CN101326161B - Novel compounds - Google Patents

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Publication number
CN101326161B
CN101326161B CN200680046177.9A CN200680046177A CN101326161B CN 101326161 B CN101326161 B CN 101326161B CN 200680046177 A CN200680046177 A CN 200680046177A CN 101326161 B CN101326161 B CN 101326161B
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Prior art keywords
phenyl
chloro
acetic acid
phenoxy group
trifluoromethyl
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CN200680046177.9A
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CN101326161A (en
Inventor
蒂莫西·J·卢克
鲁克萨纳·T·穆罕默德
斯蒂芬·汤姆
阿尼尔·帕特尔
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AstraZeneca AB
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AstraZeneca AB
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Priority claimed from GB0608299A external-priority patent/GB0608299D0/en
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Priority claimed from PCT/GB2006/003689 external-priority patent/WO2007039736A1/en
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Abstract

The invention relates to substituted phenylacetic acids as useful pharmaceutical compounds for treating respiratory disorders, pharmaceutical compositions containing them, and processes for their preparation.

Description

Novel compound
Technical field
The phenylacetic acid that the present invention relates to replace, it can be used as the medical compounds that is used for the treatment of respiratory system disease, comprises the pharmaceutical composition of described medical compounds and prepare their method.
Background technology
EPA 1 170 594 has disclosed and has identified the method that can be used for treating by the compound of the illness of PGD2 mediation, and PGD2 is the part of orphan receptor CRTH2.GB 1356834 disclosed a series of it is said have anti-inflammatory, the compound of pain relieving and antipyretic activity.Have been found that some phenylacetic acid is that tool is activated to the CRTH2 acceptor, therefore expectation can be used for treating various respiratory system diseases, comprises asthma and COPD.
Disclosed the phenylacetic acid of being combined with CRTh2 among the WO2004/058164.These compounds have double activity, both the CRTh2 acceptor are had activity, again the DP acceptor are had activity.The amino that compound disclosed in the WO2004/058164 has the embedding substituting group (embeddedamino derived substituents) of deriving, these substituting groups form the aniline (mutagenic anilines) of mutagenesis potentially by metabolism.
EP91402638 has disclosed related compound, and these compounds it is said and can be used for treating various inflammatory diseasess and/or allergic disease, especially asthma, allergic rhinitis, sacroiliitis and inflammation.
Summary of the invention
The present invention relates to the compound of selectivity and CRTh2 receptors bind.These phenylacetic acids do not comprise any aniline (embedded anilines) with embedding of genotoxic potential, therefore can be advantageously as potential drug molecule.
Therefore, first aspect of the present invention provides formula (I) compound or pharmaceutically acceptable salt thereof:
Figure S2006800461779D00021
Wherein
A and D are independently selected from hydrogen, halogen, CN, OR 3, S (O) nR 3(wherein n is 0,1 or 2), nitro, aryl, heteroaryl, C 3-8Cycloalkyl or C 1-6Alkyl, wherein said C 3-8Cycloalkyl or C 1-6Alkyl is optional to be replaced by halogen atom;
E is O, S, NR 6Or CR 1R 2
V is N or C (H);
W is nitrogen, or W is carbon atom, and described carbon atom is by hydrogen, halogen, CN, SO 2R 9Or C 1-3Alkyl replaces, wherein said C 1-3Alkyl is optional to be replaced by halogen atom;
X is nitrogen, or X is carbon atom, and described carbon atom is by hydrogen, halogen, CN, SO 2R 9Or C 1-3Alkyl replaces, wherein said C 1-3Alkyl is optional to be replaced by halogen atom;
Y is selected from hydrogen, CN, halogen or C 1-6Alkyl, wherein said C 1-6Alkyl is optional to be replaced by one or more halogen atoms;
Z is selected from hydrogen, halogen, CN, SO 2NR 4R 5, CONR 4R 5, COR 6, CO 2R 6, SO 2R 9Or OR 9
R 1And R 2Represent independently hydrogen atom, halogen or C 1-6Alkyl; Or
R 1And R 2Can form together 3-8 unit ring, optional one or more O of being selected from, S and the NR of containing of described 3-8 unit's ring 6Atom, and described 3-8 unit ring itself is chosen wantonly by one or more C 1-3Alkyl or halogen replace;
R 3Be hydrogen, SO 2R 7, or optional by halogen or NR 4R 5The C that replaces 1-6Alkyl;
R 4And R 5Represent independently hydrogen, C 3-8Cycloalkyl or C 1-6Alkyl, wherein said C 3-8Cycloalkyl or C 1-6Alkyl is optional to be independently selected from following substituting group and to replace by one or more: halogen, CN, C 3-7Cycloalkyl, C 1-6Alkyl, OR 3, NR 7R 8, aryl, heteroaryl, S (O) nR 9(wherein n=0,1 or 2), CONR 7R 8, NR 3COR 10, SO 2NR 4R 5And NR 3SO 2R 9Or
R 4And R 5Can form with the nitrogen-atoms that they connect 3-8 unit saturated rings, optional one or more O of being selected from, N, the S (O) of containing of described 3-8 unit's saturated rings n(wherein n=0,1 or 2) and NR 3Atom, and described 3-8 unit saturated rings itself is chosen wantonly by one or more halogens, OR 3, C 3-8Cycloalkyl or C 1-6Alkyl replaces, wherein said C 3-8Cycloalkyl or C 1-6Alkyl is optional to be replaced by one or more halogens;
R 6Expression aryl, heteroaryl, C 3-8Cycloalkyl or C 1-6Alkyl, all these groups are all chosen wantonly by one or more and are independently selected from following substituting group and replace: halogen, C 3-7Cycloalkyl, C 1-6Alkyl, OR 3, CN, NR 7R 8, aryl, heteroaryl, S (O) nR 9(wherein n=0,1 or 2), CONR 7R 8, NR 3COR 10, SO 2NR 4R 5And NR 3SO 2R 9
R 7Represent independently hydrogen atom or C 1-C 6Alkyl, wherein said C 1-C 6Alkyl is optional to be replaced by one or more halogen atoms;
R 8Be hydrogen, C 1-4Alkyl ,-COC 1-C 4Alkyl, CO 2C 1-C 4Alkyl or CONR 6C 1-C 4Alkyl;
R 9Expression aryl, heteroaryl, C 3-C 7Cycloalkyl or C 1-6Alkyl, wherein said C 3-C 7Cycloalkyl or C 1-6Alkyl is optional to be independently selected from following substituting group and to replace by one or more: halogen, C 3-C 7Cycloalkyl, aryl, heteroaryl, OR 6, NR 10R 11, S (O) nR 6(wherein n=0,1 or 2), CONR 6R 7, NR 6COR 7, SO 2NR 4R 5And NR 6SO 2R 7
R 10And R 11Represent independently aryl, heteroaryl, hydrogen, C 3-7Cycloalkyl or C 1-6Alkyl, wherein said C 3-7Cycloalkyl or C 1-6Alkyl is optional to be independently selected from following substituting group and to replace by one or more: halogen, C 3-7Cycloalkyl, aryl, heteroaryl, OH, OR 9, NR 4R 5, S (O) nR 6(wherein n=0,1 or 2), CONR 4R 5, NR 6COR 7, SO 2NR 4R 5And NR 6SO 2R 7Or
R 10And R 11Can form with the nitrogen-atoms that they connect 3-8 unit saturated heterocyclic, optional one or more O of being selected from, the S (O) of containing of described 3-8 unit's saturated heterocyclic n(wherein n=0,1 or 2) and NR 8Atom, and described 3-8 unit saturated heterocyclic itself is chosen wantonly by halogen or C 1-C 3Alkyl replaces;
Condition is:
● A and D are not hydrogen simultaneously;
● A and D are not contraposition quilt-S (O) nThe aryl of-replacement, wherein n is 0,1 or 2;
● when V, W and X were carbon, all substituting groups on the phenyl ring (V, W, X, Y and Z) not all were hydrogen.
In the context of the present specification, except as otherwise noted, the alkyl or alkenyl in alkyl or alkenyl or the substituting group partly can be straight or branched, and can choose wantonly by one or more halogen atoms and replace.
The example of aryl comprises phenyl and naphthyl.
Heteroaryl is defined as 5-7 unit aromatic ring, maybe can be two rings that 6,6-or 6,5-condense, and described heteroaryl contains the heteroatoms of one or more N of being selected from, S and O.Described two rings can connect by carbon or nitrogen, can connect by 5 or 6 yuan of rings, and can be saturated wholly or in part.
Example includes but not limited to pyridine, pyrimidine, thiazole, oxazole, pyrazoles, imidazoles, furans, isoxazole, pyrroles, isothiazole, azulene (azulene), naphthyl, indenes, quinoline, isoquinoline 99.9, indoles, indolizine, benzo [b] furans, benzo [b] thiophene, 1H-indazole, benzoglyoxaline, benzothiazole, benzoxazole, purine, 4H-quinolizine, cinnolines, phthalazines, quinazoline, quinoxaline, 1,8-naphthyridine, pteridine, quinolone and 1,2-methylenedioxybenzenes.
Can choose wantonly by one or more as substituent aryl or heteroaryl and to be independently selected from following substituting group and to replace: halogen, CN, OR 7, SO 2R 3, CONR 7R 8, SO 2NR 4R 5, C 3-8Cycloalkyl or C 1-6Alkyl, wherein said C 3-8Cycloalkyl or C 1-6Alkyl is optional by one or more halogen and OR of being independently selected from 3Substituting group replace.
Preferably, A is hydrogen, halogen, CN, OR 3, aryl, heteroaryl or C 1-6Alkyl, wherein said C 1-6Alkyl is optional to be replaced by one or more halogen atoms;
More preferably, A is hydrogen, halogen or C 1-6Alkyl, wherein said C 1-6Alkyl is optional to be replaced by one or more halogen atoms;
Preferably, D is hydrogen, halogen or C 1-6Alkyl, wherein said C 1-6Alkyl is optional to be replaced by one or more halogen atoms;
Preferably, not in the situation of hydrogen at D, A is hydrogen; Be not in the situation of hydrogen at A, D is hydrogen;
Preferably, E is oxygen or sulphur; More preferably, E is oxygen;
Preferably, V is C (H);
Preferably, W is carbon atom, and described carbon atom is by hydrogen, halogen, CN or C 1-3Alkyl replaces, wherein said C 1-3Alkyl is optional to be replaced by halogen atom; More preferably, W is carbon atom, and described carbon atom is by hydrogen, halogen or C 1-3Alkyl replaces, wherein said C 1-3Alkyl is optional to be replaced by halogen atom; Most preferably, W is C (H);
Preferably, X is carbon atom, and described carbon atom is replaced by hydrogen or halogen; More preferably, X is C (H);
Preferably, Y is halogen, cyano group or the optional C that is replaced by halogen atom 1-3Alkyl;
Preferably, Z is selected from SO 2R 9, SO 2NR 4R 5, CONR 4R 5Or COR 6
More preferably, Z is SO 2R 9
Preferably, R 1And R 2All be hydrogen, or R 1Or R 2In one be methyl, and another is hydrogen.More preferably, R 1And R 2All be hydrogen.
Preferred compound of the present invention comprises:
4-chloro-3-[2-chloro-4-(methyl sulphonyl) phenoxy group] and phenyl } acetic acid;
4-chloro-3-[4-(methyl sulphonyl)-2-(trifluoromethyl) phenoxy group] and phenyl } acetic acid;
4-chloro-3-[2-chloro-4-(ethylsulfonyl) phenoxy group] and phenyl } acetic acid;
4-chloro-3-[4-(ethylsulfonyl)-2-(trifluoromethyl) phenoxy group] and phenyl } acetic acid;
4-chloro-3-[4-(methyl sulphonyl) phenoxy group] and phenyl } acetic acid;
2-{4-chloro-3-[2-chloro-4-(methyl sulphonyl) phenoxy group] phenyl } propionic acid;
(4-chloro-3-{2-chloro-4-[(dimethylamino) alkylsulfonyl] phenoxy group } phenyl) acetic acid;
[4-chloro-3-(3-cyano-benzene oxygen) phenyl] acetic acid;
4-chloro-3-[2-fluoro-4-(methyl sulphonyl) phenoxy group] and phenyl } acetic acid;
4-chloro-3-[4-(ethylsulfonyl)-2-fluorophenoxy] and phenyl } acetic acid;
4-chloro-3-[2-cyano group-4-(methyl sulphonyl) phenoxy group] and phenyl } acetic acid;
4-chloro-3-[2-cyano group-4-(ethylsulfonyl) phenoxy group] and phenyl } acetic acid;
4-chloro-3-[4-(methyl sulphonyl)-3-(trifluoromethyl) phenoxy group] and phenyl } acetic acid;
4-chloro-3-[2-cyano group-5-(trifluoromethyl) phenoxy group] and phenyl } acetic acid;
(4-chloro-3-{2-fluoro-4-[(4-luorobenzyl) alkylsulfonyl] phenoxy group } phenyl) acetic acid;
[3-(4-benzoyl-2-fluorophenoxy)-4-chloro-phenyl-] acetic acid;
(4-chloro-3-{2-chloro-4-[(isobutylamino) carbonyl] phenoxy group } phenyl) acetic acid;
3-chloro-5-[2-chloro-4-(methyl sulphonyl) phenoxy group] and phenyl } acetic acid;
3-chloro-5-[2-chloro-4-(ethylsulfonyl) phenoxy group] and phenyl } acetic acid;
3-[2-chloro-4-(ethylsulfonyl) phenoxy group]-the 5-fluorophenyl } acetic acid;
3-fluoro-5-[4-(methyl sulphonyl)-2-(trifluoromethyl) phenoxy group] and phenyl } acetic acid;
3-[2-chloro-4-(ethylsulfonyl) phenoxy group]-the 4-fluorophenyl } acetic acid;
4-fluoro-3-[4-(methyl sulphonyl)-2-(trifluoromethyl) phenoxy group] and phenyl } acetic acid;
4-chloro-3-[2-fluoro-4-(phenyl sulfonyl) phenoxy group] and phenyl } acetic acid;
[3-[2-chloro-4-(methyl sulphonyl) phenoxy group]-5-(trifluoromethyl) phenyl] acetic acid;
[3-[2-chloro-4-(ethylsulfonyl) phenoxy group]-5-(trifluoromethyl) phenyl] acetic acid;
3-chloro-5-[2-fluoro-4-(methyl sulphonyl) phenoxy group] and phenyl } acetic acid;
3-chloro-5-[2-cyano group-4-(ethylsulfonyl) phenoxy group] and phenyl } acetic acid;
3-chloro-5-[2-chloro-4-(phenyl sulfonyl) phenoxy group] and phenyl } acetic acid;
3-chloro-5-[4-(ethylsulfonyl)-2-fluorophenoxy] and phenyl } acetic acid;
3-chloro-5-[2-fluoro-4-(phenyl sulfonyl) phenoxy group] and phenyl } acetic acid;
[3-{2-fluoro-4-[(4-luorobenzyl) alkylsulfonyl] phenoxy group }-5-(trifluoromethyl) phenyl] acetic acid;
(3-chloro-5-{2-fluoro-4-[(4-luorobenzyl) alkylsulfonyl] phenoxy group } phenyl) acetic acid;
(3-chloro-5-{2-chloro-4-[(4-luorobenzyl) alkylsulfonyl] phenoxy group } phenyl) acetic acid;
3-chloro-5-[4-(methyl sulphonyl)-2-(trifluoromethyl) phenoxy group] and phenyl } acetic acid;
3-chloro-5-[4-(ethylsulfonyl)-2-(trifluoromethyl) phenoxy group] and phenyl } acetic acid;
[3-[2-fluoro-4-(phenyl sulfonyl) phenoxy group]-5-(trifluoromethyl) phenyl] acetic acid;
[3-[2-chloro-4-(phenyl sulfonyl) phenoxy group]-5-(trifluoromethyl) phenyl] acetic acid;
[3-[4-(ethylsulfonyl)-2-fluorophenoxy]-5-(trifluoromethyl) phenyl] acetic acid;
[3-[2-cyano group-4-(ethylsulfonyl) phenoxy group]-5-(trifluoromethyl) phenyl] acetic acid;
[3-[4-(ethylsulfonyl)-2-(trifluoromethyl) phenoxy group]-5-(trifluoromethyl) phenyl] acetic acid;
3-[4-(benzyl alkylsulfonyl)-2-chlorophenoxy]-the 5-chloro-phenyl-} acetic acid;
3-chloro-5-[4-(phenyl sulfonyl)-2-(trifluoromethyl) phenoxy group] and phenyl } acetic acid;
3-chloro-5-[2-cyano group-4-(phenyl sulfonyl) phenoxy group] and phenyl } acetic acid;
3-[4-(benzyl alkylsulfonyl)-2-fluorophenoxy]-the 5-chloro-phenyl-} acetic acid;
(3-chloro-5-{2-fluoro-4-[(3-luorobenzyl) alkylsulfonyl] phenoxy group } phenyl) acetic acid;
3-[4-(benzyl alkylsulfonyl)-2-(trifluoromethyl) phenoxy group]-the 5-chloro-phenyl-} acetic acid;
(3-chloro-5-{2-fluoro-4-[(2-luorobenzyl) alkylsulfonyl] phenoxy group } phenyl) acetic acid;
(3-chloro-5-{4-[(4-chlorobenzyl) alkylsulfonyl]-the 2-fluorophenoxy } phenyl) acetic acid;
2-[3-[4-(ethylsulfonyl)-2-(trifluoromethyl) phenoxy group]-5-(trifluoromethyl) phenyl] propionic acid;
2-[3-[2-chloro-4-(ethylsulfonyl) phenoxy group]-5-(trifluoromethyl) phenyl] propionic acid;
2-[3-[2-chloro-4-(phenyl sulfonyl) phenoxy group]-5-(trifluoromethyl) phenyl] propionic acid;
2-[3-{2-chloro-4-[(4-luorobenzyl) alkylsulfonyl] phenoxy group }-5-(trifluoromethyl) phenyl] propionic acid;
(3-chloro-5-{4-[(4-chlorobenzyl) alkylsulfonyl]-the 2-fluorophenoxy } phenyl) acetic acid;
3-bromo-5-[2-chloro-4-(ethylsulfonyl) phenoxy group] and phenyl } acetic acid;
3-[2-chloro-4-(ethylsulfonyl) phenoxy group]-the 5-aminomethyl phenyl } acetic acid;
3-[2-chloro-4-(ethylsulfonyl) phenoxy group]-5-cyano-phenyl methyl acetate;
[3-{[2-chloro-4-(ethylsulfonyl) phenyl] sulfenyl }-5-(trifluoromethyl) phenyl] acetic acid;
3-[2-chloro-4-(ethylsulfonyl) phenoxy group]-the 5-p-methoxy-phenyl } acetic acid;
[3-{2-chloro-4-[(2-luorobenzyl) alkylsulfonyl] phenoxy group }-5-(trifluoromethyl) phenyl] acetic acid;
[3-{[3-methyl-5-(phenyl sulfonyl) pyridine-2-yl] oxygen base }-5-(trifluoromethyl) phenyl] acetic acid;
[3-[2-chloro-4-(morpholine-4-base alkylsulfonyl) phenoxy group]-5-(trifluoromethyl) phenyl] acetic acid;
[3-(4-benzoyl-2-chlorophenoxy)-5-(trifluoromethyl) phenyl] acetic acid;
[3-{2-chloro-4-[(3-luorobenzyl) alkylsulfonyl] phenoxy group }-5-(trifluoromethyl) phenyl] acetic acid;
3-bromo-5-[2-fluoro-4-(phenyl sulfonyl) phenoxy group] and phenyl } acetic acid;
[3-{2-fluoro-4-[(4-fluorophenyl) alkylsulfonyl] phenoxy group }-5-(trifluoromethyl) phenyl] acetic acid;
3-chloro-5-[4-(ethylsulfonyl)-3-(trifluoromethyl) phenoxy group] and phenyl } acetic acid;
3-chloro-5-[5-chloro-2-fluoro-4-(pyrrolidin-1-yl carbonyl) phenoxy group] and phenyl } acetic acid;
3-cyano group-5-[2-fluoro-4-(phenyl sulfonyl) phenoxy group] and phenyl } acetic acid;
(3-chloro-5-{2-fluoro-4-[(4-fluorophenyl) alkylsulfonyl] phenoxy group } phenyl) acetic acid;
(3-chloro-5-{[2-cyano group-4-(ethylsulfonyl) phenyl] sulfenyl } phenyl) acetic acid;
(3-chloro-5-{[4-(ethylsulfonyl)-2-(trifluoromethyl) phenyl] sulfenyl } phenyl) acetic acid;
(3-chloro-5-{[2-fluoro-4-(phenyl sulfonyl) phenyl] sulfenyl } phenyl) acetic acid;
[3-(4-benzoyl-3,5-difluoro phenoxy group)-5-chloro-phenyl-] acetic acid;
3-chloro-5-[2-chloro-4-(4-fluoro benzoyl) phenoxy group] and phenyl } acetic acid;
3-[2-fluoro-4-(phenyl sulfonyl) phenoxy group]-the 5-aminomethyl phenyl } acetic acid;
3-ethyl-5-[2-fluoro-4-(phenyl sulfonyl) phenoxy group] and phenyl } acetic acid;
[3-{2-chloro-4-[(4-luorobenzyl) alkylsulfonyl] phenoxy group }-5-(trifluoromethyl) phenyl] acetic acid;
[3-[2-cyano group-4-(phenyl sulfonyl) phenoxy group]-5-(trifluoromethyl) phenyl] acetic acid;
5-[2-chloro-4-(ethylsulfonyl) phenoxy group] and biphenyl-3-yl } acetic acid;
3-[2-chloro-4-(ethylsulfonyl) phenoxy group]-5-pyridine-2-base phenyl } acetic acid;
3-[2-chloro-4-(ethylsulfonyl) phenoxy group]-5-[2-(dimethylamino) oxyethyl group] phenyl } acetic acid;
[3-{2-chloro-4-[(pyridine-2-ylmethyl) alkylsulfonyl] phenoxy group }-5-(trifluoromethyl) phenyl] acetic acid;
With its pharmacologically acceptable salt.
Some formula (I) compound can exist with stereoisomeric forms in any ratio.It should be understood that the present invention contains all geometrical isomers of formula (I) compound and optically active isomer and composition thereof, comprise racemic modification.Tautomer and its mixture also consist of one aspect of the present invention.
Can with changing into its pharmacologically acceptable salt or solvate with following formula (I) compound, be preferably base addition salt (such as sodium salt, sylvite, calcium salt, aluminium salt, lithium salts, magnesium salts, zinc salt, benzyl star (benzathine) salt, chloroprocaine salt, choline salt, diethanolamine salt, ethanolamine salt, ethylenediamine salt, tert-butylamine salt, meglumine salt, tromethamine salt or procaine salt) or acid salt (such as hydrochloride, hydrobromate, phosphoric acid salt, acetate, fumarate, maleate, tartrate, Citrate trianion, oxalate, mesylate or tosilate).
It will be understood by those skilled in the art that in the method for the invention some functional group in initial reagent or the midbody compound may need to protect with protecting group.Thereby the preparation of formula (I) compound may be involved in the suitable stage and remove one or more protecting groups.Protection and the deprotection of functional group fully are documented in ' Protective Groups in Organic Chemistry ', edited by J.W.F.McOmie, Plenum Press (1973) and ' Protective Groups in Organic Synthesis ', 3rdedition, T.W.Greene ﹠amp; P.G.M.Wuts is among the Wiley-Interscience (1999).
Formula (I) compound can prepare by the following method: make formula (II) compound and formula (III) compound as reacting summarizing in the scheme 1:
Figure S2006800461779D00081
Scheme 1
Wherein A, D, E, V, W, X, Y, Z, R 1And R 2Such as in formula (I) definition, or be its shielded deriveding group.L 1Be leavings group, such as halogen, be preferably fluorine or chlorine.J is alkyl, for example methyl, ethyl or the tertiary butyl.Reaction is carried out in the presence of alkali (such as cesium carbonate etc.) in polar solvent (such as NMP or DMF) in the temperature that raises.Subsequently, ester group utilizes alkali (such as sodium hydroxide) to remove in suitable organic solvent (such as methyl alcohol, ethanol or THF).
Formula (I) compound also can be directly by making formula (IV) compound and formula (III) compound react to prepare.
Formula (II) and formula (IV) compound can be as preparing summarizing in the scheme 2:
Figure S2006800461779D00091
Scheme 2
Wherein A, D and Y such as in formula (I) definition, or be its shielded deriveding group.J is as defining with regard to formula (II) compound.R 21Be C 1-3Alkyl is such as methyl.
The hydrolysis of ester group J can utilize ordinary method to carry out, and for example methyl esters and ethyl ester are processed with aqueous sodium hydroxide solution, and the tert-butyl ester is processed with acid (such as trifluoroacetic acid).
Formula (IV) compound (wherein E is O) can be as preparing being summarized among the scheme 2A:
Figure S2006800461779D00092
Scheme 2A
Wherein A and D such as in formula (I) definition, or be its shielded deriveding group.L 2Be chlorine or fluorine.L 3Be suitable leavings group, such as chlorine, bromine or methylsulfonic acid ester group.
Group L in formula (VIII) compound 2In suitable solvent (such as DMPU or HMPA), utilize sodium methylate to replace.Then, the phenylformic acid group utilizes lithium aluminium hydride or borine to be reduced into alcohol in suitable solvent (such as THF).Leavings group L 3Can introduce by the following method: with thionyl chloride or phosphorus tribromide reduction-type (X) compound, or by in suitable organic solvent (such as methylene dichloride), converting it into methanesulfonates with methylsulfonyl chloride reduction-type (X) compound in the presence of the alkali (such as triethylamine).Then, group L 3In polar solvent (such as DMF), replace with sodium cyanide in the temperature that raises, obtain formula (XII) compound.Resulting nitrile hydrolyzable becomes acid, and group Y can utilize moisture HBr to come deprotection in the temperature that raises in acetic acid in a step.
Some formula (VIII) compound is purchased.
(wherein in the substituting group is SO to some formulas (III) compound 2R 9) can prepare by general reaction scheme 3:
Figure S2006800461779D00101
Scheme 3
L wherein 1, V, W, X, Y and R 9Such as in formula (III) definition, or be its shielded deriveding group.Diazotization is carried out in suitable organic solvent (for example acetonitrile) in the temperature (such as 60 ℃) that raises.Corresponding thioether (sulfide) utilizes MCPBA or ozone (as oxygenant) to come oxidation in suitable solvent (for example methylene dichloride).
Some formula (III) compound (containing the sulfone part) also can be as preparing summarizing in the reaction scheme 4:
Figure S2006800461779D00102
Scheme 4
L wherein 1, V, W, X, Y and R 9Such as in formula (III) definition, or be its shielded deriveding group.
L 4For suitable leavings group, such as halogen, be preferably iodine, bromine or chlorine.Make the reaction of described mercaptan and formula (XIII) compound, then utilize suitable oxygenant (such as MCPBA or ozone) to come oxidation.
(wherein Z is COR to some formula (III) compound 6) can be as summarizing in the scheme 5, preparing:
Figure S2006800461779D00111
Scheme 5
L wherein 1, V, W, X, Y and R 6Such as in formula (III) definition, or be its shielded deriveding group.Formula (XIV) compound usable criterion condition (for example heating in the presence of suitable Lewis acid (LewisAcid) (such as iron(ic) chloride (III))) is carried out Knut Fridell-Kerafyrm thatch acidylate (Friedel-Crafts acylation).Formula (XIV) compound is purchased, or utilizes known literature method to prepare.
(wherein Z is SO to some formula (III) compound 2NR 4R 5Or CONR 4R 5) as summarizing in the scheme 6, preparing:
Scheme 6
L wherein 1, V, W, X, Y, R 4And R 5Such as in formula (III) definition, or be its shielded deriveding group, and wherein J is C (O) or SO 2, L is suitable leavings group (such as halogen), or replacedly, L is hydroxyl.Described coupling utilizes the acid amides of standard or sulphonamide coupling method to carry out.For example, be in the situation of halogen at L, reaction can be carried out by the following method: in suitable solvent (such as DCM), in the presence of suitable alkali (such as Hunigs alkali (Hunigs base) or triethylamine), stir.Replacedly, be in the situation of hydroxyl at L, reaction can be carried out under the following conditions: utilize suitable coupling agent (such as PyBOP or HATU or CDI), with suitable alkali (such as Hunigs alkali or DBU), in suitable solvent (such as DCM or THF), carry out described reaction.Formula (XV) compound is purchased, or utilizes known literature method to prepare.
Formula (IV) compound (wherein E is S) can be as preparing from formula (IV) compound (wherein E is O) being summarized in the scheme 7:
Figure S2006800461779D00121
Side poly-7
Wherein A and D such as in formula (I) definition, or be its shielded deriveding group.Formula (IV) compound and dimethyl sulphide heat in suitable solvent (such as the tetradecane or diphenyl ether) in the temperature that raises subsequently for chloroformamide (dimethylthiocarbamoyl chloride) coupling, and reset this moment.After being hydrolyzed with suitable alkali (such as sodium hydroxide), obtain formula (II) compound.
(wherein A is CN, C to formula (I) compound 1-6Alkyl, aryl or heteroaryl) can be as summarizing in the scheme 8, preparing:
Figure S2006800461779D00122
Scheme 8
Wherein D, E, V, W, X, Y, Z, R 1And R 2Such as in formula (I) definition, or be its shielded deriveding group.Reaction utilizes the metal catalytic coupling technology of standard to carry out.For example, described linked reaction can be carried out by the following method: the palladium catalyst (such as two diphenylphosphino ferrocene palladiums (II)) with suitable activation is reacting the boric acid affixture of formula (XVI) compound and A in suitable solvent (such as toluene, THF Huo diox) in the presence of the suitable alkali (such as yellow soda ash or salt of wormwood or cesium carbonate).Reaction is being carried out in the temperature (for example 80 ℃) that raises usually.Replacedly, described linked reaction can be carried out by the following method: the palladium catalyst (such as two diphenylphosphino ferrocene palladiums (II)) with suitable activation makes the zinc affixture of formula (XVI) compound and A react in suitable solvent (such as toluene, THF Huo diox) in the temperature (for example 80 ℃) that raises.
(wherein A is OR to some compound of formula (I) 3) can prepare according to scheme 9:
Figure S2006800461779D00131
Scheme 9
Wherein D, E, V, W, X, Y, Z, R 1And R 2Such as in formula (I) definition, or be its shielded deriveding group.E 1Such as in formula (II) definition.L 2Be suitable leavings group, such as the alcohol radical (such as methylsulfonic acid ester group (mesylate) or toluenesulphonic acids ester group (tosylate)) of halogen or activation.Formula (XVII) compound and formula (XVIII) compound utilize suitable alkali (such as yellow soda ash or salt of wormwood or cesium carbonate) to come coupling in suitable solvent (such as acetonitrile or DMF).Subsequently, ester group is removed as described above like that.
In yet another aspect, the invention provides formula (I) compound or its prodrug, pharmacologically acceptable salt or the solvate purposes in treatment.
Formula (I) compound or pharmaceutically acceptable salt thereof has as medicine particularly as the activity of CRTh2 receptor activity modulators, and can be used for disposing among (therapeutic or preventative) human and non-human animal by PGD 2The condition/disease that produces with the excessive of its metabolite or imbalance and worsen or cause.
Compound or pharmaceutically acceptable salt thereof of the present invention can be used for treating following disease:
1. respiratory tract: airway obstructive disease, comprise asthma, comprise bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma, exercise-induced asthma, drug-induced property (comprising what acetylsalicylic acid and NSAID brought out) asthma and bringing out property of dust asthma, intermission asthma and persistent asthma, and the asthma of various severities, reach the airway hyperreactivity that other reason causes; Chronic obstructive pulmonary disease (COPD); Bronchitis comprises infectious bronchitis and acidophilia bronchitis; Pulmonary emphysema; Bronchiectasis; Cystic fibrosis; Sarcoidosis; Farmer lung and relative disease; Hypersensitivity pneumonitis; Pulmonary fibrosis comprises the concurrent fibrosis of CFA, idiopathic interstitial pneumonia, antineoplaston and chronic infection (comprising tuberculosis and aspergillosis and other fungi infestation); The complication of lung transplantation; Pulmonary vascular vasculitis and thrombotic disease and pulmonary hypertension; Antitussive activity comprises chronic cough and iatrogenic cough that treatment and airway inflammation are relevant with the secretion situation; Acute rhinitis and chronic rhinitis comprise medicamentous rhinitis and vasomotor rhinitis; Property (perennial) allergic rhinitis and seasonal allergic rhinitis comprise nervous rhinitis's (pollinosis) throughout the year; Nasal polyposis; Acute viral infection comprises common cold and the infection that is caused by respiratory syncytial virus, influenza, coronavirus (comprising SARS) and adenovirus;
2. bone and joint: relevant with osteoarthritis/osteoarthropathy or comprise and the sacroiliitis of osteoarthritis/osteoarthropathy comprise primary and post-traumatic arthritis, for example congenital hip dysplasia; Neck and lumbar spine inflammation and lumbago and backache and cervical pain; Rheumatoid arthritis and Still disease (Still ' s disease); Seronegative spondyloanthropathy comprises ankylosing spondylitis, arthritic psoriasis, reactive arthritis and does not break up SpA; Septic arthritis infects relevant joint disease and osteopathia with other, and tuberculosis for example comprises Pott's disease (Potts ' disease) and Poncet syndrome (Poncet ' s syndrome); Acute and the chronic synovitis that crystal brings out comprises urate deposition is sick, calcium pyrophosphate deposition disease is relevant with apatite calcium tendon, mucous bursa and synovial membrane inflammation; Behcet's disease (Behcet ' s disease); Primary and Secondary cases xerodermosteosis (Sjogren ' s syndrome); Sjogren's syndrome and local scleroderma; Systemic lupus erythematous, mixed connective tissue disease and undifferentiated connective tissue disease; Inflammatory myopathy comprises dermatomyositis and polymyositis; Polymyalgia rheumatica; Juvenile arthritis comprises the idiopathic inflammatory arthritis and related syndromes and rheumatic fever and the general complication thereof that are distributed in any joint; Vasculitis (vasculitis) comprises giant cell arteritis, aortic arch syndrome (Takayasu ' s arteritis), Qiu-Shi syndrome (Churg-Strauss syndrome), polyarteritis nodosa, microscope polyarteritis and the vasculitis relevant with virus infection, allergy, cryoglobulin and M-band; Lumbago and backache; Familial Mediterranean fever, Mu-Wei syndrome (Muckle-Wells syndrome) and familial Ireland heat (FamilialHibernian Fever), Kikuchi sick (Kikuchi disease); Drug-induced property arthrodynia, tendonitis and myopathy;
3. the musculoskeletal disease that the pain that is caused by damage (for example sport injury) or disease and reticular tissue reproduce: sacroiliitis (rheumatoid arthritis for example, osteoarthritis, gout or crystallographic joint disease), other joint disease (for example degeneration of intervertebral disc or temporomandibular joint (TMJ) sex change), bone remodelling disease (osteoporosis for example, Paget's disease (Paget ' s disease) or osteonecrosis), polychondritis, scleroderma, mixed connective tissue disease, spondyloarthropathy or periodontopathy (for example periodontitis);
4. skin: psoriasis, atopic dermatitis, contact dermatitis or other eczema dermatoses and delayed type hypersensitivity; Vegetalitas and solar dermatitis; Seborrheic dermatitis, dermatitis herpetiformis, lichen planus, atrophic sclerosis lichen, PG, cutaneous sarcoidosis, discoid lupus erythematosus, pemphigus, pemphigoid, epidermolysis bullosa, urticaria, angioedema, vasculitis, erythema toxicum, skin eosinophilia, alopecia areata, male pattern alopecia, sweet's syndrome (Sweet ' ssyndrome), Wei-Ke syndrome (Weber-Christian syndrome), erythema multiforme; Cellulitis comprises infectivity and non-infectious cellulitis; Pimelitis; Lymphoma cutis, non-melanoma skin cancer and other dysplasia damage; Drug-induced disease comprises fixed drug eruption;
The eye: blepharitis; Conjunctivitis, comprise the perennial allergic conjunctivitis or spring anaphylaxis conjunctivitis; Iritis; Anterior uveitis and posterior uveitis; Choroiditis; Autoimmunization; Affect amphiblestroid sex change or inflammatory diseases; Ophthalmia comprises sympathetic ophthalmia; Sarcoidosis; Infect, comprise that virus, fungus and bacterium infect;
6. gi tract: glossitis, oulitis, periodontitis; Esophagitis comprises and backflowing; Eosinophilic Gastroenteritis, Mastocytosis, Crohn's disease (Crohn ' s disease), colitis comprise ulcerative colitis, rectitis, pruritus ani; Coeliac disease, irritable bowel syndrome, and have away from the relevant transformation reactions (for example migraine, rhinitis or eczema) of the food of intestines effect;
7. belly: hepatitis comprises autoimmunity, Alcoholic and viral hepatitis; Hepatic fibrosis and sclerosis; Cholecystitis; Pancreatitis comprises acute and chronic pancreatitis;
8. urogenital system: ephritis comprises interstitial nephritis and glomerulonephritis; Nephrotic syndrome; Urocystitis comprises acute and chronic (matter) urocystitis and hunner's ulcer (Hunner ' s ulcer); Acute and chronic urethritis, prostatitis, epididymitis, ovaritis and salpingitis; Vulvo-vaginitis; Perun alunite disease (Peyronie ' s disease); Erectile dysfunction (masculinity and femininity);
9. allograft rejection: the acute and chronic allograft rejection that after for example kidney, heart, liver, lungs, marrow, skin or corneal transplantation or in blood transfusion, occurs afterwards; Or chronic graft versus host disease;
10.CNS: degenerative brain disorder (Alzheimer ' s disease) and other dementia disease comprise CJD and nvCJD; Amyloidosis; Multiple sclerosis and other demyelination syndrome; Cerebral atherosclerosis and vasculitis; Temporal arteritis; Myasthenia gravis; Acute and chronic pain (acute, intermittence or rest pain, no matter be maincenter source property or outer perigene), comprise Encelialgia, headache, migraine, trigeminal neuralgia, atypical facial pain, joint and ostalgia, invade the pain, the neuropathic pain syndrome that cause by cancer and tumour and comprise the neuropathy relevant with HIV after diabetic, the bleb; The nervosa sarcoidosis; Maincenter and the peripheral nervous system complication of pernicious, infectivity or autoimmunity process;
11. other autoimmunity and allergic disorder comprise Hashimoto thyroiditis (Hashimoto ' s thyroiditis), Graves disease (Graves ' disease), bronzed disease (Addison ' sdisease), diabetes, idiopathic thrombocytopenic purpura, eosinophilic fasciitis, hyper-IgE syndrome, antiphospholipid syndrome;
12. other comprises acquired immune deficiency syndrome (AIDS) (AIDS), leprosy, Sezary syndrome (Sezary syndrome) and paraneoplastic syndrome with the disease of inflammatory or immunity composition;
13. cardiovascular: the atherosclerosis that affects coronary artery and peripheral circulation; Pericarditis; Myocarditis; Inflammatory and autoimmune cardiomyopathy comprise myocardial sarcoisosis; Ischemic damage and reperfusion damage; Endocarditis, cardiovalvulitis and aortitis comprise infectivity (for example syphilis); Vasculitis; The disease of near-end and peripheral vein comprises that phlebitis and thrombosis comprise venous thrombosis and cirsoid complication;
14. tumour: to the treatment of general cancer, comprise prostate gland, mammary gland, lung, ovary, pancreas, intestines and colon, stomach, skin and cerebral tumor and affect marrow (comprising leukemia) and the malignant tumour of lymphocytic hyperplasia system (for example He Jiejin (Hodgkin ' s) and non Hodgkin lymphoma); Comprise prevention and treatment to metastatic disease and tumor recurrence and paraneoplastic syndrome; With
15. gi tract: coeliac disease, rectitis, Eosinophilic Gastroenteritis, Mastocytosis, Crohn's disease, ulcerative colitis, microscope colitis, uncertain colitis, intestines stress disease, irritable bowel syndrome, non-inflammatory diarrhoea, have away from the relevant transformation reactions (for example migraine, rhinitis or eczema) of the food of intestines effect.
16. with PGD 2Or the relevant disease of its metabolite level rising.
Thereby, the invention provides above defined formula (I) compound or pharmaceutically acceptable salt thereof or solvate, it is used for the treatment of.
Preferably, compound of the present invention is used for the treatment of the disease that Chemokine Receptors wherein belongs to CRTh2 acceptor subfamily.
The disease specific of available the compounds of this invention treatment is asthma, rhinitis and PGD wherein 2Or the Other diseases of its metabolite level rising.Preferably, compound of the present invention is used for the treatment of asthma.
In yet another aspect, the invention provides defined formula (I) compound or pharmaceutically acceptable salt thereof above or solvate for the preparation of the purposes in the medicine for the treatment of.
In yet another aspect, the invention provides defined formula (I) compound or pharmaceutically acceptable salt thereof above or solvate at preparation and the medicine that is used for the treatment of asthma and rhinitis (such as sucking and oral steroid class, the β of suction 2Receptor stimulant and oral LTRA) coupling and purposes in the medicine that is used for the treatment of.
The invention still further relates to combination therapy, wherein compound or pharmaceutically acceptable salt thereof of the present invention comprise the pharmaceutical composition of the compounds of this invention or preparation and another kind of therapeutical agent or multiple therapeutical agent simultaneously or successively give, or give as combination preparation with another kind of therapeutical agent or multiple therapeutical agent, be used for the treatment of in the listed illness one or more.
Particularly, in order to treat inflammatory disease, such as (but being not limited to) rheumatoid arthritis, osteoarthritis, asthma, allergic rhinitis, chronic obstructive pulmonary disease (COPD), psoriasis and inflammatory bowel, can be with compound of the present invention and following listed drug regimen:
Nonsteroidal anti-inflammatory agent (being NSAID hereinafter) comprises the non-selective cyclooxygenase COX-1/COX-2 inhibitor that topical application no matter or whole body use (piroxicam for example; Diclofenac; Phenoxy propionic acid, for example Naproxen Base, flurbiprofen, fenoprofen, Ketoprofen and Ibuprofen BP/EP; Fragrant that acids, for example mefenamic acid, indomethacin, sulindac, Azapropazone (azapropazone); Pyrazolone, for example Phenylbutazone; Salicylate (ester), for example acetylsalicylic acid); Selective COX-2-2 inhibitor (for example meloxicam, celecoxib, rofecoxib, valdecoxib, Lu Makao former times (lumarocoxib), parecoxib and L-791456); The nitric oxide donors (CINODs) that suppresses cyclooxygenase; Glucocorticosteroid (no matter still coming administration by the intraarticular approach by local, oral, intramuscular, intravenous route); Methotrexate; Leflunomide; Oxychloroquine; The d-Trolovol; Auranofin or other are non-through intestines or New Oral Gold preparation; Anodyne; Diacerein (diacerein); Intraarticular therapeutical agent, for example derivatives of hyaluronic acids; And nutritional supplement, for example glucosamine.
The invention still further relates to the combination of the compounds of this invention or its pharmacologically acceptable salt and following material: the agonist of cytokine or cytokine function or antagonist (comprise the medicine that acts on the cytokine signaling conducting path, the conditioning agent of SOCS system for example), comprise α-, β-and gamma-interferon; I type rhIGF-1 (IGF-1); Interleukin (IL) comprises IL1 to 17 and interleukin antagonist or inhibitor (for example Kineret); Cachectin (TNF-α) inhibitor, for example anti-TNF monoclonal antibody (for example infliximab (infliximab), adalimumab (adalimumab) and CDP-870) and TNF receptor antagonist (comprising immunoglobulin molecules (for example etanercept) and low-molecular-weight drug (for example pentoxifylline (pentoxyfylline))).
In addition, the present invention relates to the combination of the compounds of this invention or its pharmacologically acceptable salt and following material: target is in the monoclonal antibody (for example CD20 (Rituximab (rituximab)), MRA-aIL16R) of bone-marrow-derived lymphocyte and target in the lymphocytic monoclonal antibody of T (CTLA4-Ig, HuMax I1-15).
The invention still further relates to the combination of the compounds of this invention or its pharmacologically acceptable salt and following material: chemokine receptor function conditioning agent, for example antagonist of CCR1, CCR2, CCR2A, CCR2B, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCR10 and CCR11 (C-C family); The antagonist of CXCR1, CXCR2, CXCR3, CXCR4 and CXCR5 (C-X-C family); And CX 3CR1 (C-X 3-C family) antagonist.
The invention still further relates to the combination of the compounds of this invention or its pharmacologically acceptable salt and following material: the instant stromatin enzyme of matrix metalloproteinase (MMPs) (stromelysin), collagenase and gelatinase and proteoglycan enzyme (aggrecanase) (collagenase-1 (MMP-1) especially, collagenase-2 (MMP-8), collagenase-3 (MMP-13), molten stromatin enzyme-1 (MMP-3), molten stromatin enzyme-2 (MMP-10) and mmp-3 (MMP-11) and MMP-9 and MMP-12) inhibitor, comprise medicine, for example Vibravenos.
The invention still further relates to the combination of the compounds of this invention or its pharmacologically acceptable salt and following material: inhibitors of leukotriene biosynthesis, 5-lipoxidase (5-LO) inhibitor or 5-lipoxidase activated protein (FLAP) antagonist, for example zileuton; ABT-761; Fenleuton; Tepoxalin; Abbott-79175; Abbott-85761; N-(5-replaces)-thiophene-2-alkyl sulfonamide; 2,6-, two-tert.-butyl phenol hydrazone; Methoxyl group tetrahydropyrans, for example Zeneca ZD-2138; Compound S B-210661; The 2-cyano group naphthalene compound that pyridyl replaces, L-739 for example, 010; 2-cyano quinolines compound, L-746 for example, 530; Or indoles or quinoline compound, for example MK-591, MK-886 and BAY * 1005.
The invention still further relates to the combination of the compounds of this invention or its pharmacologically acceptable salt and following material: the receptor antagonist of leukotriene (LT) B4, LTC4, LTD4 and LTE4 is selected from thiodiphenylamine-3-based compound, L-651 for example, 392; Amidino compounds, for example CGS-25019c; Ben Bing Evil amine (benzoxalamine), for example Ontazolast; Benzenyl amidine (benzenecarboximidamide), for example BIIL 284/260; And compound, for example Zafirlukast, Ro 23-3544, Singulair, pranlukast, verlukast (MK-679), RG-12525, Ro-245913, iralukast (CGP 45715A) and BAY * 7195.
The invention still further relates to the combination of the compounds of this invention or its pharmacologically acceptable salt and following material: phosphodiesterase (PDE) inhibitor, for example methyl xanthine (methylxanthanine) comprises theophylline and aminophylline; Selectivity PDE isozyme inhibitor comprises PDE4 inhibitor, isoform PDE4D inhibitor or PDE5 inhibitor.
The invention still further relates to the combination of the compounds of this invention or its pharmacologically acceptable salt and following material: histamine 1 receptor antagonist, for example cetirizine, Loratadine, Desloratadine, fexofenadine, acrivastine, terfenadine, astemizole, nitrogen
Figure S2006800461779D00181
Si Ting, levocabastine, chlorphenamine, promethazine, cyclizine (cyclizine) or mizolastine; Oral, local or non-through enteral administration.
The invention still further relates to the combination of the compounds of this invention or its pharmacologically acceptable salt and following material: proton pump inhibitor (for example omeprazole) or stomach protectiveness histamine 2 receptor antagonist.
The invention still further relates to the combination of the compounds of this invention or its pharmacologically acceptable salt and following material: histamine 4 receptor antagonists.
The invention still further relates to the combination of the compounds of this invention or its pharmacologically acceptable salt and following material: α 1/ α 2 adrenoceptor agonists, vasoconstrictor, sympathomimetic, for example propylhexedrine (propylhexedrine), phenylephrine, Phenylpropanolamine, ephedrine,d-pseudo-ephedrine, naphcon, oxymetazoline hydrochloride, tetrahydrozoline hydrochloride, xylometazoline hydrochloride, tramazoline hydrochloride or ethylnorephinephrine hydrochloride.
The invention still further relates to the combination of the compounds of this invention or its pharmacologically acceptable salt and following material: anticholinergic, comprise M-ChR (M1, M2 and M3) antagonist, for example coromegine, Scopolamine, GLYCOPYRRONIUM (glycopyrrrolate), ipratropium bromide (ipratropium bromide), tiotropium bromide (tiotropium bromide), oxitropium bromide (oxitropium bromide), pirenzepine (pirenzepine) or telenzepine (telenzepine).
The invention still further relates to the combination of the compounds of this invention or its pharmacologically acceptable salt and following material: beta-2 adrenoceptor (comprising beta receptor hypotype 1-4) agonist, such as Racemic isoproterenol, salbutamol, formoterol, Salmeterol, terbutaline, Orciprenaline, bitolterol mesilate or pirbuterol or their chirality enantiomer.
The invention still further relates to the combination of the compounds of this invention or its pharmacologically acceptable salt and following material: chromone, for example Sodium Cromoglicate or sodium nedocromil.
The invention still further relates to the combination of the compounds of this invention or its pharmacologically acceptable salt and following material: glucocorticosteroid, for example flunisolide, Triamcinolone Acetonide, Beconase Nasal Syray, budesonide, fluticasone propionate, ciclesonide or furoic acid momisone.
The invention still further relates to the combination of the compounds of this invention or its pharmacologically acceptable salt and following material: the medicine of regulating nuclear hormone receptor (for example PPARs).
The invention still further relates to the combination of the compounds of this invention or its pharmacologically acceptable salt and following material: immunoglobulin (Ig) (Ig) or Ig goods; Or antagonist or the antibody of adjusting Ig function, for example anti-IgE (for example omalizumab (omalizumab)).
The invention still further relates to the combination of the compounds of this invention or its pharmacologically acceptable salt and following material: the antiphlogiston of another kind of whole body or topical application, for example Thalidomide (thalidomide) or derivatives thereof, retinoid, Dithranol (dithranol) or calcipotriol (calcipotriol).
The invention still further relates to the combination of the compounds of this invention or its pharmacologically acceptable salt and following material: the combination of aminosalicylate (ester) and sulfapyridine (for example sulfasalazine, mesalazine, Balsalazide and Olsalazine); And immunomodulator, for example thio-purine and reflunomide (for example budesonide).
The invention still further relates to the combination of the compounds of this invention or its pharmacologically acceptable salt and following material: antimicrobial drug, for example penicillin derivative, tsiklomitsin, macrolide, beta-lactam, fluoroquinolone, metronidazole, imbedibility aminoglycoside; Antiviral drug comprises acyclovir, Famciclovir, valacyclovir, ganciclovir, cidofovir, amantadine, Rimantadine, ribavirin, zanamivir (zanamavir) and special quick clothes (oseltamavir); Proteinase inhibitor, for example Indinavir, viracept see nelfinaivr, ritonavir and Saquinavir; Nucleoside reverse transcriptase inhibitor, for example didanosine, lamivudine, stavudine (stavudine), zalcitabine or zidovudine; Or non-nucleoside reverse transcriptase inhibitor, for example nevirapine (nevirapine) or efavirenz (efavirenz).
The invention still further relates to the combination of the compounds of this invention or its pharmacologically acceptable salt and following material: cardiovascular drug, for example calcium channel blocker, receptor,β blocker, angiotensin-converting enzyme (ACE) inhibitor, hypertensin 2 receptor antagonist; Lipid lowerers, for example special class of statin or shellfish; The blood cell morphology conditioning agent is for example joined the appropriate western film (pentoxyfylline); Thrombolytic Drugs or anticoagulation, for example anticoagulant.
The invention still further relates to the combination of the compounds of this invention or its pharmacologically acceptable salt and following material: CNS medicine, for example thymoleptic (for example Sertraline), anti-Parkinson medicine (selegiline for example, L-3,4 dihydroxyphenylalanine, Ropinirole, pramipexole, MAOB inhibitor (for example selegiline and rasagiline), comP inhibitor (for example tolcapone (tasmar)), the A-2 inhibitor, the dopamine reuptake inhibitor, nmda antagonist, the Nicotine agonist, dopamine agonist or neuronal nitric oxide synthase inhibitor) or anti-Alzheimer medicine (E2020 (donepezil) for example, EXELON, tacrine, cox 2 inhibitor, propentofylline or Metrifonate).
The invention still further relates to the combination of the compounds of this invention or its pharmacologically acceptable salt and following material: be used for the treatment of the medicine of acute or chronic pain, the anodyne (for example opioid or derivatives thereof), Carbamzepine, Phenytoin Sodium Salt, Sodium Valproate, amitriptyline (amitryptiline) or other thymoleptic, paracetamol or the nonsteroidal anti-inflammatory agent that for example play a role in maincenter or periphery.
The invention still further relates to the combination of the compounds of this invention or its pharmacologically acceptable salt and following material: non-through (the comprising suction) of intestines or topical application local anaesthetics, for example lignocaine or derivatives thereof.
Compound or pharmaceutically acceptable salt thereof of the present invention also can with following material coupling: anti-osteoporotic comprises hormonal medicaments (for example raloxifene (raloxifene)) or diphosphonate (for example alendronate (alendronate)).
The invention still further relates to the combination of the compounds of this invention or its pharmacologically acceptable salt and following material: (i) tryptase (tryptase) inhibitor; (ii) platelet activation factor (PAF) antagonist; (iii) interleukin converting enzyme (ICE) inhibitor; (iv) IMPDH inhibitor; (v) adhesion molecule inhibitor comprises the VLA-4 antagonist; (vi) kethepsin; (vii) kinase inhibitor, Tyrosylprotein kinase (for example Btk, Itk, Jak3 or MAP) inhibitor (for example Gefitinib (gefitinib) or imatinib mesylate (imatinib)), serine/threonine kinase inhibitor (map kinase (p38 for example for example for example, JNK, protein kinase A, B or C, or IKK) inhibitor) or the inhibitor of the kinases (for example cell cycle protein dependent kinase) that in Cycle Regulation, involves; (viii) glucose-6 monophosphate dehydrogenase inhibitor; (ix) kassinin kinin B 1Acceptor or kassinin kinin B 2Receptor antagonist; (x) antigout drug, for example colchicine; (xi) xanthine oxidase inhibitor, for example allopurinol; (xii) uricosuric, for example probenecid, sulfinpyrazone or benzbromarone; (xiii) growth hormone secretagogues; (xiv) transforming growth factor (TGF β); (xv) platelet-derived growth factor (PDGF); (xvi) fibroblast growth factor, for example basic fibroblast growth factor (bFGF); (xvii) rHuGM-CSF (GM-CSF); (xviii) capsicum vegetable oil (capsaicin cream); (xix) tachykinin NK-1 1Acceptor or tachykinin NK-1 3Receptor antagonist, for example NKP-608C, SB-233412 (Talnetant (talnetant)) or D-4418; (xx) elastatinal, for example UT-77 or ZD-0892; (xxi) TNF-α converting enzyme inhibitor (TACE); The nitricoxide synthase of (xxii) inducing (iNOS) inhibitor; The chemoattractant receptor homolog molecule of (xxiii) expressing on the TH2 cell (for example CRTH2 antagonist); (xxiv) inhibitor of P38; (xxv) medicine of adjusting Toll sample acceptor (TLR) function; (xxvi) medicine of adjusting purinergic receptor activity, for example P2X7; Or (xxvii) transcription factor activation inhibitor, for example NFkB, API or STATS.
Also compound or pharmaceutically acceptable salt thereof of the present invention and existing medicine coupling can be used for the treatment of cancer, suitable medicine for example comprises:
(i) antiproliferative/antitumour drug that in medical oncology, uses or its combination, for example alkylating agent (for example cis-platinum, carboplatin, endoxan, mustargen, melphalan, Chlorambucil, busulfan or nitrosourea); Antimetabolite (for example antifol, for example 5-FU sample 5 FU 5 fluorouracil or Tegafur, Raltitrexed, methotrexate, cytosine arabinoside, hydroxyurea, gemcitabine or taxol); Antitumor antibiotics (for example anthracycline antibiotics, for example Zorubicin, bleomycin, Dx, daunorubicin, epirubicin, idarubicin, ametycin, gengshengmeisu or Plicamycin); Antimitotic agent (for example catharanthus alkaloid, for example vincristine(VCR), vinealeucoblastine(VLB), vindesine or vinorelbine; Or Taxan, for example PTX (taxol) or taxotere (taxotere)); Or topological isozyme inhibitor (for example epipodophyllotoxin, for example Etoposide, teniposide, Amsacrine, Hycamtin or camptothecine);
(ii) cell growth inhibition medicine, for example antiestrogen (for example tamoxifen, toremifene, raloxifene, droloxifene or iodoxyfene); Adjust under the estrogen receptor (for example fulvestrant); Antiandrogen (for example bicalutamide, flutamide, Nilutamide or CPA); Lhrh antagonist or LHRH agonist (for example goserelin, Leuprolide or buserelin); Progestogen (for example acetic acid megestrol); Aromatization enzyme (aromatase) inhibitor (for example being Anastrozole, letrozole, vorozole (vorazole) or Exemestane); Or 5α-reductase inhibitor (for example finasteride);
(iii) medicine (for example inhibitors of metalloproteinase (for example Marimastat) or UPA function of receptors inhibitor) of anticancer intrusion;
(iv) somatomedin depressant of functions, for example: growth factor antibodies (for example anti-erb b2 antibody trastuzumab or anti-erb b1 antibody Cetuximab [C225]); Farnesyl transferase inhibitor; Tyrosine kinase inhibitor or serine/threonine kinase inhibitor; Epidermal growth factor family inhibitor (EGFR family tyrosine kinase inhibitor for example, N-(3-chloro-4-fluorophenyl)-7-methoxyl group-6-(3-morpholino propoxy-) quinazoline-4-amine (Gefitinib for example, AZD1839), N-(3-ethynyl phenyl)-6,7-two (2-methoxy ethoxy) quinazoline-4-amine (erlotinib (erlotinib), OSI-774) or 6-acrylamido-N-(3-chloro-4-fluorophenyl)-7-(3-morpholino propoxy-) quinazoline-4-amine (CI 1033)); Platelet-derived growth factor man group inhibitor; Or pHGF man group inhibitor;
(v) anti-angiogenic drugs for example suppresses the anti-angiogenic drugs (for example anti-vascular endothelial cell growth factor antibody rhuMAb-VEGF, the compound that discloses) of vascular endothelial growth factor effect in WO 97/22596, WO 97/30035, WO 97/32856 or WO 98/13354; Or the compound (for example linomide, beta 2 integrin alpha v β 3 depressant of functions or angiostatin) that plays a role by another kind of mechanism;
(vi) blood vessel injury agent, for example compound of combretastatin A4 or disclosure in WO 99/02166, WO 00/40529, WO 00/41669, WO 01/92224, WO 02/04434 or WO 02/08213;
(vii) medicine that in antisense therapy, uses, the antisense therapy medicine of one of listed target, for example ISIS 2503, anti-ras antisense thing more than for example pointing to;
(viii) medicine that in following gene therapy method for example, uses: the method for displacement aberrant gene (for example unusual p53 or unusual BRCA1 or BRCA2); The GDEPT enzyme prodrug of the gene mediated (treatment) method is for example used the GDEPT method of Isocytosine deaminase, thymidine kinase or bacterium nitroreductase; With the method that improves Chemotherapy in Patients or radiotherapy tolerance, for example multi-medicament opposing gene therapy; Or
(ix) medicine that in following immunotherapy method for example, uses: improve exsomatizing and at body method, for example using cytokine (for example interleukin-22, IL-4 or granulocyte-macrophage colony stimutaing factor) transfection of patient tumors cell immunogenicity; Reduce the method for T cell anergy; Use the method for the immunocyte (for example dendritic cell of cytokine transfection) of transfection; Use the method for the tumor cell line of cytokine transfection; With the method for using anti-id AB.
In yet another aspect, the invention provides defined formula (I) compound or pharmaceutically acceptable salt thereof above or the solvate purposes in the medicine that for the preparation for the treatment of to the adjusting of CRTh2 receptor active is useful human diseases or illness.
In the context of the present specification, term " treatment " also comprises " prevention ", unless opposite specifying arranged in addition.Term " treatment " and " treatment ground " also should correspondingly be explained.
The present invention also provides treatment by PGD 2Or the method for the disease of its metabolite mediation (wherein prostanoid and its acceptor (especially CRTh2 acceptor) combination), described method comprises that above defined formula (I) compound or pharmaceutically acceptable salt thereof, solvate or the prodrug that will treat significant quantity give the patient.
The present invention also provides treatment to suffer from inflammatory diseases (especially psoriasis) or faces the method for disease described in the patient of described disease danger, described method comprise will the treatment significant quantity above defined formula (I) compound or pharmaceutically acceptable salt thereof or solvate give described patient.
With regard to therepic use mentioned above, the dosage that gives changes with employed compound, mode of administration, desired treatment and indication certainly.
Formula (I) compound or its prodrug, pharmacologically acceptable salt and solvate can use separately, but the form with pharmaceutical composition gives usually, its Chinese style (I) compound/salt/solvate (activeconstituents) and pharmaceutically acceptable auxiliaries, diluent or carrier combination.Based on mode of administration, pharmaceutical composition can preferably include 0.05 to 99%w (weight percent) more preferably 0.05 to 80%w still more preferably 0.10 to 70%w even 0.10 to 50%w activeconstituents more preferably, and all wt per-cent all is based on total composition.
The present invention also provides pharmaceutical composition, and it comprises above defined formula (I) compound or pharmaceutically acceptable salt thereof or solvate and pharmaceutically acceptable auxiliaries, diluent or carrier.
Pharmaceutical composition can come topical (for example be administered into lung and/or air flue or be administered into skin) by following form: solution, suspensoid, Sevoflurane hydrocarbon aerosol and dry powder formulations; Or can for example come by the following method the whole body administration: the form with tablet, capsule, syrup, pulvis or granule is come oral administration, or come administered parenterally with the form of solution or suspensoid, or subcutaneous administration, or come rectal administration with the form of suppository, or percutaneous dosing.Preferably, compound of the present invention comes administration by oral.
The present invention is existing to be illustrated by following nonrestrictive embodiment, wherein, and except as otherwise noted:
(i) when providing, quote with the δ value form of principal character proton 1H NMR data are to represent with respect to 1,000,000/(ppm) form as interior target tetramethylsilane (TMS);
(ii) mass spectrum (MS): the ion of general only report indication parent quality, (MM)=multiplex mode;
(iii) title compound of embodiment and method utilizes ACD/Name and ACD/NameBatch (6.0 editions) (Advanced Chemical Development Inc, Canada) to name;
(iv) except as otherwise noted, reversed-phase HPLC (RPHPLC) utilizes Symmetry, and NovaPak or Ex-Terra reverse phase silica gel post carry out;
(v) solvent MgSO 4Or Na 2SO 4Dry;
(vi) except as otherwise noted, reaction is carried out in room temperature;
(vii) use following abbreviation:
Aq. the aqueous solution
The BuLi butyllithium
HCl hydrochloric acid
NBS N-bromine succinimide
The DCM methylene dichloride
The DMF DMF
The Ether ether
The EtOAc ethyl acetate
The HBr hydrogen bromide
The MeI methyl-iodide
The NMP 1-Methyl-2-Pyrrolidone
The THF tetrahydrofuran (THF)
MCPBA 3-chloroperoxybenzoic acid (Aldrich 77%max)
The RT room temperature
Embodiment 1
4-chloro-3-[2-chloro-4-(methyl sulphonyl) phenoxy group] and phenyl } acetic acid
Figure S2006800461779D00241
(i) 4-(brooethyl)-1-chloro-2-anisole
With 2-chloro-5-methylphenol (20g), K 2CO 3(30g), acetone (200ml) and methyl-iodide (9.4ml) pack in the flask, then stirs 24h.Then removal of solvent under reduced pressure distributes resistates between ether and water.Separate organic layer, with 2M sodium hydroxide and water washing, dry (MgSO 4), reduction vaporization then.Resistates is dissolved among the EtOAc, then adds NBS (25g) and benzoyl peroxide (0.5g), reaction mixture shines 3h with halogen lamp.Removal of solvent under reduced pressure, then resistates obtains subhead compound (30g) through flash column chromatography (elutriant is isohexane) purifying, and it directly uses and is not further purified or characterizes.
(ii) (4-chloro-3-p-methoxy-phenyl) acetic acid
Product, DMF (200ml) and the sodium cyanide (20g) of step (i) are packed in the flask, then at stirring at room 2h.Resistates is distributed between ether and water, separate organic layer, wash with water, dry (MgSO 4), reduction vaporization then.Add potassium hydroxide (aqueous solution of 40g), then with mixture reflux 24h.Reaction mixture is cooled to room temperature, then uses extracted with diethyl ether.It is 1 that water layer is acidified to pH with dense HCl, then uses ethyl acetate extraction.Organic layer washes with water, dry (MgSO 4), reduction vaporization then.Resistates is ground with isohexane/ether, then filter, obtain subhead compound (12.2g).
(iii) (4-chloro-3-hydroxyl phenyl) acetic acid
Product (12.2g), HBr (48% aqueous solution) and the acetic acid (10ml) of step (ii) are packed in the flask into reflux 24h then, cooling, then reduction vaporization.Resistates is ground with ether/isohexane, then filter, obtain subhead compound (10.6g).
1H?NMR?CDCl 3-d 6：δ7.32(1H，d)，6.85(1H，s)，6.82(1H，d)，3.9(3H，s)，3.63(2H，s)。
(iv) (4-chloro-3-hydroxyl phenyl) ethyl acetate
The product (4g) of step (iii) is added to ethanol (40ml) solution of Acetyl Chloride 98Min. (10ml).With mixture at stirring at room 1h, then reduction vaporization.(elutriant is the purifying of 2: 1 isohexanes/EtOAc) to resistates, obtains subhead compound (4.4g) through flash column chromatography.
(v) 4-chloro-3-[2-chloro-4-(methyl sulphonyl) phenoxy group] and phenyl } ethyl acetate
Product (4.4g), 3-chloro-4-fluorophenyl methyl sulfone (4.27g), cesium carbonate (6.5g) and the NMP (40ml) of step (iv) packed in the flask, then stir 2h at 90 ℃.The reaction mixture dilute with water, with the EtOAc extraction, dry (MgSO 4), reduction vaporization then.Resistates obtains subhead compound (3.6g) through flash column chromatography (elutriant is 2: 1 isohexane/ether) purifying.
MS：ESI-ve?401(M-H)。
(vi) 4-chloro-3-[2-chloro-4-(methyl sulphonyl) phenoxy group] and phenyl } acetic acid
Water (40ml) solution of sodium hydroxide (0.72g) is added in THF (40ml) solution of product (3.6g) of step (v), in stirred overnight at room temperature.Reaction extracts with EtOAc with 2M HCl cancellation, dry (MgSO 4), reduction vaporization then.With resistates recrystallization in the EtOAc/ isohexane, obtain title compound (2.6g).
1H?NMR?DMSO-d 6：δ12.46(1H，s)，8.15-8.14(1H，s)，7.84(1H，d)，7.63-7.59(1H，d)，7.28-7.24(2H，m)，6.93(1H，d)，3.64(2H，s)，3.27(3H，s)。
MS：ESI-ve?372(M-H)。
Embodiment 2
4-chloro-3-[4-(methyl sulphonyl)-2-(trifluoromethyl) phenoxy group] and phenyl } acetic acid
Figure S2006800461779D00261
(i) 4-fluoro-3-(trifluoromethyl) phenyl methyl thioether
Isopentyl nitrite (1.13ml) is added to acetonitrile (50ml) solution of diethyl disulfide (0.69ml) and 4-fluoro-3-(trifluoromethyl) aniline (1g).With solution at 60 ℃ of reflux 2h, then reduction vaporizations.Resistates obtains subhead compound (0.57g) through flash column chromatography (elutriant is 2: 1 isohexane/ether) purifying.
1H?NMR?CDCl 3-d 6：δ7.41(2H，m)，7.10(1H，t)，2.5(3H，s)。
(ii) 4-fluoro-3-(trifluoromethyl) phenyl methyl sulfone
MCPBA (1.1g) is added to DCM (20ml) solution of the product (0.57g) of step (i), stirring is spent the night.Solution washs with metabisulfite solution.Organic phase is carried out dry MgSO 4), then reduction vaporization obtains subhead compound (0.4g).
1H?NMR?CDCl 3-d 6：δ8.26-8.18(2H，dd)，7.44(1H，t)，3.10(3H，s)。
(iii) 4-chloro-3-[4-(methyl sulphonyl)-2-(trifluoromethyl) phenoxy group] and phenyl } acetic acid
Product (125mg), cesium carbonate (437mg) and the NMP (10ml) of the product (150mg) of step (ii), embodiment 1 step (iii) packed in the flask, then at 80 ℃ of heating 10h.With the solution acidifying, then use ethyl acetate extraction.Organic extract liquid is carried out drying (MgSO 4), reduction vaporization then.Resistates obtains title compound (117mg) through the RPHPLC purifying.
1H?NMR?DMSO-d 6：δ12.48(1H，s)，8.27(1H，s)，8.16-8.14(1H，d)，7.66-7.64(1H，d)，7.33-7.31(2H，m)，6.96(1H，d)，3.67(2H，s)，3.31(3H，s)。
MS：APCI-ve?407(M-H)。
Embodiment 3
4-chloro-3-[2-chloro-4-(ethylsulfonyl) phenoxy group] and phenyl } acetic acid
(i) 3-chloro-4-fluorophenyl ethyl sulfone
3-chloro-4-fluoro thiophenol (10g), iodoethane (4.9ml), salt of wormwood (8.51g) and DMF (40ml) are packed in the flask, then stir 2h.Resistates is distributed between ether and water, separate organic layer, then dry (MgSO 4), reduction vaporization.Resistates is dissolved among the DCM (100ml), is cooled to 0 ℃, add MCPBA (26.5g).The reaction mixture stirring is spent the night, then with the DCM dilution, with metabisulfite solution and sodium bicarbonate aqueous solution washing, then dry (MgSO 4), reduction vaporization.Resistates obtains subhead compound (9.5g) through flash column chromatography (elutriant is 1: 1 isohexane/ether) purifying.
1H?NMR?CDCl 3-d 6：δ7.99(1H，d)，7.79-7.84(1H，m)，7.37-7.31(1H，m)，3.12(2H，q)，1.33-1.26(3H，t)。
(ii) 4-chloro-3-[2-chloro-4-(ethylsulfonyl) phenoxy group] and phenyl } acetic acid
Utilize the method for embodiment 2 steps (iii), prepare title compound by the product of step (i) and the product of embodiment 1 step (iii).
1H?NMR?DMSO-d 6：δ8.1(1H，s)，7.81(1H，dd)，7.6(1H，d)，7.28-7.25(2H，m)，6.95-6.92(1H，d)，3.62(2H，s)，3.42-3.32(2H，q)，1.47-1.07(3H，t)。
MS：ESI-ve?386(M-H)。
Embodiment 4
4-chloro-3-[4-(ethylsulfonyl)-2-(trifluoromethyl) phenoxy group] and phenyl } acetic acid
Figure S2006800461779D00272
(i) ethyl 4-fluoro-3-(trifluoromethyl) aralkyl sulfid
Utilize embodiment 2 steps (i) and method (ii) to prepare the subhead compound.
1H?NMR?CDCl 3-d 6：δ7.51(2H，dd)，7.13(1H，t)，2.95(2H，q)，1.28(3H，t)。
(ii) 4-chloro-3-[4-(ethylsulfonyl)-2-(trifluoromethyl) phenoxy group] and phenyl } acetic acid
Utilize the method for embodiment 2 steps (iii), prepare title compound by the product of step (i) and the product of embodiment 1 step (iii).
1H?NMR?DMSO-d 6：δ8.19(1H，s)，8.11(1H，d)，7.6(1H，d)，7.29(2H，m)，6.97-6.95(1H，d)，3.52(2H，s)，3.43-3.36(2H，q)，1.15-1.05(3H，t)。
MS：ESI-ve?421(M-H)。
Embodiment 5
4-chloro-3-[4-(methyl sulphonyl) phenoxy group] and phenyl } acetic acid
Figure S2006800461779D00281
Utilize the method for embodiment 2 steps (iii), prepare title compound by product and the 4-fluorophenyl methyl sulfone of embodiment 1 step (iii).
1H?NMR?DMSO-d 6：δ7.93-7.89(2H，m)，7.59-7.54(1H，m)，7.23-7.06(4H，m)，3.52(2H，s)，3.18(3H，s)。
MS：APCI-ve?339(M-H)。
Embodiment 6
2-{4-chloro-3-[2-chloro-4-(methyl sulphonyl) phenoxy group] phenyl } propionic acid
Figure S2006800461779D00282
(i) (4-chloro-3-p-methoxy-phenyl) methyl acetate
Product (1g), methyl-sulfate (1ml), salt of wormwood (1.48g) and the acetone (20ml) of embodiment 1 step (iii) are packed in the flask, then reflux 16h.The reaction mixture dilute with water, with the EtOAc extraction, dry (MgSO 4), then reduction vaporization obtains subhead compound (1.5g).
1H?NMR?CDCl 3-d 6：δ7.31-7.26(1H，m)，6.86-6.79(2H，m)，3.9(3H，s)，3.73(3H，s)，3.59(2H，s)。
(ii) 2-(4-chloro-3-p-methoxy-phenyl) methyl propionate
The product (0.5g) of step (i) is added to n-Butyl Lithium (1.75ml at-78 ℃, 1.6M THF solution) and THF (10ml) solution of diisopropylamine (0.4ml), stir 1h, then add methyl-iodide (0.18ml), stir 1h at-78 ℃, then at stirring at room 1h, the water cancellation.The product extracted with diethyl ether, dry (MgSO 4), reduction vaporization then.Resistates obtains subhead compound (0.21g) through flash column chromatography (elutriant is 1: 1 isohexane/ether) purifying.
1H?NMR?CDCl 3-d 6：δ7.3-7.26(1H，m)，6.87-6.81(2H，m)，3.9(3H，s)，3.67(3H，s)，3.48(1H，q)，1.47(3H，d)。
(iii) 2-(4-chloro-3-hydroxyl phenyl) methyl propionate
The HBr aqueous solution (10ml) with 48% adds to acetic acid (10ml) solution of the product (0.21g) of step (ii), then at 100 ℃ of heating 10h.
MS：ESI-ve?199(M-H)。
(iv) 2-{4-chloro-3-[2-chloro-4-(methyl sulphonyl) phenoxy group] phenyl } propionic acid
Utilize the method for embodiment 2 steps (iii), prepare title compound by product and the 3-chloro-4-fluorophenyl methyl sulfone of step (iii).
1H?NMR?DMSO-d 6：δ8.14(1H，s)，7.82(1H，d)，7.61(1H，d)，7.27(2H，m)，6.88(1H，d)，3.71(1H，q)，3.26(3H，s)，1.34(3H，d)。
MS：APCI-ve?387(M-H)。
Embodiment 7
(4-chloro-3-{2-chloro-4-[(dimethylamino) alkylsulfonyl] phenoxy group } phenyl) acetic acid
Figure S2006800461779D00291
Utilize the method for embodiment 2 steps (iii), by 3-chloro-4-fluoro-N, the product of N-dimethyl benzene sulfonamide and embodiment 1 step (iii) prepares title compound.
1H?NMR?DMSO-d 6：δ7.93(1H，s)，7.7(2H，m)，7.24(2H，m)，6.93(1H，d)，3.61(2H，s)，2.64(6H，s)。
MS：APCI-ve?401(M-H)。
Embodiment 8
[4-chloro-3-(3-cyano-benzene oxygen) phenyl] acetic acid
Figure S2006800461779D00301
With the product (0.5g) of embodiment 1 step (iii), 3-bromobenzylcyanide (0.73g), cesium carbonate (2.61g), cuprous chloride (I) (0.13g), 2,2,6,6-tetramethyl--3,5-heptadione (0.06ml) and NMP (10ml) pack in the flask, then at 120 ℃ of heating 16h.Mixture is distributed between ether and 2M NaOH, with the water layer acidifying, then with the EtOAc extraction, dry (MgSO 4), reduction vaporization then.Resistates obtains title compound (0.015g) through the RPHPLC purifying.
1H?NMR?DMSO-d 6：δ7.57-7.42(4H，m)，7.28-7.12(3H，m)，3.46(2H，s)。
MS：APCI-ve?286(M-H)。
Embodiment 9
4-chloro-3-[2-fluoro-4-(methyl sulphonyl) phenoxy group] and phenyl } acetic acid
Figure S2006800461779D00302
Utilize the method for embodiment 2 steps (iii), prepare title compound by the product of 3,4-difluorophenyl methyl sulfone and embodiment 1 step (iii).
1H?NMR?DMSO-d 6：δ7.98(1H，d)，7.7(1H，d)，7.54(1H，d)，7.2(2H，m)，7.01(1H，t)，7.06(1H，s)，3.27(3H，s)，3.48(2H，s)。
MS：APCI-ve?357(M-H)。
Embodiment 10
4-chloro-3-[4-(ethylsulfonyl)-2-fluorophenoxy] and phenyl } acetic acid
Figure S2006800461779D00311
(i) 3,4-difluorophenyl ethyl thioether
3,4-difluoro thiophenol (3g), iodoethane (1.6ml), salt of wormwood (2.64g) and DMF (40ml) are packed in the flask, then stir 2h.Solution is distributed between ethyl acetate and water.Organic extract liquid is carried out drying (MgSO 4), then reduction vaporization obtains subhead compound (3.84g).
1H?NMR?CDCl 3-d 6：δ7.19-7.032(3H，m)，2.95(2H，q)，1.29(3H，t)。
(ii) 3,4-difluorophenyl ethyl sulfone
Utilize the method for embodiment 2 steps (ii), prepare the subhead compound by the product of step (i).
1H?NMR?CDCl 3-d6：δ7.75(2H，m)，7.4(1H，q)，3.15(2H，q)，1.33(3H，t)。
(iii) 4-chloro-3-[4-(ethylsulfonyl)-2-fluorophenoxy] and phenyl } acetic acid
Utilize the method for embodiment 2 steps (iii), prepare title compound by the product of step (ii) and the product of embodiment 1 step (iii).
1H?NMR?DMSO-d 6：δ7.93(1H，d)，7.6(2H，m)，7.23-7.21(2H，m)，7.04(1H，t)，3.55(2H，s)，3.35(2H，q)，1.1(3H，t)。
MS：APCI-ve?371(M-H)。
Embodiment 11
4-chloro-3-[2-cyano group-4-(methyl sulphonyl) phenoxy group] and phenyl } acetic acid
Figure S2006800461779D00312
(i) 2-chloro-5-(methyl sulphonyl) cyanobenzene
Utilize embodiment 2 steps (i) and method (ii), prepare the subhead compound by 5-amino-2-chlorobenzonitrile and dimethyl disulfide.
1H?NMR?CDCl 3-d 6：δ8.26(1H，s)，8.09(1H，d)，7.76(1H，d)，3.1(3H，s)。
(ii) 4-chloro-3-[2-cyano group-4-(methyl sulphonyl) phenoxy group] and phenyl } acetic acid
Utilize the method for embodiment 2 steps (iii), prepare title compound by the product of step (i) and the product of embodiment 1 step (iii).
1H?NMR?DMSO-d 6：δ8.48(1H，s)，8.11(1H，d)，7.58(1H，d)，7.37-7-27(2H，m)，6.9(1H，d)，3.46(2H，s)，3.26(3H，s)。
MS：APCI-ve?364(M-H)。
Embodiment 12
4-chloro-3-[2-cyano group-4-(ethylsulfonyl) phenoxy group] and phenyl } acetic acid
Figure S2006800461779D00321
(i) 2-chloro-5-(ethylsulfonyl) cyanobenzene
Utilize embodiment 2 steps (i) and method (ii), prepare the subhead compound by 5-amino-2-chlorobenzonitrile and diethyl disulfide.
1H?NMR?CDCl 3-d 6：δ8.21(1H，s)，8.05(1H，d)，7.75(1H，d)，3.6(2H，q)，1.32(3H，t)。
(ii) 4-chloro-3-[2-cyano group-4-(ethylsulfonyl) phenoxy group] and phenyl } acetic acid
Utilize the method for embodiment 2 steps (iii), prepare title compound by the product of step (i) and the product of embodiment 1 step (iii).
1H?NMR?DMSO-d 6：δ8.43(1H，s)，8.07(1H，d)，7.59(1H，d)，7.39-7.21(2H，m)，6.9(1H，d)，3.49(2H，s)，3.35(2H，q)，1.09(3H，t)。
MS：APCI-ve?378(M-H)。
Embodiment 13
4-chloro-3-[4-(methyl sulphonyl)-3-(trifluoromethyl) phenoxy group] and phenyl } acetic acid
Figure S2006800461779D00322
(i) 4-fluoro-2-(trifluoromethyl) phenyl methyl sulfone
Utilize embodiment 2 steps (i) and method (ii), prepare the subhead compound by 4-fluoro-2-(trifluoromethyl) aniline and dimethyl disulfide.
1H?NMR?CDCl 3-d 6：δ8.22(2H，d)，7.44(1H，t)，3.1(3H，s)。
(ii) 4-chloro-3-[4-(methyl sulphonyl)-3-(trifluoromethyl) phenoxy group] and phenyl } acetic acid
Utilize the method for embodiment 2 steps (iii), prepare title compound by the product of step (i) and the product of embodiment 1 step (iii).
1H?NMR?DMSO-d 6：δ8.19(1H，d)，7.56-7.55(2H，m)，7.28-7.23(3H，m)，3.43(2H，s)，3.26(3H，s)。
MS：APCI-ve?407(M-H)。
Embodiment 14
4-chloro-3-[2-cyano group-5-(trifluoromethyl) phenoxy group] and phenyl } acetic acid
Figure S2006800461779D00331
Utilize the method for embodiment 2 steps (iii), prepare title compound by the product of 2-fluoro-4-(trifluoromethyl) cyanobenzene and embodiment 1 step (iii).
1H?NMR?DMSO-d 6：δ8.22(1H，d)，7.7(2H，d)，7.36-7.27(2H，m)，7(1H，s)，3.59(2H，s)。
MS：APCI-ve?354(M-H)。
Embodiment 15
(4-chloro-3-{2-fluoro-4-[(4-luorobenzyl) alkylsulfonyl] phenoxy group } phenyl) acetic acid
(i) 3,4-difluorophenyl 4-luorobenzyl sulfone
Utilize the method for embodiment 10 steps (i) and embodiment 2 steps (ii), prepare the subhead compound by 3,4-difluoro thiophenol and 1-(brooethyl)-4-fluorobenzene.
1H?NMR?CDCl 3-d 6：δ7.51-7.46(1H，m)，7.41-7.37(1H，m)，7.29-7.23(1H，m)，7.12-7.00(4H，m)，4.29(2H，s)。
(ii) (4-chloro-3-{2-fluoro-4-[(4-luorobenzyl) alkylsulfonyl] phenoxy group } phenyl) acetic acid
Utilize the method for embodiment 2 steps (iii), prepare title compound by the product of step (i) and the product of embodiment 1 step (iii).
1H?NMR?DMSO-d 6：δ7.79(1H，d)，7.6(1H，d)，7.48(1H，d)，7.25-7.14(6H，m)，7.03-6.98(1H，t)，4.75(2H，s)，3.57(2H，s)。
MS：APCI-ve?451(M-H)。
Embodiment 16
[3-(4-benzoyl-2-fluorophenoxy)-4-chloro-phenyl-] acetic acid
Figure S2006800461779D00341
Utilize the method for embodiment 2 steps (iii), prepare title compound by product and 3, the 4-difluoro benzophenone of embodiment 1 step (iii).
1H?NMR?DMSO-d 6：δ7.70-7.75(1H，d)，7.-6-7.57(1H，d)，7.48-7.44(1H，d)，7.25-7.14(6H，m)，7.03-6.98(1H，t)，4.75(2H，s)，3.57(2H，s)。
MS：APCI-ve?385(M-H)。
Embodiment 17
(4-chloro-3-{2-chloro-4-[(isobutylamino) carbonyl] phenoxy group } phenyl) acetic acid
Figure S2006800461779D00342
(i) 3-chloro-4-fluoro-N-isobutyl-benzene methane amide
Isobutylamine (2 molar equivalents) is added to DCM (10ml) solution of 3-chloro-4-fluorobenzoyl chloride (1g), stir 2h.Reaction mixture dilutes with DCM, washes with water, dry (MgSO 4), then reduction vaporization obtains white solid (1.2g).
MS：ESI+ve?230(M+H)。
(ii) (4-chloro-3-{2-chloro-4-[(isobutylamino) carbonyl] phenoxy group } phenyl) acetic acid
Utilize the method for embodiment 2 steps (iii), prepare title compound by the product of step (i) and the product of embodiment 1 step (iii).
1H?NMR?DMSO-d 6：δ8.53(1H，t)，8.07(1H，s)，7.8(1H，d)，7.57(1H，d)，7.17(1H，d)，7.06(1H，s)，6.88(1H，d)，3.58(2H，s)，3.08(2H，t)，1.82(1H，q)，0.88(6H，d)。
MS：APCI-ve?396(M+H)。
Embodiment 18
3-chloro-5-[2-chloro-4-(methyl sulphonyl) phenoxy group] and phenyl } acetic acid
Figure S2006800461779D00351
(i) 3-chloro-5-methoxyl phenylformic acid
Sodium methylate (25%wt., 7ml) is added to 3 of stirring, and DMPU (10ml) solution of 5-dichlorobenzoic acid (2g) is then 170 ℃ of heating 5 days.Reaction mixture is poured on the 1M HCl (50ml).Resulting solid is filtered, wash with water, then vacuum-drying obtains subhead compound (0.8g).
1H?NMR?DMSO-d 6：δ13.34(1H，s)，7.46(1H，s)，7.38(1H，s)，7.3(1H，s)，3.77(3H，s)。
(ii) (3-chloro-5-methoxyl phenyl) methyl alcohol
(the THF solution of 1M 8.76ml) dropwise adds to THF (40ml) solution of product (1.63g) of the step (i) of stirring, stirs 2h with lithium aluminium hydride.Then reaction mixture uses ethyl acetate extraction with 2M HCl dilution.Organic layer washs with sodium bicarbonate aqueous solution, dry (MgSO 4), then reduction vaporization obtains subhead compound (1.53g).
1H?NMR?CDCl 3-d 6：δ6.93(1H，s)，6.82-6.71(2H，m)，4.63(2H，s)，3.79(3H，s)。
(iii) (3-chloro-5-methoxyl phenyl) acetonitrile
Phosphorus tribromide (0.28ml) at 0 ℃ of ether (20ml) solution that adds to the product (1.55g) of step (ii), was then stirred 30 minutes.Reaction mixture is distributed between ether and sodium bicarbonate aqueous solution, separate organic layer, then dry (MgSO 4), reduction vaporization.Resistates is dissolved among the DMF (20ml), then adds sodium cyanide (0.5g).The mixture stirring is spent the night, then between ether and water, distribute, separate organic layer, wash with sodium bicarbonate aqueous solution, then dry (MgSO 4), reduction vaporization.Resistates obtains subhead compound (0.53g) through flash column chromatography (elutriant is 1: 1 ether/isohexane) purifying.
1H?NMR?CDCl 3-d 6：δ6.91-6.9(1H，m)，6.86-6.85(1H，m)，6.77-6.76(1H，m)，3.79(3H，s)，3.69(2H，s)。
(iv) (3-chloro-5-hydroxy phenyl) acetic acid
The HBr aqueous solution (10ml) of the product (0.53g) of step (iii), tetrabutylammonium chloride (0.123g) and 48% is packed in the flask, then at 125 ℃ of heating 36h.Reaction mixture is distributed between water and ethyl acetate, separate organic layer, then dry (MgSO 4), reduction vaporization.
1H?NMR?DMSO-d 6：δ12.33(1H，s)，9.87(1H，s)，6.75-6.65(3H，m)，3.50(2H，s)。
(v) 3-chloro-5-[2-chloro-4-(methyl sulphonyl) phenoxy group] and phenyl } acetic acid
Utilize the method for embodiment 2 steps (iii), prepare title compound by product and the 3-chloro-4-fluorophenyl methyl sulfone of step (iv).
1H?NMR?DMSO-d 6：δ8.14(1H，s)，7.87(1H，d)，7.33-7.02(4H，m)，3.62(2H，s)，3.27(3H，s)。
MS：APCI+ve?392(M+NH 4)。
Embodiment 19
3-chloro-5-[2-chloro-4-(ethylsulfonyl) phenoxy group] and phenyl } acetic acid
Figure S2006800461779D00361
Utilize the method for embodiment 2 steps (iii), prepare title compound by the product of embodiment 3 steps (i) and the product of embodiment 18 steps (iv).
1H?NMR?DMSO-d 6：δ8.07(1H，s)，7.82(1H，d)，7.2(3H，m)，7.03(1H，s)，3.59(2H，s)，3.35(2H，q)，1.1(3H，t)。
MS：APCI-ve?386(M-H)。
Embodiment 20
3-[2-chloro-4-(ethylsulfonyl) phenoxy group]-the 5-fluorophenyl } acetic acid
(i) 3-fluoro-5-methoxybenzoic acid
Utilize the method for embodiment 18 steps (i), prepare the subhead compound by 3,5-, two fluoro-phenylformic acid.
MS：APCI-ve?169(M-H)。
(ii) (3-fluoro-5-p-methoxy-phenyl) methyl alcohol
Utilize the method for embodiment 18 steps (ii), prepare the subhead compound by the product of step (i).
1H?NMR?CDCl 3-d 6：δ6.68(2H，m)，6.53(1H，m)，4.67(2H，d)，3.8(3H，s)。
(iii) (3-fluoro-5-p-methoxy-phenyl) acetonitrile
Thionyl chloride (0.95ml) at 0 ℃ of DCM (20ml) solution that adds to the product (0.95ml) of step (ii), is then stirred 1h.Reaction mixture separates organic layer with 2M HCl washing, then dry (MgSO 4), reduction vaporization.Resistates is dissolved among the DMF (10ml), then adds sodium cyanide (0.3g).Mixture is stirred 2h, then between ether and water, distribute, separate organic layer, then dry (MgSO 4), reduction vaporization.Resistates obtains subhead compound (0.47g) through flash column chromatography (elutriant is 1: 1 ether/isohexane) purifying.
1H?NMR?CDCl 3-d 6：δ6.66(3H，m)，3.81(3H，s)，3.70(2H，s)。
(iv) (3-fluoro-5-hydroxy phenyl) acetic acid
Utilize the method for embodiment 18 steps (iv), prepare the subhead compound by the product of step (iii).
1H?NMR?DMSO-d 6：δ12.10(1H，s)，9.79(1H，s)，6.42(3H，m)，3.44(2H，s)。
(v) 3-[2-chloro-4-(ethylsulfonyl) phenoxy group]-the 5-fluorophenyl } acetic acid
Utilize the method for embodiment 2 steps (iii), prepare title compound by the product of step (iv) and the product of embodiment 3 steps (i).
1H?NMR?DMSO-d 6：δ8.07(1H，m)，7.82(1H，d)，7.22(1H，d)，7.03-6.89(3H，m)，3.58(2H，s)，3.32(2H，q)，1.12(3H，t)。
MS：APCI-ve?371(M-H)。
Embodiment 21
3-fluoro-5-[4-(methyl sulphonyl)-2-(trifluoromethyl) phenoxy group] and phenyl } acetic acid
Figure S2006800461779D00381
Utilize the method for embodiment 2 steps (iii), prepare title compound by the product of embodiment 2 steps (ii) and the product of embodiment 20 steps (iv).
1H?NMR?DMSO-d 6：δ8.23(1H，s)，8.15(1H，d)，7.23(1H，d)，7.01(3H，m)，3.51(2H，s)，3.3(3H，s)。
MS：APCI-ve?391(M-H)。
Embodiment 22
3-[2-chloro-4-(ethylsulfonyl) phenoxy group]-the 4-fluorophenyl } acetic acid
Figure S2006800461779D00382
(i) 4-fluoro-3-methoxyl group-phenylformic acid
Utilize the method for embodiment 1 step (i), prepare the subhead compound by 4-fluoro-3-hydroxy-benzoic acid.
MS：APCI-ve?169(M-H)。
(ii) 2-fluoro-5-(hydroxymethyl) phenol
Utilize the method for embodiment 18 steps (ii), prepare the subhead compound by the product of step (i).
1H?NMR?CDCl 3-d 6：δ7.07-6.98(2H，m)，6.88-6.80(1H，m)，4.6(2H，s)，3.89(3H，s)。
(iii) (4-fluoro-3-hydroxy phenyl) acetonitrile
Utilize the method for embodiment 20 steps (iii), prepare the subhead compound by the product of step (ii).
1H?NMR?CDCl 3-d 6：δ7.11(1H，m)，7.03(1H，m)，6.86(1H，m)，3.91(3H，s)，3.72(2H，s)。
(iv) (4-fluoro-3-hydroxy phenyl) acetic acid
Utilize the method for embodiment 18 steps (iv), prepare the subhead compound by the product of step (iii).
1H?NMR?DMSO-d 6：δ7.06-7.0(2H，m)，6.88-6.83(1H，m)，4.65-4.63(2H，d)，3.89(3H，s)。
(v) 3-[2-chloro-4-(ethylsulfonyl) phenoxy group]-the 4-fluorophenyl } acetic acid
Utilize the method for embodiment 2 steps (iii), prepare title compound by the product of step (iv) and the product of embodiment 3 steps (i).
1H?NMR?DMSO-d 6：δ8.07(1H，s)，7.79(1H，d)，7.4-7.35(1H，m)，7.26-7.2(2H，m)，7.03(1H，d)，3.50(2H，s)，3.36(2H，q)，1.09(3H，t)。
MS：APCI-ve?371(M-H)。
Embodiment 23
4-fluoro-3-[4-(methyl sulphonyl)-2-(trifluoromethyl) phenoxy group] and phenyl } acetic acid
Figure S2006800461779D00391
Utilize the method for embodiment 2 steps (iii), prepare title compound by the product of embodiment 22 steps (iv) and the product of embodiment 2 steps (ii).
1H?NMR?DMSO-d 6：δ8.24(1H，s)，7.39-7.21(3H，m)，7.10-7.07(1H，d)，3.3(3H，s)。
MS：APCI-ve?391(M-H)。
Embodiment 24
4-chloro-3-[2-fluoro-4-(phenyl sulfonyl) phenoxy group] and phenyl } acetic acid
Figure S2006800461779D00392
(i) 3,4-difluorophenyl phenylsulfone
3,4-difluoroaniline (3.5g), acetonitrile (60ml), Diphenyl disulfide ether (6g) and Isopentyl nitrite (8ml) are packed in the flask, at 60 ℃ of heating 2h, then reduction vaporizations.Resistates obtains the subhead compound through flash column chromatography (elutriant is isohexane) purifying.Product (3,4-difluorophenyl aralkyl sulfid) is dissolved in the acetonitrile (60ml).Add water (10ml) and ozone (20g), at stirring at room 72h.Reaction mixture is distributed between ether/water, separate organic layer, wash with water, then dry (MgSO 4), reduction vaporization.Resistates obtains subhead compound (2.14g) through flash column chromatography (elutriant is 5-10% ethyl acetate/isohexane) purifying.
1H?NMR?CDCl 3-d 6：δ7.93(2H，d)，7.81-7.71(2H，m)，7.64-7.51(3H，m)，7.34-7.28(1H，m)。
(ii) 4-chloro-3-[2-fluoro-4-(phenyl sulfonyl) phenoxy group] and phenyl } acetic acid
Utilize the method for embodiment 2 steps (iii), prepare title compound by the product of step (i) and the product of embodiment 1 step (iii).
1H?NMR?DMSO-d 6：δ8.07-7.99(3H，m)，7.78-7.51(5H，m)，7.21-7.19(2H，m)，6.93(1H，t)，3.43(2H，s)。
MS：APCI-ve?419(M-H)。
Embodiment 25
[3-[2-chloro-4-(methyl sulphonyl) phenoxy group]-5-(trifluoromethyl) phenyl] acetic acid
Figure S2006800461779D00401
(i) 3-methoxyl group-5-(trifluoromethyl) phenylformic acid
Utilize the method for embodiment 1 step (i), prepare the subhead compound by 3-fluoro-5-(trifluoromethyl) phenylformic acid.
MS：APCI-ve?219(M-H)。
(ii) [3-methoxyl group-5-(trifluoromethyl) phenyl] methyl alcohol
Utilize the method for embodiment 18 steps (ii), prepare the subhead compound by the product of step (i).
1H?NMR?CDCl 3-d 6：δ7.26-7.04(3H，m)，4.72(2H，s)，4.08(3H，s)。
(iii) [3-methoxyl group-5-(trifluoromethyl) phenyl] acetonitrile
Triethylamine (2.04ml) is added to DCM (30ml) solution of the product (3.02g) of step (ii), be cooled to 0 ℃, add afterwards methylsulfonyl chloride (1.13ml).With reaction mixture at stirring at room 2h.The reaction mixture dilute with water extracts with DCM, then dry (MgSO 4), reduction vaporization obtains oily matter.Oily matter is dissolved among the DMF (20ml), then adds sodium cyanide (1.07g), stir 2h at 100 ℃.The reaction mixture dilute with water is used extracted with diethyl ether, dry (MgSO 4), reduction vaporization then.Resistates obtains subhead compound (1.9g) through flash column chromatography (elutriant is ether) purifying.
1H?NMR?CDCl 3-d 6：δ7.16-7.06(3H，m)，3.87(3H，s)，3.78(2H，s)。
(iv) [3-hydroxyl-5-(trifluoromethyl) phenyl] acetic acid
Utilize the method for embodiment 18 steps (iv), prepare the subhead compound by the product of step (iii).
1H?NMR?DMSO-d 6：δ7.02-6.83(3H，m)，3.60(2H，s)。
(v) [3-[2-chloro-4-(methyl sulphonyl) phenoxy group]-5-(trifluoromethyl) phenyl] acetic acid
Utilize the method for embodiment 2 steps (iii), prepare title compound by product and the 3-chloro-4-fluorophenyl methyl sulfone of step (iv).
1H?NMR?DMSO-d 6：δ8.16(1H，s)，7.89(1H，d)，7.53(1H，s)，7.37-7.23(3H，m)，3.65(2H，s)，3.29(3H，s)。
MS：APCI-ve?407(M-H)。
Embodiment 26
[3-[2-chloro-4-(ethylsulfonyl) phenoxy group]-5-(trifluoromethyl) phenyl] acetic acid
Figure S2006800461779D00411
Utilize the method for embodiment 2 steps (iii), prepare title compound by the product of embodiment 25 steps (iv) and the product of embodiment 3 steps (i).
1H?NMR?DMSO-d 6：δ8.09(1H，s)，7.83(1H，d)，7.54-7.17(4H，m)，3.70(2H，s)，3.37(2H，q)，1.12(3H，t)。
MS：APCI-ve?421(M-H)。
Embodiment 27
3-chloro-5-[2-fluoro-4-(methyl sulphonyl) phenoxy group] and phenyl } acetic acid
Figure S2006800461779D00412
Utilize the method for embodiment 2 steps (iii), prepare title compound by the product of 3,4-difluorophenyl methyl sulfone and embodiment 18 steps (iv).
1H?NMR?DMSO-d 6：δ7.81(1H，dd)，7.71(1H，d)，7.15(2H，s)，6.96(1H，d)，6.89(1H，s)，3.61(2H，s)，3.09(3H，s)。
MS：APCI-ve?343(M-CH 3)。
Embodiment 28
3-chloro-5-[2-cyano group-4-(ethylsulfonyl) phenoxy group] and phenyl } acetic acid
Figure S2006800461779D00421
Utilize the method for embodiment 2 steps (iii), prepare title compound by the product of embodiment 12 steps (ii) and the product of embodiment 18 steps (iv).
1H NMR DMSO-d 6: δ 8.41 (1H, d), 8.08 (1H, dd), 7.40 (1H, dd), 7.37 (1H, dd), 7.21 (1H, d), 7.13 (1H, d), 3.66 (2H, s), 3.37 (2H, q) and 1.12 (3H, t).
MS：APCI-ve?334(M-CO 2)。
Embodiment 29
3-chloro-5-[2-chloro-4-(phenyl sulfonyl) phenoxy group] and phenyl } acetic acid
Figure S2006800461779D00422
(i) 3-chloro-4-fluorophenyl phenyl sulfone
Iron(ic) chloride (0.47g) is added to the 3-chloro-4-fluorobenzene SULPHURYL CHLORIDE (1.5g) of stirring and the mixture of benzene (10ml).Then, with reaction mixture reflux 18h, then be cooled to room temperature.Then vacuum evaporating solvent distributes resistates between DCM and sodium bicarbonate aqueous solution, then use DCM (* 2) extraction.The organic extract liquid salt water washing that merges, dry (MgSO 4), reduction vaporization then.Solid recrystallization in ethanol with remnants obtains subhead compound (1.1g), is pale yellow crystals.
1H?NMR?CDCl 3：δ8.02-7.31(8H，m)。
(ii) 3-chloro-5-[2-chloro-4-(phenyl sulfonyl) phenoxy group] and phenyl } acetic acid
Utilize the method for embodiment 2 steps (iii), prepare title compound by the product of step (i) and the product of embodiment 18 steps (iv).
1H?NMR?DMSO-d 6：δ8.19(1H，d)，8.02(2H，d)，7.91(1H，dd)，7.76-7.63(3H，m)，7.28(1H，s)，7.18-7.13(2H，m)，7.03(1H，s)，3.56(2H，s)。
MS：APCI-ve?391(M-CO 2)。
Embodiment 30
3-chloro-5-[4-(ethylsulfonyl)-2-fluorophenoxy] and phenyl } acetic acid
Figure S2006800461779D00431
Utilize the method for embodiment 2 steps (iii), prepare title compound by the product of embodiment 10 steps (ii) and the product of embodiment 18 steps (iv).
1H?NMR?DMSO-d 6：δ7.77(1H，dd)，7.67(1H，dd)，7.21-7.12(2H，m)，6.98(1H，d)，6.89(1H，s)，3.62(2H，s)，3.15(2H，q)，1.32(3H，t)。
MS：APCI-ve?327(M-CO 2)。
Embodiment 31
3-chloro-5-[2-fluoro-4-(phenyl sulfonyl) phenoxy group] and phenyl } acetic acid
Utilize the method for embodiment 2 steps (iii), prepare title compound by the product of embodiment 24 steps (i) and the product of embodiment 18 steps (iv).
1H?NMR?DMSO-d 6：δ7.96-7.93(2H，dd)，7.76-7.62(2H，m)，7.61-7.48(3H，m)，7.06-7.03(2H，m)，6.88(2H，d)，3.55(2H，s)。
MS：APCI-ve?419(M-H)。
Embodiment 32
[3-{2-fluoro-4-[(4-luorobenzyl) alkylsulfonyl] phenoxy group }-5-(trifluoromethyl) phenyl] acetic acid
Figure S2006800461779D00441
Utilize the method for embodiment 2 steps (iii), prepare title compound by the product of embodiment 25 steps (iv) and the product of embodiment 15 steps (i).
1H?NMR?DMSO-d 6：δ7.76-7.80(1H，d)，7.48-7.53(2H，m)，7.12-7.34(7H，m)，4.76(2H，s)，3.74(2H，s)。
MS：APCI-ve?441(M-CO 2)。
Embodiment 33
(3-chloro-5-{2-fluoro-4-[(4-luorobenzyl) alkylsulfonyl] phenoxy group } phenyl) acetic acid
Figure S2006800461779D00442
Prepare title compound described in embodiment 2 steps (iii), different is to be prepared by the product of embodiment 18 steps (iv) and the product of embodiment 15 steps (i).
1H?NMR?DMSO-d 6：δ7.77-7.74(1H，d)，7.53-7.47(1H，d)，7.41-7.11(8H，m)，4.76(2H，s)，3.61(2H，s)。
MS：ESI-ve?407(M-CO 2)。
Embodiment 34
(3-chloro-5-{2-chloro-4-[(4-luorobenzyl) alkylsulfonyl] phenoxy group } phenyl) acetic acid
Figure S2006800461779D00443
(i) 2-chloro-1-fluoro-4-[(4-luorobenzyl) alkylsulfonyl] benzene
With DMF (10ml) solution of 3-chloro-4-fluoro thiophenol (1.0g), 1-(brooethyl)-4-fluorobenzene (1.15g) and salt of wormwood (0.85g) in stirred overnight at room temperature, then dilute with water, use extracted with diethyl ether, organic phase is carried out drying (MgSO 4), reduction vaporization then.Resulting oily matter is dissolved among the DCM (10ml), then adds MCPBA (1.2g), in stirred overnight at room temperature.Then, solution washs with metabisulfite solution and sodium bicarbonate aqueous solution, dry (MgSO 4), then reduction vaporization obtains oily matter, and it obtains subhead compound (1.3g) through flash column chromatography (elutriant is 3: 2 isohexane/ether) purifying, is white solid.
1H?NMR?CDCl 3：δ7.74-7.71(1H，d)，7.53-7.49(1H，m)，7.28-7.20(2H，m)，7.08-7.06(1H，m)，6.92-6.86(2H，m)，4.31(2H，s)。
(ii) (3-chloro-5-{2-chloro-4-[(4-luorobenzyl) alkylsulfonyl] phenoxy group } phenyl) acetic acid
Prepare title compound described in embodiment 2 steps (iii), different is to be prepared by the product of step (i) and the product of embodiment 18 steps (iv).
1H?NMR?DMSO-d 6：δ7.89-7.87(1H，s)，7.64-7.59(1H，d)，7.33-7.00(8H，m)，4.76(2H，s)，3.62(2H，s)。
MS：ESI-ve?423(M-CO 2)。
Embodiment 35
3-chloro-5-[4-(methyl sulphonyl)-2-(trifluoromethyl) phenoxy group] and phenyl } acetic acid
Figure S2006800461779D00451
Prepare title compound described in embodiment 2 steps (iii), different is to be prepared by the product of embodiment 18 steps (iv) and the product of embodiment 2 steps (ii).
1H?NMR?DMSO-d 6：δ8.24-8.15(2H，m)，7.27-7.16(3H，m)，7.05(1H，s)，3.46(2H，s)，3.30(3H，s)。
MS：ESI-ve?363(M-CO 2)。
Embodiment 36
3-chloro-5-[4-(ethylsulfonyl)-2-(trifluoromethyl) phenoxy group] and phenyl } acetic acid
Figure S2006800461779D00461
Prepare title compound described in embodiment 2 steps (iii), different is to be prepared by the product of embodiment 18 steps (iv) and the product of embodiment 4 steps (i).
1H?NMR?DMSO-d 6：δ8.24-8.15(2H，m)，7.27-7.16(3H，m)，7.05(1H，s)，3.54(2H，s)，3.46(2H，q)，1.15-1.06(3H，t)。
MS：ESI-ve?377(M-CO 2)。
Embodiment 37
[3-[2-fluoro-4-(phenyl sulfonyl) phenoxy group]-5-(trifluoromethyl) phenyl] acetic acid
Figure S2006800461779D00462
Prepare title compound described in embodiment 2 steps (iii), different is to be prepared by the product of embodiment 25 steps (iv) and the product of embodiment 24 steps (i).
1H?NMR?DMSO-d 6：δ8.11-8.01(3H，m)，7.82-7.63(4H，m)，7.54(1H，s)7.45(1H，s)7.32(1H，s)，7.28-7.24(1H，t)，3.74(2H，s)。
MS：ESI-ve?409(M-CO 2)。
Embodiment 38
[3-[2-chloro-4-(phenyl sulfonyl) phenoxy group]-5-(trifluoromethyl) phenyl] acetic acid
Figure S2006800461779D00463
Prepare title compound described in embodiment 2 steps (iii), different is to be prepared by the product of embodiment 25 steps (iv) and the product of embodiment 29 steps (i).
1H?NMR?DMSO-d 6：δ8.17(1H，s)，8.01-7.99(2H，d)，7.91-7.88(1H，d)，7.72-7.61(3H，m)7.50(1H，s)7.37-7.31(2H，d)，7.12-7.09(1H，d)，3.57(2H，s)。
MS：ESI-ve?425(M-CO 2)。
Embodiment 39
[3-[4-(ethylsulfonyl)-2-fluorophenoxy]-5-(trifluoromethyl) phenyl] acetic acid
Figure S2006800461779D00471
Prepare title compound described in embodiment 2 steps (iii), different is to be prepared by the product of embodiment 25 steps (iv) and the product of embodiment 10 steps (ii).
1H?NMR?DMSO-d 6：δ7.96-7.92(1H，d)，7.73-7.71(1H，d)，7.50(1H，s)，7.37-7.30(3H，m)，3.58(2H，s)，3.38-3.33(2H，q)，1.17-1.11(3H，t)。
MS：ESI-ve?361(M-CO 2)。
Embodiment 40
[3-[2-cyano group-4-(ethylsulfonyl) phenoxy group]-5-(trifluoromethyl) phenyl] acetic acid
Figure S2006800461779D00472
Prepare title compound described in embodiment 2 steps (iii), different is to be prepared by the product of embodiment 25 steps (iv) and the product of embodiment 12 steps (i).
1H?NMR?DMSO-d 6：δ8.46-8.45(1H，m)，8.13-8.09(1H，d)，7.65(2H，bm)，7.54(1H，s)，7.15-7.12(1H，d)，3.69(2H，s)，3.43-3.35(2H，q)，1.16-1.11(3H，t)。
MS：ESI-ve?368(M-CO 2)。
Embodiment 41
[3-[4-(ethylsulfonyl)-2-(trifluoromethyl) phenoxy group]-5-(trifluoromethyl) phenyl] acetic acid
Figure S2006800461779D00481
Prepare title compound described in embodiment 2 steps (iii), different is to be prepared by the product of embodiment 25 steps (iv) and the product of embodiment 4 steps (i).
1H?NMR?DMSO-d 6：δ8.21-8.14(2H，m)，7.62(1H，s)，7.52(1H，s)，7.46(1H，s)，7.26-7.24(1H，d)，3.73(2H，s)，3.46-3.39(2H，q)，1.17-1.11(3H，t)。
MS：ESI-ve?411(M-CO 2)。
Embodiment 42
3-[4-(benzyl alkylsulfonyl)-2-chlorophenoxy]-the 5-chloro-phenyl-} acetic acid
Figure S2006800461779D00482
(i) 4-(benzyl alkylsulfonyl)-2-chloro-1-fluorobenzene
Utilize the method for embodiment 34 steps (i), by 3-chloro-4-fluoro thiophenol (1.0g) and bromotoluene (0.73ml) preparation subhead compound, obtain white solid (1.2g).
1H?NMR?CDCl 3：δ7.68-7.65(1H，d)，7.49-7.09(7H，m)，4.31(2H，s)。
(ii) 3-[4-(benzyl alkylsulfonyl)-2-chlorophenoxy]-the 5-chloro-phenyl-} acetic acid
Prepare title compound described in embodiment 2 steps (iii), different is to be prepared by the product of step (i) and the product of embodiment 18 steps (iv).
1H?NMR?DMSO-d 6：δ7.88-7.87(1H，s)，7.65-7.61(1H，d)，7.35-7.19(7H，m)，7.08-6.99(2H，m)，4.76(2H，s)，3.60(2H，s)。
MS：APCI-ve?449(M-H)。
Embodiment 43
3-chloro-5-[4-(phenyl sulfonyl)-2-(trifluoromethyl) phenoxy group] and phenyl } acetic acid
Figure S2006800461779D00491
(i) 1-fluoro-4-(phenyl sulfonyl)-2-(trifluoromethyl) benzene
Acetonitrile (60ml) solution of 4-fluoro-3-(trifluoromethyl) aniline (5.0g), Diphenyl disulfide ether (6.0g) and Isopentyl nitrite (8ml) is heated 2h at 60 ℃, then cooling, reduction vaporization.Then resistates is dissolved in the acetonitrile (60ml) through flash column chromatography (elutriant is isohexane) purifying, adds water (10ml), then adds ozone (20g), with mixture at stirring at room 72h.Mixture extracts between ether and water, and organic phase is carried out drying (MgSO 4), reduction vaporization then.Resistates obtains subhead compound (2.14g) through flash column chromatography (elutriant is the isohexane solution of 5 to 10% ethyl acetate) purifying.
1H?NMR?DMSO-d 6：δ8.24-8.13(2H，m)，7.95(2H，d)，7.66-7.53(3H，m)，7.32(1H，t)。
(ii) 3-chloro-5-[4-(phenyl sulfonyl)-2-(trifluoromethyl) phenoxy group] and phenyl } acetic acid
Prepare title compound described in embodiment 2 steps (iii), different is to be prepared by the product of step (i) and the product of embodiment 18 steps (iv).
1H?NMR?DMSO-d 6：δ8.25-8.20(2H，m)，8.06-8.03(2H，d)，7.76-7.63(3H，m)，7.38-7.10(4H，m)，3.56(2H，s)。
MS：APCI-ve?469(M-H)。
Embodiment 44
3-chloro-5-[2-cyano group-4-(phenyl sulfonyl) phenoxy group] and phenyl } acetic acid
Figure S2006800461779D00492
(i) 2-chloro-5-(phenyl sulfonyl) cyanobenzene
Acetonitrile (100ml) solution of 5-amino-2-chlorobenzonitrile (6.6g), Diphenyl disulfide ether (11.0g) and Isopentyl nitrite (10ml) is heated 6h, then reduction vaporizations at 60 ℃.Then resistates is dissolved in resulting solid among the DCM through flash column chromatography (elutriant is that isohexane is to the isohexane solution of 1%EtOAc) purifying.Dropwise add MCPBA (8.0g), mixture is stirred 2h, filter, then then filtrate wash with water with metabisulfite solution and sodium bicarbonate aqueous solution washing, and organic phase is carried out drying (MgSO 4), then reduction vaporization obtains subhead compound (2.9g).
1H?NMR?CDCl 3：δ8.22(1H，s)，8.08(1H，d)，7.95(2H，d)，7.68-7.54(4H，m)。
(ii) 3-chloro-5-[2-cyano group-4-(phenyl sulfonyl) phenoxy group] and phenyl } acetic acid
Prepare title compound described in embodiment 2 steps (iii), different is to be prepared by the product of step (i) and the product of embodiment 18 steps (iv).
1H?NMR?DMSO-d 6：δ8.59(1H，s)，8.19-8.15(1H，d)，8.04-8.01(2H，d)，7.76-7.63(3H，m)，7.30-7.29(2H，m)，7.13(1H，s)，7.06-7.03(1H，d)，3.41(2H，s)。
MS：APCI-ve?426(M-H)。
Embodiment 45
3-[4-(benzyl alkylsulfonyl)-2-fluorophenoxy]-the 5-chloro-phenyl-} acetic acid
Figure S2006800461779D00501
(i) 4-(benzyl alkylsulfonyl)-1, the 2-difluorobenzene
Utilize the method for embodiment 34 steps (i), by 3,4-difluoro thiophenol (1.3g) and bromotoluene (1.5ml) preparation subhead compound, obtain white solid (2.4g).
1H?NMR?CDCl 3：δ7.48-7.20(8H，m)，4.33(2H，s)。
(ii) 3-[4-(benzyl alkylsulfonyl)-2-fluorophenoxy]-the 5-chloro-phenyl-} acetic acid
Prepare title compound described in embodiment 2 steps (iii), different is to be prepared by the product of step (i) and the product of embodiment 18 steps (iv).
1H?NMR?DMSO-d 6：δ7.77-7.73(1H，d)，7.66-7.51(1H，d)，7.35-7.18(7H，m)，7.05-6.99(2H，m)，4.75(2H，s)，3.61(2H，s)。
MS：APCI-ve?433(M-H)。
Embodiment 46
(3-chloro-5-{2-fluoro-4-[(3-luorobenzyl) alkylsulfonyl] phenoxy group } phenyl) acetic acid
(i) 1,2-two fluoro-4-[(3-luorobenzyls) alkylsulfonyl] benzene
Utilize the method for embodiment 34 steps (i), by 3,4-difluoro thiophenol (1.0g) and 1-(brooethyl)-3-fluorobenzene (1.28g) preparation subhead compound, obtain white solid (1.4g).
1H?NMR?CDCl 3：δ7.53-7.39(2H，m)，7.32-7.22(2H，m)，7.09-7.03(1H，m)，6.90-6.86(2H，m)，4.30(2H，s)。
(ii) (3-chloro-5-{2-fluoro-4-[(3-luorobenzyl) alkylsulfonyl] phenoxy group } phenyl) acetic acid
Prepare title compound described in embodiment 2 steps (iii), different is to be prepared by the product of step (i) and the product of embodiment 18 steps (iv).
1H?NMR?DMSO-d 6：δ7.78-7.74(1H，d)，7.52-7.49(1H，d)，7.41-7.15(4H，m)，7.06-6.96(4H，m)，4.79(2H，s)，3.48(2H，s)。
MS：APCI-ve?407(M-CO 2)。
Embodiment 47
3-[4-(benzyl alkylsulfonyl)-2-(trifluoromethyl) phenoxy group]-the 5-chloro-phenyl-} acetic acid
(i) 4-(benzyl alkylsulfonyl)-1-fluoro-2-(trifluoromethyl) benzene
Utilize the method for embodiment 44 steps (i), prepare the subhead compound by 3-trifluoromethyl-4-fluoroaniline (2.0g) and benzyldithio toluene, obtain white solid (0.42g).
1H?NMR?CDCl 3：δ7.80-7.77(2H，m)，7.39-7.25(4H，m)，7.10-7.07(2H，d)，4.34(2H，s)。
(ii) 3-[4-(benzyl alkylsulfonyl)-2-(trifluoromethyl) phenoxy group]-the 5-chloro-phenyl-} acetic acid
Prepare title compound described in embodiment 2 steps (iii), different is to be prepared by the product of step (i) and the product of embodiment 18 steps (iv).
1H?NMR?DMSO-d 6：δ7.94-7.86(2H，d)，7.33-7.28(4H，m)，7.20-7.16(4H，m)，7.05(1H，s)，4.76(2H，s)，3.54(2H，s)。
MS：APCI-ve?439(M-CO 2)。
Embodiment 48
(3-chloro-5-{2-fluoro-4-[(2-luorobenzyl) alkylsulfonyl] phenoxy group } phenyl) acetic acid
Figure S2006800461779D00521
(i) 1,2-two fluoro-4-[(2-luorobenzyls) alkylsulfonyl] benzene
Utilize the method for embodiment 34 steps (i), by 3,4-difluoro thiophenol (1.0g) and 1-(brooethyl)-2-fluorobenzene (1.28g) preparation subhead compound, obtain white solid (2.3g).
1H?NMR?CDCl 3：δ7.62-7.14(6H，m)，6.97-6.90(1H，t)，4.41(2H，s)。
(ii) (3-chloro-5-{2-fluoro-4-[(2-luorobenzyl) alkylsulfonyl] phenoxy group } phenyl) acetic acid
Prepare title compound described in embodiment 2 steps (iii), different is to be prepared by the product of step (i) and the product of embodiment 18 steps (iv).
1H?NMR?DMSO-d 6：δ7.81-7.75(1H，d)，7.57-7.39(2H，d)，7.33-7.16(5H，m)，7.06-6.97(2H，m)，4.78(2H，s)，3.49(2H，s)。
MS：APCI-ve?407(M-CO 2)。
Embodiment 49
(3-chloro-5-{4-[(4-chlorobenzyl) alkylsulfonyl]-the 2-fluorophenoxy } phenyl) acetic acid
Figure S2006800461779D00522
(i) 4-[(4-chlorobenzyl) alkylsulfonyl]-1, the 2-difluorobenzene
Iron(ic) chloride (1.27g) is added to 3 of stirring, the mixture of 4-difluoro chloride (5g) and 1-chloro-4-methylbenzene (4.65ml).With reaction mixture reflux 16h, then be cooled to room temperature.The reaction mixture dilute with water is with ethyl acetate (* 2) extraction.The organic extract liquid salt water washing that merges, dry (MgSO 4), reduction vaporization then.Solid recrystallization in ethanol with remnants obtains subhead compound (4.35g), is pale yellow crystals.
1H?NMR?CDCl 3：δ7.53-7.48(2H，m)，7.30-7.22(3H，m)，7.07-7.04(2H，d)，4.28(2H，s)。
(ii) (3-chloro-5-{4-[(4-chlorobenzyl) alkylsulfonyl]-the 2-fluorophenoxy } phenyl) acetic acid
Prepare title compound described in embodiment 2 steps (iii), different is to be prepared by the product of step (i) and the product of embodiment 18 steps (iv).
1H?NMR?DMSO-d 6：δ12.49(1H，s)，7.80-7.77(1H，d)，7.51-7.19(7H，m)，7.11(1H，s)，7.02(1H，s)，4.77(2H，s)，3.64(2H，s)。
MS：APCI-ve?409(M-CO 2)。
Embodiment 50
2-[3-[4-(ethylsulfonyl)-2-(trifluoromethyl) phenoxy group]-5-(trifluoromethyl) phenyl] propionic acid
Figure S2006800461779D00531
(i) [3-methoxyl group-5-(trifluoromethyl) phenyl] methyl acetate
The product (1.0g) of embodiment 25 steps (iv) is dissolved in the dry DMF (10ml), then uses methyl iodide (0.6ml) and salt of wormwood (1.25g) to process.With mixture in stirred overnight at room temperature.The mixture dilute with water is used extracted with diethyl ether, dry (MgSO 4), then reduction vaporization obtains oily matter.Oily matter obtains subhead compound (1.30g) through flash column chromatography (elutriant is 2: 1 ether/isohexanes) purifying.
1H?NMR?DMSO-d 6?δ7.13(1H，s)，7.04-7.01(2H，d)，3.85(3H，s)，3.70(3H，s)，3.65(2H，s)。
(ii) 2-[3-methoxyl group-5-(trifluoromethyl) phenyl] methyl propionate
With the product (1.3g) of step (i)-78 ℃ add to preformed butyllithium (hexane solution of 2.5M, 2.51ml) and anhydrous THF (30ml) solution of diisopropylamine (0.88ml).Mixture was kept 1 hour at-78 ℃, add afterwards methyl iodide (0.4ml).Mixture slowly is warmed to room temperature, spends the night.Mixture is used extracted with diethyl ether with 2M HCl dilution, dry (MgSO 4), then reduction vaporization obtains oily matter.Oily matter obtains subhead compound (0.8g) through flash column chromatography (elutriant is 2: 1 isohexane/ether) purifying.
1H?NMR?DMSO-d 6：δ7.17-7.13(1H，s)，7.02(2H，s)，3.84(3H，s)，3.74(1H，q)，3.68(3H，s)，1.52-1.50(3H，d)。
(iii) 2-[3-hydroxyl-5-(trifluoromethyl) phenyl] propionic acid
The product (0.8g) of step (ii) is dissolved in the Glacial acetic acid (20ml), then uses 48% the HBr aqueous solution (20ml) processing.Mixture is heated 16h at 100 ℃.With the mixture cooling, then with 2M NaOH dilution, use ethyl acetate extraction, dry (MgSO 4), then reduction vaporization obtains oily matter, and it obtains colorless oil (0.5g) through the RPHPLC purifying.
MS：APCI-ve?233(M-H)。
(iv) 2-[3-[4-(ethylsulfonyl)-2-(trifluoromethyl) phenoxy group]-5-(trifluoromethyl) phenyl] propionic acid
Prepare title compound described in embodiment 2 steps (iii), different is to be prepared by the product of step (iii) and the product of embodiment 4 steps (i).
1H?NMR?DMSO-d 6：δ8.20-8.19(1H，s)，8.14-8.11(1H，d)，7.60(1H，s)，7.50-7.47(2H，d)，7.26-7.21(1H，d)，3.85-3.80(1H，q)，3.43-3.38(2H，q)，1.39-1.38(3H，d)，1.15-1.11(3H，t)。
MS：ESI-ve?425(M-CO 2)。
Embodiment 51
2-[3-[2-chloro-4-(ethylsulfonyl) phenoxy group]-5-(trifluoromethyl) phenyl] propionic acid
Figure S2006800461779D00541
Prepare title compound described in embodiment 2 steps (iii), different is to be prepared by the product of embodiment 50 steps (iii) and the product of embodiment 3 steps (i).
1H?NMR?DMSO-d 6：δ8.10-8.09(1H，s)，7.84-7.82(1H，d)，7.54(1H，s)，7.39-7.38(2H，d)，7.22-7.20(1H，d)，3.80-3.74(1H，q)，3.40-3.35(2H，q)，1.37-1.35(3H，d)，1.14-1.11(3H，t)。
MS：ESI-ve?391(M-CO 2)。
Embodiment 52
2-[3-[2-chloro-4-(phenyl sulfonyl) phenoxy group]-5-(trifluoromethyl) phenyl] propionic acid
Prepare title compound described in embodiment 2 steps (iii), different is to be prepared by the product of embodiment 50 steps (iii) and the product of embodiment 29 steps (i).
1H?NMR?DMSO-d 6：δ8.19(1H，s)，8.02-8.00(2H，d)，7.91-7.88(1H，d)，7.73-7.62(3H，m)，7.53(1H，s)，7.39-7.37(2H，d)，7.12-7.09(1H，d)，3.73-3.71(1H，q)，1.34-1.32(3H，d)。
MS：ESI(-ve)439(M-CO 2)。
Embodiment 53
2-[3-{2-chloro-4-[(4-luorobenzyl) alkylsulfonyl] phenoxy group }-5-(trifluoromethyl) phenyl] propionic acid
Figure S2006800461779D00552
Prepare title compound described in embodiment 2 steps (iii), different is to be prepared by the product of embodiment 50 steps (iii) and the product of embodiment 34 steps (i).
1H?NMR?DMSO-d 6：δ7.92-7.91(1H，s)，7.60-7.53(2H，m)，7.34(2H，s)，7.25-7.14(5H，m)，4.77(2H，s)，3.90-3.84(1H，q)，1.40-1.39(3H，d)。
MS：ESI-ve?471(M-CO 2)。
Embodiment 54
(3-chloro-5-{4-[(4-chlorobenzyl) alkylsulfonyl]-the 2-fluorophenoxy } phenyl) acetic acid
Figure S2006800461779D00553
(i) 4-[(4-chlorobenzyl) alkylsulfonyl]-1, the 2-difluorobenzene
With 3, DMF (10ml) solution of 4-difluoro thiophenol (1.0g), 1-(brooethyl)-4-chlorobenzene (1.28g) and salt of wormwood (0.94g) is in stirred overnight at room temperature, then dilute with water is used extracted with diethyl ether, and organic phase is carried out drying (MgSO 4), reduction vaporization then.Resulting oily matter is dissolved among the DCM (10ml), then adds MCPBA (2.94g), in stirred overnight at room temperature.Then, solution washs with metabisulfite solution and sodium bicarbonate aqueous solution, dry (MgSO 4), then reduction vaporization obtains solid, and it is ground with isohexane, obtains subhead compound (2.3g), is white solid.
1H?NMR?CDCl 3：δ7.53-7.48(2H，m)，7.30-7.22(3H，m)，7.07-7.04(2H，d)，4.28(2H，s)。
(ii) (3-chloro-5-{4-[(4-chlorobenzyl) alkylsulfonyl]-the 2-fluorophenoxy } phenyl) acetic acid
Prepare title compound described in embodiment 2 steps (iii), different is to be prepared by the product of step (i) and the product of embodiment 18 steps (iv).
1H?NMR?DMSO-d 6：δ12.49(1H，s)，7.80-7.77(1H，d)，7.51-7.19(7H，m)，7.11(1H，s)，7.02(1H，s)，4.77(2H，s)，3.64(2H，s)。
MS：APCI-ve：423(M-CO 2)。
Embodiment 55
3-bromo-5-[2-chloro-4-(ethylsulfonyl) phenoxy group] and phenyl } acetic acid
Figure S2006800461779D00561
(i) 3-bromo-5-anisole formonitrile HCN
Sodium methylate (2.02g) is added to DMPU (20ml) solution of the 3-fluoro-5-bromobenzylcyanide (5.0g) of stirring, at stirring at room 2h.Then the reaction mixture dilute with water filters resulting solid, washes with water, and then vacuum-drying obtains subhead compound (5.10g).
1H?NMR?DMSO-d 6：δ7.39-7.38(1H，s)，7.30-7.26(1H，m)，7.11(1H，s)，3.83(3H，s)。
(ii) 3-bromo-5-methoxybenzoic acid
The product (5.10g) of step (i) is dissolved among methyl alcohol (20ml) and the 6N NaOH (20ml), then reflux 6h.Mixture is used ethyl acetate extraction with 2M HCl dilution, dry (MgSO 4), then reduction vaporization obtains white solid (5.10g).
MS：APCI-ve?229(M-H)。
(iii) (3-bromo-5-p-methoxy-phenyl) methyl alcohol
(the THF solution of 1M is 22.07ml) at THF (50ml) solution of the product (5.1g) of 0 ℃ of step (ii) that dropwise adds to stirring, then in stirred overnight at room temperature with lithium aluminium hydride.Extracted with diethyl ether is used in reaction cancellation in 2M HCl, dry (MgSO 4), then reduction vaporization obtains oily matter, and it obtains subhead compound (5.38g) through flash column chromatography (elutriant is 1: 1 isohexane/ether) purifying.
1H?NMR?CDCl 3：δ7.08(1H，s)，6.96-6.91(1H，s)，6.83-6.81(1H，s)，4.62(2H，s)，3.79(3H，s)。
(iv) (3-bromo-5-p-methoxy-phenyl) acetonitrile
The product (5.38g) of step (iii) is dissolved among the anhydrous DCM (50ml), then adds dry DMF (2.3ml), next add thionyl chloride (2.17ml).Reaction mixture in stirred overnight at room temperature, then with the sodium bicarbonate aqueous solution dilution, is extracted dry (MgSO with DCM 4), then reduction vaporization obtains oily matter.Oily matter is dissolved among the DMF (20ml), then adds sodium cyanide (1.30g), in stirred overnight at room temperature.The reaction mixture dilute with water is used extracted with diethyl ether, dry (MgSO 4), reduction vaporization then.Resistates obtains subhead compound (4.50g) through flash column chromatography (elutriant is 1: 2 ether/isohexane) purifying.
1H?NMR?CDCl 3：δ7.07-7.02(2H，m)，6.81(1H，s)，3.83(3H，s)，3.70(2H，s)。
(v) (3-bromo-5-hydroxy phenyl) acetic acid
Glacial acetic acid (30ml) solution of the product (4.5g) of step (iv) is processed with 48% the HBr aqueous solution (30ml), then at 100 ℃ of heating 24h.Reaction mixture is distributed between water and ethyl acetate, separate organic layer, then dry (MgSO 4), reduction vaporization obtains the tawny solid, and it is ground with ether/isohexane, obtains subhead compound (4.24g).
MS：APCI-ve?229/231(M-H)。
(vi) 3-bromo-5-[2-chloro-4-(ethylsulfonyl) phenoxy group] and phenyl } acetic acid
Prepare title compound described in embodiment 2 steps (iii), different is to be prepared by the product of step (v) and the product of embodiment 3 steps (i).
1H?NMR?DMSO-d 6：8.08-8.07(1H，s)，7.84-7.81(1H，d)，7.38-7.20(3H，m)，7.07(1H，s)，3.59(2H，s)，3.39-3.34(2H，q)，1.14-1.07(3H，t)。
MS：APCI-ve?431/433(M-H)。
Embodiment 56
3-[2-chloro-4-(ethylsulfonyl) phenoxy group]-the 5-aminomethyl phenyl } acetic acid
Figure S2006800461779D00581
(i) 3-bromo-5-hydroxyphenyl acetic acid methyl esters
The product (3.24g) of embodiment 55 steps (v) is added to the solution of preformed methyl alcohol (200ml) and Acetyl Chloride 98Min. (20ml), in stirred overnight at room temperature.Mixture is carried out reduction vaporization, obtain oily matter.Oily matter obtains subhead compound (3.16g) through flash column chromatography (elutriant is 1: 1 ether/isohexane) purifying.
1H?NMR?CDCl 3：δ6.98-6.97(1H，s)，6.92-6.91(1H，s)，6.70-6.69(1H，m)，5.71(1H，bs)，3.71-3.70(3H，s)，3.50(2H，s)。
(ii) 3-bromo-5-[2-chloro-4-(ethylsulfonyl) phenoxy group] the phenylacetic acid methyl esters
Preparation subhead compound described in embodiment 2 steps (iii), different is to be prepared by the product of step (i) and the product of embodiment 3 steps (i).
MS：APCI-ve?446(M-H)。
(iii) 3-[2-chloro-4-(ethylsulfonyl) phenoxy group]-the 5-aminomethyl phenyl } acetic acid
With anhydrous THF (10ml) solution of the product (0.6g) of two diphenylphosphino ferrocene palladiums (0.1g) and 2.0M methyl chloride zinc (2.01ml) treatment step (ii), the preparation title compound.With the mixture heating up 2h that refluxes, then between water and ethyl acetate, distribute, separate organic phase, then dry (MgSO 4), reduction vaporization obtains oily matter.Then oily matter be dissolved in the methyl alcohol (10ml) through flash column chromatography (elutriant is ether) purifying, adds 2M NaOH (10ml), in stirred overnight at room temperature.The mixture dilute with water, with extracted with diethyl ether (abandoning ether extraction liquid), then water layer is used ethyl acetate extraction with 2M HCl acidifying, and ethyl acetate layer is carried out drying (MgSO 4), then reduction vaporization obtains oily matter.Oily matter obtains title compound through the RPHPLC purifying.
1H?NMR?DMSO-d 6：δ8.04(1H，s)，7.80-7.78(1H，d)，7.08-6.77(4H，m)，3.43(2H，s)，3.37-3.31(2H，q)，2.29(3H，s)，1.13-1.10(3H，t)。
MS：APCI-ve?367(M-H)。
Embodiment 57
3-[2-chloro-4-(ethylsulfonyl) phenoxy group]-5-cyano-phenyl methyl acetate
Figure S2006800461779D00591
The method of utilization described in embodiment 56 steps (iii) prepares title compound, and different is, is prepared by product and the zinc cyanide of embodiment 56 steps (ii).
1H?NMR?DMSO-d 6：8.05(1H，s)，7.84-7.82(1H，d)，7.64-7.07(3H，s)，6.99-6.97(1H，d)，3.49(2H，s)，3.38-3.34(2H，q)，1.15-1.11(3H，t)。
MS：APCI-ve?334(M-H)。
Embodiment 58
[3-{[2-chloro-4-(ethylsulfonyl) phenyl] sulfenyl }-5-(trifluoromethyl) phenyl] acetic acid
Figure S2006800461779D00592
(i) [the 3-{[(dimethylamino) thiocarbonyl] the oxygen base }-5-(trifluoromethyl) phenyl] acetic acid
Product (0.5g), the dimethyl sulphide of embodiment 25 steps (iv) are stirred 15h Wu Shui diox (10ml) solution at 100 ℃ for chloroformamide (0.32ml), DMAP (0.026g) and triethylamine (0.60ml).The mixture dilute with water is used ethyl acetate extraction, dry (MgSO 4), then reduction vaporization obtains oily matter.Oily matter obtains subhead compound (0.52g) through flash column chromatography (elutriant is ether) purifying.
1H?NMR?CDCl 3：δ7.42(1H，s)，7.26-7.23(2H，m)，3.72(5H，m)，3.44(3H，s)，3.35(3H，s)。
(ii) [the 3-{[(dimethylamino) carbonyl] sulfenyl }-5-(trifluoromethyl) phenyl] acetic acid
With diphenyl ether (5ml) solution of the product (0.51g) of step (i) at 200 ℃ of heating 20h.Reaction mixture obtains subhead compound (0.49g) through flash column chromatography (elutriant is that DCM is to ether) purifying.
MS：APCI(+ve)：322(M+H)。
(iii) [3-sulfydryl-5-(trifluoromethyl) phenyl] acetic acid
The product (0.49g) of step (ii) is dissolved among methyl alcohol (10ml) and the 2M NaOH (10ml), in stirred overnight at room temperature.Mixture is used ethyl acetate extraction with 2M HCl dilution, dry (MgSO 4), then reduction vaporization obtains solid (0.30g).
1H?NMR?CDCl 3：δ7.45(1H，s)，7.32(1H，s)，7.27-7.26(1H，s)，3.76-3.66(2H，s)，2.91(1H，s)。
(iv) [3-{[2-chloro-4-(ethylsulfonyl) phenyl] sulfenyl }-5-(trifluoromethyl) phenyl] acetic acid
Prepare title compound described in embodiment 2 steps (iii), different is to be prepared by the product of step (iii) and the product of embodiment 3 steps (i).
1H?NMR?DMSO-d 6：δ7.97(1H，s)，7.81-7.79(3H，d)，7.73-7.69(1H，d)，7.01-6.94(1H，d)，3.63(2H，s)，3.41-3.30(2H，q)，1.19-1.06(3H，t)。
MS：APCI-ve?393(M-CO 2)。
Embodiment 59
3-[2-chloro-4-(ethylsulfonyl) phenoxy group]-the 5-p-methoxy-phenyl } acetic acid
Figure S2006800461779D00601
(i) 3-[2-chloro-4-(ethylsulfonyl) phenoxy group]-the 5-hydroxy phenyl } methyl acetate
Preparation subhead compound described in embodiment 2 steps (iii), different is, is prepared by product and (3,5-dihydroxy phenyl) methyl acetate of embodiment 3 steps (i).
MS：APCI-ve?383(M-H)。
(ii) 3-[2-chloro-4-(ethylsulfonyl) phenoxy group]-the 5-p-methoxy-phenyl } acetic acid
The product of step (i) is absorbed in toluene (3ml) and the methyl alcohol (1ml), then adds TMS-diazomethane (0.6ml, the diethyl ether solution of 2M), with mixture at stirring at room 3h, then reduction vaporization.Resistates is absorbed in THF (2ml) and the methyl alcohol (1ml), then adds 3M NaOH (2ml), with mixture at stirring at room 2h.Then, it is 2 that mixture is acidified to pH, then uses ethyl acetate extraction.Organic phase is carried out drying (MgSO 4), then reduction vaporization is loaded into Varian NH 2(use successively the DCM eluant solution of ethyl acetate, acetonitrile, methyl alcohol, DCM and 20% acetic acid) on the resin.Acidic fraction is carried out reduction vaporization, then through the RPHPLC purifying, obtain white solid.
1H?NMR?DMSO-d 6：δ8.07(1H，d)，7.82(1H，dd)，7.13(1H，d)，6.78(1H，s)，6.66(1H，t)，6.63(1H，s)，3.77(3H，s)，3.54(2H，s)，3.37(3H，q)，1.14(3H，t)。
MS：APCI-ve?383(M-H)。
Embodiment 60
[3-{2-chloro-4-[(2-luorobenzyl) alkylsulfonyl] phenoxy group }-5-(trifluoromethyl) phenyl] acetic acid
Figure S2006800461779D00611
(i) 2-chloro-1-fluoro-4-[(2-luorobenzyl) alkylsulfonyl] benzene
Preparation subhead compound described in embodiment 54 steps (i), different is to be prepared by 3-chloro-4-fluoro thiophenol and 1-(brooethyl)-2-fluorobenzene.
1H?NMR?CDCl 3：δ7.71-7.68(1H，m)，7.57-7.51(1H，m)，7.39-7.32(2H，m)，7.27-7.15(2H，m)，6.98-6.92(1H，m)，4.41(2H，s)。
(ii) [3-{2-chloro-4-[(2-luorobenzyl) alkylsulfonyl] phenoxy group }-5-(trifluoromethyl) phenyl] acetic acid
Prepare title compound described in embodiment 2 steps (iii), different is to be prepared by the product of embodiment 25 steps (iv) and the product of step (i).
1H?NMR?DMSO-d 6：δ8.02-7.94(1H，m)，7.82-7.55(2H，m)，7.45-7.12(7H，m)，4.82-4.79(2H，s)，3.76(2H，s)。
MS：APCI-ve?457(M-CO 2)。
Embodiment 61
[3-{[3-methyl-5-(phenyl sulfonyl) pyridine-2-yl] oxygen base }-5-(trifluoromethyl) phenyl] acetic acid
Figure S2006800461779D00612
(i) 2-chloro-3-methyl-5-(phenyl sulfenyl) pyridine
With 2-chloro-3-methyl-5-bromopyridine (1.0g) at-78 ℃ of butyllithium (hexane solution of 2.5M, anhydrous THF (20ml) solution 1.94ml) that add to stirring.Mixture was placed 5 minutes at-78 ℃, used afterwards Diphenyl disulfide ether (1.06g) to process.Mixture is warmed to room temperature.Behind the 1h, mixture is with 2M HCl cancellation, and with extracted with diethyl ether (abandoning), then water layer is used ethyl acetate extraction with saturated sodium hydrogen carbonate solution alkalization, and dry (MgSO4), then reduction vaporization obtains brown oil.Oily matter is carried out flash column chromatography (elutriant is 3: 2 DCM/ ethyl acetate), obtain subhead compound (2.30g).
MS：APCI(-ve)：236(M+H)。
(ii) 2-chloro-3-methyl-5-(phenyl sulfonyl) pyridine
The product (2.30g) of step (i) is dissolved among DCM (10ml) and the TFA (5ml).Mixture is carried out reduction vaporization, obtain yellow oil.Oily matter is dissolved among the DCM (50ml), then adds MCPBA (4.20g), in stirred overnight at room temperature.Then, solution washs with metabisulfite solution and sodium bicarbonate aqueous solution, dry (MgSO 4), then reduction vaporization obtains oily matter, and it obtains subhead compound (0.89g) through flash column chromatography (elutriant is 1: 1 isohexane/ether) purifying.
1H?NMR?CDCl 3：δ?8.75-8.74(1H，s)，8.02-7.89(2H，m)，7.69-7.49(3H，m)，7.26(1H，s)，2.31(3H，s)。
(iii) [3-{[3-methyl-5-(phenyl sulfonyl) pyridine-2-yl] oxygen base }-5-(trifluoromethyl) phenyl] acetic acid
Prepare title compound described in embodiment 2 steps (iii), different is to be prepared by the product of embodiment 25 steps (iv) and the product of step (ii).
1H?NMR?DMSO-d 6：δ?8.54-8.53(1H，s)，8.28(1H，s)，8.01-7.98(2H，m)，7.73-7.42(6H，m)，3.74(2H，s)，2.27(3H，s)。
MS：APCI-ve?450(M-H)。
Embodiment 62
[3-[2-chloro-4-(morpholine-4-base alkylsulfonyl) phenoxy group]-5-(trifluoromethyl) phenyl] acetic acid
Figure S2006800461779D00621
(i) 4-[(3-chloro-4-fluorophenyl) alkylsulfonyl] morpholine
4-fluoro-3-chlorobenzene sulfonyl chloride (0.9g) is stirred in anhydrous DCM (10ml), then add morpholine (0.69ml).At stirring at room 1h, then water cancellation extracts with DCM with mixture, dry (MgSO 4), then reduction vaporization obtains white solid (1.10g).
1H?NMR?CDCl 3：δ?7.86-7.83(1H，m)，7.69-7.64(1H，m)，7.36-7.26(1H，t)，3.78-3.75(4H，m)，3.01(4H，m)。
(ii) [3-[2-chloro-4-(morpholine-4-base alkylsulfonyl) phenoxy group]-5-(trifluoromethyl) phenyl] acetic acid
Prepare title compound described in embodiment 2 steps (iii), different is to be prepared by the product of embodiment 25 steps (iv) and the product of step (i).
1H?NMR?DMSO-d 6：δ?12.52(1H，bs)，7.95-7.93(1H，m)，7.73-7.33(4H，m)，7.24-7.21(1H，d)，3.76(2H，s)，3.64(4H，m)，2.93(4H，m)。
MS：APCI-ve?434(M-CO 2)。
Embodiment 63
[3-(4-benzoyl-2-chlorophenoxy)-5-(trifluoromethyl) phenyl] acetic acid
Figure S2006800461779D00631
(i) (3-chloro-4-fluorophenyl) (phenyl) ketone
With 3-chloro-4-fluorobenzoyl chloride (1.0g), benzene (2ml) and iron(ic) chloride (0.28g) reflux 16h, then dilute with water is used ethyl acetate extraction, and organic phase is carried out drying (MgSO 4), then reduction vaporization obtains subhead compound (0.8g), is brown solid.
1H?NMR?CDCl 3：δ7.91-7.88(1H，d)，7.77-7.48(6H，m)，7.28-7.22(1H，t)。
(ii) [3-(4-benzoyl-2-chlorophenoxy)-5-(trifluoromethyl) phenyl] acetic acid
Prepare title compound described in embodiment 2 steps (iii), different is to be prepared by the product of embodiment 25 steps (iv) and the product of step (i).
1H?NMR?DMSO-d 6：7.95-7.93(1H，m)，7.78-7.49(7H，m)，7.25(2H，s)，7.20-7.18(1H，d)，3.60(2H，s)。
MS：APCI-ve?389(M-CO 2)。
Embodiment 64
[3-{2-chloro-4-[(3-luorobenzyl) alkylsulfonyl] phenoxy group }-5-(trifluoromethyl) phenyl] acetic acid
Figure S2006800461779D00632
(i) 2-chloro-1-fluoro-4-[(3-luorobenzyl) alkylsulfonyl] benzene
Preparation subhead compound described in embodiment 54 steps (i), different is to be prepared by 3-chloro-4-fluoro thiophenol and 1-(brooethyl)-3-fluorobenzene.
1H?NMR?CDCl 3：δ7.71-7.68(1H，m)，7.57-7.51(1H，m)，7.39-7.32(2H，m)，7.27-7.15(2H，m)，6.98-6.92(1H，m)，4.41(2H，s)。
(ii) [3-{2-chloro-4-[(3-luorobenzyl) alkylsulfonyl] phenoxy group }-5-(trifluoromethyl) phenyl] acetic acid
Prepare title compound described in embodiment 2 steps (iii), different is to be prepared by the product of embodiment 25 steps (iv) and the product of step (i).
1H?NMR?DMSO-d 6：δ7.75(1H，m)，7.68-6.97(9H，m)，4.81(2H，s)，3.65(2H，s)。
MS：APCI-ve?501(M-H)。
Embodiment 65
3-bromo-5-[2-fluoro-4-(phenyl sulfonyl) phenoxy group] and phenyl } acetic acid
Figure S2006800461779D00641
Prepare title compound described in embodiment 2 steps (iii), different is to be prepared by the product of embodiment 55 steps (v) and the product of embodiment 24 steps (i).
1H?NMR?DMSO-d 6：8.05-7.99(3H，m)，7.80-7.62(4H，m)，7.32(1H，s)，7.21-7.17(2H，m)，7.02(1H，s)，3.35(2H，s)。
MS：APCI-ve?419(M-CO 2)。
Embodiment 66
[3-{2-fluoro-4-[(4-fluorophenyl) alkylsulfonyl] phenoxy group }-5-(trifluoromethyl) phenyl] acetic acid
(i) 1,2-two fluoro-4-[(4-fluorophenyls) alkylsulfonyl] benzene
Prepare title compound described in embodiment 29 steps (i), different is to be prepared by 3,4-difluoro chloride and fluorobenzene.
1H?NMR?CDCl 3：δ7.98-7.93(2H，m)，7.78-7.70(2H，m)，7.36-7.19(3H，m)。
(ii) [3-{2-fluoro-4-[(4-fluorophenyl) alkylsulfonyl] phenoxy group }-5-(trifluoromethyl) phenyl] acetic acid
Prepare title compound described in embodiment 2 steps (iii), different is to be prepared by the product of embodiment 25 steps (iv) and the product of step (i).
1H?NMR?DMSO-d 6：δ8.12-8.08(3H，m)，7.82-7.80(1H，d)，7.53-7.44(4H，m)，7.37(1H，s)，7.27-7.23(1H，t)，3.71(2H，s)。
MS：APCI-ve?471(M-H)。
Embodiment 67
3-chloro-5-[4-(ethylsulfonyl)-3-(trifluoromethyl) phenoxy group] and phenyl } acetic acid
Figure S2006800461779D00651
(i) 4-bromo-1-(ethylsulfonyl)-2-(trifluoromethyl) benzene
4-bromo-1-(ethyl sulfenyl)-2-(trifluoromethyl) benzene (3.80g) is dissolved among the DCM (50ml), then adds MCPBA (5.71g), in stirred overnight at room temperature.Then, solution washs with metabisulfite solution and sodium bicarbonate aqueous solution, dry (MgSO 4), then reduction vaporization obtains solid, and (elutriant is the purifying of 1: 1 isohexane/DCM), obtains subhead compound (4.10g) through flash column chromatography for it.
1H?NMR?CDCl 3：δ8.13-7.87(3H，m)，3.31-3.24(2H，q)，1.34-1.26(3H，t)。
(ii) 3-chloro-5-[4-(ethylsulfonyl)-3-(trifluoromethyl) phenoxy group] and phenyl } acetic acid
Prepare title compound described in embodiment 2 steps (iii), different is to be prepared by the product of step (i) and the product of embodiment 18 steps (iv).
1H?NMR?DMSO-d 6：δ8.16-8.14(1H，d)，7.63-7.62(1H，s)，7.41-7.38(1H，d)，7.29-7.12(3H，m)，3.59(2H，s)，3.42-3.31(2H，q)，1.18-1.14(3H，t)。
MS：APCI-ve?377(M-CO 2)。
Embodiment 68
3-chloro-5-[5-chloro-2-fluoro-4-(pyrrolidin-1-yl carbonyl) phenoxy group] and phenyl } acetic acid
Figure S2006800461779D00661
(i) 1-(2-chloro-4,5-difluoro benzoyl) tetramethyleneimine
2-chloro-4, DCM (10ml) solution of 5-difluoro-benzoic acid (1.0g) is processed with oxalyl chloride (0.45ml), next processes with 1 DMF.With mixture at stirring at room 1h, afterwards reduction vaporization.Solid is dissolved among the DCM (20ml), then adds tetramethyleneimine (2ml), in stirred overnight at room temperature.The mixture dilute with water, with the DCM extraction, dry (MgSO 4), then reduction vaporization obtains oily matter (1.45g).
1H?NMR?CDCl 3：δ7.27-7.23(1H，m)，7.19-7.15(1H，m)，3.66-3.62(2H，t)，3.23-3.20(2H，t)，2.05-1.88(4H，m)。
(ii) 3-chloro-5-[5-chloro-2-fluoro-4-(pyrrolidin-1-yl carbonyl) phenoxy group] and phenyl } acetic acid
Prepare title compound described in embodiment 2 steps (iii), different is to be prepared by the product of step (i) and the product of embodiment 18 steps (iv).
1H?NMR?DMSO-d 6：δ7.59-7.56(1H，d)，7.40-7.38(1H，d)，7.14(1H，s)，7.02-7.01(1H，s)，6.94(1H，s)，3.44(4H，m)，3.19-3.15(2H，t)，1.90-1.81(4H，m)。
MS：APCI+ve?412(M+H)。
Embodiment 69
3-cyano group-5-[2-fluoro-4-(phenyl sulfonyl) phenoxy group] and phenyl } acetic acid
Figure S2006800461779D00662
(i) 3-bromo-5-[2-fluoro-4-(phenyl sulfonyl) phenoxy group] and phenyl } acetic acid
Preparation subhead compound described in embodiment 56 steps (ii), different is to be prepared by the product of embodiment 56 steps (i) and the product of embodiment 24 steps (i).Crude product uses in situation about further not characterizing.
(ii) 3-cyano group-5-[2-fluoro-4-(phenyl sulfonyl) phenoxy group] and phenyl } acetic acid
Prepare title compound described in embodiment 56 steps (iii), different is, is prepared by the product of zinc cyanide and step (i).
1H?NMR?DMSO-d 6：8.08-8.00(3H，m)，7.80-7.55(6H，m)，7.34(1H，s)，7.29-7.18(1H，t)，3.53(2H，s)。
MS：APCI-ve?366(M-CO 2)。
Embodiment 70
(3-chloro-5-{2-fluoro-4-[(4-fluorophenyl) alkylsulfonyl] phenoxy group } phenyl) acetic acid
Figure S2006800461779D00671
Prepare title compound described in embodiment 2 steps (iii), different is to be prepared by the product of embodiment 18 steps (iv) and the product of embodiment 66 steps (i).
1H?NMR?DMSO-d 6：δ8.10-8.00(3H，m)，7.80-7.78(1H，d)，7.50-7.46(2H，t)，7.24-7.02(2H，m)，6.87?&?6.82(2H，2xs)，3.41-3.39(2H，s)。
MS：APCI-ve?437(M-H)。
Embodiment 71
(3-chloro-5-{[2-cyano group-4-(ethylsulfonyl) phenyl] sulfenyl } phenyl) acetic acid
(i) (3-chloro-5-sulfydryl phenyl) acetic acid
Preparation subhead compound described in embodiment 58 steps (i) to (iii), different is, is prepared by the product of embodiment 18 steps (iv).
1H?NMR?CDCl 3：δ7.32-7.31(1H，s)，7.26(1H，s)，7.08-7.07(1H，s)，3.56(2H，s)，2.9(1H，s)。
(ii) (3-chloro-5-{[2-cyano group-4-(ethylsulfonyl) phenyl] sulfenyl } phenyl) acetic acid
Prepare title compound described in embodiment 2 steps (iii), different is to be prepared by the product of step (i) and the product of embodiment 12 steps (i).
1H?NMR?DMSO-d 6：δ8.36(1H，s)，8.02-7.99(1H，m)，7.59-7.48(3H，m)，7.25-7.22(1H，m)，3.54(2H，s)，3.40(2H，q)，1.13-1.08(3H，t)。
MS：APCI-ve?394(M-H)。
Embodiment 72
(3-chloro-5-{[4-(ethylsulfonyl)-2-(trifluoromethyl) phenyl] sulfenyl } phenyl) acetic acid
Figure S2006800461779D00681
Prepare title compound described in embodiment 2 steps (iii), different is to be prepared by the product of embodiment 71 steps (i) and the product of embodiment 2 steps (ii).
1H?NMR?DMSO-d 6：δ12.53(1H，bs)，8.21-8.20(1H，s)，8.07-8.04(1H，d)，7.57-7.53(2H，m)，7.47(1H，s)，7.34-7.32(1H，d)，3.69(2H，s)，3.30(3H，s)。
MS：APCI-ve?379(M-CO 2)。
Embodiment 73
(3-chloro-5-{[2-fluoro-4-(phenyl sulfonyl) phenyl] sulfenyl } phenyl) acetic acid
Figure S2006800461779D00682
Prepare title compound described in embodiment 1 step (vi), different is to be prepared by the product of embodiment 71 steps (i) and the product of embodiment 24 steps (i).
1H?NMR?DMSO-d 6：δ12.51(1H，s)，8.00-7.91(3H，m)，7.73-7.60(4H，m)，7.49-7.29(3H，m)，7.24-7.18(1H，t)，3.65(2H，s)。
MS：APCI-ve?435(M-H)。
Embodiment 74
[3-(4-benzoyl-3,5-difluoro phenoxy group)-5-chloro-phenyl-] acetic acid
Figure S2006800461779D00691
(i) phenyl (2,4,6-trifluorophenyl) ketone
2,4,6-trifluorobenzoyl chloride (5.0g), benzene (5ml) and iron(ic) chloride (1.39g) at 80 ℃ of heating 16h, then are cooled to room temperature.The reaction mixture dilute with water is with ethyl acetate (* 2) extraction, the salt water washing of the organic extract liquid of merging, dry (MgSO 4), then reduction vaporization obtains subhead compound (5.80g).
1H?NMR?CDCl 3：δ7.86-7.84(2H，m)，7.66-7.61(1H，m)，7.52-7.47(2H，m)，6.81-6.74(2H，m)。
(ii) [3-(4-benzoyl-3,5-difluoro phenoxy group)-5-chloro-phenyl-] acetic acid
Prepare title compound described in embodiment 2 steps (iii), different is to be prepared by the product of step (i) and the product of embodiment 18 steps (iv).
1H?NMR?DMSO-d 6：δ7.87-7.68(3H，m)，7.62-7.55(2H，t)，7.26-7.24(2H，m)，7.13-7.12(1H，s)，7.01-6.92(2H，d)，3.62(2H，s)。
MS：APCI+ve?357(M-CO 2)。
Embodiment 75
3-chloro-5-[2-chloro-4-(4-fluoro benzoyl) phenoxy group] and phenyl } acetic acid
Figure S2006800461779D00692
(i) (3-chloro-4-fluorophenyl) (4-fluorophenyl) ketone
Preparation subhead compound described in embodiment 74 steps (i), different is to be prepared by 3-chloro-4-fluorobenzoyl chloride and fluorobenzene.
1H?NMR?CDCl 3-d6：δ7.88-7.78(3H，m)，7.57-7.53(1H，m)，7.29-7.15(3H，m)。
(ii) 3-chloro-5-[2-chloro-4-(4-fluoro benzoyl) phenoxy group] and phenyl } acetic acid
Prepare title compound described in embodiment 2 steps (iii), different is to be prepared by the product of step (i) and the product of embodiment 18 steps (iv).
1H?NMR?DMSO-d 6：δ7.92-7.84(3H，m)，7.72-7.69(1H，d)，7.44-7.39(2H，m)，7.21-7.17(2H，m)，7.10-7.08(1H，m)，7.00(1H，s)，3.55(2H，s)。
MS：APCI+ve?373(M-CO 2)。
Embodiment 76
3-[2-fluoro-4-(phenyl sulfonyl) phenoxy group]-the 5-aminomethyl phenyl } acetic acid
Figure S2006800461779D00701
(i) 3-[2-fluoro-4-(phenyl sulfonyl) phenoxy group]-the 5-hydroxy phenyl } acetic acid
Preparation subhead compound described in embodiment 2 steps (iii), different is, is prepared by the product of 3,5-dihydroxy-benzene guanidine-acetic acid and embodiment 24 steps (i).
MS：APCI-ve?415(M-H)。
(ii) (3-[2-fluoro-4-(phenyl sulfonyl) phenoxy group]-the 5-{[(trifluoromethyl) alkylsulfonyl] the oxygen base } phenyl) acetic acid
Anhydrous DCM (20ml) solution of the product (4.16g) of step (i) is processed with pyridine (0.81ml), then is cooled to 0 ℃, adds afterwards trifluoromethanesulfanhydride anhydride (1.68ml).In stirred overnight at room temperature, then dilute with water extracts with DCM with mixture, dry (MgSO 4), then reduction vaporization obtains subhead compound (2.09g).
1H?NMR?CDCl 3-d 6：δ7.97-7.95(2H，d)，7.80-7.72(2H，m)，7.65-7.52(3H，m)，7.18-7.10(1H，t)，7.05-6.85(3H，s)，3.71(3H，s)，3.63(2H，s)。
(iii) 3-[2-fluoro-4-(phenyl sulfonyl) phenoxy group]-the 5-aminomethyl phenyl } acetic acid
With the product (0.25g) of toluene (0.40ml) solution treatment steps (ii) of two diphenylphosphino ferrocene palladiums (0.02g) and 2.0M zinc methide Wu Shui diox (10ml) solution, the preparation title compound.With the mixture heating up 3h that refluxes, then between water and ethyl acetate, distribute, separate organic phase, dry (MgSO 4), then reduction vaporization obtains oily matter.Oily matter is dissolved in the methyl alcohol (10ml), then adds 2M NaOH (10ml), in stirred overnight at room temperature.The mixture dilute with water is with extracted with diethyl ether (abandoning).Water layer is used ethyl acetate extraction with 2M HCl acidifying, dry (MgSO 4), then reduction vaporization obtains oily matter, and it obtains white solid (0.085g) through the RPHPLC purifying.
1H?NMR?DMSO-d 6：δ8.03-7.97(3H，m)，7.77-7.60(4H，m)，7.13-7.07(1H，t)，6.94(1H，s)，6.81(2H，s)，3.34(2H，s)，2.26(3H，s)。
MS：APCI-ve?355(M-CO 2)。
Embodiment 77
3-ethyl-5-[2-fluoro-4-(phenyl sulfonyl) phenoxy group] and phenyl } acetic acid
Figure S2006800461779D00711
Prepare title compound described in embodiment 76 steps (iii), different is to be prepared by the product of embodiment 76 steps (ii) and the toluene solution of 2.0M zinc ethyl.
1H?NMR?DMSO-d 6：δ8.04-7.97(3H，m)，7.78-7.60(4H，m)，7.12-7.07(1H，t)，6.98(1H，s)，6.86-6.84(2H，d)，3.48(2H，s)，2.61-2.51(2H，q)，1.17-1.12(3H，t)。
MS：APCI-ve?369(M-CO 2)。
Embodiment 78
[3-{2-chloro-4-[(4-luorobenzyl) alkylsulfonyl] phenoxy group }-5-(trifluoromethyl) phenyl] acetic acid
Figure S2006800461779D00712
Prepare title compound described in embodiment 2 steps (iii), different is to be prepared by the product of embodiment 25 steps (iv) and the product of embodiment 34 steps (i).
1H?NMR?DMSO-d 6：δ7.92(1H，d)，7.61(1H，dd)，7.55(1H，s)，7.35(2H，d)，7.27-7.13(5H，m)，4.77(2H，s)，3.76(2H，s)。
MS：MM-ve?501(M-H)。
Embodiment 79
[3-[2-cyano group-4-(phenyl sulfonyl) phenoxy group]-5-(trifluoromethyl) phenyl] acetic acid
Figure S2006800461779D00721
Prepare title compound described in embodiment 2 steps (iii), different is to be prepared by the product of embodiment 25 steps (iv) and the product of embodiment 44 steps (i).
1H?NMR?DMSO-d 6：δ12.57(1H，s)，8.62(1H，d)，8.17(1H，dd)，8.03(2H，dt)，7.76-7.61(5H，m)，7.54(1H，s)，7.04(1H，d)，3.77(2H，s)。
MS：MM-ve?416(M-CO 2)。
Embodiment 80
5-[2-chloro-4-(ethylsulfonyl) phenoxy group] and biphenyl-3-yl } acetic acid
Figure S2006800461779D00722
With the product (0.45g) of embodiment 55 steps (vi), phenyl-boron dihydroxide (0.190g), yellow soda ash (0.44g) and two diphenylphosphino ferrocene palladium (II) (0.04g) be heated to 80 ℃ Wu Shui diox (20ml) solution, keep 20h.Mixture is used ethyl acetate extraction with 2M HCl dilution, dry (MgSO 4), then reduction vaporization obtains oily matter, and it obtains title compound through the RPHPLC purifying, is cream-colored solid (0.23g).
1H?NMR?DMSO-d 6：δ8.07(1H，s)，7.82-7.79(1H，d)，7.69-7.66(2H，d)，7.50-7.35(5H，m)，7.18-7.06(2H，m)，3.69(2H，s)，3.39-3.31(2H，q)，1.14-1.09(3H，t)。
MS：MM-ve?385(M-CO 2)。
Embodiment 81
3-[2-chloro-4-(ethylsulfonyl) phenoxy group]-5-pyridine-2-base phenyl } acetic acid
Figure S2006800461779D00731
With the product (0.45g) of embodiment 55 steps (vi), 2-pyridyl zinc bromide (0.89ml) and two diphenylphosphino ferrocene palladium (II) (0.04g) be heated to 90 ℃ Wu Shui diox (20ml) solution, keep 20h.The mixture dilute with water, with the DCM extraction, dry (MgSO 4), then reduction vaporization obtains oily matter, and it obtains title compound through the RPHPLC purifying, is white solid (3mg).
1H?NMR?DMSO-d 6：δ8.65-8.64(1H，m)，8.09-7.72(6H，m)，7.39-7.36(1H，m)，7.19-7.15(2H，m)，3.66(2H，s)，3.39-3.35(2H，q)，1.14-1.10(3H，t)。
MS：MM+ve?432(M+H)。
Embodiment 82
3-[2-chloro-4-(ethylsulfonyl) phenoxy group]-5-[2-(dimethylamino) oxyethyl group] phenyl } acetic acid
Figure S2006800461779D00732
(i) 3-[2-chloro-4-(ethylsulfonyl) phenoxy group]-the 5-hydroxy phenyl } methyl acetate
With the anhydrous nmp solution of the product of 3,5-dihydroxy phenyl methyl acetate (0.20g), cesium carbonate (1.08g) and embodiment 3 steps (i) at 50 ℃ of heating 4h.Add 2M HCl, then use ethyl acetate extraction.Organic phase is carried out drying (MgSO 4), then reduction vaporization obtains brown oil, and it is through flash column chromatography (elutriant is 1: 1 ethyl acetate/isohexane) purifying, obtain the mixture of single coupled product and two coupled products, it uses in next step in situation about not being further purified.
MS：MM-ve?383(M-H)。
(ii) 3-[2-chloro-4-(ethylsulfonyl) phenoxy group]-5-[2-(dimethylamino) oxyethyl group] phenyl } methyl acetate
Salt of wormwood (0.46g) is added to the product (1.10mmol) of step (i) and the DMF solution of 2-dimethylamino ethyl chloride hydrochloride (0.16g) in room temperature.Behind the 1h, any obvious reaction does not occur, so with mixture heating up to 60 ℃, keep 18h.Add water, then the mixture ethyl acetate extraction washs by (salt solution), and organic phase is carried out drying (MgSO 4), then concentrated, obtain green oily matter, it obtains subhead compound (100mg) through flash column chromatography (elutriant is the ethyl acetate solution of 1% triethylamine and 2% methyl alcohol) purifying, is colorless oil.
MS：MM+ve?456(M+H)。
(iii) 3-[2-chloro-4-(ethylsulfonyl) phenoxy group]-5-[2-(dimethylamino) oxyethyl group] phenyl } acetic acid
1M sodium hydroxide (0.44ml) is added to 1: 1 THF/ methyl alcohol (6ml) solution of the product (100mg) of step (ii), stir 48h.Mixture is carried out reduction vaporization, then through the RPHPLC purifying, obtain title compound (0.04g), be white solid.
1H?NMR?CD 3ODδ8.00(1H，d)，7.75(1H，dd)，7.41(1H，d)，6.87(1H，s)，6.69(1H，s)，6.59(1H，t)，4.27(2H，t)，3.46(2H，s)，3.34(2H，t)，3.22(2H，q)，2.79(6H，s)，1.23(3H，t)。
MS：MM+ve?442(M+H)。
Embodiment 83
[3-{2-chloro-4-[(pyridine-2-ylmethyl) alkylsulfonyl] phenoxy group }-5-(trifluoromethyl) phenyl] acetic acid
Figure S2006800461779D00741
(i) 2-{[(3-chloro-4-fluorophenyl) sulfenyl] methyl } pyridine
Pyridine-2-ylmethyl chloride hydrochloride (2-picolyl chloride hydrochloride) (3.03g) is added to the 3-chloro-4-fluoro thiophenol (3.0g) of stirring and DMF (50ml) suspension of cesium carbonate (12.0g), with mixture in stirred overnight at room temperature.Mixture is poured in the water, organic substance extraction in ether, is then washed (salt solution) to ether extraction liquid, dry (MgSO 4), then reduction vaporization obtains green oily matter (4.0g).
1H?NMR?DMSO-d 6：δ8.48(1H，d)，7.74(1H，td)，7.62-7.58(1H，m)，7.43-7.32(3H，m)，7.26(1H，ddd)，4.36(2H，s)。
(ii) 2-{[(3-chloro-4-fluorophenyl) alkylsulfonyl] methyl } pyridine
TFA (0.59ml) is added to DCM (50ml) solution of the product (2.0g) of step (i).Then, MCPBA (6.6g) is dropwise added to mentioned solution, next add extra DCM (20ml).Mixture at stirring at room 2h, is then added DCM (150ml), and mixture washs with sodium bicarbonate aqueous solution, then uses the salt water washing.Organic phase is carried out drying (MgSO 4), reduction vaporization then, (elutriant is the purifying of 1: 1 isohexane/ethyl acetate to 10% ethanol/DCM) to resistates, obtains subhead compound (1.3g), is white solid through flash column chromatography.
1H?NMR?DMSO-d 6：δ8.42(1H，ddd)，7.92(1H，dd)，7.81(1H，td)，7.70-7.61(2H，m)，7.40(1H，d)，7.34(1H，ddd)，4.92(2H，s)。
(iii) [3-{2-chloro-4-[(pyridine-2-ylmethyl) alkylsulfonyl] phenoxy group }-5-(trifluoromethyl) phenyl] acetic acid
Prepare title compound described in embodiment 2 steps (iii), different is to be prepared by the product of embodiment 25 steps (iv) and the product of step (ii).
1H?NMR?DMSO-d 6：δ8.43(1H，dd)，7.89(1H，d)，7.81(1H，td)，7.61(1H，dd)，7.55(1H，s)，7.42(1H，d)，7.37-7.32(3H，m)，7.20(1H，d)，4.91(2H，s)，3.77(2H，s)。
MS：MM+ve?486(M+H)。
Pharmacology data
Ligand binding is measured
[ 3H] PGD 2Available from Perkin Elmer Life Sciences, its specific activity is 100-210Ci/mmol.All other chemical substances all are AG.
Express the HEK cell of rhCRTh2/G α 16 and support routinely in DMEM, described DMEM contains 10% foetal calf serum (HyClone), 1mg/ml Geneticin, 2mM L-glutaminate and 1% non-essential amino acid.In order to carry out film preparation, the HEK cell of adhesion transfection is cultivated in factory's (Fisher, catalog number (Cat.No.) are TKT-170-070E) in two layers of tissue grown to fusion.At last 18 hours that cultivate, add the highest level that the 500mM Sodium propanecarboxylate is induced expression of receptor.AC phosphate buffered saline buffer (PBS, the 50ml/ cell factory) then washing is once added the ice-cold film homogenize damping fluid [20mM HEPES (pH 7.4), 0.1mM dithiothreitol (DTT), 1mM EDTA, 0.1mM phenyl methyl sulfonic acid fluoride and 100 μ g/ml bacitracins] of 50ml to every cell factory and is made cell separately.4 ℃ with 220 * g centrifugal 10 minutes, make cell precipitation, in the fresh film homogenize damping fluid of half initial volume, then utilize the Polytron homogenizer to carry out fragmentation (2 * 20 seconds) the throw out Eddy diffusion, test tube is remained in the ice.Removed not broken cell at 4 ℃ in centrifugal 10 minutes with 220 * g, the film fraction was precipitated with 90000 * g at 4 ℃ in centrifugal 30 minutes.With regard to every cell factory, final precipitation Eddy diffusion in the film homogenize damping fluid of 4ml, is then measured protein content.Film is stored in-80 ℃ of temperature with the form of suitable aliquot.
All mensuration are all carried out in hole NBS plate (Fisher) of the transparent white ends 96 of Corning.Before the mensuration, the HEK cytolemma that will contain CRTh2 is coated on the SPA PVT WGA pearl (Amersham).In order to apply, 4 ℃ of overnight incubation, constant speed stirs simultaneously with film and pearl (being generally 25 μ g membranin/mg pearls).The best concentration that applies depends on every batch of film.Centrifugal (at 4 ℃ with centrifugal 7 minutes of 800 * g) make the pearl deposition, with measuring damping fluid (50mM HEPES pH 7.4 contains the 5mM magnesium chloride) washing once, at last with its Eddy diffusion in measuring damping fluid, bead concentration is 10mg/ml.
Every part of mensuration all contains the 6.25nM[of 20 μ l 3H] PGD 2, SPA pearl that 20 μ l films are saturated (the two is all in measuring damping fluid) and 10 μ l compound solution or 13,14-dihydro-15-ketone group PGD 2(DK-PGD 2, be used for determining non-specific binding, Cayman Chemical Company).
With compound and DK-PGD 2Be dissolved among the DMSO, then in identical solvent, be diluted to 100 * required ultimate density.Add and measure damping fluid, the ultimate density that makes DMSO is 10% (compound concentration is 10 * required ultimate density now), and this is the solution that adds in the assay plate.With assay plate incubated at room 2 hours, then at Wallac Microbeta liquid scintillation counter counting (1 minute/hole).
Formula (I) compound has the IC less than (＜) 10 μ M 50Value.
Particularly, the pIC of embodiment 7 compounds 50Value is the pIC of 8.10, embodiment, 9 compounds 50Value is 7.85, and the pIC of embodiment 11 compounds 50Value is 8.05.

Claims (11)

1. formula (I) compound or pharmaceutically acceptable salt thereof:
Wherein
A is selected from hydrogen, halogen or C 1-6Alkyl, wherein said C 1-6Alkyl is optional to be replaced by one or more halogen atoms;
D is selected from hydrogen, halogen or C 1-6Alkyl, wherein said C 1-6Alkyl is optional to be replaced by one or more halogen atoms;
E is O;
V is C (H);
W is carbon atom, and described carbon atom is by hydrogen, halogen or C 1-3Alkyl replaces, wherein said C 1-3Alkyl is optional to be replaced by halogen atom;
X is carbon atom, and described carbon atom is replaced by hydrogen or halogen;
Y is selected from hydrogen, CN, halogen or C 1-6Alkyl, wherein said C 1-6Alkyl is optional to be replaced by one or more halogen atoms;
Z is selected from hydrogen, SO 2R 9, SO 2NR 4R 5, CONR 4R 5Or COR 6
R 1And R 2All be hydrogen, or R 1Or R 2In one be methyl, and another is hydrogen;
R 4And R 5Represent independently hydrogen or C 1-6Alkyl; Or
R 4And R 5The nitrogen-atoms that randomly connects with them forms 3-8 unit saturated rings, the optional atom that contains one or more O of being selected from and N of described 3-8 unit's saturated rings;
R 6The expression phenyl, described phenyl is optional to be replaced by one or more halogens;
R 9Optional phenyl or the R that is replaced by one or more halogens of expression 9Expression C 1-6Alkyl, wherein said C 1-6Alkyl is optional to be replaced by one or more substituting groups that are independently selected from phenyl and pyridyl, and described phenyl is optional to be replaced by one or more halogens;
Condition is:
● A and D are not hydrogen simultaneously.
2. the compound of claim 1 is not in the situation of hydrogen at D wherein, and A is hydrogen; Be not in the situation of hydrogen at A, D is hydrogen.
3. each compound in the claim 1 to 2, wherein W is C (H).
4. each compound in the claims 1 to 3, wherein X is C (H).
5. each compound in the claim 1 to 4, wherein Y is halogen, cyano group or the optional C that is replaced by one or more halogen atoms 1-3Alkyl.
6. formula (I) compound or pharmaceutically acceptable salt thereof, described compound is selected from:
4-chloro-3-[2-chloro-4-(methyl sulphonyl) phenoxy group] and phenyl } acetic acid;
4-chloro-3-[4-(methyl sulphonyl)-2-(trifluoromethyl) phenoxy group] and phenyl } acetic acid;
4-chloro-3-[2-chloro-4-(ethylsulfonyl) phenoxy group] and phenyl } acetic acid;
4-chloro-3-[4-(ethylsulfonyl)-2-(trifluoromethyl) phenoxy group] and phenyl } acetic acid;
4-chloro-3-[4-(methyl sulphonyl) phenoxy group] and phenyl } acetic acid;
2-{4-chloro-3-[2-chloro-4-(methyl sulphonyl) phenoxy group] phenyl } propionic acid;
(4-chloro-3-{2-chloro-4-[(dimethylamino) alkylsulfonyl] phenoxy group } phenyl) acetic acid;
4-chloro-3-[2-fluoro-4-(methyl sulphonyl) phenoxy group] and phenyl } acetic acid;
4-chloro-3-[4-(ethylsulfonyl)-2-fluorophenoxy] and phenyl } acetic acid;
4-chloro-3-[2-cyano group-4-(methyl sulphonyl) phenoxy group] and phenyl } acetic acid;
4-chloro-3-[2-cyano group-4-(ethylsulfonyl) phenoxy group] and phenyl } acetic acid;
4-chloro-3-[2-cyano group-5-(trifluoromethyl) phenoxy group] and phenyl } acetic acid;
(4-chloro-3-{2-fluoro-4-[(4-luorobenzyl) alkylsulfonyl] phenoxy group } phenyl) acetic acid;
[3-(4-benzoyl-2-fluorophenoxy)-4-chloro-phenyl-] acetic acid;
(4-chloro-3-{2-chloro-4-[(isobutylamino) carbonyl] phenoxy group } phenyl) acetic acid;
3-chloro-5-[2-chloro-4-(methyl sulphonyl) phenoxy group] and phenyl } acetic acid;
3-chloro-5-[2-chloro-4-(ethylsulfonyl) phenoxy group] and phenyl } acetic acid;
3-[2-chloro-4-(ethylsulfonyl) phenoxy group]-the 5-fluorophenyl } acetic acid;
3-fluoro-5-[4-(methyl sulphonyl)-2-(trifluoromethyl) phenoxy group] and phenyl } acetic acid;
3-[2-chloro-4-(ethylsulfonyl) phenoxy group]-the 4-fluorophenyl } acetic acid;
4-fluoro-3-[4-(methyl sulphonyl)-2-(trifluoromethyl) phenoxy group] and phenyl } acetic acid;
4-chloro-3-[2-fluoro-4-(phenyl sulfonyl) phenoxy group] and phenyl } acetic acid;
[3-[2-chloro-4-(methyl sulphonyl) phenoxy group]-5-(trifluoromethyl) phenyl] acetic acid;
[3-[2-chloro-4-(ethylsulfonyl) phenoxy group]-5-(trifluoromethyl) phenyl] acetic acid;
3-chloro-5-[2-fluoro-4-(methyl sulphonyl) phenoxy group] and phenyl } acetic acid;
3-chloro-5-[2-cyano group-4-(ethylsulfonyl) phenoxy group] and phenyl } acetic acid;
3-chloro-5-[2-chloro-4-(phenyl sulfonyl) phenoxy group] and phenyl } acetic acid;
3-chloro-5-[4-(ethylsulfonyl)-2-fluorophenoxy] and phenyl } acetic acid;
3-chloro-5-[2-fluoro-4-(phenyl sulfonyl) phenoxy group] and phenyl } acetic acid;
[3-{2-fluoro-4-[(4-luorobenzyl) alkylsulfonyl] phenoxy group }-5-(trifluoromethyl) phenyl] acetic acid;
(3-chloro-5-{2-fluoro-4-[(4-luorobenzyl) alkylsulfonyl] phenoxy group } phenyl) acetic acid;
(3-chloro-5-{2-chloro-4-[(4-luorobenzyl) alkylsulfonyl] phenoxy group } phenyl) acetic acid;
3-chloro-5-[4-(methyl sulphonyl)-2-(trifluoromethyl) phenoxy group] and phenyl } acetic acid;
3-chloro-5-[4-(ethylsulfonyl)-2-(trifluoromethyl) phenoxy group] and phenyl } acetic acid;
[3-[2-fluoro-4-(phenyl sulfonyl) phenoxy group]-5-(trifluoromethyl) phenyl] acetic acid;
[3-[2-chloro-4-(phenyl sulfonyl) phenoxy group]-5-(trifluoromethyl) phenyl] acetic acid;
[3-[4-(ethylsulfonyl)-2-fluorophenoxy]-5-(trifluoromethyl) phenyl] acetic acid;
[3-[2-cyano group-4-(ethylsulfonyl) phenoxy group]-5-(trifluoromethyl) phenyl] acetic acid;
[3-[4-(ethylsulfonyl)-2-(trifluoromethyl) phenoxy group]-5-(trifluoromethyl) phenyl] acetic acid;
3-[4-(benzyl alkylsulfonyl)-2-chlorophenoxy]-the 5-chloro-phenyl-} acetic acid;
3-chloro-5-[4-(phenyl sulfonyl)-2-(trifluoromethyl) phenoxy group] and phenyl } acetic acid;
3-chloro-5-[2-cyano group-4-(phenyl sulfonyl) phenoxy group] and phenyl } acetic acid;
3-[4-(benzyl alkylsulfonyl)-2-fluorophenoxy]-the 5-chloro-phenyl-} acetic acid;
(3-chloro-5-{2-fluoro-4-[(3-luorobenzyl) alkylsulfonyl] phenoxy group } phenyl) acetic acid;
3-[4-(benzyl alkylsulfonyl)-2-(trifluoromethyl) phenoxy group]-the 5-chloro-phenyl-} acetic acid;
(3-chloro-5-{2-fluoro-4-[(2-luorobenzyl) alkylsulfonyl] phenoxy group } phenyl) acetic acid;
(3-chloro-5-{4-[(4-chlorobenzyl) alkylsulfonyl]-the 2-fluorophenoxy } phenyl) acetic acid;
2-[3-[4-(ethylsulfonyl)-2-(trifluoromethyl) phenoxy group]-5-(trifluoromethyl) phenyl] propionic acid;
2-[3-[2-chloro-4-(ethylsulfonyl) phenoxy group]-5-(trifluoromethyl) phenyl] propionic acid;
2-[3-[2-chloro-4-(phenyl sulfonyl) phenoxy group]-5-(trifluoromethyl) phenyl] propionic acid;
2-[3-{2-chloro-4-[(4-luorobenzyl) alkylsulfonyl] phenoxy group }-5-(trifluoromethyl) phenyl] propionic acid;
(3-chloro-5-{4-[(4-chlorobenzyl) alkylsulfonyl]-the 2-fluorophenoxy } phenyl) acetic acid;
3-bromo-5-[2-chloro-4-(ethylsulfonyl) phenoxy group] and phenyl } acetic acid;
3-[2-chloro-4-(ethylsulfonyl) phenoxy group]-the 5-aminomethyl phenyl } acetic acid;
[3-{2-chloro-4-[(2-luorobenzyl) alkylsulfonyl] phenoxy group }-5-(trifluoromethyl) phenyl] acetic acid;
[3-[2-chloro-4-(morpholine-4-base alkylsulfonyl) phenoxy group]-5-(trifluoromethyl) phenyl] acetic acid;
[3-(4-benzoyl-2-chlorophenoxy)-5-(trifluoromethyl) phenyl] acetic acid;
[3-{2-chloro-4-[(3-luorobenzyl) alkylsulfonyl] phenoxy group }-5-(trifluoromethyl) phenyl] acetic acid;
3-bromo-5-[2-fluoro-4-(phenyl sulfonyl) phenoxy group] and phenyl } acetic acid;
[3-{2-fluoro-4-[(4-fluorophenyl) alkylsulfonyl] phenoxy group }-5-(trifluoromethyl) phenyl] acetic acid;
3-chloro-5-[4-(ethylsulfonyl)-3-(trifluoromethyl) phenoxy group] and phenyl } acetic acid;
3-chloro-5-[5-chloro-2-fluoro-4-(pyrrolidin-1-yl carbonyl) phenoxy group] and phenyl } acetic acid;
(3-chloro-5-{2-fluoro-4-[(4-fluorophenyl) alkylsulfonyl] phenoxy group } phenyl) acetic acid;
[3-(4-benzoyl-3,5-difluoro phenoxy group)-5-chloro-phenyl-] acetic acid;
3-chloro-5-[2-chloro-4-(4-fluoro benzoyl) phenoxy group] and phenyl } acetic acid;
3-[2-fluoro-4-(phenyl sulfonyl) phenoxy group]-the 5-aminomethyl phenyl } acetic acid;
3-ethyl-5-[2-fluoro-4-(phenyl sulfonyl) phenoxy group] and phenyl } acetic acid;
[3-{2-chloro-4-[(4-luorobenzyl) alkylsulfonyl] phenoxy group }-5-(trifluoromethyl) phenyl] acetic acid;
[3-[2-cyano group-4-(phenyl sulfonyl) phenoxy group]-5-(trifluoromethyl) phenyl] acetic acid; With
[3-{2-chloro-4-[(pyridine-2-ylmethyl) alkylsulfonyl] phenoxy group }-5-(trifluoromethyl) phenyl] acetic acid.
7. the formula of claim 1 (I) compound or pharmaceutically acceptable salt thereof, described compound are { 3-chloro-5-[2-chloro-4-(methyl sulphonyl) phenoxy group] phenyl } acetic acid.
8. the formula of claim 1 (I) compound or pharmaceutically acceptable salt thereof, described compound are { 3-chloro-5-[2-chloro-4-(ethylsulfonyl) phenoxy group] phenyl } acetic acid.
9. the formula of claim 1 (I) compound or pharmaceutically acceptable salt thereof, described compound are { 3-[2-chloro-4-(ethylsulfonyl) phenoxy group]-5-aminomethyl phenyl } acetic acid.
In the claim 1 to 9 each formula (I) compound or pharmaceutically acceptable salt thereof for the preparation of the treatment by the purposes in the medicine of prostaglandin mediated disease.
11. the purposes of each formula (I) compound or pharmaceutically acceptable salt thereof in the medicine of the disease that is mediated by PGD2 for the preparation for the treatment of in the claim 1 to 9.
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