TRNA synthetase inhibitors

Patent metadata

Field	Value
Publication number	US-11261201-B2
Application number	US-201916961516-A
Country	US
Kind code	B2
Filing date	Jan 11, 2019
Priority date	Jan 12, 2018
Publication date	Mar 1, 2022
Grant date	Mar 1, 2022

Abstract

Disclosed herein are secondary amine compounds that inhibit tRNA synthetase. The compounds of the invention are useful in inhibiting tRNA synthetase in Gram-negative bacteria and are useful in killing Gram-negative bacteria. The secondary amine compounds of the invention are also useful in the treatment of tuberculosis.

First claim

What is claimed is:

1. A compound having the structure of formula (II′):

or a pharmaceutically acceptable salt thereof;
wherein:
X is O or S;
each of R 10 , R 11 , R 12 , and R 13 is independently selected from H, OH, —NH 2 , halide, sulfonamido, (C 1 -C 6 )alkylsulfonyl, —OC(O)((C 1 -C 8 )alkyl), —C(O)O((C 1 -C 8 )alkyl), —C(O)OH, optionally substituted —NHC(O)(aryl), —C(O)NH 2 , —B(OH) 2 , tri((C 1 -C 8 )alkyl)silyl, optionally substituted (C 1 -C 8 )alkyl, optionally substituted (C 1 -C 8 )alkoxy, optionally substituted (C 1 -C 8 )aminoalkyl, optionally substituted (C 1 -C 8 )hydroxyalkyl, optionally substituted (C 1 -C 8 )haloalkyl, optionally substituted (C 1 -C 8 )haloalkoxy, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aryloxy, optionally substituted arylalkoxy, optionally substituted heteroaryloxy, optionally substituted heteroarylalkoxy, optionally substituted (C 3 -C 10 )cycloalkyl, optionally substituted (C 3 -C 10 )cycloalkoxy, optionally substituted (C 2 -C 9 )heterocycloalkyl, optionally substituted (C 2 -C 9 )heterocycloalkoxy, (H 3 CSO 2 )(C 1 -C 8 )alkylene, (H 2 NSO 2 )(C 1 -C 8 )alkylene, optionally substituted di((C 1 -C 8 )alkyl)amino;
or R 10 and R 11 , R 11 and R 12 , or R 12 and R 13 , taken together with the intervening atoms, form an aryl, heteroaryl, cycloalkyl, or heterocycloalkyl group;
R 14 is H or (C 1 -C 6 )alkyl;
R 15 is optionally substituted (C 3 -C 10 )cycloalkyl or (C 3 -C 10 )cycloalkenyl;

represents a heterocyclic group substituted by oxo (═O) and optionally substituted by one or more additional substituents; and
n is an integer from 1-3.

2. The compound of claim 1 , wherein R 15 is optionally substituted cyclohexyl or cyclohexenyl.

3. The compound of claim 1 , wherein

represents a heterocyclic group substituted by oxo (═O) and optionally substituted by one or more additional substituents; and wherein the heterocyclic group substituted by oxo (═O) and optionally substituted by one or more additional substituents is optionally substituted oxazolidinone.

4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, selected from the following table:

5. A compound having the structure of formula (III′):

or a pharmaceutically acceptable salt thereof;
wherein:
each of R 40 , R 41 , R 42 , and R 43 is independently selected from H, OH, —NH 2 , halide, sulfonamido, (C 1 -C 6 )alkylsulfonyl, —OC(O)((C 1 -C 8 )alkyl), —C(O)O((C 1 -C 8 )alkyl), —C(O)OH, optionally substituted —NHC(O)(aryl), —C(O)NH 2 , —B(OH) 2 , tri((C 1 -C 8 )alkyl)silyl, optionally substituted (C 1 -C 8 )alkyl, optionally substituted (C 1 -C 8 )alkoxy, optionally substituted (C 1 -C 8 )aminoalkyl, optionally substituted (C 1 -C 8 )hydroxyalkyl, optionally substituted (C 1 -C 8 )haloalkyl, optionally substituted (C 1 -C 8 )haloalkoxy, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aryloxy, optionally substituted arylalkoxy, optionally substituted heteroaryloxy, optionally substituted heteroarylalkoxy, optionally substituted (C 3 -C 10 )cycloalkyl, optionally substituted (C 3 -C 10 )cycloalkoxy, optionally substituted (C 2 -C 9 )heterocycloalkyl, optionally substituted (C 2 -C 9 )heterocycloalkoxy, (H 3 CSO 2 )(C 1 -C 8 )alkylene, (H 2 NSO 2 )(C 1 -C 8 )alkylene, optionally substituted di((C 1 -C 8 )alkyl)amino;
or R 40 and R 41 , R 41 and R 42 , or R 42 and R 43 , taken together with the intervening atoms, form an aryl, hetero

Assignees

• Harvard College

Inventors

• Kahne Daniel E
• Baidin Vadim

Classifications

• A61K45/06 Primary

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

• C07C211/49

  having at least two amino groups bound to the carbon skeleton · CPC title

• C07C225/12

  with doubly-bound oxygen atoms bound to carbon atoms being part of rings · CPC title

• C07C215/42

  having amino groups or hydroxy groups bound to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton · CPC title

• C07C2602/20

  the ring system containing seven carbon atoms · CPC title