Modulators of cystic fibrosis transmembrane conductance regulator

1. A compound of formula Ia:

a deuterated derivative thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein, independently for each occurrence:

Ring B is a C6-C10 aryl ring or C3-C10 heteroaryl or heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR;

Ring C is a C6-C10 aryl ring, C3-C14 heteroaryl or heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently N, O, or S, or a C3-C10 cycloalkyl ring;

X is O or NR;

Y is CRR, CO, O, S, SO, SO 2 , S(O)NH or NR;

R 1 is halo; CN; F 5 S; SiR 3 ; OH; NRR; C1-C6 alkyl; C1-C6 fluoroalkyl; C1-C6 alkoxy; C1-C6 fluoroalkoxy; C2-C6 alkenyl; C2-C6 alkynyl; (C1-C9 alkylene)-R 4 wherein up to four CH 2 units are independently replaced with O, CO, S, SO, SO 2 or NR; C6-C10 aryl; C3-C10 heteroaryl or heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; or C3-C10 cycloalkyl;

R 2 is halo; OH; NRR; azide; CN; CO 2 R; C1-C6 alkyl; C1-C6 fluoroalkyl; C1-C6 alkoxy; 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)-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 may form a ═CH 2 or ═O group;

R 3 is halo; CN; CO 2 R; C1-C6 alkyl; C1-C6 fluoroalkyl; C2-C6 alkenyl; C2-C6 alkynyl; C1-C6 alkoxy; C1-C6 fluoroalkoxy; or C6-C10 aryl; C3-C10 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)-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 may form a ═CH 2 or ═O group;

R 4 is H; azide; CF 3 ; CHF 2 ; OR; CCH; CO 2 R; 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 SO 2 R;

R is independently H; OH; CO 2 H; CO 2 ; C1-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, N, or NR; or C3-C10 cycloalkyl;

n is 0, 1, 2 or 3;

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

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

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

2. The compound, deuterated derivative, or salt 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.

3. The compound, deuterated derivative, or salt of claim 1 , wherein ring B is selected from

4. The compound, deuterated derivative, or salt of claim 1 , wherein ring C is phenyl, indole, cycloalkyl, pyridyl, pyrrolidine, naphthalene, piperidine, or dihydroindene.

5. The compound, deuterated derivative, or salt of claim 1 , wherein ring C is

6. The compound, deuterated derivative, or salt of claim 1 , wherein Y is O.

7. The compound, deuterated derivative, or salt of claim 1 , wherein Y is CH 2 .

8. The compound, deuterated derivative, or salt of claim 1 , wherein Y is CH(C1-C6 alkyl).

9. The compound, deuterated derivative, or salt of claim 1 , wherein Y is CH(CH 3 ).

10. The compound, deuterated derivative, or salt of claim 1 , wherein Y is CH(CH 2 CH 3 ).

11. The compound, deuterated derivative, or salt of claim 1 , wherein R 1 is halo, CN, C1-C6 alkyl, 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 alkyl, C1-C6 alkoxy, C1-C6 fluoroalkyl, C1-C6 fluoroalkoxy, OH, CH 2 OH, CH 2 OCH 3 , CN, CO 2 H, amino, amido, C3-C10 heteroaryl, C3-C10 heterocycloalkyl, or a (C1-C8 alkyl)-R 4 wherein up to three CH 2 units may be replaced with O, CO, S, SO, SO 2 or NR.

12. The compound, deuterated derivative, or salt 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 ,

13. The compound, deuterated derivative, or salt of claim 1 , wherein R 2 is halo, OH, CN, azide, amino, C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 alkoxy, C1-C6 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 alkyl)-R 4 wherein up to three CH 2 units may be replaced with O, CO, S, SO, SO 2 or NR.

14. The compound, deuterated derivative, or salt of claim 1 , wherein R 2 is selected from 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 ,

and CO 2 H.

15. The compound, deuterated derivative, or salt of claim 1 , wherein R 3 is selected from halo, CN, C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 alkoxy, and C3-C10 mono- or bicyclic heteroaryl wherein up to 4 carbon atoms may be replaced by O, S, N, or NR.

16. The compound, deuterated derivative, or salt of claim 1 , wherein R 3 is selected from 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,

17. The compound, deuterated derivative, or salt of claim 1 , wherein o is 0.

18. The compound, deuterated derivative, or salt of claim 1 , wherein o is 1.

19. The compound, deuterated derivative, or salt of claim 1 , wherein n is 0.

20. The compound, deuterated derivative, or salt of claim 1 , wherein n is 1.

21. The compound, deuterated derivative, or salt of claim 1 , wherein n is 2.

22. The compound, deuterated derivative, or salt of claim 1 , wherein p is 0.

23. The compound, deuterated derivative, or salt of claim 1 , wherein p is 1.

24. The compound, deuterated derivative, or salt of claim 1 , wherein p is 2.

25. The compound, deuterated derivative, or salt of claim 1 , wherein ring B is phenyl.

26. The compound, deuterated derivative, or salt of claim 1 , wherein ring B and ring C are phenyl.

27. A compound selected from:

deuterated derivatives thereof, and pharmaceutically acceptable salts of the foregoing.

28. A pharmaceutical composition comprising the compound, deuterated derivative, or salt of claim 1 and a pharmaceutically acceptable carrier.

29. The pharmaceutical composition of claim 28 , further comprising one or more additional therapeutic agent(s).

30. The pharmaceutical composition of claim 29 , wherein the one or more additional therapeutic agent(s) comprises a CFTR modulator.

31. The pharmaceutical composition of claim 29 , wherein the one or more additional therapeutic agent(s) comprises

or pharmaceutically acceptable salt thereof.

32. The pharmaceutical composition of claim 29 , wherein the one or more additional therapeutic agent(s) comprises

or pharmaceutically acceptable salt thereof.

33. The pharmaceutical composition of claim 29 , wherein the one or more additional therapeutic agent(s) comprises

or pharmaceutically acceptable salts thereof.

34. A method of treating cystic fibrosis in a patient comprising administering to the patient an effective amount of the compound, deuterated derivative, or salt of claim 1 .

35. The method of claim 34 , further comprising administering to the patient one or more additional therapeutic agent(s) prior to, concurrent with, or subsequent to the compound, deuterated derivative, or salt of claim 1 .

36. The method of claim 35 , wherein the one or more additional therapeutic agent(s) comprises a CFTR modulator.

37. The method of claim 35 , wherein the one or more additional therapeutic agent(s) comprises

or a pharmaceutically acceptable salt thereof.

38. The method of claim 35 , wherein the one or more additional therapeutic agent(s) comprises

or a pharmaceutically acceptable salt thereof.

39. The method of claim 34 , wherein the patient is homozygous in the ΔF508 CFTR mutation.

40. The method of claim 34 , wherein the patient is heterozygous in the ΔF508 CFTR mutation.

41. A method of treating cystic fibrosis in a patient comprising administering to the patient an effective amount of the pharmaceutical composition of claim 28 .

42. The method of claim 41 , further comprising administering to the patient one or more additional therapeutic agent(s) prior to, concurrent with, or subsequent to the pharmaceutical composition.

43. The method of claim 42 , wherein the one or more additional therapeutic agent(s) comprises a CFTR modulator.

44. The method of claim 42 , wherein the one or more additional therapeutic agent(s) comprises

or a pharmaceutically acceptable salt thereof.

45. The method of claim 42 , wherein the one or more additional therapeutic agent(s) comprises

or a pharmaceutically acceptable salt thereof.

46. The method of claim 42 , wherein the one or more additional therapeutic agent(s) comprises

or pharmaceutically acceptable salts thereof.