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 method of treating or lessening the severity of a disease in a patient, wherein said disease is pancreatic insufficiency or male infertility comprising the step of administering to said patient an effective amount of a compound of formula I:
or a pharmaceutically acceptable salt thereof, wherein:
Each R 1 is independently an optionally substituted C 1-6 aliphatic, an optionally substituted aryl, an optionally substituted C 3-10 membered cycloaliphatic, carboxy, amido, amino, halo, or hydroxy, provided that at least one R 1 is an optionally substituted aryl and said R 1 is attached to the 3- or 4-position of the phenyl ring;
R 2 is hydrogen, an optionally substituted C 1-6 aliphatic, an optionally substituted C 3-6 cycloaliphatic, an optionally substituted phenyl, or an optionally substituted heteroaryl;
Ring A is an optionally substituted cycloaliphatic;
R 4 is an optionally substituted benzo[d][1,3]dioxolyl ring; and
n is 1, 2, 3, 4, or 5.
2. The method of claim 1 , wherein the one R 1 attached to the 3- or 4-position of the phenyl ring is an aryl optionally substituted with 1, 2, or 3 of R A , wherein R A is —Z A R 5 ; in which 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 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, —B(OH) 2 , —OH, —NH 2 , —NO 2 , —CN, or —OCF 3 ; and each R B is independently hydrogen, an optionally substituted C 1-8 aliphatic group, an optionally substituted cycloaliphatic, an optionally substituted heterocycloaliphatic, an optionally substituted aryl, or an optionally substituted heteroaryl.
3. The method of claim 2 , wherein the one R 1 attached to the 3- or 4-position of the phenyl ring is a phenyl optionally substituted with 1, 2, or 3 of R A .
4. The method of claim 1 , wherein R 2 is hydrogen or methyl.
5. The method of claim 1 , wherein ring A is an unsubstituted C 3-7 cycloaliphatic.
6. The method of claim 5 , wherein ring A is an unsubstituted cyclopropyl, an unsubstituted cyclopentyl, or an unsubstituted cyclohexyl.
7. The compound of claim 6 , wherein ring A is an unsubstituted cyclopropyl.
8. The compound of claim 1 , wherein R 4 is one selected from
9. The method of claim 1 , wherein the compound is selected from
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959
10. The method of claim 1 , wherein the compound is