Heterocyclic modulators of lipid synthesis and combinations thereof
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 dysregulation of a fatty acid synthase pathway by the administration of such compounds and combinations of such compounds and other therapeutic agents.
1. A method of treating a cancer in a subject by administering to the subject a therapeutically effective amount of:
(i) a first therapeutic agent, wherein the first therapeutic agent is a compound of Formula II:
or pharmaceutically acceptable salts 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; and
R 24 is H, C 1 -C 4 alkyl, —(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; and
(ii) a second therapeutic agent selected from the group consisting of paclitaxel, gemcitabine, and irinotecan.
2. The method of claim 1 , wherein, in the compound of Formula II, L-Ar is
3. The method of claim 2 , wherein, in the compound of Formula II Ar is
4. The method of claim 1 , wherein, in the compound of Formula II (i) R 1 is halogen, —CN or C 1 -C 2 haloalkyl; or (ii) R 1 is —CN.
5. The method of claim 1 , wherein, in the compound of Formula II, R 2 is H.
6. The method of claim 1 , wherein, in the compound of Formula II, (i) R 21 is halogen, C 1 -C 4 alkyl or C 3 -C 5 cycloalkyl; or (ii) R 21 is C 1 -C 4 alkyl or C 3 -C 5 cycloalkyl; or (iii) R 21 is C 1 -C 2 alkyl or C 3 -C 5 cycloalkyl; or (iv) R 21 is C 3 -C 5 cycloalkyl; or (v) R 21 is C 1 -C 2 alkyl; or (vi) R 21 is —CH 3 .
7. The method of claim 1 , wherein, in the compound of Formula II, (i) R 22 is H or C 1 -C 2 alkyl; or (ii) R 22 is C 1 -C 2 alkyl; or (iii) R 22 is H or —CH 3 ; or (iv) R 22 is H; or (v) R 22 is —CH 3 .
8. The method of claim 1 , wherein, in the compound of Formula II, (i) R 21 is halogen, C 1 -C 4 alkyl, C 3 -C 5 cycloalkyl or 4- to 6-membered heterocycle; (ii) R 21 is H, C 1 -C 4 alkyl, C 3 -C 5 cycloalkyl or 4- to 6-membered heterocycle.
9. The method of claim 1 , wherein, in the compound of Formula II, (i) R 24 is C 1 -C 4 alkyl or —(C 1 -C 4 alkyl) t -O—(C 1 -C 4 alkyl); or (ii) R 24 is —(C 1 -C 2 alkyl) t -O—(C 1 -C 2 alkyl).
10. The method of claim 1 , wherein the cancer is selected from the group consisting of breast cancer; ovarian cancer; lung cancer; colon cancer; and pancreatic cancer.
11. The method of claim 1 , wherein the second therapeutic agent is paclitaxel.
12. The method of claim 1 , wherein the second therapeutic agent is gemcitabine.
13. The method of claim 1 , wherein the second therapeutic agent is irinotecan.
14. The method of claim 10 , wherein the cancer is lung cancer.
15. The method of claim 10 , wherein the cancer is ovarian cancer.
16. The method of claim 10 , wherein the cancer is pancreatic cancer.
17. The method of claim 10 , wherein the cancer is colon cancer.
18. The method of claim 10 , wherein the cancer is breast cancer.