Modulators of cystic fibrosis transmembrane conductance regulator

1. A compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein, independently for each occurrence:

Ring A is pyridine;

Ring B is phenyl;

Ring C is pyrrolidine;

W is O;

X is O;

Y is a bond;

Z is NH;

R 1 is halo; CN; F 5 S; SiR 3 ; OH; NRR; C 1 -C 6 alkyl or fluoroalkyl; C 1 -C 6 alkoxy or fluoroalkoxy; C 1 -C 6 alkenyl; C 1 -C 6 alkynyl; (C 1 -C 9 alkylene)-R 4 wherein up to four CH 2 units are independently replaced with O, CO, S, SO, SO 2 , or NR; C 6 -C 10 aryl; C 3 -C 10 heteroaryl or heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; or C 3 -C 10 cycloalkyl;

R 2 is halo; OH; NRR; azide; CN; CO 2 R; C 1 -C 6 alkyl or fluoroalkyl; C 1 -C 6 alkoxy or fluoroalkoxy; C 1 -C 6 alkenyl; C 1 -C 6 alkynyl; C 6 -C 10 aryl; C 3 -C 13 heteroaryl or heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; C 3 -C 10 cycloalkyl; or a (C 1 C 9 alkylene)-R 4 wherein up to four CH 2 units are independently replaced with O, CO, S, SO, SO 2 or NR;

or two R 2 groups taken together may form a ═CH 2 or ═O group;

R 3 is halo; CN; OH; CO 2 R; C 1 -C 6 alkyl or fluoroalkyl; C 1 -C 6 alkenyl; C 1 -C 6 alkynyl; C 1 -C 6 alkoxy or fluoroalkoxy; or C 6 -C 10 aryl; C 3 -C 10 heteroaryl or heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; C 3 -C 10 cycloalkyl; or a (C 1 -C 9 alkylene)-R 4 wherein up to four CH 2 units are independently replaced with O, CO, S, SO, SO 2 or NR;

or two R 3 groups taken together may form a ═CH 2 or ═O group;

R 4 is H; azide; CF 3 ; CHF 2 ; OR; CCH; CO 2 R; OH; C 6 -C 10 aryl, C 3 -C 10 heteroaryl or heterocycloalkyl wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; C 3 -C 10 cycloalkyl; NRR, NRCOR, CONRR, CN, halo, or SO 2 R;

R is independently H; OH; CO 2 H; CO 2 ; C 1 -C 6 alkyl; C 1 -C 6 alkyl; C 1 -C 6 alkenyl; C 1 -C 6 alkynyl; C 6 -C 10 aryl; C 3 -C 10 heteroaryl or heterocycloalkyl wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; or C 3 -C 10 cycloalkyl;

n is 0, 1, 2 or 3;

p is 0, 1, 2, or 3; and

q is 0, 1, 2, 3, 4, or 5;

is a single bond or a double bond;

provided that the moieties containing ring B and ring C are substituted at adjacent positions on ring A.

2. The compound of claim 1 , wherein R 1 is halo, CN, C 1 -C 6 aliphatic, C 1 -C 6 alkoxy, C 3 -C 8 cycloalkyl, or a phenyl, pyridyl, pyrimidine, indole, aza-indole, azetidine, or thiophene ring, wherein all rings may be substituted with halo, C 1 -C 6 aliphatic, C 1 -C 6 alkoxy, C 1 -C 6 fluoroaliphatic, C 1 -C 6 fluoroalkoxy, OH, CH 2 OH, CH 2 OCH 3 , CN, CO 2 H, amino, amido, C 3 -C 10 heteroaryl, C 3 -C 10 heterocycloalkyl, or a (C 1 -C 8 aliphatic)-R 4 wherein up to three CH 2 units may be replaced with O, CO, S, SO, SO 2 or NR.

3. The compound of claim 1 , wherein R 1 is selected from CH 3 , Cl, F, CN, OCH 3 , CF 3 , CH 2 , CH 3 , tBu, CH(CH 3 ) 2

4. The compound of claim 1 , wherein R 2 is halo, OH, CN, azide, amino, C 1 -C 6 aliphatic or fluoroaliphatic, C 1 -C 6 alkoxy or fluoroalkoxy, C 3 -C 10 mono- or bicyclic heterocyclic ring wherein up to 4 carbon atoms may be replaced with O, S, N, or NR; or a (C 1 -C 8 aliphatic)-R 4 wherein up to three CH 2 units may be replaced with O, CO, S, SO, SO 2 or NR.

5. The compound of claim 1 , wherein R 2 is Cl, F, OH, CN, N 3 , NH 2 , NH(CH 3 ), N(CH 3 ) 2 , CH 3 , CH 2 OH, CH 2 CH 3 , CH(CH 3 ) 2 , CHF 2 OCH 3 , OCF 3 , OCHF 2 , OCH(CH 3 ) 2 , C(O)CH 3 , CH 2 CH 2 OH, CH 2 NH 2 , NH(CH 2 ) 2 OH, NH(CH 2 ) 2 N(CH 3 ) 2 , NH(CH 2 ) 2 NH 2 , NH(CH 2 ) 3 NH 2 , NH(CH 2 ) 2 OCH 3 , NHCH(CH 3 ) 2 ,

or CO 2 H.

6. The compound of claim 1 , wherein R 3 is halo, CN, C 1 -C 6 aliphatic or fluoroaliphatic, C 1 -C 6 alkoxy, or C 3 -C 10 mono- or bicyclic heteroaryl or heterocycloalkyl wherein up to 4 carbon atoms may be replaced by O, S, N, or NR.

7. The compound of claim 1 , wherein R 3 is Cl, F, CN, CH 3 , OCH 3 , CF 3 , CH 2 CH 3 , CH 2 CF 3 , CH 2 CH 2 CH 3 , OCH 2 CH 3 , CH 2 OCH 3 , CH(CH 3 ) 2 , CCH, CO 2 CH 3 , tBu, ═CH 2 , ═O,

8. The compound of claim 1 , wherein n is 1.

9. The compound of claim 1 , wherein n is 2.

10. The compound of claim 1 , wherein p is 0.

11. The compound of claim 1 , wherein p is 1.

12. The compound of claim 1 , wherein p is 2.

13. A pharmaceutical composition comprising a compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein, independently for each occurrence:

Ring A is pyridine;

Ring B is phenyl;

Ring C is pyrrolidine;

W is O;

X is O;

Y is a bond;

Z is NH;

R 1 is halo; CN; F 5 S; SiR 3 ; OH; NRR; C 1 -C 6 alkyl or fluoroalkyl; C 1 -C 6 alkoxy or fluoroalkoxy; C 1 -C 6 alkenyl; C 1 -C 6 alkynyl; (C 1 -C 9 alkylene)-R 4 wherein up to four CH 2 units are independently replaced with O, CO, S, SO, SO 2 or NR; C 6 -C 10 aryl; C 3 -C 10 heteroaryl or heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; or C 3 -C 10 cycloalkyl;

R 2 is halo; OH; NRR; azide; CN; CO 2 R; C 1 -C 6 alkyl or fluoroalkyl;C 1 -C 6 alkoxy or fluoroalkoxy;C 1 -C 6 alkenyl; C 1 -C 6 alkynyl; C 6 -C 10 aryl; C 3 -C 13 heteroaryl or heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; C 3 -C 10 cycloalkyl; or a (C 1 -C 9 alkylene)-R 4 wherein up to four CH 2 units are independently replaced with O, CO, S, SO, SO 2 or NR;

or two R 2 groups taken together may form a ═CH 2 or ═O group;

R 3 is halo; CN; OH; CO 2 R; C 1 -C 6 alkyl or fluoroalkyl; C 1 -C 6 alkenyl; C 1 -C 6 alkynyl; C 1 -C 6 alkoxy or fluoroalkoxy; or C 6 -C 10 aryl; C 3 -C 10 heteroaryl or heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; C 3 -C 10 cycloalkyl; or a (C 1 -C 9 alkylene)-R 4 wherein up to four CH 2 units are independently replaced with O, CO, S, SO, SO 2 or NR:

or two R 3 groups taken together may form a ═CH 2 or ═O group;

R 4 is H; azide; CF 3 ; CHF 2 ; OR; CCH; CO 2 R; OH; C 6 -C 10 aryl, C 3 -C 10 heteroaryl or heterocycloalkyl wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; C 3 -C 10 cycloalkyl; NRR, NRCOR, CONRR, CN, halo, or SO 2 R;

R is independently H; OH; CO 2 H; CO 2 C 1 -C 6 alkyl; C 1 -C 6 alkyl; C 1 -C 6 alkenyl; C 1 -C 6 alkynyl; C 6 -C 10 aryl; C 3 -C 10 heteroaryl or heterocycloalkyl wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; or C 3 -C 10 cycloalkyl;

n is 0, 1, 2 or 3;

p is 0, 1, 2, or 3; and

q is 0, 1, 2, 3, 4, or 5;

is a single bond or a double bond;

provided that the moieties containing ring B and ring C are substituted at adjacent positions on ring A; and

a pharmaceutically acceptable carrier.

14. The pharmaceutical composition of claim 13 , further comprising one or more additional therapeutic agent(s).

15. The pharmaceutical composition of claim 14 , wherein the additional therapeutic agent is a mucolytic agent, bronchodialator, an antibiotic, an anti-infective agent, a CFTR modulator, or an anti-inflammatory agent.

16. The pharmaceutical composition of claim 14 , wherein the additional therapeutic agent is a CFTR modulator.

17. The pharmaceutical composition of claim 14 , wherein the additional therapeutic agent is a CFTR corrector.

18. The pharmaceutical composition of claim 14 , wherein the additional therapeutic agent is

or pharmaceutically acceptable salt thereof.

19. The pharmaceutical composition of claim 14 , wherein the additional therapeutic agent is

or pharmaceutically acceptable salt thereof.

20. The pharmaceutical composition of claim 14 , wherein the additional therapeutic agent is

or pharmaceutically acceptable salt thereof.

21. The pharmaceutical composition of claim 14 , wherein the additional therapeutic agent is a CFTR potentiator.

22. The pharmaceutical composition of claim 14 , wherein the additional therapeutic agent is

or pharmaceutically acceptable salt thereof.

23. The pharmaceutical composition of claim 14 , wherein the additional therapeutic agents are a CFTR corrector and a CFTR potentiator.

24. The pharmaceutical composition of claim 14 , wherein the additional therapeutic agents are

or pharmaceutically acceptable salts thereof.

25. The pharmaceutical composition of claim 14 , wherein the additional therapeutic agents are

or pharmaceutically acceptable salts thereof.

26. The pharmaceutical composition of claim 14 , wherein the additional therapeutic agents are

or pharmaceutically acceptable salts thereof.

27. A kit comprising a compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein, independently for each occurrence:

Ring A is pyridine;

Ring B is phenyl;

Ring C is pyrrolidine;

W is O;

X is O;

Y is a bond;

Z is NH;

R 1 is halo; CN; F 5 S; SiR 3 ; OH; NRR; C 1 -C 6 alkyl or fluoroalkyl; C 1 -C 6 alkoxy or fluoroalkoxy; C 1 -C 6 alkenyl; C 1 -C 6 alkynyl; (C 1 -C 9 alkylene)-R 4 wherein up to four CH 2 units are independently replaced with O, CO, S, SO, SO 2 or NR; C 6 -C 10 aryl; C 3 -C 10 heteroaryl or heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; or C 3 -C 10 cycloalkyl;

R 2 is halo; OH; NRR; azide; CN; CO 2 R; C 1 -C 6 alkyl or fluoroalkyl; C 1 -C 6 alkoxy or fluoroalkoxy; C 1 -C 6 alkenyl; C 1 -C 6 alkynyl; C 6 -C 10 aryl; C 3 -C 13 heteroaryl or heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; C 3 -C 10 cycloalkyl; or a (C 1 -C 9 alkylene)-R 4 wherein up to four CH 2 units are independently replaced with O, CO, S, SO SO 2 or NR;

or two R 2 groups taken together may form a ═CH 2 or ═O group;

R 3 is halo; CN; OH; CO 2 R; C 1 -C 6 alkyl or fluoroalkyl; C 1 -C 6 alkenyl; C 1 -C 6 alkynyl; C 1 -C 6 alkoxy or fluoroalkoxy; or C 6 -C 10 aryl; C 3 -C 10 heteroaryl or heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; C 3 -C 10 cycloalkyl; or a (C 1 -C 9 alkylene)-R 4 wherein up to four CH 2 units are independently replaced with O, CO, S, SO, SO 2 or NR;

or two R 3 groups taken together may form a ═CH 2 or ═O group;

R 4 is H; azide; CF 3 ; CHF 2 ; OR; CCH; CO 2 R; OH; C 6 -C 10 aryl, C 3 -C 10 heteroaryl or heterocycloalkyl wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; C 3 -C 10 cycloalkyl; NRR, NRCOR, CONRR, CN, halo, or SO 2 R;

R is independently H; OH; CO 2 H; CO 2 ; C 1 -C 6 alkyl; C 1 -C 6 alkyl; C 1 -C 6 alkenyl; C 1 -C 6 alkynyl; C 6 -C 10 aryl; C 3 -C 10 heteroaryl or heterocycloalkyl wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; or C 3 -C 10 cycloalkyl;

n is 0, 1, 2, or 3;

p is 0, 1, 2, or 3; and

q is 0, 1, 2, 3, 4, or 5;

is a single bond or a double bond;

provided that the moieties containing ring B and ring C are substituted at adjacent positions on ring A.

28. The kit of claim 27 , further comprising one or more additional therapeutic agent(s).

29. The kit of claim 28 , wherein the additional therapeutic agent is a mucolytic agent, bronchodialator, an antibiotic, an anti-infective agent, a CFTR modulator, or an anti-inflammatory agent.

30. The kit of claim 28 , wherein the additional therapeutic agent is a CFTR modulator.

31. The kit of claim 28 , wherein the additional therapeutic agent is a CFTR corrector.

32. The kit of claim 28 , wherein the additional therapeutic agent is

or a pharmaceutically acceptable salt thereof.

33. The kit of claim 28 , wherein the additional therapeutic agent is

or a pharmaceutically acceptable salt thereof.

34. The kit of claim 28 , wherein the additional therapeutic agent is

or a pharmaceutically acceptable salt thereof.

35. The kit of claim 28 , wherein the additional therapeutic agent is a CFTR potentiator.

36. The kit of claim 28 , wherein the additional therapeutic agent is

or a pharmaceutically acceptable salt thereof.

37. The kit of claim 28 , wherein the additional therapeutic agents are a CFTR corrector and a CFTR potentiator.

38. The kit of claim 28 , wherein the additional therapeutic agents are

or pharmaceutically acceptable salts thereof.

39. The kit of claim 28 , wherein the additional therapeutic agents are

or pharmaceutically acceptable salts thereof.

40. The kit of claim 28 , wherein the additional therapeutic agents are

or pharmaceutically acceptable salts thereof.

41. The kit of claim 28 , wherein the compound of claim 1 and the one or more additional therapeutic agent(s) are in separate containers.

42. The kit of claim 28 , wherein the compound of claim 1 and the one or more additional therapeutic agent(s) are in the same container.

43. The kit of claim 28 , wherein the container(s) is a bottle, vial, or blister pack, or combination thereof.

44. A compound, wherein the compound is:

395

620

1114

1171

1184

1356

1396

1452

1515

1538

1581

1750

1836

1868

1876

1885

2092

2133

2246

2277

2411

2560

2706

or a pharmaceutically acceptable salt thereof.

45. A compound, wherein the compound has the following formula:

46. A pharmaceutically acceptable salt of a compound having the following formula:

47. A pharmaceutical composition comprising:

(i) a compound according to claim 45 ; and

(ii) a pharmaceutically acceptable carrier.

48. A pharmaceutical composition comprising:

(i) a pharmaceutically acceptable salt according to claim 46 ; and

(ii) a pharmaceutically acceptable carrier.

49. The pharmaceutical composition of claim 47 , further comprising an additional therapeutic agent having the following structural formula:

or a pharmaceutically acceptable salt thereof.

50. The pharmaceutical composition of claim 47 , further comprising an additional therapeutic agent having the following structural formula:

or a pharmaceutically acceptable salt thereof.

51. The pharmaceutical composition of claim 47 , further comprising additional therapeutic agents having the following structural formulae:

or pharmaceutically acceptable salts thereof.

52. The pharmaceutical composition of claim 48 , further comprising an additional therapeutic agent having the following structural formula:

or a pharmaceutically acceptable salt thereof.

53. The pharmaceutical composition of claim 48 , further comprising an additional therapeutic agent having the following structural formula:

or a pharmaceutically acceptable salt thereof.

54. The pharmaceutical composition of claim 48 , further comprising additional therapeutic agents having the following structural formulae:

or pharmaceutically acceptable salts thereof.

55. A compound, wherein the compound has the following formula:

56. A pharmaceutically acceptable salt of a compound having the following formula:

57. A pharmaceutical composition comprising:

(i) a compound according to claim 55 ; and

(ii) a pharmaceutically acceptable carrier.

58. A pharmaceutical composition comprising:

(i) a pharmaceutically acceptable salt according to claim 56 ; and

(ii) a pharmaceutically acceptable carrier.

59. The pharmaceutical composition of claim 57 , further comprising an additional therapeutic agent having the following structural formula:

or a pharmaceutically acceptable salt thereof.

60. The pharmaceutical composition of claim 57 , further comprising an additional therapeutic agent having the following structural formula:

or a pharmaceutically acceptable salt thereof.

61. The pharmaceutical composition of claim 57 , further comprising additional therapeutic agents having the following structural formulae:

or pharmaceutically acceptable salts thereof.

62. The pharmaceutical composition of claim 58 , further comprising an additional therapeutic agent having the following structural formula:

or a pharmaceutically acceptable salt thereof.

63. The pharmaceutical composition of claim 58 , further comprising an additional therapeutic agent having the following structural formula:

or a pharmaceutically acceptable salt thereof.

64. The pharmaceutical composition of claim 58 , further comprising additional therapeutic agents having the following structural formulae:

or pharmaceutically acceptable salts thereof.

65. A compound, wherein the compound has the following formula:

66. A pharmaceutically acceptable salt of a compound having the following formula:

67. A pharmaceutical composition comprising:

(i) a compound according to claim 65 ; and

(ii) a pharmaceutically acceptable carrier.

68. A pharmaceutical composition comprising:

(i) a pharmaceutically acceptable salt according to claim 66 ; and

(ii) a pharmaceutically acceptable carrier.

69. The pharmaceutical composition of claim 67 , further comprising an additional therapeutic agent having the following structural formula:

or a pharmaceutically acceptable salt thereof.

70. The pharmaceutical composition of claim 67 , further comprising an additional therapeutic agent having the following structural formula:

or a pharmaceutically acceptable salt thereof.

71. The pharmaceutical composition of claim 67 , further comprising additional therapeutic agents having the following structural formulae:

or pharmaceutically acceptable salts thereof.

72. The pharmaceutical composition of claim 68 , further comprising an additional therapeutic agent having the following structural formula:

or a pharmaceutically acceptable salt thereof.

73. The pharmaceutical composition of claim 68 , further comprising an additional therapeutic agent having the following structural formula:

or a pharmaceutically acceptable salt thereof.

74. The pharmaceutical composition of claim 68 , further comprising additional therapeutic agents having the following structural formulae:

or pharmaceutically acceptable salts thereof.

75. A compound, wherein the compound has the following formula:

76. A pharmaceutically acceptable salt of a compound having the following formula:

77. A pharmaceutical composition comprising:

(i) a compound according to claim 75 ; and

(ii) a pharmaceutically acceptable carrier.

78. A pharmaceutical composition comprising:

(i) a pharmaceutically acceptable salt according to claim 76 ; and

(ii) a pharmaceutically acceptable carrier.

79. The pharmaceutical composition of claim 77 , further comprising an additional therapeutic agent having the following structural formula:

or a pharmaceutically acceptable salt thereof.

80. The pharmaceutical composition of claim 77 , further comprising an additional therapeutic agent having the following structural formula:

or a pharmaceutically acceptable salt thereof.

81. The pharmaceutical composition of claim 77 , further comprising additional therapeutic agents having the following structural formulae:

or pharmaceutically acceptable salts thereof.

82. The pharmaceutical composition of claim 78 , further comprising an additional therapeutic agent having the following structural formula:

or a pharmaceutically acceptable salt thereof.

83. The pharmaceutical composition of claim 78 , further comprising an additional therapeutic agent having the following structural formula:

or a pharmaceutically acceptable salt thereof.

84. The pharmaceutical composition of claim 78 , further comprising additional therapeutic agents having the following structural formulae:

or pharmaceutically acceptable salts thereof.