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 method for treating a patient with abnormal cellular proliferation comprising administering an effective amount of a compound optionally in a pharmaceutically acceptable carrier, to a patient in need thereof, wherein the compound is of Formula:
or a pharmaceutically acceptable salt thereof;
wherein
is selected from the group consisting of:
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 the group consisting of 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 the group consisting of 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 the group consisting of: 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 the group consisting of 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 the group consisting of alkyl, alkenyl, alkynyl, C(O)H, —C(O)OH, —C(O)alkyl, and —C(O)Oalkyl; and
R 12 is independently selected from the group consisting of 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 method of claim 1 , wherein the patient is a human.
3. The method of claim 2 , wherein
is selected from the group consisting of:
4. The method of claim 2 , wherein the compound is selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
5. The method of claim 4 , wherein the compound is selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
6. The method of claim 4 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
7. The method of claim 2 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
8. The method of claim 2 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
9. The method of claim 2 , wherein the abnormal cellular proliferation is a cancer.
10. The method of claim 9 , wherein the cancer is a solid tumor.
11. The method of claim 9 , wherein the cancer is a hematological cancer.
12. The method of claim 9 , wherein the cancer is multiple myeloma.
13. The method of claim 9 , wherein the cancer is leukemia.
14. The method of claim 9 , wherein the cancer is T-cell lineage acute lymphoblastic leukemia.
15. The method of claim 9 , wherein the cancer is large granular lymphocytic leukemia.
16. The method of claim 9 , wherein the cancer is Hodgkin's lymphoma.
17. The method of claim 9 , wherein the cancer is non-Hodgkin's lymphoma.
18. The method of claim 9 , wherein the cancer is sarcoma.
19. The method of claim 9 , wherein the cancer is synovial sarcoma.
20. The method of claim 9 , wherein the cancer is Ewing's sarcoma, hemangiosarcoma, Kaposi's sarcoma, liposarcoma, or myosarcoma.