Isoquinolin-3-YL carboxamides and preparation and use thereof

A method of treating a fibrotic disorder in a patient, wherein the fibrotic disorder is selected from:

• skin fibrosis, scleroderma, lung fibrosis, muscle fibrosis, kidney fibrosis, uterine fibrosis, renal fibrosis, liver fibrosis, and pulmonary fibrosis, the method comprising administering to the patient a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof:
• wherein:
• R1, R2, R4, and R5 are independently selected from the group consisting of H, halide, amino, unsubstituted —(C1-3 haloalkyl), and unsubstituted —(C1-3 alkyl);
• R3 is selected from the group consisting of:
• wherein each of R7-R35 is, independently, a substituent as defined anywhere herein or a single bond connecting R3 to the isoquinoline ring;
• wherein only one of R7-R10 (when present) is a bond, only one of R11-R14 (when present) is a bond, only one of R15-R17 (when present) is a bond, only one of R18-R20 (when present) is a bond, only one of R21-R23 (when present) is a bond, only one of R24-R26 (when present) is a bond, only one of R27-R29 (when present) is a bond, only one of R30-R31 (when present) is a bond, only one of R32-R33 (when present) is a bond, and only one of R34-R35 (when present) is a bond;
• wherein any one of the nitrogen atoms attached to R7, R11, R15, R18, or R21 can serve as the point of attachment of R3 to the isoquinoline ring;
• wherein any one of the carbon atoms attached to R8, R9, R10, R12, R13, R14, R16, R17, R19, R20, R23, R23, R24, R25, R26, R27, R28, R29, R30, R31, R32, R33, R34, or R35 can serve as the point of attachment of R3 to the isoquinoline ring;
• as that:
• when the nitrogen atom to which R7 is attached serves as the point of attachment of R3 to the isoquinoline ring, then R7 is a single bond connecting R3 to the isoquinoline ring;
• when the carbon atom to which R8 is attached serves as the point of attachment of R3 to the isoquinoline ring, then R8 is a single bond connecting R3 to the isoquinoline ring;
• when the carbon atom to which R9 is attached serves as the point of attachment of R3 to the isoquinoline ring, then R9 is a single bond connecting R3 to the isoquinoline ring;
• when the carbon atom to which R10 is attached serves as the point of attachment of R3 to the isoquinoline ring, then R10 is a single bond connecting R3 to the isoquinoline ring;
• when the nitrogen atom to which R11 is attached serves as the point of attachment of R3 to the isoquinoline ring, then R11 is a single bond connecting R3 to the isoquinoline ring;
• when the carbon atom to which R12 is attached serves as the point of attachment of R3 to the isoquinoline ring, then R12 is a single bond connecting R3 to the isoquinoline ring;
• when the carbon atom to which R13 is attached serves as the point of attachment of R3 to the isoquinoline ring, then R13 is a single bond connecting R3 to the isoquinoline ring;
• when the carbon atom to which R14 is attached serves as the point of attachment of R3 to the isoquinoline ring, then R14 is a single bond connecting R3 to the isoquinoline ring;
• when the nitrogen atom to which R15 is attached serves as the point of attachment of R3 to the isoquinoline ring, then R15 is a single bond connecting R3 to the isoquinoline ring;
• when the carbon atom to which R16 is attached serves as the point of attachment of R3 to the isoquinoline ring, then R16 is a single bond connecting R3 to the isoquinoline ring;
• when the carbon atom to which R17 is attached serves as the point of attachment of R3 to the isoquinoline ring, then R17 is a single bond connecting R3 to the isoquinoline ring;
• when the nitrogen atom to which R18 is attached serves as the point of attachment of R3 to the isoquinoline ring, then R18 is a single bond connecting R3 to the isoquinoline ring;
• when the carbon atom to which R19 is attached serves as the point of attachment of R3 to the isoquinoline ring, then R19 is a single bond connecting R3 to the isoquinoline ring;
• when the carbon atom to which R20 is attached serves as the point of attachment of R3 to the isoquinoline ring, then R20 is a single bond connecting R3 to the isoquinoline ring;
• when the nitrogen atom to which R21 is attached serves as the point of attachment of R3 to the isoquinoline ring, then R21 is a single bond connecting R3 to the isoquinoline ring;
• when the carbon atom to which R22 is attached serves as the point of attachment of R3 to the isoquinoline ring, then R22 is a single bond connecting R3 to the isoquinoline ring;
• when the carbon atom to which R23 is attached serves as the point of attachment of R3 to the isoquinoline ring, then R23 is a single bond connecting R3 to the isoquinoline ring;
• when the carbon atom to which R24 is attached serves as the point of attachment of R3 to the isoquinoline ring, then R24 is a single bond connecting R3 to the isoquinoline ring;
• when the carbon atom to which R25 is attached serves as the point of attachment of R3 to the isoquinoline ring, then R25 is a single bond connecting R3 to the isoquinoline ring;
• when the carbon atom to which R26 is attached serves as the point of attachment of R3 to the isoquinoline ring, then R26 is a single bond connecting R3 to the isoquinoline ring;
• when the carbon atom to which R27 is attached serves as the point of attachment of R3 to the isoquinoline ring, then R27 is a single bond connecting R3 to the isoquinoline ring;
• when the carbon atom to which R28 is attached serves as the point of attachment of R3 to the isoquinoline ring, then R28 is a single bond connecting R3 to the isoquinoline ring;
• when the carbon atom to which R29 is attached serves as the point of attachment of R3 to the isoquinoline ring, then R29 is a single bond connecting R3 to the isoquinoline ring;
• when the carbon atom to which R30 is attached serves as the point of attachment of R3 to the isoquinoline ring, then R30 is a single bond connecting R3 to the isoquinoline ring;
• when the carbon atom to which R31 is attached serves as the point of attachment of R3 to the isoquinoline ring, then R31 is a single bond connecting R3 to the isoquinoline ring;
• when the carbon atom to which R32 is attached serves as the point of attachment of R3 to the isoquinoline ring, then R32 is a single bond connecting R3 to the isoquinoline ring;
• when the carbon atom to which R33 is attached serves as the point of attachment of R3 to the isoquinoline ring, then R33 is a single bond connecting R3 to the isoquinoline ring;
• when the carbon atom to which R34 is attached serves as the point of attachment of R3 to the isoquinoline ring, then R34 is a single bond connecting R3 to the isoquinoline ring;
• when the carbon atom to which R35 is attached serves as the point of attachment of R3 to the isoquinoline ring, then R35 is a single bond connecting R3 to the isoquinoline ring;
• R6 is selected from the group consisting of -phenyl substituted with 1-5 R36, —(C1-3 alkylene)ppyridinyl optionally substituted with 1-6 R37, and a 6-10 membered heteroaryl optionally substituted with 1-6 R37;
• wherein the carbonyl of Formula I is attached to an aromatic ring of the heteroaryl;
• wherein —(C1-3 alkylene) is optionally substituted with one or more substituents as defined anywhere herein;
• R7 is selected from the group consisting of a single bond, unsubstituted —(C1-9 alkyl), unsubstituted —(C2-9 alkenyl), unsubstituted —(C2-9 alkynyl), unsubstituted —(C1-9 haloalkyl), —(C1-4 alkylene)N(R48)2, —(C1-4 alkylene)OR49, —C(═O)N(R48)2, —(C1-4 alkylene)pheterocyclyl optionally substituted with 1-10 R38, and -carbocyclyl optionally substituted with 1-12 R39;
• wherein —(C1-4 alkylene) is optionally substituted with one or more substituents as defined anywhere herein;
• R8, R9, and R10 are independently selected from the group consisting of a single bond, H, halide, unsubstituted —(C1-9 alkyl), unsubstituted —(C2-9 alkenyl), unsubstituted —(C2-9 alkynyl), unsubstituted —(C1-9 haloalkyl), —(C1-4 alkylene)pN(R48)2, —(C1-4 alkylene)pOR49, —C(═O)N(R48)2, —(C1-4 alkylene)pheterocyclyl optionally substituted with 1-10 R38, and -carbocyclyl optionally substituted with 1-12 R39;
• wherein each —(C1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein;
• alternatively, one of R7 and R8, R8 and R9, or R9 and R10 are taken together to form a ring which is selected from the group consisting of -heterocyclyl optionally substituted with 1-10 R40 and -carbocyclyl optionally substituted with 1-12 R41;
• R11 is selected from the group consisting of a single bond, H, unsubstituted —(C1-9 alkyl), unsubstituted —(C2-9 alkenyl), unsubstituted —(C2-9 alkynyl), unsubstituted —(C1-9 haloalkyl), —(C1-4 alkylene)N(R48)2, —(C1-4 alkylene)OR49, —C(═O)N(R48)2, —(C1-4 alkylene)pheterocyclyl optionally substituted with 1-10 R38, and -carbocyclyl optionally substituted with 1-12 R39;
• wherein —(C1-4 alkylene) is optionally substituted with one or more substituents as defined anywhere herein;
• R12, R13, and R14 are independently selected from the group consisting of a single bond, H, halide, unsubstituted —(C1-9 alkyl), unsubstituted —(C2-9 alkenyl), unsubstituted —(C2-9 alkynyl), unsubstituted —(C1-9 haloalkyl), —(C1-4 alkylene)pN(R48)2, —(C1-4 alkylene)pOR49, —C(═O)N(R48)2, —(C1-4 alkylene)pheterocyclyl optionally substituted with 1-10 R38, and -carbocyclyl optionally substituted with 1-12 R39;
• wherein each —(C1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein;
• alternatively, one of R11 and R12, R12 and R13, or R14 and R11 are taken together to form a ring which is selected from the group consisting of -heterocyclyl optionally substituted with 1-10 R40 and -carbocyclyl optionally substituted with 1-12 R41;
• R15 is selected from the group consisting of a single bond, H, unsubstituted —(C1-9 alkyl), unsubstituted —(C2-9 alkenyl), unsubstituted —(C2-9 alkynyl), unsubstituted —(C1-9 haloalkyl), —(C1-4 alkylene)N(R48)2, —(C1-4 alkylene)OR49, —C(═O)N(R48)2, —(C1-4 alkylene)pheterocyclyl optionally substituted with 1-10 R38, and -carbocyclyl optionally substituted with 1-12 R39;
• wherein —(C1-4 alkylene) is optionally substituted with one or more substituents as defined anywhere herein;
• R16 and R17 are independently selected from the group consisting of a single bond, H, halide, unsubstituted —(C1-9 alkyl), unsubstituted —(C2-9 alkenyl), unsubstituted —(C2-9 alkynyl), unsubstituted —(C1-9 haloalkyl), —(C1-4 alkylene)pN(R48)2, —(C1-4 alkylene)pOR49, —C(═O)N(R48)2, —(C1-4 alkylene)pheterocyclyl optionally substituted with 1-10 R38, and -carbocyclyl optionally substituted with 1-12 R39;
• wherein each —(C1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein;
• alternatively, one of R15 and R16 or R16 and R17 are taken together to form a ring which is selected from the group consisting of -heterocyclyl optionally substituted with 1-10 R40 and -carbocyclyl optionally substituted with 1-12 R41;
• R18 is selected from the group consisting of a single bond, H, unsubstituted —(C1-9 alkyl), unsubstituted —(C2-9 alkenyl), unsubstituted —(C2-9 alkynyl), unsubstituted —(C1-9 haloalkyl), —(C1-4 alkylene)N(R48)2, —(C1-4 alkylene)OR49, —C(═O)N(R48)2, —(C1-4 alkylene)pheterocyclyl optionally substituted with 1-10 R38, and -carbocyclyl optionally substituted with 1-12 R39;
• wherein —(C1-4 alkylene) is optionally substituted with one or more substituents as defined anywhere herein;
• R19 and R20 are independently selected from the group consisting of a single bond, H, halide, unsubstituted —(C1-9 alkyl), unsubstituted —(C2-9 alkenyl), unsubstituted —(C2-9 alkynyl), unsubstituted —(C1-9 haloalkyl), —(C1-4 alkylene)pN(R48)2, —(C1-4 alkylene)pOR49, —C(═O)N(R48)2, —(C1-4 alkylene)pheterocyclyl optionally substituted with 1-10 R38, and -carbocyclyl optionally substituted with 1-12 R39;
• wherein each —(C1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein;
• alternatively, one of R18 and R19 or R18 and R20 are taken together to form a heterocyclyl optionally substituted with 1-10 R40;
• R21 is selected from the group consisting of a single bond, H, unsubstituted —(C1-9 alkyl), unsubstituted —(C2-9 alkenyl), unsubstituted —(C2-9 alkynyl), unsubstituted —(C1-9 haloalkyl), —(C1-4 alkylene)N(R48)2, —(C1-4 alkylene)OR49, —C(═O)N(R48)2, —(C1-4 alkylene)pheterocyclyl optionally substituted with 1-10 R38, and -carbocyclyl optionally substituted with 1-12 R39;
• wherein —(C1-4 alkylene) is optionally substituted with one or more substituents as defined anywhere herein;
• R22 and R23 are independently selected from the group consisting of a single bond, H, halide, unsubstituted —(C1-9 alkyl), unsubstituted —(C2-9 alkenyl), unsubstituted —(C2-9 alkynyl), unsubstituted —(C1-9 haloalkyl), —(C1-4 alkylene)pN(R48)2, —(C1-4 alkylene)pOR49, —C(═O)N(R48)2, —(C1-4 alkylene)pheterocyclyl optionally substituted with 1-10 R38, and -carbocyclyl optionally substituted with 1-12 R39;
• wherein each —(C1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein;
• alternatively, R22 and R23 are taken together to form a ring which is selected from the group consisting of -heterocyclyl optionally substituted with 1-10 R40 and -carbocyclyl optionally substituted with 1-12 R41;
• R24, R25, and R26 are independently selected from the group consisting of a single bond, H, halide, unsubstituted —(C1-9 alkyl), unsubstituted —(C2-9 alkenyl), unsubstituted —(C2-9 alkynyl), unsubstituted —(C1-9 haloalkyl), —(C1-4 alkylene)pN(R48)2, —(C1-4 alkylene)pOR49, —C(═O)N(R48)2, —(C1-4 alkylene)pheterocyclyl optionally substituted with 1-10 R38, and -carbocyclyl optionally substituted with 1-12 R39;
• wherein each —(C1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein;
• alternatively, one of R24 and R25 or R25 and R26 are taken together to form a ring which is selected from the group consisting of -heterocyclyl optionally substituted with 1-10 R40 and -carbocyclyl optionally substituted with 1-12 R41;
• R27, R28, and R29 are independently selected from the group consisting of a single bond, H, halide, unsubstituted —(C1-9 alkyl), unsubstituted —(C2-9 alkenyl), unsubstituted —(C2-9 alkynyl), unsubstituted —(C1-9 haloalkyl), —(C1-4 alkylene)pN(R48)2, —(C1-4 alkylene)pOR49, —C(═O)N(R48)2, —(C1-4 alkylene)pheterocyclyl optionally substituted with 1-10 R38, and -carbocyclyl optionally substituted with 1-12 R39;
• wherein each —(C1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein;
• alternatively, R27 and R28 are taken together to form a ring which is selected from the group consisting of -heterocyclyl optionally substituted with 1-10 R40 and -carbocyclyl optionally substituted with 1-12 R41;
• R30 and R31 are independently selected from the group consisting of a single bond, H, halide, unsubstituted —(C1-9 alkyl), unsubstituted —(C2-9 alkenyl), unsubstituted —(C2-9 alkynyl), unsubstituted —(C1-9 haloalkyl), —(C1-4 alkylene)pN(R48)2, —(C1-4 alkylene)pOR49, —C(═O)N(R48)2, —(C1-4 alkylene)pheterocyclyl optionally substituted with 1-10 R38, and -carbocyclyl optionally substituted with 1-12 R39;
• wherein each —(C1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein;
• alternatively, R30 and R31 are taken together to form a ring which is selected from the group consisting of -heterocyclyl optionally substituted with 1-10 R40 and -carbocyclyl optionally substituted with 1-12 R41;
• R32 and R33 are independently selected from the group consisting of a single bond, H, halide, unsubstituted —(C1-9 alkyl), unsubstituted —(C2-9 alkenyl), unsubstituted —(C2-9 alkynyl), unsubstituted —(C1-9 haloalkyl), —(C1-4 alkylene)pN(R48)2, —(C1-4 alkylene)pOR49, —C(═O)N(R48)2, —(C1-4 alkylene)pheterocyclyl optionally substituted with 1-10 R38, and -carbocyclyl optionally substituted with 1-12 R39;
• wherein each —(C1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein;
• R34 and R35 are independently selected from the group consisting of a single bond, H, halide, unsubstituted —(C1-9 alkyl), unsubstituted —(C2-9 alkenyl), unsubstituted —(C2-9 alkynyl), unsubstituted —(C1-9 haloalkyl), —(C1-4 alkylene)pN(R48)2, —(C1-4 alkylene)pOR49, —C(═O)N(R48)2, —(C1-4 alkylene)pheterocyclyl optionally substituted with 1-10 R38, and -carbocyclyl optionally substituted with 1-12 R39;
• wherein each —(C1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein;
• alternatively, R34 and R35 are taken together to form a ring which is selected from the group consisting of -heterocyclyl optionally substituted with 1-10 R40 and -carbocyclyl optionally substituted with 1-12 R41;
• each R36 is independently selected from the group consisting of halide, unsubstituted —(C1-9 alkyl), unsubstituted —(C2-9 alkenyl), unsubstituted —(C2-9 alkynyl), unsubstituted —(C1-9 haloalkyl), —XR42, —C(═O)N(R47)2, —(C1-4 alkylene)pN(R50)2, —(C1-4 alkylene)pheterocyclyl optionally substituted with 1-10 R43, and —(C1-4 alkylene)pcarbocyclyl optionally substituted with 1-12 R44;
• wherein each —(C1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein;
• each R37 is independently selected from the group consisting of halide, unsubstituted —(C1-9 alkyl), unsubstituted —(C2-9 alkenyl), unsubstituted —(C2-9 alkynyl), unsubstituted —(C1-9 haloalkyl), —XR42, —C(═O)N(R47)2, —(C1-4 alkylene)pN(R50)2, —(C1-4 alkylene)pheterocyclyl optionally substituted with 1-10 R43, and —(C1-4 alkylene)pcarbocyclyl optionally substituted with 1-12 R44;
• wherein each —(C1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein;
• each R38 is independently selected from the group consisting of halide, unsubstituted —(C1-5 alkyl), unsubstituted —(C2-5 alkenyl), unsubstituted —(C2-5 alkynyl), unsubstituted —(C1-5 haloalkyl), —CN, and —(C1-4 alkylene)pcarbocyclyl optionally substituted with 1-12 R44;
• wherein each —(C1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein;
• each R39 is independently selected from the group consisting of halide, unsubstituted —(C1-5 alkyl), unsubstituted —(C2-5 alkenyl), unsubstituted —(C2-5 alkynyl), unsubstituted —(C1-5 haloalkyl), —CN, and —(C1-4 alkylene)pcarbocyclyl optionally substituted with 1-12 R44;
• wherein each —(C1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein;
• each R40 is independently selected from the group consisting of halide, unsubstituted —(C1-5 alkyl), unsubstituted —(C2-5 alkenyl), unsubstituted —(C2-5 alkynyl), unsubstituted —(C1-5 haloalkyl), —CN, and —(C1-4 alkylene)pcarbocyclyl optionally substituted with 1-12 R44;
• wherein each —(C1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein;
• each R41 is independently selected from the group consisting of halide, unsubstituted —(C1-5 alkyl), unsubstituted —(C2-5 alkenyl), unsubstituted —(C2-5 alkynyl), unsubstituted —(C1-5 haloalkyl), and —CN;
• each R42 is independently selected from the group consisting of H, unsubstituted —(C1-5 alkyl), unsubstituted —(C2-5 alkenyl), unsubstituted —(C2-5 alkynyl), unsubstituted —(C1-5 haloalkyl), —(C1-4 alkylene)N(R48)2, —(C1-4 alkylene)paryl optionally substituted with 1-10 R46, —(C1-4 alkylene)pheterocyclyl optionally substituted with 1-12 R43, and —(C1-4 alkylene)pcarbocyclyl optionally substituted with 1-12 R44;
• wherein each —(C1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein;
• each R43 is independently selected from the group consisting of halide, unsubstituted —(C1-5 alkyl), unsubstituted —(C2-5 alkenyl), unsubstituted —(C2-5 alkynyl), unsubstituted —(C1-5 haloalkyl), —CN, —OH, —C(═O)R51, —N(R50)2, and —(C1-4 alkylene)pcarbocyclyl optionally substituted with 1-12 R44;
• wherein each —(C1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein;
• each R44 is selected from the group consisting of halide, unsubstituted —(C1-5 alkyl), unsubstituted —(C2-5 alkenyl), unsubstituted —(C2-5 alkynyl), unsubstituted —(C1-5 haloalkyl), and —CN;
• each R46 is independently selected from the group consisting of halide, unsubstituted —(C1-5 alkyl), unsubstituted —(C2-5 alkenyl), unsubstituted —(C2-5 alkynyl), unsubstituted —(C1-5 haloalkyl), and —CN;
• each R47 is independently selected from the group consisting of H, unsubstituted —(C1-5 alkyl), unsubstituted —(C2-5 alkenyl), unsubstituted —(C2-5 alkynyl), and unsubstituted —(C1-5 haloalkyl);
• each R48 is independently selected from the group consisting of H, unsubstituted —(C1-5 alkyl), unsubstituted —(C2-5 alkenyl), unsubstituted —(C2-5 alkynyl), and unsubstituted -(C1-5 haloalkyl);
• each R49 is independently selected from the group consisting of H, unsubstituted —(C1-5 alkyl), unsubstituted —(C2-5 alkenyl), unsubstituted —(C2-5 alkynyl), and unsubstituted -(C1-5 haloalkyl);
• each R50 is independently selected from the group consisting of H, unsubstituted —(C1-5 alkyl), unsubstituted —(C2-5 alkenyl), unsubstituted —(C2-5 alkynyl), unsubstituted —(C1-5 haloalkyl), and —(C1-4 alkylene)N(R48)2;
• wherein —(C1-4 alkylene) is optionally substituted with one or more substituents as defined anywhere herein;
• each R51 is a heteroaryl optionally substituted with 1-6 R52;
• each R52 is a -heterocyclyl optionally substituted with 1-10 R46;
• each X is selected from the group consisting of O, S, and NR48;
• each Y is selected from the group consisting of O and S;
• and
• each p is independently 0 or 1.