Histone demethylase inhibitors
Provided herein are substituted pyrazolylpyridine, pyrazolylpyridazine, and pyrazolylpyrimidine derivative compounds and pharmaceutical compositions comprising said compounds. The subject compounds and compositions are useful for inhibition 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 method for inhibiting a histone-demethylase enzyme comprising contacting the histone demethylase enzyme with a compound of Formula (II), wherein the compound of Formula (II) has the structure:
wherein,
R 1 is hydrogen, halogen, —OH, —OR 5 , —N(R 5 ) 2 , alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, carbocyclylalkyl, heterocyclylalkyl, aralkyl, or heteroarylalkyl;
R 2 is hydrogen, halogen, —OH, —OR 5 , —N(R 5 ) 2 , alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, carbocyclylalkyl, heterocyclylalkyl, aralkyl, or heteroarylalkyl;
R 4 is hydrogen or alkyl; and
each R 5 is independently hydrogen, alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, carbocyclylalkyl, heterocyclylalkyl, aralkyl, or heteroarylalkyl.
2. The method of claim 1 , wherein R 4 is hydrogen.
3. The method of claim 1 , wherein R 4 is alkyl.
4. The method of claim 1 , wherein R 1 or R 2 is alkyl.
5. The method of claim 1 , wherein R 1 or R 2 is carbocyclyl.
6. The method of claim 1 , wherein R 1 or R 2 is aryl.
7. The method of claim 1 , wherein R 1 or R 2 is aralkyl.
8. A method for inhibiting a histone-demethylase enzyme comprising contacting the histone demethylase enzyme with a compound of Formula (IV), wherein the compound of Formula (IV) has the structure:
wherein,
R 1 is hydrogen, halogen, —OH, —OR 5 , —N(R 5 ) 2 , alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, carbocyclylalkyl, heterocyclylalkyl, aralkyl, or heteroarylalkyl;
R 2 is hydrogen, halogen, —OH, —OR 5 , —N(R 5 ) 2 , alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, carbocyclylalkyl, heterocyclylalkyl, aralkyl, or heteroarylalkyl;
R 3 is —O—X—Y;
R 4 is hydrogen or alkyl;
each R 5 is independently hydrogen, alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, carbocyclylalkyl, heterocyclylalkyl, aralkyl, or heteroarylalkyl;
X is C 1 -C 8 alkylene or
where n is 0 to 4; and
Y is hydrogen, carbocyclyl, aryl, or heteroaryl.
9. The method of claim 8 , wherein R 4 is hydrogen.
10. The method of claim 8 , wherein R is alkyl.
11. The method of claim 8 , wherein R 1 and R 2 are hydrogen.
12. The method of claim 8 , wherein X is C 1 -C 4 alkylene.
13. The method of claim 8 , wherein X is C 1 -C 2 alkylene.
14. The method of claim 8 , wherein X is C 1 alkylene.
15. The method of claim 8 , wherein Y is hydrogen.
16. The method of claim 8 , wherein Y is carbocyclyl.
17. The method of claim 8 , wherein Y is aryl.
18. The method of claim 8 , wherein Y is a phenyl.
19. The method of claim 8 , wherein Y is heteroaryl.
20. A method for treating cancer in subject comprising administering to the subject in need thereof a composition comprising a compound of Formula (II), or pharmaceutically acceptable salt thereof, wherein the compound of Formula (II) has the structure:
wherein,
R 1 is hydrogen, halogen, —OH, —OR 5 , —N(R 5 ) 2 , alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, carbocyclylalkyl, heterocyclylalkyl, aralkyl, or heteroarylalkyl;
R 2 is hydrogen, halogen, —OH, —OR 5 , —N(R 5 ) 2 , alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, carbocyclylalkyl, heterocyclylalkyl, aralkyl, or heteroarylalkyl;
R 4 is hydrogen or alkyl; and
each R 5 is independently hydrogen, alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, carbocyclylalkyl, heterocyclylalkyl, aralkyl, or heteroarylalkyl.
21. The method of claim 20 , wherein R 4 is hydrogen.
22. The method of claim 20 , wherein R is alkyl.
23. The method of claim 20 , wherein R 1 or R 2 is alkyl.
24. The method of claim 20 , wherein R 1 or R 2 is carbocyclyl.
25. The method of claim 20 , wherein R 1 or R 2 is aryl.
26. The method of claim 20 , wherein R 1 or R 2 is aralkyl.
27. A method for treating cancer in subject comprising administering to the subject in need thereof a composition comprising a compound of Formula (IV), or pharmaceutically acceptable salt thereof, wherein the compound of Formula (IV) has the structure:
wherein,
R 1 is hydrogen, halogen, —OH, —OR 5 , —N(R 5 ) 2 , alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, carbocyclylalkyl, heterocyclylalkyl, aralkyl, or heteroarylalkyl;
R 2 is hydrogen, halogen, —OH, —OR 5 , —N(R 5 ) 2 , alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, carbocyclylalkyl, heterocyclylalkyl, aralkyl, or heteroarylalkyl;
R 3 is —O—X—Y;
R 4 is hydrogen or alkyl;
each R 5 is independently hydrogen, alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, carbocyclylalkyl, heterocyclylalkyl, aralkyl, or heteroarylalkyl;
X is C 1 -C 8 alkylene or
where n is 0 to 4; and
Y is hydrogen, carbocyclyl, aryl, or heteroaryl.
28. The method of claim 27 , wherein R 4 is hydrogen.
29. The method of claim 27 , wherein R 4 is alkyl.
30. The method of claim 27 , wherein R 1 and R 2 are hydrogen.
31. The method of claim 27 , wherein X is C 1 -C 4 alkylene.
32. The method of claim 27 , wherein X is C 1 -C 2 alkylene.
33. The method of claim 27 , wherein X is C 1 alkylene.
34. The method of claim 27 , wherein Y is hydrogen.
35. The method of claim 27 , wherein Y is carbocyclyl.
36. The method of claim 27 , wherein Y is aryl.
37. The method of claim 27 , wherein Y is a phenyl.
38. The method of claim 27 , wherein Y is heteroaryl.