Phthalazinones and isoquinolinones as rock inhibitors

Patent metadata

Field	Value
Publication number	US-9926282-B2
Application number	US-201414759495-A
Country	US
Kind code	B2
Filing date	Jan 17, 2014
Priority date	Jan 18, 2013
Publication date	Mar 27, 2018
Grant date	Mar 27, 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 (I):

or a stereoisomer, a tautomer, a pharmaceutically acceptable salt thereof, wherein:
M is CR 10 ;
L is selected from —CR 4 R 4 C(O)—, —OC(O)—, —NR 6 C(O)—, and —NR 6 —;
R 1 is selected from NR 5 R 5 , C 3-10 carbocycle and 4- to 15-membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, NR 8 , O, and S(O) p ; wherein said carbocycle and heterocycle are substituted with 1-4 R 7 ;
R 2 , at each occurrence, is independently selected from halogen, C 1-6 alkyl, C 1-4 alkoxy, C 1-4 alkylthio, C 1-4 haloalkyl, —OH, —CH 2 OH, —OCH 2 F, —OCHF 2 , —OCF 3 , CN, —NH 2 , —NH(C 1-4 alkyl), —N(C 1-4 alkyl) 2 , —CO 2 H, —CH 2 CO 2 H, —CO 2 (C 1-4 alkyl), —CO(C 1-4 alkyl), —CH 2 NH 2 , —CONH 2 , —CONH(C 1-4 alkyl), —CON(C 1-4 alkyl) 2 , —OCH 2 CO 2 H, —NHCO(C 1-4 alkyl), —NHCO 2 (C 1-4 alkyl), —NHSO 2 (C 1-4 alkyl), —SO 2 NH 2 , —C(═NH)NH 2 , 3- to 13-membered carbocycle, and 4- to 14-membered heterocycle comprising carbon atoms and 1 to 4 heteroatoms selected from N, O, S, wherein said alkyl, alkoxy, alkylthio, haloalkyl, carbocycle, and heterocycle are substituted with 0-4 R 9 ;
R 3 , at each occurrence, is independently selected from halogen, C 1-6 alkyl, C 1-4 alkoxy, C 1-4 alkylthio, C 1-4 haloalkyl, —CH 2 OH, —OCH 2 F, —OCHF 2 , —OCF 3 , CN, —NH 2 , —NH(C 1-4 alkyl), —N(C 1-4 alkyl) 2 , —CO 2 H, —CH 2 CO 2 H, —CO 2 (C 1-4 alkyl), —CO(C 1-4 alkyl), —CH 2 NH 2 , —CONH 2 , —CONH(C 1-4 alkyl), —CON(C 1-4 alkyl) 2 , —OCH 2 CO 2 H, —NHCO(C 1-4 alkyl), —NHCO 2 (C 1-4 alkyl), —NHSO 2 (C 1-4 alkyl), —SO 2 NH 2 , —C(═NH)NH 2 , 3- to 13-membered carbocycle, and 4- to 14-membered heterocycle comprising carbon atoms and 1 to 4 heteroatoms selected from N, O, S, wherein said alkyl, alkoxy, alkylthio, haloalkyl, carbocycle, and heterocycle are substituted with 0-4 R 9 ;
R 4 , at each occurrence, is independently selected from H, OH, NH 2 , CH 2 NH 2 , C 1-4 haloalkyl, OCH 2 F, OCHF 2 , OCF 3 , —NH(C 1-4 alkyl), —N(C 1-4 alkyl) 2 , C 1-4 alkoxy, CH 2 OH, CH 2 O(C 1-4 alkyl), CH 2 CO 2 H, CH 2 CO 2 (C 1-4 alkyl), C 1-4 alkyl, 3- to 13-membered carbocycle, and 4- to 14-membered heterocycle comprising carbon atoms and 1 to 4 heteroatoms selected from N, O, S, wherein said alkyl, alkoxy, haloalkyl, carbocycle, and heterocycle are substituted with 0-4 R 9 ;
R 5 , at each occurrence, is independently selected from H, C 1-4 alkyl, —(CR 6 R 6 ) n —C 3-10 carbocycle and —(CR 6 R 6 ) n — 4-10 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, NR 8 , O, and S(O) p , wherein said alkyl, carbocycle and heterocycle are substituted with 1-4 R 7 ;
alternatively, R 5 and R 5 are taken together with the nitrogen atom to which they are attached to form 4- to 15-membered heterocycle comprising carbon atoms and 1 to 4 heteroatoms selected from N, O, S, and substituted with 1-4 R 7 ;
R 6 , at each occurrence, is independently selected from H and C 1-4 alkyl;
R 7 , at each occurrence, is independently selected from H, ═O, NO 2 , halogen, C 1-4 alkyl, C 1-4 alkoxy, CN, OH, CF 3 , —(CH 2 ) n —CO 2 H, —(CH 2 ) n —CO 2 (C 1-4 alkyl), —(CH 2 ) n —NR 8 R 8 , —NHCO(C 1-4 alkyl), —NHCOCF 3 , —NHCO 2 (C 1-4 alkyl), —NHCO 2 (CH 2 ) 2 O(C 1-4 alkyl), —NHCO 2 (CH 2 ) 3 O(C 1-4 alkyl), —NHCO 2 (CH 2 ) 2 OH, —NHCO 2 (CH 2 ) 2 NH 2 , —NHCO 2 (CH 2 ) 2 N(C 1-4 alkyl) 2 , —NHCO 2 CH 2 CO 2 H, —CH 2 NHCO 2 (C 1-4 alkyl), —NHC(O)NR 8 R 8 , —NHSO 2 (C 1-4 alkyl), —SO 2 NH 2 , —SO 2 NH(C 1-4 alkyl), —SO 2 N(C 1-4 alkyl) 2 , —SO 2 NH(CH 2 ) 2 OH, —SO 2 NH(CH 2 ) 2 O(C 1-4 alkyl), —(CH 2 ) n —CONR 8 R 8 , —O(CH 2 ) n -3- to 13-membered carbocycle, —O(CH 2 ) n -4- to 14-membered heterocycle comprising carbon atoms and 1 to 4 heteroatoms selected from N, O, S, —NHCO-3- to 13-membered carbocycle, —NHCO-4- to 14-membered heterocycle comprising carbon atoms and 1 to 4 heteroatoms selected from N, O, S, —(CH 2 ) n -3- to 13-membered carbocycle, and —(CH 2 ) n -4- to 14-membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, NR 8 , O, and S(O) p , wherein said alkyl, alkenyl, alkynyl, alkoxy, carbocycle, and heterocycle are substituted with 0-4 R 9 ;
R 8 , at each occurrence, is independently selected from H, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, —(CH 2 ) n —C(O)C 1-4 alkyl, —(CH 2 ) n —C(O)-3- to 13-membered carbocycle, —(CH 2 ) n —C(O)-4- to 14-membered heterocycle comprising carbon atoms and 1 to 4 heteroatoms selected from N, O, S, —(CH 2 ) n —C(O)NR a R a , —(CH 2 ) n —C(O)O-alkyl, —(CH 2 ) n —C(O)O-3- to 13-membered carbocycle, —(CH 2 ) n —C(O)O-4- to 14-membered heterocycle comprising carbon atoms and 1 to 4 heteroatoms selected from N, O, S, —(CH 2 ) n —SO 2 alkyl, —(CH 2 ) n SO 2 -3- to 13-membered carbocycle, —(CH 2 ) n —SO 2 -4- to 14-membered heterocycle comprising carbon atoms and 1 to 4 heteroatoms selected from N, O, S, —(CH 2 ) n —SO 2 NR a R a , —(CH 2 ) n -3- to 13-membered carbocycle, and —(CH 2 ) n -4- to 14-membered heterocycle comprising carbon atoms and 1 to 4 heteroatoms selected from N, O, S, wherein said alkyl, carbocycle, and heterocycle are substituted with 0-4 R 9 ;
alternatively, R 8 and R 8 are taken together with the nitrogen atom to which they are attached to form 4- to 10-membered heterocycle comprising carbon atoms and 1 to 4 heteroatoms selected from N, O, S, and substituted with 0-4 R 9 ;
R 9 , at each occurrence, is independently selected from halogen, OH, NO 2 , CHF 2 , CF 3 , C 1-4 alkyl, C 1-4 alkoxy, CH 2 OH, CO(C 1-4 alkyl), CO 2 H, CO 2 (C 1-4 alkyl), —(CH 2 ) n NR a R a , —(CH 2 ) n CONR a R a , —O(CH 2 ) n -3- to 13-membered carbocycle, —O(CH 2 ) n -4- to 14-membered heterocycle comprising carbon atoms and 1 to 4 heteroatoms selected from N, O, S, —O(CH 2 ) n NR a R a , —(CR 10 R 10 ) n -4-10 membered heterocycle comprising carbon atoms and 1 to 4 heteroatoms selected from N, O, S, wherein said alkyl, alkoxy, carbocycle, and heterocycle are substituted with 0-4 R b ;
R 10 is selected from H and C 1-4 alkyl;
R a , at each occurrence, is independently selected from H, C 1-4 alkyl, —(CH 2 ) n OH, CO(C 1-4 alkyl), COCF 3 , CO 2 (C 1-4 alkyl), —CONH 2 , —CONH—C 1-4 alkylene-CO 2 (C 1-4 alkyl), C 1-4 alkylene-CO 2 (C 1-4 alkyl), R c , CO 2 R c , and CONHR c ; alternatively, R a and R a are taken together with the nitrogen atom to which they are attached to form 4- to 10-membered heterocycle comprising carbon atoms and 1 to 4 heteroatoms selected from N, O, S, wherein said alkyl, alkylene, and heterocycle are substituted with 0-4 R b ;
R b , at each occurrence, is independently selected from ═O, OH, halogen, C 1-4 alkyl, C 1-4 alkoxy, OCF 3 , NH 2 , NO 2 , N(C 1-4 alkyl) 2 , CO(C 1-4 alkyl), CO(C 1-4 haloalkyl), CO 2 (C 1-4 alkyl), CONH 2 , —CONH(C 1-4 alkyl), —CON(C 1-4 alkyl) 2 , —CONH—C 1-4 alkylene-O(C 1-4 alkyl), —CONH—C 1-4 alkylene-N(C 1-4 alkyl) 2 , —CONH—C 1-4 alkylene-N(C 1-4 alkyl) 2 , —C 1-4 alkylene-O—P(O)(OH) 2 , —NHCO 2 (C 1-4 alkyl), —R c , COR c , CO 2 R c , and CONHR c ;
R c , at each occurrence, is independently selected from —(CH 2 ) n —C 3-6 cycloalkyl, —(CH 2 ) n -phenyl, and —(CH 2 ) n -5- to 6-membered heterocycle containing carbon atoms and 1-4 heteroatoms selected from the group consisting of: N, NH, N(C 1-4 alkyl), O, and S(O) p ; wherein each ring moiety is substituted with 0-2 R d ;
R d , at each occurrence, is independently selected from ═O, halogen, —OH, C 1-4 alkyl, NH 2 , NH(C 1-4 alkyl), N(C 1-4 alkyl) 2 , C 1-4 alkoxy, and —NHCO(C 1-4 alkyl), and 4- to 14-membered heterocycle containing carbon atoms and 1-4 heteroatoms selected from the group consisting of: N, NH, N(C 1-4 alkyl), O, and S(O) p ;
n, at each occurrence, is independently selected from 0, 1, 2, 3, and

Assignees

• Bristol Myers Squibb Co

Inventors

• Glunz Peter W
• Zou Yan
• Quan Mimi L
• Ladziata Vladimir

Classifications

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P9/08

  Vasodilators for multiple indications · 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

• A61P43/00

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