# US 2014/0194381 A1 · Boronic acid derivatives and therapeutic uses thereof

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- Number: US 2014/0194381 A1
- Document ID: US20140194381A1
- Status: Published application
- Kind: A1
- Application number: 13/829,062
- Filed: 2013-03-14
- Published: 2014-07-10
- Earliest claimed: 2013-01-04
- Assignees: Rempex Pharmaceuticals, Inc.
- Inventors: Raja Reddy; Tomasz Glinka; Maxim Totrov; Scott Hecker
- Web page: https://patentgrep.com/patent/US20140194381A1

## CPC

- A61K 31/69: Boron compounds
- A61K 31/407: condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
- A61K 31/4196: 1,2,4-Triazoles
- A61K 31/427: not condensed and containing further heterocyclic rings
- A61K 31/546: containing further heterocyclic rings, e.g. cephalothin
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- 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
- 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
- C07F: ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM (metal-containing porphyrins C07D487/22)
- Y02A: TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE

## Abstract

Disclosed herein are antimicrobial compounds compositions, pharmaceutical compositions, the use and preparation thereof. Some embodiments relate to boronic acid derivatives and their use as therapeutic agents.

## Claims

### Claim 1

A compound having the structure of formula I:
or pharmaceutically acceptable salt thereof, wherein:
Y is selected from the group consisting of —S—, —O—, —CH2—, and —NH—;
n is 0-3;
G is selected from the group consisting of —C(O)NR1R2; —C(O)NR1OR2; —NR1C(O)R2; —NR1C(O)NR2R3; —NR1C(O)OR2; S(O)2R2; S(O)2NR2R3; C(═NR1)R2; —C(═NR1)NR2R3; —NR1CR2(═NR3); —NR1C(═NR2)NR3R4; aryl optionally substituted with 0-2 substituents selected from the group consisting of C1-4 alkyl, —OR1, —NR1R2, halogen, —C(O)NR1R2, and —NR1C(O)R2; heteroaryl optionally substituted with 0-2 substituents selected from the group consisting of C1-4 alkyl, —OR1, —NR1R2, halogen, —C(O)NR1R2, and —NR1C(O)R2; and heterocyclyl optionally substituted with 0-2 substituents selected from the group consisting of C1-4 alkyl, —OR1, —NR1R2, halogen, —C(O)NR1R2, and —NR1C(O)R2;
J, L, and M are each independently selected from the group consisting of CR7 and N;
R is selected from a group consisting of —H, —C1-9alkyl, —CR5R6OC(O)C1-9alkyl, —CR5R6OC(O)OC1-9alkyl, and
R1, R2, R3, R4, R5 and R6 are each independently selected from —H and —C1-4alkyl; and
R7 is selected from the group consisting of —H, —C1-4alkyl, —OH, —OC1-4alkyl, and halogen.

### Claim 2 (depends on 1)

The compound of claim 1, having the structure of (Ia):
or pharmaceutically acceptable salt thereof.

### Claim 3 (depends on 1)

The compound of claim 1, having the structure of (Ib):
or pharmaceutically acceptable salt thereof.

### Claim 4 (depends on 1)

The compound of claim 1, wherein n is 0 or 1.

### Claim 5 (depends on 1)

The compound of claim 1, wherein:
Y is O or S;
G is selected from the group consisting of phenyl, imidazole, pyrazole, triazole, tetrazole, thiazole, thiadiazole, oxazole, oxadiazole, isoxazole, isothiazole, pyridine, pyrazine, pyrimidine, pyridazine, and pyrazine, each optionally substituted by 0-2 substituents selected from the group consisting of —OR1, —NR1R2, halogen, —C(O)NR1R2, and —NR1C(O)R2; and
J, L and M are CR7.

### Claim 6 (depends on 5)

The compound of claim 5, wherein n is 0.

### Claim 7 (depends on 5)

The compound of claim 5, wherein G is thiadiazole.

### Claim 8 (depends on 5)

The compound of claim 5, wherein G is thiadiazole optionally substituted with NR1R2 or —NR1C(O)R2, wherein R1 and R2 are independently H or —C1-4alkyl.

### Claim 9 (depends on 5)

The compound of claim 5, wherein G is triazole optionally substituted with NR1R2, wherein R1 and R2 are independently H or —C1-4alkyl.

### Claim 10 (depends on 5)

The compound of claim 5, wherein G is tetrazole optionally substituted with methyl.

### Claim 11 (depends on 5)

The compound of claim 5, wherein G is pyridine.

### Claim 12 (depends on 5)

The compound of claim 5, wherein G is thiazole.

### Claim 13 (depends on 5)

The compound of claim 5, wherein G is phenyl.

### Claim 14 (depends on 1)

The compound of claim 1, wherein:
Y is S;
n is 1 or 2;
G is —C(O)NR1R2 or —C(═NR1)R2; and
J, L and M are CR7.

### Claim 15 (depends on 14)

The compound of claim 14, wherein R7 is H.

### Claim 16 (depends on 14)

The compound of claim 14, wherein R1 is H and R2 is H.

### Claim 17 (depends on 1)

The compound of claim 1, wherein G is selected from the group consisting of —C(O)NR1R2; —C(O)NR1OR2; —NR1C(O)R2; —NR1C(O)NR2R3; —NR1C(O)OR2; —NR1S(O)2R2; —NR1S(O)2NR2R3; —C(═NR1)NR2R3; —NR1CR2(═NR3); —NR1C(═NR2)NR3R4; aryl optionally substituted with 0-2 substituents selected from the group consisting of —OR1, —NR1R2, halogen, —C(O)NR1R2, and —NR1C(O)R2; heteroaryl optionally substituted with 0-2 substituents selected from the group consisting of —OR1, —NR1R2, halogen, —C(O)NR1R2, and —NR1C(O)R2; and heterocyclyl optionally substituted with 0-2 substituents selected from the group consisting of —OR1, —NR1R2, halogen, —C(O)NR1R2, and —NR1C(O)R2;

### Claim 18 (depends on 1)

The compound of claim 1, having the structure selected from the group consisting of:
or pharmaceutically acceptable salts thereof.

### Claim 19 (depends on 1)

The compound of claim 1, having the structure selected from the group consisting of:
or pharmaceutically acceptable salts thereof.

### Claim 20 (depends on 1)

A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 and a pharmaceutically acceptable excipient.

### Claim 21 (depends on 20)

The pharmaceutical composition of claim 20, further comprising an additional medicament.

### Claim 22 (depends on 21)

The composition of claim 21, wherein the additional medicament is selected from an antibacterial agent, antifungal agent, an antiviral agent, an anti-inflammatory agent, or an anti-allergic agent.

### Claim 23 (depends on 22)

The composition of claim 22, wherein the additional medicament is a β-lactam antibacterial agent.

### Claim 24 (depends on 23)

The composition of claim 23, wherein the β-lactam is selected from Amoxicillin, Ampicillin (Pivampicillin, Hetacillin, Bacampicillin, Metampicillin, Talampicillin), Epicillin, Carbenicillin (Carindacillin), Ticarcillin, Temocillin, Azlocillin, Piperacillin, Mezlocillin, Mecillinam (Pivmecillinam), Sulbenicillin, Benzylpenicillin (G), Clometocillin, Benzathine benzylpenicillin, Procaine benzylpenicillin, Azidocillin, Penamecillin, Phenoxymethylpenicillin (V), Propicillin, Benzathine phenoxymethylpenicillin, Pheneticillin, Cloxacillin (Dicloxacillin, Flucloxacillin), Oxacillin, Meticillin, Nafcillin, Faropenem, Tomopenem, Razupenem, Cefazolin, Cefacetrile, Cefadroxil, Cefalexin, Cefaloglycin, Cefalonium, Cefaloridine, Cefalotin, Cefapirin, Cefatrizine, Cefazedone, Cefazaflur, Cefradine, Cefroxadine, Ceftezole, Cefaclor, Cefamandole, Cefminox, Cefonicid, Ceforanide, Cefotiam, Cefprozil, Cefbuperazone, Cefuroxime, Cefuzonam, Cefoxitin, Cefotetan, Cefinetazole, Loracarbef, Cefixime, Ceftriaxone, Cefcapene, Cefdaloxime, Cefdinir, Cefditoren, Cefetamet, Cefinenoxime, Cefodizime, Cefoperazone, Cefotaxime, Cefpimizole, Cefpiramide, Cefpodoxime, Cefsulodin, Cefteram, Ceftibuten, Ceftiolene, Ceftizoxime, Flomoxef, Latamoxef, Cefepime, Cefozopran, Cefpirome, Cefquinome, Ceftobiprole, Ceftaroline, CXA-101, RWJ-54428, MC-04,546, ME1036, Ceftiofur, Cefquinome, Cefovecin, RWJ-442831, RWJ-333441, or RWJ-333442.

### Claim 25 (depends on 23)

The composition of claim 23, wherein the β-lactam is selected from Ceftazidime, Biapenem, Doripenem, Ertapenem, Imipenem, Meropenem, or Panipenem.

### Claim 26 (depends on 23)

The composition of claim 23, wherein the β-lactam is selected from Aztreonam, Tigemonam, BAL30072, SYN 2416, or Carumonam.

### Claim 27 (depends on 1)

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

### Claim 28 (depends on 27)

The method of claim 27, further comprising administering to the subject an additional medicament.

### Claim 29 (depends on 28)

The method of claim 28, wherein the additional medicament is selected from an antibacterial agent, antifungal agent, an antiviral agent, an anti-inflammatory agent, or an anti-allergic agent.

### Claim 30 (depends on 29)

The method of claim 29, wherein the additional medicament is a β-lactam antibacterial agent.

### Claim 31 (depends on 30)

The method of claim 30, wherein the β-lactam is selected from Amoxicillin, Ampicillin (Pivampicillin, Hetacillin, Bacampicillin, Metampicillin, Talampicillin), Epicillin, Carbenicillin (Carindacillin), Ticarcillin, Temocillin, Azlocillin, Piperacillin, Mezlocillin, Mecillinam (Pivmecillinam), Sulbenicillin, Benzylpenicillin (G), Clometocillin, Benzathine benzylpenicillin, Procaine benzylpenicillin, Azidocillin, Penamecillin, Phenoxymethylpenicillin (V), Propicillin, Benzathine phenoxymethylpenicillin, Pheneticillin, Cloxacillin (Dicloxacillin, Flucloxacillin), Oxacillin, Meticillin, Nafcillin, Faropenem, Tomopenem, Razupenem, Cefazolin, Cefacetrile, Cefadroxil, Cefalexin, Cefaloglycin, Cefalonium, Cefaloridine, Cefalotin, Cefapirin, Cefatrizine, Cefazedone, Cefazaflur, Cefradine, Cefroxadine, Ceftezole, Cefaclor, Cefamandole, Cefminox, Cefonicid, Ceforanide, Cefotiam, Cefprozil, Cefbuperazone, Cefuroxime, Cefuzonam, Cefoxitin, Cefotetan, Cefinetazole, Loracarbef, Cefixime, Ceftriaxone, Cefcapene, Cefdaloxime, Cefdinir, Cefditoren, Cefetamet, Cefinenoxime, Cefodizime, Cefoperazone, Cefotaxime, Cefpimizole, Cefpiramide, Cefpodoxime, Cefsulodin, Cefteram, Ceftibuten, Ceftiolene, Ceftizoxime, Flomoxef, Latamoxef, Cefepime, Cefozopran, Cefpirome, Cefquinome, Ceftobiprole, Ceftaroline, CXA-101, RWJ-54428, MC-04,546, ME1036, Ceftiofur, Cefquinome, Cefovecin, RWJ-442831, RWJ-333441, or RWJ-333442.

### Claim 32 (depends on 30)

The method of claim 30, wherein the β-lactam is selected from Ceftazidime, Biapenem, Doripenem, Ertapenem, Imipenem, Meropenem, or Panipenem.

### Claim 33 (depends on 30)

The method of claim 30, wherein the β-lactam is selected from Aztreonam, Tigemonam, BAL30072, SYN 2416, or Carumonam.

### Claim 34 (depends on 27)

The method of claim 27, wherein the subject is a mammal.

### Claim 35 (depends on 34)

The method of claim 34, wherein the mammal is a human.

### Claim 36 (depends on 27)

The method of claim 27, wherein the infection comprises a bacteria selected from Pseudomonas acidovorans, Pseudomonas alcaligenes, Pseudomonas putida, Burkholderia cepacia, Aeromonas hydrophilia, Francisella tularensis, Morganella morganii, Proteus mirabilis, Proteus vulgaris, Providencia alcalifaciens, Providencia rettgeri, Providencia stuartii, Acinetobacter baumannii, Bordetella pertussis, Bordetella parapertussis, Bordetella bronchiseptica, Haemophilus ducreyi, Pasteurella multocida, Pasteurella haemolytica, Branhamella catarrhalis, Borrelia burgdorferi, Kingella, Gardnerella vaginalis, Bacteroides distasonis, Bacteroides 3452A homology group, Clostridium difficile, Mycobacterium tuberculosis, Mycobacterium avium, Mycobacterium intracellulare, Mycobacterium leprae, Corynebacterium diphtherias, Corynebacterium ulcerans, Streptococcus pneumoniae, Streptococcus agalactiae, Streptococcus pyogenes, Enterococcus faecalis, Enterococcus faecium, Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus saprophyticus, Staphylococcus intermedius, Staphylococcus hyicus subsp. hyicus, Staphylococcus haemolyticus, Staphylococcus hominis, or Staphylococcus saccharolyticus.

### Claim 37 (depends on 27)

The method of claim 27, wherein the infection comprises a bacteria selected from Pseudomonas aeruginosa, Pseudomonas fluorescens, Stenotrophomonas maltophilia, Escherichia coli, Citrobacter freundii, Salmonella typhimurium, Salmonella typhi, Salmonella paratyphi, Salmonella enteritidis, Shigella dysenteriae, Shigella flexneri, Shigella sonnei, Enterobacter cloacae, Enterobacter aerogenes, Klebsiella pneumoniae, Klebsiella oxytoca, Serratia marcescens, Acinetobacter calcoaceticus, Acinetobacter haemolyticus, Yersinia enterocolitica, Yersinia pestis, Yersinia pseudotuberculosis, Yersinia intermedia, Haemophilus influenzae, Haemophilus parainfluenzae, Haemophilus haemolyticus, Haemophilus parahaemolyticus, Helicobacter pylori, Campylobacter fetus, Campylobacter jejuni, Campylobacter coli, Vibrio cholerae, Vibrio parahaemolyticus, Legionella pneumophila, Listeria monocytogenes, Neisseria gonorrhoeae, Neisseria meningitidis, Moraxella, Bacteroides fragilis, Bacteroides vulgatus, Bacteroides ovalus, Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroides eggerthii, or Bacteroides splanchnicus.