WO2001044179A1 - Novel succinate compounds, compositions and methods of use and preparation - Google Patents

Novel succinate compounds, compositions and methods of use and preparation Download PDF

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Publication number
WO2001044179A1
WO2001044179A1 PCT/US2000/034128 US0034128W WO0144179A1 WO 2001044179 A1 WO2001044179 A1 WO 2001044179A1 US 0034128 W US0034128 W US 0034128W WO 0144179 A1 WO0144179 A1 WO 0144179A1
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Prior art keywords
ylaminocarbonyl
alkyl
group
compound
substituted
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PCT/US2000/034128
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French (fr)
Inventor
Jeffrey W. Jacobs
Rakesh Jain
Zhi-Jie Ni
Dinesh V. Patel
Zhengyu Yuan
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Versicor, Inc.
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Priority to CA002393825A priority Critical patent/CA2393825A1/en
Priority to EP00986446A priority patent/EP1237862A1/en
Priority to AU22684/01A priority patent/AU2268401A/en
Priority to JP2001545267A priority patent/JP2003534239A/en
Publication of WO2001044179A1 publication Critical patent/WO2001044179A1/en

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    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
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    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/06—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with radicals, containing only hydrogen and carbon atoms, attached to ring carbon atoms
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    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
    • C07D207/09—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
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    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/14—Nitrogen atoms not forming part of a nitro radical
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    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
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    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • This invention is directed to novel succinate compounds. This invention is also directed to uses of these compounds in various medicinal applications, including treating disorders amenable to treatment by peptidyl deformylase inhibitors. This invention is still further directed to pharmaceutical compounds comprising these compounds and methods of synthesis thereof. State of the Art
  • Penicillin is an extremely well known example of such an agent. Penicillin acts by inhibiting biosynthesis of bacterial cell walls. Since mammalian cells do not require cell walls for survival, administration of penicillin to a human infected with bacteria can kill the bacteria without killing human cells. However, the use of antibiotics and antimicrobials has also resulted in increased resistance to these agents. As bacteria become resistant to older, more widely used antimicrobial agents, new antimicrobials must be developed in order to provide effective treatments for human and non-human animals suffering from microbial infection.
  • Peptide deformylase is a metallopeptidase found in prokaryotic organisms such as bacteria. Protein synthesis in prokaryotic organisms begins with N-formyl methionine (fMet). After initiation of protein synthesis, the formyl group is removed by the enzyme peptide deformylase (PDF); this activity is essential for maturation of proteins. It has been shown that PDF is required for bacterial growth (Chang et al. J. Bacteriol. 171 :4071-4072 (1989); Meinnel T, Blanquet S, J. Bacteriol. 176(23):7387- 90 (1994); Mazel D et al., EMBOJ. 13(4):914-23 (1994 )).
  • PDF peptide deformylase
  • Prokaryotic organisms including disease-causing prokaryotes, are described in Balows, A., H.G. Truper, M. Dworkin, W. Harder, and K.-H. Schleifer (eds.), The Prokaryotes, 2nd ed., New York: Springer-Verlag, 1992; and Holt, J.G. (editor-in- chief). Bergey's Manual of Systematic Bacteriology, Vols. 1-4, Baltimore: Williams & Wilkins, 1982, 1986, 1989.
  • PDF is part of the metalloproteinase superfamily. While PDF clearly shares many of the features which characterize metalloproteinases, it differs from other members of the superfamily in several important respects.
  • the metal ion in the active enzyme appears to be Fe (II), or possibly another divalent cationic metal, instead of the zinc ion more commonly encountered. Rajagopalan et al, J. Am. Chem. Soc, 119:12418-19 (1997).
  • the divalent ion appears to play an important role, not only in catalysis, but also in the structural integrity of the protein.
  • the third ligand of the divalent ion is a cysteine, rather than a histidine or a glutamate, as in other metalloproteinases and is not located at the C-terminal side of the HEXXH motif but far away along the amino acid sequence and N-terminal to the motif.
  • the solution structure shows significant differences in the secondary and tertiary structure of PDF compared to other prototypical metalloproteinases see Meinnel et al. J. Mol Biol 262:375-386 (1996).
  • PDF from E. coli, Bacillus stear other mophilus, and Thermus thermophilus have been characterized see Meinnel et al., J Mol Biol 267:749-761 (1997).
  • MMPs matrix metalloproteinases
  • this invention is directed to a compound of Formula (I):
  • R 2 is independently hydrogen or -R 9 wherein R 9 is as defined above;
  • the compound of Formula (I) inhibits peptidyl deformylase at an IC 50 of less than or equal to about 100 nm, preferably of less than or equal to 10 nm, more preferably of less than or equal to 1 nm.
  • the compound of Formula (I) displays a selectivity for peptidyl deformylase over at least one metalloproteinase selected from the group consisting of ACE and Matrilysin of greater than or equal to about 10 times, more preferably of greater than or equal to about 100 times, still more preferably of greater than or equal to about 1000 times.
  • this invention is directed to pharmaceutical compositions comprising a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.
  • this invention is directed to a method of treatment of a disease in a mammal treatable by administration of a peptidyl deformylase inhibitor which method comprises administration of a therapeutically effective amount of a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient either alone or in combination with other pharmacologically active agents.
  • the compounds of this invention are useful in treating microbial diseases.
  • the microbial infection can be due to bacteria, other prokaryotes, or other organisms, including parasites, dependent on peptide deformylase for growth or survival.
  • this invention is directed to the use of a compound of Formula (I) or a pharmaceutically acceptable salts thereof in the preparation of a medicament for use in the treatment of diseases mediated by peptidyl deformylase enzyme.
  • this invention is directed to a method for identifying compounds useful in treating microbial infections, comprising performing an assay to identify compounds which meet the criterion of either i) an IC 50 for peptide deformylase of less than or equal to about 1 ⁇ M, or ii) an MIC for a disease-causing pathogen of less than or equal to about 32 ⁇ g/ml; performing an assay to identify compounds which meet the criterion of iii) displaying a selectivity for peptide deformylase over at least one metalloproteinase selected from the group consisting of Angiotensin Converting Enzyme (ACE) and Matrilysin of greater than or equal to about 10 times; and selecting compounds which meet either both criteria i) and iii), or both criteria ii) and iii).
  • ACE Angiotensin Converting Enzyme
  • the compounds so identified meet the criterion of either i) an IC 50 for peptide deformylase of less than or equal to about 100 nM, or ii) an MIC for a disease-causing pathogen of less than or equal to about 10 ⁇ g/ml.
  • alkyl refers to saturated aliphatic groups including straight-chain, branched-chain, cyclic groups, and combinations thereof, having the number of carbon atoms specified, or if no number is specified, having 1 to 12 carbon atoms.
  • alkyl groups include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, neopentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclobutylmethyl, cyclobutylethyl, cyclopentylmefhyl, cyclopentylethyl, and adamantyl.
  • Cyclic alkyl groups can consist of one ring, including, but not limited to, groups such as cycloheptyl, or multiple fused rings, including, but not limited to, groups such as adamantyl or norbornyl.
  • alkylene means a saturated divalent aliphatic groups including straight-chain, branched-chain, cyclic groups, and combinations thereof, having the number of carbon atoms specified, or if no number is specified, having 1 to 12 carbon atoms, e.g., methylene, ethylene, 2,2-dimethylethylene, propylene, 2-methyl- propylene, butylene, pentylene, cyclopentylmethylene, and the like.
  • substituted alkyl means an alkyl group as defined above that is substituted with one or more substituents, preferably one to three substituents selected from the group consisting of halogen (fluoro, chloro, bromo, and iodo, preferably fluoro, chloro, or bromo), alkoxy, acyloxy, amino, mono or dialkylamino, hydroxyl, mercapto, carboxy, benzyloxy, phenyl, benzyl, cyano, nitro, thioalkoxy, carboxaldehyde, carboalkoxy and carboxamide, or a functionality that can be suitably blocked, if necessary for purposes of the invention, with a protecting group.
  • substituents preferably one to three substituents selected from the group consisting of halogen (fluoro, chloro, bromo, and iodo, preferably fluoro, chloro, or bromo), alkoxy, acyloxy, amino, mono or dialkyla
  • the phenyl group may optionally be substituted with one to three substituents selected from the group consisting of halogen (fluoro, chloro, bromo, and iodo, preferably fluoro, chloro, or bromo), alkoxy, acyloxy, amino, mono or dialkylamino, hydroxyl, mercapto, carboxy, benzyloxy, benzyl, cyano, nitro, thioalkoxy, carboxaldehyde, carboalkoxy and carboxamide.
  • substituents selected from the group consisting of halogen (fluoro, chloro, bromo, and iodo, preferably fluoro, chloro, or bromo), alkoxy, acyloxy, amino, mono or dialkylamino, hydroxyl, mercapto, carboxy, benzyloxy, benzyl, cyano, nitro, thioalkoxy, carboxaldehyde, carboalkoxy and
  • substituted alkyl groups include, but are not limited to, -CF 3 , -CF 2 -CF 3 , hydroxymethyl, 1- or 2-hydroxyethyl, methoxymethyl, 1- or 2-ethoxyethyl, carboxymethyl, 1- or 2- carboxyethyl, methoxycarbonylmethyl, 1- or 2-methoxycarbonyl ethyl, benzyl, and the like.
  • substituted alkylene means an alkylene group as defined above that is substituted with one or more substituents, preferably one to three substituents, selected from the group consisting of halogen (fluoro, chloro, bromo, and iodo, preferably fluoro, chloro, or bromo), alkoxy, acyloxy, amino, mono or dialkylamino, hydroxyl, mercapto, carboxy, benzyloxy, phenyl, benzyl, cyano, nitro, thioalkoxy, carboxaldehyde, carboalkoxy and carboxamide, or a functionality that can be suitably blocked, if necessary for purposes of the invention, with a protecting group.
  • substituents preferably one to three substituents, selected from the group consisting of halogen (fluoro, chloro, bromo, and iodo, preferably fluoro, chloro, or bromo), alkoxy, acyloxy, amino, mono or dial
  • the phenyl group may optionally be substituted with one to three substituents selected from the group consisting of halogen (fluoro, chloro, bromo, and iodo, preferably fluoro, chloro, or bromo), alkoxy, acyloxy, amino, mono or dialkylamino, hydroxyl, mercapto, carboxy, benzyloxy, benzyl, cyano, nitro, thioalkoxy, carboxaldehyde, carboalkoxy and carboxamide.
  • substituents selected from the group consisting of halogen (fluoro, chloro, bromo, and iodo, preferably fluoro, chloro, or bromo), alkoxy, acyloxy, amino, mono or dialkylamino, hydroxyl, mercapto, carboxy, benzyloxy, benzyl, cyano, nitro, thioalkoxy, carboxaldehyde, carboalkoxy and
  • substituted alkyl groups include, but are not limited to, -CF 2 -, -CF 2 -CF 2 -, hydroxymefhylene, 1- or 2-hydroxyethylene, methoxymethylene, 1- or 2-ethoxyethylene, carboxymethylene, 1- or 2-carboxy- ethylene, and the like.
  • alkynyl refers to unsaturated aliphatic groups including straight- chain, branched-chain, cyclic groups, and combinations thereof, having the number of carbon atoms specified, or if no number is specified, having 1 to 12 carbon atoms, which contain at least one triple bond ( -C ⁇ C-).
  • alkynyl groups include, but are not limited to, acetylene, 2-butynyl, and the like.
  • alkynylene refers to unsaturated divalent aliphatic groups including straight-chain, branched-chain, cyclic groups, and combinations thereof, having the number of carbon atoms specified, or if no number is specified, having 1 to 12 carbon atoms, which contain at least one triple bond ( -C ⁇ C-).
  • alkynylene groups include, but are not limited to, -C ⁇ C-, -C ⁇ C-CH 2 -, and the like.
  • substituted alkenyl or “substituted alkynyl,” refers to the alkenyl and alkynyl groups as defined above that are substituted with one or more substituents, selected from the group consisting of halogen, alkoxy, acyloxy, amino, hydroxyl, mercapto, carboxy, benzyloxy, phenyl, benzyl, cyano, nitro, thioalkoxy, carboxaldehyde, carboalkoxy and carboxamide, or a functionality that can be suitably blocked, if necessary for purposes of the invention, with a protecting group.
  • substituents selected from the group consisting of halogen, alkoxy, acyloxy, amino, hydroxyl, mercapto, carboxy, benzyloxy, phenyl, benzyl, cyano, nitro, thioalkoxy, carboxaldehyde, carboalkoxy and carboxamide, or a functionality that can be suitably blocked
  • substituted alkenylene or “substituted alkynylene,” refers to the alkenylene and alkynylene groups as defined above that are substituted with one or more substituents, selected from the group consisting of halogen, alkoxy, acyloxy, amino, hydroxyl, mercapto, carboxy, benzyloxy, phenyl, benzyl, cyano, nitro, thioalkoxy, carboxaldehyde, carboalkoxy and carboxamide, or a functionality that can be suitably blocked, if necessary for purposes of the invention, with a protecting group.
  • substituents selected from the group consisting of halogen, alkoxy, acyloxy, amino, hydroxyl, mercapto, carboxy, benzyloxy, phenyl, benzyl, cyano, nitro, thioalkoxy, carboxaldehyde, carboalkoxy and carboxamide, or a functionality that can be suitably blocked
  • aryl refers to an aromatic carbocyclic group of 6 to 14 carbon atoms having a single ring (including, but not limited to, groups such as phenyl) or multiple condensed rings (including, but not limited to, groups such as naphthyl or anthryl), and includes both unsubstituted and substituted aryl groups.
  • Substituted aryl is an aryl group that is substituted with one or more substituents, preferably one to three substituents, selected from the group consisting of alkyl, alkenyl, alkynyl, halogen, alkoxy, acyloxy, amino, mono or dialkylamino, hydroxyl, mercapto, carboxy, benzyloxy, phenyl, aryloxy, benzyl, cyano, nitro, thioalkoxy, carboxaldehyde, carboalkoxy and carboxamide, or a functionality that can be suitably blocked, if necessary for purposes of the invention, with a protecting group.
  • substituents preferably one to three substituents, selected from the group consisting of alkyl, alkenyl, alkynyl, halogen, alkoxy, acyloxy, amino, mono or dialkylamino, hydroxyl, mercapto, carboxy, benzyloxy, phenyl,
  • arylene refers to the diradical derived from aryl (including substituted aryl) as defined above and is exemplified by 1 ,2-phenylene, 1,3- phenylene, 1 ,4-phenylene, 1,2-naphthylene and the like.
  • amino refers to the group -NH 2 .
  • thioalkoxy means a radical -SR where R is an alkyl as defined above e.g., methylthio, ethylthio, propylthio, butylthio, and the like.
  • dialkylamino means a radical -NHR and -NRR' respectively where R and R' independently represent an alkyl group as defined herein.
  • Representative examples include, but are not limited to dimethylamino, methylethylamino, di(l-methylethyl)amino, (cyclohexyl)(methyl)amino, (cyclohexyl)(ethyl)amino, (cyclohexyl)(propyl)amino, (cyclohexylmethyl)(methyl)- amino, (cyclohexylmethyl)(ethyl)amino, and the like.
  • acyloxy means a radical -OC(O)R, where R is hydrogen, alkyl, aryl, heteroaryl or substituted alkyl wherein alkyl, aryl, heteroaryl, and substituted alkyl are as defined herein.
  • Representative examples include, but are not limited to formyl, acetyloxy, cylcohexylcarbonyloxy, cyclohexylmethylcarbonyloxy, benzoyloxy, benzylcarbonyloxy, and the like.
  • heteroalkyl refers to alkyl, alkenyl, and alkynyl groups respectively as defined above, that contain the number of carbon atoms specified (or if no number is specified, having 1 to 12 carbon atoms) which contain one or more heteroatoms, preferably one to three heteroatoms, as part of the main, branched, or cyclic chains in the group.
  • Heteroatoms are independently selected from the group consisting of-NR-, -NRR, (where each R is hydrogen or alkyl), -S-, -O-, -SR (R is hydrogen or alkyl), -OR (R is hydrogen or alkyl), and P; preferably -NR where R is hydrogen or alkyl and/or O.
  • Heteroalkyl, heteroalkenyl, and heteroalkynyl groups may be attached to the remainder of the molecule either at a heteroatom (if a valence is available) or at a carbon atom.
  • heteroalkyl groups include, but are not limited to, groups such as -O-CH 3 , -CH 2 -O-CH 3 , -CH 2 -CH 2 -O-CH 3 , -S-CH 2 -CH 2 -CH 3 , -CH 2 -CH(CH 3 )-S-CH 3 , -CH 2 -CH 2 -NH-CH 2 -CH 3 , 1 -ethyl-6-propylpiperidino, 2-ethylthiophenyl, piperazino, pyrrolidino, piperidino, morpholino, and the like.
  • carboalkoxy means -C(O)OR where R is alkyl as defined above and include groups such as methoxycarbonyl, ethoxycarbonyl, and the like.
  • Carboxamide means -C(O)NHR or -C(O)NRR'where R and R' are independently hydrogen or alkyl as defined above. Representative examples include groups such as aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, and the like.
  • heteroaryl or “HetAr” refers to an aromatic carbocyclic group of 3 to 9 ring atoms forming a single ring and having at least one hetero atom, preferably one to three heteroatoms including, but not limited to, heteroatoms such as N, O, P, or S, within the ring.
  • Representative examples include, but are not limited to single ring such as imidazolyl, pyrazolyl, pyrazinyl, pyridazinyl, pyrimidinly, pyrrolyl, pyridyl, thiophene, and the like, or multiple condensed rings such as indolyl, quinoline, quinazoline, benzimidazolyl, indolizinyl, benzothienyl, and the like.
  • heteroalkyl, heteroalkenyl, heteroalkynyl and heteroaryl groups can be unsubstituted or substituted with one or more substituents, preferably one to three substituents, selected from the group consisting of alkyl, alkenyl, alkynyl, benzyl, halogen, alkoxy, acyloxy, amino, mono or dialkylamino, hydroxyl, mercapto, carboxy, benzyloxy, phenyl, aryloxy, cyano, nitro, thioalkoxy, carboxaldehyde, carboalkoxy and carboxamide, or a functionality that can be suitably blocked, if necessary for purposes of the invention, with a protecting group.
  • substituents preferably one to three substituents, selected from the group consisting of alkyl, alkenyl, alkynyl, benzyl, halogen, alkoxy, acyloxy, amino, mono or dialkylamino, hydroxyl,
  • the heteroatom(s) as well as the carbon atoms of the group can be substituted.
  • the heteroatom(s) can also be in oxidized form.
  • heteroarylene refers to the diradical group derived from heteroaryl
  • heteroalkylene refers to the diradical group derived from heteroalkyl, heteroalkenyl, and heteroalkynyl (including substituted heteroalkyl, heteroalkenyl, and heteroalkynyl), as defined above.
  • alkylaryl refers to an alkyl group having the number of carbon atoms designated, appended to one, two, or three aryl groups.
  • alkoxy refers to an alkyl, alkenyl, or alkynyl linked to an oxygen atom and having the number of carbon atoms specified, or if no number is specified, having 1 to 12 carbon atoms.
  • alkoxy groups include, but are not limited to, groups such as methoxy, ethoxy, tert-butoxy, and allyloxy.
  • aryloxy refers to an aryl group linked to an oxygen atom at one of the ring carbons.
  • alkoxy groups include, but are not limited to, groups such as phenoxy, 2-, 3-, or 4-methylphenoxy, and the like.
  • halogen refers to Cl, Br, F or I substituents, preferably fluoro or chloro.
  • -(C ⁇ -C ⁇ 2 ) alkyl, substituted alkyl, or heteroalkyl means an alkyl, substituted alkyl or heteroalkyl group respectively as defined above and having 1 to 12 carbon atoms.
  • Ri when Ri is -(C]-C ⁇ 2 ) alkyl, substituted alkyl, or heteroalkyl it means that Ri can be -(C ⁇ -C ⁇ 2 ) alkyl or -(C ⁇ -C 12 )substituted alkyl, or - (C,-C ⁇ 2 )heteroalkyl.
  • alkenyl, substituted alkenyl, or heteroalkenyl means an alkenyl, substituted alkenyl, or heteroalkenyl group as defined above and having 1 to 12 carbon atoms.
  • alkynyl, substituted alkynyl, or heteroalkynyl means an alkynyl, substituted alkynyl, or heteroalkynyl group as defined above and having 1 to 12 carbon atoms.
  • -(C ⁇ -C ⁇ 2 ) alkylene, substituted alkylene, or heteroalkylene means an alkylene, substituted alkylene, or heteroalkylene group as defined above and havingl to 12 carbon atoms.
  • -(C]-C ⁇ 2 ) alkenylene, substituted alkenylene, or heteroalkenylene means that the alkenylene, substituted alkenylene, or heteroalkenylene group as defined above and having 1 to 12 carbon atoms.
  • -(C ⁇ -C ⁇ 2 ) alkynylene, substituted alkynylene, or heteroalkynylene means an alkynylene, substituted alkynylene, or heteroalkynylene group as defined above and having 1 to 12 carbon atoms.
  • -(C 3 -C ⁇ 2 arylene or heteroarylene)- means that the arylene has 6 to 12 carbon atoms (e.g., phenylene, naphtylene, and the like) and heteroaryl ene groups have 3 to 12 carbons atoms and additionally contain one to three heteroatoms including, but not limited to, heteroatoms such as N, O, P, or S, within the ring (e.g., 2,6-pyridylene, 2,4-pyridinylene, 1 ,2-quinolinylene, 1,8- quinolinylene, 1 ,4-benzofi ⁇ ranylene, 2,5-pyridylene, 2,5-indolenyl, and the like) in accordance with the definition of the heteroaryl ene above.
  • heteroatoms such as N, O, P, or S
  • Protecting group refers to a chemical group that exhibits the following characteristics: 1) reacts selectively with the desired functionality in good yield to give a protected substrate that is stable to the projected reactions for which protection is desired; 2) is selectively removable from the protected substrate to yield the desired functionality; and 3) is removable in good yield by reagents compatible with the other functional group(s) present or generated in such projected reactions.
  • protecting groups can be found in Greene et al. (1991) Protective Groups in Organic Synthesis, 2nd Ed. (John Wiley & Sons, Inc., New York).
  • Preferred amino protecting groups include, but are not limited to, benzyloxycarbonyl (CBz), t-butyl- oxycarbonyl (Boc), t-butyldimethylsilyl (TBDIMS), 9-fluorenylmethyl-oxycarbonyl (Fmoc), or suitable photolabile protecting groups such as 6-nitroveratryloxy carbonyl (Nvoc), nitropiperonyl, pyrenylmethoxycarbonyl, nitrobenzyl, dimethyl dimethoxybenzil, 5-bromo-7-nitroindolinyl, and the like.
  • Preferred hydroxyl protecting groups include Fmoc, TBDIMS, photolabile protecting groups (such as nitroveratryl oxymethyl ether (Nvom)), Mom (methoxy methyl ether), and Mem (methoxy ethoxy methyl ether).
  • Particularly preferred protecting groups include NPEOC (4-nitrophenethyloxycarbonyl) and NPEOM (4-nitrophenethyloxy- methyloxycarbonyl).
  • “Inhibitor” refers to a compound that interferes with the interaction between a target and its respective substrate(s) or endogenous ligand(s).
  • Target molecules include, but are not limited to, enzymes and receptors.
  • Enzyme inhibitors have been extensively studied from kinetic and mechanistic standpoints; see, e.g., Fersht, A., Enzyme Structure and Mechanism, 2nd Ed., New York, W.H. Freeman, 1985.
  • a useful measure of the effectiveness of a compound at inhibiting enzyme catalysis is the IC 50 of that compound.
  • Useful inhibitors have an IC 50 equal to or less than about 10 TM, preferably equal to or less than about 1 TM. More preferably, the inhibitor has an IC 50 equal to or less than about 100 nM, still more preferably equal to or less than about 10 nM, even more preferably equal to or less than about lnM.
  • inhibitors have an IC 50 equal to or less than about 100 pM, or equal to or less than about 10 pM.
  • a selective inhibitor refers to an inhibitor that will inhibit the activity of one macromolecule, typically an enzyme, while exhibiting little or no inhibitory effect on another macromolecule, typically another enzyme.
  • the compounds of the invention are particularly useful in that they display selective inhibition of peptidyl deformylase while exhibiting much lower inhibitory activity towards metalloproteinases such as matrilysin.
  • the selectivity of an enzyme inhibitor can be indicated by dividing the IC 50 of the compound for the enzyme which is not intended to be inhibited, by the IC 50 of the compound for the enzyme which is intended to be inhibited.
  • a compound has an IC 50 for matrilysin of 1 ⁇ M, and an IC 50 for peptidyl deformylase of 0.01 ⁇ M, the compound displays a 100-fold (or 100 times) selectivity for peptidyl deformylase over matrilysin, or alternatively is said to be 100 times more selective for peptidyl deformylase compared to matrilysin.
  • Useful compounds display a selectivity of greater than or equal to about 10 times, preferably greater than or equal to about 100 times, more preferably greater than or equal to about 1000 times, still more preferably greater than or equal to about 10,000, for peptidyl deformylase over one or more other metalloproteinases, for example for peptidyl deformylase over matrilysin.
  • the compounds of the invention are intended for use in eukaryotic animals.
  • the animal is a vertebrate; more preferably, the animal is a mammal; most preferably, the animal is a human.
  • isomers Compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed “isomers”. Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers”.
  • stereoisomers that are not mirror images of one another are termed “diastereomers” and those that are non-superimposable mirror images of each other are termed “enantiomers”.
  • enantiomers When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible.
  • An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or (-)-isomers respectively).
  • a chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a "racemic mixture".
  • the compounds of this invention may possess one or more asymmetric centers; such compounds can therefore be produced as individual (R)- or (S)- stereoisomers or as mixtures thereof.
  • R 6 substituent in a compound of Formula (I) is 2-hydroxyethyl
  • the carbon to which the hydroxy group is attached is an asymmetric center and therefore the compound of Formula (I) can exist as an (R)- or (S)-stereoisomer.
  • the description or naming of a particular compound in the specification and claims is intended to include both individual enantiomers and mixtures, racemic or otherwise, thereof.
  • a “pharmaceutically acceptable excipient” means an excipient that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes an excipient that is acceptable for veterinary use as well as human pharmaceutical use.
  • a “pharmaceutically acceptable excipient” as used in the specification and claims includes both one and more than one such excipient.
  • a “pharmaceutically acceptable salt” of a compound means a salt that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound.
  • Such salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1 ,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesul
  • a compound of Formula (I) may act as a pro-drug.
  • Prodrug means any compound which releases an active parent drug according to Formula (I) in vivo when such prodrug is administered to a mammalian subject.
  • Prodrugs of a compound of Formula (I) are prepared by modifying functional groups present in the compound of Formula (I) in such a way that the modifications may be cleaved in vivo to release the parent compound.
  • Prodrugs include compounds of Formula (I) wherein a hydroxy, amino, or sulfhydryl group in compound (I) is bonded to any group that may be cleaved in vivo to regenerate the free hydroxyl, amino, or sulfhydryl group, respectively.
  • prodrugs include, but are not limited to esters (e.g., acetate, formate, and benzoate derivatives), carbamates (e.g., N,N-dimethylamino-carbonyl) of hydroxy functional groups in compounds of Formula (I), and the like.
  • esters e.g., acetate, formate, and benzoate derivatives
  • carbamates e.g., N,N-dimethylamino-carbonyl
  • Treatment includes:
  • a “therapeutically effective amount” means the amount of a compound that, when administered to a mammal for treating a disease, is sufficient to effect such treatment for the disease.
  • the “therapeutically effective amount” will vary depending on the compound, the disease and its severity and the age, weight, etc., of the mammal to be treated.
  • a preferred group of compounds is that wherein Ri is hydrogen or hydroxy, preferably hydroxy.
  • the stereochemistry at the carbon carrying the Ri group is (R) or (S).
  • Ri is halo; preferably chloro or fluoro; more preferably fluoro.
  • the stereochemistry at the carbon carrying the Ri group is (R) or (S), preferably (S) when Rj is fluoro.
  • R 3 is hydrogen or R ⁇ where Rn is -C ⁇ -C ⁇ alkyl or -(C ⁇ -C 8 alkylene) n7 -(C 3 -C ⁇ 2 aryl or heteroaryl), preferably methyl, ethyl, n-propyl, wo-propyl, w-butyl, iso-buty ⁇ , tert-butyl, w-pentyl, zY-pentyl, ⁇ e ⁇ -pentyl, n-hexyl, 2-, 3-, 4-, or 5-methylpentyl, 4,4-dimethylbutyl, benzyl, 3-phenylpropyl, 2-phenylethyl, or 4-phenylbutyl, more preferably n-butyl.
  • the stereochemistry at the carbon carrying the R 3 group is (R) or (S), preferably (R).
  • R 7 is n-butylaminocarbonyl, tert-butylaminocarbonyl, benzylaminocarbonyl, 1 , 1 -dimethylpropylaminocarbonyl, 2-(cyclohexen- 1 -yl)- ethylaminocarbonyl, indan-5-ylaminocarbonyl, 4,5-dimethylthiazol-2-ylamino- carbonyl, 4-phenoxyphenylaminocarbonyl, cyclopropylmethyl-aminocarbonyl, pyridin-2-ylaminocarbonyl, pyridin-3-ylaminocarbonyl, pyridin-4-ylmethylamino- carbonyl, morpholin-4-ylcarbonyl, 3,4-methylenedioxy-phenylaminocarbonyl, quinolin-3-ylaminocarbonyl, methylaminocarbonyl, 4-biphenylaminocarbonyl, 3- phenylamin
  • R 7 is piperidin- 1 -ylcarbonyl, azetidin-1 -ylcarbonyl, ethylaminocarbonyl, phenylaminocarbonyl, pyrimidin-2-ylaminocarbonyl, or thiazol- 2-ylaminocarbonyl.
  • R is piperidin- 1 -ylcarbonyl, azetidin-1 -ylcarbonyl, ethylaminocarbonyl or thiazol-2-ylaminocarbonyl.
  • the stereochemistry at the C2 carbon atom of the pyrrolidine ring, i.e., carbon carrying the R group is either (R) or (S), preferably (S); or
  • R 14 is hydrogen, -(C ⁇ -C 12 ) alkyl, substituted alkyl, or heteroalkyl, -(C ⁇ -C] 2 ) alkenyl, substituted alkenyl, or heteroalkenyl, -(C]-C ⁇ ) alkynyl, substituted alkynyl, or heteroalkynyl, alkoxy, or -(C C 8 alkyl or substituted alkyl) n9 -(C 3 -C ⁇ 2 arylene or heteroarylene)-(C ⁇ -C 8 alkyl or substituted alkyl) n ⁇ 0 where n9 and nlO are independently 0 or 1.
  • R 7 is hydrogen or -(
  • R 2 is hydrogen or -R 9 where R 9 is as defined above;
  • a preferred group of compounds is that wherein Ri is hydrogen or hydroxy and the stereochemistry at the carbon carrying the Ri group is (R) or (S), preferably (S).
  • R 3 is hydrogen or R where R 9 is -C ⁇ -C ⁇ 2 alkyl or -(C ⁇ -C 8 alkylene) n7 -(C 3 -C ⁇ 2 aryl or heteroaryl) where n7, preferably methyl, ethyl, n-propyl, wo-propyl, n-butyl, iso-butyl, tert-butyl, n-pentyl, iso-pentyl, neo-pentyl, n-hexyl, 2-, 3-, 4-, or 5-methylpentyl, 4,4- dimethylbutyl, benzyl, 3-phenylpropyl, 2-phenylethyl, or 4-phenylbutyl, more preferably n-butyl.
  • the stereochemistry at the carbon carrying the R 3 group is (R) or (S), preferably (R).
  • n 1 or 2, preferably 1 ; and R 7 is:
  • R ]4 and R 15 are independently selected from the group consisting of hydrogen, -(C ⁇ -C ⁇ 2 ) alkyl, substituted alkyl, or heteroalkyl, -(Ci- C ⁇ 2 ) alkenyl, substituted alkenyl, or heteroalkenyl, -(C ⁇ -C ⁇ 2 ) alkynyl, substituted alkynyl, or heteroalkynyl, alkoxy, and -(C ⁇ -C 8 alkyl or substituted alkyl) n9 -(C 3 -C ⁇ 2 arylene or hetero arylene)-(C ⁇ -C 8 alkyl or substituted alkyl) n 10 where n9 and nlO are independently 0 or 1.
  • R 7 is n-butylaminocarbonyl, tert-butylaminocarbonyl, benzylaminocarbonyl, 1 , 1 -dimethylpropylaminocarbonyl, 2-(cyclohexen- 1 -yl)- ethylaminocarbonyl, indan-5 -ylaminocarbonyl, 4,5-dimethylthiazol-2-ylamino- carbonyl, 4-phenoxyphenylaminocarbonyl, cyclopropylmethylaminocarbonyl, pyridin-2-ylaminocarbonyl, pyridin-3 -ylaminocarbonyl, pyridin-4-ylmethyl- aminocarbonyl, 3,4-methylenedioxyphenylaminocarbonyl, quinolin-3- ylaminocarbonyl, methylaminocarbonyl, 4-biphenylaminocarbonyl, 3 -phenoxyphenylaminocarbonyl, 3 -phen
  • R 7 is ethylaminocarbonyl, phenylaminocarbonyl, pyrimidin-2- ylaminocarbonyl, or thiazol-2 -ylaminocarbonyl. More particularly, R 7 is phenylaminocarbonyl or pyrimidin-2-ylaminocarbonyl.
  • the stereochemistry at the C2 carbon atom of the pyrrolidine ring, i.e., carbon carrying the R 7 group is either (R) or (S), preferably (S); or
  • Rj 4 is hydrogen, -(C ⁇ -C ⁇ 2 ) alkyl, substituted alkyl, or heteroalkyl, -(C ⁇ -C ⁇ 2 ) alkenyl, substituted alkenyl, or heteroalkenyl, -(C ⁇ -C 12 ) alkynyl, substituted alkynyl, or heteroalkynyl, alkoxy, or -(C ⁇ -C 8 alkyl or substituted alkyl) n9 -(C 3 -C ⁇ 2 arylene or heteroarylene)-(C ! -C 8 alkyl or substituted alkyl) nl o where n9 and nlO are independently 0 or 1.
  • the stereochemistry at the C2 carbon atom of the pyrrolidine ring, i.e., carbon carrying the R 7 group is either (R) or (S), preferably (S).
  • R 2 is -H or -R 9 where R 9 is as defined above;
  • R ⁇ 2 is selected from the group consisting of-C]-C ⁇ 2 alkylene, substituted alkylene, or heteroalkylene, -C ⁇ -C ⁇ 2 alkenylene, substituted alkenylene, or heteroalkenylene, -C ⁇ -C ⁇ 2 alkynylene, substituted alkynylene, or heteroalkynylene, and -(C ⁇ -C 8 alkylene or substituted alkylene) n5 -(C 3 -C ⁇ 2 arylene or heteroarylene)-(C ⁇ -C 8 alkyl or substituted alkyl) n6 where n5 and n6 are independently 0 or 1 ; and Ri 1, R ⁇ a , and R ⁇ are independently selected from the group consisting of -C ⁇ -C ⁇ 2 alkyl, substituted alkyl, or heteroalkyl, -C)-C ⁇ 2 alkenyl, substituted alkyn
  • R 1 ⁇ is hydrogen or -Ri 1 where Ri 1 is as defined above;
  • a preferred group of compounds is that wherein Ri is hydroxy and the stereochemistry at the carbon carrying the Ri group is (R) or (S), preferably (S).
  • R 2 is hydrogen.
  • R 3 is hydrogen or R where R is -C 1 -C 12 alkyl or -(C ⁇ -C 8 alkylene) n5 -(C -C ⁇ 2 aryl or heteroaryl) where n5 is 0 or 1, preferably methyl, ethyl, n-propyl, w ⁇ -propyl, n-butyl, iso-bulyl, tert-butyl, n-pentyl, zso-pentyl, neo-pentyl, n-hexyl, 2-, 3-, 4-, or 5-methylpentyl, 4- dimethylbutyl, benzyl, 3-phenylpropyl, 2-phenylethyl, or 4-phenylbutyl, more preferably n-butyl.
  • the stereochemistry at the carbon carrying the R 3 group is (R) or
  • R is selected from the group consisting of -(Ci- C ⁇ 2 ) alkyl, substituted alkyl, or heteroalkyl, -(C ⁇ -C] 2 ) alkenyl, substituted alkenyl, or heteroalkenyl, -(C ⁇ -C ⁇ 2 ) alkynyl, substituted alkynyl, or heteroalkynyl, alkoxy, and - (C ⁇ -C 8 alkyl or substituted alkyl) n9 -(C 3 -C ⁇ 2 arylene or heteroarylene)-(C ⁇ -C 8 alkyl or substituted alkyl) n 10 where n9 and nlO are independently 0 or 1.
  • R 7 is n-butylaminocarbonyl, tert-butylaminocarbonyl, benzylaminocarbonyl, 1 , 1 -dimethylpropylaminocarbonyl, 2-(cyclohexen- 1 -yl)- ethylaminocarbonyl, indan- 5 -ylaminocarbonyl, 4,5-dimethylthiazol-2- ylaminocarbonyl, 4-phenoxyphenylaminocarbonyl, cyclopropylmethyl- aminocarbonyl, pyridin-2-ylaminocarbonyl, pyridin-3-ylaminocarbonyl, pyridin-4- ylmefhylaminocarbonyl, morpholin-4-ylcarbonyl, 3,4-methylenedioxy- phenylaminocarbonyl, quinolin-3-ylaminocarbonyl, methylaminocarbonyl, 4- biphenylaminocarbonyl,
  • R 7 is piperidin- 1 -ylcarbonyl, azetidin-1 -ylcarbonyl, ethylaminocarbonyl, phenylaminocarbonyl, pyrimidin-2-yl- aminocarbonyl, or thiazol-2-ylaminocarbonyl.
  • R 7 is phenylaminocarbonyl or pyrimidin-2-ylamino- carbonyl.
  • the stereochemistry at the C2 carbon atom of the pyrrolidine ring, i.e., carbon carrying the R 7 group is either (R) or (S), preferably (S); or
  • the stereochemistry at the C2 carbon atom of the pyrrolidine ring, i.e., carbon carrying the R 7 group is either (R) or (S), preferably (S).
  • Ri is -OH, -OR , -SH or -SR 9 wherein R is selected from the group consisting of -C 1 -C 12 alkyl, substituted alkyl, or heteroalkyl, -C ⁇ -C ⁇ 2 alkenyl, substituted alkenyl, or heteroalkenyl, -C ⁇ -C ⁇ 2 alkynyl, substituted alkynyl, or heteroalkynyl, and -(C ⁇ -C 8 alkyl or substituted alkyl) nl -(C -C ⁇ 2 arylene or heteroarylene)-(C ⁇ -C 8 alkyl or substituted alkyl) n2 where nl and n2 are independently O or 1;
  • R 2 is hydrogen;
  • R 3 is -Rn, -OH, -OR, ⁇ , -R 12 OR 11 , -SH, -SRn, -NH 2 , -NHRn,
  • Ri is -OH or -OR 9 .
  • R 3 is -C ⁇ -C ⁇ 2 alkyl, such as C 4 alkyl and R 4 is H.
  • R is -Rn where Rn is selected from the group consisting of -C ⁇ -C ⁇ 2 alkyl, substituted alkyl, or heteroalkyl, -C ⁇ -C ⁇ 2 alkenyl, substituted alkenyl, or heteroalkenyl, -C1-C 12 alkynyl, substituted alkynyl, or heteroalkynyl, and -(C ⁇ -C 8 alkyl or substituted alkyl) n7 -(C 3 -C ⁇ 2 arylene or heteroarylene)-(C ⁇ -C 8 alkyl or substituted alkyl) n8 where n7 and n8 are independently 0 or 1; and
  • R 3 is -(C ⁇ -C ⁇ 2 )alkyl, preferably n-butyl.
  • R is -C(O)O-C ⁇ -C ⁇ 2 alkyl, such as -C(O)O-C i -C 4 alkyl, for example -C(O)O-tert-butyl.
  • R 3 is -Rn where -Rn is selected from the group consisting of -C ⁇ -C ⁇ 2 alkyl, substituted alkyl, or heteroalkyl, -C ⁇ -C ⁇ alkenyl, substituted alkenyl, or heteroalkenyl, -C 1 -C 12 alkynyl, substituted alkynyl, or heteroalkynyl, and -(C ⁇ -C 8 alkyl or substituted alkyl) n7 -(C 3 -C ⁇ 2 arylene or heteroarylene)-(C ⁇ -C 8 alkyl or substituted alkyl) n8 where n7 and n8 are independently 0 or 1 ;
  • R 7 is -NH 2 , -NHR ⁇ 3 , or -NHR ⁇ 4 R ⁇ 5 where R ⁇ 3 , R ]4 and R 15 are independently selected from the group consisting of -C 1 -C 12 alkyl, substituted alkyl, or heteroalkyl, - C ⁇ -C ⁇ 2 alkenyl, substituted alkenyl, or heteroalkenyl, -C ⁇ -C] 2 alkynyl, substituted alkynyl, or heteroalkynyl, and -(Cj-C 8 alkyl or substituted alkyl) n9 -(C 3 -C ⁇ 2 arylene or heteroarylene)-(C ⁇ -C 8 alkyl or substituted alkyl) n ⁇ 0 where n9 and nlO are independently 0 or 1; or where R) 4 and R 15 combine to form a substituted or unsubstituted C 4 -C] 0 cyclic alkyl, cyclic heteroalkyl,
  • R 3 is C ⁇ -C ⁇ 2 alkyl, preferably n-butyl. In another embodiment of this series of compounds, R is -NHR ⁇ 3 where R ⁇ is as defined above.
  • R 3 is -Rn wherein Rn is selected from the group consisting of hydrogen
  • n7 and n8 are independently 0 or 1 ;
  • R 7a , R 7b , R 7c and R 7 a are independently selected from the group consisting of hydrogen, -C ⁇ -C 12 alkyl, substituted alkyl, or heteroalkyl, -C ⁇ -C ⁇ 2 alkenyl, substituted alkenyl, or heteroalkenyl, -C ⁇ -C ⁇ 2 alkynyl, substituted alkynyl, or heteroalkynyl, and -(C ⁇ -C 8 alkyl or substituted alkyl) n7 -(C 3 -C ⁇ 2 arylene or heteroarylene)-(C ⁇ -C 8 alkyl or substituted alkyl) n8 where n7 and n8 are independently 0 or 1 ;
  • R 7a , R 7b , R 7c and R 7 a are independently selected from the group consisting of hydrogen, -C ⁇ -C 12 alkyl, substituted alkyl, or heteroalky
  • R 3 is n-butyl.
  • R 3 is -Rn where R is selected from the group consisting of hydrogen, -Ci- C 12 alkyl, substituted alkyl, or heteroalkyl, -C 1 -C 12 alkenyl, substituted alkenyl, or heteroalkenyl, -C ⁇ -C ⁇ 2 alkynyl, substituted alkynyl, or heteroalkynyl, and -(C ⁇ -C 8 alkyl or substituted alkyl) n7 -(C 3 -C] 2 arylene or heteroarylene)-(C ⁇ -C 8 alkyl or substituted alkyl) n8 where n7 and n8 are independently 0 or 1 ; and
  • R 7a is selected from the group consisting of hydrogen, -C ⁇ -C ⁇ 2 alkyl, substituted alkyl, or heteroalkyl, -C 1 -C 12 alkenyl, substituted alkenyl, or heteroalkenyl, -C ⁇ -C ⁇ 2 alkynyl, substituted alkynyl, or heteroalkynyl, and -(C ⁇ -C 8 alkyl or substituted alkyl) n -(C 3 -C] 2 arylene or heteroarylene)-(C ⁇ -C 8 alkyl or substituted alkyl) radical ⁇ 0 where n9 and nlO are independently 0 or 1; or a pharmaceutically acceptable salt thereof.
  • R 7a is -CH 2 -R ⁇ j where R d is selected from the group consisting of H, -C 1 -C 12 alkyl, substituted alkyl, or heteroalkyl, -C ⁇ -Cj 2 alkenyl, substituted alkenyl, or heteroalkenyl, -C ⁇ -Cn alkynyl, substituted alkynyl, or heteroalkynyl, and -(C ⁇ -C 8 alkyl or substituted alkyl) n9 -(C 3 -C ⁇ 2 arylene or heteroarylene)-(C ⁇ -C 8 alkyl or substituted alkyl) n ⁇ 0 where n9 and nlO are independently 0 or 1.
  • R 3 is -Rn where Rn is selected from the group consisting of hydrogen, -Ci- C 12 alkyl, substituted alkyl, or heteroalkyl, -C ⁇ -C ⁇ 2 alkenyl, substituted alkenyl, or heteroalkenyl, -C ⁇ -C ⁇ 2 alkynyl, substituted alkynyl, or heteroalkynyl, and -(C ⁇ -C 8 alkyl or substituted alkyl) n7 -(C -C ⁇ 2 arylene or heteroarylene)-(C ⁇ -C 8 alkyl or substituted alkyl) n8 where n7 and n8 are independently 0 or 1 ; and
  • R 7 is selected from the group consisting of-R ⁇ 4 or -OR ⁇ 4 where R ⁇ 4 is selected from the group consisting of -C 1 -C 12 alkyl, substituted alkyl, or heteroalkyl, - C 1 -C 12 alkenyl, substituted alkenyl, or heteroalkenyl, -C]-C ⁇ 2 alkynyl, substituted alkynyl, or heteroalkynyl, and -(C ⁇ -C 8 alkyl or substituted alkyl) n9 -(C -C ⁇ 2 arylene or heteroarylene)-(C ⁇ -C 8 alkyl or substituted alkyl) n ⁇ 0 where n9 and nlO are independently 0 or 1 ; or a pharmaceutically acceptable salt thereof.
  • R is n-butyl.
  • R 7 is -OCH 3 or -O-tert-butyl.
  • R 3 is -Rn where Rn is hydrogen, -C ⁇ -C ⁇ 2 alkyl, substituted alkyl, or heteroalkyl, -C ⁇ -C ⁇ 2 alkenyl, substituted alkenyl, or heteroalkenyl, -C]-C ⁇ 2 alkynyl, substituted alkynyl, or heteroalkynyl, or -(C ⁇ -C 8 alkyl or substituted alkyl) n7 -(C 3 -C] 2 arylene or heteroaryl ene)-(C ⁇ -C 8 alkyl or substituted alkyl) n8 where n7 and n8 are independently 0 or 1 ; and 30a, R 30b , R 30C R30d, and R 30e are independently selected from the group consisting of hydrogen, -C1-C12 alkyl, substituted alkyl, or heteroalkyl, -C ⁇ -C ⁇ alkenyl, substituted alkenyl, or heteroalkenyl,
  • Ri is halo
  • a preferred group of compounds is that wherein the embodiments of (i) - (iii) defined below are employed either singularly or in any combination: (i) A preferred group of compounds is that wherein R t is fluoro.
  • the stereochemistry at the carbon carrying the Ri group is (R) or (S), preferably (S).
  • R 3 is hydrogen or R 9 where R 9 is -C ⁇ -C ⁇ 2 alkyl or -( -C 8 alkylene) n5 -(C 3 -C 12 aryl or heteroaryl) where n5 is 0 or 1, preferably methyl, ethyl, n-propyl, ts ⁇ -propyl, n-butyl, wo-butyl, tert-butyl, n-pentyl, wo-pentyl, neo-pentyl, n-hexyl, 2-, 3-, 4-, or 5-methylpentyl, 4,4- dimethylbutyl, benzyl, 3-phenylpropyl, 2-phenylethyl, or 4-phenylbutyl, more preferably n-butyl.
  • the stereochemistry at the carbon carrying the R 3 group is (R) or (S), preferably (R); and (iii) R 7 is:
  • R H and R ]5 are independently hydrogen, -(Ci- C 12 ) alkyl, substituted alkyl, or heteroalkyl, -(C 1 -C 12 ) alkenyl, substituted alkenyl, or heteroalkenyl, -(C ⁇ -C ⁇ 2 ) alkynyl, substituted alkynyl, or heteroalkynyl, alkoxy, or -(C ⁇ -C 8 alkyl or substituted alkyl) n9 -(C 3 -C ⁇ 2 arylene or heteroarylene)-(C ⁇ -C 8 alkyl or substituted alkyl) n 10 where n9 and nlO are independently 0 or 1 ; or Rj 4 and R ⁇ 5 combine to form a substituted or unsubstituted -(C 4 -C ⁇ o)cyclic alkyl, cyclic heteroalkyl, aryl or heteroaryl group
  • R is n-butylaminocarbonyl, tert-butylaminocarbonyl, benzylaminocarbonyl, 1,1-dimethylprop ylaminocarbonyl, 2-(cyclohexen-l-yl)- ethylaminocarbonyl, indan-5-ylaminocarbonyl, 4,5-dimethylthiazol-2- ylaminocarbonyl, 4-phenoxyphenylaminocarbonyl, cyclopropylmethyl- aminocarbonyl, pyridin-2-ylaminocarbonyl, pyridin-3-ylaminocarbonyl, pyridin-4- ylmethylaminocarbonyl, mo ⁇ holin-4-ylcarbonyl, 3 ,4-methylenedioxy- phenylaminocarbonyl, quinolin-3 -ylaminocarbonyl, methylaminocarbonyl, 4- biphenylaminocarbonyl, 3 -phenoxy
  • R 7 is piperidin- 1 -ylcarbonyl, azetidin-1 -ylcarbonyl, ethylaminocarbonyl, phenylaminocarbonyl, pyrimidin-2-ylaminocarbonyl, or thiazol- 2-ylaminocarbonyl.
  • R 7 is piperidin- 1 -ylcarbonyl, azetidin-1 -ylcarbonyl, ethylaminocarbonyl or thiazol-2-ylaminocarbonyl.
  • the stereochemistry at the C2 carbon atom of the pyrrolidine ring, i.e., carbon carrying the R 7 group is either (R) or (S), preferably (S); or
  • the stereochemistry at the C2 carbon atom of the pyrrolidine ring, i.e., carbon carrying the R 7 group is either (R) or (S), preferably (S).
  • Preferred compounds of the Invention are:
  • the starting materials and reagents used in preparing these compounds are either available from commercial suppliers such as Aldrich Chemical Co.,
  • the starting materials and the intermediates of the reaction may be isolated and purified if desired using conventional techniques, including but not limited to filtration, distillation, crystallization, chromatography, and the like. Such materials may be characterized using conventional means, including physical constants and spectral data.
  • a compound of Formula (I) where Ri, R , and R 4 are hydrogen, and R 3 , R ⁇ , R 7 , Y, and n are as defined in the Summary of the Invention can be prepared as described in Scheme A below.
  • Amines of formula 2 are commercially available or they can be prepared by methods well known in the art.
  • N, N-dialkylamines such as pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine, homopiperidine, homopiperazine, proline tert-butyl ester, Z-proline-2-methylamide, (S)-(+)-2-(methoxymethyl)- pyrrolidine, Z-proline-N-methoxy-N-methylamide, (S)-2-(pyrrolidinylmethyl)- pyrrolidine, Z-proline-N-morpholineamide, -proline-NN-dimethylamide, homoproline methyl ester, E-homoproline tert-butylester, 3-(R)- tert-butoxy-L- proline-O- t-butyl ester, pipecolinic acid, 1, 2,3, 4-tetrahydroquino line, 1- hydroxyethylpiperazine, 2-hydroxye
  • ⁇ , ⁇ -dialkylamines 2 such as 2-acetylaminomethylpyrrolidine can be prepared from N-5 ⁇ c-Z-prolinol as described in Example 16 below.
  • trans-3-Acetoxy-Z, -proline O- tert-butyl ester can be prepared from Cbz protected trans-3-hydroxy-Z,-proline as described in Example 17 below which can then be converted to trans 3-hydroxy-Z- proline O-tert-butyl ester, if desired, by hydrolysis of the acetoxy group in trans-3- acetoxy- -proline O-tert-butyl ester as described in Example 17 below.
  • Compound 3 can optionally be converted to a compound of formula 4 where prior to converting it to a compound of Formula (I). This would be desirable if certain group(s) in compound 3, e.g., R 3 , Re, and/or R 7 had to transformed to other group(s) within the scope of the invention prior to introducing the hydroxamate group in the molecule.
  • a compound of formula 3 where Re or R 7 is a tert- butoxyamino group can be converted to a corresponding compound of formula 4 where R 6 or R 7 is an acetylamino group by first treating 3 with an acid such as diluted hydrochloric acid at ambient temperature to provide a corresponding compound of formula 3 where R or R 7 is an amino group, followed by treatment with an acetylating agent such as acetic anhydride in the present of an organic base such as pyridine.
  • an acid such as diluted hydrochloric acid at ambient temperature
  • an acetylating agent such as acetic anhydride
  • a compound of formula 3 where R and ⁇ or R 7 is a hydroxy can be converted to a compound of formula 4 where R 6 and ⁇ or R is a sulfonamido group (i.e., - NHSO 2 R ⁇ 5 where R ⁇ 5 is as defined in the Summary of the Invention) by first converting the hydroxy group into amino group, followed by treatment with a sulfonylating agent.
  • R 6 and ⁇ or R is a sulfonamido group
  • a compound of formula 3 where R 6 and ⁇ or R 7 is a suitably protected carboxyl group can be converted to a compound of formula 4 where R 6 and ⁇ or R 7 is an aminocarbonyl group (i.e., -CONHRj 4 or -CONR ] R ⁇ 5 where R[ 4 and R ]5 is as defined in the Summary of the Invention) by first deprotecting the carboxy group and then treating with an amine of formula -NHR) 4 or -NR ⁇ 4 R ⁇ 5 (where R ⁇ 4 and R ⁇ 5 is as defined in the Summary of the Invention). Briefly, the reaction conditions for deprotecting of the carboxy group will depend on the nature of the protecting group.
  • amination reaction is typically carried out in the presence of an inert, polar aprotic solvent (e.g. DMF, dioxane, etc.) with a non-nucleophilic base (e.g. triethylamine, diisopropylethylamine, etc.) and a coupling reagent (e.g. EDCI, PyBOP, DIC, etc.).
  • an inert, polar aprotic solvent e.g. DMF, dioxane, etc.
  • a non-nucleophilic base e.g. triethylamine, diisopropylethylamine, etc.
  • a coupling reagent e.g. EDCI, PyBOP, DIC, etc.
  • NHR t and NHR] 4 Ri 5 are available commercially, or can be readily prepared by methods well known in the art.
  • methylamine, aniline, 2-aminothiazole, etc. are commercially available.
  • Others can be prepared, for example, via reductive amination of an aldehyde, or Fukuyama alkylation of a suitable nitroaryl sulfonamide followed by cleavage of the sulfonamide to liberate the desired amine.
  • Compound 3 or 4 is then converted to a hydroxamate compound of Formula (I) by treating it at 0 °C with aqueous 50 % hydroxylamine in a polar organic solvent such as dioxane and the like. After the reaction is complete the mixture is then purified by preparative reverse-phase (C18) HPLC to afford compound of Formula (I). If desirable, suitable O-protected hydroxylamine such as O-benzylhydroxyl- amine can also be used to give an O-protectedhydroxamate compound. Removal of the protecting group will provide a compound of Formula (I).
  • a compound of Formula (I) can be converted to other compounds of Formula (I) by methods well known in the art. Some such methods are described below.
  • Compounds of Formula (I) containing a hydroxy group may be prepared by de- alkylation/benzylation of an alkyloxy/benzyloxy substituent; and those containing an acid group, by hydrolysis of an ester group.
  • a compound of Formula (I) having an alkenyl or alkynyl group can be prepared by reacting a corresponding compound of Formula (I) containing a bromine or iodine atom with trimethylsilylacetylene under the Castro-Stephens reaction conditions.
  • a compound of Formula (I) containing an alkoxy group may be prepared by alkylation of hydroxy substituent.
  • a compound of Formula (I) containing a carboxy group can be prepared by hydrolyzing an ester group in a corresponding compound of Formula (I) under acid hydrolysis reaction conditions.
  • the resulting carboxy group can optionally be converted to an amido group, if desired, by first converting the carboxy group to an activated ester derivative e.g., treating the carboxy compound with dicyclohexyl carbodiimide, DEAD and the like, followed by treatment with an amine. It will be recognized by a person skilled in the art that some of these transformations can be carried out prior to converting the compound of formula 5 to a compound of Formula (I).
  • R 3 X Treatment of dimethyl malate 5 under strongly basic conditions with an appropriate alkylhalide R 3 X (where R 3 is alkyl, alkenyl, alkynyl, substituted, heteroalkyl and X is halo such as chloro, bromo, or iodo) provides 2-substituted dimethyl malate 6.
  • the reaction is typically carried out in a polar aprotic solvent such as THF, and the base is typically lithium diisopropylamide (LDA).
  • LDA lithium diisopropylamide
  • the reaction is initially carried out at a low temperature, preferably at about - 78 °C, and then allowed to slowly warm to room temperature. The reaction is then stirred for several hours. The reaction is typically higher yielding when R 3 X is an allylic halide.
  • the resulting olefin can be reduced, if desired, to provide a compound of formula 6 where R 3 is alkyl.
  • the typically reduction procedure involves a suspension of 6 and a catalyst (e.g., 10 % palladium on carbon) in a solvent such as ethylacetate and would be stirred under a hydrogen atmosphere for several hours to afford the corresponding compound of formula 6 where R 3 is alkyl.
  • a catalyst e.g. 10 % palladium on carbon
  • Many compounds of formula R 3 X are commercially available or they can be prepared by methods well known in the art. For example, iodomethane, benzylbromide, crotylbromide, allylbromide, vinylbromide are commercially available.
  • Others can be prepared from the corresponding alcohol by first activating the hydroxy group as ap- toluenesulfonate ester (tosyl ester), followed by tosylate displaced with a halide ion in a modified Finkelstein procedure to afford an alkylhalide as described in working examples below.
  • Treatment of 6 with a base affords a malic acid derivative of formula 7.
  • the base can be an inorganic base such as lithium hydroxide or potassium hydroxide, and is most preferably sodium hydroxide. This reaction is usually performed in a polar, protic solvent such as methanol.
  • an orthoester 8 (R a is -Ph and R b is -OMe).
  • This reaction is ideally performed with a co-solvent, preferably in a mixture of toluene.
  • the reaction is ideally performed at a higher temperature, most preferably at 110 °C.
  • the catalyst is typically a sulfonic acid, such as/7-toluenesulfonic acid, or most preferably camphorsulfonic acid.
  • Compound 10 is then optionally converted to a compound of formula 11 for reasons discussed in Scheme A such as derivatizing the R 3 , R and/or R 7 groups prior to converting it to a compound of Formula (I).
  • compound 10 it can be directly converted to a compound of Formula (I) as described in Scheme A above.
  • the hydroxy group in compound 10 can be replaced by various other Ri groups as defined in the Summary of the Invention prior to converting it to a compound of Formula (I).
  • Some representative examples are discussed below: (i) the hydroxy group in compound 10 can be replaced by a fluoro group prior to converting it to a compound of Formula (I) as shown below.
  • the hydroxyl group at the C2 carbon in compound 10 can be replaced by a fluoro group by first converting the hydroxyl group into an active ester followed by displaced with fluorine to afford compound 12.
  • the reaction is performed in a halogenated solvent, such as dichloromethane (DCM), in the presence of an organic base, such as pyridine.
  • DCM dichloromethane
  • the alcohol is typically activated as a sulfonate ester, preferably the trifluoromethane-sulfonate. This esterification reaction is typically earned out at a low temperature, preferably about -20 °C.
  • the active ester is then reacted with a fluoride ion, typically derived from tris(dimethylamino)sulfur- (trimethylsilyl)difluoride (TAS-F).
  • a fluoride ion typically derived from tris(dimethylamino)sulfur- (trimethylsilyl)difluoride (TAS-F).
  • TAS-F tris(dimethylamino)sulfur- (trimethylsilyl)difluoride
  • the stereochemistry at the C2 carbon atom is inverted during this transformation, (ii) the hydroxy group in compound 10 can be converted to an alkoxy under alkylation reaction conditions such as treatment of 10 with an alkyl halide such as methyl iodide, ethyl iodide, benzyl bromide, and the like, in the presence of a strong base such as sodium hydride and in a polar solvent such as dimethylformamide.
  • an alkyl halide such as methyl iodide, ethyl iodide, benzyl bromide, and the like
  • the hydroxy group in compound 10 can be converted to benzoyloxy group by first converting it into an activated ester such as a sulfonate ester, preferably the trifluoromethanesulfonate, followed by treatment with tetrabutyl ammomium benzoate.
  • an activated ester such as a sulfonate ester, preferably the trifluoromethanesulfonate
  • the hydroxy group in compound 10 can be converted to thiol group by first converting it into an activated ester such as a sulfonate ester, preferably the trifluoromethanesulfonate, followed by treatment potassium thioacetate.
  • Example 48 Detailed description of this procedure is provided in Example 48 below.
  • the hydroxy group in compound 10 can be converted to an azido or amino group or it's derivatives by first converting it into an activated ester such as a sulfonate ester, preferably the trifluoromethanesulfonate, followed by treatment with sodium azide.
  • an activated ester such as a sulfonate ester, preferably the trifluoromethanesulfonate
  • the azide group can optionally reducted under catalytic hydrogenation reaction conditions to give an amino group which can be further derivatized by methods well known in the art. Detailed description of this procedure is provided in Example 49 and 34 below.
  • the hydroxyl at the C-2 carbon of intermediate 10 is converted to an active ester as described above in (i) above.
  • Nucleophilic substitution with a variety of nucleophiles such as acetate anion, or more preferably, tetrabutylammonium benzoate, provides intermediate 14. This reaction proceeds in a hydrocarbon solvent, preferably in toluene.
  • a hydrocarbon solvent preferably in toluene.
  • Compound 14 is treated with a base to afford hydroxy derivative 15.
  • This base 0 is preferably the salt of an alcohol such as sodium methoxide, sodium ethoxide and the like, and more preferably sodium methoxide.
  • the reaction proceeds in an alcoholic solvent such as methanol, ethanol and the like, most preferably in methanol.
  • Compound 15 is re-activated as a sulfonate ester, preferably a trifluoromethane sulfonate as described above and then treated with a fluorination 5 reagent, preferably TAS-F, to afford the corresponding fluoro intermediate 16 which has the same stereochemistry at the C-2 carbon as in intermediate 10.
  • a fluorination 5 reagent preferably TAS-F
  • Compound 16 or 17 is then converted to a compound of Formula (I) as discussed above.
  • a compound of Formula (I) can also be prepared as illustrated in Scheme C below.
  • a compound of Formula (I) where Ri & R 2 are fluoro and R 2 , R 3 , Re, Ri, Y and n are as defined in summary of the invention can be prepared as illustrated in Scheme D below.
  • Treatment of 22 with a base such as sodium methoxide in methanol provides 2-hydroxysuccinate derivative of formula 23.
  • Compound 23 is then converted to a trifluoromethanesulfonate ester derivative 24 using triflic anhydride in the presence of a base such as triethyamine, pyridine and the like.
  • compositions which comprise a bioactive hydroxamic acid compound or derivative, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • compositions of the invention include those in a form adapted for oral, topical or parenteral use and can be used for the treatment of bacterial infection in animals, preferably mammals, more preferably humans.
  • antibiotic compounds also referred to herein as antimicrobial compounds, according to the invention can be formulated for administration in any convenient way for use in human or veterinary medicine, by analogy with other antibiotics.
  • Such methods are known in the art (see, e.g., Remington's Pharmaceutical Sciences, Easton, PA: Mack Publishing Co.) and are not described in detail herein.
  • compositions can be formulated for administration by any route known in the art, such as subdermal, inhalation, oral, topical or parenteral.
  • the compositions can be in any form known in the art, including but not limited to tablets, capsules, powders, granules, lozenges, creams or liquid preparations, such as oral or sterile parenteral solutions or suspensions.
  • the compounds can also be administered in liposome formulations.
  • the compounds can also be administered as prodrugs, where the prodrug administered undergoes biotransformation in the treated mammal to a form which is biologically active.
  • topical formulations of the present invention can be presented as, for instance, ointments, creams or lotions, solutions, salves, emulsions, plasters, eye ointments and eye or ear drops, impregnated dressings and aerosols, and can contain appropriate conventional additives such as preservatives, solvents to assist drug penetration and emollients in ointments and creams.
  • the formulations can also contain compatible conventional carriers, such as cream or ointment bases and ethanol or oleyl alcohol for lotions.
  • Such carriers can be present, for example, from about 1% up to about 99% of the formulation. For example, they can form up to about 80% of the formulation.
  • Tablets and capsules for oral administration can be in unit dose presentation form, and can contain conventional excipients such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrollidone; fillers, for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine; tabletting lubricants, for example magnesium stearate, talc, polyethylene glycol or silica; disintegrants, for example potato starch; or acceptable wetting agents such as sodium lauryl sulphate.
  • the tablets can be coated according to methods well known in standard pharmaceutical practice.
  • Oral liquid preparations can be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or can be presented as a dry product for reconstitution with water or another suitable vehicle before use.
  • Such liquid preparations can contain conventional additives, such as suspending agents, for example sorbitol, methyl cellulose, glucose syrup, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats; emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which can include edible oils), for example almond oil, oily esters such as glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid, and, if desired, conventional flavoring or coloring agents.
  • suspending agents for example sorbitol, methyl cellulose, glucose syrup, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats
  • emulsifying agents for example lecithin, sorbitan monooleate, or
  • fluid unit dosage forms are prepared utilizing the compound and a sterile vehicle, water being prefened.
  • the compound depending on the vehicle and concentration used, can be either suspended or dissolved in the vehicle or other suitable solvent.
  • the compound can be dissolved in water for injection and filter sterilized before filling into a suitable vial or ampoule and sealing.
  • agents such as a local anesthetic preservative and buffering agents can be dissolved in the vehicle.
  • the composition can be frozen after filling into the vial and the water removed under vacuum. The dry lyophilized powder is then sealed in the vial and an accompanying vial of water for injection can be supplied to reconstitute the liquid prior to use.
  • Parenteral suspensions are prepared in substantially the same manner except that the compound is suspended in the vehicle instead of being dissolved and sterilization cannot be accomplished by filtration.
  • the compound can be sterilized by exposure to ethylene oxide before suspending in the sterile vehicle.
  • a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.
  • compositions can contain, for example, from about 0.1% by weight to about 99%o by weight, e.g., from about 10-60%> by weight, of the active material, depending on the method of administration.
  • each unit will contain, for example, from about 1-500 mg of the active ingredient.
  • the dosage as employed for adult human treatment will range, for example, from about 1 to 3000 mg per day, for instance 1500 mg per day depending on the route and frequency of administration. Such a dosage corresponds to about 0.015 to 50 mg/kg per day.
  • the dosage is, for example, from about 5 to 20 mg/kg per day.
  • the hydroxamate compounds of the present invention can be used for the treatment or prevention of infectious disorders caused by a variety of bacterial or prokaryotic organisms.
  • infectious disorders caused by a variety of bacterial or prokaryotic organisms.
  • examples include Gram positive and Gram negative aerobic and anaerobic bacteria, including Staphylococci, for example S. aureus and S. epidermidis; Enterococci, for example E. faecalis and E. faecium; Streptococci, for example S pneumoniae; Haemophilus, for example H. influenza; Moraxella, for example M. catarrhalis; and Escherichia, for example E. coli.
  • Other examples include Mycobacteria, for example M.
  • compositions, for treating or preventing infectious disorders comprising a hydroxamic acid compound or derivative as disclosed herein in combination with a pharmaceutically acceptable carrier.
  • a dosage amount of a hydroxamic acid compound or derivative as disclosed herein in an effective amount for the treatment, prevention or alleviation of a disorder, such as an infectious disorder can be screened for activity against different microbial agents and appropriate dosages can be determined using methods available in the art.
  • the compounds can be used to treat a subject to treat, prevent, or reduce the severity of an infection.
  • Subjects include animals, plants, blood products, cultures and surfaces such as those of medical or research equipment, such as glass, needles, surgical equipment and tubing, and objects intended for temporary or permanent implantation into an organism.
  • Treating a subject includes, but is not limited to, preventing, reducing, or eliminating the clinical symptoms caused by an infection of a subject by a microorganism; preventing, reducing, or eliminating an infection of a subject by a microorganism; or preventing, reducing, or eliminating contamination of a subject by a microorganism.
  • the microorganism involved is preferably a prokaryote, more preferably a bacterium.
  • an infectious disorder in a subject such as a human or other animal subject
  • methods of treating or preventing an infectious disorder in a subject are provided, by administering an effective amount of a hydroxamic acid compound or derivative as disclosed herein to the subject.
  • the compound is administered in a pharmaceutically acceptable form optionally in a pharmaceutically acceptable carrier.
  • infectious disorder is any disorder characterized by the presence of a microbial infection, such as the presence of bacteria.
  • infectious disorders include, for example central nervous system infections, external ear infections, infections of the middle ear, such as acute otitis media, infections of the cranial sinuses, eye infections, infections of the oral cavity, such as infections of the teeth, gums and mucosa, upper respiratory tract infections, lower respiratory tract infections, genitourinary infections, gastrointestinal infections, gynecological infections, septicemia, bone and joint infections, skin and skin structure infections, bacterial endocarditis, burns, antibacterial prophylaxis of surgery, and antibacterial prophylaxis in immunosuppressed patients, such as patients receiving cancer chemotherapy, or organ transplant patients.
  • the compounds and compositions comprising the compounds can be administered by routes such as topically, locally or systemically.
  • Systemic application includes any method of introducing the compound into the tissues of the body, e.g., intrathecal, epidural, intramuscular, transdermal, intravenous, intraperitoneal, subcutaneous, sublingual, nasal, vaginal, rectal, and oral administration.
  • the specific dosage of antimicrobial to be administered, as well as the duration of treatment, can be adjusted as needed.
  • the compounds of this invention can also be used to prepare a composition in an inert diluent which is useful in inhibiting bacterial growth.
  • An "inert diluent" means an excipient that is useful in preparing a composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable.
  • DIAD diisopropylazodicarboxylate
  • Fmoc, FMOC 9-fluorenylmethyloxycarbonyl
  • HATU O-(7-aza-benzotriazol-l-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate
  • HBTU O-(benzotriazol-l-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate
  • HHMPA (4-hydroxymethyl-3-methoxyphenoxy)-alkanoic acid
  • HMP resin hydroxymethylphenoxy resin
  • HOAt 1 -hydroxy-7-azabenzotriazole
  • HOBt 1 -hydroxybenzotriazole
  • MeOH methanol
  • MMP matrix metalloproteinase
  • NMM N-methyl morpholine
  • NPEOC 4-nitrophenethyloxycarbonyl
  • NPEOM 4-nitrophenethylmethyloxycarbonyl
  • NVOC 6-nitroveratryloxycarbonyl
  • NVOM nitroveratryloxymethyl ether
  • PS-PS resins or PS-PEG resin polyethylene glycol-polystyrene graft copolymer resins
  • PFP-OTFA pentafluorophenyl trifluoroacetate
  • PyBOP benzotriazole-1-yl-oxy-tris-pyrrolidinophosphonium hexafluorophosphate
  • PyBROP bromotripyrrolidinophosphonium hexafluorophosphate
  • TBP tributylphosphate
  • TGS resin TENTAGEL S resin
  • TGS NH 2 resin TENTAGEL S NH 2 resin
  • THF tetrahydrofuran
  • THP 2-tetrahydropyranyl
  • TM AD N,N,N',N'-tetramethylazodicarboxamide (1,1 '- Azobis(N,N- dimethylformamide))
  • TMOF trimethylorthoformate
  • TPP triphenyl phosphine
  • TsCl tosyl chloride
  • TsOH toluenesulfonic acid
  • Trt trityl
  • Step 2 To methyl-3-(i?)-butyl-3-(2-(S)-carboxycarbonylpyrrolidin- 1 -ylcarbonyl)- propionate E-2 (100 mg) in DMF (1 mL) was added an amine (1 equivalent), DIEA (2.5 equivalents) and HATU (1 equivalent) and the reaction stirred for 4 h. The solution was then cooled to 0 °C, 50 %> aqueous hydroxylamine was added (400 ⁇ L), and the reaction stined at 4 °C for 4 hours to 3 days, depending upon the succinate.
  • Tris(dimethylamino)sulfur (trimethylsilyl)difluoride (TAS-F) was added (5 mmol) and the solution allowed to warm to rt.
  • the reaction mixture was washed with aqueous sodium bicarbonate and brine, dried (Na 2 SO 4 ) and concentrated then purified on silica gel (ethylacetate/hexanes) to afford 2.3 mmol (45 %>) of methyl 3-(S)-n- butyl-3-[2-(S)-tert-butoxycarbonylpyrrolidin-l-yl-carbonyl)-2-(/?)-fluoropropionate
  • Step 2 To methyl 3-(i?)-n-butyl-3-[2-(S)-tert-butoxycarbonylpyrrolidin-l-yl- carbonyl)-2-(i?)-benzoyloxypropionate H-2 (8.7 mmol) in methanol (25 mL) at 0 °C was added sodium methoxide (catalytic; pH adjusted to 10) and the solution stirred for 2 h.
  • Step 3 To methyl 3-(i?)-n-butyl-3-[2-(S)-tert-butoxycarbonylpyrrolidin-l-yl- carbonyl)-2-(i?)-hydroxypropionate H-3 (8.7 mmol) in DCM (10 mL) was added pyridine (25 mmol), the reaction was cooled to -20 °C, then triflic anhydride (12.5 mmol) was added. The solution was stirred for 1 hour, then worked up as described above. The intermediate triflate was resuspended in DCM and cooled to -50 °C.
  • Tris(dimethylamino)sulfur (trimethylsilyl)difluoride (TAS-F) was added (8.7 mmol) and the solution allowed to warm to rt.
  • the reaction mixture was washed with aqueous sodium bicarbonate and brine, dried (Na 2 SO 4 ) and concentrated, then purified on silica gel (ethylacetate/hexanes) to afford 4.3 mmol (50 %>) of methyl 3- (S)-n-butyl-3-[2-(S)-tert-butoxycarbonylpyrrolidin-l-yl-carbonyl)-2-(S)- fluoropropionate H-4.
  • N-Boc-(2-methylaminocarbonyl)pynolidine (3.3 g, 63%>).
  • Step 2 N-Boc-(2-methylaminocarbonyl)pyrrolidine (3.3 g, 14.5 mmol) was treated with HCl (4 N in dioxane, 10 mL) for 1 h.
  • Step 3 To mono t-butyl 2-(i?)-(n-butyl)-3-( ⁇ S)-methylsuccinic acid (680 mg, 1.39 mmol, prepared in step 2 above) in DCM (15 mL) was added L-proline methyl ester hydrochloride (3.34 mmol, 554 mg), DIEA (1.28 mL, 7.34 mmol) and then PyBOP (1.74 g, 3.34 mmol).
  • the t-butyl group was removed from mono t-butyl 3-( ?)-(n-butyl)-3-[2-(S)- methoxycarbonyl)pyrrolidin-l -ylcarbonyl] -2-(S)-methylpropionate (260 mg, 732 ⁇ mol) using 1 :2 TFA/DCM, followed by evaporation of the TFA and solvent.
  • Step 4 Phenylsulfonyl chloride (2 eq.) was added slowly to a solution of methyl 3- (i?)-(n-butyl)-3-[2-(S)-tert-butoxycarbonyl)-4-(S)-azido-pyrrolidin-l-ylcarbonyl]- propionate (ca. 0.1 g) in DCM (lmL) and pyridine (0.1 mL) at 0 °C. The solution was allowed to warm to rt and then stined an additional 2 h. The solvent was removed in vacuo, the residue dissolved in EtOAc (5 mL) and washed with HCl solution (5%), NaHCO 3 (sat.) and brine.
  • Step 1 To l-(2,2-dimethyl-4-oxo-l,3-dioxolan-5-yl)-l-(2-(S)-tert- butoxycarbonylpyrrolidin-l-ylcarbonyl)pentane (4 mmol; prepared as described previously using, tert-butyl ester of compound F-6, General Procedure F) in methanol
  • TPP triphenylphosphine
  • DIAD diisopropylazodicarboxylate
  • Methyl 3-(i?)-(n-butyl)-3-[(2-(S)-(tert-butoxycarbonyl)pyrrolidin- 1 -ylcarbonyl] -2-(i?)-benzoyloxypropionate (prepared as described in Example 37) was de- O-benzoylated by treatment with methanolic sodium methoxide at 0°C for 2 hours.
  • Step 2 To methyl 3-(i?)-(n-butyl)-3-[(2-(S)-(carboxy)pynolidin-l-yl- carbonyl]propionate (0.2 mmol) in dioxane (1 mL) was added 2-(l-cyclohexenyl)- ethyl amine (0.22 mmol), DIEA (0.22 mmol) and HATU (0.22 mmol) and the reaction stined for 2 h. Aqueous 50 %> hydroxylamine was then added (1 mL), and the reaction stined an additional 24 h. The reaction mixture was purified by preparative reverse-phase (C18) HPLC to afford the title compound. MS (APCI) m/z 394 [M+H].
  • reaction was stined for 16 h, then diluted with ethylacetate, washed with water, saturated aqueous sodium bicarbonate, and brine, then dried ( ⁇ a 2 SO 4 ) and puriifed on silica gel (ethylacetate/hexanes) to afford methyl 3-(#)-(n-butyl)-3-[(2-(S)-(tert- butoxycarbonyl)-pynolidin-l-ylcarbonyl]-2-(R)-azidopropionate.

Abstract

Novel hydroxamic acid compounds of Formula (I) are disclosed. These hydroxamates inhibit peptide deformylase (PDF), an enzyme present in prokaryotes. The hydroxymates are useful as antimicrobials and antibiotics. The compounds of the invention display selective inhibition of peptidyl deformylase versus other metalloproteinases such as matrix metalloproteinases (MMPs). Methods of synthesis and of use of the compounds are also disclosed.

Description

NOVEL SUCCINATE COMPOUNDS, COMPOSITIONS AND METHODS OF
USE AND PREPARATION
CROSS-REFERENCE TO RELATED APPLICATIONS
The application claims priority to U.S, Patent Application No. 09/466,402, filed on December 17, 1999, the disclosure of which is incorporated herein in its entirety.
BACKGROUND OF THE INVENTION
Field .of the invention
This invention is directed to novel succinate compounds. This invention is also directed to uses of these compounds in various medicinal applications, including treating disorders amenable to treatment by peptidyl deformylase inhibitors. This invention is still further directed to pharmaceutical compounds comprising these compounds and methods of synthesis thereof. State of the Art
Treatment of microbial infection in host organisms requires an effective means to kill the microbe while doing as little harm to the host as possible. Accordingly, agents which target characteristics unique to a pathology-causing microorganism are desirable for treatment. Penicillin is an extremely well known example of such an agent. Penicillin acts by inhibiting biosynthesis of bacterial cell walls. Since mammalian cells do not require cell walls for survival, administration of penicillin to a human infected with bacteria can kill the bacteria without killing human cells. However, the use of antibiotics and antimicrobials has also resulted in increased resistance to these agents. As bacteria become resistant to older, more widely used antimicrobial agents, new antimicrobials must be developed in order to provide effective treatments for human and non-human animals suffering from microbial infection.
Peptide deformylase is a metallopeptidase found in prokaryotic organisms such as bacteria. Protein synthesis in prokaryotic organisms begins with N-formyl methionine (fMet). After initiation of protein synthesis, the formyl group is removed by the enzyme peptide deformylase (PDF); this activity is essential for maturation of proteins. It has been shown that PDF is required for bacterial growth (Chang et al. J. Bacteriol. 171 :4071-4072 (1989); Meinnel T, Blanquet S, J. Bacteriol. 176(23):7387- 90 (1994); Mazel D et al., EMBOJ. 13(4):914-23 (1994 )). Since protein synthesis in eukaryotic organisms does not depend on fMet for initiation, agents that will inhibit PDF are attractive candidates for development of new antimicrobial and antibacterial drugs. Prokaryotic organisms, including disease-causing prokaryotes, are described in Balows, A., H.G. Truper, M. Dworkin, W. Harder, and K.-H. Schleifer (eds.), The Prokaryotes, 2nd ed., New York: Springer-Verlag, 1992; and Holt, J.G. (editor-in- chief). Bergey's Manual of Systematic Bacteriology, Vols. 1-4, Baltimore: Williams & Wilkins, 1982, 1986, 1989.
PDF is part of the metalloproteinase superfamily. While PDF clearly shares many of the features which characterize metalloproteinases, it differs from other members of the superfamily in several important respects. First, the metal ion in the active enzyme appears to be Fe (II), or possibly another divalent cationic metal, instead of the zinc ion more commonly encountered. Rajagopalan et al, J. Am. Chem. Soc, 119:12418-19 (1997). Second, the divalent ion appears to play an important role, not only in catalysis, but also in the structural integrity of the protein. Third, the third ligand of the divalent ion is a cysteine, rather than a histidine or a glutamate, as in other metalloproteinases and is not located at the C-terminal side of the HEXXH motif but far away along the amino acid sequence and N-terminal to the motif. Finally, the solution structure shows significant differences in the secondary and tertiary structure of PDF compared to other prototypical metalloproteinases see Meinnel et al. J. Mol Biol 262:375-386 (1996). PDF from E. coli, Bacillus stear other mophilus, and Thermus thermophilus have been characterized see Meinnel et al., J Mol Biol 267:749-761 (1997). The enzyme studied by Meinnel et al. contained a zinc ion as the divalent ion and the structural features summarized above were obtained from zinc-containing proteins. The structure of the protein has also been determined by NMR (see O'Connell et al, J. Biotnol NMR 13(4):311-24 (1999)). Metalloproteinases are critical to many aspects of normal metabolism. The class known as matrix metalloproteinases (MMPs) are involved in tissue remodeling, such as degradation of the extracellular matrix. These enzymes are believed to play a role in normal or beneficial biological events such as the formation of the corpus luteum during pregnancy (see Liu et al, Endocrinology 140(11):5330-8 (1999)), wound healing (Yamagiwa et al, Bone 25(2): 197-203 (1999)), and bone growth in healthy children (Bord et al., Bone 23(1):7-12 (1998)). Disorders involving metalloproteinases have been implicated in several diseases such as cancer, arthritis, and autoimmune diseases. Because of the importance of MMPs in normal physiological processes, it would be preferable to develop agents that inhibit PDF, a metalloproteinase present only in prokaryotes, while avoiding significant inhibition of MMPs. Alternatively, PDF inhibitors which also inhibit MMPs can be of use where the therapeutic benefits of inhibiting PDF outweigh the risk of side effects from MMP inhibition. A wide variety of compounds have been developed as candidate inhibitors of
MMPs and other metalloproteinases, and much effort has also been directed at synthetic methods for these compounds and related compounds. See Izquierdo- Martin et al. (1992) J. Am. Chem. Soc. 114:325-331; Cushman et al. (1981) Chapter 5 "Specific Inhibitors of Zinc Metallopeptidases" in Topics in Molecular Pharmacology (Burgen & Roberts, eds.); Mohler et al. Nature 370:218-220 (1994); Gearing et al., Nature 370:555-557 (1994); McGeehan et al., Nature 370:558-561 (1994); U.S. Patent Nos. 4,052,511, 4,303,662, 4,311,705, 4,321,383, 4,599,361, 4,804,676, 5,128,346, 5,256,657, 5,268,384, 5,447,929, 5,453,423, 5,552,419, 5,614,625, 5,643,908, 5,712,300, and 5,869,518; European patent publications EP 236872, EP 274453, EP 334244, EP 423943, EP 489577, EP 489579, EP 497192, EP 574758; and International PCT Patent Applications Publication Nos. WO 90/05716, WO 90/05719, WO 91/02716, WO 92/13831, WO 92/22523, WO 93/09090, WO 93/09097, WO 93/20047, WO 93/24449, WO 93/24475, WO 94/02446, WO 94/02447, WO 94/21612, WO 94/25434, WO 94/25435, WO 95/33731, WO 96/25156, WO 96/26918 WO 97/30707, WO 97/49674, WO 98/55449, and WO 99/02510.
Research on inhibitors of PDF is much less extensive than that for inhibitors of MMPs. N- formyl hydroxylamine derivatives are described in International Patent Application WO 99/39704. Peptide aldehyde inhibitors of PDFs are described in Durand et al, Arch. Biochem. Biophys., 367(2):297-302 (1999). The PDF inhibitor (S)-2-O-(H-phosphonoxy)-L-caproyl-L-leucyl-p-nitroanilide is described in Hao et al, Biochemistry 38:4712-4719 (1999), and peptidyl H-phosphonate inhibitors of PDF are discussed in Hu et al, Bioorg. Med. Chem. Lett. 8:2479-2482 (1998). Formylated peptides and pseudopeptides are described in Meinnel et al, Biochemistry 38(14):4288-4295 (1999) as inhibitors of PDF.
In view of the importance of identifying new antibiotics to treat bacteria resistant to existing antibiotics, and the relatively small amount of work that has been carried out on PDF inhibitors, it is desirable to develop novel inhibitors of PDF for evaluation and use as antibacterial and antimicrobial agents. The present invention fulfills this need.
SUMMARY OF THE INVENTION In one aspect, this invention is directed to a compound of Formula (I):
Figure imgf000005_0001
wherein:
Ri is hydrogen, halo, -OH, -R8OR9, -R9, -OR9, -SH, -SR9, -NH2, -NHR9 -NR9Ri0, -NHC(=O)H, -NR9C(=O)H, -NHC(=O)R9, -NR9C(=O)Rι0, -NHC(=O)NH2, -NR9C(=O)NH2, -NHC(=O)NHR9, -NHC(O)NR9R10, -NR9C(=O)NR9aRι0, -NHC(=O)OR9, -NR9C(=O)ORi0, -NHS(=O)2R9, -NR9S(=O)2R10, -NHS(=O)2OR9, or -NR9S(=O)2ORi0 where R8 is selected from the group consisting of -Cι-Cι2 alkylene, substituted alkylene, or heteroalkylene, -Cι-Cι2 alkenylene, substituted alkenylene, or heteroalkenylene, -C]-C]2 alkynylene, substituted alkynylene, or heteroalkynylene, and -(Cι-C8 alkylene or substituted alkylene)nl-(C3-Cι2 arylene or heteroarylene)-(Cι- C8 alkyl or substituted alkyl)n2 where nl and n2 are independently 0 or 1 ; and R , R a and Rio are independently selected from the group consisting of -Cι-Cι2 alkyl, substituted alkyl, or heteroalkyl, -Cι-Cι2 alkenyl, substituted alkenyl, or heteroalkenyl, -Cι-Cι alkynyl, substituted alkynyl, or heteroalkynyl, and -(Cι-C8 alkyl or substituted alkyl)n3-(C3-Cι2 arylene or heteroarylene)-(Cι-C8 alkyl or substituted alkyl)n4 where n3 and n4 are independently 0 or 1 ;
R2 is independently hydrogen or -R9 wherein R9 is as defined above;
R3 is hydrogen, halo, -Rn, -OH, -ORn, -R,2ORH, -SH, -SRU, -NH2, -NHRn, -NRιιR,3, -NHC(=O)H, -NR, ,C(=O)H, -NHC(=O)Rπ, -NRπC(=O)R,3, -NHC(=O)NH2, -NR„C(=O)NH2, -NHC(=O)NHRπ, -NHC(=O)NRnRι3,
Figure imgf000006_0001
Figure imgf000006_0002
where Rι2 is selected from the group consisting of -Cι-Cι2 alkylene, substituted alkylene, or heteroalkylene, -C\- C12 alkenylene, substituted alkenylene, or heteroalkenylene, -Cι-Cι2 alkynylene, substituted alkynylene, or heteroalkynylene, and -(Cι-C8 alkylene or substituted alkylene)n5-(C3-Cι2 arylene or heteroarylene)-(Cι-C8 alkyl or substituted alkyl)n6 where n5 and n6 are independently 0 or 1; and Rπ, Riia and Rj3 are independently selected from the group consisting of -Cι-Cι2 alkyl, substituted alkyl, or heteroalkyl, -Cι-Cι2 alkenyl, substituted alkenyl, or heteroalkenyl, -Cι-C12 alkynyl, substituted alkynyl, or heteroalkynyl, and -(Cι-C8 alkyl or substituted alkyl)n7-(C3-Cι2 arylene or heteroarylene)-(Cι-C8 alkyl or substituted alkyl)n8 where n7 and n8 are independently O or 1;
R4 is hydrogen or -Ri \ where -Ri 1 is as defined above; n is an integer from 1 to 5; zero or one Y is selected from the group consisting of -O-, -NRπ- where Ri 1 is as defined above, and -S-, and all remaining Y are -CRόR7- where R(, and R7 are each independently selected from the group consisting of hydrogen, -Rj4, -OH, -OR14, -SH, -SR14, -NH2, -NHR,4, -NR14R15, -C(=O)H, -C(=O)R,4, -C(=O)NH2, -C(=O)NHRi4, -C(=O)NR,4Ri5, -C(=O)OH, -C(=O)OR14, -C(=O)SH, -C(=O)SRι4, -C(=O)CH3, -C(=O)CH2Ri4, -C(=O)CHR14R15, -C(=O)CR14Rι5Rι6, -C(=O)OCH3, -C(=O)OCH2Ri4, -C(=O)OCHRI4R15, -C(=O)OCRι4Rι5Rι6, -S(=O)2NH2, -S(=O)2NHR,4, -S(=O)2NR14R]5, -NHC(=O)H, -N(R,4)C(=O)H, -NHC(=O)R15, -N(R14)C(=O)R,5, -NHC(=O)OR14, -NHS(=O)2H, -N(R14)S(=O)2H, -NHS(=O)2ORι5, -N(R,4)S(=O)2ORι5, -N(H)S(=O)2Rι5, -N(R,4)S(=O)2Rι5 and where two vicinal R6 or R7 groups combine to form a substituted or unsubstituted -C4-Cι0 cyclic alkyl, cyclic heteroalkyl, aryl or heteroaryl group where R] , R1 and R]6 are each independently selected from the group consisting of -Cι-Cι2 alkyl, substituted alkyl, or heteroalkyl, -Cι-Cι2 alkenyl, substituted alkenyl, or heteroalkenyl, -Cι-Cι2 alkynyl, substituted alkynyl, or heteroalkynyl, alkoxy, and -(Cι-C8 alkyl or substituted alkyl)n9-(C -Cι arylene or heteroarylene)-(Cι-C8 alkyl or substituted alkyl)n 10 where n9 and nlO are independently 0 or 1; or when R]4 and R15 are attached to a nitrogen atom they can combine to form a substituted or unsubstituted -C4-Cι0 cyclic alkyl, cyclic heteroalkyl, aryl or heteroaryl group; or a pharmaceutically acceptable salt thereof. Preferably the compound of Formula (I) inhibits peptidyl deformylase at an IC50 of less than or equal to about 100 nm, preferably of less than or equal to 10 nm, more preferably of less than or equal to 1 nm.
Preferably the compound of Formula (I) displays a selectivity for peptidyl deformylase over at least one metalloproteinase selected from the group consisting of ACE and Matrilysin of greater than or equal to about 10 times, more preferably of greater than or equal to about 100 times, still more preferably of greater than or equal to about 1000 times.
In a second aspect, this invention is directed to pharmaceutical compositions comprising a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.
In a third aspect, this invention is directed to a method of treatment of a disease in a mammal treatable by administration of a peptidyl deformylase inhibitor which method comprises administration of a therapeutically effective amount of a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient either alone or in combination with other pharmacologically active agents. In particular, the compounds of this invention are useful in treating microbial diseases. The microbial infection can be due to bacteria, other prokaryotes, or other organisms, including parasites, dependent on peptide deformylase for growth or survival.
In a fourth aspect, this invention is directed to the use of a compound of Formula (I) or a pharmaceutically acceptable salts thereof in the preparation of a medicament for use in the treatment of diseases mediated by peptidyl deformylase enzyme.
In a fifth aspect, this invention is directed to a method for identifying compounds useful in treating microbial infections, comprising performing an assay to identify compounds which meet the criterion of either i) an IC50 for peptide deformylase of less than or equal to about 1 μM, or ii) an MIC for a disease-causing pathogen of less than or equal to about 32 μg/ml; performing an assay to identify compounds which meet the criterion of iii) displaying a selectivity for peptide deformylase over at least one metalloproteinase selected from the group consisting of Angiotensin Converting Enzyme (ACE) and Matrilysin of greater than or equal to about 10 times; and selecting compounds which meet either both criteria i) and iii), or both criteria ii) and iii). More preferably, the compounds so identified meet the criterion of either i) an IC50 for peptide deformylase of less than or equal to about 100 nM, or ii) an MIC for a disease-causing pathogen of less than or equal to about 10 μg/ml.
DETAILED DESCRIPTION OF THE INVENTION Unless otherwise stated, the following terms as used in the specification have the following meaning.
The term "alkyl" refers to saturated aliphatic groups including straight-chain, branched-chain, cyclic groups, and combinations thereof, having the number of carbon atoms specified, or if no number is specified, having 1 to 12 carbon atoms. Examples of alkyl groups include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, neopentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclobutylmethyl, cyclobutylethyl, cyclopentylmefhyl, cyclopentylethyl, and adamantyl. Cyclic alkyl groups can consist of one ring, including, but not limited to, groups such as cycloheptyl, or multiple fused rings, including, but not limited to, groups such as adamantyl or norbornyl. The term "alkylene" means a saturated divalent aliphatic groups including straight-chain, branched-chain, cyclic groups, and combinations thereof, having the number of carbon atoms specified, or if no number is specified, having 1 to 12 carbon atoms, e.g., methylene, ethylene, 2,2-dimethylethylene, propylene, 2-methyl- propylene, butylene, pentylene, cyclopentylmethylene, and the like.
The term "substituted alkyl" means an alkyl group as defined above that is substituted with one or more substituents, preferably one to three substituents selected from the group consisting of halogen (fluoro, chloro, bromo, and iodo, preferably fluoro, chloro, or bromo), alkoxy, acyloxy, amino, mono or dialkylamino, hydroxyl, mercapto, carboxy, benzyloxy, phenyl, benzyl, cyano, nitro, thioalkoxy, carboxaldehyde, carboalkoxy and carboxamide, or a functionality that can be suitably blocked, if necessary for purposes of the invention, with a protecting group. The phenyl group may optionally be substituted with one to three substituents selected from the group consisting of halogen (fluoro, chloro, bromo, and iodo, preferably fluoro, chloro, or bromo), alkoxy, acyloxy, amino, mono or dialkylamino, hydroxyl, mercapto, carboxy, benzyloxy, benzyl, cyano, nitro, thioalkoxy, carboxaldehyde, carboalkoxy and carboxamide. Examples of substituted alkyl groups include, but are not limited to, -CF3, -CF2-CF3, hydroxymethyl, 1- or 2-hydroxyethyl, methoxymethyl, 1- or 2-ethoxyethyl, carboxymethyl, 1- or 2- carboxyethyl, methoxycarbonylmethyl, 1- or 2-methoxycarbonyl ethyl, benzyl, and the like.
The term "substituted alkylene" means an alkylene group as defined above that is substituted with one or more substituents, preferably one to three substituents, selected from the group consisting of halogen (fluoro, chloro, bromo, and iodo, preferably fluoro, chloro, or bromo), alkoxy, acyloxy, amino, mono or dialkylamino, hydroxyl, mercapto, carboxy, benzyloxy, phenyl, benzyl, cyano, nitro, thioalkoxy, carboxaldehyde, carboalkoxy and carboxamide, or a functionality that can be suitably blocked, if necessary for purposes of the invention, with a protecting group. The phenyl group may optionally be substituted with one to three substituents selected from the group consisting of halogen (fluoro, chloro, bromo, and iodo, preferably fluoro, chloro, or bromo), alkoxy, acyloxy, amino, mono or dialkylamino, hydroxyl, mercapto, carboxy, benzyloxy, benzyl, cyano, nitro, thioalkoxy, carboxaldehyde, carboalkoxy and carboxamide. Examples of substituted alkyl groups include, but are not limited to, -CF2-, -CF2-CF2-, hydroxymefhylene, 1- or 2-hydroxyethylene, methoxymethylene, 1- or 2-ethoxyethylene, carboxymethylene, 1- or 2-carboxy- ethylene, and the like.
The term "alkenyl" refers to unsaturated aliphatic groups including straight- chain, branched-chain, cyclic groups, and combinations thereof, having the number of carbon atoms specified, or if no number is specified, having 1 to 12 carbon atoms, which contain at least one double bond (-C=C-). Examples of alkenyl groups include, but are not limited to, allyl vinyl, -CH2-CH=CH-CH3, -CH2-CH2-cyclopentenyl and -CH2-CH2-cyclohexenyl where the ethyl group can be attached to the cyclopentenyl, cyclohexenyl moiety at any available carbon valence.
The term "alkenylene" refers to unsaturated divalent aliphatic groups including straight-chain, branched-chain, cyclic groups, and combinations thereof, having the number of carbon atoms specified, or if no number is specified, having 1 to 12 carbon atoms, which contain at least one double bond (-C=C-). Examples of alkenylene groups include, but are not limited to, -CH=CH-, -CH2-CH=CH-CH2-, -CH2-CH(cyclopentenyl)- and the like.
The term "alkynyl" refers to unsaturated aliphatic groups including straight- chain, branched-chain, cyclic groups, and combinations thereof, having the number of carbon atoms specified, or if no number is specified, having 1 to 12 carbon atoms, which contain at least one triple bond ( -C≡C-). Examples of alkynyl groups include, but are not limited to, acetylene, 2-butynyl, and the like.
The term "alkynylene" refers to unsaturated divalent aliphatic groups including straight-chain, branched-chain, cyclic groups, and combinations thereof, having the number of carbon atoms specified, or if no number is specified, having 1 to 12 carbon atoms, which contain at least one triple bond ( -C≡C-). Examples of alkynylene groups include, but are not limited to, -C≡C-, -C≡C-CH2-, and the like.
The term "substituted alkenyl" or "substituted alkynyl," refers to the alkenyl and alkynyl groups as defined above that are substituted with one or more substituents, selected from the group consisting of halogen, alkoxy, acyloxy, amino, hydroxyl, mercapto, carboxy, benzyloxy, phenyl, benzyl, cyano, nitro, thioalkoxy, carboxaldehyde, carboalkoxy and carboxamide, or a functionality that can be suitably blocked, if necessary for purposes of the invention, with a protecting group. Examples of substituted alkenyl and alkynyl groups include, but are not limited to, -CH=CF , hydroxyethenyl, methoxypropenyl, hydroxypropynyl, and the like.
The term "substituted alkenylene" or "substituted alkynylene," refers to the alkenylene and alkynylene groups as defined above that are substituted with one or more substituents, selected from the group consisting of halogen, alkoxy, acyloxy, amino, hydroxyl, mercapto, carboxy, benzyloxy, phenyl, benzyl, cyano, nitro, thioalkoxy, carboxaldehyde, carboalkoxy and carboxamide, or a functionality that can be suitably blocked, if necessary for purposes of the invention, with a protecting group.
The term "aryl" or "Ar" refers to an aromatic carbocyclic group of 6 to 14 carbon atoms having a single ring (including, but not limited to, groups such as phenyl) or multiple condensed rings (including, but not limited to, groups such as naphthyl or anthryl), and includes both unsubstituted and substituted aryl groups. Substituted aryl is an aryl group that is substituted with one or more substituents, preferably one to three substituents, selected from the group consisting of alkyl, alkenyl, alkynyl, halogen, alkoxy, acyloxy, amino, mono or dialkylamino, hydroxyl, mercapto, carboxy, benzyloxy, phenyl, aryloxy, benzyl, cyano, nitro, thioalkoxy, carboxaldehyde, carboalkoxy and carboxamide, or a functionality that can be suitably blocked, if necessary for purposes of the invention, with a protecting group. Representative examples include, but are not limited to, naphthyl, phenyl, chlorophenyl, iodophenyl, methoxyphenyl, carboxyphenyl, and the like.
The term "arylene" refers to the diradical derived from aryl (including substituted aryl) as defined above and is exemplified by 1 ,2-phenylene, 1,3- phenylene, 1 ,4-phenylene, 1,2-naphthylene and the like. The term "amino" refers to the group -NH2.
The term "thioalkoxy " means a radical -SR where R is an alkyl as defined above e.g., methylthio, ethylthio, propylthio, butylthio, and the like.
The term "mono and "dialkylamino" means a radical -NHR and -NRR' respectively where R and R' independently represent an alkyl group as defined herein. Representative examples include, but are not limited to dimethylamino, methylethylamino, di(l-methylethyl)amino, (cyclohexyl)(methyl)amino, (cyclohexyl)(ethyl)amino, (cyclohexyl)(propyl)amino, (cyclohexylmethyl)(methyl)- amino, (cyclohexylmethyl)(ethyl)amino, and the like. The term "acyloxy" means a radical -OC(O)R, where R is hydrogen, alkyl, aryl, heteroaryl or substituted alkyl wherein alkyl, aryl, heteroaryl, and substituted alkyl are as defined herein. Representative examples include, but are not limited to formyl, acetyloxy, cylcohexylcarbonyloxy, cyclohexylmethylcarbonyloxy, benzoyloxy, benzylcarbonyloxy, and the like. The term "heteroalkyl," "heteroalkenyl," and "heteroalkynyl" refers to alkyl, alkenyl, and alkynyl groups respectively as defined above, that contain the number of carbon atoms specified (or if no number is specified, having 1 to 12 carbon atoms) which contain one or more heteroatoms, preferably one to three heteroatoms, as part of the main, branched, or cyclic chains in the group. Heteroatoms are independently selected from the group consisting of-NR-, -NRR, (where each R is hydrogen or alkyl), -S-, -O-, -SR (R is hydrogen or alkyl), -OR (R is hydrogen or alkyl), and P; preferably -NR where R is hydrogen or alkyl and/or O. Heteroalkyl, heteroalkenyl, and heteroalkynyl groups may be attached to the remainder of the molecule either at a heteroatom (if a valence is available) or at a carbon atom. Examples of heteroalkyl groups include, but are not limited to, groups such as -O-CH3, -CH2-O-CH3, -CH2-CH2-O-CH3, -S-CH2-CH2-CH3, -CH2-CH(CH3)-S-CH3, -CH2-CH2-NH-CH2-CH3, 1 -ethyl-6-propylpiperidino, 2-ethylthiophenyl, piperazino, pyrrolidino, piperidino, morpholino, and the like. Examples of heteroalkenyl groups include, but are not limited to, groups such as -CH=CH-NH-CH(CH3)-CH3, and the like.
The term "carboxaldehyde" means -CHO.
The term " carboalkoxy" means -C(O)OR where R is alkyl as defined above and include groups such as methoxycarbonyl, ethoxycarbonyl, and the like.
The term "carboxamide" means -C(O)NHR or -C(O)NRR'where R and R' are independently hydrogen or alkyl as defined above. Representative examples include groups such as aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, and the like. The term "heteroaryl" or "HetAr" refers to an aromatic carbocyclic group of 3 to 9 ring atoms forming a single ring and having at least one hetero atom, preferably one to three heteroatoms including, but not limited to, heteroatoms such as N, O, P, or S, within the ring. Representative examples include, but are not limited to single ring such as imidazolyl, pyrazolyl, pyrazinyl, pyridazinyl, pyrimidinly, pyrrolyl, pyridyl, thiophene, and the like, or multiple condensed rings such as indolyl, quinoline, quinazoline, benzimidazolyl, indolizinyl, benzothienyl, and the like.
The heteroalkyl, heteroalkenyl, heteroalkynyl and heteroaryl groups can be unsubstituted or substituted with one or more substituents, preferably one to three substituents, selected from the group consisting of alkyl, alkenyl, alkynyl, benzyl, halogen, alkoxy, acyloxy, amino, mono or dialkylamino, hydroxyl, mercapto, carboxy, benzyloxy, phenyl, aryloxy, cyano, nitro, thioalkoxy, carboxaldehyde, carboalkoxy and carboxamide, or a functionality that can be suitably blocked, if necessary for purposes of the invention, with a protecting group. Examples of such substituted heteroalkyl groups include, but are not limited to, piperazine, pyrrolidine, morpholine, or piperidine, substituted at a nitrogen or carbon by a phenyl or benzyl group, and attached to the remainder of the molecule by any available valence on a carbon or nitrogen, -NH-SO2-phenyl, -NH-(C=O)O-alkyl, -NH-(C=O)O-alkyl-aryl, and the like. The heteroatom(s) as well as the carbon atoms of the group can be substituted. The heteroatom(s) can also be in oxidized form. The term "heteroarylene" refers to the diradical group derived from heteroaryl
(including substituted heteroaryl), as defined above, and is exemplified by the groups 2,6-pyridylene, 2,4-pyridinylene, 1 ,2-quinolinylene, 1,8-quinolinylene, 1,4- benzofuranylene, 2,5-pyridnylene, 2,5-indolenyl, and the like. The term "heteroalkylene", "heteroalkenylene", and "heteroalkynylene" refers to the diradical group derived from heteroalkyl, heteroalkenyl, and heteroalkynyl (including substituted heteroalkyl, heteroalkenyl, and heteroalkynyl), as defined above. The term "alkylaryl" refers to an alkyl group having the number of carbon atoms designated, appended to one, two, or three aryl groups.
The term "alkoxy" as used herein refers to an alkyl, alkenyl, or alkynyl linked to an oxygen atom and having the number of carbon atoms specified, or if no number is specified, having 1 to 12 carbon atoms. Examples of alkoxy groups include, but are not limited to, groups such as methoxy, ethoxy, tert-butoxy, and allyloxy.
The term "aryloxy" as used herein refers to an aryl group linked to an oxygen atom at one of the ring carbons. Examples of alkoxy groups include, but are not limited to, groups such as phenoxy, 2-, 3-, or 4-methylphenoxy, and the like.
The term "halogen" as used herein refer to Cl, Br, F or I substituents, preferably fluoro or chloro.
The term "-(Cι-Cι2) alkyl, substituted alkyl, or heteroalkyl" means an alkyl, substituted alkyl or heteroalkyl group respectively as defined above and having 1 to 12 carbon atoms. For example, when Ri is -(C]-Cι2) alkyl, substituted alkyl, or heteroalkyl it means that Ri can be -(Cι-Cι2) alkyl or -(Cι-C12)substituted alkyl, or - (C,-Cι2)heteroalkyl.
The term "-(Cι-Cι2) alkenyl, substituted alkenyl, or heteroalkenyl" means an alkenyl, substituted alkenyl, or heteroalkenyl group as defined above and having 1 to 12 carbon atoms.
The "-(Cι-C]2) alkynyl, substituted alkynyl, or heteroalkynyl" means an alkynyl, substituted alkynyl, or heteroalkynyl group as defined above and having 1 to 12 carbon atoms.
The term "-(Cι-Cι2) alkylene, substituted alkylene, or heteroalkylene" means an alkylene, substituted alkylene, or heteroalkylene group as defined above and havingl to 12 carbon atoms. The term "-(C]-Cι2) alkenylene, substituted alkenylene, or heteroalkenylene" means that the alkenylene, substituted alkenylene, or heteroalkenylene group as defined above and having 1 to 12 carbon atoms. The term " -(Cι-Cι2) alkynylene, substituted alkynylene, or heteroalkynylene" means an alkynylene, substituted alkynylene, or heteroalkynylene group as defined above and having 1 to 12 carbon atoms.
The term "and -(CpC8 alkylene or substituted alkylene)n -(C3-Cι2 arylene or heteroarylene)-(Cι-C8 alkyl or substituted alkyl)n6 where n5 and n6 are independently 0 or 1" means that "when n5 and/or n6 are 0 then -(C]-C8 alkylene or substituted alkylene)n5 and/or -(C]-C8 alkylene or substituted alkyl ene)n6" are a covalent bond or when n5 and/or n6 are 1, then the alkylene or substituted alkylene group is present and can have 1 to 8 carbon atoms. The term -(C3-Cι2 arylene or heteroarylene)- means that the arylene has 6 to 12 carbon atoms (e.g., phenylene, naphtylene, and the like) and heteroaryl ene groups have 3 to 12 carbons atoms and additionally contain one to three heteroatoms including, but not limited to, heteroatoms such as N, O, P, or S, within the ring (e.g., 2,6-pyridylene, 2,4-pyridinylene, 1 ,2-quinolinylene, 1,8- quinolinylene, 1 ,4-benzofiιranylene, 2,5-pyridylene, 2,5-indolenyl, and the like) in accordance with the definition of the heteroaryl ene above. Additionally, it will be recognized by a person skilled in the art that when "-(Cι-C8 alkylene or substituted alkylene)- " and "-(Cι-C8 alkyl or substituted alkyl)- " are a covalent bond then - (C3-Cι arylene or heteroarylene)- is an aryl or heteroaryl group as defined above. "Protecting group" refers to a chemical group that exhibits the following characteristics: 1) reacts selectively with the desired functionality in good yield to give a protected substrate that is stable to the projected reactions for which protection is desired; 2) is selectively removable from the protected substrate to yield the desired functionality; and 3) is removable in good yield by reagents compatible with the other functional group(s) present or generated in such projected reactions. Examples of suitable protecting groups can be found in Greene et al. (1991) Protective Groups in Organic Synthesis, 2nd Ed. (John Wiley & Sons, Inc., New York). Preferred amino protecting groups include, but are not limited to, benzyloxycarbonyl (CBz), t-butyl- oxycarbonyl (Boc), t-butyldimethylsilyl (TBDIMS), 9-fluorenylmethyl-oxycarbonyl (Fmoc), or suitable photolabile protecting groups such as 6-nitroveratryloxy carbonyl (Nvoc), nitropiperonyl, pyrenylmethoxycarbonyl, nitrobenzyl, dimethyl dimethoxybenzil, 5-bromo-7-nitroindolinyl, and the like. Preferred hydroxyl protecting groups include Fmoc, TBDIMS, photolabile protecting groups (such as nitroveratryl oxymethyl ether (Nvom)), Mom (methoxy methyl ether), and Mem (methoxy ethoxy methyl ether). Particularly preferred protecting groups include NPEOC (4-nitrophenethyloxycarbonyl) and NPEOM (4-nitrophenethyloxy- methyloxycarbonyl).
"Inhibitor" refers to a compound that interferes with the interaction between a target and its respective substrate(s) or endogenous ligand(s). Target molecules include, but are not limited to, enzymes and receptors. Enzyme inhibitors have been extensively studied from kinetic and mechanistic standpoints; see, e.g., Fersht, A., Enzyme Structure and Mechanism, 2nd Ed., New York, W.H. Freeman, 1985. A useful measure of the effectiveness of a compound at inhibiting enzyme catalysis is the IC50 of that compound. The IC50 of a compound can determined by the equation y = yo/(l + [In]/IC50) where y is the measured reaction velocity, y0 is the reaction velocity in the absence of inhibitor, and [In] is the inhibitor concentration. Solving this equation at the inhibitor concentration [In] when y = yJ2 yields IC50 of the inhibitor for the enzyme under study. Useful inhibitors have an IC50 equal to or less than about 10 TM, preferably equal to or less than about 1 TM. More preferably, the inhibitor has an IC50 equal to or less than about 100 nM, still more preferably equal to or less than about 10 nM, even more preferably equal to or less than about lnM. Most preferably, inhibitors have an IC50 equal to or less than about 100 pM, or equal to or less than about 10 pM. A selective inhibitor refers to an inhibitor that will inhibit the activity of one macromolecule, typically an enzyme, while exhibiting little or no inhibitory effect on another macromolecule, typically another enzyme. The compounds of the invention are particularly useful in that they display selective inhibition of peptidyl deformylase while exhibiting much lower inhibitory activity towards metalloproteinases such as matrilysin. The selectivity of an enzyme inhibitor can be indicated by dividing the IC50 of the compound for the enzyme which is not intended to be inhibited, by the IC50 of the compound for the enzyme which is intended to be inhibited. Thus, if a compound has an IC50 for matrilysin of 1 μM, and an IC50 for peptidyl deformylase of 0.01 μM, the compound displays a 100-fold (or 100 times) selectivity for peptidyl deformylase over matrilysin, or alternatively is said to be 100 times more selective for peptidyl deformylase compared to matrilysin. Useful compounds display a selectivity of greater than or equal to about 10 times, preferably greater than or equal to about 100 times, more preferably greater than or equal to about 1000 times, still more preferably greater than or equal to about 10,000, for peptidyl deformylase over one or more other metalloproteinases, for example for peptidyl deformylase over matrilysin.
The compounds of the invention are intended for use in eukaryotic animals. Preferably, the animal is a vertebrate; more preferably, the animal is a mammal; most preferably, the animal is a human.
By "hydroxamic acid derivative," "hydroxamic acid derivative compound," "hydroxamic acid compound," "hydroxamate derivative," "hydroxamate derivative compound," or "hydroxamate compound" is meant any compound containing the functional group HN(OH)-C(=O)-. Compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed "isomers". Isomers that differ in the arrangement of their atoms in space are termed "stereoisomers". Stereoisomers that are not mirror images of one another are termed "diastereomers" and those that are non-superimposable mirror images of each other are termed "enantiomers". When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible. An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or (-)-isomers respectively). A chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a "racemic mixture".
The compounds of this invention may possess one or more asymmetric centers; such compounds can therefore be produced as individual (R)- or (S)- stereoisomers or as mixtures thereof. For example, if the R6 substituent in a compound of Formula (I) is 2-hydroxyethyl, then the carbon to which the hydroxy group is attached is an asymmetric center and therefore the compound of Formula (I) can exist as an (R)- or (S)-stereoisomer. Unless indicated otherwise, the description or naming of a particular compound in the specification and claims is intended to include both individual enantiomers and mixtures, racemic or otherwise, thereof. The methods for the determination of stereochemistry and the separation of stereoisomers are well-known in the art (see discussion in Chapter 4 of "Advanced Organic Chemistry", 4th edition J. March, John Wiley and Sons, New York, 1992). A "pharmaceutically acceptable excipient" means an excipient that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes an excipient that is acceptable for veterinary use as well as human pharmaceutical use. A "pharmaceutically acceptable excipient" as used in the specification and claims includes both one and more than one such excipient.
A "pharmaceutically acceptable salt" of a compound means a salt that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound. Such salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1 ,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-napthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynapthoic acid, salicylic acid, stearic acid, muconic acid, and the like; or
(2) salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, and the like. A compound of Formula (I) may act as a pro-drug. Prodrug means any compound which releases an active parent drug according to Formula (I) in vivo when such prodrug is administered to a mammalian subject. Prodrugs of a compound of Formula (I) are prepared by modifying functional groups present in the compound of Formula (I) in such a way that the modifications may be cleaved in vivo to release the parent compound. Prodrugs include compounds of Formula (I) wherein a hydroxy, amino, or sulfhydryl group in compound (I) is bonded to any group that may be cleaved in vivo to regenerate the free hydroxyl, amino, or sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to esters (e.g., acetate, formate, and benzoate derivatives), carbamates (e.g., N,N-dimethylamino-carbonyl) of hydroxy functional groups in compounds of Formula (I), and the like. "Treating" or "treatment" of a disease includes:
(1) preventing the disease, i.e. causing the clinical symptoms of the disease not to develop in a mammal that may be exposed to or predisposed to the disease but does not yet experience or display symptoms of the disease,
(2) inhibiting the disease, i.e., arresting or reducing the development of the disease or its clinical symptoms, or
(3) relieving the disease, i.e., causing regression of the disease or its clinical symptoms.
A "therapeutically effective amount" means the amount of a compound that, when administered to a mammal for treating a disease, is sufficient to effect such treatment for the disease. The "therapeutically effective amount" will vary depending on the compound, the disease and its severity and the age, weight, etc., of the mammal to be treated.
PREFERRED EMBODIMENTS
While the broadest definition of this invention is set forth in the Summary of the Invention, certain compounds of Formula (I) are preferred. For example, (A) (i) A preferred group of compounds is that wherein Ri is hydrogen or hydroxy, preferably hydroxy. The stereochemistry at the carbon carrying the Ri group is (R) or (S).
(ii) Another preferred group of compounds is that wherein Ri is halo; preferably chloro or fluoro; more preferably fluoro. The stereochemistry at the carbon carrying the Ri group is (R) or (S), preferably (S) when Rj is fluoro.
Within the above preferred groups, a more preferred group of compounds is that wherein R2 and R4 are hydrogen.
(iii) Yet another preferred group of compounds is that wherein R3 is hydrogen or Rπ where Rn is -Cι-Cι alkyl or -(Cι-C8 alkylene)n7-(C3-Cι2 aryl or heteroaryl), preferably methyl, ethyl, n-propyl, wo-propyl, w-butyl, iso-buty\, tert-butyl, w-pentyl, zY-pentyl, Λeø-pentyl, n-hexyl, 2-, 3-, 4-, or 5-methylpentyl, 4,4-dimethylbutyl, benzyl, 3-phenylpropyl, 2-phenylethyl, or 4-phenylbutyl, more preferably n-butyl. The stereochemistry at the carbon carrying the R3 group is (R) or (S), preferably (R). (iv) Yet another preferred group of compounds is that wherein the
Figure imgf000019_0001
group is a group of formula:
R7
WJ
wherein: n is 1 or 2, preferably 1; and R7 is: (a) -C(=O)NRι4Rι5 where R1 and R15 are independently selected from the group consisting of hydrogen, -(Cι-Cι2) alkyl, substituted alkyl, or heteroalkyl, -(Cι-Cι2) alkenyl, substituted alkenyl, or heteroalkenyl, -(Cι-Cι2) alkynyl, substituted alkynyl, or heteroalkynyl, alkoxy, and -(Cj-C8 alkyl or substituted alkyl)n -(C3-C12 arylene or heteroarylene)-(CrC8 alkyl or substituted alkyl)nιo where n9 and nlO are independently 0 or 1; or R14 and R]5 combine to form a substituted or unsubstituted - (C4-Cιo)cyclic alkyl, cyclic heteroalkyl, aryl or heteroaryl group.
Preferably, R is -C(=O)NRι4Rι5 where Rι and R15 are each independently hydrogen or -(Cι-C]2) alkyl, alkoxy, aryl, heteroaryl or R1 and R15, when attached to the same carbon, combine to form a cyclic heteroalkyl, aryl or heteroaryl group.
More preferably, R7 is -C(=O)NHRι5 where Rι5 is H or -(Cι-Cι2) alkyl, aryl, or heteroaryl or -C(=O)NRι4Rι5 where Rt4 and Reform a substituted or unsubstituted -(C4-Cιo)cyclic heteroalkyl.
Even more preferably R7 is n-butylaminocarbonyl, tert-butylaminocarbonyl, benzylaminocarbonyl, 1 , 1 -dimethylpropylaminocarbonyl, 2-(cyclohexen- 1 -yl)- ethylaminocarbonyl, indan-5-ylaminocarbonyl, 4,5-dimethylthiazol-2-ylamino- carbonyl, 4-phenoxyphenylaminocarbonyl, cyclopropylmethyl-aminocarbonyl, pyridin-2-ylaminocarbonyl, pyridin-3-ylaminocarbonyl, pyridin-4-ylmethylamino- carbonyl, morpholin-4-ylcarbonyl, 3,4-methylenedioxy-phenylaminocarbonyl, quinolin-3-ylaminocarbonyl, methylaminocarbonyl, 4-biphenylaminocarbonyl, 3- phenoxyphenylaminocarbonyl, 3,4-dichlorophenyl-aminocarbonyl, 4-tert- butylphenylaminocarbonyl, 4-tert-butylaminocarbonyl, indan-2 -ylaminocarbonyl, 2,2-dimethylpropylaminocarbonyl, 4-phenylthiazol-2 -ylaminocarbonyl, 5-phenyl- thiadiazol-2-ylaminocarbonyl, 5-ethylthiadiazol-3-ylaminocarbonyl, thiadiazol-2- ylaminocarbonyl, 3-trifluoromethoxyphenyl-aminocarbonyl, 2,5-dimethylphenyl- aminocarbonyl, 2,5-dimethoxyphenylamino-carbonyl, 3,4-dichlorophenyl- aminocarbonyl, benzthiazol-2-ylaminocarbonyl, 3-phenoxyphenylaminocarbonyl, 2-hydroxybutylaminocarbonyl, 4-hydroxybutyl-aminocarbonyl, 1 ,4-benzodioxan-6- ylaminocarbonyl, isoquinolin-6-ylaminocarbonyl, methylaminocarbonyl, thiazol-2-yl- aminocarbonyl, 4-methylthiazol-2-yl-aminocarbonyl, 3-methylbutyl-aminocarbonyl, w-pentylaminocarbonyl, cyclohexylaminocarbonyl, 5-methylthiazol-2-ylamino- carbonyl, 4-methylthiazol-2-yl-aminocarbonyl, 2,4-dimethoxyphenyl-aminocarbonyl, 3,4-methylenedioxyphen-5-yl-methylaminocarbonyl, allylaminocarbonyl, 2-methyl- allylaminocarbonyl, pyrrolidin-1 -ylcarbonyl, ethylaminocarbonyl, phenylamino- carbonyl, indan-1 -ylaminocarbonyl, 2-methoxyethylaminocarbonyl, indan-5-yl- aminocarbonyl, 3,4-difluorophenyl-aminocarbonyl, 5-methylisoxazol-5-yl- aminocarbonyl, 3-fluorophenylaminocarbonyl, 4-fluorophenylaminocarbonyl, N- methyl-N-phenylaminocarbonyl, 2-propylamino-carbonyl, 2-phenylpropyl- aminocarbonyl, n-propylaminocarbonyl, N-ethyl-N-(n-butyl)aminocarbonyl, benzylaminocarbonyl, thiazolidin- 1 -ylcarbonyl, piperazin- 1 -yl-carbonyl, piperidin- 1 - ylcarbonyl, azetidin-1 -ylcarbonyl, homopiperdin-1 -ylcarbonyl, pyrimidin-2-ylamino- carbonyl, 4-methylpiperazin- 1 -ylcarbonyl, 4-methylpyrimidin-2-ylaminocarbonyl, pyrimidin-4-ylaminocarbonyl, pyrazin-2-ylaminocarbonyl, imidazol-2-yl aminocarbonyl. In particular, R7 is piperidin- 1 -ylcarbonyl, azetidin-1 -ylcarbonyl, ethylaminocarbonyl, phenylaminocarbonyl, pyrimidin-2-ylaminocarbonyl, or thiazol- 2-ylaminocarbonyl.
More particularly, R is piperidin- 1 -ylcarbonyl, azetidin-1 -ylcarbonyl, ethylaminocarbonyl or thiazol-2-ylaminocarbonyl. The stereochemistry at the C2 carbon atom of the pyrrolidine ring, i.e., carbon carrying the R group is either (R) or (S), preferably (S); or
(b) R7 is -ΝHC(=O)ORM where R14 is hydrogen, -(Cι-C12) alkyl, substituted alkyl, or heteroalkyl, -(Cι-C]2) alkenyl, substituted alkenyl, or heteroalkenyl, -(C]-Cι ) alkynyl, substituted alkynyl, or heteroalkynyl, alkoxy, or -(C C8 alkyl or substituted alkyl)n9-(C3-Cι2 arylene or heteroarylene)-(Cι-C8 alkyl or substituted alkyl)nι0 where n9 and nlO are independently 0 or 1.
Preferably, R7 is -NHC(=O)ORι4 where R,4 is hydrogen or -(Cι-Cι2) alkyl, alkoxy, aryl, heteroaryl; or (c) R7 is -C(=O)ORι4 where R]4 is hydrogen, -(Cι-C12) alkyl, substituted alkyl, or heteroalkyl, -(Cι-Cι2) alkenyl, substituted alkenyl, or heteroalkenyl, -(Ci- Cι2) alkynyl, substituted alkynyl, or heteroalkynyl, alkoxy, or -(Cι-C8 alkyl or substituted alkyl)n9-(C3-C]2 arylene or heteroarylene)-(Cι-C8 alkyl or substituted alkyl)n to where n9 and nlO are independently 0 or 1. Preferably, R7 is -C(=O)OR17 where R,4 is hydrogen or -(Cι-Cι2) alkyl, alkoxy, aryl, or heteroaryl.
More preferably, -C(=O)ORι4 where R] is alkyl, even more preferably R7 is tert-butoxycarbonyl. The stereochemistry at the C2 carbon atom of the pyrrolidine ring, i.e., carbon carrying the R7 group is either (R) or (S), preferably (S). The above defined embodiments of (i) - (iv) are employed either singularly or in any combination.
(B) Another preferred group of compounds is represented as Formula (Ila):
Figure imgf000021_0001
(Ila)
wherein:
R, is -OH, -OR9, -R8OR9, -SH, -SR9, -NH2, -NHR9 -NR9Rι0, -NHC(=O)H, -NR9C(=O)H, -NHC(=O)R9, -NR9C(=O)R10, -NHC(=O)NH2, -NR9C(=O)NH2, -NHC(=O)NHR9, -NHC(=O)NR9Rιo, -NR9C(=O)NR9aRι0, -NHC(=O)OR9, -NR9C(=O)OR,0, -NHS(=O)2R9, -NR9S(=O)2Rι0, -NHS(=O)2OR9, or -NR S(=O) ORιo where R8 is selected from the group consisting of -Cι-Cι2 alkylene, -Cι-C]2 alkenylene, and -Cι-C12 alkynylene and R9, R9a and Rio are independently selected from the group consisting of -Cι-Cι2 alkyl, -Cι-Cι2 alkenyl, and -Cι-Cι2 alkynyl;
R2 is hydrogen or -R9 where R9 is as defined above; R3 is -Rπ, -OH, -ORπ, -Rι2ORπ, -SH, -SRπ, -NH2, -NHRM -NRnRι3, -NHC(=O)H, -NR! ιC(=O)H, -NHC(=O)R, ,, -NRi ιC(=O)Rι3, -NHC(=O)NH2, -NRnC(=O)NH2, -NHC(=O)NHRπ, -NHC(=O)NRnR13, -NRnC(=O)NRιιaRι3, -NHC(=O)ORπ, -NR„C(=O)OR13, -NHS(=O)2R13, -NR„S(=O)2R13, -NHS(=O)2ORπ, or -NRnS(=O)2OR]3, where Rι2 is selected from the group consisting of-Cι-Cι2 alkylene, substituted alkylene, or heteroalkylene, -Cι-C]2 alkenylene, substituted alkenylene, or heteroalkenylene, -Cι-Cι2 alkynylene, substituted alkynylene, or heteroalkynylene, and -(Cι-C8 alkylene or substituted alkylene)π5-(C3-Cι2 arylene or heteroarylene)-(Cι-C8 alkyl or substituted alkyl)n6 where n5 and n6 are independently 0 or 1; and Rn, Rna, and Rι are independently selected from the group consisting of -Cι-Cι2 alkyl, substituted alkyl, or heteroalkyl, -Cι-Cι2 alkenyl, substituted alkenyl, or heteroalkenyl, -C\-Cn alkynyl, substituted alkynyl, or heteroalkynyl, and -(Cι-C8 alkyl or substituted alkyl)n7-(C3-Cι2 arylene or heteroarylene)-(Cι-C8 alkyl or substituted alkyl)n8 where n7 and n8 are independently O or l;
R4 is hydrogen or Rj ] where R] i is as defined above; n is an integer from 1 to 5; zero or one Y is selected from the group consisting of -O-, -NRπ- where Rn is as defined above, and -S-, and all remaining Y are -CR6R7- where R6 and R7 are each independently selected from the group consisting of hydrogen, -R[4, -OH, -OR]4, -SH, -SRi4, -NH2, -NHR14, -NR14R15, -C(=O)H, -C(=O)R,4, -C(=O)NH2, -C(=O)NHR14,
Figure imgf000022_0001
-C(=O)OH, -C(=O)OR,4, -C(=O)SH, -C(=O)SRι4, -C(=O)CH3, -C(=O)CH2R14, -C(=O)CHR14Ri5, -C(=O)CR14R]5Rι6, -C(=O)OCH3, -C(=O)OCH2R14, -C(=O)OCHR14R15, -C(=O)OCR14R15Rι6, -S(=O)2NH2, -S(=O)2NHR14, -S(=O)2NRI4R15, -NHC(=O)H, -N(R14)C(=O)H, -NHC(=O)R,5, -N(R14)C(=O)R15, -NHS( ))2H, -N(R14)S(=O)2H, -NHS(=O)2ORι5, -N(R,4)S(=O)2OR,5, -N(H)S(=O)2Rι5, -N(Rι4)S(=O)2Rι5 and where two vicinal Re or R7 groups combine to form a substituted or unsubstituted C4-Cιo cyclic alkyl, cyclic heteroalkyl, aryl or heteroaryl group; where R14, R]5 and Rι6 are each independently selected from the group consisting of -Cι-Cι2 alkyl, substituted alkyl, or heteroalkyl, -Cι-C12 alkenyl, substituted alkenyl, or heteroalkenyl, -Cι-Cι2 alkynyl, substituted alkynyl, or heteroalkynyl, and -(Cι-C8 alkyl or substituted alkyl)n9-(C3-Cι2 arylene or heteroarylene)-(Cι-C8 alkyl or substituted alkyl)nιo where n9 and nlO are independently 0 or 1 ; or a pharmaceutically acceptable salt thereof. Within this group of compounds (Ila), a preferred group of compounds is that wherein the embodiments of (i) - (iv) defined below are employed either singularly or in any combination:
(i) A preferred group of compounds is that wherein Ri is hydrogen or hydroxy and the stereochemistry at the carbon carrying the Ri group is (R) or (S), preferably (S).
(ii) Another preferred group of compounds is that wherein R2 and R4 are hydrogen.
(iii) Another preferred group of compounds is that wherein R3 is hydrogen or R where R9 is -Cι-Cι2 alkyl or -(Cι-C8 alkylene)n7-(C3-Cι2 aryl or heteroaryl) where n7, preferably methyl, ethyl, n-propyl, wo-propyl, n-butyl, iso-butyl, tert-butyl, n-pentyl, iso-pentyl, neo-pentyl, n-hexyl, 2-, 3-, 4-, or 5-methylpentyl, 4,4- dimethylbutyl, benzyl, 3-phenylpropyl, 2-phenylethyl, or 4-phenylbutyl, more preferably n-butyl. The stereochemistry at the carbon carrying the R3 group is (R) or (S), preferably (R). (iv) Another preferred group of compounds is that wherein the
Figure imgf000023_0001
group is a group of formula:
R7
-\ J)n
wherein: n is 1 or 2, preferably 1 ; and R7 is:
(a) where R]4 and R15 are independently selected from the group consisting of hydrogen, -(Cι-Cι2) alkyl, substituted alkyl, or heteroalkyl, -(Ci- Cι2) alkenyl, substituted alkenyl, or heteroalkenyl, -(Cι-Cι2) alkynyl, substituted alkynyl, or heteroalkynyl, alkoxy, and -(Cι-C8 alkyl or substituted alkyl)n9-(C3-Cι2 arylene or hetero arylene)-(Cι-C8 alkyl or substituted alkyl)n 10 where n9 and nlO are independently 0 or 1.
Preferably, R7 is -C(=O)NR] R15 where Rι4 and Rι5 are each independently hydrogen or -(C]-Cι2) alkyl, alkoxy, aryl, heteroaryl. More preferably, R7 is -C(=O)NHR,5 where Rι5 is H or -(C1-C12) alkyl, aryl, or heteroaryl.
Even more preferably R7 is n-butylaminocarbonyl, tert-butylaminocarbonyl, benzylaminocarbonyl, 1 , 1 -dimethylpropylaminocarbonyl, 2-(cyclohexen- 1 -yl)- ethylaminocarbonyl, indan-5 -ylaminocarbonyl, 4,5-dimethylthiazol-2-ylamino- carbonyl, 4-phenoxyphenylaminocarbonyl, cyclopropylmethylaminocarbonyl, pyridin-2-ylaminocarbonyl, pyridin-3 -ylaminocarbonyl, pyridin-4-ylmethyl- aminocarbonyl, 3,4-methylenedioxyphenylaminocarbonyl, quinolin-3- ylaminocarbonyl, methylaminocarbonyl, 4-biphenylaminocarbonyl, 3 -phenoxyphenylaminocarbonyl, 3 ,4-dichlorophenylaminocarbonyl, 4-tert- butylphenylaminocarbonyl, 4-tert-butylaminocarbonyl, indan-2-ylaminocarbonyl, 2,2-dimethylpropylaminocarbonyl, 4-phenylthiazol-2-ylaminocarbonyl,
5-phenylthiadiazol-2 -ylaminocarbonyl, 5-ethylthiadiazol-3-ylaminocarbonyl, thiadiazol-2-ylaminocarbonyl, 3-trifluoromethoxyphenylaminocarbonyl, 2,5-dimethylphenylaminocarbonyl, 2,5-dimethoxyphenylamino-arbonyl, 3,4-dichlorophenylaminocarbonyl, benzthiazol-2-ylaminocarbonyl, 3 -phenoxyphenylaminocarbonyl, 2-hydroxybutylaminocarbonyl, 4-hydroxybutyl- aminocarbonyl, 1 ,4-benzodioxan-6-ylaminocarbonyl, isoquinolin-6-ylaminocarbonyl, methylaminocarbonyl, thiazol-2-ylaminocarbonyl, 4-mefhylthiazol-2-yl- aminocarbonyl, 3-methylbutylaminocarbonyl, n-pentylaminocarbonyl, cyclohexylaminocarbonyl, 5-methylthiazol-2-ylaminocarbonyl, 4-methylthiazol-2-yl- aminocarbonyl, 2,4-dimethoxyphenylaminocarbonyl, 3,4-methylenedioxyphen-5-yl- methylaminocarbonyl, allylaminocarbonyl, 2-methylallylaminocarbonyl, ethylaminocarbonyl, phenylaminocarbonyl, indan-1 -ylaminocarbonyl, 2-methoxyethylaminocarbonyl, indan-5-ylaminocarbonyl, 3,4-difluorophenyl- aminocarbonyl, 5-methylisoxazol-5-ylaminocarbonyl, 3-fluorophenylaminocarbonyl, 4-fluorophenylaminocarbonyl, N-methyl-N-phenylaminocarbonyl, 2-propylamino- carbonyl, 2-phenylpropylaminocarbonyl, n-propylaminocarbonyl, N-ethyl-N-(n- butyl)aminocarbonyl, benzylaminocarbonyl, thiazolidin-1 -ylcarbonyl, pyrimidin-2- ylaminocarbonyl, 4-methylpyrimidin-2-ylaminocarbonyl, pyrimidin-4-yl- aminocarbonyl, pyrazin-2-ylaminocarbonyl, imidazol-2-ylaminocarbonyl.
In particular, R7 is ethylaminocarbonyl, phenylaminocarbonyl, pyrimidin-2- ylaminocarbonyl, or thiazol-2 -ylaminocarbonyl. More particularly, R7 is phenylaminocarbonyl or pyrimidin-2-ylaminocarbonyl. The stereochemistry at the C2 carbon atom of the pyrrolidine ring, i.e., carbon carrying the R7 group is either (R) or (S), preferably (S); or
(b) -ΝHC(=O)ORι where Ri 4 is hydrogen, -(C i -C 12) alkyl, substituted alkyl, or heteroalkyl, -(Cι-Cι2) alkenyl, substituted alkenyl, or heteroalkenyl, -(Ci- Cι2) alkynyl, substituted alkynyl, or heteroalkynyl, alkoxy, or -(Cι-C8 alkyl or substituted alkyl)n9-(C3-Cι2 arylene or heteroarylene)-(C1-C8 alkyl or substituted alkyl)n ιo where n9 and nl 0 are independently 0 or 1. Preferably, R7 is -NHC(=O)OR14 where Rι4 is hydrogen or -(Cι-Cι2) alkyl, alkoxy, aryl, heteroaryl; or
(c) -C(=O)ORι4 where Rj4 is hydrogen, -(Cι-Cι2) alkyl, substituted alkyl, or heteroalkyl, -(Cι-Cι2) alkenyl, substituted alkenyl, or heteroalkenyl, -(Cι-C12) alkynyl, substituted alkynyl, or heteroalkynyl, alkoxy, or -(Cι-C8 alkyl or substituted alkyl)n9-(C3-Cι2 arylene or heteroarylene)-(C!-C8 alkyl or substituted alkyl)nlo where n9 and nlO are independently 0 or 1. Preferably, R7 is -C(=O)ORι4 where R]4 is hydrogen or -(Cι-Cι2) alkyl, alkoxy, aryl, or heteroaryl. More preferably, -C(=O)ORι4 where R1 is alkyl, even more preferably R7 is tert-butoxycarbonyl. The stereochemistry at the C2 carbon atom of the pyrrolidine ring, i.e., carbon carrying the R7 group is either (R) or (S), preferably (S).
(C) Another preferred group of compounds is represented by Formula (lib):
Figure imgf000025_0001
(lib) wherein:
Ri is -R9, -OH, -OR9, -R8OR9, -SH, -SR9, -NH2, -NHR9 -NR9R10, -NΗC(=O)H, -NR9C(=O)H, -NHC(=O)R9, -NR9C(=O)Rι0, -NHC(=O)NH2, -NR9C(=O)NH2, -NHC(=O)NHR9, -NHC(=O)NR9R10, -NR9C(=O)NR9aR10, -NHC(=O)OR9, -NR9C(=O)ORi0, -NHS(=O)2R9, -NR9S(=O)2Rι0, -NHS(=O)2OR9, or -NR S(=O)2ORιo where R8 is selected from the group consisting of -Cι-Cι2 alkyl, substituted alkyl, or heteroalkyl, -C1-C12 alkenyl, substituted alkenyl, or heteroalkenyl, -Cι-Cι2 alkynyl, substituted alkynyl, or heteroalkynyl, and -(Cι-C8 alkyl or substituted alkyl)nι-(C3-Cι2 arylene or heteroarylene)-(Cι-C8 alkyl or substituted alkyl)n2 where nl and n2 are independently 0 or 1 ; and R , R9a, and Rio are each independently selected from the group consisting of -Cι-Cι2 alkyl, substituted alkyl, or heteroalkyl, -Cι-C]2 alkenyl, substituted alkenyl, or heteroalkenyl, -Cι-Cι2 alkynyl, substituted alkynyl, or heteroalkynyl, and -(Cι-C8 alkyl or substituted alkyl)n3-(C3-Cι2 arylene or heteroarylene)-(Cι-C8 alkyl or substituted alkyl)n4 where n3 and n4 are independently 0 or 1 ;
R2 is -H or -R9 where R9 is as defined above;
R3 is -Rn, -OH, -OR11, -Rι2OR,ι, -SH, -SRn, -NH2, -NHRn, -NRaRb, -NHC(=O)H, -NRι,C(=O)H, -NHC(=O)Rπ, -NRnC(=O)R,3, -NHC(=O)NH2, -NRnC(=O)NH2, -NHC(=O)NHRu, -NHC(=O)NR„Rι3, -NR„C(=O)NRι ,aRι3, -NHC(=O)OR,,, -NR,ιC(=O)OR,3, -NHS(=O)2R,,, -NRnS(=O)2Rι3,
-NHS(=O)2ORn, or -NRnS(=O)2ORι3 where Rι2 is selected from the group consisting of-C]-Cι2 alkylene, substituted alkylene, or heteroalkylene, -Cι-Cι2 alkenylene, substituted alkenylene, or heteroalkenylene, -Cι-Cι2 alkynylene, substituted alkynylene, or heteroalkynylene, and -(Cι-C8 alkylene or substituted alkylene)n5-(C3-Cι2 arylene or heteroarylene)-(Cι-C8 alkyl or substituted alkyl)n6 where n5 and n6 are independently 0 or 1 ; and Ri 1, Rπa, and Rι are independently selected from the group consisting of -Cι-Cι2 alkyl, substituted alkyl, or heteroalkyl, -C)-Cι2 alkenyl, substituted alkenyl, or heteroalkenyl, -Cι-Cι alkynyl, substituted alkynyl, or heteroalkynyl, and -(Cι-C8 alkyl or substituted alkyl)n7-(C3-Cι2 arylene or heteroarylene)-(Cι-C8 alkyl or substituted alkyl)n8 where n7 and n8 are independently O or 1;
1^ is hydrogen or -Ri 1 where Ri 1 is as defined above; R7 is -C(=O)H, -C(=O)Rι4, -C(=O)NH2, -C(=O)NHRι4, -C(=O)NR14R]5, -C(=0)SH, or -C(=O)SR]4 where where R]4 and Rι5 are independently selected from the group consisting of -C1-C12 alkyl, substituted alkyl, or heteroalkyl, -Cι-C]2 alkenyl, substituted alkenyl, or heteroalkenyl, -Cι-Cι2 alkynyl, substituted alkynyl, or heteroalkynyl, and -(Cι-C8 alkyl or substituted alkyl)n9-(C3-C]2 arylene or heteroarylene)-(Cι-C8 alkyl or substituted alkyl)nιo where n9 and nlO are independently 0 or 1 ; and where R7 is -C(=O)NR]4Rι5, then the Rj4 and Rι5 groups additionally can combine to form a substituted or unsubstituted C4-Cιo cyclic alkyl, cyclic heteroalkyl, aryl or heteroaryl group; or a pharmaceutically acceptable salt thereof.
Within this group of compounds, a preferred group of compounds is that wherein the embodiments of (i) - (iv) defined below are employed either singularly or in any combination:
(i) A preferred group of compounds is that wherein Ri is hydroxy and the stereochemistry at the carbon carrying the Ri group is (R) or (S), preferably (S).
(ii) Another preferred group of compounds is that wherein R2 is hydrogen. (iii) Another preferred group of compounds is that wherein R3 is hydrogen or R where R is -C1-C12 alkyl or -(Cι-C8 alkylene)n5-(C -Cι2 aryl or heteroaryl) where n5 is 0 or 1, preferably methyl, ethyl, n-propyl, wσ-propyl, n-butyl, iso-bulyl, tert-butyl, n-pentyl, zso-pentyl, neo-pentyl, n-hexyl, 2-, 3-, 4-, or 5-methylpentyl, 4- dimethylbutyl, benzyl, 3-phenylpropyl, 2-phenylethyl, or 4-phenylbutyl, more preferably n-butyl. The stereochemistry at the carbon carrying the R3 group is (R) or (S), preferably (R).
(iv) Yet another preferred group of compounds is that wherein R7 is:
(a) -C(=O)NHR[4 where R] is selected from the group consisting of -(Ci- Cι2) alkyl, substituted alkyl, or heteroalkyl, -(Cι-C]2) alkenyl, substituted alkenyl, or heteroalkenyl, -(Cι-Cι2) alkynyl, substituted alkynyl, or heteroalkynyl, alkoxy, and - (Cι-C8 alkyl or substituted alkyl)n9-(C3-Cι2 arylene or heteroarylene)-(Cι-C8 alkyl or substituted alkyl)n 10 where n9 and nlO are independently 0 or 1. Preferably, R7 is -C(=O)NHRι4 where Rι4 is -(Cι-Cι2) alkyl, alkoxy, aryl, or heteroaryl. More preferably, R7 is -C(=O)NHR]4 where Rι4 is -(Cι-C]2) alkyl, aryl, or heteroaryl. Even more preferably R7 is n-butylaminocarbonyl, tert-butylaminocarbonyl, benzylaminocarbonyl, 1 , 1 -dimethylpropylaminocarbonyl, 2-(cyclohexen- 1 -yl)- ethylaminocarbonyl, indan- 5 -ylaminocarbonyl, 4,5-dimethylthiazol-2- ylaminocarbonyl, 4-phenoxyphenylaminocarbonyl, cyclopropylmethyl- aminocarbonyl, pyridin-2-ylaminocarbonyl, pyridin-3-ylaminocarbonyl, pyridin-4- ylmefhylaminocarbonyl, morpholin-4-ylcarbonyl, 3,4-methylenedioxy- phenylaminocarbonyl, quinolin-3-ylaminocarbonyl, methylaminocarbonyl, 4- biphenylaminocarbonyl, 3 -phenoxyphenylaminocarbonyl, 3,4-dichlorophenyl- aminocarbonyl, 4-tert-butylphenylaminocarbonyl, 4-tert-butylaminocarbonyl, indan- 2-ylaminocarbonyl, 2,2-dimethylpropylaminocarbonyl, 4-phenylthiazol-2-ylamino- carbonyl, 5-phenylthiadiazol-2-ylaminocarbonyl, 5-ethylthiadiazol-3-ylamino- carbonyl, thiadiazol-2-ylaminocarbonyl, 3-trifluoromethoxyphenyl-aminocarbonyl, 2,5-dimethylphenylaminocarbonyl, 2,5-dimethoxyphenylamino-carbonyl, 3,4- dichlorophenylaminocarbonyl, benzthiazol-2-ylaminocarbonyl, 3-phenoxy- phenylaminocarbonyl, 2-hydroxybutylaminocarbonyl, 4-hydroxybutyl- aminocarbonyl, 1 ,4-benzodioxan-6-ylaminocarbonyl, isoquinolin-6-ylaminocarbonyl, methylaminocarbonyl, thiazol-2-ylaminocarbonyl, 4-methylthiazol-2-yl- aminocarbonyl, 3-methylbutyl-aminocarbonyl, n-pentylaminocarbonyl, cyclohexylaminocarbonyl, 5-methylthiazol-2-ylaminocarbonyl, 4-methylthiazol-2-yl- aminocarbonyl, 2,4-dimethoxyphenyl-aminocarbonyl, 3,4-methylenedioxyphen-5-yl- methylaminocarbonyl, allylaminocarbonyl, 2-methylallylaminocarbonyl, pyrrolidin-1- ylcarbonyl, ethylaminocarbonyl, phenylaminocarbonyl, indan-1 -ylaminocarbonyl, 2-methoxyethylaminocarbonyl, indan-5-ylaminocarbonyl, 3,4-difluorophenyl- aminocarbonyl, 5-methylisoxazol-5-ylaminocarbonyl, 3-fluorophenylaminocarbonyl, 4-fluorophenylaminocarbonyl, N-methyl-N-phenylaminocarbonyl, 2-propylamino- carbonyl, 2-phenylpropylaminocarbonyl, n-propylaminocarbonyl, N-ethyl-N-(n- butyl)aminocarbonyl, benzylaminocarbonyl, thiazolidin-1 -ylcarbonyl, piperazin- 1 -ylcarbonyl, piperidin- 1 -ylcarbonyl, azetidin-1 -ylcarbonyl, homopiperdin-1 -ylcarbonyl, pyrimidin-2-ylaminocarbonyl, 4-methylpiperazin- 1 -ylcarbonyl, 4-methylpyrimidin- 2-ylaminocarbonyl, pyrimidin-4-ylaminocarbonyl, pyrazin-2-ylaminocarbonyl, imidazol-2-ylaminocarbonyl. In particular, R7 is piperidin- 1 -ylcarbonyl, azetidin-1 -ylcarbonyl, ethylaminocarbonyl, phenylaminocarbonyl, pyrimidin-2-yl- aminocarbonyl, or thiazol-2-ylaminocarbonyl.
More particularly, R7 is phenylaminocarbonyl or pyrimidin-2-ylamino- carbonyl. The stereochemistry at the C2 carbon atom of the pyrrolidine ring, i.e., carbon carrying the R7 group is either (R) or (S), preferably (S); or
(b) R7 is -C(=O)ORι4 where R]4 is selected from the group consisting of hydrogen, -(Cι-Cι2) alkyl, substituted alkyl, or heteroalkyl, -(Cι-Cι2) alkenyl, substituted alkenyl, or heteroalkenyl, -(Cι-C) 2) alkynyl, substituted alkynyl, or heteroalkynyl, alkoxy, and -(Cι-C8 alkyl or substituted alkyl)n -(C3-Cι2 arylene or heteroarylene)-(Cι-C8 alkyl or substituted alkyl)nιo where n9 and nlO are independently 0 or 1. Preferably, R7 is -C(=O)ORι4 where R]7 is hydrogen, -(Cι-Cι2) alkyl, alkoxy, aryl, or heteroaryl. More preferably, -C(=O)ORι4 where R]4 is alkyl, even more preferably R is tert-butoxycarbonyl. The stereochemistry at the C2 carbon atom of the pyrrolidine ring, i.e., carbon carrying the R7 group is either (R) or (S), preferably (S).
(D) Another preferred group of compounds if represented by Formula (He):
Figure imgf000029_0001
wherein:
Ri is -OH, -OR , -SH or -SR9 wherein R is selected from the group consisting of -C1-C12 alkyl, substituted alkyl, or heteroalkyl, -Cι-Cι2 alkenyl, substituted alkenyl, or heteroalkenyl, -Cι-Cι2 alkynyl, substituted alkynyl, or heteroalkynyl, and -(Cι-C8 alkyl or substituted alkyl)nl-(C -Cι2 arylene or heteroarylene)-(Cι-C8 alkyl or substituted alkyl)n2 where nl and n2 are independently O or 1;
R2 is hydrogen; R3 is -Rn, -OH, -OR,ι, -R12OR11, -SH, -SRn, -NH2, -NHRn,
-NR,,Rι3, -NHC(=O)H, -NRnC(=O)H, -NHC(=O)R,ι, -NRι,C(=O)Rι3, -NHC(=O)NH2, -NRι,C(=O)NH2, -NHC(=O)NHRn, -NHC(=O)NRnR13, -NR,,C(=O)NR,,aRι3, -NHC(=O)ORn, -NR„C(=O)OR13, -NHS(=0)2R,,, -NRπS(=O)2R13, -NHS(=O)2OR,,, or -NRnS(=O)2ORι3 where R,2 is selected from the group consisting of -Cl-Cι alkylene, substituted alkylene, or heteroalkylene, -Ci- Cι2 alkenylene, substituted alkenylene, or heteroalkenylene, -Cι-Cι2 alkynylene, substituted alkynylene, or heteroalkynylene, and -(Cι-C8 alkylene or substituted alkylene)n -(C3-Cι2 arylene or heteroarylene)-(Cι-C8 alkyl or substituted alkyl) n6 where n5 and n6 are independently 0 or 1; and Rn and R) 3 are independently selected from the group consisting of -Cl-Cι2 alkyl, substituted alkyl, or heteroalkyl, -C1-C12 alkenyl, substituted alkenyl, or heteroalkenyl, -Cι-Cι2 alkynyl, substituted alkynyl, or heteroalkynyl, and -(CpC8 alkyl or substituted alkyl)n7-(C3-Cι2 arylene or heteroarylene)-(Cι-C8 alkyl or substituted alkyl)n8 where n7 and n8 are independently O or l; T 4 is hydrogen or -Ri i wherein Ri i is as defined above; and
R7 is -C(=O)OR]4, where Rι4 is selected from the group consisting of -Cι-Cι2 alkyl, substituted alkyl, or heteroalkyl, -C1-C12 alkenyl, substituted alkenyl, or heteroalkenyl, -C]-Cι2 alkynyl, substituted alkynyl, or heteroalkynyl, and -(Cι-C8 alkyl or substituted alkyl)n9-(C3-C12 arylene or heteroarylene)-(Cι-C8 alkyl or substituted alkyl)nιo where n9 and nlO are independently 0 or 1 ; or a pharmaceutically acceptable salt thereof.
In another embodiment of this series of compounds, Ri is -OH or -OR9. In another embodiment of this series of compounds, R3 is -Cι-Cι2 alkyl, such as C4 alkyl and R4 is H. In another embodiment of this series of compounds, Rι4 is -C(=O)O-Cι- C12 alkyl, such as -C(=O)O-Cι-C4 alkyl, for example -C(=O)O-t-butyl.
(E) Another preferred group of compounds if represented by Formula (lid):
Figure imgf000030_0001
(lid) wherein:
R is -Rn where Rn is selected from the group consisting of -Cι-Cι2 alkyl, substituted alkyl, or heteroalkyl, -Cι-Cι2 alkenyl, substituted alkenyl, or heteroalkenyl, -C1-C12 alkynyl, substituted alkynyl, or heteroalkynyl, and -(Cι-C8 alkyl or substituted alkyl)n7-(C3-Cι2 arylene or heteroarylene)-(Cι-C8 alkyl or substituted alkyl)n8 where n7 and n8 are independently 0 or 1; and
R7 is -C(=O)OR]4 where Rι4 is selected from the group consisting of -Cι-Cι2 alkyl, substituted alkyl, or heteroalkyl, -C]-Cι2 alkenyl, substituted alkenyl, or heteroalkenyl, -Cι-Cι2 alkynyl, substituted alkynyl, or heteroalkynyl, and -(Cι-C8 alkyl or substituted alkyl)n9-(C3-Cι2 arylene or heteroarylene)-(Cι-C8 alkyl or substituted alkyl)nιo where n9 and nlO are independently 0 or 1; or a pharmaceutically acceptable salt thereof.
In one embodiment , R3 is -(Cι-Cι2)alkyl, preferably n-butyl. In another embodiment of this series of compounds, R is -C(O)O-Cι-Cι2 alkyl, such as -C(O)O-C i -C4 alkyl, for example -C(O)O-tert-butyl.
(F) Another preferred group of compounds if represented by Formula (lie):
Figure imgf000031_0001
(He) wherein:
R3 is -Rn where -Rn is selected from the group consisting of -Cι-Cι2 alkyl, substituted alkyl, or heteroalkyl, -Cι-Cι alkenyl, substituted alkenyl, or heteroalkenyl, -C1-C12 alkynyl, substituted alkynyl, or heteroalkynyl, and -(Cι-C8 alkyl or substituted alkyl)n7-(C3-Cι2 arylene or heteroarylene)-(Cι-C8 alkyl or substituted alkyl)n8 where n7 and n8 are independently 0 or 1 ;
R7 is -NH2, -NHRι3, or -NHRι4Rι5 where Rι3, R]4 and R15 are independently selected from the group consisting of -C1-C12 alkyl, substituted alkyl, or heteroalkyl, - Cι-Cι2 alkenyl, substituted alkenyl, or heteroalkenyl, -Cι-C]2 alkynyl, substituted alkynyl, or heteroalkynyl, and -(Cj-C8 alkyl or substituted alkyl)n9-(C3-Cι2 arylene or heteroarylene)-(Cι-C8 alkyl or substituted alkyl)nι0 where n9 and nlO are independently 0 or 1; or where R)4 and R15 combine to form a substituted or unsubstituted C4-C]0 cyclic alkyl, cyclic heteroalkyl, aryl or heteroaryl group; or a pharmaceutically acceptable salt thereof.
In one embodiment of this series of compounds, R3 is Cι-Cι2 alkyl, preferably n-butyl. In another embodiment of this series of compounds, R is -NHRι3 where Rι is as defined above.
(G) Another preferred group of compounds if represented by Formula (Ilf):
Figure imgf000032_0001
(Ilf)
wherein: R3 is -Rn wherein Rn is selected from the group consisting of hydrogen,
-Cι-Cι2 alkyl, substituted alkyl, or heteroalkyl, -Cι-Cι2 alkenyl, substituted alkenyl, or heteroalkenyl, -Cι-Cι2 alkynyl, substituted alkynyl, or heteroalkynyl, and -(Cι-C8 alkyl or substituted alkyl)n7-(C3-Cι2 arylene or heteroarylene)-(Cι-C8 alkyl or substituted alkyl)n8 where n7 and n8 are independently 0 or 1 ; R7a, R7b, R7c and R7a are independently selected from the group consisting of hydrogen, -Cι-C12 alkyl, substituted alkyl, or heteroalkyl, -Cι-Cι2 alkenyl, substituted alkenyl, or heteroalkenyl, -Cι-Cι2 alkynyl, substituted alkynyl, or heteroalkynyl, and -(Cι-C8 alkyl or substituted alkyl)n9-(C3-Cι2 arylene or heteroarylene)-(Cι-C8 alkyl or substituted alkyl)nl0 where n9 and nlO are independently 0 or 1; or two vicinal R7 groups can combine to form a substituted or unsubstituted C4-Cι0 cyclic alkyl, cyclic heteroalkyl, aryl or heteroaryl group; or a pharmaceutically acceptable salt thereof.
In one embodiment of this series of compounds, R3 is n-butyl. In another embodiment of this series of compounds, at least one R7 is selected from the group consisting of -C(=O)OR14, -OH, -OR,4, -R,4, -NH(C=O)ORM, or -NH(C=O)Rι5, where R]4 and Rι5 are independently selected from the group consisting of -Cι-Cι2 alkyl, substituted alkyl, or heteroalkyl, -Cι-Cι2 alkenyl, substituted alkenyl, or heteroalkenyl, Cι-Cι2 alkynyl, substituted alkynyl, or heteroalkynyl, and (Cι-C8 alkyl or substituted alkyl)n9-(C3-Cι2 arylene or heteroarylene)-(Cι-C8 alkyl or substituted alkyl)n ιo where n9 and nlO are independently 0 or 1.
(H) Another preferred group of compounds if represented by Formula (Ilg):
Figure imgf000033_0001
(Hg) wherein:
R3 is -Rn where R is selected from the group consisting of hydrogen, -Ci- C12 alkyl, substituted alkyl, or heteroalkyl, -C1-C12 alkenyl, substituted alkenyl, or heteroalkenyl, -Cι-Cι2 alkynyl, substituted alkynyl, or heteroalkynyl, and -(Cι-C8 alkyl or substituted alkyl)n7-(C3-C]2 arylene or heteroarylene)-(Cι-C8 alkyl or substituted alkyl)n8 where n7 and n8 are independently 0 or 1 ; and
R7a is selected from the group consisting of hydrogen, -Cι-Cι2 alkyl, substituted alkyl, or heteroalkyl, -C1-C12 alkenyl, substituted alkenyl, or heteroalkenyl, -Cι-Cι2 alkynyl, substituted alkynyl, or heteroalkynyl, and -(Cι-C8 alkyl or substituted alkyl)n -(C3-C]2 arylene or heteroarylene)-(Cι-C8 alkyl or substituted alkyl)„ι0 where n9 and nlO are independently 0 or 1; or a pharmaceutically acceptable salt thereof. In another embodiment of this series of compounds, R7a is -CH2-R<j where Rd is selected from the group consisting of H, -C1-C12 alkyl, substituted alkyl, or heteroalkyl, -Cι-Cj2 alkenyl, substituted alkenyl, or heteroalkenyl, -C\-Cn alkynyl, substituted alkynyl, or heteroalkynyl, and -(Cι-C8 alkyl or substituted alkyl)n9-(C3-Cι2 arylene or heteroarylene)-(Cι-C8 alkyl or substituted alkyl)nι0 where n9 and nlO are independently 0 or 1. In another embodiment of this series of compounds, R<j is selected from the group consisting of -O-CH3, -OH, -NH-(C=O)-CH3, and
Figure imgf000033_0002
(I) Another preferred group of compounds if represented by Formula (Ilh):
Figure imgf000034_0001
(Ilh) wherein:
R3 is -Rn where Rn is selected from the group consisting of hydrogen, -Ci- C12 alkyl, substituted alkyl, or heteroalkyl, -Cι-Cι2 alkenyl, substituted alkenyl, or heteroalkenyl, -Cι-Cι2 alkynyl, substituted alkynyl, or heteroalkynyl, and -(Cι-C8 alkyl or substituted alkyl)n7-(C -Cι2 arylene or heteroarylene)-(Cι-C8 alkyl or substituted alkyl)n8 where n7 and n8 are independently 0 or 1 ; and
R7 is selected from the group consisting of-Rι4 or -ORι4 where Rι4 is selected from the group consisting of -C1-C12 alkyl, substituted alkyl, or heteroalkyl, - C1-C12 alkenyl, substituted alkenyl, or heteroalkenyl, -C]-Cι2 alkynyl, substituted alkynyl, or heteroalkynyl, and -(Cι-C8 alkyl or substituted alkyl) n9-(C -Cι2 arylene or heteroarylene)-(Cι-C8 alkyl or substituted alkyl) nι0 where n9 and nlO are independently 0 or 1 ; or a pharmaceutically acceptable salt thereof.
In one embodiment of this series of compounds, R is n-butyl. In another embodiment of this series of compounds, R7 is -OCH3 or -O-tert-butyl. (J) Another preferred group of compounds if represented by Formula (Hi):
Figure imgf000034_0002
(Hi)
wherein:
R3 is -Rn where Rn is hydrogen, -Cι-Cι2 alkyl, substituted alkyl, or heteroalkyl, -Cι-Cι2 alkenyl, substituted alkenyl, or heteroalkenyl, -C]-Cι2 alkynyl, substituted alkynyl, or heteroalkynyl, or -(Cι-C8 alkyl or substituted alkyl)n7-(C3-C]2 arylene or heteroaryl ene)-(Cι-C8 alkyl or substituted alkyl)n8 where n7 and n8 are independently 0 or 1 ; and 30a, R30b, R30C R30d, and R30e are independently selected from the group consisting of hydrogen, -C1-C12 alkyl, substituted alkyl, or heteroalkyl, -Cι-Cι alkenyl, substituted alkenyl, or heteroalkenyl, -Cι-Cι2 alkynyl, substimted alkynyl, or heteroalkynyl, and -(Cι-C8 alkyl or substituted alkyl)n9-(C3-C]2 arylene or heteroaryl ene)-(Cι-C8 alkyl or substituted alkyl)nιo where n9 and nlO are independently 0 or 1 ; or where two vicinal R o groups can combine to form a substituted or unsubstituted C4-Cιo cyclic alkyl, cyclic heteroalkyl, aryl or heteroaryl group; and all salts and stereoisomers thereof.
In one embodiment of this series of compounds, at least one R3o is selected from the group consisting of -C(=O)ORι5 and -C(=O)Rι5, where R)5 is independently selected from the group consisting of C1-C12 alkyl, substituted alkyl, or heteroalkyl, Cι-Cι2 alkenyl, substituted alkenyl, or heteroalkenyl, Cι-Cι2 alkynyl, substituted alkynyl, or heteroalkynyl, and (Cι-C alkyl or substituted alkyl)n9-(C3-Cι2 arylene or heteroarylene)-(Cι-C8 alkyl or substituted alkyl)nιo where n9 and nlO are independently 0 or 1.
(K) Another preferred group of compounds if represented by Formula (IIj):
Figure imgf000035_0001
(IIj) where:
Ri is halo;
R3 is hydrogen, Rn, -OH, -ORn, -Rι2ORn, -SH, -SR, ι, -NH2, -NHR,,, -NR11R13, -NHC(=O)H, -NR, ιC(0)H, -NHC(=O)R, ,, -NRπC(=O)Rι3, -NHC(=O)NH2, -NRuC(=O)NH2, -NHC(=O)NHRM, -NHC(=O)NR,,R,3, -NR,,C(0)NR,,aR,3, -NHC(=O)OR, ι, -NR,,C(=O)OR,3, -NHS(=O)2R,3, -NRnS(=O)2Rι3, -NHS(=O)2ORn, or -NRπS(=O)2ORι3, where R,2 is selected from the group consisting of -Cι-Cι2 alkylene, substituted alkylene, or heteroalkylene, -Ci- Cι2 alkenylene, substituted alkenylene, or heteroalkenylene, -Cι-Cι2 alkynylene, substituted alkynylene, or heteroalkynylene, and -(Cι-C8 alkylene or substituted alkylene)n5-(C -C]2 arylene or heteroarylene)-(Cι-C8 alkyl or substituted alkyl)n6 where n5 and n6 are independently 0 or 1; and Rn, Riia and Rι3 are independently selected from the group consisting of -C\-Cn alkyl, substituted alkyl, or heteroalkyl, - Ci-Ci2 alkenyl, substituted alkenyl, or heteroalkenyl, -Cι-Cι2 alkynyl, substituted alkynyl, or heteroalkynyl, and -(Cι-C8 alkyl or substituted alkyl)n7-(C3-Cι2 arylene or heteroarylene)-(Cι-C8 alkyl or substituted alkyl)n8 where n7 and n8 are independently O or 1;
R7 is hydrogen, R14, -OH, -OR,4, -SH, -SRι4, -NH2, -NHRH, -NR14Rι5, -C(=O)H, -C(=O)R,4, -C(=O)NH2, -C(=O)NHR14, -C(=O)NR14R,5, -C(=O)OH,
-C(=O)ORi4, -C(=O)SH, -C(=O)SR14, -C(=O)CH3, -C(=O)CH2R14, -C(=O)CHR14R15, -C(=O)CR,4Rι5Rι6, -C(=O)OCH3, -C(=O)OCH2R14, -C(=O)OCHR14R15, -C(=O)OCR14R15R,6, -S(=O)2NH2, -S(=O)2NHR14, -S(=O)2NR14R15, -NHC(=O)H, -N(Rι4)C(=O)H, -NHC(=O)R15,
Figure imgf000036_0001
-NHC(=O)ORι4, -NHS(=O)2H, -N(R14)S(=O)2H, -NHS(=O)2OR15, -N(R14)S(=O)2OR15, -N(H)S(=O)2Rι5, or -N(Rι4)S(=O)2Rι5, or where two vicinal R6 or R7 groups combine to form a substituted or unsubstituted -C4-Cι0 cyclic alkyl, cyclic heteroalkyl, aryl or heteroaryl group where Rι4, R15 and Rι6 are each independently selected from the group consisting of -Cι-Cι2 alkyl, substituted alkyl, or heteroalkyl, -Cι-Cι2 alkenyl, substituted alkenyl, or heteroalkenyl, -Cι-Cι2 alkynyl, substituted alkynyl, or heteroalkynyl, and -(Cι-C8 alkyl or substituted alkyl)n9-(C3-Cι2 arylene or heteroarylene)-(Cι-C8 alkyl or substituted alkyl)n]0 where n9 and nlO are independently 0 or 1 ; or when R] and R15 are attached to a nitrogen atom they can combine to form a substituted or unsubstituted C4-Cιo cyclic alkyl, cyclic heteroalkyl, aryl or heteroaryl group; or a pharmaceutically acceptable salt thereof.
Within this group of compounds, a preferred group of compounds is that wherein the embodiments of (i) - (iii) defined below are employed either singularly or in any combination: (i) A preferred group of compounds is that wherein Rt is fluoro. The stereochemistry at the carbon carrying the Ri group is (R) or (S), preferably (S).
(ii) Another preferred group of compounds is that wherein R3 is hydrogen or R9 where R9 is -Cι-Cι2 alkyl or -( -C8 alkylene)n5-(C3-C12 aryl or heteroaryl) where n5 is 0 or 1, preferably methyl, ethyl, n-propyl, tsø-propyl, n-butyl, wo-butyl, tert-butyl, n-pentyl, wo-pentyl, neo-pentyl, n-hexyl, 2-, 3-, 4-, or 5-methylpentyl, 4,4- dimethylbutyl, benzyl, 3-phenylpropyl, 2-phenylethyl, or 4-phenylbutyl, more preferably n-butyl. The stereochemistry at the carbon carrying the R3 group is (R) or (S), preferably (R); and (iii) R7 is:
(a) -C(=O)NRι4R]5, where RH and R]5 are independently hydrogen, -(Ci- C12) alkyl, substituted alkyl, or heteroalkyl, -(C1-C12) alkenyl, substituted alkenyl, or heteroalkenyl, -(Cι-Cι2) alkynyl, substituted alkynyl, or heteroalkynyl, alkoxy, or -(Cι-C8 alkyl or substituted alkyl)n9-(C3-Cι2 arylene or heteroarylene)-(Cι-C8 alkyl or substituted alkyl)n 10 where n9 and nlO are independently 0 or 1 ; or Rj4 and Rι5 combine to form a substituted or unsubstituted -(C4-Cιo)cyclic alkyl, cyclic heteroalkyl, aryl or heteroaryl group.
Preferably, R is
Figure imgf000037_0001
where Rι4 and R15 are each independently hydrogen or -(Cι-Cι2) alkyl, alkoxy, aryl, heteroaryl or Rj4 and R15, when attached to the same carbon, combine to form a cyclic heteroalkyl, aryl or heteroaryl group. More preferably, R7 is -C(=O)NHRι5 where Rι5 is H or -(Cι-Cι2) alkyl, aryl, or heteroaryl or -C(=O)NRι4Rι5 where R]4 and R15form a substituted or unsubstituted -(C4-Cιo)cyclic heteroalkyl.
Even more preferably R is n-butylaminocarbonyl, tert-butylaminocarbonyl, benzylaminocarbonyl, 1,1-dimethylprop ylaminocarbonyl, 2-(cyclohexen-l-yl)- ethylaminocarbonyl, indan-5-ylaminocarbonyl, 4,5-dimethylthiazol-2- ylaminocarbonyl, 4-phenoxyphenylaminocarbonyl, cyclopropylmethyl- aminocarbonyl, pyridin-2-ylaminocarbonyl, pyridin-3-ylaminocarbonyl, pyridin-4- ylmethylaminocarbonyl, moφholin-4-ylcarbonyl, 3 ,4-methylenedioxy- phenylaminocarbonyl, quinolin-3 -ylaminocarbonyl, methylaminocarbonyl, 4- biphenylaminocarbonyl, 3 -phenoxyphenylaminocarbonyl, 3,4-dichlorophenyl- aminocarbonyl, 4-tert-butylphenylaminocarbonyl, 4-tert-butylaminocarbonyl, indan- 2-ylaminocarbonyl, 2,2-dimethylpropylaminocarbonyl, 4-phenylthiazol-2- yla inocarbonyl, 5-phenylthiadiazol-2-ylaminocarbonyl, 5-ethylthiadiazol-3- ylaminocarbonyl, thiadiazol-2-ylaminocarbonyl, 3-trifluoromethoxyphenyl- aminocarbonyl, 2,5-dimethylphenylaminocarbonyl, 2,5-dimethoxyphenylamino- carbonyl, 3,4-dichlorophenylaminocarbonyl, benzthiazol-2-ylaminocarbonyl, 3- phenoxyphenylaminocarbonyl, 2-hydroxybutylaminocarbonyl, 4-hydroxybutyl- aminocarbonyl, 1 ,4-benzodioxan-6-ylaminocarbonyl, isoquinolin-6-yl- aminocarbonyl, methylaminocarbonyl, thiazol-2-ylaminocarbonyl, 4-methylthiazol- 2-yl-aminocarbonyl, 3-methylbutyl-aminocarbonyl, n-pentylaminocarbonyl, cyclohexylaminocarbonyl, 5-methylthiazol-2-ylaminocarbonyl, 4-methylthiazol-2- yl-aminocarbonyl, 2,4-dimethoxyphenyl-aminocarbonyl, 3,4-methylenedioxyphen-5- yl-methylaminocarbonyl, allylaminocarbonyl, 2-methylallylaminocarbonyl, pyrrolidin-1 -ylcarbonyl, ethylaminocarbonyl, phenylaminocarbonyl, indan-1- ylaminocarbonyl, 2-methoxyethylaminocarbonyl, indan-5-ylaminocarbonyl, 3,4- difluorophenyl-aminocarbonyl, 5 -methylisoxazol-5 -ylaminocarbonyl, 3-fluoro- phenylaminocarbonyl, 4-fluorophenylaminocarbonyl, N-methyl-N-phenylamino- carbonyl, 2-propylamino-carbonyl, 2-phenylprop ylaminocarbonyl, n-propylamino- carbonyl, N-ethyl-N-(n-butyl)aminocarbonyl, benzylaminocarbonyl, thiazolidin-1- ylcarbonyl, piperazin- 1 -yl-carbonyl, piperidin- 1 -ylcarbonyl, azetidin-1 -ylcarbonyl, homopiperdin- 1 -ylcarbonyl, pyrimidin-2-ylaminocarbonyl, 4-methylpiperazin- 1 - ylcarbonyl, 4-methylpyrimidin-2-ylaminocarbonyl, pyrimidin-4-ylaminocarbonyl, pyrazin-2-ylaminocarbonyl, imidazol-2-ylaminocarbonyl.
In particular, R7 is piperidin- 1 -ylcarbonyl, azetidin-1 -ylcarbonyl, ethylaminocarbonyl, phenylaminocarbonyl, pyrimidin-2-ylaminocarbonyl, or thiazol- 2-ylaminocarbonyl.
More particularly, R7 is piperidin- 1 -ylcarbonyl, azetidin-1 -ylcarbonyl, ethylaminocarbonyl or thiazol-2-ylaminocarbonyl. The stereochemistry at the C2 carbon atom of the pyrrolidine ring, i.e., carbon carrying the R7 group is either (R) or (S), preferably (S); or
(b) R7 is -ΝHC(=O)OR,4 where R]4 is hydrogen, -(Cι-d2) alkyl, substituted alkyl, or heteroalkyl, -(Cι-C]2) alkenyl, substituted alkenyl, or heteroalkenyl, -(Cι-Cι2) alkynyl, substituted alkynyl, or heteroalkynyl, alkoxy, or - (Cι-C8 alkyl or substituted alkyl)n9-(C3-Cι2 arylene or heteroarylene)-(Cι-C8 alkyl or substituted alkyl)nι0 where n9 and nlO are independently 0 or 1. Preferably, R7 is -NHC(=O)ORι4 where Rι is hydrogen or -(Ci-C]2) alkyl, alkoxy, aryl, heteroaryl; or
(c) R7 is -C(=O)OR]4 where Rι4 is hydrogen, -(Cι-C]2) alkyl, substituted alkyl, or heteroalkyl, -(Cι-Cι2) alkenyl, substituted alkenyl, or heteroalkenyl, -(Ci-
Cι2) alkynyl, substituted alkynyl, or heteroalkynyl, alkoxy, or -(C]-C8 alkyl or substituted alkyl)n9-(C3-Cι2 arylene or heteroarylene)-(C]-C8 alkyl or substituted alkyl)n ιo where n9 and nlO are independently 0 or 1. Preferably, R7 is -C(=O)ORι7 where Rι4 is hydrogen or -(C1-C12) alkyl, alkoxy, aryl, or heteroaryl. More preferably, -C(=O)ORι4 where Rι4 is alkyl, even more preferably R is tert-butoxycarbonyl. The stereochemistry at the C2 carbon atom of the pyrrolidine ring, i.e., carbon carrying the R7 group is either (R) or (S), preferably (S).
Preferred compounds of the Invention are:
N-hydroxy-3-[(S)-(n-butyl)-3-(2-(S)-l,l-dimethylethyloxycarbonyl)- pyrrolidin- 1 -carbonyl)]-2-(S)fluoropropionamide;
N-hydroxy-3-[(S)-(n-butyl)-3-(2-(S)-pyridin-l-ylcarbonyl)pyrrolidin-l- carbonyl)]-2-(S)-fluoropropionamide;
N-hydroxy-3-[(S)-(n-butyl)-3-(2-(S)-azetidin- 1 -ylcarbonyl)-pyrrolidin- 1 - carbonyl)]-2-(S)-fluoropropionamide; N-hydroxy-3-[(S)-(n-butyl)-3-(2-(S)-ethylaminocarbonyl)pyrrolidin- 1 - carbonyl)]-2-(S)-fluoropropionamide;
N-hydroxy-3-[(S)-(n-butyl)-3-(2-(S)-phenylaminocarbonyl)-pyrrolidin-l- carbonyl)]-2-(S)-hydroxypropionamide;
N-hydroxy-3-[(S)-(n-butyl)-3-(2-(S)-pyrimidin-2-ylaminocarbonyl)pyrrolidin- 1 -carbonyl)] -2-(S)-hydroxypropionamide; and
N-hydroxy-3-[(S)-(n-butyl)-3-(2-(S)-thiazol-2-ylaminocarbonyl)-pyrrolidin-l- carbonyl)]-2-(S)-fluoropropionamide.
GENERAL SYNTHETIC SCHEME
Compounds of this invention can be made by the methods depicted in the reaction schemes shown below.
The starting materials and reagents used in preparing these compounds are either available from commercial suppliers such as Aldrich Chemical Co.,
(Milwaukee, Wisconsin, USA), Bachem (Torrance, California, USA), Emka-Chemie, or Sigma (St. Louis, Missouri, USA) or are prepared by methods known to those skilled in the art following procedures set forth in references such as Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-15 (John Wiley and Sons, 1991); Rodd's Chemistry of Carbon Compounds, Volumes 1-5 and Supplemental (Elsevier Science Publishers, 1989), Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), March's Advanced Organic Chemistry, (John Wiley and Sons, 4th Edition), and Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989). These schemes are merely illustrative of some methods by which the compounds of this invention can be synthesized, and various modifications to these schemes can be made and will be suggested to one skilled in the art having referred to this disclosure.
The starting materials and the intermediates of the reaction may be isolated and purified if desired using conventional techniques, including but not limited to filtration, distillation, crystallization, chromatography, and the like. Such materials may be characterized using conventional means, including physical constants and spectral data.
Preparation of compounds of Formula (I) Compounds of Formula (I) can be prepared by methods well known in the art of organic chemistry. Representative synthetic procedures for preparing compounds of the present invention are illusted and described in detail below. For example, compounds of Formula (I) can be prepared as described in Schemes A -D below.
A compound of Formula (I) where Ri, R , and R4 are hydrogen, and R3, R^, R7, Y, and n are as defined in the Summary of the Invention can be prepared as described in Scheme A below.
Scheme A
Figure imgf000040_0001
4
(R3/R6/R7 modified) (l)
Treatment of a solution of a /nonø-protected succinate of formula 1 where R is an alkyl group such as methyl, ethyl, and the like, and R3 is as defined in the Summary of the Invention, with an N,N-dialkylamine of formula 2, where R6 and R are as defined in the Summary of the Invention, provides a 3-aminocarbonyl- propionate derivative of formula 3. The reaction is typically carried out in the presence of an inert, polar aprotic solvent (e.g. DMF, dioxane, etc.) in the presence of a non-nucleophilic base (e.g. triethylamine, diisopropylethylamine, etc.) and a coupling reagent (e.g. EDCI, PyBOP, DIC, etc.). The reaction is initially started at low temperature, such as 0 °C, and then allowed to warm to room temperature, and then stirred for several hours. Some compounds of formula 1 are commercially available. Others can be prepared by methods well known in the art. For example /nønø-methyl succinate, mono-4-methyl-2-(i?)-methylsuccinate is available commercially, while njøno-4-methyl-2-(/?)-butylsuccinate as described in detail in Example 16 below.
Amines of formula 2 are commercially available or they can be prepared by methods well known in the art. For example, N, N-dialkylamines such as pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine, homopiperidine, homopiperazine, proline tert-butyl ester, Z-proline-2-methylamide, (S)-(+)-2-(methoxymethyl)- pyrrolidine, Z-proline-N-methoxy-N-methylamide, (S)-2-(pyrrolidinylmethyl)- pyrrolidine, Z-proline-N-morpholineamide, -proline-NN-dimethylamide, homoproline methyl ester, E-homoproline tert-butylester, 3-(R)- tert-butoxy-L- proline-O- t-butyl ester, pipecolinic acid, 1, 2,3, 4-tetrahydroquino line, 1- hydroxyethylpiperazine, 2-hydroxyethylpiperidine, 3-hydroxypiperidine, 4- hydroxypiperidine, 4-hydroxyproline, -tetrahydroisoquinoline tert-butyl ester, 3-(N- Boc-amino)pyrrolidine, and N-5øc-L-prolinol are commerically available. Other Ν,Ν-dialkylamines 2 such as 2-acetylaminomethylpyrrolidine can be prepared from N-5øc-Z-prolinol as described in Example 16 below. trans-3-Acetoxy-Z, -proline O- tert-butyl ester can be prepared from Cbz protected trans-3-hydroxy-Z,-proline as described in Example 17 below which can then be converted to trans 3-hydroxy-Z- proline O-tert-butyl ester, if desired, by hydrolysis of the acetoxy group in trans-3- acetoxy- -proline O-tert-butyl ester as described in Example 17 below.
Also, it will be recognized by a person skilled in the art that if compound 1 and /or 2 have additional reactive groups, then they must be suitably protected prior to carrying out the coupling reaction. Examples of suitable protecting groups and their introduction and removal are described in T.W. Greene and G. M. Wuts, "Protecting Groups in Organic Synthesis" Third Ed., Wiley, New York, 1999 and references cited therein. For example, if Rό or R7 is a carboxyl group or a hydroxy group then it can be protected as a t-butyl ester or benzyl ester or other suitable protecting group prior to the coupling reaction.
Compound 3 can optionally be converted to a compound of formula 4 where prior to converting it to a compound of Formula (I). This would be desirable if certain group(s) in compound 3, e.g., R3, Re, and/or R7 had to transformed to other group(s) within the scope of the invention prior to introducing the hydroxamate group in the molecule. For example, a compound of formula 3 where Re or R7 is a tert- butoxyamino group, can be converted to a corresponding compound of formula 4 where R6 or R7 is an acetylamino group by first treating 3 with an acid such as diluted hydrochloric acid at ambient temperature to provide a corresponding compound of formula 3 where R or R7 is an amino group, followed by treatment with an acetylating agent such as acetic anhydride in the present of an organic base such as pyridine.
A compound of formula 3 where R and\or R7 is a hydroxy can be converted to a compound of formula 4 where R6 and\or R is a sulfonamido group (i.e., - NHSO2Rι5 where Rι5 is as defined in the Summary of the Invention) by first converting the hydroxy group into amino group, followed by treatment with a sulfonylating agent. A detailed description of this transformation is provided in Example 34 below. A compound of formula 3 where R6 and\or R7 is a suitably protected carboxyl group can be converted to a compound of formula 4 where R6 and\or R7 is an aminocarbonyl group (i.e., -CONHRj4 or -CONR] Rι5 where R[4 and R]5 is as defined in the Summary of the Invention) by first deprotecting the carboxy group and then treating with an amine of formula -NHR)4 or -NRι4Rι5 (where Rι4 and R\5 is as defined in the Summary of the Invention). Briefly, the reaction conditions for deprotecting of the carboxy group will depend on the nature of the protecting group. For example, if it is a benzyl ester, then treatment with hydrogen gas and an appropriate catalyst (e.g., 10 % palladium on carbon) will liberate the free carboxylic acid. The amination reaction is typically carried out in the presence of an inert, polar aprotic solvent (e.g. DMF, dioxane, etc.) with a non-nucleophilic base (e.g. triethylamine, diisopropylethylamine, etc.) and a coupling reagent (e.g. EDCI, PyBOP, DIC, etc.). The reaction is initially started at low temperature, such as 0 °C, and then allowed to warm to room temperature, and then stirred for several hours. Many amines of formulae NHRt and NHR]4Ri5 are available commercially, or can be readily prepared by methods well known in the art. For example, methylamine, aniline, 2-aminothiazole, etc., are commercially available. Others can be prepared, for example, via reductive amination of an aldehyde, or Fukuyama alkylation of a suitable nitroaryl sulfonamide followed by cleavage of the sulfonamide to liberate the desired amine.
Compound 3 or 4 is then converted to a hydroxamate compound of Formula (I) by treating it at 0 °C with aqueous 50 % hydroxylamine in a polar organic solvent such as dioxane and the like. After the reaction is complete the mixture is then purified by preparative reverse-phase (C18) HPLC to afford compound of Formula (I). If desirable, suitable O-protected hydroxylamine such as O-benzylhydroxyl- amine can also be used to give an O-protectedhydroxamate compound. Removal of the protecting group will provide a compound of Formula (I).
A compound of Formula (I) can be converted to other compounds of Formula (I) by methods well known in the art. Some such methods are described below. Compounds of Formula (I) containing a hydroxy group may be prepared by de- alkylation/benzylation of an alkyloxy/benzyloxy substituent; and those containing an acid group, by hydrolysis of an ester group. Similarly, a compound of Formula (I) having an alkenyl or alkynyl group can be prepared by reacting a corresponding compound of Formula (I) containing a bromine or iodine atom with trimethylsilylacetylene under the Castro-Stephens reaction conditions. Furthermore, a compound of Formula (I) containing an alkoxy group may be prepared by alkylation of hydroxy substituent. A compound of Formula (I) containing a carboxy group can be prepared by hydrolyzing an ester group in a corresponding compound of Formula (I) under acid hydrolysis reaction conditions. The resulting carboxy group can optionally be converted to an amido group, if desired, by first converting the carboxy group to an activated ester derivative e.g., treating the carboxy compound with dicyclohexyl carbodiimide, DEAD and the like, followed by treatment with an amine. It will be recognized by a person skilled in the art that some of these transformations can be carried out prior to converting the compound of formula 5 to a compound of Formula (I).
A compound of Formula (I) where Ri is hydroxy, R2, and R, are hydrogen, and R3, R , R7, Y, and n are as defined in the Summary of the Invention can be prepared as described in Scheme B below. Scheme B
Figure imgf000044_0001
Ra and R =Me or Ra= Ph and Rb =Me
Figure imgf000044_0002
11
(I)
(R3/R6/R7 different than in 10)
Treatment of dimethyl malate 5 under strongly basic conditions with an appropriate alkylhalide R3X (where R3 is alkyl, alkenyl, alkynyl, substituted, heteroalkyl and X is halo such as chloro, bromo, or iodo) provides 2-substituted dimethyl malate 6. The reaction is typically carried out in a polar aprotic solvent such as THF, and the base is typically lithium diisopropylamide (LDA). The reaction is initially carried out at a low temperature, preferably at about - 78 °C, and then allowed to slowly warm to room temperature. The reaction is then stirred for several hours. The reaction is typically higher yielding when R3X is an allylic halide. After the alkylation is complete the resulting olefin can be reduced, if desired, to provide a compound of formula 6 where R3 is alkyl. The typically reduction procedure involves a suspension of 6 and a catalyst (e.g., 10 % palladium on carbon) in a solvent such as ethylacetate and would be stirred under a hydrogen atmosphere for several hours to afford the corresponding compound of formula 6 where R3 is alkyl. Many compounds of formula R3X are commercially available or they can be prepared by methods well known in the art. For example, iodomethane, benzylbromide, crotylbromide, allylbromide, vinylbromide are commercially available. Others can be prepared from the corresponding alcohol by first activating the hydroxy group as ap- toluenesulfonate ester (tosyl ester), followed by tosylate displaced with a halide ion in a modified Finkelstein procedure to afford an alkylhalide as described in working examples below. Treatment of 6 with a base affords a malic acid derivative of formula 7. The base can be an inorganic base such as lithium hydroxide or potassium hydroxide, and is most preferably sodium hydroxide. This reaction is usually performed in a polar, protic solvent such as methanol. Treatment of 7 with an orthoacetate, such as trimethylorthobenzoate, in the presence of an acidic catalyst affords an orthoester 8 (Ra is -Ph and Rb is -OMe). This reaction is ideally performed with a co-solvent, preferably in a mixture of toluene. The reaction is ideally performed at a higher temperature, most preferably at 110 °C. The catalyst is typically a sulfonic acid, such as/7-toluenesulfonic acid, or most preferably camphorsulfonic acid.
Alternatively, treatment of 7 with 2,2-dimethoxypropane in the presence ofp- toluenesulfonic acie provides an acetonide of formula 8 where Ra and Rb are methyl. Treatment of the orthoester or acetonide 8 with a dialkylamine of formula 2 under the reaction conditions described in Scheme A provides a compound of formula 9 which upon treatment with a base, preferably the salt of an alcohol, and more preferably sodium methoxide in an alcoholic solvent then provides a 2-hydroxy-3- aminocarbonyl -propionate derivative of formula 10.
Compound 10 is then optionally converted to a compound of formula 11 for reasons discussed in Scheme A such as derivatizing the R3, R and/or R7 groups prior to converting it to a compound of Formula (I). Alternatively, compound 10 it can be directly converted to a compound of Formula (I) as described in Scheme A above. It will be recognized by a person skilled in the art that the hydroxy group in compound 10 can be replaced by various other Ri groups as defined in the Summary of the Invention prior to converting it to a compound of Formula (I). Some representative examples are discussed below: (i) the hydroxy group in compound 10 can be replaced by a fluoro group prior to converting it to a compound of Formula (I) as shown below.
Figure imgf000046_0001
(i)
(R3/RQ/R7 different than in 12)
The hydroxyl group at the C2 carbon in compound 10 can be replaced by a fluoro group by first converting the hydroxyl group into an active ester followed by displaced with fluorine to afford compound 12. The reaction is performed in a halogenated solvent, such as dichloromethane (DCM), in the presence of an organic base, such as pyridine. The alcohol is typically activated as a sulfonate ester, preferably the trifluoromethane-sulfonate. This esterification reaction is typically earned out at a low temperature, preferably about -20 °C. The active ester is then reacted with a fluoride ion, typically derived from tris(dimethylamino)sulfur- (trimethylsilyl)difluoride (TAS-F). This reaction is also carried out at a low temperature, preferably at about -50 °C, and then slowly allowed to warm to ambient temperature. Compound 12 is then converted to a compound of Formula (I) either directly or through compound 13 as described above. A detailed description of this procedure is provided in Example 6 below. It will be noted that the stereochemistry at the C2 carbon atom is inverted during this transformation, (ii) the hydroxy group in compound 10 can be converted to an alkoxy under alkylation reaction conditions such as treatment of 10 with an alkyl halide such as methyl iodide, ethyl iodide, benzyl bromide, and the like, in the presence of a strong base such as sodium hydride and in a polar solvent such as dimethylformamide. Detailed description of this procedure is provided in Example 45 below, (iii) the hydroxy group in compound 10 can be converted to benzoyloxy group by first converting it into an activated ester such as a sulfonate ester, preferably the trifluoromethanesulfonate, followed by treatment with tetrabutyl ammomium benzoate. Detailed description of this procedure is provided in Example 47 below, (iii) the hydroxy group in compound 10 can be converted to thiol group by first converting it into an activated ester such as a sulfonate ester, preferably the trifluoromethanesulfonate, followed by treatment potassium thioacetate. Detailed description of this procedure is provided in Example 48 below.
(iv) the hydroxy group in compound 10 can be converted to an azido or amino group or it's derivatives by first converting it into an activated ester such as a sulfonate ester, preferably the trifluoromethanesulfonate, followed by treatment with sodium azide. The azide group can optionally reducted under catalytic hydrogenation reaction conditions to give an amino group which can be further derivatized by methods well known in the art. Detailed description of this procedure is provided in Example 49 and 34 below.
(vi) the maintainence of the stereochemistry at the carbon atom canying the hydroxy group in compound 10, the C2 carbon, can be achieved by carrying out double inversion as illustrated and described below.
CH3O-Na+
Figure imgf000048_0001
10 14
Figure imgf000048_0002
15 16
Figure imgf000048_0003
17
(RS/R^RT- different than in 16)
The hydroxyl at the C-2 carbon of intermediate 10 is converted to an active ester as described above in (i) above. Nucleophilic substitution with a variety of nucleophiles such as acetate anion, or more preferably, tetrabutylammonium benzoate, provides intermediate 14. This reaction proceeds in a hydrocarbon solvent, preferably in toluene. One skilled in the art will understand that the above nucleophilic displacement reaction results in an inversion of stereochemistry at the C- 2 position.
Compound 14 is treated with a base to afford hydroxy derivative 15. This base 0 is preferably the salt of an alcohol such as sodium methoxide, sodium ethoxide and the like, and more preferably sodium methoxide. The reaction proceeds in an alcoholic solvent such as methanol, ethanol and the like, most preferably in methanol.
Compound 15 is re-activated as a sulfonate ester, preferably a trifluoromethane sulfonate as described above and then treated with a fluorination 5 reagent, preferably TAS-F, to afford the corresponding fluoro intermediate 16 which has the same stereochemistry at the C-2 carbon as in intermediate 10. Compound 16 or 17 is then converted to a compound of Formula (I) as discussed above.
A compound of Formula (I) can also be prepared as illustrated in Scheme C below.
Scheme C
Figure imgf000049_0001
■^ OH ii) piperidine 20
ArgoGel-OH
Figure imgf000049_0002
Treatment of a suspension of ArgoGel-Wang or ArgoGel-OH resin with an Fm-protected succinic acid of formula 19 (wherein R3 is as defined in the Summary of the Invention) in the presence of a coupling agent such as di-isopropylazo- dicarboxylate and triphenylphosphine, followed by treatment with piperidine provides a resin bound Fm-protected succinic acid 20. The coupling reaction is carried out in a polar solvent such as dichloromethane in the presence of a base such as dimethylaminopyridine. The reaction is typically carried out at ambient temperature. Treatment of 20 with PFP-OTFA and pyridine, followed by treatment with an amine 2 then provides resin bound 3-aminocarbonylpropionate 21. The reaction is carried out in the presence of a non-nucleophilic base such as pyridine, diethylisopropylamine, 2,4,6-collidine, and the like. The reaction is typically carried out at ambient temperature. Treatment of 21 with hydroxylamine then provides a compound of Formula (I).
A compound of Formula (I) where Ri & R2 are fluoro and R2, R3, Re, Ri, Y and n are as defined in summary of the invention can be prepared as illustrated in Scheme D below.
Scheme D
base
Figure imgf000050_0001
8 22
Figure imgf000050_0002
23 24
Figure imgf000050_0003
Treatment of a compound of formula 8 with an alcohol such as tert-butanol in the presence of a suitable coupling agent such as DIC and a base such as DMAP provides the corresponding tert-butyl ester of formula 22. Treatment of 22 with a base such as sodium methoxide in methanol provides 2-hydroxysuccinate derivative of formula 23. Compound 23 is then converted to a trifluoromethanesulfonate ester derivative 24 using triflic anhydride in the presence of a base such as triethyamine, pyridine and the like. Treatment of 24 with a base such as triethylamine provides a maleic acid derivative of formula 25 which upon reaction with xenon difluoride in the presence of boron trifluoride etherate provides a 2,3-difluorosuccinate derivative. Removal of the tert-butyl group with trifluoroacetic acid provides the conesponding succinic acid derivative 26 which is then converted to a compound of Formula (I) as described above.
Administration, Utility and Testing
Administration and Pharmaceutical Composition The present invention also provides pharmaceutical compositions which comprise a bioactive hydroxamic acid compound or derivative, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. The compositions of the invention include those in a form adapted for oral, topical or parenteral use and can be used for the treatment of bacterial infection in animals, preferably mammals, more preferably humans.
The antibiotic compounds, also referred to herein as antimicrobial compounds, according to the invention can be formulated for administration in any convenient way for use in human or veterinary medicine, by analogy with other antibiotics. Such methods are known in the art (see, e.g., Remington's Pharmaceutical Sciences, Easton, PA: Mack Publishing Co.) and are not described in detail herein.
The composition can be formulated for administration by any route known in the art, such as subdermal, inhalation, oral, topical or parenteral. The compositions can be in any form known in the art, including but not limited to tablets, capsules, powders, granules, lozenges, creams or liquid preparations, such as oral or sterile parenteral solutions or suspensions. The compounds can also be administered in liposome formulations. The compounds can also be administered as prodrugs, where the prodrug administered undergoes biotransformation in the treated mammal to a form which is biologically active. The topical formulations of the present invention can be presented as, for instance, ointments, creams or lotions, solutions, salves, emulsions, plasters, eye ointments and eye or ear drops, impregnated dressings and aerosols, and can contain appropriate conventional additives such as preservatives, solvents to assist drug penetration and emollients in ointments and creams.
The formulations can also contain compatible conventional carriers, such as cream or ointment bases and ethanol or oleyl alcohol for lotions. Such carriers can be present, for example, from about 1% up to about 99% of the formulation. For example, they can form up to about 80% of the formulation. Tablets and capsules for oral administration can be in unit dose presentation form, and can contain conventional excipients such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrollidone; fillers, for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine; tabletting lubricants, for example magnesium stearate, talc, polyethylene glycol or silica; disintegrants, for example potato starch; or acceptable wetting agents such as sodium lauryl sulphate. The tablets can be coated according to methods well known in standard pharmaceutical practice.
Oral liquid preparations can be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or can be presented as a dry product for reconstitution with water or another suitable vehicle before use. Such liquid preparations can contain conventional additives, such as suspending agents, for example sorbitol, methyl cellulose, glucose syrup, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats; emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which can include edible oils), for example almond oil, oily esters such as glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid, and, if desired, conventional flavoring or coloring agents.
For parenteral administration, fluid unit dosage forms are prepared utilizing the compound and a sterile vehicle, water being prefened. The compound, depending on the vehicle and concentration used, can be either suspended or dissolved in the vehicle or other suitable solvent. In preparing solutions, the compound can be dissolved in water for injection and filter sterilized before filling into a suitable vial or ampoule and sealing. Advantageously, agents such as a local anesthetic preservative and buffering agents can be dissolved in the vehicle. To enhance the stability, the composition can be frozen after filling into the vial and the water removed under vacuum. The dry lyophilized powder is then sealed in the vial and an accompanying vial of water for injection can be supplied to reconstitute the liquid prior to use. Parenteral suspensions are prepared in substantially the same manner except that the compound is suspended in the vehicle instead of being dissolved and sterilization cannot be accomplished by filtration. The compound can be sterilized by exposure to ethylene oxide before suspending in the sterile vehicle. Advantageously, a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.
The compositions can contain, for example, from about 0.1% by weight to about 99%o by weight, e.g., from about 10-60%> by weight, of the active material, depending on the method of administration. Where the compositions comprise dosage units, each unit will contain, for example, from about 1-500 mg of the active ingredient. The dosage as employed for adult human treatment will range, for example, from about 1 to 3000 mg per day, for instance 1500 mg per day depending on the route and frequency of administration. Such a dosage corresponds to about 0.015 to 50 mg/kg per day. Suitably the dosage is, for example, from about 5 to 20 mg/kg per day. Utility
The hydroxamate compounds of the present invention can be used for the treatment or prevention of infectious disorders caused by a variety of bacterial or prokaryotic organisms. Examples include Gram positive and Gram negative aerobic and anaerobic bacteria, including Staphylococci, for example S. aureus and S. epidermidis; Enterococci, for example E. faecalis and E. faecium; Streptococci, for example S pneumoniae; Haemophilus, for example H. influenza; Moraxella, for example M. catarrhalis; and Escherichia, for example E. coli. Other examples include Mycobacteria, for example M. tuberculosis; intercellular microbes, for example Chlamydia and Rickettsiae; and : Mycoplasma, for example M. pneumoniae. In one embodiment, compositions, for treating or preventing infectious disorders are provided, comprising a hydroxamic acid compound or derivative as disclosed herein in combination with a pharmaceutically acceptable carrier. In another embodiment, there is provided a dosage amount of a hydroxamic acid compound or derivative as disclosed herein in an effective amount for the treatment, prevention or alleviation of a disorder, such as an infectious disorder. Hydroxamic acid compounds or derivatives can be screened for activity against different microbial agents and appropriate dosages can be determined using methods available in the art.
The compounds can be used to treat a subject to treat, prevent, or reduce the severity of an infection. Subjects include animals, plants, blood products, cultures and surfaces such as those of medical or research equipment, such as glass, needles, surgical equipment and tubing, and objects intended for temporary or permanent implantation into an organism. Treating a subject includes, but is not limited to, preventing, reducing, or eliminating the clinical symptoms caused by an infection of a subject by a microorganism; preventing, reducing, or eliminating an infection of a subject by a microorganism; or preventing, reducing, or eliminating contamination of a subject by a microorganism. The microorganism involved is preferably a prokaryote, more preferably a bacterium.
In one embodiment, methods of treating or preventing an infectious disorder in a subject, such as a human or other animal subject, are provided, by administering an effective amount of a hydroxamic acid compound or derivative as disclosed herein to the subject. In one embodiment, the compound is administered in a pharmaceutically acceptable form optionally in a pharmaceutically acceptable carrier. As used herein, an "infectious disorder" is any disorder characterized by the presence of a microbial infection, such as the presence of bacteria. Such infectious disorders include, for example central nervous system infections, external ear infections, infections of the middle ear, such as acute otitis media, infections of the cranial sinuses, eye infections, infections of the oral cavity, such as infections of the teeth, gums and mucosa, upper respiratory tract infections, lower respiratory tract infections, genitourinary infections, gastrointestinal infections, gynecological infections, septicemia, bone and joint infections, skin and skin structure infections, bacterial endocarditis, burns, antibacterial prophylaxis of surgery, and antibacterial prophylaxis in immunosuppressed patients, such as patients receiving cancer chemotherapy, or organ transplant patients. The compounds and compositions comprising the compounds can be administered by routes such as topically, locally or systemically. Systemic application includes any method of introducing the compound into the tissues of the body, e.g., intrathecal, epidural, intramuscular, transdermal, intravenous, intraperitoneal, subcutaneous, sublingual, nasal, vaginal, rectal, and oral administration. The specific dosage of antimicrobial to be administered, as well as the duration of treatment, can be adjusted as needed. Additionally, the compounds of this invention can also be used to prepare a composition in an inert diluent which is useful in inhibiting bacterial growth. An "inert diluent" means an excipient that is useful in preparing a composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable.
Representative pharmaceutical formulations containing a compound of Formula (I) are described below.
Testing The ability of the compounds of this invention to inhibit peptide deformylase was measured by in vitro assay described in detail in Biological Example below. The antimicrobial activity of the compounds of this invention was tested as described in detail in Biological Example 2 below. The selective inhibition of PDF compared to MMP-7 (Matrilysin) by the compounds of this invention was tested as described in detail in Biological Example 3 below.
EXAMPLES
The following preparations and examples are given to enable those skilled in the art to more clearly understand and to practice the present invention. They should not be considered as limiting the scope of the invention, but merely as being illustrative and representative thereof.
Abbreviations
The following abbreviations are used: AcOH, HOAc = acetic acid
AC2O = acetic anhydride
BOC, Boc = t-butyloxycarbonyl
DCC = dicyclohexylcarbodiimide
DCM = dichloromethane DIC = diisopropylcarbodiimide
DIAD = diisopropylazodicarboxylate
DIEA = diisopropylethylamine
DMF = dimethylformamide EDC = N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide
Et = ethyl
EtOAc = ethyl acetate
Fmoc, FMOC = 9-fluorenylmethyloxycarbonyl HATU = O-(7-aza-benzotriazol-l-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate
HBTU = O-(benzotriazol-l-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate
HHMPA = (4-hydroxymethyl-3-methoxyphenoxy)-alkanoic acid
HMP resin = hydroxymethylphenoxy resin HOAt = 1 -hydroxy-7-azabenzotriazole
HOBt = 1 -hydroxybenzotriazole
Me = methyl
Mem - methoxy ethoxy methyl ether
MeOH = methanol MMP = matrix metalloproteinase
Mom = methoxy methyl ether
NMM = N-methyl morpholine
NPEOC = 4-nitrophenethyloxycarbonyl
NPEOM = 4-nitrophenethylmethyloxycarbonyl NVOC = 6-nitroveratryloxycarbonyl
NVOM = nitroveratryloxymethyl ether
PEG-PS resins or PS-PEG resin = polyethylene glycol-polystyrene graft copolymer resins
PFP-OTFA = pentafluorophenyl trifluoroacetate PyBOP = benzotriazole-1-yl-oxy-tris-pyrrolidinophosphonium hexafluorophosphate
PyBROP = bromotripyrrolidinophosphonium hexafluorophosphate
RT = room temperature
TBP = tributylphosphate
TBS, TBDIMS = t-butyldimethylsilyl tBu = t-butyl
TES = triethylsilane
TFA = trifluoroacetic acid
TGS resin = TENTAGEL S resin
TGS NH2 resin = TENTAGEL S NH2 resin THF = tetrahydrofuran THP = 2-tetrahydropyranyl
TM AD = N,N,N',N'-tetramethylazodicarboxamide (1,1 '- Azobis(N,N- dimethylformamide)) TMOF = trimethylorthoformate TPP = triphenyl phosphine TsCl = tosyl chloride TsOH = toluenesulfonic acid Trt = trityl
SYNTHETIC EXAMPLES
GENERAL PROCEDURE A
Synthesis of N-hvdroxy-3-aminocarbonylpropionamide (following Scheme A)
Figure imgf000057_0001
Step l
To a solution of mono-protected succinate e.g., nzono-4-methyl 2-(R)- butylsuccinic acid 1 (1 mmol) in DMF was added dialkylamine 2 (1 mmol), DIE A (0.4 mL, 2.3 mmol), and an activating reagent (e.g. EDC, PyBOP, DIC, DCC, etc.; 1 mmol). The mixture was stined overnight, then diluted with ethyl acetate and washed with aqueous HC1 (1 N), water, saturated sodium bicarbonate, brine, and then dried (Na2SO4). The filtrate was concentrated and then purified on silica gel (Merck 60; ethyl acetate/hexane) to afford 3-aminocarbonylpropionate 3. Step 2
3-Aminocarbonylpropionate 3 (0.1 mmol) was treated with dioxane (1 mL) and hydroxylamine (50%> in water, 2 mL) for 1 to 3 days, and then can be purified by preparative reverse-phase (C18) HPLC to afford the desired N-hydroxy-3- aminocarbonylpropionamide. GENERAL PROCEDURE B
Synthesis of N-hvdroxy-3-(i?)-n-butyl-3-aminocarbonylpropionamide-
Alternate method
Figure imgf000058_0001
To /nønø-4-methyl 2-(i?)-butylsuccinic acid (0.2 mmol) in dioxane (1 mL) was added amine 2 (0.2 mmol), DIEA (0.4 mmol) and an activating reagent (e.g. EDC, PyBOP, DIC, DCC, etc.; 0.2 mmol); and the mixture was stirred for 2 h. Aqueous 50%) hydroxylamine was added (1.5 mL) and the mixmre was stined an additional 1-2 days. The reaction mixture can then be purified by preparative reverse-phase (C18) HPLC to afford N-hydroxy-3-(i?)-n-butyl-3-aminocarbonylpropionamide.
GENERAL PROCEDURE C
Synthesis ofN-hydroxy-3-(i?)-n-butyl-3-[2-(S)-aminocarbonylpyrrolidin-l- ylcarbonyl)-2-(S)-hydroxypropionamide
Figure imgf000058_0002
NH OH
Figure imgf000058_0003
Figure imgf000058_0004
Ste l To 2-(2,2-dimethyl-4-oxo-l,3-dioxolan-5-yl)hexanoic acid C-l (prepared in four steps from dimethyl malate; see Example 21 for details) in DMF was added proline O-methyl ester, DIEA and HATU and the solution stined 4 hours. Standard aqueous workup afforded the desired amide, which was dissolved in methanol and treated with lithium hydroxide to yield l-(2,2-dimethyl-4-oxo-l,3-dioxolan-5-yl)-l- (2-(S)-carboxypynolidin-l-ylcarbonyl)pentane C-2. Step 2
To l-(2,2-dimethyl-4-oxo-l,3-dioxolan-5-yl)-l-(2-(S)-carboxypyrrolidin-l- ylcarbonyl)pentane C-2 in DMF was added an amine Rι4NH2, DIEA and HATU and the solution stined for 2 h. Aqueous workup followed by silica gel chromatography afforded l-(2,2-dimethyl-4-oxo-l,3-dioxolan-5-yl)-l-(2-(S)-aminocarbonylpyrrolidin- l-ylcarbonyl)pentane C-3. Step 3
To l-(2,2-dimethyl-4-oxo-l,3-dioxolan-5-yl)-l-(2-(S)-aminocarbonyl- pyrrolidin-l-ylcarbonyl)pentane C-3 in dioxane was treated with 50 % aqueous hydroxylamine for 4 h. The reaction mixture was then purified by preparative reverse-phase (C18) HPLC to afford N-hydroxy-3-(i?)-n-butyl-3-[2-(S)- aminocarbonylpyrrolidin- 1 -ylcarbonyl)-2-(S)-hydroxypropionamide C-4.
GENERAL PROCEDURE D
Synthesis ofN-hydroxy-3-(i?)-n-butyl-3-[2-(S)-aminocarbonylpynolidin-l-yl- carbonyl)propionamide (following Scheme C)
Figure imgf000060_0001
Step l
To ArgoGel resin (20 g) solvated in DCM was added 2-(i?)-n-butylsuccinate l-(9-fluorenyl) ester (10.0 g, 23.2 mmol), diisopropylazodicarboxylate (DIAD; 4.8 mL, 24.3 mmol) and triphenylphosphine (PPh3, 6.38 g, 24.3 mmol); the reaction mixture was shaken for 6 h. The resin is filtered and was washed with DCM (3x), MeOH (3 x) and DMF (3 x). A solution of piperidine (40 mL, 10% in DMF) was added and the resin mixture is shaken for 3 h. The resin was filtered and then washed sequentially with DMF (3x), DCM (2x), MeOH (2x) and DMF (3x) to afford intermediate D-1. Step 2
To resin D-1 in DMF was added PFP-OTFA and pyridine and the mixture was shaken for 4 h. The resin was filtered and washed with DMF (3x), MeOH (2x), DCM (2x), and ether (2x) and dried under vacuum. To a portion of the resin was added a solution of an amine (1 mmol) and DIEA (1.5 mmol) in DMF (1 mL). The resin was shaken overnight, filtered and washed with DMF, MeOH, and DCM to afford D-2. Step 3
To D-2 was added dioxane (0.5 mL) and aqueous 50%> hydroxylamine (1 mL). After 18 h, the cleavage products were drained and then purified by preparative reverse-phase (C18) HPLC to afford the desired hydroxamate D-3. GENERAL PROCEDURE E
Synthesis of N-hydroxy-3-(i?)-n-butyl-3-[2-(S)-aminocarbonylpynolidin- 1 -yl- carbonyl)propionamide
Figure imgf000061_0001
Step l
To a solution of mono-4-methyl 2-(i?)-butylsuccinic acid, (prepared in three steps from hexanoylchloride and t-butyl bromoacetate as described below; 1 mmol) in DMF was added proline O-benzyl ester (1 mmol), DIEA (0.4 mL, 2.3 mmol), and a coupling reagent (e.g. EDCI, PyBOP, DIC, etc.; 1 mmol). The mixture was stirred overnight, then diluted with ethyl acetate and washed with aqueous HC1 (1 N), water, saturated sodium bicarbonate, brine, and then dried (Na2SO4). The filtrate was concentrated and then purified on silica gel (Merck 60; ethyl acetate/hexane) to afford methyl-3-( ?)-butyl-3-(2-(S)-benzyloxycarbonylpyrrolidin-l-ylcarbonyl)propionate. To this amide (0.1 mmol) in ethylacetate ( 10 mL) was added 10 % Pd/C ( 100 mg) and the solution stined under a hydrogen atmosphere for 8 h. The suspension was filtered through a Celite plug and then concentrated to afford methyl-3-( ?)-butyl-3-(2-(S)- carboxypyrrolidin- 1 -ylcarbonyl)propionate E-2. Step 2 To methyl-3-(i?)-butyl-3-(2-(S)-carboxycarbonylpyrrolidin- 1 -ylcarbonyl)- propionate E-2 (100 mg) in DMF (1 mL) was added an amine (1 equivalent), DIEA (2.5 equivalents) and HATU (1 equivalent) and the reaction stirred for 4 h. The solution was then cooled to 0 °C, 50 %> aqueous hydroxylamine was added (400 μL), and the reaction stined at 4 °C for 4 hours to 3 days, depending upon the succinate. The crude reaction mixture was then purified by preparative reverse-phase (C18) HPLC to afford the desired compound methyl-3-(i?)-butyl-3-(2-(S)-amino- carbonylpynolidin-l-ylcarbonyl)propionate E-3.
GENERAL PROCEDURE F
Synthesis of N-hydroxy-3-(i?)-n-butyl-3-[2-(S)-aminocarbonylpyrrolidin- 1 -yl- carbonyl)-2-(S)-hydroxypropionamide
Figure imgf000062_0001
F-6 F-7
Step l
To a solution of diisopropylamine (14 mL, 100 mmol) in THF at 0°C was added n-butyllithium (2.5 M in hexane, 40 mL, 100 mmol) over 10 min. The mixture was stirred at RT for 30 min., and then added via cannula to a -78 °C solution of dimethyl malate F-1 (7.71 g, 47.6 mmol) in THF (130 mL). The mixture was warmed to -20 °C over 2 h, and then cooled to -78 °C. Crotyl bromide (8.1 g, 60 mmol) was added, then the mixture was allowed to warm to room temperature and then stined overnight. The solution was then cooled to -10 °C and quenched with NH4C1 (10%, 100 mL). The THF was removed and the residue extracted with ethyl acetate (2x200 mL). The combined organic layers were washed with HC1 (IN, 3x50 mL), saturated aqueous sodium bicarbonate (3x50 mL), and brine, then dried over Na2SO4. The solution was filtered and concentrated to give a residue, which was purified on silica gel (ethyl acetate/hexane 1 :4) to afford (2S,5i?)-3-(2-butenyl)-2-hydroxysuccinic dimethyl ester F-2 (2.5 g, 24%). Step 2
To (2S,5i?)-3-(2-butenyl)-2-hydroxysuccinic dimethyl ester F-2 (2.5 g) in ethyl acetate (50 mL) was added 10 % Pd/C (0.25g) and the reaction stined under a hydrogen atmosphere for 20 h. The suspension was filtered through a pad of Celite, washed with EtOAc (3x) and then concentrated in vacuo to afford (2S,3R)-3-(n- butyl)-2-hydroxysuccinic dimethyl ester F-3. Step 3
To (2S,ii?)-3-(n-butyl)-2-hydroxysuccinic dimethyl ester F-3 in methanol (28 mL) was added a solution of NaOH (2.2 g, 55 mmol) in water (28 mL). After 24 h the MeOH was removed, the crude reaction was acidified with HC1 (6N, 12 mL) to pH = 1, and then extracted with ethyl acetate (3 x 50mL). The combined organic layers were dried (Na2SO4) and concentrated to give (2S, ft)-3-(n-butyl)-2- hydroxysuccinic acid F-4 (1.96 g, 90%>). Step 4
To a solution of (2S, 3i?)-3-(n-butyl)-2-hydroxysuccinic acid F-4 (300 mg, 1.58 mmol) in 2,2-dimethoxypropane (10 mL) was added p-toluenesulfonic acid (20 mg) and the reaction was stined at room temperature for 16 h. The solution was diluted with dichloromethaneand washed with brine, dried (Na2SO4) and then purified by silica gel chromatography to afford 1.2 mmol 2-(2,2-dimethyl-4-oxo-l,3-dioxolan- 5-yl)hexanoic acid F-5 (78 %). Step 5
To a solution of 2-(2,2-dimethyl-4-oxo-l,3-dioxolan-5-yl)hexanoic acid F-5 (1.2 mmol) in DCM (10 mL) was added L-Pro-OBn (1.2 mmol), PyBOP (1.2 mmol), and DIEA (2.5 mmol). The mixture was stirred overnight, then concentrated, and purified on silica gel (ethylacetate/hexane 1 :4) to afford 275 mg of the desired amide (45%>). To the product in ethylacetate (25 mL) was added 10 %> Pd/C (50 mg) and the reaction stined under a hydrogen atmosphere for 8 h. The suspension was filtered through a pad of Celite, washed with EtOAc (3x) and then concentrated in vacuo to afford l-(2,2-dimethyl-4-oxo-l,3-dioxolan-5-yl)-l-(2-(S)-carboxy-pyrrolidin-l- ylcarbonyl)pentane F-6 (quant.). Step 6
To 1 -(2,2-dimethyl- 4-oxo- 1 ,3-dioxolan-5-yl)- 1 -(2-(S)-carboxy-pynolidin- 1 - ylcarbonyl)pentane F-6 (50 mg) in dioxane (1 mL) was added an amine RNH2 (1 equivalent), DIEA (2.5 equivalents) and HATU or PyBOP (1 equivalent) and the solution stined for 4 h. The reaction was then cooled to 0 °C, 50 % aqueous hydroxylamine was added (400 μL), and the solution stirred at 4 °C for 8 hours. The crude reaction mixture was then purified by preparative reverse-phase (C18) HPLC to afford N-hydroxy-3-(/?)-n-butyl-3-[2-(S)-aminocarbonylpynolidin-l-yl-carbonyl)-2- (S)-hydroxypropionamide F-7.
GENERAL PROCEDURE G
Synthesis of N-hydroxy-3-(S)-n-butyl-3-[2-(S)-aminocarbonylpyrrolidin-l-yl- carbonyl)-2-(i?)-fluoropropionamide
Figure imgf000064_0001
G-4 G-5
Figure imgf000064_0002
Step 1
To 2-(2,2-dimethyl-4-oxo-l,3-dioxolan-5-yl)hexanoic acid G-l (10 mmol; prepared as described in Method F, above) in DMF (50 mL) was added proline O-t- butyl ester (10 mmol), DIEA (25 mmol) and PyBOP (10 mmol) and the solution stined for 8 h. The reaction was diluted with ethyl acetate and washed with water, sodium bicarbonate, brine, and then dried (Na2SO4). The filtrate was concentrated and then purified on silica gel (Merck 60; ethyl acetate/hexane) to afford l-(2 ,2- dimethyl-4-oxo-l,3-dioxolan-5-yl)-l-(2-(S)-tert-butoxycarbonylpyrrolidin-l-yl- carbonyl)pentane G-2 (5 mmol, 50 %>). Step 2
To l-(2,2-dimethyl-4-oxo-l,3-dioxolan-5-yl)-l-(2-(S)-tert-butoxy- carbonylpynolidin-l-ylcarbonyl)pentane G-2 (5 mmol, 50 %) (5 mmol) in methanol (20 mL) was added sodium methoxide (catalytic; pH adjusted to 10) and the solution stined for 1 hour. Amberlite IR-120 resin (H+ form) was added, then the solution was filtered and concentrated to afford methyl 3-( ?)-n-butyl-3-[2-(S)-tert-butoxy- carbonylpynolidin-l-yl-carbonyl)-2-(S)-hydroxypropionate G-3 (quant.). Step 3
To methyl 3-(i?)-n-butyl-3-[2-(S)-tert-butoxycarbonylpynolidin-l -yl- carbonyl)-2-(S)-hydroxypropionate G-3 (5 mmol) in DCM (5 mL) was added pyridine (15 mmol), the reaction was cooled to -20 °C, then triflic anhydride was added (7.5 mmol). The solution was stirred for 1 hour, then washed with aqueous citric acid, sodium bicarbonate and brine, then dried (Na2SO4) and concentrated. The intermediate triflate was then resuspended in DCM and cooled to - 50 °C. Tris(dimethylamino)sulfur (trimethylsilyl)difluoride (TAS-F) was added (5 mmol) and the solution allowed to warm to rt. The reaction mixture was washed with aqueous sodium bicarbonate and brine, dried (Na2SO4) and concentrated then purified on silica gel (ethylacetate/hexanes) to afford 2.3 mmol (45 %>) of methyl 3-(S)-n- butyl-3-[2-(S)-tert-butoxycarbonylpyrrolidin-l-yl-carbonyl)-2-(/?)-fluoropropionate
G-4.
Step 4
To methyl 3-(S)-n-butyl-3-[2-(S)-tert-butoxycarbonylpynolidin- 1 -yl- carbonyl)-2-(/?)-fluoropropionate G-4 (2.3 mmol) was added 4 N HC1 in dioxane (10 L), the solution stined for 2 h, then evaporated to dryness to afford 2.3 mmol of methyl 3-(S)-n-butyl-3-[2-(S)-carboxypynolidin-l-yl-carbonyl)-2-(i?)- fluoropropionate G-5 (quant.). To intermediate G-5 (0.15 mmol) in dioxane (1 mL) was added an amine (0.15 mmol), DIEA (0.38 mmol), and HATU or other coupling reagent (0.15 mmol) and the solution stined for 8 h. The reaction was cooled to 0 °C, aqueous 50 % hydroxylamine was added (0.5 mL) and the reaction stined for 4 h. The crude reaction mixture was then purified by preparative reverse-phase (C18) HPLC to afford N-hydroxy- 3-(S)-n-butyl-3-[2-(S)-aminocarbonylpyrrolidin-l-yl- carbonyl)-2-(Λ)-fluoropropionamide G-6. GENERAL PROCEDURE H
Synthesis ofN-hydroxy-3-(S)-n-butyl-3-[2-(S)-aminocarbonylpyrrolidin-l-yl- carbonyl)-2-(S)-fluoropropionamide
Figure imgf000066_0001
Step 1
To methyl 3-(J?)-n-butyl-3-[2-(S)-tert-butoxycarbonylpyrrolidin-l-yl- carbonyl)-2-(S)-hydroxypropionate H-1 (10 mmol; prepared as described in Method G, above) in DCM (10 mL) was added pyridine (30 mmol), the reaction was cooled to -20 °C then triflic anhydride (15 mmol) was added. The solution was stined for 1 hour, then washed with aqueous citric acid, sodium bicarbonate and brine, then dried (Na2SO4) and concentrated. The resulting oil was dissolved in toluene (30 mL), cooled to 0 °C, then treated with tetrabutylammonium benzoate. After 1.5 h, the reaction was concentrated and then purified on silica gel (ethylacetate/hexanes) to afford 8.7 mmol of methyl 3-(i?)-n-butyl-3-[2-(S)-tert-butoxycarbonylpyrrolidin-l-yl- carbonyl)-2-(7?)-benzoyloxypropionate H-2 (87 %>). Step 2 To methyl 3-(i?)-n-butyl-3-[2-(S)-tert-butoxycarbonylpyrrolidin-l-yl- carbonyl)-2-(i?)-benzoyloxypropionate H-2 (8.7 mmol) in methanol (25 mL) at 0 °C was added sodium methoxide (catalytic; pH adjusted to 10) and the solution stirred for 2 h. Amberlite IR-120 resin (H+ form) was added, then the solution was filtered and concentrated to afford methyl 3-(i?)-n-butyl-3-[2-(S)-tert-butoxycarbonyl- pyrrolidin-l-yl-carbonyl)-2-(i?)-hydroxypropionate H-3 (quant.). Step 3 To methyl 3-(i?)-n-butyl-3-[2-(S)-tert-butoxycarbonylpyrrolidin-l-yl- carbonyl)-2-(i?)-hydroxypropionate H-3 (8.7 mmol) in DCM (10 mL) was added pyridine (25 mmol), the reaction was cooled to -20 °C, then triflic anhydride (12.5 mmol) was added. The solution was stirred for 1 hour, then worked up as described above. The intermediate triflate was resuspended in DCM and cooled to -50 °C. Tris(dimethylamino)sulfur (trimethylsilyl)difluoride (TAS-F) was added (8.7 mmol) and the solution allowed to warm to rt. The reaction mixture was washed with aqueous sodium bicarbonate and brine, dried (Na2SO4) and concentrated, then purified on silica gel (ethylacetate/hexanes) to afford 4.3 mmol (50 %>) of methyl 3- (S)-n-butyl-3-[2-(S)-tert-butoxycarbonylpyrrolidin-l-yl-carbonyl)-2-(S)- fluoropropionate H-4. Step 4
To methyl 3-(S)-n-butyl-3-[2-(S)-tert-butoxycarbonylpynolidin-l -yl- carbonyl)-2-(S)-fluoropropionate H-4 (4.3 mmol) was added 4 N HCl in dioxane (15 mL), the solution stined for 2 h, then evaporated to dryness to afford 4.3 mmol of methyl 3-(S)-n-butyl-3-[2-(S)-carboxypyπOlidin-l-yl-carbonyl)-2-(S)-fluoro- propionate H-5 (quant.). To H-5 (0.15 mmol) in dioxane (1 mL) was added an amine (0.15 mmol), DIEA (0.38 mmol), and HATU or similar coupling reagent (0.15 mmol) and the solution stirred for 8 h. The reaction was cooled to 0 °C, aqueous 50 %> hydroxylamine was added (0.5 mL) and the reaction stirred for 4 h. The crude reaction mixture was then purified by preparative reverse-phase (C18) HPLC to afford N-hydroxy-3-(S)-n-butyl-3-[2-(S)-aminocarbonylpynolidin-l-yl-carbonyl)-2- (S)-fluoropropionamide H-6.
.GENERAL PROCEDURE I
Synthesis ofN-hydroxy-3-(i?)-n-butyl-3-[2-(S)-(tert-butoxycarbonyl)-pynolidin-l-yl- carbonyl)-2-(S)-hydroxypropionamide
Figure imgf000068_0001
NHjOH
Figure imgf000068_0002
Step 1
To a solution of (2S,Ji?)-3-(n-butyl)-2-hydroxysuccinic acid F-4 (300 mg, 1.58 mmol) and powdered molecular sieves ( lg ) in trimefhyl orthobenzoate (5 mL) and toluene ( 5ml ) was added 10-Camphorsulfonic acid (20 mg) and the reaction was heated at 110°C under vacuum ( 20 torr ) for 5 h. The solution was diluted with ethyl acetate , filtered through Celite and washed with brine, dried (Na2SO4) and then purified by silica gel chromatography to afford 1.2 mmol 2-(2-methoxy-2-phenyl -4- oxo-l,3-dioxolan-5-yl)hexanoic acid 1-1 (40 %>). Step 2
To 2-(2-methoxy-2-phenyl -4-oxo-l,3-dioxolan-5-yl)hexanoic acid 1-1 (10 mmol; prepared as described in Method I, above) in DMF (50 mL) was added proline O-t-butyl ester (10 mmol), DIEA (25 mmol) and PyBOP (10 mmol) and the solution stined for 8 h. The reaction was diluted with ethyl acetate and washed with water, sodium bicarbonate, brine, and then dried (Na2SO4). The filtrate was concentrated and then purified on silica gel (Merck 60; ethyl acetate/hexane) to afford 1 -(2 - methoxy-2-phenyl -4-oxo-l,3-dioxolan-5-yl)-l-(2-(S)-tert-butoxycarbonylpynolidin- l-yl-carbonyl)pentane 1-2 (5 mmol, 50 %). Step 3
To l-(2-methoxy-2-phenyl-4-oxo-l,3-dioxolan-5-yl)-l-(2-(S)-tert-butoxy- carbonylpynolidin-l-ylcarbonyl)pentane 1-2 (5 mmol, 50 %>) (5 mmol) in methanol (20 mL) was added sodium methoxide (catalytic; pH adjusted to 10) and the solution stined for 1 hour. Amberlite IR-120 resin (H+ form) was added, then the solution was filtered and concentrated to afford methyl 3-(i?)-n-butyl-3-[2-(S)-tert-butoxy- carbonylpyirolidin- 1 -yl-carbonyl)-2-(S)-hydroxypropionate G-3 (quant.). Step 4
To G-3 and 1-2 (50mg) in dioxane (1 mL) was added aqueous 50 %> hydroxylamine (0.5 mL) and the reaction stined for 16 h. The crude reaction mixture was then purified by preparative reverse-phase (C18) HPLC to afford N- hydroxy-3-(i?)-n-butyl-3-[2-(S)-(tert-butoxycarbonyl)-pynolidin-l-yl-carbonyl)-2-(S)- hydroxypropionamide .
GENERAL PROCEDURE J
Synthesis of N-hydroxy-3-(S)-n-butyl-3-[2-(S)-aminocarbonylpyrrolidin-l-yl- carbonyl)-2-(i?S)-fluoropropionamide
Figure imgf000069_0001
Hexanoyl 4-(s)-benzyl chloride
Figure imgf000069_0002
oxazolidin-2-one
Figure imgf000069_0003
Step 1
To a solution of 4-(S)-benzyloxazolidin-2-one (56 mmol) (Aldrich, Milwaukee, Wisconsin) in THF at -78 °C was added 2.5 M n-BuLi in hexane (22.4 mL, 56 mmol) and the reaction stined at -78 °C for 2 hr. To this was added via cannula a -78 °C solution of hexanoyl chloride (65 mmol) in THF and the mixture stined at -78 °C for 2 hr, then allowed to warm to room temperature and stirred overnight. The reaction was then quenched with aqueous saturated NH4C1, extracted with ethyl acetate, dried, and purified by silica gel chromatography (hexanes/ethyl acetate) to afford N-hexanoyl-4-(S)-benzyloxazolidin-2-one J-l . Step 2 To a solution of N-hexanoyl-4-(S)-benzyloxazolidin-2-one (7.3 mmol) in THF at -78 °C was added 1.0 M sodium hexamefhyldisilazide (ΝaHMDS, 8.8 mmol) and the reaction stined at -78 °C for 1 hr. A solution of alkyl iodofluorooacetate (8.8 mmol) in THF was then added dropwise, and the resulting mixture was stined at -78 °C for 1 hr and then at room temperature overnight. The reaction was quenched with ΝH C1, concentrated, then suspended in ethyl acetate and washed with 0.5 N HCl and brine, dried, and purified by silica gel chromatography (ethyl acetate/hexanes) to afford the alkyl 3-(S)-(n-butyl)-3-[4-(S)-benzyloxazolidin-2-one-3-ylcarbonyl)-2- (7?S)-(fluoro)propionate J-2. Step 3
To alkyl 3-(S)-(n-butyl)-3-[4-(S)-benzyloxazolidin-2-one-3-ylcarbonyl)-2- (i?S)-(fluoro)propionate (1.44 mmol) in THF at 0°C was added LiOBn (5.76 mmol ) in benzyl aicohol and the reaction stirred at 0°C for 3 hr. The reaction was then quenched with 5% KHSO4, concentrated, suspended in ethyl acetate and subjected to standard aqueous workup. The crude product was purified by silica gel chromatography (methanol/dichloromethane) to afford alkyl 3-(/?)-(n-butyl)-2-(i?S)- (fluoro)propionate J-3. Step 4
To J-3 (0.15 mmol) in dioxane (1 mL) was added an amine (0.15 mmol), DIEA (0.38 mmol), and HATU or similar coupling reagent (0.15 mmol) and the solution stined for 8 h. The reaction was cooled to 0 °C, aqueous 50 %> hydroxylamine was added (0.5 mL) and the reaction stined for 4 h. The crude reaction mixture was then purified by preparative reverse-phase (C18) HPLC to afford N-hydroxy-3-(S)-n-butyl-3-[2-(S)-aminocarbonylpyrrlidin- 1 -yl-carbonyl)-2- (/?S)-fluoropropionamide J-4.
Example 1
Synthesis ofN-hydroxy-3-(i?)-(n-butyl)-3-[(2-(S)-(tert-butoxycarbonyl)- pyrrolidin- 1 -ylcarbonyl]propionamide
Figure imgf000071_0001
The title compound was prepared according to General Procedure A from nønø-methyl 2-(i?)-butylsuccinic acid and L-proline tert-butyl ester. This compound has also been prepared according to General Procedure D using L-proline tert-butyl ester as the amine. Η NMR (300 MHz, CDC13) δ 0.89 (t, J=7.2 Hz, 3 H), 1.43 (s, 9H), 1.24-1.71 (m, 6H), 1.86-2.43 (m, 5H), 2.53 (dd, J=10.5 and 13.2 Hz, 1 H), 3.06 (m, 1H), 3.45-3.80 (m, 2H), 4.28-4.40 (m, 1H).
Example 2
Synthesis of N-hydroxy-3-(i?)-(n-butyl)-3-[(2-(S)-(tert-butylaminocarbonyl)- pynolidin- 1 -ylcarbonyl]propionamide
Figure imgf000071_0002
The title compound was prepared according to General Procedure A from mono-methyl 2-(i?)-butylsuccinic acid and L-proline t-butylamide hydrochloride. Η ΝMR (300 MHz, CDC13) : δ 0.77 (t, J=7.2 Hz, 3H), 1.19 (s, 9H), 1.28-2.00 (m, 10H), 2.08 (dd, J= 4.1 and 9.6 Hz, 1H), 2.26 (dd, J =9.6 and 15 Hz, 1H), 2.99 (m, 1H), 3.47 (m, 1H), 3.63 (dd, J=9.0 and 16.8 Hz, 1H), 4.28 (dd, J=1.9 and 7.8 Hz, 1H).
Example 3 Synthesis ofN-hydroxy-3-(7?)-(n-butyl)-3-[(2-(S)-(methylaminocarbonyl)- pyrrolidin- 1 -ylcarbonyljpropionamide
Figure imgf000071_0003
Small-scale synthesis The title compound was prepared according to General Procedure A from wønø-methyl 2-(/?)-butylsuccinic acid and L-proline methylamide hydrochloride. 1H NMR (300 MHz, CDC13): δ 0.80 (t, J=7.2 Hz, 3H), 1.28-2.50 (m, 12H), 2.98 (m, 1H), 3.47 s, 3H), 3.58 (m, 2H), 4.27 (m, 1H). Large-scale synthesis Step 1
To a solution of Boc-Pro-OH (5 g, 23.2 mmol), methylamine (2M in THF, 15 mL, 30 mmol), EDC (4.79 g, 25 mmol), and HOBt (3.38 g, 25 mmol) in THF (150 mL) was added DIEA (4.35 mL, 25 mmol) and the mixture stined overnight. THF was removed, the residue was dissolved in ethyl acetate and then washed with aqueous HCl (I N, 2x), 5% KHSO4 (2x), saturated sodium bicarbonate, brine, dried (Na2SO4), concentrated, and purified on silica gel (Merck 60, ethyl acetate/hexanes) to give N-Boc-(2-methylaminocarbonyl)pynolidine (3.3 g, 63%>). Step 2 N-Boc-(2-methylaminocarbonyl)pyrrolidine (3.3 g, 14.5 mmol) was treated with HCl (4 N in dioxane, 10 mL) for 1 h. The solvent was removed and the white solid treated with mono-methyl 2-(i?)-butylsuccinic acid (2.82 g, 15 mmol), HOBt (2.02 g, 15 mmol), EDC (2.88 g, 15 mmol) and DIEA (6.96 mL, 40 mmol) in THF for 16 h. Similar work-up and purification gave the methyl ester (2.2 g). A solution of methyl ester and lithium hydroxide (400 mg, 10 mmol) in methanol (15 mL) and water (10 mL) was stined for 16 h. Methanol was removed and the aqueous layer was acidified to pH =1 and extracted with ethyl acetate (4x). The organic layers were dried (Na2SO4) and concentrated to afford 3-(/?)-(n-butyl)-3-[(2-(S)-(methylamino- carbonyl)pyrrolidin-l-ylcarbonyl]propionic acid as a white solid (1.5 g). Step 3
To a solution of 3-(i?)-(n-butyl)-3-[(2-(S)-(methylaminocarbonyl)- pyrrolidin-l-ylcarbonyl]propionic acid (1.5 g, 5.28 mmol), O-benzylhydroxylamine (932 mg, 5.84 mmol), HOBt (784 mg, 5.84 mmol), and DIEA (2.3 mL, 13.2 mmol) in THF (100 mL) was added EDC (1.12 g, 5.84 mmol) and the reaction stined for 16 h. Conventional work-up and purification gave N-benzyloxy-3-(/?)-(n-butyl)-3-[(2-(S)- (methylaminocarbonyl)pynolidin-l-ylcarbonyl]propionamide (1.56 g).
A solution of N-benzyloxy-3-(7?)-(n-butyl)-3-[(2-(S)-(methylaminocarbonyl)- pyrrolidin-l-ylcarbonyl]propionamide (1.5 g) in ethyl acetate (50 mL) was hydrogenated over Pd C for 14 h. The mixture was filtered through a pad of Celite, washed with ethyl acetate, and concentrated to give N-hydroxy-3-(i?)-(n-butyl)-3-[(2- (S)-(methylamino-carbonyl)pyrrolidin-l-ylcarbonyl]propionamide (l.l g).
Example 4 Synthesis of N-hydroxy-3-( ?)-(n-butyl)-3-[(2-(S)-(methoxymethyl)- pyrrolidin- 1 -ylcarbonyl]propionamide
Figure imgf000073_0001
The title compound was prepared according to General Procedure A from (S)-
(+)-2-(methoxymethyl)pynolidine and /nonø-methyl 2-(7?)-butylsuccinic acid. 1H ΝMR (300 MHz, CDC13): δ 0.90 (t, J=7.5 Hz, 3H), 1.22-1.64 (m, 6H), 1.84-2.05 (m, 2H), 1.84-2.05 (m, 2H), 2.25-2.42 (m, 1H), 2.51-2.66 (m, 1H), 2.99-3.16 (m, 1H), 3.33 (s, 3H), 3.38 (dd, J=1.9 and 6.9 Hz, 1H), 3.44 (bd, J = 6.9 Hz, 1H), 3.47-3.54 (m, 1H), 3.61-3.69 (m, 1H), 4.24 (m, 1H).
Example 5
Synthesis of N-hydroxy-3-(/?)-(n-butyl)-3-[(2-(S)-(N-methoxy-N-methylamino- carbonyl)pyrrolidin- 1 -ylcarbonyl]propionamide
Figure imgf000073_0002
The title compound was prepared according to General Procedure A from L- proline Ν-methoxyl Ν-methylamide hydrochloride and mono-methyl 2-(R)- butylsuccinic acid. Η ΝMR (300 MHz, CDC13): δ 0.80 (t, J=7.2 Hz, 3H), 1.27-2.60 (m, 12H), 3.05 (m, 1H), 3.19 (s, 3H), 3.72 (m, 2H), 3.78 (s, 3H), 4.85 (m, 1H). Example 6
Synthesis of N-hydroxy-3-(i?)-(n-butyl)-3-[(2-(S)-(methoxycarbonyl)- pyrrolidin- 1 -ylcarbonyl] propionamide
Figure imgf000074_0001
The title compound was prepared according to General Procedure A from L- proline methyl ester hydrochloride and mono-methyl 2-(/?)-butylsuccinic acid. 1H ΝMR (300 MHz, CDC13): δ 0.90 (m, 3H), 1.23-1.70 (m, 6H), 1.86-2.09 (m, 3H), 2.15-2.62 (m, 3H), 3.01-3.17 (m, 1 H), 3.59 -3.86 (m, 2H), 3.71 (s, 3H), 4.42-4.53(m, 1H).
Example 7
Synthesis ofN-hydroxy-3-(i?)-(3-methylpropyl)-3-[(2-(S)-(tert-butoxycarbonyl)- pyrrolidin- 1 -ylcarbonyl]propionamide
Figure imgf000074_0002
The title compound was prepared according to General Procedure A from L- proline t-butyl ester hydrochloride and mono-methyl 2-(i?)-isobutylsuccinic acid. 1H ΝMR (300 MHz, CDC13): δ 0.90-0.99 (m, 6H), 1.27-2.58 (m, 18H), 2.78-2.91 (m, 1H), 3.08-3.18 (m, 1H), 3.43-3.81 (m, 3H), 4.26-4.40 (m, 2H).
Example 8 Synthesis ofN-hydroxy-3-(i?)-(n-butyl)-3-(pynolidin-l-ylcarbonyl)propionamide
Figure imgf000075_0001
The title compound was prepared according to General Procedure A using pyrrolidine as the amine and mono methyl-2-(i?)-butylsuccinic acid. MS (APCI) m/z = 243 [M+H].
Example 9
Synthesis of N-hydroxy-3-(i?)-(n-butyl)-3-[(2-(S)-(pynolidin-l-ylmethyl)- pyrrolidin- 1 -ylcarbonyljpropionamide
Figure imgf000075_0002
The title compound was prepared according to General Procedure A from 2- (S)-(pynolidin-l-ylmethyl)pynolidine and mono-methyl 2-(i?)-butylsuccinic acid. MS (APCI) m/z = 326 [M+H].
Example 10 Synthesis of N-hydroxy-3-(i?)-(n-butyl)-3-[(2-(S)-(morpholin-4-ylcarbonyl)- pyrrolidin- 1 -ylcarbonyl]propionamide
Figure imgf000075_0003
The title compound was prepared according to General Procedure D using L- proline Ν-morpholinylamide as the amine. MS (APCI) m/z = 356 [M+H]. Example 11
Synthesis of N-hydroxy-3-(i?)-(n-butyl)-3-[(2-(S)-(dimethylaminocarbonyl)- pyrrolidin- 1 -ylcarbonyl]propionamide
Figure imgf000076_0001
The title compound was prepared according to General Procedure A from L- proline Ν,Ν-dimethylamide hydrochloride and mono-methyl 2-(i?)-butylsuccinic acid. MS (APCI) m/z = 314 [M+H].
Example 12 Synthesis of N-hydroxy-3-(i?)-(n-butyl)-3-[4-(i?)-(tert-butoxy-2-(S)-tert- butoxycarbonyl)pynolidin- 1 -ylcarbonyl]propionamide
Figure imgf000076_0002
The title compound was prepared according to General Procedure A from 3- (i?)-O-tert-butyloxy-L-proline t-butyl ester and mono-methyl 2-(i?)-butylsuccinic acid. MS (APCI) m/z = 415 [M+H].
Example 13
Synthesis ofN-hydroxy-3-(i?)-(n-butyl)-3-[2-(S)-(methoxycarbonyl)piperidin-l- ylcarbonyljpropionamide
Figure imgf000077_0001
The title compound was prepared according to General Procedure A from (±)- homoproline methyl ester and mono-methyl 2-(i?)-butylsuccinic acid. MS (APCI) m/z = 315 [M+H].
Example 14
Synthesis ofN-hydroxy-3-(i?)-(n-butyl)-3-[2-(S)-(tert-butoxycarbonyl)piperidin-l- ylcarbonyl]propionamide
Figure imgf000077_0002
The title compound was prepared according to General Procedure D using L- homoproline t-butyl ester as the amine. MS (APCI) m/z = 357 [M+H].
Example 15
Synthesis ofN-hydroxy-3-(i?)-(n-butyl)-3-[2-(S)-(tert-butoxycarbonyl)- tetrahydroisoquinolin- 1 -ylcarbonyl]propionamide
Figure imgf000077_0003
The title compound was prepared according to General Procedure A from L- tetrahydroisoquinoline t-butyl ester and mono-methyl 2-(i?)-butylsuccinic acid. MS (APCI) m/z = 405 [M+H] . Example 16
Synthesis of N-hydroxy-3-(7?)-(n-butyl)-3-[2-(S)-(acetamidomethyl)pyrrolidin- 1 - ylcarbonyl]propionamide
Figure imgf000078_0001
Step l
To a solution of 4-(S)-benzyloxazolidin-2-one (56 mmol) (Aldrich, Milwaukee, Wisconsin) in THF at -78 °C was added 2.5 M n-BuLi in hexane (22.4 mL, 56 mmol) and the reaction stirred at -78°C for 2 hr. To this was added via cannula a -78 °C solution of hexanoyl chloride (65 mmol) in THF and the mixture stirred at -78 °C for 2 hr, then allowed to warm to room temperature and stirred overnight. The reaction was then quenched with aqueous saturated ΝH4C1, extracted with ethyl acetate, dried, and purified by silica gel chromatography (hexanes/ethyl acetate) to afford N-hexanoyl-4-(S)-benzyloxazolidin-2-one. Step 2 To a solution of N-hexanoyl-4-(S)-benzyloxazolidin-2-one (7.3 mmol) in THF at -78°C was added 1.0 M sodium hexamethyldisilazide (ΝaHMDS, 8.8 mmol) and the reaction stirred at -78°C for 1 hr. A solution of methyl bromoacetate (8.8 mmol) in THF was then added dropwise, and the resulting mixture was stirred at -78°C for 1 hr and then at room temperature overnight. The reaction was quenched with ΝH4C1, concentrated, then suspended in ethyl acetate and washed with 0.5 N HCl and brine, dried, and purified by silica gel chromatography (ethyl acetate/hexanes) to afford the methyl 3-( ?)-(n-butyl)-3-[4-(S)-benzyloxazolidin-2-one-3-ylcarbonyl)propionate. Step 3
To methyl 3-(i?)-(n-butyl)-3-[4-(S)-benzyloxazolidin-2-one-3-ylcarbonyl)- propionate (1.44 mmol) in THF/water at 0°C was added 30% H2O2 (5.76 mmol) and solid lithium hydroxide (1.44 mmol) and the reaction stined at 0°C for 3 hr. The reaction was then quenched with 2.0 M Na2SO3, concentrated, suspended in ethyl acetate and subjected to standard aqueous workup. The crude product was purified by silica gel chromatography (methanol/dichloromethane) to afford methyl 3-(R)-(n- butyl)-propionate.
Step 4
To Boc-L-prolinol (1 mmol) (Advanced Chemtech, Louisville, KY) in THF at 0°C was added mesitylenesulfonyl chloride (MsCl, 1.2 mmol) and DIEA (1.5 mmol) and the solution allowed to warm to rt, then stined an additional hour. Solid sodium azide was added (1.5 mmol) and the reaction was allowed to stir overnight.
Conventional aqueous workup followed by silica gel chromatography afforded the N-
Boc-(S)-(2-azidomethyl)pyrrolidine. Step 5
A solution of the N-Boc-(S)-(2-azidomethyl)pyrrolidine in ethylacetate was added to 10% Pd/C and the reaction evacuated and flushed with hydrogen gas three times. The reaction was then stirred under a hydrogen atmosphere overnight, then filtered through a pad of celite and concentrated to dryness. The resulting amine was dissolved in DMF and then acylated with acetic anhydride to afford the N-Boc-(S)-(2- acetamidomethyl)pyrrolidine. The Boc group was deprotected with IN HCl in dioxane to afford the desired (S)-(2-acetamidomethyl)pyrrolidine.
Step 6
The title compound was prepared from (S)-(2-acetamidomethyl)pyrrolidine and methyl 3-(i?)-(n-butyl)propionate according to General Procedure A.
MS (APCI) m z = 314 [M+H].
Example 17
Synthesis of N-hydroxy-3-(i?)-(n-butyl)-3-[(4-(i?)-hydroxy-2-(S)-tert- butoxycarbonyl)pyrrolidin- 1 -ylcarbonyl]propionamide
Figure imgf000079_0001
Small-scale synthesis Step 1 Cbz-protected trans-3-hydroxy-L-proline (20 g, 75 mmol) in DCM was treated with 60 ml of acetic anhydride and 10 mL of pyridine. The solution was stirred at rt for 18 hours, then the reaction was quenched with icewater, extracted with EtOAc (3 x 200 mL), and the organic layer washed with water, brine, and dried over MgSO4. Concentration in vacuo gave Cbz-protected trøns-3-acetoxy-L-proline as a colorless oil. Step 2
To a solution of Cbz-protected trans-3-acetoxy-L-proline (75 mmol) in dry dioxane was added tert-butyl alcohol (14.2 mL, 150 mmol), diisopropylcarbodiimide (23 mL, 147 mmol), and DMAP (2.3 g) and the mixture was stirred at rt for two days. The reaction was concentrated to an oil and purified via silica gel chromatography (hexanes/ethyl acetate) to afford the desired Cbz-protected trans-3-acetoxy-L-proline t-butyl ester. ESMS (negative): 362 (M-l). Step 3 To Cbz-protected trans-3-acetoxy-L-proline t butyl ester (1 mmol) in ethyl acetate (10 mL) was added 10%> Pd/C and the reaction evacuated and flushed with hydrogen gas three times. The reaction was then stined under a hydrogen atmosphere overnight, then filtered through a pad of celite and concentrated to dryness to afford the desired trans-3-acetoxy-L-proline t-butyl ester. MS (APCI negative) m/z 357 [M- H]. 1H NMR (300 MHz, CD3OD) Λ 4.0 (m, 2H), 3.75 (m, 2H), 3.10 (m, IH), 2.85 (m, IH), 2.40 (m, 2H), 2.2 (m, 2H), 2.0 (m, 2H), 1.65 to 1.0 (m, 15H), 0.90 (m, 3H). Step 4
The title compound was prepared according to General Procedure A using tran.s-3-acetoxy-L-proline O-t-butyl ester and methyl 3-(i?)-(n-butyl)propionate. The final treatment with hydroxylamine removed the acetyl group from the 3-hydroxy group of the proline. Large-scale synthesis Step l
To trøns-3-acetyloxy-L-proline t-butyl ester (11.8 mmol) in DCM (60 mL) was added mono-methyl 2-(/?)-butylsuccinic acid (11.2 mmol), DIEA (23.6 mmol) and PyBOP (11.8 mmol) and the solution stined for 16 h. The reaction was concentrated to an oil and purified on silica gel (Merck 60; hexanes/ethylacetate) to afford 2.2 g of methyl 3-(R)-(n-butyl)-3-[(4-(Λ)-acetoxy-2-(S)-tert- butoxycarbonyl)pyrrolidin-l-ylcarbonyl]propionate as a clear oil 5 (50%>). Step 2
To methyl 3-(i?)-(n-butyl)-3-[(4-(i?)-acetoxy-2-(S)-tert-butoxycarbonyl)- pyrrolidin-l-ylcarbonyl]propionate (5.5 mmol) in methanol (25 mL) was added water (1 mL) and LiOH-H2O (12.1 mmol) and the solution stirred 20 h. Standard aqueous work-up afforded 3-( ?)-(n-butyl)-3-[(4-( ?)-hydroxy-2-(S)-tert-butoxycarbonyl)- pyrrolidin-l-ylcarbonyl]propionic acid 2 g of a colorless oil which solidified upon standing (quant.). Step 3
To a solution of 3-(i?)-(n-butyl)-3-[(4-( ?)-hydroxy-2-(S)-tert-butoxycarbonyl)- pyrrolidin-l-ylcarbonyl]propionic (5.51 mmol) in DCM (30 mL) was added O- benzylhydroxylamine-HCL (6.06 mmol), DIEA (13.3 mmol) and PyBOP and the solution stirred for 18 h. Standard aqueous work-up followed by silica gel chromatography (Merck 60; ethylacetate) afforded 1.14 g of the protected N- benzyloxy- 3-(i?)-(n-butyl)-3-[(4-(i?)-hydroxy-2-(S)-tert-butoxycarbonyl)pyrrolidin-l- ylcarbonyl]propionamide as a white gum (45%>). This was dissolved in ethylacetate (50 mL), 5% Pd/C was added (110 mg), and a hydrogen atmosphere introduced. After 16 h the reaction was filtered through celite and concentrated to afford 810 mg of the title compound as a white foam (89%>).
Example 18
Synthesis of N-hydroxy-3-(i?)-(n-butyl)-3-[(4-(S)-hydroxy-2-(S)-tert- butoxycarbonyl)pynolidin- 1 -ylcarbonyl]propionamide
Figure imgf000081_0001
To methyl 3-(i?)-(n-butyl)-3-[(4-(i?)-hydroxy-2-(S)-tert-butoxycarbonyl)- pyrrolidin-l-ylcarbonyl]propionate (prepared by General Procedure A, omitting the final treatment with ΝH2OH) in THF was added chloroacetic acid, TPP and DIAD and the reaction stined 18 h. The chloroacetate ester was purified on silica gel (Merck 60; hexanes/ethylacetate), dissolved in dioxane and then treated with aqueous 50%) hydroxylamine. The reaction mixture was purified by preparative reverse-phase (C18) HPLC to afford the title compound. MS (APCI negative) m/z 357 [M-H].
Example 19
Synthesis of N-hydroxy-3-(i?)-(n-butyl)-3-[(4-(i?)-methoxy-2-(S)-tert- butoxycarbonyl)pyιτolidin- 1 -ylcarbonyl]propionamide
Figure imgf000082_0001
To methyl 3-(i?)-(n-butyl)-3-[(4-(i?)-hydroxy-2-(S)-tert-butoxycarbonyl)- pyrrolidin-l-ylcarbonyl]propionate in THF at 0 °C was added sodium hydride (60% dispersion in mineral oil) and the mixture stirred for 1 h. Iodomethane was added, and the reaction allowed to warn to rt and then stirred an additional 2 h. Standard aqueous work-up followed by purification on silica gel afforded the penultimate methyl ester. This was dissolved in dioxane and then treated with aqueous 50%> hydroxylamine for 48 h. The reaction mixture was purified by preparative reverse- phase (C18) HPLC to afford the title compound. MS (APCI negative) m/z 371 [M- H].
Example 20 Synthesis of N-hydroxy-3-(Λ)-(n-butyl)-3-[3-(i?S)-(tert-butoxycarbonyl- amino)pyrrolidin- 1 -ylcarbonyl]propionamide
Figure imgf000083_0001
The title compound was prepared according to General Procedure B from (±)- 3-(N-Boc-amino)pyrrolidine (obtained from TCI America, Portland, Oregon) and mono-4-methyl 2-(i?)-butylsuccinic acid. MS (APCI) m/z 358[M+H].
Example 21
Synthesis ofN-hydroxy-3-(/?)-(n-butyl)-3-[2-(S)-(tert-butoxycarbonyl)pyrrolidin-l- ylcarbonyl]-2-(S)-hydroxypropionamide
Figure imgf000083_0002
The title compound was prepared according to General Procedure F or I . !H
ΝMR (300 MHz, CDC13): δ 0.93 (t, J= 7.5 Hz, 3 H), 1.31-1.49 (m, 4H), 1.44 (s, 9H), 1.76-2.23 (m, 6H), 3.23 (dt, J=2.5 and 7.5 Hz, IH), 3.67-3.77 (m, IH), 3.55-3.64 (m, IH), 4.26 (d, J=2.5 Hz, IH), 4.32 (dd, J=4.2 and 8.7 Hz, 1 H). ES-MS: calcd. For Cι7H30Ν2O6(358.43); found: 359 [M+l].
Example 22
Synthesis of N-hydroxy-3-(i?)-(n-butyl)-3-[2-(S)-(methylaminocarbonyl)pyrrolidin-l- ylcarbonyl]-2-(S)-hydroxypropionamide
Figure imgf000083_0003
The title compound was prepared according to General Procedure C from methylamine. MS (APCI negative) m z 314 [M-H]. Example 23
Synthesis of N-hydroxy-3-(i?)-(n-butyl)-3-[2-(S)-(dimethylaminocarbonyl)pyrrolidin- l-ylcarbonyl]-2-(S)-hydroxypropionamide
Figure imgf000084_0001
The title compound was prepared according to General Procedure C from Ν,Ν-dimethylamine. MS (APCI negative) m/z 328 [M-H].
Example 24
Synthesis ofN-hydroxy-3-(i?)-(n-butyl)-3-[2-(S)-(tert-butylaminocarbonyl)pyrrolidin- 1 -ylcarbonyl] -2-(S)-hydroxypropionamide
Figure imgf000084_0002
The title compound was prepared according to General Procedure C from t- butylamine. MS (APCI negative) m/z 356 [M-H].
Example 25 Synthesis ofN-hydroxy-3-(i?)-(n-butyl)-3-[2-(S)-(morpholin-4-ylcarbonyl)pyrrolidin-
1 -ylcarbonyl] -2-(S)-hydroxypropionamide
Figure imgf000084_0003
The title compound was prepared according to General Procedure C from morpholine. MS (APCI negative) m/z 370 [M-H]. Example 26
Synthesis of N-hydroxy-3-(i?)-(n-butyl)-3-[3-(i?S)-(acetylamino)pyrrolidin-l-yl- carbonyljpropionamide
Figure imgf000085_0001
To methyl 3-(i?)-(n-butyl)-3-[3-(i?S)-(tert-butoxycarbonylamino)pynolidin-l - ylcarbonyl]propionate, prepared from (±)-3-(N-i?oc-amino)pyrrolidine (TCI America, Portland, Oregon) and mono-4-methyl 2-(/?)-butylsuccinic acid, was added 4 N HCl in dioxane and the solution stined for 4 h. The solution was evaporated to dryness, dissolved in dioxane, and then treated with acetic anhydride and pyridine and stirred for 2 h. Aqueous 50%> hydroxylamine was added and the solution stined for 2 d. The crude reaction mixture was purified by preparative reverse-phase (C18) HPLC to afford the title compound. MS (APCI negative) m/z 298 [M-H].
Example 27
Synthesis ofN-hydroxy-3-(i?)-(n-butyl)-3-[3-(i?S)-(2-phenylethylcarbonylamino)- pyrrolidin- 1 -ylcarbonyl]propionamide
Figure imgf000085_0002
To methyl 3-(i?)-(n-butyl)-3-[3-(/?S)-(tert-butoxycarbonylamino)pyrrolidin-l- ylcarbonyl]propionate, prepared from (±)-3-(Ν-Boc-amino)pyrrolidine and mono-4- methyl 2-(i?)-butylsuccinic acid, was added 4 N HCl in dioxane and the solution stined for 4 h. The solution was evaporated to dryness, dissolved in dioxane, and then treated with 3-phenylpropionic acid, DIEA, and HATU and stined for 2 h. Aqueous 50%> hydroxylamine was added and the solution stined for 2 d. The crude reaction mixture was purified by preparative reverse-phase (C 18) HPLC to afford the title compound. Example 28
Synthesis of N-hydroxy-3-( ?)-(n-butyl)-3-[2-(S)-(methoxycarbonyl)pynolidin-l- ylcarbonyl]-2-(S)-methylpropionamide
Figure imgf000086_0001
Step l
To mono t-butyl 2-(Λ)-(n-butyl)succinic acid (2.0 g, 8.70 mmol; prepared in three steps from hexanoylchloride using the procedure of Example 16, Step A for the synthesis of monomethyl-2-R-butylsuccinic acid, with substitution of t-butyl bromoacetate for methyl bromoacetate) in anhydrous THF (40 mL) at -78 °C was added LDA (2.2 eq., 19.1 mmol, 9.56 ml of a 2.0 M solution in THF/hexane/ethyl- benzene) and the reaction stined for 1 h. Iodomethane (11.3 mmol, 1.6 g) was then added and the reaction allowed to warm to room temperature over 2 h. The solution was quenched with methanol (ca. 5 mL), evaporated to dryness, and the residue dissolved in ethylacetate (50 mL). This solution was extracted with saturated sodium bicarbonate (3 x 30 mL), the combined aqueous layers acidified to pH 3 with 1 Ν HCl, and these were extracted with ethylacetate (3 x 50 mL). The combined organic layers were dried (Νa2SO4), concentrated, and purified by silica gel chromatography (Merck 60; 95:5 DCM/methanol) to afford mono t-butyl 2-(/?)-(n-butyl)-3-(i?S)- methylsuccinic acid as a light orange oil (1.25 g). The ratio of R/S diastereomers was > 6:1. Step 2
An aliquot of mono t-butyl 2-(i?)-(n-butyl)-3-(ΛS)-methylsuccinic acid (1.0 g, 4.10 mmol) was epimerized by first dissolving it in THF (22 mL), cooling to - 78 °C and then adding LDA (9.02 mmol, 4.52 mL of a 2.0 M solution). The solution was allowed to warm to rt over 2 hours, then cooled back down to -78 °C and quenched with methanol (1.7 mL). This epimerization procedure was repeated once more, then an aqueous work-up was performed as described above to afford 700 mg of mono t- butyl 2-( ?)-(n-butyl)-3-(/?S)-methylsuccinic acid. 1H NMR analysis of this product suggested approximately 2:1 ratio of R/S diastereomers. Step 3 To mono t-butyl 2-(i?)-(n-butyl)-3-(ΛS)-methylsuccinic acid (680 mg, 1.39 mmol, prepared in step 2 above) in DCM (15 mL) was added L-proline methyl ester hydrochloride (3.34 mmol, 554 mg), DIEA (1.28 mL, 7.34 mmol) and then PyBOP (1.74 g, 3.34 mmol). The reaction was stirred for 16 h, concentrated to dryness, and then purified via silica gel chromotography (1 :1 hexanes/ethylacetate) to afford mono t-butyl 3-(i?)-(n-butyl)-3-[2-(S)-methoxycarbonyl)ρyrrolidin- 1 -ylcarbonyl]-2-(S)- methylpropionate (260 mg). Step 4
The t-butyl group was removed from mono t-butyl 3-( ?)-(n-butyl)-3-[2-(S)- methoxycarbonyl)pyrrolidin-l -ylcarbonyl] -2-(S)-methylpropionate (260 mg, 732 μmol) using 1 :2 TFA/DCM, followed by evaporation of the TFA and solvent. To the resulting product in DCM (5 mL) at 0 °C was added O-benzylhydroxylamine hydrochloride (129 mg, 805 μmol), HOBt (112 mg, 732 μmol), DIEA (708 μL, 1.61 mmol) and then solid EDC (154 mg, 805 μmol) and the reaction allowed to warm to rt and then stirred overnight. The reaction was evaporated to dryness, and purified on a silica gel column (1 :1 hexanes/ethylacetate) to afford N-benzyloxy-3-(i?)-(n-butyl)-3- [2-(S)-methoxycarbonyl)pyrrolidin- 1 -ylcarbonyl]-2-(S)-mefhylpropionamide as a colorless glass (212 mg). Step 5 To N-benzyloxy- 3-(i?)-(n-butyl)-3-[2-(S)-methoxycarbonyl)pyrrolidin-l- ylcarbonyl]-2-(S)-methylpropionamide (40 mg) in methanol (3 mL) was added 10%> Pd/C (10 mg). The reaction was evacuated briefly under high-vacuum, and the atmosphere replaced with 1 atm hydrogen gas (balloon). This procedure was repeated twice more, then the suspension was stined under H2 gas for 3 h. The reaction was then filtered through a plug of celite to afford the title compound as a clear, colorless gum (31 mg). MS (APCI) m/z 315 [M+H].
Example 29 Synthesis of N-hydroxy-3-(/?)-(n-butyl)-3-[2-(S)-(3-trifluoromethylbenzylamino- carbonyl)pyrrolidin- 1 -ylcarbonyl]propionamide
Figure imgf000088_0001
The title compound was prepared according to General Procedure D from L- proline-(4-trifluoromethyl)benzylamide. MS (APCI) m/z 444 [M+H].
Example 30
Synthesis ofN-hydroxy-3-(i?)-(n-butyl)-3-[2-(S)-(cyclohexylmethylaminocarbonyl)- pynolidin- 1 -ylcarbonyl]propionamide
Figure imgf000088_0002
The title compound was prepared according to General Procedure A from mono-methyl 2-(i?)-butylsuccinic acid and L-proline-(cyclohexyl)methylamide. MS (APCI) m z 382 [M+H].
Example 31
Synthesis of N-hydroxy-3-(i?)-(n-butyl)-3-[3-(i?S)-((4-trifluoromethylbenzyl)- aminocarbonyl)piperidin- 1 -ylcarbonyl]propionamide
Figure imgf000089_0001
The title compound was prepared according to General Procedure A from mono-methyl 2-(i?)-butylsuccinic acid and (±)-3-carboxypiperidine-(4-trifluoro- methylbenzyl)amide. MS (APCI) m/z 458 [M+H].
Example 32
Synthesis of N-hydroxy-3-(i?)-(n-butyl)-3-[(2-(S)-(hydroxymethyl)- pyrrolidin- 1 -ylcarbonyl]propionamide
Figure imgf000089_0002
The title compound was prepared according to General Procedure A from mono-methyl 2-(i?)-butylsuccinic acid and L-prolinol. MS (APCI) m/z 273 [M+H].
Example 33
Synthesis of N-hydroxy-3-(i?)-(n-butyl)-3-[(2-(S)-(pyrrolidin-l-ylmethyl)- pyrrolidin- 1 -ylcarbonyl]propionamide
Figure imgf000089_0003
The title compound was prepared according to General Procedure A from mono-methyl 2-(i?)-butylsuccinic acid and (S)-2-(N-pyrrolidinylmethyl)-pyrrolidine. MS (APCI) m/z 326 [M+H]. Example 34
Synthesis of N-hydroxy-3-(Λ)-(n-butyl)-3-[4-(S)-(phenylsulfonamido)-2-(S)- (tert-butyloxycarbonyl)pyrrolidin-l-ylcarbonyl]propionamide
Figure imgf000090_0001
Step 1
To mono methyl 3-(fl)-(n-butyl)-3-[2-(S)-tert-butoxycarbonyl)-4-(i?)- hydroxypynolidin-l-ylcarbonyl]propionate (1.4g, 3.92 mmol; prepared according to General Procedure A from methyl 2-(i?)-butylsuccinic acid and trans-L-hydroxy- proline tert-butyl ester) in DCM at -20°C was slowly added methanesulfonyl chloride (MeSO2Cl) (0.62mL, 7.84 mmol) and the reaction stined 4 h. DCM was removed in vacuo, and the residue was dissolved in EtOAc (100 mL), washed with saturated ΝaHCO3, dilute HCl (5%>) and brine and then dried (MgSO4). Concentration in vacuo afforded methyl 3-(i?)-(n-butyl)-3-[2-(S)-tert-butoxycarbonyl)-4-(i?)-mesyloxy- pyrrolidin-l-ylcarbonyl]propionate which was used directly without further purification. Step 2
To methyl 3-(i?)-(n-butyl)-3-[2-(S)-tert-butoxycarbonyl)-4-(i?)-mesyloxy- pyrrolidin-l-ylcarbonyl]propionate in DMF (30 mL) was added NaN3 (2.6g) and the resulting solution heated at 65°C for 48. The DMF was removed in vacuo and the residue was purified by silica gel column chromatography to afford 1.3 gram of the desired methyl 3-(i?)-(n-butyl)-3-[2-(S)-tert-butoxycarbonyl)-4-(S)-azido-pyrrolidin- 1 -ylcarbonyl]propionate. Step 3
Methyl 3-(i?)-(n-butyl)-3-[2-(S)-tert-butoxycarbonyl)-4-(S)-azido-pyrrolidin- l-ylcarbonyl]propionate (1.3 g, 3.4 mmol) was hydrogenated at rt with Pd-C (10%>) for 18 h. The reaction was filtered through a pad of celite, and washed with EtOAc. Concentration of the filtrate yielded 1.2 g of methyl 3-(#)-(n-butyl)-3-[2-(S)-tert- butoxycarbonyl)-4-(S)-aminopyττolidin- 1 -ylcarbonyl]propionate. Step 4 Phenylsulfonyl chloride (2 eq.) was added slowly to a solution of methyl 3- (i?)-(n-butyl)-3-[2-(S)-tert-butoxycarbonyl)-4-(S)-azido-pyrrolidin-l-ylcarbonyl]- propionate (ca. 0.1 g) in DCM (lmL) and pyridine (0.1 mL) at 0 °C. The solution was allowed to warm to rt and then stined an additional 2 h. The solvent was removed in vacuo, the residue dissolved in EtOAc (5 mL) and washed with HCl solution (5%), NaHCO3 (sat.) and brine. Concentration in vacuo gave the crude methyl 3-(Λ)-(n-butyl)-3-[2-(S)-tert-butoxycarbonyl)-4-(S)-phenylsulfonamido- pyrrolidin-l-ylcarbonyl]propionate which was directly converted to the conesponding hydroxamate by treatment with aqueous 50%> NH2OH (1 mL) and dioxane (2 mL) at rt for 3 days. The final product N-hydroxy-3-(i?)-(n-butyl)-3-[4-(S)-
(phenylsulfonamido)-2-(S)-(tert-butyloxycarbonyl)pynolidin-l-ylcarbonyl]- propionamide was purified by preparative HPLC. Η ΝMR (CD3OD): δ 7.90 (m, 2H), 7.60 (m, 3H), 4.15(t, J=7.9 Hz, IH), 4.0 (m, IH), 3.90 (m, IH), 3.25(m, IH), 2.90 (m, IH), 2.35 (m, 2H), 2.15 (m, 3H), 1.75(m, IH), 1.60 to 1.20 (m, 13H), 0.90 ppm (s, 3H); MS (APCI negative) m/z 496 [M-l].
Example 35
Synthesis ofN-hydroxy-3-(i?)-(n-pentyl)-3-[(2-(S)-(tert-butoxycarbonyl)- pyrrolidin- 1 -ylcarbonyl]propionamide
Figure imgf000091_0001
The title compound was prepared according to General Procedure A from mono-methyl 2-(i?)-pentylsuccinic acid and L-proline t-butyl ester. MS (APCI) m/z 357 [M+H]. Example 36
Synthesis ofN-hydroxy-3-(i?)-(n-butyl)-3-[(2-(S)-(tert-butoxycarbonyl)- pyrrolidin- 1 -ylcarbonyl]-2-(S)-methoxypropionamide
Figure imgf000092_0001
Step 1 To l-(2,2-dimethyl-4-oxo-l,3-dioxolan-5-yl)-l-(2-(S)-tert- butoxycarbonylpyrrolidin-l-ylcarbonyl)pentane (4 mmol; prepared as described previously using, tert-butyl ester of compound F-6, General Procedure F) in methanol
(20 mL) was added lm MeOΝa (1ml) and stirred for 1 h. The reaction was neutralized with H+ resin , filtered, and the filtrate was concentrated to dryness. The residue purified on silica gel to afford methyl 3-(i?)-(n-butyl)-3-[(2-(S)-(tert- butoxycarbonyl)-pynolidin-l -ylcarbonyl] -2-(S)-hydroxypropionate.
Step 2
To a solution of methyl 3-(i?)-(n-butyl)-3-[(2-(S)-(tert-butoxycarbonyl)- pyrrolidin-l-ylcarbonyl]-2-(S)-hydroxypropionate (1 mmol) in DMF (10 ml) was added ΝaH. After 30 minutes, methyl iodide (3 mmol) was added and the solution stined an additional hour. The reaction was then diluted with ethyl acetate, washed with water, dried with Νa2SO4, filtered and concentrated. The crude methyl ether was dissolved in dioxane, treated with aqueous 50%> hydroxylamine, and stined for two days. The crude reaction mixture was purified by preparative reverse-phase (C18) HPLC to afford the title compound. MS (APCI negative) m/z 371 [M-H].
Example 37
Synthesis ofN-hydroxy-3-(Λ)-(n-butyl)-3-[(2-(S)-(tert-butoxycarbonyl)- pyrrolidin- 1 -ylcarbonyl]-2-(i?)-hydroxypropionamide
Figure imgf000093_0001
To a solution of triflic anhydride (1.2 mmol) in CH2C12 (5 ml) at -15°C was added pyridine (2.5 mmol) followed by the addition of a solution of methyl 3-(i?)-(n- butyl)-3-[(2-(S)-(tert-butoxycarbonyl)pynolidin- 1 -ylcarbonyl]-2-(S)-hydroxy- propionate (1 mmol, see Example 36 for preparation) in dichloromethane. The reaction was allowed to warm to -5°C over 1 hour, then the solution was washed with aqueous 10%> citric acid, water and sodium bicarbonate solutions, then dried (Na2SO4) and concentrated. This residue was dissolved in toluene (10 ml) and treated with tetrabutylammonium benzoate (TBAB, 2 mmol) for 1 hour. After removal of solvent, the residue was purified on silica gel (hexanes/ethylacetate) to afford methyl 3-(R)-(n- butyl)-3-[(2-(S)-(tert-butoxycarbonyl)pyrrolidin-l-ylcarbonyl]-2-(i?)-benzoyloxy- propionate. Treatment of this intermediate with aqueous hydroxylamine/dioxane solution for 2 days, followed by purification via semi-preparative HPLC provided title compound. MS (APCI) m/z 359 [M+H].
Example 38
Synthesis of N-hydroxy-3-(S)-(n-butyl)-3-[(2-(S)-(tert-butoxycarbonyl)- pyrrolidin- 1 -ylcarbonyl] -2-(i?)-thiolpropionamide
Figure imgf000093_0002
To methyl 3-(i?)-(n-butyl)-3-[(2-(S)-(tert-butoxycarbonyl)pynolidin-l -yl- carbonyl]-2-(S)-hydroxypropionate (see Example 36 for preparation) in THF is added triphenylphosphine (TPP), diisopropylazodicarboxylate (DIAD) and thioacetic acid and the solution stined overnight. Aqueous work-up and purification on silica gel affords methyl 3-(S)-(n-butyl)-3-[(2-(S)-(tert-butoxycarbonyl)pynolidin-l- ylcarbonyl] -2-(i?)-acetylthiopropionate. This compound was dissolved in degassed dioxane and aqueous 50%> hydroxylamine, then stined for 2 d. The crude reaction mixture was purified by preparative reverse-phase (C18) HPLC to afford the title compound.
Example 39
Synthesis of N-hydroxy-3-(S)-(n-butyl)-3-[(2-(S)-(tert-butoxycarbonyl)- pyrrolidin-1 -ylcarbonyl] -2-(S)-thiolpropionamide
Figure imgf000094_0001
To a solution of triflic anhydride (Tf2O, 1.2 mmol) in CH2C12 (5 ml) at -15°C was added pyridine (2.5 mmol) followed by the addition of a solution of methyl 3- (i?)-(n-butyl)-3-[(2-(S)-(tert-butoxycarbonyl)pyrrolidin-l-yl-carbonyl]-2-(i?)- hydroxypropionate (1 mmol, prepared as described in Example 40, below) in DCM. The reaction was allowed to warm to -5°C over 1 hr, then the solution was washed with aqueous 10% citric acid, water, and sodium bicarbonate solution, then dried (Νa2SO4) and concentrated. This residue was dissolved in THF (5 ml) and treated with potassium thioacetate (2 mmol) for 1 h. After removal of solvent, the residue was purified on silica gel (hexanes/ethyl acetate) to afford methyl 3-(R)-(n-butyl)-3- [(2-(S)-(tert-butoxycarbonyl)pyrrolidin-l-yl-carbonyl]-2-(S)-acetylthiopropionate. Treatment of this compound with aqueous hydroxylamine/dioxane solution for 2 days, followed by purification via semi-preparative HPLC, provided the title compound. MS(APCI) m z 375 [M+H].
Example 40
Synthesis of N-hydroxy-3-( ?)-(n-butyl)-3-[(2-(S)-(tert-butoxycarbonyl)- pynolidin- 1 -ylcarbonyl]-2-(i?)-methoxypropionamide
Figure imgf000095_0001
Methyl 3-(i?)-(n-butyl)-3-[(2-(S)-(tert-butoxycarbonyl)pyrrolidin- 1 -ylcarbonyl] -2-(i?)-benzoyloxypropionate (prepared as described in Example 37) was de- O-benzoylated by treatment with methanolic sodium methoxide at 0°C for 2 hours. The solution was neutralized with IR-120 (H+) resin, filtered, concentrated and purified on silica gel (hexanes/ethyl acetate) to afford methyl 3-(i?)-(n-butyl)-3-[(2- (S)-(tert-butoxycarbonyl)pyrrolidin-l -yl-carbonyl] -2-(/?)-hydroxypropionate. To a solution of methyl 3-(/?)-(n-butyl)-3-[(2-(S)-(tert-butoxycarbonyl)pynolidin-l-yl- carbonyl]-2-(i?)-hydroxypropionate in DMF at 0°C was added sodium hydride and the reaction stirred for 1 hour. Methyl iodide was added and the reaction stined for 1 hour at 0°C, then allowed to warm to rt and stirred an additional 2 h. Conventional aqueous workup afforded the intermediate ether, which was treated with dioxane/aqueous hydroxylamine followed by purification via semi-preparative HPLC to afford the title compound. MS (APCI) m z 373 [M+H].
Example 41
Synthesis ofN-hydroxy-3-(S)-(n-butyl)-3-[(2-(S)-(tert-butoxycarbonyl)- pyrrolidin- 1 -ylcarbonyl] -2-(i?)-methylthiopropionamide
Figure imgf000095_0002
To a solution of triflic anhydride (1.2 mmol) in CH2C12 (5 ml) at -15°C is added pyridine (2.5 mmol) followed by the addition of a solution of methyl 3-(R)-(n- butyl)-3-[(2-(S)-(tert-butoxycarbonyl)pyrrolidin- 1 -yl-carbonyl] -2-(S)-hydroxy- propionate (prepared as described in Example 36 above; 1 mmol) in dichloromethane. The solution is concentrated to dryness, dissolved in DMF and then treated with sodium thiomethoxide. Aqueous work-up followed by purification on silica gel affords methyl 3-(S)-(n-butyl)-3-[(2-(S)-(tert-butoxycarbonyl)pyrrolidin-l -yl- carbonyl] -2-(Λ)-methylthiopropionate which is dissolved in dioxane, treated with aqueous 50%> hydroxylamine, and then stined for 2 d. The crude reaction mixmre is purified by preparative reverse-phase (C18) HPLC to afford title compound.
Example 42
Synthesis of N-hydroxy-3-(S)-(n-butyl)-3-[(2-(S)-(tert-butoxycarbonyl)- pyrrolidin-1 -ylcarbonyl]-2-(S)-methylthiopropionamide
Figure imgf000096_0001
To a solution of triflic anhydride (1.2 mmol) in CH C12 (5 ml) at -15°C is added pyridine (2.5 mmol) followed by the addition of a solution of methyl 3-(i?)-(n- butyl)-3-[(2-(S)-(tert-butoxycarbonyl)pyrrolidin-l-yl-carbonyl]-2-(/?)-hydroxy- propionate (prepared as described in Example 40; 1 mmol) in dichloromethane. The solution is concentrated to dryness, dissolved in DMF and then treated with sodium thiomethoxide. Aqueous work-up followed by purification on silica gel affords methyl 3-(S)-(n-butyl)-3-[(2-(S)-(tert-butoxycarbonyl)pyrrolidin- 1 -yl-carbonyl]-2-(S)- methylthiopropionate which is dissolved in dioxane, treated with aqueous 50%> hydroxylamine, and then stined for 2 d. The crude reaction mixture is purified by preparative reverse-phase (C18) HPLC to afford the title compound.
Example 43
Synthesis of N-hydroxy-3-(i?)-(n-butyl)-3-[(2-(S)-(2-cyclohex- 1 -enylethyl- aminocarbonyl)pyrrolidin- 1 -ylcarbonyl]propionamide
Figure imgf000097_0001
Step l
To methyl 3-(i?)-(n-butyl)-3-[(2-(S)-(tert-butoxycarbonyl)pyrrolidin- 1 -yl- carbonyl]propionate (1 mmol; prepared in one step from mono-4-methyl 2-(R)- butylsuccinic acid and L-proline t-butyl ester) was added 1 M HCl in dioxane (5 mL) and the solution stirred 4 h. Conventional aqueous workup afforded methyl 3-(R)-(n- butyl)-3-[(2-(S)-(carboxy)pyrrolidin-l-yl-carbonyl]propionate. Step 2 To methyl 3-(i?)-(n-butyl)-3-[(2-(S)-(carboxy)pynolidin-l-yl- carbonyl]propionate (0.2 mmol) in dioxane (1 mL) was added 2-(l-cyclohexenyl)- ethyl amine (0.22 mmol), DIEA (0.22 mmol) and HATU (0.22 mmol) and the reaction stined for 2 h. Aqueous 50 %> hydroxylamine was then added (1 mL), and the reaction stined an additional 24 h. The reaction mixture was purified by preparative reverse-phase (C18) HPLC to afford the title compound. MS (APCI) m/z 394 [M+H].
Example 44
Synthesis ofN-hydroxy-3-(i?)-(n-butyl)-3-[(2-(S)-(phenylaminocarbonyl)- pynolidin- 1 -ylcarbonyl]propionamide
Figure imgf000097_0002
The title compound was prepared as described in Example 43, above, using aniline in place of 2-(l-cyclohexenyl)ethylamine. MS (APCI) m/z 362 [M+H]. Example 45
Synthesis of N-hydroxy-3-(i?)-(n-butyl)-3-[2-(S)-(tert-butoxycarbonyl)- pyrrolidin- 1 -carbonyl]-2-(i?)-azidopropionamide
Figure imgf000098_0001
To a solution of methyl 3-(Λ)-(n-butyl)-3-[(2-(S)-(tert-butoxycarbonyl)- pyrrolidin-l-ylcarbonyl]-2-(S)-hydroxypropionate (intermediate G-3 from General Procedure G, 2 mmol) in DCM (10 mL) was added pyridine (6 mmol), the reaction was cooled to -20 °C, then triflic anhydride (4 mmol) was added. The solution was stined for 1 hour and after the usual work-up was concentrated, resuspended in DMF (10 mL), and treated with sodium azide (2.5 mmol). The reaction was stined for 16 h, then diluted with ethylacetate, washed with water, saturated aqueous sodium bicarbonate, and brine, then dried (Νa2SO4) and puriifed on silica gel (ethylacetate/hexanes) to afford methyl 3-(#)-(n-butyl)-3-[(2-(S)-(tert- butoxycarbonyl)-pynolidin-l-ylcarbonyl]-2-(R)-azidopropionate. To a solution of the azido compound (0.5 mmol) in dioxane (2 mL) was added aqueous 50 %> hydroxylamine (1 mL) and the reaction stirred for 48 h. The crude reaction mixmre was then purified by preparative reverse-phase (C18) HPLC to afford the title compound. Η NMR(CDC13): δ 4.28-4.24 (dd, J = 5.1 & 4.6Hz, IH), 3.92 (d, J = 9.8 Hz,lH), 3.80-3.74 (m, IH), 3.64-3.57 (m, IH), 3.16-3.09 (m, IH), 2.22-1.91 (m, 4H), 1.89-1.76 (m, 2H), 1.43 (s, 9H), 1.40-1.35 (m, 4H), 0.92 (t, J = 6.7 Hz). ES-MS: calcd. For C,7H29N5O5 (383.3); found: 384 [M+l].
Example 46
Synthesis of N-hydroxy-3-(S)-(n-butyl)-3-[2-(S)-(tert-butoxycarbonyl)- pyrrolidin-1 -carbonyl]-2-(S)-sulfonyloxypropionamide
Figure imgf000099_0001
To a solution of methyl 3-(i?)-(n-butyl)-3-[(2-(S)-(tert-butoxycarbonyl)- pyrrolidin-1 -ylcarbonyl] -2-(S)-hydroxypropionate (intermediate G-3 from General Procedure G, 2 mmol) in DMF (10 mL) was added pyridinium sulfurtrioxide (2.2 mmol) and the solution stined for 1 h. The reaction was diluted with ethylacetate and washed with saline, dried (Na2SO4) and concentrated to afford methyl 3-(S)-(n-butyl)- 3-[(2-(S)-(tert-butoxycarbonyl)-pyrrolidin-l-ylcarbonyl]-2-(S)-sulfonyloxypropionate. This sulfonyloxy compound was dissolved in dioxane, treated with aqueous 50 %> hydroxylamine (1 mL) and the reaction stined for 48 h. The crude reaction mixture was then purified by preparative reverse-phase (C18) HPLC to afford the title compound. 1H NMR (CDC13): δ 4.63 (m, 2H), 4.19-3.82 (m, 2H), 3.79-3.67 (m, IH), 2.36-1.83 (m, 4H), 1.81-1.59 (2H), 1.45 (s, 9H), 1.34-1.26 (m, 2H), 0.89 (t, J = 6.3 Hz). ES-MS: calcd. For Cι7H30N2O9S (438.49); found: 439.2 [M+l].
Example 47
Synthesis ofN-hydroxy-3-(S)-(n-butyl)-3-[2-(S)-(tert-butoxycarbonyl)- pyrrolidin- 1 -carbonyl] -2-(S)-fluoropropionamide
Figure imgf000099_0002
The title compound was prepared by treatment of methyl 3-(S)-(n-butyl)-3-[(2- (S)-(tert-butoxycarbonyl)pynolidin-l-ylcarbonyl]-2-(S)-fluoropropionate (intermediate H-4, General Procedure H), with aqueous 50 % hydroxylamine followed by purification on preparative reverse-phase (Cl 8) HPLC. Η ΝMR
(CDCI3) δ 5.16-4.98 (dd, JH2>3 = 6.8 Hz & JH,F = 47 Hz, IH), 4.39-4.35 (dd, J = 4.4 & 3.8 Hz, IH), 3.78 (m, IH), 3.66-3.61 (m, IH), 3.31-3.22 (m, IH), 2.24-1.91 (m, 4H), 1.77-1.70 (m, 2H), 1.44 (s, 9H), 1.40-1.23 (m, 4H), 0.89 (t, J = 6.9 & 7.2 Hz). ES- MS: calcd. For C,7H29FN2O5 (360.42); found: 361 [M+l].
Example 48 Synthesis of N-hydroxy-3-(S)-(n-butyl)-3-[2-(S)-(tert-butoxycarbonyl)- pyrrolidin- 1 -carbonyl]-2-(i?)-fluoropropionamide
Figure imgf000100_0001
The title compound was prepared by treatment of methyl 3-(S)-(n-butyl)-3-[(2-
(S)-(tert-butoxycarbonyl)pyrrolidin- 1 -ylcarbonyl] -2-(i?)-fluoropropionate (intermediate G-4, General Procedure G), with aqueous 50 % hydroxylamine followed by purification on preparative reverse-phase (C 18) HPLC. 1H ΝMR (CDC13): δ 5.32-5.13 (dd, JH2;3 = 8.3 Hz & JH,F = 48 Hz, IH), 4.54-4.51 (t, J = 4.1 Hz, IH), 3.93-3.87 (m, IH), 3.84-3.77 (m, IH), 3.45-3.40 (m, IH), 2.43-2.11 (m, 4H), 2.10-1.95 (m, 2H), 1.63 (s, 9H), 1.58-1.52 (m, 4H), 1.10 (t, J = 6.6 & 7.1 Hz, 3H). ES-MS: calcd. For C17H29FΝ2O5 (360.42); found: 361 [M+l].
Example 49 Synthesis of N-hydroxy-3-(/?)-(n-butyl)-3-[2-(S)-(tert-butoxycarbonyl)- pynolidin-l-carbonyl]-2-oxopropionamide
Figure imgf000100_0002
To a solution of methyl 3-(/?)-(n-butyl)-3-[(2-(S)-(tert-butoxycarbonyl)- pyrrolidin-l-ylcarbonyl]-2-(S)-hydroxypropionate (intermediate G-3 from General Procedure G, 2 mmol) in DCM (10 mL) at 0 °C was added pyridinium dichromate (2.2 mmol) and the solution stined for 2h. The reaction was quenched with methanol, then diluted with ethylacetate and washed with water, aqueous bicarbonate, and brine, then dried (Na SO4) and puriifed on silica gel (ethylacetate/hexanes) to afford methyl 3-(i?)-(n-butyl)-3-[(2-(S)-(tert-butoxycarbonyl)-pyrrolidin-l-ylcarbonyl]-2-oxo- propionate. To a solution of the 2-oxo intermediate (0.5 mmol) in dioxane (2 mL) was added aqueous 50 % hydroxylamine (1 mL) and the reaction stined for 48 h. The crude reaction mixture was then purified by preparative reverse-phase (C18) HPLC to afford the title compound. 1H NMR (CDC13): δ 4.41-4.39 (dd, J = 4.4 Hz), 4.29-4.24 (m, IH), 3.99-3.96 (m, IH), 3.70-3.67 (m, IH), 2.29-1.97 (m, 4H), 1.79-1.77 (m, 2H), 1.43 (s, 9H), 1.37-1.35 (m, 4H), 0.91 (t, J = 6.7 & 7.1 Hz, 3H). ES-MS: calcd. For C,7H28N2O6 (356.41); found: 357.4 [M+l].
Example 50
Synthesis ofN-hydroxy-3-(S)-(n-butyl)-3-[2-(S)-(n-butylaminocarbonyl)- pyrrolidin- 1 -carbonyl]-2-(i?)-fluoropropionamide
Figure imgf000101_0001
The title compound was prepared according to General Procedure G from n- butylamine. 1H ΝMR (CDC13): δ 7.07 (t, J = 5.2 & 5.5Hz, IH), 5.13 (dd, JH2,3 = 8.5 Hz & JH,F = 47 Hz, IH), 4.48-4.46 (dd, J = 4.9 Hz, IH), 3.68-3.55 (m, 2H), 3.25-3.16 (m, 3H), 2.23-2.18 (m, 2H), 2.15-2.09 (m,4H), 2.06-1.80(m,4H), 1.52-1.43(m,4H), 1.32(t,J=7.5Hz,3H), 0.90(t,J=6.6&7.2Hz). ES-MS: cfalcd. For Cι7H30FΝ3O4 (359.44); found: 360.3 [M+l], 382.4 [M+Na].
Example 51
Synthesis of N-hydroxy-3-(S)-(n-butyl)-3-[2-(S)-(benzylaminocarbonyl)- pynolidin- 1 -carbonyl]-2-(i?)-fluoropropionamide
Figure imgf000102_0001
The title compound was prepared according to General Procedure G from benzylamine. ]H NMR (CDC13): δ 7.47-7.40 (m, 5H), 4.66-4.60 (dd, J = 5.1 Hz & 47 Hz, IH), 4.58-4.45 (m, IH), 3.97-3.76 (m, 4H), 3.35-3.28 (m, IH), 2.31-1.94 (m, 6H), 1.61-1.45 (m, 4H), 1.07 (t, J = 6.6 Hz, 3H). ES-MS: calcd. For Cι7H28FN3O4 (393.45); found: 394.3 [M+l], 416.2 [M+Na].
Example 52
Synthesis of N-hydroxy-3-(S)-(n-butyl)-3-[2-(S)-(l , 1 -dimethylpropylamino- carbonyl)pyrrolidin- 1 -carbonyl] -2-(i?)-fluoropropionamide
Figure imgf000102_0002
The title compound was prepared according to General Procedure G from 1,1- dimethylpropylamine. 1H ΝMR (CDC13): δ 5.34-5.16 (dd, J = 7.9 8c 8.3 Hz, JH>F = 47 Hz), 4.61 (d, J = 4.6 Hz), 3.80-3.78 (m, 2H), 3.40-3.35 (m, IH), 2.39-1.84 (m, 8H), 1.53-1.44 (m, 10H), 1.09 (t, J = 6.8 Hz, 3H), 1.01 (t, J = 7.7 Hz, 3H). ES-MS: calcd. For C,8H32FΝ3O4 (373.46); found: 374.4 [M+l], 396.2 [M+Na].
Example 53
Synthesis of N-hydroxy-3-(S)-(n-butyl)-3-[2-(S)-(2-cyclohex-l-enylethylamino- carbonyl)pyrrolidin- 1 -carbonyl] -2-(i?)-fluoropropionamide
Figure imgf000103_0001
The title compound was prepared according to General Procedure G from 2- (l-cyclohexenyl)ethylamine. 1H NMR (CDC13): δ 7.11 (t, J = 4.6 & 5.2 Hz, IH), 5.62 (bs, IH), 5.32-5.13 (dd, J = 9.3 & 9.6 Hz, JH)F = 47 Hz, IH), 4.64-4.63 (m, IH), 3.81-3.73 (m, 2H), 3.59-3.52 (m, IH), 3.50-3.37 (m, 3H), 2.31-2.16 (m, 9H), 2.10- 1.99 (m, 2H), 1.79-1.52 (m, 9H), 1.09 (t, J = 6.5 & 5.5Hz). ES-MS: calcd. For C2ιH34FN3O4 (411.51); found: 412.4[M+1], 434.5 [M+Na].
Example 54
Synthesis of N-hydroxy-3-(S)-(n-butyl)-3-[2-(S)-(indan-5-ylamino- carbonyl)pyrrolidin- 1 -carbonyl] -2-( ?)-fluoropropionamide
Figure imgf000103_0002
The title compound was prepared according to General Procedure G from 5- aminoindan. ]H ΝMR (CDC13): δ 7.52 (s,lH), 7.35 (d, J = 8 Hz, IH), 7.21 (d, J = 8 Hz, IH), 5.34-5.15 (dd, J =8.2 & 8.5 Hz, JH,F = 47 Hz, IH), 4.86-4.84 (m, IH), 3.80- 3.78 (m, 2H), 3.36-3.31 (m, IH), 3.06-2.96 (m, 4H), 2.41-1.97 (m, 8H), 1.58-1.48 (m, 4H), 1.04 (t, J = 6.6 & 7.2 Hz, 3H). ES-MS: calcd. For C22H30FΝ3O4 (419.49); found: 420.3 [M+l].
Example 55
Synthesis of N-hydroxy-3-(S)-(n-butyl)-3-[2-(S)-(4,5-dimethylthiazol-2-ylamino- carbonyl)pyrrolidin-l-carbonyl]-2-(i?)-fluoropropionamide
Figure imgf000104_0001
The title compound was prepared according to General Procedure G from 2- amino-4,5-dimethylthiazole. Η NMR (CDC13): δ 5.32-5.13 (dd, J = 8.3 & 7.9 Hz, JH,F = 47 Hz, IH), 4.83-4.80 (m, IH), 3.97-3.85 (m, 2H), 3.40-3.38 (m, IH), 2.51 (s, 3H), 2.50 (s, 3H), 2.33-2.21 (m, 4H), 2.18-1.95 (m, 2H), 1.59-1.49 (m, 4H), 1.07 (t, J = 6.6 & 7.2 Hz, 3H). ES-MS: calcd. For C]8H27FN4O4S (414.50); found: 415.4 [M+l], 437.3 [M+Na].
Example 56
Synthesis of N-hydroxy-3-(S)-(n-butyl)-3-[2-(S)-(4-phenoxyphenyl)amino- carbonyl)pynolidin- 1 -carbonyl] -2-(i?)-fluoropropionamide
Figure imgf000104_0002
The title compound was prepared according to General Procedure G from 4- phenoxyaniline. 1H ΝMR (CDC13): δ 7.69-7.16 (m, 2H), 7.53-7.46 (m, 2H), 7.29- 7.24 (m, IH), 7.18-7.06 (m, 4H), 5.37-5.20 (dd, J = 7.8 Hz, JH,F = 47 Hz, IH), 4.90- 4.85 (m, IH), 3.92-3.82 (m, 2H), 3.33-3.37 (m, IH), 2.47-2.36 (m, 2H), 2.30-2.00 (m, 4H), 1.50-1.13 (m, 4H), 1.02 (t, J = 6.6 & 6.9 Hz, 3H). ES-MS: calcd. For C25H30FΝ3O5 (471.52); found: 472.4 [M+l].
Example 57
Synthesis ofN-hydroxy-3-(S)-(n-butyl)-3-[2-(S)-(cyclopropylmethylamino- carbonyl)pyrrolidin-l-carbonyl]-2-(i?)-fluoropropionamide
Figure imgf000105_0001
The title compound was prepared according to General Procedure G from (aminomethyl)cyclopropane. 1H NMR (CDC13): δ 6.90 (t, J = 5.2 Hz, IH), 4.99-4.82 (dd, J = 6.4 & 8 Hz, JH,F = 49.8 & 48.6 Hz,lH), 4.34-4.32 (m, IH), 3.56-3.47 (m, 2H), 3.09-2.85 (m, 3H), 2.09-1.83 (m, 4H), 1.67-1.64 (m, 2H), 1.30-1.11 (m, 5H), 0.72 (t, J = 6.9 & 7.1 Hz, 3H), 0.33-0.29 (dd, J = 5.3 Hz, 2H), 0.05-0.00 (dd, J = 4.6 Hz, 2H). ES-MS: calcd. For C17H28FN3O4 (357.42); found: 358.4 [M+l].
Example 58
Synthesis ofN-hydroxy-3-(S)-(n-butyl)-3-[2-(S)-(pyridin-3-yl)amino- carbonyl)pyrrolidin- 1 -carbonyl]-2-(i?)-fluoropropionamide
Figure imgf000105_0002
The title compound was prepared according to General Procedure G from 3- aminopyridine. 1H ΝMR (DMSO-D6): δ 9.15 (s, IH), 8.62 (d, J = 4.2 Hz, IH), 8.42 (d, J = 8.2 Hz, IH), 7.88-7.83 (dd, J = 5.3 & 4.9 Hz, IH), 5.09-4.91 (dd, J = 8 Hz, JH,F = 48.6 Hz, IH), 4.60-4.56 (dd, J = 4.8 Hz, IH), 3.92-3.89 (m, IH), 3.87-3.79 (m, IH), 3.42-3.35 (m, IH), 2.37-2.04 (m, 4H), 1.81-1.51 (m, 2H), 1.50-1.39 (m, 4H), 1.04 (t, J = 6.9 & 7.2 Hz, 3H). ES-MS: calcd. For C18H25FΝ4O4 (380.41); found: 381.3 [M+l].
Example 59
Synthesis of N-hydroxy-3-(S)-(n-butyl)-3-[2-(S)-((pyridin-4-ylmethyl)amino- carbonyl)pynolidin- 1 -carbonyl]-2-(i?)-fluoropropionamide
Figure imgf000106_0001
The title compound was prepared according to General Procedure G from 4- (aminomethyl)pyridine. 1H NMR (DMSO-D6): δ 8.94-8.86 (m, 3H), 7.94-7.93 (m, IH), 5.14-4.95 (dd, J = 7.7 Hz, JH,F = 48.4 Hz, IH), 4.68-4.67 (m, IH), 4.51-4.47 (m, IH), 3.95-3.75 (m, 3H), 3.38-3.35 (m, IH), 2.33-2.01 (m, 4H), 1.99-1.79 (m, 2H), 1.41-1.38 (m, 4H), 0.92 (t, J = 6.6 & 7.1 Hz, 3H). ES-MS: calcd. For Cι9H27FN4O4 (394.44); found: 395.4 [M+l].
Example 60
Synthesis ofN-hydroxy-3-(S)-(n-butyl)-3-[2-(S)-(morpholin-4-ylcarbonyl)pyrrolidin- l-carbonyl]-2-(i?)-fluoropropionarnide
Figure imgf000106_0002
The title compound was prepared according to General Procedure G from morpholine. Η ΝMR (CDC13): δ 5.30-5.11 (dd, J = 8.2 Hz, JH.F = 47.6 Hz, IH), 5.06-5.04 (t, J = 3.6 & 4.4 Hz, IH), 3.92-3.67 (m, 10H), 3.44-3.42 (m, IH), 2.40-1.98 (m, 6H), 1.74-1.52 (m, 4H), 1.10 (t, J = 6.8 & 7.4 Hz, 3H). ES-MS: calcd. For C,7H28FΝ3O5 (373.42); found: 374.3[M+1].
Example 61
Synthesis of N-hydroxy-3-(S)-(n-butyl)-3-[2-(S)-(3,4-methylenedioxyphenyl- aminocarbonyl)pyrrolidin- 1 -carbonyl] -2-(7?)-fluoropropionamide
Figure imgf000107_0001
The title compound was prepared according to General Procedure G from 3,4- (methylenedioxy)aniline. Η NMR (CDC13): δ 7.47 (s, IH), 7.34 (d, J = 2Hz, IH), 6.99-6.95 (dd, J = 2Hz, IH), 6.80 (d, J = 8.5 Hz, IH), 6.08 (s, 2H), 5.36-5.17 (dd, J = 8.5 & 8.8 Hz, JH,F = 47 Hz, IH), 4.82-4.81 (dd, J = 4.4 Hz, IH), 3.84-3.80 (m, 2H), 3.38-3.33 (m, IH), 2.40-1.97 (m, 6H), 1.57-1.52 (m, 4H), 1.059 (t, J = 6.9 & 7.1 Hz, 3H). ES-MS: calcd. For C20H26FN3O6 (423.44); found: 424.3 [M+l].
Example 62
Synthesis of N-hydroxy-3-(S)-(n-butyl)-3-[2-(S)-(quinolin-3-ylamino- carbonyl)pyrrolidin- 1 -carbonyl]-2-(i?)-fluoropropionamide
Figure imgf000107_0002
The title compound was prepared according to General Procedure G from 3- aminoquinoline. Η ΝMR (CDC13): δ 9.32 (s,lH), 8.31 (d, J = 8.8 Hz, IH), 8.03-7.81 (m, 3H), 7.48-7.46 (m, 2H), 5.35-5.17 (dd, J = 7.7 & 8 Hz, JH,F = 47 Hz, IH), 4.89- 4.85 (m, IH), 3.90-3.85 (m, 2H), 3.45-3.37 (m, IH), 2.41-2.02( m, 5H), 1.67-1.52 (m, 5H), 1.10 (t, J = 6.9 & 5.7 Hz, 3H). ES-MS: calcd. For C22H27FΝ4O4 (430.47); found: 431.3 [M+l].
Example 63 Synthesis of N-hydroxy-3-(S)-(n-butyl)-3-[2-(S)-(methylaminocarbonyl)- pyrrolidin- 1 -carbonyl]-2-( ?)-fluoropropionamide
Figure imgf000108_0001
The title compound was prepared according to General Procedure G from methylamine. 1H NMR (CDC13): δ 7.30 (d, J = 5.6 Hz, IH), 5.30-5.12 (dd, J = 7.9 & 8.8 Hz, JH,F = 47 Hz, IH), 3.84-3.82 (m, 2H), 3.41-3.39 (m, IH), 2.95 (s, 3H), 2.32- 1.99 (m, 6H), 1.63-1.51 (m, 4H), 1.09 (t, J = 6.4 & 4.9 Hz, 3H). ES-MS: calcd. For C,4H24FN3O4 (317.36); found 318.3 [M+l].
Example 64 Synthesis of N-hydroxy-3-(S)-(n-butyl)-3-[2-(S)-((4-biphenyl)aminocarbonyl)- pyrrolidin- 1 -carbonyl] -2-(i?)-fluoropropionamide
Figure imgf000108_0002
The title compound was prepared according to General Procedure G from 4- phenylaniline. Η ΝMR (CDC13): δ 7.75-7.46 (m, 10H), 5.39-5.21 (dd, J = 8.8 Hz, JH,F = 47 Hz, IH), 4.91-4.89 (m, IH), 3.85-3.83 (m, 2H), 3.41-3.36 (m, IH), 2.45-2.02 (m, 6H), 1.63-1.50 (m, 4H), 1.06 (t, J = 6.6 & 7.4 Hz, 3H). ES-MS: calcd. For C25H30FΝ3O4 (455.52); found 456.3 [M+l].
Example 65
Synthesis ofN-hydroxy-3-(S)-(n-butyl)-3-[(2-(S)-((3-phenoxyphenyl)aminocarbonyl)- pyrrolidin-1 -carbonyl] -2-(Λ)-fluoropropionamide
Figure imgf000109_0001
The title compound was prepared according to General Procedure G from 3- phenoxyaniline. 1H NMR (CDC13): δ 7.53-7.46 (m, 4H), 7.35-7.25 (m, 3H), 7.18- 7.14 (m, 2H), 6.85-6.18 (m, IH), 5.35-5.16 (dd, J = 8.8 Hz, JH)F = 47 Hz, IH), 4.84- 4.82 (m, IH), 3.81-3.78 (m, 2H), 3.36-3.31 (m, IH), 2.41-1.97 (m, 6H), 1.53-1.46 (m, 4H), 1.02 (t, J = 6.6 & 7.1 Hz, 3H). ES-MS: calcd. For C25H30FN3O5 (471.52); found 472.4 [M+l].
Example 66
Synthesis of N-hydroxy-3-(S)-(n-butyl)-3-[2-(S)-((3,4-dichlorophenyl)amino- carbonyl)pyrrolidin- 1 -carbonyl] -2-(i?)-fluoropropionamide
Figure imgf000109_0002
The title compound was prepared according to General Procedure G from 3,4- dichloroaniline. 1H ΝMR (CDC13): δ 7.78 (s, IH), 7.47-7.32 (m, 2H), 5.35-5.16 (dd, J = 8.8 Hz, JH,F = 47 Hz, IH) 4.82-4.80 (m, IH), 3.85-3.79 (m, 2H), 3.36-3.31 (m, IH), 2.35-2.03 (m, 6H), 1.67-1.54 (m,4H), 1.10 (t, J = 6.6 & 6.8 Hz, 3H). ES-MS: calcd. For C19H24Cl2FΝ3O4 (444.11); found: 448.2 [M+l].
Example 67
Synthesis of N-hydroxy-3-(S)-(n-butyl)-3-[2-(S)-((4-tert-butylphenyl)amino- carbonyl)pyrrolidin- 1 -carbonyl]-2-(/?)-fluoropropionamide
Figure imgf000110_0001
The title compound was prepared according to General Procedure G from 4- tert-butylaniline. 1H NMR (CDC13): δ 7.67(m,2H), 7.57-7.45 (m, 3H), 5.35-5.16 (dd, J = 8.2 & 8.5 Hz, JH,F = 47 Hz, IH), 4.85 (d, J = 4.4 Hz, IH), 3.83-3.80 (m, 2H), 3.39- 3.34 (m, IH), 2.43-2.00 (m,6H), 1.57-1.45 (m, 13H), 1.023 (t, J = 6.6 & 7.1 Hz, 3H). ES-MS: calcd. For C23H34FN3O4 (435.53); found: 436.4 [M+l].
Example 68
Synthesis of N-hydroxy-3-(S)-(n-butyl)-3-[2-(S)-(tert-butylaminocarbonyl)- pyrrolidin- 1 -carbonyl] -2-(i?)-fluoropropionamide
Figure imgf000110_0002
The title compound was prepared according to General Procedure G from tert- butylamine. 1H ΝMR (CDC13): δ 5.33-5.14 (dd, J = 8 Hz, JH)F = 48 Hz, IH), 4.58 (d, J = 4.7 Hz, IH), 3.81-3.79 (m, 2H), 3.42-3.39 (m, IH), 2.40-1.98 (m, 10H), 1.55-1.49 (m, 13H), 1.11 (t, J = 5.8 & 6.6 Hz, 3H). ES-MS: calcd. For C,7H30FΝ3O4 (359.44); found: 360.3 [M+l].
Example 69
Synthesis of N-hydroxy-3-(S)-(n-butyl)-3-[2-(S)-((indan-2-yl)amino- carbonyl)pyrrolidin-l-carbonyl]-2-(i?)-fluoropropionamide
Figure imgf000111_0001
The title compound was prepared according to General Procedure G from 2- aminoindan. Η NMR (CDC13): δ 7.48-7.33 (m, 4H), 5.25-5.07 (dd, J = 8.5 Hz, JH,F = 47.5 Hz, IH), 4.86-4.80 (m,lH), 4.57-4.55 (m,lH), 3.78-3.76 (m,2H), 3.51-3.42 (m,2H), 3.35-3.30 (m,lH), 3.01-2.92 (m,2H), 2.37-2.27 (m,2H), 2.17-1.92 (m,2H), 1.52-1.42 (m,4H), 1.08 (t, J = 6.8 Hz, 3H). ES-MS: calcd. For C22H30FN3O4 (419.49); found: 420.6 [M+l].
Example 70
Synthesis of N-hydroxy-3-(S)-(n-butyl)-3-[2-(S)-((2,2-dimethylpropyl)amino- carbonyl)pyrrolidin- 1 -carbonyl] -2-(i?)-fluoropropionamide
Figure imgf000111_0002
The title compound was prepared according to General Procedure G from 2,2- dimethylpropylamine. 1H ΝMR (CDC13): δ 7.28 (t, J = 6 Hz, IH), 5.36-5.18 (dd, J = 8.4 Hz, JH,F = 47.5 Hz, IH), 4.75 (d, J = 5.2 Hz, IH), 3.85-3.77 (m, 2H), 3.40-3.35 (m, IH), 3.29-3.19 (m, 2H), 2.50-2.27 (m, 2H), 2.17-2.13 (m, 2H), 2.09-1.98 (m,2H), 1.53-1.51 (m,4H ), 1.08 (bs,3H ). C,8H32FΝ3O4 (373.24); found: 374.4 [M+l].
Example 71
Synthesis of N-hydroxy-3-(S)-(n-butyl)-3-[2-(S)-((4-phenylthiazol-2-yl)amino- carbonyl)pyrrolidin-l -carbonyl] -2-(i?)-fluoropropionamide
Figure imgf000112_0001
The title compound was prepared according to General Procedure G from 2- amino-4-phenylthiazole. 1H NMR ( CDC13): δ 7.92-7.90 (m, 2H), 7.71 (m, 3H), 7.46 (s,lH), 7.28 (s,lH), 5.37 - 5.18 (dd, J = 8.5 & 8.2 Hz, JH,F = 47 Hz, IH), 4.95-4.93 (m,lH), 3.99-3.95 (m,2H), 3.43-3.38 (m,lH), 2.54-2.26 (m,4H), 2.21-1.96 (m,2H), 1.62-1.50 (m,4H), 1.08 (t, J = 6.9 & 7.1 Hz, 3H). ES-MS: calcd. For C22H27FN4O4S (462.54); found: 463.4 [M+l].
Example 72
Synthesis ofN-hydroxy-3-(S)-(n-butyl)-3-[2-(S)-((5-phenylthiadiazol-2-yl)amino- carbonyl)pyrrolidin- 1 -carbonyl]-2-(i?)-fluoropropionamide
Figure imgf000112_0002
The title compound was prepared according to General Procedure G from 2- amino-5-phenylthiadiazole. 1H ΝMR (CDC13): δ 8.08-8.05 (m,2H), 7.68-7.48 (m, 3H), 5.45-5.26 (dd, J = 9.2 Hz, JH,F = 47 Hz, IH), 4.99-4.97 (m,lH), 3.96-3.94 (m,2H), 3.38-3.36 (m,lH), 2.50-1.98 (m, 6H), 1.61-1.51 (m,4H), 1.09 (t, J = 6.9 Hz, 3H). ES-MS: calcd. For C2,H26FΝ5O4S (463.53); found: 464.2 [M+l].
Example 73 Synthesis of N-hydroxy-3-(S)-(n-butyl)-3-[2-(S)-((5-ethylthiadiazol-2-yl)amino- carbonyl)pyrrolidin- 1 -carbonyl] -2-(i?)-fluoropropionamide
Figure imgf000113_0001
The title compound was prepared according to General Procedure G from 2- amino-5-ethylthiadiazole. Η NMR (CDC13): δ 5.43-5.24 (dd, J = 9.6 Hz, JH;F = 47.5 Hz, IH), 5.00-4.98 (m, IH), 3.97-3.88 (m, IH), 3.38-3.36 (m,2H), 3.27-3.20 (m, 2H), 2.47-2.21 (m, 4H), 2.19-1.97 (m,2H), 1.58 (t, J = 7.7 Hz, 3H), 1.58-1.49 (m, 4H), 1.09 (t, J = 6.8 & 7.2 Hz, 3H). ES-MS: calcd. For Cι7H26FN5O4S (415.48); found: 416.2 [M+l].
Example 74
Synthesis ofN-hydroxy-3-(S)-(n-butyl)-3-[2-(S)-((3-trifluoromethoxyphenyl)amino- carbonyl)pyrrolidin-l-carbonyl]-2-(i?)-fluoropropionamide
Figure imgf000113_0002
The title compound was prepared according to General Procedure G from 3- (trifluoromethoxy)aniline. Η ΝMR (CDCI3): δ 7.71 (s,lH), 7.48-7.41 (m, 2H), 7.29 (t, J = 8.2 Hz, IH), 6.98 (d, J = 7.9 Hz, IH), 5.39-5.21 (dd, J = 9.3 & 8.8 Hz, IH), 4.88-4.86 (m, IH), 3.85-3.82 (m, 2H), 3.39-3.37 (m,lH), 2.41-2.04 (m, 6H), 1.61- 1.53 (m, 4H), 1.06 (t, J = 6.9 Hz, 3H). ES-MS: calcd. For C20H25F4Ν3O5 (463.42); found: 454.2 [M + l].
Example 75
Synthesis of N-hydroxy-3-(S)-(n-butyl)-3-[2-(S)-((benzthiazol-2-yl)amino- carbonyl)pyrrolidin-l-carbonyl]-2-( ?)-fluoropropionamide
Figure imgf000114_0001
The title compound was prepared according to General Procedure G from 2- aminobenzothiazole. 1H NMR (CDC13): δ 7.99-7.92 (dd, J = 7.5 & 8.2 Hz, 2H), 7.70-7.64 (dd, J = 8 & 7.6 Hz, IH), 7.56 (t, J = 7.9 & 8.5 Hz, IH), 5.43-5.24 (dd, J = 8.2 & 8.5 Hz, JH,F = 47 Hz, IH), 5.04 - 5.01 (m, IH), 4.00-3.97 (m, 2H), 3.47-3.42 (m, IH), 2.57-2.21 (m, 4H), 2.00 - 1.97 (m, 2H), 1.64-1.52 (m, 4H), 1.09 (t, J = 6.8 & 7.2 Hz, 3H). ES-MS: calcd. For C20H25FN4O4S (436.50); found: 437.3 [M+l].
Example 76
Synthesis of N-hydroxy-3-(S)-(n-butyl)-3-[2-(S)-((2,5-dimethylphenyl)amino- carbonyl)pyrrolidin- 1 -carbonyl] -2-(i?)-fluoropropionamide
Figure imgf000114_0002
The title compound was prepared according to General Procedure G from 2,5- dimethylaniline. 1H ΝMR (CDC13): δ 7.81 (s,lH), 7.22 (d, J = 7.7 Hz, IH), 7.05 (d, J = 7.9 Hz, IH), 5.42-5.23 (dd, J = 8.5 Hz, JH,F = 47 Hz, IH), 4.99-4.97 (m, IH), 3.83- 3.79 (m, 2H), 3.40-3.35 (m, IH), 2.66-2.63 (m, 2H), 2.47 (s, 3H), 2.38 (s, 3H), 2.24- 2.19 (m,2H), 2.18-1.99 (m, 2H), 1.64-1.46 (m, 4H), 0.99 (t, J = 6.6 & 6.9 Hz, 3H). ES-MS: calcd. For C2ιH30FΝ3O4 (407.48); found: 408.3 [M+l].
Example 77
Synthesis of N-hydroxy-3-(S)-(n-butyl)-3-[2-(S)-((2,5-dimethoxyphenyl)amino- carbonyl)pyrrolidin-l-carbonyl]-2-( ?)-fluoropropionamide
Figure imgf000115_0001
The title compound was prepared according to General Procedure G from 2,5- dimethoxyaniline. 1H NMR (CDC13): δ 8.22 (d, J = 3 Hz, IH), 6.96 (d, J = 8.8 Hz. IH), 6.79 - 6.75 (dd, J = 3 Hz, IH), 5.41-5.22 (dd, J = 8 Hz; JH,F = 47 Hz, IH), 4.92- 4.90 (m, IH), 4.00 (s, 3H), 3.96 (s, 3H), 3.95-3.85 (m, 2H), 3.45-3.39 (m, IH), 2.56- 2.23 (m, 4H), 2.02-1.99 (m, 2H), 1.64-1.49 (m, 4H), 1.00 (t, J = 6.3 & 7.1 Hz, 3H). ES-MS: calcd. For C2ιH30FN3O6 (439.48); found: 440.4 [M + 1].
Example 78
Synthesis of N-hydroxy-3-(S)-(n-butyl)-3-[2-(S)-((4,5-dimethylthiazol-2-yl)amino- carbonyl)pyrrolidin-l -carbonyl] -2-(S)-fluoropropionamide
Figure imgf000115_0002
The title compound was prepared according to General Procedure H from 2- amino-4,5-dimethylthiazole. 1H ΝMR (CDC13): δ 5.32-5.14 (dd, J = 5.7 Hz, JH,F = 47 Hz, IH), 4.85 - 4.81 (dd, J = 6 & 5.3 Hz, IH), 4.03-3.99 (m, 2H), 3.53-3.43 (m, IH), 2.52 (s, 3H), 2.50 (s, 3H), 2.36-2.22 (m, 4H), 2.19-1.79 (m, 2H), 1.60-1.50 (m, 4H), 1.08 (t, J = 6.6 & 6.9 Hz, 3H). ES-MS: calcd. For Cι8H27FΝ4O4S (414.50); found: 415.4 [M + l].
Example 79
Synthesis of N-hydroxy-3 -(S)-(n-butyl)-3 - [2-(S)-((3 ,4-dichlorophenyl)amino- carbonyl)pyrrolidin-l -carbonyl] -2-(S)-fluoropropionamide
Figure imgf000116_0001
The title compound was prepared according to General Procedure H from 3,4- dichloroaniline. 1H NMR (CDC13): δ 7.94 (s, IH), 7.48-7.46 (m, 2H), 5.38-5.21 (dd, J = 4.4 Hz, JH,F = 47 Hz, IH), 4.73-4.71 (m, IH), 3.92-3.91 (m, 2H), 3.53-3.52 (m, IH), 2.53-1.97 (m, 6H), 1.59-1.58 (m, 4H), 1.09 (t, J = 6.9 Hz, 3H). ES-MS: calcd. For C,9H24Cl2FN3O4S (447.11); found: 448.2 [M+l].
Example 80
Synthesis of N-hydroxy-3-(S)-(n-butyl)-3-[2-(S)-((benzthiazol-2-yl)amino- carbonyl)pyrrolidin- 1 -carbonyl]-2-(S)-fluoropropionamide
Figure imgf000116_0002
The title compound was prepared according to General Procedure H from 2- aminobenzothiazole. Η NMR (CDC13): δ 7.66 (t, J = 7.7 Hz, 2H), 7.34 (t, J = 6.9 & 7.9 Hz, IH), 7.26 (t, J=7.7 & 7.4 Hz, IH), 5.10-5.92 (dd, J = 5.8 Hz; JH,F = 47 Hz, IH), 4.75-4.73 (m, IH), 3.75-3.70 (m, 2H), 3.30-3.21 (m, IH), 2.24-1.97 (m, 4H), 1.70-1.56 (m, 2H), 1.33-1.25 (m, 4H), 0.78 (t , J = 6.8 Hz, 3H). ES-MS: calcd. For C20H25FN4O4S (436.50 ); found: 437.3 [M + 1].
Example 81
Synthesis ofN-hydroxy-3-(S)-(n-butyl)-3-[2-(S)-((3-phenoxyphenyl)amino- carbonyl)pynolidin- 1 -carbonyl]-2-(S)-fluoropropionamide
Figure imgf000117_0001
The title compound was prepared according to General Procedure H from 3- phenoxyaniline. 1H NMR (CDC13): δ 7.62-7.51 (m, 5H), 7.50-7.43 (m, IH), 7.42- 7.30 (m, IH), 7.28-7.16 (m, 2H), 6.90-6.86 (m, IH), 5.32-5.14 (dd, J = 5.3 Hz, JH)F = 47 Hz, IH), 4.76-4.74 (m, IH), 3.89-3.87 (m, 2H), 3.51-3.41 (m, IH), 2.47-1.92 (m, 6H), 1.53-1.51 (m, 4H), 1.05 (t, J = 6.9 & 7.1 Hz, 3H). ES-MS: calcd. For C25H30FN3O5 (471.52 ); found: 472.4 [M+l].
Example 82
Synthesis of N-hydroxy-3-(S)-(n-butyl)-3-[2-(S)-((2-(/?S)-hydroxybutyl)amino- carbonyl)pyrrolidin- 1 -carbonyl] -2-(S)-fluoropropionamide
Figure imgf000117_0002
The title compound was prepared according to General Procedure H from (±)- 2-hydroxy-n-butylamine. 1H ΝMR (CD3OD): δ 5.09-4.92 (dd, J = 8.8 Hz, JH>F = 47 Hz, IH), 4.63Y.59 (m, IH), 4.03-3.90 (m, IH), 3.88-3.79 (m, IH), 3.76-3.73 (m, IH), 3.51 (s, 2H), 3.46-3.23 (m, IH), 2.41-2.14 (m, 4H), 1.79-1.52 (m, 8H), 1.17 (t, J = 7.3 Hz, 3H), 1.11 (t, J = 6 & 7.4 Hz, 3H). ES-MS: calcd. For Cι7H30FΝ3O5 (375.44); found: 376.4 [M+l].
Example 83 Synthesis of N-hydroxy-3-(S)-(n-butyl)-3-[2-(S)-((4-hydroxybutyl)amino- carbonyl)pyrrolidin-l -carbonyl] -2-(S)-fluoropropionamide
Figure imgf000118_0001
The title compound was prepared according to General Procedure H from 4- aminobutanol. 1H NMR (CD3OD): δ 5.07-4.90 (dd, J = 8.8 Hz, JH,F = 47 Hz, IH), 4.60-4.55 (dd, J = 4.5 & 4.9 Hz, IH), 4.05-3.92 (m, IH), 3.90-3.81 (m, IH), 3.76 (s, 2H), 3.51 (s, 2H), 3.44-3.38 (m, IH), 2.44-2.10 (m, 6H), 1.86-1.63 (m, 4H), 1.60- 1.52 (m, 2H), 1.14 (t , J = 6.8 Hz, 3H). ES-MS: calcd. For Cι7H30FN3O5 (375.44); found: 376.4 [M+l].
Example 84
Synthesis of N-hydroxy-3-(S)-(n-butyl)-3-[2-(S)-((3,4-methylenedioxyphenyl)amino- carbonyl)pyrrolidin- 1 -carbonyl]-2-(S)-fluoropropionamide
Figure imgf000118_0002
The title compound was prepared according to General Procedure H from 3,4- (methylenedioxy)aniline. 1H ΝMR (CDC13): 7.19 (s, IH), 6.86 (d, J = 8 Hz, IH), 6.67 (d, J = 8 Hz, IH), 5.89 (s, 2H), 5.13-4.96 (dd, J = 4.4 Hz, JH,F = 47 Hz, IH), 4.55-4.53 (m, IH), 3.76-3.72 (m,2H), 3.30-3.21 (dd, J = 4.1 Hz, IH), 2.26-2.24 (m, 2H), 2.01-1.95 (m, 2H), 1.73 (bs, 2H), 1.32 (bs, 4H), 0.86 (t, J = 6.3 Hz, 3H). ES- MS: calcd. For C20H26FΝ3O6 (423.44); found: 424.3 [M+l].
Example 85 Synthesis of N-hydroxy-3-(S)-(n-butyl)-3-[2-(S)-((l ,4-benzodioxan-6-yl)amino- carbonyl)pyrrolidin- 1 -carbonyl]-2-(S)-fluoropropionamide
Figure imgf000119_0001
The title compound was prepared according to General Procedure H from 1,4- benzodioxan-6-amine. 1H NMR (CDC13): δ 7.14 (s, IH), 6.93 (d, J = 8.5 Hz, IH), 6.74, (d, J = 8.5 Hz, IH), 5.14-4.97 (dd, J = 4.5 Hz, JH)F = 47 Hz, IH), 4.58-4.56 (m, IH), 4.20 (s, 4H), 3.73-3.64 (m2H), 3.49-3.21 (m, IH), 2.30-2.27 (m, 2H), 2.01- 1.94 (m, 2H), 1.74 (bs, 2H), 1.32 (bs, 4H), 0.85 (t, J = 6.6 & 7.1 Hz, 3H). ES-MS: calcd. For C2ιH28FN3O6 (437.46); found: 438.3 [M+l].
Example 86
Synthesis of N-hydroxy-3-(S)-(n-butyl)-3-[2-(S)-((isoquinolin-3-yl)amino- carbonyl)pynolidin- 1 -carbonyl] -2-(S)-fluoropropionamide
Figure imgf000119_0002
The title compound was prepared according to General Procedure H from 6- aminoisoquinoline. 1H ΝMR (CDC13): δ 9.89 (s, IH), 9.63 (s, IH), 7.85 (d, J = 8.5 Hz, IH), 7.71 (m, 2H), 7.61 (d, J = 8.5 Hz, IH), 5.16-4.99 (dd, J = 5.8 Hz, JH,F = 47 Hz, IH), 4.76-4.73 (m, IH), 3.85 (m, 2H), 3.41-3.25 (m, IH), 2.35-1.99 (m, 4H), 1.33-1.25 (m, 6H), 0.85 (t, J = 6.8 & 7.1 Hz, 3H). ES-MS: calcd. For C22H27FΝ4O4 (430.47); found: 431.3 [M+l].
Example 87 Synthesis ofN-hydroxy-3-(S)-(n-butyl)-3-[2-(S)-(methylaminocarbonyl)pyrrolidin-l- carbonyl]-2-(S)-fluoropropionamide
Figure imgf000120_0001
The title compound was prepared according to General Procedure H from methylamine. Η NMR (CD3OD): δ 5.064.90 (dd, J = 8.7 Hz, JH,F = 47 Hz, IH), 4.58-4.54 (dd, J = 5 Hz, IH), 4.05-4.00 (m, IH), 3.99-3.82 (m, IH), 3.50-3.49 (m, IH), 2.93 (s, 3H), 2.40-2.08 (m, 4H), 1.79-1.51 (m, 6H), 1.21 (t, J = 6.8 Hz, 3H). ES-MS: calcd. For CMH24FN3O4 (317.36); found: 318.3 [M+l].
Example 88 Synthesis of N-hydroxy-3-(S)-(n-butyl)-3-[2-(S)-((5-phenylthiadiazol-2-yl)amino- carbonyl)pyrrolidin- 1 -carbonyl]-2-(S)-fluoropropionamide
Figure imgf000120_0002
The title compound was prepared according to General Procedure H from 2- amino-5-phenylthiadiazole. Η ΝMR (CDC13 + DMSO-D6): δ 7.47-7.34 (m, 5H), 5.06-5.03 (dd, J = 7.7 Hz, JH,F = 47 Hz, IH), 5.02-4.87 (m, IH), 3.80-3.71 (m, 2H), 3.31-3.28 (m, IH), 2.18-2.12 (m, 4H), 1.73-1.33 (m, 6H), 0.87 (t, J = 6.7 Hz, 3H). ES-MS: calcd. For C2ιH26FΝ5O4S (463.53); found: 464.2 [M+l].
Example 89 Synthesis of N-hydroxy-3-(S)-(n-butyl)-3-[2-(S)-(n-butylaminocarbonyl)pynolidin-l- carbonyl]-2-(S)-fluoropropionamide
Figure imgf000121_0001
The title compound was prepared according to General Procedure H from n- butylamine. 1H NMR (CDC13): δ 7.21 (t, J = 6.5 & 5.5 Hz, IH), 5.14-4.97 (dd, J = 5.8 Hz, JH;F = 47 Hz, IH), 3.65-3.57 (m, 2H), 3.30-3.16 (m, 3H), 2.23-2.17 (m, 2H), 1.97-1.72 (m, 2H), 1.69-1.50 (m, 2H), 1.48-1.25 (m, 8H), 0.92-0.87 (m, 6H). ES- MS: calcd. For C17H30FN3O4 (359.44); found: 360.3 [M+l].
Example 90
Synthesis of N-hydroxy-3-(S)-(n-butyl)-3-[2-(S)-((thiazol-2-yl)amino- carbonyl)pyrrolidin- 1 -carbonyl]-2-(S)-fluoropropionamide
Figure imgf000121_0002
The title compound was prepared according to General Procedure H from 2- aminothiazole. 1H ΝMR (CDC13 + DMSO-D6): δ 7.40 (d, J = 3.6 Hz, IH), 6.95 (d, J = 3.6 Hz, IH), 5.05Y.88 (dd, J = 7.4 Hz, JH,F = 47 Hz, IH), 4.86-4.84 (m, IH), 3.84- 3.71 (m, 2H), 3.33-3.23 (m, IH), 2.16-1.99 (m, 4H), 1.72-1.30 (m, 6H), 0.84 9 (t, J = 6.8 & 7.1 Hz, 3H). ES-MS: calcd. For Cι6H23FΝ4O4S (386.44); found: 387.4 [M+l].
Example 91
Synthesis of N-hydroxy-3-(S)-(n-butyl)-3-[2-(S)-((4-methylthiazol-2-yl)amino- carbonyl)pyrrolidin- 1 -carbon yl]-2-(S)-fluoropropionamide
Figure imgf000122_0001
The title compound was prepared according to General Procedure H from 2- amino-4-methylthiazole. 1H NMR (CDC13 + DMSO-D6): δ 6.49 (s, IH), 5.10-4.92 (dd, J = 6.6 Hz, JH>F = 47 Hz, IH), 4.85-4.83 (m, IH), 3.79-3.68 (m, 2H), 3.37-3.23 (m, IH), 2.31 (s, 3H), 2.22-1.99 (m, 4H), 1.74-1.52 (m, 2H), 1.29-1.27 (m, 4H), 0.83 (t, J = 6.6 & 7.1 Hz, 3H). ES-MS: calcd. For C17H25FN4O4S (400.47); found: 401.6 [M+l].
Example 92
Synthesis of N-hydroxy-3-(S)-(n-butyl)-3-[2-(S)-((4-phenylthiazol-2-yl)amino- carbonyl)pyrrolidin- 1 -carbonyl] -2-(S)-fluoropropionamide
Figure imgf000122_0002
The title compound was prepared according to General Procedure H from 2- amino-4-phenylthiazole. Η ΝMR (CDCI3): δ 7.38-7.26 (m, 5H), 6.95 (s, IH), 5.15- 5.01 (dd, J = 4.2 Hz, JH)F = 47Hz, IH), 4.99-4.83 (m, IH), 3.76-3.70 (m, 2H), 3.31- 3.27 (m, IH), 2.15-1.99 (m, 4H), 1.72-1.50 (m, 2H), 1.44-1.25 (m, 4H), 0.81 (t, J = 6.6 & 7.1 Hz, 3H). ES-MS: calcd. For C22H27FΝ4O4S (462.54); found: 463.5 [M+l].
Example 93
Synthesis ofN-hydroxy-3-(S)-(n-butyl)-3-[2-(S)-((2,2-dimethylpropyl)amino- carbonyl)pyrrolidin- 1 -carbonyl] -2-(S)-fluoropropionamide
Figure imgf000123_0001
The title compound was prepared according to General Procedure H from 2,2- dimethylpropylamine. Η NMR (CDC13): δ 7.16 (t, J = 6 Hz, IH), 5.14-4.96 (dd, J =
6.1 Hz, JH,F = 47 Hz, IH), 4.55-4.48 (m, IH), 3.69-3.61 (m, 2H), 3.31-3.22 (m, IH),
3.14-3.07 (m, IH), 2.98-2.91 (m, IH), 2.24-1.96 (m, 4H), 1.72-1.63 (m, 2H), 1.33-
1.30 (m, 4H), 0.88 (m, 12H). ES-MS: calcd. For Cι8H32FN3O4 (373.46); found:
374.7 [M+l].
Example 94
Synthesis of N-hydroxy-3-(S)-(n-butyl)-3-[2-(S)-((3-methylbutyl)amino- carbonyl)pyrrolidin- 1 -carbonyl] -2-(S)-fluoropropionamide
Figure imgf000123_0002
The title compound was prepared according to General Procedure H from 3- methylbutylamine. 1H ΝMR (CDC13): δ 7.17 (t, J = 5.2 Hz, IH), 5.13-4.95 (dd, J = 6.1 Hz, JHIF = 47 Hz, IH), 4.47-4.44 (m, IH), 3.66-3.57 (m, 2H), 3.31-3.17 (m, 3H), 2.23-2.17 (m, 2H), 1.96-1.91 (m, 2H), 1.74-1.54 (m, 3H), 1.42-1.32 (m, 6H), 0.91- 0.87 (m, 9H). ES-MS: calcd. For Cι8H32FΝ3O4 (373.46); found: 374.7 [M+l].
Example 95
Synthesis ofN-hydroxy-3-(S)-(n-butyl)-3-[2-(S)-((n-pentyl)amino- carbonyl)pyrrolidin- 1 -carbonyl]-2-(S)-fluoropropionamide
Figure imgf000123_0003
The title compound was prepared according to General Procedure H from amylamine. 1H NMR (CDC13): δ 7.18 (t, J = 5.2 Hz, IH), 5.13-4.95 (dd, J = 6 Hz,
JH,F = 47 Hz, IH), 4.47-4.45 (m, IH), 3.66-3.64 (m, 2H), 3.31-3.14 (m, 3H), 2.23- 2.17 (m, 2H), 1.96-1.93 (m, 2H), 1.76-1.63 (m, 2H), 1.52-1.42 (m, 3H),1.34-1.26
(m, 8H), 0.91-0.85 (m, 6H). ES-MS: calcd. For Cι8H32FN3O4 (373.46); found:
374.7 [M+l].
Example 96 Synthesis of N-hydroxy-3-(S)-(n-butyl)-3-[2-(S)-((cyclohexyl)amino- carbonyl)pyrrolidin- 1 -carbonyl]-2-(S)-fluoropropionamide
Figure imgf000124_0001
The title compound was prepared according to General Procedure H from cyclohexylamine. 1H ΝMR (CDCI3): δ 7.00 (d, J = 8.2 Hz, IH), 5.14-4.96 (dd, J = 6.2 Hz, JH,F = 47 Hz, IH), 4.46Y.44 (m, IH), 3.73-3.59 (m, 3H), 3.31-3.22 (m, IH), 2.19-2.10 (m, 4H), 1.96-1.64 (m, 6H ), 1.33-1.27 (m, 6H), 1.20-1.12 (m, 4H), 0.89 (t, J = 6.6 Hz, 3H). ES-MS: calcd. For C,9H32FΝ3O4 (385.47); found: 386.7 [M+l].
Example 97
Synthesis of N-hydroxy-3-(S)-(n-butyl)-3-[2-(S)-((n-propyl)amino- carbonyl)pyrrolidin- 1 -carbonyl] -2-(S)-fluoropropionamide
Figure imgf000124_0002
The title compound was prepared according to General Procedure H from propylamine. 1H NMR (CDC13 + DMSO-D6): δ 7.24 (t, J = 5.2 Hz, IH), 4.99-4.80
(dd, J = 8.8 Hz, JH,F = 47 Hz, IH), 4.59-4.57 (m, IH), 3.72-3.56 (m, 2H), 3.37-3.12
(m, 3H), 2.31-2.26 (m, 2H), 2.09-1.84 (m, 4H), 1.66-1.43 (m, 2H), 1.28-1.03 (m,
4H), 0.91-0.87 (m, 6H). ES-MS: calcd. For C,6H28FN3O4 (345.41); found: 346.6
[M+l].
Example 98
Synthesis of N-hydroxy-3-(S)-(n-butyl)-3-[2-(S)-((5-methylthiazol-2-yl)amino- carbonyl)pyrrolidin- 1 -carbonyl] -2-(S)-fluoropropionamide
Figure imgf000125_0001
The title compound was prepared according to General Procedure H from 2- amino-5-methylthiazole. 1H ΝMR (CDC13): δ 7.31 (s, IH), 5.32-5.14 (dd, J = 6.1 Hz, JH,F = 47 Hz, IH), 4.8Y.83 (m, IH), 4.03-3.94 (m, 2H), 3.53-3.44 (m, IH), 2.62 (s, 3H), 2.58-2.21 (m, 4H), 1.99-1.78 (m, 2H), 1.54-1.45 (m, 4H), 1.08 (t, J = 6.6 & 7.4 Hz, 3H). ES-MS: calcd. For C17H25FΝ4O4S (400.47); found: 401.6 [M+l].
Example 99 Synthesis of N-hydroxy-3-(S)-(n-butyl)-3-[2-(S)-((3 ,4-dimethoxybenzyl)amino- carbonyl)pyrrolidin-l -carbonyl] -2-(S)-fluoropropionamide
Figure imgf000125_0002
The title compound was prepared according to General Procedure H from 2,4- dimethoxybenzylamine. 1H ΝMR (CDC13): δ 7.31 (d, J = 8 Hz, IH), 6.67-6.58 (m, 2H), 5.30-5.14 (dd, J = 2 Hz, JH)F = 47 Hz, IH), 4.67-4.45 (m, 3H), 4.00 (s, 3H), 3.98 (s, 3H), 3.86-3.78 (m, 2H), 3.45-3.39 (m, IH), 2.37-2.13 (m, 4H), 1.89-1.84 (m, 2H), 1.47-145 (m, 4H), 1.04 (t, J = 6.3 & 7.1 Hz, 3H). ES-MS: calcd. For C22H32FN3O6 (453.51); found: 454.8 [M+l].
Example 100 Synthesis of N-hydroxy-3-(S)-(n-butyl)-3-[2-(S)-(piperidin-l-ylcarbonyl)pynolidin-l- carbonyl]-2-(S)-fluoropropionamide
Figure imgf000126_0001
The title compound was prepared according to General Procedure H from piperidine. 1H ΝMR (CDC13): δ 5.14-4.97 (dd, J = 6.5Hz, JH;F = 47 Hz, IH), 4.91-
4.87 (m, IH), 3.80-347 (m, 6H), 3.39-3.21 (m, IH), 2.22-1.83 (m, 3H), 1.65-1.27 (m,
13H), 0.90 (t, J = 7 Hz, 3H). ES-MS: calcd. For Cι8H30FΝ3O4(371.45); found: 372.4
[M+l]. Example 101
Synthesis of N-hydroxy-3-(S)-(n-butyl)-3-[2-(S)-(azetidin-l-ylcarbonyl)pynolidin-l- carbonyl]-2-(S)-fluoropropionamide
Figure imgf000126_0002
The title compound was prepared according to General Procedure H from azetidine. 1H ΝMR (CD3OD): δ 5.10-4.92 (dd, J = 8.7 Hz, JH,F = 47 Hz, IH), 4.73- 4.65 (m, IH), 4.60-4.57 (m, IH), 4.49-4.41 (m, IH), 4.32-4.21 (m, IH), 4.18-4.12 (m, IH), 4.06-3.99 (m, IH), 3.89-3.81 (m, IH), 2.59-2.41 (m, 2H), 241-2.30 (m, 2H), 2.28-2.05 (m, 2H), 1.84-1 9 (m, 6H), 1.11 (t, J = 7 Hz, 3H). ES-MS: calcd. For Cι6H26FΝ3O4 (343.39); found: 344.4 [M+l]. Example 102
Synthesis of N-hydroxy-3-(i?)-(n-butyl)-3-[2-(S)-((N-pyridin-2-yl)methylamino- carbonyl)-pyrrolidin-l -carbonyl] -2-(S)-hydroxypropionamide
Figure imgf000127_0001
The title compound was prepared according to General Procedure F from N- methyl-2-amino pyridine. 1H NMR (CDC13): δ 8.75-8.04 (m, 2H),7.71-746 (m,2H), 4.76 bs, IH), 4.46 (bs, IH), 3.93-3.63 (m, 2H), 3.56 (s,3H), 3.42-3.39 ( m, IH), 2.28- 2.00 (m, 6H), 1.66-1.62 (m, 4H), 1.13 (t, J = 7 Hz, 3H). ES-MS: calcd. For C19H28N4O5 (392.45); found: 393.6 [M+l].
Example 103 Synthesis of N-hydroxy-3-(S)-(n-butyl)-3-[2-(S)-((3,4-methylenedioxybenzyl)- aminocarbonyl)pyrrolidin- 1 -carbonyl] -2-(S)-fluoropropionamide
Figure imgf000127_0002
The title compound was prepared according to General Procedure H from piperonylamine. 1H ΝMR (CDC13): 7.63(s, IH), 6.93 (d, J = 9.9 Hz, 2H), 6.11 (s, 2H), 5.30-5.13 (dd, J = 5.5 Hz, JH;F= 47 Hz, IH), 4.62-4.39 (m ,3H), 3.97-3.71 ( , 2H), 3.48-3.39 (m, IH), 2.38-2.13 (m, 4H), 1.87-1.85 (m, 2H), 1.49-1 8 (m, 4H), 1.05 (t, J = 6.3 Hz, 3H). ES-MS: calcd. For C2ιH28FΝ3O6 (437.46); found: 438.7 [M+l]. Example 104 Synthesis of N-hydroxy-3-(S)-(n-butyl)-3-[2-(S)-((allyl)aminocarbonyl)p ynolidin-1- carbonyl] -2-(S)-fluoropropionamide
Figure imgf000128_0001
The title compound was prepared according to General Procedure H from allylamine. 1H NMR (CDC13): δ 6.06-5.95 (m, IH), 5.39-5.17 (m, 3H), 4.69Y.67 (m, IH), 4.05-3.85 (m, 4H), 3.51-344 (m, IH), 2.40-2.17 (m, 4H), 1.91-1.89 (m, 2H), 1.62-1.53 (m, 4H), 1.09 (t, J = 6.3 Hz, 3H). ES-MS: calcd. For Cι6H26FN3O4 (343.39); found: 344.7 [M+l].
Example 105
Synthesis of N-hydroxy-3-(S)-(n-butyl)-3-[2-(S)-((2-methylallyl)aminocarbonyl)- pynolidin- 1 -carbonyl] -2-(S)-fluoropropionamide
Figure imgf000128_0002
The title compound was prepared according to General Procedure H from 2- methylallylamine. Η ΝMR (CDC13): δ 5.34-5.16 (dd, J = 5.8 Hz, JH,F = 47 Hz, IH), 5.00 (s, 2H) 4.73-4.66 (m, IH), 4.05-3.87 (m, 4H), 3.51-343 (m, IH), 2.43-2.17 (m, 4H), 1.90 (s, 3H), 1.86-1.84 (m, 2H), 1.66-1.53 (m, 4H), 1.08 (t, J = 6.6 Hz, 3H). ES-MS: calcd. For C,7H28FΝ3O4 (357.42); found: 358.6 [M+l].
Example 106
Synthesis ofN-hydroxy-3-(S)-(n-butyl)-3-[2-(S)-(morpholin-4-ylcarbonyl)pynolidin-
1 -carbonyl] -2-(S)-fluoropropionamide
Figure imgf000129_0001
The title compound was prepared according to General Procedure H from morpholine. 1H NMR (CDC13): δ 5.34-5.16 (dd, J = 6.2 Hz, JH)F = 47 Hz, IH), 5.08-5.05 (m, IH), 4.00-3.71 (m, 10H), 3.68-3.43 (m, IH), 2.42-1.83 (m, 6H), 1.78- 1.50 (m, 4H), 1.10 (t, J = 6.6 & 7.1 Hz, 3H). ES-MS: calcd. For C17H28FN3O5 (373.42); found: 374.5 [M+l].
Example 107 Synthesis of N-hydroxy-3-(S)-(n-butyl)-3-[2-(S)-(pyrrolidin-l-carbonyl)pyrrolidin-l- carbonyl]-2-(S)-fluoropropionamide
Figure imgf000129_0002
The title compound was prepared according to General Procedure H from pyrrolidine. Η ΝMR (CDC13): δ 5.34-5.17 (dd, J = 6.5 Hz, JH>F = 47 Hz, IH), 4.86- 4.82 (m, IH), 3.94-3.89 (m, 4H), 3.77-3.71 (m, IH), 3.64-3.42 (m, 2H), 2.38-2.20 (m, 2H), 2.18-1.74 (m, 8H), 1.65-148 (m, 4H), 1.10 (t, J = 6.9 & 7.2 Hz, 3H). ES- MS: calcd. For Cι7H28FΝ3O4 (357.42); found: 358.5 [M+l].
Example 108 Synthesis of N-hydroxy-3-(S)-(n-butyl)-3-[2-(S)-((ethyl)aminocarbonyl)pyrrolidin- 1 - carbonyl]-2-(S)-fluoropropionamide
Figure imgf000129_0003
The title compound was prepared according to General Procedure H from ethylamine. Η NMR (CDC13): δ 5.35-5.19 (d, JH,F = 47 Hz, IH), 4.64-4.60 (m, IH), 3.85-3.78 (m, 2H), 345-3.19 (m, 3H), 2.44-2.13 (m, 4H), 1.93-1.84 (m, 2H), 1.55- 1.38 (m, 4H), 1.30 (t, J = 7.2 Hz & 6.9 Hz, 3H), 1.10 (bs, 3H ). ES-MS: calcd. For C15H26FN3O4 (331.38); found: 332.5 [M+l].
Example 109
Synthesis ofN-hydroxy-3-(i?)-(n-butyl)-3-[2-(S)-((4-phenoxyphenyl)amino- carbonyl)pynolidin- 1 -carbonyl] -2-(S)-hydroxypropionamide
Figure imgf000130_0001
The title compound was prepared according to General Procedure F from 4- phenoxyaniline. 1H ΝMR (CDC13): δ 7.48-6.92 (m, 9H), 4.55-4.53 (d, J = 6.0 Hz, IH), 4.29-4.29 (d, J = 2.2 Hz, IH), 3.73 (bs, 2H), 3.27 (bs, IH), 2.29-1.78 (m, 6H), 141-1.36 (m, 4H), 0.89 (t, J = 6.6 & 7.14 Hz, 3H). ES-MS: calcd. For C25H3ιΝ3O6 (469.54); found: 470.4 [M+l].
Example 110
Synthesis ofN-hydroxy-3-(i?)-(n-butyl)-3-[2-(S)-((phenyl)aminocarbonyl)-pyrrolidin- l-carbonyl]-2-(S)-hydroxypropionamide
Figure imgf000131_0001
The title compound was prepared according to General Procedure F from aniline. Η NMR (CDC13): δ 7.52-7.03 (m, 6H), 4.58-4.55 (d, J = 8.0 Hz, IH), 4.28-
4.27 (d, J = 2.4 Hz, IH), 3.71 (bs, 2H), 3.262 (bs, IH), 2.31-1.77 (m, 6H), 1.41-1.33
(m, 4H), 0.89 (t, J = 6.6 & 7.4 Hz, 3H). ES-MS: calcd. For C19H27N3O5 (377.44); found: 378.3 [M+l].
Example 111
Synthesis of N-hydroxy-3-(i?)-(n-butyl)-3-[2-(S)-((indan-l-yl)amino- carbonyl)pynolidin- 1 -carbonyl] -2-(S)-hydroxypropionamide
Figure imgf000131_0002
The title compound was prepared according to General Procedure F from 1 - aminoindan. IH ΝMR (CDC13): δ 7.27-7.15 (m, 4H), 5.38 (t, J = 8.2 & 7.7 Hz, IH), 4.45 (bs, IH), 4.18 (bs, IH), 3.64 (m, 2H), 3.20-3.18 (m, IH), 2.98-249 (m, 4H), 2.24-1.73 (m, 6H), 1.95-1.326 (m, 4H), 0.88 (t, J = 6.0 & 5.5 Hz, 3H). ES-MS: calcd. For C22H3ιΝ3O5 (417.51); found: 418.4 [M+l]
Example 112
Synthesis of N-hydroxy-3-(i?)-(n-butyl)-3-[2-(S)-((2-methoxyethyl)amino- carbonyl)pynolidin-l -carbonyl] -2-(S)-hydroxypropionamide
Figure imgf000132_0001
The title compound was prepared according to General Procedure F from 2- methoxyethylamine. 1H NMR (CDC13): δ 4.45-4.27 (d, J = 6.87 Hz, IH), 4.255 (bs, IH), 3.69-3.29 (m, 9H), 2.15-1.77 (m, 6H), 143-1.3 (m, 4H), 0.92 (t, J = 6.593 & 6.867 Hz, 3H). ES-MS: calcd. For C16H29N3O6 (359.42); found: 360.3 [M+l].
Example 113 Synthesis of N-hydroxy-3-(i?)-(n-butyl)-3-[2-(S)-((indan-5-yl)aminocarbonyl)- pynolidin- 1 -carbonyl]-2-(S)-hydroxypropionamide
Figure imgf000132_0002
The title compound was prepared according to General Procedure F from 5- aminoindan. Η ΝMR (CDC13): δ 7.46-7.08 (m, 3H), 4.57-4.55 (d, J = 67.14 Hz, IH), 4.28 (bs, IH), 3.71 (bs, 2H), 3.26 (bs, IH), 2.87-2.79 (dd, J = 6.87 & 7.14 Hz, 4H), 2.3-1.77 (m, 8H), 1.35 (bs, 4H), 0.89 (t, J = 6.32 & 6.87 Hz, 3H). ES-MS: calcd. For C22H3ιΝ3O5 (417.51); found: 4184 [M+l].
Example 114
Synthesis of N-hydroxy-3-(i?)-(n-butyl)-3-[2-(S)-((4,5-dimethylthiazol-2-yl)amino- carbonyl)-pynolidin- 1 -carbonyl]-2-(S)-hydroxypropionamide
Figure imgf000133_0001
The title compound was prepared according to General Procedure F from 2- amino-4,5-dimethylthiazole. 1H NMR (CDC13): δ 4.60 (bs, IH), 4.25 (bs, IH), 3.79 (t, J = 5.77 & 4.67 Hz, 2H), 3.26 (bs, IH), 2.30-2.24 (m, 8H), 1.74-2.12 (m, 4H), 1.36 (m, 4 H), 0.901 (t, J = 6.77 & 6.87 Hz, 3H). ES-MS: calcd. For C18H28N4O5S (412.51); found: 413.3 [M+l].
Example 115 Synthesis ofN-hydroxy-3-( ?)-(n-butyl)-3-[2-(S)-((quinolin-3-yl)aminocarbonyl)- pyrrolidin- 1 -carbonyl]-2-(S)-hydroxypropionamide
Figure imgf000133_0002
The title compound was prepared according to General Procedure F from 3- aminoquinoline. Η ΝMR (CDC13): δ 8.17-7.26 (m, 6H), 4.68 (m, IH), 4.32 (m,
IH), 3.77-3.67 (d, J = 30.217 Hz, 2H), 3.22 (bs, IH), 2.17-1.69 (m, 6H), 1.30 (bs,
4H), 0.89-0.82 (m, 3H). ES-MS: calcd. For C22H28Ν4O5 (428.49); found: 429.3
[M+l]. Example 116
Synthesis of N-hydroxy-3-(i?)-(n-butyl)-3-[2-(S)-((benzthiazol-2-yl)amino-carbonyl)- pynolidin-l-carbonyl]-2-(S)-hydroxypropionamide
Figure imgf000134_0001
The title compound was prepared according to General Procedure F from 2- aminobenzothiazole. Η NMR (DMSO-d6): δ 8.18-749 (m, 4H), 4.802 (bs, IH), 3.98-3.94 (d, J = 9.066 Hz, IH), 3.59 (bs, 2H), 3.11 (bs, IH), 2.11-1.38 (m, 10H), 1.06-1.04 (m, 3H). ES-MS: calcd. For C20H26N4O5S (434.52); found: 435.3 [M+l].
Example 117
Synthesis of N-hydroxy-3-(/?)-(n-butyl)-3-[2-(S)-((3,4-difluorophenyl)amino- carbonyl)-pyrrolidin- 1 -carbonyl]-2-(S)-hydroxypropionamide
Figure imgf000134_0002
The title compound was prepared according to General Procedure F from 3,4- difluoroaniline. Η ΝMR (CDC13): δ 7.60-6.97 (m, 3H), 4.49-4.61 (d, J = 7.97 Hz, IH), 4.29-4.28 (d, J = 2.2 Hz, IH), 3.79-3.69 (m, 2H), 3.26 (bs, IH), 2.36-1.76 (m, 6H), 1.49-1.35 (m, 4H), 0.918 (t, J = 6.867 & 7.143 Hz, 3H). ES-MS: calcd. For C,9H25F2Ν3O5 (413.42); found: 414.3 [M+l].
Example 118
Synthesis ofN-hydroxy-3-(i?)-(n-butyl)-3-[2-(S)-((3,4-dichlorophenyl)amino- carbonyl)-pynolidin- 1 -carbonyl]-2-(S)-hydroxypropionamide
Figure imgf000135_0001
The title compound was prepared according to General Procedure F from 3,4- dichloroaniline. 1H NMR (CDC13): δ 7.94-7.44 (m, 3H), 4.73-4.71 (d, J = 8.24 Hz, IH), 4.52-4.51 (d, J = 2.8 Hz, IH), 3.95-3.94 (m, 2H), 3.49 (t, J =5.8 & 6.0 Hz, IH), 2.52-1.99 (m, 6H), 1.70-1.57 (m, 4H), 1.122 (t, J = 6.9 & 7.1 Hz, 3H). ES-MS: calcd. For Cι9H25Cl2N3O5 (445.1); found: 446.3 [M+l].
Example 119 Synthesis of N-hydroxy-3-(i?)-(n-butyl)-3-[2-(S)-((5-methylisoxazol-3-yl)amino- carbonyl)pyrrolidin- 1 -carbonyl] -2-(S)-hydroxypropionamide
Figure imgf000135_0002
The title compound was prepared according to General Procedure F from 3- amino-5-methylisoxazole. Η ΝMR (DMSO-d6): δ 6.64-5.95 (m, IH), 4.66-4.62 (dd, J = 4.9 & 4.7 Hz, IH), 4.01-3.93 (m, IH), 3.76-3.70 (m, IH), 3.56 (bs, 3H), 3.11- 3.05 (t, J = 8.8, IH), 2.70-2.00 (m, 6H), 1.59-1.37 (m, 4H), 1.02 (t, J = 5.8 & 7.1 Hz, 3H). ES-MS: calcd. For Cι7H26Ν4O6 (382.42); found: 383.3 [M+l].
Example 120
Synthesis of N-hydroxy-3-(i?)-(n-butyl)-3-[2-(S)-((3-phenoxyphenyl)aminocarbonyl)- pyrrolidin- 1 -carbon yl]-2-(S)-hydroxypropionamide
Figure imgf000136_0001
The title compound was prepared according to General Procedure F from 3- phenyoxyaniline. 1H NMR (CDC13): δ 7.55-6.88 (m, 9H), 4.75-4.72 (d, J = 7.7 Hz, IH), 4.47 (bs, IH), 3.90-3.88 (m, 2H), 346-3.44 (m, IH), 2.51-1.96 (m, 6H), 1.65- 1.53 (m, 4H), 1.09 (t, J = 6.7 & 7.1 Hz, 3H). ES-MS: calcd. For C25H31N3O6 (469.54); found: 470.4 [M+l].
Example 121
Synthesis ofN-hydroxy-3-(R)-(n-butyl)-3-[2-(S)-((4-phenylthiazol-2-yl)amino- carbonyl)-pyrrolidin- 1 -carbonyl] -2-(S)-hydroxypropionamide
Figure imgf000136_0002
The title compound was prepared according to General Procedure F from 2- amino-5-phenylthiazole. 1H ΝMR (CDC13): δ 7.94-7.28 (m, 6H), 4.89-4.88 (d, J = 4.4 Hz, IH), 4.47-4.47 (d, J = 2.5 Hz, IH), 3.92-4.05 (m, 2H), 348-3.44 (m, IH), 2.54-1.95 (m, 6H), 1.57-1.48 (m, 4H), 1.10 (t, J = 6.6 8c 7.7 Hz, 3H). ES-MS: calcd. For C22H28Ν4O5S (460.55); found: 461.2 [M+l].
Example 122
Synthesis ofN-hydroxy-3-(Λ)-(n-butyl)-3-[2-(S)-((2-fluorophenyl)aminocarbonyl)- pynolidin-1 -carbonyl] -2-(S)-hydroxypropionamide
Figure imgf000137_0001
The title compound was prepared according to General Procedure F from 2- fluoroaniline. 1H NMR (CDC13): δ 8.42-7.23 (m, 4H), 4.97-4.95 (d, J = 6.9 Hz, IH), 4.49 (bs, IH), 3.96-3.83 (m, 2H), 3.49 (t, J = 5.5 & 74 Hz, IH), 2.61-2.01 (m, 6H), 1.64-1.46 (m, 4H), 1.06 (t, J = 6.6 & 7.1 Hz, 3H). ES-MS: calcd. For C19H26FN3O5 (395.43); found: 396.4 [M+l].
Example 123
Synthesis of N-hydroxy-3-(Λ)-(n-butyl)-3-[2-(S)-((3-fluorophenyl)aminocarbonyl)- pyrrolidin- 1 -carbonyl] -2-(iS)-hydroxypropionamide
Figure imgf000137_0002
The title compound was prepared according to General Procedure F from 3- fluoroaniline. 1H ΝMR (CDC13): δ 7.66-6.92 (m, 4H), 4.75-4.73 (d, J = 8.0 Hz, IH), 4.52 (bs, IH), 3.94 (t, J = 8.5 & 8.81 Hz, 2H), 3.49 (bs, IH), 2.57-1.99 (m, 6H), 1.70- 1.56 (m, 4H), 1.12 (t, J = 6.6 & 6.9 Hz, 3H). ES-MS: calcd. For Cι9H26FΝ3O5 (395.43); found: 396.3 [M+l].
Example 124 Synthesis of N-hydroxy-3-( ?)-(n-butyl)-3-[2-(S)-((4-fluorophenyl)aminocarbonyl)- pynolidin-l-carbonyl]-2-(S)-hydroxypropionamide
Figure imgf000138_0001
The title compound was prepared according to General Procedure F from 4- fluoroaniline. 1H NMR (CDC13): δ 7.71-7.13 (m, 4H), 4.74-4.71 (d, J = 8.2 Hz, IH), 4.51-4.49 (d, J = 2.8 Hz, IH), 3.96-3.90 (m, 2H), 3.52-3.46 (m, IH), 2.58-1.96 (m, 6H), 1.69-1.54 (m, 4H), 1.11 (t, J = 6.9 Hz, 3H). ES-MS: calcd. For Cι9H26FN3O5 (395.43); found: 396.3 [M+l].
Example 125
Synthesis of N-hydroxy-3-(7?)-(n-butyl)-3-[2-(S)-((N-phenyl-N-methylamino)- carbonyl)pyrrolidin- 1 -carbonyl] -2-(S)-hydroxypropionamide
Figure imgf000138_0002
The title compound was prepared according to General Procedure F from Ν- methylaniline. 1H ΝMR (CDC13): δ 7.26-7.5 (m, 5H), 4.38 (d, J = 7.1 Hz, IH), 4.24
(bs, IH), 3.69-3.65 (m, 5H), 3.33-3.20 (m, IH), 2.08-1.82 (m, 6H), 149-1.36 (m, 4H),
0.94 (t, J = 7.1 Hz, 3H). ES-MS: calcd. For C20H29Ν3O5 (391.47); found: 392.4
[M+l].
Example 126 Synthesis ofN-hydroxy-3-(i?)-(n-butyl)-3-[2-(S)-((ethyl)aminocarbonyl)-pyrrolidin-l- carbonyl]-2-(S)-hydroxypropionamide
Figure imgf000139_0001
The title compound was prepared according to General Procedure F from ethylamine. Η NMR (CDC13): δ 4.39-4.37 (d, J = 6.0 Hz, IH), 4.25-4.24 (d, J = 2.5 Hz, IH), 3.69-3.52 (m, 4H), 3.20-3.32 (m, IH), 2.25-1.76 (m, 6H), 1.44-1.25 (m, 4H), 1.183-1.11 (m, 3H), 0.94-0.85 (m, 3H). ES-MS: calcd. For Cι5H27N3O5 (329.4); found: 330.4 [M+l].
Example 127 Synthesis of N-hydroxy-3-(i?)-(n-butyl)-3-[2-(S)-((2-propyl)aminocarbonyl)- pyrrolidin- 1 -carbonyl]-2-(S)-hydroxypropionamide
Figure imgf000139_0002
The title compound was prepared according to General Procedure F from 2- aminopropane. Η ΝMR (CDC13): δ 441-4.38 (d, J = 8.0 Hz, IH), 4.26-4.25 (d, J = 2.2 Hz, IH), 4.01-3.94 (dd, J = 6.6 Hz, IH), 3.66 (t, J = 7.4 Hz, 2H), 3.25-3.22 (m, IH), 2.21-1.77 (m, 6H), 1.44-1.22 (m, 4H), 1.19-1.11 (m, 6H). 0.893 (t, J = 6.6 Hz, 3H). ES-MS: calcd. For C,6H29Ν3O5 (343.42); found: 344.4 [M+l].
Example 128
Synthesis of N-hydroxy-3-(Λ)-(n-butyl)-3-[2-(S)-((2,2-dimethylpropyl)- aminocarbonyl)pyrrolidin-l -carbonyl] -2-(S)-hydroxypropionamide
Figure imgf000140_0001
The title compound was prepared according to General Procedure F from 2,2- dimethylpropylamine. 1H NMR (CDC13): δ 4.52-4.5 (d, J = 6.0 Hz, IH), 4.26-4.25 (d, J = 2.5 Hz, IH), 3.7-3.59 (m, 2H), 3.28-3.22 (m, IH), 3.12-2.94 (m. 2H), 2.29-1.73 (m, 6H), 1.44-1.33 (m, 4H), 0.93-0.88 (m, 12H). ES-MS: calcd. For Cι8H33N3O5 (371.48); found: 372.4 [M+l].
Example 129 Synthesis of N-hydroxy-3-(i?)-(n-butyl)-3-[2-(S)-((l,l-dimethylpropyl)- aminocarbonyl)-pyrrolidin- 1 -carbonyl] -2-(S)-hydroxypropionamide
Figure imgf000140_0002
The title compound was prepared according to General Procedure F from 1,1- dimethylpropylamine. Η ΝMR (CDC13): δ 442-4.40 (d, J = 7.7 Hz, IH), 4.26 (bs, IH), 3.67-3.61 (m, 2H), 3.26-3.22 (t, J = 5.0 & 7.1 Hz, IH), 2.22-1.65 (m, 6H), 1.44- 1.24 (m, 6H), 0.94-0.79 (m, 6H). ES-MS: calcd. For C18H33Ν3O5 (371.48); found: 372.4 [M+l].
Example 130
Synthesis of N-hydroxy-3-(i?)-(n-butyl)-3-[2-(S)-((cyclohexyl)aminocarbonyl)- pynolidin- 1 -carbonyl]-2-(S)-hydroxypropionamide
Figure imgf000141_0001
The title compound was prepared according to General Procedure F from cyclohexylamine. Η NMR (CDC13): δ 443-4.40 (d, J = 8.0 Hz, IH), 4.26-4.25 (d, J = 2.5 Hz, IH), 3.66-3.63 (d, J = 7.4 Hz, 3H), 3.27-3.21 (m, IH), 2.21-1.10 (m, 20H), 0.94-0.89 (m, 3H). ES-MS: calcd. For C]9H33N3O5 (383.49); found: 384.3 [M+l].
Example 131 Synthesis ofN-hydroxy-3-(i?)-(n-butyl)-3-[2-(S)-((thiazol-2-yl)aminocarbonyl)- pyrrolidin-1 -carbonyl] -2-(S)-hydroxypropionamide
Figure imgf000141_0002
The title compound was prepared according to General Procedure F from 2- aminothiazole. Η ΝMR (CDC13): δ 7.5-7.04 (m, 2H), 4.66 (t, J = 5.0 Hz, IH), 4.27- 4.26 (d, J = 2.5 Hz, IH), 3.86-3.76 (m, 2H), 3.3-3.25 (m, IH), 2.34-1.74 (m, 6H), 1.36-1.28 (m, 4H), 0.93-0.86 (m, 3H). ES-MS: calcd. For C,6H24Ν4O5S (384.46); found: 385.2 [M+l].
Example 132
Synthesis of N-hydroxy-3-(i?)-(n-butyl)-3-[2-(S)-((4-methylthiazol-2-yl)amino- carbonyl)pyrrolidin-l -carbonyl] -2-(S)-hydroxypropionamide
Figure imgf000142_0001
The title compound was prepared according to General Procedure F from 2- amino-4-methylthiazole. 1H NMR (CDC13): δ 6.62-6.61(d, J = 1.1 Hz, IH), 4.65-4.63 (dd, J = 4.7 & 5.2 Hz, IH), 4.26-4.25 (d, J = 2.5 Hz, IH), 3.85-3.78 (dd, J = 6.0 & 7.4 Hz, 2H), 3.29-3.25 (dd, J = 5.2 & 5.0 Hz, IH), 2.46-1.69 (m, 9H), 1.38-1.27 (m, 4H), 0.893-0.85 (m, 3H). ES-MS: calcd. For Cι7H26N4O5S (398.48); found: 399.3 [M+l].
Example 133 Synthesis of N-hydroxy-3-(i?)-(n-butyl)-3-[2-(S)-((2-phenylpropyl)aminocarbonyl)- pynolidin- 1 -carbonyl] -2-(S)-hydroxypropionamide
Figure imgf000142_0002
The title compound was prepared according to General Procedure F from 1- amino-2-phenylpropane. Η ΝMR (CDC13): δ 7.3-6.78 (m, 5H), 5.17 (bs, IH), 4.34 (bs, IH), 4.21 (bs, IH), 3.61-3.16 (m, 4H), 3.25-3.22 (m, IH), 2.92 (bs, IH), 2.09- 1.09 (m, 13H), 0.94-0.83 (m, 3H). ES-MS: calcd. For C22H33Ν3O5 (419.52); found: 420.3 [M+l].
Example 134
Synthesis ofN-hydroxy-3-(/?)-(n-butyl)-3-[2-(S)-((n-propyl)aminocarbonyl)- pyrrolidin- 1 -carbonyl] -2-(S)-hydroxypropionamide
Figure imgf000143_0001
The title compound was prepared according to General Procedure F from propylamine. Η NMR (CDC13): δ 4.44-4.41 (d, J = 7.4 Hz, IH), 4.25 (bs, IH), 3.67-3.65 (d, J = 5.5 Hz, 2H), 3.24-3.14 (m, 3H), 2.23-1.79 (m, 6H), 1.54-1.35 (m, 6H), 0.94-0.85 (m, 6H). ES-MS: calcd. For C,6H29N3O5 (343.42); found: 344.4 [M+l].
Example 135
Synthesis of N-hydroxy-3-(i?)-(n-butyl)-3-[2-(S)-((N-butyl-N-methylamino)carbonyl)- pyrrolidin-l-carbonyl]-2-(S)-hydroxypropionamide
Figure imgf000143_0002
The title compound was prepared according to General Procedure F from N- ethyl-n-butylamine. Η ΝMR (CDC13): δ 4.74 (t, J = 3.9 Hz, IH), 4.25 (bs, IH), 3.73-3.02 (m, 7H), 2.16-1.74 (m, 6H), 1.53-1.23 (m, 8H), 1.08 (t, J = 6.9 & 7.1 Hz, 2H), 0.98-0.88 (m, 9H). ES-MS: calcd. For d9H35Ν3O5 (358.50); found: 386.4 [M+l].
Example 136
Synthesis ofN-hydroxy-3-(i?)-(n-butyl)-3-[2-(S)-((tert-butyl)aminocarbonyl)- pyrrolidin-1 -carbonyl] -2-(S)-hydroxypropionamide
Figure imgf000144_0001
The title compound was prepared according to General Procedure F from t- butylamine. 1H NMR (CDC13): δ 4.36-4.34 (d, J = 6.7 Hz, IH), 4.31-4.25 (d, J = 6.5 Hz, IH), 3.65-3.55 (m, 2H), 3.26-3.22 (m, IH), 2.2-1.8 (m, 6H), 1.5-1.3 (m, 13H), 0.94-0.85 (m, 3H). ES-MS: calcd. For Cι7H3ιN3O5 (357.45); found: 358.4 [M+l].
Example 137 Synthesis of N-hydroxy-3-(i?)-(n-butyl)-3-[2-(S)-((n-pentyl)aminocarbonyl)- pyrrolidin-1 -carbonyl] -2-(S)-hydroxypropionamide
Figure imgf000144_0002
The title compound was prepared according to General Procedure F from n- pentylamine. Η ΝMR (CDC13): δ 444-441 (d, J = 7.4 Hz, IH), 4.24 (d, J = 2.2 Hz, IH), 3.71-3.62 (m, 2H), 3.27-3.15 (m, 3H), 2.26-1.74 (m, 6H), 1.52-1.24 (m, 10H), 0.94-0.86 (m, 6H). ES-MS: calcd. For Cι8H33Ν3O5 (371.48); found: 372.4 [M+l].
Example 138 Synthesis of N-hydroxy-3-(Λ)-(n-butyl)-3-[2-(S)-((3-methylbutyl)aminocarbonyl)- pyrrolidin-1 -carbonyl] -2-(S)-hydroxypropionamide
Figure imgf000145_0001
The title compound was prepared according to General Procedure F from 3- methyl- 1-butylamine. 1H NMR (CDC13): δ 444-4.41 (d, J = 7.4 Hz, IH), 4.25-4.24 (d, J = 2.5 Hz, IH), 3.71-3.61 (m, 2H), 3.27-3.17 (m, 3H), 2.64-1.77 (m, 6H), 1.63- 1.33 (m, 7H), 0.94-0.88 (m, 9H). ES-MS: calcd. For Cι8H3N3O5 (271.48); found: 372.5 [M+l].
Example 139 Synthesis of N-hydroxy-3-(i?)-(n-butyl)-3-[2-(S)-((benzyl)aminocarbonyl)pynolidin-
1 -carbonyl] -2-(S)-hydroxypropionamide
Figure imgf000145_0002
The title compound was prepared according to General Procedure F from benzylamine. 1H ΝMR (CDC13): δ 7.37-7.21 (m, 5H), 4.49-4.29 (m, 3H), 4.20-4.19 (d, J = 2.5 Hz IH), 3.71-3.62 (m, 2H), 3.19 (t, J = 7.4 & 5.5 Hz, IH), 2.22-1.73 (m, 6H), 1.32-1.29 (m, 4H), 0.88 (t, J = 6.6 & 6.9 Hz, 3H). ES-MS: calcd. For C2oH29Ν3O5 (391.47); found: 392.4 [M+l].
Example 140
Synthesis ofN-hydroxy-3-(i?)-(n-butyl)-3-[2-(S)-((pyridin-2-yl)aminocarbonyl)- pyrrolidin- 1 -carbonyl]-2-(S)-hydroxypropionamide
Figure imgf000146_0001
The title compound was prepared according to General Procedure F from 2- aminopyridine. Η NMR (CDC13): δ 8.4-747 (m, 4H), 4.87-4.83 (m, IH), 4.47-446 (d, J = 2.8 Hz, IH), 4.04-3.87 (m, 2H), 3.5-3.48 (t, J = 2.8 & 4.9 Hz, IH), 2.52-1.95 (m, 6H), 1.63-1.56 (m, 4H), 1.11 (t, J = 7.1 Hz, 3H). ES-MS: calcd. For C18H26N4O5 (378.43); found: 377.2 [M-l].
Example 141 Synthesis of N-hydroxy-3-(Λ)-(n-butyl)-3-[2-(S)-((thiazolidin-l-yl)aminocarbonyl)- pyrrolidin- 1 -carbonyl] -2-(S)-hydroxypropionamide
Figure imgf000146_0002
The title compound was prepared according to General Procedure F from thiazolidine. Η ΝMR (CDC13): δ 4.94-4.66 (m, 3H), 4.46-445(d, J = 2.2 Hz, IH), 4.24-3.84 (m, 4H), 346-3.18 (m, 3H), 2.37-2.01 (m, 6H), 1.68-1.53 (m, 4H), 1.12 (t, J = 7.417 & 6.767 Hz, 3H). ES-MS: calcd. For C16H27Ν3O5S (373.47); found: 374.6 [M+l].
Example 142
Synthesis ofN-hydroxy-3-(i?)-(n-butyl)-3-[2-(S)-((thiadiazolidin-5-yl)amino- carbonyl)pyrrolidin-l -carbonyl] -2-(S)-hydroxypropionamide
Figure imgf000147_0001
The title compound was prepared according to General Procedure F from 2- aminothiadiazole. ]H NMR (CDC13): δ 7.47-746 (d, J = 5.5 Hz, IH), 5.03-5.02 (d, J = 5.5 Hz, IH), 449-4.47 (d, J = 3.4 Hz, IH), 4-3.89 (m, 2H), 3.45-344 (d, J = 3.6 Hz, IH), 2.4-1.9 (m, 6H), 1.53 (bs, 4H), 1.08 (t, J = 6.6 & 6.9 Hz, 3H). ES-MS: calcd. For Cι5H23N5O5S (385.44); found: 386.5 [M+l].
Example 143 Synthesis of N-hydroxy-3-(R)-(n-butyl)-3-[2-(S)-((5-phenylthiadiazolidin-2-yl)- aminocarbonyl)-pyrrolidin- 1 -carbonyl]-2-(S)-hydroxypropionamide
Figure imgf000147_0002
The title compound was prepared according to General Procedure F from 2- amino-5-phenylthiadiazole. !H ΝMR (CDC13): δ 7.82-7.21 (m, 5H), 4.82-4.79 (d, J 7.4 Hz, IH), 4.24-4.23 (d, J = 3.6 Hz, IH), 3.76-3.62 (m, 2H), 3.20-3.19 (d, J = 3.6 Hz, IH), 2.18-1.95 (m, 6H), 1.68-1.66 (m, 4H), 0.807 (t, J = 6.6 & 7.2 Hz, 3H). ES- MS: calcd. For C2ιH27Ν5O5S (461.54); found: 462.7 [M+l].
Example 144
Synthesis ofN-hydroxy-3-(i?)-(n-3-methylbutyl)-3-[2-(S)-(tert-butoxycarbonyl)- pynolidin- 1 -carbonyl]-2-(S)-hydroxypropionamide
Figure imgf000148_0001
The title compound was prepared according to General Procedure F from 3- methyl-l-bromo-2-butene and proline -O-t-butyl ester. Η NMR (CDC13): δ 4.52 (t, J = 4.4 Hz, IH), 4.46 (t, J = 1.3 & 2.2 Hz, IH), 3.93-3.76 (m, IH), 34-3.34 (m, 2H), 241-1.95 (m, 6H), 1.81-149 (m, 12H), 1.10 (t, J = 6.6 & 6.9 Hz, 6H). ES-MS: calcd. For C18H32N2O6 (372.46); found: 373.5 [M+l].
Example 145 Synthesis of N-hydroxy-3-(i?)-(n-butyl)-3-[2-(S)-((4-methylthiazol-2-yl)amino- carbonyl)pynolidin- 1 -carbonyl]propionamide
Figure imgf000148_0002
The title compound was prepared according to General Procedure E from 2- amino-4-methylthiazole. 1H ΝMR (DMSO-d6): δ 6.74 (s, IH), 4.48 (dd, 8.5 & 4.7 Hz, IH), 3.75-3.63 (m, IH), 3.61-3.55 (m, IH), 2.95 (bs, IH), 2.25 (s, 3H), 2.23-1.80 (m, 6H), 1.45-1.25 (m, 6H), 0.85 (t, 6.6 Hz, 3H). ES-MS: cald. For C,7H26Ν4O4S (382.17); found 383.6 [M+l].
Example 146
Synthesis of N-hydroxy-3-(Λ)-(n-butyl)-3-[2-(S)-((5-phenylthiadiazol-2-yl)amino- carbonyl)pyrrolidin- 1 -carbonyljpropionamide
Figure imgf000149_0001
The title compound was prepared according to General Procedure E from 2- amino-5-phenylthiadiazole. 1H NMR (DMSO-d6): δlθ.3 (s, IH), 7.94 (m, 2H), 7.53 (m, 3H), 4.56 (dd, 8.5 & 4.8 Hz, IH), 3.8-3.59 (m, 2H), 2.96 (bs, IH), 2.29-1.86 (m, 6H), 145-1.27 (m, 6H), 0.87 (t, 6.6 Hz, 3H). ES-MS: cald. For C21H27N5O4S (445.18); found 446.5 [M+l].
Example 147
Synthesis of N-hydroxy-3-(i?)-(n-butyl)-3-[2-(S)-((4,5-dimethylthiazol-2-yl)amino- carbonyl)pyrrolidin-l-carbonyl]propionamide
Figure imgf000149_0002
The title compound was prepared according to General Procedure E from 2- amino-4,5-dimethylthiazole. Η ΝMR (DMSO-d6): δ 4.45 (dd, 8.2 & 4.8 Hz, IH), 3.74-3.62 (m, IH), 3.60-3.55 (m, IH), 2.93 (bs, IH), 2.22 (s, 3H), 2.15 (s, 3H), 2.11- 1.78 (m, 6H), 146-1.25 (m, 6H), 0.85 (t, 6.3 Hz, 3 H). ES-MS: cald. For Cι8H28Ν4O4S (396.18); found 397.5 [M+l].
Example 148 Synthesis of N-hydroxy-3-(Λ)-(n-butyl)-3-[2-(S)-((3-phenoxyphenyl)amino- carbonyl)pyrrolidin- 1 -carbonyl]propionamide
Figure imgf000150_0001
The title compound was prepared according to General Procedure E from 3- phenoxyaniline. Η ΝMR (DMSO-d6): δ 7.42 (m, 2H), 7.37 (m, 3H), 7.15 (m, IH), 7.02 (m, 2H), 6.69 (m, IH), 4.35 (dd, 8.0 & 4.5 Hz, IH), 3.71-3.45 (m, 2H), 2.93 (bs, IH), 2.28-1.82 (m, 6H), 1.42-1.22 (m, 6H), 0.82 (t, 6.3 Hz, 3H). ES-MS: cald. For C25H31Ν3O5 (453.23); found 454.5 [M+l].
Example 149
Synthesis ofN-hydroxy-3-( ?)-(n-butyl)-3-[2-(S)-((3,4-methylenedioxybenzyl)amino- carbonyl)pyrrolidin- 1 -carbonyl]propionamide
Figure imgf000150_0002
The title compound was prepared according to General Procedure E from piperonylamine. 1H ΝMR (DMSO-d6): δ 10.4 (bs, IH), 8.18 (m, IH), 6.87-6.69 (m, 3H), 6.00-5.96 (m, 2H), 4.29-4.11 (m, 2H), 3.71-3.53 (m, 2H), 2.92 (bs, IH), 2.29- 1.76 (m, 6H), 149-1.21 (m, 6H), 0.84 (m, 3H). ES-MS: cald. For C2,H29Ν3O6 (419.21); found 420.5 [M+l].
Example 150 Synthesis of N-hydroxy-3-(S)-(n-butyl)-3-[2-(S)-((benzthiazol-2-yl)amino- carbonyl)pynolidin- 1 -carbon yl]propionamide
Figure imgf000151_0001
The title compound was prepared according to General Procedure E from 2- aminobenzothiazole. ES-MS: cald. For C20H26Ν4O4S (418.17); found 419.4 [M+l].
Example 151
Synthesis of N-hydroxy-3-(i?)-(n-butyl)-3-[2-(S)-((4-phenylthiazol-2-yl)amino- carbonyl)pyrrolidin- 1 -carbonyl]propionamide
Figure imgf000151_0002
The title compound was prepared according to General Procedure E from 2- amino-4-phenylthiazole. ES-MS: cald. For C22H28Ν4O4S (444.18); found 445.5 [M+l].
Example 152 Synthesis ofN-hydroxy-3-(i?)-(n-butyl)-3-[2-(S)-(piperazin-l-ylcarbonyl)pyrrolidin- 1 -carbonyl]-2-(S)-hydroxypropionamide
Figure imgf000152_0001
The title compound was prepared according to General Procedure F from piperazine. 1H NMR (CD3OD): δ 4.25-4.15 (m, 2H), 4.14 -3.82 (m, 4H), 3.72-345 (m, 6H), 3.36-3.29 (m, IH), 246-2.04 (m, 4H), 1.83-149 (m, 6H), 1.12 (t, J = 7 Hz). ES-MS: calcd. For Cι7H30 N4O5 (370.44); found: 371.4 [M+l].
Example 153 Synthesis of N-hydroxy-3-(i?)-(n-butyl)-3-[2-(S)-(piperidin-l-ylcarbonyl)pyrrolidin-l- carbonyl]-2-(S)-hydroxypropionamide
Figure imgf000152_0002
The title compound was prepared according to General Procedure F from piperidine. 1H ΝMR (CDC13): δ 5.07-5.03 (m, IH), 4.45 (d, J = 2.6 Hz, IH), 3.97- 3.82 (m, 4H), 3.71-3.56 (m, 2H), 3.47-3.40 (m, IH), 2.37-2.14 (m, 4H), 2.09-1.98 (m, 4H), 1.96-1.61 (m, 4H), 1.59-1.52 (m, 4H), 1.12 (t, J = 7 Hz, 3H). ES-MS: calcd. For Cι8H31Ν3O5 (369.46); found: 370.3 [M+l].
Example 154 Synthesis of N-hydroxy-3-(i?)-(n-butyl)-3-[2-(S)-(azetidin-l-ylcarbonyl)pyrrolidin-l- carbonyl]-2-(S)-hydroxypropionamide
Figure imgf000153_0001
The title compound was prepared according to General Procedure F from azetidine. Η NMR (CDC13): δ 4.67-4.55 (m, 2H), 4.53-4.31 (m, 3H), 4.28-4.16 (m, IH), 3.94-3.83 (m, IH), 3.81-3.77 (m, IH), 343-3.38 (m, IH), 2.55-245 (m, 2H), 2.37-2.22 (m, 2H), 2.20-2.07 (m, 2H), 2.05-1.91 (m, 2H), 1.66-1.47 (m, 4H), 1.01 (t, J = 7 Hz, 3H). ES-MS: calcd. For C16H27N3O5 (34140); found: 342.3 [M+l].
Example 155 Synthesis of N-hydroxy-3-(i?)-(n-butyl)-3-[2-(S)-(homopiperazin-l-ylcarbonyl)- pyrrolidin- 1 -carbonyl]-2-(S)-hydroxypropionamide
Figure imgf000153_0002
The title compound was prepared according to General Procedure F from hexamethyleneimine. ]H ΝMR (CDC13): δ 5.00-4.96 (m, IH), 4.44 (d, J = 2.7 Hz, IH), 3.97-3.82 (m, 2H), 3.79-3.59 (m, 4H), 3.44-3.38 (m, IH), 241-2.30 (m, 2H),
2.19-1.83 (m, 8H), 1.82-1.69 (m, 4H), 1.67-1.50 (m, 4H), 1.10 (t, J = 7 Hz, 3H). ES- MS: calcd. For C19H33Ν3O5 (383.48); found: 384.4 [M+l].
Example 156 Synthesis ofN-hydroxy-3-(R)-(n-butyl)-3-[2-(S)-((pyrimidin-2-yl)amino- carbonyl)pyrrolidin-l-carbonyl]-2-(S)-hydroxypropionamide
Figure imgf000154_0001
Step 1
To Cbz-protected-L-proline (20 mmol) in DCM (100 mL) was added thionylchloride (200 mmol) and the solution heated to reflux for 20 min. The reaction was concentrated to dryness and the residue coevaporated two times with DCM. An aliquot (6.7 mmol) in DCM (3 mL) was added to a 0 °C solution of 2-amino- pyrimidine in pyridine (3 mL) and the reaction stirred overnight. The reaction was concentrated, the residue dissolved in ethylacetate and then washed with water, 10 %> citric acid, saturated NaHCO3 and brine, then dried (Na2SO4) to afford N-Cbz-(2-(S)- pyrimidin-2-ylaminocarbonyl)pyrrolidine, which was used without further purification. Step 2
To afford N-Cbz-(2-(S)-pyrimidin-2-ylaminocarbonyl)pynolidine (5.0 mmol) in HO Ac (10 mL) was added 30 % HBr in acetic acid and the solution stined for 40 min. The reaction was quenched by addition of 100 mL ethylether, and the resulting precipitate collected and recrystalized from MeOH/Et2O to afford 3.5 mmol afford of 2-(S)-(pyrimidin-2-ylaminocarbonyl)pynolidine hydrobromide salt (70 %>). Step 3
To 2-(S)-(pyrimidin-2-ylaminocarbonyl)pynolidine hydrobromide (200 μmol) in DMF (2 mL) was added DIEA (500 μmol), compound G-l, (General Procedure G, 200 μmol) and solid HATU (200 μmol) and the reaction stined 4 h. The reaction was cooled to 0 °C, diluted with aqueous 50 %> hydroxylamine (600 μL), stirred for 4 h, and then purified via preparative reverse-phase (C18) HPLC to afford the title compound. Η NMR (DMSO-d6): δ 10.85 (bs, IH), 8.84 (d, J = 5.0 Hz, 2H), 7.37 (t, J = 5.0 Hz, IH), 4.98-4.83 (bs, IH), 4.04-3.95 (m, 2H), 3.78-3.65 (m, IH), 3.18-3.05 (m, IH), 2.39-2.25 (m, 4H), 1.57-1.38 (m, 6H), 1.00 (t, J = 6.6 Hz, 3H). ES-MS: calcd. For C,7H25N5O5 (3794162); found: 380.3 [M+l].
Example 157 Synthesis of N-hydroxy-3-(Λ)-(n-butyl)-3-[2-(S)-(4-methylpiperazin-l -ylcarbonyl)- pynolidin- 1 -carbonyl] -2-(S)-hydroxypropionamide
Figure imgf000155_0001
The title compound was prepared according to General Procedure F from Ν- methylpiperazine. 1H ΝMR (CD3OD): δ 4.24-4.12 (m, 2H), 3.89-3.86 (m, 2H), 3.64-3.51 (m, 4H), 3.35-3.19 (m, IH), 3.14 (s, 3H), 2.46-2.08 (m, 4H), 1.85-1.53 (m, 6H), 1.11 (t, J = 7 Hz). ES-MS: calcd. For C,8H32Ν4O5 (384.47); found: 385.3
[M+l].
Example 158
Synthesis of N-hydroxy-3-( ?)-(n-butyl)-3-[2-(S)-((4-methylpyrimidin-2-yl)amino- carbonyl)pyrrolidin- 1 -carbonyl] -2-(S)-hydroxypropionamide
Figure imgf000155_0002
The title compound was prepared as described in General Procedure F from 4- methyl-2-aminopyrimidine. Η ΝMR (DMSO-d6): δ 8.57 (d, J = 5.2 Hz, IH), 7.16 (d, J = 5.2 Hz, IH), 4.9 (bs, IH), 3.93-3.85 (m, 2H), 3.67-3.60 (m, IH), 3.02-2.90 (m, IH), 2.50 (s, 3H), 2.3-2.15 (m, IH), 2.10-1.98 (m, 3H), 1.55-1.28 (m, 6H), 0.904 (t, J = 6.2 Hz, 3H). ES-MS: calcd. For C18H27Ν5O5 (393.4431); found: 394.3 [M+l].
Example 159 Synthesis of N-hydroxy-3-(i?)-(n-butyl)-3-[2-(S)-((pyrimidin-4-yl)amino- carbonyl)pynolidin- 1 -carbonyl]-2-(S)-hydroxypropionamide
Figure imgf000156_0001
The title compound was prepared as described in General Procedure F from 4- aminopyrimidine. Η ΝMR (DMSO-d6): δ 8.91 (d, J = 0.55 Hz, IH), 8.66 (d, J = 6.1 Hz, IH), 8.04 (dd, J = 6.1 & 1.1 Hz, IH), 4.64-4.60 (m, IH), 3.87-3.75 (m, IH), 3.61- 3.51 (m, IH), 2.93-2.88 (m, IH), 2.17-2.05 (m, IH), 1.98-1.83 (m, 3H), 145-1.18 (m, 6H), 0.83 (t, J = 6.3 Hz, 3H). ES-MS: calcd. For C17H25Ν5θ5 (379.4162); found: 380.1 [M+l].
Example 160
Synthesis of N-hydroxy-3-(i?)-(n-butyl)-3-[2-(S)-((pyrazin-2-yl)amino- carbonyl)pyrrolidin- 1 -carbonyl] -2-(S)-hydroxypropionamide
Figure imgf000156_0002
The title compound was prepared as described in General Procedure F from aminopyrazine. 1H ΝMR (DMSO-d6): δ 9.30 (d, J = 1.4 Hz, IH), 8.41-8.35 (m, 2H), 4.66-4.62 (m, IH), 3.88-3.76 (m, 2H), 3.60-3.53 (m, IH), 2.94-2.89 (m, IH), 2.17- 2.11 (m, IH), 2.00-1.84 (m, 3H), 142-1.18 (m, 6H), 0.82 (t, J = 6.6 Hz, 3H). ES-MS: calcd. For Cι7H25Ν5O5 (379.4162); found: 380.4 [M+l].
Example 161 Synthesis of N-hydroxy-3-(i?)-(n-butyl)-3-[2-(S)-(pyrrolidin-l-ylcarbonyl)pyrrolidin- 1 -ylcarbonyl] -2-(S)-hydroxypropionamide
Figure imgf000157_0001
The title compound was prepared according to General Procedure F from pyrrolidine. Η ΝMR (CDC13): δ 4.83-4.79 (m, IH), 4.44 (d, J = 2.4 Hz, IH), 3.96- 3.85 (m, 2H), 3.77-3.73 (m, 2H), 3.64-3.56 (m, 2H), 3.42-3.16 (m, IH), 2.39-2.22 (m, 2H), 2.19-1.96 (m, 8H), 1.66-1.50 (m, 4H), 1.11 (t, J = 7 Hz, 3H). ES-MS: calcd. For Cι7H29Ν3O5 (355.43); found: 356.4 [M+l].
Example 162
Synthesis of N-hydroxy-3-(i?)-(n-butyl)-3-[2-(S)-((imidazol-2-yl)amino- carbonyl)pynolidin- 1 -carbonyl] -2-(S)-hydroxypropionamide
Figure imgf000157_0002
The title compound was prepared as described in General Procedure F from 2- amino-imidazole. Η ΝMR (DMSO-d6): δ 7.24 (s, 2H), 4.50-4.46 (m, IH), 3.83-3.61 (m, 3H), 2.94-2.88 (m, IH), 2.21-2.11 (m, IH), 2.05-1.94 (m, 3H), 1.41-1.18 (m, 6H), 0.81 (t, J = 6.0 Hz, 3H). ES-MS: calcd. For C,6H25Ν5O5 (367.4052); found: 368.4 [M+l].
Formulation Examples The following are representative pharmaceutical formulations containing a compound of Formula (I).
Example 1 Tablet formulation The following ingredients are mixed intimately and pressed into single scored tablets.
Quantity per Ingredient tablet, mg compound of this invention 400 cornstarch 50 croscarmellose sodium 25 lactose 120 magnesium stearate 5
Example 2 Capsule formulation
The following ingredients are mixed intimately and loaded into a hard-shell gelatin capsule.
Quantity per Ingredient capsule, mg compound of this invention 200 lactose, spray-dried 148 magnesium stearate 2
Example 3 Suspension formulation The following ingredients are mixed to form a suspension for oral administration.
Ingredient Amount compound of this invention 1.0 g fumaric acid 0.5 g sodium chloride 2.0 g methyl paraben 0.15 g propyl paraben 0.05 g granulated sugar 25.0 g sorbitol (70% solution) 13.00 g
Veegum K (Vanderbilt Co.) 1.0 g flavoring 0.035 ml colorings 0.5 mg distilled water q.s. to 100 ml
Example 4 Injectable formulation The following ingredients are mixed to form an injectable formulation.
Ingredient Amount compound of this invention 0.2 mg-20 mg sodium acetate buffer solution, 0.4 M 2.0 ml
HCl (IN) or NaOH (IN) q.s. to suitable pH water (distilled, sterile) q.s. to 20 ml
Example 5 Suppository formulation
A suppository of total weight 2.5 g is prepared by mixing the compound of the invention with Witepsol® H-15 (triglycerides of saturated vegetable fatty acid; Riches-Nelson, Inc., New York), and has the following composition:
compound of the invention 500 mg
Witepsol® H-15 balance
Biological Examples Example 1 Inhibition of peptide deformylase activity The PDF/FDH coupled assay (Lazennec, C. & Meinnel, T., Anal. Biochem. 224: 180-182 (1997)) was used. In this coupled assay, the formate released by PDF from its substrate fMAS is oxidized by the coupling enzyme FDH, reducing one molecule of NAD+ to NADH, which causes an increase in absorption at 340 nm. All assays were carried out at room temperamre in a buffer of 50 mM HEPES, pH 7.2, 10 mM NaCl, 0.2 mg/mL BSA, in half-area 96-well microtiter plates (Corning). The reaction was initiated by adding a mixture of 0.5 Unit/mL FDH, 1 mM NAD+, and fMAS at the desired concentration. To determine IC50 (the concentration needed to inhibit 50%> of enzyme activity) values, PDF was pre-incubated for 10 min with varying concentrations of actinonin, and the deformylation reaction was initiated by the addition of reaction mixture containing 4 mM fMAS. The initial reaction velocity, y, was measured as the initial rate of absorption increase at 340 nm using a SpectraMax plate reader (Molecular Devices, Sunnyvale, CA). The inhibitor concentration [In] at which 50%> of the enzyme activity is inhibited, IC50, was calculated using the following formula: y = yo/(l + [In]/IC50) where y0 is the reaction velocity in the absence of inhibitor. Solving this equation for IC5o at the [In] when y = yJ2 yields IC50. The IC50 was calculated based on a nonlinear least-square regression fit using a commercial software package (DeltaGraph 4.0).
Using this assay, the IC50 of various compounds were determined. The IC 0 for the various compounds was determined against deformylase enzyme containing nickel or zinc as the metal ion. The compound tested had an IC50 of less than 2 μM against deformylase enzyme containing nickel as the metal ion and less than 9 μM against deformylase enzyme containing zinc as the metal ion
Example 2 Assay for testing antimicrobial activity Minimum inhibitory concentrations (MICs) were determined using the microdilution method in 96-well format plates. Compounds were suspended in DMSO at 5 or 10 mg/ml and stored at 4°C until used. They were diluted in Mueller- Hinton Broth (MHB) or Trypticase Soy Broth (TSB) and used for MIC determination. The range of concentrations tested was 64-0.0625 TgAml final concentration using a two-fold dilution system.
The inoculum was prepared from cells grown on Trypticase Soy Agar (TSA) and incubated overnight at 35 °C, 5 to 10 colonies were used to inoculate MHB or TSB broths, and the culture was incubated overnight at 35°C. The overnight culture was diluted 1 :10, incubated for one hour at 35°C, diluted to the appropriate inoculum size and applied to the wells containing broth and test compound. Inoculum sizes were 2xl04 CFU/ml.
Plates were incubated at 35°C for 48 hours and MIC were recorded after 18 hours of incubation for bacteria. MIC was defined as the lowest concentration of compound that does not produce visible growth after incubation.
Minimum inhibitory concentrations for various compounds against H. influenza and S. aureus was approximately 64 μg/mL or less.
Minimum inhibitory concentrations for certain compounds of the Invention against S. aureus, S. epidermidis, E. faecium, S. pneumoniae, H. influenzae, H. influenzae acr, M. catarrhalis, E. coli and E. coli acr was approximately 64 μg/mL or less.
Example 3 Demonstration of Selective Inhibition of PDF Compared to MMP-7 (Matrilysin) As noted previously, inhibitors which are selective for peptidyl deformylase over matrix metalloproteinases are desirable in order to avoid side effects.
In order to test the compounds of the invention for possible inhibitory effects on matrix metalloproteinases, the following assay for MMP-7 (matrilysin) was used. MMP-7 (Matrilysin) Assay: Matrilysin activity is assayed using a thio-peptide (Pro-Leu-Gly-S-Leu-Leu-
Gly) as substrate. Upon enzyme hydrolysis, the thiolate is released as a product. The thiolate thus generated reacts with DTNB (dithionitrobenzene), giving rise to a yellow color which is monitored at 405 nm. The assay is carried out at room temperature; the assay buffer contains 50 mM Tricine, pH 7.5, 0.2 M NaCl, 10 mM CaCl2, and 0.05% Brij, in a half-area 96-well microtiter plate. The reaction is initiated by adding a mixture of 200 TM DTNB and 100 TM thiopeptide in buffer. To determine IC50 (the concentration needed to inhibit 50%> of enzyme activity) values, MMP-7 was preincubated for 10 minutes with varying concentrations of compounds, and the hydrolysis initiated by the addition of reaction mixture containing thiopeptide and DTNB. The reaction rate was recorded as the absorbance increase in OD405 over 30 minutes using a SpectraMax plate reader (Molecular Devices, Sunnyvale, CA). The inhibitor concentration [In] at which 50%> of the enzyme activity is inhibited, IC50, was calculated using the following formula: y = y0/(l + [In]/IC50) where y0 is the reaction velocity in the absence of inhibitor. Solving this equation for IC50 at the [In] when y = J yields IC50.
Using this assay, the IC5o of various compounds were determined. The compounds of the Invention tested were at least approximately 800 times more select for PDF than MMP-7. Similar selectivity of the compounds for peptidyl deformylase over MMP-1, MMP-2, MMP-3, MMP-9, MMP-13, MT-MMP-1, and tissue necrosis factor converting enzyme was observed. Similar selectivity was also observed over other metalloproteinases such as angiotensin converting enzyme.
Example 4 Discontinuous PDF Assay The gene for PDF was cloned from S. aureus and E. coli by PCR amplification. The PDF proteins were overexpressed in E. coli. The native Fe - containing PDF or its more stable surrogate Ni2+-containing PDF were prepared according to Wagner et al. (1998) Biochemical & Biophysical Research Communications 246:342-6. Both enzymes have similar activity as reported in the literature. Discontinuous assay is carried out in a buffer of 10 mM NaCl and 50 mM HEPES, pH 7.2. Typically, 2 nM of PDF was incubated with inhibitor for 30 minutes prior to the addition of 4 mM fMAS substrate. The deformylation proceeded at room temperature for 30 minute. The enzyme activity is directly proportional to the amount of formate released, which can be quantified by monitoring the absorbance increase at 340 nm after the addition of 1 mM of NAD+ and 0.5 U/ml of formate dehydrogenase.
Example 5
Mouse septicemia model for determining in vivo efficacy CD1 female out-bred mice (Charles River Laboratories) weighing 18-22 grams each were injected intraperitoneally with 0.5 ml of a suspension containing 5xl07 cfu of S. aureus (Smith strain) in 7% hog gastric mucosa (mucin). The mice were treated, either subcutaneously (SC), intravenously (IV) or orally (PO), lhr and 5hr after infection. Six groups of six mice each were given different dosage levels representing two-fold dilutions of each compound (range of lOOmg/kg - 0.1 mg/kg). Vancomycin was used as the control antibiotic and was administered SC. Compounds were formulated in PBS and untreated controls were dosed with vehicle alone.
Deaths in each group were monitored daily for 6 days and cumulative mortality was used to determine the 50%> protective doses (PD50), which were calculated using the method of Reed and Muench. The foregoing invention has been described in some detail by way of illustration and example, for purposes of clarity and understanding. It will be obvious to one of skill in the art that changes and modifications may be practiced within the scope of the appended claims. Therefore, it is to be understood that the above description is intended to be illustrative and not restrictive. The scope of the invention should, therefore, be determined not with reference to the above description, but should instead be determined with reference to the following appended claims, along with the full scope of equivalents to which such claims are entitled.
All patents, patent applications and publications cited in this application are hereby incorporated by reference in their entirety for all purposes to the same extent as if each individual patent, patent application or publication were so individually denoted.

Claims

What is claimed is:
1. A compound of Formula (I) :
Figure imgf000164_0001
wherein:
R, is hydrogen, halo, -OH, -R8OR9, -R9, -OR9, -SH, -SR9, -NH2, -NHR9 - NR9Rι0, -NHC(=O)H, -NR9C(=O)H, -NHC(=O)R9, -NR9C(=O)R10, -NHC(=O)NH2, -NR9C(=O)NH2, -NHC(=O)NHR9, -NHC(=O)NR9R10, -NR9C(=O)NR9aR10, -NHC(=O)OR9, -NR9C(=O)ORι0, -NHS(=O)2R9, -NR9S(=O)2R10, -NHS(=O)2OR9, or -NR S(=O) OR!o where R8 is selected from the group consisting of-Cι-Cι2 alkylene, substituted alkylene, or heteroalkylene, -d-Cι2 alkenylene, substituted alkenylene, or heteroalkenylene, -Cι-C12 alkynylene, substituted alkynylene, or heteroalkynylene, and -(Cι-C8 alkylene or substituted alkylene)nι-(C3-Cι2 arylene or heteroarylene)-(Cι- C8 alkyl or substituted alkyl)n2 where nl and n2 are independently 0 or 1 ; and R9, R9a and Rio are independently selected from the group consisting of-Cι-Cι2 alkyl, substituted alkyl, or heteroalkyl, -Cι-C]2 alkenyl, substituted alkenyl, or heteroalkenyl, -Cι-C12 alkynyl, substituted alkynyl, or heteroalkynyl, and -(Cι-C8 alkyl or substituted alkyl)n3-(C3-C12 arylene or heteroarylene)-(Cι-C8 alkyl or substituted alkyl)n4 where n3 and n4 are independently 0 or 1 ;
R is independently hydrogen or -R9 wherein R is as defined above;
R3 is hydrogen, halo, -Ru, -OH, -ORn, -Rι2ORπ, -SH, -SRn, -NH2, -NHRU, -NR,,R13, -NHC(=O)H, -NR,,C(=O)H, -NHC(=O)Rn, -NRnC(=O)Rι3, -NHC(=O)NH2, -NR, ,C(=O)NH2, -NHC(=O)NHRu, -NHC(=O)NRuR13, -NRnC(=O)NR„aR13, -NHC(=O)ORπ, -NRπC(=O)OR13, -NHS(=O)2R13, -NRnS(=O)2R,3, -NHS(=O)2ORn, or -NRnS(=O)2ORI3, where R12 is selected from the group consisting of-Cι-C]2 alkylene, substituted alkylene, or heteroalkylene, -C\- Cι2 alkenylene, substituted alkenylene, or heteroalkenylene, -Cι-Cι2 alkynylene, substituted alkynylene, or heteroalkynylene, and -(Cι-C8 alkylene or substituted alkylene)n5-(C3-Cι2 arylene or heteroarylene)-(Cι-C8 alkyl or substituted alkyl)n6 where n5 and n6 are independently 0 or 1; and Rn, Rπa and Rι3 are independently selected from the group consisting of-Cι-Cι2 alkyl, substituted alkyl, or heteroalkyl, -Cι-Cι2 alkenyl, substituted alkenyl, or heteroalkenyl, -Cι-Cι2 alkynyl, substituted alkynyl, or heteroalkynyl, and -(C]-C8 alkyl or substituted alkyl)n -(C3-Cι2 arylene or heteroarylene)-(Cι-C8 alkyl or substituted alkyl)π8 where n7 and n8 are independently O or l; t is hydrogen or -Ri i where -Ri i is as defined above; n is an integer from 1 to 5; zero or one Y is selected from the group consisting of-O-, -NRπ- where Rπ is as defined above, and -S-, and all remaining Y are -CR6R7- where R^ and R are each independently selected from the group consisting of hydrogen, -R[4, -OH, -OR14, -SH, -SRi4, -NH2, -NHR14, -NR,4R15, -C(=O)H, -C(=O)RH, -C(=O)NH2,
Figure imgf000165_0001
-C(=O)CH3, -C(=O)CH2R14,
Figure imgf000165_0002
-C(=O)CRι4Rι5Rι6, -C(=O)OCH3, -C(=O)OCH2R14, -C(=O)OCHR14R15, -C(=O)OCRι4R15Rι6, -S(=O)2NH2,
-S(=O)2NHR14, -S(=O)2NR,4R,5, -NHC(=O)H, -N(R14)C(=O)H, -NHC(=O)R15, -N(R14)C(=O)R15, -NHC(=O)OR14, -NHS(=O)2H, -N(R14)S(=O)2H, -NHS(=O)2OR15, -N(Rι4)S(=O)2ORι5, -N(H)S(=O)2Ri5, -N(RM)S(=O)2R15 and where two vicinal Re or R7 groups combine to form a substituted or unsubstituted -C4-C10 cyclic alkyl, cyclic heteroalkyl, aryl or heteroaryl group where Rj4, Rj5 and Rι6 are each independently selected from the group consisting of-Cι-C]2 alkyl, substituted alkyl, or heteroalkyl, -Cι-C12 alkenyl, substituted alkenyl, or heteroalkenyl, -Cι-Cι2 alkynyl, substituted alkynyl, or heteroalkynyl, alkoxy, and -(Cι-C8 alkyl or substituted alkyl)n -(C3-C1 arylene or heteroarylene)-(Ci-C8 alkyl or substituted alkyl)πlo where n9 and nlO are independently 0 or 1 ; or when Rι and R]5 are attached to a nitrogen atom they can combine to form a substituted or unsubstituted -C4-Cιo cyclic alkyl, cyclic heteroalkyl, aryl or heteroaryl group; or a pharmaceutically acceptable salt thereof.
2. The compound of Claim 2 wherein Ri is halo.
3. The compound of Claim 2 wherein R] is fluoro.
4. The compound of Claim 3 wherein R2 and R4 are hydrogen.
5. The compound of Claim 4 wherein R3 is alkyl.
6. The compound of Claim 5 wherein the
Figure imgf000166_0001
group is a group of formula:
R7
H
wherein: n is 1 ; and
R is -C(=O)NR]4Rι5 where Rj4 and Rj5 are independently selected from the group consisting of hydrogen, -(Cι-Cι2) alkyl, substimted alkyl, or heteroalkyl, -(Ci- Cι2) alkenyl, substituted alkenyl, or heteroalkenyl, -(CrCι2) alkynyl, substituted alkynyl, or heteroalkynyl, alkoxy, and -(Cι-C8 alkyl or substituted alkyl)n9-(C3-Cι2 arylene or heteroarylene)-(Cι-C8 alkyl or substituted alkyl)nl0 where n9 and nlO are independently 0 or 1 ; or R14 and Rι5 combine to form a substituted or unsubstituted - (C4-Cιo)cyclic alkyl, cyclic heteroalkyl, aryl or heteroaryl group.
7. The compound of Claim 5 wherein the
Figure imgf000166_0002
group is a group of formula:
Figure imgf000167_0001
wherein: n is 1 ; and
R7 is -C(=O)NRι4Rι5 where Rι4 and R15 are each independently hydrogen or (Cι-Cι2) alkyl, alkoxy, aryl, heteroaryl or R14 and Ri5, when attached to the same carbon, combine to form a cyclic heteroalkyl, aryl or heteroaryl group.
8. The compound of Claim 5 wherein the
Figure imgf000167_0002
group is a group of formula:
Figure imgf000167_0003
wherein: n is 1 ; and
R7 is -C(=O)NHRι5where Rι5 is H or -(Cι-Cι2) alkyl, aryl, or heteroaryl or
Figure imgf000167_0004
where Rj4 and R15 form a substituted or unsubstituted -(C4-Cιo)cyclic heteroalkyl.
The compound of Claim 5 wherein the
Figure imgf000168_0001
group is a group of formula:
R7
-\\A
wherein: n is 1 ; and
R is n-butylaminocarbonyl, tert-butylaminocarbonyl, benzylaminocarbonyl, 1 , 1 -dimethylpropylaminocarbonyl, 2-(cyclohexen- 1 -yl)-ethylaminocarbonyl, indan- 5 -ylaminocarbonyl, 4,5-dimethylthiazol-2 -ylaminocarbonyl, 4- phenoxyphenylaminocarbonyl, cyclopropylmethyl-aminocarbonyl, pyridin-2- ylaminocarbonyl, pyridin-3-ylaminocarbonyl, pyridin-4-ylmethylaminocarbonyl, morpholin-4-ylcarbonyl, 3,4-methylenedioxy-phenylaminocarbonyl, quinolin-3- ylaminocarbonyl, methylaminocarbonyl, 4-biphenylaminocarbonyl, 3- phenoxyphenylaminocarbonyl, 3 ,4-dichlorophenyl-aminocarbonyl, 4-tert- butylphenylaminocarbonyl, 4-tert-butylaminocarbonyl, indan-2-ylaminocarbonyl, 2,2-dimethylpropylaminocarbonyl, 4-phenylthiazol-2-ylaminocarbonyl, 5- phenylthiadiazol-2-ylaminocarbonyl, 5-ethylthiadiazol-3-ylaminocarbonyl, thiadiazol- 2-ylaminocarbonyl, 3-trifluoromethoxyphenyl-aminocarbonyl, 2,5- dimethylphenylaminocarbonyl, 2,5-dimethoxyphenylamino-carbonyl, 3,4- dichlorophenylaminocarbonyl, benzthiazol-2-ylaminocarbonyl, 3- phenoxyphenylaminocarbonyl, 2-hydroxybutylaminocarbonyl, 4-hydroxybutyl- aminocarbonyl, 1 ,4-benzodioxan-6-ylaminocarbonyl, isoquinolin-6-ylaminocarbonyl, methylaminocarbonyl, thiazol-2-ylaminocarbonyl, 4-methylthiazol-2-yl- aminocarbonyl, 3-methylbutyl-aminocarbonyl, n-pentylaminocarbonyl, cyclohexylaminocarbonyl, 5-methylthiazol-2-ylaminocarbonyl, 4-methylthiazol-2 -ylaminocarbonyl, 2,4-dimethoxyphenyl-aminocarbonyl, 3,4-methylenedioxyphen-5-yl- methylaminocarbonyl, allylaminocarbonyl, 2-methylallylaminocarbonyl, pyrrolidin-1- ylcarbonyl, ethylaminocarbonyl, phenylaminocarbonyl, indan-1 -ylaminocarbonyl, 2-methoxyethylaminocarbonyl, indan-5-ylaminocarbonyl, 3,4-difluorophenyl- aminocarbonyl, 5-methylisoxazol-5-ylaminocarbonyl, 3-fluorophenylaminocarbonyl, 4-fluorophenylaminocarbonyl, N-methyl-N-phenylaminocarbonyl, 2-propylamino- carbonyl, 2-phenylpropylaminocarbonyl, n-propylaminocarbonyl, N-ethyl-N-(n- butyl)aminocarbonyl, benzylaminocarbonyl, thiazolidin-1 -ylcarbonyl, piperazin- 1 -ylcarbonyl, piperidin- 1 -ylcarbonyl, azetidin-1 -ylcarbonyl, homopiperdin-1 -ylcarbonyl, pyrimidin-2-ylaminocarbonyl, 4-methylpiperazin- 1 -ylcarbonyl, 4-methylpyrimidin- 2-ylaminocarbonyl, pyrimidin-4-ylaminocarbonyl, pyrazin-2-ylaminocarbonyl, imidazol-2-ylaminocarbonyl.
10. The compound of Claim 5 wherein the
Figure imgf000169_0001
group is a group of formula:
R7 A
wherein: n is 1 ; and R7 is piperidin- 1 -ylcarbonyl, azetidin-1 -ylcarbonyl, ethylaminocarbonyl, phenylaminocarbonyl, pyrimidin-2-ylaminocarbonyl, or thiazol-2-ylaminocarbonyl; and the stereochemistry at the C2 carbon atom of the pyrrolidine ring, i.e., carbon canying the R7 group is (S) and R3 is n-butyl.
11. The compound of Claim 5 wherein the
Figure imgf000170_0001
group is a group of formula:
H <Y.
wherein: n is 1 ; and
R7 is -C(=O)ORι4 where R14 is hydrogen or -(Cι-Cι2) alkyl, alkoxy, aryl, or heteroaryl.
12. The compound of Claim 5 wherein the
R6 .R7 - Nχ(Y)"
R6 R7
group is a group of formula:
-\' ■CP).
wherein: n is 1; and
R is -C(=O)OR|4 where R14 is alkyl; and the stereochemistry at the C2 carbon atom of the pyrrolidine ring is (S).
13. The compound of Claim 1 wherein the
Figure imgf000171_0001
group is a group of formula:
R7
-WJ wherein: n is i; and
R7 is -C(=O)NRi4R]5 where R14 and R15 are independently selected from the group consisting of hydrogen, -(C]-Cι2) alkyl, substituted alkyl, or heteroalkyl, -(Ci- Cj2) alkenyl, substituted alkenyl, or heteroalkenyl, -(Cι-C1 ) alkynyl, substituted alkynyl, or heteroalkynyl, alkoxy, and -(CpC8 alkyl or substituted alkyl)n9-(C3-Cπ arylene or heteroarylene)-(Cι-C8 alkyl or substituted alkyl)nιo where n9 and nlO are independently 0 or 1 ; or R1 and Rι combine to form a substituted or unsubstituted - (C4-Cιo)cyclic alkyl, cyclic heteroalkyl, aryl or heteroaryl group.
14. The compound of Claim 1 wherein the
Figure imgf000171_0002
group is a group of formula:
V 1).
wherein: n is 1 ; and R7 is -C(=O)NR14R] 5 where R14 and R]5 are each independently hydrogen or (Cι-Cι2) alkyl, alkoxy, aryl, heteroaryl or Rj4 and R15, when attached to the same carbon, combine to form a cyclic heteroalkyl, aryl or heteroaryl group.
15. The compound of Claim 1 wherein the
Figure imgf000172_0001
group is a group of formula:
-\ .H' O wherein: n is 1; and
R7 is -C(=O)NHR15 where R15 is H or -(Cι-Cι2) alkyl, aryl, or heteroaryl or -C(=O)NRι4Ri5 where R]4 and R15 form a substituted or unsubstituted -(C4-Cιo)cyclic heteroalkyl.
16. The compound of Claim 1 wherein the
Figure imgf000172_0002
group is a group of formula:
R7
\
wherein: n is 1 ; and R7 is n-butylaminocarbonyl, tert-butylaminocarbonyl, benzylaminocarbonyl, 1 , 1 -dimethylpropylaminocarbonyl, 2-(cyclohexen- 1 -yl)-ethylaminocarbonyl, indan- 5 -ylaminocarbonyl, 4,5-dimethylthiazol-2-ylaminocarbonyl, 4-phenoxyphenyl- aminocarbonyl, cyclopropylmethyl-aminocarbonyl, pyridin-2-ylaminocarbonyl, pyridin-3 -ylaminocarbonyl, pyridin-4-ylmethylaminocarbonyl, morpholin-4- ylcarbonyl, 3,4-methylenedioxy-phenylaminocarbonyl, quinolin-3-ylaminocarbonyl, methylaminocarbonyl, 4-biphenylaminocarbonyl, 3-phenoxyphenylaminocarbonyl, 3 ,4-dichlorophenyl-aminocarbonyl, 4-tert-butylphenylaminocarbonyl, 4-tert- butylaminocarbonyl, indan-2 -ylaminocarbonyl, 2,2-dimethylpropylaminocarbonyl, 4- phenylthiazol-2-ylaminocarbonyl, 5-phenylthiadiazol-2 -ylaminocarbonyl, 5- ethylthiadiazol-3-ylaminocarbonyl, thiadiazol-2-ylaminocarbonyl, 3- trifluoromethoxyphenyl-aminocarbonyl, 2,5-dimethylphenylaminocarbonyl, 2,5- dimethoxyphenylamino-carbonyl, 3,4-dichlorophenylaminocarbonyl, benzthiazol-2- ylaminocarbonyl, 3-phenoxyphenylaminocarbonyl, 2-hydroxybutylaminocarbonyl, 4- hydroxybutyl-aminocarbonyl, 1 ,4-benzodioxan-6-ylaminocarbonyl, isoquinolin-6- ylaminocarbonyl, methylaminocarbonyl, thiazol-2-ylaminocarbonyl, 4-methylthiazol- 2-yl-aminocarbonyl, 3-methylbutyl-aminocarbonyl, n-pentylaminocarbonyl, cyclohexylaminocarbonyl, 5-methylthiazol-2-ylaminocarbonyl, 4-methylthiazol-2-yl- aminocarbonyl, 2,4-dimethoxyphenyl-aminocarbonyl, 3,4-mefhylenedioxyphen-5-yl- methylaminocarbonyl, allylaminocarbonyl, 2-methylallylaminocarbonyl, pynolidin-1- ylcarbonyl, ethylaminocarbonyl, phenylaminocarbonyl, indan-1 -ylaminocarbonyl, 2-methoxyethylaminocarbonyl, indan-5-ylaminocarbonyl, 3,4-difluorophenyl- aminocarbonyl, 5-methylisoxazol-5-ylaminocarbonyl, 3-fluorophenylaminocarbonyl, 4-fluorophenylaminocarbonyl, N-methyl-N-phenylaminocarbonyl, 2-propylamino- carbonyl, 2-phenylpropylaminocarbonyl, n-propylaminocarbonyl, N-ethyl-N-(n- butyl)aminocarbonyl, benzylaminocarbonyl, thiazolidin-1 -ylcarbonyl, piperazin- 1 -ylcarbonyl, piperidin- 1 -ylcarbonyl, azetidin-1 -ylcarbonyl, homopiperdin-1 -ylcarbonyl, pyrimidin-2-ylaminocarbonyl, 4-methylpiperazin- 1 -ylcarbonyl, 4-methylpyrimidin- 2-ylaminocarbonyl, pyrimidin-4-ylaminocarbonyl, pyrazin-2-ylaminocarbonyl, imidazol-2-ylaminocarbonyl.
17. The compound of Claim 1 wherein the
Figure imgf000174_0001
group is a group of formula:
-V <Y wherein: n is 1 ; and
R7 is piperidin- 1 -ylcarbonyl, azetidin-1 -ylcarbonyl, ethylaminocarbonyl, phenylaminocarbonyl, pyrimidin-2-ylaminocarbonyl, or thiazol-2-ylaminocarbonyl; and the stereochemistry at the C2 carbon atom of the pynolidine ring, i.e., carbon carrying the R7 group is (S).
18. The compound of Claim 1 wherein the
Figure imgf000174_0002
group is a group of formula:
H N ?)„
wherein: n is 1 ; and
R7 is -C(=O)ORι4 where Rι4 is hydrogen or -(Cι-Cι2) alkyl, alkoxy, aryl, or heteroaryl.
19. The compound of Claim 1 wherein the
Figure imgf000175_0001
group is a group of formula:
R7
V .
wherein: n is 1 ; and
R is -C(=O)ORι4 where Rι4 is alkyl; and the stereochemistry at the C2 carbon atom of the pynolidine ring is (S).
20. The compound of Claim 13-19 wherein R and Rt are hydrogen.
21. The compound of Claim 20 wherein Ri is halo.
22. The compound of Claim 21 wherein R3 is alkyl. 23. The compound of Claim 22 wherein R! is fluoro.
24. The compound of Claim 22 wherein R3 is n-butyl.
25. The compound of Claim 13-19 wherein Ri is halo.
26. The compound of Claim 25 wherein Ri is fluoro and R2 and R4 are hydrogen.
27. The compound of Claim 26 wherein R3 is alkyl. 28. The compound of Claim 19 wherein Ri is hydroxy.
29. The compound of Claim 28 wherein R3 is alkyl.
30. The compound of Claim 29 wherein R3 is n-butyl.
31. The compound of Claim 1 wherein Ri is hydroxy.
32. The compound of Claim 31 wherein R2 and R4 are hydrogen and R3 is alkyl.
33. The compound of Claim 31 wherein the
R6 R7 -HN χ „
Re R7
group is a group of formula:
_
\ J
wherein: n is i; and
R is
Figure imgf000176_0001
where Rι4 and Rj5 are independently selected from the group consisting of hydrogen, -(CrC12) alkyl, substituted alkyl, or heteroalkyl, -(Ci- Cι2) alkenyl, substituted alkenyl, or heteroalkenyl, -(Cι-C]2) alkynyl, substituted alkynyl, or heteroalkynyl, alkoxy, and -(Cj-Cs alkyl or substituted alkyl)n9-(C3-Cι2 arylene or heteroarylene)-(d-C8 alkyl or substituted alkyl)nιo where n9 and nlO are independently 0 or 1 ; or Rj4 and R15 combine to form a substituted or unsubstituted - (C4-Cιo)cyclic alkyl, cyclic heteroalkyl, aryl or heteroaryl group.
34. The compound of Claim 31 wherein the
Figure imgf000176_0002
group is a group of formula:
- <Y
wherein: n is 1 ; and R7 is
Figure imgf000177_0001
where Rι4 and R15 are each independently hydrogen or (Cι-C]2) alkyl, alkoxy, aryl, heteroaryl or Rι4 and Rι , when attached to the same carbon, combine to form a cyclic heteroalkyl, aryl or heteroaryl group.
35. The compound of Claim 31 wherein the
R6 R7 yγ>»
R6 R7
group is a group of formula:
R7
\ J
wherein: n is 1 ; and
R7 is -C(=O)NHRi5 where R15 is H or -(Cι-Cι2) alkyl, aryl, or heteroaryl or -C(=O)NR]4Ri5 where Rι4 and Rι5 form a substituted or unsubstituted -(C4-Cιo)cyclic heteroalkyl.
36. The compound of Claim 31 wherein the
Figure imgf000177_0002
group is a group of formula:
R7
\ J) n wherein: n is 1 ; and
R is n-butylaminocarbonyl, tert-butylaminocarbonyl, benzylaminocarbonyl, 1 , 1 -dimethylpropylaminocarbonyl, 2-(cyclohexen- 1 -yl)-ethylaminocarbonyl, indan- 5 -ylaminocarbonyl, 4,5-dimethylthiazol-2-ylaminocarbonyl, 4- phenoxyphenylaminocarbonyl, cyclopropylmethyl-aminocarbonyl, pyridin-2- ylaminocarbonyl, pyridin-3 -ylaminocarbonyl, pyridin-4-ylmethylaminocarbonyl, morpholin-4-ylcarbonyl, 3,4-methylenedioxy-phenylaminocarbonyl, quinolin-3- ylaminocarbonyl, methylaminocarbonyl, 4-biphenylaminocarbonyl, 3- phenoxyphenylaminocarbonyl, 3,4-dichlorophenyl-aminocarbonyl, 4-tert- butylphenylaminocarbonyl, 4-tert-butylaminocarbonyl, indan-2-ylaminocarbonyl, 2,2-dimethylpropylaminocarbonyl, 4-phenylthiazol-2-ylaminocarbonyl, 5- phenylthiadiazol-2-ylaminocarbonyl, 5-ethylthiadiazol-3-ylaminocarbonyl, thiadiazol- 2-ylaminocarbonyl, 3-trifluoromethoxyphenyl-aminocarbonyl, 2,5- dimethylphenylaminocarbonyl, 2,5-dimethoxyphenylamino-carbonyl, 3,4- dichlorophenylaminocarbonyl, benzthiazol-2-ylaminocarbonyl, 3- phenoxyphenylaminocarbonyl, 2-hydroxybutylaminocarbonyl, 4-hydroxybutyl- aminocarbonyl, 1 ,4-benzodioxan-6-ylaminocarbonyl, isoquinolin-6-ylaminocarbonyl, methylaminocarbonyl, thiazol-2-ylaminocarbonyl, 4-mefhylthiazol-2-yl- aminocarbonyl, 3-methylbutyl-aminocarbonyl, n-pentylaminocarbonyl, cyclohexylaminocarbonyl, 5-methylthiazol-2-ylaminocarbonyl, 4-methylthiazol-2-yl- aminocarbonyl, 2,4-dimethoxyphenyl-aminocarbonyl, 3,4-methylenedioxyphen-5-yl- meth ylaminocarbonyl, allylaminocarbonyl, 2-methylallylaminocarbonyl, pyrrolidin-1- ylcarbonyl, ethylaminocarbonyl, phenylaminocarbonyl, indan-1 -ylaminocarbonyl, 2-methoxyethylaminocarbonyl, indan-5-ylaminocarbonyl, 3,4-difluorophenyl- aminocarbonyl, 5-methylisoxazol-5-ylaminocarbonyl, 3-fluorophenylaminocarbonyl, 4-fluorophenylaminocarbonyl, N-methyl-N-phenylaminocarbonyl, 2-propylamino- carbonyl, 2-phenylpropylaminocarbonyl, n-propylaminocarbonyl, N-ethyl-N-(n- butyl)aminocarbonyl, benzylaminocarbonyl, thiazolidin-1 -ylcarbonyl, piperazin- 1-yl- carbonyl, piperidin- 1 -ylcarbonyl, azetidin- 1 -ylcarbonyl, homopiperdin- 1 -ylcarbonyl, pyrimidin-2-ylaminocarbonyl, 4-methylpiperazin-l -ylcarbonyl, 4-methylpyrimidin- 2-ylaminocarbonyl, pyrimidin-4-ylaminocarbonyl, pyrazin-2-ylaminocarbonyl, imidazol-2-ylaminocarbonyl.
37. The compound of Claim 31 wherein the
Figure imgf000179_0001
group is a group of formula:
Figure imgf000179_0002
wherein: n is 1 ; and
R7 is piperidin- 1 -ylcarbonyl, azetidin-1 -ylcarbonyl, ethylaminocarbonyl, phenylaminocarbonyl, pyrimidin-2-ylaminocarbonyl, or thiazol-2 -ylaminocarbonyl; and the stereochemistry at the C2 carbon atom of the pyrrolidine ring, i.e., carbon carrying the R7 group is (S).
38. The compound of Claim 31 wherein the
Figure imgf000179_0003
group is a group of formula:
NOι wherein: n is i; and
R7 is -C(=O)ORι where Rι4 is hydrogen or -(Cι-Cι2) alkyl, alkoxy, aryl, or heteroaryl.
39. The compound of Claim 31 wherein the
Figure imgf000180_0001
group is a group of formula:
*' <Y
wherein: n is 1 ; and
R7 is -C(=O)ORι4 where Rι is alkyl; and the stereochemistry at the C2 carbon atom of the pyrrolidine ring is (S).
40. The compound of Claim 32-38 wherein R3 is n-butyl.
41. The compound of Claim 13-19 wherein R2 and I t are hydrogen.
42. The compound of Claim 41 wherein Ri is hydroxy.
43. The compound of Claim 42 wherein R3 is alkyl.
44. The compound of Claim 41 wherein R3 is n-butyl.
45. The compound of Claim 1 selected from the group consisting of:
N-hydroxy-3-[(S)-(n-butyl)-3-(2-(S)- 1 , 1 -dimethylethyloxycarbonyl)- pyrrolidin- 1 -carbonyl)]-2-(S)-fluoropropionamide;
N-hydroxy-3-[(S)-(n-butyl)-3-(2-(S)-pyridin-l-ylcarbonyl)pyrrolidin-l- carbonyl)]-2-(S)-fluoropropionamide;
N-hydroxy-3-[(S)-(n-butyl)-3-(2-(S)-azetidin-l-ylcarbonyl)-pyrrolidin-l- carbonyl)]-2-(S)-fluoropropionamide;
N-hydroxy-3-[(S)-(n-butyl)-3-(2-(S)-ethylaminocarbonyl)pyrrolidin-l- carbonyl)]-2-(S)-fluoropropionamide; N-hydroxy-3-[(S)-(n-butyl)-3-(2-(S)-phenylaminocarbonyl)-pyrrolidin-l- carbonyl)]-2-(S)-hydroxypropionamide;
N-hydroxy-3-[(S)-(n-butyl)-3-(2-(S)-pyrimidin-2-ylaminocarbonyl)pyrrolidin- 1 -carbonyl)] -2-(S)-hydroxypropionamide; and
N-hydrδxy-3-[(S)-(n-butyl)-3-(2-(S)-thiazol-2-ylaminocarbonyl)-pyrrolidin-l- carbonyl)]-2-(S)-fluoropropionamide. 46. A pharmaceutical composition comprising a therapeutically effective amount of a compound of Claims 1-45 and a pharmaceutically acceptable excipient.
47. A method of treatment of a disease in a mammal treatable by administration of a peptidyl deformylase inhibitor which method comprises administration of a pharmaceutical composition comprising a therapeutically effective amount of a compound of Claim 1-45 and a pharmaceutically acceptable excipient.
48. The method of Claim 47 wherein the disease is a bacterial disease.
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