MX2008007352A - l , l , 3-TRI0X0-l , 2 , 5-THIADIAZ0LIDINES AND THEIR USE AS PTP-ASES INHIBITORS - Google Patents

Abstract

Compounds of the formula are inhibitors of protein tyrosine phosphatases (PTPases) and, thus, may be employed for the treatment of conditions mediated by PTPase activity. The compounds of the present invention may also be employed as inhibitors of other enzymes characterized with a phosphotyrosine binding region such as the SH2 domain. Accordingly, the compounds of formula (I) may be employed for prevention and/or treatment of insulin resistance associated with obesity, glucose intolerance, diabetes mellitus, hypertension and ischemic diseases of the large and small blood vessels, conditions that accompany type-2 diabetes, including hyperlipidemia, hypertriglyceridemia, atherosclerosis, vascular restenosis, irritable bowel syndrome, pancreatitis, adipose cell tumors and carcinomas such as liposarcoma, dyslipidemia, and other disorders where insulin resistance is indicated. In addition, the compounds of the present invention may be employed to treat and/or prevent cancer, osteoporosis, neurodegenerative and infectious diseases, and diseases involving inflammation and the immune system.

Description

1,1,3-TRIOXO-1,2,5-TIAPIAZOLIDINAS AND THEIR USE AS INHIBITORS OF PTP-ASAS Field of the Invention The present invention relates to thiadiazolidone derivatives, pharmaceutical compositions containing such compounds, methods for making them and methods for treating conditions mediated by tyrosine protein phosphatases using such compounds Background of the Invention Accordingly, the present invention provides compounds of the formula wherein Q is alkoxy, alkylthio, alkylthion, sulfonyl, cycloalkyl, aplo, heteroocichlo, alkenyl, alkynyl or (Ci) alkyl optionally substituted with one to four substituents selected from the group consisting of halogen, hydroxy, cycloalkyl, cycloalkoxy, acyl , acyloxy, alkoxy, alkyloxyalkoxy, optionally substituted amino, carbamoyl, thiol, alkylthio, alkylthion, sulfonyl, sulfamoyl, nitro, cyano, free or estepficated carboxy, aplo, aploxy, apltio, alkenyl, alkylo, aralkoxy, heteroaralkoxy, heterocyclyl and heterocyclyloxy; R1 is hydrogen, -C (O) R4, -C (O) NR5R6 or -C (O) OR7 wherein R and R5 are, independently of each other, hydrogen, cycloalkyl, aryl, heterocyclyl, aralkyl, heteroaralkyl or optionally substituted alkyl with one to four substituents selected from the group consisting of halogen, cycloalkyl, cycloalkoxy, alkoxy, alkyloxyalkoxy, amino, alkylamino, dialkylamino, aryl, aryloxy and heterocyclyl; R6 and R7 are, independently of each other, cycloalkyl, aryl, heterocyclyl, aralkyl, heteroaralkyl or alkyl optionally substituted with one to four substituents selected from the group consisting of halogen, cycloalkyl, cycloalkoxy, alkoxy, alkyloxyalkoxy, amino, alkylamino, dialkylamino, aryl , aryloxy and heterocyclyl; R2 and R3 are, independently of one another, hydrogen, halogen, (C1-3) alkyl or C-? -3 alkoxy); or a pharmaceutically acceptable salt thereof. The compounds of the present invention are inhibitors of tyrosine protein phosphatases (PTPases), in particular, the compounds of the formula (I) inhibit PTPase-1B (PTP-1B) and PTPase T cell (TC PTP) and, thus, , can be used for the treatment of conditions mediated by PTPase activity. Accordingly, the compounds of the formula (I) can be used for the treatment of resistance to insulin, glucose intolerance, obesity, diabetes mellitus, hypertension and ischemic diseases of large or small blood vessels, conditions that accompany type 2 diabetes including dyslipidemia, for example, hyperlipidemia and hypertriglyceridemia, atherosclerosis, vascular restenosis, irritable bowel syndrome , pancreatitis, adipose cell tumors and carcinomas such as liposarcoma, dyslipidemia, and other disorders where insulin resistance is indicated. In addition, the compounds of the present invention can be used to treat cancer (such as prostate or breast cancer), osteoporosis, infectious and neurodegenerative diseases, and diseases involving inflammation and the immune system. The listings below are definitions of various terms used to describe the compounds of the present invention. These definitions apply to terms as they are used throughout the specification unless they are otherwise limited in specific cases either individually or as part of a large group. In general, each time an alkyl group is referred to as a part of the structure, an optionally substituted alkyl is also intended. Accordingly, the term "optionally substituted alkyl" refers to substituted or unsubstituted straight or branched chain hydrocarbon groups having from 1 to 20 carbon atoms, preferably 1 to 8 carbon atoms. Exemplary unsubstituted alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl, and the like. Substituted alkyl groups include, but are not limited to, alkyl groups substituted by one or more of the following groups: halogen, hydroxy, cycloalkyl, cycloalkoxy, acyl, acyloxy, alkoxy, alkyloxyalkoxy, alkanoyloxy, amino, alkylamino, dialkylamino, acylamino, carbamoyl thiol, alkylthio, alkylthion, sulfonyl, sulfonamido, sulfamoyl, nitro, cyano, free or esterified carboxy, aryl, aryloxy, arylthio, alkenyl, alkynyl, aralkoxy, heteroaraloxy, heterocyclyl and heterocyclyloxy including indolyl, imidazolyl, furyl, thienyl, thiazolyl, pyrrolidyl, pyridyl, pyrimidyl, piperidyl, morpholinyl and the like. The term "lower alkyl" refers to any of the above alkyl groups as described above having 1 to 7, preferably 1 to 4, carbon atoms. The term "halogen" or "halo" refers to fluoro, chloro, bromo and iodo. The term "alkenyl" refers to any of the above alkyl groups having at least 2 carbon atoms and containing a carbon-to-carbon double bond at the point of attachment. Groups having 2 to 8 carbon atoms are preferred. The term "alkynyl" refers to any of the groups former alkyl having at least two carbon atoms and containing a carbon-carbon triple bond at the point of attachment. Preferred are groups having from 2 to 8 carbon atoms. The term "alkylene" refers to a straight chain bridge of 2-6 carbon atoms connected by single bonds, for example, - (CH2) X-, where x is 2-6, which may be interrupted with one or more heteroatoms selected from O, S, S (O), S (O) 2 or NR ', wherein R' may be hydrogen, alkyl, calkyl, aryl, heterocl, aralkyl, heteroaralkyl, acyl, carbamoyl, sulfonyl, alkoxycarbonyl, aryloxycarbonyl or aralkoxycarbonyl and the like; and the alkylene can be further substituted with one or more substituents selected from hydroxy, halogen, cyano, nitro, alkoxy, alkylthio, alkylthion, sulfonyl, free or esterified carboxy, carbamoyl, sulfamoyl, optionally substituted amino, calkyl, aryl, heterocl, alkenyl , alkynyl or (C 1-8) alkyl optionally substituted with one to four substituents selected from the group consisting of halogen, hydroxy, calkyl, calkoxy, acyl, acyloxy, alkoxy, alkyloxyalkoxy, amino, alkylamino, dialkylamino, acylamino, carbamoyl, thiol, alkylthio, alkylthion, sulfonyl, sulfonamido, sulfamoyl, nitro, cyano, free or esterified carboxy, aryl, aryloxy, arylthio, alkenyl, alkynyl, aralkoxy, heteroaralkoxy, heterocl, heterocloxy and the like. The term "calkyl" refers to hydrocarbon groups monocc, bicc or tricc optionally substituted from 3 to 12 carbon atoms, each of which may be substituted by one or more substituents such as alkyl, halo, oxo, hydroxy, alkoxy, alkanoyl, acylamino, carbamoyl, alkylamino, dialkylamino, thiol , alkylthio, nitro, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, sulfonyl, sulfonamido, sulfamoyl, heterocl, and the like. Exemplary monocc hydrocarbon groups include but are not limited to cpropyl, cbutyl, cpentyl, cpentenyl, chexyl and chexenyl and the like. Exemplary bicc hydrocarbon groups include bornyl, indyl, hexahydroindyl, tetrahydronaphthyl, decahydronaphthyl, bic [2.1.1 Jhexyl, bic [2.2.1] heptyl, bic [2.2.1] heptenyl, 6,6-dimethylbic [3.1.1] heptyl , 2,6,6-tri methyloxy [3.1.1] heptyl, bic [2.2.2] octyl and the like. Exemplary tricc hydrocarbon groups include adamantyl and the like. The term "alkoxy" refers to alkyl-O-. The term "alkanoyl" refers to C (O) - alkyl. The term "alkanoyloxy" refers to alkyl-C (O) -O-. The term "alkylamino" and "dialkylamino" refers to alkyl-NH- and (alkyl) 2N-, respectively. The term "alkanoylamino" refers to alkyl-C (O) -NH-. The term "alkylthio" refers to alkyl-S-. The term "alkylaminothiocarbonyl" refers to alkyl- NHC (S) - The term "tpalquilsihlo" refers to (alqu? Lo) 3S? - The term "tpalquilsihloxi" refers to (alqu? Lo) 3S? O- The term "alquiltiono" refers to alqu? Lo- S (O) - The term "alkylsulfonyl" refers to alkyl-S (O) 2- The term "alkoxycarbonyl" refers to alkyl-OC (O) - The term "alkoxycarbonyloxy" refers to alk? lo-O- C (O) O- The term "carboxycarbonyl" refers to HO-C (O) C (O) - The term "carbamoyl" refers to H2NC (O) -, alkyl-NHC (O) - , (alkyl) 2NC (O) -, ar-lo-NHC (O) -, alkyl (aryl) -NC (O) -, heteroaryl-NHC (O) -, alkyl (heteroaryl) -NC (O) -, aralkyl- NHC (O) -, alkyl (aralkyl) -NC (O) - and the like The term "sulfamoyl" refers to H2NS (O) 2- , alkyl-NHS (O) 2-, (alkyl) 2NS (O) 2-, aplo-N HS (O) 2-, alkyl (aryl) - NS (O) 2-, (ar ?) 2NS (O) 2-, heteroaryl-NHS (O) 2-, aralkyl-NHS (O) 2-, heteroaralkyl-NHS (O) 2- and the like The term "sulfonamido" refers to alkyl-S (O) 2-NH-, ar-lo (S) 2-NH-, aralkyl-S (O) 2-NH-, heteroaryl-S (O) 2-NH -, heteroaralqu? l oS (O) 2-NH-, alkyl-S (O) 2-N (alkyl) -, aplo- S (O) 2-N (alkyl) -, aralkyl-S (O ) 2-N (alkyl) -, heteroaryl-S (O) 2- N (alkyl) -, heteroaralkyl-S (O) 2-N (alkyl) - and the like The term "Sulfonyl" refers to alkylsulfonyl, aplsulfonyl, heteroaplsulfonyl, aralkylsulfonyl, heteroaralkylsulfonyl and the like The term "sulfonate" or "sulfonyloxy" refers to alkyl-S (O) 2-O-, aryl-S (O) 2-O-, aralkyl-S (O) 2-O-, heteroaryl α-S (O) 2-O-, heteroaralkyl-S (O) 2-O- and the like The term "optionally substituted amino" refers to a primary or secondary amino group which may be optionally substituted by a substituent such as acyl, sulfonyl, alkoxycarbonyl, cycloalkoxycarbonyl, aploxycarbonyl, heteroaploxycarbonyl, aralkoxycarbonyl, heteroaralkoxycarbonyl, carboxycarbonyl, carbamoyl, alkylamothiocarbonyl, aplaminothiocarbonyl and the like The term "aplo" refers to monocyclic or bicyclic aromatic hydrocarbon groups having from 6 to 12 carbon atoms in the ring portion, such as phenyl, naphthyl, tetrahydronaphthyl, biphenyl and diphenyl groups, each of which may optionally be substituted by one to five substituents such as alkyl, trifluoromethyl, halo, hydroxy, alkoxy, acyl, alkanoyloxy, amino optionally substituted, thiol, alkylthio, ni tro, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, carbamoyl, alkylthion, sulfonyl, sulfonamido, sulfonate, heterocyclyl, and the like The term "monocyclic aplo" refers to phenyl optionally substituted as described under aplo The term "aralkyl" refers to a group aplo linked directly through an alkyl group, such as benzyl The term "aralkanoyl" refers to aralkyl-C (O) - The term "aralkylthio" refers to aralkyl-S-. The term "aralkoxy" refers to an aryl group linked directly through an alkoxy group. The term "arylsulfonyl" refers to aryl-S (O) 2-. The term "arylthio" refers to aryl-S-. The term "aroyl" refers to aryl-C (O) -. The term "aroylamino" refers to aryl-C (O) -NH-. The term "aryloxycarbonyl" refers to aryl-O-C (O) -. The term "heterocyclyl" or "heterocycle" refers to an optionally substituted, aromatic, or non-aromatic partially or fully saturated cyclic group, for example, which is a 4- to 7-membered monocyclic, bicyclic ring system of 7 to 12 members , or tricyclic of 10 to 15 members, having at least one heteroatom in at least one ring containing a carbon atom. Each ring of the heterocyclic group containing a heteroatom may have 1, 2 or 3 heteroatoms selected from nitrogen atoms, oxygen atoms and sulfur atoms, wherein the nitrogen and sulfur heteroatoms may also optionally be oxidized. The heterocyclic group can be attached to a heteroatom or a carbon atom. Exemplary monocyclic heterocyclic groups include pyrrolidinyl, pyrrolyl, pyrazolyl, oxetanyl, pyrazolyl, imidazolyl, imidazolinyl, imidazolidinyl, oxazolyl, oxazolidinyl, isoxazolinyl, isoxazolyl, thiazolyl, thiadiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, furyl, tetrahydrofuryl, thienyl, oxadiazolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2-oxazepinyl, azepinyl, 4-piperidonyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, tetrahydropyranyl, morpholinyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, 1,3-dioxolane and tetrahydro-1,1-dioxothienyl, 1, 1, 4-trioxo-1, 2,5-thiadiazolidin-2-yl and the like. Exemplary bicyclic heterocyclic groups include indolyl, dihydroindolyl, benzothiazolyl, benzoxazinyl, benzoxazolyl, benzothienyl, benzothiazinyl, quinuclidinyl, quinolinyl, tetrahydroquinolinyl, decahydroquinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, decahydroisoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, benzofuryl, chromonyl, coumarinyl, benzopyranyl, benzodiazepinyl, I cinnolinyl , quinoxalinyl, indazolyl, pyrrolopyridyl, furopyridinyl (such as furo [2,3-c] pyridinyl, furo [3,2-b] -pyridinyl] or furo [2,3-bjpyridinyl), dihydroisoindolyl, 1,3-dioxo- 1,3-dihydroisoindol-2-yl, dihydroquinazolinyl (such as 3,4-dihydro-4-oxo-quinazolinyl), phthalazinyl and the like. Exemplary tricyclic heterocyclic groups include carazolyl, dibenzoazepinyl, dithienoazepinyl, benzindolyl, phenanthrolinyl, acridinyl, phenanthridinyl, phenoxazinyl, phenothiazinyl, xanthenyl, carbolinyl, and the like. The term "heterocyclyl" includes heterocyclic groups replaced. "Substituted heterocyclic groups" refers to heterocyclic groups that are substituted with 1, 2 or 3 substituents selected from the group consisting of the following: (a) optionally substituted alkyl; (b) hydroxy (or protected hydroxy); (c) halo; (d) oxo (ie = O); (e) optionally substituted amino, alkylamino or dialkylamino; (f) alkoxy; (g) cycloalkyl; (h) carboxy; (i) heterocycloxy; (j) alkoxycarbonyl, such as unsubstituted lower alkoxycarbonyl; (k) mercapto; (I) nitro; (m) cyano; (n) sulfamoyl or sulfonamido; (o) alkylcarbonyloxy; (p) arylcarbonyloxy; (q) arylthio; (r) aryloxy; (s) alkylthio; (t) formyl, (u) carbamoyl, (v) aralkyl, and (w) substituted by alkyl, cycloalkyl, alkoxy, hydroxy, amino, acylamino, alkylamino, dialkylamino or halo The term "heterocyclooxy" means a heterocyclic group linked to Through an oxygen bridge The term "heteropole" refers to an aromatic heterocycle, for example monocyclic or bicyclic aplo, such as pyrrole, pyrazole, imidazole, oxazole, isoxazole, thiazolyl, isothiazolyl, fuplo, thienyl, pipdoyl, pyrazinyl, pipmidinyl, pipdazmyl, indohlo, benzothiazolyl, benzoxazole, benzothienyl, nylclock, isoquinolyl, benzimidazolyl, benzofupl, and the like, optionally substituted by, for example, lower alkyl, lower alkoxy or halo The term "heteroaplsulfonyl" refers to hetero -S (O) 2- The term "heteroaroyl" refers to heteroar? Lo-C (O) - The term "heteroaroilamino" refers to heteroaplo- C (O) NH- The term "heteroaralkyl" refers to a group heteropole linked through es of an alkyl group The term "heteroaralkanoyl" refers to heteroaralkyl-C (O) - The term "heteroaralkanoylamino" refers to heteroaralkyl-C (O) NH-. The term "acyl" refers to alkanoyl, cycloalkanoyl, aroyl, heteroaroyl, aralkanoyl, heteroaralkanoyl, and the like. The term "acyloxy" refers to alkanoyloxy, cycloalkanoyloxy, aroyloxy, heteroaryloxy, aralkanoyloxy, heteroaralkanoyloxy, and the like. The term "acylamino" refers to alkanoylamino, cycloalkanoylamino, aroylamino, heteroaroylamino, aralkanoylamino, heteroaralkanoylamino, and the like. The term "esterified carboxy" refers to optionally substituted alkoxycarbonyl, cycloalkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, heterocycloxycarbonyl, and the like. Pharmaceutically acceptable salts of any compound of the present invention refers to salts formed with bases, namely cationic salts such as alkali metal and alkaline earth metal salts, such as sodium, lithium, potassium, calcium, magnesium, as well as ammonium salts, as ammonium, trimethylammonium, diethylammonium and tris (hydroxymethyl) -methyl-ammonium salts, and amino acid salts. Similarly, addition salts, such as those formed with mineral acids, organic carboxylic acids and organic sulfonic acids for example are possible hydrochloric acid, maleic acid, and methanesulfonic acid, provide a basic group, such as pyridyl, constitutes part of the structure. As described hereinbefore, the present invention provides 1,1-dioxo-1, 2,5-thiadiazolidin-3-one derivatives of the formula (I), pharmaceutical compositions containing the same, methods for preparing such compounds and methods for treating and / or preventing conditions associated with PTPase activity, in particular PTP-1B and TC PTP activity, by administering a therapeutically effective amount of a compound of the present invention, or a pharmaceutical composition thereof. Preferred are compounds of formula (I), designed as group A, wherein Q is -Y- (CH2) n-CR8R9- (CH2) mX wherein Y is oxygen or S (O) q where q is zero or an integer of 1 or 2; or Y is C = C; or And he is absent; n and m are, independently of each other, zero or an integer from 1 to 8; R8 and R9 are, independently of each other, hydrogen or lower alkyl; or R8 and R9 combined are alkylene which together with the carbon atom to which they are attached form a ring of 3 to 7 members; X is hydroxy, alkoxy, cycloalkyl, cycloalkoxy, acyl, acyloxy, carbamoyl, optionally substituted amino, cyano, trifluoromethyl, free or esterified carboxy, heterocyclyl, monocyclic aryl or monocyclic aryloxy; or a pharmaceutically acceptable salt thereof. Preferred are compounds in group A wherein R2 and R3 are hydrogen; or a pharmaceutically acceptable salt thereof. Further preferred are compounds in group A where n is zero or an integer from 1 to 3; m is zero or 1; R8 and Rg are, independently of each other, hydrogen or lower alkyl; X is hydroxy, carbamoyl, cyano, trifluoromethyl, free or esterified carboxy, heterocyclyl, monocyclic aryl or monocyclic aryloxy; or a pharmaceutically acceptable salt thereof. Especially preferred are the compounds in the group A, designed as group B, where Y is C = C; or And he is absent; or a pharmaceutically acceptable salt thereof. The compounds in group B are preferred where And it is absent; n is an integer of 5 or 6; m is zero or 1; R8 and R9 are lower alkyl; X is free or esterified hydroxy, cyano or carboxy; or a pharmaceutically acceptable salt thereof. Further preferred are compounds in group B wherein R8 and Rg are methyl; or a pharmaceutically acceptable salt thereof. Especially preferred are compounds in group B wherein Ri is hydrogen or -C (O) R in which R is monocyclic aryl; or a pharmaceutically acceptable salt thereof. Also preferred are compounds in group B, designed as group C, wherein Y is absent; n is an integer of 4 or 5; m is zero; R8 and Rg are hydrogen; X is monocyclic aryloxy; or a pharmaceutically acceptable salt thereof. Preferred are compounds in group C where Ri is hydrogen or -C (O) R in which R is aryl monocyclic; or a pharmaceutically acceptable salt thereof. Also preferred are compounds in group B, designed as group D, wherein Y is C = C; n is an integer of 2 or 3; m is zero; R8 and R9 are hydrogen; X is free or esterified hydroxy, cyano or carboxy; or a pharmaceutically acceptable salt thereof. Preferred are compounds in the group D wherein R- \ is hydrogen or -C (O) R4 in which R is monocyclic aryl; or a pharmaceutically acceptable salt thereof. Preferred are compounds of formula (I), designed as group E, wherein Q is monocyclic aryl or a 5- to 6-membered heterocyclic ring; or a pharmaceutically acceptable salt thereof. Preferred are compounds in group E, designed as group G, wherein R2 and R3 are hydrogen; or a pharmaceutically acceptable salt thereof. The compounds in the group G having the formula are preferred wherein R is hydrogen, -C (O) R4, -C (O) NR5R6 or -C (O) OR7 wherein R4 and R5 are, independently of each other, hydrogen, cycloalkyl, aplo, heterocyclic, aralkyl, heteroaralkyl or alkyl optionally substituted with one to four substituents selected from the group consisting of halogen, cycloalkyl, cycloalkoxy, alkoxy, alkyloxyalkoxy, amino, alkylamino, dialkylamino, aplo, aploxy and heterocycly, R6 and R are, independently of each other, cycloalkyl, aplo, heterocyclic, aralkyl, heteroaralkyl or alkyl optionally substituted with one to four substituents selected from the group consisting of halogen, cycloalkyl, cycloalkoxy, alkoxy, alkyloxyalkoxy, amino, alkylamino, dialkylamino, aplo, aploxy and heterocyclyl, R-io, Rn and R? 2 are , independently from each other, hydrogen, hydroxy, halogen, cyano, nitro, alkoxy, alkylthio, alkylthion, sulfonyl, free or esterified carboxy, carbamoyl, sulfamoyl, optionally substituted amino, cycloalkyl, a ryl , heterocyclyl, alkenyl, alkynyl, or (C 1-8) alkyl optionally substituted with one to four substituents selected from the group consisting of halogen, hydroxy, cycloalkyl, cycloalkoxy, acyl, acyloxy, alkoxy, alkyloxyalkoxy, optionally substituted amino, carbamoyl, thiol , alkylthio, alkylthion, sulfonyl, sulfamoyl, nitro, cyano, free or esterified carboxy, aryl, aryloxy, arylthio, alkenyl, alkynyl, aralkoxy, heteroaralkoxy, heterocyclyl and heterocyclyloxy; or C-R10, C-Rn and C-R12 are, independently of each other, replaced by nitrogen; or a pharmaceutically acceptable salt thereof. Preferred are compounds of the formula (IA) wherein Rio and Rn are hydrogen; or a pharmaceutically acceptable salt thereof. Also preferred are compounds of the formula (IA) wherein Ri is hydrogen or -C (O) R in which R 4 is monocyclic aryl; or a pharmaceutically acceptable salt thereof. Also preferred are compounds in the group G having the formula: wherein Ri is hydrogen, -C (O) R4, -C (O) NR5R6 or -C (O) OR7 wherein R4 and R5 are, independently of each other, hydrogen, cycloalkyl, aryl, heterocyclyl, aralkyl, heteroaralkyl or alkyl optionally substituted with one to four substituents selected from the group consisting of halogen, cycloalkyl, cycloalkoxy, alkoxy, alkyloxyalkoxy, amino, alkylamino, dialkylamino, aryl, aryloxy and heterocyclyl; R6 and R are, independently of each other, cycloalkyl, aryl, heterocyclyl, aralkyl, heteroaralkyl or alkyl optionally substituted with one to four substituents selected from the group consisting of halogen, cycloalkyl, cycloalkoxy, alkoxy, alkyloxyalkoxy, amino, alkylamino, dialkylamino, aryl , aryloxy and heterocyclyl; R 13 is hydrogen, sulfonyl, cycloalkyl, aryl, heterocyclyl or (C 1-8) alkyl optionally substituted with one to four substituents selected from the group consisting of halogen, hydroxy, cycloalkyl, cycloalkoxy, acyl, acyloxy, alkoxy, alkyloxyalkoxy, amino optionally substituted, carbamoyl, thiol, alkylthio, alkylthion, sulfonyl, sulfamoyl, nitro, cyano, free or esterified carboxy, aryl, aryloxy, arylthio, alkenyl, alkynyl, aralkoxy, heteroaralkoxy, heterocyclyl and heterocyclyloxy; or R 4 and R 15 are, independently of each other, hydrogen or lower alkyl; or C-R? 4 and C-R15 are, independently of each other, replaced by nitrogen; or a pharmaceutically acceptable salt thereof. Preferred are compounds of the formula (IB) wherein C-R14 is replaced by nitrogen; R15 is hydrogen; or a pharmaceutically acceptable salt thereof. Further preferred are compounds of the formula (IB) having the formula wherein Ri is hydrogen, -C (O) R4, -C (O) NR5R6 or -C (O) OR7 wherein R4 and R5 are, independently of each other, hydrogen, cycloalkyl, aryl, heterocyclyl, aralkyl, heteroaralkyl or alkyl optionally substituted with one to four substituents selected from the group consisting of halogen, cycloalkyl, cycloalkoxy, alkoxy, alkyloxyalkoxy, amino, alkylamino, dialkylamino, aryl, aryloxy and heterocyclyl; R6 and R are, independently of each other, cycloalkyl, aryl, heterocyclyl, aralkyl, heteroaralkyl or alkyl optionally substituted with one to four substituents selected from the group consisting of halogen, cycloalkyl, cycloalkoxy, alkoxy, alkyloxyalkoxy, amino, alkylamino, dialkylamino, aryl , aryloxy and heterocyclyl; R-? 3 is hydrogen, sulfonyl, cycloalkyl, aryl, heterocyclyl or (C 1-8) alkyl optionally substituted with one to four substituents selected from the group consisting of halogen, hydroxy, cycloalkyl, cycloalkoxy, acyl, acyloxy, alkoxy, alkyloxyalkoxy optionally substituted amino, carbamoyl, thiol, alkylthio, alkylthion, sulfonyl, sulfamoyl, nitro, cyano, free or esterified carboxy, aryl, aryloxy, arylthio, alkenyl, alkynyl, aralkoxy, heteroaralkoxy, heterocyclyl and heterocyclyloxy; or a pharmaceutically acceptable salt thereof. Preferred are compounds of the formula (IC) wherein R13 is - (CH2) n-CR16R17- (CH2) m -Z wherein n and m are, independently of each other, zero or an integer from 1 to 6; R16 and R are, independently of each other, hydrogen or lower alkyl; or R and R combined are alkylene which together with the carbon atom to which they are attached form a ring of 3 to 7 members; Z is hydroxy, alkoxy, cycloalkyl, cycloalkoxy, acyl, acyloxy, carbamoyl, optionally substituted amino, cyano, trifluoromethyl, free or esterified carboxy, heterocyclyl, monocyclic aryl or monocyclic aryloxy; or a pharmaceutically acceptable salt thereof. Further preferred are compounds of the formula (IC) wherein n is an integer from 1 to 3; m is zero or 1; Rie and Rw are, independently of each other, hydrogen or lower alkyl; Z is hydroxy, carbamoyl, cyano, trifluoromethyl, free or esterified carboxy, heterocyclyl, monocyclic aryl or monocyclic aryloxy; or a pharmaceutically acceptable salt thereof. More preferred are compounds of the formula (IC) wherein Ri6 and R-I7 are hydrogen; Z is free or esterified hydroxy, cyano or carboxy; or a pharmaceutically acceptable salt thereof. More preferred are compounds of the formula (IC) wherein Ri is hydrogen or -C (O) R4 in which R4 is monocyclic aryl; or a pharmaceutically acceptable salt thereof. Particular embodiments of the invention are: - [2-hydroxy-5- (1 H -pyrrol-2-yl) -phenyl] -1,1-dioxo-1, 2,5-thiadiazolidin-3-one; 5- (4-hydroxybiphenyl-3-yl) -1,1-dioxo-1,2,5-thiadiazolidin-3-one; 5- [2-hydroxy-5- (2H-pyrazol-3-yl) -phenyl] -1,1-dioxo-1, 2,5-thiadiazolidin-3-one; 5- [2-hydroxy-5- (1-methyl-1 H -pyrazol-4-yl) -phenyl] -1,1-dioxo-1,2,5-thiadiazolidin-3-one; 5- (5-furan-3-yl-2-hydroxyphenyl) -1,1-dioxo-1,2,5-thiadiazolidin-3-one; 5- [2-hydroxy-5- (1H-pyrazol-4-yl) -phenyl] -1,1-dioxo-1,2,5-thiadiazolidin-3-one; 5- (4'-Acetyl-4-hiroxibiphenyl-3-yl) -1,1-dioxo-1,2,5-thiazol-disid-3-one; 5- (4'-benzoyl-4-hiroxybiphenyl-3-yl) -1,1-dioxo-1,2,5-thiazol-disid-3-one; 5- [2-hydroxy-5- (1H-pyrrol-3-yl) -phenyl] -1,1-dioxo-1,2,5-thiadiazolidin-3-one; 4'-hydroxy-3 '- (1,1,4-trioxo-1, 2,5-thiadiazolidin-2-yl) -biphenyl-3-yl ester of methanesulfonic acid; 5- (3'-amino-4-hydroxybiphenyl-3-yl) -1,1-dioxo-1,2,5-thiadiazolidin-3-one; 5- (4-hydroxy-2'-methylbiphenyl-3-yl) -1,1-dioxo-1,2,5-thiadiazolidin-3-one; 5- [2-hydroxy-5- (1H-indol-2-yl) -phenyl] -1,1-dioxo-1,2,5-thiadiazolidin-3-one; [4-hydroxy-3 '- (1, 1, 4-trioxo-1, 2,5-thiadiazolidin-2-yl) -biphenyl-3-yl] -acetonitrile; (2-Cyanoethyl) -amide of 4'-hydroxy-3 '- (1, 1, 4-trioxo-1, 2,5-thiadiazolidin-2-yl) -biphenyl-3-carboxylic acid methyl ester 3 - [ 4'-hydroxy-3 '- (1, 1, 4-trioxo-1, 2,5-thiadiazolidin-2-yl) -biphenyl-3-yl] -propionic acid; 4'-Hydroxy-3 '- (1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl) -biphenyl-3-carboxylic acid (2-carbamoylethyl) -amide; 5- [3 '- (2-aminoethyl) -4-hydroxybiphenyl-3-yl] -1,1-dioxo-1,2,5-thiadiazolidin-3-one; 5- (3'-aminomethyl-4-hydroxibiphenyl-3-yl) -1,1-dioxo-1,2,5-thiadiazolidin-3-one; 5- (2-hydroxy-5-pyridin-3-yl-phenyl) -1,1-dioxo-1,2,5-thiazolidin-3-one; 5- (4-hydroxy-2'-methoxy-biphenyl-3-yl) -1,1-dioxo-1,2,5-thiadiazolidin-3-one; 5- (2-hydroxy-5-pyridin-4-yl-phenyl) -1,1-dioxo-1,2,5-thiadiazolidin-3-one; [4'-hydroxy-3 '- (1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl) biphenyl-4-yl] -acetic acid; 5- (4'-Chloro-4-hydroxybiphenyl-3-yl) -1,1-d -oxo-1,2,5-thiadiazolidin-3-one; 5- (3'-Chloro-4-hydroxybiphenyl-3-yl) -1,1-dioxo-1,2,5-thiadiazolidin-3-one; 5- [2-hydroxy-5- (6-methoxypyridin-3-yl) -phenyl] -1,1-dioxo-1,2,5- thiadiazolidin-3-one; 5- [5- (6-fluoropyridin-3-yl) -2-hydroxyphenyl] -1,1-dioxo-1,2,5-thiadiazolidin-3-one; 3- [4'-hydroxy-3 '- (1, 1, 4-trioxo-1, 2,5-thiadiazolidin-2-yl) -biphenyl-3-yl] -propionic acid ethyl ester; 5- (4-hydroxy-3'-methylbiphenyl-3-yl) -1,1-dioxo-1,2,5-thiadiazolidin-3-one; 5- (3'-Fluoro-4-hydroxybiphenyl-3-yl) -1,1-dioxo-1,2,5-thiadiazolidin-3-one; 5- (4'-Fluoro-4-hydroxybiphenyl-3-yl) -1,1-dioxo-1,2,5-thiadiazolidin-3-one; 5- (4-hydroxy-4'-methylbiphenyl-3-yl) -1,1-dioxo-1,2,5-thiadiazolidin-3-one; 3- [4'-hydroxy-3 '- (1, 1, 4-trioxo-1, 2,5-thiadiazolidi n-2-yl) -bifeni l-3-yl] -propionitrile; 4'-hydroxy-3 '- (1,1,4-trioxo-1,2,5-thiazolidin-2-M) -biphenyl-3-carbonitrile; 5- (4-hydroxy-3 ', 5'-dimethylbiphenyl-3-yl) -1,1-dioxo-1, 2,5-thiadiazolidin-3-one; 5- (4-hydroxy-3'-methoxybiphenyl-3-yl) -1,1-dioxo-1,2,5-thiadiazolidin-3-one; N- (2-hydroxyethyl) -2- [4'-hydroxy-3 '- (1) 1,4-trioxo-1,2,5-thiadiazolidin-2-yl) -biphenyl-4-yl] -acetamide; 2,2,2-trifluoro-N- [4'-hydroxy-3 '- (1, 1,4-trioxo-1,2,5-thiazolidin-2-yl) -biphenyl-3-yl] -acetamide; 1-etl-3- [4, -hydroxy-3, - (1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl) -biphenyl-3-yl] -urea; 1-Ethyl-3- [4'-hydroxy-3 '- (1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl) -biphenyl-3-ylmethyl] -urea; [4'-hydroxy-3 '- (1, 1, 4-trioxo-1, 2,5-thiadiazolidin-2-yl) -biphenyl-3-ylmethyl] -carbamic acid methyl ester; N- [4'-hydroxy-3, - (1,1,4-trioxo-1,2,5-thiadiazolin-2-yl) -biphenyl-3-ylmethyl-acetamide; [4'-hydroxy-3 '- (1, 1, 4-trioxo-1, 2,5-thiadiazolidin-2-yl) -biphenyl-3-ylmethyl] -carbamic acid benzyl ester; 1-ethyl-3- [4'-hydroxy-3 '- (1, 1, 4-trioxo-1, 2,5-thiadiazolidin-2-yl) -biphenyl-4-yl] -urea; 3- [4'-hydroxy-3 '- (1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl) -biphenyl-3-yl] -propionic acid; 5- acid. { 4- [4-hydroxy-3- (1, 1, 4-trioxo-1, 2,5-thiadiazolid i n-2-yl) -phenyl] -pyrazol-1-yl} -pentanoic; 5- [2-hydroxy-5- (1-propyl-1H-pyrazol-4-yl) -phenyl] -1,1-dioxo-1,2,5-thiadiazolidin-3-one; 5- [2-hydroxy-5- (1-isobutyl-1H-pyrazol-4-yl) -phenyl] -1,1-dioxo-1,2,5-thiadiazolidin-3-one; acidic ester of 5- acid. { 4- [4-hydroxy-3- (1, 1, 5-trioxo-1, 2,5-thiadiazolidin-2-yl) -phenyl] -1H-pyrazole-1-yl} -pentanoic; 5-. { 2-hydroxy-5- [1- (4,4,4-trifluorobutyl) -1H-pyrazol-4-yl] -phenyl} -1,1-dioxo-1,2,5-thiadiazolidin-3-one; 5-. { 2-hydroxy-5- [1- (3-methylbutyl) -1H-pyrazol-4-yl] -phenyl} -1, 1-dioxo- 1,2,5-thiadiazolidin-3-one; 5-. { 4- [4-hydroxy-3- (1, 1, 4-trioxo-1,2,5-thiazol-idin-2-yl) -phenyl] -1H-pyrazol-1-yl} pentanenitrile; 5-. { 4- [4-hydroxy-3- (1, 1, 4-trioxo-1, 2,5-thiadiazolid i n-2-yl) -phenyl] -1H-pyrazol-1-yl} -butyronitrile; 5- (2-hydroxy-5-phenoxyphenyl) -1,1-dioxo-1,2,5-thiadiazolidin-3-one; - (2-hydroxy-5-methoxyphenyl) -1,1-dioxo-1,2,5-thiadiazolidin-3-one; - (5-benzyl-2-hydroxyphenyl) -1,1-dioxo-1,2,5-thiadiazolidin-3-one; - (2-hydroxy-5-methylphenyl) -1,1-dioxo-1,2,5-thiadiazolidin-3-one; 5- (5-hexyl-2-hydroxyphenyl) -1,1-dioxo-1,2,5-thiadiazolidin-3-one; - (5-Butyl-2-hydroxyphenyl) -1,1-dioxo-1,2,5-thiadiazolidin-3-one; - [2-hydroxy-5- (tetrahydrofuran-3-yl) -phenyl] -1,1-dioxo-1, 2,5-thiadiazolidin-3-one; 5- [5- (4-fluorophenylenyl] -2-hydroxyphenyl] -1,1-dioxo-1,2,5-thiadiazolidin-3-one; 6- [4-hydroxy-3- (1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl) -phenyl] -hex-5-inonitrile; 6- [4-hydroxy-3- (1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl) -phenyl] -hex-5-ynoic acid; 5- [5- (3,3-dimethyl-but-1-ynyl) -2-hydroxyphenyl] -1,1-dioxo-1,2,5-triazolidin-3-one; 5- [2-hydroxy-5- (5-methylhexyl) -phenyl] -1,1-dioxo-1,2,5-thiadiazolidin-3-one; 6- [4-Hydroxy-3- (1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl) -phenyl] -hexanoic acid; - [5- (benc? Lam? Nomet?) -2-h? Drox? Phen? L] -1,1-d? Oxo-1,2,5-t? Ad? Azole? D- n- 3-one, 5- (5-but? Lam? Nomet-2-hydrox? Phen?) -1,1-d? Oxo-1,2,5-t? Ad? Azole? D? n- 3-one, 5-. { 2-h? Drox? -5 - [(2-methox? Benc? Lam? No) -met? L] -fen? L} -1,1-d? Oxo-1,2,5-t? Ad? Aolol d? N-3-one, 5-. { 5 - [(2-etox? Enc? Lam? No) -met? L] -2-h? Drox? Fen? L} -1,1-d? Oxo-1,2,5-t? Ad? Aolol d? N-3-one, 5-. { 2-h? Drox? -5 - [(2-? Sopropox? Benc? Lam? No) -met? L] -fen? L} -1,1-d? Oxo-1, 2,5-t? Ad? Azol? D? N-3-one 5- (2-h? Drox? -5- { [2- (1-met ? l-2-phen? letox?) -benz? lam? no] -met? l.}. -fen 11) -1,1-d? oxo-1, 2,5-t? ad? azole? d n-3-one, 5- [2-hydroxy? -5- (3-met? lbutox?) - phen? l] -1,1-d? oxo-1,2,5-t? ad Azole d-3-one, 5- [2-hydroxy? -5- (4-met? lpent? lox?) - phen? l] -1,1-d? oxo-1,2 , 5-t? Ad? Aolol-3-one, 5- (2-hydrox? -5-propox? Phen?) -1,1-d? Oxo-1,2,5- t? ad? azol? d? n-3-one, 2-h? Drox? -6-. { 4- [4-H? Drox? -3- (1, 1, 4-tr? Oxo-1, 2,5-t? Ad? Aolol? D? N-2-? L) -phen?] - butox ?} -N, N-d? Met? Lbenzam? Da, 2-h? Drox? -6-. { 5- [4-H? Drox? -3- (1,1,4-tr? Oxo-1,2,5-t? Ad? Aolol? D? N-2-? L) -phen?] - pent? lox ?} -N, N-d? Met? Lbenzam? Da, 2-h? Drox? -6-. { 6- [4-H? Drox? -3- (1, 1, 4-tr? Oxo-1, 2,5-t? Ad? Aolol? D? N-2-? L) -phen?] - hex? lox ?} -N, N-d? Met? Lbenzam? Da, 2-fluoro-6-. { 6- [4-H? Drox? -3- (1, 1,4-tr? Oxo-1,2,5-t? Ad? Aolol? D? N-2-? L) -phen?] - hex? lox ?} -N, N-d? Met? Lbenzam? Da, 2-hydroxy-6-. { 7- [4-hydroxy-3- (1, 1, 4 -tri oxo-1, 2,5-thiadiazolidin-2-yl) -phenyl] -heptyloxy} -N, N-dimethylbenzamide; 5- (4-hydroxy-4'-hydroxymethylbiphenyl-3-yl) -1,1-dioxo-1,2,5-thiadiazolidin-3-one; 5- (2-hydroxy-4,5-dimethyl-phenyl) -1,1-dioxo-1,2,5-thiadiazolidin-3-one; 5- [4-hydroxy-3- (1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl) -phenyl] -2,2-dimethylpentanoic acid; ethyl ester of 8- [4-hydroxy-3- (1, 1, 4-trioxo-1, 2,5-thiadiazolidin-2-yl) -phenyl] -2,2-dimethyloctanoic acid; 8- [4-hydroxy-3- (1, 1, 4-trioxo-1, 2,5-thiadiazolidin-2-yl) -phenyl] -2,2-dimethyloctanoic acid; 7- [4-hydroxy-3- (1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl) -phenyl] -2,2-dimethylheptanoic acid; 6- [4-hydroxy-3- (1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl) -phenyl] -2,2-dimethylhexanoic acid; 7- [4-hydroxy-3- (1,1-, 4-trioxo-1, 2,5-thiadiazolidin-2-yl) -phenyl] -2,2-dimethylheptanoic acid ethyl ester; 8- [4-hydroxy-3- (1,1,4-trioxo-1, 2,5-thiadiazolidin-2-yl) -phenyl] -2,2-dimethyloctanenitrile; 5- [2-hydroxy-5- (6-hydroxy-6-methyl] heptyl) -phenyl] -1,1-dioxo-1,2,5-thiadiazolidin-3-one; 5- [2-hydroxy-5- (7-hydroxy-6,6-dimethylheptyl) -phenyl] -1,1-dioxo-1,2,5-thiadiazolidin-3-one; 5- [2-hydroxy-5- (5-hydroxy-5-methylhexyl) -phenyl] -1,1-dioxo-1,2,5-thiadiazolidin-3-one; - [2-hydroxy-5- (8-hydroxy-7,7-dimethyloctyl) -phenyl] -1,1-dioxo-1, 2,5-thiadiazolidin-3-one; 7- [4-hydroxy-3- (1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl) -phenyl] -2,2-dimethylheptanonitrile; 5- [2-hydroxy-5- (5-hydroxy-5-methylhex-1-ynyl) -phenyl] -1,1-dioxo-1,2,5-thiadiazolidin-3-one; 5- [2-hydroxy-5- (2-pyridin-3-yl-ethyl) -phenyl] -1,1-dioxo-1, 2,5-thiadiazolidin-3-one; 5- (2-hydroxy-4-methyl-5-pentylphenyl) -1,1-dioxo-1,2,5-thiazole-ddin-3-one; 5- (2-hydroxy-4-methyl-5-propylphenyl) -1,1-dioxo-1,2,5-thiadiazolidin-3-one; 5- (5-heptyl-2-hydroxy-4-methylphenyl) -1,1-dioxo-1,2,5-thiadiazolidin-3-one; 5- [5- (2-cyclohexylethyl) -2-hydroxy-4-methylene] -1,1-dioxo-1,2,5-thiadiazolidin-3-one; 4- (7-hydroxy-6,6-dimethylheptyl) -2- (1, 1,4-trioxo-1,2,5-thiadiazolidin-2-yl) -f in the benzoic acid ester; and 4- (6-cyano-6,6-dimethylhexyl) -2- (1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl) -f in the benzoic acid ester; or a pharmaceutically acceptable salt thereof. The compounds of the invention which depend on the nature of the substituents may possess one or more asymmetric centers. The resulting diastereoisomers, enantiomers and geometric isomers are encompassed by the current invention. The compounds of the formula (I) can be prepared by initiating, for example, by cyclizing compounds of the formula: wherein Pg is an appropriate N-protecting group such as 4-methoxybenzyl, 2,4-dimethoxybenzyl or 2-trimethylsilylethyl, and R 8 is hydrogen to provide compounds of the formula: wherein Pg has a meaning as defined hereinbefore, by treatment with a coupling agent such as diisopropyl carbodiimide (DIC) or 1-ethyl I-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI) in the presence of a base such as triethylamine (TEA) or N-methyl-morpholine (NMM) in an organic solvent such as tetrahydrofuran (THF), N, N-dimethylformamide (DMF) or dichloromethane (DCM). The reaction can be carried out in the presence of an additive such as hydroxybenzotriazole (HOBt). Compounds of formula (II) wherein R18 is hydrogen can be obtained from compounds of formula (II), wherein R? 8 is an alkyl group according to methods well known in the art, for example, compounds of formula (II) wherein R18 is methyl or ethyl can be treated with an aqueous base such as sodium or potassium hydroxide in an organic solvent such as THF, 1,4-d-oxane, methanol (MeOH) or ethanol (EtOH) to provide compounds of formula (II) wherein R is hydrogen, or compounds of formula (II) wherein R18 is t-butyl can be treated with an acid such as hydrochloric acid (HCl) or tpfluoroacetic acid (TFA) in an organic solvent such as DCM or ethyl acetate (EtOAc) to provide compounds of formula (II) wherein R18 is hydrogen Compounds of formula (II) wherein R18 is an alkyl group such as methyl, ethyl, or t-butyl, and the like, can be obtained analogously with a literature procedure described by Ducry et al in Helvética Chimica Acta, 1999, 82, 2432 Compounds resulting from formula (III) wherein Pg has a meaning as defined herein may then be coupled with a variety of acid derivatives boronic of the formula where Ri ', R2' R3 'and Q' have the meanings as defined herein for R- ,, R2, R3 and Q, or R R2 ', R3' and Q 'are groups convertible to R ,, R2 , R3 and Q, respectively, and R and R 'are hydrogen or lower alkyl, or R and R' combined are alkylene which together with boron and oxygen atoms form a 5- or 6-membered ring, in the presence of a copper catalyst such as copper acetate (cf. ) and a base such as cesium carbonate (II) (Cs2CO3) or TEA in an organic solvent such as THF, 1,4-dioxane or DCM to form compounds of the formula: wherein Pg, RT, R2 ', R3' and Q 'have the meanings as defined herein for R1t R2, R3 and Q, or RT, R2', R3 'and Q' are groups convertible to R ^ R2, R3 and Q, respectively. Alternatively, compounds of formula (III) can be coupled with a boroxine derivative corresponding to a boronic acid derivative of formula (IV) as described, for example, by Chan et al. in 7"e Lett, 2003, 44, 3863. Compounds of formula (IV) are known, or if novel, can be prepared using methods well known in the art, or as illustrated herein in the Examples, or modifications of Alternatively, compounds of formula (V) wherein R? ', R2? R', R 'and Rs' have the meanings as defined herein for R1, R2, R3, R and R5 or R1', R2 ', R3', R 'and R5' are convertible groups for R ^ R2, R3, R4 and R5, respectively, can be obtained by reacting a compound of formula (III) wherein Pg has a meaning as defined herein with compounds of the formula: wherein Lg represents a leaving group such as halide or trifluoromethanesulfonate, preferably fluoride or chloride, and RT, R2? 3 'and Q' have the meanings as defined herein for RL R2, R3 and Q, or R-, ', R2', R3 'and Q' are convertible groups for Ri, R2, R3 and Q, respectively, using conditions well known in the art or using methods described herein or modifications thereof, for example, a compound of formula (III) can be first treated with a base such as Cs 2 CO 3, or sodium, lithium or potassium bis (trimethylsilyl) amide in an inert organic solvent such as THF or 1,4-dioxane followed by the reaction with a compound of formula (VI) at a temperature ranging from room temperature (RT) to 110 ° C. Compounds of formula (VI) are known, or if novel, can be prepared using methods well known in the art, or as illustrated herein. the Examples, or modifications thereof. Compounds of formula (V) wherein Pg, RT, R2 ', R3' and Q 'have the meanings as defined herein for Ri, R2, R3 and Q, or are groups convertible to Ri, R2, R3 and Q , respectively, can be converted to compounds of the formula: by removal of the N-protecting group according to methods well known in the art, for example in particular when Pg is a 4-methoxybenzyl or 2,4-dimethoxybenzyl group using hydrogen in the presence of a catalyst such as palladium on carbon in a solvent polar organic such as MeOH or EtOAc, or by treatment with an acid such as TFA in an organic solvent such as DCM, preferably in the presence of an additive such as t-butyldimethylsilane or triethylsilane, or in particular when Pg is a trimethylsilylethyl group using a fluoride reagent such as tetra-n-butylammonium fluoride in an organic solvent such as THF or 1,4-dioxane. In addition, compounds of formula (I ') wherein R ^, R2', R3 'and Q' have the meanings as defined herein for Ri, R2, R3 and Q, or Ri ', R2 \ R3' and Q 'are groups convertible to RL R2, R3 and Q, respectively, can be prepared by condensing compounds of the formula: wherein R 8 has a meaning as defined herein above, with sulfamoyl chloride analogues of the formula: CIS (0) 2 NHR19 (VIII) where R1? is hydrogen or alkoxycarbonyl such as t-butoxycarbonyl or 2-trimethylsilyl-ethoxycarbonyl in the presence of a base such as TEA or NMM in an organic solvent such as acetonitrile (MeCN), DCM or THF to form compounds of the formula: wherein R18 and R19 have the meanings as defined herein, and R-, ', R2', R3 'and Q' have the meanings as defined herein for Ri, R2, R3 and Q, or RT, R2 ', R3' and Q 'are groups convertible to RL R2, R3 and Q, respectively. Compounds of formula (VIII) wherein R1? is alkoxycarbonyl can be obtained by reacting chlorosulfonyl isocyanate with the appropriate alcohol in an organic solvent such as MeCN, DCM or THF. Compounds of formula (VII) can be prepared using methods well known in the art or according to methods described herein or modifications thereof, for example under conditions of reductive amination, or according to the method described by Tohru Fukuyama et al. . in Tet. Lett., 1997, 38 (33), 5831; or by reacting amines of the formula: wherein RT, R2 ', R3' and Q 'have the meanings as defined herein for RL R2, R3 and Q, or RT, R2', R3 'and Q' are groups convertible to RL R2, R3 and Q , respectively, with an acetate of the formula: Lg'-CH2-C (0) -0-R18 (XI) wherein Lg 'and R18 have the meanings as defined herein, in the presence of a base such as TEA or NMM in an inert solvent such as THF or 1,4-dioxane. Amines of formula (X) are known, or if novel, can be obtained according to methods well known in the art, or as described herein in the illustrative examples, or by using modifications thereof. D Compounds of formula (IX) wherein R-? 8 has a meaning as defined herein, and RT, R2 ', R3' and Q 'have the meanings as defined herein for RL R2, R3 and Q, or R, R2 ', R3' and Q 'are groups convertible to RL R2-R3 and Q, respectively, and R? g is alkoxycarbonyl can be converted to compounds of formula (IX) wherein R ^ is hydrogen according to known methods in the art or using methods described herein or modifications thereof, for example, compounds of formula (IX) wherein Rig is t-butoxycarbonyl can be treated with an acid such as TFA, neat or in an extrinsic organic solvent such as DCM, or compounds of formula (IX) wherein R-ig is 2-trimethylsilylethoxycarbonyl can be treated with a fluoride reagent such as tetra-n-butylammonium fluoride in an organic solvent such as THF or 1,4-dioxane to provide compounds of formula (IX) where R1? It is hydrogen. Compounds of formula (IX) wherein R-? 8 has a meaning as defined herein, and RT >; R2 R3 'and O' have the meanings as defined herein for RL R2, R3 and Q, or RT, R2 ', R3' and Q 'are groups convertible to RL R2, R3 and Q, respectively, and R19 is hydrogen can be cyclized to form compounds of formula (I ') using methods and conditions well known in the art or as illustrated by the Examples herein or modifications thereof. Alternatively, compounds of formula (IX) wherein Ría has a meaning as defined herein; RT, R2 ', R3' and Q 'have the meanings as defined herein for RL R2, R3 and Q, or Ri', R2 ', R3' and Q 'are groups convertible to RL R2 > R3 and Q, respectively; and Rig is hydrogen, can be obtained by first condensing amines of formula (X) with sulfamide in an aqueous solution and in the presence of a base such as sodium bicarbonate (NaHCO3) at an elevated temperature, preferably at the boiling point of the solution , to provide compounds of the formula: wherein Ri ', R2', R3 'and Q' have the meanings as defined herein for RL R2, R3 and Q, or R R2 ', R3' and Q 'are groups convertible to RL R2, R3 and Q , respectively. The compound of formula (XII) can then be converted to a compound of formula (IX) in which Rig is hydrogen by reaction with acetates of formula (XI) in the presence of a base such as sodium hydride in an inert solvent such as THF or DMF. In the starting compounds and intermediates which are converted to the compounds of the invention in a manner described herein, functional groups present, such as amino, thiol, carboxyl and hydroxyl groups, are protected optionally by conventional protecting groups that are common in preparative organic chemistry. Protected amino, thiol, carboxyl and hydroxyl groups are those which can be converted under mild conditions to the free amino, thiol, carboxyl and hydroxyl groups without the molecular structure being destroyed or other unwanted side reactions are carried out. The purpose for introducing protecting groups is to protect the functional groups from undesired reactions with reaction components under the conditions used to carry out a chemical transformation. The need and choice of protecting groups for a particular reaction is known to those skilled in the art and depends on the nature of the functional group that is protected (hydroxyl group, amino group, etc.), the structure and stability of the molecule of the which the substituent is a part and the reaction conditions. Well-known protecting groups that meet these conditions and their introduction and elimination are described, for example, in McOmie, "Protective Groups in Organic Chemistry," Plenum Press, London, New York (1973); and Greene and Wuts, "Protective Groups in the Organic Synthesis", John Wiley and Sons, Inc, New York (1999). The reactions mentioned above are carried out according to standard methods, in the presence or absence of a diluent, preferably such as are inert to the reactants and are solvents thereof, or catalysts, to condense or the other agents respectively and / or inert atmospheres, at low temperatures, room temperature or elevated temperatures (preferably at or near the boiling point of the solvents used), and at atmospheric or super-atmospheric pressure. Preferred solvents, catalysts and reaction conditions are set forth in the accompanying illustrative examples. The invention also includes any variant of the present processes, in which an intermediate product obtainable at any stage thereof is used as a starting material and the remaining steps are carried out, or in which the starting materials are formed in situ. under the reaction conditions, or in which the reaction components are used in the form of their optically pure salts or antipodes. Compounds of the invention and intermediates can also be converted to each other according to methods generally known per se. The invention also relates to any novel starting materials, intermediates and processes for their manufacture. Depending on the choice of starting materials and methods, the new compounds may be in the form of one of the possible isomers or mixtures thereof, for example, as substantially pure geometric isomers (cis or trans), optical isomers (enantiomers, antipodes), racemates, or mixtures thereof. The above possible isomers or mixtures thereof are within the field of view of this invention. Any resulting mixtures of isomers can be separated on the basis of the physico-chemical differences of the constituents, in the pure geometric or optical isomers, diastereoisomers, racemates, for example by chromatography and / or fractional crystallization. Any racemates resulting from final products or intermediates can be resolved in the optical antipodes by known methods, for example by separating the diastereomeric salts thereof, obtained with an optically active acid or base, and releasing the optionally active acidic or basic compound. The carboxylic acid intermediates can thus be resolved in their optical antipodes for example by fractional crystallization of D- or L- (alpha-methylbenzylamine, cinchonidine, cinchonine, quinine, quinidine, ephedrine, dehydroabietylamine, brucine or strychnine salts). Racemic products can also be resolved by chiral chromatography, for example high pressure liquid chromatography using a chiral adsorbent. Finally, compounds of the invention are either obtained in the free form, as a salt thereof if salt-forming groups are present or as derivatives of prodrugs thereof. In particular, the NH group of the 1,1-dioxo-1, 2,5-thiadiazolidin-3-one portion can be converted into salts with pharmaceutically acceptable bases. The salts can be formed using conventional methods, advantageously in the presence of an ethereal or alcoholic solvent, such as a lower alkanol. From the most recent solutions, the salts can be precipitated with ethers, for example diethyl ether. Resulting salts can be converted to the free compounds by treatment with acids. These or other salts can also be used for purification of the obtained compounds. Compounds of the invention having basic groups can be converted to acid addition salts, especially pharmaceutically acceptable salts. These are formed, for example, with inorganic acids, such as mineral acids, for example sulfuric acid, a phosphoric or hydrohalic acid, or with organic carboxylic acids, such as (C1-) alkanecarboxylic acids which, for example, are not substituted or substituted by halogen, for example acetic acid, such as saturated or unsaturated dicarboxylic acids, for example oxalic, succinic, maleic or fumaric acid, such as hydroxycarboxylic acids, for example glycolic, lactic, malic, tartaric or citric acid, such as amino acids, for example aspartic or glutamic acid, or with organic sulfonic acids, such as (C1-) alkyl sulfonic acids (eg methanesulfonic acid) or arylsulfonic acids which are unsubstituted or substituted (for example by halogen). Preferred are salts formed with hydrochloric acid, methanesulfonic acid and maleic acid. Prodrug derivatives of any compound of the present invention are derivatives of the compounds that after administration release the main compound in vivo via some chemical or physiological processes, for example, a prodrug that leads to physiological pH or through the action of the enzyme is converted to the main compound. Exemplary prodrug derivatives are, for example, esters of free carboxylic acids and S-acyl and O-acyl derivatives of thiols, alcohols or phenols, wherein acyl has a meaning as defined herein. Preferred are pharmaceutically acceptable ester derivatives convertible by solvolysis under physiological conditions to the main carboxylic acid, for example lower alkyl esters, cycloalkyl esters, lower alkenyl esters, benzyl esters, mono- or di-substituted lower alkyl esters, as the esters of α- (amino, mono- or di-lower alkylamino, carboxy, lower alkoxycarbonyl) -lower alkyl, the esters of a- (lower alkanoyloxy, lower alkoxycarbonyl or di-lower alkylaminocarbonyl) - lower alkyl, such as the pivaloyloxymethyl ester and the like conventionally used in the art. In view of the close relationship between the free compounds, the prodrug derivatives and the compounds in the form of their salts, each time a compound is referred to as in this context, a prodrug derivative and a corresponding salt is also intended, with the condition that such is possible or appropriate under the circumstances. The compounds, including their salts, may also be obtained in the form of their hydrates, or include other solvents used for their crystallization. As described hereinbefore, the compounds of the present invention are inhibitors of PTPases and, thus, can be used for the treatment of conditions mediated by PTPases. Accordingly, the compounds of formula (I) can be used for treatment of insulin resistance, glucose intolerance, obesity, diabetes mellitus, hypertension and ischemic diseases of large or small blood vessels, conditions that accompany type 2 diabetes including dyslipidemia, for example, hyperlipidemia and hypertriglyceridemia, atherosclerosis, vascular restenosis, irritable bowel syndrome, pancreatitis, adipose cell tumors and carcinomas such as liposarcoma, dyslipidemia, and other disorders where insulin resistance is indicated.

In addition, the compounds of the present invention can be used to treat cancer (such as prostate or breast cancer), osteoporosis, infectious and neurodegenerative diseases, and diseases involving inflammation and the immune system. The present invention further provides pharmaceutical compositions comprising a therapeutically effective amount of a pharmacologically active compound of the current invention, alone or in combination with one or more pharmaceutically acceptable carriers. The pharmaceutical compositions according to the invention are those suitable for enteral administration, such as orally or rectally; transdermal and parenteral to mammals, including man, for the treatment of conditions mediated by PTPase activity, in particular, PTP-1B and TC PTP activity. Such conditions include insulin resistance, glucose intolerance, obesity, diabetes mellitus, hypertension and ischemic diseases of large or small blood vessels, conditions that accompany type 2 diabetes including dyslipidemia, for example, hyperlipidemia and hypertriglyceridemia, atherosclerosis, restenosis vascular, irritable bowel syndrome, pancreatitis, adipose cell tumors and carcinomas such as liposarcoma, dyslipidemia, and other disorders where insulin resistance is indicated. In addition, the compounds of the present invention can be used to treat cancer (such as prostate or breast cancer), osteoporosis, infectious and neurodegenerative diseases, and diseases involving inflammation and the immune system. In this way, the pharmacologically active compounds of the invention can be used in the manufacture of pharmaceutical compositions comprising an effective amount thereof in combination or mixture with suitable excipients or carriers for any enteral or parenteral application. Preferred are gelatin capsules and tablets comprising the active ingredient together with: a) diluents, for example, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine; b) lubricants, for example, silica, talc, stearic acid, its magnesium or calcium salt and / or polyethylene glycol; for tablets also c) binders, for example, magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone; if desired d) disintegrants, for example, starches, agar, alginic acid or its sodium salt, or effervescent mixtures; and / or e) absorbers, colorants, flavors and sweeteners. Injectable compositions are preferably aqueous isotonic solutions or suspensions, and suppositories are advantageously prepared from emulsions or suspensions. The compositions can be sterilized and / or contain adjuvants, such as preservatives, stabilizers, wetting agents or emulsifiers, solution promoters, salts for regulating the osmotic pressure and / or buffers. In addition, they may also contain other therapeutically valuable substances. The compositions are prepared according to conventional mixing, granulation or coating methods, respectively, and contain about 0.1-75%, preferably about 1-50%, of the active ingredient. Formulations suitable for transdermal application include a therapeutically effective amount of a compound of the invention with carrier. Advantageous carriers include pharmacologically acceptable absorbable solvents to assist passage through the skin of the host. Characteristically, transdermal devices are in the form of a bandage comprising a support member, a container containing the compound optionally with carriers, optionally a barrier that controls the rate to deliver the compound of the host skin at a predetermined and controlled rate for a prolonged period of time, and means to secure the device to the skin.

Accordingly, the present invention provides pharmaceutical compositions as described above for the treatment of conditions mediated by PTPases, preferably, insulin resistance, glucose intolerance, obesity, diabetes mellitus, hypertension, and ischemic diseases of the large blood vessels. small, conditions that accompany type 2 diabetes including dyslipidemia, for example, hyperlipidemia and hypertriglyceridemia, atherosclerosis, vascular restenosis, irritable bowel syndrome, pancreatitis, adipose cell tumors and carcinomas such as liposarcoma, dyslipidemia, and other disorders where resistance is indicated to insulin. In addition, the compounds of the present invention can be used to treat cancer (such as prostate or breast cancer), osteoporosis, infectious and neurodegenerative diseases, and diseases involving inflammation and the immune system.

The pharmaceutical compositions may contain a therapeutically effective amount of a compound of the invention as defined above, either alone or in combination with another therapeutic agent, for example, each at an effective therapeutic dose as reported in the art. Such therapeutic agents include: a) anti-diabetic agents, such as insulin, insulin derivatives and mimetics; insulin secretagogues such as sulfonylureas, for example, Glipizide, glyburide and Amaril; insulinotropic sulfonylurea receptor ligands such as meglitinides, for example, nateglinide and rapaglinide; thiazolidone derivatives such as glitazones, for example, pioglitazone and rosiglitazone; glucokinase activators; inhibitors of GSK3 (glycogen synthase kinase-3) such as SB-517955, SB-4195052, SB-216763, NN-57-05441 and NN-57-05445; RXR ligands such as GW-0791 and AGN-194204; co-transporter inhibitors of sodium-dependent glucose such as T-1095; inhibitors of glycogen phosphorylase A such as BAY R3401; biguanides such as meformin; alpha-glucosidase inhibitors such as acarbose; GLP-1 (glucagon as peptide-1), GLP-1 analogs such as Exendin-4 and GLP-1 mimetics; modulators of PPARs (activated peroxisome proliferator receptors), for example, PPAR agonists? non-glitazone type such as N- (2-benzoylphenyl) -L-tyrosine analogs, for example GI-262570, and JTT501; inhibitors of DPPIV (dipeptidyl peptidase IV) such as LAF237, MK-0431, saxagliptin and GSK23A; inhibitors of SCD-1 (stearoyl-CoA desaturase-1); DGAT1 and DGAT2 inhibitors (Iglycerol acyltransferase d iaci 1 and 2); ACC2 inhibitors (acetyl CoA carboxylase 2); and AGE grinders (advanced glycol end products); b) anti-dyslipidemic agents such as coenzyme A reductase inhibitors of 3-hydroxy-3-methyl-glutaryl (HMG-CoA), for example lovastatin, pitavastatin, pravastatin, cepvastatma, mevastatin, velostatma, fluvastatin, dalvastatin, atorvastatma, rosuvastatin and pvastatin, compounds that increase HDL such as cholesterol ester transfer protein (CETP) inhibitors, for example, JTT705, Apo-A1 analogs and mimetics, inhibitors of squalene synthase, ligands of FXR (receptor of farnesoid X) and of LXR (receptor of liver X), cholestepamine, fibrates, nicotinic acid, and aspirin, c) anti-obesity agents such as phentermine, leptin, bromocpptine, dexamfetamine, amphetamine, fenfluramine, desfenfluramine, sibutramine, orhstat, dexfenfluramine, mazmdol, phentermine, phendimetrazine, diethylpropion, fluoxetine, bupropion, topiramate, diethylpropion, benzfetamine, phenylpropanolamm, ecopipam, ephedrine, and pseudoephedrine, cholesterol absorption modulators such as ZETIA® and KT6 -971, and antagonists of the cannabinoid receptor such as pmonabant, and d) anti-hypertensive agents, for example, loop diuretics such as acid and tacrinic, furosemide and torsemide, enzyme inhibitors that convert angiotensin (ACE) such as benazeppl, captoppl, enalappl, fosinoppl, hsinoppl, moexippl, pepnodoppl, qumappl, ramippl and trandolappl, inhibitors of the membrane pump of Na-K-ATPase such as digoxin, neutralendopeptidase inhibitors (NEP), ACE / NEP inhibitors such as omapatplat, sampatplat and fasidotril; angiotensin II antagonists such as candesartan, eprosartan, irbesartan, losartan, telmisartan and valsartan, in particular valsartan; renin inhibitors such as ditekiren, zankiren, terlakiren, aliskiren, RO 66-1132 and RO-66-1168; ß-adrenergic receptor blockers such as acebutolol, atenolol, betaxolol, bisoprolol, metoprolol, nadolol, propranolol, sotalol and timolol; inotropic agents such as digoxin, dobutamine and milrinone; calcium channel blockers such as amlodipine, bepridil, diltiazem, felodipine, nicardipine, nimodipine, difedipine, nisoldipine and verapamil; Aldosterone receptor antagonists such as eplerenone; and aldosterone synthase inhibitors such as anastrazole and fadrazole. Other specific anti-diabetic compounds are described in Patel Mona in Expert Opin Investig Drugs, 2003, 12 (4), 623-633, in Figures 1 to 7, which are incorporated herein by reference. A compound of the present invention can be administered either simultaneously, before or after the other active ingredient, either separately by the same or different route of administration or together in the same pharmaceutical formulation. The structure of the therapeutic agents identified by code numbers, generic or brand names can be taken from the current edition of the standard compendium "The Merck Index" or from databases, for example, Patents International (for example, IMS World Publications). The corresponding content thereof is incorporated herein by reference. Accordingly, the present invention provides pharmaceutical compositions comprising a therapeutically effective amount of a compound of the invention in combination with a therapeutically effective amount of another therapeutic agent, preferably selected from antidiabetics, hypolipidemic agents, anti-obesity agents or anti-aging agents. hypertensive, more preferably anti-diabetic or anti-obesity agents as described above. The present invention also relates to pharmaceutical compositions as described above for use as a medicament. The present invention further relates to the use of pharmaceutical compositions or combinations as described above for the preparation of a medicament for the treatment of conditions mediated by PTPase activity, in particular the activity of PTP-1B and TC PTP. Such conditions include insulin resistance, glucose intolerance, obesity, diabetes mellitus, hypertension and ischemic diseases of large or small blood vessels, conditions that accompany type 2 diabetes including dyslipidemia, for example, hyperlipidemia and hypertriglyceridemia, atherosclerosis, vascular restenosis, irritable bowel syndrome, pancreatitis, adipose cell tumors and carcinomas such as liposarcoma, dyslipidemia, and other disorders where insulin resistance is indicated. In addition, the compounds of the present invention can be used to treat cancer (such as prostate or breast cancer), osteoporosis, infectious and neurodegenerative diseases, and diseases involving inflammation and the immune system. In this way, the present invention also relates to a compound of the formula (I) for use as a medicament, for the use of a compound of the formula (I) for the preparation of a pharmaceutical composition for the treatment of conditions mediated by PTPase activity, in particular, the activity of PTP-1B and TC PTP, and to a pharmaceutical composition for use under conditions mediated by PTPase activity, in particular, activity of PTP-1B and TC PTP, comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable diluent or carrier therefor. The present invention further provides a method for the treatment of conditions mediated by PTPase activity, in particular PTP-1B and TC PTP activity, which method comprises administering an amount therapeutically effective of a compound of the present invention. A unit dosage for a mammal of about 50 to 70 kg may contain between about 1 mg and 1000 mg, advantageously between about 5 mg to 500 mg of the active ingredient. The therapeutically effective dosage of a compound of formula I is dependent on the species of warm-blooded animal (mammal), body weight, age and individual condition, in the form of administration, and on the compound involved. In accordance with the foregoing, the present invention also provides a therapeutic combination, for example, a kit, kit of parts, for example, for use in any method as defined herein, comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, to be used concomitantly or in sequence with at least one pharmaceutical composition comprising at least one other therapeutic agent, preferably selected from anti-diabetic agents, hypolipidemic agents, anti-obesity agents or anti-hypertensive agents . The team can understand instructions for its administration. Similarly, the present invention provides a kit of parts comprising: (i) a pharmaceutical composition of the invention; and (ii) a composition Pharmaceutical comprising a compound selected from an anti-diabetic agent, a hypolipidemic agent, an anti-obesity people, an anti-hypertensive agent, or a pharmaceutically acceptable salt thereof, in the form of two separate units of the components (i) ) a (ii). Similarly, the present invention provides a method as defined above comprising co-administration, for example, concomitantly or in sequence, of a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, and a second drug substance, the second drug substance being an anti-diabetic, a hypolipidemic agent, an anti-obesity agent or an anti-hypertensive agent, for example, as indicated above. Preferably, a compound of the invention is administered to a mammal in need thereof. Preferably, a compound of the invention is used for the treatment of a disease that responds to the modulation of PTPase activity, in particular, the activity of PTP-1B and TC PTP. Preferably, the condition associated with PTPase activity, in particular, activity of PTP-1B and TC PTP, is selected from insulin resistance, glucose intolerance, obesity, diabetes mellitus, hypertension and ischemic diseases of blood vessels. great small, conditions that accompany type 2 diabetes including dyslipidemia, for example, hyperlipidemia and hypertriglyceridemia, atherosclerosis, vascular restenosis, irritable bowel syndrome, pancreatitis, adipose cell tumors and carcinomas such as liposarcoma, dyslipidemia, and other disorders where resistance is indicated to insulin. In addition, the compounds of the present invention can be used to treat cancer (such as prostate or breast cancer), osteoporosis, infectious and neurodegenerative diseases, and diseases involving inflammation and the immune system. Finally, the present invention provides a method or use which comprises administering a compound of formula (I) in combination with a therapeutically effective amount of an anti-diabetic agent, a hypolipidemic agent, an anti-obesity agent or an anti-hypertensive agent. Finally, the present invention provides a method or use which comprises administering a compound of formula (I) in the form of a pharmaceutical composition as described herein. As used throughout the specification and in the claims, the term "treatment" encompasses all different forms or modes of treatment as known to those of the pertinent art and in particular includes preventive, curative, delayed and progressive treatment. palliative. The properties cited above are demonstrable tests in vitro and in vivo, advantageously using mammals, for example, mice, rats, dogs, monkeys or isolated organs, tissues and preparations thereof. The compounds can be applied in vitro in the form of solutions, for example preferably aqueous solutions, and in vivo either enterally, parenterally, advantageously intravenously, for example as a suspension or in aqueous solution. The in vitro dosage can vary between concentrations of approximately 103 molar and 10"11 molar or between concentrations of approximately 10'3 molar and 10" 10 molar. A therapeutically effective amount in vivo may vary depending on the route of administration, between about 0.1 and 500 mg / kg or between about 1 and 500 mg / kg, preferably between about 5 and 100 mg / kg. The activity of a compound according to the invention can be assessed by the following methods or by the following methods well described in the art (e.g., Peters G. et al., J. Biol. Chem., 2000, 275, 18201-09 ). For example, the inhibitory activity of PTP-1B in vitro can be determined as follows: Evaluation of the activity of human PTP-1B (hPTP-1B) in the presence of various agents is determined by measuring the amount of inorganic phosphate released from a phosphopeptide substrate using a 96-well microtiter plate format. The assay (100 μL) is performed in a test buffer comprised of 50 mM TRIS (pH 7.5), 50 mM NaCl, 3 mM DTT at room temperature. The assay is typically performed in the presence of 0.4% dimethyl sulfoxide (DMSO). However, concentrations as high as 10% are used with certain poorly soluble compounds. A typical reaction is initiated by the addition of 0.4 pmoles of hPTP-1B (1-411 amino acids) to wells containing assay buffer, 3 nmoles of the synthetic phosphopeptide substrate (GNGDp YMPMSPKS), and the test compound. After 10 minutes, a malachite green reagent of 180 μL (0.88 mM malachite green, 8.2 mM ammonium molybdate, 1 N aqueous HCl, and 0.01% Triton X-100) was added to terminate the reaction. Inorganic phosphate, a product of the reaction of the enzyme, is quantified after 15 minutes as the green color resulting from complexation with the Malichite reagent and determined as an A620 using a SpectraMAX Plus spectrophotometer, Molecular Devices (Sunnyvale, AC). Test compounds are solubilized in 100% DMSO (Sigma, D-8779) and diluted in DMSO. The activity is defined as the pure change in absorbance resulting from the activity of hPTP-1B [1-411] not inhibited less than from a tube with hPTP-1 B (1- n) inactivated with acid. B [L n] is cloned by PCR from a human hippocampal cDNA library (Clonetech) and inserted into a pET 19-b vector (Novagen) at the Ncol restriction site. The strain E. coli BL21 (DE3) is transformed with this clone and stored as a solution culture in 20% glycerol at -80 ° C. For enzyme production, a solution culture is inoculated in Lb / Amp and developed at 37 ° C. The expression of PTP-1B is initiated by induction with 1 mM IPTG after the culture has reached OD600 = 0.6. After 4 hours, the bacterial peptide was collected by centrifugation. The cells were resuspended in 70 mL of lysis buffer (50 mM Tris, 100 mM NaCl, 5 mM DTT, 0.1% Triton X-100, pH 7.6), incubated on ice for 30 minutes, then sonicated ( bursts of 4 x 10 sec in full power). The lysate was centrifuged at 100,000 x g for 60 minutes and the supernatant is buffer exchanged and purified in a PORS 20SP column cation exchange followed by a Source 30Q column anion exchange (Pharmacia), using linear NaCl gradient elutions. The enzyme was combined, adjusted to 1 mg / mL and frozen at -80 ° C. Alternatively, the assessment of the activity of human PTP-1B in the presence of various agents can be determined by measuring the hydrolysis products of known competent substrates. For example, substrate dissociation para-nitrophenyl phosphate (pNPP) results in the release of para-nitrophenol yellow (pNP) that can be monitored in real time using a spectrophotometer. Similarly, fluorogenic substrate hydrolysis ammonium phosphate salt 6,8-difluoro-4-methylumbelliferyl (DiFMUP) results in release of the fluorescent DiFMU the which can be readily followed in a continuous mode with a fluorescence reader (Anal. Biochem 273, 41, 1999; Anal. Biochem. 338, 32, 2005): pNPP assay Compounds were incubated with 1 nM recombinant human PTP-1 B [L298] or PTP-1B [1-322] in buffer (Hepes 50 mM, pH 7.0, 50 mM KCl, 1 mM EDTA, 3 mM DTT, 0.05% NP-40 for 5 minutes at room temperature The reaction was initiated by the addition of pNPP (2 mM final concentration) and run for 120 minutes at room temperature Reactions were annealed with 5 N NaOH Absorbance at 405 nm was measured using any standard 384 well plate reader DiFMUP assay Compounds were incubated with PTP-1B [1-298] or PTP -1B [i-322] 1 nM recombinant human in buffer (50 mM Hepes, pH 7.0, 50 mM KCl, 1 mM EDTA, 3 mM DTT, 0.05% NP-40 (or 0.001% BSA) for 5 minutes at room temperature. The reaction was initiated by the addition of DiFMUP (6 μM final concentration) and run kinetically in a fluorescence plate reader at excitation 355 nm wavelengths and emission 460 nm. Reaction speeds for 15 minutes they were used to calculate the inhibition. PTP-1B [298] was expressed in plasmid constructs containing E. coli BL21 (DE3) using pET19b vectors (Novagen). Bacteria develop on minimal media using an "On Demand" batch feed strategy. Typically, a 5.5-liter fermentation was started in batch mode of food and developed overnight at 37 ° C automatically. Optical densities were varied between 20-24 OD600 and the cultures were induced at 30 ° C with IPTG at a final concentration of 0.5 mM. The bacterial cells were harvested 8 hours later and produced 200-350 g (wet weight). The cells were frozen as pellets and stored at -80 ° C until use. All stages were performed at 4 ° C unless observed. Cells (-15 g) were briefly thawed at 37 ° C and resuspended in 50 mL of buffer lysis containing 50 mM Tris-HCl, 150 mM NaCl, 5 mM DTT, pH 8.0 containing one tablet of complete protease cocktail (EDTA-free) (Boehringer Mannheim), 100 μM of PMSF and 100 μg / mL of DNase I. Cells were used by sonification (bursting of 4 x 10 seconds, full power) using a Virsonic 60 ( Virtus). The pellet was collected at 35,000 x g, resuspended in 25 mL of lysis buffer using a Polytron and collected as above. The two supernatants were combined and centrifuged for 30 minutes at 100,000 x g. The lysate soluble could be stored in this stage at -80 ° C or used for another purification. Using diafiltration, a 10 kD MWCO membrane is used to buffer the protein to reduce the concentration of NaCl before cation exchange chromatography. The diafiltration buffer contained 50 mM of MES, 75 mM of NaCl, 5 mM of DTT, pH 6.5. Soluble supernatant was then loaded onto a POROS 20 SP (1 x 10 cm) column equilibrated with cation exchange buffer (50 mM MES and 75 mM NaCl, pH 6.5) at a rate of 20 mL / min. An analytical column (4.6 x 100 mm) was run in a similar manner except that the flow rate was reduced to 10 mL / min. The protein was eluted from the column using a linear salt gradient (75-500 mM NaCl in 25 CV). Fractions containing PTP-1B [1-298] were identified and combined according to the SDS-PAGE analysis. The final purification was performed using Sephacryl S-100 HR (Pharmacia). The column (2.6 x 35 cm) was equilibrated with 50 mM HEPES, 100 mM NaCl, 3 mM DTT, pH 7.5 and run at a flow rate of 2 mL / min. The final protein was combined and concentrated to ~5 mg / mL using an Ultrafree-15 concentrator (Millipore) with a MWCO 10,000. The concentrated protein was stored at -80 ° C until use. The competitive link for the active site of the enzyme can be determined as follows: Ligand binding was detected by acquiring 1H-15N HSQC spectra in 250 μL of 0.15 mM PTP-1 B [L298] in the presence and absence of the aggregate compound (1-2 mM). The linkage is determined by observing the chemical change of 15N- or 1H-amide, changing in two dimensional HSQC spectra with the addition of a compound to the protein labeled with 15N. Due to the 15N spectral wording, no signal was observed from the ligand, only protein signals. In this way, the bond can be detected in high concentrations of compound. Compounds that cause a chemical change design, changes similar to the changes observed with known active-site binders are considered positive. All proteins are expressed in plasmid constructs containing E. coli BL21 (DE3) using pET19b vectors (Novagen). Uniformly, PTP-1 BL 298 labeled with 15N was produced by developing bacteria in minimal media containing ammonium chloride labeled with 15N. All purification steps were carried out at 4 ° C. The cells were thawed (-15 g) briefly at 37 ° C and resuspended in 50 mL of lysis buffer containing 50 mM Tris-HCl, 150 mM NaCl, 5 mM DTT, pH 8.0 containing a Complete protease cocktail tablet (EDTA-free) (Boehringer Mannheim), 100 μM PMSF and 100 μg / mL DNase I. Cells were used by sonification. He This was collected at 35,000 x g, resuspended in 25 mL of lysis buffer using a Polytron and harvested as above. The two supernatants were combined and centrifuged for 30 minutes at 100,000 x g. Using diafiltration, a 10 kD MWCO membrane was used to exchange the protein buffer and reduce the NaCl concentration before cation exchange chromatography. The diafiltration buffer contained 50 mM of MES, 75 mM of NaCl, 5 mM of DTT, pH 6.5. Soluble supernatant was then loaded onto a POROS 20 SP (1 x 10 cm) column equilibrated with cation exchange buffer (50 mM MES and 75 mM NaCl, pH 6.5) at a rate of 20 mL / min. The protein was eluted from the column using a linear salt gradient (75-500 mM NaCI in 25 CM). Fractions containing PTB-1B are identified and combined according to the SDS-PAGE analyzes. PTP-1B? -29β is further purified by anion exchange chromatography using a POROS 20 HQ column (1 x 10 cm). The combination from the cation exchange chromatography was concentrated and the buffer exchanged in 50 mM Tris-HCl, pH 7.5 containing 75 mM NaCl and 5 mM DTT. The protein was loaded onto a column at 20 mL / min and eluted using a gradient of linear NaCl (75-500 mM in 25 CV). Linear purification was performed using Sephacryl S-100 HR (Pharmacia) (50 mM HEPES, 100 mM NaCl, 3 mM DTT, pH 7.5). The NMR samples are composed of PTP-1 B 298 labeled with 5N (0.15 mM) and the inhibitor (1-2 mM) in a bis-Tris-dig buffer solution of 10% D2O / 90% H2O (50 mM, pH = 6.5) containing NaCl (50 mM), DL-1, 4-Dithiothreitol-d (5 mM) and sodium azide (0.02%). The HSQC 1H-15N spectra were recorded at 20 ° C, in Bruker DRX500 or DMX500 NMR spectrometers. In all NMR experiments, pulsed field gradients were applied to provide the solvent signal suppression. The detection of quadrature in the indirectly detected dimensions is accompanied using the States -TPPI method. The data is processed using Bruker software and analyzed using NMRCompass (MSI) software on Silicon Graphics computers. The activity that decreases glucose and insulin in vivo can be evaluated as follows: Adult male C57B ob / ob mice (Jackson Lab, Bar Harbor, ME) at the age of 11 weeks were housed six per box in a quarter cycle of light Reverted (light from 6:00 pm to 6:00 am) and had access to Purina rodent food and water ad libitum. On day 1, blood samples were taken from the tail at 8:00 a.m. and plasma glucose levels were determined. The animals were randomly assigned to the control and compound groups. The means of plasma glucose values of the groups were matched. Fuero then orally dosed animals with vehicle (0.5% carboxymethylcellulose with 0.2% Tween-80) or compounds (at 30 mg / kg) in vehicle. The mice were dosed daily for a total of 3 days. On day 4, basal blood samples were taken. Plasma samples were analyzed for glucose concentrations using a YSI2700 Dual Channel Biochemistry Analyzer (Yellow Springs Instrument Co., Yellow Springs, OH) and insulin concentrations using an ELISA assay. The following Examples are intended to illustrate the invention and are not to be construed as limitations therein. Temperatures are given in degrees Celsius (° C). If not mentioned otherwise, all evaporations are carried out under reduced pressure, preferably between approximately 15 and 100 mm Hg (= 20-133 mbar). The structure of final products, intermediates and starting materials is confirmed by standard analytical methods, for example, microanalysis, melting point (p.f.) and spectroscopic characteristics (e.g., EM, IR, NMR). In general, the abbreviations used are those conventional in the art. Method A: C-8 reverse phase column of 4.6 mm x 5 cm, 3 μm particle size running a gradient of 10-90% MeCN / water (5 mM ammonium bicarbonate) for a period of 2 minutes at flow rate of 4 mL / min, at 50 ° C (injection of 3 μL). Detection of DAD-UV, 220-600 nm. Example 1 5- [2-Hydroxy-5- (1H-pyrrol-2-yl) -phenyl] -1,1-dioxo-1,2,5-thiadiazolidin-3-one A. 1-Benzyloxy-4-bromo-2-nitrobenzene A solution of 4-bromo-2-nitrophenol (226.81 g, 1.04 mol) in DMF (2 L) was treated with potassium carbonate (172.55 g, 1.24 mol). The suspension was stirred by mechanical stirring and heated to 50 ° C. Benzyl bromide (148 mL 1.25 mol) was added and the suspension was heated at 62 ° C for 3 hours and 72 ° C for an additional 40 minutes, at which point the reaction was judged complete by LCMS. (CLEM). The suspension was filtered and the filter cake was washed in portions with DMF (0.5 L). Water (5 L) was added to the DMF solution, which was then cooled gradually to 23 ° C with vigorous stirring. The precipitate was filtered and dried in a vacuum oven to provide 1-benzyloxy-4-bromo-2-nitrobenzene as a yellow solid: NMR 1H (CDCl 3) d 7.89 (d, J = 2 Hz, 1H), 7.50 (dd, J = 12, 2 Hz, 1H), 7. 30 (m, 5H), 6.93 (d, J = 12 Hz, 1H), 5.14 (s, 2H). B. 2-Benzyloxy-5-bromophenylamine To a solution of 1-benzyloxy-4-bromo-2-nitrobenzene (10.6 g, 34.4 mmol) in EtOH (70 mL) and AcOH (26 mL) were added. added iron powder (9.61 g, 172 mmol). The suspension was stirred by mechanical stirring and heated at 100 ° C for 2 hours, at which point it was judged complete by LCMS. The EtOH and AcOH were removed in vacuo. DCM (250 mL) and water (250 mL) were added and the suspension was stirred vigorously with a mechanical stirrer. Heating was continued for 4 hours and the reaction was judged complete by LCMS. The suspension was filtered through Celite and the solid was washed with DCM. The filtrate was washed with water (250 mL), extracted with DCM, dried over Na2SO4, filtered and concentrated under reduced pressure to provide 2-benzyloxy-5-bromophenylamine: 1H-NMR (CDCl3) d 7.39-7.35 (m, 5H), 6.87 (d, J = 4 Hz, 1H), 6.82 (dd, J = 8.0, 4.0 Hz, 1H), 6.72 (d, J = 8 Hz, 1H), 5.08 (s, 2H), 3.89 ( br.s, 2H); MS (M + 1) + = 278, 280. C. Ethyl ester (2-benzyloxy-5-bromophenylamino) -acetic acid A solution of 2-benzyloxy-5-bromophenylamine (138.89 g, 0.499 mol) in acetonitrile (2 L ), AcOH (1 L) and ethyl glyoxalate (153 mL, 0.749 mol) was cooled to 11 ° C and sodium triacetoxyborohydride (211.6 g, 0.998 mol) was added as a suspension. The suspension was stirred for 5 minutes, at which point the reaction was judged complete by LCMS. The AcOH and acetonitrile were removed in vacuo. The solid was dissolved in DCM and washed with saturated sodium bicarbonate. The organic layer was washed with saturated NaCl, dried over Na2SO4 and filtered at through a pad of silica gel. The product was eluted with 1 L portions of DCM. Removal of DCM in vacuo affords (2-benzyloxy-5-bromophenylamino) -acetic acid ethyl ester: 1 H NMR (CDCl 3) d 7.33 (m, 5H), 6.78 (dd, J = 8.0, 4.0 Hz, 1H), 6.68 (d, J = 8 Hz, 1H), 6.63 (d, J = 4.0 Hz, 1H), 5.08 (s, 2H), 4.25 (1, J = 8.0 Hz, 2H), 3.90 (s, 2H), 1.29 (t, J = 8 Hz, 3H); (M + H) + = 364, 366. D. 2-Benzyloxy-5-bromophenyl-N- (t-butoxycarbonylsulfamoyl) -acetic acid ethyl ester Methylene chloride (250 mL) was cooled to 0 ° C. Chlorosulfonyl isocyanate (23.97 mL, 0.27 mol) was added, followed by 2-methyl-2-propanol (28.7 mL, 0.30 mol), and the solution was stirred for 30 minutes. A solution of 2-benzyloxy-5-bromophenylaminoacetic acid ethyl ester (91.20 g, 0.25 mol) and triethylamine (38.4 mL, 0.275 mol) in DCM (250 mL) was rapidly added dropwise via an addition funnel. The solution was stirred for 5 minutes, at which point the reaction was judged complete by LCMS. The DCM was removed in vacuo. The solid was dissolved in EtOAc and washed with 1N HCl solution. The organic layer was washed with saturated sodium chloride, dried over Na2SO, filtered and concentrated in vacuo to give 2-benzyloxy-5-bromophenyl-N- (t-butoxycarbonylsulfamoyl) -acetic acid ethyl ester: 1H NMR (CDCl3 ) d 7.72 (d, J = 4 Hz, 1H), 7.47 (s, 1H), 7.31-7.27 (m, 6H), 6.75 (d, J = 12 Hz, 1H), 5.08 (s, 2H), 4.44 (s, 2H), 4.08 (q, J = 8 Hz, 2H), 1.36 (s, 9H), 1.17 (t, J = 8 Hz, 3H); MS (M-1) "= 541, 543. E. 5- (2-Benzyloxy-5-bromophenyl) -1,1-dioxo-1,2,5-thiadiazolidin-3-one To a solution of ethyl ester 2-benzyloxy-5-bromophenyl-N- (t-butoxycarbonyl-sulfamoyl) -acetic acid (114.81 g, 0.211 mol) in DCM (560 mL) was added TFA (280 mL) .The reaction was stirred for 5 minutes, then concentrated in vacuo, the resulting solid was dissolved in THF (2 L), and the solution was cooled to 0 ° C. A solution of potassium tert-butoxide in THF (1 M) was added dropwise in portions until the reaction was judged complete by LCMS Aqueous HCl (350 mL, 0.350 mol) was added and the THF was removed in vacuo NaCl was added until the aqueous phase was saturated, at which point it was extracted with EtOAc (1 L) The organic layer was extracted with saturated NaCl, dried over Na2SO, filtered and concentrated in vacuo to provide 5- (2-benzyloxy-5-bromophenyl) -1,1-dioxo-1, 2,5-thiadiazolidin-3. -one The recrystallization from acetonitrile / water (1: 1) produced 5- (2-benzyloxy-5- bromophenyl) -1,1-dioxo-1,2,5-thiadiazolidin-3-one pure: EM (M-1) "= 395, 397. F. 2- [4-benzyloxy-3] -butyl ester - (1, 1, 4-trioxo-1, 2,5-thiadiazolidin-2-yl) -phenyl] -pyrrol-1 -carboxylic acid To a stirred solution of 5- (2-benzyloxy-5-bromophenyl) -1, 1-dioxo-1, 2,5-thiadiazolidin-3-one (50 mg, 0.126 mmol) in DME (2 mL) was added Pd (PPh3) 4 (15 mg, 0.013 mmol), tert-butylester of pyrrol- 2-boronic acid-1-carboxylic acid (53 mg, 0.252) mmol) and 250 μL of a 2M Na2CO3 solution. The solution was heated at 80 ° C for 18 hours. LC / MS of the reaction mixture revealed approximately 90% consumption of the starting aryl bromide, so that the mixture is diluted with EtOAc and 1N HCl. The organic layer is separated and concentrated in vacuo to give a dark brown oil, which is purified using reverse phase chromatography to give 2- [4-benzyloxy-3- (1, 1, 4-trioxo) -butylester. -1, 2, 5-thiadiazolidin-2-yl) -f or I] - pyr ro I-1 -carboxylic acid, which is used directly in the next step: EM (M-1) ~ = 482. G. ter -2- [4-Hydroxy-3- (1, 1, 4-trioxo-1, 2,5-thiadiazolidin-2-yl) -phenyl] -pyrrol-1-carboxylic acid ester To a mixture of Pd / C (5 mg) in EtOH (5 mL) was added 2- [4-benzyloxy-3- (1, 1, 4-trioxo-l, 2,5-thiadiazolidin-2-yl) -phenyl ester, tert-butylester. ] -pyrrole-1-carboxylic acid (20 mg, 0.041 mmol) in EtOAc (5 mL). The flask was placed under an atmosphere of H2 for 18 hours, at which time LCMS of the reaction mixture reveals complete deprotection of the benzyl group, as well as some undesired pyrrole reduction to the corresponding pyrrolidine. The crude mixture was purified via preparative HPLC to give 2- [4-hydroxy-3- (1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl) -phenyl] -pyrrole tert-butylester. -1-carboxylic acid, which is used directly in the next step: MS (M-1) - = 392. H. 5- [2-Hydroxy-5- (1H-pyrrol-2-yl) -phenyl] - 1,1-dioxo-1,2,5- thiadiazolidin-3-one A 2- [4-hydroxy-3- (1,1,4-trioxo-1, 2,5-thiadiazolidin-2-yl) -phenyl] -pyrrole-1-carboxylic acid tert-butylester (5 mg, 0.013 mmol) in DCM (15 mL) was added 1 drop of TFA. The reaction was stirred for 1 hour. Concentration in vacuo, followed by preparative HPLC purification, afforded 5- [2-hydroxy-5- (1 H-pyrrol-2-yl) -phenyl] -1,1-dioxo-1,2,5-thiadiazolidin-3. -one as a transparent film: MS (M-1) ~ = 292. EXAMPLE 2 The following compounds were prepared using appropriate starting materials and general methods described in Example 1, with the exception that Stage H is eliminated. 2-2 is prepared using benzyloxymethylpyrazole-boronic acid (Tet Lett, 1993, 34, 8237).

Example 3 5- [2-Hydroxy-5- (1H-pyrrol-3-yl) -phenyl] -1,1-dioxo-1,2,5-thiadiazolidin-3-one A. 5- [2-Hydroxy-5- (1-triisopropylsilanyl-1 H -pyrrol-3-yl) -phenyl] -1,1-dioxo-1,2,5-thiadiazolidin-3-one The title compound was prepared analogously to Example 1 using 1-trisopropylsilanylpyrrole-3-boronic acid with the exception that Step HB 5- [2-Hydroxy-5- (1H-pyrrol-3-yl) -phenyl] -1,1-dioxo-1 is deleted, 2,5-thiadiazolidin-3-one To a solution of 5- [2-hydroxy-5- (1-triisopropylsilanyl-1 H -pyrrol-3-yl) -phenyl] -1, 2,5-thiadiazolidin-3 ona (20 mg, 0.04 mmol) in CH3CN (2 mL) was added HF-pyridine (50%, 0.048 mL, 0.1 mmol) and the mixture was stirred at room temperature for 1.5 hours. The mixture was concentrated and purified by RP chromatography with ammonium formate to give the title compound: Retention time = 0.63 min (Method A); MS (M-1) "= 292. EXAMPLE 4 4'-Hydroxy-3 '- (1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl) -biphenyl-3-yl ester of methanesulfonic acid A. 3- (4,4,5,5-tetramethyl- [1, 3,2] dioxaborolan-2-yl) -phenylester of methanesulfonic acid To a stirring solution of 3- (4,4,5,5- tetramethyl- [1,2] dioxaborolan-2-yl) -phenol (0.050 g, 0.228 mmol in DCM (10 mL) and triethylamine (0.064 mL, 0.449 mmol) was added MsCI (0.035 mL, 0.452 mmol) in drops at 0 ° C. The reaction mixture it was stirred for 2.5 hours. The mixture was poured into 1N HCl and extracted with DCM (3 x 15 mL). The organic layers were combined and concentrated to provide 3- (4, 4,5,5-tetramethyl- [1, 3,2] dioxaborolan-2-yl) -phenylester of methanesulfonic acid: (M + NH 4) = 316. B. 4'-Benzyloxy-3 '- (1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl) -biphenyl-3-yl ester of methanesulfonic acid In a small flask in microwave, 3- was added. (4, 4,5,5-tetramethyl- [1, 3,2] dioxaborolan-2-yl) -phenylester of methanesulfonic acid (0.060 g, 0.201 mmol), 5- (2-benzyloxy-5-bromophenyl) -1 , 1-dioxo-1, 2,5-thiadiazolidin-3-one (0.04 g, 0.101 mmol), Pd (PPh3) 4 (0.029 g, 0.025 mmol) and 2 M Na2CO3 (0.125 mL). DME was added and the small vial was capped and placed in the microwave for a total of 30 minutes at 110 ° C. The reaction mixture was filtered through Celite and washed with MeOH. The filtrate was concentrated and the residue was purified via Biotage Sp1, eluting with 5-65% EtOH / H2O to provide 4'-benzyloxy-3 '- (1, 1, 4-trioxo-1, 2,5-thiadiazolidin- 2-yl) -biphenyl-3-yl ester of methanesulfonic acid: MS (M-1) = 487.2. C. 4-Hydroxy-3 '- (1) 1,4-trioxo-1) 2,5-thiazolidin-2-yl) -biphenyl-3-yl ester of methanesulfonic acid To a stirring solution of 4 g. '-benzyloxy-3' - (1, 1, 4-trioxo-1, 2,5-thiadiazolidin-2-yl) -biphenyl-3-yl ester of methanesulfonic acid (0.010 g, 0.020 mmol) in EtOH / EtOAc (1 : 3, 10 mL) was added 5% Pd / C (0.005 g). The mixture was stirred under an H2 atmosphere of 1.5 hours. The reaction mixture was filtered over Celite, washed with EtOH and concentrated. The residue was purified via preparative HPLC to provide 4'-hydroxy-3 '- (1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl) -biphenyl-3-yl ester of methanesulfonic acid: MS ( M-1) = 397. Example 5 5- (3'-Amino-4-hydroxybiphenyl-3-yl) -1,1-dioxo-1,2,5-thiadiazolidin-3-one A. 5- (3'-Amino-4-benzyloxybiphenyl-3-yl) -1,1-dioxo-1,2,5-thiadiazolidin-3-one To a small vial of 20 mL containing 5- (2- benzyloxy-5-bromophenyl) -1, 1-dioxo-1, 2,5-thiadiazolidin-3-one (Example 1, Step E) (1.00 g, 2.52 mmol), 3- (4,4,5,5-tetramethyl-1, 3.2- dioxaborolan-2-yl) -phenylamine (690 mg, 5.04 mmol) and Pd (PPh3) 4 (291 mg, 0.252 mmol) was added DME (12 mL). The solution was separated in 4 containers in microwaves and to each of these vessels was added a 2M Na2CO3 solution (1.25 mL). The reaction mixtures were subjected to microwave irradiation at 110 ° C for 45 minutes. The contents of the 4 vessels were combined, concentrated in vacuo and purified by using reverse phase chromatography to provide 5- (3'-amino-4-benzyloxybiphenyl-3-yl) -1,1-dioxo-1,2,5-thiadiazolidin-3-one, which is used immediately in the next Stage without elimination of the EtOH / water eluant: MS (M-1) - = 408. B. 5- (3'-Amino-4-hydroxybiphenyl-3-yl) -1,1-dioxo-1,2,5 -thiadiazolidin-3-one To 5- (3'-amino-4-benzyloxybiphenyl-3-yl) -1,1-dioxo-1,2,5-thiadiazolidin-3-one in EtOH / water a mixture of Pd / C (100 mg) in EtOH (10 mL). The flask was placed under an atmosphere of H2 for 48 hours. Removal of Pd / C by filtration through a pad of Celite, followed by concentration in vacuo and purification by reverse phase chromatography afforded 5- (3'-amino-4-hydroxybiphenyl-3-yl) -1,1- dioxo-1, 2,5-thiadiazolidin-3-one as a clear coffee solid: Retention time = 0.63 min (Method A): MS (M-1) "= 318. EXAMPLE 6 The following compounds are prepared using materials from appropriate starting and general methods described in Example 5. Examples 6-17 require the conversion of methyl ester to ethyl ester prior to the debenzylation step The debenzylation of Examples 6-18 to 6-22 are performed using Pd (OH) 2 and for Examples 6-13 and 6-14, BBr3 was used in DCM, using bound resin (PPh3) 4 for Examples 6-13 to 6-22.

Example 7 N- (2-Hydroxyethyl) -2- [4'-hydroxy-3 '- (1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl) -biphenyl-4-yl] - acetamide A. 2- [4'-Benzyloxy-3 '- (1,1,4-tr.oxo-1,2,5-thiadiazolidin-2-yl) -biphenyl-4-yl] -N- (2 -hydroxyethyl) -acetamide To a solution of [4'-benzyloxy-3 '- (1, 1, 4-trioxo-1, 2,5-thiadiazolidin-2-yl) -biphenyl-4-yl] -acetic acid ( Example 6-12, before hydrogenation) (100 mg, 0.221 mmol), in THF (10 mL) was added EDCI (51 mg, 0.265 mmol), HOBt (36 mg, 0.265 mmol) and ethanolamine (0.031 mL, 0.442 mmol). The reaction mixture was stirred for 18 hours and diluted with H2O / EtOAc. The organic layer was separated, washed with brine, dried over Na2SO4, filtered and evaporated to dryness. Purification by preparative HPLC gave 2- [4'-benzyloxy-3 '- (1, 1, 4-trioxo-1,2,5-thiadiazolidin-2-yl) -biphenyl-4-yl] -N- (2 -hydroxyethyl) -acetamide, which is used directly in the next step: MS (M-1) "= 494. B. N- (2-Hydroxyethyl) -2- [4'-hydroxy-3 '- (1) 1 , 4-trioxo-1,2,5-thiadiazolidin-2-yl) -biphenyl-4-yl] -acetamide. Debenzylation was conducted according to Example 5, Step B: Retention time = 0.64 minutes (Method A); MS (M-1) "= 404. Example 8 2.2) 2-Trifluoro-N- [4'-hydroxy-3, - (1,1,4-trioxo-1,2) 5-thiadiazolidin-2- il) -biphenyl-3-yl] -acetamide A. N- [4'-Benzyloxy-3, - (1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl) -bi faith nil-3-yl] -2, 2,2- trifluoroacetamide A 5- (3'-amino-4-benzyloxy-phenyl-3-yl) -1, 1-dioxo-1, 2,5- thiadiazolidin-3-one (Example 5, Step A) (100 mg, 0.244 mmol), methyl trifluoromethylacetate (1 mL) was added. The reaction mixture was heated to 60 ° C and stirred for 2 hours. The concentration of the reaction in vacuo afforded N- [4'-benzyloxy-3 '- (1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl) -biphenyl-3-yl] -2 , 2,2-trifluoroacetamide to be used directly in the next step: MS (M-1) "= 504. B. 2,2,2-Trifluoro-N- [4'-hydroxy-3 '- (1) 1 , 4-trioxo-1,2,5-thiadiazolidin-2-yl) -biphenyl-3-yl] -acetamide The debenzylation was conducted according to Example 5, Step B: Retention time = 1.08 minutes (Method A); MS (M-1) "= 414. EXAMPLE 9 1-Ethyl-3- [4'-hydroxy-3, - (1) 1) 4-trioxo-1,2,5-thiadiazolidin-2-yl) - biphenyl-3-yl] -urea A. 1- [4'-Benzyloxy-3 '- (1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl) -bifen i-3-yl] -3-eti I-urea To a stirred solution of 5- (3'-amino-4-benzyloxybiphenyl-3-yl) -1,1-dioxo-1,2,5-thiazolidin-3-one (Example 5, Step A) (100 mg , 0.244 mmol), in DCE (10 mL) was added ethyl isocyanate (0.04 mL, 488 mmol). The reaction mixture was heated at 60 ° C for 1 hour. Concentration of the reaction mixture in vacuo afforded 1 - [4'-benzyloxy-3 '- (1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl) -biphenyl-3-yl] -3-ethylurea, to be used directly in the next step: EM (M-1) "= 479. B. 1-Ethyl-3- [4'-hydroxy-3 '- (1,1,4 -trioxo-1,2,5-thiadiazolidin-2-yl) -biphenyl-3-yl] -urea The debenzylation was conducted according to Example 5, Step B: Retention time = 0.81 minutes (Method A); MS (M-1) - = 389. EXAMPLE 10 The following compounds were prepared using the following: the general methods described in Examples 8 and 9, 3-aminomethylphenylboronic acid or 3- (4,4,5,5-tetramethyl) 1, 3,2-dioxaborolan-2-yl-aniline for the Suzuki reaction and the appropriate starting materials for the coupling reaction For Examples 10-1 to 10-4, the hydrogenation step precedes the coupling step .

EXAMPLE 11 3- [4'-Hydroxy-3 '- (1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl) -biphenyl-3-yl] -propionic acid 3- [4'-Hydroxy-3 '- (1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl) -biphenyl-3-yl] -propionic acid methyl ester was prepared according to general procedure described in Example 5, using 3- (2-methoxycarbonylethyl) phenylboronic acid. A solution of 3- [4'-hydroxy-3 '- (1, 1, 4-trioxo-1, 2,5-thiadiazolid-2-yl) -β-phenyl-3-methyl ester. il] -propionic (133.8 mg, 0.324 mmol) in acetonitrile (1 mL) was treated with aqueous NaOH (1 M, 0.648 mL). The solution was evaporated to dryness to provide 3- [4'-hydroxy-3 '- (1, 1, 4-trioxo-1, 2,5-thiadiazolidin-2-yl) -biphenyl-3-yl] -propionic acid. : MS (M-1) "= 375. EXAMPLE 12 5- [{4- [4-Hydroxy-3- (1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl) acid] - phenyl] -pyrazol-1-yl.}. -pentanoic acid Acid 5- was prepared. { 4- [4-hydroxy-3- (1, 1, 4-trioxo-1, 2,5-thiadiazolidin-2-yl) -phenyl] -pyrazol-1-yl} pentanoic analogously to Example 11: MS (M-1) "= 393. EXAMPLE 13 The following compounds were prepared using appropriate starting materials and general methods described in Example 5, with the following modification: acid ester starting materials N-alkylated pyrazolopin-choline are generated using the following procedure: It is added 4- (4,4,5,5-tetramethyl-1, 3,2-dioxoborolan-2-yl) -1 H-pyrazole to 1 equivalent of NaH in dimethoxyethane. The appropriate alkyl bromide is added to the reaction mixture, which is then heated to 60 ° C and followed by LCMS. The reaction mixture is used directly without purification in the coupling with 5- (2-benzyloxy-5-bromophenyl) -1,1-dioxo-1,2,5-thiadiazolidin-3-one (Example 1, Step E).

Example 14 5- (2-Hydroxy-5-phenoxyphenyl) -1,1-dioxo-1,2,5-thiadiazolidin-3-one A. 1-Benzyloxy-2-nitro-4-phenoxybenzene To a suspension of potassium carbonate (1.14 g, 8.26 mmol) in DMF (8 mL) was added 2-nitro-4-phenoxyphenol (1.27 g, 5.5 mmol) ( J Med Chem, 41, 1540) followed by benzyl bromide (0.95 g, 5.6 mmol). The mixture was stirred at RT for 18 hours, then poured into water and extracted with EtOAc. The organic phase was washed with water (3x), saturated NaCl (1x), and dried over sodium sulfate. The solvent was removed under reduced pressure and the residual oil was purified by flash chromatography using DCM to elute 1-benzyloxy-2-nitro-4-phenoxybenzene as a pale yellow solid: m.p. = 84-87 ° C; 1 H NMR (CDCl 3) d 7.47-7.27 (m, 8H), 7.17-7.02 (m, 3H), 6.95 (d, J = 8.34 Hz, 2H), 5.17 (s, 2H). B. 2-Benzyloxy-5-phenoxy phenylamine To a mixture of 2-benzyloxy-2-nitro-4-phenoxybenzene (0.72 g, 2.24 mmol) and indium powder (1.0 g, 8.7 mmol) in THF (8 mL) were added. added concentrated HCl (1.2 mL) in drops. The mixture was stirred at RT for 2.5 hours. To this mixture was added 2N NaOH resulting in the formation of gummy precipitate. The residue was triturated with EtOAc and centrifuged. The solution is The solvent was removed under reduced pressure to give 2-benzyloxy-5-phenoxyphenylamine as a dark oil. That material is used directly in the next stage. C. (2-Benzyloxy-5-phenoxyphenylamino) -acetic acid methyl ester To a mixture of 2-benzyloxy-5-phenoxyphenylamine (0.635 g, 2.18 mmol) and potassium carbonate (0.602 g, 4.36 mmol) in DMF (5 mL) Methyl bromoacetate (0.334 g, 2.18 mmol) was added. The mixture was stirred at 60 ° C for 90 minutes, then an additional 150 mg of methyl bromoacetate was added and the mixture was stirred at 60 ° C for 1 hour. The mixture was allowed to cool to RT and then poured into water and extracted into EtOAc. The organic phase was washed with water (3x), saturated NaCl (1x), and dried over sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by flash chromatography using DCM to elute (2-benzyloxy-5-phenoxyphenylamino) -acetic acid methyl ester as an oil: -H NMR (CDCl 3) d 7.44-7.24 (m , 7H), 7.00 (6.96-6.91 (m, 2H), 6.76 (d, J = 8.59 Hz, 1H), 6.28 (dd, J = 8.59, 2.78 Hz, 1H), 6.21 (d, = 2.53 Hz, 1H ), 5.06 (s, 2H), 4.94 (s, broad, 1H), 3.85 (s, 2H), 3.72 (s, 3H) D. N- (t-butoxycarbonylsulfamoyl) -N- (2- benzyloxy-5-phenoxyphenyl) -glycine To a solution of chlorosulfonyl isocyanate (0.23 g, 1.62 mmol) in methylene chloride (3 mL) was added dropwise a solution of t-butanol (0.12 g, 1.62 mmol) in methylene chloride (1 mL). The solution was stirred at RT for 45 minutes, then a solution of (2-benzyloxy-5-phenoxyphenylamino) acetic acid methyl ester (0.42 g, 1.16 mmol) and triethylamine (0.234 g, 2.34 mmol) in sodium chloride was added dropwise. methylene (1.5 mL). The mixture was stirred at RT for 2 hours, then washed with water. The organic phase was dried over sodium sulfate and the solvent was removed under reduced pressure. The residual oil was purified by flash chromatography using methylene chloride to elute N- (t-butoxycarbonylsulfamoyl) -N- (2-benzyloxy-5-phenoxyphenyl) glycine acid methyl ester as an oil: 1H-NMR (CDCl3) d 7.53-7.37 (m, 9H), 7.17 (t, 1H), 7.09-6.98 (m, 4H), 5.25 (s, 2H), 4.66 (s, 2H), 3.76 (s, 3H), 1.51 (s, 9H); MS (M-1) = 541. E. N-sulfamoyl-N- (2-benzyloxy-5-phenoxyphenyl) glycine methyl ester A solution of N- (t-butoxycarbonylsulfamoyl) -N- (2-benzyloxy) -methyl ester phenoxy fe ni I) g I ici na (0.35 g, 0.65 mmol) in 4 mL of trifluoroacetic acid / methylene chloride (1: 1) was stirred at RT for 20 minutes. The solvent was removed under reduced pressure. Methylene chloride was added to the residue, then removed under reduced pressure. The resulting oil was purified by flash chromatography using methylene chloride to elute N-sulfamoyl-N- (2-benzyloxy-5-phenoxyphenyl) glycine methyl ester as an oil: 1H-NMR (CDCl3) d 7.50-.32 (m, 8H), 7.11 (t, 1H), 7.03-6.98 (m, 4H), 5.12 (s, 2H), 5.00 (br s, 2H), 4.37 (s, 2H), 3.68 (s, 3H); MS (M-1) = 441. F. Potassium salt of 5- (2-benzyloxy-5-phenoxyphenyl) -1,1-dioxo-1,2,5-thiadiazolidin-3-one To a solution of methyl ester of N-sulfamoyl-N- (2-benzyloxy-5-phenoxyphenyl) glycine (0.167 g, 0.38 mmol) in 2 mL of THF was added to 1.0 M of potassium t-butoxide solution (0.38 mL) in THF. The mixture was stirred at RT for 24 hours and the solvent was removed under reduced pressure to give the potassium salt 5- (2-benzyloxy-5-phenoxyphenyl) -1,1-dioxo-1, 2,5-thiadiazolidin-3 -one as a rubber: EM (M-1) "= 409. This is used directly in the next step G. 5- (2-Hydroxy-5-phenoxyphenyl) -1, 1-dioxo-1,2,5 -thiadiazolidin-3-one A solution of potassium salt 5- (2-benzyloxy-5-phenoxyphenyl) -1,1-dioxo-1, 2,5-thiadiazolidin-3-one (0.18 g, 0.4 mmol) in water (15 mL) was hydrogenaat 1 atm over 10% Pd / C (0.05 g) for 24 hours.The catalyst was filtered and the water was removed by lyophilization.The residue was dissolved in a minimum volume of water and purified by Preparative HPLC using a gradient of 10% acetonitrile / water to 100% acetonitrile (+ 0.1% TFA) for 13 minutes to elute 5- (2-hydroxy-5-phenoxyphenyl) -1,1-dioxo-1,2. , 5-thiadiazolidin-3-one as an off-white solid: mp = 153-157 ° C; NMR-1H (DMSO-d6) d 9.68 (s, broad, 1H), 7.22-7.17 (m, 2H) , 6.95-6.89 (m, 2H), 6.80-6.82 (m, 4H), 4.32 (s, 2H); MS (M-1) "= 319. Example 15 5- (2-Hydroxy-5-methoxyphenyl) -1,1-dioxo-1,2,5-thiadiazolidin-3-one The title compound was prepared analogously to Example 14 from 4-methoxy-2-nitrophenol: NMR-1H (DMSO-d6) d 6.87 (d, J = 2.78 Hz, 1H), 6.80-6.72 (m, 2H) , 4.41 (s, 2H), 3.61 (s, 3H); MS (M-1) "= 257. EXAMPLE 16 5- (5-Benzyl-2-hydroxyphenyl) -1,1-dioxo-1,2,5-thiadiazolidin-3-one A. 5- (5-Benzyl-2-benzyloxyphenyl) -1,1-dioxo-1,2,5-thiadiazolidin-3-one To a small microwave flask containing 5- (2-benzyloxy-5-bromophenyl) -1, 1-dioxo-1, 2,5-thiadiazolidin-3-one (150 mg, 0.377 mmol) and resin bound with Pd-tetrakis (500 mg, 0.755 mmol) in DME (5 mL) was added benzyl-9 -BBN (1.51 mL, 0. 755 mmol) followed by sodium carbonate (0.75 mL, 1.50 mmol). The reaction mixture was heain the microwave for 10 minutes at 110 ° C. The mixture was filtered through Celite to remove the resin and the filtrate was concentrain vacuo. The crude oil was purified using reverse phase silica in the Biotage and the desired product is absorbed directly on the next stage. B. 5- (5-Benzyl-2-hydroxy-phenyl) -1, 1 -d -ioxo-1, 2,5-thiadiazolidin-3-one 5- (5-benzyl-2-hydroxyphenyl) -1 was prepared, 1-dioxo-1, 2,5-thiadiazolidin-3-one analogously to Example 1, Step G, replacing Pd / C with Pd (OH) 2; NMR-1H (MeOD) d 8.52 (s, 1H), 7.3 (d, J = 2.27 Hz, 1H), 7.22 (m, 2H), 7.12 (m, 3H), 6.95 (dd, J = 8.0, 2.0 Hz , 1H), 6.81 (d, J = 8.3 Hz, 1H), 4.31 (s, 2H), 3.86 (s, 2H). Retention time = 0.96 minutes (Method A); (M-H) - = 317. EXAMPLE 17 5- (2-Hydroxy-5-methylphenyD) -1,1-dioxo-1,2,5-thiadiazolidin-3-one A. 1-Benzyloxy-4-methyl-2-nitrobenzene The title compound was prepared analogously to Example 14, Step A from 4-methyl-2-nitrophenol.

B. 2-Benzyloxy-5-methylphenylamine A mixture of 1-benzyloxy-4-methyl-2-nitrobenzene (2.4 g, 9.9 mmol) and PtO2 (0.12 g) in EtOAc (45 mL) was hydrogenated at 20 psi for 1 hour . The catalyst was then filtered and the filtrate was concentrated to give the title compound as an oil. C. 5- (2-Hydroxy-5-methylphenyl) -1,1-dioxo-1,2,5-thiadiazolidin-3-one The title compound was prepared analogously to Example 14, Steps CG: MS (M-1 ) '= 241. EXAMPLE 18 5- (5-Hexyl-2-hydroxyphenyl) -1,1-dioxo-1,2,5-thiadiazolidin-3-one A. 4-Benzyloxy-3-nitrobenzaldehyde Potassium carbonate (39.75 g, 287.6 mmol) was slowly added to a solution of 4-hydroxy-3-nitrobenzaldehyde (24.03 g, 143.8 mmol) in 150 mL of DMF at room temperature. Benzyl bromide (25.6 mL, 36.86 g, 215.5 mmol) was added, and the mixture was heated to 50 ° C and stirred overnight. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with EtOAc and diethyl ether. The organic phase was washed with water and brine, dried (Na2SO) and concentrated under vacuum to provide 4- benzyloxy-3-nitrobenzaldehyde. B. 1-Benzyloxy-4 - ((Z) -hex-1-enyl) -2-nitrobenzene To a solution of pentyltriphenylphosphonium bromide (1.34 g, 3.24 mmol) in THF (50 mL) at -20 ° C was added in n-BuLi drops (208 mg, 1.6 M in hexane). The mixture was stirred at -20 ° C for 30 minutes, and 4-benzyloxy-3-nitrobenzaldehyde (760 mg, 2.96 mol) in THF (5 mL) was added dropwise. It was then stirred at -20 ° C for 5 minutes, allowed to warm to RT, warmed with water and extracted with EtOAc. The organic layer was then washed with brine, dried with Na2SO and concentrated. The residue was purified by flash column to give the title compound as a yellow oil. C. 5- (5-Hexy-2-hydroxy-faith-n -yl) -1,1-dioxo-1, 2,5-thiadiazolidin-3-one The title compound was prepared analogously to Example 17, Steps B and C: EM (M-1) "= 311. EXAMPLE 19 5- (5-Butyl-2-hydroxyphenyl) -1,1-dioxo-1,2,5-thiadiazolidin-3-one The title compound was prepared analogously to Example 18, with the exception that butyltriphenylphosphonium bromide was used in place of pentyltriphenylphosphonium bromide in Step B: MS (M-1) "= 283. EXAMPLE 20 5- [2-Hydroxy-5- (tetrahydrofuran-3-yl) -phe nyl] -1,1-dioxo-1, 2 5-thiadiazolidin-3-one - [2-Hydroxy-5- (tetrahydrofuran-3-yl) -phenyl] -1,1-dioxo-1, 2,5-thiadiazolidin-3-one was prepared from 5- (2-benzyloxy-5) -furan-3-yl-phenyl) -1,1-dioxo-1,2,5-thiadiazolidin-3-one (intermediate in the synthesis of Example 2-4) followed by hydrogenation with Pd / C: MS ( M-1) "= 297. EXAMPLE 21 5- [5- (4-Fluorophenylethynyl) -2-hydroxyphenyl] -1,1-dioxo-1,2,5-thiadiazolidin-3-one A. 5- [2-Benzyloxy-5- (4-fluorophenylethynyl) -phenyl] -1,1-dioxo-1,2,5-thiadiazolidin-3-one A solution of 5- (2-benzyloxy-5-bromophenyl) ) -1, 1 -ioxo- 1,2,5-thiadiazolidin-3-one (Example 1, Step E) (96.2 mg, 0.242 mmol) in dimethoxyethane (4 mL) was stirred with aqueous sodium carbonate (2M, 0.484 mL, 0.968 mmol), adduct dichloromethane [1, 1'-bis (diphenylphosphino) ferrocene] -palladium (II) (19.8 mg, 0.024 mmol), copper iodide (1) (9.2 mg, 0.048 mmol, 20 mol%), and 1 -ethyl-4-fluorobenzene (79.0 μL, 0.484 mmol) at 80 ° C for 16 hours. 1 N HCl was added and the suspension was extracted with EtOAc. The organic layer was washed with saturated sodium chloride, dried over Na 2 SO 4, filtered and evaporated to dryness to give 5- [2-benzyloxy-5- (4-fluorophenylethynyl) -phenyl] -1,1-dioxo-1 , 2,5-thiadiazolidin-3-one: MS (M-1) '= 435. B. 5- [5- (4-Fluorophenylethynyl) -2-hydroxyphenyl] -1,1-dioxo-1,2,5 -thiadiazolidin-3-one To a solution at -78 ° C of 5- [2-benzyloxy-5- (4-fluorophenylenyl] -phenyl] -1,1-dioxo-1,2,5-thiadiazolidin -3-one (17.4 mg, 0.040 mmol) in DCM (1 mL) was added boron tribromide (1 M in DCM, 47.9 μL, 0.0479 mmol). The reaction was heated at 23 ° C for 20 minutes, and quenched with 1N HCl (1 mL). The resulting suspension was extracted with EtOAc. The organic layer was dried over Na2SO4, filtered and evaporated to dryness to give 5- [5- (4-fluorophenylethynyl) -2-hydroxyphenyl] -1,1-dioxo-1, 2,5-thiadiazolidin-3-one. : MS (M-1) "= 345. EXAMPLE 22 The following compounds were prepared using appropriate starting materials and general methods described in Example 21.

Example 23 5- [2-Hydroxy-5- (5-methylhexyl) -phenyl] -1,1-dioxo-1,2,5-thiadiazolidin-3-one A. 5- [2-Benzyloxy-5- (5-methylhex-1 -ini I) -f in I I] -1,1-di-oxo-1, 2,5-thiadiazolidin-3-one was prepared 5- [2-benzyloxy-5- (5-methylhex-1-ynyl) -pheni I] -1,1-dioxo-1, 2,5-thiadiazolidin-3-one analogously to Example 21, Step A using 5-methylhex- 1 - except with the exception that the reaction is carried out in the microwave at 110 ° C for 20 minutes.

B. 5- [2-H id roxy-5- (5-m ethyl hexyl) -f eni] -1, 1-dioxo-1, 2,5-thiadiazolidin-3-one 5- [2- hydroxy-5- (5-methylhexyl) -phenyl] -1,1-dioxo-1, 2,5-thiadiazolidin-3-one analogously to Example 1, Step G, with the exception that Pd (OH) 2 was used in place of Pd / C: MS (M-1) - = 325. Example 24: 6- [4-Hydroxy-3- (1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl) acid) - phenyl-hexanoic A suspension of 6- [4-benzyloxy-3- (1, 1, 4-trioxo-1, 2,5-thiadiazolidin-2-yl) -phenyl] -hex-5-ynoic acid (Example 22-2) and Pd / C (10% by weight, 39 mg) in water (30 mL) was stirred under an atmosphere of H2 for 3 hours. The suspension was filtered and evaporated to dryness to provide 6- [4-hydroxy-3- (1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl) -phenyl] -hexanoic acid: MS ( M-1) - = 341. EXAMPLE 25 5- [5- (Benzylaminomethyl) -2-hydroxyphenyl] -1,1-dioxo-1,2,5-thiadiazolidin-3-one A. 4-Benzyloxy-3-nitrobenzaldehyde The title compound was prepared as described in Example 18, Step AB Benzyl- (4-benzyloxy-3-nitrobenzyl) -amine. Benzylamine (2.2 mL, 2.16 g, 20.16 mmol. ) to a solution of 4-benzyloxy-3-nitrobenzaldehyde (4.31 g, 16.77 mmol) in 50 mL of 1,2-dichloroethane (DEC) at room temperature. Two hours later, sodium triacetoxyborohydride (10.66 g, 50.31 mmol) was added, followed by an additional 20 mL of DCE. The reaction was quenched by the addition of sufficient 1N aqueous HCl to adjust the pH to 5. The mixture was then stirred for 20 minutes, basified to pH 11, and extracted with EtOAc. The organic solution was dried (Na2SO4) and concentrated in vacuo to give benzyl- (4-benzyloxy-3-nitrobenzyl) amine as a yellow solid. C. (3-Amino-4-benzyloxybenzyl) -benzylcarbamic acid benzyl ester. Benzyl chloroformate (2.485 mL, 3.01 g, 17.65 mmol) was added to a solution of benzyl- (4-benzyloxy-3-nitrobenzyl) amine and 1N NaOH. (50 mL) in dioxane (50 mL) at RT. The mixture was divided between water and ether, and the solution of ether (Na2SO4) and concentrated to give the crude product. The product was purified by chromatography on silica gel (40% EtOAc in hexane as eluent) to give the product as a yellow oil. This product was stirred in EtOAc (50 mL) with platinum oxide (0.8 g) under hydrogen (1 atm) for 6 hours. The mixture was filtered, concentrated and chromatographed on silica gel (30% EtOAc in hexane as eluent) to give (3-amino-4-benzyloxybenzyl) -benzylcarbamic acid benzyl ester as a pale yellow oil. D. Methylester of acid. { 5 [(benzyl-benzyloxycarbonylamino) -methyl] -2-benzyloxy-phenylamino) -acetic A mixture of (3-amino-4-benzyloxybenzyl) -benzylcarbamic acid benzyl ester (0.503 g, 1.11 mmol), methyl bromoacetate (0.17 g) , 1.11 mmol), and potassium carbonate (0.233 g, 1.68 mmol) in DMF (3 mL) was stirred at room temperature overnight. The mixture was taken up in EtOAc and washed with water and brine, dried (Na2SO4) and concentrated to give the crude product. Chromatography on silica gel (30% EtOAc in hexane as eluent) provides 365 mg of acid. { 5 - [(Benzylbenzyloxycarbonylamino) -methyl] -2-benzyloxyphenylamino} -Acetic as a pale yellow solid. E. N- (t-butoxycarbonylsulfamoyl) -N - (5- benzylbenzyloxycarbonylaminomethyl) -2-benzyloxyphenyl) -acetic Chlorosulfonyl isocyanate (0.129 g, 0.91 mmol) was added to a solution of t-butyl alcohol (0.067 g), 0.905 mmol) in DCM (3 mL) at room temperature. The solution was stirred for 2 hours, after which a mixture of acid methyl ester was added. { 5 - [(benzylbenzyloxycarbonylamino) -methyl] -2-benzyloxyphenylamine} -acetic (365 mg, 0.696 mmol) and Et3N (0.12 g, 1184 mmol) in 3 mL of DCM. This mixture was stirred overnight and then washed with water and brine. The organic solution was dried (Na2SO4) and concentrated to give the crude product. The crude product was chromatographed on silica gel (30% EtOAc in hexane as eluent) to provide 0.2 g of N- (t-butoxycarbonylsulfarpoyl) -N - ((5-benzylbenzyloxycarbonylaminomethyl) -2-benzyloxyphenyl) methyl ester. -Acetic as a colorless oil. F. N-sulfamoyl-N - ((5-benzylbenzyloxycarbonylaminomethyl) -2-benzyloxy-phenol) -acetic acid methyl ester N- (t-butoxycarbonylsulfamoyl) -N - ((5-benzylbenzyloxycarbonylaminomethyl) -2-benzyloxyphenyl) -acetic acid methyl ester (0.2 g, 0.286 mmol) in 4 mL of a mixture of DCM and trifluoroacetic acid 1: 1 was stirred. room temperature for 2 hours. The mixture was concentrated under vacuum, absorbed in DCM and concentrated again. This process was repeated twice more. The crude product was subjected to gel chromatography of silica using 30% EtOAc in hexane as eluent to give 112 mg of N-sulfamoyl-N - ((5-benzylbenzyloxycarbonyl-aminomethyl) -2-benzyloxyphenyl) -acetic acid methyl ester. G. Benzyl- [4-benzyloxy-3- (1,1-trioxo-1,2,5-thiadiazolidin-2-yl) -benzyl] -carbamic acid benzyl ester. Potassium t-butoxide (1 M in THF, 0.37 mL) was added to a solution of N-sulfamoyl-N - ((5-benzylbenzyloxycarbonylaminomethyl) -2-benzyloxyphenyl) -acetic acid methyl ester (111 mg, 0.184 mmol) in 1 mL of THF at room temperature. The reaction was stirred 2 hours, then quenched with 1 mL of 1N aqueous HCl. The mixture was evaporated to dryness under vacuum and purified by flash chromatography using 20% EtOH in DCM to give 100 mg of product. The potassium salt is regenerated by adding potassium t-butoxide (1 M in THF, 0.129 mL) to the product, followed by evaporation to dryness under vacuum to provide the benzyl ester salt of benzyl- [4-benzyloxy-3- ( 1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl) -benzyl] -carbamic acid. H. 5- [5- (Benzylaminomethyl) -2-hydroxyphenyl] -1,1-dioxo-1,2,5-thiadiazolidin-3-one. 5- [5- (Benzylaminomethyl) -2-hydroxyphenyl] -1 was prepared. , 1-dioxo-1, 2,5-thiadiazolidin-3-one analogously to Example 1, Step G: MS (M + 1) + = 348. EXAMPLE 26 The following compounds were prepared using appropriate starting materials and general methods described in Example 25.

Example 27 5- [2-Hydroxy-5- (3-methyl-butoxy) -phenyl] -1,1-dioxo-1,2,5-thiadiazolidin-3-one A. Acetic acid 4-benzyloxyphenylester To a stirred solution of 4-benzyloxyphenol (20 g, 0.10 mol) in pyridine (200 mL) was added acetic anhydride (20.4 g, 0.20 mol) followed by a catalytic amount of DMAP. The mixture was stirred at RT for 2 hours. The reaction product was diluted with EtOAc and washed with 1N HCl, saturated NaCl, and finally with water. The organic phase was dried over anhydrous MgSO, filtered and concentrated to provide 4-benzyloxyphenylester of acetic acid. B. 4-Benzyloxy-3-nitrophenylester of acetic acid 4-benzyloxyphenylester of acetic acid (15 g, 61. 9 mmol) in DCM (350 mL). Concentrated HNO3 was added on silica gel and the suspension was stirred at RT for 4 hours. The silica gel was filtered and washed with DCM. The solvent was evaporated and EtOAc was added to the filtrate, followed by saturated sodium bicarbonate. The organic phase was washed with water (3x) and EtOAc, and concentrated to yield a yellow solid. The solid was washed with ether, filtered and washed again with ether to provide 4-benzyloxy-3-nitrophenylester of acetic acid. C. 4-Benzyloxy-3-nitrophenol Potassium carbonate (3 g) was added to a solution of 4-benzyloxy-3-nitrophenylester of acetic acid (4.23 g, 14.7 mmol) in MeOH / THF (60 mL / 30 mL) and the mixture was stirred at RT for 1.5 hours. Ethyl acetate was added to the mixture and the mixture was washed with 1 N HCl followed by saturated sodium chloride. The organic phase was dried over MgSO 4, filtered and concentrated to provide 4-benzyloxy-3-nitrophenol. D. 1-Benzyloxy-4- (3-methyl-but-2-enyloxy) -2-nitrobenzene 1-Benzyloxy-4- (3-methylbut-2-enyloxy) -2-nitrobenzene was prepared analogously to Example 25, Step D, starting with 1-bromo-3-methyl-but-2-ene.

E. 2-Benzyloxy-5- (3-methylbutoxy) -phenylamine. 2-Benzyloxy-5- (3-methylbutoxy) -phenylamine was prepared analogously to Example 17, Step B, using Pt / C in place of PtO2. F. 2-benzyloxy-5- (3-methylbutoxyphenyl) -N- (t-butoxycarbonyl-sulfamoyl) glycine ter -Butyl ester 2-Benzyloxy-5- (3-methylbutoxyphenyl) -N- (t-butyl ester -butoxycarbonyl-sulfamoyl) glycine following the general procedures described in Example 25, Steps D and EG ter-Butyl ester of 2-benzyloxy-5- (3-methylbutoxy) -phenyl) -N- (t-butoxycarbonyl-sulfamoyl-N'-trimethylsilanylethyl) -acetic acid A solution of tert-butylester of 2- Benzyloxy-5- (3-methylbutoxyphenyl) -N- (t-butoxycarbonyl sulfamoyl) glycine (1.4, 2.42 mmol) and 2-trimethylsilylethanol (0.56 g, 4.7 mmol) in toluene (40 mL) was cooled to 0 ° C. Triphenylphosphine (1.5 g, 5.72 mmol) and diisopropyl azodicarboxylate (1.14 g, 5.63 mmol) were added. The ice bath was removed and the mixture was stirred at RT overnight. The mixture was concentrated to remove toluene. The crude material was dissolved in hexane and the triphenylphosphine oxide by-product was removed by filtration. The filtrate was concentrated and purified by flash chromatography to give 2-benzyloxy-5- (3-methylbutoxy) -phenyl) -N- (t-butoxycarbonylsulfamoyl-N'-) tert-butylester. trimethylsilanylethyl) -acetic. H. [[2-Benzyloxy-5- (3-methyl-butoxy) -phenyl] -N-sulfamoyl- (N'-trimethylsilanylethyl)] -carbamic acid [[2-benzyloxy-5- (3-methylbutoxy)] - phenyl] -N-sulfamoyl- (N'-trimethylsilanyl-ethyl)] - carbamic analogously to Example 25, Step FI 5- [2-Benzyloxy-5- (3-methyl-butoxy) -phenyl] -1,1-dioxo-2 - (2-trimethylsilanylethyl) -1,2,5-thiadiazolidin-3-one 1-hydroxy-7-azabenzotriazole (HOAt) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride were added (EDCI) to a solution of [[2-benzyloxy-5- (3-methyl-butoxy) -phenyl] -N-sulfamoyl- (N'-trimethylsilanylethyl)] carbamic acid (1.1 g, 1.75 mmol) in THF (25). mL). The reaction mixture was stirred at RT for 5 minutes, and triethylamine was added to the suspension. The mixture was stirred at RT overnight. Ethyl acetate was added to the suspension and washed with 1N HCl and then water. The organic phase was dried over MgSO, filtered and concentrated. The crude material was purified by flash chromatography to provide 5- [2-benzyloxy-5- (3-methylbutoxy) -phenyl] -1,1-dioxo-2- (2-trimethylsilanylethyl) -1,2,5-thiadiazolidin- 3-one. J. 5- [2-Benzyloxy-5- (3-methyl-butoxy) -phenyl] -1,1-dioxo-1,2,5-thiadiazolidin-3-one To a solution of 5- [2-benzyloxy-5-] (3-Methyl-butoxy) -phenyl] -1,1-dioxo-2- (2-trimethylsilanylethyl) -1,2,5-thiadiazolidin-3-one (460 mg, 0.91 mmol) in THF (16 mL) was added TBAF (0.5 M in THF, 3. 48 mL, 1.81 mmol) and the mixture was refluxed for 1.5 hours. The reaction mixture was washed with 1N HCl solution (4x) and brine (1x) after the addition of EtOAc. It was then dried with MgSO and concentrated to give the title compound. K. 5- [2-Hydroxy-5- (3-methyl-butoxy) -phenyl] -1,1-dioxo-1,2,5-thiadiazolidin-3-one 5- [2-hydroxy-5- (3 -methylbutoxy) -phenyl] -1,1-dioxo-1, 2,5-thiadiazolidin-3-one following the general procedure described in Example 1, Step G: MS (M-1) '= 313. EXAMPLE 28 - [2-Hydroxy-5- (4-methylpentyloxy) -phenyl] -1,1-dioxo-1,2,5-thiadiazolidin-3-one - [2-Hydroxy-5- (4-methylpentyloxy) -phenyl] -1,1-dioxo-1, 2,5-thiadiazolidin-3-one was prepared analogously to Example 27, using 1-bromo-4-methylpentane in Step D: MS (M-1) = 327. EXAMPLE 29 5- (2-Hydroxy-5-propoxyphenyl) -1,1-dioxo-1,2,5-thiadiazolidin-3-one - (2-Hydroxy-5-propoxyphenyl) -1,1-dioxo-1, 2,5-thiadiazolidin-3-one was prepared analogously to Example 27, with the following changes: the starting material used for Step D is 3-bromopropene, and the nitro reduction of Step E is carried out using iron in AcOH / EtOH (Example 1, Step B) to provide the aniline: MS (M-1) = 285. Example 30 2-Hydroxy -6-. { 4- [4-hydroxy-3- (1,1) 4-trioxo-1,2,5-thiadiazolidin-2-yl) -phenyl] -butoxy} -N, N-dimethylbenzamide A. 2-But-3-enyloxy-6-hydroxybenzoic acid methyl ester Prepared from methyl 2,6-dihydroxybenzoate and but-3-en-1-ol analogously to Example 27, Step G, using DEAD instead of DIAD: MS (M-1) "= 221. B. Methyl ester of 2-benzyloxy-6-but-3-enyloxybenzoic acid Prepared from 2-but-3-enyloxy-6-hydroxybenzoic acid methyl ester analogously to Example 1 , Stage A.

C. 2-Benzyloxy-6-but-3-enyloxybenzoic acid A mixture of 2-benzyloxy-6-but-3-enyloxybenzoic acid methyl ester (1.2 g, 3.68 mmol) and NaOH (589 mg, 6N solution) in water ( 2.5 mL), MeOH (6 mL) and THF (20 mL) was heated at 60 ° C for 24 hours, then at 90 ° C for 5 days. After the solvent was removed, the residue was acidified with 1N HCl solution to pH 2. EtOAc was added until removed and the organic phase was washed with water and brine. It was then dried and concentrated to give the title compound as a yellow liquid. D. 2-Benzyloxy-6-but-3-enyloxybenzoyl chloride To a stirred solution of 2-benzyloxy-6-but-3-enyloxybenzoic acid (800 mg, 2.45 mmol) in 15 mL of DCM and 1 drop of DMF was added. added oxalyl chloride (0.86 mL, 9.82 mmol). The solution was stirred at room temperature overnight. The solvent was removed under pressure and the residue was dissolved in DCM, then DCM was removed under reduced pressure again and repeated 3x to give the product as a yellow liquid.

E. 2-Benzyloxy-6-but-3-enyloxy-N, N-dimethylbenzamide A mixture of 2-benzyloxy-6-but-3-enyloxybenzoyl chloride (1.2 g, 3.6 mmol) and dimethylamine (2N in THF, 10.9 mL, 21.8 mmol) in THF (20 mL) was stirred at room temperature for 18 hours. After the solvent was removed, water was added and EtOAc was used until removed. The organic phase was then washed with water, brine and dried. HE then concentrated to give the title compound as a red liquid. F. 2-Benzyloxy-6-. { 4- [4-benzyloxy-3- (1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl) -phenyl] -butoxy} -N, N-dimethylbenzamide To a stirred solution of 2-benzyloxy-6-but-3-enyloxy-N, N-dimethylbenzamide (112 mg, 0.35 mmol) in 2 mL of THF at 0 ° C was added 9-BBN ( 0.72 mL, 0.36 mmol, 0.5 M in THF). The solution was warmed to room temperature and stirred overnight. The solvent was removed under reduced pressure and the residue was dissolved in 4 mL of DME and 0.5 mL of H2O. To this solution was added 5- (2-benzyloxy-5-bromophenyl) -1,1-dioxo-1,2,5-thiadiazolidin-3-one (Example 1, Step E, 114 mg, 0.29 mmol), Pd ( PPh3) 4 (10 mg) and K2CO3 (120 mg, 0.87 mmol). The mixture was microwaved at 120 ° C for 50 minutes. The suspension was filtered and the solvent was removed under reduced pressure to give the product as a dark red liquid: MS (M-1) - = 642. G. 2-Hydroxy-6-. { 4- [4-hydroxy-3- (1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl) -f in yl] -butoxy} -N, N-dimeti I benzamide Prepared from 2-benzyloxy-6-. { 4- [4-benzyloxy-3- (1, 1, 4-trioxo-1, 2,5-thiadiazolidin-2-yl) -phenyl] -butoxy} -N, N-dimethylbenzamide analogously to Example 1, Step G: MS (M-1) "= 462. EXAMPLE 31 The following compounds were prepared using appropriate starting materials and general methods described in Example 30 EXAMPLE 32 5- (4-Hydroxy-4'-hydroxymethylbiphenyl-3-yl) -1,1-dioxo-1,2,5-thiadiazolidin-3-one A. 5- [2-Benzyloxy-5- (4,4,5,5-tetramethyl- [1,2,2] dioxaborolan-2-yl) -phenyl] -1,1-dioxo-1,2,5 -thiadiazolidin-3-one To a stirred suspension of 5- (2-benzyl? -5-bromophen?) -1, 1 -d? oxo-1 -1, 2,5-t? ad? azole? d? n-3-one (Example 1, Step E) (100 mg, 0.25 mmol), bis (pinacolato) diboro (127 mg, 0.50 mmol) and CH3COOK (74 mg, 0.75 mmol) in 3 mL of DMF was added Pd (dppf) CI2 (10 mg, 10% by weight). The suspension was degassed and heated at 100 ° C overnight. The mixture was filtered and the filtrate was used directly for the next step: MS (M-1) '= 443. B. 5- (4-Benzyloxy-4'-hydroxymethylbiphenyl-3-yl) -1,1-dioxo- 1,2,5-thiadiazolidin-3-one To the above solution was added (4-iodophenyl) -methanol (88 mg, 0.38 mmol), Cs2CO3 (326 mg, 1.0 mmol) and Pd (PPh3) 4 (10 mg, 10% by weight). The suspension was degassed and heated at 85 ° C for 3 hours. The solvent was removed under reduced pressure to give the product as a red liquid: MS (M-1) "= 423. C. 5- (4-Hydroxy-4, -hydroxymethylbiphenyl-3-yl) -1,1-dioxo -1,2,5-thiadiazolidin-3-one Prepared from 5- (4-benzyloxy-4'-hydroxymethylbiphenyl-3-yl) -1,1-dioxo-1, 2,5-thiadiazolidin-3-one advantageously to Example 1, Step G: MS (M-1) "= 333. Example 33 5- (2-Hydroxy-4,5-dimethylphenyl) -1,1-dioxo-1,2,5-titadiazolidin-3- ona A. N- (2-Hydroxy-4,5-dimethyl-phenyl) acetamide To a stirred suspension of 2-amino-4,5-dimethylphenol (450 mg, 3.28 mmol) in 10 mL of THF and 10 mL of saturated NaHCO3. acetyl chloride (0.25 mL, 3.45 mmol) was added dropwise at 0 ° C. The suspension was warmed to room temperature and stirred for 2 hours. The suspension was filtered and the filtrate was adjusted to pH 4-5 with 1N HCl. The suspension was extracted with EtOAc. The organic layer was washed with water and brine, and dried over sodium sulfate. The solvent was removed under reduced pressure to give the crude product as a pale yellow solid: NMR (CDCl 3): d 8.47 (s, 1H), 7.32 (s, 1H), 6.80 (s, 1H), 6.68 (s, 1H ), 2.23 (s, 3H), 2.18 (s, 3H), 2.14 (s, 3H); MS (M-1) "= 178. B. N- (2-Benzyloxy-4,5-dimethyl-phenyl) -acetamide Prepared from N- (2-hydroxy-4,5-dimethylphenyl) acetamide analogously to Example 1, Step A. MS (M-1) - = 268. C. 2-Benzyloxy-4,5-dimethyl-phenylamine N- (2-Benzyloxy-4,5-dimethyphenyl) acetamide (800 mg, 2.97 mmol) reflux in 6 mL of EtOH with KOH (999 mg, 17.8 mmol) in water (2 mL) overnight The solution was diluted with water and extracted with EtOAc The organic layer was washed with water and brine, and dried over sodium sulfate The solvent was removed under reduced pressure to give the product as a pale red liquid: NMR (CDCl 3): d 7.44-7.30 (m, 5H), 6. 67 (s, 1H), 6.55 (s, 1H), 5.04 (s, 2H), 3.64 (s, 2H), 2.15 (s, 3H), 2.13 (s, 3H); MS (M + 1) + = 228. D. 5- (2-H idroxy-4,5-dimethylphenyl) -1,1-dioxo-1, 2,5-thiadiazolidin-3-one Prepared from 2 -benzyloxy-4,5-dimethylphenylamine analogously to Example 14, Steps CG: MS (M-1) "= 255. EXAMPLE 34 5- [4-Hydroxy-3- (1,1,4-trioxo-1,2 acid , 5-thiadiazolidin-2-yl) -phenyl] -2,2-dimethylpentanoic acid The title compound was prepared analogously to Example 30, Step F and G starting with 2,2-dimethylpent-4-enoic acid in Step F: MS (M-1) "= 355. EXAMPLE 35 Ethyl ester of 8- [ 4-hydroxy-3- (1, 1, 4-trioxo-1, 2,5-thiadiazolidin-2-yl) -phenyl] -2,2-dimethyloctanoic acid A. 2,2-dimethyloct-7-enoic acid ethyl ester To a solution of isobutyric acid ethyl ester (1.0 g, 8.62 mmol) in THF (2 mL) at -78 ° C was added LDA (2 M in THF, 4.31 mL, 8.62 mmol) in THF (5 mL) and the resulting mixture was allowed to warm to RT and stirred for 20 minutes. It was then cooled again to -78 ° C and 6-bromohex-1-ene (1.4 g, 8.62 mmol) in THF (2 mL) was added. The mixture was then allowed to warm to RT and was stirred at 40 ° C for 24 hours. Water was added and EtOAc was used until it was removed. The organic layer was washed with water, brine and dried. The concentrated residue was then purified by flash chromatography to give the title compound as a yellow liquid. B. 8- [4-Hydroxy-3- (1, 1, 4-trioxo-1, 2,5-thiadiazolidin-2-yl) -phenyl] -2,2-dimethyloctanoic acid ethyl ester The title compound was prepared analogously to Example 30, Steps F and G, with the exception that Pd (OAc) 2, 2- (di-t-butylphosphine) biphenyl and triethylamine are used in place of Pd (PPh3) 4 and K2CO3; MS (M-1) "= 425. EXAMPLE 36 8- [4-Hydroxy-3- (1,1-trioxo-1,2,5-thiadiazolidin-2-yl) -phenyl] -2,2-dimethyloctanoic acid A. 2,2-dimethyloct-7-enoic acid The title compound was prepared analogously to Example 30, Step CB: Acid 8- [4-hydroxy-3- (1, 1, 4-trioxo-1, 2.5- thiadiazolidin-2-yl) -phenyl] -2,2-dimethyloctanoic acid The title compound was prepared analogously to Example 35, Step B: MS (M-1) "= 397. EXAMPLE 37 7- [4-Hydroxy-3-acid - (1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl) -phenyl] -2,2-dimethylheptanoic acid The title compound was prepared analogously to Example 36, starting from 5-bromopent-1-ene: MS (M-1) "= 383. Example 38 6- [4-Hydroxy-3- (1,1, 4-trioxo-1,2,5-thiadiazolidin-2-yl) -phenyl] -2,2-dimethylhexanoic acid The title compound was prepared analogously to Example 36 starting from ethylester of isobutyric acid, MS (M-1) - = 369. EXAMPLE 39 Ethyl ester of 7- [4-hydroxy-3- (1, 1, 4) acid trioxo-1, 2,5-thiadiazolidin-2-yl) -phenyl] -2,2-dimethyl-heptanoic The title compound was prepared analogously to Example 35, starting from 5-bromopent-1-ene: MS (M-1) "= 411. Example 40 8- [4-Hydroxy-3- (1,1,4 -trioxo-1,2,5-thiadiazolidin-2-yl) -phenyl] -2,2-dimethyloctanenitrile The title compound was prepared analogously to Example 35, starting from isobutyronitrile: MS (M-1) "= 411. Example 41 5- [2-Hydroxy-5- (6-hydroxy-6-methylheptyl) -phenyl] -1,1-dioxo-1,2,5-thiadiazolidin-3-one A. 2-Methylhept-6-en-2-ol To magnesium (89 mg, 3.70 mmol) in THF (10 mL) was added dropwise 5-bromopent-1-ene (500 mg, 3.36 mmol) and the mixture was led to reflux for 2 hours. After cooling to -78 ° C, acetone (0.25 mL, 3.36 mol) was added in drops. The mixture was then stirred at room temperature for 18 hours. 5% HCl was added and the EtOAc was used until it was removed. The organic layer was washed with water, brine and dried. It was then concentrated to give the title compound as a yellow liquid pale. B. 5- [2-Hydroxy-5- (6-hydroxy-6-methylheptyl) -phenyl] -1,1-dioxo-1,2,5-thiadiazolidin-3-one The title compound was prepared analogously to Example 35, Step B: MS (M-1) "= 355. EXAMPLE 42 5- [2-Hydroxy-5- (7-hydroxy-6,6-dimethylheptyl) -phenyl] -1,1-di-oxo-1, 2,5-thiadiazolidin-3-one A. 2,2-Dimethylhept-6-en-1-ol A LiAIH4 (1 M in THF), 6.74 mL, 6.74 mmol) in THF (10 mL) at 0 ° C was added 2,2-dimethylheptanoic acid ethyl ester (intermediate of Example 37) (700 mg, 4.49 mmol) in THF (5 mL) and the mixture stirred at room temperature for 18 hours. Water was added and the mixture was extracted with EtOAc. The organic layer was washed with water and brine. It was then dried and concentrated to give the title compound as a yellow liquid. B. 7- [4-Hydroxy-3- (1, 1, 4-trioxo-1, 2,5-thiadiazolidin-2-yl) -phenyl] -2,2-dimethyl-heptanoic acid The title compound was prepared analogously to Example 35, Step B: MS (M-1) "= 369. Example 43 5- [2-Hydroxy-5- (5-hydroxy-5-methylhexyl) -phenyl] -1,1-dioxo-1,2, 5-thiadiazolidin-3-one The title compound was prepared analogously to Example 41 by starting with 4-bromobut-1-ene: MS (M-1) ~ = 341. Example 44 5- [2-Hydroxy-5- (8-hydroxy-7,7- dimethyloctyl) -phenyl] -1,1-dioxo-1,2,5-thiadiazolidin-3-one The title compound was prepared analogously to Example 42 by starting with 6-bromohex-1-ene: MS (M-1) "= 383. Example 45 7- [4-Hydroxy-3- (1,1,4-trioxo- 1,2,5-thiadiazolidin-2-yl) -phenyl] -2,2-dimethylheptanonitrile The title compound was prepared analogously to Example 35 from isobutyronitrile and 5-bromopent-1-ene: MS (M-1) - = 364. Example 46 5- [2-Hydroxy-5- (5-hydroxy-5 -methylhex-1-ynyl) -phenyl] -1,1-dioxo-1,2,5-thiadiazolidin-3-one A. Pent-4-inoic acid methyl ester To a solution of pent-4-inoic acid (3 g, 30.61 mmol) in toluene (48 mL) and MeOH (12 mL) was added dropwise trimethylsilyldiazomethane (2 M in hexane, 16.07 mL, 32.14 mmol) and the mixture was stirred at room temperature for 3 hours. 1N HCl was added dropwise and water was added. EtOAc was used until it was removed. The organic layer was washed with saturated NaHCO3, brine and dried. The solvent was removed under reduced pressure and the residue was purified by column chromatography to give the title compound as an oil colorless B. 2-Methylhex-5-in-2-ol To a solution of methyl ester of pent-4-ynyoacetic acid (440 mg, 3.9 mmol) in Et2O (10 mL) methylmagnesium bromide was added dropwise (3 M in Et 2 O, 5 2 mL, 15 6 mmol) and the mixture was stirred at room temperature for 3 hours. The reaction mixture was then poured into a mixture of HCl 1H and Et 2 O, and stirred vigorously. The ether layer was separated and washed with saturated NaHCO3, brine and dried The solvent was removed under reduced pressure to give the title compound as a pale yellow liquid C. 5- [2-Hydroxy-5- (5-hydroxy-5-methylhex- 1-inyl) -phenyl] -1,1-dioxo-1,2,5-thiadiazolidin-3-one The title compound was prepared analogously to Example 30, Step F, starting with 5- (5-bromo-2- hydrox? phen?) -1,1-d? oxo-1, 2,5-t? ad? aolol? d? n-3-one and 2-methexhex-5-? n-2- ol, with the exception that Pd (dppf) CI2, CuCI and Et3N were used instead of Pd (PPh3) and K2C03, MS (M-1) '= 364 Example 47 5- [2-Hydroxy-5- (2-pyridin-3-yl-ethyl) -phenyl] -1,1-dioxo-1 2,5-thiadiazolidin-3-one The title compound was prepared analogously to Example 35, Step B starting with 3-vinylpyridine, and Pd (OH) 2 was used in place of Pd / C for the debenzylation step: MS (M-1) - = 332. Example 48 5- (2-Hydroxy-4-methyl-5-pentylphenyl) -1,1-dioxo-1,2,5-thiadiazolidin-3-one A. 4-Benzyloxy-1-bromo-2-methylbenzene The title compound was prepared analogously to Example 1, Step A from 4-bromo-3-methylphenol. B. 1-Benzyloxy-4-bromo-5-methyl-2-nitrobenzene 4-Benzyloxy-1-bromo-2-methylbenzene (13.4 g, 48.4 mmol) was dissolved in AcOH (100 mL) with heating and then cooled at RT, NHO3 (65%, 4.4 mL, 96.8 mmol) was added in drops. Concentrated H2SO4 (0.5 mL) was added and the mixture was heated to 70 ° C. More concentrated H2SO (0.5 mL) was added and the mixture was heated to 100 ° C. The mixture was then extracted with EtOAc and hexane and concentrated. The residue was purified by flash column chromatography (2% EtOAc / hexane) to give the title compound as an orange solid.

C. 2-Benzyloxy-5-bromo-4-methyl phenylamine The title compound was prepared analogously to Example 1, Step BD 5- (2-Benzyloxy-5-bromo-4-methylphenyl) -1,1-dioxo-1. , 2,5-thiadiazolidin-3-one The title compound was prepared analogously to Example 25, Steps DG. E. 5- (2-Hydroxy-4-methyl-5-pentylphenyl) -1,1-dioxo-1,2,5-thiadiazolidin-3-one The title compound was prepared analogously to Example 1, Steps F and G , using 1-pentylboronic acid: Retention time = 1.21 minutes (Method A) MS (M-1) "= 311. EXAMPLE 49 The following compounds were prepared analogously to Example 48 using appropriate boronic acid.

Example 50 4- (7-Hydroxy-6,6-dimethylheptyl) -2- (1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl) -benzoic acid phenyl ester To the potassium salt of 5- [2-hydroxy-5- (7-hydroxy-6,6-dimethylheptyl) -phenyl] -1,1-dioxo-1,2,5-thiadiazolidin-3-one (Example 42) ) (320 mg, 0.78 mmol) in DMF (5 mL) at 0 ° C was added in drops KOtBu (1 M in THF, 0.78 mL, 0.78 mmol). After being stirred for 2 minutes, benzoyl chloride (0.090 mL, 0.78 mmol) was added dropwise. The mixture was stirred for 5 minutes. Water (5 drops) was added and the mixture was subjected to HPLC purification to isolate the title compound as a white solid: MS (M-1) ~ = 473. Example 51 4- (6-Cyano-6,6- dimethylhexyl) -2- (1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl) -phenylester of benzoic acid The title compound was prepared analogously to Example 50 by starting from 8- [4-hydroxy-3- (1, 1, 4-trioxo-1,2,5-thiadiazolidin-2-yl) -phenyl] -2, 2-dimethyloctanetrotyl (Example 40): MS (M-1) - = 378. The table below shows the inhibitory activity (IC 50 values) of representative compounds of the invention to human PTP-1 B.

Claims (2)

CLAIMS 1. A compound of the formula characterized in that Q is alkoxy, alkylthio, alkylthion, sulfonyl, cycloalkyl, aryl, heterocyclyl, alkenyl, alkynyl or (C? .8) alkyl optionally substituted with one to four substituents selected from the group consisting of halogen, hydroxy, cycloalkyl, cycloalkoxy acyl, acyloxy, alkoxy, alkyloxyalkoxy, optionally substituted amino, carbamoyl, thiol, alkylthio, alkylthion, sulfonyl, sulfamoyl, nitro, cyano, free or esterifcarboxy, aryl, aryloxy, arylthio, alkenyl, alkynyl, aralkoxy, heteroaralkoxy, heterocyclyl and heterocyclyloxy; Ri is hydrogen, -C (O) R4, -C (O) NR5R6 or -C (O) OR7 wherein R4 and R5 are, independently of each other, hydrogen, cycloalkyl, aryl, heterocyclyl, aralkyl, heteroaralkyl or optionally substituted alkyl with one to four substituents selected from the group consisting of halogen, cycloalkyl, cycloalkoxy, alkoxy, alkyloxyalkoxy, amino, alkylamino, dialkylamino, aryl, aryloxy and heterocyclyl; R6 and R are, independently of each other, cycloalkyl, aryl, heterocyclyl, aralkyl, heteroaralkyl or alkyl optionally substituted with one to four substituents selected from the group consisting of halogen, cycloalkyl, cycloalkoxy, alkoxy, alkyloxyalkoxy, amino, alkylamino, dialkylamino, aryl, aryloxy and heterocyclyl; R2 and R3 are, independently of each other, hydrogen, halogen, alkyl of (C? -3) or alkoxy of C? -3); or a pharmaceutically acceptable salt thereof. 2. A compound according to claim 1, characterized in that Q is -Y- (CH2) n-CR8R9- (CH2) mX wherein Y is oxygen or S (O) q where q is zero or an integer of 1 or 2; or Y is C = C; or And he is absent; n and m are, independently of each other, zero or an integer from 1 to 8; R8 and R9 are, independently of each other, hydrogen or lower alkyl; or R8 and Rg combined are alkylene which together with the carbon atom to which they are attached form a 3 to 7 membered ring; X is hydroxy, alkoxy, cycloalkyl, cycloalkoxy, acyl, acyloxy, carbamoyl, optionally substituted amino, cyano, trifluoromethyl, free or esterifcarboxy, heterocyclyl, aryl monocyclic or monocyclic aryloxy; or a pharmaceutically acceptable salt thereof. 3. A compound according to claim 2, characterized in that R2 and R3 are hydrogen; or a pharmaceutically acceptable salt thereof. 4. A compound according to claim 3, characterized in that n is zero or an integer from 1 to 3; m is zero or 1; R8 and R9 are, independently of each other, hydrogen or lower alkyl; X is hydroxy, carbamoyl, cyano, trifluoromethyl, free or esterifcarboxy, heterocyclyl, monocyclic aryl or monocyclic aryloxy; or a pharmaceutically acceptable salt thereof. 5. A compound according to claim 4, characterized in that Y is C = C; or And he is absent; or a pharmaceutically acceptable salt thereof. 6. A compound according to claim 5, characterized in that Y is absent; n is an integer of 5 or 6; m is zero or 1; R8 and Rg are lower alkyl; X is free or esterifhydroxy, cyano or carboxy; or a pharmaceutically acceptable salt thereof. 7. A compound according to claim 6, characterized in that R8 and Rg are methyl; or a pharmaceutically acceptable salt thereof. 8. A compound according to claim 7, characterized in that Ri is hydrogen or -C (O) R4 in which R4 is monocyclic aryl; or a pharmaceutically acceptable salt thereof. 9. A compound according to claim 5, characterized in that Y is absent; n is an integer of 4 or 5; m is zero; R8 and R9 are hydrogen; X is monocyclic aryloxy; or a pharmaceutically acceptable salt thereof. 10. A compound according to claim 9, characterized in that RT is hydrogen or -C (O) R4 in which R4 is monocyclic aryl; or a pharmaceutically acceptable salt thereof. 11. A compound according to claim 5, characterized in that Y is C = C; n is an integer of 2 or 3; m is zero; R8 and R9 are hydrogen; X is free or esterified hydroxy, cyano or carboxy; or a pharmaceutically acceptable salt thereof. 12. A compound according to claim 11, characterized in that RT is hydrogen or -C (O) R4 in which R is monocyclic aryl; or a pharmaceutically acceptable salt thereof. 13. A compound according to claim 1, characterized in that Q is monocyclic aryl or a 5-6 membered heterocyclic ring; or a pharmaceutically acceptable salt thereof. 14. A compound according to claim 13, characterized in that R2 and R3 are hydrogen; or a pharmaceutically acceptable salt thereof. 15. A compound according to claim 14 of the formula characterized in that RT is hydrogen, -C (O) R4, -C (O) NR5R6 or -C (O) OR7 wherein R4 and R5 are, independently of each other, hydrogen, cycloalkyl, aryl, heterocyclyl, aralkyl, heteroaralkyl or alkyl optionally substituted with one to four substituents selected from the group consisting of halogen, cycloalkyl, cycloalkoxy, alkoxy, alkyloxyalkoxy, amino, alkylamino, dialkylamino, aryl, aryloxy and heterocyclyl; R6 and R are, independently of each other, cycloalkyl, aryl, heterocyclyl, aralkyl, heteroaralkyl or alkyl optionally substituted with one to four substituents selected from the group consisting of halogen, cycloalkyl, cycloalkoxy, alkoxy, alkyloxyalkoxy, amino, alkylamino, dialkylamino, aryl , aryloxy and heterocyclyl; R 10, R n and R 2 are, independently of each other, hydrogen, hydroxy, halogen, cyano, nitro, alkoxy, alkylthio, alkylthion, sulfonyl, free or esterified carboxy, carbamoyl, sulfamoyl, optionally substituted amino, cycloalkyl, aryl, heterocyclyl, alkenyl, alkynyl, or (C? -8) alkyl optionally substituted with one to four substituents selected from the group consisting of halogen, hydroxy, cycloalkyl, cycloalkoxy, acyl, acyloxy, alkoxy, alkyloxyalkoxy, optionally substituted amino, carbamoyl, thiol, alkylthio, alkylthion, sulfonyl, sulfamoyl, nitro, cyano, free or esterified carboxy, aryl, aryloxy, arylthio, alkenyl, alkynyl, aralkoxy, heteroaralkoxy, heterocyclyl and heterocyclyloxy; or C-R-io, C-Rn and C-R-? 2 are, independently of each other, replaced by nitrogen; or a pharmaceutically acceptable salt thereof. 16. A compound according to claim 15, characterized in that R10 and Rn are hydrogen; or a pharmaceutically acceptable salt thereof. 17. A compound according to claim 15, characterized in that R-i is hydrogen or -C (O) R in which R4 is monocyclic aryl; or a pharmaceutically acceptable salt thereof. 18. A compound according to claim 14 of the formula characterized in that RT is hydrogen, -C (O) R4, -C (O) NR5R6 or -C (O) OR7 wherein R and R5 are, independently of each other, hydrogen, cycloalkyl, aryl, heterocyclyl, aralkyl, heteroaralkyl or alkyl optionally substituted with one to four substituents selected from the group consisting of halogen, cycloalkyl, cycloalkoxy, alkoxy, alkyloxyalkoxy, amino, alkylamino, dialkylamino, aryl, aryloxy and heterocyclyl; R6 and R are, independently of each other, cycloalkyl, aryl, heterocyclyl, aralkyl, heteroaralkyl or alkyl optionally substituted with one to four substituents selected from the group consisting of halogen, cycloalkyl, cycloalkoxy, alkoxy, alkyloxyalkoxy, amino, alkylamino, dialkylamino, aryl , aryloxy and heterocyclyl; R 3 is hydrogen, sulfonyl, cycloalkyl, aryl, heterocyclyl or (C 8 -alkyl) optionally substituted with one to four substituents selected from the group consisting of halogen, hydroxy, cycloalkyl, cycloalkoxy, acyl, acyloxy, alkoxy, alkyloxyalkoxy , optionally substituted amino, carbamoyl, thiol, alkylthio, alkylthion, sulfonyl, sulphamoyl, nitro, cyano, free or esterified carboxy, aryl, aryloxy, arylthio, alkenyl, alkynyl, aralkoxy, heteroaraichoxy, heterocyclyl and heterocyclyloxy; or R? and R15 are, independently of each other, hydrogen or lower alkyl; or C-R14 and C-R15 are, independently of each other, replaced by nitrogen; or a pharmaceutically acceptable salt thereof. 19. A compound according to claim 18, characterized in that C-R14 is replaced by nitrogen; R15 is hydrogen; or a pharmaceutically acceptable salt thereof. 20. A compound according to claim 19 of the formula characterized in that Ri is hydrogen, -C (O) R4, -C (O) NR5R6 or -C (O) OR7 wherein
1. R and R are, independently from each other, hydrogen, cycloalkyl, aplo, heterocyclyl, aralkyl, heteroaralkyl or alkyl optionally substituted with one to four substituents selected from the group consisting of halogen, cycloalkyl, cycloalkoxy, alkoxy, alkyloxyalkoxy, amino, alkylamino, dialkylamino , aplo, aploxy and heterocyclic, R6 and R are, independently of each other, cycloalkyl, aplo, heterocyclic, aralkyl, heteroaralkyl or alkyl optionally substituted with one to four substituents selected from the group consisting of halogen, cycloalkyl, cycloalkoxy, alkoxy, alkyloxyalkoxy, amino, alkylamino, dialkylamino, aplo, aploxy and heterocyclyl, R? 3 is hydrogen, sulfonyl, cycloalkyl, aplo, heterocyclyl or (C? -8) alkyl optionally substituted with one to four substituents selected from the group consisting of halogen, hydroxy , cycloalkyl, cycloalkoxy, acyl, acyloxy, alkoxy, alkyloxyalkoxy, optionally substituted amino, carbamoyl, t iol, alkylthio, alkylthion, sulfonyl, sulfamoyl, nitro, cyano, free or estepficated carboxy, aplo, aploxy, apltio, alkenyl, alkyl, aralkoxy, heteroaralkoxy, heterocyclyl, and heterocyclyloxy, or a pharmaceutically acceptable salt thereof 21 A compound of compliance with claim 20, characterized in that Ri3 is - (CH2) n-CR16R? 7- (CH2) mZ where n and m are, independently of each other, zero or a number whole from 1 to 6; R and R are, independently of each other, hydrogen or lower alkyl; or Rie and R-17 combined are alkylene which together with the carbon atom to which they are attached form a 3 to 7 membered ring; Z is hydroxy, alkoxy, cycloalkyl, cycloalkoxy, acyl, acyloxy, carbamoyl, optionally substituted amino, cyano, trifluoromethyl, free or esterified carboxy, heterocyclyl, monocyclic aryl or monocyclic aryloxy; or a pharmaceutically acceptable salt thereof. 22. A compound according to claim 21, characterized in that n is an integer from 1 to 3; m is zero or 1; Laugh and R > they are, independently of each other, hydrogen or lower alkyl; Z is hydroxy, carbamoyl, cyano, trifluoromethyl, free or esterified carboxy, heterocyclyl, monocyclic aryl or monocyclic aryloxy; or a pharmaceutically acceptable salt thereof. 23. A compound according to claim 22, characterized in that Rie and R are hydrogen; Z is free or esterified hydroxy, cyano or carboxy; or a pharmaceutically acceptable salt thereof. 24. A compound according to claim 23, characterized in that RT is hydrogen or -C (O) R in which R4 is monocyclic aryl; or a pharmaceutically acceptable salt thereof. 25. A compound according to claim 1, characterized in that it is selected from the group consisting of: 5- [2-hydroxy-5- (1H-pyrrol-2-yl) -phenyl] -1,1-dioxo-1 , 2,5-thiadiazolidin-3-one; 5- (4-hydroxybiphenyl-3-yl) -1,1-dioxo-1,2,5-thiadiazolidin-3-one; 5- [2-hydroxy-5- (2H-pyrazol-3-yl) -phenyl] -1,1-dioxo-1, 2,5-thiadiazolidin-3-one; 5- [2-hydroxy-5- (1-methyl-1 H -pyrazol-4-yl) -phenyl] -1,1-dioxo-1, 2,5-thiadiazolidin-3-one; 5- (5-furan-3-yl-2-hydroxyphenyl) -1,1-dioxo-1,2,5-thiadiazolidin-3-one; 5- [2-hydroxy-5- (1 H -pyrazol-4-yl) -phenyl] -1,1-dioxo-1, 2,5-thiadiazolidin-3-one; 5- (4'-Acetyl-4-hiroxibiphenyl-3-yl) -1,1-dioxo-1, 2,5-thiazolidin-3-one; 5- (4'-benzoyl-4-hiroxybiphenyl-3-yl) -1,1-dioxo-1,2,5-thiadiazolidin-3-one; 5- [2-hydroxy-5- (1H-pyrrol-3-yl) -phenyl] -1,1-dioxo-1,2,5-thiadiazolidin-3-one; 4'-hydroxy-3 '- (1,1,4-trioxo-1, 2,5-thiadiazolidin-2-yl) -biphenyl-3-yl ester of methanesulfonic acid; 5- (3'-amino-4-hydroxybiphenyl-3-yl) -1,1-dioxo-1,2,5-thiadiazolidin-3-one; 5- (4-hydroxy-2'-methylbiphenyl-3-yl) -1,1-dioxo-1, 2,5-thiadiazolidin-3-one; 5- [2-Hydroxy-5- (1H-indol-2-yl) -phenyl] -1,1-dioxo-1,2,5-thiadiazolidin-3-one; [4'-hydroxy-3 '- (1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl) -biphenyl-3-yl] -acetonitrile; (2-Cyanoethyl) -amide of 4'-hydroxy-3 '- (1, 1, 4-trioxo-1, 2,5-thiadiazolidin-2-yl) -b-phenyl-3-carboxylic acid methyl ester of 3- [4'-hydroxy-3 '- (1, 1, 4-trioxo-1, 2,5-thiadiazolidin-2-yl) -biphenyl-3-yl] -propionic acid; 4'-Hydroxy-3 '- (1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl) -biphenyl-3-carboxylic acid (2-carbamoylethyl) -amide; 5- [3 '- (2-aminoethyl) -4-hydroxybiphenyl-3-yl] -1,1-dioxo-1,2,5-thiadiazolidin-3-one; 5- (3'-aminometl-4-hydroxylbiphenyl-3-yl) -1,1-dioxo-1,2,5-thiadiazolidin-3-one; 5- (2-hydroxy-5-pyridin-3-yl-phenyl) -1,1-dioxo-1,2,5-thiadiazolidin-3-one; 5- (4-hydroxy-2'-methoxy-biphenyl-3-yl) -1,1-dioxo-1,2,5-thiadiazolidin-3-one; 5- (2-hydroxy-5-pyridin-4-yl-phenyl) -1,1-dioxo-1,2,5-thiadiazolidin-3- ona; [4'-hydroxy-3 '- (1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl) biphenyl-4-yl] -acetic acid; 5- (4'-Chloro-4-hydroxybiphenyl-3-yl) -1,1-dioxo-1,2,5-thiadiazolidin-3-one; 5- (3'-Chloro-4-hydroxy-phenyl-3-yl) -1,1-dioxo-1,2,5-thiadiazolidin-3-one; 5- [2-hydroxy-5- (6-methoxypyridin-3-yl) -phenyl] -1,1-dioxo-1,2,5-thiadiazolidin-3-one; 5- [5- (6-fluoropyridin-3-yl) -2-hydroxy-phenyl] -1,1-dioxo-1, 2,5-thiadiazolidin-3-one; 3- [4'-hydroxy-3 '- (1, 1, 4-trioxo-1, 2,5-thiadiazolidin-2-yl) -biphenyl-3-yl] -propionic acid ethyl ester; 5- (4-hydroxy-3'-methylbiphenyl-3-yl) -1,1-dioxo-1,2,5-thiadiazolidin-3-one; 5- (3'-Fluoro-4-hydroxybiphenyl-3-yl) -1,1-dioxo-1,2,5-thiadiazolidin-3-one; 5- (4'-Fluoro-4-hydroxybiphenyl-3-yl) -1,1-dioxo-1,2,5-thiadiazolidin-3-one; 5- (4-hydroxy-4'-methylbiphenl-3-yl) -1,1-dioxo-1,2,5-thiadiazolidin-3-one; 3- [4'-hydroxy-3 '- (1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl) -biphenyl-3-yl] -propionitrile; 4'-hydroxy-3"- (1,1,4-trioxo-1, 2,5-thiadiazolidin-2-yl) -bife nyl-3-carbonitrile; 5- (4-hydroxy-3 ', 5'-dimethylbiphenyl-3-yl) -1,1-dioxo-1,2,5-thiadiazolidin-3-one; 5- (4-hydroxy-3'-methoxybiphenyl-3-yl) -1,1-dioxo-1,2,5-thiazol-disid-3-one; N- (2-hydroxyethyl) -2- [4'-hydroxy-3 '- (1, 1, 4-trioxo-1, 2, 5-tiad i azole id i n-2-yl) -biphenyl-4 -yl] -acetamide; 2,2, 2-trif luoro-N- [4'-h id roxi-3 '- (1, 1,4-trioxo-1,2,5-thiadiazo-di-n-2-yl) -biphenyl-3- il] -acetamide; 1-ethyl-3-E4'-hydroxy-3 '- (1, 1, 4-trioxo-, 2,5-thiadiazolidin-2-yl) -bifen-3-yl] -urea; 1-Ethyl-3- [4'-hydroxy-3 '- (1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl) -biphenyl-3-ylmethyl] -urea; [4'-hydroxy-3 '- (1, 1, 4-trioxo-1, 2,5-thiadiazolidin-2-yl) -biphenyl-3-ylmethyl] -carbamic acid methyl ester; N- [4'-hydroxy-3 '- (1, 1, 4-trioxo-1, 2,5-thiadiazoiydin-2-yl) -biphenyl-3-ylmethyl] -acetamide; [4'-hydroxy-3 '- (1, 1, 4-trioxo-1, 2,5-thiadiazolidin-2-yl) -biphenyl-3-ylmethyl] -carbamic acid benzyl ester; 1-ethyl-3- [4'-hydroxy-3 '- (1, 1, 4-trioxo-1, 2,5-thiadiazolidin-2-yl) -biphenyl-4-yl] -urea; 3- [4'-hydroxy-3 '- (1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl) -biphenyl-3-yl] -propionic acid; 5- acid. { 4- [4-hydroxy-3- (1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl) -phenyl] -pyrazol-1-yl} -pentanoic; 5- [2-hydroxy-5- (1-propyl-1H-pyrazol-4-yl) -phenyl] -1,1-dioxo-1,2,5- thiadiazolidin-3-one; 5- [2-hydroxy-5- (1-isobutyl-1H-pyrazol-4-yl) -phenyl] -1,1-dioxo-1,2,5-thiadiazolidin-3-one; acidic ester of 5- acid. { 4- [4-hydroxy-3- (1, 1, 5-trioxo-1, 2,5-thiadiazolidin-2-yl) -phenyl] -1H-pyrazol-1-yl} -pentanoic; 5-. { 2-hydroxy-5- [1- (4,4,4-trifluorobutyl) -1H-pyrazol-4-yl] -phenyl} -1,1-dioxo-1,2,5-thiadiazolidin-3-one; 5-. { 2-hydroxy-5- [1- (3-methylbutyl) -1 H -pyrazol-4-yl] -phenyl} -1,1-dioxo-1,2,5-thiadiazolidin-3-one; 5-. { 4- [4-hydroxy-3- (1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl) -phenyl] -1H-pyrazol-1-yl} -pentanonitrilo; 5-. { 4- [4- hydroxy -3- (1, 1, 4-tr i oxo-1,2,5-thiazolidin-2-yl) -phenyl] -1H-pyrazol-1-yl} -butyronitrile; 5- (2-hydroxy-5-phenoxyphenyl) -1,1-dioxo-1,2,5-thiadiazolidin-3-one; 5- (2-hydroxy-5-methoxyphenyl) -1,1-dioxo-1,2,5-thiadiazolidin-3-one; 5- (5-benzyl-2-hydroxyphenyl) -1,1-d -oxo-1,2,5-thiadiazolidin-3-one; 5- (2-hydroxy-5-methylphenyl) -1,1-dioxo-1,2,5-thiadiazolidin-3-one; 5- (5-hexyl-2-hydroxyphenyl) -1,1-dioxo-1,2,5-thiadiazolidin-3-one; 5- (5-Butyl-2-hydroxyphenyl) -1,1-dioxo-1,2,5-thiadiazolidin-3-one; 5- [2-hydroxy-5- (tetrahydrofuran-3-yl) -phenyl] -1,1-dioxo-1, 2,5-thiadiazolidin-3-one; 5- [5- (4-fluorophenylethynyl) -2-hydroxyphenyl] -1,1-dioxo-1,2,5-thiadiazolidin-3-one; 6- [4-hydroxy-3- (1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl) -phenyl] -hex-5-inonitrile; 6- [4-hydroxy-3- (1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl) -phenyl] -hex-5-ynoic acid; 5- [5- (3,3-dim? T i-bu t-1-ynyl) -2 -hydroxyphenyl] -1,1-di oxo-1, 2,5-triadiazolidin-3-one; 5- [2-hydroxy-5- (5-methylhexyl) -phenyl] -1,1-dioxo-1,2,5-thiadiazolidin-3-one; 6- [4-hydroxy-3- (1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl) -phenyl] -hexanoic acid; 5- [5- (benzylaminomethyl) -2-hydroxyphenyl] -1,1-dioxo-1,2,5-thiadiazolidin-3-one; 5- (5-butylaminomethyl-2-hydroxyphenyl) -1,1-dioxo-1,2,5-thiadiazolidin-3-one; 5-. { 2-hydroxy-5 - [(2-methoxybenzylamino) -methyl] -phenyl} -1,1-dioxo-1,2,5-thiadiazolidin-3-one; 5-. { 5 - [(2-ethoxy-ethylamino) -methyl] -2-hydroxy-phenol} -1,1-dioxo-1,2,5-thiadiazolidin-3-one; 5-. { 2-hydroxy-5 - [(2-isopropoxybenzyl-amino) -methyl] -phenyl} -1,1-dioxo-1, 2,5-thiadiazolidin-3-one; 5- (2-hydroxy-5- { [2- (1-methyl-2-phenylethoxy) -benzylamino] -methyl} - phenyl) -1,1-dioxo-1,2,5-thiadiazolidin- 3-one; 5- [2-Hydroxy-5- (3-methyl-butoxy) -phenyl] -1,1-dioxo-1,2,5-thiadiazolidin-3-one; 5- [2-hydroxy-5- (4-methylpentyloxy) -phenyl] -1,1-dioxo-1,2,5-thiadiazolidin-3-one; 5- (2-hydroxy-5-propoxyphenyl) -1,1-dioxo-1,2,5-thiadiazolidin-3-one; 2-hydroxy-6-. { 4- [4-hydroxy-3- (1, 1, 4-trioxo-1, 2,5-thiadiazolidin-2-yl) -phenyl] -butoxy} -N, N-dimethylbenzamide; 2-hydroxy-6-. { 5- [4-hydroxy-3- (1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl) -phenyl] -pentyloxy} -N, N-dimethylbenzamide; 2-hydroxy-6-. { 6- [4-hydroxy-3- (1, 1, 4-trioxo-1, 2, 5-thiazolidin-2-yl) -phenyl] -hexyloxy} -N, N-dimethylbenzamide; 2-fluoro-6-. { 6- [4-hydroxy-3- (1, 1, 4-trioxo-1, 2,5-thiadiazolidin-2-yl) -phenyl] -hexyloxy} -N, N-dimethylbenzamide; 2-hydroxy-6-. { 7- [4-hydroxy-3- (1, 1,4-trioxo-1,2,5-thiadiazolidin-2-yl) -phenyl] -heptyloxy} -N, N-dimethylbenzamide; 5- (4-hydroxy-4'-hydroxymethylbiphenyl-3-yl) -1,1-dioxo-1,2,5-thiadiazolidin-3-one; 5- (2-hydroxy-4,5-dimethyl-phenyl) -1,1-dioxo-1,2,5-thiadiazolidin-3-one; 5- [4-hydroxy-3- (1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl) -phenyl] -2,2-dimethylpentanoic acid; ethyl ester of 8- [4-hydroxy-3- (1, 1, 4-trioxo-1, 2,5-thiadiazolidin-2-yl) -phenyl] -2,2-dimethyloctanoic acid; 8- [4-hydroxy-3- (1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl) -phenyl] -2,2-dimethyloctanoic acid; 7- [4-hydroxy-3- (1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl) -phenyl] -2,2-dimethylheptanoic acid; 6- [4-hydroxy-3- (1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl) -phenyl] -2,2-dimethylhexanoic acid; 7- [4-hydroxy-3- (1,1-, 4-trioxo-1, 2,5-thiadiazolidin-2-yl) -phenyl] -2,2-dimethylheptanoic acid ethyl ester; 8- [4-hydroxy-3- (1, 1, 4-trioxo-1, 2,5-thiadiazolidin-2-yl) -phenyl] -2,2-dimethyloctanenitrile; 5- [2-hydroxy-5- (6-hydroxy-6-methylheptyl) -phenyl] -1,1-dioxo-1, 2,5-thiadiazolidin-3-one; 5- [2-hydroxy-5- (7-hydroxy-6,6-dimethylheptyl) -phenyl] -1,1-dioxo-1,2,5-thiadiazolidin-3-one; 5- [2-hydroxy-5- (5-hydroxy-5-methylhexyl) -phenyl] -1,1-dioxo-1,2,5-thiadiazolidin-3-one; 5- [2-hydroxy-5- (8-hydroxy-7,7-dimethyloctyl) -phenyl] -1,1-dioxo-1,2,5-thiadiazolidin-3-one; 7- [4-hydroxy-3- (1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl) -phenyl] -2,2-dimethylheptanonitrile; 5- [2-hydroxy-5- (5-hydroxy-5-methylhex-1-ynyl) -phenyl] -1,1-dioxo-1,2,5-thiadiazolidin-3-one; 5- [2-hydroxy-5- (2-pyrid-Jn-3-yl-ethyl) -phenyl] -1,1-dioxo-1,2,5-thiadiazolidin-3-one; 5- (2-hydroxy-4-methyl-5-pentylphenyl) -1,1-dioxo-1,2,5-thiadiazolidin-3-one; 5- (2-hydroxy-4-methyl-5-propylphenyl) -1,1-dioxo-1,2,5-thiadiazolidin-3-one; 5- (5-heptyl-2-hydroxy-4-methylphenyl) -1,1-dioxo-1,2,5-thiadiazolidin-3-one; 5- [5- (2-cyclohexylethyl) -2-hydroxy-4-methylphenyl] -1,1-dioxo-1,2,5-thiadiazolidin-3-one; 4- (7-hydroxy-6,6-dimethylheptyl) -2- (1, 1, 4-trioxo-1, 2,5-thiadiazolidin-
2. 2-l) -f e n lesle r of benzoic acid; and 4- (6-cyano-6,6-dimethylhexyl) -2- (1,1,4-trioxo-1,2,5-thiadiazolidin-2-i I) -f e n i I benzoic acid ester; or a pharmaceutically acceptable salt thereof. 26. A method for inhibiting the activity of PTPase whose method is characterized in that it comprises administering to a mammal in need thereof a therapeutically effective amount of a compound according to claim 1. 27. A method for the treatment of conditions mediated by PTPase activity whose method is characterized in that it comprises administering to a mammal in need thereof a therapeutically effective amount of a compound according to claim 1. 28. A method according to claim 27, characterized in that it comprises administering a therapeutically effective amount of a combination of the compound and a anti-diabetic agent, a hypolipidemic agent, an anti-obesity agent or an anti-hypertensive agent. 29. A method for the treatment of conditions mediated by the activity of PTP-1B in mammals, which method is characterized in that it comprises administering to a mammal in need thereof a therapeutically effective amount of a compound according to claim 1. 30. A method for modulating glucose levels in mammals, which method is characterized in that it comprises administering to a mammal in need thereof, a therapeutically effective amount of a compound according to claim 1. 31. A method for the treatment of resistance to insulin, glucose intolerance, type 2 diabetes, obesity, hypertension, ischemic diseases of large or small blood vessels, dyslipidemia, atherosclerosis, vascular restenosis, irritable bowel syndrome, pancreatitis, cancer, osteoporosis, neurodegenerative diseases, infectious diseases, and diseases that involve inflammation and the immune system, which method is characterized in that it comprises administering to a mammal in need thereof, a therapeutically effective amount of a compound according to claim 1. 32. A pharmaceutical composition, characterized in that it comprises a therapeutic amount effective composition of a compound according to claim 1 in combination with one or more pharmaceutically acceptable carriers. 33. A pharmaceutical composition according to claim 32, characterized in that it is for the treatment of insulin resistance, glucose intolerance, type 2 diabetes, obesity, hypertension, ischemic diseases of the large or small blood vessels, dyslipidemia, atherosclerosis, vascular restenosis, irritable bowel syndrome, pancreatitis, cancer, osteoporosis, neurodegenerative diseases, infectious diseases, and diseases that involve inflammation and the immune system. 34. A pharmaceutical composition, characterized in that it comprises a therapeutically effective amount together of a compound according to claim 1 in combination with an anti-diabetic agent, a hypolipidemic people, an anti-obesity agent or an anti-hypertensive agent. 35. A pharmaceutical composition according to claim 34, characterized in that it is for the treatment of insulin resistance, glucose intolerance, type 2 diabetes, obesity, hypertension, ischemic diseases of the large or small blood vessels, dyslipidemia, atherosclerosis , vascular restenosis, irritable bowel syndrome, pancreatitis, cancer, osteoporosis, neurodegenerative diseases, infectious diseases, and diseases that involve inflammation and the immune system. 36. A pharmaceutical composition according to claim 34 or 35, for use as a medicament. 37. Use of a pharmaceutical composition according to claim 34 or 35, for the preparation of a medicament for the treatment of conditions mediated by the activity of PTPase. 38. Use of a compound according to claim 1, for the preparation of a pharmaceutical composition for the treatment of conditions mediated by PTPase activity. 39. Use according to claim 37 or 38, wherein the condition mediated by PTPase activity is selected from insulin resistance, glucose intolerance, type 2 diabetes, obesity, hypertension, ischemic diseases of large or small blood vessels, dyslipidemia, atherosclerosis, vascular restenosis, syndrome of irritable colon, pancreatitis, cancer, osteoporosis, neurodegenerative diseases, infectious diseases, and diseases that involve inflammation and the immune system. 40. A compound according to claim 1, for use as a medicament.