Modulators of cystic fibrosis transmembrane conductance regulator

1. A method of producing a compound of formula I or formula II:

comprising the step of reacting under a first suitable conditions a compound of formula R-1 with either a compound of formula I-A to produce said compound of formula I, or a compound of formula II-A to produce said compound of formula II:

wherein:

each R X is independently hydrogen, halo, CF 3 , C1-C4 alkyl, or —OC1-C4 alkyl; provided that both R X are not simultaneously hydrogen; or

the two R X , taken together form ring (a):

X is CH 2 , CF 2 , CH 2 —CH 2 , or CF 2 —CF 2 ;

ring A is 3-7 membered monocyclic cycloalkyl ring;

R AA and R BB , taken together with the nitrogen atom, form a pyrrolidinyl ring substituted with OR′;

R′ is hydrogen or C1-C6 aliphatic, wherein up to two carbon units of said aliphatic are optionally and independently replaced by —CO—, —CS—, —COCO—, —CONR—, —CONRNR—, —CO 2 —, —OCO—, —NRCO 2 —, —O—, —NRCONR—, —OCONR—, —NRNR, —NRNRCO—, —NRCO—, —S—, —SO, —SO 2 —, —NR—, —SO 2 NR—, NRSO 2 —, or —NRSO 2 NR—;

R is hydrogen or C1-C6 aliphatic;

Z is an electron withdrawing substituent; and

q is 0-3; and

LG 1 is a first suitable leaving group.

2. The method according to claim 1 , wherein Lth is selected from alkyl sulfonate, aryl sulfonate, halide, alkyl carboxylate.

3. The method according to claim 1 , wherein said first suitable conditions comprises a first suitable solvent, a first suitable temperature, and a suitable reducing agent.

4. The method according to claim 3 , wherein said first suitable solvent is a polar or apolar, protic or aprotic solvent.

5. The method according to claim 4 wherein said solvent is selected from methanol, ethanol, propanol, isopropanol, tert-butanol, dichloromethane, dichloroethane, toluene, tetrahydrofurane, dioxane, diethylether, dimethylether, acetonitrile, DMF, DMAC, or NMP.

6. The method according to claim 3 , wherein said first suitable temperature is between about 0° C. to about 110° C.

7. The method according to claim 3 , wherein said suitable reducing agent is a metallo-borohydride or an agent capable of catalytic hydrogenation.

8. The method according to claim 7 , wherein said suitable reducing agent is selected from sodium borohydride, sodium cyanoborohydride, lithium borohydride, sodium triacetoxyborohydride, calcium borohydride, hydrogen in the presence of a suitable metal catalyst.

9. The method according to claim 1 , wherein said compound of formula I-A and formula II-A is produced from formula I-B formula II-B, respectively:

wherein [CA] is a suitable chiral auxiliary;

said method comprising the step of removing said chiral auxilary under a second suitable conditions.

10. The method according to claim 9 , wherein said suitable chiral auxiliary is an alkylsulfoxyl group.

11. The method according to claim 9 , wherein said suitable second conditions comprises a suitable protic acid and a suitable second solvent.

12. The method according to claim 11 , wherein said suitable second solvent is selected from a polar aprotic solvent or a protic solvent.

13. The method according to claim 12 , wherein said suitable second solvent is a polar aprotic solvent.

14. The method according to claim 13 , wherein said polar aprotic solvent is selected from dioxane, tetrahydrofurane, diethyl ether, or dichloromethane.

15. The method according to claim 9 , wherein said compound of formula I-B and formula II-B is produced by reacting, respectively, a compound of formula I-C or formula II-C with a compound of formula R-2 under a third suitable conditions:

wherein:

R 1 is hydrogen or a first suitable protecting group;

[CA] is a suitable chiral auxiliary; and

LG 2 is a second suitable leaving group.

16. The method according to claim 15 , wherein LG 2 is selected from halide, OC(O)alkyl, pentafluorophenoxy, alkoxy, OCO 2 alkyl or hydroxy.

17. The method according to claim 15 , wherein R 1 is hydrogen.

18. The method according to claim 15 , wherein said third suitable conditions comprises a suitable a third suitable coupling agent and a third suitable solvent.

19. The method according to claim 18 , wherein said suitable coupling agent is selected from triethyl amine, pyridine, DIEA, lutidine, HATU, TCPH, or HBTU.

20. The method according to claim 18 , wherein said third suitable solvent is selected from dichloromethane, dioxane, DMF, dichloroethane, or tetrahydrofuran.

21. The method according to claim 15 , wherein said compound of formula I-C or formula II-C is produced from an isomeric mixture of a compound of formula R-3:

wherein:

PG 1 is a second suitable protecting group; and

[CA] is a suitable chiral auxiliary;

said method comprising two steps, wherein one of said two steps is separating said isomeric mixture using suitable separation means, and the other of said two steps is the conversion of PG 1 to R 1 in a fourth suitable conditions.

22. The method according to claim 21 , wherein said suitable separation means comprises suitable chromatographic means.

23. The method according to claim 22 , wherein said suitable chromatographic means is selected from column chromatography or thin layer chromatography.

24. The method according to claim 21 , wherein said suitable separation means comprises crystallization methods.

25. The method according to claim 21 , wherein said fourth suitable conditions comprises a suitable deprotecting reagent and a fourth suitable solvent.

26. The method according to claim 25 , wherein said suitable deprotecting reagent is trifluoroacetic acid.

27. The method according to claim 25 , wherein said fourth suitable solvent is a apolar aprotic solvent.

28. The method according to claim 27 , wherein said polar aprotic solvent is dichloromethane.

29. The method according to claim 21 , wherein said compound of formula R-3 is produced from a compound of formula R-4 and a compound of formula R-5:

wherein:

PG 1 is a second suitable protecting group;

M is a suitable metal cation; and

[CA] is a suitable chiral auxiliary;

said method comprising the steps of reacting said compound of formula R-4 with said compound of formula R-5 in a fifth suitable conditions.

30. The method according to claim 29 , wherein said M is selected from Li + , Na + , or Mg ++ .

31. The method according to claim 29 , wherein PG 1 is selected from an alkylcarbamate, trifluoroacetyl, trialkylsilyl, or pivaloyl.

32. The method according to claim 31 , wherein said PG 1 is BOC or trimethylsilyl.

33. The method according to claim 29 , wherein said fifth suitable conditions comprises a fifth suitable solvent and a fifth suitable temperature.

34. The method according to claim 33 , wherein said suitable temperature is about −78 degrees C.

35. The method according to claim 33 , wherein said fifth suitable solvent is tetrahydrofuran.

36. The method according to claim 1 , wherein said compound of formula R-1 is

37. The method according to claim 1 , wherein said compound of formula I or formula II is selected from:

1

2

3

4

5

6

7

8

9

10

11

12

or

13