Substituted Bicyclic Compounds, Compositions and Methods of Use

A compound of Formula (I) or a pharmaceutically acceptable salt thereof:

• wherein
• A is —C(O)OR2 or —S(O)2OR2;
• R2 is H or (C1-C6)alkyl;
• B is (C1-C4)alkylene;
• D is NH, CH2, or is absent;
• E is carbonyl, sulfonyl, NH, CH2 or is absent;
• Y is
• wherein
• when Y is
• X1 is a bicyclic ring comprising a 5-6 membered aryl ring, optionally having 0 to 3 heteroatoms selected independently from nitrogen, oxygen and sulfur, fused to a (C5-C7)cycloalkyl ring optionally containing 0 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur;
• X1 is optionally mono-, di- or tri-substituted independently with (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkoxy(C1-C6)alkyl, difluoromethyl, trifluoromethyl, trifluoroethyl, trifluoromethylthio, difluoromethoxy or trifluoromethoxy;
• R5 is (C5-C6)alkyl, phenyl, hetero(C5-C6)aryl, (C3-C7)cycloalkyl, (C3-C7)cycloalkenyl or hetero(C3-C7)cycloalkyl;
• said hetero(C5-C6)aryl and hetero(C3-C7)cycloalkyl each independently having 1 to 3 heteroatoms selected independently from nitrogen, oxygen and sulfur;
• wherein said R5 is optionally mono-, di- or tri-substituted independently with cyano, cyanomethyl, halo, nitro, amino, thio, mono-N— or di-N,N—(C1-C6)alkylamino, mono-N— or di-N,N—(C1-C6)alkylamino(C1-C6)alkyl, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkoxy(C1-C6)alkyl, difluoromethyl, trifluoromethyl, trifluoroethyl, trifluoromethylthio, fluoromethoxy, difluoromethoxy, trifluoromethoxy, pentafluoroethanyl, pentafluoropropanyl, mono-N— or di-N,N—(C1-C6)alkylaminocarbonyl, mono-N— or di-N,N—(C1-C6)alkylaminocarbonyloxy, (C1-C6)alkylcarbonyloxy, (C1-C6)alkylcarbonyl or (C1-C6)alkoxycarbonyl;
• or R5 forms a 5-7 membered heteroaryl or heteroalkyl ring with nitrogen, optionally said heteroaryl or heteroalkyl ring each independently having one or two additional heteroatoms selected independently from nitrogen, sulfur and oxygen having the Formula X, wherein said 5-7 membered ring formed with nitrogen is optionally substituted with (C1-C4)alkyl, or is mono- or di-substituted independently with T1;
• wherein T1 is phenoxy, hetero(C5-C6)aryloxy, (C3-C7)cycloalkoxy, (C3-C7)cycloalkenyloxy, hetero(C3-C7)cycloalkyloxy, phenylthio, hetero(C5-C6)arylthio, (C3-C7)cycloalkylthio, (C3-C7)cycloalkenylthio, hetero(C3-C7)cycloalkylthio, phenyl, hetero(C5-C6)aryl, (C3-C7)cycloalkyl, (C3-C7)cycloalkenyl or hetero(C3-C7)cycloalkyl;
• wherein said hetero(C5-C6)aryloxy, hetero(C3-C7)cycloalkyloxy, hetero(C5-C6)arylthio, hetero(C3-C7)cycloalkylthio, hetero(C5-C6)aryl or hetero(C3-C7)cycloalkyl each independently have 1 to 3 heteroatoms selected independently from oxygen, nitrogen and sulfur;
• wherein said T1 is optionally mono- di- or tri-substituted independently with cyano, cyanomethyl, halo, nitro, amino, thio, mono-N— or di-N,N—(C1-C6)alkylamino, mono-N— or di-N,N—(C1-C6)alkylamino(C1-C6)alkyl, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkoxy(C1-C6)alkyl, difluoromethyl, trifluoromethyl, trifluoroethyl, trifluoromethylthio, fluoromethoxy, difluoromethoxy, trifluoromethoxy, pentafluoroethanyl, or pentafluoropropanyl;
• and
• Z is Z1;
• and Z1 is phenyl, hetero(C5-C6)aryl, (C3-C7)cycloalkyl, (C3-C7)cycloalkenyl or hetero(C3-C7)cycloalkyl;
• wherein said hetero(C5-C6)aryl or hetero(C3-C7)cycloalkyl each independently have 1 to 3 heteroatoms selected independently from oxygen, nitrogen and sulfur;
• wherein said Zi is mono-, di- or tri-substituted independently with cyano, cyanomethyl, halo, nitro, amino, thio, mono-N— or di-N,N—(C1-C6)alkylamino, mono-N— or di-N,N—(C1-C6)alkylamino(C1-C6)alkyl, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkoxy(C1-C6)alkyl, (C3-C6)cycloalkyl, difluoromethyl, trifluoromethyl, trifluoroethyl, trifluoromethylthio, fluoromethoxy, difluoromethoxy, trifluoromethoxy, pentafluoroethanyl, or pentafluoropropanyl;
• or wherein said Z1 is mono- or di-substituted independently with Q1;
• wherein Q1 is phenoxy, hetero(C5-C6)aryloxy, (C3-C7)cycloalkyloxy, (C3-C7)cycloalkenyloxy, hetero(C3-C7)cycloalkyloxy, phenylthio, hetero(C5-C6)arylthio, (C3-C7)cycloalkylthio, (C3-C7)cycloalkenylthio, hetero(C3-C7)cycloalkylthio, phenyl, hetero(C5-C6)aryl, (C3-C7)cycloalkyl, (C3-C7)cycloalkenyl or hetero(C3-C7)cycloalkyl;
• wherein hetero(C5-C6)aryloxy, hetero(C3-C7)cycloalkyloxy, hetero(C5-C6)arylthio, hetero(C3-C7)cycloalkylthio, hetero(C5-C6)aryl or hetero(C3-C7)cycloalkyl each independently have 1 to 3 heteroatoms selected independently from oxygen, nitrogen and sulfur;
• wherein said Q1 is optionally mono- di- or tri-substituted independently with cyano, cyanomethyl, halo, nitro, amino, thio, mono-N— or di-N,N—(C1-C6)alkylamino, mono-N— or di-N,N—(C1-C6)alkylamino(C1-C6)alkyl, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkoxy(C1-C6)alkyl, difluoromethyl, trifluoromethyl, trifluoroethyl, trifluoromethylthio, fluoromethoxy, difluoromethoxy, trifluoromethoxy, pentafluoroethanyl, or pentafluoropropanyl;
• or Z is Z1 and Z1 forms a 5-7 membered heteroaryl or heteroalkyl ring with R5, optionally said heteroaryl or heteroalkyl each independently having one or two additional heteroatoms selected independently from nitrogen, sulfur and oxygen having the Formula XI:
• or
• when Y is
• X2 is a bicyclic ring comprising a 5-6 membered aryl ring optionally having 0 to 3 heteroatoms selected independently from nitrogen, oxygen and sulfur fused to a (C5-C7)cycloalkyl ring optionally containing 0 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur;
• X2 is optionally mono-, di- or tri-substituted with (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkoxy(C1-C6)alkyl, difluoromethyl, trifluoromethyl, trifluoroethyl, trifluoromethylthio, difluoromethoxy or trifluoromethoxy;
• R4 is (C5-C6)alkyl, phenyl, hetero(C5-C6)aryl, (C3-C7)cycloalkyl, (C3-C7)cycloalkenyl or hetero(C3-C7)cycloalkyl;
• said hetero(C5-C6)aryl and hetero(C3-C7)cycloalkyl each independently having 1 to 3 heteroatoms selected independently from nitrogen, oxygen and sulfur;
• wherein said R4 is optionally mono-, di- or tri-substituted independently with cyano, cyanomethyl, halo, nitro, amino, thio, mono-N— or di-N,N—(C1-C6)alkylamino, mono-N— or di-N,N—(C1-C6)alkylamino(C1-C6)alkyl, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkoxy(C1-C6)alkyl, difluoromethyl, trifluoromethyl, trifluoroethyl, trifluoromethylthio, fluoromethoxy, difluoromethoxy, trifluoromethoxy, pentafluoroethanyl, pentafluoropropanyl, mono-N— or di-N,N—(C1-C6)alkylaminocarbonyl, mono-N— or di-N,N—(C1-C6)alkylaminocarbonyloxy, (C1-C6)alkylcarbonyloxy, (C1-C6)alkylcarbonyl or (C1-C6)alkoxycarbonyl;
• or R4 forms a 5-7 membered heteroaryl or heteroalkyl ring with nitrogen, said heteroaryl or heteroalkyl ring each optionally having one or two additional heteroatoms selected independently from nitrogen, sulfur and oxygen having the Formula X2;
• wherein said ring formed with nitrogen is optionally substituted with (C1-C4)alkyl;
• or wherein said R4 is mono- or di-substituted independently with T2;
• wherein T2 is phenoxy, hetero(C5-C6)aryloxy, (C3-C7)cycloalkyloxy, (C3-C7)cycloalkenyloxy, hetero(C3-C7)cycloalkyloxy, phenylthio, hetero(C5-C6)arylthio, (C3-C7)cycloalkylthio, (C3-C7)cycloalkenylthio, hetero(C3-C7)cycloalkylthio, phenyl, hetero(C5-C6)aryl, (C3-C7)cycloalkyl, (C3-C7)cycloalkenyl or hetero(C3-C7)cycloalkyl;
• wherein said hetero(C5-C6)aryloxy, hetero(C3-C7)cycloalkyloxy, hetero(C5-C6)arylthio, hetero(C3-C7)cycloalkylthio, hetero(C5-C6)aryl or hetero(C3-C7)cycloalkyl each independently have 1 to 3 heteroatoms selected independently from oxygen, nitrogen and sulfur;
• wherein said T2 is optionally mono- di- or tri-substituted independently with cyano, cyanomethyl, halo, nitro, amino, thio, mono-N— or di-N,N—(C1-C6)alkylamino, mono-N— or di-N,N—(C1-C6)alkylamino(C1-C6)alkyl, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkoxy(C1-C6)alkyl, difluoromethyl, trifluoromethyl, trifluoroethyl, trifluoromethylthio, fluoromethoxy, difluoromethoxy, trifluoromethoxy, pentafluoroethanyl, or pentafluoropropanyl;
• and
• Z is Z2;
• and Z2 is phenyl, hetero(C5-C6)aryl, (C3-C7)cycloalkyl, (C3-C7)cycloalkenyl or hetero(C3-C7)cycloalkyl;
• wherein said hetero(C5-C6)aryl or hetero(C3-C7)cycloalkyl each independently have 1 to 3 heteroatoms selected independently from oxygen, nitrogen and sulfur;
• wherein said Z2 is mono-, di- or tri-substituted independently with cyano, cyanomethyl, halo, nitro, amino, thio, mono-N— or di-N,N—(C1-C6)alkylamino, mono-N— or di-N,N—(C1-C6)alkylamino(C1-C6)alkyl, (C1-C6)alkoxy(C1-C6)alkyl, difluoromethyl, trifluoromethyl, trifluoroethyl, trifluoromethylthio, pentafluoroethanyl, or pentafluoropropanyl;
• or Z2 is mono- or di-substituted independently with Q2
• wherein Q2 is phenoxy, hetero(C5-C6)aryloxy, (C3-C7)cycloalkyloxy, (C3-C7)cycloalkenyloxy, hetero(C3-C7)cycloalkyloxy, phenylthio, hetero(C5-C6)arylthio, (C3-C7)cycloalkylthio, (C3-C7)cycloalkenylthio, hetero(C3-C7)cycloalkylthio, phenyl, hetero(C5-C6)aryl, (C3-C7)cycloalkyl, (C3-C7)cycloalkenyl or hetero(C3-C7)cycloalkyl;
• wherein hetero(C5-C6)aryloxy, hetero(C3-C7)cycloalkyloxy, hetero(C5-C6)arylthio, hetero(C3-C7)cycloalkylthio, hetero(C5-C6)aryl or hetero(C3-C7)cycloalkyl each independently have 1 to 3 heteroatoms selected independently from oxygen, nitrogen and sulfur;
• wherein said Q2 is optionally mono- di- or tri-substituted independently with cyano, cyanomethyl, halo, nitro, amino, thio, mono-N— or di-N,N—(C1-C6)alkylamino, mono-N— or di-N,N—(C1-C6)alkylamino(C1-C6)alkyl, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkoxy(C1-C6)alkyl, difluoromethyl, trifluoromethyl, trifluoroethyl, trifluoromethylthio, fluoromethoxy, difluoromethoxy, trifluoromethoxy, pentafluoroethanyl, or pentafluoropropanyl;
• or Z is Z2;
• and Z2 forms a 5-7 membered heteroaryl or heteroalkyl ring with R4, optionally said heteroaryl or heteroalkyl each independently having one or two additional heteroatoms selected independently from nitrogen, sulfur and oxygen having the formula X3
• or
• when Y is
• X3 is a bicyclic ring comprising a 5-6 membered aryl ring optionally having 0-3 heteroatoms selected independently from nitrogen, oxygen and sulfur fused to a (C5-C7)cycloalkyl ring optionally containing 0 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur;
• X3 is optionally mono-, di- or tri-substituted with (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkoxy(C1-C6)alkyl, difluoromethyl, trifluoromethyl, trifluoroethyl, trifluoromethylthio, difluoromethoxy or trifluoromethoxy;
• R3 is (C5-C6)alkyl, phenyl, hetero(C5-C6)aryl, (C3-C7)cycloalkyl, (C3-C7)cycloalkenyl or hetero(C3-C7)cycloalkyl;
• said hetero(C5-C6)aryl and hetero(C3-C7)cycloalkyl each independently having 1 to 3 heteroatoms selected independently from nitrogen, oxygen and sulfur;
• wherein said R3 is optionally mono-, di- or tri-substituted independently with cyano, cyanomethyl, halo, nitro, amino, thio, mono-N— or di-N,N—(C1-C6)alkylamino, mono-N— or di-N,N—(C1-C6)alkylamino(C1-C6)alkyl, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkoxy(C1-C6)alkyl, difluoromethyl, trifluoromethyl, trifluoroethyl, trifluoromethylthio, fluoromethoxy, difluoromethoxy, trifluoromethoxy, pentafluoroethanyl, pentafluoropropanyl, mono-N— or di-N,N—(C1-C6)alkylaminocarbonyl, mono-N— or di-N,N—(C1-C6)alkylaminocarbonyloxy, (C1-C6)alkylcarbonyloxy, (C1-C6)alkylcarbonyl or (C1-C6)alkoxycarbonyl;
• or R3 forms a 5-7 membered heteroaryl or heteroalkyl ring with nitrogens, said heteroaryl or heteroalkyl ring each optionally having one or two additional heteroatoms selected independently from nitrogen, sulfur and oxygen having the formula X4 wherein said ring formed with nitrogens is optionally substituted with (C1-C4)alkyl;
• or wherein said R3 is mono- or di-substituted independently with T3;
• wherein T3 is phenyloxy, hetero(C5-C6)aryloxy, (C3-C7)cycloalkyloxy, (C3-C7)cycloalkenyloxy, hetero(C3-C7)cycloalkyloxy, phenylthio, hetero(C5-C6)arylthio, (C3-C7)cycloalkylthio, (C3-C7)cycloalkenylthio, hetero(C3-C7)cycloalkylthio, phenyl, hetero(C5-C6)aryl, (C3-C7)cycloalkyl, (C3-C7)cycloalkenyl or hetero(C3-C7)cycloalkyl;
• wherein said hetero(C5-C6)aryloxy, hetero(C3-C7)cycloalkyloxy, hetero(C5-C6)arylthio, hetero(C3-C7)cycloalkylthio, hetero(C5-C6)aryl or hetero(C3-C7)cycloalkyl each independently have 1 to 3 heteroatoms selected independently from oxygen, nitrogen and sulfur;
• wherein said T3 is optionally mono- di- or tri-substituted independently with cyano, cyanomethyl, halo, nitro, amino, thio, mono-N— or di-N,N—(C1-C6)alkylamino, mono-N— or di-N,N—(C1-C6)alkylamino(C1-C6)alkyl, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkoxy(C1-C6)alkyl, difluoromethyl, trifluoromethyl, trifluoroethyl, trifluoromethylthio, fluoromethoxy, difluoromethoxy, trifluoromethoxy, pentafluoroethanyl, or pentafluoropropanyl;
• and
• Z is Z3;
• and Z3 is phenyl, hetero(C5-C6)aryl, (C3-C7)cycloalkyl, (C3-C7)cycloalkenyl or hetero(C3-C7)cycloalkyl;
• wherein said hetero(C5-C6)aryl or hetero(C3-C7)cycloalkyl each independently have 1 to 3 heteroatoms selected independently from oxygen, nitrogen and sulfur;
• wherein said Z3 is mono-, di- or tri-substituted independently with cyano, cyanomethyl, nitro, amino, thio, mono-N— or di-N,N—(C1-C6)alkylamino, mono-N— or di-N,N—(C1-C6)alkylamino(C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkoxy(C1-C6)alkyl, difluoromethyl, trifluoroethyl, trifluoromethylthio, pentafluoroethanyl, or pentafluoropropanyl;
• or Z3 is mono- or di-substituted independently with Q3;
• wherein Q3 is phenyloxy, hetero(C5-C6)aryloxy, (C3-C7)cycloalkyloxy, (C3-C7)cycloalkenyloxy, hetero(C3-C7)cycloalkyloxy, phenylthio, hetero(C5-C6)arylthio, (C3-C7)cycloalkylthio, (C3-C7)cycloalkenylthio, hetero(C3-C7)cycloalkylthio, phenyl, hetero(C5-C6)aryl, (C3-C7)cycloalkyl, (C3-C7)cycloalkenyl or hetero(C3-C7)cycloalkyl;
• wherein hetero(C5-C6)aryloxy, hetero(C3-C7)cycloalkyloxy, hetero(C5-C6)arylthio, hetero(C3-C7)cycloalkylthio, hetero(C5-C6)aryl or hetero(C3-C7)cycloalkyl each independently have 1 to 3 heteroatoms selected independently from oxygen, nitrogen and sulfur;
• wherein said Q3 is mono- di- or tri-substituted independently with cyano, cyanomethyl, halo, nitro, amino, thio, mono-N— or di-N,N—(C1-C6)alkylamino, mono-N— or di-N,N—(C1-C6)alkylamino(C1-C6)alkyl, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkoxy(C1-C6)alkyl, difluoromethyl, trifluoromethyl, trifluoroethyl, trifluoromethylthio, fluoromethoxy, difluoromethoxy, trifluoromethoxy, pentafluoroethanyl, or pentafluoropropanyl;
• or Z is Z3;
• and Z3 forms a 5-7 membered heteroaryl or heteroalkyl ring with R3, optionally said heteroaryl or heteroalkyl each independently having one or two additional heteroatoms selected independently from nitrogen, sulfur and oxygen having the formula X5
• with the proviso that the compound of Formula (I) is not N—({1-[(trans-4-tert-butylcyclohexyl)({[4-(trifluoromethoxy)phenyl]amino}carbonyl]amino)-2,3-dihydro-1H-inden-5-yl}carbonyl)-B-alanine.