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 compound of Formula (I)
or a pharmaceutically acceptable salt thereof, 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 hydrogen, halogen, —N(R 5 ) 2 , OR 6 , alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, carbocyclylalkyl, heterocyclylalkyl, aralkyl, or heteroarylalkyl;
R 4 is hydrogen or alkyl; and wherein
each R 5 is independently hydrogen, alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, carbocyclylalkyl, heterocyclylalkyl, aralkyl, or heteroarylalkyl, and
each R 6 is independently alkyl, heterocyclyl, carbocyclylalkyl, heterocyclylalkyl, aralkyl, or heteroarylalkyl;
with the provision:
if R 2 and R 3 are both hydrogen, then R 1 is not hydrogen, methyl, trifluoromethyl, isopropyl, or cyclopropyl; or
if R 1 and R 3 are both hydrogen, then R 2 is not methyl, trifluoromethyl, bromine, or chlorine; or
if R 1 and R 3 are both methyl, then R 2 is not hydrogen, methyl, or ethyl; or
if R 1 and R 2 are hydrogen, then R 3 is not
2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 is hydrogen.
3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 is alkyl.
4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 is C 2 -C 10 alkyl.
5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 is aralkyl.
6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 is —OR 6 .
7. The compound of claim 6 , or a pharmaceutically acceptable salt thereof, wherein R 6 is carbocyclylalkyl, heterocyclylalkyl, aralkyl, or heteroarylalkyl.
8. The compound of claim 6 , or a pharmaceutically acceptable salt thereof, wherein R 6 is aralkyl or heteroarylalkyl.
9. The compound of claim 6 , or a pharmaceutically acceptable salt thereof, wherein R 6 is carbocyclylalkyl or heterocyclylalkyl.
10. The compound of claim 6 , or a pharmaceutically acceptable salt thereof, wherein R 5 is aryl.
11. The compound of claim 6 , or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 are both hydrogen.
12. The compound of claim 6 , or a pharmaceutically acceptable salt thereof, wherein R 1 is hydrogen.
13. The compound of claim 6 , or a pharmaceutically acceptable salt thereof, wherein R 2 is hydrogen.
14. The compound of claim 7 , or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 are both hydrogen.
15. The compound of claim 10 , or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 are both hydrogen.
16. The compound of claim 10 , or a pharmaceutically acceptable salt thereof, wherein R 3 is phenyl substituted with at least one substituent selected from alkyl, halogen, hydroxy, alkoxy, or alkylsulfone.
17. The compound of claim 16 , or a pharmaceutically acceptable salt thereof, wherein R 3 is phenyl substituted at the 4-position.
18. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of Formula (I) as described in claim 1 , or a pharmaceutically acceptable salt thereof.
19. A method for inhibiting a histone-demethylase enzyme comprising contacting a histone demethylase enzyme with a compound of Formula (I) as described in claim 1 .
20. A method for treating cancer in subject in need thereof comprising administering to the subject a composition comprising a compound of Formula (I) as described in claim 1 , or pharmaceutically acceptable salt thereof.
21. A compound of Formula (I)
or a pharmaceutically acceptable salt thereof, 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 hydrogen, halogen, —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;
with the proviso that:
if R 2 and R 3 are both hydrogen, then R 1 is not hydrogen, methyl, trifluoromethyl, isopropyl, or cyclopropyl; or
if R 1 and R 3 are both hydrogen, then R 2 is not methyl, trifluoromethyl, bromine, or chlorine; or
if R 1 and R 3 are both methyl, then R 2 is not hydrogen, methyl, or ethyl; or
if R 1 and R 2 are hydrogen, then R 3 is not
22. A pharmaceutical composition comprising the compound of claim 21 , or a pharmaceutically acceptable salt thereof.