PEPTIDE DEFORMYLASE INHIBITORS
(19) AUSTRALIAN PATENT OFFICE (54) (51)6 (21) (87) (30) (31) (43) (43) (71) (72) Title PEPTIDE DEFORMYLASEINHIBITORS International Patent Classification(s) A61K 031/4245 C07D 277/10 Application No: 2003304490 WIPO No: WO05/032550 (22) Application Date: 2003.12.18 Priority Data Number 60/434,466 (32) Date 2002.12.18 (33) Country US Publication Date : Publication Journal Date : 2005.04.21 2005.06.09 Applicant(s) SMITHKLINE BEECHAM CORPORATION Inventor(s) LEBER, Jack, B., IVDale; LI, Mei; LEE, Jinhwa; AUBART, Kelly, M.; CHRISTENSEN, Siegfried, Novel PDF inhibitors and novel methods for their use are provided. A compound according to Formula (1):
wherein:
X is selected from the group consisting of CH2,NR2,O,NR2CO,CONR2 and a bond; Y represents O, CH2 or a bond: Z represents H or F; R is selected from the group consisting of:
C2-6 alkyl optionally substituted by alkoxy, halogen, or C1-3 alkylsulfanyl; C2-6 alkenyl optionally substituted by alkoxy, halogen, or C1-3 alkylsulfanyl; C2-6 alkynyl optionally substituted by alkoxy, halogen, or C1-3 alkylsulfanyl; (CH2)n-C3-6 carbocycle optionally substituted by alkoxy, halogen, or C1-3 alkylsulfanyl; (CH2)n-R3 {where R3 is phenyl, furan, benzofuran, thiophene, benzothiophene, tetrahydrofuran, tetrahydropyran, dioxane, 1,4-benzodioxane or benzo[1,3]dioxole; R3 is optionally substituted by one or more Cl, Br, I, C1-3 alkyl optionally substituted by one to three F, or C1-2 alkoxy, optionally substituted by one to three F}; R1 is selected from the group consisting of:
hydrogen, C1-3 substituted alkyl, C2-3 substituted alkenyl, C2-3 substituted alkynyl, (CH2)n-C3-6 substituted carbocycle, aryl, heteroaryl, heterocyclic, and aminocarbonyl provided that X is (CH2)n when R1 represents aminocarbonyl; R2 represents:
hydrogen, or C1-3 substituted alkyl,; X represents (CH2)n, NR2, O, NR2CO, CONR2 or a bond; Y represents O, CH2 or a covalent bond; Z represents hydrogen or fluorine; preferably fluorine; and n represents an integer between 0 and 2 or a salt, solvate, or physiologically functional derivative thereof. A compound as claimed in claim 1, with the following absolute configuration:
wherein:
X is selected from the group consisting of CH2,NR2,O,NR2CO,CONR2 and a bond; Y represents O, CH2 or a bond: Z represents H or F; A compound as claimed in claim 1, wherein X = CH2 or a bond; or a salt, solvate, or physiologically functional derivative thereof. A compound as claimed in claim 1, wherein X = NR2; or a salt, solvate, or physiologically functional derivative thereof. 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-Benryl-[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-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-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-[(5)-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. 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-[(5)-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. A compound according to any one of claims 1 to 6 for use in therapy. A compound according to anyone of claims 1 to 6 for the use in the treatment of a bacterial infection. A pharmaceutical composition comprising a compound of formula (1) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6 and a pharmaceutically acceptable carrier.