Amide derivatives as therapeutic agents

A compound of formula (I)

• 158
• wherein
• G is —S(O2)—, or —C(O)—;
• A is >N—, and
• X is a direct bond, —O—, —S—, —S(O)—, —S(O2)—, or —N(R6)—, wherein
• R6 is hydrogen or alkyl, which may optionally be substituted with one or more substituents R16, R17, and R18, and
• L1 is —(CH2)n—C(R9)(R10)m—Y—, or a direct bond, wherein
• n is an integer of from 1 to 6,
• R9 and R10 independently of each other are selected from alkyl, or cycloalkyl, optionally substituted by one or more substituents R19, R20, and R21;
• or from aryl optionally substituted by one or more substituents R40, R41, R42, and R43,
• m is an integer of 0 to 1, and
• Y is a direct bond, —O— or —N(R7)—, wherein
• R7 is hydrogen or alkyl, which may optionally be substituted with one or more substituents R22, R23, and R24;
• or
• X is alkylene, which may optionally be substituted with one or more substituents R25, R26, and R27, or a direct bond, and
• L1 is —O—, or —N(R8)—, wherein
• R8 is hydrogen or alkyl, which may optionally be substituted with one or more substituents R28, R29, and R30;
• or
• A is >C(R2)—, wherein R2 is hydrogen or alkyl, optionally substituted with one or more substituents R31, R32, and R33, and
• X is —O—, —S—, —S(O)—, —S(O2)—, or —N(R6)—, wherein
• R6 is as defined above, and
• L1 is —(CH2)n—Y—, or a direct bond, wherein
• n is an integer of from 1 to 6, and
• Y is a direct bond, O, or —N(R7)—, wherein
• R7 is as defined above;
• or
• X is alkylene, which may optionally be substituted with one or more substituents R25, R26, and R27, or a direct bond, and
• L1 is —O—, or —N(R8)—, wherein
• R8 is as defined above;
• R1 and R3 independently of each other are selected from alkyl, alkenyl, alkynyl, cycloalkyl, and heterocyclyl, optionally substituted with one or more substituents R34, R35, and R36;
• or from aryl, heteroaryl, fused heterocyclylaryl, fused heteroarylheterocyclyl, fused heterocyclylheteroaryl, fused arylcycloalkyl, fused cycloalkylaryl, fused heteroarylcycloalkyl, and fused cycloalkylheteroaryl, optionally substituted with one or more substituents R44, R45, R46, and R47;
• or
• R1 and R3 may be taken together with the atoms to which they are attached to form a cycloalkyl or heterocyclyl ring, optionally substituted with one or more substituents R34, R35, and R36, and optionally fused to a heteroaryl or aryl ring, optionally substituted with one or more substituents R44, R45, R46, and R47;
• or, when A is >C(R2)—, then
• R1 and R2 may be taken together with the atoms to which they are attached to form a cycloalkyl or heterocyclyl ring, optionally substituted with one or more substituents R34, R35, and R36, and optionally fused to a heteroaryl or aryl ring, optionally substituted with one or more substituents R44, R45, R46, and R47;
• or
• R2 and R3 may be taken together with the atoms to which they are attached to form a cycloalkyl or heterocyclyl ring, optionally substituted with one or more substituents R34, R35, and R36, and optionally fused to a heteroaryl or aryl ring, optionally substituted with one or more substituents R44, R45, R46, and R47;
• R4 is hydrogen or alkyl, optionally substituted with one or more substituents R37, R38, and R39;
• and
• R5 is aryl or heteroaryl, optionally substituted with one or more substituents R48, R49, R50, and R51;
• wherein
• R16, R17, R18, R19, R20, R21, R22, R23, R24, R25, R26, R27 R28, R29, R30;
• R31, R32, R33, R34, R35, R36, R37, R38, and R39 independently of each other are selected from
• —CHF2, —CF3, —OCF3, —OCHF2, —OCH2CF3, —OCF2CHF2, —S(O)2CF3, —SCF3, —OR52, —NR52R53, —SR52, —NR52S(O)2R53, —S(O)2NR52R53, —S(O)NR52R53, —S(O)R52, —S(O)2R52, —C(O)NR52R53, —OC(O)NR52R53, —NR52C(O)R53, —CH2C(O)NR52R53, —OCH2C(O)NR52R53, —CH2OR52, —CH2NR52R53, —OC(O)R52, —C(O)R52 and —C(O)OR52;
• C2-6-alkenyl and C2-6-alkynyl, which may optionally be substituted with one or more substituents selected from —CN, —CF3, —OCF3, —OR52, —NR52R53 and C1-6-alkyl;
• C3-8-cycloalkyl, C4-8-cycloalkenyl, heterocyclyl, C3-8-cycloalkyl-C1-6-alkyl, C3-8-cycloalkyl-C1-6-alkoxy, C3-8-cycloalkyloxy, C3-8-cycloalkyl-C1-6-alkylthio, C3-8-cycloalkylthio, C3-8-cycloalkyl-C2-6-alkenyl, C3-8-cycloalkyl-C2-6-alkynyl, C4-8-cycloalkenyl-C1-6-alkyl, C4-8-cycloalkenyl-C2-6-alkenyl, C4-8-cycloalkenyl-C2-6-alkynyl, heterocyclyl-C1-6-alkyl, heterocyclyl-C2-6-alkenyl, heterocyclyl-C2-6-alkynyl, aryl, aryloxy, aryloxycarbonyl, aroyl, aryl-C1-6alkoxy, aryl-C1-6-alkyl, aryl-C2-6-alkenyl, aryl-C2-6-alkynyl, heteroaryl, heteroaryl-C1-6-alkyl, heteroaryl-C2-6-alkenyl and heteroaryl-C2-6-alkynyl, of which the aryl and heteroaryl moieties optionally may be substituted with one or more substituents selected from halogen, —C(O)OR52, —CN, —CF3, —OCF3, —NO2, —OR52, —NR52R53 and C1-6-alkyl;
• and
• R40, R41, R42, R43, R44, R45, R46, and R47 independently of each other are selected from
• halogen, —CN, —CH2CN, —CHF2, —CF3, —OCF3, —OCHF2, —OCH2CF3, —OCF2CHF2, —S(O)2CF3, —SCF3, —NO2, —OR52, —NR52R53, —SR52, —NR52S(O)2R53, —S(O)2NR52R53, —S(O)NR52R53, —S(O)R52, —S(O)2R52, —C(O)NR52R53, —OC(O)NR52R53, —NR52C(O)R53, —CH2C(O)NR52R53, —OCH2C(O)NR52R53, —CH2OR52, —CH2NR52R53, —OC(O)R52, —C(O)R52, and —C(O)OR52;
• C1-6-alkyl, C2-6-alkenyl and C2-6-alkynyl, which may optionally be substituted with one or more substituents selected from —CN, —CF3, —OCF3, —OR52, —NR52R53, and C1-6-alkyl;
• C3-8-cycloalkyl, C4-8-cycloalkenyl, heterocyclyl, C3-8-cycloalkyl-C1-6-alkyl, C3-8-cycloalkyl-C1-6-alkoxy, C3-8-cycloalkyloxy, C3-8-cycloalkyl-C1-6-alkylthio, C3-8-cycloalkylthio, C3-8-cycloalkyl-C2-6-alkenyl, C3-8-cycloalkyl-C2-6-alkynyl, C4-8-cycloalkenyl-C1-6-alkyl, C4-8-cycloalkenyl-C2-6-alkenyl, C4-8-cycloalkenyl-C2-6-alkynyl, heterocyclyl-C1-6-alkyl, heterocyclyl-C2-6-alkenyl, heterocyclyl-C2-8-alkynyl, aryl, aryloxy, aryloxycarbonyl, aroyl, aryl-C1-6-alkoxy, aryl-C1-6-alkyl, aryl-C2-6-alkenyl, aryl-C2-6-alkynyl, heteroaryl, heteroaryl-C1-6-alkyl, heteroaryl-C2-6-alkenyl and heteroaryl-C2-6-alkynyl, of which the aryl and heteroaryl optionally may be substituted with one or more substituents selected from halogen, —C(O)OR52, —CN, —CF3, —OCF3, —NO2, —OR52, —NR52R53, and C1-6-alkyl;
• and
• two of R40, R41, R42, and R43, or two of R44, R45, R46, and R47 on adjacent carbon atoms may independently be taken together to form —O—CH2—O—;
• wherein
• R52 and R53 independently of each other are hydrogen, C1-6-alkyl, aryl-C1-6-alkyl or aryl;
• or
• R52 and R53, when attached to the same nitrogen atom, together with the said nitrogen atom may form a 3 to 8 membered heterocyclic ring optionally containing one or two further heteroatoms selected from nitrogen, oxygen and sulfur, and optionally containing one or two double bonds;
• and
• R48, R49, R50, and R51 independently of each other are selected from
• halogen, perfluoroalkyl, cyano, alkyl-Z-, aryl-Z-, aryl-alkylene-Z-, N(R63)(R64)-alkylene-Z-;
• and R65-W-alkylene-Z-;
• wherein
• Z and W independently of each other are selected from a direct bond, alkylene, —O—, —N(R66)—, —S—, —SO2—, —C(O)N(R66)—, —N(R66)C(O)—, —N(R66)C(O)N(R67)—, —N(R66)SO2—, —SO2N(R66)—, —C(O)C—, —OC(O)—, and —N(R66)SO2N(R67)—;
• wherein
• R66 and R67 independently of each other are hydrogen or alkyl;
• R63, R64, and R65 are selected from the group consisting of hydrogen, aryl, alkyl, and aryl-alkylene-;
• or
• R63 and R64 may be taken together to form a ring having the formula —(CH2)j-E-(CH2)k— bonded to the nitrogen atom to which R63 and R64 are attached, wherein
• j is an integer of from 1 to 4;
• k is an integer of from 1 to 4;
• and
• E is a direct bond, —CH2—, —O—, —S—, —S(O2)—, —C(O)—, —C(O)N(H)—, —NHC(O)—, —NHC(O)N(H)—, —NHSO2—, —SO2NH—, —C(O)O—, —OC(O)—, —NHSO2NH—,
• 159
• wherein
• R68 and R69 are selected from the group consisting of hydrogen, aryl, alkyl, and aryl-alkylene-;
• or a pharmaceutically acceptable salt, solvate or prodrug thereof.