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 IIc:
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 —; and
each R 4 is independently R A , halo, —OH, —NH 2 , —NO 2 , —CN, or —OCF 3 ;
and wherein
each R A is independently selected from hydrogen, an optionally substituted aliphatic, an optionally substituted cycloaliphatic, an optionally substituted heterocycloaliphatic, an optionally substituted aryl, and an optionally substituted heteroaryl;
each R 2 is —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 —; and
each R 5 is independently selected from R B , halogen, —OH, —NH 2 , —NO 2 , —CN, CF 3 , and —OCF 3 ;
and wherein
each R B is independently selected from hydrogen, an optionally substituted aliphatic, an optionally substituted cycloaliphatic, an optionally substituted heterocycloaliphatic, an optionally substituted aryl, and an optionally substituted heteroaryl;
or wherein 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; and
each R 3 and R′3 is independently —Z C R 6 ; 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 6 is independently selected from R C , halogen, —OH, —NH 2 , —NO 2 , —CN, and —OCF 3 ;
and wherein
each R C is independently selected from hydrogen, an optionally substituted aliphatic, an optionally substituted cycloaliphatic, an optionally substituted heterocycloaliphatic, an optionally substituted aryl, and an optionally substituted heteroaryl;
or wherein any two adjacent R 3 groups, together with the atoms to which they are attached, form an optionally substituted carbocycle or an optionally substituted heterocycle;
n is 1-3; and
p is 0-3.
2. A compound of formula IId:
or a pharmaceutically acceptable salt thereof; wherein:
both R 2 groups, together with the atoms to which they are attached, form a group selected from:
R′ 3 is independently selected from:
each R 3 is independently selected from —H, —CH 3 , —CH 2 OH, —CH 2 CH 3 , —CH 2 CH 2 OH, —CH 2 CH 2 CH 3 , —NH 2 , halo, —OCH 3 , —CN, —CF 3 , —C(O)OCH 2 CH 3 , —S(O) 2 OCH 3 , —CH 2 NH 2 , —C(O)NH 2 ,
3. A compound according to claim 2 , wherein both R 2 groups, together with the atoms to which they are attached, is selected from the groups:
4. A compound according to claim 3 , wherein R′ 3 is hydrogen or the group:
wherein
R 31 is H or a C 1-2 aliphatic that is optionally substituted with 1-3 halogen, —OH, or combinations thereof;
R 32 is -L-R 33 ;
and 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, C 1-2 aliphatic, cycloaliphatic, heterocycloaliphatic, or heteroaryl, each of which is optionally substituted with one of —OH, —NH 2 , or —CN.
5. A compound according to claim 4 , wherein R 31 is hydrogen and R 32 is C 1-2 aliphatic optionally substituted with one of —OH, NH 2 , or —CN.
6. A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 - 4 , and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
7. A pharmaceutical composition according to claim 6 , wherein the pharmaceutical composition further comprises one or more additional therapeutic agents.
8. A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt thereof according to claim 5 , and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
9. A pharmaceutical composition according to claim 8 , wherein the pharmaceutical composition further comprises one or more additional therapeutic agents.
10. A method of treating or lessening the severity of cystic fibrosis in a patient, comprising the step of administering to a patient an effective amount of a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 - 4 .
11. A method of treating or lessening the severity of cystic fibrosis in a patient, comprising the step of administering to a patient an effective amount of a compound or a pharmaceutically acceptable salt thereof according to claim 5 .