Patent EA-004887-B1 (EA)
Title: COMPOUNDS FOR THE MODULATION OF PPARgamma ACTIVITY
Inventor: MCGEE LAWRENCE R
IPC: C07D213/71
Filed: 2000-06-28
Abstract: 1. A compound having the formula: wherein Ar<1> is an unsubstituted 2-benzothiazolyl or substituted 2-benzothiazolyl having from 1 to 3 substituents, independently selected from the group consisting of halogen, -OR', -OC(O)R', -NR'R'', -SR', -R', -CN, -NO2, -CO2R', -CONR'R'', -C(O)R', -NR''C(O)R', -S(O2)R', -S(O2)R', -S(O2)NR'R'', perfluoro(C1-C4)alkoxy and perfluoro(C1-C4)alkyl, wherein R' and R'' are independently selected from the group consisting of hydrogen, (C1-C8)alkyl, heteroalkyl, unsubstituted aryl, (unsubstituted aryl)-(C1-C4)alkyl and (unsubstituted aryl)oxy-(C1-C4)alkyl; X is -S(O)k, wherein the subscript k is an integer of from o to 2; Y is a divalent linkage selected from the group selected from the group consisting of (C1-C6)alkylene, -O-, -C(O)-, N(R12)-S(O)m, N(R12)-S(O)m-N(R13)-, N(R12)C(O)-, S(O)n, wherein R<12> and R<13> are substituents independently selected from the group consisting of hydrogen, (C1-C8)alkyl, (C2-C8)heteroalkyl, and aryl(C1-C4)alkyl; and the subscripts m and n are independently integers of from 0 to 2; R<1> is a substituent selected from the group consisting of hydrogen, (C2-C8)heteroalkyl, aryl, aryl (C1-C4)alkyl, halogen, cyano, nitro, (C1-C8) alkyl, (C1-C8) alkoxy, -C(O)R<14>, -CO2R<14>, -C(O)NR<15>R<16>, -S(O)p-R<14>, -S(O)q-NR<15>R<16>, -O-C(O)-NR<15>R<16>, -N(R<14>)-C(O)-, -O-C(O)-R<17>, and-N(R<14>)-C(O)-OR<17>, NR<15>R<16>, -N(R<14>)-C(O)-R<17>; wherein R<14> is a substituent selected from the group consisting of hydrogen, (C1-C8) alkyl,(C2-C8) heteroalkyl, aryl and aryl(C1-C4) alkyl; R<15> and R<16> are substituents independently selected from the group consisting of hydrogen, (C1-C8) alkyl, (C2-C8) heteroalkyl, aryl, and aryl(C1-C4) alkyl, or taken together with the nitrogen to which each is attached form a 5-, 6- or 7-membered ring; R<17> is a substituent selected from the group consisting of (C1-C8)alkyl, (C2-C8)heteroalkyl, aryl and aryl(C1-C4) alkyl; the subscript p is an integer of from 0 to 3; and the subscript q is an integer of from 1 to 2; and R<2> is a substituted or unsubstituted aryl having from 1 to 3 substituents, independently selected from the group consisting of halogen, -OR', -OC(O)R', -NR'R'', -SR', -R', -CN, -NO2, -CO2R', -CONR'R'', -C(O)R', -NR''C(O)R', -S(O2)R', -S(O2)R', -S(O2)NR'R'', perfluoro(C1-C4)alkoxy and perfluoro(C1-C4)alkyl, wherein R' and R'' are independently selected from the group consisting of hydrogen, (C1-C8)alkyl, heteroalkyl, unsubstituted aryl, (unsubstituted aryl)-(C1-C4)alkyl and (unsubstituted aryl)oxy-(C1-C4)alkyl; R<3> is a substituent selected from the group consisting of halogen, cyano, nitro and (C1-C8)alkoxy; or a pharmaceutically acceptable salt thereof. 2. The compound of claim 1, wherein R<2> is a substituted or unsubstituted aryl selected from the group consisting of phenyl, pyridyl, naphthyl and pyridazinyl and having from 1 to 3 substituents, independently selected from the group consisting of halogen, -OR', -OC(O)R', -NR'R'', -SR', -R', -CN, -NO2, -CO2R', -CONR'R'', -C(O)R', -NR''C(O)R', -S(O2)R', -S(O2)R', -S(O2)NR'R'', perfluoro(C1-C4)alkoxy and perfluoro(C1-C4)alkyl, wherein R' and R'' are independently selected from the group consisting of hydrogen, (C1-C8)alkyl, heteroalkyl, unsubstituted aryl, (unsubstituted aryl)-(C1-C4)alkyl and (unsubstituted aryl)oxy-(C1-C4)alkyl. 3. The compound of claim 1 represented by a formula selected from the group consisting of 4. The compound of claim 1 represented by a formula selected from the group consisting of 5. The compound of claim 4, wherein X is -S; Y is -N(R<12>)-S(O)2-, wherein R<12> is a substituent selected from the group consisting of hydrogen and (C1-C8)alkyl; R<1> is a substituent selected from the group consisting of hydrogen, halogen, (C1-C8) alkyl, (C2-C8)heteroalkyl, (C1-C8)alkoxy, -C(O)R<14>, -CO2R<14>, -C(O)NR<15>R<16>, -S(O)p-R<14>, -S(O)q-NR<15>R<16>, -O-C(O)-NR<15>R<16>, -N(R<14>)-C(O)-, -O-C(O)-R<17>and -N(R<14>)-C(O)-OR<17>; wherein R<14> is a substituent selected from the group consisting of hydrogen, (C1-C8)alkyl, (C2-C8)heteroalkyl, aryl and aryl(C1-C4) alkyl; R<15> and R<16> are substituents independently selected from the group consisting of hydrogen, (C1-C8)alkyl, (C2-C8)heteroalkyl or taken together with the nitrogen to which each is attached form a 5-, 6- or 7-membered ring; R<17> is a substituent selected from the group consisting of hydrogen, (C1-C8)alkyl, (C2-C8)heteroalkyl; the subscript p is an integer of from 0 to 2; and the subscript q is an integer of 2; and R<2> is a substituted or unsubstituted phenyl having from 1 to 3 substituents, independently selected from the group consisting of halogen, -OR', -OC(O)R', -NR'R'', -SR', -R', -CN, -NO2, -CO2R', -CONR'R'', -C(O)R', -NR''C(O)R', -S(O2)R', -S(O2)R', -S(O)2NR'R'', perfluoro(C1-C4)alkoxy and perfluoro(C1-C4)alkyl, wherein R' and R'' are independently selected from the group consisting of hydrogen, (C1-C8)alkyl, heteroalkyl, unsubstituted aryl, (unsubstituted aryl)-(C1-C4)alkyl and (unsubstituted aryl)oxy-(C1-C4)alkyl; R<3> is a substituent selected from the group consisting of halogen, and (C1-C8)alkoxy. 6. The compound of claim 5, wherein X is -S; Y is -NH-SO2-; R<1> is a substituent selected from the group consisting of halogen, (C1-C8)alkyl, (C2-C8)heteroalkyl, (C1-C8)alkoxy, -C(O)R<14>, -CO2R<14>, -C(O)NR<15>R<16>, -S(O)p-R<14>, -S(O)q-NR<15>R<16>; R<2> is a phenyl group having from 0 to 3 substituents selected from the group consisting of halogen, -OCF3, -OH, -O(C1-C8)alkyl, C(O)-(C1-C8)alkyl, CN, -CF3, (C1-C8)alkyl and-NH2; and R<3> is a substituent selected from the group consisting of halogen, methoxy and trifluoromethoxy. 7. The compound of claim 6, wherein Ar<1> is a benzothiazolyl group having from 1 to 3 substituents selected from the group consisting of halogen, -OCF3, -OH, O(C1-C6) alkyl, -CF3, (C1-C8)alkyl and-NO2; R<1> is a substituent selected from the group consisting of halogen, (C1-C8)alkyl, (C2-C8) heteroalkyl and (C1-C8)alkoxy; R<2> is a phenyl group having from 0 to 3 substituents selected from the group consisting of halogen, OCF3, -OH, -O(C1-C8)alkyl, -C(O)-(C1-C8)alkyl, -CN, -CF3, (C1-C8)alkyl and-NH2; and R<3> is a substituent selected from the group consisting of halogen, methoxy and trifluoromethoxy. 8. The compound of claim 1 having the formula: 9. A compound having the formula: wherein Ar<1> is unsubstituted 3-quinolinyl or substituted -3-quinolinyl, having from 1 to 3 substituents, independently selected from the group consisting of halogen, -OR', -OC(O)R', -NR'R'', -SR', -R', -CN, -NO2, -CO2R', -CONR'R'', -C(O)R', -NR''C(O)R', -S(O2)R', -S(O)2NR'R'', perfluoro(C1-C4)alkoxy and perfluoro(C1-C4)alkyl, wherein R' and R'' are independently selected from the group consisting of hydrogen, (C1-C8)alkyl, heteroalkyl, unsubstituted aryl, (unsubstituted aryl)-(C1-C4)alkyl and (unsubstituted aryl)oxy-(C1-C4)alkyl; X is a divalent linkage selected from the group consisting of (C1-C6)alkylene, (C1-C6)alkylenoxy, (C1-C6)alkylenamin, (C1-C6)alkylene-S(O)k-O-, -C(O)-, N(R<11>)-, N(R<11>)C(O)-, -S(O)k-and a simple bond, wherein R<11> is a substituent selected from the group consisting of hydrogen, (C1-C8)alkyl, (C2-C8)heteroalkyl and aryl(C1-C4) alkyl; the subscript k is an integer of from 0 to 2; Y is a divalent linkage selected from the group consisting of (C1-C6)alkylene, -O-, -C(O)-, -N(R<12>)-S(O)m-, -N(R<12>)-S(O)m-N(R<13>)-, N(R<12>)C(O)-, -S(O)n-, wherein R<12> and R<13> are substituents independently selected from the group consisting of hydrogen, (C1-C8)alkyl, (C2-C8) heteroalkyl and aryl(C1-C4) alkyl; and the subscripts m and n are independently integers of from 0 to 2; R<1> is a substituent selected from the group consisting of hydrogen, (C2-C8) heteroalkyl, aryl, aryl (C1-C4) alkyl, halogen, cyano, nitro, (C1-C8) alkyl, (C1-C8)alkoxy, -C(O)R<14>, -CO2R<14>, -C(O)NR<15>R<16>, -S(O)p-R<14>, -S(O)q-NR<15>R<16>, -O-C(O)-NR<15>R<16>, -N(R<14>)-C(O)-, -O-C(O)-R<17>, and-N(R<14>)-C(O)-OR<17>, NR<15>R<16>, -N(R<14>)-C(O)-R<17>; wherein R<14> is a substituent selected from the group consisting of hydrogen, C1-C8)alkyl,(C2-C8)heteroalkyl, aryl and aryl(C1-C4) alkyl; R<15> and R<16> are substituents independently selected from the group consisting of hydrogen, (C1-C8)alkyl, (C2-C8)heteroalkyl, aryl, and aryl(C1-C4) alkyl, or taken together with the nitrogen to which each is attached form a 5-, 6- or 7-membered ring; R<17> is a substituent selected from the group consisting of (C1-C8)alkyl, (C2-C8)heteroalkyl, aryl and aryl(C1-C4) alkyl; the subscript p is an integer of from 0 to 3; and the subscript q is an integer of from 1 to 2; and R<2> is a substituted or unsubstituted aryl having from 1 to 3 substituents, independently selected from the group consisting of halogen, -OR', -OC(O)R', -NR'R'', -SR', -R', -CN, -NO2, -CO2R', -CONR'R'', -C(O)R', -NR''C(O)R', -S(O2)R', -S(O)2NR'R'', perfluoro(C1-C4)alkoxy and perfluoro(C1-C4)alkyl, wherein R' and R'' are independently selected from the group consisting of hydrogen, (C1-C8)alkyl, heteroalkyl, unsubstituted aryl, (unsubstituted aryl)-(C1-C4)alkyl and (unsubstituted aryl)oxy-(C1-C4)alkyl; R<3> is a substituent selected from the group consisting of halogen, cyano, nitro and (C1-C8)alkoxy; or a pharmaceutically acceptable salt thereof. 10. The compound of claim 9, wherein R<2> is a substituted or unsubstituted aryl selected from the group consisting of phenyl, pyridyl, naphthyl and pyridazinyl and having from 1 to 3 substituents, independently selected from the group consisting of halogen, -OR', -OC(O)R', -NR'R'', -SR', -R', -CN, -NO2, -CO2R', -CONR'R'', -C(O)R', -NR''C(O)R', -S(O2)R', -S(O2)R', -S(O)2NR'R'', perfluoro(C1-C4)alkoxy and perfluoro(C1-C4)alkyl, wherein R' and R'' are independently selected from the group consisting of hydrogen, (C1-C8)alkyl, heteroalkyl, unsubstituted aryl, (unsubstituted aryl)-(C1-C4)alkyl and (unsubstituted aryl)oxy-(C1-C4)alkyl. 11. The compound of claim 9 represented by a formula