Rho kinase inhibitors

Patent metadata

Field	Value
Publication number	US-10624882-B2
Application number	US-201715858995-A
Country	US
Kind code	B2
Filing date	Dec 29, 2017
Priority date	Sep 20, 2006
Publication date	Apr 21, 2020
Grant date	Apr 21, 2020

Abstract

Disclosed are novel substituted 2H-isoquinolin-1-one and 3H-quinazolin-4-one derivatives useful as inhibitors of Rho kinase and for treating a variety of diseases and disorders that are mediated or sustained through the activity of Rho kinase, including cardiovascular diseases, pharmaceutical compositions comprising such compounds, methods for using such compounds and processes for making such compounds.

First claim

The invention claimed is:

1. A compound selected from:
1-(4-Chloro-phenyl)-cyclopentanecarboxylic acid (4-oxo-3,4-dihydro-quinazolin-7-yl)-amide;
2-Benzylamino-N-(4-oxo-3,4-dihydro-quinazolin-7-yl)-acetamide;
1-Benzyl-piperidine-4-carboxylic acid (4-oxo-3,4-dihydro-quinazolin-7-yl)-amide;
Pyrrolidine-2-carboxylic acid (4-oxo-3,4-dihydro-quinazolin-7-yl)-amide;
2-Amino-4-methyl-pentanoic acid (4-oxo-3,4-dihydro-quinazolin-7-yl)-amide;
(R)-2-Amino-N-(4-oxo-3,4-dihydro-quinazolin-7-yl)-3-phenyl-propionamide;
(S)-2-Amino-N-(4-oxo-3,4-dihydro-quinazolin-7-yl)-3-phenyl-propionamide;
2-(Cyclohexylmethyl-amino)-N-(4-oxo-3,4-dihydro-quinazolin-7-yl)-acetamide;
2-Methylamino-N-(4-oxo-3,4-dihydro-quinazolin-7-yl)-2-phenyl-acetamide;
2-Amino-N-(4-oxo-3,4-dihydro-quinazolin-7-yl)-2-phenyl-acetamide;
2-Cyclopropylamino-N-(4-oxo-3,4-dihydro-quinazolin-7-yl)-2-phenyl-acetamide;
(R)-2-Amino-N-(4-oxo-3,4-dihydro-quinazolin-7-yl)-2-phenyl-acetamide;
(R)-Pyrrolidine-2-carboxylic acid (4-oxo-3,4-dihydro-quinazolin-7-yl)-amide;
(R)-2-Amino-3-methyl-N-(4-oxo-3,4-dihydro-quinazolin-7-yl)-butyramide;
2-(Cyclopropylmethyl-amino)-N-(4-oxo-3,4-dihydro-quinazolin-7-yl)-acetamide;
N-(4-oxo-3,4-dihydro-quinazolin-7-yl)-2-(2-thiophen-2-yl-ethylamino)-acetamide;
2-(Cyclohexyl-methyl-amino)-N-(4-oxo-3,4-dihydro-quinazolin-7-yl)-acetamide;
N-(6-Chloro-4-oxo-3,4-dihydro-quinazolin-7-yl)-2-dimethylamino-2-phenyl-acetamide;
N-(6-Chloro-4-oxo-3,4-dihydro-quinazol in-7-yl)-2-cyclopropylamino-2-phenyl-acetamide;
2,5-Dimethyl-2H-pyrazole-3-carboxylic acid (4-oxo-3,4-dihydro-quinazolin-7-yl)-amide;
(trans)-4-(3-Bromo-phenyl)-pyrrolidine-3-carboxylic acid (6-chloro-4-oxo-3,4-dihydro-quinazolin-7-yl)-amide;
(R)—N-(6-Chloro-4-oxo-3,4-dihydro-quinazolin-7-yl)-2-(4-chloro-phenyl)-2-hydroxy-propionamide;
(R)-2-(4-Chloro-phenyl)-2-hydroxy-N-(4-oxo-3,4-dihydro-quinazolin-7-yl)-propionamide;
or a pharmaceutically acceptable salt thereof.

2. A composition comprising the compound of claim 1 .

3. A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable excipient or carrier.

4. The compound of claim 1 , wherein the compound is selected from:
(R)-2-Amino-N-(4-oxo-3,4-dihydro-quinazolin-7-yl)-3-phenyl-propionamide;
(S)-2-Amino-N-(4-oxo-3,4-dihydro-quinazolin-7-yl)-3-phenyl-propionamide;
(R)-2-Amino-N-(4-oxo-3,4-dihydro-quinazolin-7-yl)-2-phenyl-acetamide;
(R)-Pyrrolidine-2-carboxylic acid (4-oxo-3,4-dihydro-quinazolin-7-yl)-amide;
(R)-2-Amino-3-methyl-N-(4-oxo-3,4-dihydro-quinazolin-7-yl)-butyramide;
(trans)-4-(3-Bromo-phenyl)-pyrrolidine-3-carboxylic acid (6-chloro-4-oxo-3,4-dihydro-quinazolin-7-yl)-amide;
(R)—N-(6-Chloro-4-oxo-3,4-dihydro-quinazolin-7-yl)-2-(4-chloro-phenyl)-2-hydroxy-propionamide;
(R)-2-(4-Chloro-phenyl)-2-hydroxy-N-(4-oxo-3,4-dihydro-quinazolin-7-yl)-propionamide;
or a pharmaceutically acceptable salt thereof.

5. The compound of claim 1 , wherein the compound is 1-(4-Chloro-phenyl)-cyclopentanecarboxylic acid (4-oxo-3,4-dihydro-quinazolin-7-yl)-amide or a pharmaceutically acceptable salt thereof.

6. The compound of claim 1 , wherein the compound is 2-Benzylamino-N-(4-oxo-3,4-dihydro-quinazolin-7-yl)-acetamide or a pharmaceutically acceptable salt thereof.

7. The compound of claim 1 , wherein the compound is 1-Benzyl-piperidine-4-carboxylic acid (4-oxo-3,4-dihydro-quinazolin-7-yl)-amide or a pharmaceutically acceptable salt thereof.

8. The compound of claim 1 , wherein the compound is Pyrrolidine-2-carboxylic acid (4-oxo-3,4-dihydro-quinazolin-7-yl)-amide or a pharmaceutically acceptable salt thereof.

9. The compound of claim 1 , wherein the compound is 2-Amino-4-methyl-pentanoic acid (4-oxo-3,4-dihydro-quinazolin-7-yl)-amide or a pharmaceutically acceptable salt thereof.

10. The compound of claim 1 , wherein the compound is 2-(Cyclohexylmethyl-amino)-N-(4-oxo-3,4-dihydro-quinazolin-7-yl)-acetamide or a pharmaceutically acceptable salt thereof.

11. The compound of claim 1 , wherein the compound is 2-Methylamino-N-(4-oxo-3,4-dihydro-quinazolin-7-yl)-2-phenyl-acetamide or a pharmaceutically acceptable salt thereof.

12. The compound of claim 1 , wherein the compound is 2-Amino-N-(4-oxo-3,4-dihydro-quinazolin-7-yl)-2-phenyl-acetamide or a pharmaceutically acceptable salt thereof.

13. The compound of claim 1 , wherein the compound is 2-Cyclopropylamino-N-(4-oxo-3,4-dihydro-quinazolin-7-yl)-2-phenyl-acetamide or a pharmaceutically acceptable salt thereof.

14. The compound of claim 1 , wherein the compound is 2-(Cyclopropylmethyl-amino)-N-(4-oxo-3,4-dihydro-quinazolin-7-yl)-acetamide or a pharmaceutically acceptable salt thereof.

15. The compound of claim 1 , wherein the compound is N-(4-oxo-3,4-dihydro-quinazolin-7-yl)-2-(2-thiophen-2-yl-ethylamino)-acetamide or a pharmaceutically acceptable salt thereof.

16. The compound of claim 1 , wherein the compound is 2-(Cyclohexyl-methyl-amino)-N-(4-oxo-3,4-dihydro-quinazolin-7-yl)-acetamide or a pharmaceutically acceptable salt thereof.

17. The compound of claim 1 , wherein the compound is N-(6-Chloro-4-oxo-3,4-dihydro-quinazolin-7-yl)-2-dimethylamino-2-phenyl-acetamide or a pharmaceutically acceptable salt thereof.

18. The compound of claim 1 , wherein the compound is N-(6-Chloro-4-oxo-3,4-dihydro-quinazolin-7-yl)-2-cyclopropylamino-2-phenyl-acetamide or a pharmaceutically acceptable salt thereof.

19. The compound of claim 1 , wherein the compound is 2,5-Dimethyl-2H-pyrazole-3-carboxylic acid (4-oxo-3,4-dihydro-quinazolin-7-yl)-amide or a pharmaceutically acceptable salt thereof.

Assignees

• Aerie Pharmaceuticals Inc

Inventors

• Bosanac Todd
• Ginn John David
• Hickey Eugene Richard
• Kirrane Jr Thomas Martin
• Liu Weimin
• Prokopowicz Anthony S
• Schlyer Sabine K
• Shih Cheng-Kon
• Snow Roger John
• Turner Michael Robert
• Wu Frank
• YOUNG Erick Richard

Classifications

• A61K31/472 Primary

  Non-condensed isoquinolines, e.g. papaverine · CPC title

• C07D239/90

  with acyclic radicals attached in position 2 or 3 · CPC title

• C07D217/24

  Oxygen atoms · CPC title

• A61K31/496

  Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin · CPC title

• C07D487/08

  Bridged systems · CPC title