KRAS G12C inhibitors and methods of using the same
Provided herein are KRAS G12C inhibitors, such as composition of the same, and methods of using the same. These inhibitors are useful for treating a number of disorders, including pancreatic, colorectal, and lung cancers.
1. A compound of having a structure of Formula I
wherein
R 1 is a -C 1 -C 6 alkyl or -C 3 -C 6 cycloalkyl group;
R 1a is a -C 1 -C 6 heteroalkyl, aryl, heteroaryl, -C 3 -C 6 cycloalkyl, or -C 3 -C 6 heterocycloalkyl group; or
R 1 and R 1a together with the carbon atom to which they are attached, form a carbocyclic or heterocycloalkyl ring, wherein the carbocyclic or heterocycloalkyl ring can be unsubstituted or fused to an aromatic ring;
R 2 is an aryl substituted with a halo, -OH, or NH 2;
R 3 is halo;
R 4 is H or methyl;
R 5 is H or methyl; or a stereoisomer thereof, an atropisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer thereof, or a pharmaceutically acceptable salt of the atropisomer thereof.
2. The compound of claim 1 , wherein R 1 is an -C 1 -C 6 alkyl or -C 3 -C 6 cycloalkyl group.
3. The compound of claim 2 , wherein R 1 is methyl.
4. The compound of claim 2 , wherein R 1 is a cyclopropyl group.
5. The compound of claim 1 , wherein R 1a is an -C 1 -C 6 alkyl, aryl, or -C 3 -C 6 cycloalkyl group.
6. The compound of claim 5 , wherein R 1a is an ethyl group.
7. The compound of claim 5 , wherein R 1a branched C 4 alkyl group.
8. The compound of claim 5 , wherein R 1a is a cyclopropyl group.
9. The compound of claim 5 , wherein R 1a cyclobutyl group.
10. The compound of claim 5 , wherein R 1a is a cyclopentyl group.
11. The compound of claim 5 , wherein R 1a is a phenyl group.
12. The compound of claim 1 , wherein R 1 and R 1a , together with the carbon atom to which they are attached, form a 4-10 membered ring.
13. The compound of claim 12 , wherein R 1 and R 1a , together with the carbon atom to which they are attached, form a cyclopentane.
14. The compound of claim 12 , wherein R 1 and R 1a , together with the carbon atom to which they are attached, form a cyclohexane.
15. The compound of claim 12 , wherein R 1 and R 1a together with the carbon atom to which they are attached, form a 5-membered carbocyclic ring, wherein the carbocyclic ring can be unsubstituted or fused to an aromatic ring.
16. The compound of claim 1 , wherein R 2 is a fluorinated phenyl.
17. The compound of claim 1 , wherein R 3 is Cl.
18. The compound of claim 1 , wherein R 4 is H.
19. The compound of claim 1 , wherein R 4 is methyl.
20. A compound, wherein the compound is selected from the group consisting of
or a stereoisomer thereof, an atropisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer thereof, or a pharmaceutically acceptable salt of the atropisomer thereof.
21. A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable excipient.
22. A method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the compound of claim 1 , wherein the cancer is selected from lung cancer and colorectal cancer.
23. The method of claim 22 , wherein the cancer is lung cancer.
24. The method of claim 22 , wherein the cancer is colorectal cancer.
25. The method of claim 23 , wherein the lung cancer is non-small cell lung cancer.
26. A pharmaceutical composition comprising a compound of claim 20 and a pharmaceutically acceptable excipient.
27. A method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the compound of claim 20 , wherein the cancer is selected from lung cancer and colorectal cancer.
28. The method of claim 27 , wherein the cancer is lung cancer.
29. The method of claim 27 , wherein the cancer is colorectal cancer.
30. The method of claim 27 , wherein the lung cancer is non-small cell lung cancer.