Monobactam organic compounds for the treatment of bacterial infections

Patent metadata

Field	Value
Publication number	US-9174978-B2
Application number	US-201514665245-A
Country	US
Kind code	B2
Filing date	Mar 23, 2015
Priority date	Mar 24, 2014
Publication date	Nov 3, 2015
Grant date	Nov 3, 2015

Abstract

This invention pertains generally to antibacterial compounds of Formula I,

as further described herein, and pharmaceutically acceptable salts and formulations thereof. In certain aspects, the invention pertains to methods of using such compounds to treat infections such as those caused by Gram-negative bacteria.

First claim

The invention claimed is:

1. A compound of Formula (IA):

or a pharmaceutically acceptable salt thereof,
wherein:
Z is CH;
the group —O—CR 1 R 2 R 3 is selected from

and
Het is selected from

2. The compound of claim 1 , wherein the group —OCR′R 2 R 3 is selected from:

or a pharmaceutically acceptable salt thereof.

3. The compound of claim 1 , wherein the group —O—CR′R 2 R 3 is

or a pharmaceutically acceptable salt thereof.

4. The compound of claim 1 , wherein Het is selected from:

or a pharmaceutically acceptable salt thereof.

5. The compound of claim 1 , wherein Het is selected from:

or a pharmaceutically acceptable salt thereof.

6. The compound of claim 1 , wherein Het is selected from:

or a pharmaceutically acceptable salt thereof.

7. The compound of claim 1 , wherein Het is selected from:

or a pharmaceutically acceptable salt thereof.

8. The compound of claim 1 , which is selected from:
1-(((Z)-(2-(((2R,3S)-2-((4-(aminomethyl)-2-oxoimidazolidin-1-yl)methyl)-4-oxo-1-sulfoazetidin-3-yl)amino)-1-(2-aminothiazol-4-yl)-2-oxoethylidene)amino)oxy)cyclopropanecarboxylic acid;
1-(((Z)-(2-(((2R,3S)-2-(((R)-5-((3-(2-aminoethyl)ureido)methyl)-2-oxooxazolidin-3-yl)methyl)-4-oxo-1-sulfoazetidin-3-yl)amino)-1-(2-aminothiazol-4-yl)-2-oxoethylidene)amino)oxy)cyclopropanecarboxylic acid;
1-(((Z)-(1-(2-aminothiazol-4-yl)-2-oxo-2-(((3S,4R)-2-oxo-4-((2-oxoimidazolidin-1-yl)methyl)-1-sulfoazetidin-3-yl)amino)ethylidene)amino)oxy)cyclopropanecarboxylic acid;
1-(((Z)-(2-(((2R,3S)-2-(((R)-5-(((2-aminoethyl)amino)methyl)-2-oxooxazolidin-3-yl)methyl)-4-oxo-1-sulfoazetidin-3-yl)amino)-1-(2-aminothiazol-4-yl)-2-oxoethylidene)amino)oxy)cyclopropanecarboxylic acid;
1-(((Z)-(2-(((2R,3S)-2-(((R)-5-(aminomethyl)-2-oxooxazolidin-3-yl)methyl)-4-oxo-1-sulfoazetidin-3-yl)amino)-1-(2-aminothiazol-4-yl)-2-oxoethyl idene)amino)oxy)-cyclopropanecarboxylic acid;
1-(((Z)-(1-(2-aminothiazol-4-yl)-2-oxo-2-(((3S,4R)-2-oxo-4-((2-oxooxazolidin-3-yl)methyl)-1-sulfoazetidin-3-yl)amino)ethylidene)amino)oxy)cyclopropanecarboxylic acid; and
1-(((Z)-(1-(2-aminothiazol-4-yl)-2-(((2R,3S)-2-(((R)-5-(guanidinomethyl)-2-oxooxazolidin-3-yl)methyl)-4-oxo-1-sulfoazetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-cyclopropanecarboxylic acid,
or a pharmaceutically acceptable salt thereof.

9. The compound of claim 1 , which is selected from:
1-(((Z)-(1-(2-aminothiazol-4-yl)-2-(((2R,3S)-2-((4-(guanidinomethyl)-2H-1,2,3-triazol-2-yl)methyl)-4-oxo-1-sulfoazetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-cyclopropanecarboxylic acid;
1-(((Z)-(2-(((2R,3S)-2-((4-(aminomethyl)-1H-1,2,3-triazol-1-yl)methyl)-4-oxo-1-sulfoazetidin-3-yl)amino)-1-(2-aminothiazol-4-yl)-2-oxoethylidene)amino)oxy)cyclopropanecarboxylic acid;
(S)-2-(((Z)-(2-(((2R,3S)-2-((1H-1,2,4-triazol-1-yl)methyl)-4-oxo-1-sulfoazetidin-3-yl)amino)-1-(2-aminothiazol-4-yl)-2-oxoethylidene)amino)oxy)-3-(4-(N-(2-aminoethyl)carbamimidoyl)phenoxy)propanoic acid;
1-(((Z)-(1-(2-aminothiazol-4-yl)-2-(((2R,3S)-2-((4-(((3-guanidinopropyl)amino)methyl)-2H-1,2,3-triazol-2-yl)methyl)-4-oxo-1-sulfoazetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)cyclopropanecarboxylic acid;
1-(((Z)-(1-(2-aminothiazol-4-yl)-2-(((2R,3S)-2-((4,5-bis(aminomethyl)-2H-1,2,3-triazol-2-yl)methyl)-4-oxo-1-sulfoazetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)cyclopropanecarboxylic acid;
1-(((Z)-(2-(((2R,3S)-2-((4-((3-aminoazetidin-1-yl)methyl)-2H-1,2,3-triazol-2-yl)methyl)-4-oxo-1-sulfoazetidin-3-yl)amino)-1-(2-aminothiazol-4-yl)-2-oxoethylidene)amino)oxy)cyclopropanecarboxylic acid;
1-(((Z)-(1-(2-aminothiazol-4-yl)-2-oxo-2-(((3S,4R)-2-oxo-4-((4-(((S)-pyrrolidin-3-ylamino)methyl)-2H-1,2,3-triazol-2-yl)methyl)-1-sulfoazetidin-3-yl)amino)ethylidene)amino)oxy)cyclopropanecarboxylic acid;
(S)-2-(((Z)-(2-(((2R,3S)-2-((1H-1,2,4-triazol-1-yl)methyl)-4-oxo-1-sulfoazetidin-3-yl)amino)-1-(2-aminothiazol-4-yl)-2-oxoethylidene)amino)oxy)-3-(4-(N-((1R,5S,6s)-3-azabicyclo[3.1.0]hexan-6-yl)carbamimidoyl)phenoxy)propanoic acid; and
(S)-2-(((Z)-(2-(((2R,3S)-2-((1H-1,2,4-triazol-1-yl)methyl)-4-oxo-1-sulfoazetidin-3-yl)amino)-1-(2-aminothiazol-4-yl)-2-oxoethylidene)amino)oxy)-3-(4-(N-(3-aminopropyl)carbamimidoyl)phenoxy)propanoic acid;
or a pharmaceutically acceptable salt thereof.

10. The compound of claim 1 , which is selected from:
1-(((Z)-(2-(((2R,3S)-2-((4-(aminomethyl)-2-oxoimidazolidin-1-yl)methyl)-4-oxo-1-sulfoazetidin-3-yl)amino)-1-(2-aminothiazol-4-yl)-2-oxoethylidene)amino)oxy)cyclopropanecarboxylic acid;
1-(((Z)-(2-(((2R,3S)-2-(((R)-5-((3-(2-aminoethyl)ureido)methyl)-2-oxooxazolidin-3-yl)methyl)-4-oxo-1-sulfoazetidin-3-yl)amino)-1-(2-aminothiazol-4-yl)-2-oxoethylidene)amino)oxy)cyclopropanecarboxylic acid; and
1-(((Z)-(1-(2-aminothiazol-4-yl)-2-oxo-2-(((3S,4R)-2-oxo-4-((2-oxoimidazolidin-1-yl)methyl)-1-sulfoazetidin-3-yl)amino)ethylidene)amino)oxy)cyclopropanecarboxylic acid;
or a pharmaceutically acceptable salt thereof.

11. The compound of claim 1 , which is selected from:
1-(((Z)-(2-(((2R,3S)-2-(((R)-5-(((2-aminoethyl)amino)methyl)-2-oxooxazolidin-3-yl)methyl)-4-oxo-1-sulfoazetidin-3-yl)amino)-1-(2-aminothiazol-4-yl)-2-oxoethylidene)amino)oxy)cyclopropanecarboxylic acid;
1-(((Z)-(2-(((2R,3S)-2-(((R)-5-(aminomethyl)-2-oxooxazolidin-3-yl)methyl)-4-oxo-1-sulfoazetidin-3-yl)amino)-1-(2-aminothiazol-4-yl)-2-oxoethylidene)amino)oxy)-cyclopropanecarboxylic acid;
1-(((Z)-(1-(2-aminothiazol-4-yl)-2-oxo-2-(((3S,4R)-2-oxo-4-((2-oxooxazolidin-3-yl)methyl)-1-sulfoazetidin-3-yl)amino)ethylidene)amino)oxy)cyclopropanecarboxylic acid; and
1-(((Z)-(1-(2-aminothiazol-4-yl)-2-(((2R,3S)-2-(((R)-5-(guanidinomethyl)-2-oxooxazolidin-3-yl)methyl)-4-oxo-1-sulfoazetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-cyclopropanecarboxylic acid,
or a pharmaceutically acceptable salt thereof.

12. The compound of claim 1 , which is selected from:
1-(((Z)-(1-(2-aminothiazol-4-yl)-2-(((2R,3S)-2-((4-(guanidinomethyl)-2H-1,2,3-triazol-2-yl)methyl)-4-oxo-1-sulfoazetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-cyclopropanecarboxylic acid;
1-(((Z)-(2-(((2R,3S)-2-((4-(aminomethyl)-1H-1,2,3-triazol-1-yl)methyl)-4-oxo-1-sulfoazetidin-3-yl)amino)-1-(2-aminothiazol-4-yl)-2-oxoethylidene)amino)oxy)cyclopropanecarboxylic acid;
(S)-2-(((Z)-(2-(((2R,3S)-2-((1H-1,2,4-triazol-1-yl)methyl)-4-oxo-1-sulfoazetidin-3-yl)amino)-1-(2-aminothiazol-4-yl)-2-oxoethylidene)amino)oxy)-3-(4-(N-(2-aminoethyl)carbamimidoyl)phenoxy)propanoic acid;
or a pharmaceutically acceptable salt thereof.

Assignees

• Aulakh Virender Singh
• Casarez Anthony
• Lin Xiaodong
• Lindvall Mika
• Mcenroe Glenn
• Moser Heinz Ernst
• Reck Folkert
• Tjandra Meiliana
• Simmons Robert Lowell
• Yifru Aregahegn
• Zhu Qingming
• Novartis Ag

Inventors

• Aulakh Virender Singh
• Casarez Anthony
• Lin Xiaodong
• Lindvall Mika
• Mcenroe Glenn
• Moser Heinz Ernst
• Reck Folkert
• Tjandra Meiliana
• Simmons Robert Lowell
• Yifru Aregahegn
• Zhu Qingming

Classifications

• A61P31/04

  Antibacterial agents · CPC title

• A61P31/00

  Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics · CPC title

• C07D417/14 Primary

  containing three or more hetero rings · CPC title

• C07D487/04

  Ortho-condensed systems · CPC title

• A61K2300/00

  Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00 · CPC title