Modulators of cystic fibrosis transmembrane conductance regulator

A compound of formula I:

• or a pharmaceutically acceptable salt thereof, wherein, independently for each occurrence:
• Ring A is a C6-C10 aryl ring;
• a C3-C10 cycloalkyl ring;
• or a C3-C14 heteroaryl or heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR;
• Ring B is a C3-C10 cycloalkyl ring;
• a C6-C10 aryl ring;
• or a C3-C10 heteroaryl or C3-C10 heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR;
• W is O, S, or NR;
• X is O or NR;
• Z is NR or C(R)2;
• R1 is halo;
• CN;
• NRR;
• C1-C6 alkyl or C1-C6 fluoroalkyl;
• C3-C6 cycloalkyl;
• C1-C8 alkoxy or C1-C8 fluoroalkoxy;
• C2-C6 alkenyl;
• C2-C6 alkynyl;
• (C1-C9 alkylene)-R3 wherein up to four CH2 units are independently replaced with O, CO, S, SO, SO2 or NR;
• C6-C10 aryl;
• C3-C10 heteroaryl or C3-C10 heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR;
• or C3-C10 cycloalkyl;
• R2 is halo;
• NRR;
• CN;
• CO2R;
• C1-C6 alkyl or C1-C6 fluoroalkyl;
• C1-C6 alkoxy or C1-C6 fluoroalkoxy;
• C2-C6 alkenyl;
• C2-C6 alkynyl;
• C6-C10 aryl;
• C3-C13 heteroaryl or heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR;
• C3-C10 cycloalkyl;
• or a (C1-C9 alkylene)-R3 wherein up to four CH2 units are optionally and independently replaced with O, CO, S, SO, SO2 or NR;
• or two R2 may form a ═CH2 or ═O group;
• R3 is H;
• CF3;
• CHF2;
• OR;
• C≡CH;
• CO2R;
• OH;
• C6-C10 aryl, C3-C10 heteroaryl or heterocycloalkyl wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR;
• C3-C10 cycloalkyl;
• NRR, NRCOR, CONRR, CN, halo, or SO2R;
• R is independently H;
• OH;
• CO2H;
• CO2C1-C6 alkyl;
• C1-C6 alkyl;
• C2-C6 alkenyl;
• C2-C6 alkynyl;
• C6-C10 aryl;
• C3-C10 heteroaryl or heterocycloalkyl wherein anywhere from 1 to 4 ring atoms are independently O, S, or N;
• or C3-C10 cycloalkyl;
• n is 2 or 3;
• p is 0, 1, 2, or 3;
• and
• Provided that 1) when R1 is adjacent to the C═W attached to Ring A, R1 does not contain a ring moiety, 2) at least one R1 is adjacent to the C═W attached to Ring A, and at least one R1 is C1-C6 alkyl or C1-C6 fluoroalkyl, C6-C10 aryl;
• C3-C10 heteroaryl or C3-C10 heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR;
• or C3-C10 cycloalkyl;
• 3) when Ring A is phenyl or six-membered mono-heteroaryl wherein anywhere from 1 to 3 ring atoms are N, R1 is not 4,5-dihydroisoxazole;
• 4) when Ring A is phenyl, R1 is not
• ureido, or aminocarbonyl;
• 5) when Ring A and the at least one R1 is pyridine, R1 (pyridine) is not further substituted by —CONHSO2—;
• and 6) when Ring A is pyridine or thiazole, and C═W wherein W is O in formula I is adjacent to the N on the pyridine or thiazole, R1 which is adjacent to the N on the pyridine or on the thiazole is not

A method of treating cystic fibrosis in a patient comprising administering to the patient in need thereof an effective amount of

• 1) a compound of formula II or a pharmaceutically acceptable salt thereof, or
• 2) a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of formula II or a pharmaceutically acceptable salt thereof:
• wherein, independently for each occurrence:
• Ring A is a C6-C10 aryl ring;
• C3-C10 cycloalkyl ring;
• or a C3-C14 heteroaryl or heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR;
• Ring B is a C3-C10 cycloalkyl ring;
• a C6-C10 aryl ring;
• or a C3-C10 heteroaryl or C3-C10 heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR;
• W is O, S, or NR;
• X is O or NR;
• Z is NR;
• R1 is halo;
• CN;
• NRR;
• C1-C6 alkyl or C1-C6 fluoroalkyl;
• C3-C6 cycloalkyl;
• C1-C8 alkoxy or C1-C8 fluoroalkoxy;
• C2-C6 alkenyl;
• C2-C6 alkynyl;
• (C1-C9 alkylene)-R3 wherein up to four CH2 units are independently replaced with O, CO, S, SO, SO2 or NR;
• C6-C10 aryl;
• C3-C10 heteroaryl or C3-C10 heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR;
• or C3-C10 cycloalkyl;
• R2 is halo;
• NRR;
• CN;
• CO2R;
• C1-C6 alkyl or C1-C6 fluoroalkyl;
• C1-C6 alkoxy or C1-C6 fluoroalkoxy;
• C2-C6 alkenyl;
• C2-C6 alkynyl;
• C6-C10 aryl;
• C3-C13 heteroaryl or heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR;
• C3-C10 cycloalkyl;
• or a (C1-C9 alkylene)-R3 wherein up to four CH2 units are optionally and independently replaced with O, CO, S, SO, SO2 or NR;
• or two R2 may form a ═CH2 or ═O group;
• R3 is H;
• CF3;
• CHF2;
• OR;
• C≡CH;
• CO2R;
• OH;
• C6-C10 aryl, C3-C10 heteroaryl or heterocycloalkyl wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR;
• C3-C10 cycloalkyl;
• NRR, NRCOR, CONRR, CN, halo, or SO2R;
• R is independently H;
• OH;
• CO2H;
• CO2C1-C6 alkyl;
• C1-C6 alkyl;
• C2-C6 alkenyl;
• C2-C6 alkynyl;
• C6-C10 aryl;
• C3-C10 heteroaryl or heterocycloalkyl wherein anywhere from 1 to 4 ring atoms are independently O, S, or N;
• or C3-C10 cycloalkyl;
• n is 2 or 3;
• p is 0, 1, 2, or 3;
• and
• provided that 1) when R1 is adjacent to C═W attached to Ring A, R1 does not contain a ring moiety, and 2) at least one R1 is adjacent to the C═W attached to Ring A.