IP Library Granted Patent US 7,166,624
Granted Patent B2
US 7,166,624 · App. 10/539,674 · Granted Jan 23, 2007

Peptide deformylase inhibitors

Assignee: SmithKline Beecham Corporation
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Quick Facts
Patent No.
US 7,166,624
App. No.
10/539,674
Granted
Jan 23, 2007
Kind
B2
Abstract

Novel PDF inhibitors and novel methods for their use are provided.

Claims (72)

1. A compound according to Formula (I):

wherein:

X is selected from the group consisting of: (CH 2 ) n , NR2, O, NR2CO, CONR2 and a bond;

Y is selected from the group consisting of: O, CH 2 and a covalent bond;

Z is selected from the group consisting of: hydrogen and fluorine;

R is selected from the group consisting of:

C 2-6 alkyl optionally substituted by alkoxy, halogen, or C 1-3 alkylsulfanyl; C 2-6 alkenyl optionally substituted by alkoxy, halogen, or C 1-3 alkylsulfanyl; C 2-6 alkynyl optionally substituted by alkoxy, halogen, or C 1-3 alkylsulfanyl; (CH 2 ) n —C 3-6 carbocycle optionally substituted by alkoxy, halogen, or C 1-3 alkylsulfanyl; and (CH 2 ) n —R3;

R1 is selected from the group consisting of:

hydrogen, C 1-3 substituted alkyl, C 2-3 substituted alkenyl, C 2-3 substituted alkynyl, (CH 2 ) n —C 3-6 substituted carbocycle, aryl, heteroaryl, heterocyclic, and aminocarbonyl; provided that X is (CH 2 ) n when R 1 represents aminocarbonyl;

R2 is selected from the group consisting of:

hydrogen and C 1-3 substituted alkyl;

R3 is selected from the group consisting of:

phenyl, furan, benzofuran, thiophene, benzothiophene, tetrahydrofuran, tetrahydropyran, dioxane, 1,4-benzodioxane and benzo[1,3]dioxole, each of which is optionally substituted by one or more substituents each independently selected from: Cl, Br, I, C 1-3 alkyl optionally substituted by one to three F, and C 1-2 alkoxy, optionally substituted by one to three F;

and

n represents an integer between 0 and 2; or a pharmaceutically acceptable salt or solvate thereof.

2. A compound according to claim 1 , or a pharmaceutically acceptable salt or solvate thereof, with the following absolute configuration:

3. A compound according to claim 1 , wherein X is CH 2 or a bond; or a pharmaceutically acceptable salt or solvate thereof.

4. A compound according to claim 1 , wherein X is NR2; or a pharmaceutically acceptable salt or solvate thereof.

5. A compound according to claim 3 selected from the group consisting of:

N-[(R)-2-(5-Benzo[1,3]dioxol-5-yl-[1,3,4]oxadiazol-2-yl)-heptyl]-N-hydroxyformamide;

N-[(R)-2-(5-Benzyl-[1,3,4]oxadiazol-2-yl)-heptyl]-N-hydroxyformamide;

N-Hydroxy-N-{(R)-2-[5-(7-methoxy-benzofuran-2-yl)-[1,3,4]oxadiazol-2-yl]-heptyl}-formamide;

N-Hydroxy-N-{(R)-2-[5-(1,2,3,4-tetrahydroquinolin-6-yl)-[1,3,4]oxadiazol-2-yl]-heptyl}-formamide;

N-Hydroxy-N-{(R)-2-[5-(1,2,3,4-tetrahydro-quinolin-8-yl)-[1,3,4]oxadiazol-2-yl]-heptyl}-formamide;

N-Hydroxy-N-[(R)-2-(5-pyridin-3-ylmethyl-[1,3,4]oxadiazol-2-yl)-heptyl]-formamide;

N-{(R)-2-[5-(3,4-Dichloro-benzyl)-[1,3,4]oxadiazol-2-yl]-heptyl}-N-hydroxy-formamide;

N-{(R)-2-[5-(3,4-Dichloro-benzyl)-[1,3,4]oxadiazol-2-yl]-heptyl}-N-hydroxy-formamide;

N-{(R)-2-[5-(3,4-Dichloro-benzyl)-[1,3,4]oxadiazol-2-yl]-heptyl}-N-hydroxy-formamide;

N-Hydroxy-N-{(R)-2-[5-(2-morpholin-4-yl-ethyl)-[1,3,4]oxadiazol-2-yl]-heptyl}-formamide;

N-Hydroxy-N-{(R)-2-[5-(2-morpholin-4-yl-ethyl)-[1,3,4]oxadiazol-2-yl]-heptyl}-formamide;

N-{(R)-2-[5-(2,3-Dichloro-phenoxymethyl)-[1,3,4]oxadiazol-2-yl]-heptyl}-N-hydroxy formamide;

N-Hydroxy-N-{(R)-2-[5-(4-methoxy-phenoxymethyl)-[1,3,4]oxadiazol-2-yl]-heptyl}-formamide;

N-((R)-2-{5-[4-(4-Acetyl-piperazin-1-yl)-phenoxymethyl]-[1,3,4]oxadiazol-2-yl}-heptyl)-N-hydroxy-formamide;

N-Hydroxy-N-{(R)-2-[5-(1-methyl-1H-pyrrol-2-ylmethyl)-[1,3,4]oxadiazol-2-yl]-heptyl}-formamide;

N-Hydroxy-N-[(R)-2-(5-pyridin-2-ylmethyl-[1,3,4]oxadiazol-2-yl)-heptyl]formamide;

N-Hydroxy-N-[(R)-2-(5-pyridin-4-ylmethyl-[1,3,4]oxadiazol-2-yl)-heptyl]-formamide;

N-Hydroxy-N-{(R)-2-[5-(2,6-dichloro-benzyl)-[1,3,4]oxadiazol-2-yl]-heptyl}formamide;

N-Hydroxy-N-{(R)-2-[5-(1H-indol-3-ylmethyl)-[1,3,4]oxadiazol-2-yl]-heptyl}-formamide;

N-{(R)-2-[(S)-5-(2,3-Dihydro-benzo[1,4]dioxin-2-yl)-[1,3,4]oxadiazol-2-yl]-heptyl}-N-hydroxy-formamide;

N-[(R)-2-(5-Benzofuran-4-ylmethyl-[1,3,4]oxadiazol-2-yl)-heptyl]-N-hydroxy-formamide;

N-Hydroxy-N-[(R)-2-(5-pyrimidin-2-yl-[1,3,4]oxadiazol-2-yl)-heptyl]-formamide;

N-{(R)-2-[5-(2,3-Dihydro-benzo[d]isoxazol-3-ylmethyl)-[1,3,4]oxadiazol-2-yl]-heptyl}-N-hydroxy-formamide;

N-Hydroxy-N-[(R)-2-(5-phenoxymethyl-[1,3,4]oxadiazol-2-yl)-heptyl]-formamide;

N-Hydroxy-N-{(R)-2-[(S)-5-(1,2,3,4-tetrahydro-isoquinolin-3-yl)-[1,3,4]oxadiazol-2-yl]-heptyl}-formamide;

N-Hydroxy-N-{(R)-2-[5-(4-imidazol-1-yl-phenoxymethyl)-[1,3,4]oxadiazol-2-yl]-heptyl}-formamide;

N-Hydroxy-N-{(R)-2-[5-(quinolin-6-yloxymethyl)-[1,3,4]oxadiazol-2-yl]-heptyl}-formamide;

5-{(R)-1-[(Formyl-hydroxy-amino)-methyl]-hexyl}-[1,3,4]oxadiazole-2-carboxylic acid phenylamide;

N-Hydroxy-N-[(R)-2-(5-phenylaminomethyl-[1,3,4]oxadiazol-2-yl)-heptyl]-formamide;

N-{(R)-2-[5-(2-Chloro-benzyl)-[1,3,4]oxadiazol-2-yl]-heptyl}-N-Hydroxy-formamide;

N-[(R)-2-(5-Benzyl-[1,3,4]oxadiazol-2-yl)-3-cyclohexyl-propyl]-N-hydroxyformamide;

N-((R)-2-{5-[2-(1H-Benzoimidazol-2-yl)-ethyl]-[1,3,4]oxadiazol-2-yl}-heptyl)-N-Hydroxy-formamide;

N-Hydroxy-N-{(R)-2-[5-(4-pyrimidin-2-yl-piperazin-1-ylmethyl)-[1,3,4]oxadiazol-2-yl]-heptyl}-formamide;

N-Hydroxy-N-{(R)-2-[5-(3-methyl-isoxazol-5-ylmethyl)-[1,3,4]oxadiazol-2-yl]-heptyl}-formamide;

N-Hydroxy-N-{(R)-2-[5-(5-methyl-2-phenyl-oxazol-4-ylmethyl)-[1,3,4]oxadiazol-2-yl]-heptyl}-formamide;

N-Hydroxy-N-(2-{5-[(4-trifluoromethyl-pyrimidin-2-ylamino)-methyl]-[1,3,4]oxadiazol-2-yl}-heptyl)-formamide;

N-{(R)-2-[5-(1H-Benzoimidazol-2-ylmethyl)-[1,3,4]oxadiazol-2-yl]-heptyl}-N-hydroxy-formamide;

N-Hydroxy-N-[(R)-2-(5-morpholin-4-ylmethyl-[1,3,4]oxadiazol-2-yl)-heptyl]-formamide;

N-Hydroxy-N-((R)-2-{5-[(3-trifluoromethyl-phenylamino)-methyl]-[1,3,4]oxadiazol-2-yl}-heptyl)-formamide;

N-[(R)-2-(5-Benzyl-[1,3,4]oxadiazol-2-yl)-3-cyclopentyl-propyl]-N-hydroxyformamide;

N-Hydroxy-N-[(R)-2-(5-methyl-[1,3,4]oxadiazol-2-yl)-heptyl]-formamide; and

N-Hydroxy-N-((R)-2-{5-[2-(1H-indol-3-yl)-ethyl]-[1,3,4]oxadiazol-2-yl}-heptyl)-formamide; and pharmaceutically acceptable salts or solvates thereof.

6. A compound according to claim 5 selected from the group consisting of:

N-Hydroxy-[(R)-2-(5-phenylamino-[1,3,4]oxadiazol-2-yl)-heptyl]-formamide;

N-(5-{(R)-1-[(Formyl-hydroxy-amino)-methyl]-hexyl}-[1,3,4]oxadiazol-2-yl)-benzamide;

N-{(R)-2-[5-(Chloro-trifluoromethyl-phenylamino)-[1,3,4]oxadiazol-2-yl]-heptyl}-N-hydroxy-formamide;

N-Hydroxy-N-{(R)-2-[5-(methyl-phenyl-amino)-[1,3,4]oxadiazol-2-yl]-heptyl}-formamide;

Benzo[1,3]dioxole-5-carboxylic acid(5-{(R)-1-[(formyl-hydroxy-amino)-methyl]-hexyl}-[1,3,4]oxadiazol-1,2-yl)-amide;

N-{(R)-2-[5-(3,5-Dichloro-phenylamino)-[1,3,4]oxadiazol-2-yl]-heptyl}-N-hydroxy formamide;

N-[(S)-2-Fluoro-2-(5-phenylamino-[1,3,4]oxadiazol-2-yl)-heptyl]-N-hydroxy formamide; and

N-{(R)-2-[5-(2,3-Dihydro-benzo[1,4]dioxin-6-ylamino)-[1,3,4]oxadiazol-2-yl]-heptyl}-N-hydroxy-formamide; and pharmaceutically acceptable salts or solvates thereof.

7. A method of treating a bacterial infection by administering to a subject in need of such treatment a compound according to claim 1 ; or a pharmaceutically acceptable salt or solvate thereof.

8. A pharmaceutical composition comprising a compound according to claim 1 , or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.

Assignments (2)
CHANGE OF NAME Recorded Jan 8, 2010
From: SMITHKLINE BEECHAM CORPORATION
To: GLAXOSMITHKLINE LLC
Reel/Frame 023750/0387 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jul 7, 2005
From: LEBER, JACK DALE; LI, MEI; LEE, JINHWA; AUBART, KELLY M.; CHRISTENSEN, SIEGFRIED B., IV
To: SMITHKLINE BEECHAM CORPORATION
Reel/Frame 016486/0196 →
Continuity (2)
Provisional Application 6043446600 · Dec 18, 2002
Related Publication 20060052423A1 · Mar 9, 2006