MXPA06003180A - 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 - ((FENOXALALYCLE) TIO) -FENOXYACETHYLS AND ANALOGS CROSS REFERENCE TO RELATED REQUESTS This application claims priority to U.S. Provisional Patent Application No. 60/504089, filed September 19, 2003, which is incorporated herein 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 disease states such as diabetes and obesity. Many population studies have attempted to identify 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. Peroxisome proliferator-activated receptors (PPARs) are metabolic sensors that regulate the expression of genes involved in glucose and lipid homeostasis. 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 nar receptor family, the peroxisome proliferator-activated receptor delta (PPAR delta or PPARd) is also a necessary transcription factor reported to be involved in regulatory genes involved in lipid metabolism and energy expenditure. It has been shown that PPAR delta acts as a "gateway" receptor that modulates the expression of the other PPARs (Shi et al., 2002, Proc Nati, 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, potent ligands for PPARd have been published, 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. Clin. 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 hypercholesterolemia includes statin 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, like fibrates, PPARd 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). 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 following formula (I): (i) wherein X is selected from a covalent bond, S and O; And it's S or O; Z is O or CH2, provided that when Y is O, Z is O; Ri and R2 are independently selected from H, C---3 alkyl, C?-3 alkoxy, halogen, and NRaRD wherein Ra and R are independently H or C 1-3 alkyl; R3 and R4 are independently selected from H, halogen, cyano, C1-5 alkyl, hydroxy, C2-4 acyl, C4-4 alkoxy, and NRcRd wherein Rc and d are independently H or C?-3 alkyl , provided that R3 and R4 are not both H; R5 and R6 are independently selected from halogen, phenyl, C1-9 alkyl, Ci-β alkoxy, C2.g alkenyl, C2.9 alkenyloxy, C3-7 cycloalkyl, C3- cycloalkoxy, C3- cycloalkyl -C1-7 alkyl, cycloalkyl C3-7-C-? -7-alkoxy, C3-7-cycloalkyloxy-C1-6-alkyl, and C3-cycloalkyloxy-C1-7-alkoxy, or R5 and Re together form C-1-9 alkynyl or C3-9 alkenyldenyl, or R5 and R and the carbon atom to which they are attached form C3-7 cycloalkyl or 5- or 6-membered heterocycle; n is 0, 1 or 2; and m is 0, 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 pharmaceutically 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-cholesterolemia, 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 can be treated with a PPAR delta agonist include, without limitation, diabetes, cardiovascular diseases, metabolic syndrome X, hypercholesterolemia, hyper-HDL-cholesterolemia, hyper-LDL-cholesterolemia, dyslipidemia, atherosclerosis and obesity. Dyslipidemia includes hypertriglyceridemia and mixed hyperlipidemia.

For example, dyslipidemia (including hyperlipidemia) may be one or more of the following conditions: low HDL (<or 40 or 40 mg / dL), high triglycerides (> 200 mg / dL), and high LDL (> 150) mg / dl). Additional features and advantages of the invention will be apparent 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 syndrome X metabolic: 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. further, the reduced level of triglycerides and free fatty acids contributes to reduce obesity and relieve or prevent diabetes. PPAR delta, being ubiquitously expressed, can act as a gate receptor that regulates the expression / activity 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 clinician, which includes the relief, prevention, treatment, or delay of the initiation or progression of the symptoms of the disease or disorder being treated. Conditions directly or indirectly mediated by PPAR delta include, but are not limited to, diabetes, cardiovascular disease, metabolic syndrome X, hypercholesterolemia, hypo-HDL-cholesterolemia, hyper-LDL-cholesterolemia, dyslipidemia, atherosclerosis, 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 treated. For prophylactic purposes (i.e., inhibition of the onset 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, which treats or inhibits in a subject the start or progression of a disorder that is being sought by a researcher, veterinarian, doctor or other clinical 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, as C -? - 6, C? _4, C3-8, C2-5, or any other range, and unless otherwise indicated, include both substituted and unsubstituted portions. For example, the d-β-alkyl radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, 3- (2-methyl) butyl, -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 different (chlorobenzyl-or aminomethyl-substituted). Examples of substituted alkyl include halogenoalkyl (such as fluoromethyl, chloromethyl, difluoromethyl, perchloromethyl, 2-bromoetyl, trifluoromethyl and 3-iodocyclopentyl), hydroxyalkyl (such as hydroxymethyl, hydroxyethyl, 2-hydroxypropyl), aminoalkyl (such as aminomethyl, 2- aminoethyl, 3-aminopropyl and 2-aminopropyl), alkoxylalkyl, nitroalkyl, alkylalkyl, cyanoalkyl, phenylalkyl, heteroarylalkyl, heterocyclylalkyl, phenoxyalkyl, heteroaryloxyalkyl (such as 2-pyridyloxyalkyl), heterocyclyloxy-alkyl (such as 2-tetrahydropyranoxy-alkyl), thioalkylalkyl (such as MeS-alkyl), thiophenylalauyl (such as phS-alkyl), carboxylalkyl, etc. A di (C1-3 alkyl) amino group includes independently selected alkyl groups, to form, for example, methylpropylamino and isopropylmethylamino, further dialkylamino groups having two of the same alkyl group such as dimethylamino or diethylamino. The term "alkenyl" includes straight and branched chain hydrocarbon radicals optionally substituted as above with at least one carbon-carbon double bond (sp2). Alkyl esters include ethenyl (or vinyl), prop-1-enyl, prop-2-enyl (or allyl), ε-propenyl (or 1-methylvinyl), but-1-enyl, but-2-enyl, butadienyl, pentenyl, hexa-2,4-dhenyl, etc. The hydrocarbon radicals having a mixture of double bonds and triple bonds, such as 2-penten-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). Alkynyl include ethynyl, propynyl, butynyl and pentynyl. The hydrocarbon radicals having a mixture of double bonds and triple bonds, such as 2-penten-4-ynyl, 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 "acyl", as used herein, refers to a substituent having a carbonyl group (C = 0) and one or more alkyl or alkylene groups. For example, C2-4 acyl includes, without limitation, acetyl, CH3CH2- (C = O) -CH2- and CH3CH2CH2- (C = 0) -. 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 C 8 Cr alkyl, C 1 -C 8 alkoxy, fluorinated C 1 -C 8 alkyl (e.g., trifluoromethyl) , fluorinated CrC8 alkoxy (e.g., trifluoromethoxy), halogen, cyano, C8 alkylcarbonyl such as acetyl, carboxyl, hydroxy, amino, nitro, C1-C4 alkylamino (i.e., -NH- C1-6alkyl- C4), dialkylamino of CrC4 (ie, -N- [C4] alkyl] 2 wherein the alkyl groups may be the same or different), or unsubstituted, mono-, di- or tri-substituted phenyl wherein the Substituents on the phenyl are independently selected from CrC8 alkyl, C---C8 alkoxy, fluorinated C-pC alkyl, fluorinated C -?-C8 alkoxy, halogen, cyano, acetyl, carboxyl, hydroxy, amino, nitro, five or six membered alkylamino, dialkylamino or heteroaryl having 1-3 heteroatoms selected from N, O and S. The term "heteroaryl", as used herein, represents a of a stable or unsubstituted or substituted five or six membered monocyclic or bicyclic aromatic 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 atom that results in the creation of a stable structure. Examples of heteroaryl groups include, but are not limited to, benzimidazolyl, benzisoxazolyl, benzofuranyl, benzopyrazolyl, benzothiadiazolyl, benzothiazolyl, benzothienyl, benzotriazolyl, benzoxazolyl, furanyl, furazanyl, furyl, imidazolyl, indazolyl, indolizinyl, indolinyl, indolyl, isobenzofuranyl, soindolyl. , isothiazolyl, isoxazolyl, oxazolyl, purinyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, quinolinyl, quinolyl, thiadiazolyl, thiazolium, thiophenyl or triazolyl. When the heteroaryl group is substituted, the heteroaryl group may have one to three substituents including, but not limited to, C?-C8 alkyl, halogen, and aryl.

The term "heterocyclyl" includes optionally substituted non-aromatic rings having carbon atoms and at least one heteroatom (O, S, N) or heteroatom portion (S02, CO, CONH, COO) in the ring. A heterocyclyl can be saturated, partially saturated, non-aromatic or fused. Examples of heterocyclyl include cyclohexylimino, imdazolidinyl, imidazolinyl, morpholinyl, piperazinyl, piperidyl, pyridyl, pyranyl, pyrazolidinium, pyrazolinyl, pyrrolidinyl, pyrrolinyl and thienyl. Unless otherwise indicated, heteroaryl and heterocyclyl can have a valence that connects 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 has between 5 and 7 ring atoms, or between 5 and 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 to 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 may contain 1, 2 or 3 nitrogen atoms where is a ring of six members, or 1, 2 or 3 heteroatoms selected from oxygen, nitrogen and sulfur where it 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, 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 phenyl group linked 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, alkeniio, alkynyl, cycloalkyl, cycloalkenyl, etc.) or heterocarbyl (heterocyclyl, heteroaryl, heteroatom such as sulfonyl, amino, amido, etc.). ) can be substituted or unsubstituted, for example, "alkyl" includes unsubstituted and substituted alkyl and "heterocyclyl" and "aryl" and "alkoxy", etc., can also be substituted or unsubstituted. For example, where R is "methyl or methoxy", unless otherwise indicated, these terms collectively include: methyl, methoxy, trifluoromethyl, trifluoromethoxy, difluoromethyl, difluoromethoxy, fluoromethyl, fluoromethoxy, chlorodifluoromethyl, chlorodifluoromethoxy, dichlorofluoromethyl and dichlorofluoromethoxy, etc. Examples 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) m is 1; (i) m is 2; (k) n is 1; (I) R-i and R2 are independently selected from H, C? -3 alkyl, C? -3 alkoxy, F, Cl, and Br; (m) Ri and R2 are independently selected from H, methyl, methoxy, F and Cl; (n) R3 and R4 are independently selected from H, halogen, cyano, acetyl, C? -2alkyl, and C1-2alkoxy; (o) R3 is independently selected from H, F, Cl, methyl and methoxy; (p) R4 is independently selected from H, halogen, cyano, C-? -2 alkyl, and C? -2 alkoxy; (q) R3 is independently selected from H, halogen, cyano, C -? - 2 alkyl, and C? -2 alkoxy, and R4 is independently selected from F, Cl, methyl, and methoxy; (r) 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 is selected from H, Cl and methyl; (s) R5 and Re together form alkyldenyl of C-i.g or alkenyldenyl of C3-9, or R5, Re and the carbon atom to which they are attached together form cycloalkyl of C3-7; (t) R5 and Re are independently selected from halogen, phenyl, C-? 9 alkyl, C-? 8 alkoxy, C2-9 alkenyl, C2-g alkenyloxy, C3- cycloalkyl, C3 cycloalkoxy -7, C3-7 cycloalkyl-C-? 7 alkyl, cycloalkyl of C- -alkoxy of C? -7) cycloalkoxy of C3-7-alkyl of C? -6, and cycloalkyloxy of C -7-alkoxy; from C1-7; (u) R3 is selected from H, F, Cl, methyl and methoxy, and R4 = e is selected from F, Cl, acetyl, methyl, methoxy, trifluoromethyl, trifluoromethoxy, difluoromethyl, difluoromethoxy, fluoromethyl, fluoromethoxy; (v) R-i is selected from H, CF3, methyl, Cl and methoxy, and R2 is selected from H, Cl and methyl; (w) X is O and Y is O; (x) Z is O and Y is O; (y) 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 R4 is selected from F, Cl , methyl and methoxy; (z) X is O, Y is O, R3 is selected from H, F, Cl, methyl and methoxy, and R4 is selected from F, Cl, methyl and methoxy; (z2) Z is O, Y is O, R3 is selected from H, F, Cl, methyl and methoxy, and R4 is selected from F, Cl, methyl, and methoxy; (aa) 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, R4 is selected from F, Cl , methyl and methoxy, and R5 and Re together form alkyldenyl of C-μg or alkenyldenyl of C3.g, or R5, R6 and the carbon atom to which they are attached together form cycloalkyl of C3-7; (bb) X is O, Y is O, Z is O, 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, R4 is selected from F, Cl, methyl and methoxy, and R5 and Re are independently selected from halogen, phenyl, Cig alkyl, C1-8 alkoxy, C2-g alkenyl, C2-g alkenyl loxy, cycloalkyl of C3-7, C3-7 cycloalkoxy, C3-7 cycloalkyl-C? -alkyl, C3-7 cycloalkyl- C7-7alkoxy, C3-7cycloalkyloxy- Ci.ssalkyl and C3 cycloalkyloxy -7-C-alkoxy?; (ce) X is O, Y is O, Z is O, 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, and R 4 is selected from F, Cl, methyl and methoxy; (dd) X is O, Y is O, Z is O, 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 and methoxy, and R 5 and R 6 together form Ci-g alkyl or C 3 -g alkenyldenyl, or R 5, RT and the carbon atom to which they are attached together form cycloalkyl of C3-7; (ee) X is O, Y is O, Z is O, 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 and methoxy, and R5 and Re are independently selected from halogen, phenyl, Cig alkyl, C1-8 alkoxy, C2-g alkenyl, C2-T alkenyloxy, cycloalkyl of C3-7, C3-7 cycloalkoxy > C3-7-cycloalkyl-C-? 7 -alkyl, C3-7-cycloalkyl-C-? -alkoxy, C3-7-cycloalkyloxy-C? -6-alkyl, and C3-7-cycloalkyloxy- C1- alkoxy; (ff) X is O, Y is O or S, Z is O, 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 and methoxy, m is 1, and n is 1; (gg) X is O, Y is O or S, Z is O, 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, R4 is selected from F, Cl, methyl and methoxy, m is 1, n is 1, and R5 and R6 are independently selected from halogen, phenyl, C- | g alkyl, Cs alkoxy , C2-9 alkenyl, C2-9 alkenyloxy, C3-7 cycloalkyl, C3-7 cycloalkoxy, C3- cycloalkyl-Ct-7alkyl, C3- cycloalkyl- C3- alkoxy, C3 cycloalkyloxy - C -? - 6 alkyl, and C3-7 cycloalkyloxy-C-? -7 alkoxy; or combinations of the above. The compounds of the present invention can also be selected from: acid. { 2-methyl-4- [2- (4-trifluoromethyl-phenoxymethyl) -allylsulfanyl] -phenoxy-acetic acid; (2-methyl-4- { 2- [2- (4-trifluoromethyl-phenyl) -ethyl] -allylsulfanyl} -phenoxy) -acetic acid; acid { 2-methyl-4- [2- (4-trifluoromethoxy-phenoxymethyl) -allylsulfanyl] -phenoxy} -acetic; acid { 2-Chloro-4- [2- (4-trifluoromethyl-phenoxymethyl) -al] sulphonyl] -phenoxy-acetic acid; acid { 2-methyl-4- [3-methyl-2- (4-trifluoromethyl-1-phenoxymethyl) -but-2-enylsulfanyl] -phenoxy} -acetic; acid { 4- [3,3-difluoro-2- (4-trifluoromethyl-phenoxymethyl) -allylsufanyl] -2-methyl-phenoxy} -acetic; acid { 3-Chloro-4- [2- (4-trifluoromethyl-phenoxymethyl) -allylsulfanyl] -phenyl} - acetic; acid { 2-methyl-4- [1- (4-trifluoromethyl-phenoxymethyl) -cycIopropylmethylsulfanyl] -phenoxy} -acetic; acid { 2-methyl-4- [2-propyl-2- (4-trifluoromethyl-phenoxymethyl) -pentylsulfanyl] -phenoxy} -acetic; acid { 4- [2- (4-acetyl-3-hydroxy-2-propyl-phenoxymethyl) -allylsulfanyl] -2-methyl-phenoxy} -acetic; acid { 4- [2- (4-Chloro-phenoxymethyl) -allylsulfanyl] -2-methyl-phenoxy} -acetic; acid { 4- [2- (3,4-Dichloro-phenoxymethyl) -allylsulfanyl] -2-methyl-phenoxy} -acetic; acid { 4- [2- (2,4-dichloro-phenoxymethyl) -allylsulfanyl] -2-methyl-phenoxy} -acetic; acid { 4- [3-Cyano-2- (4-trifluoromethyl-phenoxymethyl) -allylsulfanyl] -2-methyl-phenoxy} -acetic; acid { 2-methyl-4- [3-phenyl-2- (4-trifluoromethyl-phenoxymethyl) -allysulfanyl] -phenoxy} -acetic; acid { 2-methyl-4- [3-naphthalen-1-yl-2- (4-trifluoromethyl-phenoxymethyl) -allylsulfanyl] -phenoxy} -acetic; acid { 4- [2,2-difluoro-3- (4-trifluoromethyl-phenoxy) -propylsulfanyl] -2-methyl-phenoxy} -acetic; acid { 2-Methyl-4- [2- (4-trifluoromethyl-phenoxymethyl) - [1, 3] d -oxan-2-ylmethylsulfanyl] -phenoxy} -acetic; acid { 4- [2,2-dimethyl-4- (4-trifluoromethyl-phenoxymethyl) - [1,3] dioxolan-4-ylmethylsulfanyl] -2-methyl-phenoxy} -acetic; [2-methyl-4- (2-phenoxymethyl-allylsulfanyl) -phenoxy] -acetic acid; acid { 4- [2- (4-chloro-3-trifluoromethyl-phenoxymethyl) -allylsulfanyl] -2-methyl-phenoxy-acetic acid; acid { 4- [2- (4-methoxy-phenoxymethyl) -allylsulfanyl] -2-methyl-phenoxy} -acetic; acid { 4- [2- (4-dimethylamino-phenoxymethyl) -aylsulfanyl] -2-methyl-phenoxy} -acetic; acid { 2-trifluoromethyl-4- [2- (4-trifluoromethyl-phenoxymethyl) -aylsulfanyl] -phenoxy} -acetic; acid { 3-chloro-4- [2- (4-trifluoromethyl-phenoxymethyl) -allylsulfanyl] -phenoxy-acetic acid; acid { 2-methoxy-4- [2- (4-trifluoromethyl-phenoxymethyl) -allylsulfanyl] -phenoxy-acetic acid; acid { 2-methyl-4- [3- (4-trifluoromethyl-phenoxy) -but-3-enylsulfanyl] -phenoxy-acetic acid; acid { 2-methyl-4- [2- (4-trifluoromethyl-phenoxy) -allylsulfanyl] -phenoxy} - acetic; acid { 4- [2-hydroxy-2- (4-trifluoromethyl-phenoxymethyl) -butylsulfanyl] -2-methyl-phenoxy} -acetic; acid { 4- [2- (4-tert-Butyl-phenoxymethyl) -allylsulfanyl] -2-methyl-phenoxy} - acetic; acid { 4- [2- (4-isopropyl-phenoxymethyl) -allylsulfanyl] -2-methyl-phenoxy} -acetic; acid { 2-Chloro-4- [2- (3,4-dichloro-phenoxymethyl) -al-sulfonyl] -phenoxy} -acetic; acid { 2-Chloro-4- [2- (4-trifluoromethoxy-phenoxymethyl) -allylsulfanyl] -phenoxy} -acetic; acid { 4- [2,2-dimethyl-3- (4-trifluoromethyl-phenoxy) -propylsulfanyl] -2-methyl-phenoxy} -acetic; acid { 2-Chloro-4- [2,2-dimethyl-3- (4-trifluoromethyl-phenoxy) -propylsulfanyl] -phenoxy} -acetic; acid { 2-Chloro-4- [1- (4-trifluoromethyl-phenoxymethyl) -cyclopropylmethylsulfanyl] -phenoxy} -acetic; acid { 3-Chloro-4- [2,2-d.methyl-3- (4-trifluoromethyl-phenoxy) -propylsulfanyl] -phenyl} -acetic; acid { 2-methyl-4- [2- (4-trifluoromethyl-phenoxymethyl) -allylsulfanyl] -phenoxy-acetic acid; acid { 3-Chloro-4- [2,2-dimethyl-3- (4-trifluoromethoxy-phenoxy) -propylsulfanyl] -phenyl} -acetic; and acid. { 3-Chloro-4- [3-methyl-2- (4-trifluoromethyl-phenoxymethyl) -but-2-enylsulfanyl] -phenyl} -acetic. In addition, the following is a compound of the present invention: [2-methyl-4 - [[2 - [[4- (trifluoromethyl) phenoxy] methyl] -2-propenyl] thio] 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 The present invention also relates to compounds of the formula (II): in 11 X it is selected from a covalent bond, S and O; And it's S or O; R i and R 2 are independently selected from H, C 1 -C 3 alkyl, C 1-3 alkoxy, halogen and NR a R b where R a and R b are independently H or C 3 alkyl.; R3 and 4 are independently selected from H, halogen, cyano, C1-5 alkyl, hydroxy, C2- acyl, C4-4 alkoxy, and NRcRd wherein Rc and d are independently H or C3-alkyl, provided that R3 and R4 are not both H; R5 and Re are independently selected from halogen, phenyl, C1-9alkyl, C? -8alkoxy, C2-g alkenyl, C2-g alkenyloxy, C3-7 cycloalkyl, C3-7 cycloalkoxy, cycloalkyl C3-7-C1-7 alkyl, cycloalkyl of C7-C7-alkoxy, C3- cycloalkyloxy-C1-6alkyl, and C3-7cycloalkyloxy-C1-7alkoxy, or R5 and Re together form C1-go alkenylidene of C3- alkenyldenyl g, or R5 and Re and the carbon atom to which they are attached form cycloalkyl of C3. 7 or 5 or 6 membered heterocycle; n is 0, 1 or 2; and m is 0, 1 or 2; or a pharmaceutically acceptable salt thereof. A particular example of such compounds is [2-methyl-4 - [[2 - [[[4- (trifluoromethyl] phenyl] thio] methyl] -2-propenyl] thio] phenoxy] -acetic acid, 1 H NMR ( 400 MHz, CDCI3) d 10.64 (brs, 1 H), 7.46 (d, J = 8.4 Hz, 2 H), 7.33 (d, J = 8.3 Hz, 2 H), 7.17 (s, 1 H), 7.12 ( dd, J = 8.4, 1.5 Hz, 1 H), 6.59 (d, J = 8.4 Hz, 1 H), 4.98 (s, 1 H), 4.87 (s, 1 H), 4.60 (s, 2 H), 3.75 (s, 2 H), 3.58 (s, 2 H), 2.21 (s, 3 H); MS (ES) m / z: 451 (M + Na +); (PPARdelta EC50: 80, 45, 38 nM). 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. Moreover, some of the crystalline forms for the compounds may exixt 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 said solvates are also encompassed within the scope of this invention. The following are other compounds of interest: acid { 4- [2- (2-methyl-phenoxy) } - acetic; 1 H NMR (300 MHz, CDCl 3) d 7.56 (d, J = 9.0 Hz, 1 H), 7.-20 (s, 1 H), 7.17 (d, J = 8.4 Hz, 1 H), 6.61 (d, J = 8.4 Hz, 1 H), 6.42 (d, J = 9.0 Hz, 1 H), . 15 (s, 1 H), 4.99 (s, 1 H), 4.67 (s, 2 H), 4.61 (s, 2 H), 3.57 (s, 2 H), 2.63 (t, J) = 7.6 Hz, 2 H), 2.56 (s, 3 H), 2.21 (s, 3 H), 1.52 (m, 2 H), 0.92 (t, J = 7.4 Hz, 3 H); MS (ES) m / z: 467 (M + Na +); (PPARdelta EC50: 13, 18 nM); [2-methyl-4 - [[2 - [[4- (trifluoromethyl) phenoxy] methyl] -2-propenyl] sulfinyl] phenoxy] -acetic acid 1 H NMR (400 MHz, CDCl 3) d 7.52 (m, 3 H) , 7.35 (s, 1 H), 6.93 (d, J = 8.6 Hz, 2 H), 6.75 (d, J = 8.5 Hz, 1 H), 5.44 (s, 1 H), 5.20 (s, 1 H) , 4.68 (s, 2 H), 4.52 (d, J = 12.7 Hz, 1 H), 4.42 (d, J = 12.7 Hz, 1 H), 3.77 (d, = 12.9 Hz, 1 H), 3.64 (d , J = 12.9 Hz, 1 H), 2.28 (s, 3 H); MS (ES) m / z: 427 (M-H +); (PPARdelta EC50: > 3000 nM); [2-methyl-4 - [[2 - [[5- (trifluoromethyl) -2-pyridinyl] oxy] methyl] -2-propenyl] thio] phenoxy] -acetic acid 1 H NMR (300 MHz, CD 3 OD) d 8.02 (s, 1 H), 7.67 (dd, J = 2.6, 9.6 Hz, 1 H), 7.18 (m, 2 H), 6.72 (d, J = 8.4 Hz, 1 H), 6.65 (d, J = 9.6 Hz, 1 H), 4.82 (s, 1 H), 4.78 (s, 2 H), 4.70 (s, 2 H), 4.66 (s, 1 H), 4.56 (s, 2 H), 3.48 (s) , 2 H), 2.25 (s, 3 H); MS (ES) m / z: 414 (M + H +). Analysis calculated for C21H22F3N04S + 0.4 H2O: C, 54.26; H, 4.51; N, 3.33. Found: C, 54.12; H, 4.28; N, 3.56; (PPARdelta EC50: > 3000 [5-Chloro-2 - [[2 - [[4- (trifluoromethyl] phenoxy] methyl] -2-propenyl] thio] phenoxy] -acetic acid 1 H NMR (300 MHz, CDCl 3) d 9.78 (brs) , 1 H), 7.27 (d, J = 8.4 Hz, 1 H), 6.95-6.91 (m, 3 H), 6.76 (d, J = 1.8 Hz, 1 H), 5.13 (s, 1 H), 5.03 (s, 1 H), 4.71 (s, 2 H), 4.63 (s, 2 H), 3.67 (s, 2 H); MS (ES) m / z: 455 (M + Na +). Analysis calculated for C19H16CIF3? 4S: C, 52.72; H, 3.73. Found: C, 52.53; H, 3.52; (PPARdelta EC50: > 3000 nM); Y [2-Methylene-4 - [[2 - [[[4- (trifluoromethyl) pheny] amine] methyl] -2-propenyl] thio] phenoxy] -acetic acid 1 H NMR (400 MHz) , MeO -d4) d 7.29 (d, J = 8.6 Hz, 2 H), 7.21 (s, H), 7.19 (dd, J = 8.5, 2.0 Hz, 1 H), 6.72 (d, J = 8.3 Hz, 1 H), 6.60 (d, J = 8.6 Hz, 2 H), 4.94 (s, 1 H), 4.80 (s, 1 H), 4.61 (s, 2 H), 3.88 (s, 2 H), 3.49 (s, 2 H), 2.21 (s, 3 H); MS (ES) m / z: 412 (M + H +); (PPARdelta EC50: > 500 nM). The invention provides the disclosed compounds and closely related pharmaceutically acceptable forms of the disclosed compounds, such as salts, esters, amides, hydrates or solvates 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., C-8 alkyl, cycloalkyl, aryl, heteroaryl or non-aromatic heterocyclic), amino acid addition salts, esters and amides which are within a ratio risk / reasonable benefit, 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, primary d-β-amines alkyl and secondary di (d-β-amines) 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, C 1 -C 3 alkyl primary amines, and di (C 2 -2) amines. Representative pharmaceutically acceptable esters of the invention include C-? -7-alkyl, C5-7 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 substituted methyl ethers include methoxymethyl, methylthiomethyl, f-butylthiomethyl, (phenyldimethylsilyl) methoxymethyl, benzyloxymethyl, p-methoxybenzyloxymethyl, (4-methoxyphenoxy) methyl, guaiacolmethyl, f-butoxymethyl, 4-pentenyloxymethyl, syloxymethyl, 2-methoxyethoxymethyl , 2,2,2-trichloroethoxymethyl, bis (2-chloroethoxy) methyl, 2- (trimethylsilyl) ethoxymethyl, tetrahydropyranyl, 3-bromotetrahydropyranyl, tetrahydrothiopyranyl, 1-methoxycyclohexyl, 4-methoxytetrahydropyranyl, 4-methoxytetrahydrothiopyranyl, S, S-dioxide 4- methoxytetrahydrothiopyranyl, 1 - [(2-chloro-4-methyl) phenyl] -4-methoxypiperidin-4-yl, 1,4-dioxan-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl and 2,3,3a, 4, 5, 6,7,7a-octahydro-7,8,8-trimethyl-4J-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-benzyloxyethyl, 1-methyl-1-benzyloxy-2-fluoroethyl, 2,2,2-trichloroethane, 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-dichlorobenzyl, p-cyanobenzyl, p-phenylbenzyl, 2- and 4- picolyl, 3-Methyl-2-picolyl N-oxide, diphenylmethyl, p.p'-dinitrobenzhydryl, 5-dibenzosuberyl, triphenylmethyl, α-naphthyridiphenylmethyl, p-methoxyphenyldiphenylmethyl, di (p-methoxyphenyl) phenylmethyl, tri (p-methoxyphenyl) ) methyl, 4- (4'-bromophenacyloxy) phenyldiphenylmethyl, 4,4 ', 4"-tris (4,5-dichlorophthalimidophenyl) methyl, 4,4,, 4" -tris (levulinoyloxyphenyl) methyl, 4,4', 4"-tris (benzoyloxyphenyl) methyl, 3- (imidazol-1-ylmethyl) bis (4 ', 4" -d-methoxyphenyl) methyl, 1,1-bis (4-methoxyphenyl) -1'-pyrenilomethyl, 9- anthryl, 9- (9-phenyl) xanthenyl, 9- (9-phenyl-10-oxo) anthryl, 1,3-benzodithiolan-2-yl, and S, S-benzisothiazolyl-di-oxide.

Silyl ethers Examples of silyl ethers include trimethylsilyl, triethylsilyl, triisopropylsilyl, dimethylisopropylsilyl, diethylisopropylsilyl, dimethylthshexylsilyl, t-butyldimethylsilyl, f-butyldiphenylsilyl, tribenzylsilyl, tri-p-xylsilyl, 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, triphenylmethoxyacetate, phenoxyacetate, p-chlorophenoxyacetate, pP-phenylacetate, 3-phenylpropionate, 4-oxopentanoate (levulinate), 4,4- (ethyleneiodide) ) pentanoate, pivaloate, adamanthoate, crotonate, 4-methoxyrotonate, benzoate, p-phenylbenzoate, 2,4,6-trimethylbenzoate (mesitoate) Carbonates Examples of carbonates include methyl, 9-fluorenylmethyl, ethyl, 2,2,2-trichloroethyl, 2- (trimethylsilyl) etyl, 2- (phenylsulfonyl) ethyl, 2- (triphenylphosphonium) ethyl, isobutyl, vinyl, allyl, p-nitrophenyl, benzyl, p-methoxybenzyl, 3,4 -methoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, S-benzylthiocarbonate, 4-ethoxy-1-naphthyl and methyldithiocarbonate.

Assisted segmentation Examples of assisted segmentation include 2-iodo benzoate, 4-azidobutyrate, 4-nitro-4-methylpentanoate, o- (dibromomethyl) benzoate, 2-formylbenzenesulfonate, 2- (methylthiomethoxy) ethylcarbonate, 4- (methylthiomethoxy) butyrate and 2 - (methylthiomethoxymethyl) benzoate.

Miscellaneous 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, isobutyrate, monosuccinate, (E) -2-methyl-2-butenoate (tigloate), o- (methoxycarbonyl) benzoate, pP-benzoate, a-naphthoate, nitrate, alkyl-N, N, N \ N ^ Emethylphosphorodiamidate, N-phenylcarbamate, borate, dimethylphosphinothioyl and 2,4-dinitrophenyl sulfenate Sultanates Examples of sulfonates include sulfate, methanesulfonate (mesylate), benzylsulphonate 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) fluorenylmethyl, 2,7-di-t-butyl- [9- ( 10,10-dioxo-10,10,10,10-tetrahydrothioxanthyl)] methyl and 4-methoxyphenacyl.

Substituted Ethyl Examples of substituted ethylcarbamates include 2,2,2-trichloroethyl, 2-trimethylsilylethyl, 2-phenylethyl, 1- (1-adamantyl) -1-methylethyl, 1,1-dimethyl-2-halogenoethyl, 1,1-dimethyl. -2,2-dibromoethyl, 1,1-dimethyl-2,2,2-trichloroethyl, 1-methyl-1- (4-biphenylyl) ethyl, 1- (3,5-di-t-butylphenyl) -1- methylethyl, 2- (2'-y) 4'-pyridyl) ethylene, 2- (N, N-dicyclohexylcarboxamido) ethyl, t-butyl, 1-adamantyl, vinyl, allyl, 1-isopropylallyl, cinnamyl, 4-nitrocinnamyl, 8-quinolyl, N- hydroxypiperidinyl, alkyldithium, benzyl, p-methoxybenzyl, p-nitrobenzyl, p-bromobenzyl, p-chlorobenzyl, 2,4-dichlorobenzyl, 4-methylsulfinylbenzyl, 9-anthrylmethyl and diphenylmethyl.

Assisted segmentation Examples of assisted segmentation include 2-methylthioethyl, 2-methylsulfonylethyl, 2- (p-toluenesulfonyl) ethyl, [2- (1,3-dithianyl)] methyl, 4-methylthiophenyl, 2,4-dimethylthiophenyl, 2-phosphonionethyl, 2-triphenylphosphonium isopropyl, 1,1-dimethyl-2-cyanoethyl, m-chloro-p-acyloxybenzyl, p- (dihydroxybenzyl) benzyl, 5-benzisoxazolylmethyl, and 2- (trifluoromethyl) -6-chromonylmethyl.

Photolytic segmentation Examples of photolytic cleavage include m-nitrophenol, 3,5-dimethoxybenzyl, o-nitrobenzyl, S-dimethoxy-e-nitrobenzyl 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 f-amyl, S-benzylthiocarbamate, p-cyanobenzyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclopropylmethyl, p-decyloxybenzyl, diisopropylmethyl, 2,2-dimethoxycarbonylvinyl, o- (N, N-dimethylcarboxamido) benzyl, 1,1-dimethyl-3- (N, N-dimethylcaridoamido) propyl, 1,1-dimethylpropynyl, 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, 1-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-phenylpropionium, N-picolinoyl, N-3-pyridylcarboxamide, N-benzoylphenylalanyl derivative, N-benzoyl , Np-phenylbenzoyl.

Assisted segmentation Non-nitrophenylacetyl, Non-nitrophenoxyacetyl, N-acetoacetyl, (N -diobenzyloxycarbonylamino) 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, N-nitrocinnamoyl, N-acetylmethionine derivative, No -nitrobenzoyl, N- (benzoyloxymethyl) benzoyl and 4,5-diphenyl-3-oxazolin-2-one.

Derivatives of cyclic measure N-phthalimide, N-dithiasuccinoyl, N-2,3-diphenylmayleoyl, N-2,5-dimethylpyrrolyl, adduct of N-1, 1,4,4-tetramethyldisilylazacyclopentane, 1,3-dimethyl-1 , 5-substituted 3,5-triazacyclohexan-2-one, 1,3-dibenzyl-1, 3,5-triazacyclohexan-2-one 5-substituted and 3,5-dinitro-4-pyridonyl-1-substituted.

Special protective NH groups Examples of special protective NH groups include N-alkyl and N-aryl amines N-methyl, N-allyl, N- [2- (trimethylsilyl) ethoxy] methyl, N-3-acetoxypropyl, N- (1-isopropyl-4-nitro-2-oxo-3-pyrrolin-3-yl), quaternary ammonium salts, N-benzyl, N-di (4-methoxyphenyl) methyl, N-5-dibenzosuberyl, N -triphenylmethyl, N- (4-methoxyphenyl) diphenylmethyl, N-9-phenyl fluorenyl, N-2,7-dichloro-9-fluorenylmethylene, N-ferrocenylmethyl and N'-oxide of N-2-picolylamine.

Derivatives of imine N-1, 1-dimethylthiomethylene, N-benzylidene, N-p-methoxybenzylidene, 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, trido roacetate, trifluoroacetate, methoxyacetate, phenoxyacetate, p-chlorophenoxyacetate, benzoate.

Substituted methyl esters Examples of substituted methyl esters include 9-fluorenylmethyl, methoxymethyl, methylthiomethyl, tetrahydropyranyl, tetrahydrofuranyl, methoxyethoxymethyl, 2- (trimethylsilyl) ethoxymethyl, benzyloxymethyl, 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-trichloroethyl, 2-halogenoethyl, β-chloroalkyl, 2- (trimethylsilyl) ethyl, 2-methylthioethyl, 1,3-dithianyl-2-methyl, 2- (p-nitrophenylsulfenyl) ethyl, 2- (p-toluenesulfonyl) ethyl, 2- (2'-pyridyl) ethyl, 2- (diphenylphosphino) etyl, 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) methyl, 9-anthrylmethyl, 2- (9,10-dioxo) antrylmethyl, 5- dibenzosuberyl, 1-pyrimidomethyl, 2- (trifluoromethyl) - 6-Chromylmethyl, 2,4,6-trimethylbenzyl, p-bromobenzyl, o-nitrobenzyl, p-nitrobenzyl, p-methoxybenzyl, 2,6-dimethoxybenzyl, 4- (methylsulfinyl) -cyclic, 4-sulfobenzyl, piperonyl, 4-picolyl and pP-benzyl.

Silyl Esters Examples of silyl esters include trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, / -propyldimethylsilyl, phenyldimethylsilyl and di-t-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-oxazolidines, 5-alkyl-4-oxo-1,3-dioxolanes, ortho esters, phenyl group and pentaaminocobalt complex (III).

Esters are alkyl Examples of stanilic esters include triethylstannyl and tri-p-butylstannyl.

C. Synthesis The invention provides methods for making the disclosed compounds according to traditional organic synthesis methods as well as matrix or combination synthesis methods. Schemes A to G describe suggested synthesis routes. Using these schemes, the following guidelines, and the examples of compounds 1-28, one skilled in the art can develop analogous or similar methods for a given compound, which are within the scope of 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. Wherein 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. The 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 7. The 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 guide A preferred synthesis of formula (I) is demonstrated in schemes A-G.

SCHEME A Synthesis of A-D A-A A-B According to scheme A, phenol AA, 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 alkylated to form phenoxyacetic acid ethyl ester AB with a halogenoacetic acid ethyl ester such as bromoacetic acid ethyl ester, in the presence of an appropriate base such as Cs 2 CO 3, K 2 CO 3 or NaH, in a solvent suitable such as CH3CN or THF. The sulfonation of the phenoxyacetic acid ethyl ester A-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 A-C. The transformation of sulfonyl chloride A-C to benzenethiol A-D is achieved using a metal as a reducing agent, such as tin or zinc, in an acidic medium such as ethanol or dioxane. In schemes B, D and E, R8 and Rg can be selected, for example, from H, C? -8 alkyl, C2-8 alkenyl, phenyl, halogen and can.

SCHEME B In scheme B, the Mitsunobu reaction of 1,3-diol B-B with phenol B-A provides alcohol B-C using a triarylphosphine such as triphenylphosphine, and an azodicarbonyl reagent such as diisopropyl azodicarboxylate, in a suitable solvent such as THF. Ethyl phenoxyacetic acid ester BD is obtained in two steps: (1) conversion of alcohol BC to mesylate under standard conditions using methanesulfonyl chloride and triethylamine in an appropriate solvent such as CH2Cl2, and (2) alkylation of benzenethiol BD, prepared in accordance with scheme A above, with the mesylate intermediate using a suitable base such as CS2CO3, K2C? 3, or NaH, in an appropriate solvent such as CH3CN or THF, under nitrogen. Under standard saponification conditions, phenoxyacetic acid ethyl ester B-D is converted to B-E 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 C O O Reduction XA * _ * - = _ HO ^ OH s = «x ?, C-A °" B ° "C In scheme C, R5 and RT, the substituted malonate C-A is reduced to propane-1,3-diol C-B using a suitable reducing agent such as lithium aluminum hydride or diisobutylaluminium hydride. After the propane-1, 3-diol CB is converted to CC dimesylate using methanesulfonyl chloride and triethylamine in an appropriate solvent such as CH 2 Cl 2, CC reacts with phenol BA in the presence of a suitable base such as Cs 2 CO 3, K 2 CO 3 or NaH in an appropriate solvent such as CH3CN or THF to produce CD mesylate. Phenoxyacetic acid ethyl ester C-E is obtained by alkylation of benzenethiol A-D, prepared according to scheme A above, with mesylate C-D using a suitable base such as CS2CO3, K2CO3 or NaH in an appropriate solvent such as CH3CN or THF under nitrogen. Under specific saponification conditions, the phenoxyacetic acid ethyl ether C-E is converted to C-F acid under nitrogen. Preferred hydrolysis conditions include the use of NaOH as a base in an aqueous alkylic solvent system such as water-methanol, or using LiOH as a base in a light THF-water system.

SCHEME D In accordance with scheme D, aldehyde D-B could be prepared in two steps by methylation of D-A acid using (trimethylsilyl) diazomethane as a methylating agent followed by reduction of the methyl ester intermediate with a suitable reducing agent such as diisobutylaluminum hydride. The aldehyde D-B is converted to epoxide D-C 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 epoxy ring opening D-C with benzenethiol A-D in the presence of a catalytic amount of tetrabutylammonium fluoride gives the alcohol D-D, which is oxidized to ketone D-E under oxidation conditions • light using acetic anhydride and dimethyl sulfoxide. Various types of olefination of ketone D-E can be carried out to provide D-F alkene.

For example, the Wittig reaction and olefination of D-E with Tebbe reagent will give all D-F. Finally, the saponification of ethyl ester D-F under standard conditions gives D-G acid.

SCHEME E Scheme E shows another way to prepare EE acid as demonstrated in Scheme B. In Scheme E, the epoxide EB is obtained by treating phenol BA with an appropriate base such as cesium carbonate followed by alkylation with 2-chloromethyl- EA oxirane. The epoxide ring opening of EB with benzenethiol AD, prepared in scheme A above, in the presence of a catalytic amount of tetrabutylammonium fluoride gives the alcohol EC, which is oxidized to ED ketone under light oxidation conditions using acetic anhydride and sulfoxide of dimethyl. Various types of olefination of ketone E-D can be carried out to provide B-D alkene. For example, the Wittig reaction and olefination of D-E with Tebbe reagent will give all B-D. Finally, the saponification of ethyl ester B-D under standard conditions gives B-E acid.

SCHEME F Synthesis of F-E FE According to Scheme F, (4-hydroxyphenyl) acetic acid FA, a variety of which are commercially available (such as 3-bromo-4-hydroxyphenylacetic acid, 3-chloro-4-hydroxyphenylacetic acid, 3-fluoro acid) 4-hydroxyphenylacetic acid, 4-hydroxy-3-methoxyphenylacetic acid, and 4-hydroxy-3-nitrophenylacetic acid), is methylated to form methyl (4-hydroxyphenyl) acetic acid methyl ester FB in methanol in the presence of a catalytic amount of a suitable acid such as sulfuric acid or hydrochloric acid. The phenol F-B is converted to (4-dimethylthiocarbamoyloxyphenyl) acetic acid methyl ester F-C by reacting with dimethylthiocarbamoyl 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, F-C is rearranged to (4-dimethylcarbamoylsulfanylphenyl) acetic acid methyl ester F-D in a high boiling solvent such as tetradecane. By treatment with a suitable base such as sodium methoxide F-D is converted to methyl ester of (4-mercapto-phenyl) acetic acid F-E.

SCHEME G In Scheme G, the acetic acid methyl ester GA is obtained by alkylation of benzenethiol FE, prepared according to scheme F above, with CD mesylate using a suitable base such as Cs 2 CO 3, K 2 CO 3 or NaH in an appropriate solvent such as CH 3 CN or THF under nitrogen. Under specific saponification conditions, the methyl ester G-A is hydrolyzed to G-B acid.

EXAMPLES EXAMPLE I SCHEME 1 1-C, B% (4-Chlorosulfonyl-2-methyl-phenoxy) -acetic acid ethyl ester To a flask containing chlorosulfonic acid (15.0 ml, 226 mmol) at 4 ° C was added (2-methylphenoxy) -acetate. ethyl 1-A (10.0 g, 51.6 mmol) slowly. 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 1-B as a white solid; 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, 3 H); MS (ES) m / z: 315 (M + Na +).

Ethyl ester of (4-mercapto-2-methyl-phenoxy) -acetic acid To a solution of 1-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 mmol) 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 1-C 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, 2 H), 4.25 (q, J = 7.1 Hz, 2 H), 2.24 (s, 3 H), 1.29 (t, J = 7.1 Hz, 3 H).

SCHEME 2 2-A 2- (4-Trifluoromethyl-phenoxymethyl) -prop-2-en-1-ol To a mixture of 4-trifluoromethylphenol (49.0 g, 302 mmol), 2-methylene-1,3-propanediol (40.0 g, 454 mmoles), and azodicarboxylate of Diisopropyl (67.4 g, 333 mmol) in CH 2 Cl 2 (400 mL) at 0 ° C was added dropwise a solution of triphenylphosphine (87.2 g, 333 mmol) in CH 2 Cl 2 (400 mL).

After the mixture was stirred at 0 ° C and then allowed to warm to room temperature overnight, CH2Cl2 was evaporated under reduced pressure. To the residue was added Et2O and hexane, and the mixture was cooled to 0 ° C. The precipitated solid was filtered, and the filtrate was concentrated and subjected to column chromatography (EtOAc / hexane: 1/4) to give 35.2 g (50%) of 2-A; 1 H NMR (300 MHz, CDCl 3) d 7.55 (d, J = 8.6 Hz, 2 H), 6.99 (d, J = 8.6 Hz, 2 H), 5.33 (d, J = 0.9 Hz, 1 H), 5.29 ( d, J = 0.9 Hz, 1 H), 4.65 (s, 2 H), 4.27 (d, J = 6.0 Hz, 2 H). 2-B Ethyl ester of acid. { 2-metii-4- [2- (4-trifluoromethyl-phenoxymethyl) -allylsulfanyl] -phenoxy-acetic acid General procedure 1 for the formation of thioether: To a solution of 2-A (18.1 g, 78.2 mmol) in CH 2 Cl 2 (400 mL) at 0 ° C were added Et ^N (23.0 mL, 165 mmol) and methanesulfonyl chloride ( 13.4 g, 117 mmol). The mixture was stirred at 0 ° C for 1 hr and at room temperature overnight and was diluted with saturated NaHCO3 (100 ml). The organic layer was separated and the aqueous layer was extracted with CH2Cl2 (x3). The combined organic phases were dried and concentrated to provide 24.2 g of the crude product. A mixture of the above crude product, (4-mercapto-2-methyl-phenoxy) -acetic acid ethyl ester 1-C (21.2 g, 93.8 mmol), and Cs2CO3 (76.2 g, 234 mmol) in CH3CN (290 mL) were stirred at room temperature for 2 hr. Water was added and the mixture was extracted with CH2Cl2. The combined organic layers were dried, concentrated and subjected to column chromatography (EtOAc / hexane: 1/10) to provide 28.8 g (84%) of 2-B; 1 H NMR (300 MHz, CDCl 3) d 7.53 (d, J = 8.7 Hz, 2 H), 7.20 (s, 1 H), 7.16 (dd, J = 8.4, 2.2 Hz, 1 H), 6.96 (d, J = 8.6 Hz, 2H), 6.59 (d, J = 8.4 Hz, 1 H), 5.13 (d, J = 0.9 Hz, 1 H), 4.98 (s, 1 H), 4.65 (s, 2 H), 4.60 (s, 2 H), 4.26 (q, J = 7.1 Hz, 2 H), 3.56 (s, 2 H), 2.24 (s, 3 H), 1.29 (t, J = 7.1 Hz, 3 H); MS (ES) m / z: 463 (M + Na +).

Compound 1 Acid. { 2-methyl-4- [2- (4-trifluoromethyl-phenoxymethyl) -allylsulfanyl] -phenoxy} -acetic General procedure 2 for the hydrolysis of ethyl and methyl esters: To a solution of 2-B (28.8 g, 65.5 mmol) in THF (576 ml) at 0 ° C under N2 was added 1.0 M LiOH (131 ml, 131 mmol) ). After stirring at 0 ° C for 45 min and at room temperature for 2.5 hr, the mixture was cooled to 0 ° C, acidified with 1 M HCl, and extracted with EtOAc (x 3). The extracts were dried, concentrated and purified by column chromatography to give 26.7 g (99%) of compound 1; 1 H NMR (300 MHz, CDCl 3) d 7.52 (d, J = 8.6 Hz, 2 H), 7.21 (s, 1 H), 7.17 (dd, J = 8.4, 2.2 Hz, 1 H), 6.95 (d, J = 8.6 Hz, 2 H), 6.62 (d, J = 8.4 Hz, 1 H), 5.14 (d, J = 1.0 Hz, 1 H), 4.99 (d, J = 1.0 Hz, 1 H), 4.65 (s) , 4 H), 3.57 (s, 2 H), 2.23 (s, 3 H); MS (ES) m / z: 435 (M + Na +).

Analysis calculated for C20H? 9O4F3S.0.1 H20: C, 57.99; H, 4.67; S, 7.74; F, 13.76, found: C, 58.06; H, 4.64; S, 7.46; F, 13.91.

EXAMPLE 11 SCHEME 4 Compound 2 4-B 3- (4-Trifluoromethyl-phenyl) -propionic acid methyl ester To a solution of 4-A (1.00 g, 4.59 mmol) in Et20 (20 mL) and MeOH (10 mL) was added (trimethylsilyl ) 1.0 M dichromethane (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 dissolved in Et20, washed with saturated NaHCO3 and brine, dried and concentrated to give 1.04 g (98%) of 4-B; 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, 2 H), 2.65 (t, J = 7.7 Hz, 2 H); MS (ES) m / z: 255 (M + Na +). 4-C 3- (4-Trifluoromethyl-phenyl) -propionaldehyde To a solution of 4-B (1.10 g, 4.74 mmol) in CH2Cl2 (20 mL) a -78 ° C 1.0 M diisobutylaluminum hydride (4J4 ml, 4J4 mmoles) was added. The mixture was stirred at -78 ° C for 10 min and quenched with 10% HCl in MeOH (5 mL). After warming to room temperature, the mixture was filtered and the filtrate was concentrated and subjected to column chromatography to provide 796 mg (83%) of 4-C; 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 (t, J = 7.4 Hz, 2 H), 2.82 (t, J = 7.3 Hz, 2H). 4-0 2- [2- (4-Trifluoromethyl-phenyl) -ethyl] -oxitan A mixture of NaH (52 mg, 1.3 mmol, 60% in mineral oil) in DMSO (15 ml) was heated to 70 ° C. C for 30 min and allowed to cool to room temperature. After dilution with THF (10 ml), a solution of trimethylsulfonium 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 4-C (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 extracts were dried, concentrated, and subjected to column chromatography (EtOAc / hexane: 1/7) to provide 147 mg (68%) of 4-D; 1 H NMR (300 MHz, CDCl 3) d 7.54 (d, J = 8.1 Hz, 2 H), 7.31 (d, J = 8.0 Hz, 2 H), 2.97-2.90 (m, 1 H), 2.88-2.78 (m, 2 H), 2J5 (m, 1 H), 2.47 (dd, j = 4.9, 2.7 Hz, 1 H) , 1.98-1.73 (m, 2 H). 4-E Ethyl ester of acid. { 4- [2-hydroxy-4- (4-trifluoromethyl-phenyl) -butylsulfanylj-2-methyl-phenoxy-acetic acid A mixture of 4-D (251 mg, 1.16 mmol), ethyl ester of (4-mercapto-2) -methylphenoxy) acetic acid 1-C (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 4-E; 1 H NMR (300 MHz, CDCl 3) d 7.51 (d, J = 8.0 Hz, 2 H), 7.26 (d, J = 8.0 Hz, 2 H), 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, 2 H), 4.26 (q, J = 7.1 Hz, 2 H), 3.63-3.55 (m, 1 H), 3.01 (dd, J = 13.6 , 3.4 Hz, 1 H), 2.91-2.81 (m, 1 H), 2.79-2.66 (m, 2 H), 2.56 (brs, 1 H), 2.25 (s, 3 H), 1.84-1.76 (m, 2 H), 1.30 (t, J = 7.1 Hz, 3 H); MS (ES) m / z: 465 (M + Na +).

Ethyl ester of acid. { 2-methyl-4- [2-oxo-4- (4-trifluoromethyl-phenyl) -butylsulfanyl] -phenoxy-acetic acid A mixture of 4-E (370 mg, 0.837 mmol) in Ac2O (2.5 ml) and DMSO (4 ml) was stirred at room temperature for 24 hr, diluted with water, and extracted with Et20. The extracts were dried, concentrated and purified by column chromatography to give 278 mg (75%) of 4-F; 1 H NMR (300 MHz, CDCl 3) d 7.51 (d, J = 8.1 Hz, 2 H), 7.26 (d, J = 8.0 Hz, 2 H), 7.15 (d, J = 1.7 Hz, 1 H), 7.04 ( dd, J = 8.5, 2.3 Hz, 1 H), 6.57 (d, J = 8.5 Hz, 1 H), 4.60 (s, 2 H), 4.26 (q, J = 7.1 Hz, 2 H), 3.52 (s) , 2 H), 2.92 (s, 4 H), 2.23 (s, 3 H), 1.29 (t, J = 7.1 Hz, 3 H); MS (ES) m / z: 463 (M + Na +).

Ethyl ester of (2-methyl-4-. {2- [2- (4-trifluoromethyl-phenyl) -ethyl] -alkylsulfanyl] -phenoxy) -acetic acid To a solution of 4-F (53 mg, 0.12 mmol) in THF (1 mL) at -78 ° C was slowly added 0.5 M Tebbe reagent (0.24 mL, 0.12 mmol) in toluene. The mixture was gradually warmed to 0 ° C, stirred at the same temperature for 4.5 hr, diluted with saturated NaHC 3 3, and extracted with Et20. The combined organic layers were dried, concentrated, and subjected to column chromatography (EtOAc / hexane: 1/10) to give 10 mg (19%) of 4-G; 1 H NMR (300 MHz, CDCl 3) d 7.53 (d, J = 8.1 Hz, 2 H), 7.29 (d, J = 8. 0 Hz, 2 H), 7.18 (d, J = 1.9 Hz, 1H), 7.12 (dd, J = 8.4, 2.2 Hz, 1 H), 6.60 (d, J = 8.4 Hz, 1 H), 4.79 (s, 2 H), 4.61 (s, 2 H), 4.26 (q, J = 7.1 Hz, 2 H), 3.45 (s, 2 H), 2.82 (t, J = 8.0 Hz, 2 H), 2.50 (t, J = 8.0 Hz, 2 H), 2.25 (s, 3 H), 1.28 (t, J = 7.1 Hz, 3 H); MS (ES) m / z: 461 (M + Na +).

Compound 2 Acid (2-methyl-4- { 2- [2- (4-trifluoromethyl-phenyl) -ethyl] -allylsulfanyl} -phenoxy) -acetic Following the general procedure 2, compound 2 was obtained (85 %); 1 H NMR (300 MHz, CDCl 3) d 7.51 (d, J = 8.0 Hz, 2 H), 7.25 (d, J = 7.7 Hz, 2 H), 7.11 (s, 1 H), 7.06 (d, J = 7.5 Hz, 1 H), 6.56 (d, J = 6.8 Hz, 1 H), 4.78 (s, 1 H), 4.77 (s, 1 H), 3.41 (s, 2 H), 2.79 (t, J = 8.0 Hz, 2 H), 2.47 (t, J = 8.0 Hz, 2 H), 2.15 (s, 3 H); MS (ES) m / z: 433 (M + Na +).

EXAMPLE Hl SCHEME 5 -A Methanesulfonic acid 2-chloromethyl-allyl ester To a solution of 2-methylenepropane-1,3-diol (257 mg, 2.92 mmol) in CH 2 Cl 2 (4 ml) and CH 3 CN (4 ml) at 0 ° C were added Et3N (1.76 ml, 12. 6 mmoles) and methanesulfonyl chloride (1.01 g, 8.79 mmoles). After the mixture was stirred at 0 ° C for 2 hr and then allowed to warm to room temperature overnight, saturated NaHCO3 was added. The organic layer was separated and the aqueous layer was extracted with CH2Cl2. The combined organic phases were dried, concentrated and subjected to column chromatography (EtOAc / hexane: 1/3) to give 313 mg (58%) of 5-A; 1 H NMR (300 MHz, CDCl 3) d 5.47 (s, 1 H), 5.42 (s, 1 H), 4.82 (s, 2 H), 4.16 (s, 2 H), 3.06 (s, 3 H); MS (ES) m / z: 207 (M + Na +).

-B (2-Chloromethyl-allyloxy) -benzene To a suspension of NaH (40 mg, 1.0 mmol, 60% in mineral oil) in THF (2 ml) was added a solution of phenol (94 mg, 1.0 mmol) in THF (1 ml). After stirring at room temperature for 15 min, the mixture was transferred to a solution of 2-A methanesulfonic acid 2-chloromethylallyl ester (185 mg, 1.00 mmol) in THF (2 ml). The mixture was stirred at room temperature for 1 hr, then warmed to 40 ° C overnight, diluted with water, and extracted with EtOAc. The extracts were dried, concentrated and subjected to column chromatography (EtOAc / hexane: 1/9) to provide 148 mg (81%) of 5-B; 1 H NMR (300 MHz, CDCl 3) d 7.30-7.27 (m, 2 H), 6.97-6.91 (m, 3 H), 5.35 (s, 1 H), 5.34 (s, 1 H), 4.60 (s, 2 H), 4.16 (s, 2 H).

Ethyl ester of [2-methyl-4- (2-phenoxymethyl-allylsulfanyl) -phenoxy] -acetic acid General procedure 3 for the formation of thioether: A mixture of 5-B (96 mg, 0.53 mmole), ethyl ester of acid (4-mercapto-2-methyl-phenoxy) -acetic acid 1-C (145 mg, 0.642 mmol), and Cs2CO3 (417 mg, 1.28 mmol) in CH3CN (3 mL) was stirred for 5 h 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 168 mg (85%) of 5-C; 1 H NMR (400 MHz, CDCl 3) d 7.28-7.23 (m, 2 H), 7.20 (d, J = 2.0 Hz, 1 H), 7.16 (dd, J = 8.4, 2.3 Hz, 1 H), 6.95-6.89 (m, 3 H), 6.59 (d, J = 8.4 Hz, 1 H), 5.13 (s, 1 H), 4.95 (s, 1 H), 4.60 (s, 2 H), 4.58 (s, 2 H) ), 4.24 (q, J = 7.1 Hz, 2 H), 3.56 (s, 2 H), 2.23 (s, 3 H), 1.27 (t, J = 7.1 Hz, 3 H); MS (ES) m / z: 395 (M + Na +).

Compound 3 [2-Methyl-4- (2-phenoxymethyl-allylsulfanyl) -phenoxy] -acetic acid Following the general procedure 2, compound 3 (86%) was obtained; 1 H NMR (300 MHz, CDCl 3) d 7.29-7.24 (m, 2 H), 7.21 (s, 1 H), 7. 18 (d, J = 8.4 Hz, 1 H), 6.97-6.89 (m, 3 H), 6.62 (d, J = 8.4 Hz, 1 H), 5.15 (s, 1 H), 4.98 (s, 1 H) ), 4.66 (s, 2 H), 4.61 (s, 2 H), 3.58 (s, 2 H), 2.23 (s, 3 H); MS (ES) m / z: 367 (M + Na +).

EXAMPLE IV SCHEME 6 HO- -OH H ° -Q0CF *, HO- -0-T OCF3 ™ '* # - "DIAD, Ph3P, CHZC12" - CH2Cl2 51%, 6-A Cs2C03. CH3CN s 3n0o% ¿, ft 6.-RB S j [° '- "O-' 6-A 2- (4-Trifluoromethoxy-phenoxymethyl) -prop-2-en-1-ol To a mixture of 4-trifluoromethoxyphenol (2.37 g, 13.1 mmol), 2-methylene-propan-1 , 3-diol (1.73 g, 19.6 mmol), and diisopropyl azodicarboxylate (3.96 g, 19.6 mmol) in CH2Cl2 (50 mL) was added a solution of PhsP (5.13 g, 19.6 mmol) in 50 mL of CH2Cl2 in 30 minutes . After After stirring for 5 hours, the mixture was diluted with Et2O (100 ml), washed with 1 N NaOH, dried, concentrated and subjected to column chromatography to give 1.7 g (51%) of 6-A; 1 H NMR (300 MHz, CDCl 3) d 7.13 (d, J = 9.1 Hz, 2 H), 6.91 (dd, J = 9.2, 2.3 Hz, 2 H), 5.31 (d, J = 0.9 Hz, 1 H), 5.28 (d, J = 0.9 Hz, 1 H), 4.59 (s, 2 H), 4.26 (d, J = 6.1 Hz, 2 H), 1.63 (t, J = 6.1 Hz, 1 H).

Ethyl ester of acid. { 2-methyl-4- [2- (4-trifluoromethoxy-phenoxymethyl) -alkylsulfanyl-phenoxy-acetic Following general procedure 1, 6-B was obtained; 1 H NMR (300 MHz, CDCl 3) d 7.21-7.11 (m, 4 H), 6.88 (dd, J = 9.2, 2.3 Hz, 2H), 6.60 (d, J = 8.4 Hz, 1H), 5.13 (d, J = 1.1 Hz, 1 H), 4.96 (d, J = OJ Hz, 1 H), 4.60 (s, 4 H), 4.26 (q, J = 7.1 Hz, 2 H), 3.56 (s, 2 H), 2.24 (s, 3 H), 1.29 (t, J = 7.1 Hz, 3 H); MS (ES) m / z: 479 (M + Na +).

Compound 4 [2-Methyl-4- (2-p-tolyloxymethyl-allylsulfanyl) -phenoxy] -acetic acid. Following general procedure 2, compound 4 was obtained; 1 H NMR (300 MHz, CDCl 3) d 7.19-7.10 (m, 4 H), 6.88 (d, J = 9.2 Hz, 2 H), 6.62 (d, J = 7.9 Hz, 1 H), 5.13 (s, 1 H), 4.98 (s, 1 H), 4.59 (s, 4 H), 3.56 (s, 2 H), 2.21 (s, 3 H); MS (ES) m / z: 428 (M + H +); Analysis calculated for C2oH19F3? 5S * 0.2H20: C, 55.60; H, 4.53.

Found: C, 55.61; H, 4.36.

EXAMPLE V SCHEME 7 7-A Ethyl ester of acid. { 4- [2- (4-Chloro-phenoxymethyl) -allylsulfanyl] -2-methyl-phenoxy} - acetic General procedure 4 for the formation of both ether and thioether: To a suspension of NaH (28 mg, 0.70 mmol, 60% in mineral oil) in THF (1 ml) was added a solution of 4-chlorophenol (89 mg, 0.69 mmoles) in THF (1 ml). After stirring at room temperature for 30 min, a solution of 2-A methanesulfonic acid 2-chloromethylallyl ester (128 mg, 0.693 mmol) in THF (1 ml) was added and the mixture was heated at 50 ° C overnight. To the mixture, (4-mercapto-2-methylphenoxy) acetic acid ethyl ester 1-C (204 mg, 0.901 mmol), Cs2CO3 (450 mg, 1.38 mmol), and CH3CN (5 mL) were added sequentially. After stirring at room temperature for 1 hr, the reaction mixture was diluted with water and extracted with Et2O. The organic phase was dried, concentrated and subjected to column chromatography (EtOAc / hexane) to provide 180 mg (64%) of 7-A; 1 H NMR (400 MHz, CDCl 3) d 7.20 (d, J = 8.9 Hz, 2 H), 7.21-7.19 (m, 1 H), 7.15 (dd, J = 8.4, 2.2 Hz, 1 H), 6.82 (d, J = 9.0 Hz, 2 H), 6.59 (d, J = 8.4 Hz, 1 H), 5.11 ( d, J = 1.0 Hz, 1 H), 4.95 (s, 1 H), 4.60 (s, 2 H), 4.57 (s, 2 H), 4.25 (q, J = 7.1 Hz, 2 H), 3.55 (s, 2 H), 2.24 (s, 3 H), 1.28 (t, J = 7.1 Hz, 3 H); MS (ES) m / z: 429 (M + Na +).

Compound 5 Acid. { 4- [2- (4-Chloro-phenoxymethyl) -allylsulfanyl] -2-methyl-phenoxy} -acetic Following the general procedure 2, compound 5 (93%) was obtained; 1 H NMR (400 MHz, CDCl 3) d 7.22-7.20 (m, 1 H), 7.20 (d, J = 8.8 Hz, 2 H), 7.16 (d, J = 8.4 Hz, 1 H), 6.82 (d, J = 8.9 Hz, 2H), 6.61 (d, J = 8.4 Hz, 1 H), 5.12 (s, 1 H), 4.97 (s, 1 H), 4.66 (s, 2 H), 4.57 (s, 2 H) ), 3.56 (s, 2 H), 2.23 (s, 3 H); MS (ES) m / z: 401 (M + Na +).

EXAMPLE VI SCHEME 8 Ethyl ester of acid. { 4- [2- (3,4-dichloro-phenoxymethyl) -allylsulfanyl-J-2-methyl-phenoxy} - acetic Following the general procedure 4, 8-A (62%) was obtained; H NMR (400 MHz, CDCl 3) d 7.28 (d, J = 8.9 Hz, 1 H), 7.20 (d, J = 2.0 Hz, 1 H), 7.15 (dd, J = 8.4, 2.2 Hz, 1 H), 6.99 (d, J = 2.9 Hz, 1 H), 6.74 (dd, J = 8.9, 2.9 Hz, 1 H), 6.59 (d, J = 8.4 Hz, 1 H), 5.09 (s, 1 H), 4.95 (s, 1 H), 4.60 (s, 2 H), 4.56 (s, 2 H), 4.25 (q, J = 7.1 Hz, 2 H), 3.53 (s, 2 H), 2.24 (s, 3 H) ), 1.28 (t, J = 7.1 Hz, 3 H); MS (ES) m / z: 463 (M + Na +).

Compound 6 Acid. { 4- [2- (3,4-dichloro-phenoxymethyl) -allysulfanyl] -2-methylo-phenoxy} -acetic Following the general procedure 2, compound 6 (90%) was obtained; 1 H NMR (300 MHz, CDCl 3) d 7.28 (d, J = 8.9 Hz, 1 H), 7.20 (s, 1 H), 7.16 (dd, J = 8.4, 1.9 Hz, 1 H), 6.98 (d, J = 2.8 Hz, 1 H), 6.73 (dd, J = 8.9, 2.9 Hz, 1 H), 6.61 (d, J = 8.4 Hz, 1 H), 5.10 (s, 1 H), 4.97 (s, 1 H) ), 4.65 (s, 2 H), 4.56 (s, 2 H), 3.54 (s, 2 H), 2.22 (s, 3 H); MS (ES) m / z: 435 (M + Na +).

EXAMPLE VII 9-A Ethyl ester of acid. { 4- [2- (2,4-dichloro-phenoxymethyl) -allylsulfanyl] -2-methyl-phenoxy} - acetic Following the general procedure 4, the title compound 9-A (56%) was obtained; 1 H NMR (400 MHz, CDCl 3) d 7.34 (d, J = 2.5 Hz, 1 H), 7.19 (s, 1 H), 7.16 (m, 1 H), 7.13 (dd, J = 8.6, 2.4 Hz, 1 H), 6.81 (d, J = 8.8 Hz, 1 H), 6.58 (d, J = 8.4 Hz, 1 H), 5.15 (s, 1 H), 4.98 (s, 1 H), 4.63 (s, 2 H), 4.59 (s, 2 H), 4.25 (q, J = 7.1 Hz, 2 H), 3.59 (s, 2 H), 2.23 (s, 3 H), 1.28 (t, J = 7.1 Hz, 3 H); MS (ES) m / z: 463 (M + Na +). Analysis calculated for C2? H22CI204S: C, 57.15; H, 5.02. Found: C, 57.52; H, 4.92.

Compound 7 Acid. { 4- [2- (2,4-dichloro-phenoxymethyl) -allylsulfanyl] -2-methyl-phenoxy} -acetic Following the general procedure 2, compound 7 (91%) was obtained; 1 H NMR (400 MHz, CDCl 3) d 7.35 (d, J = 2.5 Hz, 1 H), 7.20 (s, 1 H), 7.18-7.12 (m, 2 H), 6.81 (d, J = 8.8 Hz, 1 H), 6.61 (d, J = 8.4 Hz, 1 H), 5.16 (s, 1 H), 5.01 (s, 1 H), 4.66 (s, 2 H), 4.64 (s, 2 H), 3.60 ( s, 2 H), 2.23 (s, 3 H); MS (ES) m / z: 435 (M + Na +).

EXAMPLE HIV -A Ethyl ester of acid. { 4- [2- (4-chloro-3-trifluoromethyl-phenoxymethyl) -allylsulfanyl] -2-methyl-phenoxy) -acetic Following the general procedure 4, the title compound 10-A (83%) was obtained; 1 H NMR (400 MHz, CDCl 3) d 7.36 (d, J = 8.8 Hz, 1 H), 7.21 (d, J = 3.0 Hz, 1 H), 7.20 (d, J = 8.0 Hz, 1 H), 7.15 ( dd, J = 8.4, 2.1 Hz, 1 H), 6.97 (dd, J = 8.8, 2.9 Hz, 1 H), 6.59 (d, J = 8.4 Hz, 1 H), 5.11 (s, 1 H), 4.97 (s, 1 H), 4. 61 (s, 2 H), 4.60 (s, 2 H), 4.25 (q, J = 7.1 Hz, 2 H), 3.55 (s, 2 H), 2.23 (s, 3) H), 1.28 (t, J = 7.1 Hz. 3 H); MS (ES) m / z: 497 (M + Na +). Analysis calculated for C22H22CIF3O4S: C, 55.64; H, 4.67. Found: C, 55.76; H, 4.52.

Compound 8 Acid. { 4- [2- (4-chloro-3-trifluoromethyl-phenoxymethyl) -allylsulfanyl] -2-methyl-phenoxy} - acetic Following the general procedure 2, compound 8 (86%) was obtained; 1 H NMR (300 MHz, CDCl 3) d 7.35 (d, J = 8.8 Hz, 1 H), 7.21 (s, 1 H), 7.20 (s, 1 H), 7.16 (dd, J = 8.5, 2.1 Hz, 1 H), 6.96 (dd, J = 8.8, 3.0 Hz, 1 H), 6. 61 (d, J = 8.4 Hz, 1 H), 5.12 (d, J = 0.9 Hz, 1 H), 4.99 (s, 1 H), 4.65 (s, 2 H), 4. 61 (s, 2 H), 3.56 (s, 2 H), 2.23 (s, 3 H); MS (ES) m / z: 469 (M + Na +).

EXAMPLE IX 11-A Ethyl ester of acid. { 4- [2- (4-methoxy-phenoxymethyl) -allylsulfanyl] -2-methyl-phenoxy} - acetic Following the general procedure 4, the title compound 11 -A (60%) was obtained; 1 H NMR (300 MHz, CDCl 3) d 7.19 (d, J = 1.8 Hz, 1 H), 7.14 (dd, J = 8.4, 2.2 Hz, 1 H), 6.85-6.77 (m, 4 H), 6.58 (d, J = 8.4 Hz, 1 H), 5.11 (s, 1 H), 4. 57 (s, 2 H), 4.54 (s, 2 H), 4.23 (q, J = 7.1 Hz, 2 H), 3.73 (s, 3 H), 3.55 (s, 2 H), 2.23 (s, 3 H), 1.26 (t, J = 7.1 Hz, 3 H); MS (ES) m / z: 425 (M + Na +).

Compound 9 Acid. { 4- [2- (4-methoxy-phenoxymethyl) -allylsulfanyl] -2-methyl-phenoxy} -acetic Following the general procedure 2, compound 9 was obtained (90%); MS (ES) m / z: 397 (M + Na +).

EXAMPLE X Ethyl ester of acid. { 4- [2- (4-dimethylamino-phenoxymethyl) -allylsulfanyl-2-methyl-phenoxy-acetic acid Following the general procedure 4, the title compound 12-A (80%) was obtained; 1 H NMR (300 MHz, CDCl 3) d 7.20 (s, 1 H), 7.16 (dd, J = 8.4, 2.2 Hz, 1 H), 6.73 (d, J = 9.0 Hz, 2 H), 6.60 (d, J = 8.4 Hz, 1 H), 6.85 (d, J = 9.1 Hz, 2 H), 5.13 (d, J = 1.1 Hz, 1 H), 4.94 (s, 1 H), 4.60 (s, 2 H), 4.56 (s, 2 H), 4. 25 (q, J = 7.1 Hz, 2 H), 3.57 (s, 2 H), 2.87 (s, 6 H), 2.24 (s, 3 H), 1.29 (t, J = 7. 1 Hz, 3 H); MS (ES) m / z: 416 (M + Na +).

Compound 10 Acid. { 4- [2- (4-dimethylamino-phenoxymethyl) -allylsulfanyl] -2-methyl-phenoxy} -acetic Following the general procedure 2, compound 10 (85%) was obtained; 1 H NMR (400 MHz, MeOH-d 4) d 7.17 (s, 1 H), 7.15 (dd, J = 8.5, 2.1 Hz, 1 H), 6.92 (d, J = 9.1 Hz, 2 H), 6.82 (d , J = 9.2 Hz, 2 H), 6.69 (d, J = 8.4 Hz, 1 H), 5.04 (d, J = 1.3 Hz, 1 H), 4.90 (s, 1 H), 4.56 (s, 2 H) ), 4.54 (s, 2 H), 3.55 (s, 2 H), 2.88 (s, 6 H), 2.18 (s, 3 H); MS (ES) m / z: 388 (M + H +).

EXAMPLE XI SCHEME 13 CsaCOji.CHaCN 13-A 1- (2-Chloromethylalloyloxy) -4-trifluoromethyl-benzene To a suspension of NaH (60 mg, 1.5 mmol, 60% in mineral oil) in THF (2 ml) was added a solution of 4 ml. -trifluoromethylphenol (162 mg, 1.00 mmol) in THF (1 ml). After stirring at room temperature for 15 min, the mixture was transferred to a solution of 2-A methanesulfonic acid 2-chloromethylallyl ester (185 mg, 1.00 mmol) in THF (3 ml) at 0 ° C. The mixture was heated at 60-70 ° C for 3 hr and 40-50 ° C overnight, diluted with water, and extracted with EtOAc. The extracts were dried, concentrated, and subjected to column chromatography (EtOAc / hexane: 1/10) to provide 221 mg (88%) of 13-A; 1 H NMR (300 MHz, CDCl 3) d 7.55 (d, J = 8.6 Hz, 2 H), 7.00 (d, J = 8.6 Hz, 2 H), 5.42 (s, 1 H), 5.37 (s, 1 H) , 4.68 (s, 2 H), 4.19 (s, 2 H). 3-C Ethyl ester of acid. { 2-Chloro-4- [2- (4-trifluoromethyl-phenoxymethyl) -alkylsulfanyl] -phenoxy-acetic acid Replacing ethyl ester of (4-mercapto-2-methyl-phenoxy) -acetic acid 1-C with ethyl ester of acid (2) -chloro-4-mercapto-phenoxy) -acetic 13-B and following general procedure 3, 13-C (80%) was obtained; 1 H NMR (400 MHz, CDCl 3) d 7.53 (d, J = 8.8 Hz, 2 H), 7.43 (d, J = 2.3 Hz, 1 H), 7.20 (dd, J = 8.5, 2.3 Hz, 1 H), 6.96 (d, J = 8.8 Hz, 2 H), 6.73 (d, J = 8.6 Hz, 1 H), 5.17 (s, 1 H), 5.01 (s, 1 H), 4.66 (s, 2 H), 4.65 (s, 2 H), 4.26 (q, J = 7.1 Hz, 2 H), 3.59 (s, 2 H) ), 1.28 (t, J = 7.1 Hz, 3 H); MS (ES) m / z: 483 (M + Na +).

Compound 11 Acid. { 2-Chloro-4- [2- (4-trifluoromethyl-phenoxymethyl) -alkylsulfanyl] -phenoxy} -acetic Following the general procedure 2, compound 11 was obtained (95%); H NMR (300 MHz, CDCl 3) d 7.54 (d, J = 8.6 Hz, 2 H), 7.44 (d, J = 2.2 Hz, 1 H), 7.22 (dd, J = 8.5, 2.2 Hz, 1 H), 6.96 (d, J = 8.6 Hz, 2H), 6.77 (d, J = 8.5 Hz, 1 H), 5.19 ( s, 1 H), 5.04 (s, 1 H), 4.71 (s, 2 H), 4.65 (s, 2 H), 3.61 (s, 2 H); MS (ES) m / z: 455 (M + Na +).

Analysis calculated for C19H16CIF3O4S: C, 52.72; H, 3.72. Found: C, 52.79; H, 3.59.

EXAMPLE Xll SCHEME 14 1F-A (4-Chlorosulfonyl-2-trifluoromethyl-phenoxy) -acetic acid methyl ester A mixture of 2-trifluoromethylphenol (4.66 g, 28.8 mmol), ester bromoacetic acid methyl ester (4.01 g, 26.2 mmol), and Cs2CO3 (18.8 g, 57.6 mmol) in CH3CN (50 mL) was stirred at room temperature overnight, filtered and washed with CH3CN. The filtrate was concentrated, the residue was dissolved in Et20 and washed with 1 N NaOH (x3) and H20 (x2). The organic phase was dried and concentrated to give 5.87 g (87%) of the alkylated product, (2-trifluoromethylphenoxy) acetic acid methyl ester. To a flask containing chlorosulfonic acid (5.93 g, 50.9 mmol) at 0 ° C was slowly added the compound prepared above (2.65 g, 11.3 mmol). After the resulting solution was stirred at 0 ° C for 30 min and at room temperature for 2 hr, it was emptied on ice with stirring. The precipitated solid was filtered, dissolved in CH2Cl2, washed with brine, dried and concentrated to provide 2.50 g (66%) of 14-A; 1 H NMR (300 MHz, CDCl 3) d 8.28 (d, J = 2.3 Hz, 1 H), 8.17 (dd, J = 9.0, 2.4 Hz, 1 H), 7.04 (d, J = 9.0 Hz, 1 H), 4.90 (s, 2 H), 3.84 (s, 3 H); MS (ES) m / z: 355 (M + Na +). 14-B (4-mercapto-2-trifluoromethyl-phenoxy) -acetic acid methyl ester To a solution of 14-A (2.30 g, 6.91 mmol) in MeOH (12 mL) was added a solution of 4 M HCl in dioxane (12 ml, 48 mmol) followed by tin powder (4.10 g, 34.5 mmol) in portions. The resulting mixture was refluxed for 3 h, emptied on ice / CH 2 Cl 2 The aqueous layer was separated and extracted with CH 2 Cl 2. The organic extracts were dried and concentrated to give 14-B; 1 H NMR (300 MHz, CDCl 3) d 8.28 (d, J = 2.3 Hz, 1 H), 7.41 (dd, J = 8.6, 2.3 Hz, 1 H), 6.78 (d, J = 8.6 Hz, 1 H), 4.70 (s, 2 H), 3.79 (s, 3 H), 3.47 (s, 1 H); MS (ES) m / z: 289 (M + Na +). 14-C Methyl acid ester. { 2-trifluoromethyl-4- [2- (4-trifluoroemtl-phenoxymethyl) -allylsulfanyl] -phenoxy} -acetic Replacing ethyl ester (4-mercapto-2-methyl-phenoxy) acetic acid 1-C by methyl ester of (4-mercapto-2-trifluoromethyl-phenoxy) -acetic acid 14-B and following general procedure 3 obtained 14-C (85%); 1 H NMR (400 MHz, CDCl 3) d 7.63 (d, J = 2.2 Hz, 1 H), 7.53 (d, J = 8.8 Hz, 2 H), 7.47 (dd, J = 8.6, 2.2 Hz, 1 H), 6.96 (d, J = 8.8 Hz, 2 H), 6.77 (d, J = 8.6 Hz, 1 H), 5.19 (s, 1 H), 5.01 (s, 1 H), 4.70 (s, 2 H), 4.65 (s, 2 H), 3.79 (s, 3 H), 3.61 (s, 2 H); MS (ES) m / z: 503 (M + Na +).

Compound 12 Acid. { 2-trifluoromethyl-4- [2- (4-trifluoromethyl-phenoxymethyl) -allysu-imanyl] -phenoxy} - acetic Following the general procedure 2, compound 12 (90%) was obtained; 1 H NMR (300 MHz, CDCl 3) d 7.63 (d, J = 2.1 Hz, 1 H), 7.53 (d, J = 8.7 Hz, 2 H), 7.48 (dd, J = 8.6, 2.2 Hz, 1 H), 6.95 (d, J = 8.7 Hz, 2 H), 6.80 (d, J = 8.6 Hz, 1 H), 5.19 (s, 1 H), 5.02 (s, 1 H), 4.71 (s, 2 H), 4.65 (s, 2 H), 3.61 (s, 2 H); MS (ES) m / z: 489 (M + Na +). Analysis calculated for C2oH? 6F6? 4S: C, 52.72; H, 3J3. Found: C, 52.53; H, 3.52.

EXAMPLE XIII -A (3-Chloro-4-chlorosulfonyl-phenoxy) -acetic acid methyl ester Following the same procedure as in the preparation of 14-A, 15-A (75%) was provided; 1 H NMR (300 MHz, CDCl 3) d 8.09 (d, J = 2.3 Hz, 1 H), 7.13 (d, J = 2.6 Hz, 1 H), 6.92 (dd, J = 9.1, 2.6 Hz, 1 H), 4.75 (s, 2 H), 3.84 (s, 3 H); MS (ES) m / z: 321 (M + Na +).

-B (3-Chloro-4-mercapto-phenoxy) -acetic acid methyl ester Following the same procedure as in the preparation of 14-B, the title compound 15-B (94%) was provided; 1 H NMR (300 MHz, CDCl 3) d 7.27 (d, J = 8.6 Hz, 1 H), 6.97 (d, J = 2.7 Hz, 1 H), 6.74 (dd, J = 8.7, 2 J Hz, 1 H), 4.60 (s, 2 H), 3.81 (s, 3 H), 3.71 (d, J = 5.6 Hz, 1 H); MS (ES) m / z: 231 (M-H +).

-C Methyl acid ester. { 3-Chloro-4- [2- (4-trifluoromethyl-phenoxymethyl) -alkylsulfanyl] -phenoxy-acetic acid Replacing ethyl ester of (4-mercapto-2-methyl-phenoxy) -acetic acid 1-C by methyl ester of acid (3 -chloro-4-mercapto-phenoxy) -acetic 15-B and following the general procedure 3 the title compound 15-C (88%) was obtained; 1 H NMR (300 MHz, CDCl 3) d 7.53 (d, J = 8.6 Hz, 2 H), 7.35 (d, J = 8.7 Hz, 1 H), 6.98-6.95 (m, 3 H), 6.73 (dd, J = 8.7, 2.8 Hz, 1 H), 5.14 (d, J = 1.0 Hz, 1 H), 5.00 (d, J = 0.8 Hz, 1 H), 4.66 (s, 2 H), 4.59 (s, 2 H) ), 3.81 (s, 3 H), 3.62 (s, 2 H); MS (ES) m / z: 469 (M + Na +). Analysis calculated for C2oH? 8CIF3? 4S: C, 53.76; H, 4.06. Found: C, 54.05; H, 3.78.

Compound 13 Acid. { 3-Chloro-4- [2- (4-trifluoromethyl-phenoxymethyl) -allylsulfanyl] -phenoxy} -acetic Following the general procedure 2, compound 13 (95%) was obtained; 1 H NMR (300 MHz, CDCl 3) d 7.52 (d, J = 8.7 Hz, 2 H), 7.34 (d, J = 8.7 Hz, 1 H), 6.99-6.94 (m, 3 H), 6.74 (dd, J = 8.7, 2.6 Hz, 1 H), 5.15 (d, J = OJ Hz, 1 H), 5.00 (s, 1 H), 4.66 (s, 2 H), 4.62 (s, 2 H), 3.62 (s) 2 H); MS (ES) m / z: 455 (M + Na +).

EXAMPLE XIV 6-A Methyl acid ester. { 2-methoxy-4- [2- (4-trifluoromethyl-phenoxymethyl) -allylsulfanyl] -phenoxy} -acetic Following the general procedure 3, the title compound 16-A (87%) was obtained; 1 H NMR (300 MHz, CDCl 3) d 7.53 (d, J = 8.6 Hz, 2 H), 7.03 (dd, J = 8.4, 2.1 Hz, 1 H), 6.97 (d, J = 8.6 Hz, 2 H), 6.91 (d, J = 2.1 Hz, 1 H), 6.79 (d, J = 8.4 Hz, 1 H), 5.13 (d, J = 1.0 Hz, 1 H), 4.96 (s, 1 H), 4.65 (s) , 4 H), 3.85 (s, 3 H), 3.78 (s, 3 H), 3.55 (s, 2 H); MS (ES) m / z: 465 (M + Na +).

Compound 14 Acid. { 2-methoxy-4- [2- (4-trifluoromethyl-phenoxymethyl) -allylsulfanyl] -phenoxy} -acetic Following the general procedure 2, compound 14 (94%) was obtained; 1 H NMR (300 MHz, MeOH-d 4) d 7.54 (d, J = 8.6 Hz, 2 H), 7.04 (d, J = 8.6, 2 H), 7.03-6.99 (m, 2 H), 6.88 (d, J = 8.3 Hz, 1 H), 5.11 (s, 1 H), 4.97 (s, 1 H), 4.69 (s) , 2 H), 4.55 (s, 2 H), 3.81 (s, 3 H), 3.60 (s, 2 H); MS (ES) m / z: 451 (M + Na +).

EXAMPLE XV SCHEME 17 Cs2C03? CH3CN 17-A 2-lsopropylidene-propane-1,3-diol To a solution of diisobutylaluminum hydride (1.0 M in CH2Cl2, 6. 75 ml, 6.75 mmol) in CH 2 Cl 2 (5 ml) at -78 ° C was added a solution of 2-isopropylidene malonic acid diethyl ester (300 mg, 1.50 mmol) in CH 2 Cl 2 (2 ml). The reaction mixture was allowed to warm to 0 ° C, stirred at this temperature for 1 hr, and quenched with MeOH (8 ml). The precipitated solid was filtered through Celite and washed with CH2Cl2 / MeOH. The filtrate was concentrated to give 61 mg (35%) of 17-A; 1 H NMR (300 MHz, CDCl 3) d 4.27 (s, 4 H), 3.25 (brs, 2 H), 1.78 (s, 6 H). 17-B 1-Chloro-2-chloromethyl-3-methyl-but-2-ene To a solution of 17-A (200 mg, 1.72 mmol) in CH2Cl2 (3 ml) at 0 ° C, Et3N (0.960 ml, 6.90 mmol) and methanesulfonyl chloride (592 mg, 5.17 mmol) were added. The mixture was allowed to warm to room temperature, stirred at the same temperature for 3 hr, and diluted with saturated NaHCO3. The organic layer was separated and the aqueous layer was extracted with CH2Cl2. The combined organic phases were dried, concentrated and they were subjected to column chromatography (EtOAc / hexane: 1/7) to provide 171 mg (65%) of 17-B; 1 H NMR (300 MHz, CDCl 3) d 4.26 (s, 4 H), 1.87 (s, 6 H). 17-C [4- (2-Chloromethyl-3-methyl-but-2-enylsulfanyl) -2-methyl-phenoxy] -acetic acid ethyl ester Following general procedure 3, 17-C (38%) was obtained; 1 H NMR (300 MHz, CDCl 3) d 7.20 (s, 1 H), 7.17 (dd, J = 8.4, 2.1 Hz, 1 H), 6.61 (d, J = 8.4 Hz, 1 H), 4.62 (s, 2 H), 4.28 (s, 2 H), 4.26 (q, J = 7.1 Hz, 2 H), 3.61 ( s, 2 H), 2.26 (s, 3 H), 1.78 (s, 3 H), 1.53 (s, 3 H), 1.29 (t, J = 7.1 Hz, 3 H); MS (ES) m / z: 365 (M + Na +). 17-D Ethyl ester of acid. { 2-methyl-4- [3-methyl-2- (4-trifluoromethyl-phenoxymethyl) -but-2-enylsulfanyl] -phenoxy} -acetic Replacing ethyl ester (4-mercapto-2-methyl-phenoxy) -acetic acid 1-C by 4-trifluoromethyl-phenol and following general procedure 3 gave 17-D (68%); 1 H NMR (300 MHz, CDCl 3) d 7.54 (d, J = 8.6 Hz, 2 H), 7.20 (s, 1 H), 7.17 (dd, J = 8.4, 2.2 Hz, 1 H), 6.97 (d, J = 8.6 Hz, 2 H), 6.59 (d, J = 8.4 Hz, 1 H), 4.65 (s, 2 H), 4.60 (s, 2 H), 4.25 (q, J = 7.1 Hz, 2 H), 3.65 (s, 2 H), 2.23 (s, 3 H), 1.78 (s, 3 H), 1.59 (s, 3 H), 1.29 (t, J = 7.1 Hz, 3 H); MS (ES) m / z: 491 (M + Na +). Analysis calculated for C24H27F304S: C, 61.52; H, 5.81. Found: C, 61.69; H, 5.99.

Compound 15 Acid. { 2-Methyl-4- [3-methyl-2- (4-trifluoromethyl-phenoxymethyl) -but-2-en-sulphanil] -phenoxy-acetic Following procedure general 2, compound 15 (95%) was obtained; 1 H NMR (400 MHz, CDCl 3) d 7.52 (d, J = 8.6 Hz, 2 H), 7.18 (s, 1 H), 7.15 (d, J = 8.5 Hz, 1 H), 6.96 (d, J = 8.6 Hz, 2 H), 6.57 (d, J = 8.1 Hz, 1 H), 4.64 (s, 2 H), 4.56 (s, 2 H), 3.65 (s, 2 H), 2.18 (s, 3 H) , 1.78 (s, 3 H), 1.60 (s, 3 H); MS (ES) m / z: 463 (M + Na +).

EXAMPLE XVI SCHEME 18 18-A 2- (4-Trifluoromethyl-phenoxymethyl) -oxirane A mixture of 4-trifluoromethylphenol (7.80 g, 48.1 mmol), 2-chloromethyloxirane (11.2 g, 121 mmol), and Cs2C? 3 (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 Et2O were added, the organic phase was separated, and the aqueous phase was extracted with Et2O. The combined organic layers were dried, concentrated and subjected to column chromatography (CH2Cl2 / hexane: 1/1) to provide 8.40 g (80%) of 18-A; 1 H NMR (300 MHz, CDCl 3) d 7.55 (d, J = 8.5 Hz, 2 H), 6.99 (d, J = 8.5 Hz, 2 H), 4.29 (dd, J = 11.1, 3.0 Hz, 1 H), 3.98 (dd, J = 11.1, 5.8 Hz, 1 H), 3.37 (m, 1 H), 2.93 (m, 1 H), 2.77 (dd, J = 4.9, 2.6 Hz, 1 H). 18-B Ethyl ester of acid. { 4- [2-hydroxy-3- (4-trifluoromethyl-phenoxy) propylsulfanyl] -2-methyl-phenoxy} -acetic To a mixture of 18-A (2.57 g, 11.8 mmol) and ethyl ester (4-mercapto-2-methyl-phenoxy) -acetic acid 1-C (4.00 g, 17.7 mmol) in THF (20 ml) was added. added 1.0 M tetrabutylammonium fluoride in THF (0.44 ml, 0.44 mmole). 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 (CH2Cl2) to give 4.45 g (85%) of 18-B; 1 H NMR (400 MHz, CDCl 3) d 7.50 (d, J = 8.9 Hz, 2 H), 7.25 (d, J = 2.2 Hz, 1 H), 7.21 (dd, J = 8.4, 2.3 Hz, 1 H), 6.89 (d, J = 8.8 Hz, 2 H), 6.58 (d, J = 8.4 Hz, 1 H), 4.58 (s, 2 H), 4.24 (q, J = 7.1 Hz, 2 H), 4.05-4.00 (m, 3 H), 3.13 (dd, J = 13.7, 5.1 Hz, 1 H), 3.04 (dd, J = 13.9, 6.5 Hz, 1 H), 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 +). 18-C Ethyl ester of acid. { 2-methyl-4- [2-oxo-3- (4-trifluoromethyl-phenoxy) -propylsulfanyl] -phenoxy} -acetic A reaction mixture of 18-B (1.08 g, 2.43 mmole), Ac2O (2.56 mL, 27.2 mmol) and DMSO (3.84 mL) was stirred at room temperature for 24 h, and diluted with saturated NaHCO and Et2O. The organic phase was separated, washed with water (x 3), dried and subjected to column chromatography (EtOAc / hexane: 1/4) to give 892 mg (83%) of 18-C; 1 H NMR (300 MHz, CDCl 3) d 7.53 (d, J = 8.6 Hz, 2 H), 7.24 (d, J = 2.0 Hz, 1 H), 7.20 (dd, J = 8.4, 2.3 Hz, 1 H), 6.88 (d, J = 8.6 Hz, 2 H), 6.61 (d, J = 8.4 Hz, 1 H), 4J7 (s, 2 H), 4.60 (s, 2 H), 4.25 (q, J = 7.1 Hz , 2 H), 3.72 (s, 2 H), 2.24 (s, 3 H), 1.29 (t, J = 7.1 Hz, 3 H); MS (ES) m / z: 465 (M + Na +). 1B-D Ethyl ester of acid. { 4- [3,3-difluoro-2- (4-trifluoromethyl-phenoxymethyl) -allylsulfanyl] -2-methyl-phenoxy} -acetic To a flask containing THF (3 ml) at 0 ° C was injected Br2CF2 (0.091 ml, 1.0 mmol) followed by HMPT (0.364 ml, 2.00 mmol). The mixture was allowed to warm to room temperature, and a solution of 18-C (221 mg, 0.500 mmol) in THF (2 mL) was added. After stirring overnight, the mixture was diluted with water and extracted with EtOAc. The extracts were dried, concentrated and subjected to chromatography (EtOAc / hexane: 1/9) to give 186 mg (78%) of 18-D; 1 H NMR (400 MHz, CDCl 3) d 7.53 (d, J = 8.6 Hz, 2 H), 7.22 (s, 1 H), 7.18 (d, J = 8.4 Hz, 1 H), 6.93 (d, J = 8.6 Hz, 2 H), 6.59 (d, J = 8.4 Hz, 1 H), 4.65 (s, 2 H), 4.59 (s, 2 H), 4.24 (q, J = 7.1 Hz, 2 H), 3.57 ( s, 2 H), 2.23 (s, 3 H), 1.27 (t, J = 7.1 Hz, 3 H); MS (ES) m / z: 499 (M + Na +).

Compound 16 Acid. { 4- [3,3-difluoro-2- (4-trifluoromethyl-phenoxymethyl) -allylsulfanyl] -2-methyl-phenoxy} - acetic Following the general procedure 2, compound 16 (91%) was obtained; 1 H NMR (300 MHz, CDCl 3) d 7.54 (d, J = 8.7 Hz, 2 H), 7.22 (s, 1 H), 7.19 (dd, J = 8.4, 2.2 Hz, 1 H), 6.94 (d, J = 8.7 Hz, 2 H), 6.62 (d, J = 8.4 Hz, 1 H), 4.66 (s, 4 H), 3.58 (t, J = 1.7 Hz, 2 H), 2.22 (s, 3 H); MS (ES) m / z: 471 (M + Na +).

EXAMPLE XVII SCHEME 19 19-A Ethyl ester of acid. { 4- [3-cyano-2- (4-trifluoromethyl-phenoxymethyl) -allylsulfanyl] -2-methyl-phenoxy} -acetic A mixture of 18-C (80 mg, 0.18 mmol) and (triphenylphosphoranylidene) acetonitrile (109 mg, 0.362 mmol) in CH 2 Cl 2 (2 mL) was stirred at room temperature overnight and concentrated. The residue was purified by column chromatography (CH2Cl2 / hexane: 1/1) to give 76 mg (90%) of 19-A; 1 H NMR (300 MHz, CDCl 3) d 7.56 (d, J = 8.7 Hz, 2 H), 7.28-7.23 (m, 2 H), 6.93 (d, J = 8.7 Hz, 2 H), 6.64 (d, J = 8.4 Hz, 1 H), 5.49 (s, 1 H), 4.76 (d, J = 1.7 Hz, 2 H), 4.62 (s, 2 H), 4.25 (q, J = 7.1 Hz, 2 H), 3.81 (s, 2 H), 2.25 (s, 3 H), 1.28 (t, J = 7.1 Hz, 3 H); MS (ES) m / z: 488 (M + Na +).

Compound 17 Acid. { 4- [3-cyano-2- (4-trifluoromethy1-phenoxymethyl) -allylsulfanyl] -2-methyl-phenoxy} - acetic Following the general procedure 2, compound 17 (85%) was obtained; MS (ES) m / z: 460 (M + Na +).

EXAMPLE XVIII SCHEME 20 -A Ethyl ester of acid. { 2-methyl-4- [3-phenyl-2- (4-trifluoromethyl-phenoxymethyl) -allylsulfanyl] -phenoxy} -acetic A solution of benzyltriphenylphosphonium chloride (98 mg, 0.25 mmol) in THF (2 ml) was treated with 1.0 M NaHMDS in THF (0.230 ml, 0.230 mmol) at 0 ° C for 30 min, and then a solution was added of 18-C (100 mg, 0.226 mmol) in THF (1 ml). The reaction mixture was allowed to warm to room temperature, stirred for 2 h, diluted with saturated NaHCO3, and extracted with Et2O. The extracts were dried, concentrated, and subjected to column chromatography (EtOAc / hexane: 1/9) to give 52 mg (44%) of 20-A as a mixture of E- and Z- isomers. Major component (58% of the mixture): H NMR (300 MHz, CDCl 3) d 7.50 (d, J = 8.7 Hz, 2 H), 7.34-7.17 (m, 5 H), 7.11-7.06 (m, 2 H), 6.89 (d, J = 8.7 Hz , 2 H), 6.60 (d, J = 8.4 Hz, 1 H), 6.38 (s, 1 H), 4.80 (s, 2 H), 4.59 (s, 2 H), 4.24 (q, J = 7.1 Hz , 2 H), 3.69 (s, 2 H), 2.23 (s, 3 H), 1.27 (t, J = 7.1 Hz, 3 H); MS (ES) m / z: 539 (M + Na +). Minor component (42% of the mixture): 1 H NMR (300 MHz, CDCl 3) d 7.54 (d, J = 8.7 Hz, 2H), 7.34-7.17 (m, 5H), 7.11-7.06 (m, 2H), 6.99 (d, J = 8.7 Hz, 2 H), 6.72 (s, 1 H), 6.52 (d, J = 9.1 Hz, 1 H), 4.76 (s, 2 H), 4.57 (s, 2 H), 4.25 (q, J = 7.1 Hz, 2 H), 3.80 (s, 2 H), 2.16 (s, 3 H), 1.28 (t, J = 7.1 Hz, 3 H).

Compound 18 Acid. { 2-methyl-4- [3-phenyl-2- (4-trifluoromethyl-phenoxymethyl) -allylsulfanyl] -phenoxy} - acetic Following the general procedure 2, compound 18 (90%) was obtained. Major component (58% of the mixture in E- and Z- isomers); H NMR (300 MHz, CDCl 3) d 7.46-6.40 (m, 13 H), 4.74 (s, 2 H), 4. 28 (s, 2 H), 3.64 (s, 2 H), 2.07 (s, 3 H); MS (ES) m / z: 511 (M + Na +). Minor component (42% of the mixture in E- and Z- isomers); 1 H NMR (300 MHz, CDCl 3) d 7.49-6.47 (m, 13 H), 4.69 (s, 2 H), 4. 28 (s, 2 H), 3.75 (s, 2 H), 2.01 (s, 3 H).

EXAMPLE XIX SCHEME 21 21-A Ethyl ester of acid. { 2-methyl-4- [3-naphthalen-1-yl-2- (4-trifluoromethyl-phenoxymethyl) -allylsulfanyl-phenoxy} acetic A solution of (l-naphthylmethyl) triphenylphosphonium chloride (111 mg, 0.253 mmol) in THF (3 ml) was treated with 1.0 M NaHMDS in THF (0.230 ml, 0. 230 mmoles) at 0 ° C for 20 min, and then a solution of 18-C (100 mg, 0.226 mmol) in THF (1 ml). The reaction mixture was allowed to warm to room temperature, stirred for 3 h, concentrated and subjected to column chromatography (EtOAc / hexane: 1/10) to give 49 mg (38%) of 21 -A as a mixture of 1: 1 of E- and Z- isomers; 1 H NMR (300 MHz, CDCl 3) d 7.82 (d, J = 8.1 Hz, 2 H), 7.76 (d, J = 8.2 Hz, 2 H), 7.59-7.56 (m, 3 H), 7.49-7.15 (m , 13 H), 7.09-7.06 (m, 3 H), 6.95-6.92 (m, 2 H), 6.83-6.80 (m, 3 H), 6.65 (d, J = 8.2 Hz, 1 H), 6.29 ( d, J = 8.3 Hz, 1 H), 4.95 (d, J = 1.0 Hz, 2 H), 4.71 (s, 2 H), 4.61 (s, 2 H), 4.47 (s, 2 H), 4.25 ( q, J = 7.1 Hz, 2 H), 4.23 (q, J = 7.1 Hz, 2 H), 3.84 (s, 2 H), 3.72 (s, 2 H), 2.26 (s, 3 H), 2.00 ( s, 3 H), 1.28 (t, J = 7.1 Hz, 3 H), 1.25 (t, J = 7.1 Hz, 3 H); MS (ES) m / z: 589 (M + Na +).

Compound 19 Acid. { 2-methyl-4- [3-naphthalen-1-yl-2- (4-trifluoromethyl-phenoxymethyl) -aylsulfanyl] -phenoxy} -acetic Following the general procedure 2, compound 19 (91%) was obtained as a mixture of 1: 1 of E- and Z- isomers; 1 H NMR (300 MHz, CDCl 3) d 7.64-6.66 (m, 30 H), 4.76 (s, 2 H), 4.56 (s, 2 H), 3.92 (s, 4 H), 3.68 (s, 2 H) , 3.57 (s, 2 H), 1.97 (s, 3 H), 1.72 (s, 3 H); MS (ES) m / z: 537 (M-H +).

EXAMPLE XX SCHEME 22 Compound 20 22-A 4-trifluoromethyl-phenyl ester of acrylic acid To a solution of trifluoromethylphenol (2.00 g, 12.3 mmole) in CH 2 Cl 2 (20 ml) at 0 ° C was added 3-bromopropionyl chloride (2.55 g, 14.9 mmole) and triethylamine (3.4 ml, 24 mmol). After stirring at room temperature overnight, the solvent was evaporated under reduced pressure. Et2O was added to the residue, and the solid was filtered and rinsed with Et2O. The filtrate was washed with water, dried, concentrated and purified by column chromatography to give 2.04 g (77%) of 22-A as a yellow oil; 1 H NMR (300 MHz, CDCl 3) d 7.67 (d, J = 8.4 Hz, 2 H), 7.27 (d, J = 8.3 Hz, 2 H), 6.64 (dd, J = 17.3, 1.2 Hz, 1 H), 6.33 (dd, J = 17.3, 10.4 Hz, 1 H), 6.06 (dd, J = 10.4, 1.2 Hz, 1 H); 22-B 3- (4-Ethoxycarbonylmethoxy-3-methyl-phenylsulfanyl) -propionic acid 4-trifluoromethyl-phenyl ester Following general procedure 3, 22-B (70%, clear oil) was obtained; 1 H NMR (300 MHz, CDCl 3) d 7.65 (d, J = 8.5 Hz, 2 H), 7.29 (s, 1 H), 7.26 (dd, J = 8.3, 2.3 Hz, 1 H), 7.21 (d, J = 8.7 Hz, 2 H), 6.65 (d, J = 8.3 Hz, 1 H), 4.63 (s, 2 H), 4.27 (q, J = 7.1 Hz, 2 H), 3.16 (t, J = 7.2 Hz , 2 H), 2.84 (t, J = 7.2 Hz, 2 H), 2.28 (s, 3 H), 1.30 (t, J = 7.1 Hz, 3 H); MS (ES) m / z: 465 (M + Na +). 22-C Ethyl ester of acid. { 2-methyl-4- [3- (4-trifluoromethyl-phenoxy) -but-3-enylsulfanyl] -phenoxy} -acetic To a solution of 22-B (540 mg, 1.22 mmol) in THF (10 ml) at -20 ° C was added 0.5 M Tebbe reagent (3.0 ml, 1.5 mmol) in toluene. The mixture was stirred at -20 ° C for 1 hr, then allowed to warm to 0 ° C, quenched with saturated NH 4 Cl, and partitioned between Et 20 and water. The organic layer was dried, concentrated and purified by column chromatography and preparative CCD (Si02) twice to give 44 mg (8%) of 22-C as a clear oil; 1 H NMR (400 MHz, CDCl 3) d 7.59 (d, J = 8.7 Hz, 2 H), 7.25 (d, J = 2.2 Hz, 1 H), 7.20 (dd, J = 8.4, 2.3 Hz, 1 H), 7.13 (d, J = 8.6 Hz, 2 H), 6.63 (d, J = 8.4 Hz, 1 H), 4.63 (s, 2 H), 4.36 (d, J = 2.0 Hz, 1 H), 4.27 (q, J = 7.1 Hz, 2H), 4.16 (d, J = 2.1 Hz, 1 H), 3.08 (t, J = 7.5 Hz, 2 H), 2.55 (t, J = 7.5 Hz, 2H), 2.27 (s, 3 H), 1.30 (t, J = 7.1 Hz, 3 H); MS (ES) m / z: 463 (M + Na +).

Compound 20 Acid. { 2-methyl-4- [3- (4-trifluoromethyl-phenoxy) -but-3-enylsulfanyl] -phenoxy} -acetic Following the general procedure 2, compound 20 (100%, clear oil) was obtained; 1 H NMR (300 MHz, CDCl 3) d 7.59 (d, J = 8.6 Hz, 2 H), 7.24 (s, 1 H), 7.20 (d, J = 8.2 Hz, 1 H), 7.12 (d, J = 8.3 Hz, 2 H), 6.66 (d, J = 8.2 Hz, 1 H), 4.67 (s, 2 H), 4.36 (d, J = 1.9 Hz, 1 H), 4.16 (d, J = 2.1 Hz, 1 H), 3.08 (t, J = 7.4 Hz, 2 H), 2.54 (t, J = 7.4 Hz, 2 H), 2.26 (s, 3 H); MS (ES) m / z: 435 (M + Na +).

EXAMPLE XXI SCHEME 23 Chloroacetic acid 4-trifluoromethyl-phenyl ester To a solution of trifluoromethylphenol (300 mg, 1.85 mmol) in CH 2 Cl 2 (5 mL) at 0 ° C were added chloroacetyl chloride (255 mg, 2.26 mmol) and triethylamine (290 mg, 2.87 mmol). After stirring at room temperature overnight, the reaction mixture was diluted with water and extracted with CH2Cl2. The extracts were dried, concentrated and purified by column chromatography to give 370 mg (84%) of 23-A as a yellow oil; 1 H NMR (300 MHz, CDCl 3) d 7.68 (d, J = 8.5 Hz, 2 H), 7.28 (d, J = 8.4 Hz, 2 H), 4.32 (s, 2 H).

Ethyl ester of [2-methyl-4- (4-trifluoromethyl-phenoxycarbonylmethylsulfanyl) -phenoxy-acetic acid Following general procedure 3, 23-B (75%, clear oil) was obtained; 1 H NMR (300 MHz, CDCl 3) d 7.63 (d, J = 8.6 Hz, 2 H), 7.37 (s, 1 H), 7.34 (d, J = 8.4 Hz, 1 H), 7.11 (d, J = 8.5 Hz, 2 H), 6.65 (d, J = 8.4 Hz, 1 H), 4.64 (s, 2 H), 4.26 (q, J = 7.1 Hz, 2 H), 3.73 (s, 2 H), 2.27 ( s, 3 H), 1.29 (t, J = 7.1 Hz, 3 H); MS (ES) m / z: 451 (M + Na +).

Ethyl ester of acid. { 2-methyI-4- [2- (4-trifluoromethyl-phenoxy) -allylsulfanyl] -phenoxy} - acetic To a solution of 23-B (180 mg, 0.421 mmol) in THF (1 ml) at -78 ° C was added 0.5 M Tebbe reagent (1.0 ml, 0.5 mmol) in toluene. The mixture was stirred at -78 ° C at 0 ° C for 1 hr, quenched with 6 drops of 2 M aqueous NaOH solution, and filtered through Celite. The filtrate was dried over Na2SO4, concentrated and purified by column chromatography to give 37 mg (21%) of 23-C as a clear oil; 1 H NMR (400 MHz, CDCl 3) d 7.58 (d, J = 8.4 Hz, 2 H), 7.29 (s, 1 H), 7.25 (d, J = 2.4 Hz, 1 H), 7.09 (d, J = 8.5 Hz, 2 H), 6.64 (d, J = 8.4 Hz, 1 H), 4.64 (s, 2 H), 4.40 (d, J = 2.0 Hz, 1 H), 4.27 (q, J = 7.1 Hz, 2 H), 4.19 (d, J = 2.0 Hz, 1 H), 3.59 (s, 2 H), 2.27 (s, 3 H), 1.30 (t, J = 7.1 Hz, 3 H); MS (ES) m / z: 449 (M + Na +). omitted 21 Acid. { 2-methyl-4- [2- (4-trifluoromethyl-phenoxy) -allylsulfanyl-3-phenoxy} -acetic Following the general procedure 2, compound 21 (100%, light oil) was obtained; 1 H NMR (300 MHz, CDCl 3) d 7.58 (d, J = 8.5 Hz, 2 H), 7.27 (m, 2 H), 7.09 (d, J = 8.3 Hz, 2 H), 6.67 (d, J = 8.1 Hz, 1 H), 4.69 (s, 2 H), 4.40 (d, J = 2.4 Hz, 1 H), 4.19 (d, J = 2.3 Hz, 1 H), 3.59 (s, 2 H), 2.26 ( s, 3 H); MS (ES) m / z: 421 (M + Na +); FAB-HRMS (M +). Calculated 398.0800, found 398.0800.

EXAMPLE XXII SCHEME 26 Methyl ester of acid. { 3-Chloro-4- [2- (4-trifluoromethyl-phenoxymethyl) -ali-sulphanil] -phenyl} -acetic Replacing ethyl ester (4-mercapto-2-methyl-phenoxy) -acetic acid 1-C by methyl (3-chloro-4-mercapto-phenyl) -acetic acid methyl ester 26-A (see WO 9932465) and following the procedure 3 was obtained the title compound 26-B (80%); 1 H NMR (300 MHz, CDCl 3) d 7.53 (d, J = 8.5 Hz, 2 H), 7.31 (d, J = 1.8 Hz, 1 H), 7.29 (d, J = 8.1 Hz, 1 H), 7.09 ( dd, J = 8.1, 1, 9 Hz, 1 H), 6.96 (d, J = 8.5 Hz, 2 H), 5.23 (s, 1 H), 5.18 (d, J = 0.7 Hz, 1 H), 4.67 (s, 2 H), 3J0 (s, 5 H), 3.56 (s, 2 H); MS (ES) m / z: 453 (M + Na +).

Analysis calculated for C2oH18CIF3? 3S: C, 55.75; H, 4.21. Found: C, 55.58; H, 3.86.

Compound 22 Acid. { 3-Chloro-4- [2- (4-trifluoromethyl-phenoxymethyl) -allylsulfanyl] -phenyl} -acetic Following the general procedure 2, compound 22 (93%) was obtained; 1 H NMR (300 MHz, CDCl 3) d 7.52 (d, J = 8.7 Hz, 2 H), 7.31 (d, J = 1.7 Hz, 1 H), 7.28 (d, J = 8.1 Hz, 1 H), 7.08 (dd, J = 8.1, 1.7 Hz, 1 H), 6.96 (d, J = 8.7 Hz, 2 H), 5.24 (s, 1 H), 5.19 (s, 1 H), 4.66 (s, 2 H), 3.71 (s, 2 H), 3.57 (s, 2 H); MS (ES) m / z: 439 (M + Na +). Analysis calculated for C19H-16CIF3O3S: C, 54.75; H, 3.87. Found: C, 54.45; H, 3.54.

EXAMPLE XXIII SCHEME 28 28-B (1-Hydroxymethyl-cyclopropyl) -methanol To a solution of dimethyl 1,1-cyclopropanedicarboxylate 28-A (791 mg, 5.01 mmol) in Et 2 O (20 ml) at 0 ° C was added lithium aluminum hydride. (569 mg, 15.0 mmol) in portions. The reaction mixture was stirred at room temperature for 4 hr and quenched with saturated Na 2 SO 4 at 0 ° C. The precipitated solid was filtered and washed with THF. The filtrate was concentrated and purified by column chromatography (EtOAc) to give 440 mg (86%) of 28-B; 1 H NMR (300 MHz, CDCl 3) d 4.02 (s, 2 H), 3.56 (s, 4 H), 0.48 (s, 4 H); MS (ES) m / z: 125 (M + Na +).

Mscr ^ ^ WHO 1-Methanesulfonyloxymethyl-cyclopropylmethyl methanesulfonic acid ester To a solution of 28-B (440 mg, 4.31 mmol) in CH 2 Cl 2 (6 ml) at 0 ° C were added Et ^N (2.59 ml, 17.2 mmol) and a chloride solution of methanesulfonyl (1.48 g, 12.9 mmol) in CH2Cl2 (4 mL). The mixture was stirred at room temperature for 2 hr and diluted with 1.0 N HCl. 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 901 mg (81%) of 28-C; 1 H NMR (300 MHz, CDCl 3) d 4.17 (s, 4 H), 3.06 (s, 6 H), 0.83 (s, 4 H); MS (ES) m / z: 281 (M + Na +). 28-D Ester 1- (4-trifluoromethyl-phenoxymethyl) -cyclopropylmethyl methanesulfonic acid To a suspension of NaH (44 mg, 1.1 mmol; 60% in mineral oil) in THF (1 ml) was added a solution of 4-trifluoromethylphenol (178 mg, 1.10 mmol) in THF (1 ml). After stirring for 30 min at room temperature, the mixture was transferred to a flask containing a solution of 28-C (310 mg, 1.20 mmol) in DMF (2 ml). The resulting mixture was refluxed for 6 hr and allowed to cool to room temperature, diluted with water and extracted with Et2O. The extracts were dried, concentrated and subjected to column chromatography (EtOAc / hexane: 1/4) to give 141 mg (40%) of 28-D; 1 H NMR (300 MHz, CDCl 3) d 7.54 (d, J = 8.7 Hz, 2 H), 6.96 (d, J = 8.6 Hz, 2 H), 4.26 (s, 2 H), 3.92 (s, 2 H) , 2.97 (s, 3 H), 0.802 (s, 2 H), 0.798 (s, 2 H); MS (ES) m / z: 347 (M + Na +). 28-E Ethyl ester of acid. { 2-methyl-4- [1- (4-trifluoromethyl-phenoxymethyl) -cyclopropylmethylsulfanyl] -phenoxy} -acetic Following the general procedure 3, 28-E (55%) was obtained; 1 H NMR (300 MHz, CDCl 3) d 7.50 (d, J = 8.6 Hz, 2 H), 7.20 (d, J = 1.8 Hz, 1 H), 7.15 (dd, J = 8.4, 2.2 Hz, 1 H), 6.88 (d, J = 8.6 Hz, 2 H), 6.50 (d, J = 8.4 Hz, 1 H), 4.53 (s, 2 H), 4.24 (q, J = 7.1 Hz, 2 H), 3.91 (s) , 2 H), 3.05 (s, 2 H), 2.17 (s, 3 H), 1.28 (t, J = 7.1 Hz, 3 H), 0.65-0.55 (m, 4 H); MS (ES) m / z: 477 (M + Na +). Analysis calculated for C 23 H 25 F 3 O 4 S: C, 60.78; H, 5.54. Found: C, 60.98; H, 5.43.

Compound 23 Acid. { 2-methyl-4- [1- (4-trifluoromethyl-phenoxymethyl) -cyclopropylmethylsulfanyl] -phenoxy} - acetic Following the general procedure 2, compound 23 (92%) was obtained; 1 H NMR (300 MHz, CDCl 3) d 9.67 (brs, 1 H), 7.49 (d, J = 8.7 Hz, 2 H), 7.20 (s, 1 H), 7.16 (dd, J = 8.4, 2.1 Hz, 1 H), 6.87 (d, J = 8.6 Hz, 2 H), 6.52 (d, J = 8.4 Hz, 1 H), 4.58 (s, 2 H), 3.91 (s, 2 H), 3.06 (s, 2 H), 2.16 (s, 3 H), 0.66-0.56 (m, 4 H); MS (ES) m / z: 449 (M + Na +).

EXAMPLE XXIV SCHEME 29 Diethyl ester of 2,2-dipropyl malonic acid A mixture of diethyl propylmalonate (2.02 mg, 1.00 mmol), 1-iodopropane (255 mg, 1.50 mmol), and Cs2C03 (424 mg, 1.30 mmol) in 2-butanone (5 ml) was heated at 70 ° C for 15 h and filtered. The filtrate was concentrated and subjected to column chromatography (EtOAc / hexane: 1/19) to give 170 mg (70%) of 29-A; 1 H NMR (300 MHz, CDCl 3) d 4.17 (q, J = 7.1 Hz, 4 H), 1.88-1.82 (m, 4 H), 1.25-1.12 (m, 4 H), 1.24 (t, J = 7.1 Hz, 6 H), 0.92 (t, J = 7.2 Hz, 6 H); MS (ES) m / z: 267 (M + Na +). 29-B 2,2-Dipropyl-propane-1,3-diol To a suspension of lithium aluminum hydride (52 mg, 1.4 mmol) in THF (1 mL) at 0 ° C was added a solution of 29-A (167 mg, 0.684 mmol) in THF. The reaction mixture was stirred at room temperature for 2 hr, quenched with water (0.1 ml) at 0 ° C, and diluted with NaOH 5.0 M (0.1 ml) and water (1 ml). The precipitated solid was filtered and washed with MeOH / CH2Cl2. The filtrate was concentrated and purified by column chromatography (EtOAc / hexane: 1/1) to give 101 mg (92%) of 29-B; 1 H NMR (300 MHz, CDCl 3) d 3.57 (s, 4 H), 2.47 (s, 2 H), 1.26-1.23 (m, 8 H), 0.95-0.90 (m, 6 H); MS (ES) m / z: 183 (M + Na +). 29-C 2-methanesulfonyloxymethyl-2-propyl-pentyl methanesulfonic acid ester To a solution of 29-B (96 mg, 0.60 mmol) in CH 2 Cl 2 (1.5 ml) at 0 ° C were added EtsN (0.334 ml, 2.40 mmoles) and methanesulfonyl chloride (207 mg, 1.81 mmol). The mixture was stirred at room temperature for 1 hr and diluted with saturated NaHC 3. 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 182 mg (96%) of 29-C; 1 H NMR (300 MHz, CDCl 3) d 4.04 (s, 4 H), 3.04 (s, 6 H), 1.31-1.28 (m, 8 H), 0.96-0.91 (m, 6 H); MS (ES) m / z: 339 (M + Na +). 29-D [4- (2-Methanesulfonyloxymethyl-2-propyl-pentylsulfanyl) -2-methyl-phenoxy-acetic acid ethyl ester Following general procedure 3, 29-D (35%) was obtained; 1 H NMR (300 MHz, CDCl 3) d 7.23 (d, J = 1.6 Hz, 1 H), 7.19 (dd, J = 8.5, 2.1 Hz, 1 H), 6.62 (d, J = 8.4 Hz, 1 H), 4.61 (s, 2 H), 4.25 (q, J = 7.1 Hz, 2 H), 4.06 (s, 2 H), 2.89 (s, 2 H), 2.88 (s, 3 H), 2.26 (s, 3 H), 1.36-1.24 (m, 8 H), 1.29 (t, J = 7.1 Hz, 3 H), 1.20 (t, J = 7.0 Hz, 6 H); MS (ES) m / z: 469 (M + Na +). 29-E Ethyl acid ester. { 2-methyl-4- [2-propyl-2- (4-trifluoromethyl-phenoxymethyl) -pentylsulfanyl] -phenoxy} -acetic A mixture of 29-D (78 mg, 0.17 mmol), Cs2CO3 (111 mg, 0. 341 mmole) and trifluoromethylphenol (85 mg, 0.52 mmole) in CH 3 CN (2 ml) was refluxed overnight. More Cs2C03 (111 ntn, 0.341 mmol) and trifluoromethylphenol (85 mg, 0.52 mmol) were added, and the mixture was refluxed for 24 hr. CCD showed very little amount of the desired product and a large amount of starting materials. More Cs2CO3 (111 mg, 0.341 mmol) and trifluoromethylphenol (85 mg, 0.52 mmol) were added, and the mixture was refluxed for a further 24 hr. Water was added, and the mixture was extracted with Et 2 O (x 3). The extracts were dried, concentrated and subjected to column chromatography (EtOAc / hexane: 1/9) to provide 3 mg (3%) of 29- E; 1 H NMR (400 MHz, CDCl 3) d 7.47 (d, J = 8.7 Hz, 2 H), 7.15 (s, 1 H), 7.11 (dd, J = 8.4, 1.8 Hz, 1 H), 6.81 (d, J = 8.6 Hz, 2 H), 6.43 (d, J = 8.4 Hz, 1 H), 4.49 (s, 2 H), 4.24 (q, J = 7.1 Hz, 2 H), 3.76 (s, 2 H), 3.00 (s, 2 H), 2.14 (s, 2 H), 1.43-1.39 (m, 4 H), 1.30-1.20 (m, 7 H), 0.89 (t, J = 7.1 Hz, 6 H); MS (ES) m / z: 535 (M + Na +).

Compound 24 Acid. { 2-methyl-4- [2-propyl-2- (4-trifluoromethyl-phenoxymethyl) -pentylsulfanyl] -phenoxy} - acetic Following the general procedure 2, compound 24 (90%) was obtained; 1 H NMR (300 MHz, CDCl 3) d 7.45 (d, J = 8.5 Hz, 2 H), 7.09 (s, 1 H), 7.06 (m, 1 H), 6.80 (d, J = 8.5 Hz, 2 H), 6.44 (m, 1 H), 4.34 (s, 2 H), 3.75 (s, 2 H), 2.97 ( s, 2 H), 2.05 (s, 3 H), 1.41-1.38 (m, 3 H), 1.33-1.19 (m, 5 H), 0.88 (t, J = 6.9 Hz, 6 H); MS (ES) m / z: 507 (M + Na +).

EXAMPLE XXV SCHEME 30 -A Ethyl ester of acid. { 4- [2,2-difluoro-3- (4-trifluoromethyl-phenoxy) -propylsulfanyl] -2-methyl-phenoxy} -acetic A reaction mixture of 18-C (50 mg, 0.11 mmol), [bis (2-methoxyethyl) amino] sulfur trifluoride (49 mg, 0.22 mmol), and ethanol (0.0012 mL, 0.022 mmol) in CH2CI2 (2 mL) was stirred at room temperature for 14 hr, then diluted with saturated NaHCOs until the evolution of C02. The mixture was extracted with CH2Cl2, and the extracts were dried, concentrated and subjected to column chromatography (EtOAc / hexane: 1/7) to provide 47 mg (92%) of 30-A; 1 H NMR (300 MHz, CDCl 3) d 7.52 (d, J = 8.7 Hz, 2 H), 7.24 (s, 1 H), 7.21 (dd, J = 8.4, 2.0 Hz, 1 H), 6.82 (d, J = 8.7 Hz, 2 H), 6.47 (d, J = 8.4 Hz, 1 H), 4.50 (s, 2 H), 4.29-4.22 (m, 4 H), 3.42 (t, J = 14.1 Hz, 2H) , 2.16 (s, 3H), 1.28 (t, J = 7.1 Hz, 3H); MS (ES) m / z: 487 (M + Na +). Analysis calculated for C2? H2? F50 S: C, 54.31; H, 4.56. Found: C, 54.52; H, 4.55.

Compound 25 Acid. { 4- [2,2-difluoro-3- (4-trifluoromethyl-phenoxy) -propylsulfanyl] -2-methyl-phenoxy} - acetic Following the general procedure 2, compound 25 (91%) was obtained; 1 H NMR (300 MHz, CDCl 3) d 10.47 (brs, 1 H), 7.51 (d, J = 8.6 Hz, 2 H), 7.21 (m, 2 H), 6.81 (d, J = 8.6 Hz, 2 H) , 6.49 (d, J = 8.3 Hz, 1 H), 4.56 (s, H), 4.25 (t, J = 11.1 Hz, 2H), 3.42 (t, J = 14.1 Hz, 2 H), 2.15 (s, 3 H); MS (ES) m / z: 459 (M + Na +).

EXAMPLE XXVI SCHEME 31 31 -. 31 -A-Ethyl ester of acid. { 2-methyl-4- [2- (4-trifluoromethyl-phenoxymethyl) - [1,3] dioxan-2-ylmethylsulfanyl] -phenoxy} -acetic A mixture of 18-C (270 mg, 0.611 mmol) and trimethylsilyl chloride (265 mg, 2.44 mmol) in 1,3-propanediol (1 ml) was stirred at room temperature overnight, diluted with 5% of NaHCOs and extracted with Et2O. The extracts were washed with 5% NaHCO3 and brine, dried and concentrated to give crude 31-A; 1 H NMR (300 MHz, CDCl 3) d 7.48 (d, J = 8.8 Hz, 2 H), 7.19 (m, 2 H), 6.86 (d, J = 8.8 Hz, 2 H), 6.43 (d, J = 8.4 Hz, 1 H), 4.48 (s, 2 H), 4.24 (q, J = 7.1 Hz, 2 H), 4.16 (s, 2 H), 3.94 (m, 4 H), 3.48 (s, 2 H) , 2.14 (s, 3 H), 1.90 (m, 1 H), 1.66 (m, 1 H), 1.28 (t, J = 7.1 Hz, 3 H); MS (ES) m / z: 523 (M + Na +).

Compound 26 Acid. { 2-Methyl-4- [2- (4-trifluoromethyl-phenoxymethyl) - [1, 3] dioxan-2-ylmethylsulfanii] -phenoxy} -acetic Following the general procedure 2, compound 26 (90%) was obtained; 1 H NMR (300 MHz, CDCl 3) d 7.46 (d, J = 8.7 Hz, 2 H), 7.15 (m, 2 H), 6.86 (d, J = 8.7 Hz, 2 H), 6.43 (d, J = 8.2 Hz, 1 H), 4.36 (s, 2 H), 4.15 (s, 2 H), 3.91 (m, 4 H), 3.45 (s, 2 H), 2.06 (s, 3 H), 1.86 (m, 1 H), 1.64 (m, 1 H); MS (ES) m / z: 495 (M + Na +).

EXAMPLE XXVII SCHEME 32 32-A Ethyl ester of acid. { 2-methyl-4- [2- (4-trifluoromethyl-phenoxymethyl) -oxiranylmethylsulfanyl] -phenoxy} -acetic A mixture of trimethylsulfoxonium iodide (69 mg, 0.31 mmol) and NaH (10 mg, 0.25 mmol, 60% in mineral oil) in DMSO (0.5 mL) was stirred at room temperature for 1 hr, and then an 18-C solution (100 mg, 0.226 mmol) in DMSO (0.5 ml). The reaction mixture was heated to ~60 ° C for 2 hr, quenched with water, and extracted with Et2O. The extracts were dried, concentrated and purified by column chromatography (EtOAc / hexane: 1/4) to give 41 mg (40%) of 32-A; 1 H NMR (300 MHz, CDCl 3) d 7.52 (d, J = 8.5 Hz, 2 H), 7.25 (d, J = 1.8 Hz, 1 H), 7.21 (dd, J = 8.4, 2.1 Hz, 1 H), 6.91 (d, J = 8.5 Hz, 2 H), 6.54 (d, J = 8.4 Hz, 1 H), 4.56 (s, 2 H), 4.37 (d, J = 10.6 Hz, 1 H), 4.25 (q, J = 7.1 Hz, 2 H), 4.00 (d, J = 10.6 Hz, 1 H), 3.42 (d, J = 14.3 Hz, 1 H), 2.95 (d, J = 14.2 Hz, 1 H), 2.81 (d, J = 5.4, 0.9 Hz, 1 H), 2.67 (d, J = 5.4 Hz, 1 H), 2.20 (s, 3 H), 1.29 (t, J = 7.1 Hz, 3 H); MS (ES) m / z: 479 (M + Na +). 32-B Ethyl ester of acid. { 4- [2,2-dimethyl-4- (4-trifluoromethyl-phenoxymethyl) - [1,3] dioxolan-4-ylmethylsulfanyl] -2-methyl-phenoxy} -acetic A solution of 32-A (80 mg, 0.17 mmol) in acetone (5 ml) was treated with 5 N H2SO4 (0.1 ml) at room temperature for 24 hr, and concentrated. The residue was partitioned between EtOAc and water. The organic layer was dried, concentrated and subjected to column chromatography (EtOAc / hexane: 1: 7) to give 55 mg (60%) of 32-B; 1 H NMR (300 MHz, CDCl 3) d 7.48 (d, J = 8.5 Hz, 2 H), 7.19 (d, J = 1.7 Hz, 1 H), 7.15 (dd, J = 8.4, 2.2 Hz, 1 H), 6.80 (d, J = 8.6 Hz, 2 H), 6.43 (d, J = 8.4 Hz, 1 H), 4.48 (s, 2 H), 4.24 (q, J = 7.1 Hz, 2 H), 4.08-3.95 (m, 4 H), 3.35 (d, J = 13.8 Hz, 1 H), 3.19 (d, J = 13.8 Hz, 1 H), 2.14 (s, 3H), 1.44 (s, 3H), 1.43 (s, 3 H), 1.28 (t, J = 7.1 Hz, 3 H); MS (ES) m / z: 537 (M + Na +).

Compound 27 Acid. { 4- [2,2-dimethyl-4- (4-trifluoromethyl-phenoxymethyl) - [1,3] dioxolan-4-ylmethylsulfanyl] -2-methyl-phenoxy} -acetic Following the general procedure 2, compound 27 was obtained (90%); 1 H NMR (300 MHz, CDCl 3) d 9.42 (brs, 1 H), 7.46 (d, J = 8.6 Hz, 2 H), 7.19 (s, 1 H), 7.15 (d, J = 8.4 Hz, 1 H) , 6.79 (d, J = 8.6 Hz, 2H), 6.44 (d, J = 8.4 Hz, 1 H), 4.52 (s, 2 H), 4.14-3.93 (m, 4 H), 3.36 (d, J = 13.8 Hz, 1 H), 3.20 (d, J = 13.8 Hz, 1 H), 2.12 (s, 3 H), 1.45 (s, 3 H), 1.43 (s, 3 H); MS (ES) m / z: 509 (M + Na +).

EXAMPLE XXVIII SCHEME 33 33 -. 33 -A Ethyl ester of acid. { 4- [2-hydroxy-2- (4-trifluoromethyl] -phenoxymethyl) -butylsulfanyl] -2-methyl-phenoxy} -acetic To a suspension of Cul (61 mg, 0.32 mmol) in Et 2 O (0.8 ml) at 0 ° C was added 1.4 M MeLi (0.457 ml, 0.640 mmol) in THF. After the mixture was stirred for 1 hr, a solution of 32-A (145 mg, 0.32 mmol) in Et 2 O (1 mL) was added. The mixture was allowed to warm to room temperature in 2 hr and was partitioned between Et20 and water. The combined organic layers were dried, concentrated and subjected to column chromatography (EtOAc / hexane: 1/7) to provide 98 mg (65%) of 33-A; 1 H NMR (300 MHz, CDCl 3) d 7.48 (d, J = 8.6 Hz, 2 H), 7.20 (s, 1 H), 7.16 (dd, J = 8.4, 2.2 Hz, 1 H), 6.79 (d, J = 8.6 Hz, 2H), 6.44 (d, J = 8.4 Hz, 1 H), 4.47 (s, 2 H), 4.24 (q, J = 7.1 Hz, 2 H), 3.86 (d, J = 9.0 Hz, 1 H), 3.79 (d, J = 9.0 Hz, 1 H), 3.27 (d, J = 13.8 Hz, 1 H), 3.10 (d, J = 13.8 Hz, 1 H), 2.59 (s, 1 H) , 2.13 (s, 3 H), 1.74 (q, J = 7.6 Hz, 2H), 1.28 (t, J = 7.1 Hz, 3H), 0.96 (t, J = 7.5 Hz, 3H); MS (ES) m / z: 495 (M + Na +).

Compound 28 Acid. { 4- [2-hydroxy-2- (4-trifluoromethyl-phenoxymethyl) -butyl sulfanyl] -2-methyl-phenoxy} - acetic Following the general procedure 2, compound 28 (91%) was obtained; 1 H NMR (300 MHz, CDCl 3) d 7.46 (d, J = 8.6 Hz, 2 H), 7.20 (s, 1 H), 7.17 (d, J = 8.4, 1 H), 6.77 (d, J = 8.6 Hz, 2 H), 6.45 (d, J = 8.4 Hz, 1 H), 4.52 (s, 2 H), 3.86 (d, J = 9.0 Hz, 1 H), 3.78 (d, J = 9.0 Hz, 1 H), 3.27 (d, J = 13.8 Hz, 1 H), 3.12 (d, J = 13.8 Hz, 1 H) , 2.12 (s, 3 H), 1.75 (q, J = 7.6 Hz, 2 H), 0.96 (t, J = 7.5 Hz, 3 H); MS (ES) m / z: 467 (M + Na +).

EXAMPLE XXIX -A 1- [4- (2-Chloromethyl-allyloxy) -2-hydroxy-3-propyl-phenyl] -ethanone A mixture of 1- (2,4-dihydroxy-3-propyl-phenyl) -ethanone (158 mg, 0.814 mmol), methanesulfonic acid 2-chloromethyl-allyl ester 5-A (750 mg, 4.06 mmol), and CS2CO3 (662 mg, 2.03 mmol) in 2-butanone (3 mL) was stirred at room temperature for 6 hours. hr, acidified with 1 N HCl, and extracted with Et2O. The extracts were dried, concentrated and subjected to column chromatography (EtOAc / hexane: 1/7) to provide 190 mg (83%) of the title compound 35-A; 1 H NMR (300 MHz, CDCl 3) d 7.59 (d, J = 9.0 Hz, 1 H), 6.46 (d, J = 9.0 Hz, 1 H), 5.41 (s, 1 H), 5.37 (s, 1 H) , 4.70 (s, 2 H), 4.20 (s, 2 H), 2.66 (t, J = 7.6 Hz, 2 H), 2.56 (s, 3 H), 1.55 (m, 2 H), 0.95 (t, J = 7.4 Hz, 3 H); MS (ES) m / z: 305 (M + Na +).

EXAMPLE XXX SCHEME 36 96%, Compound 29 36-B Replacing ethyl ester (4-mercapto-2-methyl-phenoxy) -acetic acid 1-C by methyl ester of (4-hydroxy-2-methyl-phenoxy) -acetic acid 36- A, which can be easily made in accordance with, for example, Sznaidman et al., Bioorganic & Medicinal Chemistry Letters 13 (2003) 1517-1521, and following general procedure 3 the title compound 36-B (76%) was obtained; 1 H NMR (400 MHz, CDCl 3) d 7.53 (d, J = 8.8 Hz, 2 H), 6.99 (d, J = 8.7 Hz, 2 H), 6.76 (d, J = 1.8 Hz, 1 H), 6.66 (m, 2 H), 5.41 (s, 1 H), 5.39 (s, 1 H), 4.67 (s, 2 H), 4.59 (s, 2 H), 4.57 (s, 2 H), 3.79 (s, 3 H), 2.26 (s, 3 H); MS (ES) m / z: 433 (M + Na +).

Compound 29 Following general procedure 2, compound 29 was obtained (96%); 1 H NMR (400 MHz, CDCl 3) d 7.54 (d, J = 8.7 Hz, 2 H), 6.99 (d, J = 8.7 Hz, 2 H), 6.78 (s, 1 H), 6.69 (m, 2 H) , 5.42 (s, 1 H), 5.40 (s, 1 H), 4.67 (s, 2 H), 4.63 (s, 2 H), 4.58 (s, 2 H), 2.26 (s, 3 H); MS (ES) m / z: 419 (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 several 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 labeled or coated 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. In contrast, the salt form can be converted by alkali treatment into 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 bivalent cyclic saturated radicals can have either the cis 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. Said forms, although not explicitly indicated in the above and following formulas, are intended to be included within the scope of the 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 treated, the age, and general 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, preclinical 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 complications. atherosclerotic, 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) may be between 5 and 200 mg, such as 10, 15, 25, 35, 50 mg, 60 mg and 100 mg and may 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), intracystemal, intravaginal, intraperitoneal, 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 lecithin, a surfactant, or by maintaining 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; isotonic 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 lowering 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 sub-therapeutic or sub-prophylactic if administered alone, but are therapeutic or prophylactic when administered together. Antidiabetic agents include insulin sensitizers of thiazolidinedione and not thiazolidinedione, 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 (PPAR?), Which increases the transcription of specific insulin-responsive genes. Examples of PPAR-gamma agonists are thiazolidinediones such as: (1) rosiglitazone (2,4-thiazolidinedione, 5 - ((4- (2- (methyl-2-pyridinylammon) ethoxy) phenyl) methyl) -, ( Z) -2-butenedioate (1: 1) or 5 - ((4- (2- (methyl-2-pyridinylamino) ethoxy) phenyl) methyl) -2,4-thiazolidinedione, 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-pyridinol) ethoxy) phenyl) methyl) -, monohydrochloride, (+ -) - or - ((4- (2- (5-ethyl-2-pyridyl) ethoxy) phenyl) methy1) -2,4-thiazolidinedione, 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 methylene) -2,4-thiazolidinedione, known as NOSCAL, REZULIN, ROMOZIN or PRELAY, also known as Cl 991, CS 045, GR 92132, GR 92132X); (4) isaglitazone ((+) - 5 - [[6 - [(2-fluorophenyl) methoxy] -2-naphthalenyl] methyl] -2,4-thiazolidinedione or 5 - ((6 - ((2-fluorophenyl) methoxy] ) -2- naphthalenyl) methyl-2,4-thiazolidinedione or 5- (6- (2-fluorobenzyloxy) naphthalen-2-ylmethyl) thiazole-2,4-dione, also known as MCC-555 or neoglitazone ) and (5) 5-BTZD In addition, non-thiazolidinediones 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: isoxazolidino-3,5-dione, 4 - ((4- (2-phenyl-5-methyl) -1, 3-oxazolyl) ethylphenyl-4) methyl-); (2) KRP-297 (5- (2,4-D-oxothiazolidin-5-ylmethyl) -2-methoxy-N- (4- (trifluoromethyl) benzyl) benzamide or 5 - ((2,4-dioxo-5-thiazolidinyl) methyl) - 2-methoxy-N - ((4- (trifluoromethyl) phenyl) methyl) benzamide); and (3) Farglitazar (L-tyrosine, N- (2-benzoylphenyl) -o- (2- (5-methyl-2- phenyl-4-oxazolyl) ethyl) - or N- (2-benzoylphenyl) -0- (2- (5-methyl-2-phenyl-4-oxazolyl) ethyl) -L-tyrosine, or GW2570 or GI-262570) Other agents have also shown activity PPAR modulator 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 proliferator-activated receptor agonist gamma); (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 agonist); (15) AR-H049020 (PPAR agonist); (16) GW 0072 acid (4- (4 - ((2S, 5S) -5- (2- (bis (phenylmethyl) amino) -2-oxoethyl) -2-heptyl-4-oxo-3-thiazolidinyl) 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-benzo-phenyl) -O- (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-) acid (2-benzoxazolyl) -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 proliferator activated receptor agonist); (35) bexarotene (4- (1 - (3,5, 5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthalenyl) 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-nositol or D-1, 2,3,4,5,6-hexahydroxycyclohexane); (2) inhibitors of protein 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) etl) -N- (2-hydroxy-2-phenethyl) chloride ammonium, also known as ICI D 2079) or AZ 40140; (5) glycogen phosphorylase inhibitors; (6) fructose-1, 6-bisphosphatase inhibitors; (7) chromic picolinate, 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- (thiazoidino-2,4-dione); (12) TS 971; (13) T 174 (( + -) - 5- (2,4-dioxothiazoiidin-5-ylmethyl) -2- (2-naphthylmethyl) benzoxazole) (14) SDZ PGU 693 ((+) - trans-2 (S - ((4-chlorophenoxy) ) methyl) -7alpha- (3,4-dichlorophenyl) tetrahydropyrrolo (2,1-b) oxazole-5 (6H) -one); (15) S 15261 ((-) - 4- (2 - ((9H)) acid -fluoren-9-ylacetyl) amino) ethyl) benzoic ethyl ester of 2 - ((2-methoxy-2- (3- (trifluoromethyl) phenyl) ethyl) amino)); (16) AZM 134 (Alizyme); ) ARIAD; (18) R 102380; (19) PNU 140975 (1- (hydrazinoiminomethyl) hydrazino) acetic acid; (20) PNU 106817 acid (2- (hydrazinoiminomethyl) hydrazino) acetic acid; (21) NC 2100 (5 - ((7- (phenylmethoxy) -3-quinoline) methyl) -2,4-thiazolidinedione; (22) MXC 3255; (23) MBX 102; (24) ALT 4037; (25) AM 454; (26) JTP 20993 (2- (4- (2- (5-Methy-2-phenyl-4-oxazolyl) ethoxy) benzyl) -malonic acid dimethyl diester (27) Dexlipotam acid (5 (R) - (1,2-dithiolan-3-yl) pentanoic acid, also known as (R) -a acid? lipoic or acid (R) -thioctic acid); (28) BM 170744 acid (2,2-dichloro-12- (p-chlorophenyl) dodecanoic); (29) BM 152054 (5- (4- (2- (5-methyl-2- (2-thienyl) oxazol-4-yl) ethoxy) benzothien-7-ylmethyl) tlazolidino-2,4-dione); (30) BM 131258 (5- (4- (2- (5-methyl-2-phenyloxazol-4-yl) ethoxy) benzothien-7-ylmethyl) thiazolidino-2,4-dione); (31) CRE 16336 (EML 16336); (32) HQL 975 (3- (4- (2- (5-methyl-2-phenyloxazol-4-yl) ethoxy) phenyl) -2 (S) - (propylamino) propionic acid); (33) DRF 2189 (5 - ((4- (2- (1-indolyl) ethoxy) phenyl) methyl) thiazolidino-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) Insulin receptor recyclers of insulin (41) modulators of Glucose transporter 4 (42) TNF-a antagonists (43) plasma cell differentiation antigen antagonists -1 (PC-1) (44) Adipocyte lipid binding protein inhibitors (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 antagonists; 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 (N, N-dimethylimidodicarbonimide diamido 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 down the digestion of carbohydrates.Un-digested 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, O-4,6-dideoxy-4 - (((1S- (1alpha, 4alpha, dbeta, 6aIfa)) - 4,5,6 -trihydroxy-3- (hydroxymethyl) -2-cyclohexen-1-yl) amino) -aIfa-D-glucopyranosyl- (1-4) -0-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, 5beta)) -o (2R, 3R, 4R, 5S ) -1- (2-hydroxyethyl) -2- (hydroxymethyl-3,4,5-piperidinetriol, 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-trihydroxycyclohexane-1-yl) amino) -alpha-b-glucopyranosyl- (1-4) -alpha-D-glucopyranosyl- (1-4) -D-glucopyranose) (4) Emiglitarate, ethyl ester of (4- (2 - ((2R, 3R, 4R, 5S) -3) , 4,5-tri- hydroxy-2- (hydroxymethyl) -1-piperidinyl) ethoxy) benzoic acid, also known as BAY or 1248 or MKC 542); (5) MOR 14 (3,4,5-piperidinetriol, 2- (hydroxymethyl) -l-methyl-, (2R- (2alpha, 3beta, 4alpha, dbeta)), also known as N-methyloxynojirimycin or N-methylmoranoline), and (6) Voglibose (3,4-dideoxy-) 4 - ((2-hydroxy-1- (hydroxymethyl) ethyl) amino) -2-C- (hydroxymethyl) -D-epi-inositol or D-epi-Inositol, 3,4-dideoxy-4 - ((2- hydroxy-1- (hydroxymethyl) ethyl) amino) -2-C- (hydroxymethyl) -, 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) -oxobis (1-pyrrolidincarbodithioate-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); (5) 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 27dd8d, HUMALOG, HUMALOG MIX 75/25 or HUMALOG MIX 50/50); (7) insulin glargine (human (A21 -glycine, B31 -arginine, B32-arginine) insulin HOE 901, also known as orno LANTUS, OPTISULIN); (8) Insulin suspension -zinc, extended (Ultralente), also known as HUMULIN U or ULTRALENTE; (9) Suspension of insulin-zinc (Lens), a suspension of insulin 70% crystalline and 30% amorphous, also known as LENTE ILETIN II, HUMULIN L or NOVOLIN L; (10) HUMULIN 50/50 (50% insulin isophane and 50% insulin injection); (11) HUMULIN 70/30 (70% insulin isofano 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 NPHILETIN 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-dOO (Concentrated); (14) ARIAD; (15) LY 197535; (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 mimetics; (3) exendin and its mimetics; (4) dipeptyl protease inhibitors (DPP or DPPIV) such as (4a) DPP-728 or LAF 237 (2-pyrrolidinecarbonitrile, 1 - (((2 - ((5-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- (3N - ((2S, 3S) -2-amino-3-methyl-pentanoyl) -1, 3-thiazolidin)); (4c) TSL 225 acid (triptophyl-1, 2,3,4-tetrahydroisoquinoline-3-carboxylic acid); (4d) Valine pyrrolidide (valpir); (4e) 1-aminoalkylisoquinolinone-4-carboxylates and analogs thereof; (4f) SDZ 272-070 (1- (L-Valyl) pyrrolidine); (4g) TMC-2A, TMC-2B or TMC-2C; (4h) Dipeptide nitriles (2-cyanopyrrolodes); (4¡) CD26 inhibitors; and (4j) SDZ 274-444; (5) glucagon antagonists such as AY-279955; and (6) amylin agonists which include, but are not limited to, pramlintide (AC-137, Symlin, tripro-amylin 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, meglitinides, 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 Colestid, Locholest, Questran, Atromid, Lopid and Tricor. Examples of blood pressure lowering 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 11 receptor antagonists (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, Monoket, 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 test method 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 (PPARa.? D) and Gal4-Luciferase reporter using the DMRIE-C reagent. The next day, the medium was replaced with 5% growth medium of FBS treated with carbon. After six hours, the cells were trypsinized and seeded at a density of 50,000 cells / well in 96-well plates and incubated overnight at 37 ° C in a 5% CO2 incubator. 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 Luciferase 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 EC5o'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 G. Other Modes The characteristics and principles of the invention are illustrated in the discussion, examples and claims herein. 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 (44)

NOVELTY OF THE INVENTION CLAIMS

1. - A compound of the formula (I): wherein X is selected from a covalent bond, S and O; And it's S or O; Z is O or CH2, provided that when Y is O, Z is O; R-i and R2 are independently selected from H, C1-3 alkyl, C---3 alkoxy, halogen, and NRaRb wherein Ra and R are independently H or C? -3 alkyl; R3 and R4 are independently selected from H, halogen, cyano, C1-5 alkyl, hydroxy, C2- acyl, C4-alkoxy, and NRcRd wherein Rc and Rd are independently H or C3-alkyl, provided that R3 and R4 are not both H; R5 and Re are independently selected from halogen, phenyl, C? -g alkyl, C-? 8 alkoxy, C2-9 alkenyl, C2-g alkenyloxy, C3-7 cycloalkyl, C3-7 cycloalkoxy, C3-7 cycloalkylC1-7alkyl, C3-7cycloalkyl-C- alkoxy-, C3-7cycloalkyloxy- C6-6alkyl, and C3-7cycloalkyloxy- C7-7alkoxy , or R5 and Re together form C1-9 alkynyl or alkenyldenyl of 03.9, or R5 and Re and the carbon atom to which they are attached form cycloalkyl of C3-7 or heterocycle of d or 6 members; n is 0, 1 or 2; and m is 0, 1 or 2; or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1, further characterized in that X is S or O.

3. The compound according to claim 2, further characterized in that X is O.

4. The compound according to claim 1 further characterized in that Y is O.

5. The compound according to claim 1, further characterized in that Y is S.

6. The compound according to claim 1, further characterized in that Z is O.

7. The compound according to claim 1, further characterized in that Z is CH or CH2.

8. The compound according to claim 1, further characterized in that m is 1.

9. The compound according to claim 1, further characterized in that m is 2.

10. The compound according to claim 1, further characterized in that n is 1.

11. The compound according to claim 1, further characterized in that Ri and R2 are independently selected from H, C? -3 alkyl, C1-3 alkoxy, F, Cl and Br.

12. The compound according to claim 11, further characterized in that Ri and R2 are independently selected from H, methyl, methoxy, F and Cl.

13. The compound according to claim 1, further characterized in that R3 and R are selected independently of H, halogen, cyano, acetyl, C? -2 alkyl and C? _2 alkoxy.

14. The compound according to claim 13, further characterized in that R is independently selected from H, F, Cl, hydroxy, methyl and methoxy.

15. The compound according to claim 13, further characterized in that R4 is independently selected from F, Cl, methyl, methoxy, trifluoromethyl, trifluoromethoxy, difluoromethyl, difluoromethoxy, fluoromethyl, fluoromethoxy, chlorodifluoromethyl, chlorodifluoromethoxy, dichlorofluoromethyl and dichlorofluoromethoxy.

16. 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) 2l-O-CH2COOH and -COCH3, and R4 is selected from H, Cl and methyl.

17. The compound according to claim 1, further characterized in that R5 and R6 together form C9-9 alkyldenyl or C3-g alkenyldenyl, or R5, Re and the carbon atom to which they are bonded together form cycloalkyl of C3 -7-

18. The compound according to claim 1, further characterized in that R5 and Re are independently selected from halogen, phenyl, C1.9 alkyl, ds alkoxy, C2-g alkenyl, C2-g alkenyloxy , C3.7 cycloalkyl. C3-7 cycloalkoxy, C3- cycloalkyl-C? -7-alkyl, C3-cycloalkyl-C? -7-alkoxy, C3-7 cycloalkyloxy-C? -6 alkyl, and C3-7 cycloalkyloxy- C7 _7 alkoxy.

19. The compound according to claim 1, further characterized in that R3 is selected from H, F, Cl, methyl and methoxy, and R is selected from F, Cl, acetyl, methyl, methoxy, trifluoromethyl, trifluoromethoxy, difluoromethyl, difluoromethoxy, fluoromethyl, fluoromethoxy, chlorodifluoromethyl, chlorodifluoromethoxy, dichlorofluoromethyl and dichlorofluoromethoxy.

20. The compound according to claim 1, further characterized in that R1 is selected from H, CF3, methyl, Cl and methoxy, and R2 is selected from H, Cl and methyl.

21. The compound according to claim 1, further characterized in that X is O and Y is O.

22. The compound according to claim 1, further characterized in that Z is O and Y is S. 23.- The compound according to claim 1, further characterized in that X is O and Y is S. The compound according to claim 1, further characterized in that X is a covalent bond and Y is S. The compound of according to claim 1, 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, methyl and methoxy; and R4 is selected from F, Cl, methyl and methoxy. 26. 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, methyl, methoxy, trifluoromethyl, trifluoromethoxy, difluoromethyl, difluoromethoxy, fluoromethyl and fluoromethoxy. 27. 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, methoxy, trifluoromethyl, trifluoromethoxy, difluoromethyl, difluoromethoxy, fluoromethyl and fluoromethoxy. 28. 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 is selected from F, Cl, methyl, methoxy, methyl, methoxy, trifluoromethyl, trifluoromethoxy, difluoromethyl, difluoromethoxy, fluoromethyl and fluoromethoxy. 29. 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, methyl and methoxy; R 4 is selected from F, Cl, methyl, methoxy and methyl, methoxy, trifluoromethyl, trifluoromethoxy, difluoromethyl, difluoromethoxy, fluoromethyl and fluoromethoxy; and R5 and Re together form alkylaryl of Ci.g or alkenyldenyl of 03.9, or R5 and R and the carbon atom to which they are attached form cycloalkyl. The compound according to claim 25, further characterized in that X is O; And it is O or S; and Z is O. 31.- The compound according to claim 25, further characterized in that R5 and Re together form alkyldenyl of Ci.go alkenyldenyl of C3-g, or R5, Re and the carbon atom to which they are attached together they form C3-7-32 cycloalkyl.- The compound according to claim 25, further characterized in that R5 and Re are independently selected from halogen, phenyl, Ci.alkyl, Cysalkoxy, C2-alkenyl, alkenyloxy of C2-g, C3-7 cycloalkyl. C3-7-cycloalkoxy, C3-7-cycloalkyl-C7-7-alkyio, C3-7-cycloalkyl-C7-alkoxy, C3.7-cycloalkyloxy-C1-6-alkyl, and C3-cycloalkyloxy-alkoxy of C? -7. 33. The compound according to claim 25, further characterized in that m is 1 and n is 1. 34.- The compound according to claim 25, further characterized in that Y is S. 35.- The compound according to claim 1, further characterized in that it is selected from: acid. { 2-met! -4- [2- (4-trifluoromethyl-phenoxymethyl) -allylsulfanyl] -phenoxy} -acetic; (2-methyl-4- { 2- [2- (4-trifluoromethyl-phenyl) -etl] -alkylsulfanyl] -phenoxy) -acetic acid; acid { 2-methyl-4- [2- (4-trifluoromethoxy-phenoxymethyl) -aliisulfanyl] -phenoxy} -acetic; acid { 2-Chloro-4- [2- (4-trifluoromethyl-phenoxymethyl) -allylsulfanyl] -phenoxy} -acetic; acid { 2-methyl-4- [3-methyl-2- (4-trifluoromethyl-phenoxymethyl) -but-2-enylsulfanyl] -phenoxy} -acetic; acid { 4- [3,3-difluoro-2- (4-trifluoromethyl-phenoxymethyl) -allysulfanyl] -2-methyl-phenoxy} -acetic; acid { 3-Chloro-4- [2- (4-trifluoromethyl-phenoxymethyl) -allylsulfanyl] -phenyl} -acetic; acid { 2- methyl-4- [1- (4-trifluoromethyl-phenoxymethyl) -cyclopropylmethylsulfanyl] -phenoxy} -acetic; acid { 2-methyl-4- [2-propyl-2- (4-trifluoromethyl-phenoxymethyl) -pentylsulfanyl] -phenoxy} - acetic; acid { 4- [2- (4-chloro-phenoxymethyl) -aylsulfanyl] -2-methyl-phenoxy} -acetic; acid { 4- [2- (3,4-Dichloro-phenoxymethyl) -allylsulfanyl] -2-methyl-phenoxy} -acetic; acid { 4- [2- (2,4-dichloro-phenoxymethyl) -allylsulfanyl] -2-methyl-phenoxy} -acetic; acid { 4- [3-cyano-2- (4-trifluoromethyl-phenoxymethyl) -allylsulfanyl] -2-methyl-phenoxy} -acetic; acid { 2-methyl-4- [3-phenyl-2- (4-trifluoromethyl-phenoxymethyl) -allysu-imanyl] -phenoxy} -acetic; acid { 2-methyl-4- [3-naphthalen-1-yl-2- (4-trifluoromethyl-phenoxymethyl) -allylsulfaniI] -phenoxy} -acetic; acid { 4- [2,2-difluoro-3- (4-trifluoromethyl-phenoxy) -propylsulfanyl] -2-methyl-phenoxy} -acetic; acid { 2-methyl-4- [2- (4-trifluoromethyl-phenoxymethyl) - [1,3] dioxan-2-ylmethylsulfanyl] -phenoxy} -acetic; acid { 4- [2,2-dimethyl-4- (4-trifluoromethyl-phenoxymethyl) - [1,3] dioxolan-4-ylmethylsulfanyl] -2-methyl-phenoxy} -acetic; [2-methyl-4- (2-phenoxymethyl-allylsulfanyl) -phenoxy] -acetic acid; acid { 4- [2- (4-chloro-3-trifluoromethyl-phenoxymethyl) -allylsulfanyl] -2-methyl-phenoxy} -acetic; acid { 4- [2- (4-methoxy-phenoxymethyl) -allylsulfanyl] -2-methyl-phenoxy} -acetic; acid { 4- [2- (4-dimethylamino-phenoxymethyl) -alkylsulfanyl] -2-methy1-phenoxy} -acetic; acid { 2-trifluoromethyl-4- [2- (4-trifluoromethyl-phenoxymethyl) -allylsulfanyl] -phenoxy} -acetic; acid { 3-Chloro-4- [2- (4-trifluoromethyl-phenoxymethyl) -allylsulfanyl] -phenoxy} -acetic; acid { 2-methoxy-4- [2- (4-trifluoromethyl-phenoxymethyl) -ali-sulphanil] -phenoxy} -acetic; acid { 2-methyI-4- [3- (4-trifluoromethyl-phenoxy) -but-3-enylsulfanyl] -phenoxy} -acetic; acid { 2- methyl-4- [2- (4-trifluoromethyl-phenoxy) -allylsulfanyl] -phenoxy} -acetic; acid { 4- [2-hydroxy-2- (4-trifluoromethyl-phenoxymethyl) -butylsulfanyl] -2-methyl-phenoxy} -acetic; acid { 4- [2- (4-tert-Butyl-phenoxymethyl) -allylsulfanyl] -2-methyl-phenoxy} -acetic; acid { 4- [2- (4-isopropyl-phenoxymethyl) -allylsufanyl] -2-methyl-phenoxy} -acetic; acid { 2-Chloro-4- [2- (3,4-dichloro-phenoxymethyl) -allylsulfanyl] -phenoxy} -acetic; acid { 2-Chloro-4- [2- (4-trifluoromethoxy-phenoxymethyl) -allylsulfanyl-3-phenoxy} -acetic; acid { 4- [2,2-dimethyl-3- (4-trifluoromethyl-phenoxy) -propylsulfanyl] -2-methyl-phenoxy} -acetic; acid { 2-Chloro-4- [2,2-dimethyl-3- (4-trifluoromethyl-phenoxy) -propylsulfanyl] -phenoxy} -acetic; acid { 2-Chloro-4- [1- (4-trifluoromethyl-phenoxymethyl) -cyclopropylmethylsulfanyl] -phenoxy} -acetic; acid { 3-Chloro-4- [2,2-dimethyl-3- (4-trifluoromethyl-phenoxy) -propylsulfanyl] -phenyl} -acetic; acid { 3-Chloro-4- [2,2-dimethyl-3- (4-trifluoromethoxy-phenoxy) -propylsulfanyl] -phenyl-acetic acid; and acid. { 3-Chloro-4- [3-methyl-2- (4-trifluoromethyl-phenoxymethyl) -but-2-enylsulfanyl] -fenii} -acetic. 36. The compound according to claim 1 further characterized in that it is [2-methyl-4 - [[2 - [[4- (trifluoromethyl) phenoxy] methyl] -2-propenyl] thio] phenoxy] -acetic acid. 37.- A pharmaceutical composition comprising a compound of any of claims 1, 16, 17, 19, 26, 26, 29, 3d and 36. 38.- The use of the composition defined in the claim 37, to prepare a medicament for the treatment or inhibition of progression of a PPAR-delta-mediated condition in a patient. 39.- The compound according to claim 1 further characterized in that it is acid. { 2-methyl-4- [2- (4-trifluoromethyl-phenoxymethyl) -allylsulfanyl] -phenoxy} -acetic. 40.- A compound of the formula (II): wherein X is selected from a covalent bond, S and O; And it's S or O; Ri and R2 are independently selected from H, C? -3 alkyl, C1-3 alkoxy, halogen and NRaRb where R a and R b are independently H or alkyl? C? -3; R3 and R4 are independently selected from H, halogen, cyano, C? -5 alkyl, hydroxy, C2-4 acyl, C1-4 alkoxy, and NRcRd wherein Rc and Rd are independently H or C3 alkyl? , provided that R3 and R4 are not both H; R5 and Re are independently selected from halogen, phenyl, C1-9 alkyl, Ci-s alkoxy, C2.g alkenyl, C2.9 alkenyloxy, C3-7 cycloalkyl, C3-7 cycloalkoxy, C3 cycloalkyl -7-C-7-alkyl, cycloalkyl C3- -alkoxy of C? -, cycloalkyloxy of C3- -alkyl of C? _6, and cycloalkyloxy of C3-7-alkoxy of C1-7, or R5 and R together form alkenyl of C1-9 or alkenyldenyl of C3-9 , or R5 and R6 and the carbon atom to which they are attached form cycloalkyl of C3-7 or heterocycle of d or 6 members; n is 0, 1 or 2; and m is 0, 1 or 2; or a pharmaceutically acceptable salt thereof. 41. The compound according to claim 40, further characterized in that X is S or O. 42. The compound according to claim 41, further characterized in that X is O. 43. The compound according to claim 40, further characterized in that Y is O. 44. The compound according to claim 40, further characterized in that Y is S. 4d.- The compound according to claim 40, further characterized because m is 1. 46.- The compound according to claim 40, further characterized in that m is 2. 47. The compound according to claim 40, further characterized in that n is 1. 48. The compound according to claim 40, further characterized in that Ri and R2 are independently selected from H, C - - - 3 alkyl, C-- 3 alkoxy, F, Cl and Br. 49 - The compound according to claim 48, further characterized in that R1 and R2 are selected independent H, methyl, methoxy, F and Cl. dO.- The compound according to claim 40, further characterized in that R 3 and R 4 are independently selected from H, halogen, cyano, acetyl, C 2 -alkyl and alkoxy C -? - 2. 51. The compound according to claim 50, further characterized in that R3 is independently selected from H, F, Cl, hydroxy, methyl and methoxy. 52. The compound according to claim 50, further characterized in that R4 is independently selected from F, Cl, methyl, methoxy, trifluoromethyl, trifluoromethoxy, difluoromethyl, difluoromethoxy, fluoromethyl, fluoromethoxy, chlorodifluoromethyl, chlorodifluoromethoxy, dichlorofluoromethyl and dichlorofluoromethoxy. 53. The compound according to claim 40, further characterized in that 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 is selected from H, Cl and methyl. 54.- The compound according to claim 40, further characterized in that R5 and R together form C3-alkenyldenyl alkyldenyldenyl of C3-g, or R5, Re and the carbon atom to which they are attached together form cycloalkyl of C3 -7. 5d.- The compound according to claim 40, further characterized in that R5 and Re are independently selected from halogen, phenyl, Ci-g alkyl, Cis alkoxy, C2-g alkenyl, C2-g alkenyloxy, cycloalkyl C3-, cycloalkoxy of C3..7, cycloalkyl of C3- -alkyl of C1-7, cycloalkyl of C3- -alkoxy of C-? -, cycloalkyloxy of C3- -alkyl of C-? -6, and cycloalkyloxy of C3 - -alcoxy of C? -7. 66.- The compound according to claim 40, further characterized in that R3 is selected from H, F, Cl, methyl, and methoxy, and F? 4 is selected from F, Cl, acetyl, methyl, methoxy, trifluoromethyl, trifluoromethoxy, difluoromethyl, difluoromethoxy, fluoromethyl, fluoromethoxy, chlorodifluoromethyl, chlorodifluoromethoxy, dichlorofluoromethyl and dichlorofluoromethoxy. 57. The compound according to claim 40, further characterized in that R-i is selected from H, CF3, methyl, Cl and methoxy, and R2 is selected from H, Cl and methyl. 58.- The compound according to claim 40, further characterized in that X is O and Y is O. 59.- The compound according to claim 40, further characterized in that X is O and Y is S. 60.- The compound according to claim 40, further characterized in that X is a covalent bond and Y is S. 61. The compound according to claim 40 further characterized because it is acid [2-methyl-4 - [[2 - [[ [4- (trifluoromethyl) phenyl] thio] methyl] -2-propenyl] thio] phenoxy] -acetic acid.