CRBN modulators
Disclosed are degraders, pharmaceutical compositions containing them, and methods of making and using the degraders to treat diseases and disorders characterized by dysregulated or dysfunctional protein activity that can be targeted by cereblon.
1. A compound having a structure represented by formula (I):
wherein R 1 and R 2 independently represent H, halo, hydroxyl, optionally substituted C1-C5 alkyl, optionally substituted C1-C5 alkoxy, or optionally substituted amine, optionally substituted amide, acyl, or
provided that one of R 1 and R 2 represents
wherein the targeting ligand (TL) has a structure represented by:
the linker (L) comprises an alkylene chain or a polyethylene glycol chain, either of which may be interrupted by, and/or terminate at either or both termini in at least one of —O—, —S—, —N(R′)—, —C≡C—, —C(O)—, —C(O)O—, —OC(O)—, —OC(O)O—, —C(NOR′)—, —C(O)N(R′)—, —C(O)N(R′)C(O)—, —C(O)N(R′)C(O)N(R′)—, —N(R′)C(O)—, —N(R′)C(O)N(R′)—, —N(R′)C(O)O—, —OC(O)N(R′)—, —C(NR′)—, —N(R′)C(NR′)—, —C(NR′)N(R′)—, —N(R′)C(NR′)N(R′)—, —OB(Me)O—, —S(O) 2 —, —OS(O)—, —S(O)O—, —S(O)—, —OS(O) 2 —, —S(O) 2 O—, —N(R′)S(O) 2 —, —S(O) 2 N(R′)—, —N(R′)S(O)—, —S(O)N(R′)—, —N(R′)S(O) 2 N(R′)—, —N(R′)S(O)N(R′)—, C 3 -C 12 carbocyclene, 3- to 12-membered heterocyclene, 5- to 12-membered heteroarylene or any combination thereof, wherein R′ is H or C 1 -C 6 alkyl, wherein the interrupting and the one or both terminating groups may be the same or different,
or a pharmaceutically acceptable salt or stereoisomer thereof.
2. The compound of claim 1 , wherein R 1 represents
and R 2 represents H, halo, hydroxyl, optionally substituted C1-C5 alkyl, optionally substituted C1-C5 alkoxy, optionally substituted amine, optionally substituted amide, or acyl.
3. The compound of claim 2 , wherein R 2 represents H.
4. The compound of claim 1 , wherein R 2 represents
and R 1 represents H, halo, hydroxyl, optionally substituted C1-C5 alkyl, optionally substituted C1-C5 alkoxy, optionally substituted amine, optionally substituted amide, or acyl.
5. The compound of claim 4 , wherein R 2 represents H.
6. The compound of claim 1 , wherein the targeting ligand (TL) has a structure represented by:
7. The compound of claim 6 , wherein the targeting ligand binds bromodomain-containing-protein 2, 3, 4 and bromodomain testis-specific protein.
8. The compound of claim 1 , wherein the linker has a structure represented by any one of:
9. The compound of claim 1 , which has a structure as follows:
or a pharmaceutically acceptable salt or stereoisomer thereof.
10. The compound of claim 1 , which has a structure as follows:
or a pharmaceutically acceptable salt or stereoisomer thereof.
11. The compound of claim 1 , which is:
or a pharmaceutically acceptable salt or stereoisomer thereof.
12. A pharmaceutical composition, comprising a therapeutically effective amount of the compound of claim 1 or pharmaceutically acceptable salt or stereoisomer thereof, and a pharmaceutically acceptable carrier.
13. The pharmaceutical composition of claim 12 , which is in the form of a capsule.
14. A method of treating cancer, wherein the cancer is leukemia or multiple myeloma, comprising administering to a subject in need thereof a therapeutically effective amount of the compound of claim 1 or pharmaceutically acceptable salt or stereoisomer thereof.
15. The method of claim 14 , wherein the cancer is multiple myeloma.
16. The compound of claim 1 , which is:
or a pharmaceutically acceptable salt or stereoisomer thereof.
17. A pharmaceutical composition, comprising a therapeutically effective amount of the compound of claim 16 or pharmaceutically acceptable salt or stereoisomer thereof, and a pharmaceutically acceptable carrier.
18. The compound of claim 1 , wherein the targeting ligand (TL) has a structure represented by:
19. The compound of claim 1 , wherein the targeting ligand (TL) has a structure represented by: