JP2008521792A - Diazepine oxazolidinone as an antibacterial agent - Google Patents

Abstract

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

Description

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

BACKGROUND OF THE INVENTION Antibiotic resistance is a major clinical and public health problem that has emerged surprisingly rapidly in recent years and will surely expand in the near future. Resistance is a problem in communities and health care facilities where bacterial transmission is greatly amplified. As multidrug resistance is a growing problem, physicians are currently facing infections without effective therapy. As a result, new structured antibacterial agents with novel modes of action have become more important in the treatment of bacterial infections.

  Of the relatively new antibacterials, oxazolidinone compounds are the most recent synthetic antibacterial class. The present invention provides a new class of oxazolidinone derivatives containing a diazepine ring. They are effective against a number of human and animal pathogens, including multidrug resistant strains.

Disclosure of information
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 2003072081, WO 2003119817, WO 2003008389, WO 2003007870, WO 200206278, WO 200032599, WO 9924428, WO 2004014392, WO 2004002967, WO 2004009587, WO 2004018439, published US patent applications No. US 2004/0044052, USP No. 5547950, USP No. 5700799, DE 10034627 disclose oxazolidinone compounds having antibacterial activity useful for the treatment of microbial infections.

SUMMARY OF THE INVENTION The present invention relates to compounds of formula I

Or a pharmaceutically acceptable salt thereof:
In the formula:
A is a structure of formula i, ii, iii, or iv:

W is:
(a) CONHR ² ,
(b) CH ₂ NHCO (NH) C _1-6 alkyl,
(c) CH ₂ NHCOOC _1-6 alkyl,
(d) CH ₂ OH,
(e) CH (OH) -CH = CHR ² ,
(f) CH (OH) C≡CR ² ,
(g) CH ₂ NH-het,
(h) CH ₂ O-het,
(i) CH ₂ S-het, or
(j) CH ₂ het;
Y ¹ is CH, CF, or N;
Y ² and Y ³ are independently CH or CF;
Q is O or S;
R ¹ is H or C _1-6 alkyl;
R ² is H, C _1-6 alkyl, or OC _1-6 alkyl;
Each "....." is independently a bond or absent;
In each case, C _1-6 alkyl is one or more CF ₃ , halo, OH, OC _1-4 alkyl, CN, N ₃ , O (C═O) C _1-4 alkyl, C _3-6 cycloalkyl, Optionally substituted with NH ₂ , NHC (═O) C _1-4 alkyl, or C (═O) C _1-4 alkyl; and
het is a 5- or 6-membered heterocyclic ring having 1 to 4 heteroatoms in the ring selected from the group consisting of oxygen, sulfur and nitrogen, wherein each carbon atom in het is 1 or more CF ₃ , halo, OH, OC _1-4 alkyl, CN, N ₃ , O (C═O) C _1-4 alkyl, C _3-6 cycloalkyl, NH ₂ , NHC (═O) C _{1 Optionally} substituted with _-4 alkyl, or C (= O) C _1-4 alkyl.

In another aspect, the present invention also provides:
A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of formula I;
A method of treating a microbial infection in a mammal by administering to a subject in need thereof a therapeutically effective amount of a compound of formula I, as well as a compound of formula I or a medicament thereof for the manufacture of a medicament for use in the treatment of a microbial infection Use of chemically acceptable salts.

The present invention also provides novel intermediates and novel methods 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 following meanings:
The carbon atom content of various hydrocarbon-containing moieties is indicated by a subscript representing the minimum and maximum number of carbon atoms in the moiety. That is, the subscript C _ij generally indicates a portion including carbon atoms from the integer “i” to the integer “j”. For example, C _1-6 alkyl generally represents an alkyl of 1 to 6 carbon atoms.

  The terms alkyl or alkenyl and the like represent both straight-chain and branched-chain groups, but the expression individual groups, such as “propyl”, includes only straight-chain groups, and branched-chain isomers, such as “isopropyl,” are specific. Are expressed

The term “halo” refers to fluoro (F), chloro (Cl), bromo (Br), or iodo (I).
The term “pharmaceutically acceptable salt” of a compound means a compound that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound.

  The term “het” is a 5- or 6-membered heterocyclic ring having 1 to 4 heteroatoms in the ring selected from the group consisting of oxygen, sulfur and nitrogen. Examples of het include, but are not limited to: azetidine, pyrrole, imidazole, pyrazole, 1,2,3-triazole, 1,3,4-triazole, oxazole, thiazole, isoxazole, iso Thiazole, 1,3,4-oxadiazole, 1,3,4-thiadiazole, 1,2,3-thiadiazole, tetrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, dihydroindole, indazole , Purine, quinolidine, isoquinoline, quinoline, phthalazine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, isoxazolinone, phenoxazine, phenothi Gin, 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 called thiamorpholine), piperidine, pyrrolidine, tetrahydrofuran and the like. Other examples of het include, but are not limited to: pyridine, thiophene, furan, pyrazole, pyrimidine, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, 3-pyrazinyl, 4-oxo-2-imidazolyl, 2-imidazolyl, 4-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 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-iso Thiazole, 2-fura Nyl, 3-furanyl, 2-thienyl, 3-thienyl, 2-pyrrolyl, 3-pyrrolyl, 3-isopyrrolyl, 4-isopyrrolyl, 5-isopyrrolyl, 1,2,3, -oxathiazole-1-oxide, 1, 2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, 5-oxo-1,2,4-oxadiazol-3-yl, 1,2,4- Thiadiazol-3-yl, 1,2,5-thiadiazol-3-yl, 1,2,4-thiadiazol-5-yl, 3-oxo-1,2,4-thiadiazol-5-yl, 1,3, 4-thiadiazol-5-yl, 2-oxo-1,3,4-thiadiazol-5-yl, 1,2,3-triazol-1-yl, 1,2,4-triazol-3-yl, 1, 2,4-triazol-5-yl, tetrazol-1-yl, 1,2,3,4-tetrazol-5-yl, 5-oxazolyl, 3-isothiazolyl, 4-isothiazolyl and 5-isothiazolyl, 1,3, 4, -oxadiazole, 4-oxo-2-thiazolinyl, or 5-methyl-1,3,4-thiadia Lumpur-2-yl, thiazole-dione, 1,2,3,4-thiatriazole, or 1,2,4 Jichiazoron.

  The term “pharmaceutically acceptable carrier” refers to a carrier that is useful in preparing a pharmaceutical composition, is generally safe and non-toxic, and is not biologically or otherwise undesirable. This includes carriers that are acceptable as both animal and human medicines. As used herein and in the claims, “pharmaceutically acceptable carrier” includes one or more than one such carrier.

  The term “mammal” refers to humans or warm-blooded animals, including livestock and pets. Livestock refers to animals suitable for human meat intake. Examples include pigs, cows, chickens, fish, turkeys, rabbits and the like. A pet animal represents an animal bred as a pet, such as a dog or a cat.

  The term “optional” or “optionally” means that the event or situation described below may occur but need not occur, and this description includes when and what happens that event or situation occurs. The case where there is no.

  The term “treating” or “treatment” of a disease includes: (1) Preventing the disease: ie, having the potential to develop or predispose to the disease Do not develop clinical symptoms of the disease in mammals who have not yet experienced or presented with symptoms of the disease; (2) block the disease, ie stop or reduce the development of the disease or its clinical symptoms; or (3) Alleviate the disease: regress 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. A “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 formula, for example by hydrolysis in blood. For a detailed discussion, see T. Higuchi and V. Stella, “Pro-drugs as Novel Delivery Systems” Vol. 14, the ACS Symposium Series, and Bioreversible Carriers in Drug Design, Editor Edward B. Roche, American Pharmaceutical Association and Pergamon Press, Shown in 1987.

  The term “leaving group” has the meaning generally associated with it in synthetic organic chemistry, ie, an atom or group that can be displaced by a nucleophilic group and is 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 in the spatial arrangement of their atoms are called “isomers”. Isomers that differ in the arrangement of their atoms in space are called "stereoisomers".

  One skilled in the art will recognize that compounds of the present invention having chiral centers exist in optically active and racemic forms and may be isolated. Certain compounds may exhibit polymorphism. The present invention should be understood to include any racemic, optically active, polymorphic, tautomeric or stereoisomeric form of the compounds of the present invention having the useful properties described herein, or mixtures thereof. is there. Methods for producing optically active forms (eg, by resolving racemic forms by recrystallization, by synthesis from optically active starting materials, by chiral synthesis, or by chromatographic separation using a chiral stationary phase), and the specification Methods for measuring antibacterial activity using the standard test methods described in or using other similar test methods well known in the art are well known in the art.

The compounds of the invention are generally named according to the IUPAC or CAS nomenclature system.
Abbreviations well known to those skilled in the art are used (eg, “Ph” for phenyl, “Me” for methyl, “Et” for ethyl, “h” for time, and “rt” for room temperature).

  The specific and preferred meanings given below for groups, substituents and ranges are for illustration only; they have other meanings defined, or other meanings within the ranges defined for groups and substituents. It is not excluded.

  Specifically, alkyl represents both a straight chain group and a branched chain group, but the individual group, for example, the expression “propyl” includes only the straight chain group, and the branched chain isomer, for example, “isopropyl” Expressed specifically.

In particular, alkyl is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, and isomeric forms thereof.
In particular, alkenyl is vinyl, propenyl, allyl, butenyl, and isomeric forms thereof.

In particular, halo is fluoro (F) or chloro (Cl).
In particular, the present invention provides compounds of formula Ia:

Wherein Y ¹ and Y ² are independently CH or CF; W is CONHR ² or CH ₂ NHCO (NH) C _1-6 alkyl.
In particular, the present invention provides compounds of formula Ib:

Wherein Y ¹ and Y ² are independently CH or CF; R ¹ is H or methyl; R ² is H, CH ₃ or OCH ₃ .
Examples of the present invention are:
(1) (5R) -3- [3-Fluoro-4- (5-oxo-1,4-diazepan-1-yl) phenyl] -2-oxo-1,3-oxazolidine-5-carboxamide,
(2) (5R) -3- [3-Fluoro-4- (5-oxo-1,4-diazepan-1-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-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-1,4-diazepan-1-yl) phenyl] -N-methyl-2-oxo-1, 3-oxazolidine-5-carboxamide,
(7) (5R) -3- [3,5-difluoro-4- (5-oxo-1,4-diazepan-1-yl) phenyl] -2-oxo-1,3-oxazolidine-5-carboxamide,
(8) (5R) -3- [3,5-Difluoro-4- (5-oxo-1,4-diazepan-1-yl) phenyl] -N-methyl-2-oxo-1,3-oxazolidine- 5-carboxamide,
(9) (5R) -3- [3,5-Difluoro-4- (5-oxo-2,3,4,5-tetrahydro-1H-1,4-diazepin-1-yl) phenyl] -2- Oxo-1,3-oxazolidine-5-carboxamide, or
(10) (5R) -3- [3,5-Difluoro-4- (5-oxo-2,3,4,5-tetrahydro-1H-1,4-diazepin-1-yl) phenyl] -N- Methyl-2-oxo-1,3-oxazolidine-5-carboxamide.

  The compounds of the present invention can be prepared according to one or more schemes described below. All starting materials are commercially available or can be prepared by methods well known to those skilled in organic chemistry. The variables used in the scheme are as defined below or are in accordance with the summary of the invention or the claims.

  Scheme I describes the synthesis of an oxazolidinone ring with a C-5 carboxamide side chain starting from the commercially available aniline 1. First, aniline 1 is reacted with alkyl (2R) -epoxypropanoate and a Lewis acid such as lithium triflate (described in US Patent Application Publication No. US 2004/0044052) to give amino alcohol 2. The amino alcohol 2 is then cyclized by methods known to those skilled in the art to give the aryloxazolidinone 3. For example, intermediate 2 is treated with 1,1′-carbonyldiimidazole in a solvent such as acetonitrile or tetrahydrofuran at a suitable temperature, generally 20-80 ° C., to give oxazolidinone 3. Alternatively, reacting 2 and 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, generally -10-25 ° C, provides oxazolidinone 3. This product can be used as collected, or first purified by conventional methods such as preparative TLC or HPLC, chromatography, precipitation, or crystallization.

Treatment of oxazolidinone ester 3 with ammonia or optionally with a substituted amine (R ² NH ₂ ) in a suitable solvent such as methanol or acetonitrile yields amide 4 (R ² = H or optionally substituted alkyl) Is obtained. Similarly, ester 3 is treated with O-alkylhydroxylamine to a hydroxamate (R ² = O-alkyl). This product can be used as collected, or first purified by conventional methods such as preparative TLC or HPLC, chromatography, precipitation, or crystallization.

Scheme II describes the synthesis of aniline intermediate 9 with a diazepanone ring. Diazepanone 5 (see Scheme III for synthesis) is reacted with fluoronitrobenzenes (eg, with 3,4, -difluoronitrobenzene) via an nucleophilic aromatic substitution reaction to an intermediate, eg, 6. Such reactions are well known to those skilled in the art and there are general reports describing these reactions (see Zoltewicz, Top. Curr. Chem. 1975, vol. 59, pp. 33-64). These transformations are generally performed at a temperature of about 40 to about 90 ° C. using a polar aprotic solvent such as acetonitrile or dimethyl sulfoxide in the presence of an acid scavenging base such as triethylamine or N, N-diisopropylethylamine. . Intermediate 6 is then optionally alkylated at the nitrogen atom to form intermediate 7. For example, 6 and methyl iodide are reacted with potassium hydroxide as the base and tetrabutylammonium bromide as the phase transfer catalyst to intermediate 7 (R ¹ = methyl). Intermediate 7 is then reduced to aniline intermediate 8. This reduction is generally accomplished by reacting 7 with a reducing metal (eg, with iron powder). This reaction is carried out at a temperature of about 60 to about 90 ° C. in a mixture of water as a solvent and alcohols (methanol, ethanol, etc.) in the presence of ammonium chloride to buffer the reaction mixture. preferable. In some cases, this type of reduction is carried out by reaction with other metals such as tin or zinc or by hydrogenation under palladium or platinum catalysts (Rylander, Hydrogenation Methods; Academic Press: New York, 1985, pp. 104-116). The product can be used as collected or can be first purified by conventional methods such as preparative TLC or HPLC, chromatography, precipitation, or crystallization. An aniline intermediate, such as 9, can then be converted to an oxazolidinone analog as described in Scheme I.

  Scheme III describes the synthesis of diazepanone heterocycle 5. This compound can be prepared in three steps from a commercially available piperidone compound such as benzyl 4-oxopiperidine-1-carboxylate (10, commercially available) or t-butyl 4-oxopiperidine-1-carboxylate. 10 and hydroxylamine are reacted in a solvent such as pyridine in the presence of molecular sieves (to remove water formed during the reaction) to give oxime intermediate 11.

  Intermediate 11 is then converted to protected diazepanone intermediate 12. This reaction, known as the Beckmann rearrangement, is well known to those skilled in the art and can be accomplished under a variety of conditions (for review see Gawley, Organic Reactions, 1988, 35, pp 1-420). For intermediate 11, this reaction is carried out using tosyl chloride to activate the oxime in a solvent such as acetone, water, or mixtures thereof in the presence of an acid scavenging base such as sodium carbonate. Is preferred. This product can be used as collected, or first purified by conventional methods such as preparative TLC or HPLC, chromatography, precipitation, or crystallization.

  Finally, the protecting group (eg Cbz or Boc) is removed from intermediate 12 to diazepanone 5. Removal of the benzyl carbamate protection is preferably accomplished by hydrogenolysis, generally using a palladium catalyst with a solvent such as ethyl acetate, alcohols or mixtures thereof under a hydrogen gas atmosphere. The cleavage of t-butyl carbamate is generally achieved by treatment with an acid such as hydrochloric acid or trifluoroacetic acid. Treatment with trimethylsilyl trifluoromethanesulfonate and 2,6-lutidine (described in Ohfune, Y. and Sakaitani, M., J. Org. Chem. 1990, 55, 870-876) when more relaxed conditions are required Is also effective. Diazepanone 5 can then be used in the synthesis of final analogs outlined in Schemes I and II.

  Scheme IV outlines the synthesis of aniline intermediates with a tetrahydrodiazepinone ring. The starting material used is a dihydropyridone intermediate, for example 13 (prepared as described in PCT publication WO 2004/033449). Reaction of 13 with hydroxylamine as described in Scheme III above provides oxime intermediate 14. The oxime intermediate 14 is then converted to the protected diazepanone intermediate 15 by the Beckmann rearrangement described in Scheme III above. Intermediate 15 is then converted to intermediate 16, optionally with a heterocyclic nitrogen atom alkylated. Finally, the carbamate functional group of intermediate 16 is removed to give the desired aniline intermediate 17. The reaction conditions for this step will depend on the type of carbamate used (eg, benzyl carbamate is preferably removed by the hydrogenolysis described in Scheme III above). Intermediate 17 can then be used in the synthesis of the oxazolidinone analog described in Scheme I.

  Schemes V-VIII describe the synthesis of aryl isoxazolinones, aryl isoxazolines, and aryl butyrolactone compounds of the type diazepanone and related heterocycles described in Schemes I-VII. The following scheme describes a general method for making the inventive structures where A is (ii), (iii) or (iv). Although diazepanones and related heterocycles can be prepared as described in Schemes I-VII above, it will be appreciated by those skilled in the art that suitable protecting groups may be required to protect and later appear on sensitive functional groups. I will.

Scheme V summarizes the synthesis of the required substituted benzaldehyde intermediates. The general methods described in each of the above schemes can be applied, but starting materials such as fluorinated benzonitrile (29) or benzoate are used instead of fluorinated nitrobenzene. Necessary starting materials (eg 3,4,5-trifluorobenzonitrile) are commercially available. Conversion of these starting materials to intermediate 30 can be accomplished in a series of steps using the same methods described for the preparation of aniline intermediates in Schemes II-IV. The intermediate 30 is then converted to the benzaldehyde intermediate 31 by reduction, for example with SnCl ₂ / HCl to an imine, followed by hydrolysis by methods well known to those skilled in the art (Stephen aldehyde synthesis).

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

  Scheme VII describes a general method for making aryl isoxazoline compounds having diazepanone or related heterocycles of the type described in each of the preceding schemes. In the first step of Scheme X, benzaldehyde intermediate 31 and hydroxylamine hydrochloride are reacted in a polar protic solvent such as methanol in the presence of a base such as pyridine to yield oxime intermediate 35. Oxime 35 is then oxidized with N-chlorosuccinimide (NCS) in a suitable solvent, such as dichloromethane, to give hydroxyiminoyl chloride intermediate 36. This material is then reacted with an alkene, such as allyl alcohol, in the presence of a base, such as triethylamine, in a solvent, such as dichloromethane, to the hydroxymethyl substituted isoxazoline 37. The 37 hydroxymethyl function is then converted to acetamidomethyl or related moieties (eg R ′ = Et, OMe, etc. at 38) by established synthetic methods (eg as described in US PCT Publication US 2004/0127530) to 38 can do. Alternatively, hydroxyiminoyl chloride 36 can be reacted with N-acetylallylamine directly to the acetamidomethyl substituted isoxazoline product (38, W = O and R ′ = Me). Optionally, the hydroxyiminoyl chloride intermediate can be formed in situ as described above and then treated directly with the alkene to produce the isoxazoline intermediate directly from 35.

  Scheme VIII describes the synthesis of arylbutyrolactone analogs such as 42. The synthesis of saturated (as in 41) and unsaturated (as in 42) 3-arylbutyrolactone ring systems is described in the literature (eg Bioorganic & Medicinal Chemistry Letters, 1994, 4, 1925-1930 See). Aldehyde intermediate 31 is converted to phenylacetic acid intermediate 39 in an established manner (eg as described in USP 5,708,169 to Hester et al.). The 39 dianions and R-benzyloxymethyloxirane are then reacted in THF. The resulting hydroxy acid is cyclized to lactone 40 under an acid catalyst (eg, using p-toluenesulfonic acid). The benzyl group is then removed by hydrogenolysis and the resulting hydroxymethyl functionality is obtained by established synthetic methods (eg USP Publication US 2004/0127530) or acetamidomethyl or related moieties (eg R ′ = Et, OMe etc. at 41) ) To 41. Finally, butyrolactone is oxidized to 42 using a two-step protocol with bromination (eg using N-bromosuccinimide) followed by removal by treatment with a suitable base such as pyridine or DBU.

Use as pharmaceuticals and veterinary drugs The compounds of the present invention can be used to treat infectious diseases caused by various bacteria.
Examples include gram positive bacteria, such as multidrug resistant staphylococci, such as S. aureus and S. epidermidis; multidrug resistant streptococci, such as pneumonia S. pneumoniae and S. pyogenes; and multi-drug resistant Enterococci, such as Enterococcus faecalis; Gram-negative aerobic bacteria, such as Haemophilus Eg, H. influenzae, and Moraxella, such as Moraxella catarrhalis; and anaerobes such as bacteroides and clostridia, and acid-fast bacteria, For example, Mycobacteria, such as M. tuberculosis and / Or included avium (Mycobacterium avium) is. Other examples include Escherichia, such as E. coli, intracellular microorganisms, such as Chlamydia and Rickettsiae.

  Examples of infections that can be treated with the compounds of the present invention include: central nervous system infections, outer ear infections, middle ear infections such as acute otitis media, dural sinus infections, ocular infections, Oral infections such as teeth, gums and mucous membrane infections, upper respiratory tract infections, lower respiratory tract infections, genitourinary infections, gastrointestinal infections, gynecological infections, sepsis, bone and joint infections, skin and Antibacterial prophylaxis of tissue infections, cellular endocarditis, burns, surgical procedures, as well as immunosuppressed patients, such as patients receiving cancer chemotherapy or organ transplant patients. In particular, infectious diseases that can be treated with the compounds of the invention are Gram-positive bacterial infections such as osteomyelitis, endocarditis and diabetic foot.

Antibacterial Activity The in vitro antibacterial activity of the compounds of the present invention can be evaluated by the following recommended method: (1) National Committee for Clinical Laboratory Standards (January 2003) , Methods for dilution antimicrobial tests for bacteria that grow aerobically, Approved Standard (6th edition), M7-A6, NCCLS, Wayne, Pennsylvania; (2) National Committee for Clinical Laboratory Standards (March 2001), Methods for antimicrobial susceptibility testing of anaerobic bacteria, Approved Standard (5th edition), M11 -A4, NCCLS, Wayne, PA; (3) National Committee for Clinical Laboratory Standards (January 2003), MIC testing supplemental tables, M100-S13 (used for M7-A6), NCCLS, Pennsylvania . A Wayne; and (4) Murray PR, Baron EJ, Jorgensen JH, et al, Manual of Clinical Microbiology (8th ed.) Washington, DC: American Society for Microbiology Press, 2003. Antimicrobial activity can be expressed in the form of MIC values. The MIC value is the minimum drug concentration at which visible growth was blocked under the test conditions. The test results are shown in Table 1.

Pharmaceutical Salts Compounds of formula I can be used in their natural form or as salts. If it is desired to form a stable non-toxic acid or base salt, it may be appropriate to administer the compounds of the invention as a pharmaceutically acceptable salt. Examples of pharmaceutically acceptable salts of the compounds of the present invention include inorganic salts such as hydrochloride, hydrobromide, sulfate, nitrate, bicarbonate, carbonate, and organic salts such as tosylate, methane Examples include sulfonate, acetate, citrate, malonate, tartrate, succinate, benzoate, ascorbate, etoglutarate, and glycerophosphate.

  Pharmaceutically acceptable salts can be obtained by standard methods well known in the art, for example by reaction of a sufficiently basic compound, such as an amine, with a suitable acid that provides 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 prepared.

Route of administration For therapeutic uses to treat or combat bacterial infections in mammals (eg, humans and animals), the compounds of the invention or pharmaceutical compositions thereof are administered orally, parenterally, topically, rectally, transmucosally, or intestine. It can be administered internally.

  Parenteral administration includes indirect injection to generate a systemic effect or direct injection into the affected area. Examples of parenteral administration are subcutaneous, intravenous, intramuscular, intradermal, subarachnoid (intrathecal), intraocular, intranasal, intraventricular injection, or infusion.

  For topical administration, infected areas or organs easily accessible by topical application, eg eyes, ears (including outer and middle ear infections), vagina, open wounds, skin (including epidermis and subcutaneous tissue) or other lower parts Intestinal treatment is included. This includes transdermal delivery to generate systemic effects.

Rectal administration includes suppository forms.
Transdermal administration includes nasal aerosol or inhalation administration.
Preferred routes of administration are oral and parenteral.

Compositions / Formulations The pharmaceutical compositions of the present invention can be prepared by methods well known in the art, eg, general mixing, dissolution, granulation, dragee manufacturing, kneading, emulsification, encapsulation, capture, lyophilization treatment. Or it can be prepared by spray drying.

  Pharmaceutical compositions for use in accordance with the present invention can be formulated in conventional manner using one or more physiologically acceptable carriers, which facilitates processing of the active compound into a pharmaceutical usable formulation. Excipients and auxiliaries are included. Proper formulation is dependent upon the route of administration chosen.

  For oral administration, the compounds of the invention can be formulated by combining the active compounds with pharmaceutically acceptable carriers well known in the art. Such carriers enable tablets, pills, lozenges, dragees, capsules, liquids, solutions, emulsions, gels, syrups, slurries, suspensions, etc. It can mix | blend as a turbid liquid agent etc. The carrier may be at least one substance that can 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, starch Gelatin, cellulosic materials, low melting wax, cocoa butter or cocoa powder, polymers such as polyethylene glycol, and other pharmaceutically acceptable materials.

  An appropriate coating can be applied to the core of the sugar-coated maru. For this, concentrated sugar solutions can be used, which may optionally include gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol and / or titanium dioxide, lacquer solutions, and suitable organic solvents or solvents. You may contain a mixture. 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 that 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. A slip-fit capsule may contain the active ingredient mixed with a filler, such as lactose, a binder, such as starch, and / or a lubricant, such as talc or magnesium stearate, and optionally a stabilizer. it can. In the case of soft capsules, the active ingredient is dissolved or dissolved in a suitable liquid such as fatty oil, liquid paraffin, liquid polyethylene glycol, cremophor, capmul, medium or long chain mono-, di- or triglycerides Can be suspended. Stabilizers can also be added to these formulations.

  Liquid compositions include solutions, suspensions and emulsions. For example, a solution of the compound of the present invention dissolved in water and water-propylene glycol and water-polyethylene glycol systems can be provided. These optionally contain suitable common colorants, flavoring agents, stabilizers and thickeners.

  The composition of the present invention can also be formulated for parenteral administration, eg, by injection, bolus injection or continuous infusion. Formulations for parenteral administration can be provided in unit dosage form, eg, in ampoules or multiple dose containers, with the addition of a preservative. The compositions of the present invention can take the form of suspensions, solutions or emulsions in oily or aqueous vehicles and can contain formulating agents such as suspending agents, stabilizers and / or dispersing agents.

  For injection, the compounds of the invention can be formulated in aqueous solutions, preferably in physiologically compatible buffers or physiological salt buffers. Suitable buffering agents include trisodium orthophosphate, sodium bicarbonate, sodium citrate, N-methylglucamine, L (+)-lysine and L (+)-arginine.

  Parenteral administration also includes aqueous solutions of the active compounds, such as aqueous solutions of salts (but not limited). In addition, suspensions of the active compounds can be prepared in lipophilic vehicles. Suitable lipophilic vehicles include materials such as fatty oils such as sesame oil, synthetic fatty acid esters such as ethyl oleate and triglycerides, or 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 substances that increase the solubility of the compounds of the invention and allow the preparation of highly concentrated solutions.

Alternatively, the active ingredient may be in powder form for constitution prior to use with a suitable vehicle (eg, sterile pyrogen-free water).
For suppository administration, a compound of the invention may be formulated by mixing with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and therefore melts in the rectum to release the drug. You can also. Such materials include cocoa butter, beeswax and other glycerides.

  For administration by inhalation, the compounds of the invention are conveniently delivered by aerosol spray in the form of a solution, dry powder or suspension. The aerosol can be a pressurized pack or nebulizer and a suitable propellant. In the case of a pressurized aerosol, the dosage unit can be controlled by providing a valve to deliver a metered amount. For example, capsules and cartridges made of gelatin for use in an inhaler can be formulated to contain a powder base such as lactose or starch.

  For topical applications, the pharmaceutical compositions of the invention can be formulated in a suitable ointment containing the active compound 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 paraffin, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene blend, emulsifying wax and water. Alternatively, the pharmaceutical composition can be formulated in a suitable lotion such as a suspension, emulsion or cream containing the active ingredient suspended or dissolved in one or more carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl ester wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.

  For use in ophthalmic and otitis, the pharmaceutical composition of the invention as a fine suspension in a pH adjusted isotonic sterile saline solution, or preferably as a solution in a pH adjusted isotonic sterile saline solution Can be formulated with or without a preservative, such as benzalkonium chloride. Alternatively, for ophthalmic use, the pharmaceutical composition may be formulated in an ointment such as petrolatum.

  In addition to the blends described above, the compound of the present invention can be blended as a depot preparation. Such long acting formulations may be in the form of implants. The compounds of the invention can be formulated for this route of administration with a suitable polymer, hydrophobic material, or as a poorly soluble derivative such as a poorly soluble salt, including but not limited to.

  Furthermore, the compounds of the present invention can be delivered by sustained release systems. Various sustained-release materials have been established and are well known by those skilled in the art. Sustained release capsules can release compounds over a period of 24 hours to several days, depending on their chemical nature.

Dosage A pharmaceutical composition suitable for use in the present invention includes a composition containing an active ingredient in an amount sufficient to achieve the intended purpose, ie, the treatment or prevention of infectious diseases. More specifically, a therapeutically effective amount refers to the amount of a compound that is effective to prevent, reduce or ameliorate symptoms of disease or to prolong the survival of the subject being treated.

  The amount of the active ingredient in the pharmaceutical composition and unit dosage form thereof, that is, the compound of the present invention, can be widely changed or adjusted depending on the mode of administration, the potency of the compound and the target concentration. The determination of the therapeutically effective amount is within the range that can be easily made by those skilled in the art. In general, the amount of active ingredient will be from 0.5 to 90% by weight of the composition.

  Generally, a therapeutically effective amount of the active ingredient will be about 0.1 to about 400 mg / kg body weight / day, more preferably about 1.0 to about 50 mg / kg body weight / day. It should be understood that the dosage may vary depending on the requirements of each subject and the severity of the bacterial infection to be treated. On average, the effective amount of active ingredient is about 200-800 mg, preferably 600 mg per day.

  Conveniently, the target amount is provided as a daily dose, or as divided doses administered, for example, 2, 3, 4 or more small doses per day at appropriate intervals. This small dose itself may be subdivided and administered at irregular intervals, for example in multiple doses; for example, multiple inhalations from an inhaler, or application of multiple drops to the eye.

  It should also be understood that the initial dosage may be increased above the upper limit in order to quickly reach the desired plasma concentration. On the other hand, the initial amount is less than the optimal amount, and the daily amount can be gradually increased depending on the situation during the course of the treatment. If desired, the daily dose may be divided into multiple doses, for example 2-4 times a day.

In cases of local administration or selective uptake, the effective local concentration of the drug may be independent of plasma concentration, and other methods known in the art can be employed to determine the desired dosage.
Oral efficacy

In the discussion above and in the following examples, the following abbreviations have the following meanings. If an abbreviation is not defined, it has its generally accepted meaning.

bm = wide multiple line
BOC = t-butoxycarbonyl
bd = wide double line
bs = wide single line
bt = wide triple line
CDI = 1,1'-carbodiimidazole
d = double wire
dd = double double line
dq = double quadruple
dt = double triple wire
dm = double multiple line
DMF = dimethylformamide
DMAP = dimethylaminopyridine
DIEA = diisopropylethylamine
DMSO = dimethyl sulfoxide
eq. = equivalent
g = grams
h = time
HPLC = high performance liquid chromatography
HATU = N-[(dimethylamino) -1H-1,2,3-triazolo- [4,5-b] pyridin-1-yl-methylene] -N-methylmethananium hexafluorophosphate N-oxide
LG = leaving group
m = multiple line
M = molar concentration
M% = mol%
max = maximum
meq = milliequivalent
mg = milligram
mL = milliliter
mm = millimeter
mmol = mmol
q = quadruple line
s = single line
t or tr = triple line
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 = 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 = t-butoxycarbonyl
CBZ = benzyloxycarbonyl
BCC = 1,3-dicyclohexylcarbodiimide
PyBop = benzotriazol-1-yl-oxy-trispyrrolidinophosphonium hexafluorophosphate.

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

(5R) -3- [3-Fluoro-4- (5-oxo-1,4-diazepan-1-yl) phenyl] -2-oxo-1,3-oxazolidine-5-carboxylate methyl (0.14 g, To a suspension of 0.40 mmol) in methanol (5 mL) is added methanolic ammonia solution (5.0 mL, 2.0 M) at 23 ° C. The suspension is stirred at the same temperature for 1 hour, concentrated and purified by preparative TLC (6% MeOH—CH ₂ Cl ₂ ) to give the title compound;
HPLC (SYMMETRY C ₁₈ 3.5 μM, 4.6 × 30 mm column; gradient elution 2% -98% MeCN (with 0.1% TFA) over 5 min; rate of 2 mL / min): retention time = 1.39 min;
¹ H NMR (300 MHz, DMSO-d ₆ ): 2.59 (m, 2H), 3.09 (m, 4H), 3.25 (m, 2H), 3.95 (m, 1H), 4.22 (t, J = 9.3 Hz, 1H), 5.0 (m, 1H), 7.09 (t, J = 9.0 Hz, 1H), 7.20 (d, J = 8.7 Hz 1H), 7.48 (d, J = 14.9 Hz, 1H), 7.60 (s, 1H ), 7.67 (m, 1H), 7.84 (s, 1H).

The intermediate for the preparation of Example 1 is synthesized as follows:
I. Production of t-butyl 4- (hydroxyimino) piperidine-1-carboxylate
To a solution of t-butyl 4-oxopiperidine-1-carboxylate (50 g, 251 mmol) in pyridine (500 mL) was added molecular sieve (50 g) and the mixture was stirred at room temperature for 10 minutes, Subsequently NH ₂ OH.HCl (30.25 g, 427 mmol) is added. The resulting reaction is stirred at room temperature overnight and the reaction mixture is filtered through a pad of celite to remove molecular sieves. The filtrate is diluted with water, the layers are separated and the aqueous phase is further extracted with ethyl acetate. The combined organic phases are washed with brine, dried over MgSO ₄ , filtered and concentrated in vacuo to give the title compound. This material is used in the next step without further purification;
¹ H NMR (300 MHz, DMSO-d ₆ ): 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 t-butyl 5-oxo-1,4-diazepane-1-carboxylate
To a solution of t-butyl 4- (hydroxyimino) piperidine-1-carboxylate (1.0 g, 4.67 mmol) in acetone (20 mL) was added Na ₂ CO ₃ (1.48 g, 14 mmol) in water (20 The mixture is stirred for 5 minutes and then slowly added to a solution of p-toluenesulfonic acid chloride (1.33 g, 7 mmol) in acetone (5 mL). The reaction is stirred at room temperature for 3 hours, then the acetone is removed in vacuo, water is added and the solution is extracted with dichloromethane. The organic layer is dried over MgSO ₄ , filtered, concentrated in vacuo and purified by chromatography (6% MeOH in dichloromethane) to give the title compound;
¹ H NMR (300 MHz, DMSO-d ₆ ): 1.41 (s, 9H), 2.40 (m, 2H), 3.09 (m, 2H), 3.39-3.44 (m, 4H), 7.62 (m, 1H).

III. Production of 1,4-diazepan-5-one
HCl solution (20 mL, 2M in dioxane) is added to t-butyl 5-oxo-1,4-diazepane-1-carboxylate (1.0 g, 4.67 mmol) and the reaction mixture is stirred at room temperature for 2 hours. The solvent is removed in vacuo to give the title compound as the hydrochloride salt. This is used in the next step without further purification;
¹ H NMR (300 MHz, DMSO-d ₆ ): 2.36 (m, 2H), 2.65-2.72 (m, 4H), 3.05 (m, 2H), 3.17 (s, 1H), 7.47 (s, 1H).

IV. Preparation of 1- (2-fluoro-4-nitrophenyl) -1,4-diazepan-5-one
To a solution of 1,4-diazepan-5-one (3.25 g, 28.5 mmol) in acetonitrile (30 mL) was added N, N-diisopropylethylamine (24.8 mL, 142 mmol) followed by 3,4-difluoronitrobenzene. (3.5 mL, 31.3 mmol) is added. The reaction mixture is heated to 70 ° C. overnight, cooled to room temperature and the solvent is removed in vacuo. Dichloromethane is then added and the solution is washed with brine, dried over MgSO ₄ , filtered and concentrated in vacuo to give the title compound. This material is used directly in the next step without further purification;
¹ H NMR (300 MHz, DMSO-d ₆ ): 2.62 (m, 2H), 3.30 (m, 2H), 3.47-3.55 (m, 4H), 7.08-7.14 (m, 1H), 7.67 (m, 1H ), 7.94-8.02 (m, 2H).
V. Preparation of 1- (4-amino-2-fluorophenyl) -1,4-diazepan-5-one
1- (2-Fluoro-4-nitrophenyl) -1,4-diazepan-5-one (6.5 g, 25.7 mmol) and NH ₄ Cl powder (13.7 g, 257 mmol), EtOH: H ₂ O (2 : 1, 200 mL) is heated to 95 ° C. and treated with iron powder (4.3 g, 77 mmol) in small portions over 1 hour. The reaction mixture is then stirred at 95 ° C. 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 is taken up in dichloromethane and water. The layers are separated and the organic layer is dried over MgSO ₄ , filtered and concentrated to give the title compound. This is used directly in the next step without further purification;
¹ H NMR (300 MHz, DMSO-d ₆ ): 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, 1H), 7.63 (m, 1H).

VI. Preparation of methyl (2R) -3-{[3-fluoro-4- (5-oxo-1,4-diazepan-1-yl) phenyl] amino} -2-hydroxypropanoate
To a solution of 1- (4-amino-2-fluorophenyl) -1,4-diazepan-5-one (500 mg, 2.24 mmol) in acetonitrile (5 mL) at 23 ° C., lithium triflate (380 mg, 2.46 mmol) followed by methyl (R) -glycidate (0.22 mL, 2.46 mmol). The reaction mixture is then stirred at 60 ° C. for 20 hours and further treated with methyl (R) -glycidate (0.06 mL, 0.67 mmol). After an additional day at 60 ° C., the reaction mixture is cooled to 23 ° C., concentrated and 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. Combine and concentrate the relevant fractions to obtain the title compound;
¹ H NMR (300 MHz, DMSO-d ₆ ): 2.51 (m, 2H), 2.89-2.93 (m, 4H), 3.12-3.19 (m, 3H), 3.61 (s, 3H), 4.09 (m, 1H ), 4.17 (m, 1H), 5.61 (m, 1H), 5.68 (d, c, 1H), 6.25-6.43 (m, 2H), 6.79-6.89 (m, 1H), 7.63 (m, 1H).

VII. Preparation of methyl (5R) -3- [3-fluoro-4- (5-oxo-1,4-diazepan-1-yl) phenyl] -2-oxo-1,3-oxazolidine-5-carboxylate
(2R) -3-{[3-Fluoro-4- (5-oxo-1,4-diazepan-1-yl) phenyl] amino} -2-hydroxypropanoic acid methyl ester (0.40 g, 1.23 mmol) and 1, To a mixture of 1′-carbonyldiimidazole (0.31 g, 1.84 mmol) is added acetonitrile (15 mL) at 23 ° C. The resulting mixture is stirred at 50 ° C. overnight, then cooled to 23 ° C. and concentrated. The residue is taken up in ethyl acetate (300 mL), washed with 0.5 M aqueous HCl, brine, dried (Na ₂ SO ₄ ), 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. Combine and concentrate the relevant fractions to obtain the title compound;
¹ H NMR (300 MHz, DMSO-d ₆ ): 2.57 (m, 2H), 3.06 (m, 4H), 3.27 (m, 2H), 3.75 (s, 3H), 4.12 (m, 1H), 4.32 ( t, J = 9.6 Hz, 1H), 5.30 (m, 1H), 7.09 (t, J = 9.0 Hz, 1H), 7.20 (m, 1H), 7.43-7.48 (m, 1H), 7.66 (m, 1H ).

  Example 2 (5R) -3- [3-Fluoro-4- (5-oxo-1,4-diazepan-1-yl) phenyl] -N-methyl-2-oxo-1,3-oxazolidine-5- Carboxamide production

(5R) -3- [3-Fluoro-4- (5-oxo-1,4-diazepan-1-yl) phenyl] -2-oxo-1,3 under similar conditions according to the method of Example 1 -Methyl oxazolidine-5-carboxylate (0.14 g, 0.40 mmol) is treated with a methanolic methylamine solution (5.0 mL, 2.0 M). The suspension is stirred for 1 hour at the same temperature, concentrated and the residue is purified by preparative TLC (6% MeOH / CH ₂ Cl ₂ ) to give the title compound;
HPLC (SYMMETRY C ₁₈ 3.5 μM, 4.6 × 30 mm column; gradient elution 2% -98% MeCN (with 0.1% TFA), over 5 min; rate of 2 mL / min): retention time = 1.48 min;
¹ H NMR (300 MHz, DMSO-d ₆ ): 2.56 (m, 2H), 2.64 (d, J = 4.8 Hz, 3H), 3.09 (m, 4H), 3.25 (m, 2H), 3.96 (m, 1H), 4.23 (t, J = 9.3 Hz, 1H), 5.04 (m, 1H), 7.09 (t, J = 9.3 Hz, 1H), 7.20 (d, J = 8.7 Hz 1H), 7.45-7.51 (m , 1H), 7.67 (m, 1H), 8.36 (s, 1H).

  Example 3 (5R) -3- [3-Fluoro-4- (4-methyl-5-oxo-1,4-diazepan-1-yl) phenyl] -2-oxo-1,3-oxazolidine-5- Carboxamide production

(5R) -3- [3-Fluoro-4- (4-methyl-5-oxo-1,4-diazepan-1-yl) phenyl] -2-oxo-1,3-oxazolidine-5-carboxylate methyl To a suspension of (0.15 g, 0.41 mmol) in methanol (4 mL) is added methanolic ammonia solution (4.0 mL, 2.0 M) at 23 ° C. The suspension is stirred at the same temperature for 2 hours, concentrated and the residue is purified by preparative TLC (6% MeOH / CH ₂ Cl ₂ ) to give the title compound;
HPLC (SYMMETRY C ₁₈ 3.5 μM, 4.6 × 30 mm column; gradient elution 2% -98% MeCN (with 0.1% TFA), over 5 min; rate of 2 mL / min): retention time = 1.53 min;
¹ H NMR (300 MHz, DMSO-d ₆ ): 2.66 (m, 2H), 2.88 (s, 3H), 3.06-3.13 (m, 4H), 3.56 (m, 2H), 3.96 (m, 1H), 4.22 (t, J = 9.6 Hz, 1H), 5.0 (m, 1H), 7.08 (t, J = 8.7 Hz, 1H), 7.19-7.22 (m, 1H), 7.46-7.52 (m, 1H), 7.60 (s, 1H), 7.84 (s, 1H).

The intermediate for the preparation of Example 3 is synthesized as follows:
I. Preparation of 1- (2-fluoro-4-nitrophenyl) -4-methyl-1,4-diazepan-5-one Powdered KOH (1.16 g, 20.7 mmol) and tetrabutylammonium bromide (0.91 g, 2.76 mmol) ) In THF (250 mL) was added to 1- (2-fluoro-4-nitrophenyl) -1,4-diazepan-5-one (3.5 g, 13.8 mmol) and methyl iodide (1.3 mL, A solution of 20.7 mmol) in THF (40 mL) is added. The resulting reaction mixture is kept at room temperature overnight, diluted with ethyl acetate, washed with water and brine, dried (MgSO ₄ ), filtered and concentrated. The residue is purified by column chromatography (2% MeOH in dichloromethane) to give the title compound;
¹ H NMR (300 MHz, DMSO-d ₆ ): 2.74 (m, 2H), 2.85 (s, 3H), 3.46-3.52 (m, 4H), 3.61 (m, 2H), 7.07-7.13 (m, 1H ), 7.95-8.02 (m, 2H).

II. Preparation of 1- (4-amino-2-fluorophenyl) -4-methyl-1,4-diazepan-5-one
1- (2-Fluoro-4-nitrophenyl) -4-methyl-1,4-diazepan-5-one (1.75 g, 6.55 mmol) and NH ₄ Cl (3.5 g, 65.5 mmol) in ethanol-H ₂ A solution in O (2: 1, 125 mL) is heated to 95 ° C. and then treated with iron powder (1.1 g, 19.6 mmol) in small portions over 1 hour. The reaction mixture is then stirred at 95 ° C. for 4 hours, 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 MgSO ₄ , filtered and concentrated in vacuo to give the title compound. This material is used directly in the next step without further purification;
¹ H NMR (300 MHz, DMSO-d ₆ ): 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, 1H).

III. Preparation of methyl (2R) -3-{[3-fluoro-4- (4-methyl-5-oxo-1,4-diazepan-1-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. Lithium (1.16 g, 7.43 mmol) is added followed by methyl (R) -glycidate (0.65 mL, 7.43 mmol). The reaction mixture is stirred at 65 ° C. for 2 days, 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. Combine and concentrate the relevant fractions to obtain the title compound;
MS (m / z): [M + Na] ⁺ = 362.3.

IV. (5R) -3- [3-Fluoro-4- (4-methyl-5-oxo-1,4-diazepan-1-yl) phenyl] -2-oxo-1,3-oxazolidine-5-carvone Production of methyl acid
(2R) -3-{[3-Fluoro-4- (4-methyl-5-oxo-1,4-diazepan-1-yl) phenyl] amino} -2-hydroxypropanoic acid methyl ester (1.0 g, 2.95 mmol ) And 1,1′-carbonyldiimidazole (0.74 g, 4.42 mmol) are 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 up in ethyl acetate (300 mL), washed with 0.5 M aqueous HCl, brine, dried (Na ₂ SO ₄ ), 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. Combine and concentrate the relevant fractions to obtain the title compound;
¹ H NMR (300 MHz, DMSO-d ₆ ): 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, 1H), 4.32 (t, J = 9.6 Hz, 1H), 5.30 (m, 1H), 7.09 (t, J = 9.0 Hz, 1H), 7.19-7.23 (m, 1H), 7.43-7.49 (m, 1H).

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

Under similar conditions according to the method of Example 3, (5R) -3- [3-fluoro-4- (4-methyl-5-oxo-1,4-diazepan-1-yl) phenyl] -2-oxo Methyl -1,3-oxazolidine-5-carboxylate (0.15 g, 0.41 mmol) is treated with a methanolic methylamine solution (4.0 mL, 2.0 M). The suspension is stirred at the same temperature for 2 hours, concentrated and purified by preparative TLC (6% MeOH—CH ₂ Cl ₂ ) to give the title compound;
HPLC (SYMMETRY C ₁₈ 3.5 μM, 4.6 × 30 mm column; gradient elution 2% -98% MeCN (with 0.1% TFA), over 5 min; rate of 2 mL / min): retention time = 1.64 min;
¹ H NMR (300 MHz, DMSO-d ₆ ): 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, 1H), 4.23 (t, J = 9.3 Hz, 1H), 5.03 (m, 1H), 7.07 (t, J = 9.0 Hz, 1H), 7.19-7.23 (m, 1H ), 7.46-7.51 (m, 1H), 8.38 (m, 1H).

  Example 5 (5R) -3- [3,5-Difluoro-4- (4-methyl-5-oxo-1,4-diazepan-1-yl) phenyl] -2-oxo-1,3-oxazolidine- 5-Carboxamide production

(5R) -3- [3,5-Difluoro-4- (4-methyl-5-oxo-1,4-diazepan-1-yl) phenyl] -2-oxo-1,3-oxazolidine-5-carvone To a suspension of methyl acid (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 1 hour, concentrated and purified by preparative TLC (6% MeOH / CH ₂ Cl ₂ ) to give the title compound;
HPLC (SYMMETRY C ₁₈ 3.5 μM, 4.6 × 30 mm column; gradient elution 2% -98% MeCN (with 0.1% TFA) over 5 min; rate of 2 mL / min): retention time = 1.69 min;
¹ H NMR (300 MHz, DMSO-d ₆ ): 2.63 (m, 2H), 2.88 (s, 3H), 3.07-3.14 (m, 4H), 3.52 (m, 2H), 3.97 (m, 1H), 4.22 (t, J = 9.6 Hz, 1H), 5.01 (m, 1H), 7.32 (m, 2H), 7.62 (s, 1H), 7.86 (s, 1H).

The intermediate for the preparation of Example 5 is 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) was added N, N-diisopropylethylamine (50 mL, 280 mmol) followed by 3,4, Add 5-trifluoronitrobenzene (6.1 mL, 51 mmol). The reaction mixture is heated to 70 ° C. overnight, cooled to room temperature and the solvent is removed in vacuo. Dichloromethane is added and the solution is washed with brine, dried over MgSO ₄ , filtered and concentrated in vacuo. The resulting residue is purified by column chromatography (0-3% MeOH-dichloromethane) to give the title compound;
¹ H NMR (300 MHz, DMSO-d ₆ ): 2.58 (m, 2H), 3.27 (m, 2H), 3.36 (m, 4H), 7.70 (br tr, 1H), 8.04 (d, J = 10 Hz , 2H).

II. Preparation of 1- (2,6-difluoro-4-nitrophenyl) -4-methyl-1,4-diazepan-5-one Powdered KOH (0.79 g, 14 mmol) and tetrabutylammonium bromide (0.60 g, 1.87 mmol) in THF (60 mL) was added to 1- (2,6-difluoro-4-nitrophenyl) -1,4-diazepan-5-one (2.55 g, 9.4 mmol) and iodine. Add a solution of methyl chloride (0.88 mL, 14 mmol) in THF (40 mL). The resulting reaction mixture is kept at room temperature overnight, diluted with ethyl acetate, washed with water and brine, dried (MgSO ₄ ), filtered and concentrated. The residue is purified by column chromatography (2% MeOH in dichloromethane) to give the title compound;
¹ H NMR (300 MHz, DMSO-d ₆ ): 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 1- (4-amino-2,6-difluorophenyl) -4-methyl-1,4-diazepan-5-one
1- (2,6-difluoro-4-nitrophenyl) -4-methyl-1,4-diazepan-5-one (2.2 g, 7.5 mmol) and NH ₄ Cl (4.1 g, 75 mmol) in ethanol- A solution in H ₂ O (2: 1, 90 mL) is heated to 95 ° C. and treated with iron powder (1.25 g, 23 mmol) in small portions over 1 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 is taken up in ethyl acetate and water. The layers are separated and the organic layer is dried over MgSO ₄ , filtered and concentrated in vacuo to give the title compound. This is used directly in the next step without further purification;
MS (m / z): [M + H] ⁺ = 256.2.

IV. Preparation of methyl (2R) -3-{[3,5-difluoro-4- (4-methyl-5-oxo-1,4-diazepan-1-yl) phenyl] amino} -2-hydroxypropanoate
To a solution of 1- (4-amino-2,6-difluorophenyl) -4-methyl-1,4-diazepan-5-one (1 g, 3.92 mmol) in acetonitrile (20 mL) at 23 ° C. Lithium triflate (0.73 g, 4.7 mmol) is added followed by methyl (R) -glycidate (0.41 mL, 4.7 mmol). The reaction mixture is stirred at 95 ° C. for 20 hours and then further treated with methyl R-glycidate (0.1 mL, 1.17 mmol). After an additional 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. Combine and concentrate the relevant fractions to obtain the title compound;
MS (m / z): [M + Na] ⁺ = 380.1;
HPLC (SYMMETRY C ₁₈ 3.5 μM, 4.6 × 30 mm column; gradient elution 2% -98% MeCN (with 0.1% TFA), over 5 min; rate of 2 mL / min): Retention time = 1.85 min.

V. (5R) -3- [3,5-Difluoro-4- (4-methyl-5-oxo-1,4-diazepan-1-yl) phenyl] -2-oxo-1,3-oxazolidine-5 -Production of methyl carboxylate
(2R) -3-{[3,5-Difluoro-4- (4-methyl-5-oxo-1,4-diazepan-1-yl) phenyl] amino} -2-hydroxypropanoic acid methyl ester (0.60 g, 1.68 mmol) and 1,1′-carbonyldiimidazole (0.42 g, 2.52 mmol) are added acetonitrile (15 mL) at 23 ° C. The resulting mixture is stirred at 75 ° C. for 2 days, cooled to 23 ° C. and concentrated in vacuo. The residue is taken up in ethyl acetate (300 mL), washed with 0.5 M aqueous HCl, brine, dried (Na ₂ SO ₄ ), 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. Combine and concentrate the relevant fractions to obtain the title compound;
MS (m / z): [M + H] ⁺ = 452.2;
HPLC (SYMMETRY C ₁₈ 3.5 μM, 4.6 × 30 mm column; gradient elution 2% -98% MeCN (with 0.1% TFA), over 5 min; rate of 2 mL / min): retention time = 2.12 min.

  Example 6 (5R) -3- [3,5-Difluoro-4- (4-methyl-5-oxo-1,4-diazepan-1-yl) phenyl] -N-methyl-2-oxo-1, Production of 3-oxazolidine-5-carboxamide

(5R) -3- [3,5-Difluoro-4- (4-methyl-5-oxo-1,4-diazepan-1-yl) phenyl] -2 under similar conditions according to the method of Example 1 Methyl -oxo-1,3-oxazolidine-5-carboxylate (0.15 g, 0.39 mmol) is treated with a methanolic methylamine solution (4.0 mL, 2.0 M). The suspension is stirred at the same temperature for 2 hours, concentrated and purified by preparative TLC (6% MeOH / CH ₂ Cl ₂ ) to give the title compound;
HPLC (SYMMETRY C ₁₈ 3.5 μM, 4.6 × 30 mm column; gradient elution 2% -98% MeCN (with 0.1% TFA), over 5 min; rate of 2 mL / min): retention time = 1.78 min;
¹ H NMR (300 MHz, DMSO-d ₆ ): 2.63-2.65 (m, 5H), 2.88 (s, 3H), 3.07-3.14 (m, 4H), 3.53 (m, 2H), 3.98 (m, 1H ), 4.22 (t, J = 9.3 Hz, 1H), 5.05 (m, 1H), 7.31 (m, 2H), 8.38 (m, 1H).

  Example 7 (5R) -3- [3,5-Difluoro-4- (5-oxo-1,4-diazepan-1-yl) phenyl] -2-oxo-1,3-oxazolidine-5-carboxamide Manufacturing

(5R) -3- [Methyl 3,5-difluoro-4- (5-oxo-1,4-diazepan-1-yl) phenyl] -2-oxo-1,3-oxazolidine-5-carboxylate (0.20) To a suspension of 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 1 hour, concentrated and purified by preparative TLC (3% MeOH-dichloromethane) to give the title compound;
HPLC (SYMMETRY C ₁₈ 3.5 μM, 4.6 × 30 mm column; gradient elution 2% -98% MeCN (with 0.1% TFA), over 5 min; rate of 2 mL / min): retention time = 1.54 min;
¹ H NMR (300 MHz, DMSO-d ₆ ): 2.53 (m, 2H), 3.09 (m, 4H), 3.22 (m, 2H), 3.97 (dd, J = 9, 6 Hz, 1H), 4.22 ( tr, J = 9 Hz, 1H), 5.01 (dd, J = 9, 6 Hz, 1H), 7.32 (d, J = 11 Hz, 2H), 7.62, (s, 1H), 7.67 (tr, J = 5 Hz, 1H), 7.86 (s, 1H).

The intermediate for the synthesis of Example 7 is prepared as follows:
I. Preparation of 1- (4-amino-2,6-difluorophenyl) -1,4-diazepan-5-one
1- (2,6-difluoro-4-nitrophenyl) -1,4-diazepan-5-one (4.0 g, 14.7 mmol) and NH ₄ Cl (7.8 g, 147 mmol) were added to ethanol-H ₂ O ( 2: 1, 90 mL) is heated to 95 ° C. and treated with iron powder (2.5 g, 44 mmol) in small portions over 1 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 is taken up in ethyl acetate and water. The layers are separated and the organic layer is dried over MgSO ₄ , filtered and concentrated to give the title compound. This 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-1,4-diazepan-1-yl) phenyl] amino} -2-hydroxypropanoate
To a solution of 1- (4-amino-2,6-difluorophenyl) -1,4-diazepan-5-one (3.42 g, 14.2 mmol) in acetonitrile (80 mL) at 23 ° C. lithium triflate ( 2.43 g, 15.6 mmol), followed by methyl (R) -glycidate (1.36 mL, 15.6 mmol). The reaction mixture is then stirred at 80 ° C. for 20 hours and further treated with methyl (R) -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 charged with ethyl acetate and water. The layers are separated and the organic phase is washed with brine, dried (MgSO ₄ ), 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. Combine and concentrate the relevant fractions to obtain the title compound;
¹ H NMR (300 MHz, DMSO-d ₆ ): 2.48 (m, 2H), 2.97 (m, 4H), 3.18 (m, 3H), 3.27 (m, 1H), 3.62 (s, 3H), 4.17 ( m, 1H), 5.73 (tr, J = 7 Hz, 1H), 6.10 (tr, J 5 Hz, 1H), 6.24 (d, J = 12 Hz, 2H), 7.61 (tr, J = 5 Hz, 1H ).

III. Methyl (5R) -3- [3,5-difluoro-4- (5-oxo-1,4-diazepan-1-yl) phenyl] -2-oxo-1,3-oxazolidine-5-carboxylate Manufacturing of
(2R) -3-{[3,5-difluoro-4- (5-oxo-1,4-diazepan-1-yl) phenyl] amino} -2-hydroxypropanoic acid methyl ester (3.97 g, 11.6 mmol) and To a mixture of 1,1′-carbonyldiimidazole (5.6 g, 34.7 mmol) is added acetonitrile (70 mL) at 23 ° C. The resulting mixture is stirred at 60 ° C. overnight, 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. Combine and concentrate the relevant fractions to obtain the title compound;
¹ H NMR (300 MHz, DMSO-d ₆ ): 2.53 (m, 2H), 3.1 (m, 4H), 3.21 (m, 2H), 3.75 (s, 3H), 4.13 (dd, J = 10, 5 Hz, 1H), 4.31 (tr, J = 10 Hz, 1H), 5.32 (dd, J = 10, 5 Hz, 1H), 7.29 (d, J = 11 Hz, 2H), 7.66 (tr, J = 5 Hz, 1H).

  Example 8 (5R) -3- [3,5-Difluoro-4- (5-oxo-1,4-diazepan-1-yl) phenyl] -N-methyl-2-oxo-1,3-oxazolidine- 5-Carboxamide production

(5R) -3- [3,5-Difluoro-4- (4-methyl-5-oxo-1,4-diazepan-1-yl) phenyl] -2 under similar conditions according to the method of Example 7 Methyl -oxo-1,3-oxazolidine-5-carboxylate (0.20 g, 0.54 mmol) is treated with a methanolic methylamine solution (3.0 mL, 2.0 M). The suspension is stirred at the same temperature for 1 hour, concentrated and the residue is purified by preparative TLC (3% MeOH-dichloromethane) to give the title compound;
MS (m / z): [M + H] ⁺ = 369.3;
HPLC (SYMMETRY C ₁₈ 3.5 μM, 4.6 × 30 mm column; gradient elution 2% -98% MeCN (with 0.1% TFA), over 5 min; rate of 2 mL / min): retention time = 1.64 min;
¹ H NMR (300 MHz, DMSO-d ₆ ): 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, 1H), 4.22 (tr, J = 9 Hz, 1H), 5.05 (dd, J = 10, 6 Hz, 1H), 7.31 (d, J = 12 Hz, 2H), 7.67 ( tr, J = 5 Hz, 1H), 8.38 (q, J = 4 Hz, 1H).

  Example 9 (5R) -3- [3,5-difluoro-4- (5-oxo-2,3,4,5-tetrahydro-1H-1,4-diazepin-1-yl) phenyl] -2- Preparation of oxo-1,3-oxazolidine-5-carboxamide

Methanolic ammonia (2.5 mL, 2.0 M solution) was added to (5R) -3- [3,5-difluoro-4- (5-oxo-2,3,4,5-tetrahydro-1H-1,4-diazepine) 1-yl) phenyl] -2-oxo-1,3-oxazolidine-5-carboxylate (0.11 g, 0.3 mmol) is added to a solution in methanol (4 mL). The reaction mixture is stirred at 23 ° C. for 2 hours, concentrated and the residue is purified by column chromatography (0-6% MeOH in dichloromethane) and lyophilized to give the title compound;
¹ H NMR (300 MHz, DMSO-d ₆ ): 3.35 (m, 2H), 3.62 (m, 2H), 4.02 (m, 1H), 4.25 (t, J = 10 Hz, 1H), 4.48 (dd, J = 9, 2 Hz, 1H), 5.04 (m, 1H), 6.42 (d, J = 10 Hz, 1H), 7.42-7.48 (m, 3H), 7.63 (s, 1H), 7.89 (s, 1H ).

The intermediate for the synthesis of Example 9 is 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) Molecular sieves of benzyl 3,5-difluoro-4- (4-oxo-3,4-dihydropyridin-1 (2H) -yl) phenylcarbamate (8.0 g, 22.3 mmol, prepared as described in WO 2004/033449) Add to solution in pyridine (80 mL) containing (40 g). The reaction is stirred at room temperature overnight and the reaction mixture is filtered through celite, assisted with ethyl acetate. The filtrate is washed with water, dried over MgSO ₄ , filtered and concentrated in vacuo to give the title compound as a mixture of isomers. This crude residue is used in the next step without further purification.

II. Preparation of benzyl 3,5-difluoro-4- (5-oxo-2,3,4,5-tetrahydro-1H-1,4-diazepin-1-yl) phenylcarbamate
Solution of benzyl 3,5-difluoro-4- [4- (hydroxyimino) -3,4-dihydropyridin-1 (2H) -yl] phenylcarbamate (1.2 g, 3.21 mmol) in acetone (20 mL) To a solution of Na ₂ CO ₃ (1.36 g, 12.8 mmol) in water (20 mL). The mixture is stirred for 5 minutes and then a solution of p-toluenesulfonyl chloride (1.33 g, 7.0 mmol) in acetone (10 mL) is added slowly. The reaction is stirred at room temperature overnight, then the acetone is removed in vacuo, water is added and the solution is extracted with dichloromethane. The organic phase is dried over MgSO ₄ , filtered, concentrated in vacuo and purified by silica gel flash chromatography (6% MeOH in dichloromethane) to give the title compound;
¹ H NMR (300 MHz, DMSO-d ₆ ): 3.34 (m, 2H), 3.59 (m, 2H), 4.45 (dd, J = 2.1, 8.1 Hz, 1H), 5.16 (s, 2H), 6.38 ( d, J = 10.2 Hz, 1H), 7.24 (m, 2H), 7.32-7.43 (m, 6H), 10.24 (s, 1H).

III. Preparation of 1- (4-amino-2,6-difluorophenyl) -1,2,3,4-tetrahydro-5H-1,4-diazepin-5-one Palladium catalyst (20% Pd (OH on carbon) ) ₂ , 0.5 g), benzyl 3,5-difluoro-4- (5-oxo-2,3,4,5-tetrahydro-1H-1,4-diazepin-1-yl) phenylcarbamate (1.25 g , 3.35 mmol) in ethyl acetate (200 mL) and the mixture is stirred under a hydrogen gas atmosphere. After 16 hours, the reaction mixture is filtered through celite and the filtrate is concentrated to give the title compound. This is used directly in the next step without further purification;
¹ H NMR (300 MHz, DMSO-d _-6 ) 3.33 (m, 2H), 3.51 (m, 2H), 4.34 (dd, J = 2.1, 8.1 Hz, 1H), 5.79 (s, 2H), 6.19- 6.25 (m, 1H), 6.28 (d, J = 10.2 Hz, 2H), 8.30 (m, 1H).

IV. (2R) -3-{[3,5-Difluoro-4- (5-oxo-2,3,4,5-tetrahydro-1H-1,4-diazepin-1-yl) phenyl] amino}- Preparation of methyl 2-hydroxypropanoate Lithium triflate (0.68 g, 4.35 mmol) followed by methyl (R) -glycidate (0.38 mL, 4.35 mmol) and 1- (4-amino-2,6-difluorophenyl) -1,2,3,4-Tetrahydro-5H-1,4-diazepin-5-one (0.8 g, 3.34 mmol) is added to a solution 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 give the title compound;
¹ H NMR (300 MHz, DMSO-d ₆ ): 3.22 (m, 1H), 3.34 (m, 2H), 3.52 (m, 2H), 3.63 (s, 3H), 4.08 (m, 2H), 4.18 ( m, 1H), 4.36 (dd, J = 2.1, 8.1 Hz, 1H), 5.75 (d, J = 6.9 Hz, 1H), 6.29-6.39 (m, 3H), 7.31 (m, 1H).

  V. (5R) -3- [3,5-Difluoro-4- (5-oxo-2,3,4,5-tetrahydro-1H-1,4-diazepin-1-yl) phenyl] -2-oxo Preparation of methyl 1,3-oxazolidine-5-carboxylate

(2R) -3-{[3,5-Difluoro-4- (5-oxo-2,3,4,5-tetrahydro-1H-1,4-diazepin-1-yl) phenyl] amino} -2- A mixture of methyl hydroxypropanoate (0.85 g, 2.49 mmol) and 1,1′-carbonyldiimidazole (0.83 g, 5.0 mmol) is suspended in acetonitrile (30 mL) at 23 ° C. The reaction mixture is stirred at 75 ° C. overnight, then cooled to 23 ° C. and concentrated in vacuo. The residue is purified by silica gel flash chromatography (0-5% MeOH in dichloromethane) to give the title compound;
¹ H NMR (300 MHz, DMSO-d ₆ ): 3.35 (m, 2H), 3.61 (m, 2H), 3.75 (s, 3H), 4.17 (m, 1H), 4.37 (t, J = 9.6 Hz, 1H), 4.48 (dd, J = 2.4, 8.1 Hz, 1H), 5.36 (m, 1H), 6.42 (d, J = 10.5 Hz, 1H), 7.44 (m, 3H).

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

Methanolic methylamine (2.5 mL, 2.0 M solution) was added to (5R) -3- [3,5-difluoro-4- (5-oxo-2,3,4,5-tetrahydro-1H-1,4- To a solution of methyl diazepin-1-yl) phenyl] -2-oxo-1,3-oxazolidine-5-carboxylate (0.11 g, 0.3 mmol) in methanol (4 mL). The reaction mixture is stirred at 23 ° C. for 4 hours, concentrated and the residue is purified by column chromatography (0-6% MeOH in dichloromethane) and lyophilized to give the title compound;
¹ H NMR (300 MHz, DMSO-d ₆ ): 2.64 (d, J = 4.8 Hz, 3H), 3.35 (m, 2H), 3.62 (m, 2H), 4.02 (m, 1H), 4.25 (t, J = 9.6 Hz, 1H), 4.48 (d, J = 10.5 Hz, 1H), 5.09 (m, 1H), 6.42 (d, J = 10.5 Hz, 1H), 7.44-7.48 (m, 3H), 8.42 ( m, 1H).

Claims (13)

Compound of formula I

Or a pharmaceutically acceptable salt thereof [wherein:
A is a structure of formula i, ii, iii, or iv:

W is:
(a) CONHR ² ,
(b) CH ₂ NHCO (NH) C _1-6 alkyl,
(c) CH ₂ NHCOOC _1-6 alkyl,
(d) CH ₂ OH,
(e) CH (OH) -CH = CHR ² ,
(f) CH (OH) C≡CR ² ,
(g) CH ₂ NH-het,
(h) CH ₂ O-het,
(i) CH ₂ S-het, or
(j) CH ₂ het;
Y ¹ is CH, CF, or N;
Y ² and Y ³ are independently CH or CF;
Q is O or S;
R ¹ is H or C _1-6 alkyl;
R ² is H, C _1-6 alkyl, or OC _1-6 alkyl;
Each "....." is independently a bond or absent;
In each case, C _1-6 alkyl is one or more CF ₃ , halo, OH, OC _1-4 alkyl, CN, N ₃ , O (C═O) C _1-4 alkyl, C _3-6 cycloalkyl, Optionally substituted with NH ₂ , NHC (═O) C _1-4 alkyl, or C (═O) C _1-4 alkyl; and
het is a 5- or 6-membered heterocyclic ring having 1 to 4 heteroatoms in the ring selected from the group consisting of oxygen, sulfur and nitrogen, wherein each carbon atom in het is 1 or more CF ₃ , halo, OH, OC _1-4 alkyl, CN, N ₃ , O (C═O) C _1-4 alkyl, C _3-6 cycloalkyl, NH ₂ , NHC (═O) C _{1 -4} alkyl, or optionally substituted with C (= O) C _1-4 alkyl]. Compound of formula Ib

2. The compound of claim ¹ , wherein R < ¹ > is H or methyl. The compound of claim 2, wherein R ² is H, CH ₃ , or OCH ₃ . The compound of claim 1, which is:
(1) (5R) -3- [3-Fluoro-4- (5-oxo-1,4-diazepan-1-yl) phenyl] -2-oxo-1,3-oxazolidine-5-carboxamide,
(2) (5R) -3- [3-Fluoro-4- (5-oxo-1,4-diazepan-1-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-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-1,4-diazepan-1-yl) phenyl] -N-methyl-2-oxo-1, 3-oxazolidine-5-carboxamide,
(7) (5R) -3- [3,5-difluoro-4- (5-oxo-1,4-diazepan-1-yl) phenyl] -2-oxo-1,3-oxazolidine-5-carboxamide,
(8) (5R) -3- [3,5-Difluoro-4- (5-oxo-1,4-diazepan-1-yl) phenyl] -N-methyl-2-oxo-1,3-oxazolidine- 5-carboxamide,
(9) (5R) -3- [3,5-Difluoro-4- (5-oxo-2,3,4,5-tetrahydro-1H-1,4-diazepin-1-yl) phenyl] -2- Oxo-1,3-oxazolidine-5-carboxamide, or
(10) (5R) -3- [3,5-Difluoro-4- (5-oxo-2,3,4,5-tetrahydro-1H-1,4-diazepin-1-yl) phenyl] -N- Methyl-2-oxo-1,3-oxazolidine-5-carboxamide.   A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.   Use of the compound of claim 1 for the manufacture of a medicament for use in the treatment of a bacterial infectious disease.   7. Use according to claim 6, wherein the compound of claim 1 is administered orally, parenterally, topically, rectally, or intranasally.   7. Use according to claim 6, wherein the compound is administered in an amount of about 0.1 to about 100 mg / kg body weight / day.   7. The bacterial infectious disease of claim 6, which is an ear infection, eye infection, respiratory infection, skin and skin tissue infection, bacterial endocarditis, osteomyelitis, endocarditis or diabetic foot.   7. The bacterial infectious disease of claim 6, caused by gram positive bacteria, gram negative bacteria, anaerobic bacteria, and acid-fast bacteria.   Staphylococci, Streptococci, Enterococci, Haemophilus, Moraxella, Bacteroides, Clostridia, Mycobacterium ( 7. The bacterial infectious disease of claim 6 caused by a bacterium comprising Mycobacteria, or Chlamydia.   Staphylococci is S. aureus and S. epidermidis; Streptococci is S. pneumoniae or S. pyogenes Enterococci is Enterococcus faecalis; Haemophilus is H. influenzae; Moraxella is Moraxella catarrhalis (M. 12. The bacterium of claim 11, wherein the bacterium is Mycobacteria; M. tuberculosis or Mycobacterium avium.   The bacterial infectious disease according to claim 6, which is an infection caused by out-of-hospital pneumonia or multi-drug resistant S. aureus.