Spirocyclic degronimers for target protein degradation
This invention provides compounds that have spirocyclic E3 Ubiquitin Ligase targeting moieties (Degrons), which can be used as is or linked to a targeting ligand for a protein that has been selected for in vivo degradation, 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:
W 1 is C═O;
W 2 is C═O;
X is NH;
n is 0, 1, 2, or 3;
is a single or double bond;
Y and Z are each independently selected from the group consisting of CH 2 , CHR 12 , C(R 12 ) 2 , C(O), N, NH, NR 13 , O, S, and S(O) as permitted by valency;
R 5 is selected at each instance from the group consisting of alkyl, alkene, alkyne, halogen, hydroxyl, alkoxy, amino, cyano, —NHalkyl, —N(alkyl) 2 , —NHSO 2 alkyl, —N(alkyl)SO 2 alkyl, —NHSO 2 alkenyl, —N(alkyl)SO 2 alkenyl, —NHSO 2 alkynyl, —N(alkyl)SO 2 alkynyl, and haloalkyl;
R 15 is selected from
is selected from:
R 11 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, carbocyclic, halogen, hydroxyl, amino, cyano, alkoxy, aryl, heteroaryl, heterocyclic, carbocyclic, alkylamino, alkylhydroxyl, and haloalkyl;
R 12 is selected from the group consisting of alkyl, alkene, alkyne, halogen, hydroxyl, alkoxy, azide, amino, —C(O)H, —C(O)OH, —C(O)(aliphatic), —C(O)O(aliphatic), —NH(aliphatic), —N(independently aliphatic) 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, aliphatic, heteroaliphatic, aryl, heteroaryl, heterocyclic, carbocyclic, cyano, nitro, nitroso, —SH, —Salkyl, and haloalkyl;
R 13 is selected from the group consisting of alkyl, alkenyl, alkynyl, —C(O)H, —C(O)OH, —C(O)alkyl, and —C(O)Oalkyl.
2. The compound of claim 1 , wherein n is O.
3. The compound of claim 1 , wherein n is 1.
4. The compound of claim 1 , wherein n is 2.
5. The compound of claim 1 , wherein
is selected from:
6. The compound of claim 1 , wherein
is selected from:
7. The compound of claim 1 , wherein
is selected from:
8. The compound of claim 1 , wherein
is selected from:
9. The compound of claim 1 , wherein Y is C(O), NH, NR 13 , O, or S, and Z is CH 2 .
10. The compound of claim 3 , wherein R 5 is methyl.
11. The compound of claim 3 , wherein R 5 is alkyl or haloalkyl.
12. The compound of claim 3 , wherein R 5 is halogen.
13. The compound of claim 3 , wherein R 5 is hydroxyl, alkoxy, amino, or haloalkyl.
14. The compound of claim 1 , wherein R 11 is hydrogen.
15. The compound of claim 1 , wherein R 11 is alkyl, halogen, or haloalkyl.
16. The compound of claim 1 , wherein R 11 is alkyl.
17. The compound of claim 1 , wherein R 11 is —C(O)alkyl.
18. A pharmaceutical composition comprising a compound of claim 1 .
19. A method for treating a patient with an abnormal cellular proliferation comprising administering an effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof to a patient in need thereof.
20. The method of claim 19 , wherein the patient is a human.
21. The compound of claim 1 , wherein the compound is of structure:
or a pharmaceutically acceptable salt thereof.