SUBSTITUTED CHROMANES AND METHOD OF USE

摘要

The invention provides for compounds of formula (I);;wherein R1, X, Y, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, m, and R″ 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 having formula (I) or a pharmaceutically acceptable salt thereofwherein
X is CR2 and Y is CR3; or X is N and Y is CR3; or X is CR2 and Y is N; m is 0, 1, 2, or 3; R″ are optional substituents on the cyclopropyl ring, and at each occurrence, are each independently halogen, C1-C6 haloalkyl, or C1-C6 alkyl; R1 and R2, are each independently hydrogen, halogen, C1-C6 haloalkyl, C1-C6 alkyl, —OR1A, —C(O)OR1B, —NR1AR2A, or —C(O)NR1AR2A; R1A and R2A, at each occurrence, are each independently hydrogen, C1-C6 haloalkyl, G1A, 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 —ORZA, —SRZA, —S(O)2RZA, —C(O)RZA, —C(O)ORZA, —C(O)N(RZA)2, —N(RZA)2, —N(RZA)C(O)RZB, —N(RZA)S(O)2RZB, —N(RZA)C(O)ORZB, —N(RZA)C(O)N(RZA)2, —CN, and G1A; or R1A and R2A together with the nitrogen atom to which they are attached form a 4-6 membered heterocycle wherein the 4-6 membered heterocycle is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 haloalkyl, —ORj, and N(Rj)2; wherein RZA, at each occurrence, is independently hydrogen, C1-C6 haloalkyl, C1-C6 alkyl, G1A, or —(C1-C6 alkylenyl)-G1A; and RZB, at each occurrence, is independently C1-C6 haloalkyl, C1-C6 alkyl, G1A, or —(C1-C6 alkylenyl)-G1A; R1B is hydrogen, C1-C6 haloalkyl, or C1-C6 alkyl; R3 and R14, are each independently hydrogen, halogen, C1-C6 haloalkyl, C1-C6 alkyl, —OH, or —O—(C1-C6 alkyl); R4 is hydrogen, C1-C6 haloalkyl, or C1-C6 alkyl; R5 is hydrogen, —C(O)Ri, —C(O)OH, —C(O)O(C1-C6 alkyl), —C(O)N(Rh)2, C1-C6 haloalkyl, C1-C6 alkyl, or G2A; 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 —ORh, —OC(O)N(Rh)2, —C(O)Rh, —C(O)ORh, —C(O)N(Rh)2, —N(Rh)2, —N(Rh)C(O)Ri, —N(Rh)S(O)2Ri, —N(Rh)C(O)O(Ri), —N(Rh)C(O)N(Rh)2, and G2A; or R4 and R5, together with the carbon atom to which they are attached, form a C3-C6 cycloalkyl or a 4-6 membered heterocycle; wherein the C3-C6 cycloalkyl and the 4-6 membered heterocycle are each optionally substituted with 1, 2, or 3 independently selected Rp groups; G2A, at each occurrence, is independently cycloalkyl, cycloalkenyl, heterocycle, aryl, or heteroaryl, each of which is independently unsubstituted or substituted with 1, 2, or 3 independently selected Rq groups; Rp and Rq, at each occurrence, are each independently C1-C6 alkyl, halogen, C1-C6 haloalkyl, —CN, oxo, NO2, —ORh, —OC(O)Ri, —OC(O)N(Rh)2, —SRh, —S(O)2Rh, —S(O)2N(Rh)2, —C(O)Rh, —C(O)ORh, —C(O)N(Rh)2, —C(O)N(Rh)S(O)2Rh, —N(Rh)2, —N(Rh)C(O)Ri, —N(Rh)S(O)2Ri, —N(Rh)C(O)O(Ri), —N(Rh)C(O)N(Rh)2, or GA, 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 —ORh, —OC(O)Ri, —OC(O)N(Rh)2, —SRh, —S(O)2Rh, —S(O)2N(Rh)2, —C(O)Rh, —C(O)ORh, —C(O)N(Rh)2, —C(O)N(Rh)S(O)2Rh, —N(Rh)2, —N(Rh)C(O)Ri, —N(Rh)S(O)2Ri, —N(Rh)C(O)O(Ri), —N(Rh)C(O)N(Rh)2, —CN, and GA; Rh, at each occurrence, is independently hydrogen, C1-C6 haloalkyl, C1-C6 alkyl, or GA, 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 —ORj, —OC(O)N(Rj)2, —SRj, —C(O)ORj, —C(O)N(Rj)2, —N(Rj)2, —CN, and GA; Ri, at each occurrence, is independently C1-C6 haloalkyl, C1-C6 alkyl, or GA, 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 —ORj, —OC(O)N(Rj)2, —SRj, —C(O)ORj, —C(O)N(Rj)2, —N(Rj)2, —CN, and GA; R6 is hydrogen, halogen, C1-C6 haloalkyl, or C1-C6 alkyl; R7 is hydrogen, halogen, —ORj, —N(Rj)2, —N(Rj)C(O)Rk, C1-C6 haloalkyl, C1-C6 alkyl, C2-C6 alkenyl, or —(C1-C6 alkylenyl)-G3A; R8 is hydrogen, C1-C6 haloalkyl, or C1-C6 alkyl; R9, R10, and R13, are each independently hydrogen, halogen, —ORj, C1-C6 haloalkyl, or C1-C6 alkyl; R11 and R12 are each independently hydrogen, C1-C3 alkyl, or halogen; G1A, G3A, and GA, at each occurrence, are each independently cycloalkyl, cycloalkenyl, heterocycle, aryl, or heteroaryl, each of which is independently unsubstituted or substituted with 1, 2, or 3 independently selected Rs groups; wherein Rs, at each occurrence, is independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 haloalkyl, —CN, oxo, NO2, —ORj, —OC(O)Rk, —OC(O)N(Rj)2, —SRj, —S(O)2Rj, —S(O)2N(Rj)2, —C(O)Rj, —C(O)ORj, —C(O)N(Rj)2, —N(Rj)2, —N(Rj)C(O)Rk, —N(Rj)S(O)2Rk, —N(Rj)C(O)O(Rk), —N(Rj)C(O)N(Rj)2, —(C1-C6 alkylenyl)-ORj, —(C1-C6 alkylenyl)-OC(O)Rk, —(C1-C6 alkylenyl)-OC(O)N(Rj)2, —(C1-C6 alkylenyl)-SRj, —(C1-C6 alkylenyl)-S(O)2Rj, —(C1-C6 alkylenyl)-S(O)2N(Rj)2, —(C1-C6 alkylenyl)-C(O)Rj, —(C1-C6 alkylenyl)-C(O)ORj, —(C1-C6 alkylenyl)-C(O)N(Rj)2, —(C1-C6 alkylenyl)-N(Rj)2, —(C1-C6 alkylenyl)-N(Rj)C(O)Rk, —(C1-C6 alkylenyl)-N(Rj)S(O)2Rk, —(C1-C6 alkylenyl)-N(Rj)C(O)O(Rk), —(C1-C6 alkylenyl)-N(Rj)C(O)N(Rj)2, or —(C1-C6 alkylenyl)-CN; Rj, at each occurrence, is independently hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl; and Rk, at each occurrence, is independently C1-C6 alkyl or C1-C6 haloalkyl.