HK1009449B - Spirocyclic and bicyclic diazinyl and carbazinyl oxazolidinones - Google Patents

Description

Spirocyclic and bicyclic diazinyl and carbozinyl oxazolidinones

The present invention discloses novel and useful oxazolidinone compounds having a spiro or bicyclic diazinyl or carbozinyl group. The compounds are useful antibacterial agents against a number of human and animal pathogenic bacteria including gram-positive aerobic bacteria such as multidrug-resistant staphylococci, streptococci and enterococci, as well as aerobic organisms such as bacteroides and clostridia species and acid-fast organisms such as tubercle bacilli and other mycobacterial species. The compounds of the present invention are related to the phenyl oxazolidinone ring structure disclosed in the publications listed below, except that the compounds of the present invention have a spiro or bicyclic diazinyl or carbooxazinyl group. The compounds of the present invention have useful antibacterial activity.

PCT/US94/08904 application discloses oxazolidinone antibacterial compounds with morpholine or thiomorpholine substituents.

PCT/US93/03570 application discloses oxazolidinones containing a substituted diazine moiety and their use as antimicrobials.

PCT/US92/08267 application discloses substituted aryl and heteroaryl-phenyl-oxazolidinones useful as antibacterial agents.

PCT/US89/03548 application discloses 5' -indolyl-5 β -aminomethyl-oxazolidinones, 3- (fused ring substituted) phenyl-5 β -aminomethyl-oxazolidinones and 3- (nitrogen substituted) phenyl-5 β -aminomethyl-oxazolidinones for use as antibacterial agents.

Other documents disclosing various oxazolidinones include U.S. Pat. Nos. 4,801,600,4,921,869, Gregory W.A. et al, J.Med.chem., 32,1673-81 (1989); gregory w.a. et al, journal of pharmaceutical chemistry (j.med.chem.),33,2569-78 (1990); wang C, et al, Tetrahedron, 45,1323-26 (1989); and Britterli et al, J.Med.Chem., 35,1156 (1992).

European patent publication 352,781 discloses phenyl and pyridyl substituted phenyl oxazolidinones.

European patent publication 316,594 discloses 3-substituted styryl oxazolidinones.

European patent publication 312,000 discloses phenyl methyl and pyridylmethyl substituted phenyl oxazolidinones.

In one aspect, the invention provides compounds of the structure of formula I:in another aspect, the invention includes a compound having the structure of formula II:formula II wherein R¹Is (a) NR⁵,

(b)CR⁶R⁷；R²Independently is H or CH₃；R³Independently is H, F, Cl or methoxy; r⁴Is a reaction product of (a) hydrogen,

(b)C₁-C₈alkyl (optionally substituted by one or more of F, Cl, hydroxy, C₁-C₈Alkoxy radical, C₁-C₈An acyloxy group),

(c)C₃-C₆a cycloalkyl group,

(d) an amino group, a carboxyl group,

(e)C₁-C₈an alkylamino group,

(f)C₁-C₈a dialkylamino group, or a dialkylamino group,

(g)C₁-C₈alkoxy radical, R⁵Is a compound of (a) a hydrogen atom,

(b)C_1-6alkyl (optionally substituted by one or more of Cl, F, CN, OH, C_1-4Alkoxy, amino, hydroxyamino, alkoxyamino, C_1-4Acyloxy radical, C_1-4Alkylsulfinyl radical, C_1-4Alkylsulfinyl group, C_1-4Alkylsulfonyl, aminosulfonyl, C_1-4Alkylaminosulfonyl radical, C_1-4Dialkylaminosulfonyl, 4-morpholinylsulfonyl, phenyl (optionally substituted by one or more F, Cl, CN, OH, C_1-4Alkoxy substituted), 5-isoxazolyl, ethyleneoxy, ethynyl),

(c)C_1-6acyl (optionally substituted by one or more of Cl, F, OH, SH, C_1-4Alkoxy, naphthyloxy, phenoxy (optionally substituted by one or more of Cl, F, OH, C_1-4Alkoxy, amino, C₁-C₄An amido group,C₁-C₄alkyl), amino, C₁-C₄Acylamino, hydroxylamino, alkoxyamino, C_1-4Acyloxy, phenyl, C₁-C₄Alkylcarbonyl group, C₁-C₄Alkylamino radical, C₁-C₄Dialkylamino radical, C₁-C₄Hydroxy acyloxy, C₁-C₄Alkylsulfinyl, phthalimido, maleimido, succinimido),

(d)C_1-6alkylsulfonyl (optionally substituted by one or more of Cl, F, OH, C_1-4Alkoxy, amino, hydroxyamino, alkoxyamino, C_1-4Acyloxy group, phenyl group),

(e) arylsulfonyl (optionally substituted with one or more groups selected from Cl, F, OCH₃OH or C_1-4An alkyl group),

(f)C_1-6alkoxycarbonyl (optionally substituted by one or more of F, Cl, OH, C_1-4Alkoxy radical, C_1-4Acyloxy group, phenyl group),

(g) aminocarbonyl group, C_1-6Alkylamino carbonyl or C_1-6Dialkylaminocarbonyl (in which the alkyl group is optionally substituted by one or more groups selected from Cl, F, OH, C_1-4Alkoxy, phenyl),

(h) 5-or 6-membered heterocycles, in particular 2-oxazolyl, 2-thiazolyl, 3-isoxazolyl, 3-isothiazolyl and dihydro derivatives of these ring systems (all heterocycles are optionally substituted by one or more of Cl, F, OH, amino, C_1-4Amido, C_1-4Alkylsulfonylamino group, C_1-4Alkoxycarbonylamino group, C_1-4Alkoxy radical, C_1-4Acyloxy, which may be substituted by F, OH, or C_1-4Alkoxy-substituted C_1-4An alkyl group),

(i)C₃-C₆cycloalkylcarbonyl (optionally substituted with one or more groups F, Cl, OH, C₁-C₄Alkoxy, CN),

(j) benzoyl radical(optionally substituted by one or more groups selected from F, Cl, OH, C₁-C₄Alkoxy radical, C₁-C₄Alkyl, amino, C₁-C₄Amido),

(k) pyrrolylcarbonyl (optionally substituted by one or more C₁-C₄Alkyl-substituted),

(l)C₁-C₂acyloxyacetyl (acyl optionally substituted by one or more of amino, C₁-C₄Alkylamino radical, C₁-C₄Dialkylamino, 4-morpholino, 4-aminophenyl, 4- (dialkylamino) phenyl, 4- (glycinamido) phenyl); r⁶Is a compound of (a) a hydrogen atom,

(b)OH，

(c)C₁-C₆an alkoxy group,

(d) amino group, C_1-6Alkylamino radical, C_1-6Dialkylamino, hydroxyamino, or C_1-2Alkoxyamino (all of these groups optionally substituted on the nitrogen by C substituted by 1-2 Cl or OH_1-6Acyl, C optionally substituted by 1-2 Cl or OH_1-6Alkylsulfonyl radical, C_1-6An alkoxycarbonyl group),

(e) cl or F; r⁷Is a compound of (a) a hydrogen atom,

(b)C_1-6alkyl (optionally substituted by one or more of Cl, F, CN, OH, C_1-4Alkoxy radical, C_1-4Acyloxy group, amino group),

(c)CN，

(d) phenyl (optionally substituted by one or more of Cl, F, OH, C_{1 -4}Alkoxy) or R⁶And R⁷Together are (a) a carbonyl or thiocarbonyl group,

(b) ethylene glycol ketal group (-OCH)₂CH₂O-), propylene glycol ketal group (-OCH)₂CH₂CH₂O-), ethyleneglycol thioketal group (-SCH)₂CH₂S-), propylene glycol sulfideSubstituted ketal group (-SCH)₂CH₂CH₂S-), dimethylketal group, diethylketal group, dimethylthioketal group, and diethylthioketal group,

(c) oximes (optionally substituted by H, C)_1-6Alkyl (optionally substituted by Cl, F, or C)_1-4Alkoxy-substituted), C_1-6Acyl (optionally substituted by one or more of Cl, F, OH, C_1-4Alkoxy radical, C_1-4Acyloxy) substituted),

(d) hydrazone (optionally substituted by H, C)_1-6Alkyl (optionally substituted by one or more Cl, F, OH, C_1-4Alkoxy radical, C_1-4Acyloxy, phenyl substituted), C_1-6Acyl (optionally substituted by one or more Cl, F, OH, C_1-4Alkoxy radical, C_1-4Acyloxy, phenyl substituted), C_1-6Alkoxycarbonyl (optionally substituted by one or more of Cl, F, OH, C_1-4Alkoxy radical, C_1-4Acyloxy, phenyl), C_1-6Alkylsulfonyl substituted),

(e) imino (optionally substituted by H or C)_1-6Alkyl (optionally substituted by Cl, F, OH, C_{1 -4}Alkoxy radical, C_1-4Acyloxy, phenyl substituted),

(f) carbon-to-carbon double bonds (optionally substituted by H, C)_1-4Alkoxycarbonyl radical, C_1-4Alkyl (optionally substituted by Cl, F, OH, C_1-4Alkoxy, phenyl substituted); m is 0 to 2; n is 1 to 3; o is 0 to 3; and p is 1 to 3.

In another aspect, the invention relates to a method of treating microbial infections in humans or other warm-blooded animals by administering to a patient in need thereof an effective amount of a compound of formula I or II as described above. The compounds can be administered orally, parenterally or topically in pharmaceutical compositions. The compounds are preferably administered orally or parenterally in a dosage of about 0.1 to about 100mg/kg body weight/day, more preferably about 3.0 to about 50mg/kg body weight/day.

The present invention discloses novel spirocyclic and fused bicyclic diazinyl and carbazinyl oxazolidinones of the formula I and II above. The compounds are useful antibacterial agents, effective against a number of human and animal pathogenic bacteria, particularly gram-positive aerobic bacteria such as multiply-resistant staphylococci, streptococci and enterococci, as well as aerobic organisms such as bacteroides and clostridia species and acid-fast organisms such as tubercle bacilli and other mycobacterial species.

The R groups are as described above. The term C as used herein_n-mComprising C_1-8Compounds, i.e. compounds of 1 to 8 carbon atoms and isomers thereof. The various carbon moieties are defined as follows: alkyl refers to aliphatic hydrocarbon groups and includes straight or branched chain forms such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, n-heptyl, isoheptyl, and n-octyl. Acyl refers to a group having 1 to 6 carbon atoms such as formyl, acetyl, propionyl, and the like, and isomeric forms thereof.

R³The substituents are preferably fluorine, more preferably fluorine and hydrogen, wherein R³One may be fluorine and the other hydrogen, or each R³Is fluorine.

R⁴The substituents are preferably hydrogen, methyl, difluoromethyl, dichloromethyl, hydroxymethyl or methoxy. R⁴More preferably methoxy, difluoromethyl, dichloromethyl or methyl. R⁴Most preferred is methyl.

R⁵The substituent is preferably a hydroxyacetyl group.

The absolute configuration of the C-5 position of the oxazolidinone ring of the compounds of the invention is preferably represented by the structures of formulae I and II. This absolute configuration is referred to as (S) in the Cahn-Ingold-Prelog nomenclature system. It is this (S) enantiomer that has pharmacological activity. The racemic mixture thereof is used in the same way and for the same purpose as the pure (S) -enantiomer; except that two times the racemate is used to produce the same antibacterial effect. It will be appreciated by those skilled in the art that diastereoisomers are possible when chiral centres are present in the diazinyl or carbozinyl moieties of the compounds of formulae I and II. These racemates and enantiomerically enriched diastereoisomers also fall within the scope of the compounds of formulae I and II of the present invention.

If desired, organic or inorganic acids may be used to form non-toxic pharmaceutically acceptable acid addition salts of the compounds of the present invention. Acids which may be mentioned are sulfuric acid, nitric acid, phosphoric acid, hydrochloric acid, citric acid, acetic acid, lactic acid, tartaric acid, pamoic acid, ethanedisulfonic acid, sulfamic acid, succinic acid, cyclohexylsulfamic acid, fumaric acid, maleic acid and benzoic acid. These salts are readily prepared by methods known in the art.

The pharmaceutical compositions of the present invention may be prepared by mixing a compound of formula I or II with solid or liquid pharmaceutically acceptable carriers and, optionally, pharmaceutically acceptable adjuvants and excipients using standard and conventional techniques. Such pharmaceutical compositions are useful in the treatment of microbial infections in humans or other warm-blooded animals (patients) by various routes of administration in effective or therapeutically effective amounts. Typical amounts may range from about 0.1 to about 100mg/kg body weight/day, more preferably from about 3.0 to about 50mg/kg body weight/day.

Solid form compositions include powders, tablets, dispersible granules, capsules, cachets, and suppositories. The solid carrier may be at least one functional substance such as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, tablet disintegrating agents, encapsulating agents. Inert solid carriers include magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, cellulosic materials, low melting waxes, cocoa butter, and the like. Liquid form compositions include solutions, suspensions and emulsions. For example, solutions of the compounds of the present invention dissolved in water and water-propylene glycol and water-polyethylene glycol systems may be provided, optionally with suitable conventional coloring, flavoring, stabilizing and thickening agents.

Preferably, pharmaceutical compositions are provided in unit dosage forms containing an effective or appropriate amount of the active compound, i.e., a compound of formula I of the present invention, prepared by conventional techniques.

The amount of active compound, i.e., a compound of formula I or II of the present invention, in a pharmaceutical composition or unit dosage form thereof can be adjusted over a wide range depending upon the particular application, the potency of the particular compound, and the desired concentration. Typically the active compound is present in an amount of from 0.5% to 90% by weight of the composition.

In use in the treatment or prophylaxis of bacterial infections in warm-blooded animals, the compounds or pharmaceutical compositions thereof will be administered in oral and/or parenteral dosage forms to achieve and maintain a concentration, i.e., level or blood level, of the active ingredient which is effective against the bacteria in the animal undergoing treatment. Typically, such an antibacterially effective amount of the active ingredient is in a dosage range of from about 0.1 to about 100, more preferably from about 3.0 to about 50mg/kg body weight/day. It will be appreciated that such dosages may vary according to the needs of the patient, the severity of the bacterial infection to be treated and the particular compound used. It is also understood that the initial dose administered to achieve the desired blood level quickly should be increased above the above level, or the initial dose may be less than optimal and the daily dose gradually increased as the case may be during the course of treatment. The daily dose may also be divided into multiple doses, for example 2-4 times per day, if desired.

The compounds of formula I or II of the present invention may be administered parenterally, i.e. by injection, for example intravenously or by other parenteral routes. Pharmaceutical compositions for parenteral administration will generally comprise a pharmaceutically acceptable amount of a compound of formula I or II as a soluble salt (acid addition or base salt) in a pharmaceutically acceptable liquid carrier, for example, water for injection and a buffer which provides a suitably buffered, isotonic solution, for example, a solution having a pH of about 3 to 7. Suitable buffers include, for example, trisodium orthophosphate, sodium bicarbonate, sodium citrate, N-methylglucamine, L (+) -lysine and L (+) -arginine, but are not limited to these representative buffers. The compounds of formula I or II are typically dissolved in a sufficient amount of carrier to provide a pharmaceutically acceptable injection solution at a concentration ranging from about 1mg/ml to about 400 mg/ml. The resulting liquid pharmaceutical composition is administered to obtain the above antibacterial effective dose.

Processes for preparing enantiomerically pure forms of oxazolidinones of formula I or II are illustrated in schemes I-VI.

As shown in scheme I, fused bicyclic diazines and carboxazines of structure 1 are known in the literature. EP0350733a2, Dave, p.r.; forohar, F.; axenrod, t.; qi, l.; watnick, c.; yazdekhaust, H. (Tetrahedron Lett),1994,35, 8965. Jacqut, j. -p.; bouzard, d.; kiechel, J. -R.; remuzon, P. (Tetrahedron Lett),1991,32,1565, JP 8956673, chemical abstracts (chem. Abstr.),1989,111,153779 w. Loftus, p.; et al, journal of heterocyclic chemistry (J.heterocyclic. chem.),1983,20, 321. Gobeaux, b.; ghosez, L. (Heterocycles),1989,28, 29. Xu, w.; zhang, x. -m.; Mariano, p.s. (j.am.chem.soc.),1991,113,8863. In addition, spirocyclic diazines and carbazines of structure 2 are also known. Culbertson, t.p., Sanchez, j.p., Gambino, l., Sesnie, j.a., journal of pharmaceutical chemistry (j.med.chem.),1990,33, 2270. Domagala, j.m.; et al U.S. patent 4638067,1987, Xu, w.; Zhang, x. -m.; Mariano, p.s. "american society for chemistry" (j.am.chem.soc.),1991,113,8863.

Routes ii-vi summarize the synthesis of oxazolidinone antibacterial agents of structural formula i and ii from diazine or carbazine 1 and 2.

As shown in scheme ii, diazine or carbozine 1 is reacted with functionalized nitrobenzene 3(X = halogen or triflate) in the presence of a suitable base/solvent mixture such as dimethylsulfoxide of potassium phosphate dibasic or N, N-diisopropylethylamine in acetonitrile or THF, and at a suitable temperature, typically room temperature to 70 ℃, to give adduct 4. It will be appreciated by those skilled in the art that the R1 group of compound 1 may require the presence of an appropriate protecting group. For example, for diazines, when R¹When it is nitrogen, blocking of the benzyl protecting group at this position is effective. In addition, for the carbozine variants (R)¹= functionalized carbon) can be protected as its t-butyldimethylsilyl ester. For R in the formula¹In the case of carbonyl groups, the functional group may be protected with a ketal before conversion for further chemical conversion. It will be appreciated by those skilled in the art that these protecting groups are representative only and that we may of course use other protecting groups such as those described in Greene, T.W.; Wuts, P.G.M. "(protective groups in Organic Synthesis), second edition, John Wiley&Sons, New York, 1991. The nitro group of 4 is then introduced into the reaction mixture by reaction with a suitable catalyst such as 10% palladium on charcoal or W-2 Raney nickel in the presence of a suitable solvent such as THF/H₂Catalytic hydrogenation in O. When the latter solvent system is used, the reaction mixture is first filtered to remove the catalyst and the filtrate containing the intermediate aniline is treated with, for example, sodium bicarbonate and benzyl or methyl chloroformate to give the corresponding benzyl group (R = CH)₂Ph) or methyl (R = CH)₃) A urethane derivative 5. When R is¹Is benzylamino, the benzyl group is lost under hydrogenation conditions and is substituted, for example, by Cbz in a subsequent urethane formation reaction. The urethane 5 is then deprotonated with a suitable base such as n-butyllithium (n-BuLi), Lithium Diisopropylamide (LDA) or lithium bis (trimethylsilyl) amide in a suitable solvent such as Tetrahydrofuran (THF) and at a suitable temperature such as-78 deg.C to-60 deg.C to give a lithiated intermediate which is then treated with the commercial (-) - (R) -glycidylbutyrate. Warming to room temperature directly affords 5- (hydroxymethyl) oxazolidinone 6 in enantiomerically enriched form.

As shown in scheme iii, compound 6 is converted to the corresponding mesylate 7(R = methyl) or arylsulfonate 7(R = ArSO) by the action of, for example, methanesulfonyl chloride/pyridine or methanesulfonyl chloride/triethylamine/dichloromethane or p-toluenesulfonyl chloride/pyridine₂Such as p-toluenesulfonyl). The resulting sulfonate ester derivative 7 is then reacted with an azide source, such as sodium or potassium azide, in an aprotic solvent such as N, N-Dimethylformamide (DMF) or 1-methyl-2-pyrrolidone, optionally in the presence of a catalyst such as 18-crown-6, and at a temperature of 50-90 ℃ to give the azide. The azide is then hydrogenated with a palladium-on-carbon or platinum catalyst in a suitable solvent such as ethyl acetate or methanol to reduce it to the corresponding amine 9. Alternatively, reduction is carried out by treatment of the azide 8 with a trivalent phosphorus compound such as triphenylphosphine in a suitable solvent such as tetrahydrofuran followed by addition of water. The intermediate amine 9 can also be prepared by ethanol/H with methylamine₂O is prepared by treating phthalimide derivative 10 (obtained by reacting sulfonate ester 7 with potassium phthalimide in a suitable solvent such as acetonitrile and at reflux temperature) at reflux temperature. Or the amine 9 may be directly from the formazanThe benzenesulfonyl ester 7 is soaked in oil bath at 70-95 deg.C in H₂Prepared by ammonolysis in a sealed reaction vessel of an O/isopropanol/THF solvent system. Amine 9 is then acylated using reactions known to those skilled in the art to provide oxazolidinones of structure 11. For example, the amine may be reacted with an acid chloride or anhydride in a basic solvent such as pyridine at a temperature in the range of-30 to 30 ℃ to provide acylated compound 11 (R)⁴= optionally substituted alkyl). Those skilled in the art will appreciate that the acylation may be carried out using standard acylation techniques, such as March, j. "Advanced Organic Chemistry", 3 rd edition; john Wiley&Sons, New York,1985, p370-375, other carbonyl groups within the scope of the invention can be readily introduced onto the amine 9 to give other examples of 11. Oxazolidinone 11 is an example of structural formula I of the present invention.

Selected examples of oxazolidinones 11 containing fused bicyclic and carboxazines (per se, antibacterial agents of formula I) can be further synthesized into other compounds of formula I, as shown in schemes IV and V.

The corresponding Cbz protected derivative 11 (R)¹= CbzN) catalytic hydrogenolysis effectively resulting compound 12 (see scheme iv) can be N-alkylated by methods known in the art including treatment of 12 with an alkyl halide or tosylate in the presence of a suitable base to give compound 13. Alternatively, such as March, j. "Advanced Organic Chemistry", 4 th edition; john Wiley&Sons, New York,1992, p898-900 introduces the selected alkyl group onto the nitrogen of 12 by reductive alkylation. Compound 12 can also be converted to the various acylated derivatives 14 by treating 12 with various carbonyl derivatives such as acid chlorides, acid anhydrides, and the like in the presence of an appropriate base and in an appropriate solvent as is known in the art. Similarly, sulfonamide derivatives 15 can be prepared by reacting 12 with alkyl and aryl sulfonyl chlorides in the presence of a suitable amine base and in a suitable solvent as known in the art. Urethane 16 is prepared by reacting compound 12 with chloroformate or the like in the presence of a suitable base and in a suitable solvent system known in the art. Indeed, the above discussion should be considered merely representative, as other derivatives of 12 are possible, e.g.Reaction of 12 with isocyanate gives urine 14(R = NHY, where Y is optionally substituted alkyl or phenyl). Compounds 12-16 are examples of fused bicyclic diazines of structural formula I, which are the subject of the present invention.

From ketals 11[ R ]¹=C(OCH₂CH₂O)]Acid hydrolysis of (e.g., with p-toluenesulfonic acid in acetone/water), compound 17 (see scheme V), which is readily available, can be further synthesized as additional examples of structural formula I. For example, such as Greene, T.W.; Wuts, P.G.M. "Protective Groups in Organic Synthesis", second edition, John Wiley&Sons New York,1991, p212-213 and March, J. "advanced organic Chemistry", 4 th edition; john Wiley&Various hydrazone derivatives 18 can be prepared by reacting 17 with hydrazine according to the method described by Sons, New York,1992, and p 904-905. The oxime 19 is readily prepared by reaction of 17 with, for example, hydroxylamine hydrochloride or methoxyamine hydrochloride in the presence of a suitable base such as pyridine and in a suitable solvent such as methanol at room temperature. Such as March, j. "Advanced Organic Chemistry", 4 th edition; john Wiley&Imine 20 was synthesized by treating 17 with a primary amine as described by Sons, New York,1992, p 896-897. The olefinic derivatives 21 are prepared by reacting 17 with various olefinating agents such as phosphonium lactonate salts and the like as known in the art. Representative examples are described in March, j. "Advanced organic chemistry", 4 th edition; john Wiley&Sons, New York,1992, p 956-963. The ketone moiety of 17 is suitable for further modification. Such as March, j. "Advanced Organic Chemistry", 4 th edition; john Wiley&Sons, New York,1992, p893-894, 17 reacted with Lawesson's reagent or other reagents to give the corresponding thioketone 22. It will be appreciated by those skilled in the art that further transformations of 17-22 are possible. For example, selective reduction of the ketone, oxime and olefinic moieties of 17,19 and 21, respectively, using catalytic hydrogenation conditions or borane-based reduction methods, yields the corresponding hydroxyl, amino and alkyl derivatives, respectively. By reacting 17 with diols, dithiols, alcohols or thiols as in Greene, T.W.; Wuts, P.G.M. "Protective Groups in organic Synthesis", second edition, John Wiley &Sons New York,1991, p177-207 also converts Compound 17 to the corresponding cyclic and acyclic ketals and dithioketals. Compounds 17-22 and the above oxides represent examples of the subject fused bicyclic carbazinyl oxazolidinone class of antibacterial agents.

It will be appreciated by those skilled in the art that the above-described methods for preparing fused bicyclic diazinyl and carbazinyl oxazolidinone antibacterial agents are merely representative in nature and that other synthetic methods are known, such as some of the methods described in the cited literature. It will also be appreciated by those skilled in the art that the synthetic procedures outlined above can also be used substantially unchanged to prepare the subject spirobicyclic diazinyl and carbazinyl oxazolidinone antibacterial agents of formula II (see scheme VI).

Example 1: (S) -N- [ [3- [4- [ cis-3- (benzyloxycarbonyl) -3, 7-diazabicyclo [3.3.0] octan-7-yl ] -3-fluorophenyl ] -2-oxo-oxazolidinyl ] methyl ] acetamide step 1: cis-3-benzyl-7- (2-fluoro-4-nitrophenyl) -3, 7-diazabicyclo [3.3.0] octane

Cis-3-benzyl-3, 7-diazabicyclo [3.3.0] in a nitrogen atmosphere at room temperature]To a solution of octane (0.35g,1.73mmol) in acetonitrile (10ml) were added 3, 4-difluoronitrobenzene (0.19ml,1.73mmol) and potassium carbonate (0.60g,4.33 mmol). The reaction was stirred for 15 h, concentrated in vacuo and diluted with ethyl acetate (100 ml). The organic phase was washed with water (3X 20ml) and brine (20ml), dried over sodium sulphate, concentrated in vacuo and chromatographed on silica gel (230-. The appropriate eluates (Rf =0.49, TLC, chloroform/methanol, 95/5) were combined and concentrated in vacuo to give the title compound, NMR (CDCl)₃)7.94,7.88,7.29,6.62,3.73,3.64,3.44,2.97,2.75,2.55. Step 2: cis-3- (benzyloxycarbonyl) -7- [4- [ (benzyloxycarbonyl) amino group]-2-fluorophenyl group]-3, 7-diazabicyclo [3.3.0]Octane

Cis-3-benzyl-7- (2-fluoro-4-nitrophenyl) -3, 7-diazabicyclo [3.3.0] octane (9.11g,26.71mmol), THF (100ml), and methanol (50ml) were heated at reflux with 10% palladium-on-carbon (6.67g) and ammonium formate (16.83g,266.90mmol) under nitrogen for 2.5 hours, cooled to room temperature, stirred for 15 hours, filtered through celite, and concentrated in vacuo to give crude cis-3- (4-amino-2-fluorophenyl) -3, 7-diazabicyclo [3.3.0] octane. Cis-3- (4-amino-2-fluorophenyl) -3, 7-diazabicyclo [3.3.0] octane, water (100ml), acetone (100ml) and potassium carbonate (7.75g,56.07mmol) were combined, cooled to 0 ℃ and benzyl chloroformate was added slowly. The reaction was warmed to room temperature, stirred for 15 hours, concentrated in vacuo, and diluted with ethyl acetate. The organic phase was washed with water (2X 150ml) and brine (150ml), dried over sodium sulfate, concentrated in vacuo and chromatographed on silica gel (230-. The appropriate effluents were combined (Rf =0.41, TCL, hexane/ethyl acetate, 50/50) and concentrated in vacuo to give the title compound, mp121-122 ℃. And step 3: (R) - [3- [4- [ cis-3- (benzyloxycarbonyl) -3, 7-diazabicyclo [3.3.0] octan-7-yl ] -3-fluorophenyl ] -2-oxo-5-oxazolidinyl ] methanol

An oven dried flask cooled to-78 ℃ and fitted with a nitrogen inlet was charged with cis-3- (benzyloxycarbonyl) -7- [4- [ (benzyloxycarbonyl) amino ] -2-fluorophenyl ] -3, 7-diazabicyclo [3.3.0] octane (7.25g,14.81mmol), THF (100ml), and 1.6M butyllithium (9.72ml,15.55 mmol). The reaction was stirred at-78 ℃ for 1 hour, then (R) - (-) glycidylbutyrate (2.26ml,15.99mmol) was added slowly and stirred at-78 ℃ for 2 hours and at room temperature for 15 hours. Saturated ammonium chloride (50ml) was added and the aqueous phase was extracted with ethyl acetate (2X 50 ml). The combined extracts were washed with brine (50ml), dried over sodium sulfate, concentrated in vacuo and chromatographed on silica gel (230-400 mesh, 100ml) eluting with chloroform/methanol (99/1). The appropriate effluents were combined (Rf =0.13, TCL, chloroform/methanol, 95/5) and concentrated in vacuo to give the title compound, mp 168-. And 4, step 4: (S) -N- [ [3- [4- [ cis-3- (benzyloxycarbonyl) -3, 7-diazabicyclo [3.3.0] octan-7-yl ] -3-fluorophenyl ] -2-oxo-5-oxazolidinyl ] methyl ] acetamide

An oven-dried flask equipped with a nitrogen inlet was charged with (R) - [ [3- [4- [ cis-3- (benzyloxycarbonyl) -3, 7-diazabicyclo [3.3.0] octane-7-yl ] -3-fluorophenyl ] -2-oxo-5-oxazolidinyl ] methanol (1.75g,3.84mmol) and dichloromethane (100ml) cooled to 0 ℃. Triethylamine (0.80ml,5.76mmol) and methanesulfonyl chloride were added, stirred at 0 ℃ for 2 hours and warmed to room temperature for 1 hour. The reaction was washed with water (30ml), saturated sodium bicarbonate (30ml) and brine (30ml), dried over sodium sulfate and concentrated in vacuo to give crude (R) - [ [3- [4- [ cis-3- (benzyloxycarbonyl) -3, 7-diazabicyclo [3.3.0] octan-7-yl ] -3-fluorophenyl ] -2-oxo-5-oxazolidinyl ] methyl ] methanesulfonate. (R) - [ [3- [4- [ cis-3- (benzyloxycarbonyl) -3, 7-diazabicyclo [3.3.0] octan-7-yl ] -3-fluorophenyl ] -2-oxo-5-oxazolidinyl ] methyl ] methanesulfonate was combined in a resealable tube with THF (5ml), isopropanol (5ml), and concentrated ammonium hydroxide (10ml) and heated at 95 ℃ for 10 hours. The reaction was diluted with dichloromethane (50ml) and washed with brine (30ml), dried over sodium sulphate and concentrated in vacuo to give (S) - [ [3- [4- [ cis-3- (benzyloxycarbonyl) -3, 7-diazabicyclo [3.3.0] octan-7-yl ] -3-fluorophenyl ] -2-oxo-5-oxazolidinyl ] methyl ] amine. Crude (R) - [ [3- [4- [ cis-3- (benzyloxycarbonyl) -3, 7-diazabicyclo [3.3.0] octan-7-yl ] -3-fluorophenyl ] -2-oxo-5-oxazolidinyl ] methyl ] amine (1.67g,3.67mmol) was dissolved in dichloromethane (20ml), cooled to 0 ℃ under nitrogen, pyridine (0.89ml,11.02mmol) and acetic anhydride (0.43ml,4.59mmol) were added and the reaction was stirred at room temperature for 15 hours. The reaction was diluted with dichloromethane (50ml), washed with 1N HCl (25ml), saturated sodium bicarbonate (25ml), brine (25ml), dried over sodium sulfate, concentrated in vacuo and chromatographed on silica gel (230-400 mesh, 200ml) eluting with chloroform/methanol (98/2). The appropriate effluents were combined (Rf =0.15, TCL, chloroform/methanol, 95/5) and concentrated in vacuo to give the title compound, mp 165-. Example 2: (S) -N- [ [3- [ 3-fluoro-4- [ cis-3- (benzyloxyacetyl) -3, 7-diazabicyclo [3.3.0] octan-7-yl ] phenyl ] -2-oxo-5-oxazolidinyl ] methyl ] acetamide

(S) -N- [ [3- [4- [ cis-3- (benzyloxycarbonyl) -3, 7-diazabicyclo [3.3.0] octan-7-yl ] -3-fluorophenyl ] -2-oxo-5-oxazolidinyl ] methyl ] acetamide (150mg,0.30mmol), dichloromethane (5ml), and methanol (10ml) were combined with 10% palladium-on-charcoal (30mg) and placed under nitrogen (spherical) for 15 hours. The reaction was filtered through celite and concentrated in vacuo to give crude (S) -N- [ [3- [4- [ cis-3, 7-diazabicyclo [3.3.0] octan-7-yl ] -3-fluorophenyl ] -2-oxo-5-oxazolidinyl ] methyl ] acetamide, which was dissolved in dichloromethane (15ml), cooled to 0 ℃ and triethylamine (0.09ml,0.67mmol) and benzyloxyacetyl chloride (0.06ml,0.40mmol) were added. The reaction was warmed to room temperature, stirred for 15 h, and diluted with dichloromethane (100 ml). The organic phase was washed with water (2X 50ml) and brine (150ml), dried over sodium sulphate, concentrated in vacuo and chromatographed on silica gel (230-400 mesh, 100ml) eluting with chloroform/methanol (95/5). The appropriate effluents were combined (Rf =0.41, TCL, chloroform/methanol, 90/10) and concentrated in vacuo to give the title compound, mp 138-. Example 3: (S) -N- [ [3- [ 3-fluoro-4- [ cis-3- (hydroxyacetyl) -3, 7-diazabicyclo [3.3.0] octan-7-yl ] phenyl ] -2-oxo-5-oxazolidinyl ] methyl ] acetamide

(S) -N- [ [3- [ 3-fluoro-4- [ cis-3- (benzyloxyacetyl) -3, 7-diazabicyclo [3.3.0] octan-7-yl ] phenyl ] -2-oxo-5-oxazolidinyl ] methyl ] acetamide (110mg,0.22mmol) and methanol (25ml) were combined with 10% palladium on charcoal (100mg), placed in 40 pascal hydrogen (balloon) and shaken for 5 days. The reaction was filtered through celite, concentrated in vacuo and chromatographed on silica gel (230-400 mesh, 100ml) eluting with chloroform/methanol (95/5). The appropriate effluents were combined (Rf =0.20, TCL, chloroform/methanol, 90/10) and concentrated in vacuo to give the title compound, mp 167-. Example 4: (S) -N- [ [3- [ 3-fluoro-4- [ cis-3- (5-isoxazolinoyl) -3, 7-diazabicyclo [3.3.0] octan-7-yl ] phenyl ] -2-oxo-5-oxazolidinyl ] methyl ] acetamide

(S) -N- [ [3- [4- [ cis-3- (benzyloxycarbonyl) -3, 7-diazabicyclo [3.3.0] octan-7-yl ] -3-fluorophenyl ] -2-oxo-5-oxazolidinyl ] methyl ] acetamide (150mg,0.30mmol), dichloromethane (5ml), and methanol (10ml) were combined with 10% palladium-on-charcoal (30mg) and placed under nitrogen (balloon) for 15 hours. The reaction mixture was filtered through celite and concentrated in vacuo to give crude (S) -N- [ [3- [4- [ cis-3, 7-diazabicyclo [3.3.0] octan-7-yl ] -3-fluorophenyl ] -2-oxo-5-oxazolidinyl ] methyl ] acetamide, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (70mg,0.35mmol), 4-dimethylaminopyridine (5mg,0.05mmol) and isoxazole-5-carboxylic acid (40mg,0.35 mmol). The reaction was warmed to room temperature, stirred for 15 hours, and diluted with dichloromethane (30 ml). The organic phase was washed with 1N HCl (20) and brine (20ml), dried over sodium sulfate, concentrated in vacuo and chromatographed on silica gel (230-400 mesh, 100ml) eluting with chloroform/methanol (97/3). The appropriate effluents were combined (Rf =0.16, TCL, chloroform/methanol, 95/5) and concentrated in vacuo to give the title compound, mp 172-. Example 5: (S) -N- [ [3- [ 3-fluoro-4- [ cis-3- (2-indolylcarbonyl) -3, 7-diazabicyclo [3.3.0] octan-7-yl ] phenyl ] -2-oxo-5-oxazolidinyl ] methyl ] acetamide

A variation without essential distinction was prepared according to the general procedure of example 4 except that indole-2-carboxylic acid (60mg,0.35mmol) was used instead of isoxazole-5-carboxylic acid to give the title compound, mp 211 ℃. Example 6: (S) -N- [ [3- [ 3-fluoro-4- [ cis-3- (methoxycarbonyl) -3, 7-diazabicyclo [3.3.0] octan-7-yl ] phenyl ] -2-oxo-5-oxazolidinyl ] methyl ] acetamide

A variation which does not differ substantially is prepared according to the general procedure of example 2 except that benzyloxyacetyl chloride is replaced by methyl chloroformate (80mg,0.80mmol), triethylamine is replaced by sodium bicarbonate (240mg,2.80mmol) and acetone (5ml) and water (5ml) are used as solvents to give the title compound, mp 128-propanoic acid 132 ℃. Example 7: (S) -N- [ [3- [ 3-fluoro-4- [ cis-3- (formyl) -3, 7-diazabicyclo [3.3.0] octan-7-yl ] phenyl ] -2-oxo-5-oxazolidinyl ] methyl ] acetamide

A variation which is not essential to the preparation was prepared according to the general procedure of example 4, except that formic acid (40mg,0.60mmol) was used instead of isoxazole-5-carboxylic acid to give the title compound, C₁₉H₂₃N₄FO₄HRMS analysis of (a): calculated values: 390.1703, found: 390.1709. example 8: (S) -N- [ [3- [ 3-fluoro-4- [ cis-3- (acetyl) -3, 7-diazabicyclo [3.3.0]]Octane-7-yl]Phenyl radical]-2-oxo-5-oxazolidinyl]Methyl radical]Acetamide

A variation which does not differ substantially is prepared according to the general procedure of example 2, except that the benzyloxyacetyl chloride is replaced by acetyl chloride (80mg,1.05mmol) to give the title compound, mp 168-170 ℃. Example 9: (S) -N- [ [3- [4- [ cis-3- (benzyloxycarbonyl) -3, 7-diazabicyclo [3.3.0] octan-7-yl ] phenyl ] -2-oxo-5-oxazolidinyl ] methyl [ acetamide step 1: cis-3-benzyl-7- (4-nitrophenyl) -3, 7-diazabicyclo [3.3.0] octane

A variant which is not substantially different was prepared according to the general method of example 1 step 1, except that 4-fluoronitrobenzene (8.16g,57.80mmol) was used instead of 3, 4-difluoronitrobenzene to give the title intermediate compound, mp 121-123 ℃. Step 2: cis-3- (benzyloxycarbonyl) -7- [4- [ (benzyloxycarbonyl) amino ] phenyl ] -3, 7-diazabicyclo [3.3.0] octane

A variant which is not substantially different from the other variant was prepared according to the general method of example 1, step 2, except that cis-3-benzyl-7- (4-nitrophenyl) -3, 7-diazabicyclo [3.3.0] octane (1.00g,3.10mmol) was used instead of cis-3-benzyl-7- (2-fluoro-4-nitrophenyl) -3, 7-diazabicyclo [3.3.0] octane to give the title intermediate compound, mp 145-. And step 3: (R) - [3- [4- [ cis-3- (benzyloxycarbonyl) -3, 7-dichloroheterobicyclo [3.3.0] octan-7-yl ] phenyl ] -2-oxo-5-oxazolidinyl ] methanol

A variant which is not substantially different from the other variant was prepared according to the general method of example 1, step 3, except that cis-3- (benzyloxycarbonyl) -7- [4- [ (benzyloxycarbonyl) amino ] phenyl ] -3, 7-diazabicyclo [3.3.0] octane (575mg,1.22mmol) was used instead of cis-3- (benzyloxycarbonyl) -7- [4- [ (benzyloxycarbonyl) amino ] -3-fluorophenyl ] -3, 7-diazabicyclo [3.3.0] octane to give the title intermediate compound, mp 163-164 ℃. And 4, step 4: (S) -N- [ [3- [4- [ cis-3- (benzyloxycarbonyl) -3, 7-diazabicyclo [3.3.0] octan-7-yl ] phenyl ] -2-oxo-5-oxazolidinyl ] methyl ] acetamide

A variant which is not substantially different from the other variant was prepared according to the general method of example 1, step 4, except that (R) - [3- [4- [ cis-3- (benzyloxycarbonyl) -3, 7-diazabicyclo [3.3.0] octan-7-yl ] phenyl ] -2-oxo-5-oxazolidinyl ] methanol (280mg,0.65mmol) was used instead of (R) - [ [3- [4- [ cis-3- (benzyloxycarbonyl) -3, 7-diazabicyclo [3.3.0] octan-7-yl ] -3-fluorophenyl ] -2-oxo-5-oxazolidinyl ] methanol to give the title compound, mp 135-. Example 10: (S) -N- [ [3- [ 3-fluoro-4- [ cis-2- (benzyloxycarbonyl) -2, 8-diazabicyclo [4.3.0] nonan-8-yl ] phenyl ] -2-oxo-5-oxazolidinyl ] methyl ] acetamide step 1:

mixing (+/-) -cis-2, 8-diazabicyclo [4.3.0]Nonane (24.6mmol) was dissolved in 30ml of anhydrous DMSO. Successively using K₂HPO₄(8.6g,49.2mmol) and 3, 4-difluoronitrobenzene (3.9g,24,6 mmol). The mixture turned bright orange. Adding the mixture to N₂And stirred at room temperature for 20 hours. The mixture was then mixed with CHCl₃Poured together into a separatory funnel. The solution was washed with water and brine. The organic phase was separated and washed with anhydrous Na₂SO₄And (5) drying. The solution was filtered and concentrated to give an orange oil which was purified by chromatography on silica gel with 1-5% MeOH/CHCl₃Gradient elution afforded 4.2g of product as an orange waxy solid. MP at 77-79 deg.c. Step 2:

the nitroaromatic product from step 1 (1.5g,5.65mmol) was dissolved in 50ml THF. The solution is added to N₂The stream was treated with 10% Pd/C catalyst. The mixture is degassed by evacuation and is treated with N₂Rinsing (3 times), followed by evacuation and application of H₂Rinse (3 times). The mixture was maintained at 35 pascals (psi) H₂And shaken on a peltier bottle. TLC after 4 hours of reaction showed the starting material had been consumed. With 50ml of 1: 1 acetone/H₂O dilutes the solution and cools the mixture to 0 ℃. Successively using solid NaHCO₃(1.4g,17.0mmol) and benzyl chloroformate (2.0g,11.9 mmol). The mixture was stirred overnight while warming to room temperature. After 16 hours CH was used₂Cl₂The reaction mixture was diluted and filtered through celite. Mixing the filtrate with H₂The O is poured into a separating funnel together. The mixture was shaken and the organic phase was separated, washed with brine and then with anhydrous Na₂SO₄And (5) drying. The solution was filtered and concentrated to give a solid which was chromatographed on silica gel eluting with 5: 1 hexanes/EtOAc to give 2.0g of U-141248 as a yellow solid. The material was recrystallized from 10% EtOAc/hexanes to give a white solid. MP 139-140 ℃. And step 3:

the product of step 2 (505mg,1.00mmol) was dissolved in 10ml of anhydrous THF and the solution was cooled to-78 ℃. The solution was treated with n-BuLi (1.6M in hexane; Aldrich; 656. mu.L, 1.05mmol) via syringe. After 10 min, (R) -glycidylbutyrate (151mg,1.05mmol) was added and the mixture was stirred overnight while warming to room temperature. After 14 hours the mixture was checked by TLC indicating that the starting material had been consumed. The reaction was poured into a separatory funnel with EtOAc. With saturated NH₄The mixture was washed with aqueous Cl and brine. The organic phase was separated and washed with anhydrous Na₂SO₄And (5) drying. Filtration and concentration gave a residue which was purified by radial chromatography with 1-3% MeOH/CHCl₃Gradient elution afforded 294mg of 5- (hydroxymethyl) oxazolidinone intermediate as a brown foam. MP at 71-73 deg.c. And 4, step 4:

the alcohol obtained in step 3 (880mg,1.90mmol) was dissolved in 15ml of anhydrous CH₂Cl₂And the solution was cooled to 0 ℃. Et solution₃N (336mg,3.32mmol) and stirred for 5 min, then solid 3-nitrobenzenesulfonyl chloride (NosylCl,561mg,2.53mmol) was added and the mixture was placed in the refrigerator overnight. TLC after 15 hours showed that the starting material had been consumed with the formation of higher Rf product. Reacting the reactant with CH₂Cl₂Poured together into a separatory funnel. The solution was washed with 1.0N aqueous HCl and saturated sodium bicarbonate. The organic phase was separated and washed with anhydrous Na₂SO₄And (5) drying. Filtration and concentration gave 1.3g of benzenesulfonate (nosylate) as an orange foam. The material was not purified. And 5:

the crude benzenesulfonate (1.9mmol) was dissolved in 10ml CH₃CN and the solution was transferred to a resealable tube. With 5ml of isopropanol and 10ml of 28% NH₄The aqueous OH solution dilutes the solution. The tube was sealed and heated to 65 ℃. After 15 hours the solution was cooled to room temperature and TLC showed the benzenesulfonate had been consumed. Reacting the reactant with CH₂Cl₂Poured together into a separatory funnel. With saturated NaHCO₃The solution was washed with aqueous solution and brine. The organic phase was separated and washed with anhydrous Na₂SO₄Drying. Filtration and concentration gave the crude amine as a foam. This material was dissolved in 20ml of anhydrous CH₂Cl₂And the solution was cooled to 0 ℃. With 500. mu.L of anhydrous pyridine with excess Ac₂O (200. mu.L) treated the reaction together. The mixture was stirred overnight while warming to room temperature. After 18 hours the reaction mixture is reacted with CH₂Cl₂Poured together into a separatory funnel. The solution was washed with 1.0N aqueous HCl and saturated aqueous sodium bicarbonate. The organic phase was separated and washed with anhydrous Na₂SO₄And (5) drying. The solution was filtered and concentrated to give a brown foam which was purified by radial silica gel chromatography with 3% MeOH/CHCl₃Elution gave 776mg of the title compound (mixture of diastereomers) as a brown foam. MP at 74-76 deg.c. C₂₇H₃₁FN₄O₅HRMS analysis of (a): calculated values: 510.2278, found: 510.2278. example 11: (S) -N- [ [3- [ 3-fluoro-4- [ cis-2- (methoxycarbonyl) -28-diazabicyclo [4.3.0]]Nonan-8-yl]Phenyl radical]-2-oxo-5-oxazolidinyl]Methyl radical]Acetamide step 1:

the starting material (example 10) (850mg,1.7mmol) was dissolved in 20ml MeOH. In N₂The solution was treated with 10% Pd/C (85mg) catalyst in a gas stream. Empty the Pair bottle and use N₂Rinsing (3 times), followed by evacuation and application of H₂Rinse (3 times). The mixture was maintained at Pascal 35(psi) H₂And shaken in a peltier bottle. TLC after 10 hours of reaction showed the starting material had been consumed. The solution was filtered through celite and the filtrate was concentrated under reduced pressure to give 585mg of a brown foamy substance. The crude amine was not purified. Step 2:

the crude amine (380mg,1.01mmol) was dissolved in 2: 1 acetone/H₂O and the solution was cooled to 0 ℃. Adding solid NaHCO₃(170mg,2.02mmol) and methyl chloroformate (119mg,1.26 mmol). The mixture was stirred overnight while warming to room temperature. After 16 hours the reaction mixture is reacted with CH₂Cl₂Poured together into a separatory funnel. The mixture was washed with water and brine. The organic phase was separated and washed with anhydrous Na₂SO₄And (5) drying. Filtering the solution and concentrating to obtain a white foam, applying itRadial chromatography with 20% CH₃CN/CHCl₃Elution gave 367mg of the title compound (diastereomer mixture) as a white foam. MP at 83-85 deg.c. C₂₁H₂₇FN₄O₅Hrms (ei) analysis of (a): calculated values: 434.1965, found: 434.1971. example 12: (S) -N- [ [3- [ 3-fluoro-4- [ cis-2- (acetoxyacetyl) -2, 8-diazabicyclo [4.3.0]]Nonan-8-yl]Phenyl radical]-2-oxo-5-oxazolidinyl]Methyl radical]Acetamide step 1:

the crude amine intermediate obtained in step 1 of example 11 (500mg,1.33mmol) was dissolved in 10ml of anhydrous CH₂Cl₂In (1). The solution was cooled to 0 ℃ and treated with 1.0ml of anhydrous pyridine followed by acetoxyacetyl chloride (218mg,1.59 mmol). The mixture was stirred overnight while warming to room temperature. After 18 hours the TCL showed that the starting material had been consumed. Reacting the reaction mixture with CH₂Cl₂Poured together into a separatory funnel. The solution was taken up in 0.5N aqueous HCl, saturated NaHCO₃Aqueous solution and brine. The organic phase was separated and washed with anhydrous Na₂SO₄And (5) drying. Filtration and concentration gave a gum which was purified by radial chromatography on 10% CH₃CN/2％CHCl₃Elution gave 426mg of the title compound as a white foamy solid (mixture of diastereomers). MP 113-116 ℃. C₂₃H₂₉FN₄O₆Hrms (ei) analysis of (a): calculated values: 476.2071, found: 476.2065. example 13: (S) -N- [ [3- [ 3-fluoro-4- [ cis-2- (hydroxyacetyl) -2, 8-diazabicyclo [4.3.0]]Nonan-8-yl]Phenyl radical]-2-oxo-5-oxazolidinyl]Methyl radical]Acetamide step 1:

the starting material (example 12) (325mg,0.68mmol) was dissolved in 6ml MeOH. In N₂The solution was cooled to 0 ℃. With 3.0ml 10% K₂CO₃The solution is treated with an aqueous solution. The mixture was stirred for 2 hours. Thereafter, the TCL showed that U-141950 had been depleted. Reacting the reaction mixture with CH₂Cl₂Poured together into a separatory funnel. The solution was washed with water and brine. The organic phase was separated and washed with anhydrous Na₂SO₄And (5) drying. Filtered and concentrated to give 276mg of whiteThe title compound (mixture of diastereomers) was in the form of a colored foam. MP 102-110 ℃. C₂₁H₂₇FN₄O₅Hrms (ei) analysis of (a): calculated values: 434.1965, found: 434.1975.

according to the general methods outlined in the schemes and the techniques used in examples 1-13, in particular (S) -N- [ [3- [ 3-fluoro-4- [ cis-3- [ benzyloxycarbonyl) -3, 7-diazabicyclo [3.3.0] octan-7-yl ] phenyl ] -2-oxo-oxazolidinyl ] methyl ] acetamide (example 1), (S) -N- [ [3- [ 3-fluoro-4- [ cis-3- (benzyloxyacetyl) -3, 7-diazabicyclo [3.3.0] octan-7-yl ] phenyl ] -2-oxo-5-oxazolidinyl ] methyl ] acetamide (example 2); (S) -N- [ [3- [ 3-fluoro-4- [ cis-3- (hydroxyacetyl) -3, 7-diazabicyclo [3.3.0] octan-7-yl ] phenyl ] -2-oxo-5-oxazolidinyl ] methyl ] acetamide (example 3); and (S) -N- [ [3- [ 3-fluoro-4- [ cis-3- (5-isoxazolinoyl) -3, 7-diazabicyclo [3.3.0] octan-7-yl ] phenyl ] -2-oxo-5-oxazolidinyl ] methyl ] acetamide (example 4), other compounds of the following formula i may also be prepared: (S) -N- [ [3- [ 3-fluoro-4- [ cis-3- (acetoxyacetyl) -3, 7-diazabicyclo [3.3.0] octan-7-yl ] phenyl ] -2-oxo-5-oxazolidinyl ] methyl ] acetamide; (S) -N- [ [3- [ 3-fluoro-4- [ cis-3- (formyl) -3, 7-diazabicyclo [3.3.0] octan-7-yl ] phenyl ] -2-oxo-5-oxazolidinyl ] methyl ] acetamide; (S) -N- [ [3- [ 3-fluoro-4- [ cis-3- (methylsulfonyl) -3, 7-diazabicyclo [3.3.0] octan-7-yl ] phenyl ] -2-oxo-5-oxazolidinyl ] methyl ] acetamide; (S) -N- [ [3- [ 3-fluoro-4- [ cis-3- (2-fluoroethyl) -3, 7-diazabicyclo [3.3.0] octan-7-yl ] phenyl ] -2-oxo-5-oxazolidinyl ] methyl ] acetamide; (S) -N- [ [3- [ 3-fluoro-4- [ cis-3- (2-hydroxyethyl) -3, 7-diazabicyclo [3.3.0] octan-7-yl ] phenyl ] -2-oxo-5-oxazolidinyl ] methyl ] acetamide; (S) -N- [ [3- [ 3-fluoro-4- [ cis-3- (2-methoxyethyl) -3, 7-diazabicyclo [3.3.0] octan-7-yl ] phenyl ] -2-oxo-5-oxazolidinyl ] methyl ] acetamide; (S) -N- [ [3- [ 3-fluoro-4- [ cis-3- (cyanomethyl) -3, 7-diazabicyclo [3.3.0] octan-7-yl ] phenyl ] -2-oxo-5-oxazolidinyl ] methyl ] acetamide; (S) -N- [ [3- [ 3-fluoro-4- [ cis-3- (methoxycarbonyl) -3, 7-diazabicyclo [3.3.0] octan-7-yl ] phenyl ] -2-oxo-5-oxazolidinyl ] methyl ] acetamide; (S) -N- [ [3- [ 3-fluoro-4- [ (S, S) -2- (benzyloxycarbonyl) -2, 8-diazabicyclo [4.3.0] nonan-8-yl ] phenyl ] -2-oxo-5-oxazolidinyl ] methyl ] acetamide; (S) -N- [ [3- [ 3-fluoro-4- [ (S, S) -2- (hydroxyacetyl) -2, 8-diazabicyclo [4.3.0] nonan-8-yl ] phenyl ] -2-oxo-5-oxazolidinyl ] methyl ] acetamide; (S) -N- [ [3- [ 3-fluoro-4- [ (S, S) -2- (acetoxyacetyl) -2, 8-diazabicyclo [4.3.0] nonan-8-yl ] phenyl ] -2-oxo-5-oxazolidinyl [ methyl ] acetamide; (S) -N- [ [3- [ 3-fluoro-4- [ (S, S) -2- (formyl) -2, 8-diazabicyclo [4.3.0] nonan-8-yl ] phenyl ] -2-oxo-5-oxazolidinyl ] methyl ] acetamide; (S) -N- [ [3- [ 3-fluoro-4- [ (S, S) -2- (methylsulfonyl) -2, 8-diazabicyclo [4.3.0] nonan-8-yl ] phenyl ] -2-oxo-5-oxazolidinyl ] methyl ] acetamide; (S) -N- [ [3- [ 3-fluoro-4- [ (S, S) -2- (2-fluoroethyl) -2, 8-diazabicyclo [4.3.0] nonan-8-yl ] phenyl ] -2-oxo-5-oxazolidinyl ] methyl ] acetamide; (S) -N- [ [3- [ 3-fluoro-4- [ (S, S) -2- (2-hydroxyethyl) -2, 8-diazabicyclo [4.3.0] nonan-8-yl ] phenyl ] -2-oxo-5-oxazolidinyl ] methyl ] acetamide; (S) -N- [ [3- [ 3-fluoro-4- [ (S, S) -2- (2-methoxyethyl) -2, 8-diazabicyclo [4.3.0] nonan-8-yl ] phenyl ] -2-oxo-5-oxazolidinyl ] methyl ] acetamide; (S) -N- [ [3- [ 3-fluoro-4- [ (S, S) -2- (cyanomethyl) -2, 8-diazabicyclo [4.3.0] nonan-8-yl ] phenyl ] -2-oxo-5-oxazolidinyl ] methyl ] acetamide; (S) -N- [ [3- [ 3-fluoro-4- [ (S, S) -2- (methoxycarbonyl) -2, 8-diazabicyclo [4.3.0] nonan-8-yl ] phenyl ] -2-oxo-5-oxazolidinyl ] methyl ] acetamide; (S) -N- [ [3- [ 3-fluoro-4- [ (R, R) -2- (benzyloxycarbonyl) -2, 8-diazabicyclo [4.3.0] nonan-8-yl ] phenyl ] -2-oxo-5-oxazolidinyl ] methyl ] acetamide; (S) -N- [ [3- [ 3-fluoro-4- [ (R, R) -2- (hydroxyacetyl) -2, 8-diazabicyclo [4.3.0] nonan-8-yl ] phenyl ] -2-oxo-5-oxazolidinyl ] methyl ] acetamide; (S) -N- [ [3- [ 3-fluoro-4- [ (R, R) -2- (acetoxyacetyl) -2, 8-diazabicyclo [4.3.0] nonan-8-yl ] phenyl ] -2-oxo-5-oxazolidinyl ] methyl ] acetamide; (S) -N- [ [3- [ 3-fluoro-4- [ (R, R) -2- (formyl) -2, 8-diazabicyclo [4.3.0] nonan-8-yl ] phenyl ] -2-oxo-5-oxazolidinyl ] methyl ] acetamide; (S) -N- [ [3- [ 3-fluoro-4- [ (R, R) -2- (methylsulfonyl) -2, 8-diazabicyclo [4.3.0] nonan-8-yl ] phenyl ] -2-oxo-5-oxazolidinyl ] methyl ] acetamide; (S) -N- [ [3- [ 3-fluoro-4- [ (R, R) -2- (2-fluoroethyl) -2, 8-diazabicyclo [4.3.0] nonan-8-yl ] phenyl ] -2-oxo-5-oxazolidinyl ] methyl ] acetamide; (S) -N- [ [3- [ 3-fluoro-4- [ (R, R) -2- (2-hydroxyethyl) -2, 8-diazabicyclo [4.3.0] nonan-8-yl ] phenyl ] -2-oxo-5-oxazolidinyl ] methyl ] acetamide; (S) -N- [ [3- [ 3-fluoro-4- [ (R, R) -2- (2-methoxyethyl) -2, 8-diazabicyclo [4.3.0] nonan-8-yl ] phenyl ] -2-oxo-5-oxazolidinyl ] methyl ] acetamide; (S) -N- [ [3- [ 3-fluoro-4- [ (R, R) -2- (cyanomethyl) -2, 8-diazabicyclo [4.3.0] nonan-8-yl ] phenyl ] -2-oxo-5-oxazolidinyl ] methyl ] acetamide; (S) -N- [ [3- [ 3-fluoro-4- [ (R, R) -2- (methoxycarbonyl) -2, 8-diazabicyclo [4.3.0] nonan-8-yl ] phenyl ] -2-oxo-5-oxazolidinyl ] methyl ] acetamide; (S) -N- [ [3- [ 3-fluoro-4- [ cis-3- (benzyloxycarbonyl) -3, 6-diazabicyclo [3.2.0] heptan-6-yl ] phenyl ] -2-oxo-5-oxazolidinyl ] methyl ] acetamide; (S) -N- [ [3- [ 3-fluoro-4- [ cis-3- (hydroxyacetyl) -3, 6-diazabicyclo [3.2.0] heptan-6-yl ] phenyl ] -2-oxo-5-oxazolidinyl ] methyl ] acetamide; (S) -N- [ [3- [ 3-fluoro-4- [ cis-3- (acetoxyacetyl) -3, 6-diazabicyclo [3.2.0] heptan-6-yl ] phenyl ] -2-oxo-5-oxazolidinyl ] methyl ] acetamide; (S) -N- [ [3- [ 3-fluoro-4- [ cis-3- (formyl) -3, 6-diazabicyclo [3.2.0] heptan-6-yl ] phenyl ] -2-oxo-5-oxazolidinyl ] methyl ] acetamide; (S) -N- [ [3- [ 3-fluoro-4- [ cis-3- (methylsulfonyl) -3, 6-diazabicyclo [3.2.0] heptan-6-yl ] phenyl ] -2-oxo-5-oxazolidinyl ] methyl ] acetamide; (S) -N- [ [3- [ 3-fluoro-4- [ cis-3- (2-fluoroethyl) -3, 6-diazabicyclo [3.2.0] heptan-6-yl ] phenyl ] -2-oxo-5-oxazolidinyl ] methyl ] acetamide; (S) -N- [ [3- [ 3-fluoro-4- [ cis-3- (2-hydroxyethyl) -3, 6-diazabicyclo [3.2.0] heptan-6-yl ] phenyl ] -2-oxo-5-oxazolidinyl ] methyl ] acetamide; (S) -N- [ [3- [ 3-fluoro-4- [ cis-3- (2-methoxyethyl) -3, 6-diazabicyclo [3.2.0] heptan-6-yl ] phenyl ] -2-oxo-5-oxazolidinyl ] methyl ] acetamide; (S) -N- [ [3- [ 3-fluoro-4- [ cis-3- (cyanomethyl) -3, 6-diazabicyclo [3.2.0] heptan-6-yl ] phenyl ] -2-oxo-5-oxazolidinyl ] methyl ] acetamide; (S) -N- [ [3- [ 3-fluoro-4- [ cis-3- (methoxycarbonyl) -3, 6-diazabicyclo [3.2.0] heptan-6-yl ] phenyl ] -2-oxo-5-oxazolidinyl ] methyl ] acetamide; (S) -N- [ [3- [ 3-fluoro-4- [ cis-6- (benzyloxycarbonyl) -3, 6-diazabicyclo [3.2.0] heptan-3-yl ] phenyl ] -2-oxo-5-oxazolidinyl ] methyl ] acetamide; (S) -N- [ [3- [ 3-fluoro-4- [ cis-6- (hydroxyacetyl) -3, 6-diazabicyclo [3.2.0] heptan-3-yl ] phenyl ] -2-oxo-5-oxazolidinyl ] methyl ] acetamide; (S) -N- [ [3- [ 3-fluoro-4- [ cis-6- (acetoxyacetyl) -3, 6-diazabicyclo [3.2.0] heptan-3-yl ] phenyl ] -2-oxo-5-oxazolidinyl ] methyl ] acetamide; (S) -N- [ [3- [ 3-fluoro-4- [ cis-6- (formyl) -3, 6-diazabicyclo [3.2.0] heptan-3-yl ] phenyl ] -2-oxo-5-oxazolidinyl ] methyl ] acetamide; (S) -N- [ [3- [ 3-fluoro-4- [ cis-6- (methylsulfonyl) -3, 6-diazabicyclo [3.2.0] heptan-3-yl ] phenyl ] -2-oxo-5-oxazolidinyl ] methyl ] acetamide; (S) -N- [ [3- [ 3-fluoro-4- [ cis-6- (2-fluoroethyl) -3, 6-diazabicyclo [3.2.0] heptan-3-yl ] phenyl ] -2-oxo-5-oxazolidinyl ] methyl ] acetamide; (S) -N- [ [3- [ 3-fluoro-4- [ cis-6- (2-hydroxyethyl) -3, 6-diazabicyclo [3.2.0] heptan-3-yl ] phenyl ] -2-oxo-5-oxazolidinyl ] methyl ] acetamide; (S) -N- [ [3- [ 3-fluoro-4- [ cis-6- (2-methoxyethyl) -3, 6-diazabicyclo [3.2.0] heptan-3-yl ] phenyl ] -2-oxo-5-oxazolidinyl ] methyl ] acetamide; (S) -N- [ [3- [ 3-fluoro-4- [ cis-6- (cyanomethyl) -3, 6-diazabicyclo [3.2.0] heptan-3-yl ] phenyl ] -2-oxo-5-oxazolidinyl ] methyl ] acetamide; (S) -N- [ [3- [ 3-fluoro-4- [ cis-6- (methoxycarbonyl) -3, 6-diazabicyclo [3.2.0] heptan-3-yl ] phenyl ] -2-oxo-5-oxazolidinyl ] methyl ] acetamide; (S) -N- [ [3- [ 3-fluoro-4- [ cis-3-aza-6-oxobicyclo [3.2.0] heptan-3-yl ] phenyl ] -2-oxo-5-oxazolidinyl ] methyl ] acetamide; (S) -N- [ [3- [ 3-fluoro-4- [ cis-3-aza-6- (hydroxyimino) bicyclo [3.2.0] heptan-3-yl ] phenyl ] -2-oxo-5-oxazolidinyl ] methyl ] acetamide; (S) -N- [ [3- [ 3-fluoro-4- [ cis-3-aza-6- (methoxyimino) bicyclo [3.2.0] heptan-3-yl ] phenyl ] -2-oxo-5-oxazolidinyl ] methyl ] acetamide; (S) -N- [ [3- [ 3-fluoro-4- [ cis-3-aza-6-oxobicyclo [3.2.0] heptan-3-yl ] phenyl ] -2-oxo-5-oxazolidinyl ] methyl ] acetamide ethyleneketal; (S) -N- [ [3- [ 3-fluoro-4- [ trans-3-aza-7-oxobicyclo [4.4.0] decan-3-yl ] phenyl ] -2-oxo-5-oxazolidinyl ] methyl ] acetamide; (S) -N- [ [3- [ 3-fluoro-4- [ trans-3-aza-7- (methoxyimino) bicyclo [4.4.0] decan-3-yl ] phenyl ] -2-oxo-5-oxazolidinyl ] methyl ] acetamide; (S) -N- [ [3- [ 3-fluoro-4- [ trans-3-aza-7- (hydroxyimino) bicyclo [4.4.0] decan-3-yl ] phenyl ] -2-oxo-5-oxazolidinyl ] methyl ] acetamide; (S) -N- [ [3- [ 3-fluoro-4- [ trans-3-aza-7-oxobicyclo [4.4.0] decan-3-yl ] phenyl ] -2-oxo-5-oxazolidinyl ] methyl ] acetamide ethylene ketal; (S) -N- [ [3- [ 3-fluoro-4- [ cis-3- [2- (ethylsulfinyl) ethyl ] -3, 7-diazabicyclo [3.3.0] octan-7-yl ] phenyl ] -2-oxo-5-oxazolidinyl ] methyl ] acetamide; (S) -N- [ [3- [ 3-fluoro-4- [ cis-3- [2- [ (4-morpholinyl) sulfonyl ] ethyl ] -3, 7-diazabicyclo [3.3.0] octan-7-yl ] phenyl ] -2-oxo-5-oxazolidinyl ] methyl ] acetamide; (S) -N- [ [3- [ 3-fluoro-4- [ (S, S) -2- [2- (ethylsulfinyl) ethyl ] -2, 8-diazabicyclo [4.3.0] nonan-8-yl ] phenyl ] -2-oxo-5-oxazolidinyl ] methyl ] acetamide; (S) -N- [ [3- [ 3-fluoro-4- [ (S, S) -2- [2- [ (4-morpholinyl) sulfonyl ] ethyl ] -2, 8-diazabicyclo [4.3.0] nonan-8-yl ] phenyl ] -2-oxo-5-oxazolidinyl ] methyl ] acetamide; (S) -N- [ [3- [ 3-fluoro-4- [ (R, R) -2- [ (4-morpholinyl) sulfonyl ] ethyl ] -2, 8-diazabicyclo [4.3.0] nonan-8-yl ] phenyl ] -2-oxo-5-oxazolidinyl ] methyl ] acetamide; (S) -N- [ [3- [ 3-fluoro-4- [ (R, R) -2- [2- (ethylsulfinyl) ethyl ] -2, 8-diazabicyclo [4.3.0] nonan-8-yl ] phenyl ] -2-oxo-5-oxazolidinyl ] methyl ] acetamide; (S) -N- [ [3- [ 3-fluoro-4- [ cis-3- (2-fluorobenzoyl) -3, 7-diazabicyclo [3.3.0] octan-7-yl ] phenyl ] -2-oxo-5-oxazolidinyl ] methyl ] acetamide; (S) -N- [ [3- [ 3-fluoro-4- [ cis-3- [ (cyclopropyl) carbonyl ] -3, 7-diazabicyclo [3.3.0] octan-7-yl ] phenyl ] -2-oxo-5-oxazolidinyl ] methyl ] acetamide; (S) -N- [ [3- [ 3-fluoro-4- [ (S, S) -2- (2-fluorobenzoyl) -2, 8-diazabicyclo [4.3.0] nonan-8-yl ] phenyl ] -2-oxo-5-oxazolidinyl ] methyl ] acetamide; (S) -N- [ [3- [ 3-fluoro-4- [ (S, S) -2- [ (cyclopropyl) carbonyl ] -2, 8-diazabicyclo [4.3.0] nonan-8-yl ] phenyl ] -2-oxo-5-oxazolidinyl ] methyl ] acetamide; (S) -N- [ [3- [ 3-fluoro-4- [ (R, R) -2- (2-fluorobenzoyl) -2, 8-diazabicyclo [4.3.0] nonan-8-yl ] phenyl ] -2-oxo-5-oxazolidinyl ] methyl ] acetamide; (S) -N- [ [3- [ 3-fluoro-4- [ (R, R) -2- [ (cyclopropyl) carbonyl ] -2, 8-diazabicyclo [4.3.0] nonan-8-yl ] phenyl ] -2-oxo-5-oxazolidinyl ] methyl ] acetamide; (S) -N- [ [3- [ 3-fluoro-4- [ cis-3- (methoxyacetyl) -3, 7-diazabicyclo [3.3.0] octan-7-yl ] phenyl ] -2-oxo-5-oxazolidinyl ] methyl ] acetamide; (S) -N- [ [3- [ 3-fluoro-4- [ cis-3- (methoxyacetyl) -3, 7-diazabicyclo [3.3.0] octan-7-yl ] phenyl ] -2-oxo-5-oxazolidinyl ] methyl ] acetamide; (S) -N- [ [3- [ 3-fluoro-4- [ (S, S) -2- (methoxyacetyl) -2, 8-diazabicyclo [4.3.0] nonan-8-yl ] phenyl ] -2-oxo-5-oxazolidinyl ] methyl ] acetamide; (S) -N- [ [3- [ 3-fluoro-4- [ (S, S) -2- (methoxyacetyl) -2, 8-diazabicyclo [4.3.0] nonan-8-yl ] phenyl ] -2-oxo-5-oxazolidinyl ] methyl ] acetamide; (S) -N- [ [3- [ 3-fluoro-4- [ (R, R) -2- (methoxyacetyl) -2, 8-diazabicyclo [4.3.0] nonan-8-yl ] phenyl ] -2-oxo-5-oxazolidinyl ] methyl ] acetamide; (S) -N- [ [3- [ 3-fluoro-4- [ (R, R) -2- (methoxyacetyl) -2, 8-diazabicyclo [4.3.0] nonan-8-yl ] phenyl ] -2-oxo-5-oxazolidinyl ] methyl ] acetamide;

other compounds of the following formula II may be prepared using techniques for preparing formula I and as shown in scheme VI: (S) -N- [ [3- [ 3-fluoro-4- [7- (hydroxyacetyl) -2, 7-diazaspiro [4.4] nonan-2-yl ] phenyl ] -2-oxo-5-oxazolidinyl ] methyl ] acetamide; (S) -N- [ [3- [ 3-fluoro-4- [7- (acetoxyacetyl) -2, 7-diazaspiro [4.4] nonan-2-yl ] phenyl ] -2-oxo-5-oxazolidinyl ] methyl ] acetamide; (S) -N- [ [3- [ 3-fluoro-4- [7- (formyl) -2, 7-diazaspiro [4.4] nonan-2-yl ] phenyl ] -2-oxo-5-oxazolidinyl ] methyl ] acetamide; (S) -N- [ [3- [ 3-fluoro-4- [7- (methylsulfonyl) -2, 7-diazaspiro [4.4] nonan-2-yl ] phenyl ] -2-oxo-5-oxazolidinyl ] methyl ] acetamide; (S) -N- [ [3- [ 3-fluoro-4- [7- (2-fluoroethyl) -2, 7-diazaspiro [4.4] nonan-2-yl ] phenyl ] -2-oxo-5-oxazolidinyl ] methyl ] acetamide; (S) -N- [ [3- [ 3-fluoro-4- [7- (cyanomethyl) -2, 7-diazaspiro [4.4] nonan-2-yl ] phenyl ] -2-oxo-5-oxazolidinyl ] methyl ] acetamide; (S) -N- [ [3- [ 3-fluoro-4- [7- (methoxycarbonyl) -2, 7-diazaspiro [4.4] nonan-2-yl ] phenyl ] -2-oxo-5-oxazolidinyl ] methyl ] acetamide; (S) -N- [ [3- [ 3-fluoro-4- [1- (hydroxyacetyl) -1, 7-diazaspiro [4.4] nonan-7-yl ] phenyl ] -2-oxo-5-oxazolidinyl ] methyl ] acetamide; (S) -N- [ [3- [ 3-fluoro-4- [1- (acetoxyacetyl) -1, 7-diazaspiro [4.4] nonan-7-yl ] phenyl ] -2-oxo-5-oxazolidinyl ] methyl ] acetamide; (S) -N- [ [3- [ 3-fluoro-4- [1- (formyl) -1, 7-diazaspiro [4.4] nonan-7-yl ] phenyl ] -2-oxo-5-oxazolidinyl ] methyl ] acetamide; (S) -N- [ [3- [ 3-fluoro-4- [1- (methylsulfonyl) -1, 7-diazaspiro [4.4] nonan-7-yl ] phenyl ] -2-oxo-5-oxazolidinyl ] methyl ] acetamide; (S) -N- [ [3- [ 3-fluoro-4- [1- (2-fluoroethyl) -1, 7-diazaspiro [4.4] nonan-7-yl ] phenyl ] -2-oxo-5-oxazolidinyl ] methyl ] acetamide; (S) -N- [ [3- [ 3-fluoro-4- [1- (cyanomethyl) -1, 7-diazaspiro [4.4] nonan-7-yl ] phenyl ] -2-oxo-5-oxazolidinyl ] methyl ] acetamide; (S) -N- [ [3- [ 3-fluoro-4- [1- (methoxycarbonyl) -1, 7-diazaspiro [4.4] nonan-7-yl ] phenyl ] -2-oxo-5-oxazolidinyl ] methyl ] acetamide; (S) -N- [ [3- [ 3-fluoro-4- [ 2-aza-7-oxospiro [4.5] decan-2-yl ] phenyl ] -2-oxo-5-oxazolidinyl ] methyl ] acetamide; (S) -N- [ [3- [ 3-fluoro-4- [ 2-aza-7- (methoxyimino) spiro [4.5] decan-2-yl ] phenyl ] -2-oxo-5-oxazolidinyl ] methyl ] acetamide; (S) -N- [ [3- [ 3-fluoro-4- [ 2-aza-7- (hydroxyimino) spiro [4.5] decan-2-yl ] phenyl ] -2-oxo-5-oxazolidinyl ] methyl ] acetamide; and (S) -N- [ [3- [ 3-fluoro-4- [ 2-aza-7-oxospiro [4.5] decan-2-yl ] phenyl ] -2-oxo-5-oxazolidinyl ] methyl ] acetamide ethylene ketal.

Antibacterial activity

The oxazolidinone antibacterial agents of the invention have useful activity against a variety of microorganisms. The in vitro activity of the compounds of the invention is assessed by measuring the Minimum Inhibitory Concentration (MIC) by the agar Dilution method using standard test Methods such as those described in "Methods For Dilution inhibition assays For Bacteriz thin Grow Aerobacter" (MFT), published 1.1983, National Committee For Clinical Laboratory Standards,771East Lancaster Avenue, Villanova, Pennsylvania 19084, USA. The activity of selected compounds of the invention against staphylococcus aureus and streptococcus pneumoniae is shown in table 1.

TABLE 1 minimum inhibitory concentration (μ g/mL)

Example No. 2	Staphylococcus aureus UC9213	Streptococcus pneumoniae UC9912
			1	4	2
2	8	1
			3	4	＜0.5
Vancomycin	1	0.5

Route I

Route II

Route III

Route IV

Route V

Route VI

Claims (9)

1. A compound of structural formula I:in which R is¹Is (a) NR⁵,

(b)CR⁶R⁷；R²Independently is H or CH₃；R³Independently is H, F, Cl or methoxy; r⁴Is a reaction product of (a) hydrogen,

(b) c optionally substituted by one or more of the following groups₁-C₈Alkyl groups: f, Cl, hydroxy, C₁-C₈Alkoxy radical, C₁-C₈An acyloxy group (a group of acyl groups),

(c)C₃-C₆a cycloalkyl group,

(d) an amino group, a carboxyl group,

(e)C₁-C₈an alkylamino group,

(f)C₁-C₈a dialkylamino group, or a dialkylamino group,

(g)C₁-C₈alkoxy radical, R⁵Is a compound of (a) a hydrogen atom,

(b) c optionally substituted by one or more of the following groups_1-6Alkyl groups: cl, F, CN, OH, C_1-4Alkoxy, amino, hydroxyamino, alkoxyamino, C_1-4Acyloxy radical, C_1-4Alkylsulfinyl radical, C_1-4Alkylsulfinyl group, C_1-4Alkylsulfonyl, aminosulfonyl, C_1-4Alkylaminosulfonyl radical, C_1-4Dialkylaminosulfonyl, 4-morpholinylsulfonyl, phenyl (optionally substituted by one or more F, Cl, CN, OH, C_1-4Alkoxy substituted), 5-isoxazolyl, ethyleneoxy, ethynyl,

(c) c optionally substituted by one or more of the following groups_1-6Acyl group: cl, F, OH, SH, C_1-4Alkoxy, naphthyloxy, phenoxy (optionally substituted by one or more of Cl, F, OH, C_1-4Alkoxy, amino, C₁-C₄Amido, C₁-C₄Alkyl), amino, C₁-C₄Acylamino, hydroxylamino, alkoxyamino, C_1-4Acyloxy, phenyl, C₁-C₄Alkylcarbonyl group, C₁-C₄Alkylamino radical, C₁-C₄Dialkylamino radical, C₁-C₄Hydroxy acyloxy, C₁-C₄Alkylsulfinyl, phthalimido, maleimido, succinimido,

(d) c optionally substituted by one or more of the following groups_1-6An alkylsulfonyl group: cl, F, OH, C_1-4Alkoxy, amino, hydroxyamino, alkoxyamino, C_1-4The acyloxy group, the phenyl group,

(e) arylsulfonyl optionally substituted with one or more of the following groups: f, Cl, OCH₃OH or C_1-4An alkyl group, a carboxyl group,

(f) c optionally substituted by one or more of the following groups_1-6An alkoxycarbonyl group: cl, F, OH, C_1-4Alkoxy radical, C_1-4The acyloxy group, the phenyl group,

(g) aminocarbonyl group, C_1-6Alkylamino carbonyl or C_1-6Dialkylaminocarbonyl (in which the alkyl group is optionally substituted by one or more groups selected from Cl, F, OH, C_1-4Alkoxy, phenyl),

(h) a 5-or 6-membered heterocyclic ring optionally substituted with one or more of the following groups: cl, F, OH, amino, C_1-4Amido, C_1-4Alkylsulfonylamino group, C_1-4Alkoxycarbonylamino group, C_1-4Alkoxy radical, C_1-4Acyloxy, which may be substituted by F, OH, or C_1-4Alkoxy-substituted C_1-4An alkyl group, a carboxyl group,

(i) c optionally substituted by one or more of the following groups₃-C₆Cycloalkyl carbonyl group: f, Cl, OH, C₁-C₄An alkoxy group, CN,

(j) benzoyl optionally substituted with one or more of the following groups: f, Cl, OH, C₁-C₄Alkoxy radical, C₁-C₄Alkyl, amino, C₁-C₄An amido group,

(k) optionally by one or more C₁-C₄An alkyl-substituted pyrrolylcarbonyl group,

(1)C₁-C₂acyloxyacetyl wherein the acyl group is optionally substituted with one or more of the following groups: amino group, C₁-C₄Alkylamino radical, C₁-C₄Dialkylamino, 4-morpholino, 4-aminophenyl, 4- (dialkylamino) phenyl, 4- (glycinamido) phenyl; r⁶Is a compound of (a) a hydrogen atom,

(b)OH，

(c)C₁-C₆an alkoxy group,

(d) amino group, C_1-6Alkylamino radical, C_1-6Dialkylamino, hydroxyamino, or C_1-2Alkoxyamino, all of which may be optionally substituted on the nitrogen atom by: c substituted by 1-2 Cl or OH_1-6Acyl, C optionally substituted by 1-2 Cl or OH_1-6Alkyl sulfonyl radicalOr C_{1 -6}An alkoxycarbonyl group, a carbonyl group,

(e) cl or F; r⁷Is a compound of (a) a hydrogen atom,

(b) -6 alkyl optionally substituted with one or more of the following groups: cl, F, CN, OH, C_1-4Alkoxy radical, C_1-4An acyloxy group, an amino group,

(c)CN，

(d) phenyl optionally substituted with one or more of the following groups: cl, F, OH, C_1-4An alkoxy group; or R⁶And R⁷Together are (a) a carbonyl or thiocarbonyl group,

(b) ethylene glycol ketal group (-OCH)₂CH₂O-), propylene glycol ketal group (-OCH)₂CH₂CH₂O-), ethyleneglycol thioketal group (-SCH)₂CH₂S-), propyleneglycol thioketal group (-SCH)₂CH₂CH₂S-), a dimethylketal group, a diethylketal group, a dimethylthioketal group, or a diethylthioketal group,

(c) optionally by H, C_1-6Alkyl (optionally substituted by Cl, F, or C)_1-4Alkoxy-substituted), C_1-6Acyl (optionally substituted by one or more of Cl, F, OH, C_1-4Alkoxy radical, C_1-4Acyloxy) substituted oximes such as, for example,

(d) optionally by H, C_1-6Alkyl (optionally substituted by one or more Cl, F, OH, C_1-4Alkoxy radical, C_1-4Acyloxy, phenyl substituted), C_1-6Acyl (optionally substituted by one or more Cl, F, OH, C_1-4Alkoxy radical, C_1-4Acyloxy, phenyl substituted), C_1-6Alkoxycarbonyl (optionally substituted by one or more of Cl, F, OH, C_1-4Alkoxy radical, C_1-4Acyloxy, phenyl), C_1-6The hydrazone substituted with an alkylsulfonyl group,

(e) optionally substituted by H or C_1-6Alkyl (optionally substituted by Cl, F, OH, C_1-4Alkoxy radical, C_1-4Acyloxy, phenyl-substituted) imino groups,

(f) optionally by H, C_1-4Alkoxycarbonyl radical, C_1-4Alkyl (optionally substituted by Cl, F, OH, C_1-4Alkoxy, phenyl-substituted) carbon-carbon double bonds; m is 0 to 2; n is 1 to 3; o is 0 to 3; and p is 1 to 3.

2. The compound of claim 1, wherein one R³Is fluorine and the other is hydrogen.

3. The compound of claim 1, wherein each R³Is fluorine.

4. The compound of claim 1, wherein R⁴Is hydrogen, methyl, difluoromethyl, dichloromethyl, hydroxymethyl or methoxy.

5. The compound of claim 4, wherein R⁴Is methyl, difluoromethyl, dichloromethyl or methoxy.

6. The compound of claim 5, wherein R⁴Is methyl.

7. The compound of claim 1, wherein R⁵Is hydroxyacetyl.

8. The compounds of claim 1 which are (a) (S) -N- [ [3- [ 3-fluoro-4- [ cis-3- (benzyloxycarbonyl) -3, 7-diazabicyclo [3.3.0] octan-7-yl ] phenyl ] -2-oxo-oxazolidinyl ] methyl ] acetamide (example 1), (b) (S) -N- [ [3- [ 3-fluoro-4- [ cis-3- (benzyloxyacetyl) -3, 7-diazabicyclo [3.3.0] octan-7-yl ] phenyl ] -2-oxo-5-oxazolidinyl ] methyl ] acetamide (example 2), (c) (S) -N- [ [3- [ 3-fluoro-4- [ cis-3- (hydroxyacetyl) -3, 7-diazabicyclo [3.3.0] octan-7-yl ] phenyl ] -2-oxo-5-oxazolidinyl ] methyl ] acetamide (example 3), (d) (S) -N- [ [3- [ 3-fluoro-4- [ cis-3- (5-isoxazolinoacyl) -3, 7-diazabicyclo [3.3.0] octan-7-yl ] phenyl ] -2-oxo-5-oxazolidinyl ] methyl ] acetamide (example 4), (e) (S) -N- [ [3- [ 3-fluoro-4- [ cis-3- (2-indolylcarbonyl) -3, 7-diazabicyclo [3.3.0] octan-7-yl ] phenyl ] -2-oxo-5-oxazolidinyl ] methyl ] acetamide (c: (c) (S) -N- [ [3- [ 3-fluoro-4- [ cis-3- (2-indolylcarbonyl) -3, 7-diazabicyclo [3.3.0] octan-7-yl Example 5), (f) (S) -N- [ [3- [ 3-fluoro-4- [ cis-3- (methoxycarbonyl) -3, 7-diazabicyclo [3.3.0] octan-7-yl ] phenyl ] -2-oxo-5-oxazolidinyl ] methyl ] acetamide (example 6), (g) (S) -N- [ [3- [ 3-fluoro-4- [ cis-3- (formyl) -3, 7-diazabicyclo [3.3.0] octan-7-yl ] phenyl ] -2-oxo-5-oxazolidinyl ] methyl ] acetamide (example 7), (h) (S) -N- [ [3- [ 3-fluoro-4- [ cis-3- (acetyl) -3, 7-diazabicyclo [3.3.0] octan-7-yl ] phenyl ] -2-oxo-5-oxazolidinyl ] methyl ] acetamide (example 8), (i) (S) -N- [ [3- [4- [ cis-3- (benzyloxycarbonyl) -3, 7-diazabicyclo [3.3.0] octan-7-yl ] phenyl ] -2-oxo-5-oxazolidinyl ] methyl ] acetamide (example 9), (j) (S) -N- [ [3- [ 3-fluoro-4- [ cis-2- (benzyloxycarbonyl) -2, 8-diazabicyclo [4.3.0] nonan-8-yl ] phenyl ] -2-oxo-5-oxazolidinyl ] methyl ] acetamide (example 10), (k) (S) -N- [ [3- [ 3-fluoro-4- [ cis-2- (methoxycarbonyl) -2, 8-diazabicyclo [4.3.0] nonan-8-yl ] phenyl ] -2-oxo-5-oxazolidinyl ] methyl ] acetamide (example 11), (l) (S) -N- [ [3- [ 3-fluoro-4- [ cis-2- (acetoxyacetyl) -2, 8-diazabicyclo [4.3.0] nonan-8-yl ] phenyl ] -2-oxo-5-oxazolidinyl ] methyl ] acetamide (example 12), or (m) (S) -N- [ [3- [ 3-fluoro-4- [ cis-2- (hydroxyacetyl) -2, 8-diazabicyclo [4.3.0] nonan-8-yl ] phenyl ] -2-oxo-5-oxazolidinyl ] methyl ] acetamide (example 13).

9. The use of a compound as claimed in any one of claims 1 to 8 in the manufacture of a medicament for the treatment of microbial infections in warm-blooded animals.