Pyridyl derivatives as CFTR modulators

1. A compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein:

R N is H, or alkyl;

A is an optionally substituted 3 membered monocyclic ring;

B is optionally fused to a 5-7 membered ring selected from the group consisting of cycloaliphatic, aryl, heterocyclic, and heteroaryl;

R 1 is halo, alkyl, OH, alkoxy, thioalkyl, trifluoromethoxy; or

two R 1 on adjacent atoms, taken together, form

wherein J is selected from the group consisting of CH 2 , CF 2 , or C(CH 3 ) 2 ;

W is independently a (C1-C6) alkylidene chain wherein up to two methylene units of W are independently replaced by —O—, —S—, SO 2 —, or —NR′—;

R′ is independently H, alkyl, aryl, heteroaryl, aralkyl, cycloalkyl, or heterocyclic;

R W is independently H, halo, CN, NO 2 , N(R) 2 , CF 3 , OCF 3 , OH, OR, C(O)R, CO 2 R, C(O)N(R) 2 , —O(C1-C6)alkylidene-OR, —O(C1-C6)alkylidene-N(R) 2 , —O(C1-C6)alkylidene-heterocyclic, or an optionally substituted aliphatic, cycloaliphatic, aryl, aryloxy, heterocyclic, or heteroaryl, wherein, when substituted, R W is substituted with up to two R 2 ;

R 2 is halo, CN, NO 2 , CF 3 , OCF 3 , OR, OC(O)R, OC(O)N(R) 2 , SR, S(O)R, SO 2 R, SO 2 N(R) 2 , SO 3 R, C(O)R, CO 2 R, C(O)N(R) 2 , N(R) 2 , NRC(O)R, NRCO 2 R, NRC(O)N(R) 2 , NRSO 2 R, B(OR) 2 , or NRSO 2 N(R) 2 ;

R is independently H, alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl;

n is 1 or 2;

w is an integer from 1 to 4 inclusive; and

x is an integer from 1 to 5 inclusive.

2. The compound of claim 1 , wherein A is

wherein

R 3 is alkyl, alkaryl, aryl, or heteroaryl; and

q is an integer from 0 to 4 inclusive.

3. The compound of claim 2 , wherein A is

4. The compound of claim 1 , wherein R 1 is selected from the group consisting of chloro, OH, methoxy, thiomethyl, and trifluoromethoxy.

5. The compound of claim 1 , wherein two R 1 on adjacent atoms, taken together, form

wherein J is selected from the group consisting of CH 2 , CF 2 , or C(CH 3 ) 2 .

6. The compound of claim 5 , wherein J is CH 2 .

7. The compound of claim 5 , wherein J is CF 2 .

8. The compound of claim 1 , wherein W is an optionally substituted (C1-C6) alkylidene chain.

9. The compound of claim 1 , wherein W is selected from the group consisting of —CH 2 —, —NH—, —O—, and —OCH 2 —.

10. The compound of claim 1 , wherein R w is selected from the group consisting of H, OH, heterocyclic, aryl, phenyl, heteroaryl, pyridyl, alkoxy, cycloalkyl, and cyclohexyl.

11. The compound of claim 1 , wherein —W—R w is acyclic.

12. The compound of claim 1 , wherein —W(R w ) n is selected from the following:

—CH 3 , —CH 2 CH 3 , —CN, —CF 3 , —CONH 2 , —CH 2 CH(CH 3 ) 2 ,

13. The compound according to claim 1 , having formula Ia:

or a pharmaceutically acceptable salt thereof, wherein:

J is CH 2 or CF 2 ;

W is independently a (C1-C6) alkylidene chain optionally substituted with R 2 wherein up to two methylene units of W are independently replaced by —O—, or —NR′—;

R′ is independently H or alkyl;

R W is independently H, halo, CN, N(R) 2 , CF 3 , OH, CO 2 R, C(O)N(R) 2 , —O(C1-C6)alkylidene-OR, —O(C1-C6)alkylidene-N(R) 2 , —O(C1-C6)alkylidene-heterocyclic, or an optionally substituted aliphatic, cycloaliphatic, aryl, aryloxy, heterocyclic, or heteroaryl, wherein, when substituted, R w is substituted with up to two R 2 ;

R 2 is halo, OR, CO 2 R, C(O)N(R) 2 , SO 2 N(R) 2 , B(OR) 2 , or N(R) 2 ;

R is independently H, alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl;

n is 1 or 2; and

w is an integer from 1 to 4 inclusive.

14. The compound of claim 13 , wherein J is CH 2 .

15. The compound of claim 13 , wherein J is CF 2 .

16. The compound of claim 13 , wherein —W—R w is acyclic.

17. The compound of claim 13 , wherein —W(R w ) n is selected from the following:

—CH 3 , —CH 2 CH 3 , —CN, —CF 3 , —CONH 2 , —CH 2 CH(CH 3 ) 2 ,

18. The compound according to claim 1 , having formula Ib:

or a pharmaceutically acceptable salt thereof, wherein:

R 1 is halo, alkyl, OH, alkoxy, thioalkyl, trifluoromethoxy; or

two R 1 on adjacent atoms, taken together, form

wherein J is selected from the group consisting of CH 2 , CF 2 , or C(CH 3 ) 2 ;

W is —NR′, or CH 2 —;

R′ is independently H or alkyl;

R W is independently H, halo, CN, N(R) 2 , CF 3 , OH, CO 2 R, C(O)N(R) 2 , —O(C1-C6)alkylidene-OR, —O(C1-C6)alkylidene-N(R) 2 , —O(C1-C6)alkylidene-heterocyclic, or an optionally substituted aliphatic, cycloaliphatic, aryl, aryloxy, heterocyclic, or heteroaryl, wherein, when substituted, R w is substituted with up to two R 2 ;

R 2 is halo, OR, CO 2 R, C(O)N(R) 2 , SO 2 N(R) 2 , B(OR) 2 , or N(R) 2 ;

R is independently H, alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl;

n is 1 or 2;

w is an integer from 1 to 4 inclusive; and

x is an integer from 1 to 5 inclusive.

19. The compound of claim 18 , wherein two R 1 on adjacent atoms, taken together, form

and J is CH 2 .

20. The compound of claim 18 , wherein two R 1 on adjacent atoms, taken together, form

and J is CF 2 .

21. The compound of claim 18 , wherein —W(R w ) n is selected from the following:

—CH 3 , —CH 2 CH 3 , —CH 2 CH(CH 3 ) 2 ,

22. The compound according to claim 1 having formula Ic:

or a pharmaceutically acceptable salt thereof, wherein:

R 1 is halo, alkyl, OH, alkoxy, thioalkyl, trifluoromethoxy; or

two R 1 on adjacent atoms, taken together, form

wherein J is selected from the group consisting of CH 2 , CF 2 , or C(CH 3 ) 2 ;

W is —NR′, or CH 2 —;

R′ is independently H or alkyl;

R W is independently H, halo, CN, N(R) 2 , CF 3 , OH, CO 2 R, C(O)N(R) 2 , —O(C1-C6)alkylidene-OR, —O(C1-C6)alkylidene-N(R) 2 , —O(C1-C6)alkylidene-heterocyclic, or an optionally substituted aliphatic, cycloaliphatic, aryl, aryloxy, heterocyclic, or heteroaryl, wherein, when substituted, W w is substituted with up to two R 2 ;

R 2 is halo, OR, CO 2 R, C(O)N(R) 2 , SO 2 N(R) 2 , B(OR) 2 , or N(R) 2 ;

R is independently H, alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl;

n is 1 or 2;

w is an integer from 1 to 4 inclusive; and

x is an integer from 1 to 5 inclusive.

23. The compound of claim 22 , wherein two R 1 on adjacent atoms, taken together, form

and J is CH 2 .

24. The compound of claim 22 , wherein two R 1 on adjacent atoms, taken together, form

and J is CF 2 .

25. The compound of claim 22 , wherein —W(R w ) n is selected from the following:

—CH 3 , —CH 2 CH 3 , —CH 2 CH(CH 3 ) 2 ,

26. The compound of claim 1 , wherein the compound is selected from

27. A pharmaceutical composition comprising

(i) a compound of claim 1 ; and

(ii) a pharmaceutically acceptable carrier.

28. The composition of claim 27 , further comprising an additional agent selected from the group consisting of a mucolytic agent, bronchodialator, an anti-biotic, an anti-infective agent, an anti-inflammatory agent, CFTR corrector, and a nutritional agent.

29. A kit for use in measuring the activity of a ABC transporter or a fragment thereof in a biological sample in vitro or in vivo, comprising:

(i) a first composition comprising a compound according to claim 1 ; and

(ii) instructions for:

a) contacting the composition with the biological sample;

b) measuring activity of said ABC transporter or a fragment thereof.