Inhibitors of lysine specific demethylase-1
The present invention relates generally to compositions and methods for treating cancer and neoplastic disease. Provided herein are substituted heterocyclic derivative compounds and pharmaceutical compositions comprising said compounds. The subject compounds and compositions are useful for inhibition of lysine specific demethylase-1. 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 having the structure of Formula (IV), or a pharmaceutically acceptable salt thereof,
wherein,
X and Y are each independently chosen from CH, CF, C—CH 3 , or N;
Z is -G, —CH 2 -G, —CH 2 —CH 2 -G, —N(R 1 )-G, —N(R 1 )—CH 2 -G, —O-G, —O—CH 2 -G, or —C(O)N(R 2 )(R 3 );
X 1 , X 2 , and X 3 are each independently selected from N or C—R 4 , provided that at least one of X 1 , X 2 , or X 3 is N;
G is carbocyclyl, aryl, or heterocyclyl;
R 1 is hydrogen or alkyl;
R 2 and R 3 are independently selected from hydrogen, alkyl, heterocyclyl, heterocyclylalkyl, or optionally, R 2 and R 3 join to form an N-linked heterocyclyl ring system;
R 4 is hydrogen, halogen, C 1 -C 3 alkyl or C 1 -C 3 alkoxy; and
R is heteroaryl, alkynyl, or cycloalkylalkynylene.
2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R is heteroaryl.
3. The compound of claim 1 , or pharmaceutically acceptable salt thereof, wherein Formula (IV) is Formula (IVc):
4. The compound of claim 1 , or pharmaceutically acceptable salt thereof, wherein X is C—F.
5. The compound of claim 1 , or pharmaceutically acceptable salt thereof, wherein Y is C—H.
6. The compound of claim 1 , or pharmaceutically acceptable salt thereof, wherein Z is —N(R 1 )-G.
7. The compound of claim 1 , or pharmaceutically acceptable salt thereof, wherein R 1 is alkyl.
8. The compound of claim 1 , or pharmaceutically acceptable salt thereof, wherein R 4 is hydrogen.
9. The compound of claim 1 , or pharmaceutically acceptable salt thereof, wherein G is a heterocyclyl.
10. The compound of claim 1 , or pharmaceutically acceptable salt thereof, wherein G is a nitrogen-containing heterocyclyl.
11. The compound of claim 10 , or pharmaceutically acceptable salt thereof, wherein the nitrogen-containing heterocyclyl is a 5- or 6-membered heterocyclyl.
12. The compound of claim 10 , or pharmaceutically acceptable salt thereof, wherein the heterocyclyl is chosen from:
13. The compound of claim 2 , or pharmaceutically acceptable salt thereof, wherein R is a bicyclic nitrogen-containing heteroaryl.
14. The compound of claim 13 , or pharmaceutically acceptable salt thereof, wherein R is chosen from:
15. A compound having the structure of Formula (IVc)
wherein the compound of Formula (IVc) includes pharmaceutically acceptable salts thereof, and wherein
X is C—F;
Y is C—H;
Z is -G, —CH 2 -G, —CH 2 —CH 2 -G, —N(R 1 )-G, —N(R 1 )—CH 2 -G, —O-G, —O—CH 2 -G, or —C(O)N(R 2 )(R 3 ), wherein
G is carbocyclyl, aryl, heterocyclyl or heteroaryl;
R 1 is hydrogen or alkyl, and R 2 and R 3 are independently selected from hydrogen, alkyl, heterocyclyl, or heterocyclylalkyl, or optionally, R 2 and R 3 join to form an N-linked heterocyclyl ring system;
R is aryl, heteroaryl, alkynyl, or cycloalkylalkynylene; and
R 4 is hydrogen.
16. The compound of claim 15 , wherein R is a bicyclic nitrogen-containing heteroaryl.
17. The compound of claim 16 , wherein R is:
18. The compound of claim 15 , wherein G is
19. A pharmaceutical composition comprising a compound of Formula (IV) as described in claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
20. A pharmaceutical composition comprising the compound of claim 15 and at least one pharmaceutically acceptable excipient.