Isoxazole hydroxamic acid compounds as LpxC inhibitors

1. A compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein:

X is —NH—, and R 1 is —CH(OH)—Y;

or

X is —CH 2 —, and R 1 is —CH(OH)—Y or —SO 2 R 2 where R 2 is C 1 -C 3 alkyl;

R 3 is H or halo;

Y is selected from a 5-membered heteroaryl ring containing 1-3 heteroatoms selected from N, O and S as ring members, phenyl, and C 1-3 alkyl, and each Y is optionally substituted with one to three R 4 ;

each R 4 is independently selected from halo, C 1-3 alkyl, and C 3-6 cycloalkyl, wherein the C 1-3 alkyl and C 3-6 cycloalkyl are each optionally substituted with up to three groups selected from halo, CN and —OH;

L is —C═C— or —CR 5 ═CR 5 —;

R 5 is independently selected at each occurrence from H, halo and methyl;

and

Z is selected from C 1-6 alkyl, C 3 -C 6 cycloalkyl, pyridinyl, and phenyl, each of which is optionally substituted with up to three groups selected from halogen, hydroxy, C 1-4 alkoxy, C 1-4 haloalkoxy, CN, and C 1-4 alkyl that is optionally substituted with one to three groups selected from halogen, hydroxy, amino, CN, and C 1-3 alkoxy;

or, when L is —CR 5 ═CR 5 —, Z taken together with one of the R 5 groups and any atoms connecting Z with the R 5 group can form a 3-7 membered cycloalkyl or cycloalkenyl group that is optionally substituted with up to three groups selected from halogen, hydroxy, C 1-4 alkoxy, C 1-4 haloalkoxy, CN, and C 1-4 alkyl that is optionally substituted with one to three groups selected from halogen, hydroxy, amino, CN, and C 1-3 alkoxy.

2. The compound of claim 1 , wherein R 1 is —CH(OH)—Y.

3. The compound of claim 1 , wherein R 1 is —SO 2 R 2 .

4. The compound of claim 1 , wherein X is —CH 2 —.

5. The compound of claim 1 , wherein X is —NH—.

6. The compound of claim 1 , wherein Y is isoxazole, optionally substituted with one or two R 4 .

7. The compound of claim 6 , wherein Y is

8. The compound of claim 1 , wherein Z is phenyl substituted with up to three groups selected from halogen, C 1-4 alkoxy, C 1-4 haloalkoxy, CN, and C 1-4 alkyl optionally substituted with one to three groups selected from halogen, hydroxy, amino, CN, and C 1-3 alkoxy.

9. The compound of claim 1 , wherein Z is C 1 -C 4 alkyl or C 3 -C 6 cycloalkyl, and Z is optionally substituted with up to three groups selected from halogen, C 1-4 alkoxy, C 1-4 haloalkoxy, CN, and C 1-4 alkyl optionally substituted with one to three groups selected from halogen, hydroxy, amino, CN, and C 1-3 alkoxy.

10. The compound of claim 1 , wherein L is —C═C—.

11. The compound of claim 1 , wherein the compound is of Formula (II):

12. The compound of claim 1 , wherein the compound is of Formula (III):

13. A pharmaceutical composition, comprising:

a compound of claim 1 and

a pharmaceutically acceptable carrier.

14. A pharmaceutical combination composition, comprising:

a compound of claim 1 ,

an antibacterially effective amount of a second therapeutic agent, and

a pharmaceutically acceptable carrier.

15. The pharmaceutical combination composition of claim 14 , 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, Ceftazidime, Ciprofloxacin, Levofloxacin, Clindamycin, Doxycycline, Gentamycin, Amikacin, Tobramycin, Tetracycline, Tigecycline, Rifampicin, Vancomycin and Polymyxin.

16. A method of inhibiting a deacetylase enzyme in a Gram-negative bacterium, comprising contacting the Gram-negative bacteria with the compound of claim 1 .

17. A method for treating a subject with a Gram-negative bacterial infection, comprising:

administering to the subject in need thereof an antibacterially effective amount of the compound of claim 1 .

18. The method of claim 17 , wherein the Gram negative bacterial infection is an infection comprising at least one bacterium selected from the group consisting of Pseudomonas aeruginosa and other Pseudomonas spp., Stenotrophomonas maltophilia, Burkholderia cepacia and other Burkholderia spp., Alcaligenes xylosoxidans, Acinetobacter spp., Achromobacter spp., Aeromonas spp., Enterobacter spp., Eschericia coli, Haemophilus spp., Klebsiella spp., Moraxella spp., Bacteroides spp., Francisella spp., Shigella spp., Proteus spp., Porphyromonas spp., Prevotella spp., Mannheimia haemolyiticus, Pastuerella spp., Providencia spp., Vibrio spp., Salmonella spp., Bordetella spp., Borrelia spp., Helicobacter spp., Legionella spp., Citrobacter spp., Cedecea spp., Serratia spp., Campylobacter spp., Yersinia spp., Fusobacterium spp., and Neisseria spp.

19. The method of claim 18 , wherein the bacterium is an Enterobacteriaceae which is selected from the Pseudomonadales and Enterobacteriaceae species which is selected from the group consisting of organisms such as Pseudomonas, Acinetobacter, Stenotrophomonas, Burkholderia, Serratia, Proteus, Klebsiella, Enterobacter, Citrobacter, Salmonella, Shigella, Providencia, Morganella, Cedecea, Yersina and Edwardsiella species and Escherichia coli.

20. A compound selected from the group consisting of:

(R)-4-(5-(cyclopropylethynyl)isoxazol-3-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide,

(R)-4-(5-(cyclobutylethynyl)isoxazol-3-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide,

(R)-4-(5-(3,3-dimethylbut-1-yn-1-yl)isoxazol-3-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide,

(R)—N-hydroxy-2-methyl-2-(methylsulfonyl)-4-(5-(prop-1-yn-1-yl)isoxazol-3-yl)butanamide,

(R)-4-(5-(but-1-yn-1-yl)isoxazol-3-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide,

(R)—N-hydroxy-2-methyl-4-(5-(3-methylbut-1-yn-1-yl)isoxazol-3-yl)-2-(methylsulfonyl)butanamide,

(R)—N-hydroxy-2-methyl-2-(methylsulfonyl)-4-(5-(pent-1-yn-1-yl)isoxazol-3-yl)butanamide,

(R)—N-hydroxy-2-methyl-4-(5-((1-methylcyclopropyl)ethynyl)isoxazol-3-yl)-2-(methylsulfonyl)butanamide,

(R)-4-(5-(5-fluorobut-1-yn-1-yl)isoxazol-3-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide,

(R)-4-(5-(5-fluoropent-1-yn-1-yl)isoxazol-3-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide,

(R)-4-(5-(5,5-Difluoropent-1-yn-1-yl)isoxazol-3-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide,

(R)-4-(5-((3,3-difluorocyclobutyl)ethynyl)isoxazol-3-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide,

(R)-4-(5-((3-fluorocyclobutyl)ethynyl)isoxazol-3-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide,

(R)—N-hydroxy-4-(5-(5-hydroxy-5-methyl hex-1-yn-1-yl)isoxazol-3-yl)-2-methyl-2-(methylsulfonyl)butanamide,

(R)—N-hydroxy-4-(5-((3-(methoxymethyl)cyclobutyl)ethynyl)isoxazol-3-yl)-2-methyl-2-(methylsulfonyl)butanamide,

(R)—N-hydroxy-4-(5-((3-(2-hydroxpropan-2-yl)cyclobutyl)ethynyl)isoxazol-3-yl)-2-methyl-2-(methylsulfonyl)butanamide,

N-hydroxy-4-(5-((4-(hydroxymethyl) phenyl)ethynyl)isoxazol-3-yl)-2-methyl-2-(methylsulfonyl)butanamide,

N-hydroxy-4-(5-((4-(2-hydroxyethyl)phenyl)ethynyl)isoxazol-3-yl)-2-methyl-2-(methylsulfonyl)butanamide,

N-hydroxy-4-(5-((4-(2-hydroxy-1-methoxyethyl)phenyl)ethynyl)isoxazol-3-yl)-2-methyl-2-(methylsulfonyl)butanamide,

N-hydroxy-2-methyl-2-(methylsulfonyl)-4-(5-(phenylethynyl) isoxazol-3-yl) butanamide,

N-hydroxy-4-(5-((4-((R)-2-hydroxypropyl)phenyl)ethynyl)isoxazol-3-yl)-2-methyl-2-(methylsulfonyl)butanamide,

(R)—N-hydroxy-4-(5-((4-((S)-2-hydroxy-1-methoxyethyl)phenyl)ethynyl)-isoxazol-3-yl)-2-methyl-2-(methylsulfonyl)butanamide,

(R)-4-(5-((4-((S)-1,2-dihydroxyethyl)phenyl)ethynyl)isoxazol-3-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide,

(R)-4-(5-((4-((R)-1,2-dihydroxyethyl)phenyl)ethynyl)isoxazol-3-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide,

(2S,3R)-2-(((5-(cyclopropylethynyl)isoxazol-3-yl)methyl)amino)-N,3-dihydroxy-2-methyl-3-(5-methylisoxazol-3-yl)propanamide,

(2S,3R)-2-(((5-(cyclobutylethynyl)isoxazol-3-yl)methyl)amino)-N,3-dihydroxy-2-methyl-3-(5-methylisoxazol-3-yl)propanamide,

(2S,3R)—N,3-dihydroxy-2-methyl-3-(5-methylisoxazol-3-yl)-2-(((5-(phenylethynyl)isoxazol-3-yl)methyl)amino)propanamide,

N,3-dihydroxy-3-(5-(hydroxymethyl)isoxazol-3-yl)-2-methyl-2-(((5-(phenylethynyl)isoxazol-3-yl)methyl)amino)propanamide,

(2S,3R)—N,3-dihydroxy-2-(((5-(6-methoxyhex-1-yn-1-yl)isoxazol-3-yl)methyl)amino)-2-methyl-3-(5-methylisoxazol-3-yl)propanamide,

2-(((5-(cyclopropylethynyl) isoxazol-3-yl) methyl) amino)-3-(5-cyclopropylisoxazol-3-yl)-N, 3-dihydroxy-2-methylpropanamide,

(R,E)-4-(5-(but-1-en-1-yl)isoxazol-3-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide,

(R,E)-4-(5-(2-cyclopropylvinyl)isoxazol-3-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide,

(R,E)-4-(5-(but-2-en-2-yl)isoxazol-3-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide,

(R,Z)-4-(5-(but-2-en-2-yl)isoxazol-3-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide,

(R,Z)-4-(5-(2-cyclopropyl-1-fluorovinyl)isoxazol-3-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide,

(R,E)-4-(5-(2-cyclopropyl-1-fluorovinyl)isoxazol-3-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide,

(R,Z)-4-(5-(2-cyclopropyl-2-fluorovinyl) isoxazol-3-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide,

(R)-4-(5-(cyclohex-1-en-1-yl)isoxazol-3-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide,

and the pharmaceutically acceptable salts of any of these compounds.