Modulators of ATP-binding cassette transporters

1. A method of treating or lessening the severity of a disease in a patient, wherein said disease is dry-eye disease, said method comprising the step of administering to said patient an effective amount of a compound of formula I:

or a pharmaceutically acceptable salt thereof,

wherein:

Each R 1 is an optionally substituted C 1-6 aliphatic, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted C 3-10 cycloaliphatic, an optionally substituted 3 to 10 membered heterocycloaliphatic, carboxy, amido, amino, halo, or hydroxy, provided that at least one R 1 is an optionally substituted cycloaliphatic, an optionally substituted heterocycloaliphatic, an optionally substituted aryl, or an optionally substituted heteroaryl attached to the 5- or 6-position of the pyridyl ring;

Each R 2 is hydrogen, an optionally substituted C 1-6 aliphatic, an optionally substituted C 3-6 cycloaliphatic, an optionally substituted phenyl, or an optionally substituted heteroaryl;

Each R 3 and R′ 3 together with the carbon atom to which they are attached form an optionally substituted C 3-7 cycloaliphatic or an optionally substituted heterocycloaliphatic;

Each R 4 is an optionally substituted aryl or an optionally substituted heteroaryl; and

Each n is 1, 2, 3 or 4.

2. The method according to claim 1 , wherein one R 1 that is attached to 5- or 6-position of the pyridyl ring is aryl or heteroaryl, each optionally substituted with 1, 2, or 3 of R D ; wherein R D is -Z D R 9 ; wherein each Z D is independently a bond or an optionally substituted branched or straight C 1-6 aliphatic chain wherein up to two carbon units of Z D are optionally and independently replaced by —CO—, —CS—, —CONR E —, —CONR E NR E —, —CO 2 —, —OCO—, —NR E CO 2 —, —O—, —NR E CONR E —, —OCONR E —, —NR E NR E —, —NR E CO—, —S—, —SO—, —SO 2 —, —NR E —, —SO 2 NR E —, —NR E SO 2 —, or —NR E SO 2 NR E —; each R 9 is independently R E , halo, —OH, —NH 2 , NO 2 , —CN, —CF 3 , or —OCF 3 ; and each R E is independently hydrogen, an optionally substituted C 1-8 aliphatic group, an optionally substituted cycloaliphatic, an optionally substituted heterocycloaliphatic, an optionally substituted aryl, or an optionally substituted heteroaryl.

3. The method according to claim 2 , wherein the one R 1 attached to the 5- or 6-position of the pyridyl ring is phenyl optionally substituted with 1, 2, or 3 of R D .

4. The method according to claim 2 , wherein the one R 1 attached to the 5- or 6-position of the pyridyl ring is heteroaryl optionally substituted with 1, 2, or 3 of R D .

5. The method according to claim 2 , wherein one R 1 attached to the 5- or 6-position of the pyridyl ring is a 5 or 6 membered heteroaryl having 1, 2, or 3 heteroatom selected from the group consisting of oxygen, nitrogen, and sulfur, wherein the heteroaryl is substituted with 1 of R D , wherein R D is -Z D R 9 ; each Z D is independently a bond or an optionally substituted branched or straight C 1-6 aliphatic chain wherein up to two carbon units of Z D are optionally and independently replaced by —O—, —NHC(O)—, —C(O)NR E —, —SO 2 —, —NHSO 2 —, —NHC(O)—, —NR E SO 2 —, —SO 2 NH—, —SO 2 NR E —, —NH—, or —C(O)O—.

6. The method according to claim 5 , wherein one carbon unit of Z D is replaced by —O—, —NHC(O)—, —C(O)NR E —, —SO 2 —, —NHSO 2 —, —NHC(O)—, —SO—, —NR E SO 2 —, —SO 2 NH—, —SO 2 NR E —, —NH—, or —C(O)O—.

7. The method according to claim 2 , wherein R 9 is independently an optionally substituted aliphatic, an optionally substituted cycloaliphatic, an optionally substituted heterocycloaliphatic, an optionally substituted aryl, or an optionally substituted heteroaryl, H, or halo.

8. The method according to claim 1 , wherein one R 1 that is attached to the 5- or 6-position of the pyridyl ring is cycloaliphatic or heterocycloaliphatic, each optionally substituted with 1, 2, or 3 of R D .

9. The method according to claim 8 , wherein one R 1 that is attached to the 5- or 6-position of the pyridyl ring is an optionally substituted C 3 -C 8 cycloalkyl or an optionally substituted C 3 -C 8 cycloalkenyl.

10. The method according to claim 1 , wherein the one R 1 attached to the 5- or 6-position of the pyridyl ring is selected from the group consisting of

11. The method according to claim 1 , wherein R 2 is hydrogen.

12. The method according to claim 1 , wherein R 3 and R′ 3 together with the carbon atom to which they are attached form an unsubstituted C 3-7 cycloaliphatic or an unsubstituted heterocycloaliphatic.

13. The method according to claim 12 , wherein R 3 and R′ 3 together with the carbon atom to which they are attached form an unsubstituted cyclopropyl, an unsubstituted cyclopentyl, or an unsubstituted cyclohexyl.

14. The method according to claim 1 , wherein R 4 is an aryl or heteroaryl optionally substituted with 1, 2, or 3 of -Z C R 8 , wherein each Z C is independently a bond or 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 —; each R 8 is independently R C , halo, —OH, —NH 2 , —NO 2 , —CN, or —OCF 3 ; and each R C is independently an optionally substituted C 1-8 aliphatic group, an optionally substituted cycloaliphatic, an optionally substituted heterocycloaliphatic, an optionally substituted aryl, or an optionally substituted heteroaryl.

15. The method according to claim 14 , wherein R 4 is an aryl optionally substituted with 1, 2, or 3 of -Z C R 8 .

16. The method according to claim 15 , wherein R 4 is an optionally substituted phenyl.

17. The method according to claim 14 , wherein R 4 is a heteroaryl optionally substituted with 1, 2, or 3 of -Z C R 8 .

18. The method according to claim 14 , wherein R 4 is one selected from

19. The method according to claim 1 , wherein said compound has formula (IV):

or a pharmaceutically acceptable salt thereof, wherein

R D is -Z D R 9 , wherein each Z D is independently a bond or an optionally substituted branched or straight C 1-6 aliphatic chain wherein up to two carbon units of Z D are optionally and independently replaced by —CO—, —CS—, —CONR E —, —CONR E NR E —, —CO 2 —, —OCO—, —NR E CO 2 —, —O—, —NR E CONR E —, —OCONR E —, —NR E NR E —, —NR E CO—, —S—, —SO—, —SO 2 —, —NR E —, —SO 2 NR E —, —NR E SO 2 —, or —NR E SO 2 NR E —;

R 9 is independently R E , halo, —OH, —NH 2 , —NO 2 , —CN, —CF 3 , or —OCF 3 ;

Each R E is independently hydrogen, an optionally substituted C 1-8 aliphatic group, an optionally substituted cycloaliphatic, an optionally substituted heterocycloaliphatic, an optionally substituted aryl, or an optionally substituted heteroaryl;

R 2 is C 1-4 aliphatic, C 3-6 cycloaliphatic, phenyl, or heteroaryl, each of which is optionally substituted, or R 2 is hydrogen;

R 3 and R′ 3 together with the carbon atom to which they are attached form a C 3-7 cycloaliphatic or a C 3-7 heterocycloaliphatic, each of which is optionally substituted with 1, 2, or 3 of -Z B R 7 , wherein each Z B is independently a bond, or an optionally substituted branched or straight C 1-4 aliphatic chain wherein up to two carbon units of Z B are optionally and independently replaced by —CO—, —CS—, —CONR B —, —CONR B NR B —, —CO 2 —, —OCO—, —NR B CO 2 —, —O—, —NR B CONR B —, —OCONR B —, —NR B NR B —, —NR B CO—, —S—, —SO—, —SO 2 —, —NR B —, —SO 2 NR B —, —NR B SO 2 —, or —NR B SO 2 NR B —;

Each R 7 is independently R B , halo, —OH, —NH 25 —NO 2 , —CN, —CF 3 , or —OCF 3 ;

Each R B is independently hydrogen, an optionally substituted C 1-8 aliphatic group, an optionally substituted cycloaliphatic, an optionally substituted heterocycloaliphatic, an optionally substituted aryl, or an optionally substituted heteroaryl;

Each R 4 is an aryl or heteroaryl, each of which is optionally substituted with 1, 2, or 3 of -Z C R 8 , wherein each Z C is independently a bond or 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 —;

Each R 8 is independently R C , halo, —OH, —NH 2 , —NO 2 , —CN, —CF 3 , or —OCF 3 ; and

Each R C is independently an optionally substituted C 1-8 aliphatic group, an optionally substituted cycloaliphatic, an optionally substituted heterocycloaliphatic, an optionally substituted aryl, or an optionally substituted heteroaryl.

20. The method according to claim 19 , wherein said compound has formula V-A or formula V-B:

or a pharmaceutically acceptable salt thereof,

wherein:

T is an optionally substituted C 1-2 aliphatic chain, wherein each of the carbon units is optionally and independently replaced by —CO—, —CS—, —COCO—, —SO 2 —, —B(OH)—, or —B(O(C 1-6 alkyl))-;

Each of R 1 ′ and R 1 ″ is an optionally substituted C 1-6 aliphatic, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted 3 to 10 membered cycloaliphatic, an optionally substituted 3 to 10 membered heterocycloaliphatic, carboxy, amido, amino, halo, or hydroxy;

R D1 is attached to carbon number 3″ or 4″;

each R D1 and R D2 is -Z D R 9 , wherein each Z D is independently a bond or an optionally substituted branched or straight C 1-6 aliphatic chain wherein up to two carbon units of Z D are optionally and independently replaced by —CO—, —CS—, —CONR E —, —CONR E NR E —, —CO 2 —, —OCO—, —NR E CO 2 —, —O—, —NR E CONR E —, —OCONR E —, —NR E NR E —, —NR E CO—, —S—, —SO—, —SO 2 —, —NR E —, —SO 2 NR E —, —NR E SO 2 —, or —NR E SO 2 NR E —;

R 9 is independently R E , halo, —OH, —NH 2 , —NO 2 , —CN, —CF 3 , or —OCF 3 ;

or R D1 and R D2 , taken together with atoms to which they are attached, form a 3-8 membered saturated, partially unsaturated, or aromatic ring with up to 3 ring members independently selected from the group consisting of O, NH, NR E , and S; and

each R E is independently hydrogen, an optionally substituted C 1-8 aliphatic group, an optionally substituted cycloaliphatic, an optionally substituted heterocycloaliphatic, an optionally substituted aryl, or an optionally substituted heteroaryl.

21. The method according to claim 20 , wherein up to two methylene units of T are independently and optionally replaced by —CO—, —CS—, -B(OH), or —B(O(C 1-6 alkyl).

22. The method according to claim 20 , wherein T is an optionally substituted chain selected from the group consisting of —CH 2 — and —CH 2 CH 2 —.

23. The method according to claim 20 , wherein T is optionally substituted by F, Cl, C 1-6 alkyl, C 3-8 cycloalkyl, phenyl, naphthyl, —O—(C 1-6 alkyl), —O—(C 3-8 cycloalkyl), —O-phenyl, or C 3-8 spiroaliphatic.

24. The method according to claim 20 , wherein T is selected from the group consisting of —CH 2 —, —CH 2 CH 2 —, —CF 2 —, —C(CH 3 ) 2 —, —C(O)—,

—C(Phenyl) 2 —, —B(OH)—, and —CH(OEt)-.

25. The method according to claim 24 , wherein T is selected from the group consisting of —CH 2 —, —CF 2 —, and —C(CH 3 ) 2 —.

26. The method according to claim 20 , wherein Z D is independently a bond or an optionally substituted branched or straight C 1-6 aliphatic chain wherein one carbon unit of Z D is optionally replaced by —CO—, —SO—, —CO 2 —, —COO—, —OCO—, —CONR E —, —NR E CO—, NR E CO 2 —, —O—, —NR E SO 2 —, or —SO 2 NR E —.

27. The method according to claim 20 , wherein R D1 is -Z D R 9 , wherein R 9 is halo, —OH, —NH 2 , —CN, —CF 3 , —OCF 3 , or an optionally substituted group selected from the group consisting of C 1-6 aliphatic, C 3-8 cycloaliphatic, 3-8 membered heterocycloaliphatic, C 6-10 aryl, and 5-10 membered heteroaryl.

28. The method according to claim 27 , wherein R 9 is F, Cl, —OH, —CN, —CF 3 , or —OCF 3 .

29. The method according to claim 27 , wherein R 9 is selected from the group consisting of C 1-6 straight or branched alkyl or C 2-6 straight or branched alkenyl; wherein said alkyl or alkenyl is optionally substituted by 1 or 2 substituents independently selected from the group consisting of R E , oxo, halo, —OH, —NR E R E , —OR E , —COOR E , and —CONR E R E .

30. The method according to claim 27 , wherein R 9 is C 3-8 cycloaliphatic optionally substituted by 1 or 2 substituents independently selected from the group consisting of R E , oxo, halo, —OH, —NR E R E , —OR E , —COOR E , and —CONR E R E .

31. The method according to claim 30 , wherein R 9 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl.

32. The method according to claim 27 , wherein R 9 is a 3-8 membered heterocyclic with 1 or 2 heteroatoms independently selected from the group consisting of 0, NH, NR E , and S; wherein said heterocyclic is optionally substituted by 1 or 2 substituents independently selected from the group R E , oxo, halo, —OH, —NR E R E , —OR E , —COOR E , and —CONR E R E .

33. The method according to claim 32 , wherein R 9 is an optionally substituted 3-8 membered heterocyclic is

34. The method according to claim 32 , wherein R 9 is optionally substituted by 1 or 2 substituents independently selected from the group consisting of oxo, F, Cl, methyl, ethyl, i-propyl, t-butyl, —CH 2 OH, —CH 2 CH 2 OH, —C(O)OH, —C(O)NH 2 , —CH 2 O(C 1-6 alkyl), —CH 2 CH 2 O(C 1-6 alkyl), and —C(O)(C 1-6 alkyl).

35. The method according to claim 27 , wherein R 9 is 5-8 membered heteroaryl with 1 or two ring atom independently selected from the group consisting of O, S, and NR E ; wherein said heteroaryl is optionally substituted by 1 or 2 substituents independently selected from the group R E , oxo, halo, —OH, —NR E R E , —OR E , —COOR E , and —CONR E R E .

36. The method according to claim 35 , wherein R 9 is

37. The method according to claim 35 , wherein R 9 is optionally substituted by 1 or 2 substituents independently selected from the group consisting of F, Cl, methyl, ethyl, i-propyl, t-butyl, —CH 2 OH, —CH 2 CH 2 OH, —C(O)OH, —C(O)NH 2 , —CH 2 O(C 1-6 alkyl), —CH 2 CH 2 O(C 1-6 alkyl), and —C(O)(C 1-6 alkyl).

38. The method according to claim 20 , wherein R D1 and R D2 , taken together with carbons to which they are attached, form an optionally substituted 3-8 membered saturated, partially unsaturated, or aromatic ring with 0-2 ring atoms independently selected from the group consisting of O, NH, NR E , and S.

39. The method according to claim 38 , wherein R D1 and R D2 , taken together with phenyl containing carbon atoms 3″ and 4″, is

40. The method according to claim 38 , wherein R D1 and R D2 , taken together with phenyl containing carbon atoms 3″ and 4″, is optionally substituted by 1 or 2 substituents independently selected from the group consisting of R E , oxo, halo, —OH, —NR E R E , —OR E , —COOR E , and —CONR E R E .

41. The method according to claim 20 , wherein R D2 is selected from the group consisting of H, C 1-6 aliphatic, halo, —CN, —NH 2 , —CH 2 NH 2 , —OH, —O(C 1-6 aliphatic), —CH 2 OH, —SO 2 (C 1-6 aliphatic), —NH—SO 2 (C 1-6 aliphatic), —C(O)O(C 1-6 aliphatic), —C(O)OH, —NHC(O)(C 1-6 aliphatic), —C(O)NH 2 , —C(O)NH(C 1-6 aliphatic), and —C(O)N(C 1-6 aliphatic) 2 .

42. The method according to claim 20 , wherein R 1 ″ is hydrogen.

43. The method according to claim 20 , wherein R 1 ′ and R 1 ″ are both hydrogen.

44. The method according to claim 1 , wherein the compound is selected from

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