| Title of Invention | THIAZOLE DERIVATIVES |
|---|---|
| Abstract | The present invention provides compounds of formula (I). These compounds are used for the treatment of PPAR rclated diseases. |
| Full Text | THIAZOLE DERIVATIVES The present invention refates to certain novel compounds. In particular, the present invention relates to compounds that activate human peroxisome proliferator activated receptors ("hPPARs"). The present invention also relates to method for preparing the compounds, their use in medicine, pharmaceutical compositions containing them and methods for the prevention or treatment of PPAR mediated diseases or conditions. Several independent risk factors have been associated with cardiovascular disease. These include hypertension, increased fibrinogen levels, high levels of triglycerides, elevated LDL cholesterol, elevated total cholesterol, and low levels of HDL cholesterol. HMG CoA reductase inhibitors ("statins") are useful for treating conditions characterized by high LDL-c levels. It has been shown that lowering LDL-c is not sufficient for reducing the risk of cardiovascular disease in some patients, particularly those with normal LDL-c levels. This population pool is identified by the independent risk factor of low HDL-c. The increased risk of cardiovascular disease associated with low HDL-c levels has not yet been successfully addressed by drug therapy (i.e. currently there are no drugs on the market that are useful for raising HDL-c'.. (Bisgaier, C. L.; Pape, M. E. Curr. Pharm. Des. 1998, 4, 53-70). Syndrome X (including metabolic syndrome) is loosely defined as a collection of abnormalities including hyperinsulemta, obesity, elevated levels of triglycerides, uric acid, fibrinogen, small dense LDL particles, and plasminogen activator inhibitor 1 (PAI-1), and decreased levels of HDL-C;. NIDDM is described as insulin resistance, which in turn causes anomalous glucose output and a decrease in glucose uptake, by skeletal muscle. These factors eventually lead to impaired glucose tolerance (IGT) and hyperinsuiinemia. Peroxisome Proliferator Activated Receptors (PPARs) are orphan receptors belonging to the steroid/retinoid receptor superfamily of ligand-activated transcription factors. See, for example Willson T.M. and Wahli, W., Curr. Opin. Chem. BioL, 1, pp235-241 (1997) and Willson T.M. et. al., J. Med. Chem., 43, p527-549 (2000). The binding of agonist ligands to the receptor results in changes in the expression level of MRNA's enclded by PPAR target genes. Three mammalian Peroxisome Proliferator-Activated Receptors have been isolated and termed PPAR-alpha, PPAR-gamma, and PPAR-delta (also known as NUC1 or PPAR-beta). These PPARs regulate expression of target genes by binding to DNA sequence elements, termed PPAR response elements (PPRE). To date, PPRE's have been identified in the enhancers of a number of genes encoding proteins that regulate lipid metabolism suggesting that PPARs play a pivotal role in the adipogenic signalling cascade and lipid homeostasis (H. Keller and W. Wahli, Trends Endocrinol. Metab 291-296, 4 (1993)). 2 It has now been reported that thiazolidinediones are potent and selective activators of PPAR-gamma and bind directly to the PPAR-gamma receptor (J. M. Lehmann et. a!., J. Biol. Chem. 12953-12956, 270 (1995)), providing evidence that PPAR-gamma is a possible target for the therapeutic actions of the thiazolidtnediones. Activators of the nuclear receptor PPARy, for example troglitazone, have been shown in the clinic to enhance insulin-action, reduce serum glucose and have small but significant effects on reducing serum triglyceride levels in patients with Type 2 diabetes. See, for example, D. E. Kelly et a!., Curr. Opin. Endocrinol. Diabetes, 90-96, 5 (2), (1998); M. D. Johnson et a!., Ann. Pharmacother., 337-348, 32 (3), (1997); and M. Leutenegger etal., Curr. Then Res., 403-416, 58 (7), (1997). The mechanism for this triglyceride lowering effect appears to be predominantly increased clearance of very low density lipoproteins (VLDL) through induction of lipoprotein lip'ase (LPL) gene expression. See, for example, B. Staels et al., Arierioscler. Thromb., Vase. Biol., 1756-1764, 17(9), (1997). Fibrates are a class of drugs which may lower serum triglycerides 20-50%, lower LDLc 10-15%, shift the LDL particle size from the more atherogenic small dense to normal dense LDL, and increase HDLc 10-15%. Experimental evidence indicates that the effects of fibrates on serum lipids are mediated through activation of PPARcx. See, for example, B. Staels et a!., Curr. Pharm. Des., 1-14, 3 (1), (1997). Activation of PPARoc results in transcription of enzymes that increase fatty acid catabolism and decrease de-novo fatty acid synthesis in the liver resulting in decreased triglyceride synthesis and VLDL production/secretion. In addition, PPARa activation decreases production of apoC-III. Reduction in apoC-lll, an inhibitor of LPL activity, increases clearance of VLDL. See, for example, J. Auwerx et al., Atherosclerosis, (Shannon, Irel.), S29-S37,124 (Suppl), (1996). Certain compounds that activate or otherwise interact with one or more of the PPARs have been implicated in the regulation of triglyceride and cholesterol levels in animal models. See, for example, U.S. Patents 5,847,008 (Doebber et al.) and 5,859,051 (Adams et al.) and PCT publications WO 97/28149 (Leibowitz et al.) and WO99/04815 (Shimokawa et al.). In a recent report (Berger et al., J. Biol. Chem. 1999), vol. 274, pp. 6718-6725) it was stated that PPARS activation does not appear to modulate glucose or triglyceride levels. Accordingly the invention provides a compound of formula 1 and pharmaceutically acceptable salts and solvates and hydrolysable esters thereof. 3 (1) wherein: R1 and R2 are independently H or C1-3 alkyl, or R1 and R2 may together with the carbon atom to which they are bonded form a 3-6 membered cycloalkyl ring, and at least one of R1 and R2 must be other than H; X2 is O, S, or (CRl0R11)n where n is 1 or 2 and R10 and R11 are independently-H, fluorine, or Chalky!; R3, R4, and R5 are independently H, C1-3alkyl, OCH3l CF3, ailyl, or halogen. one of Y and 2 is N, the other is S or O; R6 and R7 are independently H, phenyl, benzyl, fluorine, OH, d-e alkyl, allyl, or R6 and R7 may together with the carbon atom to which they are bonded form a carbonyl group; R9 is H, CF3l or Chalky!; Each R8 is independently CF3, Chalky!, OCH3, or halogen; yisO, 1,2, 3,4, or 5. In another aspect, the present invention discloses a method for prevention or treatment of a disease or condition mediated by one or more human PPAR alpha, gamma or delta ("hPPARs") comprising administration of a therapeutically effective amount of a compound of this invention. hPPAR mediated diseases or conditions include dyslipidemia including associated diabetic dyslipidemia and mixed dyslipidemia, syndrome X (as defined in this application this embraces metabolic syndrome), heart failure, hypercholesteremia, cardiovascular disease including atherosclerosis, arteriosclerosis, and hypertriglyceridemia, type II diabetes mellitus, type ! diabetes, insulin resistance, hyperlipidemia, inflammation, epithelial hyperproliferative diseases including eczema and psoriasis and conditions associated with the lung and gut and regulation of appetite and food intake in subjects suffering from disorders such as obesity, anorexia bulimia, and anorexia nervosa. In particular, the compounds of this invention are useful in the treatment and prevention of diabetes and cardiovascular diseases and conditions including atherosclerosis, arteriosclerosis, hypertriglyceridemia, and mixed dyslipidaemia. In another aspect, the present invention provides pharmaceutical compositions comprising a compound of the invention, preferably in association with a pharmaceuticaily acceptable diluent or carrier. 4 In another aspect, the present invention provides a compound of the invention for use in therapy, and in particular, in human medicine. In another aspect, the present invention provides the use of a compound of the invention for the manufacture of a medicament for the treatment of a hPPAR mediated disease or condition. As used herein, "a compound of the invention" means a compound of formula (I) or a pharmaceutically acceptable salt, or solvate, or hydrolysable ester thereof. While hydrolyzable esters are included in the scope of this invention, the acids are preferred because the data suggests that while the esters are useful compounds, it may actually be the acids to which they hydrolyse that are the active compounds. Esters that hydrolyse readily can produce the carboxylic acid in the assay conditions or in vivo. Generally the carboxylic acid is active in both the binding and transient transfection assays, while the ester does not usually bind weil but is active in the transient transfection assay presumably due to hydrolysis. Preferred hydrolysable esters are C^ alkyl esters wherein the alkyl group may be straight chain or branched chain. Methyl or ethyl esters are more preferred. Preferably at least one of R1 and R2 is CH3- More preferably R1 and R2 are both CH3; Preferably X2 is O, S, or C(R10R11). Most preferably X2 is O or S; Preferably R3 is CH3; Preferably R4 and R5 are independently H or methyl; Preferably Z is N; Preferably Y is S. Preferably R10 and R11 are H; Preferably R9 is CH3. Preferably R6 is H, CH3iCH2CH3 or allyl, Most preferably R6 is H, CH3, or CH2CH3. Preferably R7 is H. Preferably each R8 is independently F or CF3. Preferably y is 1 or 2. When y is 2, preferably one of the substituents is halogen and the other is CF3. When y is 1, preferably the substituent is in the para position on the ring. White the preferred groups for each variable have generally been listed above separately for each variable, preferred compounds of this invention include those in which several or each variable'iri Formula (I) is selected from the preferred, more preferred, or most preferred groups for each variable. Therefore, this invention is intended to include all combinations of preferred and most preferred groups. Preferred compounds of formula 1 include: 2-{4-[({2-[2-fluoro-4-(trifluoromethyi)phenyl]-4-methyl-1,3-thiazol-5-yl}methyl)sulfanyI]-2- methylphenoxy}-2-methylpropanoicacid 2-methyl-2-(2-methyl-4-{1-[4-methyl-2-(4-trifluoromethylphenyl)thiazol-5-yl]ethoxy}phenoxy)propionic acid ethyl ester 5 2-methyl-2-(2-methyl-4-{1-[4-methyl-2-(4-trifIuoromethylphenyl)thiazol-5-yl]propoxy}phenoxy)propionic acid ethyl ester 2-methyl-2-(2-methyl-4-{1-[4-methy!-2-(4-trifluoromethylphenyl)thiazol-5-yl]but-3-enyloxy}phenoxy)propionic acid ethyl ester 2-methyl-2-(2-methyl-4-{1-[4-methyl-2-(4-trifluoromethylphenyl)-thiazol"5-y!]phenylmethoxy}phenoxy)propionic acid ethyl ester (2-methyl-4- {1-[4-methyl-2- (4-trifiuoromethylphenyl)-thiazol-5-yl] ethoxyj-phenoxy)-acetic acid ethyl ester 2-methyl-2- (2-methyl-4- {1-[4-methy|-2- (3-Fluoro-4-trifluoromethylphenyl)-thiazol-5-yl] ethoxy}-phenoxy)-propionic acid ethyl ester (S)-2-methyI-2- (2-methyl-4- {1-[4-methyl-2- (4-trifluoromethylphenyI)-thiazo!-5-yO ethoxy}-phenoxy)-propionic acid ethyl ester (R)-2-methyl-2- (2-methyl-4- {1-[4-methyl-2- (4-trifIuoromethylphenyl)-thiazol-5-yl] ethoxy}-phenoxy)-propionic acid ethyl ester 2-(4-{1-[2~(4-chloro-phenyl)-4-methyl-thiazol-5-y(]-ethoxy}-2-methyl-phenoxy)-2-rnethyl-propionic acid ethyl ester 2-(4-{1-[2-(3,4-dtchloro-phenyl)-4-methyi-thiazol-5-yl3-ethoxy}-2-methyl-phenoxy)-2-methyl-propionic acid ethyl ester 2-(4-{1-[2-(4-ethyI-phenyl)-4-methyl-thiazol-5-yi]-ethoxy}-2-methyl-phenoxy)-2-methyi-propionic acid ethyl ester 2-(4-{1-[2-(2-fluorc-4-trifluoromethyl-phenyl)-4-methyl-thiazol-5-yI]-ethoxy}-2~methyl- phenoxy)-2-methyl-propionic acid ethyl ester 2-methyl-2-(2-methyU-{1-[2-(4-trifluoromethyl-phenyl)-thiazot-5-yl]-ethoxy}-phenoxy)- propionic acid ethyl ester 2-memyl-2-(2-methyl-4-{1-methyl-1-[4-rTiethyl-2-(4-trifluorornethyl-phenylHhiazol-5-yl]- ethoxy}-phenoxy)-propionic acid ethyl ester 2-rnethyl-2-(2-methyl-4-{1-rnethyl-1-[2-(4-trifluoromethyl-phenyl)-thiazol-5-yI]-ethoxy}- phenoxy)-propionic acid ethyl ester (R)-2-methyl-2- (2-methyl-4- {1-[4-methyt-2- (4-trifiuoromethyl-phenyl)-thiazol-5-yl] propoxy}-phenoxy)-propidnic acid ethyl ester (S)-2-methyl-2- (2-methyl-4- {1-[4-methyl-2- (4-trifluoromethyl-phenyl)-thiazol-5-yl] propoxy}-phenoxy)-propionic acid ethyl ester 2-methyl-2- (2-methyl-4- {1-[4-methy!-2- (4-trifluoromethyl-phenyl)-thiazo!-5-yl] butoxy}-phenoxy)-propionic acid ethyl ester 2-methyH2-methyl-2- (2-methyl-4- {1-[4-methyl-2- (4-trifluoromethyl-phenyl)-thiazol-5-yl]-propoxy}-phenoxy)}-propionic acid ethyl ester 6 2-methyl-2- (2-methyl-4- {1-[4-methyl-2- (4-trifluoromethyl-phenyl)-thiazof-5-yl] pentyloxy}-phenoxy)-propionic acid ethyl ester 2-(4-{cyclopentyl-[4-rnethyl-2-(4-trifluoromethyl-phenyI)-thiazol-5-yl]-methoxy}-2-methyl-phenoxy)-2-methyl-propionic acid ethyl ester 2-methyl-2-(2-methyl-4-[4-methyl-2-(4-trifluoromethylphenyl)thiazo!-5-yl-methoxy]phenoxy)propionic acid ethyl ester 2-methyl-2-(2-methyl-4-{1-[4-methyl-2-(4-trifluoromethyl-phenyl)-thia2ol-5-yl]-2-phenyl-ethoxy}-phenoxy)-prop ionic acid ethyl ester 2-methyl-2-(2-methy!-4-{1-[4-methyl-2-(4-trif)uoromethyl-phenyI)-thia2o[-S-yl]-ethylsulfanyl}-phenoxy)-propionic acid ethyl ester 2-methyl-2-(2-methyl-4-{1-[2-(4-trif!uoromethyi-phenyl)-thiazol-5-yl]-ethylsulfanyl}-phenoxy)-propionic acid ethyl ester 2-methyl-2-(2-nnethyl-4-{1-nnethyl-1-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yr|-ethylsulfanyl}-phenoxy)-propionic acid ethyl ester 2-methyl-2-(2-methyl-4-{1-methyl-1-[2-(4-trif]uoromethyl-phenyl)-th'a2ol-5-yl]-ethylsulfanyl}-phenoxy)-propionic acid eOiyl ester 2-methy!-2-(2-methyl-4-{1-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-propylsu!fanyl}-phenoxy)-propionic acid ethyl ester 2-methyl-2-(2-methyl-4-{1-[4-methyl-2-(4-trifluoromethylphenyl)-thiazol-5-yl]phenylmethoxy}phenoxy)propionicacid 2-methyl-2-(2-methyl-4-{1-[4-methyl-2-(4-trifluoromethylphenyl)thia2ol-5-yl]ethoxy}phenoxy)propionic acid 2-methyl-2-{2-methyl-4-{1-[4-methyl-2-{4-trifluoromethylphenyl)thia2ol-5-yl]propoxy}phenoxy)propionic acid 2-methyl-2-(2-methyl-4-{1-[4-methyl-2-(4-trif!uoromethylphenylHhiazol-5-yl]but-3-enyloxy}phenoxy)propionic acid (2-methyl-4- {1-[4-methyl-2- (4-trifluoromethylphenyl)-thiazol-5-yt] ethoxy}-phenoxy)-acetic acid 2-methyl-2- (2-methyl-4- {1-[4-methyl-2- (3-F!uoro-4-trifluoromethylphenyl)-thiazol-5-yl] ethoxy}-phenoxy)-propionic acid (S)-2-methyl-2- (2-methyl-4- {1-[4-methyl-2- (4-tr'rfluoromethylphenyl)-thiazo!-5-yl] ethoxy}-phenoxy)-propionic acid (R)-2-methyl-2- (2-methyl-4-{1-[4-methyl-2- (4-trifluoromethylphenyl)-thiazoI-5-yl] ethoxy}-phenoxy)-propionic acid 2-(4-{1-[2-(4-ch!oro-phenyl)-4-methy]-thiazol-5-yl]-ethoxy}-2-methyl-phenoxy)-2-methyl-propionic acid 7 2-(4-{1-t2-(3,4-dichloro-phenyl)-4-methyl-thiazol-5-yl]-ethoxy}~2-methyl-phenoxy)-2-methyl-propionic acid 2-(4-{1-[2-(4-ethyl-phenyl)-4-methyl-thiazol-5-y!]-ethoxy}-2-methyl-phenoxy)-2-methyl-propionic acid 2-(4-{1-t2-(2-fluoro-4-trifIuoromethyl-phenyl)-4-methyI-thiazol-5-yl]-ethoxy}-2-methyl-phenoxy)-2-methyl-propionic acid 2-methyl-2-(2-methyl-4-{1-[2-(4-trifiuoromethyl-phenyi)-thiazol-5-yl]-ethoxy}-phenoxy)-propionic acid 2-methyl-2-(2-methyl-4-{1-methyI-1-[4-methyl-2-{4-trifluoromethyl-phenyl)-thiazoi-5-yl]-ethoxy}-phenoxy)-propionic acid 2-methyI-2-(2-methy!-4-{1-methyi-1-[2~(4-trifiuoronnethyI-phenyl)-thiazol-5-yl]-ethoxy}-phenoxy)-propionic acid (R)-2-methyl-2- (2-methyl-4-{1-[4-methyl-2- (4-trifluoromethyl-phenyl)-thiazoI-5-yl] propoxy}-phenoxy)-propionic acid (S>-2-methyl-2- (2-methy!-4- {1-[4-methyl-2- (4-trifluoromethyl-phenyl)-thiazol-5-yl] propoxy)-phenoxy)-propionic acid 2-methyl-2- (2-methyl-4- {1-[4-methyl~2- (4-trifiuoromethyl-phenyl)-thiazol-5-yi] butoxy}-phenoxy)-propionic acid 2-methyl-{2-methyl-2- (2-methyM- {1 -[4-methyl-2- (4-trifiuoromethyl-phenyl)-tniazol-5-yl]-propoxy}-phenoxy)}-propionic acid 2-methyl-2- (2-methyl-4- {1-[4-methyl-2- (4-trifIuoromethyl-phenyl)-thiazol-5-yl] pentyloxy^ phenoxy)-propionic acid 2-(4-{cyclopentyl-[4-methyl-2-(4-trifluo^omethyi-phenyl)-thiazol-5-yl]-methoxy^2-methyl- phenoxy)-2-methyl-propionic acid 2-methyI-2-(2-methyl-4-[4-methyi-2-(4-trifluoromethylphenyl)thiazol-5-yl- methoxy]phenoxy)propionic acid 2-methyl-2-(2-methyl-4-(1-[4-methyl-2-{4-trifluoromethyl-phenyl)-thiazol-5-y!]-2-phenyl- ethoxy}-phenoxy)-propionic acid 2-methyl-2-(2-methyl-4-{1-[4-methyl-2-{4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethylsulfanyl}- phenoxy)-propionic acid 2-methyl-2-(2-methyl-4-{1-[2-{4-trif]uoromethyl-phenylHhiazol-5-yl]-ethylsulfanyl}-phenoxy)- propionic acid 2-methyl-2-(2-methyl-4-{1-methyl-1-[4-methy!-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]- ethylsulfanyl}-phenoxy)-propionicacid 2-methyl-2-(2-methyl-4-{1-methyl-1-[2-(4-trmuoromethyl-phenyt)-thiazol-5-yi]-ethylsulfanyl}- phenoxyj-propionic acid 8 2-methyl-2-(2-methyl-4-{1-[4-methyl-2-{44rifiuoromethy[-phenyl)-thia2ol-5-yl]-propylsulfanyl}-phenoxy)-propionicacid Most preferred compounds of formula 1 include: 2-{4-[({2-[2-fluoro-4-(trif!uoromethyl)phenyl]-4-methyt-1,3-thiazol-5-y!}methyl)sulfanyl3-2-methylphenoxy}-2-methylpropanoicacid (R)-2-methyl-2- (2-methyl-4-{1-[4-methyl-2- (4-trifluoromethyl-pheny!)-thiazol-5-yi] propoxy}-phenoxy)-propionic acid (S)-2-methyl-2- (2-methyl-4-{1-4-methyl-2~ (4-trifluoromethyl-phenyl)-triia20l-5-yl] propoxy}-phenoxy)-propionic acid Those skilled in the art will recognize that stereocenters exist in compounds of formula (I). Accordingly, the present invention includes all possible stereoisomers and geometric isomers of formula (I) and includes not only racemlc compounds but this invention is also intended to cover each of these isomers in their racemic, enriched, or purified forms. When a compound of formula (I) is desired as a single enantiomer, it may be obtained either by resolution of the final product or by stereospecific synthesis using an optically active catalyst or a catalytic system with optically active ligands or isomericaily pure starting material or any convenient intermediate. Resolution of the final product, an intermediate or a starting material may be effected by any suitable method known in the art. See, for example. Stereochemistry of Carbon Compounds by E. L. Eltel (Mcgraw Hill, 1962) and Tables of Resolving Agents by S. H. Wilen. Additionally, in situations where tautomers of the compounds of formula (I) are possible, the present invention is intended to include all tautomeric forms of the compounds. In particular, in many of the preferred compounds of this invention the carbon atom to which R6 and R7 are bonded is chiral. In some of these chiral compounds the activities at the various PPAR receptors varies between the S and R isomers. Which of these isomers is preferred depends on the particular desired utility of the compound. In other words, even with the same compound, it is possible that the S isomer will be preferred for some uses, while the R isomer will be preferred for others. The hPPAR agonists of formula (I) may be agonists of only one type ("selective agonists"), agonists for two PPAR subtypes ("dual agonists"), or agonists for all three subtypes ("pan agonists"). As used herein, by "agonist", or "activating compound", or "activator", or the like, is meant those compounds which have a pKi of at least 6.0 preferably at least 7.0 to the relevant PPAR, for example hPPARS, in the binding assay described below, and which achieve at least 9 50% activation of the relevant PPAR relative to the appropriate indicated positive control in the transfection assay described below at concentrations of 10~5 M or less. More preferably, the agonists of this invention achieve 50% activation of at least one human PPAR in the relevant transfection assay at concentrations of 10"6 M or less. Preferably, the compounds of formula (I) are hPPAR agonists. More preferably the compounds are hPPARS agonists. Most preferably they are dual agonists of hPPAR8 and hPPARct, or pan agonists. It will also be appreciated by those skilled in the art that the compounds of the present invention may also be utilised in the form of a pharmaceutically acceptable salt or solvate thereof. The physiologically acceptable salts of the compounds of formula (I) include conventional salts formed from pharmaceutically acceptable inorganic or organic acids or bases as well as quaternary ammonium acid addition salts. More specific examples of suitable acid salts include hydrochloric, hydrobromic, sulfuric, phosphoric, nitric, perchloric, fumaric, acetic, propionic, succintc, glycolic, formic, lactic, maleic, tartaric, citric, palmoic, malonic, hydroxymateic, phenylacetic, glutamic, benzoic, salicylic, fumaric, toluenesulfonic, methanesulfonic, naphthalene-2-sulfonic, benzenesulfonic hydroxynaphthoic, hydroiodic, malic, steroic, tannic and the like. Other acids such as oxalic, while not in themselves pharmaceutically acceptable, may be useful in the preparation of salts useful as intermediates in obtaining the compounds of the invention and their pharmaceutically acceptable salts. More specific examples of suitable basic salts include sodium, lithium, potassium, magnesium, aluminium, calcium, zinc, N.N'-dibenzylethylenediamine, chtoroprocaine, choline, diethanolamine, ethylenedfamine, N-methylglucamtne and procaine salts. Those skilled in the art of organic chemistry will appreciate that many organic compounds can form complexes with solvents in which they are reacted or from which they are precipitated or crystallized. These complexes are known as "solvents". For example, a complex with water is known as a "hydrate". Solvates of the compound of formula (I) are within the scope of the invention. References hereinafter to a compound according to the invention include both compounds of formula (I) and their pharmaceutically acceptable salts and solvates. The compounds of the invention and their pharmaceutically acceptable derivatives are conveniently administered in the form of pharmaceutical compositions. Such compositions may conveniently be presented for use in conventional manner in admixture with one or more physiologically acceptable carriers or excipients. While it is possible that compounds of the present invention may be therapeutically administered as the raw chemical, it is preferable to present the active ingredient as a pharmaceutical formulation. The carrier(s) must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. Accordingly, the present invention further provides for a pharmaceutical formulation comprising a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof 10 together with one or more pharmaceutically acceptable carriers therefore and, optionally, other therapeutic and/or prophylactic ingredients. The formulations include those suitable for oral, parenteral (including subcutaneous e.g. by injection or by depot tablet, intradermaf, intrathecal, intramuscular e.g. by depot and intravenous), rectal and topical (including dermal, buccal and sublingua!) administration although the most suitable route may depend upon for example the condition and disorder of the recipient. The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing into association the compounds ("active ingredient") with the carrier, which constitutes one or more accessory ingredients. In general the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product into the desired formulation. Formulations suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets (e.g. chewable tablets in particular for paediatric administration) each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The active ingredient may also be presented as a bolus, electuary or paste. A tablet may be made by compression or moulding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a other conventional excipients such as binding agents, {for example, syrup, acacia, gelatin, sorbitol, tragacanth, mucilage of starch or polyvinylpyrroiidone), fillers (for example, lactose, sugar, microcrystalline cellulose, maize-starch, calcium phosphate or sorbitol), lubricants (for example, magnesium stearate, stearic acid, talc, polyethylene glycol or silica), disintegrants (for example, potato starch or sodium starch glycollate) or wetting agents, such as sodium lauryl sulfate. Moulded tablets may be made by moulding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein. The tablets may be coated according to methods well-known in the art. Alternatively, the compounds of the present invention may be incorporated into oral liquid preparations such as aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, for example. Moreover, formulations containing these compounds may be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents such as sorbitol syrup, methyl cellulose, glucose/sugar syrup, gelatin, hydroxyethylcellulose, carboxymethyl cellulose, aluminum stearate gel or hydrogenated edible fats; emulsifying agents such as lecithin, sorbitan mono- 11 oleate or acacia; non-aqueous vehicles (which may include edible oils) such as almond oil, fractionated coconut oil, oily esters, propylene glycol or ethyl alcohol; and preservatives such as methyl or propyl p~hydroxybenzoates or sorbic acid. Such preparations may also be formulated as suppositories, e.g., containing conventional suppository bases such as cocoa butter or other glycerides. Formulations for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. The formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilised) condition requiring only the addition of a sterile liquid carrier, for example, water-for-injection, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described. Formulations for rectal administration may be presented as a suppository with the usual carriers such as cocoa butter, hard fat or polyethylene glycol. Formulations for topical administration in the mouth, for example buccally or sublingually, include lozenges comprising the active ingredient in a flavoured basis such as sucrose and acacia or tragacanth, and pastilles comprising the active ingredient in a basis such as gelatin and glycerin or sucrose and acacia. The compounds may also be formulated as depot preparations. Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt. In addition to the ingredients particularly mentioned above, the formulations may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavouring agents. It will be appreciated by those skilled in the art that reference herein to treatment extends to prophylaxis as well as the treatment of established diseases or symptoms. Moreover, it will be appreciated that the amount of a compound of the invention required for use in treatment will vary with the nature of the condition being treated and the age and the condition of the patient and will be ultimately at the discretion of the attendant physician or veterinarian. In general, however, doses employed for adult human treatment will typically be in the range of 0.02-5000 mg per day, preferably 1-1500 mg per day. The desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example as two, three, four or more 12 sub-doses per day. The formulations according to the invention may contain between 0.1-99% of the active ingredient, conveniently from 30-95% for tablets and capsules and 3-50% for liquid preparations. The compound of formula (I) for use in the instant invention may be used in combination with other therapeutic agents for example, statins and/or other lipid lowering drugs for example MTP inhibitors and LDLR upreguiators. The compounds of the invention may also be used in combination with antidiabetic agents, e.g. metformin, sulfonyiureas and/or PPAR gamma, PPAR alpha or PPAR alpha/gamma agonists (for example thiazolidinediones such as e.g. Pioglitazone and Rosiglitazone). The compounds may also be used in combination with antihypertensive agents such as angistensin antagonists e.g. telmisartan, calcium channel antagonists e.g. lacidipine and ACE inhibitors e.g. enalapril. The invention thus provides in a further aspect the use of a combination comprising a compound of formula (I) with a further therapeutic agent in the treatment of a hPPAR mediated disease. When the compounds of formula (I) are used in combination with other therapeutic agents, the compounds may be administered either sequentially or simultaneously by any convenient route. The combinations referred to above may conveniently be presented for use in the form of a pharmaceutical formulation and thus pharmaceutical formulations comprising a combination as defined above optimally together with a pharmaceutically acceptable carrier or excipient comprise a further aspect of the invention. The individual components of such combinations may be administered either sequentially or simultaneously in separate or combined pharmaceutical formulations. When combined in the same formulation it will be appreciated that the two compounds must be stable and compatible with each other and the other components of the formulation and may be formulated for administration. When formulated separately they may be provided in any convenient formulation, conveniently in such a manner as are known for such compounds in the art. When a compound of formula (I) is used in combination with a second therapeutic agent active against the same hPPAR mediated disease, the dose of each compound may differ from that when the compound is used alone. Appropriate doses will be readily appreciated by those skilled in the art. Compounds of this invention may be conveniently prepared by a general process wherein a moiety like A is coupled to an alcohol (B and D) using the Mitsunobu protocol (O. Mitsunobu, 1981 Synthesis, p 1) or by alkylation of A using a suitable non nucleophilic base such as K2CO3, Cs2CO3 or NaH, with an alkyl halide (C, E and F). Note that this synthesis is preferably carried out with the acid group protected by R. Preferably, R is 1-6 alkyl which can be hydrolysed to give an acid of Formula (I), or if readily hydrolyzable, the resulting ester can be administered. 13 Some of the intermediates of type (A) are commercially available while others can be synthesised as outlined below. The synthesis of intermediates of type (B-F) are also illustrated below. For example Y is S, 2 is N, R1, R2, R3 and R6 are CH3l R7 is H, X2 is 0 and R8 is para-CF3: Compounds of the invention may be made by an alternative method in which compounds of formula (G) are reacted with the phosphonium salts of formula (H) under standard Wittig conditions to afford the alkene of formula (J) which can be reduced with Pd/C under a hydrogen atmosphere to afford the ethyl ester of the compound of formula (I) which may be hydrolysed to produce the free acid. Compounds of formula (H) may be prepared from the reaction between compounds of formula (C) and PPh3 in CH3CN at reflux for 1h. 14 The following illustrates Intermediates and Examples of Formula 1 which should not be construed as constituting a limitation thereto. The structures of the compounds were confirmed either by nuclear magnetic resonance (NMR) or mass spectrometry (MS). 1H NMR spectra were recorded on a Brucker 300MHz spectrometer at ambient temperature. NMR shifts (5) are given in parts per million (ppm), "mp" is melting point and is given in °C. Column chromatography was carried out using the technique described by W.C. Still et a!, J.Org.Chem. 1978, 43, 2923-2925 on Merck silica gel 60 (40-63 uM). Compounds used as starting materials are either commercially available compounds or known compounds. 15 Intermediate 1: To a well stirred solution of LiAIH4 (1.52 g, 40 mmo!) in dry THF (50 ml_) at 0°C, was slowly added a solution of ethyl 4-methyl-2-[4-(trifluoromethyl)-phenyl]-thiazole-5-carboxylate (12.6 g, 40 mmol) in dry THF (50 mL4). The mixture was stirred at room temperature for 2h. The reaction was quenched by slow addition at 0 °C of water (2 mL), 5N NaOH (2 mL) and water (6 ml_). The precipitate was filtered, washed with EtOAc, MeOH, CH2CI2and THF, After evaporation, a yellow solid was obtained, that was crystallised from MeOH-water to afford intermediate 1 depicted above (9.90 g, 36 mmol, 90%) as a yellow solid mp 120-122 °C. Intermediate 2: To a solution of 2-fluoro-4-(trifluorornethyI)benzonitrile (5.2g, 27.5mmol) in 50mL methanol was added 10ml of water (I37.5mmol) followed by NaSH'H20 (7.7g, 137.5mmol). After heating at 50°C for 12 hours, the solvent was removed in vacuo and the residue treated with water (200mL) and extracted with EtOAc (2 x 150mL). The organic layers were dried (MgSO4) and the solvent evaporated to give crude residue which was purified on a Biotage FlashElute with a 40M silica cartridge, eluting with hexane / ethyl acetate (4:1) to yield the title compound as a yellow solid (3.27g, 53%). MS C8H6F4NS: m/z 224 (M+1); HPLC RT 2.013 (C18 4.6x60mm, 1% MeOH / 0-90% CH3CN / HaO (0.1 % TFA) / (50mM TEA / TFA), 4min @ 3ml / min @ 254 / 220nm). Intermediate 3: Intermediate 2 was treated with ethyl 2-ch!oro-3-oxobutanoate in refluxing ethanol overnight and evaporated. The residue was passed through a plug of silica gel with hexanerethyl acetate (4:1) to afford the title compound as a light yellow solid after evaporation (71%). MS C14H12F4NO2S: m/z 333 (M+1) Intermediate 4 : To a solution of NaOEt (9.94g, 14.6mmol) in EtOH (50mL), under a nitrogen atmosphere, were added Ethyl formate (11.81 mL,14.6mmol) and chloro acetic acid ethyl ester 16 (10.96mL,14.6mmol) in solution in 50mL of dry Et2O. The mixture was stirred at rt for 20hours and filtered after addition of 50mL of dry Et2O. The resulting solid was dissolved in 100mL EtOH and after addition of 4-trifluoro methyl thiobenzamide (3g, I4.6mmol) stirring to reflux was accomplished for 20 hours. EtOH was removed under reduced pressure and 250mL of CH2C!2 5 and 50 mL of water were added. The organic layer was separated and dried over Na2SO4, filtered, concentrated to dryness and purified by flash chromatography C6H12/EtOAc (80:20) to afford the title compound (750mg, 2.49mmol) as a white powder in a 17% yield. GC/MS C13H10F3NO2S: m/z 301 10 Intermediate 5: Intermediate 3 was reacted as described in a general LiAlH4 reduction procedure to afford the title compound as a tight yelfow solid (83%) MS C12H9F4NOS: m/z 291 (M+1) 15 Intermediate 6: Intermediate 5 was reacted with mesylchloride to afford the title compound as a light yellow solid (100%). Rf of starting alcohol in 3:1 hexanes / ethyl acetate 0.25 Rf of chloride in 3:1 hexanes / ethyl acetate 0.75 20 Intermediate 7: Intermediate 6 was treated with 2-methyl-4-sulfanylpheno! as described in a general alkylation procedure to afford the title compound as a yellow oil (0.242g, 49%). 'H NMR (CDCI3): 5 2.22 (s, 3H), 2.25 (s, 3H), 4.15 (s. 2H), 6.69 (d, 1H), 7.13 (d, 1H), 7.20 (s, 1 H), 7.50 (m, 2H), 8.39 (t, 1H), 25 MS C19H16F4NOS2: m/z 414 (M+1). Intermediate 8. 17 To a solution of Intermediate 1 (75.5g, 0.276 mmol, 1 eq) in CH2CI2 was added pyridinium chlorochromate (119g, 0.552 mmol, 2 eq). Then the resulting mixture was stirred at room temperature for 3 hours. The mixture was decanted one night and then filtered over celite and evaporated off. The residue was purified by flash chromatography using CH2CI2 as eluent to give the title compound as a yellow solid (46 g, 0.17 mmol) in a 61.5% yield. GC/MS: C12H8F3NOS: m/z271 Intermediate 9 : To a solution of intermediate 4 (0.8g, 2.65mmol) was added dropwise LiAlH4 (2.7mL / 1N in THF, 2.7mmo!). The resulting mixture was stirred 30 min at rt and the reaction was-quenched by the cautious addition of NH4CI and water. The precipitate was filtered, the filtrate was concentrated under vacuo and the residue obtained was flash chromatographed CH2CI2/MeOH (99:1) to afford the title compound (500mg, 1.93mmol) as a white solid in a 73% yield. 1H NMR (CDCI3) ?: 3.48 (br t, 1H), 4.73 (br d, 2H), 7.52 (m, 3H), 7.82 (d, 2H) Intermediate 10 : To a solution of intermediate 9 (500mg, 1.93mmol) in CH2CI2 (20mL) was added PCC (830mg, 2eq.). After stirring for 2 hours at rt the solvent was evaporated off and the residue flash chromatographed with CH2CI2 to give the title compound (460mg, 1.78mmol) as a white powder in a 93% yield. 1H NMR (CDCI3) 6: 7.68 (d, 2H). 8.07 (d, 2H), 8.41 (s,1H), 10.01(s,1H) Intermediate 11: A solution of 4-trifluoromethyl-thiobenzamide (5g, 24.3mmol) and 3-ch!oro-pentane-2,4-dione (3.2ml, 24.3mmoles) in 50 ml_ of EtOH was heated to reflux during 18 hours and evaporated to dryness. The residue was diluted with 250 mL of CH2CI2 and washed with 50mL of saturated solution of NaHCO3. The organic phase was separated and dried over Na2SO4. After filtration and concentration under vacuo the residue was purified by flash chromatography (CH2Cl2) to give the title compound as a tan powder (6.3g, 22mmol) in a 90% yield. GC/MS C13H10F3NOS : m/z 285 18 Intermediate 12: A solution of 3-fluoro-4-trifluoromethyl-thiobenzamide (540mg, 2.42mmol) and 3-chloro-pentane-2,4-dione (577?L, 4.9mmoles) in 50 mL of EtOH was heated to reflux during 48 hours and evaporated to dryness. The residue was diluted with 250 mL of CH2Cl2 and washed with 50mL of a saturated solution of NaHCO3. The organic phase was separated and dried over Na2SO4. After filtration and concentratio/n under vacuo the residue was purified by flash chromatography (CH2CI2) to give the title compound as a tan powder (500mg, 1.65mmol) in a 68% yield. GC/MS Ci3H9F4NOS : m/z 303 Intermediate 13 : A solution of 4-ethyl-thiobenzamide (2g, 12mmol) and 3-chloro-pentane-2,4-dione (2.2ml, 14 mmol) in 30 mL of EtOH was heated to reflux during 18 hours and evaporated to dryness. The residue was diluted with 250 mL of CH2CI2 and washed with 50mL of a saturated solution of NaHCO3. The organic phase was separated, dried over Na2SO4, filtered and concentrated under vacuo to give the title compound (2.94g, 12mmol) in a quantitative crude yield. 1H NMR (CDCI3) S: 1.15 (t,3H), 2.52 (s, 3H), 2.61(q,2H), 2.72(s,3H), 7.20 {d, 2H), 7.85(d,2H) Intermediate 14 : A solution of 3,4-dichloro-thiobenzamide (1.5g, 7.3mmol) and 3-chloro-pentane-2,4-dione (1.2mL, 11 mmol) in 30 mL of EtOH was heated to reflux during 18 hours and evaporated to dryness. The residue was diluted with 250 mL of CH2CI2 and washed with 5GmL of saturated solution of NaHC03. The organic phase was separated, dried over Na2SO4, filtered and concentrated under vacuo to give the title compound as an off white powder (1.5g, 5.2mmol) in a 71 % yield after trituration of the residue in water and washing with pentane. 1H NMR (CDCi3) 5: 2.52 19 Intermediate 15 : A solution of 4-chloro-thiobenzamide (5g, 29mmol) and 3-chloro-pentane-2,4-dione (3.2mL, 27mmol) in 50 mL of EtOH was heated to reflux during 5 hours and evaporated to dryness. The residue was diluted with 250 mL of CH2CI2 and washed with 50mL of saturated solution of NaHCO3. The organic phase was separated and dried over Na2SO4. After filtration and concentration under vacuo the residue was purified by flash chromatography (CH2CI2) to give the title compound as (7.2g, 28.5mmol) in a quantitative yield. 1H NMR (CDCI3) 5: 2.54 (s, 3H), 2.83 (s, 3H), 7.41 (d, 2H), 8.01 (d, 2H) Intermediate 16; To a solution of intermediate 8 (1.9g, 7mmol) in 25 mL of THF was added slowly at -10°C, a solution of 1.4M methyl magnesium bromide in tetrahydrofuran (7mL, 11.9 mmol, 1.4 eq). The mixture was naturally warmed at room temperature and then stirred for 1,5 hour. The resulting mixture was quenched with saturated NH4CI solution (100mL) and extracted with Ethyl Acetate (2 x 250ml_). The organic phase was washed with brine and water, and then dried over Na2SO4 and evaporated off to give the title compound as a yellow solid (1.9g, 6.96 mmol) in a 99% crude yield. GC/MS C13H12F3NOS: m/z 287 mp: 147°C Intermediate 17 : To a solution of the intermediate 10(1 -35g, 5.25mmol) was added slowly at -10°C, a solution of 1.4M methylmagnesium bromide in tetrahydrofuran (4.1 ml, 5.8 mmol, 1.1 eq). The mixture was naturally warmed at room temperature and then stirred for 1,5 hour. The resulting mixture was quenched with saturated NH4CI solution (100ml) and extracted with Ethyl Acetate{2 x 250ml). The organic phase was washed with brine and water, and then dried over Na2SO4 and evaporated off to give the title compound as an off white solid (700mg, 2.58 mmol) in a 49 % yield after purification by flash chromatography CH2CI2/MeOH (99:1). 20 Intermediate 18 : To a solution of intermediate 11 (5g, 17.5mmol) and (S)-2-methyl-CBS-oxazaboroiidine (3,5mL, 3.5mmoi, 1N solution in toluene) in anhydrous THF was added slowly at 0°Ct a solution of borane-methylsulfide complex(10.5 mL, 21 mmol, 2M solution in THF). The solution was stirred 2,5 hours and a tic monitoring of an hydrolyzed aliquot indicated that the reaction was completed. 20 mL of MeOH and 100 mL of 0.5 N HCI were added to the solution to quench the reaction. EtOAC extraction ( 3 x 200mL) and acidic washing with diluted HCI (3 x 50 mL) afforded after drying over Na2SO4, filtration and concentration under vacuo , 5g of a white solid. Recrystallization in Hexane /EtOH (200mL / 6mL) gave after filtration 1.12g of a racemic powder. The filtrate was evaporated to dryness and the resulting yellow solid was triturated with 100 mL of hexane to yield 3.5g of a white solid after filtration with an ee = 95.5 %. 1H NMR(CDCI3, 300Mhz) 5: 1.4(d, 3H), 2.26 (s, 3H), 5.03 (q,1H), 7.06 (s,1H), 7.46 (d, 2H), 7.8 (d, 2H) HPLC Chiralpak AD-RH (4.6x150mm, 65% CH3CN / 35% H2O, 0.3mL/min) Rt:17.0min [?]aD = + 38.1 (c= 0.25 / CHCI3) for ee = 95.5 % Intermediate 19 The same experimental procedure as for intermediate 18 was applied to a 3g quantity of the methylketone using the ( R)-2-Methyl-CBS-oxazaboroItdine. The title compound (1.7g; 5.9 mmol) was obtained as a white powder in a 56% yield and with an enantiomeric excess of 79.4% as determined by HPLC. To increase the enantiomeric excess, the resulting alcohol (1.7g, 5.9 " mmol) was coupled with the (R)-(-)-a Methoxyphenylacetic acid (1.1 g; 6.5 mmol) with DCC (1.5g) and a catalytic amount of DMAP. The two diatereomeric esters had ARf = 0.1 which allowed the isolation of the less polar fraction, the major one (2.35g, 5.4 mmol) after flash chromatography using Petroleum Ether/ EtOAc (85:15). Finally this ester in solution in 50 mL of EtOH was saponified at O°C using 1N NaOH (5.7mL, 5.7mmol). After completion the reaction was quenched by dropwise addition at 0°C of 1N HCI (5.7mL). After removing EtOH under reduced pressure, 21 extraction with Et2O (200mL) washing of the organic phase with 25mL of saturated NaHCO3 afforded the title compound (1.4g, 4.8 mmol) in 86% yield as a pate oil with an e.e.-98%. 1H NMR(CDCI3, 300Mhz) 5: 1.60 (d, 3H), 2.44 (s, 3H), 5.21 (q, 1H), 7.Q6 (d, 2H), 8.0 5 Rt: 15.54 min [?]25D = - 31 (c = 0.32 / CHCI3) for ee = 86% Intermediate 20 To a solution of intermediate 12 (500mg, 1.65mmol) in MeOH (25mL) was added at once 10 NaBH4 (69mg,1.7mmol). The solution was stirred 30 min and concentrated to dryness. Hydrolysis with 1N HCf (5mL), followed by Et2O extraction (2x75mL),drying of the organic phase over Na2SO4, filtration and concentration under vacuo gave a residue which was flash chromatographed CHzCl2/ MeOH (99:1) to afford 380 mg of the title compound. fH NMR(CDCI3) 5:1.53 (d, 3H), 2.39 (s, 3H), 5.12 (q, 1H), 7.15 (s, 1H), 7.57 (m, 1H). 7.68 15 (m, 2H) Intermediate 21 : To a solution of methylketone intermediate 13 (3.5g, 14.2mmo!) in EtOH (50mL) was added at once NaBH4 (1.1g, 25mmol, 2eq.) at 0°C. After stirring 3 hours at room temperature EtOH was 20 removed under reduced pressure and 1N HCI was added. The resulting precipitate was filtered off, washed with water and dried under vacuum to afford the title compound (1.9g, 7.6mmol) in a 54% yield as a white solid. 1H NMR (CDCI3) 5: 1.22 (t, 3H), 1.54(d, 3H), 2.37 (s, 3H), 2.64{q, 2H)r 5.14(qf1H), 7,20 (d, 2H), 7.76(d, 2H) 25 Intermediate 22 : To a solution of methylketone intermediate 14 (1.7g, 5.9mmol) in EtOH (25mL) was added at once NaBH4 (450mg, 12mmot, 2eq.) at 0°C. After stirring 3 hours at room temperature EtOH 22 was removed under reduced pressure and 1N HCl was added. The resulting precipitate was filtered off, washed with water and dried under vacuum to afford the title compound (1.58g, 5.48mmol) in a 92% yield as a white solid. 1H NMR (CDCI3) 5: 1.50(d, 3H), 2.01(d,lH), 2.35 (s, 3H), 5.12(m,1H), 7.37 (d, 1H, J = 8.48 5 Hz), 7.60(dd,iH, J = 8.3 Hz and 2.07 Hz), 7.92(d,1H, J = 2.1 Hz) Intermediate 23 : To a solution of methylketone intermediate 15 (2.5g, 9.9mmo!) in EtOH (25mL) was added at once NaBH4 ( 750mg, 20mmol, 2eq.) at 0°C. After stirring 3 hours at room temperature EtOH 10 was removed under reduced pressure and 1N HCl was added. The resulting precipitate was filtered off, washed with water and dried under vacuum to afford the title compound (2.4g, 9.4mmol) in a 95% yield as a white solid. *H NMR (CDCI3) 6: 1.56(d,3H, J= 6H2), 2.39 (s, 3H), 5.16(m,1H), 7.37 (d, 2H, J= 8.0Hz), 7.79 To a solution of ethyl-4-methyl-2-[4-(trifluoromethyl)-phenyl]-thiazoIe-5-carboxylate (2g, 6.4mmol) was added slowly at -10°C, a solution of 1,4M methylmagnesium bromide in toluene (10 mL, 14 mmol, 2 eq). The mixture was naturally warmed at room temperature and then stirred for 20 72 hours. The resulting mixture was quenched with saturated NH4CI solution (100mL) and extracted.with EtOAc (2 x 250mL). The organic phase was washed with brine and water, and then dried over Na2SO4 and evaporated off to give the title compound as a yellow solid (1 g, 3.3 mmol) in a 52% yield. 1H NMR (CDCl3) 5: 1.70 (s, 6H), 2.65 (s. 3H), 7.60 (d, 2H), 7.95 (d, 2H) 25 Intermediate 25 : To a solution of intermediate 4 (750mg, 2.5mmol) was added slowly at -10°C, a solution of 1.4M methylmagnesium bromide in toluene (8.95mL, 12.5 mmol, 5 eq). The mixture was naturally warmed at room temperature and then stirred for 24 hours. The resulting mixture was quenched 23 with saturated NH4CI solution (100mL) and extracted with EtOAc (2 x 250mL). The organic phase was washed with brine and water, and then dried over Na2SO4 and evaporated off to give the title compound (460mg, 1.6 mmol) in a 64% yield after flash chromatography CH2CI2/MeOH (99:1). GC/MS : C13H12F3NOS m/z : 287 5 Intermediate 26: To a solution of intermediate 8 {4.05g, 15mmol) in 50 mL of THF was added slowly at - 10°C, a solution of3M ethylmagnesium bromide in Et2O (5.5 mL, 16.5mmol, 1.1 eq). The mixture was naturally warmed at room temperature and then stirred for 1,5 hour. The resulting mixture 10 was quenched with saturated NH4CI solution (100mL) and extracted with ethyl Acetate. The organic phase was washed with brine and water, and then dried over Na2SO4 and evaporated off. The residue was taken up with a mixture of isopropyi ether and petroleum ether. The white solid obtained was filtered to give the title compound (4.31g, 14.3 mmol) in a 95% yield. GC/MS: C14H14F3NOS: m/z 301 15 mp: 104-106°C Intermediate 27: Intermediate 26 (8,23g,27.3 mmol) was added to a mixture of (R)-(-)-ct-Methoxyphenylacetic acid (5g, 30 mmol), DCC (6.18g, 30 mmol) and 20 DMAP (catalytic) in 250 ml THF The mixture was stirred at room temperature 24 hours and passed through a plug of silica gel. The filtrate was concentrated to dryness and flash chromatographed using Petroleum ether / EtOAc (95:5). The less polar fraction was collected to afford 2.9g of the title compound (2.9g, 6mmol). 1H NMR(CDCI3) 5: 0.73 (t, 3H), 1.83 (m,2 H), 2.49 (s, 3H), 3.37 (s, 3H), 4.74 (s, 1H), 5.97 (t, 25 1H), 7.33 (m, 3H), 7.43 (m, 2H), 7.66 (d, 2H), 8.00 (d, 2H) Intermediate 28 : To a well-stirred solution of Intermediate 27 (2.75g, 6mmol) in THF/EtOH was added 30 dropwise at 0°C a solution of 18 mL of 1N NaOH in 15 mL of water. After 5 min the cleavage was 24 completed and slowly at 0°C was added 18mL of 1 N HCI in 15 ml H2O. The organic solvents were removed under reduced pressure and extraction with EtOAc { 250 mL) washing with brine (25 mL) and drying over Na2S04 gave a residue which was chromatograhed CH2CI2/EtOAc (90:10) to afford in a 82% yield (1.49g, 3.3mmo!) the title compound with an e.e. = 98%. 5 . GC/MS : C14H14F3NOS m/z 301 [ctfV -10 (c = 0.279, CHCI3) for e.e. = 98% HPLC Chiralpak AD-RH (4.6x150mm, 65% CH3CN / 35% H2O, 0.3mL/min) Rt:21,2 min 10 . Intermediate 29 : The same esterification protocol as described for intermediate 27 was applied with 10 g of racemic Intermediate 26 and 6g of (S)-(+)-a-Methoxyphenylacetic acid to afford 2.85g of the less polar diastereomer. 'H NMR(CDCI3) 5: 0.73 (t, 3H), 1.82 (m, 2H), 2.49 (s, 3H), 3.37 (s, 3H), 4.74 (s,1 H), 5.97 (t, 15 1H), 7.33 (m, 3H), 7.43 (m, 2H), 7.66 (d, 2H), 8.0(d, 2H) Intermediate 30: The same saponification protocol as used to obtain Intermediate 28 was applied to intermediate 29 (2.85g, 6.35 mmol) to afford the title compound (1.58g,5.25mmol) as a pale 20 yellow oil in a 82.5% yield and with an e.e. = 98% 1H NMR(CDCl3) 6: 0.98 (t, 3H), 1.96 (m, 2H), 2.45 (5, 3H), 4.92 (t, 1H), 7.66 (d, 2H), 8.0 (d, 2H) [aft = + 11 (c = 0.29, CHCI3) for e.e. = 98% HPLC Chiralpak AD-RH (4.6x150mm, 65% CH3CN / 35% H2O, 0.3ml_/min) 25 Rt: 25.04 min Intermediate 31 : To a solution of intermediate 8 (2.71g, 10mmol) was added slowly at -12°C, a 2M solution of isopropylbromide magnesium in THF (5.5 ml, 11 mmol). The mixture was naturally warmed at 25 room temperature and then stirred for 1,5 hour. The resulting mixture was quenched with saturated NH4CI solution (100ml) and extracted with EtOAC (2 x 150ml). The organic phase was washed with brine and water, and then dried over Na2SO4 and evaporated off to give the title compound (2g, 6.34 mmol) in a 63.5% yield as a slightly yellow powder after crystallisation in 5 hexane/Ethanol. *H NMR(CDCI3, 300MHz) 5: 0.8 (d, 3H),1.05(d, 3H),1.9(m, 1H), 2.35{s, 3H), 4.55 (d, 1H), 7.6{d, 2H), 7.95(d, 2H) Intermediate 32: 10. To a solution of intermediate 8 (5.42g, 20mmot) in 50 mL of THF was added slowly at - 78°C, a 1M solution of allyimagnesium bromide in Et2O (22mL, 22mmol, 1.1 eq). The mixture was stirred 30 minutes at -78°C and was naturally warmed at RT and then stirred for 1 hour. The resulting mixture was quenched with saturated NH4CI solution (100mL) and extracted with ethyl acetate. The organic phase was washed with brine and water, and then dried over Na^CU and 15 evaporated off. The residue was taken up in heptane to yield the title compound after filtration as a white solid (5g, 16 mmol) in a 80% yield. LC/MS: C15H15F3NOS: m/z 314.00 (M+1) Intermediate 33 : 20 To a solution of intermediate 8 {813mg. 3mmol) was added slowly at -78°C, a 2M solution of butyl lithium in tetrahydrofuran (1.6 mL, 3 mmot). The mixture was naturally warmed at room temperature and then stirred for 1,5 hour. The resulting mixture was quenched with saturated NH4CI solution (100ml_) and extracted with EtOAc (2x100mL). The organic phase was washed with brine and water, and then dried over Na2SO4 and evaporated off f 25 as a yellow solid (770mg, 6.96 mmol) in a 99 % crude yield. 1H NMR(CDCI3, 300MHz) 5: 0.8 (t, 3H),1.25 26 Intermediate 34 : To a solution of intermediate 8 (5g, 18.45mmol) was added slowly at 0°C, a 2M solution of cyclopentylmagnesium bromide in Et2O (11 mL, 22 mmol). The mixture was naturally warmed at room temperature and then stirred for 1,5 hour. The resulting mixture was quenched with saturated NH4CI solution (100mL) and extracted with EtOAc(2 x 250mL). The organic phase was washed with brine and water, and then dried over NaaSO4, evaporated off to give the title compound (2.2g, 6.4 mmol) in a 35% yield after flash chromatography using C6H12/EtOAc (85:15) LC/MS Cl7H19F3NOS:m/z342(M-t-1) 10 Intermediate 35: To a solution of intermediate 8 (1.4g, 5.17mmol) in 50 ml- of THF was added slowly at - 78"C, a 1M solution of phenylmagnesium bromide in THF (5.7ml_, 5.7mmol. 1.1 eq). The mixture was stirred 30 min at -78°C and was naturally warmed at room temperature and then stirred for 2 hours. The resulting mixture was quenched with saturated NH4CI solution and extracted with ethyl 15 acetate. The organic phase was washed with water, dried over Na2SO4, evaporated off and the residue was crystallized in hexane. The white solid obtained was filtered and washed with hexane to give the title compound (1.7g, 4.9 mmol) in a 86% yield. GC/MS: C1BH14F3NOS m/z 349 20 Intermediate 36: To a solution of intermediate 8 (4.48g, 16.5mmol)was added slowly at-10°C, a solution of 1.3M benzylmagnesium chloride in tetrahydrofuran (20 ml, 26.5 mmol, 1.6 eq). The mixture was naturally warmed at room temperature and then stirred for 1,5 hour. The resulting mixture was quenched with saturated NH4CI solution (100mL) and extracted with Ethyl Acetate(2 x 250mL). 25 The organic phase was washed with brine and water, and then dried over Na2SO4 and evaporated off to give a pale yellow solid. After sonication in petroleum ether and filtration, the title compound (2.8g, 7.7 mmol) was obtained in a 48 % yield as a white powder. LC/MS: C18H17NOS m/z 364.13 (M+1) 27 mp; 126-129°C Intermediate 37: A suspension of 20g (0.133 mole) of 4-acetyl-2-methy I phenol and 30g of potassium carbonate ( 0.2 mole) in 500 mL of acetone was heated at reflux for 24 hours. 30mL of ethyl 2-bromo-2-methylpropionate in solution in 30 mL of acetone was added dropwise. The mixture was stirred at reflux during 20 hours and a tic monitoring showed that the reaction was not complete. Then two supplementary equivalent portions of potassium carbonate and halide were added with a 7 hours interval. The mixture was stirred for 24 hours at reflux and stirred at room temperature for 2 days then filtered off and concentrated under vacuo. The residue was taken up with 300 mL of EtOAc and washed with 10OmL of 1N NaOH and 10OmL of brine. The organic layer was dried over Na2SO4, filtered and concentrated under vacuo to give 32.6g of the title compound as a yellow oil in a 92% yield. 1H NMR (CDCI3): 5 1.19 ft, 3H), 1.63 (s, 6H), 2.24(s, 3H), 2.50 (s, 3H), 4.20 (q, 2H), 6.58 (d,1H), 7.67 (d, 1H), 7.75 (s,1H), Intermediate 38: To a solution of 30g (0.11mole) of intermediate 37 in 300 mL of CH2CI2 was added at once 2.2g (0.011 mole) of p-toluenesulfonic acid and 35.9g (0.125 mol) of m-chloroperbenzoic acid. The solution was heated at 50°C for 21 hours then filtered and washed consecutively with a solution of 20 20 of Kl in 200mL of water, 20g of Na2SO3 in 200 mL of water, 150 mL of 1N NaOH and 100mL of brine. The organic layer was dried over Na2SO4, filtered and concentrated under vacuo to afford 28.54g of the expected compound in a 89% yield. GC/MS C15H20O5: m/z 280 25 Intermediate 39: To a solution of 25g (0.089 mol) of intermediate 38 in 250mL of anhydrous EtOH was added 9.1g of NaOEt (0.134 mo!). The solution was heated at 50°C for 6 hours and concentrated under vacuo. The residue was taken up with 200mL of water and acidified cautiously to pH = 1 with 150mL of 1N HCI. Extraction with 3 x 200mL of EtOAc and drying of the gathered organic 30 layers over MgSO4 led after filtration and evaporation under vacuo to 21.62g of the title compound. 28 GC/MS C13H18O4: m/z 238 Intermediate 40: To a cold (0°C) stirred solution of intermediate 1 (8.2g, 30 mmol) and Et3N (6.07g, 8.36mL, 60 mmol), in dry CH2CI2 (120mL) was slowly added MeSO2CI (5.49g, 3.71mL, 48 mmol). After 2 hours at 0°C more Et3N (6 mmol) and MeSO2CI (4.8 mmol) were added. After 2 more hours a tic (hexane : EtOAc, 1:1) showed complete reaction. The reaction mixture was diluted with CH2CI2 (120mL) and washed with NaHCO3 (sat.) (2 x 240mL) and water (2 x 240mL), dried, filtered and evaporated to afford the title compound (8.0g, 27 mmol, 90%) as a yellow solid. Intermediate 41 : A solution of 2-fluoro-4-trifIuoromethyl-thiobenzamide (1.02g, 4.57mmol) and 3-chloro-pentane-2,4-dione (654uL, 5.5mmol) in 30 mL of EtOH was heated to reflux during 18 hours. A supplementary 1,2equivalent of 3-chio-pentane-2,4-dione (654pL, 5.5mmol) was added, the reaction heated to reflux for an additional 18 hours and evaporated to dryness. The residue was diluted with 250 mL of CH2CI2 and washed with 50mL of saturated solution of NaHCO3. The organic phase was separated, dried over Na2SO4, filtered and concentrated under vacuo to give the title compound (850mg, 12mmol)in a61%yieidasayellow solid after flash chromatography CH2CI2. GC/MS C13H9R,NOS m/z 303 Intermediate 42 To a solution of methylketone intermediate 41 (850mg, 2.8mmo!) in EtOH (50mL) was added at once NaBH4 (117mg, 3mmol, 1.1 eq.) at 0°C, After stirring 30 minutes at room temperature MeOH was removed under reduced pressure, 1N HCI was added and extraction with Et2O (2 x 100mL) followed by drying over Na2SO4 and filtration afforded the title compound (770mg, 2.53mmol) in a 90% yield as a pale yellow solid. GC/MS C13H11F4NOS m/z 305 29 Intermediate 43 To a solution of chlorosulfonic acid (90 mL, 4.4eq.) was added dropwise at 0°C in 1 hour 2-Methyl-2-o-tolyloxy-propionic acid ethyl ester (68g, 0.306 moi). After stirring for 1 hour at 0°C and an additional 30 min at 15DC the mixture was poured into crushed ice and the precipitate thus obtained was filtered and washed with cold water. The title compound was obtained as an off white powder (62.2g, 0.194 mot) in a 63% yield. GC/MS : C13H17C1O5S m/z :320.5 Intermediate 44: In a three neck round bottom flask under a nitrogen atmosphere containing Zn (13.1g, 0.2mol, 3.5eq) in dry EtOAc (i50mL) was added intermediate 43 (18.32g, 0.057mol). After stirring for 30 min, dichloromethylsilane (24.4 mL, 0.2 mol, 3.5 eq) was added slowly in 90 min at 70°C. After stirring for 5 hours at 70°C a supplementary portion of Zn (3g, 45mmol) was added to complete the reaction. Then the resulting mixture was stirred overnight .filtered and the zinc precipitate washed with EtOAc. A back extraction was carried out on the filtrate with 1N NaOH (3x300mL) and the gathered basic phases were washed with EtOAc (400mL). Acidification of basic aqueous phases to pH = 3-4 with concentrated HCI, extraction with EtOAc (3 x 300mL), drying of the organic phase over MgSO4, filtration and concentration to dryness gave a colorless oil. The title compound (10.01g, 39.4mmol) was obtained after flash chromatography C6Hi2/EtOAc (90:10) as a colorless oil in a 69% yield. GC/MS : C13Hi8O3S m/z :254 i Example 1: 2-{4-[({2-[2-fluoro-4-(trifluoromethyl)phenyl]^-methyl-1,34hiazol-5-yl}methyl)sujfanyj]-2l methylphenoxy)-2-methylpropanoicactd To a 25ml round-bottom flask equipped with a magnetic stir-bar and N2 inlet was added intermediate 7 (240mg, 0.58 mmol, 1eq) in acetone (4ml) followed by the addition of 2-trichloromethyl-2-propanol (210 mg, 1.18 mmol, 2eq). The reaction was cooled to 0°C and then NaOH (pellets, 190 mg, 4.8 mmol, 8eq) were added. The reaction mixture warmed to room 30 temperature and stirred at room temperature overnight after which the acetone was removed in vacuo and the resulting residue was partitioned between EtOAc and water acidified to pH2 with cone. HCI. The phases were then separated and the organic fraction was washed with brine, dried over MgSO4 and concentrated in vacuo to yield after chromatography (0.05g, 17%) of the title compound as a cream colored solid. 1H NMR (CD3OD): 6 1.59 (s, 6H), 2.17 (s, 3H), 2.20 (s, 3H), 4.24 (s, 2H),), 6.72 (d, 1H), 7.12 (d, 1H), 7,20 (s, 1H), 7.65 (m, 2H), 8,38 (t, 1H) MS C23H22F4NO3S2 m/z 500 (M+1). Example 2: 2-methyl-2-(2-methyl-4-{1-[4-methyl-2-(4-trifluorornethylphenyl)-thiazol-5-yl]ethoxy}phenoxy)propionic acid ethyl ester To a solution of intermediate 39 (238 mg, 1 mmo!) and intermediate 16 (287 mg, 1mmol, 1 eq) in dry THF was added PBu3 (0.37mL, 1.5 mmol, 1.5 eq). The resulting mixture was stirred at 0°C, and then TMAD (258 mg, 1.5 mmol, 1,5 eq) was added all at once. The mixture was stirred at 0°C for 10 minutes, and at room temperature for 24 hours. The resulting mixture was filtered off and concentrated in vacuo, and the title compound was obtained as a yellow oil (270mg, 0.532 mmol) in a 53% yield after flash chromatography using cyclohexane / ethyl acetate (95:5) as eluent. MS: C26H29F3NO4S m/z 507.96 (M+1) Example 3: 2-methyl-2-(2-methyl-4-{1-[4-methyl-2-(4-trifluoromethylphenyl)-thiazol-5-yl]ethoxy}phenoxy)propionic acid To a solution of Example 2 (200mg, 0.394 mmol) in ethanol was added 1N NaOH (5 mmol, 12.7 eq). The resulting mixture was stirred at 80°C for 1.5 hour, and after cooling at room temperature 1N HCI (5 mmol, 12.7 eq) was added. The resulting mixture was concentrated in vacuo and the residue was purified by flash chromatography using CH2CI2 / MeOH (95:5) as eluent to give an oil. The product was crystallized with a mixture of water / EtOH / MeOH, filtered off and washed with water to give the title compound (50mg, 0.104 mmol) in a 26% yield. LC/MS: C24H25F3NO4S m/z480.25 (M+1)/C24H23F3NO4S: m/z 478.31 (M-1) 31 Example 4: (2-methyl-4- {1-f4-methyl-2- (4-trifluoromethylphenyl)-thiazol-5-yl] ethoxy}-phenoxy)-acetic acid ethyl ester A solution of ethyl {4-hydroxy-2-methylphenoxy)acetate (0.073g) and intermediate 16 (100mg) in dry tetrahydrofuran (20mL) was cooled to 0°C and tributylphosphine (0.092mg) added followed by azodicarbonyldimorpholide (0.115g) and the mixture stirred overnight. The reaction mixture was then concentrated and the residue partitioned between EtOAc (40mL) and water (40mL). The organic phase was collected, dried over magnesium sulphate and concentrated. The residue was purified by chromatography eiuting with cyclohexane/ethyl acetate (10:1) to give the title compound as a colourless oil 1H NMR(CDCI3, 300 MHz) 8: 1.27 (t, 3H), 1.70 (d, 3H),), 2.24 (s, 3H),), 2.45 (s, 3H), 4.24 (q, 2H), 4.54 (s, 2H), 5.47 (q, 1H), 6.60 (m, 2H), 6.75 (d, 1H), 7.65 (d, 2H), 7.98 (d, 2H) Example 5 (2-methyl-4- {1-4-methyl-2- (4-trifluoromethylphenyl)-thiazol-5-yl] ethoxy)-phenoxy)-acetic acid A solution of example 4 (0.105g) in methanol (15mL) was treated with 2N NaOH (0.5mL) and the mixture heated to reflux for 20 minutes. The cooled reaction was concentrated and the residue diluted with water (20mL) 2N hydrochloric acid was added and the resulting suspension extracted with dichloromethane (20mL). The organic extract was dried over MgSO4 and concentrated to give the title compound as a yellow solid. 1H NMR(CDCI3, 300Mhz) 6: 1.70 (d, 3H), 2.22 (s, 3H), 2.44 (s, 3H), 4.58 (s, 2H), 5.47 {q, 1H), 6.60 (m, 2H), 6.75 (s, 1H), 7.65 (d, 2H), 7.95 (d, 2H) LC/MS C22H21F3NO4S m/z 452 (M+1) Example 6 : 2-methyl-2- (2-methyl-4- {1-[4-methyl-2- (3-fluoro-4-trifluoromethylphenyl)-thiazol-5-yl3 ethoxy)-phenoxy)-prop ionic acid ethyl ester 32 To a solution of PBu2 (460ML, 1.5 eq) and TMAD (321 mg, 1.5 eq) in dry THF(50mL) were added intermediate 39 ( 356mg, 1.4 mmol) and intermediate 20 (380mg, 1.24mmol, 1.1 eq).The resulting mixture was stirred to room temperature for 18 hrs and was concentrated to dryness to afford the title compound (270mg, 0.51mmol) as a colorless oil after flash chromatography CH2Cl2/ C6H12 (80:20). 1H NMR(CDCI3) 6: 1.15 (t, 3H), 1.35(s, 6H), 1.62(d, 3H), 2.08{s, 3H), 2.34(s, 3H), 4.12(q, 2H), 5.38(q,1H), 6.45(dd,1H), 6.51(d,1H), 6.6(d,1H), 7.52(d, 2H), 7.63(d, 2H), Example 7: / 2-methyl-2- (2-methyl-4- {1-[4-methyl-2- (3-fluoro^-trifluoromethylphenyIHhi'azol-5-yl] ethoxy)-phenoxy)-propionic acid A solution of example 6 (270mg) in EtOH (15mL) was treated with 1N sodium hydroxide (1.54mL, 3eq.) and the mixture heated to reflux for 3 hours. The cooled reaction was concentrated and the residue diluted with water (20mL); 1N hydrochloric acid (2mL) was added and the resulting suspension extracted with dichloromethane (20mL). The organic extract was dried over magnesium sulphate and concentrated to give the title compound in 74% yield as a yellow solid (190 mg). 1H NMR(CDCl3) 5: 1.80 (s, 6H), 1.95 (d, 3H), 2.43 (s, 3H), 2.70 (s, 3H), 5.82 (q, 1H), 6.82 (dd, 1H), 6.97 (m, 2H), 7.85 (m, 1H), 7.95 (m, 2H), LC/MS: C24H22F4NO4S m/z 495.7 (M-1) Example 8 : (S)-2-methyl-2- (2-methyl-4- {1-[4-methyl-2- (44rifluoromethylphenyl)-thiazol-5-yl] ethoxy}^ phenoxy)-propionic acid ethyl ester The same Mitsunobu protocol as described for example 2 was applied with intermediate 18 (1.722g, 6mmol; e.e.= 95.5%) and intermediate 39 (1.43g, 6mmol, 1 eq.)- The title compound was obtained as a pale yellow oil (1.6g, 3.15 mmol) in a 52.5% yield. 1H NMR (CDCI3, 300 MHz) 5: 1.15 (t, 3H), 1.44 (s, 6H), 1.61 (d, 3H), 2.09 (s, 3H), 2.36 (s, 3H), 4.13 (q, 2H), 5.39 (q, 1H), 6.47 (dd, 1H), 6.53 (d, 1H), 6.63 (d, 1H), 7.57 (d, 2H), 7.90 (d, 2H) 33 Example 9 . (S)-2-methyl-2- (2-methyl-4- {1-[4-methyl-2- (4-trifluoromethylphenyl)-thiazol-5-yl] ethoxyK phenoxy)-propionic acid The same saponification protocol as for example 3 was applied usingi ,6g of Example 8 5 (1,6g, 3.15 mmol). The white powder obtained after work up was recrystallized in Hexane / EtOH to give the title compound as a white powder (780mg, 1.628mmol) in a 52.5% yield with an e.e.= 99.9% mp134-135°C 1H NMR (CDCI3) 5: 1.41 (s, 6H), 1.58 (d, 3H), 2.06 (s, 3H), 2.33 (s, 3H), 5.36.(q, 1H), 6.46 10 (dd, 1H), 6.61 (m, 2H), 7.50 (d, 2H), 7.82 (d, 2H) [aj^o = - 169.9 (c = 0.275, CHCI3 ) for e,e. = 99.9% HPLC Chiralpak AD (4.6x250mm, 95% Hexane / 5% BOH) Rt: 8.79 min Example 10: 15 (R)-2-methyl-2- (2-methyl-4- {1-[4-methyl-2- (4-trifluoromethylphenylHhiazol-5-yl] ethoxy)- phenoxy)-propionic acid ethyl ester The same Mitsunobu protocol as described for example 2 was applied with Intermediate 19 (1.4g, 4.9mmol, e.e. = 98%) and intermediate 39 (1.17g, 4.9 mmol). The title compound was. obtained as a pale yellow oil (1.4g, 2.9 mmol) in a 60% yield. 20 1H NMR (CDCl3) 5: 1.04 (t, 3H), 1.33 (s, 6H), 1.50 (d, 3H), 1.98 (s, 3H), 2.25 (s, 3H), 4.02 (q, 2H), 5.27 (q, 1H), 6.35 (dd, 1H), 6.42 (d, 1H), 6.52 (d, 1H), 7.46 (d, 2H), 7.80 (d, 2H) Example 11: 25 (R)-2-methyl-2- (2-methyl-4- {1-[4-methyl-2- (4-trifluoromethylphenyl)-thiazol-5-yl] ethoxy}- phenoxy)-propionic acid The same saponification protocol as described for example 3 was applied using Example 10 (400mg, 0.79 mmol). The residue was purified by flash chromatography CH2CI2/ MeOH (99:1) 34 to give the title compound (220mg, 0.458mmol) as a pale yellow oil in a 58% yield with an e.e.=87% 'H NMR (CDCI3,300 MHz) 6: 1.47 {s, 6H), 1.63 (d, 3H), 2.12 (s, 3H), 2.38 (s, 3H), 5.42 (q, 1H), 6.52 (dd, 1H), 6.67 {m, 2H), 7.56 LC/MS: C24 H25 F3NO4S m/z 480.0 (M+1) Example 12 : / 2-(4^1-[2-(4-chloro-phenylM-nriethyl-thiazol-5-yl1-ethoxy}-2-rnethyl-phenoxy)-2-methyl-propionic acid ethyl ester The same Mitsunobu conditions as described for racemic example 2 were applied to Intermediate 23 (520mg, 2 mmol) and Phenol Intermediate 39 (530mg, 2.2mmol) and afforded in a 33% yield the title compound (320mg, 0.67 mmol) as a colorless oil. 1H NMR (CDCI3) 6: 1.15 (t, 3H), 1.44 (s, 6H), 1.60 (d, 3H), 2.09 (s, 3H), 2.33 (s, 3H), 4.13 (qt 2H), 5.36 (q, 1H), 6.46 (dd, 1H), 6.52 (d, 1H), 6.62 (d, 1H), 7.27 (dt 2H), 7.72 (d, 2H) Example 13 : ' 2-(4-{1-[2-(4-chloro-phenyl)^-methyl-thiazol-5-yll-ethoxy}-2-methyl-phenoxy)-2-methyl-propionic acid The same saponification conditions as described for racemic example 3 were applied to example 12 (320mg, 0.67mmol) and gave in a 70% yield the title compound (210 mg, 0.47 mmol). LC/MS :C23H23ClNO4S m/z 444.1 (M-1) LC/MS :C23H25CINO4S m/z 446 (M+1) Example 14 : 35 2-(4-(1-[2-(3,4-dichloro-phenyl)-4-methyl4hiazol-5-yl]-ethoxy}-2-methyl-phenoxy)-2-methyl--propionic acid ethyl ester The same Mitsunobu conditions as described for racemic example 2 were applied to Intermediate 22 (580mg, 2mmol) and Phenol Intermediate 39 (530mg, 2.2mmol) and afforded in a 42% yield the title compound (430mg, 0.84 mmol) as a colorless oil. 1H NMR (CDCI3) 5: 1.15 (t, 3H), 1.43 (s, 6H), 1.59 (d, 3H), 2.09 (s, 3H), 2.33 (s, 3H), 4.13 (q, 2H), 5.37 (q, 1H), 6.46 (dd, 1H), 6.52 (d, 1H), 6.63 (d, 1H), 7.36 (d, 1H), 7.59 (dd, 1H), 7.91 (d, 1H) Example 15: 2-(4-{1-r2-(3I4-dichloro-phenyl)-4-methyl-thiazol-5-yn-ethoxy}-2-methyl-phenoxy)-2-methyl-propionic acid The same saponification conditions as described for racemic example 3 were applied to example 14 (480mg, 0.94mrnol) and gave in a 67% yield the title compound (300 mg, 0.63 mmol). LC/MS :C23H22C12NO4S m/z 478 and 480 (M-1) Example 16: 2-(4-{1-[2-(4-ethyl-phenyl)-4-rnethyl-thiazol-5-yn-ethoxy}-2-methy1-phenoxy)-2-methyl-propionic acid ethyl ester The same Mitsunobu conditions as described for racemic example 2 were applied to Intermediate 21 (500mg, 2mmol) and Phenol Intermediate 39 (530rng,2.2mmol) and afforded in a 30% yield the title compound (280mg, 0.6 mmol) as a colorless oil. 1H NMR (CDCI3) 6:1.25 (m, 6H), 1.53 (s, 6H), 1.70 (d, 3H), 2.19 (s, 3H), 2.42 (s, 3H), 4.23 c Example 17: 2-(4-{1-[2-(4-ethyl-phenyl)-4-methyl-thiazol-5-yl]-€thoxy}-2-methyl-phenoxy)-2-methyl-propionic acid 36 The same saponification conditions as described for racemic example 3 were applied to example 16 (280mg, 0.6mmol) and gave in a 76% yield the title compound (200 mg, 0.45 mmol). LC/MS :C25H3oN04S m/z 440.0 (M+1) Example 18 : / 2-(4-{1-[2-(2-fluoro-4-trifluoromethyl-phenyl)-4-methyl-thiazol--5-yl]-ethoxy}-2-methyl-phenoxy)-2-methyl-propionic acid ethyl ester The same Mitsunobu conditions as described for racemic example 2 were applied to Intermediate 42 (400mg,1.31 mmol) and Phenol Intermediate 39 (312mg,1.31mmoJj and afforded in a 35% yield the title compound (240mg, 0.456 mmol) as a colorless oil. 1H NMR (CDCI3) 5: 1.16 (t. 3H), 1.44 (s, 6H), 1.63 (d, 3H)t 2.1 (s, 3H), 2.38 (s, 3H), 4.14 (q, 2H), 5.42 (q, 1H), 6.47 (dd, 1H), 6.52 (d, 1H), 6.65 (d, 1H), 7.38 (d, 2H), 8.3 (m, 1H) Example 19: 2-(4-{1-r2-(2-fiuoro-4-trifluoromethyl-phenyl)-4-methyl-thiazol-5-yl]-ethoxy}-2-methyl-phenoxy)-2-methyl-propionic acid The same saponification conditions as described for racemic example 3 were applied to example 18 (240mg, O.46mmol) and gave in a 97% yield the title compound as a white powder (220 mg, 0.442 mmol). mp 133°C LC/MS :C24H22F4NO4S m/z 495.9 (M-1) Example 20 : 2-methyl-2-(2-methyl-4-{1-[2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethoxy}-phenoxy>-propionic acid ethyl ester The same Mitsunobu conditions as described for racemic example 2 were applied to Intermediate 17 (400mg,1.46rnrnol) and phenol Intermediate 39 37 1HNMR(CDCl3)?:1.17(t,3H), 1.45 (s, 6H). 1.67 (d, 3H), 2.11 (s, 3H), 4.14 (q, 2H), 5.46 (q, 1H), 6.55 (s, 2H), 6.69 (br s, 1H), 7.60 (d, 2H),7.66(s, 1H), 7.95 (d, 2H) Example 21: 2-methvl-2-(2-methyl-4-{1-[2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethoxy}-phenoxy)-propionic acid The same saponifi cation conditions as described for racemic example 3 were applied to example 20 (150mg, o.3mmol) and gave in a 64% yield the title compound as a yellow powder (90 mg, 0.193 mmol). LC/MS :C23H23F3NO4S m/z 465.99 (M+1) Example 22 : 2-jrie^hyl-2-(2-methyI^{1-methyl-1-[4-methyl-2-(4-trifluoromethyl--phenyl)-thiazol-5-yn-ethoxy}-phenoxy)-propionic acid ethyl ester The same Mitsunobu conditions as described for racemic example 2 were applied to Intermediate 24 (50Gmg,1.66mmol) and phenol Intermediate 39 (440mg,1.85mmol) and afforded in a 70% yield the title compound (610mg, 1.17 mmol) as an oil after purification by flash chromatography CH2CI2. 1H NMR (CDCI3) 5: 1.20 (t, 3H), 1.50 (s, 6H), 1.72 (s, 6H), 2.11 (s, 3H), 2.56 (s, 3H), 4.18 (q, 2H), 6.45 (dd, 1 H), 6.49 (d, 1H), 6.64 (d, 1H), 7.64 (d, 2H), 7.96 (d, 2H), t- Example 23 : 2jjr^thyl-2-(2--methyl-4-{1-rnethyl-1-[4-methyl-2-(4-trifluoromethyl-pheny1)-thiazol-5-yl]-ethoxy}-phenoxy)-propionic acid The same saponification conditions as described for racemic example 3 were applied to example 22 (300mg, 0.58mmo!) and gave in a 20% yield the title compound as a yellow powder (60 mg, 0.12rnmol). LC/MS :C25H27F3NO4S m/z 494.0 (M+1) 38 Example 24: 2-methyl-2-(2-methy)-4-f1-methyl-1-[2-(4-lrifluoromethyl-phenyl)-thiazol-5-yl]-ethoxy}-phenQxy)~propionic acid ethyl ester The same Mitsunobu conditions as described for racemic example 2 were applied to Intermediate 25 (460mg,1.6mmol) and phenol Intermediate 39 (381mg,1.85mmol) and afforded in a 13.5% yield the title compound (110mg, 1.17 mmoi) as an oil after purification by flash chromatography C6H12 / EtOAc (80:20) 1H NMR (CDCI3) 5: 1.15 (t, 3H), 1.46 (s, 6H), 1.50 (s, 3H),1.68 (s, 6H), 2.06'(s, 3H), 4.13 (q, 2H), 5.46 (q, 1H), 6.55 (s, 2H), 6.69 (br s, 1H), 7.60 (d, 2H), 7.66 (s, 1H), 7.95 (d, 2H) Example 25 . 2-methyl-2-(2-methyl-4-{1-methyl-1-f2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]--ethoxy}-phenoxy)-propionic acid The same saponification conditions as described for racemic example 3 were applied to example 24 (110mg, 0.217mmol) and gave in a 58% yield the title compound as a brown oil (60 mg, 0.125 mmol). LC/MS :C24H23F3NO4S m/z 478.1 (M-1) Example 26: 2-methyl-2-(2-methyl-4-{1-t4-methyl-2-(4-trifiuoromethylphenyl)-thiazol-5-yl]propoxy}phenoxy)propionic acid ethyl ester To a solution of intermediate 39 {1.03g, 4.3 mmol) and intermediate 26 (1.24g, 4.3 mmol, 1 eq) in dry toluene was added PBu3 (1.6mL, 6.45 mmol, 1.5 eq). The resulting mixture was allowed to stir at 0°C, and then TMAD (1.11 g, 6.45 mmol, 1.5 eq) was added. The mixture was stirred at 0°C for 1 hour, and at room temperature for 24 hours. The resulting mixture was filtered off, concentrated in vacuo, to afford after flash chromatography ( cyclohexane/ EtOAc : 95/5) the title compound as a yellow oil (1.3g, 2.49 mmol) in a 58% yield. 39 LC/MS: C27H3F3NO4S m/z 522.19 (M+1) i Example 27: 2-methvl-2-(2-methyl-4-{1-[4-methyl-2-(4-trifluoromethylphenyl)-thia2ol-5-yl]propoxy}phenoxy)propionicacid To a solution of example 26 (1.1g, 2.17 mmol)inTHF/ethanol (1/1) was added 1N NaOH (10 mmol, 4.6 eq). The resulting mixture was stirred at 80°C for 1.5 hour, and after cooling at room temperature 1N HCl (10 mmol, 4.6 eq) was added. The resulting mixture was concentrated in vacuo, and the residue was sonicated in water / EtOH. The resulting solid was filtered off and washed with water, diluted HCl, and water to give the title compound (680mg, 1.38 mmol) in a 64% yield as a white powder. LC/MS: C25H27F3NO4S: m/z 493.79 (M+1) Example 28 : (R)-2-methyl-2- (2-methyl~4- (1-[4-methyl-2~ (4-trifluorornethyl-phenyl)-thiazol-5-y[l propoxy}-phenoxy)-propionic acid ethyl ester The same Mitsunobu conditions as described for racemic example 2 were applied to intermediate 28 (1.4g, 4.65 mmol;e.e.= 98%) and phenol intermediate 39 (1.11g, 4.65 mmol) and gave in a 54% yield the title compound (1.3g, 2.5mmol) with an e.e. = 89%. MS : C27H31F3NO4S m/z: 522.1 (M+1) N^D = + 147.5 (c = 0.268, CHCI3) for ee = 89% HPLC : Chiralpak-AD (4.6x250 mm, 95%Hexane / 5% EtOH ) Rt: 8.98 min Example 29 : (R)-2-methyl-2- (2-methyl-4- {1-[4-methyl-2- (4-trifluoromethyl-phenyl)-thiazol-5-yl] propoxy}-phenoxy)-propionic acid The same saponification conditions as described for racemic example 3 were applied to example 28 (1.245g,2.4mmol, e.e. = 89%) and gave in a 68% yield the title compound as a white powder (800 mg, 1.6mmol) with an e.e. = 89%. 40 MS : C25H27F3NO4S: m/z 494.1 (M+1) [a]Z5D= + 145.2 (c = 0.259, CHCI3) for e.e. = 89% HPLC : Chiralpak-AD (4.6x250 mm, 95%Hexane/ 5% EtOH ) Rt: 15.88 min Example 30 : 1H NMR (CDCl3l 300 Mhz) 6 :1.02 (t, 3H), 1.20 (t, 3H), 1.49 (s, 6H)r 1.88 (m, 1H), 2.11 (m, 1H), 2.14 (s, 3H), 2.42 (s, 3H), 4.16 (q, 2H), 5.16 (t,1H), 6.51 (dd, 1H), 6.56 (d, 1H), 6.67 (d, 1H), 7.62{d, 2H), 7.96 (d, 2H), Example 31 . , (S)-2-methyl-2- (2-methyl-4- {1-[4-methyl-2- (4-trifluoromethy)-phenyl)-thiazol-S-yl] propoxy}-phenoxy)-propionic acid The same saponification conditions as described for racemic example 3 were applied to example 30 (1.6g, 3mmol) and gave in a 74% yield the title compound as a viscous oil (1.1g, 2.2 mmol) with an e.e. = 83%. *H NMR(CDCI3) 6: 1.03 (t, 3H), 1.51 (s, 6H), 1.89 (m, 1H), 2.12 (m, 1H), 2.16 (s, 3H), 2.24 (s, 3H), 5.18 (t, 1H), 6.55 (dd, 1H), 6.71 (m, 2H), 7.60 (d, 2H), 7.93 (d, 2H) [a]25D= -129 {c = 0.322, CHCl3) for e.e. = 83% HPLC : Chiralpak-AD (4.6x250 mm, 95%Hexane / 5% EtOH ) Rt: 7.57 min Example 32: 2-methyl-2-(2-methyl-4-{1-f4-methyl-2-(4-trifluoromethylphenyl)-thiazol-5-yl]but-3-enyloxy}phenoxy)propionic acid ethyl ester To a solution of intermediate 39 (1.5g, 6.3 mmol) and intermediate 32 (1.97g, 6.3 mmol, 1 eq) in dry toluene was added PBu* (2.35mL, 9.45 mmol, 1.5 eq). The resulting mixture was 41 stirred at 0°C, and then TMAD (1.63g, 9.45 mmol, 1.5 eq) was added. The mixture was stirred at O°C for 1 hour, and at RT for 24 hours. The resulting mixture was filtered off and concentrated in vacuo, and the title compound was obtained by flash chromatography using cyclohexane / ethyl acetate (8/2) as eluent, as a yellow oil (2.08g, 3.9 mmol) in a 62% yield. 1H NMR (CDCl3): 5 1.21 (t, 3H), 1.5 (s, 6H), 2.15 (s, 3H)t 2.42 (s, 3H), 2.65 (m, 1H), 2.85 (m, 1H), 4.2 (q, 2H), 5.15 (m, 2H), 5.30 (t, 1H), 5.85 (m, 1H), 6.55 (m, 2H), 6.7 (d, 1H), 7.65 (d, 2H), 7.97 (d, 2H), LC/MS: C2aH31F3NO4S: m/z 534.21 (M+1) H Example 33: 2-methyl-2-(2-methyl-4-{1>-[4-methyl-2-(4-trifIuoromethylph6nyl)-thiazQl-5-yribut-3-enyioxy}phenoxy) prop ionic acid To a solution of example 32 (1 g, 1.87 mmol) in THF / ethanol (1 /1) was added dropwise 0.2N NaOH (5.6 mmol, 3 eq). The resulting mixture was stirred at 50 °C for 3 hours, and after cooling at 0°C 0.2N HCI (5.6 mmol, 3eq) was added. The resulting mixture was concentrated in vacuo, then the residue was taken up in water and extracted with ethyl acetate. The organic phase was evaporated off and the residue was purified by flash chromatography using CH2CI2 / MeOH (97/3) as eluent. The residue was vigorously treated with 0.2N NaOH for 1 hour and then 0.2N HCI was added dropwise to yield to the precipitation of a white solid. After filtration, the white solid was washed with a small quantity of heptane to give the title compound (100mg, 0.2 mmol) in a 11 % yield as a white powder. LC/MS: C26H27F3NO4S: m/z 505.97 (M+1)/ C^HSSFSNCMS: m/z504.04 (M-1) Example 34: 2-methyl-2- (2-methy|-4- (1 -[4-methyl-2- (4-trifluoromethyl-phenyl)-thiazQl-5-yl] butoxyV-phenoxy)-propionic acid ethyl ester A mixture of 1 g of example 32 (1.8mmol), 100mg of 10% Pd on charcoal in EtOH (50mL) was stirred under an Hydrogen atmosphere at room temperature during 4 hours. The mixture was filtered through a celite pad and rinsed with 25 mL EtOH. The filtrate was concentrated to dryness to give the title compound (1.0g, 2mmol) as a brown powder in a quantitative crude yield. MS : C2aH33F3NO4S : m/z 536.1 (M+1) 42 i Example 35 : ' 2-methy!-2- (2-methyl-4- (1-[4-methyl-2- (4-trifluoromethyI-phenyl)-thiazol-5-yl] butoxy}-phenoxy)-propionic acid To a solution of example 34 (800 mg, 1.5 mmol) in THF/Ethanol (5/20mL) was added 1N NaOH {10 mmol, 10mL). The resulting mixture was stirred at 50 °C for 2 hours, and after cooling at room temperature 1N HCI (10 mmol, 10mL) was added. The resulting mixture was concentrated in vacuo, then the residue was flash chromatographed CH2Cl2/ MeOH (98:2) to give the title compound (310 mg, 0.61 mmol) in a 40% yield as a colorless oil. MS : C26H27F3NO4S : m/z 506.16 (M-1) MS : C26H29F3NO4S : m/z 508.0 (M+1) Example 36: 2-methyl-{2-methyl-2- (2-methyl-4- (1-[4-methyl-2- (4-trifluoromethy[-phenyl)-thiazol-5-yl]-propoxy)-phenoxy))-propionic acid ethyl ester To a solution of phenol intermediate 39 (1.58 g, 6.6 mmo!) and intermediate 31 (1.9g, 6.6mmol, 1.1 eq) in dry toluene was added PBu3 (1.66mL, 1.5 eq). The resulting mixture was allowed to warm to 0°C, and then TMAD (1.15g, 1.5 eq) was added. The mixture was stirred at 0°C for 1 hour, and at room temperature for 24 hours. The resulting mixture was filtered off and concentrated in vacuo, and the title compound was obtained by flash chromatography using Cyclohexane/Ethyl acetate (95/5), as a yellow oil (450mg, 0.84 mmol) in a 14% yield. MS : C28H33F3NO4S : m/z 536.1 (M+1) Example 37 ; 2-methyl-{2-methyl-2- (2-methyI-4- {1-[4-methyl-2- (4-trifluoromethyl-phenyl)-thlazql:5-yJh propoxy}-phenoxy)}-propionic acid To a solution of example 36 (450 mg, 0.84 mmol) in THF/Ethanol (5/20mL) was added 1N NaOH (5mmol, 5mL). The resulting mixture was stirred at 50 °C for 2 hours, and after cooling at room temperature 1N HCI (5 mmol, 5mL) was added. The resulting mixture was concentrated in 43 vacuo and the residue was flash chromatographed CH2CI2/ EtOAc (95:5) to give the title compound (290 mg, 0.57 mmol) in a 68 % yield as an amorphous yellow powder. MS : C26H27F3NO4S : m/z 506.24 (M-1) MS : C29H29F3NO4S : m/z 508.1 (M+1) Example 38: 2-methyl-2- (2-methyl-4- {H4-methyl-2- (4-trifluoromethyl-phenylHhiazol-5-yl] pentyloxy}-phenoxy)-propionic acid ethyl ester To a solution of Intermediate 39 (238mg, 1 mmol) and intermediate 33 (329mg, 1 mmol, 1 eq) in dry toluene was added PBu3 (1.5 mmol, 1.5 eq). The resulting mixture was allowed to warm to 0°C, and then TMAD (1.55 mmol, 1.5 eq) was added. The mixture was stirred at 0°C for 1 hour, and at room temperature for 24 hours. The resulting mixture was filtered off and concentrated in vacuo, and the title compound was obtained by flash chromatography using Cyclohexane/EtOAc (90:10), as a yellow oil (100mg, 0.18 mmol) in a 18% yield. 1H NMR(CDCI3) 5: 0.8 (t, 3H), 1.15 (t, 3H), 1.25 (m, 2H), 1.4 (s, 6H), 1.75 (m, 1H), 2.05 (m. 4H), 2.3 (s, 3H), 4.1 (q, 2H), 5.15 (t, 1H), 6.45 (dd, 1H), 6.55 (d, 1H), 6.6 (d, 1H), 7.55 (d, 2H), 7.9 (d, 2H) Example 39: 2-methyl-2- (2-methyl-4- {1-[4-methyl-2- (4-trifluoromethyl-prtenyl)-thiazol-5-yl] pentyloxy}-phenoxy)-propionic acid To a solution of example 38 (90 mg, 0.164 mmol) in THF/Ethanol (1/1) was added 1N NaOH (5 mmol, 5mL). The resulting mixture was stirred at 80 °C for 1.5 hour, and after cooling at room temperature 1N HCI (5 mmol, 5mL) was added. The resulting mixture was concentrated in vacuo, then the residue was flash chromatographed eluting with CH2Cl2/ EtOAc" (90:10) to give the title compound (20 mg, 0.038 mmol) in a 23% yield as a colorless oil. 1H NMR(CDCI3) 6: 0.8 (t, 3H), 1.15-1.35 (m, 4H), 1.45 (s, 6H), 1.8 (m, 1H), 2.05 (m, 4H), 2.35 (s, 3H); 5.15 (t, 1H), 6.45 (m, 1H), 6.65 (m, 2H), 7.55 (d, 2H), 7.9 (d, 2H) 44 Example 40 : 2-(4-{cyclopentyl-[4-nnethyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yll-methoxy}-2-tnethyl-phenoxy)-2-methyl-propionic acid ethyl ester To a solution of Intermediate 39 ( 714mg, 3 mmo!) and intermediate 34 (1.024g, 3mmol, 1.1 eq) in dry toluene was added PBu3 (1.1 mL, 1.5 eq). The resulting mixture was allowed to warm to 0°G, and then TMAD (774mg, 1.5 eq) was added. The mixture was stirred et 0°C for 1 hour, and at room temperature for 24 hours. The resulting mixture was filtered off and concentrated in vacuo, and the title compound was obtained as a viscous yellow oil (950mg, 0.84 mmo!) in a 56 % yield by flash chromatography using Cyclohexane/EtOAc (95:5) LC/MS ; C3oH35F3N04S : m/z 562.0 (M+1) Example 41 : 2-(4-(cycIopentyl-[4-methyl-2-(4-trifluoromethyl-phenyl)-triiazol-5-yl]-methoxy}-2-methyl-phenoxy)-2-methyl-propionic acid To a solution of example 40 (930 mg, 1.66 mmol) in THF/Ethanol (10/60mL) was added dropwise 1N NaOH (8.3mmol, 8.3mL) diluted in 15mL of water. The resulting mixture was stirred at 60 °C for 4 hours, and after cooling at room temperature 1N HCI (9 mmol, 9mL) diluted in 2"GmL of water was added. The resulting mixture was concentrated in vacuo and the residue was flash chromatographed CH2CI2/ MeOH (98:2) to give the title compound (690 mg, 1.29 mmol) in a 78 % yield as a white amorphous powder. LC/MS : C28H29F3NCXtS : m/z 532.2 (M-1) LC/MS : C2flH31F3NO4S : m/z 534.2 (M+1) Example 42: 2-methyl-2-f2-methyl-4-{1-[4-methyl-2-(4-trifluoromethylphenyl)-thiazol-5-yl]phenylmethoxy}phenoxy)propionic acid ethyl ester To a solution of intermediate 39 (715mg, 3 mmol) and intermediate 35 (1.05g, 3 mmol, 1 eq) in dry toluene was added PBu3 (1.11 mL, 4,5 mmol, 1.5 eq). The resulting mixture was allowed to stir at 0°C, and then TMAD (775mg, 4.5 mmol, 1.5 eq) was added. The mixture was stirred at 45 0°C for 1 hour, and at room temperature for 24 hours. The resulting mixture was filtered off and concentrated in vacuo, and the title compound was obtained by flash chromatography using cyclohexane / ethyl acetate (85:15) as eluent, as a yellow oil (870mg, 1.53 mmol) in a 51% yield. LC/MS: C3iH31F3NO4S: m/z 569.99 (M+1) Example 43: 2-methyl-2-(2-methyl-4-{1-[4-methyl-2-(4-trifluoromethylphenyl)-thia2ol-5-ylphenylmethoxy)phenoxy)propionicacid To a solution of example 42 (740mg, 1.3 mmol) in THF / ethanol (1/1) was added dropwise 0.2N NaOH (6.5 mmol, 5 eq). The resulting mixture was stirred at 50°C for 4 hours, and after cooling at 0°C 0.2N HCI (6.5 mmol, 5 eq) was added. The resulting mixture was concentrated in vacuo, then the residue was taken up in water and extracted with ethyl acetate. The organic phase was evaporated off and the residue was purified by flash chromatography using CH2CI2 / ethyl acetate (80/20) as eluent. The residue was vigorously treated with 0.2N NaOH for 1 hour and then 0.2N HCI was added dropwise to yield to the precipitation of a white solid. After filtration, the white solid was washed with a small quantity of heptane to give the title compound (300mg, 0.55 mmol) in a 43% yield. LC/MS: C29H27F3NO4S: m/z 541.94 (M+1)/C29H25F3NO4S: m/z540.03 (M-1) Example 44: 2-methyl-2-(2-methyl-4-[4-methyl-2-(4--trif1uoromethylphenyl)thiazol-5-y|-. methoxy]phenoxy)propionic acid ethyl ester 480mg of Intermediate 39 (2 mmol) in 50mL of acetone were stirred with 1g of Cs2CO3 for 15 minutes. Intermediate 40 ( 651 mg, 2.2mmol) was added and the mixture heated to reflux for 1 hour. After filtration and concentration under vacuo the residue was taken up with 200mL of CH2CI2 and washed with water. The organic layer was dried over Na2SO4l filtered and concentrated to afford 0.9g of the expected compound as an oil. 1H NMR (CDCI3): 5 1.21 (t, 3H), 1.5 (s. 6H), 2.17 (s, 3H), 2.42 (s, 3H), 4.2 (q, 2H), 5.05 (s. 2H), 6.62 (dd, 1H), 6.75 (m, 2H), 7.58 (d, 2H), 7.92 (d, 2H), 46 Example 45: 2-methyl-2-f2-methy)-4-[4-methyl-2-(4-trifluoro methyl phenyQthi azol-5-yl-methoxy]phenoxy)propionic acid 900mg of example 44 dissolved in 30mL of EtOH and 10mL of IN NaOH were heated to reflux for 1 hour. After cooling to room temperature the solution was acidified with 1N HC! and concentrated under vacuo. Trituration of the residue with water afforded after filtration and washing with water an off white powder which was recrystallized with CH3CN to give 370mg of the title compound as slightly yellow crystals. mp: 154°C Example 46: / 2-methyI-2-(2-methyl-4-(1-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazoI-5-vl1-2-phenyl-ethoxy)-phenoxy)-propionic acid ethyl ester The same Mitsunobu conditions as described for racemic example 2 were applied to Intermediate 36 (1g, 2.75mmol) and phenol Intermediate 39 {655mg, 2.75mmol) and afforded in a 21% yield the title compound (340mg, 0.58 mmol) as a brown residue after purification by flash chromatography C6Hi2/EtOAc (9:1). LC/MS C32H33F3NO4S m/z 584.2 (M+1) c Example 47: 2-methyl-2-{2-methyi-4-{1-[4-methyl-2-(4-triflucromethyl-phenylHhia2ol-5-yn-2-phenyl- ethoj LC/MS C3oH27F3NCX,S m/z 554.3 (M-1) 47 Example 48 : 2-methyl-2-(2-methyl-4"{1-[4-methyl-2-(4-trif[uoromethyl-phenyl)-thiazol-5-yl]-ethylsulfanyl}-phenoxy)-propionic acid ethyl ester To a suspension of intermediate 16 (287mg, 1 mmol) and Znl2 (160mg, 0.5mmol) in 10mL CH2CI2 was added intermediate thiophenol 44 {305mg, 1.2mmol) in solution in 10 mL of CH2CI2. After stirring 24 hours at rt the reaction was not complete and a supplementary equivalent of Znl2 (319mg, 1 mmol) was added. The mixture was stirred 24 hours at rt quenched with water (10 mL) and 100 mL of CH2Cl2 were added and the organic phase separated dried over Na2SO4 concentrated under vacuo and purified by flash chromatography C6H12/Et0Ac (90:1.0). The title compound (320mg, 0.61 mmol) was obtained as a colorless viscous oil in a 61% yield. LC/MS :C25H29F3NO3S2 m/z 523.98 (M+1) Example 49: 2-methyi-2-(2-nnethyl-4-{1-[4-methyl-2-(4-trifluoromethyl-phenylHhiazol-5-yl]-ethylsulfanyl}-phenoxy)-propionic acid The same saponification conditions as described for racemic example 3 were applied to example 48 (290mg, 0.56mmo!) and gave in a 47% yield the title compound as a white powder1 (130 mg, 0.262 mmol). 1H NMR (CDCI3) 5:1.59 (s, 6H), 1.68 (d, 3H), 1.99 (s, 3H), 2.14 (s, 3H), 4.41 (q, 1H), 6.61 (dd, 1H), 6.95 (dd, 1H), 7.04 ( brs, 1H), 7.15 (d, 1H), 7.66 (d, 2H), 7.94 (d, 2H) Example 50 : 2-methyl-2-(2-methyl-4-{1-[2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethylsulfanyl}-phenoxy)-propionic acid ethyl ester The same Mitsunobu conditions as described for racemic exampie 2 were applied to Intermediate 17 (35Omg,1.3mrnol) and thiophenol Intermediate 44 (358mg,1.3mmol) and afforded in a 80% yield the title compound (520mg, 1.02 mmol) as an oil after purification by flash chromatography CH2CI2 48 jH NMR (CDCI3) S; 1.24 (f, 3H), 1.82 (s, 6H), 1.74 {d, 3H}, 2.20 (s, 3H), 4.24 (q, 2H), 4.50 (q, 1H), 6,58 (d, 1H). 7.07 (dd, 1H), 7.20 (d, 1H), 7,71 (d. 2H), 8.03 (d, 2H) Example 51 : 2-methyl-2-(2-methvl-4-{1-f2-(44rifluoromethyl-pheny[Hhiazo[-5-yi}-ethyisuIfanyi}-phenoxy)-propionic acid The same saponificafjors conditions as described for racemfe example 3 were applied to example 50 (520mg, 1,02mmol) and gave in a quantitative yield the title compound as an off-white powder. LC/MS C23H23F3NO3S2 m/z 481.93 (M+1) LC/MS C23H2iF3NO3S2 m/z 480.00 (M-1) Example 52: 2-me^yl-2-(2-methyM^1-methyl-1-[4-methyl-2-(4-trifiuorometriyl-pheriyl)-thiazol-5-yl}-ethylsulfanyl}-phenoxy)-propioniG acid ethyl ester The same coupling conditions as described for example 48 were applied to Intermediate 24 {350mgt1.16mmoO and thioprtenol intermediate 44 (354mg,1.3mmol) and afforded in a 22% yield the title compound (140mg, 0.26mmoi) as a colorless oil after purification by flash chromatography C6H12/EtOAc (80:20) LC/MS C27Ha1F3NO3Sa m/z 538 (M+1) Example 53: 2-methy t~2-(2-roetliyl-4-{ 1 -methyl-1 -[4-mef hyl-2-(4~trifluoromethyl-phenyl )-triiazol-5-y]]-ethylsuifanyl)-phenoxy)-propionicacid 49 The same saponification conditions as described for racemie example 3 were applied to example 52 (140mg, 0,28mmol) and gave fn a 52% yield the title compound {70mg,0.13mmol) as a colorless oil. LC/MS CasHsjFsNOsSj: m/z 510,1 (M+1) LC/MS C25H25F3NO3S2 m/z 508.2 (M-1) Example 54: 2-methyl~2-(2-methyM~{1-methyl-H2-(44rffl^ phenoxy)-propionic acid ethyl ester The sam© coupling conditions as described for example 48 were applied to Intermediate 25 (350mg,1.22mmol) and thiophenof intermediate 44 {371mg,1.4nvno!)and afforded in a 46% yield the title compound |300mg, 0.57 mmol) as a colorless oil after purification by flash chromatography CH2CI2. 1H NMR {CDCI3) 8: 1.1 (t, 3H), 1,46 (s, 6H), 1.63 (s, 6H), 2.05 (s, 3H), 4.1 (q, 2H), 6.4 (d, 1H), 6.85 (dd, 1H), 6.98 (d, 1H), 7.62 (d, 2H), 7.95 (d, 2H) Example 55: 2-methyl-2-(2-methyS-4^1-methyl-1-[2-(4-trifluorornethyl-phenyl)-thiazol-5-yl]-ethylsulfanyl}--phenoxy)-propionic acid The same saponification conditions as described for racemie example 3 were applied to example 54(300mg, Q.54mmoi) and gave in a 48% yield the title compound (130mg, G.262mmol) as a gummy solid. ' LC/MS G24H2sF3NO3S2 rn/z 496.0 {M+1} Example 56: 50 2-methy[-2-(2-methyl-4-{1-[4-mefhyl-2-(4-trifluoromethyl-phenylj-thiazof-5-y[]-propylsulfanyi}-phenoxy)-propionic add ethyl ester The same coupling conditions as described for example 48 were applied-to Intermediate 26 {800mg,2.6mmol) and thiophenol intermediate 44 {eeomg^.emmol) and afforded in a 71% yield the title compound {1000mg, 1,86mmol) as a stightly yellow oil after purification by flash chromatograpfty C6Hi2/EtOAc (95:5). LC/MS C^HstFaNOaSa m/z 538,01 (M+1) Example 57: 2-methyl-2-(2-methyl^41-|4-methyl-2-(4-trifluofomethyl-phenyl)-thia20i-5-yl]-propyisulfanyl}-phenoxy)-propionicacid The same saponification conditions as described for racemic example 3 were applied to exampie 56 (1g, 1.86mmol) and gave in a 88% yield the title compound (840mg, 1.65 mmol) as an amorphous white powder. LC/MS C2SH27F3NO3S2 m/z 510.0 (M+1) LC/MS C25H25F3NO3S2 m/z 508.1 (M-1) The foiiowing intermediates and iigands were prepared for the 'binding and transfection assays described below: (0 2-f2-methyl-4-[C{4-methyi~2-f4-(trifluoromethyi)phenyl1-1,3-thiazol-5- yl}methyl)sulfanyl]phenoxy}acetic acid. This compound was used as a PPARdelta reference in the transfection assays described below and was prepared according to the method reported in WO200100603-A1 (ii) 2-methyl-2-{4-{[f4-methyi-2-[4-tr>fluorornethylphenyi|-thiaz,ol-5-yl carbonyl)3m'tno]methyl)-phenoxy]propionicacid. This compound was used as a PPAR alpha reference in the transfection assay described below and was prepared according to method reported in WO200140207-A1 pit) 5-{4-[2-(Methyt-pyridin-2-y[-amIno)-ethoxy]-benzytHhiazolidine-2,4 -dione 51 This compound was used as a PPAR gamma reference in the fransfection assay described below and was prepared according to method reported in JMed.Chem. 1994, 37(23), 3977 Binding Assay: Compounds were tested for their ability to bind to hPPAR gamma hPPARialpha or PPARdelta using a Scintillation Proximity Assay (SPA). The PPAR ligand binding domain (LBD) was expressed in E. coli as poiyHis tagged fusion proteins and purified. The LBD was then labelled with biotin and immobilised on streptavidin-modified scintillation proximity beads. The beads were then incubated with a constant amount of the appropriate radioligand {3H-BRL 49653 for PPARgamma, radiolabelled 2-{4-(2-(2,3-Ditritfo-1-heptyl-3-(2,4- difluorophenyl)ureido)ethyl)phenoxy^2-methylbutanoic acid for hPPAR alpha {see WO 00/08002J and labelled GW 2433 (see Brown, P, J et al. Chem. Biol., 4, 909-918 (1997). For the structure and synthesis of this ligand) for PPAR delta) and variable concentrations of test compound, and after equilibration the radioactivity bound to the beads was measured by a scintillation counter. The amount of nonspecific binding, as assessed by control wells containing 50 py of the corresponding unlabeled ligand, was subtracted from each data point. For each compound tested, plots of ligand concentration vs. CPM of radioligand bound were constructed and apparent KI values were estimated from nonlinear least squares fit of the data assuming simple competitive binding. The details of this assay have been reported elsewhere (see, Blanchard, S. G. et. al. Development of a Scintillation Proximity Assay for Peroxisome Proliferator-Aciwaied Receptor gamma Ligand Binding Domain. Anal. Biochem,, 257,112-119 (1998)). Transfection assay: Compounds were screened for functional potency in transient transfection assays In CV-1 cells for their ability to activate the PPAR subtypes (transactivation assay). A previously established chimerie receptor system was utilized to allow comparison of the relative transcriptional activity of the receptor subtypes on the same target gene and to prevent endogenous receptor activation from complicating the interpretation of results. See, for example, Lehmann, J. M.; Moore, L. B.; Smith-Oliver. T. A.; Wilkison, W. O.; Wiilson, T. M.; Kliewer, S. A., An antidiabetic thiazoitdinedione is a high affinity iigand for peroxisome proliferator-activated receptor gamma (PPARgammaJ, J. Biol. Chem., 270,12953-6 (1995). The ligand binding domains for murine and human PPAR alpha, PPAR gamma, and PPAR delta were each fused to the yeast transcription factor GAL4 DNA binding domain. CV-1 cells were transiently transfected with expression vectors for the respective PPAR chimera along with a reporter construct containing five copies of the GAL4 DNA binding site driving expression of secreted placenta! alkaline phosphafase (SPAP) and beta-gafacfosidase. After 16 h, the medium was exchanged to DME medium supplemented with 10% deiipidated fetal calf serum and the test compound at the appropriate concentration. After an additional 24h, cell extracts were prepared and assayed for 52 alkaline phosphatase and p-galactosidase activity. Alkaline phosphatase activity was corrected for transfection efficiency using the beta-galactosidase activity as an internal standard (see, for example, Kliewer, S. A., et. al. Cell 83, 813-819 (1995)). Rosiglitazone (BRL 49653) was used as a positive control in the hPPAR gamma assay. The positive control in the hPPAR alpha assays was 2-methy!-2-[4-{[(4-methyl-2-[4-trifluoromethylphenyI]-thiazol-5-yl-carbonyl)amino]methyl}-phenoxyjpropionic acid. The positive control for PPAR delta assays was 2-{2-methyl-4-[({4-methyI-2-{trifluoromethyl)phenyIJ-1,3-th iazol-5-yl}methyl)sulfanyl]phenoxy}acetic acid. All of the above acid Examples showed at least 50% activation of hPPARS relative to the positive control at concentrations of 10"7 M or less. Activities in three hPPAR subtypes are reported in the table below for the most preferred compounds and are expressed in nanomolar. S3 WE CLAIM : 1. Thiazole derivatives of formula (I) or a pharmaceutically acceptable salt, solvate, or hydrolysable ester thereof, wherein: (1) R1 and R2 are independently H or CM alkyl, or R1 and R2 which are bonded to the same carbon atom may together with the carbon atom to which they are bonded form a 3-6 membered cycloalkyl ring, and at least one of R1 and R2 must be other than H; X2 is O, S, or (CRl0Ru)n where n is 1 or 2; R3, R4, and R5 are independently H, C^alkyl, OCH3, CF3, allyl, or halogen; R10 and R" are independently H, fluorine, or Ci^alkyl; one of Y and Z is N, the other is S or O; R6 and R7 are independently H, phenyl, benzyl, fluorine OH, Cw alkyl, allyl, R6 and R7 may, together with the carbon atom to which they are bonded, represent a carbonyl group; R9isH,CF3orCH3; Each R8 is independently CF3, Ci.3alkyl, OCH3 or halogen; y is 0, 1, 2, 3, 4, or 5. 2. A compound as claimed in claim 1 wherein at least one of R1 and R2 is CH3. 3. A compound as claimed in claim 2 wherein R1 and R2 are both CH3. 4. A compound as claimed in any of claims 1-3 wherein X2 is O, S, or C(R10R"). 54 5. A compound as claimed in claim 4 wherein X2 is O or S. 6. A compound as claimed in any of claims 1-5 wherein Z is N. 7. A compound as claimed in any of claims 1-6 wherein Y is S. 8. A compound as claimed in any of claims 1-8 wherein R3 is CH3 and R4 and R5 are independently H or CH3. 9. A compound as claimed in any preceding claim wherein R6 is H, CH2CH3, or CH3. 10. A compound as claimed in any preceding claim wherein R7 is H. 11. A compound as claimed in any of claims 1-10 wherein y is 1 or 2. 12. A compound as claimed in claim 11 wherein y is 2. 13. A compound as claimed in claim 12 wherein the one of R8 substituents is halogen. 14. A compound as claimed in claim 13 wherein one of the R8 substituents is halogen and the other is CF3. 15. A compound as claimed in claim 10 wherein y is 1. 16. A compound as claimed in claim 15 wherein the R8 substituent is in the para position. 17. A compound as claimed in claim 18 wherein R8 is CF3. 18. A compound as claimed in claim 1 selected from the group consisting of: 55 2-{4-[({2-[2-fluoro-4-(trifluoromethyl)phenyI]-4-methyl-l,3-thiazol-5-yl}methyl) sulfanyl]-2-methylphenoxy}-2-methylpropanoic acid 2-methyl-2-(2-methyl-4-{l-[4-methyl-2-(4-trifluoromethylphenyl)thiazol-5-yl]ethoxy} phenoxy)propionic acid ethyl ester 2-methyl-2-(2-methyl-4- {1 -[4-methyl-2-(4-trifluoromethylphenyl)thiazol-5-yl]propoxy } phenoxy)propionic acid ethyl ester 2-methyl-2-(2-methyl-4-{l-[4-methyl-2-(4-trifluoromethylphenyl)thiazol-5-yl]but-3- enyloxy}phenoxy)propionic acid ethyl ester 2-methyl-2-(2-methyl-4~{l-[4-methyl-2-(4-trifluoromethylphenyl)-thiazol-5-yl] phenylmethoxy}phenoxy)propionic acid ethyl ester (2-methyl-4- {l-[4-methyl-2- (4-trifluoromethylphenyl)-thiazol-5-yl] ethoxy}-phenoxy)- acetic acid ethyl ester 2-methyl-2- (2-methyl-4- {l-[4-methyl-2- (3-Fluoro-4-trifluoromethylphenyl)-thiazol-5- yl] ethoxy}-phenoxy)-propionic acid ethyl ester (S)-2-methyl-2- (2-methyl-4- {l-[4-methyl-2- (4-trifluoromethylphenyl)-thiazol-5-yl] ethoxy}-phenoxy)-propionic acid ethyl ester (R)-2-methyl-2- (2-methyl-4- {l-[4-methyl-2- (4-trifluoromethylphenyl)-thiazol-5-yI] ethoxy}-phenoxy)-propionic acid ethyl ester 2-(4-{l-[2-(4-chloro-phenyl)-4-methyl-thiazol-5-yl]-ethoxy}-2-methyl-phenoxy)-2- methyl-propionic acid ethyl ester 2-(4-{l-[2-(3,4-dichloro-phenyl)-4-methyl-thiazol-5-yl]-ethoxy}-2-methyl-phenoxy)-2- methyl-propionic acid ethyl ester 2-(4-{l-[2-(4-ethyl-phenyl)-4-methyl-thiazol-5-yl]-ethoxy}-2-methyl-phenoxy)-2-methyl- propionic acid ethyl ester 2-(4-{l-[2-(2-fluoro-4-trifluoromethyl-phenyl)-4-methyl-thiazol-5-yl]-ethoxy}-2 -methyl- phenoxy)-2-methyl-propionic acid ethyl ester 2-methyl-2-(2-methyl-4-{l-[2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethoxy}- phenoxy)-propionic acid ethyl ester 2-methyl-2-(2-methyl-4- {1 -methyl-1 -[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5- yl]-ethoxy}-phenoxy)-propionic acid ethyl ester 56 2-methyl-2-(2-methyl-4- {1 -methyl-1 -[2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethoxy} - phenoxy)-propionic acid ethyl ester (R)-2-methyl-2- (2-methyI-4- {l-[4-methyl-2- (4-trifluoromethyl-phenyl)-thiazol-5-yl] propoxy}-phenoxy)-propionic acid ethyl ester (S)-2-methyl-2- (2-methyl-4- {l-[4-methyl-2- (4-trifluoromethyl-phenyl)-thiazol-5-yl] propoxy}-phenoxy)-propionic acid ethyl ester 2-methyl-2- (2-methyl-4- {l-[4-methyl-2- (4-trifluoromethyl-phenyl)-thiazol-5-yl] butoxy}-phenoxy)-propionic acid ethyl ester 2-methyl-{2-methyl-2- (2-methyl-4- {l-[4-methyl-2- (4-trifluoromethyl-phenyl)-thiazol- 5-yl]- propoxy}-phenoxy)}-propionic acid ethyl ester 2-methyl-2- (2-methyl-4- {l-[4-methyl-2- (4-trifluoromethyl-phenyl)-thiazol-5-yl] pentyloxy}-phenoxy)-propionic acid ethyl ester 2-(4-{cyclopentyl-[4-methyI-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-methoxy}-2- methyl-phenoxy)-2-methyl-propionic acid ethyl ester 2-methyl-2-(2-methyl-4-[4-rnethyl-2-(4-trifluoromethylphenyl)thiazol-5-yl-rnethoxy] phenoxy)propionic acid ethyl ester 2-methyI-2-(2-methyl-4-{l-[4-methyl-2-(4-trifluoromethyI-phenyl)-thiazol-5-yl]-2- phenyl-ethoxy}-phenoxy)-propionic acid ethyl ester 2-methyl-2-(2-methyl-4-{l-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]- ethylsulfanyl}-phenoxy)-propionic acid ethyl ester 2-methyl-2-(2-methyl-4-{l-[2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethylsulfanyl}- phenoxy)-propionic acid ethyl ester 2-methyl-2-(2-methyl-4-{l-methyl-l-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5- yl]-ethylsulfanyl}-phenoxy)-propionic acid ethyl ester 2-methyI-2-(2-methyl-4-{l-methyl-l-[2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]- ethylsulfanyl}-phenoxy)-propionic acid ethyl ester 2-methyl-2-(2-rnethyl-4-{l-[4-rnethyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]- propylsulfanyl}-phenoxy)-propionic acid ethyl ester 2-methyl-2-(2-methyl-4-{l-[4-methyl-2-(4-trifluoromethylphenyl)-thiazol-5-yl] phenylmethoxy}phenoxy)propionic acid 57 2-methyl-2-(2-methyl-4- {1 -[4-methyl-2-(4-trifluoromethylphenyl)thiazol-5-yl]ethoxy } phenoxy)propionic acid 2-methyl-2-(2-methyl-4-{l-[4-methyl-2-(4-trifluoromethylphenyl)thiazol-5-yl]propoxy} phenoxy)propionic acid 2-methyl-2-(2-methyI-4-{l-[4-methyl-2-(4-trifluoromethylphenyl)-thiazol-5-yl]but-3- enyloxy}phenoxy)propionic acid (2-methyl-4- {l-[4-methyl-2- (4-trifluoromethylphenyl)-thiazol-5-yl] ethoxy}-phenoxy)- acetic acid 2-methyl-2- (2-methyl-4- {l-[4-methyl-2~ (3-Fluoro-4-trifluoromethylphenyl)-thiazol-5- yl] ethoxy}-phenoxy)-propionic acid (S)-2-methyl-2- (2-methyI-4- {l-[4-methyl-2- (4-trifluoromethylphenyl)-thiazol-5-yl] ethoxy}-phenoxy)-propionic acid (R)-2-methyl-2- (2-methyl-4- {1 -[4-methyl-2- (4-trifluoromethylphenyl)-thiazol-5-yl] ethoxy}-phenoxy)-propionic acid 2-(4-{l-[2-(4-chloro-phenyl)-4-methyl-thiazoI-5-yl]-ethoxy}-2-methyl-phenoxy)-2- methyl-propionic acid 2-(4-{l-[2-(3,4-dichloro-phenyl)-4-methyl-thiazol-5-yl]-ethoxy}-2-methyl-phenoxy)-2- methyl-propionic acid 2-(4-{l-[2-(4-ethyl-phenyl)-4-methyl-thiazol-5-yl]-ethoxy}-2-methyl-phenoxy)-2-methyl- propionic acid 2-(4-{l-[2-(2-fluoro-4-trifluoromethyl-phenyl)-4-methyl-thiazol-5-yl]-ethoxy}-2-methyl- phenoxy)-2-methyl-propionic acid 2-methyl-2-(2-methyl-4-{l-[2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethoxy}- phenoxy)-propionic acid 2-methyl-2-(2-methyl-4-{l-methyl-l-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5- yl]-ethoxy} -phenoxy)-propionic acid 2-methyl-2-(2-methyl-4-{l-methyl-l-[2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethoxy}- phenoxy)-propionic acid (R)-2-methyl-2- (2-methyl-4- {l-[4-methyl-2- (4-trifluoromethyl-phenyl)-thiazol-5-yl] propoxy}-phenoxy)-propionic acid 58 (S)-2-methyl-2- (2-methyl-4- {1 -[4-methyl-2- (4-trifluoromethyl~phenyl)-thiazol-5-yl] propoxy}-phenoxy)-propionic acid 2-methyl-2- (2-methyl-4- {1 -[4-methyl-2- (4-trifluoromethyl-phenyl)-thiazol-5-yl] butoxy}-phenoxy)-propionic acid 2-methyl-{2-methyl-2- (2-methyl-4- {l-[4-methyl-2- (4-trifluoromethyl-phenyl)-thiazol- 5-yl]- propoxy}-phenoxy)}-propionic acid 2-methyl-2- (2-methyl-4- {l-[4-methyI-2- (4-trifluoromethyl-phenyl)-thiazol~5~yl] pentyloxy}-phenoxy)-propionic acid 2-(4-{cyclopentyl-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-methoxy}-2- methyl-phenoxy)-2-methyl-propionic acid 2-methyl-2-(2-methyl-4-[4-methyl-2-(4-trifluoromethylphenyl)thiazol-5-yl-methoxy] phenoxy)propionic acid 2-methyl-2-(2-methyl-4-{l-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yI]-2- phenyl-ethoxy} -phenoxy)-propionic acid 2-methyl-2-(2-methyl-4-{l-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]- ethylsulfanyl}-phenoxy)-propionicacid 2-methyl-2-(2-methyl-4-{l-[2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethylsulfanyl}- phenoxy)-propionic acid 2-methyi-2-(2-methyl-4-{l-methyl-l-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5- yl]-ethylsulfanyl}-phenoxy)-propionic acid 2-methyl-2-(2-methyI-4-{l-methyl-l-[2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]- ethylsulfanyl}-phenoxy)-propionic acid 2-methyl-2-(2-methyl-4-{l-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]- propylsulfanyl} -phenoxy)-propionic acid and phannaceutically acceptable salts and solvates thereof. 19. A compound as claimed in claim 1 selected from the group consisting of: 2-{4-[({2-[2-fluoro-4-(trifluoromethyl)phenyl]-4-methyl-l,3-thiazol-5-yl}methyl) sulfanyl]-2-methylphenoxy} -2-methylpropanoic acid (S)-2-methyi-2- (2-methyl-4- {1 -[4-methyl-2- (4-trifluoromethylphenyl)-thiazol-5-yl] ethoxy}-phenoxy)-propionic acid 59 (R)-2-methyl-2- (2-methyl-4- {1 -[4-methyl-2- (4-trifluoromethyIphenyl)-thiazol-5-yl] ethoxy}-phenoxy)-propionic acid (R)-2-methyl-2- (2-methyl-4- {l-[4-methyl-2- (4-trifluoromethyl-phenyl)-thiazol-5-yl] propoxy}-phenoxy)-propionic acid (S)-2-methyl-2- (2-methyl-4- {l-[4-methyI-2- (4-trifluoromethyl-phenyl)-thiazol-5-yl] propoxy}-phenoxy)-propionic acid and pharmaceutically acceptable salts and solvates thereof. 20. A compound as claimed in any preceding claim which is a hPPAR agonist. 21. A compound as claimed in any of claims 1-20 for use in therapy. 22. A pharmaceutical composition comprising a compound as claimed in any of claims 1-20. 23. A pharmaceutical composition as claimed in claims 1-20 for the manufacture of a medicament for the treatment of a hPPAR disease or condition. 24. A pharmaceutical composition as claimed in claim 23 wherein the hPPAR mediated disease or condition is dyslipidemia, syndrome X, heart failure, hypercholesteremia, cardiovascular disease, type II diabetes mellitus, type I diabetes, insulin resistance, hyperlipidemia, obesity, anorexia bulimia and anorexia nervosa 25. A pharmaceutical composition as claimed in claim 22 for treating a hPPAR mediated disease or condition in a patient. 26. A pharmaceutical composition as claimed in claim 25 wherein the hPPAR mediated disease or condition is dyslipidemia, syndrome X, heart failure, hypercholesteremia, cardiovascular disease, type II diabetes mellitus, type I diabetes, insulin resistance, hyperlipidemia, obesity, anorexia bulimia and anorexia nervosa. 60 27. A compound of the formula: or a pharmaceutically acceptable salt or solvate thereof. 28. A pharmaceutical composition comprising a compound as claimed in claim 27. 29. A pharmaceutical composition as claimed in claim 27, capable of being used in the manufacture of a medicament for the treatment of an hPPAR mediated disease or condition in a patient wherein the hPPAR mediated disease or condition is selected from the group consisting of dyslipidemia, syndrome X, heart failure, hypercholesteremia, cardiovascular disease, type II diabetes mellitus, type I diabetes, insulin resistance, hyperlipidemia, obesity, anorexia bulimia and anorexia nervosa. The present invention provides compounds of formula (I). These compounds are used for the treatment of PPAR rclated diseases. |
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| Patent Number | 210099 | |||||||||||||||
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| Indian Patent Application Number | 00757/KOLNP/2003 | |||||||||||||||
| PG Journal Number | 38/2007 | |||||||||||||||
| Publication Date | 21-Sep-2007 | |||||||||||||||
| Grant Date | 18-Sep-2007 | |||||||||||||||
| Date of Filing | 11-Jun-2003 | |||||||||||||||
| Name of Patentee | GLAXO GROUP LIMITED | |||||||||||||||
| Applicant Address | GLAXCO WELLCOME HOUSE,BERKELEY AVENUE, GREENFORD,MIDDLESEX, UB6 ONN, | |||||||||||||||
Inventors:
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| PCT International Classification Number | C07 D 277/26 | |||||||||||||||
| PCT International Application Number | PCT/US01/49230 | |||||||||||||||
| PCT International Filing date | 2001-12-19 | |||||||||||||||
PCT Conventions:
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