Tetrahydroisoquinoline compounds as nrf2 activators

A compound according to Formula IC or Formula IF, or a pharmaceutically acceptable salt thereof:

• wherein:
• R1 is selected from C1-4alkylene-R11, heterocyclyl and 8-10 membered bicyclic heteroaryl, wherein said heterocyclyl is optionally substituted with one or more substituents independently selected from C1-4alkyl, —C(O)—R12, SO2—R13, C1-3alkylene-OR14 and heteroaryl which is optionally substituted with one or more substituents independently selected from C1-4alkyl, C3-7cycloalkyl, halo, OH, C1-3alkoxy and cyano;
• and wherein said 8-10 membered bicyclic heteroaryl is optionally substituted with one or more substituents independently selected from C1-4alkyl, C3-7cycloalkyl, halo, OH and C1-3alkoxy;
• R2 is selected from hydrogen, fluoro, chloro and C1-3alkyl;
• R3 is selected from hydrogen, fluoro, chloro, bromo, C1-3alkoxy, C1-3alkyl, C1-3haloalkyl and cyano;
• R4 is hydrogen or C1-4alkyl;
• R5 is —C(O)—C1-4alkyl, —C(O)—C3-7cycloalkyl, —C(O)-heteroaryl or —C(O)-aryl, wherein said heteroaryl and aryl are optionally substituted with one or more substituents selected from C1-4alkyl, halo, hydroxy, C1-3alkoxy, CO2R15 and cyano;
• or
• R4 and R5, taken together with the nitrogen atom to which they are attached, form a 4-, 5-, or 6-membered heterocyclyl ring, wherein said heterocyclyl ring:
• comprises one or more —C(O)— moieties attached to the nitrogen atom;
• optionally contains one or more additional heteroatoms selected from oxygen, nitrogen and sulfur;
• optionally is fused to an aryl or heteroaryl ring;
• optionally is spiro-attached to a C3-7cycloalkyl group or a 3- to 6-membered heterocyclyl ring;
• and
• optionally is substituted with one or more substituents independently selected from C1-4alkyl, halo, OH, C1-3alkoxy, C1-3haloalkyl, cyano, NR16R17, C(O)R18, S(O)R19 and SO2R20;
• R6 is selected from hydrogen, C1-4alkyl, and C3-7cycloalkyl;
• R8 is C(═O)NR8aR8b or —C(═O)R8c;
• R8a is hydrogen or C1-6alkyl;
• R8b is hydrogen, C1-6alkyl or C3-7cycloalkyl, wherein the C1-6alkyl or C3-7cycloalkyl groups are optionally substituted with one or more substituents independently selected from C1-4alkyl, C3-7cycloalkyl, halo, OH, C1-3alkoxy, C1-3haloalkyl, cyano, NR16R17, C(O)R18, S(O)R19 and SO2R20;
• or
• R8a and R8b, taken together with the nitrogen atom to which they are attached, form a 3-, 4-, 5-, 6-, or 7-membered heterocyclyl ring, wherein the heterocyclyl ring:
• optionally contains one or more additional heteroatoms selected from oxygen, nitrogen and sulfur;
• and
• is optionally substituted with one or more substituents independently selected from C1-4alkyl, C3-7cycloalkyl, halo, OH, C1-3alkoxy, C1-3haloalkyl, cyano, NR16R17, C(O)R18, S(O)R19 and SO2R20;
• R8c is C1-3alkyl or C1-3haloalkyl;
• R9 is methyl;
• R11 is selected from —C(O)—R24, —SO2—R25, —NR26C(O)—R27, —NR28SO2—R29, heterocyclyl, aryl and heteroaryl, wherein said aryl and heteroaryl groups are optionally substituted with one or more substituents independently selected from C1-4alkyl, C1-3haloalkyl, C3-7cycloalkyl, C1-4alkylene-R30, halo, OH, C1-3alkoxy, heterocyclyl and cyano;
• and
• said heterocyclyl group is optionally substituted with one or more substituents independently selected from C1-4alkyl, C1-3haloalkyl, C3-7cycloalkyl, C1-4alkylene-R30, halo, OH, C1-3alkoxy, oxo and cyano;
• R12 is selected from C1-4alkyl, C3-7cycloalkyl, OR31, NR32R33, aryl and heteroaryl, wherein said aryl and heteroaryl are optionally substituted with one or more substituents independently selected from C1-4alkyl, halo, OH, C1-3alkoxy and cyano;
• R13 is selected from C1-4alkyl, C3-7cycloalkyl, heteroaryl, heterocyclyl and NR34R35, wherein said heteroaryl and heterocyclyl are optionally substituted with one or more substituents independently selected from C1-4alkyl, halo, OH, C1-3alkoxy and cyano;
• R17 is selected from hydrogen, C1-4alkyl, C(O)C1-3alkyl and C(O)NR36R37;
• R18, R19 and R20 are independently selected from C1-4alkyl, OH, C1-3alkoxy and NR38R39;
• R24 is selected from C1-4alkyl, NR40R41 and OR42;
• R25 is selected from C1-4alkyl and NR43R44;
• R27 is selected from C1-4alkyl, C3-7cycloalkyl, C1-3haloalkyl, heterocyclyl, aryl and heteroaryl, wherein said aryl and heteroaryl are optionally substituted with one or more substituents independently selected from C1-4alkyl, C1-3haloalkyl, C3-7cycloalkyl, C1-4alkylene-R45, halo, OH, C1-3alkoxy and cyano;
• R29 is selected from C1-4alkyl, C3-7cycloalkyl, C1-3haloalkyl, aryl and heteroaryl, wherein said aryl and heteroaryl are optionally substituted with one or more substituents independently selected from C1-4alkyl, C1-3haloalkyl, C3-7cycloalkyl, C1-4alkylene-R46, halo, OH, C1-3alkoxy and cyano;
• R30 is selected from hydroxy, C1-3alkoxy, C3-7cycloalkyl, cyano and NR47R48;
• R40 is selected from hydrogen and C1-4alkyl;
• R41 is selected from hydrogen, C1-4alkyl, C3-7cycloalkyl, C1-3alkoxy, aryl and heteroaryl;
• or
• R40 and R41, taken together with the nitrogen atom to which they are attached, form a 4-, 5-, or 6-membered heteroaryl or heterocyclyl ring, wherein said heteroaryl and heterocyclyl rings are optionally substituted with one or more substituents independently selected from C1-4alkyl, halo, OH, C1-3alkoxy, C3-7cycloalkyl and cyano;
• R45 and R46 are independently selected from hydroxy, C1-3alkoxy and C3-7cycloalkyl;
• and
• R14, R15, R16, R26, R28, R31, R32, R33, R34, R35, R36, R37, R38, R39, R42, R43, R44, R47 and R48 are independently selected from hydrogen, C1-4alkyl and C3-7cycloalkyl;
• provided that the compound is not (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxamide.