A method for the treatment of cystic fibrosis, comprising administering to a mammal afflicted with cystic fibrosis a pharmaceutical composition comprising a pharmaceutically acceptable carrier, a pharmaceutically effective amount of a compound according to Formula I, or pharmaceutically acceptable salt thereof, and at least one additional therapeutic agent selected from the group consisting of aminoglycosides, colistin, azetreonam, ciprofloxacin, azithromycin, hypertonic saline, acetylcysteine, dornase alfa, denufosol, VX-809, VX-661, VX-983, pancreatin, and pancrelipase for the treatment of cystic fibrosis, in an amount sufficient to effect the treatment:
- wherein
- R1 is H, —CH3, —CF3, or cyclopropyl;
- L is —NR4—;
- the subscript m is 0, or 1;
- R2 is
- C1-4 alkyl or C1-4 alkyl substituted with one or more independently selected R5 groups,
- C3-7 cycloalkyl,
- 4-10 membered monocyclic, bridged-, spiro-, or fused bicyclic heterocycloalkyl comprising one or more heteroatoms independently selected from N, O, and S, and optionally substituted with one or more independently selected Ra groups,
- 5-6 membered monocyclic heterocycloalkenyl comprising one or more heteroatoms independently selected from N, O, and S, and optionally substituted with one or more independently selected Ra groups,
- C6-10 mono or bicyclic aryl optionally substituted with one or more independently selected Rb, or
- 5-10 membered monocyclic or fused bicyclic heteroaryl, comprising one or more heteroatoms independently selected from N, O, and S, and optionally substituted with one or more independently selected Rb;
- R3 is
- C3-7 cycloalkyl optionally substituted with one or more independently selected Rc groups,
- 4-7 membered monocyclic heterocycloalkyl comprising one or more heteroatoms independently selected from O, and S, and optionally substituted with Rc,
- C6-10 mono or bicyclic aryl optionally substituted with one or more independently selected Rd groups,
- phenyl fused to a 5-6 membered heterocycloalkyl comprising one or more heteroatoms independently selected from N, O, and S, and optionally substituted with one or more independently selected Rd groups,
- phenyl fused to a C5-6 cycloalkyl, optionally substituted with one or more independently selected Rd groups,
- 5-10 membered mono or fused bicyclic heteroaryl comprising one or more heteroatoms independently selected from N, O, and S, and optionally substituted with one or more independently selected Rd groups,
- 5-6 membered monocyclic heteroaryl comprising one or more heteroatoms independently selected from N, O, and S, fused to a 5-6 membered heterocycloalkyl comprising one or more heteroatoms independently selected from N, O, and S, and optionally substituted with one or more independently selected Rd groups,
- 5-6 membered monocyclic heteroaryl comprising one or more heteroatoms independently selected from N, O, and S, fused to a C5-6 cycloalkyl comprising one or more heteroatoms independently selected from N, O, and S, and optionally substituted with one or more independently selected Rd groups,
- C2-6 alkenyl,
- C3-6 alkyl, or
- C1-6 alkyl substituted with one or more independently selected Re groups;
- R4 is
- C1-6 alkyl or C1-6 alkyl substituted with one or more independently selected R6 groups, or
- C3-7 cycloalkyl;
- each R5 is independently selected from
- halo,
- OH,
- —CN,
- C1-4 alkoxy,
- —NR8eR8f,
- C3-7 cycloalkyl,
- 6 membered mono or fused bicyclic heteroaryl comprising one or more heteroatoms independently selected from N, O, and S, and
- phenyl optionally substituted with one or more independently selected
- halo,
- C1-4 alkyl optionally substituted with one or more independently selected halo, or
- C1-4 alkoxy;
- each R6, is independently selected from
- halo,
- OH,
- —CN,
- —NR8gR8h, and
- C1-4 alkoxy;
- each Ra is selected from
- halo,
- CN,
- oxo,
- C1-4 alkyl or C1-4 alkyl substituted with one or more independently selected R7a,
- C1-4 alkoxy or C1-4 alkoxy substituted with one or more independently selected R7a,
- —C(═O)O—C1-4 alkyl,
- phenyl,
- 5-10 membered mono, or fused bicyclic heteroaryl comprising one or more heteroatoms independently selected from N, O, or S, and optionally substituted with one or more independently selected C1-4 alkyl, and
- —NR8aR8b;
- each Rb is selected from
- halo,
- —CN,
- C1-4 alkyl or C1-4 alkyl substituted with one or more independently selected R7b,
- C1-4 alkoxy or C1-4 alkoxy substituted with one or more independently selected R7b,
- —OC(═O)C1-4 alkyl, and
- —NR8cR8d;
- each Rc is selected from
- halo,
- OH,
- —CN,
- oxo,
- C1-4 alkyl or C1-4 alkyl substituted with one or more independently selected R7c,
- C1-4 alkoxy or C1-4 alkoxy substituted with one or more independently selected R7c,
- phenyl or phenyl substituted with one or more independently selected halo, C1-4 alkyl, C1-4 alkoxy, —CN, or —NR9aR9b, and
- 5-6 membered monocyclic heteroaryl comprising one or more heteroatoms independently selected from N, O, or S or N, O, or S substituted with one or more independently selected halo, C1-4 alkyl, C1-4 alkoxy, CN, —NR9cR9d;
- each Rd is selected from
- halo,
- —CN,
- —OH,
- C1-4 alkyl or C1-4 alkyl substituted with one or more independently selected R7d,
- C1-4 alkoxy or C1-4 alkoxy substituted with one or more independently selected R7d,
- C3-7 cycloalkyl,
- 5-10 membered mono or fused bicyclic heteroaryl comprising one or more heteroatoms independently selected from N, O, or S, and
- —NH-Phenyl;
- each Re is selected from
- halo,
- OH,
- —CN,
- C1-4 alkoxy or C1-4 alkoxy substituted with one or more independently selected R7e,
- C3-7 cycloalkyl,
- phenyl or phenyl substituted with one or more independently selected halo, C1-4 alkyl, C1-4 alkoxy, CN, and —NR9eR9f, and
- 5-6 membered monocyclic heteroaryl comprising one or more heteroatoms independently selected from N, O, and S or N, O, and S substituted with one or more independently selected halo, C1-4 alkyl, C1-4 alkoxy, CN, and —NR9gR9h;
- each R7a, R7b, R7c, R7d, and R7e is independently selected from
- halo,
- OH,
- —CN,
- —NR8iR8j, and
- C1-4 alkoxy;
- each R8a, R8b, R8c, R8d, R8e, R8f, R8g, R8h, R8i, or R8j is independently selected from H, and C1-4 alkyl;
- each R9a, R9b, R9c, R9d, R9e, R9f, R9g, or R9h is independently selected from H, and C1-4 alkyl;
- or a pharmaceutically acceptable salt, or a solvate, or a pharmaceutically acceptable salt of a solvate thereof.