Naphthyridin-2 (1 H)-one compounds useful as antibacterials
Compounds of Formula (I), wherein substituents R 1 , R 2 and R 5 are as defined, and Ar represents substituted phenyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, furanyl, imidazolyl and thiophenyl substituted by a hydroxyalkyl substituent and an optional other substituent; compositions containing them, their use in therapy, including their use as antibacterials, for example in the treatment of tuberculosis, and methods for the preparation of such compounds, are provided.
1. A compound of Formula (I) or a pharmaceutically acceptable salt thereof:
wherein in Formula (I):
R 1 represents hydrogen; halo; or C 1-3 alkoxy-;
R 2 represents hydrogen or hydroxy;
Ar represents a group selected from: phenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, furanyl, imidazolyl and thiophenyl;
wherein
Ar is substituted by a first substituent R 3 , wherein R 3 represents C 1-5 hydroxyalkyl;
Ar is optionally substituted by a second substituent R 4 selected from halo, CF 3 , C 1-3 alkyl, nitro and C 1-3 alkoxy-;
and if R 2 is hydrogen then R 5 is hydrogen or C 1-3 alkyl, and if R 2 is hydroxyl then R 5 is hydrogen.
2. A compound of Formula (I) or a pharmaceutically acceptable salt thereof as claimed in claim 1 wherein Ar represents a group selected from: phenyl, pyridazinyl, pyridiminyl,
pyrazinyl, thiazolyl, furanyl and thiophenyl.
3. A compound of Formula (I) or a pharmaceutically acceptable salt thereof as claimed in claim 1 wherein Ar is pyridinyl.
4. A compound of Formula (I) or a pharmaceutically acceptable salt thereof as claimed in claim 3 wherein Ar is a 3-pyridinyl substituent and the C 1-5 hydroxyalkyl substituent R 3 is in the 6-position relative to the ring nitrogen.
5. A compound of Formula (I) or a pharmaceutically acceptable salt thereof as claimed in claim 1 wherein the C 1-5 hydroxyalkyl substituent R 3 is hydroxymethyl.
6. A compound of Formula (I) or a pharmaceutically acceptable salt thereof as claimed in claim 1 wherein the substituent R 4 is present and is halo.
7. A compound of Formula (I) or a pharmaceutically acceptable salt thereof as claimed in claim 6 wherein R 4 is present and is chloro.
8. A compound of Formula (I) or a pharmaceutically acceptable salt thereof according to claim 5 , wherein Ar is 5-chloro-6-(hydroxymethyl)-3-pyridinyl.
9. A compound of Formula (I) or a pharmaceutically acceptable salt thereof as claimed in claim 1 wherein R 2 represents hydroxy, and the absolute stereochemistry of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is:
10. A compound of Formula (I) or a pharmaceutically acceptable salt thereof as claimed in claim 1 selected from:
1-{2-[4-({[5-chloro-6-(hydroxymethyl)-3-pyridinyl]methyl}amino)-1-piperidinyl]ethyl}-7-fluoro-1,5-naphthyridin-2(1H)-one;
1-{2-[4-({[5-chloro-6-(hydroxymethyl)-3-pyridinyl]methyl}amino)-1-piperidinyl]ethyl}-7-fluoro-1,5-naphthyridin-2(1H)-one hydrochloride;
1-{2-[(3R,4S)-4-({[5-chloro-6-(hydroxymethyl)-3-pyridinyl]methyl}amino)-3-hydroxy-1-piperidinyl]ethyl}-7-fluoro-1,5-naphthyridin-2(1H)-one;
1-{2-[(3R,4S)-4-({[5-chloro-6-(hydroxymethyl)-3-pyridinyl]methyl}amino)-3-hydroxy-1-piperidinyl]ethyl}-7-fluoro-1,5-naphthyridin-2(1H)-one hydrochloride;
1-{2-[4-({[5-chloro-6-(hydroxymethyl)-3-pyridinyl]methyl}amino)-1-piperidinyl]ethyl}-7-(methyloxy)-1,5-naphthyridin-2(1H)-one;
1-{2-[4-({[5-bromo-6-(hydroxymethyl)-3-pyridinyl]methyl}amino)-1-piperidinyl]ethyl}-7-fluoro-1,5-naphthyridin-2(1H)-one;
1-{2-[(3R,4S)-4-({[5-chloro-6-(hydroxymethyl)-3-pyridinyl]methyl}amino)-3-hydroxy-1-piperidinyl]ethyl}-7-(methyloxy)-1,5-naphthyridin-2(1H)-one;
and
1-{2-[(3R,4S)-4-({[5-chloro-6-(hydroxymethyl)-3-pyridinyl]methyl}amino)-3-hydroxy-1-piperidinyl]ethyl}-7-(methyloxy)-1,5-naphthyridin-2(1H)-one hydrochloride.
11. A pharmaceutical composition comprising a) a compound of Formula (I) or a pharmaceutically acceptable salt thereof as claimed in claim 1 , and b) one or more pharmaceutically acceptable carriers, excipients or diluents.
12. A method of treatment of tuberculosis in a mammal which method comprises the administration to a mammal in need of such treatment an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof as claimed in claim 1 .
13. A method of treatment of bacterial infections in a mammal which method comprises the administration to a mammal in need of such treatment an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof as claimed in claim 1 .
14. A process for the preparation of a compound of Formula (I)according to claim 1 , by a reaction between a compound of Formula (II), wherein R 1 , R 2 and R 5 are as defined for Formula (I), or an acid salt of a compound of Formula (II) such as a hydrochloride salt, and an aldehyde of Formula (III), wherein Ar is as defined for Formula (I), according to the scheme below:
15. A process for the preparation of a compound of Formula (I) wherein R 1 and Ar are as defined for Formula (I) and R 2 is hydrogen, by a reaction between a compound of Formula (II), wherein R 1 is as defined for Formula (I) and R 2 is hydrogen, and an alkylating agent of Formula (IV), wherein hal is a halo substituent, according to the scheme below:
16. A combination comprising a) a compound of Formula (I) or a pharmaceutically acceptable salt thereof as claimed in claim 1 , and b) one or more additional therapeutic agents.
17. The method of claim 12 wherein said mammal is a human.
18. The method of claim 13 wherein said mammal is a human.