HK1128469B - Dual action antibiotics - Google Patents

Description

Dual action antibiotics

The present application is a divisional application of chinese patent application 02819724.0 entitled "dual action antibiotic" filed on 4/10/2002.

Technical Field

The present invention describes novel compounds in which quinolone (quinolones) and oxazolidinone (oxazolidinoneidinones) pharmacophores are chemically linked through a linking group that is stable under physiological conditions, and antibacterial pharmaceutical compositions containing these compounds. These dual action compounds are useful antimicrobial agents that are effective against a variety of human and animal pathogens, including gram-positive aerobic bacteria such as multidrug-resistant staphylococci, streptococci and enterococci, as well as gram-negative bacteria such as Moraxella catarrhalis (Moraxella catarrhalis) and Haemophilus influenzae (Haemophilus influenza), as well as anaerobic microorganisms such as Bacteroides spp and Clostridium spp, and acid-fast microorganisms such as Mycobacterium tuberculosis, Mycobacterium avium spp.

Background

The widespread use of antibiotics has placed selective evolutionary pressure on microorganisms to generate genetically based resistance mechanisms. Recent medical and socioeconomic behavior exacerbates the problem of resistance development by causing pathogenic microbes to slow down their growth, such as infections associated with artificial joints, and by supporting long-term host supply, such as immunocompromised patients.

In the hospital setting, an increasing number of Staphylococcus aureus (Staphylococcus aureus), Streptococcus pneumoniae (Streptococcus pneumoniae), Enterococcus (Enterococcus sp.) and Pseudomonas aeruginosa (Pseudomonas aeruginosa) strains are major sources of infection, which are becoming multidrug resistant and therefore difficult, if not impossible, to treat:

staphylococcus aureus is resistant to β -lactams, quinolones, and is now even resistant to vancomycin.

Streptococcus pneumoniae is becoming resistant to penicillins and even to new macrolides.

Enterococci are resistant to quinolones and vancomycin, whereas β -lactams have been ineffective against these strains. The only option is to use oxazolidinones, but these compounds have no bactericidal effect and their safety margin is rather low. Furthermore, even with these drugs, resistance has emerged in clinical practice.

In addition, microorganisms causing persistent infections are increasingly being considered as pathogens or cofactors of serious chronic diseases such as gastric ulcers or heart diseases.

Disclosure of Invention

The present invention provides novel compounds of formula (I) or a pharmacologically acceptable salt, solvate, hydrate or formulation thereof, which are useful antimicrobial agents and are effective against a wide variety of multi-drug resistant bacteria:

wherein

A is a direct bond, NH, O, S, SO₂、SO₂NH、PO₄-NH-CO-NH-, -CO-O-, -NH-CO-O-, alkylene, alkenylene, alkynylene, heteroalkylene, alkynyleneAryl, heteroarylene, cycloalkylene, heterocycloalkylene, alkylarylene, or heteroarylalkylene, or a combination of two or more of these atoms or groups;

x is CR5 or N;

y is CR6 or N;

u is F or Cl;

n is 0, 1, 2 or 3;

r1 is H, F, Cl, Br, I, OH, NH₂Alkyl or heteroalkyl;

r2 is H, F or Cl;

r3 is H, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl, or heteroarylalkyl; all of these groups may be substituted with one, two or more halogen atoms such as F or Cl.

R4 is heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl, or heteroarylalkyl;

r5 is H, F, Cl, OH, NH₂Alkyl or heteroalkyl, or

R3 and R5 may be linked via an alkylene, alkenylene, or heteroalkylene group, or may be part of a cycloalkylene or heterocycloalkylene group; if R3 is not H and R5 is not H, F, OH, NH₂Or Cl;

r6 is H, F, Cl or OMe.

Detailed Description

It is to be understood that certain compounds of formula (I) may have tautomeric forms, only one of which is specifically mentioned or described in the following description, and certain compounds of formula (I) may have different geometric isomers (which are generally represented as cis/trans isomers, or more generally as (E) and (Z) isomers) or different optical isomers (which are generally named under the order or R/S system) as a result of one or more chiral carbon atoms. In addition, some compounds may exhibit polymorphism. All such tautomeric forms, geometric or optical isomers (as well as racemates and diastereomers) and polymorphs are included within the present invention.

The term alkyl refers to saturated or unsaturated (i.e., alkenyl and alkynyl) straight or branched chain alkyl groups containing 1 to 10, preferably 1 to 6, carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, 2-dimethylbutyl, n-octyl; vinyl, propenyl (allyl), isopropenyl, n-pentyl, butenyl, isoprenyl or hex-2-enyl; ethynyl, propynyl or butynyl. Any alkyl group as defined herein may be substituted by one, two or more substituents, e.g. F, Cl, Br, I, NH₂OH, SH or NO₂And (4) substitution.

The terms alkenyl and alkynyl refer to unsaturated straight or branched alkyl groups containing 1 to 10, preferably 1 to 6, carbon atoms (having one, two or more double and/or triple bonds, alkenyl preferably having one or two double bonds and alkynyl preferably having one or two triple bonds), such as vinyl, propenyl (allyl), isopropenyl, n-pentenyl, butenyl, isoprenyl or hex-2-enyl; ethynyl, propynyl or butynyl. Any alkenyl or alkynyl group as defined herein may be substituted by one, two or more substituents, e.g. F, Cl, Br, I, NH₂OH, SH or NO₂And (4) substitution.

The term heteroalkyl refers to an alkyl group as defined herein in which one or more carbon atoms are replaced by an oxygen, nitrogen, phosphorus or sulfur atom, for example, an alkoxy group such as methoxy, ethoxy, propoxy, isopropoxy, butoxy or tert-butoxy, an alkoxyalkyl group such as methoxymethyl, ethoxymethyl, 1-methoxyethyl, 1-ethoxyethyl, 2-methoxyethyl or 2-ethoxyethyl, an alkylamino group such as methylamino, ethylamino, propylamino, isopropylamino, dimethylamino or diethylamino, an alkylthio group such as methylthio, ethylthio or isopropylthio, or a cyano group. It can alsoTo mean one of the above groups containing a keto group. The term heteroalkyl further refers to a group derived from a carboxylic acid or carboxylic acid amide such as acetyl, propionyl, acetoxy, propionyloxy, acetylamino, or propionylamino, a carboxyalkyl group such as carboxymethyl, carboxyethyl, or carboxypropyl, a carboxyalkyl ester, an alkylthiocarboxamido, an alkoxyimino, an alkylaminothiocarboxamido, or an alkoxycarbonylamino group. The heteroalkyl groups described herein may be substituted with one, two or more substituents, e.g., F, Cl, Br, I, NH₂OH, SH or NO₂And (4) substitution.

The term cycloalkyl refers to a saturated or partially unsaturated (having one, two or more double and/or triple bonds) cyclic group having one, two or more rings, having 3 to 14 carbon ring atoms, preferably 5 or 6 to 10 carbon ring atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetralin, cyclopentene or cyclohex-2-enyl. Any cycloalkyl group as defined herein may be substituted by one, two or more substituents, e.g. F, Cl, Br, I, OH, NH₂、SH、N₃、NO₂Alkyl such as methyl or ethyl, heteroalkyl such as methoxy, methylamino, dimethylamino or cyano.

The term heterocycloalkyl refers to a cycloalkyl group as defined herein, wherein one, two or more carbon ring atoms are interrupted by one, two or more oxygen, nitrogen, phosphorus or sulfur atoms or S (0)_1-2Groups, such as piperidino, morpholino or piperazino (piperazino) groups.

The term aryl refers to aromatic ring groups having one, two or more rings having 5 to 14 carbon ring atoms, preferably 5 or 6 to 10 carbon ring atoms, such as phenyl or naphthyl. Any aryl group as defined herein may be substituted by one, two or more substituents, e.g. F, Cl, Br, I, OH, NH₂、SH、N₃、NO₂Alkyl such as methyl or ethyl, heteroalkyl such as methoxy, methylamino, dimethylamino or cyano.

The term heteroaryl refers to an aryl group as defined herein wherein one, two or more ring carbon atoms are replaced by an oxygen, nitrogen, boron, phosphorus or sulfur atom, for example pyridyl, imidazolyl, pyrazolyl, quinolinyl, isoquinolinyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1, 2, 3-triazolyl, 1, 2, 4-triazolyl, oxadiazolyl, thiadiazolyl, indolyl, indazolyl, tetrazolyl, pyrazinyl, pyrimidinyl and pyridazinyl.

The terms arylalkyl, alkylaryl and heteroarylalkyl, heteroarylaryl refer to groups which comprise, simultaneously or separately, aryl, heteroaryl and alkyl and/or heteroalkyl and/or cycloalkyl and/or heterocycloalkyl groups.

Preferred and/or advantageous embodiments of the invention are the subject matter of the dependent claims.

Preferred are compounds of formula (I) wherein R1 is H or NH₂。

Further preferred are compounds of formula (I) wherein R2 is H or F.

More preferred are compounds of formula (I) wherein R3 is ethyl, 2-propyl, C3-C6 cycloalkyl, phenyl or pyridyl. All of these groups may be substituted with one, two or more fluorine atoms or amino groups.

More preferred are compounds of formula (I) wherein R3 is cyclopropyl.

Further preferred are compounds of formula (I) wherein R3 and R5 together form the formula-O-CH₂-N (Me) -or-O-CH₂A bridge of-CH (Me) -. Herein, the preferred stereochemistry of the chiral center gives the final compound the S configuration.

Further preferred are compounds of formula (I) wherein R4 is of formula-NHCOCH ═ CH aryl, -O heteroaryl (especially-oxa-3-oxazolyl), -NHSO₂Me、-NHCOOMe、NHCS₂Me、NHCSNH₂A group of-NHCSOMe or-NHCOMe.

Particular preference is given to compounds of the formula (I) in which R4 is acetylamino.

More preferred are compounds of formula (I) wherein R5 is H, F, Cl or methoxy which may be substituted by one, two or three fluorine atoms.

Further preferred are compounds of formula (I) wherein X is N or CH.

Further preferred are compounds of formula (I) wherein Y is N or CF.

Further preferred are compounds of formula (I) wherein n is 0.

Further preferred are compounds of formula (I) wherein a is a bond.

Further preferred are compounds of formula (I) wherein A is a group of formula

Wherein

The group B is an alkylene group which may be substituted by one, two or more fluorine atoms, -NH-group, or a heteroalkylene group which may be substituted by one, two or more fluorine atoms and/or by an alkyl or acyl group on the optionally present nitrogen atom;

the radicals D are, independently of one another, heterocycloalkylene having 1, 2, 3 or 4 nitrogen atoms, optionally anellated, each heterocycloalkylene being substituted by one, two or more fluorine atoms and/or being substituted on one, two, three or four nitrogen atoms by alkyl or acyl;

the radicals E are, independently of one another, alkylene which may be substituted by one, two or more fluorine atoms, -NH-groups or heteroalkylene which may be substituted by one, two or more fluorine atoms and/or by alkyl or acyl groups on the optionally present nitrogen atoms;

the radicals G are, independently of one another, heterocycloalkylene having 1, 2, 3 or 4 nitrogen atoms, optionally anellated, each heterocycloalkylene being substituted by one, two or more fluorine atoms and/or being substituted on one, two, three or four nitrogen atoms by alkyl or acyl;

the group K is an alkylene group which may be substituted by one, two or more fluorine atoms, -NH-group, or a heteroalkylene group which may be substituted by one, two or more fluorine atoms and/or by an alkyl or acyl group on the optionally present nitrogen atom; and is

m is 1, 2, 3 or 4.

More preferred are compounds of formula (I) wherein a is cycloalkylene or alkylcycloalkylene containing 2, 3 or 4 nitrogen atoms, which may be substituted by one, two or more fluorine atoms, and the nitrogen atom may be substituted by an alkyl or acyl group.

Further preferred are compounds of formula (I) wherein a is selected from the group consisting of the following, which may be substituted by one, two or more fluorine atoms, or by alkyl which may be substituted by one, two or more fluorine atoms, wherein amino may be substituted by alkyl or acyl:

further preferred are compounds of formula (I) wherein the absolute configuration at C-5 of the oxazolidinone ring is of the (S) type according to the sequential naming system.

More preferred are the following compounds:

-7- (4- {4- [5- (acetylamino-methyl) -2-oxo-oxazolidin-3-yl ] -2-fluoro-phenyl } -piperazin-1-yl) -1-cyclopropyl-6-fluoro-4-oxo-1, 4-dihydro-quinoline-3-carboxylic acid

-9- (4- {4- [5- (acetylamino-methyl) -2-oxo-oxazolidin-3-yl ] -2-fluoro-phenyl } -piperazin-1-yl) -8-fluoro-3-methyl-6-oxo-2, 3-dihydro-6H-1-oxa-3 a-aza-phenalene-5-carboxylic acid

-7- [ (3R) -3- {4- [ (5S) -5- (acetylamino-methyl) -2-oxo-oxazolidin-3-yl ] -2-fluoro-phenylamino } -pyrrolidin-1-yl ] -1-cyclopropyl-6-fluoro-4-oxo-1, 4-dihydro-quinoline-1-carboxylic acid

-7- (4- {4- [ (5S) -5- (acetylamino-methyl) -2-oxo-oxazolidin-3-yl ] -2-fluoro-phenyl } -piperazin-1-yl) -6-fluoro-1- (5-fluoro-pyridin-2-yl) -4-oxo-1, 4-dihydro-quinoline-3-carboxylic acid

-7- (4- { (5S) -5- (acetylamino-methyl) -2-oxo-oxazolidin-3-yl } -2-fluoro-phenyl) -piperazin-1-yl) -1- (2, 4-difluoro-phenyl) -6-fluoro-4-oxo-1, 4-dihydro-quinoline-3-carboxylic acid

-7- (4- {4- [ (5S) -5- (acetylamino-methyl) -2-oxo-oxazolidin-3-yl ] -2-fluoro-phenyl) -piperazin-1-yl) -1-cyclopropyl-8-methoxy-4-oxo-1, 4-dihydro-quinoline-3-carboxylic acid

-9- (4- {4- [ (5S) -5- (acetylamino-methyl) -2-oxo-oxazolidin-3-yl ] -2-fluoro-phenyl } -piperazin-1-yl) -8-fluoro-3-methyl-6-oxo-2, 3-dihydro-6H-1-oxa-3, 3 a-diaza-phenalene-5-carboxylic acid

-7- (4- { [ (5S) -5- (acetylamino-methyl) -2-oxo-oxazolidin-3-yl ] -2-fluoro-phenyl } -piperazin-1-yl) -1-cyclopropyl-6-fluoro-4-oxo-1, 4-dihydro- [1, 8] naphthyridine-3-carboxylic acid

-7- {4- [2- (4- {4- [5- (acetylamino-methyl) -2-oxo-oxazolidin-3-yl ] -2-fluoro-phenyl } -piperazin-1-yl) -ethyl ] -piperazin-1-yl } -1-cyclopropyl-6-fluoro-4-oxo-1, 4-dihydro-quinoline-3-carboxylic acid

-7- {4- [2- (4- {4- [5- (acetylamino-methyl) -2-oxo-oxazolidin-3-yl ] -2-fluoro-phenyl } -piperazin-1-yl) -ethyl ] -piperazin-1-yl } -1-cyclopropyl-6-fluoro-4-oxo-1, 4-dihydro-quinoline-3-carboxylic acid

-7- {4- [2- (4- {4- [ (5S) -5- (acetylamino-methyl) -2-oxo-oxazolidin-3-yl ] -2-fluoro-phenyl } -piperazin-1-yl) -2-oxo-ethyl ] -piperazin-1-yl } -1-cyclopropyl-6-fluoro-4-oxo-1, 4-dihydro-quinolone-3-carboxylic acid

-7- (3- {4- [5(S) -5- (acetylamino-methyl) -2-oxo-oxazolidin-3-yl ] -2-fluoro-phenylamino } -azetidin-1-yl) -1-cyclopropyl-6-fluoro-4-oxo-1, 4-dihydro- [1, 8] naphthyridine-3-carboxylic acid

-7- [ (3R) -3- {4- [ (5S) -5- (acetylamino-methyl) -2-oxo-oxazolidin-3-yl ] -2-fluoro-phenylamino } -pyrrolidin-1-yl) -1-cyclopropyl-6-fluoro-4-oxo-1, 4-dihydro- [1, 8] naphthyridine-3-carboxylic acid

-7- [ (3R) -3- (4- {4[ (5S) -5- (acetylamino-methyl) -2-oxo-oxazolidin-3-yl ] -2-fluoro-phenyl } -piperazin-1-yl ] -pyrrolidin-1-yl ] -1-cyclopropyl-6-fluoro-4-oxo-1, 4-dihydro- [1, 8] naphthyridine-3-carboxylic acid

-1-cyclopropyl-6-fluoro-7- (4- { 2-fluoro-4- [ (5S) -5- (methoxycarbonothioylamino-methyl) -2-oxo-oxazolidin-3-yl ] -phenyl } -piperazin-1-yl) -4-oxo-1, 4-dihydro- [1, 8] naphthyridine-3-carboxylic acid

-1-cyclopropyl-6-fluoro-7- (4- { 2-fluoro-4- [ (5S) -5- (methylsulfanylthiocarbonylamino-methyl) -2-oxo-oxazolidin-3-yl ] -phenyl } -piperazin-1-yl) -4-oxo-1, 4-dihydro- [1, 8] naphthyridine-3-carboxylic acid

-1-cyclopropyl-6-fluoro- {4- [ 2-fluoro-4- { (5S) -2-oxo-5-thioureidomethyl-oxazolidin-3-yl } -phenyl ] -piperazin-1-yl } -4-oxo-1, 4-dihydro- [1, 8] naphthyridine-3-carboxylic acid

The invention also relates to pharmacologically acceptable salts, or solvates and hydrates, respectively, of the compounds of formula (I), as well as compositions and formulations. The invention describes methods for the production of pharmaceutically useful formulations (agents) containing these compounds, as well as the use of these compounds for the production of pharmaceutically useful formulations.

The pharmaceutical compositions according to the invention contain at least one compound of formula I as active ingredient, and optionally carriers and/or diluents and/or adjuvants. Optionally, the pharmaceutical composition according to the invention may also contain additional known antibiotics.

Examples of pharmacologically acceptable salts of sufficiently basic compounds of formula (I) are salts of physiologically acceptable inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid; or salts of organic acids such as methanesulfonic acid, p-toluenesulfonic acid, lactic acid, acetic acid, trifluoroacetic acid, citric acid, succinic acid, fumaric acid, maleic acid and salicylic acid. Furthermore, sufficiently acidic compounds of formula (I) may form salts of alkali metals or alkaline earth metals, for example sodium, potassium, lithium, calcium or magnesium salts; an ammonium salt; or an organic base salt such as methylamine, dimethylamine, trimethylamine, triethylamine, ethylenediamine, ethanolamine, choline hydroxide, meglumine, piperidine, morpholine, tris- (2-hydroxyethyl) amine, lysine or arginine salt. The compounds of formula (I) may be solvated, especially hydrated. Water and may occur during the manufacturing process or as a result of the hygroscopicity of the initially anhydrous compound of formula (I). The compounds of formula (I) contain asymmetric carbon atoms and may exist as achiral compounds, mixtures of diastereomers, mixtures of enantiomers or as optically pure compounds.

The invention also relates to prodrugs consisting of a compound of formula (I) and at least one pharmacologically acceptable protecting group which can be removed under physiological conditions, such as alkoxy, aralkoxy, acyl, acyloxymethyl (such as pivaloyloxymethyl), 2-alkyl, 2-aryl or 2-aralkyloxycarbonyl-2-alkylenoethyl or acyloxy, such as ethoxy, benzyloxy, acetyl or acetoxy, as defined herein.

As noted above, therapeutically effective formulations containing compounds of formula (I), their solvates, salts or formulations are also included within the scope of the present invention. In general, the compounds of formula (I) will be administered alone or in combination with any other therapeutic agent, by using well known and acceptable modes known in the art. Such therapeutically effective formulations may be administered by one of the following routes: oral, e.g. in the form of tablets, dragees, coated tablets, pills, semi-solids, soft or hard capsules, e.g. soft and hard gelatine capsules, aqueous or oily solutions, emulsions, suspensions or syrups, parenteral, including intravenous, intramuscular and subcutaneous injections, e.g. in injectable solutions or suspensions, rectal, e.g. suppositories, administration by inhalation or insufflation, e.g. in powder formulations, in microcrystals or in sprays (e.g. liquid aerosols), transdermal, e.g. via a Transdermal Delivery System (TDS), e.g. plaster containing the active ingredient, or intranasal. For the manufacture of such tablets, pills, semi-solids, coated tablets, dragees and hard, e.g. gelatin capsules, the therapeutically effective product may be mixed with pharmaceutically inert, inorganic or organic excipients, such as lactose, sucrose, glucose, gelatin, malt, silica gel, starch or derivatives thereof, talc, stearic acid or its salts, dried skim milk and the like. For the production of soft capsules, excipients such as vegetable, petroleum, animal or synthetic oils, waxes, fats, polyols can be used. For the production of liquid solutions, emulsions or suspensions or syrups, it is possible to use, for example, water, alcohols, saline solutions, aqueous glucose solutions, polyols, glycerol, lipids, phospholipids, cyclodextrins, vegetable oils, petroleum, animal oils or synthetic oils as excipients. Particularly preferred are lipids, more preferred are phospholipids (preferably of natural origin; particularly preferred particle sizes between 300 and 350 nm), preferably in phosphate buffered saline (pH 7-8, preferably 7.4). For suppositories, for example, vegetable, petroleum, animal or synthetic oils, waxes, fats and polyols can be used as excipients. For aerosol formulations, compressed gases suitable for this purpose may be used, such as oxygen, nitrogen and carbon dioxide. Pharmaceutically useful formulations may also contain additives for preservation, stabilization, such as UV stabilizers, emulsifiers, sweeteners, aromatics, salts for varying the osmotic pressure, buffers, coating additives and antioxidants.

Daily dosages of about 1mg to about 4000mg, particularly about 50mg-3g, per patient are commonly employed by those skilled in the art, and those skilled in the art will appreciate that dosages will also depend upon the age, condition of the mammal, and the type of disease being treated or prevented. The daily dose may be administered once, or may be administered in several divided doses. The average primary dose may be about 50mg, 100mg, 250mg, 500mg, 1000mg and 2000 mg.

The compounds of formula (I) can be obtained, for example, as follows: reacting the oxazolidinone containing an amino group with the group a described above with a 7-chloro or 7-fluoroquinolone derivative. To facilitate the reaction, the quinolone reactant may be reacted prior to use by reaction with a Lewis acid such as BF₃Activation by complexation with diethyl ether or any boron-containing complex such as boron acetate. The reaction is carried out in a polar solvent such as acetonitrile, 1-methyl-2-pyrrolidone, water, DMSO, and an organic base such as triethylamine, N' -dimethyl-p-toluidine, N-methylmorpholineIn the presence of quinoline, DBU, DABCO at 20-200 deg.C, preferably 80-130 deg.C. The reaction may be carried out under microwave activation.

Alternatively, the product can be prepared from the corresponding 7-chloro-quinolone as follows: substituted with 4-nitrophenyl derivatives bearing amine-containing groups and then reacted with polyhydroxyalcohol esters by reduction of the nitro group, reaction with benzyl chloroformate, deprotonation with n-butyl lithium, and construction of oxazolidinones.

The present invention is described in more detail below with reference to examples. These examples are intended to illustrate the invention and are not intended to limit it.

Examples

Example 1: 7- (4- {4- [5- (acetylamino-methyl) -2-oxo-oxazolidin-3-yl ] -2-fluoro-phenyl } -piperazin-1-yl) -1-cyclopropyl-6-fluoro-4-oxo-1, 4-dihydro-quinoline-3-carboxylic acid

A mixture of 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1, 4-dihydro-quinoline-3-carboxylic acid boron diacetate (7-chloro-1-cyclopropy-6-fluoro-4-oxo-1, 4-dihydro-quinoline-3-carboxlate borone diacetate) (described in WO 7998; 103mg, 0.25mmol), N- [3- (3-fluoro-4-piperazin-1-yl-phenyl) -2-oxo-oxazolidin-5-ylmethyl ] acetamide (described in J.Med Chem 1996, 39, 673-one 679 and US 5547950; 100mg, 0.3mmol) and N, N' -dimethyl-p-toluidine (0.054ml, 0.375mmol) at 120 ℃ is reacted, stirred in 0.5ml of 1-methyl-2-pyrrolidone for 12 hours. The reaction mixture was poured into water, and the resulting crystals were collected by filtration and purified by silica gel chromatography. The fractions of interest were combined to yield 38mg (26%) of beige material.

C₂₉H₂₉F₂N₅O₆(581.5812)

mp 315-320℃(dec)

MS：582.4(M+H)；580.4(M-H)。

Example 2: 9- (4- {4- [5- (acetylamino-methyl) -2-oxo-oxazolidin-3-yl ] -2-fluoro-phenyl } -piperazin-1-yl) -8-fluoro-3-methyl-6-oxo-2, 3-dihydro-6H-1-oxa-3 a-aza-phenalene-5-carboxylic acid:

a suspension of 9, 10-difluoro-2, 3-dihydro-3-methyl-7-oxo-7H-pyrido- [1, 2, 3-nor ] -1, 4-benzoxazine-6-carboxylic acid (commercially available from Aldrich (47267-0), described in chem.Pharm.Bull.1987, 35, 1896-son-1902, 84 mg; 0.3mmol), N- [3- (3-fluoro-4-piperazin-1-yl-phenyl) -2-oxo-oxazolidin-5-ylmethyl ] acetamide (described in J.Med Chem 1996, 39, 673-9 and US 5547950; 121mg, 0.36mmol) and DABCO (43.7mg, 0.39mmol) in acetonitrile/water (7ml, 2: 1) was refluxed for 12 days. Acetonitrile was removed under basic pressure and the residue was poured into water. The crystals were collected by filtration and further stirred in methanol (5 ml). The resulting crystals were recrystallized from DMF/water (4: 1) to yield 95mg of beige (53%).

C₂₉H₂₉F₂N₅O₇(597.5806)

mp 258℃(dec)

MS：596.8(M-H)；598.5(M+H)。

Example 3: 7- ((3R, S) -3- {4- [ (5S) -5- (acetylamino-methyl) -2-oxo-oxazolidin-3-yl ] -2-fluoro-phenylcarbamoyl } -piperazin-1-yl) -1-cyclopropyl-6-fluoro-4-oxo-1, 4-dihydro-quinoline-3-carboxylic acid

2([ (5S) -5- (acetylaminomethyl) -2-oxo-oxazolidin-3-yl ] -2-fluoro-phenylcarbamoyl) -piperazine-1, 4-dicarboxylic acid di-tert-butyl ester

0.210ml of phosphorus oxychloride (phoroxychlride) was added at-15 ℃ to 0.4g N [ (5S) -3- (4-amino-3-fluoro-phenyl) -2-oxo-oxazolidin-5-ylmethyl ] acetamide (1.5mmol) and 0.545g of 1-4-di-tert-butyl piperazine-1, 2, 4-tricarboxylate (1.65mmol) in 10ml of pyridine. The reaction was monitored by TLC. The reaction mixture was poured onto ice, diluted with dichloromethane, the organic layer was washed with water and brine, dried over magnesium sulfate, filtered and evaporated. The residue was purified by chromatography using 95/5 dichloromethane/methanol as eluent to give a colorless foam.

Yield: 0.390g, 45%, C₂₇H₃₈FN₅O₈(579.63)

MS：580.5(M+H)⁺，578.8(M-H)^-Method ESI⁺，ESI^-

(2R, S) -2([ (5S) -5- (acetylaminomethyl) -2-oxo-oxazolidin-3-yl ] -2-fluoro-phenylcarbamoyl) -piperazine

A solution of 0.376g di-tert-butyl 2([ (5S) -5- (acetylaminomethyl) -2-oxo-oxazolidin-3-yl ] -2-fluoro-phenylcarbamoyl) -piperazine-1, 4-dicarboxylate in 10ml dichloromethane was diluted with 10ml 1.25N HCl in methanol. The reaction was monitored by TLC. The solvent was evaporated, the residue was dissolved in 10ml of water, neutralized with sodium bicarbonate and the aqueous layer was evaporated to dryness. The residue was digested in 1/1 dichloromethane/methanol solution, the insoluble salts were filtered and the filtrate evaporated. The residue was digested in ethyl acetate and the solid was filtered.

Yield: 0.250g, quantitative, C₁₇H₂₂FN₅O₄(379.39)

MS：380.5(M+H)⁺The method comprises the following steps: ESI⁺

7- ((3R, S) -3- {4- [ (5S) -5- (acetylamino-methyl) -2-oxo-oxazolidin-3-yl ] -2-fluoro-phenylcarbamoyl } -piperazin-1-yl) -1-cyclopropyl-6-fluoro-4-oxo-1, 4-dihydro-quinoline-3-carboxylic acid

A mixture of 175mg of 2([5- (acetylaminomethyl) -2-oxo-oxazolidin-3-yl ] -2-fluoro-phenylcarbamoyl) -piperazine (0.46mmol), 188mg of 7-chloro-6-fluoro-1-cyclopropyl-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid boron diacetate and 154mg of 1, 4-diazabicyclo [2.2.2] octane (1.38mmol) in 2ml of N-methylpyrrolidone is stirred at 100 ℃ under inert gas. The reaction was monitored by TLC. The mixture was poured into ether, the solid filtered and dried. The solid was purified by chromatography using 9/1 dichloromethane/methanol mixture containing 1% acetic acid. Fractions with rf 0.1 were collected and evaporated.

Yield: 0.043g, 18%. C₃₀H₃₀F₂N₆O₇(624.61)

MS：625.5(M+H)⁺，623.8(M-H)^-

Known structural units:

piperazine-1, 2, 4-tricarboxylic acid 1-4-di-tert-butyl ester: CAS 181955-79-3; sources of compounds: chem. pacific Product List N ° 33681,

7-chloro-6-fluoro-1-cyclopropyl-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid boron diacetate: offen. (1996), DE 4428985,

(S) -N [3- (4-amino-3-fluoro-phenyl) -2-oxo-oxazolidin-5-ylmethyl ] acetamide: genin, Michael et al, Journal of Medicinal Chemistry (2000), 43(5), 953-

Example 4: 7- [ (3R) -3- {4- [ (5S) -5- (acetylamino-methyl) -2-oxo-oxazolidin-3-yl ] -2-fluoro-phenylamino } -pyrrolidin-1-yl ] -1-cyclopropyl-6-fluoro-4-oxo-1, 4-dihydro-quinoline-1-carboxylic acid

(3R) -3- (2-fluoro-4-nitro-phenylamino) -pyrrolidine-1-carboxylic acid allyl ester

5.01g of 3, 4-difluoronitrobenzene, 5.1g of (3R) -1-allyloxycarbonyl-3-aminopyrrolidine (30mmol) and 6.27ml of triethylamine (31.5mmol) are stirred under reflux in 100ml of ethyl acetate. The reaction was monitored by HPLC. The reaction was diluted with ethyl acetate and washed with water and brine, the organic layer was dried over magnesium sulfate, filtered and evaporated. The residue was crystallized from an ether/hexane mixture.

Yield: 5.76g, 59%. MW: 309.29, C₁₄H₁₆FN₃O₄

¹H-NMR(δppm，400 MHz，D₆-DMSO)：1.09-2.24(m，2H，N-CH2-CH2-CH)；3.29-3.72(m，4H，CH2-N-CH2)；4.21-4.28(m，1H，N-CH)；4.52(d，2H，O-CH2)；5.15-5.32(m，2H，CH＝CH2)；5.87-5.99(m，1H，CH＝CH2)；6.94(t，1H，Ph-CH)；7.19(d，1H，NH)；7.9-7.99(m，2H，Ph-CH)；

(3R) -3- (2-fluoro-4-nitro-phenylamino) -pyrrolidine-1-carboxylic acid tert-butyl ester

To a solution of 5.76g (3R) -3- (2-fluoro-4-nitro-phenylamino) -pyrrolidine-1-carboxylic acid allyl ester (18.6mmol) in 60ml THF was added 130mg PdCl₂{P(Ph)₂0.186mmol, 12.12ml acetic acid (37.2mmol) and 49.87ml tributyltin hydride (37.2 mmol). The reaction was stirred at room temperature for 1 hour and monitored by TLC. A pale yellow solid precipitated. The suspension is diluted with 100ml of diethyl ether, the solid is filtered, washed with diethyl ether and hexane and dried. The solid was suspended in 10ml THF, 4.87g BOC anhydride (30mmol) was added and the reaction stirred at room temperature for 3 hours and monitored by TLC. The reaction was diluted with ethyl acetate, the organic layer was washed with water and brine, dried over magnesium sulfate, filtered and the filtrate was evaporated. The residue was crystallized from an ether/hexane mixture.

Yield: 4.15g, 68%. MW: 325.34 (C)₁₅H₂₀FN₃O₄)

¹H-NMR(400 MHz，D₆-DMSO；δppm)：1.25(s，9H，t-but)；1.75-2.07(m，2H，N-CH2-CH2-CH)；3.07-3.5(m，4H，CH2-N-CH2)；4.05-4.1(m，1H，N-CH)；6.77-6.83(t，1H，Ph-CH)；7.01(d，1H，NH)；7.77-7.858(m，2H，Ph-CH)；

(3R) -3- [ benzyloxycarbonyl- (4-benzyloxycarbonylamino-2-fluoro-phenyl) -amino ] -pyrrolidine-1-carboxylic acid tert-butyl ester

To a solution of 4g (3R) -3- (2-fluoro-4-nitro-phenyl-amino) -pyrrolidine-1-carboxylic acid tert-butyl ester (12.29mmol) in 100ml ethyl acetate and 50ml methanol was added 1g Pd/C10%. The suspension was stirred under hydrogen. The reaction was monitored by TLC. The crystals were filtered, the filtrate was evaporated to dryness and the residue was dissolved in 100ml of acetone. 25ml of saturated sodium bicarbonate solution were added, followed by 3.63ml of benzyl chloroformate (25.8mmol) at 0 ℃. The reaction was stirred at rt overnight and monitored by TLC. The acetone was evaporated, the aqueous layer was extracted twice with ethyl acetate, the organic layer was washed with water and brine, dried over magnesium sulfate, filtered and the filtrate was evaporated to dryness. The residue was purified by chromatography using 1/1 ethyl acetate/hexane mixture as eluent.

Yield: 6.03g, 99%. MW: 563.63, C₃₁H₃₄FN₃O₆

MS：562.4(M-H)^-Method ESI^-

(3R) -3- { benzyloxycarbonyl- [ 2-fluoro-4- ((5R) -5-hydroxymethyl-2-oxo-oxazolidin-3-yl) -phenyl ] -amino } -pyrrolidine-1-carboxylic acid tert-butyl ester

To a solution of 6.02g (3R) -3- [ benzyloxycarbonyl- (4-benzyloxycarbonylamino-2-fluoro-phenyl) -amino ] -pyrrolidine-1-carboxylic acid tert-butyl ester (10.8mmol) in 40ml THF at-78 deg.C was added dropwise a solution of 7.62ml of 1.6M n-butyllithium (12.2mmol) in n-hexane. The mixture was stirred at-78 ℃ for 10 minutes, then allowed to warm to 0 ℃. 2.11g R (-) -glycidyl butyrate (14.6mmol) was added. The reaction was allowed to reach 20 ℃ and monitored by TLC. The reaction was diluted with ethyl acetate, washed with water and brine, dried over magnesium sulfate, filtered and the filtrate evaporated. The residue was crystallized from an ethyl acetate/hexane mixture.

Yield: 3.36g, 60%. MW: 529.47 (C)₂₇H₃₂FN₃O₇)

MS：530.3(M+H)⁺Method ESI^-

(3R) -3- { [4- { (5R) -5-Azidomethyl-2-oxo-oxazolidin-3-yl } -2-fluoro-phenyl ] -benzyloxycarbonyl-amino } -pyrrolidine-1-carboxylic acid tert-butyl ester

To a solution of 3.36g (3R) -3- (benzyloxycarbonyl- [ 2-fluoro-4- { (5R) -5-hydroxymethyl-2-oxo-oxazolidin-3-yl } -phenyl ] -amino) -pyrrolidine-1-carboxylic acid tert-butyl ester (10.8mmol) and 2.05ml triethylamine (10.8mmol) in 40ml dichloromethane at 0 deg.C was added 0.805ml methanesulfonyl chloride (10.8 mmol). The reaction was stirred at room temperature and monitored by TLC. The reaction was diluted with water and washed with water and brine. The organic layer was dried over magnesium sulfate, filtered and the filtrate was evaporated. The solid residue was dissolved in 10ml DMF, 1.38g of sodium azide (10.8mmol) were added and the mixture was stirred at 80 ℃ under inert gas for 20 hours. DMF was evaporated, the residue was dissolved in ethyl acetate, washed with water and brine, dried over magnesium sulfate, filtered and evaporated

Yield: 4.07g, 99%. MW: 554.58 (C)₂₇H₃₁FN₆O₆)

MS：555.5(M+H)⁺Square, squareLegal ESI (empirical mode Effect)⁺

(3R)3- {4- [ (5S) -5- (acetylaminomethyl) -2-oxo-oxazolidin-3-yl ] -2-fluoro-phenylamino } -pyrrolidine-1-carboxylic acid tert-butyl ester

To a stirred solution of 4.2g (3R) -3- { [4- { (5R) -5-azidomethyl-2-oxo-oxazolidin-3-yl } -2-fluoro-phenyl ] -benzyloxycarbonyl-amino } -pyrrolidine-1-carboxylic acid tert-butyl ester (7.3mmol) in 50ml ethyl acetate was added 400mg Pd/C10%, and the mixture was stirred under hydrogen overnight. The reaction was controlled by TLC. The Pd/C was filtered and the filtrate was evaporated to dryness. The residue was dissolved in 5ml of acetic acid, and 2ml of acetic anhydride was added. The reaction was stirred at room temperature for 2 hours and monitored by TLC. The solvent was evaporated, the residue was dissolved in ethyl acetate, washed with water and brine, dried over magnesium sulfate, filtered and the filtrate was evaporated to dryness.

Yield: 3.1g, quantitative. MW: 436.48 (C)₂₁H₂₉FN₄O₅)

MS：437.5(M+H)⁺Method ESI⁺

N- { (5S) -3- [ 3-fluoro-4- { (3R) -pyrrolidin-3-ylamino } -phenyl ] -2-oxo-oxazolidin-5-ylmethyl } -acetamide

Will be in 40ml 1/1 CH₂Cl₂0.93ml triethylsilane (7.3mmol) (3R)3- (4- [ (5S) -5- (acetylaminomethyl) -2-oxo-oxazolidin-3-yl) in TFA mixture]A solution of tert-butyl (7.3mmol) of-2-fluoro-phenylamino) -pyrrolidine-1-carboxylate was stirred at room temperature and monitored by TLC. The solvent was evaporated and the residue was dissolved in water and neutralized with saturated sodium bicarbonate solution. Evaporating the water and dissolving the residue in 1: 1 CH₂Cl₂Digested in MeOH, treated with 500mg of bleaching earth, filtered and the filtrate evaporated.

Yield: 2.1g, 85%. MW: 336.36 (C)₁₆H₂₁FN₄O₃)

MS：337.6(M+H)⁺Method ESI⁺

7- [ (3R) -3- {4- [ (5S) -5- (acetylamino-methyl) -2-oxo-oxazolidin-3-yl ] -2-fluoro-phenylamino ] -pyrrolidin-1-yl ] -1-cyclopropyl-6-fluoro-4-oxo-1, 4-dihydro-quinoline-1-carboxylic acid

A solution of 204mg of 7-chloro-6-fluoro-1-cyclopropyl-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid boron diacetate (0.5mmol), 252mg of N- { (5S) -3- [ 3-fluoro-4- { (3R) -pyrrolidin-3-ylamino } -phenyl ] -2-oxo-oxazolidin-5-ylmethyl } -acetamide (0.75mmol) and 112mg of DABCO (MW: 112.0, 1mmol) in 5ml of DMSO was stirred for 50 h. The DMSO was evaporated. The residue was suspended in 10ml of ethanol containing 100. mu.l of triethylamine and stirred at room temperature for 20 hours. The mixture was diluted with 20ml of water. The mixture was filtered and the solid collected. The solid was crystallized from a methanol/ethanol/dichloromethane mixture.

Yield: 16mg, 3.6%. MW: 582.4 (C)₂₉H₂₉F₂N₅O₆)

MS：582.4(M+H)⁺Method ESI⁺

Example 5: 7- (4- {4- [ (5S) -5- (acetylamino-methyl) -2-oxo-oxazolidin-3-yl ] -2-fluoro-phenyl } -piperazin-1-yl) -6-fluoro-1- (5-fluoro-pyridin-2-yl) -4-oxo-1, 4-dihydro-quinoline-3-carboxylic acid

7-chloro-6-fluoro-1- (5-fluoro-pyridin-2-yl) -4-oxo-1, 4-dihydroquinoline-3-carboxylic acid ethyl ester

A solution of 0.747g 2- (2, 4-dichloro-5-fluoro-benzoyl) -3-ethoxy-acrylic acid ethyl ester (2.23mmol) and 0.250g 2-amino-5-fluoropyridine (2.23mmol) in 5ml ethanol was stirred at reflux for 25 h. The reaction was monitored by TLC. The ethanol was evaporated and the last traces of ethanol were distilled from the azeotrope with a mixture of 10ml heptane and 10ml ethyl acetate. The yellow oil was dissolved in 10ml THF, reacted with 120mg of a 50% NaH suspension in oil and stirred under reflux overnight. The solvent was evaporated, the residue was dissolved in 9: 1 dichloromethane/methanol, washed with water and brine, dried over magnesium sulfate, filtered and evaporated. The residue was digested in ethyl acetate and the solid was filtered.

Yield: 583mg, 72%. MW: 364.73 (C)₁₇H₁₁ClF₂N₂O₃)

MS：365.4(M+H)⁺Method ESI⁺

7-chloro-6-fluoro-1- (5-fluoro-pyridin-2-yl) -4-oxo-1, 4-dihydroquinoline-3-carboxylic acid

A suspension of 0.5g of 7-chloro-6-fluoro-1- (5-fluoro-pyridin-2-yl) -4-oxo-1, 4-dihydro-quinoline-3-carboxylic acid ethyl ester (1.37mmol) in a mixture of 1.5ml acetic acid and 1.5ml 25% HCl was stirred at 90 ℃ overnight. The reaction was monitored by HPLC. The suspension is poured into 50ml of water, the colourless crystals are filtered off and dried.

Yield: 461mg, quantitative. MW: 336.68 (C)₁₅H₇ClF₂N₂O₃)

MS：337.5(M+H)⁺Method ESI⁺

7-chloro-6-fluoro-1- (5-fluoro-pyridin-2-yl) -4-oxo-1, 4-dihydro-quinoline-3-carboxylic acid boron diacetate

To a stirred suspension of 380mg 7-chloro-6-fluoro-1- (5-fluoro-pyridin-2-yl) -4-oxo-1, 4-dihydro-quinoline-3-carboxylic acid (1.12mmol) in 4ml dichloromethane were added 0.31ml triethylamine (d ═ 0.726, 2.25mmol) and 0.12ml (d ═ 1.1050, 1.68mmol) acetyl chloride at 0 ℃. The reaction mixture was allowed to warm to room temperature, diluted with dichloromethane and washed twice with ice-cold water and brine. The organic layer was dried over sodium sulfate, filtered and evaporated. The residue was crystallized from a dichloromethane/hexane mixture. 332mg of colorless crystals were suspended in 0.63ml of acetic anhydride (MW: 102.9, d ═ 1.08, 6.6mmol) and 78mg of anhydrous boric acid (MW: 61.83, 1.26mmol) and 1mg of zinc chloride (MW: 136.28, 0.7mmol) were added. The mixture was stirred at 80 ℃ for two hours. The reaction was poured onto 10g of ice in 20ml of water and stirred. The colorless crystals were filtered, digested twice in 100ml of ethanol, filtered, washed with diethyl ether and hexane and dried under vacuum at room temperature

Yield: 226mg, 43%. MW: 464.57 (C)₁₉H₁₂BClF₂N₂O₇)

¹H-NMR(δppm；DMSO-D₆): 1.96(s, 6H, acetate); 8.15(d, 1H, pyridine), 8.25(m, 2H, pyridine), 8.53(d, 1H, quinoline); 8.87(d, 1H, quinoline); 9.71(s, 1H, allyl).

7- (4- {4- [ (5S) -5- (acetylamino-methyl) -2-oxo-oxazolidin-3-yl ] -2-fluoro-phenyl } -piperazin-1-yl) -6-fluoro-1- (5-fluoro-pyridin-2-yl) -4-oxo-1, 4-dihydro-quinoline-3-carboxylic acid

212mg of 7-chloro-6-fluoro-1- (5-fluoro-pyridin-2-yl) -4-oxo-1, 4-dihydro-quinoline-3-carboxylic acid boron diacetate (0.45mmol), 306mg of N- { [ (5S) -3- [ 3-fluoro-4- (1-piperazinyl) phenyl ] -2-oxo-5-oxazolidinyl ] methyl } -acetamide (0.9mmol) and 2ml of DMSO were irradiated in a microwave oven under 250W in a sealed reaction vessel under an inert gas for 7 periods of 2.30 minutes. The reaction was monitored by HPLC.

The DMSO was evaporated, the crude product was digested in 10ml water and filtered. The residue was chromatographed using CH₂Cl₂the/MeOH 5% mixture was purified.

Yield: 5mg, 2%. MW: 636.59 (C)₃₁H₂₇F₃N₆O₆)

MS：637.2(M+H)⁺Method ESI⁺

Known structural units:

2-amino-5-fluoropyridine: 21717-96-4, aldrich 51868-9

2- (2, 4-dichloro-5-fluoro-benzoyl) -3-ethoxy-acrylic acid ethyl ester: 86483-52-5, WO0217916A1

Example 6: 7- (4- { (5S) -5- (acetylamino-methyl) -2-oxo-oxazolidin-3-yl } -2-fluoro-phenyl) -piperazin-1-yl) -1- (2, 4-difluoro-phenyl) -6-fluoro-4-oxo-1, 4-dihydro-quinoline-3-carboxylic acid

7-chloro-1- (2, 4-difluoro-phenyl) -6-fluoro-4-oxo-1, 4-dihydro-quinoline-3-carboxylic acid ethyl ester

A solution of 2g of 2- (2, 4-dichloro-5-fluoro-benzoyl) -3-ethoxy-acrylic acid ethyl ester (5.97mmol) and 0.6ml of 2, 4-difluoroaniline (5.97mmol) in 15ml of ethanol was stirred at reflux for 25 hours. The reaction was monitored by TLC. The ethanol was evaporated and the remaining ethanol was distilled from an azeotrope with 20ml heptane and 20ml ethyl acetate. The yellow oil was dissolved in 20ml THF, reacted with 315mg of a 50% NaH suspension in oil (6.56mmol) and stirred at reflux for 20 h. The solution was diluted with ethyl acetate, washed with water and brine, dried over magnesium sulfate, filtered and the filtrate evaporated.

Yield: 2.0g, 90%. MW: 381.74 (C)₁₈H₁₁ClF₃NO₃)

MS：382.3(M+H)⁺Method ESI⁺

7-chloro-1- (2, 4-difluoro-phenyl) -6-fluoro-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid

A mixture of 2.0g of ethyl 7-chloro-1- (2, 4-difluoro-phenyl) -6-fluoro-4-oxo-1, 4-dihydro-quinoline-3-carboxylate (5.23mmol) in 16ml of acetic acid and 16ml of 37% HCl was stirred at 90 ℃ for 25 h and evaporated.

Yield: 1.71g, quantitative. MW: 353.68 (C)₁₆H₇ClF₃NO₃)

MS：354.3(M+H)⁺Method ESI⁺

7-chloro-1- (2, 4-difluoro-phenyl) -6-fluoro-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid boron diacetate

To a stirred suspension of 1.71g 7-chloro-1- (2, 4-difluorophenyl) -6-fluoro-4-oxo-1, 4-dihydro-quinoline-3-carboxylic acid (4.84mmol) in 4ml dichloromethane were added successively 1.35ml triethylamine (MW: 101.19, 9.68mmol) and 0.517ml acetyl chloride (MW: 78.50, d ═ 1.1050, 726mmol) at 0 ℃. The reaction mixture was allowed to warm to room temperature, diluted with dichloromethane and washed twice with ice-cold water and brine. The organic layer was dried over sodium sulfate, filtered and evaporated. The residue was crystallized from a dichloromethane/hexane mixture.

1.91g of colorless crystals were suspended in 3.21ml of acetic anhydride (33.88mmol), and 400mg of anhydrous boric acid (6.47mmol) and 5mg of zinc chloride (0.04mmol) were added. The mixture was stirred at 80 ℃ for two hours. The reaction was poured onto 10g of ice in 20ml of water and stirred. The colorless crystals were filtered, digested twice in 100ml of ethanol, filtered, washed with diethyl ether and hexane and dried.

Yield: 1.7g, 74%. MW: 481.58 (C)₂₀H₁₂BClF₃NO₇)

MS：482.4(M+H)⁺Method ESI⁺

7- (4- { (5S) -5- (acetylamino-methyl) -2-oxo-oxazolidin-3-yl } -2-fluoro-phenyl) -piperazin-1-yl) -1- (2, 4-difluoro-phenyl) -6-fluoro-4-oxo-1, 4-dihydro-quinoline-3-carboxylic acid

A suspension of 240mg of 7-chloro-1- (2, 4-difluoro-phenyl) -6-fluoro-4-oxo-1, 4-dihydro-quinoline-3-carboxylic acid boron diacetate (0.5mmol) and 336mg of N- ({ (5S) -3- [ 3-fluoro-4- (1-piperazinyl) phenyl ] -2-oxo-5-oxazolidinyl } -methyl) -acetamide (1mmol) in 2ml of DMSO was irradiated in a microwave oven under inert gas at 250W for 3 periods of 2.30 minutes in a closed vessel. The reaction was monitored by HPLC. The DMSO was evaporated and the residue was digested in acetonitrile/water. The solid was filtered off, the filtrate was evaporated and purified by chromatography.

Yield: 11mg, 4%. MW: 653.60(C₃₂H₂₇F₄N₅O₆)

MS：652.5(M-H)^-method ESI^-

Known component

2, 4-difluoroaniline: 367-25-9, Aldrich D10-140-0

2- (2, 4-dichloro-5-fluoro-benzoyl) -3-ethoxy-acrylic acid ethyl ester: 86483-52-5, WO0217916A 120020307

Example 7: 7- (4- {4- [ (5S) -5- (acetylamino-methyl) -2-oxo-oxazolidin-3-yl ] -2-fluoro-phenyl } -piperazin-1-yl) -1-cyclopropyl-8-methoxy-4-oxo-1, 4-dihydro-quinoline-3-carboxylic acid

1-cyclopropyl-7-fluoro-8-methoxy-4-oxo-1, 4-dihydro-quinoline-3-carboxylic acid boron diacetate

To a stirred suspension of 1.12g 1-cyclopropyl-7-fluoro-8-methoxy-4-oxo-1, 4-dihydro-quinoline-3-carboxylic acid (4mmol) in 20ml dichloromethane at 0 ℃ were added successively 1.2ml triethylamine (8mmol) and 0.454ml acetyl chloride (MW: 78.50). The reaction mixture was allowed to warm to room temperature, diluted with dichloromethane and washed twice with ice-cold water and brine. The organic layer was dried over sodium sulfate, filtered and evaporated. The crystals were suspended in 3ml of acetic anhydride (MW: 102.9, 28mmol) and 354mg of anhydrous boric acid (MW: 61.83, 5.6mmol) and 10mg of zinc chloride (MW: 136.28, 0.07mmol) were added. The mixture was stirred at 80 ℃ for two hours. The reaction was poured onto 10g of ice in 20ml of water and stirred. The colorless crystals were filtered.

Yield: 600mg, 46%. MW: 405.14 (C)₁₈H₁₇BFNO₈)

MS：406.5(M+H)⁺Method ESI⁺

7- (4- {4- [ (5S) -5- (acetylamino-methyl) -2-oxo-oxazolidin-3-yl ] -2-fluoro-phenyl } -piperazin-1-yl) -1-cyclopropyl-8-methoxy-4-oxo-1, 4-dihydro-quinoline-3-carboxylic acid

A solution of 100mg of 1-cyclopropyl-7-fluoro-8-methoxy-4-oxo-1, 4-dihydro-quinoline-3-carboxylic acid boron diacetate (0.24mmol), 166mg of N- [ [3- [ (5S) -3-fluoro-4- (1-piperazinyl) phenyl ] -2-oxo-5-oxazolidinyl ] methyl ] -acetamide (0.49mmol) and 59. mu.L of ethyldiisopropylamine (0.336mmol) in 1ml of DMSO was irradiated in a microwave oven at 150 ℃ for 10 minutes. The reaction was monitored by HPLC. The DMSO was evaporated and the residue was purified by chromatography using a dichloromethane/methanol 5% mixture.

Yield: 14mg, 10%. MW: 593.62 (C)₃₀H₃₂FN₅O₇)

MS：594.6(M+H)⁺Method ESI⁺

Known component

1-cyclopropyl-7-fluoro-8-methoxy-4-oxo-1, 4-dihydro-quinacrine-3-carboxylic acid: 221221-16-5, US6329391

N- [ [3- [ 3-fluoro-4- (1-piperazinyl) phenyl ] -2-oxo-5-oxazolidinyl ] methyl ] -acetamide: 154590-43-9, US5547950

Example 8: 9- (4- {4- [ (5S) -5- (acetylamino-methyl) -2-oxo-oxazolidin-3-yl ] -2-fluoro-phenyl } -piperazin-1-yl-8-fluoro-3-methyl-6-oxo-2, 3-dihydro-6H-1-oxa-3, 3 a-diaza-phenalene-5-carboxylic acid

9- (4- {4- [ (5S) -5- (acetylamino-methyl) -2-oxo-oxazolidin-3-yl ] -2-fluoro-phenyl } -piperazin-1-yl) -8-fluoro-3-methyl-6-oxo-2, 3-dihydro-6H-1-oxa-3, 3 a-diaza-phenalene-5-carboxylic acid ethyl ester

A solution of 100mg of 8, 9-difluoro-3-methyl-6-oxo-2, 3-dihydro-6H-1-oxa-3, 3 a-diaza-phenalene-5-carboxylic acid ethyl ester (0.32mmol) and 216mg of N- [ { (5S) -3[ 3-fluoro-4- (1-piperazinyl) phenyl ] -2-oxo-5-oxazolidinyl } -methyl ] -acetamide (0.64mmol) was dissolved in a mixture of 1ml of pyridine and 1ml of DMSO. The reaction was monitored by TLC. The DMSO was evaporated, the residue was digested in water and the solid was collected. The solid was purified by chromatography using 9/1 dichloromethane/methanol mixture as eluent.

Yield: 44mg 22%. MW: 626.62 (C)₃₀H₃₂F₂N₆O₇)

MS：627.7(M+H)⁺Method ESI⁺

9- (4- {4- [ (5S) -5- (acetylamino-methyl) -2-oxo-oxazolidin-3-yl ] -2-fluoro-phenyl } -piperazin-1-yl) -8-fluoro-3-methyl-6-oxo-2, 3-dihydro-6H-1-oxa-3, 3 a-diaza-phenalene-5-carboxylic acid

44mg of 9- (4- {14- [ (5S) -5- (acetylamino-methyl) -2-oxo-oxazolidin-3-yl ] -2-fluoro-phenyl) -piperazin-1-yl) -8-fluoro-3-methyl-6-oxo-2, 3-dihydro-6H-1-oxa-3, 3 a-diaza-phenalene-5-carboxylic acid ethyl ester (0.32mmol) were heated at 80 ℃ in 2ml 1/1 mixture of concentrated hydrochloric acid and acetic acid. The reaction was monitored by HPLC. The HCl/AcOH mixture was evaporated, the residue was dissolved in 1/1 methanol/dichloromethane mixture, treated with triethylamine and evaporated. The deacetylated residue was dissolved in a mixture of 1/1 acetic acid and acetic anhydride and the reaction was monitored by HPLC. The solvent was evaporated and the residue was purified by preparative HPLC.

Yield: 9.1mg, 21%. MW: 598.56 (C)₂₈H₂₈F₂N₆O₇)

MS：599.2(M+H)⁺，597.7(M-H)^-Method ESI⁺，ESI^-

Example 9: 7- { (3RS) -3- [ ({4- [ (5S) -5- (acetylamino-methyl) -2-oxo-oxazolidin-3-yl ] -2-fluoro-phenyl } -ethyl-amino) methyl ] -piperazin-1-yl } -1-cyclopropyl-6-fluoro-4-oxo-1, 4-dihydro-quinoline-3-carboxylic acid

(1, 4-dibenzyl-piperazin-2-ylmethylene) -ethyl-amine

To a solution of 0.5g of (1, 4-bis (phenylmethyl) -2-piperazine-carboxaldehyde (carboxaldehyd) in 5ml of dichloromethane were added 0.54ml of ethylamine and 0.5g of molecular sieves.

Yield: 385mg, 71%. MW: 321.46 (C)₂₁H₂₇N₃)

¹H-NMR(400 MHz，D₆-DMSO；δppm)：1.07(t，3H，N-CH2-CH3)；2.07-2.22(m，3H，N-CH2)；2.63-2.73(m，3H，N-CH2)；2.92(m，1H，pip.H2)；3.25-3.74(AB，2H，CH2-Ph)；3.41-3.53(AB，2H，CH2-Ph); 7.22-7.35(m, 10H, Ph); 7.6(d, 1H, methylene).

[ (2R, S) - (1, 4-dibenzyl-piperazin-2-ylmethyl) ] -ethyl-amine

0.92g of sodium borohydride is added under inert gas to 5.24g of [ (2R, S) -1, 4-dibenzyl-piperazin-2-ylmethylene ] -ethylamine in 50ml of anhydrous THF and 3ml of methanol. The reaction mixture was stirred at room temperature for 6 hours. The second and third batches of 0.92g sodium borohydride were added after 8 and 12 hours, respectively. The reaction was stopped with 20ml of 0.1M HCl. The reaction mixture was diluted with ethyl acetate, and the organic layer was washed with water and brine, dried over magnesium sulfate, filtered, and the filtrate was evaporated to obtain 5.5g of an oil. The oil was purified by chromatography on silica using 1/1 hexane/acetone mixture containing 1% triethylamine.

Yield: 2.1g, 40%. MW: 323.48 (C)₂₁H₂₉N₃)

¹H-NMR(400 MHz，D₆-DMSO；δppm)：0.91(t，3H，N-CH2-CH3)；2.07-2.23(m，3H，N-CH2)；2.38-2.52(m，4H，N-CH2)；2.60-2.70(m，4H，N-CH，N-CH2) (ii) a 3.21-3.26 and 3.97-4.01(AB, 2H,CH2-Ph)；3.36-3.47(AB，2H， CH2-Ph)；7.18-7.33(m，10H，Ph-H)

[ (2R, S) -1, 4-dibenzyl-piperazin-2-ylmethyl ] -ethyl- (2-fluoro-4-nitro-phenyl) -amine

A mixture of 1.057g 3, 4-difluoro-nitrobenzene (6.34mmol), 2.05g [ (2R, S)1, 4-dibenzyl-piperazin-2-ylmethyl ] -ethylamine (6.34mmol) and 1.4ml triethylamine (9.9mmol) in 10ml ethyl acetate was stirred at 60 ℃ and the reaction monitored by TLC. The reaction was diluted with ethyl acetate, washed with water and brine, dried over magnesium sulfate and filtered. The filtrate was evaporated and the residue was purified by chromatography using 3/7 ethyl acetate/hexane mixture as eluent. The fractions of interest were collected and evaporated to yield a yellow viscous oil.

Yield: 2.58g, 88%. MW: 462.57 (C)₂₇H₃₁FN₄O₂)

MS：463.3(M+H)⁺Method ESI⁺

(4- [ { (2R, S) -1, 4-dibenzyl-piperazin-2-ylmethyl } -ethyl-amino ] -3-fluoro-phenyl) -carbamic acid benzyl ester

To a solution of 2.58g ((2R, S) -1, 4-dibenzyl-piperazin-2-ylmethyl) -ethyl- (2-fluoro-4-nitro-phenyl) -amine in 100ml methanol were added in succession 50ml of a saturated aqueous ammonium chloride solution and 0.5g of zinc powder. The mixture was stirred vigorously and monitored by TLC. The solid was filtered, the filtrate was concentrated, and the dark red solid material was filtered from the aqueous layer. The solid was dissolved in ethyl acetate, washed twice with water and brine, dried over magnesium sulfate, filtered and evaporated.

The dark red oily residue was dissolved in 100ml acetone. 50ml of saturated sodium bicarbonate solution were added. 1.17ml of benzyl chloroformate are added at 0 ℃ with vigorous stirring. The reaction was stirred at rt overnight, acetone was evaporated and the aqueous layer was extracted twice with ethyl acetate. The organic layer was washed with water and brine, dried over magnesium sulfate, filtered and the filtrate evaporated. The residue was purified by chromatography using 95/5 in dichloromethane/methanol mixture as eluent.

Yield: 3.1g, quantitative. MW: 566.72 (C)₃₅H₃₉FN₄O₂)

¹H-NMR(400 MHz，D₆-DMSO；δppm)：0.95(t，3H，N-CH2-CH3)；2.26-2.39(m，3H，N-CH2)；2.55-2.70(m，2H，N-CH2)；2.99-3.05(m，2H，N-CH2) (ii) a 3.18-3.25(m, 1H, N-CH 2); 3.43-3.50(m, 3H, -NH 2); 4.04-5.25 and 4.54-5.20(AB, 4H,CH2-Ph)；3.36-3.47(AB，2H，CH2-Ph); 6.96-7.07(t, 1H, Ph-H); 7.09-7.12(dd, 1H, Ph-H); 7.23-7.49(m, 16H, Ph-H); 9.82(s, 1H, N-H). (5R) -3- {4- [ { (2R, S) -1, 4-dibenzyl-piperazin-2-ylmethyl } -ethyl-amino]-3-fluoro-phenyl } -5-hydroxymethyl-oxazolidin-2-one

To a solution of 3.1g (4- [ { (2R, S) -1, 4-dibenzyl-piperazin-2-ylmethyl } -ethyl-amino ] -3-fluoro-phenyl) -carbamic acid benzyl ester (5.4mmol) in 25ml THF at-78 deg.C was added dropwise a solution of 4.38ml butyllithium in n-hexane (1.6M, 7 mmol). The mixture was stirred at-78 ℃ for 10 minutes, then allowed to warm to-40 ℃ for 10 minutes. 1.28g R (-) -glycidyl butyrate (8.92mmol) was added. The reaction was allowed to reach 20 ℃ and monitored by TLC. The reaction was diluted with ethyl acetate, washed with water and brine, dried over magnesium sulfate, filtered and the filtrate evaporated. The residue was purified by chromatography using a 92.5/7.5 dichloromethane/methanol mixture as eluent.

Yield: 2.35g, 69%. MW: 532.68 (C)₃₁H₃₇FN₄O₃)

MS：533.1(M+H)⁺Method ESI⁺

Methanesulfonic acid (5R) -3- {4- [ { (2R, S) -1, 4-dibenzyl-piperazin-2-ylmethyl } -ethyl-amino ] -3-fluoro-phenyl } -2-oxo-oxazolidin-5-ylmethyl ester

To a solution of 1.2g (5R) -3- {4- [ { (2R, S) -1, 4-dibenzyl-piperazin-2-ylmethyl } -ethyl-amino ] -3-fluoro-phenyl } -5-hydroxymethyl-oxazolidin-5-one (2.25mmol) and 0.5ml triethylamine (4.5mmol) in 10ml dichloromethane was added 0.272g methanesulfonyl chloride (2.4mmol) at 0 ℃. The reaction was stirred at 25 ℃ and monitored by TLC. The reaction was quenched with water, the organic layer was washed with water and brine, dried over magnesium sulfate, filtered and the filtrate was evaporated. The oily residue was purified by chromatography using 95/5 dichloromethane/methanol mixture containing 0.5% triethylamine. Fractions with rf 0.18 were collected and evaporated.

Yield: 1.02g, 75%, MW: 610.75C₃₂H₃₉FN₄O₅S)

MS：611.1(M+H)⁺Method ESI⁺

(5R) -5-azidomethyl-3- {4- [ { (2R, S) -1, 4-dibenzyl-piperazin-2-ylmethyl } -ethyl-amino ] -3-fluoro-phenyl } -oxazolidin-2-one

A suspension of 1.16g of methanesulfonic acid- (5R) -3- {4- [ { (2R, S) -1, 4-dibenzyl-piperazin-2-ylmethyl } -ethyl-amino ] -3-fluoro-phenyl } -2-oxo-oxazolidin-5-ylmethyl ester (1.89mmol), 0.245mg of sodium azide (MW: 65.01, 3.7mmol) and 29mg of sodium iodide (0.0189mmol) in 5ml of DMF was stirred at 80 ℃ under an inert gas. The reaction was monitored by TLC. DMF was evaporated and the residue was dissolved in ethyl acetate, washed with water and brine, dried over magnesium sulfate, then filtered and the filtrate evaporated. The oily residue was purified by chromatography using 95/5 dichloromethane/methanol mixture containing 0.25% triethylamine as eluent. Fractions with rf 0.19 were collected and dried.

Yield: 0.89g and 84 percent. MW: 557.67 (C)₃₁H₃₆FN₇O₂)

MS：558.3(M+H)⁺Method ESI⁺

N- [ (5S) -3- {4- [ { (2R, S) - (1, 4-dibenzyl-piperazin-2-ylmethyl) ethyl-amino } -3-fluoro-phenyl ] -2-oxo-oxazolidin-5-ylmethyl } -acetamide

A solution of 889mg (5R) -5-azidomethyl-3- {4- [ { (2R, S) -1, 4-dibenzyl-piperazin-2-ylmethyl } -ethyl-amino ] -3-fluoro-phenyl } -oxazolidin-2-one (1.59mmol), 459mg triphenylphosphine (1.75mmol) and 286mg water (15.94mmol) in 20ml THF was stirred at 50 ℃ for 22 h. The reaction was monitored by TLC. THF was evaporated and the residue was dissolved in 2ml of acetic anhydride. The reaction was monitored by TLC. The solvent was evaporated and the residue was purified by chromatography using 95/5 dichloromethane/methanol mixture containing 0.5% triethylamine as eluent to give a viscous oil.

Yield: 0.6g, 65%. MW: 573.71 (C)₃₃H₄₀FN₅O₃)

MS：574.2(M+H)⁺Method ESI⁺

N- [ (5S) -3- {4- [ { (2R, S) -piperazin-2-ylmethyl } ethyl-amino ] -3-fluoro-phenyl } -2-oxo-oxazolidin-5-ylmethyl ] -acetamide

A suspension of 0.59g n- [ (5S) -3- {4- [ { (2R, S) -1, 4-dibenzyl-piperazin-2-ylmethyl } -ethyl-amino ] -3-fluoro-phenyl } -2-oxo-oxazolidin-5-ylmethyl ] -acetamide (1.028mmol) and 300mg Pd/Cd in 20ml 1/1 ethyl acetate/methanol mixture was stirred at room temperature under hydrogen. The reaction was monitored by TLC. The Pd/C was filtered and the filtrate was evaporated to dryness. The glassy residue is dried.

Yield: 0.3g, 86%. MW: 393.46 (C)₁₉H₂₈FN₅O₃)

MS：394.3(M+H)⁺Method ESI⁺

7- { (3R, S) -3- [ ({4- [ (5S) -5- (acetylamino-methyl) -2-oxo-oxazolidin-3-yl ] -2-fluoro-phenyl } -ethyl-amino) methyl-piperazin-1-yl ] -1-cyclopropyl-6-fluoro-4-oxo-1, 4-dihydroquinacriline-3-carboxylic acid

A suspension of 115mg of 7-chloro-6-fluoro-1-cyclopropyl-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid boron diacetate (0.282mmol), 100mg of N- [ (5S) -3- {4- [ { (2R, S) -piperazin-2-ylmethyl } -ethyl-amino ] -3-fluoro-phenyl } -2-oxo-oxazolidin-5-ylmethyl ] -acetamide in 1ml of DMSO and 35mg of DABCO was heated in a microwave oven at 240W for 10 periods of 2.5 minutes. The reaction was monitored by TLC. The DMSO was evaporated, the residue was dissolved in 10ml dichloromethane and the solid was collected. The solid was digested in 3ml water, filtered and purified by preparative HPLC. The fractions were concentrated by evaporation and the water was freeze dried.

Yield: 13.5mg, 7.6%. MW: 638.67 (C)₃₂H₃₆F₂N₆O₆)

MS：639.4(M+H)⁺Method ESI⁺

Known structural units:

(1, 4-bis (phenylmethyl) -2-piperazinecarboxaldehyde

Nat. naylor Alan and all. eur. pat. appl (1989), EP 343900

Example 10: 7- (4- { [ (5S) -5- (acetylamino-methyl) -2-oxo-oxazolidin-3-yl ] -2-fluoro-phenyl } -piperazin-1-yl) -1-cyclopropyl-6-fluoro-4-oxo-1, 4-dihydro- [1, 8] naphthyridine-3-carboxylic acid

7- (4- { [ (5S) -5- (acetylamino-methyl) -2-oxo-oxazolidin-3-yl ] -2-fluoro-phenyl } -piperazin-1-yl) -1-cyclopropyl-6-fluoro-4-oxo-1, 4-dihydro- [1, 8] naphthyridine-3-carboxylic acid

A suspension of 100mg of 7-chloro-1-cyclopropyl-6-fluoro-1, 4-dihydro-4-oxo- [1, 8] naphthyridine-3-carboxylic acid (0.35mmol), 130mg of N- [ { (5S) -3[ 3-fluoro-4- (1-piperazinyl) phenyl ] -2-oxo-5-oxazolidinyl } methyl ] -acetamide (0.39mmol), 119mg of triethylamine (MW: 101.19, 1.17mmol) and 85mg of trimethylchlorosilane (0-78mmol) in 2ml of DMSO was heated in a microwave oven at 150 ℃ for 10 minutes with stirring. The reaction was monitored by TLC. The DMSO was evaporated, the residue digested in water, filtered and the solid purified by chromatography using a dichloromethane/methanol mixture as eluent. Fractions were collected and evaporated. The residue was crystallized from acetonitrile.

Yield: 84mg, 42%. MW: 582.57 (C)₂₈H₂₈F₂N₆O₆)

MS：583.3(M+H)⁺，581.6(M+H)^-Method ESI⁺，ESI^-

Known component

7-chloro-1-cyclopropyl-6-fluoro-1, 4-dihydro-4-oxo- [1, 8] naphthyridine-3-carboxylic acid lit: US 4777175; US 5281612; CAS: 100361-18-0

N- [ { (5S) -3[ 3-fluoro-4- (1-piperazinyl) phenyl ] -2-oxo-5-oxazolidinyl } methyl ] -acetamide lit: US 5547950; CAS: 154590-66-6

Example 11: 7- {4- [2- (4- {4- [5- (acetylamino-methyl) -2-oxo-oxazolidin-3-yl ] -2-fluoro-phenyl } -piperazin-1-yl) -ethyl ] -piperazin-1-yl } -1-cyclopropyl-6-fluoro-4-oxo-1, 4-dihydro-quinoline-3-carboxylic acid

4- [2- (4- {4- [ (5S) -5- (acetylamino-methyl) -2-oxo-oxazolidin-3-yl ] -2-fluoro-phenyl } -piperazin-1-yl) ethyl ] piperazine-1-carboxylic acid tert-butyl ester

A solution of 336mg of N- ({ (5S) -3- [ -3-fluoro-4- (1-piperazinyl) phenyl ] -2-oxo-5-oxazolidinyl } methyl) -acetamide (1mmol), 308mg of 4- [2- {2- (methylsulfonyl) -oxy } -ethyl ] -1-piperazinecarboxylic acid 1, 1-dimethylethyl ester (1mmol), 32.2mg of tetrabutylammonium iodide (0.08mmol) and 203mg of potassium carbonate (2.5mmol) in 2ml of DMF is stirred at 80 ℃ for 20 h. The solvent was evaporated and the residue was purified by preparative HPLC.

Yield: 200mg, 36%. C₂₇H₄₁FN₆O₅(MW：548.6)

MS：(M+H)⁺549.5 method ESI⁺

N- [ (5S) -3- { 3-fluoro-4- [4- (2-piperazin-1-yl-ethyl) -piperazin-1-yl ] -phenyl } -2-oxo-oxazolidin-5-ylmethyl ] -acetamide

A solution of 200mg of tert-butyl 4- [2- (4- {4- [ (5S) -5- (acetylamino-methyl) -2-oxo-oxazolidin-3-yl ] -2-fluoro-phenyl } -piperazin-1-yl) ethyl ] piperazine-1-carboxylate (0.36mmol) in 2ml of dichloromethane and 2ml of trifluoroacetic acid was stirred for 10 minutes. The solvent was evaporated, the residue was digested in ether and the solid was filtered. The solid was dissolved in water and neutralized with saturated sodium bicarbonate solution. The water is evaporated and the product is dried as a mixture with salt.

Yield: 136mg, 100%. C₂₂H₃₃FN₆O₃(Mw：448.5)

MS：449.4(M+H)⁺Method ESI⁺

6, 7-difluoro-1-cyclopropyl-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid boron diacetate

To a suspension of 2g of 1-cyclopropyl-6, 7-difluoro-1, 4-dihydro-4-oxo-3-quinolinecarboxylic acid (0.754mmol) in 30ml of dichloromethane were added 2.10ml of triethylamine (1.52mmol) and 804. mu.l of acetyl chloride (1.1mmol) at 0 ℃. The solution was allowed to warm to room temperature. The mixture was then diluted with dichloromethane and washed twice with water and brine. The organic layer was dried over magnesium sulfate, filtered and the filtrate was evaporated. The solid was suspended in 5.08ml of acetic anhydride (5.2mmol) and 628mg of anhydrous boric acid (MW: 61.83, 1mmol) and 20mg of zinc chloride (0.14mmol) were added. The mixture was stirred at 80 ℃ for 20 hours. The reaction was poured onto 10g of ice in 20ml of water and stirred. The solid was filtered.

Yield: 1.4g, 47%. C₁₇H₁₄BF₂NO₇(Mw：393.1)

MS：394.1(M+H)⁺Method ESI⁺

7- {4- [2- (4- {4- [ (5S) -5- (acetylamino-methyl) -2-oxo-oxazolidin-3-yl ] -2-fluoro-phenyl } -piperazin-1-yl) -ethyl ] -piperazin-1-yl } -1-cyclopropyl-6-fluoro-4-oxo-1, 4-dihydro-quinoline-3-carboxylic acid

163mg of N- [ (5S) -3- { 3-fluoro-4- [4- (2-piperazin-1-yl-ethyl) -piperazin-1-yl ] -phenyl } -2-oxo-oxazolidin-5-ylmethyl ] -acetamide (0.36mmol), 142.85mg of 6, 7-difluoro-1-cyclopropyl-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid boron diacetate (0.36mmol) and 44.77mg of DABCO (0.36mmol) were irradiated in a microwave oven for 3 min periods. The reaction was then subjected to HPLC. DMSO was evaporated and the residue was purified by preparative HPLC.

Yield: 40mg, 16%. C₃₅H₄₁F₂N₇O₆；(Mw：693.7)

MS：694.3(M+H)⁺，692.6(M-H)^-Method ESI⁺Method ESI^-

Known structural units:

1-piperazinecarboxylic acid, 4- [2- [2- [ methylsulfonyl ] oxy ] -ethyl ] -1-piperazinecarboxylic acid-1, 1-dimethylethyl ester: WO 8808424

1-cyclopropyl-6, 7-difluoro-1, 4-dihydro-4-oxo-3-quinolinecarboxylic acid: EP 1160241

N- [ [3- [ 3-fluoro-4- (1-piperazinyl) phenyl ] -2-oxo-5-oxazolidinyl ] methyl ] -acetamide: 154590-43-9: US5547950

Example 12: 7- [4- (4- {4- [ (5S) -5- (acetylamino-methyl) -2-oxo-oxazolidin-3-yl ] -2-fluoro-phenyl } -piperazin-1-yl) -piperidin-1-yl ] -1-cyclopropyl-6-fluoro-4-oxo-1, 4-dihydro-quinoline-3-carboxylic acid

1- (1-benzyl-piperidin-4-yl) -4- (2-fluoro-4-nitro-phenyl) -piperazine

To a solution of 10g of 2, 2- [ (2-fluoro-4-nitrophenyl) -imino ] di-ethanol (40.5mmol) and 12.3g of triethylamine (120mmol) in 200ml of dichloromethane at 0 ℃ was added 11.12g of methanesulfonyl chloride (97.3 mmol). The reaction mixture was stirred at room temperature and monitored by TLC. The mixture was diluted with 50ml dichloromethane and washed with water, sodium bicarbonate solution and brine at 0 ℃. The organic layer was dried over magnesium sulfate, filtered and the filtrate evaporated to give a yellow solid. The solid was dissolved in 200ml of toluene, and 8.48g of 4-amino-1-benzylpiperidine and 16.9ml of triethylamine were added. The suspension was stirred at 120 ℃ for 72 hours. The reaction was monitored by TLC. The solvent was evaporated, the residue was dissolved in ethyl acetate, washed with water and brine, dried over magnesium sulfate, filtered and evaporated. The residue was purified by chromatography using 9/1 dichloromethane/methanol mixture as eluent. The fractions of interest were collected and evaporated. The residue was crystallized from an ethyl acetate/hexane mixture.

Yield: 6.05g, 40%. MW: 398.48 (C)₂₂H₂₇FN₄O₂)

MS：399.4(M+H)⁺Method ESI⁺

4- [4- (4-benzyloxycarbonylamino-2-fluoro-phenyl) -piperazin-1-yl ] -piperidine-1-carboxylic acid benzyl ester

To a solution of 6.05g 1- (1-benzyl-piperidin-4-yl) -4- (2-fluoro-4-nitro-phenyl) -piperazine (15.2mmol) in 50ml methanol and 5ml acetic acid was added 2g Pd/C10%. The suspension was mechanically stirred under hydrogen. The reaction was monitored by TLC. The Pd/C was filtered and the filtrate was evaporated to dryness. The residue was dissolved in 250ml of acetone, diluted with 125ml of saturated sodium bicarbonate solution and reacted with 8ml of benzyl chloroformate. The reaction was monitored by TLC. The acetone was evaporated, the viscous oil was dissolved in ethyl acetate, washed with water and brine, and dried over magnesium sulfate. The magnesium sulfate was filtered and the filtrate was evaporated to dryness. The residue was crystallized from an ethyl acetate/hexane mixture.

Yield: 6.40g, 77%. MW: 546.64 (C)₃₁H₃₅FN₄O₄)

MS：547.4(M+H)⁺Method ESI⁺

4- {4- [ 2-fluoro-4 { (5R) -5-hydroxymethyl-2-oxo-oxazolidin-3-yl } -phenyl ] -piperazin-1-yl } -piperidine-1-carboxylic acid benzyl ester

To a solution of 6.3g of benzyl 4- [4- (4-benzyloxycarbonylamino-2-fluoro-phenyl) -piperazin-1-yl ] -piperidine-1-carboxylate (11.52mmol) in 60ml of anhydrous THF was added a solution of 5.7ml of 2.25M LDA (12.8mmol) in THF with stirring at-20 ℃. The reaction was allowed to warm to 0 deg.C and 2.1ml of R (-) -carboxyglyceryl butyrate (14.9mmol) was added. The reaction was stirred at room temperature and monitored by TLC. The reaction was quenched with ammonium chloride solution, diluted with water, and the organic layer was washed with 10% sodium bicarbonate solution and brine. The organic layer was dried over magnesium sulfate and filtered. The filtrate was evaporated to dryness and the residue was crystallized from an ethyl acetate/hexane mixture.

Yield: 3.87g, 65.5%. MW: 512.58 (C)₂₇H₃₃FN₄O₅)

MS：513.7(M+H)⁺Method ESI⁺

4- {4- [4- { (5R) -5-azidomethyl-2-oxo-oxazolidin-3-yl } -2-fluoro-phenyl ] -piperazin-1-yl } -piperidine-1-carboxylic acid benzyl ester

To a solution of 3.67g of 4- {4- [ 2-fluoro-4 { (5R) -5-hydroxymethyl-2-oxo-oxazolidin-3-yl } -phenyl ] -piperazin-1-yl } -piperidine-1-carboxylic acid benzyl ester (7.16mmol) and 1.99ml of triethylamine (14.3mmol) in 50ml of dichloromethane was added 0.66ml of methanesulfonyl chloride (8.59mmol) at 0 ℃. The reaction was stirred at room temperature and monitored by TLC. The reaction was diluted with water and washed with water and brine. The organic layer was dried over magnesium sulfate, filtered and evaporated. The oily residue was dissolved in 15ml DMF. 100mg tetrabutylammonium iodide and 0.930g sodium azide (14.32mmol) were added and the mixture was stirred at 80 ℃ under nitrogen. The reaction was monitored by TLC. DMF was evaporated and the residue was dissolved in ethyl acetate and washed with water and brine. The organic layer was dried over magnesium sulfate, filtered and evaporated. The residue was crystallized from an ethyl acetate/diethyl ether mixture.

Yield: 2.65g, 69%. MW: 537.59 (C)₂₇H₃₂FN₇O₄)

MS：538.8(M+H)⁺Method ESI⁺

4- (4- (4- [ (5S) -5- (acetylamino-methyl) -2-oxo-oxazolidin-3-yl ] -2-fluoro-phenyl) -piperazin-1-yl) -piperidine-1-carboxylic acid benzyl ester

A solution of 2.65g of benzyl 4- {4- [4- { (5R) -5-azidomethyl-2-oxo-oxazolidin-3-yl } -2-fluoro-phenyl ] -piperazin-1-yl } -piperidine-1-carboxylate (4.93mmol), 1.55g of triphenylphosphine (5.91mmol) and 0.88g of water (49.3mmol) in 40ml of THF was stirred at reflux for 22 h. The reaction was controlled by TLC. THF was evaporated, the residue was dissolved in 10ml acetic acid and 2ml acetic anhydride and the reaction was monitored by TLC. The solvent was evaporated and the residue was crystallized from ethyl acetate.

Yield: 2.57g, 94%. MW: 553.63 (C)₂₉H₃₆FN₅O₅)

MS：554.5(M+H)⁺Method ESI⁺

N- { (5S) -3- [ 3-fluoro-4- (4-piperidin-4-yl-piperazin-1-yl) phenyl ] -2-oxo-oxazolidin-5-ylmethyl } -acetamide

A suspension of 500mg Pd/C10% and 2.5g benzyl 4- (4- {4- [ (5R) -5- (acetylamino-methyl) -2-oxo-oxazolidin-3-yl ] -2-fluoro-phenyl } -piperazin-1-yl) -piperidine-1-carboxylate (5.51mmol) in 50ml methanol was stirred under hydrogen. The reaction was monitored by TLC. The Pb/C was filtered off, the filtrate was evaporated to dryness and the residue was digested in an ethyl acetate/hexane mixture. The glassy solid was filtered, washed with hexane and dried.

Yield: 1.805g, 78%. MW: 419.50 (C)₂₁H₃₀FN₅O₃)

MS：420.5(M+H)⁺Method ESI⁺

7- [4- (4- {4- [ (5S) -5- (acetylamino-methyl) -2-oxo-oxazolidin-3-yl ] -2-fluoro-phenyl } -piperazin-1-yl) -piperidin-1-yl ] -1-cyclopropyl-6-fluoro-4-oxo-1, 4-dihydro-quinoline-3-carboxylic acid

A suspension of 130mg of 6, 7-difluoro-1-cyclopropyl-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid boron diacetate (0.33mmol), 147mg of N- {3- [ 3-fluoro-4- (4-piperidin-4-yl-piperazin-1-yl) -phenyl ] -2-oxo-oxazolidin-5-ylmethyl } -acetamide (0.35mmol) and 56mg of DABCO (0.5mmol) in 10ml of acetonitrile was heated in a microwave oven under stirring at 150 ℃ for 10 min. The solvent was evaporated, the residue was digested overnight in ethanol and the solid was filtered off. The solid was digested in 4/1 methanol/1N hydrochloric acid mixture and the solid was filtered.

Yield: 65mg, 29%. MW: 664.72 (C)₃₄H₃₈F₂N₆O₆)

MS：665.5(M+H)⁺，663.4(M-H)^-Method ESI⁺，ESI^-

Example 13: 7- [ (3R, 4R) and (3S, 4S) -3- {4- [ (5S) -5- (acetylamino-methyl) -2-oxo-oxazolidin-3-yl ] -2-fluoro-phenyl } -4-aminomethyl-pyrrolidin-1-yl ] -1-cyclopropyl-6-fluoro-4-oxo-1, 4-dihydro-quinoline-3-carboxylic acid

(4-bromo-3-fluoro-phenyl) -carbamic acid benzyl ester

To a solution of 10g of 4-bromo-3-fluoroaniline (52mmol) in 300ml of acetone were added successively 150ml of a saturated sodium bicarbonate solution and 9ml of benzyl chloroformate (63mmol) at 0 ℃. The reaction was monitored by TLC. The acetone was evaporated, the residue was extracted twice with ethyl acetate, washed with water and brine, dried and evaporated. The residue was crystallized from an ethyl acetate/hexane mixture.

Yield: 15.7g, 92%. MW: 324.15 (C)₁₄H₁₁BrFNO₂)

MS：322.4(M-H)^-Method ESI^-

3- (4-benzyloxycarbonylamino-2-fluoro-phenyl) -acrylic acid ethyl ester

A suspension of 9.72g (4-bromo-3-fluoro-phenyl) -carbamic acid benzyl ester (30mmol), 6g ethyl acrylate (60mmol), 10.2ml DIPEA (60mmol), 112mg palladium acetate (3mmol) and 1.57g triphenylphosphine (6mmol) in 10ml DMF was stirred at 130 ℃ for 48 h. The reaction was monitored by TLC. DMF was evaporated, the residue was dissolved in dichloromethane, washed with water and brine, dried over magnesium sulfate, filtered and the filtrate evaporated. The residue was purified by chromatography using 7/3 n-hexane/ethyl acetate mixture as eluent.

Yield: 4.50g, 43%. MW: 343.35 (C)₁₉H₁₈FNO₄)

MS：342.1(M-H)^-Method ESI^-

(3S, 4R) and (3R, 4S) -1-benzyl-4- (4-benzyloxycarbonylamino-2-fluoro-phenyl) -pyrrolidine-3-carboxylic acid ethyl ester

To a solution of 4.5g of 3- (4-benzyloxycarbonylamino-2-fluoro-phenyl) -acrylic acid ethyl ester (13.1mmol) and 7.68g N- [ (pentyloxy) methyl ] -N- [ (trimethylsilylmethyl) -methyl ] -benzylamine (26.2mmol) in 50ml of dichloromethane was added 10. mu.L of trifluoroacetic acid. The reaction was monitored by TLC. The reaction was complete after 10 minutes. The mixture was diluted with dichloromethane, washed with saturated sodium bicarbonate solution and brine, dried over magnesium sulfate, filtered and the filtrate evaporated. The residue was purified by filtration over a short silica gel column using 7/3 hexane/ethyl acetate mixture as eluent.

Yield: 4.93g of a coarse powder,79％。MW：476.55(C₂₈H₂₉FN₂O₄)

MS：477.4(M+H)⁺method ESI⁺

[4- { (3R, 4S) and (3S, 4R) -1-benzyl-4-hydroxymethyl-pyrrolidin-3-yl } -3-fluoro-phenyl ] -carbamic acid benzyl ester.

A solution of 4.05g (3R, 4S) and ethyl (3S, 4R) -1-benzyl-4- (4-benzyloxycarbonylamino-2-fluoro-phenyl) -pyrrolidine-3-carboxylate (10.3mmol) in 10ml of diethyl ether is added to a suspension of 480mg LAH (15.5mmol) in 100ml of diethyl ether at room temperature. The reaction was monitored by TLC. The excess LAH was hydrolyzed by saturated sodium/potassium tartrate solution. The reaction was diluted with ethyl acetate, washed with water and brine, dried over magnesium sulfate, filtered and the filtrate evaporated to dryness. The residue was crystallized from an ethyl acetate/hexane mixture.

Yield: 4.93g, 79%. MW: 434.51 (C)₂₆H₂₇FN₂O₃)

MS：435.6(M+H)⁺Method ESI⁺

[4- { (3R, 4S) and (3S, 4R) -4-Azidomethyl-1-benzyl-pyrrolidin-3-yl } -3-fluoro-phenyl ] -carbamic acid benzyl ester

In an analogous procedure to that described in example 12, this compound was synthesized using 4.73g of [4- { (3R, 4S) and (3S, 4R) -1-benzyl-4-hydroxymethyl-pyrrolidin-3-yl } -3-fluoro-phenyl ] -carbamic acid benzyl ester (10.9 mmol).

Yield: 5.0g, quantitative. MW: 459.52 (C)₂₆H₂₆FN₅O₂)

MS：460.6(M+H)⁺Method ESI⁺

{4- [ (3R, 4S) and (3S, 4R) -1-benzyl-4 (tert-Butoxycarbonyl-aminomethyl) -pyrrolidin-3-yl ] -3-fluoro-phenyl } -carbamic acid benzyl ester

[4- { (3R, 4S) and (3S, 4R) -4-Azidomethyl in 80ml of THF1-benzyl-pyrrolidin-3-yl-3-fluoro-phenyl-yl]Benzyl carbamate (10.3mmol), 3.39g triphenylphosphine (12.96mmol) and 1.8g H₂A solution of O (MW: 18.0, 100mmol) was stirred at reflux for 22 hours. The reaction was controlled by TLC. 2.25ml triethylamine (16.2mmol) and 2.82g BOC were added₂O (12.9mmol), and the mixture was stirred at room temperature. The reaction was monitored by TLC. The solvent was evaporated and the residue was purified by chromatography using 7/3 ethyl acetate/hexane mixture as eluent.

Yield: 5.0g, quantitative. MW: 533.64 (C)₃₁H₃₆FN₃O₄)

MS：534.4(M+H)⁺Method ESI⁺

{ (3R, 4S) and (3S, 4R) -1-benzyl-4- [ 2-fluoro-4- { (5R) -5-hydroxymethyl-2-oxo-oxazolidin-3-yl } -phenyl ] -pyrrolidin-3-ylmethyl } -carbamic acid tert-butyl ester

This compound was synthesized in a similar procedure as described in example 12 using 4.45g {4- [ (3R, 4S) and (3S, 4R) -1-benzyl-4- (tert-butoxycarbonylamino-methyl) -pyrrolidin-3-yl ] -3-fluoro-phenyl } -carbamic acid benzyl ester (8.33 mmol).

Yield: 2.65g, 63.6%. MW: 499.58 (C)₂₇H₃₄FN₃O₅)

MS：500.4，(M+H)⁺Method ESI⁺

{ (3R, 4S) and (3S, 4R) -1-benzyl-4- [ 2-fluoro-4- { (5R) -5-hydroxymethyl-2-oxo-oxazolidin-3-yl } -phenyl ] -pyrrolidin-3-ylmethyl } -carbamic acid tert-butyl ester

In an analogous procedure to that described in example 12, the compound was synthesized from 2.60g { (3R, 4S) and (3S, 4R) -1-benzyl-4- [ 2-fluoro-4- { (5R) -5-hydroxymethyl-2-oxo-oxazolidin-3-yl } -phenyl ] -pyrrolidin-3-ylmethyl } -carbamic acid tert-butyl ester (5.20 mmol).

Yield: 2.70g, quantitative. MW: 524.6 (C)₂₇H₃₃FN₆O₄)

MS：525.6，(M+H)⁺Method ESI⁺

[ (3R-4S) and (3S-4R) -4- {4- [ (5S) -5- (acetylamino-methyl) -2-oxo-oxazolidin-3-yl ] -2-fluoro-phenyl } -1-benzyl-pyrrolidin-3-ylmethyl ] -carbamic acid tert-butyl ester

This compound was synthesized in a similar procedure as described in example 9 using 2.7g { (3R, 4S) and (3S, 4R) -1-benzyl-4- [ 2-fluoro-4- { (5R) -5-hydroxymethyl-2-oxo-oxazolidin-3-yl } -phenyl ] -pyrrolidin-3-ylmethyl } -carbamic acid tert-butyl ester (5.20 mmol).

Yield: 2.54g, 90%. MW: 540.64 (C)₂₉H₃₇FN₄O₅)

MS：541.3，(M+H)⁺Method ESI⁺

[ (3R, 4S) and (3S, 4R) -4- {4- [ (5S) -5- (acetylamino-methyl) -2-oxo-oxazolidin-3-yl ] -2-fluoro-phenyl } -pyrrolidin-3-ylmethyl ] -carbamic acid tert-butyl ester

This compound was synthesized in a similar procedure as described in example 12 using 2.5g of [ (3R, 4S) and (3S, 4R) -4- {4- [ (5S) -5- (acetylamino-methyl) -2-oxo-oxazolidin-3-yl ] -2-fluoro-phenyl } -1-benzyl-pyrrolidin-3-ylmethyl ] -carbamic acid tert-butyl ester (4.6 mmol).

Yield: 1.69g, 81%. MW: 450.51 (C)₂₂H₃₁FN₄O₅)

MS：451.5，(M+H)⁺Method ESI⁺

7- [ (3R, 4R) and (3S, 4S) -3- {4- [ (5S) -5- (acetylamino-methyl) -2-oxo-oxazolidin-3-yl ] -2-fluoro-phenyl } -4-aminomethyl-pyrrolidin-1-yl ] -1-cyclopropyl-6-fluoro-4-oxo-1, 4-dihydro-quinoline-3-carboxylic acid

A suspension of 130mg of 6, 7-difluoro-1-cyclopropyl-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid boron diacetate (MW: 393.11.0.33mmol), 163mg of [ (3R-4S) and (3S-4R) -4- {4- [ (5S) -5-acetylamino-methyl ] -2-oxo-oxazolidin-3-yl } -2-fluoro-phenyl ] -pyrrolidin-3-ylmethyl ] -carbamic acid tert-butyl ester (0.36mmol) and 56mg of DABCO (0.5mmol) in 10ml of acetonitrile is heated at 150 ℃ for 10 minutes under stirring in a microwave oven. The reaction was monitored by TLC. Acetonitrile was evaporated and the residue was dissolved in 3ml methanol and treated with 3ml 1.25M HCl in methanol. The reaction was stirred for 20 hours and purified by preparative HPLC.

Yield: 75mg, 36%. MW: 595.61 (C)₃₀H₃₁F₂N₅O₆)

MS：596.5，(M+H)⁺Method ESI⁺

Example 14: 7- {4- [2- (4- {4- [ (5S) -5- (acetylamino-methyl) -2-oxo-oxazolidin-3-yl ] -2-fluoro-phenyl } -piperazin-1-yl) -2-oxo-ethyl ] -piperazin-1-yl } -1-cyclopropyl-6-fluoro-4-oxo-1, 4-dihydro-quinolone-3-carboxylic acid

4- [2- (4- {4- [ (5S) -5- (acetylamino-methyl) -2-oxo-oxazolidin-3-yl ] -2-fluoro-phenyl } -piperazin-1-yl) -2-oxo-ethyl ] -piperazine-1-carboxylic acid tert-butyl ester

To a stirred suspension of 672mg of N- [ (5S) -3- (3-fluoro-4-piperazin-1-yl-phenyl) -2-oxo-oxazolidin-5-ylmethyl ] -acetamide (2mmol) and 0.42ml of triethylamine (3mmol) in 30ml of dichloromethane was added 484mg of bromoacetyl bromide (2.4mmol) in 2ml of dichloromethane at room temperature. The reaction was monitored by TLC. The reaction solution was washed with water and brine, the dichloromethane layer was dried over magnesium sulfate, filtered, and the filtrate was evaporated to dryness. The residue was digested in 20ml of diethyl ether, the solid filtered and dried. The colorless solid was dissolved in 10ml of DMF, and 372mg of N-Boc piperazine (2mmol) and 276mg of potassium carbonate (2mmol) were added. The reaction was stirred at 60 ℃ overnight and monitored by TLC. DMF was evaporated to dryness and the residue was purified by chromatography using 19/1 dichloromethane/methanol mixture as eluent.

Yield: 0.494g, 44%. MW: 562.64 (C)₂₇H₃₉FN₆O₆)，

MS：563.5(M+H)⁺Method ESI⁺

N- [ (5S) -3- { 3-fluoro-4- [4- (2-piperazin-1-yl-acetyl) -piperazin-1-yl ] -phenyl } -2-oxo-oxazolidin-5-ylmethyl ] -acetamide

A solution of 0.490g of 4- [2- (4- {4- [ (5S) -5- (acetylamino-methyl) -2-oxo-oxazolidin-3-yl ] -2-fluoro-phenyl } -piperazin-1-yl) -2-oxo-ethyl ] -piperazine-1-carboxylic acid tert-butyl ester (0.87mmol) in 2ml of dichloromethane was treated with 2ml of TFA. The reaction was monitored by TLC. The solvent was evaporated and the residue was dissolved in water. The aqueous layer was neutralized with ammonium hydroxide and freeze dried.

Yield: 0.494g, 44%. MW: 462.52 (C)₂₂H₃₁FN₆O₄)

MS：463.6(M+H)⁺Method ESI⁺

7- {4- [2- (4- {4- [ (5S) -5- (acetylamino-methyl) -2-oxo-oxazolidin-3-yl ] -2-fluoro-phenyl } -piperazin-1-yl) -2-oxo-ethyl ] -piperazin-1-yl } -1-cyclopropyl-6-fluoro-4-oxo-1, 4-dihydro-quinolone-3-carboxylic acid

A suspension of 169mg of 6, 7-difluoro-1-cyclopropyl-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid boron diacetate (0.33mmol), 198mg of N- [ (5S) -3- { 3-fluoro-4- [4- (2-piperazin-1-yl-acetyl) -piperazin-1-yl ] -phenyl } -2-oxo-oxazolidin-5-ylmethyl ] -acetamide (0.43mmol) and 120mg of DABCO (1.07mmol) in 10ml acetonitrile was stirred in a microwave oven at 150 ℃ for 10 min. The reaction was monitored by TLC. Acetonitrile was evaporated and the residue was dissolved in 3ml methanol and treated with 3ml 1.25M HCl in methanol. The reaction was stirred overnight and the solid was filtered off. The solid was purified by preparative HPLC.

Yield: 29mg, 9.6%. MW: 707.74 (C)₃₅H₃₉F₂N₇O₇)

MS：708.7，(M+H)⁺，706.6，(M-H)^-Method ESI⁺，ESI^-

Example 15: 7- (3- {4- [5(S) -5- (acetylamino-methyl) -2-oxo-oxazolidin-3-yl ] -2-fluoro-phenylamino } -azetidin-1-yl) -1-cyclopropyl-6-fluoro-4-oxo-1, 4-dihydro- [1, 8] naphthyridine-3-carboxylic acid

(1-benzhydryl-azetidin-3-yl) - (2-fluoro-4-nitro-phenyl) -amine

A solution of 7.96g of 1-benzhydrylazetidin-3-ylamine (33.41mmol), 3.69ml of 3, 4-difluoronitrobenzene (33.41mmol) and 4.65ml of triethylamine (33.41mmol) in 50ml of ethyl acetate is stirred at 60 ℃ for 2 weeks. The reaction was diluted with water and the product was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over magnesium sulfate, filtered and evaporated.

Yield: 13.2g, quantitative. MW: 393.46 (C)₂₃H₂₄FN₃O₂)

¹H-NMR(δppm DMSO-d₆)：2.78(m，2H，CH₂)；3.54(m，2H，CH₂) (ii) a 4.02(m, 1H, CH); 4.46(s, 1H, CH); 6.69(t, 1H, aromatic ring); 7.1-7.5(m, 8H, diphenyl); 7.90(m, 2H, aromatic ring)

3- [ (benzyloxycarbonyl- (4-benzyloxycarbonylamino-2-fluoro-phenyl) -amino) -azetidine-1-carboxylic acid benzyl ester

A suspension of 1g (1-benzhydryl-azetidin-3-yl) - (2-fluoro-4-nitro-phenyl) -amine (2.54mmol) and 200mg Pd/C10% in 10ml methanol in 5% acetic acid was stirred under hydrogen for 20 h. Pd/C was filtered off and the filtrate was evaporated. The oily residue was digested in hexane and decanted to remove hexane-soluble diphenylmethane. MS 182 (M)+H)⁺Method ESI⁺. The remaining viscous oil was dissolved in 10ml of acetone. 10.0ml of a saturated sodium bicarbonate solution and 1.25ml of benzyl chloroformate (7.62mmol) were added at 0 ℃. The mixture was stirred at room temperature for 4 hours. Acetone was evaporated and the residue was diluted with ethyl acetate. The organic layer was washed with water and brine, dried over magnesium sulfate, filtered and the filtrate evaporated. The residue was purified by chromatography using 4/5 ethyl acetate/hexane mixture as eluent.

Yield: 916mg, 63%. MW: 583.62 (C)₃₃H₃₀FN₃O₆)

MS：584.5(M+H)⁺Method ESI⁺

3- { benzyloxycarbonyl- [ 2-fluoro-4- { (5R) -5-hydroxymethyl-2-oxo-oxazolidin-3-yl } -phenyl ] -amino } -aziridine-1-carboxylic acid benzyl ester

To a solution of 0.916g of benzyl 3- (benzyloxycarbonyl- (4-benzyloxycarbonylamino-2-fluoro-phenyl) -amino) -aziridine-1-carboxylate (1.56mmol) in 5ml of THF at-15 deg.C was added 0.767ml of a 2.25M solution of LDA (1.7mmol) in THF. The mixture was allowed to warm to 0 ℃ and stirred for 5 minutes. Then, 0.26ml of (R) -glycidyl butyrate (1.87mmol) was added, and the yellow solution was stirred at room temperature for 2 hours. The reaction was quenched with saturated ammonium chloride solution. The mixture was diluted with ethyl acetate, and the organic layer was washed with water and brine and dried over magnesium sulfate. The residue was purified by chromatography using 95/5 dichloromethane/methanol mixture as eluent.

Yield: 377mg, 43%. MW: 549.56 (C)₂₉H₂₈FN₃O₇)

MS：550.7(M+H)⁺Method ESI⁺

3- { [4- { (5R) -5-azidomethyl-2-oxo-oxazolidin-3-yl } -2-fluoro-phenyl ] -benzyloxycarbonyl-amino } -azetidine-1-carboxylic acid benzyl ester

To 1.08g of 3- { benzyloxycarbonyl- [ 2-fluoro-4 ] in 20ml of dichloromethane at 0 deg.C- { (5R) -5-hydroxymethyl-2-oxo-oxazolidin-3-yl } -phenyl]To a solution of benzyl (2mmol) amino } -azetidine-1-carboxylate was added 0.56ml triethylamine (4mmol) and 0.17ml methanesulfonyl chloride (2.2 mmol). The reaction was stirred at room temperature for 1 hour and quenched with water. The organic layer was washed with brine, dried over magnesium sulfate, filtered and the filtrate evaporated. Yield: 391mg, 90%. Ms 584.0(M + H)⁺Method ESI⁺

A suspension of intermediate in 15ml DMF, 260mg sodium azide (65.01, 4mmol) and 37mg tetrabutylammonium iodide (0.1mmol) was stirred at 80 ℃ for 16h and DMF was evaporated. The residue was diluted with water and ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered and the filtrate evaporated.

Yield: 1,15g and 93 percent. MW: 574.57 (C)₂₉H₂₇FN₆O₆)

MS：575.4(M+H)⁺Method ESI⁺

3- ({4- [ (5S) -5- (acetylamino-methyl) -2-oxo-oxazolidin-3-yl ] -2-fluoro-phenyl } -benzyloxycarbonyl-amino) -azetidine-1-carboxylic acid benzyl ester

1.15g of benzyl 3- { [4- { (5R) -5-azidomethyl-2-oxo-oxazolidin-3-yl } -2-fluoro-phenyl ] -benzyloxycarbonyl-amino } -azetidine-1-carboxylate (2mmol), 0.36ml of water (20mmol) and 0.277g of triphenylphosphine (2.2mmol) were stirred at 50 ℃ for 16 h. The solvent was evaporated. The residue was dissolved in 5ml of acetic acid and 2ml of acetic anhydride. The solution was stirred for 30 minutes and evaporated. The residue was purified by chromatography using 9/1 ethyl acetate/methanol mixture as eluent.

Yield: 1.1g, 93%. MW: 590.61 (C)₃₁H₃₁FN₄O₇)

MS：547.4(M+H)⁺，546.5(M-H)^-Method ESI⁺Method ESI^-N- { (5S) -3- [4- (azetidin-3-ylamino) -3-fluoro-phenyl]-2-Oxazolidin-5-ylmethyl } -acetamide

A suspension of 1.11g of 3- ({4- [ (5S) -5- (acetylamino-methyl) -2-oxo-oxazolidin-3-yl ] -2-fluoro-phenyl } -benzyloxycarbonyl-amino) -azetidine-1-carboxylic acid benzyl ester (1.88mmol) and 200mg Pd/c 10% in methanol was stirred under hydrogen for 5 h. The Pd/C was filtered and the filtrate was evaporated to dryness.

Yield: 340mg, 56%. MW: 322.34 (C)₁₅H₁₉FN₄O₃)

MS：323.5(M+H)⁺Method ESI⁺

7- (3- {4- [5(S) -5- (acetylamino-methyl) -2-oxo-oxazolidin-3-yl ] -2-fluoro-phenylamino } -azetidin-1-yl) -1-cyclopropyl-6-fluoro-4-oxo-1, 4-dihydro- [1, 8] naphthyridine-3-carboxylic acid

85mg of 7-chloro-1-cyclopropyl-6-fluoro-1, 4-dihydro-4-oxo-1, 8-naphthyridine-3-carboxylic acid (0.3mmol), 97mg of N- { (5S) -3- [4- (azetidin-3-ylamino) -3-fluoro-phenyl-4-carboxylic acid in 2ml of DMSO]A solution of-2-oxo-oxazolidin-5-ylmethyl } -acetamide (0.3mmol), 40mg triethylamine (0.4mmol) and 0.065ml trimethylchlorosilane (0.6mmol) was heated in a microwave oven at 150 ℃ for 10 minutes with stirring. The reaction was monitored by HPLC. The DMSO was evaporated, the residue digested in water, filtered and the solid purified by chromatography using 95/5 dichloromethane/methanol mixture as eluent. Yield: 52mg, 30%. MW: 568.54 (C)₂₇H₂₆F₂N₆O₆)

MS：569(M+H)⁺Method ESI⁺

Known mechanism units:

1-Diphenylmethylazetidin-3-ylamine, 40432-52-8, Beta Pharma Catalog

Example 16: 7- [ (3R) -3- {4- [ (5S) -5- (acetylamino-methyl) -2-oxo-oxazolidin-3-yl ] -2-fluoro-phenylamino } -pyrrolidin-1-yl ] -1-cyclopropyl-6-fluoro-4-oxo-1, 4-dihydro- [1, 8] naphthyridine-3-carboxylic acid

7- [ (3R) -3- {4- [ (5S) -5- (acetylamino-methyl) -2-oxo-oxazolidin-3-yl ] -2-fluoro-phenylamino } -pyrrolidin-1-yl ] -1-cyclopropyl-6-fluoro-4-oxo-1, 4-dihydro- [1, 8] naphthyridine-3-carboxylic acid

A suspension of 119mg of N- { (5S) -3- [ 3-fluoro-4- (pyrrolidin-3-ylamino) -phenyl ] -2-oxo-oxazolidin-5-ylmethyl } -acetamide (0.35mmol), 100mg of 7-chloro-1-cyclopropyl-6-fluoro-1, 4-dihydro-4-oxo-1, 8-naphthyridine-3-carboxylic acid, 148. mu.l of triethylamine (1.05mmol) and 89. mu.L of trimethylchlorosilane (0.70mmol) in 2ml of DMSO is stirred in a microwave oven at 150 ℃ for 10 minutes. The DMSO was evaporated, the residue was digested in water, and the solid was filtered. The solid was purified by chromatography using 95/5 dichloromethane/methanol mixture.

Yield: 10mg, 5%. MW: 582.56 (C)₂₈H₂₈F₂N₆O₆)

MS：583.2(M+H)⁺Method ESI⁺

Known structural units:

7-chloro-1-cyclopropyl-6-fluoro-1, 4-dihydro-4-oxo-1, 8-naphthyridine-3-carboxylic acid: CAS100361-18-0, Louston International

Example 17: 7- [ (3R, 4S) and (3S, 4R) -3- (4- {4- [ (5S) -5- (acetylamino-methyl) -2-oxo-oxazolidin-3-yl ] -2-fluorophenyl } -piperazine-1-carbonyl) -4-aminomethyl-pyrrolidin-1-yl ] -1-cyclopropyl-6-fluoro-4-oxo-1, 4-dihydro-quinolinecarboxylic acid

(3R, 4R) and (3S, 4S) -1-benzyl-4- (tert-Butoxycarbonylamino-methyl) -pyrrolidine-3-carboxylic acid ethyl ester

To a solution of 2g ethyl 4-tert-butoxycarbonylamino-but-2-enoate (8.72mmol) and 5.12g N- [ (pentyloxy) methyl ] -N- [ (trimethylsilyl) methyl ] -benzene-methanamine (17.4mmol) in 50ml dichloromethane was added 10. mu.l trifluoroacetic acid. The reaction was monitored by TLC. The reaction was complete after 10 minutes. The mixture was diluted with dichloromethane, washed with saturated sodium bicarbonate solution and brine, dried over magnesium sulfate, filtered and the filtrate evaporated. The residue was purified by filtration over a short silica gel column using 7/3 hexane/ethyl acetate mixture as eluent.

Yield: 2.96g, 93%. MW: 362.47 (C)₂₀H₃₀N₂O₄)

MS：363.6(M+H)⁺Method ESI⁺

(3R, 4R) and (3S, 4S) -1-benzyl-4- (tert-Butoxycarbonylamino-methyl) -pyrrolidine-3-carboxylic acid

To a solution of 2.9g (3R, 4R) and ethyl (3S, 4S) -1-benzyl-4- (tert-butoxycarbonylamino-methyl) -pyrrolidine-3-carboxylate (8.0mmol) in 50ml THF were added 671mg lithium hydroxide monohydrate (16mmol) and 0.5ml water. The solution was stirred at 40 ℃ and the reaction was monitored by TLC. After 72 hours, the solvent was evaporated, the residue was dissolved in dichloromethane, washed with water and brine, dried over magnesium sulfate, filtered and evaporated. The residue was crystallized from a dichloromethane/hexane mixture.

Yield: 1.9g, 71%. MW: 334.41 (C)₁₈H₂₆N₂O₄)

MS：335.3(M+H)⁺，333.3(M-H)^-Method ESI⁺，ESI^-

[ (3R, 4R) and (3S, 4S) -4- (4- {4- [ (5S) -5- (acetylamino-methyl) -2-oxo-oxazolidin-3-yl ] -2-fluoro-phenyl } -piperazine-1-carbonyl) -1-benzyl-pyrrolidin-3-ylmethyl ] -carbamic acid tert-butyl ester

To a solution of 0.668g 1-benzyl-4- (tert-butoxycarbonylamino-methyl) -pyrrolidine-3-carboxylic acid (2mmol), 0.6ml triethylamine (4mmol) and 0.662g N- [ { (5S) -3- [ 3-fluoro-4- (1-piperazinyl) phenyl ] -2-oxo-5-oxazolidinyl } methyl ] -acetamide (2mmol) in 50ml dry DMF was added 0.796g O- (benzotriazol-1-yl) -N, N, N ', N' -tetramethyluronic acid-hexafluorophosphate (252.1 mmol). The reaction was stirred at room temperature for 20 hours. DMF was evaporated, the residue was dissolved in ethyl acetate, washed with water and brine, dried over magnesium sulfate, filtered and the filtrate was evaporated. The residue was purified by chromatography using 9/1 dichloromethane/methanol mixture as eluent.

Yield: 1.14g, 87%. MW: 652.77 (C)₃₄H₄₅FN₆O₆)

MS：653.7(M+H)⁺Method ESI⁺

[ [ (3R, 4R) and (3S, 4S) -4- (4- {4- [ (5S) -5- (acetylamino-methyl) -2-oxo-oxazolidin-3-yl ] -2-fluoro-phenyl } -piperazine-1-carbonyl) -pyrrolidin-3-ylmethyl ] -carbamic acid tert-butyl ester

A suspension of 1.1g [ (3R, 4R) and (3S, 4S) -4- (4- {4- [ (5S) -5- (acetylamino-methyl) -2-oxo-oxazolidin-3-yl ] -2-fluoro-phenyl } -piperazine-1-carbonyl) -1-benzyl-pyrrolidin-3-yl-methyl ] -carbamic acid tert-butyl ester (1.68mmol) and 0.2g pd/C10% in 10ml methanol and 2ml acetic acid was stirred under hydrogen. The reaction was monitored by TLC. The solvent was evaporated to give an amorphous solid.

Yield: 1.14g, 87%. MW: 562.64 (C)₂₇H₃₉FN₆O₆)

MS：563.3，(M+H)⁺Method ESI⁺

7- [ (3R, 4S) and (3S, 4R) -3- (4- {4- [ (5S) -5- (acetylamino-methyl) -2-oxo-oxazolidin-3-yl ] -2-fluoro-phenyl } -piperazine-1-carbonyl) -4-aminomethyl-pyrrolidin-1-yl ] -1-cyclopropyl-6-fluoro-4-oxo-1, 4-dihydro-quinoline carboxylic acid

A solution of 141mg of [ [ (3R, 4R) and (3S, 4S) -4- (4- {4- [ (5S) -5- (acetylamino-methyl) -2-oxo-oxazolidin-3-yl ] -2-fluoro-phenyl } -piperazine-1-carbonyl) -pyrrolidin-3-ylmethyl ] -carbamic acid tert-butyl ester (0.25mmol), 102mg of 7-chloro-6-fluoro-1-cyclopropyl-4-oxo-1, 4-dihydro-quinoline-3-carboxylic acid boron diacetate (0.25mmol) and 61mg of DABCO (0.5mmol) in 2ml of DMSO is stirred in a microwave oven at 150 ℃ for 12 minutes. The reaction was monitored by TLC. DMSO was evaporated, the residue dissolved in acetonitrile, diluted with water and concentrated. The solid was filtered and purified by preparative HPLC.

Yield: 20mg, 11.3%. MW: 707.74 (C)₃₅H₃₉F₂N₇O₇)

MS：708.7，(M+H)⁺Method ESI⁺

Example 18: 7- [ (3R, 4S) and (3S, 4R) -3- (4- {4- [ (5S) -5- (acetylamino-methyl) -2-oxo-oxazolidin-3-yl ] -2-fluoro-phenyl } piperazine-1-carbonyl) -4-aminomethyl-pyrrolidin-1-yl) -1-cyclopropyl-6-fluoro-4-oxo-1, 4-dihydro- [1, 8] naphthyridine-3-carboxylic acid

7- [ (3R, 4S) and (3S, 4R) -3- (4- {4- [ (5S) -5- (acetylamino-methyl) -2-oxo-oxazolidin-3-yl ] -2-fluoro-phenyl } -piperazine-1-carbonyl) -4-aminomethyl-pyrrolidin-1-yl) -1-cyclopropyl-6-fluoro-4-oxo-1, 4-dihydro- [1, 8] naphthyridine-3-carboxylic acid

A solution of 99mg of 7-chloro-1-cyclopropyl-6-fluoro-1, 4-dihydro-4-oxo- [1, 8] naphthyridine-3-carboxylic acid (0.35mmol), 197mg of [ (3R, 4R) and (3S, 4S) -4- (4- {4- [5- (acetylamino-methyl) -2-oxo-oxazolidin-3-yl ] -2-fluoro-phenyl } -piperazine-1-carbonyl) -pyrrolidin-3-ylmethyl ] -carbamic acid tert-butyl ester (0.35mmol), 146. mu.L of triethylamine (1.05mmol) and 76mg of trimethylchlorosilane (0.70mmol) were dissolved in 2ml of DMSO. The solution was heated at 150 ℃ for 10 minutes in a microwave oven with stirring. The reaction was monitored by TLC. The DMSO was evaporated, the residue digested in water, filtered and the solid purified by chromatography using a dichloromethane/methanol mixture as eluent. The intermediate was crystallized in acetonitrile. The crystals were dissolved in 1.25M HCl and stirred at room temperature. The reaction was monitored by TLC. Methanol was evaporated and the residue was purified by preparative HPLC.

Yield: 130mg, 52%. MW: 708.72 (C)₃₄H₃₈F₂N₈O₇)

MS：709.6，(M+H)⁺Method ESI⁺

Example 19: 7- (4- {5- [ (5S) -5- (acetylamino-methyl) -2-oxo-oxazolidin-3-yl ] -pyridin-2-yl } -1-piperazin-1-yl) -1-cyclopropyl-6-fluoro-4-oxo-1, 4-dihydro- [1, 8] naphthyridine-3-carboxylic acid

4- (benzyloxycarbonylamino-pyridin-2-yl) -piperazine-1-carboxylic acid tert-butyl ester

To a solution of 4g of tert-butyl 4- (5-nitro-pyridin-2-yl) -piperazine-1-carboxylate (12.9mmol) in 50ml of ethyl acetate and 50ml of methanol was added 0.5g of Pd/C10%. The suspension was stirred under hydrogen. The reaction was monitored by TLC. Pd/C was filtered off, the filtrate was evaporated to dryness, the residue was dissolved in 150ml of acetone, diluted with 75ml of saturated sodium bicarbonate solution and reacted with 2.65g of benzyl chloroformate (15.56 mmol). The reaction was monitored by TLC. Acetone was evaporated, the residue was dissolved in ethyl acetate, the organic layer was washed with water and brine, dried over magnesium sulfate, filtered and the filtrate was evaporated to dryness. The residue was crystallized from an ethyl acetate/hexane mixture.

Yield: 4.79g, 89%. MW: 412.49 (C)₂₂H₂₈N₄O₄)

MS：413.4，(M+H)⁺Method ESI⁺

4- [ (5R) -5- (hydroxymethyl-2-oxo-oxazolidin-3-yl) -pyridin-2-yl ] -piperazine-1-carboxylic acid tert-butyl ester

To a stirred solution of 4.96g of 4- (benzyloxycarbonylamino-pyridin-2-yl) -piperazine-1-carboxylic acid tert-butyl ester (11.37mmol) in 50ml of THF at-70 ℃ was added 7.46ml of a 1.6M solution of n-butyllithium in n-hexane (11.93 mmol). The mixture was stirred at 0 ℃ for 15 minutes, and 2.06ml of R (-) -glycidyl butyrate (14.7mmol) were added. The reaction was monitored by TLC. The reaction was quenched with saturated ammonium chloride solution, diluted with ethyl acetate, and washed with water and brine. The organic layer was dried over magnesium sulfate, filtered and the filtrate was evaporated to dryness. The residue was purified by chromatography using 9/1 ethyl acetate/dichloromethane mixture as eluent.

Yield: 2.58g, 60%. MW: 378.43 (C)₁₈H₂₆N₄O₅)

MS：379.6(M+H)⁺Method ESI⁺

4- [ (5R) -5- (azidomethyl-2-oxo-oxazolidin-3-yl) -pyridin-2-yl ] piperazine-1-carboxylic acid tert-butyl ester

This compound was synthesized by using 2.5g of tert-butyl 4- [ (5R) -5- (hydroxymethyl-2-oxo-oxazolidin-3-yl) -pyridin-2-yl ] -piperazine-1-carboxylate (6.62mmol) in a similar procedure as described in example 12.

Yield: 2.3g, 86%. MW: 403.44 (C)₁₈H₂₅N₇O₄)

MS：404.4，(M+H)⁺Method ESI⁺

4- {5- [ (5S) -5- (acetylamino-methyl) -2-oxo-oxazolidin-3-yl ] -pyridin-2-yl } -piperazine-1-carboxylic acid tert-butyl ester

A suspension of 2.25g of tert-butyl 4- [ (5R) -5- (azidomethyl-2-oxo-oxazolidin-3-yl) -pyridin-2-yl ] piperazine-1-carboxylate (6.62mmol) and Pd/C10% in methanol was stirred under hydrogen. The reaction was monitored by TLC. The solvent was evaporated and the residue was dissolved in 10ml acetic acid. To the solution was added 2ml of acetic anhydride and the reaction was monitored by TLC. The solvent was evaporated and the residue was purified by chromatography using 9/1 dichloromethane/methanol mixture as eluent.

Yield: 0.572g, 24%. MW: 419.48 (C)₂₀H₂₉N₅O₅)

MS：420.4，(M+H)⁺Method ESI⁺

N- [ (5S) -2-oxo-3- (6-piperazin-1-yl-pyridin-3-yl) -oxazolidin-5-ylmethyl ] -acetamide

0.54g of 4- {5- [ (5S) -5- (acetylamino-methyl) -2-oxo-oxazolidin-3-yl ] -pyridin-2-yl } -piperazine-1-carboxylic acid tert-butyl ester (1.28mmol) was dissolved in 1.25M HCl solution in methanol. The solution was stirred and the reaction was monitored by TLC. The methanol was evaporated, the residue was dissolved in water, neutralized with sodium bicarbonate and the water was evaporated to dryness. The residue was digested in 9/1 dichloromethane/methanol. Insoluble salts were filtered off and the filtrate was evaporated to dryness to give a light brown solid.

Yield: 0.381g, 93%. MW: 3198.36 (C)₁₅H₂₁N₅O₃)

MS：320.1，(M+H)⁺Method ESI⁺

7- (4- {5- [ (5S) -5- (acetylamino-methyl) -2-oxo-oxazolidin-3-yl ] -pyridin-2-yl } -1-piperazin-1-yl) -1-cyclopropyl-6-fluoro-4-oxo-1, 4-dihydro- [1, 8] naphthyridine-3-carboxylic acid

In an analogous procedure to that described in example 10, the compound was synthesized with 0.135g N- [ 2-oxo-3- (6-piperazin-1-yl-pyridin-3-yl) -oxazolidin-5-ylmethyl ] -acetamide (0.42mmol) and 120mg 7-chloro-1-cyclopropyl-6-fluoro-1, 4-dihydro-4-oxo- [1, 8] naphthyridine-3-carboxylic acid (0.42 mmol).

Yield: 0.113g, 47%. MW: 565.57 (C)₂₇H₂₈FN₇O₆)

MS：566.8，(M+H)⁺，564.8，(M-H)^-Method ESI⁺，ESI^-

Example 20: 7- (4- {5- [ (5S) -5- (acetylamino-methyl) -2-oxo-oxazolidin-3-yl ] -pyridin-2-yl } -piperazin-1-yl) -1-cyclopropyl-6-fluoro-4-oxo-1, 4-dihydro-quinoline-3-carboxylic acid

A solution of 127mg (S) -N- [ 2-oxo-3- (6-piperazin-1-yl-pyridin-3-yl) -oxazolidin-5-ylmethyl ] -acetamide (0.4mmol), 163mg 7-chloro-6-fluoro-1-cyclopropyl-4-oxo-1, 4-dihydro-quinoline-3-carboxylic acid boron diacetate (0.4mmol) and 90 mg DABCO in 2ml DMSO was stirred in a microwave oven at 150 ℃ for 12 minutes. The reaction was monitored by TLC. The DMSO was evaporated and the residue was digested in water. The solid was filtered and purified by chromatography using dichloromethane/methanol as eluent.

Yield: 0.027g, 11.9%. MW: 564.58 (C)₂₈H₂₉FN₆O₆)

MS：565.8(M+H)⁺，563.6(M-H)^-Method ESI⁺，ESI^-

Example 21: 7- [ (3R) -3- (4- {4- [ (5S) -5- (acetylamino-methyl) -2-oxo-oxazolidin-3-yl ] -2-fluoro-phenyl } -piperazin-1-yl) -pyrrolidin-1-yl ] -1-cyclopropyl-6-fluoro-4-oxo-1, 4-dihydro- [1, 8] naphthyridine-3-carboxylic acid

(3R) -3- [4- (2-fluoro-4-nitro-phenyl) -piperazin-1-yl ] -pyrrolidine-1-carboxylic acid allyl ester

This compound was synthesized using (3R) -3-amino-pyrrolidine-1-carboxylic acid allyl ester (1.28mmol) and 2, 2- [ (2-fluoro-4-nitrophenyl) imino ] di-ethanol (40.5mmol) in a similar procedure as described in example 12.

Yield: 3.38g, 32%. MW: 378.40 (C)₁₈H₂₃FN₄O₄)

MS：379.5，(M+H)⁺Method ESI⁺

(3R) -3- [4- (2-fluoro-4-nitro-phenyl) -piperazin-1-yl ] -pyrrolidine-1-carboxylic acid tert-butyl ester

To a solution of 3.33g of (3R) -3- [4- (2-fluoro-4-nitrophenyl) piperazin-1-yl ] pyrrolidine-1-carboxylic acid allyl ester (8.8mmol) in 60ml of THF were added 130mg of bis (triphenylphosphine) -palladium (II) dichloride (0.088mmol), 1.0ml of acetic acid (17.6mmol) and 4.66ml of tributyltin hydride (17.6 mmol). The reaction was stirred at room temperature for 1 hour and monitored by TLC. The suspension was diluted with 100ml of ether and a pale yellow solid precipitated. The solid was filtered, washed with diethyl ether and hexanes and dried. The solid was diluted with 100ml dichloromethane, 2.30g BOC anhydride (MW: 218.25, 17.6mmol) was added, and the reaction was stirred at room temperature overnight and monitored by TLC. The reaction was diluted with dichloromethane and the organic layer was washed with water and brine, dried over magnesium sulfate and filtered. The filtrate was evaporated. The residue was purified by chromatography using ethyl acetate as eluent.

Yield: 0.740g, 21%. MW: 394.44 (C)₁₉H₂₇FN₄O₄)

MS：395.3，(M+H)⁺Method ESI⁺

(3R) -3- [4- (4-benzyloxycarbonylamino-fluoro-phenyl) -piperazin-1-yl ] -pyrrolidine-1-carboxylic acid tert-butyl ester

This compound was synthesized in a similar procedure as described in example 19 using 0.780g of tert-butyl (3R) -3- [4- (2-fluoro-4-nitro-phenyl) -piperazin-1-yl ] -pyrrolidine-1-carboxylate (1.97 mmol).

Yield: 0.768g, 78%. MW: 498.6 (C)₂₇H₃₅FN₄O₄)

MS：499.7，(M+H)⁺Method ESI⁺

(3R) -3- {4- [ 2-fluoro-4- { (5R) -5-hydroxymethyl-2-oxo-oxazolidin-3-yl } -phenyl ] -piperazin-1-yl } -pyrrolidine-1-carboxylic acid tert-butyl ester

This compound was synthesized in a similar procedure as described in example 19 using 0.780g of tert-butyl (3R) -3- [4- (4-benzyloxycarbonylamino-fluoro-phenyl) -piperazin-1-yl ] -pyrrolidine-1-carboxylate (1.54 mmol).

Yield: 0.475g, 66%. MW: 464.54 (C)₂₃H₃₃FN₄O₅)

MS：465.4，(M+H)⁺Method ESI⁺

(3R) -3- {4- [4- { (5R) -5-Azidomethyl-2-oxo-oxazolidin-3-yl } -2-fluoro-phenyl ] -piperazin-1-yl } -pyrrolidine-1-carboxylic acid tert-butyl ester

In an analogous procedure to that described in example 19, this compound was synthesized from 0.475g (3R) -3- {4- [ 2-fluoro-4- { (5R) -5-hydroxymethyl-2-oxo-oxazolidin-3-yl } -phenyl ] -piperazin-1-yl } -pyrrolidine-1-carboxylic acid tert-butyl ester (1.02 mmol).

Yield: 0.500g, quantitative. MW: 489.55 (C)₂₃H₃₂FN₇O₄)

MS：490.4，(M+H)⁺Method ESI⁺

(3R) -3- {4- [4- { (5S) -5-Acetaminomethyl-2-oxo-oxazolidin-3-yl } 2-fluoro-phenyl ] -piperazin-1-yl } -pyrrolidine-1-carboxylic acid tert-butyl ester

In an analogous procedure to that described in example 19, this compound was synthesized using 0.475g (3R) -3- {4- [4- { (5R) -5-azidomethyl-2-oxo-oxazolidin-3-yl } 2-fluoro-phenyl ] -piperazin-1-yl } -pyrrolidine-1-carboxylic acid tert-butyl ester (1.02 mmol).

Yield: 0.398g, 77%. MW: 505.59 (C)₂₅H₃₆FN₅O₅)

MS：506.4，(M+H)⁺Method ESI⁺

N- { (5S) -3- [ 3-fluoro-4- (4- { (3R) -pyrrolidin-3-yl } -piperazin-1-yl) -phenyl ] -2-oxo-oxazolidin-5-ylmethyl } -acetamide

In an analogous procedure to that described in example 19, this compound was synthesized using 0.398g (3R) -3- {4- [4- { (5S) -5-acetamidomethyl-2-oxo-oxazolidin-3-yl } 2-fluoro-phenyl ] -piperazin-1-yl } -pyrrolidine-1-carboxylic acid tert-butyl ester (0.79 mmol).

Yield: 0.398g, 77%. MW: 405.47 (C)₂₀H₂₈FN₅O₃)

MS：406.8，(M+H)⁺Method ESI⁺

7- [ (3R) -3- (4- {4- [ (5S) -5- (acetylamino-methyl) -2-oxo-oxazolidin-3-yl ] -2-fluoro-phenyl } -piperazin-1-yl) -pyrrolidin-1-yl ] -1-cyclopropyl-6-fluoro-4-oxo-1, 4-dihydro- [1, 8] naphthyridine-3-carboxylic acid

In an analogous procedure to that described in example 19, the compound was synthesized with 0.090g N- { (5S) -3- [ 3-fluoro-4- (4- { (3R) -pyrrolidin-3-yl } -piperazin-1-yl) -phenyl ] -2-oxo-oxazolidin-5-ylmethyl } -acetamide (0.22mmol) and 7-chloro-1-cyclopropyl-6-fluoro-1, 4-dihydro-4-oxo- [1, 8] naphthyridine-3-carboxylic acid (0.22 mmol).

Yield: 47mg, 32%. MW: 651.68 (C)₃₂H₃₅F₂N₇O₆)

MS：652.5，(M+H)⁺；650.8，(M-H)^-Method ESI⁺，ESI^-

Example 22: 1-cyclopropyl-6-fluoro-7- (4- { 2-fluoro-4- [ (5R) -5- (methylsulfonylamino-methyl) -2-oxo-oxazolidin-3-yl ] -phenyl } -piperazin-1-yl) -4-oxo-1, 4-dihydro- [1, 8] naphthyridine-3-carboxylic acid

4- { 2-fluoro-4- [ (5R) -5- (methanesulfonamide-methyl) -2-oxo-oxazolidin-3-yl ] -phenyl } -piperazine-1-carboxylic acid tert-butyl ester

This compound was synthesized using tert-butyl 4- [4- { (5S) -5-aminomethyl-2-oxo-oxazolidin-3-yl } -2-fluoro-phenyl ] -piperazine-1-carboxylate (1.5mmol) in an analogous procedure to that described in example 9.

Yield: 0.505g, 71%. MW: 472.53 (C)₂₀H₂₉FN₄O₆S)

MS：473.4，(M+H)⁺；471.7，(M-H)^-Method ESI⁺，ESI^-

N- [ (5R) -3- (3-fluoro-4-piperazin-1-yl-phenyl) -2-oxo-oxazolidin-5-ylmethyl ] -methanesulfonamide

In a similar procedure to that described in example 19, the compound was synthesized with 0.5g of tert-butyl 4- { 2-fluoro-4- [ (5R) -5- (methylsulfonylamino-methyl) -2-oxo-oxazolidin-3-yl ] -phenyl } -piperazine-1-carboxylate (1.06 mmol).

Yield: 0.39g, quantitative. MW: 372.42 (C)₁₅H₂₁FN₄O₄S)

MS：373.0，(M+H)⁺Method ESI⁺

1-cyclopropyl-6-fluoro-7- (4- { 2-fluoro-4- [ (5R) -5- (methylsulfonylamino-methyl) -2-oxo-oxazolidin-3-yl ] -phenyl } -piperazin-1-yl) -4-oxo-1, 4-dihydro- [1, 8] naphthyridine-3-carboxylic acid

This compound was synthesized in an analogous procedure to that described in example 10 using 0.082g N- [ (5R) -3- (3-fluoro-4-piperazin-1-yl-phenyl-2-oxo-oxazolidin-5-ylmethyl ] -methanesulfonamide (0.22mmol) and 0.067g 7-chloro-1-cyclopropyl-6-fluoro-1, 4-dihydro-4-oxo- [1, 8] naphthyridine-3-carboxylic acid (0.22 mmol).

Yield: 0.079g, 58%. MW: 618.62 (C)₂₇H₂₈F₂N₆O₇S)

MS：619.8，(M+H)⁺；617.7，(M-H)^-Method ESI⁺，ESI^-

Example 23: 7- (4- {4- [5(S) -5- (acetylamino-methyl) -2-oxo-oxazolidin-3-yl ] -2-fluoro-phenylamino } -piperidin-1-yl) -1-cyclopropyl-6-fluoro-4-oxo-1, 4-dihydro- [1, 8] naphthyridine-3-carboxylic acid

(1-benzyl-piperidin-4-yl) - (2-fluoro-4-nitro-phenyl) -amine

9.54g (MW: 159.09, 60mmol) of 3, 4-difluorobenzene, 11.4g (60mmol) of 4-amino-N-benzylpiperidine and 9.1g (66mmol) of triethylamine are stirred in acetonitrile at reflux for 16 h. The solution was diluted with ethyl acetate, washed with water and brine, dried over magnesium sulfate and filtered. The filtrate was evaporated and the crystals were recrystallized from an ethyl acetate/hexane mixture.

Yield: 13.5g, 70%. MW: 329.37 (C)₁₈H₂₀FN₃O₂)

MS：430.1(M+H)⁺Method ESI⁺

2-fluoro-N' -piperidin-4-yl-benzene-1, 4-diamines

A mixture of 5g (15mmol) of (1-benzyl-piperidin-4-yl) - (2-fluoro-4-nitro-phenyl) -amine and Pd/C10% in methanol/ethyl acetate was stirred at room temperature under hydrogen. The reaction was monitored by TLC. The Pd/C was filtered and the filtrate was evaporated to dryness.

Yield: 3.2g, quantitative. MW: 209.26 (C)₁₁H₁₆FN₃)

MS：210.3(M+H)⁺Method ESI⁺

4- (4-Benzyloxycarbonylamino-2-fluoro-phenylamino) -piperidine-1-carboxylic acid benzyl ester

To a mixture of 3.2g (15mmol) 2-fluoro-N' -piperidin-4-yl-benzene-1, 4-diamine in 150ml acetone was added 75ml saturated NaHCO₃And 5.3ml (37.5mmol) of benzyl chloroformate. After stirring for 2 hours, the acetone was evaporated and the aqueous layer was extracted twice with ethyl acetate. The organic layer was washed with water and brine, dried over magnesium sulfate, filtered and the filtrate evaporated. The residue was purified by chromatography using a 1: 1 hexane/ethyl acetate mixture.

Yield: 1.5g, quantitative. MW: 477.54 (C)₂₇H₂₈FN₃O₄)

MS：478.4(M+H)⁺Method ESI⁺

4- [ 2-fluoro-4- { (5R) -5-hydroxymethyl-2-oxo-oxazolidin-3-yl } -phenylamino ] -piperidine-1-carboxylic acid benzyl ester

To a solution of 6.6g (15mmol) of benzyl 4- (4-benzyloxycarbonylamino-2-fluoro-phenylamino) -piperidine-1-carboxylate in 50ml of THF at-78 deg.C was added dropwise 12.12ml of 1.6M (19.5mmol) n-butyllithium. The mixture was stirred at this temperature for a further 10 minutes. The resulting yellow solution was allowed to reach-40 ℃ in 10 minutes. Then 3.0ml (21mmol) of (R) -glycidyl butyrate were added and the solution was slowly brought to room temperature and stirred for a further 16 hours. The reaction was quenched with saturated ammonium chloride solution and diluted with 400 ml of ethyl acetate. The organic layer was washed with water and brine, dried over magnesium sulfate, filtered and evaporated to dryness. The residue was purified by chromatography using a dichloromethane/methanol 5% mixture.

Yield: 2.58g, 50%. MW: 443.47 (C)₂₃H₂₆FN₃O₅)MS：444.6(M+H)⁺Method ESI⁺

4- [4- { (5R) -5-Azidomethyl-2-oxo-oxazolidin-3-yl } -2-fluoro-phenylamino ] -piperidine-1-carboxylic acid benzyl ester

To a solution of 2.5g of benzyl 4- [ 2-fluoro-4- { (5R) -5-hydroxymethyl-2-oxo-oxazolidin-3-yl } -phenylamino ] -piperidine-1-carboxylate (5.6mmol) and 1.57ml (11.2mmol) of triethylamine in 60ml of dichloromethane at 0 deg.C was added 0.48ml of methanesulfonyl chloride (6.16 mmol). The reaction mixture was allowed to warm to room temperature and stirred for a further 30 minutes. The reaction was quenched with water, the organic layer was washed with water and brine, dried over magnesium sulfate, filtered and the filtrate was evaporated.

Yield: 2.88g, 98%. MS 522.3(M + H)⁺Method ESI⁺

The residue in 10ml DMF, 717mg sodium azide (11.04mmol) and 100mg tetrabutylammonium iodide (0.27mmol) were stirred at 80 ℃ for 20 h. DMF was evaporated, the residue was dissolved in ethyl acetate, washed with water and brine, the organic layer was dried over magnesium sulfate, filtered and the filtrate was evaporated to dryness.

Yield: 2.5g, 97%. MW: 468.49 (C)₂₃H₂₅FN₆O₄)

MS：469.7(M+H)⁺Method ESI⁺

4- [4- { (5S) -5-aminomethyl-2-oxo-oxazolidin-3-yl } -2-fluoro-phenylamino ] -piperidine-1-carboxylic acid benzyl ester

A solution of 2.51g (5.35mmol) of benzyl 4- [4- { (5R) -5-azidomethyl-2-oxo-oxazolidin-3-yl } -2-fluoro-phenylamino ] -piperidine-1-carboxylate, 1.54g (5.88mmol) of triphenylphosphine and 964. mu.L (53.5mmol) of water in 30ml of THF is stirred at 50 ℃ for 16 h. The THF was evaporated. The residue was purified by chromatography using 9/1 dichloromethane/methanol mixture containing 1% ammonia.

Yield: 1.44g, 78%. MW: 442.49 (C)₂₃H₂₇FN₄O₄)

MS：443.6(M+H)⁺Method ESI⁺

4- {4- [ (5S) -5- (acetylamino-methyl) -2-oxo-oxazolidin-3-yl ] -2-fluoro-phenylamino } -piperidine-1-carboxylic acid benzyl ester

A solution of 4- [4- { (5S) -5-aminomethyl-2-oxo-oxazolidin-3-yl } -2-fluoro-phenylamino ] -piperidine-1-carboxylic acid benzyl ester (1.01mmol), 2ml acetic acid and 0.093ml (1mmol) acetic anhydride was stirred at room temperature for 1 hour. The solvent was evaporated.

Yield: 484mg, quantitative. MW: 484.53 (C)₂₅H₂₉FN₄O₅)

MS：485.7(M+H)⁺Method ESI⁺

N- { (5S) -3- [ 3-fluoro-4- (piperidin-4-ylamino) -phenyl ] -2-oxo-oxazolidin-5-ylmethyl } -acetamide

A suspension of 480mg (1mmol) of benzyl 4- {4- [ (5S) -5- (acetylamino-methyl) -2-oxo-oxazolidin-3-yl ] -2-fluoro-phenylamino } -piperidine-1-carboxylate in 2ml of 1/1 methanol/acetic acid mixture and Pd/C was stirred at H2 for 4 hours. The Pd/C was filtered and the filtrate was evaporated to dryness.

Yield: 350mg, quantitative. MW: 350.39 (C)₁₇H₂₃FN₄O₃)

MS：351.6(M+H)⁺Method ESI⁺

7- (4- {4- [ (5S) -5- (acetylamino-methyl) -2-oxo-oxazolidin-3-yl ] -2-fluoro-phenylamino } -piperidin-1-yl) -1-cyclopropyl-6-fluoro-4-oxo-1, 4-dihydro- [1, 8] naphthyridine-3-carboxylic acid

A suspension of 100mg of N- { (5S) -3- [ 3-fluoro-4- (piperidin-4-ylamino) -phenyl ] -2-oxo-oxazolidin-5-ylmethyl } acetamide (0.28mmol), 80.66mg of 7-chloro-1-cyclopropyl-6-fluoro-1, 4-dihydro-4-oxo-1, 8-naphthyridine-3-carboxylic acid (0.28mmol), 0.108ml of trimethylchlorosilane (0.84mmol) and 0.16ml of triethylamine (1.12mmol) in 2ml of DMSO is heated at 150 ℃ for 7 minutes under stirring in a microwave oven. The DMSO was evaporated and the residue was purified by chromatography.

Yield: 54mg, 31%. MW: 596.60 (C)₂₉H₃₀F₂N₆O₆)

MS：597.5(M+H)⁺Method ESI⁺

Known structural units:

3, 4-difluorobenzene: 369-34-6, Aldrich 28-836-5

4-amino-N-benzylpiperidine: 50541-93-0, Acros 18766

1, 8-naphthyridine-3-carboxylic acid, 7-chloro-1-cyclopropyl-6-fluoro-1, 4-dihydro-4-oxo- (9 Cl): 100361-18-0, Louston International

Example 24: 1-cyclopropyl-6-fluoro-7- (4- { 2-fluoro-4- [ (5S) -5- (methoxythiocarbonylamino-methyl) -2-oxo-oxazolidin-3-yl ] -phenyl } -piperazin-1-yl) -4-oxo-1, 4-dihydro- [1, 8] -naphthyridine-3-carboxylic acid

1-cyclopropyl-6-fluoro-7- (4- { 2-fluoro-4- [ (5S) -5- (methoxycarbonothioylamino-methyl) -2-oxo-oxazolidin-3-yl ] -phenyl } -piperazin-1-yl) -4-oxo-1, 4-dihydro- [1, 8] naphthyridine-3-carboxylic acid

A mixture of 100mg { [ (5S) -3- [ 3-fluoro- (1-piperazinyl) phenyl ] -2-oxo-5-oxazolidinyl ] methyl } -carbamoylthio acid (carbamothioic acid) methyl ester (0.27mmol), 76.71mg 7-chloro-1-cyclopropyl-6-fluoro-1, 4-dihydro-4-oxo-1, 8-naphthyridine-3-carboxylic acid (0.27mmol), 68.65. mu.L trimethylchlorosilane (0.54mmol) and 113.49. mu.L triethylamine (0.81mmol) in 3ml acetonitrile was stirred in a microwave oven at 150 ℃ for 8 min. The reaction was diluted with water, the precipitate filtered and purified by chromatography using 9/1 dichloromethane/methanol with 1% acetic acid.

Yield: 50mg, 23%. MW: 614.63 (C)₂₈H₂₈F₂N₆O₆S)

MS：615.2(M+H)⁺，613.5(M-H)^-Method ESI⁺Method ESI^-

Known structural units:

carbamoylthioic acid, { [ (5S) -3- [ 3-fluoro- (1-piperazinyl) phenyl ] -2-oxo-5-oxazolidinyl ] methyl } -, O-methyl ester (9 cl): 268208-73-7; WO 0027830

1, 8-naphthyridine-3-carboxylic acid, 7-chloro-1-cyclopropyl-6-fluoro-1, 4-dihydro-4-oxo- (9 Cl): CAS100361-18-0, Louston International

Example 25: 1-cyclopropyl-6-fluoro-7- (4- { 2-fluoro-4- ((5S) -5- (methylsulfanyl thiocarbonylamino-methyl) -2-oxo-oxazolidin-3-yl) -phenyl } -piperazin-1-yl) -4-oxo-1, 4-dihydro- [1, 8] naphthyridine-3-carboxylic acid

4- { 2-fluoro-4- [ (5S) -5- (methylsulfanyl thiocarbonylamino-methyl) -2-oxo-oxazolidin-3-yl ] -phenyl } -piperazine-1-carboxylic acid tert-butyl ester

A mixture of 500mg of 1-piperazinecarboxylic acid, 4- [4- [ (5S) -5- [ (acetylamino) methyl ] -2-oxo-3-oxazolidinyl ] -2-fluoro-phenyl ] -1, 1-dimethylethyl ester (1.26mmol), 0.152ml of carbon disulfide (2.53mmol) and 0.176ml of triethylamine (1.26mmol) in 5ml of THF was stirred at 0 ℃ for 7 hours. 79 μ L of methyl iodide (1.26mmol) was added dropwise to the reaction at 0 ℃ and the mixture was stirred at room temperature for 1 hour. The mixture was diluted with ethyl acetate, the organic layer was washed with water and brine, dried over magnesium sulfate, filtered and the filtrate was evaporated.

Yield: 510mg, 83%. MW: 484.61 (C)₂₁H₂₉FN₄O₄S₂)

MS：485.0(M+H)⁺Method ESI⁺

[ (5S) -3- (3-fluoro-4-piperazin-1-yl-phenyl) -2-oxo-oxazolidin-5-ylmethyl ] -dithiocarbamic acid methyl ester

A suspension of 510mg of 4- { 2-fluoro-4- [ (5S) -5- (methyl-sulfanyl thiocarbonylamino-methyl) -2-oxo-oxazolidin-3-yl ] -phenyl } -piperazine-1-carboxylic acid tert-butyl ester (1.05mmol) in 1.25M/methanol was stirred for 5 days. The solvent was evaporated and the residue was digested in water. The aqueous layer was neutralized to pH7 with saturated sodium bicarbonate solution and evaporated to dryness. The residue was digested in dichloromethane/methanol. The salt was filtered and the solvent was evaporated.

Yield: 250mg, 25%. MW: 384.49 (C)₁₆H₂₁FN₄O₂S₂)

MS：385.5(M+H)⁺Method ESI⁺

1-cyclopropyl-6-fluoro-7- (4- { 2-fluoro-4- ((5S) -5- (methylsufanyl thiocarbonylamino-methyl) -2-oxo-oxazolidin-3-yl) -phenyl } -piperidin-1-yl) -4-oxo-1, 4-dihydro- [1, 8] naphthyridine-3-carboxylic acid

A mixture of 100mg of [ (5S) -3- (3-fluoro-4-piperazin-1-ylphenyl) -2-oxo-oxazolidin-5-ylmethyl ] -dithiocarbamic acid methyl ester (0.26mmol), 73.51mg of 7-chloro-1-cyclopropyl-6-fluoro-1, 4-dihydro-4-oxo-1, 8-naphthyridine-3-carboxylic acid (0.26mmol), 108. mu.L of triethylamine (0.78mmol) and 65. mu.L of trimethylchlorosilane (0.52mmol) in acetonitrile was stirred in a microwave oven at 150 ℃ for 8 minutes. The solution was decanted from the viscous solid, evaporated and the residue digested in water. The solid was filtered and purified by chromatography using 9/1 dichloromethane/methanol mixture containing 1% acetic acid.

Yield: 50mg 30%. MW: 630.70 (C)₂₈H₂₈F₂N₆O₅S₂)

MS：631(M+H)⁺

Known structural units:

1-piperazinecarboxylic acid, 4- [4- [ (5S) -5- [ (acetylamino) -methyl ] -2-oxo-3-oxazolidinyl ] -2-fluorophenyl ] -1, 1-dimethylethyl ester, (S) - (9 cl): 154990-65-5, US5547950

1, 8-naphthyridine-3-carboxylic acid, 7-chloro-1-cyclopropyl-6-fluoro-1, 4-dihydro-4-oxo- (9 Cl): 100361-18-0, Louston International

Example 26: 1-cyclopropyl-6-fluoro- {4- [ 2-fluoro-4- { (5S) -2-oxo-5-thioureidomethyl-oxazolidin-3-yl } -phenyl ] -piperazin-1-yl } -4-oxo-1, 4-dihydro- [1, 8] naphthyridine-3-carboxylic acid

4- [ 2-fluoro-4- { (5S) -2-oxo-5-thioureidomethyl-oxazolidin-3-yl } -phenyl ] -piperazine-1-carboxylic acid tert-butyl ester

A suspension of 1g of tert-butyl 4- [ 2-fluoro-4- [ (5R) -5- (isothiocyanatomethyl) -2-oxo-3-oxazolidinyl ] phenyl ] -1-piperazine-carboxylate (2.29mmol) in 5ml of methanol and 5ml of a 2N solution of ammonia in ethanol was stirred at 0 ℃ for 3 hours and at room temperature for 1 hour. The precipitate was filtered and washed with diethyl ether.

Yield: 649mg, 62%. MW: 453.53 (C)₂₀H₂₈FN₅O₄S)

MS：454(M+H)⁺Method ESI⁺

[ (5S) -3- (3-fluoro-4-piperazin-1-yl-phenyl) -2-oxo-oxazolidin-5-ylmethyl ] -thiourea

A solution of 649mg of 4- [ 2-fluoro-4- { (5S) -2-oxo-5-thioureidomethyl-oxazolidin-3-yl) -phenyl ] -piperazine-1-carboxylic acid tert-butyl ester (1.43mmol) in a mixture of 6ml of 1.25M methanolic hydrochloric acid solution and 1 drop of water was stirred for 4 days. The solvent was evaporated and the residue was neutralized to pH7 with saturated sodium bicarbonate solution. The water was evaporated, the residue was digested in 95/5 dichloromethane/methanol mixture, and the solid was filtered. The filtrate was purified by chromatography using 95/5 dichloromethane/methanol mixture containing 1% acetic acid.

Yield: 250mg, 50%. MW: 353.42 (C)₁₅H₂₀FN₅O₂S)

MS：354(M+H)⁺Method ESI⁺

1-cyclopropyl-6-fluoro- {4- [ 2-fluoro-4- { (5S) -2-oxo-5-thioureidomethyl-oxazolidin-3-yl } -phenyl ] -piperazin-1-yl } -4-oxo-1, 4-dihydro- [1, 8] naphthyridine-3-carboxylic acid

A mixture of 100mg of [ (5S) -3- (3-fluoro-4-piperazin-1-yl-phenyl) -2-oxo-oxazolidin-5-ylmethyl ] -thiourea (0.28mmol), 87.98mg of 7-chloro-1-cyclopropyl-6-fluoro-1, 4-dihydro-4-oxo-1, 8-naphthyridine-3-carboxylic acid (0.31mmol), 71.57. mu.L of trimethylchlorosilane (0.56mmol) and 118.31. mu.L of triethylamine (1.4mmol) in acetonitrile was stirred in a microwave oven at 150 ℃ for 8 min. The reaction mixture was diluted with water and the solid was filtered. The solid was purified by chromatography using 95/5 dichloromethane/methanol mixture with 1% acetic acid as eluent to give 50mg of an oily residue which was crystallized from an ethyl acetate/hexane mixture.

Yield: 30mg, 17%. MW: 599.62 (C)₂₇H₂₇F₂N₇O₅S)

MS：600(M+H)⁺Method ESI⁺

Known structural units:

1-piperazinecarboxylic acid, 4- [ 2-fluoro-4- [ (5R) -5- (isothiocyanatomethyl) -2-oxo-3-oxazolidinyl ] phenyl ] -1, 1-dimethyl ester (9 cl): WO 0027830

7-chloro-1-cyclopropyl-6-fluoro-1, 4-dihydro-4-oxo-1, 8-naphthyridine-3-carboxylic acid: 100361-18-0, Louston International

Example 27: 7- (4- {4- [5(S) -5- (acetylamino-methyl) -2-oxo-oxazolidin-3-yl ] -2-fluoro-phenoxy } -piperidin-1-yl) -1-cyclopropyl-6-fluoro-4-oxo-1, 4-dihydro- [1, 8] naphthyridine-3-carboxylic acid

A mixture of 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1, 4-dihydro- [1, 8] naphthyridine-3-carboxylate (80mg), (S) -N- [ [3- (3-fluoro-4- (4-piperidinyloxy) -phenyl) -2-oxo-5-oxazolidinyl ] methyl ] acetamide (described in WO 0146164; 100mg), triethylamine (120. mu.L) and trimethylchlorosilane (72. mu.L) in DMSO (2ml) was stirred at 150 ℃ for 5 minutes (microwave). The solvent was evaporated and the crude reaction was taken up in (take up) water. The resulting solid was filtered and chromatographed on silica gel (95: 5 dichloromethane/methanol). The fractions of interest were collected and recrystallized from ethyl acetate/n-hexane to yield 70mg (41%) of a colorless material.

C₂₉H₂₉F₂N₅O₇(5 97.58)

MS：598.5(M+H)；596.4(M-H)

Example 28: 7- (4- {4- [5(S) -5- (acetylamino-methyl) -2-oxo-oxazolidin-3-yl ] -2-fluoro-phenoxy } -piperidin-1-yl) -1-cyclopropyl-6-fluoro-4-oxo-1, 4-dihydro-quinoline-3-carboxylic acid

A mixture of 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1, 4-dihydro-quinoline-3-carboxylic acid boron diacetate (described in WO 8807998; 175mg, 0.42mmol), (S) -N- [ [3- (3-fluoro-4- (4-piperidinyloxy) -phenyl) -2-oxo-5-oxazolidinyl ] methyl ] acetamide (150mg, 0.42mmol) and DABCO (47mg, 0.42mmol) was stirred in 2ml DMSO at 150 ℃ for 7 min (microwave). The solvent was evaporated and the crude reaction was taken up in water. The resulting solid was filtered and chromatographed on silica gel (95: 5 dichloromethane/methanol). The fractions of interest were collected and crystallized in acetonitrile to yield 23mg (9%) of colorless material.

C₃₀H₃₀F₂N₄O₇(596.59)

MS：597.5(M+H)

Example 29: 7- (4- {4- [5(S) -5- (acetylamino-methyl) -2-oxo-oxazolidin-3-yl ] -2-fluoro-phenylsulfanyl } -piperidin-1-yl) -1-cyclopropyl-6-fluoro-4-oxo-1, 4-dihydro-quinoline-3-carboxylic acid

This compound is prepared in a similar manner to example 28 starting from 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1, 4-dihydro-quinoline-3-carboxylic acid boron diacetate and (S) -N- [ [3- (3-fluoro-4- (4-piperidinyl sulfonyl) -phenyl ] -2-oxo-5-oxazolidinyl ] methyl ] -acetamide obtained from 4-mercapto-piperidine-1-carboxylic acid tert-butyl ester (J.Antibiotics, 1995, 48, 408-16)

C₃₀H₃₀F₂N₄O₆S(6 12.66)

MS：613.8(M+H)⁺

Example 30: 7- (4- {4- [5(S) -5- (acetylamino-methyl) -2-oxo-oxazolidin-3-yl ] -2-fluoro-phenylsulfanyl } -piperidin-1-yl) -1-cyclopropyl-6-fluoro-4-oxo-1, 4-dihydro- [1, 8] naphthyridine-3-carboxylic acid

The compound is prepared in a similar manner to example 27 starting from 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1, 4-dihydro- [1, 8] naphthyridine-3-carboxylic acid ester and (S) -N- [ [3- (3-fluoro-4- (4-piperidinylsulfanyl) -phenyl ] -2-oxo-5-oxazolidinyl ] methyl ] -acetyl.

C₂₉H₂₉F₂N₅O₆S(612.66)

MS：613.8(M+H)

All examples were tested against several gram-positive and gram-negative bacteria. Both have broader and more pronounced activity compared to the corresponding quinolones and oxazolidinones and 1+1 combinations of these two compounds.

Typical MIC range (mg/l)

Staphylococcus Aureus (MRSA): 0.125-2 (linezolid): 1-2, ciprofloxacin: 0.5-32) staphylococcus aureus (MSSA): 0.06-1 (linezolid: 1-2, ciprofloxacin: 0.125-1) enterococcus faecalis (E.faecalis) < 0.03-1 (linezolid: 0.5-2, ciprofloxacin: 0.5-32) enterococcus faecalis < 0.03-1 (linezolid: 1-2, ciprofloxacin: 0.25-32) streptococcus pneumoniae < 0.03-1 (linezolid: 0.125-1, ciprofloxacin: 1-4)

In summary, the compounds, pharmaceutical compositions and products of the present invention may be used as antimicrobial agents, in particular antibacterial agents.

Claims (12)

1. A compound of formula (I):

wherein

A is a group of the formula-V-W-wherein V is O or S and W is heterocycloalkyl having 4 to 7 ring atoms or alkylheterocycloalkyl having 4 to 7 ring atoms and 1 to 4 carbon atoms in the alkyl chain, wherein the term heterocycloalkyl means a group having one ring and optionally one ringOr two F, Cl, Br, I, OH, NH₂、SH、N₃、NO₂Methyl, ethyl, methoxy, methylamino, dimethylamino, or cyano-substituted saturated cyclic group in which one or two carbon ring atoms are replaced by one or two nitrogen atoms;

or A is selected from the following groups, wherein the amino group may be substituted with an alkyl group having 1 to 10 carbon atoms:

x is CR5 or N;

y is CR6 or N;

u is F;

n is 0 or 1;

r1 is H;

r2 is H or F;

r3 is H, cyclopropyl or phenyl or pyridyl, which may be substituted by one or two fluorine atoms;

r4 is of the formula-NHSO₂Me、-NHCS₂Me、-NHCSNH₂A group of-NHCSOMe or-NHCOMe;

r5 is H, F, Cl, methyl or methoxy, or

R3 and R5 together form the formula-O-CH₂-N (Me) -or-O-CH₂A bridge of-CH (Me) -;

r6 is H or F.

2. A compound according to claim 1, wherein R4 is acetylamino.

3. A compound according to claim 1, wherein X is N or CH.

4. A compound according to claim 1, wherein Y is N or CF.

5. A compound according to claim 1, wherein n is 0.

6. A compound according to claim 1, wherein a is a group of formula

Wherein

V is O or S;

a is 0, 1 or 2;

b is 1, 2 or 3;

c is 1, 2 or 3; and is

1 or 2 hydrogen atoms may be replaced by F, methyl or methoxy.

7. The compound according to claim 6, wherein V is O; a is 0 or 1; b is 1 or 2; and c is 1 or 2.

8. A compound according to claim 1, wherein a is a group of formula

9. The compound according to claim 1, wherein the absolute configuration of C-5 of the oxazolidone ring is (S) according to the sequential naming system.

10. A pharmaceutical composition comprising a compound according to any one of claims 1 to 9 and optionally a carrier and/or diluent.

11. Pharmaceutical compositions comprising a compound according to any one of claims 1 to 9 and optionally adjuvants.

12. Use of a compound or pharmaceutical composition according to any one of claims 1 to 11 for the manufacture of a medicament for the treatment of a bacterial infection.