SUBSTITUTED PYRAZOLO[3,4-b]PYRIDIN-6-CARBOXYLIC ACIDS AND METHOD OF USE

摘要

The present invention provides for compounds of formula (I);;wherein R1, R2, R3, and R4 have any of the values defined in the specification, and pharmaceutically acceptable salts thereof, that are useful as agents in the treatment of diseases and conditions mediated and modulated by CFTR, including cystic fibrosis, Sjögren's syndrome, pancreatic insufficiency, chronic obstructive lung disease, and chronic obstructive airway disease. Also provided are pharmaceutical compositions comprised of one or more compounds of formula (I).

主权项

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof,wherein
R1 is G1A, -G1B-G1C, -G1B-L1A-G1C, C1-C6 haloalkyl, C1-C6 alkyl, —(C1-C6 alkylenyl)-CN, —(C1-C6 alkylenyl)-G1D, or -G1D-O-benzyl; L1A is —O— or —O—(C1-C3 alkylenyl)-; wherein the left end of the L1A moiety is attached to G1B; G1A is phenyl, aryl, 5-6 membered monocyclic heteroaryl, 4-7 membered monocyclic heterocycle, fused bicyclic heterocycle, or C3-C6 monocyclic cycloalkyl; wherein each G1A is optionally substituted with 1, 2, 3, or 4 independently selected R1a groups; G1B is phenyl or 5-6 membered monocyclic heteroaryl; wherein each G1B is optionally substituted with 1, 2, 3, or 4 independently selected R1b groups; G1C is 4-7 membered monocyclic heterocycle which is optionally substituted with 1, 2, 3, or 4 independently selected R1c groups; G1D, at each occurrence, is a 4-7 membered monocyclic heterocycle, 5-6 membered monocyclic heteroaryl, or a C3-C6 monocyclic cycloalkyl; wherein each G1D is optionally substituted with 1, 2, 3, or 4 independently selected R1d groups; R2 is C2-C4 alkenyl, C1-C6 alkyl, C1-C6 haloalkyl, —OR2xa, —(C1-C6 alkylenyl)-OR2xb, —(C1-C6 alkylenyl)-N(R2xb)2, —C(O)OR2xb, —C(O)N(R2xb)2, or -G2A; R2xa is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or G2B; R2xb, at each occurrence, is independently hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl; G2A and G2B are each independently 4-7 membered monocyclic heterocycle or C3-C6 monocyclic cycloalkyl; wherein G2A and G2B are each optionally substituted with 1, 2, or 3 independently selected R2a groups; R3 is halogen, G3A, -G3B-L1-G3C, -G3B-L3-G3C-L4-G3F, —(C1-C6 alkylenyl)-G3E, —OR3a, —N(R3a)(R3b), —N(R3b)C(O)G3D, or —C(O)G3D; R3a, at each occurrence, is independently G3E, C1-C6 haloalkyl, or C1-C6 alkyl; wherein the C1-C6 haloalkyl and the C1-C6 alkyl are each optionally substituted with one or two substituents independently selected from the group consisting of G3E, —OR3xa, —C(O)G3D, —N(R3xb)2, and —S(O)2R3xc; R3xa, R3xb, and R3xc, at each occurrence, are each independently hydrogen, C1-C6 haloalkyl, C1-C6 alkyl, G3E, —(C1-C6 alkylenyl)-OR3ya, or —(C1-C6 alkylenyl)-N(R3ya)2; wherein R3ya, at each occurrence, is independently hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl; R3b, at each occurrence, is hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl; L1 is a bond, C1-C6 alkylenyl, (C1-C6 alkylenyl)r-L2-(C1-C6 alkylenyl)s, or O—(C1-C6 alkylenyl)-C(O), wherein the left end of the L1 moiety is attached to G3B; L2 is O, N(Rx), C(O), N(Rx)C(O), or C(O)N(Rx); wherein each Rx is independently hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl; L3 is a bond or C1-C6 alkylenyl; L4 is a bond, C1-C6 alkylenyl, O, N(R2x), C(O), N(R2x)C(O), or C(O)N(R2x); wherein each R2x is independently hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl; r is 0 or 1; s is 0 or 1; G3A, G3B, and G3C, are each independently C3-C11 cycloalkyl, phenyl, 5-6 membered monocyclic heteroaryl, or 4-11 membered heterocycle, wherein G3A, G3B, and G3C are each optionally substituted with 1, 2, 3, or 4 independently selected Re groups; G3D, at each occurrence, is 4-7 membered monocyclic heterocycle which is optionally substituted with 1, 2, 3, or 4 independently selected Re groups; G3E, at each occurrence, is independently C3-C8 monocyclic cycloalkyl or 4-11 membered heterocycle; wherein each G3E is optionally substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of Re and G3F; G3F, at each occurrence, is independently a 4-7 membered monocyclic heterocycle or a C3-C6 monocyclic cycloalkyl; wherein each G3F is optionally substituted with 1, 2, 3, or 4 independently selected Re groups; Re, at each occurrence, is independently C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkyl, C1-C6 haloalkyl, halogen, oxo, —CN, —N3, NO2, —ORf, —OC(O)Rg, —OC(O)NRfRh, —SRf, —S(O)2Rf, —S(O)2NRfRh, —C(O)Rf, —C(O)ORf, —C(O)NRfRh, —C(O)N(Rh)S(O)2Rf, —N(Rf)2, —N(Rh)C(O)Rf, —N(Rh)S(O)2Rg, —N(Rh)C(O)O(Rg), —N(Rh)C(O)NRfRh, or —N(Rh)S(O)2NRfRh; wherein the C1-C6 haloalkyl and the C1-C6 alkyl are each optionally substituted with 1 or 2 substituents independently selected from the group consisting of halogen, —CN, NO2, —ORf, —OC(O)Rg, —OC(O)NRfRh, —SRf, —S(O)2Rf, —S(O)2NRfRh, —C(O)R, —C(O)OR, —C(O)NRfRh, —C(O)N(Rh)S(O)2Rf, —N(Rf)2, —N(Rh)C(O)Rf, —N(Rh)S(O)2Rg, —N(Rh)C(O)O(Rg), —N(Rh)C(O)NRfRh, and —N(Rh)S(O)2NRfRh; Rf, at each occurrence, is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, —(C1-C6 alkylenyl)-CN, —(C1-C6 alkylenyl)-ORm, —(C1-C6 alkylenyl)-OC(O)Rn, —(C1-C6 alkylenyl)-OC(O)N(Rm)2, —(C1-C6 alkylenyl)-SRm, —(C1-C6 alkylenyl)-S(O)2Rm, —(C1-C6 alkylenyl)-S(O)2N(Rm)2, —(C1-C6 alkylenyl)-C(O)Rm, —(C1-C6 alkylenyl)-C(O)ORm, —(C1-C6 alkylenyl)-C(O)N(Rm)2, —(C1-C6 alkylenyl)-C(O)N(Rm)S(O)2Rn, —(C1-C6 alkylenyl)-N(Rm)2, —(C1-C6 alkylenyl)-N(Rm)C(O)Rn, —(C1-C6 alkylenyl)-N(Rm)S(O)2Rn, —(C1-C6 alkylenyl)-N(Rm)C(O)O(Rn), —(C1-C6 alkylenyl)-N(Rm)C(O)N(Rm)2, or —(C1-C6 alkylenyl)-N(Rm)S(O)2N(Rm)2; Rg, at each occurrence, is independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, —(C1-C6 alkylenyl)-CN, —(C1-C6 alkylenyl)-ORm, —(C1-C6 alkylenyl)-OC(O)Rn, —(C1-C6 alkylenyl)-OC(O)N(Rm)2, —(C1-C6 alkylenyl)-SRm, —(C1-C6 alkylenyl)-S(O)2Rm, —(C1-C6 alkylenyl)-S(O)2N(Rm)2, alkylenyl)-C(O)Rm, —(C1-C6 alkylenyl)-C(O)ORm, —(C1-C6 alkylenyl)-C(O)N(Rm)2, —(C1-C6 alkylenyl)-C(O)N(Rm)S(O)2Rn, —(C1-C6 alkylenyl)-N(Rm)2, —(C1-C6 alkylenyl)-N(Rm)C(O)Rn, —(C1-C6 alkylenyl)-N(Rm)S(O)2Rn, —(C1-C6 alkylenyl)-N(Rm)C(O)O(R″), —(C1-C6 alkylenyl)-N(Rm)C(O)N(Rm)2, or —(C1-C6 alkylenyl)-N(Rm)S(O)2N(Rm)2; Rh, at each occurrence, is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or —(C1-C6 alkylenyl)-ORm; R1a, R1b, R1c, R1d, and R2a, at each occurrence, are each independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 haloalkyl, oxo, —CN, NO2, —ORm, —OC(O)Rn, —OC(O)N(Rm)2, —SRm, —S(O)2Rm, —S(O)2N(Rm)2, —C(O)Rm, —C(O)ORm, —C(O)N(Rm)2, —C(O)N(Rm)S(O)2Rn, —N(Rm)2, —N(Rm)(alkoxyalkyl), —N(alkoxyalkyl)2, —N(Rm)C(O)Rn, —N(Rm)S(O)2Rn, —N(Rm)C(O)O(Rn), —N(Rm)C(O)N(Rm)2, —N(Rm)S(O)2N(Rm)2, —(C1-C6 alkylenyl)-CN, —(C1-C6 alkylenyl)-ORm, —(C1-C6 alkylenyl)-OC(O)Rn, —(C1-C6 alkylenyl)-OC(O)N(Rm)2, —(C1-C6 alkylenyl)-SRm, —(C1-C6 alkylenyl)-S(O)2Rm, —(C1-C6 alkylenyl)-S(O)2N(Rm)2, —(C1-C6 alkylenyl)-C(O)Rm, —(C1-C6 alkylenyl)-C(O)ORm, —(C1-C6 alkylenyl)-C(O)N(Rm)2, —(C1-C6 alkylenyl)-C(O)N(Rm)S(O)2Rn, —(C1-C6 alkylenyl)-N(Rm)2, —(C1-C6 alkylenyl)-N(Rm)C(O)Rn, —(C1-C6 alkylenyl)-N(Rm)S(O)2Rn, —(C1-C6 alkylenyl)-N(Rm)C(O)O(Rn), —(C1-C6 alkylenyl)-N(Rm)C(O)N(Rn)2, or —(C1-C6 alkylenyl)-N(Rm)S(O)2N(Rn)2; Rm, at each occurrence, is independently hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl; Rn, at each occurrence, is independently C1-C6 alkyl or C1-C6 haloalkyl; and R4 is hydrogen, C1-C3 alkyl, or C1-C3 haloalkyl; with the proviso that when R1 is C1-C6 alkyl or G1A, wherein G1A is optionally substituted phenyl, optionally substituted 5-6 membered monocyclic heteroaryl, or optionally substituted 4-7 membered monocyclic heterocycle, R2 is C1-C6 alkyl, and R3 is G3A, then G3A is not optionally substituted phenyl or optionally substituted 5-6 membered monocyclic heteroaryl.