Beta-lactamase inhibitors

Patent metadata

Field	Value
Publication number	US-9511142-B2
Application number	US-201514737323-A
Country	US
Kind code	B2
Filing date	Jun 11, 2015
Priority date	Jun 11, 2014
Publication date	Dec 6, 2016
Grant date	Dec 6, 2016

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 (I) or a pharmaceutically acceptable salt, N-oxide, or isomer thereof:

wherein:
L is a bond, —C(R 1 R 2 )—, —C(═O)—, or ═C(R 1 )—;
M is a bond, —O—, —S—, —S(O)—, —S(O) 2 —, or —N(R 4 )—;
m is 0, 1, or 2;
n is 0, 1, 2, or 3;
p is 1, 2, 3, or 4;
Z is —C(═O)—, —C(═S), or —S(O) 2 —;
A is CycA, ArA or HetA, wherein
CycA is an optionally substituted 3-10 membered non-aromatic carbocycle, wherein an optional olefin functionality of the non-aromatic carbocycle is not directly attached to an oxygen, sulfur, or nitrogen substituent;
ArA is an aromatic or heteroaromatic ring system optionally substituted with one or more substituents selected from the group consisting of fluoro, chloro, bromo, —CN, optionally substituted C 1 -C 6 alkyl, optionally substituted C 3 -C 6 cycloalkyl, optionally substituted heterocycle, optionally substituted aryl, optionally substituted heteroaryl, —OH, —OR 10 , and —SR 10 ;
HetA is an optionally substituted non-aromatic heterocyclic ring system;

each R 1 and R 2 is independently selected from the group consisting of hydrogen, fluoro, chloro, bromo, optionally substituted C 1 -C 6 alkyl, optionally substituted C 3 -C 6 cycloalkyl, —OH, —OR 10 , —SR 10 , and —NR 4 R 5 ,
or R 1 and R 2 taken together form an oxo, oxime, or an optionally substituted carbocycle or optionally substituted heterocycle with the carbon to which they are attached;

each R d , R 4 , and R 5 is independently selected from the group consisting of hydrogen, —OH, —CN, optionally substituted C 1 -C 6 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 R 4 and R 5 taken together form an optionally substituted heterocycle with the nitrogen to which they are attached;

each R 10 is independently selected from the group consisting of C 1 -C 6 alkyl and optionally substituted C 3 -C 6 cycloalkyl;
each Y, provided that Y is not attached directly to a heteroatom of HetA, is selected from the group consisting of:
chloro, bromo, —CN, optionally substituted heteroaryl, —OR 10 , —SR 10 , —(CR 6 R 7 ) v NR 4 R 5 , —NR 4 (CR 6 R 7 ) v NR 4 R 5 , —S(O) 0,1,2 (CR 6 R 7 ) v NR 4 R 5 , —N(R 4 )C(O)(CR 6 R 7 ) v NR 4 R 5 , —(CR 6 R 7 ) v N(R 4 )C(O)(CR 6 R 7 ) v NR 4 R 5 , —(CR 6 R 7 ) v NR 4 (CR 6 R 7 ) v NR 4 R 5 , —NR 4 (CR 6 R 7 ) v OR 10 , —NR 4 (CR 6 R 7 ) v S(O) 0,1,2 R 10 , —C(O)NR 4 (CR 6 R 7 ) v NR 4 R 5 , —S(O) 0,1,2 NR 4 (CR 6 R 7 ) v NR 4 R 5 , —NR 5 C(O)NR 4 (CR 6 R 7 ) v NR 4 R 5 , —OC(O)NR 4 (CR 6 R 7 ) v NR 4 R 5 , —NR 5 C(═NR 7 )NR 4 (CR 6 R 7 ) v NR 4 R 5 , —N(R 4 )C(═NR 5 )R 6 , —(CR 6 R 7 ) v N(R 4 )C(═NR 5 )R 6 , —NR 4 (CR 6 R 7 ) v N(R 4 )C(═NR 5 )R 6 , —O(CR 6 R 7 ) v N(R 4 )C(═NR 5 )R 6 , —S(O) 0,1,2 (CR 6 R 7 ) v N(R 4 )C(═NR 5 )R 6 , —(CR 6 R 7 ) v C(═NR 5 )NR 4 R 5 , —NR 4 (CR 6 R 7 ) v C(═NR 5 )NR 4 R 5 , —O(CR 6 R 7 ) v C(═NR 5 )NR 4 R 5 , —S(O) 0,1,2 (CR 6 R 7 ) v C(═NR 5 )NR 4 R 5 , —(CR 6 R 7 ) v N(R 4 )C(═NR 5 )NR 4 R 5 , —NR 4 (CR 6 R 7 ) v N(R 4 )C(═NR 5 )NR 4 R 5 , —O(CR 6 R 7 ) v N(R 4 )C(═NR 5 )NR 4 R 5 , —S(O) 0,1,2 (CR 6 R 7 ) v N(R 4 )C(═NR 5 )NR 4 R 5 , —NR 4 C(═NR 5 )NR 4 C(═NR 5 )NR 4 R 5 , —(CR 6 R 7 ) v C(═NR 4 )NR 5 C(═NR 4 )NR 4 R 5 , —NR 4 (CR 6 R 7 ) v C(═NR 4 )NR 5 C(═NR 4 )NR 4 R 5 , —O(CR 6 R 7 ) v C(═NR 4 )NR 5 C(═NR 4 )NR 4 R 5 , —S(O) 0,1,2 —(CR 6 R 7 ) v C(═NR 4 )NR 5 C(═NR 4 )NR 4 R 5 , —NR 4 C(═NR 5 )NR 4 R 5 , —C(═NR 4 )NR 4 R 5 , —C(═NR 4 )NR 4 C(O)R 6 , —NR 4 SO 2 R 6 , —NR 4 C(O)R 6 , —NR 4 C(═O)OR 6 , —C(O)NR 4 R 5 , —(CR 6 R 7 ) v C(O)NR 4 R 5 , —SO 2 NR 4 R 5 , -Heteroaryl-NR 4 R 5 , -Heterocyclyl-NR 4 R 5 , -Heteroaryl-N(R 4 )C(═NR 5 )NR 4 R 5 , -Heterocyclyl-N(R 4 )C(═NR 5 )NR 4 R 5 , —N(R 4 )—Heteroaryl-NR 4 R 5 , —N(R 4 )—Heterocyclyl-NR 4 R 5 , —(CR 6 R 7 ) v Heteroaryl-NR 4 R 5 , —(CR 6 R 7 ) v Heterocyclyl-NR 4 R 5 , —(CR 6 R 7 ) v Heteroaryl-N(R 4 )C(═NR 5 )NR 4 R 5 , —(CR 6 R 7 ) v Heterocyclyl-N(R 4 )C(═NR 5 )NR 4 R 5 , —(CR 6 R 7 ) v Heterocyclyl, —O-Heteroaryl, —O-Heterocyclyl, —NR 4 (CR 6 R 7 ) v Heteroaryl, —NR 4 (CR 6 R 7 ) v Heterocyclyl, —O(CR 6 R 7 ) v Heteroaryl, —O(CR 6 R 7 ) v Heterocyclyl, —NR 4 (CR 6 R 7 ) v NR 5 -Heteroaryl, —NR 4 (CR 6 R 7 ) v NR 5 -Heterocyclyl, —O(CR 6 R 7 ) v NR 5 -Heteroaryl, —O(CR 6 R 7 ) v NR 5 -Heterocyclyl, —O(CR 6 R 7 ) v O-Heterocyclyl, —NR 4 R 5 R 9+ Q − , —(CR 6 R 7 ) v NR 4 R 5 R 9+ Q − , —NR 4 (CR 6 R 7 ) v NR 4 R 5 R 9+ Q − , —NR 4 R 9+ (CR 6 R 7 ) v NR 4 R 5 R 9+ Q − 2 , —(CR 6 R 7 ) v (T) + Q − , and —O(CR 6 R 7 ) v NR 4 R 5 R 9+ Q − ;
wherein:
T is pyridin-1-yl, pyrimidin-1-yl, or thiazol-3-yl;
Q is a pharmaceutically acceptable counterion;
each R 6 and R 7 are independently selected from the group consisting of hydrogen, fluoro, chloro, bromo, optionally substituted C 1 -C 6 alkyl, optionally substituted alkoxyalkyl, optionally substituted hydroxyalkyl, optionally substituted C 3 -C 6 cycloalkyl, —OH, —OR 10 , —SR 10 , —NR 4 R 5 , —NR 4 C(O)R 5 , —C(O)NR 4 R 5 , —NR 4 SO 2 R 5 , optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;
or R 6 and R 7 taken together form an oxo, oxime, or an optionally substituted carbocycle or an optionally substituted heterocycle with the carbon to which they are attached;
R 9 is optionally substituted C 1 -C 6 alkyl; 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; or

each Y, in the case where Y is attached directly to a heteroatom of HetA, is selected from the group consisting of:
—(CR 6 R 7 ) v NR 4 R 5 , —S(O) 1,2 (CR 6 R 7 ) v NR 4 R 5 , —C(O) (CR 6 R 7 ) v NR 4 R 5 , —(CR 6 R 7 ) w N(R 4 )C(O)(CR 6 R 7 ) v NR 4 R 5 , —(CR 6 R 7 ) w NR 4 (CR 6 R 7 ) w NR 4 R 5 , —NR 4 (CR 6 R 7 ) w OR 10 , —(CR 6 R 7 ) w S(O) 0,1,2 R 10 , —C(O)NR 4 (CR 6 R 7 ) w NR 4 R 5 , —S(O) 1,2 NR 4 (CR 6 R 7 ) w NR 4 R 5 , —C(═NR 7 )NR 4 (CR 6 R 7 ) v NR 4 R 5 , —C(═NR 5 )R 6 , —(CR 6 R 7 ) w N(R 4 )C(═NR 5 )R 6 , —S(O) 1,2 (CR 6 R 7 ) v N(R 4 )C(═NR 5 )R 6 , —(CR 6 R 7 ) v C(═NR 5 )NR 4 R 5 , —(CR 6 R 7 ) w C(═NR 5 )NR 4 R 5 , —S(O) 1,2 (CR 6 R 7 ) v C(═NR 5 )NR 4 R 5 , —(CR 6 R 7 ) w N(R 4 )C(═NR 5 )NR 4 R 5 , —S(O) 1,2 (CR 6 R 7 ) v N(R 4 )C(═NR 5 )NR 4 R 5 , —C(═NR 5 )NR 4 C(═NR 5 )NR 4 R 5 , —(CR 6 R 7 ) v C(═NR 4 )NR 5 C(═NR 4 )NR 4 R 5 , —S(O) 1,2 —(CR 6 R 7 ) v C(═NR 4 )NR 5 C(═NR 4 )NR 4 R 5 , —C(═NR 4 )NR 4 R 5 , —C(═NR 4 )NR 4 C(O)R 6 , —SO 2 R 6 , —C(O)R 6 , —C(═O)OR 6 , —C(O)NR 4 R 5 , —(CR 6 R 7 ) v C(O)NR 4 R 5 , —SO 2 NR 4 R 5 , -aryl, -heteroaryl, —C(O)N(R 4 )—Heteroaryl-NR 4 R 5 , -Heteroaryl-NR 4 R 5 , -Heterocyclyl-NR 4 R 5 , -Heteroaryl-N(R 4 )C(═NR 5 )NR 4 R 5 , -Heterocyclyl-N(R 4 )C(═NR 5 )NR 4 R 5 , -Heteroaryl-NR 4 R 5 , -Heterocyclyl-NR 4 R 5 , —(CR 6 R 7 ) v Heteroaryl-NR 4 R 5 , —(CR 6 R 7 ) v Heterocyclyl-NR 4 R 5 , —(CR 6 R 7 ) v Heteroaryl-N(R 4 )C(═NR 5 )NR 4 R 5 , —(CR 6 R 7 ) v Heterocyclyl-N(R 4 )C(═NR 5 )NR 4 R 5 , —(CR 6 R 7 ) v Heteroaryl, —(CR 6 R 7 ) v Heterocyclyl, —(CR 6 R 7 ) v NR 5 -Heteroaryl, —(CR 6 R 7 ) v NR 5 -Heterocyclyl, —(CR 6 R 7 ) v O-Heterocyclyl, —R 9+ Q − , —(CR 6 R 7 ) w NR 4 R 5 R 9+ Q − , —R 9+ (CR 6 R 7 ) v NR 4 R 5 R 9+ Q − 2 and —(CR 6 R 7 ) v (T) + Q;
wherein:
T is pyridin-1-yl, pyrimidin-1-yl, or thiazol-3-yl;
Q is a pharmaceutically acceptable counterion;
each R 6 and R 7 are independently selected from the group consisting of hydrogen,

Assignees

• Venatorx Pharmaceuticals Inc

Inventors

• Burns Christopher J
• Daigle Denis
• Liu Bin
• Mcgarry Daniel
• Pevear Daniel C
• Trout Robert E Lee

Classifications

• A61K45/06 Primary

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

• C07F5/025 Primary

  Boronic and borinic acid compounds · CPC title

• A61K31/69

  Boron compounds · CPC title

• Y02A50/30

  Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change · CPC title