Modulators of ATP-binding cassette transporters

1. A method of modulating ABC transporter activity comprising the step of contacting said ABC transporter with a compound of the formula:

or a pharmaceutically acceptable salt thereof, wherein

R 1 is —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 —,

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

Each 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;

Each R 2 is independently —Z B R 5 , wherein each Z B is independently a bond or an optionally substituted branched or straight C 1-6 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 5 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 aliphatic, an optionally substituted cycloaliphatic, an optionally substituted heterocycloaliphatic, an optionally substituted aryl, or an optionally substituted heteroaryl,

Or, any two adjacent R 2 groups together with the atoms to which they are attached form an optionally substituted carbocycle or an optionally substituted heterocycle;

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

Ring B is a group having formula Ia:

or a pharmaceutically acceptable salt thereof, wherein

p is 0-2,

Each R 3 and R′ 3 is independently —Z C R 6 , where 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 6 is independently R C , halo, —OH, —NH 2 , —NO 2 , —CN, or —OCF 3 ,

Each R C is independently hydrogen, an optionally substituted aliphatic, an optionally substituted cycloaliphatic, an optionally substituted heterocycloaliphatic, an optionally substituted aryl, or an optionally substituted heteroaryl,

Or, any two adjacent R 3 groups together with the atoms to which they are attached form an optionally substituted heterocycle; and

n is 1-3.

2. The method of claim 1 , wherein the ABC transporter is CFTR.

3. A method of treating or lessening the severity of a disease in a patient, wherein said disease is selected from cystic fibrosis, hereditary emphysema, COPD, or dry-eye disease, said method comprising the step of administering to said patient an effective amount of a compound of the formula:

or a pharmaceutically acceptable salt thereof, wherein

R 1 is —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 —,

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

Each 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;

Each R 2 is independently —Z B R 5 , wherein each Z B is independently a bond or an optionally substituted branched or straight C 1-6 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 —, —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 8 —, —NR B SO 2 —, or —NR B SO 2 NR B —,

Each R 5 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 aliphatic, an optionally substituted cycloaliphatic, an optionally substituted heterocycloaliphatic, an optionally substituted aryl, or an optionally substituted heteroaryl,

Or, any two adjacent R 2 groups together with the atoms to which they are attached form an optionally substituted carbocycle or an optionally substituted heterocycle;

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

Ring B is a group having formula Ia:

or a pharmaceutically acceptable salt thereof, wherein

p is 0-2,

Each R 3 and R′ 3 is independently —Z C R 6 , where 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 6 is independently R C , halo, —OH, —NH 2 , —NO 2 , —CN, or —OCF 3 ,

Each R C is independently hydrogen, an optionally substituted aliphatic, an optionally substituted cycloaliphatic, an optionally substituted heterocycloaliphatic, an optionally substituted aryl, or an optionally substituted heteroaryl,

Or, any two adjacent R 3 groups together with the atoms to which they are attached form an optionally substituted heterocycle; and

n is 1-3.

4. The method of claim 3 , wherein:

R 1 is —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 —;

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

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

n is 2 and the two R 2 are adjacent to each other and together with the atoms to which they are attached form

Ring A is an optionally substituted 3-7 membered monocyclic ring;

Ring B is a group of the formula

or a pharmaceutically acceptable salt thereof, wherein

p is 0-2;

Each R 3 and R′ 3 is independently —Z C R 6 , where 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 6 is independently R C , halo, —OH, —NH 2 , —NO 2 , —CN, or —OCF 3 ; and

Each R C is independently hydrogen, an optionally substituted aliphatic, an optionally substituted cycloaliphatic, or an optionally substituted aryl;

Or, any two adjacent R 3 groups together with the atoms to which they are attached form an optionally substituted heterocycle.

5. The method of claim 4 , wherein R 1 is —Z A R 4 , Z A is a bond, and R 4 is hydrogen.

6. The method of claim 4 , wherein ring A is a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl, each of which is optionally substituted with 1-3 of halo, hydroxy, C 1-5 aliphatic, or combinations thereof.

7. The method of claim 4 , wherein ring A is an optionally substituted 3-7 membered monocyclic heterocycloaliphatic.

8. The method claim 4 , wherein ring A is one selected from

wherein

Each R 9 is independently —Z E R 10 , wherein each Z E is independently a bond or an optionally substituted branched or straight C 1-6 aliphatic chain wherein up to two carbon units of Z E are optionally and independently replaced by —CO—, —CS—, —CONR 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 10 is independently R E , —OH, —NH 2 , —NO 2 , —CN, —CF 3 , oxo, or —OCF 3 ,

Each R E is independently hydrogen, an optionally substituted cycloaliphatic, an optionally substituted heterocycloaliphatic, an optionally substituted aryl, or an optionally substituted heteroaryl; and

q is 0-5.

9. The method of claim 4 , wherein R′ 3 is H.

10. The method of claim 4 , wherein one of R 3 or R′ 3 is an optionally substituted acyl group.

11. The method of claim 4 , wherein one of R 3 or R′ 3 is an (alkoxy)carbonyl optionally substituted with 1-3 of halo, hydroxy, or combinations thereof.

12. The method of claim 4 , wherein one of R 3 or R′ 3 is an (aliphatic)carbonyl optionally substituted with 1-3 of halo, hydroxy, or combinations thereof.

13. The method of claim 4 , wherein one of R 3 or R′ 3 is a (cycloaliphatic)carbonyl or a (heterocycloaliphatic)carbonyl, each is optionally substituted with 1-3 of aliphatic, halo, hydroxy, nitro, cyano, or combinations thereof.

14. The method claim 13 , wherein one of R 3 or R′ 3 is (piperidine-1-yl,)carbonyl, (pyrrolidine-1-yl)carbonyl, (morpholine-4-yl)carbonyl, (piperazine-1-yl)carbonyl, (cyclopropyl)carbonyl, (cyclobutyl)carbonyl, (cyclopentyl)carbonyl, (cyclohexyl)carbonyl, or (cycloheptyl)carbonyl, each of which is each of which is optionally substituted with 1-3 of halo, hydroxy, cyano, nitro, aliphatic, or combinations thereof.

15. The method of claim 4 , wherein R 3 is optionally substituted (aliphatic)amido that is attached to the 2 or 3 position on the indole ring of formula Ia.

16. The method of claim 15 , wherein R 3 is (N,N-dimethyl(amino))carbonyl, (methyl(amino))carbonyl, (ethyl(amino))carbonyl, (propyl(amino))carbonyl, (prop-2-yl(amino))carbonyl, (dimethyl(but-2-yl(amino)))carbonyl, (tertbutyl(amino))carbonyl, (butyl(amino))carbonyl, each of which is optionally substituted with 1-3 of halo, hydroxy, cycloaliphatic, heterocycloaliphatic, aryl, heteroaryl, or combinations thereof.

17. The method of claim 4 , wherein R′ 3 is

wherein R 31 is H or a C 1-2 aliphatic that is optionally substituted with 1-3 of halo, —OH, or combinations thereof, R 32 is -L-R 33 , wherein L is a bond, —CH 2 —, —CH 2 O—, —CH 2 NHS(O) 2 —, —CH 2 C(O)—, —CH 2 NHC(O)—, or —CH 2 NH—, and R 33 is hydrogen, or C 1-2 aliphatic, cycloaliphatic, heterocycloaliphatic, or heteroaryl, each of which is optionally substitututed with 1 of —OH, —NH 2 , or —CN.

18. The method of claim 4 , wherein R′ 3 is independently selected from one of the following: —H, —CH 3 , —CH 2 CH 3 , —C(O)CH 3 , —CH 2 CH 2 OH, —C(O)OCH 3 ,

19. The method of claim 3 , wherein the compound is: