# US 11,999,759 B2 · Boronic acid derivatives and therapeutic uses thereof

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- Number: US 11,999,759 B2
- Document ID: US11999759B2
- Status: Granted
- Kind: B2
- Application number: 17/520,365
- Filed: 2021-11-05
- Published: 2022-02-24
- Granted: 2024-06-04
- Earliest claimed: 2016-06-30
- Assignees: Qpex Biopharma, Inc.
- Applicants: Qpex Biopharma, Inc.
- Inventors: Scott J. Hecker; Raja K. Reddy; Tomasz Glinka; Olga Rodny
- Web page: https://patentgrep.com/patent/US11999759B2

## CPC

- C07F 5/05: Cyclic compounds having at least one ring containing boron but no carbon in the ring
- A61K 31/407: condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
- A61K 31/4196: 1,2,4-Triazoles
- A61K 31/426: 1,3-Thiazoles
- A61K 31/69: Boron compounds
- 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
- C07F 5/025: {Boronic and borinic acid compounds}
- 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
- C07F: ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM (metal-containing porphyrins C07D487/22)
- 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
- Y02A: TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE

## Abstract

Disclosed herein are antimicrobial compounds compositions, pharmaceutical compositions, the method of use and preparation thereof. Some embodiments relate to boronic acid derivatives and their use as therapeutic agents, for example, β-lactamase inhibitors (BLIs).

## Claims

### Claim 1

A compound having the structure of Formula V, or pharmaceutically acceptable salts thereof:
wherein
Y1 is N or CR4;
m is an integer of 0 or 1;
r is an integer of 0 or 1;
R2 and R3 together with the atoms to which they are attached form a fused ring or ring system selected from the group consisting of C3-7carbocyclyl and 3-10 membered heterocyclyl, each optionally substituted with one or more R5, and
each of R1, R4, Ra, and Rb is independently selected from the group consisting of H, amino, halogen, cyano, hydroxy, optionally substituted C1-6 alkyl, optionally substituted C1-6 haloalkyl, optionally substituted C1-6 alkoxy, optionally substituted C1-6 haloalkoxy, optionally substituted (C1-6 alkoxy)C1-6 alkyl, optionally substituted C2-10alkenyl, optionally substituted C2-10alkynyl, optionally substituted C3-7 carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted C6-10aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted (C3-7carbocyclyl)C1-6 alkyl, optionally substituted (3-10 membered heterocyclyl)C1-6alkyl, optionally substituted (C6-10aryl)C1-6 alkyl, (C6-10aryl)C1-6alkoxy, optionally substituted (5-10 membered heteroaryl)C1-6alkyl, acyl, C-carboxy, O-carboxy, C-amido, N-amido, S-sulfonamido, N-sulfonamido, —SRc, —C(O)(CH2)0-3SRc, —C(O)(CH2)1-3Rd, —NRfC(O)NRfRg, —NRfS(O)2NRfRg, —C(═NRe)Rc, —C(═NRe)NRfRg, —NRfCRc(═NRe), —NRfC(═NRe)NRfRg, —S(O)(CH2)1-3Rc, and —NRfS(O)2NRfORd;
R5 is —Y5—(CH2)t-G;
t is an integer of 0 or 1;
G is selected from the group consisting of H, amino, halogen, cyano, hydroxy, optionally substituted C1-6 alkyl, optionally substituted C1-6 haloalkyl, optionally substituted C1-6 alkoxy, optionally substituted C1-6 haloalkoxy, optionally substituted (C1-6 alkoxy)C1-6 alkyl, optionally substituted C2-10alkenyl, optionally substituted C2-10alkynyl, optionally substituted C3-7 carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted C6-10aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted (C3-7carbocyclyl)C1-6alkyl, optionally substituted (3-10 membered heterocyclyl)C1-6 alkyl, optionally substituted (C6-10aryl)C1-6alkyl, (C6-10aryl)C1-6alkoxy, optionally substituted (5-10 membered heteroaryl)C1-6alkyl, acyl, C-carboxy, O-carboxy, C-amido, N-amido, S-sulfonamido, N-sulfonamido, —SRc, —C(O)(CH2)0-3 SRc, —C(O)(CH2)1-3Rd, —NRfC(O)NRfRg, —NRfS(O)2NRfRg, —C(═NRe)Rc, —C(═NRe)NRfRg, —NRfCRc(═NRe), —NRfC(═NRe)NRfRg, —S(O)(CH2)1-3Rc, and —NRfS(O)2NRfORd;
R6 is (CH2)nC(O)OR or a carboxylic acid isostere;
n is an integer selected from 0 to 6;
R is selected from the group consisting of H, C1-9 alkyl, —CR10R11OC(O)C1-9alkyl, —CR10R11OC(O)C3-7carbocyclyl, —CR10R11OC(O) (3 to 7 membered heterocyclyl), —CR10R11OC(O)C2-8alkoxyalkyl, —CR10R11OC(O)OC1-9alkyl, —CR10R11OC(O)OC3-7carbocyclyl, —CR10R11OC(O)O (3 to 7 membered heterocyclyl), —CR10R11OC(O)OC2-8alkoxyalkyl, —CR10R11OC(O)C6-10 aryl, —CR10R11OC(O)OC6-10aryl, —CR10R11C(O)NR13R14, —CR10R11OC(O)O(CH2)1-3C(O)NR13R14, —CR10R11OC(O)O(CH2)2-3OC(O)C1-4 alkyl, —CR10R11OC(O)O(CH2)1-3C(O)OC1-4 alkyl, —CR10R11OC(O)(CH2)1-3OC(O)C1-4 alkyl, and
R7 is selected from the group consisting of —OH, optionally substituted C1-6 alkoxy, amino, and —N(OR8)R9;
each R8 and R9 is independently selected from the group consisting of H, halogen, optionally substituted C1-4alkyl, optionally substituted C3-7 carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted C6-10aryl, and optionally substituted 5-10 membered heteroaryl;
each R10 and R11 is independently selected from the group consisting of H, optionally substituted C1-4alkyl, optionally substituted C3-7 carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted C6-10aryl, and optionally substituted 5-10 membered heteroaryl;
each R13 and R14 is independently selected from the group consisting of H, optionally substituted C1-6alkyl, optionally substituted C3-7 carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted C6-10aryl, and optionally substituted 5-10 membered heteroaryl;
R15 is optionally substituted C1-6 alkyl;
Y2 is O;
Y5 is selected from the group consisting of —S—, —S(O)—, —S(O)2—, —O—, —CRfRg—, and —NRg—, or Y5 is absent;
each Rc, Rd, Re, Rf, and Rg are independently selected from the group consisting of H, halogen, optionally substituted C1-4alkyl, optionally substituted C3-7 carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted C6-10 aryl, and optionally substituted 5-10 membered heteroaryl; and
each Rh and Ri is independently selected from the group consisting of H, halogen, cyano, amino, C-amido, N-amido, optionally substituted C1-4alkyl, optionally substituted C3-7 carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted C6-10aryl, and optionally substituted 5-10 membered heteroaryl; or Rh and Ri together with the atoms to which they are attached form a spirocyclic ring or ring system selected from the group consisting of C3-7 carbocyclyl, 3-10 membered heterocyclyl, C6-10 aryl, and 5-10 membered heteroaryl, each optionally substituted with one or more R5.

### Claim 2 (depends on 1)

The compound of claim 1, wherein R is H, C1-9 alkyl, —CR10R11OC(O)C1-9alkyl, —CR10R11OC(O)OC1-9alkyl, —CR10R11OC(O)C6-10aryl, —CR10R11OC(O)OC6-10aryl, or

### Claim 3 (depends on 1)

The compound of claim 1, having the structure of Formula Vb, or pharmaceutically acceptable salts thereof:

### Claim 4 (depends on 1)

The compound of claim 1, wherein both Ra and Rb are H.

### Claim 5 (depends on 1)

The compound of claim 1, wherein R2 and R3 together with the atoms to which they are attached form C3-7 carbocyclyl optionally substituted with one or more R5.

### Claim 6 (depends on 5)

The compound of claim 5, wherein R2 and R3 together with the atoms to which they are attached form cyclopropyl optionally substituted with one or more R5.

### Claim 7 (depends on 1)

The compound of claim 1, wherein r is 1, and both Rh and Ri are H.

### Claim 8 (depends on 1)

The compound of claim 1, wherein R6 is —(CH2)nC(O)OR and n is 0.

### Claim 9 (depends on 8)

The compound of claim 8, having the structure of Formula Vc, or pharmaceutically acceptable salts thereof:
wherein the cyclopropyl moiety
is optionally substituted with one or more R5.

### Claim 10 (depends on 9)

The compound of claim 9, having the structure of Formula Vc-1 or Vc-2, or pharmaceutically acceptable salts thereof:

### Claim 11 (depends on 1)

The compound of claim 1, wherein R7 is —OH.

### Claim 12 (depends on 1)

A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

### Claim 13 (depends on 12)

The pharmaceutical composition of claim 12, further comprising a β-lactam antibacterial agent.

### Claim 14 (depends on 1)

A method of treating a bacterial infection, comprising administering a compound of claim 1, or a pharmaceutically acceptable salt thereof to a subject in need thereof.

### Claim 15 (depends on 14)

The method of claim 14, wherein the bacterial infection is caused by β-lactam antibacterial agent-resistant enterobacteriaceae.

### Claim 16 (depends on 14)

The method of claim 14, further comprising administering a β-lactam antibacterial agent to the subject.

### Claim 17 (depends on 16)

The method of claim 16, wherein the β-lactam antibacterial agent is administered separately from the compound or pharmaceutically acceptable salt thereof, or the β-lactam antibacterial agent and the compound or pharmaceutically acceptable salt thereof are in a single dosage form.

### Claim 18 (depends on 16)

The method of claim 16, wherein the bacterial infection is caused by Carbapenem-resistant enterobacteriaceae.

### Claim 19 (depends on 3)

The compound of claim 3, wherein both Ra and Rb are H.

### Claim 20 (depends on 19)

The compound of claim 19, wherein r is 1.

### Claim 21 (depends on 20)

The compound of claim 20, wherein R7 is —OH.