Selective estrogen receptor degraders and uses thereof
The present disclosure provides compounds of Formula (I) and Formula (II). The compounds described herein may be useful in treating proliferative diseases (e.g., cancer). Also provided in the present disclosure are pharmaceutical compositions, kits, methods, and uses including or using a compound described herein.
1. A compound of Formula (II):
or a pharmaceutically acceptable salt thereof,
wherein:
A is —CH═ or N═, as valency permits;
W is —NH—, —O—, or —S—;
a is 1;
R 1 is hydrogen or halogen, which is fluorine or chlorine;
R 2 is methyl, ethyl, or —CF 3 ;
R 3 is hydrogen, fluorine, unsubstituted C 1 -C 6 alkyl;
R 4 is hydrogen, fluorine, unsubstituted C 1 -C 6 alkyl, or R 3 and R 4 are taken together with the intervening atoms to form unsubstituted cyclopropyl;
R 8 is hydrogen, fluorine, or methyl;
R A1 is unsubstituted C 1 -C 6 alkyl, chlorine, or fluorine;
R A2 is unsubstituted C 1 -C 6 alkyl, chlorine, or fluorine, wherein: (i) either R A1 or R A2 is chlorine; or (ii) both of R A1 and R A2 are chlorine.
2. The compound of claim 1 , wherein the compound is of the Formula (IIA):
or a pharmaceutically acceptable salt thereof.
3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein A is —CH═.
4. The compound of claim 3 , or a pharmaceutically acceptable salt thereof, wherein W is —NH.
5. The compound of claim 4 , or a pharmaceutically acceptable salt thereof, wherein R 1 is hydrogen.
6. The compound of claim 5 , or a pharmaceutically acceptable salt thereof, wherein R 2 is methyl.
7. The compound of claim 6 , or a pharmaceutically acceptable salt thereof, wherein R 3 is methyl, R 4 is methyl and R 8 is fluorine.
8. The compound of claim 7 , or a pharmaceutically acceptable salt thereof, wherein both of R A1 and R A2 are chlorine.
9. The compound of claim 1 , wherein the compound is of the formula:
or a pharmaceutically acceptable salt thereof.
10. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
11. A method of treating breast cancer, the method comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition of claim 10 .
12. The method of claim 11 , wherein the breast cancer is ER+ breast cancer.
13. A compound having a formula of:
or a pharmaceutically acceptable salt thereof.
14. The compound of claim 13 , which has a formula of
or a pharmaceutically acceptable salt thereof.
15. The compound of claim 13 , which has a formula of
or a pharmaceutically acceptable salt thereof.
16. The compound of claim 13 , which has a formula of
or a pharmaceutically acceptable salt thereof.
17. The compound of claim 13 , which has a formula of
or a pharmaceutically acceptable salt thereof.
18. A pharmaceutical composition comprising the compound of claim 13 , or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.
19. A method of treating breast cancer, the method comprising administering to a subject in need thereof an effective amount of the compound of claim 13 , or a pharmaceutically acceptable salt thereof.
20. The method of claim 19 , wherein the breast cancer is ER+ breast cancer.
21. A method of treating breast cancer, the method comprising administering to a subject in need thereof an effective amount of the compound of claim 14 , or a pharmaceutically acceptable salt thereof.
22. The method of claim 21 , wherein the breast cancer is ER+ breast cancer.
23. A method of treating breast cancer, the method comprising administering to a subject in need thereof an effective amount of the compound of claim 15 , or a pharmaceutically acceptable salt thereof.
24. The method of claim 23 , wherein the breast cancer is ER+ breast cancer.
25. A method of treating breast cancer, the method comprising administering to a subject in need thereof an effective amount of the compound of claim 16 , or a pharmaceutically acceptable salt thereof.
26. The method of claim 25 , wherein the breast cancer is ER+ breast cancer.
27. A method of treating breast cancer, the method comprising administering to a subject in need thereof an effective amount of the compound of claim 17 , or a pharmaceutically acceptable salt thereof.
28. The method of claim 27 , wherein the breast cancer is ER+ breast cancer.