Inhibitors of lysine specific demethylase-1

Patent metadata

Field	Value
Publication number	US-10597376-B2
Application number	US-201815991222-A
Country	US
Kind code	B2
Filing date	May 29, 2018
Priority date	Jun 27, 2014
Publication date	Mar 24, 2020
Grant date	Mar 24, 2020

Abstract

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 as exemplified as follows,

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.

First claim

We claim:

1. A compound, or a pharmaceutically acceptable salt thereof, having the structure of Formula (I):

wherein,
A is N or CH;
W 1 and W 2 are independently chosen from N, C—H, or C—F;
X is hydrogen, halogen, optionally substituted aryl, or optionally substituted heteroaryl;
Y is optionally substituted alkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclylalkyl, or optionally substituted aralkyl; and
Z is an optionally substituted group chosen from N-heterocyclyl, —O-heterocyclylalkyl, —N(H)-heterocyclylalkyl, or —N(Me)-heterocyclylalkyl;
wherein if Z is an optionally substituted heterocyclylalkyl group selected from —O— heterocyclylalkyl, —N(H)-heterocyclylalkyl or —N(Me)-heterocyclylalkyl, then heterocyclylalkyl group has the formula —R c -heterocyclyl, wherein R c is an optionally substituted C 1 -C 3 alkylene chain and the heterocyclyl is an optionally substituted nitrogen-containing 5-membered heterocyclyl.

2. The compound of claim 1 , wherein W 2 is C—H.

3. The compound of claim 2 , wherein W 1 is C—H.

4. The compound of claim 2 , wherein W 1 is N.

5. The compound of claim 1 , wherein X is hydrogen.

6. The compound of claim 1 , wherein X is optionally substituted aryl, or optionally substituted heteroaryl.

7. The compound of claim 6 , wherein the optionally substituted aryl is an optionally substituted phenyl.

8. The compound of claim 6 , wherein the optionally substituted heteroaryl is chosen from an optionally substituted pyridinyl, optionally substituted pyrazolyl, or optionally substituted indazolyl.

9. The compound of claim 1 , wherein Z is an optionally substituted heterocyclylalkyl group selected from —O-heterocyclylalkyl, —N(H)-heterocyclylalkyl or —N(Me)-heterocyclylalkyl.

10. The compound of claim 1 , wherein Z is an optionally substituted N-heterocyclyl selected from 4-, 5-, 6-, or 7-membered N-heterocyclyl.

11. The compound of claim 10 , wherein the 6-membered N-heterocyclyl is an optionally substituted piperidine.

12. The compound of claim 11 , wherein the optionally substituted piperidine is an optionally substituted 4-aminopiperidine.

13. The compound of claim 1 , wherein Y is an optionally substituted alkyl.

14. The compound of claim 13 , wherein the optionally substituted alkyl is an optionally substituted C 1 -C 3 alkyl.

15. The compound of claim 1 , wherein Y is optionally substituted cycloalkylalkyl.

16. The compound of claim 1 , wherein Y is optionally substituted heterocyclylalkyl.

17. The compound of claim 1 , wherein Y is optionally substituted aralkyl.

18. A compound, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:
4-[6-(4-aminopiperidin-1-yl)-4-benzyl-5-oxo-4,5-dihydropyrazin-2-yl]benzonitrile;
4-[6-(4-aminopiperidin-1-yl)-4-[(4-methylphenyl)methyl]-5-oxo-4,5-dihydropyrazin-2-yl]benzonitrile;
4-[6-(4-aminopiperidin-1-yl)-4-[(2-fluorophenyl)methyl]-5-oxo-4,5-dihydropyrazin-2-yl]benzonitrile;
4-[6-(4-aminopiperidin-1-yl)-4-(3-chloro-benzyl)-5-oxo-4,5-dihydro-pyrazin-2-yl]-benzonitrile;
4-[6-(4-amino-piperidin-1-yl)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-fluoro-benzonitrile;
4-[6-(4-Amino-piperidin-1-yl)-4-ethyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-fluoro-benzonitrile;
4-[6-(4-amino-piperidin-1-yl)-4-cyclopropylmethyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-fluoro-benzonitrile;
4-[6-(4-aminopiperidin-1-yl)-4-[(3-fluorophenyl)methyl]-5-oxo-4,5-dihydropyrazin-2-yl]benzonitrile;
4-[6-(4-aminopiperidin-1-yl)-4-[(4-fluorophenyl)methyl]-5-oxo-4,5-dihydropyrazin-2-yl]benzonitrile;
4-[6-(4-aminopiperidin-1-yl)-4-[(3-methoxyphenyl)methyl]-5-oxo-4,5-dihydropyrazin-2-yl]benzonitrile;
4-[6-(4-aminopiperidin-1-yl)-4-[(4-methoxyphenyl)methyl]-5-oxo-4,5-dihydropyrazin-2-yl]benzonitrile;
4-[6-(4-aminopiperidin-1-yl)-5-oxo-4-[(1R)-1-phenylethyl]-4,5-dihydropyrazin-2-yl]benzonitrile;
4-[6-(4-aminopiperidin-1-yl)-5-oxo-4-[(1S)-1-phenylethyl]-4,5-dihydropyrazin-2-yl]benzonitrile;
4-[6-(4-amino-piperidin-1-yl)-5-oxo-4-(tetrahydro-furan-3-ylmethyl)-4,5-dihydro-pyrazin-2-yl]-2-fluoro-benzonitrile;
4-[6-(4-amino-piperidin-1-yl)-5-oxo-4-(tetrahydro-pyran-4-ylmethyl)-4,5-dihydro-pyrazin-2-yl]-2-fluoro-benzonitrile;
4-[6-(4-aminopiperidin-1-yl)-4-methyl-3-(4-methylphenyl)-5-oxo-4,5-dihydropyrazin-2-yl]benzonitrile;
4-[4-methyl-3-(4-methylphenyl)-5-oxo-6-{[(3S)-pyrrolidin-3-ylmethyl]amino}-4,5-dihydropyrazin-2-yl]benzonitrile;
4-[4-methyl-3-(4-methylphenyl)-5-oxo-6-{[(3R)-pyrrolidin-3-ylmethyl]amino}4-4,5-dihydropyrazin-2-yl]benzonitrile;
5-[6-(4-aminopiperidin-1l-yl)-4-methyl-3-(4-methylphenyl)-5-oxo-4,5-dihydropyrazin-2-yl]pyridine-2-carbonitrile;
4-{4-methyl-6-[4-(methylamino)piperidin-1-yl]-3-(4-methylphenyl)-5-oxo-4,5-dihydropyrazin-2-yl}benzonitrile;
4-[6-(4-amino-4-methylpiperidin-1-yl)-4-methyl-3-(4-methylphenyl)-5-oxo-4,5-dihydropyrazin-2-yl]benzonitrile;
4-[6-(3-aminopiperidin-1l-yl)-4-methyl-3-(4-methylphenyl)-5-oxo-4,5-dihydropyrazin-2-yl]benzonitrile;
4-[4-methyl-3-(4-methylphenyl)-6-{octahydro-1H-pyrrolo[3,4-c]pyridin-5-yl}-5-oxo-4,5-dihydropyrazin-2-yl]benzonitrile;
4-(6-{2,8-diazaspiro[4.5]decan-8-yl}-4-methyl-3-(4-methylphenyl)-5-oxo-4,5-dihydropyrazin-2-yl)benzonitrile;
4-(6-{decahydropyrrolo[3,4-d]azepin-6-yl}-4-methyl-3-(4-methylphenyl)-5-oxo-4,5-dihydropyrazin-2-yl)benzonitrile;
4-[6-(4-aminopiperidin-1-yl)-4-ethyl-3-(4-methylphenyl)-5-oxo-4,5-dihydropyrazin-2-yl]benzonitrile;
4-[6-(4-aminopiperidin-1-yl)-3-(4-ethylphenyl)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl]benzonitrile;
4-[3-(4-ethylphenyl)-4-methyl-5-oxo-6-{[(3S)-pyrrolidin-3-ylmethyl]amino}-4,5-dihydropyrazin-2-yl]benzonitrile;
4-[3-(4-ethylphenyl)-4-methyl-5-oxo-6-{[(3R)-pyrrolidin-3-ylmethyl]amino}-4,5-dihydropyrazin-2-yl]benzonitrile;
4-[6-(4-aminopiperidin-1-yl)-3-(4-methoxyphenyl)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl]benzonitrile;
4-[3-(4-methoxyphenyl)-4-methyl-5-oxo-6-{[(3S)-pyrrolidin-3-ylmethyl]amino}4-4,5-dihydropyrazin-2-yl]benzonitrile 4-[3-(4-methoxyphenyl)-4-methyl-5-oxo-6-{[(3R)-pyrrolidin-3-ylmethyl]amino}-4,5-dihydropyrazin-2-yl]benzonitrile;
4-[6-(4-aminopiperidin-1-yl)-3-(4-cyclopropylphenyl)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl]benzonitrile;
4-[3-(4-cyclopropylphenyl)-4-methyl-5-oxo-6-{[(3S)-pyrrolidin-3-ylmethyl]amino}4-4,5-dihydropyrazin-2-yl]benzonitrile;
4-[3-(4-cyclopropylphenyl)-4-methyl-5-oxo-6-{[(3R)-pyrrolidin-3-ylmethyl]amino}-4,5-dihydropyrazin-2-yl]benzonitrile;
4-[6-(4-amino-piperidin-1l-yl)-4-(2-methoxy-ethyl)-5-oxo-3-p-tolyl-4,5-dihydro-pyrazin-2-yl]-benzonitrile;
4-[6-(4-amino-piperidin-1l-yl)-4-(2-hydroxy-ethyl)-5-oxo-3-p-tolyl-4,5-dihydro-pyrazin-2-yl]-benzonitrile;
4-[6-(4-amino-piperidin-1-yl)-3-(4-cyclopropyl-phenyl)-4-(2-hydroxy-ethyl)-5-oxo-4,5-dihydro-pyrazin-2-yl]-benzonitrile;
4-[6-(4-amino-piperidin-1-yl)-4-(3-methoxy-propyl)-5-oxo-3-p-tolyl-4,5-dihydro-pyrazin-2-yl]-benzonitrile;
4-[6-(4-amino-piperidin-1-yl)-4-(3-hydroxy-propyl)-5-oxo-3-p-tolyl-4,5-dihydro-pyrazin-2-yl]-benzonitrile;
4-[6-(4-amino-piperidin-1-yl)-4-(2-methoxy-ethyl)-5-oxo-3-p-tolyl-4,5-dihydro-pyrazin-2-yl]-2-fluoro-benzonitrile;
4-[6-(4-amino-piperidin-1-yl)-4-(2-hydroxy-ethyl)-5-oxo-3-p-tolyl-4,5-dihydro-pyrazin-2-yl]-2-fluoro-benzonitrile;
4-(6-{[((3S)-pyrrolidin-3-yl)methyl]amino}-4-(2-methoxyethyl)-3-(4-methylphenyl)-5-oxo(4-hydropyrazin-2-yl))-2-fluorobenzenecarbonitrile;
4-(6-{[((3S)-pyrrolidin-3-yl)methyl]amino}-4-(2-hydroxyethyl)-3-(4-methylphenyl)-5-ox

Assignees

• Celgene Quanticel Res Inc

Inventors

• Chen Young K
• Kanouni Toufike
• Stafford Jeffrey Alan
• Veal James Marvin

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• C07D401/14

  containing three or more hetero rings · CPC title

• C07D471/04

  Ortho-condensed systems · CPC title

• C07D471/10

  Spiro-condensed systems · CPC title