OXAZOLK ⁾ INONE CARBOXAMIDES CONTAINING AZETIDINE AND CYCLOBUTANE AS ANTIBACTERIAL AGENTS

FIELD OF INVENTION

The present invention relates to novel oxazolidinones carboxamide derivatives bearing azetidine and cyclobutane rings, pharmaceutical compositions thereof, methods for their use, and methods for preparing these compounds. These compounds have potent activities against gram-positive and/or gram-negative bacteria.

BACKGROUND OF THE INVENTION

Antibacterial resistance is a global clinical and public health problem that has emerged with alarming rapidity in recent years and undoubtedly will increase in the near future. Resistance is a problem in the community as well as in health care settings, where transmission of bacteria is greatly amplified. Because multiple drug resistance is a growing problem, physicians are now confronted with infections for which there is no effective therapy. As result, structurally novel antibacterials with a new mode of action have become increasingly important in the treatment of bacterial infections.

Among newer antibacterial agents, oxazolidinone compounds are the most recent synthetic class of antimicrobials. This invention provides azetidine and cyclobutane derivatives of oxazolidinones as an inhibitors of bacterial protein synthesis for the treatment of serious infections caused by a number of human and veterinary pathogens, including multiple resistant strains of bacteria.

INFORMATION DISCLOSURE

DE10129725, JPl 1322729, US4705799, WO9613502, WO9710223, WO9854161, WO9912914, WO200027830, WO200032599, WO200232857, WO200206278, WO2003072553, WO2003008389, WO2003007870, WO2003006440, WO2004014392 disclose oxazolidinone compounds useful as antibacterial agents.

SUMMARY OF THE INVENTION The present invention provides a compound of formula I

I or a pharmaceutically acceptable salt thereof wherein: W is O or S; Y ¹ , Y ² , Y ³ , Y ⁴ are independently CH or CF; Z is CH or N; R ¹ and R ² are independently

(a) -H,

(b) halo,

(c) -CN

(d) -C(=W)NR ³ R ⁴

(e) -(C=O)C _1-6 alkyl (f) -(C=O)C ₃ . ₈ cycloalkyl

(g) -COOH

(h) -Ci-βalkyl, (i) -WC _1-6 alkyl, (j) -C _3-8 CyClOaIlCyI, (k) -OC ₃ . ₈ cycloalkyl, or

(1) R ¹ and R ² taken together form =O, =N-OH, =N-OC _1-4 alkyl, =CH-CN; R ³ is -H, -Ci _-6 alkyl, or -OCi. ₆ alkyl; at each occurrence, Ci _-6 alkyl, or C _3-8 cycloalkyl is optionally substituted with CF ₃ , 1-3 halo, OH, OCi _-4 alkyl, CN, N ₃ , 0(C=O)C _1-4 alkyl, C ₃ . ₆ cycloalkyl, NH ₂ , NHC(=O)Ci _-4 alkyl, or C(=O)C _1-4 alkyl; and n is 0, 1, or 2.

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 or gram-negative 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 Q. _j indicates a moiety of the integer "i" to the integer "j" carbon atoms, inclusive. Thus, for example, Ci. ₆ alkyl 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 _3-8 CyClOaIlCyI" or "Ca^cycloalkyl" refers to a cyclic saturated monovalent hydrocarbon group of three to eight or three to six carbon atoms, e.g., cyclopropyl, cyclohexyl, and the like.

The term "halo" refers to fluoro (F), chloro (Cl), bromo (Br), or iodo (I). 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.

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".

It will be appreciated by those skilled in the art that compounds of the invention having a chiral center may exist in and be isolated in optically active and racemic forms.

Some compounds may exhibit polymorphism. It is to be understood that the present invention encompasses any racemic, optically-active, polymorphic, tautomeric, or stereoisomeric form, or mixture thereof, of a compound of the invention, which possesses the useful properties described herein, it being well known in the art how to prepare optically active forms (for example, by resolution of the racemic form by recrystallization techniques, by synthesis from optically-active starting materials, by chiral synthesis, or by chromatographic separation using a chiral stationary phase) and how to determine antiviral activity using the standard tests described herein, or using other similar tests which are well known in the art.

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 amino 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 is methyl or ethyl.

Specifically, halo is fluoro (F). Specifically, R ¹ and R ² are independently H, F, OH, OCi _-2 alkyl, C _1-2 alkyl, or CF ₃ .

Specifically, Y ² and Y ⁴ are CH; and Y'and Y ³ are independently CH or CF. Specifically, R ³ is H or CH ₃ .

Examples of the present invention are

(1) (5R)-3-[3,5-difluoro-4~(3-fluoroazetidin-l-yl)phenyl]-2-oxo- l,3-oxazolidine-5- carboxamide,

(2) (5R)-3-[4-(3,3-difluoroazetidin-l-yl)-3,5-difluorophenyl]-2- oxo-l,3-oxazolidine-5- carboxamide,

(3) (5R)-3-[4-(3-methoxyazetidin-l-yl)-3,5-difluorophenyl]-2-oxo - 1 ,3oxazolidine-5- carboxamide,

(4) (5R)-3- { 3,5-difluoro-4-[3-hydroxy-3-(trifluoromethyl)azetidin- 1 -yl]phenyl } -2-oxo- 1 ,3-oxazolidine-5-carboxamide, (5) (5R)-3-[4-(3,3-difluoroazetidin-l -yl)-3-fluorophenyl]-2-oxo-l ,3-oxazolidine-5- carboxamide,

(6) (5R)-N-methyl-3-[4-(3,3-difluoroazetidin-l-yl)-3-fluoropheny l]-2-oxo-l,3- oxazolidine-5-carboxamide,

(7) (5R)-3-[3-fluoro-4-(3-hydroxycyclobutyl)phenyl]-2-oxo-l,3-ox azolidine-5- carboxamide, (8) (5R)-3-[3-fluoro-4-(3-methoxycyclobutyl)phenyl]-2-oxo-l ,3-oxazolidine-5- carboxamide,

(9) (5R)-3-[4-(2,2-dioxido-2-thia-6-azaspiro[3.3]hept-6-yl)-3,5- difluorophenyl]-2- oxo-l,3-oxazolidine-5-carboxamide, or

(10) (5R)-3-[4-(2,2-dioxido-2-thia-6-azaspiro[3.3]hept-6-yl)-3,5- difluorophenyl]-N- methyl-2-oxo~l,3-oxazolidine-5-carboxamide.

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.

Scheme I

Scheme I describes the synthesis of analogs bearing carboxamide substitution at C-5 of the oxazolidinone. First, the aniline intermediate 1 is reacted with an alkyl (2R)- epoxypropanoate and a Lewis acid such as lithium triflate as described in US Patent Application Publication No. US 2004/0044052.

In step 2, the amino alcohol (2) is cyclized to give the aryl oxazolidinones 3 using methods known to one skilled in the art. For instance, treatment of intermediate 2 with 1,1'- carbonyldiimidazole in a solvent such as acetonitrile or tetrahydrofuran at an appropriate temperature, typically in a range of 20 ⁰ C to 80 ⁰ C provides the oxazolidinone 3. Alternatively, reaction of 2 with phosgene in a solvent such as toluene or methylene chloride, or mixtures thereof, in the presence of a base such as triethylamine at an appropriate temperature, typically in a range from -10 ⁰ C to 25 ⁰ C, affords the oxazolidinone 3. The

product may be used as collected or may first be purifed using conventional techniques such as preparative TLC or HPLC, chromatography, precipitation, crystallization and the like. Subsequent treatment of oxazolidinone ester 3 with ammonia or optionally with substituted amines (RNH ₂ ) in a suitable solvent such as methanol or acetonitrile affords amides 4 (R = H or optionally substituted alkyl). Similarly, treatment of ester 3 with O- alkylhydoxylamines or hydrazines gives the hydroxamate (R = O-alkyl) or the hydrazide (R = NH ₂ ) respectively. The product may be used as collected or may first be purifed using conventional techniques such as preparative TLC or HPLC, chromatography, precipitation, crystallization and the like. Scheme π

Intermediates bearing azetidine substitution are conveniently prepared by the nucleophilic aromatic substitution reaction of 3-hydroxyazetidine with fluorinated nitro aromatic compounds. Such reactions are well known those skilled in the art and review articles describing these reactions are available (see Zoltewicz in Top. Curr. Chem. 1975, vol. 59, pp. 33-64). These transformations are generally performed at 40 ⁰ C to 90 ⁰ C using polar aprotic solvents such as acetonitrile or dimethylformamide and in the presence of acid- scavenging bases such as triethylamine or N,N-diisopropylethylamine. The 3- hydroxyazetidine 1 is prepared by hydrogenolysis (for example with Pd/C in methanol) of 1- benzyl-3-trimethylsilyloxyazetidine (prepared as described by Higgins, R. H. J. Heterocyclic Chem. 1987, 24, 1489). . The product may be used as collected or may first be purifed using conventional techniques such as preparative TLC or HPLC, chromatography, precipitation, crystallization and the like.

Step 2 of Scheme 4 represents one or more steps required for the protection, oxidation, or otherwise conversion of the hydroxyazetidine ring to a more highly functionalized state. A person of ordinary skill in organic chemistry will be well acquainted with the various reactions that will be required for this functionalization. This may involve, for example, protection as a silyl ether, fluorination, oxidation to the azetidinone, olefination of the azetidione thus obtained, reaction of the azetidinone thus obtained with nucleophiles,

or activation of the hydroxy group and substitution with nucleophiles. The products may be used as collected or may first be purifed using conventional techniques such as preparative TLC or HPLC, chromatography, precipitation, crystallization and the like.

Finally, step 3 involves reduction of the nitro group to provide the aniline intermediate 5. This reduction is generally accomplished by reacting the nitro intermediate 4 with iron metal. The reaction is carried out at temperatures between 6O ⁰ C and 90 ⁰ C in mixtures of water and alcohol (methanol, ethanol, etc.) as solvent, and in the presence of ammonium chloride to buffer the reaction mixture. Optionally, reductions of this type are conducted by reaction with other metals such as tin or zinc or by hydrogenation under palladium or platinum catalysis (see Rylander Hydrogenation Methods; Academic Press: New York, 1985, pp. 104-116). . The product may be used as collected or may first be purifed using conventional techniques such as preparative TLC or HPLC, chromatography, precipitation, crystallization and the like.

Scheme HI

15

NHCbz

1 2 3

-* „ ^R 2> ; CV>-/ γ3= V/ ^NHCb i ⁰

Scheme HI describes the synthesis of intermediates bearing a cyclobutane ring. The intermediate 2 can be prepared in a single step involving the transition metal catalyzed reaction of a 4-bromo benzaldehyde starting material (1) with an alkyl carbamate, for example benzyl carbamate. Reactions of this type are well known to those skilled in the art (see for example Buchwald et.al. /. Am. Chem. Soc. 2002, 124, 7421-7428) and are typically carried out with palladium or copper catalysts and employing ligands such as BINAP or related phosphine or arsine ligands. The reaction is favorably carried out in solvents such as toluene or benzene and at temperatures of about 50 °C up to 110 ⁰ C. The product may be used as collected or may first be purifed using conventional techniques such as preparative TLC or HPLC, chromatography, precipitation, crystallization and the like.

Step 2 of Scheme 5 involves the conversion of benzaldehyde intermediate 2 to the styrene 3. Olefination of 2 is accomplished under conditions well-known to those of ordinary skill in organic chemistry, for example by reaction of the aldehyde with a phophorus ylide (generated by the reaction of a methyltriphenylphosphonium salt with a base such as sodium

hydride or potassium bis(trimethylsilyl)amide). The reaction is typically carried out in solvents such as THF or DMF and at temperatures of about -50 ⁰ C up to 25 ⁰ C. The product may be used as collected or may first be purifed using conventional techniques such as preparative TLC or HPLC, chromatography, precipitation, crystallization and the like. In step 3 of Scheme 5, the cyclobutanone ring is formed by the reaction of the styrene intermediate 3 with dichlorocarbene followed by a dechlorination step to provide 4. The generation and [2+2] cycloaddition of dichlorocarbene with olefins is well known and review articles describing these reactions are available (for example, see Brady, W. T. Tetrahedron 1981, 17, 2949-2966). The dichlorocyclobutanone intermediate formed in the cycloaddition reaction is then dechlorinated by reaction with reducing metals (for example with Zn-Cu couple) to form the desired cyclobutanone intermediate. Such reduction reactions are well known and are discussed in review articles, including that referenced above. The products of these reactions may be used as collected or may first be purifed using conventional techniques such as preparative TLC or HPLC, chromatography, precipitation, crystallization and the like.

Step 4 of Scheme 5 represents one or more steps required for the protection, reduction, or otherwise conversion of the azetidinone ring to a more highly functionalized state. This may involve, for example, reduction, protection of the alcohol thus formed as a silyl ether, fluorination, olefination reactions, oxime formation, or reaction with nucleophiles. The product may be used as collected or may first be purifed using conventional techniques such as preparative TLC or HPLC, chromatography, precipitation, crystallization and the like. Medical and Veterinary Uses

The compounds of the present invention may be used for the treatment of infectious, Gram-positive bacterial infections caused by a variety of bacterial organisms, including those that require long-term therapy (>28 days).

Examples of the bacterial organisms 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 Activities

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 for bacteria that grow aerobically, Approved Standard (6 ^th 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 (5 ^th ed), M11-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 (8 ^th ed) Washington, DC: American Society for Microbiology Press, 2003. The antibacterial activity can be presented in the form of MIC value. The MIC value is the lowest concentration of drug which prevented macroscopically visible growth under the conditions of the test. The antibacterial activities are shown in Table 1.

Table 1 Results of in vitro antibacterial activity MIC ₉ O (μg/mL)

Pharmaceutical Salts

The compound of formula I may be used in its native form or as a salt. In cases where forming a stable nontoxic acid or base salt is desired, administration of the compound as a pharmaceutically acceptable salt may be appropriate. Examples of pharmaceutically

acceptable salts of the present invention include inorganic salts such as hydrochloride, hydrobromide, sulfate, nitrate, bicarbonate, carbonate salts, and organic salts such as tosylate, methanesulfonate, acetate, citrate, malonate, tartarate, succinate, benzoate, ascorbate, etoglutarate, and glycerophosphate. Pharmaceutically acceptable salts may be obtained using standard procedures well known in the art, for example, reacting a sufficiently basic compound such as an amine with a suitable acid affording a physiologically acceptable anion. Alkali metal (for example, sodium, potassium or lithium) or alkaline earth metal (for example calcium) salts of carboxylic acids can also be made. 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. Oral Efficacy

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 bd = broad doublet bs = broad singlet bt = broad triplet br = broad signal

CDI = 1,1 0-carbodiimidazole d = doublet dd = doublet of doublets dq = doublet of quartets dt = doublet of triplets dm = doublet of multiplets

DMF = dimethylformamide

DMAP = dimethylaminopyridine

DIEA = diisopropylethylamine

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- l-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

HCl = hydrochloric acid

ACN = acetonitrile

MS = mass spectrometry rt = room temperature

EtOAc = ethyl acetate

EtO = ethoxy

Ac = acetate

NMP = l-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 = te/t-butoxycarbonyl

CBZ = benzyloxycarbonyl

DCC = l^-dicyclohexylcarbodiimide

PyBop = benzotriazole- 1 -yl-oxy-trispyrrolidinophosphonium hexafluorophosphate

Example 1 Preparation of (5R)-3-[3,5-difluoro-4-(3-fluoroazetidin-l-yl)phenyl]-2-oxo- 1 ,3-oxazolidine-5-carboxamide

l,l'-Carbonyldiimidazole (0.163 g, 0.98 mmol) is added to a solution of methyl (2R)-

3-{[3,5-difluoro-4-(3-fluoroazetidin-l-yl)phenyl]amino}-2-hy droxypropanoate (0.150 g, 0.49 mmol) in acetonitrile (8 mL) and the solution heated to 50 ⁰ C for three days. After cooling, ethyl acetate is added and the solution washed with dilute citric acid, twice with dilute NaHCO ₃ , brine, and dried (MgSO ₄ ), filtered and concentrated to provide methyl (5R)-3-[3,5-

difluoro-4-(3-fluoroazetidin-l-yl)phenyl]-2-oxo-l,3-oxazo lidine-5-carboxylate which is used without further purification.

Methanolic ammonia (2.0 mL of a 2.0 M solution, 4.0 mmol) is added to a solution of methyl (5R)-3-[3 ,5-difluoro-4-(3 -fluoroazetidin- 1 -yl)pheny 1] -2-oxo- 1 ,3 -oxazolidine-5- carboxylate (0.160 g, 0.49 mmol) in 3 mL of methanol. After 90 minutes, the solution is concentrated and the residue purified by preparative TLC (5% MeOH-dichloromethane) to afford the title compound.

MS (m/z): [M+H] ⁺ = 316

¹ H NMR (300 MHz, CD ₃ CN): 3.96 (dd, J = 9, 6 Hz, IH), 4.18 (m, 3H), 4.42 (m, 2H), 4.93 (dd, J = 10, 6 Hz, IH), 5.22- 5.42 (dm, J = 58 Hz, IH), 6.17 (br s, IH), 6.70 (br s, IH), 7.12 (dd, / = 10, 2 Hz, 2H)

Intermediates for the synthesis of example 1 are prepared as follows.

I. Preparation of methyl (2R)-3-{ [3, 5-difluoro-4-(3 -fluoroazetidin- l-yl)phenyl] amino }- 2-hydroxypropanoate

A solution of l-(2,6-difluoro-4-nitrophenyl)-3-fluoroazetidine (0.36 g, 1.5 mmol) in 2 mL of methanol containing 10% Pd/C (0.04 g) is stirred under an atmosphere of hydrogen.

After 18 hours, the solution is filtered through celite with the aid of methanol and the filtrate concentrated to provide l-(4-amino-2,6-difluorophenyl)-3-fluoroazetidine which is used directly in the next step.

A solution of l-(4-amino-2,6-difluorophenyl)-3-fluoroazetidine (1.5 mmol) in acetonitrile (5 mL) is treated with (i?)-methyl glycidate (0.18 g, 1.8 mmol) and lithium triflate

(0.28 g, 1.8 mmol), heated to 70 ⁰ C for 3 hours and then cooled and concentrated. The residue is purified by preparative TLC (2% MeOH-dichloromethane) to afford the title compound.

¹ H NMR (300 MHz, CDCl ₃ ): 3.04 (br s, IH), 3.35-3.48 (m, 2H), 3.81 (s, 3H), 3.91

(br s, IH), 4.06-4.17 (m, 2H), 4.31-4.50 (m, 3H), 5.19-5.39 (dm, J= 58 Hz, IH), 6.16 (dd, J =

10, 2 Hz, 2H)

Example 2 Preparation of (5R)-3-[4-(3,3-difluoroazetidin-l-yl)-3,5-difluorophenyl]-2- oxo-l,3-oxazolidine-5-carboxamide

l,l'-Carbonyldiimidazole (0.155 g, 0.93 mmol) is added to a solution of methyl (2R)- 3-{ [4-(3,3-difluoroazetidin-l-yl)-3,5-difluorophenyl]amino}-2-h ydroxypropanoate (0.10 g, 0.31 mmol) in acetonitrile (4.0 mL) and the solution heated to 50 ⁰ C for three days. After cooling, ethyl acetate is added and the solution washed with dilute citric acid, twice with dilute NaHCO ₃ , brine, and dried (MgSO ₄ ), filtered and concentrated to provide methyl (5R)- 3-[4-(3,3-difluoroazetidin-l-yl)-3,5-difluorophenyl]-2-oxo-l ,3-oxazolidine-5-carboxylate which is used without further purification.

Methanolic ammonia (2.0 mL of a 2.0 M solution, 4.0 mmol) is added to a solution of methyl (5R)-3 - [4-(3 ,3-difluoroazetidin- 1 -y l)-3 ,5-difluoropheny 1] -2-oxo- 1 ,3-oxazolidine-5- carboxylate (0.107 g, 0.31 mmol) in 3 mL of methanol. After 90 minutes, the solution is concentrated and the residue purified by preparative TLC (5% MeOH-dichloromethane) to afford the title compound.

MS (m/z): [M+H] ⁺ = 334

¹ H NMR (300 MHz, CD ₃ CN): 3.96 (m, IH), 4.18 (m, IH), 4.40-4.52 (m, 4H), 4.93 (dd, / = 10, 6 Hz, IH), 6.16 (br s, IH), 6.70 (br s, IH), 7.17 (dd, J = 10, 2 Hz, 2H)

Intermediates for the synthesis of example 2 are prepared as follows. I. Preparation of methyl (2R)-3-{ [4-(3,3-difluoroazetidin-l-yl)-3,5- difluorophenyl] amino } -2-hydroxypropanoate

A solution of l-(2,6-difluoro-4-nitrophenyl)-3,3-difluoroazetidine (0.25 g, 1.0 mmol) in 2 mL of methanol containing 10% PoVC (0.050 g) is stirred under an atmosphere of hydrogen. After 2.5 hours, the solution is filtered through celite with the aid of methanol and the filtrate concentrated to provide 4-(3,3-difluoroazetidin-l-yl)-3,5-difluoroaniline which is used directly in the next step.

A solution of 4-(3,3-difluoroazetidin-l-yl)-3,5-difluoroaniline (1.0 mmol) in acetonitrile (4 mL) is treated with (i?)-methyl glycidate (0.185 g, 1.2 mmol) and lithium triflate (0.236 g, 1.5 mmol), heated to 70 °C for 3 hours and then cooled and concentrated. The residue is purified by preparative TLC (2% MeOH-dichloromethane) to afford the title compound.

¹ H NMR (300 MHz, CDCl ₃ ): 3.17 (br s, IH), 3.30-3.45 (m, 2H), 3.81 (s, 3H), 3.91 (br s, IH), 4.39 (m, 5 H), 6.16 (dd, J = 10, 2 Hz, 2H)

Example 3 Preparation of (5R)-3-[4-(3-methoxyazetidin-l-yl)-3,5-difluorophenyl]-2- oxo- 1 ,3-oxazolidine-5-carboxamide

n-Butyllithium solution (2.1 mL of a 1.6 M hexanes solution, 3.32 mmol) is added to a cooled (-78 ⁰ C) solution of benzyl 3,5-difluoro-4-(3-methoxyazetidin-l-yl)phenylcarbamate (0.77 g, 2.21 mmol) in THF (11 mL). After 10 minutes, ethyl (2R)-2,3-epoxypropanoate (0.77 g, 6.63 mmol) is added and the solution allowed to warm to room temperature and stirred for 18 h. Saturated aqueous ammonium chloride is added to the reaction mixture and extracted with dichloromethane. The aqueous phase is acidified to pH 1 with IN HCl and extracted with dichloromethane twice. The combined organic phases are then dried (MgSO ₄ ), filtered and concentrated to provide crude (5R)-3-[4-(3-methoxyazetidin-l-yl)-3,5- difluorophenyl]-2-oxo-l,3-oxazolidine-5-carboxylic acid that is used directly in the next reaction. (Trimethylsilyl)diazomethane solution (0.24 mL of a 2M diethylether solution, 0.48 mmol) is added to a solution of (5R)-3-[4-(3-methoxyazetidin-l-yl)-3,5-difluorophenyl]-2- oxo-l,3-oxazolidine-5-carboxylic acid (0.24 mmol) in MeOH (0.5 mL). After stirring at room temperature for 2 hours, the reaction mixture is concentrated and treated with methanolic ammonia (1.0 mL of a 2.0 M solution, 2.0 mmol). After 24 hours, the solution is concentrated and the residue purified by preparative TLC (5% MeOH-dichloromethane) to afford the title compound.

MS (m/z): [M+H] ⁺ = 328

¹ H NMR (300 MHz, J ₆ -DMSO): 3.20 (s, 3H), 3.84-3.95 (m, 3H), 4.14-4.27 (m, 4H), 4.98 (m, IH), 7.22 (dd, /= 9, 2 Hz, 2H), 7.60 (br s, IH), 7.83 (br s, IH)

Example 4 Preparation of (5R)-3-{ 3,5-difluoro-4-[3-hydroxy-3- (trifluoromethyl)azetidin- 1 -yl]pheny 1 } -2-oxo- 1 ,3-oxazolidine-5-carboxamide

l,l'-Carbonyldiimidazole (0.018 g, 0.108 mmol) is added to a solution of methyl

(2R)-3-({3,5-difluoro-4-[3-hydroxy-3-(trifluoromethyl)aze tidin-l-yl]phenyl}amino)-2- hydroxypropanoate (0.020 g, 0.054 mmol) in acetonitrile (0.8 mL) and the solution heated to

50 °C for three days. After cooling, ethyl acetate is added and the solution washed with dilute citric acid, twice with dilute NaHCO ₃ , brine, and dried (MgSO ₄ ), filtered and concentrated to provide (5R)-3-{3,5-difluoro-4-[3-hydroxy-3-(trifluoromethyl)azetidi n-l- yl]phenyl}-2-oxo-l,3-oxazolidine-5-carboxylate which is used without further purification. Methanolic ammonia (2.0 mL of a 2.0 M solution, 4.0 mmol) is added to a solution of methyl (5R)-3-{3,5-difluoro-4-[3-hydroxy-3-(trifluoromethyl)azetidi n-l-yl]phenyl}-2-oxo-l,3- oxazolidine-5-carboxylate (0.021 g, 0.054 mmol) in 0.5 mL of methanol. After 90 minutes, the solution is concentrated and the residue purified by preparative TLC (5% MeOH- dichloromethane) to afford the title compound. MS (m/z): [M-H] ^" = 380

¹ H NMR (300 MHz, CD ₃ CN): 3.96 (dd, J = 9, 6 Hz, IH), 4.18 (m, 3H), 4.42 (m, 2H), 4.80 (s, IH), 4.93 (dd, J = 10, 6 Hz, IH), 6.16 (br s, IH), 6.70 (br s, IH), 7.12 (dd, / = 10, 2 Hz, 2H) Intermediates for the synthesis of example 4 are prepared as follows. I. Preparation of l-(2,6-difluoro-4-nitrophenyl)azetidin-3-one

A solution of DMSO (0.84 mL, 12 mmol) in dichloromethane (10 mL) is added to a cooled (-65 ⁰ C) solution of oxallyl chloride (3.0 mL, 6.0 mmol) in dichloromethane (20 mL). After stirring for 25 minutes, a solution of l-(2,6-difluoro-4-nitrophenyl)azetidin-3-ol (1.25 g, 5.4 mmol) in 20 mL of 5% DMSO-dichloromethane is added dropwise. The reaction mixture is stirred for 30 minutes at -60 ⁰ C and then treated with triethylamine (3.7 mL, 27 mmol) and allowed to warm to room temperature. After stirring for 4 hours, the reaction mixture is poured into water, the layers separated and the aqueous phase extracted with more dichloromethane. The combined organic phases washed with saturated NaHCO ₃ , brine, and dried (MgSO ₄ ), filtered and concentrated. The residue is purified by column chromatography (0-30% ethyl acetate-hexane) to provide the title compound.

¹ H NMR (300 MHz, CDCl ₃ ): 5.17 (tr, J = 1 Hz, 4H), 7.80 (dd, J = 8, 2 Hz, 2H)

H. Preparation of l-(2,6-difluoro-4-nitrophenyl)-3-(trifluoromethyl)azetidin-3 -ol (Trifluoromethyl)trimethylsilane (0.11 mL, 0.75 mmol) and then tetrabutylammonium fluoride (0.028 mL of a 1.0 M solution, 0.028 mmol) is added to a THF (3.5 mL) solution of l-(2,6-difluoro-4-nitrophenyl)azetidin-3-one (0.16 g, 0.70 mmol) cooled to 0 ⁰ C. After warming to room temperature and stirring for 5 hours, saturated ammonium chloride solution (1.2 mL) and tetrabutylammonium fluoride (1.1 mL of a 1.0 M solution, 1.1 mmol) are added and the reaction mixture stirred for another hour. Ethyl acetate and water are then added, the layers separated, and the aqueous phase extracted with more ethyl acetate. Combined organic phases are washed with water, brine, and dried (MgSO ₄ ), filtered and

concentrated. The crude residue is purified by preparative TLC (20% ethyl acetate-hexane) to afford the title compound.

¹ H NMR (300 MHz, CDCl ₃ ): 2.84 (s, IH), 4.40 (d, 7 = 10 Hz, 2H), 4.68 (d, / = 10

Hz, 2H), 7.74 (dd, / = 8, 2 Hz, 2H)

m. Preparation of methyl (2R)-3-({3,5-difluoro-4-[3-hydroxy-3-

(trifluoromethyl)azetidin-l-yl]phenyl}amino)-2-hydroxypro ρanoate

A solution of l-(2,6-difluoro-4-nitrophenyl)-3-(trifluoromethyl)azetidin-3 -ol (0.027 g, 0.091 mmol) in 2 mL of methanol containing 10% Pd/C (0.020 g) is stirred under an atmosphere of hydrogen. After 2.5 hours, the solution is filtered through celite with the aid of methanol and the filtrate concentrated to provide l-(4-amino-2,6-difluorophenyl)-3-

(trifluoromethyl)azetidin-3-ol which is used directly in the next step.

A solution of l-(4-amino-2,6-difluorophenyl)-3-(trifluoromethyl)azetidin-3 -ol (0.091 mmol) in acetonitrile (0.3 mL) is treated with (R)-methyl glycidate (0.014 g, 0.14 mmol) and lithium triflate (0.022 g, 0.14 mmol), heated to 70 ⁰ C for 3 hours and then cooled and concentrated. The residue is purified by preparative TLC (5% MeOH-dichloromethane) to afford the title compound.

¹ H NMR (300 MHz, CDCl ₃ ): 2.78 (br s, IH), 3.04 (br s, IH), 3.30-3.45 (m, 2H), 3.81

(s, 3H), 3.91 (br s, IH), 4.06 (d, J = 10 Hz, 2H), 4.38 (app d, /= 10 Hz, 3H), 6.16 (dd, J = 10, 2 Hz, 2H)

Example 5 Preparation of (5R)-3 - [4-(3 ,3-difluoroazetidin- 1 -yl)-3 -fluorophenyl] -2-oxo- 1 ,3-oxazolidine-5-carboxamide

l,l'-Carbonyldiimidazole (0.14 g, 0.83 mmol) is added to a solution of methyl (2R)- 3-{[4-(3,3-difluoroazetidin-l-yl)-3-fluorophenyl]amino}-2-hy droxypropanoate (0.13 g, 0.43 mmol) in acetonitrile (5 mL) and the solution heated to 50 ⁰ C for three days. After cooling, ethyl acetate is added and the solution washed with dilute citric acid, twice with dilute NaHCO ₃ , brine, and dried (MgSO ₄ ), filtered and concentrated to provide methyl (5R)-3-[4- (3,3-difluoroazetidin-l-yl)-3-fluorophenyl]-2-oxo-l,3-oxazol idine-5-carboxylate which is used without further purification.

Methanolic ammonia (2.0 mL of a 2.0 M solution, 4.0 mmol) is added to a solution of methyl (5R)-3-[4-(3,3-difluoroazetidin-l-yl)-3-fluorophenyl]-2-oxo- l,3-oxazolidine-5-

carboxylate (0.10 g, 0.31 mmol) in 3 mL of methanol. After 90 minutes, the solution is concentrated and the residue purified by preparative TLC (5% MeOH-dichloromethane) to afford the title compound.

MS (m/z): [M+H] ⁺ = 316 ¹ H NMR (300 MHz, CD ₃ CN): 4.02 (dd, / = 9, 6 Hz, IH), 4.17-4.32 (m, 5H), 4.93

(dd, / = 10, 6 Hz, IH), 6.17 (br s, IH), 6.63 (m, IH), 6.70 (br s, IH), 7.12 (m, IH), 7.42 (dd, J = 15, 3 Hz, IH)

Intermediates for the synthesis of example 5 are prepared as follows. I. Preparation of methyl (2R)-3-{[4-(3,3-difluoroazetidin-l-yl)-3-fluorophenyl]amino} -

2-hydroxypropanoate

A solution l-(2-fluoro-4-nitrophenyl)-3,3-difluoroazetidine (0.19 g, 0.84 mmol) in 10 mL of methanol containing 10% Pd/C (0.020 g) is stirred under an atmosphere of hydrogen.

After 2.5 hours, the solution is filtered through celite with the aid of methanol and the filtrate concentrated to provide l-(4-amino-2-fluorophenyl)-3,3-difluoroazetidine which is used directly in the next step.

A solution l-(4-amino-2-fluorophenyl)-3,3-difluoroazetidine (0.84 mmol) in acetonitrile (5 mL) is treated with (/?)-methyl glycidate (0.13 g, 1.3 mmol) and lithium triflate

(0.21 g, 1.3 mmol), heated to 70 ⁰ C for 3 hours and then cooled and concentrated. The residue is purified by preparative TLC (2% MeOH-dichloromethane) to afford the title compound.

¹ H NMR (300 MHz, CDCl ₃ ): 3.25-3.50 (m, 4H), 3.78 (s, 3H), 4.18 (m, 4H), 4.36 (m,

IH), 6.43 (m, 3H)

Example 6 Preparation of (5R)-N-methyl-3-[4-(3,3-difluoroazetidin-l-yl)-3- fluorophenyl]-2-oxo-l,3-oxazolidine-5-carboxamide

Methylamine (1.0 mL o a 2.0 M solutio mmol) is added to a solution of methyl (5R)-3-[4-(3,3-difluoroazetidin-l-yl)-3-fluorophenyl]-2-oxo- l,3-oxazolidine-5-carboxylate (0.030 g, 0.091 mmol) in 0.5 mL of methanol. After 90 minutes, the solution is concentrated and the residue purified by preparative TLC (3% MeOH-dichloromethane) to afford the title compound.

MS (m/z): [MH-H] ⁺ = 330

¹ H NMR (300 MHz, CD ₃ CN): 2.73 (d, /= 3 Hz, 3H), 3.98 (m, IH), 4.16-4.32 (m, 5H), 4.93 (dd, J = 10, 6 Hz, IH), 6.63 (m, IH), 6.96 (br s, IH), 7.14 (m, IH), 7.43 (dd, J = 15,3 Hz, IH)

Example 7 Preparation of (5R)-3-[3-fluoro-4-(3-hydroxycyclobutyl)phenyl]-2-oxo-l,3- oxazolidine-5-carboxamide

Methanolic ammonia (2.0 mL of a 2.0 M solution, 4.0 mmol) is added to methyl (5R)-3-[3-fluoro-4-(3-hydroxycyclobutyl)phenyl]-2-oxo-l,3-ox azolidine-5-carboxylate (0.12 g, 0.39 mmol) and stirred at room temperature. After an hour, the solution is concentrated and the residue purified by preparative TLC (5% MeOH-dichloromethane) to afford the title compound.

MS (m/z): [M+H] ⁺ = 295 ¹ H NMR (300 MHz, ^ ₆ -DMSO): 1.82-1.92 (m, 2H), 2.55-2.61 (m, 2H), 2.98 (m, IH),

3.95-4.08 (m, 2H), 4.24 (tr, J= 9 Hz, IH), 4.98-5.03 (m, IH), 5.11 (d, J = 6 Hz, IH), 7.30- 7.35 (m, 2H), 7.42 (d, 7 = 12 Hz, IH) 7.60 (s, IH), 7.84 (s, IH)

Intermediates for the synthesis of example 7 are prepared as follows. I. Preparation of 3-fluoro-4-(3-{ferr-butyldimethylsilyloxy}-cyclobutyl)anilin e

A solution of benzyl 3-fluoro-4-(3-{teff-butyldimethylsilyloxy}- cyclobutyl)phenylcarbamate (1.2 g, 2.79 mmol) in 25 mL of methanol containing 20% Pd(OHVC (0.3 g) is stirred under an atmosphere of hydrogen. After 4 hours, the solution is filtered through celite with the aid of methanol and the filtrate concentrated to provide the title compound, which is used directly in the next step. MS (m/z): [M+H] ⁺ = 296

¹ H NMR (300 MHz, CDCl ₃ ): 0.067 (s, 6H), 0.89 (s, 9H), 1.94-2.01 (m, 2H), 2.58- 2.63 (m, 2H), 2.94 (m, IH), 3.45 (s, 2H), 4.19 (m, IH), 6.29 (dd, J= 12, 2 Hz, IH), 6.40 (dd, J = 9, 2 Hz, IH) 6.99 (tr, J = 9 Hz, IH)

π. Preparation of methyl (5R)-3-[3-fluoro-4-(3-{ferf-butyldimethylsilyloxy}- cyclobutyl)phenyl]-2-oxo-l,3-oxazolidine-5-carboxylate

A solution of 3-fluoro-4-(3-{^rt-butyldimethylsilyloxy}-cyclobutyl)aniline (0.83 g, 2.8 mmol) in acetonitrile (10.0 mL) is treated with (/?)-methyl glycidate (0.43 g, 4.2 mmol)

and lithium triflate (0.66 g, 4.2 mmol), heated to 60 ⁰ C for 16 hours and then cooled and concentrated to provide methyl (2R)-3-{[3-fluoro-4-(3-{fer?-butyldimethylsilyloxy}- cyclobutyl)phenyl]amino}-2-hydroxypropanoate that is used in the next step without further purification. l,r-Carbonyldiimidazole (0.9 g, 5.6 mmol) is added to a solution of methyl (2R)-3-

{ [3-fluoro-4-(3- { te?f-butyldimethylsilyloxy } -cyclobutyl)phenyl]amino } -2- hydroxypropanoate (1.1 g, 2.8 mmol) in acetonitrile (28 mL) and the solution heated to 65 ⁰ C for 16 hours. After cooling, ethyl acetate is added and the solution washed with dilute citric acid, saturated NaHCO ₃ , brine, and dried (MgSO ₄ ), filtered and concentrated. Column chromatography (0-4% MeOH-dichloromethane) afforded the title compound. MS (m/z): [M+H] ⁺ = 424

¹ H NMR (300 MHz, CDCl ₃ ): 0.043 (s, 6H), 0.87 (s, 9H), 1.93-2.03 (m, 2H), 2.61- 2.69 (m, 2H), 3.03 (m, IH), 3.84 (s, 3H), 4.06-4.11 (m, IH), 4.21-4.28 (m, 2H), 5.02-5.07 (m, IH), 7.11 (dd, J = 9, 2 Hz, IH), 7.22 (tr, J = 9 Hz, IH), 7.33 (dd, J = 12, 2 Hz, IH)

HI. Preparation of methyl (5R)-3-[3-fluoro-4-(3-hydroxycyclobutyl)phenyl]-2-oxo-l,3- oxazolidine-5-carboxylate

Hydrogen fluoride triethylamine complex (0.58 mL, 3.54 mmol) is added to a THF (12.0 mL) solution of methyl (5R)-3-[3-fluoro-4-(3-{fert-butyldimethylsilyloxy}- cyclobutyl)phenyl]-2-oxo-l,3-oxazolidine-5-carboxylate (0.5 g, 1.18 mmol) at room temperature. After 5 hours, the solution is treated with dilute NaHCC> ₃ dropwise and extracted with dichloromethane. The organic extracts are washed with brine, dried (MgSO ₄ ), filtered, and concentrated. Purification by column chromatography (0-4% MeOH- dichloromethane) afforded the title compound. MS (m/z): [M+H] ⁺ = 310

¹ H NMR (300 MHz, CDCl ₃ ): 1.93-2.03 (m, 2H), 2.70-2.79 (m, 2H), 3.04-3.08 (m, IH), 3.85 (m, 3H), 4.06-4.11 (m, IH), 4.21-4.32 (m, 2H), 5.02-5.07 (m, IH), 7.11-7.20 (m, 2H), 7.33 (dd, /= 12, 2 Hz, IH)

Example 8 Preparation of (5R)-3-[3-fluoro-4-(3-methoxycyclobutyl)phenyl]-2-oxo-l,3- oxazolidine-5-carboxamide

Methanolic ammonia (1.0 mL of a 2.0 M solution, 2.0 mmol) is added to methyl (5R)-3-[3-fluoro-4-(3-methoxycyclobutyl)phenyl]-2-oxo-l,3-ox azolidine-5-carboxylate (0.08 g, 0.25 mmol) and stirred at room temperature. After an hour, the solution is concentrated to afford the title compound. MS (m/z): [M+H] ⁺ = 309

¹ H NMR (300 MHz, CDCl ₃ ): 1.93-2.02 (m, 2H), 2.67-2.73 (m, 2H), 3.15 (m, IH), 3.25 (s, 3H), 3.87 (m, IH), 4.17-4.29 (m, 2H), 4.94-4.99 (m, IH), 5.61 (s, IH), 6.55 (s, IH), 7.10-7.22 (m, 2H), 7.36 (dd, / = 12, 2 Hz, IH)

Synthesis of example 8 is prepared as follows.

I. Preparation of methyl (5R)-3-[3-fluoro-4-(3-methoxycyclobutyl)phenyl]-2-oxo-

1 ,3-oxazolidine-5-carboxylate π.

Trimethyloxonium tetrafluoroborate (0.077 g, 0.52 mmol) is added to a cooled (0 ⁰ C) solution of methyl (5R)-3-[3-fluoro-4-(3-hydroxycyclobutyl)phenyl]-2-oxo-l,3-ox azolidine- 5-carboxylate (0.16 g, 0.52 mmol) and 2,6-di-terf-butyl-4-methyl pyridine (0.21 g, 1.0 mmol) in dicloromethane (3.25 mL). After stirring at 4 ⁰ C for 16 h, the reaction mixture is diluted with dichloromethane, washed with saturated NaHCO ₃ and brine, and dried (MgSO ₄ ), filtered and concentrated. The crude residue is purified by pTLC (4% MeOH-dichloromethane) to provide the title compound.

MS (m/z): [M+H] ⁺ = 324

¹ H NMR (300 MHz, CDCl ₃ ): 1.92-2.02 (m, 2H), 2.64-2.72 (m, 2H), 3.11-3.18 (m, IH), 3.24 (s, 3H), 3.81-3.89 (m, 4H), 4.06-4.11 (m, IH), 4.24 (tr, J = 9 Hz, IH), 5.02-5.06 (m, IH), 7.11 (dd, J = 9, 2 Hz, IH), 7.21 (tr, / = 6 Hz, IH), 7.34 (dd, J = 12, 2 Hz, IH)