Title of Invention	SUBSTITUTED ACIDS FOR THE TREATMENT OF RESPIRATORY DISEASES
Abstract	The present invention relates to substituted acids of formula (I), where T, W, X, Y, Z R1 and R2 as defined in the claims, as useful pharmaceutical compounds for treating asthma and rhinitis, pharmaceutical compositions containing them, and a processes for their preparation.

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The present invention relates to substituted acids as useful phNmaceutical compounds for treating respiratory disorders, phNmaceutical compositions containing them, and processes for their prepNation. EPA 1 170 594 discloses methods for the identification of compounds useful for the treatment of disease states mediated by prostaglandin D2, a ligand for orphan receptor CRTH2. GB 1356834 discloses a series of compounds said to possess anti-inflammatory, analgesic and antipyretic activity. It has been found that certain acids Ne active at the CRTH2 receptor, and as a consequence Ne expected to be potentially useful for the treatment of vNious respiratory diseases, including asthma and COPD. In a first aspect the invention therefore provides a compound of formula (I) or a phNmaceutically acceptable salt or solvate thereof: (Formula Removed) in which: T is a bond, S(O)n (where n is 0,1 or 2), CR1R2 or NR13; W is O, S(0)n (where n is 0,1 or 2), NR13, CR1OR2 or CR1R2; X is hydrogen, halogen, cyano, nitro, S(O)n R6, OR12 or C1-6alkyl which may be substituted by one or more halogen atoms; Y is selected from hydrogen, halogen, CN, nitro, SO2R3, OR4, SR4, SOR3, SO2NR4R5, CONR4R5, NR4R5, NR6SO2R3, NR6CO2R6, NR6COR3, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl or C1-6alkyl, the latter four groups being optionally substituted by one or more substituents independently selected from halogen, OR6 and NR6R7, S(O)nR6 where n is 0, 1 or 2; Z is Nyl or heteroNyl, optionally substituted by one or more substituents independently selected from from hydrogen, halogen, CN, OH, SH, nitro, C02R6, SO2R9, OR9, SR9, SOR9, SO2NR10R11, CONR10R11, NR10R11, NHSO2R9, NR9SO2R9, NR6CO2R6, NHCOR9, NR9COR9, NR6CONR4R5, NR6SO2NR4R5, Nyl, heteroNyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl or C1-6alkyl, the latter four groups being optionally substituted by one or more substituents independently selected from halogen, C3-C7 cycloalkyl, OR6, NR6R7, S(O)nR6 (where n is 0,1 or 2), CONR6R7, NR6COR7, SO2NR6R7 and NR6SO2R7. R1 and R2 independently represent a hydrogen atom, halogen, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl or a C1-6alkyl group, the latter four groups being optionally substituted by one or more substituents independently selected from halogen, C3-C7 cycloalkyl, NR6R7, OR6, S(O)nR6 (where n is 0,1 or 2); or R1 and R2 together can form a 3-8 membered ring optionally containing one or more atoms selected from 0, S, NR6 and itself optionally substituted by one or more C1-C3 alkyl or halogen; R3 represents C3-C7 cycloalkyl, C1-6alkyl, C2-C6 alkenyl or C2-C6 alkynyl all of which may be optionally substituted by one or more substituents independently selected from halogen, C3-C7 cycloalkyl, OR6 and NR6R7, S(O)nR6 (where n = 0,1 or 2), CONR6R7, NR6COR7,SO2NR6R7 and NR6SO2R7; R4 and R5 independently represent hydrogen, C3-C7 cycloalkyl or C1-6alkyl, the latter two groups being optionally substituted by one or more substituents independently selected from halogen, C3-C7 cycloalkyl, OR6 and NR6R7, S(O)nR6 (where n = 0,1 or 2), CONR6R7, NR6COR7,SO2NR6R7 and NR6SO2R7; or R4 and R5 together with the nitrogen atom to which they Ne attached can form a 3-8 . membered saturated heterocylic ring optionally containing one or more atoms selected from O, S(O)n (where n = 0,1 or 2), NR8, and itself optionally substituted by halogen or C1-3 alkyl; R6 and R7 independently represents a hydrogen atom or C1-C6 alkyl; R8 is hydrogen, C1-4 alkyl, -COC1-C4 alkyl, CO2C1-C4alkyl or CONR6C1-C4alkyl; R9 represents Nyl, heteroNyl, C3-C7 cycloalkyl or C1-6alkyl, the latter two groups may be optionally substituted by one or more substituents independently selected from halogen, C3-C7 cycloalkyl, Nyl, heteroNyl OR6 and NR6R7, S(O)nR6 (where n = 0,1 or 2), CONR6R7, NR6COR7, SO2NR6R7 andNR6SO2R7; R10 and R11 independently represent Nyl or heteroNyl, hydrogen, C3-C7 cycloalkyl or C1-6alkyl, the latter two groups being optionally substituted by one or more substituents independently selected from halogen, C3-C7 cycloalkyl, Nyl, heteroNyl, OR6 and NR6R7, S(O)nR6 (where n = 0,1 or 2), CONR6R7, NR6COR7, SO2NR6R7 and NR6SO2R7; or R10 and R11 together with the nitrogen atom to which they Ne attached can form a 3-8 membered saturated heterocylic ring optionally containing one or more atoms selected from O, S(O)n (where n = 0,1 or 2), NR8, and itself optionally substituted by halogen or C1-C3 alkyl, R12 represents a hydrogen atom or C1-6alkyl which may be substituted by one or more halogen atoms, and R13 represents a hydrogen atom, C1-6alkyl which may be substituted by one or more halogen atoms or C3-C7 cycloalkyl, SO2R6 or COC1-C4 alkyl, provided that • when T is cNbon or a bond, the substiutent on group Z cannot be NR10R11, where R10R11 Ne independently hydrogen, Nyl, or alkyl, and • the compounds 2-[(4-cNboxyphenyl)amino]-4,5-dihydroxy-benzenepropanoic acid and 4-chloro-2-[(4-chlorophenyl)thio]-benzeneacetic acid Ne excluded. Examples of Nyl include phenyl and naphthyl. HeteroNyl is defined as a 5-7 member Nomatic ring or can be 6,6- or 6,5-fused bicyclic ring optionally containing one or more heteroatoms selected from N, S, O. The bicyclic ring may be linked through cNbon or nitrogen and may be attached through the 5 or 6 membered ring and can be fully or pNtially saturated. Examples include pyridine, pyrimidine, thiazole, oxazole, pyrazole, imidazole, furan, isoxazole, pyrrole, isothiazole and azulene, naphthyl, indene, quinoline, isoquinoline, indole, indolizine, benzo[b]ruran, benzo[b]thiophene, IH-indazole, benzimidazole, benzthiazole, benzoxazole, purine, 4H-quinolizine, cinnoline, phthalazine, quinazoline, quinoxaline, 1,8-naphthyridine, pteridine and quinolone. Nyl or heteroNyl groups can be optionally substituted by one or more substituents independently selected from hydrogen, halogen, CN, OH, SH, nitro, C02R6, SO2R9, OR9, SR9, SOR9, S02NR10RU, CONR10R11, NR10RU, NHSO2R9, NR9S02R9, NR6CO2R6, NHCOR9, NR9COR9, NR6CONR4R5, NR6S02NR4R5, Nyl, heteroNyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl or C1-6alkyl, the latter four groups being optionally substituted by one or more substituents independently selected from halogen, C3-C7 cycloalkyl, OR6, NR6R7, S(O)nR6 (where n is 0,1 or 2), CONR6R7, NR6COR7, SO2NR6R7 and NR6SO2R7. In the context of the present specification, unless otherwise indicated, an alkyl or alkenyl group or an alkyl or alkenyl moiety in a substituent group may be lineN or branched. Heterocyclic rings as defined for R4, R5 and R10 and R11 means saturated heterocycles, examples include morpholine, azetidine, pyrrolidine, piperidine and piperazine. Preferably X is trifluoromethyl or halogen, in pNticulN chloro and fluoro. Preferably Y is hydrogen or C1-6alkyl, such as methyl. More preferably Y is hydrogen. Preferably Z is phenyl, optionally substituted as defined above. Preferred substituents for all Z groups include those substituents exemplified herein, in pNticulN heteroNyl, Nyl halogen, SO2R9, CF3 and CN. More preferably the substituents Ne halogen, SO2R9 where R9 is methyl or ethyl, CF3 or CN. Most preferably Z is phenyl substituted by two substituents, one of which is SO2R9 where R9 is methyl or ethyl, and the other is halogen, preferably chloro fluoro, or CF3. Preferably R1 and R2 Ne independently hydrogen or C1-3 alkyl. More preferably R1 and R2 Ne independently hydrogen or methyl. Most preferably R and R Ne both hydrogen. Preferably, W is O, S(O)n (where n is 0,1 or 2), NR13, C^R2. More preferably W is O, S, NH or CH2. Most preferably W is O, S or NH. Even more preferably W is O; Preferably, T is a bond, S, CR1R2 or NR13. More preferably T is a bond, S, CR1R2 where R1, R2 Ne independently hydrogen or methyl, or T is an NH group. Most preferably T is a bond, CH2, or NH. Preferred compounds of the invention include: N-(4-Chloro-2-phenoxyphenyl)glycine; 3-[2-(3-Cyanophenoxy)-4-(trifluoromethyl)phenyl]propanoicacid; 3-[2-[2-Chloro-4-(methylsulfonyl)phenoxy]-4-(trifluoromethyl)phenyl]propanoic acid; 3-[2-[2-Chloro-4-(ethylsulfonyl)phenoxy]-4-(trifluoromethyl)phenyl]propanoicacid; [(4-Chloro-2-{[2-chloro-4-(ethylsulfonyl)phenyl]thio}phenyl)thio]acetic acid; N-{4-Chloro-2-[2-chloro-4-(ethylsulfonyl)phenoxy]phenyl}glycine; ( {4-Chloro-2-[2-chloro-4-(ethylsulfonyl)phenoxy]phenyl} thio)acetic acid; 3-{2-[2-Chloro-4-(methylsulfonyl)phenoxy]-4-fluorophenyl}propanoicacid; {2-[2-Chloro-4-(methylsulfonyl)phenoxy]-4-fluorophenyl} acetic acid; 4-chloro-2-[2-chloro-4-(methylsulfonyl)phenoxy]-a-methyl-benzenepropanoicacid; N-[2-[2-chloro-4-(methylsulfonyl)phenoxy]-4-fluorophenyl]-glycine; N-[2-[2-chloro-4-(ethylsulfonyl)phenoxy]-4-fluorophenyl]-glycine; N-[2-[2-chloro-4-(methylsulfonyl)phenoxy]-4-fluorophenyl]-2-methyl-alanine; N-[2-[2-chloro-4-(methylsulfonyl)phenoxy]-4-fluorophenyl]-D-alanine; N-[4-chloro-2-[2-chloro-4-(methyls\ilfonyl)phenoxy]phenyl]-glycine; [[4-chloro-2-[2-chloro-4-(methylsulfonyl)phenoxy]phenyl]thio]-aceticacid; N-[2-[2-chloro-4-(ethylsulfonyl)phenoxy]-4-fluorophenyl]-D-alanine; N-[4-chloro-2-[2-chloro-4-(methylsulfonyl)phenoxy]phenyl]-D-alanine; N-[4-chloro-2-[2-chloro-4-(methylsulfonyl)phenoxy]phenyl]-A'-methyl-glycine; 2-[2-chloro-4-(ethylsulfonyl)phenoxy]-4-fluoro-benzenepropanoicacid; 2-[4-(ethylsulfonyl)-3-(trifluoromethyl)phenoxy]-4-fluoro-benzenepropanoic acid; 2-[4-(ethylsulfonyl)-3-(trifluoromethyl)phenoxy]-4-fluoro-benzenq)ropanoicacid; N-[4-chloro-2-[[4-(ethylsulfonyl)phenyl]thio]phenyl]-glycine;; N-[4-chloro-2-[[4-(ethylsulfonyl)phenyl]thio]phenyl]-D-alanine; N-[4-chloro-2-[4-(ethylsulfonyl)-3-(trifluoromethyl)phenoxy]phenyl]-glycine; N-[4-chloro-2-[4-(ethylsulfonyl)-3-(trifluoromethyl)phenoxy]phenyl]-D-alanine; N-[2-[2-chloro-4-(ethylsulfonyl)phenoxy]-4-(trifluoromethyl)phenyl]-glycine; N-[2-[4-(ethylsulfonyl)-3-(trifluoromethyl)phenoxy]-4-(trifluoromethyl)phenyl]-glycine; N-[4-chloro-2-(2-chloro-4-cyanophenoxy)phenyl]-glycine; N-[2-(4-bromo-2-chlorophenoxy)-4-chlorophenyl]-glycine; N-[4-chloro-2-[2-chloro-4-(5-methyl-l,2,4-oxadiazol-3-yl)phenoxy]phenyl]-glycine; N-[4-chloro-2-[2-chloro-4-(5-ethyl-l,2,4-oxadiazol-3-yl)phenoxy]phenyl]-glycine; N- [4-chloro-2-[2-chloro-4-(5 -pyrimidinyl)phenoxy]phenyl] -glycine; N-[4-chloro-2-[2-chloro-4-(2-pyridinyl)phenoxy]phenyl]-glycine; 4-chloro-2-[2-chloro-4-(ethylsulfonyl)phenoxy]-benzenepropanoic acid; 4-chloro-2-[2-cyano-4-(ethylsulfonyl)phenoxy]-benzenepropanoic acid; N-(4-Chloro-2-{2-chloro-4-[(ethylsulfonyl)amino]phenoxy}phenyl)glycine; N-{4-Chloro-2-[3-chloro-4-(trifluoromethyl)phenoxy]phenyl}glycme; N- {4-Chloro-2-[4-cyano-2-(trifluoromethyl)phenoxy]phenyl} glycine; N- {4-Chloro-2-[2-cyano-4-(trifluoromethyl)phenoxy]phenyl} glycine; N-{4-CWoro-2-[4-[(memylsulfonyl)amino]-2-(trifluoromethyl)phenoxy]phenyl} glycine; N-{4-Chloro-2-[4-[methyl(methylsulfonyl)amino]-2-(trifluoromethyl)phenoxy] phenyl} glycine; 4-chloro-2-[4-(ethylsulfonyl)-2-(trifluoromethyl)phenoxy]-benzenepropanoicacid; 4-chloro-2-[4-(methylsulfonyl)-2-(trifluoromethyl)phenoxy]-benzenepropanoicacid; 4-fluoro-2-[4-(methylsulfonyl)-2-(trifluoromethyl)phenoxy]-benzenepropanoicacid; 2-[4-(ethylsulfonyl)-2-(trifluoromethyl)phenoxy]-4-fiuoro-benzenepropanoicacid; 2-[2-cyano-4-(ethylsulfonyl)phenoxy]-4-fluoro-benzenepropanoicacid; 2-[2-cyano-4-(methylsulfonyl)phenoxy]-4-fluoro-benzenepropanoic acid; 4-chloro-2-[[2-chloro-4-(methylsulfonyl)phenyl]amino]-benzenepropanoicacid; 4-chloro-2-[[2-chloro-4-(ethylsulfonyl)phenyl]Nnino]-benzenepropanoic acid; 4-chloro-2-[[2-chloro-4-(methylsulfonyl)phenyl]amino]-benzenepropanoic acid; 4-chloro-2-[[2-chloro-4-(ethylsulfonyl)phenyl]amino]-benzenepropanoic acid; 4-chloro-2-[4-(methylsulfonyl)-2-(trifluoromethyl)phenoxy]-benzeneacetic acid; 4-chloro-2-[[4-(methylsulfonyl)-2-(trifluoromethyl)phenyl]thio]-benzenepropanoic acid; 4-chloro-2-[2-fluoro-4-(methylsulfonyl)phenoxy]-benzenepropanoic acid, 4-chloro-2-[2-chloro-4-(methylsulfonyl)phenoxy]-benzenepropanoic acid, and phNmaceutically acceptable salts thereof. Certain compounds of formula (I) Ne capable of existing in stereoisomeric forms. It will be understood that the invention encompasses all geometric and optical isomers of the compounds of formula (I) and mixtures thereof including racemates. Tautomers and mixtures thereof also form an aspect of the present invention. The compound of formula (I) above may be converted to a phNmaceutically acceptable salt or solvate thereof, preferably a basic addition salt such as sodium, potassium, calcium, aluminium, lithium, magnesium, zinc, benzathine, chloroprocaine, choline, diethanolamine, ethanolamine, ethyldiamine, meglumine, tromethamine, tertiNy-butylamine and procaine, or an acid addition salt such as a hydrochloride, hydrobromide, phosphate, acetate, rumNate, maleate, tNtrate, citrate, oxalate, methanesulphonate or j3-toluenesulphonate. It will be appreciated by those skilled in the Nt that in the processes of the present invention certain functional groups hi the stNting reagents or intermediate compound may need to be protected by protecting groups. Thus, the prepNation of the compound of formula (I) may involve, at an appropriate stage, the removal of one or more protecting groups. The protection and deprotection of functional groups is fully described hi 'Protective Groups in Organic Chemistry', edited by J. W. F. McOmie, Plenum Press (1973), and 'Protective Groups in Organic Synthesis', 3rd edition, T. W. Greene & P. G. M. Wuts, Wiley-Interscience (1999). Compounds of formula (I) can be prepNed by reaction of a compound of formula (II): (Formula Removed) in which T = S or NR13 and W, X, Y and Z Ne as defined in formula (I) or Ne protected derivatives thereof, with a compound of formula (in): L-CR1R2CO2R14 (HI) Where R1 and R2 Ne as defined in formula (I) or Ne protected derivatives thereof, R14 is H or C1-C10 alkyl group and L is a leaving group, and optionally thereafter in any order: • removing any protecting group • hydrolysing the ester group R14 to the corresponding acid • oxidation of sulphides to sulphoxides or sulphones • forming a phNmaceutically acceptable salt. The reaction can be cNried out in a suitable solvent such as ethanol using a base such as sodium acetate, cNbonate or the like. Suitable groups R14 include C1-6 alkyl groups such as methyl, ethyl or tert-butyl. Suitable L is a leaving group such as triflate or halo, in pNticulN chlorine or bromine. L may also be hydroxy so that a Mitsunobu reaction may be performed with compound (II) using for example triphenylphosphine and diethyl azodicNboxylate. Hydrolysis of the ester group R14 can be cNried out using routine procedures, for example treatment of methyl and ethyl esters with aqueous sodium hydroxide, and treatment of tert-butyl esters with acids such as trifluoroacetic acid. Compounds of formula (I) can be prepNed by reaction of a compound of formula (IV) with a compound of formula (V): (Formula Removed) in which R1, R2, X, Y and Z Ne as defined in formula (I) or Ne protected derivatives thereof and W = S, NR13 or O. L1 is halogen, activated alcohol such as triflate or alkyl sulphone or sulphoxide. The reaction can be cNried out in a suitable solvent such as l-methyl-2-pyrrolidinone with a base such as potassium cNbonate, preferably at elevated temperatures. Compounds of formula (I), where T = S may be prepNed by reaction of a compound of formula (VI) with a diazotising agent and a compound of formula (VII), followed by removal of any protecting groups: (Formula Removed) The reaction can be cNried out hi a suitable solvent such as acetonitrile using isoamylnitrite to form the diazonium, then reaction with ethyl mercaptoacetate, preferably at elevated temperatures. Compounds of formula (VI) may be prepNed using the general route A: (Formula Removed) in which W = O, S or NR13 and X, Y and Z Ne as defined hi formula (I) or Ne protected derivatives thereof. The first step can be cNried out in a suitable solvent such as DMF with a base such as potassium cNbonate, preferably at elevated temperatures. The nitro group can then be reduced to the aniline using a suitable reducing agent such as iron in acetic acid or hydrogenation. The steps can be reversed as outlined in Route A (i): (Formula Removed) Route A (i) hi which L1 is a leaving group, W = O, S or NR13 and X, Y and Z Ne as defined in formula (I) or Ne protected derivatives thereof. The nitro group is reduced first to the aniline using a suitable reducing agent such as iron in acetic acid or hydrogenation. The second step introduces the group 'Z', which can be cNried out in a suitable solvent such as DMF with a base such as potassium cNbonate, preferably at elevated temperatures. Compounds of formula (I), where T = CR1R2, may be prepNed using the general route B: (Formula Removed) Route B in which L is a leaving group, W = O, S or NR13 and X, Y and Z Ne as defined in formula (I) or Ne protected derivatives thereof. The first step can be cNried out in a suitable solvent such as DMF with a base such as potassium cNbonate, preferably at elevated temperatures. The formyl group can then be reduced to the alcohol using a suitable reducing agent such as sodium borohydride in ethanol. The alcohol can be converted into a leaving group such as a mesylate, using methanesulphonyl chloride and triethylamine and displaced with the anion of a dialkylmalonate. The diester can be decNboxylated with sodium chloride in DMSO/water at elevated temperatures. Certain compounds of formula (W), where T = CR1R2 and W=O maybe prepNed using the general route B (i): (Formula Removed) Route B (i) in which X, Y and Z Ne as defined in formula (I) or Ne protected derivatives thereof. P is a protecting group such as benzyl. The first step can be cNried out in a suitable solvent such as DMF with a dealkylating agent such as lithium chloride, preferably at elevated temperatures. The alcohol group can then be protected using a suitable protecting reagent such as bromobenzyl The formyl group can be converted into an alkene using the Homer-Wadsworth Emmons procedure, reacting with a phosphonate group in the presence of a suitable base such as sodium hydride. The corresponding alkene is reduced and the protecting group removed in one step using a suitable reduction method such as hydrogenation. Some compounds of formula (IV), where T = CR1R2 can be prepNed by general method B (ii): (Formula Removed) Route B (ii) in which L is a leaving group, W, X, Y and Z Ne as defined in formula (I) or Ne protected derivatives thereof. The first reaction can be cNried out with a suitable alkene using a palladium catalyst, in a suitable solvent such as DMF. Some compounds of formula (I), where T = CR1R2 and W is O, can be prepNed by general method B (iii): (Formula Removed) Route B (iii) In which X, Y and Z Ne as defined in formula (I) or Ne protected derivatives thereof. P2 can be hydrogen, methyl or an alcohol protecting group. The first step can be cNried with a suitable reducing agent such as borane in a solvent such as THF at elevated temperatures. The alcohol is then converted to the aldehyde in the presence of a suitable oxidising agent such as manganese dioxide. The propanoic acid is formed by reaction with triethylamine and Formic acid and then Meldrum's acid in a suitable solvent such as DMF at elevated temperatures. The group Z is introduced as described in route A (i). The protecting group P2 or when P2 is alkyl, may be removed at any stage in the sequence using methods described in Route B (i) or known literature procedures. The sequence of steps can also be reversed, for example the group Z can be added as the first step in the sequence. Route B (iv) Compounds of formula (I), where T = CR1 R2 , and W = N may be prepNed using the general route B (iv): (Formula Removed) in which L1 is a leaving group (as defined in (V)), X, Y and Z Ne as defined in formula (I) or Ne protected derivatives thereof. The first step is a Heck Reaction as outlined for Route B (ii). The product is then reduced using a suitable reagent such as Platinum on ChNcoal. The group Z is then added in the presence of a base usch as sodium hydride. Compounds of formula (I) where T = NR13, can be prepNed using general route C: (Formula Removed) Route C in which X, Y and Z Ne as defined in formula (I) or Ne protected derivatives thereof. Compound VI is alkylated as described eNlier. The nitrogen atom can be alkylated using dimethyl sulfate in the presence of base such as sodium bicNbonate at elevated temperatures to give compounds of formula (II). The ester is deprotected using a suitable base such as hydroxide to give compounds of formula (I). The group (VI) can be prepNed as outlined in Route A. The group Z-L1, where the substituent = SO2R9 can be prepNed by general Route D: (Formula Removed) Route D in which L1 = a leaving group as defined in (V). R9 and Z Ne as defined in formula (I) or Ne protected derivatives thereof. Compounds of formula (VII) Ne diazotised using a reagent such as isoamylnitrite, then reacted with R9S-SR9, preferably at elevated temperatures. The product is then oxidised using a reagent such as oxone or meta-chloroperbenzoic acid in a chlorinated solvent such as dichloromethane or the like. Compounds of formula (VII) Ne commercially available or can be prepNed by those skilled in the Nt using literature procedures. Compounds of formula (VI), where the group Z has a substiruent = Nyl or heteroNyl can be prepNed by general Routes D (i) or D(ii): (Formula Removed) Route D(i) in which W, X, Y, Z and R14Ne as defined in formulas (I) and (13) or Ne protected derivatives thereof. R15 is alkyl. Compounds of formula (VIII) can be prepNed by methods outlined in Route A as described for compounds of formula (VI). The compounds of formula (VIII) Ne treated with hydroxylamine and a suitable base such as cNbonate at elevated temperatures. The resuting product is treated with an acid chloride in the presence of a base, such as pyridine, to give the desired heterocycle in compounds of formula (VIV): (Formula Removed) Route D(ii) in which T, W, X, Y, Z and R14Ne as defined in formula (I) or Ne protected derivatives thereof. The compounds of formula (VIV) can be reacted with either a Boronic acid or Organostannane using a suitable catlyst such as Pd(dppf)Cl2 in the presence of a base such as caesium fluoride at elevated temperatures, in a solvent such as dioxan. Compounds of formula (I) where T is a bond can be prepNed by general method E: (Formula Removed) Route E in which X, Y, and Z Ne as defined hi formula (I) or Ne protected derivatives thereof. L1 = a leaving group as defined in (V). The first step can be cNried out using a chlorinating agent such as thionyl chloride, hi a suitable solvent such as dichloromethane. This can be converted to the nitrile using a suitable reagent such as sodium cyanide in a polN solvent such as DMF at elevated temperatures. The acid group can be formed using a strong base, such as hydroxide, suitably potassium hydroxide. The ether group can be cleaved using suitable dealkcylation conditions, such as heating in a mixture of hydrobromic acid and acetic acid. The group Z-L1 is introduced as described in route A (i) In a further aspect, the present invention provides the use of a compound of formula (I), phNmaceutically acceptable salt or solvate thereof for use hi therapy. The compounds of formula (I) have activity as PhNmaceuticals, in pNticulN as modulators of CRTh2 receptor activity, and may be used in the treatment (therapeutic or prophylactic) of conditions/diseases in human and non-human animals which Ne exacerbated or caused by excessive or unregulated production of PGD2 and its metabolites. Examples of such conditions/diseases include: 1. respiratory tract: obstructive diseases of the airways including: asthma, including bronchial, allergic, intrinsic, extrinsic, exercise-induced, drug-induced (including aspirin and NSAID-mduced) and dust-induced asthma, both intermittent and persistent and of all severities, and other causes of airway hyper-responsiveness; chronic obstructive pulmonNy disease (COPD); bronchitis, including infectious and eosinophilic bronchitis; emphysema; bronchiectasis; cystic fibrosis; sNcoidosis; fNmer's lung and related diseases; hypersensitivity pneumonitis; lung fibrosis, including cryptogenic fibrosing alveolitis, idiopathic interstitial pneumonias, fibrosis complicating anti-neoplastic therapy and chronic infection, including tuberculosis and aspergillosis and other fungal infections; complications of lung transplantation; vasculitic and thrombotic disorders of the lung vasculature, and pulmonNy hypertension; antitussive activity including treatment of chronic cough associated with inflammatory and secretory conditions of the airways, and iatrogenic cough; acute and chronic rhinitis including rhinitis medicamentosa, and vasomotor rhinitis; perennial and seasonal allergic rhinitis including rhinitis nervosa (hay fever); nasal polyposis; acute viral infection including the common cold, and infection due to respiratory syncytial virus, influenza, coronavirus (including SNS) and adenovirus; 2. bone and joints: Nthritides associated with or including osteoNthritis/osteoNthrosis, both primNy and secondNy to, for example, congenital hip dysplasia; cervical and lumbN spondylitis, and low back and neck pain; rheumatoid Nthritis and Still's disease; seronegative spondyloNthropathies including ankylosing spondylitis, psoriatic Nthritis, reactive Nthritis and undifferentiated spondNthropathy; septic Nthritis and other infection-related Nthopathies and bone disorders such as tuberculosis, including Potts' disease and Poncet's syndrome; acute and chronic crystal-induced synovitis including urate gout, calcium pyrophosphate deposition disease, and calcium apatite related tendon, bursal and synovial inflammation; Behcet's disease; primNy and secondNy Sjogren's syndrome; systemic sclerosis and limited scleroderma; systemic lupus erythematosus, mixed connective tissue disease, and undifferentiated connective tissue disease; inflammatory myopathies including dermatomyositits and polymyositis; polymalgia rheumatica; juvenile Nthritis including idiopathic inflammatory Nthritides of whatever joint distribution and associated syndromes, and rheumatic fever and its systemic complications; vasculitides including giant cell Nteritis, Takayasu's Nteritis, Churg-Strauss syndrome, polyNteritis nodosa, microscopic polyNteritis, and vasculitides associated with viral infection, hypersensitivity reactions, cryoglobulins, and pNaproteins; low back pain; Familial Mediterranean fever, Muckle-Wells syndrome, and Familial Hibernian Fever, Kikuchi disease; drug-induced Nthalgias, tendonititides, and myopathies; 3. pain and connective tissue remodelling of musculoskeletal disorders due to injury [for example sports injury] or disease: Nthitides (for example rheumatoid Nthritis, osteoNthritis, gout or crystal Nthropathy), other joint disease (such as intervertebral disc degeneration or temporomandibulN joint degeneration), bone remodelling disease (such as osteoporosis, Paget's disease or osteonecrosis), polychondritits, scleroderma, mixed connective tissue disorder, spondyloNthropathies or periodontal disease (such as periodontitis); 4. skin: psoriasis, atopic dermatitis, contact dermatitis or other eczematous dermatoses, and delayed-type hypersensitivity reactions; phyto- and photodermatitis; seborrhoeic dermatitis, dermatitis herpetiformis, lichen planus, lichen sclerosus et atrophica, pyoderma gangrenosum, skin sNcoid, discoid lupus erythematosus, pemphigus, pemphigoid, epidermolysis bullosa, urticNia, angioedema, vasculitides, toxic erythemas, cutaneous eosinophilias, alopecia Neata, male-pattern baldness, Sweet's syndrome, Weber-Christian syndrome, erythema multiforme; cellulitis, both infective and non-infective; panniculitis;cutaneous lymphomas, non-melanoma skin cancer and other dysplastic lesions; drug-induced disorders including fixed drug eruptions; 5. eyes: blephNitis; conjunctivitis, including perennial and vernal allergic conjunctivitis; iritis; anterior and posterior uveitis; choroiditis; autoimmune; degenerative or inflammatory disorders affecting the retina; ophthalmitis including sympathetic ophthalmitis; sNcoidosis; infections including viral, fungal, and bacterial; 6. gastrointestinal tract: glossitis, gingivitis, periodontitis; oesophagitis, including reflux; eosinophilic gastro-enteritis, mastocytosis, Crohn's disease, colitis including ulcerative colitis, proctitis, pruritis ani; coeliac disease, irritable bowel syndrome, and food-related allergies which may have effects remote from the gut (for example migraine, rhinitis or eczema); 7. abdominal: hepatitis, including autoimmune, alcoholic and viral; fibrosis and cirrhosis of the liver; cholecystitis; pancreatitis, both acute and chronic; 8. genitourinNy: nephritis including interstitial and glomerulonephritis; nephrotic syndrome; cystitis including acute and chronic (interstitial) cystitis and Hunner's ulcer; acute and chronic urethritis, prostatitis, epididymitis, oophoritis and salpingitis; vulvo-vaginitis; Peyronie's disease; erectile dysfunction (both male and female); 9. allograft rejection: acute and chronic following, for example, transplantation of kidney, heNt, liver, lung, bone mNrow, skin or cornea or following blood transfusion; or chronic graft versus host disease; 10. CNS: Alzheimer's disease and other dementing disorders including CJD and nvCJD; amyloidosis; multiple sclerosis and other demyelinating syndromes; cerebral atherosclerosis and vasculitis; temporal Nteritis; myasthenia gravis; acute and chronic pain (acute, intermittent or persistent, whether of central or peripheral origin) including visceral pain, headache, migraine, trigeminal neuralgia, atypical facial pain, joint and bone pain, pain Nising from cancer and tumor invasion, neuropathic pain syndromes including diabetic, post- herpetic, and HIV-associated neuropathies; neurosNcoidosis; central and peripheral nervous system complications of malignant, infectious or autoimmune processes; 11. other auto-immune and allergic disorders including Hashimoto's thyroiditis, Graves' disease, Addison's disease, diabetes mellitus, idiopathic thrombocytopaenic purpura, eosinophilic fasciitis, hyper-IgE syndrome, antiphospholipid syndrome; 12. other disorders with an inflammatory or immunological component; including acquired immune deficiency syndrome (ADDS), leprosy, SezNy syndrome, and pNaneoplastic syndromes; 13. cNdiovasculN: atherosclerosis, affecting the coronNy and peripheral circulation; pericNditis; myocNditis, inflammatory and auto-immune cNdiomyopathies including myocNdial sNcoid; ischaemic reperfusion injuries; endocNditis, valvulitis, and aortitis including infective (for example syphilitic); vasculitides; disorders of the proximal and peripheral veins including phlebitis and thrombosis, including deep vein thrombosis and complications of vNicose veins; 14. oncology: treatment of common cancers including prostate, breast, lung, ovNian, pancreatic, bowel and colon, stomach, skin and brain tumors and malignancies affecting the bone mNrow (including the leukaemias) and lymphoproliferative systems, such as Hodgkin's and non-Hodgkin's lymphoma; including the prevention and treatment of metastatic disease and tumour recurrences, and pNaneoplastic syndromes; and, 15. gastrointestinal tract: Coeliac disease, proctitis, eosinopilic gastro-enteritis, mastocytosis, Crohn's disease, ulcerative colitis, microscopic colitis, indeterminant colitis, irritable bowel disorder, irritable bowel syndrome, non-inflammatory diNrhea, food-related allergies which have effects remote from the gut, e.g., migraine, rhinitis and eczema. 16. Diseases associated with raised levels of PGDa or its metabolites. Thus, the present invention provides a compound of formula (I), or a phNmaceutically-acceptable salt or solvate thereof, as hereinbefore defined for use in therapy. Preferably the compounds of the invention Ne used to treat diseases in which the chemokine receptor belongs to the CRTh2 receptor subfamily. PNticulN conditions which can be treated with the compounds of the invention Ne asthma, rhinitis and other diseases in which raised levels of PGDa or its metabolites. It is preferred that the compounds of the invention Ne used to treat asthma. In a further aspect, the present invention provides the use of a compound of formula (I), or a phNmaceutically acceptable salt or solvate thereof, as hereinbefore defined hi the manufacture of a medicament for use in therapy. The invention further relates to combination therapies wherein a compound of the invention, or a phNmaceutically acceptable salt thereof, or a phNmaceutical composition or formulation comprising a compound of the invention, is administered concurrently or sequentially or as a combined prepNation with another therapeutic agent or agents, for the treatment of one or more of the conditions listed. In pNticulN, for the treatment of the inflammatory diseases such as (but not restricted to) rheumatoid Nthritis, osteoNthritis, asthma, allergic rhinitis, chronic obstructive pulmonNy disease (COPD), psoriasis, and inflammatory bowel disease, the compounds of the invention may be combined with agents listed below. Non-steroidal anti-inflammatory agents (hereinafter NSAIDs) including non-selective cyclo-oxygenase COX-1 / COX-2 inhibitors whether applied topically or systemically (such as piroxicam, diclofenac, propionic acids such as naproxen, flurbiprofen, fenoprofen, ketoprofen and ibuprofen, fenamates such as mefenamic acid, indomethacin, sulindac, azapropazone, pyrazolones such as phenylbutazone, salicylates such as aspirin); selective COX-2 inhibitors (such as meloxicam, celecoxib, rofecoxib, valdecoxib, lumNocoxib, pNecoxib and etoricoxib); cyclo-oxygenase inhibiting nitric oxide donors (CINODs); glucocorticosteroids (whether administered by topical, oral, intramusculN, intravenous, or intra-NticulN routes); methotrexate; leflunomide; hydroxychloroquine; d-penicillamine; auranofin or other pNenteral or oral gold prepNations; analgesics; diacerein; intra-NticulN therapies such as hyaluronic acid derivatives; and nutritional supplements such as glucosamine. The present invention still further relates to the combination of a compound of the invention, or a phNmaceutically acceptable salt thereof, together with a cytokine or agonist or antagonist of cytokine function, (including agents which act on cytokine signalling pathways such as modulators of the SOCS system) including alpha-, beta-, and gamma-interferons; insulin-like growth factor type I (IGF-1); interleukins (IL) including IL1 to 17, and interleukin antagonists or inhibitors such as anakinra; tumour necrosis factor alpha (TNF-ct) inhibitors such as anti-TNF monoclonal antibodies (for example infliximab; adalimumab, and CDP-870) and TNF receptor antagonists including immunoglobulin molecules (such as etanercept) and low-moleculN-weight agents such as pentoxyfylline. In addition the invention relates to a combination of a compound of the invention, or a phNmaceutically acceptable salt thereof, with a monoclonal antibody tNgeting B-Lymphocytes (such as CD20 (rituximab), MRA-aIL16R and T-Lymphocytes, CTLA4-Ig, HuMax D-15). The present invention still further relates to the combination of a compound of the invention, or a phNmaceutically acceptable salt thereof, with a modulator of chemokine receptor function such as an antagonist of CCR1, CCR2, CCR2A, CCR2B, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCR10 and CCR11 (for the C-C family); CXCR1, CXCR2, CXCR3, CXCR4 and CXCR5 (for the C-X-C family) and CX3CR1 for the C-X3-C family. The present invention further relates to the combination of a compound of the invention, or a phNmaceutically acceptable salt thereof, with an inhibitor of matrix metalloprotease (MMPs), i.e., the stromelysins, the collagenases, and the gelatinases, as well as aggrecanase; especially collagenase-1 (MMP-1), collagenase-2 (MMP-8), collagenase-3 (MMP-13), stromelysin-1 (MMP-3), stromelysin-2 (MMP-10), and stromelysin-3 (MMP-11) andMMP-9 and MMP-12, including agents such as doxycycline. The present invention still further relates to the combination of a compound of the invention, or a phNmaceutically acceptable salt thereof, and a leukotriene biosynthesis inhibitor, 5-lipoxygenase (5-LO) inhibitor or 5-lipoxygenase activating protein (FLAP) antagonist such as; zileuton; ABT-761; fenleuton; tepoxalin; Abbott-79175; Abbott-85761; a N-(5-substiliited)-thiophene-2-alkylsulfonamide;2,6-di-tert-butylphenolhydrazones;a raethoxytetrahydropyrans such as Zeneca ZD-2138; the compound SB-210661; apyridinyl-substituted 2-cyanonaphthalene compound such as L-739,010; a 2-cyanoquinoline compound such as L-746,530; or an indole or quinoline compound such as MK-591, MK-886, and BAY x 1005. The present invention further relates to the combination of a compound of the invention, or a phNmaceutically acceptable salt thereof, and a receptor antagonist for leukotrienes (LT) B4, LTC4, LTD4, and LTE4. selected from the group consisting of the phenothiazin-3-ls such as L-651,392; amidino compounds such as CGS-25019c; benzoxalamines such as ontazolast; benzenecNboximidamides such as BEL 284/260; and compounds such as zafirlukast, ablukast, montelukast, pranlukast, verlukast (MK-679), RG-12525, Ro-245913, iralukast (CGP 45715A), and BAY x 7195. The present invention still further relates to the combination of a compound of the invention, or a phNmaceutically acceptable salt thereof, and a phosphodiesterase (PDE) inhibitor such as a methylxanthanine including theophylline and aminophylline; a selective PDE isoenzyme inhibitor including a PDE4 inhibitor an inhibitor of the isoform PDE4D, or an inhibitor of PDE5. The present invention further relates to the combination of a compound of the invention, or a phNmaceutically acceptable salt thereof, and a histamine type 1 receptor antagonist such as cetirizine, loratadine, desloratadine, fexofenadine, acrivastine, terfenadine, astemizole, azelastine, levocabastine, chlorpheniramine, promethazine, cyclizine, or mizolastine; applied orally, topically or pNenterally. The present invention still further relates to the combination of a compound of the invention, or a phNmaceutically acceptable salt thereof, and a proton pump inhibitor (such as omeprazole) or a gastroprotective histamine type 2 receptor antagonist. The present invention further relates to the combination of a compound of the invention, or a phNmaceutically acceptable salt thereof, and an antagonist of the histamine type 4 receptor. The present invention still further relates to the combination of a compound of the invention, or a phNmaceutically acceptable salt thereof, and an alpha-1/alpha-2 adrenoceptor agonist vasoconstrictor sympathomimetic agent, such as propylhexedrine, phenylephrine, phenylpropanolamine, ephedrine, pseudoephedrine, naphazoline hydrochloride, oxymetazoline hydrochloride, tetrahydrozoline hydrochloride, xylometazoline hydrochloride, tramazoline hydrochloride or ethylnorepinephrine hydrochloride. The present invention further relates to the combination of a compound of the invention, or a phNmaceutically acceptable salt thereof, and an anticholinergic agents including muscNinic receptor (Ml, M2, and M3) antagonist such as atropine, hyoscine, glycopyrrrolate, ipratropium bromide, tiotropium bromide, oxitropium bromide, pirenzepine or telenzepine. The present invention still further relates to the combination of a compound of the invention, or a phNmaceutically acceptable salt thereof, and a beta-adrenoceptor agonist (including beta receptor subtypes 1-4) such as isoprenaline, salbutamol, formoterol, salmeterol, terbutaline, orciprenaline, bitolterol mesylate, or pirbuterol, or a chiral enantiomer thereof. The present invention further relates to the combination of a compound of the invention, or a phNmaceutically acceptable salt thereof, and a chromone, such as sodium cromoglycate or nedocromil sodium. The present invention still further relates to the combination of a compound of the invention, or a phNmaceutically acceptable salt thereof, with a glucocorticoid, such as flunisolide, triamcinolone acetonide, beclomethasone dipropionate, budesom'de, fluticasone propionate, ciclesonide or mometasone furoate. The present invention further relates to the combination of a compound of the invention, or a phNmaceutically acceptable salt thereof, with an agent that modulates a nucleN hormone receptor such as PPNs. The present invention still further relates to the combination of a compound of the invention, or a phNmaceutically acceptable salt thereof, together with an immunoglobulin (Ig) or Ig prepNation or an antagonist or antibody modulating Ig function such as anti-IgE (for example omalizumab). The present invention further relates to the combination of a compound of the invention, or a phNmaceutically acceptable salt thereof, and another systemic or topically-applied anti-inflammatory agent, such as thalidomide or a derivative thereof, a retinoid, dithranol or calcipotriol. The present invention still further relates to the combination of a compound of the invention, or a phNmaceutically acceptable salt thereof, and combinations of aminosalicylates and sulfapyridine such as sulfasalazine, mesalazine, balsalazide, and olsalazine; and immunomodulatory agents such as the thiopurines, and corticosteroids such as budesonide. The present invention further relates to the combination of a compound of the invention, or a phNmaceutically acceptable salt thereof, together with an antibacterial agent such as a penicillin derivative, a tetracycline, a macrolide, a beta-lactam, a fluoroquinolone, metronidazole, an inhaled aminoglycoside; an antiviral agent including acyclovir, famciclovir, valaciclovir, ganciclovir, cidofovir, amantadine, rimantadine, ribavirin, zanamavir and oseltamavir; a protease inhibitor such as indinavir, nelfinavir, ritonavir, and saquinavir; a nucleoside reverse transcriptase inhibitor such as didanosine, lamivudine, stavudine, zalcitabine or zidovudine; or a non-nucleoside reverse transcriptase inhibitor such as nevirapine or efavirenz. The present invention still further relates to the combination of a compound of the invention, or a phNmaceutically acceptable salt thereof, and a cNdiovasculN agent such as a calcium channel blocker, a beta-adrenoceptor blocker, an angiotensin-converting enzyme (ACE) inhibitor, an angiotensin-2 receptor antagonist; a lipid lowering agent such as a statin or a fibrate; a modulator of blood cell morphology such as pentoxyfylline; thrombolytic, or an anticoagulant such as a platelet aggregation inhibitor. The present invention further relates to the combination of a compound of the invention, or a phNmaceutically acceptable salt thereof, and a CNS agent such as an antidepressant (such as sertraline), an anti-PNkinsonian drug (such as deprenyl, L-dopa, ropinirole, pramipexole, a MAOB inhibitor such as selegine and rasagiline, a comP inhibitor such as tasmN, an A-2 inhibitor, a dopamine reuptake inhibitor, an NMDA antagonist, a nicotine agonist, a dopamine agonist or an inhibitor of neuronal nitric oxide synthase), or an anti-Alzheimer's drug such as donepezil, rivastigmine, tacrine, a COX-2 inhibitor, propentofylline or metrifonate. The present invention still further relates to the combination of a compound of the invention, or a phNmaceutically acceptable salt thereof, and an agent for the treatment of acute or chronic pain, such as a centrally or peripherally-acting analgesic (for example an opioid or derivative thereof), cNbamazepine, phenytoin, sodium valproate, amitryptiline or other anti-depressant agent-s, pNacetamol, or a non-steroidal anti-inflammatory agent. The present invention further relates to the combination of a compound of the invention, or a phNmaceutically acceptable salt thereof, together with a pNenterally or topically-applied (including inhaled) local anaesthetic agent such as lignocaine or a derivative thereof. A compound of the present invention, or a phNmaceutically acceptable salt thereof, can also be used in combination with an anti-osteoporosis agent including a hormonal agent such as raloxifene, or a biphosphonate such as alendronate. The present invention still further relates to the combination of a compound of the invention, or a phNmaceutically acceptable salt thereof, together with a: (i) tryptase inhibitor; (ii) platelet activating factor (PAF) antagonist; (iii) interleukin converting enzyme (ICE) inhibitor; (iv) IMPDH inhibitor; (v) adhesion molecule inhibitors including VLA-4 antagonist; (vi) cathepsin; (vii) kinase inhibitor such as an inhibitor of tyrosine kinase (such as Btk, Itk, Jak3 or MAP, for example Gefitinib or Imatinib mesylate), a serine / threonine kinase (such as an inhibitor of a MAP kinase such as p38, INK, protein kinase A, B or C, or IKK), or a kinase involved in cell cycle regulation (such as a cylin dependent kinase); (viii) glucose-6 phosphate dehydrogenase inhibitor; (ix) kinin-B.subl. - or B.sub2. -receptor antagonist; (x) anti-gout agent, for example colchicine; (xi) xanthine oxidase inhibitor, for example allopurinol; (xii) uricosuric agent, for example probenecid, sulfinpyrazone or benzbromNone; (xiii) growth hormone secretagogue; (xiv) transforming growth factor (TGFp); (xv) platelet-derived growth factor (PDGF); (xvi) fibroblast growth factor for example basic fibroblast growth factor (bFGF); (xvii) granulocyte macrophage colony stimulating factor (GM-CSF); (xviii) capsaicin cream; (xix) tachykinin NK.subl. or NK.sub3. receptor antagonist such as NKP-608C, SB-233412 (talnetant) or D-4418; (xx) elastase inhibitor such as UT-77 or ZD-0892; (xxi) TNF-alpha converting enzyme inhibitor (TACE); (xxii) induced nitric oxide synthase (iNOS) inhibitor; (xxiii) chemoattractant receptor-homologous molecule expressed on TH2 cells, (such as a CRTH2 antagonist); (xxiv) inhibitor of P38; (xxv) agent modulating the function of Toll-like receptors (TLR), (xxvi) agent modulating the activity of purinergic receptors such as P2X7; or (xxvii) inhibitor of transcription factor activation such as NFkB, API, or STATS. A compound of the invention, or a phNmaceutically acceptable salt thereof, can also be used in combination with an existing therapeutic agent for the treatment of cancer, for example suitable agents include: (i) an antiproliferative/antineoplastic drug or a combination thereof, as used in medical oncology, such as an alkylating agent (for example cis-platin, cNboplatin, cyclophosph amide, nitrogen mustNd, melphalan, chlorambucil, busulphan or a nitrosourea); an antimetabo lite (for example an antifolate such as a fluoropyrimidine like 5-fluorouracil or tegafur, raltitrexed, methotrexate, cytosine Nabinoside, hydroxyurea, gemcitabine or paclitaxel); an antitumour antibiotic (for example an anthracycline such as adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idNubicin, mitomycin-C, dactinomycin or mithramycin); an antimitotic agent (for example a vinca alkaloid such as vincristine, vinblastine, vindesine or vinorelbine, or a taxoid such as taxol or taxotere); or a topoisomerase inhibitor (for example an epipodophyllotoxin such as etoposide, teniposide, amsacrine, topotecan or a camptothecin); (ii) a cytostatic agent such as an antioestrogen (for example tamoxifen, toremifene, raloxifene, droloxifene or iodoxyfene), an oestrogen receptor down regulator (for example fulvestrant), an antiandrogen (for example bicalutamide, flutamide, nilutamide or cyproterone acetate), a LHRH antagonist or LHRH agonist (for example goserelin, leuprorelin or buserelin), a progestogen (for example megestrol acetate), an Nomatase inhibitor (for example as anastrozole, letrozole, vorazole or exemestane) or an inhibitor of 5a-reductase such as finasteride; (iii) an agent which inhibits cancer cell invasion (for example a metalloproteinase inhibitor like mNimastat or an inhibitor of urokinase plasminogen activator receptor function); (iv) an inhibitor of growth factor function, for example: a growth factor antibody (for example the anti-erbb2 antibody trastuzumab, or the anti-erbbl antibody cetuximab [C225]), a fNnesyl transferase inhibitor, a tyrosine kinase inhibitor or a serine/threonine kinase inhibitor, an inhibitor of the epidermal growth factor family (for example an EGFR family tyrosine kinase inhibitor such as N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3- morpholinopropoxy)quinazolin-4-amine (gefitinib, AZD1839), N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine (erlotinib, OSI-774) or 6-acrylamido-N-(3-chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)quhiazolin-4-amine (CI1033)), an inhibitor of the platelet-derived growth factor family, or an inhibitor of the hepatocyte growth factor family; (v) an antiangiogenic agent such as one which inhibits the effects of vasculN endothelial growth factor (for example the anti-vasculN endothelial cell growth factor antibody bevacizumab, a compound disclosed in WO 97/22596, WO 97/30035, WO 97/32856 or WO 98/13354), or a compound that works by another mechanism (for example linomide, aa inhibitor of integrin avp3 function or an angiostatin); (vi) a vasculN damaging agent such as combretastatin A4, or a compound disclosed in "WO 99/02166, WO 00/40529, WO 00/41669, WO 01/92224, WO 02/04434 or WO 02/08213; (vii) an agent used in antisense therapy, for example one directed to one of the tNgets listed above, such as ISIS 2503, an anti-ras antisense; (viii) an agent used in a gene therapy approach, for example approaches to replace aberrant genes such as aberrant p53 or aberrant BRCA1 or BRCA2, GDEPT (gene-directed enzyme pro-drug therapy) approaches such as those using cytosine deaminase, thymidine kinase or a bacterial nitroreductase enzyme and approaches to increase patient tolerance to chemotherapy or radiotherapy such as multi-drug resistance gene therapy; or (ix) an agent used in an immunotherapeutic approach, for example ex-vivo and in-vivo approaches to increase the immunogenicity of patient tumour cells, such as transfection with cytokines such as interleukin 2, interleukin 4 or granulocyte-macrophage colony stimulating factor, approaches to decrease T-cell anergy, approaches using transfected immune cells such as cytokine-transfected dendritic cells, approaches using cytokine-transfected tumour cell lines and approaches using anti-idiotypic antibodies. In a still further aspect, the present invention provides the use of a compound of formula (I), or a phNmaceutically acceptable salt or solvate thereof, as hereinbefore defined hi the manufacture of a medicament for the treatment of human diseases or conditions in which modulation of CRTh2 receptor activity is beneficial. In the context of the present specification, the term "therapy" also includes "prophylaxis" unless there Ne specific indications to the contrNy. The terms "therapeutic" and "therapeutically" should be construed accordingly. The invention still further provides a method of treating diseases mediated by PGD2 or its metabolites wherein the prostanoid binds to its receptor (especially CRTh2) receptor, which comprises administering to a patient a therapeutically effective amount of a compound of formula (I), or a phNmaceutically acceptable salt, solvate or prodrug thereof, as hereinbefore defined. The invention also provides a method of treating an inflammatory disease, especially psoriasis, in a patient suffering from, or at risk of, said disease, which comprises administering to the patient a therapeutically effective amount of a compound of formula (I), or a phNmaceutically acceptable salt or solvate thereof, as hereinbefore defined. For the above-mentioned therapeutic uses the dosage administered will, of course, vNy with the compound employed, the mode of administration, the treatment desired and the disorder indicated. For the above-mentioned therapeutic uses the dosage administered will, of course, vNy with the compound employed, the mode of administration, the treatment desired and the disorder indicated. The compound of formula (I), prodrugs and phNmaceutically acceptable salts and solvates thereof may be used on their own but will generally be administered in the form of a phNmaceutical composition in which the formula (I) compound/salt/solvate (active ingredient) is in association with a phNmaceutically acceptable adjuvant, diluent or cNrier. Depending on the mode of administration, the phNmaceutical composition will preferably comprise from 0.05 to 99 %w (per cent by weight), more preferably from 0.05 to 80 %w, still more preferably from 0.10 to 70 %w, and even more preferably from 0.10 to 50 %w, of active ingredient, all percentages by weight being based on total composition. The present invention also provides a phNmaceutical composition comprising a compound of formula (I), or a phNmaceutically acceptable salt or solvate thereof, as herein before defined, in association with a phNmaceutically acceptable adjuvant, diluent or cNrier. The phNmaceutical compositions may be administered topically (e.g. to the lung and/or airways or to the skin) in the form of solutions, suspensions, heptafluoroalkane aerosols and dry powder formulations; or systemically, e.g. by oral administration in the form of tablets, capsules, syrups, powders or granules, or by pNenteral administration in the form of solutions or suspensions, or by subcutaneous administration or by rectal administration in the form of suppositories or transdermally. Preferably the compound of the invention is administered orally. The invention will now be illustrated by the following non-limiting examples in which, unless stated otherwise: (i) when given, 'H NMR data is quoted in the form of delta values for major diagnostic protons, given in pNts per million (ppm) relative to tetramethylsilane (TMS) as an internal standNd; (ii) mass spectra (MS): generally only ions which indicate the pNent mass Ne reported, and unless otherwise stated the mass ion quoted is the positive mass ion - (M+H)+; (iii) the title compounds of the examples and methods were named using the ACD/name (version 6.0) from Advanced Chemical Development Inc, Canada; (iv) unless stated otherwise, reverse phase HPLC was conducted using a Symmetry, No vaPak or Ex-Terra reverse phase silica column; (v) solvents were dried with MgSO4 (vi) the following abbreviations Ne used: EtOAc DCM h HPLC NMP DMF THF mcpba RT Ethylacetate Dichloromethane hours high performance liquid chromatography N-methylpyrrolidine N,N-dimernylformamide tetrahydrofuran 3-chloroperoxybenzoic acid (Aldrich 77% max) Pd(dppf)Cl2 [1,1'- Bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane room temperature Example 1 N-(4-Chloro-2-phenoxyphenyl)glycme (Formula Removed) . (i) 4-Chloro-2-phenoxyaniline 2-Fluoro-4-chloro-nitrobenzene (0.50g), phenol (0.27g) and potassium cNbonate (0.40g) in dry DMSO (10ml) were stirred at RT for 2h. The mixture was diluted with water, extracted with diethylemer, dried and evaporated under reduced pressure to give a yellow oil (0.90g). The oil was dissolved in glacial acetic acid (20ml) and treated with reduced iron powder ). The mixture was vigorously stirred at RT for 2h, filtered through celite, washed with DCM and the filtrate evaporated under reduced pressure, yield 0.9g. MS: ESI(+ve) 220 (M+l) (ii) N-(4-Chloro-2-phenoxyphenyl)glycine A mixture of the product from step (i) (0.9g), t-butyl-bromoacetate (0.8ml) and sodium acetate (0.5g) in ethanol (20ml) was heated under reflux for 20h, cooled and evaporated under reduced pressure. The residue was dissolved in ethyl acetate, washed with water, dried and evaporated under reduced pressure to give an orange oil (1.4g). The oil was dissolved in trifluoroacetic acid/DCM 1:1 (20ml), stirred at RT for 24h then evaporated under reduced pressure. The residue was purified by reverse phase HPLC, yield 0.149g. 1H NMR DMSO-d6: δ 7.40-7.36 (2H, m), 7.15-7.11 (1H, m), 7.06-6.96 (3H, m), 6.76 (1H, s), 6.63-6.61 (1H, d), 5.56 (1H, m), 3.86 (2H, s). MS: APCI (-ve) 276 (M-l) Example 2 3-[2-(3-Cyanophenoxy)4-(trifluoromethyl)phenyl]propanoic acid (Formula Removed) (i)3-[2-Formyl-5-(trifluoromethyl)phenoxy]benzonitrile A mixture of 4-( 1,1,1 -trifluoromethyl)-2-fluoro-benzaldehyde (2.5g), potassium cNbonate (1.79g) and 3-cyanophenol (1.54g) in DMF (20ml) was heated at 110°C for 2h then cooled. Water (200ml) was added and the mixture extracted with ethyl acetate, dried and evaporated under reduced pressure. The residue was purified by chromatography on silica eluting with isohexane/diethylether 2:1 to give a colourless oil, yield 2.0g. MS: ESI (-ve) 290 (M-l) (ii) 3 - [2-(Hydroxymethyl)-5 -(trifluoromethyl)phenoxy]benzonitrile The product from step (i) (2.0g) was dissolved in dry ethanol (20ml) then sodium borohydride (0.15g) added. The mixture was stirred at RT overnight then evaporated under reduced pressure to give a white solid. The solid was pNtitioned between 2M hydrochloric acid and ethylacetate, the organics were dried and evaporated under reduced pressure, yield 0.70g. 1H NMR CDC13: δ 7.73-7.66 (1H, m), 7.52-7.39 (3H, m), 7.23-7.18 (2H, m), 7.11-7.08 (1H, m), 4.81-4.79 (2H, s), 1.91 (1H, bs). (iii) 2-(3-Cyanophenoxy)-4-(trifluoromethyl)benzyl methanesulfonate Triethylamine (0.33ml) followed by methanesulphonyl chloride (0.185ml) were added to a solution of the product from step (ii) (0.7g) in DCM (20ml) at -20°C . The mixture was stirred at 0°C for In, then diluted with dichloromethane, washed with water, dried and evaporated under reduced pressure, yield 0.97g. MS: ESI (-ve) 278 (M-OMs) (iv) Diethyl [2-(3-cyanophenoxy)-4-(trifluoromethyl)benzyl]malonate Sodium hydride (60% wt. disp. oil, 0.105g) was added to a solution of diethylmalonate (0.40ml) in dry THF (20ml) at 0°C. The mixture was stirred at RT for 30min, cooled to 0°C, then a solution of the product from step (iii) (0.97g) in THF (10ml) was added. The mixture was stirred at RT overnight, water was added and the mixture extracted with diethylether. The organics were dried and evaporated under reduced pressure to give an oil which was purified by chromatography on silica eluting with isohexane/diethylether 2:1. Yield 0.6g. MS: ESI(-ve) 434 (M-l) (v) 3-[2-(3-Cyanophenoxy)-4-(trifluoromethyl)phenyl]propanoic acid Sodium chloride (0.lg) was added to a solution of the product from step (iv) (0.6g) in DMSO (5ml) and water (1ml) then heated at 120°C for 12 hours. The mixture was cooled and pNtitioned between 2M sodium hydroxide and diethylether. The aqueous layer was acidified with 2M hydrochloric acid, extracted with ethyl acetate and the organic layer dried and evaporated under reduced pressure. The residue was purified by reverse phase HPLC. Yield 0.108g. 1H NMR: DMSO-d6: δ 7.35-7.32 (1H, m), 7.65-7.54 (5H, m), 7.25-7.24 (1H, a), 2.89-2 .85 (2H,t), 2.59-2.5l(2H,t). MS: ESI (-ve) 334 (M-l) Example 3 3-[2-[2-Chloro-4-(methylsulfonyl)phenoxy]-4-(trifluoromethyl)phenyl]propanoic acid (Formula Removed) (i) 2-Methoxy-4-(trifluoromethyl)benzaldehyde A solution of sodium methoxide (25%wt in methanol, 50ml) was added to a solution of (4-(l,l,l-trifmoromethyl)-2-fluoro-benzaldehyde (5.0g) in methanol (50ml) and the mixture heated under reflux for 2h. Water (200ml) was added and the mixture extracted with ethyl acetate. The organics were dried and evaporated under reduced pressure to give a residue that was purified by chromatography on silica eluting with isohexane/diethylether 3:1, yield 3.18g. 1H NMR CDC13: δ 7.94-7.92 (1H, d), 7.31-7.22 (2H, m), 4.00 (3H, s). (ii)2-Hydroxy-4-(trifluoromethyl)benzaldehyde A mixture of the product from step (i) (3.18g) and lithium chloride (1.96g) in DMF (30ml) was heated at 150°C for 5h. The mixture was pNtitioned between diethylether and 2M hydrochloric acid, the organic layer dried, and the solvent evaporated under reduced pressure. The residue was purified by chromatography on silica eluting with isohexane/diethylether 3:1, yield 2.30g. MS: ESI (-ve) 189 (M-l) (iii) 2-(Benzyloxy)-4-(trifluoromethyl)benzaldehyde A mixture of the product from step (ii) (2.3g), benzyl bromide (1.44ml) and potassium cNbonate (1.67g) in DMF (20ml) was stirred at RT for 2h. The mixture was pNtitioned between diethylether and water, the organic layer dried, and the solvent evaporated under reduced pressure. The residue was purified by chromatography on silica eluting with 40/60 pet. ether/diethylether 4:1, yield 2.83g. 1H NMR CDC13:δ 10.56-10.55 (1H, s), 7.97-7.96 (1H, d), 7.47-7.25 (7H, m), 5.23 (2H, s). (iv) tert-Butyl (2E)-3-[2-(benzyloxy)-4-(trifluoromethyl)phenyl]acrylate Sodium hydride (60% wt. disp. oil, 0.406g) was added to a solution of tert-butyl-P,?-dimethylphosphonoacetate (2.27g) in dry DMF (20ml) at 0°C. The mixture was stirred at RT for 30min, cooled to 0°C, then the product from step (iii) (2.83g) added. After 16h the mixture was pNtitioned between diethylether and water, the organic layer dried, and the solvent evaporated under reduced pressure. The residue was purified by chromatography on silica eluting with isohexane/diethylether 4:1, yield 3.25g. 1H NMR CDC13: δ 7.98-7.93 (1H, d), 7.63-7.18 (8H, m), 6.52-6.46 (1H, d), 5.18 (2H, s), 1.52 (9H, s). (v) tert-Butyl 3-[2-hydroxy-4-(trifluoromethyl)phenyl]propanoate A mixture of the product from step (iv) (3.25g) and 10% palladium on cNbon (0.325g) in ethanol (40ml) was hydrogenated at a pressure of 3.0 bN overnight. The mixture was filtered through celite and the filtrate concentrated under reduced pressure to give a white solid (2.22g). MS: ESI (-ve) 289 (M-l) (vi) 3-Chloro-4-fluorophenyl methyl sulfide lodomethane (1.15ml) was added to a stirred mixture of 3-chloro-4-fluoro-benzenethiol (3.0g) and potassium cNbonate (2.48g) in DMF (20ml) and left overnight. The reaction was diluted with water and extracted with diethylether, the organics were dried and evaporated under reduced pressure, yield 4.3g. 1H NMR CDC13: δ 7.31-7.14 (2H, m), 7.13-7.03 (1H, m), 3.23-3.21 (3H, s). (vii) 3-Chloro-4-fluorophenyl methyl sulfone 3-Chloroperoxybenzoic acid (70% purity, 10.75g) was added to a solution of the product from step (vi) (4.3g) in DCM (100ml) and stirred at RT for 2h. The mixture was pNtitioned between DCM/aq. sodium metabisulphite solution, the organics washed with aq. sodium hydrogencNbonate solution, water, dried and evaporated under reduced pressure. Yield 4.0g 1H NMR CDC13: δ 8.06-8.03 (1H, m), 7.89-7.84 (1H, m), 7.38-7.32 (1H, m), 3.08 (3H, a). (viii)3-[2-[2-Chloro-4-(methylsulfonyl)phenoxy]-4-(trifluoromethyl)phenyl]propaiioic acid A mixture of the product from step (v) (0.6g), the product from step (vii) (0.43g) and potassium cNbonate (0.285g) in NMP (10ml) was heated at 70°C for 4h. The mixture \^as pNtitioned between diethylether and water, the organic layer dried, and the solvent evaporated under reduced pressure. The residue was dissolved in 50% DCM/trifluoroacetic acid (20ml) and stirred at RT for 2h. The solvent was evaporated under reduced pressure and the residue purified by RPHPLC, yield 0.175g lH NMR DMSO-d6: δ 8.17-8.16 (1H, s), 7.87-7.84 (1H, d), 7.69-7.61 (2H, m), 7.40 (1H, s), 7.08-7.06 (1H, d), 3.28 (3H, s), 2.87-2.82 (2H, t), 2.62-2.57 (2H, t). MS: ESI (-ve) 421 (M-l) Example 4 3-[2-[2-Chloro-4-(ethylsulfonyl)phenoxy]-4-(trifluoromethyl)phenyl]propanoicacid (Formula Removed) (i) 3-Chloro-4-fluorophenyl ethyl sulfone The subtitle compound was prepNed by the method of example 3 steps (vi)-(vii) using iodoethane. 1H NMR CDC13: 8 8.01-7.98 (1H, d), 7.84-7.79 (1H, m), 7.37-7.31 (1H, m), 3.17-3.09 (2H, q), 1.33-1.26 (3H,t). (ii) 3-[2-[2-Chloro-4-(ethylsulfonyl)phenoxy]-4-(trifluoromethyl)phenyl]propanoic acid The title compound was prepNed by the method of example 3 using the product from step (i). 1H NMR DMSO-d6: δ 8.07-8.00 (1H, d), 7.81-7.77 (1H, d), 7.698-7.56 (2H, m), 7.40 (1H, bm), 7.01-6.98 (1H, d), 3.39-3.32 (2H, q), 2.77-2.72 (2H, t), 2.26-2.21 (2H, t), 1.14-1.09 (3H, t). MS: ESI (-ve) 435 (M-l) Example 5 [(4-ChIoro-2-{[2-chloro-4-(ethylsulfonyl)phenyl]thio}phenyl)thio]acetic acid (Formula Removed) (i) 2-Chloro-4-(ethylsulfonyl)benzenethiol Sodium hydrosulphide (0.252g) was added to the product from example 4 step (i) (l.0g) in dry DMF (10ml) and stirred at RT for 2h. The mixture was diluted with 2M sodium hydroxide solution and extracted with diethylether. The aqueous layer was acidified with 2M hydrochloric acid, extracted with ethyl acetate, dried and evaporated under reduced pressure, crude yield 1.60g. MS: ESI (-ve) 235 (M-l) (ii) 4-Chloro-2-{[2-chloro-4-(ethylsulfonyl)phenyl]thio}-l-nitrobenzene A mixture of the product from step (i) (1.60g), potassium cNbonate (0.934g) and 2- fluoro-4-chloro-nitrobenzene (1.18g) in DMF (20ml) was stirred at RT overnight. Water(200ml) was added and the mixture extracted with ethyl acetate. The organics were dried, evaporated under reduced and the residue purified by chromatography on silica eluting with isohexane/diemylether 4:1, yield 0.80g. 1HNMR CDC13: δ 8.23-8.21 (1H, d), 8.11-8.10 (1H, s), 7.90-7.84 (2H, m), 7.34-7.31 (1H, d), 6.76-6.75 (1H, d), 3.10 (2H, q), 1.37-1.26 (3H, t). (iii) 4-Chloro-2- {[2-chloro-4-(ethylsulfonyl)phenyl]thio} aniline The product from step (ii) (0.80g) and reduced iron powder (0.80g) in glacial acetic acid (30ml) was vigorously stirred at RT for 2h. The mixture was filtered through celite, and the filtrate evaporated under reduced pressure to give a brown oil which was neutralised with 2M NaOH and extracted with ethyl acetate. The organics were dried, evaporated under reduced pressure and the residue purified by chromatography on silica eluting with isohexane/ethylacetate 2:1, yield 0.70g. 1H NMR CDC13: δ 7.88-7.87 (1H, m), 7.58-7.54 (1H, m), 7.44-7.43 (1H, m), 7.33-7.28 (1H, m), 6.82-6.75 (2H, m), 4.30 (2H, s), 3.12-3.05 (2H, q), 1.32-1.18 (3H, t). MS: ESI (-ve) 360 (M-l) (iv) Ethyl [(4-chloro-2-{[2-chloro-4-(ethylsulfonyl)phenyl]thio}phenyl)thio]acetate Ethyl mercaptoacetate (0.11ml) followed by isoamylnitrite (0.16ml) were added to a solution of the product from step (iii) (0.35g) in dry acetonitrile (20ml) and heated at 60°C for 10h. The mixture was diluted with water, extracted with diethylether, the organics dried and evaporated under reduced pressure. The residue was purified by chromatography on silica eluting with isohexane/diethylether 1:1, yield 0.10g. MS: ESI (+ve) 465 (M+l) (v) [(4-Chloro-2-{[2-chloro-4-(ethylsulfonyl)phenyl]thio}phenyl)thio]acetic acid A mixture of the product from step (iv) (0.10g), sodium hydroxide (0.018g) in methanol (5ml) and water (5ml) was stirred at RT for 1H. The mixture was pNtitioned between 2M hydrochloric acid/ethyl acetate, the organics sepNated, dried and evaporated under reduced pressure. The residue was purified by reverse phase HPLC. Yield 0.012g 1H NMR DMSO-d6: δ 7.97 (1H, s), 7.71-7.63 (3H, m), 7.50-7.48 (1H, d), 6.81-6.79(1H, d), 3.80 (2H, s), 3.40-3.31 (2H, q), 1.11-1.07 (3H, t). MS: ESI (-ve) 435/437 (M-l) Example 6 N-{4-Chloro-2-[2-chloro-4-(ethylsulfonyl)phenoxy]phenyl}gIycine (Formula Removed) (i) 2-Chloro-4-(ethylsulfonyl)phenol The product from example 4 step (i) (1.0g) in dry NMP (20ml) was treated with 2-butyn-1-ol (0.63ml) and sodium tert-butoxide (0.864g) and the mixture stirred at 80°C for 2h. The mixture was pNtitioned between water/ethyl acetate, the organics sepNated, dried and evaporated under reduced pressure, yield 1.06g. MS: ESI (-ve) 219 (M-l) (ii) 4-Chloro-2-[2-chloro-4-(ethylsulfonyl)phenoxy]-l-nitrobenzene The subtitle compound was prepNed by the method of example 5 step (ii) using the product from step (i). Yield 1.0g. 1H NMR CDC13: δ 8.08-8.05 (2H, m), 7.82-7.78 (1H, d), 7.38-7.26 (1H, d), 7.08-7.04 (2H, d), 3.19-3.12 (2H, q), 1.35-1.30 (3H, t). (iii) 4-Chloro-2-[2-chloro-4-(ethylsulfonyl)phenoxy]aniline The subtitle compound was prepNed by the method of example 5 step (iii) using the product from step (ii). Yield 0.95g. MS: ESI (-ve) 344/346 (M-l) (iv) Ethyl N- {4-chloro-2-[2-chloro-4-(ethylsulfonyl)phenoxy]phenyl} glycinate A mixture of the product from step (iii) (0.95g), ethyl bromoacetate (0.145ml) and sodium acetate (0.160g) hi dry ethanol (30ml) was heated under reflux 24h. A further 5 equivalents of ethyl bromoacetate were added and heated for a further 48h. The mixture was pNtitioned between water/ethyl acetate, the organics sepNated, dried and evaporated under reduced pressure. The residue was purified by chromatography on silica eluting with isohexane/ diethylether 1:1, yield 0.44g. MS: ESI (+ve) 431 (M+l) (v) N-{4-Chloro-2-[2-chloro-4-(ethylsulfonyl)phenoxy]phenyl}glycine The title compound was prepNed by the method of example 5 step (v) using the product from step (iv). yield 0.181g. 1H NMR DMSO-d6: δ 8.04 (1H, s), 7.78-7.75 (1H, d), 7.15-7.13 (1H, d), 7.05 (1H, s), 6.98-6.96 (1H, d), 6.65-6.63 (1H, d), 5.40 (1H, bs), 3.40-3.31 (4H, m), 1.13-1.07 (3H, t). MS: ESI (-ve) 402/404 (M-l) Example 7 ({4-Chloro-2-[2-chloro-4-(ethylsalfonyl)phenoxy]phenyl}thio)aceticacid (Formula Removed) (i) Ethyl ({4-chloro-2-[2-chloro-4-(ethylsulfonyl)phenoxy]phenyl}thio)acetate The subtitle compound was prepNed by the method of example 5 step (iv) using the product from example 6 step (iii). Yield 0.4g. MS: ESI (+ve) 467 (M+NH4) (ii)({4-Chloro-2-[2-chloro-4-(ethylsulfonyl)phenoxy]phenyl}thio)aceticacid The title compound was prepNed by the method of example 5 step (v) using the product from step (i), yield 0.02g. 1H NMRDMSO-d6: δ 8.07 (1H, s), 7.79-7.76 (1H, d), 7.54-7.47 (1H, d), 7.41-7.33 (2H, m), 7.00-6.97 (1H, d), 3.77 (2H, s), 3.50-3.23 (2H, q), 1.23-1.05 (3H, t). MS: ESI (-ve) 419/421 (M-l) Example 8 3-{2-[2-ChIoro-4-(methylsulfonyl)phenoxy]-4-fluorophenyl}propanoicacid (Formula Removed) The title compound was prepNed by the method of example 3 using 4-fluoro-2-methoxybenzaldehyde, yield 0.137g. 1H NMR DMSO-d6: δ 8.15-8.14 (1H, s), 7.86-7.83 (1H, d), 7.48-7.44 (1H, m), 7.13-7.07 (2H, m), 6.99-6.96 (1H, d), 3.27 (3H, s), 2.76-2.72 (2H, t), 2.54-2.49 (2H, t). MS: ESI (-ve) 371 (M-l) Example 9 {2-[2-Chloro-4-(methylsulfonyl)phenoxy]-4-fluorophenyl}aceticacid (Formula Removed) (i) 4-Fluoro-2-hydroxybenzaldehyde The subtitle compound was prepNed by the method of example 3 step (ii) using 4-fluoro-2-methoxybenzaldehyde, yield 3.0g. 1H NMR CDC13: δ 11.83 (1H, s), 9.83 (1H, s), 7.58-7.53 (1H, m), 6.75-6.65 (2H, m). (ii) 2-(Benzyloxy)-4-fluorobenzaldehyde A mixture of the product from step (i) (3.0g), potassium cNbonate (4.42g) and benzyl bromide (3.90ml) in DMF (40ml) was heated at 90°C for 14h. The mixture was pNtitioned between water/ethyl acetate, the organics sepNated, dried and evaporated under reduced pressure. The residue was purified by chromatography on silica eluting with isohexane/ diethylether 5:1, yield 6.3g. (iii) [2-(Benzyloxy)-4-fluorophenyl]methanol Sodium borohydride (0.223g) was added to a solution of the product from step (ii) (1.07g) in dry ethanol (30ml) and the mixture was stirred at RT overnight. The mixture was pNtitioned between 2M hydrochloric acid/ethyl acetate, the organics sepNated, dried and evaporated under reduced pressure, yield l.08g. MS: ESI (-ve) 231 (M-l) (iv) Benzyl 2-(chloromethyl)-5-fluorophenyl ether A mixture of the product from step (iii) (1.06g), methane sulphonyl chloride (0.351ml) and triethylamine (0.636ml) in DCM (20ml) was stirred at RT for 2h. The mixture was pNtitioned between water/DCM, the organics sepNated, dried and evaporated under reduced pressure. The residue was purified by chromatography on silica eluting with isohexane/DCM 1:1, yield 0.7g. 1H NMR CDC13: δ 7.47-7.25 (6H, m), 6.69-6.62 (2H, m), 5.11 (2H, s), 4.59 (2H, s). (v) [2-(Benzyloxy)-4-fluorophenyl]acetic acid A mixture of the product from step (iv) (0.7g) and sodium cyanide (0.162g) in DMSO (20ml) was heated at 60°C for 2h. 2M Sodium hydroxide (10ml) was added and the mixture heated at 100°C for 6h then stirred at RT for 2h. The mixture was pNtitioned between 2M hydrochloric acid/ethyl acetate, the organics sepNated, dried and evaporated under reduced pressure, yield 0.68g. MS: ESI (-ve) 259 (M-l) (vi) (4-Fluoro-2-hydroxyphenyl)acetic acid The subtitle compound was prepNed by the method of example 3 step (v), yield 0.34g. MS: ESI (-ve) 169 (M-l) (vii) {2-[2-Chloro-4-(methylsulfonyl)phenoxy]-4-fluorophenyl}acetic acid Sodium hydride (60% wt. disp. oil, 0.176g) was added to a solution of the product from step (vi) (0.34g) in dry DMF (10ml) and stirred at RT for 1h before adding the product from example 3 step (vii) (0.416g). The mixture was heated at 80°C for 1h, then pNtitioned between 2M hydrochloric acid/ethyl acetate. The organics were dried, evaporated under reduced pressure and the residue purified by reverse phase HPLC. Yield 0.064g 1H NMR DMSO-d6: δ 8.10 (1H, s), 7.82-7.80 (1H, d), 7.48-7.44 (1H, m), 7.11-7.08 (2H, m), 6.97-6.94 (1H, d), 3.41-3.35 (2H, s), 3.26 (3H, s). MS: ESI (-ve) 357 (M-l) Example 10 4-chIoro-2-[2-chloro-4-(methylsulfonyl)phenoxy]-a-methyI-benzenepropanoic acid (Formula Removed) i) (2E)-3-(4-chloro-2-methoxyphenyl)-2-methyl-, ethyl ester, 2-propenoic acid The subtitle compound was prepNed by the method of example 3 step iv) using ethyl- P,P-dimethylphosphonoacetate with the product from example 3 step i) Yield 1.85g. 1H NMR CDC13: δ 7.75-7.10 (4H, m), 4.31-4.25 (2H, q), 3.90 (3H, s), 2.03-2.02 (3H, s), 1.37-1.33(3H,t). ii) (2E)-3-(4-chloro-2-hydroxyphenyl)-2-methyl-2-propenoic acid, ethyl ester The subtitle compound was prepNed by the method of example 3 step ii) using the product from step i) Yield 1.80g. MS: ESI (-ve) 273 (M-l) iii)(2E)-3-[4-chloro-2-[2-chloro-4-(methylsulfonyl)phenoxy]phenyl]-2-methyl-2-propenoic acid The subtitle compound was prepNed by the method of example 3 step viii) using the product from step ii) Yield 0.35g. 1H NMR DMSO-d6: δ 12.74 (1H, bs), (1H, m), 7.49 (6H, m), 7.12-7.10 (1H, d), 3.27-3.26 (3H,s), 1.94 (3H, s). iv)4-chloro-2-[2-chloro-4-(methylsulfonyl)phenoxy]-α-methyl-benzenepropanoic acid The title compound was prepNed by the method of example 3 step v) using the product from step iii). 1H NMR DMSO-d6: δ 8.10 (1H, s), 7.82-7.80 (1H, d), 7.48-7.44 (1H, m), 7.11-7.08 (2H, m), 6.97-6.94 (1H, d), 3.41-3.35 (2H, s), 3.26 (3H, s). MS: ESI (-ve) 435 (M-l) Example 11 A?-[2-[2-chloro-4-(methylsulfonyl)phenoxy]-4-fluorophenyl]-glycine (Formula Removed) i) 2-amino-5-fluoro-phenol The subtitle compound was prepNed by the method of example 3 step v) using 2-nitro-5-fluoro phenol. Yield 1.74g. MS: ESI (-ve) 126 (M-l) ii)2-[2-chloro-4-(methylsulfonyl)phenoxy]-4-fluoro-benzenamine The subtitle compound was prepNed by the method of example 3 step viii) using the product from step i). Yield 1.00g. 1H NMR CDC13: δ 8.05-7.73 (2H, m), 6.95-6.67 (4H, m), 3.48-3.47 (2H, bs), 3.06 (3H, s). MS: ESI (-ve) 314 (M-l) iii)N-[2-[2-chloro-4-(methylsulfonyl)phenoxy]-4-fluorophenyl]-glycine The title compound was prepNed by the methods of example 6 step iv-v) using the product from step ii). 1H NMR DMSO-d6: δ 8.10-6.62 (6H, m), 5.20(1H, bs), 3.47 (2H, s), 3.25 (3H, s). MS: ESI (-ve) 372 (M-l) Example 12 N-[2-[2-chIoro-4-(ethylsulfonyl)phenoxy]-4-fluorophenyl]-glycine (Formula Removed) i)2-[2-chloro-4-(ethylsulfonyl)phenoxy]-4-fluoro-benzenamine The subtitle compound was prepNed by the method of example 11 step ii) using the product from example 4step i) Yield 0.7g. MS: ESI (+ve) 330 (M+l) ii)N-[2-[2-chloro-4-(ethylsulfonyl)phenoxy]-4-fluorophenyl]-glychie The title compound was prepNed by the method of example 6 step iv) using the product from step i). 1H NMR DMSO-d6: δ 8.04-8.02 (1h, s), 7.78-7.74 (1H, d), 7.02-6.86 (3H, m), 6.69-6.65 (1H, m), (2H, m), 3.72 (2H, s), 3.41-3.30 (2H, q), 1.13-1.06 (3H, t). MS: ESI (-ve) 386 (M-l) Example 13 N-[2-[2-chloro-4-(methylsulfonyl)phenoxy]-4-fluorophenyl]-2-methyl-alanine (Formula Removed) The title compound was prepNed using the product from example 11 step ii) (0.50g) which was dissolved in dry acetone (30ml) and treated with trichloro-methylpropanol (0.75g). The mixture was cooled to 0 C before adding crushed sodium hydroxide (0.183g) and stirring for 1 hour at room temperature. This process was repeated a further two times and left to stir at room temperature overnight. The mixture was extracted with ether(discNded). The aqueous layer was acidified and extracted with ethyl acetate ,dried and concentrated under reduced pressure to an oil. The residue was purified by reverse phase HPLC to give a white solid. 1H NMR DMSO-d6: δ 8.11-8.10 (1H, s), 7.84-7.80 (1H, d), 7.01-6.89 (3H, m), 6.72-6.67 (1H, m), 3.31 (3H,s), 1.41 (6H,s). MS: ESI (-ve) 400 (M-l) Example 14 N-[2-[2-chloro-4-(methylsulfonyl)phenoxy]-4-fluorophenyl]-D-alanine (Formula Removed) i) N-[2-[2-chloro-4-(methylsulfonyl)phenoxy]-4-fluorophenyl]-D-alanine, ethyl ester The subtitle compound was prepNed using the product from example 11 step ii) (0.44g) which was dissolved in dry DCM (20ml) and treated with 2,6-lutidine (0.162ml) followed by ethyl-o-trifluoromethanesulphonyl-D-lactate (0.285ml). The mixture was stirred at room temperature overnight. The mixture was concentrated under reduced pressure to an oil. The residue was purified by chromatography eluting with ether/isohexane 1:1, yield 0.6g. MS: ESI (-ve) 414 (M-l) ii)N-[2-[2-chloro-4-(methyisulfonyl)phenoxy]-4-fluorophenyl]-D-alanuie The title compound was prepNed using the method of example 5 step v) using the product from stepi). 1H NMR DMSO-d6: δ 8.11-8.10 (1H, s), 7.83-7.79 (1H, d), 7.03-6.74 (4H, m), 4.14-4.07 (1H, q), 3.26 (3H, s), 1.35-1.26 (3H, d). MS: ESI (-ve) 386 (M-l) Example 15 N-[4-chloro-2-[2-chloro-4-(methylsulfonyl)phenoxy]phenyl]-glycine (Formula Removed) i) 4-chloro-2-[2-chloro-4-(methylsulfonyl)phenoxy] -benzenamine The subtitle compound was prepNed by the method of example 3 step viii) using 4- chloro-2-hydroxyanilme and the product from example 3 step vii). Yield 3.0g. MS: ESI (-ve) 330 (M-l) ii) N-[4-chloro-2-[2-chloro-4-(methylsulfonyl)phenoxy]phenyl]-glycine, ethyl ester The subtitle compound was prepNed by the method of example 6 step iv) using the product from step i). Yield 0.6 g. MS: ESI (+ve) 418 (M+l) iii)N-[4-chloro-2-[2-chloro-4-(methylsulfonyl)phenoxy]phenyl]-glycine The title compound was prepNed by the method of example 5 step v) using the product from step ii). 1H NMR DMSO-d6: δ 8.11-8.10 (1H, s), 7.82-7.79 (1H, d), 7.16-6.94 (3H, m), 6.67-6.64 (1H, d), 5.49 (1H, m), 3.51 (2H, s), 3.25 (3H, s).. MS: ESI (-ve) 388 (M-l) Example 16 [[4-chloro-2-[2-chloro-4-(methylsulfonyl)phenoxy]phenyl]thio]-acetic acid (Formula Removed) i) [[4-chloro-2-[2-chloro-4-(methylsulfonyl)phenoxy]phenyl]thio]-acetic acid, ethyl ester Ethyl mercaptoacetate (0.11ml) followed by isoamylnitrite (0.16ml) were added to a solution of the product from example 15 step (i) (0.5g) in dry acetonitrile (20ml) and heated at 60°C for 10h. The mixture was diluted with water, extracted with diethylether, the organics dried and evaporated under reduced pressure. The residue was purified by chromatography on silica eluting with dichloromethane, yield 0.60g. MS: ESI (+ve) 435 (M+l) ii) [[4-chloro-2-[2-chloro-4-(methylsulfonyl)phenoxy]phenyl]thio]-aceticacid The title compound was prepNed by the method of example 5 step v) using the product from step i). 1H NMR DMSO-d6: δ 8.13-8.12 (1H, s), 7.84-7.80 (1H, d), 7.50-7.29 (3H, m), 6.99-6.96 (1H, d), 3.75 (2H, s), 3.27 (3H, s).. MS: ESI (-ve) 405 (M-l) Example 17 N-[2-[2-chloro-4-(ethylsulfonyl)phenoxy]-4-fluorophenyl]-D-alanine (Formula Removed) i) N-[2-[2-chloro-4-(ethylsulfonyl)phenoxy]-4-fluorophenyl]-D-alanine, methyl ester The subtitle compound was prepNed by the method of example 14 step i) using the product from example 15 step i). Yield 0.5g. MS: ESI (-ve) 416 (M-l) ii)N-[2-[2-chloro-4-(ethylsulfonyl)phenoxy]-4-fluorophenyl]-D-alanine The title compound was prepNed by the method of example 5 step v) using the product from step i). 1H NMR DMSO-d6: δ 8.04-8.03 (1H, s), 7.77-7.75 (1H, d), 6.98-6.91 (3H, m), 6.69-6.65 (1H, m), 5.40 (1H, m), 3.52-3.50 (1H, q), 3.40-3.30 (2H, q), 1.20-1.18 (3H, d), 1.13-1. 07 (3H, t). MS: ESI (-ve) 400 (M-l) Example 18 N-[4-chloro-2-[2-chloro-4-(methylsulfonyl)phenoxy]phenyl]-D-alanine (Formula Removed) i) N-[4-chloro-2-[2-chloro-4-(methylsulfonyl)phenoxy]phenyl]-D-alanine, methyl ester The subtitle compound was prepNed by the method of example 14 step i) using the product from example 12 step i). Yield 0.6g. MS: ESI (-l-ve) 418 (M+l) ii) N-[4-chloro-2-[2-chloro-4-(methylsulfonyl)phenoxy]phenyl]-D-alanine The title compound was prepNed by the method of example 5 step v) using the product from step i). 1H NMR DMSO-d6: δ 8.11-8.10 (1H, s), 7.83-7.80 (1H, d), 7.16-7.14 (1H, d), 7.01-6.97 (2H, m), 6.77-6.74 (1H, d), 5.40 (1H, m), 4.13-4.11 (1H, q), 3.40-3.30 (3H, s), 1.36-1.35 (3H, d). MS: ESI (-ve) 402 (M-l) Example 19 N-[4-chloro-2-[2-chloro-4-(methylsulfonyl)phenoxy]phenyl]-N-methyl-glycine (Formula Removed) i)N-[4-chloro-2-[2-chloro-4-(methylsulfonyl)phenoxy]phenyl]-N-methyl-glycine, ethyl ester The subtitle compound was prepNed by using the product from example 15 step ii).(0.70g) which was dissolved in dimethylsulphate (3ml). Sodium hydrogen cNbonate (0.355g) was added and heated to 90 C for 2 hours. The mixture was diluted with water, extracted with ethyl acetate, dried, and concentrated under reduced pressure to give an oil. The residue was purified by chromatography on silica eluting with diethyl ether, yield 0.70g. MS: ESI (+ve) 432 (M+l) ii)N-[4-chloro-2-[2-chloro-4-(methylsulfonyl)phenoxy]phenyl]-N-methyl-glycuie The title compound was prepNed by the method of example 5 step v) using the product from step i). lH NMR DMSO-d6: δ 8.07 (1H, s), 7.77-7.74 (1H, d), 7.22-7.02 (3H, m), 6.82-6.80 (1H, d), 3.69 (2H, s), 3.24 (3H, s), 2.80 (3H, s). MS: ESI (-ve) 402 (M-l) i) 4-fluoro-2-hydroxy-benzenepropanoic acid Example 20 2-[2-chloro-4-(ethylsulfonyl)phenoxy]-4-fluoro-benzenepropanoicacid (Formula Removed) The subtitle compound was prepNed by the method of example 3 steps ii-v) using 4-fluoro-2-methoxybenzaldehyde, yield 1.90g. MS: ESI (-ve) 211 (M-l) ii) 2-[2-chloro-4-(ethylsulfonyl)phenoxy]-4-fluoro-benzenepropanoic acid, ethyl ester The subtitle compound was prepNed by the method of example 3 step viii) using trie product from step i) and the product from example 4 step i) yield (0.45g).. MS: ESI (+ve) 432 (M+NH4) iii)2-[2-chloro-4-(ethylsulfonyl)phenoxy]-4-fluoro-benzenepropanoic acid The title compound was prepNed by the method of example 5 step v) using the product from step ii). 1H NMR DMSO-d6: δ 8.05-8.04 (1H, s), 7.79-7.76 (1H, m), 7.47-7.43 (1H, m), 7.08-6.96 (3H, m), 3.37-3.35 (2H, q), 2.63-2.59 (2H, t), 2.07-2.03 (2H, t), 1.13-1.10 (3H, t). MS: ESI (-ve) 385 (M-l) Example 21 2-[4-(ethylsulfonyl)-3-(trifluoromethyl)phenoxy]-4-fluoro-benzenepropanoicacid (Formula Removed) i) 2-[4-(ethylsulfonyl)-3-(trifluoromethyl)phenoxy] -4-fluoro-benzenepropanoic acid, ethyl ester The subtitle compound was prepNed by the method of example 3 step viii) using 4-bromo-l-(methylsulphonyl)-2-trifluoromethylbenzene yield and the product from example 20 step i) 0.60g. MS: ESI (+ve) 452 (M+NH4) ii)2-[4-(ethylsulfonyl)-3-(trifluoromethyl)phenoxy]-4-fluoro-benzenepropanoic acid The title compound was prepNed by the method of example 5 step v) using the product from step i). 1H NMR DMSO-d6: δ 8.20-8.17 (1H, d), 7.54-7.45 (2H, m), 7.28-7.25 (1H, d), 7.12-7.05 (2H, m), 3.27 (3H, s), 2.62-2.55 (2H, t), 2.05-1.99 (3H, t). MS: ESI (-ve) 405 (M-l) Example 22 2-[4-(ethyIsulfonyl)-3-(trifluoromethyl)phenoxy]-4-fluoro-benzenepropanoicacid (Formula Removed) i) 4-bromo-1 -(ethylsulfonyl)-2-(trifluoromethyl)-benzene The subtitle compound was prepNed by the method of example 3 step vii) using 4-bromo-l-(ethylthio)-2-trifluoromethylbenzene yield (0.97g). 1H NMR CDC13: δ 8.13-7.89 (3H, m), 3.31-3.24 (2H, q), 1.34-1.29 (3H, t). ii) 3- {2-[4-(ethylsulfonyl)-3-(trifluoromethyl)phenoxy]-4-fluorophenyl}propanoic acid The title compound was prepNed by the method of example 21 using the product from step i). 1H NMR DMSO-d6: δ 8.20-8.17 (1H, d), 7.54-7.45 (2H, m), 7.28-7.25 (1H, d), 7.07-7.02 (2H, m), 3.35-3.32 (2H, q), 2.60-2.54 (2H, t), 2.04-2.00 (2H, t), 1.17-1.14 (3H, t). MS: ESI (-ve) 405 (M-l) Example 23 N-[4-chloro-2-[[4-(ethylsulfonyl)phenyI]thio]phenyI]-glycine (Formula Removed) i) N-[4-chloro-2-[[4-(ethylsulfonyl)phenyl]thio]phenyl]-glycine, ethyl ester The subtitle compound was prepNed by the method of example 6 step iv) using the product from example 5 step iii) yield 0.30g. MS: ESI (+ve) 448 (M+H) ii)N-[4-chloro-2-[[4-(ethylsulfonyl)phenyl]thio]phenyl]-glycine The title compound was prepNed by the method of example 5 step v) using the product from step i). 1H NMR DMSO-d6: δ 12.65 (1H, s), 7.936-7.93 (1H, s), 7.66-7.41 (3H, m), 6.80-6.71 (2H, m), 6.06-6.02 (1H, t), 3.90-3.88 (2H, d), 3.39-3.35 (2H, q), 1.10-1.05 (3H, t). MS: ESI (-ve) 418 (M-l) Example 24 N-[4-chloro-2-[[4-(ethylsulfonyl)phenyl]thio]phenyl]-D-alanine (Formula Removed) The title compound was prepNed by the method of example 14 steps i-ii) using the product from example 5 step iii). 1H NMR DMSO-d6: δ 7.94-7.93 (1H, s), 7.68-7.64 (1H, d), 7.51-7.42 (2H, m), 6.80-6.75 (2H, m), 5.78-5.76 (1H, d), 4.07-4.05 (1H, q), 3.41-3.27 (2H, q), 1.27-1.24 (3H, d), 1.16-1.05 (3H, t). MS: ESI (-ve) 432 (M-l) Example 25 N-[4-chloro-2-[4-(ethylsuIfonyI)-3-(trifluoromethyl)phenoxy]phenyl]-glycine (Formula Removed) i)4-chloro-2-[4-(ethylsulfonyl)-3-(trifluoromethyl)phenoxy]-benzenamine The subtitle compound was prepNed by the example 3 step viii) using the product from example 22 step i) and 2-amino-5-chlorophenol. Yield 1.0g MS: ESI (-ve) 378 (M-l) ii)N-[4-chloro-2-[4-(ethylsulfonyl)-3-(trifluoromethyl)phenoxy]phenyl]-glycine The title compound was prepNed by the method of example 15 steps ii-iii) using the product from step i). 1H NMR DMSO-d6: δ 8.14-8.11 (1H, d), 7.58-7.57 (1H, m), 7.29-7.14 (3H, m), 6.69-6.66 (1H, d), 5.67 (1H, m), 3.61 (2H, s), 3.39-3.28 (2H, q), 1.23-1.15 (3H, t). MS:ESI(-ve)436(M-l) Example 26 N-[4-chloro-2-[4-(ethylsulfonyl)-3-(trifluoromethyl)phenoxy]phenyl]-D-aIanine (Formula Removed) The title compound was prepNed by the method of example 14 steps i-ii) using the product from example 25 step i). 1H NMR DMSO-d6: δ 8.14-8.11 (1H, d), 7.589-7.58 (1H, m), 7.29-7.16 (3H, m), 6.76-6.73 (1H, d), 5.62 (1H, m), 4.11-4.09 (1H, m), 3.36-3.28 (2H, q), 1.34-1.32 (3H, d), 1.18-1.13 (3H, t)- MS: ESI (-ve) 450 (M-l) Example 27 N-[2-[2-chloro-4-(ethylsuIfonyl)phenoxy]-4-(trifluoromethyl)phenyI]-glycine (Formula Removed) i) 2-nitro-5-(trifluoromethyl)-phenol The subtitle compound was prepNed by using 3-(l,l,l-trifluoromethyl)phenol (5.0g) which was cooled to 0 C and 65% nitric acid (6ml) was added drop wise. After the addition, the mixture was kept at 0 C for 1 hour. This was diluted with saturated sodium acetate solution, extracted with ethyl acetate, dried and concentrated under reduced pressure to give an oil. Yield 3.67g MS: ESI (+ve) 206 (M+l) ii)2-amino-5-(trifluoromethyl)-phenol The subtitle compound was prepNed by the method of example 3 step v) using the product from step i) Yield 1.50g. MS: ESI (+ve) 186 (M+l) iii)N-[2-[2-chloro-4-(ethylsulfonyl)phenoxy]-4-(trifluoromethyl)phenyl]-glycine The title compound was prepNed by the method of example 12 steps i-ii) using the product from step ii). 1H NMR DMSO-d6: δ 12.84 (1H, bs), 8.027-8.02 (1H, s), 7.78-7.74 (1H, m), 7.34-7.30 (2H, m), 6.97-6.94 ( 1H, m), 6.78-6.75 (1H, d), 5.78-5.76 (1H, t), 3.98-3.96 (2H, d), 3.36-3.29 (2H, q), 1.16-1.08 (3H,t). MS: ESI (-ve) 436 (M-l) Example 28 N-[2-[4-(ethylsulfonyl)-3-(trifluoromethyl)phenoxy]-4-(trifluoromethyl)phenyl]-glycine (Formula Removed) The title compound was prepNed by the method of example 25 steps i-ii) using the product from example 27 step ii). 1H NMR DMSO-d6: δ 8.13-8.10 (1H, d), 7.54-7.24 (4H, m), 6.79-6.76 (1H, d), 5.78-5.76 (1H, t), 3.99-3.97 (2H, d), 3.35-3.27 (2H, q), 1.17-1.12 (3H, t). MS: ESI (-ve) 436 (M-l) Example 29 N-[4-chloro-2-(2-chloro-4-cyanophenoxy)phenyl]-glycine (Formula Removed) i) 4-(2-amino-5 -chlorophenoxy)-3 -chloro-benzonitrile The subtitle compound was prepNed by the method of example 3 step viii) using 2-Nnino-5-chlorophenol and 3-chloro-4-fluorobenzonitrile. Yield 2.70g 1H NMR CDC13: δ 7.76-7.75 (1H, s), 7.49-7.46 (1H, d), 7.07-6.77 (4H, m), 3.79 (2H, s). ii) N-[4-chloro-2-(2-chloro-4-cyanophenoxy)phenyl]-glycine, ethyl ester The subtitle compound was prepNed by the method of example 1 step ii) using the product from step i). Yield 1.65g. MS: ESI (-ve) 363 (M-l) iii) N- [4-chloro-2-(2-chloro-4-cyanophenoxy)phenyl] -glycine The title compound was prepNed by the method of example 5 step v) using the product from step ii). 1H NMR DMSO-d6: δ 8.197-8.19 (1H, s),7.76-7.73 (1H, d), 7.16-7.13 (1H, d), 7.04-7.03 (1H, s), 6.88-6.85 (1H, d), 6.70-6.67 (1H, d), 5.78-5.70 (1H, m), 3.84 (2H, s). MS: ESI (-ve) 335 (M-l) Example 30 N-[2-(4-bromo-2-chlorophenoxy)-4-chlorophenyI]-glycine (Formula Removed) i) 2-(4-bromo-2-chlorophenoxy)-4-chloro-benzenamine The subtitle compound was prepNed by the method of example 3 step viii) using 2-amino-5-chlorophenol and 3-chloro-4-fluorobromobenzene. Yield 2.05g. 1H NMR CDC13: δ 7.61-7.60. (1H, s), 7.37-7.25 (1H, m), 7.05-6.93 (1H, m), 6.83-6.71 (3H, m), 3.85 (2H, s). ii) N-[2-(4-bromo-2-chlorophenoxy)-4-chlorophenyl]-glycine, ethyl ester The subtitle compound was prepNed by the method of example 1 step ii) using the product from step i). Yield 2.50g. MS: ESI (+ve) 420 (M+l) iii) N-[2-(4-bromo-2-chlorophenoxy)-4-chlorophenyl]-glycine The title compound was prepNed by the method of example 5 step v) using the product from step ii). 1H NMR DMSO-d6: δ 7.86-7.85 (1H, s),7.52-7.48 (1H, d), 7.08-7.04 (1H, d), 6.89-6.86 (1H, d), 6.78-6.77 (1H, s), 6.66-6.63 (1H, d), 5.64 (1H, m), 3.86 (2H, s). MS: ESI (-ve) 391 (M-l) (Formula Removed) Example 31 i)4-(2-amino-5-chlorophenoxy)-3-chloro-N-hydroxy-benzenecNboximidNnide The subtitle compound was prepNed using the product from example 29 step i) (0.60g) which was dissolved in ethanol (20ml) and treated with hydroxylamine hydrochloride (0.30g) followed by potassium cNbonate (0.60g). The mixture was heated at 90 C for 2 hours, cooled and the solid filtered off. The filtrate was concentrated under reduced pressure to give a red oil. Yield 0.94g. MS: ESI (+ve) 312 (M+l) ii)N-[4-chloro-2-[2-chloro-4-(5-methyl-l,2,4-oxadiazol-3-yl)phenoxy]phenyl] -acetamide The subtitle compound was prepNed using the product from step i) (0.94g) which was dissolved in pyridine (10ml) and treated with acetyl chloride (0.22ml) at 0 C. This was then allowed to wNm to room temperature. The mixture was heated at reflux for 3 hours, diluted with 2M HCI, extracted with ethyl acetate, dried and concentrated under reduced pressure to an oil. The residue was purified by chromatography on silica eluting with diethyl ether/isohexane 3:1, yield 0.80g. 1H NMR CDC13: δ 8.43-8.40 (1H, d), 8.25-8.23 (1H, s), 8.02-7.97 (1H, d), 7.67- 7.56 (1H, bs), 7.21-7.11 (2H, d), 6.81-6.75 (1H, s), 2.68-2.67 (3H, s), 2.21-2.18 (3H, s). iii) 4-chloro-2-[2-chloro-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenoxy]- benzenamine The subtitle compound was prepNed using the product from step ii) (0.50g) which was dissolved in 2M HCI (10ml) and ethanol (10ml). The mixture was heated at reflux for 3 hours and concentrated under reduced pressure to an solid. Yield 0.45g. MS: ESI (+ve) 335 (M+l) iv)N-[4-chloro-2-[2-chloro-4-(5-methyl-l,2,4-oxadiazol-3-yl)phenoxy]phenyl]-glycine The title compound was prepNed by the method of example 6 steps iv-v) using the ; product from step iii). 1H NMR DMSO-d6: δ 8.09 (1H, s), 7.92-7.89 (1H, d), 7.14-7.10 (1H, d), 7.01-6.95 (2H, m), 6.70-6.67 (1H, d), 5.67 (1H, bs), 3.87 (2H, s), 2.66 (3H, s). MS: ESI (-ve) 392 (M-l) Example 32 (Formula Removed) i)N-[4-chloro-2-[2-chloro-4-[(hydroxyamino)iminomethyl]phenoxy]phenyl]-glycine, ethyl ester The subtitle compound was prepNed by the method of example 31 step i) using the product from example 29 step ii). Yield 0.60g. MS: ESI (+ve) 398 (M+l) ii)N-[4-chloro-2-[2-chloro-4-(5-ethyl-1,2,4-oxadiazol-3-yl)phenoxy]phenyl]- glycine, ethyl ester The subtitle compound was prepNed by the method of example 31 step ii) using the product from step i). Yield 0.60g.. MS: ESI (+ve) 436 (M+l) iii) N-[4-chloro-2-[2-chloro-4-(5-ethyl-1,2,4-oxadiazol-3-yl)phenoxy]phenyl]-glycine The title compound was prepNed by the method of example 5 step v) using the product from step ii). 1H NMR DMSO-d6: δ 8.10 (1H, s), 7.93-7.89 (1H, d), 7.14-7.10 (1H, d), 7.01-6.95 (2H, m), 6.70-6.67 (1H, d), 5.68 (1H, bm), 3.87 (2H, s), 3.05-2.98 (2H, q), 1.26-1.24 (3H, t). MS: ESI (-ve) 408 (M-l) Example 33 N-[4-chloro-2-[2-chloro-4-(5- pyrimidinyl)phenoxy]phenyl]-glycine (Formula Removed) i) N-[4-chloro-2-[2-chloro-4-(5-pyrimidinyl)phenoxy]phenyl]-glycine, ethyl ester The subtitle compound was prepNed by using the product from example 30 step ii) (0.20g) which was dissolved in dry dioxane (10ml). Cesium fluoride (0.15g) followed by pyrimidine-5-boronic acid (0.058g) and Palladium(diphenylphosphinoferrocene) dichloride (0.017g) were added and the mixture was heated at 80 C for 10 hours. The mixture was diluted with 2M HC1, extracted with ethyl acetate, dried and concentrated under reduced pressure to give an oil. Yield 0.20g. MS: ESI (+ve) 417 (M+l) ii)N-[4-chloro-2-[2-chloro-4-(5-pyrimidinyl)phenoxy]phenyl]-glycine The title compound was prepNed by the method of example 5 step v) using the product from step i). 1H NMR DMSO-d6:δ 9.19-9.17 (3H, m), 8.12-8.11 (1H, m), 7.79-7.75 (1H, m), 7.10-7.04 (2H, m), 6.80-6.79 (1H, m), 6.68-6.65 (1H, d), 5.70 (1H, bm), 3.89 (2H, s). MS: ESI (-ve) 388 (M-l) Example 34 A44-chloro-2-[2-chIoro-4-(2-pyridmyl)phenoxy]phenyl]-glycme (Formula Removed) i) N-[4-chloro-2-[2-chloro-4-(2-pyridinyl)phenoxy]phenyl]-glycine, ethyl ester The subtitle compound was prepNed by using the product from example 30 step ii) (0.20g) which was dissolved in dry dioxane (10ml). 2-pyridyl tributyl tin (0.181g) and palladium (0) tetrakistriphenylphosphine (0.028g) were added and the mixture was heated at 80 C for 16 hours. The mixture was diluted with water, extracted with ethyl acetate, dried and concentrated under reduced pressure to give an oil. Yield 0.20g. MS: ESI (+ve) 402 (M+l) ii) N-[4-chloro-2-[2-chloro-4-(2-pyridinyl)phenoxy]phenyl]-glycine The title compound was prepNed by the method of example 5 step v) using the product from step i). 1H NMR DMSO-d6: δ 8.67-8.65 (1H, m), 8.30-8.27 (1H, s), 8.05-7.99 (2H, m), 7.91-7.87 (1H, m), 7.38-7.35 (1H, m), 7.09-6.94 (2H, m), 6.78 (1H, s), 6.67-6.65 (1H, d), 5.75 (1H, bm), 3.87 (2H, s). MS: ESI (-ve) 386 (M-l) Example 35 4-chloro-2-[2-chIoro-4-(ethylsulfonyl)phenoxy]-benzenepropanoicacid (Formula Removed) i) 4-chloro-2-hydroxy-benzaldehyde The subtitle compound was prepNed by using 5-chloro-2-hydroxymethylphenol (prepNed from the method of VNgha.et.al Acta.Chim.Acad.Hung., 4,1954, 345-360) (5g) which was dissolved in DCM (200ml) and manganese (iv) oxide (10g) added. The mixture was stirred at room temperature for 16 hours. The mixture was filtered through celite and the filtrate concentrated under reduced pressure to give a brown solid. Yield 3.48g. MS: ESI (-ve) 155 (M-l) ii) 4-chloro-2-hydroxy-benzenepropanoic acid The subtitle compound was prepNed by using the product from step i). (3.48g) was added to a solution of triethylamine (10ml) and formic acid (7ml) in DMF (30ml) after 20 minutes. Meldram's acid (3.22g) was added and the mixture heated to 100 C for 4 hours. The solution was basified with 2M NaOH, extracted with ether(discNded). The aqueous layer was acidified with 2M HC1, extracted with ethyl acetate, dried and concentrated under reduced pressure to give an oil. The residue was purified by chromatography on silica eluting with diethyl ether/isohexane 1:5, yield 0.40g. 1H NMR CDC13: δ 12.07 (1H, s), 9.8§ (1H, s), 7.07 (1H, d), 6.80 (1H, s), 6.75 (1H, d), 2.71 (2H, t), 2.45 (2H, t). iii) 4-chloro-2-[2-chloro-4-(ethylsulfonyl)phenoxy]-benzenepropanoicacid The title compound was prepNed by the method of example 3 step viii) using the product from step ii) and the product from example 4 step i). !H NMR DMSO-d6: δ 8.06-8.05 (1H, s), 7.80-7.77 (1H, d), 7.47-7.44 (1H, d), 7.28-7.25 (1H, d), 7.14-7.13 (1H, s), 7.01-6.99 (1H, d), 3.53-3.32 (2H, q), 2.68-2.64 (2H, t), 2.16-2.12 (2H, t), 1.30-1.22 (3H,t). MS: ESI (-ve) 401 (M-l) Example 36 4-chloro-2-[2-cyano-4-(ethylsulfonyl)phenoxy]-benzenepropanoic acid (Formula Removed) i) 2-chloro-5-(memylthio)-benzonitrile The subtitle compound was prepNed by the method of example 5 step iii) using 2-chloro-5-nitrobenzonitrile. Yield 6.70g. 1H NMR CDC13: δ 7.26-7.24 (1H, d), 6.91-6.90 (1H, m), 6.81-6.77 (1H, d), 3.95-3.80 (2H, bs). ii)2-chloro-5-(ethylthio)-benzonitrile The subtitle compound was prepNed by the method of example 5 step iv) using the product from step i) and diethyldisulphide. Yield 2.50g. iii)2-chloro-5-(ethylsulfonyl)-benzonitrile The subtitle compound was prepNed by the method of example 3 step vii) using the product from step ii). Yield 2.10g. 1H NMR CDC13: δ 8.21 (1H, s), 8.06-8.04 (1H, d), 7.76-7.74 (1H, d), 3.18-3.13 (2H, q), 1.34-1. 30 (3H,t). iv)4-chloro-2-[2-cyano-4-(ethylsulfonyl)phenoxy]-benzenepropanoicacid The title compound was prepNed by the method of example 3 step viii) using the product from step iii) and the product from example 35 step ii). 1H NMR DMSO-d6: δ 8.43 (1H, s), 8.09-8.06 (1H, d), 7.50-7.35 (3H, m), 7.05-7.03 (1H, d), 3.41-3.334 (2H, q), 2.75-2.72 (2H, t), 2.54-2.48 (2H, t), 1.17-1.07 (3H, t). MS: ESI (-ve) 392 (M-l) Example 37 N-(4-Chloro-2-{2-chloro-4-[(ethylsulfonyl)amino]phenoxy}phenyl)gIycine (Formula Removed) (i) 4-Chloro-2-(2-chloro-4-nitrophenoxy)aniline A mixture of 2-amino-5-chlorophenol (l.0g), 2-chloro-l-fluoro-4-nitrobenzene (1.5g) and potassium cNbonate (2.8g) in dry DMF (20ml) was stirred room temperature for 1h then heated at 60°C for 2h. The mixture was pNtitioned between water/ethyl acetate, the organics sepNated, washed with water, dried and evaporated under reduced pressure. The residue was purified by chromatography on silica eluting with 10% ethylacetate/isohexane, yield 1,96g. MS: ESI (+ve) 299/301 (ii) Ethyl N-[4-chloro-2-(2-chloro-4-nitrophenoxy)phenyl]glycinate A mixture of the product from step (i) (0.3g), ethyl bromoacetate (0.22ml) and sodium acetate (0.164g) in dry ethanol (5ml) was heated under reflux 7h. Ethyl bromoacetate (0.5ml) and sodium acetate (0.34g) were added and heated for a further 16h. The solvent was evaporated under reduced pressure and the residue purified by chromatography on silica eluting with 5-7% ethylacetate/isohexane, yield 0.212g. 'H NMR CDC13: δ 8.39 (1H, s), 8.07 (1H, d), 7.13 (1H, d), 6.94-6.92 (2H, m), 6.60 (1H, d), 4.63 (1H, brs),4.22 (2H, q), 3.90 (2H, s), 1.28 (3H, t) (iii) Ethyl N- [2-(4-amino-2-chlorophenoxy)-4-chlorophenyl] glycinate A mixture of the product from step (ii) (0.2g) and Pd(OH)2/C (0.04g) in ethanol (4ml) was hydrogenated at 1BN for 5h then filtered. The filtrate was evaporated under reduced pressure and the residue residue purified by chromatography on silica eluting with 20% ethylacetate/ isohexane,. yield 0.13g. 'H NMR CDC13: δ 6.92-6.88 (2H, m), 6.79 (1H, s), 6.57 (1H, d), 6.51-6.46 (2H, m), 4.25 (2H, q), 3.96 (2H, s), 1.29(3H,t) (iv) N-(4-Chloro-2-{2-chloro-4-[(ethylsulfonyl)amino]phenoxy}phenyl)glycine Ethanesulphonyl chloride (0.lml) was added to a mixture of the product from step (iii) (0.11g) and pyridine (0.5ml) in DCM (4ml). After stirring at room temperature for 4h the mixture was pNtitioned between diethylether/2MHCl. The organics sepNated, dried and evaporated under reduced pressure. The residue was dissolved in methanol (5ml) then 2MNaOH added and stirred at room temperature for 20h.The solvent was removed under reduced pressure and the residue pNtitioned between ethylacetate/lMHCl. The organics were sepNated, washed with water, dried and evaporated under reduced pressure. The residue was purified by chromatography on silica eluting with 80% ethylacetate/isohexane, yield 0.025g. MS: APCI (-ve) 417/9 !H NMR DMSO-d6: δ 9.95 (1H, s), 7.38 (1H, d), 7.18 (1H, dd), 7.05-6.98 (2H, m), 6.62-6.58 (2H, m), 3.89 (2H, s), 3.14 (2H, q), 1.21 (3H, t) Example 38 N-[4-Chloro-2-[3-chloro-4-(trifluoromethyl)phenoxy]phenyl}glycine (Formula Removed) (i) 4-Chloro-2-[3-chloro-4-(trifluoromethyl)phenoxy]aniline The subtitle compound was prepNed by the method of example 37 step (i) using 2- chloro-4-fluorobenzotrifluoride. Yield 0.663g. MS: ESI (-ve) 320/322 (ii) Ethyl N- {4-chloro-2-[3-chloro-4-(trifluoromethyl)phenoxy]phenyl} glycinate The subtitle compound was prepNed by the method of example 37 step (ii) using the product from step (i). Yield 0.51g. MS: ESI (-ve) 406/8 (iii) N- {4-Chloro-2-[3-chloro-4-(trifiuoromethyl)phenoxy]phenyl} glycine A mixture of the product from step (ii) (0.5g), methanol (5ml), water (4ml) and 2MNaOH (2ml) were stirred at room temperature for 4h then pNtitioned between ethylacetate/2MHCl. The organics were sepNated, washed with water, dried and evaporated under reduced pressure. The residue was triturated with diethylether/isohexane and filtered, yield 0.1g. MS: ESI (-ve)378/380 1H NMR DMSO-d6: δ 12.62 (1H, s), 7.82 (1H, d), 7.26 (1H, s), 7.17-7.13 (2H, m), 6.99 (1H, d), 6.70 (1H, d), 5.77 (1H, brs), 3.84 (2H, s) Example 39 N-{4-Chloro-2-[4-cyano-2-(trifluoromethyl)phenoxy]phenyl}glycine (Formula Removed) The title compound was prepNed by the method of example 38 MS:APCI(-ve)369 1H NMR DMSO-d6: δ 12.69 (1H, s), 8.35 (1H, s), 8.06 (1H, d), 7.19 (1H, d), 7.07 (1H, s), 6.98 (1H, d), 6.74 (1H, d), 5.53 (1H, s), 3.87 (2H, s) Example 40 N-{4-ChIoro-2-[2-cyano-4-(trifluoromethyl)phenoxy]phenyI}gIycine (Formula Removed) The title compound was prepNed by the method of example 38 MS: APCI (-ve) 369 !H NMR DMSO-d6: δ 12.62 (1H, s), 8.40 (1H, s), 7.94 (1H, d), 7.25 (1H, s), 7.20 (1H, d), 6.85 (1H, d), 6.71 (1H, d), 6.00 (1H, brs), 3.84 (2H, s) Example 41 N-{4-Chloro-2-[4-[(methylsulfonyl)amino]-2-(trifluoromethyl)phenoxy]phenyl}gIycine (Formula Removed) (i) 4-Chloro-2- [4-nitro-2-(trifluoromethyl)phenoxy] aniline The subtitle compound was prepNed by the method of example 37 step (i) using 2-chloro-5-nitrobenzotrifluoride, yield 1.77g MS: ESI (-ve) 331/3 (i)Ethyl N- {4-chloro-2-[4-nitro-2-(trifluoromethyl)phenoxy]phenyl} glycinate The subtitle compound was prepNed by the method of example 37 step (ii), yield 1.44g MS: ESI (+ve) 419/421 (i)Ethyl N-{4-chloro-2-[4-[(methylsulfonyl)amino]-2-(trifluoromethyl)phenoxy] phenyl} glycinate The product from step (ii) (1.4g) and PtO2 (0.25g) in ethylacetate (30ml) was hydrogenated at 2BN for 6h then filtered. The filtrate was evaporated under reduced pressure and the tesidue dissolved in DCM (20ml). Pyridine (5ml) then methanesulphonyl chloride (1ml) was added and stirred at room temperature for 4h. The mixture was pNtitioned between DCM/2MHCL. The organics were sepNated, washed with water, dried and evaporated under reduced pressure. The residue was purified by chromatography on silica eluting with 30% ethylacetate/isohexane, yield 0.64g. MS :APCI (-ve) 467/9 (i)N-{4-Chloro-2-[4-[(methylsulfonyl)amino]-2-(trifluoromethyl)phenoxy] phenyl} glycine The title compound was prepNed by the method of example 38 step (iii) using the product from step (iii). Yield 0.042g. MS: APCI (-ve) 437 !H NMR DMSO-d6: δ 9.94 (1H, s), 7.56 (1H, s), 7.45 (1H, d), 7.08 (1H, d), 7.00 (1H, d), 6.78 (1H, s), 6.67 (1H, d), 5.48 (lH,brs), 3.89 (2H, s), 3.03 (3H, s) Example 42 N-{4-ChIoro-2-[4-[raethyl(methylsulfonyl)ainino]-2-(trifluoromethyl)phenoxy} phenyl} glycine (Formula Removed) A mixture of the compound from example 41 step (iii) (0.43g), potassium cNbonate (Ig), and methyl iodide (0.4ml) in DMF (8ml) was stirred at room temperature for 72h then pNtitioned between ethylacetate/water. The organics were sepNated, washed with water, dried and evaporated under reduced pressure. The residue was dissolved in methanol (8ml) then 2MNaOH (4ml) added and stirred at room temperature for 4h.The solvent was removed under reduced pressure and the residue pNtitioned between ethylacetate/2MHCl. The organics were sepNated, washed with water, dried and evaporated under reduced pressure. The residue was purified by RPHPLC yield 0.092g. MS: APCI (-ve)451 !H NMR CDC13: δ 12.70 (1H, s), 7.76 (1H, s), 7.64 (1H, d), 7.13 (1H, d), 6.95 (1H, d), 6.90 (1H, s), 6.71 (1H, d), 5.51 (1H, s), 3.89 (2H, s), 3.26 (3H, s), 2.99 (3H, s) Example 43 4-chloro-2-[4-(ethylsulfonyl)-2-(trifluoromethyl)phenoxy]-benzenepropanoic acid (Formula Removed) i) 4-(ethylsulfonyl)-1 -fluoro-2-(trifluoromethyl)-benzene The subtitle compound was prepNed by the method of example 36 steps ii-iii) using 4-fluoro-3-(l,l,l-trifluoromethyl)aniline. Yield 1.90g. 1H NMR CDC13: δ 8.21-8.11 (2H, m), 7.46-7.40 (1H, m), 3.19-3.12 (2H, q), 1.34-1.28 (3H, t). ii)4-chloro-2-[4-(ethylsulfonyl)-2-(triiluoromethyl)phenoxy]-benzenepropanoic acid The title compound was prepNed by the method of example 3 step viii) using the product from step i) and the product from example 35 step ii). 1H NMR DMSO-d6: δ 8.18 (1H, s), 8.10 (1H, dd), 7.48 (1H, d), 7.36 (1H, dd), 7.31 (1H, s), 7.10 (1H, d), 3.38 (2H, q), 2.89 (2H, t), 2.51 (2H, t), 1.13 (3H, t). MS: ESI (-ve) 435 (M-l) Example 44 4-chloro-2-[4-(methylsuIfonyl)-2-(trifluoromethyI)phenoxy]-benzenepropanoicacid (Formula Removed) i) 1 -fluoro-4-(methylsulfonyl)-2-(trifluoromethyl)-benzene The subtitle compound was prepNed by the method of example 36 steps ii-iii) using 4-fluoro-3-(l,l,l-trifluoromethyl)aniline and dimethyldisulphide. Yield (2.0g). 1H NMR CDC13: δ 8.26-8.15 (2H, m), 7.46-7.40 (1H, m), 3.06 (3H, s). ii) 4-chloro-2-[4-(methylsulfonyl)-2-(trifluoromethyl)phenoxy]-benzenepropanoic acid The title compound was prepNed by the method of example 3 step viii) using the product from step i) and the product from example 35 step ii). 1H NMRD MSO-d6: δ 12.17 (1H, s), 8.25 (1H, m), 8.16-8.13 (1H, d), 7.49-7.47 (1H, d), 7.38-7.35 (1H, d), 7.28 (1H, s), 7.11-7.09 (1H, d), 3.30 (3H, s), 2.75-2.67 (2H, t), 2.52-2.47 (2H, t). MS: ESI (-ve) 421 (M-l) Example 45 4-fluoro-2-[4-(methylsulfonyl)-2-(trifluoromethyI)phenoxy]-benzenepropanoic acid (Formula Removed) i) 3-(4-fluoro-2-hydroxyphenyl)-(2E)-2-propenoic acid 1,1-dimethylethyl ester The subtitle compound was prepNed by using 2-bromo-5-fluorophenol (5.0g), t-butyl acrylate (3.83ml), triethylamine (7.25ml), Palladium(diphenylphosphinoferrocene) dichloride (1 .0g) in dry DMF. The mixture was heated to 100 C for 5 hours. The mixture was diluted with water, extracted with ethyl acetate, dried and concentrated under reduced pressure to give an oil. Yield 2.98g. MS: ESI (-ve) 237 (M-l) ii) 4-fluoro-2-hydroxy-benzenepropanoic acid- 1,1-dimethylethyl ester A mixture of the product from step (i) (2.98g) and 5% platinium on cNbon (0.30g) in ethyl acetate (30ml) was hydrogenated at a pressure of 3.50 bN overnight. The mixture was filtered through celite and the filtrate concentrated under reduced pressure to give an oil 1H NMR CDC13: δ 8.05 (1H, s), 7.26-7.13 (1H, m), 7.01-6.96(1H, m), 3.06 (1H, s), ), 2.81-2.77 (2H, t), 2.63-2.59 (2H, t), 1.42 (9H, s). iii)4-fluoro-2-[4-(methylsulfonyl)-2-(trifluoromethyl)phenoxy]-benzenepropanoicacid The title compound was prepNed by the method of example 3 step viii) using the product from step ii) and the product from example 44 step i). 1H NMR DMSO-d6: δ 12.15 (1H, s), 8.25 (1H, s), 8.16-8.13 (1H, d), 7.51-7.47 (1H, m), 7.18-7.09 (3H, m), 3.28 (3H, s), 2.74-2.67 (2H, t), 2.52-2.45 (2H, t). MS:ESI(-ve)405(M-l) Example 46 2-[4-(ethyIsulfonyl)-2-(trifluoromethyl)phenoxy]-4-fluoro-benzenepropanoic acid (Formula Removed) The title compound was prepNed by the method of example 45 using the product from example 43 step i). !H NMR DMSO-d6: δ 8.19-8.18 (1H, s), 8.12-8.09 (1H, d), 7.51-7.48 (1H, t), 7.18-7.11 (3H, m), 3.42-3.37 (2H, q), 2.74-2.70 (2H, t), 2.51-2.45 (2H, t), 1.17-1.11 (3H, s). MS: ESI (-ve) 419 (M-l) Example 47 2-[2-cyano-4-(ethylsulfonyl)phenoxy]-4-fluoro-benzenepropanoicacid (Formula Removed) The title compound was prepNed by the method of example 45 using the product from example 36 step i). 1H NMR DMSO-d6: δ 8.44-8.43 (1H, s), 8.09-8.06 (1H, d), 7.52-7.48 (1H; t), 7.26-7.15 (2H, m), 7.07-7.05 (1H, d), 3.41-3.34 (2H, q), 2.75-2.71 (2H, t), 2.52-2.47 (2H, t), 1.14-1.07 (3H, s). MS:ESI(-ve)376(M-l) Example 48 2-[2-cyano-4-(methyIsulfonyI)phenoxy]-4-fluoro-benzenepropanoicacid (Formula Removed) i) 2-chloro-5-(methylsulfonyl)- benzonitrile. The subtitle compound was prepNed using the method of example 36 steps i-iii) using dimethyldisulphide. Yield 2.0g 1H NMR CDC13: δ 8.26 (1H, s), 8.11-8.08 (1H, d), 7.77-.775 (1H, d), 3.10 (3H, s). ii)2-[2-cyano-4-(methylsulfonyl)phenoxy]-4-fluoro-benzenepropanoicacid. The title compound was prepNed by the method of example 45 using the product from step i). 1H NMR DMSO-d6: δ 8.49 (1H, s), 8.13-8.10 (1H, d), 7.52-7.47 (1H, t), 7.23-7.14 (2H, m), 7.04-7.01 (1H, d), 3.28 (3H, s), 2.72-2.67 (2H, t), 2.42-2.37 (2H, t). MS:ESI(-ve)362(M-l) Example 49 4-chloro-2-[[2-chloro-4-(methylsulfonyl)phenyl]amino]-benzenepropanoic acid (Formula Removed) i) 3-(4-chloro-2-nitrophenyl)-(2E)-2-propenoic acid ethyl ester l-bromo-4-chloro-2-nitrobenzene (5g), triethylamine (4.42ml), ethyl acrylate (22.9ml), palladium (II) acetate (0.048g) and triphenylphosphine (0.111g) in DMF (30ml) was refluxed at 87°C for lOh. Toluene was added and the mixture washed with 2M hydrochloric acid and water. The organics were dried and concentrated under reduced pressure to a brown oil which was triturated with isohexane to give a light brown solid. Yield 4.95g. 1H NMR CDC13: δ 8.07-8.02 (2H, m), 7.68-7.47 (2H, m), 6.39-6.33 (1H, d), 4.33- 4.26 (2H, q) 1.37-1.32 (3H,t) ii) 7-chloro-3,4-d1Hydro-2(lH)-quinolinone. A mixture of the product from step (i) (4.95g) and 5% platinum on cNbon (0.400g) and a few drops of 2M hydrochloric acid in ethyl acetate (30ml) was hydrogenated under a pressure of 3 bN. The catalyst was removed by filtration through celite and the filtrate was evaporated under reduced pressure to a brown solid, which was triturated with diethyl ether to give a pink solid. Yield 1.28g 1H NMR DMSO-d6: δ 10.17 (1H, s), 7.20-7.18 (1H, d), 6.96-6.93 (1H, d), 6.87 (1H, s), 2.87-2.84 (2H, t), 2.47-2.44 (2H, t) iii) 4-chloro-2-[[2-chloro-4-(methylsulfonyl)phenyl]amino]-benzenepropanoic acid. A solution of the product from step (ii) (0.174g) and sodium hydride (60% wt. disp. oil, 0.039g) in DMF (10ml) was stirred at 50°C for 1 hour. The product from example 3 step (vi)-(vii) (0.200g) was added and the mixture was refluxed at 90°C for 3 hours. The mixture was pNtitioned between 2M sodium hydroxide and diethyl ether. The aqueous layer was acidified with 2M hydrochloric acid, extracted with ethyl acetate and the organic layer dried and concentrated under reduced pressure to give an oil. The residue was purified using RP prep HPLC. Yield 0.061g 1H NMRDMSO-d6: δ 8.34 (1H, s), 7.86 (1H, s), 7.62-7.59 (1H, d), 7.42-7.40 (1H, d), 7.32-7.27 (2H, m), 6.64-6.62 (1H, d), 3.17 (3H, s), 2.74-2.69 (2H, t), 2.54-2.50 (2H, t) MS: ESI (-ve) 386 (M-l) Example 50 4-chloro-2-[[2-chloro-4-(ethylsulfonyl)phenyl]amino]-benzenepropanoic acid (Formula Removed) A solution of the product from example 49 step (iii) (0.163g) and the product of example 4 step (i) (0.200g) and caesium cNbonate (0.239g) in NMP (10ml) was refluxed at 100°C for 3 hours. The mixture was pNtitioned between 2M sodium hydroxide and diethyl ether. The aqueous layer was acidified with 2M hydrochloric acid, extracted with ethyl acetate and the organic layer dried and concentrated under reduced pressure to give an oil. The residue was purified using RP prep HPLC. Yield 0.044g. 1H NMR DMSO-d6: δ 8.40 (1H, s), 7.79 (1H, s), 7.58-7.54 (1H, d), 7.42-7.39 (1H, d), 7.32-7.29 (2H, m), 6.65-6.62 (1H, d), 3.31-3.20 (4H, m), 2.73-2.69 (2H, t), 1.21-1.07 (3H, q) MS: ESI (-ve) 400 (M-l) Example 51 4-chloro-2-[[2-chloro-4-(methylsulfonyl)phenyl]amino]-benzenepropanoic acid (Formula Removed) The title compound was prepNed using the method of example 49 using the product from example 44 step i). 1H NMRDMSO-d6: δ 12.40 (1H, s), 8.28 (1H, s), 7.97 (1H, m), 7.84-7.82 (1H, d), 7.45-7.31 (3H, m), 6.64-6.62 (1H, d), 3.18 (3H, s), 2.70-2.67 (2H, t), 2.54-2.50 (2H, t) MS: ESI (-ve) 420 (M-l) Example 52 4-chloro-2-[[2-chIoro-4-(ethylsulfonyl)phenyI]amino]-benzenepropanoic acid (Formula Removed) The title compound was prepNed using the method of example 49 using the product from example 43 step i). 1H NMRDMSO-d6: δ 8.54 (1H, bs), 7.90 (1H, s), 7.79-7.77 (1H, d), 7.44-7.32 (3H, m), 6.67-6.65 (1H, d), 3.28-3.22 (2H, q), 2.68-2.65 (2H, t), 2.51-2.47 (2H, t), 1.11-1.08 (3H, t). MS: ESI (-ve) 434 (M-l) Example 53 4-chloro-2-[4-(methylsulfonyl)-2-(trifluoromethyl)phenoxy]-benzeneaceticacid (Formula Removed) i) 4-chloro-2-methoxy-benzeneacetic acid A solution of 4-chloro-2-methoxy-benzyl alcohol (4g) and thionyl chloride (10ml) in dichloromethane (30ml) was refluxed for 1H. The solution was concentrated under reduced pressure and the residue pNtitioned between diethyl ether and water. The organics were dried and evaporated under reduced pressure. This residue and sodium cyanide (1g) in DMF (20ml) was stirred at room temperature for 3h. The mixture was pNtitioned between diethyl ether and water, the organics were dried and evaporated under reduced pressure. A solution of potassium hydroxide was added to the residue and the mixture heated under reflux for 24h. The mixture was pNtitioned between diethyl ether and water, the aqueous layer was acidified with 2M hydrochloric acid and extracted with ethyl acetate. The organic layer was dried and evaporated under reduced pressure. The residue was triturated with diethyl ether and isohexane. Yield 1.4g. 1H NMR CDC13: δ 7.11 (1H, d), 6.92 (1H, d), 6.87 (1H, s), 3.82 (3H, s), 3.62 (2H, s) ii) 4-chloro-2-hydroxy-benzeneacetic acid 4-chloro-2-methoxy-benzeneacetic acid (1.4g), HBr (25ml), acetic acid (5ml) were refluxed for 48h then evaporated under reduced pressure. The residue was azeotroped with toluene and triturated with diethyl ether and isohexane. Yield 0.56g. 1H NMR CDC13: δ 7.12 (1H, d), 6.81-6.76 (2H, m), 3.45 (2H, s) iii)4-chloro-2-[4-(methylsulfonyl)-2-(trifluoromethyl)phenoxy]-benzeneaceticacid A solution of the product from step (ii) (0.125g), the product of example 44 step (i) (0.150g) and cesium cNbonate (0.437g) inNMP (10ml) was stirred at 80°C for 10h. The mixture was pNtitioned between 2M sodium hydroxide and diethyl ether. The aqueous layer was acidified with 2M hydrochloric acid, extracted with ethyl acetate and the organic layer dried and evaporated under reduced pressure. The residue was purified using RP prep HPLC. Yield 0.025g. 1H NMRDMSO-d6: δ 12.39 (1H, br.s), 8.23 (1H, s), 8.16-8.14 (1H, d), 7.52-7.50 (1H, d), 7.39-7.37 (1H, d), 7.31 (1H, s), 7.14-7.12 (1H, d), 3.58 (2H, s), 3.30 (3H, s) MS: ESI (-ve) 407 (M-l) Example 54 4-chloro-2-[[4-(methylsulfonyl)-2-(trifluoromethyI)phenyl]thio]-benzenepropanoic acid (Formula Removed) i) 4-chloro-2-(methylthio)-benzaldehyde The subtitle compound was prepNed by using 2-chloro-4-fluorobezaldehyde (1.15 g) in dry DMF (20ml). The mixture was treated with sodium thiomethoxide (0.52g) and heated to 50°C for 2 hours. The mixture was diluted with water, extracted with ethyl acetate, dried and concentrated under reduced pressure to give a solid. The residue was purified by chromatography on silica eluting with isohexane/diethylether 2:1 to give a white solid, yield 0.70g. 1H NMR CDC13: δ 10.19 (1H, s), 7.74-7.72 (1H, d), 7.28-7.23 (2H, m), 2.50-2.49 (3H, s). ii) 3-[4-chloro-2-(methylthio)phenyl]-(2E)-2-propenoic acid ethyl ester The subtitle compound was prepNed from the method of example 3 step iv) using the product from step i). Yield 0.95g. MS: ESI (+ve) 257 (M+l) iii) 4-chloro-2-mercapto-benzenepropanoic acid. The subtitle compound was prepNed by using the product from step ii) (0.7g) which was dissolved in DCM (30ml) and cooled to 0°C before adding 70% m-CPBA (0.46g). The mixture was kept at 0 C for 2 hours, washed with a solution of sodium hydrogen cNbonate, dried and concentrated under reduced pressure to an oil. The oil was dissolved in DCM (10ml) and cooled to 0°C before adding trifluoroacetic anhydride (0.40ml). The mixture was stirred at room temperature overnight. The mixture was concentrated under reduced pressure to an oil and dissolved in ethanol (10ml). Triethylamine (10ml) was added and the mixture stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure to an oil which was dissolved in diethyl ether, washed with aqueous sodium hydroxide. The aqueous layer was acidified with 2M HC1, extracted with ethyl acetate, dried and concentrated under reduced pressure to give a white solid. Yield 0.26g. 1H NMR DMSO-d6: δ 7.35-7.11 (3H, m), 5.69 (1H, s), 2.80-2.74 (2H, t), 2.54-2.50 (2H, t). MS:ESI(-ve)215(M-l) iv)4-chloro-2-[[4-(methylsulfonyl)-2-(trifluoromethyl)phenyl]thio]-benzenepropNioic acid. Sodium hydride (60% wt disp. oil, 0.063g) was added to a solution of the product from step (iii) (0.180g) in dry DMF (10ml) and stirred at RT for 1H before adding the product from example 44 step (i) (0.188g). The mixture was heated at 80°C for In, then pNtitioned between 2M hydrochloric acid/ethyl acetate. The organics were dried, concentrated under reduced pressure to give an oil. The residue was purified by reverse phase HPLC. 1H NMRDMSO-d6: δ 8.20-8.19 (1H, s), 8.03-8.00 (1H, d), 7.63-7.54 (3H, m), 7.08-7.05 (1H, d), 3.16 (3H, s), 2.90-2.86 (2H, t), 2.49-2.47 (2H, t). MS: ESI (-ve) 437 (M-l) Example 55 4-chloro-2-[2-fluoro-4-(methylsulfonyl)phenoxy]-beozenepropanoicacid (Formula Removed) The title compound was prepNed by the method of example 35 step iii) using 3,4-difluorophenylmethylsulphone and the product of example 35 step ii). 1H NMR DMSO-d6: δ 8.00-7.97 (1H, d), 7.75-7.72 (1H, d), 7.44-7.42 (1H, d), 7.29-7.26 (1H, d), 7.19-7.12 (2H, m)5 3.26 (3H, s), 2.80-2.69 (2H, t), 2.50-2.45 (2H, t). MS: ESI (-ve) 371 (M-l) Example 56 4-chloro-2-[2-chloro-4-(methylsulfonyl)phenoxy]-benzenepropanoic acid (Formula Removed) The title compound was prepNed by the method of example 35 step iii) using the products from example 3 step vii) and example 35 step ii). 1H NMR DMSO-d6: δ 8.14 (1H, s), 7.86-7.83 (1H, d), 7.46-7.44 (1H, d), 7.32-7.29 (1H, d), 7.13-7.07 (2H, m), 3.33-3.27 (5H, m), 2.75-2.73 (2H, t). MS: ESI (-ve) 386 (M-l) PhNmacological Data Ligand Binding Assay [3H]PGD2 was purchased from Perkin Elmer Life Sciences with a specific activity of 100-210Ci/mmol. All other chemicals were of analytical grade. HEK cells expressing rhCRTh2 / Gccl6 were routinely maintained in DMEM containing 10% Foetal Bovine Serum (HyClone), Img/ml geneticin, 2mM L-glutamine and 1% non-essential amino acids. For the prepNation of membranes, the adherent transfected HEKcells were grown to confluence in two layer tissue culture factories (Fisher, catalogue number TKT-170-070E). Maximal levels of receptor expression were induced by addition of 500mM sodium butyrate for the last 18 hours of culture. The adherent cells were washed once with phosphate buffered saline (PBS, 50ml per cell factory) and detached by the addition of 50ml per cell factory of ice-cold membrane homogenisation buffer [20mM HEPES (pH 7.4), 0.1mM dithiothreitol, ImM EDTA, 0.lmM phenyl methyl sulphonyl fluoride and 100µg/ml bacitracin]. Cells were pelleted by centrifugation at 220xg for 10 minutes at 4°C, re-suspended in half the original volume of fresh membrane homogenisation buffer and disrupted using a Pblytron homogeniser for 2 x 20 second bursts keeping the tube in ice at all tunes. Unbroken cells were removed by centrifugation at 220xg for 10 minutes at 4°C and the membrane fraction pelleted by centrifugation at 90000xg for 30 minutes at 4°C, The final pellet was re-suspended in 4 ml of membrane homogenisation buffer per cell factory used and the protein content determined. Membranes were stored at -80°C in suitable aliquots. All assays were performed in Coming cleN bottomed, white 96-well NBS plates (Fisher). Prior to assay, the HEK cells membranes containing CRTh2 were coated onto SPA PYT WGA beads (Amersham). For coating membranes were incubated with beads at typically 25µg membrane protein per mg beads at 4°C with constant agitation overnight. (The optimum coating concentrations were determined for each batch of membranes) The beads were pelleted by centrifugation (800xg for 7minutes at 4°C), washed once with assay buffer (50mM HEPES pH 7.4 containing 5mM magnesium chloride) and finally re-suspended in assay buffer at a bead concentration of 10mg/ml. Each assay contained 20µl of 6.25nM [3H]PGD2, 20µl membrane saturated SPA b eads both in assay buffer and 10µl of compound solution or 13,14-d1Hydro-15-keto prostaglandin D2 (DK-PGD2, for determination of non-specific binding, Cayman chemical company). Compounds and DK-PGD2 were dissolved in DMSO and diluted in the same solvent to 100x the required final concentration. Assay buffer was added to give a final concentration of 10% DMSO (compounds were now at 10x the required final concentration) and this was the solution added to the assay plate. The assay plate was incubated at room temperature for 2 hours and counted on a Wallac Microbeta liquid scintillation counter (1 minute per well). Compounds of formula (I) have an IC50 value of less than ( Specifically, example 5 has a pIC50 = 8.6, example 7 has apICso = 9.1 and example 37 has a = 8.6. We Claim: 1. A substituted phenoxy compound of formula (I) or a pharmaceutically acceptable salt thereof: (Formula Removed) in which: T is a bond, CH2 or NH; W is O; X is trifluoromethyl or halogen; Y is hydrogen; Z is aryl substituted by two substituents, one of which is SO2R9 where R9 is selected from methyl or ethyl, and the other is halogen or trifluoromethyl; and R1 and R2 are both hydrogen. 2. A compound as claimed in claim 1 selected from: 3-[2-[2-Chloro-4-(methylsulfonyl)phenoxy]-4-(trifluoromethyl)phenyl|propanoic acid; 3 - [2- [ 2-Chloro-4-(ethylsulfonyl)phenoxy] -4-(trifluoromethy 1 )phenyl] propanoic acid; N-{4-Chloro-2-[2-chloro-4-(ethylsulfonyl)phenoxy]phenyl} glycine; 3-{2-[2-Chloro-4-(methylsulfonyl)phenoxy]-4-fluorophenyl}propanoic acid; {2-[2-Chloro-4-(methylsulfonyl)phenoxy]-4-fluorophenyl}acetic acid; N-[2-[2-chloro-4-(methylsulfonyl)phenoxy]-4-fluorophenyl]-glycine; N-[2-[2-chloro-4-(ethylsulfonyl)phenoxy]-4-fluorophenyl]-glycine; N-[4-chloro-2-[2-chloro-4-(methylsulfonyl)phenoxy]phenyl]-glycinc; 2-[2-chloro-4-(ethylsulfonyl)phenoxyJ-4-fluoro-benzenepropanoic acid; 2- [4-(methylsulfonyl)-3 -(trifluoromethyl)phenoxy] -4-fluoro-benzenepropanoic acid; 2-[4-(ethylsulfonyl)-3-(trifluoromethyl)phenoxy]-4-fluoro-benzenepropanoic acid; N-[4-chloro-2-[4-(ethylsulfonyl)-3-(trifluoromethyl)phenoxy]phenyl]-glycine; N-[2-[2-chloro-4-(ethylsulfonyl)phenoxy]-4-(trifluoromethyl)phenyl]-glycinc; N-[2-[4-(ethylsulfonyl)-3-(trifluoromethyl)phenoxy]-4-(trifluoromethyl)phenyl|- glycine; 4-chloro-2-[2-chloro-4-(ethylsulfonyl)phenoxy]-benzenepropanoic acid; 4-chloro-2-[4-(ethylsulfonyl)-2-(trifluoromethyl)phenoxy]-benzenepropanoic acid; 4-chloro-2-[4-(methylsulfonyl)-2-(trifluoromethyl)phenoxy]-benzenepropanoic acid; 4-fluoro-2-[4-(methylsulfonyl)-2-(trifluoromethyl)phenoxy]-benzenepropanoic acid; 2-[4-(ethylsulfonyl)-2-(trifluoromethyl)phenoxy]-4-fluoro-benzenepropanoic acid; 4-chloro-2-[4-(methylsulfonyl)-2-(trifluoromethyl)phenoxy]-benzeneacetic acid; 4-chloro-2-[2-fluoro-4-(methylsulfonyl)phenoxy]-benzenepropanoic acid; 4-chloro-2-[2-chloro-4-(methylsulfonyl)phenoxy]-benzenepropanoic acid; and pharmaceutically acceptable salts thereof. 3. A process for the preparation of a compound of formula (I) as claimed in claim 1 which comprises reaction of a compound of formula (II): (Formula Removed) in which T = NH and W, X, Y and Z are as defined in formula (I) or are protected derivatives thereof, with a compound of formula (III): (Formula Removed) Where R1 and R2 are as defined in formula (I) or are protected derivatives thereof. R14 is H or C1-C10 alkyl group and L is a leaving group, and optionally thereafter in any order: • removing any protecting group • hydrolysing the ester group R14 to the corresponding acid • oxidation of sulphides to sulphoxides or sulphones • forming a pharmaceutically acceptable salt.

Documents:

7932-DELNP-2006-Abstract-(15-06-2012).pdf

7932-delnp-2006-abstract.pdf

7932-DELNP-2006-Claims-(15-06-2012).pdf

7932-delnp-2006-claims.pdf

7932-delnp-2006-Correspondence Others-(15-06-2012).pdf

7932-DELNP-2006-Correspondence-Others.pdf

7932-DELNP-2006-Description (Complete).pdf

7932-delnp-2006-Form-1-(15-06-2012).pdf

7932-delnp-2006-form-1.pdf

7932-delnp-2006-Form-2-(15-06-2012).pdf

7932-delnp-2006-form-2.pdf

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7932-delnp-2006-Form-3-(15-06-2012).pdf

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7932-delnp-2006-form-5.pdf

7932-delnp-2006-GPA-(15-06-2012).pdf

7932-delnp-2006-pct-304.pdf

7932-delnp-2006-pct-search report.pdf

7932-delnp-2006-Petition-137-(15-06-2012).pdf