Patent ID: 6630487
Filing Date: 2003-10-07
Classification: A61K,A61P,C07D,Y02P

Abstract:
A method for treating insulin resistance in a mammal, which comprises administering to said mammal an effective amount of a compound of formula I or the stereoisomeric mixtures, diastereomerically enriched, diastereomerically pure, enantiomerically enriched or enantiomerically pure isomers, or the pharmaceutically acceptable salts and prodrugs thereof,whereine is 0 or 1; n and w are each 1; Y is oxygen or sulfur; R1 is hydrogen, â€”CN, â€”(CH2)qN(X6)C(O)X6, â€”(CH2)qN(X6)C(O)(CH2)tâ€”A1, â€”(CH2)qN(X6)SO2(CH2)tâ€”A1, â€”(CH2)qN(X6)SO2X6, â€”(CH2)qN(X6)C(O)N(X6)(CH2)tâ€”A1, â€”(CH2)qN(X6)C(O)N(X6)(X6), â€”(CH2)qC(O)N(X6)(X6), â€”(CH2)qC(O)N(X6)(CH2)tâ€”A1, â€”(CH2)qC(O)OX6, â€”(CH2)qC(O)O(CH2)tâ€”A1, â€”(CH2)qOX6, â€”(CH2)qOC(O)X6, â€”(CH2)qOC(O)(CH2)tâ€”A1, â€”(CH2)qOC(O)N(X6)(CH2)tâ€”A1, â€”(CH2)qOC(O)N(X6)(X6), â€”(CH2)qC(O)X6, â€”(CH2)qC(O)(CH2)tâ€”A1, â€”(CH2)qN(X6)C(O)OX6, â€”(CH2)qN(X6)SO2N(X6)(X6), â€”(CH2)qS(O)mX6, â€”(CH2)qS(O)m(CH2)tâ€”A1, â€”(C1-C10)alkyl, â€”(CH2)tâ€”A1, â€”(CH2)qâ€”(C3-C7)cycloalkyl, â€”(CH2)qâ€”Y1â€”(C1-C6)alkyl, â€”(CH2)qâ€”Y1â€”(CH2)tâ€”A1 or â€”(CH2)qâ€”Y1â€”(CH2)tâ€”(C3-C7)cycloalkyl; where the alkyl and cycloalkyl groups in the definition of R1 are optionally substituted with (C1-C4)alkyl, hydroxyl, (C1-C4)alkoxy, carboxyl, â€”CONH2, â€”S(O)m(C1-C6)alkyl, â€”CO2(C1-C4)alkyl ester, 1H-tetrazol-5-yl or 1, 2 or 3 fluoro; Y1 is O, S(O)m, â€”C(O)NX6â€”, â€”CH&boxH;CHâ€”, â€”Câ‰¡Câ€”, â€”N(X6)C(O)â€”, â€”C(O)NX6â€”, â€”C(O)Oâ€”, â€”OC(O)N(X6)â€” or â€”OC(O)â€”; q is 0, 1, 2, 3 or4; t is 0, 1, 2 or 3; said (CH2)q group and (CH2)t group may each be optionally substituted with hydroxyl, (C1-C4)alkoxy, carboxyl, â€”CONH2, â€”S(O)m(C1-C6)alkyl, â€”CO2(C1-C4)alkyl ester, 1H-tetrazol-5-yl, 1, 2 or 3 fluoro, or 1 or 2 (C1-C4)alkyl; R2 is hydrogen, (C1-C8)alkyl, â€”(C0-C3)alkyl-(C3-C8)cycloalkyl, â€”(C1-C4)alkyl-A1 or A1; where the alkyl groups and the cycloalkyl groups in the definition of R2 are optionally substituted with hydroxyl, â€”C(O)OX6, â€”C(O)N(X6)(X6), â€”N(X6)(X6), â€”S(O)m(C1-C6)alkyl, â€”C(O)A1, â€”C(O)(X6), CF3, CN or 1, 2 or 3 halogen; R3 is A1, (C1-C10)alkyl, â€”(C1-C6)alkyl-A1, â€”(C1-C6)alkyl-(C3-C7)cycloalkyl, â€”(C1-C5)alkyl-X1â€”(C1-C5)alkyl, â€”(C1-C5)alkyl-X1â€”(C0-C5)alkyl-A1 or â€”(C1-C5)alkyl-X1â€”(C1-C5)alkyl-(C3-C7)cycloalkyl; where the alkyl groups in the definition of R3 are optionally substituted with â€”S(O)m(C1-C6)alkyl, â€”C(O)OX3, 1, 2, 3, 4 or 5 halogens, or 1, 2 or 3 OX3; X1 is O, S(O)m, â€”N(X2)C(O)â€”, â€”C(O)N(X2)â€”, â€”OC(O)â€”, â€”C(O)Oâ€”, â€”CX2&boxH;CX2â€”, â€”N(X2)C(O)Oâ€”, â€”OC(O)N(X2)â€” or â€”Câ‰¡Câ€”; R4 is hydrogen, (C1-C6)alkyl or (C3-C7)cycloalkyl, or R4 is taken together with R3 and the carbon atom to which they are attached and form (C5-C7)cycloalkyl, (C5-C7)cycloalkenyl, a partially saturated or fully saturated 4- to 8-membered ring having 1 to 4 heteroatoms independently selected from the group consisting of oxygen, sulfur and nitrogen, or is a bicyclic ring system consisting of a partially saturated or fully saturated 5- or 6-membered ring, fused to a partially saturated, fully unsaturated or fully saturated 5- or 6-membered ring, optionally having 1 to 4 heteroatoms independently selected from the group consisting of nitrogen, sulfur and oxygen; X4 is hydrogen or (C1-C6)alkyl or X4 is taken together with R4 and the nitrogen atom to which X4 is attached and the carbon atom to which R is attached and form a five to seven membered ring; R6 is a bond or is â€ƒwhere a and b are independently 0, 1, 2 or 3; X5 and X5a are each independently selected from the group consisting of hydrogen, trifluoromethyl, A1 and optionally substituted (C1-C6)alkyl; the optionally substituted (C1-C6)alkyl in the definition of X5 and X5a is optionally substituted with a substituent selected from the group consisting of A1, OX2, â€”S(O)m (C1-C6)alkyl, â€”C(O)OX2, (C3-C7)cycloalkyl, â€”N(X2)(X2) and â€”C(O)N(X2)(X2); or the carbon bearing X5 or X5a forms one or two alkylene bridges with the nitrogen atom bearing R7 and R8 wherein each alkylene bridge contains 1 to 5 carbon atoms, provided that when one alkylene bridge is formed then X5 or X5a but not both may be on the carbon atom and R7 or R8 but not both may be on the nitrogen atom and further provided that when two alkylene bridges are formed then X5 and X5a cannot be on the carbon atom and R7 and R8 cannot be on the nitrogen atom; or X5 is taken together with X5a and the carbon atom to which they are attached and form a partially saturated or fully saturated 3- to 7-membered ring, or a partially saturated or fully saturated 4- to 8-membered ring having 1 to 4 heteroatoms independently selected from the group consisting of oxygen, sulfur and nitrogen; or X5 is taken together with X5a and the carbon atom to which they are attached and form a bicyclic ring system consisting of a partially saturated or fully saturated 5- or 6-membered ring, optionally having 1 or 2 heteroatoms independently selected from the group consisting of nitrogen, sulfur and oxygen, fused to a partially saturated, fully saturated or fully unsaturated 5- or 6-membered ring, optionally having 1 to 4 heteroatoms independently selected from the group consisting of nitrogen, sulfur and oxygen; Z1 is a bond, O or Nâ€”X2, provided that when a and b are both 0 then Z1 is not Nâ€”X2 or O; R7 and R8 are independently hydrogen or optionally substituted (C1-C6)alkyl; where the optionally substituted (C1-C6)alkyl in the definition of R7 and R8 is optionally independently substituted with A1, â€”C(O)Oâ€”(C1-C6)alkyl, â€”S(O)m(C1-C6)alkyl, 1 to 5 halogens, 1 to 3 hydroxy, 1 to 3 â€”Oâ€”C(O)(C1-C10)alkyl or 1 to 3 (C1-C6)alkoxy; or R7 and R8 can be taken together to form â€”(CH2)râ€”Lâ€”(CH2)râ€”; where L is C(X2)(X2), S(O)m or N(X2); A1 for each occurrence is independently (C5-C7)cycloalkenyl, phenyl or a partially saturated, fully saturated or fully unsaturated 4- to 8-membered ring optionally having 1 to 4 heteroatoms independently selected from the group consisting of oxygen, sulfur and nitrogen, a bicyclic ring system consisting of a partially saturated, fully unsaturated or fully saturated 5- or 6-membered ring, optionally having 1 to 4 heteroatoms independently selected from the group consisting of nitrogen, sulfur and oxygen, fused to a partially saturated, fully saturated or fully unsaturated 5- or 6-membered ring, optionally having 1 to 4 heteroatoms independently selected from the group consisting of nitrogen, sulfur and oxygen; A1 for each occurrence is independently optionally substituted, in one or optionally both rings if A1 is a bicyclic ring system, with up to three substituents, each substituent independently selected from the group consisting of F, Cl, Br, I, OCF3, OCF2H, CF3, CH3, OCH3, â€”OX6, â€”C(O)N(X6)(X6), â€”C(O)OX6, oxo, (C1-C6)alkyl, nitro, cyano, benzyl, â€”S(O)m(C1-C6)alkyl, 1H-tetrazol-5-yl, phenyl, phenoxy, phenylalkyloxy, halophenyl, methylenedioxy, â€”N(X6)(X6), â€”N(X6)C(O)(X6), â€”SO2N(X6)(X6), â€”N(X6)SO2-phenyl, â€”N(X6)SO2X6, â€”CONX11X12, â€”SO2NX11X12, â€”NX6SO2X12, â€”NX6CONX11X12, â€”NX6SO2NX11X12, â€”NX6C(O)X12, imidazolyl, thiazolyl and tetrazolyl, provided that if A1 is optionally substituted with methylenedioxy then it can only be substituted with one methylenedioxy; where X11 is hydrogen or optionally substituted (C1-C6)alkyl; the optionally substituted (C1-C6)alkyl defined for X11 is optionally independently substituted with phenyl, phenoxy, (C1-C6)alkoxycarbonyl, â€”S(O)m(C1-C6)alkyl, 1 to 5 halogens, 1 to 3 hydroxy, 1 to 3 (C1-C10)alkanoyloxy or 1 to 3 (C1-C6)alkoxy; X12 is hydrogen, (C1-C6)alkyl, phenyl, thiazolyl, imidazolyl, furyl or thienyl, provided that when X12 is not hydrogen, X12 is optionally substituted with one to three substituents independently selected from the group consisting of Cl, F, CH3, OCH3, OCF3 and CF3; or X11 and X12 are taken together to form â€”(CH2)râ€”L1â€”(CH2)râ€”; where L1 is C(X2)(X2), O, S(O)m or N(X2); r for each occurrence is independently 1, 2 or 3; X2 for each occurrence is independently hydrogen, optionally substituted (C1-C6)alkyl, or optionally substituted (C3-C7)cycloalkyl, where the optionally substituted (C1-C6)alkyl and optionally substituted (C3-C7)cycloalkyl in the definition of X2 are optionally independently substituted with â€”S(O)m(C1-C6)alkyl, â€”C(O)OX3, 1 to 5 halogens or 1-3 OX3; X3 for each occurrence is independently hydrogen or (C1-C6)alkyl; X6 is independently hydrogen, optionally substituted (C1-C6)alkyl, (C2-C6)halogenated alkyl, optionally substituted (C3-C7)cycloalkyl, (C3-C7)-halogenatedcycloalkyl, where optionally substituted (C1-C6)alkyl and optionally substituted (C3-C7)cycloalkyl in the definition of X6 is optionally independently substituted by 1 or 2 (C1-C4)alkyl, hydroxyl, (C1-C4)alkoxy, carboxyl, CONH2, â€”S(O)m(C1-C6)alkyl, carboxylate (C1-C4)alkyl ester, or 1H-tetrazol-5-yl; or when there are two X6 groups on one atom and both X6 are independently (C1-C6)alkyl, the two (C1-C6)alkyl groups may be optionally joined and, together with the atom to which the two X6 groups are attached, form a 4- to 9-membered ring optionally having oxygen, sulfur or NX7; X7 is hydrogen or (C1-C6)alkyl optionally substituted with hydroxyl; and m for each occurrence is independently 0, 1 or 2; with the proviso that: X6 and X12 cannot be hydrogen when it is attached to C(O) or SO2 in the form C(O)X6, C(O)X12, SO2X6 or SO2X12; and when R6 is a bond then L is N(X2) and each r in the definition â€”(CH2)râ€”Lâ€”(CH2)râ€” is independently 2 or 3.