# US 2014/0194386 A1 · Beta-lactamase inhibitors

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- Number: US 2014/0194386 A1
- Document ID: US20140194386A1
- Status: Published application
- Kind: A1
- Application number: 14/152,916
- Filed: 2014-01-10
- Published: 2014-07-10
- Earliest claimed: 2013-01-10
- Assignees: Venatorx Pharmaceuticals, Inc.
- Applicants: VenatoRx Pharmaceuticals, Inc.
- Inventors: Christopher J. BURNS; Denis DAIGLE; Bin LIU; Daniel McGARRY; Daniel C. PEVEAR; Robert E. Lee TROUT; Randy W. JACKSON
- Web page: https://patentgrep.com/patent/US20140194386A1

## CPC

- C07F 5/025: {Boronic and borinic acid compounds}
- A61K 31/407: condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
- A61K 31/496: Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
- A61K 31/546: containing further heterocyclic rings, e.g. cephalothin
- A61K 31/69: Boron compounds
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 31/04: Antibacterial agents
- 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

Described herein are compounds and compositions that modulate the activity of beta-lactamases. In some embodiments, the compounds described herein inhibit beta-lactamase. In certain embodiments, the compounds described herein are useful in the treatment of bacterial infections.

## Claims

### Claim 1

A compound of Formula (I) or Formula (Ia), a pharmaceutically acceptable salt, polymorph, solvate, prodrug, N-oxide, or isomer thereof:
wherein:
M is a bond, —O—, —S—, —S(O)—, SO2—, or —N(R4)—;
m is 0, 1, or 2;
n is 0, 1, 2, or 3;
provided that
when n is 0, then M is a bond;
p is 0, 1, 2, or 3;
X1 and X2 are independently selected from —OH, —OR8, or F;
Z is >C═O, >C═S, or >SO2;
ArA is an optionally substituted aromatic or heteroaromatic ring system;
each Y is selected from the group consisting of
fluoro, chloro, bromo, —CN, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted heterocycle, optionally substituted aryl, optionally substituted heteroaryl, —OH, —OR10, —SR10, —NR4R5, —(CR6R7)vNR4R5, —NR4(CR6R7)vNR4R5, —O(CR6R7)vNR4R5, —S(O)0,1,2(CR6R7)vNR4R5, —N(R4)C(O)(CR6R7)vNR4R5, —(CR6R7)vN(R4)C(O)(CR6R7)vNR4R5, —(CR6R7)vNR4(CR6R7)vNR4R5, —NR4(CR6R7)vOR10, —NR4(CR6R7)vS(O)0,1,2R10, —C(O)NR4(CR6R7)vNR4R5, —S(O)0,1,2NR4(CR6R7)vNR4R5, —NR5C(O)NR4(CR6R7)vNR4R5, —OC(O)NR4(CR6R7)vNR4R5, —NR5C(═NR7)NR4(CR6R7)vNR4R5, —N(R4)C(═NR5)R6, —(CR6R7)vN(R4)C(═NR5)R6, —NR4(CR6R7)vN(R4)C(═NR5)R6, —O(CR6R7)vN(R4)C(═NR5)R6, —S(O)0,1,2(CR6R7)vN(R4)C(═NR5)R6, —(CR6R7)vC(═NR5)NR4R5, —NR4(CR6R7)vC(═NR5)NR4R5, —O(CR6R7)vC(═NR5)NR4R5, —S(O)0,1,2(CR6R7)vC(═NR5)NR4R5, —(CR6R7)vN(R4)C(═NR5)NR4R5, —NR4(CR6R7)vN(R4)C(═NR5)NR4R5, —O(CR6R7)vN(R4)C(═NR5)NR4R5, —S(O)0,1,2(CR6R7)vN(R4)C(═NR5)NR4R5, —NR4C(═NR5)NR4C(═NR5)NR4R5, —(CR6R7)vC(═NR4)NR5C(═NR4)NR4R5, —NR4(CR6R7)vC(═NR4)NR5C(═NR4)NR4R5, —O(CR6R7)vC(═NR4)NR5C(═NR4)NR4R5, —S(O)0,1,2—(CR6R7)vC(═NR4)NR5C(═NR4)NR4R5, —NR4C(═NR5)NR4R5, —C(═NR4)NR4R5, —C(═NR4)NR4C(O)R6, —NR4SO2R6, —NR4C(O)R6, —NR4C(═O)OR6, —C(O)NR4R5, —(CR6R7)vC(O)NR4R5, —SO2NR4R5, -Heteroaryl-NR4R5, -Heterocyclyl-NR4R5, -Heteroaryl-N(R4)C(═NR5)NR4R5, -Heterocyclyl-N(R4)C(═NR5)NR4R5, —N(R4)-Heteroaryl-NR4R5, —N(R4)-Heterocyclyl-NR4R5, —(CR6R7)vHeteroaryl-NR4R5, —(CR6R7)vHeterocyclyl-NR4R5, —(CR6R7)vHeteroaryl-N(R4)C(═NR5)NR4R5, —(CR6R7)vHeterocyclyl-N(R4)C(═NR5)NR4R5, —(CR6R7)vHeteroaryl, —(CR6R7)vHeterocyclyl, —O-Heteroaryl, —O-Heterocyclyl, —NR4(CR6R7)vHeteroaryl, —NR4(CR6R7)vHeterocyclyl, —O(CR6R7)vHeteroaryl, —O(CR6R7)vHeterocyclyl, —NR4(CR6R7)vNR5—Heteroaryl, —NR4(CR6R7)vNR5—Heterocyclyl, —O(CR6R7)vNR5—Heteroaryl, —O(CR6R7)vNR5—Heterocyclyl, —O(CR6R7)vO-Heterocyclyl, —NR4R5R9+Q−, —(CR6R7)vNR4R5R9+Q−, —NR4(CR6R7)vNR4R5R9+Q−, —NR4R9+(CR6R7)vNR4R5R9+Q−2, —(CR6R7)v(T)+Q−, and —O(CR6R7)vNR4R5R9+Q−;
wherein:
T is pyridine-1-yl, pyrimidin-1-yl, or thiazol-3-yl;
Q is a pharmaceutically acceptable counterion; and
v is 1-4;
or two Ys taken together with the carbon atoms to which they are attached form an optionally substituted carbocycle or an optionally substituted heterocycle;
Ra, Rb, and Rc are independently selected from the group consisting of hydrogen, fluoro, chloro, bromo, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —OH, —OR10, —NR4R5, and —SR10;
R1 and R2 are independently selected from the group consisting of hydrogen, fluoro, chloro, bromo, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, —OH, —OR10, —SR10, and —NR4R5,
or R1 and R2 taken together form an oxo, oxime, or an optionally substituted carbocycle or optionally substituted heterocycle with the carbon to which they are attached;
R3 is hydrogen, optionally substituted C1-C6 alkyl, or a pharmaceutically acceptable prodrug;
Rd, R4 and R5 are independently selected from the group consisting of hydrogen, —OH, —CN, optionally substituted C1-C6 alkyl, optionally substituted alkoxyalkyl, optionally substituted hydroxyalkyl, optionally substituted aminoalkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclylalkyl, optionally substituted aralkyl, optionally substituted heteroaralkyl, (poly-ethylene-glycol)-ethyl, and an optionally substituted saccharide;
or R4 and R5 taken together form an optionally substituted heterocycle with the nitrogen to which they are attached;
R6 and R7 are independently selected from the group consisting of hydrogen, fluoro, chloro, bromo, optionally substituted C1-C6 alkyl, optionally substituted alkoxyalkyl, optionally substituted hydroxyalkyl, optionally substituted C3-C6 cycloalkyl, —OH, —OR10, —SR10, —NR4R5, —NR4C(O)R5, —C(O)NR4R5, —NR4SO2R5, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;
or R6 and R7 taken together form an oxo, oxime, or an optionally substituted carbocycle or an optionally substituted heterocycle with the carbon to which they are attached;
R8 is optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, or a pharmaceutically acceptable boronate ester group;
R9 is optionally substituted C1-C6 alkyl;
R10 is optionally substituted C1-C6 alkyl or optionally substituted C3-C6 cycloalkyl.

### Claim 2

(canceled)

### Claim 3

(canceled)

### Claim 4 (depends on 1)

The compound of claim 1, wherein Ra, Rb, and Rc are hydrogen.

### Claim 5

(canceled)

### Claim 6 (depends on 1)

The compound of claim 1, wherein R3 is hydrogen.

### Claim 7 (depends on 1)

The compound of claim 1, wherein X1 and X2 are —OH.

### Claim 8 (depends on 1)

The compound of claim 1, wherein Rd is hydrogen or C1-C4-alkyl.

### Claim 9

(canceled)

### Claim 10 (depends on 1)

The compound of claim 1, wherein Z is >C═O.

### Claim 11 (depends on 1)

The compound of claim 1, wherein:
M is —O—, —S—, —SO2—, or —N(R4)—;
m is 0 or 1; and
n is 1 or 2.

### Claim 12

(canceled)

### Claim 13 (depends on 1)

The compound of claim 1, wherein:
M is a bond; and
m and n are 0.

### Claim 14 (depends on 1)

The compound of claim 1, wherein:
M is a bond; and
m or n are 1.

### Claim 15

(canceled)

### Claim 16 (depends on 1)

The compound of claim 1, wherein ArA is selected from the group consisting of benzene, pyridine, pyrimidine, thiophene, thiazole, triazole, indole, benzimidazole, azaindole, thienopyrazole, quinoline, quinazoline, and quinoxaline.

### Claim 17

(canceled)

### Claim 18

(canceled)

### Claim 19 (depends on 1)

The compound of claim 1, wherein at least one Y is selected from the group consisting of —NR4R5, —NR4C(═NR5)NR4R5, —C(═NR4)NR4R5, —N(R4)C(═NR5)R6, —(CR6R7)vNR4R5, —(CR6R7)vN(R4)C(═NR5)NR4R5, —NR4(CR6R7)vNR4R5, —NR4(CR6R7)vOR10, —(CR6R7)vNR4(CR6R7)vNR4R5, NR5C(═NR5)NR4(CR6R7)vNR4R5, —NR4(CR6R7)vN(R4)C(═NR5)NR4R5, —NR5C(O)CR6(NR4R5)(CR6R7)vNR4R5, —(CR6R7)vC(═NR5)NR4R5, —(CR6R7)vN(R4)C(O)(CR6R7)vNR4R5, —C(═NR4)NR4C(O)R6, —NR4(CR6R7)vHeteroaryl, and —O(CR6R7)vNR4R5.

### Claim 20

(canceled)

### Claim 21

(canceled)

### Claim 22 (depends on 1)

The compound of claim 1, wherein two Y groups taken together with the carbon atoms to which they are attached form an optionally substituted carbocycle or an optionally substituted heterocycle.

### Claim 23

(canceled)

### Claim 24 (depends on 22)

The compound of claim 22, wherein two Y groups, together with the atoms to which they are attached form a pyrrolidine ring.

### Claim 25 (depends on 1)

The compound of claim 1, wherein p is 1 or 2.

### Claim 26

(canceled)

### Claim 27 (depends on 1)

The compound of claim 1, wherein R4 and R5 are independently hydrogen or optionally substituted C1-C6 alkyl.

### Claim 28

(canceled)

### Claim 29 (depends on 1)

The compound of claim 1, wherein R6 and R7 are independently hydrogen, fluoro, or optionally substituted C1-C6 alkyl.

### Claim 30 (depends on 1)

The compound of claim 1, wherein the compound is selected from the group represented by the following structures:
or a pharmaceutically acceptable salt, solvate, polymorph, stereoisomer, tautomer, prodrug, metabolite, N-oxide, or isomer thereof, wherein the compound is present in a closed, cyclic form according to Formula I and as shown in the structures above, an open, acyclic form according to Formula Ia, or mixtures thereof.

### Claim 31 (depends on 1)

A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt, polymorph, solvate, prodrug, N-oxide, or isomer thereof, and a pharmaceutically acceptable excipient.

### Claim 32 (depends on 31)

The pharmaceutical composition of claim 31, further comprising a beta-lactam antibiotic.

### Claim 33

(canceled)

### Claim 34 (depends on 31)

A method of treating a bacterial infection in a subject, comprising administering to the subject a pharmaceutical composition of claim 31, optionally in combination with a beta-lactam antibiotic.