WO2006056877A2

WO2006056877A2 - Diazepine oxazolidinones as antibacterial agents

Info

Publication number: WO2006056877A2
Application number: PCT/IB2005/003559
Authority: WO
Inventors: Prudencio Sancon Herradura; Vara Prasad Venkata Nagendra Josyula; Adam Robert Renslo
Original assignee: Pharmacia & Upjohn Company Llc
Priority date: 2004-11-29
Filing date: 2005-11-17
Publication date: 2006-06-01
Also published as: JP2008521792A; CA2589250A1; WO2006056877A3; EP1819699A2

Abstract

The present invention relates to a new class of oxazolidinone derivatives, to their use as antibacterial agents, to pharmaceutical compositions containing these compounds and to methods for their preparation.

Description

DIAZEPINE OXAZOLIDINONES AS ANTIBACTERIAL AGENTS

FIELD OF INVENTION

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 a new class of oxazolidinone derivatives containing a diazepine ring, which are active against a number of human and veterinary pathogens, including multiple resistant strains of bacteria.

INFORMATION DISCLOSURE WO 9323384, WO 20028084, WO 2003072553, WO 2003072576, WO 2003072575, WO 200142229, WO 200264575, WO 9615130, WO 200216960, WO 200027830, WO 200146185, WO 200281469, WO 200281470, WO 2001080841, WO 2003084534, WO 2003093247, WO 200202095, WO 200230395, WO 200272066, WO 2003063862, WO 2003072141, WO 2003072081, WO 2003119817, WO 2003008389, WO 2003007870, WO 200206278, WO 200032599, WO 9924428, WO 2004014392, WO 2004002967, WO 2004009587, WO

2004018439, US Patent Application Publication No. US 2004/0044052, US Patent No. 5547950, US Patent No. 5700799, DE 10034627 disclose oxazolidinone compounds having antibacterial activity useful for treating microbial infections. SUMMARY OF THE INVENTION The present invention provides a compound of formula I

I or a pharmaceutically acceptable salt thereof wherein: A is a structure of the following formula i, ii, iii, or iv

W is

(a) CONHR²,

(b) CH₂NHCO(NH)C₁.₆alkyl,

(c) CH₂NHCOOC_1-6alkyl (d) CH₂OH,

(e) CH(OH)-CH=CHR²,

(f) CH(OH)C = CR²,

(g) CH₂NH-het, (h) CH₂O-het, (i) CH₂S-het, or

(j) CH₂het;

YMs CH₅ CF₅ Or N;

Y² and Y³ are independently CH₅ or CF;

Q is O, or S; R¹ is H₅ or C^alkyl;

R² is H, C_1-6 alkyl, or OC^alkyl; each " " is independently a bond or absence, at each occurrence,

is optionally substituted with one or more CF₃, halo, OH₅

alkyl, or C(O)C_1-4 alkyl; and 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 one or more CF₃, halo, OH, OC_Malkyl, CN, N₃, 0(C=O)C_1-4 alkyl, C_3-6cycloalkyl, NH₂, NHC(=0)C_1-4 alkyl, or C(=O)Ci-₄ alkyl.

In another aspect, the present invention also provides: a pharmaceutical composition which comprises a pharmaceutically acceptable carrier and a compound of formula I, a method for treating 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 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, C₁^ 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 "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 "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, fiiran, 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, l,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, l,3,4-thiadiazol-5-yl, 2-oxo-l,3,4-thiadiazol-5-yl, 1,2,3- triazole-1-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 "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. Livestock refers to animals suitable for human meat consumption. Examples include pigs, cattle, chickens, fish, turkeys, rabbits, etc. Companion animals refer to animals kept as pets such as dogs, cats, etc. 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.

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, Le., 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 "prodrug" refers to compounds that are rapidly transformed in vivo to yield the parent compound of the above formulas, for example, by hydrolysis in blood. A thorough discussion is provided in T. Higuchi and V. Stella, "Pro-drugs as Novel Delivery Systems," Vol. 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987. 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. 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 stereoisomers 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 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 "it" 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, alkenyl is vinyl, propenyl, allyl, butenyl, and their isomeric forms thereof.

Specifically, halo is fluoro (F), or chloro (Cl).

Specifically the present invention provides a compound of formula Ia

Ia wherein Y¹ and Y² are independently. CH or. CF; and W. is CONHR² or CH₂NHCO(NH)Ci.₆alkyl,

Specifically the present invention provides a compound of formula Ib

Ib wherein Y¹ and Y² are independently CH or CF, R¹ is H or methyl; and R² is H, CH₃, or OCH₃. Examples of the present invention are:

(1) (5R)-3-[3-fluoro-4-(5-oxo-l,4-diazepan-l-yl)phenyl]-2-oxo-l,3-oxazolidine-5- carboxamide,

(2) (5R)-3-[3-fluoro-4-(5-oxo-l ,4-diazepan- 1 -yl)phenyl]-N-methyl-2-oxo- 1 ,3- oxazolidine-5-carboxamide, (3) (5R)-3-[3-fluoro-4-(4-methyl-5-oxo-l ,4-diazepan- l-yl)phenyl]-2-oxo-l ,3- oxazolidine-5-carboxamide,

(4) 5R)-3-[3-fluoro-4-(4-methyl-5-oxo-l,4-diazepan-l-yl)phenyl]-N-methyl-2- oxo- 1 ,3-oxazolidine-5-carboxamide,

(5) (5R)-3-[3,5-difluoro-4-(4-methyl-5-oxo- 1 ,4-diazepan- 1 -yl)phenyl]-2-oxo- 1 ,3- oxazolidine-5-carboxamide,

(6) (5R)-3-[3,5-difluoro-4-(4-methyl-5-oxo-l,4-diazepan-l-yl)phenyl]-N-methyl- 2-oxo- 1 ,3-oxazolidine-5-carboxamide,

(7) (5R)-3-[3,5-difluoro-4-(5-oxo-l,4-diazepan-l-yl)phenyl]-2-oxo-l,3- oxazolidine-5-carboxamide, (8) (5R)-3-[3,5-difluoro-4-(5-oxo-l,4-diazepan-l-yl)phenyl]-N-methyl-2-oxo-l,3- oxazolidine-5-carboxamide,

(9) 5R)-3-[3,5-difluoro-4-(5-oxo-2,3,4,5-tetrahydro-lH-l,4-diazepin-l- yl)phenyl]-2-oxo-l ,3-oxazolidine-5-carboxamide, or

(10) (5R)-3-[3,5-difluoro-4-(5-oxo-2,3,4,5-tetrahydro-lH-l,4-diazepin-l- yl)phenyl]-N-methyl-2-oxo- 1 ,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 the oxazolidinone ring with its C-5 carboxamide side chain, starting from commercially available aniline 1. First, the aniline 1 is reacted with an alkyl (2i?)-epoxypropanoate and a Lewis acid such as ithium triflate (as described in US Patent Application Publication No. US 2004/0044052) to provide amino alcohol 2. Next 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 l,r-carbonyldiimidazole in a solvent such as acetonitrile or tetrahydrofuran at an appropriate temperature, typically in a range of 20 ⁰C to 80 ⁰C 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 ⁰C to 25 ⁰C, affords the oxazolidinone 3. The product may be used as collected or may first be purified 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 (R²NH₂) in a suitable solvent such as methanol or acetonitrile affords amides 4 (R² = H or optionally substituted alkyl). Similarly, treatment of ester 3 with O-alkylhydroxylamines provides hydroxamates (R² = O-alkyl). The product may.be used as collected or may. first be purified using conventional techniques. such as preparative TLC or HPLC, chromatography, precipitation, crystallization and the like.

SCHEME II

7 8

Scheme II describes the synthesis of aniline intermediates 9 bearing the diazepanone ring. The diazepanone 5 (for synthesis see Scheme III) is reacted in a nucleophilic aromatic substitution reaction with a fluoronitrobenzene (for example, with 3,4,-difluoronitrobenzene) to provide intermediates such as 6. 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 a temperature in a range from about 4O⁰C to about 90°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. Intermediate 6 is then optionally alkylated on the nitrogen atom to form intermediate 7. For instance, reaction of 6 with methyl iodide using potassium hydroxide as a base and tetrabutylammonium bromide as a phase-transfer catalyst provides intermediate 7 where R¹ = methyl. Intermediate 7 is then reduced to provide the aniline intermediate 8. This reduction is generally accomplished by reacting 7 with reducing metals (for example with iron powder). The reaction is favorably carried out at temperatures in a range from about 60°C to about 9O⁰C 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 purified. using conventional techniques such as preparative TLC or HPLC, chromatography, precipitation, crystallization and the like. Aniline intermediates such as 9 can then be converted to oxazolidinone analogs as described in Scheme I.

SCHEME III.

Scheme III describes the synthesis of the diazepanone heterocycle 5. This compound may be prepared in three steps from commerically available piperidone compounds such as benzyl 4-oxopiperidine-l-carboxylate (10, commercially available) or tert-butyl 4-oxopiperidine-l-carboxylate. Reaction of 10 with hydroxylamine in the presence of molecular sieves (to remove water formed in the reaction) and in a solvent such as pyridine provides the oxime intermediate 11.

Next, intermediate 11 is converted to the protected diazepanone intermediate 12. This reaction, known as the Beckmann rearrangement, is well known to those of ordinary skill in the art and may be accomplished under a variety of conditions (for a review see Gawley Organic Reactions, 1988, 35, pp 1-420). With intermediate 11, the reaction is favorably carried out with tosyl chloride to activate the oxime, and in solvents such as acetone, water, or mixtures thereof and in the presence of an acid scavenging base such as sodium carbonate. The product may be used as collected or may first be purified using conventional techniques such as preparative TLC or HPLC, chromatography, precipitation, crystallization and the like. Finally, the protecting group (e.g., Cbz or Boc) is removed from intermediate

12 to provide the diazepanone 5. Removal of benzyl carbamate protection is favorably accomplished by hydrogenolysis, typically employing a palladium catalyst under an atmosphere of hydrogen gas and using solvents such as ethyl acetate, alcohols, or mixtures thereof. Cleavage of tert-butyl carbamates is typically accomplished by treatment with acids such as hydrochloric acid or trifluoroacetic acid. If less harsh conditions are required, treatement with trimethylsilyltrifluoromethane sulfonate and 2,6-lutidine (as described by Ohfune, Y- and Sakaitani, M. J. Org. Chem. .1990, 55, 870-876) is also effective. The diazepanone 5 may then be employed in the synthesis of final analogs as outlined in Schemes I and II.

SCHEME IV

° \ P \v ^- NHCbz *^• H=\ H— (\ />— NHCbz

13 14

15

Scheme IV outlines the synthesis of aniline intermediates bearing a tetrahydrodiazepinone ring. The starting materials employed are dihydropyridone intermediates such as 13 (prepared as described in the PCT publication

WO2004/033449). Reaction of 13 with hydroxylamine as described above in Scheme III provides the oxime intermediate 14. Next, oxime intermediate 14 is converted to the protected diazepanone intermediate 15 using a Beckmann rearrangement reaction as described above in Scheme III. Intermediate 15 is then optionally converted to the intermediate 16 in which the nitrogen atom of the heterocyclic ring has been alkylated. Finally, the carbamate function of intermediate 16 is removed to provide the desired aniline intermediate 17. The reaction conditions for this step will depend upon the type of carbamate employed (for example, a benzyl carbamate is favorably removed by hydrogenolysis as described above in Scheme III). Intermediate 17 may then be used in the synthesis of oxazolidinone analogs as described in Scheme I.

Schemes V-VIII describe the synthesis of aryl isoxazolinone, aryl isoxazoline and aryl butyrolactone compounds bearing diazepanone and related heterocyclic rings of the type described in Schemes I- VII. The following schemes describe general methods to prepare claimed structures in which A is (ii), (iii), or (iv). The diazepanone and related heterocycles may be prepared as described above in Schemes I-VII but it will be understood by those of ordinary skill in the art that suitable, protecting groups may be required to protect and later reveal sensitive functional groups.

Scheme V summarizes the synthesis of the requisite substituted benzaldehyde intermediates. The general methods described in the previous Schemes are applicable but with the use of fluorinated benzonitrile (29) or benzoate ester starting materials in the place of fluorinated nitrobenzenes. The required starting materials (e.g., 3,4,5- trifluorobenzonitrile) are commercially available. Conversion of these starting materials to intermediate 30 is accomplished in a series of steps using the same methods described in Schemes II-IV for the preparation of aniline intermediates. Intermediate 30 is then converted to the benzaldehyde intermediate 31 using methods that are well known to those of ordinary skill in the art, for example by reduction to the imine with SnCl₂/HCl followed by hydrolysis (Stephen aldehyde synthesis).

SCHEME V

²⁹ Scheme VI describes the preparation of aryl isoxazolinone analogs. The first step involves reaction of benzaldehyde intermediate 31 with ethyl diazoacetate (as described by Mahmood et al. in J. Org. Chem., 1998, 63, 3333-3336) to provide the ester aldehyde intermediate 32. Reaction of this material with hydroxylamine, followed by warming to reflux in aqueous methanol forms the isoxazolinone ring and intermediate 33. This intermediate is then converted to the corresponding methylacetamide 34 by reaction with N-(hydroxymethyl)acetamide acetate (prepared as described by Barnes et al. in US Patent 5,284,863) in a polar aprotic solvent such as DMF. SCHEME VI

Scheme VII describes a general method for preparing aryl isoxazoline compounds bearing diazepanone or related heterocycles of the type described in the Schemes above. In the first step of Scheme X the benzaldehyde intermediate 31 is reacted with hydroxylamine hydrochloride in a polar protic solvent, such as methanol, in the presence of a base, such as pyridine, to afford the oxime intermediate 35. The oxime 35 is then oxidized with TV-chlorosuccinimide (NCS) in an appropriate solvent, such as dichloromethane, to give the hydroximinoyl chloride intermediate 36. This material is then reacted with an alkene, for example with allyl alcohol, in the presence of a base such as triethylamine and in a solvent such as dichloromethane, to provide the hydroxymethyl-substituted isoxazoline 37. The hydroxymethyl function of 37 may then be converted to acetamidomethyl or related moieties (e.g. 38, where R' = Et, OMe, etc.) using established synthetic procedures (for example, as described in US PCT publication US2004/0127530) to provide 38. Alternatively, the hydroximinoyl chloride 36 may be reacted with iV-acetylallylamine to directly provide acetamidomethyl-substituted isoxazoline products (38, W = O and R' = Me). Optionally, the hydroximinoyl chloride intermediate may be formed in situ as described above and then directly treated with the alkenes to generate the isoxazoline intermediates directly from 35. SCHEME VII

Z^ J= ²^ _/¹⁼W^{~0H z2}^ ,^Y1=v /^~OH

35 36

Scheme VIII describes the synthesis of aryl butyrolactone analogs such as 42. The synthesis of the saturated (as in 41) and unsaturated (as in 42) 3-arylbutyrolactone ring system is described in the literature (for example, see Bioorganic & Medicinal Chemistry Letters, 1994, 4, 1925-1930). Aldehyde intermediate 31 is converted to phenyl acetic acid intermediate 39 using established procedures (for example as described by Hester, et al. in US Patent 5,708,169). The dianion of 39 is then reacted with i?-benzyloxymethyloxirane in THF. The resulting hydroxyacid is cyclized under acid catalysis (for example, using p-toluenesulfonic acid) to provide lactone 40. The benzyl group is then removed by hydrogenoh/sis and the resulting hydroxymethyl function converted to acetamidomethyl or related moieties (e.g. 41, where R' = Et, OMe, etc.) using established synthetic procedures (for example, as described in US PCT publication US2004/0127530) to provide 41. Finally the butyrolactone is oxidized using a two-step protocol involving bromination (using for example N- bromosuccinimide) and subsequent elimination by treatment with a suitable base such as pyridine or DBU to provide 42.

SCHEME VIII

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 (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), 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 (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 test result is shown in Table 1.

Table 1 ( Minimum Inhibitor/ concentrations fμ|2/mD

Example S. S. pyogenes S pneumoniae aureus

(SV-I) OJC-76Ϊ

1 4 4 8

2 8 4 8

3 8 8 16

4 8 8 8

5 8 4 8

6 8 4 8

7 4 2 4

8 4 4 4

9 4 2 16

10 8 4 16

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), a compound 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

BOC = tert-butoxycarbonyl bd = broad doublet bs = broad singlet bt = broad triplet

CDI = 1,10-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)- 1 H- 1 ,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 trichloroacetic 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 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 (5R)-3-[3-fluoro-4-(5-oxo-l,4-diazepan-l-yl)phenyl]-2- oxo-l^-oxazolidine-S-carboxamide

To a suspension of methyl (5R)-3-[3-fluoro-4-(5-oxo-l,4-diazepan-l- yl)phenyl]-2-oxo-l,3-oxazolidine-5-carboxylate (0.14 g, 0.40 mmol) in methanol (5 mL) at 23°C is added methanolic ammonia solution (5.0 mL, 2.0 M). The suspension is stirred at the same temperature for Ih, concentrated, and purified by preparative TLC (6% MeOH-CH₂Cl₂), to afford the title compound.

HPLC (SYMMETRY C₁₈ 3.5 μM, 4.6 x 30 mm column; gradient elution 2%- 98% MeCN with 0.1% TFA over 5 min; 2 mL/min rate): retention time = 1.39 min ¹H NMR (300 MHz, DMSO-dδ): 2.59 (m, 2H), 3.09 (m, 4H), 3.25 (m, 2H),

3.95 (m, IH), 4.22 (t, J=9.3 Hz, IH), 5.0 (m, IH), 7.09 (t, J=9.0 Hz, IH), 7.20 (d, J=8.7 Hz IH), 7.48 (d, J=14.9 Hz, IH), 7.60 (s, IH), 7.67 (m, IH), 7.84 (s, IH).

Intermediates for the preparation of example 1 are synthesized as follows. I. Preparation of /ert-butyl 4-(hydroxyimino)piperidine-l-carboxylate

To a solution of /ert-butyl 4-oxopiperidine-l-carboxylate (50 g, 251 mmol) in pyridine (500 mL) is added molecular sieves (50 g) and the mixture is stirred at room temperature for 10 minutes, followed by the addition of NH₂OH HCl (30.25 g, 427 mmol). The resulting reaction is stirred at room temperature overnight, and the reaction mixture filtered through a pad of celite to remove the molecular sieves. The filtrate is diluted with water, the layers separated and the aqueous phase extracted with more ethyl acetate. The combined organic phases are washed with brine, dried over MgSO₄, filtered, and concentrated in vacuo to provide the title compound. This material is used in the next step without further purification.

¹H NMR (300 MHz, DMSO-dδ): 1.52 (s, 9H), 2.36 (t, J=6.0 Hz, 2H), 2.58 (t, J=6.0 Hz, 2H), 3.50-3.58 (m, 4H). II. Preparation of ter/-butyl 5-oxo-l,4-diazepane-l-carboxylate

To a solution of tert-butyl 4-(hydroxyimino)piperidine-l-carboxylate (1 O g, 4.67 mmol) in acetone (20 mL) is added a solution OfNa₂CO₃ (1.48 g, 14 mmol) in water (20 mL), and the mixture is stirred for 5 minutes, then a solution of p- toluenesulfonyl chloride (1.33 g, 7 mmol) in acetone (5 mL) is added slowly. The reaction is stirred at room temperature for 3h, then the acetone is removed in vacuo, water is added, and the solution extracted with dichloromethane. The organic layer is dried over MgSO₄, filtered, concentrated in vacuo, and purified by chromatography (6% MeOH in dichloromethane) to afford the title compound.

¹H NMR (300 MHz, DMSO-ds): 1.41 (s, 9H), 2.40 (m, 2H), 3.09 (m, 2H), 3.39-3.44 (m, 4H), 7.62 (m, IH).

III. Preparation of l,4-diazepan-5-one

A solution of HCl (20 mL, 2M in dioxane) is added to

5-oxo-l,4- diazepane-1-carboxylate (1.0 g, 4.67 mmol) and the reaction mixture is stirred at room temperature for 2h. The solvent is removed in vacuo to afford the title compound as the hydrochloride salt, which is used without further purification in the next step.

¹H NMR (300 MHz, DMSO-ds): 2.36 (m, 2H), 2.65-2.72 (m, 4H), 3.05 (m, 2H), 3.17 (s, IH), 7.47 (s, IH).

IV. Preparation of 1 -(2-fluoro-4-nitrophenyl)- 1 ,4-diazepan-5-one

To a solution of l,4-diazepan-5-one (3.25 g, 28.5 mmol) in acetonitrile (30 mL) is added N,N-diisopropylethylamine (24.8 mL, 142 mmol), followed by 3,4- difluoronitrobenzene (3.5 mL, 31.3 mmol). The reaction mixture is heated to 7O⁰C overnight, cooled to room temperature, and the solvent removed in vacuo. Then dichloromethane is added and the solution washed with brine, dried over MgSO₄, filtered, and concentrated in vacuo to afford the title compound. This material is used directly in the next step without further purification.

¹H NMR (300 MHz, DMSO-de): 2.62 (m, 2H), 3.30 (m, 2H), 3.47-3.55 (m, 4H), 7.08-7.14 (m, IH), 7.67 (m, IH), 7.94-8.02 (m, 2H).

V. Preparation of 1 -(4-amino-2-fluorophenyl)- 1 ,4-diazepan-5-one To a solution of l-(2-fluoro-4-nitrophenyl)-l,4-diazepan-5-one (6.5 g, 25.7 mmol) and NH₄Cl powder (13.7 g, 257 mmol) in EtOHiH₂O (2: 1,200 mL) is heated to 95 ⁰C, and treated with iron powder (4.3 g, 77 mmol) in portions over one hour. The reaction mixture is then stirred at 95 ⁰C for 2.5 hours, cooled to room temperature, and filtered through a pad of celite with the aid of dichloromethane. The filtrate is concentrated, and the residue taken into dichloromethane and water. The layers are separated and the organic layer is dried over MgSO₄, filtered, and concentrated to afford the title compound which is used directly in the next step without further purification. ¹H NMR (300 MHz, DMSO-d_δ): 2.52 (m, 2H), 2.88-2.91 (m, 4H), 3.18 (m,

2H), 5.07 (s, 2H), 6.25-6.34 (m, 2H), 6.79 (m, IH), 7.63 (m, IH).

VI. Preparation of methyl (2R)-3-{[3-fluoro-4-(5-oxo-l,4-diazepan-l- yl)phenyl]amino} -2-hydroxypropanoate

To a solution of l-(4-amino-2-fluorophenyl)-l,4-diazepan-5-one (500 mg, 2.24 mmol) in acetonitrile (5 mL) at 23⁰C is added Lithium triflate (380 mg, 2.46 mmol), followed by (R) -methyl glycidate (0.22 mL, 2.46 mmol). The reaction mixture is then stirred at 6O⁰C for 2Oh and treated with additional (i?>methyl glycidate (0.06 mL, 0.67 mmol). After another day at 60⁰C, the reaction mixture is cooled to 23°C, concentrated, and the residue purified by chromatography on a silica gel column, eluting with a gradient increasing in polarity from 2% to 5% MeOH in dichloromethane. Relevant fractions are combined and concentrated to afford the title compound.

¹H NMR (300 MHz, DMSO-de): 2.51 (m, 2H), 2.89-2.93 (m, 4H), 3.12-3.19 (m, 3H), 3.61 (s, 3H), 4.09 (m, IH), 4.17 (m, IH), 5.61 (m, IH), 5.68 (d, c, IH), 6.25-6.43 (m, 2H), 6.79-6.89 (m, IH), 7.63 (m, IH).

VII. Preparation of methyl (5R)-3-[3-fluoro-4-(5-oxo-l ,4-diazepan-l-yl)phenyl]-2- oxo-1 ,3-oxazolidine-5-carboxylate

To a mixture of methyl (2R)-3-{[3-fluoro-4-(5-oxo-l,4-diazepan-l- yl)phenyl] amino} -2-hydroxypropanoate (0.40 g, 1.23 mmol) and 1,1'- carbonyldiimidazole (0.31 g, 1.84 mmol) at 23⁰C is added acetonitrile (15 mL). The resulting mixture is stirred at 50°C overnight and then cooled to 23°C and concentrated. The residue is taken into ethyl acetate (300 mL), washed with 0.5 M aqueous HCl, brine, and dried (Na₂SO₄), filtered, concentrated. The residue is purified by chromatography on a silica gel column, eluting with a gradient increasing in polarity from 2% to 5% MeOH in dichloromethane. Relevant fractions are combined to afford the title compound.

¹H NMR (300 MHz, DMSO-dβ): 2.57 (m, 2H), 3.06 (m, 4H), 3.27 (m, 2H), 3.75 (s, 3H), 4.12 (m, IH), 4.32 (t, J=9.6 Hz, IH), 5.30 (m, IH), 7.09 (t, J=9.0 Hz, IH), 7.20 (m, IH), 7.43-7.48 (m, IH), 7.66 (m, IH).

Example 2 Preparation of (5R)-3-[3-fluoro-4-(5-oxo-l,4-diazepan-l-yl)phenyl]-N- methyl-2-oxo- 1 ,3-oxazolidine-5-carboxamide

Following the procedure in Example 1 and under analogous conditions, methyl (5R)-3-[3-fiuoro-4-(5-oxo- 1 ,4-diazepan- 1 -yl)phenyl]-2-oxo- 1 ,3-oxazolidine-5- carboxylate (0.14 g, 0.40 mmol) is treated with methanolic methylamine solution (5.0 mL, 2.0 M). The suspension is stirred at the same temperature for Ih, concentrated, and the residue purified by preparative TLC (6% MeOHZCH₂Cl₂) to afford the title compound.

HPLC (SYMMETRY C₁₈ 3.5 μM, 4.6 x 30 mm column; gradient elution 2%- 98% MeCN with 0.1% TFA over 5 min; 2 mL/min rate): retention time = 1.48 min ¹U NMR (300 MHz, DMSO-de): 2.56 (m, 2H), 2.64 (d, J=4.8 Hz, 3H), 3.09

(m, 4H), 3.25 (m, 2H), 3.96 (m, IH), 4.23 (t, J=9.3 Hz, IH), 5.04 (m, IH), 7.09 (t, J=9.3 Hz, IH), 7.20 (d, J=8.7 Hz IH), 7.45-7.51 (m, IH), 7.67 (m, IH), 8.36 (s, IH).

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

To a suspension of methyl (5R)-3,-[3-fluoro-4-(4-methyl-5_Toxo-l,4-diazepan-l- yl)phenyl]-2-oxo-l,3-oxazolidine-5-carboxylate (0.15 g, 0.41 mmol) in methanol (4 mL) at 23 °C is added methanolic ammonia solution (4.0 mL, 2.0 M). The suspension is stirred at the same temperature for 2h, concentrated, and the residue purified by preparative TLC (6% MeOH/CH₂Cl₂) to afford the title compound.

HPLC (SYMMETRY Ci₈ 3.5 μM, 4.6 x 30 mm column; gradient elution 2%- 98% MeCN with 0.1% TFA over 5 min; 2 mL/min rate): retention time = 1.53 min

¹H NMR (300 MHz, DMSO-dβ): 2.66 (m, 2H), 2.88 (s, 3H), 3.06-3.13 (m, 4H), 3.56 (m, 2H), 3.96 (m, IH), 4.22 (t, J=9.6 Hz, IH), 5.0 (m, IH), 7.08 (t, J=8.7 Hz, IH), 7.19-7.22 (m, IH), 7.46-7.52 (m, IH), 7.60 (s, IH), 7.84 (s, IH).

Intermediates for the preparation of example 3 are synthesized as follows:

I. Preparation of 1 -(2-fluoro-4-nitrophenyl)-4-methyl- 1 ,4-diazepan-5-one

To a mixture of powdered KOH (1.16 g, 20.7 mmol) and tetrabutylammonium bromide (0.91 g, 2.76 mmol) in THF (250 mL) is added a solution of l-(2-fluoro-4- nitrophenyl)-l,4-diazepan-5-one (3.5 g, 13.8 mmol) and methyl iodide (1.3 mL, 20.7 mmol) in THF (40 mL). The resulting reaction mixture is kept at room temperature overnight, diluted with ethyl acetate, and washed with water and brine, and dried (MgSO₄), filtered, and concentrated. The residue is purified by column chromatography (2% MeOH in dichloromethane) to afford the title compound.

¹U NMR (300 MHz, DMSO-de): 2.74 (m, 2H), 2.85 (s, 3H), 3.46-3.52 (m, 4H), 3.61 (m, 2H), 7.07-7.13 (m, IH), 7.95-8.02 (m, 2H).

II. Preparation of 1 -(4-amino-2-fluorophenyl)-4-methyl- 1 ,4-diazepan-5-one

A solution of l-(2-fluoro-4-nitrophenyl)-4-methyl-l,4-diazepan-5-one (1.75 g, 6.55 mmol) and NH₄Cl (3.5 g, 65.5 mmol) in ethanol-H₂O (2: 1, 125 mL) is heated to 95 °C, and then treated with iron powder (1.1 g, 19.6 mmol) in portions over one hour. The reaction mixture is stirred at 95 °C for 4h, cooled to room temperature, and filtered through a pad of celite, with the aid of dichloromethane. The solvent is removed in vacuo, and dichloromethane and water are added. The layers are separated and the organic layer is dried over MgSO₄, filtered, and concentrated in vacuo to afford the title compound. This material is used directly in the next step without further purification. ¹H NMR (300 MHz, DMSO-d*): 2.59-2.63 (m, 2H), 2.86 (s, 3H), 2.89-2.94 (m, 4H), 3.50 (m, 2H), 5.04 (s, 2H), 6.25-6.33 (m, 2H), 6.79 (t, J=9.9 Hz, IH).

III. Preparation of methyl (2R)-3-{[3-fluoro-4-(4-methyl-5-oxo-l,4-diazepan-l- yl)phenyl] amino} -2-hydroxypropanoate To a solution of 1 -(4-amino-2-fluorophenyl)-4-methyl- 1 ,4-diazepan-5-one

(1.47 g, 6.19 mmol) in acetonitrile (15 mL) at 23°C is added Lithium triflate (1.16 g, 7.43 mmol), followed by (φ-methyl glycidate (0.65 mL, 7.43 mmol). The reaction mixture is stirred at 65°C for 2 days, cooled to 23⁰C, concentrated, and purified by chromatography on a silica gel column, eluting with a gradient increasing in polarity from 2% to 5% MeOH in dichloromethane. Relevant fractions are combined and concentrated to afford the title compound. MS (m/z): [M+Na]⁺ = 362.3

IV. Preparation of methyl (5R)-3-[3-fluoro-4-(4-methyl-5-oxo-l,4-diazepan-l- yl)phenyl]-2-oxo- 1 ,3-oxazolidine-5-carboxylate To a mixture of methyl (2R)-3-{[3-fluoro-4-(4-methyl-5-oxo-l,4-diazepan-l- yl)phenyl]amino}-2-hydroxypropanoate (1.0 g, 2.95 mmol) and 1,1'- carbonyldiimidazole (0.74 g, 4.42 mmol) is added acetonitrile (20 mL). The resulting mixture is stirred at 50°C overnight, cooled to 23 °C, and concentrated in vacuo. The residue is taken into ethyl acetate (300 mL), washed with 0.5 M aqueous HCl, brine, and dried (Na₂SO₄), filtered, and concentrated. The residue is purified by chromatography on a silica gel column, eluting with a gradient increasing in polarity from 2% to 5% MeOH in dichloromethane. Relevant fractions are combined and concentrated to afford the title compound.

¹H. NMR (300 MHz, DMSO-ds): 2.66 (m, 2H), 2.88 (s, 3H), 3.07-3.15 (m, 4H), 3.56 (m, 2H), 3.75 (s, 3H), 4.13 (m, IH), 4.32 (t, J=9.6 Hz, IH), 5.30 (m, IH), 7.09 (t, J=9.0 Hz, IH), 7.19-7.23 (m, IH), 7.43-7.49 (m, IH).

Example 4 Preparation of (5R)-3-[3-fluoro-4-(4-methyl-5-oxo-l,4-diazepan-l- yl)phenyl]-N-methyl-2-oxo-l,3-oxazolidine-5-carboxamide

Following the procedure in Example 3 and under analogous conditions, methyl (5R)-3-[3-fluoro-4-(4-methyl-5-oxo-l,4-diazepan-l-yl)phenyl]-2-oxo-l,3-oxazolidine- 5-carboxylate (0.15 g, 0.41 mmol) is treated with methanolic methylamine solution (4.0 mL, 2.0 M). The suspension is stirred at the same temperature for 2h, concentrated, and purified by preparative TLC (6% MeOH-CH₂Cl₂), to afford the title compound.

HPLC (SYMMETRY Ci₈ 3.5 μM, 4.6 x 30 mm column; gradient elution 2%- 98% MeCN with 0.1 % TFA over 5 min; 2 mL/min rate): retention time = 1.64 min

¹K NMR (300 MHz, DMSO-de): 2.64 (d, J=4.5 Hz, 3H), 2.68 (m, 2H), 2.87 (s, 3H), 3.06-3.13 (m, 4H), 3.56 (m, 2H), 3.97 (m, IH), 4.23 (t, J=9.3 Hz, IH), 5.03 (m, IH), 7.07 (t, J=9.0 Hz, IH), 7.19-7.23 (m, IH), 7.46-7.51 (m, IH), 8.38 (m, IH).

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

To a suspension of methyl (5R)-3-[3,5-difluoro-4-(4-methyl-5-oxo-l,4- diazepan-l-yl)phenyl]-2-oxo-l,3-oxazolidine-5-carboxylate (0.14 g, 0.40 mmol) in methanol (5 mL) at 23°C is added methanolic ammonia solution (5.0 mL, 2.0 M). The suspension is stirred at the same temperature for Ih, concentrated, and purified by preparative TLC (6% MeOHZCH₂Cl₂) to afford the title compound.

HPLC (SYMMETRY C₁₈ 3.5 μM, 4.6 x 30 mm column; gradient elution 2%- 98% MeCN with 0.1% TFA over 5 min; 2 mL/min rate): retention time = 1.69 min

¹H NMR (300 MHz, DMSO-ds): 2.63 (m, 2H), 2.88 (s, 3H), 3.07-3.14 (m, 4H), 3.52 (m, 2H), 3.97 (m, IH), 4.22 (t, J=9.6 Hz, IH), 5.01 (m, IH), 7.32 (m, 2H), 7.62 (s, IH), 7.86 (s, IH).

Intermediates for the preparation of example 5 are synthesized as follows: I. Preparation of 1 -(2,6-difluoro-4-nitrophenyl)- 1 ,4-diazepan-5-one To a solution of 1 ,4-diazepan-5-one hydrochloride (7.0 g, 46.7 mmol) in acetonitrile (60 mL) is added N,N-diisopropylethylaπώie (50 mL, 280 mmol), followed by 3,4,5-trifluoronitrobenzene (6.1 mL, 51 mmol). The reaction mixture is heated to 70°C overnight, cooled to room temperature, and the solvent removed in vacuo. Dichloromethane is added and the solution is washed with brine, dried over MgSO₄, filtered, and concentrated in vacuo. The resulting residue is purified by column chromatography (0-3% MeOH-dichloromethane) to afford the title compound.

¹H ΝMR (300 MHz, DMSOd₆): 2.58 (m, 2H), 3.27 (m, 2H), 3.36 (m, 4H), 7.70 (br tr, IH), 8.04 (d, J= 10 Hz, 2H). II. Preparation of l-(2,6-difluoro-4-nitrophenyl)-4-methyl-l,4-diazepan-5-one

To a mixture of powdered KOH (0.79 g, 14 mmol) and tetrabutylammonium bromide (0.60 g, 1.87 mmol) in THF (60 mL) is added a solution of l-(2,6-difluoro-4- nitrophenyl)-l,4-diazepan-5-one (2.55 g, 9.4 mmol) and methyl iodide (0.88 mL, 14 mmol) in THF (40 mL). The resulting reaction mixture is kept at room temperature overnight, diluted with ethyl acetate, and washed with water and brine, and dried (MgSO₄), filtered, and concentrated. The residue is purified by column chromatography (2% MeOH in dichloromethane) to afford the title compound.

¹H NMR (300 MHz, DMSO-de): 2.70 (m, 2H), 2.87 (s, 3H), 3.32-3.43 (m, 4H), 3.58 (m, 2H), 7.99 (d, J= 10 Hz, 2H). III. Preparation of l-(4-amino-2,6-difluorophenyl)-4-methyl-l,4-diazepan-5-one

A solution of l-(2,6-difluoro-4-nitrophenyl)-4-methyl-l,4-diazepan-5-one (2.2 g, 7.5 mmol) and NH₄Cl (4.1 g, 75 mmol) in ethanol-H₂O (2: 1, 90 mL) is heated to 95 °C, and treated with iron powder (1.25 g, 23 mmol) in portions over one hour. The reaction mixture is then stirred at 95 °C for 3 hours, cooled to room temperature, and filtered through a pad of celite with the aid of dichloromethane. The solvent is removed in vacuo, and the residue taken into ethyl acetate and water. The layers are separated and the organic layer is dried over MgSO₄, filtered, and concentrated to afford the title compound which is used directly in the next step without further purification. MS (m/z): [M+H]⁺ = 256.2

IV. Preparation o f methyl (2R)-3-{[3,5-difiuoro-4-(4-methyl-5-oxo-l,4-diazepan- 1 -yl)phenyl]amino} -2-hydroxypropanoate To a solution of l-(4-amino-2,6-difluorophenyl)-4-methyl-l,4-diazepan-5-one (1 g, 3.92 mmol) in acetonitrile (20 mL) at 23°C is added Lithium triflate (0.73 g, 4.7 mmol), followed by (φ-methyl glycidate (0.41 mL, 4.7 mmol). The reaction mixture is stirred at 95°C for 2Oh and then treated with additional i?-methyl glycidate (0.1 mL, 1.17 mmol). After another day at 95°C, the reaction mixture is cooled to 23°C, concentrated, and purified by chromatography on a silica gel column, eluting with a gradient increasing in polarity from 2% to 5% MeOH in dichloromethane. Relevant fractions are combined and concentrated to afford the title compound. MS (m/z): [M+Na]⁺ = 380.1 HPLC (SYMMETRY C₁₈ 3.5 μM, 4.6 x 30 mm column; gradient elution 2%-

98% MeCN with 0.1% TFA over 5 min; 2 mL/min rate): retention time = 1.85 min. V. Preparation of methyl (5R)-3-[3,5-difluoro-4-(4-methyl-5-oxo-l,4-diazepan-l- yl)phenyl]-2-oxo- 1 ,3-oxazolidine-5-carboxylate

To a mixture of methyl (2R)-3-{[3,5-difluoro-4-(4-methyl-5-oxo-l,4-diazepan- l-yl)phenyl]amino}-2-hydroxypropanoate (0.60 g, 1.68 mmol) and 1,1'- carbonyldiimidazole (0.42 g, 2.52 mmol) at 23°C is added acetonitrile (15 mL). The resulting mixture is stirred at 75°C for 2 days, cooled to 23 °C, and concentrated in vacuo. The residue is taken into ethyl acetate (300 mL), washed with 0.5 M HCl aqueous, brine, and dried (Na₂SO₄), filtered, and concentrated in vacuo. The residue is purified by chromatography on a silica gel column, eluting with a gradient increasing in polarity from 2% to 5% MeOH in dichloromethane. Relevant fractions are combined and concentrated to afford the title compound. MS (m/z): [M+H]⁺ = 452.2 HPLC (SYMMETRY C₁₈ 3.5 μM, 4.6 x 30 mm column; gradient elution 2%- 98% MeCN with 0.1% TFA over 5 min; 2 mL/min rate): retention time = 2.12 min.

Example 6 Preparation of (5R)-3-[3,5-difluoro-4-(4-rnethyl-5-oxo-l,4-diazepan-l- yl)phenyl]-N-methyl-2-oxo-l,3-oxazolidine-5-carboxamide

Following the procedure in Example 1 and under analogous conditions, methyl

(5R)-3-[3,5-difluoro-4-(4-methyl-5-oxo-l,4-diazepan-l-yl)phenyl]-2-oxo-l,3- oxazolidine-5-carboxylate (0.15 g, 0.39 mmol) is treated with methanolic methylamine solution (4.0 mL, 2.0 M). The suspension is stirred at the same temperature for 2h, concentrated, and purified by preparative TLC (6% MeOH/CHkCy to afford the title compound.

HPLC (SYMMETRY Ci₈ 3.5 μM, 4.6 x 30 mm column; gradient elution 2%- 98% MeCN with 0.1% TFA over 5 min; 2 mL/min rate): retention time = 1.78 min ¹H NMR (300 MHz, DMSOd₆): 2.63-2.65 (m, 5H), 2.88 (s, 3H), 3.07-3.14 (m, 4H), 3.53 (m, 2H), 3.98 (m, IH), 4.22 (t, J=9.3 Hz, IH), 5.05 (m, IH), 7.31 (m, 2H), 8.38 (m, IH).

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

To a suspension of methyl (5R)-3-[3,5-difluoro-4-(5-oxo-l,4-diazepan-l- yl)phenyl]-2-oxo-l,3-oxazolidine-5-carboxylate (0.20 g, 0.54 mmol) in methanol (2 mL) at 23°C is added methanolic ammonia solution (3.0 mL, 2.0 M). The suspension is stirred at the same temperature for Ih, concentrated, and purified by preparative TLC (3% MeOH-dichloromethane) to afford the title compound.

HPLC (SYMMETRY Ci₈ 3.5 μM, 4.6 x 30 mm column; gradient elution 2%-

98% MeCN with 0.1% TFA over 5 min; 2 mL/min rate): retention time = 1.54 min ¹Ji NMR (300 MHz, DMSO-ds): 2.53 (m, 2H), 3.09 (m, 4H), 3.22 (m, 2H), 3.97 (dd, J= 9, 6 Hz, IH), 4.22 (tr, J= 9 Hz, IH), 5.01 (dd, J= 9, 6 Hz, IH), 7.32 (d, J= 11 Hz, 2H), 7.62, (s, IH), 7.67 (tr, J= 5 Hz, IH), 7.86 (s, IH).

Intermediates for the synthesis of example 7 are prepared as follows:

I. Preparation of 1 -(4-amino-2,6-difluorophenyl)- 1 ,4-diazepan-5-one

A solution of l-(2,6-difluoro-4-nitrophenyl)-l,4-diazepan-5-one (4.0 g, 14.7 mmol) and NH₄Cl (7.8 g, 147 mmol) in ethanol-H₂O (2: 1, 90 mL) is heated to 95 °C, and treated with iron powder (2.5 g, 44 mmol) in portions over one hour. The reaction mixture is stirred at 95 °C for 6 hours, cooled to room temperature, and filtered through a pad of celite with the aid of dichloromethane. The filtrate is concentrated in vacuo, and the residue taken into ethyl acetate and water. The layers are separated and the organic layer is dried over MgSO₄, filtered, and concentrated to afford the title compound which is used directly in the next step without further purification. MS (m/z): [M + Na]⁺ = 264.0

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

To a solution of l-(4-amino-2,6-difluorophenyl)-l,4-diazepan-5-one (3.42 g, 14.2 mmol) in acetonitrile (80 mL) at 23°C is added Lithium triflate (2.43 g, 15.6 mmol), followed by (R) -methyl glycidate (1.36 mL, 15.6 mmol). The reaction mixture is then stirred at 80°C for 2Oh and treated with additional (Λj-methyl glycidate (0.62 mL, 7 mmol) and Lithium triflate (1.11 g, 7.1 mmol). After another 2 days at 60°C, the reaction mixture is cooled to 23°C, concentrated, and taken into ethyl acetate and water. The layers are separated and the organic phase washed with brine, dried (MgSO₄), filtered, and concentrated. The crude residue is purified by chromatography on a silica gel column, eluting with a gradient increasing in polarity from 0% to 10% MeOH in dichloromethane. Relevant fractions are combined and concentrated to afford the title compound.

¹K NMR (300 MHz, DMSO-dδ): 2.48 (m, 2H), 2.97 (m, 4H), 3.18 (m, 3H), 3.27 (m, IH), 3.62 (s, 3H), 4.17 (m, IH), 5.73 (tr, J= 7 Hz, IH), 6.10 (tr, J= 5 Hz, IH), 6.24 (d, J= 12 Hz, 2H), 7.61 (tr, J= 5 Hz, IH).

III. Preparation of methyl (5R)-3-[3,5-difluoro-4-(5-oxo-l,4-diazepan-l- yl)phenyi]-2-oxo-l,3-oxazolidine-5-carboxylate To a mixture of methyl (2R)-3-{[3,5-difluoro-4-(5-oxo-l,4-diazepan-l- yl)phenyl] amino }-2-hydroxypropanoate (3.97 g, 11.6 mmol) and 1,1'- carbonyldiimidazole (5.6 g, 34.7 mmol) at 23⁰C is added acetonitrile (70 mL). The resulting mixture is stirred at 60°C overnight and then cooled to 23°C and concentrated. The residue is purified by chromatography on a silica gel column, eluting with a gradient increasing in polarity from 0% to 3% MeOH in dichloromethane. Relevant fractions are combined and concentrated to afford the title compound.

¹H NMR (300 MHz, DMSO-ds): 2.53 (m, 2H), 3.1 (m, 4H), 3.21 (m, 2H), 3.75 (s, 3H), 4.13 (dd, J= 10, 5 Hz, IH), 4.31 (tr, J= 10 Hz, IH), 5.32 (dd, J= 10, 5 Hz, IH), 7.29 (d, J= 11 Hz, 2H), 7.66 (tr, J= 5 Hz, IH).

Example 8 Preparation of (5R)-3-[3,5-difluoro-4-(5-oxo-l,4-diazepan-l- yl)phenyl]-N-methyl-2-oxo- 1 ,3-oxazolidine-5-carboxamide

Following the procedure in Example 7 and under analogous conditions, methyl (5R)-3-[3,5-difluoro-4-(5-oxo-l,4-diazepan-l-yl)phenyl]-2-oxo-l,3-oxazolidine-5- carboxylate (0.20 g, 0.54 mmol) is treated with methanolic methylamine solution (3.0 mL, 2.0 M). The suspension is stirred at the same temperature for Ih, concentrated, and the residue purified by preparative TLC (3% MeOH-dichloromethane ) to afford the title compound.

MS (m/z): [M+H]⁺ = 369.3

HPLC (SYMMETRY Ci₈ 3.5 μM, 4.6 x 30 mm column; gradient elution 2%- 98% MeCN with 0.1% TFA over 5 min; 2 mL/min rate): retention time = 1.64 min.

¹K NMR (300 MHz, DMSO-dβ): 2.55 (m, 2H), 2.64 (d, J = 4 Hz, 3H), 3.09 (m, 4H), 3.22 (m, 2H), 3.98 (dd, J= 9, 6 Hz, IH), 4.22 (tr, J= 9 Hz₅ IH), 5.05 (dd, J = 10, 6 Hz, IH), 7.31 (d, J = 12 Hz, 2H), 7.67 (tr, J = 5 Hz, IH), 8.38 (q, J= 4 Hz, IH). Example 9 Preparation of (5R)-3-[3,5-difluoro-4-(5-oxo-2,3,4,5-tetrahydro-lH- 1 ,4-diazepin- 1 -yl)phenyl]-2-oxo- 1 ,3-oxazolidine-5-carboxamide

Methanolic ammonia (2.5 mL ofa 2.0 M solution) is added to a solution of methyl (5R)-3-[3,5-difluoro-4-(5-oxo-2,3,4,5-tetrahydro-lH-l,4-diazepin-l- yl)phenyl]-2-oxo-l,3-oxazolidine-5-carboxylate (0.11 g, 0.3 mmol) in methanol (4 mL). The reaction mixture is stirred at 23⁰C for 2h, concentrated, and the residue purified by column chromatography (0- 6% MeOH in dichloromethane), and lyophilized to afford the title compound.

¹H NMR (300 MHz, DMSO-ds): 3.35 (m, 2H), 3.62 (m, 2H), 4.02 (m, IH), 4.25 (t, J= 10 Hz, IH), 4.48 (dd, J= 9, 2 Hz, IH), 5.04 (m, IH), 6.42 (d, J= 10 Hz, IH), 7.42-7.48 (m, 3H), 7.63 (s, IH), 7.89 (s, IH).

Intermediates for the synthesis of example 9 are prepared as follows.

I. Preparation of benzyl 3,5-difluoro-4-[4-(hydroxyimino)-3,4-dihydropyridin- 1 (2H)-yl]phenylcarbamate

Hydroxylamine hydrochloride (3.96 g, 55.8 mmol) was added to a solution of benzyl 3,5-difluoro-4-(4-oxo-3,4-dihydropyridin-l(2H)-yl)phenylcarbamate (8.0 g, 22.3 mmol, prepared as described in WO 2004/033449) in pyridine (80 mL) containing molecular sieves (40 g). The reaction was stirred at room temperature overnight, and the reaction mixture filtered through celite with the aid of ethyl acetate. The filtrate was washed with water, dried over MgSO₄, filtered, and concentrated in vacuo to afford the title compound as mixtures of isomers. The crude residue was used in the next step without further purification.

II. Preparation of benzyl 3,5-difluoro-4-(5-oxo-2,3,4,5-tetrahydro-lH-l,4- diazepin- 1 -yl)phenylcarbamate.

To a solution of benzyl 3,5-difluoro-4-[4-(hydroxyimino)-3,4-dihydropyridin- l(2H)-yl]phenylcarbamate (1.2 g, 3.21 mmol) in acetone (20 mL) was added a solution Of Na₂CO₃ (1.36 g, 12.8 mmol) in water (20 mL). The mixture was stirred for 5 minutes, and then a solution of p-toluenesulfonyl chloride (1.33 g, 7.0 mmol) in acetone (10 mL) was added slowly. The reaction was stirred at room temperature overnight, and then the acetone was removed in vacuo, water was added, and the solution extracted with dichloromethane. The organic phases were dried over MgSO₄, filtered, concentrated in vacuo, and purified by silica gel flash chromatography (6% MeOH in dichloromethane) to afford the title compound. ¹H NMR (300 MHz, DMSO-(I₆): 3.34 (m, 2H), 3.59 (m, 2H), 4.45 (dd, J =

2.1, 8.1 Hz, IH), 5.16 (s, 2H), 6.38 (d, J = 10.2 Hz, IH), 7.24 (m, 2H), 7.32-7.43 (m, 6H), 10.24 (s, IH).

III. Preparation of l-(4-amino-2,6-difluorophenyl)-l,2,3,4-tetrahydro-5H-l,4- diazepin-5-one Palladium catalyst (20% Pd(OH)₂ on carbon, 0.5 g) is added to a solution of benzyl 3 ,5-difluoro-4-(5-oxo-2,3 ,4,5-tetrahydro- IH-1 ,4-diazepin- 1 - yl)phenylcarbamate (1.25 g, 3.35 mmol) in ethyl acetate (200 mL) and the mixture stirred under an atmosphere of hydrogen gas. After 16 hours, the reaction mixture is filtered through celite and the filtrate concentrated to provide the title compound, which is used directly in the next step without further purification.

¹H NMR (300 MHz, DMSO-d*) 3.33 (m, 2H), 3.51 (m, 2H), 4.34 (dd, J= 2.1, 8.1 Hz, IH), 5.79 (s, 2H), 6.19-6.25 (m, IH), 6.28 (d, J = 10.2 Hz, 2H), 8.30 (m, IH)

IV. Preparation of methyl (2R)-3-{[3,5-difluoro-4-(5-oxo-2,3,4,5-tetrahydro-lH- 1 ,4-diazepin- 1 -yl)phenyl] amino } -2-hydroxypropanoate Lithium triflate (0.68 g, 4.35 mmol) and then (φ-methyl glycidate (0.38 mL,

4.35 mmol) are added to a solution of l-(4-amino-2,6-difluorophenyl)-l,2,3,4- tetrahydro-5H-l,4-diazepin-5-one (0.8 g, 3.34 mmol) in acetonitrile (10 mL). The reaction mixture is stirred at 95°C for 16 hours, cooled to 23°C, concentrated, and purified by flash chromatography (0-5% methanol in dichloromethane) to afford the title compound.

¹H NMR (300 MHz, DMSO-(I₆): 3.22 (m, IH), 3.34 (m, 2H), 3.52 (m, 2H), 3.63 (s, 3H), 4.08 (m, 2H), 4.18 (m, IH), 4.36 (dd, J= 2.1, 8.1 Hz, IH), 5.75 (d, J = 6.9 Hz, IH), 6.29-6.39 (m, 3H), 7.31 (m, IH).

V. Preparation of methyl (5R)-3-[3,5-difluoro-4-(5-oxo-2,3,4,5-tetrahydro-lH- l,4-diazepin-l-yl)phenyl]-2-oxo-l,3-oxazolidine-5-carboxylate

A mixture of methyl (2R)-3-{[3,5-difluoro-4-(5-oxo-2,3,4,5-tetrahydro-lH- l,4-diazepin-l-yl)phenyl]amino}-2-hydroxypropanoate (0.85 g, 2.49 mmol) and 1,1'- carbonyldiimidazole (0.83 g, 5.0 mmol) at 23°C is suspended in acetonitrile (30 mL). The reaction mixture is stirred at 75⁰C overnight, then cooled to 23⁰C and concentrated in vacuo. The residue is purified by silica gel flash chromatography (0- 5% MeOH in dichloromethane) to afford the title compound.

¹H NMR (300 MHz, DMSO-dδ): 3.35 (m, 2H), 3.61 (m, 2H), 3.75 (s, 3H), 4.17 (m, IH), 4.37 (t, J= 9.6 Hz, IH), 4.48 (dd, J= 2.4, 8.1 Hz, IH), 5.36 (m, IH), 6.42 (d, J- 10.5 Hz, IH), 7.44 (m, 3H).

Example 10 Preparation of (5R)-3-[3,5-difluoro-4-(5-oxo-2,3,4,5-tetrahydro-lH- 1 ,4-diazepin- 1 -yl)phenyl]-N-methyl-2-oxo- 1 ,3-oxazolidine-5-carboxamide

Methanolic methylamine (2.5 mL of a 2.0 M solution) is added to a solution of methyl (5R)-3-[3,5-difluoro-4-(5-oxo-2,3,4,5-tetrahydro-lH-l,4-diazepin-l- yl)phenyl]-2-oxo-l,3-oxazolidine-5-carboxylate (0. H g, 0.3 mmol) in methanol (4 mL). The reaction mixture is stirred at 23°C for 4 hours, concentrated, and the residue purified by column chromatography (0-6% MeOH in dichloromethane), and lyophilized to afford the title compound.

¹H NMR (300 MHz, DMSO-dδ): 2.64 (d, J= 4.8 Hz, 3H), 3.35 (m, 2H), 3.62 (m, 2H), 4.02 (m, IH), 4.25 (t, J= 9.6 Hz, IH), 4.48 (d, J= 10.5 Hz, IH), 5.09 (m, IH), 6.42 (d, J= 10.5 Hz, IH), 7.44-7.48 (m, 3H), 8.42 (m, IH).

Claims

CLAIMSWe claim:

1. A compound of formula I

W is

(a) CONHR², (b) CH₂NHCO(NH)Ci.6alkyl,

(C) CH₂NHCOOC_1-6alkyl

(d) CH₂OH,

(e) CH(OH)-CH=CHR²,

(f) CH(OH)C ≡ CR²,

(g) CH₂NH-het,

(h) CH₂O-het,

(O CH₂S-het, or

O) CH₂het; Y¹ Is CH₅ CF₃ Or N;

Y² and Y³ are independently CH, or CF; Q is O, or S; R¹ is H, or Ci-βalkyl;

R² is H, C_1-6 alkyl, or OC_1-6alkyl; each " " is independently a bond or absence, at each occurrence,

is optionally substituted with one or more CF₃, halo, OH, alkyl, or

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 one or more CF₃, halo, OH, OCwalkyl, CN, N₃, 0(C=O)Ci_-4 alkyl, C_3-6cycloalkyl, NH₂, NHC(O)C_1-4 alkyl, or C(O)C₁^ alkyl.

2. A compound of claim 1 which is a compound of formula Ib

Ib wherein R¹ is H or methyl.

3. A compound of claim 2 wherein R² is H, CH₃, or OCH3.

4. A compound of claim 1 which is

(1) (5R)-3-[3-fluoro-4-(5-oxo-l,4-diazepan-l-yl)phenyl]-2-oxo-l,3-oxazolidine-5- carboxamide, (2) (5R)-3-[3-fluoro-4-(5-oxo- 1 ,4-diazepan-l -yl)phenyl]-N-methyl-2-oxo- 1 ,3- oxazolidine-5-carboxamide,

(3) (5R)-3-[3-fluoro-4-(4-methyl-5-oxo- 1 ,4-diazepan- 1 -yl)phenyl]-2-oxo- 1 ,3- oxazolidine-5-carboxamide,

(4) (5R)-3-[3-fluoro-4-(4-methyl-5-oxo- 1 ,4-diazepan- 1 -yl)phenyl]-N-methyl-2- oxo-l,3-oxazolidine-5-carboxamide,

(5) (5R)-3-[3,5-difluoro-4-(4-methyl-5-oxo-l,4-diazepan-l-yl)phenyl]-2-oxo-l,3- oxazolidine-5-carboxamide,

(6) (5R)-3-[3,5-difluoro-4-(4-methyl-5-oxo-l,4-diazepan-l-yl)phenyl]-N-methyl- 2-oxo-l ,3-oxazolidine-5-carboxamide, (7) (5R)-3-[3_>5-difluoro-4-(5-oxo-l,4-diazepan-l-yl)phenyl]-2-oxo-l,3- oxazolidine-5-carboxamide,

(8) (5R)-3-[3,5-difluoro-4-(5-oxo-l,4-diazepan-l-yl)phenyl]-N-methyl-2-oxo-l,3- oxazolidine-5-carboxamide, (9) (5R)-3-[3,5-difluoro-4-(5-oxo-2,3,4,5-tetrahydro-lH-l,4-diazepin-l- yl)phenyl]-2-oxo- 1 ,3-oxazolidine-5-carboxamide, or

(10) (5R)-3-[3,5-difluoro-4-(5-oxo-2,3,4,5-tetrahydro-lH-l,4-diazepin-l- yl)phenyl]-N-methyl-2-oxo- 1 ,3-oxazolidine-5-carboxamide.

5. A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

6. A use of a compound of claim 1 for the preparation of a medicament for treating bacteria infectious diseases.

7. The use of claim 6 wherein the compound of claim 1 is administered orally, parenterally, topically, rectally, or intranasally.

8. The use of claim 6 wherein said compound is administered in an amount of from about 0.1 to about 100 mg/kg of body weight/day.

9. The bacteria infectious diseases of claim 6 which is ear infections, eye infections, respiratory tract infections, skin and skin structure infections, bacterial endocarditis, osteomyelitis, endocarditis or diabetic foot.

10. The bacteria infectious diseases of claim 6 which is caused by gram-positive bacteria, gram negative bacteria, anaerobic organisms, and acid-fast organisms.

11. The bacteria infectious diseases of claim 6 which is caused by bacteria comprising staphylococci, streptococci, Enterococci, Haemophilus, Moraxella, bacteroides, Clostridia, Mycobacteria, or Chlamydia.

12. The bacteria of claim 11 wherein staphylococci is S. aureus and S. epidermidis; wherein streptococci is S. pneumoniae of S. pyogenes; wherein Enterococci is E. faecalis; wherein Haemophilus is H. influenzae; wherein Moraxella is M. catarrhalis; and wherein Mycobacteria is M. tuberculosis; or Mycobacterium avium.

13. The bacteria infectious diseases of claim 6 which is community-acquired pneumoniae or infections caused by multi-drug resistant S. aureus.