WO2005082897A1 - Oxazolidinone antibacterial agents - Google Patents

Oxazolidinone antibacterial agents Download PDF

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Publication number
WO2005082897A1
WO2005082897A1 PCT/IB2005/000102 IB2005000102W WO2005082897A1 WO 2005082897 A1 WO2005082897 A1 WO 2005082897A1 IB 2005000102 W IB2005000102 W IB 2005000102W WO 2005082897 A1 WO2005082897 A1 WO 2005082897A1
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Prior art keywords
methyl
oxo
benzo
oxazolidin
oxazin
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PCT/IB2005/000102
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French (fr)
Inventor
Mikhail Fedorovich Gordeev
Rama Jain
Vara Prasad Venkata Nagendra Josyula
Gary Wayne Luehr
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Pharmacia & Upjohn Company Llc
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Publication of WO2005082897A1 publication Critical patent/WO2005082897A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • the present invention relates to a new class of amidoxime and amidine oxazolidinone derivatives, to their use as antibacterial agents, to pharmaceutical compositions containing these compounds and to methods for their preparation.
  • oxazolidinone compounds are the most recent synthetic class of antimicrobials active against a number of pathogenic microorganisms. This invention provides novel amidoxime derivatives of oxazolidinones, and their preparation.
  • PCT publication WO 9964416 discloses oxazolidinone derivatives.
  • PCT publication WO 9964417 discloses oxazolidinone derivatives.
  • PCT publication WO 200021960 discloses heterocyclyl aminomethyl oxazolidinone derivatives.
  • PCT publication WO 200029409 discloses oxazolidinone derivatives.
  • PCT publication WO 200181350 discloses oxazolidinone derivatives and their salts or in vivo hydrolysable esters.
  • PCT publication WO 200281470 discloses oxazolidinone compounds and their salts or in vivo hydrolysable esters.
  • X is a structure of the following formula i, ii, iii, or iv
  • Y 1 , Y 2 and Y 3 are independently (a) CH, (b) N, (c) N + -O ⁇ or (d) CF;
  • G is -(CR 3 R 4 ) literal-;
  • R 2 is H or Ci- alkyl, optionally substituted with 1-3 fuloro;
  • R 3 and R 4 are independently (a) H (b) Ci- 6 alkyl, or (c) R 3 and R 4 taken together with the carbon atom to which they attach form C 3 - 7 cycloalkyl;
  • V is N, or C;
  • R 5 and R 6 are independently (a) H, or (b) Ci- alkyl, optional aryl is phenyl, biphenyl, or naphthyl, optionally substituted with halo, OR 5 , SR 5 , CN,
  • het is a five- (5) or six- (6) membered heterocyclic ring having 1-4 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen within the ring, wherein each carbon atom in het is optionally substituted with halo, OR 5 , SR 5 , CN,
  • the present invention also provides: a pharmaceutical composition which comprises a pharmaceutically acceptable carrier and an effective amount of a compound of formula I, a method for treating gram-positive microbial infections in a mammal by administering to the subject in need a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof, and a use of a compound of formula I or a pharmaceutically acceptable salt thereof to prepare a medicament for treating gram-positive microbial infections.
  • the invention may also provide novel intermediates and novel processes that are useful for preparing compounds of formula I.
  • C - 7 cycloalkyl refers to a cyclic saturated monovalent hydrocarbon group of three to seven carbon atoms, e.g., cyclopropyl, cyclohexyl, and the like.
  • halo refers to fluoro (F), chloro (CI), bromo (Br), or iodo (I).
  • heterocyclic ring having 1-4 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen within the ring.
  • An examples of het includes, but are not limited to, azetidine, pyrrole, imidazole, pyrazole, 1,2,3-triazole, 1,3,4-triazole, oxazole, thiazole, isoxazole, isothiazole, 1,3,4-oxadiazole, 1,3,4-thiadiazole, 1,2,3-thiadiazole, tetrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, dihydroindole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, is
  • het includes, but are not limited to, pyridine, thiophene, furan, pyrazole, pyrimidine, 2-pyridyl, 3-pyridyl, 4- pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, 3- pyrazinyl, 4-oxo-2-imidazolyl, 2-imidazolyl, 4-imidazolyl, 3-isoxaz-olyl, 4-is-oxaz- olyl, 5-isoxaz-olyl, 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, 2-oxazolyl, 4-oxazolyl, 4- oxo-2-oxazolyl, 5-oxazolyl, 1,2,3-oxathiazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,2,5-o
  • a pharmaceutically acceptable salt of a compound means a salt that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound.
  • Such salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2- hydroxyethanesulfonic acid, benzenesulfonic acid, 4-
  • pharmaceutically acceptable carrier means a carrier that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes a carrier that is acceptable for veterinary use as well as human pharmaceutical use.
  • a pharmaceutically acceptable carrier as used in the specification and claims includes both one and more than one such carrier.
  • mamal refers to human or warm-blooded animals including livestock and companion animals.
  • optional or “optionally” means that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not.
  • isomers Compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed “isomers”. Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers”. Stereoisomers that are not mirror images of one another are termed “diastereomers” and those that are non-superimposable mirror images of each other are termed “enantiomers”. When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible.
  • An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or (-)-isomers respectively).
  • a chiral compound can exist as either individual enantiomer or as a mixture thereof.
  • a mixture containing equal proportions of the enantiomers is called a "racemic mixture".
  • the compounds of this invention may possess one or more asymmetric centers; such compounds can therefore be produced as individual (R)- or (S)- stereoisomers or as mixtures thereof.
  • terapéuticaally effective amount means the amount of a compound that, when administered to a mammal for treating a disease, is sufficient to effect such treatment for the disease.
  • the "therapeutically effective amount” will vary depending on the compound, the disease and its severity and the age, weight, etc., of the mammal to be treated.
  • leaving group has the meaning conventionally associated with it in synthetic organic chemistry i.e., an atom or group capable of being displaced by a nucleophile and includes halogen, alkylsulfonyloxy, ester, or arnino such as chloro, bromo, iodo, mesyloxy, tosyloxy, trifluorosulfonyloxy, methoxy, N,O- dimethylhydroxyl-amino, and the like.
  • the compounds of the present invention are generally named according to the
  • alkyl is methyl, ethyl, propyl, isopropyl, butyl, iso-butyl, sec- butyl, and their isomeric forms thereof.
  • alkyl is methyl, ethyl, propyl, isopropyl, butyl, iso-butyl, sec- butyl, and their isomeric forms thereof.
  • cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and their isomeric forms thereof.
  • halo is fluoro (F), chloro (CI).
  • R 1 is Ci- 4 alkyl, optionally substituted with one, two or three fluoro (F), or chloro (CI).
  • R 1 is CH 3 , or CH 2 CH 3 .CHF 2 , CF 3 , or CHC1 2 .
  • R 1 is CHF 2 , CF 3 , or CHC1 2 .
  • W is CH het.
  • W is 1,2,3-triazole-l-yl methyl, or tetrazole- 1-yl methyl.
  • Y 1 , Y 2 , or Y 3 is CH.
  • one of the Y 1 , Y 2 and Y 3 is N, the other two are CH.
  • Y 1 is CF
  • Y 2 and Y 3 are CH.
  • G is CH 2 .
  • U is CH 2 .
  • U is O ir S.
  • R 2 is CH 3 .
  • R 2 is CH 2 F or CHF 2 .
  • V is N.
  • Z is CN.
  • Z is OCi. 6 alkyl, optionally substituted with OH, or O ⁇ alkyl.
  • Z is substituted with OC ⁇ - alkyl which may may be further substituted with a phenyl.
  • Z is OH or OCH 3 .
  • X is a structure of formula ii
  • Examples of the present invention include: a. (5S)-N-[3-(3-Methoxyimino-4-methyl-3,4-dihydro-2H-benzo[l,4]oxazin-7- yl)-2-oxo-oxazolidin-5-ylmethyl]-acetamide, b. (5S)-N-[3-(3-Methoxyimino-4-methyl-3, 4-dihydro-2H-benzo[l,4]oxazin-7- yl)-2-oxo-oxazolidin-5-ylmethyl]-propionamide, c.
  • R 1 , R 2 , Y 1 , Y 2 and Y 3 are as described previously), conveniently prepared as described by Bartel et al. in WO 9937641, is protected as a carbamate and converted to the thione using various thionation reagents, such as Lawesson, Davy, Yokahama or Belleau reagents, Na 2 P 4 S ⁇ ,
  • the reaction is most conveniently conducted using Lawesson' s reagent in a suitable organic solvent, such as dioxane or tetrahydrofuran, and is typically performed at temperatures in a range of from 25 °C to about 100 °C.
  • a suitable organic solvent such as dioxane or tetrahydrofuran
  • the intermediate thione compound lb is reacted with an alkxoyamine or a salt thereof such as methoxylamine hydrochloride and a suitable base at temperatures ranging from 25 °C to about 100 °C to give the desired benzazinone oxime intermediate lc.
  • Solvents for this transformation may include pyridine, an alcohol such as methanol or ethanol, or dimethylformamide.
  • Suitable bases include inorganic bases such as potassium carbonate or organic bases such as pyridine, triethylamine or N,N- diisopropylethylamine.
  • the synthesis of Scheme I continues with construction of the requisite oxazolidinone substituent using known chemistry methods such as described in US Patent No. 6,107,519. It is further understood that the amidoxime syntheses described herein are generally applicable to amidoxime derivatives bearing other groups in place of the oxazolidinone substituent (such as isoxazoline, isoxazolinone, or butenolide groups).
  • the Boc-protected oxazolidinone derivatives Id can be deprotected to give the corresponding amine. It is convenient to remove the Boc group with 20 to 60% trifluoroacetic acid in dichloroethane or hydrogen chloride in dioxane at temperatures ranging from 0 °C to 24 °C.
  • the synthesis is then completed by an acylation of the penultimate amine intermediate using known art. Thus, acylations can be routinely performed by reactions of the amines with carboxylic acid anhydrides or esters.
  • the compound 2b is then converted to the thione 2c using various thionation reagents, such as Lawesson, Davy, Yokahama or Belleau reagents, Na 2 P 4 S ⁇ , Na 2 P 4 S 10 O, or alike known reagents capable of converting amides into thioamides.
  • the reaction is most conveniently conducted using Lawesson' s reagent in a suitable organic solvent, such as dioxane or tetrahydrofuran, and is typically performed at temperatures in a range of from 25 °C to about 100 °C.
  • the Boc-protected oxazolidinone intermediate 2c is then deprotected to give the corresponding amine.
  • the intermediate thione compound 2d is reacted with hydroxylamine or a salt thereof such as hydroxylamine hydrochloride and a suitable base, a protected source of hydroxylamine such as O-(trimethylsilyl)hydroxylamine or N,O-bis- (trimethylsilyl)hydroxylamine in a protic solvent to provide 2e.
  • Solvents for this transformation may include pyridine, an alcohol such as methanol or ethanol, or dimethylformamide.
  • Suitable bases include inorganic bases such as potassium carbonate or organic bases such as pyridine, triethylamine or N,N- diisopropylethylamine.
  • the amidoxime benzazinone oxazolidinone 2e may be converted to an amidoxime ether le by reaction with a suitable electrophilic alkylating agent such as an alkyl halide, sulfate or tosylate, or a reagent containing an electrophilic multiple bond such as acrylonitrile in the presence of a suitable inorganic or organic base, such as sodium hydride or lithium bis(trimethylsilyl)amide.
  • a suitable electrophilic alkylating agent such as an alkyl halide, sulfate or tosylate, or a reagent containing an electrophilic multiple bond such as acrylonitrile in the presence of a suitable inorganic or organic base, such as sodium hydride or lithium bis(trimethylsilyl)amide.
  • the amidoxime benzazine oxazolidinone 2e may be acylated using known art to provide O-acyloximes 2f.
  • Solvents for the transformations may include tetrahydrofuran or dimethylformamide, and the reaction is typically performed in the range of about 0 °C to about 80°C.
  • Scheme HI illustrates one general synthetic route to amidoxime triazoloylmethyl oxazolidinone derivatives.
  • Scheme IN illustrates a general synthetic route to amidoxime isoxazolylaminomethyl and isoxazolyl ether oxazolidinone derivatives.
  • the hydroxymethyl amidoxime benzazine derivative 3b is coupled with an appropriate amino-isoxazole or hydroxy-isoxazole, for example 3-(2,2,2- trichloroethoxycarbonyl-amino)isoxazole (may be prepared as described in PCT publication WO 0021960) or 3-hydroxyisoxazole (may be prepared as described in US Patent 3,687,968).
  • an appropriate amino-isoxazole or hydroxy-isoxazole for example 3-(2,2,2- trichloroethoxycarbonyl-amino)isoxazole (may be prepared as described in PCT publication WO 0021960) or 3-hydroxyisoxazole (may be prepared as described in US Patent 3,687,968).
  • a suitable coupling reagent such as diisopropylazo-dicarboxylate (DIAD).
  • the coupling reaction is typically conducted in a polar aprotic solvent, such as dimethylformamide, acetonitrile, tetrahydrofuran, or mixtures thereof, in the presence of organic base, such as triphenylphosphine.
  • a polar aprotic solvent such as dimethylformamide, acetonitrile, tetrahydrofuran, or mixtures thereof
  • organic base such as triphenylphosphine.
  • the process is typically carried out at about 0 to about 50.
  • the resulting carbamic acid intermediate can then be reduced to the heteroaryl amine 4b.
  • Schemes V and VI illustrate general synthetic routes to cyanoimine and nitromethylene benzazine oxazolidinone derivatives.
  • amidino derivative 7a provides nitroamidino derivative 8a.
  • 7a may be acylated or sulfonylated to provide amidino amide, or sulfonamide derivative as shown in
  • Scheme VIE Schemes IX-XII describe the synthesis of aryl isoxazolinone, aryl isoxazoline and aryl butyrolactones bearing amidoxime groups.
  • Scheme IX describes the synthesis of aryl isoxazolinone amidoximes.
  • the aldehyde group is conveniently protected as an acetal or other suitable protecting group and the benzazinone converted to the thione using various thionation reagents as previously described.
  • the intermediate thione compound 9c is reacted with an alkoxyamine or a salt thereof as described previously to give the desired benzazinone oxime intermediate 9d.
  • the acetal protecting group is removed using various reaction conditions that are well known in the art (see “Protecting Groups” by Philip J. Kocienski; publisher : Georg Thieme Nerlag: Stuttgart, 1994).
  • Benzaldehyde intermediate 9e may be reacted with ethyl diazoacetate (as described by Mahmood, et al. in J. Org. Chem., 1998, Vol. 63, pp. 3333-3336) to provide ester aldehyde intermediate If.
  • Scheme X describes the synthesis of aryl isoxazoline amidoximes.
  • Aldehyde 9e is reacted with hydroxylamine hydrochlori.de in a polar protic solvent, such as methanol, in the presence of a base, such as pyridine, to afford oxime 10a.
  • the oxime is oxidized with N-chlorosuccinimide in a suitable solvent, such as dichloromethane, to give the intermediate N-hydroxyoximidoyl chloride 10b.
  • N-hydroxyoximidoyl chloride is reacted with an allylic compound such as allyl alcohol or N-acetylamine, in the presence of a base, such as triethylamine, in a solvent such as dichloromethane, to provide the hydroxymethyl or acetamidomethyl substituted isoxazolines.
  • the resulting D-hydroxyacid is cyclized with catalytic p-toluenesulfonic acid to provide lactone lib as a mixture of diastereomers.
  • the Z-group functionality may be introduced by a known sequence of hydrogenolytic benzyl deprotection, mesylate formation, nucleophilic substitution by azide ion, hydrogenolytic reduction and acetyl formation with acetic anhydride.
  • the saturated butyrolactone is then brominated with N-bromosuccinimde, and the double bond introduced by elimination with pyridine in a suitable solvent such as pyridine to provide lid.
  • Medical and Veterinary Uses The compounds of the present invention may be used for the treatment of infectious diseases caused by a variety of bacterial organisms. Examples include gram-positive bacteria such as multiple resistant staphylococci, for example S. aureus and S. epidermidis; multiple resistant streptococci, for example S. pneumoniae and S. pyogenes; and multiple resistant Enterococci, for example E. faecalis; gram negative aerobic bacteria such as Haemophilus, for example H. influenzae and Moraxella, for example M.
  • catarrhalis as well as anaerobic organisms such as bacteroides and clostridia species, and acid- fast organisms such as Mycobacteria, for example M. tuberculosis; and/or Mycobacterium avium.
  • anaerobic organisms such as bacteroides and clostridia species
  • acid- fast organisms such as Mycobacteria, for example M. tuberculosis; and/or Mycobacterium avium.
  • Other examples include Escherichia, for example E. coli. intercellular microbes, for example Chlamydia and Rickettsiae.
  • infections examples include central nervous system infections, external ear infections, infections of the middle ear, such as acute otitis media, infections of the cranial sinuses, eye infections, infections of the oral cavity, such as infections of the teeth, gums and mucosa, upper respiratory tract infections, lower respiratory tract infections, genitourinary infections, gastrointestinal infections, gynecological infections, septicemia, bone and joint infections, skin and skin structure infections, bacterial endocarditis, burns, antibacterial prophylaxis of surgery, and antibacterial prophylaxis in immunosuppressed patients, such as patients receiving cancer chemotherapy, or organ transplant patients.
  • infectious diseases that may be treated with the compounds of the present invention are gram-positive infections such as osteomyelitis, endocarditis and diabetic foot.
  • Antibacterial activity The in vitro antibacterial activity of the compounds of the present invention may be assessed by following procedures recommended in (1) National Committee for Clinical Laboratory Standards (Jan. 2003), Methods for dilution antimicrobial tests or bacteria that grow aerobically, Approved Standard (6 th ed), M7-A6, NCCLS, Wayne, PA; (2) National Committee for Clinical Laboratory Standards (Mar.
  • an oxazolidinone prodrug of the present invention or its pharmaceutical compositions can be administered orally, parenterally, topically, rectally, transmucosally, or intestinally.
  • Parenteral administrations include indirect injections to generate a systemic effect or direct injections to the afflicted area. Examples of parenteral administrations are subcutaneous, intravenous, intramuscular, intradermal, intrathecal, intraocular, intranasal, intravetricular injections or infusions techniques.
  • Topical administrations include the treatment of infectious areas or organs readily accessibly by local application, such as, for example, eyes, ears including external and middle ear infections, vaginal, open wound, skins including the surface skin and the underneath dermal structures, or other lower intestinal tract. It also includes transdermal delivery to generate a systemic effect.
  • the rectal administration includes the form of suppositories.
  • the transmucosal administration includes nasal aerosol or inhalation applications.
  • the preferred routes of administration are oral and parenteral.
  • compositions of the present invention may be manufactured by processes well known in the art, e.g., by means of conventional mixing, dissolving, granulation, dragee-making, levigating, emulsifying, encapsulating, entrapping, lyophilizing processes or spray drying.
  • Pharmaceutical compositions for use in accordance with the present invention may be formulated in conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen.
  • the compounds can be formulated by combining the active compounds with pharmaceutically acceptable carriers well known in the art.
  • Such carriers enable the compounds of the invention to be formulated as tablets, pills, lozenges, dragees, capsules, liquids, solutions, emulsions, gels, syrups, slurries, suspensions and the like, for oral ingestion by a patient.
  • a carrier can be at least one substance which may also function as a diluent, flavoring agent, solubilizer, lubricant, suspending agent, binder, tablet disintegrating agent, and encapsulating agent.
  • Such carriers or excipients include, but are not limited to, magnesium carbonate, magnesium stearate, talc, sugar, lactose, sucrose, pectin, dextrin, mannitol, sorbitol, starches, gelatin, cellulosic materials, low melting wax, cocoa butter or powder, polymers such as polyethylene glycols and other pharmaceutical acceptable materials.
  • Dragee cores are provided with suitable coatings.
  • concentrated sugar solutions may be used which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.
  • Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.
  • Pharmaceutical compositions which can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol.
  • the push-fit capsules can contain the active ingredients in admixture with a filler such as lactose, a binder such as starch, and/or a lubricant such as talc or magnesium stearate and, optionally, stabilizers.
  • the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, liquid polyethylene glycols, cremophor, capmul, medium or long chain mono-, di- or triglycerides.
  • suitable liquids such as fatty oils, liquid paraffin, liquid polyethylene glycols, cremophor, capmul, medium or long chain mono-, di- or triglycerides.
  • Stabilizers may be added in these formulations, also.
  • Liquid form compositions include solutions, suspensions and emulsions.
  • solutions of the compounds of this invention dissolved in water and water-propylene glycol and water-polyethylene glycol systems, optionally containing suitable conventional coloring agents, flavoring agents, stabilizers and thickening agents.
  • the compounds may also be formulated for parenteral administration, e.g., by injections, bolus injection or continuous infusion.
  • Formulations for parenteral administration may be presented in unit dosage form, e.g., in ampoules or in multi- dose containers, with an added preservative.
  • the compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulating materials such as suspending, stabilizing and/or dispersing agents.
  • the compounds of the invention may be formulated in aqueous solution, preferably in physiologically compatible buffers or physiological saline buffer.
  • Suitable buffering agents include trisodium orthophosphate, sodium bicarbonate, sodium citrate, N-methylglucamine, L(+)-lysine and L(+)-arginine.
  • Parenteral administrations also include aqueous solutions of a water soluble form, such as, without limitation, a salt, of the active compound.
  • suspensions of the active compounds may be prepared in a lipophilic vehicle.
  • Suitable lipophilic vehicles include fatty oils such as sesame oil, synthetic fatty acid esters such as ethyl oleate and triglycerides, or materials such as liposomes.
  • Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran.
  • the suspension may also contain suitable stabilizers and/or agents that increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.
  • the active ingredient may be in powder form for constitution with a suitable vehicle, e.g., sterile, pyrogen-free water, before use.
  • a suitable vehicle e.g., sterile, pyrogen-free water
  • the compounds may also be formulated by mixing the agent with a suitable non-irritating excipient which is solid at room temperature but liquid at rectal temperature and therefore will melt in the rectum to release the drug.
  • suitable non-irritating excipient which is solid at room temperature but liquid at rectal temperature and therefore will melt in the rectum to release the drug.
  • suitable non-irritating excipient include cocoa butter, beeswax and other glycerides.
  • compounds of the present invention can be conveniently delivered through an aerosol spray in the form of solution, dry powder, or suspensions.
  • the aerosol may use a pressurized pack or a nebulizer and a suitable propellant.
  • the dosage unit may be controlled by providing a valve to deliver a metered amount.
  • Capsules and cartridges of, for example, gelatin for use in an inhaler may be formulated containing a power base such as lactose or starch.
  • the pharmaceutical composition may be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers.
  • Carriers for topical administration of the compounds of this invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water.
  • the pharmaceutical compositions can be formulated in a suitable lotion such as suspensions, emulsion, or cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers.
  • suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, ceteary alcohol, 2-octyldodecanol, benzyl alcohol and water.
  • the pharmaceutical compositions may be formulated as micronized suspensions in isotonic, pH adjusted sterile saline, or preferably, as solutions in isotonic, pH adjusted sterile saline, either with or without a preservative such as a benzylalkonium chloride.
  • the pharmaceutical compositions may be formulated in an ointment such as petrolatum.
  • the compounds may also be formulated as depot preparations. Such long acting formulations may be in the form of implants.
  • a compound of this invention may be formulated for this route of administration with suitable polymers, hydrophobic materials, or as a sparing soluble derivative such as, without limitation, a sparingly soluble salt. Additionally, the compounds may be delivered using a sustained-release system. Various sustained-release materials have been established and are well known by those skilled in the art. Sustained-release capsules may, depending on their chemical nature, release the compounds for 24 hours or for up to several days. Dosage Pharmaceutical compositions suitable for use in the present invention include compositions wherein the active ingredients are contained in an amount sufficient to achieve the intended purpose, i.e., the treatment or prevent of infectious diseases.
  • a therapeutically effective amount means an amount of compound effective to prevent, alleviate or ameliorate symptoms of disease or prolong the survival of the subject being treated.
  • the quantity of active component, that is the compound of this invention, in the pharmaceutical composition and unit dosage form thereof may be varied or adjusted widely depending upon the manner of administration, the potency of the particular compound and the desired concentration. Determination of a therapeutically effective amount is well within the capability of those skilled in the art. Generally, the quantity of active component will range between 0.5% to 90% by weight of the composition. Generally, a therapeutically effective amount of dosage of active component will be in the range of about 0.1 to about 400 mg/kg of body weight/day, more preferably about 1.0 to about 50 mg/kg of body weight/day.
  • the dosages may vary depending upon the requirements of each subject and the severity of the bacterial infection being treated.
  • the effective amount of active component is about 200 mg to 800 mg and preferable 600 mg per day.
  • the desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example, as two, three, four or more sub-doses per day.
  • the sub-dose itself may be further divided, e.g., into a number of discrete loosely spaced administrations; such as multiple inhalations from an insufflator or by application of a plurality of drops into the eye.
  • the initial dosage administered may be increased beyond the above upper level in order to rapidly achieve the desired plasma concentration.
  • the initial dosage may be smaller than the optimum and the daily dosage may be progressively increased during the course of treatment depending on the particular situation.
  • the daily dose may also be divided into multiple doses for administration, e.g., two to four times per day.
  • the effective local concentration of the drug may not be related to plasma concentration and other procedures know in the art may be used to determine the desired dosage amount.
  • Step 1 Preparation of 7-nitro-4H-benzo[l,4]oxazin-3-one.
  • 2-amino-5-nitrophenol (10 g, 0.065 M) and potassium carbonate (23 g, 0.162 M) in DMF (30 ml) are heated at 90 °C for 24 h.
  • the reaction mixture is allowed to cool and diluted with water.
  • the resulting precipitate is collected by filtration and dried under vacuum to give the title compound as a brown solid. (11.5g, 91%); HPLC r.t. 4.23 rnin.
  • Step 2 Preparation of 4-methyl-7-nitro-4H-benzo[l,4]oxazin-3-one.
  • 7- ⁇ itro-4H-benzo[l,4]oxazin-3-one (6.0 g, 0.031 mol), iodomethane (5.8 ml, 0.093 mol) and potassium carbonate (4.3 g, 0.031 mol) in DMF (30 ml) are stirred for 24 h at room temperature.
  • the reaction mixture is diluted with ethyl acetate, washed with water and brine, dried (Na 2 SO 4 ) and evaporated to give the title compound as a brown solid (6.2 g, 96.8%); HPLC r.t. 4.78 rnin.
  • Step 3 Preparation of 7-amino-4-methyl-4H-benzo[l,4]oxazin-3-one.
  • Iron powder (6.45 g, 0.11 mol) is added in small portions to 4-methyl-7-nitro- 4H-benzo[l,4]oxazin-3-one (6.0 g, 0.0288 mol) and ammonium chloride (15.4 g, 0.288 mol) in ethanol (150 ml) and water (75 ml) at 90 °C.
  • the reaction mixture is stirred vigorously and heated for 1 hour, allowed to cool to room temperature, and diluted with dichloromethane (500 ml).
  • Step 4 Preparation of (4-methyl-3-oxo-3,4-dihydro-2H-benzo[l,4]oxazin-7-yl)- carbamic acid benzyl ester.
  • Benzyl chloroformate (4.37ml, 0.031M) is added dropwise to 7-amino-4- methyl-4H-benzo[l,4]oxazin-3-one (5.0g, 0.028M) and pyridine (4.53ml, 0.056M) in dichloromethane (50ml) at 0 °C.
  • the reaction mixture is stirred at 0 °C for 30 rnin, allowed to warm at room temperature and then diluted with water.
  • Step 4 Preparation of (4-methyl-3-thioxo-3,4-dihydro-2H-benzo[l,4]oxazin-7-yl)- carbamic acid benzyl ester.
  • Step 6 Preparation of (5S)-[3-(3-methoxyimino-4-methyl-3,4-dihydro-2H-benzo [1,4] oxazin-7-yl)-2-oxo-oxazolidin-5-ylmethyl]-carbamic acid tert-butyl ester.
  • Lithium t-butoxide (1.0 M solution in THF, 4.38 ml, 4.38 mmol) is added at 0 °C to 3-methoxyimino-4-methyl-3, 4-dihydro-2H-benzo[l,4]oxazin-7-yl)-carbamic acid benzyl ester (0.5 g, 1.46 mmol) and (3-chloro-2-hydroxy-propyl)-carbamic acid tert-butyl ester (0.45 g, 2.2 mmol) in DMF (5 ml). The reaction mixture is allowed to warm at room temperature and stirred for 24h. The reaction is quenched with saturated aqueous ammonium chloride, diluted with water and extracted with dichloromethane.
  • Step 7 Preparation of (5R)-7-(5-aminomethyl-2-oxo-oxazolidin-3-yl)-4-methyl-4H- benzo[l,4]oxazin-3-one O-methyl-oxime.
  • 3-(3-Methoxyimino-4-methyl-3 ,4-dihydro-2H-benzo [ 1 ,4]oxazin-7-yl)-2-oxo- oxazolidin-5-ylmethyl]-carbamic acid tert-butyl ester (0.35 g, 0.86 mmol) is stirred with 50% TFA/DCM (4 ml) for 1 h at room temperature. The solvent is evaporated to give the title compound as the TFA salt (0.36 g, 99%); HPLC r.t. 3.54 min; MS for C 14 H 18 N 4 O 4 m/z 307.0(M+H) + .
  • Step 8 Preparation of (5S)-N-[3-(3-methoxyimino-4-methyl-3,4-dihydro-2H- benzo[ 1 ,4] oxazin-7-yl)-2-oxo-oxazolidin-5-ylmethyl] -acetamide.
  • Acetic anhydride (0.163 ml, 1.71 mmol) is added dropwise at 0 °C to (5R)-7- (5-aminomethyl-2-oxo-oxazolidin-3-yl)-4-methyl-4 ⁇ -benzo[l ,4]oxazin-3-one O- methyl-oxime (0.35 g, 1.14 mmol) and diisopropylethylamine (0.6 ml, 3.42 mmol) in dichloromethane (5 ml). The reaction mixture is stirred at 0 °C for 30 min. then allowed to warm at room temperature. The reaction mixture is diluted with dichloromethane, washed with water, citric acid and brine, dried ( ⁇ a 2 SO 4 ) and evaporated to give the title compound as an off white solid (0.3 g, 75%); HPLC r.t.
  • Methyl chloroformate (0.177 ml, 2.28 mmol) is added at 0 °C to 7-(5- aminomethyl-2-oxo-oxazolidin-3 -yl)-4-methyl-4H-benzo [ 1 ,4] oxazin-3 -one O-methyl- oxime (Example 1, Step 7, 0.35 g, 1.14 mmol) and diisopropylethylamine (0.6 ml, 3.42 mmol) in dichloromethane (5 ml). The reaction mixture is allowed to warm at room temperature and stirred for 1 h.
  • reaction mixture is diluted with dichloromethane, washed with water, citric acid and brine, dried ( ⁇ a 2 SO ), and evaporated to give the title compound as an off white solid solid (0.31 g, 74%); HPLC r.t.
  • Methyl isocyanate (0.036 ml, 0.636 mmol) was added to (5R)-7-(5-aminomethyl-2- oxo-oxazolidin-3-yl)-4-methyl-4H-benzo [1,4] oxazin-3-one O-methyl-oxime (Example 1, Step 7, 0.134 g, 0.318 mmol) and diisopropylethylamine (0.33ml, 1.908mmol) in dichloromethane (5ml) at 0 °C. The mixture was allowed to warm at room temperature and stirred for 1 hour.
  • Step 1 Preparation of 7-(5-hydroxymethyl-2-oxo-oxazolidin-3-yl)-4-methyl-4H- benzo[l ,4]oxazin-3-one O-methyl-oxime.
  • Lithium bis(trimethylsilyl)amide (1.0 M in THF, 3.21 ml, 0.00321 mol) is added dropwise at -78 °C to (3-methoxyimino-4-methyl-3,4-dihydro-2H- benzo[l,4]oxazin-7-yl)-carbamic acid benzyl ester (1.0 g, 0.00292 mol) in THF (10 ml).
  • Step 2 Preparation of (5R)-methanesulfonic acid 3-(3-methoxyimino-4-methyl-3,4- dihydro-2H-benzo[l,4]oxazin-7-yl)-2-oxo-oxazolidin-5-ylmethyl ester.
  • Methanesulfonyl chloride (0.162 ml, 2.1 mmol) is added dropwise at 0 °C to
  • Step 3 Preparation of (5R)-7-(5-azidomethyl-2-oxo-oxazolidin-3-yl)-4-methyl-4H- benzo[l,4]oxazin-3-one O-methyl-oxime.
  • Step 4 Preparation of (5R)-4-methyl-7-(2-oxo-5-[l,2,3]triazol-l-ylmethyl- oxazolidin-3-yl)-4H-benzo [ 1 ,4]oxazin-3-one O-methyl- 1 -oxime.
  • Step 1 Preparation of [3-(4-methyl-3-oxo-3, 4-dihydro-2H-benzo[l,4]oxazin-7-yl)-2- oxo-oxazolidin-5-ylmethyl]-carbamic acid tert-butyl ester.
  • Lithium t-butoxide (1.0 M solution in THF, 42.2 ml, 42.24 mmol) is dropwise at 0 °C to 4-methyl-3-oxo-3,4-dihydro-2H-benzo[l,4]oxazin-7-yl)-carbamic acid benzyl ester (5.5 g, 17.6 mmol) and (3-chloro-2-hydroxy-propyl)-carbamic acid tert- butyl ester (4.58 g, 22.18 mmol) in DMF (50 ml). The reaction mixture is allowed to warm to room temperature and stirred for 24 h.
  • Step 2 Preparation of (5S)-[3-(4-methyl-3-thioxo-3,4-dihydro-2H-benzo[l,4]oxazin- 7-yl)-2-oxo-oxazolidin-5-ylmethyl]-carbamic acid tert-butyl ester.
  • Step 3 Preparation of (5R)-aminomethyl-3-(4-methyl-3-thioxo-3,4-dihydro-2H- benzo[l,4]oxazin-7-yl)-oxazolidin-2-one.
  • Step 4 Preparation of (5S)-N-[3-(4-methyl-3-thioxo-3,4-dihydro-2H- benzo[l,4]oxazin-7-yl)-2-oxo-oxazolidin-5-ylmethyl]-acetamide.
  • Acetic anhydride (0.585 ml, 6.12 mmol) is added at 0 °C to (5R)- aminomethyl-3-(4-methyl-3-thioxo 3,4-dihydro-2H-benzo[l,4]oxazin-7-yl)- oxazolidin-2-one (1.2 g, 4.08 mmol) and diisopropylethylamine (2.13 ml, 12.2 mmol) in dichloromethane (15 ml). The reaction mixture is stirred at 0 °C for 30 min, allowed to warm at room temperature and diluted with dichloromethane. The organic layer is separated, washed with water, citric acid and brine, dried ( ⁇ a 2 SO 4 ) and evaporated. The residue is purified to give the title compound as a light brown solid (1.3 g, 95%); HPLC r.t. 4.28 min; MS for C 15 H ⁇ 7 N 3 O 4 S m/z 336.0(M+H) + .
  • Step 5 Preparation of (5S)-N-[3-(3-ethoxyimino-4-methyl-3,4-dihydro-2H- benzo[l,4]oxazin-7-yl)-2-oxo-oxazolidin-5-ylmethyl]-acetamide. N-[3-(4-methyl-3-thioxo-3,4-dihydro-2H-benzo[l,4]oxazin-7-yl)-2-oxo- oxazolidin-5-ylmethyl]-acetamide (50 mg, 0.15 mmol) and O-ethyl hydroxylamine (88.5 mg, 0.90 mmol) in pyridine (2 ml) are heated overnight at 70 °C.
  • Step 1 Preparation of (3-Hydroxyimino-4-methyl-3,4-dihydro-2H-benzo[l,4]oxazin- 7-yl)-carbamic acid benzyl ester 4-Methyl-3-thioxo-3,4-dihydro-2H-benzo [1,4] oxazin-7-yl)- carbamic acid benzyl ester (1.2 g, 3.65 mmol)(Example 1, step 5) and N, O-bis(trimethylsilyl) hydroxylamine (1.4 ml, 6.55 mmol) in ethanol (25 ml) were heated overnight at 70 °C.
  • Step 2 Preparation of [4-Methyl-3-(tetrahydro-pyran-2yloxyimino)-3,4-dihydro-2H- benzo[l,4]oxazin-7-yl)-carbamic acid benzyl ester (3-Hydroxyimino-4-methyl-3,4-dihydro-2H-benzo[l,4]oxazin-7-yl)-carbamic acid benzyl ester (0.93 g, 2.84 mmol), 3,4-dihydro-2H-pyran (0.57 ml, 6.25 mmol) and p-toluene sulfonic acid (0.108 g, 0.568 mmol) in DMF (6 ml) were stirred at room temperature for 72 hours.
  • Step 3 Preparation of (5S)- ⁇ 3-[4-Methyl-3-(tetrahydro-pyran-2yloxyimino)-3,4- dihydro-2H-benzo[l,4]oxazin-7-yl)-2-oxo-oxazolidin-5-ylmethyl ⁇ -carbamic acid tert- butyl ester Lithium t-butoxide (1.0 M solution in THF, 5.82 ml, 5.82 mmol) was added at 0 °C to [4-methyl-3-(tetrahydro-pyran-2yloxyimino)-3,4-dihydro-2H- benzo[l,4]oxazin-7-yl)-carbamic acid benzyl ester (0.80 g, 1.94 mmol) and (3-chloro- 2-hydroxy-propyl)-carbamic acid tert-butyl ester (0.609 g, 2.91 mmol) in DMF (7 ml
  • Step 4 Preparation of (5R)-7-(5-aminomethyl-2-oxo-oxazolidin-3-yl)-4-methyl-4H- benzo[l,4]oxazin-3-one oxime.
  • Step 5 (5S)-[3-(3-Hydroxyimino -4-methyl-3,4-dihydro-2H-benzo[l,4]oxazin-7-yl)- 2-oxo-oxazolidin-5-ylmethyl] -carbamic acid methyl ester Methyl chloroformate (0.046 ml, 0.588 mmol) was added to (5R)-7-(5- aminomethyl-2-oxo-oxazolidin-3-yl)-4-methyl-4H-benzo [ 1 ,4] oxazin-3-one oxime.
  • Step 1 Preparation of (5S)-N-[3-(3-hydroxyimino-4-methyl-3,4-dihydro-2H- benzo[l,4]oxazin-7-yl)-2-oxo-oxazolidin-5-ylmethyl]-acetamide.
  • Step 2 Preparation of (5S)-N-[3-(3-isopropoxyimino-4-methyl-3,4-dihydro-2H- benzo[l,4]oxazin-7-yl)-2-oxo-oxazolidin-5-ylmethyl]-acetamide.
  • reaction is quenched with sat. ammonium chloride, diluted with ethyl acetate, washed with water and brine, dried ( ⁇ a 2 SO 4 ) and evaporated.
  • residue is purified by PTLC (10% MeO ⁇ /DCM) to give product as a white solid (0.45 g, 64%); ⁇ PLC r.t.
  • Step 1 Preparation of (4-methyl-3-oxo-3,4-dihydro-2H-benzo[l,4]thiazin-7-yl)- carbamic acid benzyl ester.
  • Benzyl chloroformate (4.01 mL, 28.08 mmol) is added at 0 °C to a stirred solution of 7-amino-4-methyl-4H-benzo[l,4]thiazin-3-one (prepared accordind to the method described in WO/03072553) (3.41 g, 17.55 mmol) and pyridine (3.12 mL, 38.62 mmol) in dry DCM (20 ml).
  • the reaction mixture is allowed to warm to room temperature and then washed with 2N HC1.
  • Step 2 Preparation of (5S)-[3-(4-methyl-3-oxo-3,4-dihydro-2H-benzo[l,4]thiazin-7- yl)-2-oxo-oxazolidin-5-ylmethyl]-carbamic acid tert-butyl ester.
  • Lithium t-butoxide (1.0 M solution in THF, 35.45 ml, 35.45 mmol) is added dropwise at 0 °C to (4-methyl-3-oxo-3,4-dihydro-2H-benzo[l,4]thiazin-7-yl)- carbamic acid benzyl ester (3.88g, 11.8 mmol) and (3-chloro-2-hydroxy-propyl)- carbamic acid tert-butyl ester (3.714 g, 17.7 mmol) in DMF (9 ml). The reaction mixture is allowed to warm at room temperature and stirred for 16 h.
  • Step 3 Preparation of (5S)-[3-(4-methyl-3-thioxo-3,4-dihydro-2H-benzo[l,4]thiazin- 7-yl)-2-oxo-oxazolidin-5-ylmethyl]-carbamic acid tert-butyl ester.
  • Step 4 Preparation of (5S)-N-[3-(4-methyl-3-thioxo-3,4-dihydro-2H- benzo[l,4]thiazin-7-yl)-2-oxo-oxazolidin-5-ylmethyl]-acetamide.
  • Step 5 Preparation of (5S)-N-[3-(3-hydroxyimino-4-methyl-3,4-dihydro-2H- benzo[l,4]thiazin-7-yl)-2-oxo-oxazolidin-5-ylmethyl]-acetamide.
  • Step 1 Preparation of (l-methyl-2-oxo-l,2,3,4-tetrahydro-quinolin-6-yl)-carbamic acid benzyl ester.
  • Benzyl chloroformate (0.171 mL, 1.2 mmol) is added at 0 °C to a stirred solution of 6-amino-l-methyl-3,4-dihydro-lH-quinolin-2-one (prepared according to the method described in WO/03072553) (0.176 g, 1.00 mmol) and pyridine (0.194 mL, 2.40 mmol) in dry DCM (5 ml).
  • the reaction mixture is allowed to warm to room temperature and then washed with 2 ⁇ HCl.
  • Step 2 Preparation of (5S)-[3-(l-methyl-2-oxo-l,2,3,4-tetrahydro-quinolin-6-yl)-2- oxo-oxazolidin-5-ylmethyl]-carbamic acid tert-butyl ester.
  • Lithium t-butoxide (1.0 M solution in THF, 2.3 ml, 2.33 mmol) is added dropwise at 0 °C to (l-methyl-2-oxo-l,2,3,4-tetrahydro-quinolin-6-yl)-carbamic acid benzyl ester (2.0 g, 6.41 mmol) and (3-chloro-2-hydroxy-propyl)-carbamic acid tert- butyl ester (0.300 g, 0.97 mmol) in DMF (2 ml). The reaction mixture is allowed to warm at room temperature and stirred overnight. The reaction is quenched with saturated aqueous ammonium chloride, diluted with water and extracted with dichloromethane.
  • Step 3 Preparation of (5S)-[3-(l-methyl-2-thioxo-l,2,3,4-tetrahydro-quinolin-6-yl)-2- oxo-oxazolidin-5-ylmethyl]-carbamic acid tert-butyl ester.
  • Step 4 Preparation of (5S)-N-[3-(l-methyl-2-thioxo-l,2,3,4-tetrahydro-quinolin-6- yl)-2-oxo-oxazolidin-5-ylmethyl]-acetamide.
  • TFA (1.50 ml) in dichloroethane (2 ml) is added to [3-(l-Methyl-2-thioxo- 1 ,2,3,4-tetrahydro-quinolin-6-yl)-2-oxo-oxazolidin-5-ylmethyl]-carbamic acid tert- butyl ester (0.39 g, 4.0 mmol).
  • Step 5 Preparation of (5S)-N-[3-(2-Hydroxyimino-l-methyl-l,2,3,4-tetrahydro- quinolin-6-yl)-2-oxo-oxazolidin-5-ylmethyl]-acetamide.
  • Step 1 Preparation of (l-Methyl-2-thioxo-l,2,3,4-tetrahydro-quinolin-6-yl)-carbamic acid benzyl ester.
  • Step 2 Preparation of (2-Methoxyimino-l-methyl-l,2,3,4-tetrahydro-quinolin-6-yl)- carbamic acid benzyl ester.
  • Methoxylamine hydrochloride (3.157 g, 37.8 mmol) and (l-methyl-2-thioxo- l,2,3,4-tetrahydro-quinolin-6-yl)-carbamic acid benzyl ester (3.00 g , 9.22 mmol) in pyridine (45 mL), was added) was heated for 48 hours at 70 °C. The reaction was evaporated, diluted with dichloromethane, washed with water and brine, dried (MgSO ) and evaporated.
  • Step 3 Preparation of (5S)-[3-(2-Methoxyimino-l-methyl-l,2,3,4-tetrahydro-quinolin- 6-yl)-2-oxo-oxazolidin-5-ylmethyl]-carbamic acid tert-butyl ester.
  • Lithium t-butoxide (1M in THF, 7.13 mL, 7.13 mmol) was added at 0 °C to (2- methoxyimino-l-methyl-l,2,3,4-tetrahydro-quinolin-6-yl)-carbamic acid benzyl ester (1.10 g , 3.24 mmol) and (3-chloro-2-hydroxy-propyl)-carban ic acid tert-butyl ester (1.024 g, 4.884 mmol)in DMF (10 mL). The mixture was allowed to warm to room temperature and stirred for 24 hours. The reaction was quenched with saturated aqueous ammonium chloride and extracted with dichloromethane.
  • Propionic anhydride (0.325 ml, 2.538 mmol) was added to (5R)-6-(5- aminomethyl-2-oxo-oxazolidin-3-yl)-l-methyl-3,4-dihydro-lH-quinolin-2-one O- methyl-oxime (0.531 g , 1.27 mmol) and diisopropylethylamine (0.629 ml, 3.081 mmol) in dichloromethane (5 ml) was added) at 0 °C. The mixture was stirred at 0 °C for 30 minutes and then allowed to warm to room temperature.
  • Step 1 Preparation of 2-amino-3-fluoro-5-nitro-phenol.
  • 4-Fluoro-6-nitro-l, 3-benzoxazol-2 (3H)-one (prepared according to the method described in WO/03072553) (5.0 g, 0.02 mol) and sodium hydroxide (5.05 g, 0.126 mol) in water (125 ml) is heated at 100 °C for 3 h.
  • the reaction mixture is cooled to room temperature and carefully neutralized with 6 ⁇ hydrochloric acid.
  • the resulting precipitate is filtered, washed with water and dried under vacuum to provide pure the title compound as orange solid (3.1 g, 72%); HPLC r.t. 4.05 min.
  • Step 3 Preparation of 5-fluoro-4-methyl-7-nitro-4H-benzo[l,4]oxazin-3-one.
  • Iodomethane (1.65 ml, 0.0283 mol)
  • 5-fluoro-7-nitro-4H-benzo[l,4]oxazin-3- one 2.0 g, 0.0094 mol
  • potassium carbonate 1.3 g, 0.0094 mol
  • the reaction mixture is diluted with ethyl acetate, washed with water and brine, dried (Na 2 SO ) to give the title compound as a brown solid suitable for use directly in the next step (1.8 g, 84.5%); HPLC r.t. 4.82 min.
  • Step 4 Preparation of 7-amino-5-fluoro-4-methyl-4H-benzo[l,4]oxazin-3-one.
  • Iron powder (2.27 g, 0.0406 mol) is added in small portion to a mixture of 5- fluoro-4-methyl-7-nitro-4H-benzo[l,4]oxazin-3-one (2.3 g, 0.010 mol) and ammonium chloride (5.41 g , 0.102 mol) in ethanol (100 ml) and water (50 ml) at 90 °C.
  • the reaction mixture is stirred vigorously and heated for 1 hour, cooled to room temperature and diluted with dichloromethane (200 ml).
  • the mixture is filtered through celite, washed with water and brine, dried over sodium sulfate and evaporated to give the title compound as a brown solid (1.77 g, 89%); HPLC r.t. 2.47min.
  • Step 5 Preparation of (5-fluoro-4-methyl-3-oxo-3,4-dihydro-2H-benzo[l,4]oxazin-7- yl)-carbamic acid benzyl ester.
  • Benzyl chloroformate (1.38 ml, 0.00981 mol) is added dropwise to a mixture of 7-amino-5-fluoro-4-methyl-4H-benzo[l,4]oxazin-3-one (1.75 g, 0.00892 mol) and pyridine (1.44 ml, 0.0178 mol) in dichloromethane (15 ml) at 0 °C.
  • Step 6 Preparation of (5-fluoro-4-methyl-3-thioxo-3, 4-dihydro-2H- benzo[l,4]oxazin-7-yl)-carbamic acid benzyl ester.
  • 5-Fluoro-4-methyl-3-oxo-3,4-dihydro-2H-benzo[l,4]oxazin-7-yl)-carbamic acid benzyl ester (2.2 g, 0.0066 mol) and Lawesson's reagent (2.04 g, 0.005 mol) in dioxane (15 ml) are heated overnight at 70 °C.
  • Step 7 Preparation of (5-fluoro-3-methoxyimino-4-methyl-3,4-dihydro-2H- benzo[l,4]oxazin-7-yl)-carbamic acid benzyl ester.
  • 5-Fluoro-4-methyl-3-thioxo-3,4-dihydro-2H-benzo[l,4]oxazin-7-yl)- carbamic acid benzyl ester (0.85 g, 2.45 mmol) and methoxylamine hydrochloride (1.22 g, 14.7 mmol) in pyridine (8 ml) are heated overnight at 70 °C. The reaction mixture is evaporated to dryness.
  • Step 8 Preparation of (5S)-[3-(5-fluoro-3-methoxyimino-4-methyl-3, 4-dihydro-2H- benzo[l,4]oxazin-7-yl)-2-oxo-oxazolidin-5-ylmethyl]-carbamic acid tert-butyl ester.
  • Lithium t-butoxide (1.0 M solution in THF, 7.35 ml, 7.35 mmol) is added dropwise at 0 °C to 5-fIuoro-3-methoxyimino-4-methyl-3,4-dihydro-2H- benzo[l,4]oxazin-7-yl)-carbamic acid benzyl ester (0.8g, 2.4mmol) and (3-chloro-2- hydroxy-propyl)-carbamic acid tert-butyl ester (0.77 g, 3.67 mmol) in DMF (10 ml). The reaction mixture is allowed to warm at room temperature and stirred for 144 h.
  • Step 9 Preparation of (5S)-7-(5-aminomethyl-2-oxo-oxazolidin-3-yl)-5-fluoro-4- methyl-4H-benzo [ 1 ,4] oxazin-3 -one O-methyl-oxime.
  • 3-(5-Fluoro-3-methoxyimino-4-methyl-3,4-dihydro-2H-benzo[l,4]oxazin-7- yl)-2-oxo-oxazolidin-5-ylmethyl] -carbamic acid tert-butyl ester (0.47 g, 1.11 mmol) is stirred with 50% TFA/DCM (4 ml) for 1 h at room temperature.
  • Step 10 Preparation of (5S)-N-[3-(5-fluoro-3-methoxyimino-4-methyl-3, 4-dihydro- 2H-benzo[l,4]oxazin-7-yl)-2-oxo-oxazolidin-5-ylmethyl]-acetamide.
  • Acetic anhydride (0.156 ml, 1.64 mmol) is added dropwise at 0 °C to (5R)-7- (5-aminomethyl-2-oxo-oxazolidin-3-yl)-5-fluoro-4-methyl-4H-benzo[l,4]oxazin-3- one O-methyl-oxime (0.355 g, 1.09 mmol) and diisopropylethylamine (0.57 ml, 3.27 mmol) in dichloromethane (5 ml). The reaction mixture is stirred at 0 °C for 30 min then allowed to warm at room temperature.
  • Methyl chloroformate (0.12 ml, 1.55 mmol) was added dropwise to (5R)-7-(5- aminomethyl-2-oxo-oxazolidin-3-yl)-5-fluoro-4-methyl-4H-benzo [1,4] oxazin-3-one O-methyl-oxime (0.34 g, 0.775 mmol) (from Example 21, step 9) and diisopropyl ethylamine (0.80 ml, 4.65 mmol) in dichloromethane (5 ml) at 0 °C. The mixture was stirred at 0 °C for 30 minutes and then allowed to warm to room temperature.
  • Step 1 Preparation of 7-nitro-4H-benzo [1,4] oxazin-3 -thione 7-Nitro-4H-benzo [1,4] oxazin-3-one (5.0 g, 25.75 mmol) and Lawesson's reagent (7.78 g, 19.31mmol) in tetrahydrofuran (50 ml) was heated 3 hours at 55 °C. The mixture was evaporated and residue triturated with dichloromethane and dried under vacuum to give product as a greenish yellow solid (5.3 g, 97.9%); HPLC r.t. 4.87 min; MS for C 8 H 6 N 2 O 3 S m/z 209.0 (M-H) " .
  • Step 2 Preparation of 7-nitro-4H-benzo [1,4] oxazin-3-one O-methyl-oxime 7-Nitro-4H-benzo [1,4] oxazin-3 -thione (2.5 g, 11.89 mmol) and methoxylamine hydrochloride (2.97 g, 35.67 mmol) in pyridine (15 ml) was heated overnight at 70°C. The mixture was evaporated and the residue diluted with ethyl acetate, washed with 5% aqueous citric acid, water and brine, dried (Na 2 SO 4 ) and evaporated to give product as a yellow solid (2.55 g, 96%); HPLC r.t. 4.59 min; MS for C 9 H 9 N 3 O 4 m/z 222.2 (M-H) " .
  • Step 3 Preparation of 7-Amino-4H-benzo [1,4] oxazin-3-one O-methyl-oxime
  • Iron powder (1.18g, 21.5mmol) was added in small portion to a mixture of 7- nitro-4H-benzo [1,4] oxazin-3-one O-methyl-oxime (1.2 g, 5.37 mmol) and ammonium chloride (2.82 g, 53.7 mmol) in ethanol (50 ml) and water (25 ml) at 90 °C.
  • the reaction mixture was stirred vigorously and heated for 1 hour, cooled to room temperature and diluted with dichloromethane (200 ml).
  • Step 4 Preparation of (3-Methoxyimino-3,4-dihydro-2H-benzo [1,4] oxazin-7-yl) - carbamic acid benzyl ester
  • Benzyl chloroformate (0.497 ml, 3.53 mmol) was added dropwise to a mixture of 7-amino-4H-benzo [1,4] oxazin-3-one O-methyl-oxime (0.62 g, 3.21 mmol) and pyridine (0.52 ml, 6.42 mmol) in dichloromethane (10 ml) at 0 °C.
  • the reaction mixture was stirred at 0 °C for 30 minutes, allowed to warm at room temperature and then poured into water.
  • Step 5 Preparation of (5S)-[3-(3-Methoxyimino-3,4-dihydro-2H-benzo [1,4] oxazin- 7-yl) -2-oxo-oxazolidin-5-ylmethyl]-carbamic acid tert-butyl ester Lithium t-butoxide (1.0 M, 4.2 ml, 4.2 mmol) was added to (3-methoxyimino-
  • Step 7 Preparation of (5S)-[3-(3-Hydroxyimino -4-methyl-3,4-dihydro-2H- benzo[ 1 ,4]oxazin-7-yl)-2-oxo-oxazolidin-5-ylmethyl]-carbamic acid methyl ester.
  • Lithium bis(trimethylsilyl)amide (1.0 M in T ⁇ F, 3.21 ml, 0.00321 mol) is added dropwise at -78 °C to (3-methoxyimino-4-methyl-3,4-dihydro-2H- benzo[l,4]oxazin-7-yl)-carbamic acid benzyl ester (1.0 g, 0.00292 mol) in T ⁇ F (10 ml).
  • the reaction mixture is stirred at -78 °C for lh and then (R)-glycidyl butyrate (0.46 ml, 0.00321 mol) added dropwise.
  • the mixture is allowed to warm to room temperature and stirred overnight.
  • Step 1 Preparation of 4-Methyl-7-nitro-4H-benzo[l,4]oxazin-3-ylidene-cyanamide.
  • Methyl trifilate (0.50 ml, 4.44 mmol) was added to 4-methyl-7-nitro-4H- benzo[l, 4] oxazine-3 -thione (0.50 g, 2.22 mmol) in dichloromethane (10 ml) at 0 °C. The mixture was allowed to warm to room temperature and stirred overnight to provide a solution of 4-methyl-3-methylsulfanyl-7-nitro-2H-benzo[l,4]oxazin-4-ium triflate in dichloromethane.
  • Step 2 Preparation of 7- Amino-4-methyl-4H-benzo[ 1,4] oxazin-3 -ylidene-cyanamide Iron powder (0.182 g, 3.27 mmol) was added in small portions to 4-methyl-7- nitro-4H-benzo[ 1,4] oxazin-3 -ylidene-cyanamide (0.19 g, 0.818 mmol) and ammonium chloride (0.433 g, 8.18 mmol) in ethanol (20 ml) and water (10 ml) at 90 °C. The reaction mixture was stirred vigorously and heated for 30 minutes, allowed to cool to room temperature, and diluted with dichloromethane (50 ml).
  • Step 3 Preparation of [3-(3-Cyanoimino-4-methyl-3,4-dihydro-2H-benzo[l,4]oxazin- 7-ylamino)-(2R)-hydroxy- ⁇ ropyl]-carbamic acid tert-butyl ester.
  • Step 4 Preparation of (5S)-[3-(3-Cyanoimino-4-methyl-3,4-dihydro-2H- benzo[l,4]oxazin-7-yl)-2-oxo-oxazolidin-5-ylmethyl]-carbamic acid tert-butyl ester.
  • Step 5 Preparation of (5R)-7-(5-Aminomethyl-2-oxo-oxazolidin-3-yl)-4-methyl-4H- benzo[l,4]oxazin-3-ylidene-cyanamide.
  • Step 6 Preparation of (5S)-N-[3-(3-Cyanoimino-4-methyl-3,4-dihydro-2H- benzo[l,4]oxazin-7-yl)-2-oxo-oxazolidin-5-ylmethyl]-acetamide.
  • Acetic anhydride (0.014ml, 0.144mmol) was added to (5R)-7-(5-aminomethyl- 2-oxo-oxazolidin-3-yl)-4-methyl-4H-benzo[l,4]oxazin-3-ylidene-cyanamide (0.040 g, 0.096 mmol) and diisopropylethylamine (0.066 ml, 0.384 mmol) in dichloromethane (3 ml) at 0°C. The reaction mixture was stirred at 0 °C for 30 minutes and then allowed to warm to room temperature. The mixture was diluted with dichloromethane, washed with water, citric acid and brine, dried ( ⁇ a 2 SO 4 ), and evaporated.

Abstract

The present invention relates to novel amidoxime and amidine oxazolidinones of formula I , wherein R2, Y1, Y 2, Y3, X, W, G and U are as defined herein in the specification. The compounds of the present invention have potent activities against gram-positive bacteria.

Description

OXAZOLIDINONE ANTIBACTERIAL AGENTS
FIELD OF INVENTION - The present invention relates to a new class of amidoxime and amidine oxazolidinone derivatives, to their use as antibacterial agents, to pharmaceutical compositions containing these compounds and to methods for their preparation.
BACKGROUND OF THE INVENTION Due to ever-increasing antibiotic resistance, structurally novel antibacterials with a new mode of action have become increasingly important in the treatment of bacterial infections. Effective antibacterials should exhibit potent activity against a number of human and veterinary pathogens, including gram-positive aerobic bacteria such as multiple-resistant staphylococci and streptococci, anaerobic organisms such as bacteroides and clostridia species, and acid-fast organisms such as Mycobacterium tuberculosis and Mycobacterium avium. Among newer antibacterial agents, oxazolidinone compounds are the most recent synthetic class of antimicrobials active against a number of pathogenic microorganisms. This invention provides novel amidoxime derivatives of oxazolidinones, and their preparation.
INFORMATION DISCLOSURE PCT publication WO 9964416 discloses oxazolidinone derivatives. PCT publication WO 9964417 discloses oxazolidinone derivatives. PCT publication WO 200021960 discloses heterocyclyl aminomethyl oxazolidinone derivatives. PCT publication WO 200029409 discloses oxazolidinone derivatives. PCT publication WO 200181350 discloses oxazolidinone derivatives and their salts or in vivo hydrolysable esters. PCT publication WO 200281470 discloses oxazolidinone compounds and their salts or in vivo hydrolysable esters. PCT publication WO 2003035648 discloses aryl substituted oxazolidinones, their salts or esters. DE 19604223 discloses oxazolidinone derivatives. DE 19805117 discloses oxazolidinone derivatives. DE 19901306 discloses oxazolidinone derivatives. DE 19905278 discloses oxazolidinone derivatives. DE 19962924 discloses N-oxazolidinylmethyl-substituted (benzo)thiophene carboxamides. EP 738726 discloses oxazolidinone derivatives. EP 785201 discloses oxazolidinone derivatives. SUMMARY OF THE INVENTION The present invention provides a compound of formula I
Figure imgf000003_0001
I or a pharmaceutically acceptable salt thereof wherein: X is a structure of the following formula i, ii, iii, or iv
Figure imgf000003_0002
W is (a) CH2NHC(=O)R1, (b) CH2NHC(=S)R1, (c) CH2NH-het, (d) CH2O-het, (e) CH2S-het, (f) CH2het, (g) CH2OH, (h) CH(OH)-CH=CHR1, or (i) CHCOHOC≡CR1; Y1, Y2 and Y3 are independently (a) CH, (b) N, (c) N+-O\ or (d) CF;
G is -(CR3R4)„-; U is (a) CH2, (b) CF2, (c) O, or (d) S(=O)m; R s (a) NH2, (b) NH -ealkyl, (c) Ci-ealkyl, (d) C2.6alkenyl, (e) (CH2)jC(=O)C1.4alkyl, (f) Od-ealkyl, (g) Sd-ealkyl, or (h) (CH2)jC3.7cycloalkyl; R2 is H or Ci- alkyl, optionally substituted with 1-3 fuloro; R3 and R4 are independently (a) H (b) Ci-6 alkyl, or (c) R3 and R4 taken together with the carbon atom to which they attach form C3-7cycloalkyl;
V is N, or C; Z is (a) H, (b) OH, (c) CN, (d) NO2, (e) Cι_6alkyl, (f) Od-galkyl, (g) aryl, (h) het, (i) C(=O)C1-6alkyl, 0) C(=O)-het, (k) OC(=O)Cι.6alkyl, (1) C(=O)NR5R6, (m) SO2-C1-6alkyl, or (n) SO2-NR5R6;
R5 and R6 are independently (a) H, or (b) Ci- alkyl, optional aryl is phenyl, biphenyl, or naphthyl, optionally substituted with halo, OR5, SR5, CN,
NO2, NR5R6, CF3, OCF3, C(=O)Cι-4alkyl, OC(=O)d-4alkyl, C(=O)OR5, or
S(O)„C1-4alkyl; het is a five- (5) or six- (6) membered heterocyclic ring having 1-4 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen within the ring, wherein each carbon atom in het is optionally substituted with halo, OR5, SR5, CN,
NO2, NR5R6, oxo, CF3, OCF3,
Figure imgf000005_0001
C(=O)OR5, or
S(O)„C1-4alkyl; at each occurrence, -βalkyl, C2-6alkenyl, or C3-7cycloalkyl is ptionally substituted with 1-3 halo, OR5, SR5, CN, N3, NO2, NR5R6, C(=O)C1-4alkyl,
Figure imgf000005_0002
C(=O)OC1-4alkyl, C3-6cycloalkyl, or S(O)„C1-4alkyl; each n is independently 1 or 2; m is 0, 1, or 2; and each j is independently 0-4. In another aspect, the present invention also provides: a pharmaceutical composition which comprises a pharmaceutically acceptable carrier and an effective amount of a compound of formula I, a method for treating gram-positive microbial infections in a mammal by administering to the subject in need a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof, and a use of a compound of formula I or a pharmaceutically acceptable salt thereof to prepare a medicament for treating gram-positive microbial infections. The invention may also provide novel intermediates and novel processes that are useful for preparing compounds of formula I. DETAILED DESCRIPTION OF THE INVENTION Unless otherwise stated, the following terms used in the specification and claims have the meanings given below: The carbon atom content of various hydrocarbon-containing moieties is indicated by a prefix designating the minimum and maximum number of carbon atoms in the moiety, i.e., the prefix -j indicates a moiety of the integer "i" to the integer "j" carbon atoms, inclusive. Thus, for example, Cι.-6alkyl refers to alkyl of one to six carbon atoms, inclusive. The term alkyl, or alkenyl, etc. refer to both straight and branched groups, but reference to an individual radical such as "propyl" embraces only the straight chain radical, a branched chain isomer such as "isopropyl" being specifically referred to. The term "C -7cycloalkyl" refers to a cyclic saturated monovalent hydrocarbon group of three to seven carbon atoms, e.g., cyclopropyl, cyclohexyl, and the like. The term "halo" refers to fluoro (F), chloro (CI), bromo (Br), or iodo (I). The term "aryl" refers to aryl is phenyl, biphenyl, or naphthyl, optionally substituted with halo, OR5, SR5, CN, NO2, NR5R6, CF3, OCF3, C(=O)Cι-4alkyl, OC(=O)Q-4alkyl, C(=O)OR5, or S(O)nC1-4alkyl. The term "het" is a five- (5) or six- (6) membered heterocyclic ring having 1-4 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen within the ring. An examples of het includes, but are not limited to, azetidine, pyrrole, imidazole, pyrazole, 1,2,3-triazole, 1,3,4-triazole, oxazole, thiazole, isoxazole, isothiazole, 1,3,4-oxadiazole, 1,3,4-thiadiazole, 1,2,3-thiadiazole, tetrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, dihydroindole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, isoxazolinone, phenoxazine, phenothiazine, imidazolidine, imidazoline, piperidine, piperazine, indoline, phthalimide, 1,2,3,4-tetrahydroisoquinoline, 4,5,6,7-tetrahydrobenzo[b]thiophene, thiazole, thiadiazole, tetrazole, thiazolidine, thiophene, benzo[b]thiophene, morpholine, thiomorpholine, (also referred to as thiamorpholine,), piperidine, pyrrolidine, tetrahydrofuran, or the like. Another example of het includes, but are not limited to, pyridine, thiophene, furan, pyrazole, pyrimidine, 2-pyridyl, 3-pyridyl, 4- pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, 3- pyrazinyl, 4-oxo-2-imidazolyl, 2-imidazolyl, 4-imidazolyl, 3-isoxaz-olyl, 4-is-oxaz- olyl, 5-isoxaz-olyl, 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, 2-oxazolyl, 4-oxazolyl, 4- oxo-2-oxazolyl, 5-oxazolyl, 1,2,3-oxathiazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 3-isothiazole, 4-isothiazole, 5-isothiazole, 2-furanyl, 3-furanyl, 2-thienyl, 3-thienyl, 2-pyrrolyl, 3- pyrrolyl, 3-isopyrrolyl, 4-isopyrrolyl, 5-isopyrrolyl, 1, 2,3, -oxathiazole-1 -oxide, 1,2,4- oxadiazol-3-yl, l,2,4-oxadiazol-5-yl, 5-oxo-l,2,4-oxadiazol-3-yl, l,2,4-thiadiazol-3- yl, l,2,5-thiadiazol-3-yl, l,2,4-thiadiazol-5-yl, 3-oxo-l,2,4-thiadiazol-5-yl, 1,3,4- thiadiazol-5-yl, 2-oxo-l,3,4-thiadiazol-5-yl, 1,2,3-triazole-l-yl, l,2,4-triazol-3-yl, l,2,4-triazol-5-yl, tetrazole- 1-yl, l,2,3,4-tetrazol-5-yl, 5-oxazolyl, 3-isothiazolyl, 4- isothiazolyl and 5-isothiazolyl, 1,3,4,-oxadiazole, 4-oxo-2-thiazolinyl, or 5-methyl- l,3,4-thiadiazol-2-yl, thiazoledione, 1,2,3,4-thiatriazole, or 1,2,4-dithiazolone. The term "a pharmaceutically acceptable salt" of a compound means a salt that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound. Such salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2- hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2- naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4- methylbicyclo[2.2.2]oct-2-ene-l-carboxylic acid, glucoheptonic acid, 4,4'- methylenebis-(3-hydroxy-2-ene-l-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like; or (2) salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, and the like. The term "pharmaceutically acceptable carrier" means a carrier that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes a carrier that is acceptable for veterinary use as well as human pharmaceutical use. "A pharmaceutically acceptable carrier" as used in the specification and claims includes both one and more than one such carrier. The term "mammal" refers to human or warm-blooded animals including livestock and companion animals. The term "optional" or "optionally" means that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not. Compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed "isomers". Isomers that differ in the arrangement of their atoms in space are termed "stereoisomers". Stereoisomers that are not mirror images of one another are termed "diastereomers" and those that are non-superimposable mirror images of each other are termed "enantiomers". When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible. An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or (-)-isomers respectively). A chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a "racemic mixture". The compounds of this invention may possess one or more asymmetric centers; such compounds can therefore be produced as individual (R)- or (S)- stereoisomers or as mixtures thereof. Unless indicated otherwise, the description or naming of a particular compound in the specification and claims is intended to include both individual enantiomers and mixtures, racemic or otherwise, thereof. The methods for the determination of stereochemistry and the separation of stereoisomers are well- known in the art (see discussion in Chapter 4 of "Advanced Organic Chemistry", 4th edition J. March, John Wiley and Sons, New York, 1992). The term "treating" or "treatment" of a disease includes: (1) preventing the disease, i.e. causing the clinical symptoms of the disease not to develop in a mammal that may be exposed to or predisposed to the disease but does not yet experience or display symptoms of the disease; (2) inhibiting the disease, i.e., arresting or reducing the development of the disease or its clinical symptoms; or (3) relieving the disease, i.e., causing regression of the disease or its clinical symptoms. The term "therapeutically effective amount" means the amount of a compound that, when administered to a mammal for treating a disease, is sufficient to effect such treatment for the disease. The "therapeutically effective amount" will vary depending on the compound, the disease and its severity and the age, weight, etc., of the mammal to be treated. The term "leaving group" has the meaning conventionally associated with it in synthetic organic chemistry i.e., an atom or group capable of being displaced by a nucleophile and includes halogen, alkylsulfonyloxy, ester, or arnino such as chloro, bromo, iodo, mesyloxy, tosyloxy, trifluorosulfonyloxy, methoxy, N,O- dimethylhydroxyl-amino, and the like. The compounds of the present invention are generally named according to the
IUPAC or CAS nomenclature system. Abbreviations which are well known to one of ordinary skill in the art may be used (e.g. "Ph" for phenyl, "Me" for methyl, "Et" for ethyl, "h" for an hour or hours and "rt" for room temperature). Specific and preferred values listed below for radicals, substituents, and ranges, are for illustration only; they do not exclude other defined values or other values within defined ranges for the radicals and substituents. Specifically, alkyl denotes both straight and branched groups; but reference to an individual radical such as "propyl" embraces only the straight chain radical, a branched chain isomer such as "isopropyl" being specifically referred to. Specifically, alkyl is methyl, ethyl, propyl, isopropyl, butyl, iso-butyl, sec- butyl, and their isomeric forms thereof. Specifically, alkyl is methyl, ethyl, propyl, isopropyl, butyl, iso-butyl, sec- butyl, and their isomeric forms thereof. Specifically, cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and their isomeric forms thereof. Specifically, halo is fluoro (F), chloro (CI). Specifically W is CH2NHC(=O)R1. Specifically, R1 is Ci-4alkyl, optionally substituted with one, two or three fluoro (F), or chloro (CI). Specifically, R1 is CH3, or CH2CH3.CHF2, CF3, or CHC12. Specifically, R1 is CHF2, CF3, or CHC12. Specifically, W is CH het. Specifically, W is 1,2,3-triazole-l-yl methyl, or tetrazole- 1-yl methyl. Specifically, Y1, Y2, or Y3 is CH. Specifically one of the Y1, Y2 and Y3 is N, the other two are CH. Specifically, Y1 is CF, Y2 and Y3 are CH. Specifically, G is CH2. Specifically, U is CH2. Specifically, U is O ir S. Specifically, R2 is CH3. Specifically, R2 is CH2F or CHF2. Specifically, V is N. Specifically, Z is CN. Specifically, Z is OCi.6alkyl, optionally substituted with OH, or O ^alkyl. Specifically, Z is
Figure imgf000010_0001
substituted with OCι- alkyl which may may be further substituted with a phenyl. Specifically, Z is OH or OCH3. Specifically, X is a structure of formula ii
11. Examples of the present invention include: a. (5S)-N-[3-(3-Methoxyimino-4-methyl-3,4-dihydro-2H-benzo[l,4]oxazin-7- yl)-2-oxo-oxazolidin-5-ylmethyl]-acetamide, b. (5S)-N-[3-(3-Methoxyimino-4-methyl-3, 4-dihydro-2H-benzo[l,4]oxazin-7- yl)-2-oxo-oxazolidin-5-ylmethyl]-propionamide, c. (5S)-N- [3-(3-Methoxyimino-4-methyl-3 , 4-dihydro-2H-benzo [ 1 ,4]oxazin-7- yl)-2-oxo-oxazolidin-5-ylmethyl]-carbamic acid methyl ester, d. (5S)-l-[3-(3- Methoxyimino-4-methyl-3,4-dihydro-2H-benzo[l,4]oxazin-7- yl)-2-oxo-oxazolidin-5-ylmethyl] -3 -methyl-urea, e. (5R)-4-Methyl-7-(2-oxo-5-[l,2,3]triazol-l-ylmethyl-oxazolidin-3-yl)-4H- benzo [1,4] oxazin-3-one O-methyl-1-oxime, f. (5S)-N-[3-(3-Ethoxyimino-4-methyl-3,4-dihydro-2H-benzo[l,4]oxazin-7-yl)- 2-oxo-oxazolidin-5-ylmethyl]-acetamide, g. (5S)-N-[3-(3-Hydroxyimino-4-methyl-3,4-dihydro-2H-benzo[l,4]oxazin-7-yl)- 2-oxo-oxazolidin-5-ylmethyl]-acetamide, h. (5S)-[3-(3-Hydroxyimino -4-methyl-3,4-dihydro-2H-benzo[l ,4]oxazin-7-yl)-
2-oxo-oxazolidin-5-ylmethyl]-carbamic acid methyl ester, i. (5S)-N-[3-(3-Isopropoxyimino-4-methyl-3,4-dihydro-2H-benzo[l,4]oxazin-7- yl)-2-oxo-oxazolidin-5-ylmethyl]-acetamide, j. (5S)-N-{3-[3-(2-Fluoro-ethoxyimino)-4-methyl-3,4-dihydro-2H- benzo [ 1 ,4] oxazin-7-yl)-2-oxo-oxazolidin-5-ylmethyl } -acetamide, k. (5S)-N- { 3-[3-(2-Methoxy-ethoxyimino)-4-methyl-3,4-dihydro-2H- benzo [ 1 ,4] oxazin-7-yl)-2-oxo-oxazolidin-5-ylmethyl } -acetamide, 1. (5S)-N-[3-(3-Methoxy-methoxyimino)-4-methyl-3,4-dihydro-2H- benzo[l,4]oxazin-7-yl)-2-oxo-oxazolidin-5-ylmethyl}-acetamide, m. (5S)-Ν-[3-(3-Cyclopropyl-methoxyimino)-4-methyl-3,4-dihydro-2H- benzo[l,4]oxazin-7-yl)-2-oxo-oxazolidin-5-ylmethyl}-acetamide, n. (5S)-N-[3-(3-Cyclohexyl-methoxyimino)-4-methyl-3,4-dihydro-2H- benzo [ 1 ,4] oxazin-7-yl)-2-oxo-oxazolidin-5-ylmethyl } -acetamide, o. (5S)-N-[3-(3-Cyclobutyl-methoxyimino)-4-methyl-3,4-dihydro-2H- benzo[l,4]oxazin-7-yl)-2-oxo-oxazolidin-5-ylmethyl}-acetamide, p. (5S)-N-{3-[3-(2-Dimethylamino-ethoxyimino)-4-methyl-3,4-dihydro-2H- benzo[ 1 ,4]oxazin-7-yl)-2-oxo-oxazolidin-5-ylmethyl } -acetamide, q. (5S)-N-{3-[3-(2-Benzyloxy-ethoxyimino)-4-methyl-3,4-dihydro-2H- benzo[ 1 ,4]oxazin-7-yl)-2-oxo-oxazolidin-5-ylmethyl }-acetamide, r. (5S)-N-{ 3-[3-(2-Hydroxy-ethoxyimino)-4-methyl-3,4-dihydro~2H- benzo[ 1 ,4]oxazin-7-yl)-2-oxo-oxazolidin-5-ylmethyl }-acetamide, s. (5S)-N-[3-(3-Hydroxyimino-4-methyl-3,4-dihydro-2H-benzo[l,4]thiazin-7-yl)-
2-oxo-oxazolidin-5-ylmethyl]-acetamide, t. (5S)-N-[3-(3-Methoxyimino-4-methyl-3,4-dihydro-2H-benzo[l,4]thiazin-7- yl)-2-oxo-oxazolidin-5-ylmethyl]-acetamide, u. (5S)-N-[3-(2-Hydroxyimino-l-methyl-l,2,3,4-tetrahydro-quinolin-6-yl)-2-oxo- oxazolidin-5-ylmethyl]-acetamide, v. (5S)-N-[3-(2-Methoxyimino-l-methyl-l,2,3,4-tetrahydro-quinolin-6-yl)-2-oxo- oxazolidin-5-ylmethyl]-acetamide, w. (5S)-N-[3-(2-Methoxyimino-l-methyl-l,2,3,4-tetrahydro-quinolin-6-yl)-2-oxo- oxazolidin-5-ylmethyl]-propionamide, x. (5S)-[3-(2-Methoxyimino-l-methyl-l,2,3,4-tetrahydro-quinolin-6-yl)-2-oxo- oxazolidin-5-ylmethyl] -carbamic acid methyl ester, y. (5S)-N-[3-(5-Fluoro-3-methoxyimino-4-methyl-3,4-dihydro-2H- benzo[l,4]oxazin-7-yl)-2-oxo-oxazolidin-5-ylmethyl]-acetamide, z. (5S)-l-[3-(5-Fluoro-3-methoxyimino-4-methyl-3,4-dihydro-2H- benzo [ 1 ,4] oxazin-7-yl)-2-oxo-oxazolidin-5-ylmethyl] -carbamic acid methyl ester, aa. [3-(3-Hydroxyimino -4-methyl-3,4-dihydro-2H-benzo[l,4]oxazin-7-yl)-2-oxo- oxazolidin-5-ylmethyl]-carbamic acid methyl ester, bb. 7-(5R-hydroxymethyl-2-oxo-oxazolidin-3-yl)-4-methyl-4H-benzo[l,4]oxazin-
3 -one O-methyl-oxime, or cc. (5S)-N-[3-(3-Cyanoimino-4-methyl-3,4-dihydro-2H-benzo[l ,4]oxazin-7-yl)-2- oxo-oxazolidin-5-ylmethyl]-acetamide. The compounds of this invention can be prepared in accordance with one or more of the Schemes discussed below. All of the starting materials are either commercially available or can be prepared by procedures that would be well known to one of ordinary skill in organic chemistry. The variables used in the Schemes are as defined below, or as in the summary of the invention or claims. Schemes I and II illustrate general synthetic routes to amidoxime derivatives.
SCHEME I
Figure imgf000013_0001
1a 1b 1c
Figure imgf000013_0002
1d 1e
As shown in Scheme I, an N-alkylated amino substituted 1,4-benzazinone (X =
CH2, O, S, SO, or SO2; R' = C^alkyl; R1, R2, Y1, Y2 and Y3 are as described previously), conveniently prepared as described by Bartel et al. in WO 9937641, is protected as a carbamate and converted to the thione using various thionation reagents, such as Lawesson, Davy, Yokahama or Belleau reagents, Na2P4Sπ,
Na2P4S10O, or alike known reagents capable of converting amides into thioamides. The reaction is most conveniently conducted using Lawesson' s reagent in a suitable organic solvent, such as dioxane or tetrahydrofuran, and is typically performed at temperatures in a range of from 25 °C to about 100 °C. Next, the intermediate thione compound lb is reacted with an alkxoyamine or a salt thereof such as methoxylamine hydrochloride and a suitable base at temperatures ranging from 25 °C to about 100 °C to give the desired benzazinone oxime intermediate lc. Solvents for this transformation may include pyridine, an alcohol such as methanol or ethanol, or dimethylformamide. Suitable bases include inorganic bases such as potassium carbonate or organic bases such as pyridine, triethylamine or N,N- diisopropylethylamine. The synthesis of Scheme I continues with construction of the requisite oxazolidinone substituent using known chemistry methods such as described in US Patent No. 6,107,519. It is further understood that the amidoxime syntheses described herein are generally applicable to amidoxime derivatives bearing other groups in place of the oxazolidinone substituent (such as isoxazoline, isoxazolinone, or butenolide groups). In the final step of the synthesis of Scheme I, the Boc-protected oxazolidinone derivatives Id can be deprotected to give the corresponding amine. It is convenient to remove the Boc group with 20 to 60% trifluoroacetic acid in dichloroethane or hydrogen chloride in dioxane at temperatures ranging from 0 °C to 24 °C. The synthesis is then completed by an acylation of the penultimate amine intermediate using known art. Thus, acylations can be routinely performed by reactions of the amines with carboxylic acid anhydrides or esters. These transformations are generally performed at 0°C to 50°C using polar solvents, such as acetonitrile, dimethylformamide, tetrahydrofuran, and methanol or mixtures thereof with optional apolar solvents, such as dichloromethane. These reactions are preferably conducted in presence of an organic or inorganic base, such as pyridine, triethylamine, or potassium carbonate. In this reaction it is often convenient to employ an excess of the tertiary amine base with the amine salt prepared by Boc deprotection without first isolating the free base. Solvents such as tetrahydrofuran, methylene chloride or preferably methanol and temperatures in the range of about 24°C to about 50°C can be used for this reaction. SCHEME π
Figure imgf000014_0001
As shown in Scheme U, the N-alkylated 1,4-benzazinone (X = CH2, O, S, SO, or SO2; R' = C1.4alkyl; R1, R2, Y1, Y2 and Y3 are as described previously) is converted to the Boc-protected oxazolidinone substituent 2b using known chemistry such as the methods described in US Patent publication No. 6,107,519. The compound 2b is then converted to the thione 2c using various thionation reagents, such as Lawesson, Davy, Yokahama or Belleau reagents, Na2P4Sπ, Na2P4S10O, or alike known reagents capable of converting amides into thioamides. The reaction is most conveniently conducted using Lawesson' s reagent in a suitable organic solvent, such as dioxane or tetrahydrofuran, and is typically performed at temperatures in a range of from 25 °C to about 100 °C. The Boc-protected oxazolidinone intermediate 2c is then deprotected to give the corresponding amine. It is convenient to remove the Boc group with 20 to 60% trifluoroacetic acid in dichloroethane or hydrogen chloride in dioxane at temperatures ranging from 0 °C to 24 °C. The amine intermediate is then acylated using known art to give 2d. Acylations can be routinely performed by reactions of the amines with carboxylic acid anhydrides or esters. These transformations are generally performed at 0°C to 50°C using polar solvents, such as acetonitrile, dimethylformamide, tetrahydrofuran, and methanol or mixtures thereof with optional apolar solvents, such as dichloromethane. These reactions are preferably conducted in presence of an organic or inorganic base, such as pyridine, triethylamine, or potassium carbonate. In this reaction it is often convenient to employ an excess of the tertiary amine base with the amine salt prepared by Boc deprotection without first isolating the free base. Solvents such as tetrahydrofuran, methylene chloride or preferably methanol and temperatures in the range of about 24°C to about 50°C can be used for this reaction. Next, the intermediate thione compound 2d is reacted with hydroxylamine or a salt thereof such as hydroxylamine hydrochloride and a suitable base, a protected source of hydroxylamine such as O-(trimethylsilyl)hydroxylamine or N,O-bis- (trimethylsilyl)hydroxylamine in a protic solvent to provide 2e. Solvents for this transformation may include pyridine, an alcohol such as methanol or ethanol, or dimethylformamide. Suitable bases include inorganic bases such as potassium carbonate or organic bases such as pyridine, triethylamine or N,N- diisopropylethylamine. In the final step of the synthesis of Scheme U, the amidoxime benzazinone oxazolidinone 2e may be converted to an amidoxime ether le by reaction with a suitable electrophilic alkylating agent such as an alkyl halide, sulfate or tosylate, or a reagent containing an electrophilic multiple bond such as acrylonitrile in the presence of a suitable inorganic or organic base, such as sodium hydride or lithium bis(trimethylsilyl)amide. Alternatively, the amidoxime benzazine oxazolidinone 2e may be acylated using known art to provide O-acyloximes 2f. Solvents for the transformations may include tetrahydrofuran or dimethylformamide, and the reaction is typically performed in the range of about 0 °C to about 80°C. Scheme HI illustrates one general synthetic route to amidoxime triazoloylmethyl oxazolidinone derivatives.
SCHEME HI
Figure imgf000016_0001
Figure imgf000016_0002
As shown in Scheme HI, the N-alkylated 1,4-benzazinone (X = CH2, O, S, SO, or SO2; R' = Cι. alkyl; R1, R2, Y1, Y2 and Y3 are as described previously) is converted to the azido oxazolidinone substituent 3c using the sequence of chemical transformations described by Brickner et al. in J. Med. Chem., 1996, vol. 39, pp. 673- 679. Cycloaddition of the intermediate azido compound with norbornadiene in a suitable solvent, such as dioxane at reaction temperatures in the range of about 50 °C to about 100°C affords the 1,2,3-triazolyl derivative. Scheme IN illustrates a general synthetic route to amidoxime isoxazolylaminomethyl and isoxazolyl ether oxazolidinone derivatives. SCHEME IV
Figure imgf000017_0001
In Scheme IV, C-5 hydroxymethyl amidoxime derivatives of Scheme HJ can be further converted to heteroaryl amine analogs using chemistry described for non- amidoxime compounds by Perova et al. in Zh. Org. Khim. 1994, vol. 30, pp.1660- 1663 and the methods described in PCT publication WO 9964417. In these procedures the hydroxymethyl amidoxime benzazine derivative 3b is coupled with an appropriate amino-isoxazole or hydroxy-isoxazole, for example 3-(2,2,2- trichloroethoxycarbonyl-amino)isoxazole (may be prepared as described in PCT publication WO 0021960) or 3-hydroxyisoxazole (may be prepared as described in US Patent 3,687,968). These reactions can be performed with a suitable coupling reagent, such as diisopropylazo-dicarboxylate (DIAD). The coupling reaction is typically conducted in a polar aprotic solvent, such as dimethylformamide, acetonitrile, tetrahydrofuran, or mixtures thereof, in the presence of organic base, such as triphenylphosphine. The process is typically carried out at about 0 to about 50. When coupling to an amino-isoxazole, the resulting carbamic acid intermediate can then be reduced to the heteroaryl amine 4b. Schemes V and VI illustrate general synthetic routes to cyanoimine and nitromethylene benzazine oxazolidinone derivatives.
SCHEME V
Figure imgf000017_0002
Figure imgf000017_0003
In Scheme V, the appropriately substituted thiono benzazine intermediate 2c described previously above is reacted with an alkylating agent such as methyl trifluoromethanesulfonate or a trialkyloxonium salt, such as trimethyloxonium tetrafluoroborate in a suitable solvent, such as dichloromethane or dimethoxyethane at temperatures ranging from 0 °C to about 24 °C. The S-alkylated compound 5a is then treated with cyanamide in the presence of an organic base, such as lithium bis(trimethylsilyl)amide or lithium dicyclohexylamide to give the cyanoimine derivative 5b. The Boc-protected oxazolidinone intermediate is then deprotected to give the corresponding amine that can be acylated under conditions discussed previously.
SCHEME VI
Figure imgf000018_0001
In Scheme VI, the S-alkylated compound 5a from Scheme V is treated with nitromethane in the presence of an organic base, such as lithium bis(trimethylsilyl)amide or lithium dicyclohexylamide to give the nitromethylene derivative 6a. The Boc-protected oxazolidinone intermediate is then deprotected to give the corresponding amine which is acylated under conditions discussed previously to provide the desired final product 6b. SCHEME Nπ
Figure imgf000019_0001
In Scheme Nil, the S-alkylated compound 5a from Scheme N is treated with ammonia in a suitable solvent such as methanol, dioxane or water at temperatures ranging from 0 ° C to about 80 ° C to give the imino Boc-protected oxazolidinone intermediate 7a. Deprotection and acylation under conditions discussed previously provides amidino derivative 7b. Using the similar comditions and procedures, 7a may be reacted with an alkyl, het or aryl amine to provide the desired compounds 7c (R" = alkyl, het or aryl).
SCHEME Nm
Figure imgf000019_0002
Z' = N02, alkyl. -S02-alkyl, -S02NR5R6, or -C(=0)NR5R6 Utilizing procedures known to those skilled in the art, nitration of amidino derivative 7a provides nitroamidino derivative 8a. Alternatively, 7a may be acylated or sulfonylated to provide amidino amide, or sulfonamide derivative as shown in
Scheme VIE. Schemes IX-XII describe the synthesis of aryl isoxazolinone, aryl isoxazoline and aryl butyrolactones bearing amidoxime groups. SCHEME IX AmIk
Figure imgf000020_0001
9b 9c
Figure imgf000020_0002
Scheme IX describes the synthesis of aryl isoxazolinone amidoximes.
Benzoxazinone aldehyde (X = O) intermediates 9a may be prepared following methods described by Petrov, et al. in Collect. Czech. Chem. Commun., 1997, vol. 62(3), pp. 494-497. Benzothiazinone (X = S) and dihydroquinolinone (X = CH2) aldehyde intermediates may be prepared by similar known methods. The aldehyde group is conveniently protected as an acetal or other suitable protecting group and the benzazinone converted to the thione using various thionation reagents as previously described. The intermediate thione compound 9c is reacted with an alkoxyamine or a salt thereof as described previously to give the desired benzazinone oxime intermediate 9d. The acetal protecting group is removed using various reaction conditions that are well known in the art (see "Protecting Groups" by Philip J. Kocienski; publisher : Georg Thieme Nerlag: Stuttgart, 1994). Benzaldehyde intermediate 9e may be reacted with ethyl diazoacetate (as described by Mahmood, et al. in J. Org. Chem., 1998, Vol. 63, pp. 3333-3336) to provide ester aldehyde intermediate If. Addition of hydroxylamine, followed by warming to reflux in a suitable solvent such as aqueous methanol, yields the desired isoxazolinone 9g. This intermediate is then converted to the corresponding methylacetamide 9h by reaction with Ν-(hydroxymethyl)acetamide acetate (prepared as described by Barnes et al. in US Patent 5,284,863) in a polat aprotic solvent such as dimethylformamide. SCHEME X
Figure imgf000021_0001
10c 10d
Scheme X describes the synthesis of aryl isoxazoline amidoximes. Aldehyde 9e is reacted with hydroxylamine hydrochlori.de in a polar protic solvent, such as methanol, in the presence of a base, such as pyridine, to afford oxime 10a. The oxime is oxidized with N-chlorosuccinimide in a suitable solvent, such as dichloromethane, to give the intermediate N-hydroxyoximidoyl chloride 10b. The N-hydroxyoximidoyl chloride is reacted with an allylic compound such as allyl alcohol or N-acetylamine, in the presence of a base, such as triethylamine, in a solvent such as dichloromethane, to provide the hydroxymethyl or acetamidomethyl substituted isoxazolines. Hydroxymethyl intermediate 10c may be converted to compounds lOd in which Z is a group other than NH(C=O)Me or to a heterocyclic substituent (Z = NH-het1, O-het1, S-het1 or het2) by methods known in the art.
SCHEME XI
Figure imgf000021_0002
9e 11a 11b
Figure imgf000021_0003
11c 11d Scheme II describes the synthesis of aryl butyrolactone amidoximes. Aldehyde intermediate 9e is conveniently converted to phenyl acetic acid intermediate 11a following methods described by Hester, et al. in US Patent 5,708,169. The synthesis of the saturated and unsaturated 3-arylbutyrolactone system parallels that described in Biorganic & Medicinal Chemistry Letters, 1994, Vol. 4, No. 16, pp. 1925-1930. The lithiated dianion of the phenyl acetic acid intermediate 11a is reacted with R-benzyloxymethyloxirane in THF. The resulting D-hydroxyacid is cyclized with catalytic p-toluenesulfonic acid to provide lactone lib as a mixture of diastereomers. The Z-group functionality may be introduced by a known sequence of hydrogenolytic benzyl deprotection, mesylate formation, nucleophilic substitution by azide ion, hydrogenolytic reduction and acetyl formation with acetic anhydride. Alternatively, heterocyclic substituents (Z = NH-het1, O-het1, S-het1 or het2) may be introduced from appropriate intermediates by methods known in the art. The saturated butyrolactone is then brominated with N-bromosuccinimde, and the double bond introduced by elimination with pyridine in a suitable solvent such as pyridine to provide lid. Medical and Veterinary Uses The compounds of the present invention may be used for the treatment of infectious diseases caused by a variety of bacterial organisms. Examples include gram-positive bacteria such as multiple resistant staphylococci, for example S. aureus and S. epidermidis; multiple resistant streptococci, for example S. pneumoniae and S. pyogenes; and multiple resistant Enterococci, for example E. faecalis; gram negative aerobic bacteria such as Haemophilus, for example H. influenzae and Moraxella, for example M. catarrhalis; as well as anaerobic organisms such as bacteroides and clostridia species, and acid- fast organisms such as Mycobacteria, for example M. tuberculosis; and/or Mycobacterium avium. Other examples include Escherichia, for example E. coli. intercellular microbes, for example Chlamydia and Rickettsiae. Examples of infections that may be treated with the compounds of the present invention include central nervous system infections, external ear infections, infections of the middle ear, such as acute otitis media, infections of the cranial sinuses, eye infections, infections of the oral cavity, such as infections of the teeth, gums and mucosa, upper respiratory tract infections, lower respiratory tract infections, genitourinary infections, gastrointestinal infections, gynecological infections, septicemia, bone and joint infections, skin and skin structure infections, bacterial endocarditis, burns, antibacterial prophylaxis of surgery, and antibacterial prophylaxis in immunosuppressed patients, such as patients receiving cancer chemotherapy, or organ transplant patients. Specifically, infectious diseases that may be treated with the compounds of the present invention are gram-positive infections such as osteomyelitis, endocarditis and diabetic foot. Antibacterial activity The in vitro antibacterial activity of the compounds of the present invention may be assessed by following procedures recommended in (1) National Committee for Clinical Laboratory Standards (Jan. 2003), Methods for dilution antimicrobial tests or bacteria that grow aerobically, Approved Standard (6th ed), M7-A6, NCCLS, Wayne, PA; (2) National Committee for Clinical Laboratory Standards (Mar. 2001), Methods for antimicrobial susceptibility testing of anaerobic bacteria, Approved Standard (5th ed), Ml 1-A4, NCCLS, Wayne, PA; (3) National Committee for Clinical Laboratory Standards (Jan.2003), MIC testing supplemental tables, M100-S13 (for use with M7-A6), NCCLS, Wayne, PA; and (4) Murray PR, Baron EJ, Jorgensen JH, et al. Manual of Clinical Microbiology (8th ed) Washington, DC: American Society for Microbiology Press, 2003. The antibacterial activity is presented in Table 1 in the form of MIC value (Minimum Inhibitory concentrations). The MIC value is the lowest concentration of drug which prevented macroscopically visible growth under the conditions of the test.
Figure imgf000023_0001
Routes of Administration In therapeutic use for treating, or combating, bacterial infections in a mammal (i.e. human and animals) an oxazolidinone prodrug of the present invention or its pharmaceutical compositions can be administered orally, parenterally, topically, rectally, transmucosally, or intestinally. Parenteral administrations include indirect injections to generate a systemic effect or direct injections to the afflicted area. Examples of parenteral administrations are subcutaneous, intravenous, intramuscular, intradermal, intrathecal, intraocular, intranasal, intravetricular injections or infusions techniques. Topical administrations include the treatment of infectious areas or organs readily accessibly by local application, such as, for example, eyes, ears including external and middle ear infections, vaginal, open wound, skins including the surface skin and the underneath dermal structures, or other lower intestinal tract. It also includes transdermal delivery to generate a systemic effect. The rectal administration includes the form of suppositories. The transmucosal administration includes nasal aerosol or inhalation applications. The preferred routes of administration are oral and parenteral. Composition/Formulation Pharmaceutical compositions of the present invention may be manufactured by processes well known in the art, e.g., by means of conventional mixing, dissolving, granulation, dragee-making, levigating, emulsifying, encapsulating, entrapping, lyophilizing processes or spray drying. Pharmaceutical compositions for use in accordance with the present invention may be formulated in conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. For oral administration, the compounds can be formulated by combining the active compounds with pharmaceutically acceptable carriers well known in the art. Such carriers enable the compounds of the invention to be formulated as tablets, pills, lozenges, dragees, capsules, liquids, solutions, emulsions, gels, syrups, slurries, suspensions and the like, for oral ingestion by a patient. A carrier can be at least one substance which may also function as a diluent, flavoring agent, solubilizer, lubricant, suspending agent, binder, tablet disintegrating agent, and encapsulating agent. Examples of such carriers or excipients include, but are not limited to, magnesium carbonate, magnesium stearate, talc, sugar, lactose, sucrose, pectin, dextrin, mannitol, sorbitol, starches, gelatin, cellulosic materials, low melting wax, cocoa butter or powder, polymers such as polyethylene glycols and other pharmaceutical acceptable materials. Dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions may be used which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses. Pharmaceutical compositions which can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. The push-fit capsules can contain the active ingredients in admixture with a filler such as lactose, a binder such as starch, and/or a lubricant such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, liquid polyethylene glycols, cremophor, capmul, medium or long chain mono-, di- or triglycerides. Stabilizers may be added in these formulations, also. Liquid form compositions include solutions, suspensions and emulsions. For example, there may be provided solutions of the compounds of this invention dissolved in water and water-propylene glycol and water-polyethylene glycol systems, optionally containing suitable conventional coloring agents, flavoring agents, stabilizers and thickening agents. The compounds may also be formulated for parenteral administration, e.g., by injections, bolus injection or continuous infusion. Formulations for parenteral administration may be presented in unit dosage form, e.g., in ampoules or in multi- dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulating materials such as suspending, stabilizing and/or dispersing agents. For injection, the compounds of the invention may be formulated in aqueous solution, preferably in physiologically compatible buffers or physiological saline buffer. Suitable buffering agents include trisodium orthophosphate, sodium bicarbonate, sodium citrate, N-methylglucamine, L(+)-lysine and L(+)-arginine. Parenteral administrations also include aqueous solutions of a water soluble form, such as, without limitation, a salt, of the active compound. Additionally, suspensions of the active compounds may be prepared in a lipophilic vehicle. Suitable lipophilic vehicles include fatty oils such as sesame oil, synthetic fatty acid esters such as ethyl oleate and triglycerides, or materials such as liposomes. Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers and/or agents that increase the solubility of the compounds to allow for the preparation of highly concentrated solutions. Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, e.g., sterile, pyrogen-free water, before use. For suppository administration, the compounds may also be formulated by mixing the agent with a suitable non-irritating excipient which is solid at room temperature but liquid at rectal temperature and therefore will melt in the rectum to release the drug. Such materials include cocoa butter, beeswax and other glycerides. For administration by inhalation, compounds of the present invention can be conveniently delivered through an aerosol spray in the form of solution, dry powder, or suspensions. The aerosol may use a pressurized pack or a nebulizer and a suitable propellant. In the case of a pressurized aerosol, the dosage unit may be controlled by providing a valve to deliver a metered amount. Capsules and cartridges of, for example, gelatin for use in an inhaler may be formulated containing a power base such as lactose or starch. For topical applications, the pharmaceutical composition may be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers. Carriers for topical administration of the compounds of this invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water. Alternatively, the pharmaceutical compositions can be formulated in a suitable lotion such as suspensions, emulsion, or cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, ceteary alcohol, 2-octyldodecanol, benzyl alcohol and water. For ophthalmic and otitis uses, the pharmaceutical compositions may be formulated as micronized suspensions in isotonic, pH adjusted sterile saline, or preferably, as solutions in isotonic, pH adjusted sterile saline, either with or without a preservative such as a benzylalkonium chloride. Alternatively, for ophthalmic uses, the pharmaceutical compositions may be formulated in an ointment such as petrolatum. In addition to the formulations described previously, the compounds may also be formulated as depot preparations. Such long acting formulations may be in the form of implants. A compound of this invention may be formulated for this route of administration with suitable polymers, hydrophobic materials, or as a sparing soluble derivative such as, without limitation, a sparingly soluble salt. Additionally, the compounds may be delivered using a sustained-release system. Various sustained-release materials have been established and are well known by those skilled in the art. Sustained-release capsules may, depending on their chemical nature, release the compounds for 24 hours or for up to several days. Dosage Pharmaceutical compositions suitable for use in the present invention include compositions wherein the active ingredients are contained in an amount sufficient to achieve the intended purpose, i.e., the treatment or prevent of infectious diseases. More specifically, a therapeutically effective amount means an amount of compound effective to prevent, alleviate or ameliorate symptoms of disease or prolong the survival of the subject being treated. The quantity of active component, that is the compound of this invention, in the pharmaceutical composition and unit dosage form thereof may be varied or adjusted widely depending upon the manner of administration, the potency of the particular compound and the desired concentration. Determination of a therapeutically effective amount is well within the capability of those skilled in the art. Generally, the quantity of active component will range between 0.5% to 90% by weight of the composition. Generally, a therapeutically effective amount of dosage of active component will be in the range of about 0.1 to about 400 mg/kg of body weight/day, more preferably about 1.0 to about 50 mg/kg of body weight/day. It is to be understood that the dosages may vary depending upon the requirements of each subject and the severity of the bacterial infection being treated. In average, the effective amount of active component is about 200 mg to 800 mg and preferable 600 mg per day. The desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example, as two, three, four or more sub-doses per day. The sub-dose itself may be further divided, e.g., into a number of discrete loosely spaced administrations; such as multiple inhalations from an insufflator or by application of a plurality of drops into the eye. Also, it is to be understood that the initial dosage administered may be increased beyond the above upper level in order to rapidly achieve the desired plasma concentration. On the other hand, the initial dosage may be smaller than the optimum and the daily dosage may be progressively increased during the course of treatment depending on the particular situation. If desired, the daily dose may also be divided into multiple doses for administration, e.g., two to four times per day. In cases of local administration or selective uptake, the effective local concentration of the drug may not be related to plasma concentration and other procedures know in the art may be used to determine the desired dosage amount. EXAMPLES In the discussion above and in the examples below, the following abbreviations have the following meanings. If an abbreviation is not defined, it has its generally accepted meaning. bm = broad multiplet BOC = tert-butoxycarbonyl bd = broad doublet bs = broad singlet CDI = 1 , 10-carbodiimidazole d = doublet dd = doublet of doublets dq = doublet of quartets dt = doublet of triplets DMF = dimethylformamide DMAP = dimethylaminopyridine DMSO — dimethyl sulfoxide eq. = equivalents g = grams h = hours HPLC = high pressure liquid chromatography
HATU N-[(dimethylamino)-lH-l,2,3-triazolo-[4,5-b]pyridin- 1 -yl-methylene] -N-methylmethanaminium hexafluorophosphate N-oxide
LG = leaving group m = multiplet
M = molar
M% = mole percent max = maximum meq milliequivalent mg milligram mL milliliter mm millimeter mmol millimol q quartet s singlet t or tr triplet
TBS tributylsilyl
TFA trifluoroacetic acid
THF tetrahydrofuran
TLC thin layer chromatography p-TLC preparative thin layer chromatography μL microliter
N normality
MeOH methanol
DCM dichloromethane
HC1 hydrochloric acid
ACN acetonitrile
MS mass spectrometry rt room temperature
EtOAc ethyl acetate
EtO ethoxy
Ac acetate
NMP 1 -methyl-2-pyrrolidinone μL microliter
J coupling constant
NMR Nuclear magnetic resonance
MHz megahertz
Hz hertz m/z mass to charge ratio min minutes
Boc tert-butoxycarbonyl
CBZ benzyloxycarbonyl
DCC 1 ,3-dicyclohexylcarbodiimide
PyBop benzotriazole- 1 -yl-oxy-trispyrrolidinophosphonium hexafluorophosphate EXAMPLE 1 Preparation of (5S)-N-[3-(3-Methoxyimino-4-methyl-3,4- dihydro-2H-benzo [ 1 ,4] oxazin-7-yl)-2-oxo-oxazolidin-5-ylmethyl] -acetamide.
Figure imgf000030_0001
Step 1: Preparation of 7-nitro-4H-benzo[l,4]oxazin-3-one. Methyl bromoacetate (7.17 g, 0.078 M), 2-amino-5-nitrophenol (10 g, 0.065 M) and potassium carbonate (23 g, 0.162 M) in DMF (30 ml) are heated at 90 °C for 24 h. The reaction mixture is allowed to cool and diluted with water. The resulting precipitate is collected by filtration and dried under vacuum to give the title compound as a brown solid. (11.5g, 91%); HPLC r.t. 4.23 rnin.
Step 2: Preparation of 4-methyl-7-nitro-4H-benzo[l,4]oxazin-3-one. 7-Νitro-4H-benzo[l,4]oxazin-3-one (6.0 g, 0.031 mol), iodomethane (5.8 ml, 0.093 mol) and potassium carbonate (4.3 g, 0.031 mol) in DMF (30 ml) are stirred for 24 h at room temperature. The reaction mixture is diluted with ethyl acetate, washed with water and brine, dried (Na2SO4) and evaporated to give the title compound as a brown solid (6.2 g, 96.8%); HPLC r.t. 4.78 rnin.
Step 3: Preparation of 7-amino-4-methyl-4H-benzo[l,4]oxazin-3-one. Iron powder (6.45 g, 0.11 mol) is added in small portions to 4-methyl-7-nitro- 4H-benzo[l,4]oxazin-3-one (6.0 g, 0.0288 mol) and ammonium chloride (15.4 g, 0.288 mol) in ethanol (150 ml) and water (75 ml) at 90 °C. The reaction mixture is stirred vigorously and heated for 1 hour, allowed to cool to room temperature, and diluted with dichloromethane (500 ml). The mixture is filtered through celite, washed with water and brine, dried (Na SO ) and evaporated to give the title compound as a brown solid (5.0 g, 97%); HPLC R.T. 2.10 rnin; MS (m/z): [M+H]+ =179.2.
Step 4: Preparation of (4-methyl-3-oxo-3,4-dihydro-2H-benzo[l,4]oxazin-7-yl)- carbamic acid benzyl ester. Benzyl chloroformate (4.37ml, 0.031M) is added dropwise to 7-amino-4- methyl-4H-benzo[l,4]oxazin-3-one (5.0g, 0.028M) and pyridine (4.53ml, 0.056M) in dichloromethane (50ml) at 0 °C. The reaction mixture is stirred at 0 °C for 30 rnin, allowed to warm at room temperature and then diluted with water. The organic layer is separated, washed with brine, dried (Na2SO ) and evaporated to give the title compound as a brown solid (8.2g, 93.6%); HPLC r.t. 5.5min; MS (m/z): [M+H]+ =313.0.
Step 4: Preparation of (4-methyl-3-thioxo-3,4-dihydro-2H-benzo[l,4]oxazin-7-yl)- carbamic acid benzyl ester. 4-Methyl-3-oxo-3,4-dihydro-2H-benzo[l,4]oxazin-7-yl)-carbamic acid benzyl ester (6.5 g, 0.0208 mol) and Lawesson's reagent (6.33 g, 0.0156 mol) in dioxane (50 ml) are heated overnight at 70 °C. The solvent is removed under vacuum and the residue triturated with dichloromethane. The resulting yellow solid is filtered and dried under vacuum (5.9 g, 86 %); HPLC r.t. 6.44 rnin; MS (m z): [M+H]+ =329.2.
Step 5: Preparation of (3-methoxyimino-4-methyl-3,4-dihydro-2H-benzo[l,4]oxazin-
7-yl)-carbamic acid benzyl ester. 4-Methyl-3-thioxo-3,4-dihydro-2H-benzo[l,4]oxazin-7-yl)-carbamic acid benzyl ester (1.0 g, 3.04 mmol) and methoxylamine hydrochloride (1.04 g, 12.45 mmol) in pyridine (15 ml) are heated overnight at 70 °C. The reaction mixture is evaporated, diluted with ethyl acetate, washed with water and brine, dried (Na SO ) and evaporated to give the title compound as a light brown solid (1.0 g, 96%); HPLC r.t. 6.30 rnin; MS for C18H19N3O4 m/z 342.0(M+H)+.
Step 6: Preparation of (5S)-[3-(3-methoxyimino-4-methyl-3,4-dihydro-2H-benzo [1,4] oxazin-7-yl)-2-oxo-oxazolidin-5-ylmethyl]-carbamic acid tert-butyl ester. Lithium t-butoxide (1.0 M solution in THF, 4.38 ml, 4.38 mmol) is added at 0 °C to 3-methoxyimino-4-methyl-3, 4-dihydro-2H-benzo[l,4]oxazin-7-yl)-carbamic acid benzyl ester (0.5 g, 1.46 mmol) and (3-chloro-2-hydroxy-propyl)-carbamic acid tert-butyl ester (0.45 g, 2.2 mmol) in DMF (5 ml). The reaction mixture is allowed to warm at room temperature and stirred for 24h. The reaction is quenched with saturated aqueous ammonium chloride, diluted with water and extracted with dichloromethane. The organic layer is washed with brine, dried (Na2SO4) and evaporated. The residue is purified by flash column chromatography (40% EtOAc/Hexane) to give the title compound (0.475 g, 80%); HPLC r.t. 5.62 rnin; MS for C19H26N4O6 m z 407.1(M+H)+.
Step 7: Preparation of (5R)-7-(5-aminomethyl-2-oxo-oxazolidin-3-yl)-4-methyl-4H- benzo[l,4]oxazin-3-one O-methyl-oxime. 3-(3-Methoxyimino-4-methyl-3 ,4-dihydro-2H-benzo [ 1 ,4]oxazin-7-yl)-2-oxo- oxazolidin-5-ylmethyl]-carbamic acid tert-butyl ester (0.35 g, 0.86 mmol) is stirred with 50% TFA/DCM (4 ml) for 1 h at room temperature. The solvent is evaporated to give the title compound as the TFA salt (0.36 g, 99%); HPLC r.t. 3.54 min; MS for C14H18N4O4 m/z 307.0(M+H)+.
Step 8: Preparation of (5S)-N-[3-(3-methoxyimino-4-methyl-3,4-dihydro-2H- benzo[ 1 ,4] oxazin-7-yl)-2-oxo-oxazolidin-5-ylmethyl] -acetamide. Acetic anhydride (0.163 ml, 1.71 mmol) is added dropwise at 0 °C to (5R)-7- (5-aminomethyl-2-oxo-oxazolidin-3-yl)-4-methyl-4Η-benzo[l ,4]oxazin-3-one O- methyl-oxime (0.35 g, 1.14 mmol) and diisopropylethylamine (0.6 ml, 3.42 mmol) in dichloromethane (5 ml). The reaction mixture is stirred at 0 °C for 30 min. then allowed to warm at room temperature. The reaction mixture is diluted with dichloromethane, washed with water, citric acid and brine, dried (Νa2SO4) and evaporated to give the title compound as an off white solid (0.3 g, 75%); HPLC r.t.
4.16 min; 1H NMR (300 MHz, DMSO-ig) δ 8.23 (t, 1H), 7.20-7.00 (m, 3H), 4.91 (s, 2H), 4.71-4.63 (m, 1H), 4.05 (t, 1H), 3.69-3.64 (m, 4H), 3.38 (t, 1H), 3.22 (s, 3H),
3.17 (s, 3H), 1.82 (s, 3H); MS for C16H20N4O5 m/z 349.0(M+H)+.
EXAMPLE 2 Preparation of (5S)-N-[3-(3-Methoxyimino-4-methyl-3, 4- dihydro-2H-benzo[l,4]oxazin-7-yl)-2-oxo-oxazolidin-5-ylmethyl]-propionamide.
Figure imgf000032_0001
Propionic anhydride (0.295 ml, 2.28 mmol) is added at 0 °C to (5R)-7-(5- aminomethyl-2-oxo-oxazolidin-3-yl)-4-methyl-4H-benzo[l,4]oxazin-3-one O-methyl- oxime (Example 1, Step 7, 0.35 g, 1.14 mmol) and diisopropylethylamine (0.6 ml,
3.42 mmol) in dichloromethane (5 ml). The reaction mixture is allowed to warm at room temperature and stirred for 1 h. The reaction mixture is diluted with dichloromethane, washed with water, citric acid and brine, dried (Na2SO ), and evaporated to give the title compound as an off white solid (0.3 g, 72%); HPLC r.t. 4.38 min; 1H NMR (300 MHz, DMSO-^ δ 8.16 (t, IH), 7.20-7.00 (m, 3H), 4.92 (s, 2H), 4.70-4.66 (m, IH), 4.05 (t, IH), 3.68 (dd, IH), 3.39 (m, 2H), 3.17 (s, 3H), 2.09 (q, 2H), 0.95 (t, 3H); MS for C17H22N O5 m/z 363.2(M+H)+.
EXAMPLE 3 Preparation of (5S)-N-[3-(3-Methoxyimino-4-methyl-3, 4- dihydro-2H-benzo[l,4]oxazin-7-yl)-2-oxo-oxazolidin-5-ylmethyl]-carbamic acid methyl ester.
Figure imgf000033_0001
Methyl chloroformate (0.177 ml, 2.28 mmol) is added at 0 °C to 7-(5- aminomethyl-2-oxo-oxazolidin-3 -yl)-4-methyl-4H-benzo [ 1 ,4] oxazin-3 -one O-methyl- oxime (Example 1, Step 7, 0.35 g, 1.14 mmol) and diisopropylethylamine (0.6 ml, 3.42 mmol) in dichloromethane (5 ml). The reaction mixture is allowed to warm at room temperature and stirred for 1 h. The reaction mixture is diluted with dichloromethane, washed with water, citric acid and brine, dried (Νa2SO ), and evaporated to give the title compound as an off white solid solid (0.31 g, 74%); HPLC r.t. 4.61 min; 1H NMR (300 MHz, DMSO-^ δ 7.52 (t, IH), 7.20-7.01 (m, 3H), 4.91 (s, 2H), 4.69-4.64 (m, IH), 4.06 (t, IH), 3.91 (dd, IH), 3.68 (s, 3H), 3.53 (s, 3H), 3.38 (m, 2H), 3.17 (s, 3H); MS for Cι6H20N4O6 m/z 365.1(M+H)+.
EXAMPLE 4 Preparation of (5S)-l-[3-(3- Methoxyimino-4-methyl-3,4- dihydro-2H-benzo[l,4]oxazin-7-yl)-2-oxo-oxazolidin-5-ylmethyl]-3-methyl-urea.
Figure imgf000033_0002
Methyl isocyanate (0.036 ml, 0.636 mmol) was added to (5R)-7-(5-aminomethyl-2- oxo-oxazolidin-3-yl)-4-methyl-4H-benzo [1,4] oxazin-3-one O-methyl-oxime (Example 1, Step 7, 0.134 g, 0.318 mmol) and diisopropylethylamine (0.33ml, 1.908mmol) in dichloromethane (5ml) at 0 °C. The mixture was allowed to warm at room temperature and stirred for 1 hour. The reaction was diluted with dichloromethane, washed with water, citric acid and brine, dried (Na2SO4) and evaporated to give product as an off white solid (0.10 g, 87%); HPLC r.t. 4.07 min; 1H NMR (300 MHz, CDCl3-d) δ 7.11 (dd, J = 2.4, 14.4 Hz, IH), 6.86 (dd, J = 1.8, 2.7 Hz, IH), 5.16 (t, IH), 4.88 (s, 2H), 4.70-4.79 (m, IH), 3.98 (t, J = 8.7 Hz, IH), 3.78 (s, 3H), 3.68 (s, 3H), 3.47-3.75 (m, 3H), 3.36 (d, J = 4.8 Hz, 3H); MS for C16H21N5O5 m/z 364.4(M+H)+.
EXAMPLE 5 Preparation of (5R)-4-Methyl-7-(2-oxo-5-[l,2,3]triazol-l- ylmethyl-oxazolidin-3-yl)-4H-benzo [1,4] oxazin-3-one O-methyl-1 -oxime.
Figure imgf000034_0001
Step 1: Preparation of 7-(5-hydroxymethyl-2-oxo-oxazolidin-3-yl)-4-methyl-4H- benzo[l ,4]oxazin-3-one O-methyl-oxime. Lithium bis(trimethylsilyl)amide (1.0 M in THF, 3.21 ml, 0.00321 mol) is added dropwise at -78 °C to (3-methoxyimino-4-methyl-3,4-dihydro-2H- benzo[l,4]oxazin-7-yl)-carbamic acid benzyl ester (1.0 g, 0.00292 mol) in THF (10 ml). The reaction mixture is stirred at -78 °C for lh and then (R)-glycidyl butyrate (0.46 ml, 0.00321 mol) added dropwise. The mixture is allowed to warm to room temperature and stirred overnight. The reaction is quenched with saturated ammonium chloride, diluted with water and extracted with ethyl acetate. The extract is washed with water and brine, dried (Na SO4) and evaporated to give the title compound as crude product. Trituration with dichloromethane/hexane to gave product as a light brown solid (0.65 g, 72%); HPLC r.t. 4.18 min; MS for C14Hι7N3O5 m/z 308.0(M+H)+.
Step 2: Preparation of (5R)-methanesulfonic acid 3-(3-methoxyimino-4-methyl-3,4- dihydro-2H-benzo[l,4]oxazin-7-yl)-2-oxo-oxazolidin-5-ylmethyl ester. Methanesulfonyl chloride (0.162 ml, 2.1 mmol) is added dropwise at 0 °C to
(5R)-7-(5-hydroxymethyl-2-oxo-oxazolidin-3-yl)-4-methyl-4H-benzo[l,4]oxazin-3- one O-methyl-oxime (0.615 g, 2.0 mmol) and triethylamine (0.418 ml, 3.0 mmol) in dichloromethane (10 ml). The reaction mixture is stirred at 0 °C for 30 min, allowed to warm to room temperature and then diluted with water. The organic layer is separated, washed with water, sat. aq. sodium bicarbonate and brine, dried (Na2SO ) and evaporated to give the title compound as a brown solid (0.7 g, 90.7%); HPLC r.t. 4.93 min; MS for C14Hι6ClN3O7S m/z 386.1(M+H)+.
Step 3: Preparation of (5R)-7-(5-azidomethyl-2-oxo-oxazolidin-3-yl)-4-methyl-4H- benzo[l,4]oxazin-3-one O-methyl-oxime. (5R)-Methanesulf onic acid 3 -(3 -methoxyimino-4-methyl-3 ,4-dihydro-2H- benzo[l,4]oxazin-7-yl)-2-oxo-oxazolidin-5-ylmethyl ester (0.68 g, 1.76 mmol) and sodium azide (0.573 g, 8.82 mmol) in DMF (10 ml) are heated overnight at 70 °C. The reaction mixture is cooled, diluted with water and extracted with ethyl acetate. The organic extract is washed with water and brine, dried (Na2SO4) and evaporated. The residue is purified by flash column chromatography to give the title compound as a yellow solid (0.4 g, 68%); HPLC r.t. 5.36 min; MS for C14Hι6N6O4 m/z 333.3(M+H)+.
Step 4: Preparation of (5R)-4-methyl-7-(2-oxo-5-[l,2,3]triazol-l-ylmethyl- oxazolidin-3-yl)-4H-benzo [ 1 ,4]oxazin-3-one O-methyl- 1 -oxime. (5R)-7-(5-Azidomethyl-2-oxo-oxazolidin-3-yl)-4-methyl-4H- benzo[l,4]oxazin-3-one O-methyl-oxime (0.34 g, 1.02 mmol) and bicyclo[2,2,l]hepta-2,5-diene (0.222 ml, 2.05 mmol) in dioxane (5 ml) are heated at 100 °C for 8 hour. The reaction mixture is evaporated and the resideue purified by PTLC (10% MeOH/DCM) to give the title compound as an off white solid (0.11 g, 30%); HPLC r.t. 4.35 min; 1H NMR (300 MHz, CDClsJD 7.78 (d, IH), 7.73 (d, IH), 6.99-6.74 (m, 3H), 5.04-4.99 (m, IH), 4.90 (s, 2H), 4.76 (m, 2H), 4.10 (t, IH), 3.75 (s, 3H), 3.22 (s, 3H); MS for Cι6Hι8N6O4 m/z 359.1(M+H)+.
EXAMPLE 6 Preparation of (5S)-N-[3-(3-Ethoxyimino-4-methyl-3,4- dihydro-2H-benzo[l,4]oxazin-7-yl)-2-oxo-oxazolidin-5-ylmethyl]-acetamide.
Figure imgf000036_0001
Step 1: Preparation of [3-(4-methyl-3-oxo-3, 4-dihydro-2H-benzo[l,4]oxazin-7-yl)-2- oxo-oxazolidin-5-ylmethyl]-carbamic acid tert-butyl ester. Lithium t-butoxide (1.0 M solution in THF, 42.2 ml, 42.24 mmol) is dropwise at 0 °C to 4-methyl-3-oxo-3,4-dihydro-2H-benzo[l,4]oxazin-7-yl)-carbamic acid benzyl ester (5.5 g, 17.6 mmol) and (3-chloro-2-hydroxy-propyl)-carbamic acid tert- butyl ester (4.58 g, 22.18 mmol) in DMF (50 ml). The reaction mixture is allowed to warm to room temperature and stirred for 24 h. The reaction is quenched with saturated aqueous ammonium chloride, diluted with water, and extracted with dichloromethane. The organic layer is washed with brine, dried (Na2SO4) and evaporated. The residue is purified by flash column chromatography (40% EtOAc/Ηexane) to give the title compound as a white solid (5.3 g, 80%); ΗPLC r.t. 4.62 min; MS for Cι8Η23N3O6 m/z 378.1(M+H)+.
Step 2: Preparation of (5S)-[3-(4-methyl-3-thioxo-3,4-dihydro-2H-benzo[l,4]oxazin- 7-yl)-2-oxo-oxazolidin-5-ylmethyl]-carbamic acid tert-butyl ester. [3-(4-methyl-3-oxo-3,4-dihydro-2H-benzo[l,4]oxazin-7-yl)-2-oxo-oxazolidin- 5-ylmethyl]-carbamic acid tert-butyl ester (3.0 g, 7.9 mmol) and Lawesson's reagent (2.44 g, 6 mmol) in dioxane (20 ml) are heated overnight at 70 °C. The reaction mixture is evaporated and the residue purified by flash column chromatography (50% EtOAc/Hexane) to give the title compound as a yellow solid (2.16 g, 69%); HPLC r.t. 5.61min, MS for d8H23N3O5S m/z 394.1(M+H)+.
Step 3: Preparation of (5R)-aminomethyl-3-(4-methyl-3-thioxo-3,4-dihydro-2H- benzo[l,4]oxazin-7-yl)-oxazolidin-2-one. (5S)-3-(4-Methyl-3-thioxo-3,4-dihydro-2H-benzo[l,4]oxazin-7-yl)-2-oxo- oxazolidin-5-ylmethyl]-carbamic acid tert-butyl ester (1.65 g, 4.19 mmol) is stirred with 50% TFA/DCM (10 ml) for 1 h at room temperature. The solvent is removed under vacuum to give the title compound as the TFA salt (1.68 g, 99%); HPLC r.t. 3.57 min; MS for Cι3Hι5N3O3S m/z 294.0(M+H)+. Step 4: Preparation of (5S)-N-[3-(4-methyl-3-thioxo-3,4-dihydro-2H- benzo[l,4]oxazin-7-yl)-2-oxo-oxazolidin-5-ylmethyl]-acetamide. Acetic anhydride (0.585 ml, 6.12 mmol) is added at 0 °C to (5R)- aminomethyl-3-(4-methyl-3-thioxo 3,4-dihydro-2H-benzo[l,4]oxazin-7-yl)- oxazolidin-2-one (1.2 g, 4.08 mmol) and diisopropylethylamine (2.13 ml, 12.2 mmol) in dichloromethane (15 ml). The reaction mixture is stirred at 0 °C for 30 min, allowed to warm at room temperature and diluted with dichloromethane. The organic layer is separated, washed with water, citric acid and brine, dried (Νa2SO4) and evaporated. The residue is purified to give the title compound as a light brown solid (1.3 g, 95%); HPLC r.t. 4.28 min; MS for C15Hι7N3O4S m/z 336.0(M+H)+.
Step 5: Preparation of (5S)-N-[3-(3-ethoxyimino-4-methyl-3,4-dihydro-2H- benzo[l,4]oxazin-7-yl)-2-oxo-oxazolidin-5-ylmethyl]-acetamide. N-[3-(4-methyl-3-thioxo-3,4-dihydro-2H-benzo[l,4]oxazin-7-yl)-2-oxo- oxazolidin-5-ylmethyl]-acetamide (50 mg, 0.15 mmol) and O-ethyl hydroxylamine (88.5 mg, 0.90 mmol) in pyridine (2 ml) are heated overnight at 70 °C. The reaction mixture is evaporated, the residue dissolved in ethyl acetate, washed with water and brine, dried (Νa2SΟ4) and evaporated. The residue is purified by PTLC (10% MeOH/DCM) to give the title compound as an off white solid (30 mg, 55%); HPLC r.t. 4.56 min; 1H NMR (300 MHz, CDCla) . 7.12-6.76 (m, 3H), 6.13 (t, IH), 4.92 (s, 2H), 4.73 (m, IH), 4.02-3.94 (m, 3H), 3.73-3.54 (m, 3H), 3.23 (s, 3H), 2.00 (s, 3H), 1.23 (t, 3H); MS for Cι7H22N4O5 m/z 363.0(M+H)+.
EXAMPLE 7 Preparation of (5S)-N-[3-(3-Hydroxyimino-4-methyl-3,4- dihydro-2H-benzo[l,4]oxazin-7-yl)-2-oxo-oxazolidin-5-ylmethyl]-acetamide.
Figure imgf000037_0001
(5S)-N- [3-(4-methyl-3-thioxo-3 ,4-dihydro-2H-benzo [ 1 ,4]oxazin-7-yl)-2-oxo- oxazolidin-5-ylmethyl]-acetamide (from Example 6, Step 4) (250 mg, 0.74 mmol) and N, O-bis(trimethylsilyl) hydroxylamine (0.160 ml, 0.74 mmol) in ethanol (20 ml) is heated at 70 °C for 3 h. The reaction mixture is evaporated and the resulting residue triturated with cold ethanol to obtain product as a white solid (168 mg, 68%); 1H NMR (300 MHz, DMSO) δ 9.75 (s, IH), 8.25-8.21 (m, IH), 7.18-6.95 (m, 3H), 4.91 (s, 2H), 4.69-4.64 (m, IH), 4.05(t, J = 8.7 Hz, IH), 3.69-3.64 (m, IH), 3.39-3.36 (m, 2H), 3.16 (s, 3H), 1.82 (s, 3H); MS (m/z) 335 (m+1).
EXAMPLE 8 Preparation of (5S)-[3-(3-Hydroxyimino -4-methyl-3,4- dihydro-2H-benzo[l,4]oxazin-7-yl)-2-oxo-oxazolidin-5-ylmethyl]-carbamic acid methyl ester.
Figure imgf000038_0001
Step 1: Preparation of (3-Hydroxyimino-4-methyl-3,4-dihydro-2H-benzo[l,4]oxazin- 7-yl)-carbamic acid benzyl ester 4-Methyl-3-thioxo-3,4-dihydro-2H-benzo [1,4] oxazin-7-yl)- carbamic acid benzyl ester (1.2 g, 3.65 mmol)(Example 1, step 5) and N, O-bis(trimethylsilyl) hydroxylamine (1.4 ml, 6.55 mmol) in ethanol (25 ml) were heated overnight at 70 °C. The reaction mixture was evaporated and the resulting residue triturated with cold ethanol to give product as a white solid (1.17 g, 98.3%); HPLC r.Tt. 5.05 min; MS for C17Hι7Ν3Ο4 m/z 328.0 (M+H)+.
Step 2: Preparation of [4-Methyl-3-(tetrahydro-pyran-2yloxyimino)-3,4-dihydro-2H- benzo[l,4]oxazin-7-yl)-carbamic acid benzyl ester (3-Hydroxyimino-4-methyl-3,4-dihydro-2H-benzo[l,4]oxazin-7-yl)-carbamic acid benzyl ester (0.93 g, 2.84 mmol), 3,4-dihydro-2H-pyran (0.57 ml, 6.25 mmol) and p-toluene sulfonic acid (0.108 g, 0.568 mmol) in DMF (6 ml) were stirred at room temperature for 72 hours. The reaction was diluted with ethyl acetate, washed with water and brine, dried (Na2SO4) and evaporated. The residue was purified by flash column chromatography (20%EtOAc / Hexane) to give product as a white solid (0.81 g, 69%); HPLC r.t. 6.21 min; MS for C22H25N3O5 m z 412.4 (M+H)+. Step 3: Preparation of (5S)-{3-[4-Methyl-3-(tetrahydro-pyran-2yloxyimino)-3,4- dihydro-2H-benzo[l,4]oxazin-7-yl)-2-oxo-oxazolidin-5-ylmethyl}-carbamic acid tert- butyl ester Lithium t-butoxide (1.0 M solution in THF, 5.82 ml, 5.82 mmol) was added at 0 °C to [4-methyl-3-(tetrahydro-pyran-2yloxyimino)-3,4-dihydro-2H- benzo[l,4]oxazin-7-yl)-carbamic acid benzyl ester (0.80 g, 1.94 mmol) and (3-chloro- 2-hydroxy-propyl)-carbamic acid tert-butyl ester (0.609 g, 2.91 mmol) in DMF (7 ml). The mixture was allowed to warm to room temperature and stirred for 72 hours. The reaction was quenched with saturated aqueous ammonium chloride and extracted with dichloromethane. The organic layer was separated, washed with brine, dried
(Na2SO ) and evaporated. The residue was purified by flash column chromatography (50% EtOAc/Hexane) to give product as an off white solid (0.67 g, 72.3%); HPLC r.t. 5.63 min; MS for C23H32N4O7 m/z 477.1 (M+H)+.
Step 4: Preparation of (5R)-7-(5-aminomethyl-2-oxo-oxazolidin-3-yl)-4-methyl-4H- benzo[l,4]oxazin-3-one oxime. (5S)-3-[4-Methyl-3-(tetrahydro-pyran-2yloxyimino)-3,4-dihydro-2H- benzo[l,4]oxazin-7-yl)-2-oxo-oxazolidin-5-ylmethyl}-carbamic acid tert-butyl ester
(0.28 g, 0.587 mmol) was stirred with 50% TFA/DCM (4 ml) for 30 minutes at room temperature. The solvent was evaporated to give the title compound as the TFA salt
(0.172 g, 100%); HPLC r.t. 2.54 min; MS for Cι3H16N4O4 m/z 293.0 (M+H)+.
Step 5: (5S)-[3-(3-Hydroxyimino -4-methyl-3,4-dihydro-2H-benzo[l,4]oxazin-7-yl)- 2-oxo-oxazolidin-5-ylmethyl] -carbamic acid methyl ester Methyl chloroformate (0.046 ml, 0.588 mmol) was added to (5R)-7-(5- aminomethyl-2-oxo-oxazolidin-3-yl)-4-methyl-4H-benzo [ 1 ,4] oxazin-3-one oxime. (0.172 g, 0.588 mmol) (from Example 21, step 9) and diisopropylethylamine (0.606 ml, 3.52 mmol) in dichloromethane (5 ml) was added) at 0 °C. The mixture was stirred at 0 °C for 30 minutes and then allowed to warm to room temperature. The reaction was diluted with dichloromethane, washed with water, citric acid and brine, dried (Na2SO ) and evaporated. The residue was purified by PTLC (10%MeOΗ / DCM) to give product as an off white solid (0.90 g, 43.6%); HPLC r.t. 3.38min; 1H NMR (300 MHz, OMSO-dά 9.72 (br s, IH), 7.48 (br s, IH), 7.14 (m, IH), 6.93-7.04 (m, 2H), 4.88 (s, 2H), 4.62 (m, IH), 4.02 (t, J = 9 Hz, IH), 3.65-3.70 (m, IH), 3.49 (s, 3H), 3.13 (s, 3H); MS for Cι5Hι8N4O6 m/z 351.1 (M+H)+.
EXAMPLE 9 Preparation of (5S)-N-[3-(3-Isopropoxyimino-4-methyl-3,4- dihydro-2H-benzo[l,4]oxazin-7-yl)-2-oxo-oxazolidin-5-ylmethyl]-acetamide.
Figure imgf000040_0001
Step 1: Preparation of (5S)-N-[3-(3-hydroxyimino-4-methyl-3,4-dihydro-2H- benzo[l,4]oxazin-7-yl)-2-oxo-oxazolidin-5-ylmethyl]-acetamide. (5S)-N-[3-(4-methyl-3-thioxo-3,4-dihydro-2H-benzo[l,4]oxazin-7-yl)-2-oxo- oxazolidin-5-ylmethyl]-acetamide (0.8 g, 2.38 mmol) andN,O-bis(trimethylsilyl) hydroxylamine (0.89 ml, 4.17 mmol) in ethanol are heated overnight at 70 °C . The reaction mixture is cooled and the resulting precipitate filtered, washed with ethanol, and dried under vacuum to give the title compound an off white solid (0.65 g, 81%); HPLC r.t. 3.19 min; MS for C15Hι8Ν4Ο5 m/z 33.5.0(M+H)+.
Step 2: Preparation of (5S)-N-[3-(3-isopropoxyimino-4-methyl-3,4-dihydro-2H- benzo[l,4]oxazin-7-yl)-2-oxo-oxazolidin-5-ylmethyl]-acetamide. Sodium hydride (60% dispersion in oil, 12 mg, 0.298 mmol) is added portionwise at 0 °C to (5S)-N-[3-(3-hydroxyimino-4-methyl-3,4-dihydro-2H- benzo[l,4]oxazin-7-yl)-2-oxo-oxazolidin-5-ylmethyl]-acetamide (50 mg, 0.149 mmol) in DMF (3 ml). The reaction mixture is stirred at 0 °C for 30 min and then 2- iodopropane (0.030 ml, 0.298 mmol) is added dropwise. The reaction is allowed to warm to room temperature and stirred overnight. The reaction is quenched with sat. aqueous ammonium chloride, diluted with ethyl acetate, washed with water and brine, dried (Νa2SO4) and evaporated. The residue is purified by PTLC (10% MeOH DCM) to give the title compound as a white solid (36 mg, 65%); HPLC r.t. 4.96 min; 1H NMR (300 MHz, CDCla) δ 7.11-6.74 (m, 3H), 6.32 (t, IH), 4.90 (s, 2H), 4.73 (m, IH), 4.14 (m, IH), 3.98 (t, IH), 3.73-3.54 (m, 3H), 3.22 (s, 3H), 2.00 (s, 3H), 1.42 (d, 6H); MS for C18H24N4O5 m/z 377.0 (M+H)+. EXAMPLE 10 Preparation of (5S)-N-{ 3-[3-(2-Fluoro-ethoxyimino)-4- methyl-3,4-dihydro-2H-benzo[l,4]oxazin-7-yl)-2-oxo-oxazolidin-5-ylmethyl}- acetamide.
Figure imgf000041_0001
Sodium hydride (95%, 9.0 mg, 0.358 mmol) was added at 0 °C to (5S)-N-[3- (3-hydroxyimino-4-methyl-3,4-dihydro-2H-benzo[l,4]oxazin-7-yl)-2-oxo-oxazolidin- 5-ylmethyl]-acetamide (Example 9, Step 1, 60 mg, 0.179 mmol) in DMF (3 ml). The reaction mixture was stirred at 0 °C for 30 minutes and l-fluoro-2-iodoethane (47 mg, 0.268 mmol) added dropwise. The reaction was allowed to warm to room temperature and stirred overnight. The reaction was quenched with saturated aqueous ammonium chloride, diluted with ethyl acetate, washed with water and brine, dried (Νa2SO4) and evaporated. The residue was purified by PTLC (10% MeOH/DCM) to give product as a white solid (50 mg, 73.5%); HPLC r.t. 4.304 min; 1H NMR (300 MHz, CDC -d) δ 7.14 (d, J = 2.4 Hz, IH), 7.08 (dd, J = 2.4, 8.7 Hz, IH), 6.80 (d, J = 9 Hz, IH), 6.03 (t, IH), 4.97 (s, 2H), 4.71-4.78 (m, 2H), 4.56 (m, IH), 4.23 (m, IH), 4.13 (m. IH), 4.01 (t, J = 9 Hz, IH), 3.56-3.75 (m, 3H), 3.24 (s, 3H), 2.02 (s, 3H); MS for Cι7H2ιFN4O5 m/z 381.2 (M+H)+.
EXAMPLE 11 Preparation of (5S)-N- { 3-[3-(2-Methoxy-ethoxyimino)-4- methyl-3,4-dihydro-2H-benzo[l,4]oxazin-7-yl)-2-oxo-oxazolidin-5-ylmethyl}- acetamide.
Figure imgf000041_0002
Sodium hydride (95%, 9.0 mg, 0.358 mmol) was added at 0 °C to (5S)-N-[3-
(3-hydroxyimino-4-methyl-3,4-dihydro-2H-benzo[l,4]oxazin-7-yl)-2-oxo-oxazolidin- 5-ylmethyl]-acetamide (Example 9, Step 1, 60 mg, 0.179 mmol) in DMF (3 ml). The reaction mixture was stirred at 0 °C for 30 minutes and then 2-bromoethyl methyl ether (0.021 ml, 0.223 mmol) added dropwise. The reaction was allowed to warm to room temperature and stirred overnight. The reaction was quenched with saturated aqueous ammonium chloride, diluted with ethyl acetate, washed with water and brine, dried (Na2SO4) and evaporated. The residue was purified by PTLC (10% MeOH/DCM) to give product as a white solid (42 mg, 60%); HPLC r.t. 4.07 min; 1H NMR (300 MHz, CDCl3--i) δ 7.13 (d, I = 2.4 Hz, IH), 7.07 (dd, J = 2.4, 8.7 Hz, IH), 6.80 (d, J = 9 Hz, IH), 6.06 (t, IH), 4.97 (s, 2H), 4.72-4.77 (m, IH), 4.10 (dd, I = 3.6, 4.8 Hz, 2H), 4.01 (t, I = 9 Hz, IH), 3.53-3.75 (m, 5H), 3.40 (s, 3H), 3.24 (s, 3H), 2.02 (s, 3H); MS for C18H24N4O6 m/z 393.1 (M+H)+.
EXAMPLE 12 Preparation of (5S)-N-[3-(3-Methoxy-methoxyimino)-4-methyl-
3 ,4-dihydro-2H-benzo [ 1 ,4] oxazin-7-yl)-2-oxo-oxazolidin-5-ylmethyl } -acetamide.
Figure imgf000042_0001
Sodium hydride (95%, 9.0 mg, 0.358 mmol) was added at 0 °C to (5S)-N-[3-
(3-hydroxyimino-4-methyl-3,4-dihydro-2H-benzo[l,4]oxazin-7-yl)-2-oxo-oxazolidin- 5-ylmethyl]-acetamide (Example 9, Step 1, 60 mg, 0.179 mmol) in DMF (3 ml). The reaction mixture was stirred at 0 °C for 30 minutes and then bromomethyl methyl ether (0.018 ml, 0.223 mmol) added dropwise. The reaction was allowed to warm to room temperature and stirred overnight. The reaction was quenched with saturated aqueous ammonium chloride, diluted with ethyl acetate, washed with water and brine, dried (Νa SO4) and evaporated. The residue was purified by PTLC (10% MeOΗ DCM) to give product as a white solid (23.7 mg, 35%); ΗPLC r.t. 4.06 min; 1H NMR (300 MHz, CDCl3-d) δ 7.17 (d, I = 2.4 Hz, IH), 7.08 (dd, J = 2.4, 8.7 Hz, IH), 6.82 (d, I = 9 Hz, IH), 6.00 (t, IH), 5.01 (s, 2H), 4.99 (s, 2H), 4.73-4.81 (m, IH), 4.02 (t, J = 9 Hz, IH), 3.54-3.75 (m, 3H), 3.54 (s, 3H), 3.46 (s, 3H), 2.02 (s, 3H); MS for C17H22N4O6m/z 379.1 (M+H)+.
EXAMPLE 13 Preparation of (5S)-N-[3-(3-Cycloproρyl-methoxyimino)-4- methyl-3 ,4-dihydro-2H-benzo [ 1 ,4]oxazin-7-yl)-2-oxo-oxazolidin-5-ylmethyl } - acetamide.
Figure imgf000043_0001
Sodium hydride (95%, 9.0 mg, 0.358 mmol) was added at 0 °C to (5S)-N-[3- (3 -hydroxyimino-4-methyl-3 ,4-dihydro-2H-benzo [ 1 ,4] oxazin-7-yl)-2-oxo-oxazolidin- 5-ylmethyl]-acetamide (Example 9, Step 1, 60 mg, 0.179 mmol) in DMF (3 ml). The reaction mixture was stirred at 0 °C for 30 minutes and then (bromomethyl)cyclopropane (0.022 ml, 0.223 mmol) added dropwise. The reaction was allowed to warm to room temperature and stirred overnight. The reaction was quenched with saturated aqueous ammonium chloride, diluted with ethyl acetate, washed with water and brine, dried (Νa2SO4) and evaporated. The residue was purified by PTLC (10% MeOH/DCM) to give product as a white solid (46 mg, 66%); HPLC r.t. 4.93 min; 1H NMR (300 MHz, CDCl3-d) δ 7.14 (d, I = 2.4 Hz, IH), 7.07 (dd, J = 2.4, 8.7 Hz, IH), 6.79 (d, I = 9 Hz, IH), 6.03 (t, IH), 4.98 (s, 2H), 4.73-4.79 (m, IH), 4.01 (t, J = 9 Hz, IH), 3.54-3.76 (m, 5H), 3.25 (s, 3H), 2.02 (s, 3H), 1.46 (m, IH), 0.60 (m, 2H), 0.42 (m, 2H); MS for C19H24N4O5 m/z 389.2 (M+H)+.
EXAMPLE 14 Preparation of (5S)-N-[3-(3-Cyclohexyl-methoxyimino)-4- methyl-3 ,4-dihydro-2H-benzo [ 1 ,4]oxazin-7-yl)-2-oxo-oxazolidin-5-ylmethyl } - acetamide.
Figure imgf000043_0002
Sodium hydride (95%, 9.0 mg, 0.358 mmol) was added at 0 °C to (5S)-N-[3- (3 -hydroxyimino-4-methyl-3 ,4-dihydro-2H-benzo [ 1 ,4] oxazin-7-yl)-2-oxo-oxazolidin- 5-ylmethyl]-acetamide (Example 9, Step 1, 60 mg, 0.179 mmol) in DMF (3 ml). The reaction mixture was stirred at 0 °C for 30 min and then (bromomethyl)cyclohexane (0.031 ml, 0.223 mmol) added dropwise. The reaction was allowed to warm to room temperature and stirred overnight. The reaction was quenched with saturated aqueous ammonium chloride, diluted with ethyl acetate, washed with water and brine, dried (Na2SO4) and evaporated. The residue was purified by PTLC (10% MeOH/DCM) to give product as a white solid (34 mg, 44%); HPLC r.t. 6.23 min; 1H NMR (300 MHz, CDC -d) δ 7.14 (d, J = 2.4 Hz, IH), 7.07 (dd, J = 2.4, 8.7 Hz, IH), 6.79 (d, J = 9 Hz, IH), 6.00 (t, IH), 4.94 (s, 2H), 4.75 (m, IH), 4.01 (t, I = 9 Hz, IH), 3.55-3.75 (m, 5H), 3.24 (s, 3H), 2.02 (s, 3H), 1.73\m, IH), 0.94-1.28 (m, 10H); MS for C22H3oN4O5 m/z 431.3 (M+H)+.
EXAMPLE 15 Preparation of (5S)-N-[3-(3-Cyclobutyl-methoxyimino)-4- methyl-3,4-dihydro-2H-benzo[l,4]oxazin-7-yl)-2-oxo-oxazolidin-5-ylmethyl}- acetamide.
Figure imgf000044_0001
Sodium hydride (95%, 9.0 mg, 0.358 mmol) was added at 0 °C to (5S)-N-[3- (3-hydroxyimino-4-methyl-3,4-dihydro-2H-benzo[l,4]oxazin-7-yl)-2-oxo-oxazolidin- 5-ylmethyl]-acetamide (Example 9, Step 1, 60 mg, 0.179 mmol) in DMF (3 ml). The reaction mixture was stirred at 0 °C for 30 minutes and then (bromomethyl)cyclobutane (0.025 ml, 0.223 mmol) added dropwise. The reaction was allowed to warm to room temperature and stirred overnight. The reaction was quenched with saturated aqueous ammonium chloride, diluted with ethyl acetate, washed with water and brine, dried (Νa2SO4) and evaporated. The residue was purified by PTLC (10% MeOH/DCM) to give product as a white solid (43.3 mg, 60%); HPLC r.t. 5.51 min; 1H NMR (300 MHz, CDCl3-ci) δ 7.14 (d, I = 2.4 Hz, IH), 7.07 (dd, J = 2.4, 8.7 Hz, IH), 6.79 (d, J = 9 Hz, IH), 6.04 (t, IH), 4.93 (s, 2H), 4.71- 4.78 (m, IH), 4.01 (t, J = 9 Hz, IH), 3.91 (d, J = 6.9 Hz, 2H), 3.67-3.75 (m, 2H), 3.53- 3.62 (m, IH), 3.23 (s, 3H), 2.66 (m, IH), 2.02 (s, 3H), 1.75-2.12 (m, 6H); MS for C20H26N4O5 m/z 403.3 (M+H)+. EXAMPLE 16 Preparation of (5S)-N-{3-[3-(2-Dimethylamino-ethoxyimino)-
4-methyl-3 ,4-dihydro-2H-benzo [ 1 ,4]oxazin-7-yl)-2-oxo-oxazolidin-5-ylmethyl } - acetamide.
Figure imgf000045_0001
(5S)-N-[3-(4-methyl-3-thioxo-3,4-dihydro-2H-benzo[l,4]oxazin-7-yl)-2-oxo- oxazolidin-5-ylmethyl]-acetamide (100 mg, 0.298 mmol) and O-(2-dimethylamino- ethyl)-hydroxylamine (211 mg, 1.19 mmol) in pyridine (4 ml) was heated for 48 hours at 70 °C. The reaction mixture was evaporated and the residue purified by prep HPLC to give product as an off white solid (30.2 mg, 25%); HPLC r.t. 3.14 min; 1H ΝMR (300 MHz, DMSO- ) 8.44 (t, I = 4.5 Hz, IH), 7.23-7.47 (m, 3H), 5.19 (s, 2H), 4.84-4.91 (m, IH), 4.36-4.40 (m, 4H), 4.25 (t, I = 9Hz, IH), 3.85-3.93 (m, 3H), 3.39 (s, 3H), 3.03 (d, 3.3 Hz, 6H), 2.02 (s, 3H); MS for C19H27Ν5O5 m/z 406.0 (M+H)+.
EXAMPLE 17 Preparation of (5S)-N-{ 3-[3-(2-Benzyloxy-ethoxyimino)-4- methyl-3,4-dihydro-2H-benzo[ 1 ,4]oxazin-7-yl)-2-oxo-oxazolidin-5-ylmethyl } - acetamide.
Figure imgf000045_0002
Sodium hydride (95%, 80 mg, 3.3 mmol) is added portionwise at 0 °C to (5S)~ N-[3-(3-hydroxyimino-4-methyl-3,4-dihydro-2H-benzo[l,4]oxazin-7-yl)-2-oxo- oxazolidin-5-ylmethyl]-acetamide (from Example 9, step 1, 0.5 g, 1.49 mmol) in DMF (15 ml). The reaction mixture is stirred at 0 °C for 30 min and then benzyl-2- bromo ethyl ether (0.360 ml, 2.27 mmol) added dropwise. The reaction is allowed to warm to room temperature and stirred overnight. The reaction is quenched with sat. ammonium chloride, diluted with ethyl acetate, washed with water and brine, dried (Νa2SO4) and evaporated. The residue is purified by PTLC (10% MeOΗ/DCM) to give product as a white solid (0.45 g, 64%); ΗPLC r.t. 5.26 min; 1H NMR (300 MHz, COCh-d) δ 7.28-7.35 (m, 5H),7.15 (d, I = 2.4 Hz, IH), 7.09 (dd, J = 2.4, 8.7 Hz, IH), 6.80 (d, J = 9 Hz, IH), 6.10 (t, IH), 4.98 (s, 2H), 4.76 (m, IH), 4.58 (s, 2H), 4.13 (m, 2H), 4.02 (t, I = 9 Hz, IH), 3.68-3.76 (m, 4H), 3.56-3.63 (m, IH), 3.22 (s, 3H), 2.03 (s, 3H); MS for C24H28N4O6 m/z 469.0 (M+H)+.
EXAMPLE 18 Preparation of (5S)-N-{3-[3-(2-Hydroxy-ethoxyimino)-4- methyl-3 ,4-dihydro-2H-benzo [ 1 ,4] oxazin-7-yl)-2-oxo-oxazolidin-5-ylmethyl } - acetamide.
Figure imgf000046_0001
10% Pd/C (48 mg, 20 %) is added to (5S)-N-{3-[3-(2-Benzyloxy- ethoxyimino)-4-methyl-3,4-dihydro-2H-benzo[l,4]oxazin-7-yl)-2-oxo-oxazolidin-5- ylmethyl}-acetamide (from Example 8) (0.24 g, 0.512 mmol) in ethanol/acetic acid (10 ml, 4:1) and stirred under hydrogen (1 atmosphere) for 8 h. The reaction mixture is filtered through celite, evaporated and purified by PTLC (10% MeOΗ DCM) to give the title compound as a white solid (0.116 g, 60%); ΗPLC r.t. 3.50 min; 1H ΝMR (300 MHz, CDCla) δ 7.15-6.78 (m, 3H), 6.10 (t, IH), 4.94 (s, 2H), 4.73 (m, IH), 4.08- 4.05 (m, 2H), 3.96 (t, IH), 3.89 (m, 2H), 3.73-3.55 (m, 3H), 3.21 (s, 3H), 2.00 (s, 3H); MS (m/z): [M+H]+ =379.
EXAMPLE 19 Preparation of (5S)-N-[3-(3-Hydroxyimino-4-methyl-3,4- dihydro-2H-benzo[l,4]thiazin-7-yl)-2-oxo-oxazolidin-5-ylmethyl]-acetamide.
Figure imgf000046_0002
Step 1: Preparation of (4-methyl-3-oxo-3,4-dihydro-2H-benzo[l,4]thiazin-7-yl)- carbamic acid benzyl ester. Benzyl chloroformate (4.01 mL, 28.08 mmol) is added at 0 °C to a stirred solution of 7-amino-4-methyl-4H-benzo[l,4]thiazin-3-one (prepared accordind to the method described in WO/03072553) (3.41 g, 17.55 mmol) and pyridine (3.12 mL, 38.62 mmol) in dry DCM (20 ml). The reaction mixture is allowed to warm to room temperature and then washed with 2N HC1. The organic layer is separated, washed with brine, dried (MgSO ) and evaporated to give a dark oil which is purified by flash column chromatography (100 % DCM) to give product as a yellow solid (3.88 g, 68 %). MS (m/z): 329.5 [m+H]+.
Step 2: Preparation of (5S)-[3-(4-methyl-3-oxo-3,4-dihydro-2H-benzo[l,4]thiazin-7- yl)-2-oxo-oxazolidin-5-ylmethyl]-carbamic acid tert-butyl ester. Lithium t-butoxide (1.0 M solution in THF, 35.45 ml, 35.45 mmol) is added dropwise at 0 °C to (4-methyl-3-oxo-3,4-dihydro-2H-benzo[l,4]thiazin-7-yl)- carbamic acid benzyl ester (3.88g, 11.8 mmol) and (3-chloro-2-hydroxy-propyl)- carbamic acid tert-butyl ester (3.714 g, 17.7 mmol) in DMF (9 ml). The reaction mixture is allowed to warm at room temperature and stirred for 16 h. The reaction is quenched with saturated aqueous ammonium chloride, diluted with water and extracted with dichloromethane. The organic layer is washed with brine, dried (Na2SO ) and evaporated. The residue is purified by flash column chromatography (100 % EtOAc) to give the title compound as a yellow solid (4.03 g, 87 %); MS (m z): 394.5 [m+H]+.
Step 3: Preparation of (5S)-[3-(4-methyl-3-thioxo-3,4-dihydro-2H-benzo[l,4]thiazin- 7-yl)-2-oxo-oxazolidin-5-ylmethyl]-carbamic acid tert-butyl ester. [3-(4-Methyl-3-oxo-3,4-dihydro-2H-benzo[l,4]thiazin-7-yl)-2-oxo-oxazolidin- 5-ylmethyl]-carbamic acid tert-butyl ester (2.50 g, 6.354 mmol) and Lawesson's reagent (3.855 g, 9.531 mmol) in dry dioxane (40 mL) are heated at 80 °C for 2 h. The reaction is cooled to room temperature and evaporated under vacuum. The residue is triturated with EtOAc to remove unreacted Lawesson's reagent and then purified by flash column chromathography (60 % EtOAc/Ηex) to give the title compound as a yellow solid (2.0 g, 77 %); MS (m/z): 410.5 [m+Η]+.
Step 4: Preparation of (5S)-N-[3-(4-methyl-3-thioxo-3,4-dihydro-2H- benzo[l,4]thiazin-7-yl)-2-oxo-oxazolidin-5-ylmethyl]-acetamide. 20% TFA in dichloroethane (4 ml) is added to (5S)-[3-(4-Methyl-3-thioxo-3,4- dihydro-2H-benzo[ 1 ,4]thiazin-7-yl)-2-oxo-oxazolidin-5-ylmethyl]-carbamic acid tert- butyl ester (1.75 g, 4.27 mmol) in dichloroethane (20 ml). The resulting mixture is stirred at room temperature for 1.5 h and evaporated under vacuum. The residue is purified by flash column chromatography (15 % MeOH/DCM) to give the title compound as a yellow solid (1.50 g, Quant %); MS ( /z) 310.5 [m+H]+. The compound is dissolved in pyridine (1.96 ml, 24.2 mmol), cooled to 0 °C, and acetic anhydride (1.37 mL, 14.54 mmol) added dropwise. The reaction mixture is allowed to warm to room temperature and stirred for 4 h. The mixture is evaporated under vacuum and the residue diluted with 2N HCl. The resulting precipitate is filtered and dried under vacuum, and purified by column chromatography (5 % MeOH/DCM) to give the title compound as a yellow solid (0.860 g, 50 %); MS (m/z): 352.5 [m+H]+.
Step 5: Preparation of (5S)-N-[3-(3-hydroxyimino-4-methyl-3,4-dihydro-2H- benzo[l,4]thiazin-7-yl)-2-oxo-oxazolidin-5-ylmethyl]-acetamide. N-[3-(4-Methyl-3-thioxo-3,4-dihydro-2Η-benzo[l,4]thiazin-7-yl)-2-oxo- oxazolidin-5-ylmethyl]-acetamide (300 mg, 0.853 mmol) and N, O-bis(trimethylsilyl) hydroxylamine (1.02 mL, 4.78 mmol) in methanol (5 ml) is heated at 70 °C for 24 h. The reaction mixture is evaporated and the resulting residue triturated with ether to obtain the title compound as a white solid. (250 mg, 83 %). 1H ΝMR (300 MHz,
DMSQ) δ 9.75 (br s, IH), 7.83 (br s, IH), 7.59 (br s, IH), 7.21 (s, IH), 7.10 (d, I = 9.9 Hz, IH), 6.97 (d, I = 9.0 Hz, IH), 4.97 (dd, J = 6.6 Hz, 9.0 Hz, IH), 4.91 (s, 2H), 4.21 (t, J = 9.3 Hz, IH), 3.93 (t, I = 8.7 Hz, IH), 3. 16 (s, 3H); MS (m/z): 351.5 [m+H]+.
EXAMPLE 20 Preparation of (5S)-N-[3-(3-Methoxyimino-4-methyl-3,4- dihydro-2H-benzo[l,4]thiazin-7-yl)-2-oxo-oxazolidin-5-ylmethyl]-acetamide.
Figure imgf000048_0001
Sodium hydride (8.56 mg, 0.357 mmol) is added portionwise at 0 °C to (5S)- N-[3-(3-hydroxyimino-4-methyl-3,4-dihydro-2H-benzo[l,4]thiazin-7-yl)-2-oxo- oxazolidin-5-ylmethyl]-acetamide (125 mg, 0.357 mmol) in DMF (3 ml). The reaction mixture is stirred at 0 °C until hydrogen evolution ceased and iodomethane (0.1 ml, 0.309 mmol) is added in one portion. The reaction is allowed to warm to room temperature and stirred for 2 h. Water is added and the mixture extracted with ethyl acetate. The extracts are washed with brine, dried (MgSO4) and evaporated. The residue is purified by flash column chromatography (5% MeOH/DCM) to give the title compound as a white solid (43 mg, 33%); 1H ΝMR (300 MHz, DMSO) δ9.75 (br s, IH), 7.83 (br s, IH), 7.59 (br s, IH), 7.21 (s, IH), 7.10 (d, I = 9.9 Hz, IH), 6.97 (d, J = 9.0 Hz, IH), 4.97 (dd, J = 6.6 Hz, 9.0 Hz, IH), 4.91 (s, 2H), 4.21 (t, J = 9.3 Hz, IH), 3.93 (t, I = 8.7 Hz, IH), 3. 16 (s, 3H); MS (m/z) 365.5 [m+H]+.
EXAMPLE 21 Preparation of (5S)-N-[3-(2-Hydroxyimino-l-methyl-l,2,3,4- tetrahydro-quinolin-6-yl)-2-oxo-oxazolidin-5-ylmethyl]-acetamide.
Figure imgf000049_0001
Step 1: Preparation of (l-methyl-2-oxo-l,2,3,4-tetrahydro-quinolin-6-yl)-carbamic acid benzyl ester. Benzyl chloroformate (0.171 mL, 1.2 mmol) is added at 0 °C to a stirred solution of 6-amino-l-methyl-3,4-dihydro-lH-quinolin-2-one (prepared according to the method described in WO/03072553) (0.176 g, 1.00 mmol) and pyridine (0.194 mL, 2.40 mmol) in dry DCM (5 ml). The reaction mixture is allowed to warm to room temperature and then washed with 2Ν HCl. The organic layer is separated, washed with brine, dried (MgSO4) and evaporated to give oil which is purified by flash column chromatography (25% EtO Ac/Hex) to give the title compound as a white solid (0.301 g, 97%).
Step 2: Preparation of (5S)-[3-(l-methyl-2-oxo-l,2,3,4-tetrahydro-quinolin-6-yl)-2- oxo-oxazolidin-5-ylmethyl]-carbamic acid tert-butyl ester. Lithium t-butoxide (1.0 M solution in THF, 2.3 ml, 2.33 mmol) is added dropwise at 0 °C to (l-methyl-2-oxo-l,2,3,4-tetrahydro-quinolin-6-yl)-carbamic acid benzyl ester (2.0 g, 6.41 mmol) and (3-chloro-2-hydroxy-propyl)-carbamic acid tert- butyl ester (0.300 g, 0.97 mmol) in DMF (2 ml). The reaction mixture is allowed to warm at room temperature and stirred overnight. The reaction is quenched with saturated aqueous ammonium chloride, diluted with water and extracted with dichloromethane. The organic layer is washed with brine, dried (Na2SO4) and evaporated. The residue is purified by flash column chromatography (50% EtOAc/Hex) to give the title compound as a white solid (0.325 g, 89%).
Step 3: Preparation of (5S)-[3-(l-methyl-2-thioxo-l,2,3,4-tetrahydro-quinolin-6-yl)-2- oxo-oxazolidin-5-ylmethyl]-carbamic acid tert-butyl ester. [3-(l-Methyl-2-oxo-l,2,3,4-tetrahydro-quinolin-6-yl)-2-oxo-oxazolidin-5- ylmethyl] -carbamic acid tert-butyl ester (0.325 g, 0.87 mmol) and Lawesson's reagent (0.526 g, 1.31 mmol) in dry dioxane (5 mL) are heated at 50 °C for 48 h. The reaction is cooled to room temperature and evaporated under vacuum. The residue is purified by flash column chromathography (50 % EtO Ac/Hex) to give the title compound as yellow oil (0.320 g, 94%).
Step 4: Preparation of (5S)-N-[3-(l-methyl-2-thioxo-l,2,3,4-tetrahydro-quinolin-6- yl)-2-oxo-oxazolidin-5-ylmethyl]-acetamide. TFA (1.50 ml) in dichloroethane (2 ml) is added to [3-(l-Methyl-2-thioxo- 1 ,2,3,4-tetrahydro-quinolin-6-yl)-2-oxo-oxazolidin-5-ylmethyl]-carbamic acid tert- butyl ester (0.39 g, 4.0 mmol). The resulting mixture is stirred at room temperature for 1.5 h and evaporated under vacuum. The residue is dissolved in DCE (2 ml) and triethylamine (2 ml) and cooled to 0 °C. Acetic anhydride (1.0 ml) is added and the reaction mixture stirred at room temperature for 1 h. The mixture is evaporated under vacuum and the residue purified by column chromatography (12.5 % MeOH/DCM) to give the title compound as a yellow solid (0.250 g, 75 %).
Step 5: Preparation of (5S)-N-[3-(2-Hydroxyimino-l-methyl-l,2,3,4-tetrahydro- quinolin-6-yl)-2-oxo-oxazolidin-5-ylmethyl]-acetamide. (5S)-N-[3-(l-Methyl-2-thioxo-l,2,3,4-tetrahydro-quinolin-6-yl)-2-oxo- oxazolidin-5-ylmethyl]-acetamide (150 mg, 0.450 mmol) and N, O-bis(trimethylsilyl) hydroxylamine (0.3 mL) in ethanol (2 ml) is heated at 70 °C for 24 h. The reaction mixture is evaporated and the resulting residue purified by flash column chromatography to give the title compound as yellow solid. (100 mg, 99 %); 1H ΝMR (300 MHz, DMSO-dø 9.47 (s, IH), 8.23 (t, IH), 7.33-7.29 (m, 2H), 6.90 (d, IH), 4.69-4.63 (m, IH), 4.06 (t, IH), 3.68 (dd, IH), 3.38 (m, 2H), 3.14 (s, 3H), 2.69 (m, 4H), 1.83 (s, 3H); MS (m/z): 333 [m+H]+.
EXAMPLE 22 Preparation of (5S)-N-[3-(2-Methoxyimino-l -methyl- 1,2,3, 4- tetrahydro-quinolin-6-yl)-2-oxo-oxazolidin-5-ylmethyl]-acetamide.
Figure imgf000051_0001
Sodium hydride (2.60 mg, 0.11 mmol) is added portionwise at 0 °C to 3-(2- hydroxyimino- 1 -methyl- 1 ,2,3 ,4-tetrahydro-quinolin-6-yl)-2-oxo-oxazolidine-5- carboxylic acid amide (from Example 17) (36 mg, 0.11 mmol) in DMF (1 ml). The reaction mixture is stirred at 0 °C until hydrogen evolution ceased and iodomethane (0.036 ml, 0.11 mmol) is added in one portion. The reaction is allowed to warm to room temperature and stirred for 2 h. Water is added and the mixture extracted with ethyl acetate. The extracts are washed with brine, dried (MgSO4) and evaporated. The residue is purified by flash column chromatography (5% MeOH/DCM) to give the title compound as a white solid (39 mg, 54%); 1H ΝMR (300 MHz, DMSO-d^) 8.24 (t, IH), 7.35-7.31 (m, 2H), 6.94 (d, IH), 4.71-4.63 (m, IH), 4.06 (t, IH), 3.68 (s, 3H), 3.38 (m, 2H), 3.15 (s, 3H), 2.69 (m, 4H), 1.82 (s, 3HfcMS (m/z): 349 [m+H]+.
EXAMPLE 23 Preparation of (5S)-N-[3-(2-Methoxyimino-l-methyl-l,2,3,4- tetrahydro-quinolin-6-yl)-2-oxo-oxazolidin-5-ylmethyl]-propionamide.
Figure imgf000051_0002
Step 1. Preparation of (l-Methyl-2-thioxo-l,2,3,4-tetrahydro-quinolin-6-yl)-carbamic acid benzyl ester. (l-Methyl-2-oxo-l,2,3,4-te1ιahydro-quinolin-6-yl)-carbamic acid benzyl ester (5.00 g , 16.11 mmol) and Lawesson's reagent (4.887 g, 12.08 mmol) in dioxane (40 ml) was heated for 24 hours at 70 °C. The reaction was evaporated and the residue triturated with dichloromethane to give product as a yellow solid (2.85 g, 54%); HPLC r.t. 5.88 min; MS (m/z): 326 [m+H]+.
Step 2. Preparation of (2-Methoxyimino-l-methyl-l,2,3,4-tetrahydro-quinolin-6-yl)- carbamic acid benzyl ester. Methoxylamine hydrochloride (3.157 g, 37.8 mmol) and (l-methyl-2-thioxo- l,2,3,4-tetrahydro-quinolin-6-yl)-carbamic acid benzyl ester (3.00 g , 9.22 mmol) in pyridine (45 mL), was added) was heated for 48 hours at 70 °C. The reaction was evaporated, diluted with dichloromethane, washed with water and brine, dried (MgSO ) and evaporated. The residue was purified by flash column chromatography (20% ethyl acetate/hexanes) to give product as a white solid (1.16 g, 37%). (HPLC r.t. 4.93 min; MS (m/z): 340 [m+H]+.
Step 3. Preparation of (5S)-[3-(2-Methoxyimino-l-methyl-l,2,3,4-tetrahydro-quinolin- 6-yl)-2-oxo-oxazolidin-5-ylmethyl]-carbamic acid tert-butyl ester. Lithium t-butoxide (1M in THF, 7.13 mL, 7.13 mmol) was added at 0 °C to (2- methoxyimino-l-methyl-l,2,3,4-tetrahydro-quinolin-6-yl)-carbamic acid benzyl ester (1.10 g , 3.24 mmol) and (3-chloro-2-hydroxy-propyl)-carban ic acid tert-butyl ester (1.024 g, 4.884 mmol)in DMF (10 mL). The mixture was allowed to warm to room temperature and stirred for 24 hours. The reaction was quenched with saturated aqueous ammonium chloride and extracted with dichloromethane. The organic layer was separated, washed with brine, dried (Na2SO4) and evaporated. The residue was purified by flash column chromatography (30% ethyl acetate/hexanes) to give product as a pale yellow oil (1.10 g, 37%); HPLC r.t. 4.57 min; MS (m/z): 405 [m+H]+.
Step 4. Preparation of (5R)-6-(5-Aminomethyl-2-oxo-oxazolidin-3-yl)-l-methyl-3,4- dihydro- lH-quinolin-2-one O-methyl-oxime (5S)- [3-(2-Methoxyimino- 1 -methyl- 1 ,2,3 ,4-tetrahydro-quinolin-6-yl)-2-oxo- oxazolidin-5-ylmethyl]-carbamic acid tert-butyl ester (1.00 g , 2.47 mmol) was stirred with 50% TFA/DCM (4 ml) for 90 minutes at room temperature. The solvent was evaporated to give pure product quantitatively as a pale yellow oil; HPLC r.t. 2.93 min; MS (m/z): 419 [m+H]+.
Step 5. Preparation of (5S)-N-[3-(2-Methoxyimino-l-methyl-l,2,3,4-tetrahydro- quinolin-6-yl)-2-oxo-oxazolidin-5-ylmethyl]-propionamide. Propionic anhydride (0.325 ml, 2.538 mmol) was added to (5R)-6-(5- aminomethyl-2-oxo-oxazolidin-3-yl)-l-methyl-3,4-dihydro-lH-quinolin-2-one O- methyl-oxime (0.531 g , 1.27 mmol) and diisopropylethylamine (0.629 ml, 3.081 mmol) in dichloromethane (5 ml) was added) at 0 °C. The mixture was stirred at 0 °C for 30 minutes and then allowed to warm to room temperature. The reaction was diluted with dichloromethane, washed with water, citric acid and brine, dried (Νa2SO4) and evaporated. The residue was purified by PTLC (3%MeOH / DCM) to give product as an off white solid (0.061 g, 13%); HPLC r.t. 3.45 min; 1H NMR (300 MHz, CDC -d) δ 7.27 (d, I = 2.4 Hz, IH), 7.20 (dd, I = 2.4, 8.7 Hz, IH), 6.79 (d, J = 9 Hz, IH), 6.24 (t, J = 6.3 Hz, IH), 4.69-4.78 (m, IH), 4.00 (t, J = 9 Hz, IH), 3.77 (s, 3H), 3.58-3.76 (m, 3H), 3.22 (s, 3H), 2.67-2.82 (m, 4H), 2.22 (q, J = 7.5 Hz, 2H), 1.10 (t, I = 7.5 Hz, 3H); MS (m/z): 361 [m+H]+.
EXAMPLE 24 Preparation of (5S)-[3-(2-Methoxyimino-l-methyl-l,2,3,4- tetrahydro-quinolin-6-yl)-2-oxo-oxazolidin-5-ylmethyl] -carbamic acid methyl ester.
Figure imgf000053_0001
Methyl chloroformate (0.220 ml, 2.538 mmol) was added to (5R)-7-(5- aminomethyl-2-oxo-oxazolidin-3-yl)-4-methyl-4H-benzo[ 1 ,4]oxazin-3-one oxime. (0.600 g, 1.40 mmol) (from Example 21, step 9) and diisopropylethylamine (0.7 ml, 4.20 mmol) in dichloromethane (6 ml) was added) at 0 °C. The mixture was stirred at 0 °C for 30 minutes and then allowed to warm to room temperature. The reaction was diluted with dichloromethane, washed with water, citric acid and brine, dried
(Na2SO4) and evaporated. The residue was purified by PTLC (3%MeOH / DCM) to give product as an off white solid (181 mg, 36%); HPLC r.t. 3.650 min; 1H NMR (300 MHz, COC - ) δ 7.31 (d, J = 2.4 Hz, IH), 7.21 (dd, J = 2.4, 8.7 Hz, IH), 6.80 (d, J = 9 Hz, IH), 5.11 (t, J = 6.3 Hz, IH), 4.69-4.77 (m, IH), 4.01 (t, J = 9 Hz, IH), 3.77 (s, 3H), 3.67 (s, 3H), 3.43-3.61 (m, 4H), 3.23 (s, 3H), 2.69-2.83 (m, 4H); MS (m/z): 363 [m+H]+.
EXAMPLE 25 Preparation of (5S)-N-[3-(5-Fluoro-3-methoxyimino-4-methyl-
3,4-dihydro-2H-benzo[l,4]oxazin-7-yl)-2-oxo-oxazolidin-5-ylmethyl]-acetamide.
Figure imgf000054_0001
Step 1: Preparation of 2-amino-3-fluoro-5-nitro-phenol. 4-Fluoro-6-nitro-l, 3-benzoxazol-2 (3H)-one (prepared according to the method described in WO/03072553) (5.0 g, 0.02 mol) and sodium hydroxide (5.05 g, 0.126 mol) in water (125 ml) is heated at 100 °C for 3 h. The reaction mixture is cooled to room temperature and carefully neutralized with 6Ν hydrochloric acid. The resulting precipitate is filtered, washed with water and dried under vacuum to provide pure the title compound as orange solid (3.1 g, 72%); HPLC r.t. 4.05 min.
Step 2: Preparation of 5-fluoro-7-nitro-4H-benzo[l,4]oxazin-3-one. Methyl bromoacetate (1.64 g, 0.0107 mol), 3-fluoro-2-amino-5-nitrophenol
(1.68 g, 0.00976 mol) and potassium carbonate (2.7 g, 0.0195 mol) in DMF (20 ml) are heated at 90 °C for 24 h. The reaction mixture is cooled, diluted with water and extracted with ethyl acetate. The organic layer is washed with brine, dried (Na SO4) and evaporated to give the title compound as a brown solid suitable for use directly in the next step (2.03 g, 98%); HPLC r.t. 4.07 min.
Step 3: Preparation of 5-fluoro-4-methyl-7-nitro-4H-benzo[l,4]oxazin-3-one. Iodomethane (1.65 ml, 0.0283 mol), 5-fluoro-7-nitro-4H-benzo[l,4]oxazin-3- one (2.0 g, 0.0094 mol) and potassium carbonate (1.3 g, 0.0094 mol) in DMF (20 ml) are stirred at room temperature for 24 h. The reaction mixture is diluted with ethyl acetate, washed with water and brine, dried (Na2SO ) to give the title compound as a brown solid suitable for use directly in the next step (1.8 g, 84.5%); HPLC r.t. 4.82 min.
Step 4: Preparation of 7-amino-5-fluoro-4-methyl-4H-benzo[l,4]oxazin-3-one. Iron powder (2.27 g, 0.0406 mol) is added in small portion to a mixture of 5- fluoro-4-methyl-7-nitro-4H-benzo[l,4]oxazin-3-one (2.3 g, 0.010 mol) and ammonium chloride (5.41 g , 0.102 mol) in ethanol (100 ml) and water (50 ml) at 90 °C. The reaction mixture is stirred vigorously and heated for 1 hour, cooled to room temperature and diluted with dichloromethane (200 ml). The mixture is filtered through celite, washed with water and brine, dried over sodium sulfate and evaporated to give the title compound as a brown solid (1.77 g, 89%); HPLC r.t. 2.47min.
Step 5: Preparation of (5-fluoro-4-methyl-3-oxo-3,4-dihydro-2H-benzo[l,4]oxazin-7- yl)-carbamic acid benzyl ester. Benzyl chloroformate (1.38 ml, 0.00981 mol) is added dropwise to a mixture of 7-amino-5-fluoro-4-methyl-4H-benzo[l,4]oxazin-3-one (1.75 g, 0.00892 mol) and pyridine (1.44 ml, 0.0178 mol) in dichloromethane (15 ml) at 0 °C. The reaction mixture is stirred at 0 °C for 30 min, allowed to warm at room temperature and then poured into water. The organic layer is separated, washed with brine, dried (Na2SO4) and evaporated to give nearly pure the title compound as a brown solid (2.9 g, 98%); HPLC r.t. 5.7 min.
Step 6: Preparation of (5-fluoro-4-methyl-3-thioxo-3, 4-dihydro-2H- benzo[l,4]oxazin-7-yl)-carbamic acid benzyl ester. 5-Fluoro-4-methyl-3-oxo-3,4-dihydro-2H-benzo[l,4]oxazin-7-yl)-carbamic acid benzyl ester (2.2 g, 0.0066 mol) and Lawesson's reagent (2.04 g, 0.005 mol) in dioxane (15 ml) are heated overnight at 70 °C. The reaction mixture is evaporated and the residue purified by flash column chromatography (30% EtOAc/Hexane) to give the title compound as a yellow solid (1.7 g, 74%); HPLC r.t. 6.68 min; MS for C17Hι5FN2O3S m/z 345.2(M-H)".
Step 7: Preparation of (5-fluoro-3-methoxyimino-4-methyl-3,4-dihydro-2H- benzo[l,4]oxazin-7-yl)-carbamic acid benzyl ester. 5-Fluoro-4-methyl-3-thioxo-3,4-dihydro-2H-benzo[l,4]oxazin-7-yl)- carbamic acid benzyl ester (0.85 g, 2.45 mmol) and methoxylamine hydrochloride (1.22 g, 14.7 mmol) in pyridine (8 ml) are heated overnight at 70 °C. The reaction mixture is evaporated to dryness. The residue is diluted with ethyl acetate, washed with water and brine, dried (Na2SO4) and evaporated to give the title compound (0.88 g, 100%); HPLC r.t. 6.65 min; MS for C18H18FN3O4 m/z 360.2 (M+H)+.
Step 8: Preparation of (5S)-[3-(5-fluoro-3-methoxyimino-4-methyl-3, 4-dihydro-2H- benzo[l,4]oxazin-7-yl)-2-oxo-oxazolidin-5-ylmethyl]-carbamic acid tert-butyl ester. Lithium t-butoxide (1.0 M solution in THF, 7.35 ml, 7.35 mmol) is added dropwise at 0 °C to 5-fIuoro-3-methoxyimino-4-methyl-3,4-dihydro-2H- benzo[l,4]oxazin-7-yl)-carbamic acid benzyl ester (0.8g, 2.4mmol) and (3-chloro-2- hydroxy-propyl)-carbamic acid tert-butyl ester (0.77 g, 3.67 mmol) in DMF (10 ml). The reaction mixture is allowed to warm at room temperature and stirred for 144 h. The reaction is quenched with saturated aqueous ammonium chloride, diluted with water and extracted with dichloromethane. The organic layer is washed with brine, dried (Na2SO4) and evaporated. The residue is purified by flash column chromatography (20% EtOAc/Hexane) to give the title compound as a light yellow solid (0.75 g, 72%); HPLC r.t. 5.87 min; MS for d9H25FN4O6 m z 425.3(M+H)+.
Step 9: Preparation of (5S)-7-(5-aminomethyl-2-oxo-oxazolidin-3-yl)-5-fluoro-4- methyl-4H-benzo [ 1 ,4] oxazin-3 -one O-methyl-oxime. 3-(5-Fluoro-3-methoxyimino-4-methyl-3,4-dihydro-2H-benzo[l,4]oxazin-7- yl)-2-oxo-oxazolidin-5-ylmethyl] -carbamic acid tert-butyl ester (0.47 g, 1.11 mmol) is stirred with 50% TFA/DCM (4 ml) for 1 h at room temperature. The reactiuon mixture is evaporated to give the title compound as the TFA salt (0.48 g, 99%); HPLC r.t. 3.76 min; MS for C14Hι7FN4O4 m/z 325.2(M+H)+.
Step 10: Preparation of (5S)-N-[3-(5-fluoro-3-methoxyimino-4-methyl-3, 4-dihydro- 2H-benzo[l,4]oxazin-7-yl)-2-oxo-oxazolidin-5-ylmethyl]-acetamide. Acetic anhydride (0.156 ml, 1.64 mmol) is added dropwise at 0 °C to (5R)-7- (5-aminomethyl-2-oxo-oxazolidin-3-yl)-5-fluoro-4-methyl-4H-benzo[l,4]oxazin-3- one O-methyl-oxime (0.355 g, 1.09 mmol) and diisopropylethylamine (0.57 ml, 3.27 mmol) in dichloromethane (5 ml). The reaction mixture is stirred at 0 °C for 30 min then allowed to warm at room temperature. The reaction mixture is diluted with dichloromethane washed with water, citric acid and brine, dried (Na2SO ) and evaporated to give the title compound as a light brown solid (0.305 g, 76%); HPLC r.t. 4.53 min; 1H NMR (300 MHz, DMSC fø δ 8.22 (t, IH), 7.16 (dd, IH), 7.01 (d, IH), 4.92 (s, 2H), 4.69 (m, IH), 4.05 (t, IH), 3.69 (s, 3H), 3.64 (dd, IH), 3.37 (m, 2H), 3.26 (s, 3H), 1.82 (s, 3H); MS for C16H19FN4O5 m/z 367.3(M+H)+.
EXAMPLE 26 Preparation of (55)- 1 -[3-(5-Fluoro-3-methoxyimino-4-methyl- 3 ,4-dihydro-2H-benzo [ 1 ,4]oxazin-7-yl)-2-oxo-oxazolidin-5-ylmethyl] -carbamic acid methyl ester.
Figure imgf000057_0001
Methyl chloroformate (0.12 ml, 1.55 mmol) was added dropwise to (5R)-7-(5- aminomethyl-2-oxo-oxazolidin-3-yl)-5-fluoro-4-methyl-4H-benzo [1,4] oxazin-3-one O-methyl-oxime (0.34 g, 0.775 mmol) (from Example 21, step 9) and diisopropyl ethylamine (0.80 ml, 4.65 mmol) in dichloromethane (5 ml) at 0 °C. The mixture was stirred at 0 °C for 30 minutes and then allowed to warm to room temperature. The reaction was diluted with dichloromethane, washed with water, citric acid and brine, dried (Na2SO ) and evaporated. The residue was purified by PTLC (10%MeOH / DCM) to give product as an off white solid (0.24 g, 80.7%); HPLC r.r. 4.90 min; 1H NMR (300 MHz, CDCl3-d) δ 7.11 (dd, I = 2.4, 14.4 Hz, IH), 6.86 (dd, I = 1.8, 2.7 Hz, IH), 5.16 (t, IH), 4.88 (s, 2H), 4.70-4.79 (m, IH), 3.98 (t, J = 8.7 Hz, IH), 3.78 (s, 3H), 3.68 (s, 3H), 3.47-3.75 (m, 3H), 3.36 (d, I = 4.8 Hz, 3H); MS for Cι6H19FN4O6 m/z 383.0(M+H)+.
EXAMPLE 27 Preparation of [3-(3-Hydroxyimino -4-methyl-3,4-dihydro-2H- benzo[l,4]oxazin-7-yl)-2-oxo-oxazolidin-5-ylmethyl]-carbamic acid methyl ester
Figure imgf000057_0002
Step 1: Preparation of 7-nitro-4H-benzo [1,4] oxazin-3 -thione 7-Nitro-4H-benzo [1,4] oxazin-3-one (5.0 g, 25.75 mmol) and Lawesson's reagent (7.78 g, 19.31mmol) in tetrahydrofuran (50 ml) was heated 3 hours at 55 °C. The mixture was evaporated and residue triturated with dichloromethane and dried under vacuum to give product as a greenish yellow solid (5.3 g, 97.9%); HPLC r.t. 4.87 min; MS for C8H6N2O3S m/z 209.0 (M-H)".
Step 2: Preparation of 7-nitro-4H-benzo [1,4] oxazin-3-one O-methyl-oxime 7-Nitro-4H-benzo [1,4] oxazin-3 -thione (2.5 g, 11.89 mmol) and methoxylamine hydrochloride (2.97 g, 35.67 mmol) in pyridine (15 ml) was heated overnight at 70°C. The mixture was evaporated and the residue diluted with ethyl acetate, washed with 5% aqueous citric acid, water and brine, dried (Na2SO4) and evaporated to give product as a yellow solid (2.55 g, 96%); HPLC r.t. 4.59 min; MS for C9H9N3O4 m/z 222.2 (M-H)".
Step 3: Preparation of 7-Amino-4H-benzo [1,4] oxazin-3-one O-methyl-oxime Iron powder (1.18g, 21.5mmol) was added in small portion to a mixture of 7- nitro-4H-benzo [1,4] oxazin-3-one O-methyl-oxime (1.2 g, 5.37 mmol) and ammonium chloride (2.82 g, 53.7 mmol) in ethanol (50 ml) and water (25 ml) at 90 °C. The reaction mixture was stirred vigorously and heated for 1 hour, cooled to room temperature and diluted with dichloromethane (200 ml). The mixture was filtered through celite, washed with water and brine, dried (Na SO4) and evaporated to give product as a brown solid (0.621g, 60%); HPLC r.t. 1.83 min; MS for C9HπN3O2 m/z 194.0 (M+H)+.
Step 4: Preparation of (3-Methoxyimino-3,4-dihydro-2H-benzo [1,4] oxazin-7-yl) - carbamic acid benzyl ester Benzyl chloroformate (0.497 ml, 3.53 mmol) was added dropwise to a mixture of 7-amino-4H-benzo [1,4] oxazin-3-one O-methyl-oxime (0.62 g, 3.21 mmol) and pyridine (0.52 ml, 6.42 mmol) in dichloromethane (10 ml) at 0 °C. The reaction mixture was stirred at 0 °C for 30 minutes, allowed to warm at room temperature and then poured into water. The organic layer was separated, washed with brine, dried (Na2SO ) and evaporated. The residue was purified by flash column chromatography (20%EtOAc / Hexane) to give product as a white solid (0.56 g, 53.3%); HPLC r.t. 5.19 min; MS for C17H17N3O4 m/z 328.0 (M+H)+.
Step 5: Preparation of (5S)-[3-(3-Methoxyimino-3,4-dihydro-2H-benzo [1,4] oxazin- 7-yl) -2-oxo-oxazolidin-5-ylmethyl]-carbamic acid tert-butyl ester Lithium t-butoxide (1.0 M, 4.2 ml, 4.2 mmol) was added to (3-methoxyimino-
3,4-dihydro-2H-benzo [1,4] oxazin-7-yl) -carbamic acid benzyl ester (0.46 g, 1.40 mmol) and (3-chloro-2-hydroxy-propyl)-carbamic acid tert-butyl ester (0.445 g, 2.10 mmol) in DMF (5 ml) at 0°C. The mixture was allowed to warm at room temperature and stirred for 144 hours. The reaction was quenched with saturated aqueous ammonium chloride and extracted with dichloromethane. The extract was washed with brine, dried (Na2SO ) and evaporated. The residue was purified by PTLC
(5%MeOH / DCM) to give product as a white solid (0.18g, 32.6%); HPLC r.t.
4.58min; MS for C18H24N4O6 m/z 393.1(M+H)+.
Step 6: Preparation of (5R)-7-(5-Aminomethyl-2-oxo-oxazolidin-3-yl)- 4H-benzo
[1,4] oxazin-3 -one O-methyl-oxime. (5R)-3-(3-Methoxyimino-3,4-dihydro-2H-benzo [1,4] oxazin-7-yl) -2-oxo- oxazolidin-5-ylmethyl]-carbamic acid tert-butyl ester (0.06 g, 0.153 mmol) was treated with 50% TFA / DCM (1 ml) for 30 min at room temperature. Solvent was evaporated and product was isolated as the TFA salt. (0.062 g, 99.9%); HPLC r.t. 2.76 min; MS for d3H16N4O4 m/z 293.0(M+H)+.
Step 7: Preparation of (5S)-[3-(3-Hydroxyimino -4-methyl-3,4-dihydro-2H- benzo[ 1 ,4]oxazin-7-yl)-2-oxo-oxazolidin-5-ylmethyl]-carbamic acid methyl ester. Methyl chloroformate (0.016ml, 0.205mmol)was added to (5R)-7-(5- aminomethyl-2-oxo-oxazolidin-3-yl)- 4Η-benzo [1,4] oxazin-3-one O-methyl-oxime (0..06 g, 0.171 mmol) and diisopropylethylamine (0.117 ml, 0.68 mmol) in dichloromethane (2 ml) at 0°C. The mixture was stirred at 0 °C for 30minutes. The reaction was diluted with dichloromethane, washed with water and brine, dried
(Na2SO4) and evaporated. The residue was purified by PTLC (5%MeOH / DCM) to give product as a white solid (0.04 g, 74%); HPLC r.t. 3.68 min; 1H NMR (300 MHz, CDCl3-d) δ 7.23 (br s, 1H),7.13 (d, J = 2.4 Hz, IH), 7.09 (dd, J = 2.4, 8.7 Hz, IH), 6.77 (d, I = 9 Hz, IH), 5.13 (t, IH), 4.74 (m, 2H), 4.55 (s, 2H), 4.01 (t, I = 9 Hz, IH), 3.85 (s, 3H), 3.68 (s, 3H), 3.47-3.78 (m, 3H); MS for C15H18N4O6 m/z 351.1(M+H)+.
EXAMPLE 28 Preparation of 7-(5R-hydroxymethyl-2-oxo-oxazolidin-3-yl)-4- methyl-4H-benzo[l,4]oxazin-3-one O-methyl-oxime.
Figure imgf000060_0001
Lithium bis(trimethylsilyl)amide (1.0 M in TΗF, 3.21 ml, 0.00321 mol) is added dropwise at -78 °C to (3-methoxyimino-4-methyl-3,4-dihydro-2H- benzo[l,4]oxazin-7-yl)-carbamic acid benzyl ester (1.0 g, 0.00292 mol) in TΗF (10 ml). The reaction mixture is stirred at -78 °C for lh and then (R)-glycidyl butyrate (0.46 ml, 0.00321 mol) added dropwise. The mixture is allowed to warm to room temperature and stirred overnight. The reaction is quenched with saturated ammonium chloride, diluted with water and extracted with ethyl acetate. The extract is washed with water and brine, dried (Na2SO4) and evaporated to give the title compound as crude product. Trituration with dichloromethane/hexane to gave product as a light brown solid (0.65 g, 72%); ΗPLC r.t. 4.18 min; 1H NMR (300 MHz, CDCl3-d) δ 7.14-7.16 (m, 2H),7.13, 6.82 (d, I = 9.6 Hz, IH), 4.94 (m, 2H), 4.74 (m, IH), 3.90-4.03 (m, 3H), overlapping 3.78 (s, 3H) and 3.74-3.79 (m, IH), 3.26 (s, 3H); MS for Cι4H17N3O5 m/z 308.0(M+H)+.
Example 29 Preparation of (5S)-N-[3-(3-Cyanoimino-4-methyl-3,4-dihydro-2H- benzo[ 1 ,4]oxazin-7-yl)-2-oxo-oxazolidin-5-ylmethyl]-acetamide.
Figure imgf000060_0002
Step 1: Preparation of 4-Methyl-7-nitro-4H-benzo[l,4]oxazin-3-ylidene-cyanamide.
Methyl trifilate (0.50 ml, 4.44 mmol) was added to 4-methyl-7-nitro-4H- benzo[l, 4] oxazine-3 -thione (0.50 g, 2.22 mmol) in dichloromethane (10 ml) at 0 °C. The mixture was allowed to warm to room temperature and stirred overnight to provide a solution of 4-methyl-3-methylsulfanyl-7-nitro-2H-benzo[l,4]oxazin-4-ium triflate in dichloromethane. Cyanamide (0.186 g, 4.44 mmol) was added portionwise to diisopropylethylamine (0.76 ml, 4.44 mmol) in THF (5 ml) at room temperature and stirred for 30 minutes . The solution was then transferred via canula to the benzoxazinium salt solution prepared above at 0 °C. The mixture was allowed to warm to room temperature and stirred for 40 minutes, and then diluted with water and extracted with ethyl acetate. The organic layer was separated, washed with water, aqueous ammonium chloride and brine, dried (Na2SO4) and evaporated.. The residue wa purified by flash column chromatography (40% EtOAc / Hexane) to give the product as a yellow solid (0.23 g, 44%); HPLC r.t. 4.38 min; MS for C10H8N4O3 m/z 231.0.1 (M-H)".
Step 2: Preparation of 7- Amino-4-methyl-4H-benzo[ 1,4] oxazin-3 -ylidene-cyanamide Iron powder (0.182 g, 3.27 mmol) was added in small portions to 4-methyl-7- nitro-4H-benzo[ 1,4] oxazin-3 -ylidene-cyanamide (0.19 g, 0.818 mmol) and ammonium chloride (0.433 g, 8.18 mmol) in ethanol (20 ml) and water (10 ml) at 90 °C. The reaction mixture was stirred vigorously and heated for 30 minutes, allowed to cool to room temperature, and diluted with dichloromethane (50 ml). The mixture was filtered through celite, washed with water and brine, dried (Na SO4) and evaporated to give product as a yellow solid (0.165 g, 100%); ΗPLC r.t. 2.39 min; MS for C10Ηι0N4O m/z 203.1 (M+H)+.
Step 3: Preparation of [3-(3-Cyanoimino-4-methyl-3,4-dihydro-2H-benzo[l,4]oxazin- 7-ylamino)-(2R)-hydroxy-ρropyl]-carbamic acid tert-butyl ester. 7-Amino-4-methyl-4H-benzo[l,4]oxazin-3-ylidene-cyanamide (0.17 g, 0.84 mmol), oxiranylmethyl-carbamic acid tert-butyl ester (0.145 g, 0.84 mmol) and lithium trifluoromethanesulfonate (0.13 g, 0.84 mmol) in acetonitrile (5 ml) was heated at 90 °C overnight. The reaction mixture was diluted with ethyl acetate, washed with water and brine, dried (Na2SO4) and evaporated. Purification by flash column chromatography (20% Acetone / DCM) gave product as a light brown solid (0.090g, 28.5%); HPLC r.t. 4.15min; MS for C18H25N5O4 m/z 376.3(M+H)+. Step 4: Preparation of (5S)-[3-(3-Cyanoimino-4-methyl-3,4-dihydro-2H- benzo[l,4]oxazin-7-yl)-2-oxo-oxazolidin-5-ylmethyl]-carbamic acid tert-butyl ester. [3-(3-Cyanoimino-4-methyl-3,4-dihydro-2H-benzo[l,4]oxazin-7-ylamino)- (2R)-hydroxy-propyl] -carbamic acid tert-butyl ester(0.09 g, 0.239 mmol) and 1,1- carbonyldiimidazole (0.043 g, 0.239 mmol) in acetonitrile (3 ml) was stirred and heated at 60 °C for 2 hours. The reaction mixture was diluted with ethyl acetate, washed with water and brine, dried (Na SO4) and evaporated. The residue was purified by PTLC (10%MeOΗ / DCM) to give product as an off white solid (0.05 g, 52%); HPLC r.t. 4.74 min; MS for C19H23N5O5 m/z 402.4(M+H)+.
Step 5: Preparation of (5R)-7-(5-Aminomethyl-2-oxo-oxazolidin-3-yl)-4-methyl-4H- benzo[l,4]oxazin-3-ylidene-cyanamide. (5S)-[3-(3-Cyanoimino-4-methyl-3,4-dihydro-2H-benzo[l,4]oxazin-7-yl)-2-oxo- oxazolidin-5-ylmethyl]-carbamic acid tert-butyl ester (0.040 g, 0.0996 mmol) was treated with 50% TFA / DCM (1 ml) for 30 minutes at room temperature. The reaction was evaporated and the product isolated as the TFA salt (0.040g, 96%); HPLC r.t. 2.96 min; MS for C14Hι5N5O3 m/z 302.1(M+H)+.
Step 6: Preparation of (5S)-N-[3-(3-Cyanoimino-4-methyl-3,4-dihydro-2H- benzo[l,4]oxazin-7-yl)-2-oxo-oxazolidin-5-ylmethyl]-acetamide. Acetic anhydride (0.014ml, 0.144mmol) was added to (5R)-7-(5-aminomethyl- 2-oxo-oxazolidin-3-yl)-4-methyl-4H-benzo[l,4]oxazin-3-ylidene-cyanamide (0.040 g, 0.096 mmol) and diisopropylethylamine (0.066 ml, 0.384 mmol) in dichloromethane (3 ml) at 0°C. The reaction mixture was stirred at 0 °C for 30 minutes and then allowed to warm to room temperature. The mixture was diluted with dichloromethane, washed with water, citric acid and brine, dried (Νa2SO4), and evaporated. The residue was purified by HPLC (Acetonitrile / Water) to give product as an off white solid (0.010 g, 29.4%); 1H NMR (300 MHz, CDCl3-d) δ 7.31 (d, J = 2.4 Hz, IH), 7.24 (dd, J = 2.4, 8.7 Hz, IH), 7.06 (d, I = 9 Hz, IH), 6.02 (t, IH), 5.05 (s, 2H), 4,80 (m, IH), 4.04 (t, J = 9 Hz, IH), 3.58-3.81 (m, 3H), 3,50 (s, 3H), 2.03 (s, 3H); MS for Cι6Hι7N5O4 m/z 344.1(M+H)+.

Claims

CLAIMSWhat is claimed is:
1. A compound of formula I
Figure imgf000063_0001
I or a pharmaceutically acceptable salt thereof wherein: X is a structure of the following formula i, ii, iii, or iv
Figure imgf000063_0002
W is (a) CH2NHC(=O)R1, (b) CH2NHC(=S)R1, (c) CH2NH-het, (d) CH2O-het, (e) CH2S-het, (f) CH2het, (g) CH2OH, (h) CH(OH)-CH=CHR1, or (i) CH OH^C ≡ CR1; γ 2 and Y are independently (a) CH, (b) N, (c) N+-O", or (d) CF;
G is -(CR3R4)n-;
U is (a) CH2, (b) CF2, (c) O, or (d) S(=O)m; R s (a) NH2, (b) NHCι-6alkyl, (c) Cj-ealkyl, (d) C2-6alkenyl, (e) (CH2)jC(=O)C1.4alkyl, (f) OCι-6alkyl, (g) Sd-βalkyl, or (h) (CH2)jC3-7cycloalkyl;
R2 is H or Q^alkyl, optionally substituted with 1-3 fluoro;
R3 and R4 are independently (a) H (b) Cι-6 alkyl, or (c) R3 and R4 taken together with the carbon atom to which they attach form C3-7cycloalkyl; V is N, or C; Z is (a) H, (b) OH, (c) CN, (d) NO2, (e) d-ealkyl, (f) OCι-6alkyl, (g) aryl, (h) het, (i) C(=O)C1-6alkyl, G) C(=O)-het, (k) OC(=O)Cι-6alkyl, (1) C(=O)NR5R6, (m) SO2-Cι-6alkyl, or (n) SO2-NR5R6; R5 and R6 are independently (a) H, or (b) Ci-4alkyl, optionally substituted with OH, phenyl, or OQ^alkyl; aryl is phenyl, biphenyl, or naphthyl, optionally substituted with halo, OR5, SR5, CN, NO2, NR5R6, CF3, OCF3, C(=O)C1-4alkyl, OC(=O)d-4alkyl, C(=O)OR5, or S(O)nC1-4alkyl; het is a five- (5) or six- (6) membered heterocyclic ring having 1-4 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen within the ring, wherein each carbon atom in het is optionally substituted with halo, OR5, SR5, CN, NO2, NR5R6, oxo, CF3, OCF3, C(=O)Cι-4alkyl,
Figure imgf000065_0001
C(=O)OR5, or S(O)nC1.4alkyl; at each occurrence, Q-βalkyl, C2-6alkenyl, or C3. cycloalkyl is ptionally substituted with 1-3 halo, OR5, SR5, CN, N3, NO2, NR5R6, C(=O)Cι-4alkyl, OC(=O)C1-4alkyl, C(=O)OC1-4alkyl, C3.6cycloalkyl, or S(O)nCι-4alkyl; each n is independently 1 or 2; m is O, l, or 2; and each j is independently 0-4.
2. A compound of claim 1 wherein X is a structure of formula ii
Figure imgf000065_0002
ii.
3. A compound of claim 2 wherein W is CH2NHC(=O)R1.
4. A compound of claim 5 wherein R1 is CH3, CH2CH3.CHF2, CF3, or CHC12
5. A compound of claim 2-4 wherein Y1, Y2, or Y3 is CH.
6. A compound of claim 2-4 wherein Y1 is CF, Y2 and Y3 are CH.
7. A compound of claim 2-4 wherein G is CH2.
8. A compound of claim 2-4 wherein U is CH2, O, or S
9. A compound of claim 2-4 wherein N is Ν.
10. A compound of claim 2-4 wherein R2 is CH3, CH2F, or CHF2.
11. A compound of claim 2-4 wherein Z is OCi-βalkyl, optionally substituted with OH, or OC1.4alkyl, wherein OCι-4alkyl may be further substituted with a phenyl.
12. A compound of claim 2-4 wherein Z is OCH3, or OH.
13. A compound of claim 2 which is
(a) (5S)-N-[3-(3-Methoxyimino-4-methyl-3,4-dihydro-2H-benzo[l,4]oxazin-7- yl)-2-oxo-oxazolidin-5-ylmethyl]-acetamide, (b) (5S)-N-[3-(3-Methoxyimino-4-methyl-3, 4-dihydro-2H-benzo[l,4]oxazin-7- yl)-2-oxo-oxazolidin-5-ylmethyl]-propionamide,
(c) (5S)-N-[3-(3-Methoxyimino-4-methyl-3, 4-dihydro-2H-benzo[l,4]oxazin-7- yl)-2-oxo-oxazolidin-5-ylmethyl]-carbamic acid methyl ester,
(d) (5S)-l-[3-(3- Methoxyimino-4-methyl-3,4-dihydro-2H-benzo[l,4]oxazin-7- yl)-2-oxo-oxazolidin-5-ylmethyl]-3-methyl-urea,
(e) (5R)-4-Methyl-7-(2-oxo-5-[ 1 ,2,3]triazol- 1 -ylmethyl-oxazolidin-3-yl)-4H- benzo [1,4] oxazin-3 -one O-methyl-1 -oxime,
(f) (5S)-N-[3-(3-Ethoxyimino-4-methyl-3,4-dihydro-2H-benzo[l,4]oxazin-7-yl)- 2-oxo-oxazolidin-5-ylmethyl]-acetamide, (g) (5S)-N-[3-(3-Hydroxyimino-4-methyl-3,4-dihydro-2H-benzo[l,4]oxazin-7-yl)-
2-oxo-oxazolidin-5-ylmethyl]-acetamide,
(h) (5S)-[3-(3-Hydroxyimino -4-methyl-3,4-dihydro-2H-benzo[l,4]oxazin-7-yl)-
2-oxo-oxazolidin-5-ylmethyl] -carbamic acid methyl ester,
(i) (5S)-N-[3-(3-Isopropoxyirnino-4-methyl-3,4-dihydro-2H-benzo[l,4]oxazin-7- yl)-2-oxo-oxazolidin-5-ylmethyl]-acetamide,
(j) (5S)-N- { 3-[3-(2-Fluoro-ethoxyimino)-4-methyl-3,4-dihydro-2H- benzo[l,4]oxazin-7-yl)-2-oxo-oxazolidin-5-ylmethyl}-acetamide, (k) (5S)-N- { 3- [3-(2-Methoxy-ethoxyimino)-4-methyl-3 ,4-dihydro-2H- benzo [1,4] oxazin-7-yl)-2-oxo-oxazolidin-5-ylmethyl } -acetamide, (1) (5S)-N-[3-(3-Methoxy-methoxyimino)-4-methyl-3,4-dihydro-2H- benzo[ 1 ,4]oxazin-7-yl)-2-oxo-oxazolidin-5-ylmethyl } -acetamide, (m) (5S)-Ν-[3-(3-Cycloρroρyl-methoxyimino)-4-methyl-3,4-dihydro-2H- benzo [ 1 ,4] oxazin-7-yl)-2-oxo-oxazolidin-5-ylmethyl } -acetamide, (n) (5S)-N-[3-(3-Cyclohexyl-methoxyimino)-4-methyl-3,4-dihydro-2H- benzo [ 1 ,4] oxazin-7-yl)-2-oxo-oxazolidin-5-ylmethyl } -acetamide, (o) (5S)-N-[3-(3-Cyclobutyl-methoxyimino)-4-methyl-3,4-dihydro-2H- benzo [l,4]oxazin-7-yl)-2-oxo-oxazolidin-5-ylmethyl} -acetamide,
(p) (5S)-N-{3-[3-(2-Dimethylamino-ethoxyimino)-4-methyl-3,4-dihydro-2H- benzo[l,4]oxazin-7-yl)-2-oxo-oxazolidin-5-ylmethyl}-acetamide,
(q) (5S)-N- { 3-[3-(2-Benzyloxy-ethoxyimino)-4-methyl-3,4-dihydro-2H- benzo[ 1 ,4]oxazin-7-yl)-2-oxo-oxazolidin-5-ylmethyl } -acetamide, (r) (5S)-N-{ 3-[3-(2-Hydroxy-ethoxyimino)-4-methyl-3,4-dihydro-2H- benzo [ 1 ,4] oxazin-7-yl)-2-oxo-oxazolidin-5-ylmethyl } -acetamide, (s) (5S)-N-[3-(3-Hydroxyimino-4-methyl-3,4-dihydro-2H-benzo[l,4]thiazin-7-yl)- 2-oxo-oxazolidin-5-ylmethyl]-acetamide, (t) (5S)-N-[3-(3-Methoxyimino-4-methyl-3,4-dihydro-2H-benzo[l,4]thiazin-7- yl)-2-oxo-oxazolidin-5-ylmethyl]-acetamide,
(u) (5S)-N- [3-(2-Ηydroxyimino- 1 -methyl- 1 ,2,3 ,4-tetrahydro-quinolin-6-yl)-2-oxo- oxazolidin-5-ylmethyl]-acetamide,
(v) (5S)-N-[3-(2-Methoxyimino- 1 -methyl- 1 ,2,3,4-tetrahydro-quinolin-6-yl)-2-oxo- oxazolidin-5-ylmethyl]-acetamide, (w) (5S)-N-[3-(2-Methoxyimino- 1 -methyl- 1 ,2,3 ,4-tetrahydro-quinolin-6-yl)-2-oxo- oxazolidin-5-ylmethyl]-propionamide,
(x) (5S)-[3-(2-Methoxyimino-l-methyl-l,2,3,4-tetrahydiO-quinolin-6-yl)-2-oxo- oxazolidin-5-ylmethyl]-carbamic acid methyl ester, (y) (5S)-N-[3-(5-Fluoro-3-methoxyimino-4-methyl-3,4-dihydro-2H- benzo[l,4]oxazin-7-yl)-2-oxo-oxazolidin-5-ylmethyl]-acetamide,
(z) (5S)-l-[3-(5-Fluoro-3-methoxyimino-4-methyl-3,4-dihydro-2H- benzo[l,4]oxazin-7-yl)-2-oxo-oxazolidin-5-ylmethyl]-carbamic acid methyl ester, (aa) [3-(3-Hydroxyimino -4-methyl-3,4-dihydro-2H-benzo[l,4]oxazin-7-yl)-2-oxo- oxazolidin-5-ylmethyl]-carbamic acid methyl ester,
(bb) 7-(5R-hydroxymethyl-2-oxo-oxazolidin-3-yl)-4-methyl-4H-benzo[l,4]oxazin- 3 -one O-methyl-oxime, or (cc) (5S)-N-[3-(3-Cyanoirnino-4-methyl-3,4-dihydro-2H-benzo[l,4]oxazin-7-yl)-2- oxo-oxazolidin-5-ylmethyl]-acetamide.
14. A use of a compound of claim 1 for the preparation of a medicament for treating bacteria infectious diseases.
15. The bacteria infectious diseases of claim 14 which is ear infections, eye infections, respiratory tract infections, skin and skin structure infections, joint and bone infections, bacterial endocarditis, osteomyelitis, or diabetic foot.
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