Glutarimide-containing pan-KRAS-mutant degrader compounds and uses thereof
The present disclosure relates to novel pan-KRAS glutarimide-containing compounds with KRAS degradation activities, pharmaceutical compositions containing such compounds, and their use in prevention and treatment diseases and conditions.
1. A compound, wherein the compound is represented by Formula IB′ or is a pharmaceutically acceptable salt thereof:
wherein:
each R b is independently selected from halogen, hydroxy, amino, and C 1 -C 4 alkyl;
n′ is 1 or 2;
R 2 is H;
R 3 is halogen;
Q is selected from
and
L is selected from
2. The compound of claim 1 , wherein Q is
3. The compound of claim 1 , wherein L is selected from
4. The compound of claim 1 , wherein L is selected from
5. The compound of claim 1 , wherein L is selected from
6. The compound of claim 1 , wherein R 1 is selected from
7. The compound of claim 6 , wherein R 1 is selected from
8. The compound of claim 7 , wherein R 1 is
9. The compound of claim 7 , wherein R 1 is
10. The compound of claim 1 , wherein the compound is selected from
or a pharmaceutically acceptable salt thereof.
11. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to claim 10 and one or more pharmaceutically acceptable carriers, pharmaceutically acceptable vehicles, pharmaceutically acceptable excipients, or combinations thereof.
12. A method of treating cancer in a subject in need thereof, comprising administering to the subject an effective amount of at least one compound according to claim 11 , wherein the cancer is selected from lung cancer, pancreatic cancer, small bowel cancer, colorectal cancer, gall bladder cancer, thyroid cancer, liver cancer, bile duct cancer, cervical cancer, bladder cancer, prostate cancer, esophageal cancer, and blood cancer.
13. The compound of claim 1 , wherein the compound is
14. The compound of claim 1 , wherein the compound is
15. The compound of claim 1 , wherein the compound is
16. The compound of claim 1 , wherein the compound is
17. The compound of claim 1 , wherein the compound is
18. The compound of claim 1 , wherein the compound is
19. The compound of claim 1 , wherein the compound is
20. The compound of claim 1 , wherein the compound is
21. The compound of claim 1 , wherein the compound is
22. The compound of claim 1 , wherein the compound is
23. The compound of claim 1 , wherein the compound is
24. The compound of claim 1 , wherein the compound is
25. The compound of claim 1 , wherein the compound is
26. The compound of claim 1 , wherein the compound is selected from
27. The compound of claim 1 , wherein the compound is selected from
28. The compound of claim 1 , wherein the compound is selected from
29. The compound of claim 1 , wherein the compound is selected from
30. The method of claim 12 , wherein the cancer is pancreatic cancer.
31. The method of claim 12 , wherein the cancer is lung cancer.
32. The method of claim 12 , wherein the cancer is colorectal cancer.