CN104326950A - Phenoxyacetic acid derivative, preparation process thereof and use thereof as medicaments - Google Patents
Phenoxyacetic acid derivative, preparation process thereof and use thereof as medicaments Download PDFInfo
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Abstract
The invention discloses a phenoxyacetic acid derivative, a preparation process thereof and use thereof as medicaments, and provides a compound shown as formula (I) and a physiologically acceptable salt thereof, wherein the symbols are as defined in the specification. The compound or physiologically acceptable salt thereofhas GPR40 (G-protein-coupled receptor) regulation function, can cause increase in insulin release, and is useful to be used as an insulin secretagogue or medicaments for prevention or treatment of diabetes and the like.
Description
Technical field
The present invention relates to a kind of new phenoxy acetic acid analog derivative, its preparation method and containing the drug regimen group of this derivative and its as therapeutical agent particularly as the purposes of GPR40 agonist and the medicine in disease such as preparation treatment diabetes and metabolic disorder etc.
Background technology
Diabetes are a kind of energy metabolism diseases, are divided into type 1 diabetes (insulin-dependent diabetes mellitus) and diabetes B (non-insulin-dependent diabetes).About there are 3.66 hundred million diabetic subjects in the current whole world, accounts for 6.4% of world population, and wherein diabetes B patient accounts for 90 ~ 95% of diabetic subject's sum.
Diabetes can by dietary adjustments and exercise treatment.When these can not relief of symptoms time, need to carry out pharmacological agent.The drug treatment of current diabetes comprises: biguanides, as N1,N1-Dimethylbiguanide, can reduce the formation of glucose in liver; Sulfonylurea, can the more Regular Insulin of stimulating pancreas β emiocytosis as Glyburide; Thiazolidinediones, as U-721017E, strengthens the Purificatiou of Regular Insulin by activating peroxisome proliferator activated receptor γ (PPAR-γ); Alpha-glucosidase inhibitor, as acarbose, can suppress the generation of glucose in enteron aisle; Glucagon-like-peptide-1 (GLP-1) analogue, as Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37], can promote the β cells secrete insulin of pancreas; DPP IV (DPP-IV) inhibitor, as Xi Gelieting, can suppress the degraded of GLP-1 in body.But the method for current existing treatment diabetes has certain defect.Such as injection of insulin agent and sulfonylurea, may cause hypoglycemia and body weight to increase side effect; N1,N1-Dimethylbiguanide class, alpha-glucosidase inhibitor and GLP-1 analogue may cause gastrointestinal side effect; PPAR-gamma agonist may cause body weight to increase and oedema side effect; DPP-IV inhibitor may cause epipharyngitis, headache and infection side effect.Research for multiple field is carried out, to bringing more effective novel blood sugar lowing medicine for market.
Free-fat acid acceptor (FFAR) is the g protein coupled receptor (GPCRs) going orphanization in recent years.Current fixed free fatty acid acceptor has g protein coupled receptor 40 (GPR40) family, comprise GPR40 and (also claim free-fat acid acceptor 1, FFA1), GPR41 (also claims also to claim free-fat acid acceptor 3, FFA3), GPR84, GPR120 of GPR43 (also claiming also to claim free-fat acid acceptor 2, FFA2) and other family.GPR40 is the orphan type GPCR found when finding new galanin-galanin receptors (GALR) hypotype, expresses at the clone camber of pancreatic beta cell and excreting insulin.GPR40 can in conjunction with such as Palmiticacid, and stearic acid, oleic acid, the lipid acid in the blood plasma such as linoleic acid plus linolenic acid realizes various physiological-function.Such as, activate after long-chain free fatty acids is combined with GPR40, in inducing cell, calcium ion level raises, and strengthens the secretion (GSIS) of the Regular Insulin that glucose stimulates.GPR40 conditioning agent play incretin be used for promotion GSIS, in addition also can with multiple treatment diabetes medicament conbined usage.Based on more than, GPR40 agonist can treat diabetes and relevant indication, especially diabetes B, obese insulin resist, glucose intolerance, and other indications.With the therapy target that GPR40 is potential, find and transform the compound with GPR40 agonist activity and there is important researching value and application prospect.
Disclose the patent application of a series of GPR40 agonist at present, comprising WO2004041266, WO2005087710, WO2005051890, WO2006083781, WO2007013689, WO2008066097, WO2009054390, WO2010085525 etc.
The present invention relates to the Phenoxiacetic acid derivatives of novel structure, it has the exciting ability of GPR40 and hypoglycemic activity.Therefore described general formula (I) compound and potential being used for the treatment of or prevent diabetes and relative disease of pharmaceutical salts thereof.
Summary of the invention
The object of the present invention is to provide the compound shown in a kind of general formula (I) or its pharmaceutically useful salt:
Wherein:
X is O, CH
2, S, NH, N (C
1-C
4alkyl);
Y is (CH
2)
m;
R
1and R
2identical or different, and be H, F, Cl, Br, substituted or unsubstituted C separately
1-C
6alkyl;
R
3and R
4identical or different, and be H, F, Cl, Br, CN, CF separately
3, substituted or unsubstituted C
1-C
6alkyl, substituted or unsubstituted C
1-C
6alkyl-O-, substituted or unsubstituted C
1-C
6alkyl-CO-;
R
5and R
6identical or different, and be H, F, Cl, Br, CN, CF separately
3, substituted or unsubstituted C
1-C
6alkyl, substituted or unsubstituted C
1-C
6alkyl-O-, C
3-C
10carbocyclic ring;
R
7and R
8identical or different, and be H, F, Cl, Br, CN, CF separately
3, substituted or unsubstituted C
1-C
6alkyl, substituted or unsubstituted C
1-C
6alkyl-O-, C
3-C
10carbocyclic ring;
R
9for substituted or unsubstituted C
1-C
6alkyl, replacement or do not replace C
1-C
6alkyl-S (O)
n-, NH
2, NH (C
1-C
4alkyl), N (C
1-C
4alkyl)
2, CONH
2, CONH (C
1-C
4alkyl), CON (C
1-C
4alkyl)
2, C
3-C
10carbocyclic ring, carbon atoms and 1-4 is selected from N, O, S and S (O)
nheteroatomic 3 to 10 yuan of heterocyclic radicals;
M is 0,1,2,3,4,5 or 6 when occurring; N is 0,1 or 2 when occurring;
Preferred version of the present invention, the compound of a kind of general formula (I) or its pharmaceutically useful salt, it is the compound shown in general formula (II) or its pharmaceutically useful salt:
Wherein:
X is O, NH or N (C
1-C
4alkyl);
Y is (CH
2)
m;
R
1and R
2identical or different, and be H or substituted or unsubstituted C separately
1-C
6alkyl;
R
3and R
4identical or different, and be H, F, Cl, Br, CN, CF separately
3, substituted or unsubstituted C
1-C
6alkyl or substituted or unsubstituted C
1-C
6alkyl-O-;
R
5and R
6identical or different, and be H, F, Cl, Br, CN, CF separately
3, substituted or unsubstituted C
1-C
6alkyl, substituted or unsubstituted C
1-C
6alkyl-O-, C
3-C
10carbocyclic ring;
R
9for substituted or unsubstituted C
1-C
6alkyl, replacement or do not replace C
1-C
6alkyl-S (O)
n-, NH
2, NH (C
1-C
4alkyl), N (C
1-C
4alkyl)
2, CONH
2, CON (C
1-C
4alkyl)
2, C
3-C
6carbocyclic ring, carbon atoms and 1-4 is selected from N, O, S and S (O)
nheteroatomic 3 to 6 yuan of heterocyclic radicals;
M is 0,1,2,3,4,5 or 6 when occurring; N is 0,1 or 2 when occurring;
Preferred version of the present invention, the compound of a kind of general formula (I) or its pharmaceutically useful salt, it is the compound shown in general formula (III) or its pharmaceutically useful salt:
Wherein:
Y is (CH
2)
m;
R
1and R
2identical or different, and be H or substituted or unsubstituted C separately
1-C
4alkyl;
R
3and R
4identical or different, and be H, F, Cl, Br, CN, CF separately
3, substituted or unsubstituted C
1-C
6alkyl or substituted or unsubstituted C
1-C
6alkyl-O-;
R
5and R
6identical or different, and be H, F, Cl, Br, substituted or unsubstituted C separately
1-C
6alkyl;
R
9for substituted or unsubstituted C
1-C
6alkyl, replacement or do not replace C
1-C
6alkyl-S (O)
n-, NH
2, NH (C
1-C
4alkyl), N (C
1-C
4alkyl)
2, CONH
2, CON (C
1-C
4alkyl)
2, C
3-C
6carbocyclic ring, carbon atoms and 1-4 is selected from N, O, S and S (O)
nheteroatomic 3 to 6 yuan of heterocyclic radicals;
M is 0,1,2,3,4,5 or 6 when occurring; N is 0,1 or 2 when occurring;
Typical compound of the present invention includes, but are not limited to:
2-(4-((2 ', 6 '-dimethyl-4 '-(3-(methylsulfonyl) propyl group)-[1,1 '-xenyl]-3-) methoxyl group) benzene oxygen) acetic acid (I-1);
2-(4-((2 ', 6 '-dimethyl-4 '-(3-(methylsulfonyl) propyl group)-[1,1 '-xenyl]-3-) methoxyl group) 2-methylenedioxy phenoxy) acetic acid (I-2);
2-(the chloro-4-of 2-((2 ', 6 '-dimethyl-4 '-(3-(first sulphur formyl radical) propyl group)-[1,1 '-xenyl]-3-) methoxyl group) phenoxy group) acetic acid (I-3);
2-(4-((2 ', 6 '-methyl-4 '-(3-(methylsulfonyl) propyl group)-[1,1 '-xenyl]-3-) methoxyl group) 2-fluorobenzene oxygen) acetic acid (I-4);
2-(4-((2 ', 6 '-dimethyl-4 '-(3-(methylsulfonyl) propyl group)-[1,1 '-xenyl]-3-) methoxyl group) 2-anisole oxygen) acetic acid (I-5);
2-(4-((2 ', 6 '-methyl-4 '-(3-(methylsulfonyl) propyl group)-[1,1 '-xenyl]-3-) methoxyl group) 2-ethylbenzene oxygen) acetic acid (I-6);
2-(4-((2 ', 6 '-dimethyl-4 '-(3-(methylsulfonyl) propyl group)-[1,1 '-xenyl]-3-) methoxyl group) phenoxy group)-2 Methylpropionic acid (I-7);
2-(4-((2 ', 6 '-dimethyl-4 '-(3-(methylsulfonyl) propyl group)-[1,1 '-xenyl]-3-) methoxyl group)-2-ethyl phenoxy group)-2 Methylpropionic acid (I-8);
2-(2-chlorine 4-((2 ', 6 '-dimethyl-4 '-(3-(methylsulfonyl) propyl group)-[1,1 '-xenyl]-3-) methoxyl group) phenoxy group)-2 Methylpropionic acid (I-9);
2-(4-((2 ', 6 '-dimethyl-4 '-(3-(methylsulfonyl) propyl group)-[1,1 '-xenyl]-3-) methoxyl group) 2-fluorophenoxy)-2 Methylpropionic acid (I-10);
2-(4-((2 ', 6 '-dimethyl-4 '-(3-(methylsulfonyl) propyl group)-[1,1 '-xenyl]-3-) methoxyl group) 2-methoxyphenoxy)-2 Methylpropionic acid (I-11);
2-(4-((2 ', 6 '-dimethyl-4 '-(3-(methylsulfonyl) propyl group)-[1,1 '-xenyl]-3-yl) methoxyl group) 2,6-dimethyl phenoxies)-2 Methylpropionic acid (I-12);
2-(4-((4 '-oxyethyl group-2 ', 6 '-dimethyl-[1,1 '-xenyl]-3-) methoxyl group)-2 fluorobenzene oxygen) acetic acid (I-13);
2-(4-((4 '-(3-methoxy propoxy)-2 ', 6 '-methyl-[1,1 '-xenyl]-3-) methoxyl group) 2-fluorobenzene oxygen) acetic acid (I-14);
2-(4-((4 '-(2-(dimethylamino)-2-oxoethoxy)-2 ', 6 '-dimethyl-[1,1 '-xenyl]-3-) methoxyl group)-2-fluorobenzene oxygen) acetic acid (I-15);
Another aspect of the present invention relates to the purposes of compound or pharmaceutically acceptable salt thereof in preparation GPR40 agonist described in general formula (I).
Another aspect of the present invention relates to compound described in general formula (I) or the pharmaceutically useful salt purposes in the medicine of preparation treatment diabetes and metabolic syndrome.
Another aspect of the present invention relates to a kind of pharmaceutical composition, and it contains the compound described in general formula (I) or its pharmaceutically useful salt and pharmaceutically useful carrier, thinner or vehicle for the treatment of effective dose.This pharmaceutical composition prepares the purposes in GPR40 agonist.The purposes of this drug regimen group in the medicine preparing treatment diabetes and metabolic syndrome.
Another aspect of the present invention relates to general formula (I) described compound or its pharmaceutically useful salt, or pharmaceutical composition regulates the purposes of the medicine of Regular Insulin in preparation.
Detailed description of the invention
Unless otherwise stated, in specification sheets and claims term there is following implication.
" C
1-C
4alkyl " such as methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, sec-butyl, the tertiary butyl etc. can be mentioned.
" C
1-C
6alkyl " can mention as methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, sec-butyl, the tertiary butyl, amyl group, isopentyl, neo-pentyl, hexyl etc.
" C
3-C
10carbocyclic ring " such as cyclopropane, tetramethylene, pentamethylene, hexanaphthene etc. can be mentioned.
" heterocyclic radical " can mention such as 5-10 unit (monocycle, dicyclo or three rings) heterocyclic radical, form the atom of heterocycle except containing except carbon atom, also be selected from 1 to 4 heteroatoms of N, S, O containing one or both, preferred 5-10 first nonaromatic heterocycles or 5-10 membered aromatic heterocycle etc.Particularly, nonaromatic heterocycles such as tetrahydrofuran (THF), tetrahydropyrans, pyrrolidyl, oxazolidinyl, imidazolidyl, piperidyl, piperazinyl, morpholinyl etc.; Aromatic heterocycle is thienyl, furyl, pyridyl, thiazolyl, pyrimidyl, pyrazolyl, imidazolyl etc. such as.
" pharmaceutical composition " represents containing one or more general formula of the present invention (I) described compounds or its pharmaceutically useful salt, or the mixture of its prodrug and other chemical compositions, and other chemical compositions are pharmaceutically useful carrier and vehicle such as.The object of pharmaceutical composition promotes that organism is to the absorption of activeconstituents, is beneficial to activeconstituents and plays biological activity in vivo.
The synthetic method of the compounds of this invention.
Can as shown in scheme one compound of preparation formula (I).
The compound (being called for short compound (IV) and compound (V) respectively) that compound (VI) can be represented by the compound that represented by general formula (IV) and logical formula V reacts preparation in the presence of base, the compound (VI) obtained ester hydrolysis in the presence of a base further, obtains compound (I).
Scheme one:
Wherein: W is leavings group; R is alkyl such as methyl, ethyl, propyl group, phenyl etc.; X, Y, R
1~ R
9definition as described in general formula (I).
W represents leavings group, can mention the C of such as Cl, Br, I, optional halo
1-C
6alkyl sulphonyl oxygen base (such as, methylsulfonyl oxygen base, ethylsulfonyl oxygen base, three chloromethanesulfonyl), optionally there is substituent C
6-C
10aryl sulfonyl oxygen base (such as, phenyl sulfonyl oxygen base, p-toluenesulfonyl oxygen base, m-nitrobenzenesulfonyl oxygen base etc.) etc.
Comprise mineral alkali and organic bases as described alkali, described mineral alkali can be mentioned such as, and alkaline carbonate class is sodium carbonate, salt of wormwood, cesium carbonate etc. such as; Alkali metal hydrocarbonate class such as saleratus etc.; Alkali metal hydroxide is lithium hydroxide, sodium hydroxide, potassium hydroxide etc. such as; Described mineral alkali can mention such as triethylamine, pyridine, lutidine, n-Butyl Lithium, tertiary butyl potassium etc.
Or can as shown in scheme two compound of preparation formula (I).
Compound (VIII) can by the compound that represented by general formula (VII) and R
9-L reacts preparation in the presence of base, and the compound (VIII) obtained ester hydrolysis in the presence of a base further, obtains compound (I).
Scheme two:
Wherein: L is leavings group; R is alkyl such as methyl, ethyl, propyl group, phenyl etc.; X, Y, R
1~ R
9definition as described in general formula (I).
L is " leavings group ", is somebody's turn to do " leavings group " those leavings groups cited by aforementioned W;
In the program alkali used be aforementioned in mentioned alkali.
Biological assessment
Following biology testing example describes explains the present invention.
The condition that in test case of the present invention, the usual conditioned disjunction routinely of the experimental technique of actual conditions is advised according to commodity manufacturer.The reagent in unreceipted concrete source is the common agents that market is bought.
Test case 1 the compounds of this invention surely turns the agonist activity of cell to hGPR40-CHO
The present invention uses following methods to measure the agonist activity of the GPR40 of the compounds of this invention:
HGPR40-CHO surely turns cell with 3X10
4the density in/hole is seeded to 96 orifice plates, is placed in 37 DEG C, 5%CO
2cell culture incubator incubated overnight; Discard substratum, after every hole adds 100ul HBSS cleaning, add 100ul and hatch 90min containing the Fluo-4 dye solution 37 DEG C of Probenecid; After hatching end, sucking-off Fluo-4 dye solution, adds 100 μ l HBSS damping fluids, washes away dyestuff; Every hole adds the HBSS of 100 μ l containing Probenecid, hatches 10min for 37 DEG C; In 96 orifice plates, every hole adds the medicine of different concns, and HBSS prepares: according to optimum configurations table FlexStation3 reading.Analysis design mothod result.Exciting multiple is the ratio of compound well fluorescent value and blank control wells fluorescent value.The results are shown in Table 1.
Table 1: the function of receptors regulating effect on GPR40
Conclusion: the compounds of this invention has obvious agonist activity to GPR40, wherein I-1, I-2, I-3, I-4, I-13 and I-14 have stronger GPR40 agonist activity.
In test case 2 the present invention compound body in hypoglycemic activity can measure by using Analytical system as described below:
Normal mouse oral glucose tolerance test (OGTT): 10 week age Kunming kind cleaning grade mouse, body weight 18 ~ 22g, male, be divided into 17 groups at random, blank group (blank solvent: the carboxymethyl cellulose of 0.5%), positive drug control group (TAK-875:20mg/kg), test-compound group (20mg/kg), often organize 8, before experiment, mouse fasting can't help water 12 hours, each group of equal oral administration gavage administration, blood is got in docking, measures blood glucose value (being designated as-30min).Then 3 groups of mouse respectively gavage measure blood glucose value after giving blank solvent, TAK-875 and I-4,30min and be designated as 0min, give by 10ml/kg gavage the glucose solution that concentration is 2g/10ml immediately afterwards, and measure blood glucose value in 15,30,60,120min.The results are shown in Table 2.
Table 2: compound on the impact of normal Mouse oral sugar tolerance (
n=8)
The tolerance test of normal mouse oral glucose shows: I-1, I-2, I-3, I-4, I-13 and I-14 obviously can improve the oral glucose tolerance of normal mouse in vivo, show good hypoglycemic activity.
Diabetes B Mouse oral carbohydrate tolerance test (OGTT): diabetes B C57BL/6 mouse, male, be divided into 4 groups at random, blank group (blank solvent: the carboxymethyl cellulose of 0.5%), I-4 (10-60mg/kg), often organizes 6, before experiment, mouse fasting can't help water 12 hours, each group of equal oral administration gavage administration, blood is got in docking, measures blood glucose value (being designated as-30min).Then 4 groups of mouse respectively gavage give blank solvent, I-4 (10mg/kg, 30mg/kg and 60mg/kg), measure blood glucose value after 30min and be designated as 0min, the glucose solution that concentration is 1g/10ml is given immediately afterwards by 10ml/kg gavage, and in 15,30,60,120min measures blood glucose value.The results are shown in Table 3.
Table 3: various dose Compound I-4 on the impact of diabetes B Mouse oral sugar tolerance (
n=6)
The carbohydrate tolerance test of diabetes B Mouse oral shows: I-4 (30mg/kg) obviously can improve the oral glucose tolerance of diabetic mice, and has dose-dependently, shows good hypoglycemic activity in diabetic mice.
Embodiment
Below in conjunction with embodiment, the invention will be further described.It should be noted that, following embodiment be only for illustration of, and not for limiting the present invention.The various changes that those skilled in the art's training centre according to the present invention is made all should within the protection domain required by the application's claim.
Embodiment 1
2-(4-((2 ', 6 '-dimethyl-4 '-(3-(methylsulfonyl) propyl group)-[1,1 '-xenyl]-3-) methoxyl group) benzene oxygen) acetic acid (I-1)
Compound IV (200mg, 0.49mmol) is dissolved in 10mL acetone, adds K successively
2cO
3(134mg, 0.97mmol), the KI of catalytic amount and compound V-1 (88mg, 0.49mmol), heating reflux reaction spends the night, and after reaction terminates, filters, concentrating under reduced pressure filtrate.Resistates silica gel column chromatography is separated (eluent system: sherwood oil and ethyl acetate), obtains target product VI-1 (210mg, white solid), productive rate: 84.3%.
Compound VI-1 (200mg, 0.39mmol) be dissolved in 6mL tetrahydrofuran (THF), in first alcohol and water (2: 3: 1) three components solvent, add the sodium hydroxide solution (0.78mL of 2M, 1.56mmol), stirring at room temperature reaction 2h, after reaction terminates, add 10mL water, dripping 1M hydrochloric acid is 3 to reaction solution pH, be extracted with ethyl acetate (30mL × 3), merge organic phase, organic phase saturated nacl aqueous solution washs, anhydrous sodium sulfate drying, filter, concentrating under reduced pressure filtrate, resistates silica gel column chromatography is separated (eluent system: methylene dichloride and methyl alcohol), obtain target product I-1 (150mg, white solid), productive rate: 77.1%, mp:106-108 DEG C.
1H NMR(300MHz，DMSO-d
6)δ7.47-7.37(m，2H)，7.14(s，1H)，7.05(d，J＝7.1Hz，1H)，6.92(d，J＝9.0Hz，2H)，6.82(d，J＝9.0Hz，2H)，6.71(s，2H)，5.08(s，2H)，4.52(s，2H)，4.09(t，J＝6.0Hz，2H)，3.27(t，J＝7.5Hz，2H)，3.03(s，3H)，2.19-2.10(m，2H)，1.91(s，6H)；
13CNMR(75MHz，DMSO-d
6)δ＝170.7，156.9，152.5，152.1，140.2，137.5，136.6，133.9，128.7，128.5，125.8，115.7，115.2，113.2，69.5，65.4，50.5，22.0，20.7；MS(ESI，m/z)：497.0[M-H]
-。
Embodiment 2
2-(4-((2 ', 6 '-dimethyl-4 '-(3-(methylsulfonyl) propyl group)-[1,1 '-xenyl]-3-) methoxyl group) 2-methylenedioxy phenoxy) acetic acid (I-2)
Compound IV (200mg, 0.49mmol) is dissolved in 10mL acetone, adds K successively
2cO
3(134mg, 0.97mmol), the KI of catalytic amount and compound V-2 (95mg, 0.49mmol), heating reflux reaction spends the night, and after reaction terminates, filters, concentrating under reduced pressure filtrate.Resistates silica gel column chromatography is separated (eluent system: sherwood oil and ethyl acetate), obtains target product VI-2 (180mg, white solid), productive rate: 70.3%.
Compound VI-2 (170mg, 0.32mmol) be dissolved in 6mL tetrahydrofuran (THF), in first alcohol and water (2: 3: 1) three components solvent, add the sodium hydroxide solution (0.64mL of 2M, 1.28mmol), stirring at room temperature reaction 2h, after reaction terminates, add 10mL water, dripping 1M hydrochloric acid is 3 to reaction solution pH, be extracted with ethyl acetate (30mL × 3), merge organic phase, organic phase saturated nacl aqueous solution washs, anhydrous sodium sulfate drying, filter, concentrating under reduced pressure filtrate, resistates silica gel column chromatography is separated (eluent system: methylene dichloride and methyl alcohol), obtain target product I-2 (120mg, white solid), productive rate: 72.5%, mp:118-120 DEG C.
1H NMR(300MHz，DMSO-d
6)δ7.46-7.36(m，2H)，7.14(s，1H)，7.05(d，J＝7.3Hz，1H)，6.81(s，1H)，6.75-6.67(m，4H)，5.05(s，2H)，4.42(s，2H)，4.09(t，J＝6.1Hz，2H)，3.27(t，J＝7.7Hz，2H)，3.03(s，3H)，2.18-2.09(m，5H)，1.92(s，6H)；
13CNMR(75MHz，DMSO-d
6)δ＝170.6，156.9，152.2，150.3，140.2，137.6，136.6，133.9，128.6，128.5，127.2，125.7，117.7，113.3，112.3，112.2，69.4，65.5，65.4，50.6，22.0，20.7，16.1；MS(ESI，m/z)：511.0[M-H]
-。
Embodiment 3
2-(the chloro-4-of 2-((2 ', 6 '-dimethyl-4 '-(3-(first sulphur formyl radical) propyl group)-[1,1 '-xenyl]-3-) methoxyl group) phenoxy group) acetic acid (I-3)
Compound IV (200mg, 0.49mmol) is dissolved in 10mL acetone, adds K successively
2cO
3(134mg, 0.97mmol), the KI of catalytic amount and compound V-3 (105mg, 0.49mmol), heating reflux reaction spends the night, and after reaction terminates, filters, concentrating under reduced pressure filtrate.Resistates silica gel column chromatography is separated (eluent system: sherwood oil and ethyl acetate), obtains target product VI-3 (220mg, white solid), productive rate: 82.7%.
Compound VI-3 (210mg, 0.40mmol) be dissolved in 6mL tetrahydrofuran (THF), in first alcohol and water (2: 3: 1) three components solvent, add the sodium hydroxide solution (0.79mL of 2M, 1.58mmol), stirring at room temperature reaction 2h, after reaction terminates, add 10mL water, dripping 1M hydrochloric acid is 3 to reaction solution pH, be extracted with ethyl acetate (30mL × 3), merge organic phase, organic phase saturated nacl aqueous solution washs, anhydrous sodium sulfate drying, filter, concentrating under reduced pressure filtrate, resistates silica gel column chromatography is separated (eluent system: methylene dichloride and methyl alcohol), obtain target product I-3 (170mg, white solid), productive rate: 83.7%, mp:118-120 DEG C.
1H NMR(300MHz，DMSO-d
6)δ7.47-7.37(m，2H)，7.16(s，1H)，7.11(d，J＝7.3Hz，1H)，6.97-6.90(m，2H)，6.71(s，2H)，5.12(s，2H)，4.68(s，2H)，4.09(t，J＝6.2Hz，2H)，3.27(t，J＝7.6Hz，2H)，3.03(s，3H)，2.19-2.10(m，2H)，1.95(s，6H)；
13CNMR(75MHz，DMSO-d
6)δ169.9，156.9，152.5，147.6，140.3，137.0，136.6，133.9，128.8，128.6，125.9，121.6，116.8，114.6，114.5，113.3，69.8，65.6，65.4，50.6，29.0，22.0，20.7；MS(ESI，m/z)：531.2[M-H]
-。
Embodiment 4
2-(4-((2 ', 6 '-dimethyl-4 '-(3-(methylsulfonyl) propyl group)-[1,1 '-xenyl]-3-) methoxyl group) 2-fluorobenzene oxygen) acetic acid (I-4)
Compound IV (200mg, 0.49mmol) is dissolved in 10mL acetone, adds K successively
2cO
3(134mg, 0.97mmol), the KI of catalytic amount and compound V-4 (97mg, 0.49mmol), heating reflux reaction spends the night, and after reaction terminates, filters, concentrating under reduced pressure filtrate.Resistates silica gel column chromatography is separated (eluent system: sherwood oil and ethyl acetate), obtains target product VI-4 (180mg, white solid), productive rate: 69.8%.
Compound VI-4 (170mg, 0.32mmol) be dissolved in 6mL tetrahydrofuran (THF), in first alcohol and water (2: 3: 1) three components solvent, add the sodium hydroxide solution (0.64mL of 2M, 1.28mmol), stirring at room temperature reaction 2h, after reaction terminates, add 10mL water, dripping 1M hydrochloric acid is 3 to reaction solution pH, be extracted with ethyl acetate (30mL × 3), merge organic phase, organic phase saturated nacl aqueous solution washs, anhydrous sodium sulfate drying, filter, concentrating under reduced pressure filtrate, resistates silica gel column chromatography is separated (eluent system: methylene dichloride and methyl alcohol), obtain target product I-4 (130mg, white solid), productive rate: 78.6%, mp:106-107 DEG C.
1H NMR(300MHz，DMSO-d
6)δ7.47-7.38(m，2H)，7.15(s，1H)，7.07-6.94(m，3H)，6.77-6.71(m，3H)，5.11(s，2H)，4.65(s，2H)，4.09(t，J＝6.1Hz，2H)，3.28(t，J＝7.6Hz，2H)，3.03(s，3H)，2.19-2.10(m，2H)，1.92(s，6H)；
13CNMR(75MHz，DMSO-d
6)δ167.0，156.9，153.4，152.8，152.6，150.2，140.3，139.8，137.0，136.6，133.9，128.8，128.6，128.6，125.9，115.9，113.3，110.3，104.3，104.0，69.7，65.8，65.4，50.6，22.0，20.7；MS(ESI，m/z)：515.3[M-H]
-。
Embodiment 5
2-(4-((2 ', 6 '-dimethyl-4 '-(3-(methylsulfonyl) propyl group)-[1,1 '-xenyl]-3-) methoxyl group) 2-anisole oxygen) acetic acid (I-5)
Compound IV (200mg, 0.49mmol) is dissolved in 10mL acetone, adds K successively
2cO
3(134mg, 0.97mmol), the KI of catalytic amount and compound V-5 (103mg, 0.49mmol), heating reflux reaction spends the night, and after reaction terminates, filters, concentrating under reduced pressure filtrate.Resistates silica gel column chromatography is separated (eluent system: sherwood oil and ethyl acetate), obtains target product VI-5 (210mg, white solid), productive rate: 79.6%.
Compound VI-5 (200mg, 0.37mmol) be dissolved in 6mL tetrahydrofuran (THF), in first alcohol and water (2: 3: 1) three components solvent, add the sodium hydroxide solution (0.74mL of 2M, 1.47mmol), stirring at room temperature reaction 2h, after reaction terminates, add 10mL water, dripping 1M hydrochloric acid is 3 to reaction solution pH, be extracted with ethyl acetate (30mL × 3), merge organic phase, organic phase saturated nacl aqueous solution washs, anhydrous sodium sulfate drying, filter, concentrating under reduced pressure filtrate, resistates silica gel column chromatography is separated (eluent system: methylene dichloride and methyl alcohol), obtain target product I-5 (160mg, white solid), productive rate: 82.1%, mp:122-124 DEG C.
1H NMR(300MHz，DMSO-d
6)δ7.43-7.39(m，2H)，7.15(s，1H)，7.05(d，1H)，6.77(d，J＝8.8Hz，1H)，6.69(s，2H)，6.65(d，J＝2.6Hz，1H)，6.45(dd，1H)，5.07(s，2H)，4.51(s，2H)，4.07(t，J＝6.1Hz，2H)，3.72(s，3H)，3.26(t，J＝7.5Hz，2H)，3.01(s，3H)，2.15-2.13(m，2H)，1.91(s，6H)；
13CNMR(75MHz，DMSO-d
6)δ167.0，156.9，153.4，152.8，152.6，150.2，140.3，139.8，137.0，136.6，133.9，128.8，128.6，128.6，125.9，115.9，113.3，110.3，104.3，104.0，69.7，65.8，65.4，50.6，22.0，20.7；MS(ESI，m/z)：527.3[M-H]
-。
Embodiment 6
2-(4-((2 ', 6 '-dimethyl-4 '-(3-(methylsulfonyl) propyl group)-[1,1 '-xenyl]-3-) methoxyl group) 2-ethylbenzene oxygen) acetic acid (I-6)
Compound IV (200mg, 0.49mmol) is dissolved in 10mL acetone, adds K successively
2cO
3(134mg, 0.97mmol), the KI of catalytic amount and compound V-6 (102mg, 0.49mmol), heating reflux reaction spends the night, and after reaction terminates, filters, concentrating under reduced pressure filtrate.Resistates silica gel column chromatography is separated (eluent system: sherwood oil and ethyl acetate), obtains target product VI-6 (200mg, white solid), productive rate: 76.1%.
Compound VI-6 (190mg, 0.35mmol) be dissolved in 6mL tetrahydrofuran (THF), in first alcohol and water (2: 3: 1) three components solvent, add the sodium hydroxide solution (0.70mL of 2M, 1.40mmol), stirring at room temperature reaction 2h, after reaction terminates, add 10mL water, dripping 1M hydrochloric acid is 3 to reaction solution pH, be extracted with ethyl acetate (30mL × 3), merge organic phase, organic phase saturated nacl aqueous solution washs, anhydrous sodium sulfate drying, filter, concentrating under reduced pressure filtrate, resistates silica gel column chromatography is separated (eluent system: methylene dichloride and methyl alcohol), obtain target product I-6 (150mg, white solid), productive rate: 81.1%, mp:110-112 DEG C.
1H NMR(300MHz，DMSO-d
6)δ7.42-7.37(m，2H)，7.15(s，1H)，7.05(d，J＝7.3Hz，1H)，6.81(s，1H)，6.75(s，2H)，6.71(s，2H)，5.08(s，2H)，4.59(s，2H)，4.09(t，J＝6.1Hz，2H)，3.27-3.25(d，2H)，3.03(s，3H)，2.59-2.54(t，2H)，2.17-2.11(m，2H)，1.92(s，6H)，1.11(t，J＝7.4Hz，3H)；
13CNMR(75MHz，DMSO-d
6)δ170.5，156.9，152.4，149.8，140.2，137.6，136.6，134.0，133.2，128.6，128.5，128.4，125.8，116.2，113.3，112.3，112.1，69.4，65.4，50.6，22.8，22.1，20.7，14.1；MS(ESI，m/z)：525.3[M-H]
-。
Embodiment 7
2-(4-((2 ', 6 '-dimethyl-4 '-(3-(methylsulfonyl) propyl group)-[1,1 '-xenyl]-3-) methoxyl group) phenoxy group)-2 Methylpropionic acid (I-7)
Compound IV (200mg, 0.49mmol) is dissolved in 10mL acetone, adds K successively
2cO
3(134mg, 0.97mmol), the KI of catalytic amount and compound V-7 (102mg, 0.49mmol), heating reflux reaction spends the night, and after reaction terminates, filters, concentrating under reduced pressure filtrate.Resistates silica gel column chromatography is separated (eluent system: sherwood oil and ethyl acetate), obtains target product VI-7 (210mg, white solid), productive rate: 79.9%.
Compound VI-7 (190mg, 0.35mmol) be dissolved in 6mL tetrahydrofuran (THF), in first alcohol and water (2: 3: 1) three components solvent, add the sodium hydroxide solution (0.70mL of 2M, 1.40mmol), stirring at room temperature reaction 2h, after reaction terminates, add 10mL water, dripping 1M hydrochloric acid is 3 to reaction solution pH, be extracted with ethyl acetate (30mL × 3), merge organic phase, organic phase saturated nacl aqueous solution washs, anhydrous sodium sulfate drying, filter, concentrating under reduced pressure filtrate, resistates silica gel column chromatography is separated (eluent system: methylene dichloride and methyl alcohol), obtain target product I-7 (140mg, white solid), productive rate: 75.7%, mp:110-112 DEG C.
1H NMR(300MHz，DMSO-d
6)δ7.45-7.38(m，2H)，7.14(s，1H)，7.05(d，J＝7.1Hz，1H)，6.91(d，J＝9.1Hz，2H)，6.80(d，J＝9.1Hz，2H)，6.70(s，2H)，5.09(s，2H)，4.09(t，J＝6.2Hz，2H)，3.27(t，J＝8.0Hz，2H)，3.03(s，3H)，2.18-2.09(m，2H)，1.91(s，6H)，1.42(s，6H)；
13CNMR(75MHz，DMSO-d
6)δ175.1，156.9，153.4，148.9，140.2，137.4，136.6，133.9，128.7，128.5，125.9，120.9，115.4，113.3，78.9，69.4，65.4，50.6，24.9，22.0，20.7；MS(ESI，m/z)：525.3[M-H]
-。
Embodiment 8
2-(4-((2 ', 6 '-dimethyl-4 '-(3-(methylsulfonyl) propyl group)-[1,1 '-xenyl]-3-) methoxyl group)-2-ethyl phenoxy group)-2 Methylpropionic acid (I-8)
Compound IV (200mg, 0.49mmol) is dissolved in 10mL acetone, adds K successively
2cO
3(134mg, 0.97mmol), the KI of catalytic amount and compound V-8 (116mg, 0.49mmol), heating reflux reaction spends the night, and after reaction terminates, filters, concentrating under reduced pressure filtrate.Resistates silica gel column chromatography is separated (eluent system: sherwood oil and ethyl acetate), obtains target product VI-8 (200mg, white solid), productive rate: 72.3%.
Compound VI-8 (190mg, 0.33mmol) be dissolved in 6mL tetrahydrofuran (THF), in first alcohol and water (2: 3: 1) three components solvent, add the sodium hydroxide solution (0.67mL of 2M, 1.34mmol), stirring at room temperature reaction 2h, after reaction terminates, add 10mL water, dripping 1M hydrochloric acid is 3 to reaction solution pH, be extracted with ethyl acetate (30mL × 3), merge organic phase, organic phase saturated nacl aqueous solution washs, anhydrous sodium sulfate drying, filter, concentrating under reduced pressure filtrate, resistates silica gel column chromatography is separated (eluent system: methylene dichloride and methyl alcohol), obtain target product I-8 (120mg, white solid), productive rate: 64.8%, mp:112-114 DEG C.
1H NMR(300Hz，DMSO-d
6)δ7.44-7.37(m，2H)，7.14(s，1H)，7.05(d，J＝7.2Hz，1H)，6.81(d，J＝2.9Hz，1H)，6.75-6.64(m，4H)，5.08(s，2H)，4.09(t，J＝6.2Hz，2H)，3.32-3.25(m，2H)，3.03(s，3H)，2.56-2.504(m，2H)，2.17-2.12(m，2H)，1.91(s，6H)，1.44(s，6H)，1.09(t，J＝6.9Hz，3H)；
13CNMR(75MHz，DMSO-d
6)δ175.5，156.9，152.7，147.0，140.2，137.6，136.6，135.9，133.9，128.6，128.5，125.8，117.7，115.9，113.3，112.0，78.4，69.3，65.4，50.5，25.0，23.1，22.0，20.7，14.2；MS(ESI，m/z)：553.3[M-H]
-。
Embodiment 9
2-(2-chlorine 4-((2 ', 6 '-dimethyl-4 '-(3-(methylsulfonyl) propyl group)-[1,1 '-xenyl]-3-) methoxyl group) phenoxy group)-2 Methylpropionic acid (I-9)
Compound IV (200mg, 0.49mmol) is dissolved in 10mL acetone, adds K successively
2cO
3(134mg, 0.97mmol), the KI of catalytic amount and compound V-9 (119mg, 0.49mmol), heating reflux reaction spends the night, and after reaction terminates, filters, concentrating under reduced pressure filtrate.Resistates silica gel column chromatography is separated (eluent system: sherwood oil and ethyl acetate), obtains target product VI-9 (230mg, white solid), productive rate: 82.3%.
Compound VI-9 (220mg, 0.38mmol) be dissolved in 6mL tetrahydrofuran (THF), in first alcohol and water (2: 3: 1) three components solvent, add the sodium hydroxide solution (0.76mL of 2M, 1.52mmol), stirring at room temperature reaction 2h, after reaction terminates, add 10mL water, dripping 1M hydrochloric acid is 3 to reaction solution pH, be extracted with ethyl acetate (30mL × 3), merge organic phase, organic phase saturated nacl aqueous solution washs, anhydrous sodium sulfate drying, filter, concentrating under reduced pressure filtrate, resistates silica gel column chromatography is separated (eluent system: methylene dichloride and methyl alcohol), obtain target product I-9 (170mg, white solid), productive rate: 79.2%, mp:112-114 DEG C.
1H NMR(300MHz，DMSO-d
6)δ7.49-7.38(m，2H)，7.15(s，1H)，7.11(d，J＝2.5Hz，1H)，7.06(d，J＝7.3Hz，1H)，6.95-6.93(m，2H)，6.71(s，2H)，5.13(s，2H)，4.09(t，J＝6.2Hz，2H)，3.28-3.19(m，2H)，3.03(s，3H)，2.17-2.12(m，2H)，1.91(s，6H)，1.45(s，6H)；
13CNMR(75MHz，DMSO-d
6)δ174.8，156.9，153.5，145.0，140.3，136.9，136.6，133.9，128.9，128.6，126.0，121.2，116.3，114.6，113.3，80.4，69.6，65.4，50.6，24.7，22.0，20.7；MS(ESI，m/z)：559.2[M-H]
-。
Embodiment 10
2-(4-((2 ', 6 '-dimethyl-4 '-(3-(methylsulfonyl) propyl group)-[1,1 '-xenyl]-3-) methoxyl group) 2-fluorophenoxy)-2 Methylpropionic acid (I-10)
Compound IV (200mg, 0.49mmol) is dissolved in 10mL acetone, adds K successively
2cO
3(134mg, 0.97mmol), the KI of catalytic amount and compound V-10 (111mg, 0.49mmol), heating reflux reaction spends the night, and after reaction terminates, filters, concentrating under reduced pressure filtrate.Resistates silica gel column chromatography is separated (eluent system: sherwood oil and ethyl acetate), obtains target product VI-10 (190mg, white solid), productive rate: 70.0%.
Compound VI-10 (180mg, 0.32mmol) be dissolved in 6mL tetrahydrofuran (THF), in first alcohol and water (2: 3: 1) three components solvent, add the sodium hydroxide solution (0.64mL of 2M, 1.28mmol), stirring at room temperature reaction 2h, after reaction terminates, add 10mL water, dripping 1M hydrochloric acid is 3 to reaction solution pH, be extracted with ethyl acetate (30mL × 3), merge organic phase, organic phase saturated nacl aqueous solution washs, anhydrous sodium sulfate drying, filter, concentrating under reduced pressure filtrate, resistates silica gel column chromatography is separated (eluent system: methylene dichloride and methyl alcohol), obtain target product I-10 (120mg, white solid), productive rate: 68.4%, mp:124-126 DEG C.
1H NMR(300MHz，DMSO-d
6)δ7.53-7.41(m，3H)，7.21-7.06(m，4H)，6.71(s，2H)，5.23(s，2H)，4.09(t，J＝6.1Hz，2H)，3.28(t，J＝7.6Hz，2H)，3.03(s，3H)，2.19-2.10(m，2H)，1.92(s，6H)，1.41(s，6H)；
13CNMR(75MHz，DMSO-d
6)δ175.1，156.9，154.5，152.9，140.2，138.0，137.3，136.6，133.9，128.7，128.5，125.9，121.8，113.3，107.7，105.0，101.0，79.7，69.4，65.4，55.4，50.6，24.5，22.0，20.7；MS(ESI，m/z)：543.3[M-H]
-。
Embodiment 11
2-(4-((2 ', 6 '-dimethyl-4 '-(3-(methylsulfonyl) propyl group)-[1,1 '-xenyl]-3-) methoxyl group) 2-methoxyphenoxy)-2 Methylpropionic acid (I-11)
Compound IV (200mg, 0.49mmol) is dissolved in 10mL acetone, adds K successively
2cO
3(134mg, 0.97mmol), the KI of catalytic amount and compound V-11 (116mg, 0.49mmol), heating reflux reaction spends the night, and after reaction terminates, filters, concentrating under reduced pressure filtrate.Resistates silica gel column chromatography is separated (eluent system: sherwood oil and ethyl acetate), obtains target product VI-11 (220mg, white solid), productive rate: 79.3%.
Compound VI-11 (210mg, 0.37mmol) be dissolved in 6mL tetrahydrofuran (THF), in first alcohol and water (2: 3: 1) three components solvent, add the sodium hydroxide solution (0.74mL of 2M, 1.48mmol), stirring at room temperature reaction 2h, after reaction terminates, add 10mL water, dripping 1M hydrochloric acid is 3 to reaction solution pH, be extracted with ethyl acetate (30mL × 3), merge organic phase, organic phase saturated nacl aqueous solution washs, anhydrous sodium sulfate drying, filter, concentrating under reduced pressure filtrate, resistates silica gel column chromatography is separated (eluent system: methylene dichloride and methyl alcohol), obtain target product I-11 (170mg, white solid), productive rate: 83.0%, mp:128-130 DEG C.
1H NMR(300MHz，DMSO-d
6)δ7.45-7.42(m，2H)，7.16(s，1H)，7.06(d，J＝7.1Hz，1H)，6.83(d，J＝8.8Hz，1H)，6.71(s，2H)，6.65(d，J＝2.8Hz，1H)，6.48(dd，J＝8.8Hz，2.8，1H)，5.10(s，2H)，4.09(t，J＝6.2Hz，2H)，3.70(s，3H)，3.32-3.25(t，2H)，3.03(s，3H)，2.17-2.12(m，2H)，1.92(s，6H)，1.36(s，6H)；
13CNMR(75MHz，DMSO-d
6)δ175.1，156.9，154.5，152.9，140.2，138.0，137.3，136.6，133.9，128.7，128.5，125.9，121.8，113.3，107.7，105.0，101.0，79.7，69.4，65.4，55.4，50.6，24.5，22.0，20.7；MS(ESI，m/z)：555.3[M-H]
-。
Embodiment 12
2-(4-((2 '; 6 '-dimethyl-4 '-(3-(methylsulfonyl) propyl group)-[1; 1 '-xenyl]-3-yl) methoxyl group) 2,6-dimethyl phenoxies)-2 Methylpropionic acid (I-12)
Compound IV (200mg, 0.49mmol) is dissolved in 10mL acetone, adds K successively
2cO
3(134mg, 0.97mmol), the KI of catalytic amount and compound V-12 (116mg, 0.49mmol), heating reflux reaction spends the night, and after reaction terminates, filters, concentrating under reduced pressure filtrate.Resistates silica gel column chromatography is separated (eluent system: sherwood oil and ethyl acetate), obtains target product VI-12 (210mg, white solid), productive rate: 72.3%.
Compound VI-12 (200mg, 0.35mmol) be dissolved in 6mL tetrahydrofuran (THF), in first alcohol and water (2: 3: 1) three components solvent, add the sodium hydroxide solution (0.70mL of 2M, 1.40mmol), stirring at room temperature reaction 2h, after reaction terminates, add 10mL water, dripping 1M hydrochloric acid is 3 to reaction solution pH, be extracted with ethyl acetate (30mL × 3), merge organic phase, organic phase saturated nacl aqueous solution washs, anhydrous sodium sulfate drying, filter, concentrating under reduced pressure filtrate, resistates silica gel column chromatography is separated (eluent system: methylene dichloride and methyl alcohol), obtain target product I-12 (130mg, white solid), productive rate: 66.6%, mp:116-118 DEG C.
1H NMR(300MHz，DMSO-d
6)δ7.47-7.37(m，2H)，7.14(s，1H)，7.05(d，J＝7.3Hz，1H)，6.71(s，2H)，6.64(s，2H)，5.07(s，2H)，4.09(t，J＝6.1Hz，2H)，3.32-3.19(m，2H)，3.03(s，3H)，2.19-2.11(m，8H)，1.92(s，6H)，1.32(s，6H)；
13CNMR(75MHz，DMSO-d
6)δ175.3，156.9，153.7，146.2，140.2，137.5，136.6，133.9，133.1，128.6，128.5，128.5，125.8，114.4，113.3，79.8，69.0，65.4，50.6，24.8，22.0，20.6，17.7；MS(ESI，m/z)：553.4[M-H]
-。
Embodiment 13
2-(4-((4 '-oxyethyl group-2 ', 6 '-dimethyl-[1,1 '-xenyl]-3-) methoxyl group)-2 fluorobenzene oxygen) acetic acid (I-13)
Compound VI I (200mg, 0.49mmol) is dissolved in 10mLDMF, adds K
2cO
3(134mg, 0.97mmol) and monobromethane (106mg, 0.98mmol), 80 DEG C of heated overnight at reflux, after reaction terminates, add water to K
2cO
3dissolve, be extracted with ethyl acetate (40mL × 3), merge organic phase, organic phase is with using water and saturated sodium-chloride washing respectively, anhydrous sodium sulfate drying, concentrating under reduced pressure filtrate.Resistates silica gel column chromatography is separated (eluent system: sherwood oil and ethyl acetate), obtains target product VIII-13 (170mg, white solid), productive rate: 79.6%.
Compound VI-13 (160mg, 0.36mmol) be dissolved in 6mL tetrahydrofuran (THF), in first alcohol and water (2: 3: 1) three components solvent, add the sodium hydroxide solution (0.72mL of 2M, 1.44mmol), stirring at room temperature reaction 2h, after reaction terminates, add 10mL water, dripping 1M hydrochloric acid is 3 to reaction solution pH, be extracted with ethyl acetate (30mL × 3), merge organic phase, organic phase saturated nacl aqueous solution washs, anhydrous sodium sulfate drying, filter, concentrating under reduced pressure filtrate, resistates silica gel column chromatography is separated (eluent system: methylene dichloride and methyl alcohol), obtain target product I-13 (110mg, white solid), productive rate: 71.0%, mp:102-104 DEG C.
1HNMR(300MHz，DMSO-d
6)δ：7.47-7.37(m，2H)，7.15(s，1H)，7.07-7.03(t，1H)，7.00-6.94(m，2H)，6.75(d，J＝7.8Hz，1H)，6.68(s，2H)，5.11(s，2H)，4.66(s，2H)，4.02(q，J＝6.9Hz，2H)，1.99(s，6H)，1.32(t，J＝6.9Hz，3H)。
13CNMR(75MHz，DMSO-d
6)δ170.0，157.2，150.1，140.3，137.0，136.5，133.5，128.9，128.7，128.6，125.9，115.8，113.1，110.3，104.3，104.0，69.7，65.7，62.7，20.7，14.7；MS(ESI，m/z)：423.0[M-H]
-。
Embodiment 14
2-(4-((4 '-(3-methoxy propoxy)-2 ', 6 '-dimethyl-[1,1 '-xenyl]-3-) methoxyl group) 2-fluorobenzene oxygen) acetic acid (I-14)
Compound VI I (200mg, 0.49mmol) is dissolved in 10mL DMF, adds K
2cO
3(134mg, 0.97mmol) and 2-methoxyl group-1 monobromethane (136mg, 0.98mmol), 80 DEG C of heated overnight at reflux, after reaction terminates, add water to K
2cO
3dissolve, be extracted with ethyl acetate (40mL × 3), merge organic phase, organic phase is with using water and saturated sodium-chloride washing respectively, anhydrous sodium sulfate drying, concentrating under reduced pressure filtrate.Resistates silica gel column chromatography is separated (eluent system: sherwood oil and ethyl acetate), obtains target product VIII-14 (180mg, white solid), productive rate: 78.8%.
Compound VI-14 (170mg, 0.35mmol) be dissolved in 6mL tetrahydrofuran (THF), in first alcohol and water (2: 3: 1) three components solvent, add the sodium hydroxide solution (0.70mL of 2M, 1.40mmol), stirring at room temperature reaction 2h, after reaction terminates, add 10mL water, dripping 1M hydrochloric acid is 3 to reaction solution pH, be extracted with ethyl acetate (30mL × 3), merge organic phase, organic phase saturated nacl aqueous solution washs, anhydrous sodium sulfate drying, filter, concentrating under reduced pressure filtrate, resistates silica gel column chromatography is separated (eluent system: methylene dichloride and methyl alcohol), obtain target product I-14 (110mg, white solid), productive rate: 66.7%, mp:113-115 DEG C.
1HNMR(300MHz，DMSO-d
6)δ：7.45(t，J＝7.5Hz，1H)，7.38(d，J＝7.5Hz，1H)，7.15(s，1H)，7.06(d，J＝7.2Hz，1H)，7.03-6.94(m，2H)，6.75(d，J＝9.2Hz，1H)，6.69(s，2H)，5.10(s，2H)，4.65(s，2H)，4.01(t，J＝6.3Hz，2H)，3.48(t，J＝6.2Hz，2H)，1.98-1.94(m，2H)，1.91(s，6H)。
13CNMR(75MHz，DMSO-d
6)δ＝170.0，157.1，153.4，152.7，152.6，150.2，140.3，139.8，139.6，137.0，136.5，133.7，128.8，128.6，128.5，125.9，115.8，113.2，110.3，104.3，104.0，73.5，70.4，69.7，66.6，65.8，58.1，20.7；MS(ESI，m/z)：453.0[M-H]
-。
Embodiment 15
2-(4-((4 '-(2-(dimethylamino)-2-oxoethoxy)-2 ', 6 '-dimethyl-[1,1 '-xenyl]-3-) methoxyl group)-2-fluorobenzene oxygen) acetic acid (I-15)
Compound VI I (200mg, 0.49mmol) is dissolved in 10mLDMF, adds K
2cO
3(134mg, 0.97mmol) and N, N-dimethyl chloride ethanamide (118mg, 0.98mmol), 80 DEG C of heated overnight at reflux, after reaction terminates, add water to K
2cO
3dissolve, be extracted with ethyl acetate (40mL × 3), merge organic phase, organic phase is with using water and saturated sodium-chloride washing respectively, anhydrous sodium sulfate drying, concentrating under reduced pressure filtrate.Resistates silica gel column chromatography is separated (eluent system: sherwood oil and ethyl acetate), obtains target product VIII-15 (190mg, white solid), productive rate: 78.7%.
Compound VI II-15 (180mg, 0.36mmol) be dissolved in 6mL tetrahydrofuran (THF), in first alcohol and water (2: 3: 1) three components solvent, add the sodium hydroxide solution (0.72mL of 2M, 1.44mmol), stirring at room temperature reaction 2h, after reaction terminates, add 10mL water, dripping 1M hydrochloric acid is 3 to reaction solution pH, be extracted with ethyl acetate (30mL × 3), merge organic phase, organic phase saturated nacl aqueous solution washs, anhydrous sodium sulfate drying, filter, concentrating under reduced pressure filtrate, resistates silica gel column chromatography is separated (eluent system: methylene dichloride and methyl alcohol), obtain target product I-15 (120mg, white solid), productive rate: 68.6%, mp:127-129 DEG C.
1H NMR(300MHz，DMSO-d
6)：δ7.47-7.37(m，2H)，7.15(s，1H)，7.06(d，J＝7.2Hz，1H)，7.03-6.94(m，2H)，6.75(d，J＝9.2Hz，1H)，6.69(s，2H)，5.10(s，2H)，4.77(s，2H)，4.66(s，2H)，3.00(s，3H)，2.85(s，3H)，1.90(s，6H)。
13CNMR(75MHz，DMSO-d
6)δ170.0，167.2，156.7，153.4，152.7，152.6，150.1，140.3，139.8，139.6，137.9，136.4，133.9，128.8，128.6，125.9，115.8，113.3，110.3，104.3，104.0，69.7，65.8，65.7，20.7；MS(ESI，m/z)：480.0[M-H]
-。
Embodiment 16
3 '-(brooethyl)-2,6-dimethyl-4-(3-(methyl sulphonyl) propoxy-)-1,1 '-biphenyl (IV)
The first step
3-(methylthio group) propyl group-4-Methyl benzenesulfonyl ester
By 3-methylthio group-1-propyl alcohol (5.0g, 47.09mmol) be dissolved in 10mL pyridine, be cooled to-10 ~ 0 DEG C, slow dropping 20mL pyridinium dissolution to the yellow acyl chlorides (10.77g of toluene, 56.50mmol), stirring reaction 5h at adding latter 0 DEG C, add 50mL shrend to go out reaction, be extracted with ethyl acetate (100mL × 3), merge organic phase, organic phase 1N HCl and saturated sodium-chloride washing, anhydrous sodium sulfate drying, filters, concentrating under reduced pressure filtrate colourless liquid 9.6g, productive rate: 78.3%, directly does next step.
Second step
3-(methylsulfonyl) propyl group 4-Methyl benzenesulfonyl ester
By 3-(methylthio group) propyl group-4-Methyl benzenesulfonyl ester (9.0g, 34.57mml) be dissolved in 50mL methyl alcohol, be cooled to-10 ~ 0 DEG C, slowly drip 200mL water-soluble peroxosulphuric hydrogen potassium (21.3g, 69.14mmol), 12h is reacted at adding latter 0 DEG C, concentrating under reduced pressure, resistates suction filtration, filter cake washes with water, drying obtains white solid 8.2g, productive rate: 81.1%.
1HNMR(300MHz，CDCl
3)δ：7.72(d，J＝8.2Hz，2H)，7.30(d，J＝8.1Hz，1H)，7.15(s，1H)，4.11(t，J＝5.8Hz，2H)，3.04(t，J＝7.5Hz，2H)，2.85(s，3H)，2.40(s，3H)，2.20-2.12(m，2H)。
3rd step
Bromo-1, the 3-dimethyl-5-of 2-(3-(methylsulfonyl) propyl group oxygen) benzene
By 3-(methylsulfonyl) propyl group 4-Methyl benzenesulfonyl ester (8.0g, 27.36mmol) be dissolved in 40mL DMF, add 2, 5-dimethyl-4-bromophenol (5.5g, 27.36mmol) with salt of wormwood (7.6g, 54.72mmol), add rear 80 DEG C of reflux 24h, cooling, add water to salt of wormwood to dissolve, be extracted with ethyl acetate (60mL × 3), merge organic phase, organic phase washed with water and saturated nacl aqueous solution washing, anhydrous sodium sulfate drying, filter, concentrating under reduced pressure filtrate, resistates silica gel column chromatography is separated (eluent system: ethyl acetate and sherwood oil) and obtains white solid 7.5g, productive rate: 85.3%.
1HNMR(300MHz，CDCl
3)δ：6.65(s，J＝8.2Hz，2H)，4.08(t，J＝5.7Hz，2H)，3.26(t，J＝7.5Hz，2H)，2.97(s，3H)，2.40(s，6H)，2.36-2.18(m，2H)。
4th step
2 ', 6 '-dimethyl-4 '-(3-(methylsulfonyl) propoxy-)-[1,1 '-biphenyl]-3-formaldehyde
By bromo-for 2-1, 3-dimethyl-5-(3-(methylsulfonyl) propyl group oxygen) benzene (7.0g, 21.79mmol) with 3-carboxaldehyde radicals phenylo boric acid (3.3g, 21.79mmol) be dissolved in 50mL 1, in 2-dimethyl second diether, add the aqueous sodium carbonate (21.8mL of 2N, 43.58mmol) He four (triphenyl phosphorus) palladium (1.3g, 1.09mmol), nitrogen protection, reaction solution reflux 24h, cooling, suction filtration, be extracted with ethyl acetate (60mL × 3), merge organic phase, organic phase saturated nacl aqueous solution washs, anhydrous sodium sulfate drying, filter, concentrating under reduced pressure filtrate, resistates silica gel column chromatography is separated (eluent system: ethyl acetate and sherwood oil), obtain white solid 5.6g, productive rate: 74.2%.
1HNMR(300MHz，DMSO-d
6)δ：10.05(s，1H)，7.49(d，J＝7.4Hz，1H)，7.70-7.65(m，2H)，7.48(d，J＝7.5Hz，1H)，6.75(d，J＝9.2Hz，1H)，6.69(s，2H)，4.11(t，J＝6.3Hz，2H)，3.29(t，J＝8.3Hz，2H)，3.04(s，3H)，2.17-2.12(m，2H)，1.95(s，6H)。
5th step
(2 ', 6 '-dimethyl-4 '-(3-(methylsulfonyl) propyl group oxygen)-[1,1 '-biphenyl]-3-) methyl alcohol
By 2 '; 6 '-dimethyl-4 '-(3-(methylsulfonyl) propoxy-)-[1; 1 '-biphenyl]-3-formaldehyde (5.0g; 14.43mmol) be dissolved in 20mL tetrahydrofuran (THF) and methyl alcohol; be cooled to 0 DEG C; add sodium borohydride (0.54g, 14.43mmol), stirring reaction 1h at adding latter 0 DEG C in batches; drip 1N HCl cancellation reaction; be extracted with ethyl acetate (50mL × 3), merge organic phase, organic phase saturated nacl aqueous solution washs; anhydrous sodium sulfate drying; filter, concentrating under reduced pressure filtrate obtains white solid 4.7g, productive rate: 93.5%.
1HNMR(300MHz，DMSO-d
6)δ：7.37(t，J＝7.5Hz，1H)，7.27(d，J＝7.0Hz，1H)，7.02(s，1H)，6.95(d，J＝7.2Hz，1H)，6.69(s，2H)，5.18(t，J＝5.6Hz，1H)，4.52(d，J＝5.7Hz，2H))，4.07(t，J＝6.0Hz，2H)，3.27(t，J＝7.4Hz，2H)，3.02(s，3H)，2.15-2.08(m，2H)，1.92(s，6H)。
6th step
3 '-(brooethyl)-2,6-dimethyl-4-(3-(methylsulfonyl) propyl group oxygen)-1,1 '-biphenyl
By (2 ', 6 '-dimethyl-4 '-(3-(methylsulfonyl) propyl group oxygen)-[1, 1 '-biphenyl]-3-) methyl alcohol (4.5g, 12.91mmol) be dissolved in 30mL methylene dichloride, be cooled to 0 DEG C, phosphorus tribromide (the 1.75g that slow dropping methylene dichloride dissolves, 6.46mmol), add rear reaction solution stirring reaction 1h at 0 DEG C, the cancellation that adds water is reacted, with dichloromethane extraction (40mL × 3), merge organic phase, organic phase saturated nacl aqueous solution washs, anhydrous sodium sulfate drying, filter, concentrating under reduced pressure filtrate, resistates silica gel column chromatography is separated (eluent system: ethyl acetate and sherwood oil), obtain white solid 4.6g, productive rate: 86.6%.
1HNMR(300MHz，DMSO-d
6)δ：7.43-7.41(m，2H)，7.19(s，1H)，7.07-7.04(m，1H)，6.72(s，2H)，4.74(s，2H))，4.09(t，J＝6.2Hz，2H)，3.28(t，J＝8.0Hz，2H)，3.03(s，3H)，2.19-2.10(m，2H)，1.94(s，6H)。
Embodiment 17
2-(the fluoro-4-of 2-((4 '-hydroxyl-2 ', 6 '-dimethyl-[1,1 '-biphenyl]-3-) methoxyl group) benzene oxygen) methyl acetate (VII)
The first step
3 '-formyl radical-2,6-dimethyl-[1,1 '-biphenyl]-4-acetonyl ester
By 4 '-hydroxyl-2 ', 6 '-dimethyl-[1, 1 '-biphenyl]-3-aldehyde radical (5.0g, 22.10mmol) be dissolved in 30mL methylene dichloride, add pyridine (3.5g, 44.19mmol), be cooled to 0 DEG C, Acetyl Chloride 98Min. (the 1.2g that slow dropping 10mL methylene dichloride dissolves, 26.52mmol), stirring reaction 1h at adding latter 0 DEG C, the cancellation that adds water is reacted, with dichloromethane extraction (60mL × 3), merge organic phase, organic phase 1N HCl, 1N NaOH and saturated nacl aqueous solution washing, anhydrous sodium sulfate drying, filter, concentrating under reduced pressure filtrate, resistates silica gel column chromatography is separated (eluent system: ethyl acetate and sherwood oil), obtain white solid 4.8g, productive rate: 81.0%.
1HNMR(300MHz，CDCl
3)δ：10.05(s，1H)，7.89(d，J＝7.7Hz，1H)，7.67(s，1H)，7.61(t，J＝7.6Hz，1H)，7.43(s，J＝7.6Hz，1H)，6.86(s，2H))，2.32(s，3H)，2.00(s，6H)。
Second step
3 '-(methylol)-2,6-dimethyl-[1,1 '-biphenyl]-4-acetonyl ester
By 3 '-formyl radical-2; 6-dimethyl-[1; 1 '-biphenyl]-4-acetonyl ester (4.5g; 16.77mmol) be dissolved in 20mL tetrahydrofuran (THF) and methyl alcohol; be cooled to 0 DEG C; add sodium borohydride (0.63g, 16.77mmol), stirring reaction 1h at adding latter 0 DEG C in batches; drip 1N HCl cancellation reaction; be extracted with ethyl acetate (50mL × 3), merge organic phase, organic phase saturated nacl aqueous solution washs; anhydrous sodium sulfate drying; filter, concentrating under reduced pressure filtrate obtains white solid 4.2g, and yield is 92.6%.
1HNMR(300MHz，DMSO-d
6)δ：7.44-7.39(t，1H)，7.32(d，J＝7.7，1H)，7.08(s，1H)，7.00(d，J＝7.4，2H)，6.89(s，2H)，5.21(t，J＝5.7，1H)，4.55(d，J＝5.4，2H)，2.27(s，3H)，1.96(s，6H)。
3rd step
3 '-(brooethyl)-2,6-dimethyl-[1,1 '-biphenyl]-4-acetonyl ester
By 3 '-(methylol)-2, 6-dimethyl-[1, 1 '-biphenyl]-4-acetonyl ester (4.2g, 14.80mmol) be dissolved in 30mL methylene dichloride, be cooled to 0 DEG C, phosphorus tribromide (the 2.0g that slow dropping methylene dichloride dissolves, 7.40mmol), add rear reaction solution stirring reaction 1h at 0 DEG C, the cancellation that adds water is reacted, with dichloromethane extraction (40mL × 3), merge organic phase, organic phase saturated nacl aqueous solution washs, anhydrous sodium sulfate drying, filter, concentrating under reduced pressure filtrate, resistates silica gel column chromatography is separated (eluent system: ethyl acetate and sherwood oil), obtain white solid 4.3g, productive rate: 87.2%.
1HNMR(300MHz，CDCl
3)δ：7.44-7.39(m，1H)，7.34(d，J＝7.9Hz，1H)，7.14(s，1H)，7.10-7.06(m，1H)，6.82(s，2H)，4.52(s，2H)，2.31(s，3H)，1.97(s，6H)。
4th step
2-(4-((4 '-acetoxyl group-2 ', 6 '-dimethyl-[1,1 '-biphenyl]-3-) methoxyl group)-2-fluorophenoxy) acetoxymethyl ester
By 3 '-(brooethyl)-2,6-dimethyl-[1,1 '-biphenyl]-4-acetonyl ester (4.0g, 12.00mmol) and 2-(2-fluoro-4-hydroxybenzene oxygen) methyl acetate (2.4g, 12mmol) be dissolved in 30mL acetone, add salt of wormwood (3.32g, 24.01mmol) and the potassiumiodide of catalytic amount, add post-heating back flow reaction and spend the night, after reaction terminates, filter, concentrating under reduced pressure filtrate.Resistates silica gel column chromatography is separated (eluent system: sherwood oil and ethyl acetate), obtains white solid 4.2g, productive rate: 77.3%.
5th step
2-(the fluoro-4-of 2-((4 '-hydroxyl-2 ', 6 '-dimethyl-[1,1 '-biphenyl]-3-) methoxyl group) phenoxy group) methyl acetate
By 2-(4-((4 '-acetoxyl group-2 ', 6 '-dimethyl-[1, 1 '-biphenyl]-3-) methoxyl group)-2-fluorophenoxy) acetoxymethyl ester (4.2g, 8.84mmol) be dissolved in 50mL methyl alcohol, add sodium methylate (0.96g in batches, 17.68mmol), add rear stirring at room temperature reaction 4h, adding 1N HCl adjust pH is 1-6, concentrated, with acetic acid ethyl dissolution (150mL), organic phase saturated sodium-chloride washs, anhydrous sodium sulfate drying, filter, concentrating under reduced pressure filtrate, resistates silica gel column chromatography is separated (eluent system: ethyl acetate and sherwood oil), obtain white solid 2.9g, productive rate: 79.9%.
1HNMR(300MHz，DMSO-d
6)δ：7.36-7.26(m，2H)，7.05(s，1H)，6.97-6.91(t，3H)，6.66(d，J＝9.0Hz，1H)，6.42(t，3H)，5.01(s，2H)，4.69(s，2H)，3.59(s，3H)，1.79(s，6H)。
Embodiment 18
Tablet containing promoting agent I-4:
According to a conventional method supplementary material is mixed, granulate, dry, compressing tablet.
Claims (6)
1. the compound shown in claim general formula (I) or its pharmaceutically useful salt:
Wherein:
X is O, CH
2, S, NH, N (C
1-C
4alkyl);
Y is (CH
2)
m;
R
1and R
2identical or different, and be H, F, Cl, Br, substituted or unsubstituted C separately
1-C
6alkyl;
R
3and R
4identical or different, and be H, F, Cl, Br, CN, CF separately
3, substituted or unsubstituted C
1-C
6alkyl, substituted or unsubstituted C
1-C
6alkyl-O-, substituted or unsubstituted C
1-C
6alkyl-CO-;
R
5and R
6identical or different, and be H, F, Cl, Br, CN, CF separately
3, substituted or unsubstituted C
1-C
6alkyl, substituted or unsubstituted C
1-C
6alkyl-O-, C
3-C
10carbocyclic ring;
R
7and R
8identical or different, and be H, F, Cl, Br, CN, CF separately
3, substituted or unsubstituted C
1-C
6alkyl, substituted or unsubstituted C
1-C
6alkyl-O-, C
3-C
10carbocyclic ring;
R
9for H, F, Cl, Br, substituted or unsubstituted C
1-C
6alkyl, replacement or do not replace C
1-C
6alkyl-S (O)
n-, NH
2, NH (C
1-C
4alkyl), N (C
1-C
4alkyl)
2, CONH
2, CONH (C
1-C
4alkyl), CON (C
1-C
4alkyl)
2, C
3-C
10carbocyclic ring, carbon atoms and 1-4 is selected from N, O, S and S (O)
nheteroatomic 3 to 10 yuan of heterocyclic radicals;
M is 0,1,2,3,4,5 or 6 when occurring; N is 0,1 or 2 when occurring.
2. the compound of general formula according to claim 1 (I) or its pharmaceutically useful salt, it is the compound shown in general formula (II) or its pharmaceutically useful salt:
Wherein:
X is O, NH or N (C
1-C
4alkyl);
Y is (CH
2)
m;
R
1and R
2identical or different, and be H or substituted or unsubstituted C separately
1-C
6alkyl;
R
3and R
4identical or different, and be H, F, Cl, Br, CN, CF separately
3, substituted or unsubstituted C
1-C
6alkyl or substituted or unsubstituted C
1-C
6alkyl-O-;
R
5and R
6identical or different, and be H, F, Cl, Br, CN, CF separately
3, substituted or unsubstituted C
1-C
6alkyl, substituted or unsubstituted C
1-C
6alkyl-O-, C
3-C
10carbocyclic ring;
R
9for H, F, Cl, Br, substituted or unsubstituted C
1-C
6alkyl, replacement or do not replace C
1-C
6alkyl-S (O)
n-, NH
2, NH (C
1-C
4alkyl), N (C
1-C
4alkyl)
2, CONH
2, CON (C
1-C
4alkyl)
2, C
3-C
6carbocyclic ring, carbon atoms and 1-4 is selected from N, O, S and S (O)
nheteroatomic 3 to 6 yuan of heterocyclic radicals;
M is 0,1,2,3,4,5 or 6 when occurring; N is 0,1 or 2 when occurring.
3. the compound of general formula according to claim 1 (I) or its pharmaceutically useful salt, it is the compound shown in general formula (III) or its pharmaceutically useful salt:
Wherein:
Y is (CH
2)
m;
R
1and R
2identical or different, and be H or substituted or unsubstituted C separately
1-C
4alkyl;
R
3and R
4identical or different, and be H, F, Cl, Br, CN, CF separately
3, substituted or unsubstituted C
1-C
6alkyl or substituted or unsubstituted C
1-C
6alkyl-O-;
R
5and R
6identical or different, and be H, F, Cl, Br, substituted or unsubstituted C separately
1-C
6alkyl;
R
9for H, F, Cl, Br, substituted or unsubstituted C
1-C
6alkyl, replacement or do not replace C
1-C
6alkyl-S (O)
n-, NH
2, NH (C
1-C
4alkyl), N (C
1-C
4alkyl)
2, CONH
2, CON (C
1-C
4alkyl)
2, C
3-C
6carbocyclic ring, carbon atoms and 1-4 is selected from N, O, S and S (O)
nheteroatomic 3 to 6 yuan of heterocyclic radicals;
M is 0,1,2,3,4,5 or 6 when occurring; N is 0,1 or 2 when occurring.
4. general formula (I) compound defined according to claim 1-3 and pharmacologically acceptable salt thereof, this compound is selected from:
2-(4-((2 ', 6 '-dimethyl-4 '-(3-(methylsulfonyl) propyl group)-[1,1 '-xenyl]-3-) methoxyl group) benzene oxygen) acetic acid;
2-(4-((2 ', 6 '-dimethyl-4 '-(3-(methylsulfonyl) propyl group)-[1,1 '-xenyl]-3-) methoxyl group) 2-methylenedioxy phenoxy) acetic acid;
2-(the chloro-4-of 2-((2 ', 6 '-dimethyl-4 '-(3-(first sulphur formyl radical) propyl group)-[1,1 '-xenyl]-3-) methoxyl group) phenoxy group) acetic acid;
2-(4-((2 ', 6 '-dimethyl-4 '-(3-(methylsulfonyl) propyl group)-[1,1 '-xenyl]-3-) methoxyl group) 2-fluorobenzene oxygen) acetic acid;
2-(4-((2 ', 6 '-dimethyl-4 '-(3-(methylsulfonyl) propyl group)-[1,1 '-xenyl]-3-) methoxyl group) 2-anisole oxygen) acetic acid;
2-(4-((2 ', 6 '-dimethyl-4 '-(3-(methylsulfonyl) propyl group)-[1,1 '-xenyl]-3-) methoxyl group) 2-ethylbenzene oxygen) acetic acid;
2-(4-((2 ', 6 '-dimethyl-4 '-(3-(methylsulfonyl) propyl group)-[1,1 '-xenyl]-3-) methoxyl group) phenoxy group)-2 Methylpropionic acid;
2-(4-((2 ', 6 '-dimethyl-4 '-(3-(methylsulfonyl) propyl group)-[1,1 '-xenyl]-3-) methoxyl group)-2-ethyl phenoxy group)-2 Methylpropionic acid;
2-(2-chlorine 4-((2 ', 6 '-dimethyl-4 '-(3-(methylsulfonyl) propyl group)-[1,1 '-xenyl]-3-) methoxyl group) phenoxy group)-2 Methylpropionic acid;
2-(4-((2 ', 6 '-dimethyl-4 '-(3-(methylsulfonyl) propyl group)-[1,1 '-xenyl]-3-) methoxyl group) 2-fluorophenoxy)-2 Methylpropionic acid;
2-(4-((2 ', 6 '-dimethyl-4 '-(3-(methylsulfonyl) propyl group)-[1,1 '-xenyl]-3-) methoxyl group) 2-methoxyphenoxy)-2 Methylpropionic acid;
2-(4-((2 ', 6 '-dimethyl-4 '-(3-(methylsulfonyl) propyl group)-[1,1 '-xenyl]-3-y1) methoxyl group) 2,6-dimethyl phenoxies)-2 Methylpropionic acid;
2-(4-((4 '-oxyethyl group-2 ', 6 '-dimethyl-[1,1 '-xenyl]-3-) methoxyl group)-2 fluorobenzene oxygen) acetic acid;
2-(4-((4 '-(3-methoxy propoxy)-2 ', 6 '-dimethyl-[1,1 '-xenyl]-3-) methoxyl group) 2-fluorobenzene oxygen) acetic acid;
2-(4-((4 '-(2-(dimethylamino)-2-oxoethoxy)-2 ', 6 '-dimethyl-[1,1 '-xenyl]-3-) methoxyl group)-2-fluorobenzene oxygen) acetic acid.
5. a pharmaceutical composition, described pharmaceutical composition contains the treatment compound according to general formula described in any one (I) in claim 1-4 of effective dose, its pharmaceutically useful salt and pharmaceutically useful carrier, thinner or vehicle.
6. general formula (I) compound, its pharmacologically acceptable salt or pharmaceutical composition according to claim 5 described in claim 1-4 treat the purposes in the medicine of the disease of diabetes and metabolic syndrome in preparation.
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| US20210122704A1 (en) * | 2017-05-27 | 2021-04-29 | China Pharmaceutical University | Novel phenoxuacetic acid derivative, preparation method therefor and uses of derivative as drug |
| US11905230B2 (en) * | 2017-05-27 | 2024-02-20 | China Pharmaceutical University | Phenoxyacetic acid derivatives, preparation method thereof and use thereof as medicament |
| CN112759515A (en) * | 2020-12-28 | 2021-05-07 | 广东药科大学 | Novel FFA1 and PPAR alpha/gamma/delta quadruple agonist, preparation method thereof and application thereof as medicament |
| CN112759515B (en) * | 2020-12-28 | 2023-06-13 | 广东药科大学 | Novel FFA1 and PPAR alpha/gamma/delta quadruple agonist, preparation method thereof and application thereof as medicine |
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