Heterocyclic degronimers for target protein degradation
This invention provides heterocyclic compounds that bind to E3 Ubiquitin Ligase (typically through cereblon) (“Degrons”), which can be used as is or linked to a Targeting Ligand for a selected Target Protein for therapeutic purposes and methods of use and compositions thereof as well as methods for their preparation.
1. A compound of Formula:
or a pharmaceutically acceptable salt thereof;
wherein
is selected from:
A is CR 8 R 9 , C═O, C═S, C═CH 2 , SO 2 , S(O), P(O)Oalkyl, P(O)NHalkyl, P(O)N(alkyl) 2 , P(O)alkyl, P(O)OH, or P(O)NH 2 ;
A′ is CR 1 R 2 , C═O, C═S, C═CH 2 , SO 2 , S(O), P(O)Oalkyl, P(O)NHalkyl, P(O)N(alkyl) 2 , P(O)alkyl, P(O)OH, or P(O)NH 2 ;
A″ is CR 3 R 4 , C═O, C═S, C═CH 2 , SO 2 , S(O), P(O)Oalkyl, P(O)NHalkyl, P(O)N(alkyl) 2 , P(O)alkyl, P(O)OH, or P(O)NH 2 ;
X is independently selected from NH, NR 11 , CH 2 , CHR 12 , C(R 12 ) 2 , O, and S;
Z is O, S, CH 2 , CH(C 1 -C 4 alkyl), or C(C 1 -C 4 alkyl) 2 ;
n is 0, 1, 2, 3, 4, or 5;
is a single or double bond;
R 1 , R 2 , R 3 , R 4 , R 8 , R 9 , and R 13 are independently selected from hydrogen, alkyl, hydroxyl, alkoxy, amine, —NHalkyl, and —Nalkyl 2 ;
or R 1 and R 2 form a 3-, 4-, 5-, or 6-membered spirocarbocycle, or a 4-, 5-, or 6-membered spiroheterocycle comprising 1 or 2 heteroatoms selected from N and O;
or R 3 and R 4 form a 3-, 4-, 5-, or 6-membered spirocarbocycle, or a 4-, 5-, or 6-membered spiroheterocycle comprising 1 or 2 heteroatoms selected from N and O;
or R 8 and R 9 form a 3-, 4-, 5-, or 6-membered spirocarbocycle, or a 4-, 5-, or 6-membered spiroheterocycle comprising 1 or 2 heteroatoms selected from N and O;
or R 13 and R 5 form a 3, 4, 5, or 6 carbon fused ring wherein R 5 is on the carbon alpha to
R 13 or a 1, 2, 3, or 4 carbon bridged ring wherein R 5 is not on the carbon alpha to R 13 ;
R 5 is selected at each instance from: alkyl, alkene, alkyne, halogen, hydroxyl, alkoxy, azide, amino, —NHalkyl, —N(alkyl) 2 , —NHSO 2 alkyl, —N(alkyl)SO 2 alkyl, —NHSO 2 aryl, —N(alkyl)SO 2 aryl, —NHSO 2 alkenyl, —N(alkyl)SO 2 alkenyl, —NHSO 2 alkynyl, —N(alkyl)SO 2 alkynyl, and haloalkyl;
or two R 5 substituents together with the carbon atom(s) to which they are bound can form a 3, 4, 5 or 6 membered ring;
Q 1 , Q 2 , Q 3 , and Q 4 are independently selected from CH, CR 12 , and N; and wherein no more than two of Q 1 , Q 2 , Q 3 , and Q 4 are N;
R 11 is independently selected from alkyl, alkenyl, alkynyl, C(O)H, —C(O)OH, —C(O)alkyl, and —C(O)Oalkyl; and
R 12 is independently selected from alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkoxy, azide, amino, —C(O)H, —C(O)OH, —C(O)alkyl, —C(O)Oalkyl, —NHalkyl, —N(alkyl) 2 , —NHSO 2 alkyl, —N(alkyl)SO 2 alkyl, —NHSO 2 aryl, —N(alkyl)SO 2 aryl, —NHSO 2 alkenyl, —N(alkyl)SO 2 alkenyl, —NHSO 2 alkynyl, —N(alkyl)SO 2 alkynyl, cyano, nitro, nitroso, —SH, —Salkyl, and haloalkyl.
2. The compound of claim 1 , wherein A is C═O, C═S, or C═CH 2 .
3. The compound of claim 1 , wherein A′ is C═O, C═S, or C═CH 2 .
4. The compound of claim 1 , wherein A″ is C═O, ═C═S, or C═CH 2 .
5. The compound of claim 1 , wherein A is C═O.
6. The compound of claim 1 , wherein A″ is C═O.
7. The compound of claim 1 , wherein X is NH, S, or O.
8. The compound of claim 1 , wherein X is NH.
9. The compound of claim 1 , wherein Q 1 , Q 2 , Q 3 , and Q 4 are CH.
10. The compound of claim 1 , wherein Q 1 is CR 12 and one of Q 2 , Q 3 , and Q 4 is N.
11. The compound of claim 10 , wherein R 12 is amino.
12. The compound of claim 1 wherein
is selected from
13. The compound of claim 1 selected from:
or a pharmaceutically acceptable salt thereof.
14. The compound of claim 13 selected from:
or a pharmaceutically acceptable salt thereof.
15. The compound of claim 14 selected from
or a pharmaceutically acceptable salt thereof.
16. The compound of claim 1 selected from:
or a pharmaceutically acceptable salt thereof.
17. The compound of claim 16 selected from
or a pharmaceutically acceptable salt thereof.
18. The compound of claim 17 selected from:
or a pharmaceutically acceptable salt thereof.
19. The compound of claim 18 , wherein R 12 is amino and any one of Q 1 , Q 2 , Q 3 , and Q 4 is N.
20. The compound of claim 1 selected from:
or a pharmaceutically acceptable salt thereof.
21. The compound of claim 20 selected from:
or a pharmaceutically acceptable salt thereof.
22. The compound of claim 21 selected from:
or a pharmaceutically acceptable salt thereof.
23. The compound of claim 22 selected from:
or a pharmaceutically acceptable salt thereof; wherein R 12 is amino.
24. The compound of claim 1 selected from:
or a pharmaceutically acceptable salt thereof.
25. The compound of claim 24 selected from
or a pharmaceutically acceptable salt thereof.
26. The compound of claim 25 , selected from
or a pharmaceutically acceptable salt thereof.
27. The compound of claim 1 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
28. The compound of claim 1 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.