Kynurenine-3-monooxygenase inhibitors, pharmaceutical compositions, and methods of use thereof

Patent metadata

Field	Value
Publication number	US-9884853-B2
Application number	US-201414392304-A
Country	US
Kind code	B2
Filing date	Sep 23, 2014
Priority date	Sep 26, 2013
Publication date	Feb 6, 2018
Grant date	Feb 6, 2018

Abstract

Certain compounds, or pharmaceutically acceptable salts or prodrugs thereof, are provided herein. Also provided are pharmaceutical compositions comprising at least one compound, or pharmaceutically acceptable salt or prodrug thereof, described herein and one or more pharmaceutically acceptable vehicle. Methods of treating patients suffering from certain diseases and disorders responsive to the inhibition of KMO activity are described, which comprise administering to such patients an amount of at least one compound, or pharmaceutically acceptable salt or prodrug thereof, described herein effective to reduce signs or symptoms of the disease or disorder are disclosed. These diseases include neurodegenerative disorders such as Huntington's disease. Also described are methods of treatment include administering at least one compound, or pharmaceutically acceptable salt or prodrug thereof, described herein as a single active agent or administering at least one compound, or pharmaceutically acceptable salt or prodrug thereof, described herein in combination with one or more other therapeutic agents. Also provided are methods for screening compounds capable of inhibiting KMO activity.

First claim

What is claimed is:

1. A compound of Formula I

or a pharmaceutically acceptable salt or prodrug thereof, wherein
R 1 is 1,3-benzothiazol-2-yl, 2-methyl-1,3-benzothiazol-6-yl, 8-chloroquinoxalin-6-yl, 8-chloroquinolin-6-yl, 7-chloro-2-methyl-1-benzofuran-5-yl, 7-chloro-1-benzofuran-5-yl, 8-chloroisoquinolin-6-yl, 5-chloroquinazolin-7-yl, 8-chloroquinazolin-6-yl, 8-chlorocinnolin-6-yl, 4-chlorobenzo[d]oxazol-6-yl, 4-chloro-2-methylbenzo[d]oxazol-6-yl, 4-chloro-1H-benzo[d]imidazol-6-yl, 7-chlorobenzo[d]oxazol-5-yl, 7-chloro-2-methylbenzo[d]oxazol-5-yl, 7-chlorobenzo[d]thiazol-5-yl, 7-chloro-2-methylbenzo[d]thiazol-5-yl, 7-chloro-1H-indol-5-yl, 7-chloro-1H-indazol-5-yl, 7-chloro-1-methyl-1H-indazol-5-yl, 7-chlorobenzo[d]isoxazol-5-yl, 7-chloro-1-methyl-1H-indol-5-yl, or 7-chlorobenzofuran-5-yl;
X is —CR 2 R 3 —;
R 2 and R 3 are independently chosen from hydrogen, optionally substituted amino, hydroxyl, lower alkoxy, and optionally substituted lower alkyl;
L is —C(O)O—;
R 5 is hydrogen; and
R 6 and R 7 are independently chosen from hydrogen, halo, optionally substituted amino, hydroxyl, lower alkoxy, and optionally substituted lower alkyl.

2. The compound of claim 1 , or a pharmaceutically acceptable salt or prodrug thereof, wherein R 2 is hydrogen, hydroxyl, lower alkoxy, amino optionally substituted with one or more alkyl groups, or lower alkyl optionally substituted with one or more groups independently chosen from halo, hydroxyl, lower alkoxy, and amino optionally substituted with one or more alkyl groups.

3. The compound of claim 2 , or a pharmaceutically acceptable salt or prodrug thereof, wherein R 2 is hydrogen, amino, methylamino, dimethylamino, hydroxyl, methyl, methoxy, difluoromethyl, trifluoromethyl, hydroxymethyl, methoxymethyl, aminomethyl, (methylamino)methyl, or (dimethylamino)methyl.

4. The compound of claim 1 , or a pharmaceutically acceptable salt or prodrug thereof, wherein R 3 is hydrogen or lower alkyl.

5. The compound of claim 4 , or a pharmaceutically acceptable salt or prodrug thereof, wherein R 3 is hydrogen or methyl.

6. The compound of claim 1 , or a pharmaceutically acceptable salt or prodrug thereof, wherein R 2 and R 3 are hydrogen.

7. The compound of claim 1 , or a pharmaceutically acceptable salt or prodrug thereof, wherein R 2 is methyl and R 3 is hydrogen.

8. The compound of claim 1 , or a pharmaceutically acceptable salt or prodrug thereof, wherein R 2 and R 3 are methyl.

9. The compound of claim 1 , or a pharmaceutically acceptable salt or prodrug thereof, wherein R 1 is 7-chlorobenzofuran-5-yl, 7-chloro-2-methylbenzo[d]oxazol-5-yl, or 4-chlorobenzo[d]oxazol-6-yl.

10. The compound of claim 1 , or a pharmaceutically acceptable salt or prodrug thereof, wherein R 7 is hydrogen, amino, methylamino, dimethylamino, aminomethyl, (methylamino)methyl, (dimethylamino)methyl, methoxymethyl, methyl, 1-aminoethyl, 1-methoxy-ethyl, methoxy, or halo.

11. The compound of claim 10 , or a pharmaceutically acceptable salt or prodrug thereof, wherein R 7 is methyl.

12. The compound of claim 10 , or a pharmaceutically acceptable salt or prodrug thereof, wherein R 7 is hydrogen.

13. The compound of claim 1 , or a pharmaceutically acceptable salt or prodrug thereof, wherein R 6 is hydrogen, amino, methylamino, dimethylamino, aminomethyl, methylaminomethyl, (dimethylamino)methyl, or methyl.

14. The compound of claim 13 , or a pharmaceutically acceptable salt or prodrug thereof, wherein R 6 is hydrogen.

15. A compound, or a pharmaceutically acceptable salt or prodrug thereof, selected from:
(1S,2S)-2-(2-methyl-1,3-benzothiazole-6-carbonyl)cyclopropane-1-carboxylic acid,
(1S,2S)-2-(7-chloro-1-benzofuran-5-carbonyl)cyclopropane-1-carboxylic acid,
(1S,2S)-2-(7-chloro-2-methyl-1-benzofuran-5-carbonyl)cyclopropane-1-carboxylic acid,
(1S,2S)-2-(8-chloroquinoline-6-carbonyl)cyclopropane-1-carboxylic acid,
(1S,2S)-2-(8-chloroquinoxaline-6-carbonyl)cyclopropane-1-carboxylic acid,
(1S,2S)-2-[(1,3-Benzothiazol-2-yl)carbonyl]cyclopropane-1-carboxylic acid,
(1S,2S)-2-(8-chloroisoquinoline-6-carbonyl)cyclopropanecarboxylic acid,
(1S,2S)-2-(5-chloroquinazoline-7-carbonyl)cyclopropanecarboxylic acid,
(1S,2S)-2-(8-chloroquinazoline-6-carbonyl)cyclopropanecarboxylic acid,
(1S,2S)-2-(8-chlorocinnoline-6-carbonyl)cyclopropanecarboxylic acid,
(1S,2S)-2-(4-chlorobenzo[d]oxazole-6-carbonyl)cyclopropanecarboxylic acid,
(1S,2S)-2-(4-chloro-2-methylbenzo[d]oxazole-6-carbonyl)cyclopropanecarboxylic acid,
(1S,2S)-2-(4-chloro-1H-benzo[d]imidazole-6-carbonyl)cyclopropanecarboxylic acid,
(1S,2S)-2-(7-chlorobenzo[d]oxazole-5-carbonyl)cyclopropanecarboxylic acid,
(1S,2S)-2-(7-chloro-2-methylbenzo[d]oxazole-5-carbonyl)cyclopropanecarboxylic acid,
(1S,2S)-2-(7-chlorobenzo[d]thiazole-5-carbonyl)cyclopropanecarboxylic acid,
(1S,2S)-2-(7-chloro-2-methylbenzo[d]thiazole-5-carbonyl)cyclopropanecarboxylic acid,
(1S,2S)-2-(7-chloro-1H-indole-5-carbonyl)cyclopropanecarboxylic acid,
(1S,2S)-2-(7-chloro-1H-indazole-5-carbonyl)cyclopropanecarboxylic acid,
(1S,2S)-2-(7-chloro-1-methyl-1H-indazole-5-carbonyl)cyclopropanecarboxylic acid,
(1S,2S)-2-(7-chlorobenzo[d]isoxazole-5-carbonyl)cyclopropanecarboxylic acid,
(1S,2S)-2-(7-chloro-1-methyl-1H-indole-5-carbonyl)cyclopropanecarboxylic acid,
(1R,2S)-1-amino-2-(7-chlorobenzofuran-5-carbonyl)cyclopropanecarboxylic acid,
(1R,2S)-2-(7-chlorobenzofuran-5-carbonyl)-1-(methylamino)cyclopropanecarboxylic acid,
(1R,2S)-2-(7-chlorobenzofuran-5-carbonyl)-1-(dimethylamino)cyclopropanecarboxylic acid,
(1S,2S)-1-(aminomethyl)-2-(7-chlorobenzofuran-5-carbonyl)cyclopropanecarboxylic acid,
(1S,2S)-2-(7-chlorobenzofuran-5-carbonyl)-1-((methylamino)methyl)cyclopropanecarboxylic acid,
(1S,2S)-2-(7-chlorobenzofuran-5-carbonyl)-1-((dimethylamino)methyl)cyclopropanecarboxylic acid,
(1S,2S)-2-(7-chlorobenzofuran-5-carbonyl)-1-methylcyclopropanecarboxylic acid,
(1R,2R)-2-(7-chlorobenzofuran-5-carbonyl)-1-fluorocyclopropanecarboxylic acid,
(1R,2S)-2-(7-chlorobenzofuran-5-carbonyl)-1-methoxycyclopropanecarboxylic acid,
(1S,2S)-2-(7-chlorobenzofuran-5-carbonyl)-1-(methoxymethyl)cyclopropanecarboxylic acid,
(1R,3R)-2-amino-3-(7-chlorobenzofuran-5-carbonyl)cyclopropanecarboxylic acid,
(1R,2R)-2-(7-chlorobenzofuran-5-carbonyl)-3-(methylamino)cyclopropanecarboxylic acid,
(1R,2R)-2-(7-chlorobenzofuran-5-carbonyl)-3-(dimethylamino)cyclopropanecarboxylic acid,
(1S,2S)-2-(7-chlorobenzofuran-5-carbonyl)-3-methylcyclopropanecarboxylic acid,
(1R,3R)-3-(7-chlorobenzofuran-5-carbonyl)-2,2-dimethylcyclopropanecarboxylic acid,
(1R,3R)-3-(7-chlorobenzofuran-5-carbonyl)-2-hydroxy-2-methylcyclopropanecarboxylic acid,
(1R,3R)-3-(7-chlorobenzofuran-5-carbonyl)-2-(hydroxymethyl)-2-methylcyclopropanecarboxylic acid,
(1R,3R)-3-(7-chlorobenzofuran-5-carbonyl)-2-(methoxymethyl)-2-methylcyclopropanecarboxylic acid,
(1R,3R)-2-(aminomethyl)-3-(7-chlorobenzofuran-5-carbonyl)-2-methylcyclopropanecarboxylic acid,
(1R,3R)-3-(7-chlorobenzofuran-5-carbonyl)-2-methyl-2-((methylamino)methyl)cyclopropanecarboxylic acid,
(1R,3R)-2-amino-3-(7-chlorobenzofuran-5-carbonyl)-2-methylcyclopropanecarboxylic acid,
(1R,3R)-3-(7-chlorobenzofuran-5-carbonyl)-2-methyl-2-(methylamino)cyclopropanecarboxylic acid,
(1S,3S)-2-(aminomethyl)-3-(7-chlorobenzofuran-5-carbonyl)cyclopropanecarboxylic acid,
(1S,2S)-2-(7-chlorobenzofuran-5-carbonyl)-3-((methylamino)methyl)cyclopropanecarboxylic acid,
(1S,2S)-2-(7-chlorobenzofuran-5-carbonyl)-3-

Assignees

• Chdi Foundation Inc

Inventors

• Toledo Sherman Leticia M
• Dominguez Celia
• Prime Michael
• Mitchell William
• Went Naomi

Classifications

• A61P43/00

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

• A61P25/28

  for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia · CPC title

• A61P25/14

  for treating abnormal movements, e.g. chorea, dyskinesia · CPC title

• A61P25/00

  Drugs for disorders of the nervous system · CPC title

• C07D333/10

  Thiophene · CPC title