Tricyclic rho kinase inhibitors

Patent metadata

Field	Value
Publication number	US-10654860-B2
Application number	US-201716461029-A
Country	US
Kind code	B2
Filing date	Nov 29, 2017
Priority date	Nov 30, 2016
Publication date	May 19, 2020
Grant date	May 19, 2020

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 according to formula (I):

or a stereoisomer, tautomer, pharmaceutically acceptable salt thereof, wherein
X is independently selected from —CR 3 R 4 —, —O—, and NR 5a ;
Y is independently selected from —CR 2 and N;
Z is independently selected from —NR 5 C(O)NR 5 (CR 6 R 7 ) q —R 8 , —NR 5 C(O)(CR 6 R 7 ) q —R 8 , —C(O)NR 5 (CR 6 R 7 ) q —R 8 ,

--- is an optional bond;
L is independently selected from —(CR 6 R 7 ) q —, —NR 5a (CR 6 R 7 ) q —, and —O(CR 6 R 7 ) q —;
R 1 is independently selected from H, F, Cl, Br, CN, NR a R a , —OC 1-4 alkyl substituted with 0-3 R e , C 1-4 alkyl substituted with 0-3 R e , and —(CH 2 ) r OR b ;
R 2 is independently selected from H, F, Cl, Br, CN, NR a R a , —OC 1-4 alkyl substituted with 0-3 R e , C 1-4 alkyl substituted with 0-3 R e , —(CH 2 ) r OR b ;
R 3 and R 4 are independently selected from H and C 1-4 alkyl substituted with 0-3 R e ;
R 5 is independently selected from H and C 1-4 alkyl;
R 5a is independently selected from H and C 1-4 alkyl;
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 NR 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 ;

is independently selected from carbocyclyl and heterocyclyl;
R 8 is selected from C 3-10 carbocyclyl and heterocyclyl, each substituted with 1-5 R 9 ;
R 9 is independently selected from H, 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 10 is independently selected from H, ═O, C 1-4 alkyl substituted with 0-4 R e , —(CH 2 ) r OR b , C(═O)R b , and —C(═O)OR b ;
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 , 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 , 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, and Br, 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, 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 zero, 1, 2, and 3; and
r, at each occurrence, is independently selected from zero, 1, 2, 3, and 4.

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

or a stereoisomer, tautomer, pharmaceutically acceptable salt thereof, wherein
X is independently selected from —CH 2 —, and —O—;
Y is independently selected from —CR 2 and N;
R 1 is independently selected from H, F, Cl, Br, CN, NR a R a , —OC 1-4 alkyl substituted with 0-3 R e , C 1-4 alkyl substituted with 0-3 R e , and —(CH 2 ) r OR b ;
R 2 is independently selected from H, F, Cl, Br, CN, NR a R a , —OC 1-4 alkyl substituted with 0-3 R e , C 1-4 alkyl substituted with 0-3 R e , and —(CH 2 ) r OR b ;
R 6 and R 7 are independently selected from H and C 1-4 alkyl substituted with 0-4 R e ;
R 8 is selected from phenyl, C 3-6 cycloalkyl and heterocyclyl, each substituted with 1-5 R 9 ;
R 9 is independently selected from H, F, Cl, C 1-4 alkyl substituted with 0-5 R e , —C(═O)NR a R a —NR a S(O) p C 1-4 alkyl, —OR b , and —CN;
R a , at each occurrence, is independently selected from H, C 1-6 alkyl 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 b , at each occurrence, is independently selected from H and C 1-6 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, and Br, OH), F, Cl, Br, CN, NO 2 , —(CH 2 ) r OC 1-5 alkyl, —(CH 2 ) r OH;
p, at each occurrence, is independently selected from zero, 1, and 2;
q, at each occurrence, is independently selected from zero, 1, 2, and 3; and
r, at each occurrence, is independently selected from zero, 1, 2, 3, and 4.

3. The compound of claim 2 , having Formula (III):

or a stereoisomer, tautomer, pharmaceutically acceptable salt thereof, wherein
R 1 is independently selected from H, F, Cl, Br, CN, NR a R a , —OC 1-4 alkyl substituted with 0-3 R e , C 1-4 alkyl substituted with 0-3 R e , and —(CH 2 ) r OR b ;
R 2 is independently selected from H, F, Cl, Br, CN, NR a R a , —OC 1-4 alkyl substituted with 0-3 R e , C 1-4 alkyl substituted with 0-3 R e , and —(CH 2 ) r OR b ;
R 6 and R 7 are independently selected from H and Me;
R 9 is independently selected from H, F, Cl, C 1-4 alkyl substituted with 0-5 R e , and —OC 1-4 alkyl;
R a , at each occurrence, is independently selected from H, C 1-6 alkyl s

Assignees

• Bristol Myers Squibb Co

Inventors

• Yang Wu
• Glunz Peter W
• Bhide Rajeev S
• Thiyagarajan Kamalraj

Classifications

• C07D231/54

  condensed with carbocyclic rings or ring systems · CPC title

• C07D403/04

  directly linked by a ring-member-to-ring-member bond · CPC title

• A61P9/04

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

• C07D491/052

  the oxygen-containing ring being six-membered · 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