Modulators of Cystic Fibrosis Transmembrane Conductance Regulator

• US 20160095858A1
• Filed: 10/06/2015
• Published: 04/07/2016
• Est. Priority Date: 10/06/2014
• Status: Active Grant

• Current Assignee: Vertex Pharmaceuticals Incorporated
• Original Assignee: Vertex Pharmaceuticals Incorporated
• Inventors: Miller, Mark Thomas, Anderson, Corey, Arumugam, Vijayalaksmi, Bear, Brian Richard, Binch, Hayley Marie, Cleveland, Thomas, Coon, Timothy Richard, Frieman, Bryan A., Grootenhuis, Peter Diederik Jan, Hadida-Ruah, Sara Sabina, McCartney, Jason, Silina, Alina, Termin, Andreas P., Uy, Johnny, Zhou, Jinglan, Clemens, Jeremy J., Conroy, Erica, Gross, Raymond Stanley, Haripada, Khatuya, Joshi, Pramod Virupax, Krenitsky, Paul John, Lin, Chun-Chieh, Marelius, Gulin Erdgogan, Melillo, Vito, Nicholls, Georgia McGaughey, Pierre, Fabrice Jean Denis
• Granted Patent: US 9,782,408 B2
• Time in Patent Office: Days
• US Class Current: 1/1
• CPC Class Codes: A61J 1/035 Blister-type containers blisters in general B65D75/36
• CPC Class Codes: A61K 31/404 Indoles, e.g. pindolol
• CPC Class Codes: A61K 31/415 1,2-Diazoles
• CPC Class Codes: A61K 31/44 Non condensed pyridines; Hydrogenated derivatives thereof
• CPC Class Codes: A61K 31/4418 having a carbocyclic group directly attached to the heterocyclic ring, e.g. cyproheptadine
• CPC Class Codes: A61K 31/4439 containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole nicotine A61K31/465
• CPC Class Codes: A61K 31/444 containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
• CPC Class Codes: A61K 31/4525 containing a five-membered ring with oxygen as a ring hetero atom
• CPC Class Codes: A61K 31/4545 containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
• CPC Class Codes: A61K 31/4709 Non-condensed quinolines and containing further heterocyclic rings
• CPC Class Codes: A61K 31/496 Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
• CPC Class Codes: A61K 31/497 containing further heterocyclic rings
• CPC Class Codes: A61K 31/506 not condensed and containing further heterocyclic rings
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 209/18 Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 209/42 Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 209/49 and having in the molecule an acyl radical containing a saturated three-membered ring, e.g. chrysanthemumic acid esters
• CPC Class Codes: C07D 213/64 attached in position 2 or 6
• CPC Class Codes: C07D 213/73 Unsubstituted amino or imino radicals
• CPC Class Codes: C07D 213/82 : in position 3
• CPC Class Codes: C07D 213/84 : Nitriles
• CPC Class Codes: C07D 231/12 : with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 231/14 : with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 231/20 : One oxygen atom attached in position 3 or 5
• CPC Class Codes: C07D 235/24 : with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
• CPC Class Codes: C07D 239/34 : One oxygen atom
• CPC Class Codes: C07D 401/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 401/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 401/14 : containing three or more hetero rings
• CPC Class Codes: C07D 403/10 : linked by a carbon chain containing aromatic rings
• CPC Class Codes: C07D 403/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 405/14 : containing three or more hetero rings
• CPC Class Codes: C07D 407/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 413/14 : containing three or more hetero rings
• CPC Class Codes: C07D 417/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: Y02A 50/30 : Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

The present invention features a compound of formula I:

or a pharmaceutically acceptable salt thereof, where R₁, R₂, R₃, W, X, Y, Z, n, o, p, and q are defined herein, for the treatment of CFTR mediated diseases, such as cystic fibrosis. The present invention also features pharmaceutical compositions, method of treating, and kits thereof.

Claims

1. A compound of formula I:

2. The compound of claim 1, wherein ring A is a pyridyl, indole, indoline, isoindoline, pyrazole, pyrimidine, phenyl, quinoline, 5,6,7,8-tetrahydroquinoline, 1,2,3,4-tetrahydroisoquinoline, pyrrolidine, aza-indole, pyrrole, oxazole, pyrazine, triazole, benzimidazole, indazole, or imidazole ring.

3. The compound of claim 1, wherein ring A is selected from

4. The compound of claim 1, wherein ring B is phenyl, pyridyl, pyridine-2(1H)-one, pyrazole, indole, thiophene, dihydrobenzofuran, pyrazine, indazole, thiazole, pyridine-4(1H)-one, pyrrolidinone, or quinoline.

5. The compound of claim 1, wherein ring B is selected from

6. The compound of claim 1, wherein ring C is phenyl, indole, cycloalkyl, pyridyl, pyrrolidine, naphthalene, piperidine, azetidine, or dihydroindene.

7. The compound of claim 1, wherein ring C is

8. The compound of claim 1, wherein Y is O.

9. The compound of claim 1, wherein Y is CH₂.

10. The compound of claim 1, wherein Y is CH(C1-C6 aliphatic).

11. The compound of claim 1, wherein Y is CH(CH₃).

12. The compound of claim 1, wherein Y is CH(CH₂CH₃).

13. The compound of claim 1, wherein Y is N(C1-C6 aliphatic).

14. The compound of claim 1, wherein Y is N(CH₃).

15. The compound of claim 1, wherein R₁ is halo, CN, C1-C6 aliphatic, C1-C6 alkoxy, C3-C8 cycloalkyl, or a phenyl, pyridyl, pyrimidine, indole, aza-indole, azetidine, or thiophene ring, wherein all rings may be substituted with halo, C1-C6 aliphatic, C1-C6 alkoxy, C1-C6 fluoroaliphatic, C1-C6 fluoroalkoxy, OH, CH₂OH, CH₂OCH₃, CN, CO₂H, amino, amido, C3-C10 heteroaryl, C3-C10 heterocycloalkyl, or a (C1-C8 aliphatic)-R₄ wherein up to three CH₂ units may be replaced with O, CO, S, SO, SO₂ or NR.

16. The compound of claim 1, wherein R₁ is selected from CH₃, Cl, F, CN, OCH₃, CF₃, CH₂CH₃, tBu, CH(CH₃)₂,

17. The compound of claim 1, wherein R₂ is selected from halo, OH, CN, azide, amino, C1-C6 aliphatic or fluoroaliphatic, C1-C6 alkoxy or fluoroalkoxy, C3-C10 mono- or bicyclic heterocyclic ring wherein up to 4 carbon atoms may be replaced with O, S, N, or NR;

or a (C1-C8 aliphatic)-R₄ wherein up to three CH₂ units may be replaced with O, CO, S, SO, SO₂ or NR.

18. The compound of claim 1, wherein R₂ is selected from Cl, F, OH, CN, N₃, NH₂, NH(CH₃), N(CH₃)₂, CH₃, CH₂OH, CH₂CH₃, CH(CH₃)₂, CHF₂, OCH₃, OCF₃, OCHF₂, OCH(CH₃)₂, C(O)CH₃, CH₂CH₂OH, CH₂NH₂, NH(CH₂)₂OH, NH(CH₂)₂N(CH₃)₂, NH(CH₂)₂NH₂, NH(CH₂)₃NH₂, NH(CH₂)₂OCH₃, NHCH(CH₃)₂,

19. The compound of claim 1, wherein R₃ is selected from halo, CN, C1-C6 aliphatic or fluoroaliphatic, C1-C6 alkoxy, or C3-C10 mono- or bicyclic heteroaryl or heterocycloalkyl wherein up to 4 carbon atoms may be replaced by O, S, N, or NR.

20. The compound of claim 1, wherein R₃ is selected from Cl, F, CN, CH₃, OCH₃, CF₃, CH₂CH₃, CH₂CF₃, CH₂CH₂CH₃, OCH₂CH₃, CH₂OCH₃, CH(CH₃)₂, CCH, CO₂CH₃, tBu, ═

CH₂, ═

O,

21. The compound of claim 1, wherein o is 0.

22. The compound of claim 1, wherein o is 1.

23. The compound of claim 1, wherein o is 2.

24. The compound of claim 1, wherein n is 0.

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

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

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

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

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

30. The compound of claim 1, wherein the compound is of formula Ia:

31. The compound of claim 30, wherein ring B is phenyl, pyridyl, pyridine-2(1H)-one, pyrazole, indole, thiophene, dihydrobenzofuran, pyrazine, indazole, thiazole, pyridine-4(1H)-one, pyrrolidinone, or quinoline.

32. The compound of claim 30, wherein ring B is selected from

33. The compound of claim 30, wherein ring C is phenyl, indole, cycloalkyl, pyridyl, pyrrolidine, naphthalene, piperidine, or dihydroindene.

34. The compound of claim 30, wherein ring C is

35. The compound of claim 30, wherein Y is O.

36. The compound of claim 30, wherein Y is CH₂.

37. The compound of claim 30, wherein Y is CH(C1-C6 aliphatic).

38. The compound of claim 30, wherein Y is CH(CH₃).

39. The compound of claim 30, wherein Y is CH(CH₂CH₃).

40. The compound of claim 30, wherein R₁ is halo, CN, C1-C6 aliphatic, C1-C6 alkoxy, C3-C8 cycloalkyl, or a phenyl, pyridyl, pyrimidine, indole, aza-indole, or thiophene ring, wherein all rings may be substituted with halo, C1-C6 aliphatic, C1-C6 alkoxy, C1-C6 fluoroaliphatic, C1-C6 fluoroalkoxy, OH, CH₂OH, CH₂OCH₃, CN, CO₂H, amino, amido, C3-C10 heteroaryl, C3-C10 heterocycloalkyl, or a (C1-C8 aliphatic)-R₄ wherein up to three CH₂ units may be replaced with O, CO, S, SO, SO₂ or NR.

41. The compound of claim 30, wherein R₁ is selected from CH₃, Cl, F, CN, OCH₃, CF₃, CH₂CH₃, tBu, CH(CH₃)₂,

42. The compound of claim 30, wherein R₂ is selected from halo, OH, CN, azide, amino, C1-C6 aliphatic or fluoroaliphatic, C1-C6 alkoxy or fluoroalkoxy, C3-C10 mono- or bicyclic heterocyclic ring wherein up to 4 carbon atoms may be replaced with O, S, N, or NR;

or a (C1-C8 aliphatic)-R₄ wherein up to three CH₂ units may be replaced with O, CO, S, SO, SO₂ or NR.

43. The compound of claim 30, wherein R₂ is selected from Cl, F, OH, CN, N₃, NH₂, NH(CH₃), N(CH₃)₂, CH₃, CH₂OH, CH₂CH₃, CH(CH₃)₂, CHF₂, OCH₃, OCF₃, OCHF₂, OCH(CH₃)₂, C(O)CH₃, CH₂CH₂OH, CH₂NH₂, NH(CH₂)₂OH, NH(CH₂)₂N(CH₃)₂, NH(CH₂)₂NH₂, NH(CH₂)₃NH₂, NH(CH₂)₂OCH₃, NHCH(CH₃)₂,

44. The compound of claim 30, wherein R₃ is selected from halo, CN, C1-C6 aliphatic or fluoroaliphatic, C1-C6 alkoxy, or C3-C10 mono- or bicyclic heteroaryl wherein up to 4 carbon atoms may be replaced by O, S, N, or NR.

45. The compound of claim 30, wherein R₃ is selected from Cl, F, CN, CH₃, OCH₃, CF₃, CH₂CH₃, CH₂CF₃, CH₂CH₂CH₃, OCH₂CH₃, CH₂OCH₃, CH(CH₃)₂, CCH, CO₂CH₃, tBu, ═

CH₂, ═

O,

46. The compound of claim 30, wherein o is 0.

47. The compound of claim 30, wherein o is 1.

48. The compound of claim 30, wherein n is 0.

49. The compound of claim 30, wherein n is 1.

50. The compound of claim 30, wherein n is 2.

51. The compound of claim 30, wherein p is 0.

52. The compound of claim 30, wherein p is 1.

53. The compound of claim 30, wherein p is 2.

54. The compound of claim 30, wherein ring B is phenyl.

55. The compound of claim 30, wherein ring B and ring C are independently phenyl or pyridyl.

56. The compound of claim 1, wherein the compound is of formula Ib:

57. The compound of claim 56, wherein ring B is phenyl, pyridyl, pyridine-2(1H)-one, pyrazole, indole, thiophene, dihydrobenzofuran, pyrazine, indazole, thiazole, pyridine-4(1H)-one, pyrrolidinone, or quinoline.

58. The compound of claim 56, wherein ring B is selected from

59. The compound of claim 56, wherein ring C is phenyl, indole, cycloalkyl, pyridyl, pyrrolidine, naphthalene, or dihydroindene.

60. The compound of claim 56, wherein ring C is

61. The compound of claim 56, wherein Y is O.

62. The compound of claim 56, wherein Y is CH₂.

63. The compound of claim 56, wherein Y is CH(C1-C6 aliphatic).

64. The compound of claim 56, wherein Y is CH(CH₃).

65. The compound of claim 56, wherein Y is CH(CH₂CH₃).

66. The compound of claim 56, wherein R₁ is halo, CN, C1-C6 aliphatic, C1-C6 alkoxy, C3-C8 cycloalkyl, or a phenyl, pyridyl, pyrimidine, indole, aza-indole, or thiophene ring, wherein all rings may be substituted with halo, C1-C6 aliphatic, C1-C6 alkoxy, C1-C6 fluoroaliphatic, C1-C6 fluoroalkoxy, OH, CH₂OH, CH₂OCH₃, CN, CO₂H, amino, amido, C3-C10 heteroaryl, C3-C10 heterocycloalkyl, or a (C1-C8 aliphatic)-R₄ wherein up to three CH₂ units may be replaced with O, CO, S, SO, SO₂ or NR.

67. The compound of claim 56, wherein R₁ is selected from CH₃, Cl, F, CN, OCH₃, CF₃, CH₂CH₃, tBu, CH(CH₃)₂,

68. The compound of claim 56, wherein R₂ is selected from halo, OH, CN, azide, amino, C1-C6 aliphatic or fluoroaliphatic, C1-C6 alkoxy or fluoroalkoxy, C3-C10 mono- or bicyclic heterocyclic ring wherein up to 4 carbon atoms may be replaced with O, S, N, or NR;

or a (C1-C8 aliphatic)-R₄ wherein up to three CH₂ units may be replaced with O, CO, S, SO, SO₂ or NR.

69. The compound of claim 56, wherein R₂ is selected from Cl, F, OH, CN, N₃, NH₂, NH(CH₃), N(CH₃)₂, CH₃, CH₂OH, CH₂CH₃, CH(CH₃)₂, CHF₂, OCH₃, OCF₃, OCHF₂, OCH(CH₃)₂, C(O)CH₃, CH₂CH₂OH, CH₂NH₂, NH(CH₂)₂OH, NH(CH₂)₂N(CH₃)₂, NH(CH₂)₂NH₂, NH(CH₂)₃NH₂, NH(CH₂)₂OCH₃, NHCH(CH₃)₂,

70. The compound of claim 56, wherein R₃ is selected from halo, CN, C1-C6 aliphatic or fluoroaliphatic, C1-C6 alkoxy, or C3-C10 mono- or bicyclic heteroaryl wherein up to 4 carbon atoms may be replaced by O, S, N, or NR.

71. The compound of claim 56, wherein R₃ is selected from Cl, F, CN, CH₃, OCH₃, CF₃, CH₂CH₃, CH₂CF₃, CH₂CH₂CH₃, OCH₂CH₃, CH₂OCH₃, CH(CH₃)₂, CCH, CO₂CH₃, tBu, ═

CH₂, ═

O,

72. The compound of claim 56, wherein o is 0.

73. The compound of claim 56, wherein o is 1.

74. The compound of claim 56, wherein o is 2.

75. The compound of claim 56, wherein n is 0.

76. The compound of claim 56, wherein n is 1.

77. The compound of claim 56, wherein n is 2.

78. The compound of claim 56, wherein p is 0.

79. The compound of claim 56, wherein p is 1.

80. The compound of claim 56, wherein p is 2.

81. The compound of claim 56, wherein ring B is pyridyl.

82. The compound of claim 56, wherein ring B is phenyl.

83. The compound of claim 56, wherein ring B and ring C are phenyl.

84. The compound of claim 1, wherein the compound is of formula Ic:

85. The compound of claim 84, wherein ring B is phenyl, pyridyl, pyridine-2(1H)-one, pyrazole, indole, thiophene, dihydrobenzofuran, pyrazine, indazole, thiazole, pyridine-4(1H)-one, pyrrolidinone, or quinoline.

86. The compound of claim 84, wherein ring B is selected from

87. The compound of claim 84, wherein ring C is phenyl, indole, cycloalkyl, pyridyl, pyrrolidine, naphthalene, or dihydroindene.

88. The compound of claim 84, wherein ring C is

89. The compound of claim 84, wherein Y is O.

90. The compound of claim 84, wherein Y is CH₂.

91. The compound of claim 84, wherein Y is CH(C1-C6 aliphatic).

92. The compound of claim 84, wherein Y is CH(CH₃).

93. The compound of claim 84, wherein Y is CH(CH₂CH₃).

94. The compound of claim 84, wherein R₁ is halo, CN, C1-C6 aliphatic, C1-C6 alkoxy, C3-C8 cycloalkyl, or a phenyl, pyridyl, pyrimidine, indole, aza-indole, or thiophene ring, wherein all rings may be substituted with halo, C1-C6 aliphatic, C1-C6 alkoxy, C1-C6 fluoroaliphatic, C1-C6 fluoroalkoxy, OH, CH₂OH, CH₂OCH₃, CN, CO₂H, amino, amido, C3-C10 heteroaryl, C3-C10 heterocycloalkyl, or a (C1-C8 aliphatic)-R₄ wherein up to three CH₂ units may be replaced with O, CO, S, SO, SO₂ or NR.

95. The compound of claim 84, wherein R₁ is selected from CH₃, Cl, F, CN, OCH₃, CF₃, CH₂CH₃, tBu, CH(CH₃)₂,

96. The compound of claim 84, wherein R₂ is selected from halo, OH, CN, azide, amino, C1-C6 aliphatic or fluoroaliphatic, C1-C6 alkoxy or fluoroalkoxy, C3-C10 mono- or bicyclic heterocyclic ring wherein up to 4 carbon atoms may be replaced with O, S, N, or NR;

or a (C1-C8 aliphatic)-R₄ wherein up to three CH₂ units may be replaced with O, CO, S, SO, SO₂ or NR.

97. The compound of claim 84, wherein R₂ is selected from Cl, F, OH, CN, N₃, NH₂, NH(CH₃), N(CH₃)₂, CH₃, CH₂OH, CH₂CH₃, CH(CH₃)₂, CHF₂, OCH₃, OCF₃, OCHF₂, OCH(CH₃)₂, C(O)CH₃, CH₂CH₂OH, CH₂NH₂, NH(CH₂)₂OH, NH(CH₂)₂N(CH₃)₂, NH(CH₂)₂NH₂, NH(CH₂)₃NH₂, NH(CH₂)₂OCH₃, NHCH(CH₃)₂,

98. The compound of claim 84, wherein R₃ is selected from halo, CN, C1-C6 aliphatic or fluoroaliphatic, C1-C6 alkoxy, or C3-C10 mono- or bicyclic heteroaryl wherein up to 4 carbon atoms may be replaced by O, S, N, or NR.

99. The compound of claim 84, wherein R₃ is selected from Cl, F, CN, CH₃, OCH₃, CF₃, CH₂CH₃, CH₂CF₃, CH₂CH₂CH₃, OCH₂CH₃, CH₂OCH₃, CH(CH₃)₂, CCH, CO₂CH₃, tBu, ═

CH₂, ═

O,

100. The compound of claim 84, wherein o is 0.

101. The compound of claim 84, wherein o is 1.

102. The compound of claim 84, wherein o is 2.

103. The compound of claim 84, wherein n is 0.

104. The compound of claim 84, wherein n is 1.

105. The compound of claim 84, wherein n is 2.

106. The compound of claim 84, wherein p is 0.

107. The compound of claim 84, wherein p is 1.

108. The compound of claim 84, wherein p is 2.

109. The compound of claim 84, wherein ring B is phenyl.

110. The compound of claim 84, wherein ring C is phenyl or pyridyl.

111. The compound of claim 84, wherein ring B and ring C are phenyl.

112. The compound of claim 1, wherein the compound is of formula Id:

113. The compound of claim 112, wherein ring B is phenyl, pyridyl, pyridine-2(1H)-one, pyrazole, indole, thiophene, dihydrobenzofuran, pyrazine, indazole, thiazole, pyridine-4(1H)-one, pyrrolidinone, or quinoline.

114. The compound of claim 112, wherein ring B is selected from

115. The compound of claim 112, wherein ring C is phenyl, indole, cycloalkyl, pyridyl, pyrrolidine, naphthalene, or dihydroindene.

116. The compound of claim 112, wherein ring C is

117. The compound of claim 112, wherein Y is O.

118. The compound of claim 112, wherein Y is CH₂.

119. The compound of claim 112, wherein Y is CH(C1-C6 aliphatic).

120. The compound of claim 112, wherein Y is CH(CH₃).

121. The compound of claim 112, wherein Y is CH(CH₂CH₃).

122. The compound of claim 112, wherein R₁ is halo, CN, C1-C6 aliphatic, C1-C6 alkoxy, C3-C8 cycloalkyl, or a phenyl, pyridyl, pyrimidine, indole, aza-indole, or thiophene ring, wherein all rings may be substituted with halo, C1-C6 aliphatic, C1-C6 alkoxy, C1-C6 fluoroaliphatic, C1-C6 fluoroalkoxy, OH, CH₂OH, CH₂OCH₃, CN, CO₂H, amino, amido, C3-C10 heteroaryl, C3-C10 heterocycloalkyl, or a (C1-C8 aliphatic)-R₄ wherein up to three CH₂ units may be replaced with O, CO, S, SO, SO₂ or NR.

123. The compound of claim 112, wherein R₁ is selected from CH₃, Cl, F, CN, OCH₃, CF₃, CH₂CH₃, tBu, CH(CH₃)₂,

124. The compound of claim 112, wherein R₂ is selected from halo, OH, CN, azide, amino, C1-C6 aliphatic or fluoroaliphatic, C1-C6 alkoxy or fluoroalkoxy, C3-C10 mono- or bicyclic heterocyclic ring wherein up to 4 carbon atoms may be replaced with O, S, N, or NR;

or a (C1-C8 aliphatic)-R₄ wherein up to three CH₂ units may be replaced with O, CO, S, SO, SO₂ or NR.

125. The compound of claim 112, wherein R₂ is selected from Cl, F, OH, CN, N₃, NH₂, NH(CH₃), N(CH₃)₂, CH₃, CH₂OH, CH₂CH₃, CH(CH₃)₂, CHF₂, OCH₃, OCF₃, OCHF₂, OCH(CH₃)₂, C(O)CH₃, CH₂CH₂OH, CH₂NH₂, NH(CH₂)₂OH, NH(CH₂)₂N(CH₃)₂, NH(CH₂)₂NH₂, NH(CH₂)₃NH₂, NH(CH₂)₂OCH₃, NHCH(CH₃)₂,

126. The compound of claim 112, wherein R₃ is selected from halo, CN, C1-C6 aliphatic or fluoroaliphatic, C1-C6 alkoxy, or C3-C10 mono- or bicyclic heteroaryl wherein up to 4 carbon atoms may be replaced by O, S, N, or NR.

127. The compound of claim 112, wherein R₃ is selected from Cl, F, CN, CH₃, OCH₃, CF₃, CH₂CH₃, CH₂CF₃, CH₂CH₂CH₃, OCH₂CH₃, CH₂OCH₃, CH(CH₃)₂, CCH, CO₂CH₃, tBu, ═

CH₂, ═

O,

128. The compound of claim 112, wherein o is 0.

129. The compound of claim 112, wherein o is 1.

130. The compound of claim 112, wherein o is 2.

131. The compound of claim 112, wherein n is 0.

132. The compound of claim 112, wherein n is 1.

133. The compound of claim 112, wherein n is 2.

134. The compound of claim 112, wherein p is 0.

135. The compound of claim 112, wherein p is 1.

136. The compound of claim 112, wherein p is 2.

137. The compound of claim 112, wherein ring B is phenyl.

138. The compound of claim 112, wherein ring B is pyridyl.

139. The compound of claim 112, wherein ring C is phenyl.

140. The compound of claim 112, wherein ring B and ring C are phenyl.

141. The compound of claim 112, wherein ring B is pyridyl and ring C is phenyl.

143. A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier.

144. The pharmaceutical composition of claim 143, further comprising one or more additional therapeutic agent(s).

145. The pharmaceutical composition of claim 144, wherein the additional therapeutic agent is selected from a mucolytic agent, bronchodialator, an antibiotic, an anti-infective agent, a CFTR modulator, or an anti-inflammatory agent.

146. The pharmaceutical composition of claim 144, wherein the additional therapeutic agent is a CFTR modulator.

147. The pharmaceutical composition of claim 144, wherein the additional therapeutic agent is a CFTR corrector.

148. The pharmaceutical composition of claim 144, wherein the additional therapeutic agent is

149. The pharmaceutical composition of claim 144, wherein the additional therapeutic agent is

150. The pharmaceutical composition of claim 144, wherein the additional therapeutic agent is

151. The pharmaceutical composition of claim 144, wherein the additional therapeutic agent is a CFTR potentiator.

152. The pharmaceutical composition of claim 144, wherein the additional therapeutic agent is

153. The pharmaceutical composition of claim 144, wherein the additional therapeutic agents are a CFTR corrector and a CFTR potentiator.

154. The pharmaceutical composition of claim 144, wherein the additional therapeutic agents are

155. The pharmaceutical composition of claim 144, wherein the additional therapeutic agents are

156. The pharmaceutical composition of claim 144, wherein the additional therapeutic agents are

157. A method of treating cystic fibrosis in a patient comprising administering to the patient an effective amount of the compound of claim 1.

158. The method of claim 157, further comprising administering to the patient one or more additional therapeutic agent(s) prior to, concurrent with, or subsequent to the compound of claim 1.

159. The method of claim 158, wherein the additional therapeutic agent is selected from a mucolytic agent, bronchodialator, an antibiotic, an anti-infective agent, a CFTR modulator, or an anti-inflammatory agent.

160. The method of claim 158, wherein the additional therapeutic agent is a CFTR modulator.

161. The method of claim 158, wherein the additional therapeutic agent is a CFTR corrector.

162. The method of claim 158, wherein the additional therapeutic agent is

163. The method of claim 158, wherein the additional therapeutic agent is

164. The method of claim 158, wherein the additional therapeutic agent is

165. The method of claim 158, wherein the additional therapeutic agent is a CFTR potentiator.

166. The method of claim 158, wherein the additional therapeutic agent is

167. The method of claim 157, wherein the patient is homozygous in the F508del mutation.

168. The method of claim 157, wherein the patient is heterozygous in the F508del mutation.

169. A kit comprising the compound of claim 1, and instructions for use thereof.

170. The kit of claim 169, further comprising one or more additional therapeutic agent(s).

171. The kit of claim 170, wherein the additional therapeutic agent is selected from a mucolytic agent, bronchodialator, an antibiotic, an anti-infective agent, a CFTR modulator, or an anti-inflammatory agent.

172. The kit of claim 170, wherein the additional therapeutic agent is a CFTR modulator.

173. The kit of claim 170, wherein the additional therapeutic agent is a CFTR corrector.

174. The kit of claim 170, wherein the additional therapeutic agent is

175. The kit of claim 170, wherein the additional therapeutic agent is

176. The kit of claim 170, wherein the additional therapeutic agent is

177. The kit of claim 170, wherein the additional therapeutic agent is a CFTR potentiator.

178. The kit of claim 170, wherein the additional therapeutic agent is

179. The kit of claim 170, wherein the additional therapeutic agents are a CFTR corrector and a CFTR potentiator.

180. The kit of claim 170, wherein the additional therapeutic agents are

181. The kit of claim 170, wherein the additional therapeutic agents are

182. The kit of claim 170, wherein the additional therapeutic agents are

183. The kit of claim 170, wherein the compound of claim 1 and the one or more additional therapeutic agent(s) are in separate containers.

184. The kit of claim 170, wherein the compound of claim 1 and the one or more additional therapeutic agent(s) are in the same container.

185. The kit of claim 170, wherein the container(s) is a bottle, vial, or blister pack, or combination thereof.

142. A compound selected from Table 1.