WO2004087643A1 - Deformylase inhibitor, process for preparing the same, and antibacterial composition comprising the same - Google Patents

Deformylase inhibitor, process for preparing the same, and antibacterial composition comprising the same Download PDF

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Publication number
WO2004087643A1
WO2004087643A1 PCT/KR2004/000502 KR2004000502W WO2004087643A1 WO 2004087643 A1 WO2004087643 A1 WO 2004087643A1 KR 2004000502 W KR2004000502 W KR 2004000502W WO 2004087643 A1 WO2004087643 A1 WO 2004087643A1
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Prior art keywords
methyl
hydroxycarbamoyl
urea
carbamoyl
cyclopentylmethyl
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PCT/KR2004/000502
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French (fr)
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Bong-Jin Lee
Seung-Kyu Lee
Kwang-Hyun Choi
Sang-Jae Lee
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Promeditech Inc.
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Publication of WO2004087643A1 publication Critical patent/WO2004087643A1/en

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    • B42—BOOKBINDING; ALBUMS; FILES; SPECIAL PRINTED MATTER
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
    • C07D295/135—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
    • B—PERFORMING OPERATIONS; TRANSPORTING
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    • C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C275/28—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C275/28—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C275/30—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by halogen atoms, or by nitro or nitroso groups
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C275/28—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C275/32—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by singly-bound oxygen atoms
    • C07C275/34—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by singly-bound oxygen atoms having nitrogen atoms of urea groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C275/28—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C275/38—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by doubly-bound oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C275/28—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C275/42—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
    • C07K5/06034—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06191—Dipeptides containing heteroatoms different from O, S, or N
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/04—Systems containing only non-condensed rings with a four-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
    • C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated

Definitions

  • the present invention relates to a novel compound useful for a deformylase inhibitor, and more particularly, to a novel compound useful for a deformylase inhibitor with excellent antibacterial activity or a pharmaceutically acceptable salt thereof, a process for preparing the same, and an antibacterial composition comprising the same as an active ingredient.
  • Deformylase is metallopeptidase found in prokaryotes sich as bacteria. In prokaryotes, protein synthesis is initiated with N-formyl methionine (fMet). The formyl group is removed by deformylase before a protein reaches its mature form. Since such deformylation is a prerequisite for protein maturation, it is known that deformylase is essential for bacterial growth (Chang et al, J. Bacteriol. Ill: 4071-4072(1989); Meinnel T, Blanquet S, /. Bacteriol. 176(23): 7387-90(1994); Mazel D et. al, EMBO J. 13(4): 914-23(1994)). fbwever, fMet is not a requisite for initiation of eukaryotic protein synthesis, and thus, deformylase inhibitors can be effectively used as antibacterial agents with broad-spectrum.
  • fbwever fMet is not a requisite for initiation of
  • Deformylase inhibitors are disclosed in WO 02/102791 (pyrrolidine bicyclic derivatives), WO 02/102790 (N-formyl hydroxyl amine derivatives), WO 01/44179 (suxinate derivatives), WO 01/44178 (urea derivatives), and WO 01/85170 (petide derivatives).
  • the present invention provides a novel compound useful for a deformylase inhibitor with multi-polypeptide bonds and a process for preparing the same.
  • the present invention also provides an antibacterial composition comprising the compound as an active ingredient.
  • R is a straight or branched C C alkyl group; or a C ⁇ C alkyl
  • R is a straight or branched C ⁇ C alkyl group
  • X is a phenyl group; or a heteroaryl group selected from the group consisting of 1,4-benzodioxolyl, pyridinyl, quinolinyl, and benzothiazolyl (wherein, the phenyl group or the heteroaryl group may be substituted with 1 to 3 substituent(s) selected from the group consiting of C ⁇ C alkyl, C ⁇ C alkoxy, hydroxy, halogen, cyano,
  • R , R , and X are the same as defined above and R is C ⁇ C alkyl.
  • an antibacterial composition comprising a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
  • R is a straight or branched C C alkyl group; or a C ⁇ C alkyl
  • R is a straight or branched C ⁇ C alkyl group
  • X is a phenyl group; or a heteroaryl group selected from the group consisting of 1,4-benzodioxolyl, pyridinyl, quinolinyl, and benzothiazolyl (wherein, the phenyl group or the heteroaryl group may be substituted with 1 to 3 substituent(s) selected from the group consiting of C ⁇ C alkyl, C ⁇ C alkoxy, hydroxy, halogen, cyano,
  • X is a phenyl group substituted with 1 to 3 substituent(s) selected from the group consiting of C ⁇ C
  • X is a heteroaryl group selected from the group consisting of 1,4-benzodioxolyl, pyridinyl, quinolinyl, and benzothiazolyl, which may be substituted with 1 or 2 substituent(s) selected from the group consiting of C ⁇ C alkyl, C ⁇ C alkoxy, and halogen.
  • the compounds of formula (I) are : [20] l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-butylcarbamoyl)-2,2-dimethylpropyl)- 3-(3-chlorophenyl)urea;
  • a compound of the present invention may be in the form of a pharmaceutically acceptable salt, hydrate(s), or solvate(s).
  • the pharmaceutically acceptable salts which may be applied to a compound of the present invention include, but are not limited to, hydrochloride, hydrobromide, sulfate, methylsulfonate, p-tolunesulfonate, phosphate, acetate, citrate, suxinate, lactate, tartarate, fumarate, malate, a sodium salt, a magnesium salt, and a calcium salt.
  • a compound of the present invetnion may also be in the form of racemates or optical isomers due to presence of chiral centers. Therefore, a compound of the present invention includes both racemates and optical isomers.
  • R , R , and X are the same as defined above and R is C ⁇ C alkyl.
  • Reacting the compound of formula (II) with hydroxyl amine may be carried out in a lower alkanol solvent sich as methanol and ethanol at room temperature for about 3 to 6 hours.
  • a compound of formula (III) or its salt e.g., HCl salt
  • R , R , R , and X are the same as defined above and R is chloro or imidazole.
  • organic solvent sich as dichloromethane, acetonitrile, tetrahydrofuran, dimethyl sulfoxide, and toluene
  • a base such as tri- ethylamine, N,N-diisopropylethylamine, and N-methylmorpholine.
  • organic solvent sich as dichloromethane, acetonitrile, tetrahydrofuran, dimethyl sulfoxide, and toluene, with stirring under reflux.
  • the compound of formula (III) or its salt may be obtained by a process comprising (a) reacting a compound of formula (V) with a compound of formula (VI); and then (b) deprotecting the predict of Step (a):
  • R , R , and R are the same as defined above and R is a amino protecting group.
  • the amino protecting group may be a commonly used protecting group, for example, t-butoxycarbonyl, benzyloxycarbonyl, or p-nitrobenzyloxycarbonyl.
  • the compound of formula (V) may be obtained by reacting a compound of formula (VII) or its salt with a compound of formula (VIII) in the presence of a base:
  • R and R are the same as defined above and Z is chloro, p-tolunesulfonyl, or methanesulfonyl.
  • the base that can be used in reacting the compound of formula (VII) or its salt with the compound of formula (VIII) may be an inorganic base sich as potassium carbonate, sodium bicarbonate (NaHCO ), and cesium carbonate. Reacting the
  • compound of formula (VII) or its salt with the compound of formula (VIII) may be carried out in a solvent sich as acetonitrile, acetone, methanol, and ethanol.
  • the present invention also provides an antibacterial composition
  • an antibacterial composition comprising a therapeutically effective amount of the compound of formula (I) or its pharmaceutically acceptable salt and a pharmaceutically acceptable carrier.
  • the composition of the present invetnion is useful for treating patients or animals with bacterial infections by administration or spreading over infected skins.
  • the composition of the present invetion is also useful for antibacterial purification and disinfection.
  • the composition of the present invetnion may be orally or parenterally administered.
  • the composition of the present invention for oral administration may be in the form of tablet, capsule, powder, granule, solution, suspension, or gel, and may comprise common additives sich as a diluent, a disintegrating agent, and a lubricant.
  • the additives include a diluent sich as syrup, Arabic gum, gellatin, sorbitol, lactose, power, corn starch, calcium phosphate, glycine, magenesium stearate, talc, polyethylene glycol, silica, potato starch, and sodium lauryl sulfate, a flavorant, and a colorant.
  • the composition (e.g., injection) of the present invention for parenteral administration may be an isotonic solution or may be sterilized.
  • the composition of the present invention may comprise common additives such as a preservative and a stabilizer.
  • the antibacterial composition of the present invetnion may be administered in an average adult (about 70 kg) dosage of about 7mg/day to 35 g/day for antibacterial treatment.
  • An adequate dosage is determined depending on the type and the degree of severity of diseases.
  • an average adult dosage may comprise about 0.7 mg to 2.8 g of the compound of the present invention together with a pharmaceutically acceptable carrier.
  • Step 1 Butylaminoacetic acid ethyl ester
  • Step 2 [((S)-2-tert-butoxycarbonylamino-3,3-dimethylbutyryl)butylamino]acetic acid ethyl ester
  • Step 4 (butyl- ⁇ (S)-2-[3-(3-chlorophenyl)ureido]-3,3-dimethylbutyryl ⁇ amino)acetic acid ethyl ester
  • Step 5 l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-butylcarbamoyl)-2,2-dimethylpropyl)-3-(
  • Example 1 except that bromomethylcyclohexane, p- tolunesulfonylmethylcyclopentane, l-p-tolunesulfonyl-3-methylbutane, l-p-tolunesulfonyl-2-cyclopentylethane, or p-tolunesulfonylmethylcyclobutane was used instead of 1-bromobutane of Step 1, L-N-t-butoxycarbonyl-valine, L- N-t-butoxycarbonyl-leicine, or L-N-t-butoxycarbonyl-isoleicine was used instead of L-N-t-butoxycartonyl-t-butyl-leicine of Step 2, or substituted isccyanate was used instead of 3-chlorophenylisccyanate of Step 4.
  • Example 36 l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(2-cyclopentylethyl)carbamoyl)-2,2-dimet hylpropyl)-3-(2-methoxyphenyl)urea [299] 'H-NMRTCDCl ) ⁇ 1.03 (m, 13H), 1.46-1.77 (m, 7H), 3.60-4.65 (m, 8H), 6.29 (bs,
  • Example 62 l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(2-cyclopentylethyl)carbamoyl)-2-methyl propyl)-3-(2,5-difluorophenyl)urea [377] 1H-NMR(CDC1 ) ⁇ 0.92-114 (m, 8H), 1.57-2.05 (m, 1(H), 319-4.55 (m, 5H),
  • Example 72 l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-isopentylcarbamoyl)-2-methylpropyl)-3-(
  • Example 80 l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-isopentylcarbamoyl)-2,2-dimethylpropyl)
  • Example 84 l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(2-cyclopentylethyl)carbamoyl)-2,2-dimet hylpropyl)-3-(5-chloro-2-methoxyphenyl)urea [443] 'H-NMRrCDCl ) ⁇ 1.04 (m, 1 IH), 1.43 - 1.76 (m, 7H), 3.00 - 4.69 (m, 8H), 6.57
  • Step 1 Cyclopentylmethylaminoacetic acid ethyl ester
  • Step 2 [(2S-t-butoxycarbonylamino-3,3-dimethylbutyryl)cyclopentylmethylamino] acetic acid ethyl ester
  • N-t-butoxycarbonyl-phenylalanine 0.5 g, 2.2 mmol
  • dichloromathane solution 4.3 ml
  • cyclopentylmethylaminoacetic acid ethyl ester 0.4 g, 2.2 mmol
  • the reaction mixture was stirred at room temperature for 18 hours and washed with distilled water and a solution of 1 N HCl.
  • the organc layer was dried on anhydrous sodium sulfate and concentrated under vacuum.
  • the resultant concentrate was purified by silica gel chromatography to give 0.5 g (yield 57.4%) of the title compound.
  • Step 3 [(2S-amino-3,3-dimethylbutyryl)cyclopentylamino]acetic acid ethyl ester hydrochloride
  • Step 4 (cyclopentylmethyl- ⁇ (S)-2-[(imidazol-l-carbonyl)amino] -
  • Step 5 ( ⁇ (S)-2-[3-(2 ;hloropyridin-3-yl)ureido] -
  • Step 6 l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclopentylmethyl)carbamoyl)-2,2-dimet hylpropyl)-3-(2-chloropyridin-3-yl)urea [495] A methanol solution (0.3 ml) of 3 M KOH was dropwise added to a methanol solution (0.3 ml) of 2 M NH OH HCl and then stirred for 30 minutes. The precipitate
  • Example 94 except that l-p-toluenesulfonyl-3-methylbutane, l-p-toluenesulfonyl-2-cyclopentylethane, or p-toluenesulfonylmethylcyclobutane was used instead of p-toluenesulfonylmethylcyclopentane of Step 1, L- N-t-butoxycarbonyl-valine was used instead of L-N-t-butoxycarbonyl-t-butyl-leicine of Step 2, or substituted amine was used instead of 3-amino-2-chloropyridine of Step
  • Example 100 l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclopentylmethyl)carbamoyl)-2,2-dimet hy lpropy 1) -3 - (5 - (trifluoromethyl) -2-morpholinopheny l)urea [516] 1H-NMR(CDC1 ) ⁇ 1.02 (s, 9H), 1.24 (m, 2H), 2.21 (m, IH), 2.88 (m, 4H),
  • Example 104 l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclopentylmethyl)carbamoyl)-2,2-dimet hylpropyl)-3-(5-fluoro-2-(pyrrolidin-l-yl)phenyl)urea [528] 'H-NMRrCDCl ) ⁇ 1.03 (s, 9H), 1.23 (m, 2H), 1.56-1.71 (m, 1CH), 2.20 (m, IH),
  • Deformylase-producing bacteria strains (Novagen, America, cat. no. 69041) were inoculated into 50 °C LB media (tryptone 8g/l, yeast extract 5g/l, NaCl 5g/l, IN NaOH 2.5ml) containing ampicillin and then cultured at 37 °C . The cultures were then inoculated into new LB media (3L) with the same composition as in the above- described LB media. When O.D (660 nm) reached 0.5, protein expression was indiced by addition of 1 mM isopropyl- ⁇ -D-thiogalactopyranoside to the LB media.
  • cell pellets were harvested by centrifugation, incubated at -80 °C for 30 minutes, resuspended in a phosphate buffer, followed by lysis of bacteria cells by sonification with 8 seconds interval between each pulse (1 second). The supernatant was obtained by ultracentrifugation, loaded onto an affinity column, followed by elution with an elution buffer. The eluted fractions containing peptide deformylase were identified by SDS-PAGE, followed by elution by gel chromatography. At this time, a buffer containing 5 mM NiCl was used as a stabilizer for the enzyme source, and SDS-
  • the purified enzyme source was kept at -80 °C until use.
  • each of the compounds prepared in Examples was dissolved in dimethyl sulfoxide to a concentration of 2 mM. 7 ⁇ Jl of each of the reaction mixtures was loaded into each well of microtiter plates.
  • the deformylase as prepared in section (1) was diluted with a buffer (50mM HEPES, pH7.0, lOmM NaCl, 5mM NiCl , 0.1% Triton X-100) to a con-
  • the obtained samples were treated with 50 ⁇ i of fluorescamine and 50 ⁇ i of 50 mM borate-sodium hydroxide buffer (pH 9.5) to measure fluorescence at an excitation wavelength of 390 nm and an emission wavelength of 465 nm. Based on the fluorescence thus measured, the concentrations (IC ) of the samples that decrease
  • Hemophilus influenza and Moraxella cararrhalis were inoculated into culture media such as brain heart infusion (37 g/1, Ditco, America) supplemented with NAD lOmg/1 and hemin 5mg/l and then cultured for 24 and 48 hours, respectively.
  • Streptococcus pneumoniae was inoculated into GC media containing 5% horse serum and cultured for 48 hours. The cultures were diluted to a concentration of 1 x 10 CFU/ml and inoculated into wells of microtiter plates. After incubation at 37 °C , 5% CO for 24 hours for Hemophilus influenza and 48 hours for Moraxella

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Abstract

Provided are a novel compound useful for a deformylase inhibitor with excellent antibacterial activity or a pharmaceutically acceptable salt thereof, a process for preparing the same, and an antibacterial composition including the same as an active ingredient. The deformylase inhibitor effectively acts against a broad spectrum of bacteria, including bacteria with resistance to existing antibacterial agents.

Description

Description DEFORMYLASE INHIBITOR, PROCESS FOR PREPARING THE SAME, AND ANTIBACTERIAL COMPOSITION COMPRISING THE SAME
Technical Field
[1] The present invention relates to a novel compound useful for a deformylase inhibitor, and more particularly, to a novel compound useful for a deformylase inhibitor with excellent antibacterial activity or a pharmaceutically acceptable salt thereof, a process for preparing the same, and an antibacterial composition comprising the same as an active ingredient. Background Art
[2] Deformylase is metallopeptidase found in prokaryotes sich as bacteria. In prokaryotes, protein synthesis is initiated with N-formyl methionine (fMet). The formyl group is removed by deformylase before a protein reaches its mature form. Since such deformylation is a prerequisite for protein maturation, it is known that deformylase is essential for bacterial growth (Chang et al, J. Bacteriol. Ill: 4071-4072(1989); Meinnel T, Blanquet S, /. Bacteriol. 176(23): 7387-90(1994); Mazel D et. al, EMBO J. 13(4): 914-23(1994)). fbwever, fMet is not a requisite for initiation of eukaryotic protein synthesis, and thus, deformylase inhibitors can be effectively used as antibacterial agents with broad-spectrum.
[3] Deformylase inhibitors are disclosed in WO 02/102791 (pyrrolidine bicyclic derivatives), WO 02/102790 (N-formyl hydroxyl amine derivatives), WO 01/44179 (suxinate derivatives), WO 01/44178 (urea derivatives), and WO 01/85170 (petide derivatives).
[4] E wever, development of novel deformylase inhibitors which are active against a broad spectrum of bacteria, including bacteria with resistance to existing antibacterial agents, is still required. Disclosure of Invention
[5] The present invention provides a novel compound useful for a deformylase inhibitor with multi-polypeptide bonds and a process for preparing the same. The present invention also provides an antibacterial composition comprising the compound as an active ingredient.
[6] In one aspect of the present invention, there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof:
Figure imgf000003_0001
[7] wherein, R is a straight or branched C C alkyl group; or a C ~ C alkyl
6 1 2 substituted with a C C cycloalkyl group,
6
[8] R is a straight or branched C ~ C alkyl group,
1 6 [9] X is a phenyl group; or a heteroaryl group selected from the group consisting of 1,4-benzodioxolyl, pyridinyl, quinolinyl, and benzothiazolyl (wherein, the phenyl group or the heteroaryl group may be substituted with 1 to 3 substituent(s) selected from the group consiting of C ~ C alkyl, C ~ C alkoxy, hydroxy, halogen, cyano,
1 4 1 4 nitro, acetyl, phenyl, trifluoromethyl, trifluoromethoxy, methanesulfonyl, piperidinyl, morpholinyl, pyrrolidinyl, and benzoyl).
[10] In another aspect of the present invention, there is provided a process for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, which comprises reacting a compound of formula (II) with hydroxyl amine:
Figure imgf000003_0002
[11] wherein, R , R , and X are the same as defined above and R is C ~ C alkyl.
1 4 [12] In still another aspect of the present invention, there is provided an antibacterial composition comprising a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. Best Mode for Carrying Out the Invention
[13] In one aspect of the present invention, there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof:
Figure imgf000004_0001
[14] wherein, R is a straight or branched C C alkyl group; or a C ~ C alkyl
6 1 2 substituted with a C C cycloalkyl group,
6
[15] R is a straight or branched C ~ C alkyl group,
1 6 [16] X is a phenyl group; or a heteroaryl group selected from the group consisting of 1,4-benzodioxolyl, pyridinyl, quinolinyl, and benzothiazolyl (wherein, the phenyl group or the heteroaryl group may be substituted with 1 to 3 substituent(s) selected from the group consiting of C ~ C alkyl, C ~ C alkoxy, hydroxy, halogen, cyano,
1 4 1 4 nitro, acetyl, phenyl, trifluoromethyl, trifluoromethoxy, methanesulfonyl, piperidinyl, morpholinyl, pyrrolidinyl, and benzoyl).
[17] Among the compounds of the present invention, preferably X is a phenyl group substituted with 1 to 3 substituent(s) selected from the group consiting of C ~ C
1 4 alkyl, C ~ C alkoxy, hydroxy, halogen, cyano, nitro, acetyl, phenyl, trifluoromethyl,
1 4 trifluoromethoxy, methanesulfonyl, piperidinyl, morpholinyl, pyrrolidinyl, and benzoyl.
[18] Further, among the compounds of the present invention, preferably X is a heteroaryl group selected from the group consisting of 1,4-benzodioxolyl, pyridinyl, quinolinyl, and benzothiazolyl, which may be substituted with 1 or 2 substituent(s) selected from the group consiting of C ~ C alkyl, C ~ C alkoxy, and halogen.
1 4 1 4
[19] More preferably, the compounds of formula (I) are : [20] l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-butylcarbamoyl)-2,2-dimethylpropyl)- 3-(3-chlorophenyl)urea;
[21] l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclopentylmethyl)carbamoyl)-2,2-di methylpropyl)-3-(3-chlorophenyl)urea;
[22] l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(2-cyclopentylethyl)carbamoyl)-2,2-di methylpropyl)-3-(3-chlorophenyl)urea;
[23] l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(2-cyclopentylethyl)carbamoyl)-2,2-di methylpropyl)-3-p-tolylurea;
[24] l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(2-cyclopentylethyl)carbamoyl)-2,2-di methylpropyl)-3-m-tolylurea; [25] l-((S)-l-(N-((hydroxycarbamoyl)methyl ■N-(2-cyclopentylethyl)carbamoyl)-2,2-di methylpropyl)-3-(3-methoxyphenyl)urea; [26] l-((S)-l-(N-((hydroxycarbamoyl)methyl ■N-(cyclopentylmethyl)carbamoyl)-2,2-di methylpropyl)-3-m-tolylurea; [27] l-((S)-l-(N-((hydroxycarbamoyl)methyl ■N-(cyclohexylmethyl)carbamoyl)-2,2-di methylpropyl)-3-(3-chlorophenyl)urea; [28] l-((S)-l-(N-((hydroxycarbamoyl)methyl ■N-(cyclohexylmethyl)carbamoyl)-2,2-di methylpropyl)-3-m-tolylurea; [29] l-((S)-l-(N-((hydroxycarbamoyl)methyl ■N-(cyclohexylmethyl)carbamoyl)-2,2-di methylpropyl)-3-(3-methoxyphenyl)urea [30] l-((S)-l-(N-((hydroxycarbamoyl)methyl ■N-(cyclopentylmethyl)carbamoyl)-2,2-di methylpropyl)-3-(biphenyl-4-yl)urea; [31] l-((S)-l-(N-((hydroxycarbamoyl)methyl ■N-(cyclopentylmethyl)carbamoyl)-2,2-di methylpropyl)-3-(2-methoxyphenyl)urea; [32] l-((S)-l-(N-((hydroxycarbamoyl)methyl ■N-(cyclopentylmethyl)carbamoyl)-2,2-di methylpropyl)-3-(2-chlorophenyl)urea; [33] l-((S)-l-(N-((hydroxycarbamoyl)methyl ■N-(cyclopentylmethyl)carbamoyl)-2,2-di methylpropyl)-3-(3-cyanophenyl)urea; [34] l-((S)-l-(N-((hydroxycarbamoyl)methyl ■N-isopentylcarbamoyl)-2,2-dimethylprop yl)-3-(3-chlorophenyl)urea; [35] l-((S)-l-(N-((hydroxycarbamoyl)methyl ■N-isopentylcarbamoyl)-2,2-dimethylprop yl)-3-p-tolylurea; [36] l-((S)-l-(N-((hydroxycarbamoyl)methyl ■N-isopentylcarbamoyl)-2,2-dimethylprop yl)-3-m-tolylurea; [37] l-((S)-l-(N-((hydroxycarbamoyl)methyl ■N-isopentylcarbamoyl)-2,2-dimethylprop yl)-3-(3-methoxyphenyl)urea; [38] l-((S)-l-(N-((hydroxycarbamoyl)methyl ■N-(θ)Clopentylmethyl)carbamoyl)-2,2-di methylpropyl)-3-(4-cyanophenyl)urea; [39] l-((S)-l-(N-((hydroxycarbamoyl)methyl ■N-(cyclopentylmethyl)carbamoyl)-2,2-di methylpropyl)-3-(3-fluorophenyl)urea; [40] 1-((S)- l-(N-((hydroxycarbamoyl)methyl ■N-(cyclopentylmethyl)carbamoyl)-2,2-di methylpropyl)-3-(2-fluorophenyl)urea; [41] l-((S)-l-(N-((hydroxycarbamoyl)methyl ■N-(cyclopentylmethyl)carbamoyl)-2,2-di methylpropyl)-3-(4-fluorophenyl)urea; [42] 1-((S)- l-(N-((hydroxycarbamoyl)methyl ■N-(cyclopentylmethyl)carbamoyl)-2,2-di methylpropyl)-3-(2-nitrophenyl)urea; [43] l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclopentylmethyl)carbamoyl)-2,2-di methylpropyl)-3-(3-nitrophenyl)urea; [44] l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclopentylmethyl)carbamoyl)-2,2-di methylpropyl)-3-(2,3-dichlorophenyl)urea; [45] l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclopentylmethyl)carbamoyl)-2,2-di methylpropyl)-3-(2,4-dichlorophenyl)urea; [46] l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclopentylmethyl)carbamoyl)-2,2-di methylpropyl)-3-(2,5-dichlorophenyl)urea; [47] l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclopentylmethyl)carbamoyl)-2,2-di methylpropyl)-3-(3,4-dichlorophenyl)urea [48] l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclopentylmethyl)carbamoyl)-2,2-di methylpropyl)-3-(3,5-dichlorophenyl)urea; [49] l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclopentylmethyl)carbamoyl)-2,2-di methylpropyl)-3-(4-nitrophenyl)urea; [50] l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclopentylmethyl)carbamoyl)-2,2-di me thy lpropy 1)- 3 - (4- acety lpheny l)urea ; [51] 1-((S)- l-(N-((hydroxycarbamoyl)methyl)-N-(cyclopentylmethyl)carbamoyl)-2,2-di methylpropyl)-3-(4-(trifluoromethoxy)phenyl)urea; [52] l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclopentylmethyl)carbamoyl)-2,2-di methylpropyl)-3-(benzo[d][l,3]dioxol-5-yl)urea; [53] l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(2-cyclopentylethyl)carbamoyl)-2,2-di methylpropyl)-3-(2,4-dichlorophenyl)urea; [54] l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(2-cyclopentylethyl)carbamoyl)-2,2-di methylpropyl)-3-(2,5-dichlorophenyl)urea; [55] l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(2-cyclopentylethyl)carbamoyl)-2,2-di methylpropyl)-3-(2-methoxyphenyl)urea; [56] l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-isopentylcarbamoyl)-2,2-dimethylprop yl)-3-(2,4-dichlorophenyl)urea; [57] l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-isopentylcarbamoyl)-2,2-dimethylprop yl)-3-(2,5-dichlorophenyl)urea; [58] l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-isopentylcarbamoyl)-2,2-dimethylprop yl)-3-(3,4-dichlorophenyl)urea; [59] l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-isopentylcarbamoyl)-2,2-dimethylprop yl)-3-(2-methoxyphenyl)urea; [60] l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclopentylmethyl)carbamoyl)-2,2-di methylpropyl)-3-(4-(trifluoromethyl)phenyl)urea; [61] l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclopentylmethyl)carbamoyl)-2,2-di methylpropyl)-3-(2-ethylphenyl)urea; [62] l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclopentylmethyl)carbamoyl)-2,2-di methylpropyl)-3-(2-ethoxyphenyl)urea; [63] l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclopentylmethyl)carbamoyl)-2,2-di methylpropyl)-3-(3,4-difluorophenyl)urea; [64] l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclopentylmethyl)carbamoyl)-2,2-di methylpropyl)-3-(3,5-difluorophenyl)urea; [65] l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclopentylmethyl)carbamoyl)-2,2-di methylpropyl)-3-(2,5-difluorophenyl)urea; [66] l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclopentylmethyl)carbamoyl)-2-met hylpropyl)-3-(2-methoxyphenyl)urea; [67] l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclopentylmethyl)carbamoyl)-2-met hylpropyl)-3-(2-chlorophenyl)urea; [68] l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclobutylmethyl)carbamoyl)-2,2-dim ethylpropyl)-3-(2-methoxyphenyl)urea; [69] l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclobutylmethyl)carbamoyl)-2,2-dim ethylpropyl)-3-(2-chlorophenyl)urea; [70] l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclobutylmethyl)carbamoyl)-2-meth ylpropyl)-3-(2-methoxyphenyl)urea; [71] 1-((S)- l-(N-((hydroxycarbamoyl)methyl)-N-(cyclobutylmethyl)carbamoyl)-2-meth ylpropyl)-3-(2-chlorophenyl)urea; [72] l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclobutylmethyl)carbamoyl)-2-meth ylpropyl)-3-(3-chlorophenyl)urea; [73] l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclobutylmethyl)carbamoyl)-2-meth ylpropyl)-3-(2,4-dichlorophenyl)urea; [74] l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclobutylmethyl)carbamoyl)-2-meth ylpropyl)-3-(2-fluorophenyl)urea; [75] l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclobutylmethyl)carbamoyl)-2-meth ylpropyl)-3-(2,4-difluorophenyl)urea; [76] l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(2-cyclopentylethyl)carbamoyl)-2-met hylpropyl)-3-(2-methoxyphenyl)urea; [77] l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(2-cyclopentylethyl)carbamoyl)-2-met hylpropyl)-3-(2-chlorophenyl)urea; [78] l-((S)-l-(N-((hydroxycarbamoyl)methyl ■N-(2-cyclopentylethyl)carbamoyl)-2-met hylpropyl)-3-(3,4-dichlorophenyl)urea; [79] l-((S)-l-(N-((hydroxycarbamoyl)methyl ■N-(2-cyclopentylethyl)carbamoyl)-2-met hylpropyl)-3-(2,4-dichlorophenyl)urea; [80] l-((S)-l-(N-((hydroxycarbamoyl)methyl ■N-(2-cyclopentylethyl)carbamoyl)-2-met hylpropyl)-3-(2,5-dichlorophenyl)urea; [81] l-((S)-l-(N-((hydroxycarbamoyl)methyl ■N-(2-cyclopentylethyl)carbamoyl)-2-met hylpropyl)-3-(2,5-difluorophenyl)urea; [82] l-((S)-l-(N-((hydroxycarbamoyl)methyl ■N-(cyclopentylmethyl)carbamoyl)-2-met hylpropyl)-3-(2,4-dichlorophenyl)urea; [83] l-((S)-l-(N-((hydroxycarbamoyl)methyl ■N-(cyclopentylmethyl)carbamoyl)-2-met hylpropyl)-3-(2,5-dichlorophenyl)urea; [84] l-((S)-l-(N-((hydroxycarbamoyl)methyl ■N-(cyclopentylmethyl)carbamoyl)-2-met hylpropyl)-3-(2,5-difluorophenyl)urea; [85] l-((S)-l-(N-((hydroxycarbamoyl)methyl ■N-(cyclobutylmethyl)carbamoyl)-2-meth ylpropyl)-3-(3,4-dichlorophenyl)urea; [86] l-((S)-l-(N-((hydroxycarbamoyl)methyl ■N-(cyclobutylmethyl)carbamoyl)-2-meth ylpropyl)-3-(2,5-dichlorophenyl)urea; [87] l-((S)-l-(N-((hydroxycarbamoyl)methyl ■N-(cyclobutylmethyl)carbamoyl)-2-meth ylpropyl)-3-(2,5-difluorophenyl)urea; [88] l-((S)-l-(N-((hydroxycarbamoyl)methyl ■N-isopentylcarbamoyl)-2-methylpropyl)-
3 - (2-methoxypheny l)urea; [89] l-((S)-l-(N-((hydroxycarbamoyl)methyl ■N-isopentylcarbamoyl)-2-methylpropyl)-
3 - (2-chloropheny l)urea; [90] l-((S)-l-(N-((hydroxycarbamoyl)methyl ■N-isopentylcarbamoyl)-2-methylpropyl)-
3-(2,4-dichlorophenyl)urea; [91] l-((S)-l-(N-((hydroxycarbamoyl)methyl ■N-isopentylcarbamoyl)-2-methylpropyl)-
3-(2,5-dichlorophenyl)urea; [92] l-((S)-l-(N-((hydroxycarbamoyl)methyl ■N-isopentylcarbamoyl)-2-methylpropyl)-
3-(2,5-difluorophenyl)urea; [93] l-((S)-l-(N-((hydroxycarbamoyl)methyl ■N-(cyclopentylmethyl)carbamoyl)-2,2-di mmeethylpropyl)-3-(5-chloro-2-methoxyphenyl)urea; [94] l-((S)-l-(N-((hydroxycarbamoyl)methyl ■N-(cyclopentylmethyl)carbamoyl)-2,2-di methylpropyl)-3-(2-(trifluoromethoxy)phenyl)urea; [95] l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclopentylmethyl)carbamoyl)-2-met hylbutyl)-3-(2,5-dichlorophenyl)urea; [96] l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclopentylmethyl)carbamoyl)-3-met hylbutyl)-3-(2,5-dichlorophenyl)urea; [97] l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclobutylmethyl)carbamoyl)-2,2-dim ethylpropyl)-3-(2,5-dichlorophenyl)urea; [98] l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclobutylmethyl)carbamoyl)-2,2-dim ethylpropyl)-3-(2,4-dichlorophenyl)urea; [99] l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-isopentylcarbamoyl)-2,2-dimethylprop y 1) - 3 -(2-chloropheny l)urea ; [100] l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(2-cyclopentylethyl)carbamoyl)-2,2-di methylpropyl)-3-(2-chlorophenyl)urea; [101] l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclobutylmethyl)carbamoyl)-2,2-dim ethylpropyl)-3-(5-chloro-2-methoxyphenyl)urea; [102] l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-isopentylcarbamoyl)-2,2-dimethylprop yl)-3-(5-chloro-2-methoxyphenyl)urea; [103] l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(2-cyclopentylethyl)carbamoyl)-2,2-di methylpropyl)-3-(5-chloro-2-methoxyphenyl)urea; [104] l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclobutylmethyl)carbamoyl)-2-meth ylpropyl)-3-(5-chloro-2-methoxyphenyl)urea; [105] l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclopentylmethyl)carbamoyl)-2-met hylpropyl)-3-(5-chloro-2-methoxyphenyl)urea; [106] l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-isopentylcarbamoyl)-2-methylpropyl)-
3 - (5 -chloro-2-methoxypheny l)urea ; [107] l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(2-cyclopentylethyl)carbamoyl)-2-met hylpropyl)-3-(5-chloro-2-methoxyphenyl)urea; [108] l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclobutylmethyl)carbamoyl)-2,2-dim ethylpropyl)-3-(2,5-dimethoxyphenyl)urea; [109] l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclobutylmethyl)carbamoyl)-2,2-dim ethylpropyl)-3-(2-methoxy-5-methylphenyl)urea; [110] l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclobutylmethyl)carbamoyl)-2-meth ylpropyl)-3-(2-methoxy-5-methylphenyl)urea; [111] l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclobutylmethyl)carbamoyl)-2,2-dim ethylpropyl)-3-(2,4-dimethoxyphenyl)urea; [112] l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclobutylmethyl)carbamoyl)-2-meth ylpropyl)-3-(2,4-dimethoxyphenyl)urea; 113] l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclopentylmethyl)carbamoyl ■2,2-di methylpropyl)-3-(2-chloropyridin-3-yl)urea; 114] l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclopentylmethyl)carbamoyl ■2,2-di methylpropyl)-3-(4-chloro-2-methoxy-5-methylphenyl)urea; 115] l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclopentylmethyl)carbamoyl ■2,2-di methylpropyl)-3-(2-benzoyl-3-chlorophenyl)urea; 116] l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclopentylmethyl)carbamoyl ■2,2-di methylpropyl)-3-(quinolin-8-yl)urea; 117] l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclopentylmethyl)carbamoyl ■2,2-di methylpropyl)-3-(benzo[d]thiazol-6-yl)urea; 118] l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclopentylmethyl)carbamoyl ■2,2-di methylpropyl)-3-(2-(piperidin-l-yl)phenyl)urea; 119] l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclopentylmethyl)carbamoyl ■2,2-di me thy lpropy 1)- 3 - (5 - (trifluoromethyl) -2-morpholinopheny l)urea; 120] l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclopentylmethyl)carbamoyl ■2,2-di methylpropyl)-3-(3-chloro-4-morpholinophenyl)urea; 121] l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclopentylmethyl)carbamoyl ■2,2-di methylpropyl)-3-(quinolin-5-yl)urea; 122] l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclopentylmethyl)carbamoyl ■2,2-di methylpropyl)-3-(2-(pyrrolidin-l-yl)phenyl)urea; 123] l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclopentylmethyl)carbamoyl ■2,2-di methylpropyl)-3-(5-fluoro-2-(pyrrolidin-l-yl)phenyl)urea; 124] l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclopentylmethyl)carbamoyl ■2,2-di methylpropyl)-3-(5-fluoro-2-(piperidin-l-yl)phenyl)urea; T25] l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclopentylmethyl)carbamoyl ■2,2-di methylpropyl)-3-(5-fluoro-2-morpholinophenyl)urea; 126] l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclopentylmethyl)carbamoyl ■2,2-di methylpropyl)-3-(3-fluoro-4-(pyrrolidin-l-yl)phenyl)urea; 127] l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclopentylmethyl)carbamoyl ■2,2-di methylpropyl)-3-(3-fluoro-4-(piperidin-l-yl)phenyl)urea; 128] l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclopentylmethyl)carbamoyl ■2,2-di methylpropyl)-3-(3-fluoro-4-morpholinophenyl)urea; 129] l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclopentylmethyl)carbamoyl ■2,2-di methylpropyl)-3-(5-chloroquinolin-8-yl)urea; l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclopentylmethyl)carbamoyl)-2,2-di methylpropyl)-3-(2-chloro-4-(methylsulfonyl)phenyl)urea; l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclobutylmethyl)carbamoyl)-2,2-dim ethylpropyl)-3-(4-chloro-2-methoxy-5-methylphenyl)urea; l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclobutylmethyl)carbamoyl)-2,2-dim ethylpropyl)-3-(5-fluoro-2-(pyrrolidin-l-yl)phenyl)urea; l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclobutylmethyl)carbamoyl)-2,2-dim ethylpropyl)-3-(quinolin-8-yl)urea; l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-isopentylcarbamoyl)-2,2-dimethylprop yl)-3-(4-chloro-2-methoxy-5-methylphenyl)urea; l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-isopentylcarbamoyl)-2,2-dimethylprop yl)-3-(quinolin-8-yl)urea; l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(2-cyclopentylethyl)carbamoyl)-2,2-di methylpropyl)-3-(4-chloro-2-methoxy-5-methylphenyl)urea; l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(2-cyclopentylethyl)carbamoyl)-2,2-di methylpropyl)-3-(5-fluoro-2-(pyrrolidin-l-yl)phenyl)urea; l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(2-cyclopentylethyl)carbamoyl)-2,2-di methylpropyl)-3-(quinolin-8-yl)urea; l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclobutylmethyl)carbamoyl)-2-meth ylpropyl)-3-(4-chloro-2-methoxy-5-methylphenyl)urea; l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclobutylmethyl)carbamoyl)-2-meth ylpropyl)-3-(5-fluoro-2-(pyrrolidin-l-yl)phenyl)urea l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclobutylmethyl)carbamoyl)-2-meth ylpropyl)-3-(quinolin-8-yl)urea; l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclopentylmethyl)carbamoyl)-2-met hylpropyl)-3-(4-chloro-2-methoxy-5-methylphenyl)urea; l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclopentylmethyl)carbamoyl)-2-met hylpropyl)-3-(5-fluoro-2-(pyrrolidin-l-yl)phenyl)urea; l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclopentylmethyl)carbamoyl)-2-met hylpropyl)-3-(quinolin-8-yl)urea; l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-isopentylcarbamoyl)-2-methylpropyl)-
3-(4-chloro-2-methoxy-5-methylphenyl)urea; l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-isopentylcarbamoyl)-2-methylpropyl)-
3 - (quinolin- 8 - y l)urea; l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(2-cyclopentylethyl)carbamoyl)-2-met hylpropyl)-3-(4-chloro-2-methoxy-5-methylphenyl)urea;
[148] l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(2-cyclopentylethyl)carbamoyl)-2-met hylpropyl)-3-(5-fluoro-2-(pyrrolidin-l-yl)phenyl)urea; [149] l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(2-cyclopentylethyl)carbamoyl)-2-met hylpropyl)-3-(quinolin-8-yl)urea; [150] l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclobutylmethyl)carbamoyl)-2,2-dim ethylpropyl)-3-(6-methoxyquinolin-8-yl)urea; [151] 1 -((S)- 1 -(N-((hy droxycarbamoyl)methyl)-N-(cyclobutylmethyl)carbamoyl)-2-meth ylpropyl)-3-(6-methoxyquinolin-8-yl)urea; and [152] l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclobutylmethyl)carbamoyl)-2,2-dim ethylpropyl)-3-(2-hydroxyphenyl)urea. [153] A compound of the present invention may be in the form of a pharmaceutically acceptable salt, hydrate(s), or solvate(s). The pharmaceutically acceptable salts which may be applied to a compound of the present invention include, but are not limited to, hydrochloride, hydrobromide, sulfate, methylsulfonate, p-tolunesulfonate, phosphate, acetate, citrate, suxinate, lactate, tartarate, fumarate, malate, a sodium salt, a magnesium salt, and a calcium salt.
[154] A compound of the present invetnion may also be in the form of racemates or optical isomers due to presence of chiral centers. Therefore, a compound of the present invention includes both racemates and optical isomers.
[155] In accordance with another aspect of the present invention, there is provided a process for preparing the compound of formula (I) or its pharmaceutically acceptable salt. In other words, there is provided a process for preparing the compound of formula (I) or its pharmaceutically acceptable salt, which comprises reacting a compound of formula (II) with hydroxy 1 amine:
Figure imgf000012_0001
[156] wherein, R , R , and X are the same as defined above and R is C ~ C alkyl.
1 4 [157] Reacting the compound of formula (II) with hydroxyl amine may be carried out in a lower alkanol solvent sich as methanol and ethanol at room temperature for about 3 to 6 hours.
[158] The compound of formula (II) may be obtained by reacting a compound of formula (III) or its salt (e.g., HCl salt) with 0=C=N-X. And also, the compound of formula (II) may obtained by a process comprising reacting a compound of formula (III) or its salt with triphosgen or 1,1 '-carbonyldiimidazole to obtain a compound of formula (IV); and then reacting the compound of formula (IV) with NH -X.
2
Figure imgf000013_0001
[159] wherein, R , R , R , and X are the same as defined above and R is chloro or imidazole.
[160] Preferably, reacting the compound of formula (III) or its salt with 0=C=N-X may be carried out in an organic solvent sich as dichloromethane, acetonitrile, tetrahydrofuran, dimethyl sulfoxide, and toluene in the presence of a base such as tri- ethylamine, N,N-diisopropylethylamine, and N-methylmorpholine.
[161] Reacting the compound of formula (IV) with NH -X may be carried out in an
2 organic solvent sich as dichloromethane, acetonitrile, tetrahydrofuran, dimethyl sulfoxide, and toluene, with stirring under reflux.
[162] The compound of formula (III) or its salt may be obtained by a process comprising (a) reacting a compound of formula (V) with a compound of formula (VI); and then (b) deprotecting the predict of Step (a):
Figure imgf000013_0002
Figure imgf000014_0001
[163] wherein, R , R , and R are the same as defined above and R is a amino protecting group. [164] The amino protecting group may be a commonly used protecting group, for example, t-butoxycarbonyl, benzyloxycarbonyl, or p-nitrobenzyloxycarbonyl. [165] The compound of formula (V) may be obtained by reacting a compound of formula (VII) or its salt with a compound of formula (VIII) in the presence of a base:
Figure imgf000014_0002
-R (VIII)
1 3
[166] wherein, R and R are the same as defined above and Z is chloro, p-tolunesulfonyl, or methanesulfonyl.
[167] The base that can be used in reacting the compound of formula (VII) or its salt with the compound of formula (VIII) may be an inorganic base sich as potassium carbonate, sodium bicarbonate (NaHCO ), and cesium carbonate. Reacting the
3 compound of formula (VII) or its salt with the compound of formula (VIII) may be carried out in a solvent sich as acetonitrile, acetone, methanol, and ethanol.
[168] The present invention also provides an antibacterial composition comprising a therapeutically effective amount of the compound of formula (I) or its pharmaceutically acceptable salt and a pharmaceutically acceptable carrier. The composition of the present invetnion is useful for treating patients or animals with bacterial infections by administration or spreading over infected skins. The composition of the present invetion is also useful for antibacterial purification and disinfection.
[169] The composition of the present invetnion may be orally or parenterally administered. The composition of the present invention for oral administration may be in the form of tablet, capsule, powder, granule, solution, suspension, or gel, and may comprise common additives sich as a diluent, a disintegrating agent, and a lubricant. Examples of the additives include a diluent sich as syrup, Arabic gum, gellatin, sorbitol, lactose, suger, corn starch, calcium phosphate, glycine, magenesium stearate, talc, polyethylene glycol, silica, potato starch, and sodium lauryl sulfate, a flavorant, and a colorant. The composition (e.g., injection) of the present invention for parenteral administration may be an isotonic solution or may be sterilized. In this case, the composition of the present invention may comprise common additives such as a preservative and a stabilizer.
[170] The antibacterial composition of the present invetnion may be administered in an average adult (about 70 kg) dosage of about 7mg/day to 35 g/day for antibacterial treatment. An adequate dosage is determined depending on the type and the degree of severity of diseases. In this regard, an average adult dosage may comprise about 0.7 mg to 2.8 g of the compound of the present invention together with a pharmaceutically acceptable carrier.
[171] The following Examples are given for the purpose of illustration only, and are not intended to limit the scope of the invention.
[172] Example 1. l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-butylcarbamoyl)-2,2-dimethylpropyl)-3-( 3 -chloropheny l)urea
[173] The title compound was prepared according to the following Scheme 1:
[174] Scheme 1
Figure imgf000015_0001
[175] Step 1: Butylaminoacetic acid ethyl ester
[176] An acetonitrile suspension (358 ml) of glycine ethyl ester hydrochloride (10 g, 71.6 mmol), 1-bromobutane (7.7 ml, 71.6 mmol), and potassium carbonate (9.9 g, 71.6 mmol) was heated at 60 °C and then stirred for 18 hours. The precipitate was removed by filtration of the reaction suspension and the filtrate was concentrated under vacuum. The resultant concentrate was purified by silica gel chromatography to give 4 g (yield 35%) of the title compound.
[177] 1H-NMR(CDC1 ) δ 0.91 (t, J=7.2Hz, 3H), 1.28 (t, 1=7.1Hz, 3H,), 1.34 (m, 2H),
3
1.46 (m, 2H), 2.60 (t, 1=7.1 Hz, 2H), 3.40 (s, 2H), 4.19 (q, J=14.3Hz, J=7.4Hz, 2H) [178]
[179] Step 2: [((S)-2-tert-butoxycarbonylamino-3,3-dimethylbutyryl)butylamino]acetic acid ethyl ester
[180] 1-hydroxybenzotriazole (3.0 g, 22.1 mmol), l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (4.2 g, 22.1 mmol), N,N-diisopropylethylamine (6.3 ml, 36.7 mmol), and L- N-t-butoxycarbonyl-t-butyl-leicine (3.4 g, 14.7 mmol) were added to a dichloromethane solution (73 ml) of butylaminoacetic acid ethyl ester (2.3 g, 14.7 mmol). The reaction mixture was stirred at room temperature for 18 hours and then washed with distilled water and a solution of IN HCl. The organic layer was dried on anhydrous sodium sulfate and concentrated under vacuum. The resultant concentrate was purified by silica gel chromatography to give 4.3 g (yield 78%) of the title compound.
[181] 'H-NMRrCDCl ) δ 1.02 (m, 12H), 1.24 - 1.58 (m, 16H), 3.2 (m, 1H), 3.6 (m, 2H),
3
4.17 (m, 2.5H), 4.54 (m, 1.5H), 5.25 (m, 1H)
[182]
[183] Step 3: (S)-l-(butylethoxycarbonylmethylcarbamoyl)-2,2-dimethylpropylamine hydrochloride
[ 184] A 1 ,4-dioxane solution (3.4 ml) of 4N HCl was added to
[((S)-2-tert-butoxycarbonylamino-3,3-dimethylbutyryl)butylamino]acetic acid ethyl ester (4.2 g, 11.3 mmol). The reaction mixture was stirred at room temperature for 18 hours and then concentrated under vacuum. The resultant concentrate was used in the next step without further purification.
[185]
[186] Step 4: (butyl-{(S)-2-[3-(3-chlorophenyl)ureido]-3,3-dimethylbutyryl}amino)acetic acid ethyl ester
[187] Triethylamine (0.1 ml, 0.70 mmol) and 3-chlorophenylisccyanate (0.04 ml, 0.31 mmol) were added to a dichlorometane solution (0.9 ml) of
(S)- 1 -(butylethoxycarbonylmethylcarbamoyl)-2,2-dimethylpropylamine hydrochloride (0.1 g, 0.35 mmol). The reaction mixture was stirred at room temperature for 18 hours and then washed with water. The organic layer was dried on anhydrous sodium sulfate and concentrated under vacuum. The resultant concentrate was purified by silica gel chromatography to give 0.05 g (yield 40%) of the title compound.
[188] 'H-NMRrCDCl ) δ 0.88-1.04 (m, 12H), 1.26-1.70 (m, 7H), 3.40-5.25 (m, 7H),
3
6.87-7.54 (m, 4H) [189]
[190] Step 5: l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-butylcarbamoyl)-2,2-dimethylpropyl)-3-(
3 -chloropheny l)urea [191] A methanol solution (0.5 ml) of 3 M KOH was drop wise added to a methanol solution (0.5 ml) of 2 M NH OH HCl and stirred for 30 minutes. The precipitate was
2 removed by filtration. Then, butyl- {(S)-2-[3-(3-chlorophenyl)ureido] - 3,3-dimethylbutyryl}amino)acetic acid ethyl ester (0.05 g, 0.12 mmol) was dissolved in the filtrate and stirred for 2 hours. After concentration and water addition, the reaction mixture was neutralized with a solution of 1 N HCl, extracted with dichloromethane, dried on anhydrous sodium sulfate, and concentrated under vacuum. The resultant concentrate was purified by silica gel chromatography to give 0.032 g (yield 61%) of the title compound. [192] 'H-NMRrCDCl ) δ 0.88-1.04 (m, 12H), 1.26-1.70 (m, 4H), 3.42-5.32(m, 5H),
3
6.87-7.54 (m, 4H)
[193]
[194] The compounds of the following Examples were prepared in the same manner as in
Example 1 except that bromomethylcyclohexane, p- tolunesulfonylmethylcyclopentane, l-p-tolunesulfonyl-3-methylbutane, l-p-tolunesulfonyl-2-cyclopentylethane, or p-tolunesulfonylmethylcyclobutane was used instead of 1-bromobutane of Step 1, L-N-t-butoxycarbonyl-valine, L- N-t-butoxycarbonyl-leicine, or L-N-t-butoxycarbonyl-isoleicine was used instead of L-N-t-butoxycartonyl-t-butyl-leicine of Step 2, or substituted isccyanate was used instead of 3-chlorophenylisccyanate of Step 4.
[195]
[196] Example 2. l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclopentylmethyl)carbamoyl)-2,2-dimet hy lpropy 1) -3 - (3 -chloropheny l)urea
[197] 'H-NMRrCDCl ) δ 1.03 (s, 9H), 1.22-1.67 (m, 8H), 219(m, 1H), 3.37-4.64 (m,
3
5H), 6.92-7.49(m, 4H) [198] [199] Example 3. l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(2-cyclopentylethyl)carbamoyl)-2,2-dimet hy lpropy 1) -3 - (3 -chloropheny l)urea [200] 1H-NMR(CDC1 ) δ 1.01-111 (m, 13H), 1.44-1.78(m, 7H), 3.55-4.79 (m, 5H),
3 6.92-7.5 l(m, 4H) [201] [202] Example 4. l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(2-cyclopentylethyl)carbamoyl)-2,2-dimet hylpropyl)-3-p-tolylurea [203] 'H-NMRrCDCl ) δ 1.00-111 (m, 13H), 1.51-1.77 (m, 7H), 1.28 (s, 3H), 3.41-4.51
3
(m, 5H), 7.06-7.25 (m, 4H) [204] [205] Example 5. l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(2-cyclopentylethyl)carbamoyl)-2,2-dimet hylpropyl)-3-m-tolylurea [206] 'H-NMRTCDCl ) δ 0.98-1.01 (m, 13H), 1.48-1.75 (m, 7H), 1.29 (s, 3H), 3.58-4.62
3
(m, 5H), 6.82-7.23(m, 4H) [207] [208] Example 6. l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(2-cyclopentylethyl)carbamoyl)-2,2-dimet hylpropyl)-3-(3-methoxyphenyl)urea [209] 1H-NMR(CDC1 ) δ 0.92-112 (m, 13H), 1.50-1.75 (m, 7H), 3.58-4.62 (m, 8H),
3
6.54-7.23 (m, 4H), 7.63 (s, 1H) [210] [211] Example 7. l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclopentylmethyl)carbamoyl)-2,2-dimet hylpropyl)-3-m-tolylurea [212] Ti-NMRTCDCl ) δ 1.01 (s, 9H), 115-1.67 (m, 8H), 217-2.27(m, 4H), 3.48-4.73
3
(m, 5H), 6.79-718 (m, 4H) [213] [214] Example 8. l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclohexylmethyl)carbamoyl)-2,2-dimet hy lpropy 1) -3 - (3 -chloropheny l)urea [215] 1H-NMR(CDC1 ) δ 1.00-1.28 (m, 15H), 1.63 (s, 5H), 3.42-4.73 (m, 5H), 6.69-7.41
(m, 4H) [216] [217] Example 9. l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclohexylmethyl)carbamoyl)-2,2-dimet hylpropyl)-3-m-tolylurea [218] 1H-NMR(CDC1 ) δ 1.00-1.28 (m, 15H), 1.62 (s, 5H), 2.26 (s, 3H), 3.42-4.73(m,
3
5H), 6.79-718 (m, 4H) [219] [220] Example 10. l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclohexylmethyl)carbamoyl)-2,2-dimet hylpropyl)-3-(3-methoxyphenyl)urea [221] Ti-NMRTCDCl ) δ 1.00-1.28 (m, 15H), 1.63 (s, 5H), 3.41-4.71(m, 8H), 6.50-712
(m, 4H) [222] [223] Example 11. l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclopentylmethyl)carbamoyl)-2,2-dimet hylpropyl)-3-(biphenyl-4-yl)urea [224] 1H-NMR(CDC1 ) δ 1.02 (s, 9H), 1.48 (m, 8H), 2.17 (m, 1H), 4.02 (m, 3H), 4.64
3
(m, 1H), 6.26 (m, 1H), 7.42 (m, lCTf), 7.89 (m, 1H) [225] [226] Example 12. l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclopentylmethyl)carbamoyl)-2,2-dimet hylpropyl)-3-(2-methoxyphenyl)urea [227] 'H-NMRTCDCl ) δ 1.04 (s, 9H), 1.48 (m, 8H), 2.18 (m, 1H), 3.57 (m, 1H), 3.81 (s,
3
3H), 4.10 (m, 3H), 4.64 (m, 1H), 6.28 (m, 1H), 6.85 (m, 3H), 7.45 (m, 1H), 8.00 (m,
1H) [228] [229] Example 13. l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclopentylmethyl)carbamoyl)-2,2-dimet hylpropyl)-3-(2-chlorophenyl)urea [230] 'H-NMRTCDCl ) δ 1.02 (s, 9H), 1.53 (m, 8H), 2.20 (m, 1H), 3.49 - 4.79 (m, 5H),
3
6.79 (m, 1H), 7.21 (m, 3H), 7.62 (m, 1H), 7.98 (m, 1H) [231] [232] Example 14. l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclopentylmethyl)carbamoyl)-2,2-dimet hylpropyl)-3-(3-cyanophenyl)urea [233] 1H-NMR(CDC1 ) δ 1.05 (s, 9H), 1.58 (m, 8H), 2.20 (m, 1H), 3.58 - 4.70 (m, 5H),
3
7.12 - 7.65 (m, 4H) [234] [235] Example 15. l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-isopentylcarbamoyl)-2,2-dimethylpropyl) - 3 - (3 -chloropheny l)urea [236] 1H-NMR(CDC1 ) δ 0.89-1.05 (m, 15H), 1.42-1.85 (m, 3H), 3.57-4.61(m, 5H),
3
6.87-7.53(m, 4H) [237] [238] Example 16. l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-isopentylcarbamoyl)-2,2-dimethylpropyl)
-3-p-tolylurea [239] 'H-NMRrCDCl ) δ 0.85-1.04 (m, 15H), 1.30-1.65 (m, 3H), 2.27 (s, 3H),
3
3.57-4.61(m, 5H), 6.87-7.53(m, 4H) [240] [241] Example 17. l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-isopentylcarbamoyl)-2,2-dimethylpropyl)
-3-m-tolylurea [242] 1H-NMR(CDC1 ) δ 0.85-1.02(m, 15H), 1.35-1.59 (m, 3H), 2.28(s, 3H),
3
3.58-4.57(m, 5H), 6.82-7.20(m, 4H) [243] [244] Example 18. l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-isopentylcarbamoyl)-2,2-dimethylpropyl)
-3-(3-methoxyphenyl)urea [245] 'H-NMRrCDCl ) δ 0.85-1.02 (m, 15H), 1.37-1.61 (m, 3H), 3.58-4.57(m, 8H),
3
6.54-7.13(m, 4H) [246] [247] Example 19. l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclopentylmethyl)carbamoyl)-2,2-dimet hylpropyl)-3-(4-cyanophenyl)urea [248] 1H-NMR(CDC1 ) δ 1.06 (s, 9H), 1.57 (m, 8H), 2.27 (m, 1H), 3.05 - 4.11 (m, 5H),
3
6.15 - 7.76 (m, 6H) [249] [250] Example 20. l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclopentylmethyl)carbamoyl)-2,2-dimet hylpropyl)-3-(3-fluorophenyl)urea [251] 'H-NMRrCDCl ) δ 1.05 (s, 9H), 1.53 (m, 8H), 2.24 (m, 1H), 3.51 - 4.80 (m, 5H),
3
6.61 - 8.09 (m, 6H) [252] [253] Example 21. l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclopentylmethyl)carbamoyl)-2,2-dimet hylpropyl)-3-(2-fluorophenyl)urea [254] 'H-NMRTCDCl ) δ 1.01 (s, 9H), 1.52 (m, 8H), 2.23 (m, 1H), 3.45 - 4.79 (m, 5H),
3
6.89 - 8.09 (m, 6H) [255] [256] Example 22. l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclopentylmethyl)carbamoyl)-2,2-dimet hylpropyl)-3-(4-fluorophenyl)urea [257] 1H-NMR(CDC1 ) δ 1.01 (s, 9H), 1.56 (m, 9H), 2.23 (m, 1H), 3.45 - 4.79 (m, 5H),
3
6.89 - 8.09 (m, 6H) [258] [259] Example 23. l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclopentylmethyl)carbamoyl)-2,2-dimet hylpropyl)-3-(2-nitrophenyl)urea [260] 'H-NMRTCDCl ) δ 1.02 (s, 9H), 1.54 (m, 8H), 2.20 (m, 1H), 3.50 - 4.88 (m, 5H),
3
6.97 - 8.49 (m, 4H) [261] [262] Example 24. l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclopentylmethyl)carbamoyl)-2,2-dimet hylpropyl)-3-(3-nitrophenyl)urea [263] 1H-NMR(CDC1 ) δ 1.02 (s, 9H), 1.55 (m, 8H), 2.21 (m, 1H), 3.59 - 4.88 (m, 5H),
3
6.74 - 8.25 (m, 6H) [264] [265] Example 25. l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclopentylmethyl)carbamoyl)-2,2-dimet hylpropyl)-3-(2,3-dichlorophenyl)urea [266] 'H-NMRrCDCl ) δ 1.02 (s, 9H), 110-1.74 (m, 8H), 2.19 (m, 1H), 3.48-4.80 (m,
3
5H), 6.70-8.28 (m, 4H) [267] [268] Example 26. l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclopentylmethyl)carbamoyl)-2,2-dimet hylpropyl)-3-(2,4-dichlorophenyl)urea [269] 'H-NMRTCDCl ) δ 1.03 (s, 9H), 1.05-1.68 (m, 8H), 2.19 (m, 1H), 3.48-4.84 (m,
3
5H), 6.75-8.30 (m, 5H) [270]
[271] Example 27. l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclopentylmethyl)carbamoyl)-2,2-dimet hylpropyl)-3-(2,5-dichlorophenyl)urea [272] 1H-NMR(CDC1 ) δ 1.03 (s, 9H), 110-1.67 (m, 8H), 2.22 (m, 1H), 3.48-4.81 (m,
3
5H), 6.70-810 (m, 5H) [273] [274] Example 28. l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclopentylmethyl)carbamoyl)-2,2-dimet hylpropyl)-3-(3,4-dichlorophenyl)urea [275] 'H-NMRrCDCl ) δ 1.03 (s, 9H), 1.25-1.69 (m, 8H), 2.25 (m, 1H), 3.47-4.72 (m,
3
5H), 7.21-7.65 (m, 3H) [276] [277] Example 29. l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclopentylmethyl)carbamoyl)-2,2-dimet hylpropyl)-3-(3,5-dichlorophenyl)urea [278] 1H-NMR(CDC1 ) δ 1.02 (s, 9H), 1.23-1.69 (m, 8H), 2.24 (m, 1H), 3.49-4.74 (m,
3
5H), 6.51-7.36 (m, 4H) [279] [280] Example 30. l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclopentylmethyl)carbamoyl)-2,2-dimet hylpropyl)-3-(4-nitrophenyl)urea [281] 1H-NMR(CDC1 ) δ 1.05 (s, 9H), 1.23-1.69 (m, 8H), 2.23 (m, 1H), 3.49-4.72 (m,
3
5H), 7.29-813 (m, 4H) [282] [283] Example 31. l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclopentylmethyl)carbamoyl)-2,2-dimet hy lpropy 1) -3 - (4- acety lpheny l)urea [284] 'H-NMRrCDCl ) δ 1.06 (s, 9H), 1.21-1.77 (m, 8H), 2.26 (m, 4H), 3.55-4.67 (m,
3
5H), 77.21-7.52 (m, 4H) [285] [286] Example 32. l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclopentylmethyl)carbamoyl)-2,2-dimet hylpropyl)-3-(4-(trifluoromethoxy)phenyl)urea [287] 1H-NMR(CDC1 ) δ 1.05 (s, 9H), 1.21-1.66 (m, 8H), 2.28 (m, 1H), 3.53-4.70 (m,
3 5H), 7.07-7.43 (m, 4H) [288] [289] Example 33. l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclopentylmethyl)carbamoyl)-2,2-dimet hylpropyl)-3-(benzo[d][l,3]dioxol-5-yl)urea [290] 'H-NMRTCDCl ) δ 0.99 (s, 9H), 1.60 (m, 8H), 2.24 (m, 1H), 3.54 - 3.91 (m, 3H),
3
4.25 (m, 1H), 4.52 (m, 1H), 5.92 (s, 2H), 6.72 - 6.95 (m, 3H) [291] [292] Example 34. l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(2-cyclopentylethyl)carbamoyl)-2,2-dimet hylpropyl)-3-(2,4-dichlorophenyl)urea [293] Ti-NMRTCDCl ) δ 1.02-1.11 (m, 13H), 1.45-1.76 (m, 7H), 3.48-4.69 (m, 5H), 6.81
3
(bs, 1H), 715-7.26 (m, 2H), 7.68 (s, 1H), 8.25 (m, 1H) [294] [295] Example 35. l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(2-cyclopentylethyl)carbamoyl)-2,2-dimet hylpropyl)-3-(2,5-dichlorophenyl)urea [296] 1H-NMR(CDC1 ) δ 1.03-112 (m, 13H), 1.41-1.88 (m, 7H), 3.53-4.75 (m, 5H),
3
6.84-717 (m, 2H), 7.69 (bs, 1H), 8.32 (s, 1H) [297] [298] Example 36. l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(2-cyclopentylethyl)carbamoyl)-2,2-dimet hylpropyl)-3-(2-methoxyphenyl)urea [299] 'H-NMRTCDCl ) δ 1.03 (m, 13H), 1.46-1.77 (m, 7H), 3.60-4.65 (m, 8H), 6.29 (bs,
3
1H), 6.82-6.99 (m, 2H), 7.92 (s, 1H), 8.07 (m, 1H) [300] [301] Example 37. l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-isopentylcarbamoyl)-2,2-dimethylpropyl)
-3-(2,4-dichlorophenyl)urea [302] 1H-NMR(CDC1 ) δ 0.80-1.03 (m, 15H), 1.51-1.62 (m, 3H), 3.54-4.67 (m, 5H), 6.85
3
(bs, 1H), 714-7.26 (m, 2H), 7.70 (s, 1H), 7.14 (m, 1H) [303] [304] Example 38. l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-isopentylcarbamoyl)-2,2-dimethylpropyl)
-3-(2,5-dichlorophenyl)urea [305] 1H-NMR(CDC1 ) δ 0.80-117 (m, 15H), 1.51-1.62 (m, 3H), 3.56-4.71 (m, 5H),
3
6.89-718 (m, 2H), 7.67(s, 1H), 8.32 (s, 1H) [306] [307] Example 39. l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-isopentylcarbamoyl)-2,2-dimethylpropyl)
-3-(3,4-dichlorophenyl)urea [308] 'H-NMRTCDCl ) δ 0.90-1.04 (m, 15H), 1.36-1.62 (m, 3H), 3.56-4.65 (m, 5H), 6.56
3
(bs, 1H), 716-7.33 (m, 2H), 7.68 (s, 1H), 8.62 (m, 1H) [309] [310] Example 40. l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-isopentylcarbamoyl)-2,2-dimethylpropyl)
-3-(2-methoxyphenyl)urea [311] 1H-NMR(CDC1 ) δ 0.82-1.04 (m, 15H), 1.28-1.68 (m, 3H), 3.59-4.63 (m, 8H), 6.24
3
(bs, 1H), 6.83-1.99 (m, 2H), 7.44 (m, 1H), 8.06 (m, 1H) [312] [313] Example 41. l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclopentylmethyl)carbamoyl)-2,2-dimet hylpropyl)-3-(4-(trifluoromethyl)phenyl)urea [314] 'H-NMRrCDCl ) δ 1.10 (S, 9H), 1.28 (m, 2H), 1.63 (m, 6H), 2.30 (m, 1H),
3
3.61-4.75 (m, 5H), 7.52 (m, 4H) [315] [316] Example 42. l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclopentylmethyl)carbamoyl)-2,2-dimet hylpropyl)-3-(2-ethylphenyl)urea [317] 1H-NMR(CDC1 ) δ 0.99 (s, 9H), 1.22 (m, 5H), 1.61 (m, 6H), 2.22 (m, 1H), 2.65
3
(m, 2H), 3.53-4.62 (m, 5H), 7.31 (m, 4H) [318] [319] Example 43. l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclopentylmethyl)carbamoyl)-2,2-dimet hylpropyl)-3-(2-ethoxyphenyl)urea [320] 'H-NMRrCDCl ) δ 1.04 (s, 9H), 1.20 (m, 2H), 1.40-1.70 (m, 9H), 2.24 (m, 1H),
3
3.45-4.76 (m, 7H), 5.90 (m, 1H), 6.85-716 (m, 4H) [321] [322] Example 44. l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclopentylmethyl)carbamoyl)-2,2-dimet hylpropyl)-3-(3,4-difluorophenyl)urea [323] 'H-NMRTCDCl ) δ 1.03 (s, 9H), 1.26 (m, 2H), 1.55-1.76 (m, 6H), 2.25 (m, 1H),
3
3.40 - 4.72 (m, 5H), 6.34 (m, 1H), 6.55 (m, 1H), 6.98 (m, 2H), 8.75 (m, 1H) [324] [325] Example 45. l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclopentylmethyl)carbamoyl)-2,2-dimet hylpropyl)-3-(3,5-difluorophenyl)urea [326] 1H-NMR(CDC1 ) δ 1.04 (s, 9H), 1.24 (m, 2H), 1.54-1.86 (m, 6H), 2.23 (m, 1H),
3
3.40 - 4.70 (m, 5H), 6.48 (m, 1H), 6.98 (m, 2H), 7.51 (m, 1H), 8.60 (m, 2H) [327] [328] Example 46. l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclopentylmethyl)carbamoyl)-2,2-dimet hylpropyl)-3-(2,5-difluorophenyl)urea [329] 'H-NMRTCDCl ) δ 0.97 (s, 9H), 1.20 (m, 2H), 1.48-1.62 (m, 6H), 2.18 (m, 1H),
3
315-4.74 (m, 5H), 6.73 (m, 1H), 7.22 (m, 2H), 8.00 (m, 2H), 8.83 (m, 2H) [330] [331] Example 47. l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclopentylmethyl)carbamoyl)-2-methyl propy 1) -3 - (2-methoxypheny l)urea [332] 1H-NMR(CDC1 ) δ 0.96-1.28 (m, 8H), 1.53-216 (m, 8H), 3.20-4.52 (m, 8H),
3
6.71-6.91 (m, 4H), 7.57-811 (m, 2H) [333] [334] Example 48. l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclopentylmethyl)carbamoyl)-2-methyl propy 1) -3 - (2-chloropheny l)urea [335] 'H-NMRrCDCl ) δ 0.97-1.28 (m, 8H), 1.57-217 (m, 8H), 3.37-4.56 (m, 5H),
3
6.87-7.26 (m, 4H), 7.63 (m, 1H), 8.12 (m, 1H) [336] [337] Example 49.
1 -((S)- 1 -(N-((hydroxycarbamoyl)methyl)-N-(cyclobutylmethyl)carbamoyl)-2,2-dimeth ylpropyl)-3-(2-methoxyphenyl)urea [338] 1H-NMR(CDC1 ) δ 1.04 (s, 9H), 1.75-2.04 (m, 6H), 2.65 (m, 1H), 3.53-4.70 (m,
3
8H), 6.15 (bs, 1H), 6.84-6.98 (m, 3H), 7.51 (m, 1H), 8.07 (m, 1H) [339] [340] Example 50. 1 -((S)- 1 -(N-((hydroxycarbamoyl)methyl)-N-(cyclobutylmethyl)carbamoyl)-2,2-dimeth y lpropy 1) -3 - (2-chloropheny l)urea [341] 1H-NMR(CDC1 ) δ 1.03 (s, 9H), 1.75-2.05 (m, 6H), 2.65 (m, 1H), 3.72-4.75 (m,
3
5H), 6.20 (bs, 1H), 6.90-7.30 (m, 3H), 7.56 (m, 1H), 8.29 (m, 1H) [342] [343] Example 51.
1 -((S)- 1 -(N-((hydroxycarbamoyl)methyl)-N-(cyclobutylmethyl)carbamoyl)-2-methylp ropy 1) -3 - (2-methoxypheny l)urea [344] 'H-NMRrCDCl ) δ 0.94-0.02 (m, 6H), 1.80-2.08 (m, 7H), 2.60 (m, 1H), 3.52-4.5
3
(m, 8H), 6.74-6.93 (m, 4H), 7.63-810 (m, 2H) [345] [346] Example 52.
1 -((S)- 1 -(N-((hydroxycarbamoyl)methyl)-N-(cyclobutylmethyl)carbamoyl)-2-methylp ropy 1) -3 - (2-chloropheny l)urea [347] 1H-NMR(CDC1 ) δ 0.96-1.02 (m, 6H), 1.74-1.90 (m, 7H), 2.62 (m, 1H), 3.53-4.54
3
(m, 8H), 6.87-7.26 (m, 4H), 7.69-8.65 (m, 2H) [348] [349] Example 53.
1 -((S)- 1 -(N-((hydroxycarbamoyl)methyl)-N-(cyclobutylmethyl)carbamoyl)-2-methylp ropyl)-3-(3-chlorophenyl)urea [350] 'H-NMRrCDCl ) δ 0.95-1.04 (m, 6H), 1.83-211 (m, 7H), 2.65 (m, 1H), 3.30-4.67
3
(m, 5H), 6.93-7.22( m, 3H), 7.54 (s, 1H) [351] [352] Example 54.
1 -((S)- 1 -(N-((hydroxycarbamoyl)methyl)-N-(cyclobutylmethyl)carbamoyl)-2-methylp ropyl)-3-(2,4-dichlorophenyl)urea [353] 1H-NMR(CDC1 ) δ 0.96-1.03 (m, 6H), 1.77-2.09 (m, 7H), 2.57 (m, 1H), 3.53-4.46
3
(m, 5H), 7.09-811 (m, 3H) [354] [355] Example 55.
1 -((S)- 1 -(N-((hydroxycarbamoyl)methyl)-N-(cyclobutylmethyl)carbamoyl)-2-methylp ropy 1) -3 - (2-fluoropheny l)urea [356] 'H-NMRrCDCl ) δ 0.94-1.04 (m, 6H), 1.75-2.04 (m, 7H), 2.62 (m, 1H), 3.52-4.53
3
(m, 5H), 6.82-7.05 (m, 4H), 7.75-811 (m, 2H) [357] [358] Example 56.
1 -((S)- 1 -(N-((hydroxycarbamoyl)methyl)-N-(cyclobutylmethyl)carbamoyl)-2-methylp ropyl)-3-(2,4-difluorophenyl)urea [359] 'H-NMRrCDCl ) δ 0.94-1.05 (m, 6H), 1.73-2.05 (m, 7H), 2.62 (m, 1H), 3.52-4.51
3
(m, 5H), 6.53-6.99 (m, 3H), 7.66-7.99 (m, 2H) [360] [361] Example 57. l-((S)-l-(N-((h ydroxy- carbamoyl)methyl)-N-(2-cyclopentylethyl)carbamoyl)-2-methylpropyl)-3-(2-methoxy phenyl)urea [362] 1H-NMR(CDC1 ) δ 0.96-110 (m, 8H), 1.33-2.05 (m, 1(H), 310-4.46 (m, 8H),
3
6.78-6.93 (m, 4H), 7.62-810 (m, 2H) [363] [364] Example 58. l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(2-cyclopentylethyl)carbamoyl)-2-methyl propy 1) -3 - (2-chloropheny l)urea [365] Ti-NMRTCDCl ) δ 0.95-111 (m, 8H), 1.33-2.05 (m, 1(H), 319-4.50 (m, 5H),
3
6.85-7.26 (m, 4H), 7.74-817 (m, 2H) [366] [367] Example 59. l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(2-cyclopentylethyl)carbamoyl)-2-methyl propyl)-3-(3,4-dichlorophenyl)urea [368] 1H-NMR(CDC1 ) δ 0.95-115 (m, 8H), 1.53-2.00 (m, 1(H), 319-4.41 (m, 5H),
3
711-7.56(m, 3H) [369] [370] Example 60. l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(2-cyclopentylethyl)carbamoyl)-2-methyl propyl)-3-(2,4-dichlorophenyl)urea [371] Ti-NMRTCDCl ) δ 0.96115 (m, 8H), 1.51-2.01 (m, 1(H), 319-4.41 (m, 5H),
3
7.07-812 (m, 3H) [372] [373] Example 61. l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(2-cyclopentylethyl)carbamoyl)-2-methyl propyl)-3-(2,5-dichlorophenyl)urea [374] Ti-NMRTCDCl ) δ 0.95-111 (m, 8H), 1.54-2.05 (m, 1(H), 319-4.54 (m, 5H),
3
6.8-8.29 (m, 5H) [375]
[376] Example 62. l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(2-cyclopentylethyl)carbamoyl)-2-methyl propyl)-3-(2,5-difluorophenyl)urea [377] 1H-NMR(CDC1 ) δ 0.92-114 (m, 8H), 1.57-2.05 (m, 1(H), 319-4.55 (m, 5H),
3
6.49-7.92 (m, 5H) [378] [379] Example 63. l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclopentylmethyl)carbamoyl)-2-methyl propyl)-3-(2,4-dichlorophenyl)urea [380] Ti-NMRTCDCl ) δ 1.04-1.25 (m, 8H), 1.47-1.81 (m, 6H), 2.17 (m, 2H), 3.55-4.60
3
(m, 5H), 6.66-7.05 (m, 2H), 7.62-8.56 (m, 3H) [381] [382] Example 64. l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclopentylmethyl)carbamoyl)-2-methyl propyl)-3-(2,5-dichlorophenyl)urea [383] 1H-NMR(CDC1 ) δ 0.99 (m, 6H), 1.23 (m, 2H), 1.58-217 (m, 8H), 3.71-4.60 (m,
3
5H), 6.82-712 (m, 2H), 7.68-8.31 (m, 2H) [384] [385] Example 65. l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclopentylmethyl)carbamoyl)-2-methyl propyl)-3-(2,5-difluorophenyl)urea [386] 1H-NMR(CDC1 ) δ 0.92-1.07(m, 6H), 1.26 (m, 2H), 1.60-216 (m, 8H), 3.35-4.60
3
(m, 5H), 6.48 (m, 1H), 6.90 (m, 1H), 7.26-7.92 (m, 3H) [387] [388] Example 66.
1 -((S)- 1 -(N-((hydroxycarbamoyl)methyl)-N-(cyclobutylmethyl)carbamoyl)-2-methylp ropyl)-3-(3,4-dichlorophenyl)urea [389] 'H-NMRrCDCl ) δ 0.99 (m, 6H), 1.76-211 (m, 7H), 2.61 (m, 1H), 3.20-4.48 (m,
3
5H), 7.12-7.6 l (m, 3H) [390] [391] Example 67.
1 -((S)- 1 -(N-((hydroxycarbamoyl)methyl)-N-(cyclobutylmethyl)carbamoyl)-2-methylp ropyl)-3-(2,5-dichlorophenyl)urea [392] 1H-NMR(CDC1 ) δ 0.99 (m, 6H), 1.78-2.07 (m, 7H), 2.60 (m, 1H), 3.53-4.58 (m,
3 5H), 6.82-6.85 (m, 2H), 7.68-8.29 (m, 2H) [393] [394] Example 68.
1 -((S)- 1 -(N-((hydroxycarbamoyl)methyl)-N-(cyclobutylmethyl)carbamoyl)-2-methylp ropyl)-3-(2,5-difluorophenyl)urea [395] 'H-NMRTCDCl ) δ 0.93-1.08 (m, 6H), 1.80-2.05 (m, 7H), 2.62 (m, 1H), 3.52-4.56
3
(m, 5H), 6.52 (m, 1H), 6.91 (m, 1H), 7.20-7.94 (m, 3H) [396] [397] Example 69. l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-isopentylcarbamoyl)-2-methylpropyl)-3-(
2-methoxyphenyl)urea [398] 'H-NMRrCDCl ) δ 0.79-1.03 (m, 12H), 1.25-2.05 (m, 4H), 315-4.47 (m, 8H),
3
6.75-6.92 (m, 4H), 7.59-810 (m, 2H) [399] [400] Example 70. l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-isopentylcarbamoyl)-2-methylpropyl)-3-(
2-chlorophenyl)urea [401] 1H-NMR(CDC1 ) δ 0.82-1.02 (m, 12H), 1.23-2.05 (m, 4H), 3.66-4.52 (m, 5H),
3
6.87-7.26 (m, 4H), 7.67-818 (m, 2H) [402] [403] Example 71. l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-isopentylcarbamoyl)-2-methylpropyl)-3-(
2,4-dichlorophenyl)urea [404] 'H-NMRrCDCl ) δ 0.83-1.02 (m, 12H), 1.28-2.02 (m, 4H), 3.40-4.48 (m, 5H),
3
7.02-7.22 (m, 3H), 7.66-814 (m, 2H) [405] [406] Example 72. l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-isopentylcarbamoyl)-2-methylpropyl)-3-(
2,5-dichlorophenyl)urea [407] 1H-NMR(CDC1 ) δ 0.83-1.02 (m, 12H), 1.23-2.00 (m, 4H), 3.41-4.55 (m, 5H),
3
6.8-7.26 (m, 3H), 7.76-8.29 (m, 2H) [408] [409] Example 73. l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-isopentylcarbamoyl)-2-methylpropyl)-3-(
2,5-difluorophenyl)urea [410] 1H-NMR(CDC1 ) δ 0.90-1.07 (m, 12H), 1.39-1.95 (m, 4H), 3.41-4.54 (m, 5H), 6.50
3
(m, IH), 6.87 (m, IH), 7.23 (m, IH), 7.36-7.92 (m, 2H) [411] [412] Example 74. l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclopentylmethyl)carbamoyl)-2,2-dimet hylpropyl)-3-(5-chloro-2-methoxyphenyl)urea [413] H-NMR(CDC1 ) δ 1.03 (9H, s), 1.16 (m, 2H), 1.55 - 1.68 (m, 6H), 2.17 (m, IH),
3
3.50 - 4.12 (m, 6H), 4.59 (m, IH), 4.77 (m, IH), 6.52 (m, IH), 6.70 (m, IH), 6.84 (m, lH), 7.63 (d, IH), 8.19 (d, IH) [414] [415] Example 75. l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclopentylmethyl)carbamoyl)-2,2-dimet hylpropyl)-3-(2-(trifluoromethoxy)phenyl)urea [416] 'H-NMRrCDCl ) δ 1.01 (s, 9H), 1.24 (m, 2H), 2.21 (m, IH), 3.47-4.80 (m, 5H),
3
6.78-7.24 (m, 3H), 7.72-8.20 (m, 2H) [417] [418] Example 76. l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclopentylmethyl)carbamoyl)-2-methyl butyl)- 3 -(2,5 -dichloropheny l)urea [419] 1H-NMR(CDC1 ) δ 0.90 (m, 6H), 1.22 (m, 4H), 1.66 (6H), 2.94 - 4.63 (m, 6H),
3
6.82 (m, IH), 7.10 (m, IH), 7.42 - 7.92 (m, 2H), 8.28 (d, IH) [420] [421] Example 77. l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclopentylmethyl)carbamoyl)-3-methyl butyl)- 3 -(2,5 -dichloropheny l)urea [422] 'H-NMRTCDCl ) δ 0.93 (m, 6H), 1.26 (3H), 1.63 (m, 8H), 2.95 - 4.73 (5H), 6.79
3
(m, IH), 7.09 (m, IH), 7.45 - 8.18 (m, 3H) [423] [424] Example 78.
1 -((S)- 1 -(N-((hydroxycarbamoyl)methyl)-N-(cyclobutylmethyl)carbamoyl)-2,2-dimeth ylpropyl)-3-(2,5-dichlorophenyl)urea [425] 1H-NMR(CDC1 ) δ 1.03 (s, 9H), 1.71 - 2.06 (m, 7H), 2.65 (m, IH), 3.51 - 5.29 (m,
3
4H), 6.84 (m, 2H), 7.12 (m, IH), 7.70 (d, IH), 8.30 (d, IH) [426] [427] Example 79. 1 -((S)- 1 -(N-((hydroxycarbamoyl)methyl)-N-(cyclobutylmethyl)carbamoyl)-2,2-dimeth ylpropyl)-3-(2,4-dichlorophenyl)urea [428] 1H-NMR(CDC1 ) δ 1.03 (s, 9H), 1.70 - 1.95 (m, 7H), 2.65 (m, IH), 3.51 - 5.29 (m,
3
4H), 6.84 (m, IH), 7.14 (m, IH), 7.25 (m, IH), 7.70 (d, IH), 8.11 (m IH) [429] [430] Example 80. l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-isopentylcarbamoyl)-2,2-dimethylpropyl)
- 3 - (2-chloropheny l)urea
[431] 'H-NMRTCDCl ) δ 0.94 (m, 15H), 1.62 (m, 3H), 3.00 - 4.69 (m, 5H), 6.61 (m, IH),
3
6.91 (m, IH), 7.20 (m, 2H), 7.56 (s, IH), 8.17 (d, IH) [432] [433] Example 81. l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(2-cyclopentylethyl)carbamoyl)-2,2-dimet hylpropyl)-3-(2-chlorophenyl)urea [434] 1H-NMR(CDC1 ) δ 1.03 (m, 1 IH), 1.50 - 1.75 (m, 9H), 3.00 - 4.70 (m, 5H), 6.77
3
(m, IH), 6.90 (m, IH), 7.19 (m, 2H), 7.65 (s, IH), 8.17 (m, IH) [435] [436] Example 82.
1 -((S)- 1 -(N-((hydroxycarbamoyl)methyl)-N-(cyclobutylmethyl)carbamoyl)-2,2-dimeth ylpropyl)-3-(5-chloro-2-methoxyphenyl)urea [437] 'H-NMRrCDCl ) δ 1.03 (s, 9H), 1.75 - 2.09 (m, 7H), 2.51 - 4.74 (m, 8H), 6.27 (m,
3
IH), 6.72 (m, IH), 6.87 (m, IH), 7.49 (s, IH), 8.20 (s, IH) [438] [439] Example 83. l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-isopentylcarbamoyl)-2,2-dimethylpropyl)
- 3 - (5 -chloro-2-methoxypheny l)urea
[440] 1H-NMR(CDC1 ) δ 0.81 - 1.04 (m, 15H), 1.25 - 1.82 (m, 3H), 3.00 - 4.67 (m, 8H),
3
6.48 (m, IH), 6.67 (m, IH), 6.85 (m, IH), 7.64 (s, IH), 8.20 (s, IH) [441] [442] Example 84. l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(2-cyclopentylethyl)carbamoyl)-2,2-dimet hylpropyl)-3-(5-chloro-2-methoxyphenyl)urea [443] 'H-NMRrCDCl ) δ 1.04 (m, 1 IH), 1.43 - 1.76 (m, 7H), 3.00 - 4.69 (m, 8H), 6.57
3
(m, 2H), 6.84 (m, IH), 7.75 (m, IH), 8.21 (m, IH) [444] [445] Example 85.
1 -((S)- 1 -(N-((hydroxycarbamoyl)methyl)-N-(cyclobutylmethyl)carbamoyl)-2-methylp ropyl)-3-(5-chloro-2-methoxyphenyl)urea [446] 'H-NMRrCDCl ) δ 1.01 (m, 6H), 1.74 - 2.08 (m, 8H), 2.61 - 4.53 (m, 8H), 6.70
3
(m, 3H), 7.51 (m, IH), 8.47 (m, IH) [447] [448] Example 86. l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclopentylmethyl)carbamoyl)-2-methyl propyl)-3-(5-chloro-2-methoxyphenyl)urea [449] 1H-NMR(CDC1 ) δ 1.00 (m, 6H), 1.20 (m, 2H), 1.50 (m, 6H), 2.01 (m, IH), 2.16
3
(m, IH), 2.90 - 4.56 (m, 8H), 6.70 (m, 3H), 7.55 (m, IH), 8.22 (m, IH) [450] [451] Example 87. l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-isopentylcarbamoyl)-2-methylpropyl)-3-(
5-chloro-2-methoxyphenyl)urea [452] 'H-NMRrCDCl ) δ 0.86-1.04 (m, 12H), 1.26-1.66 (m, 3H), 2.00 (m, IH), 3.01-4.51
3
(m, 8H), 6.60-6.87 (m, 3H), 7.99 (m,lH), 8.20 (m, IH) [453] [454] Example 88. l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(2-cyclopentylethyl)carbamoyl)-2-methyl propyl)-3-(5-chloro-2-methoxyphenyl)urea [455] 1H-NMR(CDC1 ) δ 0.97-1.03 (m, 8H), 1.54-1.77 (m, 9H), 2.00(m, IH), 3.05-4.47
3
(m, 8H), 6.58-6.94 (m, 3H), 7.69-819 (m, 2 H) [456] [457] Example 89.
1 -((S)- 1 -(N-((hydroxycarbamoyl)methyl)-N-(cyclobutylmethyl)carbamoyl)-2,2-dimeth ylpropyl)-3-(2,5-dimethoxyphenyl)urea [458] 'H-NMRTCDCl ) δ 1.04 (s, 9H), 1.70-1.89 (m, 6H), 2.60 (m, IH), 3.50-4.67 (m,
3
11H), 6.29-6.72 (m, 3H), 7.56-7.84 (m, 2H) [459] [460] Example 90.
1 -((S)- 1 -(N-((hydroxycarbamoyl)methyl)-N-(cyclobutylmethyl)carbamoyl)-2,2-dimeth ylpropyl)-3-(2-methoxy-5-methylphenyl)urea [461] 'H-NMRTCDCl ) δ 1.04 (s, 9H), 1.70-1.93 (m, 6H), 2.51 (m, IH), 2.27 (s, 3H),
3
3.55-4.72 (m, 8H), 6.20 (m, IH), 6.78 (m, 2H), 7.34-7.92 (m, 2H) [462]
[463] Example 91.
1 -((S)- 1 -(N-((hydroxycarbamoyl)methyl)-N-(cyclobutylmethyl)carbamoyl)-2-methylp ropy 1) -3 - (2-methoxy- 5 -me thy lpheny l)urea [464] 1H-NMR(CDC1 ) δ 0.96-1.05 (m, 6H), 1.73-1.90 (m, 6H), 2.24 (s, 3H), 2.55 (m,
3
IH), 3.51-4.49 (m, 8H), 6.70 (m, 3H), 7.38-8.35 (m, 2H) [465] [466] Example 92.
1 -((S)- 1 -(N-((hydroxycarbamoyl)methyl)-N-(cyclobutylmethyl)carbamoyl)-2,2-dimeth ylpropyl)-3-(2,4-dimethoxyphenyl)urea [467] 'H-NMRTCDCl ) δ 1.00 (s, 9H), 1.69-2.07 (m, 6H), 2.60 (m, IH), 3.50-4.66 (m,
3
11H), 6.00 (m, IH), 6.44 (s, 2H), 7.02-7.78 (m, 2H) [468] [469] Example 93.
1 -((S)- 1 -(N-((hydroxycarbamoyl)methyl)-N-(cyclobutylmethyl)carbamoyl)-2-methylp ropyl)-3-(2,4-dimethoxyphenyl)urea [470] 1H-NMR(CDC1 ) δ 0.98 (m, 6H), 1.71-1.97 (m, 6H), 2.64 (m, IH), 3.51-4.45 (m,
3
11H), 6.28-6.44 (m, 3H), 719-7.80 (m, 2H) [471] [472] Example 94. l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclopentylmethyl)carbamoyl)-2,2-dimet hylpropyl)-3-(2-chloropyridin-3-yl)urea [473] The title compound was prepared according to the following Scheme 2:
[474] Scheme 2
Figure imgf000033_0001
[475] Step 1: Cyclopentylmethylaminoacetic acid ethyl ester
[476] An acetonitrile suspension (84 ml) of glycine ethyl ester hydrochloride (5.8 g, 41.8 mmol), p-tolunesulfonylmethylcyclopentane (10.6 g, 41.8 mmol), and potassium carbonate (5.8 g, 41.8 mmol) was heated at 60 °C and then stirred for 18 hours. The precipitate was removed by filtration of the reaction suspension and the filtrate was concentrated under vacuum. The resultant concentrate was purified by silica gel chromatography to give 1.3 g (yield 16.8%) of the title compound. [477] 'H-NMRrCDCl ) δ 1.19 (m, 2H), 1.27 (t, I=71Hz, 3H), 1.54 (m, 4H), 1.77 (m,
3
2H), 2.01 (m, IH), 2.51 (d, I=71Hz), 3.40 (s, 2H), 4.20 (q, I=71Hz, I=14.2Hz, 2H)
[478]
[479] Step 2: [(2S-t-butoxycarbonylamino-3,3-dimethylbutyryl)cyclopentylmethylamino] acetic acid ethyl ester
[480] 1-hydroxybenzotriazole (0.44 g, 3.2 mmol), l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.62 g, 3.2 mmol), N,N-diisopropylethylamine (0.93 ml, 5.4 mmol), and L-
N-t-butoxycarbonyl-phenylalanine (0.5 g, 2.2 mmol) were added to a dichloromathane solution (4.3 ml ) of cyclopentylmethylaminoacetic acid ethyl ester (0.4 g, 2.2 mmol). The reaction mixture was stirred at room temperature for 18 hours and washed with distilled water and a solution of 1 N HCl. The organc layer was dried on anhydrous sodium sulfate and concentrated under vacuum. The resultant concentrate was purified by silica gel chromatography to give 0.5 g (yield 57.4%) of the title compound.
[481] 1H-NMR(CDC1 ) δ 1.02 (s, 9H), 1.25 (m, 5H), 1.29 (s, 9H), 1.44-1.69 (m, 6H),
3
2.22 (m, IH), 3.15 (m, IH), 3.66 (m, 2H), 414-4.63 (m, 4H), 5.32 (s, IH)
[482]
[483] Step 3: [(2S-amino-3,3-dimethylbutyryl)cyclopentylamino]acetic acid ethyl ester hydrochloride
[484] A 1 ,4-dioxane solution ( 1.6 ml) of 4N HCl was added to
[(2S-t-butoxycarbonylamino-3,3-dimethylbutyryl)cyclopentylmethylamino]acetic acid ethyl ester (0.5 g, 1.24 mmol). The reaction mixture was stirred at room temperature for 18 hours and concentrated under vacuum. The resultant concentrate was used in the next step without further purification.
[485]
[486] Step 4: (cyclopentylmethyl-{(S)-2-[(imidazol-l-carbonyl)amino] -
3,3-dimethylbutyryl}amino)acetic acid ethyl ester
[487] Carbonyldiimidazole (0.34 g, 2.11 mmol) was added to a dichloromethane solution
(10 ml) of [(2S-amino-3,3-dimethylbutyryl)cyclopentylamino]acetic acid ethyl ester hydrochloride (0.47 g, 1.41 mmol) and then N,N-diisopropylethylamine (0.24 ml, 1.41 mmol) was dropwise added thereto. The reaction mixture was stirred at room temperature for 4 hours and washed with water. The organic layer was dried on anhydrous sodium sulfate and concentrated under vacuum to give 0.49 g (yield 88%) of the title compound. [488] 1H-NMR(CDC1 ) δ 1.11 (s, 9H), 1.26 (m, 5H), 2.22 (m, IH), 1.65 (m, 6H), 2.04
3
(m, IH), 3.24 (m, IH), 3.71 (m, 2H), 4.18 (m, 2H), 4.48 (m, IH), 5.00 (m, IH), 6.5 (m, IH), 7.1 (s, IH), 7.35 (s, IH), 8.13 (s, IH)
[489]
[490] Step 5: ({(S)-2-[3-(2 ;hloropyridin-3-yl)ureido] -
3,3-dimethylbutyryl}cyclopentylmethylamino)acetic acid ethyl ester
[491] 3-amino-2-chloropyridine (0.039 g, 0.3 mmol) was added to a toluene solution (1.5 ml) of (cyclopentylmethyl-{(S)-2-[(imindazol-l-carbonyl)amino] - 3,3-dimethylbutyryl}amino)acetic acid ethyl ester (0.12 g, 0.3 mmol) and stirred under reflux for 18 hours. The reaction mixture was concentrated under vacuum and purified by silica gel chromatography to give 0.014 g (yield 10%) of the title compound.
[492] 'H-NMRrCDCl ) δ 1.05 (s, 9H), 114-1.74 (m, 11H), 2.22 (m, IH), 3.47-4.83 (m,
3
7H), 7.04 -7.83 (m, 3H) [493] [494] Step 6: l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclopentylmethyl)carbamoyl)-2,2-dimet hylpropyl)-3-(2-chloropyridin-3-yl)urea [495] A methanol solution (0.3 ml) of 3 M KOH was dropwise added to a methanol solution (0.3 ml) of 2 M NH OH HCl and then stirred for 30 minutes. The precipitate
2 was removed by filtration. ({(S)-2-[3-(2-chloropyridin-3-yl)ureido] - 3,3-dimethylbutyryl}cyclopentylmethylamino)acetic acid ethyl ester (0.014 g, 0.03 mmol) was dissolved in the resultant filtrate and stirred for 2 hours. The reaction mixture was neutralized with Dowex 50WX4-100. Dowex resin was removed by filtration and the filtrate was concentrated. The resultant concentrate was purified by silica gel chromatography to give 0.002 g (yield 14.3%) of the title compound. [496] 'H-NMRrCDCl ) δ 1.03 (s, 9H), 114-1.25 (m, 2H), 1.52-1.74 (m, 6H), 2.22 (m,
3
IH), 3.47-4.83 (m, 5H), 7.08 (m, 2H), 7.82-7.91(m, 2H), 8.52 (m, IH)
[497]
[498] The comounds of the following Examples were prepared in the same manner as in
Example 94 except that l-p-toluenesulfonyl-3-methylbutane, l-p-toluenesulfonyl-2-cyclopentylethane, or p-toluenesulfonylmethylcyclobutane was used instead of p-toluenesulfonylmethylcyclopentane of Step 1, L- N-t-butoxycarbonyl-valine was used instead of L-N-t-butoxycarbonyl-t-butyl-leicine of Step 2, or substituted amine was used instead of 3-amino-2-chloropyridine of Step
5. [499] [500] Example 95. l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclopentylmethyl)carbamoyl)-2,2-dimet hylpropyl)-3-(4-chloro-2-methoxy-5-methylphenyl)urea [501] 'H-NMRrCDCl ) δ 1.02 (s, 9H), 1.16 (m, 2H), 1.54 - 1.68 (m, 6H), 2.17 (m, 4H),
3
3.52 - 4.11 (m, 6H), 4.58 (m, IH), 4.75 (m, IH), 6.46 (m, IH), 6.76 (m, IH), 7.50 (d,
IH), 7.98 (d, IH) [502] [503] Example 96. l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclopentylmethyl)carbamoyl)-2,2-dimet hylpropyl)-3-(2-benzoyl-3-chlorophenyl)urea [504] 'H-NMRTCDCl ) δ 1.02 (s, 9H), 1.26 (m, 2H), 1.66 (m, 6H), 2.18 (m, IH), 3.48 -
3
4.09 (m, 3H), 4.52 - 4.71 (m, 2H), 7.43 (m, 5H), 7.66 (m, 3H), 8.36 (m, IH), 9.99 (d,
IH) [505] [506] Example 97. l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclopentylmethyl)carbamoyl)-2,2-dimet hylpropyl)-3-(quinolin-8-yl)urea [507] 'H-NMRTCDCl ) δ 1.06 (s, 9H), 1.63 (m, 8H), 2.17 (m, IH), 3.63 - 4.29 (m, 3H),
3
4.65 (m, IH), 4.84 (m, IH), 6.87 - 7.03 (m, IH), 7.34 (m, 3H), 8.04 - 8.62 (m, 3H),
9.26 (d, IH) [508] [509] Example 98. l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclopentylmethyl)carbamoyl)-2,2-dimet hylpropyl)-3-(benzo[d]thiazol-6-yl)urea [510] 'H-NMRTCDCl ) δ 1.05 (s, 9H), 1.21 (m, 2H), 2.20 (m, IH), 3.46-4.66 (m, 5H),
3
7.13 (m, IH), 7.74-8.88 (m, 3H) [511] [512] Example 99. l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclopentylmethyl)carbamoyl)-2,2-dimet hy lpropy 1) -3 - (2- (piperidin- 1 - y l)pheny l)urea [513] 'H-NMRrCDCl ) δ 1.04 (s, 9H), 1.23 (m, 2H), 1.57-1.72 (m, 1CH), 2.21 (m, IH),
3
2.80 (m, 4H), 3.56-4.75 (m, 5H), 7.05 (m, 3H), 7.61-7.89 (m, 2H) [514]
[515] Example 100. l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclopentylmethyl)carbamoyl)-2,2-dimet hy lpropy 1) -3 - (5 - (trifluoromethyl) -2-morpholinopheny l)urea [516] 1H-NMR(CDC1 ) δ 1.02 (s, 9H), 1.24 (m, 2H), 2.21 (m, IH), 2.88 (m, 4H),
3
3.53-4.76 (m, 9H), 6.67 (m, IH), 710-7.26 (m, 2H), 7.95-8.49 (m, 2H) [517] [518] Example 101. l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclopentylmethyl)carbamoyl)-2,2-dimet hylpropyl)-3-(3-chloro-4-morpholinophenyl)urea [519] Ti-NMRTCDCl ) δ 1.01 (s, 9H), 1.21 (m, 2H), 1.28-1.64 (m, 6H), 2.18 (m, IH),
3
2.98 (m, 4H), 3.55-4.70 (m, 9H), 6.20-7.54 (m, 4H) [520] [521] Example 102. l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclopentylmethyl)carbamoyl)-2,2-dimet hylpropyl)-3-(quinolin-5-yl)urea [522] 1H-NMR(CDC1 ) δ 1.06 (s, 9H), 1.63 (m, 8H), 2.17 (m, IH), 3.63 - 4.29 (m, 3H),
3
4.65 (m, IH), 4.84 (m, IH), 6.60-8.80 (m, 8H) [523] [524] Example 103. l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclopentylmethyl)carbamoyl)-2,2-dimet hy lpropy 1) -3 - (2- (pyrrolidin- 1 - y l)pheny l)urea [525] 1H-NMR(CDC1 ) δ 0.93 (s, 9H), 1.24 (m, 2H), 1.52-1.65 (m, 6H), 1.90 (m, 4H),
3
2.17 (m, IH), 311-4.61 (m, 9H), 6.07 (m, IH), 6.85-7.44 (m, 5H) [526] [527] Example 104. l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclopentylmethyl)carbamoyl)-2,2-dimet hylpropyl)-3-(5-fluoro-2-(pyrrolidin-l-yl)phenyl)urea [528] 'H-NMRrCDCl ) δ 1.03 (s, 9H), 1.23 (m, 2H), 1.56-1.71 (m, 1CH), 2.20 (m, IH),
3
2.73 (m, 4H), 3.64-4.84 (m, 5H), 6.61 (m, IH), 6.99 (m, IH), 7.81-8.07 (m, 2H) [529] [530] Example 105. l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclopentylmethyl)carbamoyl)-2,2-dimet hy lpropy 1) -3 - (5 -fluoro-2- (piperidin- 1 - y l)pheny l)urea [531] 1H-NMR(CDC1 ) δ 1.03 (s, 9H), 1.20 (m, 2H), 1.57-1.68 (m, 6H), 2.17 (m, IH),
3 3.42-4.78 (m, 9H), 6.35-6.66 (m, 2H), 7.04 (m, IH), 7.89-817 (m, 2H) [532] [533] Example 106. l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclopentylmethyl)carbamoyl)-2,2-dimet hylpropyl)-3-(5-fluoro-2-morpholinophenyl)urea [534] 'H-NMRrCDCl ) δ 1.03 (s, 9H), 1.16 (m, 2H), 1.52-1.70 (m, 6H), 2.17 (m, IH),
3
2.90 (m, 4H), 3.50-4.72 (m, 9H), 6.30 (m, IH), 6.80-7.37 (m, 3H), 7.90 (m, IH) [535] [536] Example 107. l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclopentylmethyl)carbamoyl)-2,2-dimet hylpropyl)-3-(3-fluoro-4-(pyrrolidin-l-yl)phenyl)urea [537] 'H-NMRTCDCl ) δ 0.99 (s, 9H), 1.15 (m, 2H), 1.49-1.69 (m, 6H), 1.91 (m, 4H),
3
2.17 (m, IH), 3.27 (s, 4H), 3.86-4.70 (m, 5H), 6.09 (bs, IH), 6.51-712 (m, 3H), 7.60
(s, IH) [538] [539] Example 108. l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclopentylmethyl)carbamoyl)-2,2-dimet hy lpropy 1) -3 - (3 -fluoro-4- (piperidin- 1 - y l)pheny l)urea [540] 'H-NMRrCDCl ) δ 1.00 (s, 9H), 1.21 (m, 2H), 1.52-1.68 (m, 12H), 1.91 (m, 4H),
3
2.17 (m, IH), 2.90 (m, 4H), 3.50-4.72 (m, 5H), 6.27 (bs, IH), 6.76-718 (m, 3H),
7.84(s, IH) [541] [542] Example 109. l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclopentylmethyl)carbamoyl)-2,2-dimet hylpropyl)-3-(3-fluoro-4-morpholinophenyl)urea [543] Ti-NMRTCDCl ) δ 1.01 (s, 9H), 1.21 (m, 2H), 1.28-1.64 (m, 6H), 2.18 (m, IH),
3
2.98 (m, 4H), 3.55-4.70 (m, 9H), 6.20 (m, IH), 6.78-7.54 (m, 3H) [544] [545] Example 110. l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclopentylmethyl)carbamoyl)-2,2-dimet hylpropyl)-3-(5-chloroquinolin-8-yl)urea [546] 1H-NMR(CDC1 ) δ 1.04-1.28 (m, 17H), 2.25 (m, IH), 3.64-4.81 (m, 5H), 6.8-919
3
(m, IH), 6.76-718 (m, 7H) [547] [548] Example 111. l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclopentylmethyl)carbamoyl)-2,2-dimet hylpropyl)-3-(2-chloro-4-(methylsulfonyl)phenyl)urea [549] 1H-NMR(CDC1 ) δ 1.04 (s, 9H), 1.26 (m, 2H), 1.55 - 1.68 (m, 6H), 2.18 (m, IH),
3
3.43 - 4.15 (m, 4H), 4.60 - 4.80 (m, IH), 7.74 (m, 2H), 8.03 - 8.49 (m, 2H) [550] [551] Example 112.
1 -((S)- 1 -(N-((hydroxycarbamoyl)methyl)-N-(cyclobutylmethyl)carbamoyl)-2,2-dimeth ylpropyl)-3-(4-chloro-2-methoxy-5-methylphenyl)urea [552] 'H-NMRTCDCl ) δ 1.03 (s, 9H), 1.68 - 2.04 (m, 7H), 2.25 (s, 3H), 2.45 - 4.67 (m,
3
8H), 6.50 (m, IH), 6.76 (s, IH), 7.57 (m, IH), 7.98 (s, IH) [553] [554] Example 113.
1 -((S)- 1 -(N-((hydroxycarbamoyl)methyl)-N-(cyclobutylmethyl)carbamoyl)-2,2-dimeth ylpropyl)-3-(5-fluoro-2-(pyrrolidin-l-yl)phenyl)urea [555] 1H-NMR(CDC1 ) δ 1.02 (s, 9H), 1.72 - 2.08 (m, 1 IH), 2.62 (m, IH), 3.00 (m, 4H),
3
3.54 - 4.66 (m, 4H), 6.31 (m, IH), 6.66 (m, IH), 6.94 (m, IH), 7.38 - 7.90 (m, 2H) [556] [557] Example 114. l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclobutylmethyl
)carbamoyl)-2,2-dimethylpropyl)-3-(quinolin-8-yl)urea [558] 1H-NMR(CDC1 ) δ 1.08 (s, 9H), 1.70 - 2.09 (m, 7H), 2.54 - 4.81 (m, 5H), 6.65 (m,
3
IH), 7.34 (m, 2H), 7.47 (m, IH), 8.05 (m, IH), 8.45 (m, IH), 8.64 (m, IH), 9.15 (m,
IH) [559] [560] Example 115. l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-isopentylcarbamoyl)-2,2-dimethylpropyl)
- 3 - (4-chloro-2-methoxy- 5 -methy lpheny l)urea
[561] 1H-NMR(CDC1 ) δ 0.83 - 1.04 (m, 15H), 1.25 - 1.65 (m, 3H), 2.27 (s, 3H), 3.00 -
3
4.62 (m, 8H), 6.14 (m, IH), 6.78 (s, IH), 7.36 (m, IH), 7.98 (m, IH) [562] [563] Example 116. l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-isopentylcarbamoyl)-2,2-dimethylpropyl)
- 3 - (quinolin- 8 -y l)urea
[564] 'H-NMRrCDCl ) δ 0.80 - 1.10 (m, 15H), 1.25 - 1.69 (m, 3H), 3.00 - 4.77 (m, 5H),
3
6.66 (m, IH), 7.31 (m, 3H), 8.04 (m, IH), 8.47 (m, IH), 8.63 (m, IH), 9.15 (m, IH)
[565] [566] Example 117. l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(2-cyclopentylethyl)carbamoyl)-2,2-dimet hylpropyl)-3-(4-chloro-2-methoxy-5-methylphenyl)urea [567] 'H-NMRrCDCl ) δ 1.03 (m, 1 IH), 1.42 - 1.75 (m, 7H), 2.21 (s, 3H), 3.00 - 4.64
3
(m, 8H), 6.52 (m, IH), 6.75 (m, IH), 7.62 (s, IH), 8.00 (s, IH) [568] [569] Example 118. l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(2-cyclopentylethyl)carbamoyl)-2,2-dimet hylpropyl)-3-(5-fluoro-2-(pyrrolidin-l-yl)phenyl)urea [570] 1H-NMR(CDC1 ) δ 0.88 - 1.13 (m, 11H), 1.53 - 1.95 (m, 7H), 3.05 (m, 4H), 3.55 -
3
4.60 (m, 5H), 6.13 (m, IH), 6.68 (m, IH), 6.98 (m, IH), 7.46 - 7.87 (m, 2H) [571]
[572] Example 119. l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(2-cyclopentylethyl)carbamoyl)-2,2-dimet hylpropyl)-3-(quinolin-8-yl)urea [573] 'H-NMRrCDCl ) δ 0.89 - 1.03 (m, 1 IH), 1.38 - 1.73 (m, 7H), 3.00 - 4.74 (m, 5H),
3
7.03 - 7.45 (m, 4H), 7.98 (m, IH), 8.47 (m, 2H), 9.37 (m, IH) [574] [575] Example 120.
1 -((S)- 1 -(N-((hydroxycarbamoyl)methyl)-N-(cyclobutylmethyl)carbamoyl)-2-methylp ropyl)-3-(4-chloro-2-methoxy-5-methylphenyl)urea [576] 1H-NMR(CDC1 ) δ 1.01 (m, 6H), 1.67 - 2.22 (m, 8H), 2.62 - 4.44 (8H), 6.68 (m,
3
2H), 7.39 (m, IH), 7.89 (m, IH) [577] [578] Example 121.
1 -((S)- 1 -(N-((hydroxycarbamoyl)methyl)-N-(cyclobutylmethyl)carbamoyl)-2-methylp ropyl)-3-(5-fluoro-2-(pyrrolidin-l-yl)phenyl)urea [579] 'H-NMRrCDCl ) δ 0.96 (m, 6H), 1.84 (m, 12H), 2.62 - 4.47 (m, 9H), 6.46 (m, IH),
3
6.65 (m, IH), 6.99 (m, IH), 7.70 (m, IH), 7.94 (m, IH) [580] [581] Example 122.
1 -((S)- 1 -(N-((hydroxycarbamoyl)methyl)-N-(cyclobutylmethyl)carbamoyl)-2-methylp ropyl)-3-(quinolin-8-yl)urea [582] 'H-NMRrCDCl ) δ 0.88 (m, 3H), 1.12 (m, 3H), 1.80 - 2.16 (m, 7H), 2.62 (m, IH),
3
3.61 (m, 2H), 4.09 (m, IH), 4.80 (m, 2H), 7.43 (m, 2H), 7.56 (m, IH), 8.02 (m, IH), 8.19 (m, IH), 8.54 (m, IH), 8.71 (m, 2H) [583] [584] Example 123. l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclopentylmethyl)carbamoyl)-2-methyl propyl)-3-(4-chloro-2-methoxy-5-methylphenyl)urea [585] 'H-NMRrCDCl /CD OD) δ 1.00 (m, 6H), 1.22 (m, 2H), 1.55 (m, 6H), 2.01 (m,
3 3
IH), 2.14 (m, 4H), 3.05 - 4.41 (m, 8H), 6.80 (s, IH), 7.95 (s, IH) [586] [587] Example 124. l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclopentylmethyl)carbamoyl)-2-methyl propyl)-3-(5-fluoro-2-(pyrrolidin-l-yl)phenyl)urea [588] 'H-NMRTCDCl ) δ 0.98 (m, 6H), 1.18 (m, 2H), 1.59 (m, 6H), 1.92 (m, 5H), 2.18
3
(m, IH), 3.04 (m, 4H), 3.34 - 4.49 (m, 5H), 6.55 (m, IH), 6.65 (m, IH), 6.98 (m, IH),
7.72 (m, IH), 7.96 (m, IH) [589] [590] Example 125. l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclopentylmethyl)carbamoyl)-2-methyl propy 1) -3 - (quinolin- 8 - y l)urea [591] Ti-NMRTCDCl ) δ 0.88-1.31 (m, 8H), 1.57-1.80 (m, 6H), 2.18 (m, 2H), 3.44-3.65
3
(m, 2H), 4.10 (m, IH), 4.73-4.87 (m, 2H), 7.43-7.59 (m, 3H), 7.94-8.22 (m, 2H),
8.56-8.77 (m, 3H) [592] [593] Example 126. l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-isopentylcarbamoyl)-2-methylpropyl)-3-(
4-chloro-2-methoxy-5-methylphenyl)urea [594] 'H-NMRTCDCl ) δ 0.83-1.05 (m, 12H), 1.26-1.60 (m, 3H), 1.99 (m, IH), 2.21 (s,
3
3H), 310-4.38 (m, 8H), 6.71-6.99 (m, 2H), 7.50-7.91 (m,2H) [595] [596] Example 127. l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-isopentylcarbamoyl)-2-methylpropyl)-3-( quinolin-8-yl)urea [597] 1H-NMR(CDC1 ) δ 0.86-114 (m, 12H), 1.40-1.70 (m, 3H), 2.16 (m, IH), 3.55 (m,
3
2H), 4.12 (m, IH), 4.62-4.87 (m, 2H), 7.43-7.59 (m, 3H), 7.99-8.23 (m, 2H), 8.55-8.79 (m, 3H) [598] [599] Example 128. l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(2-cyclopentylethyl)carbamoyl)-2-methyl propyl)-3-(4-chloro-2-methoxy-5-methylphenyl)urea [600] 'H-NMRTCDCl ) δ 0.96-1.04 (m, 8H), 1.52-7.79 (m, 9H), 1.98 (m, IH), 2.21 (s,
3
3H), 3.03-4.39 (m, 8H), 6.72-7.00 (m, 2H), 7.53-7.91 (m, 2 H) [601] [602] Example 129. l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(2-cyclopentylethyl)carbamoyl)-2-methyl propyl)-3-(5-fluoro-2-(pyrrolidin-l-yl)phenyl)urea [603] 1H-NMR(CDC1 ) δ 0.96-119 (m, 8H), 1.55-1.96 (m, 14H), 2.99 (m, 4H), 3.38-4.45
3
(m, 5H), 6.44-7.00 (m, 3H), 7.71-7.85 (m, 2 H) [604] [605] Example 130. l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(2-cyclopentylethyl)carbamoyl)-2-methyl propy 1) -3 - (quinolin- 8 - y l)urea [606] Ti-NMRTCDCl ) δ 0.88-114 (m, 8H), 1.51-1.82 (m, 9H), 2.15 (m, IH), 3.53 (m,
3
2H), 4.11 (m, IH), 4.64-4.46 (m, 2H), 7.43-7.59 (m, 3H), 7.99-8.21 (m, 2H), 8.55-8.79
(m, 3H) [607] [608] Example 131.
1 -((S)- 1 -(N-((hydroxycarbamoyl)methyl)-N-(cyclobutylmethyl)carbamoyl)-2,2-dimeth ylpropyl)-3-(6-methoxyquinolin-8-yl)urea [609] 1H-NMR(CDC1 ) δ 1.09 (s, 9H), 1.75-1.89 (m, 6H), 2.50 (m, IH), 3.50-4.80 (m,
3
8H), 6.58-6.76 (m, 2H), 7.62-918 (m, 5H) [610] [611] Example 132.
1 -((S)- 1 -(N-((hydroxycarbamoyl)methyl)-N-(cyclobutylmethyl)carbamoyl)-2-methylp ropyl)-3-(6-methoxyquinolin-8-yl)urea [612] 'H-NMRrCDCl ) δ 0.92-1.23 (m, 6H), 1.80-1.93 (m, 6H), 2.63 (m, IH), 3.57-4.84
3
(m, 8H), 6.73 (s, IH), 7.40 (m, IH), 8.04-8.76 (m, 5H) [613] [614] Example 133.
1 -((S)- 1 -(N-((hydroxycarbamoyl)methyl)-N-(cyclobutylmethyl)carbamoyl)-2,2-dimeth ylpropyl)-3-(2-hydroxyphenyl)urea [615] 1H-NMR(CDC1 ) δ 0.99 (s, 9H), 1.63-2.04 (m, 6H), 2.57 (m, IH), 3.40-4.70 (m,
3 5H), 6.74-7.06 (m, 5H), 7.89 (bs, IH)
[616]
[617] Experimental Example 1: Evaluation of deformylase inhibitory activity
[618] ( 1 ) Prodiction and purification of deformylase
[619] Deformylase-producing bacteria strains (Novagen, America, cat. no. 69041) were inoculated into 50 °C LB media (tryptone 8g/l, yeast extract 5g/l, NaCl 5g/l, IN NaOH 2.5ml) containing ampicillin and then cultured at 37 °C . The cultures were then inoculated into new LB media (3L) with the same composition as in the above- described LB media. When O.D (660 nm) reached 0.5, protein expression was indiced by addition of 1 mM isopropyl- β -D-thiogalactopyranoside to the LB media. Then, cell pellets were harvested by centrifugation, incubated at -80 °C for 30 minutes, resuspended in a phosphate buffer, followed by lysis of bacteria cells by sonification with 8 seconds interval between each pulse (1 second). The supernatant was obtained by ultracentrifugation, loaded onto an affinity column, followed by elution with an elution buffer. The eluted fractions containing peptide deformylase were identified by SDS-PAGE, followed by elution by gel chromatography. At this time, a buffer containing 5 mM NiCl was used as a stabilizer for the enzyme source, and SDS-
2
PAGE and Dynamic Light Scattering were used to identify the purification of the enzyme source. The purified enzyme source was kept at -80 °C until use.
[620] (2) Deformylase inhibition test
[621] Each of the compounds prepared in Examples was dissolved in dimethyl sulfoxide to a concentration of 2 mM. 7 μJl of each of the reaction mixtures was loaded into each well of microtiter plates. The deformylase as prepared in section (1) was diluted with a buffer (50mM HEPES, pH7.0, lOmM NaCl, 5mM NiCl , 0.1% Triton X-100) to a con-
2 centration of 250 nM and then loaded into each well of the microtiter plates. Then, continuous dilution for each of the compounds of Examples was performed with a dilution ratio of 7:2 to make a final volume of 50 βi for each well, followed by incubation at room temperature for 5 minutes. Then, 50 βi of 5 mM formyl- Met-Ala-Ser used as a substrate source was loaded into each well and incubated at 30 °C for 10 minutes to indice enzyme reaction. When the enzyme reaction was completed, the obtained samples were treated with 50 βi of fluorescamine and 50 βi of 50 mM borate-sodium hydroxide buffer (pH 9.5) to measure fluorescence at an excitation wavelength of 390 nm and an emission wavelength of 465 nm. Based on the fluorescence thus measured, the concentrations (IC ) of the samples that decrease
50 enzyme activity by 50% were calculated and the results are presented in Table 1 below. Table 1
Figure imgf000044_0001
Figure imgf000045_0001
Figure imgf000046_0001
[624] [625] Experimental Example 2: Antibacterial effect test [626] Minimal inhibitory concentrations (MICs) of the compounds of Examples were determined for Hemophilus influenza (ATCC 51907), Streptococcus pneumoniae (ATCC 6305), and Moraxella cararrhalis (ATCC 43617).
[627] Each of the compounds of Examples was dissolved in dimethyl sulfoxide to a concentration of 2 mg/ml. At this time, actinonin (Sigma, America) or ampicillin (Sigma, America) was used as standard antibiotic in a concentration of 2 mg/ml.
[628] For bacteria culture, Hemophilus influenza and Moraxella cararrhalis were inoculated into culture media such as brain heart infusion (37 g/1, Ditco, America) supplemented with NAD lOmg/1 and hemin 5mg/l and then cultured for 24 and 48 hours, respectively. Streptococcus pneumoniae was inoculated into GC media containing 5% horse serum and cultured for 48 hours. The cultures were diluted to a concentration of 1 x 10 CFU/ml and inoculated into wells of microtiter plates. After incubation at 37 °C , 5% CO for 24 hours for Hemophilus influenza and 48 hours for Moraxella
2 cararrhalis and Streptococcus pneumoniae , Cs, the lowest concentrations able to inhibit visual growth, were determined and the results are presented in Table 2 below. Table 2
Figure imgf000047_0001
Figure imgf000048_0001
Figure imgf000049_0001
Figure imgf000050_0001
Figure imgf000051_0001

Claims

Claims
[1] A compound of formula (I) or a pharmaceutically acceptable salt thereof:
Figure imgf000052_0001
Wherein, R is a straight or branched C ~ C alkyl group; or a C C alkyl
2 substituted with a C C cycloalkyl group,
6
R is a straight or branched C C alkyl group,
6 X is a phenyl group; or a heteroaryl group selected from the group consisting of 1,4-benzodioxolyl, pyridinyl, quinolinyl, and benzothiazolyl (wherein, the phenyl group or the heteroaryl group may be substituted with 1 to 3 substituent(s) selected from the group consiting of C ~ C alkyl, C ~ C alkoxy,
1 4 1 4 hydroxy, halogen, cyano, nitro, acetyl, phenyl, trifluoromethyl, trifluoromethoxy, methanesulfonyl, piperidinyl, morpholinyl, pyrrolidinyl, and benzoyl). 5. A process for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, which comprises reacting a compound of formula (II) with hydroxyl amine:
[2] The compound of formula (I) or its pharmaceutically acceptable salt of claim 1, wherein X is a phenyl group substituted with 1 to 3 substituent(s) selected from the group consiting of C ~ C alkyl, C ~ C alkoxy, hydroxy, halogen, cyano,
1 4 1 4 nitro, acetyl, phenyl, trifluoromethyl, trifluoromethoxy, methanesulfonyl, piperidinyl, morpholinyl, pyrrolidinyl, and benzoyl.
[3] The compound of formula (I) or its pharmaceutically acceptable salt of claim 1, wherein X is a heteroaryl group selected from the group consisting of 1,4-benzodioxolyl, pyridinyl, quinolinyl, and benzothiazolyl, which may be substituted with 1 or 2 substituent(s) selected from the group consiting of C ~ C alkyl, C ~ C alkoxy, and halogen.
4 1 4
[4] The compound of formula (I) or its pharmaceutically acceptable salt of claim 1, which is selected from the group consisting of: l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-butylcarbamoyl)-2,2-dimethylpropy l)-3-(3-chlorophenyl)urea; l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclopentylmethyl)carbamoyl)-2,2- dimethylpropyl)-3-(3-chlorophenyl)urea; l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(2-cyclopentylethyl)carbamoyl)-2,2
-dimethy lpropy 1) - 3 -(3 -chloropheny l)urea ; l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(2-cyclopentylethyl)carbamoyl)-2,2
-dimethylpropyl)-3-p-tolylurea; l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(2-cyclopentylethyl)carbamoyl)-2,2
-dimethylpropyl)-3-m-tolylurea; l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(2-cyclopentylethyl)carbamoyl)-2,2
-dimethylpropyl)-3-(3-methoxyphenyl)urea; l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclopentylmethyl)carbamoyl)-2,2- dimethylpropyl)-3-m-tolylurea; l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclohexylmethyl)carbamoyl)-2,2- dimethylpropyl)-3-(3-chlorophenyl)urea; l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclohexylmethyl)carbamoyl)-2,2- dimethylpropyl)-3-m-tolylurea; l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclohexylmethyl)carbamoyl)-2,2- dimethylpropyl)-3-(3-methoxyphenyl)urea l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclopentylmethyl)carbamoyl)-2,2- dimethylpropyl)-3-(biphenyl-4-yl)urea; l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclopentylmethyl)carbamoyl)-2,2- dimethylpropyl)-3-(2-methoxyphenyl)urea; l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclopentylmethyl)carbamoyl)-2,2- dimethylpropyl)-3-(2-chlorophenyl)urea; l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclopentylmethyl)carbamoyl)-2,2- dimethylpropyl)-3-(3-cyanophenyl)urea; l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-isopentylcarbamoyl)-2,2-dimethylpr opyl)-3-(3-chlorophenyl)urea; l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-isopentylcarbamoyl)-2,2-dimethylpr opyl)-3-p-tolylurea; l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-isopentylcarbamoyl)-2,2-dimethylpr opyl)-3-m-tolylurea; l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-isopentylcarbamoyl)-2,2-dimethylpr opyl)-3-(3-methoxyphenyl)urea; l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclopentylmethyl)carbamoyl)-2,2- dimethylpropyl)-3-(4-cyanophenyl)urea; l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclopentylmethyl)carbamoyl)-2,2- dimethylpropyl)-3-(3-fluorophenyl)urea; l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclopentylmethyl)carbamoyl)-2,2- dimethylpropyl)-3-(2-fluorophenyl)urea; l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclopentylmethyl)carbamoyl)-2,2- dimethylpropyl)-3-(4-fluorophenyl)urea; l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclopentylmethyl)carbamoyl)-2,2- dimethylpropyl)-3-(2-nitrophenyl)urea; l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclopentylmethyl)carbamoyl)-2,2- dimethylpropyl)-3-(3-nitrophenyl)urea; l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclopentylmethyl)carbamoyl)-2,2- dimethylpropyl)-3-(2,3-dκhlorophenyl)urea; l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclopentylmethyl)carbamoyl)-2,2- dimethylpropyl)-3-(2,4-dichlorophenyl)urea; l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclopentylmethyl)carbamoyl)-2,2- dimethylpropyl)-3-(2,5-dichlorophenyl)urea; l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclopentylmethyl)carbamoyl)-2,2- dimethylpropyl)-3-(3,4-dichlorophenyl)urea l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclopentylmethyl)carbamoyl)-2,2- dimethylpropyl)-3-(3,5-dichlorophenyl)urea; l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclopentylmethyl)carbamoyl)-2,2- dimethylpropyl)-3-(4-nitrophenyl)urea; l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclopentylmethyl)carbamoyl)-2,2- dimethy lpropy 1)- 3 - (4- acety lpheny l)urea ; l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclopentylmethyl)carbamoyl)-2,2- dimethylpropyl)-3-(4-(trifluoromethoxy)phenyl)urea; l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclopentylmethyl)carbamoyl)-2,2- dimethylpropyl)-3-(benzo[d][l,3]dioxol-5-yl)urea; l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(2-cyclopentylethyl)carbamoyl)-2,2
-dimethylpropyl)-3-(2,4-dichlorophenyl)urea; l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(2-cyclopentylethyl)carbamoyl)-2,2
-dimethylpropyl)-3-(2,5-dichlorophenyl)urea; l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(2-cyclopentylethyl)carbamoyl)-2,2
-dimethylpropyl)-3-(2-methoxyphenyl)urea; l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-isopentylcarbamoyl)-2,2-dimethylpr opyl)-3-(2,4-dichlorophenyl)urea; l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-isopentylcarbamoyl)-2,2-dimethylpr opyl)-3-(2,5-dichlorophenyl)urea; l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-isopentylcarbamoyl)-2,2-dimethylpr opyl)-3-(3,4-dichlorophenyl)urea; l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-isopentylcarbamoyl)-2,2-dimethylpr opyl)-3-(2-methoxyphenyl)urea; l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclopentylmethyl)carbamoyl)-2,2- dimethylpropyl)-3-(4-(trifluoromethyl)phenyl)urea; l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclopentylmethyl)carbamoyl)-2,2- dimethylpropyl)-3-(2-ethylphenyl)urea; l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclopentylmethyl)carbamoyl)-2,2- dimethylpropyl)-3-(2-ethoxyphenyl)urea; l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclopentylmethyl)carbamoyl)-2,2- dimethylpropyl)-3-(3,4-difluorophenyl)urea; l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclopentylmethyl)carbamoyl)-2,2- dimethylpropyl)-3-(3,5-difluorophenyl)urea; l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclopentylmethyl)carbamoyl)-2,2- dimethylpropyl)-3-(2,5-difluorophenyl)urea; l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclopentylmethyl)carbamoyl)-2- methylpropyl)-3-(2-methoxyphenyl)urea; l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclopentylmethyl)carbamoyl)-2- methylpropyl)-3-(2-chlorophenyl)urea; l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclobutylmethyl)carbamoyl)-2,2- dimethylpropyl)-3-(2-methoxyphenyl)urea; l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclobutylmethyl)carbamoyl)-2,2- dimethylpropyl)-3-(2-chlorophenyl)urea; l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclobutylmethyl)carbamoyl)-2-m ethylpropyl)-3-(2-methoxyphenyl)urea; l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclobutylmethyl)carbamoyl)-2-m ethylpropyl)-3-(2-chlorophenyl)urea; l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclobutylmethyl)carbamoyl)-2-m ethylpropyl)-3-(3-chlorophenyl)urea; l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclobutylmethyl)carbamoyl)-2-m ethylpropyl)-3-(2,4-dichlorophenyl)urea; l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclobutylmethyl)carbamoyl)-2-m ethylpropyl)-3-(2-fluorophenyl)urea; l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclobutylmethyl)carbamoyl)-2-m ethylpropyl)-3-(2,4-difluorophenyl)urea; l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(2-cyclopentylethyl)carbamoyl)-2- methylpropyl)-3-(2-methoxyphenyl)urea; l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(2-cyclopentylethyl)carbamoyl)-2- methylpropyl)-3-(2-chlorophenyl)urea; l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(2-cyclopentylethyl)carbamoyl)-2- methylpropyl)-3-(3,4-dichlorophenyl)urea; l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(2-cyclopentylethyl)carbamoyl)-2- methylpropyl)-3-(2,4-dichlorophenyl)urea; l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(2-cyclopentylethyl)carbamoyl)-2- methylpropyl)-3-(2,5-dichlorophenyl)urea; l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(2-cyclopentylethyl)carbamoyl)-2- methylpropyl)-3-(2,5-difluorophenyl)urea; l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclopentylmethyl)carbamoyl)-2- methylpropyl)-3-(2,4-dichlorophenyl)urea; l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclopentylmethyl)carbamoyl)-2- methylpropyl)-3-(2,5-dichlorophenyl)urea; l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclopentylmethyl)carbamoyl)-2- methylpropyl)-3-(2,5-difluorophenyl)urea; l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclobutylmethyl)carbamoyl)-2-m ethylpropyl)-3-(3,4-dichlorophenyl)urea; l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclobutylmethyl)carbamoyl)-2-m ethylpropyl)-3-(2,5-dichlorophenyl)urea; l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclobutylmethyl)carbamoyl)-2-m ethylpropyl)-3-(2,5-difluorophenyl)urea; l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-isopentylcarbamoyl)-2-methylpropy l)-3-(2-methoxyphenyl)urea; l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-isopentylcarbamoyl)-2-methylpropy
1) - 3 -(2-chloropheny l)urea ; l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-isopentylcarbamoyl)-2-methylpropy l)-3-(2,4-dichlorophenyl)urea; l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-isopentylcarbamoyl)-2-methylpropy l)-3-(2,5-dichlorophenyl)urea; l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-isopentylcarbamoyl)-2-methylpropy l)-3-(2,5-difluorophenyl)urea; l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclopentylmethyl)carbamoyl)-2,2- dimethylpropyl)-3-(5-chloro-2-methoxyphenyl)urea; l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclopentylmethyl)carbamoyl)-2,2- dimethylpropyl)-3-(2-(trifluoromethoxy)phenyl)urea; l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclopentylmethyl)carbamoyl)-2- methylbutyl)-3-(2,5-dichlorophenyl)urea; l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclopentylmethyl)carbamoyl)-3- methylbutyl)-3-(2,5-dichlorophenyl)urea; l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclobutylmethyl)carbamoyl)-2,2- dimethylpropyl)-3-(2,5-dichlorophenyl)urea; l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclobutylmethyl)carbamoyl)-2,2- dimethylpropyl)-3-(2,4-dichlorophenyl)urea; l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-isopentylcarbamoyl)-2,2-dimethylpr opy 1) - 3 -(2-chloropheny l)urea ; l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(2-cyclopentylethyl)carbamoyl)-2,2
-dimethy lpropy 1) - 3 -(2-chloropheny l)urea ; l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclobutylmethyl)carbamoyl)-2,2- dimethylpropyl)-3-(5-chloro-2-methoxyphenyl)urea; l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-isopentylcarbamoyl)-2,2-dimethylpr opyl)-3-(5-chloro-2-methoxyphenyl)urea; l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(2-cyclopentylethyl)carbamoyl)-2,2
-dimethylpropyl)-3-(5-chloro-2-methoxyphenyl)urea; l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclobutylmethyl)carbamoyl)-2-m ethylpropyl)-3-(5-chloro-2-methoxyphenyl)urea; l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclopentylmethyl)carbamoyl)-2- methylpropyl)-3-(5-chloro-2-methoxyphenyl)urea; l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-isopentylcarbamoyl)-2-methylpropy l)-3-(5-chloro-2-methoxyphenyl)urea; l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(2-cyclopentylethyl)carbamoyl)-2- methylpropyl)-3-(5-chloro-2-methoxyphenyl)urea; l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclobutylmethyl)carbamoyl)-2,2- dimethylpropyl)-3-(2,5-dimethoxyphenyl)urea; l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclobutylmethyl)carbamoyl)-2,2- dimethylpropyl)-3-(2-methoxy-5-methylphenyl)urea; l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclobutylmethyl)carbamoyl)-2-m ethylpropyl)-3-(2-methoxy-5-methylphenyl)urea; l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclobutylmethyl)carbamoyl)-2,2- dimethylpropyl)-3-(2,4-dimethoxyphenyl)urea; l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclobutylmethyl)carbamoyl)-2-m ethylpropyl)-3-(2,4-dimethoxyphenyl)urea;
1 -((S)- 1 -(N-((hydroxycarbamoyl)methyl)-N-(cyclopentylmethyl)carbamoyl ■2,2- dimethylpropyl)-3-(2-chloropyridin-3-yl)urea;
1 -((S)- 1 -(N-((hydroxycarbamoyl)methyl)-N-(cyclopentylmethyl)carbamoyl ■2,2- dimethylpropyl)-3-(4-chloro-2-methoxy-5-methylphenyl)urea;
1 -((S)- 1 -(N-((hydroxycarbamoyl)methyl)-N-(cyclopentylmethyl)carbamoyl ■2,2- dimethylpropyl)-3-(2-benzoyl-3-chlorophenyl)urea;
1 -((S)- 1 -(N-((hydroxycarbamoyl)methyl)-N-(cyclopentylmethyl)carbamoyl ■2,2- dimethylpropyl)-3-(quinolin-8-yl)urea;
1 -((S)- 1 -(N-((hydroxycarbamoyl)methyl)-N-(cyclopentylmethyl)carbamoyl ■2,2- dimethylpropyl)-3-(benzo[d]thiazol-6-yl)urea;
1 -((S)- 1 -(N-((hydroxycarbamoyl)methyl)-N-(cyclopentylmethyl)carbamoyl ■2,2- dimethylpropyl)-3-(2-(piperidin-l-yl)phenyl)urea;
1 -((S)- 1 -(N-((hydroxycarbamoyl)methyl)-N-(cyclopentylmethyl)carbamoyl ■2,2- dimethylpropyl)-3-(5-(trifluoromethyl)-2-morpholinophenyl)urea;
1 -((S)- 1 -(N-((hydroxycarbamoyl)methyl)-N-(cyclopentylmethyl)carbamoyl ■2,2- dimethylpropyl)-3-(3-chloro-4-morpholinophenyl)urea;
1 -((S)- 1 -(N-((hydroxycarbamoyl)methyl)-N-(cyclopentylmethyl)carbamoyl ■2,2- dimethylpropyl)-3-(quinolin-5-yl)urea;
1 -((S)- 1 -(N-((hydroxycarbamoyl)methyl)-N-(cyclopentylmethyl)carbamoyl ■2,2- dimethylpropyl)-3-(2-(pyrrolidin-l-yl)phenyl)urea;
1 -((S)- 1 -(N-((hydroxycarbamoyl)methyl)-N-(cyclopentylmethyl)carbamoyl ■2,2- dimethylpropyl)-3-(5-fluoro-2-(pyrrolidin-l-yl)phenyl)urea;
1 -((S)- 1 -(N-((hydroxycarbamoyl)methyl)-N-(cyclopentylmethyl)carbamoyl ■2,2- dimethylpropyl)-3-(5-fluoro-2-(piperidin-l-yl)phenyl)urea;
1 -((S)- 1 -(N-((hydroxycarbamoyl)methyl)-N-(cyclopentylmethyl)carbamoyl ■2,2- dimethylpropyl)-3-(5-fluoro-2-morpholinophenyl)urea;
1 -((S)- 1 -(N-((hydroxycarbamoyl)methyl)-N-(cyclopentylmethyl)carbamoyl ■2,2- dimethylpropyl)-3-(3-fluoro-4-(pyrrolidin-l-yl)phenyl)urea; l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclopentylmethyl)carbamoyl)-2,2- dimethylpropyl)-3-(3-fluoro-4-(piperidin-l-yl)phenyl)urea; l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclopentylmethyl)carbamoyl)-2,2- dimethylpropyl)-3-(3-fluoro-4-morpholinophenyl)urea; l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclopentylmethyl)carbamoyl)-2,2- dimethylpropyl)-3-(5-chloroquinolin-8-yl)urea; l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclopentylmethyl)carbamoyl)-2,2- dimethylpropyl)-3-(2-chloro-4-(methylsulfonyl)phenyl)urea; l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclobutylmethyl)carbamoyl)-2,2- dimethylpropyl)-3-(4-chloro-2-methoxy-5-methylphenyl)urea; l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclobutylmethyl)carbamoyl)-2,2- dimethylpropyl)-3-(5-fluoro-2-(pyrrolidin-l-yl)phenyl)urea; l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclobutylmethyl)carbamoyl)-2,2- dimethylpropyl)-3-(quinolin-8-yl)urea; l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-isopentylcarbamoyl)-2,2-dimethylpr opyl)-3-(4-chloro-2-methoxy-5-methylphenyl)urea; l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-isopentylcarbamoyl)-2,2-dimethylpr opyl)-3-(quinolin-8-yl)urea; l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(2-cyclopentylethyl)carbamoyl)-2,2
-dimethylpropyl)-3-(4-chloro-2-methoxy-5-methylphenyl)urea; l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(2-cyclopentylethyl)carbamoyl)-2,2
-dimethylpropyl)-3-(5-fluoro-2-(pyrrolidin-l-yl)phenyl)urea; l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(2-cyclopentylethyl)carbamoyl)-2,2
-dimethy lpropy 1) - 3 -(quinolin- 8 - y l)urea ; l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclobutylmethyl)carbamoyl)-2-m ethylpropyl)-3-(4-chloro-2-methoxy-5-methylphenyl)urea; l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclobutylmethyl)carbamoyl)-2-m ethylpropyl)-3-(5-fluoro-2-(pyrrolidin-l-yl)phenyl)urea l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclobutylmethyl)carbamoyl)-2-m ethylpropyl)-3-(quinolin-8-yl)urea; l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclopentylmethyl)carbamoyl)-2- methylpropyl)-3-(4-chloro-2-methoxy-5-methylphenyl)urea; l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclopentylmethyl)carbamoyl)-2- methylpropyl)-3-(5-fluoro-2-(pyrrolidin-l-yl)phenyl)urea; l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclopentylmethyl)carbamoyl)-2- methylpropyl)-3-(quinolin-8-yl)urea; l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-isopentylcarbamoyl)-2-methylpropy l)-3-(4-chloro-2-methoxy-5-methylphenyl)urea; l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-isopentylcarbamoyl)-2-methylpropy
1) - 3 -(quinolin- 8 - y l)urea ; l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(2-cyclopentylethyl)carbamoyl)-2- methylpropyl)-3-(4-chloro-2-methoxy-5-methylphenyl)urea; l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(2-cyclopentylethyl)carbamoyl)-2- methylpropyl)-3-(5-fluoro-2-(pyrrolidin-l-yl)phenyl)urea; l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(2-cyclopentylethyl)carbamoyl)-2- methylpropyl)-3-(quinolin-8-yl)urea; l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclobutylmethyl)carbamoyl)-2,2- dimethylpropyl)-3-(6-methoxyquinolin-8-yl)urea; l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclobutylmethyl)carbamoyl)-2-m ethylpropyl)-3-(6-methoxyquinolin-8-yl)urea; and l-((S)-l-(N-((hydroxycarbamoyl)methyl)-N-(cyclobutylmethyl)carbamoyl)-2,2- dimethylpropyl)-3-(2-hydroxyphenyl)urea.
[5] A process for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, which comprises reacting a compound of formula (II) with hydroxyl amine:
Figure imgf000060_0001
Wherein, R , R , and X are the same as defined in claim 1 and R is C ~ C
1 4 alkyl.
[6] The process of claim 5, wherein the compound of formula (II) is obtained by reacting a compound of formula (III) or its salt with 0=C=N-X:
Figure imgf000061_0001
1 2 3 wherein, R , R , and X are the same as defined in claim 1 and R is C ~ C alkyl.
1 4
[7] The process of claim 5, wherein the compound of formula (II) is obtained by a process comprising reacting a compound of formula (III) or its salt with triphosgen or 1,1 '-carbonyldiimidazole to obtain a compound of formula (IV); and then reacting the a compound of formula (IV) with NH -X:
2
Figure imgf000061_0002
wherein, R , R , and X are the same as defined in claim 1, R is C ~ C alkyl,
1 4
4 and R is chloro or imidazole.
[8] The process of Claims 6 or 7, wherein the compound of formula (III) or its salt is obtained by a process comprising (a) reacting a compound of formula (V) with a compound of formula (VI); and then (b) deprotecting the prodict of Step (a):
Figure imgf000061_0003
1 2 3 5 wherein, R and R are the same as defined in claim 1, R is C ~ C alkyl, and R
1 4 is a amino protecting group.
[9] The process of Claim 8, wherein the compound of formula (V) is obtained by reacting a compound of formula (VII) or its salt with a compound of formula (VIII) in the presence of a base:
Figure imgf000062_0001
-R (VIII) wherein, R is the same as defined in claim 1, R is C C alkyl, and Z is
1 4 chloro, p-tolunesulfonyl, or methanesulfonyl.
[10] An antibacterial composition comprising a therapeutically effective amount of the compound of formula (I) or its pharmaceutically acceptable salt of any one of claims 1 to 4 and a pharmaceutically acceptable carrier.
PCT/KR2004/000502 2003-04-01 2004-03-11 Deformylase inhibitor, process for preparing the same, and antibacterial composition comprising the same WO2004087643A1 (en)

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