CN104262330B - A kind of urea substituted biphenyl compounds and combinations thereof thing and purposes - Google Patents

Abstract

The present invention relates to biphenyl analog derivative, its preparation method and pharmaceutical composition thereof and in application pharmaceutically.Specifically, the present invention relates to a kind of new urea substituted biphenyl analog derivative, its medicinal compositions and preparation method thereof, further to described biphenyl derivatives and or pharmaceutical composition containing described derivant as therapeutic agent, especially as GPR40 agonist and the purposes in the medicine of the preparation treatment disease such as diabetes and metabolic disorder.The compound that the present invention relates to contains urea groups, and this group is unique and novelty on this compounds structure of modification.

Description

A kind of urea substituted biphenyl compounds and combinations thereof thing and purposes

Technical field

The present invention relates to there is compound active for regulation GPR40 and pharmaceutically acceptable compositions thereof and for preparing The purposes of GPR40 relevant disease medicine.Particularly, the present invention relates to a kind of urea substituted biphenyl compounds, containing these chemical combination The pharmaceutical composition of thing and these compounds are for preparing the purposes in some disease medicament being relevant to GPR40 activity.This The compound that invention relates to contains urea groups, and this group is unique and novelty on this compounds structure of modification.

Background of invention

GPR40 is the member of the gene superfamilies of G-G-protein linked receptor (" GPRs ").GPRs is to be characterized by 7 to push away The memebrane protein in fixed cross-film district, by activate Intracellular signals pipeline vital to various physiological-function and in response to Various molecules.First GPR40 is accredited as orphan receptor from human genome DNA's fragment (that is, does not has being subject to of known ligand Body).Sawzdargo et al. (1997) Biochem.Biophys.Res.Commun.239:543-547.GPR40 is thin at islets of langerhans β Born of the same parents and insulin secretory cell system are high expresseds.GPR40 activates the G with Intracellular signals transferrin_qThe regulation of family Induction with the calcium level of adjoint rising is associated.Fatty acid is as the part of GPR40, and fatty acid is adjusted by GPR40 Joint insulin secretion has been known.Itoh et al. (2003) Nature 422:173-176；Briscor et al. (2003) J.Biol.Chem.278:11303-11311；Kotarsky et al. (2003) Biochem.Biophys.Res.Commun.301: 406-410。

Although the compound of many regulation GPR40 activity is disclosed, but type ii diabetes, obesity, hypertension, cardiovascular Disease and the high incidence of dyslipidemia, pointed out effectively treating or preventing the demand of new therapy of these diseases urgent.

The futuramic biphenyl compound being substituted of the present invention, it has the ability of regulation GPR40, therefore describedization Compound is potentially served as treatment or prevention diabetes and associated conditions.

Abstract of invention

The invention provides and can be used for treating diabetes, diabetic retinopathy, diabetic neuropathy, diabetic The elevated levels of nephropathy, insulin resistance, hyperglycemia, hyperinsulinemia, fatty acid or glycerol, hyperlipemia, obesity, height Triglyceride, X syndrome, ketoacidosis, glucose intolerance, hypercholesterolemia, dyslipidemia, Metabolic syndrome Disease, cardiovascular disease, kidney disease, thrombotic disorder, nephropathy, sexual dysfunction, dermatosis, dyspepsia, hypoglycemia, cancer The compound of disease, edema, diabetic complication, atherosclerosis or hypertension, pharmaceutical composition and method.Of the present inventionization Compound or pharmaceutical composition have good regulation effect to GPR40 receptor.

On the one hand, the present invention relates to a kind of compound as shown in formula (I) or the stereoisomerism of the compound shown in formula (I) Body, geometric isomer, tautomer, nitrogen oxides, hydrate, solvate, metabolite, pharmaceutically acceptable salt or Prodrug,

Wherein, B ring is C_2-10Heterocyclic radical, C_5-12Condense miscellaneous bicyclic group, C_5-12The miscellaneous bicyclic group of spiral shell or C_5-12The miscellaneous bicyclic group of bridge；

R¹For hydrogen, C_1-6Alkyl, C_6-10Aryl or C_1-9Heteroaryl, wherein said C_1-6Alkyl, C_6-10Aryl and C_1-9Heteroaryl The most optionally it is independently selected from hydrogen, fluorine, chlorine, bromine, hydroxyl, C by 1,2,3 or 4_1-6Alkyl, C_1-6Haloalkyl, C_1-6 Alkyl sulphonyl, amino-sulfonyl or C_1-6Halogenated alkyl sulfonyl substituent group replaces；With

Each R²Independently be hydrogen, C_1-6Alkyl, C_1-6Haloalkyl, fluorine, chlorine, bromine, C_1-6Alkyl sulphonyl or C_1-6Alkyl sulphur Acyl group C_1-6Alkyl；Or two adjacent R²Coupled atom forms C together_6-10Aromatic ring or C_1-9Hetero-aromatic ring, wherein said C_6-10Aromatic ring and C_1-9Hetero-aromatic ring is the most optionally independently selected from hydrogen, fluorine, chlorine, bromine, hydroxyl, C by 1,2,3 or 4_1-4Alkane Base, C_1-4Haloalkyl, C_1-4Alkyl sulphonyl, amino-sulfonyl or C_1-4Halogenated alkyl sulfonyl substituent group replaces；With

N is 1,2,3 or 4.

In certain embodiments, the present invention relates to a kind of compound as shown in formula (II) or the compound shown in formula (II) Stereoisomer, geometric isomer, tautomer, nitrogen oxides, hydrate, solvate, metabolite, pharmaceutically may be used The salt accepted or prodrug,

Wherein, m is 0,1,2 or 3.

In certain embodiments, B ring is

In further embodiments, R¹For hydrogen, C_1-4Alkyl, C_6-10Aryl or C_1-9Heteroaryl, wherein said C_1-4Alkyl, C_6-10Aryl and C_1-9Heteroaryl is the most optionally independently selected from hydrogen, fluorine, chlorine, bromine, hydroxyl, C by 1,2,3 or 4_1-4Alkane Base, C_1-4Haloalkyl, C_1-4Alkyl sulphonyl, amino-sulfonyl or C_1-4Halogenated alkyl sulfonyl substituent group replaces；With

Each R²Independently be hydrogen, C_1-6Alkyl, C_1-6Haloalkyl, fluorine, chlorine, bromine, C_1-6Alkyl sulphonyl or C_1-6Alkyl sulphur Acyl group C_1-6Alkyl；Or two adjacent R²Coupled atom forms C together_6-10Aromatic ring or C_1-9Hetero-aromatic ring, wherein said C_6-10Aromatic ring and C_1-9Hetero-aromatic ring is the most optionally independently selected from hydrogen, fluorine, chlorine, bromine, hydroxyl, C by 1,2,3 or 4_1-4Alkane Base, C_1-4Haloalkyl, C_1-4Alkyl sulphonyl, amino-sulfonyl or C_1-4Halogenated alkyl sulfonyl substituent group replaces.

In further embodiments, R¹For hydrogen, methyl, ethyl, propyl group, butyl, the tert-butyl group or phenyl, wherein said first Base, ethyl, propyl group, butyl, the tert-butyl group and phenyl the most optionally by 1,2,3 or 4 be independently selected from hydrogen, fluorine, chlorine, Bromine, hydroxyl, methyl, ethyl, propyl group, butyl, trifluoromethyl, methyl sulphonyl, amino-sulfonyl or trifluoromethyl sulfonyl take Replace for base；With

Each R²Independently be hydrogen, methyl, ethyl, propyl group, butyl, the tert-butyl group, trifluoromethyl, fluorine, chlorine, bromine, sulfonyloxy methyl Base, sulfonyloxy methyl ylmethyl, methysulfonylethyl or methanesulphonylpropyl；Or two adjacent R²Coupled atom Forming phenyl, pyridine radicals or naphthyl, wherein said phenyl together, pyridine radicals and naphthyl are the most optionally by 1,2,3 Or 4 be independently selected from hydrogen, fluorine, chlorine, bromine, hydroxyl, methyl, ethyl, propyl group, butyl, trifluoromethyl, methyl sulphonyl, ethyl sulphur Acyl group, amino-sulfonyl or trifluoromethyl sulfonyl substituent group replace.

In further embodiments, the present invention comprises the structure of one of:

Or its stereoisomer, geometric isomer, tautomer, nitrogen oxides, hydrate, solvate, metabolism product Thing, pharmaceutically acceptable salt or prodrug.

On the other hand, the invention provides a kind of pharmaceutical composition, described pharmaceutical composition comprises any of the above described oneization Compound, comprises pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle or a combination thereof further.

In other embodiment schemes, described pharmaceutical composition further comprises antidiabetic medicine, anti-high blood Sugar medicine, anti-obesity medicine, antihypertensive drug, antiplatelet drug, Antiatherosclerosis medicine, fat-reducing medicament, disappear Scorching medicine or a combination thereof.

In other embodiment schemes, described pharmaceutical composition, it further comprises at least one GPR40 and is subject to Body agonist.

On the other hand, the present invention provides a kind of described compound and described pharmaceutical composition in preparation for preventing, controlling Treat, alleviate or delay diabetes, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, insulin resistance, The elevated levels of hyperglycemia, hyperinsulinemia, fatty acid or glycerol, hyperlipemia, obesity, hypertriglyceridemia, X combine Close disease, ketoacidosis, glucose intolerance, hypercholesterolemia, dyslipidemia, metabolic syndrome, cardiovascular disease, kidney Dirty disease, thrombotic disorder, nephropathy, sexual dysfunction, dermatosis, dyspepsia, hypoglycemia, cancer, edema, diabetes are also Send out disease, atherosclerosis or hypertension or for increasing the purposes in hdl level medicine.

The method of another aspect of the present invention relates to formula (I) or formula (II) is comprised the preparation of compound, separation and purification.

Content noted earlier only outlines certain aspects of the invention, but is not limited to these aspects.These aspects and The content of his aspect will make more specific complete description below.

The detailed description of the invention

Definition and general terms

Certain embodiments of the present invention be will now be described in more detail, and the example is by the structural formula enclosed and chemical formula explanation.This Invention intention contains all of replacement, amendment and equivalent technical solutions, and they are included in such as the present invention of claim definition In the range of.Those skilled in the art will appreciate that many similar with the described herein or method of equivalent and material can be used in reality Trample the present invention.The present invention is not limited to method described herein and material.At the document combined, patent and similar material one Or many different from the application or conflicting in the case of (include but not limited to defined term, term application, described Technology, etc.), be as the criterion with the application.

It will further be appreciated that some feature of the present invention, for clearly visible, carry out in multiple independent embodiments Describe but it also may provide in combination in single embodiment.Otherwise, the various features of the present invention, for brevity, Single embodiment is described but it also may individually or with the sub-portfolio being arbitrarily suitable for provide.

Unless otherwise indicated, all scientific and technical terminologies used in the present invention have with those skilled in the art of the invention's It is generally understood that identical implication.The all patents that the present invention relates to and public publication are integrally incorporated this by reference Bright.

Unless otherwise indicated, it should apply following definition used herein.For purposes of the present invention, chemical element with Periodic table of elements CAS version, and " Handbook of Chemistry and Physics ", the 75th edition, 1994 is consistent.Additionally, organic chemistry General Principle can be joined Examine " Organic Chemistry ", Thomas Sorrell, University Science Books, Sausalito:1999, " March's Advanced Organic Chemistry " by Michael B.Smith and Jerry March, John Description in Wiley&Sons, New York:2007, entire contents is incorporated herein by.

Term used in the present invention " study subject " refers to animal.The most described animal is mammal.Tested right As, the most also refer to primate (the such as mankind, sex), cattle, sheep, goat, horse, dog, cat, rabbit, rat, little Mus, fish, bird etc..In certain embodiments, described study subject is primate.In other embodiments, described it is subject to Try liking people.

Term used in the present invention " patient " refers to people's (including adult and child) or other animals.Implement at some In scheme, " patient " refers to people.

Stereochemical definitions used in the present invention and rule typically follow S.P.Parker, Ed., McGraw-Hill Dictionary of Chemical Terms McGraw-Hill Book Company,New York,1984；and Eliel,E.and Wilen,S.,“Stereochemistry of Organic Compounds”,John Wiley&Sons, Inc.,New York,1994.

Many organic compound exist with optical active forms, and i.e. they have and make the plane of linearly polarized light rotate Ability.When describing optically active compound, prefix D and L or R and S is used to represent that molecule is about one or more hands The absolute configuration at property center.Prefix d and l or (+) and (-) are the symbols rotated for linearly polarized light caused by appointed compound, Wherein (-) or l represent that compound is left-handed.Prefix for (+) or the compound of d be dextrorotation.A kind of concrete stereoisomerism Body is enantiomer, and the mixture of this isomer is referred to as enantiomeric mixture.The 50:50 mixture of enantiomer Be referred to as racemic mixture or racemic modification, when chemical reaction or during there is no stereo selectivity or stereospecificity time, May occur in which this situation.

Come into the open any asymmetric atom (such as, carbon etc.) of compound of the present invention can be enriched with raceme or enantiomer Presented in, such as (R)-, (S)-or (R, S)-configuration exist.In certain embodiments, each asymmetric atom exists (R)-or (S)-configuration aspect there is at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomer mistake Amount, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomer Excess.

According to starting material and the selection of method, the compounds of this invention can with in possible isomer or they Mixture, the such as form of racemic modification and non-corresponding isomer mixture (this depends on the quantity of asymmetric carbon atom) is deposited ?.Optically active (R)-or (S)-isomer can use chiral synthon or chiral reagent to prepare, or use routine techniques to tear open Point.If compound contains a double bond, substituent group may be E or Z configuration；If containing dibasic cycloalkanes in compound Base, the substituent group of cycloalkyl may have cis or trans configuration.

The mixture of any stereoisomer of gained can be separated into according to the difference in component physicochemical properties Pure or the purest geometric isomer, enantiomer, diastereomer, such as, by chromatography and/or fractional crystallization Method.

By known method, the racemic modification of any gained end-product or intermediate can be passed through those skilled in the art The method being familiar with splits into optical antipode, e.g., by separating its diastereoisomeric salt obtained.Racemic product Thing can also be separated by chiral chromatogram, e.g., uses the high performance liquid chromatography (HPLC) of chiral sorbent.Especially, mapping Isomer can be prepared by asymmetric synthesis, such as, refers to Jacques, et al., Enantiomers, Racemates and Resolutions(Wiley Interscience,New York,1981)；Principles of Asymmetric Synthesis(2^ndEd.Robert E.Gawley,Jeffrey Aubé,Elsevier,Oxford,UK,2012)；Eliel, E.L.Stereochemistry of Carbon Compounds(McGraw-Hill,NY,1962)；Wilen,S.H.Tables of Resolving Agents and Optical Resolutions p.268(E.L.Eliel,Ed.,Univ.of Notre Dame Press,Notre Dame,IN 1972)；Chiral Separation Techniques:A Practical Approach(Subramanian,G.Ed.,Wiley-VCH Verlag GmbH&Co.KGaA,Weinheim,Germany, 2007)。

What term " tautomer " or " tautomeric form " referred to have different-energy can be by low energy barrier (low Energy barrier) constitutional isomer of mutual inversion of phases.If tautomerism is possible (as in the solution), then can reach The chemical equilibrium of tautomer.Such as, (also referred to as proton translocation makes a variation proton tautomer (protontautomer) mutually Structure body (prototropic tautomer) includes being migrated the mutual inversion of phases carried out by proton, such as keto-enol isomerization and Imine-enamine isomerizations.Valence tautomerism body (valence tautomer) includes being come by the restructuring of some bonding electronss The mutual inversion of phases carried out.The instantiation of ketoenol tautomerization be pentane-2,4-diketone and 4-hydroxyl amyl-3-alkene-2-ketone mutual The change of tautomeric.Another example tautomeric is phenol-keto tautomerism.One concrete reality of phenol-keto tautomerism Example is pyridine-4-alcohol and the change of pyridine-4 (1H)-one tautomer.Unless otherwise noted, the compounds of this invention is all Tautomeric forms is within the scope of the present invention.

As described in the invention, the compound of the present invention can optionally be replaced by one or more substituent groups, as General formula compound above, or as example special inside embodiment, subclass, and the compounds that the present invention is comprised. Should be appreciated that " being optionally substituted " this term and " substituted or non-substituted " this term can exchange use.General and Speech, term " substituted " represents that the one or more hydrogen atoms in given structure are replaced by concrete substituent group.Unless its other party Face shows, an optional substituted radical can replace in each commutable position of group.When given structural formula Middle more than one position can be selected from one or more substituent groups of concrete group and be replaced, then substituent group can be identical or not Replace in each position with ground.

In addition, it is necessary to explanation, unless otherwise explicitly pointed out, the describing mode used in the present invention " each ... to independently be " and " ... be each independently " and " ... independently be " can exchange, and all should be interpreted broadly, and it both may be used To refer in different groups, do not affect mutually between concrete option expressed between same-sign, it is also possible to represent in phase In same group, do not affect mutually between concrete option expressed between same-sign.Such as structureStructure, the R in both²Concrete option is the most unaffected, goes out in same structure meanwhile Existing multiple R², multiple R²Between concrete option be independent of each other, i.e. R²Concrete option can be identical, it is also possible to different.

At each several part of this specification, the come into the open substituent group of compound of the present invention is open according to radical species or scope.Special Not pointing out, the present invention includes each independent sub-combinations thereof of each member of these radical species and scope.Such as, term “C_1-6Alkyl " refer in particular to individually disclosed methyl, ethyl, C₃Alkyl, C₄Alkyl, C₅Alkyl and C₆Alkyl.

At each several part of the present invention, describe connection substituent group.When this structure clearly needs linking group, for this Ma Kushi variable cited by group is interpreted as linking group.Such as, if this structure needs linking group and for this The Ma Kushi group definition of variable lists " alkyl " or " aryl ", then it should be understood that should " alkyl " or " aryl " represent respectively The alkylidene group connected or arylene group.

Terminology used in the present invention " alkyl " or " alkyl group ", represent containing 1 to 20 carbon atom, saturated straight chain or Side chain univalent hydrocarbyl group, wherein, the substituent group institute that described alkyl group can optionally be described by one or more present invention Replace.Unless otherwise detailed instructions, alkyl group contains 1-20 carbon atom.In some embodiments, alkyl group contains 1-12 carbon atom；In other embodiments, alkyl group contains 1-6 carbon atom；In other embodiment, alkane Base group contains 1-4 carbon atom；The most in some embodiments, alkyl group contains 1-3 carbon atom.The reality of alkyl group Example comprises, but is not limited to, methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, isobutyl group, sec-butyl, the tert-butyl group, n-pentyl, 3-methyl isophthalic acid-butyl, 3-hexyl, n-heptyl, n-octyl etc..

Term " haloalkyl " represents that alkyl is replaced by one or more halogen atoms, and such example comprises, but also It is not limited to, trifluoromethyl etc..

Term " heterocyclic radical " and " heterocycle " are used interchangeably herein, all referring to comprising the saturated of 3-12 annular atoms or portion Dividing undersaturated monocycle, at least one of which annular atoms is selected from nitrogen, sulfur and oxygen atom.Unless otherwise indicated, heterocyclic radical can be Carbon back or nitrilo, and-CH₂-group can be optionally by-C (=O)-replacement.The sulphur atom of ring can optionally be oxidized to S- Oxide.The nitrogen-atoms of ring can optionally be oxidized to N-oxygen compound.The example of heterocyclic radical includes, but are not limited to: epoxy Ethyl group, azelidinyl, oxetanylmethoxy, thietanyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazoline Base, pyrazolidinyl, imidazolinyl, hexahydropyrimidine base etc..

Term " thick miscellaneous bicyclic group " represents saturated or undersaturated and bicyclic system, relates to the also member ring systems of non-aromatic. Such system can comprise undersaturated condition that is independent or that be conjugated, but its core texture does not comprise aromatic rings or heteroaromatic (but aromatic series can be as substituent group thereon).And at least one member ring systems comprises one or more hetero atom, the most often One member ring systems comprises 3-7 ring, i.e. comprises 1-6 carbon atom and 1-3 the hetero atom selected from N, O, P, S, appoints at this S or P Selection of land is replaced by one or more oxygen atoms and obtains such as SO, SO₂、PO、PO₂Group.Described annelated heterocycles base can be to take In generation or unsubstituted, wherein substituent group is it may be that but be not limited to, deuterium, oxo (=O), hydroxyl, amino, halogen, cyano group, virtue Base, heteroaryl, alkoxyl, alkylamino, alkyl, thiazolinyl, alkynyl, heterocyclic radical, sulfydryl, nitro.

Term " spiro heterocyclic radical " represents that a ring originates from particularly ring-shaped carbon on another ring.Such as, as retouched above Stating, ring A and ring B shares a carbon atom in two saturated member ring systems, then be referred to as " volution ".And at least one ring body System comprise one or more hetero atom, each of which member ring systems comprises 3-7 ring, i.e. comprise 1-6 carbon atom and be selected from N, 1-3 the hetero atom of O, P, S, is optionally replaced by one or more oxygen atoms at this S or P and obtains such as SO, SO₂、PO、PO₂ Group.And described spiro heterocyclic radical can be substituted or unsubstituted, wherein substituent group is it may be that but be not limited to, deuterium, oxygen Generation (=O), hydroxyl, amino, halogen, cyano group etc..

Term " bridge heterocyclic radical " represents saturated or undersaturated bridged-ring system, relates to the bridged-ring system of non-aromatic.So System can comprise the independent or undersaturated condition of conjugation, but its core texture do not comprise aromatic rings or heteroaromatic (but Aromatic series can be as substituent group thereon).And at least one member ring systems comprises one or more hetero atom, each of which ring System comprises 3-7 ring, i.e. comprises 1-6 carbon atom and selected from 1-3 the hetero atom of N, O, P, S, this S or P optionally by One or more oxygen atoms are replaced obtains such as SO, SO₂、PO、PO₂Group, and described miscellaneous bridged ring base can be replace or Unsubstituted, wherein substituent group is it may be that but be not limited to, deuterium, oxo (=O), hydroxyl, amino, halogen, cyano group etc..

Term " halogen " refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).

Term " aryl " or " aromatic ring " represent containing 6-14 annular atoms, or 6-12 annular atoms, or 6-10 annular atoms The carbocyclic ring system with armaticity of monocycle, dicyclo and three rings, and have the remainder of one or more attachment point and molecule It is connected.The example of aromatic yl group can include, but are not limited to phenyl, naphthyl and anthracene etc..

Term " heteroaryl " or " hetero-aromatic ring " represent containing 5-12 annular atoms, or 5-10 annular atoms, or 5-6 ring is former Monocycle, dicyclo and three rings of son have the system of armaticity, and at least one member ring systems comprises one or more hetero atom, and has one Individual or multiple attachment points are connected with molecule remainder.The example of heteroaryl groups includes, but is not limited to, 2-furyl, N- Imidazole radicals, 3-isoxazolyl, 2-oxazolyl, 2-pyrrole radicals, 2-pyridine radicals, 4-pyrimidine radicals, 5-pyrimidine radicals, pyridazinyl, 4-thiazole Base, tetrazole radical, triazolyl, 2-thienyl, pyrazolyl benzimidazolyl, benzofuranyl, benzothienyl, indyl, purine Base, quinolyl, imidazo [1,2-a] pyridine radicals etc..

Term " alkyl sulphonyl " refers to be connected with alkyl defined in a present invention on sulfonyl, sulfonyl and molecule Remainder is connected.

Term " amino-sulfonyl " refers to be connected with an amino on sulfonyl, and sulfonyl is connected with the remainder of molecule.

Term " halogenated alkyl sulfonyl " refers to be connected with haloalkyl defined in a present invention, sulfonyl on sulfonyl It is connected with the remainder of molecule.

Term " Alkylsulfonylalkyl " refers to that the present invention defined " alkyl sulphonyl " is connected in a present invention and is determined On the alkyl of justice, alkyl is connected with the remainder of molecule.

Term " two adjacent R²Coupled atom forms aromatic ring or hetero-aromatic ring together " refer to two adjacent former Sub with coupling part R thereon²Composition aromatic ring or hetero-aromatic ring together.Some of them embodiment is, such as in structure H1 adjacent two R², form aromatic ring or hetero-aromatic ring together with the atom being connected, such as structure H2, M ring is aromatic ring or hetero-aromatic ring.

Term " leaving group " refers to atom or the functional group departed from from relatively macromole in chemical reaction.At nucleophilic In substitution reaction, it is referred to as substrate by the reactant of nucleopilic reagent attack, and ruptures away with pair of electrons from substrate molecule Atom or atomic group be referred to as leaving group.It is easily accepted by electronics, bears the leaving group that the strong group of negative charge ability has been.

The when that term " blocking group " or " PG " referring to a substituent group and other reacted with functional groups, it is commonly used to resistance Disconnected or protect special functional.Such as, " blocking group of amino " refers to that a substituent group is connected with amino group and blocks Or amino functional in protection compound, suitable amido protecting group includes acetyl group, trifluoroacetyl group, tertbutyloxycarbonyl (BOC, Boc), benzyloxycarbonyl group (CBZ, Cbz) and 9-fluorenes Asia methoxycarbonyl group (Fmoc).Similarly, " hydroxy-protective group " refers to hydroxyl The substituent group of base is used for blocking or protect the functional of hydroxyl, suitable blocking group to include acetyl group and silicyl." carboxyl Blocking group " refer to the substituent group of carboxyl for blocking or protect the functional of carboxyl, general carboxyl-protecting group includes- CH₂CH₂SO₂Ph, cyano ethyl, 2-(TMS) ethyl, 2-(TMS) ethoxyl methyl, 2-are (to toluene Sulfonyl) ethyl, 2-(p-nitrophenyl sulfonyl) ethyl, 2-(diphenylphosphino) ethyl, nitro-ethyl etc..For protection group The general description of group refers to document: T W.Greene, Protective Groups in Organic Synthesis, John Wiley&Sons,New York,1991；and P.J.Kocienski,Protecting Groups,Thieme, Stuttgart,2005.

Term used in the present invention " prodrug ", represents a compound and is converted in vivo shown in formula (I) or formula (II) Compound.Such conversion hydrolyzed in blood by prodrug or blood or tissue in through enzymatic conversion be precursor structure Impact.Prodrug compounds of the present invention can be ester, and in existing invention, ester can have phenyl ester as prodrug Class, aliphatic (C_1-24) esters, pivaloyloxymethyl esters, carbonic ester, carbamates and amino acid esters.The such as present invention In a compound comprise hydroxyl, i.e. can be acylated the compound obtaining prodrug form.Other prodrug Form includes phosphate ester, if these phosphate compounds are that the di on parent obtains.About prodrug Complete discussion is referred to documents below: T.Higuchi and V.Stella, Pro-drugs as Novel Delivery Systems,Vol.14of the A.C.S.Symposium Series,Edward B.Roche,ed.,Bioreversible Carriers in Drug Design,American Pharmaceutical Association and Pergamon Press,1987,J.Rautio et al.,Prodrugs:Design and Clinical Applications,Nature Review Drug Discovery,2008,7,255-270,and S.J.Hecker et al.,Prodrugs of Phosphates and Phosphonates,Journal of Medicinal Chemistry,2008,51,2328-2345。

" metabolite " refers to that concrete compound or its salt is in vivo by the product obtained by metabolism.One change The metabolite of compound can be identified by technology known to art, and its activity can be retouched by such as the present invention Adopt as stating and experimentally characterize.Such product can be by passing through oxidation, reduction, water to drug compound Solution, amidated, desamido-effect, esterification, degreasing, enzymatic lysis etc. method obtains.Correspondingly, the present invention includes compound Metabolite, be fully contacted metabolite produced by a period of time including by the compound of the present invention and mammal.

" pharmaceutically acceptable salt " used in the present invention refers to organic salt and the inorganic salt of the compound of the present invention.Medicine On, acceptable salt is known to us at art, such as document: S.M.Berge et al., describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences, 1977,66:1-19. it is described.The salt that pharmaceutically acceptable nontoxic acid is formed includes, but is not limited to, with amino base The inorganic acid salt that group's reaction is formed has hydrochlorate, hydrobromate, phosphate, sulfate, perchlorate and acylate such as acetic acid Salt, oxalates, maleate, tartrate, citrate, succinate, malonate or by described on books document Additive method such as ion exchange obtain these salt.Other pharmaceutically acceptable salts include adipate, alginate, resist Bad hematic acid salt, aspartate, benzene sulfonate, benzoate, bisulphate, borate, butyrate, Camphora hydrochlorate, Camphora sulphur Hydrochlorate, cyclopentyl propionate, digluconate, lauryl sulfate, esilate, formates, fumarate, Portugal Heptose hydrochlorate, glycerophosphate, gluconate, Hemisulphate, enanthate, caproate, hydriodate, 2-hydroxy-ethanesulfonic acid Salt, lactobionate, lactate, laruate, lauryl sulfate, malate, malonate, mesylate, 2-naphthalene sulphur Hydrochlorate, nicotinate, nitrate, oleate, palmitate, pamoate, pectate, persulfate, 3-phenylpropionic acid salt, bitterness Hydrochlorate, pivalate, propionate, stearate, rhodanate, tosilate, undecylate, valerate etc..Pass through The salt that suitable alkali obtains includes alkali metal, alkaline-earth metal, ammonium and N⁺(C_1-4Alkyl)₄Salt.The present invention is also intended to contemplate any The quaternary ammonium salt that the compound of the group of comprised N is formed.Water solublity or oil-soluble or dispersion product can be turned into by quaternary ammonium With obtaining.Alkali metal or alkali salt include sodium, lithium, potassium, calcium, magnesium etc..Pharmaceutically acceptable salt farther includes to fit When, nontoxic ammonium, the amine cation that quaternary ammonium salt and gegenions are formed, such as halogenide, hydroxide, carboxylate, sulphuric acid Compound, phosphoric acid compound, nitric acid compound, C_1-8Azochlorosulfonate acid compound and aromatic sulphonic acid compound.

" solvate " of the present invention refers to the association that the compound of one or more solvent molecule and the present invention is formed Thing.The solvent forming solvate includes, but is not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, second Acid and ethylaminoethanol.Term " hydrate " refers to that solvent molecule is the associated complex that water is formed.

Any disease or disease " treated " in term as used in the present invention, and some embodiment middle fingers improve disease wherein Disease or disease (i.e. slow down or stop or palliate a disease or the development of its at least one clinical symptoms).In other embodiments In, " treatment " refers to relax or improve at least one body parameter, including the body parameter may not discovered by patient.At another In a little embodiments, " treatment " refers to (such as stablize perceptible symptom) from health or physiologically (such as stablize health Parameter) or above-mentioned two aspect regulation disease or diseases.In other embodiments, " treat " and refer to prevention or postpone disease or disease The outbreak of disease, occur or deteriorate.

Pharmaceutically useful acid-addition salts can be formed with mineral acid and organic acid, such as acetate, aspartate, benzoic acid Salt, benzene sulfonate, bromide/hydrobromate, bicarbonate/carbonate, disulfate/sulfate, camsilate, chlorination Thing/hydrochlorate, chloro theophylline salt, citrate, ethanedisulphonate, fumarate, gluceptate, gluconate, glucuronic acid Salt, hippurate, hydriodate/iodide, isethionate, lactate, lactobionate, lauryl sulfate, Fructus Mali pumilae Hydrochlorate, maleate, malonate, mandelate, mesylate, Methylsulfate, naphthoate, naphthalene sulfonate, nicotinate, Nitrate, octadecanoate, oleate, oxalates, palmitate, pamoate, phosphate/phosphor acid hydrogen salt/dihydric phosphate, poly-half Lactobionate, propionate, stearate, succinate, sulfosalicylate, tartrate, toluene fulfonate and trifluoroacetic acid Salt.

Such as hydrochloric acid, hydrobromic acid, sulphuric acid, nitric acid, phosphoric acid etc. can be included by its derivative mineral acid obtaining salt.

Can by its derivative organic acid obtaining salt include such as acetic acid, propanoic acid, hydroxyacetic acid, oxalic acid, maleic acid, the third two Acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethyl sulfonic acid, p-methyl benzenesulfonic acid, sulfo group water Poplar acid etc..

Pharmaceutically acceptable base addition salts can be formed with inorganic base and organic base.

Can be included by its derivative inorganic base obtaining salt, the metal of the I race of such as ammonium salt and periodic chart to XII race.? In some embodiment, this salt is derived from sodium, potassium, ammonium, calcium, magnesium, ferrum, silver, zinc and copper；Particularly suitable salt include ammonium, potassium, Sodium, calcium and magnesium salt.

Can be included that primary amine, secondary amine and tertiary amine, substituted amine include naturally occurring by its derivative organic base obtaining salt Substituted amine, cyclic amine, deacidite etc..Some organic amine includes, such as, and 2-aminopropane., benzathine benzylpenicillin (benzathine), choline salt (cholinate), diethanolamine, diethylamine, lysine, meglumine (meglumine), piperazine And trometamol.

The officinal salt of the present invention can be synthesized by parent compound, alkalescence or acidic moiety with conventional chemical processes. It is said that in general, such salt can free acid form Yu stoichiometry by making these compounds suitable alkali (as Na, Ca, The hydroxide of Mg or K, carbonate, bicarbonate etc.) reaction, or by making free alkali form and the chemistry of these compounds The suitable acid reaction of metered amount is prepared.Such reaction is generally carried out in water or organic solvent or the mixture of the two. Usually, in the case of suitably, need to use non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile.? Such as " Remington ' s Pharmaceutical Sciences ", the 20th edition, Mack Publishing Company, Easton,Pa.,(1985)；" pharmaceutical salts handbook: character, select and apply (Handbook of Pharmaceutical Salts:Properties, Selection, and Use) ", Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002) list of the suitable salt of other can be found in.

It addition, compound disclosed by the invention, include their salt, it is also possible to their hydrate forms or comprise it The form of solvent (such as ethanol, dimethyl sulfoxide (DMSO), etc.) obtains, for their crystallization.The present invention comes into the open compound Inherently or design forming solvate can be passed through with pharmaceutically acceptable solvent (including water)；Therefore, it is contemplated that Including solvation and unsolvated form.

As described in the present invention, substituent group draws the member ring systems formed on a ring being bonded the center of receiving (such as formula (a) institute Show) represent substituent R⁵Can replace any commutable position on ring.Such as, formula (a) represents on W1 ring or W2 ring Any position that may be replaced all can be replaced.

As described in the present invention, member ring systems there are two junction points be connected with molecule remainder, as shown in formula (b), Represent both can be E end can also be E ' end be connected with molecule remainder, i.e. the connected mode at two ends can be exchanged.

The compositions of the compounds of this invention, preparation and administration

The invention provides the pharmaceutical composition being suitable to medicinal, to comprise one or more present invention compound.This medicine Compositions can also comprise pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle or a combination thereof further. Described pharmaceutical composition may be used for treating diabetes, diabetic retinopathy, diabetic neuropathy, diabetic kidney The elevated levels of disease, insulin resistance, hyperglycemia, hyperinsulinemia, fatty acid or glycerol, hyperlipemia, obesity, height are sweet Oil three ester mass formed by blood stasis, X syndrome, ketoacidosis, glucose intolerance, hypercholesterolemia, dyslipidemia, Metabolic syndrome Disease, cardiovascular disease, kidney disease, thrombotic disorder, nephropathy, sexual dysfunction, dermatosis, dyspepsia, hypoglycemia, cancer Disease, edema, diabetic complication, atherosclerosis or hypertension or be used for increasing hdl level disease, special Not, it has good regulation effect to GPR40 receptor.

The compounds of this invention can be administered alone or use with one or more combination with other therapeutic agents.Pharmaceutical composition more enters One step ground comprises other antidiabetic medicines, hyperglycemia medicine, anti-obesity medicine, antihypertensive drug, antiplatelet drug Thing, Antiatherosclerosis medicine, fat-reducing medicament, anti-inflammation drugs or a combination thereof.Described antidiabetic medicine can be any That knows is different from other of the compounds of this invention for antidiabetic medicine.Such as, SGLT-2 inhibitor, biguanides, sulphur Sulfonylurea, alpha-glucosidase inhibitors, PPAR agonist, α P2 inhibitor, PPAR α/γ double activator, dipeptide amido peptidase TV (DPP-IV) inhibitor, glinides, insulin, glucagon-like-peptide-1 (GLP-1) inhibitor, PTP1B inhibitor, Glycogen phosphorylase inhibitors or Robison ester enzyme inhibitor.

When can be used for treatment time, the compounds of this invention of therapeutically effective amount, especially formula (I) or formula (II) compound and Pharmaceutically acceptable salt can give as unprocessed chemical drugs, and the active component being alternatively arranged as pharmaceutical composition provides. Therefore, the pharmaceutical composition that present invention provides includes the compounds of this invention of therapeutically effective amount, especially formula (I) or formula (II) compound or its pharmaceutically acceptable salt and one or more pharmaceutically acceptable carriers, diluent or excipient. Term as used herein " therapeutically effective amount " refers to be enough to demonstrate that significant patient benefit's (such as blood glucose reduction) is each The total amount of active component.When using single active component individually dosed, this term only refers to this composition.When combination application, No matter this term then refers to combination, is sequentially or simultaneously administered, all cause the combined amount of the active component of therapeutic effect.The present invention Compound, especially formula (I) or formula (II) compound and pharmaceutically acceptable salt thereof are described above.From with other compositions of preparation Compatible and to its receiver harmless in the sense that from the point of view of, carrier, diluent or excipient must be acceptable.According to this The another aspect of bright content, also provides for the method for preparing pharmaceutical preparation, and the method includes the compounds of this invention, especially Formula (I) or formula (II) compound or its pharmaceutically acceptable salt and one or more pharmaceutically acceptable carrier, diluent Or excipient mixing.Term used in the present invention " pharmaceutically acceptable " refers to such compound, raw material, compositions And/or dosage form, they rational medicine judge in the range of, it is adaptable to patient tissue contacts and without excessive toxicity, zest, Allergy or the other problems symmetrical with rational interests/Hazard ratio and complication, and it is effective to given application.

When the compositions of present invention comprise the compound of present invention and one or more other treatment medicines or During the combination of prophylactic agent, the dosage level of compound and other medicine, generally in monotherapy scheme, accounts for normal administration The about 10-150% of dosage, more preferably accounts for the about 10-80% of bio-occlusion pharmaceutical quantities.Pharmaceutical preparation is suitable to by any suitable way Footpath is administered, such as by oral (including oral cavity or Sublingual), rectum, nose, locally (include oral cavity, Sublingual or percutaneous), vagina or Parenteral (in including subcutaneous, Intradermal, intramuscular, intraarticular, intrasynovial, breastbone, in sheath, intralesional, intravenous or corium bet Penetrate or infusion) approach.This kind of preparation can be prepared, such as by by active component and load by any known method of art of pharmacy Body or excipient mixing.Preferred oral is administered or drug administration by injection.

For using the pharmaceutical composition of the compounds of this invention can provide the most in a unit and can lead to Cross any method well-known in the art to prepare.All methods include making active component and constituting one or more auxiliary elements The step that combines of carrier.Generally, pharmaceutical composition is prepared by the following method: make active component and liquid carrier or in small, broken bits Solid-state carrier or both combine equably and nearly, then, if it is desired, make this product form required preparation. In pharmaceutical composition, the Active Target Compounds comprising enough amounts is to produce desired effect to the process of disease or situation Really.

Pharmaceutical composition containing active component can be to be adapted for the form being administered orally, such as, as tablet, lozenge, sugar agent, Water slurry or oil suspend, dispersible powder or granule, Emulsion, hard capsule or syrup or elixir.It is intended for mouth The compositions that clothes use can be prepared according to manufacturing any method known to pharmaceutical composition production field.Such compositions can Comprise one or more selected from sweeting agent, flavour enhancer, coloring agent and the reagent of preservative, it is therefore an objective to provide pharmaceutically graceful sum Good to eat preparation.

Tablet comprises and is suitable to manufacture the activity that other atoxic pharmaceutically acceptable excipient of tablet mix mutually Composition.It may be that such as, inert diluent, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate for these excipient；? Granule and disintegrating agent, such as corn starch or alginic acid；Binding agent, such as starch, gelatin or arabic gum；And lubricant, such as tristearin Acid magnesium, stearic acid or Talcum.Tablet can be uncoated, or they can be coated with by known technology and delay in the gastrointestinal tract Disintegrate and absorb and thus the continuous action of long period is provided.Such as, such as glyceryl monostearate or two hard can be used The time delay material of glycerol.They are also by the skill described in U.S. Patent number 4256108,4160452 and 4265874 Art and be coated with formed for control release osmotic therapeutic tablets.

Formulations for oral use is alternatively arranged as hard gelatin capsule and provides, wherein active component and such as calcium carbonate, Calcium phosphate or the mixing of kaolinic inert solid diluent；Or provide as Perle, wherein active component and water or The oil medium mixing of such as Oleum Arachidis hypogaeae semen, liquid paraffin or olive oil.

Water slurry comprises and is suitable to manufacture the active substance that the excipient of water slurry mixes.Such excipient is outstanding Floating agent, such as sodium carboxymethyl cellulose, methylcellulose, hydroxyl-propyl methylcellulose, sodium alginate, polyethylene-pyrrolidine Ketone, Tragacanth and Radix Acaciae senegalis；The phospholipid that dispersant or wetting agent can be naturally-occurring, such as lecithin, or alkylene oxide With the condensation product such as polyoxyethylene stearic acid ester of fatty acid, or oxirane and long-chain fatty alcohol such as 17 ethyleneoxy 16 The condensation product of alcohol, or the condensation product such as polyoxyethylene sorbitol list of oxirane and the partial ester deriving from fatty acid and hexitol Oleate, or oxirane is oily with the condensation product such as polyethylene sorbitan list of the partial ester deriving from fatty acid and hexitan Acid esters.Described water slurry (such as ethylparaben or P-hydroxybenzoic acid just also can comprise one or more preservative Propyl ester), one or more coloring agent, one or more flavour enhancer and one or more sweeting agents (such as sucrose or saccharin).

Oil suspension can be by being suspended in the plant of such as Oleum Arachidis hypogaeae semen, olive oil, Oleum sesami or Oleum Cocois by active component Prepare in oil or in the mineral oil of such as liquid paraffin.Oil suspension can comprise thickening agent, such as Cera Flava, hard paraffin or spermaceti Alcohol.Those sweeting agents the most set forth above and flavour enhancer can be added to provide good to eat oral formulations.These compositionss can Anticorrosion is carried out by adding the antioxidant of such as ascorbic acid.

Be suitable to prepare the dispersible powder of water slurry by adding water or granule provides and dispersant or moistening Agent, suspending agent and the active component of one or more preservative mixing.Suitably dispersant or wetting agent and suspending agent passes through Already mentioned above those carry out exemplary illustration.Also can there is other excipient, such as sweeting agent, flavour enhancer and coloring agent.

The pharmaceutical composition of the present invention can be with the form of oil in water emulsion.Oil phase can be such as olive oil or Oleum Arachidis hypogaeae semen Vegetable oil or the mineral oil of such as liquid paraffin or these mixture.The tree that suitably emulsifying agent can be naturally-occurring Glue, such as Radix Acaciae senegalis or Tragacanth；Naturally occurring phospholipid, such as Semen sojae atricolor, lecithin with derive from fatty acid and hexitan Ester or partial ester, such as Arlacel-80；And the condensation product of described partial ester and oxirane, as polyethylene is dehydrated Sorbitol monooleate.Emulsion may also include sweeting agent and flavour enhancer.

Syrup and elixir can be prepared together with the sweeting agent of such as glycerol, propylene glycol, sorbitol or sucrose.Such preparation Also can comprise demulcent, preservative and flavour enhancer and coloring agent.

Pharmaceutical composition can be with the water slurry of sterile injectable or the form of oil suspension.This suspension can be according to known Technology, use suitable dispersant already mentioned above or wetting agent and suspending agent to prepare.The system of this sterile injectable Agent can also is that solution or suspension, the example of the sterile injectable in nontoxic, the acceptable diluent of parenteral or solvent As the solution in 1,3 butylene glycol.Spendable acceptable vehicle and solvent are water, Ringer's mixture and isotonic Sodium chloride solution.Additionally, aseptic fixing oil is traditionally used as solvent or suspension media.Therefore, any gentleness can be used Fixing oil, including monoglyceride or two glyceride of synthesis.Additionally, the fatty acid of such as oleic acid is in the preparation of injectable drug Find purposes.

Pharmaceutical composition can be also used for suppository form or the enema of the rectal administration of medicine.These compositionss can be passed through Medicine is mixed with suitable non-irritating excipient and prepares, described non-irritating excipient be solid at normal temperatures but It is liquid under rectal temperature and thus will melt in the rectum to discharge medicine.Such material includes, such as, cupu oil and Polyethylene Glycol.

Local is used, uses and comprise the ointment of the compounds of this invention, ointment, suspensoid, lotion, powder, molten Liquor, paste, gel, spray, aerosol, oil formulation or transdermal patch.As used herein topical application alsos attempt to Including collutory and the purposes of mouth-wash.

Pharmaceutical composition and the method for the present invention may also include, the brightest, can be used for treating following disease The compound of other treatment activity: type ii diabetes, obesity, hyperglycemia, glucose intolerance, insulin resistant, high pancreas Island element mass formed by blood stasis, hypercholesterolemia, hypertension, hyperlipoproteinemia, hyperlipemia, HTC, dyslipidemia, Metabolism syndrome, X syndrome, cardiovascular disease, atherosclerosis, kidney disease, ketoacidosis, thrombotic disorder, kidney Disease, diabetic neuropathy, diabetic retinopathy, sexual dysfunction, dermatosis, dyspepsia, hypoglycemia, cancer and Edema.

At treatment or prevention type ii diabetes, obesity, hyperglycemia, glucose intolerance, insulin resistant, high islets of langerhans Element mass formed by blood stasis, hypercholesterolemia, hypertension, hyperlipoproteinemia, hyperlipemia, HTC, dyslipidemia, generation Thank syndrome, X syndrome, cardiovascular disease, atherosclerosis, kidney disease, ketoacidosis, thrombotic disorder, nephropathy, Diabetic neuropathy, diabetic retinopathy, sexual dysfunction, dermatosis, dyspepsia, hypoglycemia, cancer and water In swollen or other situations relevant to GPR40 or disease, suitable dosage level is typically about the every kg patient of 0.001 to 100mg Body weight every day, it can be used with single dose or multiple dose.Preferably, dosage level was about for 0.01 to about 25mg/kg every day；More excellent Selection of land, about 0.05 to about 10mg/kg every day.Suitably dosage level can be about 0.01 to 25mg/kg every day, about 0.05 to 10mg/kg every day or about 0.1 to 5mg/kg every day.Within the range, dosage can be 0.005 to 0.05,0.05 to 0.5 or 0.5 to 5.0mg/kg every day.For Orally administered, compositions provides the most in form of tablets, described tablet comprise 1.0 to 1000 milligrams of active component, particularly 1.0,3.0,5.0,10.0,15.0,20.0,25.0,50.0,75.0,100.0,150.0, 200.0,250.0,300.0,400.0,500.0,600.0,750.0,800.0,900.0 and 1000.0 milligrams of active component, use Symptom in the dosage to patient to be treated adjusts.Compound can every day the therapeutic scheme of 1 to 4 time use, preferably every day Once or twice daily.

It will be appreciated, however, that concrete dosage level and administration frequency for any particular patient can change, and will take Certainly in many factors, including the activity of particular compound used, the metabolic stability of this compound and effect duration, the age, Body weight, general health, sex, diet, mode of administration and time, rate of discharge, drug regimen, the seriousness of particular condition and just Through subject host.

The compounds of this invention can be with other pharmaceutical agent combinations or be applied in combination, and other medicaments described can be used for treating, prevent, press down System or improve the compounds of this invention to its useful disease or situation, including type ii diabetes, obesity, hyperglycemia, glucose Intolerance, insulin resistant, hyperinsulinemia, hypercholesterolemia, hypertension, hyperlipoproteinemia, hyperlipemia, height Triglyceride mass formed by blood stasis, dyslipidemia, metabolism syndrome, X syndrome, cardiovascular disease, atherosclerosis, kidney disease, Ketoacidosis, thrombotic disorder, nephropathy, diabetic neuropathy, diabetic retinopathy, sexual dysfunction, dermatosis, Dyspepsia, hypoglycemia, cancer and edema, GPR40 the disease mediated or situation.Other medicaments such or medicine can lead to Cross normally used approach and with normally used amount thus use simultaneously, sequentially or dividually with the compounds of this invention. When the compounds of this invention uses with one or more other drugs the same period, except the compounds of this invention, preferably comprise such The pharmaceutical composition of other drug.Therefore, the pharmaceutical composition of the present invention include also comprising except the compounds of this invention one or Other active component multiple or the pharmaceutical composition of therapeutic agent.

Can combine with the compounds of this invention, separate administration or the other therapeutic agents used in identical pharmaceutical composition Example includes, but are not limited to: (a) cholesterol-lowering agent, as HMG-CoA reductase inhibitor (such as, lovastatin, simvastatin, Pravastatin, fluvastatin, atorvastatin and other statinses), bile acid chelating agent (such as, colestyramine and examining Replace pool), vitamin B₃(also known as nicotinic acid or nicotinic acid), vitamin B₆(VB6), vitamin B₁₂(cyanocobalamin), fibre Dimension acid derivative (such as gemfibrozil, clofibrate, fenofibrate and bezafibrate), probucol, nitroglycerin and gallbladder are solid Alcohol absorption inhibitor (such as, cupreol and acyl-CoA-cholesterol acyltransferase (ACAT) inhibitor such as first Asia oleoyl Amine), HMG-CoA synthase inhibitor, squalene epoxidase inhibitor and squalene synthetase inhibitor；B () antithrombotic, as thrombosis is molten Solve agent (such as, streptokinase, alteplase, anistreplase and reteplase), heparin, hirudin and warfarin derivant, β-resistance Disconnected agent (such as, atenolol), beta-adrenergic excitomotor (such as, isoproterenol), ACE inhibitor and vasodilation Agent (such as, sodium nitroprusside, Licardipine Hydrochloride, nitroglycerin and enalaprilat)；(c) antidiabetic drug, such as insulin and Para-insulin drugs with function, sulphanylureas (such as, glibenclamide, meglinatide), biguanides such as metformin (), Alpha-glucosidase inhibitor (acarbose), insulin sensitizers such as thiazolidone (thiazolidinone) compound, rosiglitazone (), troglitazone (), ciglitazone, pioglitazone () and englitazone, DPP-IV inhibitor such as vildagliptin (vildagliptin) (), west it row spit of fland (sitagliptin) (JanuviaTM) and GLP-1 analog such as Exenatide (exenatide) ().Real at some Executing in scheme, the compounds of this invention can be used together with DPP-IV inhibitor or GLP-1 analog.In certain embodiments, The compounds of this invention is used with any DPP-IV inhibitor proposed in U.S. Patent Publication the 2006/0270701st, this U.S. State's patent disclosure is integrally incorporated with it and for all purposes as herein especially set out by quoting at this.

The weight ratio of the compounds of this invention and the second active component can change and will depend upon which the effective dose of every kind of composition. Generally, every kind of effective dose will be used.The combination of the compounds of this invention and other active component the most also will in aforementioned range, But in each case, it should use the effective dose of every kind of active component.

The compounds of this invention and the purposes of pharmaceutical composition

The invention provides compound or the pharmaceutical composition purposes in preparing medicine of the present invention, described medicine can For regulation G-G-protein linked receptor, described G-G-protein linked receptor is preferably GPR40 receptor.

Comprise the compounds of this invention or the Therapeutic Method of pharmaceutical composition administration, farther include patient to other GPR40 regulator, SGLT-2 inhibitor, biguanides, sulfonylureas, alpha-glucosidase inhibitors, PPAR agonist, α The double activator of P2 inhibitor, PPAR α/γ, dipeptide amido peptidase TV (DPP-IV) inhibitor, glinides, insulin, pancreas are high Blood glucose element sample peptide-1 (GLP-1) inhibitor, PTP1B inhibitor, glycogen phosphorylase inhibitors or Robison ester enzyme level Agent, thus can be by the compound of the present invention and other GPR40 regulators, SGLT-2 inhibitor, biguanides, sulfonylurea Medicine, alpha-glucosidase inhibitors, PPAR agonist, α P2 inhibitor, PPAR α/γ double activator, dipeptide amido peptidase TV (DPP- IV) inhibitor, glinides, insulin, glucagon-like-peptide-1 (GLP-1) inhibitor, PTP1B inhibitor, glycogen Phosphorglase inhibitor or Robison ester enzyme inhibitor administering drug combinations.The compounds of this invention or pharmaceutical composition are as single Dosage form, or separate compound or pharmaceutical composition are as a part for multi-pharmaceutics.Other treatment diabetes medicament can be with this Invention compound is administered simultaneously or is not administered simultaneously.The situation of the latter, administration can stagger carry out as 6 hours, 12 hours, 1 day, 2 days, 3 days, 1 week, 2 weeks, 3 weeks, 1 month or 2 months are carried out.

The compound of the present invention or " effective dose " of pharmaceutically acceptable compositions or " effective dose " refer to process or Alleviate the effective dose that one or more present invention is previously mentioned the severity of disease.The method according to the invention, compound and combination Thing can be any dosage and any route of administration is efficiently used for the order of severity that processes or palliate a disease.Required standard Situation according to patient is changed by true amount, and this depends on race, the age, the generic condition of patient, the order of severity of infection, Special factor, administering mode, etc..Compound or compositions can with one or more other therapeutic agents administering drug combinations, as The present invention is discussed.

(in this article, form of presentation is " formula (I) or formula (II) compound and stereoisomer thereof, several for the compound of the present invention What isomer, tautomer, mesomer, racemic modification, enantiomer, diastereomer, nitrogen oxides, hydration Thing, solvate, metabolite and pharmaceutically acceptable salt and prodrug " may be collectively referred to as " compound of the present invention "), permissible For producing medical product for preventing, treat, alleviate or delay diabetes, diabetic retinopathy, diabetic nerve The elevated levels of disease, diabetic nephropathy, insulin resistance, hyperglycemia, hyperinsulinemia, fatty acid or glycerol, hyperlipemia Disease, obesity, hypertriglyceridemia, X syndrome, ketoacidosis, glucose intolerance, hypercholesterolemia, blood fat Exception, metabolic syndrome, cardiovascular disease, kidney disease, thrombotic disorder, nephropathy, sexual dysfunction, dermatosis, digestion are not Good, hypoglycemia, cancer, edema, diabetic complication, atherosclerosis or hypertension or be used for increasing high density lipoprotein level White level, described in the invention including those.Further, the compound of the present invention may be used for producing regulation GPRs receptor Goods.Thus, the compound of the present invention may be used for producing a kind of pharmaceuticals for alleviating, stop, control or treating GPRs The receptor-mediated disease of the disease that receptor is mediated, particularly GPR40.Thus, the compound of the present invention can serve as medicine group The active component of compound, this pharmaceutical composition can include the compound representated by formula (I) or formula (II), it is also possible to wraps further Containing at least one pharmaceutically acceptable carrier, excipient, diluent, adjuvant and vehicle.

General building-up process

Usually, the compound of the present invention can be prepared by method described in the invention, unless there are further Explanation, wherein shown in the definition of substituent group such as formula (I) or formula (II).Following reaction scheme and embodiment are for lifting further Example explanation present disclosure.

Those skilled in the art will realize that: chemical reaction described in the invention can be used to prepare perhaps suitably Other compounds of many present invention, and it is considered as the model in the present invention for other method of the compound of preparing the present invention Within enclosing.Such as, the synthesis according to the compound of those non-illustrations of the present invention can be successfully by those skilled in the art Completed by method of modifying, as group is disturbed in suitable protection, by utilizing reagent known to other except described in the invention , or reaction condition is made the amendment of some routines.It addition, reaction disclosed in this invention or known reaction condition are also generally acknowledged Ground is applicable to the preparation of other compounds of the present invention.

The embodiments described below, unless other aspects show all of temperature and are set to degree Celsius.Reagent is bought in business Product supplier such as Aldrich Chemical Company, Inc., Arco Chemical Company and Alfa Chemical Company, the most not through being further purified, unless other aspects show during use.General reagent is western Gansu Province chemical industry from Shantou Factory, Guangdong brilliance chemical reagent factory, Guangzhou Chemical Reagent Factory, Tianjin Hao Yuyu Chemical Company, dragon chemistry examination is risen in Qingdao Agent company limited, and Haiyang Chemical Plant, Qingdao is commercially available.

Anhydrous tetrahydro furan, dioxane, toluene, ether are to be dried to obtain through metallic sodium backflow.Anhydrous methylene chloride It is to be dried to obtain through calcium hydride backflow with chloroform.Ethyl acetate, petroleum ether, normal hexane, DMAC N,N' dimethyl acetamide and N, N- Dimethylformamide is to be dried in advance through anhydrous sodium sulfate to use.

Hereinafter reaction is usually and overlaps a drying tube under nitrogen or argon gas positive pressure or on anhydrous solvent (unless other aspects Show), reaction bulb the most suitable rubber closure, substrate is squeezed into by syringe.Glass drying oven is all dried.

Chromatographic column is to use silicagel column.Silica gel (300-400 mesh) is purchased from Haiyang Chemical Plant, Qingdao.NMR (Nuclear Magnetic Resonance) spectrum with CDC1₃, DMSO-d₆,CD₃OD or acetone-d₆For solvent (report in units of ppm), with TMS (0ppm) or chloroform (7.25ppm) As reference standard.When multiplet occurs when, the abbreviation by following for use: s (singlet, unimodal), d (doublet, double Peak), t (triplet, triplet), q (quartet, quartet), m (multiplet, multiplet), br (broadened, wide Peak), dd (doublet of doublets, two are bimodal), dt (doublet of triplets, double triplets).Coupling is normal Number, represents with hertz (Hz).

By outfit G1312A binary pump and a G1316A TCC, (column temperature is maintained at 30 to Algorithm (MS) data DEG C) the spectrogrph of Agilent 6320 series LC-MS measure, G1329A automatic sampler and G1315B DAD detector Being applied to analyze, ESI source is applied to LC-MS spectrogrph.

Algorithm (MS) data are by being equipped with G1311A quaternary pump and G1316A TCC (column temperature is maintained at 30 DEG C) The spectrogrph of Agilent 6120 series LC-MS measure, G1329A automatic sampler and G1315D DAD detector should For analyzing, ESI source is applied to LC-MS spectrogrph.

Both the above spectrogrph is provided with Agilent Zorbax SB-C18 post, and specification is 2.1 × 30mm, 5 μm.Note Beam is long-pending is to be determined by sample concentration；Flow velocity is 0.6mL/min；The peak value of HPLC is by 210nm and 254nm UV-Vis wavelength records reading.Flowing be mutually 0.1% formic acid acetonitrile solution (phase A) and 0.1% formic acid ultrapure water-soluble Liquid (phase B).Condition of gradient elution is as shown in table 1:

Table 1

Time (min)	A(CH3CN, 0.1%HCOOH)	B(H2O, 0.1%HCOOH)
			0-3	5-100	95-0
3-6	100	0
			6-6.1	100-5	0-95
6.1-8	5	95

Compound purification is evaluated by Agilent 1100 series of high efficiency liquid chromatograph (HPLC), wherein UV detection At 210nm and 254nm, Zorbax SB-C18 post, specification is 2.1 × 30mm, 4 μm, 10 minutes, and flow velocity is 0.6mL/min, (0.1% aqueous formic acid) of (the 0.1% formic acid acetonitrile solution) of 5-95%, column temperature is maintained at 40 DEG C.

The use of brief word below runs through the present invention:

G gram

Mg milligram

Mmol mM

Ml, mL milliliter

L liter

DEG C degree Celsius

¹H NMR hydrogen 1 NMR (Nuclear Magnetic Resonance) spectrum

¹³C NMR carbon-13 magnetic resonance wave spectrum

MS mass spectrum

MHz megahertz

Hz hertz

DMSO-d₆Deuterated dimethyl sulfoxide

CDCl₃Deuterochloroform

Pos.ion cation

Neg.ion anion

ESI electron spray ionisation

M/z mass-charge ratio

Synthetic schemes 1:

Compound I can be obtained by synthetic schemes 1.Wherein B, R¹、R²Definition with n is as described herein；X is halogen；W For alkyl；Q is leaving group.

Compound I' and compound II at metallic catalyst (such as Hydro-Giene (Water Science). etc.) and part (such as N, N'-dimethyl second two Amine etc.) under effect, under the conditions of alkalescence (such as potassium carbonate, potassium phosphate etc.) to reaction be inert solvent (such as Isosorbide-5-Nitrae-dioxane, N-butyl alcohol etc.) in reaction obtain compound III；Compound III in the presence of reducing agent (such as sodium borohydride etc.) to reaction Inert solvent obtains compound IV (such as methanol, oxolane and their mixed solvent etc.)；Compound IV and halogenating agent (such as Phosphorous chloride. etc.) under there is no solvent or under the solvent to reactionlessness (such as N,N-dimethylformamide etc.) or with Excess halogenating agent is that solvent reaction obtains compound V；Or compounds Ⅳ and sulfonyl agent are (such as mesyl chloride, to Methyl benzenesulfonyl Chlorine etc.) react (such as N,N-dimethylformamide etc.) with in the presence of alkali (such as potassium carbonate etc.) in the solvent to reactionlessness Obtain compound V；Compound V and compound VI are being inertia (such as potassium carbonate, potassium phosphate etc.) to reaction in the basic conditions Solvent (such as N,N-dimethylformamide etc.) in reaction obtain compound VII；Compound VII is under alkaline conditions (such as hydroxide Lithium, sodium hydroxide etc.) when to reaction, inert solvent (such as methanol, oxolane, water and their mixed solvent etc.) enters Row hydrolysis obtains compound I.

Synthetic schemes 2

Compound I can be obtained by synthetic schemes 2.Wherein R¹、R²、R³Definition as described herein；X is halogen；W is Alkyl.

Compound VIII and compounds I ' at metallic catalyst (such as Hydro-Giene (Water Science). etc.) and part (such as N, N'-dimethyl second two Amine etc.) under effect, it is being that inert solvent is (such as N, N-dimethyl methyl to reaction (such as potassium carbonate, potassium phosphate etc.) under the conditions of alkalescence Amide etc.) in reaction obtain compound VII；Compound VII under alkaline conditions (such as Lithium hydrate, sodium hydroxide etc.) to reaction time The reaction that is hydrolyzed in inert solvent (such as methanol, oxolane, water and their mixed solvent etc.) obtains compound I.

Intermediate

2-(6-((the iodo-2' of 4'-, 6'-dimethyl-[1,1'-biphenyl]-3-base) methoxyl group)-2,3-Dihydrobenzofuranes- 3-yl) methyl acetate

The first step) 4'-amino-2', 6'-dimethyl-[1,1'-biphenyl]-3-methyl formate

By bromo-for 4-3,5-dimethylaniline (1g, 10mmol), (3-(methoxycarbonyl group) phenyl) boric acid (2.7g, 15mmol), Potassium carbonate (4.14g, 30mmol), [1,1'-double (diphenylphosphine) ferrocene] palladium chloride dichloromethane complex (0.37g, 0.5mmol) it is dissolved in DMF (30mL) and water (10mL), stirring reaction 1 hour at 90 DEG C.Reactant liquor is cold But it is extracted with ethyl acetate (200mL × 2) after adding water (30mL) dilution after room temperature, merges organic facies, use saturated sodium-chloride Solution washing (50mL), anhydrous sodium sulfate is dried, and filters, concentrating under reduced pressure filtrate.Residue silica gel chromatography (oil Ether: ethyl acetate=4:1), obtain faint yellow solid shape title compound (2.1g, yield 82%).

MS(ESI,pos.ion)m/z:256.1[M+H]⁺.

Second step) the iodo-2' of 4'-, 6'-dimethyl-[1,1'-biphenyl]-3-methyl formate

4'-amino-2', 6'-dimethyl-[1,1'-biphenyl]-3-methyl formate (1.5g, 5.9mmol) are dissolved in concentrated hydrochloric acid (6mL), in, the aqueous solution (5mL) of sodium nitrite (0.811g, 11.8mmol) under ice bath, is dripped.Drip and stir under reactant liquor ice bath after finishing Mix 15 minutes stand-by.Separately take a reaction bulb, potassium iodide (9.75g, 59mmol) is dissolved in water (20mL), drips above-mentioned under ice bath Stand-by solution, drips reactant liquor after finishing and is stirred at room temperature 2 hours.Reactant liquor is used with after saturated aqueous sodium thiosulfate (20mL) cancellation Ethyl acetate extraction (50mL × 2), merges organic facies, washs (50mL) with saturated nacl aqueous solution, and anhydrous sodium sulfate is dried, mistake Filter, concentrating under reduced pressure filtrate.Residue, with silica gel chromatography (petroleum ether: ethyl acetate=10:1), obtains faint yellow solid Shape title compound (1.6g, yield 74%).

3rd step) (the iodo-2' of 4'-, 6'-dimethyl-[1,1'-biphenyl]-3-base) methanol

Iodo-for 4'-2', 6'-dimethyl-[1,1'-biphenyl]-3-methyl formate (3g, 8.2mmol) is dissolved in toluene (100mL), in, add diisobutyl aluminium hydride (toluene solution of 33mL, 1M) at-10 DEG C and be the most naturally warmed to room temperature reaction overnight. Reactant liquor adds aqueous hydrochloric acid solution cancellation (50mL, 1M), and ethyl acetate extraction (50mL), organic facies saturated nacl aqueous solution washs (30mL), anhydrous sodium sulfate is dried, and filters, concentrating under reduced pressure filtrate.Residue silica gel chromatography (petroleum ether: acetic acid second Ester=4:1), obtain faint yellow title compound as oil (2.5g, yield 90%).

¹H NMR(600MHz,CDCl₃) δ 7.49 (s, 2H), 7.45 (t, J=7.6Hz, 1H), 7.38 (d, J=7.7Hz, 1H), 7.13 (s, 1H), 7.06 (d, J=7.5Hz, 1H), 4.76 (s, 2H), 1.99 (s, 6H).

4th step) 2-(6-((the iodo-2' of 4'-, 6'-dimethyl-[1,1'-biphenyl]-3-base) methoxyl group)-2,3-dihydrobenzene And furan-3-base) methyl acetate

By (the iodo-2' of 4'-, 6'-dimethyl-[1,1'-biphenyl]-3-base) methanol (2.5g, 7.4mmol) and 2-(6-hydroxyl- 2,3-Dihydrobenzofuranes-3-bases) methyl acetate (1.5g, 7.2mmol) is dissolved in toluene (120mL), is sequentially added under room temperature Room temperature reaction 3 hours after tri-n-butyl phosphine (3mL, 12mmol) and azodicarbonyldipiperidine (3g, 12mmol).Reactant liquor adds Water dilution (50mL), ethyl acetate extraction (30mL), organic facies saturated nacl aqueous solution washs (30mL), and anhydrous sodium sulfate is done Dry, filter, concentrating under reduced pressure filtrate.Residue, with silica gel chromatography (petroleum ether: ethyl acetate=10:1), obtains white solid Body shape title compound (3.2g, yield 82%).

¹H NMR(600MHz,CDCl₃) δ 7.49 (s, 2H), 7.45 (d, J=7.5Hz, 1H), 7.42 (s, 1H), 7.16 (s, 1H), 7.06 (dd, J=20.2,7.8Hz, 2H), 6.49 (m, 2H), 5.08 (s, 2H), 4.77 (t, J=9.0Hz, 1H), 4.28 (dd, J=9.2,6.1Hz, 1H), 3.85-3.80 (m, 1H), 3.74 (s, 3H), 2.77 (dd, J=16.4,5.5Hz, 1H), 2.58 (dd, J=16.4,9.3Hz, 1H), 1.98 (s, 6H).

Embodiment 1

2-(6-((2', 6'-dimethyl-4'-(3-(4-(methyl sulphonyl) phenyl)-2-imidazolidinone-1-base)-[1, 1'-biphenyl]-3-base) methoxyl group)-2,3-Dihydrobenzofuranes-3-base) acetic acid

The first step) 1-iodo-4-(methyl sulphonyl) benzene

4-(methyl sulphonyl) aniline (6g, 35mmol) is dissolved in concentrated hydrochloric acid (35mL), under ice bath, drips sodium nitrite The aqueous solution (30mL) of (4.84g, 70mmol).Drip stir under reactant liquor ice bath after finishing 15 minutes stand-by.Separately take a reaction bulb, will Potassium iodide (58.2g, 350mmol) is dissolved in water (120mL), drips above-mentioned stand-by solution under ice bath, drips reactant liquor room temperature after finishing Stir 2 hours.It is extracted with ethyl acetate (200mL × 2) after reactant liquor saturated aqueous sodium thiosulfate (200mL) cancellation, Merging organic facies, wash (50mL) with saturated nacl aqueous solution, anhydrous sodium sulfate is dried, and filters, concentrating under reduced pressure filtrate.Residue With silica gel chromatography (petroleum ether: ethyl acetate=4:1), obtain white solid title compound (7.8g, yield 79%).

MS(ESI,pos.ion)m/z:282.9[M+H]⁺.

Second step) 1-(4-(methyl sulphonyl) phenyl)-2-imidazolidinone

By 2-imidazolidinone (2.29g, 26.6mmol), N, N'-dimethyl-ethylenediamine (0.17mL, 1.6mmol), iodate is sub- Copper (0.2g, 1.1mmol), 1-iodo-4-(methyl sulphonyl) benzene (1.5g, 5.3mmol) and potassium carbonate (2.2g, 16mmol) are molten just In butanol (20mL), stir 2 hours at 100 DEG C.Reactant liquor uses dichloromethane after adding water (50mL) cancellation after being cooled to room temperature Alkane extraction (50mL × 2), merges organic facies, washs (30mL) with saturated nacl aqueous solution, and anhydrous sodium sulfate is dried, and filters, subtracts Pressure concentrated filtrate.Residue, with silica gel chromatography (dichloromethane: methanol=60:1), obtains faint yellow solid shape titled Compound (1.1g, yield 86%).

3rd step) 2', 6'-dimethyl-4'-(3-(4-(methyl sulphonyl) phenyl)-2-imidazolidinone-1-base)-[1, 1'-biphenyl]-3-methyl formate

By 1-(4-(methyl sulphonyl) phenyl)-2-imidazolidinone (492mg, 2.0mmol), N, N'-dimethyl-ethylenediamine (0.17mL, 1.6mmol), Hydro-Giene (Water Science). (0.2g, 1.1mmol), the iodo-2' of 4'-, 6'-dimethyl-[1,1'-biphenyl]-3-formic acid Methyl ester (500mg, 1.4mmol) and potassium phosphate (580mg, 2.8mmol) are dissolved in Isosorbide-5-Nitrae-dioxane (10mL), at 110 DEG C It is stirred overnight.Reactant liquor extracts (50mL × 2) with dichloromethane after adding water (50mL) cancellation after being cooled to room temperature, merges organic Phase, washs (30mL) with saturated nacl aqueous solution, and anhydrous sodium sulfate is dried, and filters, concentrating under reduced pressure filtrate.Residue silicagel column Chromatogram purification (dichloromethane: methanol=40:1), obtains faint yellow solid shape title compound (400mg, yield 60%).

4th step) 1-(3'-(methylol)-2,6-dimethyl-[1,1'-biphenyl]-4-base)-3-(4-(methyl sulphonyl) Phenyl)-2-imidazolidinone

By 2', 6'-dimethyl-4'-(3-(4-(methyl sulphonyl) phenyl)-2-imidazolidinone-1-base)-[1,1'-joins Benzene]-3-methyl formate (250mg, 0.5mmol) is dissolved in dichloromethane (20mL), adds diisobutyl aluminium hydride at-20 DEG C After (toluene solution of 1mL, 1M) 0 DEG C of reaction overnight.Reactant liquor adds aqueous hydrochloric acid solution (30mL, 1M) cancellation, and dichloromethane extracts Taking (30mL), organic facies saturated nacl aqueous solution washs (30mL), and anhydrous sodium sulfate is dried, and filters, concentrating under reduced pressure filtrate.Residual Staying thing silica gel chromatography (dichloro hexane: methanol=100:1), (150mg receives to obtain white solid title compound Rate 64%).

5th step) (2', 6'-dimethyl-4'-(3-(4-(methyl sulphonyl) phenyl)-2-imidazolidinone-1-base)-[1, 1'-biphenyl]-3-base) methylmethanesulfonate ester

By 1-(3'-(methylol)-2,6-dimethyl-[1,1'-biphenyl]-4-base)-3-(4-(methyl sulphonyl) phenyl)- 2-imidazolidinone (150mg, 0.3mmol) and triethylamine (0.04mL, 0.4mmol) are dissolved in dichloromethane (10mL), add first React 1 hour at 0 DEG C after base sulfonic acid chloride (0.03mL, 0.4mmol).Reactant liquor dilute (30mL), dichloromethane extracts (30mL), organic facies saturated nacl aqueous solution washs (30mL), and anhydrous sodium sulfate is dried, and filters, concentrating under reduced pressure filtrate.Residual Thing, with silica gel chromatography (petroleum ether: ethyl acetate=1:1), obtains white solid title compound (170mg, yield 97%).

6th step) 2-(6-((2', 6'-dimethyl-4'-(3-(4-(methyl sulphonyl) phenyl)-2-imidazolidinone-1- Base)-[1,1'-biphenyl]-3-base) methoxyl group)-2,3-Dihydrobenzofuranes-3-base) methyl acetate

Will (2', 6'-dimethyl-4'-(3-(4-(methyl sulphonyl) phenyl)-2-imidazolidinone-1-base)-[1,1'-connection Benzene]-3-base) methylmethanesulfonate ester (170mg, 0.32mmol), 2-(6-hydroxyl-2,3-Dihydrobenzofuranes-3-base) acetic acid first Ester (80mg, 0.38mmol) and cesium carbonate (74mg, 0.38mmol) are dissolved in acetonitrile (10mL), are warming up to 75 DEG C of reactions overnight. Reactant liquor shrend is gone out, ethyl acetate extraction (20mL × 2), merges organic facies, washs (10mL) with saturated nacl aqueous solution, nothing Aqueous sodium persulfate is dried, and filters, concentrating under reduced pressure filtrate.Residue with silica gel chromatography (petroleum ether: ethyl acetate=2:1), Obtain faint yellow solid shape title compound (178mg, yield 86.4%).

MS(ESI,pos.ion)m/z:641.2[M+H]+.

7th step) 2-(6-((2', 6'-dimethyl-4'-(3-(4-(methyl sulphonyl) phenyl)-2-imidazolidinone-1- Base)-[1,1'-biphenyl]-3-base) methoxyl group)-2,3-Dihydrobenzofuranes-3-base) acetic acid

By 2-(6-((2', 6'-dimethyl-4'-(3-(4-(methyl sulphonyl) phenyl)-2-imidazolidinone-1-base)-[1, 1'-biphenyl]-3-base) methoxyl group)-2,3-Dihydrobenzofuranes-3-base) methyl acetate (180mg, 0.28mmol) is dissolved in tetrahydrochysene In furan (2.8mL), after adding lithium hydroxide aqueous solution (2.8mL, 1M), it is stirred at room temperature 2 hours.It is dilute that reactant liquor adds water (5mL) With hydrochloric acid (4mL, 1M) acidifying after releasing, and extract by ethyl acetate (10mL × 2), merge organic facies, use saturated nacl aqueous solution Washing (10mL), anhydrous sodium sulfate is dried, and filters, and concentrating under reduced pressure filtrate obtains titled compound as white solid (165mg, yield 94%).

MS(ESI,neg.ion)m/z:625.6[M-H]^-；

¹H NMR(400MHz,CDCl₃) δ 7.95 (d, J=9.0Hz, 2H), 7.85 (d, J=9.0Hz, 2H), 7.46 7.42 (m, 2H), 7.34 (s, 2H), 7.19 (s, 1H), 7.09 (dd, J=15.0,7.7Hz, 2H), 6.50 (m, 2H), 5.10 (s, 2H), 4.77 (t, J=9.0Hz, 1H), 4.30 (dd, J=9.2,6.1Hz, 1H), 4.07 4.05 (m, 4H), 3.85 3.81 (m, 1H), 3.07 (s, 3H), 2.82 (dd, J=16.8,5.4Hz, 1H), 2.63 (dd, J=16.8,9.2Hz, 1H), 2.06 (s, 6H).

Embodiment 2

(S)-2-(6-((2', 6'-dimethyl-4'-(3-(3-(methyl sulphonyl) propyl group)-2-imidazolidinone-1 base)- [1,1'-biphenyl]-3-base) methoxyl group)-2,3-Dihydrobenzofuranes-3-base) acetic acid

The first step) 3-(methyl mercapto) methanesulfonic acid propyl ester

3-(methyl mercapto) propyl group-1-alcohol (2mL, 19.4mmol) and triethylamine (3.2mL, 23mmol) are dissolved in dichloromethane (30mL), in, mesyl chloride (1.84mL, 23.3mmol) under ice bath, is dripped.Drip and stir 30 minutes under reactant liquor room temperature after finishing.Instead Extract (50mL × 2) with dichloromethane after answering liquid saturated sodium bicarbonate aqueous solution (30mL) cancellation, merge organic facies, with saturated Sodium chloride solution washing (50mL), anhydrous sodium sulfate is dried, and filters, concentrating under reduced pressure filtrate.Residue silica gel chromatography (petroleum ether: ethyl acetate=1:1), obtains faint yellow title compound as oil (7.8g, yield 79%).

Second step) 1-(3-(methyl mercapto) propyl group) imidazolidin-2-one

2-imidazolidinone (2.14g, 24.9mmol) is dissolved in DMF (30mL), is dividedly in some parts hydrogenation Sodium (695mg, 17.4mmol) room temperature reaction 30 minutes afterwards, add afterwards 3-(methyl mercapto) methanesulfonic acid propyl ester (3.05g, 16.5mmol) room temperature reaction is overnight.Reactant liquor with saturated aqueous ammonium chloride cancellation (10mL), ethyl acetate extraction (20mL × 2), merging organic facies, wash (10mL) with saturated nacl aqueous solution, anhydrous sodium sulfate is dried, and filters, concentrating under reduced pressure filtrate.Residual Staying thing silica gel chromatography (dichloromethane: methanol=50:1), (1.5g receives to obtain faint yellow solid shape title compound Rate 52%).

3rd step) 1-(3-(methyl sulphonyl) propyl group) imidazolidin-2-one

Being dissolved in methanol (50mL) by 1-(3-(methyl mercapto) propyl group) imidazolidin-2-one (2g, 11.4mmol), room temperature adds It is stirred overnight under potassium hydrogen persulfate (11.2g, 17.3mmol) room temperature afterwards.Reactant liquor uses dichloromethane after adding water (50mL) cancellation Extraction (50mL × 2), merges organic facies, washs (30mL) with saturated nacl aqueous solution, and anhydrous sodium sulfate is dried, and filters, decompression Concentrated filtrate.Residue, with silica gel chromatography (dichloromethane: methanol=20:1), obtains faint yellow title compound as oil (0.75g, yield 32%).

MS(ESI,pos.ion)m/z:207.2[M+H]⁺.

4th step) (S)-2-(6-((2', 6'-dimethyl-4'-(3-(3-(methyl sulphonyl) propyl group)-2-imidazolidinone- 1 base)-[1,1'-biphenyl]-3-base) methoxyl group)-2,3-Dihydrobenzofuranes-3-base) methyl acetate

By 1-(3-(methyl sulphonyl) propyl group) imidazolidin-2-one (244mg, 1.2mmol), N, N'-dimethyl-ethylenediamine (0.04mL, 0.4mmol), Hydro-Giene (Water Science). (0.045mg, 0.23mmol), (S)-2-(6-((the iodo-2' of 4'-, 6'-dimethyl-[1, 1'-biphenyl]-3-base) methoxyl group)-2,3-Dihydrobenzofuranes-3-base) methyl acetate (500mg, 1.4mmol) and potassium carbonate (490mg, 3.6mmol) is dissolved in DMF (10mL), is stirred overnight at 120 DEG C.Reactant liquor is cooled to room Extract (50mL × 2) with dichloromethane after adding water (50mL) cancellation after temperature, merge organic facies, wash with saturated nacl aqueous solution (30mL), anhydrous sodium sulfate is dried, and filters, concentrating under reduced pressure filtrate.Residue silica gel chromatography (dichloromethane: methanol =50:1), obtain faint yellow solid shape title compound (140mg, yield 19.2%).

MS(ESI,pos.ion)m/z:607.2[M+H]⁺.

5th step) (S)-2-(6-((2', 6'-dimethyl-4'-(3-(3-(methyl sulphonyl) propyl group)-2-imidazolidinone- 1 base)-[1,1'-biphenyl]-3-base) methoxyl group)-2,3-Dihydrobenzofuranes-3-base) acetic acid

By (S)-2-(6-((2', 6'-dimethyl-4'-(3-(3-(methyl sulphonyl) propyl group)-2-imidazolidinone-1 base)- [1,1'-biphenyl]-3-base) methoxyl group)-2,3-Dihydrobenzofuranes-3-base) methyl acetate (170mg, 0.28mmol) is dissolved in four In hydrogen furan (2.8mL), after adding lithium hydroxide aqueous solution (2.8mL, 1M), it is stirred at room temperature 2 hours.Reactant liquor adds water (5mL) With hydrochloric acid (4mL, 1M) acidifying after dilution, and extract by ethyl acetate (10mL × 2), merge organic facies, molten with saturated sodium-chloride Liquid washing (10mL), anhydrous sodium sulfate is dried, and filters, and concentrating under reduced pressure filtrate obtains titled compound as white solid, and (140mg receives Rate 84.3%).

MS(ESI,pos.ion)m/z:593.2[M+H]⁺；

¹H NMR(600MHz,CDCl₃) δ 7.44 (t, J=7.5Hz, 1H), 7.39 (d, J=7.5Hz, 1H), 7.28 (s, 2H), 7.17 (s, 1H), 7.09 (d, J=7.3Hz, 1H), 7.06 (d, J=8.2Hz, 1H), 6.50 (d, J=8.2Hz, 1H), 6.48 (s, 1H), 5.08 (s, 2H), 4.77 (t, J=9.0Hz, 1H), 4.29 (dd, J=9.0,6.2Hz, 1H), 3.94 3.84 (m, 2H), 3.81 (dd, J=11.2,5.3Hz, 1H), 3.55 (t, J=7.9Hz, 2H), 3.49 (t, J=6.4Hz, 2H), 3.18 3.09 (m, 2H), 2.97 (s, 3H), 2.80 (dd, J=16.8,5.2Hz, 1H), 2.61 (dd, J=16.7,9.3Hz, 1H),2.21–2.11(m,2H),2.03(s,6H).

Embodiment 3

2-(6-((2', 6'-dimethyl-4'-(5-(methyl sulphonyl)-2-oxo-2,3-dihydro-1H-benzo [d] imidazoles Alkanone-1-base)-[1,1'-biphenyl]-3-base) methoxyl group)-2,3-Dihydrobenzofuranes-3-base) acetic acid

The first step) 2-(6-((4'-(5-bromo-2-oxo-2,3-dihydro-1H-benzo [d] imidazolidinone-1-base)-2', 6'-dimethyl-[1,1'-biphenyl]-3-base) methoxyl group)-2,3-Dihydrobenzofuranes-3-base) methyl acetate

By bromo-for 5-1H-benzo [d] imidazolidine-2 (3H)-one (2g, 9.39mmol), N, N'-dimethyl-ethylenediamine (0.05mL, 0.5mmol), Hydro-Giene (Water Science). (60mg, 0.32mmol), 2-(6-((the iodo-2' of 4'-, 6'-dimethyl-[1,1'-connection Benzene]-3-base) methoxyl group)-2,3-Dihydrobenzofuranes-3-base) methyl acetate (0.8g, 2mmol) and potassium carbonate (0.6g, 4mmol) it is dissolved in dimethyl sulfoxide (20mL), is stirred overnight at 130 DEG C.Reactant liquor adds water (50mL) after being cooled to room temperature and quenches Extract (50mL × 2) with dichloromethane after going out, merge organic facies, wash (30mL) with saturated nacl aqueous solution, anhydrous sodium sulfate It is dried, filters, concentrating under reduced pressure filtrate.Residue, with silica gel chromatography (petroleum ether: ethyl acetate=2:1), obtains yellowish Color solid, shaped title compound (195mg, yield 20%).

Second step) 2-(6-((2', 6'-dimethyl-4'-(5-(methyl sulphonyl)-2-oxo-2,3-dihydro-1H-benzo [d] imidazolidinone-1-base)-[1,1'-biphenyl]-3-base) methoxyl group)-2,3-Dihydrobenzofuranes-3-base) methyl acetate

By 2-(6-((4'-(5-bromo-2-oxo-2,3-dihydro-1H-benzo [d] imidazolidinone-1-base)-2', 6'-diformazan Base-[1,1'-biphenyl]-3-base) methoxyl group)-2,3-Dihydrobenzofuranes-3-base) methyl acetate (50mg, 0.082mmol), iodine Change cuprous (3mg, 0.016mmol), L-PROLINE sodium salt (2mg, 0.015mmol) and methyl sulfinic acid sodium (24mg, 0.23mmol) being dissolved in dimethyl sulfoxide (1mL), reactant liquor reacts 24 hours at 95 DEG C.Reactant liquor adds shrend after being cooled to room temperature Go out (30mL), ethyl acetate extraction (30mL), and organic facies saturated nacl aqueous solution washs (30mL), and anhydrous sodium sulfate is dried, Filter, concentrating under reduced pressure filtrate.Residue, with silica gel chromatography (petroleum ether: ethyl acetate=1:1), obtains faint yellow solid Shape title compound (40mg, yield 80%).

MS(ESI,pos.ion)m/z:613.2[M+H]⁺.

3rd step) 2-(6-((2', 6'-dimethyl-4'-(5-(methyl sulphonyl)-2-oxo-2,3-dihydro-1H-benzo [d] imidazolidinone-1-base)-[1,1'-biphenyl]-3-base) methoxyl group)-2,3-Dihydrobenzofuranes-3-base) acetic acid

By 2-(6-((2', 6'-dimethyl-4'-(5-(methyl sulphonyl)-2-oxo-2,3-dihydro-1H-benzo [d] miaow Oxazolidone-1-base)-[1,1'-biphenyl]-3-base) methoxyl group)-2,3-Dihydrobenzofuranes-3-base) methyl acetate (40mg, 0.065mmol) it is dissolved in oxolane (0.6mL), after adding lithium hydroxide aqueous solution (0.6mL, 1M), is stirred at room temperature 2 hours. Reactant liquor is acidified with hydrochloric acid (1mL, 1M) after adding water (5mL) dilution, and extracts by ethyl acetate (10mL × 2), merges organic Phase, washs (10mL) with saturated nacl aqueous solution, and anhydrous sodium sulfate is dried, and filters, and concentrating under reduced pressure filtrate obtains white solid mark Topic compound (30mg, yield 76.8%).

MS(ESI,neg.ion)m/z:597.0[M-H]^-；

¹H NMR(600MHz,DMSO-d₆) δ 12.32 (s, 1H), 11.65 (s, 1H), 7.61 (d, J=7.7Hz, 1H), 7.58 7.49 (m, 2H), 7.46 (d, J=6.6Hz, 1H), 7.31 (s, 2H), 7.26 (s, 1H), 7.20 (dd, J=28.3, 7.3Hz, 2H), 7.11 (d, J=7.6Hz, 1H), 6.58 6.40 (m, 2H), 5.14 (s, 2H), 4.68 (t, J=8.6Hz, 1H), 4.31 4.11 (m, 1H), 3.68 (s, 1H), 3.20 (s, 3H), 2.70 (dd, J=16.3,4.5Hz, 1H), 2.47 (s, 1H), 2.03(s,6H).

Embodiment 4

(S)-2-(6-((4'-(3-(tert-butyl group)-2-imidazolidinone-1-base)-2', 6'-dimethyl-[1,1'-biphenyl]- 3-yl) methoxyl group)-2,3-Dihydrobenzofuranes-3-base) acetic acid

Synthesis step is with embodiment 2.

MS(ESI,pos.ion)m/z:529.0[M+H]⁺；

¹H NMR(600MHz,CDCl₃) δ 7.44 (t, J=7.5Hz, 1H), 7.39 (d, J=7.6Hz, 1H), 7.29 (s, 2H), 7.18 (s, 1H), 7.10 (d, J=7.3Hz, 1H), 7.06 (d, J=8.2Hz, 1H), 6.51 (dd, J=8.2,1.9Hz, 1H), 6.49 (d, J=1.7Hz, 1H), 5.08 (s, 2H), 4.77 (t, J=9.0Hz, 1H), 4.30 (dd, J=9.1,6.2Hz, 1H), 3.82 3.79 (m, 1H), 3.78 3.70 (m, 2H), 3.52 (t, J=7.8Hz, 2H), 2.81 (dd, J=16.8, 5.2Hz, 1H), 2.62 (dd, J=16.8,9.4Hz, 1H), 2.03 (s, 6H), 1.46 (s, 9H).

Embodiment 5

2-(6-((4'-(6-bromo-2-oxo-2,3-dihydro-1H-benzo [d] imidazolidinone-1-base)-2', 6'-diformazan Base-[1,1'-biphenyl]-3-base) methoxyl group)-2,3-Dihydrobenzofuranes-3-base) acetic acid

Synthesis step is with embodiment 3.

MS(ESI,pos.ion)m/z:598.8[M+H]⁺；

¹H NMR(600MHz,DMSO-d₆) δ 11.34 (s, 1H), 7.52 (t, J=7.3Hz, 1H), 7.45 (d, J= 7.2Hz, 1H), 7.27 (d, J=6.8Hz, 3H), 7.24 (d, J=8.2Hz, 1H), 7.18 (d, J=6.9Hz, 1H), 7.11 (d, J=7.4Hz, 2H), 7.04 (d, J=8.1Hz, 1H), 6.53 6.44 (m, 2H), 5.13 (s, 2H), 4.68 (t, J=8.9Hz, 1H), 4.23 4.15 (m, 1H), 3.68 (s, 1H), 2.70 (dd, J=16.5,5.2Hz, 1H), 2.47 (s, 1H), 2.02 (s, 6H).

Embodiment 6

2-(6-((4'-(5-bromo-2-oxo-2,3-dihydro-1H-benzo [d] imidazolidinone-1-base)-2', 6'-diformazan Base-[1,1'-biphenyl]-3-base) methoxyl group)-2,3-Dihydrobenzofuranes-3-base) acetic acid

Synthesis step is with embodiment 3.

MS(ESI,pos.ion)m/z:599.1[M+H]⁺；

¹H NMR(600MHz,DMSO-d₆)δ11.34(s,1H),7.92–6.63(m,10H),6.47(s,2H),5.13(s, 2H),4.68(s,1H),4.18(s,1H),3.66(s,1H),2.68(s,1H),2.47–2.38(m,1H),2.01(s,6H).

Embodiment 7

2-(6-((2', 6'-dimethyl-4'-(2-oxo-2,3-dihydro-1H-benzo [d] imidazolidinone-1-base)-[1, 1'-biphenyl]-3-base) methoxyl group)-2,3-Dihydrobenzofuranes-3-base) acetic acid

Synthesis step is with embodiment 3.

MS(ESI,pos.ion)m/z:521.2[M+H]⁺；

¹H NMR(600MHz,DMSO-d₆) δ 12.36 (s, 1H), 11.15 (s, 1H), 7.51 (t, J=7.4Hz, 1H), 7.44 (d, J=7.4Hz, 1H), 7.28 (s, 2H), 7.25 (s, 1H), 7.16 (d, J=7.1Hz, 1H), 7.12 6.98 (m, 5H), 6.52 6.44 (m, 2H), 5.13 (s, 2H), 4.68 (t, J=8.9Hz, 1H), 4.24 4.13 (m, 1H), 3.73 3.64 (m, 1H), 2.70 (dd, J=16.5,5.0Hz, 1H), 2.50 2.45 (m, 1H), 2.02 (s, 6H).

Embodiment 8

(S)-2-(6-((2', 6'-dimethyl-4'-(3-(methyl)-2-imidazolidinone-1-base)-[1,1'-biphenyl]-3- Base) methoxyl group)-2,3-Dihydrobenzofuranes-3-base) acetic acid

Synthesis step is with embodiment 2.

MS(ESI,pos.ion)m/z:487.2[M+H]⁺；

¹H NMR(600MHz,CDCl₃) δ 7.44 (t, J=7.5Hz, 1H), 7.40 (d, J=7.6Hz, 1H), 7.30 (s, 2H), 7.18 (s, 1H), 7.10 (d, J=7.3Hz, 1H), 7.06 (d, J=8.1Hz, 1H), 6.51 (dd, J=8.2,1.9Hz, 1H),6.48(s,1H),5.08(s,2H),4.80–4.74(m,1H),4.33–4.23(m,1H),3.85–3.80(m,3H), 3.55 3.46 (m, 2H), 2.93 (s, 3H), 2.81 (dd, J=16.8,5.2Hz, 1H), 2.61 (dd, J=16.7,9.4Hz, 1H),2.03(s,6H).

Embodiment 9

2-(6-((2', 6'-dimethyl-4'-(3-(4-(methyl sulphonyl) phenyl)-2-tetrahydropyrimidine alkanone-1 (2H)- Base)-[1,1'-biphenyl]-3-base) methoxyl group)-2,3-Dihydrobenzofuranes-3-base) acetic acid

Synthesis step is with embodiment 1.

MS(ESI,pos.ion)m/z:641.2[M+H]⁺；

¹H NMR(600MHz,CDCl₃) δ 7.91 (d, J=8.4Hz, 2H), 7.62 (d, J=8.4Hz, 2H), 7.47 7.36 (m, 2H), 7.18 (s, 1H), 7.13 7.02 (m, 4H), 6.55 6.42 (m, 2H), 5.08 (s, 2H), 4.76 (t, J=8.7Hz, 1H), 4.35 4.20 (m, 1H), 3.93 3.88 (m, 4H), 3.83 3.77 (m, 1H), 3.05 (s, 3H), 2.79 (d, J= 13.8Hz, 1H), 2.60 (d, J=8.3Hz, 1H), 2.36 (d, J=5.2Hz, 2H), 2.01 (s, 6H).

Embodiment 10

2-(6-((2', 6'-dimethyl-4'-(3-(4-(methyl sulphonyl) phenyl)-2-oxo-2,3-dihydro-1H-benzene And [d] imidazolidinone-1-base)-[1,1'-biphenyl]-3-base) methoxyl group)-2,3-Dihydrobenzofuranes-3-base) acetic acid

Synthesis step is with embodiment 1.

¹H NMR(600MHz,CDCl₃) δ 8.17 (d, J=8.5Hz, 2H), 7.94 (d, J=8.5Hz, 2H), 7.51 (t, J =7.5Hz, 1H), 7.45 (d, J=7.6Hz, 1H), 7.32 (s, 2H), 7.28 7.15 (m, 6H), 7.08 (d, J=8.2Hz, 1H), 6.53 (dd, J=8.2,1.9Hz, 1H), 6.50 (s, 1H), 5.12 (s, 2H), 4.78 (t, J=9.0Hz, 1H), 4.31 (dd, J=9.1,6.1Hz, 1H), 3.86 3.79 (m, 1H), 3.15 (s, 3H), 2.82 (dd, J=16.8,5.3Hz, 1H), 2.63 (dd, J=16.8,9.3Hz, 1H), 2.09 (d, J=22.5Hz, 6H).

Biological assessment

The test case the compounds of this invention Activation Activity to GPR40 cell

In 384 orifice plates, inoculate hGPR40 high expressing cell (stably express the HEK293 cell line of hGPR40, protect promise science and technology (Beijing) company limited builds), inoculum density is 8000/hole.Cell at 37 DEG C, 5%CO₂Under the conditions of cultivate 24 hours.Real When testing, 384 orifice plates being covered with cell are taken out from incubator, discard culture medium, add calcium dyestuff (preparation of calcium dyestuff: 20mL HBSS (20mM HEPES)+2tube dye+200 μ L 10%BSA, Calcium 4assay kit, Molecular Device), 40 μ L/ hole.384 orifice plates are put back in incubator, hatch 1 hour.Setting FLIPR experimental arrangement, every hole adds 3 The compounds of this invention of times gradient dilution and positive control, 10 μ L/ holes, use FLIPR instrument to carry out the intracellular Ca increased²⁺ The detection of concentration.Initial data XLfit is fitted, and obtains the EC of each compound₅₀Value.Experimental result see table.

Compound number	EC50(nM)	Compound number	EC50(nM)	Compound number	EC50(nM)
						Embodiment 1	111	Embodiment 2	56	Embodiment 3	57
Embodiment 4	26	Embodiment 5	111	Embodiment 6	131
						Embodiment 7	81	Embodiment 8	27	Embodiment 9	120
Embodiment 10	173

Conclusion: the compounds of this invention has obvious agonist activity to GPR40.

Claims (10)

1. a compound, it is the compound as shown in formula (I), or compound pharmaceutically acceptable salt shown in formula (I),

Wherein, B ring is C_2-10Heterocyclic radical, C_5-12Condense miscellaneous bicyclic group；

R¹For hydrogen, C_1-6Alkyl, C_6-10Aryl or C_1-9Heteroaryl, wherein said C_1-6Alkyl, C_6-10Aryl and C_1-9Heteroaryl is each The most optionally it is independently selected from hydrogen, fluorine, chlorine, bromine, hydroxyl, C by 1,2,3 or 4_1-6Alkyl, C_1-6Haloalkyl, C_1-6Alkyl Sulfonyl, amino-sulfonyl or C_1-6Halogenated alkyl sulfonyl substituent group replaces；With

Each R²Independently be hydrogen, C_1-6Alkyl, C_1-6Haloalkyl, fluorine, chlorine, bromine, C_1-6Alkyl sulphonyl or C_1-6Alkyl sulphonyl C_1-6Alkyl；Or two adjacent R²Coupled atom forms C together_6-10Aromatic ring or C_1-9Hetero-aromatic ring, wherein said C_6-10Virtue Ring and C_1-9Hetero-aromatic ring is the most optionally independently selected from hydrogen, fluorine, chlorine, bromine, hydroxyl, C by 1,2,3 or 4_1-4Alkyl, C_1-4 Haloalkyl, C_1-4Alkyl sulphonyl, amino-sulfonyl or C_1-4Halogenated alkyl sulfonyl substituent group replaces；With

N is 1,2,3 or 4.

Compound the most according to claim 1, it has the structure as shown in formula (II), or compound medicine shown in formula (II) Acceptable salt on,

Wherein, m is 0,1,2 or 3.

Compound the most according to claim 1, wherein

B ring is

4. according to the arbitrary described compound of claim 1-3, wherein

R¹For hydrogen, C_1-4Alkyl, C_6-10Aryl or C_1-9Heteroaryl, wherein said C_1-4Alkyl, C_6-10Aryl and C_1-9Heteroaryl is each From being the most optionally independently selected from hydrogen, fluorine, chlorine, bromine, hydroxyl, C by 1,2,3 or 4_1-4Alkyl, C_1-4Haloalkyl, C_1-4Alkane Base sulfonyl, amino-sulfonyl or C_1-4Halogenated alkyl sulfonyl substituent group replaces；With

Each R²Independently be hydrogen, C_1-4Alkyl, C_1-4Haloalkyl, fluorine, chlorine, bromine, C_1-4Alkyl sulphonyl or C_1-4Alkyl sulphonyl C_1-4Alkyl；Or two adjacent R²Coupled atom forms C together_6-10Aromatic ring or C_1-9Hetero-aromatic ring, wherein said C_6-10Virtue Ring and C_1-9Hetero-aromatic ring is the most optionally independently selected from hydrogen, fluorine, chlorine, bromine, hydroxyl, C by 1,2,3 or 4_1-4Alkyl, C_1-4 Haloalkyl, C_1-4Alkyl sulphonyl, amino-sulfonyl or C_1-4Halogenated alkyl sulfonyl substituent group replaces.

5. according to the arbitrary described compound of claim 1-3, wherein

R¹For hydrogen, methyl, ethyl, propyl group, butyl, the tert-butyl group or phenyl, wherein said methyl, ethyl, propyl group, butyl, the tert-butyl group The most optionally it is independently selected from hydrogen, fluorine, chlorine, bromine, hydroxyl, methyl, ethyl, propyl group, fourth by 1,2,3 or 4 with phenyl Base, trifluoromethyl, methyl sulphonyl, amino-sulfonyl or trifluoromethyl sulfonyl substituent group replace；With

Each R²Independently be hydrogen, methyl, ethyl, propyl group, butyl, the tert-butyl group, trifluoromethyl, fluorine, chlorine, bromine, methyl sulphonyl, first Base sulfonvlmethvl, methysulfonylethyl or methanesulphonylpropyl；Or two adjacent R²Coupled atom is together Composition phenyl, pyridine radicals or naphthyl, wherein said phenyl, pyridine radicals and naphthyl are the most optionally by 1,2,3 or 4 Be independently selected from hydrogen, fluorine, chlorine, bromine, hydroxyl, methyl, ethyl, propyl group, butyl, trifluoromethyl, methyl sulphonyl, ethylsulfonyl, Amino-sulfonyl or trifluoromethyl sulfonyl substituent group replace.

6., according to the arbitrary described compound of claim 1-3, comprise the structure of one of:

Or its pharmaceutically acceptable salt.

7. a pharmaceutical composition, said composition comprises the compound according to any one of claim 1-6, comprises medicine further Acceptable carrier on.

Pharmaceutical composition the most according to claim 7, it further comprises antidiabetic medicine, antihyperglycemic Thing, anti-obesity medicine, antihypertensive drug, antiplatelet drug, Antiatherosclerosis medicine, fat-reducing medicament, antibiotic medicine Thing or a combination thereof.

9., according to the pharmaceutical composition according to any one of claim 7-8, it further comprises at least one GPR40 and is subject to Body agonist.

10. the compound according to any one of claim 1-6 or the medicine group described in any one in claim 7-9 Compound preparation be used for preventing, treat, alleviate or delay by the receptor-mediated diabetes of GPR40, insulin resistance, hyperglycemia, The elevated levels of hyperinsulinemia, fatty acid or glycerol, obesity, X syndrome, ketoacidosis, glucose intolerance, Dyslipidemia, metabolic syndrome, cardiovascular disease, thrombotic disorder, nephropathy, sexual dysfunction, dermatosis, dyspepsia, low Blood glucose disease, cancer, edema, diabetic complication, atherosclerosis or hypertension or be used for increasing high density lipoprotein level plain boiled water Purposes in flat medicine.