Compounds, compositions, and methods for increasing CFTR activity

A pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient and a compound having the Formula (I):

• or a pharmaceutically acceptable salt, prodrug or solvate thereof, wherein:
• X is oxygen or sulfur;
• R2a is hydrogen or fluoro;
• R3 is hydrogen or fluoro;
• R4 is selected from the group consisting of hydrogen, optionally substituted C1-C10 alkyl, optionally substituted C2-C10 alkenyl, optionally substituted C2-C10 alkynyl, optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 cycloalkenyl, optionally substituted aryl, halo, ORc, NRdRd, C(O)ORc, NO2, CN, C(O)Rc, C(O)C(O)Rc, C(O)NRdRd, NRdC(O)Rc, NRdS(O)nRc, N(Rd)(COORc), NRdC(O)C(O)Rc, NRdC(O)NRdRd, NRdS(O)nNRdRd, NRdS(O)nRc, S(O)nRc, S(O)nNRdRd, OC(O)ORc, (C═NRd)Rc, optionally substituted heterocyclic and optionally substituted heteroaryl;
• each Rc is independently selected from the group consisting of hydrogen, optionally substituted C1-C10 alkyl, optionally substituted C2-C10 alkenyl, optionally substituted C2-C10 alkynyl, optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl and optionally substituted heteroaryl;
• each Rd is independently selected from the group consisting of hydrogen, optionally substituted C1-C10 alkyl, optionally substituted C2-C10 alkenyl, optionally substituted C2-C10 alkynyl, optionally substituted C1-C10 alkoxy, optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl and optionally substituted heteroaryl;
• or two geminal Rd groups are taken together with the nitrogen atom to which they are attached to form an optionally substituted heterocyclic or an optionally substituted heteroaryl;
• each n is independently 0, 1 or 2;
• and
• p is 1 or 2;
• provided that the compound is not N-[2-(5-ethyl-1,3,4-thiadiazol-2-yl)ethyl]-5-phenyl-3-isoxazolecarboxamide.

A method of enhancing cystic fibrosis transmembrane conductance regulator (CFTR) activity in a subject in need thereof comprising administering to said subject an effective amount of a compound having the Formula (I):

• or a pharmaceutically acceptable salt, prodrug or solvate thereof, wherein:
• X is oxygen or sulfur;
• R2a is hydrogen or fluoro;
• R3 is hydrogen or fluoro;
• R4 is selected from the group consisting of hydrogen, optionally substituted C1-C10 alkyl, optionally substituted C2-C10 alkenyl, optionally substituted C2-C10 alkynyl, optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12cycloalkenyl, optionally substituted aryl, halo, ORc, NRdRd, C(O)ORc, NO2, CN, C(O)Rc, C(O)C(O)Rc, C(O)NRdRd, NRdC(O)Rc, NRdS(O)nRc, N(Rd)(COORc), NRdC(O)C(O)Rc, NRdC(O)NRdRd, NRdS(O)nNRdRd, NRdS(O)nRc, S(O)nRc, S(O)nNRdRd, OC(O)ORc, (C═NRd)Rc, optionally substituted heterocyclic and optionally substituted heteroaryl;
• each Rc is independently selected from the group consisting of hydrogen, optionally substituted C1-C10 alkyl, optionally substituted C2-C10 alkenyl, optionally substituted C2-C10 alkynyl, optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl and optionally substituted heteroaryl;
• each Rd is independently selected from the group consisting of hydrogen, optionally substituted C1-C10 alkyl, optionally substituted C2-C10 alkenyl, optionally substituted C2-C10 alkynyl, optionally substituted C1-C10 alkoxy, optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl and optionally substituted heteroaryl;
• or two geminal Rd groups are taken together with the nitrogen atom to which they are attached to form an optionally substituted heterocyclic or an optionally substituted heteroaryl;
• each n is independently 0, 1 or 2;
• and
• p is 1 or 2;
• provided that the compound is not N-[2-(5-ethyl-1,3,4-thiadiazol-2-yl)ethyl]-5-phenyl-3-isoxazolecarboxamide.

A compound represented by formula (II):

• or a pharmaceutically acceptable salt, prodrug or solvate thereof, wherein:
• X is oxygen or sulfur;
• R21, R22, R23, R24, and R25 are each independently selected from hydrogen or fluoro;
• R3 is hydrogen or fluoro;
• L1 is C2-3alkylene, optionally substituted by one, two or three substituents selected from the group consisting of halogen, hydroxyl, C1-3alkyl (optionally substituted by one, two or three substituents each selected independently from Rff);
• R44 is selected from the group consisting of halogen, hydroxyl, C1-6alkyl, C1-6alkoxy, C2-6alkenyl, C2-6alkynyl, and C3-7cycloalkyl, wherein C1-6alkyl is substituted by one, two or three substituents each independently selected from Rgg, and each of C1-6alkoxy, C2-6alkenyl, C2-6alkynyl, and C3-7cycloalkyl may be optionally substituted by one, two or three substituents each independently selected from Rgg;
• Rgg is selected from the group consisting of halogen, C1-6alkyl, C1-6alkoxy, hydroxyl, C(O)OH, —C(O)OC1-6alkyl, —O—C3-6cycloalkyl, —O-heterocycle, —O-heteroaryl, —O-phenyl, CN, N3, —NR′R″, —NR′—S(O)w—C1-3alkyl, S(O)w—NR′R″, and —S(O)w—C1-3alkyl, where w is 0, 1, or 2;
• Rff is selected for each occurrence from group consisting of halogen, hydroxyl, C1-4alkyl, C1-4alkoxy, C2-4alkenyl, C3-6cycloalkyl, —NR′R″, —NR′—S(O)w—C1-3alkyl, S(O)w—NR′R″, and —S(O)w—C1-3alkyl, where w is 0, 1, or 2, wherein C1-4alkyl, C1-4alkyoxy, C2-4alkenyl and C3-6cycloalkyl may be optionally substituted by one, two or three substituents each independently selected from the group consisting of halogen, hydroxyl, —NR′R″, —NR′—S(O)w—C1-3alkyl, S(O)w—NR′R″, and —S(O)w—C1-3alkyl;
• and
• R′ and R″ are each independently selected for each occurrence from H and C1-4alkyl or taken together with the nitrogen to which they are attached form a heterocyclic ring.