CN106748922A - The new sulfone acid derivative of one class, its preparation method and its purposes as medicine - Google Patents

The new sulfone acid derivative of one class, its preparation method and its purposes as medicine Download PDF

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CN106748922A
CN106748922A CN201710029918.2A CN201710029918A CN106748922A CN 106748922 A CN106748922 A CN 106748922A CN 201710029918 A CN201710029918 A CN 201710029918A CN 106748922 A CN106748922 A CN 106748922A
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phenyl
sulfonyl
acetic acid
methoxyl group
bases
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CN106748922B (en
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黄文龙
钱海
刘春霞
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China Pharmaceutical University
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China Pharmaceutical University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C317/00—Sulfones; Sulfoxides
    • C07C317/44—Sulfones; Sulfoxides having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D207/325—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with substituted hydrocarbon radicals directly attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
    • C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
    • C07D261/08—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D277/24—Radicals substituted by oxygen atoms

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  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

Pharmaceutical composition the present invention relates to the new sulfone acid derivative shown in a kind of logical formula (I), its preparation method and containing the derivative is used as the medicinal usage for preparing treatment diabetes and metabolic syndrome.Described sulfone acid derivative has excellent internal hypoglycemic activity, and it can be used for preventing or treating diabetes.

Description

The new sulfone acid derivative of one class, its preparation method and its purposes as medicine
Technical field
The present invention relates to the field of pharmacology related to diabetes, and in particular to a kind of new sulfone acid derivative, its system Preparation Method and the pharmaceutical composition containing the derivative are used as the application prepared in treatment diabetes and Metabolic syndrome disease drug.This The sulfone acid derivative structure being related in invention unique and novelty in the transformation of this class compound structure, and show excellent Different administration security.
Background technology
Diabetes are one group of metabolic diseases being characterized with hyperglycaemia, are divided into type 1 diabetes (insulin-dependent glycosuria Disease) and diabetes B (non-IDD).The current whole world there are about 4.15 hundred million people with diabetes, separately there is 3.18 Hundred million people hide diabetes risk very high.Diabetes mellitus in China patient is 1.096 hundred million, occupy global the first, wherein 2 types are sugared Urine patient accounts for the 90~95% of diabetic's sum.
Diabetes can be by dietary adjustments and exercise treatment.Controlled, it is necessary to carry out medicine when these are unable to relief of symptoms Treat.The medicine of current diabetes includes：Biguanides such as melbine, can reduce the formation of glucose in liver；Sulphonyl Ureas such as glibenclamide and benzoic acid derivative such as Repaglinide, being capable of the stimulating pancreas β cells more insulin of secretion；Thiophene Oxazolidinedione class such as pioglitazone, insulin is strengthened by activating peroxisome proliferator activated receptor γ (PPAR- γ) Purificatiou；Alpha-glucosidase restrainer such as acarbose, can suppress the generation of glucose in enteron aisle；Glucagon Peptide -1 (GLP-1) analog such as Liraglutide, can promote the β cells secrete insulins of pancreas；DPP IV (DPP- IV) inhibitor such as Xi Gelieting, can suppress the degraded of internal GLP-1.But, the method for treating diabetes existing at present is all There is certain defect.Such as injection of insulin agent and sulfonylurea, may cause hypoglycemia and increased weight side effect；Diformazan is double Guanidine, alpha-glucosidase restrainer and GLP-1 analogs may cause gastrointestinal side effect；PPAR- gamma agonists may draw Play increased weight and oedema side effect；DPP-IV inhibitor may cause epipharyngitis, headache and infection side effect.For multiple The research in field is carried out, to bring safer and more effective novel blood sugar lowing medicine for diabetic.
Free-fat acid acceptor (FFAR) is the g protein coupled receptor (GPCRs) for going orphanization in recent years.Have determined that at present FFA acceptor have g protein coupled receptor 40 (GPR40) family, including GPR40 (also referred to as free-fat acid acceptor 1, FFA1), GPR41 (also referred to as free-fat acid acceptor 3, FFA3), GPR43 (also referred to as free-fat acid acceptor 2, FFA2) And GPR84, GPR120 of other families.GPR40 is to find new galanin-galanin receptors (GALR) The orphan type GPCR found during hypotype, altimeter reaches in the cell line of pancreatic beta cell and excreting insulin.GPR40 can be combined Such as palmitic acid, stearic acid, oleic acid, the aliphatic acid in the blood plasma such as linoleic acid plus linolenic acid realizes various physiological-function.Such as long-chain Free fatty is activated after being combined with GPR40, and calcium ion level is raised in inducing cell, the insulin that enhancing glucose stimulates Secretion (GSIS).GPR40 conditioning agents play incretin effect to promote GISI, in addition also can be with various treatment Rezulins Thing is used in combination.More than being based on, GPR40 activators can treat diabetes and related indication, especially diabetes B, fertilizer Fat insulin resistance, GI, and other metabolic syndrome illnesss.It is potential therapy target with GPR40, hair Now there is important researching value and application prospect with compound of the transformation with GPR40 agonist activities.
A series of patent application of GPR40 activators is had been disclosed at present, including WO2004041266, WO2005087710, WO2005051890, WO2006083781, WO2007013689, WO2008066097, WO2009054390, WO2010085525, WO2015024448, WO2015088868 etc..
The present invention relates to the novel sulfone acid derivative of structure, it has excellent GPR40 agonist activities and the work of internal hypoglycemic Property, and it was unexpectedly found that the compound with this class formation shows the lower liver kidneys of more existing clinical medicine TAK-875 Risk of toxicity.Therefore the sulfone acid derivative and pharmaceutically acceptable ester or its officinal salt can potentially be used for treatment or Person prevents diabetes and relevant disease, with wide DEVELOPMENT PROSPECT.
The content of the invention
It is an object of the invention to provide the compound and pharmaceutically acceptable ester shown in a kind of logical formula (I) or its can medicine Salt：
Wherein：
Ring A is selected from aryl or heteroaryl；
Ring B is selected from aryl or heteroaryl；
R1, R2And R3Hydrogen, halogen, cyano group, alkyl, alkoxy, cycloalkyl are each independently selected from, wherein the alkyl, cycloalkanes Base, alkoxy are optionally further replaced by one or more groups selected from halogen, cyano group, alkyl, alkoxy, cycloalkyl；
R4Selected from hydrogen, alkyl, halogen；
R5And R6Selected from hydrogen, alkyl, cycloalkyl；
R7Selected from hydrogen, alkyl.
Compound and pharmaceutically acceptable ester shown in preferred scheme of the invention, preferably self-drifting (I) or its can medicine Salt：
Wherein：
Ring A preferably is selected from phenyl ring, pyrrole ring or isozole ring；
Ring B preferably is selected from phenyl ring, thiphene ring；
R1, R2And R3Hydrogen, halogen, cyano group, alkyl, alkoxy, cycloalkyl are each independently selected from, wherein the alkyl, cycloalkanes Base, alkoxy are optionally further replaced by one or more groups selected from halogen, cyano group, alkyl, alkoxy, cycloalkyl；
R4Selected from hydrogen, alkyl, halogen；
R5And R6Selected from hydrogen, alkyl, cycloalkyl；
R7Selected from hydrogen, alkyl.
It is preferred that compound and pharmaceutically acceptable ester or its pharmaceutically useful salt shown in self-drifting (I)：
Wherein：
Ring A preferably is selected from phenyl ring, pyrrole ring or isozole ring；
Ring B preferably is selected from phenyl ring, thiphene ring；
R1, R2And R3It is each independently selected from hydrogen, halogen, cyano group, C1-C4Alkyl, C1-C4Alkoxy, cycloalkyl, wherein described Alkyl, cycloalkyl, alkoxy are optionally further selected from the base of halogen, cyano group, alkyl, alkoxy, cycloalkyl by one or more Group is replaced；
R4Selected from hydrogen, methyl, halogen；
R5And R6Selected from hydrogen, C1-C2Alkyl, cyclopropyl；
R7Selected from hydrogen, alkyl.
It is preferred that compound and pharmaceutically acceptable ester or its pharmaceutically useful salt shown in self-drifting (I)：
Wherein：
Ring A preferably be selected from phenyl ring or：
Ring B preferably be selected from phenyl ring or：
R1, R2And R3It is each independently selected from hydrogen, F, Cl, cyano group, C1-C4Alkyl, C1-C4Alkoxy, cycloalkyl, wherein described Alkyl, cycloalkyl, alkoxy are optionally further selected from F, cyano group, C by one or more1-C4Alkyl, C1-C4Alkoxy, cycloalkanes The group of base is replaced；
R4Selected from hydrogen, methyl, Cl；
R5And R6Selected from hydrogen, C1-C2Alkyl, cyclopropyl；
R7Selected from hydrogen, alkyl.
More preferably logical formula (I) compound and pharmaceutically acceptable ester or its pharmaceutically useful salt：
Wherein：
Ring A preferably be selected from phenyl ring or：
Ring B preferably be selected from phenyl ring or：
R1, R2And R3It is each independently selected from hydrogen, F, Cl, cyano group, trifluoromethyl, propyl group, isopropyl, methoxyl group, the methoxy of ring third Base, ethyoxyl, propoxyl group, isobutoxy, 3- methyl sulphonyls propoxyl group, 2- methoxy ethoxies；
R4Selected from hydrogen, methyl, Cl；
R5And R6Selected from hydrogen, methyl, ethyl, cyclopropyl；
R7Selected from hydrogen, methyl.
The preferred present invention has the compound or pharmaceutically acceptable salt thereof of logical formula (I), and the compound is selected from：
2- ((4- ((2 '-chloro- [1,1 '-biphenyl] -3- bases) methoxyl group) phenyl) sulfonyl) methyl acetate (I-1)；
2- ((4- ([1,1 '-biphenyl] -3- methoxyl groups) phenyl) sulfonyl) acetic acid (I-2)；
2- ((4- ((2 '-chloro- [1,1 '-biphenyl] -3- bases) methoxyl group) phenyl) sulfonyl) acetic acid (I-3)；
2- ((4- ((2 ', 6 '-dimethyl-[1,1 '-biphenyl] -3- bases) methoxyl group) phenyl) sulfonyl) acetic acid (I-4)；
2- ((4- ((2 '-methyl-[1,1 '-biphenyl] -3- bases) methoxyl group) phenyl) sulfonyl) acetic acid (I-5)；
2- ((4- (2 '-methoxyl group-(1,1 '-biphenyl -3- base) methoxyl group) phenyl) sulfonyl) acetic acid (I-6)；
2- ((4- ((4 '-(methoxyl group of ring third) 2 ', 6 '-dimethyl-[1,1 '-biphenyl] -3- bases) methoxyl group) phenyl) sulphonyl Base) acetic acid (I-7)；
2- ((4- ((2 '-fluoro- [1,1 '-biphenyl] -3- bases) methoxyl group) phenyl) sulfonyl) acetic acid (I-8)；
2- ((4- ((2 '-(trifluoromethyl)-[1,1 '-biphenyl] -3- bases) methoxyl group) phenyl) sulfonyl) acetic acid (I-9)；
2- ((4- ((4 '-methoxyl group -2 ', 6 '-dimethyl-[1,1 '-biphenyl] -3- bases) methoxyl group) phenyl) sulfonyl) second Sour (I-10)；
2- ((4- ((2 '-cyano group-[1,1 '-biphenyl] -3- bases) methoxyl group) phenyl) sulfonyl) acetic acid (I-11)；
2- ((4- ((4- methyl -2- phenyl thiazole -5- bases) methoxyl group) phenyl) sulfonyl) acetic acid (I-12)；
2- ((4- ((4- methyl -2- (3- aminomethyl phenyls) thiazole -5- bases) methoxyl group) phenyl) sulfonyl) acetic acid (I-13)；
2- ((4- ((2- (2- fluorophenyls) -4- methylthiazol -5- bases) methoxyl group) phenyl) sulfonyl) acetic acid (I-14)；
2- ((4- ((2 '-isopropyl-[1,1 '-biphenyl] -3- bases) methoxyl group) phenyl) sulfonyl) acetic acid (I-15)；
2- ((4- ((2- (3- chlorphenyls) -4- methylthiazol -5- bases) methoxyl group) phenyl) sulfonyl) acetic acid (I-16)；
2- ((4- ((2 ', 6 '-dimethyl -4- propoxyl group-[1,1 '-biphenyl] -3- bases) methoxyl group) phenyl) sulfonyl) second Sour (I-17)；
2- ((4- ((4 '-ethyoxyl -2 ', 6 '-dimethyl-[1,1 '-biphenyl] -3- bases) methoxyl group) phenyl) sulfonyl) second Sour (I-18)；
2- (4- (2,6- dimethyl -4- (3- (methyl sulphonyl) propoxyl group)-[1,1 '-xenyl] -3- bases) methoxyl group) Phenyl) sulfonyl) acetic acid (I-19)；
2- ((4- ((4 '-isobutyl group -2 ', 6 '-dimethyl-[1,1 '-biphenyl] -3- bases) methoxyl group) phenyl) sulfonyl) second Sour (I-20)；
2- ((4- (4 '-(2- methoxy ethoxies) -2 ', 6 '-dimethyl-[1,1 '-biphenyl -3- base] methoxyl group) phenyl) Sulfonyl) acetic acid (I-21)；
2- (4- (5- (3,5- bis- Jia Ji oxazole -4- bases) -2- methyl) epoxide) phenyl) sulfonyl) acetic acid (I-22)；
2- (4- (3- (3,5- bis- Jia Ji oxazole -4- bases) -2- methyl) epoxide) phenyl) sulfonyl) acetic acid (I-23)；
2- ((4- ((the chloro- 3- of 4- (3,5- bis- Jia Ji oxazole -4- bases) benzyl) epoxide) phenyl) sulfonyl) acetic acid (I-24)；
2- (4- (3- (2- methyl isophthalic acid H- pyrroles -1- bases) phenoxy group) phenyl) sulfonyl) acetic acid (I-25)；
2- (4- (3- (3,5- bis- Jia Ji oxazole -4- bases) phenoxy group) phenyl) sulfonyl) acetic acid (I-26)；
2- ((4- ((2- (4- fluorophenyls) -4- methylthiazol -5- bases) methoxyl group) phenyl) sulfonyl) acetic acid (I-27)；
2- ((4- ((4 '-methoxyl group -2 ', 6 '-dimethyl-[1,1 '-biphenyl] -3- bases) methoxyl group) phenyl) sulfonyl) third Sour (I-28)；
2- ((4- ((the chloro- 5- of 2- (3,5- bis- Jia Ji oxazole -4- bases) benzyl) epoxide) phenyl) sulfonyl) acetic acid (I-29)；
2- ((3- ([1,1 '-biphenyl] -4- methoxyl groups) phenyl) sulfonyl) acetic acid (I-30)；
2- ((3- ((2 '-methyl-[1,1 '-biphenyl -4- methoxyl group])) phenyl) sulfonyl) acetic acid (I-31)；
2- ((4- ((3- phenoxy groups) epoxide) phenyl) sulfonyl) acetic acid (I-32)；
1- ((4- ((4 '-methoxyl group -2 ', 6 '-dimethyl-[1,1 '-biphenyl] -3- bases) methoxyl group) phenyl) sulphonyl)-ring Propane-acetic acid (I-33)；
2- ((4- ((4 '-methoxyl group -2 ', 6 '-dimethyl-[1,1 '-biphenyl] -3- bases) methoxyl group) phenyl) sulfonyl) - 2 Methylpropionic acid (I-34)；
2- ((4- ((4 '-methoxyl group -2 ', 6 '-dimethyl-[1,1 '-biphenyl] -3- bases) methoxyl group) phenyl) sulfonyl) fourth Sour (I-35)；
Another aspect of the present invention is related to a kind of pharmaceutical composition, changes described in its logical formula (I) for containing treatment effective dose Compound and pharmaceutically acceptable ester or its pharmaceutically useful salt and appropriate carrier, diluent or excipient.
Present invention simultaneously relates to described compound and pharmaceutically acceptable ester or its pharmaceutically useful salt or its medicine group Application of the compound in treatment diabetes and Metabolic syndrome disease drug is prepared.
Detailed description of the invention
Unless otherwise stated, following term in the specification and in the claims has following implications.
" alkyl " refers to the aliphatic hydrocarbon group of saturation, including 1 to 20 straight chain and branched group of carbon atom.Preferably comprise 1 To 10 alkyl of carbon atom, more preferably containing 1 to 6 alkyl of carbon atom, further preferably 1 to 3 alkyl of carbon atom, Most preferably methyl.Non-limiting example includes methyl, ethyl, propyl group, isopropyl, butyl, isobutyl group, sec-butyl, tertiary fourth Base, amyl group, isopentyl, neopentyl, hexyl etc., and its various branched chain isomers etc..Alkyl can be it is substituted or unsubstituted, When substituted, substitution base can be substituted on any usable tie point, preferably one or more following groups, solely On the spot taken selected from halogen, hydroxyl, cyano group, nitro, alkyl, alkoxy, cycloalkyl, heterocyclic radical, aryl, the group of heteroaryl Generation.
" cycloalkyl " refers to the unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent of saturation or part, and it includes 3 to 20 carbon atoms, 3 to 12 carbon atoms are preferably included, more preferably cycloalkyl ring includes 3 to 10 carbon atoms.The non-limiting reality of monocyclic cycloalkyl Apply example and include cyclopropyl, cyclobutyl, cyclopenta, cyclopentenyl, cyclohexyl, cyclohexenyl group, cyclohexadienyl, suberyl, cycloheptyl Trialkenyl, cyclooctyl etc.
" aryl " refers to that 6 to 14 yuan of full carbon of the pi-electron system with conjugation are monocyclic or fused polycycle (is namely shared and adjoined The ring of carbon atom pair) group, preferably 6 to 10 yuan, such as phenyl and naphthyl.The aryl rings can be condensed in heteroaryl, miscellaneous In ring group or cycloalkyl ring, wherein being aryl rings with the ring that precursor structure links together.
Aryl can be substituted or unsubstituted, and when substituted, substitution base is preferably one or more following groups, Independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio group, alkyl amino, halogen, mercaptan, hydroxyl, nitro, cyano group, cycloalkanes Base, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkylthio, the group of heterocycle alkylthio group are replaced.
" heteroaryl " refers to that, comprising 1 to 4 hetero atom, 5 to 14 heteroaromatic systems of annular atom, wherein hetero atom includes Oxygen, sulphur and nitrogen.Preferably 5 to 10 yuan.It is 5 yuan or 6 yuan, such as furyl, thienyl, pyridine radicals, pyrroles that heteroaryl is preferably Base, N- alkyl pyrrole radicals, pyrimidine radicals, pyrazinyl, imidazole radicals, tetrazole radical etc..The heteroaryl ring can be condensed in aryl, heterocycle On base or cycloalkyl ring, wherein being heteroaryl ring with the ring that precursor structure links together.
Heteroaryl can be it is optionally substituted or unsubstituted, when substituted, substitution base be preferably one or more with Lower group, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio group, alkyl amino, halogen, mercaptan, hydroxyl, nitro, cyanogen Base, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkylthio, the group of heterocycle alkylthio group Replaced.
" alkoxy " refers to-O- (alkyl) and-O- (unsubstituted cycloalkyl), and wherein alkyl is as defined above.Non- limit Property embodiment processed includes methoxyl group, ethyoxyl, propoxyl group, butoxy, ring propoxyl group, cyclobutoxy group, cyclopentyloxy, cyclohexyloxy Deng.Alkoxy can be optionally substituted or unsubstituted, and when substituted, substitution base is preferably one or more following bases Group, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio group, alkyl amino, halogen, mercaptan, hydroxyl, nitro, cyano group, Cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkylthio, the group of heterocycle alkylthio group are taken Generation.
" optional " or " optionally " mean ground described later event or environment can with but need not occur, the explanation includes The event or environment occur or not spot occasion.For example, " optionally by alkyl-substituted heterocyclic group " means that alkyl can be with But necessarily exist, the explanation includes heterocyclic group by alkyl-substituted situation and heterocyclic group not by alkyl-substituted situation.
" substituted " refers to one or more hydrogen atoms in group, preferably at most 5, more preferably 1~3 hydrogen atom Replaced by the substitution base of respective number independently of one another.Self-evident, substitution base is only in their possible chemical position, this Art personnel can determine that (by experiment or theoretical) may or impossible take in the case where excessive effort is not paid Generation.For example, being probably unstable when amino or hydroxyl with free hydrogen are with the carbon atom combination with unsaturated (such as olefinic) key Fixed.
" pharmaceutical composition " is represented and contains one or more compound of the present invention or its pharmaceutically useful salt, or its prodrug With the mixture of other chemical constituents, for example pharmaceutically useful carrier of other chemical constituents and excipient.The purpose of pharmaceutical composition It is the absorption for promoting organism to active component, bioactivity is played in vivo beneficial to active component.
Logical formula (I) compound of the present invention can be synthesized by following steps：
The compound that the compound and logical formula (III) that logical formula (II) is represented are represented obtains formula under the reaction of alkali (IV) compound that, logical formula (IV) is represented prepares general formula compound (I) by hydrolysis.
Wherein W is leaving group, R1-R7Definition as described in logical formula (I).
W represents leaving group, it can be mentioned that such as Cl, Br, I, the C of optional halo1-C6Alkyl sulphonyl epoxide (for example, Mesyl epoxide, ethylsulfonyl epoxide, three chloromethanesulfonyls), optionally have substitution base C6-C10Aryl sulfonyl epoxide (for example, phenyl sulfonyl epoxide, p-toluenesulfonyl epoxide, m- nitrobenzenesulfonyl epoxide etc.) etc..
Include inorganic base and organic base as described alkali, described inorganic base can be mentioned that for example, alkali carbonate Class such as sodium carbonate, potassium carbonate, cesium carbonate etc.；Alkali metal hydrogencarbonate class such as saleratus etc.；Alkali metal hydroxide is for example Lithium hydroxide, NaOH, potassium hydroxide etc.；Described organic base can be mentioned that for example triethylamine, pyridine, lutidines, N-BuLi, potassium tert-butoxide etc..
The GPR40 agonist activities and internal hypoglycemic activity of compound can be by using measure as described below in the present invention System measurement.
The present invention is explained in following biology testing example description.
The experimental technique of actual conditions generally routinely condition or is built according to commodity manufacturer in test case of the present invention The condition of view.The reagent in unreceipted specific source, is the common agents of market purchase.
The compounds of this invention of test case 1 surely turns the agonist activity of cell to hGPR40-CHO
The present invention determines the GPR40 agonist activities of the compounds of this invention using following methods：
HGPR40-CHO surely turns cell with 3 × 104The density in/hole is seeded to 96 orifice plates, is placed in 37 DEG C, 5%CO2Cell Incubator incubated overnight；Culture medium is discarded, after 100ul HBSS cleanings are added per hole, adds 100ul to contain Probenecid's 37 DEG C of incubation 90min of Fluo-4 dye solutions；After incubation terminates, Fluo-4 dye solutions, plus 100 μ l HBSS buffer solutions are suctioned out, Wash away dyestuff；HBSSs of the 100 μ l containing Probenecid, 37 DEG C of incubation 10min are added per hole；Add difference dense per hole in 96 orifice plates The medicine of degree, according to parameter setting table FLIPR (Molecular Devices) reading.Analysis experimental result.Agonist activity= (compound well fluorescent value-blank control wells fluorescent value)/(linoleic acid hole fluorescent value-blank control wells fluorescent value) × 100%, knot Fruit is shown in Table 1.
Table 1：HGPR40 receptor agonist activities
Conclusion：The all compounds of the present invention have obvious agonist activity, wherein I-3, I-4, I-5, I-7, I- to GPR40 9th, I-10 and I-15 has stronger GPR40 agonist activities.
The internal hypoglycemic activity of compound can be surveyed by using measurement system as described below in the present invention of test case 2 It is fixed：
Normal mouse oral glucose tolerance tests (OGTT)：10 week old Kunming kind cleaning grade mouse, 18~22g of body weight, male, It is randomly divided into 7 groups, blank control group (blank solvent：0.5% carboxymethylcellulose sodium solution), positive drug control group (TAK- 875：20mg/kg), test-compound group (20mg/kg), every group 8, mouse fasting can't help water 12 hours before experiment, and each group is equal Oral administration gavage is administered, and docking takes blood, determines blood glucose value (being designated as -30min).Then gavage gives blank solvent, TAK-875 respectively And test-compound, blood glucose value is determined after 30min and is designated as 0min, concentration is given for 2g/10ml by 10ml/kg gavages immediately afterwards Glucose solution, determine blood glucose values and in 15,30,60,120min.The results are shown in Table 2.
Table 2：Influence of the preferred compound to normal Mouse oral sugar tolerance
Note：*P≤0.05 is Student ' the s t assays relative to blank control group.
The experiment of normal mouse oral glucose tolerance shows：Ester prodrugs I-1, I-3, I-4, I-5 and I-10 in vivo also can be bright The aobvious oral glucose tolerance for improving normal mouse, shows preferable hypoglycemic effect.
The liver nephrotoxic risks assessment of compound can be by the assessment side described in following examples in the present invention of test case 3 Method：
10 week old ICR kind cleaning grade mouse, 18~22g of body weight, male is randomly divided into 4 groups, and (blank is molten for blank control group Matchmaker：0.5% cmc soln), positive drug control group (TAK-875：20mg/kg), test-compound I-3 groups (30mg/kg), test-compound I-5 groups (30mg/kg), every group 8, successive administration is after 30 days, and it is small that water 12 is can't help in mouse fasting When, to pluck during eyeball takes whole blood to centrifuge tube, centrifuging and taking upper serum after standing determines third turn of ammonia of paddy within 24 hours with biochemical instruments Total bilirubin (TBIL), urea nitrogen (BUN) and serum creatinine (Scr) index in enzyme (ALT), glutamic-oxalacetic transaminease (AST), serum, Investigate influence of the test-compound long term administration to liver function.
Table 3：Influence of the test-compound to hepatic and renal function
Note：#P≤0.05 is Student ' the s t assays relative to blank control group.
Result shows that after 30 days, ALT the and AST indexs of positive drug TAK-875 groups are higher compared with blank, exist for successive administration Cause hepatotoxic risk, and the index of compound I-3 and I-5 group is suitable with blank, illustrates that it causes the wind of liver renal toxicity Danger is relatively low.I.e. test-compound group dosage is that 30mg/kg still shows to be better than the administration security of TAK-875 (20mg/kg), is Further clinical development provides safeguard.
Specific embodiment
With reference to embodiment, the invention will be further described.It should be noted that following embodiments are only for It is bright, and it is not intended to limit the present invention.The various change that those skilled in the art's training centre of the invention is made all should be Within protection domain required by the application claim.
Embodiment 1
Methyl 2 ((4- hydroxy phenyls) sulfonyl) acetic acid
The first step：4- methoxybenzenethiols (0.88ml, 7.13mmol) are dissolved in 15ml acetonitriles, potassium carbonate is added (2.96g, 21.4mmol), gained mixed liquor is placed in ice bath and cools down, and the second of bromoacetate (1.03ml, 9.27mmol) is added dropwise Nitrile solution (5ml), controls Inner temperature to be less than 0 DEG C during dropwise addition, drop finishes, and gained brown reaction solution is stirred at room temperature 3h, TLC detections After reaction completely, the 30ml that adds water dilutions, ethyl acetate (30ml × 4) extraction, merge it is organic it is interdependent time with 1N NaOH (20ml × 1), 1N HCl (20ml × 1), saturation NaCl solution (20ml × 2) washing, gained organic phase with anhydrous sodium sulfate drying, suction filtration, Filtrate decompression is evaporated off solvent and obtains yellowish-brown oily liquids 1.8g, crude yield 112%.
Second step：Take above-mentioned crude product (1g, 6.63mmol) to be dissolved in 30ml methyl alcohol, ice bath is cooled to less than -5 DEG C, be added dropwise The 30ml aqueous solution of oxone (8.15g, 13.26mmol), controls Inner temperature to be less than 0 DEG C during dropwise addition, drop finishes, room temperature reaction 24h, the 50ml that adds water dilute, ethyl acetate (40ml × 4) extraction, merge organic phase and are washed with saturation NaCl solution (20ml × 2), Gained organic phase is evaporated off solvent and is obtained yellow oily liquid 0.8g, crude yield with anhydrous sodium sulfate drying, suction filtration, filtrate decompression 72%.
3rd step：Take above-mentioned crude material (0.5g, 1.94mmol) to be dissolved in the hydrogen bromide solutions of 20ml 48%, add 0.05g TBAB are catalyzed, and reaction solution is cooled to room by gained reaction solution in after 100 DEG C of heating response 8h, TLC detection reactions completely Temperature, the 50ml that adds water dilutions, ethyl acetate (40ml × 5) extraction is merged organic phase and is washed with saturation NaCl solution (25ml × 2), Gained organic phase is evaporated off solvent and is obtained yellowish-brown crystal 0.3g with anhydrous sodium sulfate drying, suction filtration, filtrate decompression.Gained crystal is molten In 15ml methyl alcohol, the 1.5ml concentrated sulfuric acids are added dropwise, drop finishes, are heated to reflux 4h, TLC detection reactions are complete, and reaction solution is cooled into room Temperature, the 30ml that adds water dilutions, ethyl acetate (40ml × 4) extraction is merged organic phase and is washed with saturation NaCl solution (20ml × 2), Gained organic phase is evaporated off solvent with anhydrous sodium sulfate drying, suction filtration, filtrate decompression, and residue is through column chromatography (petroleum ether/acetic acid second Ester, 75：25, v/v) purifying obtains white solid 0.31g, yield 70%.
1H NMR (300MHz, DMSO-d6)δ：10.67 (s, 1H), 7.72 (d, J=8.7Hz, 2H), 6.97 (d, J= 8.7Hz, 2H), 4.47 (s, 2H), 3.59 (s, 3H)
Embodiment 2
Methyl 1- ((4- ((4 '-methoxyl group -2 ', 6 '-dimethyl-[1,1 '-biphenyl] -3- bases) methoxyl group) phenyl) sulphonyl Base) cyclopropyl -1- methyl acetates
Raw material (0.2g, 0.44mmol) is dissolved in 10ml DMF, adds potassium carbonate (0.15g, 1.1mmol) and catalytic amount TEBA, after 15min is stirred at room temperature, is added dropwise 1,2- Bromofumes (0.10g, 0.55mmol), and gained reaction solution is anti-in 60 DEG C of heating 3h is answered, after TLC detection reactions completely, reaction solution is cooled to room temperature, the 30ml that adds water dilutions, ethyl acetate (30ml × 4) extraction is closed And organic phase is washed with saturation NaCl solution (20ml × 2), gained organic phase is with anhydrous sodium sulfate drying, suction filtration, filtrate decompression Solvent is evaporated off, residue obtains white solid 0.2g, yield through column chromatography (petrol ether/ethyl acetate, 85: 25, v/v) purifying 97%.
Embodiment 3
2 '-chloro- [1,1 '-biphenyl] -4- formaldehyde
Raw material II I-1 (0.5g, 2.6mmol) is dissolved in 42ml mixed solvents (toluene/ethanol/water, 3: 1: 3, v/v/v), Addition raw material II I-2 (0.3g, 2.6mmol), triphenyl phosphorus palladium (0.15g, 0.13mmol), natrium carbonicum calcinatum (0.69g, 6.5mmol), under nitrogen protection, 60 DEG C of heating response 24h.Reaction is cooled to room temperature after terminating, the 20ml that adds water dilutions, with diatom Soil is laid the groundwork suction filtration, and ethyl acetate (15ml × 3) washing filter cake, filtrate is extracted with ethyl acetate (30ml × 4), merges organic phase Washed with saturation NaCl solution (20ml × 2), gained organic phase is evaporated off solvent with anhydrous sodium sulfate drying, suction filtration, filtrate decompression, Residue obtains pale solid 0.47g, yield 84% through column chromatography (petrol ether/ethyl acetate, 70: 30, v/v) purifying.
Embodiment 4
2- ((4- ((2 '-chloro- [1,1 '-biphenyl] -3- bases) methoxyl group) phenyl) sulfonyl) acetic acid (I-3)
Raw material II I-3 (0.2g, 0.92mmol) is dissolved in the solution of (THF/MeOH, 1: 1, v/v) in 20ml mixed solvents, Sodium borohydride (0.05g, 1.2mmol) is slowly added under ice bath, after reaction terminates under ice bath, plus 20ml water quenchings are gone out reaction, acetic acid Ethyl ester extraction (30ml × 3) is merged organic phase and is washed with saturation NaCl solution (20ml × 2), and gained organic phase is with anhydrous sodium sulfate Dry, suction filtration, filtrate decompression is evaporated off solvent, not purified to be directly used in the next step.The compound that upper step is obtained is dissolved in 20ml In dichloromethane, 0.5ml thionyl chlorides are slowly dropped into, add 1 to drip DMF, 25 DEG C of heating responses, reaction removes under reduced pressure molten after terminating Agent obtains pale yellow oil III-4.III-4 (0.2g, 0.90mmol) is dissolved in 20ml acetonitriles, adds raw material II -3 (0.25g, 1.08mmol), Anhydrous potassium carbonate (0.5g, 3.62mmol), catalytic amount KI is heated to 60 DEG C of reaction 8h, and filtering subtracts Pressure is evaporated off solvent, and residue is dissolved in 30ml water, ethyl acetate (20ml × 3) extraction, merges organic phase, with saturated aqueous common salt (15ml × 2) wash, anhydrous sodium sulfate drying, and filtering, filtrate decompression is evaporated off solvent, and residue is through column chromatography (petroleum ether/acetic acid Ethyl ester, 4: 1, v/v) 0.26g white solid III-5 are purified to obtain, it is dissolved in (THF/MeOH/H in 14ml mixed solvents2O, 3: 3: 1, V/v/v), add LiOH (0.07g, 2.79mmol), room temperature reaction 8h to remove tetrahydrofuran and methyl alcohol under reduced pressure, dripped under ice-water bath Plus 1N watery hydrochloric acid regulation PH2-3, separate out white solid, suction filtration, dry white powdery solids I-3 0.25g, fusing point 103- 105 DEG C, yield 66%.
1H NMR (300MHz, DMSO-d6)δ：13.03 (s, 1H), 7.85 (d, J=8.8Hz, 2H), 7.54,7.49 (dd, J =13.2,9.2Hz, 4H), 7.45-7.40 (m, 4H), 7.27 (d, J=8.8Hz, 2H), 5.30 (s, 2H), 4.40 (s, 2H)13C NMR (75MHz, DMSO-d6)δ：164.60,162.86,139.89,139.35,136.71,131.96,131.51,130.88, 130.32,129.79,129.45,129.12,128.95,128.02,127.71,115.57,70.01,60.81.ESI-MS m/ z：371.0[M-45]-.Anal.calcd.For C21H17ClO5S：C, 60.51；H, 4.11；Cl, 8.50；Found：C, 60.46； H, 4.12；Cl, 8.51.
Embodiment 5
2- ((4- ((2 '-chloro- [1,1 '-biphenyl] -3- bases) methoxyl group) phenyl) sulfonyl) methyl acetate (I-1)
The same I-3 of synthetic method, obtains white solid 0.26g, 82-84 DEG C of fusing point, yield 70%.
1H NMR (300MHz, DMSO-d6)δ：13.03 (s, 1H), 7.85 (d, J=8.8Hz, 2H), 7.54,7.49 (dd, J =13.2,9.2Hz, 4H), 7.45-7.40 (m, 4H), 7.27 (d, J=8.8Hz, 2H), 5.16 (s, 2H), 4.46 (s, 2H), 3.73 (s, 3H)
13C NMR (75MHz, DMSO-d6)δ：164.0,160.4,141.7,139.4,136.71,132.6,132.0, 132.0,131.2,129.4,129.3,129.3,129.0,128.9,127.3,126.8,126.0,115.3,115.3,71.1, 63.7,51.6.ESI-MS m/z：430.0[M-1]-.Anal.calcd.For C22H19ClO5S：C, 61.32；H, 4.44； Found：C, 60.29；H, 4.32.
Embodiment 6
2- ((4- ([1,1 '-biphenyl] -3- methoxyl groups) phenyl) sulfonyl) acetic acid (I-2)
The same I-3 of synthetic method, obtains white solid 0.36g, 110-112 DEG C of fusing point, yield 73%.
1H NMR (300MHz, DMSO-d6)δ：7.90-7.75 (m, 3H), 7.71-7.66 (m, 3H), 7.50-7.46 (m, 4H), (s, the 2H) of 7.42-7.23 (m, 3H), 5.30 (s, 2H), 4.3713C NMR (75MHz, DMSO-d6)δ：178.88, 164.54,137.43,137.38,130.94,130.87,129.71,129.48,128.12,127.43,127.18,126.92, 126.72,115.60,70.18,61.17.ESI-MS m/z：337.1[M-45]-.Anal.calcd.For C21H18O5S：C, 65.95；H, 4.74；Found：C, 65.92；H, 4.73.
Embodiment 7
2- ((4- ((2 ', 6 '-dimethyl-[1,1 '-biphenyl] -3- bases) methoxyl group) phenyl) sulfonyl) acetic acid (I-4)
The same I-3 of synthetic method, obtains white solid 0.56g, 165-167 DEG C of fusing point, yield 85%.
1H NMR (300MHz, DMSO-d6)δ：7.83 (d, J=8.4Hz, 2H), 7.55-7.40 (m, 2H), 7.24-7.07 (m, 7H), 5.25 (s, 2H), 4.14 (s, 2H), 1.93 (s, 6H)13C NMR (75MHz, DMSO-d6)δ：164.95,162.44, 141.43,140.99,137.03,135.60,132.43,130.78,129.26,128.95,128.61,127.76,127.55, 126.68,115.36,70.04,62.56,20.97.ESI-MS m/z：365.1[M-45]-.Anal.calcd.For C23H22O5S：C, 67.30；H, 5.40；Found：C, 67.34；H, 5.41.
Embodiment 8
2- ((4- ((2 '-methyl-[1,1 '-biphenyl] -3- bases) methoxyl group) phenyl) sulfonyl) acetic acid (I-5)
The same I-3 of synthetic method, obtains white solid 0.24g, 113-114 DEG C of fusing point, yield 68%.
1H NMR (300MHz, DMSO-d6)δ：7.84 (d, J=8.5Hz, 2H), 7.55-7.42 (m, 3H), 7.39-7.16 (m, 7H), 5.29 (s, 2H), 4.34 (s, 2H), 2.21 (s, 3H)13C NMR (75MHz, DMSO-d6)δ：164.50,162.78, 141.41,140.92,136.68,130.86,129.95,129.15,128.94,127.89,126.90,126.44,115.49, 70.08,61.20,20.59.ESI-MS m/z：351.1[M-45]-.Anal.calcd.For C22H20O5S：C, 66.65；H, 5.09；Found：C, 66.61；H, 5.08.
Embodiment 9
2- ((4- (2 '-methoxyl group-(1,1 '-biphenyl -3- base) methoxyl group) phenyl) sulfonyl) acetic acid (I-6)
The same I-3 of synthetic method, obtains white solid 0.35g, 101-102 DEG C of fusing point, yield 73%.
1H NMR (300MHz, DMSO-d6)δ：7.85 (d, J=8.8Hz, 2H), 7.57 (s, 1H), 7.50-7.38 (m, 3H), (s, the 3H) of 7.38-7.19 (m, 4H), 7.15-6.97 (m, 2H), 5.27 (s, 2H), 4.38 (s, 2H), 3.7413C NMR (75MHz, DMSO-d6)δ：164.53,162.71,157.72,141.45,140.91,136.64,132.82,131.67, 129.91,129.12,128.96,127.83,126.92,126.43,116.70,115.49,70.08,61.20, 56.13.ESI-MS m/z：367.1[M-45]-.Anal.calcd.For C22H20O6S：C, 64.07；H, 4.89；Found：C, 64.01；H, 4.88.
Embodiment 10
2- ((4- ((4 '-(methoxyl group of ring third) 2 ', 6 '-dimethyl-[1,1 '-biphenyl] -3- bases) methoxyl group) phenyl) sulphonyl Base) acetic acid (I-7)
The same I-3 of synthetic method, obtains white solid 0.43g, 104-106 DEG C of fusing point, yield 76%.
1H NMR (300MHz, DMSO-d6)δ：7.82 (d, J=7.7Hz, 2H), 7.56-7.35 (m, 2H), 7.17-7.06 (m, 4H), 6.68 (s, 2H), 5.25 (s, 2H), 4.11 (s, 2H), 3.79 (d, J=5.9Hz, 2H), 1.91 (s, 6H), 1.39 (d, J=5.9Hz, 1H), 0.56 (d, J=5.8Hz, 2H), 0.30 (d, J=5.8Hz, 2H)13C NMR (75MHz, DMSO-d6) δ：164.59,162.75,156.12,141.44,140.93,136.93,132.76,131.07,130.76,128.95, 127.84,126.91,126.34,118.41,115.30,113.63,72.22,70.08,61.20,21.23,10.69, 3.57.ESI-MS m/z：435.1[M-45]-.Anal.calcd.For C27H28O6S：C, 67.48；H, 5.87；Found：C, 67.43；H, 5.86.
Embodiment 11
2- ((4- ((2 '-fluoro- [1,1 '-biphenyl] -3- bases) methoxyl group) phenyl) sulfonyl) acetic acid (I-8)
The same I-3 of synthetic method, obtains white solid 0.22g, 115-117 DEG C of fusing point, yield 67%.
1H NMR (300MHz, DMSO-d6)δ：7.85 (d, J=7.7Hz, 2H), 7.65 (s, 1H), 7.60-7.39 (m, 5H), (s, the 2H) of 7.30 (d, J=7.6Hz, 2H), 7.21 (d, J=7.7Hz, 2H), 5.28 (s, 2H), 4.0613C NMR (75MHz, DMSO-d6)δ：164.51,162.03,136.67,135.27,132.76,130.77,129.67,129.18, 128.85,128.50,128.13,127.24,124.94,116.25,115.94,115.31,69.50,43.89.ESI-MS m/ z：355.1[M-45]-.Anal.calcd.For C21H17FO5S：C, 62.99；H, 4.28；Found：C, 62.93；H, 4.27.
Embodiment 12
2- ((4- ((2 '-(trifluoromethyl)-[1,1 '-biphenyl] -3- bases) methoxyl group) phenyl) sulfonyl) acetic acid (I-9)
The same I-3 of synthetic method, obtains white solid 0.36g, 179-180 DEG C of fusing point, yield 84%.
1H NMR (300MHz, DMSO-d6)δ：7.89-7.78 (m, 3H), 7.68 (dd, J=25.1,7.1Hz, 2H), (s, the 2H) of 7.57-7.39 (m, 4H), 7.31 (s, 1H), 7.17 (d, J=8.3Hz, 2H), 5.25 (s, 2H), 3.8013C NMR (75MHz, DMSO-d6)δ：173.79,164.41,161.53,139.45,136.01,132.30,132.13,131.78, 130.20,129.14,128.37,128.15,127.96,127.18,126.07,115.33,114.48,69.45,64.08, 43.90.ESI-MS m/z：405.1[M-45]-.Anal.calcd.For C22H17F3O5S：C, 58.66；H, 3.80；Found： C, 58.61；H, 3.81.
Embodiment 13
2- ((4- ((4 '-methoxyl group -2 ', 6 '-dimethyl-[1,1 '-biphenyl] -3- bases) methoxyl group) phenyl) sulfonyl) second Sour (I-10)
The same I-3 of synthetic method, obtains white solid 0.16g, 97-98 DEG C of fusing point, yield 72%.
1H NMR (300MHz, DMSO-d6)δ：7.81 (d, J=8.4Hz, 2H), 7.46 (d, J=7.8Hz, 2H), 7.25- (s, the 6H) of 7.04 (m, 4H), 6.70 (s, 2H), 5.25 (s, 2H), 3.88 (s, 2H), 3.75 (s, 3H), 1.9313C NMR (75MHz, DMSO-d6)δ：162.49,158.41,140.89,136.99,136.88,134.00,133.19,129.58, 129.18,126.46,115.91,113.13,70.07,55.36,44.40,21.19.ESI-MS m/z：395.1[M-45]- .Anal.calcd.For C24H24O6S：C, 65.44；H, 5.49；Found：C, 65.41；H, 5.48.
Embodiment 14
2- ((4- ((2 '-cyano group-[1,1 '-biphenyl] -3- bases) methoxyl group) phenyl) sulfonyl) acetic acid (I-11)
The same I-3 of synthetic method, obtains white solid 0.25g, 187-190 DEG C of fusing point, yield 79%.
1H NMR (300MHz, DMSO-d6)δ：7.96 (d, J=6.8Hz, 1H), 7.88-7.76 (m, 3H), 7.72-7.52 (m, 6H), 7.24 (d, J=7.6Hz, 2H), 5.31 (s, 2H), 4.16 (s, 2H)13C NMR (75MHz, DMSO-d6)δ： 164.31,162.39,142.35,138.50,137.45,134.32,134.05,130.85,130.61,129.69,129.45, 128.81,128.63,115.80,114.98,110.65,69.85,61.23.ESI-MS m/z：362.1[M-45]- .Anal.calcd.For C22H17NO5S：C, 64.85；H, 4.21；N, 3.44；Found：C, 64.81；H, 4.21；N, 3.43.
Embodiment 15
4- methyl -2- phenyl thiazole -5- Ethyl formates
Thiobenzamide (1.0g, 7.3mmol), 2- chloroacetyl acetacetic esters (1.4g, 8.6mmol) are dissolved in 20ml ethanol In, catalytic amount sodium carbonate is added, 6h is heated to reflux, react, it is cooled to room temperature, insoluble matter is filtered, filtrate decompression concentration is added full With sodium bicarbonate solution to alkalescent, ethyl acetate (20ml × 3) extraction, merging organic phase, with saturated aqueous common salt (15ml × 2) Washing, anhydrous sodium sulfate drying, filtering, filtrate decompression is evaporated off solvent, residue through column chromatography (petrol ether/ethyl acetate, 5: 1, V/v 1.2g white solids, 74-76 DEG C of fusing point, yield 72.8%) are purified to obtain.
1H NMR (300MHz, DMSO-d6)δ：7.93,7.91 (dd, J=1.26,7.57Hz, 2H, ArH), 7.45-7.40 (m, 3H, ArH), 4.30 (q, J=7.07Hz, 2H ,-OCH2), 2.68 (s, 3H, ArCH3), 1.31 (t, J=7.07Hz, 3H ,- CH3).
Embodiment 16
2- ((4- ((4- methyl -2- phenyl thiazole -5- bases) methoxyl group) phenyl) sulfonyl) acetic acid (I-12)
Raw material II I-1 (0.80g, 3.23mmol) is dissolved in 15ml THF, is dividedly in some parts NaBH4(0.31g, 8.0mmol), Finish, be heated to reflux lower dropwise addition 0.5ml methyl alcohol, drop Bi Jixu backflow about 30min stop stirring, room temperature are cooled to, by reaction solution It is poured into 20ml frozen water, ethyl acetate (20ml × 3) extraction merges organic phase, is washed with saturated aqueous common salt (15ml × 2), nothing Aqueous sodium persulfate is dried, filtering, and filtrate decompression is evaporated off solvent, obtains beige solid 0.54g, and not purified to be directly used in lower step anti- Should, in being dividedly in some parts under ice bath into the thionyl chloride 5ml for pre-cooling, 60 DEG C of reaction 1h, reaction are heated to after stirring Liquid removes unnecessary thionyl chloride under reduced pressure, and gained brown oil III-2 is dissolved in 20ml THF, adds raw material II -3 (0.64g, 2.79mmol), Anhydrous potassium carbonate (1.15g, 8.34mmol), catalytic amount KI is heated to 60 DEG C of reaction 8h, and filtering subtracts Pressure is evaporated off solvent, and residue is dissolved in 30ml water, ethyl acetate (20ml × 3) extraction, merges organic phase, with saturated aqueous common salt (15ml × 2) wash, anhydrous sodium sulfate drying, and filtering, filtrate decompression is evaporated off solvent, and residue is through column chromatography (petroleum ether/acetic acid Ethyl ester, 4: 1, v/v) 0.76g white solid III-3 are purified to obtain, it is dissolved in 14mL mixed solvents (THF/MeOH/H2O, 3: 3: 1, v/ V/v), LiOH (0.1g, 3.99mmol), room temperature reaction 8h are added, is removed under reduced pressure and 1N is added dropwise under tetrahydrofuran and methyl alcohol, ice-water bath Watery hydrochloric acid adjusts PH 2-3, separates out white solid, suction filtration, dry white powdery solids I-120.61g, fusing point 155-157 DEG C, yield 80.3%.
1H NMR (300MHz, DMSO-d6)δ：8.02-7.82 (m, 4H), 7.57-7.44 (m, 3H), 7.28 (d, J= 8.8Hz, 2H), 5.46 (s, 2H), 4.43 (s, 2H), 2.47 (s, 3H)13C NMR (75MHz, DMSO-d6)δ：165.77, 163.98,161.83,151.83,132.61,131.42,130.40,129.22,125.98,115.20,62.02,60.29, 15.00.ESI-MS m/z：358.1[M-45]-.Anal.calcd.For C19H17NO5S2：C, 56.56；H, 4.25；N, 3.47； Found：C, 56.50；H, 4.26；N, 3.46.
Embodiment 17
2- ((4- ((4- methyl -2- (3- aminomethyl phenyls) thiazole -5- bases) methoxyl group) phenyl) sulfonyl) acetic acid (I-13)
The same I-12 of synthetic method, obtains white solid 0.25g, 122-124 DEG C of fusing point, yield 69%.
1H NMR (300MHz, DMSO-d6)δ：13.22 (s, 1H), 7.87 (d, J=8.9Hz, 2H), 7.78-7.66 (m, 2H), (s, the 3H) of 7.41-7.24 (m, 4H), 5.45 (s, 2H), 4.44 (s, 2H), 2.46 (s, 3H), 2.3713C NMR (75MHz, DMSO-d6)δ：164.56,162.34,152.45,139.08,133.25,131.49,130.89,129.60,126.78, 123.66,115.66,114.99,69.76,62.51,21.32,15.57.ESI-MS m/z：372.1[M-45]- .Anal.calcd.For C20H19NO5S2：C, 57.54；H, 4.59；N, 3.36；Found：C, 57.57；H, 4.58；N, 3.36.
Embodiment 18
2- ((4- ((2- (2- fluorophenyls) -4- methylthiazol -5- bases) methoxyl group) phenyl) sulfonyl) acetic acid (I-14)
The same I-12 of synthetic method, obtains white solid 0.18g, 195-196 DEG C of fusing point, yield 60%.
1H NMR (300MHz, DMSO-d6)δ：13.18 (s, 1H), 7.88 (d, J=8.6Hz, 2H), 7.81-7.64 (m, 2H), 7.56,7.51 (dd, J=13.8,7.6Hz, 1H), 7.41-7.22 (m, 3H), 5.47 (s, 2H), 4.42 (s, 2H), 2.47 (s, 3H)13C NMR (75MHz, DMSO-d6)δ：164.07,161.84,160.78,152.15,131.43,130.41, 127.06,122.21,117.16,115.17,112.44,112.12,61.98,60.31,15.00.ESI-MS m/z：376.0 [M-45]-.Anal.calcd.For C19H16FNO5S2：C, 54.15；H, 3.83；N, 3.32；Found：C, 54.12；H, 3.83； N, 3.32.
Embodiment 19
2- ((4- ((2 '-isopropyl-[1,1 '-biphenyl] -3- bases) methoxyl group) phenyl) sulfonyl) acetic acid (I-15)
The same I-3 of synthetic method, obtains white solid 0.26g, 68-70 DEG C of fusing point, yield 74%.
1H NMR (300MHz, DMSO-d6)δ：7.85 (d, J=8.9Hz, 2H), 7.48 (d, J=4.4Hz, 2H), 7.40- 7.33 (m, 3H), 7.30-7.11 (m, 5H), 5.30 (s, 2H), 4.42 (s, 2H), 2.98-2.85 (m, 1H), 1.08 (d, J= 6.8Hz, 6H)13C NMR (75MHz, DMSO-d6)δ：164.59,162.37,147.35,141.23,136.78,132.05, 131.49,130.89,129.60,128.67,126.78,126.43,125.66,115.36,69.73,62.54,28.92, 23.57.ESI-MS m/z：379.1[M-45]-.Anal.calcd.For C24H24O5S：C, 67.90；H, 5.70；Found：C, 67.95；H, 5.71.
Embodiment 20
2- ((4- ((2- (3- chlorphenyls) -4- methylthiazol -5- bases) methoxyl group) phenyl) sulfonyl) acetic acid (I-16)
The same I-12 of synthetic method, obtains white solid 0.36g, 190-192 DEG C of fusing point, yield 64%.
1H NMR (300MHz, DMSO-d6)δ：13.26 (s, 1H), 8.03-7.80 (m, 4H), 7.65-7.42 (m, 2H), (s, the 2H) of 7.28 (d, J=7.7Hz, 2H), 5.48 (s, 2H), 4.4413C NMR (75MHz, DMSO-d6)δ：164.09, 161.83,152.22,134.69,133.95,131.50,131.19,130.42,129.99,125.19,124.75,115.19, 62.00,60.29,15.06.ESI-MS m/z：392.1[M-45]-.Anal.calcd.For C19H16ClNO5S2：C, 52.11； H, 3.68；N, 3.20；Found：C, 52.15；H, 3.67；N, 3.21.
Embodiment 21
2- ((4- ((2 ', 6 '-dimethyl -4- propoxyl group-[1,1 '-biphenyl] -3- bases) methoxyl group) phenyl) sulfonyl) second Sour (I-17)
The same I-3 of synthetic method, obtains white solid 0.31g, 103-105 DEG C of fusing point, yield 64%.
1H NMR (300MHz, DMSO-d6)δ：7.82 (d, J=8.5Hz, 2H), 7.56-7.37 (m, 2H), 7.26-7.04 (m, 4H), 6.68 (s, 2H), 5.27 (s, 2H), 4.19 (s, 2H), 3.93 (t, J=6.4Hz, 2H), 1.92 (s, 6H), 1.73 (dd, J=13.8,6.8Hz, 2H), 0.99 (t, J=7.3Hz, 3H)13C NMR (75MHz, DMSO-d6)δ：164.57, 162.01,157.36,140.44,136.48,133.41,130.28,129.11,128.65,126.02,114.89,113.18, 69.57,68.68,62.54,22.08,20.72,10.41.ESI-MS m/z：423.1[M-45]-.Anal.calcd.For C26H28O6S：C, 66.65；H, 6.02；Found：C, 66.68；H, 6.02.
Embodiment 22
2- ((4- ((4 '-ethyoxyl -2 ', 6 '-dimethyl-[1,1 '-biphenyl] -3- bases) methoxyl group) phenyl) sulfonyl) second Sour (I-18)
The same I-3 of synthetic method, obtains white solid 0.47g, 128-130 DEG C of fusing point, yield 78%.
1H NMR (300MHz, DMSO-d6)δ：7.82 (d, J=8.6Hz, 2H), 7.56-7.37 (m, 2H), 7.34-7.02 (m, 4H), 6.68 (s, 2H), 5.27 (s, 2H), 4.20 (s, 2H), 4.02 (q, J=6.7Hz, 2H), 1.92 (s, 6H), 1.31 (t, J=6.7Hz, 3H)13C NMR (75MHz, DMSO-d6)δ：163.90,162.08,157.18,140.43,136.48, 136.38,133.40,131.63,130.27,129.10,128.78,128.66,126.03,115.43,114.95,113.14, 69.57,62.71,61.55,20.72,14.71.ESI-MS m/z：409.1[M-45]-.Anal.calcd.For C25H26O6S： C, 66.06；H, 5.77；Found：C, 66.09；H, 5.76.
Embodiment 23
2- (4- (2,6- dimethyl -4- (3- (methyl sulphonyl) propoxyl group)-[1,1 '-xenyl] -3- bases) methoxyl group) Phenyl) sulfonyl) acetic acid (I-19)
The same I-3 of synthetic method, obtains white solid 0.38g, 117-119 DEG C of fusing point, yield 73%.
1H NMR (300MHz, DMSO-d6)δ：7.82 (d, J=8.1Hz, 2H), 7.56-7.40 (m, 2H), 7.36-7.03 (m, 5H), 6.71 (s, 2H), 5.26 (s, 2H), 4.18 (s, 2H), 4.09 (t, J=5.9Hz, 2H), 3.37-3.20 (m, 2H), (s, the 6H) of 3.03 (s, 3H), 2.27-2.09 (m, 2H), 1.9213C NMR (75MHz, DMSO-d6)δ：164.20,162.53, 156.78,140.81,137.08,134.26,132.17,130.78,129.16,126.59,115.40,113.75,70.04, 65.84,62.06,51.00,40.67,22.51,21.22.ESI-MS m/z：501.1[M-45]-.Anal.calcd.For C27H30O8S2：C, 59.32；H, 5.53；Found：C, 59.36；H, 5.52.
Embodiment 24
2- ((4- ((4 '-isobutyl group -2 ', 6 '-dimethyl-[1,1 '-biphenyl] -3- bases) methoxyl group) phenyl) sulfonyl) second Sour (I-20)
The same I-3 of synthetic method, obtains white solid 0.32g, 113-115 DEG C of fusing point, yield 67%.
1H NMR (300MHz, DMSO-d6)δ：7.82 (d, J=8.0Hz, 2H), 7.46 (d, J=7.7Hz, 2H), 7.30- 7.00 (m, 4H), 6.69 (s, 2H), 5.27 (s, 2H), 4.08 (s, 2H), 3.74 (d, J=6.2Hz, 2H), 1.92 (s, 6H), 1.39-1.16 (m, 1H), 0.99 (d, J=6.4Hz, 6H)13C NMR (75MHz, DMSO-d6)δ：162.01,157.47, 140.44,136.47,136.38,133.40,132.69,129.10,128.69,125.96,115.42,113.20,73.52, 69.57,43.90,27.71,20.66,19.03.ESI-MS m/z：437.1[M-45]-.Anal.calcd.For C27H30O6S： C, 67.20；H, 6.27；Found：C, 67.25；H, 6.28.
Embodiment 25
2- ((4- (4 '-(2- methoxy ethoxies) -2 ', 6 '-dimethyl-[1,1 '-biphenyl -3- base] methoxyl group) phenyl) Sulfonyl) acetic acid (I-21)
The same I-3 of synthetic method, obtains white solid 0.23g, 107-109 DEG C of fusing point, yield 60%.
1H NMR (300MHz, DMSO-d6)δ：7.82 (d, J=8.0Hz, 2H), 7.43 (d, J=7.7Hz, 2H), 7.31- 7.00 (m, 4H), 6.70 (s, 2H), 5.24 (s, 2H), 4.05 (d, J=14.0Hz, 7H), 3.64 (s, 2H), 1.91 (s, 6H) .13C NMR (75MHz, DMSO-d6)δ：164.25,162.33,157.61,140.87,137.02,130.73,129.13, 126.51,115.27,114.99,113.66,70.89,67.13,58.61,21.22.ESI-MS m/z：439.1[M-45]- .Anal.calcd.For C26H28O7S：C, 64.45；H, 5.82；Found：C, 64.41；H, 5.81.
Embodiment 26
3- (3,5- dimethyl isoxazole -4- bases) benzaldehyde
By 3,5- dimethyl isoxazole -4- pinacol borates (0.4g, 2.67mmol), 3- bromobenzaldehydes (0.54g, 2.67mmol) be dissolved in 21ml mixed solvents (water/ethanol/toluene, 3: 1: 3, v/v), sequentially add sodium carbonate (0.71g, 6.67mmol), Pd (PPh3) 4 (0.09g, 0.08mmol), gained mixed liquor reacts 24h for 80 DEG C in the lower heating of nitrogen protection, cold But to room temperature, the 20ml that adds water dilutions are laid the groundwork suction filtration with diatomite, ethyl acetate (15ml × 3) washing filter cake, and filtrate is with acetic acid Ethyl ester (30ml × 4) is extracted, and is merged organic phase and is washed with saturation NaCl solution (20ml × 2), and gained organic phase is with anhydrous slufuric acid Sodium is dried, and suction filtration, filtrate decompression is evaporated off solvent, and residue is purified through column chromatography (petrol ether/ethyl acetate, 70: 30, v/v) To pale solid 0.38g, yield 71%.
1H NMR (300MHz, DMSO-d6) δ：10.08 (s, 1H), 7.99-7.85 (m, 2H), 7.81-7.63 (m, 2H), 2.43 (s, 3H), 2.25 (s, 3H)
Embodiment 27
2- (4- (3- (3,5- bis- Jia Ji oxazole -4- bases) phenoxy group) phenyl) sulfonyl) acetic acid (I-26)
Raw material II -1 (0.2g, 0.99mmol) is dissolved in the solution of (THF/MeOH, 1: 1, v/v) in 20ml mixed solvents, Sodium borohydride (0.05g, 1.2mmol) is dividedly in some parts under ice bath, after reaction terminates under ice bath, plus 20ml water quenchings are gone out reaction, acetic acid Ethyl ester extraction (30ml × 3) is merged organic phase and is washed with saturation NaCl solution (20ml × 2), and gained organic phase is with anhydrous sodium sulfate Dry, suction filtration, filtrate decompression is evaporated off solvent, not purified to be directly used in the next step.The compound that upper step is obtained is dissolved in 20ml In dichloromethane, 0.5ml thionyl chlorides are slowly dropped into, add 1 to drip DMF, 25 DEG C of heating responses, reaction removes under reduced pressure molten after terminating Agent obtains pale yellow oil II-2.II-2 (0.2g, 0.90mmol) is dissolved in 20ml acetonitriles, addition raw material II -3 (0.25g, 1.08mmol), Anhydrous potassium carbonate (0.5g, 3.62mmol), catalytic amount KI, are heated to 60 DEG C of reaction 8h, and filtering is removed under reduced pressure molten Agent, residue is dissolved in 30ml water, ethyl acetate (20ml × 3) extraction, merges organic phase, with saturated aqueous common salt (15ml × 2) Washing, anhydrous sodium sulfate drying, filtering, filtrate decompression is evaporated off solvent, residue through column chromatography (petrol ether/ethyl acetate, 4: 1, V/v 0.26g white solid II-4) are purified to obtain, (THF/MeOH/H in 14mL mixed solvents is dissolved in2O, 3: 3: 1, v/v/v), add LiOH (0.07g, 2.79mmol), room temperature reaction 8h, remove tetrahydrofuran and methyl alcohol under reduced pressure, 1N watery hydrochloric acid is added dropwise under ice-water bath and adjusts Section PH 2-3, separate out white solid, suction filtration, dry white powdery solids I-26 0.2g, 125-126 DEG C of fusing point, yield 56%.
1H NMR (300MHz, DMSO-d6)δ：7.53-7.30 (m, 4H), 7.10 (d, J=7.9Hz, 1H), 6.55-6.42 (m, 2H), 5.10 (s, 2H), 4.66 (t, J=9.0Hz, 1H), 4.21-4.12 (m, 1H), 3.68-3.64 (m, 1H), 2.71, (s, the 3H) of 2.66 (dd, J=16.6,5.5Hz, 1H), 2.49-2.40 (m, 1H), 2.36 (s, 3H), 2.1913C NMR (75MHz, DMSO-d6)δ：173.00,165.13,160.65,158.99,158.04,137.81,129.87,128.94,128.65, 128.13,127.92,126.64,124.59,121.99,117.74,115.68,106.84,96.80,77.08,68.98, 40.19,37.04,11.22,10.36.ESI-MS m/z：378.1[M-H]-Anal.calcd.For C22H21NO5：C, 69.65； H, 5.58；N, 3.69；Found：C, 69.61；H, 5.57；N, 3.68.
Embodiment 28
2- (4- (5- (3,5- bis- Jia Ji oxazole -4- bases) -2- methyl) epoxide) phenyl) sulfonyl) acetic acid (I-22)
The same I-26 of synthetic method, obtains white solid 0.48g, 88-90 DEG C of fusing point, yield 67%.
1H NMR (300MHz, DMSO-d6)δ：13.29 (s, 1H), 7.86 (d, J=7.9Hz, 2H), 7.55-7.22 (m, 5H), (s, the 3H) of 5.28 (s, 2H), 4.43 (s, 2H), 2.37 (s, 3H), 2.35 (s, 3H), 2.1813C NMR (75MHz, DMSO- d6)δ：164.59,162.89,137.90,135.17,133.00,131.26,131.21,130.88,130.38,129.52, 128.08,115.58,68.67,60.79,18.67,11.71,10.88.ESI-MS m/z：370.1[M-45]- .Anal.calcd.For C21H21NO6S：C, 60.71；H, 5.10；N, 3.37；Found：C, 60.75；H, 5.11；N, 3.37.
Embodiment 29
2- (4- (3- (3,5- bis- Jia Ji oxazole -4- bases) -2- methyl) epoxide) phenyl) sulfonyl) acetic acid (I-23)
The same I-26 of synthetic method, obtains white solid 0.36g, 86-88 DEG C of fusing point, yield 78%.
1H NMR (300MHz, DMSO-d6)δ：7.87 (d, J=8.9Hz, 2H), 7.53 (d, J=7.4Hz, 1H), 7.36- (s, the 3H) of 7.15 (m, 4H), 5.28 (s, 2H), 4.42 (s, 2H), 2.21 (s, 3H), 2.13 (s, 3H), 2.0313C NMR (75MHz, DMSO-d6)δ：165.72,164.53,162.96,159.22,136.65,135.62,131.29,130.90, 130.10,129.27,126.37,115.53,113.25,69.24,60.88,15.78,11.60,10.62.ESI-MS m/z： 370.1[M-45]-.Anal.calcd.For C21H21NO6S：C, 60.71；H, 5.10；N, 3.37；Found：C, 60.78；H, 5.11；N, 3.37.
Embodiment 30
2- ((4- ((the chloro- 3- of 4- (3,5- bis- Jia Ji oxazole -4- bases) benzyl) epoxide) phenyl) sulfonyl) acetic acid (I-24)
The same I-26 of synthetic method, obtains white solid 0.34g, 111-113 DEG C of fusing point, yield 53%.
1H NMR (300MHz, DMSO-d6)δ：7.84 (d, J=8.8Hz, 2H), 7.65 (d, J=8.2Hz, 1H), 7.60- (s, the 3H) of 7.48 (m, 2H), 7.23 (d, J=8.9Hz, 2H), 5.27 (s, 2H), 4.31 (s, 2H), 2.25 (s, 3H), 2.0713C NMR (75MHz, DMSO-d6)δ：166.20,163.98,162.01,158.55,135.89,132.91,131.67,131.51, 130.38,129.90,129.54,128.46,115.02,113.82,68.57,60.93,11.29,10.13.ESI-MS m/z： 390.1[M-45]-.Anal.calcd.For C20H18ClNO6S：C, 55.11；H, 4.16；Cl, 8.13；N, 3.21；Found：C, 55.15；H, 4.15；Cl, 8.12；N, 3.21.
Embodiment 31
2- (4- (3- (2- methyl isophthalic acid H- pyrroles -1- bases) phenoxy group) phenyl) sulfonyl) acetic acid (I-25)
The same I-3 of synthetic method, obtains white solid 0.17g, 110-112 DEG C of fusing point, yield 56%.
1H NMR (300MHz, DMSO-d6)δ：7.90-7.80 (m, 3H), 7.57-7.52 (m, 2H), 7.28-7.22 (m, 3H), (s, the 6H) of 5.80 (s, 2H), 5.31 (s, 2H), 4.33 (s, 2H), 1.9413C NMR (75MHz, DMSO-d6)δ： 164.01,162.13,138.39,137.59,131.39,130.35,129.46,127.48,127.10,126.91,115.07, 106.00,69.02,60.80,12.81.ESI-MS m/z：354.1[M-45]-.Anal.calcd.For C21H21NO5S：C, 63.14；H, 5.30；N, 3.51；Found：C, 63.11；H, 5.31；N, 3.51.
Embodiment 32
2- ((4- ((2- (4- fluorophenyls) -4- methylthiazol -5- bases) methoxyl group) phenyl) sulfonyl) acetic acid (I-27)
The same I-12 of synthetic method, obtains white solid 0.27g, 175-177 DEG C of fusing point, yield 76%.
1H NMR (300MHz, DMSO-d6)δ：8.02-7.84 (m, 4H), 7.38-7.24 (m, 4H), 5.45 (s, 2H), 4.43 (s, 2H), 2.46 (s, 3H)13CNMR (75MHz, DMSO-d6)δ：164.09,161.85,152.04,131.42, 130.41,129.46,128.31,128.19,126.29,116.37,116.08,115.17,61.98,60.27, 15.03.ESI-MS m/z：376.0[M-45]-.Anal.calcd.For C19H16FNO5S2：C, 54.15；H, 3.83；F, 4.51；N, 3.32；Found：C, 54.11；H, 3.83；F, 4.51；N, 3.32.
Embodiment 33
2- ((4- ((4 '-methoxyl group -2 ', 6 '-dimethyl-[1,1 '-biphenyl] -3- bases) methoxyl group) phenyl) sulfonyl) third Sour (I-28)
The same I-3 of synthetic method, obtains white solid 0.31g, 106-108 DEG C of fusing point, yield 59%.
1H NMR (300MHz, DMSO-d6)δ：7.76 (d, J=8.1Hz, 2H), 7.55-7.37 (m, 2H), 7.29-7.02 (m, 4H), 6.69 (s, 2H), 5.26 (s, 2H), 4.11-3.97 (m, 1H), 3.74 (s, 3H), 1.92 (s, 6H), 1.30 (d, J= 6.4Hz, 3H)13C NMR (75MHz, DMSO-d6)δ：167.22,162.17,157.92,140.41,136.52,136.38, 133.52,131.09,129.58,129.11,128.79,128.66,126.09,114.90,112.63,69.57,65.70, 54.86,20.73,12.32.ESI-MS m/z：409.1[M-45]-.Anal.calcd.For C25H26O6S：C, 66.06；H, 5.77；Found：C, 66.02；H, 5.76.
Embodiment 34
2- ((4- ((the chloro- 5- of 2- (3,5- bis- Jia Ji oxazole -4- bases) benzyl) epoxide) phenyl) sulfonyl) acetic acid (I-29)
The same I-26 of synthetic method, obtains white solid 0.26g, 73-74 DEG C of fusing point, yield 60%.
1H NMR (300MHz, DMSO-d6)δ：7.96-7.82 (m, 2H), 7.68-7.54 (m, 2H), 7.51-7.27 (m, 3H), (s, the 3H) of 5.34 (s, 2H), 4.40 (s, 2H), 2.36 (s, 3H), 2.1913C NMR (75MHz, DMSO-d6)δ： 165.56,164.07,162.09,157.99,133.99,132.12,131.42,130.74,130.46,129.98,129.13, 115.03,114.68,67.21,60.44,11.24,10.31.ESI-MSm/z：390.0[M-45]-.Anal.calcd.For C20H18ClNO6S：C, 55.11；H, 4.16；C1,8.13；N, 3.21；Found：C, 55.14；H, 4.16；Cl, 8.12；N, 3.21.
Embodiment 35
2- ((3- ([1,1 '-biphenyl] -4- methoxyl groups) phenyl) sulfonyl) acetic acid (I-30)
The same I-3 of synthetic method, obtains white solid 0.19g, 63-65 DEG C of fusing point, yield 57%.
1H NMR (300MHz, DMSO-d6)δ：7.73-7.66 (m, 4H), 7.61-7.37 (m, 9H), 5.25 (s, 2H), 4.56 (s, 2H)13C NMR (75MHz, DMSO-d6)δ：163.90,158.43,140.56,139.89,139.70,135.48, 130.45,128.94,128.46,128.12,127.53,126.79,126.66,120.59,120.18,113.72,69.48, 59.78.ESI-MS m/z：337.1[M-45]-.Anal.calcd.For C21H18O5S：C, 65.95；H, 4.74；Found：C, 65.91；H, 4.73.
Embodiment 36
2- ((3- ((2 '-methyl-[1,1 '-biphenyl -4- methoxyl group])) phenyl) sulfonyl) acetic acid (I-31)
The same I-3 of synthetic method, obtains white solid 0.23g, 113-115 DEG C of fusing point, yield 69%.
1H NMR (300MHz, DMSO-d6)δ：7.72-7.50 (m, 5H), 7.47-7.35 (m, 3H), 7.33-7.13 (m, 4H), (s, the 3H) of 5.25 (s, 2H), 4.53 (s, 2H), 2.2413C NMR (75MHz, DMSO-d6)δ：163.94,158.52, 141.05,140.84,140.59,134.89,134.68,130.45,130.33,129.47,129.08,127.79,127.36, 125.94,120.58,120.20,113.64,69.63,59.87,20.13.ESI-MS m/z：351.1[M-45]- .Anal.calcd.For C22H20O5S：C, 66.65；H, 5.09；Found：C, 66.60；H, 5.08.
Embodiment 37
2- ((4- ((3- phenoxy groups) epoxide) phenyl) sulfonyl) acetic acid (I-32)
The same I-1 of synthetic method, obtains white solid 0.20g, 73-75 DEG C of fusing point, yield 67%.
1H NMR (300MHz, DMSO-d6)δ：7.85 (d, J=8.8Hz, 2H), 7.43,7.38 (dd, J=14.7, 7.4Hz, 3H), 7.30-7.10 (m, 5H), 7.04-6.92 (m, 3H), 5.22 (s, 2H), 4.40 (s, 2H)13C NMR (75MHz, DMSO-d6)δ：164.09,162.23,156.84,156.33,138.45,131.16,130.38,130.21,130.06, 123.61,122.61,118.75,118.01,117.62,115.06,69.18,60.46.ESI-MS m/z：353.1[M- 45]-.Anal.calcd.For C21H18O6S：C, 63.31；H, 4.55；Found：C, 63.34；H, 4.56.
Embodiment 38
1- ((4- ((4 '-methoxyl group -2 ', 6 '-dimethyl-[1,1 '-biphenyl] -3- bases) methoxyl group) phenyl) sulphonyl)-ring Propane-acetic acid (I-33)
The same I-3 of synthetic method, obtains white solid 0.12g, 106-108 DEG C of fusing point, yield 73%.
1H NMR (300MHz, DMSO-d6)δ：7.88 (d, J=8.5Hz, 2H), 7.46 (d, J=6.8Hz, 2H), 7.30- 7.04 (m, 4H), 6.69 (s, 2H), 5.28 (s, 2H), 3.74 (s, 3H), 1.91 (s, 6H), 1.82-1.71 (m, 2H), 1.64- 1.50 (m, 2H)13C NMR (75MHz, DMSO-d6)δ：167.75,162.14,157.93,140.40,136.51,136.39, 133.52,131.20,129.09,128.76,128.66,126.06,114.88,112.64,69.56,54.86,43.70, 20.69,15.51.ESI-MS m/z：421.1[M-45]-.Anal.calcd.For C26H26O6S：C, 66.94；H, 5.62； Found：C, 66.96；H, 5.61.
Embodiment 39
2- ((4- ((4 '-methoxyl group -2 ', 6 '-dimethyl-[1,1 '-biphenyl] -3- bases) methoxyl group) phenyl) sulfonyl) - 2 Methylpropionic acid (I-34)
The same I-3 of synthetic method, obtains white solid 0.18g, 143-145 DEG C of fusing point, yield 62%.
1H NMR (300MHz, DMSO-d6)δ：7.73 (d, J=8.5Hz, 2H), 7.45 (d, J=6.8Hz, 2H), 7.37- (s, the 6H) of 7.00 (m, 4H), 6.69 (s, 2H), 5.28 (s, 2H), 3.74 (s, 3H), 1.91 (s, 6H), 1.4313C NMR (75MHz, DMSO-d6)δ：169.72,162.57,157.93,140.43,136.51,132.30,129.16,128.83, 126.16,114.90,112.65,69.62,54.87,43.70,20.71,19.99.ESI-MS m/z：423.1[M-45]- .Anal.calcd.For C26H28O6S：C, 66.65；H, 6.02；Found：C, 66.68；H, 6.03.
Embodiment 40
2- ((4- ((4 '-methoxyl group -2 ', 6 '-dimethyl-[1,1 '-biphenyl] -3- bases) methoxyl group) phenyl) sulfonyl) fourth Sour (I-35)
The same I-3 of synthetic method, obtains white solid 0.43g, 100-102 DEG C of fusing point, yield 53%.
1H NMR (300MHz, DMSO-d6)δ：7.76 (d, J=8.4Hz, 2H), 7.46 (d, J=6.5Hz, 2H), 7.35- 7.05 (m, 4H), 6.69 (s, 2H), 5.28 (s, 2H), 4.09 (t, J=6.9Hz, 1H), 3.73 (s, 3H), 1.91 (s, 6H), 1.83-1.67 (m, 2H), 0.88 (t, J=6.8Hz, 3H)13C NMR (75MHz, DMSO-d6)δ：166.72,162.57, 157.93,140.43,136.52,136.29,133.52,131.11,129.14,128.93,128.79,128.69,126.13, 115.22,114.50,112.65,71.15,69.66,54.88,20.71,20.34,10.97.ESI-MS m/z：423.1[M- 45]-.Anal.calcd.For C26H28O6S：C, 66.65；H, 6.02；Found：C, 66.63；H, 6.01.
Embodiment 41
Tablet containing activating agent I-3：
By the sieving of active component, pregelatinized starch and microcrystalline cellulose, it is sufficiently mixed, adds polyvinylpyrrolidone molten Liquid, mixing, softwood processed, sieving, wet granular processed, in 50-60 DEG C of drying, by Sodium carboxymethyl starch, magnesium stearate and talcum powder Sieving is added to compression molding in above-mentioned particle.
Empirical tests, above-mentioned composition also has excellent internal hypoglycemic activity.

Claims (8)

1. the compound and pharmaceutically acceptable ester or its pharmaceutically useful salt shown in a kind of logical formula (I)：
Wherein：
Ring A is selected from aryl or heteroaryl；
Ring B is selected from aryl or heteroaryl；
R1, R2And R3Be each independently selected from hydrogen, halogen, cyano group, alkyl, alkoxy, cycloalkyl, wherein the alkyl, cycloalkyl, Alkoxy is optionally further replaced by one or more groups selected from halogen, cyano group, alkyl, alkoxy, cycloalkyl；
R4Selected from hydrogen, alkyl, halogen；
R5And R6Selected from hydrogen, alkyl, cycloalkyl；
R7Selected from hydrogen, alkyl.
2. claim 1 is defined has the compound and pharmaceutically acceptable ester or its pharmaceutically useful salt for leading to formula (I)：
Wherein：
Ring A preferably is selected from phenyl ring, pyrrole ring or isozole ring；
Ring B preferably is selected from phenyl ring, thiphene ring；
R1, R2And R3Be each independently selected from hydrogen, halogen, cyano group, alkyl, alkoxy, cycloalkyl, wherein the alkyl, cycloalkyl, Alkoxy is optionally further replaced by one or more groups selected from halogen, cyano group, alkyl, alkoxy, cycloalkyl；
R4Selected from hydrogen, alkyl, halogen；
R5And R6Selected from hydrogen, alkyl, cycloalkyl；
R7Selected from hydrogen, alkyl.
3. claim 2 is defined has the compound and pharmaceutically acceptable ester or its pharmaceutically useful salt for leading to formula (I)：
Ring A preferably is selected from phenyl ring, pyrrole ring or isozole ring；
Ring B preferably is selected from phenyl ring, thiphene ring；
R1, R2And R3It is each independently selected from hydrogen, halogen, cyano group, C1-C4Alkyl, C1-C4Alkoxy, cycloalkyl, wherein the alkyl, Cycloalkyl, alkoxy are optionally further taken by one or more groups selected from halogen, cyano group, alkyl, alkoxy, cycloalkyl Generation；
R4Selected from hydrogen, methyl, halogen；
R5And R6Selected from hydrogen, C1-C2Alkyl, cyclopropyl；
R7Selected from hydrogen, alkyl.
4. claim 3 is defined has the compound and pharmaceutically acceptable ester or its pharmaceutically useful salt for leading to formula (I)：
Wherein：
Ring A preferably be selected from phenyl ring or：
Ring B preferably be selected from phenyl ring or：
R1, R2And R3It is each independently selected from hydrogen, F, Cl, cyano group, C1-C4Alkyl, C1-C4Alkoxy, cycloalkyl, wherein the alkyl, Cycloalkyl, alkoxy are optionally further selected from F, cyano group, C by one or more1-C4Alkyl, C1-C4The base of alkoxy, cycloalkyl Group is replaced；
R4Selected from hydrogen, methyl, Cl；
R5And R6Selected from hydrogen, C1-C2Alkyl, cyclopropyl；
R7Selected from hydrogen, alkyl.
5. claim 4 is defined has the compound and pharmaceutically acceptable ester or its pharmaceutically useful salt for leading to formula (I)：
Wherein：
Ring A preferably be selected from phenyl ring or：
Ring B preferably be selected from phenyl ring or：
R1, R2And R3Be each independently selected from hydrogen, F, Cl, cyano group, trifluoromethyl, propyl group, isopropyl, methoxyl group, the methoxyl group of ring third, Ethyoxyl, propoxyl group, isobutoxy, 3- methyl sulphonyls propoxyl group, 2- methoxy ethoxies；
R4Selected from hydrogen, methyl, Cl；
R5And R6Selected from hydrogen, methyl, ethyl, cyclopropyl；
R7Selected from hydrogen, methyl.
6. formula (I) compound and pharmaceutically acceptable ester or its pharmaceutically useful salt, the chemical combination are led to defined in claim 4 Thing is selected from：
2- ((4- ((2 '-chloro- [1,1 '-biphenyl] -3- bases) methoxyl group) phenyl) sulfonyl) methyl acetate；
2- ((4- ([1,1 '-biphenyl] -3- methoxyl groups) phenyl) sulfonyl) acetic acid；
2- ((4- ((2 '-chloro- [1,1 '-biphenyl] -3- bases) methoxyl group) phenyl) sulfonyl) acetic acid；
2- ((4- ((2 ', 6 '-dimethyl-[1,1 '-biphenyl] -3- bases) methoxyl group) phenyl) sulfonyl) acetic acid；
2- ((4- ((2 '-methyl-[1,1 '-biphenyl] -3- bases) methoxyl group) phenyl) sulfonyl) acetic acid；
2- ((4- (2 '-methoxyl group-(1,1 '-biphenyl -3- base) methoxyl group) phenyl) sulfonyl) acetic acid；
2- ((4- ((4 '-(methoxyl group of ring third) 2 ', 6 '-dimethyl-[1,1 '-biphenyl] -3- bases) methoxyl group) phenyl) sulfonyl) Acetic acid；
2- ((4- ((2 '-fluoro- [1,1 '-biphenyl] -3- bases) methoxyl group) phenyl) sulfonyl) acetic acid；
2- ((4- ((2 '-(trifluoromethyl)-[1,1 '-biphenyl] -3- bases) methoxyl group) phenyl) sulfonyl) acetic acid；
2- ((4- ((4 '-methoxyl group -2 ', 6 '-dimethyl-[1,1 '-biphenyl] -3- bases) methoxyl group) phenyl) sulfonyl) acetic acid；
2- ((4- ((2 '-cyano group-[1,1 '-biphenyl] -3- bases) methoxyl group) phenyl) sulfonyl) acetic acid；
2- ((4- ((4- methyl -2- phenyl thiazole -5- bases) methoxyl group) phenyl) sulfonyl) acetic acid；
2- ((4- ((4- methyl -2- (3- aminomethyl phenyls) thiazole -5- bases) methoxyl group) phenyl) sulfonyl) acetic acid；
2- ((4- ((2- (2- fluorophenyls) -4- methylthiazol -5- bases) methoxyl group) phenyl) sulfonyl) acetic acid；
2- ((4- ((2 '-isopropyl-[1,1 '-biphenyl] -3- bases) methoxyl group) phenyl) sulfonyl) acetic acid；
2- ((4- ((2- (3- chlorphenyls) -4- methylthiazol -5- bases) methoxyl group) phenyl) sulfonyl) acetic acid；
2- ((4- ((2 ', 6 '-dimethyl -4- propoxyl group-[1,1 '-biphenyl] -3- bases) methoxyl group) phenyl) sulfonyl) acetic acid；
2- ((4- ((4 '-ethyoxyl -2 ', 6 '-dimethyl-[1,1 '-biphenyl] -3- bases) methoxyl group) phenyl) sulfonyl) acetic acid；
2- (4- (2,6- dimethyl -4- (3- (methyl sulphonyl) propoxyl group)-[1,1 '-xenyl] -3- bases) methoxyl group) phenyl) Sulfonyl) acetic acid；
2- ((4- ((4 '-isobutyl group -2 ', 6 '-dimethyl-[1,1 '-biphenyl] -3- bases) methoxyl group) phenyl) sulfonyl) acetic acid；
2- ((4- (4 '-(2- methoxy ethoxies) -2 ', 6 '-dimethyl-[1,1 '-biphenyl -3- base] methoxyl group) phenyl) sulphonyl Base) acetic acid；
2- (4- (5- (3,5- bis- Jia Ji oxazole -4- bases) -2- methyl) epoxide) phenyl) sulfonyl) acetic acid；
2- (4- (3- (3,5- bis- Jia Ji oxazole -4- bases) -2- methyl) epoxide) phenyl) sulfonyl) acetic acid；
2- ((4- ((the chloro- 3- of 4- (3,5- bis- Jia Ji oxazole -4- bases) benzyl) epoxide) phenyl) sulfonyl) acetic acid；
2- (4- (3- (2- methyl isophthalic acid H- pyrroles -1- bases) phenoxy group) phenyl) sulfonyl) acetic acid；
2- (4- (3- (3,5- bis- Jia Ji oxazole -4- bases) phenoxy group) phenyl) sulfonyl) acetic acid；
2- ((4- ((2- (4- fluorophenyls) -4- methylthiazol -5- bases) methoxyl group) phenyl) sulfonyl) acetic acid；
2- ((4- ((4 '-methoxyl group -2 ', 6 '-dimethyl-[1,1 '-biphenyl] -3- bases) methoxyl group) phenyl) sulfonyl) propionic acid；
2- ((4- ((the chloro- 5- of 2- (3,5- bis- Jia Ji oxazole -4- bases) benzyl) epoxide) phenyl) sulfonyl) acetic acid；
2- ((3- ([1,1 '-biphenyl] -4- methoxyl groups) phenyl) sulfonyl) acetic acid；
2- ((3- ((2 '-methyl-[1,1 '-biphenyl -4- methoxyl group])) phenyl) sulfonyl) acetic acid；
2- ((4- ((3- phenoxy groups) epoxide) phenyl) sulfonyl) acetic acid；
1- ((4- ((4 '-methoxyl group -2 ', 6 '-dimethyl-[1,1 '-biphenyl] -3- bases) methoxyl group) phenyl) sulphonyl)-cyclopropane - Acetic acid；
2- ((4- ((4 '-methoxyl group -2 ', 6 '-dimethyl-[1,1 '-biphenyl] -3- bases) methoxyl group) phenyl) sulfonyl) -2- first Base propionic acid；
2- ((4- ((4 '-methoxyl group -2 ', 6 '-dimethyl-[1,1 '-biphenyl] -3- bases) methoxyl group) phenyl) sulfonyl) butyric acid.
7. a kind of pharmaceutical composition, containing one of claim 1-6 described compound and pharmaceutically acceptable ester or its can Pharmaceutical salts and appropriate carrier or excipient.
8. compound defined in claim 1-6 any one and pharmaceutically acceptable ester or its pharmaceutically useful salt or its medicine Purposes of the compositions in treatment diabetes and Metabolic syndrome disease drug is prepared.
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