CN104059039B

CN104059039B - There is the fused ring compound of GPR40 function of receptors adjustment effects

Info

Publication number: CN104059039B
Application number: CN201310096531.0A
Authority: CN
Inventors: 刘希杰; 校登明; 胡远东; 王树龙; 刘志华; 沈宇; 彭勇; 王欢; 罗鸿; 孔凡胜; 韩永信
Original assignee: Centaurus Biopharma Co Ltd; Chia Tai Tianqing Pharmaceutical Group Co Ltd
Current assignee: Chia Tai Tianqing Pharmaceutical Group Co Ltd
Priority date: 2013-03-22
Filing date: 2013-03-22
Publication date: 2017-03-15
Anticipated expiration: 2033-03-22
Also published as: WO2014146604A1; CN104059039A

Abstract

The present invention relates to the fused ring compound with GPR40 function of receptors adjustment effects of Formulas I, its preparation method, its pharmaceutical composition, and its for the purposes in the treatment and/or prevention disease related to the GPR40 especially medicine of diabetes.The compounds of this invention has good GPR40 agonist activities, excellent internal hypoglycemic effect.

Description

Fused ring compounds with GPR40 receptor function modulating action

Technical Field

The present invention relates to a novel fused ring compound having a GPR40 receptor function modulating effect, a process for its preparation, a pharmaceutical composition thereof, and its use as a medicament.

Background

Diabetes has become the third most serious chronic non-infectious disease threatening human health after tumor and cardiovascular disease, and is an increasingly serious public health problem. The latest published authoritative data of the World Health Organization (WHO) show that the incidence of diabetes worldwide has increased rapidly in recent years. The number of patients is over 1.77 hundred million, and is expected to reach 3.7 hundred million by 2025. The severe condition of diabetes in China is more profound, China has become the second major country of diabetes, and has 2380 thousands of diabetics, which is second to India. It is expected that by 2030, the population of diabetics will break through 4320 million. According to the latest report of Ministry of health, the trend of growth will lead to 3000 new diabetics in China every day and 120 ten thousand diabetics each year. In view of the severe situation at present, the development of new therapeutic drugs for diabetes is very necessary. Sulfonylureas, biguanides and other traditional oral hypoglycemic drugs have poor efficacy and have side effects such as hypoglycemia, liver damage and severe gastrointestinal reactions. Other traditional clinical medicines have certain curative effect, but cannot prevent the necrosis of islet beta cells, and are not suitable for patients in late stage. Therefore, there is a need to develop an effective drug that can repair and stimulate islet cells to continuously secrete insulin.

The G protein coupled receptor40 (G protein coupled receptor40, GPR40) is a member of the G protein coupled receptor superfamily, which is a seven-transmembrane receptor recently discovered, and medium and long-chain free fatty acids are specific ligands thereof, the existing research results show that the novel transmembrane receptor can be related to certain cancers and neurological diseases, especially diabetes, in the presence of high concentration of glucose, Free Fatty Acids (FFA) can amplify glucose-stimulated insulin secretion by stimulating GPR40 on the cell membrane of pancreatic island β. that is, FFA can also play a role as a signal molecule in addition to serving as a nutrient in a human body, however, insulin cells can finally weaken the insulin secretion function due to large insulin secretion for a long time if exposed to high concentration of FFA for a long time, therefore, the FFA level in the body is too high to cause diabetes related diseases, and the research proves that GPR40 receptor is activated,can lower blood sugar and hardly cause hypoglycemic reaction. Mechanism of action of GPR40 agonist in treatment of type 2 diabetes and sulfonylureas (e.g. sulfonylureas)) In contrast, stimulating insulin secretion in a blood glucose dependent manner greatly reduces the risk of hypoglycemia.

Therefore, GPR40 is used as a target for treating diabetes, and a medicament acting on GPR40 is designed, so that the medicament has very important research value and application prospect for regulating the insulin secretion function of pancreas and treating diabetes.

Disclosure of Invention

One aspect of the invention relates to a compound of formula I:

formula I

Wherein,

R¹、R²、R³、R⁴、R⁵、R⁶、R⁷、R⁸each independently selected from the group consisting of hydrogen, halogen, cyano, hydroxy, nitro, amino, alkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -NHCO-alkyl, -NHCO-cycloalkyl, -SO₂-alkyl, -SO₂-cycloalkyl, -SO-alkyl, -SO-cycloalkyl, -N (alkyl) -SO₂-alkyl, -N (alkyl) -SO₂-cycloalkyl, -N (alkyl) -SO₂-aryl, -N (alkyl) -SO₂-heteroaryl, -NHSO₂-alkyl, -NHSO₂-cycloalkyl, -NHSO₂-aryl, -NHSO₂-heteroaryl, -SO₂-NH₂、-SO₂-NH-alkyl, -SO₂N- (alkyl)₂-CO-alkyl, -COO-alkyl, -CONH-alkyl, -CON- (alkyl)₂、-CONH₂；

L¹is-CH₂O-、-CH₂NH-or

L²Is a bond, O or-NR¹²-；

R⁹、R¹⁰Each independently selected from hydrogen, halogen, alkyl, hydroxy, alkoxy, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cyano;

n is 0, 1,2, 3,4 or 5;

L³is a bond or-NR¹³-；

R¹²、R¹³Each independently selected from hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, -SO₂-alkyl, -SO₂-cycloalkyl, -SO-alkyl, -SO-cycloalkyl, -CO-alkyl, -CO-cycloalkyl, -CO-aryl, -CO-heteroaryl, or R¹²And R¹³And the N atoms to which they are attached together form a heterocycloalkyl group containing at least two N atoms;

L⁴is-P (O) (R)¹⁴) -or-SO₂-；

R¹¹is-NR¹⁵R¹⁶Halogen, hydroxy, cyano, nitro, alkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or R¹¹And R¹³To form a heterocycloalkyl group containing at least one nitrogen atom;

Z¹selected from hydrogen, halogen, hydroxyl, cyano, nitro, amino, alkyl, alkoxy, alkenyl, alkynyl;

Z²is selected from- (CR)¹⁷R¹⁸)_mCOL⁵R¹⁹；

R¹⁴、R¹⁵、R¹⁶、R¹⁷、R¹⁸Each independently selected fromHydrogen, halogen, hydroxy, alkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl, heteroaryl;

L⁵is-NH-, -N (alkyl) -, -N (cycloalkyl) -or-O-;

m is 0, 1,2, 3,4 or 5;

R¹⁹selected from hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, amino, -SO₂-alkyl, -SO₂-cycloalkyl, -SO₂-aryl, -SO₂-heteroaryl, -SO-alkyl, -SO-cycloalkyl, -SO-aryl, -SO-heteroaryl;

with the following conditions: when L is¹is-CH₂O-or-CH₂NH-, and L²Is O, R⁹=R¹⁰= hydrogen, n =2 or 3, L³Is a bond, L⁴is-SO₂-and R¹¹Is methyl or ethyl, Z²Is CH₂COOR¹⁹When R is¹⁹Selected from cycloalkyl, heterocycloalkyl, aryl, heteroaryl, amino, -SO₂-alkyl, -SO₂-cycloalkyl, -SO₂-aryl, -SO₂-heteroaryl, -SO-alkyl, -SO-cycloalkyl, -SO-aryl, -SO-heteroaryl.

In some embodiments, R¹、R²、R³、R⁴、R⁵、R⁶、R⁷、R⁸Each independently selected from hydrogen, halogen, cyano, hydroxy, alkyl, alkoxy, amino; in some preferred embodiments, R¹、R⁴、R⁵、R⁶、R⁷And R⁸Is hydrogen, R²And R³Is methyl.

In some embodiments, R⁹And R¹⁰Selected from hydrogen.

In some embodiments, when L²Is O, n is 1,2, 3 or4, L³Is a bond, L⁴is-SO₂When is, R¹¹is-NR¹⁵R¹⁶Alkyl, alkoxy, or the like,Cycloalkyl, heterocycloalkyl, aryl, heteroaryl; in some preferred embodiments, when L²Is O, n is 2 or 3, L³Is a bond, L⁴is-SO₂When is, R¹¹is-NR¹⁵R¹⁶Alkyl, cycloalkyl; in some preferred embodiments, when L²Is O, n is 3, L³Is a bond, L⁴is-SO₂When is, R¹¹is-NR¹⁵R¹⁶An alkyl group; in some more preferred embodiments, when L²Is O, n is 3, L³Is a bond, L⁴is-SO₂When is, R¹¹is-N (alkyl)₂-NH (alkyl), alkyl; in some most preferred embodiments, when L²Is O, n is 3, L³Is a bond, L⁴is-SO₂When is, R¹¹is-N (CH)₃)₂、-NHCH₃、-CH₃。

In some embodiments, when L²Is O, n is 1,2, 3 or4, L³is-NR¹³-，L⁴is-SO₂When is, R¹¹is-NR¹⁵R¹⁶Alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or R¹¹And R¹³To form a heterocycloalkyl group containing at least one nitrogen atom; in some preferred embodiments, when L²Is O, n is 2 or 3, L³is-NR¹³-，L⁴is-SO₂When is, R¹¹is-NR¹⁵R¹⁶Alkyl, cycloalkyl, heterocycloalkyl, or R¹¹And R¹³To form a 3-12 membered heterocycloalkyl group containing at least one nitrogen atom; in some more preferred embodiments, when L²Is O, n is 2 or 3, L³is-NR¹³-，L⁴is-SO₂When is, R¹¹And R¹³To a 3-, 4-, 5-or 6-membered heterocycloalkyl group containing at least one nitrogen atom, or R¹¹Is alkyl, cycloalkyl, heterocycloalkyl; in some most preferred embodiments, when L²Is O, n is 2, L³is-NR¹³-，L⁴is-SO₂When is, R¹¹And R¹³To form a heterocycloalkyl group containing at least one nitrogen atom; or when L is²Is O, n is 2, L³is-NH-, L⁴is-SO₂When is, R¹¹Is alkyl or cycloalkyl.

In some embodiments, when L²And L³Is a bond, when n is 0, L⁴is-P (O) (R)¹⁴)-，R¹¹Is alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl; in some preferred embodiments, when L²And L³Is a bond, when n is 0, L⁴is-P (O) (alkyl) -, R¹¹Is alkyl, cycloalkyl, heterocycloalkyl; in some more preferred embodiments, when L²And L³Is a bond, when n is 0, L⁴is-P (O) (CH)₃)-，R¹¹Is methyl, ethyl, isopropyl, -CH₂-cyclopropyl, cyclopropyl.

In some embodiments, when L²Is O, n is 1,2, 3 or4, L³When it is a bond, L⁴is-P (O) (R)¹⁴)-，R¹¹Is alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl; in some preferred embodiments, when L²Is O, n is 3, L³When it is a bond, L⁴is-P (O) (alkyl) -, R¹¹Is alkyl, cycloalkyl, heterocycloalkyl; in some more preferred embodiments, when L²Is O, n is 3, L³When it is a bond, L⁴is-P (O) (CH)₃)-，R¹¹Is methyl, ethyl, isopropyl, -CH₂-cyclopropyl, cyclopropyl.

In some embodiments, when L²is-NR¹²-、L³is-NR¹³-and L⁴is-SO₂When is, R¹²And R¹³And the N atoms to which they are attached together form a heterocycloalkyl group containing at least two N atoms; in some preferred embodiments, L²is-NR¹²-、L³is-NR¹³-and L⁴is-SO₂When is, R¹²And R¹³And the N atom to which they are attached together form a piperazinyl group.

In some embodiments, L is¹is-CH₂O-。

In some embodiments, L is¹is-CH₂NH-。

In some embodiments, L is¹Is composed of

In some embodiments, Z¹Is hydrogen, Z²is-CH₂COL⁵R¹⁹。

In some embodiments, when L⁵When is-NH-, R¹⁹Selected from alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -SO₂-alkyl, -SO₂-cycloalkyl, -SO₂-aryl, -SO₂-heteroaryl, -SO-alkyl, -SO-cycloalkyl, -SO-aryl, -SO-heteroaryl; preferably, R¹⁹Is selected from-SO₂-alkyl, -SO₂-cycloalkyl, -SO₂-aryl, -SO₂-heteroaryl, -SO-alkyl, -SO-cycloalkyl, -SO-aryl, -SO-heteroaryl; more preferably, R¹⁹Is selected from-SO₂-alkyl, -SO₂-a cycloalkyl group; most preferably, R¹⁹Is selected from-SO₂-methyl, -SO₂-ethyl, -SO₂-cyclopropyl, -SO₂-CH₂-cyclopropyl.

In some embodiments, when L⁵When is-O-, R¹⁹Selected from hydrogen, alkyl, cycloalkyl; preferably, R¹⁹Selected from hydrogen, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclohexyl.

In another aspect, the invention relates to a compound of the formula:

in another aspect, the invention relates to a process for the preparation of a compound of formula I or a salt thereof, wherein L¹、L²、L³、L⁴、R¹、R²、R³、R⁴、R⁵、R⁶、R⁷、R⁸、R⁹、R¹⁰、R¹¹、Z¹、Z²The same definitions as above for the compounds of formula I are included, including the broadest definition as well as all preferred definitions.

Formula I

When L is¹is-CH₂O-, the compounds of formula I or salts thereof may be prepared by the following process:

when X is hydroxy, compound I can be prepared by Mitsunobu reaction of a compound of formula 1 and a compound of formula 2. In the Mitsunobu reaction, compound 1 and compound 2 are reacted in the presence of an azodicarbonyl compound (e.g., diethyl azodicarboxylate, diisopropyl azodicarboxylate, 1' - (azodicarbonyl) dipiperidine) and an organophosphine compound (e.g., triphenylphosphine, tributylphosphine);

when X is a leaving group, compound I can be prepared by reacting a compound of formula 1 and a compound of formula 2 in the presence of a base. The leaving group may be a halogen atom, an optionally chlorinated alkylsulfonyloxy group. The base used may be an alkali metal hydroxide, an alkali metal carbonate or an organic base.

When L is¹is-CH₂NH-, the compound of formula I or a salt thereof may be prepared by the following process:

or

X is a leaving group, and the compound I can be prepared by reacting a compound represented by formula 1 with a compound represented by formula 3 in the presence of a base. Compound I can also be prepared by reacting a compound of formula 4 with a compound of formula 3 to form Schiff base, followed by reduction with a reducing agent.

When L is¹Is composed ofWhen used, the compounds of formula I or salts thereof may be prepared by the following process:

x is a leaving group, and the compound I can be prepared by a coupling reaction of a compound represented by formula 5 and a compound represented by formula 6 in the presence of a palladium metal catalyst.

The compounds represented by formulae 1,4 and 5 can be prepared by the following methods:

when X is a leaving group, the compounds represented by formulae 1,4 and 5 can be prepared by reacting the compound represented by formula 7 and the compound represented by formula 8 in the presence of a base.

Some of the compounds of formula I or salts thereof of the present invention may also be prepared by:

or

The above synthetic methods are only examples of the preparation methods of some compounds of the present invention, and the skilled person can synthesize the compounds of the present invention by similar methods based on the above synthetic schemes according to the well-known techniques in the art.

The compounds of the invention may be asymmetric, e.g., having one or more stereoisomers. Unless otherwise indicated, all stereoisomers include, for example, enantiomers and diastereomers. The compounds of the invention containing asymmetric carbon atoms can be isolated in optically active pure form or in racemic form. The optically active pure form can be resolved from a racemic mixture or synthesized by using chiral starting materials or chiral reagents.

The compounds of the invention also include tautomeric forms. Tautomeric forms result from the exchange of one single bond with an adjacent double bond and the concomitant migration of one proton.

As the salt of compound (I), for example, a metal salt, an ammonium salt, a salt with an organic base, a salt with an inorganic acid, a salt with an organic acid, a salt with a basic or acidic amino acid, and the like can be mentioned. Non-limiting examples of metal salts include, but are not limited to, alkali metal salts such as sodium salts, potassium salts, and the like; alkaline earth metal salts such as calcium salts, magnesium salts, barium salts, etc.; aluminum salts, and the like. Non-limiting examples of salts with organic bases include, but are not limited to, salts with trimethylamine, triethylamine, pyridine, picoline, 2, 6-lutidine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine, and the like. Non-limiting examples of salts with inorganic acids include, but are not limited to, salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, and the like. Non-limiting examples of salts with organic acids include, but are not limited to, salts with formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, malic acid, maleic acid, tartaric acid, citric acid, succinic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, and the like. Non-limiting examples of salts with basic amino acids include, but are not limited to, salts with arginine, lysine, ornithine, and the like. Non-limiting examples of salts with acidic amino acids include, but are not limited to, salts with aspartic acid, glutamic acid, and the like.

Yet another aspect of the invention relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I as defined herein or a salt thereof and a pharmaceutically acceptable carrier.

The pharmaceutical composition of the present invention can be prepared by combining the compound of the present invention with a suitable pharmaceutically acceptable carrier, and can be formulated, for example, into solid, semi-solid, liquid or gaseous preparations such as tablets, pills, capsules, powders, granules, pastes, emulsions, suspensions, solutions, suppositories, injections, inhalants, gels, microspheres, aerosols, and the like.

Typical routes of administration of the compounds of the present invention or pharmaceutically acceptable salts thereof or pharmaceutical compositions thereof include, but are not limited to, oral, rectal, transmucosal, enteral, or topical, transdermal, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, intravenous administration. The preferred route of administration is oral.

The pharmaceutical compositions of the present invention may be manufactured by methods well known in the art, such as conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, lyophilizing, and the like.

In a preferred embodiment, the pharmaceutical composition is in oral form. For oral administration, the pharmaceutical compositions may be formulated by mixing the active compounds with pharmaceutically acceptable carriers well known in the art. Such carriers enable the compounds of the invention to be formulated as tablets, pills, dragees, capsules, liquids, gels, slurries, suspensions and the like, for oral administration to a patient.

Solid oral compositions may be prepared by conventional mixing, filling or tableting methods. For example, it can be obtained by the following method: the active compounds are mixed with solid excipients, the resulting mixture is optionally milled, if desired with further suitable auxiliaries, and the mixture is then processed to granules, to give tablets or dragee cores. Suitable excipients include, but are not limited to: binders, diluents, disintegrants, lubricants, glidants, sweeteners or flavoring agents, and the like. Such as microcrystalline cellulose, glucose solutions, gum arabic syrups, gelatin solutions, sucrose and starch pastes; talc, starch, magnesium stearate, calcium stearate or stearic acid; lactose, sucrose, starch, mannitol, sorbitol, or dicalcium phosphate; silicon dioxide; croscarmellose sodium, pregelatinized starch, sodium starch glycolate, alginic acid, corn starch, potato starch, methylcellulose, agar, carboxymethylcellulose, crospovidone, and the like. The dragee cores may optionally be coated, in particular with enteric coatings, according to methods well known in normal pharmaceutical practice.

The pharmaceutical compositions may also be adapted for parenteral administration, as sterile solutions, suspensions or lyophilized products in suitable unit dosage forms. Suitable excipients, such as fillers, buffers or surfactants can be used.

Another aspect of the invention also relates to the use of a compound of formula I, or a salt or pharmaceutical composition thereof, of the invention in the manufacture of a medicament for the treatment and/or prevention of a disease associated with GPR 40.

In another aspect, the invention also relates to the use of a compound of formula I according to the invention or a salt thereof or a pharmaceutical composition thereof for the preparation of a medicament for the treatment and/or prevention of diabetes.

In all methods of administration of the compounds of formula I described herein, the dosage administered per day is preferably from 0.01 to 200mg/Kg body weight.

GPR40 agonistic activity, preferably EC, of the compounds of the invention₅₀Less than 10000nM, more preferably EC₅₀Less than 2000nM, more preferably EC₅₀Less than 1000nM, more preferably EC₅₀Less than 100nM, most preferably EC₅₀Less than 10 nM.

Unless otherwise indicated, the terms used herein have the following meanings:

the term "halogen" means fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine.

The term "hydroxy" refers to an-OH group in which a hydrogen atom may be substituted with a substituent.

The term "cyano" refers to the group — CN.

The term "nitro" means-NO₂A group.

The term "alkyl" refers to a straight or branched chain saturated aliphatic hydrocarbon group consisting of carbon and hydrogen atoms, which is attached to the rest of the molecule by a single bond. For example, the alkyl group may have 1 to 20 carbon atoms, preferably 1 to 8 carbon atoms, and more preferably 1 to 4 carbon atoms. The alkyl group may be unsubstituted or substituted with a substituent. Non-limiting examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl, tert-butyl, n-pentyl, 2-methylbutyl, neopentyl, n-hexyl, 2-methylhexyl, -CH₂-cyclopropyl and the like.

The term "alkoxy" refers to an-O-alkyl group, wherein alkyl is the same as defined above. Alkoxy groups having 1 to 4 carbon atoms are preferred. The alkoxy group may be unsubstituted or substituted with a substituent. Non-limiting examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, t-butoxy, n-pentoxy, 2-methylbutoxy, neopentoxy, n-hexoxy, 2-methylhexoxy, and the like.

The term "cycloalkyl" refers to a saturated or unsaturated non-aromatic cyclic hydrocarbon ring, preferably containing 1,2 or 3 rings, each ring having 3 to 7 carbon atoms. The cycloalkyl group may be unsubstituted or substituted with a substituent. Non-limiting examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like.

The term "alkenyl" refers to a straight or branched chain alkenyl group, preferably a straight or branched chain alkenyl group containing 2 to 4 carbon atoms. The alkenyl group may be unsubstituted or substituted with a substituent. Non-limiting examples of alkenyl groups include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, isobutenyl.

The term "alkynyl" refers to a straight or branched alkynyl group, preferably a straight or branched alkenyl group containing 2 to 4 carbon atoms. The alkenyl group may be unsubstituted or substituted with a substituent. Non-limiting examples of alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl.

The term "amino" refers to the group-NH₂A group in which a hydrogen atom may be substituted with a substituent.

The term "aryl" refers to an all-carbon monocyclic or fused polycyclic aromatic ring group having a conjugated pi-electron system, preferably having 6 to 14 carbon atoms, more preferably having 6 to 12 carbon atoms, and most preferably having 6 carbon atoms. The aryl group may be unsubstituted or substituted with a substituent. Non-limiting examples of aryl groups include, but are not limited to, phenyl, naphthyl, and anthracenyl.

The term "heteroaryl" refers to a monocyclic or fused ring having 5, 6, 7, 8, 9, 10, 11 or 12 ring atoms containing 1,2, 3 or4 ring atoms selected from N, O, S, the remaining ring atoms being C, and having a fully conjugated pi-electron system. The heteroaryl group preferably has a 5-or 6-membered ring, more preferably a 5-membered ring. The heteroaryl group may be unsubstituted or substituted with a substituent. Non-limiting examples of heteroaryl groups include, but are not limited to, pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl, tetrazolyl, triazolyl, triazinyl.

The term "heterocycloalkyl" refers to a monocyclic or fused ring having 3,4, 5, 6, 7, 8, 9, 10, 11, or 12 ring atoms, wherein 1,2, or 3 ring atoms are selected from N, O, S (O)_n(wherein n is 0, 1 or 2) and the remaining ring atoms are C. Such rings may be saturated or unsaturated (e.g. with one or more double bonds), but do not have a fully conjugated pi-electron system. The heterocycloalkyl group may be unsubstituted or substituted with a substituent. Examples of 3-membered heteroalicyclic include, but are not limited to, oxiranyl, thienylalkyl, cycloazenyl, examples of 4-membered heteroalicyclic include, but are not limited to, azetidinyl, oxetanyl, thietanyl, examples of 5-membered heteroalicyclic include, but are not limited to, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, isoxazolidinyl, oxazolidinyl, isothiazolidinyl, 1-dioxoisothiazolidinyl, thiazolidinyl, imidazolidinyl, tetrahydropyrazolyl, pyrrolinyl, dihydrofuranyl, dihydrothienyl, examples of 6-membered heteroalicyclic include, but are not limited to, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, piperazinyl, 1, 4-thiaoxazolidinyl, 1, 4-dioxanyl, thiomorpholinyl, 1,2-, 1, 4-dithianyl, dihydropyridinyl, tetrahydropyridinyl, morpholinyl, piperazinyl, 1, 4-dioxanyl, 1, 4-dioxane, thiomorpholinyl, 1,2-, 1, examples of dihydropyranyl, tetrahydropyranyl, thiochromanyl, 7-membered heteroalicyclic include, but are not limited to, azepanyl, oxepanyl, thiacycloheptyl. Monocyclic heterocycloalkyl groups having 5 or 6 ring atoms are preferred.

Unless otherwise indicated, the term "substituted with a substituent" means that the group is substituted with one or more substituents, non-limiting examples of which include, but are not limited to, halogen, alkyl, halogen-substituted alkyl, alkenyl, alkynyl, alkoxy, halogen-substituted alkoxy, cycloalkyl, hydroxy, mercapto, alkylmercapto, nitro, cyano, ═ O, alkanoyl, carboxy, alkanoyloxy, alkylamido, alkylsulfinyl, alkylsulfonyl, amino, carbamoyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl.

The term "therapeutically effective amount" means an amount of a compound of the invention which, when administered to a mammal, preferably a human, is sufficient to effectively treat a disease associated with GPR40, particularly a diabetes-related disease, in a mammal, preferably a human. The amount of a compound of the present invention that constitutes a "therapeutically effective amount" varies depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by those skilled in the art with their own knowledge and this disclosure.

The term "treating" means administering a compound or formulation of the invention to prevent, ameliorate or eliminate a disease or one or more symptoms associated with the disease, and includes:

(i) preventing the occurrence of a disease or condition in a mammal, particularly when such mammal is susceptible to the disease condition, but has not yet been diagnosed as having the disease condition;

(ii) inhibiting the disease or disease state, i.e., arresting its development;

(iii) alleviating the disease or condition, i.e., causing regression of the disease or condition.

The term "pharmaceutical composition" refers to a formulation of one or more compounds of the present invention or salts thereof with carriers, excipients, and/or vehicles generally accepted in the art for delivery of biologically active compounds to organisms (e.g., humans). The purpose of the pharmaceutical composition is to facilitate administration of the compounds of the invention to an organism.

The term "pharmaceutically acceptable carrier" refers to those carriers and diluents which do not significantly irritate the organism and which do not otherwise impair the biological activity and performance of the active compound. "pharmaceutically acceptable carrier" includes, but is not limited to, any carrier, excipient, vehicle, glidant, sweetener, diluent, preservative, dye/colorant, flavor enhancer, surfactant, wetting agent, dispersant, disintegrant, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier that is approved by the national food and drug administration for use in humans or livestock animals. Non-limiting examples of such excipients include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils, polyethylene glycols, and the like.

Drawings

FIG. 1 glucose tolerance test (blood glucose concentration-time)

FIG. 2 glucose tolerance test (blood glucose AUC-dose)

Detailed Description

The following specific examples are included to provide those skilled in the art with a clear understanding of the invention and are included to provide a further understanding of the invention. They should not be considered as limiting the scope of the invention but merely as being exemplary illustrations and representative of the invention. Those skilled in the art will understand that: there are other synthetic routes to the compounds of the present invention, and the following non-limiting examples are provided.

All operations involving easily oxidizable or hydrolyzable raw materials were carried out under nitrogen protection. The raw materials used in the invention can be directly purchased in the market, directly used without further purification, or prepared by adopting a similar method according to the prior literature.

The column chromatography adopts silica gel (200-300 mesh) produced by Qingdao chemical industry Co. The thin layer chromatography was carried out using a preformed plate (silica gel 60PF254,0.25 mm) manufactured by E.Merck. Nuclear magnetic resonance chromatography (NMR) was measured using a varian vnmrs-400 nuclear magnetic resonance instrument; liquid chromatography-Mass Spectrometry (LC/MS) Using FINNIGAN Thermo LCQ Advantage MAX, Agilent LC1200series (column: Waters Symmetry C18,. phi.4.6X 50mm, 5 μm, 35 ℃ C.), ESI (+) ion mode was used.

Intermediate 1: synthesis of (S) -6-hydroxy-2, 3-dihydrobenzofuran-3-acetic acid methyl ester

Step 1: synthesis of 4-chloromethyl-7-hydroxycoumarin

Ethyl 4-chloroacetoacetate (28.0g,0.17mol) was dissolved in concentrated sulfuric acid (60mL) with ice water cooling, then resorcinol (18.7g,170mmol) was added thereto in small portions, and after the addition was completed, the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into ice water, and the resulting solid was filtered, washed with water, and dried under vacuum to give 4-chloromethyl-7-hydroxycoumarin (32.2g, yield 90.0%).¹H NMR(400MHz，CDCl₃-d₃)：10.63(1H,s),7.64(1H,d,J=8.8Hz),6.80(1H,dd,J=8.8Hz,2.4Hz),6.72(1H,d,J=2.4Hz),6.39(1H,s),4.92(2H,s)。

Step 2: synthesis of 6-hydroxybenzofuran-3-acetic acid

4-chloromethyl-7-hydroxycoumarin (23.0g,0.11mol) was dissolved in 1M aqueous sodium hydroxide (600mL), the mixture was heated under reflux for 2 hours, the reaction was cooled to room temperature, the pH was adjusted to 5-6 with concentrated sulfuric acid, the mixture was extracted with ethyl acetate (500mL × 2), the organic phases were combined, dried over anhydrous sodium sulfate and concentrated to give 6-hydroxybenzofuran-3-acetic acid (19.9g, 95.0% yield).¹H NMR(400MHz，CDCl₃-d₃)：12.35-12.45(1H,brs),9.48(1H,s),7.65(1H,s),7.33(1H,d,J=8.0Hz),6.85(1H,d,J=2.0Hz),6.72(1H,dd,J=8.4Hz,2.0Hz),3.58(2H,s)。

And step 3: synthesis of methyl 6-hydroxybenzofuran-3-acetate

To a mixture of 6-hydroxybenzofuran-3-acetic acid (22.0g,0.11mol) and methanol (200mL) was added concentrated sulfuric acid (8mL), the mixture was heated under reflux for 8 hours, the reaction was cooled to room temperature and concentrated under reduced pressure, water (500mL) was added to the residue, the mixture was extracted with ethyl acetate (500mL × 2), the organic phases were combined, washed with a saturated sodium bicarbonate solution and dried over anhydrous sodium sulfate, and concentrated to give methyl 6-hydroxybenzofuran-3-acetate (22.0g, yield 93.2%).¹H NMR(400MHz，CDCl₃-d₃)：7.50(1H,s),7.34(1H,d,J=8.4Hz),6.91(1H,d,J=2.4Hz),6.76(1H,dd,J=8.4Hz,2.0Hz),5.62(1H,s),3.74(3H,s),3.67(2H,s)。

And 4, step 4: synthesis of methyl 6-hydroxy-2, 3-dihydrobenzofuran-3-acetate

A mixture of methyl 6-hydroxybenzofuran-3-acetate (22.0g,0.11mol), 10% palladium on carbon (water content 50%,8.0g) and methanol (500mL) was stirred under a hydrogen atmosphere (1 atm) at room temperature overnight. The reaction mixture was filtered through celite, and the filtrate was concentrated to give methyl 6-hydroxy-2, 3-dihydrobenzofuran-3-acetate (21.0g, yield 94.6%).¹H NMR(400MHz，CDCl₃-d₃)：6.92(1H,d,J=7.6Hz),6.31-6.33(2H,m),6.10-6.14(1H,brs),4.71(1H,t,J=8.8Hz),4.22(1H,dd,J=9.2Hz,6.0Hz),3.73-3.79(1H,m),3.70(3H,s),2.72(1H,dd,J=16.4Hz,5.6Hz),2.53(1H,dd,J=16.4Hz,5.6Hz)。

And 5: synthesis of 6-hydroxy-2, 3-dihydrobenzofuran-3-acetic acid

To a solution of methyl 6-hydroxy-2, 3-dihydrobenzofuran-3-acetate (20.8g,0.10mol), methanol (100mL) and tetrahydrofuran (100mL) in a mixed solvent was added dropwise a 2M aqueous sodium hydroxide solution (100mL), and after completion of the addition, the mixture was stirred at room temperature overnight. The reaction mixture was diluted with water and the pH adjusted to 6 with dilute hydrochloric acid. The precipitated solid was filtered, washed with water, and dried to give 6-hydroxy-2, 3-dihydrobenzofuran-3-acetic acid (17.9g, 92.3%).

Step 6: synthesis of (S) -6-hydroxy-2, 3-dihydrobenzofuran-3-acetic acid

(S) -1-phenylethylamine (22.6g,0.19mol) was added portionwise to a solution of 6-hydroxy-2, 3-dihydrobenzofuran-3-acetic acid (52.4g,0.27mol) in acetone (1.5L) at room temperature. The mixture was heated to reflux for 1 hour and cooled to room temperature. The precipitated solid was collected by filtration and recrystallized 2 times from acetone. The solid was dissolved in water, the pH was adjusted to 6 with dilute hydrochloric acid, the mixture was extracted with ethyl acetate (500 mL. times.3), the organic phases were combined and dried over anhydrous sodium sulfate, and concentrated to give (S) -6-hydroxy-2, 3-dihydrobenzofuran-3-acetic acid (10.5g, yield 20.0%).

And 7: synthesis of (S) -6-hydroxy-2, 3-dihydrobenzofuran-3-acetic acid methyl ester

Concentrated sulfuric acid (4mL) was added to a mixture of (S) -6-hydroxy-2, 3-dihydrobenzofuran-3-acetic acid (11.0g,57mmol)) and methanol (200mL), the mixture was heated under reflux for 8 hours, the reaction mixture was cooled to room temperature and concentrated under reduced pressure, water (500mL) was added to the residue, the mixture was extracted with ethyl acetate (500mL × 2), the organic phases were combined, washed with a saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, and concentrated to give methyl (S) -6-hydroxy-2, 3-dihydrobenzofuran-3-acetate (11.0g, yield 93.2%).¹H NMR(400MHz，CDCl₃-d₃):6.95(1H,d,J=8.0Hz),6.29-6.32(2H,m),4.81(1H,s),4.73(1H,t,J=8.8Hz),4.25(1H,dd,J=9.2Hz,6.0Hz),3.72-3.81(1H,m),3.70(3H,s),2.72(1H,dd,J=16.4Hz,5.6Hz),2.54(1H,dd,J=16.4Hz,9.2Hz)。

Example 1: 2- (6- ((4' - (3- (dimethylphosphonyl) propoxy) -2',6' -dimethylbiphenyl-3-yl) methoxy Synthesis of 2, 3-dihydrobenzofuran-3-yl) acetic acid

Step 1: synthesis of 4' -hydroxy-2 ',6' -dimethylbiphenyl-3-carbaldehyde

The reaction mixture was prepared by reacting 3, 5-dimethyl-4-bromophenol (10.0g,49.7mmol), 3-formylphenylboronic acid (b8.9g,59.7mmol), cesium carbonate (24.3g,74.6mmol) and [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride (1.8g,2.5mmol) was added to 1, 4-dioxane (250 mL). The mixture was heated to reflux for 8 hours and then cooled to room temperature. The reaction mixture was filtered through celite, washed with ethyl ester, and the filtrate was concentrated, and the residue was separated and purified by silica gel column chromatography to give 4' -hydroxy-2 ',6' -dimethylbiphenyl-3-carbaldehyde (8.4g, yield 75.0%).¹H NMR(400MHz，CDCl₃-d₃)：10.05(2H,s),7.86(1H,d,J=7.6Hz),7.67(1H,t,J=1.6Hz),7.59(1H,t,J=7.6Hz),7.42(1H,d,J=7.6Hz),6.64(2H,s),1.97(6H,s)。

Step 2: synthesis of 4' - (tert-butyldimethylsilyloxy) -2',6' -dimethylbiphenyl-3-carbaldehyde

To a solution of 4' -hydroxy-2 ',6' -dimethylbiphenyl-3-carbaldehyde (2.0g,8.8mmol) and imidazole (1.2g,17.6mmol) in dichloromethane (50mL) was added dropwise a solution of tert-butyldimethylchlorosilane (2.0g,13.2mmol) in dichloromethane (50mL) with cooling in an ice-water bath. After the addition was complete, the reaction was slowly warmed to room temperature and stirred overnight. The reaction mixture was filtered, and after the filtrate was concentrated, the residue was separated and purified by column chromatography on silica gel to give 4' - (tert-butyldimethylsilyloxy) -2',6' -dimethylbiphenyl-3-carbaldehyde (2.6g, yield 86.7%).¹H NMR(400MHz，CDCl₃-d₃)：10.05(1H,s),7.84(1H,d,J=7.6Hz),7.67(1H,s),7.58(1H,t,J=7.6Hz),7.42(1H,d,J=7.6Hz),6.60(2H,s),1.96(6H,s),1.01(9H,s),0.24(6H,s)。

And step 3: synthesis of (4' - (tert-butyldimethylsilyloxy) -2',6' -dimethylbiphenyl-3-yl) methanol

To a solution of 4'- (tert-butyldimethylsilyloxy) -2',6 '-dimethylbiphenyl-3-carbaldehyde (3.0g,8.8mmol) in tetrahydrofuran (40mL) and methanol (20mL) was added sodium borohydride (0.67g,17.6mmol) in small portions under cooling in an ice-water bath, and after the addition was completed, the reaction mixture was slowly warmed to room temperature and stirred overnight, after the reaction mixture was concentrated, water (200mL) was added thereto, the mixture was extracted with ethyl acetate (250mL × 3), the organic phases were combined and dried over anhydrous sodium sulfate, and concentrated to give (4'- (tert-butyldimethylsilyloxy) -2',6' -dimethylbiphenyl-3-yl) methanol (2.6g, yield 86.7%).¹HNMR(400MHz，CDCl₃-d₃)：7.40(1H,t,J=7.6Hz),7.32(1H,d,J=7.6Hz),7.13(1H,s),7.07(1H,d,J=7.2Hz),6.58(2H,s),4.73(2H,s),1.97(6H,s),1.00(9H,s),0.23(6H,s)。

And 4, step 4: synthesis of methyl 2- (6- ((4' - (tert-butyldimethylsilyloxy) -2',6' -dimethylbiphenyl-3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate

To a solution of methyl (4' - (tert-butyldimethylsilyloxy) -2',6' -dimethylbiphenyl-3-yl) methanol (2.0g,5.8mmol), 6-hydroxy-2, 3-dihydrobenzofuran-3-acetate (the product of step 5 in intermediate 1, prepared according to the method of step 7) (1.5g,7.2mmol) and triphenylphosphine (2.4g,9.0mmol) in tetrahydrofuran (150mL) was added dropwise diisopropyl azodicarboxylate (1.8g,9.0mmol) with cooling in an ice-water bath. After the addition was complete, the reaction was slowly warmed to room temperature and stirred overnight. After the reaction solution was concentrated, the residue was separated and purified by silica gel column chromatography to give methyl 2- (6- ((4' - (tert-butyldimethylsilyloxy) -2',6' -dimethylbiphenyl-3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate (2.1g, yield 67.7%).¹H NMR(400MHz，CDCl₃-d₃)：7.42(1H,t,J=7.6Hz),7.37(1H,d,J=8.0Hz),7.18(1H,s),7.09(1H,d,J=7.2Hz),7.02(1H,d,J=8.4Hz),6.59(2H,s),6.45-6.51(2H,m),5.06(2H,s),4.75(1H,t,J=8.8Hz),4.27(1H,dd,J=9.2Hz,6.4Hz),3.76-3.85(1H,m),3.72(3H,s),2.75(1H,dd,J=16.4Hz,5.2Hz),2.56(1H,dd,J=16.4Hz,5.2Hz),1.96(6H,s),1.02(9H,s),0.24(6H,s)。

And 5: synthesis of methyl 2- (6- ((4' -hydroxy-2 ',6' -dimethylbiphenyl-3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate

Tetrabutylammonium fluoride (1.3g,5.0mmol) was added to a solution of methyl 2- (6- ((4' - (tert-butyldimethylsilyloxy) -2',6' -dimethylbiphenyl-3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate (1.1g,2.1mmol) in tetrahydrofuran (50mL) with cooling in an ice-water bath. After the addition was complete, the reaction was slowly warmed to room temperature and stirred overnightThe reaction was terminated by adding 50mL of a saturated aqueous ammonium chloride solution, the mixture was extracted with ethyl acetate (50mL × 3), the organic phases were combined and dried over anhydrous sodium sulfate, and concentrated to give methyl 2- (6- ((4' -hydroxy-2 ',6' -dimethylbiphenyl-3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate (0.75g, yield 87%).¹H NMR(400MHz，CDCl₃-d₃)：7.42(1H,t,J=7.2Hz),7.37(1H,d,J=8.0Hz),7.16(1H,s),7.07(1H,d,J=7.2Hz),7.01(1H,d,J=8.0Hz),6.60(2H,s),6.45-6.50(2H,m),5.06(2H,s),4.75(1H,t,J=9.2Hz),4.26(1H,dd,J=9.2Hz,6.4Hz),3.75-3.87(1H,m),3.72(3H,s),2.74(1H,dd,J=16.4Hz,5.6Hz),2.55(1H,dd,J=16.4Hz,5.6Hz),1.97(6H,s)。

Step 6: synthesis of methyl 2- (6- ((4' - (allyloxy) -2',6' -dimethylbiphenyl-3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate

Potassium carbonate (3.3g,23.9mmol) was added to a solution of methyl 2- (6- ((4' -hydroxy-2 ',6' -dimethylbiphenyl-3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate (5.0g,11.9mmol) and allyl iodide (4.0g,23.8mmol) in acetonitrile (100 mL). The mixture was stirred at room temperature overnight, filtered, and the residue obtained by concentrating the filtrate was purified by silica gel column chromatography to give methyl 2- (6- ((4' - (allyloxy) -2',6' -dimethylbiphenyl-3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate (4.1g, yield 74.5%).¹H NMR(400MHz，CDCl₃-d₃)：7.40(1H,t,J=7.6Hz),7.35(1H,d,J=7.6Hz),7.16(1H,s),7.06(1H,d,J=7.2Hz),6.99(1H,d,J=8.4Hz),6.66(2H,s),6.43-6.48(2H,m),6.02-6.12(1H,m),5.42(1H,d,J=16.8Hz),5.27(1H,d,J=10.4Hz),5.04(2H,s),4.73(1H,t,J=8.8Hz),4.53(2H,d,J=5.2Hz),4.24(1H,dd,J=9.2Hz,2.0Hz),3.75-3.82(1H,m),3.70(3H,s),2.73(1H,dd,J=16.4Hz,5.6Hz),2.53(1H,dd,J=16.4Hz,9.2Hz),1.97(6H,s)。

And 7: synthesis of methyl 2- (6- ((4' - (3- (dimethylphosphonyl) propoxy) -2',6' -dimethylbiphenyl-3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate

Dimethyl phosphine oxide (1.0g,12.8mmol) was added to 2- (6- ((4' - (allyloxy) -2',6' -dimethylbiphenyl-3-yl) methoxy) -2, 3-dihydrobenzeneAnd furan-3-yl) acetic acid methyl ester (4.1g,9.0mmol) in methanol (100 mL). After the reaction mixture was stirred at room temperature for 10 minutes, diethylmethoxyborane (1.3g,13.0mmol) was added thereto. The reaction mixture was heated to 80 ℃ and reacted overnight. The reaction mixture was cooled to room temperature, concentrated, and the residue was subjected to column chromatography on a silica gel column to give methyl 2- (6- ((4' - (3- (dimethylphosphonyl) propoxy) -2',6' -dimethylbiphenyl-3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate (3.0g, yield 62.5%).¹H NMR(400MHz，CDCl₃-d₃)：7.41(1H,t,J=7.2Hz),7.36(1H,d,J=8.0Hz),7.15(1H,s),7.06(1H,d,J=7.2Hz),7.00(1H,d,J=8.0Hz),6.64(2H,s),6.44-6.48(2H,m),5.05(2H,s),4.73(1H,t,J=9.2Hz),4.24(1H,dd,J=9.2Hz,6.0Hz),4.06(2H,t,J=6.0Hz),3.76-3.82(1H,m),3.71(3H,s),2.73(1H,dd,J=16.4Hz,5.2Hz),2.54(1H,dd,J=16.4Hz,9.2Hz),2.04-2.16(2H,m),1.98(6H,s),1.88-1.97(2H,m),1.53(6H,d,J=12.4Hz)。

And 8: synthesis of 2- (6- ((4' - (3- (dimethylphosphonyl) propoxy) -2',6' -dimethylbiphenyl-3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetic acid

To a solution of methyl 2- (6- ((4'- (3- (dimethylphosphono) propoxy) -2',6 '-dimethylbiphenyl-3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate (3.0g,5.6mmol) in a mixed solvent of methanol (50mL) and tetrahydrofuran (100mL), a 2M aqueous solution of sodium hydroxide (8mL) was added dropwise, and the mixture was stirred at room temperature overnight after completion of the addition, the reaction mixture was diluted with water, acidified with a 10% aqueous solution of citric acid, and extracted with ethyl acetate (150mL × 3). the organic phase was dried over anhydrous sodium sulfate and concentrated, and the residue was purified by silica gel column chromatography to give 2- (6- ((4' - (3- (dimethylphosphono) propoxy) -2',6' -dimethylbiphenyl-3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetic acid (2.3g, yield 78.0%).¹H NMR(400MHz，DMSO-d₆)：12.19-12.38(1H,brs),7.41(1H,t,J=7.2Hz),7.34(1H,d,J=7.6Hz),7.10(1H,s),7.06(1H,d,J=8.0Hz),7.02(1H,d,J=7.6Hz),6.66(2H,s),6.41-6.45(2H,m),5.06(2H,s),4.64(1H,t,J=9.2Hz),4.14(1H,dd,J=9.2Hz,6.8Hz),4.00(2H,t,J=6.0Hz),3.59-3.67(1H,m),2.65(1H,dd,J=16.4Hz,5.6Hz),2.40-2.43(1H,m),1.90-1.97(2H,m),1.72-1.78(2H,m),1.36(6H,d,J=12.8Hz)。

Example 2: 2- (6- ((2',6' -dimethyl-4 ' - (2- (methylsulfonylamino) ethoxy) biphenyl-3-yl) methoxy Synthesis of 2, 3-dihydrobenzofuran-3-yl) acetic acid

Step 1: synthesis of methyl 2- (6- ((4' - (cyanomethoxy) -2',6' -dimethylbiphenyl-3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate

Potassium carbonate (2.0g,14.5mmol) was added to a solution of methyl 2- (6- ((4' -hydroxy-2 ',6' -dimethylbiphenyl-3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate (3.0g,7.2mmol) and bromoacetonitrile (1.8g,15.0mmol) in acetonitrile (100 mL). The mixture was stirred at room temperature overnight, filtered, and the residue obtained by concentrating the filtrate was purified by silica gel column chromatography to give methyl 2- (6- ((4' - (cyanomethoxy) -2',6' -dimethylbiphenyl-3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate (2.2g, yield 66.7%). MS m/z [ ESI ]]⁺:458.0[M+1]。

Step 2: synthesis of methyl 2- (6- ((4' - (2-aminoethoxy) -2',6' -dimethylbiphenyl-3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate

A mixture of methyl 2- (6- ((4'- (cyanomethoxy) -2',6 '-dimethylbiphenyl-3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate (2.2g,4.8mmol), Raney's nickel (5.0g) and methanol (100mL) was stirred under a hydrogen atmosphere (1 atm) at room temperature overnight. The reaction mixture was filtered through celite, and the filtrate was concentrated to give methyl 2- (6- ((4' - (2-aminoethoxy) -2',6' -dimethylbiphenyl-3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate (2.1g, yield 95.0%). MS m/z [ ESI ]]⁺:462.0[M+1]。

And step 3: synthesis of methyl 2- (6- ((2',6' -dimethyl-4 ' - (2- (methylsulfonylamino) ethoxy) biphenyl-3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate

To a solution of methyl 2- (6- ((4'- (2-aminoethoxy) -2',6 '-dimethylbiphenyl-3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate (0.5g,1.1mmol) in dichloromethane (50mL) was added methanesulfonyl chloride (0.19g,1.6mmol) and triethylamine (0.22g,2.2mmol) in that order, the reaction mixture was stirred overnight at room temperature, the reaction was poured into water (50mL), extracted with dichloromethane (100mL × 2), the organic phase was dried over anhydrous sodium sulfate, concentrated, and the residue was purified by silica gel column chromatography to give methyl 2- (6- ((2',6 '-dimethyl-4' - (2- (methanesulfonylamino) ethoxy) biphenyl-3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate (0.44g, yield 75.0%).¹H NMR(400MHz，CDCl₃-d₃)：7.44(1H,t,J=7.6Hz),7.40(1H,d,J=7.6Hz),7.18(1H,s),7.09(1H,d,J=7.2Hz),7.03(1H,d,J=8.0Hz),6.66(2H,s),6.47-6.52(2H,m),5.08(2H,s),4.77-4.79(2H,m),4.28(1H,dd,J=9.2Hz,6.0Hz),4.14(2H,t,J=4.8Hz),3.78-3.85(1H,m),3.74(3H,s),3.58(2H,q,J=5.6Hz),3.06(3H,s),2.76(1H,dd,J=16.8Hz,5.2Hz),2.57(1H,dd,J=16.8Hz,9.6Hz),2.01(6H,s)。

And 4, step 4: synthesis of 2- (6- ((2',6' -dimethyl-4 ' - (2- (methylsulfonylamino) ethoxy) biphenyl-3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetic acid

To a solution of methyl 2- (6- ((2',6' -dimethyl-4 '- (2- (methylsulfonylamino) ethoxy) biphenyl-3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate (0.44g,0.8mmol) in a mixed solvent of methanol (25mL) and tetrahydrofuran (50mL), a 2M aqueous solution of sodium hydroxide (2mL) was added dropwise, and the mixture was stirred at room temperature overnight after completion of the addition, the reaction mixture was diluted with water, acidified with a 10% aqueous solution of citric acid, and extracted with ethyl acetate (50mL × 3). the organic phase was dried over anhydrous sodium sulfate and concentrated, and the residue was separated and purified by silica gel column chromatography to give 2- (6- ((2',6 '-dimethyl-4' - (2- (methylsulfonylamino) ethoxy) biphenyl-3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetic acid (0.28g, yield 65.0%).¹H NMR(400MHz，DMSO-d₆)：7.43(1H,t,J=7.6Hz),7.36(1H,d,J=7.6Hz),7.25(1H,t,J=6.0Hz),7.12(1H,s),7.08(1H,d,J=8.0Hz),7.04(1H,d,J=7.2Hz),6.70(2H,s),6.43-6.47(2H,m),5.08(2H,s),4.66(1H,t,J=9.2Hz),4.16(1H,dd,J=8.8Hz,6.8Hz),4.02(2H,t,J=6.0Hz),3.58-3.70(1H,m),3.32-3.34(2H,m),2.95(3H,s),2.66(1H,dd,J=16.4Hz,5.6Hz),2.43-2.45(1H,m),1.90(6H,s)。

Example 3: 2- (6- ((2',6' -dimethyl-4 ' - (2- (ethylsulfonylamino) ethoxy) biphenyl-3-yl) methyl) Synthesis of oxy) -2, 3-dihydrobenzofuran-3-yl) acetic acid

The title compound was prepared according to the procedure for example 2, substituting ethylsulfonyl chloride for methylsulfonyl chloride.¹HNMR(400MHz，DMSO-d₆)：7.43(1H,t,J=7.6Hz),7.36(1H,d,J=7.6Hz),7.28(1H,t,J=6.4Hz),7.12(1H,s),7.08(1H,d,J=8.0Hz),7.04(1H,d,J=7.2Hz),6.69(2H,s),6.43-6.47(2H,m),5.08(2H,s),4.66(1H,t,J=8.8Hz),4.16(1H,dd,J=9.6Hz,6.8Hz),4.00(2H,t,J=5.6Hz),3.61-3.69(1H,m),3.34-3.37(2H,m),3.05(2H,q,J=7.6Hz),2.67(1H,dd,J=16.8Hz,6.0Hz),2.42-2.45(1H,m),1.90(6H,s),1.20(3H,t,J=7.2Hz)。

Example 4: 2- (6- ((2',6' -dimethyl-4 ' - (2- (cyclopropylsulfonylamino) ethoxy) biphenyl-3-yl) Synthesis of methoxy) -2, 3-dihydrobenzofuran-3-yl) acetic acid

The title compound was prepared according to the procedure for example 2, substituting cyclopropylsulfonyl chloride for methanesulfonyl chloride.^'HNMR(400MHz，CDCl₃-d₃)：7.40(1H,t,J=7.6Hz),7.35(1H,d,J=7.6Hz),7.14(1H,s),7.02-7.06(2H,m),6.63(2H,s),6.47(1H,dd,J=8.0Hz,2.0Hz),6.44(1H,d,J=2.4Hz),5.04(2H,s),4.71-4.79(2H,m),4.26(1H,dd,J=9.2Hz,6.0Hz),4.11(2H,t,J=6.0Hz),3.74-3.82(1H,m),3.55(2H,q,J=6.0Hz),2.78(1H,dd,J=16.8Hz,5.2Hz),2.59(1H,dd,J=16.8Hz,9.2Hz),2.40-2.51(1H,m),1.97(6H,s),1.18-1.22(2H,m),0.98-1.03(2H,m)。

Example 5: 2- (6- ((2',6' -dimethyl-4 ' - (2- (1, 1-dioxo-isothiazolidin-2-yl) ethoxy)) bis Synthesis of phenyl-3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetic acid

Step 1: synthesis of methyl 2- (6- ((4' - (2- (3-chloropropylsulfonylamino) ethoxy) -2',6' -dimethylbiphenyl-3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate

To a solution of methyl 2- (6- ((4'- (2-aminoethoxy) -2',6 '-dimethylbiphenyl-3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate (0.66g,1.4mmol) in dichloromethane (50mL) were added 3-chloro-1-propylsulfonyl chloride (0.38g,2.1mmol) and triethylamine (0.29g,2.9mmol) in this order, the reaction mixture was stirred at room temperature overnight, the reaction was poured into water (50mL), dichloromethane was extracted (100mL × 2), the organic phase was dried over anhydrous sodium sulfate, concentrated, and the residue was purified by silica gel column chromatography to give methyl 2- (6- ((4' - (2- (3-chloropropylsulfonylamino) ethoxy) -2',6' -dimethylbiphenyl-3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate (0.64g, yield 75.0%). m/z [ ESI ],]⁺:602.0[M+1]。

step 2: synthesis of methyl 2- (6- ((4' - (2- (1, 1-dioxo-isothiazolidin-2-yl) ethoxy) -2',6' -dimethylbiphenyl-3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate

To 2- (6- ((4' - (2- (3-chloropropylsulfonylamino) ethoxy) -2',6' -dimethylbiphenyl-3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) methyl acetate (60.0mg,0.1mmol) in N, N-dimethylformamide (10mL) was added potassium carbonate (28.0mg,0.2 mmol). The reaction mixture was stirred at 80 ℃ overnight, the reaction was poured into water (50mL), extracted with ethyl acetate (100mL × 2), the organic phase was dried over anhydrous sodium sulfate, concentrated, and the residue was purified by silica gel column chromatography to give methyl 2- (6- ((4' - (2- (1, 1-dioxo-isothiazolidin-2-yl) ethoxy) -2',6' -dimethylbiphenyl-3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate (50.0mg, yield 88.8%). MS m/z [ ESI%]⁺:566.0[M+1]。

And step 3: synthesis of 2- (6- ((4' - (2- (1, 1-dioxo-isothiazolidin-2-yl) ethoxy) -2',6' -dimethylbiphenyl-3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetic acid

To a solution of methyl 2- (6- ((4'- (2- (1, 1-dioxo-isothiazolin-2-yl) ethoxy) -2',6 '-dimethylbiphenyl-3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate (50.0mg,0.09mmol) in a mixed solvent of methanol (10mL) and tetrahydrofuran (20mL) was added dropwise an aqueous 2M sodium hydroxide solution (1mL), and the mixture was stirred at room temperature overnight after completion of the addition, the reaction mixture was diluted with water, acidified with a 10% aqueous citric acid solution, and extracted with ethyl acetate (50mL × 3), the organic phase was dried over anhydrous sodium sulfate and concentrated, and the residue was separated and purified by silica gel column chromatography to give 2- (6- ((4' - (2- (1, 1-dioxo-isothiazolin-2-yl) ethoxy) -2',6' -dimethylbiphenyl-3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetic acid (22.0mg, yield 45.1%).¹HNMR(400MHz，CDCl₃-d₃)：7.43(1H,t,J=7.2Hz),7.37(1H,d,J=7.6Hz),7.16(1H,s),7.04-7.09(2H,m),6.66(2H,s),6.49(1H,dd,J=8.0Hz,2.0Hz),6.48(1H,d,J=2.0Hz),5.07(2H,s),4.78(1H,t,J=8.8Hz),4.29(1H,dd,J=9.2Hz,6.0Hz),4.20(2H,t,J=4.2Hz),3.79-3.84(1H,m),3.48-3.53(4H,m),3.16(2H,t,J=7.6Hz),2.80(1H,dd,J=17.2Hz,5.6Hz),2.61(1H,dd,J=16.8Hz,9.2Hz),2.37(2H,quin,J=6.8Hz),1.99(6H,s)。

Example 6: 2- (6- ((2',6' -dimethyl-4 ' - (3- (N, N-dimethylaminosulfonyl) propoxy) biphenyl- 3-yl) methoxySynthesis of 2, 3-dihydrobenzofuran-3-yl) acetic acid

Step 1: synthesis of 3- (4-bromo-3, 5-dimethylphenoxy) propyl-1-sodium sulfonate

To a mixture of 4-bromo-3, 5-dimethylphenol (20.2g,0.1mol) and water (250mL) was added sodium hydroxide (5.0g,0.12 mol). The reaction mixture was stirred for 1 hour. A solution (200mL) of 2, 2-dioxo-1, 2-oxathiolane (15.3g,0.12mol) in 1, 4-dioxane was added dropwise to the reaction solution. The reaction solution was stirred overnight at room temperature, and the resulting solid was collected by filtration and dried to give sodium 3- (4-bromo-3, 5-dimethylphenoxy) propyl-1-sulfonate (29.3g, yield 85.0%).¹H NMR(400MHz，DMSO-d₆)：6.77(2H,s),3.92-4.05(2H,m),2.49-2.53(2H,m),1.90-1.97(2H,m)。

Step 2: synthesis of 3- (4-bromo-3, 5-dimethylphenoxy) propyl-1-sulfonyl chloride

Thionyl chloride (15mL) was added dropwise to a solution of sodium 3- (4-bromo-3, 5-dimethylphenoxy) propyl-1-sulfonate (10.0g,29.0mmol) in N, N-dimethylformamide (150mL) while cooling in an ice-water bath. After the completion of the dropwise addition, the reaction mixture was stirred at room temperature for 4 hours. The reaction solution was poured into water (500mL), and the resulting solid was collected by filtration and dried to give 3- (4-bromo-3, 5-dimethylphenoxy) propyl-1-sulfonyl chloride (7.5g, yield 75.8%).¹H NMR(400MHz，CDCl₃-d₃)：6.62(2H,s),4.08(2H,t,J=5.2Hz),3.88(2H,t,J=7.2Hz),2.46-2.50(2H,m),2.37(3H,s)。

And step 3: synthesis of N, N-dimethyl-3- (4-bromo-3, 5-dimethylphenoxy) propyl-1-sulfonamide

To a solution of 3- (4-bromo-3, 5-dimethylphenoxy) propyl-1-sulfonyl chloride (4.0g,11.7mmol) in tetrahydrofuran (150mL) was added dropwise an aqueous dimethylamine solution (33.0%, 10mL), and after completion of the addition, the mixture was stirred at room temperature overnight. Concentrating the solventThereafter, the residue was purified by silica gel column chromatography to give N, N-dimethyl-3- (4-bromo-3, 5-dimethylphenoxy) propyl-1-sulfonamide (4.0g, yield 97.6%).¹H NMR(400MHz，CDCl₃-d₃)：6.65(2H,s),4.06(2H,t,J=6.0Hz),3.14-3.15(2H,m),2.91(6H,s),2.39(6H,s),2.26-2.39(2H,m)。

And 4, step 4: synthesis of 4' - (3- (N, N-dimethylaminosulfonyl) propoxy) -2',6' -dimethylbiphenyl-3-carbaldehyde

N, N-dimethyl-3- (4-bromo-3, 5-dimethylphenoxy) propyl-1-sulfonamide (4.0g,11.4mmol), 3-formylphenylboronic acid (2.1g,13.7mmol), cesium carbonate (5.5g,17.1mmol) and [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride (0.4g,0.6mmol) was added to 1, 4-dioxane (150 mL). The mixture was heated to reflux for 8 hours and then cooled to room temperature. The reaction mixture was filtered through celite, washed with ethyl ester, the filtrate was concentrated and the residue was purified by column chromatography on silica gel to give 4' - (3- (N, N-dimethylaminosulfonyl) propoxy) -2',6' -dimethylbiphenyl-3-carbaldehyde (2.75g, yield 64.3%).¹H NMR(400MHz，CDCl₃-d₃)：10.05(1H,s),7.86(1H,d,J=7.6Hz),7.66(1H,s),7.59(1H,t,J=7.6Hz),7.41(1H,d,J=7.6Hz),6.67(2H,s),4.12(2H,t,J=6.0Hz),3.16(2H,t,J=7.6Hz),2.92(6H,s),2.28-2.37(2H,m),1.99(6H,s)。

And 5-7: synthesis of 2- (6- ((2',6' -dimethyl-4 ' - (3- (N, N-dimethylaminosulfonyl) propoxy) biphenyl-3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetic acid

2- (6- ((2',6' -dimethyl-4 '- (3- (N, N-dimethylaminosulfonyl) propoxy) biphenyl-3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetic acid is prepared by the method similar to the steps 3,4 and 8 in the example 1 in sequence by using the 4' - (3- (N, N-dimethylaminosulfonyl) propoxy) -2',6' -dimethylbiphenyl-3-formaldehyde obtained in the step 4 as a raw material.¹H NMR(400MHz，CDCl₃-d₃)：7.40(1H,t,J=8.0Hz),7.35(1H,d,J=8.0Hz),7.14(1H,s),7.02-7.07(2H,m),6.63(2H,s),6.47(1H,dd,J=8.0Hz,2.0Hz),6.44(1H,d,J=2.0Hz),5.04(2H,s),4.74(1H,t,J=9.2Hz),4.26(1H,dd,J=9.2Hz,6.0Hz),4.09(2H,t,J=5.2Hz),3.75-3.83(1H,m),3.14(2H,t,J=7.6Hz),2.90(6H,s),2.79(1H.dd,J=16.8Hz,5.2Hz),2.59(1H,dd,J=16.8Hz,9.2Hz),2.26-2.32(2H.m),1.97(6H,s)。

Example 7: 2- (6- ((2',6' -dimethyl-4 ' - (3- (N-methylaminosulfonyl) propoxy) biphenyl-3-yl) Synthesis of methoxy) -2, 3-dihydrobenzofuran-3-yl) acetic acid

The title compound was prepared according to the procedure for example 6, substituting methylamine for dimethylamine.¹H NMR(400MHz，CDCl₃-d₃)：7.42(1H,t,J=7.6Hz),7.37(1H,d,J=7.6Hz),7.15(1H,s),7.04-7.08(2H,m),6.64(2H,s),6.49(1H,dd,J=8.0Hz,2.0Hz),6.46(1H,d,J=2.0Hz),5.06(2H,s),4.76(1H,t,J=9.2Hz),4.28(1H,dd,J=9.2Hz,6.0Hz),4.07-4.12(3H,m),3.77-3.84(1H,m),3.26(2H,t,J=7.2Hz),2.84(3H,d,J=5.6Hz),2.80(1H,dd,J=16.8Hz,5.2Hz),2.60(1H,dd,J=16.8Hz,9.2Hz),2.24-2.33(2H,m),1.99(6H,s)。

Example 8: 2- (6- ((4' - (2- (1, 1-dioxo-isothiazolidin-2-yl) ethoxy) -2',6' -dimethylbis Synthesis of phenyl-3-yl) methylamino) -2, 3-dihydrobenzofuran-3-yl) acetic acid

Step 1: synthesis of 6-trifluoromethanesulfonyloxy-2, 3-dihydrobenzofuran-3-acetic acid methyl ester

To a mixture of methyl 6-hydroxy-2, 3-dihydrobenzofuran-3-acetate (2.08g,10.0mmol) and triethylamine (2.02g,20.0mmol) was added dichloromethane (50mL), the mixture was cooled to zero, andto the mixture was slowly dropped trifluoromethanesulfonic anhydride (3.4g, 12.0 mmol). The mixture was warmed to room temperature and stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was separated and purified by silica gel column chromatography to give methyl 6-trifluoromethanesulfonyloxy 2, 3-dihydrobenzofuran-3-acetate (2.1g, yield 63.0%).¹H NMR(400MHz，CDCl₃-d₃)：7.18(1H,d,J=8.4Hz),6.76(1H,dd,J=8.4Hz,2.0Hz),6.70(1H,d,J=2.0Hz),4.84(1H,t,J=9.2Hz),4.34(1H,dd,J=9.2Hz,6.4Hz),3.82-3.94(1H,m),3.73(3H,s),2.78(1H,dd,J=16.8Hz,5.6Hz),2.61(1H,dd,J=16.8Hz,8.4Hz)。

Step 2: synthesis of methyl 6-amino-2, 3-dihydrobenzofuran-3-acetate

Tetrahydrofuran (50mL) was added to a mixture of methyl 6-trifluoromethanesulfonyloxy-2, 3-dihydrobenzofuran-3-acetate (2.1g, 6.17mmol), benzophenone imine (1.5g, 8.3mmol), tris (dibenzylideneacetone) dipalladium (0.56g, 0.6mmol), 2-dicyclohexylphosphine-2, 4, 6-triisopropylbiphenyl (0.7g, 1.5mmol) and cesium carbonate (4.0g, 12.0mmol) under a nitrogen blanket, and the mixture was heated under reflux overnight. After the reaction mixture was cooled to room temperature, it was filtered, and the filtrate was concentrated under reduced pressure. To the resulting residue was added tetrahydrofuran (50mL), followed by 3M hydrochloric acid (10mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, dissolved in water (100mL), adjusted to a pH of between 8 and 9 with aqueous sodium hydroxide solution and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered naturally, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography to give methyl 6-amino-2, 3-dihydrobenzofuran-3-acetate (0.4g, yield 32.0%).¹H NMR(400MHz，CDCl₃-d₃)：6.88(1H,d,J=8.0Hz),6.17(1H,dd,J=8.0Hz,1.6Hz),6.15(1H,d,J=1.6Hz),4.69(1H,t,J=9.2Hz),4.20(1H,dd,J=9.2Hz,6.4Hz),3.71-3.77(1H,m),3.69(3H,s),3.51-3.70(2H,brs),2.70(1H,dd,J=16.8Hz,5.6Hz),2.51(1H,dd,J=16.8Hz,9.2Hz)。

And step 3: synthesis of methyl 2- (6- ((4' -hydroxy-2 ',6' -dimethylbiphenyl-3-yl) methylamino) -2, 3-dihydrobenzofuran-3-yl) acetate

To a solution of methyl 6-amino-2, 3-dihydrobenzofuran-3-acetate (0.41g, 1.98mmol) and 4' -hydroxy-2 ',6' -dimethylbiphenyl-3-carbaldehyde (0.45g, 1.98mmol) in ethanol (20mL) was added acetic acid (0.1mL), and the mixture was stirred at room temperature for 2 hours. To the reaction mixture was added sodium triacetoxyborohydride (0.84g, 3.96 mmol). The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic phase was washed successively with a saturated aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous sodium sulfate, and filtered. The residue obtained by concentrating the filtrate was purified by silica gel column chromatography to obtain methyl 2- (6- ((4' -hydroxy-2 ',6' -dimethylbiphenyl-3-yl) methylamino) -2, 3-dihydrobenzofuran-3-yl) acetate (0.4g, yield 50.0%). MS m/z [ ESI ]]⁺:418.0[M+1]。

And 4-8: synthesis of 2- (6- ((2',6' -dimethyl-4 ' - (2- (1, 1-dioxo-isothiazolidin-2-yl) ethoxy) biphenyl-3-yl) methylamino) -2, 3-dihydrobenzofuran-3-yl) acetic acid

The target compound was prepared using methyl 2- (6- ((4' -hydroxy-2 ',6' -dimethylbiphenyl-3-yl) methylamino) -2, 3-dihydrobenzofuran-3-yl) acetate as a starting material by sequentially referring to steps 1 and 2 in example 2 and steps 1,2 and 3 in example 5.¹H NMR(400MHz，DMSO-d₆)：7.43(1H,t,J=7.6Hz),7.36(1H,d,J=7.6Hz),7.12(1H,s),7.07(1H,d,J=8.0Hz),7.03(1H,d,J=8.4Hz),6.70(2H,s),6.42-6.47(2H,m),5.08(2H,s),4.66(1H,t,J=8.8Hz),4.09-4.18(3H,m),3.61-3.69(1H,m),3.2-3.35(4H,m),3.18(2H,t,J=7.6Hz),2.66(1H,dd,J=17.2Hz,5.6Hz),2.42-2.49(1H,m),2.21(2H,quint,J=6.8Hz),1.90(6H,s)。

Example 9: 2- (6- ((4' - (3- (dimethylphosphonyl) propoxy) -2',6' -dimethylbiphenyl-3-yl) methyl Synthesis of amino) -2, 3-dihydrobenzofuran-3-yl) acetic acid

The title compound was prepared by the method of reference example 1 starting from methyl 2- (6- ((4' -hydroxy-2 ',6' -dimethylbiphenyl-3-yl) methylamino) -2, 3-dihydrobenzofuran-3-yl) acetate.¹H NMR(400MHz，CDCl₃-d₃)：7.40(1H,t,J=7.6Hz),7.35(1H,d,J=7.6Hz),7.12(1H,s),7.02-7.06(2H,m),6.64(2H,s),6.46(1H,dd,J=8.4Hz,2.4Hz),6.42(1H,d,J=2.4Hz),5.05(2H,s),4.74(1H,t,J=8.8Hz),4.26(1H,dd,J=9.2Hz,6.0Hz),4.07(2H,t,J=5.2Hz),3.74-3.82(1H,m),2.72(1H,dd,J=16.8Hz,5.6Hz),2.53(1H,dd,J=16.8Hz,9.2Hz),2.09-2.16(2H,m),1.93-2.00(8H,m),1.56(6H,d,J=13.2Hz)。

Example 10: 2- (6- ((4' - ((4-methanesulfonyl) piperazin-1-yl) -2',6' -dimethylbiphenyl-3-yl) methoxy Synthesis of 2, 3-dihydrobenzofuran-3-yl) acetic acid

Starting from methyl 2- (6- ((4' -hydroxy-2 ',6' -dimethylbiphenyl-3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate and 1-methanesulfonylpiperazine, the title compound was prepared by the method of step 1 in reference to the reaction of step 1 in example 8, step 2 in reference to the reaction of step 6 in example 8, and step 3 in reference to step 8 in example 8. MS m/z [ ESI ]]⁺:551.0[M+1]。

Example 11: (S) -2- (6- ((2',6' -dimethyl-4 ' - (2- (1, 1-dioxo-isothiazolidin-2-yl) ethoxy) Synthesis of yl) biphenyl-3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetic acid

Step 1: synthesis of methyl (S) -2- (6- ((4' - (tert-butyldimethylsilyloxy) -2',6' -dimethylbiphenyl-3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate

To a solution of (4' - (tert-butyldimethylsilyloxy) -2',6' -dimethylbiphenyl-3-yl) methanol (2.0g,5.8mmol), (S) -6-hydroxy-2, 3-dihydrobenzofuran-3-acetic acid methyl ester (1.5g,7.2mmol) and triphenylphosphine (2.4g,9.0mmol) in tetrahydrofuran (150mL) was added dropwise diisopropyl azodicarboxylate (1.8g,9.0mmol) with cooling in an ice-water bath. After the addition was complete, the reaction was slowly warmed to room temperature and stirred overnight. After the reaction solution was concentrated, the residue was separated and purified by silica gel column chromatography to give methyl (S) -2- (6- ((4' - (tert-butyldimethylsilyloxy) -2',6' -dimethylbiphenyl-3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate (2.3g, yield 75.5%).¹H NMR(400MHz，CDCl₃-d₃)：7.42(1H,t,J=7.6Hz),7.37(1H,d,J=7.6Hz),7.18(1H,s),7.09(1H,d,J=7.2Hz),7.03(1H,d,J=8.0Hz),6.59(2H,s),6.47-6.51(2H,m),5.06(2H,s),4.76(1H,t,J=9.2Hz),4.26(1H,dd,J=9.2Hz,6.0Hz),3.77-3.85(1H,m),3.72(3H,s),2.75(1H,dd,J=16.8Hz,5.6Hz),2.56(1H,dd,J=16.8Hz,9.6Hz),1.96(6H,s),1.02(9H,s),0.24(6H,s)。

Step 2: synthesis of methyl (S) -2- (6- ((4' -hydroxy-2 ',6' -dimethylbiphenyl-3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate

To a solution of methyl (S) -2- (6- ((4' - (tert-butyldimethylsilyloxy) -2',6' -dimethylbiphenyl-3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate (1.1g,2.1mmol) in tetrahydrofuran (50mL) was added tetrabutylammonium fluoride (1.3g,5.0mmol) with cooling in an ice-water bath after the addition was complete, the reaction was slowly warmed to room temperature and stirred overnight, 50mL of a saturated aqueous ammonium chloride solution was added to terminate the reaction, the mixture was extracted with ethyl acetate (50mL × 3), the organic phases were combined and washed with anhydrous sodium sulfateDrying and concentration gave methyl (S) -2- (6- ((4' -hydroxy-2 ',6' -dimethylbiphenyl-3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate (0.82g, yield 95.0%).¹H NMR(400MHz，CDCl₃-d₃)：7.44(1H,t,J=7.6Hz),7.39(1H,d,J=7.6Hz),7.17(1H,s),7.07(1H,d,J=7.2Hz),7.03(1H,d,J=8.0Hz),6.73(2H,s),6.49(1H,dd,J=8.0Hz,2.4Hz),6.47(1H,s),5.05(2H,s),4.75(1H,t,J=9.2Hz),4.26(1H,dd,J=9.2Hz,6.0Hz),3.77-3.84(1H,m),3.72(3H,s),2.75(1H,dd,J=16.4Hz,4.2Hz),2.55(1H,dd,J=16.4Hz,9.2Hz),2.01(6H,s)。

And step 3: synthesis of methyl (S) -2- (6- ((4' - (cyanomethoxy) -2',6' -dimethylbiphenyl-3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate

Potassium carbonate (2.0g,14.5mmol) was added to a solution of methyl (S) -2- (6- ((4' -hydroxy-2 ',6' -dimethylbiphenyl-3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate (3.0g,7.2mmol) and bromoacetonitrile (1.8g,15.0mmol) in acetonitrile (100 mL). The mixture was stirred at room temperature overnight, filtered, and the residue after concentration of the filtrate was purified by silica gel column chromatography to give methyl (S) -2- (6- ((4' - (cyanomethoxy) -2',6' -dimethylbiphenyl-3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate (2.4g, yield 72.5%). MS m/z [ ESI ]]⁺:458.0[M+1]。

And 4, step 4: synthesis of methyl (S) -2- (6- ((4' - (2-aminoethoxy) -2',6' -dimethylbiphenyl-3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate

A mixture of methyl (S) -2- (6- ((4'- (cyanomethoxy) -2',6 '-dimethylbiphenyl-3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate (2.2g,4.8mmol), Raney' S nickel (5.0g) and methanol (100mL) was stirred under a hydrogen atmosphere (1 atm) at room temperature overnight. The reaction mixture was filtered through celite, and the filtrate was concentrated to give methyl (S) -2- (6- ((4' - (2-aminoethoxy) -2',6' -dimethylbiphenyl-3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate (2.2g, yield 100.0%). MSm/z [ ESI ]]⁺:462.0[M+1]。

And 5: synthesis of methyl (S) -2- (6- ((4' - (2- (3-chloropropylsulfonylamino) ethoxy) -2',6' -dimethylbiphenyl-3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate

To a solution of methyl (S) -2- (6- ((4'- (2-aminoethoxy) -2',6 '-dimethylbiphenyl-3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate (0.66g,1.4mmol) in dichloromethane (50mL) were added 3-chloro-1-propylsulfonyl chloride (0.38g,2.1mmol) and triethylamine (0.29g,2.9mmol) in this order, the reaction mixture was stirred at room temperature overnight, the reaction was poured into water (50mL), the organic phase was extracted with dichloromethane (100mL × 2), dried over anhydrous sodium sulfate, concentrated, and the residue was purified by silica gel column chromatography to give methyl (S) -2- (6- ((4' - (2- (3-chloropropylsulfonylamino) ethoxy) -2',6' -dimethylbiphenyl-3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate (0.73g, yield 85.0%).¹HNMR(400MHz，CDCl₃-d₃)：7.42(1H,t,J=7.2Hz),7.38(1H,d,J=7.6Hz),7.16(1H,s),7.07(1H,d,J=7.2Hz),7.02(1H,d,J=7.6Hz),6.45(2H,s),6.45-6.50(2H,m),5.06(2H,s),4.75(2H,t,J=8.8Hz),4.25(1H,dd,J=9.2Hz,6.0Hz),3.77-3.84(1H,m),3.72(3H,s),3.69(2H,t,J=6.0Hz),3.56(2H,q,J=4.2Hz),3.28(2H,t,J=7.6Hz),2.74(2H,dd,J=16.4Hz,5.6Hz),2.55(1H,dd,J=16.4Hz,9.2Hz),2.29-2.36(2H,m),1.99(6H,s)。

Step 6: synthesis of methyl (S) -2- (6- ((4' - (2- (1, 1-dioxo-isothiazolidin-2-yl) ethoxy) -2',6' -dimethylbiphenyl-3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate

To a solution of methyl (S) -2- (6- ((4'- (2- (3-chloropropylsulfonylamino) ethoxy) -2',6 '-dimethylbiphenyl-3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate (60.0mg,0.1mmol) in N, N-dimethylformamide (10mL) was added potassium carbonate (28.0mg,0.2 mmol). The reaction mixture was stirred overnight at 80 deg.C, poured into water (50mL), extracted with ethyl acetate (100mL × 2), the organic phase was dried over anhydrous sodium sulfate, concentrated, and the residue was purified by silica gel column chromatography to give methyl (S) -2- (6- ((4' - (2- (1, 1-dioxo-isothiazolin-2-yl) ethoxy) -2',6' -dimethylbiphenyl-3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate (50.0mg, yield 88.8%). MS m/z [ ESI]⁺:566.0[M+1]。

And 7: synthesis of (S) -2- (6- ((4' - (2- (1, 1-dioxo-isothiazolidin-2-yl) ethoxy) -2',6' -dimethylbiphenyl-3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetic acid

To a solution of methyl (S) -2- (6- ((4'- (2- (1, 1-dioxo-isothiazolidin-2-yl) ethoxy) -2',6 '-dimethylbiphenyl-3-yl) ethoxy) -2, 3-dihydrobenzofuran-3-yl) acetate (50.0mg,0.09mmol) in a mixed solvent of methanol (10mL) and tetrahydrofuran (20mL) was added dropwise a 2M aqueous solution of sodium hydroxide (1mL), and the mixture was stirred at room temperature overnight after completion of the addition, the reaction mixture was diluted with water, acidified with a 10% aqueous solution of citric acid, and extracted with ethyl acetate (50mL × 3), the organic phase was dried over anhydrous sodium sulfate and concentrated, and the residue was purified by silica gel column chromatography to give (S) -2- (6- ((4' - (2- (1, 1-dioxo-isothiazolidin-2-yl) ethoxy) -2',6' -dimethylbiphenyl-3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetic acid (36.7mg, yield 75.2%).¹H NMR(400MHz，CDCl₃-d₃)：7.38-7.42(2H,m),7.16(1H,s),7.05-7.15(2H,m),6.65(2H,s),6.39-6.55(2H,m),5.06(2H,s),4.76(1H,t,J=7.6Hz),4.24-4.39(1H,m),4.13-4.19(2H,m),3.74-3.89(1H,m),3.38-3.58(4H,m),3.07-3.23(2H,m),2.73-2.83(1H,m),2.53-2.64(1H,m),2.28-2.37(2H,m),1.99(6H,s)。

Example 12: 2- (6- ((2',6' -dimethyl-4 ' - (3- (methylsulfonyl) propoxy) biphenyl-3-yl) acetylene Synthesis of 2, 3-dihydrobenzofuran-3-yl) acetic acid

Step 1: synthesis of methyl 6-trimethylsilylethynyl-2, 3-dihydrobenzofuran-3-acetate

To 6-trifluoromethanesulfonyloxy-2, 3-dihydrobenzofuran-3-acetic acid methyl ester (1.0g, 2.9mmol), trimethylsilylacetylene (0.43g, 4.4mmol), tetrakistriphenylphosphine palladium (0.0 mmol) under a nitrogen blanket replacementTo a mixture of 16g, 0.15mmol), cuprous iodide (0.03g, 0.15mmol) and triethylamine (0.59g, 5.8mmol) was added N, N-dimethylformamide (50mL), and the mixture was reacted at 70 ℃ for 5 hours. After the reaction mixture was cooled to room temperature, it was filtered, and the filtrate was concentrated under reduced pressure. The residue was poured into water (100mL) and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered naturally, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography to give methyl 6-trimethylsilylethynyl-2, 3-dihydrobenzofuran-3-acetate (0.55g, yield 65.3%).¹H NMR(400MHz，CDCl₃-d₃)：7.06(1H,d,J=7.6Hz),6.98(1H,dd,J=7.6Hz,1.2Hz),6.86(1H,s),4.74(1H,t,J=9.2Hz),4.24(1H,dd,J=9.6Hz,6.4Hz),3.81-3.89(1H,m),3.71(3H,s),2.75(1H,dd,J=16.8Hz,5.6Hz),2.56(1H,dd,J=16.8Hz,9.6Hz),0.23(9H,s)。

Step 2: synthesis of methyl 6-ethynyl-2, 3-dihydrobenzofuran-3-acetate

To a solution of methyl 6-trimethylsilylethynyl-2, 3-dihydrobenzofuran-3-acetate (0.5g, 1.7mmol) in methanol (100mL) was added potassium carbonate (0.47g,3.4mmol), and the mixture was reacted at room temperature for 2 hours. Filtration and concentration of the filtrate under reduced pressure gave synthesis of methyl 6-ethynyl-2, 3-dihydrobenzofuran-3-acetate (0.33g, yield 89.0%).¹HNMR(400MHz，CDCl₃-d₃)：7.09(1H,d,J=7.6Hz),7.02(1H,dd,J=7.6Hz,1.2Hz),6.90(1H,s),4.76(1H,t,J=9.6Hz),4.26(1H,dd,J=9.2Hz,6.4Hz),3.83-3.90(1H,m),3.72(3H,s),2.77(1H,dd,J=16.8Hz,5.6Hz),2.58(1H,dd,J=16.8Hz,9.6Hz)。

And step 3: synthesis of 2-bromo-1, 3-dimethyl-5- (3- (methylsulfonyl) propoxy) benzene

To a solution of 3-methylmercaptopropanol (57.14g,0.54mol) and triethylamine (81.6g,0.81mol) in dichloromethane (250mL) was added dropwise trifluoromethanesulfonyl chloride (136.5g,0.81mol) at 0 ℃ and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with water and extracted with dichloromethane (150 mL. times.3). The organic phase was dried over anhydrous sodium sulfate and concentrated, and the residue was purified by column chromatography on silica gel to give 1,1, 1-trifluoromethanesulfonic acid-3-methylmercaptopropyl ester (126.0g, yield 98.0%).

To a solution of 1,1, 1-trifluoromethanesulfonic acid-3-methylmercaptopropyl ester (23.8g,0.1mol) in methanol (250mL) at 0 deg.C was added dropwise an aqueous solution (500mL) of potassium hydrogen persulfate (30g,0.2mol), and after the addition was completed, the mixture was stirred at room temperature overnight. After removing methanol on a rotary evaporator, the residue was extracted with ethyl acetate (250 mL. times.3). The organic phase was dried over anhydrous sodium sulfate and concentrated, and the residue was washed with petroleum ether to give 1,1, 1-trifluoromethanesulfonic acid-3-methanesulfonylpropyl ester (26.5g, yield 98.1%).

To a solution of 3, 5-dimethyl-4-bromophenol (4.0g,19.9mmol) and 1,1, 1-trifluoromethanesulfonic acid-3-methanesulfonylpropyl ester (5.9g,21.9mmol) in N, N-dimethylformamide (150mL) was added potassium carbonate (4.1g,29.9mmol), and the mixture was reacted at 100 ℃ for 1 hour. The reaction mixture was poured into ice water, filtered, and the solid was washed with water and dried to give 2-bromo-1, 3-dimethyl-5- (3- (methylsulfonyl) propoxy) benzene (6.0g, yield 94.0%).¹H NMR(400MHz，DMSO-d₆)：6.78(2H,s),4.02(2H,t,J=6.8Hz),3.23(2H,t,J=6.8Hz),2.99(3H,s),2.30(6H,s),2.03-2.16(2H,m)。

And 4, step 4: synthesis of 2',6' -dimethyl-4 ' - (3- (methylsulfonyl) propoxy) -biphenyl-3-ol

2-bromo-1, 3-dimethyl-5- (3- (methylsulfonyl) propoxy) benzene (0.35g,1.1mmol), 3-hydroxyphenylboronic acid (0.18g,1.3mmol), cesium carbonate (0.54g,1.65mmol) and palladium tetratriphenylphosphine (0.13g,0.11mmol) were added to 1, 4-dioxane (150 mL). The mixture was heated to reflux for 8 hours and then cooled to room temperature. The reaction mixture was filtered through celite, washed with ethyl ester, the filtrate was concentrated, and the residue was purified by column chromatography on silica gel to give 2',6' -dimethyl-4 ' - (3- (methylsulfonyl) propoxy) -biphenyl-3-ol (0.36g, yield 99.0%).¹H NMR(400MHz，CDCl₃-d₃)：7.27(1H,t,J=8.0Hz),6.80(1H,dd,J=8.0Hz,2.8Hz),6.68(1H,d,J=7.2Hz),6.63(2H,s),6.60(1H,t,J=1.2Hz),4.12(2H,t,J=5.6Hz),3.27(2H,t,J=8.0Hz),2.97(3H,s),2.32-2.38(2H,m),2.02(6H,s)。

And 5: synthesis of 2',6' -dimethyl-4 ' - (3- (methylsulfonyl) propoxy) -3-trifluoromethanesulfonyloxy-biphenyl

To a mixture of 2',6' -dimethyl-4 ' - (3- (methylsulfonyl) propoxy) -biphenyl-3-ol (0.36g,1.1mmol) and triethylamine (0.22g,2.2mmol) was added dichloromethane (50mL), the mixture was cooled to zero, and trifluoromethanesulfonic anhydride (0.46g, 1.6mmol) was slowly added dropwise to the mixture. The mixture was warmed to room temperature and stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was separated and purified by silica gel column chromatography to give 2',6' -dimethyl-4 ' - (3- (methylsulfonyl) propoxy) -3-trifluoromethanesulfonyloxy-biphenyl (0.43g, yield 85.0%).¹H NMR(400MHz，CDCl₃-d₃)：7.50(1H,t,J=8.0Hz),7.26(1H,dd,J=8.0Hz,2.4Hz),7.17(1H,d,J=7.6Hz),7.07(1H,s),6.66(2H,s),4.13(2H,t,J=6.0Hz),3.27(2H,t,J=8.0Hz),2.97(3H,s),2.33-2.39(2H,m),1.99(6H,s)。

Step 6: synthesis of methyl 2- (6- ((2',6' -dimethyl-4 ' - (3- (methylsulfonyl) propoxy) biphenyl-3-yl) ethynyl) -2, 3-dihydrobenzofuran-3-yl) acetate

To a mixture of 2',6' -dimethyl-4 '- (3- (methylsulfonyl) propoxy) -3-trifluoromethanesulfonyloxy-biphenyl (50mg, 0.1mmol), 6-ethynyl-2, 3-dihydrobenzofuran-3-acetic acid methyl ester (30mg, 0.12mmol), tris (dibenzylideneacetone) dipalladium (10mg, 0.01mmol), 2-dicyclohexylphosphine-2', 4',6' -triisopropylbiphenyl (10mg,0.2mmol), cuprous iodide (2.0mg, 0.01mmol) and cesium carbonate (52mg, 0.15mmol) was added N, N-dimethylformamide (50mL) under a nitrogen blanket, and the mixture was reacted at 130 ℃ for 5 hours. After the reaction mixture was cooled to room temperature, it was filtered, and the filtrate was concentrated under reduced pressure. The residue was poured into water (100mL) and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered naturally, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography to give methyl 2- (6- ((2',6' -dimethyl-4 ' - (3- (methylsulfonyl) propoxy) biphenyl-3-yl) ethynyl) -2, 3-dihydrobenzofuran-3-yl) acetate (30.0mg, yield 53.0%).¹H NMR(400MHz，CDCl₃-d₃)：7.49(1H,d,J=7.6Hz),7.39(1H,t,J=7.6Hz),7.30(1H,s),7.04-7.13(3H,m),6.94(1H,s),6.65(2H,s),4.78(1H,t,J=9.6Hz),4.28(1H,t,J=8.0Hz),4.13(2H,t,J=5.6Hz),3.85-3.92(1H,m),3.73(3H,s),3.28(2H,t,J=8.0Hz),2.97(3H,s),2.80(1H,dd,J=16.4Hz,5.2Hz),2.60(1H,dd,J=16.4Hz,9.2Hz),2.32-2.40(2H,m),2.02(6H,s)。

And 7: synthesis of 2- (6- ((2',6' -dimethyl-4 ' - (3- (methylsulfonyl) propoxy) biphenyl-3-yl) ethynyl) -2, 3-dihydrobenzofuran-3-yl) acetic acid

To a solution of methyl 2- (6- ((2',6' -dimethyl-4 '- (3- (methylsulfonyl) propoxy) biphenyl-3-yl) ethynyl) -2, 3-dihydrobenzofuran-3-yl) acetate (30.0mg,0.056mmol) in a mixed solvent of methanol (10mL) and tetrahydrofuran (20mL), a 2M aqueous solution of sodium hydroxide (1mL) was added dropwise, and the mixture was stirred at room temperature overnight after completion of the addition, the reaction mixture was diluted with water, acidified with a 10% aqueous solution of citric acid, and extracted with ethyl acetate (50mL × 3) — the organic phase was dried over anhydrous sodium sulfate and concentrated, and the residue was separated and purified by silica gel column chromatography to give 2- (6- ((2',6 '-dimethyl-4' - (3- (methylsulfonyl) propoxy) biphenyl-3-yl) ethynyl) -2, 3-dihydrobenzofuran-3-yl) acetic acid (21.7mg, yield 74.2%).¹HNMR(400MHz，CDCl₃-d₃)：7.49(1H,d,J=8.0Hz),7.39(1H,t,J=8.0Hz),7.30(1H,s),7.15(1H,d,J=7.2Hz),7.05-7.10(2H,m),6.95(1H,s),6.65(2H,s),4.79(1H,t,J=9.6Hz),4.31(1H,t,J=8.4Hz),4.13(2H,t,J=5.2Hz),3.83-3.94(1H,m),3.28(2H,t,J=7.6Hz),2.97(3H,s),2.85(1H,dd,J=16.8Hz,4.0Hz),2.66(1H,dd,J=16.8Hz,9.6Hz),2.30-2.39(2H,m),2.02(6H,s)。

Example 13: 2- (6- ((2',6' -dimethyl-4 ' - (dimethylphosphonyl) biphenyl-3-yl) methoxy) -2,3- Synthesis of dihydrobenzofuran-3-yl) acetic acid

Step 1: synthesis of methyl 2- (6- ((4' -trifluoromethanesulfonyloxy-2 ',6' -dimethylbiphenyl-3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate

To a mixture of methyl 2- (6- ((4' -hydroxy-2 ',6' -dimethylbiphenyl-3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate (0.46g,1.1mmol) and triethylamine (0.22g,2.2mmol) was added dichloromethane (50mL), the mixture was cooled to zero, and trifluoromethanesulfonic anhydride (0.46g, 1.6mmol) was slowly added dropwise to the mixture. The mixture was warmed to room temperature and stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was isolated and purified by silica gel column chromatography to give methyl 2- (6- ((4' -trifluoromethanesulfonyloxy-2 ',6' -dimethylbiphenyl-3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate (0.51g, yield 85.0%).¹HNMR(400MHz，CDCl₃-d₃)：7.46(1H,t,J=7.6Hz),7.42(1H,d,J=8.0Hz),7.16(1H,s),7.06(1H,d,J=7.2Hz),7.02(1H,d,J=8.0Hz),7.00(2H,s),6.48(1H,dd,J=8.0Hz,2.0Hz),5.07(2H,s),4.75(1H,t,J=8.8Hz),4.26(1H,dd,J=9.2Hz,6.0Hz),3.76-3.84(1H,m),3.72(3H,s),2.74(1H,dd,J=16.4Hz,5.6Hz),2.55(1H,dd,J=16.4Hz,9.2Hz),2.03(6H,s)。

Step 2: synthesis of methyl 2- (6- ((2',6' -dimethyl-4 ' - (dimethylphosphonyl) biphenyl-3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate

To methyl 2- (6- ((4' -trifluoromethanesulfonyloxy-2 ',6' -dimethylbiphenyl-3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate (500mg, 0.9mmol), phosphorus dimethyl oxide (phosphorus (e) (b)) under a nitrogen blanket replacement142mg, 1.8mmol), palladium acetate (20mg, 0.09mmol), 9, 9-dimethyl-4, 5-bis (di-t-butylphosphine) dibenzo- γ -pyran (100mg,0.18mmol) and potassium phosphate (220mg, 0.99mmol) to a mixture was added N, N-dimethylformamide (50mL), and the mixture was reacted at 130 ℃ for 5 hours. After the reaction mixture was cooled to room temperature, it was filtered, and the filtrate was concentrated under reduced pressure. The residue was poured into water (100mL) and extracted with ethyl acetate. Drying the organic phase with anhydrous sodium sulfate, and naturally passingFiltered and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography to give methyl 2- (6- ((2',6' -dimethyl-4 ' - (dimethylphosphonyl) biphenyl-3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate (331mg, yield 76.1%).¹H NMR(400MHz，CDCl₃-d₃)：7.40-7.48(4H,m),7.16(1H,s),7.07(1H,d,J=7.6Hz),7.02(1H,d,J=8.0Hz),6.47(1H,dd,J=8.0Hz,1.6Hz),6.45(1H,d,J=1.6Hz),5.07(2H,s),4.75(1H,t,J=9.2Hz),4.26(1H,dd,J=9.2Hz,1.6Hz),3.77-3.84(1H,m),3.71(3H,s),2.74(1H,dd,J=16.4Hz,5.2Hz),2.55(1H,dd,J=16.4Hz,9.2Hz),2.05(6H,s),1.75(6H,d,J=13.2Hz)。

And step 3: synthesis of 2- (6- ((2',6' -dimethyl-4 ' - (dimethylphosphonyl) biphenyl-3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetic acid

To a solution of methyl 2- (6- ((2',6' -dimethyl-4 '- (dimethylphosphono) biphenyl-3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate (0.056mmol) in a mixed solvent of methanol (10mL) and tetrahydrofuran (20mL), a 2M aqueous solution of sodium hydroxide (1mL) was added dropwise, and the mixture was stirred at room temperature overnight after completion of the addition, the reaction mixture was diluted with water, acidified with a 10% aqueous solution of citric acid, and extracted with ethyl acetate (50mL × 3), the organic phase was dried over anhydrous sodium sulfate and concentrated, and the residue was separated and purified by silica gel column chromatography to give 2- (6- ((2',6 '-dimethyl-4' - (dimethylphosphono) biphenyl-3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetic acid (yield 49.0%).¹H NMR(400MHz，CDCl₃-d₃)：7.38-7.49(4H,m),7.14(1H,s),7.03-7.07(2H,m),6.43-6.46(2H,m),5.08(2H,s),4.74(1H,t,J=8.8Hz),4.27(1H,dd,J=9.2Hz,6.4Hz),3.73-3.86(1H,m),2.75(1H,dd,J=16.4Hz,5.2Hz),2.55(1H,dd,J=16.4Hz,9.2Hz),2.04(3H,s),1.79(6H,d,J=12.8Hz)。

Example 14: n-methanesulfonyl-2- (6- ((2',6' -dimethyl-4 ' - (3- (methylsulfonyl) propoxy) bi-block Synthesis of phenyl-3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetamide

Step 1: synthesis of 2',6' -dimethyl-4 ' - (3- (methylsulfonyl) propoxy) -biphenyl-3-carbaldehyde

2-bromo-1, 3-dimethyl-5- (3- (methylsulfonyl) propoxy) benzene (0.35g,1.1mmol), 3-formylphenylboronic acid (0.19g,1.3mmol), cesium carbonate (0.54g,1.65mmol) and palladium tetratriphenylphosphine (0.13g,0.11mmol) were added to 1, 4-dioxane (150 mmol). The mixture was heated to reflux for 8 hours and then cooled to room temperature. The reaction mixture was filtered through celite, washed with ethyl ester, the filtrate was concentrated, and the residue was purified by column chromatography on silica gel to give 2',6' -dimethyl-4 ' - (3- (methylsulfonyl) propoxy) -biphenyl-3-carbaldehyde (0.32g, yield 85.0%).¹H NMR(400MHz，CDCl₃-d₃)：10.03(1H,s),7.84(1H,d,J=7.6Hz),7.64(1H,s),7.58(1H,t,J=7.6Hz),7.39(1H,d,J=7.6Hz),6.65(2H,s),4.12(2H,t,J=6.0Hz),3.26(2H,t,J=7.6Hz),2.96(3H,s),2.31-2.38(2H,m),1.97(6H,s)。

Step 2: synthesis of 2',6' -dimethyl-4 ' - (3- (methylsulfonyl) propoxy) -biphenyl-3-methanol

To a solution of 2',6' -dimethyl-4 '- (3- (methylsulfonyl) propoxy) -biphenyl-3-carbaldehyde (3.0g,8.8mmol) in tetrahydrofuran (40mL) and methanol (20mL) was added sodium borohydride (0.67g,17.6mmol) in small portions under cooling in an ice-water bath, after the addition was completed, the reaction was slowly warmed to room temperature and stirred overnight, after the reaction was concentrated, water (200mL) was added thereto, the mixture was extracted with ethyl acetate (250mL × 3), the organic phases were combined and dried over anhydrous sodium sulfate, and concentrated to give 2',6 '-dimethyl-4' - (3- (methylsulfonyl) propoxy) -biphenyl-3-methanol (3.0g, yield 100%).¹H NMR(400MHz，CDCl₃-d₃)：7.43(1H,t,J=7.6Hz),7.36(1H,d,J=7.6Hz),7.14(1H,s),7.08(1H,d,J=7.2Hz),6.67(2H,s),4.75(2H,d,J=6.0Hz),4.15(2H,t,J=6.0Hz),3.30(2H,t,J=7.6Hz),2.99(3H,s),2.35-2.39(2H,m),2.03(6H,s),1.73(1H,t,J=6.0Hz)。

And step 3: synthesis of methyl 2- (6- ((2',6' -dimethyl-4 ' - (3- (methylsulfonyl) propoxy) biphenyl-3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate

Diisopropyl azodicarboxylate (1.8g,9.0mmol) was added dropwise to a tetrahydrofuran solution (150mL) of 2',6' -dimethyl-4 ' - (3- (methylsulfonyl) propoxy) -biphenyl-3-methanol (2.0g,5.8mmol), methyl 6-hydroxy-2, 3-dihydrobenzofuran-3-acetate (1.5g,7.2mmol) and triphenylphosphine (2.4g,9.0mmol) with cooling in an ice-water bath. After the addition was complete, the reaction was slowly warmed to room temperature and stirred overnight. After the reaction solution was concentrated, the residue was separated and purified by silica gel column chromatography to give methyl 2- (6- ((2',6' -dimethyl-4 ' - (3- (methylsulfonyl) propoxy) biphenyl-3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate (2.33g, yield 75.5%). MS m/z [ ESI ]]⁺:539.0[M+1]。

And 4, step 4: synthesis of 2- (6- ((2',6' -dimethyl-4 ' - (3- (methylsulfonyl) propoxy) biphenyl-3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetic acid

To a solution of methyl 2- (6- ((2',6' -dimethyl-4 '- (3- (methylsulfonyl) propoxy) biphenyl-3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate (30.2mg,0.056mmol) in a mixed solvent of methanol (10mL) and tetrahydrofuran (20mL), a 2M aqueous solution of sodium hydroxide (1mL) was added dropwise, and the mixture was stirred at room temperature overnight after completion of the addition, the reaction mixture was diluted with water, acidified with a 10% aqueous solution of citric acid, and extracted with ethyl acetate (50mL × 3) — the organic phase was dried over anhydrous sodium sulfate and concentrated, and the residue was separated and purified by silica gel column chromatography to give 2- (6- ((2',6 '-dimethyl-4' - (3- (methylsulfonyl) propoxy) biphenyl-3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetic acid (47.7mg, yield 85.0%).¹H NMR(400MHz，CDCl₃-d₃)：7.42(1H,t,J=7.6Hz),7.38(1H,d,J=7.6Hz),7.16(1H,s),7.04-7.08(2H,m),6.65(2H,s),6.49(1H,dd,J=7.6Hz,2.4Hz),6.46(1H,d,J=2.0Hz),5.06(2H,s),4.76(1H,t,J=8.8Hz),4.28(1H,dd,J=9.2Hz,6.0Hz),4.13(2H,t,J=5.6Hz),3.78-3.83(1H,m),3.28(2H,t,J=8.0Hz),2.98(3H,s),2.81(1H,dd,J=16.8Hz,5.2Hz),2.61(1H,dd,J=16.8Hz,9.2Hz),2.32-2.39(2H,m),1.99(6H,s)。

And 5: synthesis of N-methanesulfonyl-2- (6- ((2',6' -dimethyl-4 ' - (3- (methylsulfonyl) propoxy) biphenyl-3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetamide

To a solution of 2- (6- ((2',6' -dimethyl-4 '- (3- (methylsulfonyl) propoxy) biphenyl-3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetic acid (0.2mmol), methylsulfonamide (28.5mg, 0.3mmol),2- (7-azobenzotriazol) -N, N' -tetramethyluronium hexafluorophosphate (114mg, 0.3mmol) in N, N-dimethylformamide (50mL) was added dropwise diisopropylethylamine (51.6mg,0.4mmol), and the mixture was reacted at room temperature for 5 hours. The reaction mixture was poured into water (100mL) and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered naturally, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography to give N-methanesulfonyl-2- (6- ((2',6' -dimethyl-4 ' - (3- (methylsulfonyl) propoxy) biphenyl-3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetamide (61.2mg, yield 52.0%).¹HNMR(400MHz，CDCl₃-d₃)：7.44(1H,t,J=7.6Hz),7.38(1H,d,J=7.6Hz),7.16(1H,s),7.09(1H,d,J=7.6Hz),7.06(1H,d,J=8.0Hz),6.66(2H,s),6.50(1H,dd,J=8.0Hz,2.0Hz),6.47(1H,d,J=2.0Hz),5.07(2H,s),4.75(1H,t,J=9.2Hz),4.29(1H,dd,J=9.2Hz,5.2Hz),4.14(2H,t,J=6.0Hz),3.83-3.90(1H,m),3.29(2H,t,J=6.0Hz),2.98(3H,s),2.90(3H,s),2.74(1H,dd,J=16.4Hz,5.6Hz),2.61(1H,dd,J=16.4Hz,8.4Hz),2.32-2.39(2H,m),2.00(6H,s)。

Biological activity assay

Establishment of a GPR40 Stable expressing cell line

1. Cloning genes: the GPR40 full-length gene is derived from a human non-small cell lung cancer cell strain A549 (Sequence: NCBIReference Sequence: NT-077812.2). Total RNA of a549 cells was extracted, the full-length gene of GPR40 was cloned by reverse transcription-polymerase chain reaction (RT-PCR) method, and two DNA restriction endonuclease sites of BamHI and EcoRV were added at 5 '-end and 3' -end, respectively, when designing primers.

2. Expression vectorAnd (3) constructing particles: vector plasmid pcDNA3.1 was purchased fromUsing the two DNA restriction endonuclease sites BamHI and EcoRV, the cloned full-length GPR40 gene was ligated to pCDNA3.1 vector by T4DNA ligase, then transfected into DH5 α competent cells, and successfully transfected monoclonals were selected on LB agar medium supplemented with antibiotic Ampilline (1. mu.g/mL), plasmids were extracted and the gene sequence was determined by DNA sequencing method.

3. Establishment of stably expressing cells: extracting high-purity pCDNA3.1-GPR40 plasmid and FugeneHD reagentTo a ratio of 2 (μ g): 6 (mu L) are mixed in proportion, transfected into human embryonic kidney epithelial cells HEK293, GPR40 expression cells are screened out in DMEM culture solution supplemented with 10% fetal bovine serum through antibiotic G418 (the final concentration is 400 mu G/mL), monoclonal is selected by gradient dilution in a 96-well cell culture plate, the expression of GPR40 protein is determined by a Western blot method, and the stably expressed monoclonal cells are amplified and cultured to establish a GPR40 stable expression cell line.

GPR40 stable expression Cell Lines can also be established by methods known in the art, such as Koener B, Hermans E.Induceable expression of G Protein-Coupled receptors, methods in Molecular biology.2011(746):3-20 and Schucht R, Lydford S, Andzinki L, Zauers J, Cooper J, Hauser H, etc., Rapid optimization of G-Protein-Coupled expression Cell Lines Site-specific expression of journal of biological science.2011 (16): 3230; or CN102421739A specification No. 24-25/106 test 1: a method in an assay for GPR40 agonist activity to obtain a GPR40 stable expressing cell line.

Determination of GPR40 agonist Activity

The calcium ion concentration of the compound in GPR40 stable expression cells is measured by adopting a calcium flow methodThe degree of elevation, thus reflecting agonism on GPR 40. The agonistic activity employs EC₅₀This index is indicative of the concentration of compound at which GPR40 activity is stimulated to 50% of the maximum.

Materials and methods:

1. materials:

1) 96-well black bottom-permeable cell culture plate(s) ((Cat.No.3603)

2) 96-well V-bottom transparent reaction plate (Cat.No.3897)

3) Fluo-4 calcium flux kit (b)Cat. No. f10471) comprising FLuo-4 calcium dye, Probenecid and FLuo-4 calcium flux reaction buffer.

4) Polylysine

5) DMEM cell culture solution (A)Cat.No.C11995500B)

6) Fetal bovine serum (Cat.No.SV30087)

7)、G418sulfate(Cat.No.345810)

8)、DMSO(Cat.No.A3672)

9) Example compounds of the invention

2. The agonistic activity of the compounds was determined according to the following procedure:

1) and coating a 96-well black bottom transmission cell culture plate with polylysine with a final concentration of 20 mu g/mL, incubating for two hours at 37 ℃, removing the liquid, and air-drying to enhance the adherence of the cells.

2) The cells stably expressing GPR40 were plated in 96-well black-bottom cell culture plates coated with polylysine at a density of 2 × 10⁴Cells/well, DMEM medium supplemented with 10% fetal bovine serum and 400. mu.g/mL G418sulfate, cultured overnight at 37 ℃ in a 5% carbon dioxide incubator.

3) The cell culture medium was removed, replaced with 50. mu.L/well serum-free DMEM and 50. mu.L/well probed with Fluo-4 calcium dye, and incubated for 1 hour at 37 ℃ in the absence of light.

4) All compounds to be tested were dissolved in DMSO to make up a 10mM stock. Gradient dilutions were performed in 96-well V-bottom clear reaction plates with DMSO filled in the 8 th well as a blank. Then, the mixture is uniformly diluted by 200 times by using Fluo-4 calcium flow reaction buffer solution, namely 5 times of the final reaction concentration for standby.

5) Using FlexStation3 (Molecular) at a constant temperature of 37 DEG C) The apparatus aspirates 25. mu.L/well of test compound from the compound plate diluted in the gradient into the cell culture plate so that the final concentrations of the compounds contained in the reaction solution in 8 wells are 0, 1nM, 3nM, 10nM, 30nM, 100nM, 300nM and 1000nM, respectively. The fluorescence signal values (excitation wavelength of 495nm and emission wavelength of 520 nm) were read once every two seconds from the time of dosing, and the fluorescence signal values at each time point were obtained by continuously recording for 150 seconds.

6) Highest (Max) and lowest (Min) fluorescence signal values per sample well readThe Δ F/F value for this well, i.e., (Max-Min)/Min, is calculated by5, drawing a calcium ion concentration change curve by statistical software, and calculating the EC of the tested compound₅₀The value is obtained.

Table 1: agonistic activity of compounds of the present examples on GPR40

Examples	EC₅₀(nM)	Examples	EC₅₀(nM)
				1	10.0	8	8.5
2	3.3	9	74.4
				3	57.0	10	7.6
4	12.9	11	6.1
				5	6.7	12	31.9
6	18.7	13	1235.0
				7	4.3	14	1100.0

In vivo Activity Studies

The invention adopts a method of Oral Glucose Tolerance Test (OGTT) of a mouse to determine the in-vivo blood sugar reduction effect of the compound.

1. Materials: male C57BL/6J mice at 7-8 weeks.

2. The blood glucose concentration of the mice was measured according to the following procedure:

1) mice were weighed and fasting blood glucose (G) values were measured after 16 hours fasting₀) According to G₀Random groups were performed, 5 mice/group.

2) The gavage method comprises administering compounds to be detected with different concentrations to mice, and administering 25% of HS-15 to blank control mice with 25% of polyethylene glycol stearate (HS-15) as solvent.

3) After 15 minutes of administration, the mice were gavaged with 2.0g/kg body weight of an oral glucose aqueous solution.

4) Through whichTaking tail vein blood, measuring blood sugar values of mice after oral administration of glucose for 15 minutes, 30 minutes, 60 minutes and 120 minutes by using a glucometer, and respectively recording as G₁₅、G₃₀、G₆₀And G₁₂₀。

5) Drawing a blood sugar change curve of the mouse and obtaining the blood sugar change curve through a formula AUC_0-120=7.5(G₀+2G₁₅+3G₃₀+6G₆₀+4G₁₂₀) Calculating the AUC value of the blood sugar of the mouse.

The experimental results are shown in fig. 1 and fig. 2, which show that the compound of the example 11 of the invention has a significant hypoglycemic effect in normal C57 mice, and the compound of the example 11 of the invention has a significant advantage in the hypoglycemic effect at 30-50 mg/kg.

Claims

1. A compound of formula I:

wherein,

R¹、R⁴、R⁵、R⁶、R⁷and R⁸Is hydrogen, R²And R³Is methyl;

L¹is-CH₂O-、-CH₂NH-or

L²Is a bond, O or-NR¹²-；

R⁹、R¹⁰Each independently selected from hydrogen, halogen, alkyl, hydroxy, alkoxy, cyano;

n is 2 or 3;

-L³-L⁴is-P (O) (R)¹⁴)-，-SO₂-, or-NR¹³-SO₂-；

R¹²、R¹³Each independently selected from hydrogen, alkyl, or R¹²And R¹³And the N atoms to which they are attached together form a heterocycloalkyl group containing at least two N atoms;

R¹¹is-NR¹⁵R¹⁶Halogen, hydroxy, cyano, nitro, alkyl, alkoxy, cycloalkyl, heterocycloalkyl, or R¹¹And R¹³To form a heterocycloalkyl group containing at least one nitrogen atom;

Z¹selected from hydrogen;

Z²is selected from-CH₂COOH；

R¹⁴、R¹⁵、R¹⁶Each independently selected from hydrogen, halogen, hydroxy, alkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl, heteroaryl;

wherein the alkyl group has 1 to 8 carbon atoms; the alkoxy group has 1 to 4 carbon atoms; the cycloalkyl group is a monocyclic ring having 3 to 7 carbon atoms; the heterocycloalkyl group is a monocyclic or fused ring having 3,4, 5, 6, or 7 ring atoms, wherein 1 or 2 ring atoms are heteroatoms selected from N, O and the remaining ring atoms are C; the aryl group has 6 to 12 carbon atoms; the heteroaryl is a5 or 6 membered ring;

with the following conditions: when L is¹is-CH₂O-or-CH₂NH-, and L²Is O, R⁹＝R¹⁰Hydrogen, -L³-L⁴is-SO₂When R is¹¹is-NR¹⁵R¹⁶。

2. A compound of formula I according to claim 1, wherein R is⁹And R¹⁰Selected from hydrogen.

3. A compound of formula I according to claim 1 or 2, or a salt thereof, wherein L²Is O, -L³-L⁴is-SO₂When R is¹¹is-NR¹⁵R¹⁶。

4. A compound of formula I according to claim 3, wherein L is²Is O, -L³-L⁴is-SO₂When R is¹¹is-N (alkyl)₂-NH (alkyl).

5. A compound of formula I according to claim 4, wherein L is²Is O, -L³-L⁴is-SO₂When R is¹¹is-N (CH)₃)₂、-NHCH₃。

6. A compound of formula I according to claim 1, wherein L is²Is O, -L³-L⁴is-NR¹³-SO₂When R is¹¹is-NR¹⁵R¹⁶Alkyl, cycloalkyl, heterocycloalkyl, or R¹¹And R¹³To form a 3-12 membered heterocycloalkyl group containing at least one nitrogen atom.

7. A compound of formula I according to claim 6, wherein L is²Is O, -L³-L⁴is-NR¹³-SO₂When R is¹¹And R¹³To a 3-, 4-, 5-or 6-membered heterocycloalkyl group containing at least one nitrogen atom, or R¹¹Alkyl, cycloalkyl, heterocycloalkyl.

8. A compound of formula I according to claim 7, wherein L is²Is O, -L³-L⁴is-NR¹³-SO₂When R is¹¹And R¹³To a5 or 6 heterocycloalkyl group containing at least one nitrogen atom, or n is 2, and-L³-L⁴is-NH-SO₂When R is¹¹Is alkyl or cycloalkyl.

9. A compound of formula I according to claim 1, wherein L is²Is O, -L³-L⁴is-P (O) (R)¹⁴)-，R¹¹Alkyl, cycloalkyl, heterocycloalkyl.

10. A compound of formula I according to claim 9, wherein n is 3, -L, or a salt thereof³-L⁴is-P (O) (alkyl) -, R¹¹Alkyl, cycloalkyl, heterocycloalkyl.

11. A compound of formula I according to claim 10, wherein-L is³-L⁴is-P (O) (CH)₃)-，R¹¹Methyl, ethyl, isopropyl and cyclopropyl.

12. A compound of formula I according to claim 1, wherein L is²is-NR¹²-、-L³-L⁴is-NR¹³-SO₂，R¹²And R¹³And the N atoms to which they are attached, together form a heterocycloalkyl group containing at least two N atoms.

13. A compound of formula I according to claim 12, wherein R is¹²And R¹³And the N atom to which they are attached together form a piperazinyl group.

14. A compound of formula I according to claim 1, wherein L is¹is-CH₂O-。

15. A compound of formula I according to claim 1, wherein L is¹is-CH₂NH-。

16. A compound of formula I according to claim 1, wherein L is¹Is composed of

17. A compound of formula I according to claim 1, or a salt thereof, selected from:

18. a pharmaceutical composition comprising a compound of claim 1 or a salt thereof and a pharmaceutically acceptable carrier.

19. Use of a compound of claim 1 or a salt thereof in the manufacture of a medicament for the treatment and/or prevention of a disease associated with GPR 40.

20. Use of the compound or salt thereof according to claim 1 for the preparation of a medicament for the treatment and/or prevention of diabetes.