Beta-lactamase inhibitors

Patent metadata

Field	Value
Publication number	US-10464952-B2
Application number	US-201816002363-A
Country	US
Kind code	B2
Filing date	Jun 7, 2018
Priority date	Dec 10, 2015
Publication date	Nov 5, 2019
Grant date	Nov 5, 2019

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.

First claim

What is claimed is:

1. A compound of Formula (Ia) or (Ib) or pharmaceutically acceptable salts, isomers, stereoisomers, dimers, trimers, tautomers, or N-oxides thereof:

wherein:

X 1 and X 2 are independently —OR 4 or F; when present;
Z is >C(═O), >C(═S), or >S(═O) 2 ;
R 3 is R 31 , —(R 30 ) q OR 31 , —(R 30 ) q O(R 30 ) q OR 31 , —R 30 OC(═O)R 31 , —R 30 OC(═O)OR 31 , —R 30 OC(═O)NHR 31 , —R 30 OC(═O)N(R 31 ) 2 , optionally substituted alkyloxyalkyl, optionally substituted acyloxyalkyl, optionally substituted alkyloxycarbonyloxyalkyl, optionally substituted cycloalkyloxycarbonyloxyalkyl, optionally substituted aryloxycarbonyloxyalkyl, or optionally substituted alkyl-[1,3]dioxol-2-one;
each q are independently 1, 2, 3, 4, 5, or 6;
each R 30 are independently —CH 2 —, —CH(R 32 )—, or —C(R 32 ) 2 —;
each R 31 are independently optionally substituted C 1 -C 12 alkyl, optionally substituted alkoxyalkyl, optionally substituted C 1 -C 12 alkenyl, optionally substituted C 1 -C 12 alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkylcycloalkyl, optionally substituted alkylheterocycloalkyl, optionally substituted alkylaryl, or optionally substituted alkylheteroaryl; or
two R 31 are taken together with the nitrogen to which they are attached to form a heterocycloalkyl;
each R 32 is independently optionally substituted C 1 -C 6 alkyl;
or two R 32 are taken together with the carbon to which they are attached to form a cycloalkyl;

R a , R b , R c are independently hydrogen, fluoro, chloro, bromo, optionally substituted C 1 -C 6 alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, —OR 4 , —N(R 4 R 5 ), or —SR 4 ; and
R d , R 4 , and R 5 are independently hydrogen, —OH, —CN, —CF 3 , optionally substituted C 1 -C 6 alkyl, optionally substituted alkoxyalkyl, optionally substituted hydroxyalkyl, optionally substituted aminoalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkylalkyl, optionally substituted heterocycloalkylalkyl, optionally substituted aralkyl, optionally substituted heteroaralkyl, (poly-ethylene-glycol)-ethyl, or an optionally substituted saccharide;
or R 4 and R 5 are taken together with the nitrogen to which they are attached to form a heterocycloalkyl.

2. The compound of claim 1 , or pharmaceutically acceptable salts, isomers, stereoisomers, dimers, trimers, tautomers, or N-oxides thereof, wherein R 3 is R 31 , —R 30 OC(═O)R 31 , or —R 30 OC(═O)OR 31 .

3. The compound of claim 1 , or pharmaceutically acceptable salts, isomers, stereoisomers, dimers, trimers, tautomers, or N-oxides thereof, wherein R a , R b , and R c are hydrogen; and R d is hydrogen or C 1 -C 4 alkyl.

4. The compound of claim 1 , or pharmaceutically acceptable salts, isomers, stereoisomers, dimers, trimers, tautomers, or N-oxides thereof, wherein X 1 and X 2 are —OH; when present and Z is >C(═O).

5. The compound of claim 1 , wherein the compound is:

or pharmaceutically acceptable salts, isomers, stereoisomers, dimers, trimers, tautomers, or N-oxides thereof, wherein the compound is present in a closed form, an open form, or mixtures thereof.

6. A pharmaceutical composition comprising at least one compound of claim 1 , or pharmaceutically acceptable salts, isomers, stereoisomers, dimers, trimers, tautomers, or N-oxides thereof, and a pharmaceutically acceptable excipient.

7. A method of treating a bacterial infection in a subject, comprising administering to the subject a compound of claim 1 , or pharmaceutically acceptable salts, isomers, stereoisomers, dimers, trimers, tautomers, or N-oxides thereof.

8. A compound of Formula (IVa) or (IVb) or pharmaceutically acceptable salts, isomers, stereoisomers, dimers, trimers, tautomers, or N-oxides thereof:

wherein:

X 1 and X 2 are independently —OR 4 or F; when present;
Z is >C(═O), >C(═S), or >S(═O) 2 ;
R a , R b , R c are independently hydrogen, fluoro, chloro, bromo, optionally substituted C 1 -C 6 alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, —OR 4 , —N(R 4 R 5 ), or —SR 4 ; and
R d , R 4 , and R 5 are independently hydrogen, —OH, —CN, —CF 3 , optionally substituted C 1 -C 6 alkyl, optionally substituted alkoxyalkyl, optionally substituted hydroxyalkyl, optionally

Assignees

• Venatorx Pharmaceuticals Inc

Inventors

• Burns Christopher J
• Pevear Daniel C
• Trout Robert E Lee
• Jackson Randy W
• Hamrick Jodie
• Zulli Allison L
• Mesaros Eugen F
• Boyd Steven A

Classifications

• A61P31/04

  Antibacterial agents · CPC title

• A61K31/546

  containing further heterocyclic rings, e.g. cephalothin · CPC title

• A61K31/43

  Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula [IMAGE cpc-sch-A61K-0952.gif], e.g. penicillins, penems · CPC title

• A61K31/427

  not condensed and containing further heterocyclic rings · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title