Modulators of cystic fibrosis transmembrane conductance regulator

1. A process for preparing a compound of Formula (Ic):

or pharmaceutically acceptable salts thereof, wherein the process comprises:

(a) reacting the acid of formula 1d with an amine of formula 2c to provide a compound of formula (Ic)

wherein:

ring A is selected from:

wherein:

R 1 is —CH 3 , —CF 3 or —CN;

R 2 is hydrogen, —CH 3 , —CF 3 , —OH, or —CH 2 OH;

R 3 is hydrogen, —CH 3 , —OCH 3 , or —CN;

provided that both R 2 and R 3 are not simultaneously hydrogen, and

R a is hydrogen or a silyl protecting group selected from the group consisting of trimethylsilyl (TMS), tert-butyldiphenylsilyl (TBDPS), tert-butyldimethylsilyl (TBDMS) triisopropylsilyl (TIPS), and [2-(trimethylsilyl)ethoxy]methyl (SEM); and

one of X and Y is nitrogen and the other is carbon.

2. The process of claim 1 , wherein the reaction of the acid of formula 1d with the amine of formula 2c occurs in a solvent in the presence of O-(7-azabenzotriazol-l-yl)-N, N,N′,N′-tetramethyluronium hexafluorophosphate (HATU) and triethylamine or in a solvent in the presence of propyl phosphonic acid cyclic anhydride (T3P®) and pyridine.

3. The process of claim 2 , wherein the solvent comprises N,N-dimethyl formamide, ethyl acetate, or 2-methyltetrahydrofuran.

4. The process of claim 1 , wherein R a is hydrogen or TBDMS.

5. The process of claim 4 , wherein R a is TBDMS.

6. The process of claim 1 , wherein ring A is

and R a is a silyl protecting group, and wherein the process further comprises a deprotection step to remove the silyl protecting group to generate a compound of formula Ic, wherein ring A is

7. The process of claim 1 , wherein the amine of formula 2c is prepared from a compound of formula 2a comprising the steps of

(a) reacting the compound of formula 2a with an amine of formula 3 to provide the compound of formula 2b

wherein:

Hal is F, Cl, Br, or I; and

the amine of formula 3 is

 and

(b) reducing the compound of formula 2b to the amine of formula 2c.

8. The process of claim 7 , wherein the amine of formula 3 in step (a) is generated in situ from the amine hydrochloride salt.

9. The process of claim 7 , wherein R a is hydrogen or TBDMS.

10. The process of claim 9 , wherein R a is TBDMS.

11. The process of claim 7 , wherein step (a) occurs in a polar aprotic solvent in the presence of a tertiary amine base.

12. The process of claim 11 , wherein step (a) occurs in acetonitrile in the presence of triethylamine.

13. The process of claim 7 , wherein the reaction temperature of step (a) is between approximately 75 ° C. and approximately 85 ° C.

14. The process of claim 7 , wherein the reaction time is between approximately 2 and approximately 30 hours.

15. The process of claim 7 , wherein step (b) occurs in a polar protic solvent in the presence of a palladium catalyst.

16. The process of claim 15 , wherein the solvent in step (b) comprises methanol or ethanol.

17. The process of claim 7 , wherein step (b) occurs in a polar protic solvent in the presence of Fe and FeSO 4 or Zn and AcOH.

18. The process of claim 17 , wherein the polar protic solvent is water.

19. A process for preparing a compound of formula Ic,

or pharmaceutically acceptable salts thereof, comprising the steps of

(a) reacting a compound of formula 2a with an amine of formula 3 to provide a compound of formula 2b

(b) converting the compound of formula 2b to the amine of formula 2c via hydrogenation

and

(c) reacting the amine of formula 2c with an acid of formula 1d to provide a compound of formula Ic

wherein Hal is F, Cl, Br, or I;

the amine of formula 3 is

 and

ring A is selected from:

wherein

R 1 is —CH 3 , —CF 3 or —CN;

R 2 is hydrogen, —CH 3 , —CF 3 , —OH, or —CH 2 OH;

R 3 is hydrogen, —CH 3 , —OCH 3 , or —CN;

provided that both R 2 and R 3 are not simultaneously hydrogen;

R a is hydrogen or a silyl protecting group selected from the group consisting of trimethylsilyl (TMS), tert-butyldiphenylsilyl (TBDPS), tert-butyldimethylsilyl (TBDMS), triisopropylsilyl (TIPS), and [2-(trimethylsilyl)ethoxy]methyl (SEM); and

one of X and Y is nitrogen and the other is carbon.

20. The process of claim 19 , wherein the amine of formula 3

 in step (a) is generated in situ from the amine hydrochloride salt.

21. The process of claim 20 , wherein R a is hydrogen or TBDMS.

22. The process of claim 21 , wherein R a is TBDMS.

23. The process of claim 19 , wherein step (a) occurs in a polar aprotic solvent in the presence of a tertiary amine base.

24. The process of claim 23 , wherein step (a) occurs in acetonitrile in the presence of triethylamine.

25. The process of claim 19 , wherein the reaction temperature of step (a) is between approximately 75 ° C. and approximately 85 ° C.

26. The process of claim 19 , wherein the reaction time is between approximately 2 and approximately 30 hours.

27. The process of claim 19 , wherein step (b) occurs in a polar protic solvent in the presence of a palladium catalyst.

28. The process of claim 27 , wherein the solvent in step (b) comprises methanol or ethanol.

29. The process of claim 19 , wherein step (b) occurs in a polar protic solvent in the presence of Fe and FeSO 4 or Zn and AcOH.

30. The process of claim 29 , wherein the polar protic solvent is water.

31. The process of claim 19 , wherein step (c) occurs in a solvent in the presence of O-(7-azabenzotriazol-1-yl)-N,N,N′N′-tetramethyluronium hexafluorophosphate (HATU) and triethylamine or in a solvent in the presence of propyl phosphonic acid cyclic anhydride (T3P®) and pyridine.

32. The process of claim 31 , wherein the solvent in step (c) comprises N,N-dimethyl formamide (DMF), ethyl acetate, or 2-methyltetrahydrofuran.

33. The process of claim 31 , wherein R a is hydrogen or TBDMS.

34. The process of claim 33 , wherein R a is TBDMS.

35. The process of claim 19 further comprising a deprotection reaction when ring A is

wherein R a is a silyl protecting group, to generate a compound of formula I wherein ring A is