Antibacterial compounds and methods for use

Patent metadata

Field	Value
Publication number	US-9650395-B2
Application number	US-201214241372-A
Country	US
Kind code	B2
Filing date	Aug 29, 2012
Priority date	Aug 29, 2011
Publication date	May 16, 2017
Grant date	May 16, 2017

Abstract

The present description relates to compounds and forms and pharmaceutical compositions thereof and methods for use thereof to treat or ameliorate bacterial infections caused by wild-type and multi-drug resistant Gram-negative and Gram-positive pathogens.

First claim

What is claimed is:

1. A compound of Formula (I):

or a form thereof, wherein
R 1 is phenyl, optionally substituted with one, two or three substituents each selected from R 5 and one additional substituent selected from R 6 ;
R 2 is halogen, cyano, C 1-8 alkyl, halo-C 1-8 alkyl, hydroxyl-C 1-8 alkyl, formyl-C 1-8 alkyl, C 1-8 alkoxy-C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynl, carboxyl, amino, C 1-8 alkyl-amino, (C 1-8 alkyl) 2 -amino, amino-C 1-8 alkyl, C 1-8 alkyl-amino-C 1-8 alkyl, (C 1-8 alkyl) 2 -amino-C 1-8 alkyl, C 3-14 cycloalkyl, C 3-8 cycloalkyl-oxy, aryl or aryl-C 1-8 alkyl, wherein each instance of aryl is optionally substituted with one halogen substituent;
R 3 is hydroxyl;
R 4 is hydrogen;
R 5 is halogen, hydroxyl, oxo, cyano, nitro, C 1-8 alkyl, hydroxyl-C 1-8 alkyl, halo-C 1-8 alkyl, C 1-8 alkoxy, halo-C 1-8 alkoxy, C 1-8 alkyl-thio, carboxyl, C 1-8 alkyl-carbonyl, C 1-8 alkoxy-carbonyl, amino-carbonyl, amino, C 1-8 alkyl-amino, (C 1-8 alkyl) 2 -amino, C 2-8 alkenyl-amino, (C 2-8 alkenyl) 2 -amino, C 2-8 alkynyl-amino, (C 2-8 alkynyl) 2 -amino, amino-C 1-8 alkyl, C 1-10 alkyl-amino-C 1-8 alkyl, (C 1-8 alkyl) 2 -amino-C 1-8 alkyl, C 2-8 alkenyl-amino-C 1-8 alkyl, (C 2-8 alkenyl) 2 -amino-C 1-8 alkyl, C 2-8 alkynyl-amino-C 1-8 alkyl, (C 2-8 alkynyl) 2 -amino-C 1-8 alkyl, halo-C 1-8 alkyl-amino, (halo-C 1-8 alkyl) 2 -amino, halo-C 1-8 alkyl-amino-C 1-8 alkyl, (halo-C 1-8 alkyl) 2 -amino-C 1-8 alkyl, C 1-8 alkoxy-C 1-8 alkyl-amino, (C 1-8 alkoxy-C 1-8 alkyl,C 1-8 alkyl)-amino, (C 1-8 alkoxy-C 1-8 alkyl) 2 -amino, C 1-8 alkoxy-C 1-8 alkyl-amino-C 1-8 alkyl, (C 1-8 alkoxy-C 1-8 alkyl,C 1-8 alkyl)-amino-C 1-8 alkyl, (C 1-8 alkoxy-C 1-8 alkyl) 2 -amino-C 1-8 alkyl, amino-C 1-8 alkyl-amino, (amino-C 1-8 alkyl,C 1-8 alkyl)amino, C 1-8 alkyl-amino-C 1-8 alkyl-amino, (C 1-8 alkyl-amino-C 1-8 alkyl,C 1-8 alkyl)amino, (C 1-8 alkyl) 2 -amino-C 1-8 alkyl-amino, [(C 1-8 alkyl) 2 -amino-C 1-8 alkyl,C 1-8 alkyl]amino, amino-C 1-8 alkyl-amino-C 1-8 alkyl, (amino-C 1-8 alkyl,C 1-8 alkyl)amino-C 1-8 alkyl, C 1-8 alkyl-amino-C 1-8 alkyl-amino-C 1-8 alkyl, (C 1-8 alkyl-amino-C 1-8 alkyl,C 1-8 alkyl)amino-C 1-8 alkyl, (C 1-8 alkyl) 2 -amino-C 1-8 alkyl-amino-C 1-8 alkyl, [(C 1-8 alkyl) 2 -amino-C 1-8 alkyl,C 1-8 alkyl]amino-C 1-8 alkyl, hydroxyl-amino, hydroxyl-C 1-8 alkyl-amino, (hydroxyl-C 1-8 alkyl,C 1-8 alkyl)amino, (hydroxyl-C 1-8 alkyl) 2 -amino, hydroxyl-C 1-8 alkyl-amino-C 1-8 alkyl, (hydroxyl-C 1-8 alkyl,C 1-8 alkyl)amino-C 1-8 alkyl, hydroxyl-C 1-8 alkyl-amino-C 1-8 alkyl-amino, (hydroxyl-C 1-8 alkyl-amino-C 1-8 alkyl,C 1-8 alkyl)amino, (hydroxyl-C 1-8 alkyl,C 1-8 alkyl)amino-C 1-8 alkyl-amino, [(hydroxyl-C 1-8 alkyl,C 1-8 alkyl)amino-C 1-8 alkyl,C 1-8 alkyl]amino, (C 1-8 alkyl-carbonyl,C 1-8 alkyl)amino-C 1-8 alkyl, C 1-8 alkyl-amino-carbonyl, (C 1-8 alkyl) 2 -amino-carbonyl or (C 1-8 alkyl) 2 -amino-carbonyl-C 1-8 alkyl-amino-C 1-8 alkyl;
R 6 is C 3-14 cycloalkyl, C 3-14 cycloalkyl-C 1-8 alkyl, C 3-14 cycloalkyl-oxy, C 3-14 cycloalkyl-C 1-8 alkoxy, C 3-14 cycloalkyl-amino, C 3-14 cycloalkyl-amino-C 1-8 alkyl, (C 3-14 cycloalkyl,C 1-8 alkyl)amino-C 1-8 alkyl, (C 3-14 cycloalkyl) 2 -amino-C 1-8 alkyl, C 3-14 cycloalkyl-C 1-8 alkyl-amino-C 1-8 alkyl, (C 3-14 cycloalkyl-C 1-8 alkyl,C 1-8 alkyl)amino-C 1-8 alkyl, (C 3-14 cycloalkyl-C 1-8 alkyl) 2 -amino-C 1-8 alkyl, aryl, aryl-C 1-8 alkyl, aryl-C 1-8 alkoxy, aryl-amino, (aryl,C 1-8 alkyl)amino, (aryl) 2 -amino, aryl-amino-C 1-8 alkyl, (aryl,C 1-8 alkyl)amino-C 1-8 alkyl, (aryl) 2 -amino-C 1-8 alkyl, aryl-C 1-8 alkyl-amino, (aryl-C 1-8 alkyl,C 1-8 alkyl)amino, (aryl-C 1-8 alkyl) 2 -amino, aryl-C 1-8 alkyl-amino-C 1-8 alkyl, (aryl-C 1-8 alkyl,C 1-8 alkyl)amino-C 1-8 alkyl, (aryl-C 1-8 alkyl) 2 -amino-C 1-8 alkyl, heteroaryl, heteroaryl-C 1-8 alkyl, heteroaryl-amino, heteroaryl-C 1-8 alkyl-amino, (heteroaryl-C 1-8 alkyl,C 1-8 alkyl)amino, (heteroaryl-C 1-8 alkyl) 2 -amino, heteroaryl-C 1-8 alkyl-amino-C 1-8 alkyl, (heteroaryl-C 1-8 alkyl,C 1-8 alkyl)amino-C 1-8 alkyl, heterocyclyl, heterocyclyl-C 1-8 alkyl, heterocyclyl-oxy, heterocyclyl-C 1-8 alkoxy, heterocyclyl-amino, (heterocyclyl,C 1-8 alkyl)amino, (heterocyclyl) 2 -amino, heterocyclyl-amino-C 1-8 alkyl, (heterocyclyl,C 1-8 alkyl)amino-C 1-8 alkyl, (heterocyclyl) 2 -amino-C 1-8 alkyl, (heterocyclyl,C 3-14 cycloalkyl-C 1-8 alkyl)amino-C 1-8 alkyl, heterocyclyl-C 1-8 alkyl-amino-C 1-8 alkyl, (heterocyclyl-C 1-8 alkyl,C 1-8 alkyl)amino-C 1-8 alkyl, (heterocyclyl-C 1-8 alkyl) 2 -amino-C 1-8 alkyl, heterocyclyl-oxy-amino, (heterocyclyl-oxy,C 1-8 alkyl)amino, (heterocyclyl-oxy) 2 -amino, (heterocyclyl-oxy-C 1-8 alkyl,C 1-8 alkyl)amino, heterocyclyl-carbonyl or heterocyclyl-carbonyl-oxy;
wherein each instance of heterocyclyl is optionally substituted with one, two or three substituents each selected from R 7 ; and,
wherein each instance of C 3-14 cycloalkyl, aryl and heteroaryl is optionally substituted with one, two or three substituents each selected from R 8 ;
R 7 is azido, halogen, hydroxyl, oxo, cyano, nitro, C 1-8 alkyl, halo-C 1-8 alkyl, hydroxyl-C 1-8 alkyl, C 1-8 alkoxy-C 1-8 alkyl, C 1-8 alkoxy, halo-C 1-8 alkoxy, hydroxyl-C 1-8 alkoxy, carboxyl, C 1-8 alkyl-carbonyl, C 1-8 alkoxy-carbonyl, amino, C 1-8 alkyl-amino, (C 1-8 alkyl) 2 -amino, halo-C 1-8 alkyl-amino, (halo-C 1-8 alkyl) 2 -amino, halo-C 1-8 alkyl-amino-C 1-8 alkyl, (halo-C 1-8 alkyl) 2 -amino-C 1-8 alkyl, amino-C 1-8 alkyl, C 1-8 alkyl-amino-C 1-8 alkyl, (C 1-8 alkyl) 2 -amino-C 1-8 alkyl, [(C 1-8 alkyl) 2 -amino-C 1-8 alkyl,C 1-8 alkyl]amino-C 1-8 alkyl C 1-8 alkyl-thio, amino-carbonyl, C 1-8 alkyl-amino-carbonyl, (C 1-8 alkyl) 2 -amino-carbonyl, C 1-8 alkyl-carbonyl-amino, (carboxyl-C 1-8 alkyl,C 1-8 alkyl)amino-carbonyl-amino, C 3-14 cycloalkyl, C 3-14 cycloalkyl-amino, aryl, aryl-C 1-8 alkyl, aryl-amino, (aryl,C 1-8 alkyl)amino, (aryl) 2 -amino, aryl-C 1-8 alkyl-amino, (aryl-C 1-8 alkyl,C 1-8 alkyl)amino, (aryl-C 1-8 alkyl) 2 -amino, aryl-C 1-8 alkyl-amino-C 1-8 alkyl, (aryl-C 1-8 alkyl,C 1-8 alkyl)amino-C 1-8 alkyl, (aryl-C 1-8 alkyl) 2 -amino-C 1-8 alkyl, aryl-amino-C 1-8 alkyl, (aryl,C 1-8 alkyl)amino-C 1-8 alkyl, (aryl) 2 -amino-C 1-8 alkyl, aryl-amino-carbonyl, aryl-C 1-8 alkoxy, aryl-C 1-8 alkoxy-carbonyl-amino, heteroaryl, heteroaryl-C 1-8 alkyl, heteroaryl-amino, (heteroaryl) 2 -amino, heteroaryl-C 1-8 alkyl-amino, (heteroaryl-C 1-8 alkyl,C 1-8 alkyl)amino, (heteroaryl-C 1-8 alkyl) 2 -amino, heteroaryl-C 1-8 alkyl-amino-C 1-8 alkyl, (heteroaryl-C 1-8 alkyl,C 1-8 alkyl)amino-C 1-8 alkyl, (heteroaryl-C 1-8 alkyl) 2 -amino-C 1-8 alkyl, heterocyclyl, heterocyclyl-C 1-8 alkyl, heterocyclyl-amino-C 1-8 alkyl or heterocyclyl-oxy;
wherein each instance of C 3-14 cycloalkyl is optionally substituted with one substituent selected from R 9 ;
wherein each instance of aryl is optionally substituted with one substituent selected from R 10 ; and,
wherein each instance of heterocyclyl and heteroaryl is optionally substituted with one substituent selected from R 11 ;
R 8 is azido, halogen, hydroxyl, cyano, nitro, C 1-8 alkyl, halo-C 1-8 alkyl, C 1-8 alkoxy, C 1-8 alkoxy-C 1-8 alkyl, halo-C 1-8 alkoxy, carboxyl, C 1-8 alkoxy-carbonyl, amino, C 1-8 alkyl-amino, (C 1-8 alkyl) 2 -amino, C 1-8 alkyl-thio, aryl, aryl-C 1-8 alkoxy, heteroaryl, heterocyclyl, heterocyclyl-C 1-8 alkyl or heterocyclyl-oxy;
R 9 is amino, C 1-8 alkyl-amino, (C 1-8 alkyl) 2 -amino, amino-C 1-8 alkyl, C 1-8 alkyl-amino-C 1-8 alkyl, (C 1-8 alkyl) 2 -amino-C 1-8 alkyl or aryl-C 1-8 alkyl-amino;
R 10 is halogen; and,
R 11 is halogen, hydroxyl, C 1-8 alkyl, halo-C 1-8 alkyl, C 1-8 alkoxy, C 1-8 alkoxy-C 1-8 alkyl, halo-C 1-8 alkoxy, amino, C 1-8 alkyl-amino or (C 1-8 alkyl) 2 -amino; wherein the form of the compound is selected from a f

Assignees

• Branstrom Arthur
• Josyula Vara Prasad Venkata Nagendra
• Arnold Michael Andrew
• Gerasyuto Aleksey I
• Karp Gary
• Wang Jiashi
• Arasu Tamil
• Baird John David
• Du Wu
• Ginzburg Olya
• Gorske Yi Jin Kim
• Narasimhan Jana
• Peddi Srinivasa
• Qi Hongyan
• Smith Sean Wesley
• Turpoff Anthony Allan
• Wilde Richard Gerald
• Yang Tianle
• Zhang Nanjing
• Zhang Xiaoyan
• Ptc Therapeutics Inc

Inventors

• Branstrom Arthur
• Josyula Vara Prasad Venkata Nagendra
• Arnold Michael Andrew
• Gerasyuto Aleksey I
• Karp Gary
• Wang Jiashi
• Arasu Tamil
• Baird John David
• Du Wu
• Ginzburg Olya
• Gorske Yi Jin Kim
• Narasimhan Jana
• Peddi Srinivasa
• Qi Hongyan
• Smith Sean Wesley
• Turpoff Anthony Allan
• Wilde Richard Gerald
• Yang Tianle
• Zhang Nanjing
• Zhang Xiaoyan

Classifications

• A01N47/38

  containing the group >N—CO—N< where at least one nitrogen atom is part of a heterocyclic ring; Thio analogues thereof · CPC title

• C07D487/08

  Bridged systems · CPC title

• A01N43/84

  six-membered rings with one nitrogen atom and either one oxygen atom or one sulfur atom in positions 1,4 · CPC title

• A61P31/04

  Antibacterial agents · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title