Isoxazoline hydroxamic acid derivatives as LpxC inhibitors

Patent metadata

Field	Value
Publication number	US-9637482-B2
Application number	US-201515304044-A
Country	US
Kind code	B2
Filing date	Apr 22, 2015
Priority date	Apr 22, 2014
Publication date	May 2, 2017
Grant date	May 2, 2017

Abstract

This invention pertains generally to compounds of Formula I and compositions containing such compounds, as well as methods of using such compounds to treat bacterial infections. In certain aspects, the invention pertains to methods and compositions for treating infections caused by Gram-negative bacteria.

First claim

The invention claimed is:

1. A compound of formula (I):

or a pharmaceutically acceptable salt thereof, wherein:
Z is N or CR 1 , where 1e is selected from H, halo, C 1-4 alkyl and C 1-4 haloalkyl;
R 2 and R 3 are independently selected from C 1-4 alkyl and C 1-4 haloalkyl,
R 4 is H or C 1-4 alkyl;
X is selected from H, halo, C 1-4 alkyl, C 1-4 haloalkyl, and CN;
L is selected from —CR 5 ═CR 6 —, —O—, —S—, and a direct bond between A and the ring containing Z;
R 5 and R 6 are independently selected from H, halo, C 1-4 alkyl, and C 1-4 haloalkyl; and
A is halo, CN, or an optionally substituted group selected from C 1-4 alkyl, C 3-6 cycloalkyl, phenyl, C 2-6 alkenyl, C 2-6 alkynyl, 5-6 membered heteroaryl containing up to four heteroatoms selected from N, O and S as ring members, and 4-6 membered heterocyclyl containing up to two heteroatoms selected from N, O and S as ring members,
wherein the C 1-4 alkyl, C 3-6 cycloalkyl, phenyl, C 2-6 alkenyl, C 2-6 alkynyl, 5-6 membered heteroaryl containing up to four heteroatoms selected from N, O and S as ring members, and 4-6 membered heterocyclyl containing up to two heteroatoms selected from N, O and S as ring members are each optionally substituted with up to three groups selected from halo, hydroxy, CN, R 10 , —(CH 2 ) 0-2 OR 10 , —SR 10 , —S(O)R 10 , —SO 2 R 10 , —S(O)(NH)R 10 , and —(CH 2 ) 0-2 N(R 10 ) 2 ;
where each R 10 is independently H or C 1-4 alkyl optionally substituted with one or two groups selected from amino, hydroxy, C 1-4 alkoxy, and CN; and —N(R 10 ) 2 can represent a 5-6 membered heterocyclic ring optionally containing an additional heteroatom selected from N, O and S as a ring member, and optionally substituted with one or two groups selected from oxo, halo, hydroxy, C 1-4 alkyl, C 1-4 alkoxy, and amino.

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein X is H or F.

3. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 2 is methyl.

4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 is methyl.

5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 is H.

6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Z is CH or CF.

7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Z is N.

8. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein A-L- is a group of the formula

where A is an optionally substituted group selected from C 1-4 alkyl and C 3-6 cycloalkyl, wherein A is optionally substituted with up to three groups selected from halo, hydroxy, CN, —OR, and —N(R 10 ) 2 where each R 10 is independently H or C 1-4 alkyl.

9. The compound of claim 8 or a pharmaceutically acceptable salt thereof, wherein A is C 1-4 alkyl or cyclopropyl and is optionally substituted with F, OH, or OMe.

10. The compound of claim 1 , which is of the formula:

or a pharmaceutically acceptable salt thereof.

11. A pharmaceutical composition, comprising:
the compound according to claim 1 , or a pharmaceutically acceptable salt thereof, and
a pharmaceutically acceptable carrier.

12. A pharmaceutical combination comprising:
a compound according to claim 1 , or a pharmaceutically acceptable salt thereof,
an antibacterially effective amount of a second therapeutic agent, and
a pharmaceutically acceptable carrier.

13. The pharmaceutical combination composition according to claim 12 , wherein the second therapeutic agent is selected from the group consisting of Ampicillin, Piperacillin, Penicillin G, Ticarcillin, Imipenem, Meropenem, Azithromycin, erythromycin, Aztreonam, Cefepime, Cefotaxime, Ceftriaxone, Cefatazidime, Ciprofloxacin, Levofloxacin, Clindamycin, Doxycycline, Gentamycin, Amikacin, Tobramycin, Tetracycline, Tegacyclin, Rifampicin, Vancomycin and Polymyxin.

14. A method of inhibiting a deacetylase enzyme in a Gram-negative bacterium, comprising:
contacting the Gram-negative bacteria with the compound according to claim 1 or a pharmaceutically acceptable salt thereof.

15. A method for treating a subject with a Gram-negative bacterial infection, comprising:
administering to the subject an antibacterially effective amount of the compound according to claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

16. The method of claim 15 , wherein the gram negative bacterial infection is an infection comprising at least one bacterium selected from the group consisting of Pseudomonas, Stenotrophomonas maltophila, Burkholderia, Alcaligenes xylosoxidans, Acinetobacter , Enterobacteriaceae, Haemophilus, Moraxella, Bacteroides, Fransicella, Shigella, Proteus, Vibrio, Salmonella, Bordetella, Helicobactor, Legionella, Citrobactor, Serratia, Campylobactor, Yersinia and Neisseria.

17. The method of claim 16 , wherein the bacterium is a Enterobacteriaceae which is selected from the group consisting of Serratia, Proteus, Klebsiella, Enterobacter, Citrobacter, Salmonella, Providencia, Morganella, Cedecea, Yersinia , and Edwardsiella species and Escherichia coli.

Assignees

• Fu Jiping
• Jin Xianming
• Karur Subramanian
• Lapointe Guillaume
• Lee Patrick
• Sweeney Zachary Kevin
• Novartis Ag

Inventors

• Fu Jiping
• Jin Xianming
• Karur Subramanian
• Lapointe Guillaume
• Lee Patrick
• Sweeney Zachary Kevin

Classifications

• C07D417/10 Primary

  linked by a carbon chain containing aromatic rings · CPC title

• A61K31/427

  not condensed and containing further heterocyclic rings · CPC title

• A61P31/04

  Antibacterial agents · CPC title

• C07D413/10

  linked by a carbon chain containing aromatic rings · CPC title

• A61K31/42

  Oxazoles · CPC title