COMPOUNDS, COMPOSITIONS, AND METHODS FOR INCREASING CFTR ACTIVITY

摘要

The invention encompasses compounds such as compounds having the Formula (I) or (II), compositions thereof, and methods of modulating CFTR activity. The invention also encompasses methods of treating a condition associated with CFTR activity or condition associated with a dysfunction of proteostasis comprising administering to a subject an effective amount of a disclosed compound.

主权项

1. 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, NRd (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; andp is 1 or 2;provided that the compound is not N-[2-(5-phenyl-1,3,4-oxadiazol-2-yl)ethyl]-5-phenyl-3-isoxazolecarboxamide, N-[2-(5-methyl-1,3,4-thiadiazol-2-yl)ethyl]-5-phenyl-3-isoxazolecarboxamide, N-[2-(5-ethyl-1,3,4-thiadiazol-2-yl)ethyl]-5-phenyl-3-isoxazolecarboxamide, or N-(3-(5-amino-1,3,4-thiadiazol-2-yl)propyl)-5-phenylisoxazole-3-carboxamide.