Compounds useful as antibiotic tolerance inhibitors

Patent metadata

Field	Value
Publication number	US-9643933-B2
Application number	US-201414786345-A
Country	US
Kind code	B2
Filing date	Apr 22, 2014
Priority date	Apr 23, 2013
Publication date	May 9, 2017
Grant date	May 9, 2017

Abstract

The disclosure provides compounds and pharmaceutical compositions of the compounds useful for treating chronic and acute bacterial infections. Certain of the compounds are compounds and salts of general Formula VIII Certain compounds of this disclosure are MvfR inhibitors. MvfR inhibitors reduce the formation of antibiotic tolerant bacterial strains and are useful for treating Gram-negative bacterial infections and reducing the virulence of Pseudomonas aeruginosa . Methods of treating bacterial infections in a patient, including Pseudomonas aeruginosa infections, are also provided by the disclosure.

First claim

What is claimed is:

1. A method for treating a Gram negative bacterial infection in a subject comprising administering to the subject a composition comprising a compound of Formula VIII:

or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier, wherein:
each of R 20 and R 21 is independently selected from hydrogen, chloro, fluoro, bromo, cyano, —OCHF 2 , and CF 3 , wherein at least one of R 20 or R 21 is other than hydrogen;
R 22 is selected from hydrogen, chloro, fluoro, bromo, methyl, ethyl, —OCH 3 , —OCH 2 CH 3 , CF 3 , and CHF 2
Y 1 is selected from NH, O and S;
Z is selected from CH 2 , NH and S;
R 23 is selected from hydrogen, chloro, fluoro, bromo, methyl, ethyl, hydroxy, —OCH 3 , —OCH 2 CH 3 , CF 3 , and CHF 2
R 24 is selected from chloro, fluoro, bromo, cyano, —OCH 3 , optionally substituted pyridinyloxy, optionally substituted pyrimidinyloxy, optionally substituted pyrazinyloxy, and optionally substituted pyridazinyl;
each R 25 is independently selected from hydrogen, hydroxy, halogen, C 1 -C 4 alkyl, and C 1 -C 4 haloalkyl;
R 9b , if present, is selected from bromo, chloro and fluoro, wherein:

when R 24 is optionally substituted pyridinyloxy, optionally substituted pyrimidinyloxy, optionally substituted pyrazinyloxy, or optionally substituted pyridazinyl, Z is S and Y 1 is NH, then each of R 20 and R 21 is other than hydrogen or cyano.

2. The method of claim 1 , wherein in the compound of Formula VIII:
R 9b is absent or chloro;
R 20 is selected from hydrogen, bromo, fluoro, chloro, cyano, OCHF 2 , CF 3 ;
R 21 is selected from hydrogen, bromo, chloro, fluoro, and cyano;
R 22 is selected from hydrogen and —OCH 3 ;
R 23 is selected from hydrogen, chloro, hydroxy, methyl, —OCH3;
R 24 is selected from chloro, fluoro, bromo, cyano, —OCH 3 , pyridin-3-yloxy, 4-methylpyridin-3-yloxy, 5-methylpyridin-3-yloxy, 6-methylpyridin-3-yloxy, 6-chloropyridin-3-yloxy, pyridin-4-yloxy, pyrazin-4-yloxy, pyrazin-2-yloxy, and pyrimidin-2-yloxy; and
each R 25 is hydrogen.

3. A pharmaceutical composition comprising a compound of Formula VIII:

or a pharmaceutically acceptable salt thereof, wherein:
each of R 20 and R 21 is independently selected from hydrogen, chloro, fluoro, bromo, cyano, —OCHF 2 , and CF 3 , wherein at least one of R 20 or R 21 is other than hydrogen;
R 22 is selected from hydrogen, chloro, fluoro, bromo, methyl, ethyl, —OCH 3 , —OCH 2 CH 3 , CF 3 , and CHF 2
Y 1 is selected from NH, O and S;
Z is selected from CH 2 , NH and S;
R 23 is selected from hydrogen, chloro, fluoro, bromo, methyl, ethyl, hydroxy, —OCH 3 , —OCH 2 CH 3 , CF 3 , and CHF 2
R 24 is selected from chloro, fluoro, bromo, cyano, —OCH 3 , optionally substituted pyridinyloxy, optionally substituted pyrimidinyloxy, optionally substituted pyrazinyloxy, and optionally substituted pyridazinyl;
each R 25 is independently selected from hydrogen, hydroxy, halogen, C 1 -C 4 alkyl, and C 1 -C 4 haloalkyl; and
R 9b , if present, is selected from bromo, chloro and fluoro, wherein:
when R 24 is optionally substituted pyridinyloxy, optionally substituted pyrimidinyloxy, optionally substituted pyrazinyloxy, or optionally substituted pyridazinyl, each R 25 is hydrogen, Z is S and Y 1 is NH, then each of R 20 and R 21 is other than hydrogen or cyano; and
wherein the compound is other than

4. The composition of claim 3 , wherein in Formula VIII:
R 9b is absent or chloro;
R 20 is selected from hydrogen, bromo, fluoro, chloro, cyano, OCHF 2 , CF 3 ;
R 21 is selected from hydrogen, bromo, chloro, fluoro, and cyano;
R 22 is selected from hydrogen and —OCH 3 ;
R 23 is selected from hydrogen, chloro, hydroxy, methyl, —OCH 3 ;
R 24 is selected from chloro, fluoro, bromo, cyano, —OCH 3 , pyridin-3-yloxy, 4-methylpyridin-3-yloxy, 5-methylpyridin-3-yloxy, 6-methylpyridin-3-yloxy, 6-chloropyridin-3-yloxy, pyridin-4-yloxy, pyrazin-4-yloxy, pyrazin-2-yloxy, and pyrimidin-2-yloxy; and
each R 25 is hydrogen.

5. A compound of Formula VIII:

or a pharmaceutically acceptable salt thereof, wherein:
each of R 20 and R 21 is independently selected from hydrogen, chloro, fluoro, bromo, cyano, —OCHF 2 , and CF 3 , wherein at least one of R 20 or R 21 is other than hydrogen;
R 22 is selected from hydrogen, chloro, fluoro, bromo, methyl, ethyl, —OCH 3 , —OCH 2 CH 3 , CF 3 , and CHF 2
Y 1 is selected from NH, O and S;
Z is selected from S, CH 2 , and NH;
R 23 is selected from hydrogen, chloro, fluoro, bromo, methyl, ethyl, hydroxy, —OCH 3 , —OCH 2 CH 3 , CF 3 , and CHF 2
R 24 is selected from chloro, fluoro, bromo, cyano, —OCH 3 , optionally substituted pyridinyloxy, optionally substituted pyrimidinyloxy, optionally substituted pyrazinyloxy, and optionally substituted pyridazinyl;
each R 25 is independently selected from hydrogen, hydroxy, halogen, C 1 -C 4 alkyl, and C 1 -C 4 haloalkyl; and
R 9b , if present, is selected from bromo, chloro and fluoro, wherein:
when R 24 is optionally substituted pyridinyloxy, optionally substituted pyrimidinyloxy, optionally substituted pyrazinyloxy, or optionally substituted pyridazinyl, Z is S, and Y 1 is NH, then each of R 20 and R 21 is other than hydrogen or cyano;
when R 24 is chloro, fluoro, bromo, or —OCH 3 , R 22 is hydrogen, and Z is S, neither of R 20 or R 21 is chloro, fluoro, or bromo; and
the compound is other than

6. The compound of claim 5 , or a pharmaceutically acceptable salt thereof, wherein in Formula VIII Z is S.

7. The compound of claim 5 , or a pharmaceutically acceptable salt thereof, wherein in Formula VIII Z is NH or CH 2 .

8. The compound of claim 5 , or a pharmaceutically acceptable salt thereof, wherein in Formula VIII:
R 9b is absent or chloro;
R 20 is selected from hydrogen, bromo, fluoro, chloro, cyano, OCHF 2 , CF 3 ;
R 21 is selected from hydrogen, bromo, chloro, fluoro, and cyano;
R 22 is selected from hydrogen and —OCH 3 ;
R 23 is selected from hydrogen, chloro, hydroxy, methyl, —OCH 3 ;
R 24 is selected from chloro, fluoro, bromo, cyano, —OCH 3 , pyridin-3-yloxy, 4-methylpyridin-3-yloxy, 5-methylpyridin-3-yloxy, 6-methylpyridin-3-yloxy, 6-chloropyridin-3-yloxy, pyridin-4-yloxy, pyrazin-4-yloxy, pyrazin-2-yloxy, and pyrimidin-2-yloxy; and
each R 25 is hydrogen.

9. The method of claim 1 , wherein the Gram negative bacterial infection is selected from an infection caused by Burkholderia sp., Acinetobacter sp., Klebsiella sp. and Pseudomonas sp.

10. The method of claim 9 , wherein the Gram negative bacterial infection is an infection caused by Pseudomonas sp.

11. The method of claim 10 , wherein the Gram negative bacterial infection is an infection caused by Pseudomonas aeruginosa.

Assignees

• Massachusetts Gen Hospital
• Inst Nat De La Rech Scient

Inventors

• Zahler Robert
• Wester Ronald Thure
• Brickner Steven Joseph

Classifications

• C07D413/04

  directly linked by a ring-member-to-ring-member bond · CPC title

• C07D401/12

  linked by a chain containing hetero atoms as chain links · CPC title

• C07D471/04

  Ortho-condensed systems · CPC title

• C07D403/04

  directly linked by a ring-member-to-ring-member bond · CPC title

• C07D235/28 Primary

  Sulfur atoms · CPC title