US 2021/0346364 A1 · OXAZOLIDINONES AS TARO INHIBITORS

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.

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 Ra;
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 Rb1 and 0-1 substituents selected from Rb2;
X is —CR8R9;
Y is selected from the group consisting of:
(1) NR3, and
(2) —CR10R11;
R1 is selected from the group consisting of:
(1) —C1-6alkyl, and
(2) —(CH2)p—OH,
wherein CH2 and alkyl are unsubstituted or substituted with 1-2 substituents selected from:
halogen, —C1-6alkyl, and —OC1-6alkyl;
R2 is selected from the group consisting of:
(1) hydrogen, and
(2) —C1-6alkyl,
wherein alkyl is unsubstituted or substituted with 1-2 substituents selected from:
halogen, —C1-6 alkyl, and —OC1-6alkyl, or R1 and R2 together with the carbon atom they are attached to form a C3-6cycloalkyl ring, wherein the cycloalkyl ring is unsubstituted or substituted with 1-2 substituents selected from:
halogen, —C1-6alkyl, and —OC1-6alkyl;
R3 is selected from the group consisting of:
(1) hydrogen, and
(2) —C1-6alkyl,
wherein alkyl is unsubstituted or substituted with one to five substituents selected from —C1-6 alkyl;
each R4 is independently selected from the group consisting of:
(1) hydrogen,
(2) halogen,
(3) —C1-6alkyl, and
(4) —(CH2)p—OH,
wherein CH2 and alkyl are unsubstituted or substituted with 1-2 substituents selected from:
halogen, —C1-6alkyl, and —OC1-6alkyl;
each R5 is independently selected from the group consisting of:
(1) hydrogen,
(2) halogen,
(3) —C1-6alkyl, and
(4) —(CH2)p—OH,
wherein CH2 and alkyl are unsubstituted or substituted with 1-2 substituents selected from:
halogen, —C1-6alkyl, and —OC1-6alkyl;
R6 is selected from the group consisting of:
(1) hydrogen,
(2) —C1-6alkyl, and
(3) —(CH2)p—OH,
wherein CH2 and alkyl are unsubstituted or substituted with 1-2 substituents selected from:
halogen, —C1-6alkyl, and —OC1-6alkyl;
R8 is selected from the group consisting of:
(1) hydrogen, and
(2) —C1-6alkyl,
wherein alkyl is unsubstituted or substituted with 1-2 substituents selected from:
halogen, C1-6 alkyl, and —OC1-6alkyl;
R9 is selected from the group consisting of:
(1) hydrogen, and
(2) —C1-6alkyl,
wherein alkyl is unsubstituted or substituted with 1-2 substituents selected from:
halogen, —C1-6 alkyl, and —OC1-6alkyl;
R10 is selected from the group consisting of:
(1) hydrogen,
(2) —C1-6alkyl, and
(3) —(CH2)p—OH,
wherein CH2 and alkyl are unsubstituted or substituted with 1-2 substituents selected from:
halogen, —C1-6alkyl, and —OC1-6alkyl;
R11 is selected from the group consisting of:
(1) hydrogen,
(2) —C1-6alkyl, and
(3) —(CH2)p—OH,
wherein CH2 and alkyl are unsubstituted or substituted with 1-2 substituents selected from:
halogen, —C1-6alkyl, and —OC1-6alkyl;
each Ra is independently selected from the group consisting of:
(1) halogen,
(2) —C1-6alkyl,
(3) —OC1-6alkyl,
(4) —OC2-6alkenyl,
(5) —OH,
(6) oxo,
(7) —CN,
(8) —NO2,
(9) —NRcRd,
(10) —CH2NRcRd,
(11) —SO2C1-6alkyl,
(12) —C3-6cycloalkyl,
(13) —C2-6cycloheteroalkyl,
(14) aryl, and
(15) heteroaryl,
wherein —CH2, alkyl, alkenyl, cycloalkyl, cycloheteroalkyl, aryl and heteroaryl are unsubstituted or substituted with 1-4 substituents selected from:
halogen, —C1-6alkyl, —OC1-6alkyl, and —CO2C1-6alkyl;
each Rb1 is independently selected from the group consisting of:
(1) halogen,
(2) —C1-6alkyl,
(3) —C2-6alkenyl,
(4) —CN,
(5) —NO2,
(6) —NRcRd,
(7) —SO2C1-6alkyl,
(8) —C3-6cycloalkyl,
(9) —C2-6cycloheteroalkyl,
(10) aryl, and
(11) heteroaryl,
wherein alkyl, alkenyl, cycloalkyl, cycloheteroalkyl, aryl and heteroaryl are unsubstituted or substituted with 1-4 substituents selected from:
halogen, —C1-6alkyl, —OC1-6alkyl, and —CO2C1-6alkyl;
each Rb2 is independently selected from the group consisting of:
(1) —OC1-6alkyl,
(2) —OC2-6alkenyl,
(3) —OH,
(4) oxo,
wherein alkyl, alkenyl are unsubstituted or substituted with 1-4 substituents selected from:
halogen, —C1-6alkyl, —OC1-6alkyl, and —CO2C1-6alkyl;
each Rc is independently selected from the group consisting of:
(1) hydrogen,
(2) C1-6alkyl,
(3) C2-6alkenyl,
(4) C1-6alkyl-OH,
(5) C3-6cycloalkyl,
(6) C(O)C1-6alkyl, and
(7) SO2C1-6alkyl,
wherein alkyl, alkenyl and cycloalkyl are unsubstituted or substituted with one to three substituents selected from halogen, —C1-6alkyl, —OC1-6alkyl, and —CO2C1-6alkyl;
each Rd is independently selected from the group consisting of:
(1) hydrogen,
(2) C1-6alkyl,
(3) C2-6alkenyl,
(4) C1-6alkyl-OH,
(5) C3-6cycloalkyl,
(6) C(O)C1-6alkyl, and
(7) SO2C1-6alkyl,
wherein alkyl, alkenyl and cycloalkyl are unsubstituted or substituted with one to three substituents selected from halogen, —C1-6alkyl, —OC1-6alkyl, and —CO2C1-6alkyl, or Rc and Rd together with the nitrogen atom they are attached to form a C4-8cycloheteroalkyl ring, wherein the C4-8cycloheteroalkyl ring is unsubstituted or substituted with 1-4 substituents selected from halogen, —C1-6alkyl, —OC1-6alkyl, and —CO2C1-6alkyl;
m is 0 or 1;
n is 0, 1, 2 or 3;
and
p is 0, 1, 2, 3, 4, 5 or 6.

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Oxazolidinones as taro inhibitors

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Oxazolidinones as taro inhibitors

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Abstract

Claims14