Tricyclic degraders of Ikaros and Aiolos
Tricyclic cereblon binders for the degradation of Ikaros or Aiolos by the ubiquitin proteasome pathway for therapeutic applications are described.
1. A compound of Formula:
or a pharmaceutically acceptable salt thereof,
wherein:
R 2 is independently selected at each occurrence from the group consisting of hydrogen, alkyl, and haloalkyl;
R 3 is hydrogen, halogen, alkyl, haloalkyl, —OR 8 , or —NR 8 R 8′ ;
R 3′ is hydrogen;
R 7 is independently selected at each occurrence from the group consisting of hydrogen, halogen, hydroxyl, cyano, nitro, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocycle, aryl, heteroaryl, —OR 8 , —NR 8 R 8′ , —C(O)R 8 , —C(O)OR 8 , —C(O)—NR 8 R 8′ , —OC(O)R 8 , —NR 8 —C(O)R 8 , —S(O)R 8 , —SO 2 R 8 , —SO 2 —OR 8 , and —SO 2 —NR 8 R 8′ ;
R 8 and R 8′ are independently selected at each occurrence from the group consisting of hydrogen, alkyl, haloalkyl, alkenyl, and alkynyl;
each R 9 is independently selected from the group consisting of hydrogen and alkyl.
2. The compound of claim 1 , wherein one R 7 is hydrogen.
3. The compound of claim 1 , wherein two R 7 s are hydrogen.
4. The compound of claim 3 , wherein the remaining R 7 s are independently selected at each occurrence from the group consisting of alkyl, halogen, and haloalkyl.
5. The compound of claim 1 , wherein three R 7 s are hydrogen.
6. The compound of claim 1 , wherein R 7 is independently selected at each occurrence from the group consisting of hydrogen, halogen, hydroxyl, alkyl, haloalkyl, alkene, alkyne, heterocycle, aryl, and heteroaryl.
7. The compound of claim 1 , wherein R 7 is independently selected at each occurrence from the group consisting of hydrogen, alkyl, halogen, and haloalkyl.
8. The compound of claim 1 , wherein R 7 is independently selected at each occurrence from the group consisting of hydrogen and halogen.
9. The compound of claim 1 , wherein all R 7 s are hydrogen.
10. The compound of claim 1 , wherein R 3 is hydrogen.
11. The compound of claim 10 , wherein both R 9 s are hydrogen.
12. The compound of claim 10 , wherein all R 7 s are hydrogen.
13. The compound of claim 1 , wherein both R 9 s are hydrogen.
14. The compound of claim 13 , wherein all R 7 s are hydrogen.
15. The compound of claim 13 , wherein R 7 is independently selected at each occurrence from the group consisting of hydrogen, halogen, hydroxyl, alkyl, haloalkyl, alkene, alkyne, heterocycle, aryl, and heteroaryl.
16. The compound of claim 13 , wherein R 7 is independently selected at each occurrence from the group consisting of hydrogen, alkyl, halogen, and haloalkyl.
17. The compound of claim 13 , wherein R 7 is independently selected at each occurrence from the group consisting of hydrogen and halogen.
18. The compound of claim 13 , wherein three R 7 s are hydrogen.
19. The compound of claim 1 , wherein the compound is
or a pharmaceutically acceptable salt thereof.
20. A compound of structure:
or a pharmaceutically acceptable salt thereof.
21. The compound of claim 1 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
22. A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutical salt thereof and a pharmaceutically acceptable excipient.
23. A pharmaceutical composition comprising a compound and a pharmaceutically acceptable excipient, wherein the compound is
or a pharmaceutically acceptable salt thereof.
24. The pharmaceutical composition of claim 23 , wherein the compound is
or a pharmaceutically acceptable salt thereof.
25. The pharmaceutical composition of claim 23 , wherein the compound is
or a pharmaceutically acceptable salt thereof.
26. The pharmaceutical composition of claim 25 , wherein the pharmaceutical composition is formulated for oral administration.
27. The pharmaceutical composition of claim 26 , wherein the pharmaceutical composition is a tablet.
28. The pharmaceutical composition of claim 26 , wherein the pharmaceutical composition is a capsule.
29. The pharmaceutical composition of claim 25 , wherein the pharmaceutical composition is formulated for parenteral administration.
30. The pharmaceutical composition of claim 25 , wherein the pharmaceutical composition is formulated for intravenous administration.