# US 10,441,576 B2 · Substituted 1,2-dihydro-3H pyrrolo[1,2-c]imidazol-3 one antibacterials

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- Number: US 10,441,576 B2
- Document ID: US10441576B2
- Status: Granted
- Kind: B2
- Application number: 15/751,596
- Filed: 2016-08-10
- Published: 2018-08-23
- Granted: 2019-10-15
- Earliest claimed: 2015-08-11
- Assignees: Idorsia Pharmaceuticals Ltd
- Applicants: Idorsia Pharmaceuticals Ltd.
- Inventors: Stefan Diethelm; Philippe Panchaud; Georg Rueedi; Jean-Luc Specklin; Jean-Philippe Surivet
- Web page: https://patentgrep.com/patent/US10441576B2

## CPC

- A61K 31/4188: condensed with other heterocyclic ring systems, e.g. biotin, sorbinil
- A61K 31/5377: not condensed and containing further heterocyclic rings, e.g. timolol
- A61P 31/04: Antibacterial agents
- C07D 487/04: Ortho-condensed systems
- 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)

## Abstract

The invention relates to antibacterial compounds of formula I wherein M is one of the groups MA, MB and MC represented below and either R1 represents H and R2 represents a cleavable group as defined in the claims or R2 represents H and R1 represents a cleavable group as defined in the claims; and salts thereof.

## Claims

### Claim 1

A compound of formula I
wherein
M is one of the groups MA, MB and MC represented below
and either R1 represents H and, when M is MA, R2 represents SO3H, phosphonooxymethyl or the group L2A represented below
wherein R2A represents (C1-C4)alkylamino(C1-C4)alkyl, [di(C2-C4)alkylamino]methyl, {(methyl)[(C2-4)alkyl]amino}methyl, [di(C1-C4)alkylamino](C2-C4)alkyl, morpholin-4-yl-(C1-C4)alkyl, phosphonooxy(C1-C4)alkyl, phosphonooxymethoxy, 2-(phosphonooxy-(C1-C4)alkyl)-phenyl, (2-(phosphonooxy)-phenyl)-(C1-C4)alkyl or [2-(phosphonooxy-(C1-C4)alkyl)-phenyl]-(C1-C4)alkyl, or, when M is MB or MC, R2 represents PO3H2, SO3H, phosphonooxymethyl or the group L2BC represented below
wherein R2BC represents (C1-C4)alkylamino(C1-C4)alkyl, [di(C1-C4)alkylamino](C1-C4)alkyl, morpholin-4-yl-(C1-C4)alkyl, phosphonooxy(C1-C4)alkyl, phosphonooxymethoxy, 2-(phosphonooxy-(C1-C4)alkyl)-phenyl, (2-(phosphonooxy)-phenyl)-(C1-C4)alkyl or [2-(phosphonooxy-(C1-C4)alkyl)-phenyl]-(C1-C4)alkyl, or R2 represents H and R1 represents PO3H2, SO3H, phosphonooxymethyl or the group L1 represented below
wherein R1A represents (C1-C4)alkylamino(C1-C4)alkyl, [di(C1-C4)alkylamino](C1-C4)alkyl, morpholin-4-yl-(C1-C4)alkyl, phosphonooxy(C1-C4)alkyl, phosphonooxymethoxy, 2-(phosphonooxy-(C1-C4)alkyl)-phenyl, (2-(phosphonooxy)-phenyl)-(C1-C4)alkyl or [2-(phosphonooxy-(C1-C4)alkyl)-phenyl]-(C1-C4)alkyl;
it being understood that the molecule is always such that its R2 group is attached to the oxygen atom of its MA, MB and MC group;
or a salt thereof.

### Claim 2 (depends on 1)

The compound of formula I according to claim 1, wherein the compound is a compound of formula ICE
wherein
M is one of MA, MB or MC represented below
and either R1 represents H and, when M is MA, R2 represents SO3H or the group L2A represented below
wherein, R2A represents morpholin-4-yl-(C1-C4)alkyl or (2-(phosphonooxy)-phenyl)-(C1-C4)alkyl, or, when M is MB or MC, R2 represents PO3H2 or the group L2BC represented below
wherein, R2BC represents (2-(phosphonooxy)-phenyl)-(C1-C4)alkyl,
or R2 represents H and R1 represents PO3H2 or the group L1 represented below
wherein R1A represents (2-(phosphonooxy)-phenyl)-(C1-C4)alkyl;
it being understood that the molecule is always such that its R2 group is attached to the oxygen atom of its MA, MB and MC group;
or a salt thereof.

### Claim 3 (depends on 1)

The compound of formula I according to claim 1, wherein M is the group MA;
or a salt thereof.

### Claim 4 (depends on 3)

The compound of formula I according to claim 3, wherein R1 represents H and R2 represents SO3H or the group L2A wherein R2A represents morpholin-4-yl-(C1-C4)alkyl or (2-(phosphonooxy)-phenyl)-(C1-C4)alkyl;
or a salt thereof.

### Claim 5 (depends on 3)

The compound of formula I according to claim 3, wherein R2 represents H and R1 represents PO3H2 or the group L1 wherein R1A represents 2-(2-(phosphonooxy)phenyl)ethyl;
or a salt thereof.

### Claim 6 (depends on 1)

The compound of formula I according to claim 1, wherein M is the group MB;
or a salt thereof.

### Claim 7 (depends on 6)

The compound of formula I according to claim 6, wherein R1 represents H and R2 represents PO3H2 or the group L2BC wherein R2BC represents 2-(2-(phosphonooxy)phenyl)ethyl;
or a salt thereof.

### Claim 8 (depends on 1)

The compound of formula I according to claim 1, wherein M is the group MC;
or a salt thereof.

### Claim 9 (depends on 8)

The compound of formula I according to claim 8, wherein R1 represents H and R2 represents PO3H2;
or a salt thereof.

### Claim 10 (depends on 1)

The compound of formula I according to claim 1, wherein:
M is the group MA, R1 represents H and R2 represents SO3H or the group L2A wherein R2A represents morpholin-4-yl-(C1-C4)alkyl or (2-(phosphonooxy)-phenyl)-(C1-C4)alkyl; or
M is the group MA, R2 represents H and R1 represents PO3H2 or the group L1 wherein R1A represents (2-(phosphonooxy)-phenyl)-(C1-C4)alkyl; or
M is the group MB, R1 represents H and R2 represents PO3H2 or the group L2BC wherein R2BC represents (2-(phosphonooxy)-phenyl)-(C1-C4)alkyl; or
M is the group MC, R1 represents H and R2 represents PO3H2;
or a salt thereof.

### Claim 11 (depends on 1)

The compound of formula I according to claim 1, wherein the compound is:
(R)-(1-((2-(4-(hydroxyamino)-3-methyl-3-(methylsulfonyl)-4-oxobutyl)-3-oxo-2,3-dihydro-1H-pyrrolo[1,2-c]imidazol-6-yl)buta-1,3-diyn-1-yl)cyclopropyl)methyl 2-morpholinoacetate;
(R)-(1-((2-(4-(hydroxyamino)-3-methyl-3-(methylsulfonyl)-4-oxobutyl)-3-oxo-2,3-dihydro-1H-pyrrolo[1,2-c]imidazol-6-yl)buta-1,3-diyn-1-yl)cyclopropyl)methyl 3-(2-(phosphonooxy)phenyl)propanoate;
(R)-2-(3-((4-(6-((1-(hydroxymethyl)cyclopropyl)buta-1,3-diyn-1-yl)-3-oxo-1H-pyrrolo[1,2-c]imidazol-2 (3H)-yl)-2-methyl-2-(methylsulfonyl)butanamido)oxy)-3-oxopropyl)phenyl dihydrogen phosphate;
-((1S,2S)-2-((2-((R)-4-(hydroxyamino)-3-methyl-3-(methylsulfonyl)-4-oxobutyl)-3-oxo-2,3-dihydro-1H-pyrrolo[1,2-c]imidazol-6-yl)buta-1,3-diyn-1-yl)cyclopropyl)methyl dihydrogen phosphate;
((1S,2S)-2-((2-((R)-4-(hydroxyamino)-3-methyl-3-(methylsulfonyl)-4-oxobutyl)-3-oxo-2,3-dihydro-1H-pyrrolo[1,2-c]imidazol-6-yl)buta-1,3-diyn-1-yl)cyclopropyl)methyl 3-(2-(phosphonooxy)phenyl)propanoate;
((1R,2R)-1-fluoro-2-((2-((R)-4-(hydroxyamino)-3-methyl-3-(methylsulfonyl)-4-oxobutyl)-3-oxo-2,3-dihydro-1H-pyrrolo[1,2-c]imidazol-6-yl)buta-1,3-diyn-1-yl)cyclopropyl)methyl dihydrogen phosphate;
(R)-((4-(6-((1-(hydroxymethyl)cyclopropyl)buta-1,3-diyn-1-yl)-3-oxo-1H-pyrrolo[1,2-c]imidazol-2(3H)-yl)-2-methyl-2-(methylsulfonyl)butanamido)oxy)phosphonic acid;
(R)-(1-((2-(4-(hydroxyamino)-3-methyl-3-(methylsulfonyl)-4-oxobutyl)-3-oxo-2,3-dihydro-1H-pyrrolo[1,2-c]imidazol-6-yl)buta-1,3-diyn-1-yl)cyclopropyl)methyl hydrogen sulfate;
or a salt thereof.

### Claim 12 (depends on 1)

A method of treating a bacterial infection comprising administering to a patient in need thereof the compound of formula I according to claim 1, or a pharmaceutically acceptable salt thereof.

### Claim 13 (depends on 1)

A pharmaceutical composition comprising, as active principle, a compound of formula I according to claim 1, or a pharmaceutically acceptable salt thereof, and at least one therapeutically inert excipient.

### Claim 14 (depends on 13)

A method of treating a bacterial infection comprising administering to a patient in need thereof the pharmaceutical composition according to claim 13, or a pharmaceutically acceptable salt thereof.

### Claim 15 (depends on 14)

The method according to claim 14, wherein the bacterial infection is a Gram-negative bacterial infection.

### Claim 16 (depends on 13)

The method according to claim 13, wherein the bacterial infection is a Gram-negative bacterial infection.