MXPA00011088A

MXPA00011088A - Naphtho[2,3-b]heteroar-4-yl derivatives

Info

Publication number: MXPA00011088A
Application number: MXPA/A/2000/011088A
Authority: MX
Inventors: Jay Edward Wrobel; Arlene Joan Dietrich; Paul Jeffrey Dollings
Original assignee: American Home Products Corporation
Priority date: 1998-05-12
Filing date: 2000-11-10
Publication date: 2001-07-31

Abstract

This invention provides compounds of structural Formula (I), wherein R1 and R2 are each, independently, hydrogen, nitrile, nitro, amino, alkylamino of 1-6 carbon atoms, dialkylamino of 1-6 carbon atoms per alkyl group, cycloalkylamino of 3-8 carbon atoms, alkyl of 1-6 carbon atoms, perfluoroalkyl of 1-6 carbon atoms, halogen, cycloalkyl of 3-8 carbon atoms, thienyl, furyl, phenyl or phenyl mono-, di-, or tri-substituted with halogen, hydroxy, alkyl of 1-6 carbon atoms, perfluoroalkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, or perfluoroalkoxy of 1-6 carbon atoms;R3 and R4 are each, independently, hydrogen, alkyl of 1-6 carbon atoms, perfluoroalkyl of 1-6 carbon atoms, hydroxyalkyl of 1-6 carbon atoms, aminoalkyl of 1-6 carbon atoms, acyl of 2-7 carbon atoms;R5 is hydrogen, halogen, alkyl of 1-6 carbon atoms, perfluoroalkyl of 1-6 carbon atoms, nitrile, alkoxy of 1-6 carbon atoms, aryloxy, arylalcoxy of 2-12 carbon atoms, arylsulfanyl;W is S, O, or NR9;R9 is hydrogen or alkyl of 1-6 carbon atoms;X is O, -NR6-, or -(CH2)pNR6-;R6 is hydrogen, or alkyl of 1-6 carbon atoms;p is 1 to 4;Y is methylene, carbonyl, -SO2-, or -SO-;Z is phenyl, heteroaryl, or naphthyl;R7 and R8 are each, independently, hydrogen, carboxyl, acyl of 2-7 carbon atoms, hydroxyl, hydroxyalkyl of 1-6 carbon atoms, hydroxyalkanoyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, perfluoroalkoxy of 1-6 carbon atoms, alkoxycarbonyl of 2-7 carbon atoms, perfluoroalkoxycarbonyl of 2-7 carbon atoms, alkyl of 1-6 carbon atoms, perfluoroalkyl of 1-6 carbon atoms, aryl, aryloxy, aryloxycarbonyl, heteroaryloxycarbonyl, arylalkoxy of 6-12 carbon atoms, heteroaryl, alkanoyloxy of 1-6 carbon atoms, perfluoroalkanoyloxy of 1-6 carbon atoms, heteroaroyloxy, aroyloxy, tetrazolyl, mercapto, nitrile, amino, carbamoy, aminoalkyl of 1-6 carbon atoms, -NHSO2CF3, carboxyaldehyde, halogen, nitro, acylamino, or pyrimidyl optionally substituted with mercapto, 3-hydroxy-cyclobut-3-ene-4-yl-1,2-dione, or tetronic acid;or a pharmaceutically acceptable salt thereof, which are useful in treating metabolic disorders related to insulin resistance or hyperglycemia.

Description

DERIVATIVES OF NAFTO G2. 3 -B] HETEROAR- - ILO BACKGROUND OF THE INVENTION The prevalence of insulin resistance in glucose-intolerant subjects has been recognized for a long time. Reaven et al (Ajnerican Journal ot Medicine 1976, 60, 80), used a continuous infusion of glucose and insulin (insulin / glucose fixation technique) and oral glucose tolerance tests to demonstrate that there is insulin resistance in a diverse group of non-obese non-ketone subjects. These subjects range from the limit of tolerant to glucose to those with hyperglycemia in evident fasting. The diabetic groups in these studies included subjects both insulin dependent (IDDM) and non-insulin dependent (NIDDM). Coincident with sustained insulin resistance is the more easily determined hyperinsulinemia, which can be measured by accurate determination of circulating plasma insulin concentration in the plasma of subjects. Hyperinsulinemia may be present as a result of insulin resistance, such as in obese and / or diabetic subjects (NIDDM) and / or glucose intolerant subjects, or in IDDM subjects, as a consequence of an excessive injection of Ref: 124381 insulin compared to the normal physiological release of the hormone by the endocrine pancreas. The association of hyperinsulinemia with obesity and ischemic diseases of large blood vessels (for example atherosclerosis) has been well established by numerous experimental, clinical and epidemiological studies (summarized by Stout, Metabolis, 1985, 34, 7, and in more detail by Pyorala et al, Diabetes / Metabolism Reviews 1987, 3, 63). Statistically significant plasma insulin elevations 1 and 2 hours after oral glucose loading correlate with an increased risk of coronary heart disease. Since most of these studies actually exclude diabetic subjects, there are not many data in relation to the risk of atherosclerotic diseases for the diabetic condition, but they point in the same direction as in non-diabetic subjects (Pyorala et al. ). However, the incidence of atherosclerotic diseases in the morbidity and mortality statistics in the diabetic population exceeds that of the non-diabetic population (Pyorala et al., Jarrett Diabetes / Metajolisjn Reviews 1989, 5, 547, Harris et al, Mortality from diabetes , in Diabetes in America 1985). The risk factors independent of obesity and hypertension for atherosclerotic diseases are also Associated with insulin resistance. Using a combination of insulin / glucose fixation techniques, tracer glucose infusion and indirect calorimetry, it has been shown that the insulin resistance of essential hypertension is localized in peripheral tissues (mainly muscles) and correlates directly with the severity of hypertension ( DeFronzo and Ferrannini, Diabetes Care 1991, 14, 173). In the hypertension of the obese, insulin resistance generates hyperinsulinemia, which is recruited as a mechanism to limit the additional weight gain via thermogenesis, but insulin also increases the renal reabsorption of sodium and stimulates the sympathetic nervous system in the kidneys , heart and vasculature, which generates hypertension. It has now been appreciated that insulin resistance is usually the result of a defect in the insulin receptor signaling system, at the site subsequent to the binding of insulin to the recipient. Accumulated scientific evidence demonstrates insulin resistance in the major tissues which respond to insulin (muscle, liver, adipose tissue), strongly suggesting that the defect in insulin signal transduction is at an early stage in this cascade , specifically in the activity of the insulin receptor kinase, which appears to be diminished (reviewed by Haring, Diabetalogia 1991, 34, 8 8).

Protein-tyrosine phosphatases (PTPases play a very important role in the regulation of protein phosphorylation) The interaction of insulin with its receptor leads to the phosphorylation of certain tyrosine molecules within the receptor protein, so the receptor is activated The PTPases deformform the activated insulin receptor, attenuating tyrosine kinase activity, PTPases can also modulate post-receptor signaling by catalyzing the dephosphorylation of cellular substrates of the insulin receptor kinase. insulin closely associated with the insulin receptor, and therefore, are more likely to regulate the activity of the insulin receptor kinase include PTP1B, LAR, PTPalpha and SH-PTP2 (BJ Goldstein, J. Cellular Biochemistry 1992, 48, 33; BJ Goldstein, Receptor 1993, 3, 1-15, F. Ahmad and BJ Goldstein Biochim, Biophys Acta 1995, 1248, 57-69) McGuire et al. (Diabetes 199 1, 40, 939), demonstrated that non-diabetic glucose intolerant subjects possess significantly higher levels of PTPase activity in muscle tissue versus normal subjects, and that insulin infusion did not suppress PTPase activity as it does in insulin sensitive subjects. . Meyerovitch et al., (J. Clinical Invest., 1989, 84, 976) observed significantly increased PTPase activity in the livers of two IDDM rodent models, the genetically diabetic BB rat and the diabetic rat induced by STZ. Sredy et al (Metabolis, 44, 1074, 1995) observed similar increased PTPase activity in the livers of obese, diabetic, ob / ob mice, the genetic rodent model of NIDDM. The compounds of this invention have been shown to inhibit PTPases derived from rat hepatic microsomes and recombinant human-derived PTPase-1B (hPTP-1B) in vi tro. They are useful in the treatment of insulin resistance associated with obesity, glucose intolerance, diabetes mellitus, hypertension and ischemic diseases of large and small blood vessels. B. Reidl, et al.- (EP 693491A1) describe oxazolodynone A as an antibacterial agent.

NHAc A. Bridges, et al. (EP 568289A2) describe thienothiophenamidine B as an inhibitor of urokinase.

H.-M. Chen et al., Indian J. Chem., Sect. B: Org. Chem. Include. Med. Chem. 1996, 35B (12), 1304-1307 describe compound C.

N. R. Guirguis, et al., J. PraJt. Chem. 1990, 332 (3), 414-418 describe compound D.

N. R. Guirguis, et al., Liebigs Ann .. Chem. 1986, 1003-1011 describe the benzothiophenes E. Also M. C. Dubroeucq et al., (EP 248734A1) describe E (Rl = C02H) as an anxiolytic.

T. Kuroda, et al., J. Org. Chem. 1994, 59, 1252-1351 and J. Chem. Soc., Chem. Commun. 1991, 1635-1636 describe benzothiophenes F.

To the. Hashem, J. Prakt. Chem. 1977, 319, 689-692 describe benzofuran G.

Y. A ao, et al., Jpn. Kokai Tokkyo Koho JP 04016854 A2 (Japanese patent, CA: 117: 36570) describe six compounds containing the 4-aryl-naphtho [2, 3-b] thiophene ring system. These compounds are dimers of cyclobutenodiilio of that ring system elaborated as f otre cept ores electof otográf icos. A typical example is shown by structure H below.

J. P. Konopelski, et al-, Snlett 1996, 609-611 describe indole I.

P. Molina, et al, Tetrahedron, 1994, 50, 5027-36 and Tetrahedron Lett. , 1993, 34, 2809-2812 describe indole derivatives J.

A. Napolitano, et al. , Tetrahedron 1989, 45, 6749-60 describe indole K.

K G. Dryhurst, et al., J. Am. Chem. Soc. 1989, 111, 719-726 describe compound L.

M. d'Ischia, et al., Tetrahedron 1987, 43, 431-434 describe compound M.

None of the above descriptions (A-M) contain the appropriate substitution necessary for the inhibition activity of PTPase in vitro or for the antidiabetic activity in vivo.

DESCRIPTION OF THE INVENTION This invention provides compounds of formula I that have the structure fifteen wherein R1 and R2 are each independently hydrogen, nitrile, nitro, amino, alkylamino of 1-6 carbon atoms, dialkylamino of 1-6 carbon atoms per alkyl group, cycloalkylamino of 5-8 carbon atoms, alkyl of 1 -6 carbon atoms, perfluoroalkyl of 1-6 carbon atoms, halogen, cycloalkyl of 5-8 carbon atoms, thienyl, furyl, phenyl or phenyl mono-, di-, or tri-substituted with halogen, hydroxy, 1-6 carbon atoms, perfluoroalkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms or perfluoroalkoxy of 1-6 carbon atoms, - R3 and R "are each independently hydrogen, alkyl of 1-6 carbon atoms, perfluoroalkyl of 1-6 carbon atoms, hydroxyalkyl of 1-6 carbon atoms, aminoalkyl of 1-6 carbon atoms, acyl of 2-7 carbon atoms, R5 is hydrogen, halogen, alkyl of 1-6 carbon atoms, perfluoroalkyl of 1-6 carbon atoms, nitrile, alkoxy of 1-6 atoms carbon, aryloxy, arylalkoxy of 2-12 carbon atoms, arylsulfañyl; W is S, 0, or NR9, - R9 is hydrogen or alkyl of 1-6 carbon atoms, - X is 0, -NR6-, O - (CH2) pNR6-; R6 is hydrogen, or alkyl of 1-6 carbon atoms; p is 1 to 4; And it is methylene, carbonyl, -S02-, or -SO-; Z is phenyl, heteroaryl, or naphthyl; R7 and R1 are each, independently hydrogen, carboxy, acyl of 2-7 carbon atoms, hydroxy, hydroxyalkyl of 1-6 carbon atoms, hydroxyalkanoyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, perfluoroalkoxy of 1-6 carbon atoms, alkoxycarbonyl 2-7 carboron atoms, perfluoroalkoxycarbonyl of 2-7 carbon atoms, alkyl of 1-6 carbon atoms, perfluoroalkyl of 1-6 carbon atoms, aryl of 6-10 carbon atoms, aryloxy of 6-10 carbon atoms carbon, aryloxycarbonyl of 7-11 carbon atoms, heteroaryloxycarbonyl, arylalkoxy of 7-13 carbon atoms, heteroaryl, alkanoyloxy of 2-7 carbon atoms, perfluoroalkanoyloxy of 2-7 carbon atoms, heteroaroyloxy, aroyloxy of 7-11 carbon atoms, aroyloxy of 7-11 carbon atoms substituted with R10, arylalkyloxyloxy of 8-17 carbon atoms, heteroarylalkyloxy, tetrazolyl, mercapto, nitrile, amino, carbamoyl, aminoalkyl of 1-6 atoms carbon, -NHS02CF3, formyl, halogen, nitro, acylamino of 1-6 carbon atoms, pyrimidyl substituted by methylsulfanyl, 5-hydroxycyclobut-3-en-4-yl-l, 2-dione or tetronic acid; R10 is hydrogen, halogen, nitro, amino, alkoxy of 1-6 carbon atoms, perfluoroalkoxy of 1-6 carbon atoms, nitrile, alkyl of 1-6 carbon atoms, perfluoroalkyl of 1-6 carbon atoms; or a pharmaceutically acceptable salt thereof, which is useful for treating metabolic disorders related to insulin resistance or hyperglycemia. The pharmaceutically acceptable salts can be formed from organic and inorganic acids, for example acetic, propionic, lactic, citric, tartaric, succinic, fumaric, maleic, malonic, mandelic, malic, phthalic, hydrochloric, hydrobromic, phosphoric, nitric, sulfuric. , methanesulfonic, taphonic, benzenesulfonic, toluenesulfonic, camphorsulfonic, and acceptable acids similarly known when a compound of this invention contains a basic portion. Salts can also be formed from organic and inorganic bases, preferably metal salts alkali, for example sodium, lithium or potassium, when a compound of this invention contains a carboxylate or phenolic portion, or a similar portion capable of forming base addition salts. The terms alkyl, alkoxy, alkanoyl and acyl used alone or together with another term are defined as 1-6 branched or straight chain carbons optionally substituted with fluorine, for example methyl, ethyl, n-propyl, i-propyl, n-butyl , i-butyl, s-butyl, t-butyl, pentyl or hexyl. The term dialkyl used alone or together with another term is defined as 2-12 carbons optionally substituted with fluorine. The term cycloalkyl, lysate alone or together with another term, is defined as 5-8 carbons optionally substituted with fluorine, for example cyclopropyl, cyclobutyl or cyclopentyl. The terms aryl, arylalkoxy, arylsulfanyl used alone or together with another term are defined as 6-10 carbons optionally substituted with fluorine. The terms perfluoroalkyl, perfluoroalkoxy, perfluoroalkyloxy, perfluoroalkoxycarbonyl, used alone or together with another term are defined as 1-6 carbons. The term "aroyl" used alone or in conjunction with another term is defined as phenylcarbonyl or naphthylcarbonyl optionally substituted with fluorine. The term "heteroaryl" used alone or together with another term is defined as a 5- or 10-membered heterocyclic mono or bicyclic ring system consisting of carbon atoms and from 1 to 5 heteroatoms which are selected from N, 0 and S, and which are selected from the group consisting of quinoline, isoquinoline, pyridine, indole, isoindol, pyrrole, quinazoline, oxazole, oxazine, isoxazole, isothiazole, pyrazine, pyridazine, pyrimidine, thiophene, furan, benzofuran, benzimidazole, benzoxadiazole, pyrazole, pyrrolidinone, benzoxazole, benzopyrazole, benzisoxazole, thiazole, thiadiazole, triazole, isobenzothiophene and benzothiophene. The compounds of this invention may contain a symmetric carbon atom and some of the compounds of this invention may contain one or more asymmetric centers and therefore may generate optical isomers and diastereomers. Although shown with respect to the stereochemistry in formula I, the present invention includes optical isomers and diastereomers; as well as the enantiomerically pure, racemic and separated R and S stereoisomers; as well as other mixtures of the stereoisomers R and S, and pharmaceutically acceptable salts thereof. Preferred compounds of this invention are those compounds of formula I in which: R1 and R2 are each independently hydrogen, alkyl of 1-6 carbon atoms, perfluoroalkyl of 1-6 carbon atoms, bromine, iodine, cycloalkyl of -8 carbon atoms, phenyl or phenyl substituted by trifluoromethyl, chloro, methoxy, -OCFj, thienyl or furyl; R3 and R * are each independently aryl of 1-6 carbon atoms, or perfluoroalkyl of 1-6 carbon atoms; R5 is hydrogen, halogen, alkyl of 1-6 carbon atoms, perfluoroalkyl of 1-6 carbon atoms, nitrile, alkoxy of 1-6 carbon atoms, aryloxy, arylalkoxy or arylsulfañil; W is S u 0; X is 0, -NRß-, or - (CH2) pNR6-; Rs is hydrogen or alkyl of 1-6 carbon atoms, - p is 1 to 4, - Y is methylene, carbonyl, -S02-, or -S0-; Z is phenyl, pyridyl, naphthyl, thienyl, furyl, pyrrolyl, pyrazolyl, isoxazolyl or isothiazolyl, - R7 and R "are each independently hydrogen, halogen, carboxy, acyl of 2-7 carbon atoms, acylamino of 1-6 atoms carbon, hydroxy, hydroxyalkyl of 1-6 carbon atoms, hydroxyalkanoyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, perfluoroalkoxy of 1-6 carbon atoms, alkoxycarbonyl of 2-7 carbon atoms, perfluoroalkoxycarbonyl of 2-7 carbon atoms, alkyl of 1-6 carbon atoms, perfluoroalkyl of 1-6 carbon atoms, aryl of 6-10 carbon atoms, aryloxy of 6-10 carbon atoms, aryloxycarbonyl of 7-11 carbon atoms, heteroaryloxycarbonyl, arylalkoxy of 7-15 carbon atoms, pyridyl, alkanoyloxy of 2-7 carbon atoms, perfluoroalcanoyloxy of 2-7 carbon atoms, heteroaroyloxy, aroyloxy of 7-11 carbon atoms, aroyloxy of 7-11 carbon atoms substituted with R10, arylalkyloxyloxy of 8-17 carbon atoms, heteroarylalkanoyloxy, tetrazolyl, pyrazolyl, oxazolyl, isoxazolyl , mercapto, nitrile, amino, -NHS02CF3, carbamoyl, aminoalkyl of 1-6 carbon atoms, formyl, nitro, pyrimidyl, pyrimidyl substituted with methylsulfanyl, 5-hydroxy-cyclobut-3-en-4-yl-2, diona; R10 is hydrogen, halogen, nitro, alkoxy of 1-6 carbon atoms, nitrile, alkyl of 1-6 carbon atoms, - or a pharmaceutically acceptable salt thereof. The most preferred compounds of this invention are those compounds of formula I in which: R1 and R2 are each independently hydrogen, alkyl of 1-6 carbon atoms, bromine or cyclopentyl; R3 and R4 are alkyl of 1-6 carbon atoms; Rs is hydrogen or bromine; is S or O; X is O, -NR6, or -CH2NR6-; R6 is hydrogen or alkyl of 1-6 carbon atoms, - Y is methylene, carbonyl or -S02-, - Z is phenyl, thienyl, pyrazolyl or thiazolyl, - R7 and Ra are each independently hydrogen, halogen, acyl 1-6 carbon atoms, carboxy, hydroxy, alkoxy of 1-6 carbon atoms, alkoxycarbonyl of 2-7 atoms carbon, alkyl of 1-6 carbon atoms, pyridyl, alkanoyloxy of 2-7 carbon atoms, aroyloxy of 7-11 carbon atoms, aroyloxy of 7-11 carbon atoms substituted with R10, heteroaryloxy, arylalkyloxyloxy of 8- 17 carbon atoms, tetrazolyl, isoxazolyl, nitrile or pyrimidyl substituted with methylsulfañilo; R10 is hydrogen, halogen, nitro, alkoxy of 1-6 carbon atoms, nitrile, alkyl of 1-6 carbon atoms, - or a pharmaceutically acceptable salt thereof. The most preferred compounds of this invention are: 4- [4- (9-bromo-2,5-dimethyl-naphtho [2,3-b] thiophen-4-yl) -2-isopropyl-phenoxysulfonyl] -2- hydroxy-benzoic; 4- [4- (9-Bromo-2,5-dimethyl-naphtho [2, 5-b] thiophen-4-yl) -2,6-dimethyl-phenoxysulfonyl] -2-hydroxybenzoic acid; 4- [4- (9-bromo-2,5-dimethyl-naphtho [2,5-b] thiophen-4-yl) -2-cyclopentyl-phenoxysulfonyl] -2-hydroxybenzoic acid; 4- [4- (9-bromo-2,5-dimethyl-naphtho [2,5-b] thiophen-4-yl) -2,6-diisopropyl-phenoxysulfonyl] -2-hydroxybenzoic acid; 2-Acetoxy-4- [4- (9-bromo-2,5-dimethyl-naphtho [2, 5-b] thiophen-4-yl) -2,6-dimethyl-phenoxysulfonyl] -benzoic acid; 2-Acetoxy-4- [4- (9-bromo-2,5-dimethyl-naphtho [2, 5-b] iofen-4-yl) -2-cyclopentyl-phenoxysulfonyl] -benzoic acid; 2-Butyryloxy-4- [4- (9-bromo-2,5-dimethyl-naph or [2, 5-b] thiophen-4-yl) -2,6-dimethyl-phenoxysulfonyl] -benzoic acid, - 2-benzoyloxy-4- [4- (9-bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -2,6-dimethyl-phenoxysulfonyl] -benzoic acid; 2-propionyloxy-4- [4- (9-bromo-2, 5-dimethyl-naphtho [2,5-b] thiophen-4-yl) -2,6-dimethyl-f-enoxysulfonyl] -benzoic acid, - 5- [4- (9-Bromo-2,5-dimethyl-naphtho [2,5-b] thiophen-4-yl) -2-cyclopentyl-f-enoxysulfonyl] -4-methoxythiofen-5-carboxylic acid; 5- [4- (9-bromo-2,5-dimethyl-naphtho [2, 5-b] thiophen-4-yl) -2-cyclopentyl-f-enoxysulfonyl] -4-hydroxythiofen-5-carboxylic acid; 4- [2-cyclopentyl-4- (2,5-dimethyl-naph to [2, 5-b] iofen-4-yl) -phenoxysulfonyl] -2-hydroxybenzoic acid; 4- [2-cyclopentyl-4- (2,3-dimethyl -napht or [2,5-b] furan-4-yl) -phenoxysulfonyl] -2-hydroxybenzoic acid; 4- [2-bromo-4- (2,5-dimethyl -naf or [2, 5-b] furan-4-yl) -phenoxysulfonyl] -2-hydroxybenzoic acid, 4- [4- (2, 3-d? Methyl-naphtho [2,3-b] furan-4-yl) -2,6-diethyl-phenoxysul-fonyl] -2-hydroxybenzoic acid; 4- [4- (9-bromo-2,3-dimethyl-naphtho [2, 3-b] thiophen-4-yl) -2,6-dimethyl-f-enoxysulfonyl] -2-hydroxybenzoic acid terbutyl ester; 2 - (4-methoxybenzoyl) -oxi -4- [4- (9-bromo-2,5-dimethyl-naph to [2, 3-b] thiophen-4-yl) -2,6-dimethyl-phenoxysulfonyl acid ] -benzoic acid; 5- [4- (2,5-Dimethyl-naphtho [2,3-b] thiophen-4-yl) -2,6-phenoxysulfonyl] -4-methoxythio-3-carboxylic acid; 2 - . 2-Cyclopentyl-4- (2, 3-dimethyl-naphtho [2, 5-b] thiophen-4-yl) -phenyl ester of 5-pyridin-2-yl-thiophene-2-sulfonic acid, - 4-benzoyloxy acid -5- [4- (2,5-dimethyl-naphtho [2, 2-b] thiophen-4-yl) -2,6-diethylphenoxysulfonyl] -thiophen-5-carboxyl? Co; 5- [2-cyclopentyl-4- (2,5-dimethyl-naphtho [2, 3-b] thiophen-4-yl) -phenoxysulfonyl] -benzoic acid; 2-cyclopentyl-4- (2,3-dimethyl-naphtho [2,3-b] iofen-4-yl) -phenyl ester of 5- (2-methylsulfanyl-pyrimidin-4-yl) -thiophen-2-sulfonic acid; 2-benzoyloxy-4- [4- (2, 3-dimethyl-naphtho [2, 3-b] thiophen-4-yl) -2,6-dimethylphenoxysulfonyl] -benzoic acid; 2- (4-chloro-benzoyl) oxy-4- [4- (2, -dimethyl-naphtho [2, 5-b] thiophen-4-yl) -2,6-dimethyl-phenoxysulfonyl] -benzoic acid, - -carboxy-5- [2- (2, 3-dimethyl-naphtho [2, 3-b] thiophen-4-yl) -2,6-dimethyl-phenoxysulfonyl] phenyl ester of nicotinic acid; 2-carboxy-5- [4- (9-bromo -2, 3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -2,6-dimethyl-phenoxysulfonyl] phenyl ester of nicotinic acid, - acid 4- [4- (9-bromo-2,5-dimethyl-naphtho [2, 5-b] thiophen-4-yl) -2,6-dimethyl-phenoxysulfonyl] -2-phenylacetoxy-benzoic acid; 2- (4-Cyano-benzoyl) oxy-4- [4- (9-bromo-2,2-dimethyl-naphtho [2,5-b] thiophen-4-yl) -2,6-dimethyl-phenoxysulfonyl] ] -benzoic, - - 25 - 2 - (- methoxy-benzoyl) oxy-4- [4- (9-bromo- (2,5-dimethyl-naphtho [2, 5-b] thiophen-4-yl) -2, 6- dimethyl-phenoxysulfonyl] -benzoic acid, 5- [4- (9-bromo- (2,5-dimethyl-naphtho [2,5-b] thiophen-4-yl) -2,6-dimethyl-phenoxysulfonyl] -2 -carboxyphenylester of isonicotinic acid, and pharmaceutically acceptable salts thereof The present invention also provides a process for the preparation of compounds of formula I, which comprises: a) reacting a compound of formula wherein Y is CO, SO or S02, Hal is halogen and R6, R7 and Z are as defined in the above, or an anhydride of (ZR7R8) wherein Rβ, R7 and Z are as defined above, with a compound of formula wherein Q is hydrogen or a metal atom, for example Na, Li, or Mg, and all other groups are as defined above, optionally in the presence of a base, for example pyridine, triethylamine or sodium acetate, for providing a compound of formula I, wherein Y is CO, SO or S02 / - b) reacting a compound of formula wherein Q 'is a leaving group such as a halogen atom (preferably I, Br or Cl) or the group -0S02R "wherein R1' is alkyl or an optionally substituted aromatic group (for example methyl or p-toyl) and R6, R7 and Z are as defined in the above, with a compound of formula wherein Q is hydrogen or a metal atom, for example Na, Li, or Mg, and all other groups are defined therein, optionally in the presence of a base, for example pyridine, triethylamine or sodium acetate, to provide a compound of formula I, wherein Y is CH2; c) reacting an activated ester of the acid of formula wherein R6, R7 and Z are as defined above, such as a 1-hydroxysuccinimide ester, a 1-hydroxybenzotriazole ester, 4-nitrophenyl ester or other suitable esters known in the art, with an amine of formula wherein X is -NR6- and all other groups, including Rs are as defined above, to provide a compound of formula I wherein Y is CO and X is -NR6-; d) reacting a compound of formula where all the groups are as defined in the above, with a reducing agent such as lithium hydride and aluminum, diisobutylaluminum hydride or a borane, to provide a compound of formula I, wherein Y is CH 2, e) reacting a secondary amine of formula wherein all groups are as defined in the above, with a compound of formula Q'R6 wherein Q 'is a leaving group such as a halogen atom (preferably I, Br or Cl) or the group -0S02R' ' wherein R "is an alkyl or an optionally substituted aromatic group (for example methyl or p-toyl), and Rs is as defined above, optionally in the presence of a base, for example pyridine, triethylamine or diisopropylethylamine to provide a compound of formula I wherein Y is CH2 and X is -NR6-, f) reacting an imine of formula wherein all groups are as defined above, with a reducing agent such as lithium aluminum hydride, sodium borohydride or hydrogen, on a catalyst such as Raney nickel, to provide a compound of formula I wherein Y is CH2 and X is NH; g) reacting a compound of formula wherein Hal is a halogen and R6, R7 and Z are as defined above, with a compound of formula wherein Q1 'is an alkyl group, such as methyl, and all other groups are as defined above, to provide a compound of formula I, wherein Y is S02 and X is O; h) reacting an alcohol of formula \; z-CH2OH Rß / wherein R6, R7 and Z are as defined above, with a compound of formula wherein all groups are as defined in the above, to provide a compound of formula I, wherein X is 0 and Y is CH2. Examples of such reactions of the invention are discussed in more detail in the following. The compounds of this invention can be prepared according to the following schemes from commercially available starting materials or starting materials which can be prepared using literature methods. These schemes show the preparation of the representative compounds of this invention.

Reaction scheme 1 In Reaction Scheme 1, 2,5-dimethylthiophene (II: W is S) is prepared from commercially available 3-methylthiophene carboxaldehyde using Wolff-Kishner conditions (hydrazine followed by KOH / ethylene glycol reflux). The compound (II) is treated with one to 1.3 molar equivalents of an alkyl lithium reagent such as N-butyl lithium, most preferably in a non-protic solvent such as THF at temperatures ranging from -78 ° C to temperature environment under an inert atmosphere such as nitrogen or argon to provide the 2-lithiated thiophene or the furan derivative. This lithiated analog is reacted in situ with one or more molar equivalents of benzaldehyde, generally from -78 ° C to room temperature for 5 min to 3 h to provide the compound of formula (III: Q = OH). The hydroxy group (Q = OH) of (III) can be removed by numerous reduction processes such as hydrogenation using palladium catalysts to produce the compound of formula (III: Q = H) but it is more conveniently removed using the method from Nutaitis, et. to the. . { Org. Prep. and Proceed. Int. 1991, 23, 403-11) in which (III: Q = OH; W is S or O) is stirred with one to ten molar equivalents of sodium borohydride in a suitable solvent such as ether, THF or dichloromethane from 0 °. C up to room temperature and from one to fifty molar equivalents of trifluoroacetic acid is added slowly over a period of 15 min to 3 h for - producing the compound of formula (III: Q = H). Alternatively, the 2-lithiated analog of the compound (II) in a non-protic solvent such as THF can be reacted with one or more molar equivalents of a benzyl halide such as benzyl bromide (PhCH2Br) of -78 ° C until the room temperature to directly provide the compound of formula (III: Q = H, is S 0). The compounds of formula (III: Q = H) can be acylated with one or more molar equivalents of a commercially available benzoic acid chloride of formula (IV: X = -OMe) to produce the acylated derivative of formula (V: X = -OMe). This asylation is most easily carried out using one to five molar equivalents of a Lewis acid catalyst such as tin tetrachloride or aluminum chloride in an inert solvent such as dichloromethane, 1,2-dichloroethane or carbon disulfide, generally at temperatures such as -78 ° C at room temperature. The benzoic acid chloride (IV: X = -OMe) is prepared from the corresponding benzoic acid by standard procedures using reagents such as oxalyl chloride and thionyl chloride. The initial benzoic acid of benzoic acid chloride (IV: X = -OMe) is commercially available or can be easily prepared by known methods. For example, the acid starting material for the benzoic acid (IV) chloride can be prepared using a modification of the g Schuster e. al., J. Org. Chem. 1988, 53, 5819. Thus, the commercially available 2,6-diisopropyl phenol is brominated in the 4-position (bromine / acetic acid), methylated (iodomethane / potassium carbonate / DMF), reacted with n-butyl lithium to carry out the exchange of halogen and lithium, and the resulting organolithium species are reacted with carbon dioxide to provide 5,5-diisopropyl, 4-methoxy benzoic acid. Alternatively, commercially available phenols 2-6- (mono- or disubstituted) can be methylated (iodomethane / potassium carbonate / DMF), acylated in the 4-position with 2-chlorobenzoyl chloride in the presence of aluminum chloride in an inert solvent such as dichloromethane, generally at room temperature and reacted with potassium t-butoxide in H20 / ethylene glycol dimethyl ether at room temperature to provide the desired 2,6- (mono or disubstituted) benzoic acid. The cyclization of the compounds of the formula (V: X = -OMe) is generally carried out in a better manner using from one to ten molar equivalents of a strong Lewis acid such as oboran tial, more conveniently tribromoborane. The reaction is best carried out at -78 ° C with heating to room temperature or heating to 50 ° C in a halocarbon solvent such as dichloromethane under an inert atmosphere such as nitrogen or argon. out - Cyclization and aromatization with concomitant loss of water, but also result in the demethylation of any portion of any methoxy-dependent portion and result in the production of compounds of formula (VI: X = -OH). The compounds of formula (VI: X = -OH) can be sulfonylated on phenolic oxygen using one or more molar equivalents of a suitable sulfonylating agent to provide the sulfonic acid esters of formula (I). The sulfonylating agent is generally aryl or heteroaryl sulfonic acid chloride. The reaction is carried out under standard conditions using a suitable base such as sodium hydride, pyridine or a Tris base in an appropriate solvent such as dichloromethane, THF or H20 at temperatures from 0 ° C to room temperature. The initial sulfonyl chloride is commercially available and can be easily prepared by known methods. For example, the aryl or heteroaryl sulfonic acid chloride can be prepared by reacting the aryl or heteroaryl sulfonic acid with one or more molar equivalents of oxalyl chloride or thionyl chloride in a suitable solvent such as dichloromethane, chloroform or diethyl ether for provide the aryl or heteroaryl sulfonic acid chloride. This reaction is often catalyzed by adding small amounts (0.01 to 0.1 molar equivalents) of dimethylformamide. Alternatively, sulfonyl chlorides can be prepared using a modification of Barraclough, et. al., Arch. Pharm. (Weinheim) 1990, 323, 507. Thus, the aniline of the sodium salt dihydrate of 4-aminosalicylic acid, commercially available, is diazotized with sodium nitrite in HOAc / HCl at -10 ° C and the salt of Subsequent diazonium can be converted to the sulfonyl chloride by introduction of sulfur dioxide in the reaction in the presence of copper (I) chloride. The groups R7 and Rβ connected to Z can be further derivatized. For example, when R7 or R8 is an ester of a carboxylic acid or an alcohol, the compound can be transformed into the respective carboxylic acid or alcohol analogue using standard conditions. The conditions for carrying out these transformations include an aqueous base in which one or more molar equivalents of an alkali metal hydroxide such as sodium hydroxide are used with a cosolvent such as THF, dioxane or a lower alcohol such as methanol or mixture. of THF and a lower alcohol at temperatures ranging from 0 ° C to 40 ° C. When R7 or R8 is a carboxylic acid or an ester, the compound can be reduced to the respective primary alcohol analog using standard concentrations such as lithium aluminum hydride in ethyl ether. When R7 or RB is an aldehyde or ketone, the compound can be reduced to the respective primary alcohol analog using a metal catalyst, sodium in alcohol, sodium borohydride or by lithium hydride and aluminum. When R7 or Rβ is an ether, the compound can be transformed to the free alcohol using one to ten molar equivalents of a strong Lewis acid such as a triaboborane, more conveniently tribromoborane in a halocarbon solvent such as dichloromethane. When R7 or Rβ is an alcohol, the compound can be oxidized to the respective aldehyde, carboxylic acid or ketone analog using a transition metal oxidant (chromium pyridine trioxide, pyridinium chlorochromate, manganese dioxide) in an inert solvent such as ether, dichloromethane. The alcohols can also be used using DMSO with various electrophilic molecules (dicycloexylcarbodiimide, acetic anhydride, trifluoroacetic anhydride, oxalyl chloride and sulfur dioxide). When R7 or R8 is a carboxylic acid, the compound can be transformed into a carboxylic acid amide analogue. This transformation can be carried out using standard methods to carry out the transformations of carboxylic acid to carboxylic acid amide. These methods include converting the acid to an activated acid and reacting with one or more molar equivalents of the desired amine. Amines in this category include ammonia in the form of ammonium hydroxide, hydroxylamine and 2-aminopropionitrile. Methods for activating the carboxylic acid include reacting the acid with one or more molar equivalents of oxalyl chloride or thionyl chloride - 58 - to provide the carboxylic acid chloride in a suitable solvent such as dichloromethane, chloroform or diethyl ether. This reaction is often catalyzed by adding small amounts (0.01 to 0.1 molar equivalents) of dimethyl formamide. Other methods for activating the carboxylic acid include reacting such an acid with one or more molar equivalents of dicyclohexylcarbodiimide with or without one or more molar equivalents of hydroxybenzotriazole in a suitable solvent such as dichloromethane or dimethyl formamide at temperatures ranging from 0 ° C to 60 ° C. When R7 or R8 is nitro, the compound can be reduced to the respective amino compound more easily using tin dichloride in ethyl acetate, from 40 to 100 ° C, or with hydrazine and Montmorillinite clay in ethanol, from 40 to 100 ° C. , or by catalytic hydrogenation in the presence of a catalyst such as palladium carbon. When R7 or R8 is an amino or an alcohol, the compound can be acylated using one or more molar equivalents of a suitable acylating agent. The acylating agent is generally a lower alkyl or an aryl carboxylic acid anhydride or a lower alkyl or aryl carboxylic acid chloride. The reaction is carried out under standard conditions, for example, the use of pyridine as a solvent, with or without a cosolvent such as dichloromethane at 0 ° C to room temperature. When R7 or R8 is an alcohol, it can be acylated with a lower alkyl or an aryl carboxylic acid anhydride in - 59 - presence of magnesium iodide in diethyl ether at room temperature until reflux. When R7 or R8 is a nitrile, it can be reduced to the aminoalkyl compound by tin (II) chloride in refluxing ethyl acetate or by catalytic hydrogenation in the presence of a catalyst such as Raney nickel or by lithium aluminum hydride in a solvent inert such as ether. When R7 or Rs is a nitrile, it can be converted to a cayboxylic acid amine using standard conditions such as HC1 / H20 at temperatures from room temperature to reflux or a more moderate process involves the reaction of nitrile with an alkaline solution of peroxide. hydrogen. When R7 or R8 is halogen or trifluoromethanesulfonate, it can be converted to 5-hydroxy-cyclobut-3-ene-4-yl-l, 2-dione by methodology of Liebeskind et. to the. (J. Orgr. Chem. 1990, 55, 5359). When R7 or R8 is an alcohol, it may be alkylated with a suitable alkylating agent such as one or more molar equivalents of alkyl halide in the presence of a base such as potassium carbonate and sodium hydroxide in a suitable solvent such as THF, DMF. or DMSO at temperatures ranging from 0 ° C to 60 ° C. When R3 or R4 is a carboxylic acid, the compound can be coupled to tetronic acid with a coupling reagent such as 1- (3-dimethylaminopropyl) -5-ethylcarbodiimide in the presence of a base such as triethylamine or DMAP in a suitable solvent such as DMF.

Reaction scheme 2 (I) Additional derivatives of the compounds of formula (I) can be prepared by the following methods. The phenols and amines of the formula (VI: X = NH2, OH, -CH2NH2) can be alkylated with one or more molar equivalents of a haloalkylaryl or haloalkylheteroaryl of formula (VIII) and with one or more molar equivalents of a metal carbonate alkali such as potassium carbonate in a polar aprotic solvent such as DMF to provide the alkylated product of formula (I). The phenols of formula (VI, -X = OH) can be reacted with a hydroxyalkylaryl or hydroxyalkylheteroaryl of formula (IX) to provide the alkylated product of formula (I) under the conditions of the Mitsunobu reaction (for a review see Heard Mitsunobu Synthesis. 1981. 1-27). The other coreactants necessary to carry out the Mitsunobu reaction include one or more molar equivalents of a lower alkyl azodicarboxylate diester such as diethyl azodicarboxylate or diisopropyl azodicarboxylate and one or more molar equivalents of triarylphosphine such as triphenylphosphine in a suitable solvent such as diethyl ether, THF, benzene or toluene at temperatures ranging from -20 ° C to 120 ° C. The starting hydroxyalkylaryl or hydroxyalkylheteroaryl of formula (IX) is commercially available and can be prepared by standard synthesis methods. For example, an heteroarylcarboxylic acid or ester can be reduced to the respective primary alcohol analogue using standard conditions such as lithium aluminum hydride in ethyl ether. An aryl or heteroaryl aldehyde or ketone can be reduced to the respective primary alcohol analog using a metal catalyst by sodium in alcohol, sodium borohydride and by lithium aluminum hydride. The starting haloalkylaryl or haloalkylheteroaryl of formula (VIII) is commercially available and can be prepared by standard synthetic methods. For example, the hydroxyalkylaryl or hydroxyalkylheteroaryl of formula (IX) can be converted to the halo derivative with reagents such as thionyl chloride, phosphorus trialide, diallyl triphenylphosphine or triphenylphosphine in the presence of carbon tetrachloride. Alternatively, the initial haloalkyl or haloalkylheteroaryl halide can be prepared by bromination of an alkylaryl or alkylheteroaryl with N-bromosuccinimide in the presence of AIBN in a solvent such as benzene, with or without ultraviolet radiation.

Reaction scheme 3 (VI: X is NH2; OH; -CH2NH2) (I; X is NH2; OH, -CH2NH-) Additional derivatives of the compounds of formula (I) in Reaction Scheme 3 can be prepared by the following methods. The compounds of formula (VI: X = NH2, OH, -CH2NH2) can be acylated at phenolic oxygen or at the amino group using one or more molar equivalents of suitable acylating agent to provide the compounds of formula - 45 - (I). The acylating agent is generally an aryl carboxylic acid anhydride or an aryl / heteroaryl carboxylic acid chloride. The reaction is carried out under standard conditions, for example, the use of pyridine as a solvent with or without a cosolvent such as dichloromethane at 0 ° C at room temperature.

Reaction scheme 4 (VI: X = OH) (X) (XI) (VI: X -CH 2NH2 In a three-step process (Reaction Scheme 4), the compounds of formula (VI: X ES OH) can be converted to compounds of formula (VI: X = -CH2NH2). Reaction of the compounds of formula (VI: X = OH) with trifluoromethanesulfonic anhydride or trifluoromethanesulfonic acid chloride in the presence of an organic base such as pyridine or triethylamine in dichloromethane at 0 ° C to room temperature provides the compound (X). The triflate (X) can be converted to carbonitrile (XI) with potassium cyanide or zinc cyanide in the presence of tetrakistriphenylphosphinaniquel (0) which can be generated in situ from bistriphenylphosphinaniquel (II) bromide and Zn / PPhj. The nitrile (XI) can be reduced to the aminoalkyl compound (VI: X = -CH2NH2) by tin (II) chloride in refluxing ethyl acetate or by catalytic hydrogenation in the presence of a catalyst such as Raney nickel or by lithium hydride and aluminum in an inert solvent such as ether. The compound prepared (VI: X = -CH2NH2) can be used in Reaction Scheme 1 to prepare sulfonamides of formula (I: X = -CH2NH-) or in Reaction Scheme 2 to prepare aminoalkyl derivatives of formula (I: X = -CH2NH-), or in Reaction Scheme 5 to prepare amines of formula (I: X = -CH2NH-).

Reaction scheme 5 (VI: Rl and / or E- is H; X is OH) (VI: Rl or 2 is H; Br; I; -CN; aryl; heteroaryl; X is OH) Additional derivatives of the compounds of formula (VI) in Reaction Scheme 5 can be prepared by the following methods. The phenol of the formula (VI: R1 and R2 is H; X is -OH) can conveniently be iodinated to the diiodophenol of the formula (VI: R1 and R2 is I; X is -OH) using at least two molar equivalents of iodine in presence of two or more molar equivalents of an alkali metal hydroxide such as NaOH in an alcohol solvent such as methanol of -20 ° C at room temperature. Similarly, monoiodophenol (VI: R1 O R2 is I; X is -OH) can be prepared from the phenol of formula (VI: R1 or R2 is H; X is -OH) using one at 1.5 molar equivalents of iodine in the presence of at least one equivalent of alkali metal hydroxide such as NaOH in a alcoholic solvent such as methanol -20 ° C to room temperature. Either monoiodophenol (VI: R2 is I; X is -OH) or diiodofenol (VI: R1 and R2 is I; X is -OH), it can be converted to the respective methyl ether derivatives of formula (VI: R2 is I; X is -OMe) or (VI: R1 and R2 is I, -X is -OMe) by reacting the phenol portion with a suitable methylating agent such as one or more molar equivalents of methyl iodide or dimethyl sulfate using a base such as an alkali metal carbonate or a hydroxide such as potassium carbonate or potassium hydroxide in a suitable solvent such as THF, DMF or DMSO. The reaction is generally carried out at temperatures ranging from 0 ° C to 60 ° C. The mono- or dibromo derivatives of formula (VI: R1 and / or R2 is Br; X is -OMe) can be prepared analogously by replacing bromine with iodine in the above sequence. The monoiodo methylether derivative of formula (VI: R2 is I; X is -OMe) or the methylether diiodide of formula (VI: R1 and R2 is I, -X is -OMe) can be reacted with one or more molar equivalents of copper cyanide (I), for the monovalent analog or two or more molar equivalents of copper (I) cyanide for the iodo derivative, to produce the monocyanomethyl ether of formula (VI: R2 is -CN; X is -OMe ) or the dicyanomethyl ether of formula (VI: R1 and R2 is -CN; X is -OMe). The cyanation reaction is generally carried out at temperatures ranging from 100 ° C to 250 ° C using polar aprotic solvents such as DMF, l-methyl-2-pyrrolidinone or HMPA. You can also use quinoline or pyridine. The mono or dicyano methoxy analogs of formula (VI: R1 and / or R2 is -CN; X is -OMe); can be converted to the corresponding mono or dicyano phenol analogs of formula (VI: R1 and / or R2 is -CN; X is -OMe) using standard demethylation procedures that include one or more molar equivalents of boron tribromide or boron trichloride in dichloromethane at -78 ° C at room temperature. The mono or diiodo methylether derivative of formula (VI: R1 and R2 is I; X is -OMe) can be reacted with an arylboronic acid or heteroarylboronic acid to provide the product of formula (VI: R1 and / or R2 is aryl or heteroaryl; X is -OMe) under Suzuki reaction conditions (Journal of the Chemical Society Chemical Communications 1979, 886 and Synthetic Communi ca ti ons 1981 11 (7) 515). The other coreactants necessary to carry out the Suzuki reaction include one or more molar equivalents of a metal catalyst such as tetrakis (triphenylphosphine) palladium or palladium (II) acetate and a base such as barium hydroxide octahydrate or sodium carbonate in a solvent such as benzene, toluene or DME / H20). The initial aryl or heteroaryl boronic acids are commercially available and can be prepared by standard synthesis methods. Mono or diaryl or mono or diethyroaryl methoxy analogs of formula (VI: R1 and / or R2 is aryl or heteroaryl; X is -OMe) can be converted to analogs corresponding mono or diaryl or mono or diheteroaryl phenol of formula (VI: R1 and / or R2 is aryl or heteroaryl; X is OH) using standard demethylation procedures including one or more molar equivalents of boron tribromide or boron trichloride in dichloromethane -78 ° C to room temperature. All the compounds prepared in Reaction Scheme 5 of formula (VI: R1 and / or R2 = H, I, Br, aryl, heteroaryl, nitrile) can be used in other schemes to prepare compounds of formula (I). For example, the compound prepared (VI: R1 and / or R2 = H, I, Br, aryl, heteroaryl, nitrile, X = OH) can be used in Reaction Scheme 1 to prepare sulfonyl esters of formula (I: R1 and / or R2 = H, I, Br, aryl, heteroaryl, nitrile) or in Reaction Scheme 2 to prepare -O-alkylated derivatives of formula (I: R1 and / or R2 = H, I, Br, aryl , heteroaryl, nitrile), or in Reaction Scheme 5 to prepare esters of formula (I: R1 and / or R2 = H, I, Br, aryl, heteroaryl, nitrile). All the compounds prepared in Reaction Scheme 5 of formula (VI: R 1 and / or R 2 = H, I, Br, aryl, heteroaryl, nitrile) can be used and can be further modified synthetically in reaction Schemes 4 , 6, 7 and 8.

Reaction scheme 6 (VI: R5 = H) (VI: R5 = I, Br, alkyl, perfluoroalkyl, nitrile, alkoxy, aryloxy, arylalkoxy, arylsulfanyl) Additional derivatives of the compounds of formula (VI: X = OH; Rs = H) in Reaction Scheme 6 can be prepared by the following methods. The compounds of formula (VI: X = OH; R5 = H) can be acylated on phenolic oxygen using one or more molar equivalents of a suitable acylating agent to provide the compounds of formula (VI: X = O-acyl; H). The acylating agent is generally an anhydride of lower alkyl or aryl carboxylic acid or an alkyl or lower aryl carboxylic acid chloride. The reaction is carried out under standard conditions, for example Safes »..« *. »--- the use of pyridine as a solvent with or without a cosolvent such as dichloromethane from 0 ° C to room temperature. Acylated phenols of formula (VI: X = O-acyl; R5 = H) can be brominated at the 9-position of the naphtho [2, 5-b] thiophene ring or of the naphtho [2, 5-b] furan ring to form the acylated bromophenols of formula (VI: X = OH-acyl, - R5 = Br). This bromination reaction is generally performed using 1 to 1.5 mol equivalents of molecular bromine in the dark with a catalytic amount of iron (III) chloride in an inert solvent such as dichloromethane or carbon tetrachloride at temperatures ranging from -78 ° C. up to room temperature. Using the similar bromination reaction, phenols of formula (VI: X = OH) can be brominated; Rs = H) at position 9 of the naphtho (2, -b] thiophene or naphtho [2, 5-b] furan ring to form the bromophenols of formula (VI: X = OH; R5 = Br). it is generally carried out using 1 to 1.5 molar equivalents of molecular bromine in the dark with a catalytic amount of iron (III) chloride in an inert solvent such as dichloromethane or carbon tetrachloride at temperatures ranging from -78 ° C to room temperature The acylated bromophenols of formula (VI: X = 0-acyl; R5 = Br) can be converted to the acylated cyanophenols of formula (VI: X = O-acyl; R5 = -CN) by reaction with one or more molar equivalents of copper cyanide (I). The cyanation reaction is generally carried out at temperatures ranging from 100 ° C to 250 ° C using aprotic solvents such as DMF, l-yl-2-pyrrolidinone or HMPA. You can also use quinoline or pyridine. The acyl group can then be removed from the prepared compounds of formula (VI: X = O-acyl; Rs = Br, CN) to give the compounds of formula (VI: X = OH; Rs = Br, CN ) using standard conditions. These conditions include an aqueous base in which one or more molar equivalents of alkali l hydroxide such as sodium hydroxide is used in water with co-solvent such as THF, dioxane or a lower alcohol such as anol or mixture of THF and a lower alcohol at temperatures ranging from 0 ° C to 40 ° C. Acid conditions can also be used in which the compound is reacted with one or more molar equivalents of a mineral acid such as HCl or sulfuric acid in water with or without a cosolvent such as THF at temperatures ranging from room temperature to 80. ° C. The compounds of formula (VI: X = OH; Rs = H) can be sulfonylated in phenolic oxygen using one or more molar equivalents of a suitable sulfonylating agent to provide the sulfonic acid esters of formula (VI: X = -OS02R '; Rs = H). The sulfonylating agent (R1) is generally an alkyl or aryl sulfonic acid anhydride or a lower alkyl aryl sulfonic acid chloride. The reaction proceeds under standard conditions such as those using pyridine as a solvent with or without a cosolvent such as dichloroane at 0 ° C to room temperature. The sulphonic acid esters of formula (VI: X = - OS02R ', - Rs = H) can be treated with iodinating reagents to carry out the iodination at position 9 of the naphtho [2, 5-b] thiophene or naphtho ring [2, 5-b] furan to provide the iodosulfonic acid esters of formula (VI: X = -OS02R ', - R5 = I). A suitable iodant reagent includes a mixture of 0.7 or more molar equivalents of molecular iodine and 0.25 or more molar equivalents of iodic acid in a mixture of THF and 80% aqueous acetic acid with a small amount of concentrated sulfuric acid at temperatures ranging from room temperature up to 80 ° C. The iodosulfonic acid esters of formula (VI: X = -OS02R ', - R5 = I) can be reacted with a reagent that catalyzes the exchange of the iron (VI) atom with a perfluoroalkyl group to provide the compound of formula ( VI: X = -OS02R ', - R5 = perfluoroalkyl). The reagent and the conditions for carrying out this exchange include reacting (RC02N: R is perfluoroalkyl) under anhydrous conditions with one to ten molar equivalents of sodium perfluorocarboxylate (RC02N: R is perfluoroalkyl) and one to five molar equivalents of sodium iodide. copper (I) in a an inert solvent with a high boiling point such as DMF, DMA or l-yl-2-pyrrolidinone at temperatures ranging from 140 ° C to 200 ° C. Alternatively, the compound of formula (VI: X = -OS02R '; R5 = perfluoroalkyl) from the compound of formula (VI: X = -OS02R', - R5 = I) by reacting the former with one to ten molar equivalents of a perfluoroalkyl iodide and one to five molar equivalents of Cu ° activated with an inert solvent with a high boiling point such as DMF, DMA or l-yl-2-pyrrolidinone at temperatures ranging from 140 ° C to 200 ° C. Additionally, alternatively, it can be reacted compound of formula (VI: X = -OS02R '; Rs = I) with 0.5 to two molar equivalents of bis (trifluoroyl) mercury and two to four molar equivalents of Cu0 activated in an inert solvent with a high boiling point such as DMF , DMA or l-yl-2-pyrrolidinone at temperatures ranging from 140 ° C to 200 ° C for to produce the compound of (VI: X = -OS02R ', - R5 = perfluoroalkyl). The alkyl derivatives of the compound of formula (VI: X = -OSO.R1; Rs = alkyl) can be prepared by the reaction of (VI: X = -OS02R '; R5 = I) with three or more molar equivalents of tetra Lower alkylquat in the presence of a palladium catalyst such as 1 to 10 mol% of bis (triphenylphosphine) palladium II chloride in a solvent Suitable such as DMFM DMA or l-methyl-2-pyrrolidinone at temperatures ranging from 140 ° C to 200 ° C. The sulphonic ester group can be removed from the sulfonic acid esters of formula (VI: X = -OS02R ', - R5 = alkyl, perfluoroalkyl) to provide the phenols of formula (VI: X = -OH; R5 is alkyl, perfluoroalkyl) using standard conditions. These conditions include an aqueous base in which one or more molar equivalents of an alkali metal hydroxide such as sodium hydroxide are used in water with a cosolvent such as HF, dioxane or a lower alcohol such as methanol or a mixture of THF and a lower alcohol at temperatures ranging from room temperature to 110 ° C. The alkoxy, arylalkoxy and aryloxy derivatives of the compound of formula (VI: X = OH; Rs = alkoxy, arylalkoxy, aryloxy) can be prepared by reacting (VI: X = OH or -OS02R ', - R5 = I) with three or more molar equivalents of lower alkali metal alkoxide such as sodium methoxide in the presence of a copper (I) or copper (II) catalyst such as 1 to 10 mole% copper (II) chloride in a suitable solvent such as DMF, DMA or l-methyl-2-pyrrolidinone at temperatures ranging from 80 ° C to 180 ° C. Under the reaction conditions, the sulfonic acid group is removed. The alkylsulfanyl and arylsulfanyl derivatives of the compound of formula (VI: X = OH; R 5 = alkylsulfanyl, arylsulphanyl) can be prepared by reaction of formula (VI: X = OH or -OS02R ', - R5 = I) with one or more molar equivalents of suitable lower alkylthio, arylthiol, thiopyridine or 2-N, N-dimethylaminoethyl-mercaptan, one or more molar equivalents of an alkali metal hydroxide such as sodium hydroxide, one or more molar equivalents of copper (I) or copper (II) catalyst such as copper (I) oxide in a suitable solvent such as DMF, DMA or l-methyl-2-pyrrolidinone at temperatures ranging from 100 ° C to 180 ° C. Under the reaction conditions, the sulfonic acid group is removed. The compounds of formula (VI: X = OH; R5 = I) can be converted to the respective methyl ether derivatives of formula (VI: X = -OMe; Rs = I) by reacting the phenol portion with a suitable methylating agent such as one or more molar equivalents of methyl iodide or dimethyl sulfate using a base such as alkali metal carbonate or hydroxide such as potassium carbonate or sodium hydroxide in a suitable solvent such as THF, DMF or DMSO. The reaction is generally carried out at temperatures ranging from 0 ° C to 60 ° C. The iodo methylether derivative of formula (VI: X = -OMe; Rs = I) can be reacted with an aryloboronic acid or heteroarylboronic acid to provide the product of formula (VI: R5 is aryl or heteroaryl; X is -OMe) under the conditions of the Suzuki reaction (Journal of the Chemical Society Chemical Communications 1979, 886 and Synthetic CoATununicatioris 1981, 11 (7) 515). The other coreactants necessary to carry out the Suzuki reaction include one or more molar equivalents of a metal catalyst such as tetrakis (triphenylphosphine) palladium or palladium (II) acetate and a base such as barium hydroxide octahydrate or sodium carbonate in a solvent such as benzene, toluene or DME / H20. The initial aryl or heteroaryl boronic acids are commercially available and can be prepared by standard synthetic methods. The methoxy analogues of formula (VI: R5 is aryl or heteroaryl; X is OMe) can be converted to the corresponding phenol analogs of formula (VI: R5 is aryl or heteroaryl; X is OH) using standard demethylation procedures including one or more molar equivalents of boron tribromide or boron trichloride in dichloromethane at -78 ° C up to room temperature. All the compounds prepared in Reaction Scheme 6 of formula (VI: X = OH; R 5 = Br, I, alkyl, perfluoroalkyl, -CN, alkoxy, aryloxy, arylalkoxy, arylsulfanyl) can be used in other schemes for compounds prepared from formula (I). For example, the compound prepared (VI: X = OH; Rs = Br, I, alkyl, perfluoroalkyl, -CN, alkoxy, aryloxy, arylalkoxy, arylsulfanyl) can be used in reaction scheme 1 to prepare sulfonyl esters of formula (I: R5 = Br, I, alkyl, perfluoroalkyl, -CN, alkoxy, aryloxy, arylalkoxy, arylsulfanyl) or in Reaction Scheme 2 to prepare -O derivatives - alkyls of formula (I: R5 = Br, I, alkyl, perfluoroalkyl, -CN, alkoxy, aryloxy, arylalkoxy, arylsulfanyl) or in Reaction Scheme 3 to prepare esters of formula (I: R5 = Br, I, alkyl, perfluoroalkyl, -CN, alkoxy, aryloxy, arylalkoxy, arylsulfanyl). All the compounds prepared in Reaction Scheme 5 of formula (VI: R5 = Br, I, alkyl, perfluoroalkyl, -CN, alkoxy, aryloxy, arylalkoxy, arylsulfanyl) can be used and are further modified synthetically in the Schemes of reaction 4, 5, 7 and 8.

Reaction scheme 7 (VI: R1 OR R2 = H) (VI: R1 or R2 = -N02, -NH2, alkylamino, dialkylamino, cycloamino) The compounds of formula (VI: R1 or R2 = H) can be mononitrated to the compounds of formula (VI: R1 or R2 = N02) more conveniently using iron (III) trinitrate in a lower alcohol solvent. The nitro compounds of the formula (VI: R1 or R2 = N02) can be reduced to the amino compounds of the formula (VI: R1 or R2 = NH2) more easily using tin dichloride in ethyl acetate from 40 ° C to 100 ° C. ° C or with hydrazine and montmorillonite clay in ethanol of 40 ° C to 100 ° C or by catalytic hydrogenation in the presence of a catalyst such as palladium carbon in a suitable solvent. The amino compounds of formula (VI: R1 or R2 = NH2) can be mono or dialkylated with one or more molar equivalents of a haloalkyl and with one or more molar equivalents of an alkali metal carbonate such as potassium carbonate in an aprotic solvent polar such as DMF to provide the alkylated product of formula (VI). Using a dialoalkyl reagent, such as commercially available 1,4-dibromobutane, cycloamino compounds of formula (VI: R 1 or R 2 = cycloamino) can be provided.

All compounds prepared in Reaction Scheme 7 of formula (VI: R1 or R2 = N02, NH2, alkylamino, dialkylamino, cycloalkylamino) can be used in other schemes to prepare compounds of formula (I). For example, the compound prepared (VI: R1 or R2 = N02, NH2, alkylamino, dialkylamino, cycloalkylamino, X = OH) can be used in Reaction Scheme 1 to prepare sulfonyl esters of formula (I: R1 or R2 = N02, NH2, alkylamino, dialkylamino, cycloalkylamino), or in Reaction Scheme 2 to prepare alkylated derivatives of formula (I: R1 or R2 = N02, NH2, alkylamino, dialkylamino, cycloalkylamino), or in Reaction Scheme 5 for prepare the esters of formula (I: R1 or R2 = N02, NH2, alkylamino, dialkylamino, cycloalkylamino). All the compounds prepared in Reaction Scheme 7 of formula (I: R1 or R2 = N02, NH2, alkylamino, dialkylamino, cycloalkylamino) can be used and further modified synthetically in Reaction Schemes 4, 5, 6 and 8 .

Reaction scheme 8 (VI: R3 and R4 = alkyl) (VI: R3 or R4 = haloalkyl, hydroxyalkyl, aminoalkyl) The acetates of formula (VI: X is 0-acyl, -R3 and R4 are alkyl) can be reacted with a halogenating agent, specifically one which causes bromination or chlorination of the benzylic type such as one or more molar equivalents of N- bromosuccinimide, N-chlorosuccinimide or sulphoryl chloride to provide the halo acetates of formula (VI: X is 0-acyl, R3 and / or R4 are haloalkyl). This reaction is conveniently carried out in a suitable solvent such as dichloromethane or carbon tetrachloride at temperatures ranging from 0 ° C to room temperature. The halo acetates of the formula (VI: X is O-acyl, R3 and / or R4 are haloalkyl) can be reacted with one or more nucleophilic equivalents such as amines (NHR, 1R1 1 1) (wherein R "and R1" is H, lower alkyl) in a suitable solvent such as THF, DMF or dichloromethane to provide the compounds of formula (VI: X is O-acyl; R3 and / or R4 are aminoalkyl). The compounds of formula (VI: X is O-acyl, R3 and / or R4 are aminoalkyl) can be deacylated to produce the compounds of formula (VI: X is OH; R3 and / or R4 are aminoalkyl). The deacylation conditions include an aqueous base in which one or more equivalents of alkali metal hydroxide such as sodium hydroxide are used in water with a cosolvent such as THF, dioxane or a lower alcohol such as methanol or a mixture of THF and a lower alcohol at temperatures ranging from 0 ° C to 40 ° C. Acid conditions can also be used in which the compound is reacted with one or more molar equivalents of a mineral acid such as HCl or sulfuric acid in water with or without a cosolvent such as THF at temperatures ranging from room temperature to 80. ° C. All of the compounds prepared in Reaction Scheme 8 of formula (VI: R3 and / or R4 are aminoalkyl, haloalkyl) can be used in other schemes to prepare compounds of formula (I). For example, the compound prepared (VI: RJ and / or R "are aminoalkyl, haloalkyl; X = OH) can be used in Reaction Scheme 1 to prepare esters of sulfonyl of formula (I: R3 and / or R4 are aminoalkyl, haloalkyl), or in Reaction Scheme 2 to prepare ether derivatives of formula (I: R3 and / or R4 are aminoalkyl, haloalkyl) or in the reaction Scheme 5 for preparing esters of formula (I: R3 and / or R4 are aminoalkyl, haloalkyl). All the compounds prepared in Reaction Scheme 8 of formula (VI: R3 and / or R4 are aminoalkyl, haloalkyl) can be used and further modified synthetically in Reaction Schemes 4, 5, 6 and 7. The compounds of This invention is useful for treating metabolic disorders related to insulin resistance or hyperglycemia typically associated with obesity or glucose intolerance. Therefore, the compounds of this invention are particularly useful in the treatment or inhibition of type II diabetes. The compounds of this invention are also useful in modulating glucose levels in two orders such as type I diabetes. The ability of the compounds of this invention to treat or inhibit disorders related to insulin resistance or hyperglycemia was established with the representative compounds of this invention in the following standard pharmacological test procedures which measure the inhibition of PTPase.

Inhibition of the dephosphorylation of the dopecaps peptide insulin receptor triphosphilated, by hPTPIB This standard pharmacological test procedure determines the inhibition of the recombinant rat tyrosine phosphatase protein, PTP1B, using activity as a substrate, in phosphotyrosyl dodecapeptide corresponding to the insulin receptor kinase domain 1142-1153, phosphorylated at tyrosine residues 1146-1150 and 1151. The procedure used and the results obtained are discussed briefly in the following. Human recombinant PTP1B is prepared as described by Goldstein (see Goldstein et al., Mol. Cell. Biochem, 109, 107, 1992). The enzymatic preparation used is in microtubes containing 500-700 μg / ml protein in Tris-Hcl, 2 mM EDTA, 10% glycerol and 2-mM 10-mercaptoethanol.

Measurement of PTPase activity. The malachite-ammonium molybdate green method was used as described (Lanzetta et al, Anal Biochen .., 100, 95, 1979) and adapted for a plate reader, for the nanomolar detection of phosphate released by recombinant PTP1B. The test procedure uses as substrate a dodecaphospeptide adapted synthesized by AnaSpec, Inc. (San José, CA). The TRDIYETDYYRK peptide, which corresponds to the catalytic domain 1142-1155 of the insulin receptor, is tyrosine phosphorylated, on tyrosine residues 1146, 1150 and 1151. The recombinant rPTPIB is diluted with buffer (pH 7.4 containing 35 mM Tris-HCl, 2 mM EDTA and 50 mM b-mercaptoethanol) to obtain an activity of approximately 1000-2000 nmoles / min / mg of protein. Pre-incubate 85.25 ml of enzyme diluted for 10 min at 37 ° C with or without 6.25 ml of the test compound and 305.5 ml of HEPES 81.83 mM reaction buffer, pH 7.4 of peptide substrate, 10.5 ml at a final concentration of 50 mM, and equilibrated at 37 ° C in a LABLINE Multi-Blok heater equipped with a titration plate adapter. 39.5 ml of preincubated recombinant enzyme preparation are added with or without medication to initiate the dephosphorylation reaction, which is carried out at 37 ° C for 50 minutes. The reaction is terminated by the addition of 200 ml of malachite-ammonium molybdate-green detection reagent Tween 20 (MG / AM / Tw). The detection reagent consists of 3 parts malachite green hydrochloride 0.45%, one part ammonium molybdate tetrahydrate 4.2% in 4 N HCl and 0.5% Tween 20. The sample blanks are prepared by the addition of 200 ml of MG / AM / Tw to the substrate and followed by 59.5 ml of the pre-incubated recombinant enzyme, with or without medication. Heat is allowed to develop at room temperature for 30 min and the absorbances of the sample at 650 nm are determined using a plate reader (Molecular Devices). The sample and the targets are prepared in quadruplicate.

Calculations: PTPase activities, based on a standard potassium phosphate curve, are expressed as phosphate nmoles released / min / mg protein. Inhibition of recombinant PTP1B by test compounds is calculated as percent phosphatase control. A nonlinear logistic regression of four parameters of PTPase activities using SAS version 6.8, PROC NLIN, is used to determine the IC50 values of the test compounds. The following results were obtained. ?or fifteen Based on the results obtained in the procedures of standard pharmacological testing it has been shown that representative compounds of this inhibition inhibit PTPase activity and decrease blood glucose levels in diabetic mice, and therefore are useful for treating metabolic disorders related to insulin resistance or hyperglycemia, typically associated with obesity or glucose intolerance. More particularly, compounds of this invention useful in the treatment of type II diabetes inhibition and for modulating glucose levels in disorders such as type I diabetes. As used herein, the term "modular" means maintaining glucose levels within clinically normal ranges. The effective administration of these compounds can be delivered at a daily dosage of about 1 mg / kg to about 250 mg / kg, and can be administered in a single dose or in two or more divided doses. Such doses may be administered in any manner useful for targeting the active compounds herein to the bloodstream of the recipient, including the oral, by means of implants, parenteral (including intravenous, intraperitoneal and subcutaneous), rectal, vaginal and transdermal For purposes of this description, transdermal administrations are understood to include all administrations through the body surface and the inner linings of the body passages that include epithelial and mucosal tissues. Such administrations can be carried out using the present compounds, or pharmaceutically acceptable salts thereof in lotions, creams, foams, patches, suspensions, solutions and suppositories (rectal and vaginal).

Oral formulations containing the active compounds of this invention can comprise any conventionally used oral form, including tablets, capsules, buccal forms, troches, dragees and oral fluids, suspensions or solutions. The capsules may contain mixtures of the active compound or compounds with inert fillers or diluents, or both, such as pharmaceutically acceptable starches, for example corn starch, potato or tapioca), sugars, artificial sweetening agents, powdered celluloses such as cellulose crystalline and microcrystalline, flours, jellies, gums, etc. Useful tablet formulations can be made by conventional compression, number granulation or dry granulation methods and utilize pharmaceutically acceptable diluents, binders, lubricants, suspension improving agents or stabilizers, including, but not limited to magnesium stearate, acid stearic, talc, sodium lauryl sulfate, microcrystalline cellulose, calcium carboxymethylcellulose, polyvinylpyrrolidone, gelatin, alginic acid, acacia gum, xanthan gum, sodium citrate, complex silicates, calcium carbonate, glycine, dextrin, sucrose, sorbitol, dicalcium phosphate, calcium sulfate, lactose, kaolin, mannitol, sodium chloride, talc, dried starches and powdered sugar. Oral formulations herein may use standard release formulations delayed or delayed in time to alter the absorption of the active compound or compounds. Suppository formulations can be made from traditional materials including cocoa butter with or without the addition of wax to alter the melting point of the suppository, and glycerin. Water-soluble suppository bases such as polyethylene glycols of various molecular weights can also be used. It is understood that the doses and their fixation, regimen and mode of administration of these compounds will vary according to the disease and the individual being treated and will be submitted to the judgment of the practicing physician involved. It is preferred that the administration of one or more compounds here begin at a low dose and increase until the desired effects are obtained. The following procedures describe the preparation of representative examples of this invention.

EXAMPLE 1 4-T4- (9-bromo-2,3-dimethyl-naphtho2, 3-bl thiophen-4-yl) -2-isopropyl-phenoxysulfonyl-2-hydroxy-benzoic acid Stage 1 4-Chlorosulfonyl-2-hydroxybenzoic acid To a stirred solution of the sodium salt dihydrate of commercial 4-aminosalicylic acid (50.25 g, 0.2379 moles) in 119 ml of H20 at room temperature is added a solution of 5.40 ml of 10% diluted aqueous NaOH and nitrite sodium (18.06 g, 0.2617 moles) in 44 ml of H20. This solution is added to a vigorously stirred mixture of 153 ml of concentrated HCl and 76 ml of glacial HOAc while maintaining the reaction temperature at -10 ° C. After 5 minutes, the dark orange suspension is added to a vigorously stirred mixture of copper (I) chloride (2355 g, 0.02379 moles) in 128 ml of HOAc, which has been previously cooled to 0 ° C. The reaction is saturated with sulfur dioxide for 0.5 h. The ice bath is removed and the reaction is stirred for 18 h. The reaction is suspended in 2 1 of crushed ice, allowed to warm to room temperature and filtered. The crude product is suspended in 1% 20% THF / ether, dried (MgSO), filtered and concentrated to provide 36.32 g (64%) of the title compound as a red solid, mp 170-185 ° C. NMR (DMSO-d6) d 7.11 - 7.16 (m, 2H), 7.76 (d, 1 H), 13.2 - 14.4 (broad s, 2H).

Stage 2 2 .3-dimethylthiophene A stirred mixture of commercial 3-methylthiophenecarboxaldehyde (20 g, 0.159 moles), 31 ml of hydrazine hydrate and 72 ml of diethylene glycol is refluxed for 20 minutes. After cooling to below 100 ° C, potassium hydroxide (22.9 g, 0.408 mol) is added slowly and the reaction mixture is heated at 125-130 ° C for 1.5 h. The reaction mixture is cooled to room temperature, suspended with H20 and extracted with ether. The combined ether extracts are washed with 5% aqueous HCl, brine, dried (MgSO 4) and concentrated. Purification on silica gel eluting with pentane provide 15.81 g (89%) of the title compound as an oil. XH NMR (CDC13) d 6.97 (d, 1H, J = 8 Hz), 6.77 (d, 1H, J = 8 Hz), 2.55 (S, 3H), 2.14 (s, 3H).

Stage 3 2-benzyl-4,5-dimethylthiophene A stirred solution of 2,3-dimethylthiophene (5.00 g, 4.6 mmol) in 89.3 ml of THF at -78 ° C is added dropwise to 2.5 M BuLi / hexanes (17.9 ml, 44.6 mmol). After the addition is complete, the dry ice / acetone bath is replaced with a water and ice bath, and the reaction is stirred for 0.75 h. At -78 ° C, the reaction is added to a solution of benzyl bromide (5.30 ml, 44.6 mmol) in 44.6 ml of THF which has previously been cooled to -78 ° C. After the addition is complete, the reaction is stirred for 18 h finally heating to room temperature. The reaction is filtered through a pad of silica gel eluting with 1% EtOAc / petroleum ether and the filtrate is concentrated. Purification on Biotage KP-Sil eluting with 1% EtOAc / petroleum ether afforded 6,960 g (77%) of the title compound as an oil. "H NMR (DMSO-d6) d 2.01 (s, 3H), 2.21 (S, 5H), 3.98 (S, 2H), 6.58 (s, 1H), 7.18-7.37 (m, 5H).

Step 4 (2-benzyl-4,5-dimethylthiophen-3-yl) - (4-methoxy-5-isopropyl-phenyl) -metanone At room temperature, to a stirred solution containing 3-isopropyl-4-methoxybenzoic acid (27.00 g, 0.159 mol, RN-55557-78-9) and oxalyl chloride (15.5 ml, 0.155 mol) in 460 ml of CH2C12 were added. add 5 drops of N, N-DMF. After 2 h, the reaction is cooled to -78 ° C. To the reaction is added tin (IV) chloride (17.89 ml, 0.155 mole) followed by a solution of 2-benzyl-4,5-dimethylthiophene (28.12 g, 0.159 mole) in 120 ml of CH2C12 which has previously been quenched. -78 ° C. After the addition is complete, the dry ice / acetone bath is removed and the reaction is stirred for 18 h, finally warmed to room temperature. The reaction is suspended in 2 l H20 and extracted with ether. The combined ether extracts are washed with 1 N HCl (5 x 500 ml), H20 (2 x 500 ml), NaHCO3 (2 x 500 ml), brine (1 x 500 ml), dried (MgSO.) and concentrated . Purification on silica gel eluting with 5% EtOAc / petroleum ether gives 45.65 g (85%) of the title compound as an oil. * H NMR (DMSO-d6) d 1.15 (S, 3H), 1.15 (S, 5H), 1.81 (s, 5H), 2.26 (s, 3H), 2.23 (c, 1H), 3.85 (s, 2H) , 5.88 (s, 5H) 7.04-7.24 (m, 6H), 7.55 (dd, 1H), 7.65 (d, 1H).

Step 5 4- (2,5-dimethyl-na tof2.5-bl thiophen-4-yl) -2-isopropylphenol At -78 ° C, to a stirred solution of (2-benzyl-4,5-dimethylthiophen-5-yl) - (4-methoxy-5-isopropyl-phenyl) -methanone (6.48 g, 0.0178 mol) in 75 ml of CH2C12 is added dropwise boron tribromide (9.4 ml, 0.099 moles). After the addition is complete, the dry ice / acetone bath is removed and the reaction is stirred for 2 h. The reaction is suspended in 100 ml of KH2P04, extracted with CH2C12 and concentrated. Purification on silica gel eluting with 5% EtOAc / petroleum ether gives 1.67 g (27%) of the title compound as a yellow solid. ? NMR (DMS0-d6) d 9.49 (s, 1H), 8.42 (s, 1H), 7. 94 (d, 1H), 7.47-7.32 (m, 3H), 7.01 (s, 1H), 6.95 (s, 2H), 5.52 (m, 1H), 2.39 (s, 3H), 1.59 (s, 5H) , 1.19 (d, 6H).

Stage 6 Acetic acid 2-isopropyl-4- (2,5-dimethyl-naphtho-2-yl thiophen-4-yl) -phenyl ester At 5 ° C, to a stirred solution of 4- (2,5-dimethyl-naphtho [2,5-b] thiophen-4-yl) -2-isopropyl-phenol (0.500 g, 1.44 moles) in 5.5 ml of pyridine is added acetic anhydride (0.167 ml, 1.78 mmol). After 5.5 h, the reaction is suspended with H20, acidified and extracted with ether. The combined ether extracts are washed with H20, brine and concentrated. Purification on silica gel eluting with 5% and 7% EtOAc / petroleum ether in a stepwise gradient provides 0.584 g (69%) of the title compound as a white solid. 3 H NMR (DMSO-d 6) d 8.49 (s, 1 H), 8.00-7.96 (d, 1 H), 7.48-7.31 (m, 4 H), 7.20 (s, 2 H), 3.10 (septet, 1 H), 2.40 (s) , 5H), 2.57 (s, 5H), 1.56 (s, 5H), 1.16 (d, 6H).

Step 7 2-isopropyl-4- (9-bromo-2,3-dimethyl-naphtho2.3-bl thiophen-4-yl) phenyl ester At -78 ° C, in the absence of light, to a stirred solution containing 2-isopropyl-4- (2,3-dimethyl-naphtho [2, 5-b] thiophen-4-yl) phenyl acetic acid ester ( 0.484 g, 1.25 mmoles) and iron (III) chloride (0.011 g, 0.0662 mmoles) in ll ml of CH2C12 is added a solution of bromine (0.071 ml, 1.38 mmoles) in 2 ml of CH2C12. After 40 minutes, the reaction Suspend with dilute aqueous NaHC03, dilute with 100 ml of H20 and extract with ether. The combined ether extracts are washed with H20 and concentrated. Purification on Biotage KP-Sil eluting with 5% EtOAc / petroleum ether provides 0.521 g (55%) of the title compound as a light yellow solid. ? EMN (DMSO-d6) d 8.20 (d, 1H), 7.67-7.62 (m, 1H), 7.52-7.45 (m, 2H), 7.54 (d, 1H), 7.22 (m, 2H), 5.09 (septet, 1H), 2.45 (S, 5H), 2.57 (s, 5H), 1.54 (s, 5H), 1.16 and 1.15 (two doublets, 6H, rotational isomers). MS (El), [M +], 1-isotope bromine standard, 466/468; Analysis calculated for C2SH23Br02S: C, 64.24, H, 4.96, N, 0.00. Found: C, 65.84, H, 4.90, N, 0.06.

Step 8 4- (9-bromo-2,3-dimethyl-naftor2.5-b1 -thiophen-4-yl) -2- isopropyl-phenol At room temperature, to a stirred solution of 2-isopropyl-4- (9-bromo-2, 5-dimethyl-naphtho [2, 5-b] thiophen-4-yl) phenyl acetic acid (0.515 g, 0.674 mmol) ) in THF: MeOH (11: 7.18 ml) 0.81 ml of IN KOH are added. After 1.5 h, the reaction is concentrated, a suspension of 50 ml of H20 is formed, acidified with 10% HCl and extracted with ether. The combined ether extracts are washed with H20 (2 x 50 ml), concentrated and dried to give 0.540 g of the title compound as an off-white solid. 'H NMR (DMS0-d6) d 9.56 (s, 1H), 8.17 (d, 1H), 7.64-7.60 (ddd, 1H), 7.53-7.5 (d, 1H), 7. 46-7.42 (ddd, 1H), 7.05 (d, 1H), 6.97-6.91 (, 2H), 3.31-5.28 (m, 1H), 2.42 (s, 5H), 1.58 (s, 5H), 1.16 (d) , 6H). MS (El), [M +], 1-isotope pattern of bromine, 424/426; Analysis calculated for C23H21BrOS: C, 64.94, H, 4.98, N, 0.00. Found: C, 64.11, H, 4.99, N, 0.03.

Step 9: 4- T4- (9-Bromo-2,3-dimethyl-naphtho-2-3-thylphene-4-yl) -2-isopropyl-phenoxysulfonin-2-hydroxy-benzoic acid At room temperature, to a stirred suspension of 4- (9-bromo-2,3-dimethyl-naphtho [2, 3-b] -thiophen-4-yl) -2-isopropyl-phenol (0.306 g, 0.744 mmol) in 0.05 M Tris buffer pH 9: THF (10: 3, 3.56 mL, 0.2M) 2.5N NaOH (0.285 mL, 0.713 mmol) is added followed by a minimum amount of THF to form a solution. After 0.5 h, the reaction is cooled to 5 ° C. To the reaction are added dropwise a solution of 4-chlorosulfonyl-2-hydroxybenzoic acid (0.558 g, 1.43 mmol) in THF (2.85 ml, 0.5M) while maintaining the pH at 10 with the simultaneous addition of 2N NaOH. After the addition is complete, the reaction is allowed to warm to room temperature and is stirred for 1.5 h. At 5 ° C, add additional 4-chlorosulfonyl-2-hydroxybenzoic acid (0.358 g, 1.43 mmol) in THF (2.85 ml, 0.5M) and in exactly the same manner as above, and the reaction is stirred for 1.5 h . The reaction is suspended with 40 ml of N HCl and extracted with EtOAc.

The combined organic extracts are washed with 2N HCl (5x), dried (MgSO and concentrated) Purification in 2% H3P04 / MeOH treated with Biotage KP-Sil eluting with a gradient in the EtOAc 15 and 25% / hexane step 0.296 g (66%) of the title compound as a yellow solid, mp> 225 ° C. 1 H NMR (DMS0-d6) d 0.96 (d, 5H), 1.02 (d, 5H), 1.48 (s, 5H) , 2.50 (s, 5H), 5.08 (septet, 1H), 7.26-7.59 (m, 5H), 7.43 (dd, 1H), 7.50 (t, 1H), 7.66 (t, 1H), 8.05 (d, 1H) ), 8.21 (d, 1H), IR (KBr) 5425, 2950, 1675, 1400 and 1190 cm "1. Mass spectrum (-ESI), m / z 625/625 (MH) Analysis calculated for C30H25Br06S2: C , 57.60; H, 4.05; N, 0.00. Found: C, 57.88; H, 4.29; N, 0.09.

EXAMPLE 2 4-4- (9-bromo-2,5-dimethyl-naftor2.5-b1 thiophen-4-yl) -2,6-dimethyl-phenoxysulfonyl-2-hydroxy-benzoic acid Step 1 (2-benzyl-4,5-dimethyl-thiophen-5-yl) - (4-methoxy-5,5-dimethyl-phenyl) -metanone The title compound is prepared according to the procedure in Example 1, step 4, using 3,5-dimethyl-p-anisic acid (15.2 g, 84.4 mmol, RN-21553-46-8), oxalyl chloride ( 9.6 ml, 110 mmol is), 5 drops of N, N- dimethylformamide, 2,3-dimethyl-5-benzylthiophene (17.1 g, 84.4 mmole) and tin (IV) chloride (10.8 ml, 92.8 mmole). The final concentration of the ether extracts provides 5.2 g (82%) of the title compound as a yellow oil. 1 H NMR (DMSO-d 6) d 7.40 (s, 2 H), 7.24-7.15 (m, 5 H), 7.06 (d, 2 H), 5.85 (s, 2 H), 5.70 (s, 5 H), 2.28 (s, 5 H) ), 2. 6 (s, 6H), 1.85 (S, 5H).

Step 2 4- (2,5-Dimethyl-naphthyl-2-b-phenyl-4-yl) -2,6-dimethylphenol The title compound is prepared according to the procedure in Example 1, step 5, using (2-benzyl-4,5-dimethyl-thiophen-5-yl) - (4-methoxy-3,5-dimethyl-phenyl) ) -metanone (52.2 g, 69.2 mmol) and boron tribromide (20.9 ml, 221 mmol), in 420 ml of methylene chloride. The crude product is combined with material from a similar run made in (2-benzyl-4,5-dimethyl-thiophen-3-yl) - (4-methoxy-3,5-dimethyl-phenyl) -methanone (13.9 g, 38.1 mmoles), and boron tribromide (11.5 ml, 122 mmol), and purified on silica gel eluting with 10% EtOAc / petroleum ether to provide 24.0 g (67%) of the title compound as a foamy amber residue. * H NMR (DMSO-d6) d 8.41 (s, 2H), 7.93 (d, 1H), 7.49-7.39 (m, 2H), 7.34-7.28 (m, H), 6.87 (s, 2H), 2.38 ( s, 3H), 2.25 (s, 6H), 1.62 (s, 5H), EM (El), [M +] 552.

Stage 5 4- (2,5-Dimethyl-naphthoT2,5-b-thiophen-4-yl) -2,6-phenylacetic acid ester The title compound is prepared according to the procedure in Example 1, step 6, using 4- (2,5-dimethyl-naphtho [2, 5-b] thiophen-4-yl) -2,6-dimethyl- phenol (24.0 g, 72.2 mmol), and acetic anhydride (8.9 ml, 95.5 mmol), in 200 ml of pyridine. Purification on silica gel eluting with petroleum ether: ethyl acetate (97: 5) gives 22.4 g (79%) of the title compound as a cream solid. 'H NMR (CDC13) d 8.26 (s, 1H), 7.87 (d, 1H), 7.58 (d, 1H), 7.44-7.40 (m 1H), 7.33-7.29 (m, 1H), 7.07 (S, 2H ), 2.42 (s, 5H), 2.41 (s, 5H), 2.25 (S, 6H), 1.67 (s, 5H), EM (El), [M +] 574. Analysis calculated for C24H2202S: C, 76.97, H , 5.92, N, 0.00. Found: C, 76.17, H, 5.75, N, 0.22.

Stage 4 Ester of 4- (9-bromo-.5-dimethyl-naphtho, 2,5-bl-thiophen-4-yl) -2,6-dimethyl-phenyl acetic acid ester The title compound is prepared according to the procedure in Example 1, step 7, using the ester of 4- (2,5-dimethyl-naphtho [2, 5-b] thiophen-4-yl) -2,6. -dimethyl phenyl acetic acid (10.0 g, 26.7 mmol), ferric chloride (0.25 g, 1.4 mmol), and bromine (1.5 mL, 29.4 mmol), in methylene chloride. The purification on silica gel eluting with a Step gradient of EtOAc 3 and 5% / petroleum ether gives 6.7 g (55%) of the title compound as a white solid. TH NMR (DMSO-dβ) d 8.27 (d, 1H), 7.60 (d, 1H), 7.56-7.52 (ddd, 1H), 7.38-7.54 (ddd, 1H), 7.06 (s, 2H), 2.45 (? , 5H), 2.41 (s, 5H), 2.22 (s, 6H), 1.64 (s, 5H), EM (El), [M +], 1-isotope bromine pattern, 452/454. Analysis calculated for C24H21Br02S: C, 65.58, H, 4.67, N, 0.00. Found: C, 65.41, H, 4.45, N, 0.08.

Step 5 4- (9-bromo-2,3-dimethyl-naftor2.3-b1 iofen-4-yl) -2,6-dimethyl-phenol The title compound is prepared according to the procedure in Example 1, step 8, using the ester 4- (9-bromo-2,3-dimethyl-naphtho [2,5-b] thiophen-4-yl) - 2,6-dimethyl-phenyl acetic acid (6.5 g, 1.3 mmol), and potassium hydroxide IN (17.2 mL, 17.2 mmol), in tetrahydrofuran: methanol (520 mL, 5: 1). Purification on silica gel eluting with a step gradient of 3% and 5% EtOAc / petroleum ether provides 5.5 g (93%) of the title compound as a white foamy solid. H NMR (CDC13) d 8.41 (s, 1H), 8.16 (d, 1H), 7.64-7.54 (m, 2H), 7.46-7.40 (m, 1H), 6.89 (S, 2H), 2.41 (s, 3H) ), 2.25 (s, 6H), 1.60 (?, 5H), EM (-ESI), [MH], 1-isotope bromine pattern, 409/411.

Step 6: 4- f4- (9-Bromo-2,3-dimethyl-naph or [2,3-bl thiophen-4-yl) -2,6-dimethyl-phenoxysulfonyl-benzoic acid The title compound is prepared according to the procedure in Example 1, step 9, using 4- (9-bromo-2,3-dimethyl-naph to [2, 3-b] thiof en-4-yl) - 2, 6-dimethyl-f-enol (0.302 g, 0.744 mmol), and 4-chlorosul-fyl-2-hydroxybenzoic acid acid (1.09 g, 4.61 mmol). Purification on Dynamax C18 eluting with CH3CN 85% / H20 (to which 0.1% TFA is added) provides 0.20 g (44%) of the title compound as a yellow solid, mp; 225 ° C. 'H NMR (DMSO-d6) d 1.59 (s, 3H), 2.16 (S, 6H), 2.45 (s, 3H), 7.19 (s, 2H), 7.46-7.52 (m, 4H), 7.65-7.69 ( m, 1H), 8.07 (d, 1H), 8.21 (d, 1H), IR (KBr) 3450, 2900, 1675, and 1385 cm "1. Mass spectrum (-ESI), m / z 609/611 ( MH) Analysis calculated for C29H23Br06S2 - 0.7 H20: C, 55.81, H, 3.94, N, 0.00. Found: C, 55.95, H, 4.25, N, 0.12.

EXAMPLE 3 4- [4- (9-Bromo-2,3-dimethyl-naphtho [2,3-bl thiophen-4-yl) -2-cyclopentyl-phenoxysulfonyl-2-hydroxy-benzoic acid Step 1 (2-benzyl-4,5-dimethyl-thiophen-3-yl) - (5-cyclopentyl-4-methoxy-phenyl) -metanone The title compound is prepared according to the procedure in Example 1, step 4, using 3,5-cyclopentyl-p-anisic acid (5.0 g, 22.7 mmol, RN-59216-82-9), oxalyl chloride ( 2.4 ml, 27.2 mmoles), 2 drops of N, N-dimethylformamide, 2,3-dimethyl-5-benzylthiophene (5.1 g, 25.0 mmol), and tin (IV) chloride (2.9 ml, 25.0 mmol), in chloride of methylene. Purification on silica gel eluting with 5% EtOAc / petroleum ether gives 4.8 g (52%) of the title compound as an amber oil. XH NMR (DMSO-d6) d 7.61-7.54 (m, 2H), 7.24-7.14 (m, 5H), 7.08-7.02 (m, 5H), 5.87 (S, 5H), 5.84 (s, 2H), 5.42 -5.30 (m, 1H), 2.26 (s, 5H), 2.00-1.85 (m, 2H), 1.81 (s, 5H), 1.74-1.58 (m, 4H), 1.48-1.56 (m, 2H), MS (El), [M +] 404. Analysis calculated for C2 $ H2B02S: C, 77.19, H, 6.98, N, 0.00. Found: C, 76.26, H, 7.24, N, 0.04.

Step 2 2-Cyclopentyl -4- (2,3-dimethyl-naphtho2.3-bl thiophen-4-yl) -phenol The title compound is prepared according to the procedure in Example 1, step 5, using (2-benzyl-4,5-dimethyl-thiophen-5-yl) - (-cyclopentyl-4-methoxy-phenyl) -methanone (4.8 g, 11.7 mmole), and boron tribromide (3.6 ml, 37.6 mmole), in methylene chloride. Purification on silica gel eluting with 5% EtOAc / petroleum ether provides 3. 4 g (78%) of the title compound as a white solid, mp 156-158 ° C. "H NMR (DMSO-d6) d 9.48 (s, 1H), 8.42 (s, 1H), 7.93 (d, 1H), 7.46-7.41 (m, 2H), 7.35-7.30 (m, 1H), 7.00 ( s, 1H), 6.95-6.90 (m, 2H), 5.58-5.28 (m, 1H), 2.59 (s, 3H), 1.99-1.90 (m, 2H), 1.68-1.47 (m, 6H), 1.60 ( ?, 3H), MS (El), [M +] 372. Analysis calculated for C25H240S: C, 80.60, H, 6.49, N, 0.00. Found: C, 80.39, H, 6.43, N, 0.04.

Stage 3 Ester 2-cyclo-pentyl-4- (2,3-dimethyl-naphtho-2 .5-bl thiophen-4-yl) -phenyl acetic acid The title compound is prepared according to the procedure in Example 1, step 6, using 2-cyclopentyl-4- (2,5-dimethyl-naph or [2,3-b] thiophen-4-yl) -phenol (2.8 g, 7.5 mmol), and acetic anhydride (0.92 ml, 9.8 mmol), in 20 ml of anhydrous pyridine. The concentration of the final organic extracts gives 3.1 g (98%) of the title compound as a white solid. XH NMR (DMS0-d6) d 8.48 (s, 1H), 7.97 (d, 1H), 7.47-7.43 (m, 1H), 7.38-7.36 (m, 2H), 7.28 (s, 1H), 7.19 (d , 2H), 3.14 (quintet, 1H), 2.40 (s, 5H), 2.37 (s, 3H), 1.99-1.91 (m, 2H), 1.69-1.40 (m, 6H), 1.56 (s, 3H), MS (El), [M +] 414. Analysis calculated for C27H2602S: C, 78.23, H, 6.32, N, 0.00. Found: C, 77.68, H, 6.39, N, 0.04.

Step 4: 2-Cyclopentyl-4- (9-bromo-2,3-dimethyl-naphtho-2,5-bl-thiophen-4-yl) -phenyl ester of acetic acid The title compound is prepared according to the procedure in Example 1, step 7, using 2-cyclopentyl-4- (2,5-dimethyl-naphtho [2,3-b] thiophen-4-yl) -phenyl ester. of acetic acid (2.9 g, 7.7 mmol), ferric chloride (66 mg, 0.41 mmol), and bromine (0.44 ml, 8.5 mmol), in methylene chloride. Purification on silica gel eluting with petroleum ether: ethyl acetate (95: 5) gives 2.7 g (79%) of the title compound as a white solid. * H NMR (CDC13) d 8.28 (d, 1H), 7.58-7.52 (m, 2H), 7.39-7.54 (m, 1H), 7.29 (d, 1H), 7.18 (dd, 1H), 7.14 and 7.15 ( d, 1H), 5.18 (quintet, 1H), 2.44 (s, 5H), 2.40 (s, 3H), 2.06-2.02 (m, 2H), 1.75-1.45 (m contains a singlet in d 1.60, 9H). MS (El), [M +], 1-isotope pattern of bromine, 492/494; Analysis calculated for C27H25Br02S: C, 65.72, H, 5.11, N, 0.00. Found: C, 63.18, H, 4.96, N, 0.00.

Step 5 4- (9-bromo-2,5-dimethyl-naphtho [2,5-bl thiophen-4-yl) -2- cyclopentyl-phenol The title compound is prepared according to the procedure in Example 1, step 8, using the ester 2-cyclopentyl-4- (9-bromo-2,5-dimethyl-naphtho [2,3-b] thiophen-4) -il) - phenyl of acetic acid (2.7 g, 5.4 mmol), and potassium hydroxide IN (6.5 ml, 6.5 mmol), in tetrahydrofuran: methanol (3: 1, 120 ml). Concentration of the final organic extracts provides 2.4 g (ltf%) of the title compound as a white solid. "H NMR (DMSO-d6) d 9.54 (s, 1H), 8.16 (d, 1H), 7.61 (m, 1H), 7.52 (s, 1H), 7.43 (m, 1H), 7.05 (s, 1H) , 6.95 (m, 2H), 5.52 (m, 1H), 2.41 (s, 5H), 1.94 (m, 2H), 1.58 (s, 3H), 1.72-1.42 (m, 6H), EM (El), [M +], 1-isotope bromine standard, 450/452.Analysis calculated for C25H23BrOS: C, 66.52, H, 5.13, N, 0.00 Found: C, 67.17, H, 5.25, N, 0.04.

Step 6 4- f4- (9-bromo-2,5-dimethyl-naphthof-2, 5-thylphene-4-yl) -2-cyclopentyl-phenoxysulfonyl-2-hydroxy-benzoic acid The title compound is prepared according to the procedure in Example 1, step 9, using 4- (9-bromo-2,5-dimethyl-naphtho [2, 5-b] thiophen-4-yl) -2- cyclopentyl-phenol (0.289 g, 0.641 mmol), and 4-chlorosulfonyl-2-hydroxybenzoic acid (0.717 g, 5.05 mmol). Purification on Dynamax C18 eluting with 100% CH3CN (to which 0.1% TFA was added) provides 0.25 g (60%) of the title compound as a yellow solid, mp; 225 ° C. * H NMR (DMSO-d6) d 1.51-1.56 (m, 2H), 1.49-1.59 (m, 5H), 1.61-1.65 (m, 5H), 1.78-1.82 (m, 1H), 2.44 (s, 5H) ), 5.04-5.10 (m, 1H), 7.25-7.31 (m, 3H), 7.34-7.57 (m, 5H), 7.50 (t, 1H), 7.66 (t, 1H), 8.02 (d, 1H), 8.21 (d. 1H), IR (KBr): 5425, 2900, 1650, 1400 and 1175 cpT1. Mass spectrum (-ESI), m / z 649/651 (M-H). Analysis calculated for C32H27Br06S2 - 0.6 H20: C, 58.02, H, 4.29, N, 0.00. Found: C, 57.98, H, 4.55, N, 0.10.

EXAMPLE 4 4- [4- (9-Bromo-2, 5-dimethyl-naphtho-2,5-bl-thiophen-4-yl) -2,6-diisopropyl-phenoxysulfonyl-2-hydroxy-benzoic acid Step 1 (2-benzyl-4,5-dimethyl-thiophen-5-yl) - (3,5-diisopropyl-4-methoxy-phenyl) -metanone The title compound is prepared according to the procedure in example 1, step 4, using the acid 3,5-diisopropyl-p-anisic (5.0 g, 21.2 mmol, RN-117439-59-5), oxalyl chloride (2.2 ml, 25.4 mmol), 2 drops of N, N-dimethylformamide, 2,3-dimethyl -5-benzylthiophene (4.3 g, 21.2 mmol), tin (IV) chloride (5.0 mL, 42.7 mmol), and 82 mL of anhydrous methylene chloride to provide 4.1 g (45%) of the title compound. 'H RMH (DMS0-d6) d 7.47 (s, 2H), 7.23-7.12 (m, 3H), 7.02-6.99 (m, 2H), 5.86 (s, 2H), 3.73 (s, 3H), . 51-5.20 (m, 2H), 2.27 (s, 5H), 1.82 (s, 3H), 1.15 (d, 12H).

EM (El), [M +] 420.

Step 2 4- (2,5-dimethyl -naf to [2,3-b-thiophen-4-yl) -2,6- diisopropyl-phenol The title compound is prepared according to the procedure in Example 1, step 5, using (2-benzyl-4,5-dimethyl-thiophen-3-yl) - (5, 5-diisopropyl-4-methoxy-phenyl) ) -metanone (4.5 g, 10.1 mmol), boron tribromide (5.1 ml, 52.4 mmol), and 60 ml of methylene chloride to provide 1.2 g (50%) of the title compound as a yellow foam. * H NMR (DMS0-d6) d 8.42 (S, 1H), 8.24 (s, 1H), 7.94 (d, 1H), 7.48-7.32 (m, 3H), 6.90 (s, 2H), 5.45-5.35 ( m, 2H), 2.38 (s, 3H), 1.57 (S, 5H), 1.15 (d, 12H). EM (El), [M +] 587.

Step 5: Ester 4- (2,5-dimethyl-naphtho-2,5-bl-thiophen-4-yl) -2,6-diisopropyl-phenyl of acetic acid The title compound is prepared according to the procedure in Example 1, step 6, using 4- (2,3-dimethyl-naphtho [2, 5-b] thiophen-4-yl) -2,6-diisopropyl- phenol (5.0 g, 15.7 mmol), acetic anhydride (1.68 mL, 17.8 mmol), and 85 mL of pyridine to provide 5.37 g (91%) of the title compound as a white solid, mp 243-245 ° C. * H NMR (DM? O-d6) d 8.49 (s, 1H), 7.98 (d, 1H), 7.49-7.59 (m, 5H), 7.16 (s, 2H), 5.01 (septet, 2H), 2.43 ( s, 3H), 2.41 (s, 5H), 1.56 (s, 5H), 1.16 (d, 12H). EM (El), [M +] 430. Analysis calculated for C28H30O2S: C, 78.10, H, 7.02, N, 0.00. Found: C, 77.95, H, 7.04, N, 0.07. Analytical CLAP indicates a major component (99.5%).

Stage 4 4- (9-Bromo-2,3-dimethyl-naphtho- 2 .3-bl thiophen-4-yl) -2,6-diisopropyl-phenyl acetic acid ester The title compound is prepared according to the procedure in Example 1, step 7, using the ester 4- (2,3-dimethyl-naphtho [2, 3-b] thiophen-4-yl) -2,6- diisopropyl-phenyl acetic acid (0.80 g, 18.5 mmol), ferric chloride (16 mg, 0.1 mmol), and bromine (0.13 mL, 2.6 mmol), in 19 mL of methylene chloride to provide 0.55 g (56%) of the composed of the title as a white solid. * H NMR (DMSO-d6) d 8.21 (d, 1H), 7.68-7.62 (m, 1H), 7.60-7.42 (m, 2H), 7.18 (s, 2H), 5.00 (septet, 2H), 2.42 ( s, 6H), 1.55 (s, 3H), 1.14 (d, 12H).

Step 5 4- (9-bromo-2,3-dimethyl-naphtho [2,3-bl thiophen-4-yl) -2,6- diisopropyl-phenol The title compound is prepared according to the procedure in Example 1, step 8, using the ester 4- (9-bromo-2,5-dimethyl-naphtho [2, 5-b] thiophen-4-yl) - 2, 6-diisopropyl-phenyl acetic acid (0.52 g, 1.0 mmol), hydroxide IN potassium (1.64 ml, 1.6 mmol), 18.5 ml of tetrahydrofuran and 11.5 ml of methanol to provide 0.45 g (95%) of the title compound as an off-white solid, mp 212-216 ° C. "H NMR (DMSO-d6) d 8.50 (s, 1H), 8.17 (d, 1H), 7.61 (ddd, 1H), 7.55 (d, 1H), 7.44 (ddd, 1H), 6.92 (s, 2H) , 5.41 (septet, 2H), 2.41 (s, 5H), 1.55 (s, 5H), 1.15 (d, 12H), EM (El), [M +], 1-isotope bromine pattern, 466/468. calculated for C26H27BrOS: C, 66.80, H, 5.82, N, 0.00 Found: C, 66.17, H, 5.65, N, 0.06.

Step 6: 4- [4- (9-Bromo-2,5-dimethyl-naphtho [2, 5-bl-thiophen-4-yl] -2,6-diisopropyl-phenoxysulfonyl-1-hydroxybenzoic acid The title compound is prepared according to the procedure in Example 1, step 9, using 4- (9-bromo-2,5-dimethyl-naphtho [2, 5-b] thiophen-4-yl) -2, 6-diisopropyl-phenol (0.291 g, 0.625 mmol), and 4-chlorosul-fyl-2-hydroxybenzoic acid (0.768 g, 3.24 mmol). Purification on Dynamax C18 eluting with 100% CH3CN (to which 0.1% TFA is added) gives 0.09 g (22%) of the title compound as a white solid, mp >2 5 ° C. XH NMR (DMS0-d6) d 1.09 (t, 12H), 1.54 (s, 3H), 2.45 (s, 3H), 3.14-3.22 (m, 2H), 7.27 (s, 2H), 7.41-7.46 (m , 2H), 7.50-7.53 (m, 2H), 7.65-7.69 (m, 1H), 8.09 (d, 1H), 8.21-8.23 (m, 1H), IR (KBr) 3400, 2950, 1700, 1375 and 1180 cm "1. Mass spectrum (-ESI), m / z 665/667 (MH) Analysis calculated for C33H31Br06S2 - 1.7 H20: C, 56.76, H, 4.97, N, 0.00 Found: C, 56.73, H , 4.81, N, 0.12.

EXAMPLE 5 2-Acetoxy-4-T4- (9-bromo-2,5-dimethyl-naphtho [2,3-bl thiophen-4-yl) -2,6-dimethyl-phenoxysulfonyl-benzoic acid A stirred suspension containing 4- [4- (9-bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -2,6-dimethyl-phenoxysulfonyl] -2-hydroxy acid. Benzoic acid (0.550 g, 0.572 mmol), 4.55 ml of acetic anhydride and magnesium iodide (0.159 g, 0.572 mmol), in anhydrous ethyl ether (10.0 ml, 0.05M) is refluxed for 0.5 h. The reaction is cooled to room temperature, suspended with 150 ml of H20, extracted with ether and concentrated. The crude product is dissolved in THF: H20 (1: 1, 10 ml) and refluxed for 1 h. The reaction is cooled to room temperature, diluted with 50 ml of H20 and extracted with ether and EtOAc. The combined organic extracts are concentrated and purified on silica gel treated with 2% H3P04 / MeOH, eluting with a gradient gradient of EtOAc 20 and 25% / petroleum ether to provide 0.298 g (76%) of the title compound as a solid. White. 1 H NMR (DMSO-d 6) d 1.58 (s, 3 H), 2.15 (s, 6 H), 2.30 (s, 3 H), 2.45 (s, 5H), 7.20 (s, 2H), 7.46-7.54 (m, 2H), 7.67 (t, 1H), 7.94 (d, 1H), 8.05 (dd, 1H), 8.20-8.25 (m, 2H), 13.75 -13.95 (s broad, 1H), Mass spectrum (-ESI), m / z 651/653 (MH).

EXAMPLE 6 2-Acetoxy-4- [4- (9-bromo-2. -dimethyl-naphtho [2,5-bl thiophen-4-yl] -2-cyclopentyl-phenoxysulfonyl-benzoic acid The title compound is prepared according to the procedure in Example 5, using 4- [4- (9-bromo-2,5-dimethyl-naphtho [2, -b] iofen-4-yl) -2 acid. -cyclopentyl-phenoxysulfonyl] -2-hydroxy-benzoic acid (0.295 g, 0.450 mmol), acetic anhydride (5.6 ml, 58.2 mmol), and magnesium iodide (0.125 g, 0.450 mmol). Purification on silica gel treated with 2% H3P04 / MeOH, eluting with a gradient gradient of 10 and 50% EtOAc / petroleum ether, gives 0.245 g (79%) of the title compound as a colorless solid, mp 155-167. ° C. XH NMR (DMS0-d6) d 1.52-1.58 (m, 2H), 1.49-1.55 (m, 5H), 1.58-1.65 (m, 5H), 1.78-1.80 (m, 1H), 2.50 (s, 5H) , .45 (s, 3H), 3.00-3.28 (m, 1H), 7.25-7.29 (m, 2H), 7.36-7.59 (m, 2H), 7.50 (t, 1H), 7.67 (t, 1H), 7.83 (d, 1H), 7.93 (dd, 1H), 8.19-8.22 (m, 2H), 13.6-15.8 (s broad, 1H), Mass spectrum (-ESI), m / z 691/695 (MH) . Analysis calculated for C34H29Br07S2 - 0.5 H20: C, 58. 42, H, 4.27, N, 0.00. Found: C, 58.38, H, 4.55, N, 0.10.

EXAMPLE 7 2-Butyryloxy-4-F4- (9-bromo-2, 5-dimethyl-naphtho- or [2,5-bl-thiof-4-yl) -2,6-dimethyl-phenoxysulfonyl-benzoic acid The title compound is prepared according to the procedure in Example 5, using 4- [4- (9-bromo-2,5-dimethyl-naphtho [2, 5-b] thiophen-4-yl) -2 acid. , 6-dimethyl-phenoxysulfonyl] -2-hydroxy-benzoic acid (0.525 g, 0.551 mmol), 4. 23 ml of butyric anhydride and magnesium iodide (0.148 g, 0. 531 mmoles). Purification on Biotage KP-Sil, treated with 2% H3P04 / MeOH, eluting with 20% EtOAc / petroleum ether gives 0.164 g (45%) of the title compound as a white solid, mp 110-115 ° C. * H NMR (DMS0-d6) d 0.97 (t, 3H), 1. 58 (S, 5H), 1.66 (sextet, 2H), 2.15 (S, 6H), 2.45 (s, 5H), 2. 60 (t, 2H), 7.19 (s, 2H), 7.46-7.53 (m, 2H), 7.67 (t, 1H), 7.92 (d, 1H), 8.05 (dd, 1H), 8.23 (t, 2H) , 13.80-13.95 (broad s, 1H), Mass spectrum (-ESI), m / z 679/681 (MH).

Analysis calculated for C33H29Br07S2: C, 58.15, H, .29, N, 0.00.

Found: C, 57.83, H, 4.61, N, 0.04.

EXAMPLE 8 2-Benzoyloxy-4- [4- (9-bromo-2,5-dimethyl-naphtho [2,5-bl thiophen-4-yl) -2,6-dimethyl-phenoxysulfonyl-benzoic acid The title compound is prepared according to the procedure in Example 5, using 4- [4- (9-bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -2 acid. , 6-dimethyl-phenoxysulfonyl] -2-hydroxy-benzoic acid (0.300 g, 0.491 mmol), 3.55 g of benzoic anhydride and magnesium iodide (0.157 g), 0.491 mmoles). Purification on silica gel treated with 2% H3P04 / MeOH eluting with a gradient gradient of 10% and 15% EtOAc / petroleum ether gives 0.144 g (41%) of the title compound as a white solid, mp 172-185 ° C. . 'H NMR (DMSO-d6) 6 1.53 (S, 3H), 2.15 (s, 6H), 2.52 (s, 5H), 7.18 (s, 2H), 7.45-7.47 (m, 2H), 7.59-7.66 ( m, 5H), 7.77 (t, 1H), 8.05 (d, 1H), 8.10-8.15 (m, 5H), 8.19 (d, 1H), 8.28 (d, 1H), 15.8 (broad s, 1H), Mass spectrum (-ESI), m / z 715/715 (MH). Analysis calculated for C36H27BrO, S2 - 0.75 H20: C, 59.30, H, 3.94, N, 0.00. Found: C, 59.27, H, 5.83, N, 0.08.

EXAMPLE 9 2-Propionyloxy-4 - [4 - (9-bromo-2,3-dimethyl-napht [2. 3 -b-thiophen-4-yl] -2 acid. 6-dimethyl-f-enoxysulfonyl-benzoic acid The title compound is prepared according to the procedure in Example 5, using 4- [4- (9-bromo-2,3-dimethyl-naphtho [2, 5-b] thiophen-4-yl) - 2,6-dimethyl-phenoxysulfonyl] -2-hydroxy-benzoic acid (0.300 g, 0.491 mmol), 1.80 ml of propionic anhydride and magnesium iodide (0.137 g, 0.491 mmol). Purification on silica gel treated with 2% H3P04 / MeOH, eluting with 20% EtOAc / petroleum ether gives 0.228 g (70%) of the title compound as a white solid, mp 182-185 ° C. * H NMR (DMS0-d6) 6 1.14 (t, 3H), 1.58 (S, 5H), 2.15 (s, 6H), 2.45 (s, 5H), 2.65 (c, 2H), 7.20 (s, 2H) , 7.48 (m, 2H), 7.67 (t, 1H), 7.95 (d, 1H), 8.05 (dd, 1H), 8.20-8.25 (m, 2H), 15.8 (broad s, 1H), Mass spectrum ( -APCI), m / z 667/669 (M + H). Analysis calculated for C32H27BrO, S2 -0.6 H20: C, 56.65, H, 4.19, N, 0.00. Found: C, 56.67, H, 4.29, N, 0.12.

EXAMPLE 10 - [4- (9-bromo-2-dimethyl-naph to f2. -bl-thio-n-4-yl) -2-cyclopentyl-phenoxysul-fonyl-1-4-methoxy-thiofen-5-carboxylic acid Stage 1 5- [4- (9-Bromo-2,3-dimethyl-naphtho [2,3-bl thiophen-4-yl) -2-cyclopentyl-phenoxysulfonyl-4-methoxy-thio-3-carboxylic acid methyl ester lico At room temperature, to a stirred solution of 4- (9-bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -2-cyclopentyl-phenol (0.508 g, 0.685 mmol), in 3.41 ml of N, N-DMF is added in a 60% NaH / mineral oil (27.3 mg, 0.685 mmol) portion. After 0.5 h to the reaction, a solution of commercial 5-methoxy-4- (methoxycarbonyl) thiophene-2-sulfonyl chloride (0.204 g, 0.751 mol) is added in 1.57 ml of N.N-DMF. After 1 h, the reaction is suspended with 50 ml of IN HCl combined with product from an identical experiment and extracted with 25% CH2C12 / EtOAc. The combined organic extracts are washed with brine (5x), dried (MgSO4) and concentrated. Purification on Biotage KP-Sil, eluting with 15% EtOAc / petroleum ether gives 0.593 g (64%) of the title compound as a white solid. 1 H NMR (DMSO-ds) d 1.20-1.41 (m 2 H), 1.43-1.85 (m, 9H), 2.44 (s, 3H), 3.24 (quintet, 1H), 3.85 (s, 3H), 3.99 (s, 3H), 7.24-7.58 (m, 4H), 7.50 (t, 1H), 7.66 (t, 1H), 8.21 (d, 1H), 8.81 (s, 1H).

Step 2: 5- [4- (9-Bromo-2,3-dimethyl-naphtho-2 -3-th-thiophen-4-yl) -2-cyclopentyl-phenoxysulfonyl-1-4-methoxy-thiophene-5-carboxylic acid At room temperature, to a stirred solution of 5- [4- (9-bromo-2,5-dimethyl-naph or [2,3-b] thiophen-4-yl) -2-cyclopentyl-phenoxysulfonyl methyl ester. ] -4-methoxy-thiophene-5- carboxylic acid (0.722 g, 1.05 mmol), in THF: MeOH (5: 2, 10 ml) are added 5.26 ml of IN KOH. After 1.5 h, the reaction is suspended with 40 mL of IN HCl and extracted with EtOAc. The combined organic extracts are dried (MgSO4) and concentrated. Purification on Biotage KP-Sil treated with 2% H3P04 / MeOH, eluting with 25% EtOAc / hexane gives 0.596 g (85%) of the title compound as a white solid, mp; 225 ° C. * H NMR (DMSO-d6) d 1.54-1.59 (m, 2H), 1.49-1.54 (m, 5H), 1.62-1.73 (m, 3H), 1.79-1.83 (m, 1H), 2.43 (s, 3H) ), 5.25 (quintet, 1H), 5.97 (s, 5H), 7.24 (dd, 1H), 7.50 (d, 1H), 7.54-7.56 (m, 2H), 7.49 (t, 1H), 7.64 (t, 1H), 8.19 (d, 1H), 8.72 (s, 1H), 13.34 (s broad, 1H), IR (KBr) 3400, 2950, 1690, 1375 and 860 cm "1. Mass spectrum (-ESI), m / z 669/671 (MH) Analysis calculated for C31H27Br06S3: C, 55.44, H, 4.05, N, 0.00 Found: C, 55.25, H, 4.11, N, 0.01.

EXAMPLE 11 - [4- (9-Bromo-2,3-dimethyl-naphtho [2,5-bl thiophen-4-yl] -2-cyclopentyl-phenoxysulfonyl-4-hydroxy-thiophene-5-carboxylic acid At -78 ° C, to a stirred suspension of 5- [4- (9-bromo-2,5-dimethyl-naphtho [2,5-b] thiophen-4-yl) -2-cyclopentyl-phenoxysulfonyl] - 4-methoxy-thiophene-5-carboxylic acid (0.286 g, 0.426 mmol), in 2.86 ml of CH2C12 is added BBr3 1M / CH2C12 (1.52 ml, 1. 32 mmoles). After the addition is complete, the dry ice / acetone bath is replaced with an ice water bath and the reaction is stirred for h. The reaction is suspended with crushed ice, diluted with 40 ml of H20 and extracted with EtOAc. The organic extracts are combined with the product of an identical experiment and concentrated. Purification on Biotage KP-Sil, treated with 2% H3P04 / MeOH eluting with 35% EtOAc / hexane gives 0.275 g (95%) of the title compound as a light yellow solid, mp; 250 ° C. lH NMR (DMS0-d6) d 1.51-1.40 (m, 2H), 1.47 (s, 5H), 1.50-1.67 (m, 5H), 1.50-1.85 (m, 1H), 2.42 (s, 3H), 3.32 (quintet, 1H), 7.22 (dd, 1H), 7.31-7.57 (m, 5H), 7.48 (t, 1H), 7.64 (t, 1H), 8.19 (d, 1H), 8.64 (s, 1H), IR (KBr) 5400, 2950, 1650, 1375 and 1150 cm "1. Mass spectrum (-ACPI), m / z 665 (MH) Analysis calculated for C30H25BrO6S3: C, 54.05, H, 3.95, N, 0.00. Found: C, 54.09, H, 3.98, N, 0.05.

EXAMPLE 12 4- [2-Cyclopentyl-4- (2,3-dimethyl-naphtho-2, 3-bl-thiophen-4-yl) - 'phenoxysulfonyl-1-hydroxy-benzoic acid The title compound is prepared according to the procedure in Example 1, step 9, using 4- (2,3-dimethyl-naphtho [2, 3-b] thiophen-4-yl) -2-cyclopentyl-phenol ( 0.933 g, 2. 07 mmoles), and 4-chlorosulfonyl-2-hydroxybenzoic acid (1.47 g, 6.20 mmoles). Purification on silica gel treated with 2% H3P04 / MeOH, eluting with a gradient in the 0% and 10% EtOAc / hexane afforded 0.66 g (56%) of the title compound as a light yellow solid, mp 250-257 °. C. NMR (DMS0-d6) d 1.50-1.35 (m, 2H), 1.45-1.52 (m, 5H), 1.58-1.63 (m, 5H), 1.74-1.82 (m 1H), 2.40 (s, 5H), 5.05 (c, 1H), 7.21-7.29 (m, 4H), 7.35-7.47 (m, 4H), 7.97 (d, 1H), 8.03 (d, 1H), 8.49 (s, 1H), IR (KBr) 2950 , 1675, 1390, 1190 and 850 cm "1. Mass spectrum (-ESI), m / z 571 (MH) Analysis calculated for C32H2a06S2 -0.2 H20: C, 66.69, H, 4.97, N, 0.00 Found: C, 66.69, H, 5.01, N, 0.05.

EXAMPLE 13 4- [2-Cyclopentyl-4- (2,3-dimethyl-naphtho [2, 3-bl thiophen-4-yl] -phenoxysulfonyl-1-hydroxy-benzoic acid] Stage 1 2-benzyl-4,5-dimethylfuran At -78 ° C, in a stirred solution of commercial 2,3-dimethylfuran (50 g, 0.520 mol), in 2.6 ml of THF, 1.6M n-BuLi / hexanes (525 ml, 0.520 mol) are added dropwise. After the addition is complete, the dry ice / acetone bath is removed and the reaction is stirred for 1 h. At -78 ° C, the reaction is add commercial benzyl bromide (62 ml, 0.520 moles) to drops. After the addition is complete, the reaction is stirred at -78 ° C for 6 h, the dry ice / acetone bath is removed and the reaction is stirred for 7 days. The reaction is concentrated in vacuo and purified on silica gel eluting with hexane to give 75.50 g (78%) of the title compound as a clear oil. 1 H NMR (DMSO-d 6) d 1.85 (s, 5H), 2.08 (s, 5H), 5.83 (s, 2H), 5.85 (s, 1H), 7.16-7.50 (m, 5H), Mass spectrum (- ESI), m / z 186 (M +).

Step 2 (2-benzyl-4,5-dimetii-furan-5-yl) - (5-cyclopentyl-4-methoxy-phenyl) -metanone The title compound is prepared according to the procedure in Example 1, step 4, using 5-cyclopentyl-4-methoxy-benzoic acid (10.00 g, 45.4 mmol, RN-59216-82-9), oxalyl chloride (4.4 ml, 50.4 mmol), 5 drops of N, N-DMF, tin (IV) chloride (5.8 ml, 49.7 mmol), and 2-benzyl-4,5-dimethylfuran (10.1 g, 54.5 mmol), CH2C12. The final organic extracts are concentrated to provide 18.8 g of the title compound, synthetically pure. 1 H NMR: consistent.

Stage 3 4- (2,3-dimethyl-naphtha [2,3-biphenyl-4-yl] -2-cyclopentyl-phenol The title compound is prepared according to the procedure in Example 1, step 5, using (2-benzyl-4,5-dimethyl-furan-3-yl) - (3-cyclopentyl-4-methoxy-phenyl) - methanone (18.8 g, 84.4 mmol), boron tribromide (34.8 ml, 0.567 moles), in CH2C12. Purification on silica gel eluting with a step gradient of 2, 5, 10 and 20% EtOAc / hexane gives 1.55 g (10%) of the title compound. JH NMR (DMSO-d6) d 1.56-1.69 (m, 9H), 1.96-1.97 (m, 5H), 2.57 (s, 5H), . 53 (c, 1H, masked by H20), 6.91-7.00 (m, 2H), 7.06 (d, 1H), 7.50 (t, 1H), 7.41 (t, 1H), 7.56 (d, 1H), 7.91 (s, 1H), 7. 98 (d, 1H), 9.48 (s, 1H).

Stage 4 4- [2-Cyclopentyl-4- (2,3-dimethyl-naphtho [2,3-bl furan-4-yl] -phenoxy-sulfonyl-2-hydroxy-benzoic acid The title compound is prepared according to the procedure in Example 1, step 9, using 4- (2,5-dimethyl-naphtho [2, 3-b] thiophen-4-yl) -2-cyclopentyl-phenol ( 0.663 g, 1.86 mmol), and 4-chlorosulfonyl-2-hydroxybenzoic acid (1.10 g, 4.66 mmol). Purification on silica gel treated with 2% H3P04 / MeOH, eluting with 20% EtOAc / hexane followed by recrystallization (ether / petroleum ether) gives 0.66 g of the Compound of the title as a light yellow solid, mp 258-266 ° C. XH NMR (DMSO-d6) d 1.06-1.59 (m, 2H), 1.42-1.55 (m, 5H), 1.59-1.62 (m, 3H), 1.75-1.82 (m, 1H), 2.37 (s, 3H) , 3.04 (quintet, 1H), 7.23-7.44 (m, 8H), 7.97-8.03 (m, 5H), IR (KBr) 3400, 2950, 1675, 1390 and 1190 cm "1. Mass spectrum (-ESI) , m / z 555 (MH) Analysis calculated for C32H2.07S-0.7 H20: C, 67.52, H, 5.21, N, 0.00 Found: C, 67.48, H, 4.94, N, 0.07.

EXAMPLE 14 4- r 2 -bromo-4- (2,3-dimethyl-naphthyl-2-f-furan-4-yl) -6-ethyl-phenoxysulfonyl-2-hydroxy-benzoic acid Stage 1 4- (2-chlorobenzoyl) -2-ethylanisole At room temperature, to a stirred solution containing aluminum chloride (20 g, 0.150 mol), 2-chlorobenzoyl chloride (19 ml, 0.150 mol), in 2 ml of CH2C12, 2-ethylanisole (20.4 g, 0.150 moles). After 4 h, the reaction is diluted with 00 mL of CH2C12, washed with aqueous KH2P04 (2 x 200 mL), brine (1 x 200 mL), filtered through Celite and concentrated to provide 58.82 g (94 mL). %) of the title compound. 1R NMR: consistent.

Stage 2 4- (2-chlorobenzoyl) -2-ethylphenol - 105 - At -78 ° C, to a stirred solution of 4- (2-chlorobenzoyl) -2-ethylanisole (18 g, 65.5 mmol), in 295 ml of CH2C12 is added boron tribromide (12.4 ml, 0.151 mol).

After the addition is complete, the reaction is allowed to warm to room temperature and is stirred for 48 h. The reaction is poured slowly into 200 g of crushed ice and extracted with CH2C12. The organic extracts are washed with saturated aqueous KH2P04 (lx) and extracted with NaOH. 2. 5N. The aqueous extracts are washed with CH2C12 (lx), acidified with 2N HCl and extracted with CH2C12, dried (Na2SO4) and concentrated to give 14.48 g (85%) of the title compound. aH NMR: consistent. Mass spectrum (+ ESI), m / z 261 (M + H). Analysis calculated for C15H13C102 - 0.2 H20: C, 68.16, H, 5.11, N, 0.00. Found: C, 68.18, H, 5.15, N, 0.00.

Step 5 2-bromo-4- (2-chlorobenzoyl) -6-ethylphenol At room temperature, to a stirred solution containing 4- (2-chlorobenzoyl) -2-ethylphenol (15.62 g, 52.24 mmol), and pyridine (0.25 ml, 5.25 mmol), in 870 ml of CH2C12 bromine is added dropwise ( 5.5 ml, 62.29 mmoles). After 48 h, the reaction is washed with 10% aqueous Na 2 SO 4 (1 x 180 ml), H 2 O (2 x 550 ml), brine (500 ml), dried (Na 2 SO 4) and concentrated to give 16.50 g (95 g). %) of the title compound. H NMR: consistent.

Stage 4 2-bromo-4- (2-chlorobenzoyl) -6-ethylanisole At room temperature, to a stirred mixture containing 2-bromo-4- (2-chlorobenzoyl) -6-ethylphenol (14.56 g, 42.82 mmol), and K2C03 (8.90 g, 64.5 mmol), in 11.6 ml of N, N -DMF is added iodomethane (5.98 ml, 64.4 mmol). After 48 h, the reaction is suspended with 500 ml of H20 and extracted with hexane. The organic extracts are washed with H20 (2 x 100 ml), brine (1 x 100 ml), dried (Na2SO4) and concentrated. Purification on Biotage KP-Sil, eluting with a gradient in the 0, 2.5 and 5% EtOAc / hexane step provides 10.0 g (66%) of the title compound. XH NMR: consistent. Mass spectrum (El), m / z 552 (M +). Analysis calculated for C 16 H 14 BrC 10 2 - 0.2 H 20: C, 53.79, H, 4.06, N, 0.00. Found: C, 53.89, H, 3.91, N, 0.08.

Stage 5 3-bromo-5-ethyl-4-methoxybenzoic acid At room temperature, to a stirred mixture containing 2-bromo-4- (2-chlorobenzoyl) -6-ethylanisole (10.0 g, 28.2 mmol), and potassium t-butoxide (51.7 g, 0.285 mol), in 157 ml of ethylene glycol dimethyl ether are added 1.52 ml of H20. After 6 h, the reaction solids are collected by filtration and washed with ether (2x). The crude product is dissolved in 200 ml of H20, acidified with 2N HCl (pH < 2) and they shake for 7 h. The precipitate is collected by filtration, washed with H20 (2x) and dried to yield 5.37 g (73%) of the title compound. 'H NMR: consistent. Mass spectrum (El), m / z 258 (M +).

Step 6 (2-benzyl-4,5-dimethyl-furan-3-yl) - (3-bromo-5-ethyl-4-methoxy-phenyl) -metanone The title compound is prepared according to the procedure in example 1, step 4, using 3-bromo-5-ethyl-4-methoxybenzoic acid (4.95 g, 19.1 mmol), oxalyl chloride (1.8 ml, 20.7 mmol) , 2 drops of N, N-DMF, tin (IV) chloride (2.50 ml, 21.4 mmol), and 2-benzyl-2,3-dimethylfuran (4.30 g, 25.1 mmol) to provide 7.85 g (96%) of the composed of the title. "H NMR: consistent.

Step 7 2-bromo-4- (2,3-dimethyl-naph or [2,3-b] furan-4-yl) -6-ethyl-phenol The title compound is prepared according to the procedure in Example 1, step 5, using (2-benzyl-4,5-dimethyl-furan-3-yl) - (3-bromo-5-ethyl-4-methoxy) phenyl) -methanone (7.85 g, 18.4 mmol), and boron tribromide (13.2 ml, 0.159 mol). Purification on silica gel eluting with 2% EtOAc / hexane, followed by trituration with hexane provided 0. 85 g (12%) of the title compound as a white solid. 3H NMR (DMS0-d6) d 1.15 (t, 5H), 1.59 (s, 5H), 2.57 (s, 5H), 2.64-2.77 (, 2H), 7.09 (d, 1H), 7.51-7.55 (m, 2H), 7.4 (d of t, 1H), 7.52 (d, 1H), 7.95 (s, 1H), 7.99 (d, 1H), 9.17 (s, 1H), Mass spectrum (El), m / z 594 (M +). Analysis calculated for C22H19Br102: C, 66.85, H, 4.84, N, 0.00. Found: C, 67.07, H, 4.85, N, 0.05.

Step 8: 4- [2-Bromo-4- (2,5-dimethyl-naftor2.5-bl furan-4-yl) -6-ethyl-phenoxysulfonyl-2-hydroxy-benzoic acid The title compound is prepared according to the procedure in Example 1, step 9, using 2-bromo-4- (2,3-dimethyl-naphtho [2, 3-b] furan-4-yl) -6- ethyl-phenol (0.458 g, 1.16 mmol), and 4-chlorosulfonyl-2-hydroxybenzoic acid (0.994 g, 4.19 mmol). Purification on silica gel treated with 2% H3P04 / MeOH, eluting with a gradient in the 0 and 10% EtOAc / hexane step gives 0.165 g of the title compound as a white solid, mp 238-243 ° C. ? MM (DMSO-d6) d 1.15 (t, 5H), 1.56 (s, 5H), 2.59 (s, 5H), 2.65-2.70 (m, 2H), 7.37-7.60 (m, 7H), 8.01-8.08 ( m, 3H), Mass spectrum (-ESI), m / z 595 (MH). Analysis calculated for C29H23BrO, S: C, 58.50, H, 3.89, N, 0.00. Found: C, 58.91, H, 4.02, N, 0.05.

EXAMPLE 15 4- [4- (2,5-dimethyl-naphtho [2,5-bl furan-4-yl) -2,6-diethyl-phenoxysulfonyl-1-hydroxy-benzoic acid Stage 1 Tetraf luoroborate of 4-bromo-2,6-diethylbenzenediazoon At 0 ° C, a stirred solution of commercial 4-bromo-2,6-diethylaniline (10.0 g, 43.9 mol), in 219 ml of absolute ethanol are added 17.2 ml of 48% aqueous fluoboric acid followed by terbutyl nitrite (5.7 ml, 48.0 mmol). After 0.5 h, the reaction is poured into 877 ml of ice-cooled ether. The resulting precipitate is washed with cold ether and dried to yield 9.39 g (66%) of the title compound. 1 H NMR: consistent.

Stage 2 4-bromo-2,6-diethylanisole A stirred solution containing 4-bromo-2,6-diethylbenzenediazonium tetrafluoroborate (17.25 g, 52.77 mmol), and freshly ground anhydrous zinc chloride (7.2 g, 52.9 mmol) in 1061 methanol is refluxed for 6 h . The reaction is cooled to room temperature, suspended with 1.21 H20, saturated with solid sodium chloride and extracted with hexane. The combined organic extracts are washed with saturated aqueous NaHCO3 (1 x 100 ml), with H20 (1 x 100 ml), with brine (1 x 100 ml), dried (Na2SO4) and concentrated to provide 12.0 g (94%). ) of the title compound. "? RMN: consistent.

Stage 3 3.5-diethyl-4-methoxybenzoic At -78 ° C, to a stirred solution of 4-bromo-2,6-diethylanisole (12.0 g, 49.4 mmol), in 329 ml of THF, n-butyllithium (27.2 ml, 43.5 mmol) was added dropwise. After 3 h, the reaction is poured into crushed dry ice and allowed to warm to room temperature. The reaction mixture is diluted with EtOAc, concentrated, suspended in H20, acidified (pH 1), filtered and the collected solids washed with H20. The crude product is suspended in 15 ml of hexane, collected by filtration and dried to give 6. 76 g (66%) of the title compound. 1 H NMR: consistent. GO (KBr) consistent. Mass spectrum (El), m / z 208 (M +). Analysis calculated for C12H1603: C, 69.21, H, 7.74, N, 0.00.

Found: C, 69.28, H, 7.49, N, 0.07.

Step 4 (2-benzyl-4,5-dimethyl-furan-3-yl) - (5,5-diethyl-4-methoxy-phenyl) -methanone The title compound is prepared according to the procedure in Example 1, step 4, using 3,5-diethyl-4-methoxybenzoic acid (10.66 g, 51.3 mmol), oxalyl chloride (4.90 mL, 56.3 mmol), two drops of N, N-DMF, tin (IV) chloride (6.60 ml, 56.3 mmol), and 2-benzyl-4,5-dimethylfuran (11.4 g, 61.3 mmol), to provide 22.0 g of the title compound. JH NMR d 1.13 (t, 6H), 1.83 (s, 3H), 2.19 (s, 5H), 2.61 (c, 4H), 5.74 (S, 3H), 3.82 (s, 2H), 7.05 (d, 2H) ), 7.25-7.27 (m, 5H), 7.42 (s, 2H), Mass spectrum (El), m / z 576 (M +).

Step 5 4- (2,5-dimethyl-naphtho-2, 5-bl furan-4-yl) -2,6-diethylphenol The title compound is prepared according to the procedure in Example 1, step 5, using (2-benzyl-, 5-dimethyl-furan-3-yl) - (3,5-diethyl-4-methoxy-phenyl) -metanone (22.0 g, 58.4 mmol), and boron tribromide (36.8 ml, 0.389 moles). Purification on Biotage KP-Sil, eluting with a gradient of 0, 2 and 5% EtOAc / hexane steps followed by trituration with hexane gives 1.34 g (8%) of the title compound an off-white solid. SH NMR (DMSO-d6) d 1.15 (t, 6H), 1.59 (s, 3H), 2.37 (s, 3H), 2.59-2.72 (m, 4H), 6.89 (s, 2H), 7.29 (d of t, 1H), 7.59 (d of t, 1H), 7.56 (d, 1H), 7.90 (s, 1H), 7.96 (d, 1H), 8.29 (s, 1H), IR (KBr) 3540, 2960, 1475, 1180 and 1140 cm "1. Mass spectrum (El), m / z 344 (M +). Analysis calculated for C24H2402 - 0.3 HO: C, 82.59, H, 7.09, N, 0.00 Found: C, 82.55, H, 7.11, N, 0.05.

Step 6: 4- \ 4- (2,5-dimethyl-naphtho \ 2 .5-bl furan-4-yl) -2,6-diethyl-phenoxysulfonyl-2-hydroxy-benzoic acid At room temperature, to a stirred suspension containing 4- (2,5-dimethyl-naphtho [2, 5-b] furan-4-yl) -2,6-diethyl-phenol (0.517 g, 0.919 mmol), and 6 ml of 0.01M aqueous Borax in 9 ml of THF are added 0.597 ml of 2.5M NaOH. To the reaction is added dropwise a solution of 4-chlorosulfonyl-2-hydroxybenzoic acid (0.655 g, 2.76 mmol), in 12 ml of THF while maintaining the pH at 10 with the simultaneous addition of 2.5M NaOH. After 48 h, additional 4-chlorosulfonyl-2-hydroxybenzoic acid (0.440 g, 1.86 mmol) in 12 ml of THF is added dropwise while maintaining the pH at 10 with the simultaneous addition of 2.5 N NaOH and the reaction Stir for an additional 48 h. The reaction is suspended with IN HCl and extracted with ether. The combined ether extracts are washed with brine (lx), dried (Na2SO4) and concentrated. Purification on silica gel treated with 2% H3P04 / MeOH, eluting with 2% EtOAc / hexane followed by recrystallization (EtOAc / hexane) gives 95 mg (19%) of the title compound as an off-white solid, mp 22-227 ° C. JH NMR (DMSO-d6) d 1.09 (t, 6H), 1.55 (S, 3H), 2.40 (s, 3H), 2.55-2.60 (m, 4H), 7.21 (s, 2H), 7.57-7.59 ( m, 1H), 7.45-7.49 (m, 5H), 7.55 (d of t, 1H), 7.99 (s, 1H), 8.01-8.04 (m, 1H), 8.08 (d, 1H), Mass spectrum ( -ESI), m / z 543 (MH). Analysis calculated for C31H280, S • 0.5 H20: C, 67.25, H, 5.28, N, 0.00. Found: C, 67.14, H, 5.21, N, 0.08.

EXAMPLE 16 Terbutyl ico ester of 4 - \ 4 - (9-bromo-2,5-dimethyl-napht [2,5-b-thiophen-4-yl) -2,6-dimethyl-phenoxysulfonyl-2-hydroxy-benzoic acid At room temperature, to a stirred suspension of 4- [4- (9-bromo-2,5-dimethyl-naphtho [2, 5-b] thiophen-4-yl) -2,6-dimethyl-phenoxysulfonyl] - 2-hydroxy-benzoic acid (1055 g, 1689 mmol), 16.89 ml of EtOAc was added a solution of 2,2,2-trichloroacetimidate (0.7690 g, 5.379 mmol) in 3,379 ml of cyclohexane. After 24 h, the reaction is concentrated in vacuo, suspended in 10 ml of CH2C12, filtered through a pad of 2.5 cm (1") silica gel and eluted with 10% acetone / hexane. concentrate to provide 0.778 g (69%) of the title compound as a solid whitish, mp 168-172 ° C. ? NMR (DMS0-d6) d 1.57 (s, 12H), 2.15 (S, 6H), 2.45 (s, 5H), 7.18 (s, 2H), 7.45-7.55 (m, 4H), 7.65 (t, 1H) , 7.96 (d, 1H), 8.19 (d, 1H), 10.75 (s, 1H), IR (KBr) 5400, 2900, 1680, 1580 and 1140 cm "1. Mass spectrum (-ESI), m / z 665/667 (MH) Analysis calculated for C33H31Br06S2: C, 59.57, H, 4.68, N, 0.00 Found: C, 59.55, H, 4.44, N, 0.10.

EXAMPLE 17 2- (4-methoxy-benzoyl) oxy-4- [4- (9-bromo-2,5-dimethyl-naphtho [5-thylphene-4-yl] -2,6-dimethyl-phenoxysulfonyl-benzoic acid) Stage 1 2- (4-methoxy-benzoyl) oxy-4-f4- (9-bromo-2. -dimethyl-naphtor2,5-bl-thiophen-4-yl) -2,6-dimethyl-phenoxysulfonyl-benzoic acid terbutyl ester At room temperature, to a stirred solution containing 4- [4- (9-bromo-2,3-dimethyl-naphtho [2, 3-b] thiophen-4-yl) -2,6-dimethyl tert-butyl ester. -phenoxysulfonyl] -2-hydroxy-benzoic acid (0.402 g, 0.602 mol), and pyridine (0.292 g, 3.61 mmol), in 6.02 ml of CH2C12 a solution of p-anisoyl chloride (0.208 ml, 1.20 mmol) is added, in 1.20 ml of CH2C12. After 18 h, the reaction is suspended with 30 ml of H20 and extracted with ether. The combined ether extracts are washed with saturated aqueous NaHC03 (3x), with saturated aqueous CuS04 (5x), with - 115 - Brine (5x), dry (MgSO4) and concentrate. The crude product is purified on Biotage KP-Sil, eluting with 15% acetone / hexane to provide 0.554 g (75%) of the title compound. XH NMR (DMS0-d6) d 1.53 (s, 9H), 1.54 (s, 3H), 2.16 (s, 6H), .34 (S, 3H), 3.90 (s, 3H), 7.15-7.19 (m, 4H), 7.46-7.48 (m, 2H), 7.60-7.70 (m, 1H), 8.08-8.15 (m, 4H), 8.20 (d, 2H).

Step 2 2- (4-Methoxy-benzoyl) oxy-4- [4- (9-bromo-2 .5-dimethyl-naphtho2,5-b-thiophen-4-yl) -2,6-dimethyl-phenoxysulfonyl acid -benzoic At room temperature, to a stirred solution of 2- (4-methoxy-benzoyl) oxy-4- [4- (9-bromo-2, -dimethyl-naphtho [2,5-b] thiophen-4-tert-butyl ester. -yl) -2,6-dimethyl-phenoxysulfonyl] -benzoic acid (0.548 g, 0.454 mol), 5.48 ml of trifluoroacetic acid are added in 5.48 ml of CH2C12. After 1.5 h, the reaction is suspended with 50 ml of H20 and extracted with EtOAc. The combined organic extracts are dried (MgSO4) and concentrated. The crude product is purified on Biotage KP-Sil, treated with 2% H3P04 / MeOH, eluting with a step gradient of 15 and 25% EtOAc / hexane to provide 0.296 g (91%) of the title compound as an off-white solid. , mp 174-177 ° C. 'H NMR (DMSO-d6) d 1.55 (s, 5H), 2.14 (s, 6H), 2.52 (S, 3H), 3.87 (s, 5H), 7.12 (d, 2H), 7.18 (s, 2H) , 7.44-7.49 (m, 2H), 7.62-7.66 (m, 1H), 7.98 (d, 1H), 8.05-8.11 (m, 5H), 8. 19 (d, 1H), 8.26 (d, 1H), 15.5-14.0 (broad s, 1H), IR (KBr) 5400, 2900, 1740, 1560 and 1180 cm "1. Mass spectrum (-ESI), m / z 745/745 (MH) Analysis calculated for C37H29BrOßS2 - 0.5 H20: C, 58.89, H, 4.01, N, 0.00 Found: C, 58.85, H, 5.89, N, 0.05.

EXAMPLE 18 -4- [4- (2,5-Dimethyl-naphtho [2,5-bl-thiophen-4-yl] -2,6-diethyl-phenoxysulfonyl-1-4-methoxy-thiophene-5-carboxylic acid] Step 1 2- (benzyl-4,5-dimethylthiophen-5-yl) - (3,5-diethyl-4-methoxy-phenyl) -metanone The title compound is prepared according to the procedure in Example 1, step 4, using 3,5-diethyl-4-methoxybenzoic acid (9.45 g, 45.5 mmol), oxalyl chloride (4.35 mL, 50.0 mmol) , two drops of N, N-DMF, tin (IV) chloride (5.85 ml, 50.0 mmol), and 2-benzyl-4,5-dimethylthiophene (11.0 g, 54.6 mmol), to give 17.67 g (99%) of the compound. ? NMR (DMSO-d6) d 1.13 (t, 6H), 1.83 (s, 3H), 2.27 (s, 5H), 2.64 (s, 2H), 7.04 (c, 4H), 5.75 (s, 5H), 5.85 (s, 2H), (d, 2H), 7.12-7.24 (, 3H), 7.43 (s, 2H).

Step 2 4- (2,5-dimethyl-naftor2,5-b1 thiophen-4-yl) -2,6-diethyl-phenol The title compound is prepared according to the procedure in Example 1, step 5, using 2- (benzyl-4,5-dimethylthiophen-5-yl) - (5,5-diethyl-4-methoxy-phenyl) - methanone (17.67 g, 45.0 mmol), and boron tribromide (12.8 ml, 0.155 mol) to provide 16.65 g of the title compound. 'H NMR (DMSO-de) d 1.15 (t, 6H), 1.61 (s, 5H), 2.40 (s, 5H), 2.59-2.75 (m, 4H), 6.86 (s, 2H), 7.52 (ddd, 1H), 7.42 (ddd, 1H), 7.47 (d, 1H), 7.93 (d, 1H), 8.31 (s, 1H), 8.41 (s, 1H), Mass spectrum (+ ESI), m / z 560 (M +).

Stage 3 5-f 4 - (2,3-dimethyl-naphtho, 3-bl thiophen-4-yl) -2,6-diethyl-phenoxysulfonin-4-methoxy-thiophene-3-carboxylic acid methyl ester The title compound is prepared according to the procedure in Example 10, Step 1, using 4- (2,5-dimethyl-naphtho [2, 5-b] thiophen-4-yl) -2,6-diethyl- phenol (0.604 g, 1.67 mmol), 60% sodium hydride / mineral oil (0.0669 g, 1.67 mmol), and 5-methoxy-4- (methoxycarbonyl) thiophene-2-sulfonyl chloride (0.499 g, 1.84 mmol), to provide 0.629 g (65%) of the title compound. ? NMR (DMS0-d6) d 1.10 (t, 6H), 1.59 (S, 3H), 2.42 (s, 3H), 2.57-2.68 (m, 4H), 5.86 (s, 5H), 4. 02 (s, 5H), 7.20 (s, 2H), 7.38-7.50 (m, 3H), 7.98 (d, 1H), 8.50 (S, 1H), 8.81 (s, 1H).

Step 4: 5- f4- (2,5-dimethyl-naphtho [2,3-bl thiophen-4-yl) -2,6-diethyl-phenoxysulfonyl-4-methoxy-thiophen-3-carboxylic acid The title compound is prepared according to the procedure in Example 10, step 2, using 5- [4- (2,5-dimethyl-naphtho [2, 5-b] thiophen-4-yl) methyl ester. -2, 6-diethyl-phenoxysulfonyl] -4-methoxy-thiophene-3-carboxylic acid (0.608 g, 1.02 mol), and 5.11 ml of INK KOH. Purification over 2% H3P04 / MeOH, treated with Biotage KP-Sil, eluting with a stepwise gradient of 25, 40 and 60% EtOAc / hexane to provide 0.390 g (66%) of the title compound as a white solid , pf > 230 ° C. ? NMR (DMSO-d6) d 1.09 (t, 6H), 1.58 (s, 3H), 2.41 (s, 3H), 2.57-2.69 (m, 4H), 4.01 (s, 3H), 7.18 (S, 2H) , 7.35-7.41 (m, 2H), 7.44-7.48 (m, 1H), 7.96 (d, 1H), 8.49 (S, 1H), 8 74 (s, 1H), 15.59 (s, 1H), IR ( KBr) 2950, 1700, 1540, 1560 and 860 cm 1. Mass spectrum (-ESI), m / z 579 (MH). Analysis calculated for C30H2806S3: C, 62.05, H, 4.86, N, 0.00. Found: C, 62.15, H, 5.09, N, 0.06.

EXAMPLE 19 2-Cyclopentyl-4- (2,5-dimethyl-naphthyl) -2,5-b-thiophen-4-yl) -phenyl ester of 5-pyridin-2-yl-thiophene-sulfonic acid The title compound is prepared according to the procedure in Example 10, step 1, using 4- (2,3-dimethyl-naphtho [2,5-b] iofen-4-yl) -2-cyclopentyl-phenol ( 0.500 g, 0.805 mmol), 60% sodium hydride / mineral oil (0.032 g, 0.805 mmol), and commercial 5- (pyrid-2-yl) -thiophen-2-sulfonyl chloride (0.243 g, 0.935 mmol). Purification on Biotage KP-Sil, eluting with a step gradient of 5 and 10% EtOAc / petroleum ether gives 0.10 g (21%) of the title compound as a white solid, mp 141-142 ° C. XH NMR (DMSO-d6) d 1.29-1.58 (m, 2H), 1.46-1.68 (m, 8H), 1.82-1.85 (m, 1H), 2.55 (s, 5H), 3.16 (quintet, 1H), 7.25 -7.34 (m, 4H), 7.39 (d, 1H), 7.42-7.46 (m, 2H), 7.92-7.97 (m, 5H), 8.02 (d, 1H), 8.15 (d, 1H), 8.48 (s) , 1H), 8.62 (d, 1H), Mass spectrum (-ESI), m / z 596 (MH). Analysis calculated for C34H29N03S3 - 0.4 H20: C, 67.72, H, 4.98, N, 2.32. Found: C, 67.79, H, 2.32, N, 2.55.

EXAMPLE 2Q 4-Benzoyloxy-5- [4- (2, -dimethyl-naphtho [2, 5-bl-thiophen-4-yl] -2,6-diethyl-phenoxysulfoniyl-thiophene-5-carboxylic acid Step 1: Acid 5-4- (2,3-dimethyl-naphthro-2,3-bl thiophen-4-yl) -2,6-diethyl-phenoxysulfonyl-thiophene-3-carboxylic acid At -78 ° C, to a stirred solution of 5- [4- (2,5-dimethyl-naphtho [2, 5-b] thiophen-4-yl) -2,6-diethyl-phenoxysulfonyl-thiophen-5 acid. -carboxylic (0.374 g, 0.644 immoles), 3.74 ml of boron tribromide 1M / CH2C12 are added in 3.74 ml of CH2C12. After the addition is complete, the dry ice / acetone bath is replaced with an ice bath with water and the reaction is stirred for 1.5 h. The reaction is carefully suspended in crushed ice, diluted with H20 and extracted with EtOAc. The combined organic extracts are dried (MgSO4) and concentrated. The crude product is purified on Biotage KP-Sil, eluting with 40% EtOAc / hexane to provide 0.300 g (82%) of the title compound as an off-white solid. ? NMR (DMSO-d6) d 1.09 (t, 6H), 1.59 (s, 3H), 2.41 (S, 3H), 2.62-2.75 (m, 4H), 7.16 (s, 2H), 7.58-7.47 (m, 3H), 7.98 (d, 1H), 8.49 (s, 1H), 8.68 (s, 1H).

Step 2: 4-Benzoyloxy-5- [4- (2,3-dimethyl-naphtho [2,5-bl-thiophen-4-yl] -2,6-diethyl-phenoxysulfonyl-thiophene-3-carboxylic acid] The title compound is prepared according to the procedure in Example 5, using the 4- Benzoyloxy-5- [4- (2,3-dimethyl-naphtho [2, 3-b] thiophen-4-yl) -2,6-diethyl-phenoxysulfonyl-4-hydroxy-thiophene-5-carboxylic acid (0.288 g, 0.508 mmoles), 5.44 g of benzoic anhydride and magnesium iodide (0.141 g, 0.508 mol). Purification on Biotage KP-Sil, treated with 2% H3P04 / MeOH eluting with 25% EtOAc / hexane gives 0.199 g (58%) of the title compound as a white solid, mp 155-145 ° C. 1 H NMR (DMSO-d 6) d 1.07 (t, 6H), 1.54 (s, 5H), 2.41 (s, 3H), 2.58-2.70 (m, 4H), 7.22 (s, 2H), 7.35-7.37 (m , 2H), 7.44-7.48 (m, 1H), 7.64 (t, 2H), 7.80 (t, 1H), 7.98 (d, 1H), 8.12 (d, 2H), 8.50 (s, 1H), 8.95- 8.94 (m, 1H), 15.4-15.7 (broad S, 1H), IR (KBr) 5400, 2950, 1760, 1700 and 1240 cm "1. Mass spectrum (-ESI), m / z 669 (MH). Analysis calculated for C36H30O7S3: C, 64.46, H, 4.51, N, 0.00 Found: C, 64.19, H, 4.54, N, 0.17.

EXAMPLE 21 Acid 5- T2-cyclopentyl-4- (2,3-dimethyl-naphtho [2,3-bl thiophen-4-yl) • phenoxysulfonyl-benzoic acid The title compound is prepared according to the procedure in Example 1, step 9, using 4- (2,5-dimethyl-naphtho [2, 3-b] thiophen-4-yl) -2-cyclopentyl-phenol ( 0.300 g, 0. 805 mmoles), and commercial 3-chlorosulfonylbenzoic acid (0.600 g, 2.71 mol). Purification in Biotage KP-Sil, treated with H3P04 2% / MeOH eluting with 20% EtOAc / hexane followed by trituration with hexane gives 0.154 g (20%) of the title compound as a white solid, mp 120-128 ° C. 'H NMR (DMSO-d6) d 1.25-1.56 (m, 2H), 1.42-1.52 (m, 6H), 1.55-1.69 (m, 5H), 2.42 (s, 3H), 2.96 (quintet, 1H), 7.23-7.29 (m, 3H), 7.33 (d, 1H), 7.39 (ddd, 1H), 7.47 (ddd, 1H), 7.90 (t, 1H), 7.97 (d, 1H), 8.23 (dd, 1H) , 8.27-8.29 (m, 1H), 8.57-8.59 (dt, 1H), 8.50 (s, 1H), 15.6-15.9 (s broad, 1H), IR (KBr) 5400, 2950, 1700, 1580 and 1190 cm "1. Mass spectrum (-ESI), m / z 555 (MH) Analysis calculated for C32H2ß05S2 - 0.65 H20: C, 67.62, H, 5.20, N, 0.00 Found: C, 67.60, H, 4.90, N , 0.09.

EXAMPLE 22 2- (2-Sulfonyl-pyrimidin-4-yl) thiophene-2-sulfonic acid 2-cyclopentyl-4- (2,3-dimethyl-naphtho [2, 3-bl-thiophen-4-yl) -phenyl ester) The title compound is prepared according to the procedure in Example 10, step 1, using 4- (2,3-dimethyl-naphtho [2, 3-b] thiophen-4-yl) -2-cyclopentyl-phenol ( 0.300 g, 0.805 mmol), 60% sodium hydride / mineral oil (0.032 g, 0.805 mmol), and commercial 5- (2- (methylthio) pyrimidin-4-yl] thiophene-2-sulfonyl chloride (0.272 g, 0.886 mmoles). Purification on Biotage KP-Sil, eluting with 25% EtOAc / ether Petroleum provides 0.299 g (58%) of the title compound as a yellow solid, mp 100-110 ° C. ? NMR (DMS0-d6) d 1.32-1.37 (m, 2H), 1.45-1.65 (m, 8H), 1.84-1.90 (m, 1H), 2.37 (s, 5H), 2.55 (s, 5H), 5.15 ( quintet, 1H), 7.25-7.58 (m, 5H), 7.4 (ddd, 1H), 7.90 (d, 1H), 7.96 (d, 1H), 8.08 (d, 1H), 8.27 (d, 1H), 8.48 (s, 1H), 8.77 (d, 1H), Mass spectrum (+ APCI), m / z 645 (M + H). C34H30N2O3S4: C, 65.52, H, 4.70, N, 4.56. Found: C, 65.18, H, 4.46, N, 4.19.

EXAMPLE 23 4-Benzoyloxy-4- [4- (2,5-dimethyl-naphtho2.5-bl thiophen-4-yl) -2 .6-dimethyl-phenoxysulfonyl-benzoic acid Step 1: 4- [4- (2,3-dimethyl-naphtho2.3-bl thiophen-4-yl) -2,6-dimethyl-phenoxysulfonyl-2-hydroxy-benzoic acid The title compound is prepared according to the procedure in Example 1, step 9, using 4- (2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -2,6-diethyl- phenol (2.052 g, 6.171 mmol), and 4-chlorosulfonyl-2-hydroxybenzoic acid (5.840 g, 4.68 mmol). Purification on Biotage KP-Sil, treated with 2% H3P04 / MeOH eluting with a step gradient of 15 and 25% EtOAc / hexane provides 2.05 g (62%) of the title compound. ? NMR (DMSO-dβ) d 1.60 (s, 3H), 2.16 (s, 6H), 2.42 (s, 3H), 7.17 (S, 2H), 7.38-7.40 (m, 2H), 7.47-7.56 (m, 3H), 7.98 (d, 1H), 8.09 (d, 1H), 8.50 (s, 1H).

Stage 2 4- [4- (2,5-Dimethyl-naphtho [2,5-bl thiophen-4-yl) -2,6-dimethyl-phenoxysulfonyl-2-hydroxy-benzoic acid terbutilic ester The title compound is prepared according to the procedure in example 16, using 4- [4- (2,5-dimethyl-naphtho [2,5-b] thiophen-4-yl) -2,6-dimethyl -phenoxysulfonyl] -2-hydroxy-benzoic acid (0.100 g, 0.188 mmol), and t-butyl 2,2,2-trichloroacetimidate (0.0822 g, 0.375 mmol), to provide 86 mg (78%) of the title compound. 3H NMR (DMS0-d6) d 1.58 (s, 9H), 1.60 (s, 3H), 2.17 (s, 6H), 2.42 (s, 3H), 7.17 (s, 2H), 7.38-7.40 (m, 2H) ), 7.46-4.47 (m, 1H), 7.54-7.57 (m, H), 7.98 (d, 2H), 8.50 (S, 1H), 11.05 (s, 1H).

Step 5 2-Benzoyloxy-4- [4- (2,5-dimethyl-naphtho2,3-b1thiophen-4-yl) -2,6-dimethyl-phenoxysuiphenyl-benzoic acid terbutilic ester The title compound is prepared according to the procedure in Example 17, Step 1, using the 4- [4- (2,3-dimethyl-naphtho [2, 5-b] thiophene-4-terbutilic ester. -yl) -2,6-dimethyl-phenoxysulfonyl] -2-hydroxy-benzoic acid (0.072 g, 0. 131 mmol), pyridine (65.4 μl, 0.784 mmol), and benzoyl chloride (50.5 μl, 0.262 mmol), to provide a quantitative yield of the title compound. H NMR (DMS0-d6) d 1.55 (s, 9H), 1.57 (s, 5H), 2.17 (s, 6H), 2.51 (s, 5H), 7.17 (s, 2H), 7.56-7.48 (m 5H) , 7.62-7.68 (m, 3H), 7.78-7.82 (m, 1H), 7.96 (t, 1H), 8.10-8.24 (m, 4H), 8.49 (s, 1H).

Step 4: 2-benzoyloxy-4- [4- (2,3-dimethyl-naphtho [2,5-bromo-4-yl] -2,6-dimethyl-phenoxysulfonyl-benzoic acid] The title compound is prepared according to the procedure in example 17, step 2, using Step 2-benzoyloxy-4- [4- (2, 5-dimethyl-naphtho [2, 5-b] terbutilic ester thiophen-4-yl) -2,6-dimethyl-phenoxysulfonyl] -benzoic acid to give 0.158 g of the title compound as a white solid, mp 185-185 ° C. XH NMR (DMSO-d6) d 1.55 (s, 5H), 2.16 (S, 6H), 2.50 (s, 3H), 7.15 (s, 2H), 7.34-7.40 (m, 2H), 7.45 (ddd, 1H ), 7.63 (t, 2H), 7.76 (ddd, 1H), 7.96 (d, 1H), 8.05 (d, 1H), 8.10-8.14 (m, 3H), 8.28 (d, 1H), 8.48 (s, 1H), 13.7-13.9 (broad s, 1H), Mass spectrum (+ APCI), m / z 637 (M + H). Analysis calculated for C36H2ß0, S2 - 0.4 H20: C, 67.15, H, 4.51, N, 0.00. Found: C, 67.23, H, 4.40, N, 0.10.

EXAMPLE 24 2- (4-Chloro-benzoyl) -oxi-4- [4- (2,3-dimethyl-naphtho [2,3-bl thiophen-4-yl) -2,6-dimethyl-phenoxysulfonyl-benzoic acid Stage 1 2- (4-Chloro-benzoyl) -oxy- (2-4-dimethyl-naphthyl-2-phenyl-4-yl) -2,6-dimethyl-phenoxysulfonyl-benzoic acid terbutyl ester The title compound is prepared according to the procedure in example 17, step 1, using 4- [4- (2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) tert-butyl ester) -2, 6-dimethyl-phenoxysulfonyl] -2-hydroxy-benzoic acid (0.362 g, 0.615 mmol), pyridine (0.298 mL, 3.69 mmol), and 4-chlorobenzoyl chloride (0.156 mL, 1.23 mmol), to provide the compound of the title. lH NMR (DMSO-d6) d 1.35 (s, 9H), 1.57 (s, 3H), 2.17 (S, 6H), 2.55 (s, 5H), 7.17 (s, 2H), 7.35-7.40 (m, 2H) ), 7.43-7.48 (m, 1H), 7.72 (d, 2H), 7.98 (d, 1H), 8.13-8.24 (m, 5H), 8.50 (s, 1H).

Step 2 2- (4-Chloro-benzoyl) -oxy- [4- (2,5-dimethyl-naphtho-2,5-bl-thiophen-4-yl) -2,6-dimethyl-phenoxysulfonyl-benzoic acid The title compound is prepared according to the procedure in example 17, step 2, using 2- (4-chloro-benzoyl) -oxy- [4- (2,5-dimethyl-naphtho [2], terbutyl ester. 5-b] thiophen-4-yl) -2,6-dime-yl-phenoxysulfonyl] -benzoic acid to give 0.282 g (68%, 2 steps) of the title compound as a yellow solid, mp 186-195 ° C. XH NMR (DMSO-d6) d 1.56 (S, 3H), 2.15 (s, 6H), 2.32 (s, 5H), 7.15 (s, 2H), 7.54-7.57 (m, 2H), 7.44 (ddd, 1H ), 7.68 (d, 2H), 7.96 (d, 1H), 8.08-8.15 (m, 4H), 8.29 (d, 1H), 8.48 (s, 1H), 15.6-14.0 (s broad, 1H), IR (KBr) 3400, 2900, 1740, 1210 and 840 cm "1. Mass spectrum (+ APCI), m / z 671 (M + H) Analysis calculated for C36H27C107S2 - 0.7 H20: C, 63.25, H, 4.19, N, 0.00 Found: C, 63.25, H, 5.89, N, 0.09.

EXAMPLE 25 2-carboxy-5- [4- (2,5-dimethyl-naphtho [2,3-bl thiophen-4-yl] -2,6-dimethyl-phenoxysulfonyl-phenyl] nicotinic acid ester Stage 1 2- (Pyrid-3-ylcarbonyl) oxy-4- (4,5-dimethyl-napht [2,5-bl thofen-4-yl) -2,6-dimethyl-f-enoxysulfonyl-benzoic acid terbutyl ester A stirred solution containing the 4- [4- (2,5-dimethyl-naphtho [2, 5-b] thiophen-4-yl) -2,6-dimethyl-phenoxysulfonyl] -2-hydroxy-tert-butyl ester. benzoic acid (0.508 g, 0.863 mmol), nicotinic acid (0.108 g, 0.863 mmol), 2-chloro-l-methylpyridinium iodide (0.272 g, 1.04 mmol), and triethylamine (0.288 ml, 2.07 mmol), in 8.63 ml of CH2C12 is heated to 75 ° C in a sealed tube for 3 days. The reaction is cooled to room temperature and concentrated. The crude product is purified on Biotage KP-Sil, eluting with a step gradient of 10 and 15% acetone / hexane to provide 0.446 g (74%) of the title compound. J H NMR (DMSO-d 6) 6 1.35 (s, 9 H), 1.58 (α, 3 H), 2.18 (s, 6 H), 2.55 (s, 5 H), 7.18 (s, 2 H), 7.56-7.46 (m, 5 H) ), 7.68-7.72 (m, 1H), 7.98 (d, 1H), 8.15 (dd, 1H), 8.22-8.26 (m, 2H), 8.50-8.55 (m, 2H), 8.95 (dd, 1H), 9.50 (d, 1H),).

Stage 2 Ester 2-carboxy-5- T4- (2,3-dimethyl-naphtho-2,5-bl-thiophen-4-yl) -2,6-dimethyl-f-enoxysulfonyl-phenyl of nicotinic acid The title compound is prepared according to the procedure in example 17, step 2, using the 2- (pyrid-5-ylcarbonyl) oxy-4- [4- (2,3-dimethyl-naphtho [2- (3-dimethyl-naphtho)] tertbutyl ester. 2,3-b] thiophen-4-yl) -2,6-dimethyl-phenoxysulfonyl] -benzoic acid (0.456 g, 0.628 mmol). Purification on Biotage KP-Sil, eluting with a gradient in steps of 900: 66: 54, 850: 100: 50 and 800: 155: 67 (EtOAc: EtOH: H20) gives 59 mg (15%) of the title compound as a yellow solid, mp 161-171-C. ? NMR (DMS0-dβ) d 1.57 (s, 3H), 2.16 (s, 6H), 2.35 (s, 3H), 7.16 (S, 2H), 7.35-7.37 (m, 2H), 7.44 (ddd, 1H) , 7.67 (dd, 1H), 7.96 (d, 1H), 8.12-8.17 (m 2H), 8.50 (d, 1H), 8.46-8.48 (m, 2H), 8.92 (s, 1H), 9.26 (s, 1H), 15.7-14.1 (broad s, 1H), Mass spectrum (-APCI), m / z 656 (MH). Analysis calculated for C35H27NO, S2-1.3 H20: C, 63.58, H, 4.51, N, 2.12. Found: C, 63.59, H, 4.35, N, 1.89.

EXAMPLE 26 Ester 2-carboxy-5- [4- (9-bromo-2,3-dimethyl-naphtho [2,3-bl-thiofen-4-yl] -2,6-dimethyl-phenoxysulfonyl-phenyl] of nicotinic acid Stage 1 2- (Pyrid-3-ylcarbonyl) oxy-4- [4- (9-bromo-2,5-dimethyl-naphtho [2-, 3-thiophen-4-yl] -2.6- dimethyl-f-enoxysulfonyl-benzoic acid The title compound is prepared according to the procedure in Example 25, Step 1, using the 4- [4- (9-bromo-2,5-dimethyl-naphtho [2,5-b] thiophene) terbutyl ester. -4-yl) -2,6-dimethyl-phenoxysulfonyl] -2-hydroxy-benzoic acid (0.500 g, 0.749 mmol), nicotinic acid (0.092 g, 0.749 mmol), 2-chloro-l-methylpyridinium iodide (0.250 g) , 0.899 mmole), and triethylamine (0.251 ml, 1.80 mmole). Purification on Biotage KP-Sil, eluting with 20% EtOAc / hexane to provide 0.460 g (80%) of the title compound. JH NMR (DMS0-ds) d 1.34 (s, 9H), 1.55 (s, 3H), 2.16 (s, 6H), 2.56 (s, 3H), 7.19 (s, 2H), 7.45-7.46 (m, 2H), 7.61-7.71 (m, 2H), 8. 12-8.25 (m, 4H), 8.50 (ddd, 1H), 8.94 (d, 1H), 9.29 (s, 1H).

Stage 2 2-Carboxy-5- [4- (9-bromo-2,3-dimethyl-naphthof-2, 5-bl-thiophen-4-yl) -2,6-dimethyl-phenoxysulfonyl-phenyl ester of nicotinic acid The title compound is prepared according to the procedure in example 17, step 2, using the 2- (pyrid-5-ylcarbonyl) oxy-4- [4- (9-bromo-2,5-) terbutyl ester. dimethyl-naphtho [2,5-b] thiophen-4-yl) -2,6-dimethyl-phenoxysulfonyl] -benzoic acid (0.391 g, 0.506 mmol). Purification by trituration with ether to provide 0.215 g (48%) of the title compound as a yellow solid, mp 235-258 ° C; ? NMR (DMS0-d6) d 1.55 (s, 5H), 2.16 (s, 6H), 2.55 (s, 5H), 7.19 (S, 2H), 7.45-7.47 (m, 2H), 7.61-7.68 (m, 2H), 8.11 (m, 3H), 8.50 (d, 1H), 8.45 (ddd, 1H) ), 8.91 (dd, 1H), 9.24 (d, 1H), 15.9 (broad s, 1H), Mass spectrum (+ APCI), m / z 714 (M + H). Analysis calculated for C35H26BrN07S2: C, 58.66, H, 5.66, N, 1.95. Found: C, 58.50, H, 3.80, N, 1.77.

EXAMPLE 27 4- [4- (9-Bromo-2,3-dimethyl-naphtho [2,3-b1 thiophen-4-yl) -2,6-dimethyl-phenoxysulfonyl-1-phenylacetyloxy-benzoic acid Step 1: 4- [4- (9-Bromo-2,5-dimethyl-naphtho [2, 3-bl thiophen-4-yl] -2,6-dimethyl-phenoxysulfonyl-1-phenylacetoxy-benzoic acid terbutyl ester The title compound is prepared according to the procedure in example 17, step 1, using the 4- [4- (9-bromo-2,5-dimethyl-naphtho [2,5-b] thiophene) terbutyl ester. -4-yl) -2,6-dimethyl-phenoxysulfonyl] -2-hydroxy-benzoic acid (0.500 g, 0.691 mmol), pyridine (0.555 ml, 4.15 mmol), and phenylacetyl hydrochloride (0.183 ml, 1.38 mmol). Purification by Biotage KP-Sil, eluting with 3% EtOAc / petroleum ether to provide 0.272 g (51%) of the title compound. "H NMR (DMS0-d6) d 1.51 (s, 9H), 1.56 (s, 5H), 2.14 (s, 6H), 2.43 (s, 3H), 4.04 (s, 2H), 7.18 (s, 2H) , 7.27-7.37 (m, 5H), 7.46-7.49 (m, 2H), 7.66 (ddd, 1H), 8.01-8.07 (m, 2H), 8.13-8.21 (m, 2H).

Step 2: 4- [4- (9-Bromo-2,3-dimethyl-naphtho [2,3-bl thiophen-4-yl) -2,6-dimethyl-phenoxysulfonyl-2-phenylacetoxybenzoic acid The title compound is prepared according to the procedure in example 17, step 2, using 4- [4- (9-bromo-2,3-dimethyl-naphtho [2, 3-b] thiophene) terbutyl ester. 4-yl) -2,6-dimethyl-phenoxysulfonyl] -2-phenoxysulfonyl] -phenylacetoxy-benzoic acid (0.272 g, 0.352 mmol). Purification in H3P04 2% / MeOH treated with silica gel eluting with 20% acetone / hexane to provide 0.207 g (81%) of the title compound as a yellow solid, mp 255-258 ° C. "H NMR (DMSO-d6) d 1.56 (s, 5H), 2.15 (s, 6H), 2.45 (s, 5H), 4.00 (s, 2H), 7.17 (s, 2H), 7.25-7.34 (m, 5H), 7.44-7.51 (m, 2H), 7.65 (ddd, 1H), 7.96 (d, 1H), 8.04 (dd, 1H), 8.19 (d, 1H), 8.23 (d, 1H), 13.8-14.1 (s broad, 1H), Mass spectrum (-ESI), m / z 727 (MH) Analysis calculated for C37H29BrN07S2: C, 60.91, H, 4.01, N, 0.00 Found: C, 60.61, H, 4.19, N, -0.36. - 151 - EXAMPLE 28 2 - (4-Cyano-benzoyl) oxy -4- [4- (9-bromo-2,5-dimethyl-naphtho-2, 5-bl thiophen-4-yl) -2,6-dimethyl-phenoxysulfonyl-benzoic acid Step 1 2- (4-Cyano-benzoyl) oxy-4- [4- (9-bromo-2,3-dimethyl-naphtho [2, 3-bl thiophen-4-yl) -2,6 acid terbutyl ester -dimethyl-phenoxysulfonyl-benzoic acid The title compound is prepared according to the procedure in Example 17, step 1, using the 4- [4- (9-bromo-2,3-dimethyl-naph or [2, 5-b] terbutyl ester) thiophen-4-yl) -2,6-dimethyl-phenoxysulfonyl] -2-hydroxy-benzoic acid (0.400 g, 0.599 mmol), pyridine (0.291 mL, 3.59 mmol), and 4-cyanobenzoyl chloride (0.199 g, 1.20 mmol) ). Purification by Biotage KP-Sil, eluting with a step gradient of 7 and 15% EtOAc / petroleum ether to provide 0.324 g (68%) of the title compound as a yellow solid. "H NMR (DMSO-d6) d 1.34 (s, 9H), 1.54 (s, 3H), 2.16 (s, 6H), 2.56 (s, 5H), 7.19 (s, 2H), 7.45-7.46 (m, 2H), 7.62-7.66 (m, 1H), 8.11-8.25 (m, 6H), 8.50 (d, 2H). - 152 - Step 2 - 2- (4-Cyano-benzoyl) oxy-4- [4- (9-bromo-2,5-dimethyl-naphtho-2, 2-biphenyl-4-yl) -2,6-dimethyl-phenoxysulfonyl-benzoic acid The title compound is prepared according to the procedure in example 17, step 2, using the 2- (4-cyano-benzoyl) oxy-4- [4- (9-bromo-2, 3-tert-butyl ester. dimethyl-naphtho [2, 3-b] thiophen-4-yl) -2,6-dimethyl-phenoxysulfonyl] -benzoic acid (0.440 g, 0.551 mmol). Purification in 2% H3P04 / MeOH treated with silica gel eluting with 25% EtOAc / hexane to provide 0.188 g (46%) of the title compound as a yellow solid. 'H NMR (DMS0-d6) d 1.54 (s, 3H), 2.16 (s, 6H), 2.56 (s, 5H), 7.19 (s, 2H), 7.45-7.46 (m, 2H), 7.62-7.66 ( m, 1H), 8.08-8.14 (m, 5H), 8.17-8.20 (m, 2H), 8.25-8.51 (m, 5H), 15.7-14.0 (broad s, 1H), Mass spectrum (-APCI), m / z 758 (MH). Analysis calculated for C37H26BrN07S2: C, 60.00, H, 5.54, N, 1.89. Found: C, 60.16, H, 5.58, N, 1.85.

EXAMPLE 29 2 - (methoxy-benzoyl) oxy-4 - [4 - (9-bromo-2,5-dimethyl-naphtho [2, 5-b-thiophen-4-yl] -2,6-dimethyl-f-enoxysulfonyl ester] -benzoic - 135 -Estapa 1 2- (4-Methoxy-benzoyl) oxy-4 .4- (9-bromo-2. -dimethyl-naphtho [2,5-bl thiophen-4-yl] -2 .6 terbutyl ester -dimethyl-phenoxysulfonyl-benzoic acid The title compound is prepared according to the procedure in example 17, step 1, using 4- [4- (9-bromo-2,5-dimethyl-naphtho [2, 5-b] thiophen-4-yl] ) -2, 6 -dimethyl-phenoxysulfonyl] -2-hydroxy-benzoic acid (0.500 g, 0.691 mmol), pyridine (0.535 ml, 4.15 mmol), and m-anisoyl hydrochloride (0.194 ml, 1.38 mmol). Purification by Biotage KP-Sil, eluting with a step gradient of 5 and 7% EtOAc / petroleum ether to provide 0.504 g (68%) of the title compound as a white solid. X H NMR (DMSO-d 6) d 1.35 (s, 9 H), 1.55 (s, 3 H), 2.15 (s, 6 H), 2.35 (s, 5 H), 5.82 (s, 5 H), 7.19 (s, 2 H), 7.36 (dd, 1H), 7.45-7.46 (m 2H), 7.55 (t, 1H), 7.61-7.65 (m 2H), 7.75 (d, 1H), 8.08 (d, 1H), 8.13 (dd, 1H) , 8.18-8.22 (m, 2H), Mass spectrum (+ APCI), m / z 818 (M + H).

Step 2 2- (3-Methoxy-benzoyl) oxy-4-f4- (9-bromo-2,5-dimethyl-naphtho [2,5-bthiophen-4-yl) -2,6-dimethyl-phenoxysulfonyl-benzoic acid The title compound is prepared according to the procedure in example 17, step 2, using 2- (4-methoxy-benzoyl) oxy-4- [4- (9-bromo-) terbutyl ester. - 154 -2,5-dimethyl-naphtho [2, 5-b] thiophen-4-yl) -2,6-dimethyl-f-enoxysulfonyl] -benzoic acid (0.470 g, 0.595 mmol). Purification in H3P042% / MeOH treated with silica gel eluting with 20% EtOAc / hexane to provide 0.443 g (98%) of the title compound as a yellow solid, mp 126-150 ° C. JH NMR (DMSO-d6) d 1.53 (s, 3H), 2.14 (s, 6H), 2.52 (s, 5H), 5.81 (S, 5H), 7.18 (s, 2H), 7.34 (dd, 1H), 7.44-7.46 (m, 2H), 7.52 (m, 1H), 7.57-7.58 (m, 1H), 7.61-7.66 (m, 1H), 7.70 (d, 1H), 8.03 (d, 1H), 8.11 ( dd, 1H), 8.18 (d, 1H), 8.28 (d, 1H), 13.7-13.9 (broad s, 1H), Mass spectrum (-APCI), m / z 743 (MH). Analysis calculated for C37H29BrN08S2: C, 59.60, H, 5.92, N, 0.00. Found: C, 59.42, H, 5.97, N, -0.02.

EXAMPLE 30 Ester 5- [4- (9-bromo-2. -dimethyl-naf to [2,5-bl thiophen-4-yl) -2,6-dimethyl-f-enoxisulfonyl-2-carboxy-phenyl of nicotinic acid Stage 1 2- (Pyrid-4-ylcarbonyl) oxy-4- [4- (9-bromo-2,3-dimethyl-naphth [2-, 3-thiophen-4-yl) -2,6-dimethyl- tert-butyl ester phenoxysulfonylbenzoic acid The title compound is prepared according to the procedure in example 25, step 1, using the ester tjjjsa 4- [4- (9-bromo-2,3-dimethyl-naphtho [2, 3-b] thiophen-4-yl) -2,6-dimethyl-phenoxysulfonyl] -2-hydroxy-benzoic acid butyl ester (0.500) g, 0.691 mmol), isonicotinic acid (0.0851 g, 0.691 mmol), 2-chloro-1-methylpyridinium iodide (0.212 g, 0.829 mmol), and triethylamine (0.327 mL, 2.55 mmol). Purification on Biotage KP-Sil, eluting with 25% EtOAc / hexane to provide 0.461 g, (86%) of the title compound. 1 H NMR (DMSO-ds) d 1.55 (s, 9H), 1.54 (s, 5H), 2.17 (s, 6H), 2.36 (S, 3H), 7.19 (S, 2HO, 7.45-7.47 (m, 2H) , 7.61-7.66 (m, 1H), 8.04 (dd, 2H), 8.15-8.25 (m, 4H), 8.92 (dd, 2H), Mass spectrum (+ ESI), m / z 772/774 (M + H).

Stage 2 Ester 5- T4- (9-bromo-. -dimethyl-naphtho- 2 .5-bl thiophen-4-yl) -2,6-dip.ethyl-phenoxysulfonyl-2-carboxy-phenyl of isonicotinic acid The title compound is prepared according to the procedure in example 17, step 2, using 2 - (pyrid-4-ylcarbonyl) oxy-4- [4- (9-bromo-2,3-dimethyl) tertbutyl ester. -naphtho [2,5-b] thiophen-4-yl) -2,6-dimethyl-phenoxysulfonyl] -benzoic acid (0.445 g, 0-576 mmol). Purification by crystallization of acetone to provide 0.365 g (88%) of the title compound as a white solid, mp 231-2 0 ° C. 'H NMR (DMSO-d6) d 1.54 (s, 3H), 2.16 (s, 6H), 2.55 (s, 3H), 7.19 (s, 2H), 7.44-7.47 (m 2H), 7.61-7.65 (m , 1H), 7.99 (dd, 2H), 8.13 (dd, 1H), 8.18-8.20 (m, 2H), 8.30 (d, 1H), 8.89 (dd, 2H), 13.8-14 | .1 (broad s, 1H), Spectrum of mass (-APCI), m / z 714/716 (MH). Analysis calculated for C35H26NBr07S2 - 0.4 H20: C, 58.08, H, 3.73, N, 1.94. Found: C, 58.15, H, 3.98, N, 1.85. It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Claims

CLAIMS Having described the invention as above, the content of the following claims is claimed as property: 1. A compound of formula I that has the structure characterized in that R1 and R2 are each independently hydrogen, nitrile, nitro, amino, alkylamino of 1-6 carbon atoms, dialkylamino of 1-6 carbon atoms per alkyl group, cycloalkylamino of 3-8 carbon atoms, alkyl of 1 -6 carbon atoms, perfluoroalkyl of 1-6 carbon atoms, halogen, cycloalkyl of 5-8 carbon atoms, thienyl, - fyl, phenyl or phenyl mono-, di-, or tri-substituted with halogen, hydroxy, alkyl of 1-6 carbon atoms, perfluoroalkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms or perfluoroalkoxy of 1-6 carbon atoms; R3 and R4 are each independently hydrogen, alkyl of 1-6 carbon atoms, perfluoroalkyl of 1-6 carbon atoms, hydroxyalkyl of 1-6 carbon atoms, aminoalkyl of 1-6 carbon atoms, acyl 2-7 carbon atoms; R5 is hydrogen, halogen, alkyl of 1-6 carbon atoms, perfluoroalkyl of 1-6 carbon atoms, nitrile, alkoxy of 1-6 carbon atoms, aryloxy, arylalkoxy of 2-12 carbon atoms, arylsulfanyl, - W is S, O, or NR9; R9 is hydrogen or alkyl of 1-6 carbon atoms, - X is O, -NR6-, or - (CH2) pNR6-; R6 is hydrogen, or alkyl of 1-6 carbon atoms; p is 1 to 4, - Y is methylene, carbonyl, -S02-, or -SO-; Z is phenyl, heteroaryl, or naphthyl; R7 and R "are each, independently hydrogen, carboxyl, acyl of 2-7 carbon atoms, hydroxyl, hydroxyalkyl of 1-6 carbon atoms, hydroxyalkanoyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, perfluoroalkoxy of 1-6 carbon atoms, alkoxycarbonyl - 159 -2-7 carbon atoms, perfluoroalkoxycarbonyl of 2-7 carbon atoms, alkyl of 1-6 carbon atoms, perfluoroalkyl of 1-6 carbon atoms, aryl, aryloxycarbonyl, heteroaryloxycarbonyl, arylalkoxy of 6-12 carbon atoms carbon, heteroaryl, alkanoyloxy of 1-6 carbon atoms, perfluoroalkanoyloxy of 1-6 carbon atoms, heteroaroyloxy, aroyloxy, tetrazolyl, mercapto, nitrile, amino, carbamoyl, aminoalkyl of 1-6 carbon atoms, -NHS02CF3, carboxyaldehyde, halogen, nitro, acylamino or pyrimidyl optionally substituted with mercapto, 3-hydroxycyclobut-3-en-4-yl-1,2-dione or tetronic acid; or a pharmaceutically acceptable salt thereof. 2. The compound according to claim 1, characterized in that R1 and R2 are each independently hydrogen, alkyl of 1-6 carbon atoms, perfluoroalkyl of 1-6 carbon atoms, bromine, iodine, cycloalkyl of 5-8 carbon atoms , phenyl or phenyl substituted with trifluoromethyl, chloro, methoxy, -OCF3, thienyl or furyl; R3 and R4 are each independently aryl of 1-6 carbon atoms, or perfluoroalkyl of 1-6 carbon atoms, - R5 is hydrogen, halogen, alkyl of 1-6 carbon atoms, perfluoroalkyl of 1-6 carbon atoms , nitrile, alkoxy of 1-6 carbon atoms, aryloxy, arylalkoxy or arylsulfañyl, - W is S or O; X is O, -NRe-, or - (CH2) pNR6-; R6 is hydrogen or alkyl of 1-6 carbon atoms, - p is 1 to 4; And it is methylene, carbonyl, -S02-, or -SO-; Z is phenyl, pyridyl, naphthyl, thienyl, furyl, pyrrolyl, pyrazolyl, isoxazolyl or isothiazolyl; R7 and R8 are each independently hydrogen, halogen, carboxy, acyl of 2-7 carbon atoms, acylamino of 1-6 carbon atoms, hydroxyl, hydroxyalkyl of 1-6 carbon atoms, hydroxyalkanoyl of 1-6 carbon atoms , alkoxy of 1-6 carbon atoms, perfluoroalkoxy of 1-6 carbon atoms, alkoxycarbonyl of 2-7 carbon atoms, perfluoroalkoxycarbonyl of 2-7 carbon atoms, alkyl of 1-6 carbon atoms, perfluoroalkyl of 1- 6 carbon atoms, aryloxy, aryloxycarbonyl, heteroaryloxycarbonyl, arylalkoxy, pyridyl, alkanoyloxy, perfluoroalkanoyloxy, heteroaryloxy, aroyloxy, tetrazolyl, pyrazolyl, oxazolyl, isoxazolyl, mercapto, nitrile, amino, -NHS02CF3, carbamoyl, aminoalkyl of 1-6 carbon atoms , carboxyaldehyde, halogen, nitro, acylamino or pyrimidyl or pyrimidyl substituted with methylsulfanyl, 5-hydroxy-cyclobut-5-en-4-yl-l, 2-dione; or a pharmaceutically acceptable salt thereof. 5. The compound according to claim 2, characterized in that R1 and R2 are each independently hydrogen, alkyl of 1-6 carbon atoms, bromine or cyclopentyl; R3 and R4 are alkyl of 1-6 carbon atoms; R5 is hydrogen or bromine; W is S u 0; X is 0, -NR6, or -CH2NR6-; R6 is hydrogen or alkyl of 1-6 carbon atoms; And it is methylene, carbonyl or -S02-; Z is phenyl, thienyl, pyrazolyl or thiazolyl; R7 and R8 are each independently hydrogen, halogen, acyl, carboxyl, hydroxyl, alkoxy of 1-6 carbon atoms, alkoxycarbonyl of 2-7 carbon atoms, alkyl of 1-6 carbon atoms, pyridyl, alkanoyloxy of 1- 6 carbon atoms, aroyloxy, tetrazolyl, isoxazolyl, nitrile or pyrimidyl or pyrimidyl substituted with mercapto; or a pharmaceutically acceptable salt thereof. 4. The compound according to claim 1, characterized in that it is 4- [4- (9-bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -2-isopropyl-phenoxysulfonyl acid. ] -2-hydroxy-benzoic acid or a pharmaceutically acceptable salt thereof. 5. The compound according to claim 1, characterized in that it is 4- [4- (9-bromo-2,3-dimethyl-naphtho [2, 5-b] thiophen-4-yl) -2,6-dimethyl- phenoxysulfonyl] -2-hydroxybenzene or a pharmaceutically acceptable salt thereof. 6. The compound according to claim 1, characterized in that it is 4- [4- (9-bromo-2,5-dimethyl-naphtho [2, 5-b] thiophen-4-yl) -2-cyclopentyl-phenoxysulfonyl] -2-hydroxybenzoic or a pharmaceutically acceptable salt thereof. 7. The compound according to claim 1, characterized in that it is 4- [4- (9-bromo-2,5-dimethyl-naphtho [2,5-b] thiophen-4-yl) -2,6-diisopropyl acid. phenoxysulfonyl] -2-hydroxybenzoic acid or a pharmaceutically acceptable salt thereof. 8. The compound according to claim 1, characterized in that it is 2-acetoxy-4- [- (9-bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -2-6 acid -dimethyl-phenoxysulfonyl] -benzoic acid or a pharmaceutically acceptable salt thereof. 9. The compound according to claim 1, characterized in that it is 2-acetoxy-4- [4- (9-bromo-2,5-dimethyl-naphtho [2,5-b] thiophen-4-yl) -2 - cyclopentyl-phenoxysulfonyl] -benzoic acid or a pharmaceutically acceptable salt thereof. 10. The compound according to claim 1, characterized in that it is 2-butyryloxy-4- [4- (9-bromo-2,3-dimethyl-naphtho [2, 3-b] thiophen-4-yl) -2 acid, 6-dimethyl-phenoxysulfonyl] -benzoic acid or a pharmaceutically acceptable salt thereof. 11. The compound according to claim 1, characterized in that it is 2-benzoyloxy-4- [4- (9-bromo-2,3-dimethyl-naphtho [2, 5-b] thiophen-4-yl) -2, 6-dimethyl-phenoxysulfonyl] -benzoic acid or a pharmaceutically acceptable salt thereof. 12. The compound according to claim 1, characterized in that it is 2-propionyloxy-4- [4- (9-bromo-2,3-dimethyl-naphtho [2, 3-b] thiophen-4-yl) -2, 6-dimethyl-phenoxysulfonyl] -benzoic acid or a pharmaceutically acceptable salt thereof. 13. The compound according to claim 1, characterized in that it is 5- [4- (9-bromo-2,3-dimethyl-naphtho-5-b] thiophen-4-yl) -2-cyclopentyl-f-enoxysulfonyl acid. ] -4-methoxythiyl-3-carboxylic acid or a pharmaceutically acceptable salt thereof. 14. The compound according to claim 1, characterized in that it is 5- [4- (9-bromo-2,5-dimethyl-naphtho [2,5-b] thiophen-4-yl) -2-cyclopentyl-f-enoxysulf acid. onyl] -4-hydroxythiophen-5-carboxylic acid or a pharmaceutically acceptable salt thereof. 15. The compound according to claim 1, characterized in that it is 4- [2-cyclopentyl-4- (2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -phenoxysulfonyl] -2-hydroxybenzoic acid or a pharmaceutically acceptable salt thereof. 16. The compound according to claim 1, characterized in that it is 4- [2-cyclopentyl-4- (2,3-dimethyl-naphtho [2, 3-b] furan-4-yl) -phenoxysulfonyl] -2-hydroxybenzoic acid or a pharmaceutically acceptable salt thereof. 17. The compound according to claim 1, characterized in that it is 4- [2-bromo-4- (2,3-dimethyl-naphtho [2, 3-b] furan-4-yl) -phenoxysulfonyl] -6-ethyl acid. -phenoxysulfonyl] -2-hydroxybenzoic acid or a pharmaceutically acceptable salt thereof. 18. The compound according to claim 1, characterized in that it is 4- [4- (2,3-dimethyl-naphtho [2, 3-b] furan-4-yl) - (phenoxysulfonyl) -2,6-diethyl- phenoxysulfonyl] -2-hydroxybenzoic acid or a pharmaceutically acceptable salt thereof. 19. The compound according to claim 1, characterized in that it is 4- [2-c-clopentyl-4- (2,3-dimethyl-napht [2, 3-b] furan-4-yl) -phenoxysulfonyl] acid] -2-Hydroxybenzoic acid or a pharmaceutically acceptable salt thereof. 20. The compound according to claim 1, characterized in that it is 4- [2-bromo-4- (2,3-dimethyl-naph to [2, 3-b] furan-4-yl) -6-ethyl-phenoxysulfonyl acid. ] -2-hydroxybenzoic or a pharmaceutically acceptable salt of the same. 21. The compound according to claim 1, characterized in that it is 4- [4- (2,5-dimethyl-naphtho [2,3-b] furan-4-yl) -2,6-diethyl-phenoxysulfonyl] - 2-hydroxybenzoic or a pharmaceutically acceptable salt of the same. 22. The compound according to claim 1, characterized in that it is terbutyl ester of 4- [4- (9-bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -2.6 -dimin-phenoxysulfonyl] -2-hydroxybenzoic acid or a pharmaceutically acceptable salt thereof. 23. The compound according to claim 1, characterized in that it is 2- (4-methoxybenzoyl) -oxy-4- [4- (9-bromo-2,3-dimethyl -naf to [2,5-b] thiof acid. en-4-yl) -2,6-dimethyl-phenoxysulfonyl] -benzoic acid or a pharmaceutically acceptable salt thereof. 24. The compound according to claim 1, characterized in that it is 5- [4- (2,5-dimethyl-naphtho [2,3-b] thiophen-4-yl) -2,6-phenoxysulfonyl] -4-methoxythi acid en-5-carboxylic acid or a pharmaceutically acceptable salt thereof. 25. The compound according to claim 1, characterized in that it is 2-cyclopentyl-4- (2,5-dimethyl-naph to [2, 5-b] thiophen-4-yl) -phenyl ester of 5-pyridin-2-acid il-thiophene-2-sulfonic acid or a pharmaceutically acceptable salt thereof. 26. The compound according to claim 1, characterized in that it is 4-benzoyloxy-5- [4- (2,5-dimethyl-naphtho [2, 5-b] thiophen-4-yl) -2,6-diethyl-enoxysulf acid onyl] -thiofen-3-carboxylic acid or a pharmaceutically acceptable salt thereof. 27. The compound according to claim 1, characterized in that it is 3- [2-cyclopentyl-4- (2,3-dimethyl-naphtho [2,5-b] thiophen-4-yl) -phenoxysulfonyl] -benzoic acid or a pharmaceutically acceptable salt thereof. 28. The compound according to claim 1, characterized in that it is 2- (2-methylsulfanyl-pyrimidine) 2-cyclopentyl-4- (2,3-dimethyl-naphtho [2,3-b] thiophen- -yl) -phenyl ester of 5- (2-methylsulfanyl-pyrimidine) -4-yl) -thiofen-2-sulfonic acid or a pharmaceutically acceptable salt thereof. 29. The compound according to claim 1, characterized in that it is 2-benzoyloxy-4- [4- (2,5-dimethyl-naphtho [2,3-b] thiophen-4-yl) -2,6-dimethylf-enoxysulfonyl] ] -benzoic acid or a pharmaceutically acceptable salt thereof. 30. The compound according to claim 1, characterized in that it is 2- (4-chloro-benzoyl) oxy-4- [4- (2,5-dimethyl-naphtho [2, 5-b] thiophen-4-yl) -2,6-dimethyl-phenoxysulfonyl] -benzoic acid or a pharmaceutically acceptable salt thereof. 31. The compound according to claim 1, characterized in that it is 2-carboxy-5- [4- (2,3-dimethyl-naphtho [2,5-b] thiophen-4-yl) -2,6-dimethyl-phenoxysulfonyl ] nicotinic acid phenylester or a pharmaceutically acceptable salt thereof. 32. The compound according to claim 1, characterized in that it is 2-carboxy-5- [4- (9-bromo-2,3-dimethyl-naphtho [2,3-b] thiophen-4-yl) -2,6. -dimethyl-phenoxysulfonyl] phenyl ester of nicotinic acid or a pharmaceutically acceptable salt thereof. 35. The compound according to claim 1, characterized in that it is 4- [4- (9-bromo-2, -dimethyl-naphtho [2, 5-b] thiophen-4-yl) -2,6-dimethyl-f enoxysulfonyl] -2-phenylacetoxybenzoic acid or a pharmaceutically acceptable salt thereof. 34. The compound according to claim 1, characterized in that it is 2- (4-cyano-benzoyl) oxy-4- [4- (9-bromo-2,3-dimethyl-naphtho [2,3-b] thiophene) 4-yl) -2,6-dimethy1-f-enoxy sulphonyl] -benzyl or a pharmaceutically acceptable salt thereof. 35. The compound according to claim 1, characterized in that it is 2- (3-methoxy-benzoyl) oxy -4- [4- (9-bromo- (2,3-dimethyl-napht [2, 3-b]] thiof en-4-yl) -2,6-dimethyl-phenoxy sulphonyl] -benzoic acid or a pharmaceutically acceptable salt thereof. 56. The compound according to claim 1, characterized in that it is 5- [4- (9-bromo- (2,5-dimethyl-naphtho [2,5-b] thiof en-4-yl) -2,6-dimethyl -phenoxysulfonyl] -2-carboxyp-enyl ester of isonicotinic acid or a pharmaceutically acceptable salt thereof. 37. A method for treating metabolic disorders mediated by insulin resistance or hyperglycemia in a mammal in need thereof, characterized in that it comprises administering to the mammal a compound of formula I having the structure: characterized in that R1 and R2 are each independently hydrogen, nitrile, nitro, amino, alkylamino of 1-6 carbon atoms, dialkylamino of 1-6 carbon atoms per alkyl group, cycloalkylamino of 3-8 carbon atoms, alkyl of 1 -6 carbon atoms, perfluoroalkyl of 1-6 carbon atoms, halogen, cycloalkyl of 3-8 carbon atoms, thienyl, furyl, phenyl or phenyl mono-, di-, or tri-substituted with halogen, hydroxy, alkyl of 1-6 carbon atoms, perfluoroalkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms or perfluoroalkoxy of 1-6 carbon atoms, - R3 and R4 are each independently hydrogen , alkyl of 1-6 carbon atoms, perfluoroalkyl of 1-6 carbon atoms, hydroxyalkyl of 1-6 carbon atoms, aminoalkyl of 1-6 carbon atoms, acyl of 2-7 carbon atoms, R5 is hydrogen, halogen, alkyl of 1-6 carbon atoms, perfluoroalkyl of 1-6 carbon atoms, nitrile, alkoxy of 1-6 carbon atoms, aryloxy, arylalkoxy of 2-12 carbon atoms, arylsulfanyl; W is S, O, or NR9; R9 is hydrogen or alkyl of 1-6 carbon atoms; X is O, -NR6-, or - (CH2) pNR6-; R6 is hydrogen, or alkyl of 1-6 carbon atoms; p is 1 to 4, - Y is methylene, carbonyl, -S02-, or -SO-, - Z is phenyl, heteroaryl, or naphthyl; R7 and R8 are each, independently hydrogen, carboxyl, acyl of 2-7 carbon atoms, hydroxyl, hydroxyalkyl of 1-6 carbon atoms, hydroxyalkanoyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, perfluoroalkoxy of 1-6 carbon atoms, alkoxycarbonyl of 2-7 carbon atoms, perfluoroalkoxycarbonyl of 2-7 atoms carbon, alkyl of 1-6 carbon atoms, perfluoroalkyl of 1-6 carbon atoms, aryl, aryloxycarbonyl, heteroaryloxycarbonyl, arylalkoxy of 6-12 carbon atoms, heteroaryl, alkanoyloxy of 1-6 carbon atoms, perfluoroalkanoyloxy of 1 -6 carbon atoms, heteroaroyloxy, aroyloxy, tetrazolyl, mercapto, nitrile, amino, carbamoyl, aminoalkyl of 1-6 carbon atoms, -NHS02CF3, carboxyaldehyde, halogen, nitro, acylamino or pyrimidyl optionally substituted with mercapto, 3-hydroxycyclobutyl 5-en-4-yl-l, 2-dione or tetronic acid; or a pharmaceutically acceptable salt thereof. 58. A method for treating or inhibiting type II diabetes in a mammal in need thereof, characterized in that it comprises administering to the mammal a compound of formula I having the structure: (I) - characterized in that R1 and R2 are each independently hydrogen, nitrile, nitro, amino, alkylamino of 1-6 carbon atoms, dialkylamino of 1-6 carbon atoms per alkyl group, cycloalkylamino of 5-8 carbon atoms, alkyl of 1-6 carbon atoms, perfluoaralkyl of 1-6 carbon atoms, halogen, cycloalkyl of 3-8 carbon atoms, thienyl, furyl, phenyl or ienyl mono-, di- -, or tri-substituted with halogen, hydroxy, alkyl of 1-6 carbon atoms, perfluoroalkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms or perfluoroalkoxy of 1-6 carbon atoms, - R3 and R4 are each independently hydrogen, alkyl of 1-6 carbon atoms, perfluoroalkyl of 1-6 carbon atoms, hydroxyalkyl of 1-6 carbon atoms, aminoalkyl of 1-6 carbon atoms, acyl of 2-7 carbon atoms carbon, - R5 is hydrogen, halogen, alkyl of 1-6 carbon atoms, perfluoroalkyl of 1-6 carbon atoms, nitrile, alkoxy of 1-6 carbon atoms, aryloxy, arylalkoxy of 2-12 carbon atoms, arylsulfanyl; W is S, O, or NR9; R9 is hydrogen or alkyl of 1-6 carbon atoms, - X is O, -NR6-, or - (CH2) pNR6-; R6 is hydrogen, or alkyl of 1-6 carbon atoms; p is 1 to 4; And it is methylene, carbonyl, -S02-, or -S0-; Z is phenyl, heteroaryl, or naphthyl; R7 and R8 are each, independently hydrogen, carboxyl, acyl of 2-7 carbon atoms, hydroxyl, hydroxyalkyl of 1-6 carbon atoms, hydroxyalkanoyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, perfluoroalkoxy of 1-6 carbon atoms, alkoxycarbonyl of 2-7 carbon atoms, perfluoroalkoxycarbonyl of 2-7 carbon atoms, alkyl of 1-6 carbon atoms, perfluoroalkyl of 1-6 carbon atoms, aryl, aryloxycarbonyl, heteroaryloxycarbonyl, arylalkoxy of 6-12 carbon atoms, heteroaryl, alkanoyloxy of 1-6 carbon atoms, perfluoroalkanoyloxy of 1-6 carbon atoms, heteroaroyloxy, aroyloxy, tetrazolyl, mercapto, nitrile, amino, carbamoyl, aminoalkyl 1-6 carbon atoms, -NHS02CF3, carboxyaldehyde, halogen, nitro, acylamino or pyrimidyl optionally substituted with mercapto, 3-hydroxycyclobut-5-en-4-yl-1,2-dione or tetronic acid; or a pharmaceutically acceptable salt thereof. 59. A method for modulating glucose levels in a mammal in need thereof, characterized in that it comprises administering to the mammal a compound of formula I having the structure: characterized in that R1 and R2 are each independently hydrogen, nitrile, nitro, amino, alkylamino of 1-6 carbon atoms, dialkylamino of 1-6 carbon atoms per alkyl group, cycloalkylamino of 5-8 carbon atoms, alkyl of 1 -6 carbon atoms, perfluoroalkyl of 1-6 carbon atoms, halogen, cycloalkyl of 5-8 carbon atoms, thienyl, furyl, phenyl or phenyl mono-, di-, or tri-substituted with halogen, hydroxy, 1-6 carbon atoms, perfluoroalkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms or perfluoroalkoxy of 1-6 carbon atoms; R3 and R4 are each independently hydrogen, alkyl of 1-6 carbon atoms, perfluoroalkyl of 1-6 carbon atoms, hydroxyalkyl of 1-6 carbon atoms, aminoalkyl of 1-6 carbon atoms, acyl of 2-7 carbon atoms; R5 is hydrogen, halogen, alkyl of 1-6 carbon atoms, perfluoroalkyl of 1-6 carbon atoms, nitrile, alkoxy of 1-6 carbon atoms, aryloxy, arylalkoxy of 2-12 carbon atoms, arylsulfanyl, - W is S, 0, or NR9, - R9 is hydrogen or alkyl of 1-6 carbon atoms; X is 0, -NR6-, or - (CH2) pNR6-; R6 is hydrogen, or alkyl of 1-6 carbon atoms, - p is 1 to 4; And it is methylene, carbonyl, -S02-, or -SO-; Z is phenyl, heteroaryl, or naphthyl; R7 and R8 are each, independently hydrogen, carboxyl, acyl of 2-7 carbon atoms, hydroxyl, hydroxyalkyl of 1-6 carbon atoms, hydroxyalkanoyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, perfluoroalkoxy of 1-6 carbon atoms, alkoxycarbonyl 2-7 carbon atoms, perfluoroalkoxycarbonyl of 2-7 carbon atoms, alkyl of 1-6 carbon atoms, perfluoroalkyl of 1-6 carbon atoms, aryl, aryloxycarbonyl, heteroaryloxycarbonyl, arylalkoxy of 6-12 carbon atoms, heteroaryl , alkanoyloxy of 1-6 carbon atoms, perfluoroalkanoyloxy of 1-6 carbon atoms, heteroaroyloxy, aroyloxy, tetrazolyl, mercapto, nitrile, amino, carbamoyl, aminoalkyl of 1-6 carbon atoms, -NHS02CF3, carboxyaldehyde, halogen, nitro, acylamino or pyrimidyl optionally substituted with mercapto, 3-hydroxycyclobut-3-en-4-yl-l, 2 -dione or tetronic acid; or a pharmaceutically acceptable salt thereof. 40. A pharmaceutical composition characterized in that it comprises a compound of formula I having the structure: characterized in that R1 and R2 are each independently hydrogen, nitrile, nitro, amino, alkylamino of 1-6 carbon atoms, dialkylamino of 1-6 carbon atoms per alkyl group, cycloalkylamino of 3-8 carbon atoms, alkyl of 1 -6 carbon atoms, perfluoroalkyl of 1-6 carbon atoms, halogen, cycloalkyl of 3-8 carbon atoms, thienyl, furyl, phenyl or phenyl mono-, di-, or tri-substituted with halogen, hydroxy, alkyl 1- 6 carbon atoms, perfluoroalkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms or perfluoroalkoxy of 1-6 carbon atoms, - R3 and R4 are each independently hydrogen, alkyl of 1-6 carbon atoms , perfluoroalkyl of 1-6 carbon atoms, hydroxyalkyl of 1-6 carbon atoms, aminoalkyl of 1-6 carbon atoms, acyl of 2-7 carbon atoms; Rs is hydrogen, halogen, alkyl of 1-6 carbon atoms, perfluoroalkyl of 1-6 carbon atoms, nitrile, alkoxy of 1-6 carbon atoms, aryloxy, arylalkoxy of 2-12 carbon atoms, arylsulfanyl, - W is S, C, or NR9; R9 is hydrogen or alkyl of 1-6 carbon atoms; X is 0, -NR6-, or - (CH2) PNR6 -, - R6 is hydrogen, or alkyl of 1-6 carbon atoms, - p is 1 to 4; And it is methylene, carbonyl, -S02-, or -SO-; Z is phenyl, heteroaryl, or naphthyl; R7 and Ra are each independently hydrogen, carboxyl, acyl of 2-7 carbon atoms, hydroxyl, hydroxyalkyl of 1-6 carbon atoms, hydroxyalkanoyl of

1-6 carbon atoms, alkoxy of 1-6 carbon atoms, perfluoroalkoxy of 1-6 carbon atoms, alkoxycarbonyl of

2-7 carbon atoms, perfluoroalkoxycarbonyl of 2-7 carbon atoms, alkyl of 1-6 carbon atoms carbon, perfluoroalkyl of 1-6 carbon atoms, aryl, aryloxycarbonyl, heteroaryloxycarbonyl, arylalkoxy of 6-12 carbon atoms, heteroaryl, alkanoyloxy of 1-6 carbon atoms, perfluoroalkanoyloxy of 1-6 carbon atoms, heteroaroyloxy, aroyloxy, tetrazolyl, mercapto, nitrile, amino, carbamoyl, aminoalkyl of 1-6 carbon atoms, -NHS02CF3, carboxyaldehyde, halogen, nitro, acylamino or pyrimidyl optionally substituted with mercapto, 5-hydroxycyclobut-5-en-4-yl-1, 2 -dione or tetronic acid; or a pharmaceutically acceptable salt thereof. 41. The use of a compound, according to any of claims 1 to 36, characterized in that it is used as a medicament. 42. The use of a compound, according to any of claims 1 to 36, in the preparation of a medicament for the treatment of metabolic disorders mediated by insulin resistance or hyperglycemia, in a mammal. 43. A process for the preparation of a compound of formula I, which has the structure characterized in that R1 and R2 are each independently hydrogen, nitrile, nitro, amino, alkylamino of 1-6 carbon atoms, dialkylamino of 1-6 carbon atoms per alkyl group, cycloalkylamino of

3-8 carbon atoms, alkyl of 1 -6 carbon atoms, perfluoroalkyl of 1-6 carbon atoms, halogen, cycloalkyl of 3-8 carbon atoms, thienyl, furyl, phenyl or phenyl mono-, di-, or tri-substituted with halogen, hydroxy, 1-6 carbon atoms, perfluoroalkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms or perfluoroalkoxy of 1-6 carbon atoms, - R3 and R4 are each independently hydrogen, alkyl of 1-6 carbon atoms, perfluoroalkyl of 1-6 carbon atoms, hydroxyalkyl of 1-6 carbon atoms, aminoalkyl of 1-6 carbon atoms, acyl 2-7 carbon atoms, - R5 is hydrogen, halogen, alkyl of 1-6 carbon atoms, perfluoroalkyl of 1-6 carbon atoms, nitrile, alkoxy of 1-6 carbon atoms, aryloxy, arylalkoxy of 2-12 carbon atoms , arylsulfanyl, - W is S, O, or NR9; R9 is hydrogen or alkyl of 1-6 carbon atoms; X is O, -NR6-, or - (CH2) pNR6-; R6 is hydrogen, or alkyl of 1-6 carbon atoms; p is 1 to 4, - Y is methylene, carbonyl, -S02-, or -SO-; Z is phenyl, heteroaryl, or naphthyl; R7 and R1 are each, independently hydrogen, carboxyl, acyl of 2-7 carbon atoms, hydroxyl, hydroxyalkyl of 1-6 carbon atoms, hydroxyalkanoyl of 1-6 carbon atoms, alkoxycarbonyl of 2-7 carbon atoms, perfluoroalkoxycarbonyl of 2-7 carbon atoms, alkyl of 1-6 carbon atoms, perfluoroalkyl of 1-6 carbon atoms, aryl of 6-12 carbon atoms, aryloxycarbonyl of 7-13 carbon atoms, heteroaryloxycarbonyl, heteroaryl, tetrazolyl , mercapto, alkylsulfanyl of 1-6 carbon atoms, nitrile, amino, carbamoyl, aminoalkyl of 1-6 carbon atoms, alkylamino of 1-6 carbon atoms, dialkylamino of 1-6 carbon atoms per alkyl group, -NHS02CF3, carboxaldehyde, halogen, nitro, acylamino of 1-6 carbon atoms, 3-hydroxycyclobut-3-en-

4-yl-l, 2-dione or tetronic acid, -OCOR10, -OR10 R10 is aryl of 6-12 carbon atoms, aralkyl of 7-13 carbon atoms, monocyclic or bicyclic heteroaryl or a monocyclic or bicyclic heteroaryl, alkyl of 1-6 carbon atoms, perfluoroalkyl of 1-6 carbon atoms, or a pharmaceutically acceptable salt thereof, the process is characterized in that it comprises: a) reacting a compound of formula ^ Z-Y- Hal wherein Y is CO, SO or S02, Hal is halogen and R6, R7 and Z are as defined above, or an anhydride of (ZR7R8) wherein R7, R8 and Z are as defined above, with a compound of formula 165 wherein Q is hydrogen or a metal atom, and all other groups are as defined above, to provide a compound of formula I, wherein Y is CO, SO or S02; b) reacting a compound of formula wherein Q 'is such a leaving group and R7, R8 and Z are as defined above, with a compound of formula wherein Q is hydrogen or a metal atom and all other groups are defined in the foregoing, to provide a compound of formula I, wherein Y is CH2; c) reacting an activated ester of the acid of formula wherein R7, R8 and Z are as defined with an amine of formula wherein X is -NR6- and all other groups, including R6 are as defined above, to provide a compound of formula I wherein Y is CO and X is -NR6-; d) reacting a compound of formula wherein all groups are as defined above, with a reducing agent to provide a compound of formula I, wherein Y is CH2, e) reacting a secondary amine of formula wherein all groups are as defined in the above, with a compound of formula Q'R6 wherein Q 'is a leaving group and R6 is as defined above, to provide a compound of formula I wherein Y is CH2 and X is -NR6-, f) reacting an imine of formula wherein all groups are as defined in the foregoing, with a reducing agent to provide a compound of formula I wherein Y is CH2 and X is NH; g) reacting a compound of formula -S02Hal R8 / wherein Hal is a halogen and R7, R8 and Z are as defined above, with a compound of formula wherein Q "is an alkyl group and all other groups are as defined above, to provide a compound of formula I, wherein Y is S02 and X is O; h) reacting an alcohol of formula \; z-CH2OH R8 / wherein R7, R8 and Z are as defined above, with a compound of formula wherein all groups are as defined in the above, to provide a compound of formula I, wherein X is O and Y is CH2.