Small molecule modulators of the androgen receptor
Provided herein are compounds useful for modulating the activity of an androgen receptor, or a variant thereof, and related compositions and methods. Compounds of the invention are useful for antagonizing the androgen receptor splice variant AR-v7, and for the treatment of castration-resistant prostate cancer.
1. A compound of Formula (II):
or a pharmaceutically acceptable salt thereof, wherein:
L 1 is absent, or is optionally substituted C 1-6 aliphatic, or optionally substituted C 1-6 heteroaliphatic;
L 2 is absent, or is optionally substituted C 1-6 aliphatic, or optionally substituted C 1-6 heteroaliphatic;
X is —O—, —S— or —N(R)—;
R is hydrogen, or optionally substituted alkyl;
Q 1 , Q 2 , and Q 3 , independently, are ═N— or ═C(R 1 )—;
R 1 is hydrogen, halogen, —CN, —NO 2 , —Ra, —OH, —OR a , —OC(O)R a , —OC(O)OR a , —OC(O)N(R a ) 2 , —NH 2 , —N(R a ) 2 , —NC(O)R a , —NC(O)OR a , or —NC(O)N(R a ) 2 ; wherein
each occurrence of R a , independently, is optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl;
R 2 is optionally substituted carbocyclyl, optionally substituted heterocyclyl wherein each heteroatom is independently selected from nitrogen and oxygen, optionally substituted aryl, or optionally substituted heteroaryl;
R 3 is optionally substituted alkyl, or optionally substituted cycloalkyl;
R 4 is hydrogen or optionally substituted alkyl; and
R 5 is optionally substituted aryl or optionally substituted heteroaryl.
2. The compound of claim 1 , having the structure selected from Formulae (IIA), (IIB), (IIC), and (IID), and pharmaceutically acceptable salts thereof:
3. The compound of claim 1 , having the structure of Formula (IIA-a):
4. The compound of claim 1 , having the structure of Formula (IIA-b):
5. The compound of claim 1 , having the structure of Formula (IIA-c):
6. The compound of claim 1 , having the structure of Formula (IIA-d):
7. The compound of claim 1 , selected from the compounds of Table 2, and pharmaceutically acceptable salts thereof.
8. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier or diluent.
9. A method of modulating the expression of a gene, wherein the gene expression is mediated by an androgen receptor, comprising exposing the androgen receptor to a compound of claim 1 .
10. A method of modulating androgen receptor function, comprising exposing the androgen receptor to a compound of claim 1 .
11. The method of claim 9 , wherein the gene is AKT1.
12. The method of claim 9 , wherein the androgen acceptor is an androgen receptor splice variant (AR-v).
13. The method of claim 12 , wherein the AR-v is AR-v7.
14. A method of treating prostate cancer in a subject in need of such treatment, comprising administering to the subject a compound of claim 1 .
15. The compound of claim 2 , having the structure of Formula (IIA), or a pharmaceutically acceptable salt thereof.
16. The compound of claim 1 , wherein R 1 is hydrogen, optionally substituted aliphatic, optionally substituted amino, optionally substituted aryl, optionally substituted heterocyclyl, or optionally substituted heteroaryl.
17. The compound of claim 1 , wherein R 2 is optionally substituted C 5-10 cycloaliphatic, optionally substituted C 6-10 aryl, or optionally substituted C 6-10 heteroaryl.
18. The compound of claim 1 , wherein R 3 is C 1-6 alkyl.
19. The compound of claim 1 , wherein R 4 is C 1-6 alkyl.
20. The compound of claim 1 , wherein R 5 is optionally substituted heteroaryl.