Substituted thienopyridone compounds with antibacterial activity
Novel bicyclic heteroaromatic compounds are provided that are inhibitors of bacterial methionyl tRNA synthetase (MetRS). Compounds of the invention generally have a left hand side chroman group or left hand side tetrahydroquinoline group and a right hand side thienopyridone group. Also disclosed are methods for their preparation and their use in therapy as antibacterial agents, particularly as anti- Clostridium difficile agents.
1. A compound of formula (I):
in which:
R 1 is selected from halo, cyano, hydroxyl, (C 1-6 )alkyl (optionally substituted by halo, hydroxyl, amino, mono to perfluoro(C 1-3 )alkyl, carboxy, or (C 1-6 )alkoxycarbonyl), (C 3-7 )cycloalkyl, (C 1-6 )alkoxy, amino, mono- or di-(C 1-6 )alkylamino, acylamino, carboxy, (C 1-6 )alkoxycarbonyl, carboxy(C 1-6 )alkyloxy, (C 1-6 )alkylthio, (C 1-6 )alkylsulphinyl, (C 1-6 )alkylsulphonyl, sulphamoyl, mono- and di(C 1-6 )alkylsulphamoyl, carbamoyl, mono- and di-(C 1-6 )alkylcarbamoyl, and heterocyclyl;
Y is a linker group having from one to six methylene groups in a straight chain and in which one or more methylene groups may have one or more (C 1-6 ) alkyl, (C 1-6 )alkoxy or (C 1-6 )alkylidenyl substituents;
R 2 is selected from halo, cyano, hydroxyl, (C 1-6 )alkyl (optionally substituted by halo, hydroxyl, amino, mono to perfluoro(C 1-3 )alkyl, carboxy, or (C 1-6 )alkoxycarbonyl), (C 3-7 )cycloalkyl, (C 1-6 )alkoxy, amino, mono- or di-(C 1-6 )alkylamino, acylamino, carboxy, (C 1-6 )alkoxycarbonyl, carboxy(C 1-6 )alkyloxy, (C 1-6 )alkylthio, (C 1-6 )alkylsulphinyl, (C 1-6 )alkylsulphonyl, sulphamoyl, mono- and di(C 1-6 )alkylsulphamoyl, carbamoyl, mono- and di-(C 1-6 )alkylcarbamoyl, and heterocyclyl;
when Z 1 is S, Z 2 and Z 3 are CH; when Z 2 is S, Z 1 and Z 3 are CH; when Z 3 is S, Z 1 and Z 2 are CH;
X is NH, S, SO, SO 2 ,O or CH 2 ;
n is one, two or three; and
m is 0 or an integer from 1 to 4.
2. A compound of claim 1 having a formula (II):
in which:
R 3 and R 4 can be the same or a different substituent and are selected from halo, cyano, hydroxyl, (C 1-6 )alkyl (optionally substituted by halo, hydroxyl, amino, mono to perfluoro(C 1-3 )alkyl, carboxy, or (C 1-6 )alkoxycarbonyl), (C 3-7 )cycloalkyl, (C 1-6 )alkoxy, amino, mono- or di-(C 1-6 )alkylamino, acylamino, carboxy, (C 1-6 )alkoxycarbonyl, carboxy(C 1-6 )alkyloxy, (C 1-6 )alkylthio, (C 1-6 )alkylsulphinyl, (C 1-6 )alkylsulphonyl, sulphamoyl, mono- and di(C 1-6 )alkylsulphamoyl, carbamoyl, mono- and di-(C 1-6 )alkylcarbamoyl, and heterocyclyl.
3. A compound of claim 1 having a formula (III):
in which:
R 3 and R 4 can be the same or a different substituent and are selected from halo, cyano, hydroxyl, (C 1-6 )alkyl (optionally substituted by halo, hydroxyl, amino, mono to perfluoro(C 1-3 )alkyl, carboxy, or (C 1-6 )alkoxycarbonyl), (C 3-7 )cycloalkyl, (C 1-6 )alkoxy, amino, mono- or di-(C 1-6 )alkylamino, acylamino, carboxy, (C 1-6 )alkoxycarbonyl, carboxy(C 1-6 )alkyloxy, (C 1-6 )alkylthio, (C 1-6 )alkylsulphinyl, (C 1-6 )alkylsulphonyl, sulphamoyl, mono- and di(C 1-6 )alkylsulphamoyl, carbamoyl, mono- and di-(C 1-6 )alkylcarbamoyl, and heterocyclyl.
4. The salt of the compound of claim 1 , wherein the salt is a pharmaceutically acceptable salt.
5. A compound of formula (I) as claimed in claim 1 selected from:
5-[3-(6,8-Dibromo-1,2,3,4-tetrahydro-quinolin-4-ylamino)-propylamino]-4H-thieno[3,2-b]pyridin-7-one;
5-[3-(6,8-Dibromo-chroman-4-ylamino)-propylamino]-4H-thieno[3,2-b]pyridin-7-one;
5-[3-(8-Bromo-6-chloro-chroman-4-ylamino)-propylamino]-4H-thieno[3,2-b]pyridin-7-one;
5-[3-(6-Chloro-8-iodo-chroman-4-ylamino)-propylamino]-4H-thieno[3,2-b]pyridin-7-one;
5-[3-(6-Bromo-8-chloro-chroman-4-ylamino)-propylamino]-4H-thieno[3,2-b]pyridin-7-one;
5-[3-(6-Bromo-8-chloro-1,2,3,4-tetrahydro-quinolin-4-ylamino)-propylamino]-4H-thieno[3,2-b]pyridin-7-one;
5-[3-(8-Bromo-6-chloro-1,2,3,4-tetrahydro-quinolin-4-ylamino)-propylamino]-4H-thieno[3,2-b]pyridin-7-one;
5-[3-(8-Bromo-6-methylsulfanyl-chroman-4-ylamino)-propylamino]-4H-thieno[3,2-b]pyridin-7-one; and
5-[3-(6-Bromo-8-fluoro-1,2,3,4-tetrahydro-quinolin-4-ylamino)-propylamino]-4H-thieno[3,2-b]pyridin-7-one.
6. A pharmaceutical composition comprising an antibacterially effective amount of a compound according to claim 1 together with a pharmaceutically accepted carrier or excipient.