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 of Formula III:
or a pharmaceutically acceptable salt thereof, wherein:
L-Ar is
Ar is
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;
R 24 is H, —CN, —(C 1 -C 4 alkyl)-CN, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, —(C 1 -C 4 alkyl)-OH, —(C 1 -C 4 alkyl)-N(R 241 ) 2 , —(C 1 -C 4 alkyl) t -O u —(C 3 -C 6 cycloalkyl), —(C 1 -C 4 alkyl) t -O u —(4- to 6-membered heterocycle) or —(C 1 -C 4 alkyl)-O—(C 1 -C 4 alkyl), wherein each of the —C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl and 4- to 6-membered heterocycle moieties is optionally substituted, and wherein:
t is 0 or 1;
u is 0 or 1;
with the proviso that when u is 1, t is 1; and
each R 241 is independently H or C 1 -C 2 alkyl; and
R 25 is halogen, —CN, —(C 1 -C 4 alkyl)-CN, C 1 -C 2 alkyl, C 1 -C 2 haloalkyl, or cyclopropyl, wherein each of the —C 1 -C 2 alkyl and cyclopropyl moieties is optionally substituted.
2. The compound of claim 1 , wherein when L-Ar is
Ar is not
3. The compound of claim 1 , wherein L-Ar is
and Ar is
4. The compound of claim 1 , wherein R 1 is halogen, —CN or C 1 -C 2 haloalkyl.
5. The compound of claim 1 , wherein R 2 is H.
6. The compound of claim 1 , wherein R 21 is halogen, C 1 -C 4 alkyl or C 3 -C 5 cycloalkyl.
7. The compound of claim 1 , wherein R 22 is H or —CH 3 .
8. The compound of claim 1 , wherein R 24 is H, —CN, —(C 1 -C 4 alkyl)-CN, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, —(C 1 -C 4 alkyl)-OH, —(C 1 -C 4 alkyl)-N(R 241 ) 2 , —(C 1 -C 4 alkyl) t -O u —(C 3 -C 6 cycloalkyl), —(C 1 -C 4 alkyl) t -O u —(4- to 6-membered heterocycle) or —(C 1 -C 4 alkyl)-O—(C 1 -C 4 alkyl).
9. The compound of claim 1 , wherein when R 24 is —(C 1 -C 4 alkyl)-CN, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, —(C 1 -C 4 alkyl)-OH, —(C 1 -C 4 alkyl)-N(R 241 ) 2 , —(C 1 -C 4 alkyl) t -O u —(C 3 -C 6 cycloalkyl), —(C 1 -C 4 alkyl) t -O u —(4- to 6-membered heterocycle) or —(C 1 -C 4 alkyl)-O—(C 1 -C 4 alkyl), R 24 is substituted with one or more substituents selected from C 1 -C 2 alkyl, oxo, —CN, halogen, alkanoyl, alkoxycarbonyl, —OH and C 1 -C 2 alkoxy.
10. The compound of claim 1 , wherein R 25 is halogen, —CN, C 1 -C 2 alkyl or cyclopropyl.
11. The compound of claim 1 , wherein when R 25 is —(C 1 -C 4 alkyl)-CN, C 1 -C 2 alkyl, C 1 -C 2 haloalkyl, or cyclopropyl, R 25 is substituted with one or more substituents selected from —OH, halogen, C 1 -C 2 alkyl, alkoxy, and alkylcarbonyloxy.
12. A compound of Formula I or Formula IV:
or
or a pharmaceutically acceptable salt thereof, wherein:
L 3 is —CH 2 —, —CH(R 50 )—, —O—, —N(R 50 )—, —N[C(O)R 50 ]— or —N[C(O)OR 50 ]—, wherein R 50 is C 1 -C 6 alkyl, C 3 -C 5 cycloalkyl, or 4- to 6-membered heterocycle;
n is 1, 2, or 3;
m is 1 or 2 with the proviso that n+m≥3;
L-Ar is
Ar is
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, le 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 a 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)-N(R 241 ) 2 , —(C 1 -C 4 alkyl) t -O u —(C 3 -C 5 cycloalkyl), —(C 1 -C 4 alkyl) t -O u -(4- to 6-membered heterocycle) or —(C 1 -C 4 alkyl)-O—(C 1 -C 4 alkyl), wherein:
t is 0 or 1;
u is 0 or 1;
with the proviso that when u is 1, t is 1; and
R 241 is H or C 1 -C 2 alkyl.
13. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, excipient, or diluent.
14. A method of treating a hepatitis C infection in a subject comprising administering to the subject a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.
15. 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 , or a pharmaceutically acceptable salt thereof.
16. A method of treating cancer in a subject comprising administering to the subject a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof, 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.
17. The method of claim 16 , wherein the cancer is breast cancer, pancreatic cancer, or colon cancer.
18. The method of claim 16 , wherein the cancer is pancreatic cancer.
19. The compound of claim 3 , wherein Ar is
20. The compound of claim 4 , wherein R 1 is —CN.
21. The compound of claim 6 , wherein R 21 is —CH 3 .
22. The compound of claim 7 , wherein R 22 is —CH 3 .
23. The compound of claim 8 , wherein R 24 is methyl, isopropyl, cyclopropyl, —CN, haloalkyl, or —(C 1 -C 2 alkyl)-CN.
24. The compound of claim 9 , wherein when R 24 is —(C 1 -C 4 alkyl)-CN, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, —(C 1 -C 4 alkyl)-OH, —(C 1 -C 4 alkyl)-N(R 241 ) 2 , —(C 1 -C 4 alkyl) t -O u —(C 3 -C 6 cycloalkyl), —(C 1 -C 4 alkyl) t -O u —(4- to 6-membered heterocycle) or —(C 1 -C 4 alkyl)-O—(C 1 -C 4 alkyl), R 24 is substituted with one or more substituents selected from methyl, —F, methoxy, —C(═O)CH 3 and —C(═O)—OCH 3 .
25. The compound of claim 11 , wherein R 25 is —CH 2 OCH 3 .
26. The compound of claim 11 , wherein when R 25 is —(C 1 -C 4 alkyl)-CN, C 1 -C 2 alkyl, C 1 -C 2 haloalkyl, or cyclopropyl, R 25 is substituted with one or more substituents selected from —F, methyl, methoxy and —O—C(═O)—CH 3 .
27. A pharmaceutical composition comprising a compound of claim 12 , or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, excipient, or diluent.
28. A method of treating a hepatitis C infection in a subject comprising administering to the subject a therapeutically effective amount of a compound of claim 12 , or a pharmaceutically acceptable salt thereof.
29. 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 12 , or a pharmaceutically acceptable salt thereof.
30. A method of treating cancer in a subject comprising administering to the subject a therapeutically effective amount of a compound of claim 12 , or a pharmaceutically acceptable salt thereof, 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.
31. The method of claim 30 , wherein the cancer is breast cancer, pancreatic cancer, or colon cancer.
32. The method of claim 30 , wherein the cancer is pancreatic cancer.
33. The compound of claim 1 , wherein R 25 is —C 1 -C 2 alkyl optionally substituted with an alkoxy group.