Modulators of ATP-binding cassette transporters
Compounds of the present invention and pharmaceutically acceptable compositions thereof, are useful as modulators of ATP-Binding Cassette (“ABC”) transporters or fragments thereof, including Cystic Fibrosis Transmembrane Conductance Regulator (“CFTR”). The present invention also relates to methods of treating ABC transporter mediated diseases using compounds of the present invention.
1. 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 —, —OC 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;
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 substited 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 compound of claim 1 , wherein R 1 is H or C 1 -C 6 aliphatic.
3. The compound of claim 1 , wherein R 1 is H.
4. The compound of claim 1 , wherein two adjacent R 2 together with the atoms to which they are attached form an optionally substituted carbocycle or an optionally substituted heterocycle.
5. The compound of claim 1 , wherein two adjacent R 2 together with the atoms to which they are attached form an optionally substituted heterocycle.
6. The compound of claim 1 , wherein two adjacent R 2 together with the atoms to which they are attached form an optionally substituted heterocycle selected from
7. The compound of claim 1 , wherein two adjacent R 2 together with the atoms to which they are attached form an optionally substituted heterocycle selected from
8. The compound of claim 1 , wherein two adjacent R 2 together with the atoms to which they are attached form
9. The compound of claim 1 , wherein ring A is selected from
10. The compound of claim 1 , wherein ring A is
11. The compound of claim 1 , wherein 1 R 3 is halo.
12. The compound of claim 1 , wherein 1 R 3 is F.
13. The compound of claim 1 , wherein R′ 3 and an adjacent R 3 together with the atoms to which they are attached form an optionally substituted heterocycle.
14. The compound of claim 1 , wherein R′ 3 and an adjacent R 3 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 compound 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. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier or adjuvant.
17. The composition 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 kit for use in measuring the activity of a CFTR or a fragment thereof in a biological sample in vitro or in vivo, comprising:
(i) a compound of formula I according to claim 1 ;
(ii) instructions for:
a) contacting the compound with the biological sample;
b) measuring activity of the CFTR or a fragment thereof.
19. The kit of claim 18 , further comprising instructions for
a) contacting an additional compound with the biological sample;
b) measuring the activity of the CFTR or a fragment thereof in the presence of the additional compound, and
c) comparing the activity of the CFTR or fragment thereof in the presence of the additional compound with the activity of the CFTR or fragment thereof in the presence of a compound of formula I.
20. The kit of claim 19 , wherein the step of comparing the activity of the CFTR or fragment thereof provides a measure of the density of the CFTR or fragment thereof.