Lactam, cyclic urea and carbamate, and triazolone derivatives as potent and selective rock inhibitors

Patent metadata

Field	Value
Publication number	US-10730858-B2
Application number	US-201716315674-A
Country	US
Kind code	B2
Filing date	Jul 6, 2017
Priority date	Jul 7, 2016
Publication date	Aug 4, 2020
Grant date	Aug 4, 2020

Abstract

The present invention provides compounds of Formula (I): Formula (I) or stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, wherein all the variables are as defined herein. These compounds are selective ROCK inhibitors. This invention also relates to pharmaceutical compositions comprising these compounds and methods of treating cardiovascular, smooth muscle, oncologic, neuropathologic, autoimmune, fibrotic, and/or inflammatory disorders using the same.

First claim

What is claimed is:

1. A compound of Formula (I):

or a stereoisomer, a tautomer, a pharmaceutically acceptable salt thereof, wherein:
Ring A is independently selected from

Ring B is independently selected from

G is independently selected from N and CR 7 ;
M is independently selected from N and CR 9 ;
X is independently selected from CR 1 , NR 2 , and O;
Y is independently selected from CR 3 and N;
L is absent or independently selected from —NR 4 —, —C(O)NR 4 (CR 4 R 4 ) n —, and —O—;
R 1 is L-R 5 ;
R 2 is —(CR 4 R 4 ) n —R 5 ;
R 3 is independently selected from H, C 1-4 alkyl substituted with 0-4 R e , —(CH 2 ) r OR b , (CH 2 ) r S(O) p R c , —(CH 2 ) r C(═O)R b , —(CH 2 ) r NR a R a , —(CH 2 ) r CN, —(CH 2 ) r C(═O)NR a R a , —(CH 2 ) r NR a C(═O)R b , —(CH 2 ) r NR a C(═O)NR a R a , —(CH 2 ) r NR a C(═O)OR b , —(CH 2 ) r OC(═O)NR a R a , —(CH 2 ) r C(═O)OR b , —(CH 2 ) r S(O) p NR a R a , —(CH 2 ) r NR a S(O) p NR a R a , —(CH 2 ) r NR a S(O) p R c , (CH 2 ) r —C 3-6 carbocyclyl substituted with 0-3 R e , and —(CH 2 ) r -heterocyclyl substituted with 0-3 R e ;
R 4 is independently selected from H and C 1-4 alkyl substituted with 0-4 R e ;
R 5 is independently selected from C 3-6 cycloalkyl, heterocyclyl, aryl and heteroaryl, each substituted with 1-5 R 6 ;
alternatively, when L is —NR 4 —, —C(O)NR 4 —, R 4 and R 5 together with the nitrogen atom to which they are both attached form a heterocyclic ring substituted with 1-5 R 6 ;
R 6 is independently selected from H, ═O, F, Cl, Br, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, nitro, —(CR d R d ) r S(O) p R c , —(CR d R d ) r S(O) p NR a R a , —(CR d R d ) r NR a S(O) p R c , —(CR d R d ) r OR b , —(CR d R d ) r CN, —(CR d R d ) r NR a R a , —(CR d R d ) r NR a C(═O)R b , —(CR d R d ) r NR a C(═O)NR a R a , —(CR d R d ) r NR a C(═O)OR b , —(CR d R d ) r C(═O)OR b , —(CR d R d ) r C(═O)NR a R a , —(CR d R d ) r C(═O)R b , —(CR d R d ) r OC(═O)R b , —(CR d R d ) r OC(═O)NR a R a , —(CR d R d ) r -cycloalkyl, —(CR d R d ) r -heterocyclyl, —(CR d R d ) r -aryl, and —(CR d R d ) r -heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is substituted with 0-4 R e ;
R 7 is independently selected from H, F, Cl, Br, CN, C 1-4 alkyl substituted with 0-3 R e , —(CH 2 ) r OR b , (CH 2 ) r S(O) p R c , —(CH 2 ) r C(═O)R b , —(CH 2 ) r NR a R a , —(CH 2 ) r C(═O)NR a R a , —(CH 2 ) r C(═O)(CH 2 ) r NR a R a , —(CH 2 ) r CN, —(CH 2 ) r NR a C(═O)R b , —(CH 2 ) r NR a C(═O)OR b , —(CH 2 ) r OC(═O)NR a R a , —(CH 2 ) r NR a C(═O)NR a R a , —(CH 2 ) r C(═O)OR b , —(CH 2 ) r S(O) p NR a R a , —(CH 2 ) r NR a S(O) p NR a R a , —(CH 2 ) r NR a S(O) p R c , (CH 2 ) r —C 3-6 carbocyclyl substituted with 0-3 R e , and —(CH 2 ) r -heterocyclyl substituted with 0-3 R e ;
R 8 is independently selected from H, F, Cl, Br, —(CH 2 ) r OR b , (CH 2 ) r S(O) p R c , —(CH 2 ) r C(═O)R b , —(CH 2 ) r NR a R a , —(CH 2 ) r CN, —(CH 2 ) r C(═O)NR a R a , —(CH 2 ) r NR a C(═O)R b , —(CH 2 ) r NR a C(═O)NR a R a , —(CH 2 ) r NR a C(═O)OR b , —(CH 2 ) r OC(═O)NR a R a , —(CH 2 ) r C(═O)OR b , —(CH 2 ) r S(O) p NR a R a , —(CH 2 ) r NR a S(O) p NR a R a , —(CH 2 ) r NR a S(O) p R c , (CH 2 ) r —C 3-6 carbocyclyl substituted with 0-3 R e , and —(CH 2 ) r -heterocyclyl substituted with 0-3 R e ;
R 9 is independently selected from H and C 1-4 alkyl substituted with 0-4 R e ;
R a is independently selected from H, C 1-6 alkyl substituted with 0-5 R e , C 2-6 alkenyl substituted with 0-5 R e , C 2-6 alkynyl substituted with 0-5 R e , —(CH 2 ) r —C 3-10 carbocyclyl substituted with 0-5 R e , and —(CH 2 ) r -heterocyclyl substituted with 0-5 R e ; or R a and R a together with the nitrogen atom to which they are both attached form a heterocyclic ring substituted with 0-5 R e ;
R b is independently selected from H, C 1-6 alkyl substituted with 0-5 R e , C 2-6 alkenyl substituted with 0-5 R e , C 2-6 alkynyl substituted with 0-5 R e , —(CH 2 ) r —C 3-10 carbocyclyl substituted with 0-5 R e , and —(CH 2 ) r -heterocyclyl substituted with 0-5 R e ;
R c is independently selected from C 1-6 alkyl substituted with 0-5 R e , C 2-6 alkenyl substituted with 0-5 R e , C 2-6 alkynyl substituted with 0-5 R e , C 3-6 carbocyclyl, and heterocyclyl;
R d is independently selected from H and C 1-4 alkyl substituted with 0-5 R e ;
R e is independently selected from C 1-6 alkyl substituted with 0-5 R f , C 2-6 alkenyl, C 2-6 alkynyl, —(CH 2 ) r —C 3-6 cycloalkyl, —(CH 2 ) r —C 4-6 heterocyclyl, —(CH 2 ) r -aryl, —(CH 2 ) r -heteroaryl, F, Cl, Br, CN, NO 2 , ═O, CO 2 H, —(CH 2 ) r OR f , S(O) p R f , C(═O)NR f R f , NR f C(═O)R d , S(O) p NR f R f , NR f S(O) p R d , NR f C(═O)OR d , OC(═O)NR f R f and —(CH 2 ) r NR f R f ;
R f is independently selected from H, F, Cl, Br, CN, OH, C 1-5 alkyl, C 3-6 cycloalkyl, and phenyl; or R f and R f together with the nitrogen atom to which they are both attached form a heterocyclic ring optionally substituted with C 1-4 alkyl;
n, at each occurrence, is independently selected from 0, 1, 2, and 3;
p, at each occurrence, is independently selected from 0, 1, and 2; and
r is independently selected from 0, 1, 2, 3, and 4.

2. The compound of claim 1 , having Formula (II):

or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein:
Ring B is selected from

G is selected from N and CR 7 ;
M is independently selected from N and CR 9 ;
X is independently selected from CR 1 , NR 2 , and O;
L is absent or independently selected from —NR 4 —, —C(O)NR 4 (CR 4 R 4 ) n —, and —O—;
R 1 is L-R 5 ;
R 2 is —(CR 4 R 4 ) n —R 5 ;
R 3 is independently selected from H, C 1-4 alkyl substituted with 0-4 R e , (CH 2 ) r —C 3-6 carbocyclyl substituted with 0-3 R e , and —(CH 2 ) r -heterocyclyl substituted with 0-3 R e ;
R 4 is independently selected from H and C 1-4 alkyl substituted with 0-4 R e ;
R 5 is independently selected from C 3-6 cycloalkyl, heterocyclyl, aryl and heteroaryl, each substituted with 1-5 R 6 ;
alternatively, when L is —NR 4 —, —C(O)NR 4 —, R 4 and R 5 together with the nitrogen atom to which they are both attached form a heterocyclic ring substituted with 1-5 R 6 ;
R 6 is independently selected from H, ═O, F, Cl, Br, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, nitro, —(CR d R d ) r S(O) p R c , —(CR d R d ) r S(O) p NR a R a , —(CR d R d ) r NR a S(O) p R c , —(CR d R d ) r OR b , —(CR d R d ) r CN, —(CR d R d ) r NR a R a , —(CR d R d ) r NR a C(═O)R b , —(CR d R d ) r NR a C(═O)NR a R a , —(CR d R d ) r NR a C(═O)OR b , —(CR d R d ) r C(═O)OR b , —(CR d R d ) r C(═O)NR a R a , —(CR d R d ) r C(═O)R b , —(CR d R d ) r OC(═O)R b , —(CR d R d ) r OC(═O)NR a R a , —(CR d R d ) r -cycloalkyl, —(CR d R d ) r -heterocyclyl, —(CR d R d ) r -aryl, and —(CR d R d ) r -heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is substituted with 0-4 R e ;
R 7 is independently selected from H, F, Cl, Br, CN, C 1-4 alkyl substituted with 0-3 R e , —(CH 2 ) r OR b ;
R 8 is independ

Assignees

• Bristol Myers Squibb Co

Inventors

• Hu Zilun
• Wang Cailan
• Quan Mimi L
• Glunz Peter W

Classifications

• C07D401/10

  linked by a carbon chain containing aromatic rings · CPC title

• C07D413/10

  linked by a carbon chain containing aromatic rings · CPC title

• C07D417/14

  containing three or more hetero rings · CPC title

• C07D495/04

  Ortho-condensed systems · CPC title

• A61P25/00

  Drugs for disorders of the nervous system · CPC title