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 II:
or a pharmaceutically acceptable salt thereof, wherein independently for each occurrence:
R is H, OH, OCH 3 or two R taken together form —OCH 2 O— or —OCF 2 O—;
R 1 is H or up to two C 1 -C 6 alkyl;
R 2 is H or halo;
R 3 is H or C 1 -C 6 alkyl; and
Y is O.
2. The compound of claim 1 of formula II, wherein two R taken together form —OCF 2 O—, R 1 is H, and R 2 is F.
3. The compound of claim 1 of formula II, wherein two R taken together form OCF 2 O—, R 1 is H, R 2 is F, and R 3 is CH 3 .
4. The compound of claim 1 , having formula IIa:
or a pharmaceutically acceptable salt thereof, wherein:
R 2 is H or halo.
5. The compound of claim 4 , wherein R 2 is F.
6. The compound of claim 1 , wherein the compound is
7. The compound of claim 1 , wherein the compound is
8. A pharmaceutical composition comprising
(i) a compound according to claim 1 ; and
(ii) a pharmaceutically acceptable carrier.
9. A method of treating cystic fibrosis, emphysema, COPD, or dry-eye disease comprising the step of administering to the subject a compound of claim 1 .
10. A process for preparing a compound of formula IIa
wherein R 2 is H or halo, comprising:
(a) contacting the compound of formula I-5 with carbonyl diimidazole (CDI) in the presence of a solvent to give a compound of formula I-4;
(b) contacting the compound of formula I-4 with an oxidant in the presence of a solvent to give a compound of formula I-3;
and
(c) contacting the compound of formula I-3 with a base in the presence of a solvent to give a compound of formula IIa:
11. The process of claim 10 , wherein R 2 is H or F.