CN104109115A - Phenylpropionic acid compounds chained by nitrogen-containing heterocyclic rings, pharmaceutical composition, preparation method, and application thereof - Google Patents

Phenylpropionic acid compounds chained by nitrogen-containing heterocyclic rings, pharmaceutical composition, preparation method, and application thereof Download PDF

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CN104109115A
CN104109115A CN201310132684.6A CN201310132684A CN104109115A CN 104109115 A CN104109115 A CN 104109115A CN 201310132684 A CN201310132684 A CN 201310132684A CN 104109115 A CN104109115 A CN 104109115A
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phenyl
oxygen
pyridine
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CN104109115B (en
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胡有洪
冷颖
李德文
宁萌萌
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Shanghai Institute of Materia Medica of CAS
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/64—One oxygen atom attached in position 2 or 6
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings

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Abstract

The invention belongs to the pharmacology field, and especially relates to phenylpropionic acid compounds chained by nitrogen-containing heterocyclic rings, pharmaceutically acceptable salts, stereoisomers, and prodrug molecules thereof, a preparation method, and an application of the compounds in preparation of drugs for treating diabetes and glucose and lipid metabolism disorder, especially drugs for treating II type diabetes. The compounds have prominent functions of reducing blood sugar and adjusting glucose and lipid metabolic activity. The phenylpropionic acid compounds chained by nitrogen-containing heterocyclic rings has a structure represented by the formula I.

Description

A kind of phenylpropionic acid compound, its pharmaceutical composition, preparation method and purposes of nitrogen heterocyclic ring link
Technical field
The invention belongs to field of pharmacology, be specifically related to acceptable salt, steric isomer or its prodrugs on the phenylpropionic acid compound, its pharmacology of a kind of nitrogen heterocyclic ring link, its pharmaceutical composition, preparation method, with and purposes in the medicine of preparation treatment diabetes and glycolipid metabolism disorder, especially in the purposes of the medicine of preparation treatment type II diabetes.Above-claimed cpd has function significant hypoglycemic and adjusting glycolipid metabolism activity.
Background technology
As everyone knows, diabetes are chronic diseases of ranking the 3rd serious threat human health after tumour, cardiovascular and cerebrovascular diseases.The report of the World Health Organization in 2011 points out that the whole world has 3.66 hundred million people to suffer from diabetes.In China, diabetic subject's total number of persons has exceeded 9,000 ten thousand, and also increases progressively with 3,500,000 to 4,000,000 people's amplitude every year.In view of the situation of current sternness, the medicine of development of new treatment diabetes is necessary.
Diabetes are divided into I type and type II diabetes according to the difference of the cause of disease, clinical manifestation and complication.The feature of insulin-dependent diabetes mellitus (IDDM) is to lack insulin secretion ability, is called insulin-dependent diabetes mellitus (IDDM), and type II diabetes is because self cannot effectively utilize Regular Insulin to cause, and is called non insulin dependent diabetes (NIDDM).Patients with NIDDM accounts for the more than 90% of global diabetes sum.The pathogenesis complexity of the diabetes of type II diabetes, its essential characteristic is that the tissues such as skeletal muscle, liver, fat produce opposing to Regular Insulin.Course of disease early stage patient beta Cell of islet can compensatory excreting insulin to offset the defect of insulin action, thereby maintain the normal glucose level of body.But, along with the development of the course of disease, beta Cell of islet insulin secretion function deficiency, patient's compensatory mechanism collapse, causes body glucose level extremely to raise, and then produces the disorderly type II diabetes that occurs of glycolipid metabolism in body.
In view of the morbidity of current diabetes, the situation is tense, and the medicine of exploitation treatment diabetes is extremely urgent.Mainly concentrate both ways for the new drug development of diabetes at present.On the one hand, drug development person expects on the basis of existing action target spot, to find more effectively and the medicine of new generation of low toxicity; Be the pathogenesis of active research diabetes on the other hand, find the novel target spot relevant with diabetes, and there is new drug brand-new mechanism of action, that there is independent intellectual property right for these novel targets designs.
GTP protein coupling receptor 40(GTP-binding protein coupling receptor40, GPR40) be seven transmembrane receptors.Expressed in abundance in pancreas islet also has expressed in addition in intestinal tract.Existing result of study shows, this transmembrane receptor may be relevant with metabolic disease with some cancer, neural class disease, especially diabetes.Research discovery, various forms of free fatty acidies (free fatty acid, FFA) are the native ligands of GPR40.FFA can amplify the insulin secretion that glucose stimulates by the GPR40 activating on beta Cell of islet film.In view of GPR40 receptor stimulant has the advantage of the promotion insulin secretion of dependence on the glucose, become the potential target spot for the treatment of diabetes.
Researched and developed the compound of multiple series for this target Ge great drugmaker and research institution.At present, reported that entering clinical compound has three, wherein the compound TAK-875 of Japanese TAKEDA company has entered III phase clinical experiment,
The LY-2881835 of Lilly Co., Eli. has entered I phase clinical experiment in Singapore; and the JTT-851 of Japanese tobacco company has also entered II phase clinical experiment in Japan; but do not announce the concrete structure of selected compound at present, and the compound general formula of the patent WO2009054479A1 of the said firm protection is as follows:
According to document (Expert Opin.Ther.Pat.2009,19,237-264; Bioorg.Med.Chem.Lett.2006,16,1840-1845; Bioorg.Med.Chem.Lett.2010,20,1298-1301; J.Med.Chem.2007,50,2807-2817.; Org.Process Res.Dev.2011,15,104-111.; ACS Med.Chem.Lett.2010,1,345-349.; J.Med.Chem.2008,51,7061-7064.; J.Med.Chem.2011,54,6691-6703.) report, as follows in the compound of preclinical study stage and announcement concrete structure formula at present:
Summary of the invention
The present invention relates to have the compound of structure shown in general formula I below, they are obviously different from the structure of reporting compound.Compound of the present invention has function significant hypoglycemic and adjusting glycolipid metabolism activity, is the novel GPR40 agonist of a class.
An object of the present invention is to provide the phenylpropionic acid compound shown in following general formula I or its pharmacy acceptable salt or its enantiomer, racemic modification and composition thereof or its steric isomer, or its prodrugs.
Another object of the present invention has been to provide the preparation method of the phenylpropionic acid compound shown in general formula I.
Another object of the present invention is to provide a kind of pharmaceutical composition, one or more and the pharmaceutically acceptable auxiliary material in the phenylpropionic acid compound shown in general formula I, its pharmacy acceptable salt, its enantiomer, racemic modification and composition thereof, its steric isomer and its prodrugs that be selected from that it comprises treatment significant quantity.
Another object of the present invention has been to provide one or more in the phenylpropionic acid compound that is selected from shown in general formula I, its pharmacy acceptable salt, its enantiomer, racemic modification and composition thereof, its steric isomer and its prodrugs purposes in the medicine of preparation treatment diabetes and glycolipid metabolism disorder.
A further object of the present invention is to provide a kind of method for the treatment of diabetes and glycolipid metabolism disorder, and it comprises to the object administration of this treatment of needs and is selected from one or more in the phenylpropionic acid compound shown in general formula I or its pharmacy acceptable salt, its enantiomer, racemic modification and composition thereof, steric isomer and its prodrugs.
One aspect of the present invention provides the compound of the phenylpropionic acid shown in general formula I:
（I）
Wherein,
X is H, D or F;
R 1and R 2independently be selected from separately H, hydroxyl, halogen, nitro, C 1-C 20alkyl, halo C 1-C 20alkyl, C 1-C 20alkoxyl group, halo C 1-C 20alkoxyl group, C 3-C 10cycloalkyl and contain 1 to 3 heteroatomic 3 to the 10 yuan of heterocyclic radical being selected from S, O and N; Be preferably selected from H, hydroxyl, halogen, nitro, C 1-C 6alkyl, halo C 1-C 6alkyl, C 1-C 6alkoxyl group, halo C 1-C 6alkoxyl group, C 3-C 8cycloalkyl and 3 to 10 yuan of heterocyclic radicals that contain at least one nitrogen-atoms; More preferably be selected from independently of one another H, hydroxyl, halogen, nitro, C 1-C 4alkyl, halo C 1-C 4alkyl, C 1-C 4alkoxyl group, halo C 1-C 4alkoxyl group, C 3-C 8cycloalkyl and ethylenimine-1-base;
R 3be selected from H; Halogen; Carboxyl; C 1-C 20alkyl; Halo C 1-C 20alkyl;-OR a;-N (R a) SO 2r b,-NR ar b;-N (R a) C (O) R b;-C (O) NR ar b;-SO 2r a;-SR b; With being selected from C 1-C 10alkoxyl group, C 3-C 10cycloalkyl ,-SR c,-SO 2r c,-NR cr dor do not replace or by C 1-C 6what alkyl, hydroxyl or oxo group replaced contains the C that the substituting group in the first heterocyclic radical of 1～3 heteroatomic 3-8 being selected from O, S and N replaces 1-C 20alkoxyl group; With use C 1-C 10alkoxyl group, C 3-C 10cycloalkyl ,-SR c,-SO 2r cor-NR cr dthe C replacing 1-C 20alkyl;
R 3be preferably selected from H; Halogen; Carboxyl; C 1-C 6alkyl; Halo C 1-C 6alkyl;-OR a;-N (R a) SO 2r b;-NR ar b;-N (R a) C (O) R b;-C (O) NR ar b;-SO 2r a;-SR b; With being selected from C 1-C 4alkoxyl group, C 3-C 8cycloalkyl ,-SR c,-SO 2r c,-NR cr dor do not replace or by C 1-C 4what alkyl, hydroxyl or oxo group replaced contains the C that the substituting group in the first heterocyclic radical of 1～3 heteroatomic 3-6 being selected from O, S and N replaces 1-C 6alkoxyl group; With use C 1-C 4alkoxyl group, C 3-C 8cycloalkyl ,-SR c,-SO 2r cor-NR cr dthe C replacing 1-C 6alkyl;
R 3further be preferably selected from H; Halogen; Carboxyl; C 1-C 6alkyl; Halo C 1-C 6alkyl;-OR a;-N (R a) SO 2r b;-NR ar b;-N (R a) C (O) R b;-C (O) NR ar b;-SO 2r a;-SR b; With being selected from C 1-C 4alkoxyl group, C 3-C 6cycloalkyl ,-SR c,-SO 2r c,-NR cr dor do not replace or by C 1-C 4what alkyl, hydroxyl or oxo group replaced contains the C that the substituting group in the first heterocyclic radical of 1～3 heteroatomic 3-6 being selected from O, S and N replaces 1-C 4alkoxyl group; With use C 1-C 4alkoxyl group, C 3-C 6cycloalkyl ,-SR c, SO 2r cor NR cr dthe C replacing 1-C 4alkyl;
Wherein,
R aand R bindependently be selected from separately H, C 1-C 6alkyl, C 3-C 8cycloalkyl and do not replace or by C 1-C 6what alkyl or oxo group replaced contains the first heterocyclic radical of 1～3 heteroatomic 3-8 being selected from O, S and N; Preferably independently be selected from separately H, C 1-C 4alkyl, C 3-C 6cycloalkyl and do not replace or by C 1-C 3what alkyl or oxo group replaced contains the first heterocyclic radical of 1～3 heteroatomic 3-6 being selected from O, S and N;
R cand R dbe selected from independently of one another H, C 1-C 6alkyl and do not replace or by C 1-C 3what alkyl replaced contains the first heterocyclic radical of 1～3 heteroatomic 3-8 being selected from O, S and N; Preferably be selected from independently of one another H, C 1-C 3alkyl and do not replace or by C 1-C 3what alkyl replaced contains the first heterocyclic radical of 1～3 heteroatomic 3-6 being selected from O, S and N;
R 4be selected from H, hydroxyl, halogen, C 1-C 20alkyl and halo C 1-C 20alkyl; Be preferably selected from H, hydroxyl, halogen, C 1-C 6alkyl and halo C 1-C 6alkyl,
R 5be selected from H, halogen and C 1-C 20alkyl; Be preferably selected from H, halogen and C 1-C 6alkyl;
Or R 4and R 5form benzo 5-8 unit heterocyclic radical together with the carbon atom being connected with it and phenyl ring, on described heterocycle, contain 1～3 heteroatoms being selected from O, N and S, and described heterocyclic radical is not substituted or by C 1-C 6alkyl replaces; Preferably R 4and R 5form 5 yuan of heterocyclic radicals of benzo together with the carbon atom being connected with it and phenyl ring, these 5 yuan of heterocyclic radicals contain 1～2 heteroatoms being selected from O, N and S, and are not substituted or by C 1-C 3alkyl replaces; Further preferably, R 4and R 5form together with the carbon atom being connected with it and phenyl ring
Further, the phenylpropionic acid compound shown in general formula I of the present invention has the structure shown in following general formula I I or general formula III:
Wherein, X, R 1～R 5definition same as described above; R 6for H or C 1-C 6alkyl, and in general formula III, in the time that Z is O or S, R 6do not exist.
In the present invention, term " halogen " comprises fluorine, chlorine, bromine and iodine.Term " halo " refers to the halogen atoms replacement being selected from fluorine, chlorine, bromine and iodine with single or multiple.
Term " C 1-C 20alkyl " refer to the straight or branched alkyl on main chain with 1 to 20 carbon atom, comprise without limitation methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl, amyl group, base, octyl group, decyl, undecyl, dodecyl, tetradecyl, hexadecyl, heptadecyl, octadecyl, eicosyl etc.Term " C 1-C 6alkyl " and " C 1-C 4alkyl " there is similar implication.
Term " C 1-C 20alkoxyl group " refer to the straight or branched alkoxyl group on main chain with 1 to 20 carbon atom, comprise without limitation methoxyl group, oxyethyl group, positive propoxy, isopropoxy, butoxy, pentyloxy, oxygen base, octyloxy, the last of the ten Heavenly stems oxygen base, undecane oxygen base, dodecyloxy, tetradecyloxyaniline, n-Hexadecane oxygen base, heptadecane oxygen base, octadecane oxygen base, eicosane oxygen base etc.Term " C 1-C 10alkoxyl group ", " C 1-C 6alkoxyl group " and " C 1-C 4alkoxyl group " there is similar implication.
Term " C 3-C 10cycloalkyl " refer to the cyclic alkyl on ring with 3 to 10 carbon atoms, comprise without limitation cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and suberyl; Term " C 3-C 8cycloalkyl " and " C 3-C 6cycloalkyl " there is similar implication.
Term " 3-8 unit heterocyclic radical " is on finger ring, to have the non-aromatic cyclic group that containing of 3-8 atom is selected from least one atom in N, O and S atom, as epoxy group(ing), pyrrolidyl, morpholinyl etc.; Term " 5-8 unit heterocyclic radical " and " 3-6 unit heterocyclic radical " have similar implication.
Term " pharmacy acceptable salt " in the present invention refers to according to mineral acids such as the compound shown in general formula I of the present invention and phosphoric acid, sulfuric acid, hydrochloric acid, or the organic acid such as acetic acid, tartrate, citric acid, oxysuccinic acid, fumaric acid, or the salt that forms of the acidic amino acid such as aspartic acid, L-glutamic acid, or after becoming ester or acid amides with above-mentioned acid again with the salt of mineral alkali formation, as sodium, potassium, calcium, aluminium salt and ammonium salt.
Compound of the present invention is preferably selected from following compounds:
Another aspect of the present invention discloses according to the preparation method of the phenylpropionic acid compound shown in general formula I of the present invention, and it one of is following method.
Method one: as shown in reaction formula 1 below:
Reaction formula 1
Step 1: by R 4replace to bromobenzyl alcohol 1 and ethyl propenoate 2, through Heck, reaction obtains intermediate 3, reduction is obtained to intermediate 4, then through bromination reaction, benzylalcohol is become to benzyl bromine and obtain intermediate 5; Described Heck reaction can be carried out under existing at the such as palladium metal catalyst such as palladium, tetrakis triphenylphosphine palladium or two (triphenylphosphine) palladium chloride in for example DMF or triethylamine equal solvent; Described double bond reduction reaction can use for example hydrogen to carry out as reductive agent under existing at for example palladium carbon composite catalyst in for example ethyl acetate, butylacetate, methyl alcohol, ethanol or n-propyl alcohol equal solvent; Described bromination reaction can use for example phosphorus tribromide, phosphorus pentabromide, and the bromizating agents such as tribromo oxygen phosphorus or dibromo sulfoxide are for example carrying out in acetonitrile, methylene dichloride or ether equal solvent;
Step 2: intermediate 5 and substrate 6 are obtained to intermediate 7 through nucleophilic substitution reaction; Described nucleophilic substitution reaction can carry out under the alkali such as such as salt of wormwood, cesium carbonate, sodium hydride, potassium hydride KH, potassium tert.-butoxide, sodium tert-butoxide or sodium hydroxide exist in the solvent of for example acetonitrile, DMF or tetrahydrofuran (THF);
Step 3: intermediate 7 Hes obtain intermediate 8 through Suzuki reaction coupling, then intermediate 8 is obtained to product 9 through hydrolysis reaction;
Described Suzuki reaction can be under the catalyzer such as such as tetrakis triphenylphosphine palladium, two (triphenylphosphine) palladium chloride, palladium or palladium carbon complex exist be carried out in mixed solvent, the mixed solvent of acetonitrile/water or the mixed solvent of ethanol/water of the mixed solvent of for example toluene/acetonitrile/water, toluene/ethanol/water; And the hydrolysis reaction of described centre 8 can be under the existence of the alkali such as such as potassium hydroxide, sodium hydroxide or lithium hydroxide in the solvent of for example acetonitrile/water mixed solvent, methanol/water mixed solvent or ethanol/water mixed solvent;
In above-mentioned steps 1～step 3, the reaction of each step is all carried out under reaction conditions known to a person of ordinary skill in the art.
Method two: as shown in reaction formula 2 below:
Reaction formula 2
Step 1: wherein, Z is O or S to compound 17(, R 6do not exist) or 20(is wherein, and Z is N, R 6for H or C 1-C 6alkyl) and substrate 6 obtain compound 21 through nucleophilic substitution reactions, described nucleophilic substitution reaction can carry out under the existence of for example catalyzer of salt of wormwood, cesium carbonate, sodium hydride, potassium tert.-butoxide or sodium tert-butoxide in the solvent of for example acetonitrile, acetone, ethyl acetate, tetrahydrofuran (THF) or DMF;
Step 2: compound 21 Hes obtain intermediate 22 through Suzuki reaction coupling, then intermediate 22 is obtained to product 23 through hydrolysis reaction; Described Suzuki reaction can be under the catalyzer such as such as tetrakis triphenylphosphine palladium, two (triphenylphosphine) palladium chloride, palladium or palladium carbon complex exist be carried out in mixed solvent, the mixed solvent of acetonitrile/water or the mixed solvent of ethanol/water of the mixed solvent of for example toluene/acetonitrile/water, toluene/ethanol/water; Described hydrolysis reaction can be under the existence of the alkali such as such as potassium hydroxide, sodium hydroxide or lithium hydroxide in the solvent of for example acetonitrile/water mixed solvent, methanol/water mixed solvent or ethanol/water mixed solvent.
In above-mentioned steps 1～step 2, the reaction of each step is all carried out under reaction conditions known to a person of ordinary skill in the art.
As an example, described compound 17 and 20 can be prepared by the following method:
Reaction formula 3
Step 1: the hydroxyl of compound 10 is obtained to compound 11 with protective material protection, then obtain compound 12 with chloroacetyl chloride through Friedel-Crafts reaction;
Described protective material can be diacetyl oxide, Acetyl Chloride 98Min. or acetyl bromide, the reaction of described protection hydroxyl can be under the catalyzer such as such as triethylamine, diisopropyl ethyl amine or DMAP exists for example carrying out in methylene dichloride, trichloromethane, acetonitrile, acetone or ethyl acetate equal solvent; Described Friedel-Crafts reaction can be under the catalyzer such as such as aluminum chloride, zinc dichloride or boron trifluoride ether solution exists for example carrying out in methylene dichloride, trichloromethane or ether equal solvent;
Step 2: compound 12 obtains compound 13 through intramolecular nucleophilic substitution reaction, then through witting, reaction obtains compound 14 with witting reagent; Described intramolecular nucleophilic substitution reaction can be under the alkali such as such as sodium-acetate, Potassium ethanoate, salt of wormwood, potassium tert.-butoxide or sodium tert-butoxide exists for example carrying out in methyl alcohol, ethanol or acetonitrile equal solvent; Described witting reaction can be for example carrying out in toluene, benzene or dimethylbenzene equal solvent
Step 3: compound 14 obtains compound 15 through hydro-reduction reaction, and in the time of Z=O or S, compound 15 obtains compound 16 through hydrolysis reaction, compound 16 is through bromination reactions, and then is added dropwise to dehydrated alcohol and obtains compound 17 through esterification; Described reduction reaction can be carried out under the catalyzer of for example palladium carbon exists in the solvent of for example methyl alcohol, ethanol or ethyl acetate; Described hydrolysis reaction can carry out under the catalyzer of for example sodium hydroxide, potassium hydroxide or lithium hydroxide exists in the solvent of for example ethanol/water, methanol/water or acetonitrile/water; Described bromination reaction can be at for example phosphorus tribromide, phosphorus pentabromide, and the bromizating agents such as tribromo oxygen phosphorus or dibromo sulfoxide carry out under existing in the solvent of for example acetonitrile or ethyl acetate;
Step 4: in the time of Z=NH, compound 15 and R 7i obtains compound 18 through alkylated reaction, and compound 18 obtains compound 19 through hydrolysis reaction, and compound 19 is through bromination reactions, and then is added dropwise to dehydrated alcohol and obtains compound 20 through esterification; Described alkylated reaction can be under the catalyzer such as such as sodium hydride, potassium hydride KH, potassium tert.-butoxide or sodium tert-butoxide exists for example carrying out in acetonitrile, acetone or tetrahydrofuran (THF) DMF equal solvent; Described hydrolysis reaction can carry out under the catalyzer of for example sodium hydroxide, potassium hydroxide or lithium hydroxide exists in the solvent of for example ethanol/water, methanol/water or acetonitrile/water; Described bromination reaction can be at for example phosphorus tribromide, phosphorus pentabromide, and the bromizating agents such as tribromo oxygen phosphorus or dibromo sulfoxide carry out under existing in the solvent of for example acetonitrile or ethyl acetate;
Wherein, Z is O, S or N, R 7for C 1-C 6alkyl;
In above-mentioned steps 1～step 4, the reaction of each step is all carried out under reaction conditions known to a person of ordinary skill in the art.
In reaction formula 1～3, X, R 1～R 5definition and above-mentioned X, R 1～R 5definition identical.
Another aspect of the present invention has been to provide a kind of pharmaceutical composition, one or more and the optional pharmaceutically acceptable auxiliary material of being selected from the phenylpropionic acid compound shown in above-mentioned general formula I, its enantiomer, racemic modification and composition thereof and its pharmacy acceptable salt that this pharmaceutical composition comprises treatment significant quantity.Described pharmaceutical composition can be used for the treatment of diabetes or glycolipid metabolism disorder.
Another aspect of the present invention be to provide the phenylpropionic acid compound that is selected from shown in general formula I, its enantiomer, racemic modification and composition thereof, its steric isomer, its prodrugs with and pharmacy acceptable salt in one or more purposes in the medicine of preparation treatment diabetes or glycolipid metabolism disorder.
Of the present invention aspect another, a kind of method for the treatment of diabetes or glycolipid metabolism disorder is provided, it comprise to have these needs patient's administering therapeutic significant quantity be selected from according in phenylpropionic acid compound of the present invention, its enantiomer, racemic modification and composition thereof, its steric isomer, its prodrugs and its pharmacy acceptable salt one or more, or according to pharmaceutical composition of the present invention.
Brief description of the drawings
Fig. 1 be the impact of HYH-013 single-dose on ob/ob mouse blood sugar (mM, n=8) *, P<0.05, compared with control group; *, P<0.01, compared with control group.
Embodiment
Further illustrate by the following examples the present invention, but described embodiment does not limit the scope of the invention.
BrukerAMX-400 type, Gemini-300 type or AMX – 600 type nuclear magnetic resonance analyser records for proton nmr spectra, the unit of chemical shift δ is ppm.Specific rotation is measured by Perkin-Elmer241 type automatic polarimeter, and microwave used is CEM-discovery microwave reactor.All reaction solvents all carry out purifying according to ordinary method.Silica gel for column chromatography (200-300 order) is that Qingdao Haiyang chemical industry subsidiary factory produces.Thin-layer chromatography uses the efficient plate of GF254, for Yantai chemical institute is produced.Preparative thin layer chromatography board is by oneself preparation; stationary phase adopts GF254 (HG/T2354-92) silica gel and Xylo-Mucine (800-1200) preparation, is respectively Qingdao Marine Chemical Co., Ltd. and China Medicine (Group) Shanghai Chemical Reagent Co., and produces.All solvents are analytical reagent, and agents useful for same is all purchased from Chemical Reagent Co., Ltd., Sinopharm Group.Adopt the method colour developings such as iodine, Ultraluminescence.Remove organic solvent under reduced pressure carries out in Rotary Evaporators.
The preparation of embodiment 1:3-(4-2-bromomethylphenyl) ethyl propionate
Take 4-bromobenzene methyl alcohol 1a(purchased from the scientific and technological (Shanghai) Co., Ltd. of splendid chemistry far away, 10.50g, 56.0mmol,) be dissolved in 100mL triethylamine, add 20.0mL ethyl propenoate 2, palladium (0.50g, 2.2mmol), triphenylphosphine (0.50g, 1.9mmol).Reaction system nitrogen replacement three times, are then placed in 95 DEG C of reactions of oil bath 72 hours, and reaction solution is cooled to room temperature, filter, and after filtrate is concentrated, silica gel column chromatography (petrol ether/ethyl acetate=4/1) separates and obtains white solid 3a10.8g, productive rate 93%. 1H?NMR(300MHz,CDCl 3)：δ=7.67(d,J=16.0Hz,1H),7.51(d,J=8.1Hz,2H),7.38(d,J=8.1Hz,2H),6.42(d,J=16.0Hz,1H),4.72(d,J=5.4Hz,2H),4.26(q,J=7.2Hz,2H),1.33(t,J=7.1Hz,3H)。
10.8g intermediate 3a is dissolved in 100mL ethyl acetate, adds 10% palladium carbon 200mg, after hydrogen exchange three times, under room temperature, react 4 hours, reaction fluid cushion diatomite filtration, after filtrate is concentrated, silica gel column chromatography separates (ethyl acetate/petroleum ether=1/8), obtain white solid 4a10.1g, productive rate 93%. 1H?NMR(300MHz,CDCl 3)：δ=7.29(d,J=8.0Hz,2H),7.20(d,J=8.0Hz,2H),4.65(s,2H),4.18–4.05(m,2H),2.94(t,J=7.8Hz,2H),2.61(dd,J=9.2,6.2Hz,3H),1.29–1.16(m,3H).
10.2g intermediate 4a is dissolved in 200mL anhydrous diethyl ether, under ice-water bath, be added dropwise to 20.0g phosphorus tribromide, then insulation reaction 1 hour, add water washing, organic layer anhydrous sodium sulfate drying, after concentrated, silica gel column chromatography separates (ethyl acetate/petroleum ether=1/15), obtains white solid 5a12.2g, productive rate 92%. 1H?NMR(300MHz,CDCl 3)：δ=7.31(d,J=8.1Hz,2H),7.18(d,J=8.1Hz,2H),4.48(s,2H),4.12(q,J=7.1Hz,2H),2.94(t,J=7.8Hz,2H),2.61(t,J=7.8Hz,2H),1.23(t,J=7.1Hz,3H)。
The preparation of embodiment 2:3-(4-brooethyl-2-fluorophenyl) ethyl propionate
According to similar method shown in embodiment 1, replace compound 1a with compound 1b, prepare compound 3-(4-brooethyl-2-fluorophenyl) ethyl propionate (compound 5b). 1H?NMR(300MHz,CDCl 3)δ7.19(t,J=7.8Hz,1H),7.11–7.03(m,2H),4.43(s,2H),4.12(q,J=7.1Hz,2H),2.96(t,J=7.6Hz,2H),2.61(t,J=7.6Hz,2H),1.23(t,J=7.1Hz,3H).
The preparation of embodiment 3:3-(4-(((6-bromopyridine-2-yl) oxygen) methylene radical) phenyl) ethyl propionate
Take 2.50g compound 6a, 3.90g compound 5a, 4.0g salt of wormwood joins in 100mL round-bottomed flask, adds anhydrous acetonitrile 50mL, and 50 DEG C are reacted 5 hours.Reaction solution is down to room temperature, filters, filtrate si-enriched plastic column chromatography separates (ethyl acetate/petroleum ether=1/10), obtains 3.63g white solid compound 7a, productive rate 69%. 1H?NMR(300MHz,CDCl 3)：δ=7.41(dd,J=15.1,7.5Hz,3H),7.22(d,J=8.0Hz,2H),7.07(d,J=7.4Hz,1H),6.72(d,J=8.2Hz,1H),5.31(s,2H),4.13(q,J=7.1Hz,2H),2.96(t,J=7.8Hz,2H),2.62(t,J=7.8Hz,2H),1.23(dd,J=8.3,6.0Hz,3H).
The preparation of embodiment 4:3-(4-(((6-phenylpyridine-2-yl) oxygen) methylene radical) phenyl) propionic acid (compound H YH-001)
Take 100.0mg compound 7a, 45.0mg phenylo boric acid, 15.0mg tetrakis triphenylphosphine palladium and 75.0mg salt of wormwood join in 10mL microwave reactor dedicated pipe, add 2.0mL toluene, 0.4mL ethanol and 0.4mL water, with nitrogen replacement 3 times, then be placed in 120 DEG C of reactions of CEM microwave reactor 30 minutes, after reaction solution is concentrated, silica gel column chromatography separates, obtaining 3-(4-(((6-phenylpyridine-2-yl) oxygen) methylene radical) phenyl) ethyl propionate 97.0mg, is colorless oil. 1H?NMR(300MHz,CDCl 3)δ8.09-8.00(m,2H),7.69-7.59(m,1H),7.51-7.36(m,5H),7.28-7.18(m,3H),6.73(dd,J=8.1,5.6Hz,1H),5.49(s,2H),4.13(q,J=7.1Hz,2H),2.97(t,J=7.8Hz,2H),2.63(t,J=7.8Hz,2H),1.24(t,J=7.1Hz,3H).
Oily matter obtained above is dissolved in 5.0mL acetonitrile, adds 1.0mL water, add lithium hydroxide 10.0mg, be placed in 40 DEG C of oil baths and react 12 hours, TLC detection reaction finishes.With 2M hydrochloric acid soln tune pH=2-3, add water, be extracted with ethyl acetate 3 times, merge organic layer saturated common salt water washing, organic layer anhydrous sodium sulfate drying, filtering and concentrating obtains 3-(4-(((6-phenylpyridine-2-yl) oxygen) methylene radical) phenyl) propionic acid 90mg, is white solid. 1H?NMR(400MHz,CDCl 3)δ8.04(dd,J=8.3,1.3Hz,2H),7.69-7.60(m,1H),7.51-7.33(m,6H),7.24(d,J=8.0Hz,2H),6.76-6.72(m,1H),5.49(s,2H),2.97(t,J=7.8Hz,2H),2.69(t,J=7.8Hz,2H).
The preparation of embodiment 5:3-(4-(((6-(2-aminomethyl phenyl) pyridine-2-yl) oxygen) methylene radical) phenyl) propionic acid (compound H YH-002)
Except using 2-methylphenylboronic acid to replace phenylo boric acid, to make compound 3-(4-(((6-(2-aminomethyl phenyl) pyridine-2-yl) oxygen) methylene radical) phenyl) propionic acid according to method similar to Example 4. 1H?NMR(400MHz,CDCl 3)δ=7.65(t,J=7.8Hz,1H),7.44(d,J=7.6Hz,1H),7.41(d,J=7.9Hz,2H),7.34-7.27(m,3H),7.23(d,J=7.9Hz,2H),7.02(d,J=7.3Hz,1H),6.77(d,J=8.1Hz,1H),5.40(s,2H),2.98(t,J=7.7Hz,2H),2.70(t,J=7.8Hz,2H),2.41(s,3H).
The preparation of embodiment 6:3-(4-(((6-(4-aminomethyl phenyl) pyridine-2-yl) oxygen) methylene radical) phenyl) propionic acid (compound H YH-003)
Except using, methylphenylboronic acid is replaced phenylo boric acid, make compound 3-(4-(((6-(4-aminomethyl phenyl) pyridine-2-yl) oxygen) methylene radical) phenyl) propionic acid according to method similar to Example 4. 1H?NMR(400MHz,CDCl 3)δ=8.18(d,J=8.2Hz,2H),7.64-7.60(m,2H),7.59-7.55(m,1H),7.40(d,J=8.2Hz,1H),7.31(dd,J=7.4,0.6Hz,1H),7.01(s,2H),6.81(dd,J=8.2,0.6Hz,1H),5.48(s,2H),2.97(t,J=7.7Hz,2H),2.73-.66(m,2H),1.42(s,3H).
The preparation of embodiment 7:3-(4-(((6-(2-ethylphenyl) pyridine-2-yl) oxygen) methylene radical) phenyl) propionic acid (compound H YH-004)
Except using 2-ethylbenzene boric acid to replace phenylo boric acid, make compound 3-(4-(((6-(2-ethylphenyl) pyridine-2-yl) oxygen) methylene radical) phenyl) propionic acid according to method similar to Example 4. 1H?NMR(400MHz,CDCl 3)δ=7.65(t,J=7.8Hz,1H),7.41(dd,J=14.6,7.7Hz,3H),7.31-.24(m,3H),7.23(d,J=7.9Hz,2H),7.02(d,J=7.3Hz,1H),6.77(d,J=8.1Hz,1H),5.40(s,2H),2.98(t,J=7.7Hz,2H),2.70(t,J=7.8Hz,2H),2.51(q,J=7.1Hz,1H,2H),1.30(d,J=8.2,6.1Hz,3H).
The preparation of embodiment 8:3-(4-(((6-(2-isopropyl phenyl) pyridine-2-yl) oxygen) methylene radical) phenyl) propionic acid (compound H YH-005)
Except using 2-isopropyl benzene boric acid to replace phenylo boric acid, make compound 3-(4-(((6-(2-isopropyl phenyl) pyridine-2-yl) oxygen) methylene radical) phenyl) propionic acid according to method similar to Example 4. 1H?NMR(300MHz,CD 3Cl)δ=7.65(t,J=7.7Hz,1H),7.46-7.30(m,5H),7.28-7.19(m,3H),6.97(d,J=7.2Hz,1H),6.78(d,J=8.1Hz,1H),5.38(s,2H),3.30(m,1H),2.97(t,J=7.6Hz,2H),2.69(t,J=7.8Hz,2H),1.21(d,J=6.8Hz,6H).
The preparation of embodiment 9:3-(4-(((6-(2-tert-butyl-phenyl) pyridine-2-yl) oxygen) methylene radical) phenyl) propionic acid (compound H YH-006)
Except using 2-isobutyl-benzene boric acid to replace phenylo boric acid, make compound 3-(4-(((6-(2-tert-butyl-phenyl) pyridine-2-yl) oxygen) methylene radical) phenyl) propionic acid according to method similar to Example 4. 1H?NMR(300MHz,CDCl 3)δ=7.69(t,J=7.7Hz,1H),7.49-7.33(m,4H),7.29-7.22(m,4H),6.99(d,J=7.2Hz,1H),6.79(d,J=8.1Hz,1H),5.38(s,2H),2.96(t,J=7.6Hz,2H),2.68(t,J=7.8Hz,2H),1.19(s,9H).
Embodiment 10:3-(the preparation of 4-(((6-(2-nitrophenyl) pyridine-2-yl) oxygen methylene) phenyl) propionic acid (compound H YH-007)
Except using 2-oil of mirbane boric acid to replace phenylo boric acid, according to making compound 3-(4-(((6-(2-nitrophenyl) pyridine-2-yl) oxygen) methylene radical) phenyl) propionic acid with similar method shown in embodiment 4. 1H?NMR(400MHz,CDCl 3)δ=8.25(t,J=7.8Hz,1H),7.84(d,J=7.6Hz,1H),7.51(d,J=7.9Hz,2H),7.34-7.27(m,3H),7.25(d,J=7.9Hz,2H),7.02(d,J=7.3Hz,1H),6.77(d,J=8.1Hz,1H),5.40(s,2H),2.98(t,J=7.7Hz,2H),2.70(t,J=7.8Hz,2H).
The preparation of embodiment 11:3-(4-(((6-(2-aminophenyl) pyridine-2-yl) oxygen) methylene radical) phenyl) propionic acid (compound H YH-008)
Except using 2-amino-benzene boric acid to replace phenylo boric acid, make compound 3-(4-(((6-(2-aminophenyl) pyridine-2-yl) oxygen) methylene radical) phenyl) propionic acid according to method similar to Example 4. 1H?NMR(400MHz,CDCl 3)δ=8.76(t,J=7.8Hz,1H),7.44(d,J=7.6Hz,1H),7.34-7.27(m,3H),7.25(d,J=7.9Hz,2H),7.02(d,J=7.3Hz,1H),6.88-6.95(m,2H),6.57(d,J=8.1Hz,1H),6.08(brs,2H),5.40(s,2H),2.98(t,J=7.7Hz,2H),2.70(t,J=7.8Hz,2H).
The preparation of embodiment 12:3-(4-(((6-(2-hydroxy phenyl) pyridine-2-yl) oxygen) methylene radical) phenyl) propionic acid (compound H YH-009)
Except using 2-hydroxybenzene boric acid to replace phenylo boric acid, make compound 3-(4-(((6-(2-hydroxy phenyl) pyridine-2-yl) oxygen) methylene radical) phenyl) propionic acid according to method similar to Example 4. 1H?NMR(400MHz,CDCl 3)δ=11.2(s,1H),8.65(t,J=7.8Hz,1H),7.44(d,J=7.6Hz,1H),7.34-7.27(m,3H),7.21(d,J=7.9Hz,2H),6.09(d,J=7.3Hz,1H),6.81(m,2H),6.57(d,J=8.1Hz,1H),5.40(s,2H),2.98(t,J=7.7Hz,2H),2.70(t,J=7.8Hz,2H).
The preparation of embodiment 13:3-(4-(((6-(2-(trifluoromethyl) phenyl) pyridine-2-yl) oxygen) methylene radical) phenyl) propionic acid (compound H YH-010)
Except using 2-trifluoromethyl phenylo boric acid to replace phenylo boric acid, make compound 3-(4-(((6-(2-(trifluoromethyl) phenyl) pyridine-2-yl) oxygen) methylene radical) phenyl) propionic acid according to method similar to Example 4. 1H?NMR(300MHz,CD 3Cl)δ=7.78(d,J=7.5Hz,1H),7.69–7.57(m,2H),7.52(t,J=7.3Hz,2H),7.39(d,J=8.1Hz,2H),7.22(d,J=8.1Hz,2H),7.02(d,J=7.3Hz,1H),6.81(dd,J=8.3,0.6Hz,1H),5.36(s,2H),2.97(t,J=7.7Hz,2H),2.69(t,J=7.7Hz,2H)。
The preparation of embodiment 14:3-(4-(((6-(2-p-methoxy-phenyl) pyridine-2-yl) oxygen) methylene radical) phenyl) propionic acid (compound H YH-011)
Except using 2-methoxyphenylboronic acid to replace phenylo boric acid, make compound 3-(4-(((6-(2-p-methoxy-phenyl) pyridine-2-yl) oxygen) methylene radical) phenyl) propionic acid according to method similar to Example 4. 1H?NMR(400MHz,CDCl 3)δ=7.64(t,J=7.8Hz,1H),7.32(dd,J=14.6,7.7Hz,3H),7.30-7.25(m,3H),7.21(d,J=7.9Hz,2H),6.98(d,J=7.3Hz,1H),6.74(d,J=8.1Hz,1H),5.38(s,2H),3.74(s,3H),2.97(t,J=7.7Hz,2H),2.780(t,J=7.8Hz,2H)。
The preparation of embodiment 15:3-(4-(((6-(2-methylamino phenyl) pyridine-2-yl) oxygen) methyl) phenyl) propionic acid (compound H YH-012)
Except using 2-methylamino-phenylo boric acid to replace phenylo boric acid, make compound 3-(4-(((6-(2-methylamino phenyl) pyridine-2-yl) oxygen) methylene radical) phenyl) propionic acid according to method similar to Example 4. 1H?NMR(400MHz,CDCl 3)δ=7.76(t,J=7.8Hz,1H),7.31(dd,J=14.6,7.7Hz,3H),7.29-7.24(m,3H),7.21(d,J=7.9Hz,2H),6.88(d,J=7.3Hz,1H),6.74(d,J=8.1Hz,1H),5.38(s,2H),3.74(s,3H),2.97(t,J=7.7Hz,2H),2.780(t,J=7.8Hz,2H).
The preparation of embodiment 16:3-(4-(((6-(2,6-3,5-dimethylphenyl) pyridine-2-yl) oxygen) methylene radical) phenyl) propionic acid (compound H YH-013)
Except using 2,6-dimethylphenyl boronic acid replaces outside phenylo boric acid, make compound 3-(4-(((6-(2,6-3,5-dimethylphenyl) pyridine-2-yl) oxygen) methylene radical) phenyl) propionic acid according to method similar to Example 4. 1H?NMR(400MHz,CDCl 3)δ=7.64(dd,J=8.3,7.3Hz,1H),7.37(d,J=8.0Hz,2H),7.20(d,J=8.1Hz,3H),7.10(d,J=7.7Hz,2H),6.80(dd,J=7.2,0.8Hz,1H),6.76(dd,J=8.3,0.8Hz,1H),5.32(s,2H),2.96(t,J=7.8Hz,2H),2.67(t,J=7.8Hz,2H),2.06(s,6H).
The preparation of embodiment 17:3-(4-(((6-(2,6-diethyl phenyl) pyridine-2-yl) oxygen) methylene radical) phenyl) propionic acid (compound H YH-014)
Except using 2,6-diethylbenzene boric acid replaces outside phenylo boric acid, make compound 3-(4-(((6-(2,6-diethyl phenyl) pyridine-2-yl) oxygen) methylene radical) phenyl) propionic acid according to method similar to Example 4.
1H?NMR(400MHz,CDCl 3)δ=7.64(dd,J=8.3,7.3Hz,1H),7.37(d,J=8.0Hz,2H),7.20(d,J=8.1Hz,3H),7.10(d,J=7.7Hz,2H),6.80(dd,J=7.2,0.8Hz,1H),6.76(dd,J=8.3,0.8Hz,1H),5.32(s,2H),2.96(t,J=7.8Hz,2H),2.67(t,J=7.8Hz,2H),2.50(q,J=7.1Hz,1H,2H)，1.25(dd,J=8.2,6.1Hz,3H).
The preparation of embodiment 18:3-(4-(((6-(2,6-Dimethoxyphenyl) pyridine-2-yl) oxygen) methylene radical) phenyl) propionic acid (compound H YH-015)
Except using 2,6-dimethoxy phenylo boric acid replaces outside phenylo boric acid, make compound 3-(4-(((6-(2,6-Dimethoxyphenyl) pyridine-2-yl) oxygen) methylene radical) phenyl) propionic acid according to method similar to Example 4. 1H?NMR(300MHz,CDCl 3)δ7.63(t,J=7.7Hz,1H),7.40(d,J=7.7Hz,2H),7.31(t,J=8.4Hz,1H),7.20(d,J=7.6Hz,2H),6.92(d,J=7.2Hz,1H),6.74(d,J=8.3Hz,1H),6.66(d,J=8.4Hz,2H),5.35(s,2H),3.74(s,6H),2.95(t,J=7.5Hz,2H),2.65(dd,J=16.0,8.3Hz,2H).
The preparation of embodiment 19:3-(4-(((6-(2,6-dichlorophenyl) pyridine-2-yl) oxygen) methylene radical) phenyl) propionic acid (compound H YH-016)
Except using 2,6-dichlorobenzene boric acid replaces outside phenylo boric acid, make compound 3-(4-(((6-(2,6-dichlorophenyl) pyridine-2-yl) oxygen) methylene radical) phenyl) propionic acid according to method similar to Example 4. 1H?NMR(300MHz,CD 2Cl)δ=7.69(dd,J=8.3,7.3Hz,1H),7.41(dd,J=4.9,3.7Hz,4H),7.28(d,J=7.3Hz,1H),7.22(t,J=6.1Hz,2H),6.92(d,J=7.2Hz,1H),6.83(d,J=8.3Hz,1H),5.34(s,2H),2.96(t,J=7.7Hz,2H),2.67(t,J=7.7Hz,2H)。
The preparation of embodiment 20:3-(4-(((6-(2,6-difluorophenyl) pyridine-2-yl) oxygen) methylene radical) phenyl) propionic acid (compound H YH-017)
Except using 2,6-difluorobenzene boric acid replaces outside phenylo boric acid, make compound 3-(4-(((6-(2,6-difluorophenyl) pyridine-2-yl) oxygen) methylene radical) phenyl) propionic acid according to method similar to Example 4. 1H?NMR(300MHz,CD 2Cl)δ=7.74(dd,J=8.3,7.3Hz,1H),7.42(dd,J=4.9,3.7Hz,4H),7.26(d,J=7.3Hz,1H),7.21(t,J=6.1Hz,2H),6.92(d,J=7.2Hz,1H),6.83(d,J=8.3Hz,1H),5.34(s,2H),2.96(t,J=7.7Hz,2H),2.67(t,J=7.7Hz,2H).
The preparation of embodiment 21:3-(4-(((6-(2,6-dimethyl-4-hydroxy phenyl) pyridine-2-yl) oxygen) methylene radical) phenyl) propionic acid (compound H YH-018)
Except using 2,6-dimethyl-4-hydroxybenzene boric acid replaces outside phenylo boric acid, make compound 3-(4-(((6-(2,6-methyl-4-hydroxy phenyl) pyridyl) oxygen) methylene radical) phenyl) propionic acid according to method similar to Example 4. 1H?NMR(400MHz,CDCl 3)δ=7.62(dd,J=8.3,7.3Hz,1H),7.38(d,J=8.0Hz,2H),7.11(d,J=7.7Hz,2H),6.98(s,2H),6.78(d,J=7.2,1H),6.76(dd,J=8.3,0.8Hz,1H),5.32(s,2H),2.96(t,J=7.8Hz,2H),2.67(t,J=7.8Hz,2H),2.06(s,6H).
The preparation of embodiment 22:3-(4-(((6-(2,4,6-trimethylphenyl) pyridine-2-yl) oxygen) methylene radical) phenyl) propionic acid (compound H YH-019)
Except using 2,4,6-Three methyl Benzene boric acid replaces outside phenylo boric acid, makes compound 3-(4-(((6-(2 according to method similar to Example 4,4,6-trimethylphenyl) pyridine-2-yl) oxygen) methylene radical) phenyl) propionic acid. 1H?NMR(400MHz,CDCl 3)δ=7.60(dd,J=8.3,7.3Hz,1H),7.35(d,J=8.0Hz,2H),7.13(d,J=7.7Hz,2H),7.02(s,2H),6.78(d,J=7.2,1H),6.76(dd,J=8.3,0.8Hz,1H),5.32(s,2H),2.96(t,J=7.8Hz,2H),2.67(t,J=7.8Hz,2H),2.05(s,6H),2.14(s,3H)。
The preparation of embodiment 23:3-(4-(((6-(4-amino-2,6-3,5-dimethylphenyl) pyridine-2-yl) oxygen) methylene radical) phenyl) propionic acid (compound H YH-020)
Except using 2,6-dimethyl-4-amino-benzene boric acid replaces outside phenylo boric acid, make compound 3-(4-(((6-(4-amino-2,6-3,5-dimethylphenyl) pyridine-2-yl) oxygen) methylene radical) phenyl) propionic acid according to method similar to Example 4. 1H?NMR(400MHz,CDCl 3)δ=7.60(dd,J=8.3,7.3Hz,1H),7.32(d,J=8.0Hz,2H),7.01(d,J=7.7Hz,2H),6.78(d,J=7.2,1H),6.69(s,2H),6.56(d,J=8.3Hz,1H),6.22(brs,2H),5.32(s,2H),2.96(t,J=7.8Hz,2H),2.67(t,J=7.8Hz,2H),2.06(s,6H)。
The preparation of embodiment 24:3-(4-(((6-(4-sulfydryl-2,6-3,5-dimethylphenyl) pyridine-2-yl) oxygen) methylene radical) phenyl) propionic acid (compound H YH-021)
Except using 2,6-dimethyl-4-sulfydryl phenylo boric acid replaces outside phenylo boric acid, make compound 3-(4-(((6-(4-sulfydryl-2,6-3,5-dimethylphenyl) pyridine-2-yl) oxygen) methylene radical) phenyl) propionic acid according to method similar to Example 4. 1H?NMR(400MHz,CDCl 3)δ=7.60(dd,J=8.3,7.3Hz,1H),7.32(d,J=8.0Hz,2H),7.18(s,2H),7.01(d,J=7.7Hz,2H),6.78(d,J=7.2,1H),6.56(d,J=8.3Hz,1H),5.32(s,2H),2.96(t,J=7.8Hz,2H),2.67(t,J=7.8Hz,2H),2.05(s,6H).
The preparation of embodiment 25:3-(4-(((6-(4-carboxyl-2,6-3,5-dimethylphenyl) pyridine-2-yl) oxygen) methylene radical) phenyl) propionic acid (compound H YH-022)
Except using 2,6-dimethyl-4-formic acid phenylo boric acid replaces outside phenylo boric acid, make compound 3-(4-(((6-(4-carboxyl-2,6-3,5-dimethylphenyl) pyridine-2-yl) oxygen) methylene radical) phenyl) propionic acid according to method similar to Example 4. 1H?NMR(400MHz,CDCl 3)δ=7.82(s,2H),7.60(dd,J=8.3,7.3Hz,1H),7.32(d,J=8.0Hz,2H),7.01(d,J=7.7Hz,2H),6.78(d,J=7.2,1H),6.56(dd,J=8.3,0.8Hz,1H),5.32(s,2H),2.96(t,J=7.8Hz,2H),2.67(t,J=7.8Hz,2H),2.08(s,6H).
The preparation of embodiment 26:3-(4-(((6-(4-amide group-2,6-3,5-dimethylphenyl) pyridine-2-yl) oxygen) methylene radical) phenyl) propionic acid (compound H YH-023)
Except using 2; 6-dimethyl-4-formamyl phenylo boric acid replaces outside phenylo boric acid; make compound 3-(4-(((6-(4-amide group-2,6-3,5-dimethylphenyl) pyridine-2-yl) oxygen) methylene radical) phenyl) propionic acid according to method similar to Example 4. 1H?NMR(400MHz,CDCl 3)δ=7.64(s,2H),7.60(dd,J=8.3,7.3Hz,1H),7.32(d,J=8.0Hz,2H),7.01(d,J=7.7Hz,2H),6.78(d,J=7.2,1H),6.56(dd,J=8.3,0.8Hz,1H),5.32(s,2H),2.96(t,J=7.8Hz,2H),2.67(t,J=7.8Hz,2H),2.06(s,6H).
The preparation of embodiment 27:3-(4-(((6-(4-bromo-2,6-3,5-dimethylphenyl) pyridine-2-yl) oxygen) methylene radical) phenyl) propionic acid (compound H YH-024)
Except using 2,6-dimethyl-4-bromobenzene boric acid replaces outside phenylo boric acid, make compound 3-(4-(((6-(4-bromo-2,6-3,5-dimethylphenyl) pyridine-2-yl) oxygen) methylene radical) phenyl) propionic acid according to method similar to Example 4. 1H?NMR(400MHz,CDCl 3)δ=7.38(dd,J=8.3,7.3Hz,1H),7.28(d,J=8.0Hz,2H),7.17(s,2H),7.02(d,J=7.7Hz,2H),6.78(d,J=7.2,1H),6.56(dd,J=8.3,0.8Hz,1H),5.32(s,2H),2.96(t,J=7.8Hz,2H),2.67(t,J=7.8Hz,2H),2.06(s,6H)。
The preparation of embodiment 28:3-(4-(((6-(4-chloro-2,6-3,5-dimethylphenyl) pyridine-2-yl) oxygen) methylene radical) phenyl) propionic acid (compound H YH-025)
Except using 2,6-dimethyl-4-chlorobenzene boric acid replaces outside phenylo boric acid, make compound 3-(4-(((6-(4-chloro-2,6-3,5-dimethylphenyl) pyridine-2-yl) oxygen) methylene radical) phenyl) propionic acid according to method similar to Example 4. 1H?NMR(400MHz,CDCl 3)δ=7.37(dd,J=8.3,7.3Hz,1H),7.29(d,J=8.0Hz,2H),7.18(s,2H),7.03(d,J=7.7Hz,2H),6.78(d,J=7.2,1H),6.56(dd,J=8.3,0.8Hz,1H),5.32(s,2H),2.96(t,J=7.8Hz,2H),2.67(t,J=7.8Hz,2H),2.06(s,6H).
The preparation of embodiment 29:3-(4-(((6-(4-fluoro-2,6-3,5-dimethylphenyl) pyridine-2-yl) oxygen) methylene radical) phenyl) propionic acid (compound H YH-026)
Except using 2,6-dimethyl-4-fluorobenzoic boric acid replaces outside phenylo boric acid, make compound 3-(4-(((6-(4-fluoro-2,6-3,5-dimethylphenyl) pyridine-2-yl) oxygen) methylene radical) phenyl) propionic acid according to method similar to Example 4. 1H?NMR(400MHz,CDCl 3)δ=7.37(dd,J=8.3,7.3Hz,1H),7.29(d,J=8.0Hz,2H),7.03(d,J=7.7Hz,2H),6.78(d,J=7.2,1H),6.72(s,2H),6.56(dd,J=8.3,0.8Hz,1H),5.32(s,2H),2.96(t,J=7.8Hz,2H),2.67(t,J=7.8Hz,2H),2.05(s,6H).
The preparation of embodiment 30:3-(4-(((6-(4-methoxyl group-2,6-3,5-dimethylphenyl) pyridine-2-yl) oxygen) methylene radical) phenyl) propionic acid (compound H YH-027)
Except using 2,6-dimethyl-4-methoxyphenylboronic acid replaces outside phenylo boric acid, make compound 3-(4-(((6-(4-methoxyl group-2,6-3,5-dimethylphenyl) pyridine-2-yl) oxygen) methylene radical) phenyl) propionic acid according to method similar to Example 4. 1H?NMR(400MHz,CDCl 3)δ=7.37(dd,J=8.3,7.3Hz,1H),7.29(d,J=8.0Hz,2H),7.03(d,J=7.7Hz,2H),6.92(s,2H),6.78(d,J=7.2,1H),6.56(dd,J=8.3,0.8Hz,1H),5.32(s,2H),3.92(s,3H),2.96(t,J=7.8Hz,2H),2.67(t,J=7.8Hz,2H),2.05(s,6H).
The preparation of embodiment 31:3-(4-(((6-(4-methylthio group-2,6-3,5-dimethylphenyl) pyridine-2-yl) oxygen) methylene radical) phenyl) propionic acid (compound H YH-028)
Except using 2,6-dimethyl-4-methyl mercapto phenylo boric acid replaces outside phenylo boric acid, make compound 3-(4-(((6-(4-methylthio group-2,6-3,5-dimethylphenyl) pyridine-2-yl) oxygen) methylene radical) phenyl) propionic acid according to method similar to Example 4. 1H?NMR(400MHz,CDCl 3)δ=7.37(dd,J=8.3,7.3Hz,1H),7.29(d,J=8.0Hz,2H),7.22(s,2H),7.03(d,J=7.7Hz,2H),6.78(d,J=7.2,1H),6.56(dd,J=8.3,0.8Hz,1H),5.32(s,2H),2.96(t,J=7.8Hz,2H),2.67(t,J=7.8Hz,2H),2.53(s,3H),2.06(s,6H).
The preparation of embodiment 32:3-(4-(((6-(2,6-dimethyl-4-methylsulfonyl phenyl) pyridine-2-yl) oxygen) methylene radical) phenyl) propionic acid (compound H YH-029)
Except using 2; 6-dimethyl-4-methyl sulphonyl phenylo boric acid replaces outside phenylo boric acid; make compound 3-(4-(((6-(2,6-dimethyl-4-methylsulfonyl phenyl) pyridine-2-yl) oxygen) methylene radical) phenyl) propionic acid according to method similar to Example 4. 1H?NMR(400MHz,CDCl 3)δ=7.76(s,2H),7.37(dd,J=8.3,7.3Hz,1H),7.29(d,J=8.0Hz,2H),7.03(d,J=7.7Hz,2H),6.78(d,J=7.2,1H),6.56(dd,J=8.3,0.8Hz,1H),5.32(s,2H),3.38(s,3H),2.96(t,J=7.8Hz,2H),2.67(t,J=7.8Hz,2H),2.06(s,6H).
The preparation of embodiment 33:3-(4-(((6-(2,6-dimethyl-4-methylamino-phenyl) pyridine-2-yl) oxygen) methylene radical) phenyl) propionic acid (compound H YH-030)
Except using 2,6-dimethyl-4-methylamino-phenylo boric acid replaces outside phenylo boric acid, make compound 3-(4-(((6-(2,6-dimethyl-4-methylamino-phenyl) pyridine-2-yl) oxygen) methylene radical) phenyl) propionic acid according to method similar to Example 4. 1H?NMR(400MHz,CDCl 3)δ=7.37(dd,J=8.3,7.3Hz,1H),7.29(d,J=8.0Hz,2H),7.03(d,J=7.7Hz,2H),6.78(d,J=7.2,1H),6.56(dd,J=8.3,0.8Hz,1H),6.48(s,2H),5.32(s,2H),2.96(t,J=7.8Hz,2H),2.72(s,3H),2.68(t,J=7.8Hz,2H),2.06(s,6H).
The preparation of embodiment 34:3-(4-(((6-(2,6-dimethyl-4-dimethylamino phenyl) pyridine-2-yl) oxygen) methylene radical) phenyl) propionic acid (compound H YH-031)
Except using 2,6-dimethyl-4-(dimethylamino) phenylo boric acid replaces outside phenylo boric acid, make compound 3-(4-(((6-(2,6-dimethyl-4-dimethylamino phenyl) pyridine-2-yl) oxygen) methylene radical) phenyl) propionic acid according to method similar to Example 4. 1H?NMR(400MHz,CDCl 3)δ=7.37(dd,J=8.3,7.3Hz,1H),7.29(d,J=8.0Hz,2H),7.03(d,J=7.7Hz,2H),6.78(d,J=7.2,1H),6.56(dd,J=8.3,0.8Hz,1H),6.48(s,2H),5.32(s,2H),2.96(t,J=7.8Hz,2H),2.72(s,6H),2.67(t,J=7.8Hz,2H),2.04(s,6H).
The preparation of embodiment 35:3-(4-(((6-(2,6-dimethyl-4-(N-methyl Toluidrin) phenyl) pyridine-2-yl) oxygen) methylene radical) phenyl) propionic acid (compound H YH-032)
Except using 2; 6-dimethyl-4-(methyl sulphonyl) (methyl) amino-benzene boric acid replaces outside phenylo boric acid; make compound 3-(4-(((6-(2,6-dimethyl-4-(N-methyl Toluidrin) phenyl) pyridine-2-yl) oxygen) methylene radical) phenyl) propionic acid according to method similar to Example 4. 1H?NMR(400MHz,CDCl 3)δ=7.37(dd,J=8.3,7.3Hz,1H),7.29(d,J=8.0Hz,2H),7.03(d,J=7.7Hz,2H),6.78(d,J=7.2,1H),6.56(dd,J=8.3,0.8Hz,1H),6.48(s,2H),5.32(s,2H),3.32(s,3H),3.18(s,3H),2.96(t,J=7.8Hz,2H),2.67(t,J=7.8Hz,2H),2.05(s,6H).
The preparation of embodiment 36:3-(4-(((6-(2,6-3,5-dimethylphenyl) pyridine-2-yl) oxygen) methylene radical)-2-fluorophenyl) propionic acid (compound H YH-033)
Except using 2,6-dimethylphenyl boronic acid replaces phenylo boric acid, and use 3-(4-(((6-bromopyridine-2-yl) oxygen) methylene radical)-2-fluorophenyl) ethyl propionate to replace outside 3-(4-(((6-bromopyridine-2-yl) oxygen) methylene radical) phenyl) ethyl propionate, make compound 3-(4-(((6-(2,6-3,5-dimethylphenyl) pyridine-2-yl) oxygen) methylene radical)-2-fluorophenyl) propionic acid according to method similar to Example 4. 1H?NMR(300MHz,CDCl 3)δ7.67(t,J=7.8Hz,1H),7.28–7.09(m,6H),6.81(dd,J=12.2,7.8Hz,2H),5.35(s,2H),2.98(t,J=7.6Hz,2H),2.69(t,J=7.7Hz,2H),2.07(s,6H).
The preparation of embodiment 37:3-(4-(((6-(2,6-, bis-cyclopropyl phenyl) pyridine-2-yl) oxygen) methylene radical)-2-fluorophenyl) propionic acid (compound H YH-034)
Except using 2,6-bis-cyclopropyl-phenyl boric acid replace phenylo boric acid, and use 3-(4-(((6-bromopyridine-2-yl) oxygen) methylene radical)-2-fluorophenyl) ethyl propionate to replace outside 3-(4-(((6-bromopyridine-2-yl) oxygen) methylene radical) phenyl) ethyl propionate, make compound 3-(4-(((6-(2,6-, bis-cyclopropyl phenyl) pyridine-2-yl) oxygen) methylene radical)-2-fluorophenyl) propionic acid according to method similar to Example 4. 1H?NMR(300MHz,CDCl 3)δ7.67(t,J=7.8Hz,1H),7.35–7.09(m,6H),6.81(dd,J=12.2,7.8Hz,2H),5.35(s,2H),2.98(t,J=7.6Hz,2H),2.69(t,J=7.7Hz,2H),1.48-1.62(m,2H),0.99-1.28(m,8H).
The preparation of embodiment 38:3-(4-(((6-(2,6-3,5-dimethylphenyl) pyridine-2-yl) oxygen) methylene radical)-2-chloro-phenyl-) propionic acid (compound H YH-035)
Except using 2,6-dimethylphenyl boronic acid replaces phenylo boric acid, and use 3-(4-(((6-bromopyridine-2-yl) oxygen) methylene radical)-2-chloro-phenyl-) ethyl propionate to replace outside 3-(4-(((6-bromopyridine-2-yl) oxygen) methylene radical) phenyl) ethyl propionate, make compound 3-(4-(((6-(2,6-3,5-dimethylphenyl) pyridine-2-yl) oxygen) methylene radical)-2-chloro-phenyl-) propionic acid according to method similar to Example 4. 1H?NMR(300MHz,CDCl 3)δ7.67(t,J=7.8Hz,1H),7.28(s,2H),7.15-7.09(m,3H),6.81(dd,J=12.2,7.8Hz,2H),5.35(s,2H),2.98(t,J=7.6Hz,2H),2.69(t,J=7.7Hz,2H),2.06(s,6H).
The preparation of embodiment 39:3-(4-(((6-(2,6-dimethyl-4-hydroxy phenyl) pyridine-2-yl) oxygen) methylene radical)-2-fluorophenyl) propionic acid (compound H YH-036)
Except using 2,6-dimethyl-4-hydroxybenzene boric acid replaces phenylo boric acid, and use 3-(4-(((6-bromopyridine-2-yl) oxygen) methylene radical)-2-fluorophenyl) ethyl propionate to replace outside 3-(4-(((6-bromopyridine-2-yl) oxygen) methylene radical) phenyl) ethyl propionate, make compound 3-(4-(((6-(2,6-methyl-4-hydroxy phenyl) pyridine-2-yl) oxygen) methylene radical)-2-fluorophenyl) propionic acid according to method similar to Example 4. 1H?NMR(400MHz,CDCl 3)δ=7.59(dd,J=8.3,7.3Hz,1H),7.27(d,J=8.0Hz,2H),7.13(d,J=7.7Hz,2H),6.98(s,2H),6.78(d,J=7.2,1H),6.76(dd,J=8.3,0.8Hz,1H),5.32(s,2H),2.96(t,J=7.8Hz,2H),2.67(t,J=7.8Hz,2H),2.06(s,6H)。
The preparation of embodiment 40:3-(4-(((6-(2,6-dimethyl-4-hydroxy phenyl) pyridine-2-yl) oxygen) methylene radical)-2-chloro-phenyl-) propionic acid (compound H YH-037)
Except using 2,6-dimethyl-4-hydroxybenzene boric acid replaces phenylo boric acid, and use 3-(4-(((6-bromopyridine-2-yl) oxygen) methylene radical)-2-chloro-phenyl-) ethyl propionate to replace outside 3-(4-(((6-bromopyridine-2-yl) oxygen) methylene radical) phenyl) ethyl propionate, make compound 3-(4-(((6-(2,6-methyl-4-hydroxy phenyl) pyridine-2-yl) oxygen) methylene radical)-2-chloro-phenyl-) propionic acid according to method similar to Example 4. 1H?NMR(400MHz,CDCl 3)δ=7.78(dd,J=8.3,7.3Hz,1H),7.48(d,J=8.0Hz,2H),7.11(d,J=7.7Hz,2H),6.98(s,2H),6.88(d,J=7.2,1H),6.76(dd,J=8.3,0.8Hz,1H),5.32(s,2H),2.96(t,J=7.8Hz,2H),2.67(t,J=7.8Hz,2H),2.06(s,6H)。
The preparation of embodiment 41:3-(4-(((6-(2,6-dimethyl-4-(2-(methylsulfonyl) oxyethyl group) phenyl) pyridine-2-yl) oxygen) methylene radical) phenyl) propionic acid (compound H YH-038)
Get 3-(4-(((6-(2; 6-dimethyl-4-hydroxy phenyl) methylene radical) phenyl) ethyl acetate 0.1g; 2-methylsulfonylethyl tolysulfonyl ester 0.103g is dissolved in 10mL acetonitrile; add salt of wormwood 0.097g; back flow reaction 8 hours; reaction solution is chilled to room temperature, removes by filter salt of wormwood, filtrate si-enriched plastic column chromatography separates (ethyl acetate/petroleum ether=1/15-1/5).Obtain 3-(4-(((6-(2; 6-dimethyl-4-(2-(methylsulfonyl) oxyethyl group) phenyl) pyridine-2-yl) oxygen) methylene radical) phenyl) ethyl propionate 85mg; for white solid, productive rate 66%.
By above-mentioned gained 85mg sample dissolution in 8mL acetonitrile; in the mixed solution of 2mL water; add 10mg lithium hydroxide; in 40 DEG C, react 4 hours; cooling; with the hydrochloric acid tune pH=2-3 of 1M; add saturated aqueous common salt 20mL; ethyl acetate extraction 2 times; merge organic layer and add anhydrous sodium sulfate drying, filtering and concentrating obtains 3-(4-(((6-(2,6-dimethyl-4-(2-(methylsulfonyl) oxyethyl group) phenyl) pyridine-2-yl) oxygen base) methylene radical) phenyl) propionic acid 68mg; for white solid, productive rate 84%. 1H?NMR(400MHz,CDCl 3)δ=7.62(dd,J=8.3,7.3Hz,1H),7.38(d,J=8.0Hz,2H),7.11(d,J=7.7Hz,2H),6.98(s,2H),6.78(d,J=7.2,1H),6.76(dd,J=8.3,0.8Hz,1H),5.35(s,2H),4.82(t,J=7.2Hz,2H),3.77(t,J=7.2Hz,2H),2.98(t,J=7.6Hz,2H),2.87(s,3H),2.69(t,J=7.6Hz,2H),2.05(s,6H)。
The preparation of embodiment 42:3-(4-(((6-(2,6-dimethyl-4-(2-(ethylsulfonyl) oxyethyl group) phenyl) pyridine-2-yl) oxygen) methylene radical) phenyl) propionic acid (compound H YH-039)
Except using 2-ethylsulfonyl ethyl tolysulfonyl ester to replace 2-methylsulfonylethyl tolysulfonyl ester; according to making compound 3-(4-(((6-(2,6-dimethyl-4-(2-(ethylsulfonyl) oxyethyl group) phenyl) pyridine-2-yl) oxygen) methylene radical) phenyl) propionic acid with the similar method of embodiment 41. 1H?NMR(400MHz,CDCl 3)δ=7.62(dd,J=8.3,7.3Hz,1H),7.38(d,J=8.0Hz,2H),7.11(d,J=7.7Hz,2H),6.98(s,2H),6.78(d,J=7.2,1H),6.76(dd,J=8.3,0.8Hz,1H),5.35(s,2H),4.82(t,J=7.2Hz,2H),3.77(t,J=7.2Hz,2H),2.98(t,J=7.6Hz,2H),2.94(q,J=7.1Hz,2H),2.69(t,J=7.6Hz,2H),2.05(s,6H),1.22(t,J=7.1Hz,,3H)。
The preparation of embodiment 43:3-(4-(((6-(2,6-dimethyl-4-(3-(methylsulfonyl) propoxy-) phenyl) pyridine-2-yl) oxygen) methylene radical) phenyl) propionic acid (compound H YH-040)
Except using 3-methylsulfonyl propyl group tolysulfonyl ester to replace 2-methylsulfonylethyl tolysulfonyl ester; according to making compound 3-(4-(((6-(2,6-dimethyl-4-(3-(methylsulfonyl) propoxy-) phenyl) pyridine-2-yl) oxygen) methylene radical) phenyl) propionic acid with the similar method of embodiment 41. 1H?NMR(400MHz,CDCl 3)δ=7.62(dd,J=8.3,7.3Hz,1H),7.38(d,J=8.0Hz,2H),7.11(d,J=7.7Hz,2H),6.98(s,2H),6.78(d,J=7.2,1H),6.76(dd,J=8.3,0.8Hz,1H),5.35(s,2H),4.82(t,J=7.2Hz,2H),3.77(t,J=7.2Hz,2H),2.98(t,J=7.6Hz,2H),2.87(s,3H),2.69(t,J=7.6Hz,2H),2.37(m,2H),2.05(s,6H)。
The preparation of embodiment 44:3-(4-(((6-(2,6-dimethyl-4-(3-(ethylsulfonyl) propoxy-) phenyl) pyridine-2-yl) oxygen) methylene radical) phenyl) propionic acid (compound H YH-041)
Except using 3-ethylsulfonyl propyl group tolysulfonyl ester to replace 2-methylsulfonylethyl tolysulfonyl ester; according to making compound 3-(4-(((6-(2,6-dimethyl-4-(3-(ethylsulfonyl) propoxy-) phenyl) pyridine-2-yl) oxygen) methylene radical) phenyl) propionic acid with the similar method of embodiment 41.
1H?NMR(400MHz,CDCl 3)δ=7.62(dd,J=8.3,7.3Hz,1H),7.38(d,J=8.0Hz,2H),7.11(d,J=7.7Hz,2H),6.98(s,2H),6.78(d,J=7.2,1H),6.76(dd,J=8.3,0.8Hz,1H),5.35(s,2H),4.82(t,J=7.2Hz,2H),3.77(t,J=7.2Hz,2H),2.98(t,J=7.6Hz,2H),2.94(q,J=8.0Hz,2H),2.69(t,J=7.6Hz,2H),2.37(m,2H),2.05(s,6H),1.42(t,,J=8.0Hz,3H)。
The preparation of embodiment 45:3-(4-(((6-(4-(2-methoxy ethoxy)-2,6-3,5-dimethylphenyl) pyridine-2-yl) oxygen) methylene radical) phenyl) propionic acid (compound H YH-042)
Except using 2-methoxy ethyl tolysulfonyl ester to replace 2-methylsulfonylethyl tolysulfonyl ester; according to making compound 3-(4-(((6-(4-(2-methoxy ethoxy)-2,6-3,5-dimethylphenyl) pyridine-2-yl) oxygen) methylene radical) phenyl) propionic acid with the similar method of embodiment 41. 1H?NMR(400MHz,CDCl 3)δ=7.62(dd,J=8.3,7.3Hz,1H),7.38(d,J=8.0Hz,2H),7.11(d,J=7.7Hz,2H),6.98(s,2H),6.78(d,J=7.2,1H),6.76(dd,J=8.3,0.8Hz,1H),5.35(s,2H),4.79(t,J=7.2Hz,2H),3.87(t,J=7.2Hz,2H),3.45(s,3H),2.98(t,J=7.6Hz,2H),2.69(t,J=7.6Hz,2H),2.05(s,6H).
The preparation of embodiment 46:3-(4-(((6-(4-(2-ethoxy ethoxy)-2,6-3,5-dimethylphenyl) pyridine-2-yl) oxygen) methylene radical) phenyl) propionic acid (compound H YH-043)
Except using 2-ethoxyethyl group tolysulfonyl ester to replace 2-methylsulfonylethyl tolysulfonyl ester; according to making compound 3-(4-(((6-(4-(2-ethoxy ethoxy)-2,6-3,5-dimethylphenyl) pyridine-2-yl) oxygen) methylene radical) phenyl) propionic acid with similar method shown in embodiment 41. 1H?NMR(400MHz,CDCl 3)δ=7.62(dd,J=8.3,7.3Hz,1H),7.38(d,J=8.0Hz,2H),7.11(d,J=7.7Hz,2H),6.98(s,2H),6.78(d,J=7.2,1H),6.76(dd,J=8.3,0.8Hz,1H),5.35(s,2H),4.79(t,J=7.2Hz,2H),3.87(t,J=7.2Hz,2H),3.45(q,J=7.1Hz,3H),2.98(t,J=7.6Hz,2H),2.69(t,J=7.6Hz,2H),2.05(s,6H),1.12(t,J=7.1Hz,3H)。
The preparation of embodiment 47:3-(4-(((6-(4-(2-dimethylamino oxyethyl group)-2,6-3,5-dimethylphenyl) pyridine-2-yl) oxygen) methylene radical) phenyl) propionic acid (compound H YH-044)
Except using 2-((dimethyl) amino) ethyl tolysulfonyl ester to replace 2-methylsulfonylethyl tolysulfonyl ester; according to making compound 3-(4-(((6-(4-(2-dimethylamino oxyethyl group)-2,6-3,5-dimethylphenyl) pyridine-2-yl) oxygen) methylene radical) phenyl) propionic acid with the similar method of embodiment 42. 1H?NMR(400MHz,CDCl 3)δ=7.62(dd,J=8.3,7.3Hz,1H),7.38(d,J=8.0Hz,2H),7.11(d,J=7.7Hz,2H),6.98(s,2H),6.78(d,J=7.2,1H),6.76(dd,J=8.3,0.8Hz,1H),5.35(s,2H),4.79(t,J=7.2Hz,2H),2.98(t,J=7.6Hz,2H),2.85(s,6H),2.77(t,J=7.2Hz,2H),2.69(t,J=7.6Hz,2H),2.05(s,6H)。
The preparation of embodiment 48:3-(4-(((6-(4-(3-dimethylamino propoxy-)-2,6-3,5-dimethylphenyl) pyridine-2-yl) oxygen) methylene radical) phenyl) propionic acid (compound H YH-045)
Except using 3-((dimethyl) amino) propyl group tolysulfonyl ester to replace 2-methylsulfonylethyl tolysulfonyl ester; according to making compound 3-(4-(((6-(4-(3-dimethylamino propoxy-)-2,6-3,5-dimethylphenyl) pyridine-2-yl) oxygen) methylene radical) phenyl) propionic acid with the similar method of embodiment 41. 1H?NMR(400MHz,CDCl 3)δ=7.62(dd,J=8.3,7.3Hz,1H),7.38(d,J=8.0Hz,2H),7.11(d,J=7.7Hz,2H),6.98(s,2H),6.78(d,J=7.2,1H),6.76(dd,J=8.3,0.8Hz,1H),5.35(s,2H),4.79(t,J=7.2Hz,2H),2.98(t,J=7.6Hz,2H),2.85(s,6H),2.69(t,J=7.6Hz,2H),2.35(t,J=7.2Hz,2H),2.06(s,6H),2.26(s,6H),1.79(q,J=7.2Hz,2H)。
The preparation of embodiment 49:3-(4-(((6-(4-(2-diethylamino ethoxy)-2,6-3,5-dimethylphenyl) pyridine-2-yl) oxygen) methylene radical) phenyl) propionic acid (compound H YH-046)
Except using 2-(diethylamino) ethyl tolysulfonyl ester to replace 2-methylsulfonylethyl tolysulfonyl ester; according to making compound 3-(4-(((6-(4-(2-diethylamino ethoxy)-2,6-3,5-dimethylphenyl) pyridine-2-yl) oxygen) methylene radical) phenyl) propionic acid with the similar method of embodiment 41. 1H?NMR(400MHz,CDCl 3)δ=7.62(dd,J=8.3,7.3Hz,1H),7.38(d,J=8.0Hz,2H),7.11(d,J=7.7Hz,2H),6.98(s,2H),6.78(d,J=7.2,1H),6.76(dd,J=8.3,0.8Hz,1H),5.35(s,2H),4.79(t,J=7.2Hz,2H),3.08(q,J=7.5Hz,4H),2.98(t,J=7.6Hz,2H),2.77(t,J=7.2Hz,2H),2.69(t,J=7.6Hz,2H),2.05(s,6H),1.18(t,J=7.5Hz,6H)。
The preparation of embodiment 50:3-(4-(((6-(4-(3-diethylin propoxy-)-2,6-3,5-dimethylphenyl) pyridine-2-yl) oxygen) methylene radical) phenyl) propionic acid (compound H YH-047)
Except using 3-(diethylin) propyl group tolysulfonyl ester to replace 2-methylsulfonylethyl tolysulfonyl ester; according to making compound 3-(4-(((6-(4-(3-diethylin propoxy-)-2,6-3,5-dimethylphenyl) pyridine-2-yl) oxygen) methylene radical) phenyl) propionic acid with the similar method of embodiment 41. 1H?NMR(400MHz,CDCl 3)δ=7.62(dd,J=8.3,7.3Hz,1H),7.36(d,J=8.0Hz,2H),7.11(d,J=7.7Hz,2H),6.98(s,2H),6.78(d,J=7.2,1H),6.76(dd,J=8.3,0.8Hz,1H),5.35(s,2H),4.79(t,J=7.2Hz,2H),3.08(q,J=7.5Hz,4H),2.98(t,J=7.6Hz,2H),2.77(t,J=7.2Hz,2H),2.67(t,J=7.6Hz,2H),2.06(s,6H),1.81(q,J=7.5Hz,2H)1.16(t,J=7.5Hz,6H)。
The preparation of embodiment 51:3-(4-(((6-(2,6-dimethyl-4-((tetrahydrochysene-2H-pyrans-4-yl) oxygen base) phenyl) pyridine-2-yl) oxygen) methylene radical) phenyl) propionic acid (compound H YH-048)
Except using tetrahydrochysene-2H-pyrans-4-tolysulfonyl ester to replace 2-methylsulfonylethyl tolysulfonyl ester; according to making compound 3-(4-(((6-(2,6-dimethyl-4-((tetrahydrochysene-2H-pyrans-4-yl) oxygen base) phenyl) pyridine-2-yl) oxygen) methylene radical) phenyl) propionic acid with the similar method of embodiment 41. 1H?NMR(400MHz,CDCl 3)δ=7.55(dd,J=8.3,7.3Hz,1H),7.34(d,J=8.0Hz,2H),7.11(d,J=7.7Hz,2H),6.98(s,2H),6.78(d,J=7.2,1H),6.76(dd,J=8.3,0.8Hz,1H),5.32(s,2H),3.75(m,1H),3.61(m,2H),3.52(m,2H),2.96(t,J=7.8Hz,2H),2.67(t,J=7.8Hz,2H),2.15(m,2H),2.06(s,6H),1.88(m,2H)。
The preparation of embodiment 52:3-(4-(((6-(2,6-dimethyl-4-((tetrahydrochysene-2H-thiapyran-4-yl) oxygen base) phenyl) pyridine-2-yl) oxygen) methylene radical) phenyl) propionic acid (compound H YH-049)
Except using tetrahydrochysene-2H-thiapyran-4-tolysulfonyl ester to replace 2-methylsulfonylethyl tolysulfonyl ester; according to making compound 3-(4-(((6-(2,6-dimethyl-4-((tetrahydrochysene-2H-thiapyran-4-yl) oxygen) phenyl) pyridine-2-yl) oxygen base) methylene radical) phenyl) propionic acid with the similar method of embodiment 41. 1H?NMR(400MHz,CDCl 3)δ=7.55(dd,J=8.3,7.3Hz,1H),7.34(d,J=8.0Hz,2H),7.11(d,J=7.7Hz,2H),6.98(s,2H),6.78(d,J=7.2,1H),6.76(dd,J=8.3,0.8Hz,1H),5.32(s,2H),3.92(m,1H),2.96(t,J=7.8Hz,2H),2.67(t,J=7.8Hz,2H),2.61(m,2H),2.52(m,2H),2.22(m,2H),2.06(s,6H),1.98(m,2H)。
Embodiment 53:3-(4-(((6-(4-((1,1-dioxo tetrahydrochysene-2H-thiapyran-4-yl) oxygen base)-2,6-3,5-dimethylphenyl) pyridine-2-yl) oxygen) methylene radical) phenyl) preparation of propionic acid (compound H YH-050)
Except using 1; 1-dioxo tetrahydrochysene-2H-thiapyran-4-tolysulfonyl ester replaces outside 2-methylsulfonylethyl tolysulfonyl ester; according to making compound 3-(4-(((6-(4-((tetrahydrochysene-2H-thiapyran-4-yl) oxygen)-2,6-dimethyl-phenyl) pyridine-2-yl) oxygen base) methylene radical) phenyl) propionic acid with the similar method of embodiment 41. 1H?NMR(400MHz,CDCl 3)δ=7.55(dd,J=8.3,7.3Hz,1H),7.34(d,J=8.0Hz,2H),7.11(d,J=7.7Hz,2H),6.98(s,2H),6.78(d,J=7.2,1H),6.76(dd,J=8.3,0.8Hz,1H),5.32(s,2H),3.69(m,1H),3.48(m,2H),3.42(m,2H),2.96(t,J=7.8Hz,2H),2.67(t,J=7.8Hz,2H),2.39(m,2H),2.14(m,2H),2.06(s,6H)。
The preparation of embodiment 54:3-(4-(((6-(2,6-dimethyl-4-(2-(pyrrolidin-1-yl) oxyethyl group) phenyl) pyridine-2-yl) oxygen) methylene radical) phenyl) propionic acid (compound H YH-051)
Except using 2-(pyrrolidin-1-yl) ethyl tolysulfonyl ester to replace 2-methylsulfonylethyl tolysulfonyl ester; according to making compound 3-(4-(((6-(2,6-dimethyl-4-(2-(pyrrolidin-1-yl) oxyethyl group) phenyl) pyridine-2-yl) oxygen) methylene radical) phenyl) propionic acid with the similar method of embodiment 41. 1H?NMR(400MHz,CDCl 3)δ=7.62(dd,J=8.3,7.3Hz,1H),7.36(d,J=8.0Hz,2H),7.11(d,J=7.7Hz,2H),6.98(s,2H),6.78(d,J=7.2,1H),6.76(dd,J=8.3,0.8Hz,1H),5.35(s,2H),4.79(t,J=7.2Hz,2H),2.98(t,J=7.6Hz,2H),2.77(t,J=7.2Hz,2H),2.67(t,J=7.6Hz,2H),2.46-2.55(m,4H),2.06(s,6H),1.66-1.73(m,4H)。
The preparation of embodiment 55:3-(4-(((6-(2,6-dimethyl-4-(2-(piperidin-1-yl) oxyethyl group) phenyl) pyridine-2-yl) oxygen) methylene radical) phenyl) propionic acid (compound H YH-052)
Except using 2-(piperidin-1-yl) ethyl tolysulfonyl ester to replace 2-methylsulfonylethyl tolysulfonyl ester; according to making compound 3-(4-(((6-(2,6-dimethyl-4-(2-(piperidin-1-yl) oxyethyl group) phenyl) pyridine-2-yl) oxygen) methylene radical) phenyl) propionic acid with the similar method of embodiment 41. 1H?NMR(400MHz,CDCl 3)δ=7.62(dd,J=8.3,7.3Hz,1H),7.36(d,J=8.0Hz,2H),7.11(d,J=7.7Hz,2H),6.98(s,2H),6.78(d,J=7.2,1H),6.76(dd,J=8.3,0.8Hz,1H),5.35(s,2H),4.79(t,J=7.2Hz,2H),2.98(t,J=7.6Hz,2H),2.77(t,J=7.2Hz,2H),2.67(t,J=7.6Hz,2H),2.45(m,4H),2.06(s,6H),1.61-1.69(m,6H)。
The preparation of embodiment 56:3-(4-(((6-(2,6-dimethyl-4-(2-morpholine oxyethyl group) phenyl) pyridine-2-yl) oxygen) methylene radical) phenyl) propionic acid (compound H YH-053)
Except using 2-morpholine ethyl tolysulfonyl ester to replace 2-methylsulfonylethyl tolysulfonyl ester; according to making compound 3-(4-(((6-(2,6-dimethyl-4-(2-morpholine oxyethyl group) phenyl) pyridine-2-yl) oxygen) methylene radical) phenyl) propionic acid with the similar method of embodiment 41. 1H?NMR(400MHz,CDCl 3)δ=7.62(dd,J=8.3,7.3Hz,1H),7.36(d,J=8.0Hz,2H),7.11(d,J=7.7Hz,2H),6.98(s,2H),6.78(d,J=7.2,1H),6.76(dd,J=8.3,0.8Hz,1H),5.35(s,2H),4.79(t,J=7.2Hz,2H),3.65(t,J=8.1Hz,4H),2.98(t,J=7.6Hz,2H),2.77(t,J=7.2Hz,2H),2.67(t,J=7.6Hz,2H),2.41(t,J=8.1Hz,4H),2.06(s,6H)。
The preparation of embodiment 57:3-(4-(((6-(2,6-dimethyl-4-(2-(piperazine-1-yl) oxyethyl group) phenyl) pyridine-2-yl) oxygen) methylene radical) phenyl) propionic acid (compound H YH-054)
Except using 2-(piperazine-1-yl) ethyl tolysulfonyl ester to replace 2-methylsulfonylethyl tolysulfonyl ester; according to making compound 3-(4-(((6-(2,6-dimethyl-4-(2-(piperazine-1-yl) oxyethyl group) phenyl) pyridine-2-yl) oxygen) methylene radical) phenyl) propionic acid with the similar method of embodiment 41. 1H?NMR(400MHz,CDCl 3)δ=7.62(dd,J=8.3,7.3Hz,1H),7.36(d,J=8.0Hz,2H),7.11(d,J=7.7Hz,2H),6.98(s,2H),6.78(d,J=7.2,1H),6.76(dd,J=8.3,0.8Hz,1H),5.35(s,2H),4.79(t,J=7.2Hz,2H),2.98(t,J=7.6Hz,2H),2.77(t,J=7.2Hz,2H),2.71(t,J=8.1Hz,4H),2.67(t,J=7.6Hz,2H),2.39(t,J=8.1Hz,4H),2.06(s,6H)。
The preparation of embodiment 58:3-(4-(((6-(2,6-dimethyl-4-(2-(4-methylpiperazine-1-yl) oxyethyl group) phenyl) pyridine-2-yl) oxygen) methylene radical) phenyl) propionic acid (compound H YH-055)
Except using 2-(4-methylpiperazine-1-yl) ethyl tolysulfonyl ester to replace 2-methylsulfonylethyl tolysulfonyl ester; according to making compound 3-(4-(((6-(2,6-dimethyl-4-(2-(4-methylpiperazine-1-yl) oxyethyl group) phenyl) pyridine-2-yl) oxygen) methylene radical) phenyl) propionic acid with the similar method of embodiment 41. 1H?NMR(400MHz,CDCl 3)δ=7.62(dd,J=8.3,7.3Hz,1H),7.36(d,J=8.0Hz,2H),7.11(d,J=7.7Hz,2H),6.98(s,2H),6.78(d,J=7.2,1H),6.76(dd,J=8.3,0.8Hz,1H),5.35(s,2H),4.79(t,J=7.2Hz,2H),2.98(t,J=7.6Hz,2H),2.77(t,J=7.2Hz,2H),2.67(t,J=7.6Hz,2H),2.44(t,J=8.1Hz,4H),2.39(t,J=8.1Hz,4H),2.18(s,3H),2.06(s,6H)。
The preparation of embodiment 59:3-(4-(((6-(2,6-dimethyl-4-(2-(methylsulfonyl) oxyethyl group) phenyl) pyridine-2-yl) oxygen) methylene radical)-2-fluorophenyl) propionic acid (compound H YH-056)
Except using 3-(4-(((6-(2; 6-dimethyl-4-hydroxy phenyl) pyridine-2-yl) oxygen) methylene radical)-2-fluorophenyl) ethyl propionate replacement 3-(4-(((6-(2; 6-dimethyl-4-hydroxy phenyl) pyridine-2-yl) oxygen) methylene radical) phenyl) outside ethyl propionate; according to making compound 3-(4-(((6-(2,6-dimethyl-4-(2-(methylsulfonyl) oxyethyl group) phenyl) pyridine-2-yl) oxygen) methylene radical)-2-fluorophenyl) propionic acid with the similar method of embodiment 41. 1H?NMR(400MHz,CDCl 3)δ=7.62(dd,J=8.3,7.3Hz,1H),7.38(d,J=8.0Hz,1H),7.11(d,J=7.7Hz,2H),6.98(s,2H),6.78(d,J=7.2,1H),6.76(dd,J=8.3,0.8Hz,1H),5.35(s,2H),4.82(t,J=7.2Hz,2H),3.78(t,J=7.2Hz,2H),2.99(t,J=7.6Hz,2H),2.89(s,3H),2.69(t,J=7.6Hz,2H),2.07(s,6H)。
The preparation of embodiment 60:3-(4-(((6-(2,6-dimethyl-4-(3-(methylsulfonyl) propoxy-) phenyl) pyridine-2-yl) oxygen) methylene radical)-2-fluorophenyl) propionic acid (compound H YH-057)
Except using 3-methylsulfonyl propyl group tolysulfonyl ester to replace 2-methylsulfonylethyl tolysulfonyl ester, and use 3-(4-(((6-(2, 6-dimethyl-4-hydroxy phenyl) pyridine-2-yl) oxygen) methylene radical)-2-fluorophenyl) ethyl propionate replacement 3-(4-(((6-(2, 6-dimethyl-4-hydroxy phenyl) pyridine-2-yl) oxygen) methylene radical) phenyl) outside ethyl propionate, according to making compound 3-(4-(((6-(2 with the similar method of embodiment 41, 6-dimethyl-4-(3-(methylsulfonyl) propoxy-) phenyl) pyridine-2-yl) oxygen) methylene radical)-2-fluorophenyl) propionic acid. 1H?NMR(400MHz,CDCl 3)δ=7.81–7.72(m,1H),7.24(t,J=8.0Hz,1H),7.15–7.05(m,2H),6.89–6.78(m,2H),6.67(s,2H),5.23(s,2H),4.13–3.94(m,2H),3.29–3.21(m,2H),3.01(s,3H),2.79–2.66(m,2H),2.18–2.08(m,4H),1.92(s,6H).
The preparation of embodiment 61:3-(4-(((6-(2,6-dimethyl-4-(2-methoxy ethoxy) phenyl) pyridine-2-yl) oxygen) methylene radical)-2-fluorophenyl) propionic acid (compound H YH-058)
Except using 2-methoxy ethyl tolysulfonyl ester to replace 2-methylsulfonylethyl tolysulfonyl ester, and use 3-(4-(((6-(2, 6-dimethyl-4-hydroxy phenyl) pyridine-2-yl) oxygen) methylene radical)-2-fluorophenyl) ethyl propionate replacement 3-(4-(((6-(2, 6-dimethyl-4-hydroxy phenyl) pyridine-2-yl) oxygen) methylene radical) phenyl) outside ethyl propionate, according to making compound 3-(4-(((6-(2 with the similar method of embodiment 41, 6-dimethyl-4-(2-methoxy ethoxy) phenyl) pyridine-2-yl) oxygen) methylene radical)-2-fluorophenyl) propionic acid. 1H?NMR(400MHz,CDCl 3)δ=7.62(dd,J=8.3,7.3Hz,1H),7.38(d,J=8.0Hz,1H),7.11(d,J=7.7Hz,2H),6.96(s,2H),6.78(d,J=7.2,1H),6.76(dd,J=8.3,0.8Hz,1H),5.35(s,2H),4.82(t,J=7.2Hz,2H),3.82(t,J=7.2Hz,2H),3.42(s,3H),2.99(t,J=7.6Hz,2H),2.69(t,J=7.6Hz,2H),2.07(s,6H)。
The preparation of embodiment 62:3-(4-(((6-(2,6-dimethyl-4-(3-methoxy propoxy) phenyl) pyridine-2-yl) oxygen) methylene radical)-2-fluorophenyl) propionic acid (compound H YH-059)
Except using 3-methoxy-propyl tolysulfonyl ester to replace 2-methylsulfonylethyl tolysulfonyl ester, and use 3-(4-(((6-(2, 6-dimethyl-4-hydroxy phenyl) pyridine-2-yl) oxygen) methylene radical)-2-fluorophenyl) ethyl propionate replacement 3-(4-(((6-(2, 6-dimethyl-4-hydroxy phenyl) pyridine-2-yl) oxygen) methylene radical) phenyl) outside ethyl propionate, according to making compound 3-(4-(((6-(2 with the similar method of embodiment 41, 6-dimethyl-4-(3-methoxy propoxy) phenyl) pyridine-2-yl) oxygen) methylene radical)-2-fluorophenyl) propionic acid. 1H?NMR(400MHz,CDCl 3)δ=7.62(dd,J=8.3,7.3Hz,1H),7.38(d,J=8.0Hz,1H),7.11(d,J=7.7Hz,2H),6.96(s,2H),6.78(d,J=7.2,1H),6.76(dd,J=8.3,0.8Hz,1H),5.35(s,2H),4.82(t,J=7.2Hz,2H),3.49(t,J=7.2Hz,2H),3.42(s,3H),2.99(t,J=7.6Hz,2H),2.69(t,J=7.6Hz,2H),2.14(m,J=7.2Hz,2H),2.07(s,6H)。
The preparation of embodiment 63:3-(4-(((6-(2,6-dimethyl-4-(2-dimethylamino oxyethyl group) phenyl) pyridine-2-yl) oxygen) methylene radical)-2-fluorophenyl) propionic acid (compound H YH-060)
Except using 2-dimethylaminoethyl tolysulfonyl ester to replace 2-methylsulfonylethyl tolysulfonyl ester, and use 3-(4-(((6-(2, 6-dimethyl-4-hydroxy phenyl) pyridine-2-yl) oxygen) methylene radical)-2-fluorophenyl) ethyl propionate replacement 3-(4-(((6-(2, 6-dimethyl-4-hydroxy phenyl) pyridine-2-yl) oxygen) methylene radical) phenyl) outside ethyl propionate, according to making compound 3-(4-(((6-(2 with the similar method of embodiment 41, 6-dimethyl-4-(2-dimethylamino oxyethyl group) phenyl) pyridine-2-yl) oxygen) methylene radical)-2-fluorophenyl) propionic acid. 1H?NMR(400MHz,CDCl 3)δ=7.62(dd,J=8.3,7.3Hz,1H),7.38(d,J=8.0Hz,1H),7.11(d,J=7.7Hz,2H),6.96(s,2H),6.78(d,J=7.2,1H),6.76(dd,J=8.3,0.8Hz,1H),5.35(s,2H),4.82(t,J=7.2Hz,2H),2.99(t,J=7.6Hz,2H),2.82(s,6H),2.69(t,J=7.2Hz,2H),2.69(t,J=7.6Hz,2H),2.07(s,6H)。
The preparation of embodiment 64:2-(6-(brooethyl)-2,3-Dihydrobenzofuranes-3-yl) ethyl acetate
Step 1: by 14.15g(102.4mmol) 3-methoxyl group benzylalcohol and 32.8mL triethylamine be dissolved in the methylene dichloride that 50mL is dry, under ice-water bath, add 1.3g DMAP, under stirring, be added dropwise to 11.1mL diacetyl oxide, then rise to stirred overnight at room temperature, concentrate and remove most of solvent, add ethyl acetate 200mL, with 1N hydrochloric acid soln washing 3 times, organic layer is with concentrated after anhydrous sodium sulfate drying, with silica gel column chromatography separation (ethyl acetate: sherwood oil=1:20), obtaining 3-methoxybenzyl alcohol acetic ester 17.7g, is colorless oil, productive rate 96%. 1H?NMR(CDCl 3,400MHz)δ：7.25(t,J=8.0Hz,1H),6.92(d,J=8.0Hz,1H),6.89(s,1H),6.85(d,J=8.0Hz,1H),5.06(s,2H),3.78(s,3H),2.08(s,3H)。
Step 2: 3-methoxybenzyl alcohol acetic ester 9.7g is dissolved in 40mL anhydrous methylene chloride, is added dropwise to 12.8mL chloroacetyl chloride under room temperature, then divide the multiple batches of 23.6g of adding Aluminum chloride anhydrous, then back flow reaction 16 hours.After being chilled to room temperature, reaction solution pours in 500mL frozen water; with dichloromethane extraction three times; after combined dichloromethane, wash with saturated sodium bicarbonate solution; then use anhydrous sodium sulfate drying; after concentrated, silica gel column chromatography separates (ethyl acetate: sherwood oil=1:9～1:1); obtaining 4-(the chloro-ethanoyl of 2-)-3-hydroxyl-benzylalcohol acetic ester 2.63g, is light brown solid, productive rate 20%. 1H?NMR(CDCl 3,400MHz)δ：11.67(s,1H),7.67(d,J=8.0Hz,1H),6.97(s,1H),6.88(d,J=8.0Hz,1H),5.09(s,2H),4.69(s,2H),2.14(s,3H)。
Step 3: 4-(the chloro-ethanoyl of 2-)-3-hydroxyl-benzylalcohol acetic ester 2.20g is dissolved in 40mL anhydrous methanol; add sodium acetate 1.49g; back flow reaction 2 hours, is chilled to room temperature, revolves to steam to remove most of solvent; residue is dissolved in methylene dichloride; water washing, dry rear column chromatography for separation (ethyl acetate: sherwood oil=1:6), obtains 3-oxo-2; 3-Dihydrobenzofuranes-6-methylol acetic ester 1.30g, productive rate 59%. 1HNMR(CDCl 3,400MHz)δ：7.67(d,J=8.0Hz,1H),7.13(s,1H),7.06(d,J=8.0Hz,1H),5.17(s,2H),4.65(s,2H),2.17(s,3H)。
Step 4: by 3-oxo-2; 3-Dihydrobenzofuranes-6-methylol acetic ester 1.50g is dissolved in 100mL dry toluene; add ethoxycarbonyl methylene tri Phenylphosphine 12.67g; mixed-liquor return reaction 24 hours, reaction solution is cooled to room temperature, revolves to steam to remove most of solvent; residue silica gel column chromatography separates (ethyl acetate: sherwood oil=1:20); obtaining (6-methylol acetic ester-cumarone-3-yl) ethyl acetate 1.15g, is off-white color solid, productive rate 57%. 1H?NMR(CDCl 3,400MHz)δ：7.65(s,1H),7.56(d,J=8.0Hz,1H),7.50(s,1H),7.26(d,J=8.0Hz,1H),5.21(s,2H),4.19(q,J=7.1Hz,2H),3.69(s,2H),2.11(s,3H),1.27(t,J=7.1Hz,3H).
Step 5: (6-methylol acetic ester-cumarone-3-yl) ethyl acetate 1.15g is dissolved in 20mL ethyl acetate, add 10%Pd/C100mg, ambient temperature overnight under the atmosphere of hydrogen of a barometric point, pad diatomite comes to remove palladium carbon, and after filtrate is concentrated, silicagel column separates, and obtains (6-methylol acetic ester-2,3-Dihydrobenzofuranes-3-yl) ethyl acetate 1.0g, for white solid, productive rate 86% 1h NMR (CDCl 3, 400MHz) and δ: 7.26 (d, J=8.0Hz, 1H), 7.05 (s, 1H), 6.73 (d, J=8.0Hz, 1H), 5.21 (s, 2H), 4.36 (m, 1H), 4.19 (q, J=7.1Hz, 2H), 4.08 (m, 1H), 3.89 (m, 1H), 2.65 (m, 1H), 2.44 (m, 1H), 2.11 (s, 3H), 1.27 (t, J=7.1Hz, 3H).
Step 6: (6-methylol acetic ester-2,3-Dihydrobenzofuranes-3-yl) ethyl acetate 1.0g is dissolved in 20mL acetonitrile, adds water 4mL, under stirring, add 100mg lithium hydroxide, at 50 DEG C, react 4 hours, be cooled to room temperature, add water 50mL, with dichloromethane extraction 3 times, merge organic layer anhydrous sodium sulfate drying, obtain (6-methylol-2,3-Dihydrobenzofuranes-3-yl) acetic acid 0.68g, for off-white color solid, productive rate 91%. 1H?NMR(CDCl 3,400MHz)δ：7.26(d,J=8.0Hz,1H),7.05(s,1H),6.73(d,J=8.0Hz,1H),5.21(s,2H),4.36(m,1H),4.08(m,1H),3.89(m,1H),2.65(m,1H),2.44(m,1H)。
Step 7: by (6-methylol-2,3-Dihydrobenzofuranes-3-yl) acetic acid 0.65g joins in 10mL round-bottomed flask, be added dropwise to 1mL phosphorus tribromide, at 80 DEG C, react 2 hours, reaction solution is chilled to 0 DEG C, slowly be added dropwise to 1.0mL dehydrated alcohol, then reaction solution is poured onto in 100mL frozen water, ethyl acetate extraction three times, merge organic layer anhydrous sodium sulfate drying, filtering and concentrating obtains (6-methylol-2,3-Dihydrobenzofuranes-3-yl) ethyl acetate 0.72g, for light yellow solid, productive rate 84%. 1H?NMR(CDCl 3,400MHz)δ：7.24(d,J=8.0Hz,1H),6.95(s,1H),6.76(d,J=8.0Hz,1H),4.48(s,2H),4.36(m,1H),4.19(q,J=7.1Hz,2H),4.08(m,1H),3.89(m,1H),2.65(m,1H),2.44(m,1H),1.27(t,J=7.1Hz,3H)。
Embodiment 65:2-(6-(((6-(2; 6-dimethyl-4-(2-(methylsulfonyl) oxyethyl group) phenyl) pyridine-2-yl) oxygen) methylene radical)-2,3-Dihydrobenzofuranes-3-yl) preparation of acetic acid (compound H YH-061)
Step 1: by 0.5g (6-methylol-2,3-Dihydrobenzofuranes-3-yl) ethyl acetate and the bromo-6-pyridone of 0.29g2-be dissolved in 20mL acetonitrile, add 0.35g salt of wormwood, then be placed in 60 DEG C of reactions 3 hours, be chilled to room temperature, evaporating column separates, and obtains 2-(6-(((6-bromopyridine-2-yl) oxygen) methylene radical)-2,3-Dihydrobenzofuranes-3-yl) ethyl acetate 0.58g, productive rate 88%. 1H?NMR(CDCl 3,400MHz)δ：7.41(dd,J=15.1,7.5Hz,1H),7.24(d,J=8.0Hz,1H),7.07(d,J=7.4Hz,1H),6.95(s,1H),6.76(d,J=8.0Hz,1H),6.72(d,J=8.2Hz,1H),5.11(s,2H),4.33-4.37(m,1H),4.19(q,J=7.1Hz,2H),4.02-4.09(m,1H),3.82-3.89(m,1H),2.61-2.67(m,1H),2.42-2.47(m,1H),1.27(t,J=7.1Hz,3H)。
Step 2: take 100.0mg compound 2-(6-(((6-bromopyridine-2-yl) oxygen) methylene radical)-2, 3-Dihydrobenzofuranes-3-yl) ethyl acetate, 65.0mg4-hydroxyl-2, 6-dimethylphenyl boronic acid, 15.0mg tetrakis triphenylphosphine palladium and 75.0mg salt of wormwood join in 10mL microwave reactor dedicated pipe, add 2.0mL toluene, 0.4mL ethanol and 0.4mL water, with nitrogen replacement 3 times, then be placed in 120 DEG C of reactions of CEM microwave reactor 30 minutes, after reaction solution is concentrated, silica gel column chromatography separates, obtain 2-(6-(((6-(4-hydroxyl-2, 6-3,5-dimethylphenyl) pyridine-2-yl) oxygen base) methylene radical)-2, 3-Dihydrobenzofuranes-3-yl) ethyl acetate 97.0mg, for white solid. 1H?NMR(CDCl 3,400MHz)δ：7.41(dd,J=15.1,7.5Hz,1H),7.24(d,J=8.0Hz,1H),7.07(d,J=7.4Hz,1H),6.95(s,1H),6.87(s,2H),6.76(d,J=8.0Hz,1H),6.72(d,J=8.2Hz,1H),5.11(s,2H),4.33-4.37(m,1H),4.19(q,J=7.1Hz,2H),4.02-4.09(m,1H),3.82-3.89(m,1H),2.61-2.67(m,1H),2.42-2.47(m,1H),2.08(s,6H),1.27(t,J=7.1Hz,3H)。
Step 3 and step 4: except using 2-(6-(((6-(4-hydroxyl-2, 6-3,5-dimethylphenyl) pyridine-2-yl) oxygen) methylene radical)-2, 3-Dihydrobenzofuranes-3-yl) ethyl acetate replacement 3-(4-(((6-(2, 6-dimethyl-4-hydroxy phenyl) pyridine-2-yl) oxygen) methylene radical) phenyl) outside ethyl propionate, according to being prepared into 2-(6-(((6-(2 with similar method shown in embodiment 42, 6-dimethyl-4-(2-(methylsulfonyl) oxyethyl group) phenyl) pyridine-2-yl) oxygen) methylene radical)-2, 3-Dihydrobenzofuranes-3-yl) acetic acid. 1H?NMR(CDCl 3,400MHz)δ：7.41(dd,J=15.1,7.5Hz,1H),7.24(d,J=8.0Hz,1H),7.07(d,J=7.4Hz,1H),6.95(s,1H),6.87(s,2H),6.76(d,J=8.0Hz,1H),6.72(d,J=8.2Hz,1H),5.11(s,2H),4.33-4.37(m,1H),4.13(q,J=6.1Hz,2H),4.02-4.07(m,1H),3.82-3.89(m,1H),3.79(q,J=6.1Hz,2H),2.97(s,3H),2.61-2.67(m,1H),2.42-2.47(m,1H),2.08(s,6H)。
Embodiment 66:2-(6-(((6-(2; 6-dimethyl-4-(3-(methylsulfonyl) propoxy-) phenyl) pyridine-2-yl) oxygen) methylene radical)-2,3-Dihydrobenzofuranes-3-yl) preparation of acetic acid (compound H YH-062)
Except using 3-methylsulfonyl propyl group tolysulfonyl ester to replace 2-methylsulfonylethyl tolysulfonyl ester; according to making compound 2-(6-(((6-(2 with the similar method of embodiment 65; 6-dimethyl-4-(3-(methylsulfonyl) propoxy-) phenyl) pyridine-2-yl) oxygen) methylene radical)-2,3-Dihydrobenzofuranes-3-yl) acetic acid. 1H?NMR(CDCl 3,400MHz)δ：7.41(dd,J=15.1,7.5Hz,1H),7.24(d,J=8.0Hz,1H),7.07(d,J=7.4Hz,1H),6.95(s,1H),6.87(s,2H),6.76(d,J=8.0Hz,1H),6.72(d,J=8.2Hz,1H),5.11(s,2H),4.33-4.37(m,1H),4.13(q,J=5.8Hz,2H),4.02-4.07(m,1H),3.82-3.89(m,1H),3.23-3.31(m,2H),2.97(s,3H),2.61-2.67(m,1H),2.42-2.47(m,1H),2.29-2.35(m,2H),2.08(s,6H)。
Embodiment 67:2-(6-(((6-(2; 6-dimethyl-4-(4-(methylsulfonyl) butoxy) phenyl) pyridine-2-yl) oxygen) methylene radical)-2,3-Dihydrobenzofuranes-3-yl) preparation of acetic acid (compound H YH-063)
Except using 4-methylsulfonyl butyl tolysulfonyl ester to replace 2-methylsulfonylethyl tolysulfonyl ester; according to making compound 2-(6-(((6-(2 with the similar method of embodiment 65; 6-dimethyl-4-(4-(methylsulfonyl) butoxy) phenyl) pyridine-2-yl) oxygen) methylene radical)-2,3-Dihydrobenzofuranes-3-yl) acetic acid. 1H?NMR(CDCl 3,400MHz)δ：7.41(dd,J=15.1,7.5Hz,1H),7.24(d,J=8.0Hz,1H),7.07(d,J=7.4Hz,1H),6.95(s,1H),6.87(s,2H),6.76(d,J=8.0Hz,1H),6.72(d,J=8.2Hz,1H),5.11(s,2H),4.33-4.37(m,1H),4.13(q,J=5.8Hz,2H),4.02-4.07(m,1H),3.82-3.89(m,1H),3.23-3.31(m,2H),2.97(s,3H),2.61-2.67(m,1H),2.42-2.47(m,1H),2.08(s,6H),1.67-1.85(m,4H)。
Embodiment 68:2-(6-(((6-(2; 6-dimethyl-4-(3-(ethylsulfonyl) propoxy-) phenyl) pyridine-2-yl) oxygen) methylene radical)-2,3-Dihydrobenzofuranes-3-yl) preparation of acetic acid (compound H YH-064)
Except using 3-ethylsulfonyl propyl group tolysulfonyl ester to replace 2-methylsulfonylethyl tolysulfonyl ester; according to making compound 2-(6-(((6-(2 with the similar method of embodiment 65; 6-dimethyl-4-(3-(ethylsulfonyl) propoxy-) phenyl) pyridine-2-yl) oxygen) methylene radical)-2,3-Dihydrobenzofuranes-3-yl) acetic acid. 1H?NMR(CDCl 3,400MHz)δ：7.41(dd,J=15.1,7.5Hz,1H),7.24(d,J=8.0Hz,1H),7.07(d,J=7.4Hz,1H),6.95(s,1H),6.87(s,2H),6.76(d,J=8.0Hz,1H),6.72(d,J=8.2Hz,1H),5.11(s,2H),4.33-4.37(m,1H),4.13(q,J=5.8Hz,2H),4.02-4.07(m,1H),3.82-3.89(m,1H),3.23-3.31(m,2H),2.94(q,J=7.2Hz,2H),2.61-2.67(m,1H),2.42-2.47(m,1H),2.29-2.35(m,2H),2.08(s,6H),1.28(t,J=7.2Hz,3H)。
Embodiment 69:2-(6-(((6-(2,6-dimethyl-4-(2-methoxy ethoxy) phenyl) pyridine-2-yl) oxygen) methylene radical)-2,3-Dihydrobenzofuranes-3-yl) preparation of acetic acid (compound H YH-065)
Except using 2-methoxy ethyl tolysulfonyl ester to replace 2-methylsulfonylethyl tolysulfonyl ester; according to making compound 2-(6-(((6-(2 with the similar method of embodiment 65; 6-dimethyl-4-(2-methoxy ethoxy) phenyl) pyridine-2-yl) oxygen) methylene radical)-2,3-Dihydrobenzofuranes-3-yl) acetic acid. 1H?NMR(CDCl 3,400MHz)δ：7.41(dd,J=15.1,7.5Hz,1H),7.24(d,J=8.0Hz,1H),7.07(d,J=7.4Hz,1H),6.95(s,1H),6.87(s,2H),6.76(d,J=8.0Hz,1H),6.72(d,J=8.2Hz,1H),5.11(s,2H),4.79(q,J=6.1Hz,2H),4.33-4.37(m,1H),4.02-4.07(m,1H),3.82-3.89(m,1H),3.87(q,J=6.1Hz,2H),3.45(s,3H),2.61-2.67(m,1H),2.42-2.47(m,1H),2.08(s,6H)。
Embodiment 70:2-(6-(((6-(2,6-dimethyl-4-(3-methoxy propoxy) phenyl) pyridine-2-yl) oxygen) methylene radical)-2,3-Dihydrobenzofuranes-3-yl) preparation of acetic acid (compound H YH-066)
Except using 3-methoxy-propyl tolysulfonyl ester to replace 2-methylsulfonylethyl tolysulfonyl ester; according to making compound 2-(6-(((6-(2 with the similar method of embodiment 65; 6-dimethyl-4-(3-methoxy propoxy) phenyl) pyridine-2-yl) oxygen) methylene radical)-2,3-Dihydrobenzofuranes-3-yl) acetic acid. 1H?NMR(CDCl 3,400MHz)δ：7.41(dd,J=15.1,7.5Hz,1H),7.24(d,J=8.0Hz,1H),7.07(d,J=7.4Hz,1H),6.95(s,1H),6.87(s,2H),6.76(d,J=8.0Hz,1H),6.72(d,J=8.2Hz,1H),5.11(s,2H),4.33-4.37(m,1H),4.13(q,J=5.8Hz,2H),4.02-4.07(m,1H),3.82-3.89(m,1H),3.45(s,3H),3.18-3.27(m,2H),2.61-2.67(m,1H),2.42-2.47(m,1H),2.11-2.17(m,2H),2.08(s,6H)。
Embodiment 71:2-(6-(((6-(2,6-dimethyl-4-(2-dimethylamino oxyethyl group) phenyl) pyridine-2-yl) oxygen) methylene radical)-2,3-Dihydrobenzofuranes-3-yl) preparation of acetic acid (compound H YH-067)
Except using 2-dimethylaminoethyl tolysulfonyl ester to replace 2-methylsulfonylethyl tolysulfonyl ester; according to making compound 2-(6-(((6-(2 with the similar method of embodiment 65; 6-dimethyl-4-(2-dimethylamino oxyethyl group) phenyl) pyridine-2-yl) oxygen) methylene radical)-2,3-Dihydrobenzofuranes-3-yl) acetic acid. 1H?NMR(CDCl 3,400MHz)δ：7.41(dd,J=15.1,7.5Hz,1H),7.24(d,J=8.0Hz,1H),7.07(d,J=7.4Hz,1H),6.95(s,1H),6.87(s,2H),6.76(d,J=8.0Hz,1H),6.72(d,J=8.2Hz,1H),5.11(s,2H),4.79(t,J=7.2Hz,2H),4.33-4.37(m,1H),4.02-4.09(m,1H),3.82-3.89(m,1H),2.85(s,6H),2.77(t,J=7.2Hz,2H),2.61-2.67(m,1H),2.42-2.47(m,1H),2.08(s,6H)。
Embodiment 72:2-(6-(((6-(2,6-dimethyl-4-(3-dimethylamino propoxy-) phenyl) pyridine-2-yl) oxygen) methylene radical)-2,3-Dihydrobenzofuranes-3-yl) preparation of acetic acid (compound H YH-068)
Except using 3-dimethylamino-propyl tolysulfonyl ester to replace 2-methylsulfonylethyl tolysulfonyl ester; according to making compound 2-(6-(((6-(2 with the similar method of embodiment 65; 6-dimethyl-4-(3-dimethylamino propoxy-) phenyl) pyridine-2-yl) oxygen) methylene radical)-2,3-Dihydrobenzofuranes-3-yl) acetic acid. 1H?NMR(CDCl 3,400MHz)δ：7.41(dd,J=15.1,7.5Hz,1H),7.24(d,J=8.0Hz,1H),7.07(d,J=7.4Hz,1H),6.95(s,1H),6.87(s,2H),6.76(d,J=8.0Hz,1H),6.72(d,J=8.2Hz,1H),5.11(s,2H),4.79(t,J=7.2Hz,2H),4.33-4.37(m,1H),4.02-4.09(m,1H),3.82-3.89(m,1H),2.85(s,6H),2.69(t,J=7.6Hz,2H),2.61-2.67(m,1H),2.42-2.47(m,1H),2.08(s,6H),1.79(q,J=7.2Hz,2H)。
Embodiment 73:2-(6-(((6-(2,6-dimethyl-4-((tetrahydrochysene-2H-pyrans-4-yl) oxygen base) phenyl) pyridine-2-yl) oxygen) methylene radical)-2,3-Dihydrobenzofuranes-3-yl) preparation of acetic acid (compound H YH-069)
Except using tetrahydrochysene-2H-pyrans-4-tolylsulfonyl ester to replace 2-methylsulfonylethyl tolysulfonyl ester; according to making compound 2-(6-(((6-(2 with the similar method of embodiment 65; 6-dimethyl-4-((tetrahydrochysene-2H-pyrans-4-yl) oxygen) phenyl) pyridine-2-yl) oxygen base) methylene radical)-2,3-Dihydrobenzofuranes-3-yl) acetic acid. 1H?NMR(CDCl 3,400MHz)δ：7.41(dd,J=15.1,7.5Hz,1H),7.24(d,J=8.0Hz,1H),7.07(d,J=7.4Hz,1H),6.95(s,1H),6.87(s,2H),6.76(d,J=8.0Hz,1H),6.72(d,J=8.2Hz,1H),5.11(s,2H),4.33-4.37(m,1H),4.02-4.09(m,1H),3.82-3.89(m,1H),3.71-3.79(m,1H),3.57-3.61(m,2H),3.50-3.55(m,2H),2.61-2.67(m,1H),2.42-2.47(m,1H),2.13-2.16(m,2H),2.08(s,6H),1.85-1.89(m,2H)。
Embodiment 74:2-(6-(((6-(2,6-dimethyl-4-((tetrahydrochysene-2H-thiapyran-4-yl) oxygen base) phenyl) pyridine-2-yl) oxygen) methylene radical)-2,3-Dihydrobenzofuranes-3-yl) preparation of acetic acid (compound H YH-070)
Except using tetrahydrochysene-2H-thiapyran-4-tolylsulfonyl ester to replace 2-methylsulfonylethyl tolysulfonyl ester; according to making compound 2-(6-(((6-(2 with the similar method of embodiment 65; 6-dimethyl-4-((tetrahydrochysene-2H-thiapyran-4-yl) oxygen) phenyl) pyridine-2-yl) oxygen base) methylene radical)-2,3-Dihydrobenzofuranes-3-yl) acetic acid. 1H?NMR(CDCl 3,400MHz)δ：7.41(dd,J=15.1,7.5Hz,1H),7.24(d,J=8.0Hz,1H),7.07(d,J=7.4Hz,1H),6.95(s,1H),6.87(s,2H),6.76(d,J=8.0Hz,1H),6.72(d,J=8.2Hz,1H),5.11(s,2H),4.33-4.37(m,1H),4.02-4.09(m,1H),3.88-3.97(m,1H),3.80-3.86(m,1H),2.61-2.67(m,3H),2.52-2.59(m,2H),2.42-2.47(m,1H),2.18-2.27(m,2H),2.08(s,6H),1.86-1.97(m,2H)。
Embodiment 75:2-(6-(((6-(2,6-dimethyl-4-(piperidin-4-yl oxygen base) phenyl) pyridine-2-yl) oxygen) methylene radical)-2,3-Dihydrobenzofuranes-3-yl) preparation of acetic acid (compound H YH-071)
Except using piperidines-4-tolylsulfonyl ester to replace 2-methylsulfonylethyl tolysulfonyl ester; according to making compound 2-(6-(((6-(2 with the similar method of embodiment 65; 6-dimethyl-4-(piperidin-4-yl oxygen base) phenyl) pyridine-2-yl) oxygen) methylene radical)-2,3-Dihydrobenzofuranes-3-yl) acetic acid. 1H?NMR(CDCl 3,400MHz)δ：7.41(dd,J=15.1,7.5Hz,1H),7.24(d,J=8.0Hz,1H),7.07(d,J=7.4Hz,1H),6.95(s,1H),6.87(s,2H),6.76(d,J=8.0Hz,1H),6.72(d,J=8.2Hz,1H),5.11(s,2H),4.33-4.37(m,1H),4.02-4.09(m,1H),3.82-3.89(m,1H),3.71-3.79(m,1H),2.61-2.67(m,5H),2.42-2.47(m,1H),2.13-2.16(m,2H),2.08(s,6H),1.85-1.89(m,2H)。
Embodiment 76:2-(6-(((6-(2,6-dimethyl-4-((1-methyl piperidine-4-yl) oxygen base) phenyl) pyridine-2-yl) oxygen) methylene radical)-2,3-Dihydrobenzofuranes-3-yl) preparation of acetic acid (compound H YH-072)
Except using 1-methyl piperidine-4-tolylsulfonyl ester to replace 2-methylsulfonylethyl tolysulfonyl ester; according to making compound 2-(6-(((6-(2 with the similar method of embodiment 65; 6-dimethyl-4-(1-methyl piperidine-4-yl) oxygen) phenyl) pyridine-2-yl) oxygen base) methylene radical)-2,3-Dihydrobenzofuranes-3-yl) acetic acid. 1H?NMR(CDCl 3,400MHz)δ：7.41(dd,J=15.1,7.5Hz,1H),7.24(d,J=8.0Hz,1H),7.07(d,J=7.4Hz,1H),6.95(s,1H),6.87(s,2H),6.76(d,J=8.0Hz,1H),6.72(d,J=8.2Hz,1H),5.11(s,2H),4.33-4.37(m,1H),4.02-4.09(m,1H),3.82-3.89(m,1H),3.71-3.79(m,1H),2.61-2.67(m,5H),2.42-2.47(m,1H),2.26(s,2H),2.13-2.16(m,2H),2.08(s,6H),1.85-1.89(m,2H)。
Embodiment 77:2-(6-(((6-(2,6-dimethyl-4-((1,1-dioxo tetrahydrochysene-2H-thiapyran-4-yl) oxygen base) phenyl) pyridine-2-yl) oxygen) methylene radical)-2,3-Dihydrobenzofuranes-3-yl) preparation of acetic acid (compound H YH-073)
Except using 1; 1-dioxo tetrahydrochysene-2H-thiapyran-4-tolylsulfonyl ester replaces outside 2-methylsulfonylethyl tolysulfonyl ester; according to making compound 2-(6-(((6-(2 with the similar method of embodiment 65; 6-dimethyl-4-((1; 1-dioxo tetrahydrochysene-2H-thiapyran-4-yl) oxygen base) phenyl) pyridine-2-yl) oxygen) methylene radical)-2,3-Dihydrobenzofuranes-3-yl) acetic acid. 1H?NMR(CDCl 3,400MHz)δ：7.41(dd,J=15.1,7.5Hz,1H),7.24(d,J=8.0Hz,1H),7.07(d,J=7.4Hz,1H),6.95(s,1H),6.87(s,2H),6.76(d,J=8.0Hz,1H),6.72(d,J=8.2Hz,1H),5.11(s,2H),4.33-4.37(m,1H),4.02-4.09(m,1H),3.82-3.89(m,1H),3.42-3.48(m,4H),2.61-2.67(m,1H),2.42-2.47(m,3H),2.11-2.19(m,2H),2.08(s,6H)。
Embodiment 78:2-(6-(((6-(4-((4-hydroxyl-1,1-dioxo tetrahydrochysene-2H-thiapyran-4-yl) methoxyl group)-2,6-3,5-dimethylphenyl) pyridine-2-yl) oxygen) methylene radical)-2,3-Dihydrobenzofuranes-3-yl) preparation of acetic acid (compound H YH-074)
Except using (4-hydroxyl-1; 1-dioxo tetrahydrochysene-2H-thiapyran-4-yl) methyl tolylsulfonyl ester replaces outside 2-methylsulfonylethyl tolysulfonyl ester; according to making compound 2-(6-(((6-(4-((4-hydroxyl-1 with the similar method of embodiment 65; 1-dioxo tetrahydrochysene-2H-thiapyran-4-yl) methoxyl group)-2; 6-3,5-dimethylphenyl) pyridine-2-yl) oxygen) methylene radical)-2,3-Dihydrobenzofuranes-3-yl) acetic acid. 1H?NMR(CDCl 3,400MHz)δ：7.41(dd,J=15.1,7.5Hz,1H),7.24(d,J=8.0Hz,1H),7.07(d,J=7.4Hz,1H),6.95(s,1H),6.87(s,2H),6.76(d,J=8.0Hz,1H),6.72(d,J=8.2Hz,1H),5.06(s,2H),4.76(t,J=9.1Hz,1H),4.29(dd,J=9.1,6.0Hz,1H),3.88(s,2H),3.75-3.86(m,1H),3.43-3.56(m,2H),2.90-3.01(m,2H),2.76-2.85(m,1H),2.56-2.67(m,1H),2.17-2.33(m,4H),2.06(s,6H)。
Embodiment 79:2-(6-(((6-(2,6-dimethyl-4-(2-(pyrrolidin-1-yl) oxyethyl group) phenyl) pyridine-2-yl) oxygen) methylene radical)-2,3-Dihydrobenzofuranes-3-yl) preparation of acetic acid (compound H YH-075)
Except using 2-(pyrrolidin-1-yl) ethyltoluene sulfonyl ester to replace 2-methylsulfonylethyl tolysulfonyl ester; according to making compound 2-(6-(((6-(2 with the similar method of embodiment 65; 6-dimethyl-4-(2-(pyrrolidin-1-yl) oxyethyl group) phenyl) pyridine-2-yl) oxygen) methylene radical)-2,3-Dihydrobenzofuranes-3-yl) acetic acid. 1H?NMR(CDCl 3,400MHz)δ：7.41(dd,J=15.1,7.5Hz,1H),7.24(d,J=8.0Hz,1H),7.07(d,J=7.4Hz,1H),6.95(s,1H),6.87(s,2H),6.76(d,J=8.0Hz,1H),6.72(d,J=8.2Hz,1H),5.11(s,2H),4.79(t,J=7.2Hz,2H),4.33-4.37(m,1H),4.02-4.09(m,1H),3.82-3.89(m,1H),2.61-2.72(m,3H),2.46-2.55(m,5H),2.06(s,6H),1.66-1.73(m,4H)。
Embodiment 80:2-(6-(((6-(2,6-dimethyl-4-(2-(piperidin-1-yl) oxyethyl group) phenyl) pyridine-2-yl) oxygen) methylene radical)-2,3-Dihydrobenzofuranes-3-yl) preparation of acetic acid (compound H YH-076)
Except using 2-(piperidin-1-yl) ethyltoluene sulfonyl ester to replace 2-methylsulfonylethyl tolysulfonyl ester; according to making compound 2-(6-(((6-(2 with the similar method of embodiment 65; 6-dimethyl-4-(2-(piperidin-1-yl) oxyethyl group) phenyl) pyridine-2-yl) oxygen) methylene radical)-2,3-Dihydrobenzofuranes-3-yl) acetic acid. 1H?NMR(CDCl 3,400MHz)δ：7.41(dd,J=15.1,7.5Hz,1H),7.24(d,J=8.0Hz,1H),7.07(d,J=7.4Hz,1H),6.95(s,1H),6.87(s,2H),6.76(d,J=8.0Hz,1H),6.72(d,J=8.2Hz,1H),5.11(s,2H),4.79(t,J=7.2Hz,2H),4.33-4.37(m,1H),4.02-4.09(m,1H),3.82-3.89(m,1H),2.77(t,J=7.2Hz,2H),2.61-2.67(m,1H),2.42-2.47(m,5H),2.06(s,6H),1.61-1.69(m,6H)。
Embodiment 81:2-(6-(((6-(2,6-dimethyl-4-(2-(morpholine-1-yl) oxyethyl group) phenyl) pyridine-2-yl) oxygen) methylene radical)-2,3-Dihydrobenzofuranes-3-yl) preparation of acetic acid (compound H YH-077)
Except using 2-(morpholine-1-yl) ethyltoluene sulfonyl ester to replace 2-methylsulfonylethyl tolysulfonyl ester; according to making compound 2-(6-(((6-(2 with the similar method of embodiment 65; 6-dimethyl-4-(2-(morpholine-1-yl) oxyethyl group) phenyl) pyridine-2-yl) oxygen) methylene radical)-2,3-Dihydrobenzofuranes-3-yl) acetic acid. 1H?NMR(CDCl 3,400MHz)δ：7.41(dd,J=15.1,7.5Hz,1H),7.24(d,J=8.0Hz,1H),7.07(d,J=7.4Hz,1H),6.95(s,1H),6.87(s,2H),6.76(d,J=8.0Hz,1H),6.72(d,J=8.2Hz,1H),5.11(s,2H),4.79(t,J=7.2Hz,2H),4.33-4.37(m,1H),4.02-4.09(m,1H),3.82-3.89(m,1H),3.65(t,J=8.1Hz,4H),2.77(t,J=7.2Hz,2H),2.61-2.67(m,1H),2.41-2.47(m,5H),2.08(s,6H)。
Embodiment 82:2-(6-(((6-(2,6-dimethyl-4-(2-(piperazine-1-yl) oxyethyl group) phenyl) pyridine-2-yl) oxygen) methylene radical)-2,3-Dihydrobenzofuranes-3-yl) preparation of acetic acid (compound H YH-078)
Except using 2-(piperazine-1-yl) ethyltoluene sulfonyl ester to replace 2-methylsulfonylethyl tolysulfonyl ester; according to making compound 2-(6-(((6-(2 with the similar method of embodiment 65; 6-dimethyl-4-(2-(piperazine-1-yl) oxyethyl group) phenyl) pyridine-2-yl) oxygen) methylene radical)-2,3-Dihydrobenzofuranes-3-yl) acetic acid. 1H?NMR(CDCl 3,400MHz)δ：7.41(dd,J=15.1,7.5Hz,1H),7.24(d,J=8.0Hz,1H),7.07(d,J=7.4Hz,1H),6.95(s,1H),6.87(s,2H),6.76(d,J=8.0Hz,1H),6.72(d,J=8.2Hz,1H),5.11(s,2H),4.79(t,J=7.2Hz,2H),4.33-4.37(m,1H),4.02-4.09(m,1H),3.82-3.89(m,1H),2.77(t,J=7.2Hz,2H),2.71(t,J=8.1Hz,4H),2.61-2.67(m,1H),2.39-2.47(m,5H),2.08(s,6H)。
Embodiment 83:2-(6-(((6-(2,6-dimethyl-4-(2-(4-methylpiperazine-1-yl) oxyethyl group) phenyl) pyridine-2-yl) oxygen) methylene radical)-2,3-Dihydrobenzofuranes-3-yl) preparation of acetic acid (compound H YH-079)
Except using 2-(4-methylpiperazine-1-yl) ethyltoluene sulfonyl ester to replace 2-methylsulfonylethyl tolysulfonyl ester; according to making compound 2-(6-(((6-(2 with the similar method of embodiment 65; 6-dimethyl-4-(2-(4-methylpiperazine-1-yl) oxyethyl group) phenyl) pyridine-2-yl) oxygen) methylene radical)-2,3-Dihydrobenzofuranes-3-yl) acetic acid. 1H?NMR(CDCl 3,400MHz)δ：7.41(dd,J=15.1,7.5Hz,1H),7.24(d,J=8.0Hz,1H),7.07(d,J=7.4Hz,1H),6.95(s,1H),6.87(s,2H),6.76(d,J=8.0Hz,1H),6.72(d,J=8.2Hz,1H),5.11(s,2H),4.79(t,J=7.2Hz,2H),4.33-4.37(m,1H),4.02-4.09(m,1H),3.82-3.89(m,1H),2.77(t,J=7.2Hz,2H),2.71(t,J=8.1Hz,4H),2.61-2.67(m,1H),2.39-2.47(m,5H),2.26(s,3H),2.08(s,6H)。
Embodiment 84:2-(6-(((6-(2; 6-dimethyl-4-(2-(methylsulfonyl) oxyethyl group) phenyl) pyridine-2-yl) oxygen) methylene radical)-2,3-dihydrobenzo thiene-3-yl-) preparation of acetic acid (compound H YH-080)
Step 1: except using 3-methylthio group benzylalcohol to replace 3-methoxyl group benzylalcohol, according to making compound 2-(6-(brooethyl)-2,3-dihydrobenzo thiene-3-yl-) ethyl acetate with the similar method of embodiment 64.
Step 2: except using 2-(6-(brooethyl)-2; 3-dihydrobenzo thiene-3-yl-) ethyl acetate replacement 2-(6-(brooethyl)-2; 3-Dihydrobenzofuranes-3-yl) outside ethyl acetate; according to making compound 2-(6-(((6-(2 with the similar method of embodiment 65; 6-dimethyl-4-(2-(methylsulfonyl) oxyethyl group) phenyl) pyridine-2-yl) oxygen) methylene radical)-2,3-dihydrobenzo thiene-3-yl-) acetic acid. 1H?NMR(CDCl 3,400MHz)δ：7.41(dd,J=15.1,7.5Hz,1H),7.24(d,J=8.0Hz,1H),7.07(d,J=7.4Hz,1H),6.95(s,1H),6.87(s,2H),6.76(d,J=8.0Hz,1H),6.72(d,J=8.2Hz,1H),5.11(s,2H),4.33-4.36(m,1H),4.11-4.19(m,3H),3.92-3.99(m,1H),3.79(q,J=6.1Hz,2H),2.97(s,3H),2.61-2.67(m,1H),2.42-2.47(m,1H),2.08(s,6H)。
Embodiment 85:2-(6-(((6-(2; 6-dimethyl-4-(3-(methylsulfonyl) propoxy-) phenyl) pyridine-2-yl) oxygen) methylene radical)-2,3-dihydrobenzene thiene-3-yl-) preparation of acetic acid (compound H YH-081)
Except using 3-methylsulfonyl propyl group tolysulfonyl ester to replace 2-methylsulfonylethyl tolysulfonyl ester; according to making compound 2-(6-(((6-(2 with the similar method of embodiment 84; 6-dimethyl-4-(3-(methylsulfonyl) propoxy-) phenyl) pyridine-2-yl) oxygen) methylene radical)-2,3-dihydrobenzo thiene-3-yl-) acetic acid. 1H?NMR(CDCl 3,400MHz)δ：7.41(dd,J=15.1,7.5Hz,1H),7.24(d,J=8.0Hz,1H),7.07(d,J=7.4Hz,1H),6.95(s,1H),6.87(s,2H),6.76(d,J=8.0Hz,1H),6.72(d,J=8.2Hz,1H),5.11(s,2H),4.33-4.37(m,1H),4.11-4.19(m,3H),3.92-3.99(m,1H),3.23-3.31(m,2H),2.97(s,3H),2.61-2.67(m,1H),2.42-2.47(m,1H),2.29-2.35(m,2H),2.08(s,6H)。
Embodiment 86:2-(6-(((6-(2; 6-dimethyl-4-(4-(methylsulfonyl) butoxy) phenyl) pyridine-2-yl) oxygen) methylene radical)-2,3-dihydrobenzo thiene-3-yl-) preparation of acetic acid (compound H YH-082)
Except using 4-methylsulfonyl butyl tolysulfonyl ester to replace 2-methylsulfonylethyl tolysulfonyl ester; according to making compound 2-(6-(((6-(2 with the similar method of embodiment 84; 6-dimethyl-4-(4-(methylsulfonyl) butoxy) phenyl) pyridine-2-yl) oxygen) methylene radical)-2,3-dihydrobenzene thiene-3-yl-) acetic acid. 1H?NMR(CDCl 3,400MHz)δ：7.41(dd,J=15.1,7.5Hz,1H),7.24(d,J=8.0Hz,1H),7.07(d,J=7.4Hz,1H),6.95(s,1H),6.87(s,2H),6.76(d,J=8.0Hz,1H),6.72(d,J=8.2Hz,1H),5.11(s,2H),4.33-4.37(m,1H),4.11-4.19(m,3H),3.92-3.99(m,1H),3.23-3.31(m,2H),2.97(s,3H),2.61-2.67(m,1H),2.42-2.47(m,1H),2.08(s,6H),1.67-1.85(m,4H)。
Embodiment 87:2-(6-(((6-(4-(2-(dimethylamino) oxyethyl group)-2,6-3,5-dimethylphenyl) pyridine-2-yl) oxygen) methylene radical)-2,3-dihydrobenzo [b] thiene-3-yl-) preparation of acetic acid (compound H YH-083)
Except using 2-dimethylaminoethyl tolysulfonyl ester to replace 2-methylsulfonylethyl tolysulfonyl ester; according to making compound 2-(6-(((6-(4-(2-(dimethylamino) oxyethyl group)-2 with the similar method of embodiment 84; 6-3,5-dimethylphenyl) pyridine-2-yl) oxygen) methylene radical)-2,3-dihydrobenzo thiene-3-yl-) acetic acid. 1H?NMR(CDCl 3,400MHz)δ：7.41(dd,J=15.1,7.5Hz,1H),7.24(d,J=8.0Hz,1H),7.07(d,J=7.4Hz,1H),6.95(s,1H),6.87(s,2H),6.76(d,J=8.0Hz,1H),6.72(d,J=8.2Hz,1H),5.11(s,2H),4.79(t,J=7.2Hz,2H),4.39-4.47(m,1H),4.12-4.19(m,2H),2.85(s,6H),2.77(t,J=7.2Hz,2H),2.61-2.67(m,1H),2.42-2.47(m,1H),2.08(s,6H)。
Embodiment 88:2-(6-(((6-(4-(3-(dimethylamino) propoxy-)-2,6-3,5-dimethylphenyl) pyridine-2-yl) oxygen) methylene radical)-2,3-dihydrobenzo thiene-3-yl-) preparation of acetic acid (compound H YH-084)
Except using 3-dimethylamino-propyl tolysulfonyl ester to replace 2-methylsulfonylethyl tolysulfonyl ester; according to making compound 2-(6-(((6-(4-(3-(dimethylamino) propoxy-)-2 with the similar method of embodiment 84; 6-3,5-dimethylphenyl) pyridine-2-yl) oxygen) methylene radical)-2,3-dihydrobenzo thiene-3-yl-) acetic acid. 1H?NMR(CDCl 3,400MHz)δ：7.41(dd,J=15.1,7.5Hz,1H),7.24(d,J=8.0Hz,1H),7.07(d,J=7.4Hz,1H),6.95(s,1H),6.87(s,2H),6.76(d,J=8.0Hz,1H),6.72(d,J=8.2Hz,1H),5.11(s,2H),4.79(t,J=7.2Hz,2H),4.39-4.47(m,1H),4.12-4.19(m,2H),2.85(s,6H),2.69(t,J=7.6Hz,2H),2.61-2.67(m,1H),2.42-2.47(m,1H),2.08(s,6H),1.79(q,J=7.2Hz,2H)。
The preparation of embodiment 89:3-(4-(((6-(4-trifluoromethyl-2-aminomethyl phenyl) pyridine-2-yl) oxygen) methylene radical)-2-fluorophenyl) propionic acid (compound H YH-085)
Except using 4-trifluoromethyl-2-methylphenylboronic acid to replace phenylo boric acid, and use 3-(4-(((6-bromopyridine-2-yl) oxygen) methylene radical)-2-fluorophenyl) ethyl propionate to replace outside 3-(4-(((6-bromopyridine-2-yl) oxygen) methylene radical) phenyl) ethyl propionate, make compound 3-(4-(((6-(4-trifluoromethyl) pyridine-2-yl) oxygen base) methylene radical)-2-fluorophenyl) propionic acid according to method similar to Example 4. 1H?NMR(400MHz,CDCl 3)δ=8.18(d,J=8.2Hz,2H),7.94-7.90(m,2H),7.69-7.61(m,2H),7.40(d,J=8.2Hz,1H),7.31(dd,J=7.4,0.6Hz,1H),7.01(s,1H),6.81(dd,J=8.2,0.6Hz,1H),5.48(s,2H),2.97(t,J=7.7Hz,2H),2.73-.66(m,2H)。
Embodiment 90: the screening of the HEK293 cell strain agonist activity of compound to stable transfection people source GPR40
HEK293 cell, transfection carrier for expression of eukaryon people source GPR40-pCDNA3.1, obtains the monoclonal cell strain of stably express people source GPR40 through screening.The HEK293 cell strain of stable transfection people source GPR40, is incubated at the DMEM in high glucose nutrient solution containing 10%FBS.Experiment is inoculated in 96 porocyte culture plates by cell, 25000, every hole cell the day before yesterday.Test the same day, preparation Fluo-8 working fluid (Hank's balanced salt solution is containing Fluo-82 μ M, probenecid 2mM, Tartrazol yellow 1.5mM, azogeramine 4mM).After abandoning cell culture fluid, add Fluo-8 working fluid, the 100 every holes of μ L, 37 DEG C of 5%CO 2hatch 1 hour.The DMSO storing solution of testing compound is placed in 96 hole sample panel with 200 times of Hank's balanced salt solution dilutions.Positive control compound is that final concentration is the TAK-875 of 10 μ M, and blank is the Hank's balanced salt solution containing 0.1%DMSO.The cell plate of having hatched, sample panel are put in to the multi-functional microplate reader workstation of Flexstation, the dosing 25 every holes of μ L are set, intracellular calcium signal after detection dosing.Calcium Signal is got MAX-MIN and is converted into raw data, according to following formula counting yield %.The EC of application GraphPad Prism computed in software compound 50.
Efficiency %=[value (compound)-value (BC)be worth]/[ (PC)-value (BC)] × 100%
Compound, test-compound; BC, blank; PC, positive control TAK-875.Result is as shown in table 1.
The agonist activity of table 1, the HEK293 cell strain of the application's compound to people source GPR40
Embodiment 91: the hypoglycemic activity of compound to type ii diabetes ob/ob mouse
The spontaneous type ii diabetes ob/ob of male genotype mouse is raised (temperature: 22-24 ° C in SPF level Animal House, humidity: 45-80%, illumination: 150-300Lx, within 12 hours, day alternates with night), when age in mouse 6-7 week, predict random blood sugar, fasting plasma glucose and body weight, according to these indexs, ob/ob mouse is divided into 3 groups, every group 8, oral giving and 100mg/kg test-compound HYH-013 respectively, 100mg/kg positive control TAK875, control group is oral to be given and 0.5%CMC, 1h before administration and after administration, 2h, 4h, 6h and 8h measure blood glucose value, observe the hypoglycemic activity of HYH-013 to type ii diabetes ob/ob mouse.
As shown in Table 2 and Figure 1, blood sugar all maintains higher level to result before the administration of control group ob/ob mouse and after administration, and the administration of 100mg/kg HYH-013 single oral can significantly reduce ob/ob mouse blood sugar.1h after administration, HYH-013 mouse blood sugar is significantly lower than control group (P<0.01), and blood sugar rate of descent is 22.3%, and positive control TAK-875 group blood sugar declines without remarkable compared with control group; After administration when 2h and 4h, HYH-013 group mouse blood sugar is still significantly lower than control group (P<0.05), blood sugar rate of descent is respectively 26.3% and 23.4%, and now decline (P=0.09) to a certain degree also appears in positive control TAK875 group mouse blood sugar, blood sugar rate of descent is respectively 27.9% and 23.3%; After administration when 6h and 8h, HYH-013 group mouse blood sugar is still significantly lower than control group (P<0.05, P<0.01), blood sugar rate of descent is respectively 24.7% and 26.8%, and positive control TAK875 group mouse blood sugar declines without obvious compared with control group.Prompting thus, HYH-013 has significant hypoglycemic activity to diabetes B ob/ob mouse, and its effect is held time and is longer than TAK875.
The impact of table 2:HYH-013 single-dose on ob/ob mouse blood sugar (mM, n=8)
*, P<0.05, compared with control group; *, P<0.01, compared with control group.
Be more than to illustrate for possible embodiments of the present invention, but this embodiment is not in order to limit the scope of the claims of the present invention, allly do not depart from the equivalence that skill spirit of the present invention does and implement or change, all should be contained in the scope of the claims of the present invention.

Claims (10)

1. the phenylpropionic acid compound shown in following general formula I, or acceptable salt, steric isomer or its prodrugs on its pharmacology:
Wherein,
X is H, D or F;
R 1and R 2independently be selected from separately H, hydroxyl, halogen, nitro, C 1-C 20alkyl, halo C 1-C 20alkyl, C 1-C 20alkoxyl group, halo C 1-C 20alkoxyl group, C 3-C 10cycloalkyl and contain 1 to 3 heteroatomic 3 to the 10 yuan of heterocyclic radical being selected from S, O and N;
R 3be selected from H; Halogen; Carboxyl; C 1-C 20alkyl; Halo C 1-C 20alkyl;-OR a;-N (R a) SO 2r b,-NR ar b;-N (R a) C (O) R b;-C (O) NR ar b;-SO 2r a;-SR b; With being selected from C 1-C 10alkoxyl group, C 3-C 10cycloalkyl ,-SR c,-SO 2r c,-NR cr dor do not replace or by C 1-C 6what alkyl, hydroxyl or oxo group replaced contains the C that the substituting group in the first heterocyclic radical of 1～3 heteroatomic 3-8 being selected from O, S and N replaces 1-C 20alkoxyl group; With use C 1-C 10alkoxyl group, C 3-C 10cycloalkyl ,-SR c,-SO 2r cor-NR cr dthe C replacing 1-C 20alkyl;
Wherein,
R aand R bindependently be selected from separately H, C 1-C 6alkyl, C 3-C 8cycloalkyl and do not replace or by C 1-C 6what alkyl or oxo group replaced contains the first heterocyclic radical of 1～3 heteroatomic 3-8 being selected from O, S and N;
R cand R dbe selected from independently of one another H, C 1-C 6alkyl and do not replace or by C 1-C 3what alkyl replaced contains the first heterocyclic radical of 1～3 heteroatomic 3-8 being selected from O, S and N;
R 4be selected from H, hydroxyl, halogen, C 1-C 20alkyl and halo C 1-C 20alkyl;
R 5be selected from H, halogen and C 1-C 20alkyl;
Or R 4and R 5form benzo 5-8 unit heterocyclic radical together with the carbon atom being connected with it and phenyl ring, on described heterocycle, contain 1～3 heteroatoms being selected from O, N and S, and described heterocyclic radical is not substituted or by C 1-C 6alkyl replaces.
2. acceptable salt, steric isomer or its prodrugs on phenylpropionic acid compound according to claim 1, its pharmacology, wherein,
X is H, D or F;
R 1and R 2independently be selected from separately H, hydroxyl, halogen, nitro, C 1-C 6alkyl, halo C 1-C 6alkyl, C 1-C 6alkoxyl group, halo C 1-C 6alkoxyl group, C 3-C 8cycloalkyl and 3 to 10 yuan of heterocyclic radicals that contain at least one nitrogen-atoms;
R 3be selected from H; Halogen; Carboxyl; C 1-C 6alkyl; Halo C 1-C 6alkyl;-OR a;-N (R a) SO 2r b;-NR ar b;-N (R a) C (O) R b;-C (O) NR ar b;-SO 2r a;-SR b; With being selected from C 1-C 4alkoxyl group, C 3-C 8cycloalkyl ,-SR c,-SO 2r c,-NR cr dor do not replace or by C 1-C 4what alkyl, hydroxyl or oxo group replaced contains the C that the substituting group in the first heterocyclic radical of 1～3 heteroatomic 3-6 being selected from O, S and N replaces 1-C 6alkoxyl group; With use C 1-C 4alkoxyl group, C 3-C 8cycloalkyl ,-SR c,-SO 2r cor-NR cr dthe C replacing 1-C 6alkyl;
R 4be selected from H, hydroxyl, halogen, C 1-C 6alkyl and halo C 1-C 6alkyl;
R 5be selected from H, halogen and C 1-C 6alkyl;
Or R 4and R 5form 5 yuan of heterocyclic radicals of benzo together with the carbon atom being connected with it and phenyl ring, these 5 yuan of heterocyclic radicals contain 1～2 heteroatoms being selected from O, N and S, and are not substituted or by C 1-C 3alkyl replaces.
3. acceptable salt, steric isomer or its prodrugs on phenylpropionic acid compound according to claim 1, its pharmacology, wherein,
X is H, D or F;
R 1and R 2independently be selected from separately H, hydroxyl, halogen, nitro, C 1-C 4alkyl, halo C 1-C 4alkyl, C 1-C 4alkoxyl group, halo C 1-C 4alkoxyl group, C 3-C 8cycloalkyl and ethylenimine-1-base;
R 3be selected from H; Halogen; Carboxyl; C 1-C 6alkyl; Halo C 1-C 6alkyl;-OR a;-N (R a) SO 2r b;-NR ar b;-N (R a) C (O) R b;-C (O) NR ar b;-SO 2r a;-SR b; With being selected from C 1-C 4alkoxyl group, C 3-C 6cycloalkyl ,-SR c,-SO 2r c,-NR cr d, or do not replace or by C 1-C 4what alkyl, hydroxyl or oxo group replaced contains the C that the substituting group in the first heterocyclic radical of 1～3 heteroatomic 3-6 being selected from O, S and N replaces 1-C 4alkoxyl group; With use C 1-C 4alkoxyl group, C 3-C 6cycloalkyl ,-SR c, SO 2r cor NR cr dthe C replacing 1-C 4alkyl;
R aand R bindependently be selected from separately H, C 1-C 4alkyl, C 3-C 6cycloalkyl and do not replace or by C 1-C 3what alkyl or oxo group replaced contains the first heterocyclic radical of 1～3 heteroatomic 3-6 being selected from O, S and N;
R cand R dbe selected from independently of one another H, C 1-C 3alkyl and do not replace or by C 1-C 3what alkyl replaced contains the first heterocyclic radical of 1～3 heteroatomic 3-6 being selected from O, S and N;
R 4and R 5form together with the carbon atom being connected with it and phenyl ring or .
4. acceptable salt, steric isomer or its prodrugs on phenylpropionic acid compound according to claim 1, its pharmacology, wherein, it has the structure shown in lower general formula I I or general formula III:
Wherein, X, R 1～R 5definition identical with the definition in upper claim 1;
And in general formula III, when Z is N, R 6for H or C 1-C 6alkyl; In the time that Z is O or S, R 6do not exist.
5. acceptable salt, steric isomer or its prodrugs on phenylpropionic acid compound according to claim 1, its pharmacology, it has following structure:
6. acceptable salt, steric isomer or its prodrugs on phenylpropionic acid compound according to claim 1, its pharmacology, described pharmacy acceptable salt is the salt that the compound shown in general formula I and phosphoric acid, sulfuric acid, hydrochloric acid, acetic acid, tartrate, citric acid, oxysuccinic acid, fumaric acid, aspartic acid or L-glutamic acid form, or after becoming ester or acid amides with described acid again with the salt of mineral alkali formation.
7. prepare a method for phenylpropionic acid compound claimed in claim 1, it is preparation one of by the following method:
Method one: as shown in reaction formula 1 below:
Reaction formula 1
Step 1: by R 4replace to bromobenzyl alcohol 1 and ethyl propenoate 2, through Heck, reaction obtains intermediate 3, reduction is obtained to intermediate 4, then through bromination reaction, benzylalcohol is become to benzyl bromine and obtain intermediate 5;
Step 2: intermediate 5 and substrate 6 are obtained to intermediate 7 through nucleophilic substitution reaction;
Step 3: intermediate 7 Hes obtain intermediate 8 through Suzuki reaction coupling, then intermediate 8 is obtained to product 9 through hydrolysis reaction;
Method two: as shown in reaction formula 2 below:
Reaction formula 2
Step 1: compound 17 or 20 and substrate 6 obtain compound 21 through nucleophilic substitution reactions, wherein, in compound 17, Z is O or S, R 6do not exist; And in compound 20, Z is N, R 6for H or C 1-C 6alkyl;
Step 2: compound 21 Hes obtain intermediate 22 through Suzuki reaction coupling, then intermediate 22 is obtained to product 23 through hydrolysis reaction;
Preferably, described compound 17 and 20 is prepared by the following method:
Reaction formula 3
Step 1: the hydroxyl of compound 10 is obtained to compound 11 with protective material protection, then obtain compound 12 with chloroacetyl chloride through Friedel-Crafts reaction, described protective material is diacetyl oxide, Acetyl Chloride 98Min. or acetyl bromide;
Step 2: compound 12 obtains compound 13 through intramolecular nucleophilic substitution reaction, then through witting, reaction obtains compound 14 with witting reagent;
Step 3: compound 14 obtains compound 15 through hydro-reduction reaction,
In the time of Z=O or S, compound 15 obtains compound 16 through hydrolysis reaction, and compound 16 is through bromination reactions, and then is added dropwise to dehydrated alcohol and obtains compound 17 through esterification;
Step 4: in the time of Z=NH, compound 15 and R 7i obtains compound 18 through alkylated reaction, and compound 18 obtains compound 19 through hydrolysis reaction, and compound 19 is through bromination reactions, and then is added dropwise to dehydrated alcohol and obtains compound 20 through esterification;
Wherein, R 7for C 1-C 6alkyl;
In reaction formula 1～3, R 1～R 5, X definition identical with the definition in claim 1.
8. a pharmaceutical composition, it comprises the phenylpropionic acid compound shown in the general formula I for the treatment of significant quantity, its pharmacy acceptable salt, steric isomer or its prodrugs and pharmaceutically acceptable auxiliary material.
9. phenylpropionic acid compound according to claim 1 or its pharmacy acceptable salt, steric isomer, the purposes of its prodrugs in the medicine of preparing glycolipid metabolism disorder.
10. purposes according to claim 9, described glycolipid metabolism disorder is diabetes.
CN201310132684.6A 2013-04-16 2013-04-16 Phenylpropionic acid compound, its pharmaceutical composition, preparation method and the purposes of a kind of nitrogen heterocyclic ring link Expired - Fee Related CN104109115B (en)

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