Histone demethylase inhibitors
The present invention relates generally to compositions and methods for treating cancer and neoplastic disease. Provided herein are substituted amidopyridine or amidopyridazine 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 (XI), or a pharmaceutically acceptable salt thereof,
wherein:
Q is —CO 2 R, —C(O)N(H)CN, —C(O)N(H)OH, or tetrazolyl;
R is hydrogen or optionally substituted alkyl;
G is —X—Y;
X is —C 1 alkylene;
Y is optionally substituted tetralinyl, optionally substituted tetrahydroquinolinyl, substituted pyridyl, optionally substituted naphthyl, optionally substituted indolyl, optionally substituted benzofuranyl, optionally substituted adamantyl, or
optionally substituted indanyl.
2. A compound of Formula (XI), or a pharmaceutically acceptable salt thereof,
wherein:
Q is —CO 2 R, —C(O)N(H)CN, —C(O)N(H)OH, or tetrazolyl;
R is hydrogen or optionally substituted alkyl;
G is —X—Y;
X is —C 1 alkylene;
Y is phenyl substituted with alkenyl, alkynyl, fluoro, chloro, fluoroalkyl, nitro, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, —R b —OR a , —R b —OC(O)—R a , —R b —OC(O)—OR a , —R b —OC(O)—N(R a ) 2 , —R b —N(R a ) 2 , —R b —C(O)R a , —R b —C(O)OR a , —R b —O—R c —C(O)N(R a ) 2 , —R b —N(R a )C(O)OR a , —R b —N(R a )C(O)R a , —R b —N(R a )S(O) t R a , —R b —S(O) t OR a , —R b —S(O) t OR a , and —R b —S(O) t N(R a ) 2 ;
wherein:
each R a is independently hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl;
each R b is independently a direct bond or a straight or branched alkylene or alkenylene chain;
each R c is a straight or branched alkylene or alkenylene chain; and
t is 1 or 2.
3. A compound of Formula (XV), or a pharmaceutically acceptable salt thereof,
wherein,
Q is —CO 2 R, —C(O)N(H)CN, —C(O)N(H)OH, or tetrazolyl;
R is hydrogen or optionally substituted alkyl;
G is —X—Y;
X is —C 1 alkylene;
Y is carbocyclyl, heterocyclyl, aryl, or heteroaryl;
with the provisio that G is not
4. The compound, or pharmaceutically acceptable salt thereof, of any one of claims 1 - 3 , wherein Q is —CO 2 R, and R is hydrogen.
5. The compound, or pharmaceutically acceptable salt thereof, of any one of claims 1 - 3 , wherein Q is —C(O)N(H)CN.
6. The compound, or pharmaceutically acceptable salt thereof, of any one of claims 1 - 3 , wherein Q is —C(O)N(H)OH.
7. The compound, or pharmaceutically acceptable salt thereof, of any one of claims 1 - 3 , wherein Q is tetrazolyl.
8. The compound, or pharmaceutically acceptable salt thereof, of any one of claims 1 - 3 , wherein Q is —CO 2 R and R is optionally substituted alkyl.
9. The compound, or pharmaceutically acceptable salt thereof, of claim 1 , wherein Y is optionally substituted tetralinyl.
10. The compound, or pharmaceutically acceptable salt thereof, of claim 1 , wherein Y is optionally substituted tetrahydroquinolinyl.
11. The compound, or pharmaceutically acceptable salt thereof, of claim 1 , wherein Y is substituted pyridyl.
12. The compound, or pharmaceutically acceptable salt thereof, of claim 1 , wherein Y is optionally substituted naphthyl.
13. The compound, or pharmaceutically acceptable salt thereof, of claim 1 , wherein Y is optionally substituted indolyl.
14. The compound, or pharmaceutically acceptable salt thereof, of claim 1 , wherein Y is optionally substituted benzofuranyl.
15. The compound, or pharmaceutically acceptable salt thereof, of claim 1 , wherein Y is optionally substituted adamantyl.
16. The compound, or pharmaceutically acceptable salt thereof, of claim 1 , wherein Y is optionally substituted indanyl.
17. A compound, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:
18. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of claim 1 , 2 , 3 , or 17 , or a pharmaceutically acceptable salt thereof.