Heterocyclic modulators of lipid synthesis
Heterocyclic modulators of lipid synthesis are provided as well as pharmaceutically acceptable salts thereof; pharmaceutical compositions comprising such compounds; and methods of treating conditions characterized by disregulation of a fatty acid synthase pathway by the administration of such compounds.
1. A compound having Structure II:
or pharmaceutically acceptable salts thereof, wherein:
L-Ar is
Ar is
with the proviso that when L-Ar is
Ar is not
Het is a 5- to 6-membered heteroaryl;
R 1 is H, —CN, halogen, C 1 -C 4 alkyl, —O—(C 3 -C 5 cycloalkyl), —O-(4- to 6-membered heterocycle) or —O—(C 1 -C 4 alkyl), wherein when R 1 is not H, —CN or halogen, R 1 is optionally substituted with one or more halogens;
each R 2 is independently hydrogen, halogen or C 1 -C 4 alkyl;
R 3 is H or F;
R 11 is H or —CH 3 ;
R 21 is H, halogen, C 1 -C 4 alkyl, C 3 -C 5 cycloalkyl or 4- to 6-membered heterocycle;
R 22 is H, halogen, or C 1 -C 2 alkyl; and
R 24 is H, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, —(C 1 -C 4 alkyl)-OH, —(C 1 -C 4 alkyl) t -N(R 241 ) 2 , —(C 1 -C 4 alkyl) t -O t —(C 3 -C 5 cycloalkyl), —(C 1 -C 4 alkyl) t -O t -(4- to 6-membered heterocycle) or —(C 1 -C 4 alkyl) t -O—(C 1 -C 4 alkyl), wherein:
each t is independently 0 or 1; and
each R 241 is independently H or C 1 -C 2 alkyl.
2. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier, excipient, or diluent.
3. A method of treating hepatitis C in a subject comprising administering to the subject a therapeutically effective amount of a compound of claim 1 .
4. A method of inhibiting fatty acid synthase activity in a subject by administering to the subject a therapeutically effective amount of a compound of claim 1 .
5. A method of treating cancer in a subject comprising administering to the subject a therapeutically effective amount of a compound of claim 1 wherein the cancer is selected from the group consisting of breast, lung, thyroid, lymph node, kidney, ureter, bladder, ovary, teste, prostate, bone, skeletal muscle, bone marrow, stomach, esophagus, small bowel, colon, rectum, pancreas, liver, smooth muscle, brain, spinal cord, nerves, ear, eye, nasopharynx, oropharynx, salivary gland, or heart tissue.
6. The compound of claim 1 wherein L-Ar is
and Ar is
7. The compound of claim 6 wherein L-Ar is
and Ar is
8. A compound of claim 7 wherein Ar is
9. The compound of claim 1 wherein R 1 is halogen, —CN or C 1 -C 2 haloalkyl.
10. The compound of claim 9 wherein R 1 is —CN.
11. The compound of claim 1 wherein R 2 is H.
12. The compound of claim 1 wherein R 21 is halogen, C 1 -C 4 alkyl, C 3 -C 5 cycloalkyl or 4- to 6-membered heterocycle.
13. The compound of claim 1 wherein R 21 is H, C 1 -C 4 alkyl, C 3 -C 5 cycloalkyl or 4- to 6-membered heterocycle.
14. The compound of claim 12 wherein R 21 is C 1 -C 2 alkyl or C 3 -C 5 cycloalkyl.
15. The compound of claim 14 wherein R 21 is C 1 -C 2 alkyl.
16. The compound of claim 14 wherein R 21 is C 3 -C 5 cycloalkyl.
17. The compound of claim 1 wherein R 22 is H or C 1 -C 2 alkyl.
18. The compound of claim 17 wherein R 22 is H.
19. The compound of claim 17 wherein R 22 is C 1 -C 2 alkyl.
20. The compound of claim 19 wherein R 22 is —CH 3 .
21. The compound of claim 1 wherein R 24 is C 1 -C 4 alkyl or —(C 1 -C 4 alkyl) t -O—(C 1 -C 4 alkyl).
22. The compound of claim 21 wherein R 24 is —(C 1 -C 2 alkyl) t -O—(C 1 -C 2 alkyl).