MXPA06003061A - 4-((phenoxyalkyl)thio)-phenoxyacetic acids and analogs - Google Patents

Abstract

The invention features 4-((phenoxyalkyl)thio)-phenoxyacetic acids and analogs, compositions containing them, and methods of using them as PPAR delta modulators to treat or inhibit the progression of, for example, dyslipidemia.

Description

ACIDS 4 - ((PHENOXYALYCHOTITE? -FENOXYACETICS AND ANALOGS CROSS REFERENCE TO RELATED REQUESTS This application claims priority to U.S. Provisional Patent Application No. 60/504146, filed September 19, 2003, which is hereby incorporated by reference in its entirety.

DECLARATION REGARDING RESEARCH AND DEVELOPMENT SPONSORED BY THE FEDERAL GOVERNMENT The research and development of the invention described below was not sponsored by the federal government.

BACKGROUND OF THE INVENTION Cardiovascular disease (CVD) is common in the world and is often associated with other diseases such as diabetes and obesity. Many population studies have attempted to identify the risk factors for CVD; of these, the elevated plasma levels of low density lipoprotein cholesterol (LDL-C), high levels of plasma triglycerides (> 200mg / dl), and low levels of high density lipoprotein cholesterol (HDL- C) are considered to be among the most important. Currently, there are few therapies aimed at low levels of HDL-C and triglycerides. The receptors activated by peroxisome proliferator (PPARs) are metabolic sensors that regulate the expression of genes involved in the homeostasis of glucose and lipids. PPARα subtype agonists, such as LOPID® (gemfibrozil) and TRICOR® (fenofibrate), and PPARα subtype agonists, such as AVANDIA® (rosiglitazone maleate), are used for the treatment of dyslipidemia and diabetes, respectively. Another member of this nuclear receptor family, the peroxisome proliferator-activated receptor delta (PPAR delta or PPARd) is also a necessary transcription factor reported by spher involved in regulatory genes involved in lipid metabolism and energy expenditure. It has been shown that PPAR delfa acts as a "gateway" receptor that modulates the expression of other PPARs (Shi et al., 2002, Proc Nafl Acad.Sci USA, 99 (5): 2613-2618). Each receptor subtype has a different tissue distribution: 1) PPARa shows the highest expression in the liver, 2) PPAR? appears mainly in adipose tissue, and 3) PPARd has the widest distribution - ubiquitously in adult rat (Braissant et al., 1996, Endocrinology 137 (1): 354-366) and in all human tissues tested to date , Including liver, kidney, abdominal adipose tissue and skeletal muscle (Auboeuf et al., 1997, Diabetes 46 (8): 1319-1327). Recently, powerful lectures have been published for PPARd, which provide a better understanding of their role in lipid metabolism. The main effect of these compounds in db / db mice (Leibowitz et al., 2000, FEBS Lett 473 (3): 333-336) and obese rhesus monkeys (Oliver et al., 2001, Proc. Nati. Acad. Sci USA 98 (9): 5306-5311) was an increase in high density lipoprotein cholesterol (HDL-C) and a decrease in triglycerides, with little effect on glucose (although Insulin levels were reduced in monkeys). HDL-C removes cholesterol from peripheral cells through a process called reverse cholesterol transport. The first step and rate limiter, a transfer of cellular cholesterol and phospholipids to the apolipoprotein A-1 component of HDL, is mediated by the ATP A1 binding cassette transporter (ABCA1) (Lawn et al., 1999, J. Clinical Investigation 104 (8): R25-R31). It has been shown that the activation of PPARd increases the level of HDL-C through the transcriptional regulation of ABCA1 (Oliver et al., 2001, Proc. Nati, Acad. Sci. USA 98 (9): 5306-5311). Through the induction of expression of ABCA1 mRNA in macrophages, PPARd agonists can increase HDL-C levels in patients and remove excess cholesterol from lipid-laden macrophages, thus inhibiting the development of atherosclerotic lesions. Existing therapy for hypercholesterolemics includes steroid drugs, which reduce LDL-C but show little effect on HDL-C, and fibrates, PPARα agonists that have low potency and induce only moderate elevation of HDL-C. In addition, as with fibrates, PEARd agonists can also reduce triglycerides, an additional risk factor for cardiovascular disease and diabetes. It has been shown that the high level of free fatty acid contributes to insulin resistance and progression of diabetes (Boden, G. PROCEEDINGS OF THE ASSOCIATION OF AMERICAN PHYSICIANS (May-June 1999), 111 (3), 241-8) . Examples of known PPAR delta agonists variously useful for hyperlipidemia, diabetes or atherosclerosis include L-165041 (Leibowitz et al., 2000) and GW501516 (Oliver et al., Proceedings of the National Academy of Sciences of the United States of America (2001). ), 98 (9), 5306-5311). The treatment of THP-1 monocytes differentiated with GW501516 induced the expression of ABCA1 mRNA and increased the outflow of cholesterol from these cells.

BRIEF DESCRIPTION OF THE INVENTION The invention relates to compounds of the formula (I) below: wherein X is selected from a covalent bond, S or O; And it's S or O; W represents a group selected from = CH-, -CH =, - CH2-, - CH2-CH2-, = CH-CH2 -, - CH2-CH =, = CH-CH =, and -CH = CH-; Z is selected from O, CH, and CH2, provided that when Y is O, Z is O; R i and R 2 are independently selected from H, C 1-3 alkyl, C 1-3 alkoxy, halogen, and NR a R b wherein R a and R b are independently H or C 3 alkyl; R3 and R4 are independently selected from H, halogen, cyano, hydroxy, acetyl, C? -5 alkyl, C-? -4 alkoxy, and NRcRd wherein Rc and Rd are independently H or C1-3 alkyl, always that R3 and R4 are not both H; R5 is selected from halogen, phenyl, phenoxy, (phenyl) C-15 alkoxy, (phenyl) C1-5 alkyl, C5 heteroaryloxy, C2-5 heteroaryl C15 alkoxy, C2-5 heterocyclyloxy, C? _g alkyl, Cis alkoxy, C2.g alkenyl, C2.9 alkenyloxy, C2-g alkynyl, C2.g alkynyloxy, C3-7 cycloalkyl, C3-7 cycloalkoxy, C3- cycloalkyl 7-C1- alkyl, C3-7 cycloalkyl-C- alkoxy, C3 cycloalkoxy. -alkyl of C? -6, C-? - 6-alkyloxy of C-? -6, C? -5-alkyloxy of C 1-5 alkyl, or C3-7-cycloalkoxy-C-alkoxy? 7; R6 is H when - W - represents a group selected from - CH =, -CH2-, -CH2-CH2-, -CH2-CH =, and -CH = CH-, or R6 is present when W represents a group selected from = CH-, = CH-CH2-, y = CH-CH =; and n is 1 or 2; or a pharmaceutically acceptable salt thereof. The invention also relates to compositions that include one or more compounds of the formula (I) and a pharmaceutical carrier or excipient. These compositions and the following methods may also include additional pharmaceutical active agents, such as lipid lowering agents or blood pressure lowering agents, or both. Another aspect of the invention includes methods of using the compounds or compositions described in various methods for the treatment, prevention, or inhibition of the progression of, a condition directly or indirectly mediated by PPAR delta. Said condition includes, but is not limited to, diabetes, cardiovascular diseases, metabolic syndrome X, hypercholesterolemia, hypo-HDL-cholesterol, hyper-LDL-cholesterolemia, dyslipidemia, atherosclerosis and obesity. One embodiment of the present invention is a method for the treatment of a condition mediated by PPAR-delta, said method comprising administering to a patient in need of treatment a therapeutically effective amount of a compound or composition described herein. Another embodiment of the present invention is a method for inhibiting the initiation and / or inhibiting the progression of a condition mediated by PPAR-delta, said method comprising administering to a patient in need of treatment a therapeutically effective amount of a compound or composition described herein. Examples of conditions that may occur with a PPAR delta agonist include, without limitation, diabetes, cardiovascular disease, metabolic syndrome X, hypercholesterolemia, hypo-HDL-cholesterolemia, hyper-LDL-cholesterolemia, dyslipidemia, atherosclerosis, and obesity. Dyslipidemia includes hypertriglyceridemia, and mixed hyperlipidemia. For example, dyslipidemia (including hyperlipidemia) can be one or more of the following conditions: low HDL (<35 or 40 mg / dL), high triglycerides (> 200 mg / dL), and high LDL (> 150) mg / dl). Additional features and advantages of the invention will be evident from the detailed discussion, examples and claims below.

DETAILED DESCRIPTION OF THE INVENTION The invention relates to compositions containing compounds of the formula (I) in the section of brief description above, and methods for using them. Preferred compounds of the invention are potent PPAR delta agonists having at least one and preferably two or three of the following characteristics when administered to patients with hypercholesterolemia., hypertriglyceridemia, low IHDL-C, obesity, diabetes and / or metabolic syndrome X: 1) increasing the level of HDL-C, 2) reducing triglycerides, 3) reducing free fatty acids, and 4) reducing insulin levels . The improvement in the levels of HDL-C and triglycerides is beneficial for cardiovascular health. In addition, the reduced level of triglycerides and free fatty acids contributes to reducing obesity and alleviating or preventing diabetes. PPAR delta, being ubiquitously expressed, can act as a gate receptor that regulates the expression / acfivity of other nuclear receptors such as other PPARs. For example, has PPAR delta been shown to block adipogenesis mediated by PPAR? and expression of acyl-CoA oxidase; it has also been shown to be associated with the nuclear receptor compressors SMRT (silencing mediator for retinoid and thyroid hormone receptors), SHARP (SMART and repressor protein associated with histone deacetylase), and HDACs (histone deacetylase). Therefore, conditions directly mediated by these nuclear receptors, such as obesity and type II diabetes, can be indirectly mediated by PPAR delta (See, for example, Shi et al., 2002, Proc Nati. Acad. Sci USA, 99 (5): 2613-2618). Some aspects of the invention relate to the treatment of hypertriglyceridemia, elevation of HDL levels, reduction of LDL levels, and / or reduction of total cholesterol. Preferably, the methods of treatment are associated with improvements in the extent, duration or degree of side effects, such as edema, normally associated with other existing therapies. The invention is described further below. The specification is arranged as follows: A) Terms; B) Compounds; C) Synthesis; D) Formulation and Administration; E) Use; F) Biological Examples; G) Other Modalities; and Claims.

A. Terms The term "subject", as used herein, refers to an animal, preferably a mammal, most preferably a human, which has been the object of treatment, observation or experimentation. The term "therapeutically effective amount", as used herein, means that amount of active compound or pharmaceutical agent that induces the biological or medicinal response in a tissue, animal or human system that is being sought by a researcher, veterinarian, physician or another clinical doctor, which includes the relief, prevention, fratamienio, or the delay of the initiation or progression of the symptoms of the disease or disorder that is fratada. Conditions directly or indirectly mediated by PPAR delfa include, but are not limited to, diabetes, cardiovascular disease, metabolic syndrome X, hypercholesterolemia, hypo-HDL-cholesterolemia, hyper-LDL-cholesterolemla, dyslipidemia, aerosol, and obesity. For therapeutic purposes, the term "co-effective amount", as used herein, means that amount of each active compound or pharmaceutical agent, alone or in combination, that induces the biological or medicinal response in a tissue, animal or human system that is being sought by a researcher, veterinarian, doctor or other clinician, which includes relief of the symptoms of the disease or disorder being brought. For prophylactic purposes (i.e., inhibition of the onset or progression of a disorder), the term "jointly effective amount" refers to that amount of each active compound or pharmaceutical agent, alone or in combination, that brought or inhibits in a subject the start or progression of an disorder that is being sought by a researcher, veterinarian, doctor or other clinic doctor. Therefore, the present invention provides combinations of two or more drugs wherein, for example, (a) each drug is administered in an independently therapeutically or prophylactically effective amount; (b) at least one drug in the combination is administered in an amount that is sub-therapeutic or sub-prophylactic if administered alone, but is therapeutic or prophylactic when administered in combination with the second drug or additional drugs according to the invention; or (c) both (or more) drugs are administered in an amount that is subtherapeutic or subprophylactic if administered alone, but are therapeutic or prophylactic when administered together. Unless otherwise indicated, as used herein and whether used alone or as part of a substituent group, "alkyl" and "alkoxy" include straight and branched chains having 1 to 8 carbon atoms, such as C -? - 6, C-, C3-8, C2-5, or any other range, and unless otherwise indicated, include both substituted and unsubstituted portions. For example, C?-6 alkyl radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, 3- (2-methyl) butyl, 2-pentyl, 2-methylbutyl, neopentyl, n-hexyl, 2-hexyl and 2-methylpentyl. Alkoxy radicals are formed from the straight or branched chain alkyl groups described above. "Alkyl" and "alkoxy" include unsubstituted or substituted portions with one or more substitutions, such as between 1 and 5, 1 and 3, or 2 and 4 substituents. The substituents can be the same (dihydroxy, dimethyl), similar (chloro, fluoro), or differents (chlorobenzyl-or aminomethyl-substituted). Examples of substituted alkyl include haloalkyl (such as fluoromethyl, chloromethyl, difluoromethyl, perchloromethyl, 2-bromoethyl, trifluoromethyl and 3-iodocyclopentyl), hydroxyalkyl (eg as hydroxymethyl, hydroxyethyl, 2-hydroxypropyl), aminoalkyl (such as aminomethyl, 2-aminoethyl) , 3-aminopropyl and 2-aminopropyl), alkoxylalkyl, nitroalkyl, alkylalkyl, cyanoalkyl, phenylalkyl, heteroarylalkyl, heterocyclylalkyl, phenoxyalkyl, heteroaryl oxyalkyl (eg as 2-pyridyloxyalkyl), heterocyclyloxy-alkyl (such as 2-telrahydropyranoxy-alkyl), ioalkylalkyl (such as MeS-alkyl), thiophenylalauyl (ial as phS-alkyl), carboxylalkyl, etc. A di (C? -3) amino group includes independently selected alkyl groups, to form, for example, methylpropylamino and isopropylmethalamino, further dialkylamino groups having two of the same alkyl group such as dimethylamino or dethylamino. The term "alkenyl" includes straight and branched chain hydrocarbon radicals optionally substituted as above with at least one carbon-carbon double bond (sp2). Alkenyls include ethenyl (or vinyl), prop-1-enyl, prop-2-enyl (or allyl), isopropenyl (or 1-methylvinyl), but-1-enyl, but-2-enyl, buadiene, penphenyls, hexa -2, 4-dienyl, etc. The hydrocarbon radicals having a mixture of double bonds and triple bonds, such as 2-penfen-4-ynyl, are grouped as alkynyl here. Alkenyl includes cycloalkenyl. The cis and trans or (E) and (Z) forms are included within the invention. "Alkenyl" may be substituted with one or more substitutions including, but not limited to, cyanoalkenyl and thioalkenyl. The term "alkynyl" includes straight or branched chain hydrocarbon radicals optionally substituted as above with at least one carbon-carbon triple bond (sp). Alkylnilos include ethynyl, propynyl, butynyl, and pentinyl. The hydrocarbon radicals having a mixture of double bonds and triple bonds, such as 2-penten-4-lnyl, are grouped as alkynyl here. The alkynyl does not include cycloalkynyl. The term "Ac", as used herein, whether used alone or as part of a substituent group, means acetyl (CH3CO). The term "halogen" or "halo" will include iodine, bromine, chlorine and fluoro. The term "aryl" or "Ar", as used herein, refers to an unsubstituted or substituted aromatic hydrocarbon ring system such as phenyl and naphthyl. When the Ar or aryl group is substituted, it may have one to three substituents which are independently selected from Cs alkyl, Ci-Cs alkoxy, fluorinated Ci-Cs alkyl (e.g., trifluoromethyl), Ci alkoxy Fluorinated compounds (e.g., trifluoromethoxy), halogen, clade, C? -C8 alkylcarbonyl such as acetyl, carboxyl, hydroxy, amino, nitro, C1-C4 alkylamino (ie, -NH- C1-6alkyl) C4), C1-C4 dialkylamino (ie, -N- [alkyl of wherein the alkyl groups may be the same or different), or unsubstituted phenyl, mono-, di- or tri-susiiuuide wherein the substituents in the phenol is independently selected from Ci-Cs alkyl, C-pC alkoxy, fluorinated C-β-C8 alkyl, fluoro C8 alkoxy, halogen, year, acetyl, carboxyl, hydroxy, amino, nitro, alkylamino, dialkylamino or five or six membered heteroaryl having 1-3 heteroatoms selected from N, O, and S. The term "heteroaryl," as used herein, represents a A non-substituted or unsubstituted stable or unsubstituted monocyclic or bicyclic aromatic monocyclic or bicyclic ring consisting of carbon atoms and one to three heteroatoms selected from N, O and S. The heteroaryl group may be attached at any heteroatom or carbon that results in the creation of a stable structure. Examples of heteroaryl groups include, but are not limited to, benzimidazolyl, benzisoxazolyl, benzofuranyl, benzopyrazole, benzothiadiazolyl, benzothiazolyl, benzothienyl, benzotriazolyl, benzoxazolyl, furanyl, furazanyl, furyl, imidazolyl, indazolll, indolizinyl, indolinyl, indolyl, isobenzofuranyl, isoindolyl, isothiazolyl, isoxazolyl, oxazolyl, purinyl, pyrazinyl, pyrazolyl, pyridinyl, pyridinyl, pyrimidinyl, pyrrolyl, quinolinyl, quinolyl, thiadiazolyl, thiazolyl, thiophenyl or triazolyl. When the heteroaryl group is substituted, the heteroaryl group may belong to one or more subsitutes including, but not limited to,, alkyl of C-i-Cs, halogen, and aryl. The term "heterocyclyl" includes optionally substituted non-aromatic rings having carbon atoms and at least one heteroaryl (O, S, N) or hetero-amino moiety (SO2, CO, CONH, COO) in the ring. A heteroclclil can be saturated, partially saturated, non-aromatic or fused. Examples of heterocyclyl include cyclohexylimino, imdazolidinyl, imidazolinyl, morpholinyl, piperazinyl, piperidyl, pyridyl, pyranyl, pyrazolldinyl, pyrazolinyl, pyrrolidinyl, pyrrolinyl and thienyl. Unless otherwise indicated, heteroaryl and heterocyclyl can have a valence connecting it to the rest of the molecule through a carbon atom, such as 3-furyl or 2-imidazolyl, or through a heteroatom, such as N -piperidyl or 1-pyrazolyl. Preferably, a monocyclic heterocyclyl contains 5 or 7 ring atoms, or 5 or 6 ring atoms; there may be between 1 and 5 heteroatoms or heteroatom portions in the ring, and preferably between 1 and 3, or between 1 and 2 heteroatoms or heteroatom portions. Heterocyclyl and heteroaryl also include fused, e.g., bicyclic rings, such as those optionally fused with an optionally substituted carbocyclic or heterocyclic five- or six-membered aromatic ring. For example, "heteroaryl" includes an optionally substituted six-membered heteroaromatic ring containing 1, 2 or 3 nitrogen atoms fused with an optionally substituted five or six membered carbocyclic or heterocyclic aromatic ring. Said five or six membered heterocyclic aromatic ring fused with said five or six membered aromatic ring can contain 1, 2 or 3 nihologen atoms where it is a six membered ring, or 1, 2 or 3 heteroatoms selected from oxygen, nitrogen and sulfur where is a ring of five members. It is intended that the definition of any substituent or variable in a particular place in a molecule be independent of its definitions elsewhere in that molecule. It is understood that substituents and substitution patterns on the compounds of this invention can be selected by one skilled in the art to provide compounds that are chemically stable and that can be readily synthesized by techniques known in the art as well as those methods set forth herein. Where the chemical moieties are combined, such as in ethoxymethyl or phenylethyl, the term is described in the direction of the periphery to the point of connection of the rest of the molecule. For example, ethoxymethyl is CH3CH2OCH2- and phenylethyl is a phenyl group linked by -CH2CH2- to the rest of the molecule (and not a phenol group attached to the molecule with a CH3CH2 group as a substituent on the phenyl). Where parentheses are used, they indicate a peripheral substitution. As used herein, the term "composition" encompasses a product that comprises the specified ingredients in the specified amounts, as well as any product that results, directly or indirectly, from combinations of the specified ingredients in the specified amounts. The compounds of the invention are further described in the following section.

B. Compounds The present invention relates to compositions containing the compounds of the formula (I) and methods of using them, as described above. Unless otherwise indicated, in formula (I), each hydrocarbyl (alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, etc.) or heterocarbyl (heterocyclyl, heteroaryl, heteroatom, such as sulfonyl, amino, amido, etc.). ) can be substituted or unsubstituted, for example, "alkyl" includes substituted and unsubstituted alkyl and "heterocyclyl" and "aryl" and "alkoxy", etc., can also be substituted or unsubstituted. Examples of the present invention include those compounds wherein: (a) X is S or O; (b) X is a covalent bond; (c) X is O; (d) Y is O; (e) Y is S; (f) Z is O; (g) Z is CH or CH2; (h) -W- - represents -CH2-o-CH2-CH2-; (i) - W - represents -CH2-; (j) - W- - represents = CH-, -CH =, = CH-CH2 -, - CH2-CH =, = CH-CH = or -CH = CH-; (k) Ri and R2 are independently selected from H, C-? -3 alkyl, C-1-3 alkoxy, F, Cl and Br; (I) R 3 and R 4 are independently selected from H, halogen, cyano, C 1-4 alkyl and C 1-3 alkoxy; (m) R-i and R2 are independently selected from H, methyl, methoxy, F and Cl; (n) R3 and R4 are independently selected from H, halogen, cyano, hydroxy, C2-4 acyl > C 4 alkyl, and C 1 i alkoxy; (o) R3 is independently selected from H, F, Cl, methyl and methoxy; (p) R 4 is independently selected from F, Cl, meilyo, meioxy, trifluoromethyl, fluoromethyl, difluoromethyl, chlorodifluoromethyl, dichlorofluoromethyl, fluoromeoxy, difluoromethoxy, chlorodifluoromethoxy, dichlorofluoromethoxy and trifluoromethoxy; (q) R3 is selected from methyl, methoxy, H, Cl, Br, I, OH, -CH (CF3) 2, CF3, -OCF3, -N (CH3) 2, -0-CH2COOH, and -COCH3, and R4 is selected from H, Cl and methyl; (r) R5 is selected from C1-7 alkyl, C-? 6 alkoxy, C2-7 alkenyl, C2 alkenyloxy. , C2-7 alkynyl) C2-7 alkynyloxy, C3- cycloalkyl, C3- cycloalkoxy, C6-6 alkoxy-C6-6alkyl, C5-5alkoxy-C1-5alkoxy, and C3- (C3-) alkoxy-cycloalkyloxy; (s) R5 is selected from and phenoxy, (phenyl) C1-5 alkoxy, (phenyl) C1.5 alkyl, C2.5 heteroaryloxy, C2-5 heteroaryl-C5-alkoxy, C2 heterocyclyloxy -5, C3-7 cycloalkyl-d-alkylate. 7C, C3.7-cycloalkyl-C7-alkoxy, and C3-cycloalkoxy-C-i-βalkyl; (t) Re is H; (u) R3 is selected from H, F, Cl, methyl and methoxy, and R4 is selected from F, Cl, methyl, fluoromethyl, difluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethyl, trifluoromethoxy and methoxy; (v) R-i is selected from H, CF3, methyl, Cl and methoxy, and R2 is selected from H, Cl and methyl; (w) R-i is selected from H, CF3, methyl, Cl and methoxy, and R2 is selected from H, Cl and methyl, and X is a covalent bond; (x) R-] is selected from H, CF3, methyl, Cl and methoxy, and R2 is selected from H, Cl and methyl, X is a covalent bond, Y is S, and Z is O; (y) X is O and Y is O; (z) X is O and Y is S; (aa) Y is O and Z is O; (bb) Y is S and Z is O; (ce) Re is H and R5 is selected from C? _7 alkyl, C?? 6 alkoxy, C2- alkenyl, C2-7 alkenyloxy, C? -6 alkyloxy-C6 alkyl, and C1-5 alkoxy; C1-5 alkoxy; (dd) R6 is H and R5 is selected from C1.5alkyl, C- [alpha] alkoxy, C2-5alkenyl, C2-5alkenyloxy, and C5-5alkoxy-C- [alpha] -5alkoxy; (ee) Re is H and R5 is selected from C-? -3 alkyl, C1-3 alkoxy, C2-4 alkenyl, C2-4 alkenyloxy, and C? -3-alkoxy C? -3; (ff) R6 is H and R5 is selected from methoxy, ethoxy, propoxy, isopropoxy, propenyloxy, isopropenyloxy, ethoxy-methoxy, mephoxy-methoxy, methoxy-methyl, methoxyethyl, ethoxymethyl and ethoxy-ethyl; (gg) R-i is selected from H, CF3, mephyl, Cl and methoxy; R2 is selected from H, Cl and methyl, R3 is selected from H, F, Cl, methyl and methoxy; and R 4 is selected from F, Cl, methyl, trifluoromethyl, trifluoromethoxy, fluoromethyl, fluoromethoxy, difluoromethyl, difluoromethoxy and methoxy; (hh) X is O, Y is O, R3 is selected from H, F, Cl, methyl and methoxy; and R 4 is selected from F, Cl, methyl, CF 3, OCF 3 and methoxy; (il) X is O, Y is S, R3 is selected from H, F, Cl, methyl, and methoxy, and R4 is selected from F, Cl, methyl, CF3, OCF3 and methoxy; (jj) X is covalent bond, Y is S, R3 is selected from H, F, Cl, methyl, and methoxy, and R4 is selected from F, Cl, metyl, CF3, OCF3, and meioxy; (kk) Y is O, Z is O, R3 is selected from H, F, Cl, methyl, and methoxy; and R 4 is selected from F, Cl, methyl, CF 3, OCF 3 and methoxy; (II) Y is S, Z is O, R3 is selected from H, F, Cl, methyl, and methoxy, and R4 is selected from F, Cl, methyl, CF3, OCF3 and methoxy; (mm) R is selected from H, F, Cl, methyl and methoxy, R is selected from F, Cl, methyl, CF 3, OCF 3, and methoxy, R 5 is selected from C-7 alkyl, C alkoxy -6, alkenyl of C2.7, alkenyloxy of C2-7, alkoxy of C6-6-alkyl of d-6, and alkoxy of C1.5-allokoxy of C1-5 and Re is H; (nn) X is O, Y is O, R5 is selected from C-1-3 alkyl, C1-3 alkoxy, C2-4 alkenyl, C2.4 alkenlloxl, and C- | 3-alkoxy; C1-3 alkoxy, and R6 is H; (00) X is O, Y is S, R5 is selected from C -? - 3 alkyl, C1-3 alkoxy, C2-4 alkenyl, C2-4 alkenyloxy, and C? -3-alkoxy alkoxy of C1.3, and R6 is H; (pp) X is 0, Y is 0, Ri is selected from H, CF3, methyl, Cl, and methoxy, R2 is selected from H, Cl and methyl, R3 is selected from H, F, Cl, methyl and methoxy, R 4 is selected from F, Cl, methyl, CF 3, OCF 3 and methoxy, and n is 1; (qq) X is O, Y is S, R1 is selected from H, CF3, methyl, Cl and methoxy, R2 is selected from H, Cl and methyl, R3 is selected from H, F, Cl, methyl and methoxy, and R 4 is selected from F, Cl, mephyl, CF 3, OCF 3 and methoxy; (rr) X is O, Y is S, Ri is selected from H, CF3, methyl, Cl and methoxy, R2 is selected from H, Cl and methyl, R3 is selected from H, F, Cl, methyl and methoxy, R4 is selected from F, Cl, methyl, CF3, OCF3 and methoxy, and n = 1; or (ss) X is O, Y is S, Ri is selected from H, CF3, methyl, Cl and methoxy, R2 is selected from H, Cl and methyl, R3 is selected from H, F, Cl, mephyl and methoxy, R 4 is selected from F, Cl, methyl, CF 3, OCF 3 and methoxy, R 5 is selected from C 1-3 alkyl, C 1-3 alkoxy, C 2-4 alkenyl, C 2 - alkenyloxy, and C 3 - alkoxy. -alkoxy of C1-3, Re is H, and n = 1; or combinations of the above. According to another aspect of the invention, formula (I) is modified in such a way that - W - can also be a covalent bond, and R6 is H when W represents a group selected from a covalent bond, -CH =, - CH2-, -CH2-CH2-, -CH2-CH ~ and -CH = CH-, or R6 is absent when -W- represents a group selected from = CH-, = CH-CH2- and = CH-CH =. Particularly, the examples of the formula (I) include those compounds wherein: (a) X is O and Y is O; (b) X is a covalent bond and R-i is selected from H, CF3, mephyl, Cl and methoxy, and R2 is selected from H, Cl and methyl; (c) X is O and Y is S; (d) X is covalent bond, Y is S and Z is O; (e) Y is S and Z is O; (f) Y is O and Z is O; (g) R-i is selected from H, CF3, methyl, Cl and methoxy, and R2 is selected from H, Cl and mephyl; (h) R-i and R2 are independently selected from H, methyl, meioxy, F and Cl; (i) R3 is independently selected from H, F, Cl, methyl and methoxy; 0) 4 is independently selected from F, Cl, methyl, methoxy, trifluoromethyl, fluoromethyl, difluoro, methyl, chlorodifluoromethyl, dichlorofluoromethyl, fluoromethoxy, difluoromethoxy, chlorodifluoromethoxy, dichlorofluoromethoxy and trifluoromethoxy; (k) R3 is selected from methyl, methoxy, H, Cl, Br, I, OH, -CH (CF3) 2, CF3, -OCF3, -N (CH3) 2, -O-CH2COOH and -COCH3, and R4 it is selected from H, Cl and methyl; (I) R3 is selected from H, F, Cl, methyl and methoxy, and R4 is selected from F, Cl, me yl, fluoromethyl, difluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethyl, trifluoromethoxy and methoxy; (m) R 5 is selected from C 1-7 alkyl, C-j-6 alkoxy, C 2-7 alkenyl, C 2-7 alkenyloxy, C 2-7 alkynyl, C 2 alkynyloxy. , C3-7 cycloalkyl, C3-7 cycloalkoxy, C6-6 alkoxy-C-? 6 -alkyl, C-? -5-alkoxy of C? -5 alkoxy, and C3-7 cycloalkyloxy- C 1-7 alkoxy; (n) R6 is H and R5 is selected from C1-7 alkyl, C1-6 alkoxy, C2-7 alkenyl, C2.7 alkenyloxy, C6-6 alkoxy-Ci-β alkyl, and alkoxy of C -? - 5-alkoxy of C? -5; (o) R6 is H and R5 is selected from C1-5 alkyl, C1-4 alkoxy, C2-5 alkenyl) C2-5 alkenyl loxy, and C-? 5 alkoxy C? -5 alkoxy; (p) Re is H and R5 is selected from C -? - 3alkyl, C-1.3alkoxy, C2-4alkenyl, C2-4alkenyloxy, and C? -3-C-alkoxy alkoxy; 3; (q) Re is H and R5 is selected from methoxy, ethoxy, propoxy, isopropoxy, propenyloxy, isopropenyloxy, ethoxy-meioxy, methoxy-methoxy, mephoxy-mephyl, methoxyethyl, ethoxymethyl and ethoxy-ethyl; or - W - represents a covalent bond; or combinations of the above.

In another example, the compounds of the present invention may be those of the formula (II): wherein X is selected from a covalent bond, S or O; And it's S or O; W represents a group selected from -CH =, -CH2-, -CH2-CH2-, -CH2-CH = and -CH = CH-; Z is selected from O, CH and CH2, provided that when Y is O, Z is O; > R and R2 are independently selected from H, alkyl of d-3, alkoxy of C- | .3, halogen and NRaRb wherein Ra and Rb are independently H or C-? -3 alkyl; R3 and R4 are independently selected from H, halogen, cyano, hydroxy, acetyl, C-? 5 alkyl, C- alkoxy, and NRcRd wherein Rc and Rd are independently H or C1-3 alkyl, provided that R3 and R4 are not both H; and n is 1 or 2; or a pharmaceutically acceptable salt thereof. The compounds of the present invention can also be selected from: Acid [4 - [[2-ethoxy-3- [4- (trifluoromethyl) phenoxy] propyl] thio] -2- methylphenoxy-acetic, Acid [4 - [[(2R) -2-eioxy-3- [4- (trifluoromethyl) phenoxy] propyl] thio] -2- meynylphenoxy] -acetic acid, and [4 - [[(2S) -2-ehyoxy-3- [4- (ureafluoromethoxyl) phenoxy] propyl] Iio] -2- methylophenoxy] -acetic. Specifically, the compounds of the present invention further include: Acid. { 2-methyl-4- [2- (4-trifluoromethyl-phenoxymethyl) -butylsulfanyl] -phenoxy-acetic acid; Acid { 2-methyl-4- [2- (4-trifluoromethyl-phenoxymethyl) -pentylsulfanyl] -phenoxy-acetic acid; Acid { 4- [4-Cyano-2- (4-trifluoromethyl-phenoxymethyl) -butylsulfanyl] -2-methyl-phenoxy} -acetic; Acid (R) -. { 4- [2-allyloxy-3- (4-trifluoromethyl-phenoxy) -propylsu-imanyl] -2-methyl-phenoxy} -acetic; Acid (R) -. { 4- [2-methoxymethoxy-3- (4-trifluoromethyl-phenoxy) -propylsulfanyl] -2-methyl-phenoxy} -acetic; Acid { 4- [2-ethoxy-4- (4-trifluoromethyl-phenyl) -butylsulfanyl] -2-methyl-phenoxy} -acetic; Acid { 3-Chloro-4- [2-ethoxy-3- (4-trifluoromethyl-phenoxy) -propylsulfanyl] -phen? I} -acetic; Acid { 4- [2-ethoxymethyl-3- (4-trifluoromethyl-phenoxy) -propylsulfanyl] -2-methyl-phenoxy-acetic acid; Acid { 4- [4-ethoxy-2- (4-trifluoromethyl-phenoxymethyl) -butylsufanyl] -2-methyl-phenoxy} -acetic; Acid { 4- [2- (5-chloro-thiophen-2-ylmethoxy) -3- (4-trifluoromethyl-1-phenoxy) -propylsulfanyl] -2-methyl-phenoxy} -acetic; Acid { 4- [3-cano-2- (4-frifluoromethyl-phenoxymethyl) -prop-sulfonyl] -2-methyl-phenoxy-acetic acid; Acid { 4- [5-cyano-2- (4-trifluoromethyl-phenoxymethyl) -pene-4-enylsulfanyl] -2-methyl-phenoxy} -acetic; Acid { 3-Chloro-4- [2- (4-trifluoromethyl-phenoxymethyl) -butylsulfanyl] -phenyl} -acetic; Acid { 2-methyl-4- [3- (4-trifluoromethyl-phenoxy) -2- (4-trifluoromethyl-phenoxymethyl) -propylsulfanyl-phenoxy-acetic acid; Acid { 4- [2-benzyloxy] -3- (4-trifluoromethyl-phenoxy) -propylsulfanyl] -2-methyl-phenoxy} -acetic; Acid { 4- [2- (4-Butyryl-phenoxy) -3- (4-trifluoromethyl-phenoxy) -propylsulfanyl] -2-methyl-phenoxy} -acetic; Acid { 2-methyl-4- [3- (4-trifluoromethyl-phenoxy) -propenylsulfanyl] -phenoxy-acetic acid; Acid { 2-methyl-4- [2-methylsulfanylmethoxy-4- (4-trifluoromethyl-phenyl) -buylsulfanyl-phenoxy-acetic acid; [4- [2,4-diethoxy-4- (4-trifluoromethyl-phenyl) -butylsulfanyl] -2-meityl-phenoxy-acetic acid; Acid { 4- [2-ethoxy-4- (4-trifluoromethyl-pheny] -but-3-enylsulfanyl] -2-methyl-phenoxy-acetic; Acid { 4- [2- (4-trifluoromethyl-phenoxymethyl) -butyl-fluoyl] -phenoxy} - acetic; Acid { 2-methyl-4- [2- (4-trifluoromethyl-phenoxymethyl) -heptylsulfanyl] -phenoxy-acetic acid; Acid { 4- [4-methoxy-2- (4-ylfluoromethyl-phenoxymethyl) -buflsulfanyl] -2-methy1-phenoxy} -acetic; Acid { 2-methyl-4- [3- (4-lf-fluoromethyl-phenoxy) -propylsulfanyl] -phenoxy} -acetic; Acid { 2-methyl-4- [4- (4-ylfluoromethyl-phenyl) -3,6-dihydro-2 H -pyran-2-ylmethylsulfanyl] -phenoxy} -acetic; Acid { 2-methyl-4- [4- (4-ylluoromethyl-phenyl) -bui-3-enylsulfanyl] -phenoxy-acetic acid; Acid (R) -. { 4- [2-ethoxy-3- (4-trifluoromethoxy-phenoxy) -propylsulfanyl] -2-methyl-phenoxy} -acetic; Acid (R) -. { 4- [3- (4-chloro-phenoxy) -2-ethoxy-propylsu-phenyl] -2-methyl-phenoxy-acetic; Acid (R) -. { 4- [3- (4-tert-buyl-phenoxy) -2-ethoxy-propylsulfanyl] -2-methyl-phenoxy-acetic acid; Acid (R) -. { 2-methyl-4- [2- (4-trifluoromethoxy-phenoxymethyl) -butylsulphanyl] -phenoxy} -acetic; Acid (R) -. { 4- [2- (4-Chloro-phenoxymethyl) -butylsulfanyl] -2-methyl-phenoxy} - acetic; Acid (R) -. { 4- [2- (4-tert-buyyl-phenoxymethyl) -bufilsulfanyl] -2-meityl-phenoxy} -acetic; Acid (R) -. { 3-Chloro-4- [2-ethoxy-3- (4-trifluoromethoxy-phenoxy) -propylsulfanyl) -phenyl} -acetic; Acid (R) -. { 3-chloro-4- [3- (4-chloro-phenoxy) -2-eoxy-propylsulfanyl] -phenyl-acetic acid; Acid (R) -. { 4- [2-ethoxy-3- (4-trifluoromethyl-phenoxy) -propylsulfanyl] -2-methyl-phenylsulfanyl} -acetic; Acid (R) -. { 4- [2-ethoxy-3- (4-trifluoromethoxy-phenoxy) -propylsulfanyl] -2-methyl-phenylsulfanyl} -acetic; Acid (R) -. { 2-methyl-4- [2- (4-trifluoromethyl-phenoxymethyl) -butyl-aluminum] -phenylsulfanyl} -acetic; Acid (R) -. { 2-methyl-4- [2- (4-trifluoromethoxy-phenoxymethyl) -butylsulfanyl] -phenylsulfanyl} -acetic; Acid { 4 - [(2R) -2-hydroxy-3- (4-trifluoromethyl-phenoxy) -propylsulfanyl] -2-methyl-phenoxy} -acetic; Acid { 4 - [(2S) -2-hydroxy-3- (4-trifluoromethyl-phenoxy) -propylsulfanyl] -2-methyl-phenoxy} -acetic; and Acid. { 4- [2-ethoxy-3- (4-trifluoromethyl-phenoxy) -propoxy] -2-methyl-phenoxy-acetic acid. The present invention also provides compositions containing the compounds of the formula (I) and methods of using the same.In particular, the present invention provides compositions containing the compounds of the formula (I) and methods of use thereof as illustrated above. Examples of preferred compounds include those described in Table 1 below.

TABLE 1 Where the compounds according to this invention have at least one chiral center, they can therefore exist as enantiomers. Where the compounds possess two or more chiral centers, they may additionally exist as diastereomers. It is to be understood that all such isomers and mixtures thereof are embraced within the scope of the present invention. In addition, some of the crystalline forms for the compounds may exist as polymorphs and, as such, are intended to be included in the present invention. In addition, some of the compounds may form solvates with water (ie, hydrates) or common organic solvents, and it is also intended that those solvates be encompassed within the scope of this invention. The invention provides the described compounds and closely related pharmaceutically acceptable forms of the disclosed compounds, such as salt, ester, amide, hydrate or solvate forms thereof; covered or protected forms; and racemic mixtures, or enantiomerically or optionally pure forms. The pharmaceutically acceptable salts, esters and amides include carboxylate salts (e.g., Ci-β, cycloalkyl, aryl, heteroaryl, or non-aromatic heterocyclic alkyl), amino acid addition salts, esters and amides which are within a reasonable risk / benefit ratio, pharmacologically effective and suitable for contact with the tissues of patients without inadequate toxicity, irritation or allergic response. Representative salts include hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactiobionate and lauryl sulphonate. These may include alkali metal and alkaline earth metal cations such as sodium, potassium, calcium and magnesium cations, as well as non-toxic ammonium, quaternary ammonium and amine cations such as tetramethylammonium, methylamine, trimethylamine and ethylamine. See, for example, S. M. Berge, et al., "Pharmaceutical Salts," J. Pharm. Sci., 1977, 66: 1-19, which is incorporated herein by reference. Representative pharmaceutically acceptable amides of the invention include those derived from ammonia, C- [alpha] -6 primary amines and secondary di (C6-alkyl) amines. Secondary amines include 5- or 6-membered heterocyclic or heteroaromatic ring portions containing at least one nitrogen atom and optionally between 1 and 2 additional heteroatoms. Preferred amides are derived from ammonia, C1.3 alkyl primary amines, and di (C2-2) alkylamines. Representative pharmaceutically acceptable esters of the invention include C 1-7 alkyl, C 5-7 cycloalkyl, phenyl and phenyl alkyl esters (C? -6). Preferred esters include methyl esters. The invention also includes disclosed compounds having one or more functional groups (e.g., amino or carboxyl) covered by a protecting group. Some of these covered or protected compounds are pharmaceutically acceptable; others will be useful as intermediaries. The synthetic intermediates and methods described herein, and minor modifications thereof, are also within the scope of the invention.

Hydroxyl protecting groups The protection for the hydroxyl group includes methyl esters, substituted methyl esters, substituted ethyl ethers, substituted benzyl ethers and silyl ethers.

Substituted methyl ethers Examples of susíifuidos methyl ethers include mefioxymethyl, methylthiomethyl, f-butylylomethyl, (phenyldimethylsilyl) methoxymethyl, benzyloxymethyl, p-methoxybenzyloxymethyl, (4-methoxyphenoxy) -methyl, guaiacolmethyl, f-butoxymethyl, 4-pentenlloxymethyl, siloxylmethyl, 2-methoxyethoxymethyl, 2,2,2-trichloroethoxymethyl, bis (2-chloroethoxy) mephyl, 2- (imymethylsilyl) ) ethoxymethyl, tetrahydropyranyl, 3-bromotetrahydropyranyl, tetrahydrothiopyranyl, 1-methoxycyclohexyl, 4-methoxytetrahydropyranyl, 4-methoxytetrahydrothiopyranyl, S, S-4-mefoxiteyrahydrothiopyranyl dioxide, 1 - [(2-chloro-4-methyl) phenyl] -4- methoxypidin-4-yl, 1,4-dioxan-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl and 2,3,3a, 4,5,6,7,7a-octahydro-7,8,8-trimethyl-4,7- methanobenzofuran-2-yl.

Substituted ethyl ethers Examples of substituted ethyl ethers include 1-ethoxyethyl, 1- (2-chloroethoxy) ethyl, 1-methyl-1-methoxyethyl, 1-methyl-1-benzyloxythiio, 1-methyl-1-benzyloxy-2-fluoroethyl, 2,2,2-trichloroethyl, 2-trimethylsilylethyl, 2- (phenylenyl) ethyl, t-butyl, allyl, p-chlorophenyl, p-methoxyphenyl, 2,4-dinitrophenyl and benzyl.

Substituted benzyl ethers Examples of substituted benzyl ethers include p-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, p-halobenzyl, 2,6-diclorobenzyl, p-cyanobenzyl, p-phenylbenzyl, 2- and 4- picolyl, 3-methyl-2-phenyl, N-oxide, diphenylmethyl, p.p'-dinltrobenzhydrl, 5-dibenzosuberyl, triphenylmethyl, α-naphthyridiphenylmethyl, p-methoxyphenyldiphenylmethyl, d (p-methoxyphenyl) phenylmethyl, (p-methoxyphenyl) methyl, 4- (4'-bromophenacyloxy) phenyldiphenylmethyl, 4,4,, 4"-tris (4,5-dichlorophthalimidophenyl) metyl, 4J 4, 4" -ris (Ievulinoxyphoxyphenyl) methyl, , 4 ', 4"-tris (benzoyloxyphenyl) methyl, 3- (1-dazol-1-ylmethyl) bis (4, J4" -d¡methoxyphenol) meth, 1,1-bis (4-) methoxypheni) -1'-pyrenilomethyl, 9-anthryl, 9- (9-phenyl) xanthenyl, 9- (9-phenyl-10-oxo) anthryl, 1,3-benzodithiolan-2-yl, and S, S- benzisothiazolyl dioxide.

Silyl Ethers Examples of silyl ethers include trimethylsilyl, triethylsilyl, triisopropylsilyl, dimethylisopropylsilyl, dietillsopropilsililo, dimethylthexylsilyl, t-buíildimeíllsililo, t-butyldiphenylsilyl, tribenzylsilyl, tri-p -xylylsilyl, triphenylsilyl, diphenylmethylsilyl, and f-butylmethoxyphenylsilyl.

Esters In addition to ethers, a hydroxyl group can be protected as an ester. Examples of esters include formate, benzoylformate, acetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate, methylanthoxylacetate, phenoxyacetate, p-chlorophenoxyacetafo, pP-phenylacetate, 3-phenylpropionate, 4-oxopentanoate (levulinate), 4,4- (eilenedithium) pentanoate, pivaloate, adamanioaio, crotonate, 4-methoxyrotonate, benzoate, p-phenylbenzoate, 2,4,6-trimethylbenzoate (mesiioate) Carbonafos Examples of carbonates include methyl, 9-fluorenylmethyl, ethyl, 2,2,2-trichloroethyl, 2- (trimethylsilyl) ethyl, 2- (phenylsulfonyl) ethyl, 2- (triphenylphosphonium) ethyl, isobutyl, vinyl, allyl, p-nitrophenyl, benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl , o-nitrobenzyl, p-nitrobenzyl, S-benzylthiocarbonate, 4-ethoxy-1-naphthyl and methyldithiocarbonate.

Assisted segmentation Examples of assisted segmentation include 2-iodobenzoaio, 4-azidobutyrate, 4-nitro-4-methylpentanoate, o- (dibromomefil) benzoaio, 2-formylbenzenesulfonate, 2- (meitythio-methoxy) ethylcarbonaio, 4- (methyl-iomethoxy) butyrate and 2- (methylthiomeoxymethyl) benzoate.

Various Esters Examples of various esters include 2,6-dichloro-4-methylphenoxyacetate, 2,6-dichloro-4- (1,1-, 3,3-tetramethylbutyl) phenoxyacetate, 2,4-bis (1,1-dimethylpropyl) phenoxyacetate, chlorodiphenylacetate, sobuyrate, monosuccinate, (E) -2-methyl-2-butenoate (tigloate), o- (methoxycarbonyl) benzoate, pP-benzoate, a-naphthoate, nitrate, alkyl-NNN'.N'- tetramethylphosphorodiamidate, N-phenylcarbamate, borate, dimethylphosphinothioyl and 2,4-dinitrofenyl sulfenate Sulfonates Examples of sulfonates include sulfate, methanesulfonate (mesylate), benzylsulfonate and tosylate.

Amino protecting groups The protection for the amino group includes carbamates, amides and special protective -NH groups. Examples of carbamates include methyl- and ethylcarbamates, substituted ethylcarbamates, carbamate-assisted carbamates, photolytic cleavage carbamates, urea derivatives and various carbamates.

Carbamates Examples of methyl- and ethylcarbamates include methyl and ethyl, 9-fluorenylmethyl, 9- (2-sulfo) fluorenylmethyl, 9- (2,7-dibromo) fluoreniomethyl, 2,7-di-t-butyl- [9- (10,10-d.oxo-10,10,10,10-tetrahydrothioxanthyl)] methyl and 4-methoxyphenacyl.

Substituted Ethyl Examples of substituted ethylcarbamates include 2,2,2-trichloroethyl, 2-trimethylsilylenyl, 2-phenylelyl, 1- (1-adamantyl) -1-methylethyl, 1,1-dimethyi-2-halogenoethyl, 1,1-dylmethyl. -2,2-dibromoephile, 1,1-dimethyl-2,2,2-lyrrolomethyl, 1-methyl-1- (4-biphenylyl) ethyl, 1- (3,5-di-t-butylphenyl) - 1-methylethyl, 2- (2'- and 4'-pyridyl) ethyl, 2- (N, N-dicyclohexylcarboxamido) ethyl, t-butyl, 1 -admantyl, vinyl, allyl, 1-isopropylallyl, cinnamyl, 4-nitrocinnamyl , 8-quinolyl, N-hydroxypiperidinyl, alkyldithium, benzyl, p-methoxybenzyl, p-nltrobenzyl, p-bromobenzyl, p-chlorobenzyl, 2,4-dichlorobenzyl, 4-methylsulfinylbenzyl, 9-anthrylmethyl and diphenylmetyl.

Assisted segmentation Examples of assisted segmentation include 2-methylphyoethyl, 2-methylsulfonylethyl, 2- (p-loluenesulfonyl) ethyl, [2- (1,3-dithianyl)] methyl, 4-methyl-phenyl, 2,4-dimethyl-thiophenyl, 2-phosphonio-eyl , 2-ylphenylphosphonium isopropyl, 1,1-dimethyl-2-cyanoethyl, m-chloro-p-acyloxybenzyl, p- (dihydroxyboronyl) benzyl, 5-benzisoxazolylmethyl, and 2- (trifluoromethyl) -6-chromonylmethyl.

Photolytic segmentation Examples of photolytic cleavage include m-nitrophenyl, 3,5-dimethoxybenzyl, o-nitrobenzyl, 3,4-dlmethoxy-6-n-ylbenzyl and phenyl (o-nitrophenyl) methyl.

Urea-type derivatives Examples of urea-type derivatives include phenothiazinyl- (10) -carbonyl derivative, N'-p-toluenesulfonylaminocarbonyl and N'-phenylaminothiocarbonyl.

Various Carbamates Examples of various carbamates include α-amyl, S-benzylthiocarbamate, p-cyanobenzyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclopropylmethyl, p-decyloxybenzyl, diisopropylmethyl, 2,2-dimethoxycarbonylvinyl, o- (N, N-dimefylcarboxamido) benzyl, 1, 1-dimethyl-3- (N, N-dimethylalkylcarboxamido) propyl, 1,1-dlmethylpropynyl, di (2-pyridyl) methyl, 2-furanylmethyl, 2-iodoethyl, isobornyl, isobutyl, isonicotinyl, p- (p ') -methoxyphenylazo) benzyl, 1-methylcyclobutyl, 1-methylcyclohexyl, 1-methyl-1-cyclopropylmethyl, 1-methyl-1- (3,5-dimethoxyphenyl) ethyl, 1-methyl-1- (p-phenylazophenyl) ethyl, -methyl-1-phenylethyl, 1-methyl-1- (4-pyridyl) ethyl, phenyl, p- (phenylazo) benzyl, 2,4,6-tri-t-butylphenyl, 4- (trimethylammonium) benzyl and 2, 4,6-trimethylbenzyl. Examples of amides include: Amides N-formyl, N-acetyl, N-chloroacetyl, N-trichloroacetyl, N-trifluoroacetyl, N-phenylacetyl, N-3-phenyipropionyl, N-picolinoyl, N-3-pyridylcarboxamide, N-benzoylphenylalanyl derivative, N-benzoyl , Np-phenlbenzoyl.

Assisted segmentation Non-nitrophenylacetyl, Non-nitrophenoxyacetyl, N-acetoacetyl, (N-dithiobenzyloxycarbonylamino) acetyl, N-3- (p-hydroxyphenyl) propionyl, N-3- (o-nitrophenyl) propionyl, N-2-methyl-2 - (o-nitrophenoxy) propionyl, N-2-methyl-2- (o-phenylazophenoxy) propionyl, N-4-chlorobutyryl, N-3-methyl-3-nitrobutyryl, Nitrocinnamolone, N-acetylmeithionine derivative, No -nltrobenzoyl, N- (benzoyloxymethyl) benzoyl and 4,5-diphenyl-3-oxazolin-2-one.

Derivatives of cyclic metering N-phthalimide, N-dithiasuccinoyl, N-2,3-diphenylmaleoyl, N-2,5-dimethylpyrrolyl, adduct of N-1, 1,4,4-tetramethyldysilylazacyclopentane, 1,3-dimethyl-1 , 5-substituted 3,5-triazacyclohexan-2-one, 1,3-dibenzyl-1, 3,5-triazacyclohexan-2-one 5-susitute and 3,5-dinitro-4-pyridonyl 1 - Substitute Specific protective NH groups Examples of special protective NH groups Include N-alkyl and N-aryl amines N-methyl, N-allyl, N- [2- (trimethysilyl) eioxy] methyl, N-3-aceioxypropyl, N- (1-isopropyl-4-nltro-2-oxo-3) -pyrrolin-3-yIo), quaternary ammonium salts, N-benzyl, N-di (4-methoxyphenyl) methy, N-5-dibenzosuberium, N-trifenylmethyl, N- (4-methoxyphenyl) diphenylmethyl, N-9- phenylfluorenyl, N-2,7-dichloro-9-fluorenylmethylene, N-ferrocenylmethyl and N'-oxide of N-2-picolylamine.

Imine derivatives N-1, 1-dimethylthiomethylene, N-benzylidene, N-p-mefoxibenzylidene, N-diphenylmethylene, N - [(2-pyridyl) mesityl] methylene and N- (N ', N'-dimethylaminomethylene).

Protection for the carboxyl group Esters Examples of esters include formate, benzoylformate, acetate, trichloroacetate, trifluoroacetafo, methoxylacetate, phenoxyacetate, p-chlorophenoxyacetate, benzoate.

Substituted methyl esters Examples of substituted methyl esters include 9-fluorenylmethyl, mefoximethyl, methylphomethyl, tetrahydropyranyl, tetrahydrofuranyl, methoxyethoxymethyl, 2- (trimethylsilyl) ethoxymethyl, benzyloxymeryl, phenacyl, p-bromophenacyl, a-methylphenacyl, p-methoxyphenacyl, carboxamidomethyl and N-phthalimidomethyl. 2-Substituted ethyl esters Examples of 2-substituted ethyl esters include 2,2,2-aryl glyphs, 2-halogeno-yl, β-chloroalkyl, 2- (arylsilyl) ethyl, 2-methylthioethyl, 1,3-dianaryl-2- methyl, 2- (p -nirophenylsulfenyl) ethyl, 2- (p-toluenesulfonyl) ethyl, 2- (2'-pyridyl) ethylo, 2- (diphenylphosphino) ethyl, 1-methyl-1-phenylethyl, t-butyl, cyclopentyl , cyclohexyl, allyl, 3-buten-1-yl, 4- (trimethylsilyl) -2-buten-1-yl, cinnamyl, α-methylcinnamyl, phenyl, p- (methylmercapto) phenyl and benzyl.

Substituted benzyl esters Examples of substituted benzyl esters include triphenylmethyl, diphenylmethyl, bis (o-nitrophenyl) metyl, 9-anthrylmethyl, 2- (9,10-dioxo) anilmethyl, 5-d-benzosuberyl, 1-pyrimidomethyl, 2- (trifluoromethyl) - 6-Chromylmethyl, 2,4,6-trimethylbenzyl, p-bromobenzyl, o-nitrobenzyl, p-nitrobenzyl, p-methoxybenzyl, 2,6-dimethoxybenzyl, 4- (methylsulfonyl) beryl, 4-sulfobenzyl, piperonyl, 4 -picolyl and pP-benzyl.

Silyl Esters Examples of silyl esters include trlmethylsilyl, triethylsilyl, t-butyldimethylsilyl, / -propylmethylsilyl, phenyldimethylsilyl and di-f-butylmethylsilyl.

Activated esters Examples of activated esters include thiols.

Miscellaneous Derivatives Examples of various derivatives include oxazoles, 2-alkyl-1,3-oxazolines, 4-alkyl-5-oxo-1,3-oxazoldines, 5-alkyl-4-oxo-1,3-dioxolanes, ortho esters, phenyl group and pentaaminocobalt complex (III).

Esters are alkyl Examples of stanilic esters include triethylstynyl and tri-p-butylsilyl.

C. Synomy The invention provides methods for making the compounds described in accordance with traditional organic synthesis methods as well as matrix or combination synthesis methods. Schemes 1 to 3 describe suggested synthesis routes. Using these schemes, the following guidelines, and the examples, one skilled in the art can develop analogous or similar methods for a given compound, which are within the invention. These methods are representative of the preferred synthesis schemes, but should not be considered as limiting the scope of the invention. One skilled in the art will recognize that the synthesis of the compounds of the present invention can be effected upon purchase of an intermediary or protected intermediate compounds described in any of the schemes described herein. One skilled in the art will recognize that during any of the processes for the preparation of the compounds in the present invention, it may be necessary and / or desirable to protect sensitive or reactive groups on any of the molecules in question. This can be achieved by means of conventional protecting groups, such as those described in "Protective Groups in Organic Synthesis", John Wiley & Sons, 1991. These protecting groups can be removed at a convenient stage using methods known in the art. Where the processes for the preparation of the compounds according to the invention give rise to mixture of stereoisomers, these isomers can be separated by conventional techniques such as preparative chromatography. The compounds can be prepared in racemic form, or individual enantiomers can be prepared either by enantiospecific synthesis or by resolution. Compounds can be resolved, for example, in their component enantiomers by standard techniques, such as the formation of diastereomeric pairs by salt formation. The compounds can also be resolved by formation of diastereomeric ethers or amides, followed by chromatographic separation and removal of the chiral auxiliary. Alternatively, the compounds can be resolved using a chiral HPLC column. Examples of the synthetic routes described include examples 1 to 9. Compounds analogous to the objective compounds of these examples can be made in accordance with similar routes. The disclosed compounds are useful in basic research and as pharmaceutical agents as described in the following section.

General guidance A preferred synthesis of formula (I) is demonstrated in schemes 1-9. Abbreviations or acronyms useful herein include: AcOH (glacial acetic acid); DCC (1,3-dicyclohexylcarbodiimide); DCE (1,2-dichloroethane); DIC (2-dimethylaminopropyl chloride hydrochloride); DIEA (diisopropylethylamine); DMAP (4- (dimethylamino) pyridine); DMF (dimethylformamide); EDC (1- (3-dimethylaminopropyl) -3-ethylcarbodiimide); EtOAc (acetyl ether); LAH (lithium aluminum hydride); mCPBA (3-chloroperoxybenzoic acid); NMI (1-methyl-midazole); TEA (irieilamine); TFA (trifluoroacetic acid); THF (tetrahydrofuran); TMEDA (N.N.N'.N'-tetramethyl-ethylenediamine).

SCHEME 1 Synthesis of intermediary 1-D 1-A 1-B According to scheme 1, phenol 1-A, a variety of which are commercially available (such as 3-methylphenol, 2-ethylphenol, 2-propylphenol, 2,3-dimethylphenol, 2-chlorophenol, 2,3-dichlorophenol, 2-bromophenol and 2-aminophenol), is aliquoted to form phenoxyacetic acid ethyl ester 1-B with a suitable halogenacetic acid ester such as bromoacetic acid ethyl ester, in the presence of an appropriate base such as Cs2C03, K2C03, or NaH, in a suitable solvent such as CH3CN or THF. The sulfonation of the phenoxyacetic acid ethyl ester 1-B with an appropriate sulfonating agent, such as chlorosulfonic acid, occurs selectively in the para position in order to provide 4-chlorosulfonylphenoxyacetic acid ethyl ester 1-C. The transformation of sulfonyl chloride 1-C to benzenethiol 1-D is accomplished using a metal as a reducing agent, such as tin or zinc, in an acidic medium such as ethanol or dioxane.

SCHEME 2 Synthesis of the compound In Scheme 2, diethyl malonate R5 substituted 2-A is reduced to propane-1,3-diol 2-B using a suitable reducing agent such as lithium aluminum hydride or diisobutylaluminum hydride. The Mitsunobu reaction of 2-B with phenol 2-C provides the compound 2-D using a triarylphosphine such as phenylphenylphosphine, and an azodicarbonyl reagent such as diisopropyl azodicarboxylate, in a suitable solvent such as THF. Phenoxyacetic acid ethyl ester 2-E is obtained in two steps: (1) conversion of the 2-D alcohol to mesylate under standard conditions using methanesulfonyl chloride and triethylamine in a suitable solvent such as CH 2 Cl 2, and (2) alkylation of benzenethiol 1-D, prepared according to scheme 1 above, with the mesylate intermediate using a Suitable base such as Cs2CO3, K2CO3, or NaH, in an appropriate solvent such as CH3CN or THF, under nitrogen. Under standard saponification conditions, phenoxyacetic acid ethyl ester 2-E is converted to acid under nitrogen. Preferred hydrolysis conditions include the use of NaOH as a base in an aqueous alcohol solvent system such as water-methanol, or using LiOH as a base in a lighter THF-water system.

SCHEME 3 Synthesis of compound Ia1 1. Methylation with M Mee0022CC acid. Y-OH 1. TBSC1, Iml azol H0- OTBS 2. K2CO3, MeOH Rs 2. Reduction with ester s 3-D 3-E Ia1 In scheme 3, 3-A enantiomerically pure phenylacetic acid, a variety of which are commercially available (such as (S) - (+) - 2-phenylpropionic acid, (R) - (-) - 2-phenylpropionic acid, (S) - (+) - 2-phenylbutyric acid, (R) - (-) - 2-phenylbutyric acid, (+) - 3-meityl-2-phenylbutyric acid, (S) - (+) - 2- phenylsuccinic, and (R) - (-) - 2-phenylsuccinic acid), it is reduced to alcohol using borane and the alcohol is subsequently protected as a 3-B acetamide under standard conditions known in the art. Oxidation of the phenyl group in 3-B to 3-C acid is achieved using catalytic amount of ruthenium chloride and a large excess of sodium periodate in a mixed solvent system such as CH3CN-CC4-H2O. The 3-C acid is converted to 3-E alcohol in four steps: (1) methylation of 3-C acid using (trimethylsilyl) diazomean as a mephilating agent, (2) and (3) exchange of the hydroxyl-protecting group from from acetyl in 3-C to tert-butyldimethyl silyloxy in 3-E under conventional conditions well known in the art, and (4) reduction of methyl ester using an appropriate reducing agent such as diisobutylaluminum hydride. Phenoxyacetic acid ethyl ester 3-F is obtained in two steps: (1) conversion of the alcohol 3-E to mesylate under standard conditions using methanesulfonyl chloride and triethylamine in an appropriate solvent such as CH 2 Cl 2, and (2) alkylation of benzenethiol 1-D, prepared according to scheme 1 above, with the mesylate intermediate using a suitable base such as Cs2C03, K2C? 3, or NaH, in a suitable solvent such as CH3CN or THF, under nitrogen. After revealing the hydroxyl group by removing the tert-butyldimethylsilyloxy group in 3-F, the 3-G alcohol is transformed to 3-H by reacting with phenol 2-C under Miisunobu conditions. Preferred conditions include the use of a triarylphosphine such as triphenylphosphine, and an azodicarbonyl reagent such as diisopropyl azodylcarboxylate, in a suitable solvent such as THF. Under standard saponification conditions, the phenoxyacetic acid ethyl ester 3-H is converted to acid Ia1 under nitrogen. Preferred hydrolysis conditions include the use of NaOH as a base in an aqueous alcohol solvent system such as water-methanol, or using LiOH as a base in a lighter THF-water system.

SCHEME 4 Synthesis of compound Ia2 Ia2 In scheme 4, benzenethiol 1-D is charged to phenyl disulfide 4-A in the presence of an appropriate oxidizing agent such as barium manganate. The Mitsunobu reaction of 2-hydroxymethylpropane-1,3-diol 4-B with phenol 2-C provides compound 4-C using a triarylphosphine such as triphenylphosphine, and an azodicarbonyl agent such as azodicarboxylate of 5-dilsopropane, in a solvent suitable such as THF. The carbon-sulfur bond formation in compound 4-D is carried out by Mitsunobu reaction of 4-C diol with phenyl disulfide 4-A using tri-n-butylphosphine and pyridine. The third Mitsunobu reaction of 4-D with acetone cyanohydrin converted the 4-D alcohol to the cyano 4-E compound under the reaction conditions of Miisunobu esíándares. As usual, basic hydrolysis of the elliptical ester of phenoxyacetic acid 4-E gives the acid Ia2.

SCHEME 5 Synthesis of compound Ia3 0 Ia3 As shown in scheme 5, where R is alkyl or aryl, the compound of alkyl ether 5-A could be prepared by alkylation of 4-D alcohol, an intermediate prepared in scheme 4 above, with a variety of alkylating agents such as trifluoromethanesulfonates of alkyl or alkyl halides in the presence of a suitable base such as sodium hydride or sodium bis (trimethylsilyl) amide. Similarly, the aryl ether could be synthesized by Mitsunobu 4-D reaction with many different substituted phenols available. Finally, the saponification of ethyl ester 5-A under standard conditions gives acid Ia3.

SCHEME 6 Synthesis of compound Ia4 Ia4 In accordance with scheme 6, the Mitsunobu reaction of (R) - (+) - glycidol, or (S) - (-) - glycidol, or racemic glycidol 6-A with phenol 2-C provides the epoxide 6- B using a triarylphosphine such as triphenylphosphine, and an azodicarbonyl reagent such as diisopropyl azodicarboxylate, in a solvent suitable such as THF. The opening of the 6-B epoxide ring with benzenethiol 1-D in the presence of a catalytic amount of tetrabuylamonium fluoride gives the alcohol 6-C. The 6-D alkyl ether compound could be prepared by alkylation of the 6-C alcohol with a variety of alkylating agents such as alkyl trifluoromethanesulfonates or alkyl halides in the presence of a suitable base fal as sodium hydride or bis (trimethylsilyl) amide of sodium in a suitable solvent such as THF or DMF. Similarly, aryl ether 6-D could be synthesized by the Mitsunobu reaction of 6-C with many different substituted phenols available using triphenylphosphine and an appropriate azodicarbonyl reagent such as 1,1 '- (azodicarbonyl) dipiperidine or azodicarboxylate. diethyl Finally, saponification of the 6-D ethyl ester under standard conditions gives the acid Ia4.

SCHEME 7 Synthesis of the intermediary 7-E 7-E In accordance with scheme 7, 7-A (4-hydroxyphenyl) acetic acid, a variety of which are commercially available (such as 3-bromo-4-hydroxy-phenylacetic acid, 3-cyclo-4-hydroxyphenylacetic acid, 3-fluoro-4-hydroxyphe- niacetic acid, 4-hydroxy-3-mephoxyphenylacetic acid, and 4-hydroxy-3-ni- hophenylacetic acid), is methylated to form methyl (4-hydroxyphenyl) acetic acid ester 7-B in methanol in presence of a catalytic amount of a suitable acid such as sulfuric acid or hydrochloric acid. Phenol 7-B is converted to 7-C (4-dimethylthiocarbamoyloxyphenyl) acetic acid methyl ester by reacting with dimethylisocarbamoyl chloride in the presence of some appropriate bases such as triethylamine and 4- (dimethylamino) pyridine. At high temperature, in the preferred range of 250 to 300 ° C, 7-C is rearranged to methyl (4-dimethylcarbamoylsulfanylphenyl) acetic acid 7-D methyl ester in a high boiling solvent such as teradecane. Mediate treatment with a suitable base such as sodium methoxide, 7-D is transformed to methyl ester of (4-mercapto-phenyl) -acetic acid 7-E.

SCHEME 8 Synthesis of compound Ib1 Ib1 In accordance with scheme 8, wherein R is alkyl, the 8-B epoxide is obtained by treatment of phenol 2-C with an appropriate base such as cesium carbonate followed by alkylation with 2-chlorometal-oxirane 8-A. The epoxide ring opening of 8-B with benzenethiol 7-E, prepared in scheme 7 above, in the presence of a catalytic amount of tetrabutylammonium fluoride gives the alcohol 8-C. The 8-D alkyl ester compound could be prepared by alkylation of the 8-C alcohol with a variety of alkylating agents such as trifluoromethanesulphonates alkyl or alkyl halides in the presence of a suitable base such as sodium hydride or sodium bis (trimethylsilyl) amide in a suitable solvent such as THF or DMF. Finally, saponification of the methyl ester 8-D under standard conditions gives the Ib1 acid.

SCHEME 9 Synthesis of the compound Id Id In Scheme 9, where R is as shown above, aldehyde 9-B could be prepared in two steps by methalation of 9-A acid using (tr ymethylsilyl) diazomethane as a methylating agent followed by reduction of the methyl ester with a suitable reducing agent such as diisobutylaluminum hydride. The aldehyde 9-B is transformed to 9-C epoxide by reacting with dimethylsulfonium methylide, which is generated in-situ from the treatment of trimethylsulfonium iodide with a strong base such as DMSO anion. The ring opening of epoxide 9-C with benzenethiol 1-D in the presence of a catalytic amount of terabuleylammonium fluoride gives the alcohol 9-D. The 9-E alkyl ester compound could be prepared by alkylation of the 9-D alcohol with a variety of alkylating agents such as alkyl trifluoromethanesulfonates or alkyl halides in the presence of a suitable base such as sodium hydride or bis (trimethylsilyl) amide of sodium in a suitable solvent such as THF or DMF. Finally, saponification of the ethyl ester 9-E under standard conditions gives the acid Id.

EXAMPLES EXAMPLE A Compound 1 Acid. { 2-methyl-4- [2-methyl-3- (4-trifluoromethyl-phenoxy) -propylsulfanyl) -phenoxy} -acetic SCHEME A1 A1a Ethyl ester of (4-chlorosulfonyl-2-methyl-phenoxy) -acetic acid A1c, 98% Ethyl ester of (4-mercapto-2-methyl-phenoxy) -acetic acid According to scheme A1, to a flask containing chlorosulfonic acid (15.0 ml, 226 mmol) at 4 ° C was slowly added (2-methylphenoxy) ethyl acetate A1a (10.0 g, 51.6 mmol). The mixture was stirred at 4 ° C for 30 min and room temperature for 2 hr, and then emptied into ice water. The precipitated white solid was filtered, washed with water, and dried under vacuum overnight to provide 14.0 g (93%) of A1b as a white solid; 1 H NMR (300 MHz, CDCl 3) d 7.87-7.84 (m, 2 H), 6.80 (d, J = 9.5 Hz, 1 H), 4.76 (s, 2 H), 4.29 (q, J = 7.1 Hz, 2 H) , 2.37 (s, 3 H), 1.31 (t, J = 7.1 Hz, 3H); MS (ES) m / z: 315 (M + Na +). To a solution of A1 b (4.70 g, 16.1 mmol) in EtOH (20 ml) was added a solution of 4.0 M HCl in dioxane (20 ml) followed by 100 mesh tin powder (9.80 g, 82.6 mmoles) in portions . The mixture was refluxed for 2 hr, poured into CH 2 Cl 2 / ice (100 ml), and filtered. The filtrate was separated, and the aqueous layer was extracted with CH2Cl2. The combined organic phases were washed with water, dried, and concentrated to give 3.56 g (98%) of A1c as a yellow oil; 1 H NMR (300 MHz, CDCl 3) d 7.14-7.03 (m, 2 H), 6.59 (d, J = 8.4 Hz, 1 H), 4.60 (s, 2H), 4.25 (q, J = 7.1 Hz, 2H), 2.24 (s, 3 H), 1.29 (t, J = 7.1 Hz, 3 H).

SCHEME A2 A2d, 73% Ethyl ester of acid. { 2-methyl-4- [2-methyl-3- (4-trifluoromethyl-phenoxy-propylsulfanyl) -Henoxy-acetic acid 90% Compound 1 According to scheme A2, to a suspension of lithium-aluminum hydride (152 mg, 4.00 mmol) in THF (3 ml) at 0 ° C diethyl methyl aralmalonate A2a (348 mg, 2.00 mmol) was added drop by drop. The reaction mixture was stirred at room temperature for 1.5 hr, quenched with water (0.2 ml) and 5N NaOH (0.2 ml), and then diluted with water (0.6 ml).

After stirring for 20 min, the precipitated solid was filtered through Celite and washed with MeOH / CH 2 Cl 2. The filtrate was dried, concentrated, and purified by column chromatography to give 135 mg (75%) of A2b; 1 H NMR (300 MHz, CDCl 3) d 3.68 (dd, J = 10.7, 4.5 Hz, 2H), 3. 58 (dd, J = 10.7, 7.6 Hz, 2H), 3.50 (s, 2H), 1.96-1.89 (m, 1 H), 0.86 (d, J = 7. 0 Hz, 3 H); MS (ES) m / z: 113 (M + Na +). To a mixture of A2b (113 mg, 1.26 mmol), trifluoromethylphenol (156 mg, 0.963 mmol) and triphenylphosphine (252 mg, 0.962 mmol) in THF (3 mL) at 0 ° C was added dlisopropyl azodicarboxylate (195 mg, 0.965 mmol).

The mixture was stirred at room temperature overnight and concentrated. The residue was purified by column chromatography to provide 149 mg (51 %) of A2c; 1 H NMR (400 MHz, CDCl 3) d 7.53 (d, J = 8.8 Hz, 2H), 6.96 (d, J = 8.7 Hz, 2H), 3.98 (m, 2H), 3.71 (m, 2H), 2.24-2.16 (m, 1 H), 1.80 (s, 1 H), 1.05 (d, J = 7.0 Hz, 3H); MS (ES) m / z: 235 (M + H +).

General procedure 1 for the formation of thioéíer: To a solution of A2c (135 mg, 0.577 mmoles) in CH2CI2 (3 ml) at 0 ° C were added Et3N (0.162 ml, 1.16 mmoles) and methanesulfonyl chloride (93 mg, 0.81 mmoles). The mixture was stirred at 0 ° C for 30 min and room temperature for 1 hr and diluted with saturated NaHCO3. The organic layer was separated and the aqueous layer was extracted with CH2Cl2 (x3). The combined organic phases were dried and concentrated to provide the mesylate. A mixture of the above mesylate, (4-mercapto-2-methyl-phenoxy) -acetic acid ethyl ester A1c (197 mg, 0.872 mmol), and Cs2CO3 (472 mg, 1.45 mmol) in CH3CN (5 mL) was stirred at room temperature. environment for 3 hr. Water was added and the mixture was extracted with Et2O. The combined organic layers were dried, concentrated and subjected to column chromatography (EtOAc / hexane: 1/10) to provide 187 mg (73%, two steps) of A2d; 1 H NMR (300 MHz, CDCl 3) d 7.51 (d, J = 8.6 Hz, 2 H), 7.20 (d, J = 1.7 Hz, 1 H), 7.15 (dd, J = 8.4, 2.2 Hz, 1 H), 6.89 (d, J = 8.6 Hz, 2H), 6.57 (d, J = 8.4 Hz, 1 H), 4.57 (s, 2H), 4.25 (q, J = 7.1 Hz, 2H), 3.94 (dd, J = 5.7, 2.7 Hz, 2H), 3.04 (dd, J = 13.6, 6.6 Hz, 1 H), 2.86 (dd, J = 13.3, 6.5 Hz, 1 H), 2.24-2.16 (m, 1 H), 2.23 (s, 3H), 1.29 (t, J = 7.1 Hz, 3H), 1.14 (d, J = 6.8 Hz, 3H); MS (ES) m / z: 465 (M + Na +).

General procedure 2 for the hydrolysis of the ethyl and methyl esters: To a solution of A2d (130 mg, 0.294 mmol) in THF (2 ml) under N2 was added 1.0 M LiOH (0.58 ml, 0.58 mmol). The mixture was stirred for 2 h, acidified with 1 M HCl, and extracted with EtOAc (x 3). The extracts were dried, concentrated, and purified by column chromatography (CH2Cl2 / MeOH: 10/1) to give 109 mg (90%) of compound 1; 1 H NMR (400 MHz, CDCl 3) d 7.50 (d, J = 8.7 Hz, 2H), 7.18 (s, 1 H), 7.14 (d, J = 8.4 Hz, 1 H), 6.88 (d, J = 8.7 Hz, 2H), 6.57 (d, J = 8.4 Hz, 1 H), 4.57 (s, 2H), 3.92 (d, J = 5.6 Hz, 2H), 3.04 (dd, J = 13.3, 6.5 Hz, 1 H), 2.85 (dd, J = 13.2, 6.5 Hz, 1H), 2.24-2.15 (m, 1 H), 2.19 (s, 3 H), 1.13 (d, J = 6.8 Hz, 3H); MS (ES) m / z: 415 (M + H +).

EXAMPLE B Compound 2 Acid. { 2-meityl-4- [2- (4-yl-1-fluoromethyl-phenoxymethyl) -buylsulfanyl] -phenoxy} -acetic SCHEME B i ~, u BH3.THF RuCl3, Nal04 Bl l CH3CN ~ CCI4-H2? 2-Fepil-butan-1 -ol Acetic acid 2-phenyl-butyl ester DBAL-H 2-Acetoxymethyl-butyric acid Ester methyl ester methyl 2- (tert-butyl-2-methyl-2-hydroxymethyl-butyric acid silanyloxymethyl) -butyric acid To a solution of (S) - (+) - 2-phenylbuiric acid B1 (352 mg, 2.14 mmol) in THF (3 ml) at 0 ° C was slowly added a solution of BH3 1.0 M.THF complex in THF ( 2.14 ml, 2.14 mmol). The mixture was allowed to warm to room temperature, stirred at room temperature overnight, quenched with water and was followed by 1.0 N HCl, and extracted with Et2O (x 3). The exiphats were dried, concentrated, and subjected to column chromatography to give 283 mg (88%) of B2; 1 H NMR (300 MHz, CDCl 3) d 7.34-7.29 (m, 2H), 7.24-7.16 (m, 3H), 3.70 (m, 2H), 2.65 (m, 1 H), 1.79-1.67 (m, 1 H), 1.63-1.48 (m, 2H), 0.82 (t, J = 7.4 Hz, 3H); MS (ES) m / z: 173 (M + Na +). To a mixture of B2 (283 mg, 1.88 mmol), pyridine (0.76 ml, 9.4 mmol), and DMAP (23 mg, 0.19 mmol) in CH 2 Cl 2 (3 ml) at 0 ° C was added acetyl chloride (369 mg, 4.70 mmoles). The mixture was stirred at room temperature for 2 hr, diluted with 1.0 N HCl, and extracted with CH2Cl2. The combined organic phases were washed with 1.0 N HCl (x 3) and brine, dried, concentrated and subjected to column chromatography to provide 343 mg (95%) of B3; 1 H NMR (300 MHz, CDCl 3) d 7.33-7.28 (m, 2H), 7.25-7.17 (m, 3H), 4.21 (m, 2H), 2.86-2.77 (m, 1 H), 1.98 (s, 3 H), 1.86-1.73 (m, 1H), 1.68-1.53 (m, 1 H), 0.82 (t, J = 7.4 Hz, 3H); MS (ES) m / z: 215 (M + Na +). To a solution of B3 (160 mg, 0.833 mmol) in a mixture of solvents of CCI4 (2 ml), CH3CN (2 ml), and water (3 ml) were added Nal0 (3.55 g, 16.6 mmol) and RuCI3 (12 mg, 0.058 mmol). After stirring at room temperature overnight, the mixture was partitioned between water and CH2Cl2. The combined organic layers were dried, filtered, and concentrated. The residue was redissolved in Et20 and filtered through Celite. The filtrate was dried and subjected to column chromatography (CH2Cl2 / MeOH: 9/1) to give 97 mg (73%) of B4; 1 H NMR (300 MHz, CDCl 3) d 4.24 (d, J = 6.7 Hz, 2H), 2.67 (m, 1H), 2.06 (s, 3H), 1.77-1.56 (m, 2H), 1.00 (t, J = 7.5 Hz, 3H); MS (ES) m / z: 183 (M + Na +). To a solution of B4 (218 mg, 1.36 mmol) in Et20 (4 mL) and MeOH (2 mL) was added 2.0 M TMSCHN2 (2.08 mL, 4.16 mmol) in Et20 slowly. After stirring at room temperature for 3 hr, the solvents were removed under reduced pressure to give the methyl ester. To the residue dissolved in MeOH (2 ml) was added K2CO3 (188 mg, 1.36 mmol) and the resulting mixture was stirred for 20 min. After removal of the solvent at low temperature, the residue was partitioned between Et2O and water. The organic layer was dried, concentrated and subjected to column chromatography (EtOAc / hexane: 1/2) to give 176 mg (98%) of B5; 1 H NMR (300 MHz, CDCl 3) d 3.82-3.73 (m, 2 H), 3.73 (s, 3 H), 2.53 (m, 1 H), 2.41 (brs, 1 H), 1.73-1.55 (m, 2 H) , 0.95 (t, J = 7.5 Hz, 3H); MS (ES) m / z: 155 (M + Na +). A mixture of B5 (225 mg, 1.70 mmol), urea-butyldimethylsilyl chloride (334 mg, 2.22 mmol), and imidazole (290 mg, 4.26 mmol) in DMF (1.7 mL) was stirred for 14 hr and was partitioned between water and Et20. The organic layer was dried, concentrated and subjected to column chromatography to provide 385 mg (92%) of B6; 1 H NMR (400 MHz, CDCl 3) d 3.77 (dd, J = 9.7, 7.8 Hz, 1 H), 3.70- 3.66 (m, 1 H), 3.68 (s, 3 H), 2.52 (m, 1 H) , 1.64-1.51 (m, 2H), 0.91 (t, J = 7.5 Hz, 3 H), 0.87 (s, 9 H), 0.03 (s, 6 H); MS (ES) m / z: 269 (M + Na +).

To a solution of B6 (350 mg, 1.42 mmol) in CH2Cl2 (5 mL) at -78 ° C was added dropwise 1.0 M DIBAL-H (3.55 mL, 3.55 mmol). After stirring at -78 ° C for 15 min, the mixture was allowed to warm gradually to 0 ° C, stirred at the same temperature for 10 min, quenched with MeOH. After stirring at room temperature for 1 hr, the precipitated solid was filtered through Celite and washed with CH2Cl2 / MeOH. The filtrate was dried, concentrated and subjected to column chromatography to give 273 mg (88%) of B7; 1 H NMR (300 MHz, CDCl 3) d 3.82 (dd, J = 9.9, 4.0 Hz, 1 H), 3.75 (dd, J = 11.0, 3.3 Hz, 1 H), 3.67-3.58 (m, 2H), 2.78 (brs, 1 H), 1.68-1.61 (m, 1 H), 1.33-1.23 (m, 2H), 0.93 (t, J = 7.4 Hz, 3H), 0.90 (s, 9 H), 0.08 (s, 6 H); MS (ES) m / z: 219 (M + H +). B8 (61%) was prepared following general procedure 1 of Example A; 1 H NMR (300 MHz, CDCl 3) d 7.19 (d, J = 1.8 Hz, 1 H), 7.15 (dd, J = 8.4, 2.2 Hz, 1 H), 6.62 (d, J = 8.4 Hz, 1 H), 4.60 (s, 2H), 4.26 (q, J = 7.1 Hz, 2H), 3.67 (dd, J = 10.0, 4.7 Hz, 1 H), 3.57 (dd, J = 10.0, 5.5 Hz, 1 H), 2.97 (dd, J = 12.9, 6.8 Hz, 1H), 2.79 (dd, J = 12.9, 6.0 Hz, 1H), 2.26 (s, 3H), 1.62-1.56 (m, 1 H), 1.44 (m, 2H), 1.29 (i, J = 7.1 Hz, 3H), 0.88 (i, J = 7.4 Hz, 3H), 0.88 ( s, 9H), 0.03 (s, 6H); MS (ES) m / z: 449 (M + Na +). A solution of B8 (213 mg, 0.500 mmol) in CH2Cl2 (2 ml) was spotted with a solution of 1.0 M tetrabutylammonium fluoride (1.50 ml, 1.50 mmol) in THF for 3 hr and partitioned between water and CH2Cl2. The organic layer was dried, concentrated and subjected to column chromatography to provide 33 mg (21%) of B9; 1 H NMR (300 MHz, CDCl 3) d 7.22 (d, J = 1.7 Hz, 1 H), 7.17 (dd, J = 8.4, 2.2Hz, 1 H), 6.63 (d, J = 8.4 Hz, 1 H) , 4.61 (s, 2H), 4.25 (q, J = 7.1 Hz, 2H), 3.72 (dd, J = 10.9, 4.7 Hz, 1 H), 3.64 (dd, J = 11.0, 5.8 Hz, 1 H), 2.92 (d, J = 6.4 Hz, 2H), 2.26 (s, 3H), 1.73-1.63 (m, 2H), 1.45 (m, 2H), 1.29 (t, J = 7.1 Hz, 3H), 0.91 (t, J = 7.4 Hz, 3 H); MS (ES) m / z: 335 (M + Na +). To a mixture of B9 (120 mg, 0.385 mmol), frifluoromethylphenol (93 mg, 0.57 mmol), and triphenylphosphine (150 mg, 0.573 mmol) in THF (3 mL) at 0 ° C was added dlisopropyl azodicarboxylate (115 mg, 0.569 mmol). The mixture was stirred at room temperature overnight and concentrated. The residue was purified by column chromatography twice (EtOAc / hexane: 1/10; CH2Cl2 / hexane: 2/1) to provide 121 mg (69%) of B10; 1 H NMR (300 MHz, CDCl 3) d 7.51 (d, J = 8.7 Hz, 2H), 7.19 (d, J = 1.8 Hz, 1 H), 7.15 (dd, J = 8.4, 2.3 Hz, 1 H), 6.89 (d, J = 8.6 Hz, 2H), 6.56 (d, J = 8.4 Hz, 1 H), 4.56 (s, 2H), 4.25 (q, J = 7.1 Hz, 2H), 4.01 (m, 2H), 3.00 (d, J = 6.4 Hz, 2H), 2.21 (s, 3H), 1.96 (m, 1 H), 1.59 (m, 2H), 1.28 (t, J = 7.1 Hz, 3H), 0.94 (t, J = 7.4 Hz, 3H); MS (ES) m / z: 479 (M + Na +). Compound 2 (88%) was prepared following general procedure 2 in Example A; 1 H NMR (300 MHz, CDCl 3) d 7.49 (d, J = 8.6 Hz, 2H), 7.15 (s, 1 H), 7.11 (d, J = 8.3 Hz, 1 H), 6.88 (d, J = 8.6 Hz, 2H), 6.53 (d, J = 8.2 Hz, 1H), 4.50 (s, 2H), 4.03-3.95 (m, 2H), 3.00-2.98 (m, 2H), 2.16 (s, 3H), 1.95 (m, 1 H), 1.57 (m, 2H), 0.93 (f, J = 7.4 Hz, 3H); MS (ES) m / z: 429 (M + H +).

EXAMPLE C Compound 3 Acid. { 2-methyl-4- [2- (4-trifluoromethyl-phenoxymethyl) -buylsulfanyl] -phenoxy} -acetic SCHEME C Et Compound 3 To a suspension of lithium aluminum hydride (101 mg, 2.66 mmol) in THF (3 ml) at 0 ° C was added dropwise diethyl C1-ethyl malonate (250 mg, 1.33 mmol). The reaction mixture was stirred at room temperature for 2 hr, quenched with water (0.1 ml) and 5N NaOH (0.2 ml), diluted with water (0.6 ml), filtered through Celite, and the solid was washed with MeOH / CH2Cl2. The filtrate was dried, concentrated and purified by column chromatography to give 110 mg (80%) of C2; 1 H NMR (300 MHz, CDCl 3) d 3.79 (dd, J = 10.7, 3.9 Hz, 2H), 3. 64 (dd, J = 10.7, 7.5 Hz, 2H), 3.27 (s, 2H), 1.67 (m, 1H), 1.29 (m, 2H), 0.94 (t, J = 7.5 Hz, 3H); MS (ES) m / z: 127 (M + Na +). To a mixture of C2 (108 mg, 1.04 mmol), trifluoromethylphenol (130 mg, 0.802 mmol) and triphenylphosphine (210 mg, 0.802 mmol) in THF (3 mL) at 0 ° C was added diisopropyl azodicarboxylate (162 mg, 0.802). mmoles). The mixture was stirred at room temperature overnight, diluted with water, and extracted with Et 2 O (x 3). The extracts were dried, concentrated and subjected to column chromatography to provide 134 mg (52%) of C3.; 1 H NMR (400 MHz, CDCl 3) d 7.54 (d, J = 8.8 Hz, 2H), 6.97 (d, J = 8.8 Hz, 2H), 4.05 (m, 2H), 3.80 (dd, J = 10.8, 4.4 Hz, 1 H), 3.74 (dd, J = 10.8, 6.5 Hz, 1 H), 1.94 (m, 1 H) ), 1.50 (m, 2H), 1.00 (t, J = 7.5 Hz, 3H); MS (ES) m / z: 249 (M + Na +). C4 (81%) was prepared following general procedure 1 of Example A; 1 H NMR (300 MHz, CDCl 3) d 7.50 (d, J = 8.6 Hz, 2H), 7.19 (d, J = 1. 8 Hz, 1 H), 7.15 (dd, J = 8.4, 2.2 Hz, 1 H), 6.89 (d, J = 8.6 Hz, 2H), 6.56 (d, J = 8.4 Hz, 1 H), 4.56 (s, 2H), 4.25 (q, J = 7.1 Hz, 2H), 4.01 (m, 2H), 3.00 (d, J = 6. 4 Hz, 2H), 2.21 (s, 3H), 1.96 (m, 1H), 1.59 (m, 2H), 1.28 (i, J = 7.1 Hz, 3H), 0.94 (i, J = 7.5 Hz, 3H); MS (ES) m / z: 479 (M + Na +). Analysis calculated for C 23 H 27 F 3 O 4 S: C, 60.51; H, 5.96. Found: C, 60.69; H, 5.56. Compound 3 (92%) was prepared following general procedure 2 in Example A; 1 H NMR (300 MHz, MeOH-d 4) d 7.53 (d, J = 8.6 Hz, 2H), 7.18 (s, 1 H), 7.15 (m, 1 H), 6.96 (d, J = 8.6 Hz, 2H) , 6.66 (d, J = 8.1 Hz, 1H), 4.55 (s, H), 4.04 (m, 2H), 3.00 (d, J = 6.3 Hz, 2H), 2.16 (s, 3H), 1.92 (m, 1H), 1.58 (m, 2H), 0.94 (t, J = 7.5 Hz, 3H); MS (ES) m / z: 451 (M + Na +).

EXAMPLE D Compound 4 Acid. { 4- [2- (4-ír-trifluoromethyl-phenoxymethyl) -butylsulfanyl] -phenoxy} -acéíico SCHEME D 4- [2- (4-Trifluoromethyl-phepoxymethyl) -butylsulphanyl] -phenol Replacing ethyl ester (4-mercapto-2-methyl-phenoxy) acetic acid A1c by 4-mercapto-phenol and following general procedure 1 in Example A gave D1 (28%); 1 H NMR (300 MHz, CDCl 3) d 7.51 (d, J = 8.6 Hz, 2H), 7.28 (d, J = 8.7 Hz, 2H), 6.91 (d, J = 8.6 Hz, 2H), 6.72 (d, J = 8.7 Hz, 2H), 4.84 (s, 1 H), 4.02 (dd, J = 5.2, 3.8 Hz, 2H), 2.99 (d, J = 6.0 Hz, 2H), 1.95 (m, 1H), 1.59 (m, 2H), 0.94 (t, J = 7.5 Hz, 3H); MS (ES) m / z: 357 (M + H +). A mixture of D1 (86 mg, 0.24 mmol), methyl bromoacetic acid ester (55 mg, 0.36 mmol) and Cs2C? 3 (157 mg, 0.482 mmol) in CH3CN (2 mL) was stirred for 2 hr and was divided between Et20 and water. The organic layer was dried, concentrated and subjected to column chromatography (EOAc / hexane: 1/6) to give 99 mg (96%) of the methyl ester. Following general procedure 2, the above methyl ester was converted to Compound 4 acid (89%); 1 H NMR (300 MHz, CDCl 3) d 8.91 (brs, 1 H), 7.49 (d, J = 8.7 Hz, 2H), 7.26 (d, J = 8.3 Hz, 2H), 6.88 (d, J = 8.6 Hz, 2H), 6.74 (d, J = 8.5 Hz, 2H), 4.46 (s, 2H), 3.98 (m, 2H), 3.01-2.92 (m, 2H), 1.93 (m, 1 H), 1.56 (m, 2H), 0.92 (f, J = 7.4 Hz, 3H); MS (ES) m / z: 437 (M + Na +).

EXAMPLE E Compound 5 SCHEME E Ethyl ester and acid. { 2-met? L-4- [2- (4-trifluorome-B-phenoxymethyl) -pept? SuIfap.-phenoxy} acetic acid To a solution of 1.0 M diisobutylaluminum hydride (50 ml, 50 mmol) in CH2Cl2 at -78 ° C was added diethyl propylmalonate E1 (2.02 g, 10.0 mmol). The reaction mixture was allowed to warm gradually to 0 ° C, stirred at 0 ° C for 30 min and quenched with MeOH. The precipitated solid was filtered through Celite and washed with MeOH / CH2Cl2. The filtrate was concentrated and purified by column chromatography (EtOAc) to give 709 mg (60%) of E2; 1 H NMR (300 MHz, CDCl 3) d 3.80 (dd, J = 10.7, 3.8 Hz, 2H), 3.63 (dd, J = 10.7, 7.7 Hz, 2H), 2.82 (s, 2H), 1.84-1.71 (m , 1 H), 1.42-1.28 (m, 2H), 1.24-1.17 (m, 2H), 0.91 (t, J = 7.2 Hz, 3H); MS (ES) m / z: 141 (M + Na +). To a solution of E2 (300 mg, 2.54 mmol) in CH2Cl2 (5 mL) at 0 ° C was added Et3N (1.06 mL, 7.62 mmol) and methanesulfonyl chloride (729 mg, 6.36 mmol). The mixture was stirred at 0 ° C for 2 hr and diluted with saturated NaHCO3. The organic layer was separated and the aqueous layer was extracted with CH2Cl2 (x3). The combined organic phases were dried, concentrated and subjected to column chromatography (EtOAc / hexane: 1/1) to provide 655 mg (94%) of E3; 1 H NMR (300 MHz, CDCl 3) d 4.29 (dd, J = 10.0, 4.3 Hz, 2H), 4.20 (dd, J = 10.0, 6.4 Hz, 2H), 3.05 (s, 6 H), 2.22-2.15 (m , 1H), 1.42 (m, 4 H), 0.97-0.93 (m, 3H); MS (ES) m / z: 297 (M + Na +). To a suspension of NaH (80 mg, 2.0 mmol, 60% in mineral oil) in THF (2 mL) was added a solution of 4-trifluoromethylphenol (324 mg, 2.0 mmol) in THF (2 mL). After stirring at room temperature for 30 min, a solution of E3 (659 mg, 2.40 mmol) in THF (3 mL) was added and the resulting mixture was refluxed for 6 hr. Water was added and the mixture was extracted with Et2O. The exfracti were dried, concentrated, and subjected to column chromatography (EtOAc / hexane: 1/4) to give 170 mg (25%) of E4.; 1 H NMR (300 MHz, CDCl 3) d 7.54 (d, J = 8.6 Hz, 2H), 6.96 (d, J = 8.6 Hz, 2H), 4.37 (dd, J = 9.9, 4.9 Hz, 1 H), 4.32 (dd, J = 9.9, 6.0 Hz, 1 H), 4.04 (dd, J = 9.4, 4.6 Hz, 1 H), 3.98 (dd, J = 9.3, 6.4 Hz, 1 H), 2.97 (s, 3H) , 2.25 (m, 1 H), 1.53-1.39 (m, 4 H), 0.96 (t, J = 7.0 Hz, 3H); MS (ES) m / z: 363 (M + Na +).

General procedure 3 for the formation of thioether: To a solution of E4 (165 mg, 0.485 mmol) in CH3CN (5 ml) was added Cs2CO3 (391 mg, 1.20 mmol) followed by a solution of ethyl ester of acid (4-mercapto) -2-methyl-phenoxy) acetic A1c (163 mg, 0.721 mmol) in CH3CN (3 mL). After stirring for 5 hr at room temperature, water was added and the mixture was extracted with Et2O. The combined organic layers were dried, concentrated and subjected to column chromatography (EtOAc / hexane: 1/10) to provide 158 mg (70%) of E5; 1 H NMR (300 MHz, CDCl 3) d 7.51 (d, J = 8.6 Hz, 2H), 7.19 (d, J = 1.5 Hz, 1 H), 7.14 (dd, J = 8.4, 2.3 Hz, 1 H), 6.89 (d, J = 8.6 Hz, 2H), 6.55 (d, J = 8.4 Hz, 1 H), 4.56 (s, 2H), 4.25 (q, J = 7.1 Hz, 2H), 4.03 (dd, J = 9.3, 4.9 Hz, 1 H), 3.97 (dd, J = 9.2, 5.6 Hz, 1 H), 3.00 (d, J = 6.5 Hz, 2H), 2.21 (s, 3H), 2.05 (m, 1H), 1.57-1.48 (m, 2H), 1.40-1.32 (m, 2H), 1.29 (t, J = 7.1 Hz, 3H), 0.91 (t, J = 7.2 Hz, 3H); MS (ES) m / z: 493 (M + Na +).

Analysis calculated for C 24 H 29 F 3 O 4 S: C, 61.26; H, 6.21. Found: C, 61.49; H, 6.35. Following general procedure 2 in Example A, compound 5 (94%) was obtained; 1 H NMR (400 MHz, CDCl 3): 7.50 (d, J = 8.7 Hz, 2H), 7.18 (d, J = 1. 7 Hz, 1H), 7.15 (dd, J = 8.5, 2.0 Hz, 1 H), 6.88 (d, J = 8.7 Hz, 2H), 6.57 (d, J = 8.4 Hz, 1 H), 4.60 (s, 2H), 4.02 (dd, J = 9.2, 4.7 Hz, 1H), 3.97 (dd, J = 9.2, 5.7 Hz, 1 H), 3.01 (m, 2H), 2.19 (s, 3H), 2.05 (m, 1H), 1.54-1.49 (m, 2H), 1.37 (m, 2H), 0.91 (t, J = 7.2Hz, 3H); MS (ES) m / z: 465 (M + Na +). Analysis calculated for C 22 H 25 F 3 O 4 S: C, 59.72; H, 5.69. Found: C, 59.63; H, 5.75.

EXAMPLE F Compound 6 Acid. { 2-methyl-4- [2- (4-trifluoromethyl-phenoxymethyl) -heptylsulfanyl] -phenoxy} -acetic SCHEME F 2- (4-Trifluoromethyl-1-phenoxymethyl) -heptap-1 -ol Ethyl ester of acid. { 2-methyl-4- [2- (4-trifluoromethyl-phenoxymethyl) -heptyl-sulfanyl-phenoxy)} -acetic To a suspension of lithium aluminum hydride (114 mg, 3.00 mmol) in THF (3 ml) at 0 ° C was added dropwise diethyl ester of 2-penyl-malonic acid F1 (346 mg, 1.50 mmol). The reaction mixture was agitated at room temperature for 2 hr, quenched with water (0.1 ml) and 5N NaOH (0.2 ml) at 0 ° C, and diluted with water (0.6 ml). The precipitated solid was filtered through Celite and washed with MeOH / CH2Cl2. The filtrate was dried, concentrated and purified by column chromatography (EtOAc / hexane: 1/1) to give 181 mg (82%) of F2; 1 H NMR (300 MHz, CDCl 3) d 3.79 (dd, J = 10.7, 3.8 Hz, 2H), 3.62 (dd, J = 10.7, 7.7 Hz, 2H), 3.16 (s, 2H), 1.75 (m, 1 H ), 1.34-1.18 (m, 8H), 0.88 (t, J = 6.8 Hz, 3H); MS (ES) m / z: 169 (M + Na +). To a mixture of F2 (176 mg, 1.21 mmol), trifluoromethylphenol (292 mg, 1.80 mmol) and trifluorophosphine (472 mg, 1.80 mmol) in THF (3 mL) at 0 ° C was added diisopropyl azodicarboxylate (195 mg, 1.80 mM). mmoles). The mixture was stirred at 0 ° C for 30 min and then at room temperature for 6 hr, diluted with water and extracted with Et2O. The extracts were dried, concentrated and purified by column chromatography to provide 108 mg (31%) of F3; 1 H NMR (300 MHz, CDCl 3) d 7.53 (d, J = 8 6 Hz, 2 H), 6.96 (d, J = 8.6 Hz, 2 H), 4.03 (m, 2 H), 3.75 (m, 2 H), 2.04- 1.95 (m, 1 H), 1.44-1.36 (m, 4 H), 1.31-1.25 (m, 4 H), 0.89 (t, J = 6.8 Hz, 3H); MS (ES) m / z: 313 (M + Na +). Following general procedure 1 in example A was obtained F4 (78%); 1 H NMR (300 MHz, CDCl 3) d 7.50 (d, J = 8.6 Hz, 2H), 7.19 (d, J = 1.7 Hz, 1 H), 7.14 (dd, J = 8.4, 2.2 Hz, 1 H), 6.89 (d, J = 8.6 Hz, 2H), 6.55 (d, J = 8.4 Hz, 1 H), 4.56 (s, 2H), 4.25 (q, J = 7.1 Hz, 2H), 4.00 (m, 2H), 3.01 (d, J = 6.8 Hz, 2H), 2.21 (s) , 3H), 2.03 (m, 1 H), 1.56-1.49 (m, 2H), 1.37-1.22 (m, 6H), 1. 28 (t, J = 7.1 Hz, 3H), 0.87 (t, J = 6.8 Hz, 3H); MS (ES) m / z: 521 (M + Na +). Following general procedure 2 in example A, compound 6 (91%) was obtained; 1 H NMR (300 MHz, CDCl 3) d 9.23 (brs, 1 H), 7.50 (d, J = 8.7 Hz, 2H), 7.19 (d, J = 1.8 Hz, 1 H), 7.15 (dd, J = 8.4, 2.2 Hz, 1 H), 6.89 (d, J = 8.6 Hz, 2H), 6.57 (d, J = 8.4 Hz, 1 H), 4.61 (s, 2H), 4.00 (m, 2H), 3.03-3.00 (m, 2H), 2.20 (s, 3H), 2.04 ( m, 1 H), 1.56-1.49 (m, 2H), 1.37-1.23 (m, 6 H), 0.87 (í, J = 6. 8 Hz, 3H); MS (ES) m / z: 493 (M + Na +).

EXAMPLE G Compound 7 Acid. { 2-methyl-4- [2- (4-if-fluoromethyl-phenoxy) -propylsulfanyl] -phenoxy} -acetic SCHEME G FsC? S ir I Tebbe reagent, THF OH Ett3MN. rC-.wH.-rC.tI ~, 61, 94% 4-trifluoromethyl-phenyl ester of benzyloxy-acetic acid G4, 11% Ethyl ester of acid. { 2-methyI-4- [2- (4-trifluoromethyl-phepoxy) -62% propylsulfapyl-phenoxy-acetic Compound 7 To a mixture of 4-trifluoromethylphenol (1.00 g, 6.17 mmol) and Et3N (871 mg, 8.63 mmol) in CH2Cl2 (20 mL) at 4 ° C was added phenoxylacetyl chloride (1.37 g, 7.42 mmol). After agglutination for 2 hr at room temperature, the white solid was filtered and washed with Et20. The filtrate was washed with water, dried, concentrated, and purified by column chromatography to give 1.79 g (94%) of G1 as a white solid; 1 H NMR (300 MHz, CDCl 3) d 7.66 (d, J = 8.7 Hz, 2H), 7.43-7.33 (m, 5 H), 7.25 (d, J = 8.4 Hz, 2H), 4.73 (s, 2H), 4.37 (s, 2H). To a solution of G1 (1.20 g, 3.87 mmol) in THF (20 ml) at -78 ° C was introduced a solution of 0.5 M Tebbe reagent (9.3 ml, 4.7 mmol) in toluene. The mixture was stirred at -78 ° C at 2 ° C for 2 hr and was quenched with water dropwise. The solid formed was filtered and washed with Et20. The filtrate was concentrated and purified by column chromatography to provide 890 mg (75%) of G2 as a clear oil; 1 H NMR (300 MHz, CDCl 3) d 7.60 (d, J = 8.5 Hz, 2H), 7.36-7.29 (m, 5H), 7.16 (d, J = 8.6 Hz, 2H), 4.70 (d, J = 2.1 Hz, 1H), 4.63 (s, 2H), 4.39 (d, J = 2.1 Hz, 1 H), 4.12 (s, 2H). A mixture of G2 (870 mg, 2.82 mmol) and 10% Pd / C (100 mg) in EtOH (10 ml) and THF (5 ml) was degassed and filled with H2 three times.

After hydrogenating under 1 atm overnight, the mixture was filtered through Cellte. The filtrate was concentrated and subjected to column chromatography to give 563 mg (91%) of G3 as a clear oil; 1 H NMR (300 MHz, CDCl 3) d 7.54 (d, J = 8.6 Hz, 2H), 7.99 (d, J = 8.6 Hz, 2H), 4.57 (m, 1H), 3.76 (m, 2H), 1.93 ( t, J = 6.3 Hz, 1 H), 1.30 (d, J = 6.2 Hz, 3H); MS (ES) m / z: 243 (M + Na +). Following general procedure 1 in Example A, G4 was obtained (11%, light oil); 1 H NMR (400 MHz, CDCl 3) d 7.47 (d, J = 8.9 Hz, 2H), 7.24 (s, 1H), 7.21 (dd, J = 8.5, 2.1 Hz, 1H), 6.76 (d, J = 8.9 Hz, 2H), 6.63 (d, J = 8.5 Hz, 1 H), 4.64 (s, 2H), 4.46 (dd, J = 12.0, 6.1 Hz, 1 H), 4.27 (q, J = 7.1 Hz, 2H), 3. 16 (dd, J = 13.8, 5.3 Hz, 1H), 2.90 (dd, J = 13.8, 6.9 Hz, 1 H), 2.26 (s, 3H), 1. 43 (d, J = 5.9 Hz, 3H), 1.30 (t, J = 7.1 Hz, 3H); MS (ES) m / z: 451 (M + Na +).

Following general procedure 2 in example A, compound 7 was obtained (62%, solid); 1 H NMR (300 MHz, MeOH-d 4) d 7.50 (d, J = 8.6 Hz, 2 H), 7.21 (m, 2 H), 6.83 (d, J = 8.7 Hz, 2 H), 6.75 (d, J = 7.4 Hz, 1 H), 4.62 (s, 2H), 4.54 (dd, J = 11.8, 6.0 Hz, 1 H), 3.12 (dd, J = 13.9, 5.6 Hz, 1 H), 2.96 (dd, J = 14.0 , 6.2 Hz, 1H), 2.21 (s, 3H), 1.41 (d, J = 6.2 Hz, 3H); MS (ES) m / z: 423 (M + Na +); FAB-HRMS (M +). Calculated 400.0956, found 400.0944.

EXAMPLE H Compound 9 Acid. { 3-Chloro-4- [2- (4-trifluoromethyl-phenoxymethyl) -butylsulfanyl] -phenyl} -acetic SCHEME H sCI, ElgN, CH2Cla Cs2C03l CH3CN H3, 17% 90% Acid methyl ester. { 3-Chloro-4- [2- (4-trifluoromethyl-Compound 9-phenoxymethyl) -butylsulprap] -phenyl} -acetic A mixture of (3-chloro-4-mercaptophenyl) acetic acid methyl ester H1 (758 mg, 3.48 mmol, Sahoo, SP, Preparation of arylthiazolidinediones as agonis of peroxisome proliferator activated receptor, WO99 / 32465), ester 2- (4 methanesulfonic acid-2-trifluoromethyl-phenoxymethyl) methylsulfonic acid (880 mg, 2.70 mmol;), and Cs2CO3 (2.64 g, 8.10 mmol) in CH3CN (8 mL) was stirred for 2 h, diluted with water, and extracted with Et20. The combined organic layers were dried, concentrated and subjected to column chromatography (EtOAc / hexane: 1/7) to give 205 mg (17%) of H3.; 1 H NMR (400 MHz, CDCl 3) d 7.51 (d, J = 8.7 Hz, 2H), 7.29 (s, 1 H), 7.27 (s, 1 H), 7.08 (dd, J = 8.1, 1.7 Hz, 1H ), 6.93 (d, J = 8.6 Hz, 2H), 4.09 (dd, J = 9.3, 4.7 Hz, 1 H), 4.00 (dd, J = 9.3, 5.8 Hz, 1 H), 3.69 (s, 3H) , 3.53 (s, 2H), 3.14 (dd, J = 13.0, 7.0 Hz, 1H), 3.06 (dd, J = 13.0, 5.7 Hz, 1H), 2.06 (m, 1 H), 1.69-1.61 (m, 2H), 0.99 (t, J = 7.4 Hz, 3H). Following general procedure 2 in Example A, compound 9 (90%) was obtained; 1 H NMR (300 MHz, CDCl 3) d 7.51 (d, J = 8.6 Hz, 2H), 7.26 (m, 2H), 7.06 (d, J = 8.0 Hz, 1 H), 6.92 (d, J = 8.6 Hz, 2H), 4.08 (dd, J = 9.3, 4.6 Hz, 1 H), 3.99 (dd, J = 9.3 , 5.8 Hz, 1 H), 3.54 (s, 2H), 3.14 (dd, J = 13.0, 7.0 Hz, 1 H), 3.05 (dd, J = 13.0, 5.7 Hz, 1H), 2.06 (m, 1 H) ), 1.64 (m, 2H), 0.99 (t, J = 7.4 Hz, 3H); MS (ES) m / z: 455 (M + Na +).

EXAMPLE I Compound 10 Acid. { 4- [3-cyano-2- (4-trifluoromethyl-phenoxymethyl) -propylsulfanyl] -2-methyl-phenoxy} -acetic SCHEME I Ethyl ester of [4- (4-ethoxycarbonylmethoxy-3-methy1-phenyldisulfanyl 2-methyl-phenoxy] -acetic acid ethyl ester 2, 17% 2- (4-Trifluoromethyl-phenoxymethyl) -propane-1,3-diol phenoxy) -propylsulfaniQ-2-methyl-phenoxy} acotic fepoxymethyl) -propylsulfapyl] -2-methyl-phepo > to} acetic A mixture of ethyl ester (4-mercapto-2-methyl-phenoxy) acyclic A1c (453 mg, 2.00 mmol) and barium manganate (513 mg, 2.00 mmol) in CH2Cl2 (5 ml) was stirred at room temperature for 20 min. , filtered through silica gel and washed with EtOAc / hexane (1/3). The filtrate was concentrated to give 802 mg (89%) of 11; 1 H NMR (400 MHz, CDCl 3) d 7.27 (s, 1 H), 7.23 (dd, J = 8.4, 2.3 Hz, 1 H), 6.61 (d, J = 8.5 Hz, 1 H), 4.62 (s, 2H), 4.26 (q, J = 7.1 Hz, 2H), 2.25 (s, 3H), 1.29 (t, J = 7.1 Hz, 3H); MS (ES) m / z: 473 (M + Na +).

To a mixture of 2-hydroxymethylpropane-1,3-diol (500 mg, 4.71 mmol) in DMF (1.5 ml) and THF (3 ml) were added trifluoromethylphenol (822 mg, 5.07 mmol) and triphenylphosphine (1.02 g, 3.90 mmol). ). After the mixture was cooled to 0 ° C, diisopropyl azodicarboxylate (789 mg, 3.91 mmol) was introduced. The mixture was allowed to warm to room temperature, stirred overnight, concentrated and subjected to column chromatography to provide 200 mg (17%) of 12; 1 H NMR (300 MHz, CDCl 3) d 7.50 (d, J = 8.7 Hz, 2H), 6.93 (d, J = 8.6 Hz, 2H), 4.05 (d, J = 6.1 Hz, 2H), 3.90-3.80 ( m, 4 H), 3.42 (brs, 2H), 2.20 (m, 1 H); MS (ES) m / z: 273 (M + Na +). To a mixture of 11 (97 mg, 0.22 mmol) and 12 (81 mg, 0.32 mmol) in pyridine (0.2 ml) was added tributylphosphine (44 mg, 0.22 mmol). The mixture was stirred overnight, diluted with 1N HCl, and extracted with Et2O. The exiphats were dried, concentrated and subjected to column chromatography (EtOAc / hexane: 2/5) to provide 54 mg (55%) of 13; 1 H NMR (400 MHz, CDCl 3) d 7.52 (d, J = 8.9 Hz, 2H), 7.22 (d, J = 2.2 Hz, 1H), 7.18 (dd, J = 8.4, 2.3 Hz, 1H), 6.92 (d, J = 8.8 Hz, 2H), 6.59 (d, J = 8.4 Hz, 1H), 4.59 (s, 2H), 4.26 (q, J = 7.1 Hz, 2H), 4.16-4.09 (m, 2H), 3.86 (d, J = 5.3 Hz, 2H), 3.04 ( d, J = 6.8 Hz, 2H), 2.26-2.20 (m, 1H), 2.23 (s, 3H), 1. 29 (í, J = 7.1 Hz, 3H); MS (ES) m / z: 481 (M + Na +).

To a mixture of 13 (114 mg, 0.249 mmol) and triphenylphosphine (98 mg, 0.37 mmol) in THF (2 ml) at 0 ° C was added diisopropyl azodicarboxylate (75 mg, 0.37 mmol) and acetone cyanohydrin (32 mg). , 0.38 mmole). The mixture was stirred at room temperature overnight, concentrated and subjected to column chromatography to provide 57 mg (49%) of 14; 1 H NMR (400 MHz, CDCl 3) d 7.54 (d, J = 8.7 Hz, 2H), 7.23 (s, 1 H), 7.20 (dd, J = 8.4, 2.2Hz, 1 H), 6.91 (d, J = 8.7 Hz, 2H), 6.60 (d, J = 8.4 Hz, 1 H), 4.60 (s, 2H), 4.26 (q, J = 7.1 Hz, 2H), 4.13 (dd, J = 9.5, 4.6 Hz, 1 H), 4.08 (dd, J = 9.5, 6.0 Hz, 1 H), 3.08 (dd, J = 14.0, 6.9 Hz, 1 H), 3.00 (dd, J = 13.9, 7.0 Hz, 1 H), 2.73 (dd, J = 6.3, 1.8 Hz, 2H), 2.37 (m, 1H), 2.25 (s, 3H), 1.30 (f, J = 7. 1 Hz, 3H); MS (ES) m / z: 490 (M + Na +). Analysis calculated for C23H24F3N04S: C, 59.09; H, 5.17; N, 3.00. Found: C, 59.11; H, 5.12; N, 2.93. Following general procedure 2 in Example A, compound 10 (73%) was obtained; 1 H NMR (300 MHz, CD3OD) d 7.55 (d, J = 8.6 Hz, 2H), 7.23 (m, 2H), 7.00 (d, J = 8.6 Hz, 2H), 6.71 (d, J = 8.2 Hz, 1H), 4.55 (s, 2H), 4.12 (d, J = . 2 Hz, 2H), 3.11 (dd, J = 14.0, 7.0 Hz, 1 H), 3.01 (dd, J = 14.0, 6.7 Hz, 1 H), 2.78 (d, J = 6.3 Hz, 2H), 2.33 ( m, 1 H), 2.18 (s, 3H); MS (ES) m / z: 462 (M + Na +).

EXAMPLE J Compound 11 Acid. { 4- [4-Cyano-2- (4-trifluoromethyl-phenoxymethyl) -butylsulfanyl] -2-methyl-phenoxy} - acetic SCHEME J Ethyl ester of acid. { 4- [4,4-dietoxy] -2- (4-trifluoromethyl) ethyl ester of. {2-methyl-4- [4-oxo-2- (4-trifluoromethyl-phenoxymethyl) -butylsulfani-2} -methyl-phenoxy] -acetic phenoxymethyl) -butylsulfanyl] -phenoxy} -acetic J5, 93% Ethyl ester of acid. { 4- [4-hydroxyJ-2- (4-trifluoromethy! Phenoxymethyl) -buty! Sulfapyl] -2-methy1-phenoxy} -acetic Jß, 65% g4% Ethyl ester of acid. { 4- [4-Cyano-2- (4-trifluoromethyl-Compound 11-phenoxymethyl) -butylsulfapyl] -2-methyl-phenoxy} -acetic To a mixture of 2- (2,2-diethoxyethyl) -1,3-propanediol J1 (500 mg, 2.60 mmole), trifluoromethylphenol (357 mg, 2.20 mmole), and triphenylphosphine (525 mg, 2.00 mmole) in THF (5 ml) at 0 ° C, diisopropyl azodicarboxylate (384 mg, 1.90 mmol) was added. The mixture was allowed to warm to room temperature, stirred overnight, diluted with water and extracted with Et20. The combined organic layers were dried, concentrated and subjected to column chromatography (EtOAc / hexane: 1/4) to provide 436 mg (53%) of J2; 1 H NMR (300 MHz, CDCl 3) d 7.53 (d, J = 8.7 Hz, 2H), 6.94 (dd, J = 8.8, 2.2 Hz, 2H), 5.18 (m, 1H), 4.15-4.03 (m, 2H ), 3.92-3.88 (m, 1 H), 3.85-3.78 (m, 1 H), 3.77-3.67 (m, 2H), 3.49-3.43 (m, 1 H), 2.95-2.86 (m, 1 H) , 2.28-2.18 (m, 1 H), 2.15-2.07 (m, 1 H), 1.88-1.79 (m, 1H), 1.23 (t, J = 7.0 Hz, 6H); MS (ES) m / z: 359 (M + Na +). Following general procedure 1 in example A, J3 (56%) was provided; 1 H NMR (400 MHz, CDCl 3) d 7.50 (d, J = 8.8 Hz, 2H), 7.19 (d, J = 2.1 Hz, 1 H), 7.15 (dd, J = 8.4, 2.3 Hz, 1 H), 6.88 (d, J = 8.7 Hz, 2H), 6.54 (d, J = 8.4 Hz, 1 H), 4.59 (t, J = 5.7 Hz, 1H), 4.56 (s, 2H), 4.25 (q, J = 7.1 Hz, 2H), 4.11 (dd, J = 9.3, 4.6 Hz, 1H), 4.00 (dd, J = 9.3, 5.6 Hz, 1H), 3.65-3.58 (m, 2H), 3.48-3.43 (m, 2H ), 3.06-3.04 (m, 2H), 2.26-2.20 (m, 1H), 2.20 (s, 3H), 1.88 (m, 2H), 1.29 (t, J = 7.1 Hz, 3H), 1.16 (í, J = 7.0 Hz, 3H), 1.15 (t, J = 7.0 Hz, 3H); MS (ES) m / z: 567 (M + Na +).

Analysis calculated for C27H35F306S: C, 59.54; H, 6.48. Found: C, 59.75; H, 6.45. A mixture of J3 (130 mg, 0.239 mmol) in trifluoroacetic acid (1.5 ml), water (1.5 ml), and CHCl3 (6 ml) was stirred at room temperature for 3 hr, diluted with water, and extracted with CHCl3. . The organic phases were dried, concentrated and subjected to column chromatography (CH2Cl2) to give 105 mg (93%) of J4; 1 H NMR (300 MHz, CDCl 3) d 9.78 (s, 1 H), 7.51 (d, J = 8.6 Hz, 2H), 7.21 (d, J = 1.7 Hz, 1 H), 7.16 (dd, J = 8.4, 2.2 Hz, 1H), 6.88 (d, J = 8.6 Hz, 2H), 6.58 (d, J = 8.4 Hz , 1 H), 4.58 (s, 2H), 4.25 (q, J = 7.1 Hz, 2H), 4.04 (d, J = 4.9 Hz, 2H), 3.07 (dd, J = 13.7, 6.6 Hz, 1 H), 2.97 (dd, J = 13.7, 6.1 Hz, 1H), 2.77-2.64 (m, 3H), 2.23 (s, 3H), 1.29 (t, J = 7.1 Hz, 3H); MS (ES) m / z: 493 (M + Na +). To a solution of J4 (100 mg, 0.213 mmol) in EtOH (1.2 mL) at 0 ° C was added NaBH4 (48 mg, 1.3 mmol). After stirring for 15 min at the same temperature, the mixture was diluted with EI20, acidified with 1N HCl and extracted with Et2O. The combined organic layers were dried, concentrated and subjected to column chromatography to give 93 mg (93%) of J5; 1 H NMR (300 MHz, CDCl 3) d 7.51 (d, J = 8.6 Hz, 2H), 7.20 (d, J = 1.8 Hz, 1 H), 7.15 (dd, J = 8.4, 2.2 Hz, 1 H), 6.89 (d, J = 8.6 Hz, 2H), 6.56 (d, J = 8.4 Hz, 1H), 4.57 (s) , 2H), 4.25 (q, J = 7.1 Hz, 2H), 4.05 (m, 2H), 3.73 (t, J = 6.4 Hz, 2H), 3.03 (m, 2H), 2.29-2.21 (m, 1H) , 2.21 (s, 3H), 1.82 (q, J = 6.5 Hz, 2H), 1.29 (t, J = 7.1 Hz, 3H); MS (ES) m / z: 495 (M + Na +). Analysis calculated for C23H27F305S: C, 58.46; H, 5.76. Found: C, 58.39; H, 5.53. Replacing 13 with J5 and following the same procedure as in the preparation of 14 in Example I provided J6 (65%); 1 H NMR (300 MHz, CDCl 3) d 7.53 (d, J = 8.6 Hz, 2H), 7.21 (d, J = 1.7 Hz, 1 H), 7.18 (dd, J = 8.4, 2.2 Hz, 1 H), 6.88 (d, J = 8.6 Hz, 2H), 6.58 (d, J = 8.4 Hz, 1 H), 4.58 (s, 2H), 4.25 (q, J = 7.1 Hz, 2H), 4.05-4.02 (m, 2H), 3.00 (d, J = 6.4 Hz, 2H), 2.44 (t, J = 7.4 Hz, 2H), 2.26-2.16 (m, 1 H), 2.22 (s, 3H), 2. 00-1.92 (m, 2H), 1.29 (t, J = 7.1 Hz, 3H); MS (ES) m / z: 504 (M + Na +). Analysis calculated for C 24 H 26 F 3 NO 4 S: C, 59.86; H, 5.44; N, 2.91. Found: C, 59.85; H, 5.31; N, 2.93. Following general procedure 2 in example A, compound 11 (94%) was obtained; 1 H NMR (300 MHz, CDCl 3) d 7.52 (d, J = 8.6 Hz, 2H), 7.19 (s, 1H), 7.15 (d, J = 8.2 Hz, 1H), 6.88 (d, J = 8.6 Hz, 2H ), 6.58 (d, J = 7.8 Hz, 1 H), 4.53 (s, 2H), 4.02 (m, 2H), 2.98 (d, J = 6.2 Hz, 2H), 2.42 (t, J = 7.3 Hz, 2H), 2.18 (m, 4H), 1.97-1.90 (m, 2H); MS (ES) m / z: 476 (M + Na +). Analysis calculated for C22H22F3NO4S + 0.3 H2O: C 57.58; H, 4.96; N, 3.05. Found: C, 57.40; H, 4.73; N, 2.96.

EXAMPLE K Compound 12 Acid. { 4- [5-Cyano-2- (4-trifluoromethyl-phenoxymethyl) -pent-4-en-sulfanyl] -2-methy1-phenoxy-acetic SCHEME K of acid. { 4- [5-cyano-2- (4-trifluoromethyl-4-en-1-sulfanyl) -2-methyl-phepoxy} -acetic A mixture of J4 (47 mg, 0.10 mmol) and (triphenylphosphoranylidene) acetonitrile (181 mg, 0.601 mmol) in CH2Cl2 (1 mL) was refluxed overnight, concentrated, and purified by column chromatography (EtOAc / hexane: 1/9) to give a mixture of K1 and K2. K1: 1 H NMR (300 MHz, CDCl 3) d 7.54 (d, J = 8.6 Hz, 2H), 7.20 (d, J = 1.7 Hz, 1 H), 7.16 (dd, J = 8.4, 2.2 Hz, 1H) , 6.89 (d, J = 8.6 Hz, 2H), 6.72-6.61 (m, 1H), 6.58 (d, J = 8.4 Hz, 1H), 5.33 (d, J = 16.3 Hz, 1H), 4.59 (s, 2H), 4.26 (q, J = 7.1 Hz, 2H), 3.99 (d, J = 5.1 Hz, 2H), 2.95 (m, 2H), 2.51 (m, 2H), 2.24 (s, 3H), 2.24- 2.17 (m, 1 H), 1.30 (i, J = 7.1 Hz, 3H); MS (ES) m / z: 516 (M + Na +); K2: 1 H NMR (300 MHz, CDCl 3) d 7.52 (d, J = 8.6 Hz, 2H), 7.21 (s, 1 H), 7.17 (dd, J = 8.4, 2.2 Hz, 1 H), 6.90 (d , J = 8.6 Hz, 2H), 6.58 (d, J = 8.4 Hz, 1H), 6.49 (dt, J = 10.9, 7.8 Hz, 1H), 5.40 (d, J = 10.9 Hz, 1H), 4.58 (s) , 2H), 4.26 (q, J = 7.1 Hz, 2H), 4.03-4.00 (m, 2H), 2.98 (m, 2H), 2.73 (m, 2H), 2.22 (m, 4 H), 1.30 (m , J = 7.1 Hz, 3H); MS (ES) m / z: 516 (M + Na +). Using K1 as the starting material and following general procedure 2 in Example A, compound 12 was obtained (60%); 1 H NMR (300 MHz, CDCl 3) d 7.52 (d, J = 8.6 Hz, 2H), 7.17 (s, 1 H), 7.13 (dd, J = 8.0 Hz, 1 H), 6.88 (d, J = 8.6 Hz , 2H), 6.67-6.57 (m, 2H), 5.28 (d, J = 16.3 Hz, 1 H), 4.54 (s, 2H), 3.98 (d, J = 5.0 Hz, 2H), 2.93 (m, 2H) ), 2.49 (t, J = 6.9 Hz, 2H), 2.19 (s, 3H), 2.19-2.13 (m, 1 H); MS (ES) m / z: 488 (M + Na +). \ EXAMPLE L Compound 14 Acid. { 4- [2-methoxy-3- (4-trifluoromethyl-phenoxy) -propylsulfanyl] -2-methyl-phenoxy} - acetic SCHEME L L3 Ethyl ester of acid. { 4- [2-methoxy-3- (4-trifluoromethyl-phepoxy) -propylsulfapyl] -2-methyl-phenoxy} acetic Compound 14 A mixture of 4-trifluoromethylphenol (7.80 g, 48.1 mmol), 2-chloromethyloxirane (11.2 g, 121 mmol), and CS2CO3 (15.7 g, 48.2 mmol) in dioxane (8 mL) was refluxed for 3-4. hr and then allowed to cool to room temperature. Water and Et20 were added, the organic phase was separated and the aqueous phase was extracted with Et20. The combined organic layers were dried, concentrated and subjected to column chromatography (CH2Cl2 / hexane: 1/1) to provide 8.40 g (80%) of L1; 1 H NMR (300 MHz, CDCl 3) d 7.55 (d, J = 8.5 Hz, 2H), 6.99 (d, J = 8.5 Hz, 2H), 4.29 (dd, J = 11.1, 3.0 Hz, 1H), 3.98 ( dd, J = 11.1, 5.8 Hz, 1 H), 3.37 (, 1 H), 2.93 (m, 1 H), 2.77 (dd, J = 4.9, 2.6 Hz, 1 H). To a mixture of L1 (2.57 g, 11.8 mmol) and (4-mercapto-2-methyl-phenoxy) -acetic acid ethyl ester A1c (4.00 g, 17.7 mmol) in THF (20 ml) was added 1.0 M tetrabutylammonium fluoride. in THF (0.44 ml, 0.44 mmol). The reaction mixture was stirred at room temperature for 1.5 hr, heated at 60 ° C for 1 hr, concentrated and purified by column chromatography to give 4.45 g (85%) of L2; 1 H NMR (400 MHz, CDCl 3) d 7.50 (d, J = 8.9 Hz, 2H), 7.25 (d, J = 2.2 Hz, 1H), 7.21 (dd, J = 8.4, 2.3 Hz, 1H), 6.89 (d, J = 8.8 Hz, 2H), 6.58 (d, J = 8.4 Hz, 1 H), 4.58 (s, 2H), 4.24 (q, J = 7.1 Hz, 2H), 4.05-4.00 (m, 3H), 3.13 (dd, J = 13.7, 5.1 Hz, 1H), 3.04 (dd, J = 13.9, 6.5 Hz, 1H), 2.92 (d, J = 4.2 Hz, 1 H), 2.23 (s, 3 H), 1.28 (t, J = 7.1 Hz, 3 H); MS (ES) m / z: 467 (M + Na +).

General procedure 4 for alcohol alkalization: To a suspension of NaH (20 mg, 0.50 mmol, 60% in mineral oil) in THF (1 ml) was added a solution of L2 (222 mg, 0.500 mmol) in THF (1 ml). ) at room temperature. After 30 min, CH3I (213 mg, 1.50 mmol) was introduced. The reaction mixture was stirred overnight, diluted with water and extracted with Et20. The extracts were dried, concentrated and purified by column chromatography (EtOAc / hexane: 1/6) to give L3; 1 H NMR (300 MHz, CDCl 3) d 7.52 (d, J = 8.6 Hz, 2H), 7.24 (d, J = 1.7 Hz, 1 H), 7.19 (dd, J = 8.4, 2.1 Hz, 1 H), 6.91 (d, J = 8.5 Hz, 2 H), 6.57 (d, J = 8.4 Hz, 1 H), 4.57 ( s, 2H), 4.25 (q, J = 7.1 Hz, 2H), 4.16 (dd, J = 10.0, 4.0 Hz, 1 H), 4.09 (dd, J = 10.0, 5.0 Hz, 1H), 3.67 (m, 1 H), 3.44 (s, 3 H), 3.13 (d, J = 6.2 Hz, 2 H), 2.22 (s, 3 H), 1.29 (t, J = 7.1 Hz, 3 H); MS (ES) m / z: 481 (M + Na +). Following general procedure 2 in Example A, compound 14 (92%) was obtained; 1 H NMR (400 MHz, CDCl 3) d 10.21 (brs, 1 H), 7.50 (d, J = 8.6 Hz, 2 H), 7.23 (s, 1 H), 7.20 (d, J = 8.4 Hz, 1 H) , 6.89 (d, J = 8.5 Hz, 2H), 6.58 (d, J = 8.4 Hz, 1 H), 4.61 (s, 2H), 4.16 (dd, J = 10.0, 3.9 Hz, 1 H), 4.09 ( dd, J = 9.9, 4.9 Hz, 1H), 3.68 (m, 1 H), 3.45 (s, 3H), 3.14 (d, J = 6.1 Hz, 2H), 2.20 (s, 3H); MS (ES) m / z: 453 (M + Na +).

EXAMPLE M Compound 15 Acid (R) -. { 4- [2-ethoxy-3- (4-trifluoromethyl-phenoxy) -propylsulfanyl] -2-methy1-phenoxy} - acetic Compound 16 Acid (S) -. { 4- [2-ethoxy-3- (4-ylfluoromethyl-phenoxy) -propylsulfanyl] -2-methy1-phenoxy} -acetic SCHEME M M2, 85% M3 Ethnic acid ester (RH4- [2-hydroxyl-3- (4-trifluoromethyl- (R) -4- [2-ethoxy-3- (4-trifluoromethyl-phenoxy) -propyl sulfanyl) ethyl ester ] -2-methyl-phenoxy] -acetic phenoxy) -propyl sulphapyl] -2-methyl-phenoxy.

To a mixture of (R) - (+) - glycidol (2.00 g, 27.0 mmol), 4-trifluoromethylphenol (4.38 g, 27.0 mmol), triphenylphosphine (7.08 g, 27.0 mmol) in THF (50 mL) at 0 ° C diisopropyl azodicarboxylate (5.46 g, 27.0 mmol) was added slowly. The reaction mixture was allowed to warm to room temperature, stirred at the same temperature overnight, diluted with water, and extracted with Et20. The extracts were dried and concentrated. The precipitated solid was filtered and rinsed with Et2O. The filtrate was concentrated and subjected to column chromatography (CH2Cl2 / hexane: 1/2) to provide 4.50 g (76%) of M1; [a] D + 7.3 ° (c 1.0, CHCl3); 1 H NMR (300 MHz, CDCl 3) d 7.54 (d, J = 8.7 Hz, 2H), 6.98 (d, J = 8.7 Hz, 2H), 4.29 (dd, J = 11.1, 2.9 Hz, 1 H), 3.96 (dd, J = 11.1, 5.8 Hz, 1 H), 3.39-3.33 (m, 1 H), 2.92 (t, J = 4.5 Hz, 1H), 2.76 (dd, J = 4.9, 2.6 Hz, 1H). To a mixture of M1 (2.11 g, 9.68 mmol), ethyl ester (4-mercapio-2-methyl-phenoxy) -acetic acid A1c (3.28 g, 14.5 mmol) in THF (10 mL) was added 1.0 M evaphbuylammonium fluoride. in THF (0.965 ml, 0.965 mmol). After agglutination for 8 hr, the solvent was evaporated and the residue was purified by column chromatography twice (EtOAc / hexane: 2/7 and EtOAc / CH2Cl2: 1/1) to give 3.69 g (85%) of M2; [a] D + 32.5 ° (c 1.0, CHCl3); 1 H NMR (300 MHz, CDCl 3) d 7.53 (d, J = 8.8 Hz, 2H), 7.26 (s, 1H), 7.23 (dd, J = 8.4, 2.3 Hz, 1H), 6.91 (d, J = 8.8 Hz, 2H), 6.60 (d, J = 8.4 Hz, 1 H), 4.59 (s, 2H), 4.26 (q, J = 7.1 Hz, 2H), 4.08-4.02 (m, 1 H), 4.05 (s) , 2H), 3.17-3.01 (m, 2H), 2.70 (brs, 1H), 2.24 (s, 3H), 1.29 (i, J = 7.1 Hz, 3H); MS (ES) m / z: 467 (M + Na +). Following general procedure 4 in Example L, M3 was obtained; [] D + 38.9 ° (c 1.0, CHCI3); 1 H NMR (300 MHz, CDCl 3) d 7.51 (d, J = 8.6 Hz, 2 H), 7.24 (d, J = 1.7 Hz, 1 H), 7.19 (dd, J = 8.4, 2.2 Hz, 1 H), 6.91 (d, J = 8.6 Hz, 2H), 6.57 (d, J = 8.4 Hz, 1 H), 4.57 (s, 2H), 4.25 (q, J = 7.1 Hz, 2H), 4.15 (dd, J = 9.9 , 4.3 Hz, 1 H), 4.07 (dd, J = 9.9, 5.1 Hz, 1 H), 3.76 (m, 1H), 3.61 (q, J = 7.0 Hz, 2H), 3.13-3.11 (m, 2H) , 2.23 (s, 3H), 1.29 (t, J = 7.1 Hz, 3H), 1.18 (t, J = 7.0 Hz, 3 H); MS (ES) m / z: 495 (M + Na +). Analysis calculated for C23H27F305S: C, 58.46; H, 5.76.

Found: C, 58.83; H, 5.55. Following the general procedure 2 in Example A, compound 15 was obtained; [a] D + 39.2 ° (c 1.0, CHCI3); 1 H NMR (300 MHz, CDCl 3) d 7.51 (d, J = 8.7 Hz, 2H), 7.23 (s, 1 H), 7.20 (dd, J = 8.4, 2.1 Hz, 1 H), 6.91 (d, J = 8.6 Hz, 2H), 6.59 (d, J = 8.4 Hz, 1 H), 4.61 (s, 2H) , 4.14 (dd, J = 9.9, 4.4 Hz, 1 H), 4.08 (dd, J = 9.9, 5.0 Hz, 1H), 3.77 (m, 1 H), 3.61 (q, J = 7.0 Hz, 2H), 3.20-3.07 (m, 2H), 2.21 (s, 3H), 1.19 (t, J = 7.0 Hz, 3H); MS (ES) m / z: 467 (M + Na +).

M4 (R) -2- (4-Trifluoromethyl-phenoxymethyl) -oxirane Following the same procedure as in the preparation of M1 M4 was obtained (74%); 1 H NMR (400 MHz, CDCl 3) d 7.54 (d, J = 9.0 Hz, 2 H), 6.98 (d, J = 8.9 Hz, 2 H), 4.29 (dd, J = 11.1, 2.9 Hz, 1 H), 3.96 ( dd, J = 11.1, 5.8 Hz, 1 H), 3.37 (m, 1H), 2.92 (m, 1H), 2.76 (dd, J = 4.8, 2.6 Hz, 1H); MS (ES) m / z: 241 (M + Na +).

Ethyl ester of (S) - acid. { 5- [2-Hydroxy-3- (4-trifluoromethyl-phenoxy) -propylsulfanyl] -2-methyl-phenoxy} -acetic Following the same procedure as in the preparation of M2, M5 (88%) was provided; 1 H NMR (300 MHz, CDCl 3) d 7.52 (d, J = 8.7 Hz, 2H), 7.26 (s, 1 H), 7.22 (dd, J = 8.4, 2.3 Hz, 1 H), 6.91 (d, J = 8.7 Hz, 2H), 6.59 (d, J = 8.4 Hz, 1 H), 4.59 (s, 2H) , 4.25 (q, J = 7.1 Hz, 2H), 4.07-4.01 (m, 3H), 3.17-3.01 (m, 2H), 2.72 (brs, 1 H), 2.23 (s, 3H), 1.29 (t, J = 7.1 Hz, 3H); MS (ES) m / z: 467 (M + Na +).

Ethyl ester of (S) - acid. { 4- [2-hydroxy-3- (4-trifluoromethyl-phenoxy) -propylsulfanyl] -2-methy1-phenoxy} -acetic Following general procedure 4 in Example L, M6 was obtained; 1 H NMR (400 MHz, CDCl 3) d 7.51 (d, J = 8.7 Hz, 2H), 7.24 (d, J = 2.0 Hz, 1 H), 7.19 (dd, J = 8.4, 2.3 Hz, 1 H), 6.91 (d, J = 8.7 Hz, 2H), 6.57 (d, J = 8.4 Hz, 1 H), 4.57 ( s, 2H), 4.25 (q, J = 7.1 Hz, 2H), 4.15 (dd, J = 9.9, 4.3 Hz, 1 H), 4.08 (dd, J = 9.9, 5.1 Hz, 1 H), 3.76 (m, 1H), 3.61 (q, J = 7.0 Hz, 2H), 3.13- 3.11 (m, 2H), 2.22 (s) , 3H), 1.29 (t, J = 7.1 Hz, 3H), 1.18 (t, J = 7.0 Hz, 3H); MS (ES) m / z: 495 (M + Na +).

Analysis calculated for C 23 H 27 F 3 O 5 S: C, 58.46; H, 5.76. Found: C, 58.82; H, 5.37.

Compound 16 Acid (SH4- [2-ethoxy-3- (4-ylfluoromethyl-phenoxy) -propylsulfanyl] -2-methyl-phenoxy} -acetic acid Following general procedure 2 in example A, the compound 16 was obtained. 1 H NMR (300 MHz, CDCl 3) d 7.50 (d, J = 8.6 Hz, 2H), 7.23 (s, 1 H), 7.19 (dd, J = 8.4, 1.9 Hz, 1 H), 6.90 (d, J = 8.6 Hz, 2H), 6.58 (d, J = 8.4 Hz, 1 H), 4.59 (s, 2H), 4.14 (dd, J = 9.9, 4.4 Hz, 1 H), 4.08 (dd, J = 9.9, 4.9 Hz, 1H), 3.77 (m, 1 H), 3.61 (q, J = 7.0 Hz, 2H), 3.13 (m, 2H), 2.20 (s, 3H), 1.18 (i, J = 7.0 Hz, 3H); MS (ES) m / z: 467 (M + Na +).

Ethyl ester of acid. { 4- [2-ethoxy] -3- (4-trifluoromethyl-phenoxy) -propanylsulphanyl] -2- metyl-phenoxy} -acetic Following general procedure 4 in Example L, M7 (59%) was obtained; 1 H NMR (300 MHz, CDCl 3) d 7.51 (d, J = 8.6 Hz, 2H), 7.24 (d, J = 1.7 Hz, 1 H), 7.19 (dd, J = 8.4, 2.2 Hz, 1 H), 6.91 (d, J = 8.6 Hz, 2H), 6.57 (d, J = 8.4 Hz, 1 H), 4.57 (s, 2H), 4.25 (q, J = 7.1 Hz, 2H), 4.15 (dd, J = 9.9, 4.3 Hz, 1 H), 4.07 (dd, J = 9.9 , 5.1 Hz, 1 H), 3.76 (m, 1H), 3.60 (q, J = 7.0 Hz, 2H), 3.13- 3.11 (m, 2H), 2.22 (s, 3H), 1.28 (t, J = 7.1 Hz, 3H), 1.18 (t, J = 7.0 Hz, 3H); MS (ES) m / z: 495 (M + Na +). Analysis calculated for C23H27F3? 5S: C, 58.46; H, 5.76. Found: C, 57.62; H, 5.52.

Compound 17 Acid. { 4- [2-ethoxy-3- (4-trifluoromethyl-phenoxy) -propylsulfanyl] -2-methyl-phenoxy} -acetic Following the general procedure 2 in Example A compound 17 (94%) was obtained; 1 H NMR (400 MHz, CDCl 3) d 7.50 (d, J = 8.7 Hz, 2H), 7.22 (s, 1 H), 7.18 (d, J = 8.6 Hz, 1 H), 6.90 (d, J = 8.7 Hz, 2 H), 6.57 (d, J = 8.4 Hz, 1 H), 4. 57 (s, 2H), 4.14 (dd, J = 9.9, 4.3 Hz, 1H), 4.07 (dd, J = 9.8, 5.0 Hz, 1 H), 3.77 (m, 1 H), 3.61 (q, J = 7.0 Hz, 2H), 3.18-3.08 (m, 2H), 2.19 (s, 3H), 1.18 (t, J = 7. 0 Hz, 3H); MS (ES) m / z: 467 (M + Na +). Analysis calculated for C 21 H 23 F 3 O 5 S + 0.2 H 2 O: C, 56.29; H, 5.26. Found: C, 56.23; H, 5.27.

M8 Ethyl ester of acid. { 2-methyl-4- [2-propoxy-3- (4-trifluoromethyl-phenoxy) -propylsulfanyl] -phenoxy} -acetic Replacing THF with DMF as solvent and following general procedure 4 in Example L obfused M8 (12%); 1 H NMR (300 MHz, CDCl 3) d 7.51 (d, J = 8.6 Hz, 2 H), 7.23 (d, J = 1.7 Hz, 1 H), 7.19 (dd, J = 8.4, 2.2 Hz, 1 H), 6.91 (d, J = 8.6 Hz, 2H), 6.57 (d, J = 8.4 Hz, 1H), 4.57 (s, 2H), 4.25 (q, J = 7.1 Hz, 2H), 4.15 (dd, J = 9.9 , 4.3 Hz, 1 H), 4.07 (dd, J = 9.9, 5.1 Hz, 1 H), 3.75 (m, 1 H), 3.50 (t, J = 6.7 Hz, 2H), 3.12 (d, J = 6.2 Hz, 2H), 2.23 (s, 3H), 1.63-1.51 (m, 2H), 1.29 (t, J = 7.1 Hz, 3H), 0.90 (t, J = 7.4 Hz, 3H); MS (ES) m / z: 509 (M + Na +).

Compound 18 Acid. { 2-meityl-4- [2-propoxy-3- (4-trifluoromethyl-phenoxy) -propylsulfanyl] -phenoxy} - acetic Following general procedure 2 in example A, compound 18 (92%) was obtained; 1 H NMR (400 MHz, CDCl 3) d 7.51 (d, J = 8.6 Hz, 2H), 7.24 (s, 1H), 7.20 (d, J = 8.3 Hz, 1 H), 6.91 (d, J = 8.5 Hz, 2H), 6.59 (d, J = 8.4 Hz, 1H), 4.63 (s, 2H), 4.15 (dd) , J = 9.8, 4.3 Hz, 1 H), 4.08 (dd, J = 9.8, 5.1 Hz, 1 H), 3.76 (m, 1 H), 3.51 (t, J = 6.6 Hz, 2H), 3.15 -3.13 (m, 2H), 2.22 (s, 3H), 1.57 (m, 2H), 0.90 (t, J = 7.4 Hz, 3H); MS (ES) m / z: 481 (M + Na +).

M9 Ethyl ester of acid. { 4- [2-butoxy-3- (4-trifluoromethyl-phenoxy) -propylsulfanyl] -2-methyl-phenoxy} -acetic Replacing THF with DMF as solvent and following general procedure 4 in Example L gave M9 (10%); 1 H NMR (300 MHz, CDCl 3) d 7.51 (d, J = 8.6 Hz, 2H), 7.23 (d, J = 1.9 Hz, 1H), 7.18 (dd, J = 8.4, 2.2 Hz, 1H), 6.91 ( d, J = 8.6 Hz, 2H), 6.57 (d, J = 8.4 Hz, 1 H), 4.57 (s, 2H), 4.26 (q, J = 7.1 Hz, 2H), 4.15 (dd, J = 9.9, 4.4 Hz, 1 H), 4.07 (dd, J = 9.9, 5.2 Hz, 1 H), 3.75 (m, 1 H), 3.54 (t, J = 6.6 Hz, 2H), 3.12 (d, J = 6.2 Hz, 2H), 2.23 (s, 3H), 1.58-1.48 (m, 2H), 1.41-1.34 (m, 2H), 1.29 (t, J = 7.1 Hz, 3H), 0.90 ( t, J = 7.3 Hz, 3H); MS (ES) m / z: 523 (M + Na +).

Compound 19 Acid. { 4-. { 2-Butoxy-3- (4-trifluoromethyl-phenoxy) -propylsulfanyl] -2-methyl-phenoxy} - acetic Following the general procedure 2 in example A, the compound 19 (92%) was obtained; 1 H NMR (400 MHz, CDCl 3) d 7.47 (m, 2H), 7.25-7.23 (m, 1 H), 7.13-7.12 (m, 1H), 6.87 (m, 2H), 6.52 (m, 1H), 4.37 (s, 2H), 4.08-4.05 (m, 2H), 3.71 (m, 1 H), 3.52-3.50 (m, 2H), 3.08 (m, 2H), 2.11 (s, 3H), 1.49 (m , 2H), 1.32-1.25 (m, 2H), 0.87 (m, 3H); MS (ES) m / z: 495 (M + Na +). Analysis calculated for C23H27F3O5S + 0.3 H2O: C, 57.80; H, 5.82. Found: C, 57.78; H, 6.00.

M10 Ethyl ester of (R) - acid. { 4- [2-allyloxy-3- (4-trifluoromethyl-phenoxy) -propylsulfanyl] -2-methyl-phenoxy-acetic acid Following general procedure 4 in Example L, M10 was obtained; 1 H NMR (400 MHz, CDCl 3) d 7.52 (d, J = 8.7 Hz, 2H), 7.23 (s, 1 H), 7.19 (dd, J = 8.4, 2.3 Hz, 1 H), 6.91 (d, J = 8.7 Hz, 2H), 6.57 (d, J = 8.4 Hz, 1 H), 5.93-5.83 (m, 1 H), 5.23 (dd, J = 17.2, 1.5 Hz, 1 H), 5.16 (dd, J = 10.3, 1.0 Hz, 1 H), 4.58 (s, 2H), 4.26 (q, J = 7.1 Hz, 2H), 4.17 (dd, J = 9.9, 4.1 Hz, 1 H), 4.13-4.05 (m, 3H), 3.82 (m, 1 H), 3.13 (d, J = 6.2 Hz, 2H), 2.23 (s) , 3H), 1.29 (t, J = 7.1 Hz, 3H); MS (ES) m / z: 507 (M + Na +).

Compound 20 Acid (R) -. { 4- [2-allyloxy] -3- (4-trifluoromethyl-phenoxy) -propylsulfanyl] -2-methyl-phenoxy} - acéíico Following the general procedure 2 in Example A, compound 20 was obtained; 1 H NMR (300 MHz, MeOH-d 4) d 7.54 (d, J = 8.6 Hz, 2 H), 7.24 (s, 1 H), 7.21 (d, J = 2.1 Hz, 1 H), 6.99 (d, J = 8.6 Hz, 2H), 6.70 (d, J = 8.1 Hz, 1 H), 5.93-5.80 (m, 1H), 5.20 (dd, J = 17.2, 1.6 Hz, 1 H), 5.10 (dd, J = 10.4, 1.3 Hz, 1 H), 4.62 (s, 2H), 4.19 (dd, J = 10.3, 4.0 Hz, 1 H), 4.11 (dd, J = 10.3, 5.1 Hz, 1 H), 4.09-4.06 ( m, 2H), 3.81 (m, 1 H), 3.12 (d, J = 6.4 Hz, 2H), 2.18 (s, 3 H); MS (ES) m / z: 479 (M + Na +).

Ethyl ester of acid. { 4- [2-allyloxy-3- (4-trifluoromethyl-phenoxy) -propylsulfanyl] -2-methyl-phenoxy} -acéíico Replacing NaH with NaHMDS as a base and following general procedure 4 in Example L, M11 was obtained (58%); 1 H NMR (400 MHz, CDCl 3) d 7.51 (d, J = 8.8 Hz, 2 H), 7.23 (d, J = 2.1 Hz, 1 H), 7.19 (dd, J = 8.4, 2.3 Hz, 1 H), 6.91 (d, J = 8.8 Hz, 2H), 6.57 (d, J = 8.4 Hz, 1H), 5.93-5.83 (m, 1H), 5.23 (dd, J = 17.2, 1.5 Hz, 1H), 5.16 (d , J = 10.3 Hz, 1 H), 4.57 (s, 2H), 4.25 (q, J = 7.1 Hz, 2H), 4.16 (dd, J = 10.0, 4.1 Hz, 1 H), 4.11-4.08 (m, 3H), 3.82 (m, 1 H), 3.13 (d, J = 6.1 Hz, 2H), 2.22 (s, 3H), 1.29 (t, J = 7.1 Hz, 3H). Analysis calculated for C24H27F305S: C, 59.49; H, 5.62. Found: C, 59.76; H, 5.71 Compound 21 Acid. { 4- [2-allyloxy] -3- (4-trifluoromethyl-phenoxy) -propylsulfanyl] -2-methylene-phenoxy} - acetic Following general procedure 2 in Example A, compound 21 (90%) was obtained; 1 H NMR (400 MHz, CDCl 3) d 7.49 (d, J = 8.5 Hz, 2H), 7.18 (s, 1 H), 7.14 (d, J = 7.1 Hz, 1 H), 6.89 (d, J = 8.5 Hz, 2 H), 6.53 (m, 1 H), 5.91-5.82 (m, 1 H), 5.21 (d , J = 17.2, 1 H), 5.15 (d, J = 10.3 Hz, 1 H), 4.44 (s, 2H), 4.13 (dd, J = 9.8, 4.2 Hz, 1H), 4.09-4.06 (m, 3H ), 3.82 (m, 1 H), 3.11 (d, J = 4.5 Hz, 2H), 2.15 (s, 3H); MS (ES) m / z: 455 (M-H +). 12 Ethyl ester of (R) - acid. { 4- [2-methoxymethoxy] -3- (4-ylfluoromethyl-phenoxy) -propylsulfanyl] -2-methyl-phenoxy} -acetic Replacing NaH with iPr2NEt as a base and following general procedure 4 in Example L gave M12 (79%); [a] D + 47.8 ° (c 1.0, CHCl3); 1 H NMR (400 MHz, CDCl 3) d 7.51 (d, J = 8.9 Hz, 2H), 7.23 (d, J = 2.2 Hz, 1H), 7.18 (dd, J = 8.4, 2.3 Hz, 1H), 6.90 (d, J = 8.8 Hz, 2H), 6.56 (d, J = 8.4 Hz, 1 H), 4.73 (s, 2H), 4.57 (s, 2H), 4.25 (q, J = 7.1 Hz, 2H), 4.19-4.10 (m, 2H), 4.05 (m, 1H) , 3.39 (s, 3H), 3.18-3.16 (m, 2H), 2.22 (s, 3H), 1.29 (í, J = 7. 1 Hz, 3H); MS (ES) m / z: 511 (M + Na +).

Compound 22 Acid (R) -. { 4- [2-methoxymethoxy-3- (4-trifluoromethyl-phenoxy) -propylsulfanyl] -2-methyl-phenoxy-acetic acid Following general procedure 2 in Example A, compound 22 (95%) was obtained; [a] D + 49.2 ° (c 1.0, CHCI3); 1 H NMR (400 MHz, CDCl 3) d 7.51 (d, J = 8.6 Hz, 2 H), 7.23 (s, 1 H), 7.19 (d, J = 8.4 Hz, 1 H), 6.89 (d, J = 8.6 Hz , 2H), 6.59 (d, J = 8.4 Hz, 1 H), 4.74 (s, 2H), 4.60 (s, 2H), 4.19-4.10 (m, 2H), 4.05 (m, 1H) 3.40 (s. 3H), 3.19-3.17 (m, 2H), 2.21 (s, 3H); MS (ES) m / z: 483 (M + Na +). Analysis calculated for C2? H23F3O6S: C, 54.78; H, 5.03.

Found: C, 54.51; H, 4.90.

M13 Acid (S) -. { 4- [2-methoxymethoxy-3- (4-trifluoromethyl-phenoxy) -propylsulfanyl] -2-methyl-phenoxy-acetic acid Replacing NaH with iPr2NEt as a base and following general procedure 4 gave M13 (73%); 1 H NMR (300 MHz, CDCl 3) d 7.51 (d, J = 8.7 Hz, 2H), 7.22 (s, 1 H), 7.18 (dd, J = 8.4, 2.1 Hz, 1H), 6.90 (d, J = 8.6 Hz, 2H), 6.57 (d, J = 8.4 Hz, 1 H), 4.73 (s, 2H), 4.56 (s, 2H), 4.25 (q, J = 7.1 Hz, 2H), 4.18-4.13 (m, 1 H), 4.09-4.03 (m, 1H), 3.39 (s, 3H), 3.17 (d, J = 6.2 Hz, 2H), 2.22 (s, 3H), 1.29 (t, J = 7.1 Hz, 3H); MS (ES) m / z: 511 (M + Na +).

Compound 23 Acid (S) -. { 4- [2-methoxymethoxy-3- (4-trifluoromethyl-phenoxy) -propylsulfanyl] -2-methyl-phenoxy} -acetic Following general procedure 2 in Example A, compound 23 (91%) was obtained; 1 H NMR (400 MHz, CDCl 3) d 7.51 (d, J = 8.7 Hz, 2 H), 7.23 (s, 1 H), 7.19 (d, J = 8.4 Hz, 1 H), 6.90 (d, J = 8.6 Hz , 2H), 6.59 (d, J = 8.4 Hz, 1 H), 4.74 (s, 2H), 4.60 (s, 2H), 4.19-4.10 (m, 2H), 4.08-4.04 (m, 1 H), 3.40 (s, 3H), 3.19-3.17 (m, 2H), 2.21 (s, 3H); MS (ES) m / z: 483 (M + Na +).

M14 Ethyl ester of acid. { 4- [2-methoxymethoxy-3- (4-trifluoromethyl-phenoxy) -propylsulfanyl] -2-mephyl-phenoxy} -acetic Following general procedure 4 in Example L, M14 (84%), 1 H NMR (400 MHz, CDCl3) d 7.51 (d, J = 8.7 Hz, 2H), 7.23 (d, J) were obtained. = 2.1 Hz, 1 H), 7.18 (dd, J = 8.4, 2.2 Hz, 1 H), 6.90 (d, J = 8.7 Hz, 2H), 6.56 (d, J = 8.4 Hz, 1H), 4.73 (s) , 2H), 4.57 (s, 2H), 4.25 (q, J = 7.1 Hz, 2H), 4.19-4.10 (m, 2H), 4.05 (m, 1H), 3.39 (s, 3H), 3.18-3.16 ( m, 2H), 2.22 (s, 3H), 1.29 (t, J = 7.1 Hz, 3H); MS (ES) m / z: 511 (M + Na +). Analysis calculated for C23H2 F3O6S: C, 56.55; H, 5.57. Found: C, 56.68; H, 5.38.

Compound 24 Acid. { 4- [2-methoxymethoxy-3- (4-trifluoromethyl-phenoxy) -propyl-sulphanyl] -2-methy1-phenoxy-acetic acid Following the general procedure 2 in example A, compound 24 (91%) was obtained; 1 H NMR (400 MHz, CDCl 3) d 7.50 (d, J = 8.6 Hz, 2H), 7.23 (s, 1H), 7.19 (d, J = 8.4 Hz, 1 H), 6.89 (d, J = 8.5 Hz, 2H), 6.58 (d, J = 8.4 Hz, 1H), 4.74 (s, 2H), 4.61 (s) , 2H), 4.18-4.10 (m, 2H), 4.06 (m, 1 H), 3.40 (s, 3H), 3.19-3.17 (m, 2H), 2.21 (s, 3H); MS (ES) m / z: 483 (M + Na +). Analysis calculated for C 21 H 23 F 3 O 6 S + 0.2 H 2 O: C, 54.35; H, . 08. Found: C, 54.25; H, 5.13.

M15 Ethyl ester of acid. { 2-methyl-4- [2-methylsulfanyl-methoxy-3- (4-trifluoromethyl-phenoxy) -propylsulfanyl] -phenoxy} -acetic A reaction mixture of L1b (1.08 g, 2.43 mmol), Ac 0 (2.56 ml, 27.2 mmol), and DMSO (3.84 ml) was stirred at room temperature for 24 h, and diluted with saturated NaHCO 3 and Ef 20. The organic phase was separated, washed with water (x 3), dried, and subjected to column chromatography (EtOAc / hexane: 1/4) to give 61 mg (5%) of M15 as a by-product; 1 H NMR (400 MHz, CDCl 3) d 7.51 (d, J = 8.6 Hz, 2H), 7.24 (s, 1 H), 7.20 (dd, J = 8.4, 1.9 Hz, 1 H), 6.90 (d, J = 8.6 Hz, 2H), 6.57 (d, J = 8.4 Hz, 1 H), 4.74 (d, J = 6.0 Hz, 2H), 4.57 (s, 2H), 4.25 (q, J = 7.1 Hz, 2H), 4.21-4.10 (m, 3H), 3.15 (d, J = 6.0 Hz, 2H), 2.23 (s, 3H), 2.16 (s, 3H), 1.29 (t, J = 7.1 Hz, 3H); MS (ES) m / z: 527 (M + Na +).

Compound 25 Acid. { 2-methyl-4- [2-methylsulfanylmethoxy-3- (4-fluoro-methyl-phenoxy) propylsulfanyl] -phenoxy-acetic acid Following general procedure 2 in Example A, compound 25 (92%) was obtained; 1 H NMR (300 MHz, CDCl 3) d 9.45 (brs, 1 H), 7.51 (d, J = 8.5 Hz, 2 H), 7.25 (s, 1 H), 7.21 (d, J = 8.5 Hz, 1 H) , 6.90 (d, J = 8.4 Hz, 2H), 6.59 (d, J = 8.4 Hz, 1H), 4.74 (d, J = 3.0 Hz, 2H), 4.63 (s, 2H), 4.19-4.10 (m, 3H), 3.16 (d, J = 5.7 Hz, 2H), 2.21 (s, 3H), 2.16 (s, 3H); MS (ES) m / z: 499 (M + Na +).

M16 Erythyl ester of acid. { 4- [2-Mefoxicarbonylmethoxy-3- (4-trifluoromethyl-phenoxy) -propylsulfanyl] -2-meityl-phenoxy} -acéíico Following general procedure 4 in Example L, M16 was obtained; 1 H NMR (300 MHz, CDCl 3) d 7.51 (d, J = 8.6 Hz, 2H), 7.24 (d, J = 1.9 Hz, 1H), 7.19 (dd, J = 8.4, 2.2 Hz, 1H), 6.91 ( d, J = 8.7 Hz, 2H). 6.57 (d, J = 8.4 Hz, 1 H), 4.58 (s 2H), 4.28-4.23 (m, 5H), 4.19-4.13 (m, 2H), 3.89-3.86 (m, 1 H), 3.69 (s) , 2H), 3.25-3.14 (m, 2H), 2.23 (s, 3H), 1.29 (t, J = 7.1 Hz, 3H); MS (ES) m / z: 539 (M + Na +).

Compound 26 Acid. { 4- [2-carboxymethoxy-3- (4-ylfluoromethyl-phenoxy) -propylsulfanyl] -2-methyl-phenoxy-acetic acid Following the general procedure 2 in Example A, compound 26 (97%) was obtained; 1 H NMR (300 MHz, MeOH-d 4) d 7.53 (d, J = 8.7 Hz, 2H), 7.24 (s, 1H), 7.22 (dd, J = 8.5, 2.2 Hz, 1 H), 6.97 (d, J = 8.7 Hz, 2H), 6.68 (d, J = 8.4 Hz, 1 H), 4.61 (s, 2H), 4.24-4.15 (m, 4H), 3.88-3.84 (m, 1 H), 3.20-3.16 (m, 2H), 2.17 (s, 3H); MS (ES) m / z: 497 (M + Na +).

Ethyl ester of acid. { 4- [2- (5-chloro-thiophen-2-ylmethoxy) -3- (4-frifluoromethyl-phenoxy) -propyl sulfanyl] -2-methyl-phenoxy} -acetic Replacing NaH with sodium bis (trimethylsilyl) amide and following general procedure 4 obtained M17 (26%); 1 H NMR (300 MHz, CDCl 3) d 7.52 (d, J = 8.6 Hz, 2H), 7.20 (d, J = 1.7 Hz, 1 H), 7.15 (dd, J = 8.4, 2.1 Hz, 1 H), 6.90 (d, J = 8.6 Hz, 2H), 6.72 (d, J = 3.7 Hz, 1H), 6.63 (d, J = 3.7 Hz, 1H), 6.57 (d, J = 8.4 Hz, 1 H), 4.67 (d, J = 1.5 Hz, 2H), 4.59 (s, 2H), 4.26 (q, J = 7.1 Hz, 2H), 4.18 (dd, J = 10.1, 3.9 Hz, 1 H), 4.09 (dd, J) = 10.1, 5.5 Hz, 1 H), 3.92-3.85 (m, 1 H), 3.09 (d, J = 6.2 Hz, 2H), 2.23 (s, 3H), 1.30 (t, J = 7.1 Hz, 3H); MS (ES) m / z: 597 (M + Na +).

Compound 27 Acid. { 4- [2- (5-Chloro-thiophen-2-ylmethoxy) -3- (4-trifluoromethyl-phenoxy) -propylsulfanyl] -2-methyl-phenoxy} -acetic Following general procedure 2 in Example A, compound 27 (93%) was obtained; 1 H NMR (300 MHz, CDCl 3) d 7.48 (d, J = 8.6 Hz, 2H), 7.11 (s, 1 H), 7.07 (d, J = 8.3 Hz, 1 H), 6.85 (d, J = 8.6 Hz, 2H), 6.68 (d, J = 3.7 Hz, 1 H), 6.62 (d, J = 3.7 Hz, 1 H), 6.50 (d, J = 7.9 Hz, 1H), 4.64 (s, 2H), 4.36 (s, 2H), 4.13-4.02 (m, 2H), 3.89-3.84 (m, 1H), 3.05 (d, J = 4.8 Hz, 2H), 2.11 (s, 3 H); MS (ES) m / z: 545 (M-H +).

M? 8 Ethyl ester of acid. { 4- [2-benzyloxy-3- (4-trifluoromethyl-phenoxy) -propylsulfanyl] -2- meityl-phenoxy-acetic acid Following general procedure 4 in Example L, M18 (78%) was obtained; 1 H NMR (300 MHz, CDCl 3) d 7.50 (d, J = 8.6 Hz, 2H), 7.31-7.25 (m, 5 H), 7.19 (d, J = 1.8 Hz, 1 H), 7.14 (dd, J = 8.4, 2.2 Hz, 1 H), 6.89 (d, J = 8. 6 Hz, 2H), 6.55 (d, J = 8.4 Hz, 1H), 4.62 (d, J = 4.9 Hz, 2H), 4.57 (s, 2H), 4. 25 (q, J = 7.1 Hz, 2H), 4.20-4.11 (m, 2H), 3.87 (m, 1 H), 3.14 (d, J = 6.1 Hz, 2H), 2.21 (s, 3H), 1.29 (t, J = 7.1 Hz, 3H); MS (ES) m / z: 557 (M + Na +).

Compound 28 Acid. { 4- [2-benzyloxy-3- (4-trifluoromethyl-phenoxy) -propylsulfanyl] -2-methyl-phenoxy} - acetic Following general procedure 2 in Example A, compound 28 (93%) was obtained; 1 H NMR (300 MHz, CDCl 3) d 7.50 (d, J = 8.6 Hz, 2H), 7.31-7.25 (m, 5H), 7.19 (d, J = 1.8 Hz, 1 H), 7.14 (dd, J = 8.4, 2.2 Hz, 1 H), 6.88 (d, J = 8.6 Hz, 2H), 6.56 (d, J = 8.4 Hz, 1H), 4.63 (m, 4H), 4.20-4.08 (m, 2H), 3.88 (m, 1H), 3.15 (d, J = 6.7 Hz, 2H), 2.19 (s, 3H); MS (ES) m / z: 529 (M + Na +).

EXAMPLE N Compound 29 Acid. { 4- [2- (4-methoxy-phenoxy) -3- (4-trifluoromethyl-phenoxy) -propylsulfanyl] -2-methyl-phenoxy} -acetic Compound 30 Acid. { 4- [2- (4-buyryl-phenoxy) -3- (4-fluorifomethyl-phenoxy) -propylsulfanyl] -2-methyl-phenoxy-acetic SCHEME N Ethyl ester of acid. { 4- [2- (4-methoxy-phepoxy) -3- (4-trifluoromethyl-phepoxy) -propylsulfanyl] -2-methyl-phepoxy} -acetic To a mixture of L1 b (122 mg, 0.275 mmol) and 4-mefoxiphenol (51 mg, 0.41 mmol) in CH2Cl2 (3 mL) at 0 ° C was slowly added 1.1 '- (azodicarbonyl) dlpiperidine (104 mg, 0.412 mmol) followed by a solution of triphenylphosphine (108 mg, 0.412 mmol) in CH2Cl2 (3 ml). The reaction mixture was allowed to warm to room temperature, stirred at the same temperature overnight and filtered. The filtration was concentrated and subjected to column chromatography (EtOAc / hexane: 1/7) to provide 110 mg (73%) of N1; MS (ES) m / z: 573 (M + Na +). Following the general procedure 2 in Example A, compound 29 (91%) was obtained; MS (ES) m / z: 545 (M + Na +).

N2 Ethyl ester of acid. { 4- [2- (4-butyryl-phenoxy) -3- (4-trifluoromethyl-phenoxy) -propylsulfanyl] -2-mephyl-phenoxy} -acetic To a mixture of L1 b (105 mg, 0.236 mmol) and 1- (4-hydroxyphenyl) -butan-1-one (59 mg, 0.36 mmol) in CH2Cl2 (3 mL) at 0 ° C were slowly added 1.1. '- (azodicarbonyl) dipiperidine (91 mg, 0.36 mmol) followed by a solution of triphenylphosphine (94 mg, 0.36 mmol) in CH2Cl2 (3 mL). The reaction mixture was allowed to warm to room temperature, stirred at the same temperature overnight and filtered. The filtration was concentrated and subjected to column chromatography (EtOAc / hexane: 1/7) to provide 95 mg (68%) of N2; MS (ES) m / z: 613 (M + Na +). Following the general procedure 2 in Example A, compound 30 (95%) was obfuscated; MS (ES) m / z: 585 (M + Na +).

EXAMPLE O Compound 32 Acid. { 3-Chloro-4- [2-ethoxy-3- (4-trifluoromethyl-phenoxy) -propylsulfanyl] -phenyl} -acetic SCHEME O Methyl ester of acid. { 3-Chloro- [2-ethoxy-3- (4-trifluoromethyl-phenoxy) -propylsulfanyl] -phenyl} acetic 82% Compound 32 To a mixture of L1a (171 mg, 0.784 mmol) and (3-chloro-4-mercapto-phenyl) -acetic acid methyl ester H1 (170 mg, 0.787 mmol; WO99 / 32465) in THF (3 mL) was added tetrabutylammonium fluoride. 1.0 M in THF (0.12 ml, 0.12 mmol). The reaction mixture was stirred at room temperature overnight, concentrated and purified by column chromatography (EtOAc / hexane: 1/3) to give 261 mg (77%) of 01; 1 H NMR (400 MHz, CDCl 3) d 7.53 (d, J = 8.8 Hz, 2 H), 7.38 (dd, J = 8.1 Hz, 1 H), 7.32 (d, J = 1.7 Hz, 1 H), 7.12 (dd) , J = 8.1, 1.8 Hz, 1 H), 6.94 (d, J = 8.8 Hz, 2H), 4.15-4.09 (m, 3H), 3.70 (s, 3H), 3.55 (s, 2H), 3.27 (dd) , J = 13.8, 5.4 Hz, 1 H), 3.16 (dd, J = 13.7, 6.5 Hz, 1 H), 2.75 (brs, 1 H); MS (ES) m / z: 457 (M + Na +). Analysis calculated for C19H18CIF3? 4S: C, 52.48; H, 4.17. Found: C, 52.50; H, 4.27. A solution of O1 (368 mg, 0.848 mmol) in THF (2.4 ml) was treated with 1.0 M NaHMDS in THF (0.85 ml, 0.85 mmol) at -78 ° C for 15 mln. To the mixture was added EtOTf (151 mg, 0.849 mmol) and the cooling bath was removed. The mixture was stirred at room temperature for 1 hr, diluted with saturated NaHCO 3 and extracted with E 20. The extracts were dried, concentrated and subjected to column chromatography (EtOAc / hexane) to give 37 mg (9%) of O2; 1 H NMR (300 MHz, CDCl 3) d 7.52 (d, J = 8.8 Hz, 2H), 7.36 (dd, J = 8.1 Hz, 1 H), 7.29 (d, J = 1.8 Hz, 1 H), 7.10 (d, J = 8.1, 1.8 Hz, 1 H), 6.95 (d, J = 8.7 Hz, 2H), 4.14 (dd, J = 4.9, 1.4 Hz, 2H), 3.85 (m, 1 H), 3.70 (s, 3H), 3.66 (q, J = 7.0 Hz, 2H), 3.54 (s, 2H), 3.28 (dd, J = 13.6, 6.2 Hz, 1 H), 3.19 (dd, J = 13. 6, 5.8 Hz, 1H), 1.20 (t, J = 7.0 Hz, 3H); MS (ES) m / z: 485 (M + Na +). Following the general procedure 2 in Example A, compound 32 (82%) was obfuscated; 1 H NMR (400 MHz, MeOH-d 4) d 7.56 (d, J = 8.6 Hz, 2H), 7.45 (d, J = 8.1 Hz, 1 H), 7.32 (d, J = 1.3 Hz, 1 H), 7.16 (dd, J = 8.1, 1.4 Hz, 1 H), 7.04 (d, J = 8.6 Hz, 2H), 4.22-4.14 (m, 2H), 3.86 (m, 1 H), 3.65 (q, J = 7.0 Hz, 2H), 3.55 (s, 2H), 3.30-3.28 (m, 1 H), 3.22 (dd, J = 13.8, 6.1 Hz, 1 H), 1.15 (t, J = 7.0 Hz, 3H); MS (ES) m / z: 471 (M + Na +).

EXAMPLE P Compound 33 Acid. { 4- [2-ethoxymethyl-3- (4-trifluoromethyl-phenoxy) -propylsulfanyl] -2-methyl-phenoxy} - acetic Compound 34 Acid. { 2-methyl-4- [3- (4-ylfluoromethyl-phenoxy) -2- (4-trifluoromethyl-phenoxymethyl) -propylsulfanyl] -phenoxy} -acetic SCHEME P Ethyl ester of acid. { 4- [2-ethoxymethyl-3- (4-trifluoromethyl-phepoxy-propylsulfanyl] -2-methyl-phenoxy] -acetic acid To a solution of 13 (126 mg, 0.275 mmol) in THF (2 ml) at -78 ° C was added 1.0 M sodium bis (trimethylsilyl) amide (0.27 ml, 0.27 mmol) in THF After stirring for 5 min, ethyl trifluoromethanesulfonate (48 mg, 0.27 mmol) was introduced and the cooling bath was removed. The mixture was stirred for 30 min, quenched with saturated NaHCO3 and exfoliated with E20 (x3). The extracts were dried, concentrated and purified by column chromatography (EtOAc / hexane: 1/7) to provide 62 mg (47%) of P1; 1 H NMR (300 MHz, CDCl 3) d 7.51 (d, J = 8.6 Hz, 2 H), 7.21 (d, J = 2.2 Hz, 1 H), 7.16 (dd, J = 8.4, 2.2 Hz, 1 H), 6.91 (d, J = 8.6 Hz, 2H), 6.58 (d, J = 8.4 Hz, 1 H), 4.57 (s, 2H), 4.25 (q, J = 7.1 Hz, 2H), 4.12 (dd, J = 9.3, 5.4 Hz, 1 H), 4.06 (dd, J = 9.3, 5.4 Hz, 1 H), 3.58-3.55 (m, 2H). 3.44 (q, J = 7.0 Hz, 2H), 3. 04 (d, J = 6.7 Hz, 2H), 2.29 (m, 1 H), 2.23 (s, 3H), 1.29 (t, J = 7.1 Hz, 3H), 1. 16 (t, J = 7.0 Hz, 3H); MS (ES) m / z: 509 (M + Na +). Following general procedure 2 in Example A, compound 33 (88%) was obtained; 1 H NMR (300 MHz, CDCl 3) d 7.50 (d, J = 8.6 Hz, 2H), 7.17 (s, 1 H), 7.14 (d, J = 8.3.1 H), 6.90 (d, J = 8.6 Hz, 2H), 6.57 (d, J = 8.3 Hz, 1 H), 4.50 (s, 2H), 4.11 ( dd, J = 9.3, 5.4 Hz, 1 H), 4.04 (dd, J = 9.3, 5.4 Hz, 1 H), 3.57- 3.54 (m, 2H), 3.44 (q, J = 7.0 Hz, 2H), 3.02 (d, J = 6.7 Hz, 2H), 2.27 (m, 1 H), 2. 17 (s, 3H), 1.15 (t, J = 7.0 Hz, 3H); MS (ES) m / z: 481 (M + Na +). Analysis calculated for C22H25F305S: C, 57.63; H, 5.50. Found: C, 57.77; H, 5.42.

P2 Ethyl ester of acid. { 2-methyl-4- [3- (4-ylfluoromethyl-phenoxy) -2- (4-trifluoromethyl-phenoxymethyl) -propylsulfanyl] -phenoxy} -acetic To a mixture of 13 (104 mg, 0.227 mmol), trifluoromethylphenol (56 mg, 0.35 mmol), and triphenylphosphine (91 mg, 0.35 mmol) in THF (3 mL) at 0 ° C was added diisopropyl azodicarboxylate (70 mg, 0.35 mmole). The mixture was stirred at 0 ° C for 30 min and at room temperature for 7 hr, concentrated and subjected to column chromatography (EtOAc / hexane: 1/8) to provide 110 mg (79%) of P2; 1 H NMR (300 MHz, CDCl 3) d 7.52 (d, J = 8.6 Hz, 4H), 7.22 (d, J = 1.8 Hz, 1 H), 7.17 (dd, J = 8.4, 2.3 Hz, 1 H), 6.92 (d, J = 8.6 Hz, 4H), 6.56 (d, J = 8.4 Hz, 1 H), 4.57 ( s, 2H), 4.26 (q, J = 7.1 Hz, 2H), 4.21-4.16 (m, 4H), 3.14 (d, J = 6.7 Hz, 2H), 2.54 (m, 1H), 2.21 (s, 3H) ), 1.29 (t, J = 7.1 Hz, 3H); MS (ES) m / z: 625 (M + Na +). Analysis calculated for C29H28F6O5S: C, 57.80; H, 4.68. Found: C, 57.92; H, 4.52.

Compound 34 Acid. { 2-methyl-4- [3- (4-ylfluoromethyl-phenoxy) -2- (4-trifluoromethyl-phenoxymethyl) -propylsulfanyl] -phenoxy} -acetic Following general procedure 2 in example A, compound 34 (84%) was obtained; 1 H NMR (300 MHz, MeOH-d 4) d 7.54 (d, J = 8.1 Hz, 4 H), 7.22 (m, 2 H), 7.01 (d, J = 8.1 Hz, 4 H), 6.66 (d, J = 8.1 Hz, 1 H), 4.56 (s, 2H), 4.22 (m, 4H), 3.16 (d, J = 6.2 Hz, 2H), 2.50 (m, 1 H), 2.14 (s, 3H); MS (ES) m / z: 597 (M + Na +). Analysis calculated for C27H24F6O5S: C, 56.44; H, 4.21. Found: C, 56.08; H, 4.01.

EXAMPLE Q Compound 35 Acid. { 4- [4-methoxy-2- (4-trifluoromethyl-phenoxymethyl) -butylsulfanyl] -2-methyl-phenoxy} - acetic SCHEME Q Ethyl ester of acid. { 4- [4-methoxy-2- (4-trifluoromethyl-phepoxymethyl) -butylsulfapyl] -2-methyl-phepoxy} -acetic To a solution of J5 (117 mg, 0.248 mmol) in THF (2 mL) at -78 ° C was added 1.0 M sodium bis (trimethylsilyl) amide (0.25 mL, 0.25 mmol) in THF. After stirring for 5 min, methyl trifluoromethanesulfonate (41 mg, 0.25 mmol) was introduced and the cooling bath was removed. After the temperature was raised to room temperature, the mixture was quenched with water and extracted with Et2O (x3). The extracts were dried, concentrated and purified by column chromatography (EtOAc / hexane: 1/6) to provide 35 mg (29%) of Q1; 1 H NMR (300 MHz, CDCl 3) d 7.51 (d, J = 8.6 Hz, 2H), 7.19 (d, J = 1.6 Hz, 1 H), 7.14 (dd, J = 8.4, 2.1 Hz, 1 H), 6.89 (d, J = 8.6 Hz, 2H), 6.55 (d, J = 8.4 Hz, 1 H), 4.56 (s, 2H), 4.25 (q, J = 7.1 Hz, 2H), 4.08 (dd, J = 9.3, 4.7 Hz, 1 H), 3.99 (dd, J = 9.3, 5.5 Hz, 1 H), 3.45 (t, J = 6.3 Hz, 2H), 3.31 (s, 3H), 3.04 (d, J = 6.2 Hz, 2H), 2.26-2.18 (m, 1 H), 2.21 (s, 3H), 1.82 (q, J = 6.4 Hz, 2H), 1.29 (t, J = 7.1 Hz, 3H); MS (ES) m / z: 509 (M + Na +). Following general procedure 2 in Example A, compound 35 (95%) was obtained; 1 H NMR (300 MHz, CDCl 3) d 7.49 (d, J = 8.6 Hz, 2H), 7.19-7.12 (m, 2H), 6.87 (d, J = 8.6 Hz, 2H), 6.55 (m, 1 H) , 4.51 (s, 2H), 4.07 (m, 1 H), 3.97 (m, 1H), 3.45 (t, J = 6.0 Hz, 2H), 3.30 (s, 3H), 3.03 (d, J = 6.2 Hz , 2H), 2.21-2.17 (m, 1 H), 2.17 (s, 3H), 1.82 (q, J = 6.3 Hz, 2H); MS (ES) m / z: 481 (M + Na +).

Compound 36 Acid. { 4- [4,4-diethoxy-2- (4-ylfluoromethyl-phenoxymethyl) -bufilsulfanyl] -2-methyl-phenoxy} - acetic Using J3 as the starting material and following general procedure 2 in Example A, compound 36 (85%) was obtained; 1 H NMR (300 MHz, CDCl 3) d 7.49 (d, J = 8.6 Hz, 2 H), 7.17 (s, 1 H), 7.14 (d, J = 8.7 Hz, 1 H), 6.87 (d, J = 8.6 Hz , 2H), 6.55 (d, J = 7.9 Hz, 1 H), 4.60 (t, J = 5.6 Hz, 1 H), 4.54 (s, 2H), 4.10 (dd, J = 9.3, 4.5 Hz, 1 H ), 3.99 (dd, J = 9.3, 5.7 Hz, 1 H), 3.68-3.56 (m, 2H), 3.51-3.40 (m, 2H), 3.05-3.00 (m, 2H), 2.25-2.17 (m, 1 H), 2.17 (s, 3H), 1.89-1.84 (m, 2H), 1.16 (t, J = 7.0 Hz, 3H), 1.15 (1, J = 7.0 Hz, 3H), MS (ES) m / z: 539 (M + Na +).

Q2 Ester elíllco acid. { 4- [4-Eioxy-2- (4-lu-trifluoromethyl-phenoxymethyl) -butylsulphanyl] -2- mephyl-phenoxy-acyclo Replacing methyl trifluoromethanesulfonate by ethyl trifluoromethanesulfonate and following the same procedure as in the preparation of Q1 provided the title compound Q2 (23%); 1 H NMR (300 MHz, CDCl 3) d 7.50 (d, J = 8.6 Hz, 2H), 7.19 (d, J = 1.7 Hz, 1 H), 7.14 (dd, J = 8.4, 2.2 Hz, 1 H), 6.88 (d, J = 8.6 Hz, 2H), 6.55 (d, J = 8.4 Hz, 1 H), 4.56 (s, 2H), 4.25 (q, J = 7.1 Hz, 2H), 4.10 (dd, J = 9.3, 4.6 Hz, 1 H), 4.00 (dd, J = 9.3, 5.6 Hz, 1 H), 3.51-3.40 (m, 4 H), 3.04 (d, J = 6.1 Hz, 2H), 2.27-2.21 ( m, 1 H), 2.21 (s, 3H), 1.82 (q, J = 6.5 Hz, 2H), 1.29 (t, J = 7.1 Hz, 3H), 1.16 (t, J = 7.0 Hz, 3H); MS (ES) m / z: 523 (M + Na +).

Compound 37 Acid. { 4- [4-ethoxy-2- (4-trifluoromethyl-phenoxymethyl) -butylsulfanyl] -2-methy1-phenoxy) -acetic Following the general procedure 2 in Example A, compound 37 (92%) was obtained; 1 H NMR (300 MHz, MeOH-d 4) d 7.53 (d, J = 8.6 Hz, 2H), 7.17 (m, 1 H), 7.14 (d, J = 2.1 Hz, 1 H), 6.98 (d, J = 8.6 Hz, 2 H), 6.66 (d, J = 8.2 Hz, 1 H), 4.41 (s, 2 H) ), 4.12 (dd, J = 9.5, 4.8 Hz, 1 H), 4.03 (dd, J = 9.5, 5.5 Hz, 1 H), 3.52-3.40 (m, 4 H), 3.00 (d, J = 6.4 Hz , 2H), 2.17 (s, 3H), 2.17-2.11 (m, 1 H), 1.83-1.76 (m, 2H), 1.13 (t, J = 7.0 Hz, 3H); MS (ES) m / z: 495 (M + Na +).

EXAMPLE R Compound 38 Acid. { 4- [2-ethoxy-4- (4-yl-1-fluoromethyl-phenyl) -butylsulfanyl] -2-methyl-phenoxy} -acetic SCHEME R DIBAL-H, CH2CI2 3- (4-trifluoromethyl-phenyl) -proponic acid methyl ester 3- (4-Trifluoromethyl-phenyl) -2- [2- (4-Trifluoromethyl-1-proplonaldehyde phenyl) -ethyl] -oxirane Ethyl ester of acid. { 4- [2-hydroxy-4- (4- (ethyl 4- (2-ethoxy-4-trifluoromethyl-phenyl) -butylsulfanyl] -2-methyl-phenoxy) ethyl ester} -acetic (4-trifluoromethyl-phenyI) -butylsulfanyl] -2-methyl-phenoxy} -acetic To a solution of R1 (1.00 g, 4.59 mmol) in Et2O (20 mL) and MeOH (10 mL) was added (frmethylsilyl) diazomethane 1.0 M (9.16 mL, 9.16 mmol) in hexane. After stirring at room temperature for 1 hr, the solvents were removed under reduced pressure. The residue was dissolved in Et 2 O, washed with saturated NaHCO 3 and brine, dried and concentrated to give 1.04 g (98%) of R 2; 1 H NMR (300 MHz, CDCl 3) d 7.54 (d, J = 8.1 Hz, 2 H), 7.31 (d, J = 8.1 Hz, 2 H), 3.67 (s, 3 H), 3.01 (t, J = 7.7 Hz, 2H), 2.65 (t, J = 7.7 Hz, 2H); MS (ES) m / z: 255 (M + Na +). To a solution of R 2 (1.10 g, 4.74 mmol) in CH 2 Cl 2 (20 mL) at -78 ° C was added 1.0 M diisobutylaluminum hydride (4.74 mL, 4.74 mmol). The mixture was stirred at -78 ° C for 10 min and quenched with 10% HCl in MeOH (5 mL). After being warmed to room temperature, the mixture was filtered and the filtrate was concentrated and subjected to column chromatography to provide 796 mg (83%) of R3; 1 H NMR (400 MHz, CDCl 3) d 9.82 (d, J = 1.0 Hz, 1 H), 7.54 (d, J = 8.1 Hz, 2 H), 7.31 (d, J = 8.0 Hz, 2 H), 3.01 (i , J = 7 4 Hz, 2H), 2.82 (i, J = 7.3 Hz, 2H). A mixture of NaH (52 mg, 1.3 mmol, 60% in mineral oil) in DMSO (15 ml) was heated at 70 ° C for 30 min and allowed to cool to room temperature. After being diluted with THF (10 ml), a solution of trimethylsulfonyl iodide (306 mg, 1.50 mmol) in DMSO (10 ml) was slowly added to the mixture at 0 ° C. After stirring for 10 min at 0 ° C, a solution of R3 (202 mg, 1.00 mmol) in THF (10 ml) was introduced. Stirring was continued for 1 hr at 0 ° C and the mixture was diluted with water and extracted with Et20. The exfracti were dried, concentrated and subjected to column chromatography (EtOAc / hexane: 1/7) to provide 147 mg (68%) of R4; 1 H NMR (300 MHz, CDCl 3) d 7.54 (d, J = 8.1 Hz, 2H), 7.31 (d, J = 8.0 Hz, 2H), 2.97-2.90 (m, 1 H), 2.88-2.78 (m, 2H), 2.75 (m, 1 H), 2.47 (dd, J = 4.9, 2.7 Hz, 1 H), 1.98-1.73 (m, 2H).

A mixture of R4 (251 mg, 1.16 mmol), (4-mercapto-2-methylphenoxy) acetic acid ethyl ester A1c (394 mg, 1.74 mmol), and tetrabutylammonium fluoride (0.12 ml, 0.12 mmol, 1.0 M in THF) ) in THF (5 ml) was stirred at room temperature overnight and concentrated. The residue was purified by column chromatography (EtOAc / hexane: 1/5) to give 250 mg (49%) of R5; 1 H NMR (300 MHz, CDCl 3) d 7.51 (d, J = 8.0 Hz, 2H), 7.26 (d, J = 8.0 Hz, 2H), 7.23 (d, J = 2.1 Hz, 1 H), 7.18 (dd, J = 8.4, 2.3 Hz, 1 H), 6.61 (d, J = 8.4 Hz, 1 H), 4.62 (s, 2H), 4.26 (q, J = 7.1 Hz, 2H), 3.63-3.55 (m, 1 H), 3.01 (dd, J = 13.6, 3.4 Hz, 1H ), 2.91-2.81 (m, 1 H), 2.79-2.66 (m, 2H), 2.56 (brs, 1H), 2. 25 (s, 3H), 1.84-1.76 (m, 2H), 1.30 (t, J = 7.1 Hz, 3H); MS (ES) m / z: 465 (M + Na +). A solution of R5 (44 mg, 0.10 mmol) in THF (0.5 ml) was treated with NaH (4.4 mg, 0.11 mmol, 60% in mineral oil) for 30 min and Etl (86 mg, 0.55 mmol) was introduced. After overnight agitation, the mixture was diluted with water and extracted with Et2O. The extracts were dried, concentrated and purified by column chromatography (EtOAc / hexane) to give 18 mg (38%) of R6; 1 H NMR (300 MHz, CDCl 3) d 7.52 (d, J = 8.1 Hz, 2H), 7.27 (d, J = 8.1 Hz, 2H), 7.19 (d, J = 1.8 Hz, 1H), 7.11 (dd, J = 8.4, 2.2 Hz, 1 H), 6.59 (d, J = 8.4 Hz, 1 H), 4.61 (s, 2H), 4.26 (q, J = 7.1 Hz, 2H), 3.58-3.50 (m, 1 H), 3.40- 3.31 (m, 2H), 3.06 (dd) , J = 13.3, 4.8 Hz, 1 H), 2.85 (dd, J = 13.3, 7.3 Hz, 1H), 2. 79-2.64 (m, 2H), 2.25 (s, 3H), 2.06-1.96 (m, 1 H), 1.92-1.79 (m, 1H), 1.29 (t, J 7.1 Hz, 3H), 1.17 (t, J = 7.0 Hz, 3H); MS (ES) m / z: 493 (M + Na +).

Compound 38 Acid. { 4- [2-ethoxy-4- (4-trifluoromethyl-phenyl) -butylsulfanyl] -2-methyl-phenoxy} -acetic Following the general procedure 2 in Example A, compound 38 (93%) was obtained; 1 H NMR (300 MHz, CDCl 3) d 9.25 (brs, 1 H), 7.51 (d, J = 8.0 Hz, 2H), 7.25 (d, J = 8.0 Hz, 2H), 7.17 (d, J = 1.5 Hz , 1H), 7.09 (dd, J = 8.4, 2.0 Hz, 1 H), 6.58 (d, J = 8.5 Hz, 1 H), 4.56 (s, 2H), 3.61-3.51 (m, 1 H), 3.42 -3.31 (m, 2H), 3.05 (dd, J = 13.2, 4.9 Hz, 1 H), 2.84 (dd, J = 13.2, 7.1 Hz, 1 H), 2.80-2.63 (m, 2H), 2.20 (s) , 3H), 2.05-1.94 (m, 1 H), 1.92-1.81 (m, 1 H), 1.16 (t, J = 7.0 Hz, 3H); MS (ES) m / z: 441 (M-H +).

R7 Ethyl ester of acid. { 2-methyl-4- [2-methylsulfanylmethroxy-4- (4-trifluoromethyl-phenyl) -butylsulfanyl] -phenoxy} Acetic acid A mixture of R5 (370 mg, 0.837 mmol) in Ac20 (2.5 ml) and DMSO (4 ml) was stirred at room temperature for 24 h, diluted with water, and extracted with Et2O. The extracts were dried, concentrated and purified by column chromatography to give 51 mg (12%) of the title compound R7; 1 H NMR (300 MHz, CDCl 3) d 7.52 (d, J = 8.1 Hz, 2 H), 7.27 (d, J = 8.2 Hz, 2 H), 7.22 (d, J = 1.6 Hz, 1 H), 7.14 (dd, J = 8.4, 2.1 Hz, 1 H), 6.61 (d, J = 8.5 Hz, 1 H), 4.67-4.58 (m, 2H), 4.61 (s, 2H), 4.25 (q, J = 7.1 Hz, 2H) , 3.78 (m, 1H), 3.10 (dd, J = 13.4, 4.9 Hz, 1 H), 2.91 (dd, J = 13.4, 6.9 Hz, 1H), 2.84-2.64 (m, 2H), 2.26 (s, 3H), 2.17 (s, 3H), 2.09-1.86 (m, 2H), 1.29 (t, J = 7.1 Hz, 3 H); MS (ES) m / z: 525 (M + Na +).

Compound 39 Acid. { 2-Methyl-4- [2-methylsulfanylmethoxy-4- (4-trifluoromethyl-phenyl) -butylsufanyl] -phenoxy} -acetic Following the general procedure 2 in Example A, compound 39 (90%) was obtained; 1 H NMR (300 MHz, CDCl 3) d 7.48 (d, J = 7.9 Hz, 2 H), 7.23 (d, J = 7.8 Hz, 2 H), 7.04 (m, 2 H), 6.46 (m, 1 H), 4.57 ( s, 2H), 4.53 (s, 2H), 3.76 (m, 1H), 2.98 (m, 1 H), 2.88 (m, 1 H), 2.80-2.63 (m, 2H), 2.11 (s, 3H) , 2.06 (s, 3H), 1.89 (m, 2H); MS (ES) m / z: 473 (M-H +).

EXAMPLE S Compound 42 Acid. { 4- [2-efoxy-4- (4-ylfluoromethyl-phenyl) -but-3-enylsulfanyl] -2-methyl-phenoxy} - acetic SCHEME S1 S1b 1 - (4-Benzyloxy-but-1-enyl) -4-trifluoromethyl-benzene 4- (4-Trifluoromethyl-phenyl) -but-3-en-1-ol 81%, S1d S1a Ethyl ester of acid. { 2-methyl-4- [4- [4-trifluoromethyl-Compound 40 phenyl) -but-3-enylsulfapyl] -phenoxy-acetic acid A mixture of (3-benzyloxypropyl) triphenyl-phosphono S1a bromide (614 mg, 1.25 mmol), 4-trifluoromethylbenzaldehyde (174 mg, 1.00 mmol), and K2CO3 (173 mg, 1.25 mmol) in isopropanol (1 mL) it was refluxed for 5 hr and concentrated. The residue was partitioned between water and Et2O. The organic phase was dried, concentrated, and subjected to column chromatography (1% EtOAc in hexane) to give 260 mg (85%) of S1b as a mixture of trans and cis in the ratio of 3: 1. Trans: 1 H NMR (300 MHz, CDCl 3) d 7.53 (d, J = 8.2 Hz, 2 H), 7.42 (d, J = 8.2 Hz, 2 H), 7.35-7.27 (m, 5 H), 6.49 (d, J = 16.0 Hz, 1 H), 6.35 (dt, J = 15.9, 6.7 Hz, 1 H), 4.55 (s, 2H), 3.61 (t, J = 6.5 Hz, 2H), 2.55 (m, 2H).

A solution of S1b (50 mg, 0.16 mmol) in Ac2O (0.8 ml) at 0 ° C was treated with trimethylsilyl trifluoromethanesulfonate (142 mg, 0.640 mmol) for 15 min, and quenched with saturated NaHCO3. The mixture was extracted with Et2O and the exfracti were dried, concentrated and subjected to column chromatography to give acetates as a mixture of trans and cis products. A solution of the trans and cis acetates (390 mg, 1.51 mmol) in THF (10 mL) was treated with 1.0 M LiOH (3 mL, 3.0 mmol) at room temperature overnight and extracted with Et20. The extracts were dried, concentrated and subjected to column chromatography to give S1c as a mixture of trans alcohols and cls. Trans: 1 H NMR (300 MHz, CDCl 3) d 7.55 (d, J = 8.2 Hz, 2 H), 7.44 (d, J = 8.2 Hz, 2 H), 6.53 (d, J = 15.9 Hz, 1 H), 6.33 ( dt, J = 15.9, 7.1 Hz, 1 H), 3.79 (t, J = 6.3 Hz, 2H), 2.54-2.49 (m, 2H); MS (ES) m / z: 239 (M + Na +). Following general procedure 1 in Example A, S1d (81%) was obtained as a pure compound and a mixture of trans and cis. Trans: 1 H NMR (300 MHz, CDCl 3) d 7.53 (d, J = 8.2 Hz, 2H), 7. 39 (d, J = 8.2 Hz, 2H), 7.24 (s, 1 H), 7.20 (dd, J = 8.4, 2.0 Hz, 1H), 6.63 (d, J = 8.4 Hz, 1H), 6.43 (d, J = 16.0 Hz, 1H), 6.35-6.25 (m, 1H), 4.61 (s, 2H), 4.26 (q, J = 7.1 Hz, 2H), 2.96 (t, J = 7.3 Hz, 2H), 2.51 (q, J = 7.0 Hz, 2H), 2.26 (s, 3H), 1.29 (t, J = 7.1 Hz, 3H); MS (ES) m / z: 447 (M + Na +).

Analysis calculated for C 22 H 23 F 3 O 3 S: C, 62.26; H, 5.46. Found: C, 62.43; H, 5.33. Following general procedure 2 in Example A, S1e Compound 40 (92%) was obtained; 1 H NMR (300 MHz, CDCl 3) d 10.78 (brs, 1 H), 7.53 (d, J = 8.2 Hz, 2H), 7.39 (d, J = 8.1 Hz, 2H), 7.25 (d, J = 2.5 Hz, 1 H), 7.21 (dd, J = 8.4, 2.0 Hz, 1 H), 6.66 (d, J = 8.4 Hz, 1H), 6.43 (d, J = 16.0 Hz, 1H), 6.35-6.25 (m, 1H), 4.67 (s, 2H), 2.97 (m, 2H), 2.52 (q, J = 6.9 Hz, 2H ), 2.25 (s, 3H); MS (ES) m / z: 419 (M + Na +).

SCHEME S2 S2a, 70% S2b, 75% 3- (4-Trifluoromethyl-phenyl) -pro- enal 2- [2- (4-trifluoromethyl-phenyl) vinyl] -oxanne Ethyl ester of acid. { 4- [2-hydroxy-4- (4-trifluoromethyl-phenyl) -but-3-epylsu-phenyl] -2-methy1-phenoxy} -acetic S2d, 91% Compound 41 A mixture of 4-trifluoromethylbenzaldehyde (174 mg, 1.00 mmol) and (triphenylphosphoranylidene) acetaldehyde (396 mg, 1.30 mmol) in CH2Cl2 (6 mL) was stirred at room temperature for 20 hr, concentrated and subjected to column chromatography (EtOAc / hexane: 1/8) to give 182 mg (70%) of S2a; 1 H NMR (400 MHz, CDCl 3) d 9.76 (d, J = 7.5 Hz, 1H), 7.69 (m, 4H), 7.51 (d, J = 16.0 Hz, 1 H), 6.78 (dd, J = 16.0, 7.5 Hz, 1 H); MS (ES) m / z: 223 (M + Na +). To a solution of S2a (425 mg, 2.13 mmol) in THF (6 mL) at -78 ° C was added CH2I2 (627 mg, 2.34 mmol) followed by 1.5 M MeLi (1.56 mL, 2.34 mmol, in complex with LiBr in Et2O). The mixture was allowed to warm gradually to room temperature, quenched with saturated NH4CI and extracted with Et2O. The extracts were dried, concentrated and subjected to column chromatography (CH2Cl2 / hexane: 2/3) to provide 341 mg (75%) of S2b; 1 H NMR (400 MHz, CDCl 3) d 7.58 (d, J = 8.2 Hz, 2 H), 7.47 (d, J = 8.2 Hz, 2 H), 6.84 (d, J = 16.0 Hz, 1 H), 5.99 (dd) , J = 16.0, 7.8 Hz, 1H), 3.55-3.52 (m, 1 H), 3.08 (dd, J = 5.1, 4.3 Hz, 1 H), 2.79 (dd, J = 5.2, 2.6 Hz, 1 H); MS (ES) m / z: 213 (M-H +). Following the general procedure 3 in example E was obtained S2c; , 1 H NMR (400 MHz, CDCl 3) d 7.55 (d, J = 8.2 Hz, 2H), 7.41 (d, J = 8.1 Hz, 2H), 7.29 (s, 1 H), 7.26-7.24 (m, 1 H), 6.68-6.62 (m, 2H), 6.24 (dd, J = 16. 0, 5.8 Hz, 1 H), 4.62 (s, 2H), 4.32 (m, 1 H), 4.27 (q, J = 7.1 Hz, 2H), 3.13 (dd, J = 13.7, 3.9 Hz, 1 H) , 2.92 (dd, J = 13.7, 8.5 Hz, 1 H), 2.75 (brs, 1 H), 2.26 (s, 3H), 1.30 (t, J = 7.1 Hz, 3H); MS (ES) m / z: 463 (M + Na +). Following the general procedure 2 in Example A, S2d Compound 41 (91%) was obtained; 1 H NMR (300 MHz, CDCl 3) d 7.54 (d, J = 8.2 Hz, 2H), 7.40 (d, J = 8.2 Hz, 2H), 7.28-7.25 (m, 2H), 6.68-6.63 (m, 2H), 6.24 (dd, J = 16.0, 5.7 Hz, 1 H), 4.67 (s, 2H), 4.34 (m , 1 H), 3.14 (m, 1 H), 2.99-2.95 (m, 1 H), 2.24 (s, 3 H); MS (ES) m / z: 411 (M-H +).

Ethyl ester of acid. { 4- [2-ethoxy-4- (4-ylfluoromethyl-phenyl] -but-3-en] sulphonyl] -2- mephyl-phenoxy-acetic acid Following general procedure 4 in Example L, S3 (35%) was obtained; 1 H NMR (300 MHz, CDCl 3) d 7.56 (d, J = 8.2 Hz, 2H), 7.42 (d, J = 8.2 Hz, 2H), 7.23 (s, 1 H), 7.19 (dd, J = 8.4, 2.1 Hz, 1H), 6.61 (s, 1 H), 6.57 (d, J = 8.9 Hz, 1 H), 6.17 (dd, J = 16.0, 7.3 Hz, 1H), 4.60 (s, 2H), 4.26 ( q, J = 7.1 Hz, 2H), 3.99 (q, J = 6.7 Hz, 1 H), 3.60-3.52 (m, 1 H), 3.48-3.38 (m, 1H), 3.16 (dd, J = 13.3, 6.3 Hz, 1H), 2.99 (dd, J = 13.3, 6.5 Hz, 1 H), 2.23 (s, 3H), 1.30 (t, J = 7.1 Hz, 3H), 1.21 (t, J = 7.0 Hz, 3H ); MS (ES) m / z: 491 (M + Na +).

Compound 42 Acid. { 4- [2-ethoxy-4- (4-trifluoromethyl-phenyl) -but-3-enylsulfanyl] -2-methy1-phenoxy} - acéíico Following general procedure 2 in Example A, compound 42 (93%) was obtained; 1 H NMR (300 MHz, CDCl 3) d 7.56 (d, J = 8.1 Hz, 2H), 7.42 (d, J = 8.1 Hz, 2H), 7.24 (s, 1 H), 7.21 (d, J = 8.5 Hz, 1 H), 6.64-6.56 (m, 2H), 6.21- 6.09 (dd, J = 16.0, 7.3 Hz, 1 H), 4.65 (s, 2H), 4.00 (q, J = 6.6 Hz, 1 H), 3.61-3.53 (m, 1 H), 3.49-3.39 (m, 1 H), 3.16-2.97 (m, 2H), 2.22 (s, 3H), 1.21 (t, J = 7.0 Hz, 3 H); MS (ES) m / z: 463 (M + Na +).

EXAMPLE T SCHEME T M2 Compound 43 Following general procedure 2 in example A and using M2, compound 43 (90%) was obtained; [α] D + 54.5 ° (c 1.0, MeOH); 1 H NMR (300 MHz, CD3OD) d 7.54 (d, J = 8.6 Hz, 2H), 7.23 (m, 2H), 6.99 (d, J = 8.6 Hz, 2H), 6.69 (d, J = 8.2 Hz, 1 H), 4.62 (s, 2H), 3.96-4.12 (m, 3H), 3.13 (dd, J = 6.5, 13.8 Hz, 1H), 3.02 (dd, J = 5.8, 13.8 Hz, 1H), 2.18 ( s, 3H); MS (ES) m / z: 439 (M + Na +).

Analysis calculated for C19H.19F3O5S: C, 54.80; H, 4.60. Found: C, 54.94; H, 4.51. EXAMPLE U U SCHEME 93%, Compound 45 U2 U2 A mixture of methyl (4-hydroxy-2-methyl-phenoxy) -acetic acid U1 ester (196.2 mg, 1.0 mmol), which can be easily made in accordance with, for example, Sznaidman et al. al., Bioorganic & Medicinal Chemistry Letters 13 (2003) 1517-1521, L1 (327.3 mg, 1.5 mmol), and Cs2CO3 (488.8 mg, 1.5 mmol) in acetoniiril (4 ml) was refluxed for 4 hr. Water and ether were added, the organic layer was separated, and the aqueous layer was extracted with ether. The combined organic extracts were combined, dried, concentrated and subjected to column chromatography (EtOAc / hexane: 1/2) to give 327.4 mg (79%) of U2; 1 H NMR (300 MHz, CDCl 3) d 7.55 (d, J = 8.8 Hz, 2 H), 6.99 (d, J = 8.8 Hz, 2 H), 6.77 (s, 1 H), 6.67 (m, 2 H), 4.60 ( s, 2H), 4.37 (m, 1H), 4.18 (m, 2H), 4.10 (m, 2H), 3.79 (s, 3H), 2.56 (br. s, 1 H), 2.27 (s, 3 H); MS (ES) m / z: 437 (M + Na +).

Replacing 01 with U2 and following the procedure for the preparation of 02 in Example O gave U3 (51%); 1 H NMR (300 MHz, CDCl 3) d 7.54 (d, J = 8.7 Hz, 2H), 6.99 (d, J = 8.7 Hz, 2H), 6.76 (s, 1 H), 6.66 (m, 2H), 4.59 ( s, 2H), 4.23 (m, 1H), 4.15 (m, 1 H), 4.09 (m, 2H), 4.01 (m, 1 H), 3.79 (s, 3H), 3.75 (q, J = 6.9 Hz , 2H), 2.26 (s, 3H), 1.25 (t, J = 7.0 Hz, 3H); MS (ES) m / z: 465 (M + Na +).

Compound 44 Following general procedure 2 in example A, compound 44 (92%) was obtained; 1 H NMR (300 MHz, CDCl 3) d 7.54 (d, J = 8.7 Hz, 2H), 6.98 (d, J = 8.7 Hz, 2H), 6.77 (s, 1 H), 6.68 (m, 2H), 4.61 (s, 2H), 4.23 (m, 1 H), 4.17 (m, 1H), 4.09 (m, 2H), 4.01 (m, 1H), 3.79 (s, 3H), 3.76 (q, J = 7.0 Hz , 2H), 2.26 (s, 3H), 1.25 (t, J = 7.0 Hz, 3H); MS (ES) m / z: 427 (M-H +).

Compound 45 Following general procedure 2 in example A, hydrolysis of U2 gave compound 45 (93%); 1 H NMR (300 MHz, CD 3 OD) d 7.57 (d, J = 8.7 Hz, 2 H), 7.10 (d, J = 8.6 Hz, 2 H), 6.79 (s, 1 H), 6.72 (m, 2 H), 4.59 (s) , 2H), 4.26 (m, 1 H), 4.11-4.21 (m, 2H), 4.06 (m, 2H), 2.22 (s, 3 H); MS (ES) m / z: 423 (M + Na +).

D. Formulation and administration The compounds herein are PPAR delta agonists and are therefore useful in the treatment or inhibition of the progression of conditions measured by PPAR delta, such as diabetes, cardiovascular diseases, metabolic syndrome X, hypercholesterolemia, hypo -HDL- cholesterolemia, hyper-LDL-cholesterolemia, dyslipidemia, atherosclerosis, obesity and complications thereof. For example, complications of diabetes include conditions such as neuropathy, nephropathy, and retinopathy. The invention relates to a method for treating a subject with a disease mediated by PPAR delta, said method comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising a compound of the invention. The invention also provides a method for treating or inhibiting the progression of diabetes or impaired glucose tolerance in a subject, wherein the method comprises administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising a compound of the invention. The compounds of the present invention can be formulated into various pharmaceutical forms for administration purposes. To prepare these pharmaceutical compositions, an effective amount of a particular compound, in the form of basic salt or addition acid, as the active ingredient is intimately mixed with a pharmaceutically acceptable carrier. A vehicle can take a wide variety of forms depending on the form of preparation desired for administration. These pharmaceutical compositions are desirably in the form of a unit dose suitable, preferably, for oral administration or parenteral injection. For example, when preparing the compositions in oral dosage form, any of the usual pharmaceutical media can be used. These include water, glycols, oils, alcohols and the like in the case of oral liquid preparations such as suspensions, syrups, elixirs and solutions.; or solid carriers such as starches, sugars, kaolin, lubricants, binders, disintegrating agents and the like in the case of powders, pills, capsules and tablets. In view of their ease of administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are generally used. For parenteral compositions, the carrier will generally comprise sterile water, at least in large part, although other ingredients may be included, for example, to aid solubility. For example, injectable solutions may be prepared in which the vehicle comprises saline solution, glucose solution or a mixture of saline and glucose solution. Injectable suspensions may also be prepared in which case suitable liquid carriers, suspending agents and the like may be used. In compositions suitable for percutaneous administration, the carrier optionally comprises a penetration enhancing agent and / or a suitable wetting agent, optionally combined with suitable additives of any nature in minor proportions, said additives do not cause a significant deleterious effect to the skin. Said additives may facilitate administration to the skin and / or may help to prepare the desired compositions. These compositions can be administered in various ways, e.g., as a transdermal patch, as a deposition, as an ointment. The acid addition salts of the compounds of the formula 1, due to their increased water solubility over the corresponding base form, are more suitable in the preparation of aqueous compositions. It is especially advantageous to formulate the aforementioned pharmaceutical compositions in unit dosage form for ease of administration and uniformity of dosage. The unit dosage form as used in the specification herein refers to physically discrete units suitable as unit doses, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. Examples of such unit dosage forms are tablets (including marked or scored tablets), capsules, pills, powder packets, wafers, injectable solutions or suspensions, teaspoons, tablespoons and the like, and segregated multiples thereof.

The pharmaceutically acceptable acid addition salts include the therapeutically active, non-toxic addition acid addition salts of the described compounds. The latter can be conveniently obtained by treating the base form with an appropriate acid. Suitable acids comprise, for example, inorganic acids such as hydrohalic acids, e.g., hydrochloric or hydrobromic acid; sulfuric acid; nitric acid; phosphoric acids and the like; or organic acids such as, for example, acetic, propanoic, hydroxyacetic, lactic, pyruvic, oxalic, malonic, succinic, maleic, fumaric, malic, tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclic, salicylic, p-aminosalicylic, palmoic and similar acids. The term addition salt also comprises the solvates that the described compounds, as well as the salts thereof, are capable of forming. Said solvates are, for example, hydrates, alcoholates and the like. On the other hand, the salt form can be converted by alkali treatment with the free base form. The stereoisomeric forms define all possible isomeric forms that the compounds of the formula (I) may possess. Unless otherwise mentioned or indicated, the chemical designation of the compounds denotes the mixture of all possible stereochemically isomeric forms, said mixtures containing all the diastereomers and enantiomers of the basic molecular structure. Very particularly, stereogénicos centers can have the configuration (R) or (S); substituents on saturated bivalent cyclic radicals can have either the cls or trans configuration. The invention encompasses stereochemically isomeric forms including diastereomers, as well as mixtures thereof in any proportion of the disclosed compounds. The described compounds may also exist in their tautomeric forms. These forms, although not explicitly indicated in the preceding and following formulas, are intended to be included within the scope of this present invention. Experts in the treatment of disorders or conditions mediated by PPAR delta could easily determine the effective daily amount from the test results presented below and other information. In general, it is contemplated that a therapeutically effective dose would be from 0.001 mg / kg to 5 mg / kg of body weight, most preferably from 0.01 mg / kg to 0.5 mg / kg of body weight. It may be appropriate to administer the therapeutically effective dose as two, three, four or more sub-doses at appropriate intervals throughout the day. Said sub-doses may be formulated as unit dosage forms, for example, containing 0.05 mg to 250 mg or 750 mg, and in particular 0.5 to 50 mg of active ingredient per unit dosage form. Examples include dosage forms of 2 mg, 4 mg, 7 mg, 10 mg, 15 mg, 25 mg and 35 mg. The compounds of the invention can also be prepared in release formulations over time or subcutaneously or from transdermal patches. The described compound can also be formulated as a spray or other topical or inhalable formulations.

The exact dose and frequency of administration depend on the particular compound of formula (I) used, the particular condition being treated, the severity of the condition being brought, the age, weight and general physical condition of the particular patient as well as the another medication that the patient can take, as is well known to those skilled in the art. Furthermore, it is evident that said effective daily amount may be reduced or increased depending on the response of the treated patient and / or depending on the evaluation of the prescribing physician of the compounds of the present invention. The ranges of the effective daily amount mentioned herein are therefore only as a guide. The following section includes detailed information related to the use of the compounds and compositions described.

E. Use The compounds of the present invention are pharmaceutically active, for example, as PPAR delta agonists. In accordance with one aspect of the invention, the compounds are preferably selective PPAR delta agonists, which have an activity index (e.g., PPAR delta potency over PPAR alpha / gamma potency) of 10 or more, and preferably 15, 25, 30, 50 or 100 or more. According to the invention, the compounds and compositions described are useful for the relief of symptoms associated with, the treatment, and the prevention, of the following conditions and diseases: phase I hyperlipidemia, predinic hyperlipidemia, phase II hyperlipidemia, hypertension, CAD (coronary artery disease), coronary heart disease and hypertriglyceridemia. Preferred compounds of the invention are useful for reducing serum levels of low density lipoproteins (LDL), intermediate density lipoprotein (IDL), and / or small density LDL and other atherogenic molecules, or molecules that cause atherosclerotic complications. , thus reducing cardiovascular complications. Preferred compounds are also useful for raising serum levels of high density lipoproteins (HDL) to reduce serum levels of triglycerides, LDL, and / or free fatty acids. It is also desirable to decrease fasting plasma glucose (FPG) / HbA1c. The invention also relates to pharmaceutical compositions including, without limitation, one or more of the disclosed compounds, and a pharmaceutically acceptable carrier or excipient. 1. Doses Those skilled in the art will be able to determine, in accordance with known methods, the appropriate dose for a patient, taking into account factors such as age, weight, general health, the type of symptoms requiring treatment, and the presence of other medications. . In general, an effective amount will be between 0.1 and 1000 mg / kg per day, preferably between 1 and 300 mg / kg of body weight, and daily doses will be between 10 and 5000 mg for an adult subject of normal weight. Capsules, tablets or other formulations (such as liquids and film-coated tablets) can be between 5 and 200 mg, such as 10, 15, 25, 35, 50 mg, 60 mg and 100 mg and can be administered in accordance with described methods. 2. Formulations Unit dosage forms include tablets, capsules, pills, powders, granules, aqueous and non-aqueous oral solutions and suspensions, and parenteral solutions packaged in containers adapted for subdivision into individual doses. Unit dosage forms can also be adapted for various methods of administration, including controlled release formulations, such as subcutaneous implants. Methods of administration include oral, rectal, parenteral (intravenous, intramuscular, subcutaneous), intracisternal, iniravaginal, intraperiponeal, intravesical, local (drops, powders, pomads, gels or cream), and by inhalation (a buccal or nasal spray). Parenteral formulations include solutions, dispersions, suspensions, aqueous or non-aqueous pharmaceutically acceptable emulsions, and sterile powders for the preparation thereof. Examples of vehicles include water, ethanol, polyols (propylene glycol, polyethylene glycol), vegetable oils, and injectable organic esters such as ethyl oleate. The fluidity can be maintained by the use of a coating such as lecltin, an oxidizing agent, or by manipulating the appropriate particle size. Vehicles for solid dosage forms include (a) fillers or extenders, (b) binders, (c) humectants, (d) disintegrating agents, (e) solution retarders, (f) absorption accelerators, (g) adsorbents, (h) lubricants, (i) pH regulating agents and (j) propellants. The compositions may also contain adjuvants such as preservatives, wetting agents, emulsifiers and delivery agents; antimicrobial agents such as parabens, chlorobutanol, phenol and sorbic acid; sotonic agents such as a sugar or sodium chloride; absorption enhancing agents such as aluminum monostearate and gelatin; and absorption enhancing agents. 3. Combination Therapy The compounds of the present invention can be used in combination with other pharmaceutically active agents. These agents include lipid reducing agents, and blood pressure lowering agents such as statin drugs and fibrates. Methods for determining effective doses for therapeutic and prophylactic purposes for the pharmaceutical compositions or combinations of drugs described, whether or not formulated in the same composition, are known in the art. For therapeutic purposes, the term "co-effective amount", as used herein, means that amount of each active compound or pharmaceutical agent, alone or in combination, that induces the biological or medicinal response in a tissue, animal or human system that is being sought by a researcher, veterinarian, doctor or other clinician, which includes relief of the symptoms of the disease or disorder being treated. For prophylactic purposes (i.e., inhibition of delinquency or progression of a disorder), the term "co-effective amount" refers to that amount of each active compound or pharmaceutical agent, alone or in combination, that treats or inhibits in a subject the onset or progression of a disorder that is sought by a researcher, veterinarian, doctor or other clinician. Therefore, the present invention provides combinations of two or more drugs wherein, for example, (a) each drug is administered in an independently therapeutically or prophylactically effective amount; (b) at least one drug in the combination is administered in an amount that is sub-therapeutic or sub-prophylactic if administered alone, but is therapeutic or prophylactic when administered in combination with the second drug or additional drugs according to the invention; or (c) both (or more) drugs are administered in an amount that is subtherapeutic or subprophylactic if administered alone, but are therapeutic or prophylactic when administered together. Antidiabetic agents include thiazolidinedione insulin sensitizers and non-fiazolidinedione, which decrease peripheral resistance to insulin by increasing the effects of insulin on target organs and tissues. It is known that some of the following agents bind and activate the nuclear receptor receptor, peroxisome-gamma proliferator activated receptor (PPARy), which increases the transcription of specific insulin-responsive genes. Examples of PPAR-gamma agonists are thiazolidinediones such as: (1) rosiglltazone (2,4-thiazolidinedione, 5 - ((4- (2- (methyl-2-pyridinylammon) ethoxy) phenyl) methyl) -, ( Z) -2-butenedioate (1: 1) or 5 - ((4- (2- (mephyl-2-pyridinylammon) ethoxy) phenyl) methyl) -2,4-thiazolidinodone , known as AVANDIA; also known as BRL 49653, BRL 49653C, BRL 49653c, SB 210232, or rosiglitazone maleate); (2) pioglitazone (2,4-thiazolidinedione, 5 - ((4- (2- (5-ethyl-2-pyridinyl) ethoxy) phenyl) methyl) -, monochlorhydrate, (+ -) - or 5- ((4- (2- (5-ethyl-2-pyridyl) -ioxy) -phenyl) -methyl) -2,4-yiazolidinedione, known as ACTOS, ZACTOS, or GLUSTIN; also known as AD 4833, U 72107, U 72107A, U 72107E, pioglitazone hydrochloride (USAN)); (3) troglitazone (5 - ((4 - ((3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl) methoxy) phenyl) methyl) -2,4-thiazolidinedione, known as NOSCAL, REZULIN, ROMOZIN or PRELAY, also known as Cl 991, CS 045, GR 92132, GR 92132X); (4) saglitazone ((+) - 5 - [[6 - [(2-fluorophenyl) methoxy] -2-naphthalenyl] methyl] -2,4-thiazolidinedione or 5 - ((6 - ((2-fluorophenyl)) methoxy) -2-naphthalenyl) metyl-2,4-thiazolynedione or 5- (6- (2-fluorobenzyloxy) naphthalen-2-ylmethyl) fiazolidino-2,4-dione, also known as MCC-555 or neoglitazone); (5) 5-BTZD. In addition, non-fiazolidinediones that act as insulin sensitizing agents include, but are not limited to: (1) JT-501 (JTT 501, PNU-1827, PNU-716-MET-0096, or PNU 182716: isoxazolidin-3, 5-dlone, 4 - ((4- (2-phenyl-5-methyl) -1,3-oxazolyl) ethylphenyl- 4) methyl-); (2) KRP-297 (5- (2,4-dioxothiazolidin-5-ylmethyl) -2-methoxy-N- (4- (trifluoromethyl) benzyl) benzamide or 5 - ((2,4-dioxo-5-thiazolidinyl) ) methyl) -2-mefoxi-N- ((4- (fr'fluoromethyl) phenyl) methyl) benzamide); and (3) Fargliazad (L-tyrosine, N- (2-benzoylphenyl) -o- (2- (5-meityl-2-phenyl-4-oxazolyl) ethyl) - or N- (2-benzoylphenol) - O- (2- (5-methyl-2-phenyl-4-oxazolyl) ethyl) -L-tyrosine, or GW2570 or GI-262570). Other agents have also been shown to have PPAR modulatory activity such as PPAR gamma agonist activity, gamma SPPAR, and / or PPAR delta / gamma. Some examples are listed below: (1) AD 5075; (2) R 119702 ((+ -) - 5- (4- (5-Methoxy-1 H -benzimidazol-2-ylmethoxy) benzyl) thiazolin-2,4-dione hydrochloride, or Cl 1037 or CS 011); (3) CLX-0940 (Peroxisome proliferator-activated receptor agonist / peroxisome gamma prollfector-activated receptor agonist); (4) LR-90 acid (2,5,5-tris (4-chlorophenyl) -1,3-dioxane-2-carboxylic, PPARdelta /? Agonist); (5) Tularik (PPAR agonist?); (6) CLX-0921 (PPAR agonist?); (7) CGP-52608 (PPAR agonist); (8) GW-409890 (PPAR agonist); (9) GW-7845 (PPAR agonist); (10) L-764406 (PPAR agonist); (11) LG-101280 (PPAR agonist); (12) LM-4156 (PPAR agonist); (13) Risarestat (CT-112); (14) YM 440 (PPAR agonisfa); (15) AR-H049020 (PPAR agonist); (16) GW 0072 acid (4- (4 - ((2S, 5S) -5- (2- (bis (phenylmethyl) amino) -2-oxo-yl) -2-heptyl-4-oxo-3-yiazolidin L) butyl) benzoic); (17) GW 409544 (GW-544 or GW-409544); (18) NN 2344 (DRF 2593); (19) NN 622 (DRF 2725); (20) AR-H039242 (AZ-242); (21) GW 9820 (fibrate); (22) GW 1929 (N- (2-benzoylphenyl) -0- (2- (methyl-2-pyridinylamino) ethyl) -L-tyrosine, known as GW 2331, PPAR alpha agonist /?); (23) SB 219994 ((S) -4- (2- (2-benzoxazolylmethylamino) ethoxy) -alpha- (2,2,2-trifluoroethoxy) benzenepropanoic acid or 3- (4- (2- (N- ( 2-benzoxazoli!) - N-methylamino) ethoxy) phenyl) -2 (S) - (2,2,2-trifluoroethoxy) propionic acid or benzenepropanoic acid, 4- (2- (2-benzoxazolylmethylamino) ethoxy) -alpha- ( 2,2,2-trifluoroethoxy) -, (alphaS) -, PPARalpha /? Agonist); (24) L-796449 (PPARalpha /? Agonist); (25) Fenofibrate (Propanoic acid, 2- [4- (4-chlorobenzoyl) phenoxy] -2-methyl-, 1-methyl methyl ester, known as TRICOR, LIPCOR, LIPANTIL, LIPIDIL MICRO PPAR alpha agonist); (26) GW-9578 (PPAR alpha agonist); (27) GW-2433 (PPAR alpha agonist /?); (28) GW-0207 (PPAR agnist?); (29) LG-100641 (PPAR agnist?); (30) LY-300512 (PPAR agnist?); (31) NID525-209 (NID-525); (32) VDO-52 (VDO-52); (33) LG 100754 (peroxisome proliferator activated receptor agonist); (34) LY-510929 (peroxisome prollfector-activated receptor agonist); (35) bexarotene (4- (1- (3,5,5,8,8-pentamefyl-5,6,7,8-tetrahydro-2-naphthalene) ethenyl) benzoic acid, known as TARGRETIN, TARGRETYN, TARGREXIN; also known as LGD 1069, LG 100069, LG 1069, LDG 1069, LG 69, RO 264455); and (36) GW-1536 (PPAR alpha /? agonist). (B) Other insulin sensitizing agents include, but are not limited to: (1) INS-1 (D-chiro inositol or D-1, 2,3,4,5,6-hexahydroxycyclohexane); (2) protein inhibitors tyrosine phosphatase 1 B (PTP-1 B); (3) cinase-3 glycogen synthase inhibitors (GSK3); (4) beta 3 adrenoceptor agonists such as ZD 2079 ((R) -N- (2- (4- (carboxymethyl) phenoxy) ethyl) -N- (2-hydroxy-2-phenethyl) ammonium chloride, also known as ICI D 2079) or AZ 40140; (5) glycogen phosphorylase inhibitors; (6) fructose-1, 6-bisphosphatase inhibitors; (7) chromic picollnation, vanadyl sulfate (vanadium oxysulfate); (8) KP 102 (organo-vanadium compound); (9) chromic polynicotinate; (10) potassium channel agonist NN 414; (11) YM 268 (5,5'-methylene-bis (1,4-phenylene) bismethylenebis- (thiazolidin-2,4-dione); (12) TS 971; (13) T 174 (( + -) - 5- (2,4-dioxothiazolidin-5-methylmethyl) -2- (2-naphthylmethyl) benzoxazole) (14) SDZ PGU 693 ((+) - trans-2 (S - (( 4-chlorophenoxy) methyl) -7alpha- (3,4-dichlorophenol) terahydrohydrolo (2,1-b) oxazole-5 (6H) -one); (15) S 15261 ((-) - 4) acid - (2 - ((2-mefoxi-2- (3- (trifluoromethyl) phenyl) ethyl) amino) (2 - ((9H-fluoren-9-ylacelyl) amino) ethyl) benzoic ester eylyl) (16) AZM 134 (Alizyme); (17) ARIAD; (18) R 102380; (19) PNU 140975 (1- (hydrazinoiminomethyl) hydrazino) acetic acid; (20) PNU 106817 acid (2- (hydanziminomethyl) hydraz No) acetic; (21) NC 2100 (5 - ((7- (phenylmethioxy) -3-quinolinyl) methyl) -2,4-thiazolidinodlone; (22) MXC 3255; (23) MBX 102; (24) ALT 4037; (25) AM 454; (26) JTP 20993 (2- (4- (2- (5-Methyl-2-phenyl-4-oxazolyl) ethoxy) benzyl) -malonic dimethyl diester) (27) Dexllpotam acid (5 (R) - (1, 2-d¡fiolan-3-yl) pentanoic, also known as acid (R) -alpha lipoic acid or (R) -thioctic acid); (28) BM 170744 acid (2,2-dichloro-12- (p-chlorophenyl) dodecanol); (29) BM 152054 (5- (4- (2- (5-methyl-2- (2-thienyl) oxazol-4-yl) ethoxy) benzothien-7-ylmethyl) thiazolidino-2,4-dione); (30) BM 131258 (5- (4- (2- (5-methyl-2-phenyloxazol-4-yl) ethoxy) benzothien-7-ylmethyl) -iazolidino-2,4-dione); (31) CRE 16336 (EML 16336); (32) HQL 975 (3- (4- (2- (5-meityl-2-phenylimoxazol-4-l) ethoxy) phenyl) -2 (S) - (propylamino) propionic acid); (33) DRF 2189 (5 - ((4- (2- (1-indolyl) ethoxy) phenyl) methyl) thiazole-2,4-dione); (34) DRF 554158; (35) DRF-NPCC; (36) CLX 0100, CLX 0101, CLX 0900 or CLX 0901; (37) Inhibitors of IkappaB kinase (IKK B) (38) Inhibitors of mitogen-activated protein (MAPK) stimulators of p38 MAPK (39) phosphatidyl-inositido triphosphate (40) Inhibitors of insulin receptor recycling (41) modulators of glucose transporter 4 (42) antagonists of TNF-α (43) antigen antagonisms of plasma cell differentiation -1 (PC-1) (44) Inhibitors of lipid binding protein of adipocytes (ALBP / aP2) (45) ) phosphoglycans (46) Galparan; (47) Receptron; (48) islet cell maturation factor; (49) insulin-enhancing factor (IPF or insulin-1-enhancing factor); (50) somatomedin C coupled with binding protein (also known as IGF-BP3, IGF-BP3, SomatoKine); (51) Diab II (known as V-411) or Glucanine, produced by Biotech Holdings Ltd. or Volque Pharmaceutical; (52) Glucose-6 phosphatase inhibitors; (53) fatty acid glucose transport protein, (54) glucocorticoid receptor antagonism; and (55) glutamine modulators: fructose-6-phosphate amidotransferase (GFAT). (C) Biguanides, which reduce the production of glucose in the liver and increase the absorption of glucose. Some examples include metformin such as: (1) 1,1-dimethylbiguanide (e.g., Metformin-DepoMed, Metformin-Biovail Corporation, or METFORMIN GR (metformin gastric retention polymer)); and (2) metformin hydrochloride (diamide N, N-dimethylimidodicarbonmidine monohydrochloride, also known as LA 6023, BMS 207150, GLUCOPHAGE or GLUCOPHAGE XR. (D) Alpha-glucosidase inhibitors, which inhibit alpha-glucosidase. It converts fructose to glucose, thus slowing the digestion of carbohydrates.Undigested carbohydrates are subsequently cleaved in the intestine, reducing the post-prandial glucose peak.

Some examples include, but are not limited to: (1) acarbose (D-glucose, 0-4,6-dideoxy-4 - (((1S- (1alpha, 4alpha, dbeta, 6aifa)) - 4,5,6 -trihydroxy-3- (hydroxymethyl) -2-cyclohexen-1-yl) amino) -alpha-D-glucopyranosyl- (1-4) -O-alpha-D-glucopyranosyl- (1-4) -, also known as AG-5421, Bay-g-542, BAY-g-542, GLUCOBAY, PRECOSE, GLUCOR, PRANDASE, GLUMID or ASCAROSE); (2) Miglitol (3,4,5-piperidinetriol, 1- (2-hydroxyethyl) -2- (hydroxymethyl) -, (2R (2alpha, 3beta, 4alpha, dbeta)) -o (2R, 3R, 4R, 5S ) -1- (2-hydroxyethyl) -2- (hydroxymethyl-3,4,5-pyridinephriol, also known as BAY 1099, BAY M 1099, BAY-m-1099, BAYGLITOL, DIASTABOL, GLYSET, MIGLIBAY , MITOLBAY, PLUMAROL); (3) CKD-711 (0-4-deoxy-4 - ((2,3-epoxy-3-hydroxymethyl-4,5,6-dihydroxycyclohexane-1-yl) ami no) -alpha-b-glucopyranosyl- (1-4) -alpha-D-glucopyranosyl- (1-4) -D-glucopyranose); (4) emiglysis, ethyl ester of (4- (2- ( (2R, 3R, 4R, 5S) -3,4,5-trihydroxy-2- (hydroxymethyl) -1-pyridinyl) ethoxy) benzoic acid, also known as BAY or 1248 or MKC 542); (5) MOR 14 (3,4,5-piperidinetriol, 2- (hydroxymethyl) -l-meityl-, (2R- (2alpha, 3befa, 4alpha, dbeta)) -, also known as N-methyloxynojirimycin or N-methylmoranoline ); and (6) Voglibose (3,4-dideoxy-4 - ((2-hydroxy-1- (hydroxyethyl) yl) amino) -2-C- (hydroxymethyl) -D- episyl, or D-epl-Inositol, 3,4-d-deoxy-4 - ((2-hydroxy-1- (hydroxymethyl) et) amino) -2-C- (h) droximeil) -, also known as A 71100, AO 128, BASE, GLUSTAT, VOGLISTAT.

(E) Insulins include regular or short-acting, intermediate-acting and long-acting insulins, non-injectable or inhaled insulin, tissue selective insulin, glycophosphocynin (D-chiroinositol), insulin analogues such as insulin molecules with minor differences in the sequence of natural amino acids and simulators of small molecule of insulin (insulin mimics), and endosome modulators. Some examples include, but are not limited to: (1) Biota; (2) LP 100; (3) (SP-5-21) -oxoxy (1-pyrrolidincarboditol-S, S ') vanadium, (4) insulin aspart (human insulin (28B-L-aspartic acid) or B28-Asp-insulin, also known as insulin X14, INA-X14, NOVORAPID, NOVOMIX or NOVOLOG); (d) insulin detemir (Human 29B- (N6- (1-oxotetradecyl) -L-lysine) - (1A-21A), (1B-29B) -lnsulin or NN 304); (6) insulin lispro ("28B-L-lysine-29B-L-proline human insulin, or Lys (B28), Pro (B29) human insulin analog, also known as lys-pro insulin, LY 27dd85, HUMALOG, HUMALOG MIX 75 / 2d or HUMALOG MIX 50/50); (7) insulin glarglne (human (A21 -glycine, B31 -arginine, B32-arginine) insulin HOE 901, also known as LANTUS orno, OPTISULIN); (8) Insulin suspension -zinc, extended (Ultralente), also known as HUMULIN U or ULTRALENTE; (9) Suspension of insulin-zinc (Lens), a suspension of 70% crystalline and 30% amorphous insulin, also known as LENS ILETIN II, HUMULIN L or NOVOLIN L; (10) HUMULIN 50/50 (50% insulin Insulin and 50% insulin injection); (11) HUMULIN 70/30 (70% insulin NPH and 30% insulin injection), also known as NOVOLIN 70/30, NOVOLIN 70/30 PenFill, NOVOLIN 70/30 Prefilled; (12) isophane insulin suspension such as NPH ILETIN II, NOVOLIN N, NOVOLIN N PenFill, NOVOLIN N Prefilled, HUMULIN N; (13) injection of regular insulin such as ILETIN II Regular, NOVOLIN R, VELOSULIN BR, NOVOLIN R PenFill, NOVOLIN R Prefilled, HUMULIN R or regular U-500 (Concentrated); (14) ARIAD; (1d) LY 197636; (16) L-783281; and (17) TE-17411. (F) Insulin secretion modulators such as: (1) glucagon-1-like peptides (GLP-1) and their mimetics; (2) innsulinotropic peptide-glucose (GIP) and its mnemonics; (3) exendin and its mimetics; (4) dipeptyl protease inhibitors (DPP or DPPIV) such as (4a) DPP-728 or LAF 237 (2-pyrrolidinecarbonyltrile, 1 - (((2 - ((d-cyano-2-pyridinyl) amino) ethyl) amino acetyl), known as NVP-DPP-728, DPP-728A, LAF-237); (4b) P 3298 or P32 / 98 fumarate of (di- (3 N - ((2S, 3S) -2-amino-3-methyl-pentanoyl) -1, 3-yiazolid)); (4c) TSL 226 acid (tri-phenyl-1, 2,3,4-tetrahydroxyquinoline-3-carboxylic acid); (4d) Valine pyrrolidide (valpyr); (4e) 1-aminoalkyl isoquinoline-4-carboxylates and analogs thereof; (4f) SDZ 272-070 (1- (L-Valyl) plrrolidine); (4g) TMC-2A, TMC-2B or TMC-2C; (4h) Dipeptide nitriles (2-cyanopyrrolodes); (4i) CD26 inhibitors; and (4j) SDZ 274-444; (d) glucagon antagonisms such as AY-2799dd; and (6) amylin agonists including, but not limited to, pramlintide (AC-137, Symlin, tripro-amillna or pramlintide acetate). The present compounds may also increase Insulin sensitivity with little or no increase in body weight than that found with the use of existing PPAR gamma agonists. Oral antidiabetic agents may include insulin, sulfonylureas, biguanides, meglifinides, AGI's, PPAR alpha agonists, and PPAR gamma agonists, and PPAR alpha / gamma double agonists.

The present compounds can also increase the metabolism of fats and / or lipids, providing a method for weight loss, fat weight loss, reduction in body mass index, lipid reduction (such as triglyceride reduction), or treatment of obesity or the condition of being overweight. Examples of lipid reducing agents include bile acid sequestrants, fibric acid derivatives, nicotinic acid, and HMGCoA reductase inhibitors. Specific examples include statins such as LIPITOR®, ZOCOR®, PRAVACHOL®, LESCOL® and MEVACOR®, and pitavastatin (nisvastatin) (Nissan, Kowa Kogyo, Sankyo, Novartis) and prolonged-release forms thereof, such as ADX-169 (lovastatin prolonged release), as well as Colestld, Locholest, Questran, Atromid, Lopid and Tricor. Examples of blood pressure reducing agents include antihypertensive agents, such as angiotensin-converting enzyme (ACE) inhibitors (Accupril, Altace, Captopril, Lotensin, Mavik, Monopril, Prinivil, Univasc, Vasotec and Zestril), adrenergic blockers (such as Cardura , Dibenzyline, Hylorel, Hytrin, Minipress and Minizide) alpha / beta adrenergic blockers (such as Coreg, Normodyne and Trandate), calcium channel blockers (such as Adalat, Calan, Cardene, Cardizem, Covera-HS, Dilacor, DynaCirc, Isoptin, Nimotop, Norvace, Plendil, Procardia, Procardia XL, Sula, Tiazac, Vascor and Verian), diuretics, angiotensin receptor blockers 11 (such as Atacand, Avapro, Cozaar and Diovan), beta-adrenergic blockers (such as Betapace, Btccadren, Brevibloc, Cartrol, Inderal, Kerlone, Lavatol, Lopressor, Sectral, Tenormin, Toprol-XL and Zebeta), vasodilators (such as Deponit, Dilatrate, SR, Imdur, Ismo, Isordil, Isordil Titradose, Mono ket, Nitro-BId, Nitro-Dur, Nitrolingual Spray, Nitrostat and Sorbitrate), and combinations thereof (such as Lexxel, Lotrel, Tarka, Teczem, Lotensin HCT, Prinzide, Uniretic, Vaseretic, Zestoretic).

F. Biological Examples Transfection assay period for PPAR receptors HEK293 cells were grown in DMEM / F-12 medium supplemented with 10% FBS and glutamine (GIBCOBRL). The cells were co-transfected with DNA for PPAR-Gal4 receptor (PPARoc, and or 8) and reporter of Gal4-Luciferase using the DMRIE-C reagent. The next day, the medium was replaced by d% of FBS growth medium treated with carbon. After six hours, the cells were trypsinized and seeded at a density of 60,000 cells / well in 96 well plates and incubated overnight at 37 ° C in an incubator with d% C02. The cells were then treated with test compounds or vehicle and incubated for 24 hours at 37 ° C in an incubator with d% C02. Luciferase activity was tested using the Steady-Glo Luclferase test kit from Promega. The DMRIE-C reagent was purchased from GIBCO Cat. No. 10469-014. The reduced serum medium OPTI-MEM I was purchased from GIBCO Cat. No. 31986. The Steady-Glo Luciferase test kit was purchased from Promega Part # E254B. A variety of example compounds have been made and tested, with a range of in vitro results. Compounds and representative data are given below; in some cases, where EC50's are shown, multiple measurements were taken. Naturally, different compounds in the formula (I) may not have activities identical to any of the following compounds.

TABLE 2 In vitro data The compounds in table 3 are also of interest, which have been made and tested in the same way: TABLE 3 Compounds of interest G. Other modalities The characteristics and principles of the invention are illustrated in the discussion, examples and claims here. Various adaptations and modifications of the invention will be apparent to one skilled in the art and those other embodiments are also within the scope of the invention. The publications cited herein are incorporated by reference in their entirety.

Claims (3)

1. NOVELTY OF THE INVENTION CLAIMS 1. - A compound of the formula (I): wherein X is selected from a covalent bond, S or O; And it's S or O; - W-- represents a group selected from = CH-, -CH =, -CH -, -CH2-CH2-, = CH-CH2-, -CH2-CH =, -CH-CH = and -CH = CH-; Z is selected from O, CH and CH2, provided that when Y is O, Z is O; R-i and R2 are independently selected from H, C? -3 alkyl, C? -3 alkoxy, halogen, and NRaRD wherein Ra and Rb are independently H or C- ^ alkyl; R3 and R4 are independently selected from H, halogen, cyano, hydroxy, acetyl, C1-5 alkyl, C4-4 alkoxy, and NRcRd wherein Rc and Rd are independently H or C3_3 alkyl, provided that R3 and R4 are not both H; R5 are selected from halogen, phenyl, phenoxy, (phenyl) C5-5alkoxy, (phenyl) C5-5alkyl, C2-5 heteroaryloxy, C2-5 heteroaryl-C1-5alkoxy, heterocyclyloxy C2-5, C? -9 alkyl, C? -8 alkoxy, C2-g alkenyl, C2-9 alkenyloxy, C2-g alkynyl, C2-g alkynyloxy, C3-7 cycloalkyl, cycloalkoxy of C3-7, C3-7 cycloalkyl-C? -7-alkyl, C3-7-cycloalkyl-C7-alkoxy, C3-7 cycloalkoxy-C? -6-alkyl, Ci-b-alkyl-alkoxy of C -? - 6, C-? 5 -alkoxy of C? -5 alkyl, or C3_7-cycloalkoxy-C? _7alkoxy; R6 is H when W represents a group selected from -CH =, -CH2-, -CH2- CH2-, -CH2-CH =, and -CH = CH-, or Re is absent when -W represents a group selected from = CH-, = CH-CH2-, y = CH-CH =; and n is 1 or 2; or a pharmaceutically acceptable salt thereof.
2. 2. The compound according to claim 1, further characterized in that X is S or O. 3. The compound according to claim 1, further characterized in that X is a covalent bond. 4. The compound according to claim 2, further characterized in that X is O. 5. The compound according to claim 1, further characterized in that Y is O. 6. The compound according to claim 1, further characterized in that Y is S. 7. The compound according to claim 1, further characterized in that Z is O. 8. The compound according to claim 1, further characterized in that Z is CH or CH2. 9. The compound according to claim 1, further characterized in that - W - represents -CH2- or -CH2-CH2-. 10. - The compound according to claim 9, further characterized in that - W - represents -CH2-. 11. The compound according to claim 1, further characterized in that W represents = CH-, -CH =, = CH-CH2-, - CH2-CH = = CH-CH = or -CH = CH-. 12. The compound according to claim 1, further characterized in that R3 and R4 are independently selected from H, halogen, cyano, C1-4 alkyl and C1-3 alkoxy. 13. The compound according to claim 1, further characterized in that Ri and R2 are independently selected from H, C1.3 alkyl, C? -3 alkoxy, F, Cl and Br. 14.- The compliant compound with claim 13, further characterized in that Ri and R2 are independently selected from H, methyl, methoxy, F and Cl. The compound according to claim 1, further characterized in that R3 and R4 are independently selected from H, halogen , cyano, hydroxy, C2.4 acyl, C1-4 alkyl and C1.3 alkoxy. 16. The compound according to claim 12, further characterized in that R3 is independently selected from H, F, Cl, methyl and methoxy. 17. The compound according to claim 12, further characterized in that R is independently selected from F, Cl, methyl, methoxy, trifluoromethyl, fluoromethyl, difluoromethyl, chlorodifluoromethyl, dichlorofluoromethyl, fluoromethoxy, difluoromethoxy, chlorodifluoromethoxy, dichlorofluoromethoxy and trifluoromethoxy. 18. The compound according to claim 1, further characterized in that R3 is selected from methyl, methoxy, H, Cl, Br, I, OH, -CH (CF3) 2, CF3, -OCF3, -N (CH3) 2, -0-CH2COOH, and -COCH3, and R4 is selected from H, Cl and methyl. 19. The compound according to claim 1, further characterized in that R5 is selected from C1-7 alkyl, C-i6 alkoxy, C2 alkenyl. , C2.7 alkenyloxy, C2-7 alkynyl, C2-7 alkynyloxy, C3-7 cycloalkyl, C3-7 cycloalkoxy, C6-6 alkoxy-C-6 alkyl, alkoxy C- | .5-C-5-alkoxy, and C3.7-cycloalkyloxy-C-? -7-alkoxy. 20. The compound according to claim 1, further characterized in that R5 is selected from phenoxy, (phenyl) Ci- 5 alkoxy, (phenyl) C? -5 alkyl, C2- heteroaryloxy, C2-5 heteroaryl -alcoxi of d. 5, C2-5 heterocyclyloxy, C3-7 cycloalkyl-C-7C alkyl, C3 cycloalkyl. 7-C7-alkoxy, and C3-7-cycloalkoxy-C-? -6 alkyl. 21. The compound according to claim 1, further characterized in that R6 is H. 22. The compound according to claim 1, further characterized in that R3 is selected from H, F, Cl, methyl and methoxy, and R4 is selected from F, Cl, methyl, fluoromefilo, difluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethyl, trifluoromethoxy and methoxy. 23. The compound according to claim 1, further characterized in that R-i is selected from H, CF3, methyl, Cl and methoxy, and R2 is selected from H, Cl and methyl. 24. The compound according to claim 23, further characterized in that X is a covalent bond. 25. The compound according to claim 23, further characterized in that X is covalent bond, Y is S and Z is O. 26.- The compound according to claim 1, further characterized in that X is O and Y is O 27. The compound according to claim 1, further characterized in that X is O and Y is S. 28.- The compound according to claim 1, further characterized in that Y is O and Z is O. 29.- The compound according to claim 1, further characterized in that Y is S and Z is O. 30.- The compound according to claim 1, further characterized in that Re is H and R5 is selected from C1-7 alkyl, alkoxy of C? _6, C2-7 alkenyl, C2 alkenyloxy. , C6-6 alkoxy of C-? -6 alkyl, and C? -5-alkoxy of C-? -5. 31. The compound according to claim 30, further characterized in that R5 is selected from C1-5 alkyl, C-i alkoxy. 4, C2-5 alkenyl, C2-5 alkenyloxy, and C? - alkoxy alkoxy of C -? - 5. 32. The compound according to claim 30, further characterized in that R5 is selected from C? -3 alkyl, C? -3 alkoxy, C2-4 alkenyl, C2-4 alkenyloxy, and C? Alkoxy. -3-C1-3 alkoxy. 33. The compound according to claim 30, further characterized in that R5 is selected from methoxy, ethoxy, propoxy, isopropoxy, propenyloxy, isopropenyloxy, ethoxy-methoxy, methoxy-methoxy, methoxy-methyl, methoxyethyl, ethoxymethyl and ethoxy-ethyl. . 34. The compound according to claim 1, further characterized in that R-i is selected from H, CF3, methyl, Cl and methoxy; R2 is selected from H, Cl and methyl, R3 is selected from H, F, Cl, mephyl and methoxy; and R is selected from F, Cl, methyl, trifluoromethyl, trifluoromethoxy, fluoromethyl, fluoromethoxy, difluoromethyl, difluoromethoxy and methoxy. 35.- The compound according to claim 1, further characterized in that X is O; Cast; R3 is selected from H, F, Cl, methyl and methoxy; and R 4 is selected from F, Cl, meyyl, CF 3 > OCF3 and methoxy. 36. The compound according to claim 1, further characterized in that X is O; And it's S; R3 is selected from H, F, Cl, methyl, and methoxy; and R 4 is selected from F, Cl, methyl, CF 3, OCF 3 and methoxy. The compound according to claim 1, further characterized in that X is a covalent bond; And it's S; R3 is selected from H, F, Cl, methyl and methoxy; and R 4 is selected from F, Cl, methyl, CF 3, OCF 3 and methoxy. 38.- The compound according to claim 1, further characterized in that Y is O; Z is O; R3 is selected from H, F, Cl, methyl, and methoxy; and R 4 is selected from F, Cl, methyl, CF 3, OCF 3 and methoxy. 39. - The compound according to claim 1, further characterized in that Y is S; Z is O; R3 is selected from H, F, Cl, methyl, and methoxy; and R 4 is selected from F, Cl, methyl, CF 3, OCF 3 and methoxy. 40.- The compound according to claim 1, further characterized in that R3 is selected from H, F, Cl, methyl and methoxy; R 4 is selected from F, Cl, methyl, CF 3, OCF 3, and methoxy; R 5 is selected from C 1-7 alkyl, C 1-6 alkoxy, C 2-7 alkenyl, C 2-7 alkenyloxy, alkoxy C -? - 6-C-? -6 alkyl, and C-? -5-alkoxy of C -? - 5 and Re is H. The compound according to claim 1, further characterized in that X is O; Cast; R 5 is selected from C 1 .3 alkyl, C 1-3 alkoxy, C 2-4 alkenyl, C 2-4 alkenyloxy, and C 3 -3 alkoxy-C 1-3 alkoxy; and Re is H. 42. The compound according to claim 1, further characterized in that X is O; And it's S; R5 is selected from C1.3 alkyl, C---3 alkoxy, C2-4 alkenyl, C2-4 alkenyloxy, and C3 alco 3 3 3-alkoxy of C1.3; and Re is H. 43. The compound according to claim 1, further characterized in that X is O; Cast; R is selected from H, CF3, methyl, Cl, and methoxy; R2 is selected from H, Cl and methyl; R3 is selected from H, F, Cl, methyl and methoxy; R 4 is selected from F, Cl, methyl, CF 3, OCF 3 and methoxy; and n is 1. 44. The compound according to claim 1, further characterized in that X is O; And it's S; RT is selected from H, CF3, methyl, Cl and methoxy; R2 is selected from H, Cl and methyl; R3 is selected from H, F, Cl, methyl and methoxy; and R 4 is selected from F, Cl, methyl, CF 3, OCF 3 and methoxy. 45. The compound according to claim 44, further characterized in that n = 1. 46.- The compound according to claim 45, further characterized in that R5 is selected from C1.3 alkyl, C-i alkoxy.
3. 3, C2-4 alkenyl, C2- alkenyloxy, and C? -3-alkoxy of C? -3; and R6 is H. 47. The compound according to claim 1, further characterized by being selected from [4 - [[2-ethoxy-3- [4- (trifluoromethyl) phenoxy] propyl] t or] -2-methyl-phenoxy] -acelic acid [4 - [[(2R) -2-ethoxy-3- [4- (trifluoromethyl) phenoxy] propyl] thio] -2-meitylphenoxy] -acetic acid and [4 - [[(2S) -2-Exoxy-3- [4- (trifluoromethoxyl) phenoxy] propyl] thio] -2-meitylphenoxy] -acetic acid. 48. The compound according to claim 1 further characterized because it is [4 - [[2-ethoxy-3- [4- (trifluoromethyl) phenoxy] propyl] thio] -2-methylphenoxy] -acetic acid . 49. The compound according to claim 1 further characterized because it is [4 - [[(2R) -2-ethoxy-3- [4- (trifluoromethyl) phenoxy] propyl] thio] -2-methylphenoxy acid. ]-acetic. 50.- The compound according to claim 1 further characterized because it is acid [4 - [[(2S) -2-ethoxy] -3- [4- (trifluoromethoxyl) phenoxy] propyl] thio] -2-meitylphenoxy] - acetic. 51. The compound according to claim 1 further characterized in that it is selected from acid. { 2-meityl-4- [2- (4-trifluoromethyl-phenoxymethyl) -butylsulfanyl] -phenoxy} -acetic; acid { 2-metll-4- [2- (4-trifluoromethyl-phenoxymethyl) -phenylsulfanyl] -phenoxy} -acetic; acid { 4- [4-Cyano-2- (4-trifluoromethyl-phenoxymethyl) -butylsulfanyl] -2-methy1-phenoxy} -acetic; acid (R) -. { 4- [2-allyloxy] -3- (4-trifluoromethyl-phenoxy) -propylsu-imanyl] -2-methyl-phenoxy} -acetic; acid (R) -. { 4- [2-methoxymethoxy-3- (4-trifluoromethyl-phenoxy) -propylsulfanyl] -2-methyl-phenoxy} -acetic; acid { 4- [2-ethoxy-4- (4-trifluoromethyl-phenyl] -butyl sulfanyl] -2-methyl-phenoxy} -acéíico; acid { 3-Chloro-4- [2-eoxy-3- (4-frifluoromethyl-phenoxy) -propylsulfanyl] -phenyl} -acetic; acid { 4- [2-ethoxymethyl-3- (4-trifluoromethyl-phenoxy) -propylsulfanyl] -2-methy1-phenoxy} -acetic; acid { 4- [4-ethoxy-2- (4-trifluoromethyl-phenoxymethyl) -buylsulfanyl] -2-methyl-phenoxy-acetic acid; and acid. { 4- [2- (d-chloro-thiophen-2-ylmethoxy) -3- (4-trifluoromethyl-phenoxy) -propylsulfanyl] -2-methy1-phenoxy} -acetic. 62. The compound according to claim 1 further characterized in that it is selected from acid. { 4- [3-Cano-2- (4-trifluoromethyl-phenoxymethyl) -propylsulfanyl] -2-methyl-phenoxy} -acéíco; acid { 4- [d-Cano-2- (4-trifluoromethyl-phenoxymethyl) -pene-4-enylsulfanyl] -2-mephi-phenoxy} -acetic; acid { 3-Chloro-4- [2- (4-trifluoromethyl-phenoxymethyl) -bufilsulfanyl] -phenyl} -acetic; acid { 2-methyl-4- [3- (4-trifluoromethyl-phenoxy) -2- (4-trifluoromethyl-phenoxymethyl) -propylsulfanyl] -phenoxy} -acetic; acid { 4- [2-benzyloxy-3- (4-trifluoromethyl-phenoxy) -propylsulfanyl] -2-methy1-phenoxy} -acetic; acid { 4- [2- (4-Butyryl-phenoxy) -3- (4-trifluoromethyl-phenoxy) -propylsulfanyl] -2-methy1-phenoxy} -acetic; acid { 2-methyl-4- [3- (4-trifluoromethyl-phenoxy) -propenylsulfanyl] -phenoxy} -acetic; acid { 2-methyl-4- [2-methylsulfanylmethioxy-4- (4-trifluoromethyl-phenyl) -butylsulfanyl] -phenoxy} - acetic; [4- [2,4-diethoxy-4- (4-trifluoromethyl-phenyl) -butylsulfanyl] -2-methy1-phenoxy acid} -acetic; and acid. { 4- [2-ethoxy-4- (4-trifluorometyi-phenyl) -but-3-enylsulfanyl] -2-meityl-phenoxy} -acetic. 63. The compound according to claim 1 further characterized in that it is selected from acid. { 4- [2- (4-fluoro-methoxy-phenoxymethyl) -butylsulfanyl] -phenoxy} -acetic; acid { 2-methyl-4- [2- (4-trifluoromethyl-phenoxymethyl) -heptylsulfanyl] -phenoxy} -acetic; acid { 4- [4-methoxy-2- (4-trifluoromethyl-phenoxymethyl) -bufylsulfanyl] -2-methyl-phenoxy} -acetic; acid { 2-Mephyl-4- [3- (4-trifluoromethyl-phenoxy) -propylsulfanyl] -phenoxy} -acéíico; acid { 2-Methyl-4- [4- (4-ylfluoromethyl-phenyl) -3,6-dihydro-2 H -pyran-2-ylmethylsulfanyl] -phenoxy} -acetic; and acid. { 2-methyl-4- [4- (4-trifluoromethyl-pheny] -but-3-enylsulfanyl] -phenoxy} -acetic; 64.- The compound according to claim 1 further characterized in that it is selected from (R) - acid. { 4- [2-ethoxy-3- (4-trifluoromethoxy-phenoxy) -propylsulfanyl] -2-methyl-phenoxy} -acetic; acid (R) -. { 4- [3- (4-chloro-phenoxy) -2-ethoxy-propylsulfanyl] -2-methyl-phenoxy} -acetic; acid (R) -. { 4- [3- (4-tert-Butyl-phenoxy) -2-ethoxy-propylsufanfan] -2-methyl-phenoxy} -acetic; acid (R) -. { 2-Melyl-4- [2- (4-trifluoromethoxy-phenoxymethyl) -bulsylsulfanyl] -phenoxy} -acetic; acid (R) -. { 4- [2- (4-Chloro-phenoxymethyl) -butylsulfanyl] -2-methyl-phenoxy} -acetic; acid (R) -. { 4- [2- (4-yer-butyl-phenoxymethyl) -bufilsulfanyl] -2-methyl-phenoxy} -acetic; acid (R) -. { 3-Chloro-4- [2-eoxy-3- (4-trifluoromethoxy-phenoxy) -propylsulfanyl] -phenyl} -acetic; acid (R) -. { 3-chloro-4- [3- (4-chloro-phenoxy) -2-ethoxy-propylsulfanyl] -phenyl-acetic; acid (R) -. { 4- [2-ethoxy-3- (4-trifluoromethyl-phenoxy) -propylsulfanyl] -2-methyl-phenylsulfanyl} -acetic; acid (R) -. { 4- [2-ethoxy-3- (4-trifluoromethoxy-phenoxy) -propylsulfanyl] -2-methy1-phenylsulfanyl} - acéíico; acid (R) -. { 2-methyl-4- [2- (4-l-trifluoromethyl-phenoxymethyl) -buylsulfanyl] -phenylsulfanyl-acetic acid; and (R) - acid. { 2-methyl-4- [2- (4-if-fluoro-methoxy-phenoxymethyl) -butylsulfanyl] -phenylsulfanyl} -acetic. dd.- A pharmaceutical composition comprising a compound of any of claims 1, 27, 30, 31, 32, 34, 36, 37, 39, 40, 42, 44, 4d, 46, 47, 61, 62, 63 and 64. The use of the composition defined in claim 55, for preparing a medicament for treating or inhibiting the progression of a condition mediated by PPAR-delta in a patient. 57.- A compound of the formula (II): II wherein X is selected from a covalent bond, S or O; And it's S or O; W- - represents a group selected from -CH =, -CH2-, -CH2-CH2-, -CH2-CH = and -CH = CH-; Z is selected from O, CH and CH2, provided that when Y is O, Z is O; R i and R 2 are independently selected from H, C 1-3 alkyl, C 1-3 alkoxy, halogen and NR a R b where R a and R b are independently H or C 1-3 alkyl; R3 and R4 are independently selected from H, halogen, cyano, hydroxy, acetyl, C1-5 alkyl, C1- alkoxy, and NRcRd wherein Rc and Rd are independently H or C3-alkyl, provided that R3 and R4 are not both H; and n is 1 or 2; or a pharmaceutically acceptable salt thereof. 58.- The compound according to claim 57, further characterized in that X is S or O. 59.- The compound according to claim 58, further characterized in that X is O. 60.- The compound according to the claim 57, further characterized in that X is a covalent bond. 61.- The compound according to claim 57, further characterized in that Y is O. 62.- The compound according to claim 57, further characterized in that Y is S. 63.- The compound according to claim 57, further characterized in that Z is O. 64. The compound according to claim 57, further characterized in that Z is CH or CH2. The compound according to claim 57, further characterized in that - W - represents -CH 2 - or -CH 2 -CH 2 -. 66. The compound according to claim 65, further characterized in that - W - represents -CH2-. 67. The compound according to claim 57, further characterized in that W represents -CH =, -CH2-CH =, or - CH = CH-. The compound according to claim 57, further characterized in that R 3 and R 4 are independently selected from H, halogen, cyano, C 1-4 alkyl, and C 1-3 alkoxy. 69.- The compound according to claim 67, further characterized in that Ri and R2 are independently selected from H, I, C? -3 alkyl, C1.3 alkoxy, F, Cl and Br. 70.- The compound according to claim 69, further characterized in that Ri and R2 are independently selected from H, methyl, methoxy, F and Cl. The compound according to claim 67, further characterized in that R3 and R4 are independently selected from H , halogen, cyano, hydroxy, acyl of C2-, alkyl of C- and alkoxy of C1-3. 72. The compound according to claim 71, further characterized in that R3 is independently selected from H, F, Cl, methyl and methoxy. 73. The compound according to claim 71, further characterized in that R4 is independently selected from F, Cl, methyl, methoxy, trifluoromethyl, fluoromethyl, difluoromethyl, ciorodifluoromethyl, dichlorofluoromethyl, fluoromethoxy, difluoromethoxy, chlorodifluoromethoxy, dichlorofluoromethoxy and trifluoromethoxy. The compound according to claim 67, further characterized in that R3 is selected from methyl, methoxy, H, Cl, Br, I, OH, -CH (CF3) 2, CF3, -OCF3, -N (CH3) 2, -0-CH2COOH, and -COCH3, and R4 is selected from H, Cl and methyl. 76. The compound according to claim 57, further characterized in that R3 is selected from H, F, Cl, methyl and methoxy, and R is selected from F, Cl, mephyl, fluoromethyl, difluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethyl, trifluoromethoxy and methoxy The compound according to claim 57, further characterized in that R-i is selected from H, CF3, methyl, Cl and methoxy, and R2 is selected from H, Cl and methyl. The compound according to claim 76, further characterized in that X is a covalent bond. The compound according to claim 77, further characterized in that X is a covalent bond, Y is S and Z is O. 79. The compound according to claim 57, further characterized in that X is O and Y is O 80. The compound according to claim 57, further characterized in that X is O and Y is S. 81. The compound according to claim 67, further characterized in that Y is O and Z is O. 82.- The compound according to claim 57, further characterized in that Y is S and Z is O. 83. The compound according to claim 57, further characterized in that Ri is selected from H, CF3, methyl, Cl and methoxy; R2 is selected from H, Cl and methyl; R3 is selected from H, F, Cl, mephyl and methoxy; and R 4 is selected from F, Cl, methyl, trifluoromethyl, trifluoromethoxy, fluoromethyl, fluoromethoxy, difluoromethyl, difluoromethoxy and methoxy. 84. The compound according to claim 57, further characterized in that X is O; Cast; R3 is selected from H, F, Cl, methyl and methoxy; and R 4 is selected from F, Cl, methyl, CF 3, OCF 3 and methoxy. The compound according to claim 57, further characterized in that X is O; And it's S; R3 is selected from H, F, Cl, methyl and methoxy; and R is selected from F, Cl, methyl, CF3, OCF3 and methoxy. The compound according to claim 57, further characterized in that X is a covalent bond; And it's S; R3 is selected from H, F, Cl, methyl and methoxy; and R 4 is selected from F, Cl, methyl, CF 3, OCF 3 and methoxy. The compound according to claim 57, further characterized in that Y is O, Z is O; R3 is selected from H, F, Cl, methyl and methoxy; and R is selected from F, Cl, methyl, CF3, OCF3 and methoxy. 88. The compound according to claim 57, further characterized in that Y is S; Z is O; R3 is selected from H, F, Cl, methyl and methoxy; and R 4 is selected from F, Cl, methyl, CF 3, OCF 3 and methoxy. 89. The compound according to claim 57, further characterized in that R3 is selected from H, F, Cl, methyl and methoxy; and R 4 is selected from F, Cl, methyl, CF 3, OCF 3 and methoxy. 90. The compound according to claim 57, further characterized in that X is O; Cast; R i is selected from H, CF 3, methyl, Cl and methoxy; R2 is selected from H, Cl and methyl; R3 is selected from H, F, Cl, methyl and methoxy; R 4 is selected from F, Cl, methyl, CF 3, OCF 3 and methoxy; and n is 1. 91. The compound according to claim 57, further characterized in that X is O; And it's S; R- is selected from H, CF3, methyl, Cl and methoxy; R2 is selected from H, Cl and methyl; R3 is selected from H, F, Cl, methyl and methoxy; and R 4 is selected from F, Cl, methyl, CF 3, OCF 3 and methoxy. 92. The compound according to claim 57, further characterized in that n = 1. 93.- The compound according to claim 57, further characterized in that it is selected from acid. { 4 - [(2R) -2-hydroxy-3- (4-trifluoromethyl-phenoxy) -propylsulfanyl] -2-methyl-phenoxy} -acetic; acid { 4 - [(2S) -2-hydroxy-3- (4-trifluoromethyl-phenoxy) -propylsulfanyl] -2-methyl-phenoxy} -acetic; and acid . { 4- [2-ethoxy-3- (4-trifluoromethyl-phenoxy) -propoxy] -2-methyl-phenoxy} -acetic. 94.- A pharmaceutical composition comprising a compound of any of claims 57, 80, 83, 85, 86, 88, 89, 90, 91, 92, 93 and 94. 95.- The use of the composition that is defined in claim 94, for preparing a medicament for trapping or inhibiting the progression of a condition mediated by PPAR-delia in a patient.