Patent ID: 8741939

Claim:
A method of modulating CFTR activity, comprising the step of contacting said CFTR with a compound of formula (II) or (III): or a pharmaceutically acceptable salt thereof; wherein: X 1 is a bond, O, S, CF 2 , CH 2 , or NR; R is H or R 2 A 1 is aryl, or heteroaryl; each B 1 is independently selected from 3-7 membered monocyclic, saturated, unsaturated or aromatic ring containing 0-4 heteroatoms selected from N, NH, S, or O; wherein each A 1 is optionally substituted with up to 4 substituents independently selected from R 1 , R 2 , R 3 , R 4 , or R 5 ; R 1 is R 6 or ((C1-C4)aliphatic) n -Y; n is 0 or 1; Y is halo, CN, CF 3 , OCF 3 , OH, NH 2 , NHR 6 , N(R 6 ) 2 , COOH, COOR 6 or OR 6 ; or two R 1 on adjacent ring atoms, taken together, form 1,2-methylenedioxy or 1,2-ethylenedioxy; R 2 is aliphatic, wherein each R 2 is optionally substituted with up to 2 substituents independently selected from R 1 , R 4 , or R 5 ; R 3 is a cycloaliphatic, aryl, heterocyclic, or heteroaryl ring optionally substituted with up to 3 substituents, independently selected from R 1 , R 2 , R 4 or R 5 ; R 4 is OR 5 , C(O)R 5 , C(O)OR 5 , C(O)R 6 , C(O)OR 6 , C(O)N(R 6 ) 2 , C(O)N(R 5 ) 2 , or C(O)N(R 5 R 6 ); R 5 is a cycloaliphatic, aryl, heterocyclic, or heteroaryl ring, optionally substituted with up to 3 R 1 substituents; and R 6 is H or aliphatic provided that for compounds of formula (II): (i) when both B 1 are simultaneously phenyl and X 1 is CH 2 , then A 1 is not 4-fluoro-phenyl, 4-phenyl-piperidyl, phenyl, 2,4-dichloro-phenyl, 4-methoxy-phenyl, 3,4-dichloro-phenyl, 2,5-dichloro-phenyl, 4-nitro-phenyl, 4-bromo-phenyl, 4-methyl-phenyl, 2-chloro-phenyl, 1-naphthyl, 3-trifluoromethyl-phenyl, 2,3-dichlorophenyl, N-morpholinyl, 4-chloro-phenyl, 3-chloro-phenyl, or 3-nitro-phenyl; (ii) when X 1 is a bond or CH 2 , one B 1 is a substituted phenyl and the other B 1 is cycloaliphatic, then A 1 is not (C2-C8)aliphatic; and (iii) when X 1 is a bond, then A 1 is not an optionally substituted 6-membered heteroaryl ring with 1-3 nitrogen ring atoms; and provided that for compounds of formula (III): (i) when X 1 is a bond, one B 1 is phenyl and the other B 1 is N-piperidyl, then A 1 is not: and (ii) when X 1 is a bond, then A 1 is not an optionally substituted 6-membered heteroaryl ring with 1-3 nitrogen ring atoms.