate (10mL × 3) extract, and anhydrous sodium sulfate is dried, and filter, obtain title compound (0.45g, productivity 80%) after concentration.

(3) 2-(6-((4'-(2-(1,1-dioxo-1,2,5-thiadiazolidine-2-base) ethyoxyl)-2', 6'-dimethyl- [1,1'-xenyl]-3-base) methoxyl group)-2,3-Dihydrobenzofuranes-3-base) preparation of methyl acetate

By 2-(2-(4-bromo-3,5-dimethyl phenoxy) ethyl)-1,2,5-thiadiazolidine 1,1-dioxide (100mg, 0.286mmol) it is dissolved in dioxane/water (6mL, 5:1), adds 2-(6-((3-(4,4,5,5-tetramethyl-1,3,2-dioxies Miscellaneous boron heterocycle pentane-2-base) benzyl) epoxide)-2,3-Dihydrobenzofuranes-3-base) methyl acetate (146mg, 0.344mmol), Tetrakis triphenylphosphine palladium (33mg, 0.0286mmol) and potassium carbonate (118mg, 0.86mmol), overnight, decompression removes return stirring Excess of solvent, column chromatography (petroleum ether: ethyl acetate=2:1) is isolated and purified obtains title compound (102mg, productivity 63%).

(4) 2-(6-((4'-(2-(1,1-dioxo-1,2,5-thiadiazolidine-2-base) ethyoxyl)-2', 6'-dimethyl- [1,1'-xenyl]-3-base) methoxyl group)-2,3-Dihydrobenzofuranes-3-base) preparation of acetic acid

By 2-(6-((4'-(2-(1,1-dioxo-1,2,5-thiadiazolidine-2-base) ethyoxyl)-2', 6'-dimethyl- [1,1'-xenyl]-3-base) methoxyl group)-2,3-Dihydrobenzofuranes-3-base) methyl acetate (100mg, 0.17mmol) is dissolved in In the mixed solvent of methyl alcohol (1mL), oxolane (1mL) and water (1mL), addition lithium hydroxide monohydrate (22mg, 0.51mmol), 3h is stirred under room temperature.Decompression removes excess of solvent, adds water (5mL), and watery hydrochloric acid is adjusted to pH=3, ethyl acetate (5mL × 3) extract, and anhydrous sodium sulfate is dried, and filter, separate pure through silica gel column chromatography (dichloromethane: methyl alcohol=15:1) after concentration Change and obtain title compound (32mg, productivity 34%).

Molecular formula: C₂₉H₃₂N₂O₇S molecular weight: 552.6 LC-MS (m/z): 553.3 (M+1)

¹H-NMR(400MHz,MeOD-d4)δ:7.36-7.44(m,2H),7.12(s,1H),7.02-7.07(m,2H), 6.68(s,2H),6.47(m,1H),6.40(d,J=2Hz,1H),5.06(s,2H),4.68(m,1H),4.16-4.23(m,3H), 3.71-3.75(m,1H),3.54-3.58(m,2H),3.31-3.43(m,4H),2.67-2.73(m,1H),2.47-2.53(m, 1H),1.94(s,6H).

Embodiment 82-(6-((2', 6'-dimethyl-4'-(2-(5-methyl isophthalic acid, 1-dioxo-1,2,5-thiadiazolidine-2- Base) ethyoxyl)-[1,1'-xenyl]-3-base) methoxyl group)-2,3-Dihydrobenzofuranes-3-base) system of acetic acid (compound 8) Standby

(1) 2-(2-((3'-(methylol)-2,6-dimethyl-[1,1'-xenyl]-4-base) epoxide) ethyl)-5-first The preparation of base-1,2,5-thiadiazolidine 1,1-dioxide

By 2-(2-(4-bromo-3,5-dimethyl phenoxy) ethyl)-5-methyl isophthalic acid, 2,5-thiadiazolidine 1,1-dioxide (61mg, 0.168mmol) is dissolved in dioxane/water (6mL, 5:1), addition (3-(methylol) phenyl) boric acid (51mg, 0.336mmol), tetrakis triphenylphosphine palladium (19mg, 0.0168mmol) and potassium carbonate (58mg, 0.42mmol), return stirring mistake At night, decompression removes excess of solvent, and column chromatography (petroleum ether: ethyl acetate=1:1) is isolated and purified obtains title compound (60mg, product Rate 91%).

(2) 2-(6-((2', 6'-dimethyl-4'-(2-(5-methyl isophthalic acid, 1-dioxo-1,2,5-thiadiazolidine-2-base) Ethyoxyl)-[1,1'-xenyl]-3-base) methoxyl group)-2,3-Dihydrobenzofuranes-3-base) preparation of methyl acetate

By 2-(2-((3'-(methylol)-2,6-dimethyl-[1,1'-xenyl]-4-base) epoxide) ethyl)-5-methyl- 1,2,5-thiadiazolidine 1,1-dioxide (60mg, 0.154mmol) is dissolved in oxolane (1mL), addition 2-(6-hydroxyl- 2,3-Dihydrobenzofuranes-3-bases) methyl acetate (38mg, 0.185mmol), tributylphosphine (62mg, 0.308mmol) and azo Two formyls two piperidines (78mg, 0.308mmol), stirred overnight at room temperature, decompression removes excess of solvent, adds water (5mL), acetic acid second Ester (10mL × 3) extracts, and anhydrous sodium sulfate is dried, and filters, and after concentration, column chromatography (petroleum ether: ethyl acetate=1:1) is isolated and purified Obtain title compound (62mg, productivity 70%).

(3) 2-(6-((2', 6'-dimethyl-4'-(2-(5-methyl isophthalic acid, 1-dioxo-1,2,5-thiadiazolidine-2-base) Ethyoxyl)-[1,1'-xenyl]-3-base) methoxyl group)-2,3-Dihydrobenzofuranes-3-base) preparation of acetic acid

By 2-(6-((2', 6'-dimethyl-4'-(2-(5-methyl isophthalic acid, 1-dioxo-1,2,5-thiadiazolidine-2-base) second Epoxide)-[1,1'-xenyl]-3-base) methoxyl group)-2,3-Dihydrobenzofuranes-3-base) methyl acetate (60mg, 0.1mmol) It is dissolved in the mixed solvent of methyl alcohol (1mL), oxolane (1mL) and water (1mL), addition lithium hydroxide monohydrate (13mg, 0.3mmol), 3h is stirred under room temperature.Decompression removes excess of solvent, adds water (5mL), and watery hydrochloric acid is adjusted to pH=3, ethyl acetate (5mL × 3) extract, and anhydrous sodium sulfate is dried, and filter, and (dichloromethane: methyl alcohol=15:1) is isolated and purified is marked for evaporating column chromatography Topic compound (37mg, productivity 65%).

Molecular formula: C₃₀H₃₄N₂O₇S molecular weight: 566.7 LC-MS (m/z): 567.3 (M+1)

¹H-NMR(400MHz,MeOD)δ:7.37-7.42(m,2H),7.12(s,1H),7.02-7.08(m,2H),6.69 (s,2H),6.47(m,1H),6.40(d,J=2Hz,1H),5.06(s,2H),4.69(m,1H),4.16-4.23(m,3H), 3.71-3.75(m,1H),3.52(m,2H),3.41-3.44(m,2H),3.31-3.33(m,2H),2.68-2.73(m,4H), 2.47-2.53(m,1H),1.94(s,6H).

Claims (7)

1. the compound shown in formula (I), its pharmaceutically acceptable salt or its stereoisomer:

Wherein,

R₁For methylamino, dimethylamino, cyclobutyl, cyclopenta or cyclohexyl；

X is-NH-, or R₁-the S (O) being connected with them with X₂-form 1,1-dioxo-1,2 being optionally substituted with a substituent, 5-thiadiazoles alkyl, 1,1-dioxo-1,2,3-thiadiazoles alkyl or 1,1-dioxo-1,2,4-thiadiazoles alkyl, described in take Dai Ji is selected from fluorine atom, chlorine atom, methyl, ethyl, trifluoromethyl or methoxyl group；

R₂、R₃For methyl；R₄、R₅For hydrogen atom.

2. lead to the compound shown in formula (I), its pharmaceutically acceptable salt or its stereoisomer, there is below formula (II) institute Show structure:

Wherein

R₁For methylamino, dimethylamino, cyclobutyl, cyclopenta or cyclohexyl；

X is-NH-, or R₁-the S (O) being connected with them with X₂-form 1,1-dioxo-1,2 being optionally substituted with a substituent, 5-thiadiazoles alkyl, 1,1-dioxo-1,2,3-thiadiazoles alkyl or 1,1-dioxo-1,2,4-thiadiazoles alkyl, described in take Dai Ji is selected from fluorine atom, chlorine atom, methyl, ethyl, trifluoromethyl or methoxyl group；

R₂、R₃For methyl；R₄、R₅For hydrogen atom.

3. the compound described in claim 1, its pharmaceutically acceptable salt or its stereoisomer, described compound selects From:

4. contain the compound according to any one of claim 1-3, its pharmaceutically acceptable salt, the medicine of its stereoisomer Compositions, it is characterised in that include one or more pharmaceutical carriers and/or diluent.

5. pharmaceutical composition as claimed in claim 4, it is characterised in that also include one or more other drugs, described other Medicine is selected from treating the medicine of diabetes, the medicine for the treatment of diabetic complication, the treatment medicine of hyperlipidemia, antihypertensive Thing, antiadipositas drug thing, diuretics, chemotherapeutics, immunotherapy medicaments, anti-inflammatory drug, antithrombotic reagent, for osteoporotic Medicine, cellulose family, antidementia agent, for frequent micturition or the medicine of the urinary incontinence or for dysuric curative Thing.

6. the pharmaceutical composition described in claim 4 preparation GPR40 receptor stimulating agent be used for preventing and/or treat diabetes and Application in the medicine of diabetes related diseases.

7. contain the compound according to any one of claim 1-3, its pharmaceutically acceptable salt, the medicine of its stereoisomer Thing preparation is used for the application treated and/or prevent in the medicine of diabetes and diabetes related diseases in preparation.