Oxazolidinones as TarO inhibitors

Patent metadata

Field	Value
Publication number	US-11738010-B2
Application number	US-202117385258-A
Country	US
Kind code	B2
Filing date	Jul 26, 2021
Priority date	Dec 16, 2015
Publication date	Aug 29, 2023
Grant date	Aug 29, 2023

Abstract

Novel compounds of the structural formula I, and the pharmaceutically acceptable salts thereof, are inhibitors of TarO and may be useful in the prevention, treatment and suppression of diseases mediated by TarO, such as bacterial infections, including gram negative bacterial infections and gram positive bacterial infections such as MRSA and MRSE, alone or in combination with a β-lactam antibiotic.

First claim

What is claimed is:

1. A method of treating a methicillin-resistant S. aureus infection or a methicillin-resistant S. epidermidis infection in a patient by administering to a patient in need thereof a synergistic combination of a beta-lactam antibiotic, wherein the beta-lactam antibiotic is cephalexin, imipenem, or dicloxacillin; a pharmaceutically acceptable carrier; and a compound of structural formula I:

or a pharmaceutically acceptable salt thereof; wherein
A is selected from the group consisting of:
(1) aryl,
(2) heteroaryl,
(3) —O-aryl, and
(4) —O-heteroaryl,

wherein aryl and heteroaryl are unsubstituted or substituted with 1-5 substituents selected from R a ;
B is selected from the group consisting of:
(1) aryl, and
(2) heteroaryl,

wherein aryl and heteroaryl are substituted, and wherein aryl and heteroaryl are substituted with 0-4 substituents selected from R b1 and 0-1 substituents selected from R b2 ;
X is —CR 8 R 9 ;
Y is selected from the group consisting of:
(1) NR 3 , and
(2) —CR 10 R 11 ;

R 1 is selected from the group consisting of:
(1) —C 1-6 alkyl, and
(2) —(CH 2 ) p —OH,

wherein CH 2 and alkyl are unsubstituted or substituted with 1-2 substituents selected from: halogen, —C 1-6 alkyl, and —OC 1-6 alkyl;
R 2 is selected from the group consisting of:
(1) hydrogen, and
(2) —C 1-6 alkyl,

wherein alkyl is unsubstituted or substituted with 1-2 substituents selected from: halogen, —C 1-6 alkyl, and —OC 1-6 alkyl, or R 1 and R 2 together with the carbon atom they are attached to form a C 3-6 cycloalkyl ring, wherein the cycloalkyl ring is unsubstituted or substituted with 1-2 substituents selected from: halogen, —C 1-6 alkyl, and —OC 1-6 alkyl;
R 3 is selected from the group consisting of:
(1) hydrogen, and
(2) —C 1-6 alkyl,
wherein alkyl is unsubstituted or substituted with one to five substituents selected from —C 1-6 alkyl;
each R 4 is independently selected from the group consisting of:
(1) hydrogen,
(2) halogen,
(3) —C 1-6 alkyl, and
(4) —(CH 2 ) p —OH,

wherein CH 2 and alkyl are unsubstituted or substituted with 1-2 substituents selected from: halogen, —C 1-6 alkyl, and —OC 1-6 alkyl;
each R 5 is independently selected from the group consisting of:
(1) hydrogen,
(2) halogen,
(3) —C 1-6 alkyl, and
(4) —(CH 2 ) p —OH,

wherein CH 2 and alkyl are unsubstituted or substituted with 1-2 substituents selected from: halogen, —C 1-6 alkyl, and —OC 1-6 alkyl;
R 6 is selected from the group consisting of:
(1) hydrogen,
(2) —C 1-6 alkyl, and
(3) —(CH 2 ) p —OH,

wherein CH 2 and alkyl are unsubstituted or substituted with 1-2 substituents selected from: halogen, —C 1-6 alkyl, and —OC 1-6 alkyl;
R 8 is selected from the group consisting of:
(1) hydrogen, and
(2) —C 1-6 alkyl,

wherein alkyl is unsubstituted or substituted with 1-2 substituents selected from: halogen, C 1-6 alkyl, and —OC 1-6 alkyl;
R 9 is selected from the group consisting of:
(1) hydrogen, and
(2) —C 1-6 alkyl,

wherein alkyl is unsubstituted or substituted with 1-2 substituents selected from: halogen, —C 1-6 alkyl, and —OC 1-6 alkyl;
R 10 is selected from the group consisting of:
(1) hydrogen,
(2) —C 1-6 alkyl, and
(3) —(CH 2 ) p —OH,

wherein CH 2 and alkyl are unsubstituted or substituted with 1-2 substituents selected from: halogen, —C 1-6 alkyl, and —OC 1-6 alkyl;
R 11 is selected from the group consisting of:
(1) hydrogen,
(2) —C 1-6 alkyl, and
(3) —(CH 2 ) p —OH,

wherein CH 2 and alkyl are unsubstituted or substituted with 1-2 substituents selected from: halogen, —C 1-6 alkyl, and —OC 1-6 alkyl;
each R a is independently selected from the group consisting of:
(1) halogen,
(2) —C 1-6 alkyl,
(3) —OC 1-6 alkyl,
(4) —OC 2-6 alkenyl,
(5) —OH,
(6) oxo,
(7) —CN,
(8) —NO 2 ,
(9) —NR c R d ,
(10) —CH 2 NR c R d ,
(11) —SO 2 C 1-6 alkyl,
(12) —C 3-6 cycloalkyl,
(13) —C 2-6 cycloheteroalkyl,
(14) aryl, and
(15) heteroaryl,

wherein —CH 2 , alkyl, alkenyl, cycloalkyl, cycloheteroalkyl, aryl and heteroaryl are unsubstituted or substituted with 1-4 substituents selected from: halogen, —C 1-6 alkyl, —OC 1-6 alkyl, and —CO 2 C 1-6 alkyl;
each R b1 is independently selected from the group consisting of:
(1) halogen,
(2) —C 1-6 alkyl,
(3) —C 2-6 alkenyl,
(4) —CN,
(5) —NO 2 ,
(6) —NR c R d ,
(7) —SO 2 C 1-6 alkyl,
(8) —C 3-6 cycloalkyl,
(9) —C 2-6 cycloheteroalkyl,
(10) aryl, and
(11) heteroaryl,

wherein alkyl, alkenyl, cycloalkyl, cycloheteroalkyl, aryl and heteroaryl are unsubstituted or substituted with 1-4 substituents selected from: halogen, —C 1-6 alkyl, —OC 1-6 alkyl, and —CO 2 C 1-6 alkyl;
each R b2 is independently selected from the group consisting of:
(1) —OC 1-6 alkyl,
(2) —OC 2-6 alkenyl,
(3) —OH,
(4) oxo,

wherein alkyl, alkenyl are unsubstituted or substituted with 1-4 substituents selected from: halogen, —C 1-6 alkyl, —OC 1-6 alkyl, and —CO 2 C 1-6 alkyl;
each R c is independently selected from the group consisting of:
(1) hydrogen,
(2) C 1-6 alkyl,
(3) C 2-6 alkenyl,
(4) C 1-6 alkyl-OH,
(5) C 3-6 cycloalkyl,
(6) C(O)C 1-6 alkyl, and
(7) SO 2 C 1-6 alkyl,

wherein alkyl, alkenyl and cycloalkyl are unsubstituted or substituted with one to three substituents selected from halogen, —C 1-6 alkyl, —OC 1-6 alkyl, and —CO 2 C 1-6 alkyl;
each R d is independently selected from the group consisting of:
(1) hydrogen,
(2) C 1-6 alkyl,
(3) C 2-6 alkenyl,
(4) C 1-6 alkyl-OH,
(5) C 3-6 cycloalkyl,
(6) C(O)C 1-6 alkyl, and
(7) SO 2 C 1-6 alkyl,

wherein alkyl, alkenyl and cycloalkyl are unsubstituted or substituted with one to three substituents selected from halogen, —C 1-6 alkyl, —OC 1-6 alkyl, and —CO 2 C 1-6 alkyl,
or R c and R d together with the nitrogen atom they are attached to form a C 4-8 cycloheteroalkyl ring, wherein the C 4-8 cycloheteroalkyl ring is unsubstituted or substituted with 1-4 substituents selected from halogen, —C 1-6 alkyl, —OC 1-6 alkyl, and —CO 2 C 1-6 alkyl;
m is 0 or 1;
n is 0, 1, 2 or 3; and
p is 0, 1, 2, 3, 4, 5 or 6.

2. The method according to claim 1 , wherein the compound of structural formula I is

or pharmaceutically acceptable salts thereof.

3. The method according to claim 1 , wherein A is selected from the group consisting of:
(1) aryl,
(2) heteroaryl, and
(3) —O-aryl,
wherein aryl and heteroaryl are unsubstituted or substituted with 1-5 substituents selected from R a ; or a pharmaceutically acceptable salt thereof.

4. The method according to claim 1 , wherein A is selected from the group consisting of:
(1) aryl, and
(2) heteroaryl,

wherein aryl and heteroaryl are unsubstituted or substituted with 1-5 substituents selected from R a ; or a pharmaceutically acceptable salt thereof.

5. The method according to claim 1 , wherein B is aryl, wherein aryl is unsubstitute

Assignees

• Merck Sharp & Dohme

Inventors

• Caldwell John P
• De Jesus Reynalda
• Ding Fa-Xiang
• Gill Charles J
• Ho Ginny Dai
• Ha Sookhee N
• Koseoglu Sandra J
• Labroli Marc A
• Lee Sang Ho
• Madsen-Duggan Christina
• Mandal Mihir
• Roemer Terry
• Su Jing
• Tan Christopher Michael
• Tan Zheng
• Tang Haifeng
• Wang Hao
• Yang Christine
• Yang Shu-Wei

Classifications

• A61K31/4439 Primary

  containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole (nicotine A61K31/465) · CPC title

• A61K31/407

  condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine · CPC title

• A61K31/421

  1,3-Oxazoles, e.g. pemoline, trimethadione · CPC title

• A61K31/422

  not condensed and containing further heterocyclic rings · CPC title

• A61K31/427

  not condensed and containing further heterocyclic rings · CPC title