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 is an optionally substituted C 1-6 aliphatic, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted 3 to 10 membered heterocycloaliphatic, provided that at least one R 1 is an optionally substituted heterocycloaliphatic, an optionally substituted aryl, or an optionally substituted heteroaryl attached to the 1-position of the isoquinoline ring;
R 2 is hydrogen, or an optionally substituted C 1-6 aliphatic;
R 3 and R′ 3 together with the carbon atom to which they are attached form an optionally substituted C 3-7 cycloaliphatic;
R 4 is an optionally substituted aryl or an optionally substituted heteroaryl; and
n is 1, 2, 3, 4, 5, or 6.
2. The compound according to claim 1 , wherein the one R 1 attached to the 1 -position of the isoquinoline ring is substituted with 1, 2, or 3 of —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—, —CONR E —, —CO 2 —, —O—, —NR E CO—, —SO 2 —, —NR E —, —SO 2 NR E —, or —NR E SO 2 —; each R 9 is independently R E , —OH, —NH 2 , —N(CH 3 ) 2 , or —N +(CH 3 ) 3 ; and each R E is independently hydrogen or an optionally substituted C 1-8 aliphatic group.
3. The compound according to claim 2 , wherein the one R 1 attached to the 1-position of the isoquinoline ring is phenyl optionally substituted with 1 or 2 of —Z D R 9 .
4. The compound according to claim 2 , wherein the one R 1 attached to the 1-position of the isoquinoline ring is a heteroaryl optionally substituted with 1 —Z D R 9 .
5. The compound according to claim 2 , wherein the one R 1 attached to the 1-position of the isoquinoline ring is a heterocycloaliphatic, optionally substituted with 1 —Z D R 9 .
6. The compound according to claim 1 , wherein the one R 1 attached to the 1-position of the isoquinoline ring is selected from the group consisting of
7. The compound according to claim 1 , wherein R 3 and R′ 3 together with the carbon atom to which they are attached form a C 3-7 cycloaliphatic.
8. The compound according to claim 1 , wherein R 3 and R′ 3 together with the carbon atom to which they are attached form a cyclopropyl ring.
9. The compound according to claim 1 , wherein R 4 is an optionally substituted phenyl.
10. The compound according to claim 1 , wherein R 4 is one selected from the group consisting of
11. The compound according to claim 1 , wherein said compound has formula (III):
or a pharmaceutically acceptable salt thereof, wherein independently for each occurrence:
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—, —CONR E —, —CO 2 —, —NR E CO 2 —, —O—, —NR E CO—, —SO 2 —, —NR E —, —SO 2 NR E —, or —NR E SO 2 —;
R 9 is R E , —OH, —NH 2 , —N(CH 3 ) 2 , or —+(CH 3 ) 3 ;
R E is hydrogen or an optionally substituted C 1-8 aliphatic group;
R 2 is H or C 1-4 aliphatic;
R 3 and R ′ 3 together with the carbon atom to which they are attached form a C 3-7 cycloaliphatic;
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 —O—; or R 4 is an aryl or heteroaryl substituted with two occurrences of —Z c R 8 , that taken together with carbons to which they are attached, form a 4-8 membered saturated, partially saturated, or aromatic ring with up to 2 ring atoms being O; and
R 8 is an optionally substituted C 1-8 aliphatic group.
12. The compound according to claim 1 , wherein said compound has formula IV:
or a pharmaceutically acceptable salt thereof, wherein independently for each occurrence:
T is an optionally substituted C 1-2 aliphatic chain, wherein each of the carbon units is optionally and independently replaced by —CF 2 —;
R 1 ′ is hydrogen, or an optionally substituted C 1-6 aliphatic;
R D1 is attached to carbon number 3″ or 4″;
R D1 and R D2 are —Z D R 9 , wherein each Z D is independently a bond or an optionally substituted branched or straight C 1 -C 6 aliphatic chain wherein up to two carbon units of Z D are optionally and independently replaced by —CO—, —CONR E —, —CO 2 —, —O—, —NR E CO—, —SO 2 —, —NR E —, —SO 2 NR E —, or —NR E SO 2 —; 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 0 and NR E ;
R 9 is R E , —OH, —NH 2 , —N(CH 3 ) 2 , or —+(CH 3 ) 3 ; and
R E is hydrogen or an optionally substituted C 1-8 aliphatic group.
13. The compound according to claim 12 , wherein T is selected from the group consisting of —CH 2 —and —CF 2 —.
14. The compound according to claim 12 , wherein R D1 is —CO 2 H attached to carbon number 3″, R D2 is H, T is —CF 2 —, and R 1 ′ is H.
15. The compound according to claim 12 , wherein R D1 is —CO 2 H attached to carbon number 4″, R D2 is H, T is —CF 2 —, and R 1 ′ is H.
16. The compound according to claim 12 , 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 and NR E .
17. The compound according to claim 16 , wherein R D1 and R D2 , taken together with phenyl containing carbon atoms 3″ and 4″, is
18. The compound according to claim 1 , wherein said compound has formula (VI):
wherein G is —O—, —CHR 9 —, or —NR 9 —;
X is O or H,H;
R 10 and R 11 are independently H or alkoxy; or R 10 and R 11 taken together form
T is —CH 2 —, —CF 2 —, or —C(CH 3 ) 2 —;
R 9 is hydrogen, an optionally substituted C 1-8 aliphatic group, or an optionally substituted aryl; and
R 1 ′ is H or an optionally substituted C 1-6 aliphatic.
19. The compound of claim 18 , wherein G is —O—.
20. The compound of claim 18 , wherein G is —CHR 9 —.
21. The compound of claim 18 , wherein G is —NR 9 —.
22. The compound of claim 18 , wherein X is O.
23. The compound of claim 18 , wherein X is H,H.
24. The compound of claim 18 , wherein R 9 is aliphatic.
25. The compound of claim 18 , wherein R 9 is aryl.
26. The compound of claim 18 , wherein R 9 is methyl or phenyl.
27. The compound of claim 18 , wherein R 11 is alkoxy.
28. The compound of claim 18 , wherein G is —NR 9 —, R 9 is methyl, and Xis H,H.
29. The compound of claim 18 , wherein G is —NR 9 —, R 9 is phenyl, and X is O.
30. The compound of claim 18 , wherein G is —CHR 9 —, R 9 is phenyl, and X is H,H.
31. The compound of claim 18 , wherein G is —NR 9 —, R 9 is H, and Xis O.
32. The compound of claim 18 , wherein G is —NR 9 —, R 9 is methyl, X is H,H, R 11 is methoxy, and R 10 is H.
33. The compound of claim 18 , wherein G is —CHR 9 —, R 9 is phenyl, X is H,H, R 11 is methoxy, and R 10 is H.
34. The compound of claim 18 , wherein G is —NR 9 —, R 9 is H, X is O, R 11 is methoxy, and R 10 is H.
35. The compound according to claim 1 , wherein said compound has formula (VII):
wherein Y is CH or N providing that at least one Y is N;
m is an integer from 0 to 4 inclusive;
T is an optionally substituted C 1-2 aliphatic chain, wherein each of the carbon units is optionally and independently replaced by —CF 2 —; and
R 1 ′ is hydrogen or an optionally substituted C 1-6 aliphatic.
36. The compound of claim 35 , wherein T is —CH 2 —or —CF 2 —.
37. The compound of claim 35 , wherein the meta Y is N.
38. The compound of claim 35 , wherein m is 1.
39. The compound of claim 35 , wherein R 1 is alkoxy.
40. The compound of claim 35 , wherein R 1 is methoxy.
41. The compound according to claim 1 , wherein the compound is one of the following
42. A pharmaceutical composition comprising:
(i) a compound according to claim 1 ; and
(ii) a pharmaceutically acceptable carrier.
43. The composition according to claim 42 , further comprising a mucolytic agent, a bronchodialator, an antibiotic, an anti-infective agent, an anti-inflammatory agent, a CFTR modulator, or a nutritional agent.
44. A kit for use in measuring the activity of an ABC transporter or a fragment thereof in a biological sample in vitro or in vivo, comprising:
(i) a composition comprising a compound according to claim 1 ; and
(ii) instructions for:
a) contacting the composition with the biological sample; and
b) measuring activity of said ABC transporter or a fragment thereof.
45. The kit according to claim 44 , further comprising instructions for
a) contacting an additional composition with the biological sample;
b) measuring the activity of said ABC transporter or a fragment thereof in the presence of said additional compound, and
c) comparing the activity of the ABC transporter in the presence of the additional compound with the density of the ABC transporter in the presence of a compound according to claim 1 .
46. The kit according to claim 45 , wherein the kit is used to measure the density of CFTR.