Modulators of ATP-binding cassette transporters

1. A method of activating Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) activity comprising the step of contacting the CFTR with a compound of formula I:

or a pharmaceutically acceptable salt thereof;

wherein, independently for each occurrence:

R 1 and R 2 are —Z A R 4 , wherein each Z A is independently a bond or an optionally substituted branched or straight C 1-6 aliphatic chain wherein up to two carbon units of Z A are optionally and independently replaced by —CO—, —CS—, —CONR A —, —CONR A NR A —, —CO 2 —, —OCO—, —NR A CO 2 —, —O—, —NR A CONR A —, —OCONR A —, —NR A NR A —, —NR A CO—, —S—, —SO—, —SO 2 —, —NR A —, —SO 2 NR A —, —NR A SO 2 —, or —NR A SO 2 NR A —; or any two adjacent R 2 groups together with the atoms to which they are attached form an optionally substituted carbocycle or optionally substituted heterocycle;

R 4 is independently R A , halo, —OH, —NH 2 , —NO 2 , —CN, or —OCF 3 ;

R A is independently hydrogen, an optionally substituted aliphatic, an optionally substituted cycloaliphatic, an optionally substituted heterocycloaliphatic, an optionally substituted aryl, or an optionally substituted heteroaryl;

ring A is an optionally substituted 3-7 membered monocyclic ring having 0-3 heteroatoms selected from N, O, and S;

n is and integer from 1 to 3 inclusive;

ring B is

wherein:

p is 2 or 3; and

R 3 is C 1 -C 6 aliphatic or halo, and;

R′ 3 is —Z C R 6 , where

Z C is an optionally substituted branched or straight C 1-6 aliphatic chain wherein up to two carbon units of Z C are optionally and independently replaced by —CO—, —CS—, —CONR C —, —CONR C NR C —, —CO 2 —, —OCO—, —NR C CO 2 —, —O—, —NR C CONR C —, —OCONR C —, —NR C NR C —, NR C CO—, —S—, —SO—, —SO 2 —, —NR C , —SO 2 NR C —, —NR C SO 2 —, or —NR C SO 2 NR C —;

R 6 is R C , halo, —OH, —NH 2 , —NO 2 , —CN, or —OCF 3 ;

R C is hydrogen, an optionally substituted aliphatic, an optionally substituted cycloaliphatic, an optionally substituted heterocycloaliphatic, or an optionally substituted heteroaryl;

and wherein when one of the 2 or 3 R 3 is adjacent to R′ 3 and the adjacent R 3 is C 1 -C 6 aliphatic, then R′ 3 and the adjacent R 3 , together with the atoms to which they are attached, form an optionally substituted heterocycle.

2. The method of claim 1 , wherein R 1 is H or C 1 -C 6 aliphatic in the compound of formula I.

3. The method of claim 1 , wherein R 1 is H in the compound of formula I.

4. The method of claim 1 , wherein two adjacent R 2 in the compound of formula I together with the atoms to which they are attached form an optionally substituted carbocycle or an optionally substituted heterocycle.

5. The method of claim 1 , wherein two adjacent R 2 in the compound of formula I together with the atoms to which they are attached form an optionally substituted heterocycle.

6. The method of claim 1 , wherein two adjacent R 2 in the compound of formula I together with the atoms to which they are attached form an optionally substituted heterocycle selected from

7. The method of claim 1 , wherein two adjacent R 2 in the compound of formula I together with the atoms to which they are attached form an optionally substituted heterocycle selected from

8. The method of claim 1 , wherein two adjacent R 2 in the compound of formula I together with the atoms to which they are attached form

9. The method of claim 1 , wherein ring A in the compound of formula I is selected from

10. The method of claim 1 , wherein ring A in the compound of formula I is

11. The method of claim 1 , wherein 1 R 3 in the compound of formula I is halo.

12. The method of claim 1 , wherein 1 R 3 in the compound of formula I is F.

13. The method of claim 1 , wherein R′ 3 and an adjacent R 3 in the compound of formula I together with the atoms to which they are attached form an optionally substituted heterocycle.

14. The method of claim 1 , wherein R′ 3 and an adjacent R 3 in the compound of formula I together with the atoms to which they are attached form an optionally substituted 3 to 7 membered heterocycle in which one or more of the ring atoms is N, O, S, or combination thereof.

15. The method of claim 1 , wherein R′ 3 and an adjacent R 3 together with the atoms to which they are attached form an optionally substituted 7 membered heterocycle in which one or more of the ring atoms is N, O, S, or combination thereof.

16. The method of claim 1 , wherein the compound of formula I is administered as a pharmaceutical composition additionally comprising a pharmaceutically acceptable carrier or adjuvant.

17. The method of claim 16 , wherein the composition comprises an additional agent selected from a mucolytic agent, bronchodialator, an anti-biotic, an anti-infective agent, an anti-inflammatory agent, CFTR modulator, or a nutritional agent.

18. A method of treating or lessening the severity of a disease in a patient, wherein the disease is selected from cystic fibrosis, hereditary emphysema, chronic obstructive pulmonary disease (COPD), and dry-eye disease, comprising administering to the patient a compound of claim 1 .

19. The method of claim 18 , wherein the disease is selected from cystic fibrosis, hereditary emphysema, and COPD.

20. The method of claim 18 , wherein the disease is cystic fibrosis.

21. The method of claim 20 , wherein the patient has a defective gene that causes a deletion of phenylalanine at position 508 of the CFTR amino acid sequence.

22. The method of claim 20 , wherein the patient possesses a cystic fibrosis transmembrane receptor (CFTR) with a homozygous ΔF508 mutation.

23. The method of claim 20 , wherein the patient possesses a cystic fibrosis transmembrane receptor (CFTR) with homozygous G551D mutation.