Modulators of the cystic fibrosis transmembrane conductance regulator protein and methods of use

A compound of Formula I, or a pharmaceutically acceptable salt thereof,

• wherein
• A1 is selected from the group consisting of
• R1 is selected from the group consisting of hydrogen, OH, CN, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, 6-10 membered aryl, 5-11 membered heteroaryl, C3-C11 cycloalkyl, C4-C11 cycloalkenyl, and 4-12 membered heterocyclyl;
• wherein the R1 C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C1-C6 alkoxy are optionally substituted with one or more substituents independently selected from the group consisting of R7, OR7, SR7, NHR7, N(R7)2, NH2, C(O)OH, OH, CN, NO2, F, Cl, Br and I;
• wherein the R1 6-10 membered aryl, 5-11 membered heteroaryl, C3-C11 cycloalkyl, C4-C11 cycloalkenyl, and 4-12 membered heterocyclyl are optionally substituted with one or more substituents independently selected from the group consisting of C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C(O)OH, OH, oxo, CN, NO2, F, Cl, Br and I;
• one of R2A, R2B, R2C and R2D is hydrogen, and the remaining are independently selected from the group consisting of hydrogen, R8, OR8, C(O)R8, C(O)OR8, SO2R8, NHR8, N(R8)2, NH2, C(O)OH, OH, CN, NO2, F, Cl, Br and I;
• or
• two of R2A, R2B, R2C, and R2D a on adjacent carbons form a fused ring selected from the group consisting of phenyl, 5-6 membered heteroaryl, C3-C7 cycloalkyl, C4-C7 cycloalkenyl, and 4-7 membered heterocyclyl;
• and the remaining are independently selected from the group consisting of hydrogen, R8, OR8, C(O)R8, OC(O)R8, C(O)OR8, SO2R8, NHR8, N(R8)2, NH2, C(O)OH, OH, CN, NO2, F, Cl, Br and I;
• wherein the phenyl, 5-6 membered heteroaryl, C3-C7 cycloalkyl, C4-C7 cycloalkenyl, and 4-7 membered heterocyclyl are optionally substituted with one or more substituents independently selected from the group consisting of R8, OR8, C(O)R8, OC(O)R8, C(O)OR8, SO2R8, NHR8, N(R8)2, NH2, C(O)OH, OH, CN, NO2, F, Cl, Br and I;
• R3 is selected from the group consisting of C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 6-10 membered aryl, 5-11 membered heteroaryl, C3-C11 cycloalkyl, C4-C11 cycloalkenyl, and 4-12 membered heterocyclyl;
• wherein the R3 C2-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl are optionally substituted with one or more substituents independently selected from the group consisting of C1-C6 alkoxy, phenyl, OH, oxo, CN, NO2, F, Cl, Br and I;
• wherein the R3 6-10 membered aryl, 5-11 membered heteroaryl, C3-C11 cycloalkyl, C4-C11 cycloalkenyl, and 4-12 membered heterocyclyl are optionally substituted with one or more substituents independently selected from the group consisting of R9, OR9, C(O)R9, OC(O)R9, C(O)OR9, SO2R9, C(O)NH2, C(O)NHR9, C(O)N(R9)2, NHC(O)R9, NHR9, N(R9)2, NH2, C(O)OH, OH, oxo, CN, NO2, F, Cl, Br and I;
• R4 is selected from the group consisting of hydrogen and C1-C6 alkyl;
• wherein the R4 C1-C6 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of R10, OR10, SR10, NHR10, N(R10)2, NH2, C(O)OH, OH, oxo, CN, NO2, F, Cl, Br and I;
• R5A, R5B, R5C, and R5D are each independently selected from the group consisting of hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, 6-10 membered aryl, 5-11 membered heteroaryl, C3-C11 cycloalkyl, C4-C11 cycloalkenyl, and 4-12 membered heterocyclyl;
• wherein the R5A, R5B, R5C, and R5D C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C1-C6 alkoxy are optionally substituted with one or more substituents independently selected from the group consisting of 6-10 membered aryl, 5-11 membered heteroaryl, C3-C11 cycloalkyl, C4-C11 cycloalkenyl, 4-12 membered heterocyclyl, C1-C6 thioalkyl, OH, oxo, CN, NO2, F, Cl, Br and I;
• wherein the R5A, R5B, R5C, and R5D 6-10 membered aryl, 5-11 membered heteroaryl, C3-C11 cycloalkyl, C4-C11 cycloalkenyl, and 4-12 membered heterocyclyl are optionally substituted with one or more substituents independently selected from the group consisting of C1-C6 alkyl, C(O)OH, NH2, OH, oxo, CN, NO2, F, Cl, Br and I;
• or
• R5A and R5B, together with the carbon atom to which they are attached, form a C3-C7 monocyclic cycloalkyl or a 4-7 membered monocyclic heterocycle;
• wherein the C3-C7 monocyclic cycloalkyl and the 4-7 membered monocyclic heterocycle are each optionally substituted with one or more substituents independently selected from the group consisting of C1-C6 alkyl, C(O)OH, NH2, OH, oxo, CN, NO2, F, Cl, Br and I;
• and
• R5C and R5D are each independently selected from the group consisting of hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, 6-10 membered aryl, 5-11 membered heteroaryl, C3-C11 cycloalkyl, C4-C11 cycloalkenyl, and 4-12 membered heterocyclyl;
• wherein the R5C and R5D C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C1-C6 alkoxy are optionally substituted with one or more substituents independently selected from the group consisting of 6-10 membered aryl, 5-11 membered heteroaryl, C3-C11 cycloalkyl, C4-C11 cycloalkenyl, 4-12 membered heterocyclyl, C1-C6 thioalkyl, OH, oxo, CN, NO2, F, Cl, Br and I;
• wherein the R5C and R5D 6-10 membered aryl, 5-11 membered heteroaryl, C3-C11 cycloalkyl, C4-C11 cycloalkenyl, and 4-12 membered heterocyclyl are optionally substituted with one or more substituents independently selected from the group consisting of C1-C6 alkyl, C(O)OH, NH2, OH, oxo, CN, NO2, F, Cl, Br and I;
• or
• R5C and R5D, together with the carbon atom to which they are attached, form a C3-C7 monocyclic cycloalkyl or a 4-7 membered monocyclic heterocycle;
• wherein the C3-C7 monocyclic cycloalkyl and the 4-7 membered monocyclic heterocycle are each optionally substituted with one or more substituents independently selected from the group consisting of C1-C6 alkyl, C(O)OH, NH2, OH, oxo, CN, NO2, F, Cl, Br and I;
• and
• R5A and R5B are each independently selected from the group consisting of hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, 6-10 membered aryl, 5-11 membered heteroaryl, C3-C11 cycloalkyl, C4-C11 cycloalkenyl, and 4-12 membered heterocyclyl;
• wherein the R5A and R5B C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C1-C6 alkoxy are optionally substituted with one or more substituents independently selected from the group consisting of 6-10 membered aryl, 5-11 membered heteroaryl, C3-C11 cycloalkyl, C4-C11 cycloalkenyl, 4-12 membered heterocyclyl, C1-C6 thioalkyl, OH, oxo, CN, NO2, F, Cl, Br and I;
• wherein the R5A and R5B 6-10 membered aryl, 5-11 membered heteroaryl, C3-C11 cycloalkyl, C4-C11 cycloalkenyl, and 4-12 membered heterocyclyl are optionally substituted with one or more substituents independently selected from the group consisting of C1-C6 alkyl, C(O)OH, NH2, OH, oxo, CN, NO2, F, Cl, Br and I;
• R6A, R6B, R6C, and R6D are each independently hydrogen;
• R7, at each occurrence, is independently selected from the group consisting of C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 6-10 membered aryl, 5-11 membered heteroaryl, C3-C11 cycloalkyl, C4-C11 cycloalkenyl, and 4-12 membered heterocyclyl;
• wherein each R7 C1-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of C1-C6 alkoxy, OH, oxo, CN, NO2, F, Cl, Br and I;
• wherein each R7 6-10 membered aryl, 5-11 membered heteroaryl, C3-C11 cycloalkyl, C4-C11 cycloalkenyl, and 4-12 membered heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, oxo, OH, CN, NO2, F, Cl, Br and I;
• R8, at each occurrence, is independently selected from the group consisting of C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C6-C10 membered aryl, 5-11 membered heteroaryl, C3-C11 cycloalkyl, C4-C11 cycloalkenyl, and 4-12 membered heterocyclyl;
• wherein each R8 C1-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of R11, OR11, C(O)OR11, NHR11, N(R11)2, NH2, C(O)OH, OH, CN, NO2, F, Cl, Br and I;
• wherein each R8 C6-C10 membered aryl, 5-11 membered heteroaryl, C3-C11 cycloalkyl, C4-C11 cycloalkenyl, and 4-12 membered heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of R12, OR12, C(O)OR12, NHR12, N(R12)2, NH2, C(O)OH, OH, oxo, CN, NO2, F, Cl, Br and I;
• R9, at each occurrence, is independently selected from the group consisting of C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 6-10 membered aryl, 5-11 membered heteroaryl, C3-C11 cycloalkyl, C4-C11 cycloalkenyl, and 4-12 membered heterocyclyl;
• wherein each R9 C1-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of R13, OR13, SR13, C(O)R13,NHR13, N(R13)2, C(O)OH, OH, CN, NO2, F, Cl, Br and I;
• wherein each R9 6-10 membered aryl, 5-11 membered heteroaryl, C3-C11 cycloalkyl, C4-C11 cycloalkenyl, and 4-12 membered heterocyclyl are optionally substituted with one or more substituents independently selected from the group consisting of R14, OR14, C(O)R14, OC(O)R14, C(O)OR14, SO2R14, NHR14, N(R14)2, NH2, C(O)OH, OH, oxo, CN, NO2, F, Cl, Br and I;
• R10, at each occurrence, is independently selected from the group consisting of C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C6-C10 membered aryl, 5-11 membered heteroaryl, C3-C11 cycloalkyl, C4-C11 cycloalkenyl, and 4-12 membered heterocyclyl;
• wherein each R10 C1-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of OH, oxo, CN, NO2, F, Cl, Br and I;
• wherein each R10 C6-C10 membered aryl, 5-11 membered heteroaryl, C3-C11 cycloalkyl, C4-C11 cycloalkenyl, and 4-12 membered heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, 5-6 membered heteroaryl, OH, oxo, CN, NO2, F, Cl, Br and I;
• R11, at each occurrence, is independently selected from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, C6-C10 membered aryl, C3-C11 cycloalkyl, 4-12 membered heterocyclyl, C4-C11 cycloalkenyl, and 5-6 membered heteroaryl;
• wherein each R11 C1-C6 alkyl and C1-C6 alkoxy is optionally substituted with one or more substituents independently selected from the group consisting of OH, oxo, CN, NO2, F, Cl, Br and I;
• wherein each R11 C6-C10 membered aryl, C3-C11 cycloalkyl, 4-12 membered heterocyclyl, C4-C11 cycloalkenyl, and 5-6 membered heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, F, Cl, Br and I;
• R12, at each occurrence, is independently selected from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, C6-C10 membered aryl, C3-C11 cycloalkyl, 4-12 membered heterocyclyl, C4-C11 cycloalkenyl, and 5-6 membered heteroaryl;
• wherein each R12 C1-C6 alkyl and C1-C6 alkoxy is optionally substituted with one or more substituents independently selected from the group consisting of OH, oxo, CN, NO2, F, Cl, Br and I;
• wherein each R12 C6-C10 membered aryl, C3-C11 cycloalkyl, 4-12 membered heterocyclyl, C4-C11 cycloalkenyl, and 5-6 membered heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, F, Cl, Br and I;
• R13, at each occurrence, is independently selected from the group consisting of C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C6-C10 membered aryl, 5-11 membered heteroaryl, C3-C11 cycloalkyl, C4-C11 cycloalkenyl, and 4-12 membered heterocyclyl;
• wherein each R13 C1-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of OH, oxo, CN, NO2, F, Cl, Br and I;
• wherein each R13 C6-C10 membered aryl, 5-11 membered heteroaryl, cycloalkyl, C4-C11 cycloalkenyl, and 4-12 membered heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, 5-6 membered heteroaryl, OH, oxo, CN, NO2, F, Cl, Br and I;
• and
• R14, at each occurrence, is independently selected from the group consisting of C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C6-C10 membered aryl, 5-11 membered heteroaryl, cycloalkyl, C4-C11 cycloalkenyl, and 4-12 membered heterocyclyl;
• wherein each R14 C1-C6alkyl, C2-C6 alkenyl, and C2-C6 alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, 5-6 membered heteroaryl, 4-12 membered heterocyclyl, OH, oxo, CN, NO2, F, Cl, Br and I;
• with the proviso that R3 is not C1-alkyl or thienyl;
• with the proviso that, when R2A, R2B, R2C, and R2D are each hydrogen, R1 is not hydrogen;
• with the proviso that, when R3 is imidazolyl, R9 is not CH2CH(CH3)2;
• with the proviso that when R2B is Cl, R3 is not 2,4-dimethyl-5-thiazolyl or 2-cyano-3-fluorophenyl;
• with the proviso that, when R3 is cyclohexyl, n-butyl or isopropyl, R2C is not OCH3;
• with the proviso that, when R3 is 3-pyridinyl, R2C is not Cl;
• and
• with the proviso that, when R3 is phenyl, R13 is not C(O)CH3.