Tricyclic pyrido-carboxamide derivatives as rock inhibitors

Patent metadata

Field	Value
Publication number	US-9914740-B2
Application number	US-201414900238-A
Country	US
Kind code	B2
Filing date	Jul 1, 2014
Priority date	Jul 2, 2013
Publication date	Mar 13, 2018
Grant date	Mar 13, 2018

Abstract

The present invention provides compounds of 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 (IV):

or a stereoisomer, tautomer, pharmaceutically acceptable salt thereof, wherein
R 1 and R 2 are H;
R 3 is independently selected from H and Me;
R 5 is H;
R 6 and R 7 are 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 C(═O)(CH 2 ) r N R a R a , —(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 ;
alternatively, R 6 and R 7 together with the carbon atom to which they are both attached form a cycloalkyl or heterocyclyl, each substituted with 0-5 R e ; alternatively, when q is 2 or 3, two adjacent R 6 groups form a cycloalkyl or heterocyclyl, each substituted with 0-5 R e ;
R 9 is independently selected from F, Cl, Br, C 1-4 alkyl substituted with 0-5 R e , C 2-4 alkenyl substituted with 0-5 R e , C 2-4 alkynyl substituted with 0-5 R e , ═O, nitro, —(CHR d ) r S(O) p R c , —(CHR d ) r S(O) p NR a R a , —(CHR d ) r NR a S(O) p R c , —(CHR d ) r OR b , —(CHR d ) r CN, —(CHR d ) r NR a R a , —(CHR d ) r NR a C(═O)R b , —(CHR d ) r NR a C(═O)NR a R a , —(CHR d ) r C(═O)OR b , —(CHR d ) r C(═O)R b , —(CHR d ) r OC(═O)R b , —(CHR d ) r C(═O)NR a R a , —(CHR d ) r -cycloalkyl, —(CHR d ) r -heterocyclyl, —(CHR d ) r -aryl, and —(CHR d ) r -heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is substituted with 0-4 R e ;
alternatively, two adjacent R 9 groups are combined to form a carbocyclic or heterocyclic ring comprising carbon atoms and 1-3 hetero atoms selected from N, O, and S(O) p , wherein the carbocyclic and heterocyclic rings are substituted with 0-4 R e ;
R a , at each occurrence, 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 , —(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 , at each occurrence, 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 , at each occurrence, 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 , at each occurrence, is independently selected from H and C 1-4 alkyl substituted with 0-5 R e ;
R e , at each occurrence, is independently selected from C 1-6 alkyl (optionally substituted with F, Cl, Br, and OH), C 2-6 alkenyl, C 2-6 alkynyl, —(CH 2 ) r —C 3-10 carbocyclyl, —(CH 2 ) r -heterocyclyl, F, Cl, Br, CN, NO 2 , ═O, CO 2 H, CO 2 C 1-6 alkyl, —(CH 2 ) r OC 1-5 alkyl, —(CH 2 ) r OH, —(CH 2 ) r NR f R f , —(CH 2 ) r NR f R f C(═O)C 1-4 alkyl, —C(═O)NR f R f , —C(═O)R f , S(O) p NR f R f , —NR f R f S(O) p C 1-4 alkyl, and S(O) p C 1-4 alkyl;
R f , at each occurrence, is independently selected from H, F, Cl, Br, C 1-5 alkyl, and C 3-6 cycloalkyl; or R f and R f together with the nitrogen atom to which they are both attached form a heterocyclic ring;
p, at each occurrence, is independently selected from zero, 1, and 2;
q, at each occurrence, is independently selected from 1 and 2; and
r, at each occurrence, is independently selected from zero, 1, 2, 3, and 4.

2. The compound of claim 1 or a stereoisomer, tautomer, pharmaceutically acceptable salt thereof, wherein
R 6 and R 7 are independently selected from H and C 1-4 alkyl substituted with 0-4 R e ;
R 9 is independently selected from F, Cl, Br, C 1-4 alkyl substituted with 0-5 R e , C 2-4 alkenyl substituted with 0-5 R e , ═O, nitro, —(CHR d ) r S(O) p R c , —(CHR d ) r S(O) p NR a R a , —(CHR d ) r NR a S(O) p R c , —(CHR d ) r OR b , —(CHR d ) r CN, —(CHR d ) r NR a R a , —(CHR d ) r NR a C(═O)R b , —(CHR d ) r NR a C(═O)NR a R a , —(CHR d ) r C(═O)OR b , —(CHR d ) r C(═O)R b , —(CHR d ) r OC(═O)R b , —(CHR d ) r C(═O)NR a R a , —(CHR d ) r -cycloalkyl, —(CHR d ) r -heterocyclyl, —(CHR d ) r -aryl, and —(CHR d ) r -heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is substituted with 0-4 R e ;
alternatively, two adjacent R 9 groups are combined to form a carbocyclic or heterocyclic ring comprising carbon atoms and 1-3 hetero atoms selected from N, O, and S(O) p , wherein the carbocyclic and heterocyclic rings are substituted with 0-4 R e ;
R a , at each occurrence, 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 , —(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 , at each occurrence, 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 , at each occurrence, 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 , at each occurrence, is independently selected from H and C 1-4 alkyl substituted with 0-5 R e ;
R e , at each occurrence, is independently selected from C 1-6 alkyl (optionally substituted with F, Cl, Br, and OH), C 2-6 alkenyl, C 2-6 alkynyl, —(CH 2 ) r —C 3-10 carbocyclyl, —(CH 2 ) r -heterocyclyl, F, Cl, Br, CN, NO 2 , ═O, CO 2 H, CO 2 C 1-6 alkyl, —(CH 2 ) r OC 1-5 alkyl, —(CH 2 ) r OH, —(CH 2 ) r NR f R f , —(CH 2 ) r NR f R f C(═O)C 1-4 alkyl, —C(═O)NR f R f , —C(═O)R f , S(O) p NR f R f , —NR f R f S(O) p C 1-4 alkyl, and S(O) p C 1-4 alkyl;
R f , at each occurrence, is independently selected from H, F, Cl, Br, C 1-5 alkyl, and C 3-6 cycloalkyl; or R f and R f together with the nitrogen atom to which they are both attached form a heterocyclic ring;
p, at each occurrence, is independently selected from zero, 1, and 2;
q, at each occurrence, is independently selected from 1 and 2; and
r, at each occurrence, is independently selected from zero, 1, 2, 3, and 4.

3. A pharmaceutical composition comprising one or more compounds according to claim 1 and a pharmaceutically acceptable carrier or diluent.

4. A compound or a stereoisomer, tautomer, pharmaceutically acceptable salt thereof selected from:
(R)-N-(1-(3-Methoxyphenyl)ethyl)-5H-chromeno[3,4-c]pyridine-8-carboxamide;
N-(2-chlorobenzyl)-5H-chromeno[3,4-c]pyridine-8-carboxamide;
N-(1-phenylethyl)-5H-chromeno[3,4-c]pyridine-8-carboxamide;
N-phenethyl-5H-chromeno[3,4-c]pyridine-8-carboxamide;
N-(3-phenylpropyl)-5H-chromeno[3,4-c]pyridine-8-carboxamide;
N-(1-(2-chlorophenyl)cyclopropyl)-5H-chromeno[3,4-c]pyridine-8-carboxamide;
N-(cyclohexylmethyl)-5H-chromeno[3,4-c]pyridine-8-carboxamide;
N-((tetrahydrofuran-2-yl)methyl)-5H-chromeno[3,4-c]pyrid

Assignees

• Bristol Myers Squibb Co

Inventors

• Quan Mimi L
• Hu Zilun
• Wang Cailan
• Patil Sharanabasappa

Classifications

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title

• A61P9/04

  Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure · CPC title

• A61P43/00

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

• A61P7/02

  Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors · CPC title