Modulators of ATP-Binding Cassette Transporters

1 . 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 compound 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 compound 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 compound 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 compound 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 2-5 —SO 2 NH—, —SO 2 NR E —, —NH—, or —C(O)O—.

6 . The compound 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 compound 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 compound 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 compound 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 compound 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 compound according to claim 1 , wherein R 2 is hydrogen.

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

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

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

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

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

26 . The compound 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—, —SO 2 —, —COO—, —OCO—, —CONR E —, —NR E CO—, NR E CO 2 —, —O—, —NR E SO 2 —, or —SO 2 NR E —.

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

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

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

34 . The compound 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 compound 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 compound according to claim 35 , wherein R 9 is

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

40 . The compound 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 compound 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 compound according to claim 20 , wherein R 1 ″ is hydrogen.

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

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

45 . A pharmaceutical composition comprising:

(i) a compound according to claim 1 ; and

(ii) a pharmaceutically acceptable carrier.

46 . The composition according to claim 45 , further comprising a mucolytic agent, a bronchodialator, an antibiotic, an anti-infective agent, an anti-inflammatory agent, a CFTR modulator, or a nutritional agent.

47 - 52 . (canceled)

53 . The composition according to claim 45 , further comprising a CFTR modulator.