Histone demethylase inhibitors
The present invention relates generally to compositions and methods for treating cancer and neoplastic disease. Provided herein are substituted pyrrolopyridine derivative compounds and pharmaceutical compositions comprising said compounds. The subject compounds and compositions are useful for inhibition of histone demethylase. Furthermore, the subject compounds and compositions are useful for the treatment of cancer, such as prostate cancer, breast cancer, bladder cancer, lung cancer and/or melanoma and the like.
1. A compound of the structure of Formula (I),
or a pharmaceutically acceptable salt thereof,
wherein,
R 1 is hydrogen or alkyl;
R 2 is hydrogen, halogen or alkyl;
G is
n is 0, 1, or 2;
R 3 is alkyl, carbocyclyl, carbocyclylalkyl, heterocyclyl, or heterocyclylalkyl;
R 4 is halogen, alkyl, alkoxy, carbocyclyl, heterocyclyl, aryl, heteroaryl, or X—R 5 ;
wherein:
X is —(C 1 -C 6 )alkylene-, —O—, —S—, or —NR 1 —; and
R 5 is carbocyclyl, heterocyclyl, aryl, or heteroaryl.
2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is hydrogen.
3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is alkyl.
4. The compound of claim 3 , or a pharmaceutically acceptable salt thereof, wherein R 1 is methyl.
5. The compound of any one of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is hydrogen.
6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (I) is of Formula (Ia):
7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (I) is of Formula (Ib):
8. The compound of any one of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 is alkyl.
9. The compound of claim 8 , or a pharmaceutically acceptable salt thereof, wherein R 3 is methyl.
10. The compound of any one of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 is alkyl substituted with at least one halogen.
11. The compound of any one of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 is carbocyclylalkyl or heterocyclylalkyl.
12. The compound of claim 11 , or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from a group consisting of:
13. The compound of any one of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 is halogen.
14. The compound of claim 13 , or a pharmaceutically acceptable salt thereof, wherein R 4 is chloro or fluoro.
15. The compound of any one of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 is alkyl substituted with at least one halogen.
16. The compound of claim 15 , or a pharmaceutically acceptable salt thereof, wherein R 4 is —CF 3 .
17. The compound of any one of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 is alkoxy.
18. The compound of claim 17 , or a pharmaceutically acceptable salt thereof, wherein R 4 is methoxy.
19. The compound of any one of claims 1 - 12 , or a pharmaceutically acceptable salt thereof, wherein R 4 is alkoxy substituted with at least one halogen.
20. The compound of claim 19 , or a pharmaceutically acceptable salt thereof, wherein R 4 is —OCF 3 .
21. The compound of any one of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 is carbocyclyl.
22. The compound of any one of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 is heterocyclyl.
23. The compound of claim 22 , or a pharmaceutically acceptable salt thereof, wherein the heterocyclyl is selected from a group consisting of:
24. The compound of any one of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 is X—R 5 .
25. The compound of claim 24 , or a pharmaceutically acceptable salt thereof, wherein X is —O—.
26. The compound of claim 24 , or a pharmaceutically acceptable salt thereof, wherein X is —S—.
27. The compound of claim 24 , or a pharmaceutically acceptable salt thereof, wherein X is —NR 1 —; and R 1 is methyl.
28. The compound of any one of claim 24 , or a pharmaceutically acceptable salt thereof, wherein R 5 is aryl.
29. The compound of claim 28 , or a pharmaceutically acceptable salt thereof, wherein the aryl is phenyl optionally substituted with halogen, —CN, alkyl, alkynyl, alkoxy, or carbocycle.
30. The compound of any one of claims 24 - 27 , or a pharmaceutically acceptable salt thereof, wherein R 5 is heteroaryl.
31. The compound of claim 30 , or a pharmaceutically acceptable salt thereof, wherein the heteroaryl is pyridinyl optionally substituted with halogen, —CN, alkyl, alkynyl, alkoxy, or carbocycle.
32. A pharmaceutical composition comprising a compound of any of the proceeding claim, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.
33. A method for in vitro inhibiting a histone demethylase enzyme comprising contacting the histone demethylase enzyme with a compound of any of the proceeding claim in solution.
34. A method for treating prostate cancer, breast cancer, bladder cancer, lung cancer and melanoma in subject in need thereof comprising administering to the subject a composition comprising a compound of any of the proceeding claim, or pharmaceutically acceptable salt thereof.