2-oxoquinazoline derivatives as methionine adenosyltransferase 2A inhibitors
Disclosed herein are certain 2-oxoquinazoline derivatives of Formula (IA): that are methionine adenosyltransferase 2A (MAT2A) inhibitors. Also disclosed are pharmaceutical compositions comprising such compounds and methods of treating diseases treatable by inhibition of MAT2A such as cancer, including cancers characterized by reduced or absence of methylthioadenosine phosphorylase (MTAP) activity.
1. A compound of Formula (IIIa):
or a pharmaceutically acceptable salt thereof, wherein
R 3 is hydrogen;
R 5 is C3-6 cycloalkyl;
R 4 is hydrogen or cyano;
R 6 is hydrogen;
R 1 is R 7 wherein R 7 is phenyl or 5- to 6-membered heteroaryl, wherein phenyl or heteroaryl, is unsubstituted or substituted with R d , R e , and/or R f ;
R 2 is —NR 9 R 10 ;
R 9 is hydrogen;
R 10 is hydrogen, C 1-6 alkyl, C 1-6 hydroxyalkyl, or C 3-6 cycloalkyl, wherein C 3-6 cycloalkyl is unsubstituted or substituted with halo;
R d and R e are independently selected from C 1-6 alkyl, halo, C 1-6 haloalkoxy, and C 1-6 haloalkyl; and
R f is selected from C 1-6 alkyl, halo, C 1-6 haloalkoxy, and C 1-6 haloalkyl.
2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 7 is phenyl, wherein phenyl is unsubstituted or substituted with R d , R e , and/or R f , wherein R d and R e are independently selected from C 1-6 alkyl and halo, and R f is selected from C 1-6 alkyl and halo.
3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 7 is pyridinyl or pyrazinyl, wherein pyridinyl or pyrazinyl, are independently unsubstituted or substituted with R d , R e , and/or R f , wherein R d and R e are independently selected from C 1-6 alkyl, halo, C 1-6 haloalkoxy, and C 1-6 haloalkyl, and R f is selected from C 1-6 alkyl, halo, C 1-6 haloalkoxy, and C 1-6 haloalkyl.
4. A compound that is selected from:
or a pharmaceutically acceptable salt thereof.
5. The compound according to claim 4 , or a pharmaceutically acceptable salt thereof, wherein the compound is:
6. The compound according to claim 4 , or a pharmaceutically acceptable salt thereof, wherein the compound is:
7. The compound according to claim 4 , or a pharmaceutically acceptable salt thereof, wherein the compound is:
8. The compound according to claim 4 , or a pharmaceutically acceptable salt thereof, wherein the compound is:
9. The compound according to claim 4 , or a pharmaceutically acceptable salt thereof, wherein the compound is:
10. The compound according to claim 4 , or a pharmaceutically acceptable salt thereof, wherein the compound is:
11. The compound according to claim 4 , or a pharmaceutically acceptable salt thereof, wherein the compound is:
12. The compound according to claim 4 , or a pharmaceutically acceptable salt thereof, wherein the compound is:
13. The compound according to claim 4 , or a pharmaceutically acceptable salt thereof, wherein the compound is:
14. The compound according to claim 4 , or a pharmaceutically acceptable salt thereof, wherein the compound is:
15. The compound according to claim 4 , or a pharmaceutically acceptable salt thereof, wherein the compound is:
16. The compound according to claim 4 , wherein the compound is:
17. The compound according to claim 4 , wherein the compound is:
18. The compound according to claim 4 , wherein the compound is:
19. The compound according to claim 4 , wherein the compound is:
20. The compound according to claim 4 , wherein the compound is:
21. The compound according to claim 4 , wherein the compound is:
22. The compound according to claim 4 , wherein the compound is:
23. The compound according to claim 4 , wherein the compound is:
24. The compound according to claim 4 , wherein the compound is:
25. The compound according to claim 4 , wherein the compound is:
26. The compound according to claim 4 , wherein the compound is: