# US 10,500,211 B2 · Beta-lactamase inhibitors and uses thereof

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- Number: US 10,500,211 B2
- Document ID: US10500211B2
- Status: Granted
- Kind: B2
- Application number: 16/116,489
- Filed: 2018-08-29
- Published: 2019-01-24
- Granted: 2019-12-10
- Earliest claimed: 2017-05-10
- Assignees: Arixa Pharmaceuticals, Inc.
- Applicants: Arixa Pharmaceuticals, Inc.
- Inventors: Eric M. Gordon; John Freund; Mark A. Gallop; Matthew Alexander James Duncton
- Web page: https://patentgrep.com/patent/US10500211B2

## CPC

- A61K 31/551: having two nitrogen atoms, e.g. dilazep
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 31/04: Antibacterial agents
- C07D 471/08: Bridged 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

β-Lactamase inhibiting compounds, therapeutic methods of using the β-lactamase inhibiting compounds, particularly in combination with β-lactam antibiotics and pharmaceutical compositions thereof are disclosed. The β-lactamase inhibiting compounds are suitable for oral administration.

## Claims

### Claim 1

A compound of Formula (1):
or a pharmaceutically acceptable salt thereof, wherein,
each R1 is independently selected from C1-6 alkyl, or each R1 and the geminal carbon atom to which they are bonded forms a C3-6 cycloalkyl ring, a C3-6 heterocycloalkyl ring, a substituted C3-6 cycloalkyl ring, or a substituted C3-6 heterocycloalkyl ring;
R2 is selected from a single bond, C1-6 alkanediyl, C1-6 heteroalkanediyl, C5-6 cycloalkanediyl, C5-6 heterocycloalkanediyl, C6 arenediyl, C5-6 heteroarenediyl, substituted C1-6 alkanediyl, substituted C1-6 heteroalkanediyl, substituted C5-6 cycloalkanediyl, substituted C5-6 heterocycloalkanediyl, substituted C6 arenediyl, and substituted C5-6 heteroarenediyl; and
R3 is selected from C1-6 alkyl, —O—C(O)—R4, —S—C(O)—R4, —NH—C(O)—R4, —O—C(O)—O—R4, —S—C(O)—O—R4, —NH—C(O)—O—R4, —C(O)—O—R4, —C(O)—S—R4, —C(O)—NH—R4, —O—C(O)—S—R4, —O—C(O)—NH—R4, —S—S—R4, —S—R4, —NH—R4, —CH(—NH2)(—R4), C5-6 heterocycloalkyl, C5-6 heteroaryl, substituted C5-6 cycloalkyl, substituted C5-6 heterocycloalkyl, substituted C5-6 aryl, substituted C5-6 heteroaryl, and —CH═C(R4)2, wherein,
R4 is selected from hydrogen, C1-8 alkyl, C1-8 heteroalkyl, C5-8 cycloalkyl, C5-8 heterocycloalkyl, C5-10 cycloalkylalkyl, C5-10 heterocycloalkylalkyl, C6-8 aryl, C5-8 heteroaryl, C7-10 arylalkyl, C5-10 heteroarylalkyl, substituted C1-8 alkyl, substituted C1-8 heteroalkyl, substituted C5-8 cycloalkyl, substituted C5-8 heterocycloalkyl, substituted C5-10 cycloalkylalkyl, substituted C5-10 heterocycloalkylalkyl, substituted C6-8 aryl, substituted C5-8 heteroaryl, substituted C7-10 arylalkyl, and substituted C5-10 heteroarylalkyl.

### Claim 2 (depends on 1)

The compound of claim 1, wherein each R1 is independently selected from C1-6 alkyl.

### Claim 3 (depends on 1)

The compound of claim 1, wherein R2 is selected from a single bond, C1-6 alkanediyl, C5-6 cycloalkanediyl, and C6 arenediyl.

### Claim 4 (depends on 1)

The compound of claim 1, wherein,
R3 is selected from C1-6 alkyl, —O—C(O)—R4, —S—C(O)—R4, —NH—C(O)—R4, —O—C(O)—O—R4, —S—C(O)—O—R4, —NH—C(O)—O—R4, —C(O)—O—R4, —C(O)—S—R4, —C(O)—NH—R4, —O—C(O)—S—R4, —O—C(O)—NH—R4, —S—S—R4, —S—R4, —NH—R4, —CH(—NH2)(—R4), C5-6 cycloalkyl, and —CH═C(R4)2; and
R4 is selected from hydrogen, C1-8 alkyl, C5-8 cycloalkyl, C5-10 cycloalkylalkyl, C6-8 aryl, and C7-10 arylalkyl.

### Claim 5 (depends on 1)

The compound of claim 1, wherein,
R2 is selected from a single bond, C1-6 alkanediyl, C5-6 cycloalkanediyl, C6 arenediyl;
R3 is selected from C1-6 alkyl, —O—C(O)—R4, —S—C(O)—R4, —NH—C(O)—R4, —O—C(O)—O—R4, —S—C(O)—O—R4, —NH—C(O)—O—R4, —C(O)—O—R4, —C(O)—S—R4, —C(O)—NH—R4, —O—C(O)—O—R4, —O—C(O)—S—R4, —O—C(O)—NH—R4, —S—S—R4, —S—R4, —NH—R4, —CH(—NH2)(—R4), C5-6 cycloalkyl, and —CH═C(R4)2; and
R4 is selected from hydrogen, C1-8 alkyl, C5-8 cycloalkyl, C5-10 cycloalkylalkyl, C6-8 aryl, and C7-10 arylalkyl.

### Claim 6 (depends on 1)

The compound of claim 1, wherein,
each R1 is independently selected from C1-3 alkyl, or each R1 together with the carbon atom to which they are bonded form a C3-6 cycloalkyl ring;
R2 is selected from single bond, methane-diyl, and ethane-diyl; and
R3 is selected from —C(O)—O—R4 and —S—C(O)—R4, wherein R4 is selected from C1-8 alkyl, C1-8 heteroalkyl, C7-10 arylalkyl, C5-8 heterocycloalkyl, and substituted C5-10 heterocycloalkylalkyl.

### Claim 7 (depends on 1)

The compound of claim 1, wherein,
each R1 is independently selected from C1-3 alkyl, or each R1 together with the carbon atom to which they are bonded form a C3-6 cycloalkyl ring;
R2 is a single bond; and
R3 is —(O)—O—R4, wherein R4 is selected from C1-8 alkyl, C1-8 heteroalkyl, C7-10 arylalkyl, C5-8 heterocycloalkyl, and substituted C5-10 heterocycloalkylalkyl.

### Claim 8 (depends on 1)

The compound of claim 1, wherein,
each R1 is independently selected from C1-3 alkyl, or each R1 together with the carbon atom to which they are bonded form a C3-6 cycloalkyl ring;
R2 is —(CH2)2—; and
R3 is —C(O)—O—R4 wherein R4 is selected from C1-8 alkyl, C1-8 heteroalkyl, C7-10 arylalkyl, C5-8 heterocycloalkyl, and substituted C5-10 heterocycloalkylalkyl.

### Claim 9 (depends on 1)

The compound of claim 1, wherein,
each R1 is selected from C1-3 alkyl, or each R1 together with the carbon atom to which they are bonded form a C3-6 cycloalkyl ring;
R2 is —CH2—; and
R3 is —S—C(O)—R4, wherein R4 is selected from C1-8 alkyl, C1-8 heteroalkyl, C7-10 arylalkyl, C5-8 heterocycloalkyl, and substituted C5-10 heterocycloalkylalkyl.

### Claim 10 (depends on 1)

The compound of claim 1, wherein,
each R1 together with the carbon atom to which they are bonded form a C3-6 cycloalkyl ring, a C3-6 heterocycloalkyl ring, a C3-6 cycloalkyl ring, or a C3-6 heterocycloalkyl ring;
R2 is a single bond; and
R3 is C1-3 alkyl.

### Claim 11 (depends on 1)

The compound of claim 1, wherein,
each R1 is independently selected from C1-3 alkyl;
R2 is selected from a single bond and methanediyl; and
R3 is selected from —O—C(O)—R4 and —C(O)—O—R4, wherein R4 is selected from C1-8 alkyl and substituted phenyl.

### Claim 12 (depends on 1)

The compound of claim 1, wherein,
each R1 is independently selected from C1-3 alkyl;
R2 is a single bond; and
R3 is —CH═C(R4)2, wherein each R4 is —C(O)—O—R8and
each R8 is C1-4 alkyl.

### Claim 13 (depends on 1)

The compound of claim 1, wherein,
each R1 is independently selected from C1-3 alkyl;
R2 is selected from a single bond and methanediyl; and
R3 is substituted phenyl, wherein the one or more substituents is independently selected from —CH2—O—C(O)—R4 and —O—C(O)—R4, wherein R4 is selected from C1-8 alkyl and phenyl.

### Claim 14 (depends on 1)

The compound of claim 1, wherein,
each R1 is independently selected from C1-3 alkyl;
R2 is selected from —C(R8)2— and —CH2—C(R8)2—,wherein each R8 is independently selected from C1-3 alkyl; and
R3 is selected from —C(O)—O—R4 and —OC—(O)—R4, wherein R4 is selected from C1-8 alkyl, C1-8 heteroalkyl, substituted C1-8 alkyl, substituted C1-8 heteroalkyl, and 4(yl-methyl)-5-methyl-1,3-dioxol-2-one.

### Claim 15 (depends on 1)

The compound of claim 1, wherein, each R1 together with the carbon atom to which they are bonded form a substituted C5-6 heterocyclic ring;
R2 is a single bond; and
R3 is C1-3 alkyl.

### Claim 16 (depends on 1)

A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable vehicle.

### Claim 17 (depends on 16)

The pharmaceutical composition of claim 16, further comprising an antibiotic.

### Claim 18 (depends on 17)

The pharmaceutical composition of claim 17, wherein the antibiotic comprises a β-lactam antibiotic.

### Claim 19 (depends on 16)

The pharmaceutical composition of claim 16, wherein the pharmaceutical composition is an oral dosage formulation.

### Claim 20 (depends on 16)

The pharmaceutical composition of claim 16, wherein the pharmaceutical composition is an oral dosage form.

### Claim 21 (depends on 1)

A method of treating a bacterial infection in a patient comprising administering to a patient having the bacterial infection a therapeutically effective amount of the compound of claim 1 or a pharmaceutically acceptable salt thereof; and a therapeutically effective amount of a β-lactam antibiotic, wherein bacteria causing the bacterial infection produces a β-lactamase.

### Claim 22 (depends on 21)

The method of claim 21, wherein administering comprises orally administering.

### Claim 23 (depends on 1)

A method of treating a bacterial infection in a patient comprising administering to a patient having the bacterial infection a therapeutically effective amount of the compound of claim 1 or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of a β-lactam antibiotic, wherein the bacterial infection is capable of being treated with a therapeutically effective amount of the β-lactam antibiotic when co-administered with a therapeutically effective amount of avibactam.

### Claim 24 (depends on 23)

The method of claim 23, wherein administering comprises orally administering.

### Claim 25 (depends on 1)

A method of inhibiting a β-lactamase enzyme in a patient, comprising administering to a patient an effective amount of the compound of claim 1 to the patient.

### Claim 26 (depends on 25)

The method of claim 25, wherein administering comprises orally administering.