Spiroheptane salicylamides and related compounds as inhibitors of ROCK

Patent metadata

Field	Value
Publication number	US-10829501-B2
Application number	US-202016739363-A
Country	US
Kind code	B2
Filing date	Jan 10, 2020
Priority date	Jan 13, 2016
Publication date	Nov 10, 2020
Grant date	Nov 10, 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 selected from the group consisting of:
N-[6-(2-carbamoylphenoxy)spiro[3.3]heptan-2-yl]-5-methyl-1-phenyl-1H-pyrazole-4-carboxamide,
N-[6-(2-carbamoylphenoxy)spiro[3.3]heptan-2-yl]-1-methyl-1H-indazole-3-carboxamide,
N-[6-(2-carbamoylphenoxy)spiro[3.3]heptan-2-yl]-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carboxamide,
N-[6-(2-carbamoylphenoxy)spiro[3.3]heptan-2-yl]-6-(oxolan-3-yloxy)pyrazolo[1,5-a]pyridine-3-carboxamide,
N-[6-(2-carbamoylphenoxy)spiro[3.3]heptan-2-yl]-3-methoxy-4-(1H-pyrazol-4-yl)benzamide,
2-({6-[6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-amido]spiro[3.3]heptan-2-yl}oxy)pyridine-3-carboxamide,
3-({6-[6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-amido]spiro[3.3]heptan-2-yl}oxy)pyrazine-2-carboxamide,
4-({6-[6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-amido]spiro[3.3]heptan-2-yl}oxy)pyrimidine-5-carboxamide,
2-[(6-{6-[(1,3-difluoropropan-2-yl)oxy]pyrazolo[1,5-a]pyridine-3-amido}spiro[3.3]heptan-2-yl)oxy]pyridine-3-carboxamide,
2-({6-[6-(3,3,3-trifluoropropoxy)pyrazolo[1,5-a]pyridine-3-amido]spiro[3.3]heptan-2-yl}oxy)pyridine-3-carboxamide,
2-({6-[6-(oxan-4-yloxy)pyrazolo[1,5-a]pyridine-3-amido]spiro[3.3]heptan-2-yl}oxy)pyridine-3-carboxamide,
N-{6-[(3-carbamoylpyridin-2-yl)oxy]spiro[3.3]heptan-2-yl}-2,3-dihydro-1H-indole-1-carboxamide,
N-{6-[(3-carbamoylpyridin-2-yl)oxy]spiro[3.3]heptan-2-yl}-5-cyano-2,3-dihydro-1H-isoindole-2-carboxamide,
Benzyl N-[6-(2-carbamoylphenoxy)spiro[3.3]heptan-2-yl]carbamate,
N-[(aR)-6-(2-carbamoylphenoxy)spiro[3.3]heptan-2-yl]-7-cyclopropyl-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carboxamide,
N-[(aR)-6-(2-carbamoylphenoxy)spiro[3.3]heptan-2-yl]-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carboxamide,
N-{6-[(3-carbamoylpyridin-2-yl)oxy]spiro[3.3]heptan-2-yl}-5-methoxy-2,3-dihydro-1H-indole-1-carboxamide,
N-[(aR)-6-(2-carbamoylphenoxy)spiro[3.3]heptan-2-yl]-7-(3,3,3-trifluoropropoxy)imidazo[1,2-a]pyridine-3-carboxamide,
N-[(aR)-6-(2-carbamoylphenoxy)spiro[3.3]heptan-2-yl]-6-(2-hydroxy-2-methylpropoxy)-7-(3,3,3-trifluoropropyl)pyrazolo[1,5-a]pyridine-3-carboxamide,
N-[(aR)-6-(2-carbamoylphenoxy)spiro[3.3]heptan-2-yl]-5-[2-(morpholin-4-yl)ethoxy]pyrazolo[1,5-a]pyridine-3-carboxamide,
N-[(aR)-6-(2-carbamoylphenoxy)spiro[3.3]heptan-2-yl]-6-[2-(pyrrolidin-1-yl)ethoxy]pyrazolo[1,5-a]pyridine-3-carboxamide,
N-[(aR)-6-(2-carbamoylphenoxy)spiro[3.3]heptan-2-yl]-6-(2,2-difluoroethoxy)pyrazolo[1,5-a]pyridine-3-carboxamide,
N-[(aR)-6-(2-carbamoylphenoxy)spiro[3.3]heptan-2-yl]-6-(3,3-difluoropyrrolidin-1-yl)pyrazolo[1,5-a]pyridine-3-carboxamide,
N-[(aR)-6-(2-carbamoylphenoxy)spiro[3.3]heptan-2-yl]-6-(difluoromethoxy)pyrazolo[1,5-a]pyridine-3-carboxamide,
N-[(aR)-6-(2-carbamoylphenoxy)spiro[3.3]heptan-2-yl]-7-(3,3-difluoropyrrolidin-1-yl)imidazo[1,2-a]pyridine-3-carboxamide,
N-[(aR)-6-(2-carbamoylphenoxy)spiro[3.3]heptan-2-yl]-7-[2-(pyrrolidin-1-yl)ethoxy]imidazo[1,2-a]pyridine-3-carboxamide,
methyl 3-[(3-{[(aR)-6-(2-carbamoylphenoxy)spiro[3.3]heptan-2-yl]carbamoyl}pyrazolo[1,5-a]pyridin-6-yl)oxy]azetidine-1-carboxylate,
N-[(aR)-6-(2-carbamoylphenoxy)spiro[3.3]heptan-2-yl]-6-[(1,1-dioxo-1λ 6 -thian-4-yl)oxy]pyrazolo[1,5-a]pyridine-3-carboxamide,
N-[(aR)-6-(2-carbamoylphenoxy)spiro[3.3]heptan-2-yl]-7-(morpholin-4-yl)imidazo[1,2-a]pyridine-3-carboxamide,
N-[(aR)-6-(2-carbamoylphenoxy)spiro[3.3]heptan-2-yl]-7-cyclopropyl-6-(3-methanesulfonylpropoxy)pyrazolo[1,5-a]pyridine-3-carboxamide,
N-[(aR)-6-(2-carbamoylphenoxy)spiro[3.3]heptan-2-yl]-7-cyclopropyl-6-(2-hydroxyethoxy)pyrazolo[1,5-a]pyridine-3-carboxamide,
N-[(aR)-6-(2-carbamoylphenoxy)spiro[3.3]heptan-2-yl]-7-cyclopropyl-6-(3,3,3-trifluoropropoxy)pyrazolo[1,5-a]pyridine-3-carboxamide,
N-[(aR)-6-(2-carbamoylphenoxy)spiro[3.3]heptan-2-yl]-6-(3,3,3-trifluoropropoxy)pyrazolo[1,5-a]pyridine-3-carboxamide,
N-[(aR)-6-(2-carbamoylphenoxy)spiro[3.3]heptan-2-yl]-7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide,
N-[(aR)-6-(2-carbamoylphenoxy)spiro[3.3]heptan-2-yl]-7-cyclopropyl-6-[(1,1-dioxo-1λ 6 -thian-4-yl)oxy]pyrazolo[1,5-a]pyridine-3-carboxamide,
N-[(aR)-6-(2-carbamoylphenoxy)spiro[3.3]heptan-2-yl]-7-(4-methylpiperazin-1-yl)imidazo[1,2-a]pyridine-3-carboxamide,
N-[(aR)-6-(2-carbamoylphenoxy)spiro[3.3]heptan-2-yl]-2,3-dihydro-1H-indole-1-carboxamide,
N-[(aR)-6-(2-carbamoylphenoxy)spiro[3.3]heptan-2-yl]-5-methoxy-2,3-dihydro-1H-indole-1-carboxamide,
N-[(aR)-6-(2-carbamoylphenoxy)spiro[3.3]heptan-2-yl]-5-methanesulfonyl-2,3-dihydro-1H-indole-1-carboxamide,
2-[((aR)-6-{[(4-methoxyphenyl)carbamoyl]amino}spiro[3.3]heptan-2-yl)oxy]benzamide,
N-[(aR)-6-(2-carbamoylphenoxy)spiro[3.3]heptan-2-yl]-2,3-dihydro-1H-isoindole-2-carboxamide,
N-((aR)-6-((3-carbamoylpyridin-2-yl)oxy)spiro[3.3]heptan-2-yl)-7-cyclopropyl-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carboxamide,
2-({(aR)-6-[6-(2-hydroxy-2-methylpropoxy)-7-(3,3,3-trifluoropropyl)pyrazolo[1,5-a]pyridine-3-amido]spiro[3.3]heptan-2-yl}oxy)pyridine-3-carboxamide,
4-({(aR)-6-[6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-amido]spiro[3.3]heptan-2-yl}oxy)pyridine-3-carboxamide,
3-({(aR)-6-[6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-amido]spiro[3.3]heptan-2-yl}oxy)pyridine-4-carboxamide,
N-{(aR)-6-[(3-carbamoylpyridin-2-yl)oxy]spiro[3.3]heptan-2-yl}-1-(2-hydroxy-2-methylpropyl)-6-(1-methyl-1H-pyrazol-4-yl)-1H-indazole-3-carboxamide,
2-({(aR)-6-[8-cyclopropyl-7-(2-fluoro-2-methylpropoxy)imidazo[1,2-a]pyridine-3-amido]spiro[3.3]heptan-2-yl}oxy)pyridine-3-carboxamide,
3-({(aR)-6-[6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-amido]spiro[3.3]heptan-2-yl}oxy)pyridazine-4-carboxamide,
2-({(aR)-6-[7-cyclopropyl-6-(2-fluoro-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-amido]spiro[3.3]heptan-2-yl}oxy)pyridine-3-carboxamide,
N-{(aR)-6-[(3-carbamoylpyridin-2-yl)oxy]spiro[3.3]heptan-2-yl}-1-(2-hydroxy-2-methylpropyl)-5-(1-methyl-1H-pyrazol-4-yl)-1H-indazole-3-carboxamide,
2-[((aR)-6-{3-[1-(difluoromethyl)-1H-pyrazol-4-yl]-5-methanesulfonylbenzamido}spiro[3.3]heptan-2-yl)oxy]pyridine-3-carboxamide,
2-({(aR)-6-[3-methanesulfonyl-5-(1-methyl-1H-pyrazol-4-yl)benzamido]spiro[3.3]heptan-2-yl}oxy)pyridine-3-carboxamide,
2-[((aR)-6-{3-methanesulfonyl-5-[1-(Â 2 Hâ,f)methyl-1H-pyrazol-4-yl]benzamido}spiro[3.3]heptan-2-yl)oxy]pyridine-3-carboxamide,
2-({(aR)-6-[3-(1-methyl-1H-pyrazol-4-yl)benzamido]spiro[3.3]heptan-2-yl}oxy)pyridine-3-carboxamide,
2-[((aR)-6-{3′-methanesulfonyl-[1,1′-biphenyl]-3-amido}spiro[3.3]heptan-2-yl)oxy]pyridine-3-carboxamide,
2-({(aR)-6-[3-bromo-5-(3,3,3-trifluoropropoxy)benzamido]spiro[3.3]heptan-2-yl}oxy)pyridine-3-carboxamide,
2-({(aR)-6-[3-(1-methyl-1H-pyrazol-4-yl)-5-(3,3,3-trifluoropropoxy)benzamido]spiro[3.3]heptan-2-yl}oxy)pyridine-3-carboxamide,
2-({(aR)-6-[3′-methanesulfonyl-5-(3,3,3-trifluoropropoxy)-[1,1′-biphenyl]-3-amido]spiro[3.3]heptan-2-yl}oxy)pyridine-3-carboxamide,
2-[((aR)-6-{6-methoxyimidazo[1,2-b]pyridazine-2-amido}spiro[3.3]heptan-2-yl)oxy]pyridine-3-carboxamide,
2-[((aR)-6-{6-chloro-8-methoxyimidazo[1,2-b]pyridazine-3-amido}spiro[3.3]heptan-2-yl)oxy]pyridine-3-carboxamide,
2-({(aR)-6-[6-(2,2,2-trifluoroethoxy)imidazo[1,2-b]pyridazine-2-amido]spiro[3.3]heptan-2-yl}oxy)pyridine-3-carboxamide,
2-[((aR)-6-{6-chloroimidazo[1,2-b]pyridazine-2-amido}spiro[3.3]heptan-2-yl)oxy]pyridine-3-carboxamide,
N2-{(aR)-6-[(3-carbamoylpyridin-2-yl)oxy]spiro[3.3]heptan-2-yl}imidazo[1,2-a]pyridine-2,6-dicarboxamide,
2-({(aR)-6-[6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-amido]spiro[3.3]heptan-2-yl}oxy)pyridine-3-carboxamide,
2-({(aR)-6-[8-cyclopropyl-7-(2-hydroxy-2-methylpropoxy)imidazo[1,2-a]pyridine-3-amido]spiro[3.3]heptan-2-yl}oxy)pyridine-3-carboxamide,
N-{(aR)-6-[(3-carbamoylpyridin-2-yl)oxy]spiro[3.3]heptan-2-yl}-1-methyl-1H-indazole-3-carboxamide,
N-((aR)-6-((3-carbamoylpyridin-2-yl)oxy)spiro[3.3]heptan-2-yl)-5-fluo

Assignees

• Bristol Myers Squibb Co

Inventors

• Smith Ii Leon M
• Ladziata Vladimir
• Delucca Indawati
• Pinto Donald J P
• Orwat Michael J
• Dilger Andrew K
• Pabbisetty Kumar Balashanmuga
• Yang Wu
• Shaw Scott A
• Glunz Peter W
• Panda Manoranjan

Classifications

• C07D213/64

  attached in position 2 or 6 · CPC title

• C07D471/04 Primary

  Ortho-condensed systems · CPC title

• C07D231/54 Primary

  condensed with carbocyclic rings or ring systems · CPC title

• C07D471/12

  in which the condensed system contains three hetero rings · CPC title

• C07D231/18

  One oxygen or sulfur atom · CPC title