CN1805943A - Alpha substituted carboxylic acid as PPAR modulators - Google Patents

Alpha substituted carboxylic acid as PPAR modulators Download PDF

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CN1805943A
CN1805943A CNA2004800167362A CN200480016736A CN1805943A CN 1805943 A CN1805943 A CN 1805943A CN A2004800167362 A CNA2004800167362 A CN A2004800167362A CN 200480016736 A CN200480016736 A CN 200480016736A CN 1805943 A CN1805943 A CN 1805943A
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methyl
group
phenyl
oxazole
compound
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西蒙·贝利
保罗·S·汉弗莱斯
唐纳德·J·斯卡利茨基
苏慰国
卢克·R·曾德
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Pfizer Inc
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Abstract

Alpha substituted carboxylic acids of formula (I): wherein R' and R2 are as defined in the specification and R3 is A) formula (II); B) formula (III); C) formula (IV); and D) formula (V); wherein Y, Art, Are, AP, R4, R5, R6, R7, R6, R9, R9a, R10, R'', R12, R17, ring A, and p are as defined in the specification; pharmaceutical compositions containing effective amounts of said compounds or their salts are useful for treating PPAR, specifically PPAR alpha/y related disorders, such as diabetes, dyslipidemia, obesity and inflammatory disorders.

Description

Alpha substituted carboxylic acid as the PPAR conditioning agent
Background of invention
The present invention relates to alpha substituted carboxylic acid, it regulates the activity of peroxisome proliferator-activated property acceptor (PPAR), two or more among preferred PPAR-α, PPAR-δ or the PPAR-γ, thus can be used for regulating Mammals blood sugar and increase insulin sensitivity.The invention still further relates to treatment PPAR relative disease, as diabetes, unusual lipidemia, obesity and inflammation.
Peroxisome proliferation is one group of compound that structure is various, when being applied to rodent, the size and the quantity that cause liver kidney peroxysome significantly increase, simultaneously, and by increasing the ability of expressing the required enzyme raising peroxysome fat metabolism acid of β-Yang Hua circulation.This compounds comprises the special class blood lipid-lowering medicine of shellfish, weedicide and phthalate (or ester) binder (Reddy and Lalwani, Crit.Rev.Toxicol., 12:1-58 (1983)).The propagation of peroxysome also can be caused as high fat diet and cold environment adaptability by diet or physiologic factor.
By these chemical substance activated nuclear hormone receptor superfamily members, probed into the mechanism (Isseman and Green, Nature, 347-645-650 (1990)) that peroxisome proliferation is brought into play multiple effect by research.Prove that subsequently term is that the acceptor of PPAR-α is by various media and long-chain fat acid active, the genetic expression of stimulus coding rat acetyl-CoA oxydase and hydratase-desaturase (enzyme that the peroxysome β-Yang Hua is required) and rabbit cell cytochrome p 450 4A6, the latter is a kind of lipid acid Ω-hydroxylase.
The heterodimer of PPAR-α and retinoid acceptor and term are the dna sequence dna combination of elements of peroxisome proliferator response element (PPRE), activated transcription.Retinoid receptor is activated by 9-cis-retinoic acid (sees Kliewer, etc., Nature, 358:771-774 (1992), Gearing, etc., Proc.Natl.Acad.Sci.USA, 90:1440-1444 (1993), Keller etc., Proc.Natl.Acad.Sci.USA, 90:2160-2164 (1993), Heyman etc., Cell, 68:397-406 (1992) and Levin etc., Nature, 355:359-361 (1992)).Because PPAR-α-RXR mixture can be activated by peroxisome proliferation and/or 9-cis-retinoic acid, can know vitamin A acid by inference and the lipid acid signalling channel converges at the adjusting lipid metabolism.
Since finding PPAR-α, differentiated other isoform of PPAR, as PPAR-δ or PPAR-γ, they are expressed at different positions.Each PPAR acceptor demonstrates different tissue expression patterns, has difference aspect the compound activation of different structure.For example, PPAR-γ expresses in fatty tissue at most, then expresses with lower level in skeletal muscle, heart, liver, intestines, kidney, blood vessel endothelium, smooth muscle cell and scavenger cell.There are two isoforms in PPAR-γ, is respectively γ 1And γ 2Signal conduction, the lipid of PPAR-γ mediation adipocyte store and metabolism of fat.Existing evidence supports that PPAR-γ is topmost, may be the molecular target of unique mediation thiazolidine 2,4 two ketone antidiabetic medicine sensitization Regular Insulin.
In independent treatment or combination therapy, new still is considered as having inconsistent even limited effectiveness with known oral antidiabetic thing.The effectiveness of oral administration diabetes is limited, and partly cause may be glycemic control difference or limited, or unacceptable side-effects causes very poor patient's compliance.These side effects comprise oedema, weight increase or even severe complications more.For example, in taking the patient of sulfonylurea, some observe hypoglycemia.N1,N1-Dimethylbiguanide, a kind of biguanides of replacement can cause diarrhoea and gastrointestinal upset.At last, oedema, weight increase and the hepatotoxicity that occurs sometimes are relevant with some thiazolidine 2,4 diketone antidiabetic medicines of use.Usually use above-mentioned two or more medication combined treatments, but only cause the improvement of glycemic control usually.
Therefore, be necessary to find the antidiabetic medicine that can activate PPAR-α and PPAR-γ simultaneously, this will cause finding effectively to reduce the medicine of glucose and triglyceride level, and these medicines have very big potentiality at treatment diabetes B and metabolism syndrome (being impaired glucose tolerance, insulin resistant, hypertriglyceridemia and/or obesity).
Summary of the invention
The invention provides the compound or pharmaceutically acceptable salt thereof or the solvate of novel formula (I),
Wherein:
Ring Q is (C 6-C 10) aryl or (4-10)-element heterocycle base;
R 1Be H, halogen, (C 1-C 8) alkyl, (C 1-C 8) alkoxyl group, CN, CF 3,-O-CF 3,-O-SO 2-(C 1-C 8) alkyl ,-O-SO 2-(CR 11R 12) t(C 6-C 10) aryl ,-(CR 11R 12) t(C 3-C 10) cycloalkyl-(CR 11R 12) t,-(CR 11R 12) t(C 3-C 10) cycloalkyl-(CR 11R 12) t-O-,-(CR 11R 12) t(C 6-C 10) aryl-(CR 11R 12) t,-(CR 11R 12) t(C 6-C 10) aryl-(CR 11R 12) t-O-,-(CR 11R 12) t-(4-10)-element heterocycle base-(CR 11R 12) t, or-(CR 11R 12) t-(4-10)-element heterocycle base-(CR 11R 12) t-O-; R wherein 1Ring carbon atom optional by 1～3 R 13Group replaces; R 1Theheterocyclic nitrogen atom optional by 1～3 (C 1-C 8) the alkyl replacement;
R 2Be H, (C 1-C 8) alkyl ,-(CR 11R 12) t-(C 3-C 10) cycloalkyl ,-(CR 11R 12) t-(C 6-C 10) aryl or-(CR 11R 12) t(4-10)-the element heterocycle base; R wherein 2Carbon atom optional by 1～3 R 13Group replaces; And R 2Theheterocyclic nitrogen atom optional by 1～3 (C 1-C 8) the alkyl replacement;
R 3Be selected from:
Figure A20048001673600132
Figure A20048001673600133
Y is-(C=O)-or-SO 2-;
Y " is NR 10Or-O-;
P is 0,1 or 2;
Each q, r and t are 0,1,2,3,4 or 5 independently;
Each n is 0,1,2,3 or 4 independently;
Each k is 1,2 or 3 independently;
Each m and s are 0,1,2 or 3 independently;
Each j is 0,1 or 2;
Each R 4For-(CR 11R 12) n-,-(CR 11R 12) n-S-(CR 11R 12) n-,-(CR 11R 12) n-NR 10-,-(CR 11R 12) n-NR 10-(CR 11R 12) n-O-,-(CR 11R 12) n-O-(CR 11R 12) k-NR 10-,-(CR 11R 12) n-O-(CR 11R 12) n-,-(CR 11R 12) n-O-(CR 11R 12) k-O-(CR 11R 12) n-,-(CR 11R 12) n-CR 11=CR 12-(CR 11R 12) n-or-CH=CH-(CR 11R 12)-O-(CH 2) n-;
Each R 5For key or-(CR 11R 12) m-Z-(CR 11R 12) sWherein Z is-CR 11R 12-,-O-,-NR 10a-or-S (O) j-;
Each R 6For-(C=O)-OH ,-(C=O)-OM +,-(C=O)-(C 1-C 8) alkyl ,-(C=O)-O-(C 1-C 8) alkyl ,-(C=O)-NR 10R 11,-(C=O)-NR 10-SO 2-R 11,-SO 2-NH-R 10,-NH-SO 2-R 10,-(C=O)-NH-C ≡ N, or R 6Have the following formula structure:
Figure A20048001673600141
Or
Figure A20048001673600142
M +Be alkali metal cation or alkaline earth metal cation;
Each R 7And R 8Be H, (C independently 1-C 8) alkyl, (C 1-C 8) alkoxyl group ,-(CR 11R 12) t(C 3-C 10) cycloalkyl ,-(CR 11R 12) t(C 6-C 10) aryl ,-(CR 11R 12) t(C 6-C 10) aryl-O-,-(CR 11R 12) t(4-10)-the element heterocycle base or-(CR 11R 12) t(4-10)-element heterocycle base-O-;
Or R 7And R 8Optional connected carbon atom forms (C together 3-C 10) cycloalkyl or (3-10)-element heterocycle base;
Each Ar 1, Ar 2, Ar 3And Ar 4Representative (C 6-C 10) aryl or (5-10)-element heterocycle base; Each Ar wherein 1, Ar 2, Ar 3And Ar 4Ring carbon atom optional by 1～3 R 13Group replaces;
Ring A represent 3,4,5,6 or 7-person ring, chooses wantonly to comprise 1～4 and can identical or differently be selected from-N (R 10a)-, O and S (O) jHeteroatoms, wherein j is 0,1 or 2, condition is that this ring does not contain two adjacent O or S (O) jAtom; The carbon atom that wherein encircles the A part is optional by 1～3 R 13Group replaces;
R 9Be (C 1-C 8) alkyl ,-(CR 11R 12) t(C 6-C 10) aryl or-(CR 11R 12) t(4-10)-and the element heterocycle base, wherein t is 0,1,2,3,4 or 5 independently, wherein this R 9Group is replaced by 1～3 group, and these groups are independently selected from-(CR 11R 12) qNR 10R 11,-(CR 11R 12) qNR 10(C 1-C 6) alkyloyl ,-(CR 11R 12) qO (CR 11R 12) rR 10And-(CR 11R 12) qR 10Wherein the heterocyclic radical of aforementioned group, aryl and moieties are optional by 1～3 R 13Group replaces;
R 9aAnd R 10Be H or (C independently 1-C 8) alkyl;
R 11And R 12Be H, (C independently 1-C 8) alkyl, hydroxyl or (C 1-C 6) alkoxyl group;
R 10aBe selected from H, (C 1-C 8) alkyl ,-(C=O)-R 14,-SO 2NR 15R 16Or-S (O) j(C 1-C 6) alkyl;
Each R 13And R 13aBe independently selected from halogen, cyano group, nitro, trifluoromethoxy, trifluoromethyl, azido-, hydroxyl, (C 1-C 6) alkoxyl group, (C 1-C 10) alkyl, (C 2-C 6) alkenyl, (C 2-C 6) alkynyl ,-O-(CR 11R 12) k-O-(CR 11R 12) n-,-(C=O)-R 14,-(C=O)-O-R 15,-O-(C=O)-R 15,-NR 15(C=O)-R 16,-NR 15(C=O)-O-R 16,-(C=O)-NR 15R 16,-NR 15R 16,-NR 15OR 16,-SO 2NR 15R 16,-S (O) j(C 1-C 6) alkyl ,-O-SO 2-R 14,-NR 15-SO 2-R 16, R 15-(CR 11R 12) t(C 6-C 10Aryl) ,-(CR 11R 12) t(4-10)-the element heterocycle base ,-(CR 11R 12) q(C=O) (CR 11R 12) t(C 6-C 10) aryl ,-(CR 11R 12) q(C=O) (CR 11R 12) t(4-10)-the element heterocycle base ,-(CR 11R 12) tO (CR 11R 12) q(C 6-C 10) aryl ,-(CR 11R 12) tO (CR 11R 12) q(4-10)-the element heterocycle base ,-(CR 11R 12) qSO 2(CR 11R 12) t(C 6-C 10) aryl and-(CR 11R 12) qSO 2(CR 11R 12) t(4-10)-element heterocycle; Aforementioned R 13And R 13a1 or 2 ring carbon atom of the heterocyclic moiety of group is optional by oxo (=O) group replacement, and aforementioned R 13And R 13aThe alkyl of group, alkenyl, alkynyl, aryl and heterocyclic moiety are optional to be replaced by 1～3 substituting group, these substituting groups be independently selected from halogen, cyano group, nitro, trifluoromethyl, trifluoromethoxy, azido-,-OR 15,-(C=O)-R 15,-(C=O)-O-R 15,-O-(C=O)-R 15,-NR 15(C=O)-R 16,-(C=O)-NR 15R 16,-NR 15R 16,-NR 15OR 16, (C 1-C 6) alkyl, (C 2-C 6) alkenyl, (C 2-C 6) alkynyl ,-(CR 11R 12) t(C 6-C 10) aryl and-(CR 11R 2) t(4-10)-the element heterocycle base;
Each R 14, R 15And R 16Be independently selected from H, (C 1-C 6) alkyl ,-(CR 11R 12) t(C 6-C 10) aryl and-(CR 11R 12) t(4-10)-the element heterocycle base; 1 or 2 ring carbon atom of this heterocyclic group is optional by oxo (=O) group replacement, aforementioned R 14, R 15And R 16The alkyl of group, aryl and heterocyclic moiety are optional to be replaced by 1～3 substituting group, these substituting groups be independently selected from halogen, cyano group, nitro ,-NR 11R 12, trifluoromethyl, trifluoromethoxy, (C 1-C 6) alkyl, (C 2-C 6) alkenyl, (C 2-C 6) alkynyl, hydroxyl and (C 1-C 6) alkoxyl group;
R 17Be H, (C 1-C 8) alkyl ,-O-(C 1-C 8) alkyl, halogen, CN, OH, CF 3Or-O-CF 3
Wherein, above mentioned comprising not and halogen, SO or SO 2Group or the CH that is not connected with N, O or S atom 3(methyl), CH 2Any substituting group of (methylene radical) or CH (methyne) is chosen wantonly on described group to connect and is selected from hydroxyl, halogen, (C 1-C 4) alkyl, (C 1-C 4) alkoxyl group ,-NH 2,-NH (C 1-C 8) alkyl and-N ((C 1-C 8) alkyl) 2Substituting group.
In one embodiment, the present invention relates to compound of Formula I, wherein R 3For
In another embodiment, the present invention relates to compound of Formula I, wherein R 3For
In this embodiment, preferred-R 4-Y-Y " is-(CR 11R 12) n-O-(CR 11R 12) n-(C=O)-NR 10-or-(CR 11R 12) n-NR 10-(C=O)-O-.
In another embodiment, the present invention relates to compound of Formula I, wherein R 3For
Figure A20048001673600162
In another embodiment, the present invention relates to compound of Formula I, wherein R 3For
Figure A20048001673600163
In another embodiment, the present invention relates to compound of Formula I, wherein encircle Q and be selected from
Figure A20048001673600164
Figure A20048001673600165
With
Figure A20048001673600166
In another embodiment, the present invention relates to the compound of general formula I, wherein R 1Be H, halogen, (C 1-C 8) alkyl, (C 1-C 8) alkoxyl group, CF 3,-O-CF 3,-O-SO 2-(C 1-C 8) alkyl ,-O-SO 2-(CR 11R 12) t(C 6-C 10) aryl or-(CR 11R 12) t(C 6-C 10) aryl-O-, wherein R 1Ring carbon atom optional by 1～3 R 13Group replaces.
In another embodiment, the present invention relates to compound of Formula I, wherein R 2Be H, phenyl
Figure A20048001673600171
Figure A20048001673600172
With
Figure A20048001673600173
In another embodiment, the present invention relates to compound of Formula I, wherein should
Be selected from
Figure A20048001673600181
With
In another embodiment, the present invention relates to compound of Formula I, wherein R 4For-CH 2-O-,-CH 2-O-CH 2-,-CH 2-CH 2-O-,-CH=CH-CH 2-O-or-CH 2-CH 2-CH 2-O-.
In another embodiment, the present invention relates to compound of Formula I, wherein R 4For-(CH 2) n-; Wherein n is 0,1,2 or 3 independently.
In another embodiment, the present invention relates to compound of Formula I, wherein R 5For key or-(CR 11R 12) m-Z-(CR 11R 12) sWherein Z be-O-,-NR 10a-or-S (O) j-; Wherein each m and s are 0,1,2 or 3 independently; Wherein j is 0,1 or 2.
In another embodiment, the present invention relates to compound of Formula I, wherein R 5For key ,-O-,-CH 2-,-C (CH 3) H-,-C (OH) H-or-C (O-(C 1-C 8) alkyl) H-.
In another embodiment, the present invention relates to compound of Formula I, wherein R 6For-(C=O)-OH.
In another embodiment, the present invention relates to compound of Formula I, wherein R 6For-(C=O)-OM +, M wherein +Be selected from Ca ++, Li +, Na +And K +
In another embodiment, the present invention relates to compound of Formula I, wherein each R 7And R 8Be H, (C independently 1-C 8) alkyl or (C 1-C 8) alkoxyl group.
In another embodiment, the present invention relates to compound of Formula I, wherein each R 7And R 8Connected carbon atom forms (3-7)-element heterocycle base together.
In another embodiment, the present invention relates to have the compound of following general formula:
In this embodiment, the present invention relates to these compounds, wherein said-Ar 1-Ar 2-be selected from:
Figure A20048001673600193
With
Each Ar wherein 1And Ar 2Ring carbon atom optional by 1～3 R 13Group replaces, and these groups are selected from halogen, (C 1-C 8) alkyl and (C 1-C 8) alkoxyl group.
Preferably, described-Ar 1-Ar 2-be selected from:
With
In this embodiment, particular compound of the present invention is selected from
2-methyl-2-(3 '-[2-(5-methyl-2-phenyl-1,3-oxazole-4-yl) oxyethyl group]-1,1 '-biphenyl-3-yl } the oxygen base) propionic acid;
2-methyl-2-[(3 '-{ [4-(trifluoromethyl) benzyl] oxygen base }-1,1 '-biphenyl-3-yl) oxygen base] propionic acid;
2-methyl-2-[(3 '-and 2-[1-(6-methyl pyridazine-3-yl) piperidin-4-yl] oxyethyl group }-1,1 '-biphenyl-3-yl) the oxygen base] propionic acid;
1-(3 '-[2-(5-methyl-2-phenyl-1,3-oxazole-4-yl) oxyethyl group]-1,1 '-biphenyl-3-yl } the oxygen base) cyclobutane-carboxylic acid;
2-(3 '-[2-(5-methyl-2-phenyl-1,3-oxazole-4-yl) oxyethyl group]-1,1 '-biphenyl-3-yl) the oxygen base) butyric acid;
2-(3-{6[2-(5-methyl-2-phenyl-1,3-oxazole-4-yl) oxyethyl group] pyridine-2-yl } phenoxy group) butyric acid;
1-(3-{6-[2-(5-methyl-2-phenyl-1,3-oxazole-4-yl) oxyethyl group] pyridine-2-yl } phenoxy group) cyclobutane-carboxylic acid;
2-methyl-2-(3-{6-[2-(5-methyl-2-phenyl-1,3-oxazole-4-yl) oxyethyl group] pyridine-2-yl } phenoxy group) propionic acid;
2-methyl-2-(3-{6-[2-(5-methyl-2-phenyl-1,3-oxazole-4-yl) oxyethyl group] pyrazine-2-yl } phenoxy group) propionic acid;
And pharmacologically acceptable salt.
In this embodiment, particular compound of the present invention be 1-(3 '-[2-(5-methyl-2-phenyl-1,3-oxazole-4-yl) oxyethyl group]-1,1 '-biphenyl-3-yl the oxygen base) cyclobutane-carboxylic acid or its pharmacologically acceptable salt.
In this embodiment, particular compound of the present invention be 2-(3 '-[2-(5-methyl-2-phenyl-1,3-oxazole-4-yl) oxyethyl group]-1,1 '-biphenyl-3-yl the oxygen base) butyric acid or its pharmacologically acceptable salt.
In this embodiment, particular compound of the present invention is 2-(3-{6-[2-(5-methyl-2-phenyl-1,3-oxazole-4-yl) oxyethyl group] pyridine-2-yl } phenoxy group) butyric acid or its pharmacologically acceptable salt.
In this embodiment, particular compound of the present invention is 1-(3-{6-[2-(5-methyl-2-phenyl-1,3-oxazole-4-yl) oxyethyl group] pyridine-2-yl } phenoxy group) cyclobutane-carboxylic acid or its pharmacologically acceptable salt.
In this embodiment, particular compound of the present invention is 1-[(3 '-{ [2-(3-fluorophenyl)-5-methyl isophthalic acid, 3-oxazole-4-yl] methoxyl group } biphenyl-3-yl) the oxygen base] cyclobutane-carboxylic acid or its pharmacologically acceptable salt.
In this embodiment, particular compound of the present invention is 1-({ 3 '-[3-(5-methyl-2-phenyl-1,3-oxazole-4-yl) propoxy-] biphenyl-3-yl } oxygen base) cyclobutane-carboxylic acid or its pharmacologically acceptable salt.
In this embodiment, particular compound of the present invention is 1-[(3 '-{ [5-(4-p-methoxy-phenyl)-1,2,4-oxadiazole-3-yl] methoxyl group } biphenyl-3-yl) the oxygen base] cyclobutane-carboxylic acid or its pharmacologically acceptable salt.
In this embodiment, particular compound of the present invention is 2-[(3 '-{ 2-[2-(3-fluorophenyl)-5-methyl isophthalic acid, 3-oxazole-4-yl] oxyethyl group } biphenyl-3-yl) oxygen base-2 Methylpropionic acid or its pharmacologically acceptable salt.
In this embodiment, particular compound of the present invention is 2-methyl-2-({ 3 '-[(5-methyl-2-phenyl-1,3-oxazole-4-yl) methoxyl group] biphenyl-3-yl } oxygen base) propionic acid or its pharmacologically acceptable salt.
In this embodiment, particular compound of the present invention is 2-oxyethyl group-3-{3 '-[2-(5-methyl-2-phenyl-1,3-oxazole-4-yl) oxyethyl group] biphenyl-3-yl } propionic acid or its pharmacologically acceptable salt.
In another embodiment, the present invention relates to have the compound of following general formula:
Figure A20048001673600211
Wherein Y be-(C=O)-or-SO 2-, Y " is NR 10, p is 1.
Preferably, each R 11And R 12Be H independently.
Preferably, Ar 3Be phenyl.
In this embodiment, particular compound of the present invention is selected from
1-(3-{[({2-[3-(trifluoromethyl) phenyl] oxyethyl group } carbonyl) amino] methyl } phenoxy group) cyclobutane-carboxylic acid;
2-(3-{[({2-[3-(trifluoromethyl) phenyl] oxyethyl group } carbonyl) amino] methyl } phenoxy group) butyric acid;
2-methyl-2-(3-{[({2-[3-(trifluoromethyl) phenyl] oxyethyl group } carbonyl) amino] methyl } phenoxy group) propionic acid;
2-methyl-2-{3-[({[2-(5-methyl-2-phenyl-1,3-oxazole-4-yl) oxyethyl group] carbonyl } amino) methyl] phenoxy group } propionic acid;
2-methyl-2-(3-{[({[4-(5-methyl isophthalic acid, 2,4-oxadiazole-3-yl) benzyl] the oxygen base } carbonyl) amino] methyl } phenoxy group) propionic acid;
2-{3-[({[2-(5-methyl-2-phenyl-1,3-oxazole-4-yl) oxyethyl group] carbonyl } amino) methyl] phenoxy group } butyric acid;
1-{3-[({[2-(5-methyl-2-phenyl-1,3-oxazole-4-yl) oxyethyl group] carbonyl } amino) methyl] phenoxy group } cyclobutane-carboxylic acid;
1-{3-[({[3-(5-methyl-2-phenyl-1,3-oxazole-4-yl) propoxy-] carbonyl } amino) methyl] phenoxy group } cyclobutane-carboxylic acid;
2-{3-[({[3-(5-methyl-2-phenyl-1,3-oxazole-4-yl) propoxy-] carbonyl } amino) methyl] phenoxy group } butyric acid;
2-methyl-2-{3-[({[3-(5-methyl-2-phenyl-1,3-oxazole-4-yl) propoxy-] carbonyl } amino) methyl] phenoxy group } propionic acid; And pharmacologically acceptable salt.
In this embodiment, particular compound of the present invention is 2-methyl-2-{3-[({[2-(5-methyl-2-phenyl-1,3-oxazole-4-yl) oxyethyl group] carbonyl } amino) methyl] phenoxy group } propionic acid or its pharmacologically acceptable salt.
In this embodiment, particular compound of the present invention is 2-methyl-2-{3-[({[(5-methyl-2-phenyl-1,3-oxazole-4-yl) methoxyl group] carbonyl } amino) methyl] phenoxy group } propionic acid or its pharmacologically acceptable salt.
In this embodiment, particular compound of the present invention is 2-methyl-2-{4-[({[3-(5-methyl-2-phenyl-1,3-oxazole-4-yl) propoxy-] carbonyl } amino) methyl] phenoxy group } propionic acid or its pharmacologically acceptable salt.
In this embodiment, particular compound of the present invention is 2-{3-fluoro-4-[({[2-(5-methyl-2-phenyl-1, a 3-oxazole-4-yl) oxyethyl group] carbonyl } amino) methyl] phenoxy group }-2 Methylpropionic acid or its pharmacologically acceptable salt.
In this embodiment, particular compound of the present invention is 2-{3-[({[2-(5-methyl-2-phenyl-1, a 3-oxazole-4-yl) oxyethyl group] carbonyl } amino) methyl] phenoxy group } butyric acid or its pharmacologically acceptable salt.
In this embodiment, particular compound of the present invention is 2-{3-[({[(5-methyl-2-phenyl-1,3-oxazole-4-yl) methoxyl group] carbonyl } amino) methyl] phenoxy group } butyric acid or its pharmacologically acceptable salt.
In this embodiment, particular compound of the present invention is 1-{3-[({[2-(5-methyl-2-phenyl-1, a 3-oxazole-4-yl) oxyethyl group] carbonyl } amino) methyl] phenoxy group } cyclobutane-carboxylic acid or its pharmacologically acceptable salt.
In this embodiment, particular compound of the present invention is 2-methyl-2-(3-{[({[2-(5-methyl-2-phenyl-1,3-oxazole-4-yl) ethyl] amino } carbonyl) oxygen base] methyl } phenoxy group) propionic acid or its pharmacologically acceptable salt.
In this embodiment, particular compound of the present invention is 2-oxyethyl group-3-{3-[({[3-(5-methyl-2-phenyl-1,3-oxazole-4-yl) propoxy-] carbonyl } amino) methyl] phenyl } propionic acid or its pharmacologically acceptable salt.
In this embodiment, particular compound of the present invention is 2-oxyethyl group-3-{3-[({[2-(5-methyl-2-phenyl-1,3-oxazole-4-yl) oxyethyl group] carbonyl } amino) methyl] phenyl } propionic acid or its pharmacologically acceptable salt.
In another embodiment, the present invention relates to have the compound of following general formula:
Figure A20048001673600221
In another embodiment, ring A is selected from cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
In another embodiment, ring A is selected from
Wherein---be optional two keys.
In another embodiment, ring A is selected from
Figure A20048001673600232
Wherein---be optional two keys.
In another embodiment, ring A is selected from
With
Figure A20048001673600234
Wherein---be optional two keys.
In this embodiment, Ar 4Be phenyl, naphthyl, pyridyl, pyrimidyl or pyrazinyl.
In this embodiment, particular compound of the present invention is selected from
1-{4-[2-(5-methyl-2-phenyl-1,3-oxazole-4-yl) oxyethyl group] benzyl } hexahydrobenzoic acid;
1-(4-[2-(5-methyl-2-phenyl-1,3-oxazole 4-yl) oxyethyl group] benzyl } Cyclopentane carboxylic acid;
1-{4-[3-(5-methyl-2-phenyl-1,3-oxazole-4-yl) propoxy-] benzyl } Cyclopentane carboxylic acid;
4-{4-[(5-methyl-2-phenyl-1,3-oxazole-4-yl) methoxyl group] benzyl } tetrahydrochysene-2H-pyrans-4-carboxylic acid;
4-{4-[2-(5-methyl-2-phenyl-1,3-oxazole-4-yl) oxyethyl group] benzyl } tetrahydrochysene-2H-pyrans-4-carboxylic acid;
1-{4-[2-(4 '-methoxyl group-1,1 '-biphenyl-4-yl) oxyethyl group] benzyl } cyclobutane-carboxylic acid;
1-{4-[2-(4 '-fluoro-1,1 '-biphenyl-4-yl) oxyethyl group] benzyl } cyclobutane-carboxylic acid;
1-{4-[2-(2 '-methoxyl group-1,1 '-biphenyl-4-yl) oxyethyl group] benzyl } cyclobutane-carboxylic acid;
1-(4-{2-[3 '-(trifluoromethoxy)-1,1 '-biphenyl-4-yl] oxyethyl group } benzyl) cyclobutane-carboxylic acid;
1-(4-{2-[4-(6-methoxypyridine-3-yl) phenyl] oxyethyl group } benzyl) cyclobutane-carboxylic acid;
1-(4-{2-[4 '-(methyl sulphonyl)-1,1 '-biphenyl-4-yl] oxyethyl group } benzyl) cyclobutane-carboxylic acid;
1-(4-{2-[4-(2,3-dihydro-1-cumarone-6-yl) phenyl] oxyethyl group } benzyl) cyclobutane-carboxylic acid;
1-[4-(2-{4 '-[(methyl sulphonyl) amino]-1,1 '-biphenyl-4-yl } oxyethyl group) benzyl] cyclobutane-carboxylic acid;
1-{4-[3-(5-methyl-2-phenyl-1,3-oxazole-4-yl) propoxy-] benzyl } cyclobutane-carboxylic acid;
1-{4-[(5-methyl-2-phenyl-1,3-oxazole-4-yl) methoxyl group] benzyl } cyclobutane-carboxylic acid;
1-{3-[2-(5-methyl-2-phenyl-1,3-oxazole-4-yl) oxyethyl group] benzyl } cyclobutane-carboxylic acid;
1-{4-[2-(5-methyl-2-phenyl-1,3-oxazole-4-yl) oxyethyl group] benzyl } cyclobutane-carboxylic acid;
1-{4-[(2,5-phenylbenzene-1,3-oxazole-4-yl) methoxyl group] benzyl } cyclobutane-carboxylic acid;
1-{4-[3-(2,5-phenylbenzene-1,3-oxazole-4-yl) propoxy-] benzyl) cyclobutane-carboxylic acid;
1-{4-[(2,5-phenylbenzene-1,3-oxazole-4-yl) methoxyl group] phenoxy group } cyclobutane-carboxylic acid;
1-{4-[3-(2,5-phenylbenzene-1,3-oxazole-4-yl) propoxy-] phenoxy group } cyclobutane-carboxylic acid;
1-(4-(2-[2-(1,1 '-biphenyl-4-yl)-the 5-methyl isophthalic acid, 3-oxazole-4-yl] oxyethyl group } phenoxy group) cyclobutane-carboxylic acid;
1-{4-[2-(5-methyl-2-phenyl-1,3-oxazole-4-yl) oxyethyl group] phenoxy group } cyclobutane-carboxylic acid;
1-{4-[3-(5-methyl-2-phenyl-1,3-oxazole-4-yl) propoxy-] phenoxy group } cyclobutane-carboxylic acid;
1-{4-[(5-methyl-2-phenyl-1,3-oxazole-4-yl) methoxyl group] phenoxy group } cyclobutane-carboxylic acid;
1-(6-[2-(5-methyl-2-phenyl-1,3-oxazole-4-yl) oxyethyl group] and pyridin-3-yl } methyl) cyclobutane-carboxylic acid;
1-(hydroxyl 6-[2-(5-methyl-2-phenyl-1,3-oxazole-4-yl) oxyethyl group] and pyridin-3-yl } methyl) cyclobutane-carboxylic acid;
1-(6-[2-(5-methyl-2-phenyl-1,3-oxazole-4-yl) oxyethyl group] and pyridin-3-yl } methyl) Cyclopentane carboxylic acid;
1-(6-[2-(5-methyl-2-phenyl-1,3-oxazole-4-yl) oxyethyl group] and pyridin-3-yl } methyl) hexahydrobenzoic acid;
2-(6-[2-(5-methyl-2-phenyl-1,3-oxazole-4-yl) oxyethyl group] and pyridin-3-yl } methyl) tetrahydrofuran (THF)-2-carboxylic acid;
2-(5-[2-(5-methyl-2-phenyl-1,3-oxazole-4-yl) oxyethyl group] and pyridine-2-yl } methyl) tetrahydrofuran (THF)-2-carboxylic acid;
And pharmacologically acceptable salt.
In this embodiment, particular compound of the present invention is 1-{4-[3-(5-methyl-2-phenyl-1, a 3-oxazole-4-yl) propoxy-] benzyl } cyclobutane-carboxylic acid or its pharmacologically acceptable salt.
In this embodiment, particular compound of the present invention is 1-{4-[2-(5-methyl-2-phenyl-1, a 3-oxazole-4-yl) oxyethyl group] benzyl } cyclobutane-carboxylic acid or its pharmacologically acceptable salt.
In this embodiment, particular compound of the present invention is 2-({ 6-[2-(5-methyl-2-phenyl-1,3-oxazole-4-yl) oxyethyl group] pyridin-3-yl } methyl) tetrahydrofuran (THF)-2-carboxylic acid or its pharmacologically acceptable salt.
In this embodiment, particular compound of the present invention is 2-({ 5-[2-(5-methyl-2-phenyl-1,3-oxazole-4-yl) oxyethyl group] pyridine-2-yl } methyl) tetrahydrofuran (THF)-2-carboxylic acid or its pharmacologically acceptable salt.
In this embodiment, particular compound of the present invention is 2-({ 6-[2-(5-methyl-2-phenyl-1,3-oxazole-4-yl) oxyethyl group] pyridin-3-yl } methyl) tetrahydrochysene-2H-pyrans-2-carboxylic acid or its pharmacologically acceptable salt.
In this embodiment, particular compound of the present invention is 2-[(6-{2-[2-(3-chloro-phenyl-)-5-methyl isophthalic acid, 3-oxazole-4-yl] oxyethyl group } pyridin-3-yl) methyl] tetrahydrofuran (THF)-2-carboxylic acid or its pharmacologically acceptable salt.
In this embodiment, particular compound of the present invention is 2-[(6-{2-[2-(3-p-methoxy-phenyl)-5-methyl isophthalic acid, 3-oxazole-4-yl] oxyethyl group } pyridin-3-yl) methyl] tetrahydrofuran (THF)-2-carboxylic acid or its pharmacologically acceptable salt.
In this embodiment, particular compound of the present invention is 2-{5-[2-(5-methyl-2-phenyl-oxazoles-4-yl)-oxyethyl group]-pyrazine-2-ylmethyl }-tetrahydrofuran (THF)-2-carboxylic acid or its pharmacologically acceptable salt.
In this embodiment, particular compound of the present invention is-{ 4-[2-(5-methyl-2-phenyl-1,3-oxazole-4-yl) oxyethyl group] benzyl } tetrahydrofuran (THF)-2-carboxylic acid or its pharmacologically acceptable salt.
In this embodiment, particular compound of the present invention is 2-{6-[2-(5-methyl-2-phenyl-oxazoles-4-yl)-oxyethyl group]-naphthalene-2-ylmethyl }-tetrahydrofuran (THF)-2-carboxylic acid or its pharmacologically acceptable salt.
In another embodiment, the present invention relates to have the compound of following general formula:
Figure A20048001673600261
In this embodiment, preferably, the present invention relates to have the compound of following general formula:
Figure A20048001673600262
In this embodiment, preferably, the present invention relates to have the compound of following general formula:
Figure A20048001673600263
In this embodiment, preferred R 9Be methyl, ethyl or benzyl.Preferred R 17Be H.
In this embodiment, particular compound of the present invention is 2-oxyethyl group-3{6-[2-(5-methyl-2-phenyl-1,3-oxazole-4-yl) oxyethyl group] pyridin-3-yl } propionic acid or its pharmacologically acceptable salt.
In this embodiment, particular compound of the present invention is 2-methoxyl group-3-(6-{2-[5-methyl-2-(3-aminomethyl phenyl)-1,3-oxazole-4-yl] oxyethyl group } pyridin-3-yl) propionic acid or its pharmacologically acceptable salt.
In this embodiment, particular compound of the present invention is 2-methoxyl group-3-{6-[2-(4-Phenoxyphenyl) oxyethyl group] pyridin-3-yl } propionic acid or its pharmacologically acceptable salt.
In this embodiment, particular compound of the present invention is 2-oxyethyl group-3-[6-(2-(4-[(benzenesulfonyl) oxygen base] phenyl) oxyethyl group) pyridin-3-yl] propionic acid or its pharmacologically acceptable salt.
In this embodiment, particular compound of the present invention is 2-oxyethyl group-3-{5-[2-(5-methyl-2-phenyl-oxazoles-4-yl)-oxyethyl group]-pyridine-2-yl }-propionic acid or its pharmacologically acceptable salt.
In this embodiment, particular compound of the present invention is 2-methoxyl group-2-methyl-3-{6-[3-(5-methyl-2-phenyl-oxazoles-4-yl)-propoxy-]-pyridin-3-yl }-propionic acid or its pharmacologically acceptable salt.
In this embodiment, particular compound of the present invention is 2-methoxyl group-2-methyl-3-{5-[2-(5-methyl-2-phenyl-oxazoles-4-yl)-oxyethyl group]-pyridine-2-yl }-propionic acid or its pharmacologically acceptable salt.
In this embodiment, particular compound of the present invention be 3-(6-{2-[2-(4-chloro-phenyl)-5-methyl-oxazoles-4-yl]-oxyethyl group pyridin-3-yl)-2-methoxyl group-2-methyl-propionic acid or its pharmacologically acceptable salt.
In this embodiment, particular compound of the present invention is 2-methoxyl group-2-methyl-3-{6-[2-(5-methyl-2-Ben Ji oxazole-4-yl)-oxyethyl group]-pyridin-3-yl }-propionic acid or its pharmacologically acceptable salt.
In this embodiment, particular compound of the present invention be 2-methoxyl group-3-(6-{2-[2-(3-methoxyl group-phenyl)-5-methyl-oxazoles-4-yl]-oxyethyl group-pyridin-3-yl)-2-methyl-propionic acid or its pharmacologically acceptable salt.
The present invention also provides a kind of method for the treatment of the Mammals non insulin dependent diabetes, comprises general formula (I) compound to the Mammals drug treatment significant quantity of needs.In one embodiment, described Mammals has impaired glucose tolerance.
The present invention also provides a kind of method for the treatment of the Mammals polycystic ovary syndrome, comprises general formula (I) compound to the Mammals drug treatment significant quantity of needs.
The present invention also provides a kind of method for the treatment of the Mammals obesity, comprises general formula (I) compound to the Mammals drug treatment significant quantity of needs.
The present invention also provides a kind of method that alleviates fat weight of mammal, comprises general formula (I) compound to the Mammals drug treatment significant quantity of needs.
The present invention also provides a kind of method for the treatment of the Mammals hyperglycemia, comprises general formula (I) compound to the Mammals drug treatment significant quantity of needs.
The present invention also provides a kind of method for the treatment of mammal hyperlipemia, comprises general formula (I) compound to the Mammals drug treatment significant quantity of needs.
The present invention also provides a kind of method for the treatment of the Mammals hypercholesterolemia, comprises general formula (I) compound to the Mammals drug treatment significant quantity of needs.
The present invention also provides a kind of treatment Mammals atherosclerotic method, comprises general formula (I) compound to the Mammals drug treatment significant quantity of needs.
The present invention also provides a kind of method for the treatment of the Mammals hypertriglyceridemia, comprises general formula (I) compound to the Mammals drug treatment significant quantity of needs.
The present invention also provides a kind of method for the treatment of the Mammals hyperinsulinemia, comprises general formula (I) compound to the Mammals drug treatment significant quantity of needs.
The present invention also provides a kind of method for the treatment of the patient who suffers from unusual and/or relevant with round-robin glucocorticosteroid, tethelin, catecholamine, hyperglycemic-glycogenolytic factor or the Rat parathyroid hormone 1-34 glucose disease indication of Regular Insulin, and described method comprises general formula (I) compound to described patient's drug treatment significant quantity.
The present invention also provides a kind of treatment insulin human to tolerate syndromic method, comprises according to general formula (I) compound of treatment needs to patient's drug treatment significant quantity.
The present invention also provides a kind of method of the people of treatment PPAR relative disease, comprises according to general formula (I) compound of treatment needs to patient's drug treatment significant quantity.
The present invention also provides a kind of adjusting Mammals PPAR active method, comprises general formula (I) compound to Mammals drug treatment significant quantity.
The present invention also provides a kind of method that reduces Mammals blood sugar, comprises general formula (I) compound to administration significant quantity lowering blood glucose level.
The present invention also provides a kind of method of regulating the differentiation of Mammals adipocyte, comprises general formula (I) compound to Mammals drug treatment significant quantity.
The present invention also provides a kind of method of regulating Mammals PPAR mediated process, comprises general formula (I) compound to Mammals drug treatment significant quantity.
The present invention also provides a kind of method that improves Mammals to insulin sensitivity, comprises general formula (I) compound to Mammals drug treatment significant quantity.
The present invention also provides a kind of method for the treatment of the Mammals metabolism syndrome, and these metabolism syndromes are selected from galactosemia, maple syrup uremia, pku, hypersarcosinemia, thymus pyrimidine urine disease, sulfinuria, isovaleric acidemia, Saccharopinuria, 4 hydroxybutyric acid urine, glucose 6 phosphate dehydrogenase deficiency and pyruvic dehydrogenase deficiency.
The present invention also provides a kind of composition, comprises the PPAR conditioning agent and the pharmaceutically useful carrier thereof of at least a general formula (I).Typical pharmaceutically acceptable carrier comprises and is suitable for the carrier that oral, intravenously, subcutaneous, intramuscular, intracutaneous etc. use.Can emulsifiable paste, washing lotion, tablet, dispersible pulvis, granula, syrup, elixir, aseptic aqueous solution or forms such as non-aqueous solution, suspension or emulsion use.
PPAR agonist of the present invention can be united use with other medicines such as alpha-glucosidase inhibitor, aldose reductase inhibitor, biguanides preparation, statin compound (statin base compounds), shark alkene synthetic inhibitor, fibrate (fibrate base compounds), LDL metabolic improver and angiotensin converting enzyme inhibitor.
Above-mentioned alpha-glucosidase inhibitor is a kind of inhibition digestive ferment that has, thereby stops the medicine of the digestion of starch or sucrose as the activity of amylase, maltin, limit dextrinase or sucrase.Voglibose) and miglitol the example of alpha-glucosidase inhibitor comprises acarbose, N-(1,3-dihydroxyl-2-propyl group) variolamine (popular name:.
Thereby above-mentioned aldose reductase inhibitor is a kind of medicine that polyol approach the first step rate-limiting enzyme suppresses diabetic complication that suppresses.Example comprises tolrestatin, epalrestat, 2; 7-two fluoro-spiral shells (9H-fluorenyl fluorenes-9; 4 '-imidazolidine)-2 '; 5 '-diketone (popular name: imirestat), 3-[(4-bromo-2-fluorophenyl) methyl]-7-chloro-3; 4-dihydro-2; zenarestat), 6-fluoro-2 4-dioxy-1 (2H)-quinazoline acetate (popular name:; 3-dihydro-2; 5 ＇-dioxy-spiral shell [4H-1-chromene-4; 4 ＇-imidazolidine]-2-acid amides (SNK-860), zopolrestat, sorbinil and 1-[(3-bromo-2-benzofuryl) alkylsulfonyl]-2,4-imidazole diketone (M-16209).
Above-mentioned biguanides preparation is a kind of gluconeogenesis that promotes anaerobism glycolysis-, enhancing Regular Insulin peripheral action, suppresses glucose absorption in the intestines, inhibition liver, suppresses the medicine of Fatty Acid Oxidation that example comprises phenformin, N1,N1-Dimethylbiguanide and buformin.
Above-mentioned statin compound be a kind of inhibition hydroxymethyl glutaryl CoA (HMG-CoA) thus reductase enzyme reduces the medicine of blood cholesterol levels, example Pravastatin and sodium salt thereof, Simvastatin, lovastatin, atorvastatin and fluvastatin.
Thereby above-mentioned shark alkene synthetic inhibitor is a kind of synthetic medicine that reduces blood cholesterol levels of shark alkene that suppresses, example comprises two (2, the 2-dimethyl-1-oxopropoxy) methoxyl groups of (S)-a-[] phosphinyl (phosphinyl)-3-phenoxy group benzene butyl sulfonic acid list potassium (BMS-188494).
Thereby above-mentioned fibrate is a kind of medicine that liver synthesizes and secrete triglyceride level, activation lipoprotein lipase reduction triglyceride in blood level that suppresses.Example comprises bezafibrate, Sgd-24774, binifibrate, Win-35833, S-8527, clofibrate, clofibric acid, ethofibrate, fenofibrate, gemfibrozil, nicofibrate, pirifibrate, Ronifibrate, simfibrate and etofylline clofibrate.
Above-mentioned LDL metabolic improver be a kind of increase LDL (low-density lipoprotein) thus acceptor reduces the medicine of blood cholesterol levels, example comprises those compound or its salts described in Japanese patent application Kokai Hei 7-316144, more specifically be two (4-fluorophenyl) methyl isophthalic acid-piperazinyls of N-[2-[4-] ethyl]-7,7-phenylbenzene-2,4,6-heptantriene acid amides.
Above-mentioned statin compound, shark alkene synthetic inhibitor, fibrate and LDL metabolic improver can replace by other chemicals that effectively reduces blood cholesterol or triglyceride levels.The example of this type of medicine comprises the nicotinic acid derivates preparation, as nicomol and pentaerythritol tetranicotinate; Antioxidant is as probucol; And the ion exchange resin preparation, as Colestyramine.
Above-mentioned angiotensin converting enzyme inhibitor is a kind of inhibition Zinc metallopeptidase Zace1, thereby brings high blood pressure down, and part reduces the medicine of diabetic subject's glucose level simultaneously.Example comprises captopril, enalapril, alacepril, delapril, Ramipril, lisinopril, imidapril, benazepril, SQ-29852, Yipingshu, enalaprilat, fosinopril, moveltipril, perindopril, quinapril, spirapril, temocapril and Trolapril.
For the mouth cavity liquid preparation, suitable carriers comprises emulsion, solution, suspension, syrup etc., chooses wantonly to comprise additive, as wetting agent, emulsifying agent, suspension agent, sweetener, correctives and spices etc.
For the fluid preparation that parenteral uses, suitable carriers comprises aseptic aqueous solution or non-aqueous solution, suspension or emulsion.The example of non-aqueous solvent or medium is propylene glycol, polyoxyethylene glycol, vegetables oil, as sweet oil, Semen Maydis oil, gelatin, and injectable organic ester, as ethyl oleate.These formulations also can comprise adjuvant, as sanitas, wetting agent, emulsifying agent and dispersion agent.It can be sterilized, for example, with the filter of filtering bacterium filter, with Bactericidal medicine add in the composition, with radiation exposure composition or heating combination.Also can before use it directly be prepared with sterilized water or other aseptic solvent.
Definition
For describe and claimed the present invention herein, following term is defined as follows:
Term used herein " halogen " except as otherwise noted, refers to fluorine, chlorine, bromine or iodine.Preferred halogen is fluorine, chlorine and bromine.
Term used herein " alkyl " except as otherwise noted, comprises the saturated univalence hydrocarbyl with straight or branched part.
Term used herein " alkenyl " except as otherwise noted, comprises the moieties with at least one carbon-to-carbon double bond, and wherein alkyl as above defines, and comprises the E and the Z isomer of this alkenyl part.
Term used herein " alkynyl " except as otherwise noted, comprises the moieties with at least one carbon-to-carbon three key, and wherein alkyl as above defines.
Term used herein " alkoxyl group " except as otherwise noted, comprises the O-alkyl group, and wherein alkyl as above defines.
Term " Me " nail base, " Et " refers to ethyl, " Ac " refers to ethanoyl.
Term used herein " cycloalkyl " except as otherwise noted, refers to the monocycle of non-aromatic, saturated or fractional saturation or condensed, two ring or tricyclic hydrocarbon bases that screw togather or non-condensed, comprises to add up to 3～10 carbon atoms, preferred 5-8 ring carbon atom.Typical cycloalkyl comprises having 3-7, and the monocycle of preferred 3-6 carbon atom is as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl etc.The illustrative example of cycloalkyl is derived from but is not limited to following compounds:
With
Figure A20048001673600313
Term used herein " aryl " except as otherwise noted, comprises the organic group that is derived from the aromatic hydrocarbon of sloughing a hydrogen, as phenyl or naphthyl.
Term used herein " 4-10 element heterocycle ", except as otherwise noted, comprise that containing 1～4 is selected from O, S and heteroatomic fragrance of N or nonaromatic heterocycles group, wherein each heterocyclic group has 4-10 atom in its ring system, and condition is that the ring of this group does not contain two adjacent O or S atom.The nonaromatic heterocycles group comprises the group that 4 atoms are only arranged in the ring system, but must have at least 5 atoms in the aromatic heterocycle group ring system.Heterocyclic group comprises and benzene condensed ring system.4 element heterocycle examples of groups are azelidinyl (derived from azetidine).4 element heterocycle examples of groups are thiazolyl, and 10 element heterocycle examples of groups are quinolyl.The nonaromatic heterocycles examples of groups is a pyrrolidyl, tetrahydrofuran base, the dihydrofuran base, tetrahydro-thienyl, THP trtrahydropyranyl, dihydro pyranyl, tetrahydrochysene sulfo-pyranyl, piperidyl, morpholinyl, thio-morpholinyl thioxane base, piperazinyl, azelidinyl, the oxa-cyclobutyl, the thia cyclobutyl, homopiperidinyl, the oxepane base, the thia suberyl, two oxa- bases, diaza base, thia base, 1,2,3, the 6-tetrahydro pyridyl, the 2-pyrrolinyl, the 3-pyrrolinyl, indolinyl, the 2H-pyranyl, 4H-pyranyl alkyl dioxin, 1, the 3-dioxolanyl, pyrazolinyl, the dithiane base, the dithiolane base, dihydro pyranyl, the dihydro-thiophene base, the dihydrofuran base, pyrazolidyl, imidazolinyl, imidazolidyl, 3-azabicyclo [3.1.0] hexyl, 3-azabicyclo [4.1.0] heptyl, 3H-indyl and quinolizinyl.The example of aromatic heterocycle group is a pyridyl, imidazolyl, pyrimidyl, pyrazolyl, triazolyl, pyrazinyl, tetrazyl, furyl, thienyl isoxazolyl, thiazolyl oxazolyl, isothiazolyl, pyrryl, quinolyl, isoquinolyl, indyl, the benzene imidazolyl, benzofuryl, the cinnolines base, indazolyl, the indolizine base, 2, the 3-phthalazinyl, pyridazinyl, triazinyl, pseudoindoyl, pteridyl, purine radicals oxadiazole base, thiadiazolyl group, the furazan base, benzo furazan base, benzothienyl, benzothiazolyl benzoxazolyl, quinazolyl quinoxalinyl, naphthyridine base and furo pyridyl.Aforementioned group when being derived from above-mentioned group, can be connected in carbon or nitrogen in the time of possible.For example, the group that is derived from the pyrroles can be pyrroles-1-base (linking to each other with N) or pyrroles-3-base (linking to each other with C).In addition, the group that is derived from imidazoles can be imidazoles-1-base (linking to each other with N) or imidazo-3-yl (linking to each other with C).Arbitrary ring carbon, sulphur or the nitrogen-atoms of each ring of 4-10 element heterocycle is optional to be replaced by 1～2 oxo.The example of heterocyclic group is 1,1-dioxo-thio-morpholinyl, and wherein 2 ring carbon atoms are replaced by oxygen.Other illustrative example of 4-10 element heterocycle is derived from but is not limited to following:
Figure A20048001673600321
With
Except as otherwise noted, term " oxo " refers to=O.
Term " the Ar of Shi Yonging herein 1-Ar 2-", except as otherwise noted, comprise and R 4And R 5The order that connects does not have two rings of any restriction.For example, if-Ar 1-Ar 2-be defined as
Figure A20048001673600331
Then-Ar 1-Ar 2-group can be
Figure A20048001673600332
Or
If-Ar 1-Ar 2-be defined as
Figure A20048001673600334
Then-Ar 1-Ar 2-group can be
Or
Figure A20048001673600336
Phrase used herein " pharmacologically acceptable salt " except as otherwise noted, comprises the acidity that can be present in general formula (I) compound or the salt of basic group.Basic cpd in the general formula (I) can form various salt with various mineral acids and organic acid.The acid of pharmaceutically acceptable acid additive salt that can be used for preparing general formula (I) basic cpd is for forming those compounds of the acid additive salt of non-toxicity, promptly comprise pharmaceutically acceptable anion salt, as acetate, benzene sulfonate, benzoate, supercarbonate, hydrosulfate, bitartrate, borate, bromide, Ca-EDTA, camsilate, carbonate, muriate, clavulanic acid, Citrate trianion, dihydrochloride, edetate, edislyate, propionic ester lauryl sulfate (estolate), ethyl sulfonic acid, ethylsuccinate, fumarate, gluceptate, gluconate, glutaminate, the glycolyl arsenate, hexylresorcinate, sea crust salt (hydrabamine), hydrobromate, hydrochloride, iodide, different thiosulphate, lactic acid salt, Lactobionate, dodecanoate, malate, mandelate, mesylate, Methylsulfate, the mucus hydrochlorate, naphthalenesulfonate, nitrate, oleate, oxalate, pamoic acid (grace cloth hydrochlorate), palmitate, pantothenate, phosphoric acid salt/diphosphate, polygalacturonic acid, salicylate, stearate, inferior acetate, succinate, tannate, tartrate, teoclate, tosylate, triethiodode and valerate.
In general formula (I) compound, use term as (CR 11R 12) qOr (CR 11R 12) tThe time, R 11And R 12Can be with changing greater than 1 q or the iteration of t.For example, be 2 o'clock at q or t, term (CR 11R 12) qOr (CR 11R 12) tCan equal-CH 2CH 2-or-CH (CH 3) C (CH 2CH 3) (CH 2CH 2CH 3)-, or be R 11And R 12The similar group of any amount in the range of definition.In addition, above mentioned not with halogen, SO or SO 2Any CH that comprises that group or N, O or S atom connect 3(methyl), CH 2The optional connection of the substituting group of (methylene radical) or CH (methyne) is selected from hydroxyl, C 1-C 4The substituting group of alkoxyl group and amine.
The term of Shi Yonging " treatment " except as otherwise noted, refers to reverse, alleviate, suppress the disease or the state of this term application herein, or the process of one or more symptom wherein, or prevents its generation.The term of Shi Yonging " treatment " except as otherwise noted, refers to be right after the treatment behavior of above-mentioned " treatment " indication herein.
The term of Shi Yonging " adjusting " herein, except as otherwise noted, finger can be regulated steroidal/Tiroidina superfamily member, directly (by as part and receptors bind) or indirectly (as the precursor of part or promote the inductor that part produces from precursor) induce or suppress to be subjected to hormone to express the genetic expression of control.
The term of Shi Yonging " obesity " except as otherwise noted, is often referred to the individuality above the about 20-30% of mean body weight of its age, sex and height correspondence herein.Technically, male sex's " obesity " is defined as weight index greater than 27.8kg/m 2, the women then is defined as weight index greater than 27.3kg/m 2Those skilled in the art are easy to determine that the inventive method is not limited to fall within those individualities of above-mentioned standard.In fact, the inventive method also can be applied to the individuality that exceeds conventional criteria expediently, and for example, those are easy to fat individuality.
The term of Shi Yonging " inflammation " herein, refer to these diseases, as rheumatoid arthritis, ankylosing spondylitis, arthritic psoriasis, psoriasis, chondrocalcinosis, gout, inflammatory bowel, ulcerative colitis, Crohn disease, fibromyalgia and emaciation.
The term of Shi Yonging " treatment significant quantity " herein refers to be applied to tissue, system, animal or human and causes investigator, animal doctor, doctor or the biology of other people expectation or the dosage of medical response.
The term of Shi Yonging " effectively reduces the amount of glucose level in the blood " herein, refers to that compound is enough to provide sufficiently high circulation composition to reach the level of required effect.Usually in about 10nM～2 μ M scopes, preferred concentration range is about 100nM～500nM to this concentration.As previously mentioned, because the activity of the different compounds of above-mentioned general formula (I) definition may be widely different, and may there be very big-difference in the seriousness of individual patients symptom, therefore, should determine the reaction of patient to treatment by the medical practitioner, and correspondingly change dosage.
The phrase of Shi Yonging " insulin resistant " refers to whole health or indivedual tissue herein, as skeletal muscle tissue, cardiac muscular tissue, fatty tissue or hepatic tissue, to the susceptibility reduction of insulin action.Insulin resistant betides many individualities of suffering from or not suffering from diabetes.
The phrase of Shi Yonging " insulin resistant syndrome " refers to many symptoms herein, comprises insulin resistant, hyperinsulinemia, non insulin dependent diabetes (NIDDM), Arterial Hypertention, central obesity (internal organ) and hyperlipemia.
The phrase of Shi Yonging " with ... associating (usefulness) " herein, refer to use the described other medicines of earlier paragraphs slightly before, after a while, simultaneously, or be used in combination the alpha substituted carboxylic acid compound that aforesaid way is used general formula (I).Therefore, the alpha substituted carboxylic acid compound of general formula (I) and other medicine can a kind of composition or two kinds of independent compositions use simultaneously, or successively use with two kinds of independent compositions.
Some compound of general formula (I) may have asymmetric center, thereby has different enantiomorphs.All optical isomers of general formula (I) compound and steric isomer and composition thereof are considered as within the scope of the present invention.For general formula (I) compound, the present invention includes and use raceme, one or more enantiomorph, one or more diastereomer, or its mixture.General formula (I) compound can also exist by tautomer.The present invention relates to use all these tautomers and composition thereof.
Some functional group that The compounds of this invention comprises can be replaced by bioisosteric group, promptly has similar space or electrically requirement to female group, but demonstrates the physics-chem characteristic different or that improve or the group of other characteristic.Suitable example is known for those skilled in the art, includes, but are not limited at Patini etc. Chem.Rev, 1996,96, the part of describing in 3147-3176 and the document quoted thereof.
The present invention also comprises isotope-labeled compound, and nucleidic mass of being found usually by a nucleidic mass or total mass number and occurring in nature except that one or more atom or the different atom of total mass number replaced, it was identical with those compounds that general formula (I) is represented.Can introduce the isotropic substance that the isotopic example of The compounds of this invention comprises hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, respectively as 2H, 3H, 13C, 14C, 15N, 18O, 17O, 31P, 32P, 35S, 18F reaches 36Cl.Comprise the isotopic The compounds of this invention of above-mentioned isotropic substance or other atom and the pharmacologically acceptable salt of prodrug, these compounds or its prodrug thereof, comprise within the scope of the invention.Some compound isotopically labelled of the present invention, for example, introduce radio isotope as 3H and 14The compound of C is used for the experiment of medicine and/or substrate tissue distribution.Tritium, promptly 3H, and carbon-14, promptly 14The C isotropic substance is easy to preparation because of it and detects by preferred especially.In addition, with heavier isotropic substance, as deuterium, promptly 2H replaces can provide some treatment advantage, and this comes from its bigger metabolic stability, and for example, can increase the intravital transformation period or reduce essential dosage, therefore, can be preferred in some cases.The isotope-labeled general formula of the present invention (I) compound and prodrug thereof usually can following proposal and/or embodiment and preparation in the disclosed method preparation, replace nonisotopically labelled reagent with easy-to-use isotope-labeled reagent.
The present invention also comprises the pharmaceutical compositions and the method for the treatment of infectation of bacteria, by using the prodrug of general formula (I) compound.General formula (I) compound with free amine group, amido, hydroxyl or carboxyl can change prodrug into.Prodrug comprises these compounds, amino-acid residue wherein, or two or more (as, two, three or four) polypeptide chain of amino-acid residue, covalently bound by free amine group, hydroxyl or the hydroxy-acid group of amido linkage or ester bond and general formula (I) compound.These amino-acid residues comprise, but be not limited to common 20 naturally occurring amino acid representing with 3 letter characters, also comprise 4-oxyproline, oxylysine, demosine, isodemosine, 3-Methyl histidine, norvaline, Beta-alanine, γ-An Jidingsuan, citrulline, homocysteine, homoserine, ornithine and methionine(Met) sulfone.Also comprise other type prodrug.For example, the free carboxyl can be derived and is acid amides or alkyl ester.The free hydroxyl can be derived by these groups, includes but not limited to Advanced Drug Delivery Reviews, and 1996,19, the hemisuccinic acid ester described in 115, phosphoric acid ester, dimethylamino acetic ester and phosphorus acyloxy methoxycarbonyl.Also comprise hydroxyl and amino carbamate prodrugs, also comprise carbonic ether, sulphonate and the sulfuric ester prodrug of hydroxyl.Comprising also that hydroxyl is derived turns to (acyloxy) methyl and (acyloxy) ether, and wherein acyl group can be alkane ester, is optionally replaced by following radicals, include but not limited to ether, amine and carboxylic acid functional, or acyl group is above-mentioned amino acid ester.The type prodrug such as J.Med.Chem., 1996,39, described in 10.Unhindered amina also can be derived and is acid amides, sulfanilamide (SN) or phosphamide.All these prodrug moieties can be introduced following radicals, include, but are not limited to ether, amine and carboxylic acid functional.
Others of the present invention, advantage and preferred feature will be apparent in the following specifically describes.
Detailed Description Of The Invention and preferred embodiment
The preparation of following reaction scheme explaination The compounds of this invention.Except as otherwise noted, following R-R 17, O, Y, Ar 1-Ar 4And ring A definition as above.
Scheme 1
Figure A20048001673600371
Scheme 2
Figure A20048001673600381
Scheme 3
Figure A20048001673600391
Scheme 4
R 5For-(CR 11R 12) m-Z-(CR 11R 12) sWherein Z be-O-,-NR 10a-or-S (O) j-; Wherein m and s are 0,1,2 or 3 independently; Wherein j is 0,1 or 2
Scheme 5
Figure A20048001673600411
R 5For-(CR 11R 12) m-Z-(CR 11R 12) sWherein Z be-O-,-NR 10a-or-S (O) j-; Wherein each m and s are 0,1,2 or 3 independently; Wherein j is 0,1 or 2
Scheme 6
R 5For-(CR 11R 12) m-Z-(CR 11R 12) sWherein Z is-CH 2-; Wherein each m and s are 0,1,2 or 3 independently.
Scheme 7
R 5For-(CR 11R 12) m-Z-(CR 11R 12) sWherein Z is-CH 2-; Wherein each m and s are 0,1,2 or 3 independently.
Scheme 8
Figure A20048001673600441
R 5For-(CR 11R 12) m-Z-(CR 11R 12) sWherein Z is-CH 2-; Wherein each m and s are 0,1,2 or 3 independently.
Scheme 9
R 5For-(CR 11R 12) m-Z-(CR 11R 12) sWherein Z is-CH 2-; Wherein each m and s are 0,1,2 or 3 independently.
Scheme 10
Figure A20048001673600461
R 5For-(CR 11R 12) m-Z-(CR 11R 12) sWherein Z be-O-,-NR 10a-or-S (O) j-; Wherein each m and s are 0,1,2 or 3 independently; Wherein j is 0,1 or 2.
Scheme 11
Figure A20048001673600471
Scheme 12
Scheme 13
Figure A20048001673600491
About such scheme 1, general formula 1a compound can pass through hydrolysis compound IIa (wherein, CO 2The R group is hydrolyzable ester group, as methyl esters (CO 2-CH 3) or ethyl ester (CO 2-CH 2CH 3)) prepare, reaction is heated under 0～100 ℃ or in the microwave synthesizer and is carried out with alkali metal hydroxide (for example, NaOH, LiOH, KOH) (for example, the THF aqueous solution, methanol aqueous solution or its combination) in suitable solvent.General formula I Ia compound can pass through compound IV a, wherein LV 1Be Cl, Br, I or triflate, prepare with palladium (0) or other transition-metal catalyst mediated responses, wherein Met=boric acid or ester, first stannane etc., and group CO with organometallic compound IIIa coupling 2R as mentioned above.Compound IV a can obtain by using compound VI a alkylated compound Va, wherein Lv 1As mentioned above, Lv 2Be Cl, Br, I or triflate.
About such scheme 2, the formula III a compound that uses in the scheme 1 can obtain with the linked reaction of the reagent that closes diboron hexahydride (pinacolatodiborane) such as tetramethyl ethylene ketone in palladium (0) mediation from compound VI Ia, wherein, and Lv 3Be Cl, Br, I or triflate.Compound VI Ia, wherein Lv 3As mentioned above, can obtain by using Compound I Xa alkylated compound VIIIa, wherein Lv 3As mentioned above, Lv 4Be Cl, Br, I or triflate.
About such scheme 3, the ester IIa that uses in the scheme 1, wherein CO 2R also can obtain by using compound VI a alkylated compound Xa, wherein CO as mentioned above 2R as mentioned above, Lv 2As described in scheme 1.Compounds X a can obtain from compounds X Ia, wherein CO 2R by with compounds X Ia and deprotecting regent,, in suitable solvent (for example, THF, methyl alcohol, ethanol), reacts down at 0～100 ℃ on metal catalyst (for example, the palladium charcoal) as hydrogen as mentioned above.
Compounds X Ia commercialization, or can prepare by those skilled in the art.
About such scheme 4, general formula 1b compound; R wherein 5For-(CR 11R 12) m-Z-(CR 11R 12) sWherein Z be-O-,-NH 10a-or-S (O) j-; Wherein each m and s are 0,1,2 or 3 independently; Wherein j is 0,1 or 2; Can be by hydrolysis compound IIb preparation, wherein R 5Described in general formula I b compound, and CO 2R reacts under 0～100 ℃ in suitable solvent (for example, the THF aqueous solution, methanol aqueous solution or its combination) with alkali metal hydroxide (for example, NaOH, LiOH, KOH) as mentioned above.General formula I Ib compound, wherein R 5Described in general formula I b compound, can pass through compound III b, wherein R 5Described in general formula I Ib compound, and CO 2R reacts under 0～100 ℃ of temperature in suitable solvent (for example, THF, acetonitrile, dioxane, toluene) with activatory acylating reagent such as VIb as mentioned above.Compound IV b can obtain from compound Vb and compound VI b reaction, wherein Lv 6Be leavings group.Suitable compound VIb comprises N, N '-carbonyl dimidazoles.
Compound Vb and VIb commercialization, or prepare by those skilled in the art.
About such scheme 5, the general formula III b compound that uses in the scheme 4, wherein R 5As described in scheme 4, and CO 2R can pass through compound VI Ib, wherein R as mentioned above 5As described in the previous paragraph, with suitable general formula Lv 6-C (R 7R 8)-COOR electrophilic reagent, wherein Lv 6Be leavings group,, have under the situation 0～100 ℃ of prepared in reaction in suitable solvent (for example, THF, DMF, acetonitrile or DMSO) as halogen at alkali (for example, cesium carbonate, salt of wormwood).Suitable general formula Lv 6-C (R 7R 8)-COOR electrophilic reagent comprises the 2 bromo 2 methyl propionic acid methyl esters.Compound VI Ib is commercialization, or can be prepared by those skilled in the art.
General formula I b, IIb, IIIb and VIIb compound; R wherein 5For-(CR 11R 12) m-Z-(CR 11R 12) s; Wherein Z is-CH 2-, wherein each m and s are as mentioned above; Can be by well known to a person skilled in the art the method preparation.
About such scheme 6, general formula I c compound, wherein R 5For-(CR 11R 12) m-Z-(CR 11R 12) sWherein Z is-CH 2-, can prepare by hydrolysis compound IIc, wherein CO 2R uses alkali metal hydroxide (for example, NaOH, LiOH, KOH) as mentioned above, and 0～100 ℃ is carried out down or with the heating of microwave synthesizer in suitable solvent (for example, the THF aqueous solution, methanol aqueous solution or its combination).Compound I Ic can be by using compound IV c (Lv 7Be iodine, bromine, chlorine or other leavings group) alkylated compound IIIc preparation, wherein Lv 5Be leavings group.Can use different methods to realize this reaction, as with alkali, as two (trimethyl silyl) amido sodium to compound III c (Lv 5=H) deprotonation.Compound IV c can be from compound Vc and halide reagent or halogenation system, as oxalyl chloride and dimethyl formamide, or with other halogenide (for example, with compound IV c, Lv 7=Cl and sodium iodide reaction) prepared in reaction.Compound Vc can be from compound VI c by compound VIII c and reductive agent, as the sodium borohydride prepared in reaction.Compound VI c can be from compound VI Ic (Lv 8=Br or other halogen) by metal-halogen exchange (for example), then with the dimethyl formamide prepared in reaction with butyllithium.
Perhaps, about such scheme 7, general formula I Ic compound, wherein R 5For-(CR 11R 12) m-Z-(CR 11R 12) sWherein Z is-CH 2-, can silicomethane or acid source, be generally triethyl-silicane and trifluoroacetic acid, compound VIII c reduction deoxidation is prepared.Compound VIII c can obtain by compound III c is added among the VIc.Can realize this reaction by different methods, as with alkali, as diisopropylamine lithium to compound III c (Lv 5=H) deprotonation effect, or with metal or metal-salt (for example, chromium chloride (II)) to compound III c (Lv 5=Br) carrying out Reformatsky reacts.Compound VI c can be from compound VI Ic (Lv 8=Br or other halogen) by metal-halogen exchange (for example), then with the dimethyl formamide prepared in reaction with butyllithium.
Perhaps, about such scheme 8, Compound I Ic, wherein R 5For-(CR 11R 12) m-Z-(CR 11R 12); Wherein Z is-CH 2-, can be by Compound I Xc and suitable general formula VIa coupling reagent reaction acquisition.These reactions can be used electrophilic reagent VIa (for example, Lv 2=halogenide, sulphonate) exist under the situation at alkali (for example, cesium carbonate), or with alcohol (Lv 2=OH) in Mitsunobu-type condition (for example, triphenylphosphine and diethylazodicarboxylate) reaction realization down.Compound I Xc can be prepared by the compounds X c deprotection of protection.Suitable blocking group comprises allyl group, benzyl etc.The deprotection of Xc (P=allyl group) can for example under the situation that morpholine exists, contact soluble transition metal (for example, tetrakis triphenylphosphine palladium (0)) and finish by at alkali.
The method preparation of intermediate X c-XIIIc described in can scheme 6.
Perhaps, about such scheme 9, compounds X c can pass through compounds X IVc (for example, Lv 10=halogenide, sulphonate) and compound III c prepared in reaction, wherein Lv 5As mentioned above.Compounds X IVc can be by compounds X Vc and (C=O) Cl 2At polar aprotic solvent, as prepared in reaction in the dimethyl formamide.Compounds X Vc can pass through compounds X IIc and reductive agent, as the sodium borohydride prepared in reaction.The method preparation of compounds X IIIc described in can scheme 6.
Perhaps, about such scheme 10, general formula I c compound, wherein R 5For-(CR 11R 12) m-Z-(CR 11R 12) sWherein Z be-O-,-NR 10aOr-S (O) j-; Wherein each m and s are 0,1,2 or 3 independently; Wherein j is 0,1 or 2; Can obtain by hydrolysis general formula I Ic compound, utilize alkali metal hydroxide (for example, NaOH, LiOH, KOH) in, 0～100 ℃ of following or use microwave synthesizer heating polarity in suitable solvent (for example, the THF aqueous solution, methanol aqueous solution or its composition).General formula I Ic compound can be by Compound I Xc and suitable coupling reagent reaction acquisition.These reactions can be used electrophilic reagent (for example, VIa; Lv 2=halogenide, sulphonate), under the situation that alkali (for example, cesium carbonate, salt of wormwood or potassium tert.-butoxide) exists, realize, or with alcohol (VIa; Lv 2=OH) (for example, triphenylphosphine and diethylazodicarboxylate) realizes under Mitsunobu-type condition.Compound I Xc can be by the preparation of compounds X Ic deprotection, and wherein P is the protectiveness group.Suitable protecting group P comprises allyl group, benzyl etc.The deprotection of XIc (P=allyl group) can be by under the alkali situation that for example morpholine exists; with soluble transition metal (for example; tetrakis triphenylphosphine palladium (0)) contact realizes; perhaps at metal catalyst (for example with hydrogen; the palladium charcoal) on; in suitable solvent (for example, THF, methyl alcohol, ethanol), reduction is finished under 0～100 ℃.Compounds X Ic can pass through with compound III c (Lv 5=Cl, Br, I, triflate are as above-mentioned) alkylated compound XVc acquisition.
About such scheme 11, in some cases, get compounds X Vc with the enolate anion of benzyl halogenide alkylated compound IIIc with general formula X VIc.In the known palladium mediated linked reaction in solvent of those skilled in the art's (for example, March, Advanced organic Chemistry, Fourth Edition), compounds X Vc can be exchanged into Compound I c by for example.
About such scheme 12, general formula I d compound can pass through alkali metal hydroxide (for example, NaOH, LiOH, KOH), 0～100 ℃ of following hydrolysis compound IId preparation in suitable solvent (for example, the THF aqueous solution, methanol aqueous solution or its combination).General formula I Id compound can pass through compound III d and suitable hydroborating reagent, as hydrogen (for example, the palladium charcoal) on metal catalyst, 0～100 ℃ of following prepared in reaction in suitable solvent (for example, THF, methyl alcohol, ethanol).General formula III d compound can and have general formula (C by compound IV d 6H 5) 3P +-CH (OR 9) (COOR) Cl -Suitable triphenyl phosphonium reagent the Wittig prepared in reaction takes place.Suitable triphenylphosphine reagent comprises 1,2-diethoxy-2-oxoethyl) (triphenyl) phosphonium chloride.General formula I Vd compound can be by the prepared in reaction of the method described in scheme 9 with compound Vd.General formula Vd compound can be by described method compound VI d and the VIId prepared in reaction described in scheme 9.
Perhaps, general formula I Id compound can be by the method preparation of scheme 13.About scheme 13, provide compound VIII d with the enolate anion of benzyl halogenide IXd alkylation 2-methoxypropionic acid methyl esters.Compound VIII d can be generated Compound I Id by for example palladium mediated linked reaction.Compound I Id also can prepare from compounds X d.Compounds X d can prepare by series reaction from compounds X IId, and the linked reaction palladium mediated as (i) forms compounds X Id, and (ii) ester is reduced into the pure (iii) halogenation formation Compound I Id that reaches.
Arbitrary compound of above-mentioned general formula I and the arbitrary compound among the such scheme 1-13 can be transformed into another analogue by the chemical operation of standard.These chemical operation are known for those skilled in the art, comprise a) as T.W.Greene and P.G.M.Wuts Protective Groups in OrganicSynthesis "; Second Edition; John Wiley and Sons, New York, the method deprotection base described in 1991; B) with primary amine or secondary amine, mercaptan or alcohol displacement leavings group (halogenide, methanesulfonates, methanesulfonates etc.), form secondary amine or tertiary amine, thioether or ether respectively; C) as Thavonekham, Synthesis such as B (1997), 10, the described method of p1189 is handled phenyl (or substituted phenyl) carbamate with primary amine or secondary amine, forms corresponding urea; D) as Denmark, S.E.; Jones, T.K.J.Org.Chem. (1982) 47,4595-4597 or van Benthem, R.A.T.M.; Michels, J.J.; Speckamp, W.N.Synlett (1994), the described method of 368-370 is handled with two (2-methoxy ethoxy) sodium alanates (Red-AI), and the primary amine of propargyl ethanol or different alkynes phenyl alcohol or N-BOC protection is reduced to corresponding E-allyl group or E-high allyl derivative; E) as Tomassy, Synth.Commun. such as B. (1998), 28, the described method of p1201 with hydrogen and Pd catalyst treatment, is reduced to corresponding Z-alkene derivative with alkynes; F) handle primary amine or secondary amine with isocyanic ester, acyl chlorides (or other activated carboxylic acid derivative), alkylaryl chloro-formic ester or SULPHURYL CHLORIDE, get corresponding urea, acid amides, carbaminate or sulfanilamide (SN); G) use R 1CH (O) is with primary amine or secondary amine reduction amination; And h) handles pure corresponding carbamate, ester, carbonic ether or the sulphonate of getting with isocyanic ester, acyl chlorides (or other activated carboxylic acid derivative), alkylaryl chlorocarbonate or SULPHURYL CHLORIDE.
The compounds of this invention can have asymmetric carbon atoms.Mixture of diastereomers can based on its physics, the chemistry difference with method well known to those skilled in the art, for example, be separated into its independent diastereomer with chromatography or fractional crystallization.Enantiomer can following method be separated, promptly with suitable optically active compound (for example, alcohol) reaction, change enantiomeric mixture into non-enantiomer mixture, isolate diastereomer, each corresponding pure diastereomer of refabrication (for example, hydrolysis); Or by using chiral stationary phase or moving phase chromatographic separation.All isomer comprise that mixture of diastereomers and pure enantiomorph are considered as a part of the present invention.
The basic cpd of general formula (I) can form multiple different salt with multiple mineral acid or organic acid.Although these salt must be pharmaceutically acceptable to be applied to animal, usually expect in the practice that at first separating general formula (I) compound from reaction mixture is non-pharmaceutical salts, handle with alkaline reagents then and change the latter into free alkali compound simply, again this free alkali is changed into pharmaceutically acceptable acid additive salt.The acid additive salt of basic cpd of the present invention is easy to preparation, promptly in water-soluble medium or appropriate organic solvent such as methyl alcohol or ethanol, handles this basic cpd with mineral acid or organic acid that basic equivalent is selected.Careful evaporating solvent obtains the expectation solid salt easily.Required acid-salt also can be precipitated out free base solution in organic solvent by add suitable mineral acid or organic acid in solution.
The acidic cpd of general formula (I) can form subsalt with various pharmaceutically useful positively charged ions.The example of these salt comprises an alkali metal salt or alkaline earth salt, particularly sodium salt and sylvite.All these salt all can the routine techniques preparation.Form non-toxicity subsalt as the chemical bases of the pharmaceutically acceptable subsalt of reagent preparation the present invention and the acidic cpd of general formula (I).Non-toxicity subsalt comprises that those are derived from pharmaceutically acceptable positively charged ion, as the salt of sodium, potassium, calcium and magnesium etc.These salt are easy to preparation, handle corresponding acidic cpd to contain the required pharmaceutically acceptable cationic aqueous solution, evaporate gained solution then to doing preferred reduction vaporization.Perhaps, also can following method prepare,, extremely do with aforesaid method evaporation gained solution then the low-grade alkane alcohol solution of acidic cpd and required alkoxy base metal mixed.In the whole bag of tricks, for guarantee to react completely and the end product productive rate the highest, the preferred reagent that uses metering.
The compounds of this invention is preferred PPAR γ of PPAR and alpha modulators.The compounds of this invention can be regulated the process of PPAR-γ mediation, be biology, physiology, internal secretion and other body processes, these processes (are for example mediated by acceptor or the acceptor composition to PPAR agonist sensitivity described herein, diabetes, hyperlipidaemia, obesity, impaired glucose tolerance, hypertension, fatty liver, diabetic complication (for example, retinopathy, ephrosis, neurosis, cataract coronary artery disease etc.), atherosclerosis, gestational diabetes, polycystic ovary syndrome, cardiovascular disorder (for example, ischemic heart disease etc.), the cell injury that atherosclerosis or ischemic heart disease cause (for example, the brain injury that apoplexy etc. cause), gout, inflammation (for example, osteoarthritis, pain, heating, rheumatoid arthritis, inflammatory bowel, acne, sunburn, psoriasis, eczema, allergosis, asthma, GI ulcer, emaciation, autoimmune disorder, pancreatitis etc.), cancer, osteoporosis and cataract.The adjusting of these processes can be finished in external or body.Can be at multiple object, as, for example people, rodent, sheep, pig, milk cow etc. are implemented in the bodies and regulate.
The compounds of this invention also can be used for treating and impaired other metabolism syndrome relevant with insulin resistant of glucose utilization, the main late complication that comprises NIDDM, as diabetic angiopathy, atherosclerosis, diabetic nephropathy, diabetic neuropathy and diabetic vision syndrome, as retinopathy, cataract forms and glaucoma, reach other many diseases relevant, comprise the insulin resistant of unusual lipidemia glucocorticoid inducible with NIDDM, unusual lipidemia, polycystic ovary syndrome, obesity, hyperglycemia, hyperlipidaemia, hypercholesterolemia, hypertriglyceridemia, hyperinsulinemia and hypertension.The simple and clear definition of these diseases is found in any medical science dictionary, for example, and Stedman ＇ s Medical Dictionary (Xth Ed.).
The external activity of general formula (I) compound can following method be measured.
Mensuration (SPA) experiment is got close in flicker
In the SPA experiment, 3The radiocounting signal that the PPAR protein bound that darglitazone of H mark (being used for PPAR-γ) or GW2331 (being used for PPAR-α) and SPA poly-lysine pearl catch, generation can TopCounts (Packard) detect.With the PPAR bonded 3The part of H mark can be substituted by unlabelled compound.The substitution level decision of the Ki of this compound under can different compound concentrations.
Reagent:
SPA poly-lysine pearl can be available from Amersham Bioscience.
The darglitazone of 3H mark is used for PPAR-γ.
The GW2331 of 3H mark is used for PPAR-α.
PPAR protein.
Damping fluid-PBS, 10% glycerine, 14mM beta-mercaptoethanol.
In at least once above-mentioned SPA tested, test-compound Ki of the present invention was all between 0.3nM～30 μ M.Compounds more of the present invention have different selectivity to different PPAR.Preferred one group of compound has PPAR-α above the selection activity to PPAR-γ.Another is organized preferred compound and has PPAR-γ above the selection activity to PPAR-α.Another organize preferred compound to the selectivity of PPAR-α and PPAR-γ all above selectivity to PPAR-δ.Another is organized preferred compound the selectivity of PPAR-δ is surpassed selectivity to PPAR-α and PPAR-γ.
The alpha substituted carboxylic acid compound of general formula (I) can be suitable part, pharmaceutical formulations oral and administered parenterally be used for the treatment of the disease of PPAR mediation.The compounds of this invention can tablet or capsule, oil suspension or aqueous suspensions, lozenge, lozenge, pulvis, granule, emulsion, syrup or the use of elixir oral cavity.The composition that use in the oral cavity can comprise one or more correctives, sweetener, pigment and sanitas, to produce all good pharmaceutical formulations of shape flavor.Tablet can comprise the preparation that pharmaceutically useful auxiliary material helps tablet.According to this area routine, these tablets can be covered with pharmaceutically useful enteric solubility thin layer, as Zerol or Stearic diglyceride, decompose in the stomach and intestine pipeline and absorb to delay it, thereby secular slow releasing function is provided.
Oral preparation can be the hard gelatin capsule form, wherein, activeconstituents and a kind of inert solid diluent, for example, lime carbonate, calcium phosphate or kaolin mix.They also can be the soft gelatin capsule form, and wherein, activeconstituents and water or oily medium are as peanut oil, whiteruss or mixed with olive oil.
Aqueous suspensions comprises activeconstituents and the auxiliary material that is suitable for the aqueous suspensions preparation usually.These auxiliary materials can be suspension agent, as Xylo-Mucine, methylcellulose gum, Vltra tears, sodiun alginate, polyvinylpyrrolidone, tragacanth and gum arabic; Can be natural phospholipid dispersion agent or wetting agent, as Yelkin TTS, the condenses of oxyethane and longer chain fatty acid, polyoxyethylene stearic acid ester for example, the condenses of oxyethane and long chain aliphatic alcohol, as heptadecyl vinyloxy group cetyl alcohol, oxyethane and the condenses that is derived from the partial ester of lipid acid and hexitol, as polyoxyethylene sorbitol monoleate or lipid acid hexitan, as polyoxyethylenesorbitan sorbitan monooleate.
Pharmaceutical compositions can be injectable sterile aqueous suspension or oily suspensions.This suspension can use suitable above-mentioned dispersion agent or wetting agent and suspension agent preparation according to currently known methods.But these injectable sterile preparations also can be made suspension in thinner that nontoxic parenteral uses or solvent, for example make 1,3 butylene glycol solution.In acceptable medium and solvent, can adopt water, Ringers solution and isoosmotic sodium chloride solution.Any non-irritating expressed oil be can use for this reason, synthetic monoglyceride or triglyceride comprised.In addition, lipid acid can be used for the preparation of injection as oleic acid.
The alpha substituted carboxylic acid compound of general formula (I) also can rectal administration suppository form use.These compositions can be by being mixed with medicine and suitable non-stimulated auxiliary material, and this auxiliary material at room temperature is solid but is liquid under rectal temperature, thereby discharges medicine in the internal rectum dissolving.These materials comprise theobroma oil and other glyceryl ester.
The topical formulations that can be used as that contains The compounds of this invention, for example, emulsifiable paste, ointment, gelating soln or suspension.
The alpha substituted carboxylic acid compound of general formula (I) also adopts the liposome delivery system, uses as individual layer vesicles, the big vesica of individual layer and multilamellar vesicle form.Liposome can multiple phosphatide, forms as cholesterol, stearylamide or phosphatidylcholine.
The compounds of this invention dosage level scope is about 0.5～100mg/kg body weight.The preferred dosage ratio is about 30～100mg/kg body weight.Yet, should understand, any concrete patient's concrete dosage level depends on many factors, comprises the seriousness of disease specific of activity, age, body weight, general health, sex, diet, duration of service, use approach, drainage rate, drug combination and the treatment of the particular compound of use.For improving the therapeutic activity of these compounds, can accompany with other oral anti-diabetic activity compound, as sulfonylurea, for example, tolbutamide etc.
The method for preparing various pharmaceutical compositions with the active compound of concrete amount is known to those skilled in the art, maybe will be conspicuous.For example, see Remington ＇ s PharmaceuticalSciences, Mack Publishing Company, Easter, Pa., 15th Edition (1975).
Further explaination and illustration compound of the present invention and preparation thereof of embodiment that below provides and preparation.Should understand, scope of the present invention is subjected to the restriction of the following example and preparation scope never in any form.In the following example, have the molecule of single chiral centre, except as otherwise noted, exist with racemic mixture.Those have the molecule of two or more chiral centre, except as otherwise noted, exist with diastereomeric racemic mixture.Single enantiomorph/diastereomer can obtain by method well known to those skilled in the art.
When relating to the HPLC chromatography in following preparation and embodiment, normally used condition is as follows, except as otherwise noted.The post that uses is ZORBAX TMRXC18 post (Hewlett Packard production), column length 150mm, internal diameter are 4.6mm.Sample at Hewlett Packard-1100 system A with gradient solvent 100% ammonium acetate/acetate buffer (0.2M) to 100% acetonitrile wash-out 10 minutes.This system begins flush cycle then, with 100 acetonitriles flushing 1.5 minutes, again with 100% buffered soln flushing 3 minutes.Velocity of flow is constant at this moment is 3ml/ minute.
In the following example and the preparation, " Et " refers to ethyl, and " AC " refers to ethanoyl, " Me " nail base, and " ETOAC " or " ETOAc " refers to ethyl acetate, and " THF " refers to tetrahydrofuran (THF), and " Bu " refers to butyl.
Chirality supercritical fluid chromatography (SFC) condition
The single enantiomer of some racemoid obtains by SFC, uses chiralpak AD-H post, 140 crust, 2.5mL/ minute, chiralpak AS-H post, 140 crust, 2.5mL/ minute and chirality pak OJ-H post, 140 crust, 2.5mL/ minute.
In whole following part, following general formula compound to be being similar to Heterocycles, and 2001,55 (4), the method preparation described in the 689-703.
Embodiment A-1
2-methyl-2-(3 '-[2-(5-methyl-2-phenyl-1,3-oxazole-4-yl) oxyethyl group]-1,1 '-biphenyl-3-yl } the oxygen base) propionic acid
Figure A20048001673600582
To 2-methyl-2-(3 '-[2-(5-methyl-2-phenyl-1,3-oxazole-4-yl) oxyethyl group]-1,1 '-biphenyl-3-yl } the oxygen base) (0.89g adds entry (2.6mL) and salt of wormwood (0.73g, 2.0 equivalents) to methyl propionate in methyl alcohol 1.76mmol) (20mL) solution.Behind the reflux mixture 5 hours, be chilled to room temperature.Solution is poured in the water, with the 1N hcl acidifying to pH 2, ethyl acetate extraction (3 * 30mL).Merge organic layer, with saturated sodium-chloride water solution washing, dry (anhydrous sodium sulphate), filter and be concentrated into dried, obtain title compound and be (0.6g, 70%), white crystalline solid.
Ultimate analysis: C 28H 27NO 5Calculated value C 73.51, H 5.95, N 3.06.Test value: C 73.26, H 6.08, and N 3.06.
LRMS：458(M+H) +。
1H NMR(CDCl 3，400MHz)：7.97(2H，dd，J＝3.0，6.6Hz)，7.43(2H，d，J＝2.8Hz)，7.41(1H，s)，7.31(2H，t，J＝8.0Hz)，7.23(2H，d，J＝8.6Hz)，7.17(1H，d，J＝7.6Hz)，7.12(1H，bs)，6.93(1H，dd，J＝1.4，8.2Hz)，6.87(1H，dd，J＝2.0，8.1Hz)，4.29(2H，t，J＝7.7Hz)，3.07(2H，t，J＝7.7Hz)，2.40(3H，s)，1.63(6H，s)。
Embodiment A-2
2-methyl-2-[(3 '-{ [4-(trifluoromethyl) benzyl] oxygen base }-1,1 '-biphenyl-3-yl) the oxygen base] propionic acid
As the described step of embodiment A-1, with 2-methyl-2-[(3 '-{ [4-(trifluoromethyl) benzyl] oxygen base }-1,1 '-biphenyl-3-yl) the oxygen base] methyl propionate is starting raw material, obtains title compound.
LRMS：431(M+H) +。
Embodiment A-3
2-methyl-2-[(3 '-and 2-[1-(6-methyl pyridazine-3-yl) piperidin-4-yl] oxyethyl group }-1,1 '-biphenyl-3-yl) the oxygen base] propionic acid
As the described step of embodiment A-1, with 2-methyl-2-[(3 '-{ 2-[1-(6-methyl pyridazine-3-yl) piperidin-4-yl] oxyethyl group }-1,1 '-biphenyl-3-yl) the oxygen base] methyl propionate is starting raw material, obtains the title compound into faint yellow crystalline solid.
LRMS：477(M+H) +。
1H NMR(CDCl 3，400MHz)：7.27(2H，q，J＝8.1Hz)，7.20-7.18(2H，m)，7.12(1H，bd，J＝7.8Hz)，7.08-7.06(2H，m)，6.94-6.93(1H，m)，6.91-6.90(1H，m)，6.84(1H，dd，J＝2.0，7.8Hz)，4.25(2H，bd，J＝13.1Hz)，4.04(2H，t，J＝6.1Hz)，2.88(2H，t，J＝13.4Hz)，2.48(3H，s)，1.80-1.70(5H，m)，1.65(6H，s)，1.33-1.27(2H，m)。
Embodiment A-4
1-(3 '-[2-(5-methyl-2-phenyl-1,3-oxazole-4-yl) oxyethyl group]-1,1 '-biphenyl-3-yl } the oxygen base) cyclobutane-carboxylic acid
Figure A20048001673600592
To 1-(3 '-[2-(5-methyl-2-phenyl-1,3-oxazole-4-yl) oxyethyl group]-1,1 '-biphenyl-3-yl } the oxygen base) (0.138g adds 2M lithium hydroxide solution (0.28mL) to the cyclobutane carboxylate in tetrahydrofuran (THF) 0.278mmol) (3mL) and methyl alcohol (1mL) solution.The gained mixture was at room temperature stirred 16 hours.Add entry (5mL) and ether (10mL), with gained solution stirring 10 minutes.Remove ether layer, 0 ℃ with 1N hcl acidifying water layer to pH 2, stirred 20 minutes.Filter and collect white precipitate, wash with frozen water.After drying under 40 ℃ of high vacuum, obtain title compound (0.091g, 70%), be white crystalline solid.
Ultimate analysis: C 29H 27NO 50.15LiCl calculated value C 73.18, H 5.72, N 2.94.
Measured value: C 73.08, H 5.67, and N 2.93.
LRMS：471(M+H) +。
1H NMR(CDCl 3，400MHz)：8.03-8.00(2H，m)，7.43(3H，t，J＝3.3Hz)，7.30(2H，t，J＝7.8Hz)，7.16(2H，d，J＝6.8Hz)，7.09(1H，t，J＝2.3Hz)，6.91-6.85(3H，m)，4.27(2H，t，J＝7.8Hz)，3.06(3H，t，J＝8.1Hz)，2.83-2.76(2H，m)，2.53-2.46(2H，m)，2.40(3H，s)，2.06-1.97(2H，m)。
Embodiment A-5 is to A-28
Embodiment A-5 to A-28 to be similar to the step preparation described in the embodiment A-4.
Figure A20048001673600611
Figure A20048001673600621
Figure A20048001673600631
Embodiment A-1 is to the preparation (preparation a-1 to a-11) of the starting raw material of A-28
Preparation a-1
2-(3-iodine phenoxy group)-2 Methylpropionic acid methyl esters
Figure A20048001673600642
(1.08g, N 4.9mmol) add 2-bromo-2-methyl-methyl propionate (0.76mL, 1.2 equivalents) and cesium carbonate (3.45g, 2 equivalents) in dinethylformamide (10mL) solution to the 3-iodophenol.90 ℃ of heating of gained mixture 24 hours are chilled to room temperature then.Add entry, with extracted with diethyl ether mixture (3 * 20mL).Merge organic layer, with water and saturated sodium-chloride water solution washing, dry (anhydrous sodium sulphate), filter and concentrate.Residue uses 0-30% ethyl acetate/hexane solution with the silica gel column chromatography purifying, obtains title compound (0.83g, 53%).
LRMS：321(M+H) +。
1H NMR(CDCl 3，400MHz)：7.22(1H，dt，J＝1.3，7.8Hz)，7.12(1H，dd，J＝1.6，2.4Hz)，6.84(1H，t，J＝8.1Hz)，6.66(1H，ddd，J＝0.8，2.5，8.3Hz)，3.66(3H，s)，1.47(6H，s)。
Preparation a-2
2-(3-iodine phenoxy group) methyl-butyrate
Figure A20048001673600651
As prepare the step described in the a-1, and use the 2 bromopropionic acid ethyl ester to replace 2-bromo-2-methyl-methyl propionate under the room temperature, obtain title compound with 93% productive rate.
LRMS：321(M+H) +。
1H NMR(CDCl 3，400MHz)：7.30(1H，ddd，J＝1.0，1.5，7.8Hz)，7.24(1H，dd，J＝1.6，2.4Hz)，6.97(1H，dd，J＝7.8，8.3Hz)，6.82(1H，ddd，J＝1.0，2.5，8.6Hz)，4.53(1H，dd，J＝5.8，6.6Hz)，3.75(3H，s)，2.00-1.93(2H，m)，1.05(3H，t，J＝7.5Hz)。
Preparation a-3
1-(3-bromine phenoxy group) cyclobutane carboxylate
As prepare the step described in the a-1, and, heat in acetonitrile solution as starting raw material with 3-bromophenol and 1-bromine cyclobutane carboxylate, obtain title compound with 56% productive rate.
LRMS：300(M+H) +。
Preparation a-4
4-[2-(3-iodine phenoxy group) ethyl]-5-methyl-2-phenyl-1, the 3-oxazole
As prepare the step described in the a-1, at room temperature with the 3-iodophenol with 2-(5-methyl-2-phenyl-1,3-oxazole-4-yl)-ethyl-4-toluene sulfonic acide ester is a starting raw material, obtains title compound with 77% productive rate, is water white oil.
LRMS：406(M+H) +。
1H NMR(CDCl 3，400MHz)：7.87(2H，dd，J＝1.9，7.7Hz)，7.34-7.29(3H，m)，7.15-7.13(2H，m)，6.86(1H，t，J＝8.1Hz)，6.76-6.73(1H，m)，4.10(2H，t，J＝6.6Hz)，2.85(2H，t，J＝6.6Hz)，2.26(3H，s)。
Preparation a-5
2-bromo-6-[2-(5-methyl-2-phenyl-1,3-oxazole-4-yl) oxyethyl group] pyridine
Figure A20048001673600661
Under 0 ℃, to 2-(5-methyl-2-phenyl-1,3-oxazole-4-yl)-ethanol (1.04g, 5.1mmol) and 2, the 6-dibromo pyridine (1.21g, (concentration is 60% in oil to add sodium hydride in no Shui diox (20mL) solution 5.1mmol), 0.368g, 3 equivalents).To stir 16 hours under the gained mixture room temperature.Mixture is poured in the frozen water, with ethyl acetate extraction (3 * 50mL).Merge organic layer, with saturated sodium hydrogen carbonate solution and saturated sodium chloride solution washing, drying (anhydrous sodium sulphate), filtration and concentrated.Residue uses 0-50% ethyl acetate/hexane solution with the silica gel column chromatography purifying, obtains title compound (1.19g, 65%), is white crystalline solid.
LRMS：359(M+H) +。
1H NMR(CDCl 3，400MHz)：7.97(2H，dd，J＝1.8，7.8Hz)，7.44-7.35(4H，m)，7.03(1H，d，J＝7.3Hz)，6.65(1H，d，J＝8.1Hz)，4.55(2H，t，J＝6.8Hz)，2.97(2H，t，J＝6.8Hz)，2.34(3H，s)。
Preparation a-6
2-chloro-6-[2-(5-methyl-2-phenyl-1,3-oxazole-4-yl) oxyethyl group] pyrazine
As prepare the step described in the a-5, with 2-(5-methyl-2-phenyl-1,3-oxazole-4-yl)-ethanol and 2, the 6-dichloropyrazine is a starting raw material, obtains title compound with 64% productive rate.
LRMS：316(M+H) +。
1H NMR(CDCl 3，400MHz)：8.11(2H，d，J＝10.4Hz)，7.97(2H，dd，J＝1.9，7.7Hz)，7.44-7.39(3H，m)，4.60(2H，t，J＝6.7Hz)，2.99(2H，t，J＝6.7Hz)，2.35(3H，s)。
Preparation a-7
2-[3-(4,4,5,5-tetramethyl--1,3,2-two oxa-boron heterocycles penta-2-yl) phenoxy group] methyl-butyrate
Figure A20048001673600671
To 2-(3-iodine phenoxy group)-2 Methylpropionic acid methyl esters (preparation a-2) (1.49g, 4.65mmol) dimethyl sulfoxide (DMSO) (40mL) solution in add potassium acetate (1.37g, 3 equivalents), two (tetramethyl ethylene ketone) diboron hexahydride (1.3g, 1.1 equivalent) reach [1,1 '-two (diphenylphosphino)-ferrocene] dichloromethane solution of dichloro palladium (II) mixture (0.152g, 0.04 equivalent).The gained mixture heated 16 hours down at 80 ℃, was chilled to room temperature.Add entry, mixture is with extracted with diethyl ether (3 * 30mL).Merge organic layer, with 5% sodium hydrogen carbonate solution (2 * 50mL) and saturated sodium chloride solution washing, dry (anhydrous sodium sulphate), filter and concentrate.Residue uses 0-25% ethyl acetate/hexane solution with the silica gel column chromatography purifying, obtains title compound (0.92g, 62%).LRMS：321(M+H) +。
1H NMR(CDCl 3，400MHz)：7.40(1H，d，J＝7.3Hz)，7.32(1H，d，J＝2.8Hz)，7.28(1H，d，J＝8.1Hz)，6.97(1H，ddd，J＝1.0，2.8，8.1Hz)，4.64(1H，t，J＝6.3Hz)，3.73(3H，s)，2.01-1.94(2H，m)，1.32(12H，s)，1.06(3H，t，J＝7.5Hz)。
Preparation a-8
2-methyl-2-[3-(4,4,5,5-tetramethyl--1,3,2-two oxa-boron heterocycles penta-2-yl) phenoxy group] methyl propionate
As prepare the step described in the a-7, use 2-(3-iodine phenoxy group)-2 Methylpropionic acid methyl esters (preparation 1) to be to obtain title compound with 75% productive rate by starting raw material.
LRMS：321(M+H) +。
1H NMR(CDCl 3，400MHz)：7.42(1H，d，J＝7.1Hz)，7.29(1H，d，J＝2.8Hz)，7.22(1H，t，J＝7.8Hz)，6.90(1H，ddd，J＝0.8，2.8，8.1Hz)，3.75(3H，s)，1.56(6H，s)，1.30(12H，s)。
Preparation a-9
1-[3-(4,4,5,5-tetramethyl--1,3,2-two oxa-boron heterocycles penta-2-yl) phenoxy group] cyclobutane carboxylate
Figure A20048001673600681
As prepare the step described in the a-7, use 1-(3-bromine phenoxy group) cyclobutane carboxylate (preparation 3), to obtain title compound with 80% productive rate as starting raw material.
LRMS：347(M+H) +。
Preparation a-10
2-{[3 '-(benzyloxy)-1,1 '-biphenyl-3-yl] the oxygen base }-the 2 Methylpropionic acid methyl esters
Figure A20048001673600682
To 2-(3-iodine phenoxy group)-2 Methylpropionic acid methyl esters (preparation a-1) (1.14g, 3.56mmol) benzole soln (20mL) in add 3-benzyloxy phenyl-boron dihydroxide (0.89g, 1.1 equivalent), 2M sodium carbonate solution (3.56mL) and tetrakis triphenylphosphine palladium (0) (0.2g, 0.05 equivalent).With gained mixture reflux 2 hours, be chilled to room temperature.Add entry, mixture is with extracted with diethyl ether (3 * 20mL).Merge organic layer, also concentrate with 5% sodium hydrogen carbonate solution and saturated sodium chloride solution washing, dry (anhydrous sodium sulphate).Residue uses 0-15% ethyl acetate/hexane solution with the silica gel column chromatography purifying, obtains the title compound (1.08g, 81%) of colorless oil.
LRMS：377(M+H) +。
1H NMR(CDCl 3，400MHz)：7.47-7.45(2H，m)，7.39(2H，t，J＝7.3Hz)，7.33(2H，t，J＝7.8Hz)，7.28(1H，t，J＝8.0Hz)，7.21(1H，ddd，J＝1.0，1.5，8.1Hz)，7.17(1H，dd，J＝1.8，2.3Hz)，7.14(1H，dm，J＝7.6Hz)，7.08(1H，dd，J＝1.8，2.3Hz)，6.96(1H，ddd，J＝0.8，2.5，8.3Hz)，6.79(1H，ddd，J＝1.0，2.5，8.1Hz)，5.11(2H，s)，3.78(3H，s)，1.62(6H，s)。
Preparation a-11
2-methyl-2-(3 '-[2-(5-methyl-2-phenyl-2H-1,2,3-triazole-4-yl) oxyethyl group] biphenyl-3-yl } the oxygen base) methyl propionate
Figure A20048001673600683
With 2-(5-methyl-2-phenyl-2H-1,2,3-triazole-4-yl) ethanol (51mg, 0.25mmol), 2-[(3 '-xenol-3-yl) oxygen base]-the 2 Methylpropionic acid methyl esters (86mg, 0.30mmol) and Ph 3(98mg 0.375mmol) is dissolved among the anhydrous THF (1mL) P, at room temperature drips diethylazodicarboxylate (65mg, anhydrous THF (1mL) solution 0.375mmol) with syringe then.The gained reaction soln was at room temperature stirred 18 hours, and concentrate.With the glue column purification, use 20-40% ethyl acetate/hexane solution to get 69mg (59%) light yellow oil.
1H NMR(400MHz，CDCl 3)1.55(s，6H)，2.31(s，3H)，3.10(t，2H)，3.68(s，3H)，4.25(t，2H)，6.70(m，1H)，6.82(m，1H)，7.00(s，1H)，7.05(d，1H)，7.20(m，4H)，7.32(t，2H)，7.90(d，2H)
LRMS(m/z)：472(M+H) +。
Embodiment B-1
1-(3-{[({2-[3-(trifluoromethyl) phenyl] oxyethyl group } carbonyl) amino] methyl } phenoxy group) cyclobutane-carboxylic acid
Under 0 ℃, to 1-(3-{[({2-[3-(trifluoromethyl) phenyl] oxyethyl group } carbonyl) amino] methyl } phenoxy group) cyclobutane carboxylate (0.150g, 0.32mmol) tetrahydrofuran (THF) (3mL) and methyl alcohol (0.6mL) solution in add 2M lithium hydroxide (0.32mL, 2 equivalents).The gained mixture at room temperature stirred 24 hours.Add entry (10mL), mixture is with extracted with diethyl ether (1 * 15mL discards).Water is adjusted to pH 2 with 1N hydrochloric acid, with ethyl acetate extraction (3 * 20mL).Merge organic layer, with saturated sodium chloride solution washing, dry (anhydrous sodium sulphate), filter and be concentrated into dried title compound (85%).
LRMS：438(M+H) +。
1H NMR(CDCl 3，400MHz)：7.62(1H，d，J＝7.8Hz)，7.46(1H，t，J＝7.3Hz)，7.36(1H，d，J＝7.3Hz)，7.31(1H，dd，J＝6.1，7.6Hz)，7.18(1H，t，J＝8.0Hz)，6.84(1H，d，J＝7.6Hz)，6.65(1H，s)，6.56(1H，d，J＝7.8Hz)，4.32-4.27(4H，m)，3.11(2H，t，J＝6.8Hz)，2.79-2.72(2H，m)，2.49-2.41(2H，m)，2.09-1.93(2H，m)。
Embodiment B-2 is to B-29
The method preparation that Embodiment B-2 is used to be similar to Embodiment B-1 to B-29.
Figure A20048001673600702
Figure A20048001673600711
Figure A20048001673600721
Embodiment B-1 is to the preparation (preparation b-1 to b-20) of the starting raw material of B-29
Preparation b-1
2-(3-cyano-benzene oxygen)-2 Methylpropionic acid methyl esters
To acetonitrile (20mL) solution of 3-cyanophenol (5mmol) or arbitrary polar aprotic solvent such as dimethyl sulfoxide (DMSO), N, dinethylformamide etc.) add 2-bromo-2-methyl-methyl propionate (1.2 equivalent) and cesium carbonate (2 equivalent) in the solution.The gained mixture heated 6 hours down at 60 ℃, was chilled to room temperature then.Add entry (20mL), mixture is with ethyl acetate extraction (3 * 20mL).Merge organic layer, with saturated sodium bicarbonate and saturated sodium chloride solution washing, dry (anhydrous sodium sulphate), filter and be concentrated into to do and obtain title compound with 75% productive rate.
LRMS：220(M+H) +。
1H NMR(CDCl 3，400MHz)：7.30(1H，t，J＝8.0Hz)，7.23(1H，dt，J＝1.3，7.6Hz)，7.05(1H，dd，J＝1.3，2.3Hz)，7.01(1H，ddd，J＝2.3，2.8，8.3Hz)，3.73(3H，s)，1.57(6H，s)。
Preparation b-2 to b-3
Prepare b-2 to b-3 use and be similar to the method preparation for preparing described in the b-1.
Figure A20048001673600742
Preparation b-4
2-[3-(amino methyl) phenoxy group-2 Methylpropionic acid methyl esters
Figure A20048001673600743
In 2-(3-cyano-benzene oxygen)-2 Methylpropionic acid methyl esters (preparation b-1) methyl alcohol (20mL) solution (4mmol), add 10% palladium charcoal (20% weight percent).The gained mixture stirred 24 hours under hydrogen stream, filtered with Celite.Concentrated filtrate, residue are dissolved in the ethyl acetate, with 1N salt acid elution (2 * 20mL).Merge washing soln, regulate pH＞10 with 4N sodium hydroxide, with dichloromethane extraction (3 * 20mL).Merge organic extract, with saturated sodium chloride solution washing, dry (salt of wormwood), filter and be concentrated into dried, obtain title compound with 65% productive rate.
LRMS：224(M+H) +。
Preparation b-5 to b-6
Prepare b-5 to b-6 use and be similar to the method preparation for preparing described in the b-4.
Figure A20048001673600751
Preparation b-7
1H-imidazoles-1-carboxylic acid 2-(5-methyl-2-phenyl-1,3-oxazole-4-yl) ethyl ester
Figure A20048001673600752
(1.015g, toluene solution 5mmol) (25mL) adds salt of wormwood (1.38g, 2 equivalents) and N, N ＇-carbonyl dimidazoles (0.97g, 1.2 equivalents) to 2-(5-methyl-2-phenyl-1,3-oxazole-4-yl)-ethanol.The gained mixture at room temperature stirred 24 hours, added entry (20mL) then.With ethyl acetate extraction, organic extract, the drying (anhydrous sodium sulphate) that the washing of saturated sodium chloride solution merges, filter and be concentrated into dried title compound (100%).
LRMS：298(M+H) +。
1H NMR(CDCl 3，400MHz)：8.10(1H，s)，7.97-7.93(2H，m)，7.44-7.39(5H，m)，4.68(2H，t，J＝6.7Hz)，2.98(2H，t，J＝6.7Hz)，2.34(3H，s)。
Preparation b-8 to b-10
Prepare b-8 to b-10 use and be similar to the method preparation for preparing described in the b-7.
Figure A20048001673600761
Preparation b-11
2-methyl-2-{3-[({[2-(5-methyl-2-phenyl-1,3-oxazole-4-yl) oxyethyl group] carbonyl } amino) methyl] phenoxy group } methyl propionate
Figure A20048001673600763
To 1H-imidazoles-1-carboxylic acid 2-(5-methyl-2-phenyl-1,3-oxazole-4-yl) ethyl ester (preparation 7) (0.48g, 1.6mmol) tetrahydrofuran solution (3mL) in add 2-[3-(amino methyl) phenoxy group]-2 Methylpropionic acid methyl esters (preparation b-4) (0.39g, 1.1 equivalents).With gained mixture reflux 16 hours, be chilled to room temperature then.Concentrate, and use 0-50% ethyl acetate/hexane solution, obtain title compound (0.39g, 53%) through the silica gel column chromatography purifying.
LRMS：453(M+H) +。
1H NMR(CDCl 3，400MHz)：7.96(2H，dd，J＝1.9，7.7Hz)，7.44-7.38(3H，m)，7.16(1H，t，J＝8.0Hz)，6.89(1H，d，J＝7.3Hz)，6.77(1H，s)，6.67(1H，dd，J＝2.3，8.3Hz)，4.36(2H，t，J＝6.7Hz)，4.30(2H，d，J＝5.8Hz)，3.75(3H，s)，2.83(2H，t，J＝6.7Hz)，2.32(3H，s)，1.57(6H，s)。
Preparation b-12 to b-20
Preparing b-12 to b-20 uses to be similar to and prepares the method for using among the b-11 and be prepared.
Figure A20048001673600781
Figure A20048001673600782
Preparation b-21
The preparation of imidazoles b-21c
In the toluene solution (5ml) of pure b-21b (1mmol), add N, N " carbonyl dimidazoles (1.05mmol) and salt of wormwood (1mmol).Gained solution reflux 3 hours.After being chilled to room temperature, add entry (20ml), mixture is with ethyl acetate extraction (3 * 20ml).Merge extract, obtain acylimidazole b-21c with quantitative productive rate with salt water washing, dried over sodium sulfate, vacuum concentration.
The preparation of alcohol b-21b
Acetonitrile solution (10ml) to 3-salicylic alcohol b-21a (1mmol) and cesium carbonate (1mmol) adds 2 bromo 2 methyl propionic acid methyl esters (2mmol).Mixture reflux 6 hours.After being chilled to room temperature, add entry (50ml), mixture is with ethyl acetate extraction (3 * 20ml).Merge organic layer with salt brine solution washing, dried over sodium sulfate, vacuum concentration.Silica gel column chromatography (SGC) purifying uses 10-30% ethyl acetate/hexane eluant solution, obtains pure b-21b.Productive rate is 40-85%.
Figure A20048001673600792
The preparation of methyl esters b-21q
Step described in b-11, methyl esters b-21g is with compound b-21f and compound b-21c prepared in reaction, and productive rate is 60～90%.
The preparation of amine b-21f
(weight percent 10% is 50mg) at room temperature with hydrogen treat 4 hours with the ethyl acetate solution (20ml) of trinitride b-21e (2mmol) and palladium charcoal.Remove by filter palladium and concentrate with Celite and obtain amine b-21f with quantitative productive rate.
The preparation of trinitride b-21e
In the DMF solution (5ml) of tosylate b-21d (1mmol), add sodiumazide (3mmol).The gained mixture at room temperature stirred 14 hours, added entry (50ml) then.With ethyl acetate extraction (3 * 20ml), water, saturated sodium hydrogen carbonate solution and salt brine solution washing merge organic layer, dried over sodium sulfate and concentrate trinitride b-21e, productive rate is 85%.
Embodiment C-1
1-{4-[2-(5-methyl-2-phenyl-1,3-oxazole-4-yl) oxyethyl group] benzyl } hexahydrobenzoic acid
At room temperature, with triethyl-silicane (1.03g, 8.86mmol) (0.797g is in methylene dichloride 1.77mmol) (5mL) and trifluoroacetic acid (1mL) solution for the hexahydrobenzoic acid methyl esters to add to 1-(hydroxyl 1{4-[2-(5-methyl-2-phenyl-1,3-oxazole-4-yl) oxyethyl group] phenyl } methyl).The gained mixture was stirred 1 hour, and vacuum concentration then is with the heptane azeotropic.Residue is dissolved in tetrahydrofuran (THF) (3mL) and the water (3mL), and the adding lithium hydroxide monohydrate (0.223g, 5.31mmol).The gained mixture at room temperature stirred 18 hours, with the 4N hcl acidifying to pH 2, and with ethyl acetate extraction.Dry organic phase (anhydrous magnesium sulfate), filter, evaporate title compound (0.332g, 45%).
Ultimate analysis: C 26H 29NO 4Calculated value C74.44, H6.97, N3.34.Measured value: C74.22, H6.89, N3.34.
LRMS：420(M+H) +。
1H NMR(DMSO-d 6，400MHz)：7.90(2H，dd，J＝1.8，7.8Hz)，7.51-7.46(3H，m)，6.98(2H，d，J＝8.6Hz)，6.80(2H，d，J＝8.6Hz)，4.16(2H，t，J＝6.6Hz)，2.90(2H，t，J＝6.6Hz)，2.64(2H，s)，2.34(3H，s)，1.85(2H，d，J＝12.6Hz)，1.53-1.46(3H，m)，1.29-1.11(5H，m)。
Embodiment C-2 is to C-5
Embodiment C-2 to C-5 to be similar in the Embodiment C-1 the method preparation of using, remove last hydrolysing step for crude product is dissolved in dimethyl sulfoxide (DMSO) (75mq/mL) and the 6N oxyhydroxide (1mL), and in the microwave synthesizer 150 ℃ heated 10 minutes beyond.
Figure A20048001673600811
Embodiment C-6
1-{4-[2-(4 '-methoxyl group-1,1 '-biphenyl-4-yl) oxyethyl group] benzyl } cyclobutane-carboxylic acid
Figure A20048001673600812
To 1-{4-[2-(4 '-methoxyl group-1,1 '-biphenyl-4-yl) oxyethyl group] benzyl add 1N sodium hydroxide solution (7.2mL, 8 equivalents) in cyclobutane carboxylate's's (preparation 14) (0.3921mmol, 1 equivalent) the acetonitrile solution (2mL).The gained mixture in Personal Chemistry Smith synthesizer with microwave heating (100 ℃) 40 minutes.After the reaction mixture cooling, add 1M hydrochloric acid until pH 1.With mixture with ethyl acetate extraction (3 * 50mL).The organic extract that merges with saturated sodium-chloride water solution (100mL) washing, drying (anhydrous magnesium sulfate), filtration and vacuum concentration get crude product then.Residue is ground purifying with ether get title compound (0.1321g, 81%), be white crystalline solid.
Ultimate analysis: C 27H 28O 4Calculated value C77.86, H6.78.Measured value: C77.65, H6.85.
LRMS(m/z)：416(M) -。
1H NMR (acetone-d 6, 300MHz): 7.53 (2H, d, J=6.1Hz), 7.66 (2H, d, J=5.1Hz), 7.46 (2H, d, J=8.5Hz), 7.13 (2H, d, J=8.7Hz), 7.07 (2H, d, J=8.7Hz), 6.85 (2H, d, J=8.5Hz), 4.20 (1H, t, J=6.1Hz), 3.86 (3H, s), 3.10 (2H, t, J=7.0Hz), 3.00 (2H, s), 2.40-2.30 (2H, m), and 2.07-1.98 (2H, m), 1.92-1.80 (2H, m).
Embodiment C-7 is to C-93
Embodiment C-7 to C-93 being similar in the Embodiment C-6 the method preparation of using, or under 20 ℃～75 ℃ temperature, stir in methanol aqueous solution, aqueous ethanolic solution, tetrahydrofuran aqueous solution or its mixture of ester and sodium hydroxide or lithium hydroxide.
Figure A20048001673600821
Figure A20048001673600831
Figure A20048001673600851
Figure A20048001673600861
Figure A20048001673600871
Figure A20048001673600881
Figure A20048001673600891
Figure A20048001673600921
Figure A20048001673600931
Figure A20048001673600941
Other preparation method of 2-({ 6-[2-(5-methyl-2-phenyl-1,3-oxazole-4-yl) oxyethyl group] pyridin-3-yl } methyl) tetrahydrofuran (THF)-2-carboxylic acid enantiomorph (Embodiment C-48a and C-48b)
Embodiment C-48a
The enantiomorph 1 of 2-({ 6-[2-(5-methyl-2-phenyl-1,3-oxazole-4-yl) oxyethyl group] pyridin-3-yl } methyl) tetrahydrofuran (THF)-2-carboxylic acid
Figure A20048001673600971
With lithium hydroxide monohydrate (993mg, 21.1mmol) join (4S)-4-benzyl-3-{[2-({ 6-[2-(5-methyl-2-phenyl-1,3-oxazole-4-yl) oxyethyl group] pyridin-3-yl } methyl) tetrahydrofuran (THF)-2-yl] carbonyl }-1,3-oxazolidine-2-ketone (600mg, 1.06mmol) tetrahydrofuran (THF): methyl alcohol: water (1: 1: 1,12mL) in the mixing solutions.Mixture was stirred 4.5 hours down at 50 ℃, be chilled to room temperature then, stirred 2 days.Evaporative removal volatile component, residue be with water (5mL) dilution, with 1: 1 hexane: extracted with diethyl ether.With aqueous phase as acidified to pH 5, with ethyl acetate extraction.Organic phase is with salt brine solution washing, dried over mgso, filtration and concentrated.Residue is with 2 (95: 4: 1 methylene dichloride: methyl alcohol: ammonium hydroxide), obtain the title compound (72mg) of colorless oil of rapid column chromatography purifying.
LRMS(m/z)：409(M+H) +。
1H NMR(CDCl 3，300MHz)7.99-7.94(3H，m)，7.49(1H，dd，J＝2.4，8.6Hz)，7.44-7.36(3H，m)，6.63(1H，d，J＝8.5Hz)，4.50(2H，t，J＝6.7Hz)，4.00-3.93(1H，m)，3.89-3.81(1H，m)，3.14(1H，d，J＝14.1Hz)，2.95(2H，t，J＝6.7Hz)，2.85(1H，d，J＝14.1Hz)，2.31(3H，s)，1.99-1.73(4H，m)。
Embodiment C-48b
The enantiomorph 2 of 2-({ 6-[2-(5-methyl-2-phenyl-1,3-oxazole-4-yl) oxyethyl group] pyridin-3-yl } methyl) tetrahydrofuran (THF)-2-carboxylic acid
Enantiomorph 2 uses the reaction method preparation that is similar to described in the enantiomorph 1, and except with (4R)-4-benzyl-1,3-oxazolidine-2-ketone is beyond the starting raw material.
Embodiment C-94
1-{6-[2-(5-methyl-2-phenyl-oxazoles-4-yl)-oxyethyl group]-the pyridin-3-yl methyl }-cyclopropane-carboxylic acid
Figure A20048001673600981
To 1-{6-[2-(5-methyl-2-phenyl-oxazole-4-yl)-oxyethyl group]-the pyridin-3-yl methyl }-cyclopropane carboxylic acid tert-butyl acrylate (adding trifluoroacetic acid (1.2mL) among the 0.2017g, methyl-phenoxide solution (1.2mL) 0.4642mmol).Gained solution at room temperature stirred 3 hours, then at concentrating under reduced pressure.Crude product adds saturated sodium hydrogen carbonate solution then and alkalizes to pH 5-6 with ethyl acetate (25mL) and water (10mL) dilution.Separate two-phase, water layer is with ethyl acetate extraction (3 * 25mL).The dry then organic extract (anhydrous magnesium sulfate) that merges, filtration and vacuum concentration get crude product.With the ether/hexane recrystallization, obtain pure acid (0.071g, 40%), be white solid.
LRMS(m/z)：379(M+H) +。
1H NMR(MeOD，300MHz)：7.89-7.83(3H，m)，7.53(1H，dd，J＝8.5，1.9Hz)，7.37-7.35(3H，m)，6.60(1H，d，J＝8.5Hz)，4.39(2H，t，J＝6.5Hz)，2.87(2H，t，J＝6.4Hz)，2.73(2H，s)，2.23(3H，s)，1.14-1.11(2H，m)，0.77-0.74(2H，m)。
Embodiment C-95
2-[2-(5-methyl-2-phenyl-oxazoles-4-yl)-oxyethyl group]-5-[2-(1H-tetrazolium-5-yl)-tetrahydrochysene-furans-2-ylmethyl]-pyridine
Figure A20048001673600982
With 2-{6-[2-(5-methyl-2-phenyl-oxazoles-4-yl)-oxyethyl group]-the pyridin-3-yl methyl }-tetrahydrofuran (THF)-2-nitrile (0.11g, 0.27mmol), sodiumazide (0.04g, 0.54mmol) and zinc bromide (0.03g, 0.14mmol) water: (1: 2,1.24mL) solution refluxed 23 hours Virahol.After being chilled to room temperature, reaction stops with 3N hydrochloric acid (0.14mL) and ethyl acetate (2.8mL), and mixture is stirred to fully evenly.(3 * 50mL), the merging organic extract gets crude product with water (30mL) washing, dry (anhydrous magnesium sulfate), filtration and vacuum concentration to water with ethyl acetate extraction.Product obtains title compound (0.052g, 44%) with the ether/hexane recrystallization, is white solid.
Ultimate analysis: C 22H 23N 7O 3Calculated value C60.96, H5.35, N22.62.Measured value: C63.50, H5.62, N18.80.
1H NMR(CDCl 3，300MHz)：δ7.93(2H，m)，7.86(1H，s)，7.40(3H，m)，7.11(1H，d，J＝1.7Hz)，6.49(1H，d，J＝8.5Hz)，4.42(2H，t，J＝6.6Hz)，3.88(2H，m)，3.12(2H，m)，2.92(2H，t，J＝6.5Hz)，2.62(1H，m)，2.31(3H，s)，2.23(1H，m)，1.89(2H，m)。
LRMS(m/z)：433(M+H) +。
Embodiment C-1 is to the preparation (preparation c-1 to c-130) of the starting raw material of C-95
Preparation c-1
4-[2-(5-methyl-2-phenyl-1,3-oxazole-4-yl) oxyethyl group] phenyl aldehyde
Figure A20048001673600991
Under nitrogen gas stream, to 4-hydroxy benzaldehyde (5.05g, 41.4mmol), 2-(5-methyl-2-phenyl-oxazoles-4-yl)-second-1-alcohol (8.39g, 41.4mmol) and triphenylphosphine (10.9g, 41.4mmol) anhydrous tetrahydrofuran solution (165mL) in drip the diethylazodicarboxylate (7.21g, 41.4mmol).Gained solution at room temperature stirred 8 hours, then with water dilution, ethyl acetate extraction.Dry organic phase (anhydrous magnesium sulfate), filtration and vacuum concentration.With rapid column chromatography (hexane is to ethyl acetate) purifying residue, obtain the title compound (10.2g, 80%) of white crystalline solid then.
LRMS(m/z)：308(M+H)+。
Preparation c-2
1-(hydroxyl 4-[2-(5-methyl-2-phenyl-1,3-oxazole-4-yl) oxyethyl group] and phenyl } methyl) the hexahydrobenzoic acid methyl esters
Figure A20048001673600992
To chromium chloride (II) (1.00g, 8.10mmol) and lithium iodide (0.087g, 0.648mmol) tetrahydrofuran (THF) (20mL) suspension in add 4-[2-(5-methyl-2-phenyl-1,3-oxazole-4-yl) oxyethyl group] phenyl aldehyde (preparation 1) (1.00g, 3.24mmol) and 1-bromine hexahydrobenzoic acid methyl esters (1.07g, 4.85mmol).The heating under 50 ℃ of gained mixture is analyzed demonstration until TLC and is reacted completely.Mixture is cooled to room temperature, adds saturated sodium chloride solution (15mL).The gained mixture was stirred 15 minutes, be allocated in ethyl acetate and aqueous phase then.Organic phase is with water washing and dry (anhydrous magnesium sulfate), filtration and concentrated.Residue obtains the title compound (0.797g, 55%) of colorless oil with rapid column chromatography (hexane to 50% ethyl acetate/hexane) purifying.
LRMS(m/z)：450(M+H) +。
Preparation c-3
1-(hydroxyl 4-[2-(5-methyl-2-phenyl-1,3-oxazole-4-yl) oxyethyl group] and phenyl } methyl) cyclobutane carboxylate
Use is similar to the step described in the preparation c-2, obtains the title compound of colorless oil.
LRMS(m/z)：436(M+H) +。
Preparation c-4
1-[[4-(allyl group) phenyl] (hydroxyl) methyl] cyclopentane carboxylic acid methyl
Under-78 ℃, to cyclopentane carboxylic acid methyl (3.84g, drip in tetrahydrofuran solution 30.0mmol) (30mL) diisopropyl amide base lithium solution (15.0mL, the 2M tetrahydrofuran solution, 30.0mmol).Mixture was stirred 2 hours, add then 4-allyloxy phenyl aldehyde (2.12g, 13.1mmol).Mixture is warmed to room temperature, stirs 18 hours.Mixture dilutes with water, ethyl acetate extraction.Organic phase is with saturated sodium-chloride water solution washing, dry (anhydrous magnesium sulfate), filtration and concentrated.Residue obtains the title compound (3.67g, 97%) of colorless oil with rapid column chromatography (hexane to 50% ethyl acetate/hexane) purifying.
LRMS(m/z)：273(M-OH) +。
Preparation c-5
4-[[4-(fourth-3-thiazolinyl oxygen base) phenyl] (hydroxyl) methyl] tetrahydrochysene-2H-pyrans-4-carboxylate methyl ester
To be similar to the step described in the preparation c-4, obtain the title compound of colorless oil.
LRMS(m/z)：273(M-OH) +。
Preparation c-6
1-[[4-(allyloxy) phenyl] (hydroxyl) methyl] cyclobutane carboxylate
Figure A20048001673601011
To be similar to the step described in the preparation c-4, obtain the title compound of colorless oil.
LRMS(m/z)：289(M)+。
1H NMR(CDCl 3，300MHz)7.22(2H，d，J＝8.5Hz)，6.85(2H，d，J＝8.7Hz)，6.10-5.98(1H，m)，5.39(1H，ddd，J＝1.5，3.2，17.3Hz)，5.27(1H，ddd，J＝1.5，2.8，10.4Hz)，4.85(1H，d，J＝6.4Hz)，4.51(2H，dt，J＝1.5，5.3Hz)，4.13(2H，dq，J＝0.9，7.2Hz)，3.12(1H，d，J＝6.6Hz)，2.84-2.78(1H，m)，2.64-2.58(1H，m)，2.35-2.29(2H，m)，1.89-1.83(1H，m)，1.72-1.66(1H，m)，1.19(3H，t，J＝7.0Hz)。
Preparation c-7
1-(4-hydroxybenzyl) cyclopentane carboxylic acid methyl
At room temperature, with triethyl-silicane (10.0mL, 63mmol) be added to 1-[[4-(allyloxy) phenyl] (hydroxyl) methyl] (3.66g is in methylene dichloride 12.6mmol) (30mL) and trifluoroacetic acid (30mL) solution for cyclopentane carboxylic acid methyl (preparation c-4).The gained mixture was stirred 1 hour vacuum concentration, and and methylbenzene azeotropic then.Residue is dissolved in tetrahydrofuran (THF) (32mL), add morpholine (3.62mL, 41.6mmol) and tetrakis triphenylphosphine palladium (0) (1.46g, 1.26mmol).The gained mixture at room temperature stirred 18 hours, filtered and was concentrated into dried with Celite.Residue is dissolved in ethyl acetate,, washs with saturated sodium bicarbonate solution again with 1N salt acid elution.Dry organic phase (anhydrous magnesium sulfate), filtration also concentrate, and residue obtains the title compound (1.75g, 59%) of white crystalline solid with rapid column chromatography (hexane is to ethyl acetate) purifying.
LRMS(m/z)：233(M) -。
Preparation c-8
4-(4-hydroxybenzyl) tetrahydrochysene-2H-pyrans-4-carboxylate methyl ester
Use is similar to the step described in the preparation c-7, obtains the title compound of white crystalline solid.
LRMS(m/z)：249(M) -。
Preparation c-9
1-(4-hydroxybenzyl) cyclobutane carboxylate
Use is similar to the step described in the preparation c-7, obtains the title compound of white crystalline solid.
LRMS(m/z)：234(M) -。
1H NMR(CDCl 3，300MHz)6.97(2H，d，J＝8.5Hz)，6.68(2H，d，J＝8.5Hz)，5.10(1H，bs)，4.10(2H，q，J＝7.2Hz)，3.00(2H，s)，2.44-2.35(2H，m)，2.07-1.99(2H，m)，1.91-1.80(2H，m)，1.20(3H，t，J＝7.2Hz)。
Preparation c-10
1-{4-[2-(5-methyl-2-phenyl-1,3-oxazole-4-yl) oxyethyl group] the benzyl cyclopentane carboxylic acid methyl
Figure A20048001673601023
Use is similar to the step described in the preparation c-1 to c-7, obtains the title compound of colorless oil.
LRMS(m/z)：249(M) -。
Preparation c-11
1-{4-[3-(5-methyl-2-phenyl-1,3-oxazole-4-yl) propoxy-] benzyl } cyclopentane carboxylic acid methyl
Figure A20048001673601024
Use is similar to the step described in the preparation c-1 to c-7, obtains the title compound of colorless oil.
LRMS(m/z)：434(M+H) +。
Preparation c-12
4-{4-[2-(5-methyl-2-phenyl-1,3-oxazole-4-yl) oxyethyl group] benzyl } tetrahydrochysene-2H-pyrans-4-carboxylate methyl ester
Figure A20048001673601031
Use is similar to the step described in the preparation c-1 to c-7, obtains the title compound of colorless oil.
LRMS(m/z)：436(M+H) +。
Preparation c-13
1-{4-[2-(4-bromophenyl) oxyethyl group] benzyl } cyclobutane carboxylate
Use is similar to the step described in the preparation c-1 to c-7, obtains the title compound of colorless oil.
LRMS(m/z)：417(M) +。
1H NMR(CDCl 3，300MHz)7.36(2H，d，J＝8.3Hz)，7.08(2H，d，J＝8.3Hz)，6.96(2H，d，J＝8.7Hz)，6.70(2H，d，J＝8.7Hz)，4.04(2H，t，J＝6.8Hz)，4.03(2H，q，J＝7.2Hz)，2.95(2H，t，J＝6.8Hz)，2.94(2H，s)，2.37-2.27(2H，m)，2.00-1.91(2H，m)，1.84-1.73(2H，m)，1.14(3H，t，J＝7.2Hz)。
Preparation c-14 to c-35
Preparing c-14 to c-35 uses to be similar to and prepares the method for using among the c-1.
Figure A20048001673601061
Figure A20048001673601071
Preparation c-36
1-{4-[2-(4 '-methoxyl group-1,1 '-biphenyl-4-yl) oxyethyl group] benzyl } cyclobutane carboxylate
Figure A20048001673601081
Under nitrogen gas stream, to 1-{4-[2-(4-bromophenyl) oxyethyl group] benzyl } cyclobutane carboxylate (preparation c-13) (0.25g, 0.5990mmol), tetrakis triphenylphosphine palladium (0) (0.1252g, 0.6589mmol), add the ethanolic soln (0.4mL) of boric acid (0.8640mmol, 1.1 equivalents) in the solution of benzene (1.6mL) and 2M aqueous sodium carbonate (0.8mL).With the degassing of gained mixture, reflux is 16 hours then, is chilled to room temperature again.Drip 30% aqueous hydrogen peroxide solution (0.04mL) then, gained solution at room temperature stirred 1 hour.(3 * 100mL), the merging organic extract gets crude product with saturated sodium-chloride water solution (100mL) washing, dry (anhydrous magnesium sulfate), filtration and vacuum concentration with ethyl acetate extraction solution then.Residue obtains the pure products of colorless oil with rapid column chromatography (hexane to 40% ethyl acetate/hexane) purifying.
LRMS(m/z)：462(M+H 2O) +。
1H NMR(CDCl 3，300MHz)7.51(2H，d，J＝5.7Hz)，7.49(2H，d，J＝4.7Hz)，7.32(2H，d，J＝8.1Hz)，7.03(2H，d，J＝8.5Hz)，6.97(2H，d，J＝8.9Hz)，6.80(2H，d，J＝8.5Hz)，4.15(1H，t，J＝7.2Hz)，4.10(2H，q，J＝7.2Hz)，3.84(3H，s)，3.10(2H，t，J＝7.1Hz)，3.01(2H，s)，2.43-2.34(2H，m)，2.07-1.98(2H，m)，1.90-1.80(2H，m)，1.20(3H，t，J＝7.2Hz)。
Preparation c-37 to c-43
Preparing c-37 to c-43 uses to be similar to and prepares the method for using among the c-36.
Figure A20048001673601101
Preparation c-44
4-{4-[(5-methyl-2-phenyl-1,3-oxazole-4-yl) methoxyl group] benzyl } tetrahydrochysene-2H-pyrans-4-carboxylate methyl ester
Figure A20048001673601102
With 4-(4-hydroxybenzyl) tetrahydrochysene-2H-pyrans-4-carboxylate methyl ester (preparation c-8) (0.500g, 2.0mmol), cesium carbonate (1.96g, 6.0mmol) and muriate (0.458g, acetonitrile solution 2.2mmol) be 140 ℃ of heating 10 minutes down in the microwave synthesizer.Cooling mixture, filtration and concentrated filtrate.Residue obtains the title compound (0.827g, 98%) of white crystalline solid with rapid column chromatography (hexane is to ethyl acetate) purifying.
LRMS(m/z)：422(M+H) +。
Preparation c-45
5-bromo-2-[2-(5-methyl-2-phenyl-1,3-oxazole-4-yl) oxyethyl group] pyridine
Figure A20048001673601103
Under nitrogen gas stream, to 2, and 5-two bromo-pyridines (5g, 21.1060mmol) and 2-(5-methyl-2-phenyl-oxazole-4-yl)-ethanol (5.1472g, 25.3271mmol) anhydrous tetrahydrofuran solution (85mL) in add potassium tert.-butoxide (2.8422g, 25.3271mmol).With gained mixture reflux 16 hours, be chilled to room temperature then.Mixture is concentrated into 20mL, is allocated in saturated ammonium chloride (50mL) and the ethyl acetate (50mL).Separate two-phase, water layer is with ethyl acetate extraction (2 * 50mL).Then with water (2 * 50mL), the organic extract that merges of saturated sodium-chloride water solution (50mL) washing, dry (anhydrous magnesium sulfate), filter and vacuum concentration gets crude product.Residue obtains white crystalline solid (6.3g, 83%) with rapid column chromatography (hexane to 20% ethyl acetate/hexane) purifying.
LRMS(m/z)：359(M) +.
1H NMR(CDCl 3，400MHz)8.17(1H，d，J＝2.0Hz)，7.96(2H，dd，J＝2.0，8.1Hz)，7.61(1H，dd，J＝2.7，8.7Hz)，7.43-7.38(3H，m)，6.62(1H，d，J＝8.6Hz)，4.52(2H，t，J＝6.8Hz)，2.96(2H，t，J＝6.8Hz)，2.32(3H，s)。
Preparation c-46 to c-47
Preparation c-46 to c-47 uses the ordinary method of preparation c-45.
Figure A20048001673601111
Preparation c-48
6-[2-(5-methyl-2-phenyl-1,3-oxazole-4-yl) oxyethyl group] nicotine aldehyde
Under nitrogen gas stream, with 45 fens clockwise butyllithium (27.4mL, 1.6M hexane solution, 43.8199mmol) anhydrous tetrahydrofuran solution (200mL) in add 5-bromo-2-[2-(5-methyl-2-phenyl-1,3-oxazole-4-yl) oxyethyl group] pyridine (preparation c-45) (14.31g, the solution of anhydrous tetrahydro furan 39.8363mmol) (170mL) and anhydrous diethyl ether (170mL).In this solution, drip anhydrous N then, dinethylformamide (5.7mL), mixture stirred 1 hour down at 0 ℃.Add saturated ammonium chloride (250mL) termination reaction, add ethyl acetate (250mL) then.With the gained two separate, water layer is with ethyl acetate extraction (2 * 250mL).Merge organic extract, with water (2 * 250mL), saturated sodium-chloride (250mL) washing, dry (anhydrous magnesium sulfate), filter and vacuum concentration gets crude product.Residue obtains light yellow crystalline solid (7.17g, 58%) with rapid column chromatography (hexane to 50% ethyl acetate/hexane) purifying.
LRMS(m/z)：309(M+H) +。
1H NMR(CDCl 3，300MHz)9.93(1H，s)，8.61(1H，d，J＝2.3Hz)，8.04(1H，dd，J＝2.5，8.7Hz)，7.98-7.95(2H，m)，7.43-7.39(3H，m)，6.81(1H，d，J＝8.7Hz)，4.68(2H，t，J＝6.8Hz)，3.00(2H，t，J＝6.8Hz)，2.34(3H，s)。
Preparation c-49
1-(hydroxyl 6-[2-(5-methyl-2-phenyl-1,3-oxazole-4-yl) oxyethyl group] and pyridin-3-yl } methyl) cyclobutane carboxylate
Under nitrogen gas stream, to 6-[2-(5-methyl-2-phenyl-1,3-oxazole-4-yl) oxyethyl group] nicotine aldehyde (preparation c-48) (0.65g, 2.1081mmol), chromium chloride (II) (1g, 8.1367mmol) and lithium iodide (0.0784g, 0.5859mmol) anhydrous tetrahydrofuran solution (15mL) in drip 1-bromo-cyclobutane carboxylate (0.79mL, anhydrous tetrahydrofuran solution 4.8821mmol) (5mL).The gained mixture was stirred 3 hours down at 50 ℃, be chilled to room temperature.Add entry (50mL) termination reaction then, separate organic layer, with water (2 * 50mL), saturated sodium-chloride water solution (50mL) washing, dry (anhydrous magnesium sulfate), filter and vacuum concentration gets crude product.Residue obtains yellow oil (0.3422g, 37%) with rapid column chromatography (50% ethyl acetate/hexane is to ethyl acetate) purifying.
LRMS(m/z)：437(M+H) +。
1H NMR(CDCl 3，400MHz)8.05(1H，d，J＝2.3Hz)，7.98-7.95(2H，m)，7.56(1H，dd，J＝2.5，8.7Hz)，7.44-7.37(3H，m)，6.67(1H，d，J＝8.7Hz)，4.85(1H，d，J＝6.6Hz)，4.54(2H，t，J＝6.6Hz)，4.18-4.07(2H，m)，3.31(1H，bs)，2.96(2H，t，J＝6.7Hz)，2.46-2.30(2H，m)，2.32(3H，s)，2.21-2.12(1H，m)，1.97-1.85(1H，m)，1.79-1.65(2H，m)，1.21(3H，t，J＝7.2Hz)。
Preparation c-50
1-(oxyethyl group-6-[2-(5-methyl-2-phenyl-oxazoles-4-yl)-oxyethyl group]-pyridin-3-yl }-methyl) cyclobutane carboxylate
To 1-(hydroxyl-{ 6-[2-(5-methyl-2-phenyl-oxazoles-4-yl)-oxyethyl group]-pyridin-3-yl }-methyl)-cyclobutane carboxylate (0.1711g, 0.3920mmol) anhydrous acetonitrile (2mL) in add silver suboxide (I) (1.8168g, 7.8396mmol) and iodoethane (0.64mL, 7.8396mmol).The gained mixture was stirred 5 days, and concentrating under reduced pressure gets crude product, reclaims starting raw material.Residue obtains the pure ester (0.0474g, 26%) of colorless oil with rapid column chromatography (hexane is to ethyl acetate) purifying.
LRMS(m/z)：465(M+H) +。
1H NMR(CDCl 3，400MHz)：8.05(1H，d，J＝2.3Hz)，7.98-7.95(2H，m)，7.56(1H，dd，J＝2.5，8.7Hz)，7.44-7.37(3H，m)，6.67(1H，d，J＝8.7Hz)，4.65(1H，m)，4.54(2H，t，J＝6.6Hz)，4.18-4.07(2H，m)，4.06(2H，q，J＝7.1Hz)，2.96(2H，t，J＝6.7Hz)，2.46-2.30(2H，m)，2.32(3H，s)，2.21-2.12(1H，m)，1.97-1.85(1H，m)，1.79-1.65(2H，m)，1.42(3H，t，J＝7.1Hz)，1.21(3H，t，J＝7.2Hz)。
Preparation c-51
6-[2-(5-methyl-2-phenyl-1,3-oxazole-4-yl) oxyethyl group] and pyridin-3-yl } methyl alcohol
Figure A20048001673601132
At room temperature, with sodium borohydride (0.480g, 12.7mmol) gradation is added to 6-[2-(5-methyl-2-phenyl-1,3-oxazole-4-yl) oxyethyl group] (1.30g is in methanol solution 4.22mmol) (40mL) for nicotine aldehyde (preparation c-48).The mixture stirring was concentrated after 30 minutes.Residue is allocated in saturated ammonium chloride and the ethyl acetate.Organic phase with saturated sodium-chloride water solution washing, dry (anhydrous magnesium sulfate), filter and concentrate the title compound (1.24g, 100%) of white crystalline solid.
LRMS(m/z)：311(M+H) +。
1H NMR(CDCl 3，300MHz)8.11(1H，d，J＝2.6Hz)，8.00-7.95(2H，m)，7.60(1H，dd，J＝2.5，8.5Hz)，7.45-7.38(3H，m)，6.72(1H，d，J＝8.5Hz)，4.61(2H，bs)，4.56(2H，t，J＝6.8Hz)，2.98(2H，t，J＝6.8Hz)，2.33(3H，s)。
Preparation c-52
2-[2-(5-methyl-2-phenyl-oxazoles-4-yl)-oxyethyl group]-pyrimidine-5-yl } methyl alcohol
With 5-bromo-2-[2-(5-methyl-2-phenyl-oxazoles-4-yl)-oxyethyl group]-pyrimidine (1.0g, 2.7765mmol), the tertiary butyl-dimethyl-tributyl stannane ylmethoxy-silicomethane (1.8g, 4.1648mmol) and tetrakis triphenylphosphine palladium (0) (0.3209g, 0.2777mmol) 1,4-dioxane solution (2.8mL) is 150 ℃ of down heating (with microwave irradiation) 2 hours.After gained solution is chilled to room temperature, add saturated potassium fluoride solution (10mL), stirred 30 minutes.Then with this mixture of ethyl acetate extraction (3 * 25mL), merge organic extract, dry (anhydrous magnesium sulfate), filter and vacuum concentration gets the crude product of yellow oily.In the anhydrous tetrahydrofuran solution (24mL) of crude product, add tetrabutylammonium (3.1mL, 1.0M tetrahydrofuran solution).The gained mixture was at room temperature stirred 16 hours concentrating under reduced pressure.Residue obtains the pure alcohol (0.6137g, 2 steps 71%) of white solid with rapid column chromatography (50% ethyl acetate/hexane to 10% methanol/ethyl acetate) purifying.
LRMS(m/z)：312(M+H) +。
Preparation c-53
5-benzyloxy-2-methyl-pyridine
Figure A20048001673601142
To 5-hydroxy-2-methyl pyridine (20g, 183.2677mmol) and sodium hydroxide (8.0638g, add in acetone 201.5944mmol) (400mL) and water (120mL) solution bromotoluene (24mL, 201.5944mmol).With gained mixture reflux 16 hours, be chilled to room temperature.Vacuum is removed acetone, again with ethyl acetate extraction mixture (3 * 150mL).Merge organic extract, get orange buttery pure products (31.35g, 86%) with saturated sodium-chloride water solution (200mL) washing, dry (anhydrous magnesium sulfate), filtration and vacuum concentration.
LRMS(m/z)：200(M+H) +。
1H NMR(CDCl 3，300MHz)：8.25(1H，d，J＝2.8Hz)，7.43-7.31(5H，m)，7.15(1H，dd，J＝8.5，2.8Hz)，7.04(1H，d，J＝8.5Hz)，5.06(2H，s)，2.47(3H，s)。
Preparation c-54
5-benzyloxy-2-methyl-pyridine 1-oxide compound
Figure A20048001673601151
At room temperature, to 5-benzyloxy-2-methyl-pyridine (31.35g, add in the anhydrous chloroform solution (800mL) 157.34mmol) 3-chloroperoxybenzoic acid (peak concentration 77%) (38.7888g, 173.074mmol).The gained mixture was stirred 2 hours, and (36.0805g, aqueous solution 286.5mmol) (500mL) termination reaction stirred 15 minutes with Sulfothiorine then.Separating obtained two-phase gets crude product with organic phase with water (500mL), saturated sodium-chloride water solution (500mL) washing, dry (anhydrous magnesium sulfate), filtration and vacuum concentration.Residue obtains pure products (33.1597g, 97%) with the acetone/hexane recrystallization, is white solid.
LRMS(m/z)：216(M+H) +。
1H NMR(CDCl 3，300MHz)：8.10-8.09(1H，bm)，7.38-7.34(5H，m)，7.10(1H，d，J＝8.7Hz)，6.87(1H，dd，J＝8.7，2.3Hz)，5.04(2H，s)，2.43(3H，s)。
Preparation c-55
(5-benzyloxy-pyridine-2-yl)-methyl alcohol
Under 100 ℃, with 5-benzyloxy-2-methyl-pyridine 1-oxide compound (0.92g, solution of acetic anhydride 4.2741mmol) (6.5mL) heating 30 minutes.After being chilled to room temperature, reaction mixture is poured in the ethyl acetate (50mL), got the crude acetic acid ester with saturated sodium bicarbonate solution (50mL), saturated sodium-chloride water solution (50mL) washing, dry (anhydrous magnesium sulfate), filtration and vacuum concentration.
(2.1784g, 15.7719mmol), stirred solution is 16 hours under the room temperature to add salt of wormwood in the methanol solution (45mL) of rough residue.Reaction mixture is poured in the water (50mL), and organism is removed in decompression.The gained residue with ethyl acetate extraction (3 * 50mL), merge organic extract, dry (anhydrous magnesium sulfate), filter and vacuum concentration gets crude product.Residue obtains the white solid (0.5719g, two steps 62%) of pure alcohol with rapid column chromatography (hexane to 20% methanol/ethyl acetate) purifying.
LRMS(m/z)：216(M+H) +。
1H NMR(CDCl 3，300MHz)：8.31(1H，d，J＝2.8Hz)，7.44-7.31(5H，m)，7.27(1H，dd，J＝8.7，2.8Hz)，7.17(1H，d，J＝8.5Hz)，5.11(2H，s)，4.69(2H，s)。
Preparation c-56
2-methyl-5-[2-(5-methyl-2-phenyl-oxazoles-4-yl)-oxyethyl group]-pyridine 1-oxide compound
At room temperature, to 2-methyl-5-[2-(5-methyl-2-phenyl-oxazoles-4-yl)-oxyethyl group]-pyridine (6.7973g, 23.0917mmol) anhydrous chloroform solution (140mL) in add 3-chloroperoxybenzoic acid (peak concentration 77%) (7.7629g, 34.6376mmol).The gained mixture was stirred 2 hours, then with Sulfothiorine (4.3621g, the 34.6376mmol) aqueous solution (25mL) termination reaction, restir 15 minutes.Separating obtained two-phase, organic layer gets crude product with water (50mL), saturated sodium-chloride water solution (50mL) washing, dry (anhydrous magnesium sulfate), filtration and vacuum concentration.This light yellow oil crude product (7.0689g, 98%) need not to be further purified direct use.
LRMS(m/z)：311(M+H) +。
1H NMR(CDCl 3，300MHz)：8.06(1H，d，J＝2.3Hz)，7.96-7.93(2H，m)，7.41-7.39(3H，m)，7.10(1H，d，J＝8.9Hz)，6.85(1H，dd，J＝8.8，2.4Hz)，4.23(2H，t，J＝6.6Hz)，2.95(2H，t，J＝6.6Hz)，2.43(3H，s)，2.35(3H，s)。
Preparation c-57
5-[2-(5-methyl-2-phenyl-oxazoles-4-yl)-oxyethyl group]-pyridine-2-yl }-methyl alcohol
Under 100 ℃, with 2-methyl-5-[2-(5-methyl-2-phenyl-oxazoles-4-yl)-oxyethyl group]-pyridine 1-oxide compound (3.5979g, solution of acetic anhydride 11.5181mmol) (17.5mL) heating 30 minutes.After being chilled to room temperature, reaction mixture is poured in the ethyl acetate (150mL), got the crude acetic acid ester with saturated sodium bicarbonate solution (150mL), saturated sodium-chloride water solution (150mL) washing, dry (anhydrous magnesium sulfate), filtration and vacuum concentration.(5.8705g 42.617mmol), at room temperature stirred this solution 16 hours to add salt of wormwood to the methanol solution (120mL) of rough residue.Reaction mixture is poured in the water (150mL), and organism is removed in decompression.With the gained residue with ethyl acetate extraction (3 * 150mL), merge organic extract, dry (anhydrous magnesium sulfate), filter and vacuum concentration gets crude product.Residue obtains the pure alcohol of light yellow low melting point solid (1.52g, 43%, two step) with rapid column chromatography (ethyl acetate to 10% methanol/ethyl acetate) purifying.
LRMS(m/z)：311(M+H) +。
1H NMR(CDCl 3，300MHz)：8.22(1H，d，J＝2.5Hz)，7.97-7.94(2H，m)，7.42-7.38(3H，m)，7.20(1H，dd，J＝8.5，2.6Hz)，7.15(1H，d，J＝8.7Hz)，4.67(2H，s)，4.28(2H，t，J＝6.7Hz)，2.98(2H，t，J＝6.7Hz)，2.37(3H，s)。
Preparation c-58
5-(chloromethyl)-2-[2-(5-methyl-2-phenyl-1,3-oxazole-4-yl) oxyethyl group] pyridine
Under 0 ℃, (0.30mL 3.44mmol) is added to { 6-[2-(5-methyl-2-phenyl-1,3-oxazole-4-yl) oxyethyl group] pyridin-3-yl } methyl alcohol (preparation 26) (0.97g with oxalyl chloride, 3.13mmol) methylene dichloride (30mL) and N, in dinethylformamide (3mL) solution.Mixture is chilled to room temperature, stirs after 1 hour concentrated.Residue is allocated in saturated sodium bicarbonate solution and ethyl acetate.Organic phase with saturated sodium-chloride water solution washing, dry (anhydrous magnesium sulfate), filter and concentrate the title compound (1.01g, 100%) of white crystalline solid.
LRMS(m/z)：329(M+H) +。
1H NMR(CDCl 3，300MHz)8.12(1H，d，J＝2.5Hz)，7.98-7.95(2H，m)，7.60(1H，dd，J＝2.5，8.5Hz)，7.45-7.37(3H，m)，6.72(1H，d，J＝8.5Hz)，4.57(2H，t，J＝6.8Hz)，4.53(2H，s)，2.97(2H，t，J＝6.8Hz)，2.33(3H，s)。
Preparation c-59 to c-63
Preparation c-59 to c-63 uses the ordinary method of preparation c-58 to be prepared.
Preparation c-64
5-(iodomethyl)-2-[2-(5-methyl-2-phenyl-1,3-oxazole-4-yl) oxyethyl group] pyridine
Figure A20048001673601182
Sodium iodide (0.750g) is added to 5-(chloromethyl)-2-[2-(5-methyl-2-phenyl-1,3-oxazole-4-yl) oxyethyl group] pyridine (preparation 27) (0.690g, 2.10mmol) acetone soln (5mL) in, with mixture reflux 30 minutes, cooling and concentrate.Residue is suspended in the ethyl acetate, filters with silicagel pad.With filtrate concentrate yellow crystal solid title compound, be directly used in subsequent reactions.
LRMS(m/z)：421(M+H) +。
Preparation c-65 to c-69
Preparation c-65 to c-69 uses the ordinary method of preparation c-64 to be prepared.
Figure A20048001673601191
Preparation c-70
1-(6-[2-(5-methyl-2-phenyl-1,3-oxazole-4-yl) oxyethyl group] and pyridin-3-yl } methyl) cyclobutane carboxylate
Under-60 ℃, ((0.41mL is in anhydrous tetrahydrofuran solution 3.0mmol) (5mL) 3.0mmol) to be added dropwise to the cyclobutane carboxylate for 3.0mL, 1M tetrahydrofuran solution with (two) trimethyl silyl amido sodium.After mixture stirred 1 hour, Dropwise 5-(iodomethyl)-2-[2-(5-methyl-2-phenyl-1,3-oxazole-4-yl) oxyethyl group] pyridine (preparation 28) (0.271g, anhydrous tetrahydrofuran solution 0.64mmol) (4mL).The gained mixture was stirred 1 hour down at-60 ℃,, be warmed to room temperature then with the saturated aqueous ammonium chloride termination reaction.With mixture with ethyl acetate extraction, dry organic phase (anhydrous magnesium sulfate), filter and concentrate title compound and dimeric 1: 1 mixture (0.160g), it is directly use in subsequent step.
LRMS(m/z)：421(M+H) +。
Preparation c-71
2-(6-[2-(5-methyl-2-phenyl-1,3-oxazole-4-yl) oxyethyl group] and pyridin-3-yl } methyl) tetrahydrofuran (THF)-2-carboxylic acid ethyl ester
Figure A20048001673601201
Under-50 ℃, ((0.458g is in anhydrous tetrahydrofuran solution 3.18mmol) (4mL) 3.18mmol) to be added dropwise to 2-tetrahydrofuran formic acid ethyl ester for 3.18mL, 1M tetrahydrofuran solution with (two) trimethyl silyl amido sodium.Stirred the mixture 45 minutes, then Dropwise 5-(iodomethyl)-2-[2-(5-methyl-2-phenyl-1,3-oxazole-4-yl) oxyethyl group] pyridine (preparation 28) (0.267g, anhydrous tetrahydrofuran solution 0.64mmol) (2mL).Stir the gained mixture down after 1.5 hours at-50 ℃,, be warmed to room temperature with the saturated aqueous ammonium chloride termination reaction.Mixture is with ethyl acetate extraction, dry organic phase (anhydrous magnesium sulfate), filtration and concentrated.Residue obtains the title compound (0.250g, 90%) of colorless oil with rapid column chromatography (25%～35% ethyl acetate/hexane) purifying.
LRMS(m/z)：437(M+H) +。
1H NMR(CDCl 3，300MHz)7.95(3H，m)，7.51(1H，dd，J＝2.5，8.5Hz)，7.43-7.36(3H，m)，6.61(1H，d，J＝8.5Hz)，4.51(2H，t，J＝6.8Hz)，4.29-4.18(9H，m)，4.13(2H，q，J＝7.2Hz)，3.95-3.82(2H，m)，3.10(1H，d，J＝14.1Hz)，2.95(2H，t，J＝6.8Hz)，2.86(1H，d，J＝14.1Hz)，2.31(3H，s)，2.26-2.20(1H，m)，1.92-1.77(2H，m)，1.70-1.61(1H，m)，1.21(3H，t，J＝7.2Hz)。
Preparation c-72 to c-79
Preparation c-72 to c-79 uses the ordinary method of preparation c-71 to be prepared.
Figure A20048001673601211
Preparation c-80
2-bromo-5-(brooethyl) pyridine
Phosphorus tribromide (100mmol, 27.1g, 2.0 equivalents) is added in the 2-chloro-5-hydroxy-methyl pyridine (50.0mmol, 7.18g, 1.0 equivalents) carefully.Pyridine becomes piece, with mixture heating up to 160 ℃.Stirred 5 minutes down at＞150 ℃, visible mixture color becomes very black, and emits with gas.Mixture is chilled to room temperature at stir about under the same temperature after 2.5 hours.Mixture further is chilled to 0 ℃, carefully adds saturated sodium bicarbonate solution (very exothermic! ).When foam more after a little while, ice is added in the mixture until lather collapse.Carefully add solid sodium bicarbonate then and make pH～8-9.With the ethyl acetate extraction mixture, organic layer washs with salt brine solution, anhydrous magnesium sulfate drying.Vacuum concentration gets black solid.This material is dissolved among the DCM of minimum, uses Biotage Sp4 65i, obtain the title compound (5.57g, 44%) of light yellow solid with 0-100% ethyl acetate/hexane solution gradient purifying.
LRMS：252(M+H) +。
1H NMR(DMSO-d 6，400MHz)：8.39(1H，s)7.59(1H，d，J＝8.5Hz)7.48(1H，d，J＝8.5Hz)4.46(2H，s)
Preparation c-81
2-[(6-bromopyridine-3-yl) methyl] tetrahydrofuran (THF)-2-carboxylic acid, ethyl ester
To the middle heptane/THF/ ethylbenzene mixed solution that drips 2M lithium diisopropyl amido (52.9mmol, 1.5 equivalents) of THF solution (90mL) that is chilled to tetrahydrofuran (THF)-2-carboxylic acid, ethyl ester (52.9mmol, 9.10g, 1.5 equivalents) of-78 ℃.Under same low temperature, form enolate 1 hour, drip the THF solution of 2-bromo-5-(brooethyl) pyridine (35.3mmol, 8.85g, 1.0 equivalents) then.Sluggish is chilled to ambient temperature overnight.With the saturated aqueous ammonium chloride termination reaction.Mixture is with ethyl acetate extraction, and organic extract washs with salt brine solution.Organic layer is with anhydrous magnesium sulfate drying, and vacuum concentration gets yellow oil.This crude product by 5%～95% ethyl acetate/hexane solution gradient purifying, obtains golden oil (8.70g, 78%) with Biotage Sp465i.
LRMS：315(M+H) +。
1H NMR(DMSO-d 6，400MHz)：8.21(1H，s)7.40-7.49(2H，m)3.94(2H，q，J＝7.0Hz)3.71-3.85(2H，m)3.05-3.11(1H，m)2.91-2.97(1H，m)2.38-2.47(1H，m)1.83-2.09(3H，m)1.09(3H，t，J＝7.0Hz)
Preparation c-82
The cyclopropane carboxylic acid tert-butyl acrylate
(3.45mL, (30.1987g is in the methylene dichloride suspension (250mL) 251.1326mmol) 62.7832mmol) to be added to the anhydrous magnesium sulfate of vigorous stirring with the vitriol oil.Stirred the mixture 15 minutes, add cyclopropane-carboxylic acid (5mL, 62.7832mmol) and 2-methyl-propan-2-ol (30mL, 313.9158mmol).Jam-pack mixture bottleneck at room temperature stirred 16 hours.With saturated sodium bicarbonate solution (450mL) termination reaction mixture, stir then until all sal epsom dissolvings.Separate two-phase, organic phase with water (100mL), saturated sodium-chloride water solution (100mL) washing, dry (anhydrous magnesium sulfate), filter and vacuum concentration get colourless liquid pure ester (8.3921g, 59.0162mmol).
1H NMR(CDCl 3，300MHz)：1.45(9H，s)，0.93-0.86(3H，m)，0.79-0.73(2H，m)。
Preparation c-83
1-{6-[2-(5-methyl-2-phenyl-oxazole-4-yl)-oxyethyl group]-the pyridin-3-yl methyl } the cyclopropane carboxylic acid tert-butyl acrylate
Under 0 ℃ and nitrogen gas stream, to Diisopropylamine (add among the 0.14mL, anhydrous tetrahydrofuran solution 0.9518mmol) (2.4mL) butyllithium (0.38mL, the 2.5M hexane solution, 0.9518mmol).With gained solution stirring 30 minutes, be chilled to-50 ℃ then.(0.1269g, anhydrous tetrahydrofuran solution 0.8924mmol) (1mL) continue to stir 2 hours to add the cyclopropane carboxylic acid tert-butyl acrylate.Dropwise 5-iodomethyl-2-[2-(5-methyl-2-phenyl-oxazoles-4-yl)-oxyethyl group then]-pyridine (0.25g, anhydrous tetrahydrofuran solution 0.5949mmol) (1mL), restir solution 3 hours.Add saturated aqueous ammonium chloride (25mL) termination reaction, with ethyl acetate extraction (3 * 25mL).Then organic extract drying (anhydrous magnesium sulfate), filtration and the vacuum concentration that merges got crude product and unreacted raw material iodide.Thick residue obtains light yellow solid ester (0.0827g, 32%) with rapid column chromatography (hexane to 60% ethyl acetate/hexane) purifying, wherein contains the part material iodide.
LRMS(m/z)：435(M+H) +。
Preparation c-84
2-(6-[2-(5-methyl-2-phenyl-1,3-thiazoles-4-yl) oxyethyl group] and pyridin-3-yl } methyl) tetrahydrofuran (THF)-2-carboxylic acid, ethyl ester
In the toluene solution (12mL) of the bromopyridine (0.636mmol) that argon purge is crossed, add acid chloride (II) (11.4mg, 0.0508mmol) and racemization-2-(two-tertiary butyl phosphino-)-1,1 '-dinaphthalene (25.4mg, 0.0636mmol).Formed activated complex in about 10 minutes, (414mg is 1.27mmol) with suitable alcohol (0.956mmol) to add cesium carbonate then.With mixture heating up to 115 ℃, under this temperature, stirred 12-18 hour.Mixture is chilled to room temperature, filters by silicagel pad.Filter bed is associated with machine filter liquid and vacuum concentration with the ethyl acetate washing of 2-3 part.The gained residue is with the flash chromatography purifying, or need not purifying and directly use.
Preparation c-85 to c-88
Preparing c-85 to c-88 uses to be similar to and prepares the method for using among the c-84 and be prepared.
Preparation c-89
The 5-{[tertiary butyl (phenylbenzene) silyl] the oxygen base }-2-(iodomethyl) pyridine
To 2-brooethyl-5-(tertiary butyl-phenylbenzene-silyloxy)-pyridine (Schow, S.R.; QuinnDeJoy, S.; Wick, M.M.; Kerwar, S.S.J.Org.Chem.1994,59,6850-6852) ((0.8922g 5.9526mmol), at room temperature stirred the gained heterogeneous mixture 3 hours to add sodium iodide among the 1.2692g, acetone soln 2.9763mmol) (15mL).With the reaction mixture vacuum concentration, the gained residue is with ethyl acetate (50mL) dilution, water (50mL) washing.Organic layer is again with saturated sodium bicarbonate solution (50mL) and saturated sodium thiosulfate solution (50mL) washing.(3 * 50mL), merging organic extract, drying (anhydrous magnesium sulfate), filtration and vacuum concentration get crude product to combining water layer with ethyl acetate extraction.Residue obtains light yellow oil (0.72g, 51%) with rapid column chromatography (hexane to 20% ethyl acetate/hexane) purifying.Instability when this compound concentrates, thereby directly use.
LRMS(m/z)：474(M+H) +。
Preparation c-90
Tetrahydrofuran (THF)-2-carboxylic acid, ethyl ester
(add the vitriol oil (0.46mL) among the 20g, ethanol solution 172.2356mmol) (100mL) to tetrahydrofuran (THF)-2-carboxylic acid.With gained mixture backflow stirring heating 16 hours, be chilled to room temperature then.Add entry (100mL), with extracted with diethyl ether (3 * 000mL).Merge organic extract, with saturated sodium bicarbonate solution (2 * 50mL), saturated sodium-chloride water solution (100mL) washing, dry (anhydrous magnesium sulfate), filter and vacuum concentration gets the purified product of colourless liquid (22.5964g, 91%).
LRMS(m/z)：145(M+H) +。
1H NMR(CDCl 3，300MHz)4.38(1H，dd，J＝4.9，8.1Hz)，4.14(2H，q，J＝7.2Hz)，3.99-3.92(1H，m)，3.88-3.81(1H，m)，2.24-2.12(1H，m)，2.00-1.79(3H，m)，1.22(3H，t，J＝7.2Hz)。
Preparation c-91
Tetrahydrochysene-pyrans-2-carboxylic acid, ethyl ester
Above-claimed cpd is according to Rychnovsky, S.D.; Hata, T.; Kim, A.I.; Buckmelter, A.J.Org.Lett.2001,3, the described method preparation of 807-810.
Preparation c-92
The 2-[(5-{[tertiary butyl (phenylbenzene) silyl] the oxygen base } pyridine-2-yl) methyl] tetrahydrofuran (THF)-2-carboxylic acid, ethyl ester
Figure A20048001673601263
Under-50 ℃ and nitrogen gas stream, to tetrahydrofuran (THF)-2-carboxylic acid, ethyl ester (preparation 32) (1.0965g, 7.604mmol) anhydrous tetrahydrofuran solution (7mL) in drip two (trimethyl silyl) amido sodium (7.6mL, the 1.0M tetrahydrofuran solution, 7.604mmol).Stirred reaction mixture 1 hour, Dropwise 5-(tertiary butyl-phenylbenzene-siloxy-)-2-iodomethyl-pyridine (preparation 31) (0.72g, anhydrous tetrahydrofuran solution 1.5208mmol) (7mL) then.Gained solution is after stirring 2 hours under-50 ℃, with saturated aqueous ammonium chloride (25mL) termination reaction.Then with this solution of ethyl acetate extraction (3 * 25mL), dry (anhydrous magnesium sulfate), filter and vacuum concentration gets crude product.Residue obtains water white oil (0.2438g, 33%) with rapid column chromatography (hexane to 40% ethyl acetate/hexane) purifying.
LRMS(m/z)：490(M+H) +。
1H NMR(CDCl 3，300MHz)8.07(1H，d，J＝2.5Hz)，7.67-7.63(4H，m)，7.41-7.31(6H，m)，6.97(1H，d，J＝8.5Hz)，6.86(1H，dd，J＝2.8，8.5Hz)，4.21(2H，q，J＝7.2Hz)，4.09(2H，q，J＝7.2Hz)，3.22(1H，d，J＝13.9Hz)，3.07(1H，d，J＝13.9Hz)，2.53-2.44(1H，m)，2.31-2.15(1H，m)，1.82-1.72(1H，m)，1.60-1.46(1H，m)，1.25(3H，t，J＝7.2Hz)，1.09(9H，s)。
Preparation c-93
2-[(5-pyridone-2-yl) methyl] tetrahydrofuran (THF)-2-carboxylic acid, ethyl ester
To the 2-[(5-{[tertiary butyl (phenylbenzene) silyl] the oxygen base } pyridine-2-yl) methyl] tetrahydrofuran (THF)-2-carboxylic acid, ethyl ester (preparation c-92) (0.5118g, 1.1677mmol) anhydrous tetrahydrofuran solution (10mL) in drip tetrabutylammonium (1.3mL, 1.0M tetrahydrofuran solution).The gained mixture at room temperature stirred 1 hour, and vacuum is removed volatile matter.Residue obtains water white oil (0.2321g, 79%) with rapid column chromatography (50% ethyl acetate/hexane to 10% methanol/ethyl acetate) purifying.
LRMS(m/z)：252(M+H) +。
1H NMR(CDCl 3，300MHz)8.10(1H，d，J＝2.3Hz)，7.20(1H，d，J＝8.5Hz)，7.14(1H，dd，J＝2.6，8.5Hz)，4.14(2H，q，J＝7.2Hz)，3.88(2H，q，J＝7.8Hz)，3.35(1H，d，J＝13.9Hz)，3.12(1H，d，J＝13.9Hz)，2.30-2.21(1H，m)，2.04-1.94(1H，m)，1.89-1.76(1H，m)，1.75-1.63(1H，m)，1.20(3H，t，J＝7.2Hz)。
Preparation c-93a
2-[(5-pyridone-2-yl) methyl] the another kind preparation of tetrahydrofuran (THF)-2-carboxylic acid, ethyl ester
To 2-(5-benzyloxy-pyridine-2-ylmethyl)-tetrahydrofuran (THF)-2-carboxylic acid, ethyl ester (0.6065g, add in ethanol solution 1.7765mmol) (10mL) palladium (0.0607g, account for activated carbon weight 10%).The heating 16 hours under 45 ℃ and nitrogen gas stream of gained solution.After being chilled to room temperature, solution is by 3 " the Celite layer filter, wash with ethanol (100mL).Then the filtrate vacuum concentration is got crude product, need not to be further purified direct use.
LRMS(m/z)：252(M+H) +。
1H NMR(CDCl 3，400MHz)：8.10(1H，d，J＝2.3Hz)，7.20(1H，d，J＝8.5Hz)，7.14(1H，dd，J＝2.6，8.5Hz)，4.14(2H，q，J＝7.2Hz)，3.88(2H，q，J＝7.8Hz)，3.35(1H，d，J＝13.9Hz)，3.12(1H，d，J＝13.Hz)，2.30-2.21(1H，m)，2.04-1.94(1H，m)，1.89-1.76(1H，m)，1.75-1.63(1H，m)，1.20(3H，t，J＝7.2Hz)。
Preparation c-94 to c-95
Preparation c-94 to c-95 uses the ordinary method of preparation c-93 to be prepared.
Figure A20048001673601281
Preparation c-96
2-(5-[2-(5-methyl-2-phenyl-1,3-oxazole-4-yl) oxyethyl group] and pyridine-2-yl } methyl) tetrahydrofuran (THF)-2-carboxylic acid, ethyl ester
Figure A20048001673601282
Under nitrogen gas stream, to 2-[(5-pyridone-2-yl) methyl] tetrahydrofuran (THF)-2-carboxylic acid, ethyl ester (preparation c-93) (0.2321g, 0.9237mmol), 2-(5-methyl-2-phenyl-oxazoles-4-yl)-ethanol (0.2065g, 1.0161mmol) and triphenylphosphine (0.3634g, 1.3856mmol) anhydrous tetrahydrofuran solution (10mL) in drip diethylazodicarboxylate (0.22mL, anhydrous tetrahydrofuran solution 1.3856mmol) (1mL).Gained solution at room temperature stirred 16 hours, and vacuum is removed volatile matter.With this residue of rapid column chromatography (hexane to 50% ethyl acetate/hexane) purifying, obtain light yellow oil (0.2618g, 65%) then.
LRMS(m/z)：437(M+H) +。
1H NMR(CDCl 3，300MHz)8.20(AH，d，J＝2.8Hz)，7.99(1H，d，J＝2.5Hz)，7.96(1H，d，J＝1.7Hz)，7.70-7.64(1H，m)，7.49-7.39(2H，m)，7.19(1H，d，J＝8.5Hz)，7.11(1H，dd，J＝3.0，8.5Hz)，4.26(2H，t，J＝6.6Hz)，4.17(2H，q，J＝7.2Hz)，3.95-3.81(2H，m)，3.33(1H，d，J＝13.8Hz)，3.16(1H，d，J＝13.8Hz)，2.98(2H，t，J＝6.6Hz)，2.37(3H，s)，2.34-2.22(1H，m)，2.09-2.00(1H，m)，1.87-1.76(1H，m)，1.72-1.62(1H，m)，1.23(3H，t，J＝7.2Hz)。
Preparation c-97 to c-112
Preparation c-97 to c-112 uses the ordinary method of preparation c-96 to be prepared.
Figure A20048001673601311
Preparation c-113
3-(5-methyl-2-phenyl-oxazoles-4-yl)-propionic aldehyde
Figure A20048001673601321
(1.0g, (9.9213g accounts for SiO to add pyridinium chlorochromate in methylene dichloride 4.6026mmol) (20mL) solution to 3-(5-methyl-2-phenyl-oxazoles-4-yl)-third-1-alcohol 2Weight～20%, 9.2051mmol).Under room temperature and nitrogen gas stream, the gained mixture to be stirred 16 hours, volatile matter is removed in decompression.Residue obtains the pure aldehyde (0.4752g, 48%) of colorless oil with rapid column chromatography (hexane is to ethyl acetate) purifying.
LRMS(m/z)：216(M+H) +。
1H NMR(CDCl 3，300MHz)：9.84(1H，s)，7.96-7.93(2H，m)，7.42-7.37(3H，m)，2.85(2H，dd，J＝6.0，0.9Hz)，2.80(2H，d，J＝6.0Hz)，2.33(3H，s)。
Preparation c-114
4-fourth-3-thiazolinyl-5-methyl-2-phenyl-oxazoles
Figure A20048001673601322
Under 0 ℃ and nitrogen gas stream, to iodate Jia base triphenyl phosphonium (drip among the 1.7848g, anhydrous tetrahydrofuran solution 4.4154mmol) (95mL) butyllithium (1.8mL, 2, the 5M hexane solution, 4.4154mmol).The suspension dissolving is orange.After 10 minutes, 3-(5-methyl-2-phenyl-oxazoles-4-yl)-(0.4752g, anhydrous tetrahydrofuran solution 2.2077mmol) (15mL) is warmed to room temperature with solution to propionic aldehyde in dropping.After 16 hours, add hexane (200mL), filter out precipitation.With water (200mL) extraction filtrate, dry organic phase (anhydrous magnesium sulfate), filtration and vacuum concentration get crude product then.Residue obtains the pure title compound (0.291g, 62%) of colorless oil with rapid column chromatography (hexane is to ethyl acetate) purifying.
LRMS(m/z)：214(M+H) +。
1H NMR(CDCl 3，300MHz)：7.99-7.96(2H.m)，7.43-7.38(3H，m)，5.93-5.79(1H，m)，5.09-5.02(1H，m)，5.00-4.95(1H，m)，2.57(2H，t，J＝7.4Hz)，2.42(2H，t，J＝7.4Hz)，2.31(3H，s)。
Preparation c-115
2-{6-[4-(5-methyl-2-phenyl-oxazoles-4-yl)-butyl]-the pyridin-3-yl methyl }-tetrahydrofuran (THF)-2-carboxylic acid, ethyl ester
((0.291g is in the anhydrous tetrahydro furan yellow solution (1.3mL) 1.3645mmol) 2.729mmol) to be added to 4-fourth-3-thiazolinyl-5-methyl-2-phenyl-oxazoles for 5.5mL, the tetrahydrofuran solution of 0.5M with the assorted bicyclononane of 9-boron.At room temperature stirred the mixture 4 hours, change another then over to and fill 2-(6-bromo-pyridin-3-yl methyl)-tetrahydrofuran (THF)-2-carboxylic acid, ethyl ester (0.3297g, 1.0496mmol), two (diphenyl phosphine) ferrocene palladium chloride (0.0857g, 0.1050mmol), cesium carbonate (0.9551g, 2.9389mmol), triphenylarsine (0.0322g, 0.1050mmol) N, in the flask of dinethylformamide (2.8mL) and water (0.23mL) solution.Under room temperature and nitrogen gas stream, stirred the garnet mixture 16 hours.After being chilled to 0 ℃, reaction stops with 2M sodium acetate solution (5mL) and 30% superoxol (2mL).With gained solution stirring 2 hours, with water (25mL) dilution, ethyl acetate extraction (4 * 50mL).Merge organic extract, with water (25mL) washing, dry (anhydrous magnesium sulfate), filtration, vacuum concentration gets crude product.Residue obtains the title compound (0.2805g, 60%) of light yellow oily with rapid column chromatography (hexane is to ethyl acetate) purifying.
LRMS(m/z)：449(M+H) +。
1H NMR(CDCl 3，300MHz)：8.34(1H，d，J＝1.9Hz)，7.95(2H，dd，J＝7.7，1.9Hz)，7.52(1H，dd，J＝8.0，2.2Hz)，7.42-7.36(3H，m)，7.04(1H，d，J＝7.9Hz)，4.13(2H，q，J＝7.2Hz)，3.96-3.84(2H，m)，3.16(1H，d，J＝13.9Hz)，2.90(1H，d，J＝13.9Hz)，2.77(2H，t，J＝7.3Hz)，2.50(2H，t，J＝6.9Hz)，2.31-2.19(1H，m)，2.28(3H，s)，1.92-1.64(7H，m)，1.20(3H，t，J＝7.2Hz)。
Preparation c-116
2-{6-[3-(5-methyl-2-phenyl-oxazoles-4-yl)-propyl group]-the pyridin-3-yl methyl }-tetrahydrofuran (THF)-2-carboxylic acid, ethyl ester
Figure A20048001673601332
((0.21g is in the anhydrous tetrahydro furan yellow solution (1mL) 1.04mmol) 2.07mmol) to be added to 4-allyl group-5-methyl-2-phenyl-oxazoles for 4.2mL, 0.5M tetrahydrofuran solution with the assorted bicyclononane of 9-boron.Mixture was at room temperature stirred 4 hours, change another then over to and fill 2-(6-bromo-pyridin-3-yl methyl)-tetrahydrofuran (THF)-2-carboxylic acid, ethyl ester (0.25g, 0.80mmol), two (diphenyl phosphine) ferrocene palladium chloride (0.07g, 0.1mmol), cesium carbonate (0.72g, 2.90mmol), triphenylarsine (0.02g, 0.1mmol) N, dinethylformamide: water (4: 1,2.63mL) in the flask of solution.The garnet mixture was stirred 16 hours under room temperature and nitrogen gas stream.After being chilled to 0 ℃, reaction stops with 2M sodium acetate solution (4.7mL) and 30% aqueous hydrogen peroxide solution (1.7mL).With gained solution stirring 2 hours, with water (20mL) dilution, ethyl acetate extraction (4 * 50mL).The organic extract that merges gets crude product with water (20mL) washing, dry (anhydrous magnesium sulfate), filtration and vacuum concentration.Residue obtains the title compound (0.20g, 57%) of colorless oil with rapid column chromatography (40%～90% ethyl acetate/hexane) purifying.
LRMS(m/z)：435(M+H) +。
1H NMR(DMSO-d 6，400MHz)：8.35(1H，s)，7.96(2H，d，J＝7.9Hz)，7.55(1H，d，J＝8.3Hz)，7.39(3H，t，J＝5.9Hz)，7.09(1H，d，J＝8.1Hz)，3.91(2H，m)，3.80(2H，t，J＝10.9Hz)，3.17(1H，d，J＝14.0Hz)，2.91(1H，d，J＝13.94Hz)，2.81(2H，t)，2.53(2H，t，J＝7.3Hz)，2.28(3H，s)，2.09(2H，d，J＝7.5Hz)，1.87(4H，d，J＝10.9Hz)，1.23(3H，m)。
Preparation c-117
1-{4-[(1E)-and 3-(5-methyl-2-phenyl-1,3-oxazole-4-yl) third-1-alkene-1-yl] phenoxy group } cyclobutane carboxylate
Figure A20048001673601341
With Pd (OAc) 2(12mg, 0.05mmol) and Ph 3(26mg, toluene mixed solution (2mL) 0.05mmol) stirred 1 hour under nitrogen and room temperature P, added Et then 3N (2mL) and 4-allyl group-5-methyl-2-phenyl-1, and the 3-oxazole (100mg, 0.50mmol) and 1-(4-iodine phenoxy group) cyclobutane carboxylate (173mg, toluene solution 0.50mmol) (2mL).With the heating 17 hours under 80 ℃ and nitrogen of gained reaction soln, be chilled to room temperature.After removing solvent, residue is allocated in EtOAc and the salt brine solution.Isolating organic layer washs with salt brine solution, Na 2SO 4Drying, concentrate brown oily crude product.Product silicagel column purifying uses 20%EtOAc hexane solution wash-out, obtains 85mg (41%) yellow oil.
1H NMR(400MHz，CDCl 3)1.19(t，3H)，1.98(m，2H)，2.38(s，3H)，2.43(m，2H)，2.72(m，2H)，3.41(d，2H)，4.18(q，2H)，6.20(td，1H)，6.40(d，1H)，6.60(d，2H)，7.25(d，2H)，7.40(d，3H)，8.00(d，2H)。
LRMS(m/z)：418(M+H) +。
Preparation c-118
1-{4-[3-(5-methyl-2-phenyl-1,3-oxazole-4-yl) propyl group] phenoxy group } cyclobutane carboxylate
With 1-{4-[(1E)-3-(5-methyl-2-phenyl-1,3-oxazole-4-yl) third-1-alkene-1-yl] phenoxy group } (85mg 0.20mmol) is dissolved in MeOH (5mL) to the cyclobutane carboxylate, adds 10%Pd/C (15mg) then.A balloon that is full of nitrogen is linked to each other with flask, and mixture at room temperature stirred 16 hours.Mixture is filtered by Celite, and block washes with MeOH.Concentrating filtrate obtains 85mg (100%) yellow oil.
1H NMR(400MHz，CDCl 3)1.19(t，3H)，1.92-2.02(m，4H)，2.27(s，3H)，2.39-2.51(m，4H)，2.60(t，2H)，2.66-2.77(m，2H)，4.19(q，2H)，6.60(d，2H)，7.05(d，2H)，7.36-7.47(m，3H)，7.98(dd，2H)。
LRMS(m/z)：420(M+H) +。
Preparation c-119
5-bromo-pyrazine-2-base amine
Figure A20048001673601352
Under 0 ℃, (2.0g, (3.74g, 21.03mmol), temperature is below 0 ℃ in keeping slowly to add N-bromosuccinimide in the anhydrous methylene chloride solution (120mL) 21.03mmol) to pyrazine-2-base amine.Under same temperature, stirred the mixture 24 hours, then with saturated sodium bicarbonate solution (30mL) and water (30mL) washing.The extract aqueous solution that merges is with dichloromethane extraction (3 * 100mL).Merge organic extract, drying (anhydrous magnesium sulfate), filtration and vacuum concentration and get crude product.Residue gets the title compound (2.57g, 70%) of yellow solid with rapid column chromatography (10%～50% ethyl acetate/hexane) purifying.
LRMS(m/z)：174(M) -
1H NMR(CDCl 3，300MHz)：8.08(1H，d，J＝1.3Hz)，7.76(1H，d，J＝1.3Hz)。
Preparation c-120
5-bromo-pyrazine-2-alcohol
Figure A20048001673601353
Under 0 ℃, (1.35g, 19.53mmol) gradation adds in the vitriol oil (9.8mL) with Sodium Nitrite.At 50 ℃ of heated mixt,, mixture is chilled to 0 ℃ once more until all Sodium Nitrite dissolvings.Under 0 ℃, with 5-bromo-pyrazine-(2.57g, concentrated sulfuric acid solution 14.68mmol) (14.7mL) is added dropwise in the nitre solion 2-base amine.Remove ice bath, mixture heating up to room temperature, is stirred after 15 minutes, be heated to 45 ℃, be incubated 7 minutes.After being chilled to room temperature, mixture is slowly poured in the trash ice water (100mL) carefully.Water is neutralized to pH 4 with 20% sodium hydroxide solution, then with ethyl acetate extraction (3 * 100mL).The organic extract that merges with water (50mL) washing, dry (anhydrous magnesium sulfate), filter and concentrate the title compound (1.88g, 73%) of yellow solid.
1H NMR(CDCl 3，300MHz)：8.07(1H，s)，7.62(1H，d，J＝3.0Hz)。
Preparation c-121
2-(tertiary butyl-dimethyl-silicomethane oxygen methyl)-5-[2-(5-methyl-2-phenyl-oxazoles-4-yl)-oxyethyl group]-pyrazine
Figure A20048001673601361
To 2-bromo-5-[2-(5-methyl-2-phenyl-oxazoles-4-yl)-oxyethyl group]-pyrazine (0.50g, 1.39mmol) and the tertiary butyl-dimethyl-tributyl stannyl methoxyl group-silicomethane (0.91g, 2.09mmol) anhydrous 1, adding four (triphenyl) phosphine (0) palladium in the 4-dioxane solution (8mL) (0.16g, 0.14mmol).With the mixture degassing 3 times, then 120 ℃ of heating 22 hours.After being chilled to room temperature, mixture is with ether (10mL) dilution, then with saturated potassium fluoride solution (5mL) termination reaction.The gained mixture was stirred 30 minutes, then with ethyl acetate extraction (3 * 50mL).Organic phase with water (30mL) washing, dry (anhydrous magnesium sulfate), filter and concentrate title compound, need not to be further purified.
LRMS(m/z)：426(M+H) +。
1H NMR(CDCl 3，300MHz)：8.20(1H，s)，8.09(1H，s)，7.97(2H，d，J＝7.4Hz)，7.41(3H，d，J＝5.3Hz)，4.78(2H，s)，4.58(2H，d，J＝6.6Hz)，2.98(2H，s)，2.34(3H，s)，0.97(2H，m)，0.14(6H，m)。
Preparation c-122
5-[2-(5-methyl-2-phenyl-oxazoles-4-yl)-oxyethyl group]-pyrazine-2-yl }-methyl alcohol
Figure A20048001673601362
With tetrabutylammonium (2.8mL, the 1M tetrahydrofuran solution 2.78mmol) is added dropwise to 2-(tertiary butyl-dimethyl-silicomethane oxygen methyl)-5-[2-(5-methyl-2-phenyl-oxazoles-4-yl)-oxyethyl group]-pyrazine is (in～1.39mmol) the anhydrous tetrahydrofuran solution (20mL).Mixture was at room temperature stirred 16 hours, then with water (1mL) termination reaction, with 1M acetic acid solution acidifying pH to 5.Vacuum concentration is removed organism, and water is with dichloromethane extraction (3 * 50mL).Merge organic extract, drying (anhydrous magnesium sulfate), filtration and vacuum concentration and get title compound (0.0928g, 21%).
LRMS(m/z)：312(M+H) +。
1H NMR(CDCl 3，300MHz)：8.12(2H，s)，8.05(2H，d，J＝6.0Hz)，7.40(3H，d，J＝6.0Hz)，4.72(2H，s)，4.59(2H，t，J＝6.0Hz)，2.99(2H，t，J＝6.0Hz)，2.33(3H，s)。
Preparation c-123
6-benzyloxy-naphthalene-2-benzyl carboxylate
Figure A20048001673601371
Above-claimed cpd is according to Inui, S.; Suzuki, T.; Limura, N.; Iwane, H.; Nohira, H.Mol Cryst.Liq.Cryst.Sci.Technol.Sect.A.1994,239, the method described in the 1-10 is prepared.
Preparation c-124
(6-benzyloxy-naphthalene-2-yl)-methyl alcohol
Figure A20048001673601372
Under 0 ℃ of following nitrogen gas stream, to 6-benzyloxy-naphthalene-2-benzyl carboxylate (7.09g, add in anhydrous tetrahydrofuran solution 19.24mmol) (60mL) diisobutyl aluminium hydride (58mL, the 1.0M tetrahydrofuran solution, 57.73mmol).The gained mixture is warmed to room temperature, stirred 16 hours.The aqueous solution (40mL) that is added dropwise to citric acid (19g) is (careful! Very exothermic).(3 * 50mL), the organic extract of merging is with saturated sodium-chloride water solution (50mL) washing, dry (anhydrous magnesium sulfate), and vacuum concentration gets crude product with the ethyl acetate extraction water layer then.Residue obtains title compound (4.37g, 86%) with rapid column chromatography (hexane is to ethyl acetate) purifying, is white solid.
LRMS(m/z)：287(M+Na) +。
1H NMR(CDCl 3，400MHz)：7.76-7.72(3H，m)，7.50-7.33(6H，m)，7.25-7.23(2H，m)，5.18(2H，s)，4.82(2H，d，J＝6.1Hz)。
Preparation c-125
2-[6-(5-methyl-2-phenyl-oxazoles-4-ylmethoxy)-naphthalene-2-ylmethyl]-tetrahydrochysene-furans-2-carboxylic acid, ethyl ester
Figure A20048001673601381
With 2-phenyl-4-(chloromethyl)-5-Jia Ji oxazole (0.133g, 0.639mmol), 2-(6-hydroxyl-naphthalene-2-ylmethyl)-tetrahydrofuran (THF)-2-carboxylic acid, ethyl ester (0.192g, 0.639mmol) and cesium carbonate (0.521g, anhydrous acetonitrile heterogeneous mixture (2mL) 1.59mmol) was 140 ℃ of heating (in microwave oven) 10 minutes.Add second part of 2-phenyl-4-(chloromethyl)-5-Jia Ji oxazole (0.5 equivalent), mixture was further heated 20 minutes at 200 ℃.Reaction mixture is filtered acetonitrile (200mL) washing by Celite.Vacuum concentrated filtrate, residue obtain the title compound (0.180g, 60%) of colorless oil with rapid column chromatography (hexane is to ethyl acetate) purifying.
Preparation c-126
(4S)-and 4-benzyl-3-(tetrahydrofuran (THF)-2-base carbonyl)-1,3-oxazolidine-2-ketone
Figure A20048001673601382
Under-78 ℃, (22.6mL, 2.5M hexane solution 56.4mmol) are added dropwise to (4S)-4-benzyl-1, and (10.0g is in tetrahydrofuran solution 56.4mmol) (200mL) for 3-oxazolidine-2-ketone with n-Butyl Lithium.Mixture was stirred 30 minutes, add tetrahydrofuran (THF)-2-formyl chloride (9.12g, tetrahydrofuran solution 67.7mmol) (25mL) then.Mixture was stirred 30 minutes down at-78 ℃, be warming up to 0 ℃ in 1 hour, with the saturated aqueous ammonium chloride termination reaction.With the ethyl acetate extraction mixture, with organic phase with salt brine solution washing, dried over mgso, filtration and concentrate.Residue with rapid column chromatography (1: 3 earlier, 1: 2 ethyl acetate then: purifying hexane), obtain the title compound (15.0g, 97%) of colorless oil, be about 1: 1 non-enantiomer mixture.
Preparation c-127
(4S)-4-benzyl-3-{[2-(6-[2-(5-methyl-2-phenyl-1,3-oxazole-4-yl) oxyethyl group] and pyridin-3-yl } methyl) tetrahydrofuran (THF)-2-yl] carbonyl }-1,3-oxazolidine-2-ketone
Figure A20048001673601391
Following at-50 ℃ with (two) trimethyl silyl amido sodium (3.57mL, the 1M tetrahydrofuran solution, 3.57mmol) dropping to (4S)-4-benzyl-3-(tetrahydrofuran (THF)-2-base carbonyl)-1, (0.983g is in anhydrous tetrahydrofuran solution 3.57mmol) (6mL) for 3-oxazolidine-2-ketone.Mixture was stirred 45 minutes, then Dropwise 5-(iodomethyl)-2-[2-(5-methyl-2-phenyl-1,3-oxazole-4-yl) oxyethyl group] pyridine (preparation 28) (0.500g, anhydrous tetrahydrofuran solution 1.19mmol) (6mL).The gained mixture was stirred 1.5 hours down at-50 ℃,, be warmed to room temperature then with the saturated aqueous ammonium chloride termination reaction.With the ethyl acetate extraction mixture, dry organic phase (anhydrous magnesium sulfate), filtration also concentrate.(1: 1 ethyl acetate: purifying hexane) obtains the title compound (0.617g, 90%) of the single diastereomer of colorless oil to residue with rapid column chromatography.
LRMS(m/z)：568(M+H) +。
1H NMR(CDCl 3，300MHz)8.01(1H，s)，7.96(2H，m)，7.61(1H，dd，J＝2.5，8.5Hz)，7.40(3H，m)，7.28(3H，m)，7.17(1H，m)，6.64(1H，d，J＝8.6Hz)，4.55(3H，m)，4.18(2H，m)，3.90(1H，m)，3.79(1H，m)，3.27(1H，d，J＝14Hz)，3.20(1H，m)，3.13(1H，d，J＝14Hz)，2.96(2H，t，J＝6.8Hz)，2.79(1H，m)，2.32(3H，s)，2.34(3H，m)，2.11(1H，m)，1.73(1H，m)，1.54(1H，m)
Preparation c-128
Tetrahydrofuran (THF)-2-carboxylic acid amide
Figure A20048001673601392
Under 0 ℃ of nitrogen gas stream, to tetrahydrofuran (THF)-2-carboxylic acid (2.42g, in anhydrous tetrahydrofuran solution 20.82mmol) (120mL) add triethylamine (8.5mL, 61.23mmol) and Vinyl chloroformate (2.4mL, 25.10mmol).Form white precipitate after adding Vinyl chloroformate, under 0 ℃, the gained mixture was stirred 45 minutes.Ammonia is fed solution 2 hours, remove source of the gas.Then reaction mixture is warmed to room temperature, stirred 16 hours.Add the 1N hydrochloric acid soln and transfer pH to 1, then with ethyl acetate extraction (3 * 50mL).Merge organic extract, dry (anhydrous magnesium sulfate), filtration and vacuum concentration get crude product.Residue obtains title compound (0.97g, 41%) with rapid column chromatography (hexane to 10% ethyl acetate/hexane) purifying, is white solid.
LRMS(m/z)：116(M+H) +。
1H NMR(CDCl 3，300MHz)：4.35(1H，dd，J＝8.5，5.8Hz)，3.92(2H，m)，2.18(2H，m)，1.90(2H，m)。
Preparation c-129
Tetrahydrofuran (THF)-2-nitrile
Figure A20048001673601401
With trifluoroacetic anhydride (1.55g, 7.38mmol) with per 10 seconds speed of one slowly add ice-cold (0 ℃) tetrahydrofuran (THF)-2-carboxylic acid amide (0.77g, 6.71mmol) and pyridine (1.06g, 13.42mmol) anhydrous 1 is in the 4-dioxane solution (10mL).Add trifluoroacetic anhydride, monitor internal temperature simultaneously and remain on below 5 ℃, added in 20 minutes.The gained mixture is chilled to room temperature, stirred 3 hours.Chloroform (100mL) is added mixture, then with water (30mL) and saturated sodium-chloride water solution (20mL) extraction.Dry organic extract (anhydrous magnesium sulfate), filtration and vacuum concentration get crude product.Residue obtains the title compound (0.51g, 62%) of colorless oil with rapid column chromatography (hexane to 25% ethyl acetate/hexane) purifying.
1H NMR(CDCl 3，300MHz)：4.70(1H，m)，3.96(2H，m)，2.24(2H，m)，2.08(2H，m)。
Preparation c-130
2-{6-[2-(5-methyl-2-phenyl-oxazoles-4-yl)-oxyethyl group]-the pyridin-3-yl methyl } tetrahydrofuran (THF)-2-nitrile
Under-78 ℃ of nitrogen gas stream, (1.8mL, (0.17g is in anhydrous tetrahydrofuran solution 1.79mmol) (6mL) 1.79mmol) to add tetrahydrofuran (THF)-2-nitrile with two (trimethyl silyl) amido sodium.The gained yellow solution stirs after 50 minutes, with 5-iodomethyl-2-[2-(5-methyl-2-phenyl-oxazoles-4-yl)-oxyethyl group]-(0.25g, anhydrous tetrahydrofuran solution 0.596mmol) (3mL) is added in this enolate solution pyridine.Under-78 ℃, stirred the mixture 1.5 hours, with saturated aqueous ammonium chloride (5mL) termination reaction.(3 * 50mL), the merging organic extract gets crude product with water (30mL) washing, dry (anhydrous magnesium sulfate), filtration and vacuum concentration to water with ethyl acetate extraction.Residue obtains title compound (0.11g, 46%) with rapid column chromatography (7%～45% ethyl acetate/hexane) purifying, is white solid.
LRMS(m/z)：390(M+H) +。
1H NMR(CDCl 3，300MHz)：8.03(1H，d，J＝2.5Hz)，7.96(2H，m)，7.56(1H，dd，J＝8.5，2.5Hz)，7.40(3H，m)，6.68(1H，d，J＝8.5Hz)，4.54(2H，m)，3.96(2H，m)，3.00(4H，m)，2.33(5H，d，J＝3.2Hz)，1.92(2H，m)。
Embodiment D-1
2-oxyethyl group-3-{6-[2-(5-methyl-2-phenyl-1,3-oxazole-4-yl) oxyethyl group] pyridin-3-yl } propionic acid
Figure A20048001673601411
With lithium hydroxide monohydrate (180mg, 4.31mmol) be added to 2-oxyethyl group-3-{6-[2-(5-methyl-2-phenyl-1,3-oxazole-4-yl) oxyethyl group] pyridin-3-yl } ethyl propionate (183mg, tetrahydrofuran (THF) 0.431mmol): methyl alcohol: water (1: 1: 1,6mL) in the mixed solution.Stirred the mixture 18 hours, and concentrated then and remove volatile component.Water is with 3M hcl acidifying, ethyl acetate extraction.Organic phase is washed with salt brine solution, and dried over mgso, filtration also concentrate.(98: 2 methylene dichloride: methyl alcohol) purifying twice, obtains flint glass shape title compound (31mg) with rapid column chromatography for residue.
LRMS(m/z)：396(M) +。
1H NMR(CDCl 3，300MHz)7.99(3H，m)，7.50(1H，m)，7.40(3H，m)，6.65(1H，m)，4.50(2H，t，J＝7Hz)，4.01(1H，m)，3.64(1H，m)，3.42(1H，m)，2.98(4H，m)，2.34(3H，s)，1.16(3H，t，J＝7Hz)。
Embodiment D-2 to D-45
The method preparation that embodiment D-2 to D-45 uses to be similar to embodiment D-1 promptly under 20 ℃～75 ℃, is stirred ester in methanol aqueous solution, aqueous ethanolic solution, tetrahydrofuran aqueous solution or its mixed solution of sodium hydroxide or lithium hydroxide.
Figure A20048001673601421
Figure A20048001673601501
The preparation of embodiment D-1 to D-43 starting raw material (preparation d-1 to d-42):
Preparation d-1
2-oxyethyl group-3-{6-[2-(5-methyl-2-phenyl-1,3-oxazole-4-yl) oxyethyl group] pyridin-3-yl } ethyl propenoate
Figure A20048001673601502
With N, N, N ', N '-tetramethyl guanidine (0.305mL, 2.43mmol) drop to 6-[2-(5-methyl-2-phenyl-1,3-oxazole-4-yl) oxyethyl group] nicotine aldehyde (250mg, 0.811mmol) and (1,2-diethoxy-2-oxoethyl) ((696mg is in chloroformic solution 1.62mmol) (4mL) for triphenyl) phosphonium chloride.Mixture was stirred 16 hours, be allocated in then in saturated aqueous ammonium chloride and the ethyl acetate.Organic phase is with salt brine solution washing, dried over mgso, filtration and concentrated.Residue with rapid column chromatography (1: 2 ethyl acetate: purifying hexane), obtain title compound (330g, 96%), be white solid.
LRMS(m/z)：423(M+H) +。
1H NMR(CDCl 3，300MHz)8.42(1H，m)，8.10(1H，m)，7.97(1H，m)，7.40(2H，m)，7.28(3H，m)，6.90(1H，s)，6.73(1H，m)，4.60(2H，t，J＝7Hz)，4.30(2H，q，J＝7Hz)，4.01(2H，q，J＝7Hz)，2.99(2H，t，J＝7Hz)，2.34(3H，s)，1.36(6H，m)
Preparation d-2
2-oxyethyl group-3-{6-[2-(5-methyl-2-phenyl-1,3-oxazole-4-yl) oxyethyl group] pyridin-3-yl } ethyl propionate
With 2-oxyethyl group-3-{6-[2-(5-methyl-2-phenyl-1,3-oxazole-4-yl) oxyethyl group] pyridin-3-yl ethyl propenoate (328mg, ethanolic soln 0.776mmol) (10mL) under 50psi with 10% palladium carbon (33mg) hydrogenation 3 hours.Mixture filters with Celite, and solid washs with ethyl acetate.Concentrated filtrate and washings, residue is with rapid column chromatography purifying (1: 2 ethyl acetate: hexane), obtain the title compound (183mg, 56%) of colorless oil.
LRMS(m/z)：425(M+H) +。
1H NMR(CDCl 3，300MHz)7.99(3H，m)，7.42(4H，m)，6.65(1H，m)，4.54(2H，t，J＝7Hz)，4.18(2H，q，J＝7Hz)，3.93(1H，m)，3.63(1H，m)，3.36(1H，m)，2.90(4H，m)，2.33(3H，s)，1.25(3H，t，J＝7Hz)，1.16(3H，t，J＝7Hz)。
Preparation d-3
The preparation of 2-(benzyloxy)-5-bromopyridine
In the benzole soln (170mL) of 5-bromopyridine-2 (1H)-ketone (100mmol, 17.4g, 1.0 equivalents), add silver carbonate (I) (67.0mmol, 18.5g, 0.67 equivalent).Flask wraps up with aluminium foil, adds bromotoluene (120mmol, 20.5g, 1.2 equivalents) by syringe with stable flow velocity then.With mixture heating up to 50 ℃, stir about is 24 hours in the dark.The LC/MS of reaction mixture shows two peaks, and both all have M+H=265, and is consistent with the expection molecular weight.Based on relative polarity, the peak that polarity is bigger is considered to the N-alkylate, accounts for 20% of total amount.Reaction mixture is chilled to room temperature, removes silver salt by Celite pad filtering mixt.Filter block washs with benzene, and organic layer is with 2% sodium hydrogen carbonate solution washed twice, again with twice of water washing.Organic layer is with dried over mgso, vacuum concentration.Crude product with the ethyl acetate solution gradient purifying of 5-95% hexane, obtains golden oily title compound (25.1g, 95%) on Biotage Sp465i.
LRMS：265(M+H) +。
1H NMR(DMSO-d 6，400MHz)：8.29(1H，s)7.72(1H，d，J＝8.5Hz)7.31-7.43(5H，m)6.54(1H，d，J＝8.5Hz)5.34(2H，s)
Preparation d-4
The preparation of 6-(benzyloxy) nicotine aldehyde
Figure A20048001673601521
Stir down, with n-Butyl Lithium (2.5M, 95.9mmol, 38.4mL, 1.05 equivalents) be added dropwise to by syringe 2-(the benzyloxy)-5-bromopyridine (91.3mmol, 24.1g, 1.0 equivalents) that is chilled to-78 ℃ THF solution (260mL, c=0.35) in.Adding finishes, and continues stirred solution 1 hour under same low temperature.Then, drip N, the solution of dinethylformamide (183mmol, 13.4g, 2.0 equivalents) and 5mL THF.Under same low temperature, continue to stir 30 minutes, add 5% sodium hydrogen carbonate solution termination reaction then.Mixture is transferred to separating funnel, with extracted with diethyl ether (3 * 250mL).Merge organic layer, with salt brine solution washing, anhydrous magnesium sulfate drying, vacuum concentration.The gained yellow oil with 0-50% isohexane ethyl acetate solution gradient purifying, obtains title compound (14.1g, 73%) on Biotage Sp4 65i
LRMS：214(M+H) +。
1H NMR(DMSO-d 6，400MHz)：10.02(1H，s)8.86(1H，s)8.03(1H，d，J＝9.3Hz)7.31-7.43(5H，m)6.50(1H，d，J＝9.3Hz)5.33(2H，s)
Preparation d-5
(2Z)-3-[6-(benzyloxy) pyridin-3-yl]-preparation of 2-ethoxy ethyl acrylate
(1.0 equivalents, 33.1mmol 7.05g) reach (1 to 6-(benzyloxy) nicotine aldehyde, 2-diethoxy-2-oxoethyl) (triphenyl) phosphonium chloride (2.0 equivalents, 66.2mmol, chloroformic solution (165mL 28.4g), 0.2M) middle adding tetramethyl guanidine (3.0 equivalents, 99.3mmol, 11.4g).Flask at room temperature stirs and spends the night with double glazing plug jam-pack.After about 18 hours, TLC analyzes and shows a small amount of unreacted starting raw material.With the reaction mixture reflux, analyze with TLC again after 2 hours.With the saturated aqueous ammonium chloride termination reaction.Separate two-phase, organic phase is washed with salt brine solution, dried over mgso, vacuum concentration.Be settled out a large amount of triphenylphosphine oxides.Residue grinds, filters with ether.Filter block washs with ether, and the filtrate that vacuum concentration merges obtains light yellow solid, it is dissolved among the DCM of minimum, on Biotage Sp4 65i with 10-100% hexane-ethyl acetate solution gradient elution.Get the water white oil of 12.3g (37.6mmol, quantitative reaction).
LRMS：328(M+H) +。
1H NMR(DMSO-d 6，400MHz)：8.33(1H，s)7.92(1H，d，J＝8.0Hz)7.31-7.43(5H，m)6.76(1H，d，J＝8.1Hz)6.60(1H，s)5.37(2H，s)4.23(2H，q，J＝7.1Hz)3.90-3.99(2H，m)1.34(6H，dt，J＝15.8，7.0Hz)
Preparation d-6
The preparation of 2-oxyethyl group-3-(6-oxygen-1,6-dihydropyridine-3-yl) ethyl propionate
With 10% palladium carbon (～1.23g) be added to fill (2Z)-3-[6-(benzyloxy) pyridin-3-yl]-the Parr blender jar of the ethanolic soln of 2-ethoxy ethyl acrylate in.In bottle, purge hydrogen, the decompression degassing 3 times.Mixture is placed under the 50psi hydrogen, and jolting is spent the night under the room temperature.After～20 hours, stop jolting, with bottle with vacuum outgas.TLC shows starting raw material consumption.Mixture is filtered the removal palladium by the Celite pad.Filter block is with washing with alcohol.Vacuum concentrated solution must remove the reduction pyridone of benzyl, is golden oil.This oil with the 80mL/ minute DCM solution gradient purifying with 0-10%MeOH, obtains 2.77g water white oil (11.6mmol, 31%) on Biotage Sp4 65i.
LRMS：240(M+H) +。
1H NMR(DMSO-d 6，400MHz)：7.29(1H，d，J＝9.5Hz)7.19(1H，d，J＝5.2Hz)6.55(1H，d，J＝9.5Hz)4.20(2H，q，J＝7.0Hz)4.10(1H，dd，J＝9.6，0.3Hz)3.59-3.73(2H，m)2.65-2.70(1H，m)2.53-2.61(1H，m)1.23(6H，td，J＝7.0，3.6Hz)。
Preparation d-7
5-benzyloxy-pyridine-2-formaldehyde
To (5-benzyloxy-pyridine-2-yl)-methyl alcohol (2.3619g, 10.9728mmol) methylene dichloride (120mL) and pyridine solution (2.68mL, 32.9184mmol) middle adding 1,1,1-triacetyl Oxy-1,1-dihydro-1, and 2-benzo dioxy cyclopentenes (benziodoxol)-3 (1H)-ketone (6.9812g, 16.4592mmol).Gained solution was stirred 16 hours under the room temperature nitrogen gas stream, then with ether (100mL) dilution, concentrating under reduced pressure part solution again.Residue is added in the ether (150mL), and with 1: 110% sodium thiosulfate solution: (2 * 100mL) removed precipitation in the saturated sodium bicarbonate aqueous solution extraction.Organic layer gets the pure title compound (1.1694g, 50%) of light yellow oily with water (100mL) and saturated sodium-chloride water solution (100mL) washing, dry (anhydrous magnesium sulfate), filtration and vacuum concentration.
LRMS(m/z)：214(M+H) +。
1H NMR(CDCl 3，300MHz)：9.98(1H，d，J＝0.8Hz)，8.49(1H，d，J＝2.5Hz)，7.94(1H，d，J＝8.7Hz)，7.44-7.40(4H，m)，7.38-7.33(2H，m)，5.19(2H，s)。
Preparation d-8
3-(5-benzyloxy-pyridine-2-yl)-2-oxyethyl group-ethyl propenoate
Under the room temperature nitrogen gas stream, to 5-benzyloxy-pyridine-2-formaldehyde (1.1694g, 5.4842mmol), (ethoxycarbonyl-methoxyl group-methyl)-triphenyl phosphonium chloride (4.7043g, drip in chloroformic solution 10.9684mmol) (30mL) tetramethyl guanidine (2.1mL, 16.4526mmol).With gained solution stirring 16 hours, then with saturated aqueous ammonium chloride (50mL) termination reaction.Separate two-phase, organic phase gets crude product with saturated sodium-chloride water solution (50mL) washing, dry (anhydrous magnesium sulfate), filtration and vacuum concentration.Residue obtains the pure title compound (1.8051g, 100%) of yellow oily with rapid column chromatography (hexane is to ethyl acetate) purifying.
LRMS(m/z)：328(M+H) +。
1H NMR(CDCl 3，300MHz)：8.37(1H，d，J＝2.6Hz)，8.18(1H，d，J＝8.9Hz)，7.44-7.33(5H，m)，7.25(1H，dd，J＝8.9，3.0Hz)，7.13(1H，s)，5.13(2H，s)，4.27(2H，q，J＝7.2Hz)，4.05(2H，q，J＝7.2Hz)，1.35(3H，t，J＝7.0Hz)，1.34(3H，t，J＝7.0Hz)。
Preparation d-9
2-oxyethyl group-3-(5-hydroxyl-pyridine-2-yl)-ethyl propionate
To 3-(5-benzyloxy-pyridine-2-yl)-2-oxyethyl group-ethyl propenoate (1.8051g, add in ethanol solution 5.5144mmol) (40mL) palladium (0.1805g, account for activated carbon weight 10%).Gained solution was stirred 16 hours down in room temperature and nitrogen atmosphere (50psi).With gained solution by 3 " the Celite layer filter, wash with ethanol (200mL).Vacuum concentrated filtrate then obtains the pure title compound (1.2231g, 93%) of light yellow oily.
LRMS(m/z)：240(M+H) +。
1H NMR(CDCl 3，300MHz)：8.14(1H，s)，7.20-7.11(2H，m)，4.19-4.10(3H，m)，3.71(1H，q，J＝7.0Hz)，3.63-3.53(1H，m)，3.36-3.26(1H，m)，3.18-3.03(1H，m)，1.18(3H，t，J＝7.2Hz)，1.07(3H，t，J＝7.1Hz)。
Preparation d-10
2-oxyethyl group-3-{6-[2-(4-Phenoxyphenyl) oxyethyl group] pyridin-3-yl } ethyl propionate
In the toluene solution (12mL) of the suitable bromopyridine of crossing with argon purge (0.636mmol), add acid chloride (II) (11.4mg, 0.0508mmol) and racemization-2-(two-tertiary butyl phosphino-)-1,1 '-dinaphthalene (25.4mg, 0.0636mmol).Formed activated complex in about 10 minutes, add then cesium carbonate (414mg, 1.27mmol) and suitable alcohol (0.956mmol).With mixture heating up to 115 ℃, under this temperature stir about 12-18 hour.Mixture is chilled to room temperature, filters with the silicon-dioxide pad.Filter block washs, is associated with machine filter liquid, vacuum concentration with the ethyl acetate of 2-3 part.The gained residue is with the flash chromatography purifying, or handles with the routine hydrolysis method.
Preparation d-11 to d-18
Preparing d-11 to d-18 uses and to be similar to the method that prepare the d-10 use and to be prepared.
10
Preparation d-19
2-bromo-5-(brooethyl) pyridine
Figure A20048001673601572
Phosphorus tribromide (100mmol, 27.1g, 2.0 equivalents) carefully is added in the 2-chloro-5-hydroxy-methyl pyridine (50.0mmol, 7.18g, 1.0 equivalents).Pyridine becomes piece, with mixture heating up to 160 ℃.Stir in 5 minutes down at＞150 ℃, it is very dark that the mixture color becomes, and have gas to emit.After stirring the mixture under the same temperature about 2.5 hours, be chilled to room temperature.Mixture further is chilled to 0 ℃, adds saturated sodium bicarbonate solution (very exothermic very carefully! ).When foam reduces, will ice in the adding mixture, until lather collapse.Carefully add solid sodium bicarbonate then to pH～8-9.With ethyl acetate extraction, organic layer is with salt brine solution washing, anhydrous magnesium sulfate drying with mixture.Vacuum concentration gets black solid.This material is dissolved among the DCM of minimum, uses Biotage Sp4 65i, obtain the title compound (5.57g, 44%) of light yellow solid with 0-100% ethyl acetate/hexane solution gradient purifying.
LRMS：252(M+H) +。
1H NMR(DMSO-d 6，400MHz)：8.39(1H，s)7.59(1H，d，J＝8.5Hz)7.48(1H，d，J＝8.5Hz)4.46(2H，s)
Preparation d-20
[(6-bromopyridine-3-yl) methyl] (methoxyl group) propanedioic acid dimethyl esters
Figure A20048001673601581
Add methoxyl group dimethyl malonate (46.6mmol, 7.55g, 1.3 equivalents) by syringe several times to being chilled in 0 ℃ the dry DMF soup compound (250mL) of potassium tert.-butoxide (46.6mmol, 5.22g, 1.3 equivalents).Form enolate in about 30 minutes, gradation this moment adds 2-bromo-5-(brooethyl) pyridine.In 3 hours, slowly reaction mixture is warmed to room temperature.Reaction mixture is diluted with ether, be transferred to the separating funnel that contains saturated aqueous ammonium chloride.Vibration, separation two-phase, organic phase is with water washing.Then with anhydrous magnesium sulfate drying organic layer, vacuum concentration.With 0-100% ethyl acetate/hexane solution gradient purifying, (12.1g quant.), leaves standstill curing to the gained yellow oil to obtain water white oil on Biotage Sp4 65i.LRMS：333(M+H) +。
1H NMR(DMSO-d 6，400MHz)：8.27(1H，s)7.45-7.55(2H，m)3.82(6H，s)3.57(3H，s)3.42(2H，s)
Preparation d-21
The preparation of 3-(6-bromopyridine-3-yl)-2-methoxypropionic acid methyl esters
In the anhydrous DMF solution (2mL) of [(6-bromopyridine-3-yl) methyl] (methoxyl group) propanedioic acid dimethyl esters (3.55mmol, 1.18g, 1.0 equivalents), add lithiumbromide (3.20mmol, 0.278g, 0.9 equivalent), add entry (3.55mmol then, 0.064g, 1.0 equivalents).Solution placed be preheated to 165 ℃ oil bath.Begin to discharge gas rapidly.Stopped to form bubble in 30 minutes, this moment, LC/MS showed that reaction mixture reacts completely.Be chilled to room temperature, dilute with water.With extracted with diethyl ether water layer (4 * 25mL).Merge organic layer, wash with salt brine solution.Anhydrous magnesium sulfate drying organic layer, vacuum concentration get the 536mg brown oil, and this oil is single point with the TLC detection.Need not to be further purified and be directly used in next step.
LRMS：275(M+H) +。
1H NMR(DMSO-d 6，400MHz)：8.23(1H，s)7.42-7.51(2H，m)4.26(1H，d，J＝8.1Hz)3.79(3H，s)3.51(3H，s)2.97-3.03(1H，m)2.82-2.88(1H，m)。
Preparation d-22
3-[6-(2-{4-[(ethylsulfonyl) oxygen base] phenyl } oxyethyl group) pyridin-3-yl]-2-methoxy propyl acetoacetic ester
Preparation d-23 to d-38
Preparing d-23 to d-38 uses and to be similar to the method that prepare the d-22 use and to be prepared.
Figure A20048001673601592
Figure A20048001673601601
Figure A20048001673601621
Tested the activity of anti-PPAR-γ of The compounds of this invention and PPAR-α.These activity are listed as follows with Ki (μ m).
Embodiment # PPAR- γ Ki(μm) PPAR- α Ki(μm) Embodiment # PPAR- γ Ki(μm) PPAR- α Ki(μm) Embodiment # PPAR- γ Ki(μm) PPAR- α Ki(μm)
A-02 0.55 B-02 2.2 C-03 2.9
A-03 10 19 B-03 31 9 C-05 15
A-05 E/M 0.33 2.6 B-04 1.5 48 C-06 9.5 41
A-05 S/E 3.4 7.5 B-05 1.33 2.04 C-07 11 22
A-05 S/E 0.19 1.1 B-05 2.9 3.2 C-09 1.4 4.6
A-07 0.12 B-05 2 3.6 C-10 2.1 19
A-10 1.5 4.4 B-06 0.37 0.13 C-11 2 25
A-11 0.58 0.12 B-07 0.65 12 C-12 1.6 9.4
A-12 0.051 0.35 B-08 0.48 3.1 C-14 8 3.2
A-13 3.5 10 B-09 1.9 2.2 C-15 14 3.2
A-14 1.3 0.15 B-10 0.17 0.19 C-17 26 3.2
A-15 1.2 0.16 B-11 7.9 0.96 C-18 3.5 0.065
A-16 2.8 1.5 B-12 33 0.3 C-20 1.5 3.1
A-17 1.9 1.6 B-13 9 C-21 0.053 0.066
A-18 1.7 14 B-14 2.3 0.021 C-22 0.8 2.1
A-19 0.059 0.7 B-16 1.8 0.084 C-23 0.19 2.5
A-20 0.18 0.14 B-17 1.2 0.047 C-24 0.083 0.022
A-21 0.088 0.31 B-18 0.082 C-25 0.066 0.018
A-22 0.17 0.85 B-19 0.74 0.34 C-26 0.068 0.016
A-23 0.39 0.18 B-20 1.6 C-27 0.026 0.015
A-24 0.78 0.018 E-21 0.99 4 C-28 0.03 0.088
A-25 3.2 4.2 B-22 0.15 0.46 C-29 0.006 0.12
A-26 0.15 0.33 B-23 3.4 2.7 C-30 0.033 0.11
A-27 2.4 1.3 B-24 1.6 1 C-31 0.026 0.093
A-28 E/M 0.044 0.93 E-27 0.22 C-32 0.035 0.15
A-28 S/E 0.081 1.1 B-28 7.8 C-33 0.05 0.01
A-28 S/E 0.94 2.9 C-02 0.39 C-36 1.7 21
E/M refers to diastereomeric mixture, comprises racemic mixture.
S/E refers to single enantiomer.
Embodiment # PPAR- γ Ki(μm) PPAR- α Ki(μm) Embodiment # PPAR- γ Ki(μm) PPAR- α Ki(μm) Embodiment # PPAR- γ Ki(μm) PPAR- α Ki(μm)
C-38 7.2 C-64 0.052 0.014 C-90 0.017 0.11
C-40 3.7 0.7 C-66 0.023 0.031 C-91 0.39 1.8
C-42 33 13 C-67 0.044 0.25 C-92 1.1 2.8
C-44 36 C-68 4.2 C-93 0.011 0.3
C-45 0.22 7.7 C-69 1.1 2.5 C-94 7
C-46 2 3.5 C-70 6.4 C-95 0.97 8.6
C-47 3.5 8.3 C-71 9.7 D-02 0.46 0.29
C-48 0.018 0.24 C-72 7.1 D-03 0.011 0.3
C-48 E/M 0.15 0.31 C-73 0.042 D-04 0.44 0.29
C-48 S/E 0.014 0.047 C-74 0.64 0.9 D-05 2.8
C-48 S/E 2.4 C-74 S/E D-06 0.027 0.13
C-49 0.21 1.6 C-74 S/E 0.47 4.2 D-07 0.017 0.32
C-49 21 41 C-75 0.82 D-08 0.002 0.015
C-49 0.043 0.34 C-76 2.3 7.3 D-09 0.061 0.05
C-50 0.043 1.1 C-77 0.15 2.9 D-10 0.019 0.033
C-51 0.18 2.9 C-78 0.006 0.015 D-11 6.2 5.1
C-52 0.3 0.15 C-78 S/E 3.9 D-12 8.1
C-53 0.093 0.64 C-78 S/E 0.003 0.014 D-13 0.36 0.19
C-53 S/E 3.6 C-79 0.007 0.015 D-14 1.5 2.6
C-53 S/E 0.027 0.4 C-80 0.062 0.053 D-15 0.35 0.22
C-54 0.02 1.2 C-81 0.015 0.75 D-16 6.4
C-55 6 C-82 0.016 D-17 0.031 0.91
C-56 0.081 0.078 C-83 0.008 0.004 D-18 0.45 0.62
C-57 1.1 1.8 C-84 0.021 0.064 D-19 1.7 6.4
C-59 0.009 0.054 C-85 0.004 0.013 D-20 0.48 0.84
C-60 0.015 0.065 C-86 0.005 0.013 D-21 2.1 10
C-61 0.31 0.24 C-87 0.012 0.025 D-23 E/M 0.073 6.5
C-63 0.094 0.021 C-89 0.04 0.03 D-23 S/E 5
E/M refers to diastereomeric mixture, comprises racemic mixture.
S/E refers to single enantiomer.
Embodiment # PPAR- γ Ki(μm) PPAR- α Ki(μm) Embodiment # PPAR- γ Ki(μm) PPAR- α Ki(μm)
D-23 S/E 0.039 1.1 D-33 0.69 0.55
D-24 no SPA no SPA D-34 9.1 3.2
D-24 0.58 0.93 D-35 0.56 0.33
D-25 2.9 D-35 S/E 027 0.57
D-26 no SPA no SP D-35 S/E 4.8 9
D-26 S/E 1.9 D-36 0.23 0.73
D-26 S/E 0.042 0.67 D-37 0.53 4.7
D-27 7.8 D-38 9.6
D-28 1.6 4.8 D-39 5
D-29 0.4 0.8 D-40 9.6 1.8
D-29 S/E 1.2 D-41 5.9
D-29 S/E 0.69 3 D-42 0.7 1
D-31 1 0.088 D-44 0.15 2.6
D-32 1.5 0.059 D-45 0.058 0.09
E/M refers to diastereomeric mixture, comprises racemic mixture.
S/E refers to single enantiomer.
The present invention describes in detail with embodiment preferred by concrete, it will be understood by those skilled in the art that by normal experiment of the present invention and practice, can change and revises the present invention.Thereby the present invention is not limit by aforementioned specification, but does not break away from the scope of aftermentioned claim and equivalent thereof.

Claims (15)

1. the compound or pharmaceutically acceptable salt thereof or the solvate of general formula (I),
Figure A2004800167360002C1
Wherein:
Ring Q is (C 6-C 10) aryl or (4-10)-element heterocycle base;
R 1Be H, halogen, (C 1-C 8) alkyl, (C 1-C 8) alkoxyl group, CN, CF 3,-O-CF 3,-O-SO 2-(C 1-C 8) alkyl ,-O-SO 2-(CR 11R 12) t(C 6-C 10) aryl ,-(CR 11R 12) t(C 3-C 10) cycloalkyl-(CR 11R 12) t,-(CR 11R 12) t(C 3-C 10) cycloalkyl-(CR 11R 12) t-O-,-(CR 11R 12) t(C 6-C 10) aryl-(CR 11R 12) t,-(CR 11R 12) t(C 6-C 10) aryl-(CR 11R 12) t-O-,-(CR 11R 12) t-(4-10)-element heterocycle base-(CR 11R 12) t, or-(CR 11R 12) t-(4-10)-element heterocycle base-(CR 11R 12) t-O-; R wherein 1Ring carbon atom optional by 1～3 R 13Group replaces; R 1Theheterocyclic nitrogen atom optional by 1～3 (C 1-C 8) the alkyl replacement;
R 2Be H, (C 1-C 8) alkyl ,-(CR 11R 12) t-(C 3-C 10) cycloalkyl ,-(CR 11R 12) t-(C 6-C 10) aryl or-(CR 11R 12) t(4-10)-the element heterocycle base; R wherein 2Carbon atom optional by 1～3 R 13Group replaces; And R 2Theheterocyclic nitrogen atom optional by 1～3 (C 1-C 8) the alkyl replacement;
R 3Be selected from:
Figure A2004800167360002C2
Y is-(C=O)-or-SO 2-;
Y " is NR 10Or-O-;
P is 0,1 or 2;
Each q, r and t are 0,1,2,3,4 or 5 independently;
Each n is 0,1,2,3 or 4 independently;
Each k is 1,2 or 3 independently;
Each m and s are 0,1,2 or 3 independently;
Each j is 0,1 or 2;
Each R 4For-(CR 11R 12) n-,-(CR 11R 12) n-S-(CR 11R 12) n-,-(CR 11R 12) n-NR 10-,-(CR 11R 12) n-NR 10-(CR 11R 12) n-O-,-(CR 11R 12) n-O-(CR 11R 12) k-NR 10-,-(CR 11R 12) n-O-(CR 11R 12) n-,-(CR 11R 12) n-O-(CR 11R 12) k-O-(CR 11R 12) n-,-(CR 11R 12) n-CR 11=CR 12-(CR 11R 12) n-or-CH=CH-(CR 11R 12)-O-(CH 2) n-;
Each R 5For key or-(CR 11R 12) m-Z-(CR 11R 12) sWherein Z is-CR 11R 12-,-O-,-NR 10a-or-S (O) j-;
Each R 6For-(C=O)-OH ,-(C=O)-OM +,-(C=O)-(C 1-C 8) alkyl ,-(C=O)-O-(C 1-C 8) alkyl ,-(C=O)-NR 10R 11,-(C=O)-NR 10-SO 2-R 11,-SO 2-NH-R 10,-NH-SO 2-R 10,-(C=O)-NH-C ≡ N, or R 6Have the following formula structure:
Figure A2004800167360003C1
Or
Figure A2004800167360003C2
M +Be alkali metal cation or alkaline earth metal cation;
Each R 7And R 8Be H, (C independently 1-C 8) alkyl, (C 1-C 8) alkoxyl group ,-(CR 11R 12) t(C 3-C 10) cycloalkyl ,-(CR 11R 12) t(C 6-C 10) aryl ,-(CR 11R 12) t(C 6-C 10) aryl-O-,-(CR 11R 12) t(4-10)-the element heterocycle base or-(CR 11R 12) t(4-10)-element heterocycle base-O-;
Or R 7And R 8Optional connected carbon atom forms (C together 3-C 10) cycloalkyl or (3-10)-element heterocycle base;
Each Ar 1, Ar 2, Ar 3And Ar 4Representative (C 6-C 10) aryl or (5-10)-element heterocycle base; Each Ar wherein 1, Ar 2, Ar 3And Ar 4Ring carbon atom optional by 1～3 R 13Group replaces;
Ring A represent 3,4,5,6 or 7-person ring, chooses wantonly to comprise 1～4 and can identical or differently be selected from-N (R 10a)-, O and S (O) jHeteroatoms, wherein j is 0,1 or 2, condition is that this ring does not contain two adjacent O or S (O) jAtom; The carbon atom that wherein encircles the A part is optional by 1～3 R 13Group replaces;
R 9Be (C 1-C 8) alkyl ,-(CR 11R 12) t(C 6-C 10) aryl or-(CR 11R 12) t(4-10)-and the element heterocycle base, wherein t is 0,1,2,3,4 or 5 independently, wherein this R 9Group is replaced by 1～3 group, and these groups are independently selected from-(CR 11R 12) qNR 10R 11,-(CR 11R 12) qNR 10(C 1-C 6) alkyloyl ,-(CR 11R 12) qO (CR 11R 12) rR 10And-(CR 11R 12) qR 10Wherein the heterocyclic radical of aforementioned group, aryl and moieties are optional by 1～3 R 13Group replaces;
R 9aAnd R 10Be H or (C independently 1-C 8) alkyl;
R 11And R 12Be H, (C independently 1-C 8) alkyl, hydroxyl or (C 1-C 6) alkoxyl group;
R 10aBe selected from H, (C 1-C 8) alkyl ,-(C=O)-R 14,-SO 2NR 15R 16Or-S (O) j(C 1-C 6) alkyl;
Each R 13And R 13aBe independently selected from halogen, cyano group, nitro, trifluoromethoxy, trifluoromethyl, azido-, hydroxyl, (C 1-C 6) alkoxyl group, (C 1-C 10) alkyl, (C 2-C 6) alkenyl, (C 2-C 6) alkynyl ,-O-(CR 11R 12) k-O-(CR 11R 12) n-,-(C=O)-R 14,-(C=O)-O-R 15,-O-(C=O)-R 15,-NR 15(C=O)-R 16,-NR 15(C=O)-O-R 16,-(C=O)-NR 15R 16,-NR 15R 16,-NR 15OR 16,-SO 2NR 15R 16,-S (O) j(C 1-C 6) alkyl ,-O-SO 2-R 14,-NR 15-SO 2-R 16, R 15-(CR 11R 12) t(C 6-C 10Aryl) ,-(CR 11R 12) t(4-10)-the element heterocycle base ,-(CR 11R 12) q(C=O) (CR 11R 12) t(C 6-C 10) aryl ,-(CR 11R 12) q(C=O) (CR 11R 12) t(4-10)-the element heterocycle base ,-(CR 11R 12) tO (CR 11R 12) q(C 6-C 10) aryl ,-(CR 11R 12) tO (CR 11R 12) q(4-10)-the element heterocycle base ,-(CR 11R 12) qSO 2(CR 11R 12) t(C 6-C 10) aryl and-(CR 11R 12) qSO 2(CR 11R 12) t(4-10)-element heterocycle; Aforementioned R 13And R 13a1 or 2 ring carbon atom of the heterocyclic moiety of group is optional by oxo (=O) group replacement, and aforementioned R 13And R 13aThe alkyl of group, alkenyl, alkynyl, aryl and heterocyclic moiety are optional to be replaced by 1～3 substituting group, these substituting groups be independently selected from halogen, cyano group, nitro, trifluoromethyl, trifluoromethoxy, azido-,-OR 15,-(C=O)-R 15,-(C=O)-O-R 15,-O-(C=O)-R 15,-NR 15(C=O)-R 16,-(C=O)-NR 15R 16,-NR 15R 16,-NR 15OR 16, (C 1-C 6) alkyl, (C 2-C 6) alkenyl, (C 2-C 6) alkynyl ,-(CR 11R 12) t(C 6-C 10) aryl and-(CR 11R 2) t(4-10)-the element heterocycle base;
Each R 14, R 15And R 16Be independently selected from H, (C 1-C 6) alkyl ,-(CR 11R 12) t(C 6-C 10) aryl and-(CR 11R 12) t(4-10)-the element heterocycle base; 1 or 2 ring carbon atom of this heterocyclic group is optional by oxo (=O) group replacement, aforementioned R 14, R 15And R 16The alkyl of group, aryl and heterocyclic moiety are optional to be replaced by 1～3 substituting group, these substituting groups be independently selected from halogen, cyano group, nitro ,-NR 11R 12, trifluoromethyl, trifluoromethoxy, (C 1-C 6) alkyl, (C 2-C 6) alkenyl, (C 2-C 6) alkynyl, hydroxyl and (C 1-C 6) alkoxyl group;
R 17Be H, (C 1-C 8) alkyl ,-O-(C 1-C 8) alkyl, halogen, CN, OH, CF 3Or-O-CF 3
Wherein, above mentioned comprising not and halogen, SO or SO 2Group or the CH that is not connected with N, O or S atom 3(methyl), CH 2Any substituting group of (methylene radical) or CH (methyne) is chosen wantonly on described group to connect and is selected from hydroxyl, halogen, (C 1-C 4) alkyl, (C 1-C 4) alkoxyl group ,-NH 2,-NH (C 1-C 8) alkyl and-N ((C 1-C 8) alkyl) 2 substituting group.
2. according to the compound of claim 1, R wherein 3For
Figure A2004800167360005C1
3. according to the compound of claim 1, R wherein 3For
4. according to the compound of claim 1, R wherein 3For
Figure A2004800167360005C3
5. according to the compound of claim 1, R wherein 3For
Figure A2004800167360005C4
6. according to the compound of claim 2, has general formula
Wherein said-Ar 1-Ar 2Be selected from
With
Each Ar wherein 1And Ar 2Ring carbon atom optional by 1～3 R 13Group replaces, described R 13Group is selected from halogen, (C 1-C 8) alkyl and (C 1-C 8) alkoxyl group.
7. according to the compound of claim 2, be selected from
1-(3 '-[2-(5-methyl-2-phenyl-1,3-oxazole-4-yl) oxyethyl group]-1,1 '-biphenyl-3-yl } the oxygen base) cyclobutane-carboxylic acid (embodiment A-4);
2-(3 '-[2-(5-methyl-2-phenyl-1,3-oxazole-4-yl) oxyethyl group]-1,1 '-biphenyl-3-yl } the oxygen base) butyric acid (embodiment A-5);
2-(3-{6-[2-(5-methyl-2-phenyl-1,3-oxazole-4-yl) oxyethyl group] pyridine-2-yl } phenoxy group) butyric acid (embodiment A-6);
1-(3-{6-[2-(5-methyl-2-phenyl-1,3-oxazole-4-yl) oxyethyl group] pyridine-2-yl } phenoxy group) cyclobutane-carboxylic acid (embodiment A-7);
1-[(3 '-{ [2-(3-fluorophenyl)-5-methyl isophthalic acid, 3-oxazole-4-yl] methoxyl group } biphenyl-3-yl) oxygen base] cyclobutane-carboxylic acid (embodiment A-11);
1-(3 '-[3-(5-methyl-2-phenyl-1,3-oxazole-4-yl) propoxy-] biphenyl-3-yl } the oxygen base) cyclobutane-carboxylic acid (embodiment A-12);
1-1 (3 '-{ [5-(4-p-methoxy-phenyl)-1,2,4-oxadiazole-3-yl] methoxyl group } biphenyl-3-yl) the oxygen base] cyclobutane-carboxylic acid (embodiment A-17);
2-[(3 '-and 2-[2-(3-fluorophenyl)-5-methyl isophthalic acid, 3-oxazole-4-yl] oxyethyl group } biphenyl-3-yl) the oxygen base]-2 Methylpropionic acid (embodiment A-21);
2-methyl-2-(3 '-[(5-methyl-2-phenyl-1,3-oxazole-4-yl) methoxyl group] biphenyl-3-yl } the oxygen base) propionic acid (embodiment A-24);
2-oxyethyl group-3-{3 '-[2-(5-methyl-2-phenyl-1,3-oxazole-4-yl) oxyethyl group] biphenyl-3-yl } propionic acid (embodiment A-28);
And pharmacologically acceptable salt.
8. according to the compound of claim 3, have general formula:
Wherein Y be-(C=O)-or-SO 2-, Y " is NR 10, and p is 1.
9. according to the compound of claim 3, be selected from
2-methyl-2-{3-[({[2-(5-methyl-2-phenyl-1,3-oxazole-4-yl) oxyethyl group] carbonyl } amino) methyl] phenoxy group } propionic acid (Embodiment B-5);
2-methyl-2-{3-[({[(5-methyl-2-phenyl-1,3-oxazole-4-yl) methoxyl group] carbonyl } amino) methyl] phenoxy group } propionic acid (Embodiment B-6);
2-methyl-2-{4-[({[3-(5-methyl-2-phenyl-1,3-oxazole-4-yl) propoxy-] carbonyl } amino) methyl] phenoxy group } propionic acid (Embodiment B-7);
2-{3-fluoro-4-[({[2-(5-methyl-2-phenyl-1,3-oxazole-4-yl) oxyethyl group] carbonyl } amino) methyl] phenoxy group }-2 Methylpropionic acid (Embodiment B-9);
2-{3-[({[2-(5-methyl-2-phenyl-1,3-oxazole-4-yl) oxyethyl group] carbonyl } amino) methyl] phenoxy group } butyric acid (Embodiment B-13);
2-{3-[({[(5-methyl-2-phenyl-1,3-oxazole-4-yl) methoxyl group] carbonyl } amino) methyl] phenoxy group } butyric acid (Embodiment B-14);
1-{3-[({[2-(5-methyl-2-phenyl-1,3-oxazole-4-yl) oxyethyl group] carbonyl } amino) methyl] phenoxy group } cyclobutane-carboxylic acid (Embodiment B-15);
2-methyl-2-(3-{[({[2-(5-methyl-2-phenyl-1,3-oxazole-4-yl) ethyl] amino } carbonyl) the oxygen base] methyl } phenoxy group) propionic acid (Embodiment B-21);
2-oxyethyl group-3-{3-[({[3-(5-methyl-2-phenyl-1,3-oxazole-4-yl) propoxy-] carbonyl } amino) methyl] phenyl } propionic acid (Embodiment B-23);
2-oxyethyl group-3-{3-[({[2-(5-methyl-2-phenyl-1,3-oxazole-4-yl) oxyethyl group] carbonyl } amino) methyl] phenyl } propionic acid (Embodiment B-24);
And pharmacologically acceptable salt.
10. according to the compound of claim 4, have general formula:
Wherein, ring A be selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
Figure A2004800167360008C3
With
Figure A2004800167360008C4
Wherein---be optional two keys.
11. the compound according to claim 4 is selected from
1-{4-[3-(5-methyl-2-phenyl-1,3-oxazole-4-yl) propoxy-] benzyl } cyclobutane-carboxylic acid (Embodiment C-16);
1-{4-[2-(5-methyl-2-phenyl-1,3-oxazole-4-yl) oxyethyl group] benzyl } cyclobutane-carboxylic acid (Embodiment C-19);
2-(6-[2-(5-methyl-2-phenyl-1,3-oxazole-4-yl) oxyethyl group] and pyridin-3-yl } methyl) tetrahydrofuran (THF)-2-carboxylic acid (Embodiment C-48);
2-(5-[2-(5-methyl-2-phenyl-1,3-oxazole-4-yl) oxyethyl group] and pyridine-2-yl } methyl) tetrahydrofuran (THF)-2-carboxylic acid (Embodiment C-49);
2-(6-[2-(5-methyl-2-phenyl-1,3-oxazole-4-yl) oxyethyl group] and pyridin-3-yl } methyl) tetrahydrochysene-2H-pyrans-2-carboxylic acid (Embodiment C-56);
2-[(6-{2-[2-(3-chloro-phenyl-)-5-methyl isophthalic acid, 3-oxazole-4-yl] oxyethyl group } pyridin-3-yl) methyl] tetrahydrofuran (THF)-2-carboxylic acid (Embodiment C-59);
2-[(6-{2-[2-(3-methyl oxygen base phenyl)-5-methyl isophthalic acid, 3-oxazole-4-yl] oxyethyl group } pyridin-3-yl) methyl] tetrahydrofuran (THF)-2-carboxylic acid (Embodiment C-62);
2-{5-[2-(5-methyl-2-phenyl-oxazoles-4-yl)-oxyethyl group]-pyrazine-2-ylmethyl }-tetrahydrofuran (THF)-2-carboxylic acid (Embodiment C-77);
-4-[2-(5-methyl-2-phenyl-1,3-oxazole-4-yl) oxyethyl group] and benzyl } tetrahydrofuran (THF)-2-carboxylic acid (Embodiment C-78);
2-{6-[2-(5-methyl-2-phenyl-oxazoles-4-yl)-oxyethyl group]-naphthalene-2-ylmethyl }-tetrahydrofuran (THF)-2-carboxylic acid (Embodiment C-91);
And pharmacologically acceptable salt.
12. the compound according to claim 5 has general formula:
Figure A2004800167360009C1
Or
Figure A2004800167360009C2
13. the compound according to claim 12 is selected from
2-oxyethyl group-3-{6-[2-(5-methyl-2-phenyl-1,3-oxazole-4-yl) oxyethyl group] pyridin-3-yl } propionic acid (embodiment D-1);
2-methoxyl group-3-(6-{2-[5-methyl-2-(3-aminomethyl phenyl)-1,3-oxazole-4-yl] oxyethyl group } pyridin-3-yl) propionic acid (embodiment D-3);
2-methoxyl group-3-{6-[2-(4-Phenoxyphenyl) oxyethyl group] pyridin-3-yl } propionic acid (embodiment D-13);
2-oxyethyl group-3-[6-(2-{4-[(phenyl sulfonyl) oxygen base] phenyl } oxyethyl group) pyridin-3-yl] propionic acid (embodiment D-17);
2-oxyethyl group-3-{5-[2-(5-methyl-2-phenyl-oxazoles-4-yl)-oxyethyl group]-pyridine-2-yl }-propionic acid (embodiment D-23);
2-methoxyl group-2-methyl-3-{6-[3-(5-methyl-2-phenyl-oxazoles-4-yl)-propoxy-]-pyridin-3-yl }-propionic acid (embodiment D-27);
2-methoxyl group-2-methyl-3-{5-[2-(5-methyl-2-phenyl-oxazoles-4-yl)-oxyethyl group]-pyridine-2-yl }-propionic acid (embodiment D-29);
3-(6-{2-[2-(4-chloro-phenyl)-5-methyl-oxazoles-4-yl]-oxyethyl group }-pyridin-3-yl)-2-methoxyl group-2-methyl-propionic acid (embodiment D-30);
2-methoxyl group-2-methyl-3-{6-[2-(5-methyl-2-Ben Ji oxazole-4-yl)-oxyethyl group]-pyridin-3-yl }-propionic acid (embodiment D-35);
2-methoxyl group-3-(6-{2-[2-(3-methoxyl group-phenyl)-5-methyl-oxazoles-4-yl]-oxyethyl group }-pyridin-3-yl)-2-methyl-propionic acid (embodiment D-43);
And pharmacologically acceptable salt.
14. a method for the treatment of sign, insulin resistant syndrome and the PPAR relative disease of Mammals non-insulin-dependent diabetes mellitus (NIDDM), polycystic ovary syndrome, obesity, hyperglycemia, hyperlipidaemia, hypercholesterolemia, atherosclerosis, hypertriglyceridemia, hyperinsulinemia, unusual Regular Insulin and/or glucose imbalance comprises the alpha substituted carboxylic acid compound to the claim 1 of the Mammals drug treatment significant quantity of needs treatment.
15. composition that comprises the described compound of at least a claim 1 and pharmaceutically acceptable carrier thereof; This compound is preferably united use with other medicines such as alpha-glucosidase inhibitor, aldose reductase inhibitor, biguanides preparation, statin compound, shark alkene synthetic inhibitor, fibrate, LDL metabolic improver and angiotensin converting enzyme inhibitor.
CNA2004800167362A 2003-04-15 2004-04-01 Alpha substituted carboxylic acid as PPAR modulators Pending CN1805943A (en)

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