# US 10,369,138 B2 · Monobactam organic compounds for the treatment of bacterial infections

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- Number: US 10,369,138 B2
- Document ID: US10369138B2
- Status: Granted
- Kind: B2
- Application number: 14/861,797
- Filed: 2015-09-22
- Published: 2016-02-25
- Granted: 2019-08-06
- Earliest claimed: 2014-03-24
- Assignees: Novartis AG
- Applicants: Novartis AG
- Inventors: Virender Singh Aulakh; Anthony Casarez; Xiaodong Lin; Mika Lindvall; Glenn McEnroe; Heinz Ernst Moser; Folkert Reck; Meiliana Tjandra; Robert Lowell Simmons; Aregahegn Yifru; Qingming Zhu
- Web page: https://patentgrep.com/patent/US10369138B2

## CPC

- A61K 31/427: not condensed and containing further heterocyclic rings
- A61K 31/433: Thidiazoles
- A61K 31/4439: containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole (nicotine A61K31/465)
- A61K 31/454: containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
- A61K 31/4545: containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
- A61K 31/496: Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 31/00: Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P 31/04: Antibacterial agents
- C07D 417/14: containing three or more hetero rings
- C07D 487/04: Ortho-condensed systems
- Y02A 50/30: Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- Y02A: TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE

## 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.

## Claims

### Claim 1

A method to treat a Gram-negative bacterial infection, which comprises administering to a subject in need of such treatment a compound of Formula (IA):
or a pharmaceutically acceptable salt thereof,
wherein:
Z is CH;
the group —O—CR1R2R3 is selected from
and Het is selected from

### Claim 2 (depends on 1)

The method of claim 1, wherein the compound of Formula (IA) is a compound wherein the group —OCR1R2R3 is selected from:
or a pharmaceutically acceptable salt of such compound.

### Claim 3 (depends on 1)

The method of claim 1, wherein the compound of Formula (IA) is a compound wherein —O—CR1R2R3 is
or a pharmaceutically acceptable salt of such compound.

### Claim 4 (depends on 1)

The method of claim 1, wherein the compound of Formula (IA) is a compound wherein Het is selected from:
or a pharmaceutically acceptable salt of such compound.

### Claim 5 (depends on 1)

The method of claim 1, wherein the compound of Formula (IA) is a compound wherein Het is selected from:
or a pharmaceutically acceptable salt of such compound.

### Claim 6 (depends on 1)

The method of claim 1, wherein the compound of Formula (IA) is a compound wherein Het is selected from:
or a pharmaceutically acceptable salt of such compound.

### Claim 7 (depends on 1)

The method of claim 1, wherein the compound of Formula (IA) is a compound wherein Het is selected from:
or a pharmaceutically acceptable salt of such compound.

### Claim 8 (depends on 1)

The method of claim 1, wherein the compound of Formula (IA) 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-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.

### Claim 9 (depends on 1)

The method of claim 1, wherein the compound of Formula (IA) 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.

### Claim 10 (depends on 1)

The method of claim 1, wherein the compound of Formula (IA) 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.

### Claim 11 (depends on 1)

The method of claim 1, wherein the compound of Formula (IA) 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.

### Claim 12 (depends on 1)

The method of claim 1, wherein the compound of Formula (IA) 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.

### Claim 13 (depends on 1)

The method of claim 1, wherein the compound of Formula (IA) is selected from:
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;
or a pharmaceutically acceptable salt thereof.

### Claim 14 (depends on 1)

The method of claim 1, wherein the compound of Formula (IA) is selected from:
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.

### Claim 15 (depends on 1)

The method of claim 1, wherein the bacterial infection is caused by a species of Burkholderia, Citrobacter, Enterobacter, Eschirichia, Klebsiella, Meningitidis, Morganella, Pseudomonas, Proteus, Salmonella, Serratia, Acinetobacter, Bacteroides, Burkholderia, Campylobacter, Neisseria, or Stenotrophomonas bacteria.

### Claim 16 (depends on 15)

The method of claim 15, wherein the bacterial infection is caused by Eschirichia coli.

### Claim 17 (depends on 1)

The method of claim 1, wherein the subject is also treated with a beta-lactamase inhibitor.