WO2008127025A1

WO2008127025A1 - A novel heterocycle or alkoxyaminomethyl oxazolidinone derivative and manufacturing process thereof

Info

Publication number: WO2008127025A1
Application number: PCT/KR2008/002042
Authority: WO
Inventors: Jae Hoon Kang; Cheon Ho Park; Jin Sun Kwon; Chang Sung Hong
Original assignee: Ildong Pharmaceutical Co., Ltd
Priority date: 2007-04-12
Filing date: 2008-04-11
Publication date: 2008-10-23
Also published as: KR100848232B1

Abstract

The present invention relates to a novel heterocycle or alkoxyaminomethyl oxazolidinone compound represented by formula (I) with excellent antimicrobial activity against gram-positive organism including methicillin-resistant S. aureus and Vancomydn-resistant enterococci, or a pharmaceutically arceptable salts and a process for the preparation thereof.

Description

A NOVEL HETEROCYCLE OR ALKOXYAMINOMETHYL OXAZOLIDINONE DERIVATIVE AND MANUFACTURING

PROCESS THEREOF

Technical Field

[1] The present invention relates to a novel heterocjcle or alkoxyaminomethyl oxa- zolidnone compound represented by formula (I) with excellent antimicrobial activity against gram-positive organism including methicillin-resistant S. aureus and Vancomydn-resistant enterococci, or a pharmaceutically acceptable salts and a process for the preparation thereof.

( I )

[3] wherein, A represents carbon or nitrogen atom; R is selected from the group of consisting of

or -CH NHOR ;R represents acetamide, formamide or triazole; R represents

2 4 2 3 methyl, trifluoromethyl, fluoromethyl, hydroxymethyl, hydroxyethyl, ethyl car- boxymethyl, ethyl carboxylate, methyl carboxylate, acetyl, dethoxymethyl, t - butydmethylsilyl, trimethylsilyl, carboxylic, amide, formyl, hydroxyaminomethyl or nitrile; R represents hydrogen, methyl, ethyl, t-butyl or benzyl; B represents CR or nitrogen;R represents hydrogen or ethyl carboxylate.

[4]

Background Art

[5] In 1980s, the oxazolidnones represent a new class of antibacterial agents which showed activities against a wide spectrum of gram-positive bacterial infections, includng those infections caused by strains resistant to other antibiotics. The oxazolidnones is a relatively new class of orally active, totally synthetic antibacterial agent.

[6]

[7] In 1987, Dupont Co. reported first that Dup-721 (Ibrmula A), a compound of oxa- zolidnone derivative, showed good activities against gram-positive pathogens (includng MRSA, MRSE), gram-negative anaerobes, and Mycobacterium tuberculosis . (EP 0312000, J. Med. Chem. 1989, 32, 1673)

( A )

[9] Subsequent studies at Pharmacia and Upjohn Co. have resulted in two potent oxa- zolidnone antibacterial agents, linezolid (Ibrmula B) and eperezolid (Ibrmula C). These compounds showed good activities against gram-positive bacterial infections, including the resistant strain of methicillin-resistant Staphylococcus aureus (MRSA), penicillin-resistant Streptococcus pneumoniae (PRSP) and vancomydn-resistant enter ococci (VRE). However, oxazolidnones generally do not demonstrate an activity at a useful level against aerobic gram-negative organism.

[12]

Disclosure of Invention Technical Problem

[13] Herein, we have now dscovered that the new heterocjcle or alkoxyaminomethyl ox- azolidnone (formula I) of the present invention increase the spectrum of activity to include resistant strains such as methicillin-resistant Staphylococcus aureus and vancomydn-resistant enterococci as well as showed good pharmacokinetic profile.

[14] Therefore, it is an object of the present invention to provide heterocjcle or alkoxyaminomehtyl oxazolidnone derivatives of formula (I), which can be used as an antibiotic exhibiting higher activities against gram-positive germs includng resistant strains such as methicillin-resistant Staphylococcus aureus and vancomydn-resistant enterococci as well as showed good pharmacokinetic profile.

[15] It is another object of the present invention to provide a process for preparing such an oxazolidnone derivative of formula (I), or its pharmaceutically acceptable salt. [16]

Technical Solution [17] There are provided heterocjcle or alkoxyaminomehtyl oxazolidnone compounds represented by the following formula (I).

(1-10)

(1-11)

(1-14)

(1-17)

(1-29)

(1-30)

(1-34)

(1-39)

(1-41)

(1-45)

(1-49)

(1-50) Mode for the Invention

[68] Hereinafter, a preparation method of these compounds represented by the formula (I) will be described by the following schemes 1-2. [69] Scheme 1

[70] wherein, A, R , R and R are each as defined above.

2 3 5 [71] [72] The general preparation involved nucleophilic aromatic substitution reaction between 3-cyanopyrrole or 4-cyanopyazole with 3,4-dfluoronitrobenzene 1 to give the 3-fluoro-4-azolylnitrobenzene intermedates. Reduction of the nitro group by hy- drogenation in the presence of 10% palladium on carbon catalyst and Cbz protection of the resulting aniline gave intermedates 2. Deprotonation with base (n-BuLϊ) followed by treatment with (R)-(-)-glyddyl butyrate afforded hydroxymethyl oxazoldnones 3. The hydroxymethyl side chain was then elaborated to the azide analogue 4 via standard transformations. Reduction of the azide by hydrogenation over Pd/C or triph- enylphosphine gives an amine which can be then reacted with acetic anhydride/ pyridne or acetic anhydride/formic acid to afforded acetamide or formamide analogue 5, respectively. Also, the azide analogue 4 was then cjclized by refluxing vinyl acetate to afforded triazole analogue 5.

[73]

[74] Oxidation of the nitrile by Raney nickel gave aldehyde 6 which could be then reacted with hydroxylamine hydrochloride afforded to oxime intermedate. The oxime in- termedate was then reacted with JV-chlorosuαinimide and alkyne 7 to afforded isoxazole analogue I '. The afforded analogue 5 was then reacted hydroxylamine hydrochloride in ethanol yielded the aminohydroxyimine intermedate which can be cjclized with anhydride 8 or acid chloride 9 to afforded oxadazole analogue I". The carbonyl side chain in structure was then converted to alcohol by sodum borohydride (NaBH ). This alcohol was then fluorinate with (dethylamino)sulfur trifloride (DAST)

4 to afforded fluoromethyl analogue, (formula I- 1-1-42) [75] Scheme 2

[76] wherein, A, R and R are each as defined above.

2 4

[77]

[78] And also, the aldehyde compounds 6 was then reacted with substituted alkoxylamine hydrochloride 10 to provide the oxime analogues 11, which were then reduced by Boron-pyridne complex in the presented of 10% HCl to afforded alkoxyaminomethyl analogues I. (formula I-43-I-50)

[79]

[80] The compounds of formula I- 1-1-50 may be used in its native form or as a salt. In cases where forming a stable nontoxic acid or base salt is desired, administration of the compound as a pharmaceutically arceptable salt may be appropriate. Pharmaceutically acceptable salts may be obtained using standard procedures well known in the art, alkali metal (for example, sodum or potassium) or alkaline earth metal (for example, calcium or magnesium) salts of carboxylic acids can be made. And reacting a sufficiently basic compound such as an amine with a suitable acid affording a physiologically acceptable anion (for example, ammonium, triethylamine, pyridine and N,N - dmethylethanolamine salt). Suitable inorganic salts are formed, includng hydrochloride, hydrobromide, sulfate and nitrate salts. Organic acid addtion salts may also be formed with acids which form a physiological acceptable anion, for example, formic acid, acetic acid, tartaric acid, citric acid, methylsulfonic acid, lactic acid, succinic add and benzenesulfonic acid.

[81]

[82] The compounds of the present invention have wide antibacterial spectrum, superior antibacterial activity and low toxicity, such that the compound of this invention can be used as an antibacterial agent.

[83]

[84] EXPERIMENT 1>

[85] Test for antibacterial activity

[86]

[87] The in vitro Minimum Inhibitory Concentration (MIC: βg/md,) of test compounds were determined by a standard agar dlution method. ( Chemotherapy, 1981, 29 (Y), 76). Linezolid is included in the assay and serves as a comparator and quality control compound of test compounds. The activity of compounds of this invention is shown in Tables 1-3.

[88]

[89] [Table IJ

[90] [Table 2]

[91]

[92] [Table 3]

[93] As can be seen from Tables 1~3, the oxazolidnone antibacterial agents of this invention have good activity against gram-positive bacterial infection, including MRSA and VRE strains.

[94] [95] EXPERIMENT 2> [96] Acute Toxicity [97] [98] In order to illustrate usefulness of the compounds of the present invention, acute toxicity test of the compounds synthesized in the Examples were carried out. Eεch dose of the compounds dissolved in 100% PEG (Polyethylene glyxtl), was determined in mice using oral route of administration. Mortalities of the animals was recorded 2 weeks later, the results of the acute toxicity studies are shown in Table 4.

[99] [Table 4]

* Mouse: Male ICR strain, 4 weeks

[100] [101] The compounds are shown high stability as an antimicrobial medcament from LD >

50

3000mg/kg in oral routes. Accordingly, the compounds of the present invention can be used in the therapeutic treatment of human beings or animals infected with variety of gram-positive bacteria.

[102]

[103] The present invention includes within its scope pharmaceutical compositions comprising one or more of the compound I and their derivatives as active ingredients, in association with pharmaceutically acceptable carriers, excipients or other additives, if necessary. The compositions may be formulated into various forms such as tablets, capsules, troche, suspension, solution, suppositories, ointment, cream, injection, which may contain conventional additives such as a dspersant, suspending agent, stabilizer and the like. The compounds of formula I according to this invention are administered orally and parenterally, i.e., by injection, for example, by intravenous injection or by other parenteral routes of administration. Pharmaceutical compositions for parenteral administration will generally contain a pharmaceutically acceptable amount of the compound according to formula I as a soluble salt (acid addition salt or base salt) dissolved in a pharmaceutically acceptable liquid carrier such as, for example, water- for-injection and a buffer to provide a suitably buffered isotonic solution. Suitable buffering agents include, for example, L-(+)-lysine, L-(+)-arginine, N - methylglucamine, sodum citrate, sodum bicarbonate and trisodum orthophosphate to name but a few representative buffering agents.

[104]

[105] Ibrmulation examples are described below.

[106]

[107] Formulation example 1

[108]

[ 109] Excipient Amount

[110] The compound of prepared Example 1 400. Omg

[111] Lactose NF 80. Omg

[112] Povicbne NF 4.00mg

[113] Mcrocrystalline cellulose NF 40. Omg

[114] Sod. starch Gljcolate NF 20.0mg

[115] Mg. stearate NF 5.6mg

[116] Water purified

[117]

[118] Elm coating phase

[119] Opadry 85F42138 Yellow 16.8mg [120] Water purified 129.2mg

[121]

[122] Polisher

[123] Carnauba wax 0.0224mg

[124]

[125] Description of the Preferred Embodiments

[126]

[127] The following examples are provided to further illustrate this invention but they should not be taken as limiting. [128]

[129] <Example 1>

[130] N-{(S)-3-[3-Fluoro-4-(3-formyl-pyrrol-l-yl)-phenyl]-2-oxo-oxazolidn-5-yl methyl } - acetamide :

[132]

[133] To a solution of N-{(S)-3-[4-(3-Cyano-pyrrol-l-yl)-3-fluoro-phenyl]-2-oxo- oxazolidn-5-ylmethyl} -acetamide (Ig, 2.92mmol) in formic acid (7ml) was added Raney nickel (Ig) in formic acid (8ml) at O⁰C. The mixture warmed to 65⁰C and stirred for 4h. The Raney nickel was removed by celite filtration and the filtrate was ne utralized with ammonia solution. The solution was extracted with methylene chloride. The combined organic layers were washed with brine. Drying (magnesium sulfate) and concentration in vacuo, the residue was purified by silica gel column chromatography (ethyl acetate/hexane/methanol=4:4:l) to afford the title compound (635mg, 1.83mmol) in a yield of 63%.

[134]

[135] ¹H NMR (DMSO-d ) δ 9.79 (IH, s), 8.28 (IH, t), 8.27 (IH, dd), 7.68-7.72 (2H, m),

6

7.45 (IH, dd), 7.29 (IH, s), 6.68 (IH, dd), 4.77 (IH, m), 4.18 (IH, t), 3.78 (IH, dd),

3.40-3.45 (2H, m), 1.84 (3H, s) [136]

[137] <Example 2> [138] N-((S)-3-{3-Fluoro-4-[3-(hydroxyimino-methyl)-pyrrol-l-yl]-phenyl}-2-oxo-oxazoli dn- 5 -ylmethyl) -acetamide :

[140]

[141] ΛM(S)-3-[3-Fluoro-4-(3-formyl-pyrrol-l-yl)-phenyl]-2-oxo-oxazolidn-5- ylmethylj-acetamide (690mg, 2mmol), hydroxylamine hydrochloride (276mg, 4mmol) and potassium carbonate (552mg, 4mmol) were stirred in methanol/methylene chloride (1:1) (5ml/5ml) for overnight. And then the resulting precipitate was collected, washed with water and dried under vacuum to yield 532mg, 1.48mmol (74%) of title compound.

[142]

[143] ¹H NMR (DMSO-d ) δ 8.87 (IH, s), 7.71 (IH, dd), 7.21-7.46 (2H, m), 6.81 (IH, s),

6

6.87-7.01 (2H, m), 4.88 (IH, m), 4.21 (IH, t), 3.98 (IH, dd), 3.81 (2H, dd), 1.94 (3H, s)

[144]

[145] <Example 3> [146] N-((S)-3-{4-[3-(5-Acetyl-isoxazol-3-yl)-pyrrol-l-yl]-3-fluoro-phenyl}-2-oxo-oxazoli dn-5-ylmethyl)-acetamide (1-1):

[148]

[149] To a solution of N-((S)-3-{3-Fluoro-4-[3-(hydroxyimino-methyl)-pyrrol-l-yl] - phenyl }-2-oxo-oxazolidn-5-ylmethyl)-acetamide (lOOmg, 0.27mmol) in THF (3ml) was added pyridine (2.29mg, 0.027mmol) and JV-chlorosuocinimide (44.5mg, 0.32mmol) at room temperature. The mixture was stirred at 6O⁰C for 30min. The mixture was then cooled to O⁰C and 3-butyn-2-on (55/i6, 0.32mmol) and triethylamine (55.6ιΛ, 0.40mmol) were added dropwise. The mixture was stirred at 6O⁰C for 4h. The solvent was evaporated under reduced pressure and the residue extracted with methylene chloride and water. The combined organic layers were washed with 2N HCl and brine. Drying (magnesium sulfate) and concentration in vacuo, the residue was purified by silica gel column chromatography (ethyl acetate/hexane/methanol=4:4:l) to afford the title compound (20mg, 0.046mmol) in a yield of 17%. [150] [151] ¹H NMR (CDCl ) δ 7.73 (IH, dd), 7.29-7.37 (2H, m), 7.00 (IH, dd), 6.57-6.59 (2H, m), 5.93 (IH, s), 4.86 (IH, m), 4.12 (IH, t), 3.89 (IH, dd), 3.69-3.72 (2H, m), 2.25

(3H, s), 2.23 (3H, s) [152]

[153] <Example 4> [154] 3-(l-{4-[(S)-5-(Acetylamino-methyl)-2-oxo-oxazolidn-3-yl]-2-fluoro-phenyl}-l H-p yrrol-3-yl)-isoxazole-5-carboxylic add methyl ester (1-2):

[156]

[157] To a solution of N-((S)-3-{3-Fluoro-4-[3-(hydroxyimino-methyl)-pyrrol -1-yl] - phenyl }-2-oxo-oxazolidn-5-ylmethyl)-acetamide (lOOmg, 0.27mmol) in THF (3ml) was added pyridine (2.29mg, 0.027mmol) and JV-chlorosuxinimide (44.5mg, 0.32mmol) at room temperature. The mixture was stirred at 6O⁰C for 30min. The mixture was then cooled to O⁰C and methyl propiolate (25.6/i2, 0.32mmol) and tri- ethylamine (55.6ιΛ, 0.40mmol) were added dropwise. The mixture was stirred at 6O⁰C for 4h. The solvent was evaporated under reduced pressure and the residue extracted with methylene chloride and water. The combined organic layers were washed with 2N HCl and brine. Drying (magnesium sulfate) and concentration in vacuo, the residue was purified by silica gel column chromatography (ethyl acetate/ hexane/methanol=4:4:l) to afford the title compound (38.2mg, 0.086mmol) in a yield of 31%.

[158]

[159] ¹H NMR (CDCl ) δ 7.64 (IH, dd), 7.20-7.30 (2H, m), 7.00 (IH, dd), 6.57-6.59 (2H, m), 5.93 (IH, s), 4.79 (IH, m), 4.06 (IH, t), 3.84 (IH, dd), 3.62-3.82 (4H, m), 2.00 (3H, s)

[160]

[161] <Example 5>

[162] N-((S)-3-{4-[3-(5-Diethoxymethyl-isoxazol-3-yl)-pyrrol-l-yl]-3-fluoro-phenyl}-2-ox o-oxazolidn-5-ylmethyl)-acetamide (1-3):

[164]

[165] To a solution of N-((S)-3-{3-Fluoro-4-[3-(hydroxyimino-methyl)-pyrrol -1-yl] - phenyl }-2-oxo-oxazolidn-5-ylmethyl)-acetamide (lOOmg, 0.27mmol) in THF (3ml) was added pyridine (2.29mg, 0.027mmol) and JV-chlorosuxinimide (44.5mg, 0.32mmol) at room temperature. The mixture was stirred at 6O⁰C for 30min. The mixture was then cooled to O⁰C and 3,3-dethoxy-l-propyne (38.5/i2, 0.32mmol) and triethylamine (55.6/i6, 0.40mmol) were added dropwise. The mixture was stirred at 6O⁰C for 4h. The solvent was evaporated under reduced pressure and the residue extracted with methylene chloride and water. The combined organic layers were washed with 2N HCl and brine. Drying (magnesium sulfate) and concentration in vacuo, the residue was purified by silica gel column chromatography (ethyl acetate/ hexane/methanol=4:4:l) to afford the title compound (34.15mg, 0.07mmol) in a yield of 26%.

[166]

[167] ¹H NMR (methanol-d ) δ 7.63 (IH, dd), 7.39-7.46 (2H, m), 7.28 (IH, dd), 7.00 (IH,

4 t), 6.57-6.59 (2H, m), 5.57 (IH, s), 4.72 (IH, m), 4.06 (IH, t), 3.73 (IH, dd), 3.58 (4H, q), 3.48 (2H, d), 1.87 (3H, s), 1.13 (6H, t) [168]

[169] <Example 6> [170] 3-(l-{4-[(S)-5-(Acetylamino-methyl)-2-oxo-oxazolidn-3-yl]-2-fluoro-phenyl}-l H-p yrrol-3-yl)-isoxazole-4,5-dcarboxylic add dethyl ester (1-4):

[172]

[173] To a solution of N-((S)-3-{3-Fluoro-4-[3-(hydroxyimino-methyl)-pyrrol -1-yl] - phenyl }-2-oxo-oxazolidn-5-ylmethyl)-acetamide (lOOmg, 0.27mmol) in THF (3ml) was added pyridine (2.29mg, 0.027mmol) and JV-chlorosuocinimide (44.5mg, 0.32mmol) at room temperature. The mixture was stirred at 6O⁰C for 30min. The mixture was then cooled to O⁰C and diethyl acetylenedcarboxylate (6O.8/i2, 0.32mmol) and triethylamine (55.6/i2, 0.40mmol) were added dropwise. The mixture was stirred at 6O⁰C for 4h. The solvent was evaporated under reduced pressure and the residue extracted with methylene chloride and water. The combined organic layers were washed with 2N HCl and brine. Drying (magnesium sulfate) and concentration in vacuo, the residue was purified by silica gel column chromatography (ethyl acetate/ hexane=3:l) to afford the title compound (41.6mg, 0.078mmol) in a yield of 29%.

[174]

[175] ¹H NMR (methanol-d ) δ 7.60 (IH, dd), 7.38-7.42 (2H, m), 7.24 (IH, dd), 6.98 (IH,

4 t), 6.75-6.82 (2H, m), 4.84 (IH, m), 4.06 (IH, t), 3.90 (IH, dd), 3.87 (4H, q), 3.69-3.72

(2H, m), 2.00 (3H, s), 1.28 (6H, t) [176]

[177] <Example 7> [178] N-((S)-3-{3-Fluoro-4-[3-(5-hydroxymethyl-isoxazol-3-yl)-pyrrol-l-yl]-phenyl}-2-ox o-oxazolidn-5-ylmethyl)-acetamide (1-5):

[180]

[181] To a solution of N-((S)-3-{3-Fluoro-4-[3-(hydroxyimino-methyl)-pyrrol -1-yl] - phenyl }-2-oxo-oxazolidn-5-ylmethyl)-acetamide (lOOmg, 0.27mmol) in THF (3ml) was added pyridne (2.29mg, 0.027mmol) and N-chlorosucdnimide (44.5mg, 0.32mmol) at room temperature. The mixture was stirred at 6O⁰C for 30min. The mixture was then cooled to O⁰C and propargyl alcohol (2O/i6, 0.32mmol) and triethylamine (55.6ιΛ, 0.40mmol) were added dropwise. The mixture was stirred at 6O⁰C for 4h. The solvent was evaporated under reduced pressure and the residue extracted with methylene chloride and water. The combined organic layers were washed with 2N HCl and brine. Drying (magnesium sulfate) and concentration in vacuo, the residue was purified by silica gel column chromatography (ethyl acetate/ hexane/methanol=3:3:l) to afford the title compound (40.2mg, 0.097mmol) in a yield of 36%. [182] [183] ¹H NMR (CDCl ) δ 8.37 (IH, d), 8.08 (IH, s), 7.92 (IH, s), 7.75 (IH, dd), 7.25 (IH, dd), 6.38 (IH, s), 6.08 (IH, s) 4.80-4.84 (3H, m), 4.10 (IH, t), 3.83 (IH, t), 3.82 (IH, dd), 3.64-3.74 (2H, m), 2.04 (3H, s) [184]

[185] <Example 8> [186] ΛH(S)-3-{3-Fluoro-4-[4-(5-hydroxymethyl-isoxazol-3-yl)-pyrazol-l-yl]-phenyl}-2-o xo-oxazolidn-5-ylmethyl)-acetamide (1-6):

[188]

[189] To a solution of N-((S)-3-{3-Fluoro-4-[4-(hydroxyimino-methyl)-pyrazol -1-yl] - phenyl }-2-oxo-oxazolidn-5-ylmethyl)-acetamide (lOOmg, 0.27mmol) in THF (3ml) was added pyridine (2.29mg, 0.027mmol) and JV-chlorosucάnimide (44.5mg, 0.32mmol) at room temperature. The mixture was stirred at 6O⁰C for 30min. The mixture was then cooled to O⁰C and propargyl alcohol (2O/i6, 0.32mmol) and tri- ethylamine (55.6ιΛ, 0.40mmol) were added dropwise. The mixture was stirred at 6O⁰C for 4h. The solvent was evaporated under reduced pressure and the residue extracted with methylene chloride and water. The combined organic layers were washed with 2N HCl and brine. Drying (magnesium sulfate) and concentration in vacuo, the residue was purified by silica gel column chromatography (ethyl acetate/ hexane/methanol=3:3:l) to afford the title compound (42.5mg, O.lOmmol) in a yield of 37%.

[190]

[191] ¹H NMR (CDCl ) δ 8.42 (IH, d), 8.11 (IH, s), 7.85 (IH, t), 7.78 (IH, dd), 7.37 (IH,

3 dd), 6.37 (IH, s), 4.85 (IH, m), 4.70 (2H, s), 4.17 (IH, t), 3.82 (IH, dd), 3.56-3.65

(2H, m), 2.04 (3H, s) [192]

[193] <Example 9> [194] N-[(S)-3-(4-{4-[5-(?er?-Butyl-dmethyl-silanyloxymethyl)-isoxazol-3-yl]-pyrazol-l-y l}-3-fluoro-phenyl)-2-oxo-oxazolidn-5-ylmethyl]-acetamide (1-7):

[196] [197] To a solution of N-((S)-3-{3-Fluoro-4-[4-(5-hydroxymethyl-isoxazol-3-yl)- pyrazol- 1-yl] -phenyl }-2-oxo-oxazolidn-5-ylmethyl)-acetamide (lOOmg, 0.24mmol) and imidazole (33.2mg, 0.48mmol) in DMF (0.4ml) was added dropwise tert - butyldmethylsilyl chloride (55mg, 0.36mmol) at O⁰C. The mixture was allowed to room temperature and stirred overnight. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/ hexane/methanol=4:4:l) to afford the title compound (80mg, 0.15mmol) in a yield of 64%.

[198] [199] ¹H NMR (CDCl ) δ 8.37 (IH, d), 8.08 (IH, s), 7.92 (IH, s), 7.75 (IH, dd), 7.25 (IH, dd), 6.38 (IH, s), 6.08 (IH, s) 4.80-4.84 (3H, m), 4.10 (IH, t), 3.83 (IH, t), 3.82 (IH, dd), 3.64-3.74 (2H, m), 2.04 (3H, s), 0.95 (9H, s), 0.14 (6H, s)

[200] [201] <Example 10> [202] (RJ-3-{4-[3-(5-Acetyl-isoxazol-3-yl)-pyrrol-l-yl]-3-fluoro-phenyl}-5-[l,2,3]triazol-l -ylmethyl-oxazolidn-2-one (1-8):

[204] [205] To a solution of l-[2-Fluoro-4-((/?)-2-oxo-5-[l,2,3]triazol-l-ylmethyl- oxazolidn- 3-yl)-phenyl]-lH-pyrrole-3-carbaldehyde oxime (lOOmg, 0.27mmol) in TΗF (3ml) was added pyridne (2.29mg, 0.027mmol) and JV-chlorosuocinimide (44.5mg, 0.32mmol) at room temperature. The mixture was stirred at 6O⁰C for 30min. The mixture was then cooled to O⁰C and 3-butyn-2-on {55 μJl, 0.32mmol) and triethylamine {55.6 μJl, 0.40mmol) were added dropwise. The mixture was stirred at 6O⁰C for 4h. The solvent was evaporated under reduced pressure and the residue extracted with methylene chloride and water. The combined organic layers were washed with 2N HCl and brine. Drying (magnesium sulfate) and concentration in vacuo, the residue was purified by silica gel column chromatography (ethyl acetate/hexane/methanol=3:3:l) to afford the title compound (25mg, 0.057mmol) in a yield of 21%. [206] u

[207] H NMR (CDCl ) δ 7.78-7.92 (4H, m), 7.60 (IH, dd), 7.26-7.31 (2H, m), 6.82 (IH,

3 dd), 6.60 (IH, s), 5.13 (IH, m), 4.87 (2H, m), 4.20 (IH, t), 3.89 (IH, dd), 2.24 (3H, s) [208]

[209] <Example 11> [210] 3-{ l-[2-Fluoro-4-((/?)-2-oxo-5-[l,2,3]triazol-l-ylmethyl-oxazolidn-3-yl)-phenyl]-l

H-pyrrol-S-ylj-isoxazole-S-carboxylic add ethyl ester (1-9):

[212]

[213] To a solution of l-[2-Fluoro-4-((/?)-2-oxo-5-[l,2,3]triazol-l-ylmethyl- oxazolidn- 3-yl)-phenyl]-lH-pyrrole-3-carbaldehyde oxime (lOOmg, 0.27mmol) in TΗF (3ml) was added pyridine (2.29mg, 0.027mmol) and JV-chlorosuxinimide (44.5mg, 0.32mmol) at room temperature. The mixture was stirred at 6O⁰C for 30min. The mixture was then cooled to O⁰C and ethyl propiolate (32/i2, 0.32mmol) and tri- ethylamine (55.6ιΛ, 0.40mmol) were added dropwise. The mixture was stirred at 6O⁰C for 4h. The solvent was evaporated under reduced pressure and the residue extracted with methylene chloride and water. The combined organic layers were washed with 2N HCl and brine. Drying (magnesium sulfate) and concentration in vacuo, the residue was purified by silica gel column chromatography (ethyl acetate/ hexane/methanol=4:4:l) to afford the title compound (25mg, O.053mmol) in a yield of 19%.

[214]

[215] ¹H NMR (methanol-d ) δ 8.01 (IH, s), 7.75 (IH, s), 7.51 (IH, dd), 7.41 (IH, dd),

4

7.36 (IH, t), 7.15 (IH, dd), 6.97 (IH, dd), 6.61-6.54 (2H, m), 5.53 (IH, s), 4.98 (IH, m), 4.72-4.78 (2H, m), 4.08 (IH, t), 3.87 (IH, dd), 3.59 (2H, q), 1.15 (3H, t)

[216]

[217] <Example 12> [218] (R)-3-{4-[3-(5-Diethoxymethyl-isoxazol-3-yl)-pyrrol-l-yl]-3-fluoro-phenyl}-5-[l,2,3 ] triazol- 1 -ylmethyl-oxazolidn-2-one (I- 10) :

[220] [221] To a solution of l-[2-Fluoro-4-((/?)-2-oxo-5-[l,2,3]triazol-l-ylmethyl- oxazolidn- 3-yl)-phenyl]-lH-pyrrole-3-carbaldehyde oxime (lOOmg, 0.27mmol) in TΗF (3ml) was added pyridine (2.29mg, 0.027mmol) and N-chlorosuodnimide (44.5mg, 0.32mmol) at room temperature. The mixture was stirred at 6O⁰C for 30min. The mixture was then cooled to O⁰C and 3,3-dethoxy-l-propyne (38.5/i2, 0.32mmol) and triethylamine (55.6/i6, 0.40mmol) were added dropwise. The mixture was stirred at 6O⁰C for 4h. The solvent was evaporated under reduced pressure and the residue extracted with methylene chloride and water. The combined organic layers were washed with 2N HCl and brine. Drying (magnesium sulfate) and concentration in vacuo, the residue was purified by silica gel column chromatography (ethyl acetate/ hexane/methanol=3:3:l) to afford the title compound (28.7mg, 0.057mmol) in a yield of 21%.

[222] [223] ¹H NMR (DMSO-d ) δ 7.97 (IH, s), 7.65 (IH, s), 7.49 (IH, dd), 7.43 (IH, dd), 7.37

6

(IH, t), 7.18 (IH, dd), 6.98 (IH, dd), 6.65-6.58 (2H, m), 5.57 (IH, s), 5.05 (IH, m), 4.77-4.80 (2H, m), 4.18 (IH, t), 3.90 (IH, dd), 3.57 (4H, q), 1.13 (3H, t)

[224] [225] <Example 13> [226] (/?)-3-{3-Fluoro-4-[3-(5-trimethylsilanyl-isoxazol-3-yl)-pyrrol-l-yl]-phenyl}-5-[l,2, 3]triazol-l-ylmethyl-oxazolidn-2-one (1-11):

[228] [229] To a solution of l-[2-Fluoro-4-((/?)-2-oxo-5-[l,2,3]triazol-l-ylmethyl- oxazolidn- 3-yl)-phenyl]-lH-pyrrole-3-carbaldehyde oxime (lOOmg, 0.27mmol) in TΗF (3ml) was added pyridine (2.29mg, 0.027mmol) and JV-chlorosuocinimide (44.5mg, 0.32mmol) at room temperature. The mixture was stirred at 6O⁰C for 30min. The mixture was then cooled to O⁰C and trimethylsilylacetylene (44.2/i2, 0.32mmol) and triethylamine (55.6/i2, 0.40mmol) were added dropwise. The mixture was stirred at 6O⁰C for 4h. The solvent was evaporated under reduced pressure and the residue extracted with methylene chloride and water. The combined organic layers were washed with 2N HCl and brine. Drying (magnesium sulfate) and concentration in vacuo, the residue was purified by silica gel column chromatography (methylene chloride/methanol=7:l) to afford the title compound (20.1mg, 0.043mmol) in a yield of 16%.

[230]

[231] ¹H NMR (DMSO-d ) δ 8.02 (IH, dd), 7.78 (IH, s), 7.54 (IH, dd), 7.48 (IH, dd), 7.41

6

(IH, t), 7.28 (IH, dd), 7.02 (IH, dd), 6.75-6.89 (2H, m), 5.58 (IH, s), 4.98 (IH, m),

4.77-4.80 (2H, m), 4.20 (IH, t), 3.87 (IH, dd), 0.13 (9H, s) [232]

[233] <Example 14> [234] (R)-3-{3-Fluoro-4-[4-(5-hydroxymethyl-isoxazol-3-yl)-pyrazol-l-yl]-phenyl}-5-[l,2,

3] triazol- 1 -ylmethyl-oxazolidn-2-one (I- 12) :

[236]

[237] To a solution of l-[2-Fluoro-4-((/?)-2-oxo-5-[l,2,3]triazol-l-ylmethyl- oxazolidn- 3-yl)-phenyl]-lH-pyrazole-4-carbaldehyde oxime (lOOmg, 0.27mmol) in TΗF (3ml) was added pyridine (2.29mg, 0.027mmol) and N-chlorosuodnimide (44.5mg, 0.32mmol) at room temperature. The mixture was stirred at 6O⁰C for 30min. The mixture was then cooled to O⁰C and propargyl alcohol (2O/i6, 0.32mmol) and triethylamine (55.6ιΛ, 0.40mmol) were added dropwise. The mixture was stirred at 6O⁰C for 4h. The solvent was evaporated under reduced pressure and the residue extracted with methylene chloride and water. The combined organic layers were washed with 2N HCl and brine. Drying (magnesium sulfate) and concentration in vacuo, the residue was purified by silica gel column chromatography (methylene chloride/methanol=8:l) to afford the title compound (27.55mg, 0.064mmol) in a yield of 23%. [238] [239] ¹H NMR (DMSO-d ) δ 8.75 (IH, s), 8.30 (IH, s), 8.20 (IH, s), 7.86 (IH, t), 7.78

6

(IH, s), 7.71 (IH, dd), 7.46 (IH, dd), 6.82 (IH, s), 5.74 (IH, bs), 5.19 (IH, m), 4.87

(2H, d), 4.60 (2H, s), 4.30 (IH, t), 3.98 (IH, dd) [240]

[241] <Example 15> [242] N-((S)-3- { 3-Fluoro-4- [3-(N-hydrox}carbamimiά)yl)-pyrrol- 1 -yl] -phenyl } -2-oxo-oxa zolidn- 5 -ylmethyl) -acetamide :

[244]

[245] A solution of N-{(S)-3-[4-(3-Cyano-pyrrol-l-yl)-3-fluoro-phenyl]-2-oxo- oxazolidn- 5-ylmethyl} -acetamide (428mg, 1.25mmol) and hydroxylamine hydrochloride (435mg, 6.25mmol) and sodum bicarbonate (526mg, 6.25mmol) in ethanol (4.12ml) was refluxed overnight. The solvent was evaporated under reduced pressure and resulting precipitate was collected by filtration, washed with water and dried under vacuum to provide 532mg (1.13mmol, 90%) of the title compound.

[246]

[247] ¹H NMR (DMSO-d ) δ 9.13 (IH, s), 8.28 (IH, dd), 7.73 (IH, dd), 7.62 (IH, dd), 7.50

6

(IH, s), 7.41 (IH, dd), 7.10 (IH, s), 6.51 (IH, dd), 5.56 (2H, s), 4.79 (IH, m), 4.19

(IH, t), 3.88 (IH, dd), 3.45 (2H, dd), 1.84 (3H, s) [248]

[249] <Example 16> [250] N-((S)-3-{3-Fluoro-4-[3-(5-methyl-[l,2,4]oxadazol-3-yl)-pyrrol-l-yl]-phenyl}-2-ox o-oxazolidn-5-ylmethyl)-acetamide (1-13):

[252]

[253] A solution of N-((S)-3-{3-Fluoro-4-[3-(N-hydroxy.arbamimiά)yl)-pyrrol- 1-yl] - phenyl }-2-oxo-oxazolidn-5-ylmethyl)-acetamide (30mg, 0.08mmol) and acetic anhydride (I l/i6, 0.117mmol) in pyridine (1.1ml) was refluxed overnight. The solution was diluted with water and extracted with methylene chloride. The combined organic layers were washed with 2N HCl and brine. Drying (magnesium sulfate) and concentration in vacuo, the residue was purified by silica gel column chromatography (ethyl acetate/hexane/methanol=4:4:l) to afford the title compound (28.4mg, 0.07mmol) in a yield of 89%.

[254]

[255] ¹H NMR (CDCl ) δ 7.68 (2H, dd), 7.42 (IH, dd), 7.35 (IH, dd), 7.28 (IH, dd), 7.05 (IH, s), 6.82 (IH, dd), 4.82 (IH, m), 4.11 (IH, t), 3.84 (IH, dd), 3.65 (2H, dd), 2.63 (3H, s), 2.03 (3H, s)

[256]

[257] <Example 17>

[258] iV-CCS.I-S-iS-Fluoro^-tS-CS-trifluoromethyl-tl^^loxadazol-S-y^-pynol-l-yll-pheny l}-2-oxo-oxazolidn-5-ylmethyl)-acetamide (1-14):

[260]

[261] A solution of N-((S)-3-{3-Fluoro-4-[3-(N-hydrox}carbamimiά)yl)-pyrrol- 1-yl] - phenyl }-2-oxo-oxazolidn-5-ylmethyl)-acetamide (70mg, 0.19mmol) and triflu- oroacetic anhydride (36.1/i6, 0.26mmol) in toluene (2ml) was refluxed for 2h . The solution was dluted with water and extracted with methylene chloride. The combined organic layers were washed with 2N HCl and brine. Drying (magnesium sulfate) and concentration in vacuo, the residue was purified by silica gel column chromatography (ethyl acetate/hexane/methanol=4:4:l) to afford the title compound (36.2mg, 0.08mmol) in a yield of 44%.

[262]

[263] ¹H NMR (CDCl ) δ 7.71 (2H, dd), 7.43 (IH, dd), 7.29 (IH, dd), 7.06 (IH, dd), 6.88 (IH, dd), 6.15 (IH, dd), 4.82 (IH, m), 4.12 (IH, t), 3.86 (IH, dd), 3.69 (2H, dd), 2.02 (3H, s)

[264]

[265] <Example 18> [266] 3-(l-{4-[(5)-5-(Acetylamino-methyl)-2-oxo-oxazolidn-3-yl]-2-fluoro-phenyl}-l H-p yrrol-3-yl)-[l,2,4]oxadazole-5-carboxylic add ethyl ester (1-15):

[268]

[269] To a solution of N-((S)-3-{3-Fluoro-4-[3-(N-hydrox}carbamimi(±)yl)-pyrrol- 1-yl] - phenyl }-2-oxo-oxazolidn-5-ylmethyl)-acetamide (62mg, 0.16mmol) and pyridne (4O/i2, 0.49mmol) in toluene (ImI) was added dropwise ethyl chlorooxoacetate (27AβΑ, 0.25mmol) in toluene (ImI) at O⁰C and stirred for 30min. The mixture was allowed to room temperature and stirred for Ih. And then, the mixture was refluxed overnight. The solution was dluted with water and extracted with methylene chloride. The combined organic layers were washed with 2N HCl and brine. Drying (magnesium sulfate) and concentration in vacuo, the residue was purified by silica gel column chromatography (ethyl acetate/hexane/methanol=4:4:l) to afford the title compound (30.8mg, 0.07mmol) in a yield of 41%.

[270]

[271] ¹H NMR (CDCl ) δ 7.72 (IH, dd), 7.68 (IH, dd), 7.42 (IH, dd), 7.29 (IH, dd), 7.05 (IH, s), 6.89 (IH, dd), 6.14 (IH, s), 4.85 (IH, m), 4.56 (2H, t), 4.12 (IH, t), 3.84 (IH, dd), 3.71 (2H, dd), 2.04 (3H, s), 1.47 (3H, s)

[272]

[273] <Example 19>

[274] N-((S)-3-{3-Fluoro-4-[3-(5-hydroxymethyl-[l,2,4]oxadazol-3-yl)-pyrrol-l-yl]-pheny l}-2-oxo-oxazolidn-5-ylmethyl)-acetamide (1-16):

[276]

[277] To a solution of 3-(l-{4-[(S)-5-(Acetylamino-methyl)-2-oxo-oxazolidn-3 -yl] - 2-fluoro-phenyl}-lH-pyrrol-3-yl)-[l,2,4]oxadazole-5-carboxylic add ethyl ester (42.3mg, 0.09mmol) in TΗF (ImI) was added sodum borohydride (7mg, 0.18mmol) at O⁰C. The mixture was stirred at O⁰C for 3h and then quenched with water and extracted with methylene chloride. The combined organic layers were washed with brine. Drying (magnesium sulfate) and concentration in vacuo, the residue was purified by silica gel column chromatography (ethyl acetate/hexane/methanol=4:4:l) to afford the title compound (16mg, 0.04mmol) in a yield of 42%.

[278]

[279] ¹H NMR (DMSO-d ) δ 8.30 (IH, dd), 7.78 (3H, dd), 7.46 (IH, dd), 7.31 (IH, dd),

6

6.75 (IH, s), 6.02 (IH, s), 4.77 (2H, s), 4.75 (IH, m), 4.20 (IH, t), 3.79 (IH, dd), 3.45

(2H, dd), 1.82 (3H, s) [280]

[281] <Example 20> [282] ^-((^-S-iS-Fluoro^-CS^S-fluoromethyl-Cl^^Joxacliazol-S-yO-pyrrol-l-ylJ-phenyl}

-2-oxo-oxazolidn-5-ylmethyl)-acetamide (1-17):

[284]

[285] To a solution of N-((S)-3-{3-Fluoro-4-[3-(5-hydroxymethyl-[l,2,4]oxadazol - 3-yl)-pyrrol-l-yl]-phenyl}-2-oxo-oxazolidn-5-ylmethyl)-acetamide (63.8mg, 0.153mmol) in methylene chloride (ImI) was added dropwise (dethylamino) sulfur trifluoride (DAST) (26.8/ig, 0.202mmol) in methylene chloride (3ml) at -78⁰C. The mixture was stirred at -78⁰C for 2h. Stirring was continued for Ih while the reaction mixture was allowed to room temperature. The mixture was poured into water and extracted with methylene chloride. The combined organic layers were washed with brine. Drying (magnesium sulfate) and concentration in vacuo, the residue was purified by silica gel column chromatography (ethyl acetate/hexane/methanol=4:4:l) to afford the title compound (34.8mg, 0.083mmol) in a yield of 54%.

[286]

[287] ¹H NMR (DMSO-d ) δ 8.30 (IH, dd), 7.82 (IH, dd), 7.74 (2H, dd), 7.46 (IH, dd),

6

7.31 (IH, dd), 6.78 (IH, s), 5.88 (IH, s), 5.77 (IH, s), 4.75 (IH, m), 4.20 (IH, t), 3.79

(IH, dd), 3.45 (2H, dd), 1.84 (3H, s) [288] [289] <Example 21> [290] N-[(5)-3-(3-Fluoro-4-{3-[5-(2-hydroxy-ethyl)-[l,2,4]oxadazol-3-yl]-pyrrol-l-yl}-ph enyl)-2-oxo-oxazolidn-5-ylmethyl]-acetamide (1-18):

[292]

[293] To a solution of N-((S)-3-{3-Fluoro-4-[3-(N-hydrox}carbamimi(±)yl)-pyrrol- 1-yl] - phenyl }-2-oxo-oxazolidn-5-ylmethyl)-acetamide (587.5mg, 1.56mmol) and pyridne (38O/i6, 4.69mmol) in toluene (7.8ml) was added dropwise ethyl malonylchloride (296 [d, 2.34mmol) in toluene (7.8ml) at O⁰C and stirred for 30 min. The mixture allowed to room temperature and then stirred for addtional Ih. The reaction mixture was refluxed overnight. The mixture was poured into water and extracted with methylene chloride. The combined organic layers were washed with 2N HCl and brine. Drying (magnesium sulfate) and concentration in vacuo, the residue was purified by silica gel column chromatography (ethyl acetate/hexane/methanol=4:4:l) to afford the [3-(l-{4-[(S)-5-acetylamino- methyl)-2-oxo-oxazolidn-3-yl]-2-fluoro-phenyl]-l H - pyrrole-3-yl)-[ 1,2,4] oxadazole-5-yl] -acetic acid ethyl ester (78.4mg, 0.166mmol) in a yield of 11%.

[294] A solution of [3-(l-{4-[(S)-5-Acetylamino-methyl)-2-oxo-oxazolidn-3-yl]-2- fluorophenyl]- lH-pyrrole-3-yl)-[l,2,4]oxadazole-5-yl]-acetic acid ethyl ester in ethanol (1.7ml) was treated portionwise with sodum borohydride (12mg, 0.33mmol) at O⁰C. The mixture was stirred for 30min and warm to room temperature and stirred for addtional 2h. The solution was quenched with water and extracted with methylene chloride. The combined organic layers were washed with brine. Drying (magnesium sulfate) and concentration in vacuo, the residue was purified by silica gel column chromatography (ethyl acetate/hexane/methanol=2:2:l) to afford the title compound (lOmg, 0.02mmol) in a yield of 15%.

[295]

[296] ¹H NMR (CDCl ) δ 7.69 (2H, dd), 7.45 (IH, dd), 7.35 (IH, dd), 7.23 (IH, dd), 6.83

3

(IH, s), 4.82 (IH, m), 4.12 (2H, t), 4.11 (IH, t), 3.81 (IH, dd), 3.65 (2H, dd), 3.18 (2H, t), 2.02 (3H, s) [297] [298] <Example 22>

[299] iV-CCS^-S-iS-Fluoro^-K-CS-meihyl-tl^^loxadazol-S-y^-pyrazol-l-yll-phenylJ-l-o xo-oxazolidn-5-ylmethyl)-acetamide (1-19):

[301]

[302] A solution of N-((S)-3-{3-Fluoro-4-[4-(N-hydrox}carbamimi(±)yl)-pyrazol- 1-yl] - phenyl }-2-oxo-oxazolidn-5-ylmethyl)-acetamide (89mg, 0.237mmol) and acetic anhydride (33.5/i6, 0.355mmol) in pyridine (2.3ml) was refluxed overnight. The solution was diluted with water and extracted with methylene chloride. The combined organic layers were washed with 2N HCl and brine. Drying (magnesium sulfate) and concentration in vacuo, the residue was purified by silica gel column chromatography (ethyl acetate/hexane/methanol=4:4:l) to afford the title compound (73.2mg, 0.183mmol) in a yield of 89%.

[303]

[304] ¹H NMR (DMSO-d ) δ 8.77 (2H, dd), 8.29 (IH, dd), 8.26 (IH, dd), 7.86 (IH, dd), 7.77 (IH, s), 7.51 (IH, dd), 4.81 (IH, m), 4.22 (IH, dd), 3.81 (IH, dd), 3.45 (2H, dd), 2.65 (3H, s), 1.85 (3H, s)

[305]

[306] <Example 23>

[307] N-((S)-3-{3-Fluoro-4-[4-(5-trifluoromethyl-[l,2,4]oxadazol-3-yl)-pyrazol-l-yl]-phe nyl}-2-oxo-oxazolidn-5-ylmethyl)-acetamide (1-20):

[309]

[310] A solution of N-((S)-3-{3-Fluoro-4-[4-(N-hydrox}carbamimiά)yl)-pyrazol- 1-yl] - phenyl }-2-oxo-oxazolidn-5-ylmethyl)-acetamide (103mg, 0.27mmol) and triflu- oroacetic anhydride (57.5/i6, 0.41mmol) and pyridne (33.4/i6, 0.41mmol) in toluene (4.5ml) was refluxed overnight. The mixture was dluted with water and extracted with methylene chloride. The combined organic layers were washed with 2N HCl and brine. Drying (magnesium sulfate) and concentration in vacuo, the residue was purified by silica gel column chromatography (ethyl acetate/hexane/methanol=8:8:l) to afford the title compound (58.8mg, 0.13mmol) in a yield of 44%. [311] u

[312] H NMR (DMSO-d ) δ 8.98 (2H, dd), 8.41 (IH, dd), 8.28 (IH, dd), 7.85 (IH, dd),

6

7.77 (IH, dd), 7.52 (IH, dd), 4.82 (IH, m), 4.20 (IH, dd), 3.81 (IH, dd), 3.45 (2H, dd),

1.85 (3H, s) [313]

[314] <Example 24> [315] 3-(l-{4-[(S)-5-(Acetylamino-methyl)-2-oxo-oxazolidn-3-yl]-2-fluoro-phenyl}-l H-p yrazol-4-yl)-[l,2,4]oxadazole-5-carboxylic add ethyl ester (1-21):

[317]

[318] To a solution of N-((S)-3-{3-Fluoro-4-[3-(N-hydrox}carbamimiά)yl)-pyrazol- 1-yl] - phenyl }-2-oxo-oxazolidn-5-ylmethyl)-acetamide (303mg, Qlόmmol) and pyridne (\96ιΛ, 2.42mmol) in toluene (4ml) was added dropwise ethyl chlorooxoacetate (27AβΑ, 0.25mmol) in toluene (4ml) at O⁰C and stirred for 30min. The mixture was allowed to room temperature and stirred for Ih. And then, the mixture was refluxed overnight. The solution was dluted with water and extracted with methylene chloride. The combined organic layers were washed with 2N HCl and brine. Drying (magnesium sulfate) and concentration in vacuo, the residue was purified by silica gel column chromatography (ethyl acetate/hexane/methanol=4:4:l) to afford the title compound (207.5mg, 0.454mmol) in a yield of 56%.

[319]

[320] ¹H NMR (CDCl ) δ 9.05 (IH, dd), 8.92 (IH, dd), 8.39 (IH, dd), 8.26 (IH, dd), 7.85 (IH, dd), 7.78 (IH, dd), 7.50 (IH, dd), 4.81 (IH, m), 4.48 (2H, dd), 4.20 (IH, dd), 3.99 (IH, dd), 3.79 (IH, dd), 1.83 (3H, s), 1.38 (3H, dd)

[321]

[322] <Example 25>

[323] N-((S)-3-{3-Fluoro-4-[4-(5-hydroxymethyl-[l,2,4]oxadazol-3-yl)-pyrazol-l-yl]-phe nyl}-2-oxo-oxazolidn-5-ylmethyl)-acetamide (1-22):

[325]

[326] To a solution of N-((S)-3-{3-Fluoro-4-[4-(N-hydrox}carbamimi(±)yl)-pyrazol- 1-yl] - phenyl }-2-oxo-oxazolidn-5-ylmethyl)-acetamide (150mg, 0.33mmol) in THF (3.6ml) was added sodum borohydride (25mg, 0.65mmol) at O⁰C. The mixture was stirred at O⁰C for 2h and warm to room temperature and stirred for addtional Ih. The solution was quenched with water and extracted methylene chloride. The combined organic layers were washed with brine. Drying (magnesium sulfate) and concentration in vacuo, the residue was purified by silica gel column chromatography (ethyl acetate/ hexane/methanol=4:4:l) to afford the title compound (27.7mg, 0.06mmol) in a yield of 20%.

[327]

[328] ¹H NMR (CDCl ) δ 8.58 (IH, dd), 8.25 (IH, dd), 7.89 (IH, dd), 7.74 (IH, dd), 7.41 (IH, dd), 7.31 (IH, dd), 4.89 (2H, dd), 4.81 (IH, m), 4.12 (IH, dd), 3.84 (IH, dd), 3.65 (2H, dd), 2.03 (3H, s)

[329]

[330] <Example 26>

[331] N-((S)-3-{3-Fluoro-4-[4-(5-fluoromethyl-[l,2,4]oxadazol-3-yl)-pyrazol-l-yl]-phenyl } -2-oxo-oxazolidn- 5 -ylmethyl) - acetamide (1-23 ) :

[333]

[334] To a solution of N-((S)-3-{3-Fluoro-4-[4-(5-hydroxymethyl-[l,2,4]oxadazol- 3-yl)-pyrazol- 1-yl] -phenyl }-2-oxo-oxazolidn-5-ylmethyl)-acetamide (52. lmg, 0.125mmol) in methylene chloride (ImI) was added (dethylamino) sulfur trifluoride (DAST) (20.2/ig, 0.152mmol) in methylene chloride (3ml) at -78⁰C. The mixture was stirred at -78⁰C for 2h. Stirring was continued for Ih while the reaction mixture was allowed to room temperature. The mixture was poured into water and extracted with methylene chloride. The combined organic layers were washed with brine. Drying (magnesium sulfate) and concentration in vacuo, the residue was purified by silica gel column chromatography (ethyl acetate/hexane/methanol=4:4:l) to afford the title compound (34.7mg, 0.083mmol) in a yield of 66%. [335] u

[336] H NMR (DMSO-d ) δ 8.26 (IH, dd), 7.82 (IH, dd), 7.72 (IH, dd), 7.46 (IH, dd),

6

(IH, dd), 3.45 (2H, dd), 1.84 (3H, s) [337]

[338] <Example 27> [339] N-[(S)-3-(3-Fluoro-4-{4-[5-(2-hydroxy-ethyl)-[l,2,4]oxadazol-3-yl]-pyrazol-l-yl}-p henyl)-2-oxo-oxazolidn-5-ylmethyl]-acetamide (1-24):

[341]

[342] To a solution of N-((S)-3-{3-Fluoro-4-[4-(N-hydrox}carbamimiά)yl)-pyrazol-l-yl] - phenyl }-2-oxo-oxazolidn-5-ylmethyl)-acetamide (328.6mg, 0.87mmol) and pyridne (211 id, 2.61mmol) in toluene (4.3ml) was added drop wise ethyl malonylchloride (164 μJl, 1.3mmol) in toluene (4ml) at O⁰C and stirred for 30 min. The mixture allowed to room temperature and then stirred for addtional Ih. The reaction mixture was refluxed overnight. The mixture was poured into water and extracted with methylene chloride. The combined organic layers were washed with 2N HCl and brine. Drying (magnesium sulfate) and concentration in vacuo, the residue was purified by silica gel column chromatography (ethyl acetate/hexane/methanol=4:4:l) to afford the [3-(l-{4-[(S)-5-acetylamino-methyl)-2-oxo- oxazolidn-3-yl]-2-fluoro-phenyl]-l H - pyrazole-4-yl)-[l,2,4]oxadazole-5-yl] -acetic acid ethyl ester (33.4mg, 0.073mmol) in a yield of 8%.

[343] A solution of [[3-(l-{4-[(S)-5-Acetylamino-methyl)-2-oxo-oxazolidn-3-yl]-2-fluoro- phenyl]-lH-pyrazole-4-yl)-[l,2,4]oxadazole-5-yl]-acetic acid ethyl ester in EtOH (ImI) was treated portionwise with sodum borohydride (5.5mg, 0.15mmol) at O⁰C. The mixture was stirred for 30min and warm to room temperature and stirred for addtional 2h. The solution was quenched with water and extracted with methylene chloride. The combined organic layers were washed with water and brine. Drying (magnesium sulfate) and concentration in vacuo, the residue was purified by silica gel column chromatography (ethyl acetate/hexane/methanol=2:2:l) to afford the title compound (5.8mg, 0.013mmol) in a yield of 19%. [344] u

[345] H NMR (CDCl ) δ 8.55 (IH, dd), 8.21 (IH, dd), 7.91 (IH, dd), 7.73 (IH, dd), 7.29

3

(IH, dd), 4.85 (IH, m), 4.12 (2H, dd), 4.11 (IH, dd), 3.88 (IH, dd), 3.62 (2H, dd), 3.21

(2H, dd), 2.03 (3H, s) [346]

[347] <Example 28> [348] N-((5)-3-{3-Fluoro-4-[3-(5-methyl-[l,2,4]oxadazol-3-yl)-pyrrol-l-yl]-phenyl}-2-ox o-oxazolidn-5-ylmethyl)-formamide (1-25) :

[350]

[351] A solution of l-[2-Fluoro-4-((S

)-5-formylaminomethyl-2-oxo-oxazolidn-3-yl)-phenyl ]- ΛMiydroxy- IH - pyrrole-3-carboxamidne (78.8mg, 0.218mmol) and acetic anhydride (3O.9/i6, 0.327mmol) in pyridne (2.1ml) was refluxed overnight. The solution was dluted with water and extracted with methylene chloride. The combined organic layers were washed with 2N HCl and brine. Drying (magnesium sulfate) and concentration in vacuo, the residue was purified by silica gel column chromatography (ethyl acetate/ hexane/methanol=4:4:l) to afford the title compound (31.7mg, 0.08mmol) in a yield of 38%.

[352]

[353] ¹H NMR (methanol-d ) δ 8.22 (IH, dd), 7.75 (IH, dd), 7.69 (IH, dd), 7.62 (IH, dd), 7.42 (IH, dd), 7.05 (IH, dd), 6.82 (IH, dd), 4.83 (IH, m), 4.14 (IH, t), 3.83 (IH, dd), 3.71 (IH, dd), 3.62 (IH, dd), 2.64 (3H, s)

[354]

[355] <Example 29>

[356] N-((S)-3-{3-Fluoro-4-[4-(5-methyl-[l,2,4]oxadazol-3-yl)-pyrazol-l-yl]-phenyl}-2-o xo-oxazolidn-5-ylmethyl)-formamide (1-26) :

[358]

[359] A solution of l-[2-Fluoro-4-((S)-5-formylaminomethyl-2-oxo-oxazolidn-3- yl)-phenyl]-./V-hydroxy-lH-pyrazole-4-carboxamidne (333mg, 0.92mmol) and acetic anhydride (13O.3/i2, 1.38mmol) in pyridine (9ml) was refluxed overnight. The solution was diluted with water and extracted with methylene chloride. The combined organic layers were washed with 2N HCl and brine. Drying (magnesium sulfate) and concentration in vacuo, the residue was purified by silica gel column chromatography (ethyl acetate/hexane/methanol=4:4:l) to afford the title compound (221.6mg, 0.573mmol) in a yield of 62%.

[360]

[361] ¹H NMR (DMSO-d ) δ 8.78 (IH, dd), 8.48 (IH, dd), 8.29 (IH, dd), 8.11 (IH, dd),

6

7.88 (IH, s), 7.78 (IH, dd), 7.51 (IH, dd), 4.83 (IH, m), 4.21 (IH, t), 3.82 (IH, dd),

3.52 (2H, dd), 2.65 (3H, s) [362]

[363] <Example 30> [364] N-((S)-3-{3-Fluoro-4-[4-(5-trifluoromethyl-[l,2,4]oxadazol-3-yl)-pyrazol-l-yl]-phe nyl } -2-oxo-oxazolidn-5-ylmethyl)-formamide (1-27) :

[366]

[367] A solution of l-[2-Fluoro-4-((S)-5-formylaminomethyl-2-oxo-oxazolidn-3- yl)-phenyl]-./V-hydroxy-lH-pyrazole-4-carboxamidne (76.5mg, 0.21mmol) and triflu- oroacetic anhydride (44 //#, 0.32mmol) and pyridne (25.7μ£, 0.32mmol) in toluene (3.4ml) was refluxed overnight. The mixture was dluted with water and extracted with methylene chloride. The combined organic layers were washed with 2N HCl and brine. Drying (magnesium sulfate) and concentration in vacuo, the residue was purified by silica gel column chromatography (ethyl acetate/hexane/methanol=4:4:l) to afford the title compound (21mg, 0.047mmol) in a yield of 23%. [368]

[369] ¹H NMR (CDCl ) δ 8.59 (IH, dd), 8.31 (IH, dd), 8.26 (IH, dd), 7.91 (IH, dd), 7.73

(IH, dd), 7.29 (IH, dd), 6.55 (IH, dd), 4.85 (IH, m), 4.12 (IH, dd), 4.89 (IH, dd), 4.80

(IH, dd), 4.71 (IH, dd) [370]

[371] <Example 31> [372] 3-{ l-[2-Fluoro-4-((S)-5-formylaminomethyl-2-oxo-oxazolidn-3-yl)-phenyl]-l H-pyr azol-4-yl}-[l,2,4]oxadazole-5-carboxylic add ethyl ester (1-28):

[374]

[375] To a solution of l-[2-Fluoro-4-((S)-5-formylaminomethyl-2-oxo-oxazolidn-3- yl)-phenyl]-ΛMiydroxy-lH-pyrazole-4-carboxamidne (221mg, 0.61mmol) and pyridne (148/iβ, 1.83mmol) in toluene (3ml) was added dropwise ethyl chlorooxoacetate (102/i2, 0.9mmol) in toluene (4ml) at O⁰C and stirred for 30min. The mixture was allowed to room temperature and stirred for Ih. And then, the mixture was refluxed overnight. The solution was dluted water and extracted with methylene chloride. The combined organic layers were washed with 2N HCl and brine. Drying (magnesium sulfate) and concentration in vacuo, the residue was purified by silica gel column chromatography (ethyl acetate/hexane/methanol=4:4:l) to afford the title compound (107mg, 0.24mmol) in a yield of 40%.

[376]

[377] ¹H NMR (CDCl ) δ 8.57 (IH, dd), 8.34 (IH, dd), 8.25 (IH, dd), 7.97 (IH, dd), 7.85 (IH, dd), 7.69 (IH, dd), 7.28 (IH, dd), 4.89 (IH, m), 4.58 (2H, dd), 4.16 (2H, dd), 3.89 (IH, dd), 3.71 (IH, dd), 1.52 (3H, dd)

[378]

[379] <Example 32>

[380] (3-{ l-[2-Fluoro-4-((S)-5-formylaminomethyl-2-oxo-oxazolidn-3-yl)-phenyl]-l H-py razol-4-yl}-[l,2,4]oxadazol-5-yl)-acetic aid ethyl ester (1-29):

[382]

[383] To a solution of l-[2-Fluoro-4-((S)-5-formylaminomethyl-2-oxo-oxazolidn-3- yl)-phenyl]-./V-hydroxy-lH-pyrazole-4-carboxamidne (292.6mg, 0.8mmol) and pyridine (\96ιΛ, 2.42mmol) in toluene (4ml) was added dropwise ethyl mal- onylchloride (\53ιΛ, 1.2mmol) in toluene (4ml) at O⁰C and stirred for 30min. The mixture was allowed to room temperature and stirred for Ih. And then, the mixture was refluxed overnight. The solution was diluted water and extracted with methylene chloride. The combined organic layers were washed with 2N HCl and brine. Drying (magnesium sulfate) and concentration in vacuo, the residue was purified by silica gel column chromatography (ethyl acetate/hexane/methanol=4:4:l) to afford the title compound (45.4mg, 0.098mmol) in a yield of 12%.

[384]

[385] ¹H NMR (CDCl ) δ 8.37 (IH, dd), 8.31 (IH, dd), 8.25 (IH, dd), 8.00 (IH, dd), 7.90 (IH, dd), 7.29 (IH, dd), 4.85 (IH, m), 4.28 (2H, dd), 4.12 (IH, dd), 4.02 (2H, dd), 3.88 (IH, dd), 3.75 (IH, dd), 3.70 (IH, dd), 1.28 (3H, dd)

[386]

[387] <Example 33>

[388] (^-S-iS-Fluoro^-CS^S-methyl-Cl^^oxadazol-S-yO-pyrrol-l-ylJ-phenyll-S-Cl^^ ]triazol-l-ylmethyl-oxazolidn-2-one (1-30):

[390]

[391] A solution of l-[2-Fluoro-4-((#)-2-oxo-5-[l,2,3]triazol-l-ylmethyl- oxazolidn-

3-yl)-phenyl]-Λf-hydroxy-lH-pyrrole-3-carboxamidne (186mg, 0.48mmol) and acetic anhydride (68.4/i2, 0.723mmol) in pyridne (6.9ml) was refluxed overnight. The solution was dluted with water and extracted with methylene chloride. The combined organic layers were washed with 2N HCl and brine. Drying (magnesium sulfate) and concentration in vacuo, the residue was purified by silica gel column chromatography (ethyl acetate/hexane/methanol=4:4:l) to afford the title compound (157mg,

0.382mmol) in a yield of 80%. [392] [393] ¹H NMR (DMSO-d ) δ 8.19 (IH, dd), 7.78 (IH, dd), 7.75 (IH, dd), 7.69 (IH, dd),

6

7.68 (IH, s), 7.41 (IH, dd), 6.71 (IH, dd), 5.20 (IH, m), 4.86 (IH, t), 4.32 (IH, dd),

2.65 (3H, s) [394]

[395] <Example 34> [396] (R)-3-{3-Huoro-4-[3-(5-trifluoromethyl-[l,2,4]oxadazol-3-yl)-pyrrol-l-yl]-phenyl}-

5-[l,2,3]triazol-l-ylmethyl-oxazolidn-2-one (1-31):

[398]

[399] A solution of l-[2-Fluoro-4-((R)-2-oxo-5-[l,2,3]triazol-l-ylmethyl- oxazolidn-

3-yl)-phenyl]-Λf-hydroxy-lH-pyrrole-3-carboxamidne (110.4mg, 0.286mmol) and tri- fluoroacetic anhydride (6O/i2, 0.43mmol) and pyridne (34.7μ£, 0.43mmol) in toluene (4.7ml) was refluxed overnight. The mixture was dluted with water and extracted with methylene chloride. The combined organic layers were washed with 2N HCl and brine. Drying (magnesium sulfate) and concentration in vacuo, the residue was purified by silica gel column chromatography (ethyl acetate/hexane/methanol=4:4:l) to afford the title compound (23mg, 0.049mmol) in a yield of 17%.

[400] u

[401] Η NMR (CDCl ) δ 8.08 (2Η, dd), 7.76 (IH, dd), 7.74 (IH, dd), 7.65 (IH, dd), 7.52

3

(IH, s), 7.31 (IH, dd), 7.18 (IH, dd), 6.82 (IH, dd), 5.20 (IH, m), 4.91 (IH, t), 4.31

(IH, dd), 4.05 (2H, dd) [402]

[403] <Example 35> [404] (R)-3-{3-Fluoro-4-[3-(5-hydroxymethyl-[l,2,4]oxadazol-3-yl)-pyrrol-l-yl]-phenyl}-

5-[l,2,3]triazol-l-ylmethyl-oxazolidn-2-one (I-32):

[406]

[407] To a solution of l-[2-Fluoro-4-((/?)-2-oxo-5-[l,2,3]triazol-l-ylmethyl- oxazolidn- 3-yl)-phenyl]-Λf-hydroxy-lH-pyrrole-3-carboxamidne (584mg, 1.515mmol) and pyridine (368/i2, 4.52mmol) in toluene (7.6ml) was added dropwise ethyl chlorooxoacetate (253/i6, 2.27mmol) in toluene (7ml) at O⁰C and stirred for 30min. The mixture was allowed to room temperature and stirred for Ih. And then, the mixture was refluxed overnight. The solution was diluted water and extracted with methylene chloride. The combined organic layers were washed with 2N HCl and brine. Drying (magnesium sulfate) and concentration in vacuo, the residue was purified by silica gel column chromatography (ethyl acetate/hexane/methanol=4:4:l) to afford the (#)-3-{3-fluoro-4-[3-5-hydroxymethyl- [l,2,4]oxadazole-3-yl)-pyrrol-l-yl] - phenyl}-5-[l,2,3]triazol-l-ylmethyl-oxazolidn-2-one (104mg, 0.22mmol) in a yield of 15%.

[408] A solution of (#)-3-{3-Fluoro-4-[3-5-hydroxymethyl-[l,2,4] oxadazole-

3-yl)-pyrrol-l-yl ] -phenyl} -5- [l,2,3]triazol-l-ylmethyl-oxazolidn-2-one in TΗF (2.43ml) was added sodum borohydride (16.7mg, 0.44mmol) at O⁰C. The mixture was stirred for 30min at O⁰C and then warm to room temperature and stirred for addtional 2h. The solution was quenched with water and extracted with methylene chloride. The combined organic layers were washed with 2N HCl and brine. Drying (magnesium sulfate) and concentration in vacuo, the residue was purified by silica gel column chromatography (ethyl acetate/hexane/methanol=4:4:l) to afford the title copound (40.2mg, 0.095mmol) in a yield of 14%.

[409]

[410] ¹H NMR (DMSO-d ) δ 8.20 (2H, dd), 7.79 (IH, dd), 7.78 (IH, dd), 7.70 (IH, dd),

7.68 (IH, dd), 7.42 (IH, dd), 7.31 (IH, dd), 6.75 (IH, dd), 6.04 (IH, dd), 5.20 (IH, m), 4.87 (2H, dd), 4.76 (2H, dd), 4.30 (IH, dd), 3.95 (IH, dd)

[411]

[412] <Example 36>

[413] (R)-3-{3-Fluoro-4-[3-(5-fluoromethyl-[l,2,4]oxadazol-3-yl)-pyrrol-l-yl]-phenyl}-5- [l,2,3]triazol-l-ylmethyl-oxazolidn-2-one (1-33):

[415]

[416] To a solution of (#)-3-{3-Fluoro-4-[3-(5-hydroxymethyl-[l,2,4]oxadazol-3- yl)-pyrrol- 1 -yl] -phenyl} -5- [ 1 ,2,3] triazol- 1 -ylmethyl-oxazolidn-2-one (40. lmg, O.lmmol) in methylene chloride (ImI) was added (dethylaminosulfur) trifluoride (DAST) (18.6/^β, 0.115mmol) in methylene chloride (3ml) at -78⁰C. The mixture was stirred at -78⁰C for 2h. Stirring was continued for Ih while the reaction mixture was allowed to room temperature. The mixture was poured into water and extracted with methylene chloride. The combined organic layers were washed with 2N HCl and brine. Drying (magnesium sulfate) and concentration in vacuo, the residue was purified by silica gel column chromatography (ethyl acetate/hexane/methanol=4:4:l) to afford the title copound (23mg, O.Q53mmol) in a yield of 57%.

[417]

[418] ¹H NMR (DMSO-d ) δ 8.26 (IH, dd), 7.89 (IH, dd), 7.84 (IH, dd), 7.79 (2H, dd),

6

7.49 (IH, dd), 7.40 (IH, s), 6.83 (IH, s), 5.94 (IH, s), 5.83 (IH, s), 5.25 (IH, m), 4.93

(2H, t), 4.36 (IH, dd), 4.03 (IH, dd), 1.84 (3H, s) [419]

[420] <Example 37> [421 ] (3- { 1 - [2-Fluoro-4-((#)-2-oxo-5- [ 1 ,2,3]triazol- 1 -ylmethyl-oxazolidn-3-yl)-phenyl] - 1

H-pyrrol-3-yl}-[l,2,4]oxadazol-5-yl)-acetic acid ethyl ester (1-34):

[423]

[424] To a solution of l-[2-Fluoro-4-((#)-2-oxo-5-[l,2,3]triazol-l-ylmethyl- oxazolidn- 3-yl)-phenyl]-Λf-hydroxy-lH-pyrrole-3-carboxamidne (112mg, 0.303mmol) and pyridne (57.3/i2, 0.455mmol) in toluene (1.5ml) was added dropwise malonylchloride (57.3/i6, 0.455mmol) in toluene (1.5ml) at O⁰C and stirred for 30min. The mixture was allowed to room temperature and stirred for Ih. And then, the mixture was refluxed overnight. The solution was dluted water and extracted with methylene chloride. The combined organic layers were washed with 2N HCl and brine. Drying (magnesium sulfate) and concentration in vacuo, the residue was purified by silica gel column chromatography (ethyl acetate/hexane/methanol=4:4:l) to afford the title compound (13.4 mg, 0.028mmol) in a yield of 9%. [425] u

[426] H NMR (CDCl ) δ 7.81 (IH, dd), 7.75 (IH, dd), 7.63 (IH, dd), 7.54 (IH, dd), 7.37

3

(IH, dd), 7.18 (IH, dd), 7.03 (IH, dd), 6.82 (IH, dd), 5.13 (IH, m), 4.81 (2H, dd), 4.22

(3H, dd), 4.01 (3H, dd), 1.25 (3H, s) [427]

[428] <Example 38> [429] (R)-3-(3-Fluoro-4-{3-[5-(2-hydroxy-ethyl)-[l,2,4]oxadazol-3-yl]-pyrrol-l-yl}-pheny l)-5-[l,2,3]triazol-l-ylmethyl-oxazolidn-2-one (I-35):

[431]

[432] To a solution of (3-{ l-[2-Fluoro-4-((#)-2-oxo-5-[l,2,3]triazol-l-ylmethyl- oxazolidn-3-yl)-phenyl]-l H-pyrrol-3-yl}-[l,2,4]oxadazol-5-yl)-acetic add ethyl ester (13.4mg, 0.28mmol) in ethanol (ImI) was added sodum borohydride (2.1mg, 0.056mmol) at O⁰C. The mixture was stirred for 30min and warm to room temperature and stirred for addtional 2h. The solution was quenched with water and extracted with methylene chloride. The combined organic layers were washed with 2N HCl and brine. Drying (magnesium sulfate) and concentration in vacuo, the residue was purified by silica gel column chromatography (ethyl acetate/hexane/methanol=2:2:l) to afford the title compound (2.9mg, 0.007mmol) in a yield of 24%.

[433]

1,

[434] Η NMR (CDCl ) δ 8.00 (1Η, dd), 7.75 (1Η, dd), 7.65 (1Η, dd), 7.62 (1Η, dd), 7.31

3

(1Η, dd), 7.12 (1Η, dd), 6.73 (1Η, dd), 5.13 (1Η, m), 4.88 (2Η, dd), 4.33 (IH, dd), 4.02

(IH, dd), 4.01 (2H, dd), 3.12 (2H, dd) [435]

[436] <Example 39> [437] (^-S-iS-Fluoro^-K^S-methyl-Cl^^oxadazol-S-yO-pyrazol-l-ylJ-phenylj-S-Cl^,

3]triazol-l-ylmethyl-oxazolidn-2-one (1-36):

[439]

[440] A solution of l-[2-Fluoro-4-((R)-2-oxo-5-[l,2,3]triazol-l-ylmethyl-oxazolidn - 3-yl)-phenyl]-./V-hydroxy-lH-pyrazole-4-carboxamidne (280mg, 0.724mmol) and acetic anhydride (102.7μ£, 1.08mmol) in pyridne (7ml) was refluxed overnight. The mixture was dluted with water and extracted with methylene chloride. The combined organic layers were washed with water, 2N HCl and brine. Drying (magnesium sulfate) and concentration in vacuo, the residue was purified by silica gel column chromatography (ethyl acetate/hexane/methanol=4:4:l) to afford the title compound (40mg, 0.098mmol) in a yield of 15%.

[441]

[442] ¹H NMR (CDCl ) δ 8.53 (IH, dd), 8.22 (IH, dd), 7.89 (IH, dd), 7.85 (IH, dd), 7.75 (IH, s), 7.65 (IH, dd), 7.21 (IH, dd), 5.14 (IH, m), 4.87 (2H, dd), 4.25 (IH, dd), 4.01 (IH, dd), 2.66 (3H, dd)

[443]

[444] <Example 40>

[445] (R)-3-{3-Fluoro-4-[4-(5-trifluoromethyl-[l,2,4]oxadazol-3-yl)-pyrazol-l-yl]-phenyl }-5-[l,2,3]triazol-l-ylmethyl-oxazolidn-2-one (I-37):

[447]

[448] A solution of l-[2-Fluoro-4-((R)-2-oxo-5-[l,2,3]triazol-l-ylmethyl- oxazolidn-

3-yl)-phenyl]-Λf-hydroxy-lH-pyrazole-4-carboxamidne (119mg, 0.307mmol) and tri- fluoroacetic anhydride (64/i6, 0.46mmol) and pyridne (37.2/i6, 0.46mmol) in toluene (5ml) was refluxed overnight. The mixture was dluted with water and extracted with methylene chloride. The combined organic layers were washed with 2N HCl and brine. Drying (magnesium sulfate) and concentration in vacuo, the residue was purified by silica gel column chromatography (ethyl acetate/hexane/methanol=4:4:l) to afford the title compound (68mg, 0.146mmol) in a yield of 48%. [449]

[450] ¹H NMR (CDCl ) δ 8.60 (IH, dd), 8.27 (IH, dd), 7.89 (IH, dd), 7.85 (IH, dd), 7.77

(IH, s), 7.68 (IH, dd), 7.22 (IH, dd), 5.18 (IH, m), 4.85 (2H, dd), 4.28 (IH, dd), 4.02

(IH, dd) [451]

[452] <Example 41> [453] 3-{ l-[2-Fluoro-4-((R)-2-oxo-5-[l,2,3]triazol-l-ylmethyl-oxazolidn-3-yl)-phenyl]-l

H-pyrazol-4-yl}-[l,2,4]oxadazole-5-carboxylic add ethyl ester (1-38):

[455]

[456] To a solution of l-[2-Fluoro-4-((#)-2-oxo-5-[l,2,3]triazol-l-ylmethyl- oxazolidn- 3-yl)-phenyl]-./V-hydroxy-lH-pyrazole-4-carboxamidne (500mg, 1.29mmol) and pyridne (314/i6, 3.88mmol) in toluene (7.6ml) was added dropwise ethyl chlorooxoacetate (2l6ιΛ, 1.94mmol) in toluene (6.4ml) at O⁰C and stirred for 30min. The mixture was allowed to room temperature and stirred for Ih. And then, the mixture was refluxed overnight. The solution was dluted water and extracted with methylene chloride. The combined organic layers were washed with 2N HCl and brine. Drying (magnesium sulfate) and concentration in vacuo, the residue was purified by silica gel column chromatography (ethyl acetate/hexane/methanol=4:4:l) to afford the title comound (71.3mg, 0.15mmol) in a yield of 12%.

[457]

[458] ¹H NMR (DMSO-d ) δ 8.94 (IH, dd), 8.41 (IH, dd), 8.21 (IH, dd), 7.82 (IH, dd),

6

7.80 (IH, s), 7.72 (IH, dd), 7.48 (IH, dd), 5.20 (IH, m), 4.87 (2H, dd), 4.45 (2H, dd),

4.31 (IH, dd), 3.96 (IH, dd), 1.37 (3H, dd) [459]

[460] <Example 42> [461 ] (R)-3- { 3-Fluoro-4-[4-(5-hydroxymethyl- [ 1 ,2,4]oxadazol-3-yl)-pyrazol- 1 -yl] -phenyl

} -5- [ 1 ,2,3] triazol- 1 -ylmethyl-oxazolidn-2-one (1-39) :

[463]

[464] To a solution of 3-{ l-[2-fluoro-4-((R)-2-oxo-5-[l,2,3]triazol-l-ylmethyl- oxazolidn- 3-yl)-phenyl]-lH-pyrazol-4-yl}-[l,2,4]oxadazole-5-carboxylic add ethyl ester in TΗF (4ml) was added sodum borohydride (27.2mg, 0.72mmol) at O⁰C. The mixture was stirred for 30min and then warm to room temperature and stirred for addtional 2h. The solution was quenched with water and extracted with methylene chloride. The combined organic layers were washed with brine. Drying (magnesium sulfate) and concentration in vacuo, the residue was purified by silica gel column chromatography (ethyl acetate/hexane/methanol=2:2:l) to afford title comound (11.3mg, 0.026mmol) in a yield of 8%.

[465]

[466] ¹H NMR (DMSO-d ) δ 8.87 (IH, dd), 8.39 (IH, dd), 8.25 (IH, dd), 7.91 (IH, dd),

6

7.88 (IH, s), 7.78 (IH, dd), 7.53 (IH, dd), 6.15 (IH, dd), 5.27 (IH, m), 4.93 (2H, dd),

4.85 (2H, dd), 4.38 (IH, dd), 4.05 (IH, dd) [467]

[468] <Example 43> [469] (R)-3-{ 3-Fluoro-4-[4-(5-fluoromethyl- [ 1 ,2,4]oxadazol-3-yl)-pyrazol- 1 -yl] -phenyl } -

5-[l,2,3]triazol-l-ylmethyl-oxazolidn-2-one (I-40):

[471]

[472] To a solution of (R)-3-{3-Fluoro-4-[4-(5-hydroxymethyl-[l,2,4]oxadazol-3- yl)-pyrazol-l-yl]-phenyl}-5-[l,2,3]triazol-l-ylmethyl-oxazolidn-2-one (36.3mg, 0.09mmol) in methylene chloride (ImI) was added drop wise (dethylamino) sulfur trifluoride (DAST) (18.16fd, O.lmmol) in methylene chloride (3ml) at -78⁰C. The mixture was stirred for 2h at -78⁰C. Stirring was continued for Ih while the reaction mixture was allowed to room temperature. The mixture was quenched with water and extracted with methylene chloride. The combined organic layers were washed with brine. Drying (magnesium sulfate) and concentration in vacuo, the residue was purified by silica gel column chromatography (ethyl acetate/hexane/methanol=4:4:l) to afford title compound (24mg, O.Q5mmol) in a yield of 59%. [473] [474] ¹H NMR (DMSO-d ) δ 8.26 (IH, dd), 7.89 (IH, dd), 7.79 (2H, dd), 7.49 (IH, dd),

7.40 (IH, s), 6.83 (IH, s), 5.94 (IH, s), 5.83 (IH, s), 5.25 (IH, m), 4.93 (2H, t), 4.36

(IH, dd), 4.03 (IH, dd), 1.84 (3H, s) [475]

[476] <Example 44> [477] (3-{ l-[2-Fluoro-4-((R)-2-oxo-5-[l,2,3]triazol-l-ylmethyl-oxazolidn-3-yl)-phenyl]-l

H-pyrazol-4-yl}-[l,2,4]oxadazol-5-yl)-acetic acid ethyl ester (1-41):

[479]

[480] To a solution of l-[2-Fluoro-4-((#)-2-oxo-5-[l,2,3]triazol-l-ylmethyl- oxazolidn- 3-yl)-phenyl]-N-hydroxy-lΗ-pyrazole-4-carboxamidne (152mg, 0.393mmol) and pyridne (95.3 μJl, 1.178mmol) in toluene (6.4ml) was added ethyl malonylchloride (74/i6, 0.589mmol) in toluene (6ml) at O⁰C. The mixture was stirred for 30min and warm to room temperature and stirred for addtional Ih. The reaction mixture was refluxed overnight. The mixture was poured into water and extracted with methylene chloride. The combined organic layers were washed with brine and 2N HCl. Drying (magnesium sulfate) and concentration in vacuo, the residue was purified by silica gel column chromatography (ethyl acetate/hexane/methanol=4:4:l) to afford title compound (1 lmg, 0.022mmol) in a yield of 6%.

[481]

[482] ¹H NMR (CDCl ) δ 8.55 (IH, dd), 8.23 (IH, dd), 7.91 (IH, dd), 7.79 (2H, dd), 7.65 (IH, dd), 7.19 (IH, dd), 5.13 (IH, m), 4.83 (2H, dd), 4.25 (3H, dd), 4.05 (3H, dd), 1.28 (3H, s)

[483]

[484] <Example 45>

[485] (R)-3-(3-Fluoro-4-{4-[5-(2-hydroxy-ethyl)-[l,2,4]oxadazol-3-yl]-pyrazol-l-yl}-phe nyl)-5-[l,2,3]triazol-l-ylmethyl-oxazolidn-2-one (1-42):

[487]

[488] To a solution of (3-{ l-[2-Fluoro-4-((R)-2-oxo-5-[l,2,3]triazol-l-ylmethyl- oxazolidn- 3 -yl) -phenyl] -1 H-pyrazol-4-yl}-[l,2,4]oxadazol-5-yl)-acetic add ethyl ester (125mg, 0.26mmol) in ethanol(2.75ml) was added sodum borohydride (19.6mg, 0.517mmol) at O⁰C. The mixture was stirred for 30min and warm to room temperature and stirred for 2h. The solution was dluted with water and extracted with methylene chloride. The combined organic layers were washed with brine and 2N HCl. Drying (magnesium sulfate) and concentration in vacuo, the residue was purified by silica gel column chromatography (ethyl acetate/hexane/methanol=2:2:l) to afford title compound (18.2mg, 0.04mmol) in a yield of 16%.

[489]

[490] ¹H NMR (DMSO-d ) δ 8.79 (IH, dd), 8.29 (IH, dd), 8.21 (IH, dd), 7.85 (IH, dd),

6

7.79 (IH, dd), 7.70 (IH, dd), 7.48 (IH, dd), 5.21 (IH, m), 5.05 (IH, dd), 4.88 (2H, dd),

4.31 (IH, dd), 3.98 (IH, dd), 3.88 (2H, dd), 3.12 (2H, dd) [491]

[492] <Example 46> [493] N-{ (S)-3-[3-Fluoro-4-(3-hydroxyaminomethyl-pyrrol- l-yl)-phenyl]-2-oxo-oxazolidn

-5-ylmethyl}-acetamide (1-43):

[495]

[496] To a solution of N-((S)-3-{3-Fluoro-4-[3-(hydroxyimino-methyl)-pyrrol-l- yl] - phenyl }-2-oxo-oxazolidn-5-ylmethyl)-acetamide (53.2mg, 0.15mmol) in methanol (1.2ml) was added Borane-pyridne complex (64.9/i6) at O⁰C. The mixture was stirred for 5min and added 10% HCl (0.75ml) at O⁰C. Stirring was continued for 15min while the reaction mixture was allowed to room temperature. The solution was basified with saturated sodum bicarbonate and extracted with methylene chloride. The combined organic layers were washed with brine. Drying (magnesium sulfate) and concentration in vacuo, the residue was purified by silica gel column chromatography (ethyl acetate/ hexane/methanol=2:2:l) to afford the title compound (17mg, O.Q5mmol) in a yield of

32%. [497] [498] ¹H NMR (CDCl ) δ 7.62 (IH, dd), 7.35 (2H, dd), 7.24 (IH, dd), 6.98 (2H, dd), 6.33

(IH, s), 4.81 (IH, m), 4.09 (IH, dd), 3.98 (IH, s), 3.62 (IH, dd), 2.05 (3H, s) [499]

[500] <Example 47> [501] N-((S)-3-{3-Fluoro-4-[3-(methoxyamino-methyl)-pyrrol-l-yl]-phenyl}-2-oxo-oxazol idn-5-ylmethyl)-acetamide (1-44):

[503]

[504] To a solution of N-((S)-3-{3-Fluoro-4-[3-(methoxyimino-methyl)-pyrrol-l- yl] - phenyl }-2-oxo-oxazolidn-5-ylmethyl)-acetamide (107.3mg, 0.29mmol) in methanol (2.33ml) was added Borane-pyridne complex (126.4/i6) at O⁰C. The mixture was stirred for 5min and added 10% HCl (1.45ml) at O⁰C. Stirring was continued for 15min while the reaction mixture was allowed to room temperature. The solution was basified with saturated sodum bicarbonate and extracted with methylene chloride. The combined organic layers were washed with brine. Drying (magnesium sulfate) and concentration in vacuo, the residue was purified by silica gel column chromatography (ethyl acetate/hexane/methanol=4:4:l) to afford the title compound (98.8mg, 0.262mmol) in a yield of 91%.

[505]

[506] ¹H NMR (CDCl ) δ 7.58 (IH, dd), 7.33(1H, dd), 7.29 (IH, dd), 6.93 (IH, dd), 6.90 (IH, dd), 6.31 (IH, s), 4.81 (IH, m), 4.05 (IH, dd), 3.99 (IH, s), 3.82 (IH, dd), 3.67 (2H, dd), 3.57 (IH, s), 2.04 (IH, s)

[507]

[508] <Example 48>

[509] N-((S)-3-{4-[3-(Benzyloxyamino-methyl)-pyrrol-l-yl]-3-fluoro-phenyl}-2-oxo-oxaz olidn-5-ylmethyl)-acetamide (1-45):

[511]

[512] To a solution of N-((S)-3-{4-[3-(Benzyloxyimino-methyl)-pyrrol-l-yl]-3- fluorophenyl }-2-oxo-oxazolidn-5-ylmethyl)-acetamide (91.9mg, 0.20mmol) in methanol (1.7ml) was added Borane-pyridne complex (9O.3/i6) at O⁰C. The mixture was stirred for 5min and added 10% HCl (1.04ml) at O⁰C. Stirring was continued for 15min while the reaction mixture was allowed to room temperature. The solution was basified with saturated sodum bicarbonate and extracted with methene chloride. The combined

3 organic layers were washed with brine. Drying (magnesium sulfate) and concentration in vacuo, the residue was purified by silica gel column chromatography (ethyl acetate/ hexane/methanol=4:4:l) to afford the title compound (64mg, 0.14mmol) in a yield of

71%. [513] [514] ¹H NMR (CDCl ) δ 7.60 (IH, d), 7.37 (5H, m), 7.21 (IH, dd), 6.91 (2H, dd), 6.47

(IH, bs), 6.31 (IH, s), 4.81 (IH, m), 4.74 (2H, s), 4.04 (3H, dd), 3.80 (IH, dd), 3.62

(2H, dd), 2.06 (3H, s) [515]

[516] <Example 49> [517] N-((S)-3-{4-[3-(Ethoxyamino-methyl)-pyrrol-l-yl]-3-fluoro-phenyl}-2-oxo-oxazolid n-5-ylmethyl)-acetamide (1-46):

[519]

[520] To a solution of N-((S)-3-{4-[3-(Ethoxyimino-methyl)-pyrrol-l-yl]-3- fluorophenyl }-2-oxo-oxazolidn-5-ylmethyl)-acetamide (48.2mg, 0.12mmol) in methanol (1.05ml) was added Borane-pyridne complex (56/i6) at O⁰C. The mixture was stirred for 5min and added 10% HCl (0.64ml) at O⁰C. Stirring was continued for 15min while the reaction mixture was allowed to room temperature. The solution was basified with saturated sodum bicarbonate and extracted with methylene chloride. The combined organic layers were washed with brine. Drying (magnesium sulfate) and concentration in vacuo, the residue was purified by silica gel column chromatography (ethyl acetate/ hexane/methanol=4:4:l) to afford the title compound (36.9mg, 0.09mmol) in a yield of

76%. [521] [522] ¹H NMR (CDCl ) δ 7.57 (IH, d), 7.33 (IH, dd), 7.22 (IH, dd), 6.92 (2H, dd), 6.39

(IH, dd), 6.32 (IH, dd), 4.80 (IH, m), 4.06 (IH, dd), 4.00 (2H, dd), 3.79 (3H, m), 3.67

(2H, m), 2.03 (3H, s), 1.19 (3H, t) [523]

[524] <Example 50> [525] N-((S)-3-{4-[3-(?er?-Butoxyamino-methyl)-pyrrol-l-yl]-3-fluoro-phenyl}-2-oxo-oxaz olidn-5-ylmethyl)-acetamide (1-47):

[527]

[528] To a solution of N-((S)-3-{4-[3-(tert-Butoxyimino-methyl)-pyrrol-l- yl] -

3-fluoro-phenyl}-2-oxo-oxazolidn-5-ylmethyl)-acetamide (70mg, 0.17mmol) in methanol (1.5ml) was added Borane-pyridne complex (76/i6) at O⁰C. The mixture was stirred for 5min and added 10% HCl (0.87ml) at O⁰C. Stirring was continued for 15min while the reaction mixture was allowed to room temperature. The solution was basified with saturated sodum bicarbonate and extracted with methylene chloride. The combined organic layers were washed with brine. Drying (magnesium sulfate) and concentration in vacuo, the residue was purified by silica gel column chromatography (ethyl acetate/hexane/methanol=4:4:l) to afford the title compound (36.1mg, 0.09mmol) in a yield of 51%.

[529]

[530] ¹H NMR (CDCl ) δ 7.60 (IH, d), 7.33 (IH, dd), 7.22 (IH, dd), 6.93 (2H, dd), 6.32 (IH, dd), 4.81 (IH, m), 4.07 (IH, t), 3.92 (2H, s), 3.82 (IH, dd), 3.69 (2H, m), 2.04 (3H, s), 1.25 (9H, s)

[531]

[532] <Example 51>

[533] N-{(S)-3-[3-Fluoro-4-(4-hydroxyaminomethyl-pyrazol-l-yl)-phenyl]-2-oxo-oxazolid in-5-ylmethyl}-acetamide (1-48):

[535]

[536] To a solution of N-((S)-3-{3-Fluoro-4-[4-(hydroxyimino-methyl)-pyrazol-l- yl] - phenyl }-2-oxo-oxazolidn-5-ylmethyl)-acetamide (lOOmg, 0.27mmol) in methanol (2.4ml) was added Borane-pyridne complex (151/i6) at O⁰C. The mixture was stirred for 5min and added 10% HCl (1.8ml) at O⁰C. Stirring was continued for 15min while the reaction mixture was allowed to at room temperature. The solution was basified with saturated sodum bicarbonate and extracted with methylene chloride. The combined organic layers were washed with brine. Drying (magnesium sulfate) and concentration in vacuo, the residue was purified by silica gel column chromatography (ethyl acetate/hexane/methanol=4:4:l) to afford the title compound (32.4mg, 0.09mmol) in a yield of 33%.

[537]

[538] ¹H NMR (methanol-d ) δ 7.96 (IH, dd), 7.72-7.77 (3H, m), 7.32 (IH, dd), 4.83 (IH, m), 4.61 (2H, s), 4.17 (IH, t), 3.86 (IH, dd), 3.55-3.64 (2H, m), 2.00 (3H, s)

[539]

[540] <Example 52>

[541] N-((S)-3-{3-Fluoro-4-[4-(methoxyamino-methyl)-pyrazol-l-yl]-phenyl}-2-oxo-oxaz olidn-5-ylmethyl)-acetamide (1-49):

[543]

[544] To a solution of N-((S)-3-{3-Fluoro-4-[4-(methoxyimino-methyl)-pyrazol-l- yl] - phenyl }-2-oxo-oxazolidn-5-ylmethyl)-acetamide (60mg, 0.16mmol) in methanol (1.4ml) was added Borane-pyridne complex (9O/i6) at O⁰C. The mixture was stirred for 5min and added 10% HCl (1.1ml) at O⁰C. Stirring was continued for 15min while the reaction mixture was allowed to warm at room temperature. The solution was basified with saturated sodum bicarbonate and extracted with methylene chloride. The combined organic layers were washed with brine. Drying (magnesium sulfate) and concentration in vacuo, the residue was purified by silica gel column chromatography (ethyl acetate/hexane/methanol=4:4:l) to afford the title compound (39.6mg, 0.1 lmmol) in a yield of 66%. [545] [546] ¹H NMR (methanol-d ) δ 7.98 (IH, dd), 7.65-7.77 (3H, m), 7.33 (IH, dd), 4.84 (IH,

4 m), 4.62 (2H, s), 4.17 (IH, t), 3.86 (IH, dd), 3.55-3.61 (2H, m), 3.35 (3H, s), 2.00 (3H, s)

[547] [548] <Example 53>

[549] (R)-3-[3-Fluoro-4-(3-hydroxyaminomethyl-pyrrol-l-yl)-phenyl]-5-[l,2,3]triazol-l-yl methyl-oxazolidn-2-one (1-50):

[551]

[552] To a solution of l-[2-Fluoro-4-((/?)-2-oxo-5-[l,2,3]triazol-l-ylmethyl- oxazolidn- 3-yl)-phenyl]-lH-pyrrole-3-carbaldehyde oxime (120mg, 0.32mmol) in methanol (2.8ml) was added Borane-pyridne complex (178/i2) at O⁰C. The mixture was stirred for 5min and added 10% HCl (2.1ml) at O⁰C. Stirring was continued for 15min while the reaction mixture was allowed to room temperature. The solution was basified with saturated sodum bicarbonate and extracted with methylene chloride. The combined organic layers were washed with brine. Drying (magnesium sulfate) and concentration in vacuo, the residue was purified by silica gel column chromatography (ethyl acetate/ hexane/methanol=4:4:l) to afford the title compound (22.7mg, 0.06mmol) in a yield of 19%.

[553]

[554] ¹H NMR (methanol-d ) δ 8.07 (IH, d), 7.76 (IH, d), 7.60 (IH, dd), 7.43 (IH, t), 7.25

4

(IH, dd), 7.16 (IH, d), 6.99 (IH, dd), 6.40 (IH, dd), 5.16 (IH, m), 4.83-4.97 (4H, m), 4.30 (IH, t), 4.00 (H, dd) [555]

Industrial Applicability

[556] The compound of this invention, e.g. of formula (I) or a pharmaceutically acceptable salt thereof have potent antibacterial activity against gram-positive organisms, in particular also against these microorganisms which are resistant to various antibiotics. Thus the compounds of this invention are useful as antibacterial agents for infection with resistant bacteria.

Claims

[1] A compound of formula (I) or a pharmaceutically axep table salt thereof:

( I ) wherein, A represents carbon or nitrogen atom; R is selected from the group of consisting of

or -CH NHOR ;R represents acetamide, formamide or triazole; R represents

2 4 2 3 methyl, trifluoromethyl, fluoromethyl, hydroxymethyl, hydroxyethyl, ethyl car- boxymethyl, ethyl carboxylate, methyl carboxylate, acetyl, dethoxymethyl, t - butydmethylsilyl, trimethylsilyl, carboxylic, amide, formyl, hydrox- yaminomethyl or nitrile; R represents hydrogen, methyl, ethyl, ?-butyl or benzyl;

4

B represents CR or nitrogen;R represents hydrogen or ethyl carboxylate. [2] A process for preparing a compound of formula (F) or a pharmaceutically arceptable salt thereof, which comprises reacting a compound of formula (6) with hydroxylamine hydrochloride and thereafter adding JV-chlorosurinimide in the presence of base such as pyridine and reacting with a compound of formula (7):

(6) (7) (D wherein,

A, R , R and R are the same as defined in claim 1.

2 3 5

[3] A process for preparing a compound of formula (I") or a pharmaceutically arceptable salt thereof, which comprises reacting a compound of formula (5) with hydroxylamine hydrochloride, and thereafter reacting with a formula (8) or a formula (9):

(5) (8) (9) (D wherein, A, R and R are the same as defined in claim 1.

2 3

[4] A process for preparing a compound of formula (I) or a pharmaceutically ai-ceptable salt thereof, which comprises reacting a compound of formula (6) with a compound of formula (10), and thereafter reducing with boron-pyridne complex:

(6) (10) (I'") wherein,

A, R and R are the same as defined in claim 1.

2 4