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 selected from the group:
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2. A pharmaceutical composition comprising a compound as described in claim 1 and a pharmaceutically acceptable carrier.
3. 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.
4. The kit of claim 3 , 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 composition of formula (I).
5. The kit of claim 3 , wherein the kit is used to measure the density of CFTR.
6. 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, 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 C 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.
7. The compound of claim 6 , wherein R 1 is —Z A R 4 , Z A is a bond, and R 4 is hydrogen.
8. The compound of claim 6 , 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.
9. The compound of claim 6 , wherein ring A is an optionally substituted 3-7 membered monocyclic heterocycloaliphatic.
10. The compound of claim 6 , 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.
11. The compound of claim 6 , wherein R′ 3 is H.
12. The compound of claim 6 , wherein one of R 3 or R′ 3 is an optionally substituted acyl group.
13. The compound of claim 6 , wherein one of R 3 or R′ 3 is an (alkoxy)carbonyl optionally substituted with 1-3 of halo, hydroxy, or combinations thereof.
14. The compound of claim 6 , wherein one of R 3 or R′ 3 is an (aliphatic)carbonyl optionally substituted with 1-3 of halo, hydroxy, or combinations thereof.
15. The compound of claim 6 , 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.
16. The compound of claim 15 , 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.
17. The compound of claim 6 , wherein R 3 is optionally substituted (aliphatic)amido that is attached to the 2 or 3 position on the indole ring of formula Ia.
18. The compound of claim 17 , 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.
19. The compound of claim 6 , 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 substituted with 1 of —OH, —NH 2 , or —CN.
20. The compound of claim 6 , 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 ,
21. A pharmaceutical composition comprising a compound as described in claim 6 and a pharmaceutically acceptable carrier.
22. 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 6 ; and
(ii) instructions for:
a) contacting the composition with the biological sample; and
b) measuring activity of said ABC transporter or a fragment thereof.
23. The kit of claim 22 , 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 composition of formula (I).
24. The kit of claim 22 , wherein the kit is used to measure the density of CFTR.